Kaposi's Sarcoma

An Essential Role of c-Fos in Notch1-mediated Promotion of Proliferation of KSHV-Infected SH-SY5Y Cells

Background: This study aimed to investigate the influence of Notch1 on c-Fos and the effect of c-Fos on the proliferation of Kaposi's sarcoma-associated herpesvirus (KSHV)-infected neuronal cells.

Methods: Real-time PCR and western blotting were used to determine c-Fos expression levels in KSHV-infected (SK-RG) and uninfected SH-SY5Y cells. C-Fos levels were measured again in SK-RG cells with or without Notch1 knockdown. Next, we measured c-Fos and p-c-Fos concentrations after treatment with the Notch1 γ-secretase inhibitor LY-411575 and the Notch1 activator Jagged-1. MTT and Ki-67 staining were used to evaluate the proliferation ability of cells after c-Fos levels downregulation. CyclinD1, CDK6, and CDK4 expression levels and cell cycle were analyzed by western blotting and flow cytometry, respectively. After the c-Fos intervention, the KSHV copy number and gene expression of RTA, LANA and K8.1 were analyzed by real-time TaqMan PCR.

Results: C-Fos was up-regulated in KSHV-infected SK-RG cells. However, the siRNA-mediated knockdown of Notch1 resulted in a significant decrease in the levels of c-Fos and p-c-Fos (P <0.01, P <0.001). Additionally, a decrease in Cyclin D1, CDK6, and CDK4 was also detected. The Notch1 inhibitor LY-411575 showed the potential to down-regulate the levels of c-Fos and p-c-Fos, which was consistent with Notch1 knockdown group (P <0.01), whereas the expression and phosphorylation of c-Fos were remarkably up-regulated by treatment of Notch1 activator Jagged-1 (P <0.05). In addition, our data obtained by MTT and Ki-67 staining revealed that the c-Fos down-regulation led to a significant reduction in cell viability and proliferation of the SK-RG cells (P <0.001). Moreover, FACS analysis showed that the cell cycle was arrested in the G0/G1 stage, and the expressions of Cyclin D1, CDK6, and CDK4 were down-regulated in the c-Fos-knockdown SK-RG cells (P <0.05). Reduction in total KSHV copy number and expressions of viral genes (RTA, LANA and K8.1) were also detected in c-Fos down-regulated SK-RG cells (P <0.05).

Conclusion: Our findings strongly indicate that c-Fos plays a crucial role in the promotion of cell proliferation through Notch1 signaling in KSHV-infected cells. Furthermore, our results suggest that the inhibition of expression of key viral pathogenic proteins is likely involved in this process.

A Computational Investigation on Chitosan Derivatives using Pharmacophore- based Screening, Molecular Docking, and Molecular Dynamics Simulations against Kaposi Sarcoma

Background: Cancer is one of the most dangerous illnesses to the human body due to its severity and progressive nature. Kaposi's Sarcoma (KS) tumor can appear as painless purple spots on the legs, foot, or face. This cancer develops in the lining of lymph arteries and blood vessels. Along with the enlargement of lymph nodes, the vaginal region and the mouth portion are the additional target areas of KS. DNA-binding proteins known as Sox proteins are found in all mammals and belong to the HMG box superfamily. They controlled a wide range of developmental procedures, such as the formation of the germ layer, the growth of organs, and the selection of the cell type. Human developmental abnormalities and congenital illnesses are frequently caused by the deletion or mutation of the Sox protein.

Aim: The purpose of this study is to determine the promising Kaposi's sarcoma inhibitors through computational studies.

Objective: In this present study computational approaches were used to evaluate the anti- carcinogenic efficacy against Kaposi's sarcoma.

Methods: Ligand-based pharmacophore screening was performed utilising four different chemical libraries (Asinex, Chembridge, Specs, and NCI Natural products (NSC)) depending on the top hypothesis. The top hits were examined using molecular docking, absorption, distribution, metabolism and excretion. Highest occupied molecular orbital and lowest unoccupied molecular orbital were analysed to determine the lead compounds' biological and pharmacological efficacy. The results of the study indicated that the leading candidates were possible SOX protein inhibitors.

Results: A pharmacophore model to inhibit the production of SOX protein in Kaposi Sarcoma was generated in this computational experiment using a set of 19 Chitosan compounds.

Conclusion: The results revealed that the top hits responded to all of the pharmacological druglikening criteria and had the best interaction residues, fitness scores, and docking scores. The resulting leads might be potential Kaposi's Sarcoma alternative treatments.

Significance of Beta-Blocker in Patients with Hypertensive Left Ventricular Hypertrophy and Myocardial Ischemia

Background: Arterial Hypertension (HTN) is a key risk factor for left ventricular hypertrophy (LVH) and a cause of ischemic heart disease (IHD). The association between myocardial ischemia and HTN LVH is strong because myocardial ischemia can occur in HTN LVH even in the absence of significant stenoses of epicardial coronary arteries.

Objective: To analyze pathophysiological characteristics/co-morbidities precipitating myocardial ischemia in patients with HTN LVH and provide a rationale for recommending beta-blockers (BBs) to prevent/treat ischemia in LVH.

Methods: We searched PubMed, SCOPUS, PubMed, Elsevier, Springer Verlag, and Google Scholar for review articles and guidelines on hypertension from 01/01/2000 until 01/05/2022. The search was limited to publications written in English.

Results: HTN LVH worsens ischemia in coronary artery disease (CAD) patients. Even without obstructive CAD, several pathophysiological mechanisms in HTN LVH can lead to myocardial ischemia. In the same guidelines that recommend BBs for patients with HTN and CAD, we could not find a single recommendation for BBs in patients with HTN LVH but without proven CAD. There are several reasons for the proposal of using some BBs to control ischemia in patients with HTN and LVH (even in the absence of obstructive CAD).

Conclusion: Some BBs ought to be considered to prevent/treat ischemia in patients with HTN LVH (even in the absence of obstructive CAD). Furthermore, LVH and ischemic events are important causes of ventricular tachycardia, ventricular fibrillation, and sudden cardiac death; these events are another reason for recommending certain BBs for HTN LVH.

The Role of NF-κB in Myocardial Ischemia/Reperfusion Injury

Acute myocardial infarction (AMI) is a threat to human life and physical health worldwide. Timely reperfusion is very important to limit infarct size and protect ischemic myocardium. Unfortunately, it has also caused severer myocardial damage, which is called “myocardial ischemia/ reperfusion injury (MIRI)”. There is no effective clinical treatment for it. Over the past two decades, biological studies of NF-κB have improved the understanding of MIRI. Nuclear Factor-κB (NF-κB) is a major transcription factor associated with cardiovascular health and disease. It is involved in the release of pro-inflammatory factors and apoptosis of cardiomyocytes. Recent studies have shown that inhibition of NF-κB plays a protective role in acute hypoxia and reperfusion injury. Here we review the molecular regulation of NF-κB in MIRI, better understanding of NF-κB signaling mechanisms related to inflammation and crosstalk with endogenous small molecules. We hope this review will aid in improving therapeutic approaches to clinical diagnosing. This review provides evidence for the role of NF-κB in MIRI and supports its use as a therapeutic target.

Electrochemotherapy in the Treatment of Kaposi’s Sarcoma: A Single Centre Cohort Study and a Comparison with the Literature Data

Background: Kaposi's sarcoma (KS) is a tumor of endothelial derivation, which primarily affects the skin and is mainly related to the type 8 Human Herpesvirus (HHV8). Its onset is favored by immunosuppression, although the most common form is the classic or sporadic KS mainly developing in elderly men of Mediterranean and Eastern European origin. Different therapeutic options are available, depending on the clinical variant, progression pattern, and comorbidities. The treatment of localized forms includes surgical excision, laser treatment, cryosurgery, radiotherapy, imiquimod 5%, and intra-lesion injection of cytotoxic drugs; on the other hand, the treatment of widespread disease encompasses radiotherapy and chemotherapy.

Methods: In this scenario, Electrochemotherapy (ECT), has shown to be an effective alternative to traditional treatment for disseminated KS skin lesions. The rationale of ECT relies on the local application of short, high-voltage electric pulses, able to open transient pores in the cell membrane (reversible electroporation that increases the delivery of some poorly permeant cytotoxic agents into the cytosol.

Results: Herein, we performed a retrospective analysis on 9 KS patients treated with ECT at our center between June 2016 and January 2020. The rate of Complete Response (CR) was 77.8% after the first cycle of treatment and 88.9% after the second course, with an overall response (OR) of 100%.

Conclusion: Sustained local control of treated lesions was present in 77.8% of patients 6 months after the treatment and all of them reported only mild local toxicity, together with an excellent functional and cosmetic outcome, in agreement with data obtained from the comparison with the recent literature.

The Synthesis of Nano-Doxorubicin and its Anticancer Effect

Doxorubicin (DOX) is widely used as a clinical first-line anti-cancer drug. However, its clinical application is severely limited due to the lack of tumor specificity of the drug and severe side effects such as myelosuppression, nephrotoxicity, dose-dependent cardiotoxicity, and multi-drug resistance. To improve the bioavailability of DOX, maximize the therapeutic effect, and reduce its toxicity and side effects, many studies have been done on the nanoformulations of DOX, such as liposomes, polymer micelles, dendrimer, and nanogels. Herein, we review the latest progress of DOX nano-preparations and their anti-tumor effects, hoping to provide theoretical references and new research ideas for the development of new dosage forms of the drug and the technical methods available for clinical application.

Relationship between Augmentation Index and Wall Thickening Fraction during Hypotension in an Animal Model of Myocardial Ischemia-Reperfusion and Heart Failure

Aims: Non-invasive indices to evaluate left ventricular changes during ischemic heart failure are needed to quantify the myocardial impairment and the effectiveness of therapeutic manoeuvres. The aims of this work were to calculate the Wall Thickening Fraction (WTF) and the Augmentation Index (AIx) and to assess the relationship between WTF and AIx using data obtained from an animal model with heart failure followed by a myocardial ischemia stage and a reperfusion stage.

Methods: Nine Corriedale sheep that had been monitored for 10 minutes during a basal stage underwent 5-minute myocardial ischemia, followed by 60-minute reperfusion. Seven of them were subjected to an induced heart failure through an overdose of halothane, two of which were treated with intra-aortic counterpulsation during the reperfusion stage. The remaining two animals were monitored during their ischemia-reperfusion stage.

Results: Data obtained in the 5 animals suffering from heart failure followed by myocardial ischemia showed that: a) heart failure induction determined decrease in cardiac output, cardiac index and systolic and diastolic aortic pressure (AoP) with respect to their basal values (p<0.05), b) myocardial ischemia decreased the WTF compared with basal and induced heart failure values (p<0.05), c) during the reperfusion stage accompanied by induced heart failure, WTF increased with respect to values observed during the ischemia induction stage (p<0.05); nevertheless, basal values were not recovered after reperfusion (p<0.05). During this 60-minute stage, systolic and diastolic AoP values were lower (p<0.05) than those at the basal stage.

Conclusion: AIx and WTF values calculated from synchronically recorded values of aortic pressure and left ventricular wall thickness during the reperfusion stage in all animals (n = 9) showed a negative correlation (p<0.05). Analysed data provided evidence of a negative relationship between a left ventricular index of myocardial function and an arterial index obtained from AoP waves.

Viral Envelope Membrane: A Special Entry Pathway and a Promising Drug Target

Enveloped viruses belong to a large class of pathogens responsible for multiple serious diseases. Their spread into new territories has been the cause of major epidemics throughout human history, including the Spanish flu in 1918 and the latest COVID-19 pandemic. Thanks to their outer membrane, consisting essentially of host lipids, enveloped viruses are more resistant to enzymes and are also less susceptible to host immune defenses than their naked counterparts. Therefore, the development of effective approaches to combat enveloped virus infections represents a major challenge for antiviral therapy in the current century. This review focuses on the characteristics of enveloped viruses, their importance in the entry phase, drugs targeting envelope membrane- mediated entry, and those specifically designed to target the envelope. The broad- -spectrum antiviral activity of these compounds can be attributed to their ability to affect the envelope, an essential structural feature common to several viruses. This makes this class of compounds agents of great interest when no specific drugs or vaccines are available to block viral infections.

Selection of Active Antiviral Compounds Against COVID-19 Disease Targeting Coronavirus Endoribonuclease Nendou/NSP15 Via Ligandbased Virtual Screening and Molecular Docking

Background: The rapid spread of SARS-CoV-2 has caused havoc and panic among individuals, which has further worsened due to the unavailability of a proven drug(s) regime.

Objective: The current work involves drug repurposing from the pool of USFDA approved drugs involving in silico virtual screening technique against COVID-19.

Materials and Methods: Methodology involves virtual screening of 8548 FDA approved drugs against target protein endoribonuclease NendoU (Nsp15) (PDB ID: 6VWW).

Result: Virtual screening-based analysis enabled us to identify four drugs, Eprosartan, Inarigivir soproxil, Foretinib, and DB01813 that could plausibly target Nsp15 against COVID-19 disease.

Conclusion: The work offers the scope to corroborate the findings via in vitro and in vivo techniques to identify the potential of selected leads against COVID-19. The outcome may also help in tracing their molecular mechanism(s) in addition to their development at the clinical level in the future.

OX40 and OX40L Interaction in Cancer

Background: OX40 (CD134) and its binding partner, OX40L (CD252), are expressed on activated CD4, CD8 T-cells, and several other lymphoid and non-lymphoid cells. OX40L belongs to a TNF family member, a 34 kDa type II transmembrane protein. The crystallized complex of human OX40 and OX40L is a trimeric contableuration of one OX40L (trimer) and three OX40 monomers. OX40 and OX40L regulate cytokine production from T-cells, antigen-presenting cells, and natural killer (NK) cells, and modulate cytokine receptor signaling.

Methods: In this review, an updated overview of the structural features of OX40/OX40L and their interactions with cancer are provided.

Results: Recent studies have shown that stimulation of OX40 is useful for therapeutic immunization strategies for cancer. OX40 serves as a secondary costimulatory immune checkpoint molecule; the binding of OX40 to its ligand enhances the augmentation, survival, memory formation, effector function, and recall responses of both CD4+ and CD8+ T-cells.

Conclusion: This review highlights that OX40-OX40L interactions play crucial roles in both CD4+ and CD8+ T-cells. Signals through OX40 can abolish the suppressive activity of Tregs, prevent the induction of Tregs from effector T-cells, reduce Foxp3 expression, and induce the proliferation of memory and effector T lymphocytes. Additionally, when transferred into tumor-bearing recipients, they generate proliferation capability and successfully eliminate the established tumor.

Liposomes: An Emerging Approach for the Treatment of Cancer

Background: Conventional drug delivery agents for a life-threatening disease, i.e., cancer, lack specificity towards cancer cells, producing a greater degree of side effects in the normal cells with a poor therapeutic index. These toxic side effects often limit dose escalation of anti-cancer drugs, leading to incomplete tumor suppression/ cancer eradication, early disease relapse, and ultimately, the development of drug resistance. Accordingly, targeting the tumor vasculatures is essential for the treatment of cancer.

Objective: To search and describe a safer drug delivery carrier for the treatment of cancer with reduced systemic toxicities.

Method: Data were collected from Medline, PubMed, Google Scholar, Science Direct using the following keywords: ‘liposomes’, ‘nanocarriers’, ‘targeted drug delivery’, ‘ligands’, ‘liposome for anti-cancerous drugs’, ‘treatment for cancer’ and ‘receptor targeting.’

Results: Liposomes have provided a safe platform for the targeted delivery of encapsulated anti-cancer drugs for the treatment of cancer, which results in the reduction of the cytotoxic side effects of anti-cancer drugs on normal cells.

Conclusion: Liposomal targeting is a better emerging approach as an advanced drug delivery carrier with targeting ligands for anti-cancer agents.

Liposomes as Versatile Platform for Cancer Theranostics: Therapy, Bio-imaging, and Toxicological Aspects

Liposomes are nano-sized formulations having the benefits of site-specificity, biocompatibility, and biodegradability, which make them useful for the therapy and diagnosis of major diseases like cancer. In this review, various synthetic strategies of liposomes and their biomedical application in special concern to cancer are discussed. In context to the biomedical application, this article gives a detailed insight into subcellular targeted therapy and several therapeutic modifications like immunotherapy, receptor-based therapy, phototherapy, and combination therapy. The review also describes the liposome-based imaging platforms and the toxicity associated with liposomes. Owing to a significant amount of benefits of this carrier system, several products have been approved to be launched in the market and several others have already been marketed for clinical use.

Importance of Dietary Supplements to the Health

The term “dietary supplement” defines a comprehensive and diverse category of products that are essential to our health but are absent or insufficient in the diet and may be needed to take separately; requirement of dietary supplements varies at different stages of life, such as infant, child-adult, pregnancy, lactation, and geriatrics. Dietary supplements are not medicines, nor should they be considered a substitute for food. The USFDA defines dietary supplements in part as a product taken by mouth that contains “dietary ingredients.” Nutritional ingredients comprise vitamins, minerals, amino acids, and herbs or botanicals, in addition to other substances that can be considered to supplement the diet. The market is flooded with various dosage forms of dietary supplements, such as capsules, tablets, powders, energy bars, liquids, etc. These include vitamins, minerals, herbal products containing extracts from herbs as well as algae and fungi, concentrate, metabolite, constituent, or extract, enzyme supplement, essential amino, and fatty acids. This article describes the importance of the dietary supplement, source, diseases that arise by deficiency, and the recommended doses for different groups.

Perspectives in Breast and Ovarian Cancer Chemotherapy by Nanomedicine Approach: Nanoformulations in Clinical Research

Background: Breast and ovarian carcinomas represent major health problems in women worldwide. Chemotherapy constitutes the main treatment strategy, and the use of nanocarriers, a good tool to improve it. Several nanoformulations have already been approved, and others are under clinical trials for the treatment of both types of cancers.

Objective: This review focuses on the analysis of the nanoformulations that are under clinical research in the treatment of these neoplasms.

Results: Currently, there are 6 nanoformulations in clinical trials for breast and ovarian carcinomas, most of them in phase II and phase III. In the case of breast cancer treatment, these nanomedicines contain paclitaxel; and, for ovarian cancer, nanoformulations containing paclitaxel or camptothecin analogs are being evaluated. The nanoencapsulation of these antineoplastics facilitates their administration and reduces their systemic toxicity. Nevertheless, the final approval and commercialization of nanoformulations may be limited by other aspects like lack of correlation between the efficacy results evaluated at in vitro and in vivo levels, difficulty in producing large batches of nanoformulations in a reproducible manner and high production costs compared to conventional formulations of antineoplastics. However, these challenges are not insurmountable and the number of approved nanoformulations for cancer therapy is growing.

Conclusion: Reviewed nanoformulations have shown, in general, excellent results, demonstrating a good safety profile, a higher maximum tolerated dose and a similar or even slightly better antitumor efficacy compared to the administration of free drugs, reinforcing the use of nano-chemotherapy in both breast and ovarian tumors.

Dual-target Inhibitors Based on BRD4: Novel Therapeutic Approaches for Cancer

Background: Currently, cancer continues being a dramatically increasing and serious threat to public health. Although many anti-tumor agents have been developed in recent years, the survival rate of patients is not satisfactory. The poor prognosis of cancer patients is closely related to the occurrence of drug resistance. Therefore, it is urgent to develop new strategies for cancer treatment. Multi-target therapies aim to have additive or synergistic effects and reduce the potential for the development of resistance by integrating different pharmacophores into a single drug molecule. Given the fact that majority of diseases are multifactorial in nature, multi-target therapies are being exploited with increasing intensity, which has brought improved outcomes in disease models and obtained several compounds that have entered clinical trials. Thus, it is potential to utilize this strategy for the treatment of BRD4 related cancers. This review focuses on the recent research advances of dual-target inhibitors based on BRD4 in the aspect of anti-tumor.

Methods: We have searched the recent literatures about BRD4 inhibitors from the online resources and databases, such as pubmed, elsevier and google scholar.

Results: In the recent years, many efforts have been taken to develop dual-target inhibitors based on BRD4 as anti-cancer agents, such as HDAC/BRD4 dual inhibitors, PLK1/BRD4 dual inhibitors and PI3K/BRD4 dual inhibitors and so on. Most compounds display good anti-tumor activities.

Conclusion: Developing new anti-cancer agents with new scaffolds and high efficiency is a big challenge for researchers. Dual-target inhibitors based on BRD4 are a class of important bioactive compounds. Making structural modifications on the active dual-target inhibitors according to the corresponding structure-activity relationships is of benefit to obtain more potent anti-cancer leads or clinical drugs. This review will be useful for further development of new dual-target inhibitors based on BRD4 as anti-cancer agents.

Concurrence of Talaromycosis and Kaposi Sarcoma in an HIV-Infected Patient: A Case Report

Background: Concurrence of talaromycosis, an infection caused by the opportunistic fungal pathogen Talaromyces marneffei and Kaposi sarcoma, a common vascular tumor, is a rare but severe medical condition in patients infected with the human immunodeficiency virus (HIV). Despite poor outcomes, the clinical characteristics and management strategies for HIV-infected patients with comorbid Kaposi sarcoma and talaromycosis have not been well documented.

Case presentation: A 33-year-old HIV-positive male patient presented to the Department of Infectious Diseases at Wenzhou Central Hospital with cough, sputum expectoration, hemoptysis, rashes on the feet and violaceous plaques in the oral cavity. Chest computed tomography (CT) showed bilateral nodules, patchy shadows and lymphadenectasis. Skin biopsy and histopathological examination indicated Kaposi sarcoma. T. marneffei was isolated from blood cultures and suggested talaromycosis. The patient’s overall conditions significantly improved following initiation of combination antiretroviral therapy (cART) and chemotherapy for Kaposi sarcoma and antifungal treatment for talaromycosis.

Conclusion: Severe medical conditions such as Kaposi sarcoma and talaromycosis may coexist in HIV-infected patients and pose an increased risk of mortality. Etiological diagnosis and treatment are the keys to the successful management of HIV-infected patients with these concurrent conditions.

Expression of Angiogenesis-related Genes in a Group of Iranian Cases of Breast Cancer

Aims: This study aims to design an angiogenesis gene expression profile; to study angiogenesis gene expression profile in breast cancer; and to map angiogenesis gene expression profile in individual participants.

Background: In molecular etiology of each disease, there are some important molecules involved in the related pathways. From the viewpoint of precision medicine, molecular etiology of a disease is different person by person because of genetic variations of the genes involved in these pathways. This point of view intends researchers of drug development to design novel drugs for targeted therapy based on the exact etiology. In the case of angiogenesis, there is a drug profile parallel to the molecular profile. Bevacizumab, sunitinib and aflibercept are examples of anti-angiogenic drugs.

Objectives: A hallmark of solid tumors is sustained angiogenesis. Vascular endothelial growth factors (VEGF), VEGF receptors (VEGFR) and placental growth factor (PlGF) are involved in angiogenesis. We aimed to study the gene expression profile of angiogenesis including VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2, VEGFR-3 and PlGF in an Iranian group of patients undergoing breast surgery due to breast cancer and breast fibroadenoma.

Methods: Tumor tissue samples of a group of patients with invasive ductal carcinoma (IDC) and a group of patients with fibroadenoma (Fib) were used. Gene expression was studied by real-time quantitative polymerase chain reaction (q-PCR) and fold changes (FC) with their 95% confidence intervals (CI) were reported based on calibration with normal breast tissue.

Results: All the genes showed significant up-regulation in IDC group. The extensive up-regulation was for VEGFR-2 (FC=52.68; 95% CI=17.96-154.47; P<0.001). In Fib group, PlGF showed a significant upregulation (FC=10.41; 95% CI=5.35-20.26; P=0.002). Comparison of IDC group with Fib group showed significant up-regulation of VEGFR-1, VEGFR-2 and VEGFR-3 in IDC group (P<0.05).

Conclusion: Malignancy of breast tumors is associated with overexpression of all the genes of this profile. However, only VEGFRs showed up-regulation in comparison to benign tumors. Individualized targeted therapy, according to this profile, should be studied in the future.

Antibody-Based Targeted Interventions for the Diagnosis and Treatment of Skin Cancers

Background: Cutaneous malignancies most commonly arise from skin epidermal cells. These cancers may rapidly progress from benign to a metastatic phase. Surgical resection represents the gold standard therapeutic treatment of non-metastatic skin cancer while chemo- and/or radiotherapy are often used against metastatic tumors. However, these therapeutic treatments are limited by the development of resistance and toxic side effects, resulting from the passive accumulation of cytotoxic drugs within healthy cells.

Objective: This review aims to elucidate how the use of monoclonal Antibodies (mAbs) targeting specific Tumor Associated Antigens (TAAs) is paving the way to improved treatment. These mAbs are used as therapeutic or diagnostic carriers that can specifically deliver cytotoxic molecules, fluorophores or radiolabels to cancer cells that overexpress specific target antigens.

Results: mAbs raised against TAAs are widely in use for e.g. differential diagnosis, prognosis and therapy of skin cancers. Antibody-Drug Conjugates (ADCs) particularly show remarkable potential. The safest ADCs reported to date use non-toxic photo-activatable Photosensitizers (PSs), allowing targeted Photodynamic Therapy (PDT) resulting in targeted delivery of PS into cancer cells and selective killing after light activation without harming the normal cell population. The use of near-infrared-emitting PSs enables both diagnostic and therapeutic applications upon light activation at the specific wavelengths.

Conclusion: Antibody-based approaches are presenting an array of opportunities to complement and improve current methods employed for skin cancer diagnosis and treatment.

Cancer Stem Cells and their Management in Cancer Therapy

Background: In the last decade, the proposed Cancer Stem Cell (CSC) hypothesis has steadily changed the way cancer treatment is approached. CSCs may be the source of the heterogeneous non-tumorigenic cell population included in a neoplasm. Intratumor and intertumoral heterogeneity is a well-known phenomenon that massively entangles the diagnosis and treatment of cancer. The literature seems to suggest that heterogeneity develops progressively within tumor-initiating stem cells. CSCs harbor genetic and/or epigenetic alterations that allow them to differentiate into multiple tumor cell types sequentially.

Objective: The CSC hypothesis, cellular therapy, and the most recent patents on CSCs were reviewed.

Methods: PubMed, Scopus, and Google Scholar were screened for this information. Also, an analysis of the most recent data targeting CSCs in pediatric cancer developed at two Canadian institutions is provided. The genes involved with the activation of CSCs and the drugs used to antagonize them are also highlighted.

Results: It is underlined that (1) CSCs possess stem cell-like properties, including the ability for self-renewal; (2) CSCs can start carcinogenesis and are responsible for tumor recurrence after treatment; (3) Although some limitations have been raised, which may oppose the CSC hypothesis, cancer progression and metastasis have been recognized to be caused by CSCs.

Conclusion: The significant roles of cell therapy may include an auto-transplant with high-dose treatment, an improvement of the immune function, creation of chimeric antigen receptor T cells, and the recruitment of NK cell-based immunotherapy.

Topical Lipid Based Drug Delivery Systems for Skin Diseases: A Review

Treatment of skin ailments through systemic administration is limited due to toxicity and patients discomfort. Hence, lower risk of systemic side effects from topical dosage forms like ointments, creams, emulsions and gels is more preferred for the treatment of skin disease. Application of lipid based carriers in drug delivery in topical formulations has recently become one of the major approaches to improve drug permeation, safety, and effectiveness. These delivery systems include liposomes, ethosomes, transfersomes, Nanoemulsions (NEs), Solid Lipid Nanoparticles (SLNs) Nanostructured Lipid Carriers (NLCs) and micelles. Most of the liposomes and SLNs based products are in the market while some are under investigation. Transcutaneous delivery of therapeutics to the skin layer by novel lipid based carriers has enhanced topical therapy for the treatment of skin ailments. This article covers an overview of the lipid-based carriers for topical uses to alleviate skin diseases.

The Protective of Baicalin on Myocardial Ischemia-Reperfusion Injury

Background: The aim of this study was to explore the inhibitory effect of baicalin on myocardial apoptosis induced by Ischemia-Reperfusion (I/R).

Methods: Sprague Dawley rats' heart and myocardial cells I/R model were established in vivo and vitro, then 100 mg/kg and 10 μmol/l baicalin were administrated, respectively. The experiment was randomly divided into 4 groups (n=10): Control; I/R; IR+DMEM; and I/R+baicalin groups. Postoperation, the Left Ventricular (LV) End-Diastolic Pressure (LVEDP), the maximum velocity of LV contraction (dP/dtmax) and the maximum velocity of LV diastole (dP/dtmin) were recorded by the transthoracic echocardiography; the myocardial apoptosis percentage was analyzed by Annexin VFITC/ PI and TUNEL staining, and the apoptosis gene and protein were detected by RT-PCR and western blot. Furthermore, the protein expression of the calcium-sensing receptor (CaSR) and ERK1/2 phosphorylation were observed by western blot and Fura-2-acetoxymethyl ester. Moreover, primary rats’ cardiomyocytes were cultured and ERK1/2 specific inhibitor PD98059 was added to the culture medium. The cell survival rate, vitality and apoptosis were detected by MTT, lactate dehydrogenase (LDH) and TUNEL staining assay Kit, respectively.

Results: Our present study showed that baicalin significantly improved LV hemodynamic parameters and myocardial apoptosis in myocardial I/R injury rats. Furthermore, we found that baicalin could down-regulate the protein expression of CaSR, but up-regulate the protein expression of ERK1/2. Furthermore, when the cells were pretreated with ERK1/2 inhibitor PD98059, the cells survival rate significantly decreased, but LDH activity and apoptosis significantly increased. The results indicated that the effect of baicalin on myocardial I/R injury could be inhibited by ERK1/2 inhibitor.

Conclusion: In conclusion, our data suggests that baicalin attenuates I/R-induced myocardial injury maybe through the suppression of the CaSR/ERK1/2 signaling pathway.

Recent Development of Copolymeric Nano-Drug Delivery System for Paclitaxel

Background: Paclitaxel (PTX) has been clinically used for several years due to its good therapeutic effect against cancers. Its poor water-solubility, non-selectivity, high cytotoxicity to normal tissue and worse pharmacokinetic property limit its clinical application.

Objective: To review the recent progress on the PTX delivery systems.

Methods: In recent years, the copolymeric nano-drug delivery systems for PTX are broadly studied. It mainly includes micelles, nanoparticles, liposomes, complexes, prodrugs and hydrogels, etc. They were developed or further modified with target molecules to investigate the release behavior, targeting to tissues, pharmacokinetic property, anticancer activities and bio-safety of PTX. In the review, we will describe and discuss the recent progress on the nano-drug delivery system for PTX since 2011.

Results: The water-solubility, selective delivery to cancers, tissue toxicity, controlled release and pharmacokinetic property of PTX are improved by its encapsulation into the nano-drug delivery systems. In addition, its activities against cancer are also comparable or high when compared with the commercial formulation.

Conclusion: Encapsulating PTX into nano-drug carriers should be helpful to reduce its toxicity to human, keeping or enhancing its activity and improving its pharmacokinetic property.

Mesenchymal Stem Cells: A New Generation of Therapeutic Agents as Vehicles in Gene Therapy

In recent years, mesenchymal stem cells (MSCs) as a new tool for therapeutic gene delivery in clinics have attracted much attention. Their advantages cover longer lifespan, better isolation, and higher transfection efficiency and proliferation rate. MSCs are the preferred approach for cell-based therapies because of their in vitro self-renewal capacity, migrating especially to tumor tissues, as well as anti-inflammatory and immunomodulatory properties. Therefore, they have considerable efficiency in genetic engineering for future clinical applications in cancer gene therapy and other diseases. For improving therapeutic efficiency, targeted therapy of cancers can be achieved through the sustained release of therapeutic agents and functional gene expression induction to the intended tissues. The development of a new vector in gene therapy can improve the durability of a transgene expression. Also, the safety of the vector, if administered systemically, may resolve several problems, such as durability of expression and the host immune response. Currently, MSCs are prominent candidates as cell vehicles for both preclinical and clinical trials due to the secretion of therapeutic agents in several cancers. In the present study, we discuss the status of gene therapy in both viral and non-viral vectors along with their limitations. Throughout this study, the use of several nano-carriers for gene therapy is also investigated. Finally, we critically discuss the promising advantages of MSCs in targeted gene delivery, tumor inhibition and their utilization as the gene carriers in clinical situations.

The Advances on the Protective Effects of Ginsenosides on Myocardial Ischemia and Ischemia-Reperfusion Injury

Ginseng is a traditional medicine with a complex chemical composition, wide bioactivity and unique pharmacological action. Many studies have confirmed that ginsenosides are the active ingredients of ginseng, and ginsenosides have always been the focus of different researchers. With the development of modern separation and analysis technology, more than 150 kinds of ginsenosides have been isolated. The ginsenosides Rb1, Rb2, Rc, Rg1 and Re account for more than 80% of total ginsenosides, and other saponins, such as Rd, Rg3 and Rh2, which are minor constituents, accounting for only a small portion of the total amount. In recent years, ginsenosides have been found to possess strong pharmacological activities, such as antioxidation, clearing of oxygen free radicals, reducing calcium overload and anti-apoptosis. Ginsenosides play a protective role in ischemia-reperfusion injury. This paper reviews the protective effects of ginsenosides on myocardial ischemia and ischemiareperfusion injury.

Bortezomib – First Therapeutic Proteasome Inhibitor for Cancer Therapy: A Review of Patent Literature

Background: Bortezomib is a reversible inhibitor of proteasome proteins in mammalian cells. Bortezomib is proven to be cytotoxic to a number of tumor cells by disrupting their normal homeostatic mechanism and thereby, causing cell death. Currently, Bortezomib is prescribed for patients with multiple myeloma and mantle cell lymphoma.

Objective: This assessment highlights the overview of the recent patents of Bortezomib. This review includes patents grouped in sections like product patents, process patent, composition related patents as well as the treatment methodology. The objective of this article is to facilitate researchers with all existing patents at a single place.

Methods: Data were searched from various online databases. In which, paid databases include SciFinder® and Orbit®. Free databases include Patentscope® (WIPO), Worldwide Espacenet® (EPO), Google Patents and InPASS (Indian patent database).

Results: Several new processes and composition related patents of Bortezomib have been recently patented as its orange-book listed patents are going to soon expire during July 2022. Further, due to the problem of oxidation during development and long-term storage of Bortezomib formulation, a number of excipients are tried in these patents to stabilize the same. However, there is still a need for further development of an improved formulation of Bortezomib with better characteristics.

Conclusion: Extensive research has been carried out on various processes for preparing Bortezomib and the composition thereof. This type of dynamic research will clear the path for many generic players in the United States, which lead to the reduction of the price of the composition and thereby enhancing global health care at cheaper prices.

Bone Marrow Culture Yield for the Diagnosis of Opportunistic Diseases in Patients with AIDS and Disseminated Kaposi Sarcoma

Background: Disseminated Kaposi sarcoma (DKS) is present in patients with advanced HIV infection in whom co-infection with other opportunistic pathogens can occur. Bone marrow (BM) aspirate and biopsy comprise a robust diagnostic tool in patients with fever, cytopenias, and abnormal liver tests. However, the yield in patients with DKS has not been determined.

Objective: The aim of this study was to evaluate the utility of BM aspirate and biopsy in patients with DKS.

Methods: We included 40 male patients with a recent diagnosis of DKS. BM aspirate and biopsy was performed as part of the workup to rule out co-infections.

Results: In four patients, Mycobacterium avium complex (MAC) was recovered from culture. In other four patients, intracellular yeasts were observed in the Grocott stain, diagnosed as Histoplasma. The yield of BM was calculated in 20%. Only 12 patients (30%) had fever and 11 (27.5%) had pancytopenia. Alkaline phosphatase (ALP) above normal values and C-reactive protein (CRP) were higher in patients with positive results for BM than in those with negative results (63% vs. 21.9%, and 3.0 vs. 1.2 mg/L; p = 0.03 in both comparisons). No differences were found when complete blood-count abnormalities were compared.

Conclusion: We recommend performing a BM aspirate for stains, culture, and biopsy in all HIV patients with DKS, as this will permit the early diagnosis of co-infections and prevent further complications in those who receive chemotherapy.

Roles of Medicinal Plants and Constituents in Gynecological Cancer Therapy: Current Literature and Future Directions

Gynecologic cancers, including cervical, primary peritoneal, ovarian, uterine/endometrial, vaginal and vulvar cancers and gestational trophoblastic disease, are characterized by abnormal cell proliferation in female reproductive cells. Due to the variable pathology of these cancers and the lack of appropriate screening tests in developing countries, cancer diagnosis can be reported in advanced stages in most women and this situation adversely affects prognosis and clinical outcomes of illness. For this reason, many researchers in the field of gynecological oncology have carried out many studies.

The treatment of various gynecological problems, which cause physical, biological and psychosocial conditions such as fear, shame, blame and anger, has been important throughout the history. Treatment with herbs has become popular nowadays due to the serious side effects of the synthetic drugs used in treatment and the medical and economical problems caused by them. Many scientists have identified various active drug substances through in vivo and in vitro biological activity studies on medicinal plants from the past to the present. While the intrinsic complexity of natural product-based drug discoveries requires highly integrated interdisciplinary approaches, scientific and technological advances and research trends clearly show that natural products will be among the most important new drug sources in the future.

In this review, an overview of the studies conducted for the discovery of multitargeted drug molecules in the rational treatment of gynecological cancers is presented.

Single Nucleotide Polymorphism Analysis in HIV and Kaposi's Sarcoma Disease by Microarray Technique

Background: Emergence of Kaposi's Sarcoma in the cases other than HIV, following the use of immunosuppressant drugs, demonstrates that it is related to weak immunity. The fact that this malignancy does not occur in every HIV-positive patient suggests that genetic predisposition may also be effective. Replacement of one of the base pairs of adenine, guanine, cytosine, and thymine that constitute the DNA sequence in the human genome with another base pair can affect susceptibility to disease, response to treatment, and immunity.

Objective: The purpose of this study is to analyze the Single Nucleotide Polymorphism that could predispose to Kaposi's sarcoma of an HIV-infected patient and to identify which nucleotides such SNPs correspond to, using the microarray technology.

Materials and Methods: The blood samples of individuals, one of whom was diagnosed with Kaposi's Sarcoma HIV (+) visiting the outpatient clinic of infectious diseases polyclinic of Harran University Research and Practice Hospital and of a healthy individual with no Kaposi's Sarcoma, were used in the study. Following the DNA isolation of the blood samples taken from the respective individuals, a SNP analysis was conducted on the microarray device. 204,000 SNPs obtained were scanned later on in the databases in an attempt to identify the SNPs related to Kaposi's Sarcoma.

Results: In the 204,000 SNP screenings, we scrutinized the SNPs that differ in the case of Kaposi's Sarcoma [KS (+) and HIV (+)] on the basis of Control [KS(-) and HIV(-)] and HIV+ [KS(-)], and two SNPs of the ENDRA gene, three SNPs of the ADRA1A gene, six SNPs of the STIM1 gene, four SNPs of the EFNB2 gene, and one SNP of the CD209 gene were found to be different. However, when it comes to all SNPs (all the 204.000 SNPs) screened in terms of allele, it was observed that the AA and BB alleles were lower in the patient with Kaposi's Sarcoma [KS (+) and HIV (+)] compared to other groups and AB alleles were found to be higher than others in the patient with Kaposi's sarcoma [KS] (+) and HIV (+)].

Conclusion: In the microarray study we have conducted, 204,000 SNPs were screened for Control (HIV-) HIV (+) and HIV (+) patient with Kaposi's Sarcoma. It was found that 32,362 of those SNPs had different alleles in the Kaposi's Sarcoma [KS + HIV (+)] patient, while they had the same ones in the control [KS (-) and HIV (-)] and HIV + [KS (-)] group. 16 of the 32,362 SNPs took place among the genes related to Kaposi's Sarcoma. In the cases of Kaposi's Sarcoma with suspected diagnosis, it can be used as a beneficial laboratory test.

Use of Anticancer Platinum Compounds in Combination Therapies and Challenges in Drug Delivery

As one of the leading and most important metal-based drugs, platinum-based pharmaceuticals are widely used in the treatment of solid malignancies. Despite significant side effects and acquired drug resistance have limited their clinical applications, platinum has shown strong inhibitory effects for a wide assortment of tumors. Drug delivery systems using emerging technologies such as liposomes, dendrimers, polymers, nanotubes and other nanocompositions, all show promise for the safe delivery of platinum-based compounds. Due to the specificity of nano-formulations; unwanted side-effects and drug resistance can be largely averted. In addition, combinational therapy has been shown to be an effective way to improve the efficacy of platinum based anti-tumor drugs. This review first introduces drug delivery systems used for platinum and combinational therapeutic delivery. Then we highlight some of the recent advances in the field of drug delivery for combinational therapy; specifically progress in leveraging the cytotoxic nature of platinum-based drugs, the combinational effect of other drugs with platinum, while evaluating the drug targeting, side effect reducing and sitespecific nature of nanotechnology-based delivery platforms.

Anticancer Potential of Dietary Natural Products: A Comprehensive Review

Nature is a rich source of natural drug-like compounds with minimal side effects. Phytochemicals better known as “Natural Products” are found abundantly in a number of plants. Since time immemorial, spices have been widely used in Indian cuisine as flavoring and coloring agents. Most of these spices and condiments are derived from various biodiversity hotspots in India (which contribute 75% of global spice production) and form the crux of India’s multidiverse and multicultural cuisine. Apart from their aroma, flavor and taste, these spices and condiments are known to possess several medicinal properties also. Most of these spices are mentioned in the Ayurveda, the indigenous system of medicine. The antimicrobial, antioxidant, antiproliferative, antihypertensive and antidiabetic properties of several of these natural products are well documented in Ayurveda. These phytoconstituemts are known to act as functional immunoboosters, immunomodulators as well as anti-inflammatory agents. As anticancer agents, their mechanistic action involves cancer cell death via induction of apoptosis, necrosis and autophagy. The present review provides a comprehensive and collective update on the potential of 66 commonly used spices as well as their bioactive constituents as anticancer agents. The review also provides an in-depth update of all major in vitro, in vivo, clinical and pharmacological studies done on these spices with special emphasis on the potential of these spices and their bioactive constituents as potential functional foods for prevention, treatment and management of cancer.

An HHV-8 Positive HIV Negative Multicentric Castleman’s Disease, who Responded well to Rituximab Alone

Background: Multicentric Castleman Disease (MCD) presents with enlarged lymph nodes in multiple regions and systemic inflammatory symptoms, due to the dysregulation of cytokines, most commonly interleukin-6 (IL-6). Human herpes virus-8 (HHV-8) is strongly related to MCD (HHV-8-associated MCD) and is being implicated in cytokine dysregulation in patients, the majority of whom are HIV positive or immunosuppressed. Preferred treatment of HHV-8- associated MCD depends on the presence or not of concurrent Kaposi sarcoma and on whether the patient has life-threatening organ failure or poor performance status thought to be related to HHV- 8-associated MCD.

Case Presentation: Herein, we describe a female patient with HHV-8 positive, HIV negative MCD, who responded well to the administration of rituximab once weekly for four weeks alone for three cycles.

Conclusion: HHV-8 positive, HIV negative MCD treatment modalities are only anecdotal due to the rarity of this form of MCD. Administration of rituximab alone seems to be beneficial among patients with good performance status and the absence of life-threatening organ failure in cases of HHV-8 positive, HIV negative MCD.

Interaction of Human Herpesvirus 8 Viral Interleukin-6 with Human Interleukin-6 Receptor Using In Silico Approach: The Potential Role in HHV-8 Pathogenesis

Introduction: Human Herpesvirus 8 (HHV-8) causes classical, endemic (African), and Acquired Immunodeficiency Syndrome (AIDS)-related Kaposi’s Sarcoma (KS), Body Cavity-Based Primary Effusion Lymphomas (BCBL), HHV-8-associated peritoneal Primary Effusion Lymphoma (PEL), and Multicentric Castleman’s Disease (MCD). HHV8 genome encodes several structural and non-structural proteins, among which vIL6 is a functional homologue of Interleukin-6 (IL-6). It has been established that vIL6 plays a vital role in HHV8 infections; also, it has been suggested that its function was mediated through gp130, rather than the gp80 (IL-6 receptor [IL-6R]). This study aimed to investigate the physicochemical and structural properties as well as the immunological features, and finally the interaction between vIL6 and IL6 receptor (IL6R) by using several bioinformatics tools which could provide both valuable insight into vIL6 protein and advantageous data for further studies on HHV8 inhibitors and new vaccines.

Material and Methods: vIL6, human IL6 (hIL6), and IL6R were obtained from NCBI GenBank and Uniport, which were aligned by The CLC Genomics Workbench. "Signal-BLAST" and “predisi" were employed to define signal peptide; also, “Expasy’sProtParam” was used to predict physicochemical properties as well as "DiANNA", and "SCRATCH" predicted the disulfide bonds. “NetPhosK”, “DISPHOS”, “NetPhos”, ”NetNGlyc”, and ”GlycoEP” were involved to determine post-modification sites. To define immunoinformatics analysis, “BcePred”, “ABCpred”, “Bepipred”, “AlgPred”, and "VaxiJen" were used. “SOPMA”, “I-TASSER”, “GalaxyRefine”, and “3D-Refine” predicted and refined the secondary and tertiary structures. TM-align server was used to align 3D structures. In addition, docking analysis was done by “Hex 5.0.”, and finally the results were illustrated by “Discovery Studio”.

Results: A signal peptide (1-22) was defined in the vIL6 sequences and analysis has shown that vIL6 is an acidic protein which is significantly stable in all organisms. Three Disulfide bonds were predicted and immunoinformatics analysis showed 5 distinct B-cell epitopes. vIL6 is predicted as a non-allergen protein and the majority of its structure consists of Alpha helix. TM-align pointed the significant similarity between vIL6 and hIL6 in protein folding. The high energy value between vIL6 protein and IL6R was calculated and further analysis illustrated 5 conserved regions as well as 4 conserved amino acids which had a significant role in vIL6 and IL6R interaction.

Discussion: An in silico study by numerous software determined the possible interaction between vIL6 and IL6R and the possible role of this interaction in HHV8 pathogenesis and the progress of infection. These have been overlooked by previous studies and will be beneficial to gain a more comprehensive understanding of vIL6 function during HHV8 lifecycle and infections. Structural analysis showed the significant similarity between vIL6 and hIL6 folding which can describe the similarity of the functions or interactions of both proteins. Furthermore, several conserved regions in the interaction site which interestingly were highly conserved among all vIL6 sequences can be used as new target for vIL6 inhibitors. Moreover, our results could predict immunological properties of vIL6 which suggested the ability of this protein in induction of the humoral immune response. Such a protein may be used for further studies on therapeutic vaccine fields.

Distribution and Characteristics of Intrathoracic Lymphadenopathy in TB/HIV Co-Infection

Background: Intrathoracic Lymphadenopathy (ITLN) in Human Immunodeficiency Virus (HIV) infected patients may have various etiologies and prognoses. Etiologies of ITLN can be distinguished based on the distribution of enlarged lymph nodes. Sometimes tuberculosis (TB) is the first sign of underlying HIV infection.

Objectives: We sought to determine ITLN distribution and associated pulmonary findings in TB/HIV co-infection using Computed Tomography (CT) scan.

Methods: In this retrospective, observational, cross-sectional study, chest CT scans of 52 patients with TB/HIV co-infection were assessed for enlarged intrathoracic lymph nodes (>10 mm in short axis diameter), lymphadenopathy (LAP) distribution, calcification, conglomeration, the presence of hypodense center and associated pulmonary abnormalities. LAP distribution was compared in TB/HIV co-infection with isolated TB infection.

Results: Mediastinal and/or hilar LAP were seen in 53.8% of TB/HIV co-infection patients. In all cases, LAP was multistational. The most frequent stations were right lower paratracheal and subcarinal stations. Lymph node conglomeration, hypodense center and calcification were noted in 25%, 21.4% and 3.5% of patients, respectively. LAP distribution was the same as that in patients with isolated TB infection except for the right hilar, right upper paratracheal and prevascular stations. All patients with mediastinal and/or hilar adenopathy had associated pulmonary abnormalities.

Conclusion: All patients with TB/HIV co-infection and mediastinal and/or hilar adenopathy had associated pulmonary abnormalities. Superior mediastinal lymph nodes were less commonly affected in TB/HIV co-infection than isolated TB.

Structural and Mechanistic Insights of CRAC Channel as a Drug Target in Autoimmune Disorder

Background: Calcium (Ca2+) ion is a major intracellular signaling messenger, controlling a diverse array of cellular functions like gene expression, secretion, cell growth, proliferation, and apoptosis. The major mechanism controlling this Ca2+ homeostasis is store-operated Ca2+ release-activated Ca2+ (CRAC) channels. CRAC channels are integral membrane protein majorly constituted via two proteins, the stromal interaction molecule (STIM) and ORAI. Following Ca2+ depletion in the Endoplasmic reticulum (ER) store, STIM1 interacts with ORAI1 and leads to the opening of the CRAC channel gate and consequently allows the influx of Ca2+ ions. A plethora of studies report that aberrant CRAC channel activity due to Loss- or gain-of-function mutations in ORAI1 and STIM1 disturbs this Ca2+ homeostasis and causes several autoimmune disorders. Hence, it clearly indicates that the therapeutic target of CRAC channels provides the space for a new approach to treat autoimmune disorders.

Objective: This review aims to provide the key structural and mechanical insights of STIM1, ORAI1 and other molecular modulators involved in CRAC channel regulation.

Results and Conclusion: Understanding the structure and function of the protein is the foremost step towards improving the effective target specificity by limiting their potential side effects. Herein, the review mainly focusses on the structural underpinnings of the CRAC channel gating mechanism along with its biophysical properties that would provide the solid foundation to aid the development of novel targeted drugs for an autoimmune disorder. Finally, the immune deficiencies caused due to mutations in CRAC channel and currently used pharmacological blockers with their limitation are briefly summarized.

Study of HIV Resistance Mutations Against Antiretrovirals using Bioinformatics Tools

Background: Antiretroviral drugs to HIV-1 (ARV) are divided into classes: Nucleotide Reverse Transcriptase Inhibitors (NRTIs); Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs); Protease Inhibitors (PIs); Integrase Inhibitors (INIs); fusion inhibitors and entry Inhibitors. The occurrence of mutations developing resistance to antiretroviral drugs used in HIV treatment take place in a considerable proportion and has accumulated over its long period of therapy.

Objective: This study aimed to identify resistance mutations to antiretrovirals used in the treatment of HIV-1 in strains isolated from Brazilian territory deposited at Genbank, as well as to relate to the clinical significance and mechanism of action.

Methods: Elucidation of these mutations was by comparative method of peptide sequence resulting from genes encoding therapeutic targets in HIV antiretroviral therapy (ART) of the strains with a reference sequence through bioinformatic genetic information manipulation techniques.

Results: Of the 399 sequences analyzed, 121 (30.3%) had some type of mutations associated with resistance to some class of antiretroviral drug. Resistance to NNRTIs was the most prevalent, detected in 77 (63.6%) of the 121 mutated sequences, compared to NRTIs and PIs, whose resistance was detected in 60 (49.6%) and 21 (17.3%), respectively, and to INIs, only 1 (0.8%) sample showed associated resistance mutation.

Conclusion: Resistance to HIV ARV was detected at a considerable rate of 30.3%, showing some concerns about the percentage of viral strains that escape the established therapeutic regimen and that circulate currently in Brazil. The non-use of NNRTIs in Brazil is justified by the emergence of resistance mutations. The low prevalence of mutations against INIs is because drugs in this class have a high genetic barrier.

Impaired Myocardial MIF/AMPK Activation Aggravates Myocardial Ischemia Reperfusion Injury in High-Fat Diet-Induced Obesity

Background: Obese patients are more sensitive to myocardial ischemia, which has been linked with high mortality rates. The following study investigates the effects of impaired macrophage Migration Inhibitory Factor (MIF)/AMP-Activated Protein Kinase (AMPK) activation on increased susceptibility to myocardial ischemia/reperfusion (I/R) in high-fat diet-induced obesity.

Methods: Male C57BL/6J mice were fed with a normal diet (10% kcal as fat, lean group) or a high-fat diet (60kcal as fat, obese group) for 12 consecutive weeks. To detect the MIF expression and AMPK activation in response to I/R in isolated hearts from lean and obese mice, myocardial samples were collected from left ventricular areas at different time points. To determine whether MIF supplementation is protective against I/R injury, recombined MIF (10 ng/mL) was applied before ischemia. Myocardial infarct size was estimated by triphenyltetrazolium staining. Western blot was used to detect myocardial MIF expression, AMPK activation and membrane glucose transporter 4 (Glut4) expression.

Results: The expression of MIF was remarkably higher in obese group compared to lean group. Ischemia increased myocardial MIF expression and phosphorylation of AMPK in lean mice, whereas it had no significant effect on obese mice. Furthermore, administration of recombinant MIF increased ischemic AMPK activation and membrane Glut4 expression in both lean and obese mice, while it reduced the infarct size in lean mice only.

Conclusion: An impaired MIF/AMPK activation response and consequent reduced membrane Glut4 expression may play an important role in increasing myocardial susceptibility to I/R in obesity.

Nanoparticles: Properties and Applications in Cancer Immunotherapy

Background: Tumours are no longer regarded as isolated masses of aberrantly proliferating epithelial cells. Rather, their properties depend on complex interactions between epithelial cancer cells and the surrounding stromal compartment within the tumour microenvironment. In particular, leukocyte infiltration plays a role in controlling tumour development and is now considered one of the hallmarks of cancer. Thus, in the last few years, immunotherapy has become a promising strategy to fight cancer, as its goal is to reprogram or activate antitumour immunity to kill tumour cells, without damaging the normal cells and provide long-lasting results where other therapies fail. However, the immune-related adverse events due to the low specificity in tumour cell targeting, strongly limit immunotherapy efficacy. In this regard, nanomedicine offers a platform for the delivery of different immunotherapeutic agents specifically to the tumour site, thus increasing efficacy and reducing toxicity. Indeed, playing with different material types, several nanoparticles can be formulated with different shape, charge, size and surface chemical modifications making them the most promising platform for biomedical applications.

Aim: In this review, we will summarize the different types of cancer immunotherapy currently in clinical trials or already approved for cancer treatment. Then, we will focus on the most recent promising strategies to deliver immunotherapies directly to the tumour site using nanoparticles.

Conclusion: Nanomedicine seems to be a promising approach to improve the efficacy of cancer immunotherapy. However, additional investigations are needed to minimize the variables in the production processes in order to make nanoparticles suitable for clinical use.

Research Progress of Glycyrrhizic Acid on Antiviral Activity

Glycyrrhizic acid (GA), a triterpene isolated from the roots and rhizomes of licorice, named Glycyrrhiza glabra, is the principal bioactive ingredient of anti-viral, anti-inflammatory and hepatoprotective effects. GA has been used in the clinical treatment of hepatitis, bronchitis, gastric ulcer, AIDS (acquired immunodeficiency syndrome), certain cancers and skin diseases. It has a direct effect on anti-HBV (hepatitis B virus) via affecting the HBsAg (hepatitis B surface antigen) to extracellular secretion, improving liver dysfunction in patients with chronic hepatitis B, and ultimately improving the immune status of HBV. GA can significantly inhibit the proliferation of HIV, showing an immune activation. The clinical application of GA on the prevention and treatments of various diseases may derive from its numerous pharmacological properties. This review provides the summary of the antiviral effects of GA on research progress and mechanism in recent years.

Oxidative and Inflammatory Events in Prion Diseases: Can They Be Therapeutic Targets?

Prion diseases are a group of incurable infectious terminal neurodegenerative diseases caused by the aggregated misfolded PrPsc in selected mammals including humans. The complex physical interaction between normal prion protein PrPc and infectious PrPsc causes conformational change from the α- helix structure of PrPc to the β-sheet structure of PrPsc, and this process is repeated. Increased oxidative stress is one of the factors that facilitate the conversion of PrPc to PrPsc. This overview presents evidence to show that increased oxidative stress and inflammation are involved in the progression of this disease. Evidence is given for the participation of redoxsensitive metals Cu and Fe with PrPsc inducing oxidative stress by disturbing the homeostasis of these metals. The fact that some antioxidants block the toxicity of misfolded PrPc peptide supports the role of oxidative stress in prion disease. After exogenous infection in mice, PrPsc enters the follicular dendritic cells where PrPsc replicates before neuroinvasion where they continue to replicate and cause inflammation leading to neurodegeneration. Therefore, reducing levels of oxidative stress and inflammation may decrease the rate of the progression of this disease. It may be an important order to reduce oxidative stress and inflammation at the same time. This may be achieved by increasing the levels of antioxidant enzymes by activating the Nrf2 pathway together with simultaneous administration of dietary and endogenous antioxidants. It is proposed that a mixture of micronutrients could enable these concurrent events thereby reducing the progression of human prion disease.

Nanoparticle Therapy for Prostate Cancer: Overview and Perspectives

Traditional prostate cancer therapy and especially chemotherapy has faced many challenges. Low accumulation levels, rapid clearance or drug resistance at the tumor site have been central to why the effect of chemotherapy drugs has declined. Applications of nanotechnology to biomedicine have enabled the development of nanoparticle therapeutic carriers suited for the delivery of chemotherapeutics in cancer therapy. This review describes the current nature of nanoparticle therapeutic carriers for prostate cancer. It describes typical nanocarriers commonly used for the delivery of chemotherapy or for imaging examination. Targeting strategies and related influencing factors are investigated to find ways of enhancing treatment effects of nanoparticles. The overall purpose of this review is to further understanding and to offer recommendations on the design and development of therapeutic nanoparticles for prostate cancer.

Implications of Nanotechnology in Healthcare

Introduction: Nanotechnology is a science, engineering conducted at nanoscale level for the manipulation of matter to create materials with significantly unusual, varied and new properties. Attributes of these synthesized nanomaterials promise to provide a number of applications in health including nanomedicine, nanorobots/nanobots, nanostars, nanofibers, chemotherapy and many more. There has been a remarkable interest in identification of adverse health effects associated with the use of nanotechnology too. The focus of this review is to highlight the current techniques and development of new technologies advancing medical science and disease treatment in human healthcare. Firstly, several Nano-pharmaceuticals and Nano-diagnostic methods offer numerous potential ways for targeted drug delivery, gene therapy, cancer treatment and clinical diagnosis to provide best rational use of the medicine and minimize the toxic effects. These techniques can also help to design certain drugs in a controlled way to avoid their structural complexity by dealing at the atomic and molecular level. Secondly, along with the discussion of potential applications of nanotechnology, some of the examples will be given to elaborate the various scientific and technical aspects in the real life.

Conclusion: Finally, conclusion with the future scope and challenges of nanotechnology in health will be described and discussed.

Breaking the Barrier of Cancer Through Liposome Loaded with Phytochemicals

Currently, the most important cause of death is cancer. To treat the cancer there are a number of drugs existing in the market but no drug is found to be completely safe and effective. The toxicity of the drugs is the key problem in the cancer chemotherapy. However, plants and plant derived bioactive molecule have proved safe and effective in the treatment of cancers. Phytochemicals that are found in fruits, vegetables, herbs, and plant extract have been usually used for treating cancer. It has been established that several herbal drug have a strong anticancer activity. However, their poor bioavailability, solubility, and stability have severely restricted their use. These problems can be overcome by incorporating the herbal drug in nanolipolomal vesicles. In last few decades, researcher have used herbal drug loaded nanoliposome for the treatment and management of a variety of cancers. Presently, a number of liposomal formulations are on the market for the treatment of cancer and many more are in pipe line. This review discusses about the tumor microenvironment, targeting mechanism of bioactive phytochemicals to the tumor tissue, background of nanoliposome, and the potential therapeutic applications of different bioactive phytochemicals loaded nanoliposome in cancer therapy.

Therapeutic Outcomes in AIDS-Associated Kaposi's Sarcoma Patients on Antiretroviral Therapy Treated with Chemotherapy at Two Tertiary Hospitals in Lusaka, Zambia

The incidence of HIV-associated Kaposi’s sarcoma (KS) remains high in Zambia in the antiretroviral therapy era. The most efficacious treatment regimen for KS has yet to be established. In both developed and developing countries, treatment regimens have had limited efficacy. Late presentation in Africa affects therapeutic outcomes.

Objective: The aim of this study was to determine therapeutic outcomes of epidemic KS patients on combination antiretroviral therapy (cART) after completion of six cycles of Adriamycin, Bleomycin, and Vincristine (ABV) chemotherapy.

Methods: This was a descriptive cross-sectional study. Study participants were drawn from a study database of confirmed incident KS patients seen at the Skin Clinic of the University Teaching Hospitals (UTH) during the period between August, 2015 and September, 2016.

Results: Of the 38 successfully recruited study participants, a complete response was documented in 18 (47%) after 6 cycles of ABV whereas 20 (53%) experienced a partial response. KS recurrence was observed in 8 (44%) of the individuals that experienced an initial complete response. At the time of the study, clinical assessment revealed that KS lesions had completely regressed in 21 (55%) of all the patients.

Conclusion: ABV chemotherapy appears ineffective in long-term resolution of epidemic KS patients on ART. Recurrence rates are high after chemotherapy in patients that experience initially favorable responses to treatment. There is a need to diagnose KS earlier, and to develop more efficacious treatment options in order to reduce recurrence rates for epidemic KS.

Connexin43 and Myocardial Ischemia-Reperfusion Injury

Background: Recently, the treatment and prevention of ischemic cardiomyopathy is one of the emerging research topics in the cardiovascular field. Gap junction is the basic structure of cardiac electrophysiology. Connexin is the basic unit of gap junctions. Connexin43(CX43) is the most abundant member of Cx family in the heart, the normal expression of Cx43 is important for heart development, electrically coupled cardiomyocytes activities and coordination of myocardial function. The connection between Cx43 and myocardial ischemia/reperfusion or reperfusion injury has become the focus of current research.

Methods: We undertook a structured search of bibliographic database for peer-reviewed research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers was appraised using standard tools. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to analyze the interventions and findings of included studies using a conceptual framework.

Results: Twenty-one papers were included in the review, eight papers outlined the relationship of Cx43 and reperfusion arrhythmias. Eight papers pointed out the effect on the infarct size of Cx43.

Conclusion: The findings of this review confirm that Cx43 is the most abundant member of Cx family in the heart and is vital for myocardial protection during ischemia/reperfusion process and for ischemia/reperfusion injury. Many of its mechanism are still not very clear and require future research in the future.

Smart Drug-Delivery Systems for Cancer Nanotherapy

Background: Despite all the advances achieved in the field of tumor-biology research, in most cases conventional therapies including chemotherapy are still the leading choices. The main disadvantage of these treatments, in addition to the low solubility of many antitumor drugs, is their lack of specificity, which leads to the occurrence of severe side effects due to nonspecific drug uptake by healthy cells.

Objective: The purpose of this manuscript is to review and analyze the recent progress made in cancer nanotherapy.

Results: Progress in nanotechnology and its application in medicine have provided new opportunities and different smart systems. Such systems can improve the intracellular delivery of the drugs due to their multifunctionality and targeting potential. First, we provide a global overview of cancer and different smart nanoparticles currently used in oncology. Then, we analyze in detail the development of drug-delivery strategies in cancer therapy, focusing mainly on the intravenously administered smart nanoparticles. Finally, we discuss the challenges, clinical trials, marketed nanomedicines and future directions of the nanotherapy applied to cancer treatment.

Conclusión: In this review, we have evidenced the tremendous potential that smart drug-delivery systems have to enhance the therapeutic effect of current standard treatment modalities, including chemotherapies and radiotherapies.

Recent Advances in pH-Sensitive Polymeric Nanoparticles for Smart Drug Delivery in Cancer Therapy

Background: Rapid developments in the field of nanoparticles during the last decades have led to its increased application in drug delivery approaches. The advantages of nano-based drug delivery systems include improved therapeutic efficacy of drugs and the reduction of side effects.

Objective: This review aims to highlight advances in stimuli-triggered drug delivery approaches using polymeric nanoparticles with a focus on pH-sensitive drug- and theranostic delivery systems.

Results and Conclusion: Of the various organic/inorganic nanoparticles, polymeric nanoparticles have fulfilled an integral role in the advancement of drug delivery systems by virtue of the ease to incorporate and modify targeting moieties in combination with controlled drug release over prolonged periods. Furthermore, polymeric nanoparticles facilitate theranostic treatment by the incorporation of imaging agents in addition to therapeutics. Recently, stimuli-responsive polymeric nanoparticles emerged as smart drug carriers, in which drug release is affected by physical and/or chemical structural changes induced by a specific stimulus (e.g. pH, temperature, and specific enzymes). The use of these nanocomposites reduces premature drug release and maintains effective drug levels at the pathological target.

Integrase Strand Transfer Inhibitors and the Emergence of Immune Reconstitution Inflammatory Syndrome (IRIS)

Background: Immune reconstitution inflammatory syndrome (IRIS) is a major concern when starting highly active anti-retroviral therapy (HAART) in new patients and especially late presenters. This study attempts to identify risk factors for IRIS and investigate whether certain treatment regimens increase the probability of IRIS for patients at risk.

Methods: Retrospective single-centre study of HIV patients treated with HAART.

Results: A total of 417 patients were included. We identified 45 cases of IRIS in 37 patients; an incidence of 13.3 cases over 1000 person-years. In univariate analysis, IRIS development was significantly associated with CDC stage, the presence of an opportunistic infection (OI) at diagnosis, CD4 cell count and viral load at diagnosis and HAART initiation and the use of integrase strand inhibitors (INSTIs). In multivariate analysis, INSTIs use (OR 2.89; 95%CI 1.26-6.64; p=0.012), CD4≤200/mm3 (OR 5.56; 95%CI 2.2-13.98; p<0.001), and the presence of an OI (OR 4.74; 95%CI 2.13-10.23; p=0.012) were independent risk factors. Among INSTI regimens, dolutegravir (OR 4.99 vs. NNRTI; 95%CI 1.11-22.55; p=0.037) and elvitegravir (OR 4.82 vs. NNRTI; 95%CI 1.43-16.19; p=0.011) seem to carry increased risk. Mortality was 18.9% (7/37) for IRIS patients compared to 9.7% (37/380) in the non-IRIS group. Mortality at any given time during follow-up was significantly higher in the IRIS group (HR 3.2; 95%CI 1.39-7.36; p=0.006).

Conclusion: The use of INSTIs and especially DTG and EVG is associated with a higher probability for the development of IRIS in the background of late presentation and the presence of OIs. These data highlight the need for further research.

Promising Targets in Anti-cancer Drug Development: Recent Updates

Cancer is a multifactorial disease and its genesis and progression are extremely complex. The biggest problem in the anticancer drug development is acquiring of multidrug resistance and relapse. Classical chemotherapeutics directly target the DNA of the cell, while the contemporary anticancer drugs involve molecular-targeted therapy such as targeting the proteins possessing abnormal expression inside the cancer cells. Conventional strategies for the complete eradication of the cancer cells proved ineffective. Targeted chemotherapy was successful in certain malignancies however, the effectiveness has often been limited by drug resistance and side effects on normal tissues and cells. Since last few years, many promising drug targets have been identified for the effective treatment of cancer. The current review article describes some of these promising anticancer targets that include kinases, tubulin, cancer stem cells, monoclonal antibodies and vascular targeting agents. In addition, promising drug candidates under various phases of clinical trials are also described. Multi-acting drugs that simultaneously target different cancer cell signaling pathways may facilitate the process of effective anti-cancer drug development.

Nutlin-3, A p53-Mdm2 Antagonist for Nasopharyngeal Carcinoma Treatment

Nasopharyngeal carcinoma (NPC) is a form of head and neck cancer of multifactorial etiologies that is highly prevalent among men in the population of Southern China and Southeast Asia. NPC has claimed many thousands of lives worldwide; but the low awareness of NPC remains a hindrance in early diagnosis and prevention of the disease. NPC is highly responsive to radiotherapy and chemotherapy, but radiocurable NPC is still dependent on concurrent treatment of megavoltage radiotherapy with chemotherapy. Despite a significant reduction in loco-regional and distant metastases, radiotherapy alone has failed to provide a significant improvement in the overall survival rate of NPC, compared to chemotherapy. In addition, chemo-resistance persists as the major challenge in the management of metastatic NPC although the survival rate of advanced metastatic NPC has significantly improved with the administration of chemotherapy adjunctive to radiotherapy. In this regard, targeted molecular therapy could be explored for the discovery of alternative NPC therapies. Nutlin-3, a small molecule inhibitor that specifically targets p53-Mdm2 interaction offers new therapeutic opportunities by enhancing cancer cell growth arrest and apoptosis through the restoration of the p53-mediated tumor suppression pathway while producing minimal cytotoxicity and side effects. This review discusses the potential use of Nutlin-3 as a p53-activating drug and the future directions of its clinical research for NPC treatment.

Cytochrome P450 Structure, Function and Clinical Significance: A Review

Background: The cytochrome P450 (CYP) enzymes are membrane-bound hemoproteins that play a pivotal role in the detoxification of xenobiotics, cellular metabolism and homeostasis. Induction or inhibition of CYP enzymes is a major mechanism that underlies drug-drug interactions. CYP enzymes can be transcriptionally activated by various xenobiotics and endogenous substrates through receptor-dependent mechanisms. CYP enzyme inhibition is a principal mechanism for metabolism- based drug-drug interactions. Many chemotherapeutic drugs can cause drug interactions due to their ability to either inhibit or induce the CYP enzyme system. Predictions based on in silico analyses followed by validation have identified several microRNAs that regulate CYPs. Genetic polymorphisms and epigenetic changes in CYP genes may be responsible for inter-individual and interethnic variations in disease susceptibility and the therapeutic efficacy of drugs.

Objective: The present review is a comprehensive compilation of cytochrome P450 structure, function, pharmacogenetics, pharmacoepigenetics and clinical significance.

Conclusion: Knowledge about the substrates, inducers, and inhibitors of CYP isoforms, as well as the polymorphisms of CYP enzymes may be used as an aid by clinicians to determine therapeutic strategy, and treatment doses for drugs that are metabolized by CYP gene products.

Recent Advances in Cancer Drug Development: Targeting Induced Myeloid Cell Leukemia-1 (Mcl-1) Differentiation Protein

Background: Anti-apoptotic members of the Bcl-2 family of proteins are upregulated in a majority of cancers and are potential therapeutic targets. Fragment-based design led to the development of clinical candidates that target Bcl-xL/Bcl-2. Although these BclxL/ Bcl-2 inhibitors showed promise in pre-clinical studies, resistance to several Bcl-xL inhibitors was observed, when used alone. This is attributed to the over-expression of Mcl-1, another member of the Bcl-2 family of proteins. Indeed, Mcl-1 is highly amplified in numerous cancers, suggesting that it may contribute to malignant cell growth and evasion of apoptosis. Therefore, significant efforts have been made toward the development of direct Mcl-1 inhibitors for cancer therapy.

Methods: Following an extensive search of peer-reviewed articles on the development of Mcl-1-selective inhibitors, the literature retrieved is chronologically arranged and discussed in this review article.

Results: We have included 147 articles in this review; including articles that describe the development of stapled peptides with improved binding affinity as Mcl-1-selective BH3 mimetics, those describing fragment-based and structure-based design of small molecule Mcl-1 inhibitors by various research groups, and those detailing the use of natural products and their derivatives as potential Mcl-1 inhibitors.

Conclusion: The therapeutic potential of targeting the Mcl-1 protein for cancer drug discovery is vast. Stapling BH3 peptides, as well as the development of small molecule inhibitors as BH3 mimetics, are viable strategies to develop selective Mcl-1 inhibitors. With no clinically approved candidate in hand, additional modes of perturbing the biological function of this protein will aid drug discovery efforts.

Cardioprotective Utility of Urocortin in Myocardial Ischemia- Reperfusion Injury: Where do We Stand?

Background: There has been a constant pursuit for development of newer therapies which can contribute to the relatively nascent field of cardioprotection in the setting of myocardial ischemiareperfusion injury. One novel cardioprotective agent among others, that has shown promising results in the limited number of research studies undertaken till now, is Urocortin. Urocortins are peptides belonging to the Corticotropin-Releasing Hormone family.

Results: Acting through a variety of downstream mechanisms, urocortin has been shown to alter cellular metabolism and modulate the mechanism of cell death occurring as a result of ischemia-reperfusion injury. New evidence continues to accumulate in support of urocortin’s beneficial role in cytoprotection.

Conclusion: We present here an updated review largely focused on the various mechanisms through which urocortin alters cellular metabolism, and discuss the clinical potential of urocortin’s cardioprotective ability in myocardial ischemia-reperfusion injury.

Epigenetics of Virus-Induced Tumors: Perspectives for Therapeutic Targeting

About 15–20% of human cancers worldwide have viral etiology. Seven human DNA and RNA viruses are accepted to be oncogenic viruses or oncoviruses and contribute to the development of various cancer types. Human oncoviruses have developed multiple molecular mechanisms to interfere with specific cellular pathways to promote viral replication and viral life cycle maintenance in the host. Despite the diversity of oncogenic viruses, they use similar strategies for cancer development. Viral oncoproteins and viral non-coding RNAs are the key factors that can affect multiple cellular processes on both genetic and epigenetic levels.

Epigenetics research allows better understanding of the complex interplay between oncoviruses and the host cells. This review highlights the importance of epigenetic reprogramming for virus-induced carcinogenesis. Recent progress in the development of pharmacological tools for targeting epigenetic mechanisms opens new perspectives for modulation of virus/host interaction and intervention of virus-induced cancer. Several clinical trials have been carried out or are on-going involving epigenetic drugs not only as single therapeutic but also in combination with other targeted agents against various virus-induced cancers.

Radiosensitizing Effect of Electrochemotherapy: A Systematic Review of Protocols and Efficiency

Background: Electrochemotherapy (ECT) is a combination of electroporation (EP) and chemotherapy and has been reported as a potential radiosensitizing agent for radiation therapy.

Objective: The main objective of this study was to systematically review of the literature to evaluate the effectiveness of ECT in sensitization of tumors to ionization radiation. In addition, the clinical considerations and mechanisms of action of radiosensitizing effect are discussed.

Results: Nine studies were included in this review. Bleomycin and cisplatin showed radiosensitizing effects in combined protocols with EP. EP enhances the cytotoxicity of bleomycin and cisplatin by factor of 1000 and 100, respectively. The mechanism of action of these drugs is induction of single and double strand breaks in DNA molecule. Moreover, the two main mechanisms of EP are increasing drug uptake in the tumor cells and generating reactive oxygen species. A single session ECT before radiotherapy can significantly enhance the tumor response.

Conclusion: ECT is effective for different cell lines and tumors with different levels of radiosensitivity. Our findings show that ECT can be further translated into the clinic and can be matched by singledose irradiation as well as in the fractionated regime.

New Pharmacological Approaches to the Prevention of Myocardial Ischemia- Reperfusion Injury

Background: Early reperfusion of the blocked vessel is critical to restore the blood flow to the ischemic myocardium to salvage myocardial tissue and improve clinical outcome. This reperfusion strategy after a period of ischemia, however, may elicit further myocardial damage named myocardial reperfusion injury. The manifestations of reperfusion injury include arrhythmias, myocardial stunning and micro-vascular dysfunction, in addition to significant cardiomyocyte death. It is suggested that an overproduction of reactive oxygen species, intracellular calcium overload and inflammatory cell infiltration are the most important features of myocardial ischemia-reperfusion injury.

Objective: In this review, various pharmacological interventions to treat myocardial reperfusion injury including the antioxidant flavonols, hydrogen sulfide, adenosine, opioids, incretin-based therapies and cyclosporin A which targets the mitochondrial permeability transition pore are discussed.

Conclusion: The processes involved in reperfusion injury might provide targets for improved outcomes after myocardial infarction but thus far that aim has not been met in the clinic.

Immunomodulatory Activity of MicroRNAs: Potential Implications for Multiple Myeloma Treatment

Multiple myeloma (MM) is an incurable plasma cell neoplasm accounting for about 10% of all hematologic malignancies. Recently, emerging evidence is disclosing the complexity of bone marrow interactions between MM cells and infiltrating immune cells, which have been reported to promote proliferation, survival and drug resistance of tumor cells. MicroRNAs (miRNAs) are small non-coding RNA molecules with regulatory functions in the cell, whose expression has predictive and prognostic value in different malignancies. MiRNAs are gaining increasing interest due to their capability to polarize the immune-response through different mechanisms, which include the molecular reprogramming of immune cells. This characteristic, together with the antitumor activity of miRNA mimics or inhibitors, make the miRNA network an attractive area of investigation for novel anti-MM therapeutic approaches. In this review, we will discuss the recent advances in the understanding of the interplay between MM cells and bone marrow resident immune cells, with special focus on the molecular and functional changes induced by miRNA network modulation. We will finally indicate potential targets for therapeutic intervention.

Therapeutic Applications of Liposomal Based Drug Delivery and Drug Targeting for Immune Linked Inflammatory Maladies: A Contemporary View Point

Immune-based inflammatory diseases involve immune related dysregulation in different sites of body, which includes rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, atherosclerosis, etc. Advancements in molecular research have facilitated investigation of their pathogenesis that is involved in inflammatory cytokines cells and several genes. The available drug therapy provides suboptimal therapeutic effects and higher adverse effects. Emergence of liposomal systems of the drugs meant for the above mentioned disease has gained broader importance due to their high treatment efficacy by means of optimal therapeutic drug delivery. Beyond the conventional liposomal formulations, evolution of second generation liposomes including stealth liposomes, cationic liposomes, immuno-liposomes, etc. has gained tremendous attention owing to their drug target potential, diagnostic importance and imaging in treatment of above mentioned immune mediated inflammatory disorders.

Nanocarriers in Improving Chemotherapy of Multidrug Resistant Tumors: Key Developments and Perspectives

The multidrug resistance (MDR) of tumor cells significantly reduces the efficiency of traditional anticancer therapy. Tumor MDR is complex and involves several mechanisms such as decreased drug uptake, increased drug efflux, enhanced drug exocytosis, increased drug detoxification and inactivation by drugmetabolizing enzymes, altered drug targets due to genetic and epigenetic modifications, altered DNA repair, and impaired apoptotic pathways. Implementation of nanoparticles can markedly improve drug delivery through increased stability in the plasma, prolonged half-life, enhanced specificity of transfer, and advanced drug accumulation and retention in the tumor cells. So far, many various types of nanocarriers have been used for the delivery of anticancer agents. These carriers greatly increase anti-tumor effects of cytotoxic agents since drug-carrying nanoparticles are able to reverse MDR. The promising integrative approach in cancer nanotherapy assumes the development of multifunctional delivery systems simultaneously transmitting various agents such as drugs, genes, imaging agents, and targeting ligands in order to enhance anti-tumor toxicity and nanoparticle tracking.

Regulatory Approaches to Nonclinical Reproductive Toxicity Testing of Anti-Cancer Drugs

This paper reviews the nonclinical reproductive toxicity testing of 15 drugs currently approved in the USA or Europe for the treatment of cancer. The list includes cytotoxic anti-tumour agents, small molecule inhibitors of pathways involved in neoplastic proliferation, monoclonal antibodies that target specific antigens expressed by neoplastic cells and supportive therapies used to counter the effects of chemotherapy. Most, but not all, drugs were tested for developmental or reproductive toxicity in animals prior to marketing and most were found to be embryotoxic or teratogenic. Because of the unmet need for comparative safety data on available cancer therapies for use by physicians when treating pregnant patients, at least embryofetal toxicity studies are now usually requested prior to marketing of new anti-cancer drugs, even when the pharmacological profile suggests likely side-effects on the embryo or fetus. Rats and rabbits are the preferred experimental species, but non-human primates have to be used for some biopharmaceuticals. Nonclinical study designs for anti-cancer drugs should be designed to allow the possibility of terminating the study once adverse effects have been demonstrated, without using the full number of animals specified in regulatory guidelines. All 15 drugs are currently labelled as being harmful to pregnancy, ether on the basis of animal data or documented hazards in humans. It is hoped that the forthcoming revision of the FDA drug labelling legislation will allow a better graduation of the relative risk between available anti-cancer therapies.

High Seroprevalence of Human Herpesvirus 8 Infection in HIV-positive Homosexual Men in Jiangsu Province, China

Background: HIV-infected homosexual men are more frequently diagnosed with Kaposi's sarcoma. With the increase of HIV-infected homosexual men in China, we urgently need to know the KS-related human herpesvirus (KSHV/HHV-8) seroprevalence in this population. To investigate HHV-8 prevalence among HIV-positive homosexual men, we recruited 183 patients naive of antiretroviral therapy (ART) whose blood samples presented with HIV-antibody positive as confirmed by western blot.

Methods: HIV viral load was tested using Cobas TaqMan HIV-1 test Version 2.0, and CD4 T cell counts were tested using a Flow cytometry instrument. All HIV-positive blood samples were collected and screened for KSHV. Immunofluorescence (IFA) test was conducted for HHV-8-Specific antibodies (anti-LANA) in the plasma. HHV-8 DNA in whole blood cells of IFA-positive subjects was quantified with Real-time polymerase chain reaction (RT-PCR).

Results: All samples showed HIV RNA positive. CD4+ T cell count was 23% cases (42/183) which showed ≤200 cells/μL, 51.3% cases (94/183) showed 201-500 cells/μL and 25.7% cases (47/183) showed ≥501 cells/μL. Immunofluorescence (IFA) test demonstrated an HHV-8 prevalence of 50.8% (93/183), among which 20.4% of the cases (19/93) were HHV-8 DNA positive. HHV-8 infection showed no difference among different age groups (p=0.96). Similarly, HHV-8 infection exhibited no significant difference among different HIV viral load groups (p=0.08). However, HHV-8 infection among different CD4+ T cell count showed significant difference (P=0.0004).

Conclusion: This study showed a high seroprevalence of human herpesvirus 8 infection in HIVpositive homosexual men.

Personalized Nanoparticles for Cancer Therapy: A Call for Greater Precision

Nanotechnology has brought about the advent of personalized medicine in the era of targeted therapeutic strategies for cancer therapy. The ability to exploit tumor features for therapeutic gain has made it possible to manufacture more effective nanomedicines for cancer treatment. However, known obstacles, including the inability to overcome pathophysiological barriers of tumors, have impeded disease management. In spite of this, recent efforts have been made to develop more functionalized nanosystems that utilize the active-targeting approach. This article reviews the FDA-approved cancer drug delivery systems in the general framework of personalized nanomedicine. We discuss the latest efforts in the development of functionalized nano-systems, and summarize relevant ongoing preclinical and clinical trials.

An Investigative Approach to Treatment Modalities for Squamous Cell Carcinoma of Skin

Background: Squamous cell carcinoma of skin has become an important matter of discussion worldwide due to high number of deaths. Treatment of such cancer involves use of drugs (chemotherapy) along with surgery or radiation therapy. The combination chemotherapy is preferred over single treatment modality may be due to synergistic effect of targeting agent resulting in reduced drug dose, reduced cytotoxic effect and improved efficacy and survival rate. The objective of this work is to provide insight into the squamous cell carcinoma of skin; the various approaches and challenges adapted to surmount the cancer malignancies.

Methods: Research evidence shows that nanoparticle based therapeutic delivery to squamous cell carcinoma is equanimous to lead therapeutic approaches for intervention of cancer growth. Active chemotherapeutic approach is one of the leading therapies to such cancer cells due specific selectivity towards the EGFR-receptors over-expressed in tumor cells. Review of numerous research publications revealed innate toxicity of chemotherapeutic agents, and substantiated active receptor mediated drug targeting for therapeutic regime. These actively functionalized nanoparticles have been delivered to the targeted cells with higher selectivity, minimal toxicity and better retention in the cell.

Results: Numerous approaches and strategies have been designed till date for successful delivery of drug to cancer cells. The techniques have shown tremendous improvement in getting normalcy of carcinomas but a few have been marketed so far.

Conclusion: Indeed, receptor based drug targeting approach through molecular signal transduction pathways involved in skin cancer development will provide insight into squamous carcinoma. Despite of these, other such challenges in drug delivery to squamous cell carcinoma need further clarification.

Molecular Biological Roles of Ursolic Acid in the Treatment of Human Diseases

Background: Plants and their products have been used to treat human diseases since time immemorial. Ursolic acid (UA), a pentacyclic triterpenoid found in a wide range of plants, possesses a plethora of biological traits, such as anti-inflammatory, anti-oxidative, and anti-cancer properties. Extensive research has been undertaken to elucidate the biological, pharmacological, and clinical roles of UA in the treatment of human diseases. However, the mechanism and molecular targets by which UA acts has not yet been clearly elucidated.

Methods: This review summarizes the studies, findings, and data related to UA with reference to diseases of the liver, heart, brain, and muscles, fertility, and cancer.

Results: Among 89 papers included in this review, 18 papers defined the anticancer property of UA against numerous cancers and indicated the molecular pathways and strategies involved in the therapeutic action. Eleven papers showed protective role of UA in liver diseases including its capacity to enhance liver regeneration. Ten papers included facts related to beneficial effect on cardiovascular diseases and body homeostasis, and showed UA as a remedy for heart diseases. Nine papers demonstrated the medicinal value of UA against brain and neurological disorders. UA showed healing effects in skeletal muscle diseases such as muscle atrophy in 6 papers. Seven papers defined anti-diabetic and anti-nephropathy characteristics of UA. Antimicrobial properties of UA were presented in 10 papers. Six papers showed the ability of UA to cure obesity and hyperlipidemia. In addition, 4 papers revealed negative effects of UA that inhibits sperm motility during spermatogenesis. This review identifies the multifarious therapeutic activities of UA in numerous health disorders including cancer.

Conclusion: Summarizing and correlating the published data on UA facilitates better understanding of UA on its potential as a therapeutic agent.

Safety of Systemic Biologic Agents in the Treatment of Non-malignant Skin Disorders

Introduction: The recent significant breakthroughs in the understanding of the pathogenetic mechanisms of psoriasis and other immune-mediated inflammatory disorders, have led to the emergence of a wide array of biologic agents or biologics, which are especially designed to target selective intracellular or extracellular components and pathways of the dysregulated immune response.

Method: These targeted biologic agents have altered the landscape in dermatotherapy aiming to offer higher therapeutic efficacy and an alternative in patients who either failed on conventional systemic regimens or have no other therapeutic options. In the last two decades, the number of the commercially available biologic agents and the extent of their use have dramatically increased; today, these compounds represent a substantial part of modern dermatologic armamentarium.

Results: Due to the immunosuppressive potential of biologics, serious concerns were raised about their safety profile, already during the pre-approval period. These concerns did not subside after the incorporation of the postmarketing experience, particularly after the withdrawal of a biologic agent (efalizumab) due to its serious and even fatal side effects.

Conclusion: The purpose of the present article is to review the cutaneous and systemic side effects of all systemic biologic agents used so far in modern treatment of non-malignant skin disorders and to contribute to a better and updated awareness of their safety risks among clinicians, which will enable the latter to make the best informed and personalized drug selection and therapeutic decisions. This review was mainly based on data derived from Medline and Scopus databases and from manufacturing companies, as well.

Virus, Oncolytic Virus and Human Prostate Cancer

Background: Prostate cancer (PCa), a disease, is characterized by abnormal cell growth in the prostate - a gland in the male reproductive system. Although older age and a family history of the disease have been recognized as the risk factors of PCa, the cause of this cancer remains unclear. Currently, PCa is one of the leading causes of cancer death among men of all races.

Method: In this review study, we first discuss the controversy of the contribution of virus infection to PCa, and subsequently summarize the development of oncolytic virotherapy for PCa in the past several years.

Results: Mounting evidence suggests that infections with various viruses are causally linked to PCa pathogenesis. Published studies have provided strong evidence that at least two viruses (RXMV and HPV) contribute to prostate tumourigenicity and impact on the survival of patients with malignant PCa. Traditional therapies including chemotherapy and radiotherapy are unable to distinguish cancer cells from normal cells, which are a significant drawback and leads to toxicities for PCa patients undergoing treatment. So far, few other options are available for treating patients with advanced PCa. For PCa treatment, oncolytic virotherapy appears to be much more attractive, which uses live viruses to selectively kill cancer cells. Oncolytic viruses can be genetically engineered to induce cancer cell lysis through virus replication and expression of cytotoxic proteins.

Conclusion: Virotherapy is being developed to be a novel therapy for cancers, which uses oncotropic and oncolytic viruses with their abilities to find and destroy malignant cells in the body. As oncolytic viruses are a relatively new class of anti-cancer immunotherapy agents, several important barriers still exist on the road to the use of oncolytic viruses for PCa therapy.

Epstein-Barr Virus-associated Gastric Cancer and Potential Mechanisms of Oncogenesis

Introduction: EBV-associated Gastric Cancer (EBVaGC) comprises about 9% of all cases of GC and constitutes a distinct clinicopathological and molecular entity. The pattern of viral expression in EBVaGC cannot be set to any of the previously EBV-associated malignancies. Several lines of evidence support that viral expression in EBVaGC is characterized by high transcription of the BamH1- A rightward transcript (BART), low-levels of EBNA-1 and lack of LMP1. The high transcription activity of the BamH1-A region is importantly directed to express BART miRNAs, supporting a critical role for these miRNAs during epithelial cell infection and carcinogenesis. Several studies have shown that promoter hypermethylation is also a prominent feature of EBVaGC. Based on the recent TCGA report, the specific fingerprint of genomic alterations in EBVaGC is marked by mutations in PIK3CA, ARID1A and BCOR genes, and amplification of 9p24.1 that harbors the genes for the JAK2, PD-L1 and PD-L2 proteins. The specific programs of viral gene expression, promoter methylation and genomic mutations found in EBVaGC target cell signaling pathways leading to increased proliferation, increased cell survival, immune evasion, augmented EMT and acquisition of stemness features. Less understood is the participation of EBV in chronic gastric inflammation, but some studies argue that EBV, similar to and together with Helicobacter pylori, is an early participant in the GC oncogenic process through promoting chronic inflammation and increased tissue damage.

Conclusion: Here, we discuss the principal and distinctive carcinogenic routes promoted by EBV in the gastric epithelium.

Role of the Autonomic Nervous System in the Tumor Micro-Environment and its Therapeutic Potential

Although evidence over the last 30 years suggests that the autonomic nervous system (ANS) mediates stress-induced allostatic and immune responses, the crucial role that it plays in the tumor micro-environment has only recently been reported. Here, we review the action of ANS signaling in this micro-environment. Emerging data suggest that primary tumors are innervated by the ANS which mediates stress-related effects on tumor progression. The activation of the sympathetic nervous system (SNS) takes advantage of neurotransmitters and neuropeptides from the innervating neural circuitry and/or hypothalamic-pituitary-adrenal axis glucocorticoids via their receptors to modulate the gene expression associated with oncogenesis, the proliferation and apoptosis of tumor cells, angiogenesis, and the tumor-associated immune response. The parasympathetic nervous system has also been implicated in some tumor types, but its contribution in the tumor micro-environment remains unclear. In addition to identifying the ANS signaling pathways involved in tumor progression, recent reports suggest that the ANS could be a potential biomarker to predict tumor progression, and have identified new pharmacological strategies, such as the use of β-adrenergic blockers, to inhibit tumor progression and metastasis by targeting this system. These findings are reviewed here.

Photothermal Ablation of Cancer Cells Using Folate-Coated Gold/ Graphene Oxide Composite

Objective: A new tumor targeted polymer-coated gold/graphene hybrid has been developed for achieving simultaneously thermoablation and chemoterapy of folate receptor-positive cancer cells.

Methods: The gold/graphene hybrid was prepared by depositing gold nanospheres onto graphene oxide and coating it with an inulin-folate conjugate. Paclitaxel was loaded by sonication. The hybrid was characterized by UV-Vis spectroscopy, DSC analysis and SEM microscopy. The cytotoxicity, thermoablation and anticancer activity were evaluated in vitro on MCF-7 and 16 HBE.

Results: In vitro tests showed that the paclitaxel-loaded hybrid improved the effectiveness of the drug especially after photothermal treatments.

Conclusion: On the whole, while gold/graphene composite provided an excellent time-dependent photothermal effect, the loading of paclitaxel allowed a suitable chemotherapy, thus killing cancer cells both via a selective laser beam thermoablation and hyperthermia-triggered chemotherapy.

Neuropathic Pain and Lung Delivery of Nanoparticulate Drugs: An Emerging Novel Therapeutic Strategy

Neuropathic pain is a chronic neurological disorder affecting millions of people around the world. The currently available pharmacologic agents for the treatment of neuropathic pain have limited efficacy and are associated with dose related unwanted adverse effects. Due to the limited access of drug molecules across blood-brain barrier, a small percentage of drug that is administered systematically, reaches the central nervous system in active form. These therapeutic agents also require daily treatment regimen that is inconvenient and potentially impact patient compliance. Application of nanoparticulate drugs for enhanced delivery system has been explored extensively in the last decades. Pulmonary delivery of nanomedicines for the management of various diseases has become an emerging treatment strategy that ensures the targeted delivery of drugs both for systemic and local effects with low dose and limited adverse effects. To the best of our knowledge, there are no inhaled drug products available on market for the treatment of neuropathic pain. The advantages of delivering therapeutics into deep lungs include non-invasive drug delivery, higher bioavailability with low dose, lower systemic toxicity, and potentially greater blood-brain barrier penetration. This review discusses and highlights the important issues on the application of emerging nanoparticulate lung delivery of drugs for the effective treatment of neuropathic pain.

Evaluation of Echocardiographic Abnormalities in HIV Positive Patients Treated with Antiretroviral Medications

Background: Echocardiography is a reliable means for the diagnosis of functional and valvular diseases of the heart in HIV positive and HIV negative patients. The current study was to evaluate echocardiographic abnormalities in HIV positive patients under an antiretroviral therapy (ART) program in Tehran, Imam Khomeini Hospital, Iran.

Methods: This is a descriptive cross-sectional study, conducted among 231 HIV-1 positive patients under ART. All HIV positive patients including 150 men (65%) and 81 women (35%) (mean age of 41 years) were assessed by trans-thoracic echocardiography (TTE) in Imam Khomeini Hospital, over the period from 2013 to 2014.

Results: The mean CD4 count was 408 cell/μl, and the average left ventricular ejection fraction (LVEF) was 59.5%. There was an inverse correlation between age and LVEF level. Nevirapine users showed a significantly higher LVEF than non-users. Left ventricular systolic dysfunction (LVSD) was diagnosed in 5.6% along with the increase in age, while left ventricular diastolic dysfunction (LVDD) was reported in 19.5% of patients associated with age and smoking. Here, the mean systolic pulmonary arterial pressure (SPAP) was only 20 mmHg and just four percent of the patients suffered pulmonary hypertension. Almost 44% had a heart valve disorder among which mitral valve prolapse is the most common problem. Pericardial effusion was not found in any patients.

Conclusion: It seems that heart disorders with no suggestive symptoms in HIV positive patients, and mainly older adults who have traditional risk factors for heart diseases, should be seriously considered by health providers.

Radiolabeled Nanoparticles for Cancer Diagnosis and Therapy

Cancer remains as one of the major causes of death worldwide. The emergence of nanotechnology has opened new avenues for the development of nanoparticle (NP)- based diagnostic and therapeutic tools. NPs of different chemical composition, size, shape and surface decoration can be prepared using a wide variety of synthetic strategies. Subsequent radiolabelling with positron or gamma emitters results in potential diagnostic agents which may offer improved selectivity and/or specificity for the target organ or tissue, enabling the acquisition of images with higher signal-to-contrast ratio. Incorporation of alpha or beta emitters leads to therapeutic agents with application in the field of radiotherapy. Here, we first describe the different labeling strategies reported so far for the incorporation of radionuclides into NPs. Recent advances in the use of nanoparticulate constructs both in the diagnostic and therapeutic arenas are then discussed and examples of their application are briefly discussed.

Radiotherapy for Non-Melanoma Skin Cancer

This review summarizes techniques, indications and contraindications for radiotherapy for non-melanoma skin cancer. Different radiotherapy techniques including brachytherapy, electron treatments, photon treatments with electronic brachytherapy, linear accelerator, and orthovoltage machines are available. Radiation oncologists have to select the best technique for different sites and scenarios. Details of specific radiotherapeutic preparation and clinical care discussed in this review will be of great help to the reader at the point of care.

The Roles of the Unique Prolyl Isomerase Pin1 in Cancer-Related Viral and Bacterial Infections

Infection is the process of pathogen invasion, as well as the host reaction to the foreign agents. Proline-directed phosphorylation is a major regulatory mechanism that regulates the function of fundamental proteins involved in infection and infection-induced cancer. Recently, the identification of the phosphorylation-dependent prolyl isomerase Pin1 has uncovered a unique regulatory signaling mechanism controlling protein conformation and function after phosphorylation. Pin1 is the only proline isomerase that specifically recognizes certain Pro-directed Ser/Thr phosphorylation motifs. Pin1 has emerged as a major regulator of cancerrelated viral and bacterial infections notably via activating Toll-like receptor signaling and NF-κB pathways. This paper will specifically review recent findings on the role of Pin1 in cancer-related viral and bacterial infections and also discuss newly discovered Pin1 inhibitors as promising drugs for the prevention and treatment of viral and bacterial infections and associated tumorigenesis.

Strategies for Increasing the Solubility and Bioavailability of Anticancer Compounds: β-Lapachone and Other Naphthoquinones

Quinones are among the most studied natural and synthetic products in the literature because they have considerable biological potential. These compounds exhibit activity against many microorganisms and are able to eliminate tumor cells through several mechanisms of action. Some of these compounds have become drugs that are used clinically. However, they also have problems with respect to solubility, stability and toxicity. The alternative of using controlled-release systems has been applied to quinones, with good results in some cases, indicating that these formulations may be a strategy for improving the pharmacological profile of this class of compounds.

An 8-Year Retrospective Study of Human Visceral Leishmaniasis

Background: Visceral leishmaniasis (VL) is a zooanthroponosis affecting both rural and periurban areas, and can also spread into urban areas. VL has emerged in many countries in the world, presenting new cases in new countries of occurrence. Thus, studies concerning epidemiological aspects in different world regions are very meaningful.

Methods: With this purpose, this study analyzed 89 cases of VL, treated between June 2006 and June 2014 at Eduardo de Menezes Hospital (HEM), a Reference Center of Infectious Diseases situated in Belo Horizonte, in Minas Gerais state, Brazil.

Results: According to the results, it was observed that males are mostly infected (84%/n=75) and the most affected age range was 20-49 years old (83%/n=74). The treatment liposomal amphotericin B (33%/n=29) was mostly used. Recurrences were more frequent in patients treated with Glucantime^® (17%/n=9). No side effects were reported among the 29 patients treated with liposomal amphotericin B. On the other hand, there were 23 cases related to the occurrence of acute renal failure (ARF) and the use of conventional amphotericin B, both when it was administered alone or in combination with other drugs. Additionally, we observed a close relationship between the VL and HIV infection, observing a coinfection rate of 28.1% (n=25).

Conclusion: From the survey data, it was possible to conclude that the majority of VL patient treated at HEM is male, classified as brown racial group, economically active, and may be drug addicts, chronic alcoholics and/or smokers. They may present some Non-communicable diseases (NCD), such as hypertension, diabetes mellitus, dyslipidemia and/or obesity and, predominantly present a great chance of being a carrier of the Human Immunodeficiency Virus, associated or not with tuberculosis. As symptoms, these patients possibly will present hepatosplenomegaly, fever and pronounced weight loss.

Liposomal Drug Delivery System for Cancer Therapy: Advancement and Patents

Background: In this review article, authors reviewed about the liposomes which are amongst various drug delivering systems for the delivery of the therapeutic agents at the target site.

Methods: Advances in liposomal drug delivery systems for the cancer therapy have enhanced the therapeutic levels of the anticancer moieties. Liposomes show promising action on the tumor by incorporating less amount of drug at the target site, with minimum toxic effect and maximum therapeutic effect and thereby enhancing the bioavailability.

Results: Liposome-based drug delivery systems provide the potential to elevate the effect of drug concentration in tumor cells. Manuscript briefly describes the role of liposomes in cancer therapy and various patents based on the same.

Editorial: Overview on microRNAs in Cancer Development and Virus Infection

Competition Between Tumor and Mononuclear Phagocyte System Causing the Low Tumor Distribution of Nanoparticles and Strategies to Improve Tumor Accumulation

In the past few decades, nanoparticles have shown their advantages in anti-cancer therapy. After intravenous injection, they could preferentially arrive at tumor tissue either by extravasation from tumor vasculature or targeting vascular endothelial cells. But at the same time, their quantity in mononuclear phagocyte system (MPS) is far more than that in tumor. In this review, we discuss the advantages of MPS in spleen and liver over tumor on competing nanoparticles. The biophysical causes of spleen and liver help the MPS to capture nanoparticles, such as sufficient flux of blood stream, capillary network with fenestrations in liver and venous sinuses in spleen. Meanwhile, liver and spleen are the two major organs that contain MPS. Various properties of nanoparticles may affect their biodistribution. It is suggested that nanoparticles with proper size and shape, suitable charge, polyethyleneglycol and ligands will minimize the clearance by MPS. Several novel and promising approaches for cancer therapy are introduced in this review. This review seeks to provide guidelines for improving nanoparticles accumulation in tumor through both optimizing nanoparticles design and novel ways to design nanodelivery system for cancer therapy.

Lack of Association between NOD2 rs3135500 and IL12B rs1368439 microRNA Binding Site SNPs and Colorectal Cancer Susceptibility in an Iranian Population

Objective: The purpose of this study was to evaluate the potential association between single nucleotide polymorphisms (SNPs) in microRNA (miRNA) binding sites in the NOD2 and IL12B gene 3-untranslated regions and colorectal cancer (CRC) susceptibility in an Iranian population.

Methods: We genotyped NOD2 rs3135500 [3 untranslated region (UTR) A/G] and IL12B rs1368439 (3UTR G /T) in a hospital-based study of 92 colorectal cancer cases and 105 healthy controls. All samples were genotyped by TaqMan assay via an ABI 7500 Real Time PCR System (Applied Biosystems) with DNA from FFPE tissue and peripheral blood.

Results: our results showed similar distribution of genotype and allelic frequencies of the NOD2 and IL12B polymorphisms between patients and controls. When the more common rs3135500 AA genotype was used as the reference, the rs3135500 AG and rs3135500 GG genotypes were not significantly associated with the risk of CRC (OR = 1.294, 95% CI: 0.524 -3.197; and OR = 2.230, 95% CI: 0.87 - 5.715, respectively), and The IL12B rs1368439 TG and IL12B rs1368439 GG genotypes were not significantly associated with the risk of CRC compared with the IL12B rs1368439 TT genotype (OR = 1.547 95% CI: 0.187- 12.771; and OR = 1.753, 95% CI: 0.217-14.157, respectively).

Conclusion: NOD2 rs3135500 and IL12B rs1368439 SNPs were not genetic risk factors for colorectal cancer in the studied Iranian population.

Hierarchy of Knowledge Translation: From Health Problems to Ad-Hoc Drug Design

An innovative approach to analyze the complexity of translating novel molecular entities and nanomaterials into pharmaceutical alternatives (i.e., knowledge translation, KT) is discussed. First, some key concepts on the organization and translation of the biomedical knowledge (paradigms, homophily, power law distributions, hierarchy, modularity, and research fronts) are reviewed. Then, we propose a model for the knowledge translation (KT) in Drug Discovery that considers the complexity of interdisciplinary communication.

Specifically, we address two highly relevant aspects: 1) A successful KT requires the emergence of organized bodies of inter-and transdisciplinary research, and 2) The hierarchical and modular topological organization of these bodies of knowledge. We focused on a set of previously-published studies on KT which rely on a combination of network analysis and computer-assisted analysis of the contents of scientific literature and patents. The selected studies provide a duo of complementary perspectives: the demand of knowledge (cervical cancer and Ebola hemorrhagic fever) and the supply of knowledge (liposomes and nanoparticles to treat cancer and the paradigmatic Doxil, the first nano- drug to be approved).

RBM15 Functions in Blood Diseases

RBM15, an RNA-binding protein, plays important roles in the growth and apoptosis of cells, especially blood cells through regulating multiple signal pathways such as Notch and Wnt. An increasing body of evidence has suggested that RBM15 may play a key function on the development of various blood diseases, such as acute/chronic myeloid leukemia and kaposi′s sarcoma. In this review, we will focus on the progress of the association between RBM15 and its related blood diseases.

Cell-Free Technologies for Proteomics and Protein Engineering

Cell-free translation systems facilitate rapid production of specific proteins and are particularly suited as high-throughput methods for whole-genome protein synthesis. Moreover, these systems do not rely on living cells, thereby allowing the synthesis of unstable or cytotoxic proteins in vitro. In this review, we describe the principles and potential applications of cell-free protein translation systems and the future prospects of proteomics approaches using next-generation sequencing and cell-free expression technologies.

Recent Insights into Notch Signaling in Embryonal Rhabdomyosarcoma

The Notch signaling pathway is an evolutionarily conserved developmental network critical for embryonic and postnatal regulation of tissue growth, homeostasis, and repair. Signaling is initiated when transmembrane Notch ligands bind to transmembrane Notch receptors on nearby cells. Sequential proteolytic steps generate an activated Notch fragment that translocates to the nucleus, where it drives activation of canonical Notch target genes. In skeletal muscle, Notch signaling governs myogenic cell fate and stem cell maintenance. In the human soft tissue sarcoma rhabdomyosarcoma, which bears markers of skeletal muscle commitment and so is thought to be related to the skeletal muscle lineage, Notch signaling is also found to be upregulated and dysregulated. This review provides an overview of Notch signaling during normal embryonic and postnatal myogenesis, information on the recently discovered aberrant Notch signaling occurring in muscular dystrophies, the upregulation and mechanism of Notch signaling in the embryonal variant of rhabdomyosarcoma and related soft tissue sarcomas, and Notch cross-talk with other metazoan developmental pathways including Hippo, Hedgehog, Wnt, and TGF-β. The review concludes with updates on current promising efforts to target and inhibit Notch signaling in human sarcomas including rhabdomyosarcoma.

Physiological Proteins in Therapeutics: A Current Review on Interferons

Interferons are produced in vivo and are one of the prime components of natural defense system of animals. They are released by the viral infected cells and provide protection to the neighboring cells against viral infection. The cyto-protective property of the proteins ignited the thought of their pharmaceutical adaptation for therapeutic use against viral diseases in individuals in whom the interferons released naturally are not sufficient to combat the situation. Interferon supplements have been found to complement various antiviral drugs. Considering the efficacy of interferons in regulating angiogenesis and immunomodulation, they can be adapted for therapy of the killer diseases like cancer and AIDS. We have come ahead more than twenty five years after the approval of clinical use of interferon as drugs and are today really in a position to promise a disease free life to our present and next generation. Interferon therapy will be contributing a big share to the upcoming remedies for the new diseases and we are thus armed to fight back the deadly viral threats. Interferons have been modified [pegylated etc.] and have already been adapted to some extent in certain diseases and are in regular use in some. Thus interferons if modified as per need and used in combination with either antiviral drugs, antibiotics, antioxidants may strengthen our defense system effectively to bring about a strong protection against wide range of diseases.

Prognostic Significance of Asymptomatic Myocardial Ischemia in Women vs. Men

Background: Silent myocardial ischemia is a recognized but suboptimally studied condition in patients with and without known coronary artery disease. Limited work has focused on the association between silent myocardial ischemia and future prognosis however the majority of these analyses have focused mostly on male cohorts. As signs and symptoms of myocardial ischemia are known to be different in women, it is important to discuss and highlight any differences in association between silent myocardial ischemia and adverse cardiovascular outcomes based on gender. Methods: The aim of this review is to summarize the current literature available discussing silent myocardial ischemia and potential gender differences. We searched English language studies on PUBMED and the Cochrane Database of Systematic Reviews from the database start dates to November 2015. Conclusion: As data on the presence of silent myocardial ischemia in women is limited, whether a differential association based on gender between this condition and cardiovascular prognosis remains unknown. Future studies should target women especially those without epicardial coronary disease and suspected coronary microvascular dysfunction.

Lymphatic Delivery of Anti-HIV Drug Nanoparticles

Background: HIV infection persists for a longer time in AIDS patient compared to many other viral diseases. This is mainly because the HIV resides maximally in lymphatic system mainly the lymph nodes. Most of the present anti-HIV drugs have very poor bioavailability at lymphatic tissue. Hence, pharmaceutical scientists have made many efforts to formulate anti-HIV drugs for targeting lymphatic system. The exploration of nanoparticulate drug delivery systems have been popularly investigated for lymphatic targeting and for improving therapeutic efficacy.

Methods: An electronic search was undertaken to review the recent publications and patents from the available resources on nanoformulations of anti-HIV drugs for lymphatic delivery.

Results: Various carrier systems such as liposomes, polymeric nanoparticles, solid-lipid nanoparticles, nanostructured lipid carriers, polymeric micelles, dendrimers, and nanocrystals have been tried for lymphatic targeting. These nanoparticles are widely studied as passive targeting carriers for lymphatic systems. There is dearth of active targeting for anti-HIV drugs. The studies on surface modified nanoparticles have shown promising results for lymphatic targeting.

Conclusion: One of the reasons for low success rate in targeting the lymphatic tissue is poor-understanding of pharmacokinetic interactions of novel delivery systems in disease pathology. Apart from this, there are several hurdles in biological screening models and clinical trials. These issues should never be neglected in developing newer targeted delivery systems for treatment of AIDS.

Disease Progression in HIV Late Presenters: the Role of HIV Clinical Indicator Diseases Prior to HIV Diagnosis

Background: Late diagnosis represents a major challenge in the control of HIV epidemics. The rate of disease progression is higher among late presenters. In Europe, HIV Clinical Indicator Diseases (CIDs) have been proposed to improve early diagnosis.

Objectives: Our observational study evaluated the presence of these HIV CIDs prior to HIV diagnosis among a population of late presenters and assessed its correlation to disease progression.

Method: A retrospective cohort study was conducted in HIV late presenters diagnosed from 2007 to 2013 at University Hospital of Ferrara (Italy). Hazard Ratios (H.R.s) for disease progression (new AIDS-events and death) were estimated by Cox proportional hazard model.

Results: We analysed 77 patients and we found that those with CIDs prior to HIV diagnosis (22%) had a 2.8 fold higher rate of disease progression compared to those without HIV CIDs (H.R. 2.82; 95% CI 1.21-6.53; P 0.02). Other factors associated with disease progression were AIDS presentation, HCV coinfection and Haemoglobin levels, with H.R.s of 3.14 (95%CI 1.23-7.99), 2.95 (95% CI 1.14-7.61) and 0.74 (95% CI 0.60-0.91), respectively.

Conclusion: HIV CIDs confer a higher risk for disease progression even after adjustment for these confounding factors. Evaluation of previous HIV CIDs at HIV diagnosis could be an additional tool to identify and better manage HIV late presenters with higher risks of disease progression.

Role of Vitamin D in Vascular Complications and Vascular Access Outcome in Patients with Chronic Kidney Disease

Vitamin D has been known for a long time as a major factor involved in the calcium- phosphate balance and homeostasis, along with parathyroid hormone (PTH). While vitamin D effects on calcium and phosphate are fully known, recent studies attempted to link vitamin D status and cardiovascular diseases.

The involvement of vitamin D on vascular remodeling is mediated by several mechanisms such as activation of renin-angiotensin-aldosterone system (RAAS), cell proliferation and anti-apoptotic cell pathways. This correlation is highlighted by the fact that the activated form of vitamin D (1,25 (OH)₂ D3) can be synthesized by the same endothelial cells, due to the constitutive presence of endothelial 1α-hydroxylase. Vitamin D reduces the expression of angiotensin 2 receptor (AT2R) on the endothelial cell surface (AT2R), leading to a cascade of events that result in the synthesis of vasodilators, such as nitric oxide. The activation of vitamin D receptors (VDRs) on endothelial cells induces changes in the metabolic activity of the endothelium and is responsible for cell survival, proliferation and neoangiogenesis. Moreover, altered signaling of VDR due to gene polymorphisms has been demonstrated in patients with cardiac disorders and chronic kidney disease (CKD). Recently, vascular access outcome has been associated with vitamin D status. Future studies will help to better define the need of vitamin D supplementation for a better cardiovascular as well as vascular access outcome in patients with CKD.

Revisiting Non-Cancer Drugs for Cancer Therapy

Although tremendous effort has been made over the past century to treat cancer effectively, the pace of drug development is far behind the increasing rate of cancer incidence and mortality. There are two major hurdles in anticancer drug development: dose-limiting toxic side effects that reduce either drug effectiveness or the quality of life of patients and complicated drug development processes that are costly and time consuming. Drug repositioning has recently gained increasing attention among cancer researchers as this approach utilizes existing drugs and is significantly cost- and time-effective. Existing drugs, particularly non-cancer drugs, have favorable safety profiles in humans and serve as an ever-increasing source for new anticancer drug discovery. Here we review the recent examples of drug repositioning of existing non-cancer drugs for preclinical and clinical introductions of cancer therapy.

Prospects of Bacteriotherapy with Nanotechnology in Nanoparticledrug Conjugation Approach for Cancer Therapy

Bacteriotherapy and nanotechnology have shown remarkable potential in diagnostic and therapeutic applications for various diseases. Individual impacts of these micro-nano systems over different aspects of human health are well studied; however, an integrated system of bacteria-nanoparticle (NP) conjugation is less explored. The untamed potential of bacteria-NP conjugation could be a new tool for diagnosis and treatment of invasive diseases like malaria, tuberculosis and cancer. Mammalian cells exhibit cytosis as their defense mechanism when they encounter foreign elements such as bacteria. In these mammalian cells, during phagocytosis, bacteria are ruptured and lysed by lysozymes. A bacterium carrying the drug-tagged NP would be engulfed in the same manner and ultimately reaches the target cells. Rapid and continuous cell divisions in the cancer tissues lead to defective vessels, underdeveloped cellcell interconnects, development of hypoxic areas and heterogeneous population of tumor cells. This unorganized and poorly developed angiogenesis in tumor cells makes it difficult for conventional chemotherapeutic drugs to localize the tumors selectively. In the present scenario of diagnosis and treatment of cancer/tumor cells, it could be expected that the existing bacteriotherapy with the advanced nanotechnology would be a way further in the targeted drug delivery for cancer therapy. This review emphasizes the potential applications of bacteriotherapy with nanotechnology for the diagnosis and treatment of cancer.

Molecular Mechanisms Underlying Psychological Stress and Cancer

Psychological stress is an emotion experienced when people are under mental pressure or encounter unexpected problems. Extreme or repetitive stress increases the risk of developing human disease, including cardiovascular disease (CVD), immune diseases, mental disorders, and cancer. Several studies have shown an association between psychological stress and cancer growth and metastasis in animal models and case studies of cancer patients. Stress induces the secretion of stress-related mediators, such as catecholamine, cortisol, and oxytocin, via the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis or the sympathetic nervous system (SNS). These stress-related hormones and neurotransmitters adversely affect stress-induced tumor progression and cancer therapy. Catecholamine is the primary factor that influences tumor progression. It can regulate diverse cellular signaling pathways through adrenergic receptors (ADRs), which are expressed by several types of cancer cells. Activated ADRs enhance the proliferation and invasion abilities of cancer cells, alter cell activity in the tumor microenvironment, and regulate the interaction between cancer and its microenvironment to promote tumor progression. Additionally, other stress mediators, such as glucocorticoids and oxytocin, and their cognate receptors are involved in stress-induced cancer growth and metastasis. Here, we will review how each receptor-mediated signal cascade contributes to tumor initiation and progression and discuss how we can use these molecular mechanisms for cancer therapy.

Interleukin 10 in Antiviral Responses

The type of immune response a host can raise against an invading parasite may often be decisive between chronicity or clearance, and in the worst cases between host survival and death. Helper T cells are key to determining whether antibody-mediated, inflammatory or cytolytic responses will be predominant. Interleukin 10 (IL10) is widely recognized to be the most important cytokine for anti-inflammatory reactions and tends to be associated to chronicity in quite a few types of viral infections. On the other hand, it has also been associated to tissue preservation in chronic viral disease. This review summarizes the most recent data available in the literature on this pivotal cytokine during experimental viral infection and in the clinical setting.

Eosinophils in Cancer: Favourable or Unfavourable?

Eosinophils are granulocytic leukocytes residing in blood and tissues in the lung, breast, gastrointestinal and reproductive systems. Eosinophilia is uncommon in healthy individuals, however, it is associated with allergies, helminth infections and some inflammatory states. Eosinophilia has also been observed in cancer, including colorectal, breast, ovarian, cervical, oral squamous, Hodgkin’s lymphoma and prostate cancer. Whether an increase in eosinophils leading to a favourable or unfavourable prognosis still remains controversial and depends on many factors including the type of cancer. Eosinophil infiltration is considered unfavourable in Hodgkin’s lymphoma, conversely it has also been linked to a favourable prognosis in colorectal, breast and prostate cancers. Eosinophils secrete a variety of cytokines and factors including eosinophil cationic protein, eosinophil-derived neurotoxin, peroxidase and major basic protein which have either anti-tumor effects or stimulate tumor progression. Herein, we discuss the role of eosinophils in tumor immunity and propose mechanisms accounting for their functional differences in tumorigenesis.

Anti-HIV Factors: Targeting Each Step of HIV’s Replication Cycle

Background: Similar to other animal viruses, HIV-1 relies on the contributions of the cellular machinery to ensure efficient virus propagation. However, human cells have evolved refined mechanisms to block key steps of the virus life-cycle, thereby suppressing viral replication. These cellular proteins are generally known as restriction factors, and they provide an early antiviral defense. So far, five potent restriction factors have been shown to effectively block HIV and/or SIV replication. These are TRIM5 proteins, SAMHD-1, members of the APOBEC3 (A3) family, Mx2 and Tetherin/BST-2. Results: Here, we review the antiviral mechanisms of these and other antiviral factors, their interaction with the innate immune responses, and how their functions might be exploited to clear and prevent HIV infection. Conclusion: Since the majority of vaccine approaches against HIV have failed so far, it is imperative to start looking at alternative strategies for vaccine and therapy development. By better understanding how HIV hijacks the cellular machinery for its own benefit in completing its life-cycle, and how the virus adapts to circumvent our intrinsic immunity, we will be better equipped to design compounds that specifically interrupt virus replication and spread.

Liposome-Nanogel Structures for Future Pharmaceutical Applications: An Updated Review

Nature uses combination of lipid bilayers and cross-linked macromolecular networks to achieve workability, multifunctionality, and dynamism in living cells of different types. Despite the concept of liposome-nanogel structures (lipobeads) is known for about 30 years, lipobead-based drug delivery systems are still largely experimental. The data available on nano- and giant lipobeads are reviewed to demonstrate technological achievability of lipobeads and to support the expectations that additional expenses on their production will be reimbursed by the potential advantages of their use. Indeed, lipobeads exhibit the properties attractive for the next generation of drug delivery systems: (i) retaining all the important benefits of polymeric and liposomal drug carriers, the hydrogel core brings mechanical stability and environmental responsiveness to the formulation in one construct, (ii) lipobeaddelivered combination therapy shows no toxicity on intravenously administered mice, accumulation of drug-loaded lipobeads both in the area surrounding tumor and within the tumor itself outside the vasculature, high therapeutic activity at the targeted site, and drastically increased survival, (iii) bipartite structure of lipobeads can provide a number of novel and unique options (e.g., consecutive multistep triggering and combined drug delivery systems). In addition, some ideas on the conceptually new drug delivery systems, new mechanisms of lipobead internalization into the cell and new schemes of drug release regulated by specific signaling are discussed.

Structural Insight of NICD-MAML Interactions: Virtual Screening, Docking and Molecular Dynamics Study for Identification of Potential Inhibitor

Activation of Notch signalling pathway is triggered by binding of NICD to transcription factor CSL and transcriptional co-activator MAML, which involves in various biological functions as well as progression of diseases. Recent prediction shows suppression of cancer causing genes of this pathway through inhibition of NICD-MAML interaction. Through virtual screening against “NCI Diversity 3” of Zinc database, we identified a potential inhibitor “ZINC01690699” (1-N,4-N-bis[3-(1Hbenzimidazol- 2-yl)phenyl]benzene-1,4-dicarboxamide; 1-N,4-dicarboxamide) possessing highest binding affinity to block the two distinct Binding Sites of NICD to inhibit NICD-MAML interaction and also found the most imperative and essential Binding Site (Site I). Inhibition of this interaction caused by binding of ZINC01690699 is validated by protein-protein docking and the prolonged binding as well as stability of NICD-Inhibitor complex is supported by molecular dynamics simulation. The study not only identifies the best inhibitor but also proposes a potential drug for the treatment of cancers.

Targeting the Atypical Chemokine Receptor ACKR3/CXCR7: Phase 1 - Phage Display Peptide Identification and Characterization

One of the greatest challenges in fighting cancer is cell targeting and biomarker selection. The Atypical Chemokine Receptor ACKR3/CXCR7 is expressed on many cancer cell types, including breast cancer and glioblastoma, and binds the endogenous ligands SDF1/CXCL12 and ITAC/CXCL11. A 20 amino acid region of the ACKR3/CXCR7 N-terminus was synthesized and targeted with the NEB PhD™-7 Phage Display Peptide Library. Twenty-nine phages were isolated and heptapeptide inserts sequenced; of these, 23 sequences were unique. A 3D molecular model was created for the ACKR3/CXCR7 N-terminus by mutating the corresponding region of the crystal structure of CXCR4 with bound SDF1/CXCL12. A ClustalW alignment was performed on each peptide sequence using the entire SDF1/CXCL12 sequence as the template. The 23-peptide sequences showed similarity to three distinct regions of the SDF1/CXCL12 molecule. A 3D molecular model was made for each of the phage peptide inserts to visually identify potential areas of steric interference of peptides that simulated CXCL12 regions not in contact with the receptor’s Nterminus. An ELISA analysis of the relative binding affinity between the peptides identified 9 peptides with statistically significant results. The candidate pool of 9 peptides was further reduced to 3 peptides based on their affinity for the targeted N-terminus region peptide versus no target peptide present or a scrambled negative control peptide. The results clearly show the Phage Display protocol can be used to target a synthesized region of the ACKR3/CXCR7 N-terminus. The 3 peptides chosen, P20, P3, and P9, will be the basis for further targeting studies.

Methionine AminoPeptidase Type-2 Inhibitors Targeting Angiogenesis

Angiogenesis has been identified as a crucial process in the development and spread of cancers. There are many regulators of angiogenesis which are not yet fully understood. Methionine aminiopeptidase is a metalloenzyme with two structurally distinct forms in humans, Type-1 (MetAP-1) and Type-2 (MetAP-2). It has been shown that small molecule inhibitors of MetAP-2 suppress endothelial cell proliferation. The initial discovery by Donald Ingber of MetAP-2 inhibition as a potential target in angiogenesis began with a fortuitous observation similar to the discovery of penicillin activity by Sir Alexander Fleming. From a drug design perspective, MetAP-2 is an attractive target. Fumagillin and ovalicin, known natural products, bind with IC50 values in low nanomolar concentrations. Crystal structures of the bound complexes provide 3-dimensional coordinates for advanced computational studies. More recent discoveries have shown other biological activities for MetAP-2 inhibition, which has generated new interests in the design of novel inhibitors. Semisynthetic fumagillin derivatives such as AGM-1470 (TNP-470) have been shown to have better drug properties, but have not been very successful in clinical trials. The rationale and development of novel multicyclic analogs of fumagillin are reviewed.

Utilising Nanotechnology and Nanosystems for Treatment of Rare Diseases

Background: Rare, or ‘orphan’, diseases are defined as lifethreatening or chronic debilitating conditions affecting a small number of patients, and present a significant public health challenge in terms of the lack of scientific knowledge, clinical expertise, and available therapies for these complex pathologies. Indeed, the difficulties involved in generating new treatments for a limited patient population, and the likely financial loss in bringing such products to market, has deterred research and development by the pharmaceutical industry. To address these issues, sponsors of new therapies can apply to regulatory authorities for ‘orphan designation’, which confers incentives for development such as reduced fees for scientific advice, tax incentives, and market exclusivity for an approved product; although the qualifying criteria vary between regions.

Focus: This review provides a global overview of orphan diseases and designation, and focuses on the potential of the rapidly expanding and exciting field of pharmaceutical nanotechnology and fabricated nanosystems (nanomaterials and nanodevices), including nanomedicines and nanosimilars for the therapeutic, diagnostic, or theranostic (development of more specific, individualised therapies for various diseases, and combining diagnostic and therapeutic capabilities into a single system) applications for rare diseases.

Nanomaterials in the Pharmaceuticals: Occurrence, Behaviour and Applications

Nanoparticles are an emerging class of multi-functional materials defined by size-dependent properties. The ever-growing interest in nanotechnology research has been attributed to the significant properties and parameters of the nanoparticles that make them more versatile than their bulk counter parts that are expected to have large spectrum impact on existing technologies such as drug delivery, biomedical, therapeutics, healthcare and pharmaceutical. The main objectives of this review are to study the impact, occurrence and behaviour of nanomaterials and their applications in pharmaceuticals. Nano-approaches are being explored globally to enhance bioavailability of drugs and diagnostics. This is due to the extremely small size and large specific surface areas of the nanoparticles that may interact directly with cellular system. Biomacromolecule surface recognition by nanoparticles acts as artificial receptors, which provide a potential tool for controlling cellular and extracellular processes for numerous biological applications such as diagnostics, therapy, drug delivery and biosensing. This review article is expected to broaden our understanding towards the development of nanoparticles based diagnostics, combination therapies in treating different diseases and other pharmaceutical applications.