Choriocarcinoma

MR Imaging of Typical Ovarian Hemangioma: A Case Report

Background: Ovarian hemangioma is an extremely rare tumor with atypical clinical manifestations, often discovered incidentally during autopsy or surgery. Approximately 60 cases have been reported in the past, but no more than 10 cases have been investigated by MRI and ultrasound (US).

Case Presentation: ln this paper, we reported a 51-year-old female patient with Ovarian Hemangioma who had no symptoms of abdominal pain, abnormal vaginal bleeding or discharge, or any other discomfort. Laboratory tests revealed an elevated serum carbohydrate antigen (CA125) of 48.99U/ml (reference range: 0-35U/ml). Multiparametric 3.0T magnetic resonance imaging (MRI) showed a cystic solid mass with a clear boundary and regular shape in the left ovarian area and minimal ascites in the abdominal cavity. The histological examination of the mass confirmed an ovarian hemangioma.

Conclusion: The MRI findings of ovarian hemangiomas are highly similar to those observed in hepatic hemangiomas, emphasizing the distinctive radiological characteristics specific to this condition in the ovary. This paper presents an overview of the typical MRI findings associated with ovarian hemangioma, which holds great importance for accurate diagnosis and effective treatment.

Imaging Characteristics of Clear Cell Papillary Renal Cell Carcinoma: Identifying the Sheep in Wolf’s Clothing

Objective: This study aimed to describe the characteristics of computed tomography (CT) and magnetic resonance imaging (MRI) of clear cell papillary renal cell carcinoma (CCPRCC).

Methods: This retrospective study comprised 27 patients diagnosed with 29 tumors of CCPRCC. The study was approved by the Medical Ethics Committee and the requirement for the informed consent was waived. The inclusion criteria stipulated pathology-confirmed CCPRCCs with at least one preoperative imaging examination, including CT or MRI. Two experienced radiologists independently analyzed the imaging characteristics, including size, location, growth mode, morphology, texture, density, and enhancement pattern. Paired t-test was used to compare differences in CT Hounsfield unit values and apparent diffusion coefficient (ADC) imaging between the tumor and the renal cortex.

Results: The mean age of the 27 patients was 57.0 ± 14.2 years. Nineteen patients underwent CT, while 12 underwent MRI (There are 4 patients underwent not only CT but also MRI). Among the cases, 26 (96%) were single, and 1 (4%) was multiple, consisting of three lesions. Out of the 29 tumors, 15 (52%) were located in the left kidney and 14 (48%) in the right kidney. The mean tumor diameter was 3.3 ± 1.7 cm. Furthermore, 19 (66%), 3 (10%), and 7 (24%) tumors were solid, cystic, mixed solid, and cystic type, respectively. The growth mode was endogenous and exogenous in 8 (28%) and 21 (72%) tumors, respectively. The tumor shape was irregular and round in 5 (17%) and 24 (83%) tumors, respectively. The CT value of the tumor was approximately 33.2 ± 9.8 HU, which was not significantly different from that of the renal cortex(31.1 ± 6.3HU)(p = 0.343). Furthermore, 7 (24%), 12 (41%), and 3 (10%) had calcification, cystic degeneration, and hemorrhage, respectively. In 12 tumors, hypointense and hyperintense were predominant on T1 and T2-weighted images, respectively. The tumor capsule was found at the edge of 12 tumors. The average ADC value of the tumor (1.54 ± 0.74 × 10⁻³ mm²/s) and that of the renal cortex(1.68 ± 0.63×10–3mm2 /s) was not statistically significantly different (p = 0.260). The enhancement scanning revealed “wash-in and wash-out” enhancement in 19 (68%) tumors, continuous or progressive enhancement in 6 (21%) tumors, and enhanced cystic wall and central separation in 3 (11%) tumors.

Conclusion: CCPRCC occurs more likely in middle-aged and elderly individuals, and the tumor is prone to cystic degeneration, with rare bleeding and calcification, and no obvious limitation on MRI diffusion-weighted imaging, which enhancement form performs as mainly “wash-in and washout,” but the final diagnosis depends on histopathology.

Comparative Investigation of Color Doppler Ultrasonography Parameters of the Uterine Artery in Patients with Post-molar GTN and Patients Recovered from Molar Pregnancy and its Role in Predicting the Probability of Occurrence

Objectives: Hydatiform mole can progress to gestational trophoblastic neoplasia (GTN), and we are looking for non-invasive methods to predict it. Old age, higher serum BHCG levels, and expression of genes, such as VEGF-EG, HIF-1α, and TGF-ß are known as predictive factors. We performed this study to evaluate the role of bilateral uterine artery doppler ultrasound in predicting postmolar- GTN.

Methods: In this prospective cohort study, 42 patients with complete molar pregnancy were examined. Inclusion criteria confirmed molar pregnancy by histopathological examination. Exclusion criteria were patients more than 40 years old, patients with completed family childbearing planning, and diagnosis of GTN during the routine histopathological study. Before molar evacuation and four weeks later, bilateral uterine artery doppler sonography to determine the PI, RI, and PSV was performed. Serum BHCG levels were also measured before molar evacuation and weekly after evacuation until it exhibited spontaneous remission or developed GTN.

Results: About 36 patients were cured, and six others developed post-molar GTN. The bilateral uterine artery doppler sonography between the two groups showed a lower UA RI in the post-molar-GTN group before evacuation (P=0.048). Data demonstrated significant increases in Right.UA.RI (P=0/008), Left.UA.PI (P=0/037), and Right.UA.PSV (P=0/024) in the spontaneous remission group during 28 days follow-up period. There were no significant differences in these parameters in the GTN group throughout the time of follow-up.

Conclusion: It seems that Doppler ultrasound plays a role in predicting GTN following uterine evacuation. A lower resistance in the uterine artery before evacuation and the remaining uterine artery blood flow constant after evacuation is associated with the development of post-molar- GTN.

Carbon Nanotubes for Targeted Therapy: Safety, Efficacy, Feasibility and Regulatory Aspects

It is crucial that novel and efficient drug delivery techniques be created in order to improve the pharmacological profiles of a wide variety of classes of medicinal compounds. Carbon nanotubes (CNTs) have recently come to the forefront as an innovative and very effective technique for transporting and translocating medicinal compounds. CNTs were suggested and aggressively researched as multifunctional novel transporters designed for targeted pharmaceutical distribution and used in diagnosis. CNTs can act as vectors for direct administration of pharmaceuticals, particularly chemotherapeutic medications. Multi-walled CNTs make up the great majority of CNT transporters, and these CNTs were used in techniques to target cancerous cells. It is possible to employ Carbon nanotubes (CNTs) to transport bioactive peptides, proteins, nucleic acids, and medicines by functionalizing them with these substances. Due to their low toxicity and absence of immunogenicity, carbon nanotubes are not immunogenic. Ammonium-functionalized carbon nanotubes are also attractive vectors for gene-encoding nucleic acids. CNTs that have been coupled with antigenic peptides have the potential to be developed into a novel and efficient approach for the use of synthetic vaccines. CNTs bring up an enormous number of new avenues for future medicine development depending on targets within cells, which have until now been difficult to access. This review focuses on the numerous applications of various CNT types used as medicine transport systems and on the utilization of CNTs for therapeutical purposes.

A Comprehensive Review on Targeted Cancer Therapy: New Face of Treatment Approach

Cancer is one of life's most difficult difficulties and a severe health risk everywhere. Except for haematological malignancies, it is characterized by unchecked cell growth and a lack of cell death, which results in an aberrant tissue mass or tumour. Vascularization promotes tumor growth, which eventually aids metastasis and migration to other parts of the body, ultimately resulting in death. The genetic material of the cells is harmed or mutated by environmental or inherited influences, which results in cancer. Presently, anti-neoplastic medications (chemotherapy, hormone, and biological therapies) are the treatment of choice for metastatic cancers, whilst surgery and radiotherapy are the mainstays for local and non-metastatic tumors. Regrettably, chemotherapy disturbs healthy cells with rapid proliferation, such as those in the gastrointestinal tract and hair follicles, leading to the typical side effects of chemotherapy. Finding new, efficient, targeted therapies based on modifications in the molecular biology of tumor cells is essential because current chemotherapeutic medications are harmful and can cause the development of multidrug resistance. These new targeted therapies, which are gaining popularity as demonstrated by the FDA-approved targeted cancer drugs in recent years, enter molecules directly into tumor cells, diminishing the adverse reactions. A form of cancer treatment known as targeted therapy goes after the proteins that regulate how cancer cells proliferate, divide, and disseminate. Most patients with specific cancers, such as chronic myelogenous leukemia (commonly known as CML), will have a target for a particular medicine, allowing them to be treated with that drug. Nonetheless, the tumor must typically be examined to determine whether it includes drug targets.

The (Pro)renin Receptor - A Regulatory Nodal Point in Disease Networks

Experimental inhibition of the (pro)renin receptor [(P)RR] is a promising therapeutic strategy in different disease models ranging from cardiorenal to oncological entities. Here, we briefly review the direct protein-protein interaction partners of the (P)RR and the plethora of distinct diseases in which the (P)RR is involved.

The first structural work on the (P)RR using AlphaFold, which was recently published by Ebihara et al., is the center of this mini-review since it can mechanistically link the protein-protein interaction level with the pathophysiological level.

More detailed insights into the 3D structure of the (P)RR and its interaction domains might guide drug discovery on this novel target. Finally, antibody- and small molecule-based approaches to inhibit the (P)RR are shortly discussed.

Εmerging Biomarkers in the Diagnosis and Treatment of Testicular Tumors

Testicular germ cell tumors (TGCT) are the leading cause of cancer-related death in young males between the ages of 20-40. Surgical resection and cisplatin-based chemotherapy can achieve a cure for the majority of patients with TGCTs, with survival rates of up to 97% for patients diagnosed at an early stage. The use of serum biomarkers, such as AFP β-HCG, and LDH, plays a significant role in both diagnosis and evaluation of response to treatment, and despite their low sensitivity and specificity levels, they are an integral part of the current tumor staging system and daily practice. Molecular biomarkers, including micro-RNAs and gene-expression profiles, are currently being developed in TGCTs and could potentially hold a prominent place in the future diagnosis, treatment selection, surveillance, and prognostication of these tumors. This review discusses how current advances in our understanding of the underlying biology of TGCTs have helped biomarker discovery, with a focus on the recognition of key molecular alterations that could serve as potential indicators of disease onset, response to systemic or/and surgical therapies, and overall clinical course.

Diagnostic and Management Challenges of Rapid Lung Metastasis of Gestational Trophoblastic Neoplasia after a Non-molar Pregnancy: A Case Report

:Background: Pulmonary metastasis of pregnancy-related rare gestational trophoblastic disease is common, and a patient’s rapid clinical deterioration leads to a poor prognosis.

Case Presentation: We report a case of a non-pregnant woman with severe respiratory symptoms masquerading as pulmonary infection who was diagnosed with pulmonary metastasis of the gestational trophoblastic disease.

Conclusion: The timely diagnosis of pulmonary metastasis was the key aspect in the management of our case, and she survived and was discharged to home after a long hospitalization course.

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.

Involvement of Metabolites and Non-coding RNAs in Diseases

Non-coding RNAs have a role in gene regulation and cellular metabolism control. Metabolism produces metabolites which are small molecules formed during the metabolic process. So far, a direct relationship between metabolites and genes is not fully established; however, pseudogenes and their progenitor genes regulate health and disease states. Other non-coding RNAs also contribute to this regulation at different cellular processes. Accumulation and depletion of metabolites accompany the dynamic equilibrium of health and disease state. In this study, metabolites, their roles in the cell, and the link between metabolites and non-coding RNAs are discussed.

Long Noncoding RNAs in Human Cancer and Apoptosis

Genome annotations have uncovered the production of at least one transcript from nearly all loci in the genome at some given time throughout the development. Surprisingly, many of these transcripts do not code for proteins and are relatively long in size, thus called long noncoding RNAs (lncRNAs). Next- and third-generation sequencing technologies have amassed numerous lncRNAs expressed under different phenotypic conditions, yet many remain to be functionally characterized. LncRNAs regulate gene expression by functioning as scaffold, decoy, signaling, and guide molecules both at the transcriptional and post-transcriptional levels, interacting with different types of macromolecules, such as proteins, DNA, and RNA. Here, we review the potential regulatory role of lncRNAs in apoptosis and cancer as some of these lncRNAs may have the diagnostic and therapeutic potential in cancer.

Plant Secondary Metabolites as Apoptosis-inducing Agents

Apoptosis or programmed cell death is a carefully synchronized collapse of cells due to protein degradation and fragmentation of DNA. It is an essential part of the life cycle of every multicellular organism, including worms to humans. Apoptosis plays a major role in cancer development as well. Various studies confirm the potential of many drugs to change the regulation and ratio of pro-apoptotic and antiapoptotic factors. Plants are the best-known source of drugs for various diseases, including cancer. Plant secondary metabolites (alkaloids, terpenes and phenolics) are the major constituents used as drugs. Several studies confirm that these secondary metabolites can induce apoptosis by triggering pro-apoptotic and antiapoptotic factors. This article has studied some of the important secondary metabolites and their mode of action as apoptotic triggering agents.

Severe Lower Gastrointestinal Bleeding Due to Choriocarcinoma with AVM to the Ileum: A Case Report

Background: Choriocarcinoma and other placental tumors are rare, and metastasis to the gastrointestinal, especially the small bowel, is extremely rare. Furthermore, about 5% of all metastasis belongs to the GI tract.

Case Presentation: We reported an 18 -year-old patient with severe GI bleeding. Serum BHCG level was 57322 mIU/mL. CT angiography and Pelvic MRI suggested a metastatic arteriovenous malformation to the small bowel. In surgery, we detected the AVM from the right side of the uterus to the ileum, and pathological findings confirmed the choriocarcinoma with metastatic AVM to the ileum.

Conclusion: Chemotherapy started after surgery, and the patient was asymptomatic on follow-up after 14 months. The results showed that GTN was a differential diagnosis when patients are referred with these signs and symptoms.

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.

Beneficial Outcomes of Cancer Therapeutic Modalities Based on Targeting Apoptosis

Background: In the clinical setting, anticancer therapy is routinely administered to stimulate programmed cell death or “apoptosis.” The goal is to eliminate tumor cells. Whether selective activation of apoptosis facilitates aggressive disease relapse in the longer term is still unaddressed. Apoptosis defects have a crucial role in cancer progression and carcinogenesis. Thus, targeting apoptosis may be important in developing new cancer therapeutic modalities.

Methods: We summarize the shift in thinking that, while apoptosis is a barrier to oncogenesis, it paradoxically drives cancer formation and progression when executed incompletely, i.e., sublethal apoptosis. Also, we review apoptotic mechanisms, the role of apoptosis in carcinogenesis, and how it contributes to cancer treatment.

Result and Conclusion: Most current research focuses on the extent of cell death in vitro, but no evidence exists that protein regulation of cell death in vitro is similar to what happens in vivo. Future research requires identifying targets upstream and downstream of such proteins through identifying protein-protein interactions in different survival/apoptosis pathways. Finding nexuses where such pathways interconnect is critical, along with possible mechanisms for regulation.

Genitourinary Tract Tumors in Children: An Update

Background: Genitourinary tract tumors in children are less common than in adults. Most of these tumors have different genetic backgrounds, clinical presentation, and oncologic behavior than their adult counterpart. As a result of low prevalence in children, some of the treatment approaches and recommendations are based on treatment experience in adult patients. However, thanks to scientific and technological development, survival rates have risen considerably.

Objective: This paper presents a review of the principal features of the tumors involving the genitourinary tract in children and an update in genetic background, diagnosis, and treatment.

Methods: A narrative review was performed on published literature about genitourinary tract tumors in pediatric patients. Papers presented in English and Spanish literature were reviewed. PubMed, Science Direct, and SciELO databases were used to collect information and present this article.

Results: Kidney tumors are the most common type of genitourinary tumors in children. Among those, Wilms tumor represents the majority of cases and shows the successful work of clinical trial groups studying this tumor type. Other tumors involving the genitourinary tract in children include Rhabdomyosarcoma, Transitional cell carcinoma, Testicular, and Adrenal tumors.

Conclusion: Genitourinary tract tumors in children represent significant morbidity and economic burden, so awareness in early diagnosis represents improvement in treatment, clinical, and oncological outcomes.

Promising Protective Effects of Chrysin in Cardiometabolic Diseases

Cardiometabolic diseases (CMD) have caused a great burden in terms of morbidity and mortality worldwide. The vicious cycle of CMD consists of type II diabetes, hypertension, dyslipidemia, obesity, and atherosclerosis. They have interlinked pathways, interacting and interconnecting with each other. The natural flavonoid chrysin has been shown to possess a broad spectrum of therapeutic activities for human health. Herein, we did an in-depth investigation of the novel mechanisms of chrysin’s cardioprotection against cardiometabolic disorders. Studies have shown that chrysin protects the cardiovascular system by enhancing the intrinsic antioxidative defense system. This antioxidant property enhanced by chrysin protects against several risk factors of cardiometabolic disorders, including atherosclerosis, vascular inflammation and dysfunction, platelet aggregation, hypertension, dyslipidemia, cardiotoxicity, myocardial infarction, injury, and remodeling, diabetes-induced injuries, and obesity. Chrysin also exhibited anti-inflammatory mechanisms through inhibiting pro-inflammatory pathways, including NF-κB, MAPK, and PI3k/Akt. Furthermore, chrysin modulated NO, RAS, AGE/RAGE, and PPARs pathways which contributed to the risk factors of cardiometabolic disorders. Taken together, the mechanisms in which chrysin protects against cardiometabolic disorder are more than merely antioxidation and anti-inflammation in the cardiovascular system.

Treatment for Diabetic Peripheral Neuropathy: What have we Learned from Animal Models?

Introduction: Animal models have been widely used to investigate the etiology and potential treatments for diabetic peripheral neuropathy. What we have learned from these studies and the extent to which this information has been adapted for the human condition will be the subject of this review article.

Methods: A comprehensive search of the PubMed database was performed, and relevant articles on the topic were included in this review.

Results: Extensive study of diabetic animal models has shown that the etiology of diabetic peripheral neuropathy is complex, with multiple mechanisms affecting neurons, Schwann cells, and the microvasculature, which contribute to the phenotypic nature of this most common complication of diabetes. Moreover, animal studies have demonstrated that the mechanisms related to peripheral neuropathy occurring in type 1 and type 2 diabetes are likely different, with hyperglycemia being the primary factor for neuropathology in type 1 diabetes, which contributes to a lesser extent in type 2 diabetes, whereas insulin resistance, hyperlipidemia, and other factors may have a greater role. Two of the earliest mechanisms described from animal studies as a cause for diabetic peripheral neuropathy were the activation of the aldose reductase pathway and increased non-enzymatic glycation. However, continuing research has identified numerous other potential factors that may contribute to diabetic peripheral neuropathy, including oxidative and inflammatory stress, dysregulation of protein kinase C and hexosamine pathways, and decreased neurotrophic support. In addition, recent studies have demonstrated that peripheral neuropathy-like symptoms are present in animal models, representing pre-diabetes in the absence of hyperglycemia.

Conclusion: This complexity complicates the successful treatment of diabetic peripheral neuropathy, and results in the poor outcome of translating successful treatments from animal studies to human clinical trials.

Recent Developments of Flavonoids with Various Activities

Flavonoids, a series of compounds with a C6-C3-C6 structure, mostly originate from plant metabolism. Flavonoids have shown beneficial effects on many aspects of human physiology and health. Recently, many flavonoids with various activities have been discovered, which has led to more and more studies focusing on their physiological and pharmacodynamic activities. The anticancer and anti-viral activities especially have gained the attention of many researchers. Therefore, the discovery and development of flavonoids as anti-disease drugs has great potential and may make a significant contribution to fighting diseases. This review focus on the discovery and development of flavonoids in medicinal chemistry in recent years.

SET Protein in Cancer: A Potential Therapeutic Target

SET protein is a multi-functional oncoprotein that is ubiquitously expressed in most tumor cells. Dysregulation of SET has been associated with many types of cancer. Due to ever-accumulating evidence of its strong correlation with both poor prognosis and drug resistance, the targeting of SET is starting to be explored. SET is currently regarded as a potential target for cancer therapy, and several inhibitors are being developed for clinical trials. In this review, the physiological and pathological functions of SET, as well as its antagonists, will be discussed along with the prospects and challenges involved with translating SET inhibitors into bona fide therapeutic options.

Drug Targeting Approaches and Use of Drug Delivery Systems in Management of Cancer

Mutations and their manifestations in the form of various diseases and disorders result in cancer which is a major cause of human death worldwide. A considerable amount of information is available at the cellular, molecular and genetic levels regarding the occurrence and spread of precarious cancer; yet, there is no cure. The traditional methods of treatment such as chemotherapy, radiotherapy and surgical intervention have shown to be moderately effective and to keep some types of cancer under control, but each modality has its own advantages and disadvantages. In recent years, more advanced methods such as targeted therapies, immunotherapy, and precision medicine are shown to be promising, and these fields continue to expand rapidly along with the conventional methods. This review focuses on the reports of advanced methods of treatment from a scientific standpoint to recognize many new and modern approaches. Selective targeting of the tumour cells by nanoparticle-based novel drug delivery approaches includes the latest innovations in their preparation strategies and applications. The concept of precision medicine and its impact on treatment are highlighted here with the hope of individualised therapy with minimum side effects as a part of ever-expanding treatment strategies. Additional challenges related to cancer treatment like multi-drug resistance and toxicity are also deliberated in brief. Based on the available reports and scientific evidence, better targeted approaches with better quality clinical outcomes and more precise drug delivery to fit individual treatment needs are anticipated in the near future to control this deadly disease.

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.

Impact of Curcumin on Microsomal Enzyme Activities: Drug Interaction and Chemopreventive Studies

Curcumin, a yellow pigment in Asian spice, is a natural polyphenol component of Curcuma longa rhizome. Curcuminoid components include curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC). Previous studies established curcumin as a safe agent based on preclinical and clinical evaluations and curcuminoids have been approved by the US Food and Drug Administration (FDA) as “Generally Recognized as Safe” (GRAS). The present review collects and summarizes clinical and preclinical studies of curcumin interactions, with an emphasis on the effect of curcumin and curcumin analogs on the mRNA and protein levels of microsomal CYP450 enzymes (phase I metabolism) and their interactions with toxicants, drugs and drug probes. The literature search was conducted using keywords in various scientific databases, including Web of Science, Scopus, PubMed, and Google Scholar. Studies concerning the impact of curcumin and curcumin analogs on microsomal enzyme activity are reviewed and include oral, topical, and systemic treatment in humans and experimental animals, as well as studies from in vitro research. When taken together, the data identified some inconsistent results between various studies. The findings showed significant inhibition of CYP450 enzymes by curcumin and its analogs. However, such effects are often differed when curcumin and curcumin analogs were coadministered with toxicant and other drugs and drug probes. We conclude from this review that herb-drug interactions should be considered when curcumin and curcumin analogs are consumed.

Recent Advances in the Development of Casein Kinase 1 Inhibitors

Background: The casein kinase 1 (CK1) family is involved in regulating many cellular processes, including membrane trafficking, DNA damage repair, cytoskeleton dynamics, cytoskeleton maintenance and apoptosis. CK1 isoforms, especially CK1δ and CK1ε have emerged as important therapeutic targets for severe disorders such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), familial advanced sleep phase syndrome and cancer. Due to the importance of CK1 for the pathogenesis of disorders, there are great interests in the development of CK1 inhibitors.

Methods: Using SciFinder® as a tool, the publications about the biology of CK1 and the recent developments of CK1 inhibitors were surveyed with an exclusion of those published as patents.

Results: This review presents the current state of knowledge on the development of CK1 inhibitors, including both synthetic small molecular inhibitors that were divided into 7 categories according to structural features, and the natural compounds. An overview of the advancement of CK1 inhibitors was given, with the introduction of various existing CK1 inhibitors, their inhibitory activities, and the structure-activity relationships.

Conclusion: Through physicochemical characterization and biological investigations, it is possible to understand the structure-activity relationship of CK1 inhibitors, which will contribute to better design and discovery of potent and selective CK1 inhibitors as potential agents for severe disorders such as AD, ALS and cancer.

Effects of Maternal Obesity and Gestational Diabetes Mellitus on the Placenta: Current Knowledge and Targets for Therapeutic Interventions

Obesity and gestational diabetes mellitus (GDM) are becoming more common among pregnant women worldwide and are individually associated with a number of placenta-mediated obstetric complications, including preeclampsia, macrosomia, intrauterine growth restriction and stillbirth. The placenta serves several functions throughout pregnancy and is the main exchange site for the transfer of nutrients and gas from mother to fetus. In pregnancies complicated by maternal obesity or GDM, the placenta is exposed to environmental changes, such as increased inflammation and oxidative stress, dyslipidemia, and altered hormone levels. These changes can affect placental development and function and lead to abnormal fetal growth and development as well as metabolic and cardiovascular abnormalities in the offspring. This review aims to summarize current knowledge on the effects of obesity and GDM on placental development and function. Understanding these processes is key in developing therapeutic interventions with the goal of mitigating these effects and preventing future cardiovascular and metabolic pathology in subsequent generations.

Stromal Cell-Derived Factor (SDF) 2 and the Endoplasmic Reticulum Stress Response of Trophoblast Cells in Gestational Diabetes Mellitus and In vitro Hyperglycaemic Condition

Background and Aim: The endoplasmic reticulum (ER) stress response and the unfolded protein response (UPR) are essential cellular mechanisms to ensure the proper functioning of ER in adverse conditions. However, activation of these pathways has also been associated with insulin resistance and cell death in pathological conditions such as diabetes mellitus. In the present study, we investigated whether stromal cell-derived factor 2 (SDF2)—an ER stress-responsive factor—is related to ER response in placental cells exposed to maternal gestational diabetes mellitus (GDM) or to a hyperglycaemic in vitro condition.

Objective: The study aimed to investigate the role of SDF2 in BeWo cells , a trophoblast cell line originating from choriocarcinoma , and in placental tissue under hyperglycaemic conditions.

Methods: Protein levels of SDF2 and UPR factors, glucose-related protein 78 (GRP78) and eukaryotic initiation factor 2 alpha (elF2 alpha) were evaluated in the placentae of pregnant women diagnosed with GDM and treated by diet-control (insulin was added when necessary). The mRNA expression of SDF2 and UPR factors CHOP and sXBP1 were assessed in cultured BeWo cells challenged with glucose and treated with or without insulin.

Results: SDF2 expression was increased in the placentae of GDM women treated with diet. However, its values were similar to those of normoglycemic controls when the GDM women were treated with insulin and diet. BeWo cells cultured with high glucose and insulin showed decreased SDF2 expression, while high glucose increased CHOP and sXBP1 expression, which was then significantly reverted with insulin treatment.

Conclusion: Our findings extend the understanding of ER stress and SDF2 expression in placentae exposed to hyperglycaemia, highlighting the relevance of insulin in reducing the levels of ER stress factors in placental cells. Understanding the effect of ER stress partners such as SDF2 on signalling pathways involved in gestation, complicated by hyperglycaemia, is pivotal for basic biomedical research and may lead to new therapeutic possibilities.

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.

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.

The CXCL12-CXCR4 Signaling Axis Plays a Key Role in Cancer Metastasis and is a Potential Target for Developing Novel Therapeutics against Metastatic Cancer

Metastasis is the main cause of death in cancer patients; there is currently no effective treatment for cancer metastasis. This is primarily due to our insufficient understanding of the metastatic mechanisms in cancer. An increasing number of studies have shown that the C-X-C motif chemokine Ligand 12 (CXCL12) is overexpressed in various tissues and organs. It is a key niche factor that nurtures the pre-metastatic niches (tumorigenic soil) and recruits tumor cells (oncogenic “seeds”) to these niches, thereby fostering cancer cell aggression and metastatic capabilities. However, the C-X-C motif chemokine Receptor 4 (CXCR4) is aberrantly overexpressed in various cancer stem/progenitor cells and functions as a CXCL12 receptor. CXCL12 activates CXCR4 as well as multiple downstream multiple tumorigenic signaling pathways, promoting the expression of various oncogenes. Activation of the CXCL12-CXCR4 signaling axis promotes Epithelial-Mesenchymal Transition (EMT) and mobilization of cancer stem/progenitor cells to pre-metastatic niches. It also nurtures cancer cells with high motility, invasion, and dissemination phenotypes, thereby escalating multiple proximal or distal cancer metastasis; this results in poor patient prognosis. Based on this evidence, recent studies have explored either CXCL12- or CXCR4-targeted anti-cancer therapeutics and have achieved promising results in the preclinical trials. Further exploration of this new strategy and its potent therapeutics effect against metastatic cancer through the targeting of the CXCL12- CXCR4 signaling axis may lead to a novel therapy that can clean up the tumor microenvironment (“soil”) and kill the cancer cells, particularly the cancer stem/progenitor cells (“seeds”), in cancer patients. Ultimately, this approach has the potential to effectively treat metastatic cancer.

Metastatic Brain Tumors: To Treat or Not to Treat, and with What?

A long time ago, metastatic brain tumors were often not treated and patients were only given palliative care. In the past decade, researchers selected those with single or 1-3 metastases for more aggressive treatments like surgical resection, and/or stereotactic radiosurgery (SRS), since the addition of whole brain radiotherapy (WBRT) did not increase overall survival for the vast majority of patients. Different studies demonstrated significantly less cognitive deterioration in 0-52% patients after SRS versus 85-94% after WBRT at 6 months. WBRT is the treatment of choice for leptomeningeal metastases. WBRT can lower the risk for further brain metastases, particularly in tumors of fast brain metastasis velocity, i.e. quickly relapsing, often seen in melanoma or small cell lung carcinoma. Important relevant literature is quoted to clarify the clinical controversies at point of care in this review. Synchronous primary lung cancer and brain metastasis represent a special situation whereby the oncologist should exercise discretion for curative treatments, with reported 5-year survival rates of 7.6%-34.6%. Recent research suggests that those patients with Karnofsky performance status less than 70, not capable of caring for themselves, are less likely to derive benefit from aggressive treatments. Among patients with brain metastases from non-small cell lung cancer (NSCLC), the QUARTZ trial (Quality of Life after Radiotherapy for Brain Metastases) helps the oncologist to decide when not to treat, depending on the performance status and other factors.

Flavonoid-Based Cancer Therapy: An Updated Review

As cancers are one of the most important causes of human morbidity and mortality worldwide, researchers try to discover novel compounds and therapeutic approaches to decrease survival of cancer cells, angiogenesis, proliferation and metastasis. In the last decade, use of special phytochemical compounds and flavonoids was reported to be an interesting and hopeful tactic in the field of cancer therapy. Flavonoids are natural polyphenols found in plant, fruits, vegetables, teas and medicinal herbs. Based on reports, over 10,000 flavonoids have been detected and categorized into several subclasses, including flavonols, anthocyanins, flavanones, flavones, isoflavones and chalcones. It seems that the anticancer effect of flavonoids is mainly due to their antioxidant and anti inflammatory activities and their potential to modulate molecular targets and signaling pathways involved in cell survival, proliferation, differentiation, migration, angiogenesis and hormone activities. The main aim of this review is to evaluate the relationship between flavonoids consumption and cancer risk, and discuss the anti-cancer effects of these natural compounds in human cancer cells. Hence, we tried to collect and revise important recent in vivo and in vitro researches about the most effective flavonoids and their main mechanisms of action in various types of cancer cells.

Development of A Novel System Based on Green Magnetic / Graphene Oxide / Chitosan /Allium Sativum / Quercus / Nanocomposite for Targeted Release of Doxorubicin Anti-Cancer Drug

Background: Doxorubicin, as a strong anti-cancer agent for clinical treatment of various cancer types along with other drugs, is widely utilized. Due to the physiology of the human body and cancerous tissues, the applicability of doxorubicin is still limited and the targeted treatment of the different types of cancers is considered. Also, the side effects of the conventional forms of chemotherapy medicines, damaging and stressing the normal cells are considerable.

Objective: This study introduces a novel and effective system for the targeted release of doxorubicin by successfully fabricating the green magnetic graphene oxide, chitosan, allium sativum, and quercus nanocomposite.

Methods: The in vitro release of doxorubicin loaded on the nanocomposite was evaluated and investigated at pH 7.4 and 6.5, respectively. The drug diffusivity in the plasma environment was assessed for a more accurate analysis of the drug diffusion process. The nanocomposite loaded drug release mechanism and kinetics, as well as cytotoxicity assay was investigated.

Results: The efficiency of the drug encapsulation was significantly enhanced using natural extract ingredients and consequently, the efficacy of the targeted treatment of cancerous tissues was improved. The developed nanocomposite provided a controlled release of doxorubicin in similar acidic conditions of the normal and cancerous cells and affirming that the fabricated system is thoroughly pH-dependent.

Conclusion: The cytotoxicity assay confirmed that the fabricated nanocomposite at a high growth rate of cancerous cells has an anticancer property and acts as a toxic agent against tumor cells, suggesting that in conjunction with doxorubicin, it can be highly improved for killing cancerous cells.

Malignant Mesothelioma of the Tunica Vaginalis Testis: A Rare Malignant Tumor without Asbestos Exposure

Malignant mesothelioma of the tunica vaginalis testis is an extremely rare and often a deadly tumor. Preoperative diagnosis is very difficult due to the lack of specific clinical manifestations, mainly including hydrocele formation and painless inguinal mass. In this abstract, we presented a case of a young patient with hydrocele and dull pain of left testes, who was planned for laparoscopic repair of left inguinal hernia, during which a mass attached to the scrotal cord was discovered. Dissection and release of the mass from the cord structure were performed, and postoperative pathological examination revealed malignant mesothelioma arising from the left tunica vaginalis testis. The case was then referred to an oncology center where intraperitoneal hyperthermic chemotherapy with cytoreductive surgery was performed.

Cubilin, the Intrinsic Factor-Vitamin B12 Receptor in Development and Disease

Gp280/Intrinsic factor-vitamin B12 receptor/Cubilin (CUBN) is a large endocytic receptor serving multiple functions in vitamin B12 homeostasis, renal reabsorption of protein or toxic substances including albumin, vitamin D-binding protein or cadmium. Cubilin is a peripheral membrane protein consisting of 8 Epidermal Growth Factor (EGF)-like repeats and 27 CUB (defined as Complement C1r/C1s, Uegf, BMP1) domains. This structurally unique protein interacts with at least two molecular partners, Amnionless (AMN) and Lrp2/Megalin. AMN is involved in appropriate plasma membrane transport of Cubilin whereas Lrp2 is essential for efficient internalization of Cubilin and its ligands. Observations gleaned from animal models with Cubn deficiency or human diseases demonstrate the importance of this protein. In this review addressed to basic research and medical scientists, we summarize currently available data on Cubilin and its implication in renal and intestinal biology. We also discuss the role of Cubilin as a modulator of Fgf8 signaling during embryonic development and propose that the Cubilin-Fgf8 interaction may be relevant in human pathology, including in cancer progression, heart or neural tube defects. We finally provide experimental elements suggesting that some aspects of Cubilin physiology might be relevant in drug design.

Therapeutic Potential of Medicinal Plant Proteins: Present Status and Future Perspectives

Biologically active molecules obtained from plant sources, mostly including secondary metabolites, have been considered to be of immense value with respect to the treatment of various human diseases. However, some inevitable limitations associated with these secondary metabolites like high cytotoxicity, low bioavailability, poor absorption, low abundance, improper metabolism, etc., have forced the scientific community to explore medicinal plants for alternate biologically active molecules. In this context, therapeutically active proteins/peptides from medicinal plants have been promoted as a promising therapeutic intervention for various human diseases. A large number of proteins isolated from the medicinal plants have been shown to exhibit anti-microbial, anti-oxidant, anti-HIV, anticancerous, ribosome-inactivating and neuro-modulatory activities. Moreover, with advanced technological developments in the medicinal plant research, medicinal plant proteins such as Bowman-Birk protease inhibitor and Mistletoe Lectin-I are presently under clinical trials against prostate cancer, oral carcinomas and malignant melanoma. Despite these developments and proteins being potential drug candidates, to date, not a single systematic review article has documented the therapeutical potential of the available biologically active medicinal plant proteome. The present article was therefore designed to describe the current status of the therapeutically active medicinal plant proteins/peptides vis-à-vis their potential as future protein-based drugs for various human diseases. Future insights in this direction have also been highlighted.

miR-146a-5p Regulated Cell Proliferation and Apoptosis by Targeting SMAD3 and SMAD4

Background: microRNAs (miRNAs) are a small, endogenous non-coding RNAs that are involved in post-transcriptional gene regulation of many biological processes, including embryo implantation and placental development. In our previous study, miR-146a-5p was found expressed higher in the serum exosomes of pregnant sows than non-pregnant. The research on miR-146a-5p has been mainly related to human diseases, but there are few studies on its effects on the reproduction of sows in early pregnancy.

Objective: In this article, our motivation is to study the role of miR-146a-5p in the early pregnancy of sows on the cell proliferetion and apoptosis by targeting SMAD3 and SMAD4.

Methods: Bioinformatics software was used to identify the target genes of miR-146a-5p. The wildtype and mutant-type recombinant plasmids of dual-luciferase reporter with 3'-UTR of Smad3 or 3'- UTR of Smad4 were constructed, and co-transfected in porcine kidney cell (PK-15 cell) with miR- 146a-5p mimic, mimic-NC(M-NC), inhibitor and inhibitor-NC(IN-NC), then dual-luciferase activity analysis, qRT-PCR and Western blot were performed to verify the target genes. After the transfection of BeWo choriocarcinoma cell (BeWo cell) with miR-146a-5p mimic, M-NC, inhibitor and IN-NC, the mRNA expression of Caspase-3, BAX and Bcl-2 was measured using qRT-PCR, and the cell proliferation was measured using CCK-8 kit.

Results: The luciferase, mRNA and protein expression of Smad3 in PK-15 cells treated by Smad3- 3'-UTR-W co-transfected with miR-146a-5p mimic were significantly lower than that with miR- 146a-5p M-NC, and the results of Smad4 were similar to Smad3, but the protein expression had a trend to lower in mimic group. The expression level of Bcl-2 in the miR-146a-5p mimic group was significantly lower than that in the miR-146a-5p M-NC group, but the expression pattern of Caspase-3 was just opposite. The mimic of miR-146a-5p reduced the proliferation of BeWo cells, however the inhibitor increased.

Conclusion: Smad3 and Smad4 are the direct target genes of miR-146a-5p. The expression of Smad3 and Smad4 were affected by the mimic and inhibitor of miR-146a-5p. miR-146a-5p affects cell apoptosis and proliferation by regulating their target genes. This study provided new data to understand the regulation mechanism of early pregnancy in sows.

Kinetic Evaluation of Anti-tumor Chlorambucil Release from O-stearoyl Mannose PLGA Nanoparticles

Purpose: This study assesses the kinetics of the anti-tumor drug chlorambucil (CLB) incorporated into PLGA nanoparticles (NP-CLB) with and without the presence of the O-stearoyl mannose (OEM) functionalizing agent (NP-CLBMAN).

Methods: OEM was synthesized and used in the NP-CLB-MAN formulation. The nanoparticles were characterized by dynamic light scattering, electrophoretic light scattering, scanning electron microscopy, and Fourier-transform infrared spectroscopy.

Results: The nanoparticles presented an encapsulation efficiency greater than 61% and a PdI between 0.186–0.217. The mean size was 185 nm for NP-CLB and 220 nm for NPCLB- MAN, and the zeta potential values were -17.7 mV for NP-CLB and -14.2 mV for NP- CLB-MAN. Scanning electron microscopy showed that NPs with OEM have a surface with a different shape, and FTIR analyses showed binding of CLB to the drug delivery system, as well as functionalization with OEM. In vitro release studies showed a biphasic release profile for both systems, and they were analyzed considering the mathematical Korsmeyer-Peppas, first-order, and Fick diffusion models, and the combination of the first-order and Fick diffusion models.

Conclusion: The experimental results obtained for the release of CLB were better described using a combination of the first order and Fick diffusion mathematical models.

Phytochemical-Mediated Glioma Targeted Treatment: Drug Resistance and Novel Delivery Systems

Glioma, especially its most malignant type, Glioblastoma (GBM), is the most common and the most aggressive malignant tumour in the central nervous system. Currently, we have no specific therapies that can significantly improve its dismal prognosis. Recent studies have reported promising in vitro experimental results of several novel glioma-targeting drugs; these studies are encouraging to both researchers and patients. However, clinical trials have revealed that novel compounds that focus on a single, clear glioma genetic alteration may not achieve a satisfactory outcome or have side effects that are unbearable. Based on this consensus, phytochemicals that exhibit multiple bioactivities have recently attracted much attention. Traditional Chinese medicine and traditional Indian medicine (Ayurveda) have shown that phytocompounds inhibit glioma angiogenesis, cancer stem cells and tumour proliferation; these results suggest a novel drug therapeutic strategy. However, single phytocompounds or their direct usage may not reverse comprehensive malignancy due to poor histological penetrability or relatively unsatisfactory in vivo efficiency. Recent research that has employed temozolomide combination treatment and Nanoparticles (NPs) with phytocompounds has revealed a powerful dual-target therapy and a high blood-brain barrier penetrability, which is accompanied by low side effects and strong specific targeting. This review is focused on major phytocompounds that have contributed to glioma-targeting treatment in recent years and their role in drug resistance inhibition, as well as novel drug delivery systems for clinical strategies. Lastly, we summarize a possible research strategy for the future.

Synthesis, Biological Evaluation and Molecular Dynamics Simulation Studies of Novel Diphenyl Ethers

Background: The well-known antibacterial agent Triclosan (TCL) that targets bacterial enoylacyl protein reductase has been described to inhibit human fatty acid synthase (FASN) via the enoylacyl reductase domain. A Literature survey indicates that TCL is selectively toxic to cancer cells and furthermore might indeed reduce cancer incidence in vivo. A recent study found that TCL inhibits FASN by acting as an allosteric protein-protein interface (PPI) inhibitor. It induces dimer orientation changes that effect in a downstream reorientation of catalytic residues in the NADPH binding site proposing TCL as a viable scaffold to design a superior molecule that might have more inhibitory potential. This unveils tons of potential interaction space to take advantage of future inhibitor design.

Objectives: Synthesis of TCL mimicking novel diphenyl ether derivatives, biological evaluation as potential antiproliferative agents and molecular docking and molecular dynamics simulation studies.

Methods: A series of novel N-(1-(3-hydroxy-4-phenoxyphenyl)-3-oxo-3-phenylpropyl)acetamides (3a-n) and N-(3(3-hydroxy-4phenoxyphenyl)-3-oxo-1-phenylpropyl) acetamides (6a-n) were designed, synthesized, characterized and evaluated against HepG2, A-549, MCF-7 and Vero cell lines. The induction of antiproliferative activity of selected compounds (3d and 6c) was done by AO/EB (acridine orange/ethidium bromide) nuclear staining method, DNA fragmentation study, and cell cycle analysis was performed by flow cytometry. Molecular docking and dynamics simulation study was also performed.

Results: Among the tested compounds, compound 3d was most active (IC50 13.76 ± 0.43 µM) against A-549 cell line. Compounds 3d and 3g were found to be moderately active with IC50 30.56 ± 1.1 µM and 25.05 ± 0.8 µM respectively against MCF-7 cell line. Morphological analysis of A-549 cells treated with 3d and 6c clearly demonstrated the reduction of cell viability and induction of apoptosis. DNA fragmentation was observed as a characteristic of apoptosis in treated cells. Further, cell cycle analysis by flow cytometry confirmed that compounds 3d and 6c significantly arrested the cell cycle at the G0/G1 phase. Molecular docking study demonstrated that these compounds exhibit high affinity for the human fatty acid synthase (hFASN) target. Molecular dynamics simulation study of the most active compound 3d was performed for calculating binding free energies using Molecular Mechanics–Generalized Born Surface Area (MM/GBSA).

Conclusion: Compound 3d (IC50 13.76 ± 0.43 µM) has been identified as a potential lead molecule for anticancer activity against A-549 cells followed by 3l, 6c, and 3g. Thus, the design of diphenyl ether derivatives with enhanced affinity to the binding site of hER may lead to the discovery of potential anticancer agents.

Anti-tumor Activity of Propofol: A Focus on MicroRNAs

Background: MicroRNAs are endogenous, short, non-coding RNAs with the length as low as 20 to 25 nucleotides. These RNAs are able to negatively affect the gene expression at the post-transcriptional level. It has been demonstrated that microRNAs play a significant role in cell proliferation, cell migration, cell death, cell differentiation, infection, immune response, and metabolism. Besides, the dysfunction of microRNAs has been observed in a variety of cancers. So, modulation of microRNAs is of interest in the treatment of disorders.

Objective: The aim of the current review is to investigate the modulatory effect of propofol on microRNAs in cancer therapy.

Methods: This review was performed at PubMed, SCOPUS and Web of Science data-bases using keywords “propofol’, “microRNA”, “cancer therapy”, “propofol + microRNA” and “propofol + miR”.

Results: It was found that propofol dually down-regulates/upregulates microRNAs to exert its antitumor activity. In terms of oncogenesis microRNAs, propofol exert an inhibitory effect, while propofol significantly enhances the expression of oncosuppressor microRNAs.

Conclusion: It seems that propofol is a potential modulator of microRNAs and this capability can be used in the treatment of various cancers.

Characteristics of Natural Killer Cell Interaction with Trophoblast Cells During Pregnancy

Background: Maternal natural killer cells (NK cells) are a prevailing leukocyte population in the uteroplacental bed. Current descriptions of the effect of cytokines from the placental microenvironment on the expression of receptors by trophoblast and NK cells are inadequate and contradictory. There is insufficient information about the ability of NK cells to migrate through trophoblast cells.

Objective: To assess the impact of conditioned media obtained during culturing of placentas from the first and the third trimesters of healthy pregnancies on the phenotype of trophoblast and NK cells and impact on adhesion and transmigration of NK cells through trophoblast cell layer.

Results: We established that conditioned media obtained from both first and third trimester placentas increased the intensity of CD106, CD49e, CD49a, CD31, CD51/61, and integrin β6 expression by trophoblast cells. Conditioned media obtained from first trimester placentas increased the intensity of CD11a, CD29, CD49d, CD58, CD29 expression by NK cells. The presence of conditioned media from third trimester placentas resulted in more intense CD29, CD49d, CD11a, CD29, CD49d, and CD58 expression by NK cells. Migration of NK cells through trophoblast cells in the presence of conditioned media from first trimester placentas was increased compared with the migration level in the presence of conditioned media from third trimester placentas. This may be associated with increased expression of CD18 by NK cells.

Conclusion: First trimester placental secretory products increase adhesion receptor expression by both trophoblast and NK cells. Under these conditions, trophoblast is capable of ensuring NK cell adhesion and transmigration.

ADCs, as Novel Revolutionary Weapons for Providing a Step Forward in Targeted Therapy of Malignancies

Antibody drug conjugates (ADCs), as potent pharmaceutical trojan horses for cancer treatment, provide superior efficacy and specific targeting along with low risk of adverse reactions compared to traditional chemotherapeutics. In fact, the development of these agents combines the selective targeting capability of monoclonal antibody (mAb) with high cytotoxicity of chemotherapeutics for controlling the neoplastic mass growth. Different ADCs (more than 60 ADCs) in preclinical and clinical trials were introduced in this novel pharmaceutical field. Various design-based factors must be taken into account for improving the functionality of ADC technology, including selection of appropriate target antigen and high binding affinity of fragment (miniaturized ADCs) or full mAbs (preferentially use of humanized or fully human antibodies compared to murine and chimeric ones), use of bispecific antibodies for dual targeting effect, linker engineering and conjugation method efficacy to obtain more controlled drug to antibody ratio (DAR). Challenging issues affecting therapeutic efficacy and safety of ADCs, including bystander effect, on- and off-target toxicities, multi drug resistance (MDR) are also addressed. 4 FDA-approved ADCs in the market, including ADCETRIS ®, MYLOTARG®, BESPONSA ®, KADCYLA®. The goal of the current review is to evaluate the key parameters affecting ADCs development.

Apigenin, A Plant Flavone Playing Noble Roles in Cancer Prevention Via Modulation of Key Cell Signaling Networks

Background: Cancer is a global health problem and the continuous rise in incidence and mortality due to cancer carries a real economic burden to all countries. Accumulation of genetic mutation, exposure of environmental carcinogens and food habits due to change in lifestyles are the key reasons for cancer. Targeting cancer cells, we need a multitargeting molecule with low/no toxicity.

Objective: To review the current update of the research status of chemopreventive/therapeutic molecule, Apigenin.

Methods: Compare the results of the published articles and granted patents on this compound. We also discuss the pros and cons of the present research and future direction.

Results: Cancer cells have characteristic alterations and dysregulation of various cell signaling pathways that control cell homeostasis, proliferation, motility, and survival in normal cells. Natural flavonoids are the compounds well known for their anti-inflammatory, anti-oxidant, and anti-cancerous properties. Apigenin, along with several other physiological effects, has a very low intrinsic toxicity and striking effects on the proliferation of cancer cells. Interestingly, this multitargeting molecule is getting wide acceptance among researchers. It is evident from the recent patents filed in this compound. At present, three patents have been granted only on the anticancer properties of apigenin.

Conclusion: This mini-review will explain the present research status of apigenin and will further shine some light on how apigenin performs its anti-cancerous actions by interfering with the key cellsignaling pathways.

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.

Achievements in Cancer Research and its Therapeutics in Hundred Years

Cancer research has progressed leaps and bounds over the years. This review is a brief overview of the cancer research, milestone achievements and therapeutic studies on it over the one hundred ten years which would give us an insight into how far we have come to understand and combat this fatal disease leading to millions of deaths worldwide. Modern biology has proved that cancer is a very complex disease as still we do not know precisely how it triggers. It involves several factors such as protooncogene, oncogene, kinase, tumor suppressor gene, growth factor, signalling cascade, micro RNA, immunity, environmental factors and carcinogens. However, modern technology now helps the cancer patient on the basis of acquired and established knowledge in the last hundred years to save human lives.

Using Cell Cultures for the Investigation of Treatments for Attention Deficit Hyperactivity Disorder: A Systematic Review

Background: Advances in basic and molecular biology have promoted the use of cell cultures in a wide range of areas, including the evaluation of drug efficacy, safety and toxicity.

Objective: This article aims to provide a general overview of the methodological parameters of cell cultures used to investigate therapeutic options for Attention Deficit Hyperactivity Disorder.

Method: A systematic search was performed in the electronic databases PubMed, Scopus, and DOAJ. In vitro experimental studies using cell cultures were included.

Results: A total of 328 studies were initially identified, with 16 included for qualitative synthesis. Seven studies used neuronal cells (SH-SY5Y neuroblastoma and PC12 cell line) and nine used nonneuronal cells. All the studies described the culture conditions, but most studies were inconsistent with regard to reporting results and raw data. Only one-third of the studies performed cell viability assays, while a further 30% conducted gene expression analysis. Other additional tests included electrophysiological evaluation and transporter activity. More than 50% of the studies evaluated the effects of drugs such as methylphenidate and atomoxetine, while plant extracts were assessed in four studies and polyunsaturated fatty acids in one.

Conclusion: We suggested a flowchart to guide the planning and execution of studies, and a checklist to be completed by authors to allow the standardized reporting of results. This may guide the elaboration of laboratory protocols and further in vitro studies.

Current Status and Future Perspective for Research on Medicinal Plants with Anticancerous Activity and Minimum Cytotoxic Value

Cancer is the second leading cause of morbidity and mortality worldwide. Although chemotherapy and radiotherapy enhance the survival rate of cancerous patients but they have several acute toxic effects. Therefore, there is a need to search for new anticancer agents having better efficacy and lesser side effects. In this regard, herbal treatment is found to be a safe method for treating and preventing cancer. Here, an attempt has been made to screen some less explored medicinal plants like Ammania baccifera, Asclepias curassavica, Azadarichta indica, Butea monosperma, Croton tiglium, Hedera nepalensis, Jatropha curcas, Momordica charantia, Moringa oleifera, Psidium guajava, etc. having potent anticancer activity with minimum cytotoxic value (IC50 >3μM) and lesser or negligible toxicity. They are rich in active phytochemicals with a wide range of drug targets. In this study, these medicinal plants were evaluated for dose-dependent cytotoxicological studies via in vitro MTT assay and in vivo tumor models along with some more plants which are reported to have IC50 value in the range of 0.019-0.528 mg/ml. The findings indicate that these plants inhibit tumor growth by their antiproliferative, pro-apoptotic, anti-metastatic and anti-angiogenic molecular targets. They are widely used because of their easy availability, affordable price and having no or sometimes minimal side effects. This review provides a baseline for the discovery of anticancer drugs from medicinal plants having minimum cytotoxic value with minimal side effects and establishment of their analogues for the welfare of mankind.

Ectonucleotidases: Potential Target in Drug Discovery and Development

Targeting Nodal and Cripto-1: Perspectives Inside Dual Potential Theranostic Cancer Biomarkers

Background: Elucidating the mechanisms of recurrence of embryonic signaling pathways in tumorigenesis has led to the discovery of onco-fetal players which have physiological roles during normal development but result aberrantly re-activated in tumors. In this context, Nodal and Cripto-1 are recognized as onco-developmental factors, which are absent in normal tissues but are overexpressed in several solid tumors where they can serve as theranostic agents.

Objective: To collect, review and discuss the most relevant papers related to the involvement of Nodal and Cripto-1 in the development, progression, recurrence and metastasis of several tumors where they are over-expressed, with a particular attention to their occurrence on the surface of the corresponding sub-populations of cancer stem cells (CSC).

Results: We have gathered, rationalized and discussed the most interesting findings extracted from some 370 papers related to the involvement of Cripto-1 and Nodal in all tumor types where they have been detected. Data demonstrate the clear connection between Nodal and Cripto-1 presence and their multiple oncogenic activities across different tumors. We have also reviewed and highlighted the potential of targeting Nodal, Cripto-1 and the complexes that they form on the surface of tumor cells, especially of CSC, as an innovative approach to detect and suppress tumors with molecules that block one or more mechanisms that they regulate.

Conclusion: Overall, Nodal and Cripto-1 represent two innovative and effective biomarkers for developing potential theranostic anti-tumor agents that target normal as well as CSC subpopulations and overcome both pharmacological resistance and tumor relapse.

ABC Transporters: Regulation and Association with Multidrug Resistance in Hepatocellular Carcinoma and Colorectal Carcinoma

For most cancers, the treatment of choice is still chemotherapy despite its severe adverse effects, systemic toxicity and limited efficacy due to the development of multidrug resistance (MDR). MDR leads to chemotherapy failure generally associated with a decrease in drug concentration inside cancer cells, frequently due to the overexpression of ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2), which limits the efficacy of chemotherapeutic drugs. The aim of this review is to compile information about transcriptional and post-transcriptional regulation of ABC transporters and discuss their role in mediating MDR in cancer cells.

This review also focuses on drug resistance by ABC efflux transporters in cancer cells, particularly hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) cells. Some aspects of the chemotherapy failure and future directions to overcome this problem are also discussed.

Modulation of ABC Transporters by Nuclear Receptors: Physiological, Pathological and Pharmacological Aspects

ABC transporters are membrane proteins mediating the efflux of endo- and xenobiotics. Transporter expression is not static but instead is subject to a dynamic modulation aiming at responding to changes in the internal environment and thus at maintaining homeostatic conditions. Nuclear receptors are ligand modulated transcription factors that get activated upon changes in the intracellular concentrations of the respective agonists and bind to response elements within the promoter of ABC transporters, thus modulating their expression and, consequently, their activity. This review compiles information about transporter regulation by nuclear receptors classified according to the perpetrator compounds and the biological effects resulting from the regulation. Modulation by hormone receptors is involved in maintaining endocrine homeostasis and may also lead to an altered efflux of other substrates in cases of altered hormonal levels. Xenobiotic receptors play a key role in limiting the accumulation of potentially harmful compounds. In addition, their frequent activation by therapeutic agents makes them common molecular elements mediating drug-drug interactions and cancer multidrug resistance. Finally, lipid and retinoid receptors are usually activated by endogenous molecules, thus sensing metabolic changes and inducing ABC transporters to counteract potential alterations. Furthermore, the axis nuclear receptor-ABC transporter constitutes a promising therapeutic target for the treatment of several disease states like cancer, atherosclerosis and dyslipidemia. In the current work, we summarize the information available on the pharmacological potential of nuclear receptor modulators and discuss their applicability in the clinical practice.

MicroRNA in Cervical Carcinogenesis: Window of Therapeutic Potential

Background: Cervical cancer is the second leading malignancy for women. In developing countries, it is becoming a public health trouble in adult women. Persistent cervical infection with high-risk human papillomavirus (HPV) may contribute to the development of cervical cancer. The danger is in the fact that woman with HPV can go unnoticed for years. So, women with early cervical cancer and pre-malignant neoplastic disease show no symptoms, until cancer becomes invasive and grows into the nearby tissue. A large number of females die from the disease each year due to late diagnosis and resistance to conventional treatment. In particular, in advanced tumor stage, low response to chemotherapy results in poor prognosis and recurrence. Therefore, new therapies and indicators are needed to overcome chemo-resistance as well as early diagnosis of cancer. There is a continuous search for prognostic and predictive markers in order to help optimize and personalize treatment for improvement in the outcome of cervical cancer.

Recent Findings: Non-coding regulatory RNAs that control gene expression at the posttranscriptional level are seeking the attention of scientists in this area. Certain microRNAs have been located near cancer susceptibility loci that correlate tumorgenesis. Multiple profiling studies have revealed a significant change in miRNA expression in cervical cancer patients. A number of miRNAs have shown a consistent up-regulation or down regulation throughout the different stages of cervical cancer.

Conclusion: Investigation of microRNAs involved in carcinogenesis and progression of cervical cancer in tissue-specific manner is opening a window in early diagnosis and therapeutics.

Exploiting Cancer Metal Metabolism using Anti-Cancer Metal- Binding Agents

Metals are vital cellular elements necessary for multiple indispensable biological processes of living organisms, including energy transduction and cell proliferation. Interestingly, alterations in metal levels and also changes in the expression of proteins involved in metal metabolism have been demonstrated in a variety of cancers. Considering this and the important role of metals for cell growth, the development of drugs that sequester metals has become an attractive target for the development of novel anti-cancer agents. Interest in this field has surged with the design and development of new generations of chelators of the thiosemicarbazone class. These ligands have shown potent anticancer and anti-metastatic activity in vitro and in vivo. Due to their efficacy and safe toxicological assessment, some of these agents have recently entered multi-center clinical trials as therapeutics for advanced and resistant tumors. This review highlights the role and changes in homeostasis of metals in cancer and emphasizes the pre-clinical development and clinical assessment of metal ion-binding agents, namely, thiosemicarbazones, as antitumor agents.

New Anti-Cancer Strategies in Testicular Germ Cell Tumors

Background: The most common solid malignancy of young men aged 20 to 34 years is testicular germ cell tumor. In addition, the incidence of these tumors has significantly increased throughout the last years. Testicular germ cell tumors are classified into seminoma and nonseminoma germ cell tumors, which take in yolk sac tumor, embryonal cell carcinoma, choriocarcinoma, and teratoma. There are noteworthy differences about therapy and prognosis of seminomas and nonseminoma germ cell tumors, even though both share characteristics of the primordial germ cells.

Objectives: The study is focused on different molecular mechanisms strongly involved in testicular germ cell line tumors underlying new strategies to treat this human neoplasia.

Methods: Bibliographic data from peer-reviewed research, patent and clinical trial literature, and around eighty papers and patents have been included in this review.

Results: Our study reveals that several biomarkers are usefully utilized to discriminate among different histotypes. Moreover, we found new patents regarding testicular germ cell tumor treatments such as the expression of claudin 6, monoclonal antibody (Brentuximab Vedotin), immune checkpoint blockade (ICB) with the FDA-approved drugs pembrolizumab and nivolumab or the oncolytic virus Pelareorep, the combination of selective inhibitors of Aurora kinase.

Conclusion: Finally, the pathogenesis of testicular germ cell tumor needs to be deeply understood so that it will improve data on stem cells, tumorigenesis and disease tumor management by more selective treatment.

Perspectives of Plant Natural Products in Inhibition of Cancer Invasion and Metastasis by Regulating Multiple Signaling Pathways

Background: Metastasis is often derived from increased invasion and migration of tumor cells, and is the most frequent cause of cancer-associated death. Either the prophylactic or therapeutic treatment of metastatic cancer remains very challenging today by virtue of the complex histopathology and genetic or epigenetic variations. Medicinal scientists had discovered many potential anti-invasive and anti-metastatic compounds from plant materials. However, data on currently available plant-based compounds inhibiting cancer invasion and metastasis is relatively scanty and no published article has been found with updated information in this unique and important aspect.

Methods: We obtained relevant information from a structured search of 327 peer-reviewed articles, including both research- and review-based papers, related to the use of plant materials in cancer treatments, particularly for the suppression of invasion and metastasis.

Results: We have categorized the plant-based products with anti-invasive or anti-metastatic properties into alkaloids, flavonoids, terpenes, quinones, phenolics, xanthone and sulfur-containing compounds, and complemented with their chemical structures, sources of isolation and biological targets in the present review article.

Conclusion: We aim to provide readers a convenient way in reviewing the potential anti-invasive and anti-metastatic plant-based products with links to different mechanistic pathways, and to inspire researchers with updated information for the development of new anticancer remedies.

Clinical Use of Toxic Proteins and Peptides from Tian Hua Fen and Scorpion Venom

Traditional Chinese Medicine (TCM) has been practiced in China for thousands of years. As a complementary and alternative treatment, herbal medicines that are frequently used in the TCM are the most accepted in the Western world. However, animal materials, which are equally important in the TCM practice, are not well-known in other countries. On the other hand, the Chinese doctors had documented the toxic profiles of hundreds of animals and plants thousand years ago. Furthermore, they saw the potential benefits of these materials and used their toxic properties to treat a wide variety of diseases, such as heavy pain and cancer. Since the 50s of the last century, efforts of the Chinese government and societies to modernize TCM have achieved tremendous scientific results in both laboratory and clinic. A number of toxic proteins have been isolated and their functions identified. Although most of the literature was written in Chinese, this review provide a summary, in English, regarding our knowledge of the clinical use of the toxic proteins isolated from a plant, Tian Hua Fen, and an animal, scorpion, both of which are famous toxic prescriptions in TCM.

Antifungal Proteins with Antiproliferative Activity on Cancer Cells and HIV-1 Enzyme Inhibitory Activity from Medicinal Plants and Medicinal Fungi

A variety of fungi, plants, and their different tissues are used in Traditional Chinese Medicine to improve health, and some of them are recommended for dietary therapy. Many of these plants and fungi contain antifungal proteins and peptides which suppress spore germination and hyphal growth in phytopathogenic fungi. The aim of this article is to review antifungal proteins produced by medicinal plants and fungi used in Chinese medicine which also possess anticancer and human immunodeficiency virus-1 (HIV-1) enzyme inhibitory activities.

Chinese Medicine Protein and Peptide in Gene and Cell Therapy

The success of gene and cell therapy in clinic during the past two decades as well as our expanding ability to manipulate these biomaterials are leading to new therapeutic options for a wide range of inherited and acquired diseases. Combining conventional therapies with this emerging field is a promising strategy to treat those previously-thought untreatable diseases. Traditional Chinese medicine (TCM) has evolved for thousands of years in China and still plays an important role in human health. As part of the active ingredients of TCM, proteins and peptides have attracted long-term enthusiasm of researchers. More recently, they have been utilized in gene and cell therapy, resulting in promising novel strategies to treat both cancer and non-cancer diseases. This manuscript presents a critical review on this field, accompanied with perspectives on the challenges and new directions for future research in this emerging frontier.

7-O-aminoalkyl-2,3-dehydrosilibinins: Synthesis and in vitro Anti-cancer Efficacy

Background: The heptaprotective flavonolignan silibinin and dehydrosilibinin have exhibited moderate antiproliferative activities toward many cancer cell lines. Considering of the nontoxic profile of these natural products, chemical modification to enhance the anticancer potentials is promising.

Method: A series of 7-O-aminoalkyl-2,3-dehydrosilibinin derivatives were synthesized and evaluated for their antiproliferative activities against several cancer cell lines.

Results: A number of the synthesized dehydrosilibinin derivatives exhibited greatly enhanced potency with 50% growth inhibition at low micromolar concentrations. Structure activity study indicated that the distance between N and 7-O on the side chain has a limited influence on the antiproliferative activity, while the presence of a morpholino group decreases the antiproliferative activities dramatically. Flow cytometry based assays on human colon cancer HCT116 cells revealed that 6a and 6c, two of the most potent derivatives, effectively arrested the cell cycle in the G2 phase and stimulated cell apoptosis.

Conclusion: Our findings suggest that attaching an appropriate tertiary amino alkyl side chain through 7-Oalkylation on 2,3-dehydrosilibinin, would be a viable strategy for the development of silibinin derivatives as anticancer agents.

Factors Regulating Human Extravillous Trophoblast Invasion: Chemokine-peptidase and CD9-integrin Systems

The invasion of an extravillous trophoblast (EVT) into maternal decidual tissues, especially towards maternal spiral arteries, is an essential process in the human placental formation and subsequent normal fetal development. However, the precise regulatory mechanisms to induce EVT invasion towards arteries and/or to protect EVT from further invasion are not well understood. We found that a chemokine receptor, CCR1, was specifically expressed on EVT migrating towards maternal arteries. Using EVT isolated from a primary villous explant culture, RANTES, which is one of the ligands for CCR1, was shown to enhance EVT invasion. Furthermore, we observed that the platelets were deposited among intravascular EVT and platelet-derived soluble factors, which contained RANTES, enhanced EVT invasion. On the one hand, dipeptidyl peptidase IV (DPPIV), which can metabolize RANTES on the cell surface, was expressed on non-invading EVT and was demonstrated to suppress EVT invasion. In contrast, laeverin/aminopeptidase Q, which is specifically expressed on EVT, was shown to induce EVT invasion. Also, CD9 which is a cell surface marker of platelets and a regulator of integrin function was expressed on EVT and gene knockdown of the CD9 molecule enhanced EVT invasion. These findings suggest that the chemokine-chemokine receptor, chemokine-peptidase, and CD9-integrin systems play important roles in the regulation of EVT invasion during early human placental formation.

Evaluation and Management of Adnexal Masses in Postmenopausal Women

In the postmenopausal women, adnexal masses can have numerous etiologies. They can range from benign to neoplastic, with origins from a variety of organ systems. The diagnostic work up includes a thorough history, physical exam, as well as potential imaging and laboratory testing. There should be a low threshold for consultations with oncologists when there are cancer concerns. Specifically for gynecologic neoplasms, a referral to a gynecologic oncologist should be strongly considered. In this paper, there is particular attention to ovarian cancer given the gravity of delayed diagnosis.

Targeting the Folate Receptor: Improving Efficacy in Inorganic Medicinal Chemistry

The discovery of the high-affinity, high-specificity folate receptor in mamalian kidney cells, coupled with the ability of folate to enter cells by folate receptor-mediated endocytosis and the subsequent elucidation of the folate receptor’s overexpression in specific cancer cell types; heralded the arrival of the area of chemotherapeutic folate targeting. The application of purely organic folate-based small-molecule drug conjugates that selectively target the folate receptor, which is over expressed in several diseases such as cancer, is well established. The application of inorganic folate-targeted drugs offers significant potential to expand and enhance this therapeutic approach. From the data made available to date, it is apparent that this aspect of inorganic medicinal chemistry is in its youth but has the capability to contribute greatly to cancer research, both in therapy and diagnosis. The union of folate-receptor targeting and inorganic medicine may also lead to the development of treatments for disorders such as chronic-inflammation, tuberculosis, neurodegenerative disease and leishmaniasis. In this review, we summarize what is known about the coordination chemistry of folic acid and the therapeutic potential of such complexes. We also describe approaches adopted to conjugate platinum drugs to folate- or folate-carrier- systems and their prospective ability to overcome problems associated with unwanted side-effects and resistance by improving their delivery and/or selectivity. The literature pertaining to non-platinum metal complex conjugates with folic acid is also reviewed revealing that this is an area that offers significant potential to develop targeted therapeutic approaches in areas such as chemotherapy and molecular imaging for diagnostics.

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.

Recent Advances in New Discovered Molecular Targets in Testicular Germ Cell Tumors

Background: Testicular germ cell tumor (TGCT) is the most common solid malignancy occurring in young men between 20 and 34 years of age, and its incidence has increased significantly over the last decades. TGCTs can be subdivided into seminoma and nonseminoma germ cell tumors (NSGCTs), which includes yolk sac tumor, choriocarcinoma, embryonal cell carcinoma, and teratoma. Seminomas and NSGCTs present significant differences in therapy, prognosis, and both show characteristics of the Primordial Germ Cells (PGCs).

Methods: I undertook a search of bibliographic data from peer-reviewed research literature.

Results: Seventy papers were included in the mini-review showing that a large number of new biomarkers have given further advantages to discriminate the different histotypes and could represent useful novel molecular targets for anticancer strategies.

Conclusion: A deeper understanding of the pathogenesis of TGCTs is likely to significantly improve not only our knowledge on stem cells and oncogenesis but also the disease management with more selective tumor treatment.

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.

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.

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.

Dysregulation of LncRNAs in Placenta and Pathogenesis of Preeclampsia

Background: Preeclampsia, a gestational disease characterized by hypertension and proteinuria twenty weeks into pregnancy, is one of the leading causes of fetal and maternal mortality. Although multiple genetic and environmental factors are found to be related to the preeclampsia risk, the pathogenic pathways remain largely undefined. The placenta plays a critical role in the fetal development by carrying out the barrier, fetal-maternal exchange, and endocrine functions during pregnancy. Accumulated data indicated that the expression of multiple long noncoding RNA (LncRNA) is dysregulated in preeclamptic placentas. Moreover, manipulation of LncRNA expression led to functional alterations in trophoblast cell cultures, including changes in proliferation, differentiation, apoptosis, and migration.

Objective: This article reviews published data on this subject and provides detailed information on the regulation and function of LncRNAs IGF2/H19, MEG3, SPRY4-IT1, HOTAIR, MALAT1, and FLT1P1 and CEACAMP8 in placental trophoblasts. The potential mechanisms underlying the action of these LncRNAs are also discussed to facilitate a better understanding on the potential role of these LncRNAs for the pathogenesis of preeclampsia.

Conclusion: It is elaborated that some lncRNAs probably contribute to the pathogenesis of preeclampsia through methylation, Notch-EGFL7 signaling pathway and Wnt/β-catenin pathway.

CEBP Epigenetic Dysregulation as a Drug Target for the Treatment of Hematologic and Gynecologic Malignancies

Background: The CCAAT/enhancer binding proteins (C/EBPs) form a family of transcription factors regulating many genes’ expression in a variety of cells/tissues/organs at different developmental stages. With their capability of binding to their cognate DNA elements and through protein-protein interactions, C/EBPs modulate diverse functions including cell differentiation, metabolism, and immune response, under both physiological and pathological conditions such as the establishment of hematological lineages, the maintenance of normal reproductive function, and the development of malignancies.

Objectives: This review concentrates on the role(s) and epigenetic alterations of C/EBP genes in hematologic malignancies and gynecologic organs and disorders. New research findings on molecular pathways involved in C/EBP function and regulation are reviewed and analyzed. The potential therapeutic values of these findings are also discussed.

Conclusion: Unlike in hematologic malignancies in which C/EBP mutations and their disruption of wild type C/EBP tumor suppressive activities have been well documented, mutation of C/EBP does not appear to be a common event in gynecologic cancers, raising some doubt if C/EBPs may have tumor suppressor activity in gynecologic cancers. However, this notion could not exclude the possibility that downregulation or DNA methylation-meditated epigenetic silencing of C/EBPs may contribute to the development of gynecologic malignancies.

Gynecomastia in Infants, Children, and Adolescents

Background: Gynecomastia may occur physiologically in the neonatal period, during puberty, and in old age. It may also develop in association with various pathologic states. The challenge for the physician is to distinguish physiological gynecomastia from those with an underlying pathology.

Objective: To review in depth the pathophysiology, clinical manifestations, and treatment of gynecomastia.

Method: A PubMed search was completed in Clinical Queries using the key term “gynecomastia”. Patents were searched using the key term “gynecomastia” from www.google.com/patents, www.uspto.gov, and www.freepatentsonline.com.

Results: Gynecomastia is caused by an imbalance between the stimulatory effect of estrogen and the inhibitory effect of androgen at the breast tissue level. Clinically, gynecomastia is characterized by the presence of a firm or rubbery, discrete, subareolar ridge of glandular tissue that is symmetrical in shape, freely movable, and nonadherent to skin or underlying tissue. Since most cases of physiological gynecomastia regress spontaneously with time, reassurance is all that is necessary. For pathological gynecomastia, treatment should be directed at the underlying cause, if possible. If gynecomastia persists in spite of the above measures, pharmacologic therapy and reduction mammoplasty may be considered. Recent patents related to the management of gynecomastia are discussed.

Conclusion: The majority of cases are physiological and do not require treatment other than reassurance. For pathological cases, the underlying cause should be treated if possible. If gynecomastia persists in spite of the above measures and treatment becomes necessary, tamoxifen is the treatment of choice. Reduction mammoplasty may be considered for resistant cases.

Polyphenols Beyond Barriers: A Glimpse into the Brain

Background: Ageing can be simply defined as the process of becoming older, which is genetically determined but also environmentally modulated. With the continuous increase of life expectancy, quality of life during ageing has become one of the biggest challenges of developed countries. The quest for a healthy ageing has led to the extensive study of plant polyphenols with the aim to prevent age-associated deterioration and diseases, including neurodegenerative diseases. The world of polyphenols has fascinated researchers over the past decades, and in vitro, cell-based, animal and human studies have attempted to unravel the mechanisms behind dietary polyphenols neuroprotection.

Methods: In this review, we compiled some of the extensive and ever-growing research in the field, highlighting some of the most recent trends in the area.

Results: The main findings regarding polypolyphenols neuroprotective potential performed using in vitro, cellular and animal studies, as well as human trials are covered in this review. Concepts like bioavailability, polyphenols biotransformation, transport of dietary polyphenols across barriers, including the blood-brain barrier, are here explored.

Conclusion: The diversity and holistic properties of polypolyphenol present them as an attractive alternative for the treatment of multifactorial diseases, where a multitude of cellular pathways are disrupted. The underlying mechanisms of polypolyphenols for nutrition or therapeutic applications must be further consolidated, however there is strong evidence of their beneficial impact on brain function during ageing. Nevertheless, only the tip of the iceberg of nutritional and pharmacological potential of dietary polyphenols is hitherto understood and further research needs to be done to fill the gaps in pursuing a healthy ageing.

Role of Imaging in Testicular Cancer

Testicular malignancy is the most common nonhematologic malignancy in young men. Around 95% of them are germ cell tumors (GCTs), and with correct assessment of the disease and application of chemotherapy and radiotherapy survival rates of more than 90% can be achieved. Imaging studies not only aid in the diagnosis of testicular cancer but also help determine the tumor extent and site of metastatic disease, in monitoring treatment response, surgical planning and detecting sites of relapse and residual disease. Scrotal sonography combined with clinical examination has a high sensitivity for diagnosing testicular cancer and thus is often the first imaging modality to be performed on patients presenting with testicular mass. Abdominal and pelvic CT and chest CT remain the preferred techniques for staging, monitoring of treatment response, and detecting relapse and residual disease in patients with testicular cancer but MRI, PET with 18F-FDG (fluorodeoxyglucose) and sonography also show promises in certain situations. This article reviews the literatures on the role of imaging in the management of testicular germ cell cancer.

Quality Survival with Fertility after Gynaecological and other Cancers

Introduction: Earlier, diagnosis of cancer ultimately led to death but now with complex therapies, not only many survive, but they have quality life too. Even preservation of fertility is possible. In addition to this, with early diagnosis, complete cure is possible.

Objectives: To look into the existing evidence, challenges and possibilities.

Methodology: Simple review of literature was done with the help of various search engines, Pubmed, Google, Uptodate and other databases to evaluate the relevant studies, reviews and short commentaries to get information as per the objectives.

Evidence: Because of long-term effects of various cancers and their therapies, problems like quality of life, sexuality and fertility are the real concerns. Gonadal dysfunction is common, especially in gynaecological cancers and their therapies. Germ cell tumors of ovary are most common in young girls but with conservative surgery and chemotherapy the results are excellent. Same is true even for stage I epithelial ovarian cancers. Conservative therapies for cervical cancer, conization, simple / radical trachelectomy can do wonders. Endometrial cancer usually occurs after menopause, and there are no standard recommendations for conservative management, which is possible in younger women. Choriocarcinoma is highly malignant but has high cure rate too. So, quality survival is possible. Studies with Breast cancer, Hodgkin lymphoma have also revealed menstrual function resumption after chemotherapy. Presurgery assessment and close follow-up are necessary. Side effects of radiochemotherapy are real. Effects are drug, dose, and age dependent with possibilities of infertility and adverse pregnancy outcomes. Gonadotoxic effects may cause early menopause. Challenges increase if cancer occurs during pregnancy.

Preventive Possibilities and Conclusion: Mission of any cancer therapy needs to be quality long life, preservation of pregnancy prospects: natural or assisted. Prepubertal ovary is least susceptible to gonadotoxicity with chances of better reproductive life. Ovarian transposition / shielding or transplantation is possible. Ovarian tissue rather than oocyte or embryo cryopreservation is better. Early diagnosis and safe therapy can do miracles for women who are diagnosed with cancer. Conservative surgery, safe chemotherapy and focused radiation can reduce gonadotoxicity and preserve fertility. Multidisciplinary treatments are essential. Role of psychotherapy is important. For quality survival with reduced risk of cardiac, renal, neurological problems, bone osteoporosis and also for preservation of fertility, therapy needs proper planning for all cancers.

Killing Glioma ‘Stem-like’ Cells via Drug-Induced Relocation of Endosomal Urokinase Proteins

High grade gliomas (HGGs) are primary CNS cancers with more than 95% of patients experiencing tumor recurrence following radiation therapy, chemotherapy, and/or an anti-angiogenic therapy. Populations of glioma ‘stem-like’ cells (GSCs) exist in both proliferative and non-proliferative states and are capable of tumor regrowth. These GSCs survive within hypoxic tumor regions and avascular tumor margins, while retaining the capability to regenerate. Successful treatment of HGGs depends on therapeutic targeting of GSCs to avert tumor regeneration. Here, we review novel intracellular mechanisms by which 3-amino-5-arylamino-6-chloro-N-(diaminomethylene) pyrazine-2-carboximide (UCD38B) and the much more potent 5’-substituted arylamino compounds (cmpd 10357) irreversibly kill GSCs utilizing caspase-independent, programmed necrotic cell death. Drug-induced relocation of a subset of endosomes to perinuclear mitochondria triggers the mitochondrial release and nuclear translocation of apoptosis inducible factor (AIF) that is followed by nuclear condensation and cancer cell demise. This drug-induced endosomal ‘mis-trafficking’ affects a subset of endosomes containing proteins belonging to the urokinase plasminogen activator system (uPAS) and guided by lipoprotein receptor protein type 1 (LRP-1). UCD38B and congeners act intracellularly and bind to intracellular urokinase plasminogen activator (uPA) to disrupt uPA binding to PAI-1 and the endosomal LRP-1 guidance protein. These small molecules are cytotoxic to persistently hypoxic and acidotic HGG cell lines and to high grade gliomas from patient derived xenografts (PDX). Immunodeficient mice with intracerebral PDX glial tumors demonstrate drug-specific, AIF- mediated necrosis after 24h of treatment. The propensity of these small molecules to kill non-proliferating and proliferating hypoxic GSCs, suggests a potential synergistic therapeutic role with radiotherapy, anti-mitotic and anti-angiogenic therapies.

New Molecular Targets of Anticancer Therapy – Current Status and Perspectives

Molecularly targeted anticancer therapy involves the use of drugs or other substances affecting specific molecular targets that play a part in the development, progression and spread of a given neoplasm. By contrast, the majority of classical chemotherapeutics act on all rapidly proliferating cells, both healthy and cancerous ones. Target anticancer drugs are designed to achieve a particular aim and they usually act cytostatically, not cytotoxically like classical chemotherapeutics. At present, more than 300 biological molecular targets have been identified. The proteins involved in cellular metabolism include (among others) receptor proteins, signal transduction proteins, mRNA thread matrix synthesis proteins participating in neoplastic transformation, cell cycle control proteins, functional and structural proteins.

The receptor proteins that are targeted by currently used anticancer drugs comprise the epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor(VEGFR). Target anticancer drugs may affect extracellular receptor domains (antibodies) or intracellular receptor domains (tyrosine kinase inhibitors).

The blocking of the mRNA thread containing information about the structure of oncogenes (signal transduction proteins) is another molecular target of anticancer drugs. That type of treatment, referred to as antisense therapy, is in clinical trials.

When the synthesis of genetic material is disturbed, in most cases the passage to the next cycle phase is blocked. The key proteins responsible for the blockage are cyclines and cycline- dependent kinases (CDK). Clinical trials are focused on natural and synthetic substances capable of blocking various CDKs.

The paper discusses the molecular targets and chemical structure of target anticancer drugs that have been approved for and currently applied in antineoplastic therapy together with indications and contraindications for their application.

Passive Targeting of Cyclophosphamide-Loaded Carbonate Apatite Nanoparticles to Liver Impedes Breast Tumor Growth in a Syngeneic Model

Despite being widely used for treating cancer, chemotherapy is accompanied by numerous adverse effects as a result of systemic distribution and nonspecific interactions of the drugs with healthy tissues, eventually leading to therapeutic inefficacy and chemoresistance. Cyclophosphamide (Cyp) as one of the chemotherapeutic pro-drugs is activated in liver and used to treat breast cancer in high dose and in combination with other drugs. In an attempt to reduce the off-target effects and enhance the therapeutic efficacy, pH-sensitive carbonate apatite nanoparticles that had predominantly and size-dependently been localized in liver following intravenous administration, were employed to electrostatically immobilize Cyp and purposely deliver it to the liver for activation. Cyp-loaded particles formed by simple 30 min incubation at 37ºC of the DMEM (pH 7.4) medium containing CaCl2 and Cyp, enhanced in vitro cytotoxicity at different degrees depending on the cell types. The size of the particles could be tightly controlled by the amount of CaCl2 required to prepare the particles and thus the bio-distribution pattern inside different organs of the body. Unlike the small particles (~ 200 nm), the large size particles (~ 600 nm) which were more efficiently accumulated in liver, significantly reduced the tumor volume following intravenous injection in 4T1-induced murine breast cancer model at a very low dose (0.17 mg/Kg) of the drug initially added for complex formation, thus shedding light on the potential applications of the Cyp-loaded nano-formulations in the treatment of breast cancer.

Cell Proliferation and Cytotoxicity Assays

Cell viability is defined as the number of healthy cells in a sample and proliferation of cells is a vital indicator for understanding the mechanisms in action of certain genes, proteins and pathways involved cell survival or death after exposing to toxic agents. Generally, methods used to determine viability are also common for the detection of cell proliferation. Cell cytotoxicity and proliferation assays are generally used for drug screening to detect whether the test molecules have effects on cell proliferation or display direct cytotoxic effects. Regardless of the type of cell-based assay being used, it is important to know how many viable cells are remaining at the end of the experiment. There are a variety of assay methods based on various cell functions such as enzyme activity, cell membrane permeability, cell adherence, ATP production, co-enzyme production, and nucleotide uptake activity. These methods could be basically classified into different categories: (I) dye exclusion methods such as trypan blue dye exclusion assay, (II) methods based on metabolic activity, (III) ATP assay, (IV) sulforhodamine B assay, (V) protease viability marker assay, (VI) clonogenic cell survival assay, (VII) DNA synthesis cell proliferation assays and (V) raman micro-spectroscopy. In order to choose the optimal viability assay, the cell type, applied culture conditions, and the specific questions being asked should be considered in detail. This particular review aims to provide an overview of common cell proliferation and cytotoxicity assays together with their own advantages and disadvantages, their methodologies, comparisons and intended purposes.

Standardization of Epitopes for Human Chorionic Gonadotropin (hCG) Immunoassays

hCG and its variants are markers for pregnancy tests, pregnancyrelated complications, trophoblastic diseases, pre-natal screening of Down’s syndrome and doping controls. Strong demands are imposed on diagnostic methods by the dynamic changes in the absolute and relative levels of hCG protein backbone variants and glycosylation isoforms in serum and urine during development of pregnancy or the progression/remission of tumors. Observed differences in the results between commercial diagnostic immunoassays reflect the unequal molar recognition of the different metabolic hCG variants, in particular the hCG beta core fragment (hCGβcf), by the diagnostic antibodies (Abs), as their epitopes are not standardized, and the fact that suboptimal hCG standards are used. To rapidly characterize Abs by their epitope recognition and specificity to evaluate their suitability for diagnostic immunoassays a procedure of comparative epitope mapping has been developed using epitope-defined reference Abs. Comparative epitope mapping of diagnostic Abs will provide the basis for the standardization of diagnostic antigenic domains/epitopes and consequently for improved reliability of hCG measurements. Diagnostic first line assays likely consist of pairs of Abs that recognize specific epitopes at the top of the neighboring peptide loops 1 and 3 (Ł1+3) and the cystine knot (ck) of hCGβ, respectively. In future, significant improvements of reliability, robustness and comparability of the results of immunoassays for complex glycoproteins such as hCG will be achieved by the use (i) of standardized diagnostic Abs against welldefined epitopes and (ii) of the new International Standards for hCG and for five hCG variants established by WHO, that are calibrated in molar (SI) units.

Epigenetic Targeting of Platinum Resistant Testicular Cancer

The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, little is known of the epigenetic alterations in testicular cancer and particularly in platinum refractory germ cell tumors. Germ cell derived testicular cancers, as compared to somatic tumors, appear to have a unique epigenetic profile that features more extensive DNA hypomethylation. Emerging data from clinical specimens suggest that epigenetic aberrations, especially DNA hypermethylation, can contribute to chemotherapy resistance and poor clinical outcomes in testicular germ cell tumors. Recent data indicate that testicular cancer cells, even those resistant to platinum, are highly sensitive to low doses of demethylating agents. Based on these promising preclinical studies, we suggest that DNA methylation inhibitors in combination with chemotherapeutic agents may offer a path to overcome acquired drug resistance in testicular cancer, laying the foundation and rationale for testing this class of epigenetic drugs in the clinical setting. In this mini-review we provide a brief overview of the promise of DNA methylation therapy to treat patients with refractory cancer of the testes.

Advances of Phenoxazines: Synthesis, Reactivity and Their Medicinal Applications

Phenoxazines are an important class of heterocycles, which are emerging in the field of medicinal chemistry. They exhibit numerous biological activities, including antiviral, anticancer, anti-Alzheimer, antidiabetic, antioxidant, anti-inflammatory, antibiotic and many more. The present review focuses on the chemistry along with the medicinal applications of the phenoxazine moiety, in order to provide a greater insight for the development of future phenoxazine therapeutics.

Ribosome-inactivating Proteins from Root Tubers and Seeds of Trichosan-thes kirilowii and Other Trichosanthes Species

Ribosome-inactivating proteins have been isolated from Trichosanthes kirilowii root tubers and seeds, including trichosanthin, karasurin and T 33 from root tubers and trichosanthrip, trichokirin, alpha-kirilowin, beta-kirilowin and trichoanguin from seeds. The aforementioned proteins show structural and functional similarities. Among them trichosanthin is the best known and most intensely studied. Trichosanthin manifests anticancer activity in vitro and in tumor bearing mice against a variety of cancers/cancer cell lines. It also exhibits anti-HIV-1 and anti-HSV-1 activities. Trichosanthin has been found to be useful for treatment of cesarean scar pregnancies and ectopic pregnancy, and for preventing acute rejection of major histocompatibility complex-mismatched mouse skin allograft. Trichosanthin selectively lesions some neurons and thus can be used in neuroscience research.

P-Glycoprotein Mediated Multidrug Resistance Reversal by Phytochemicals: A Review of SAR & Future Perspective for Drug Design

A major impediment for cancer chemotherapy is the development of multidrug-resistance (MDR). Continuous use of chemotherapeutic drugs during cancer therapy induces the expression of PGlycoprotein (P-gp, MDR1), an ATP dependant transporter, which in turn reduces the intracellular accumulation of chemotherapeutic drugs leading to MDR. Extensive research over the years has identified several potential P-gp inhibitors, both synthetic as well as natural origin, to overcome the MDR during cancer chemotherapy. In this review, we discuss the cellular pathways involved and transcription factors regulating the expression of P-gp. A number of phytochemicals are reported to inhibit P-gp activity and MDR1 expression; the structure-activity relationship (SAR) among the phytochemicals for P-gp inhibition and the effect of these phytochemicals on cellular signaling pathways regulating P-gp expression are discussed in detail. Moreover, structural biology and mutagenesis studies on P-gp along with docking studies throw light on the structural requirements for P-gp inhibition. Insight provided in the review about the phytochemicals molecular mechanism and SAR could catalyze the design of potent P-gp inhibitors in the future and could help to overcome MDR in cancer chemotherapy.

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.

Dextran-based Nanocarriers for Delivery of Bioactives

Background: Dextran (DX) is a natural polysaccharide produced in the laboratory by fermentation of sucrose under the effect of the enzyme DX sucrase (1,6-α-D-glucan-α- glucosyltransferase). After harvesting and purification DX is subjected to cracking and separation to obtain the desired molecular weight. Methods: The hydroxyl groups present in DX offer many sites for derivatization allowing the production of functionalized glycoconjugates biocompatible compound. DX and its derivatives are getting increased attention for use in core decoration or as carriers in novel drug delivery systems. This includes, among others, ion-pairing, self-aggregate, protein and drug conjugates. DX carriers and camouflaged particles will be dealt with in this review to give emphasis on the great versatility of this natural biocompatible polysaccharide. Conclusion: With the continuous development in the area of drug delivery, we believe that the unique properties of this versatile nanocarrier platform will elect it as one of the cornerstones of safe nanodelivery systems.

An Insight into Drug Repositioning for the Development of Novel Anti-Cancer Drugs

Increased investments and development of new technologies in drug discovery have barely improved the outcome of medicinal entities in the drug discovery market from a long time. Minimal success rates of drug approvals, poor safety profiles, and long development processes are some of many hurdles encountered in the drug discovery field. Therefore, drug repurposing can provide an alternative approach to meet the demands of the new, potent and safe anti-cancer agents in terms of both economic cost and time efficiency. The common molecular pathways of different diseases and secondary indications of most of the approved drugs, and advances in genomics, informatics and biology, as well as the availability of approved or safe drug libraries can certainly provide an improved and efficient way of screening safer drugs for new indications. Promising results of drug repurposing in different therapeutic areas have encouraged the scientific community to discover new drugs for different diseases using this methodology. Herein, we provide a general overview of structurally and functionally diverse approved drugs that have been repurposed as anti-cancer drugs.

Targeted Drug Delivery System for Platinum-based Anticancer Drugs

Platinum-based (Pt-based) anticancer drugs have been recognised as one of the most effective drugs for clinical treatment of malignant tumors due to its unique mechanism of action and broad range of anticancer spectrum. But, there are still some limitations such as side effects, drug resistance/cross resistance, no-specific targeting, becoming obstacles to restrict its expanding of clinical application. Targeted drug delivery system (TDDS) is a promising strategy for the research of novel Pt-based anticancer drugs. A variety of TDDS have been explored to improve the antitumor activity of Pt-based drugs such as nanoparticle drug systems, polymer-drug systems, drugs-macrocyclic compounds systems, etc. The review concentrates on recent development of various targeted drug delivery techniques, which could provide more opportunities for the development of Pt-based drugs with better efficiency, lower toxicity and less resistance.

Comparative Proteomic Profiling of Extracellular Proteins between Normal and Gastric Cancer Cells

Gastric cancer is the second leading cause of cancer-related deaths worldwide. Gastric cancer is often detected at a late stage when treatment is difficult. Biomarkers for early detection and drug targets for gastric cancer therapy are critical for effective management of gastric cancer. Secreted proteins not only play integral roles in cancer progression and metastasis, they are also easily accessible. Secreted proteins within the tumor microenvironment are therefore an attractive source of biomarkers and drug targets. In this study, iTRAQ-based liquid chromatography/tandem mass spectrometry was used for comparative profiling of the secretomes of 11 gastric cancer cell lines versus a normal gastric epithelial cell line. Of the close to 800 proteins detected, about 600 proteins were detected to display differential expression in one or more gastric cancer cell lines compared to normal cells. These differentially expressed proteins predominantly have binding or enzymatic activities and are largely associated with cellular and metabolic processes. Overexpression of ARPC4 was validated in gastric cell lines and its novel function in gastric cancer cell migration and invasion demonstrated in vitro. The findings support the notion of ARPC4 as a potential biomarker/drug target for metastatic gastric cancer.

Current Understanding of HSP90 as a Novel Therapeutic Target: An Emerging Approach for the Treatment of Cancer

Heat Shock Protein 90 (HSP90) is a ubiquitous molecular chaperone that is considered to be the most abundantly expressed protein in various human cancers such as breast, lung, colon, prostate, leukemia and skin. The master regulator, HSP90 plays a pivotal role in the conformational stabilization, maturation and activity of its various labile oncogenic client proteins such as p53, ErbB2, Bcr-Abl, Akt, Her-2, Cdk4, Cdk6, Raf-1 and v-Src in altered cells. Hence, making a guaranteed attempt to inhibit such a master regulator for cancer therapy appears to be a potential approach for combinatorial inhibition of numerous oncogenic signaling pathways simultaneously. Considerable efforts are being under way to develop novel molecular targets and its inhibitors that may block key signaling pathways involved in the process of tumorigenesis and metastasis. In this regards, HSP90 has acquired immense interest as a potent anticancer drug-target due to its key functional link with multiple signaling pathways involved in the process of cell proliferation and cell survival. Notably, geldanamycin and its derivatives (17-AAG, 17-DMAG) have shown quite encouraging results in inhibiting HSP90 function in several cancers and currently almost 17 drug candidates known to be target HSP90 are being under clinical trials either as single agents or combinatorial therapy. Hence, this review is an attempt to get new insight into novel drug target therapy by focusing on recent advances made in understanding HSP90 chaperone structure-function relationships, identification of new HSP90 client proteins and, more importantly, on the advancements of HSP90 targeted therapy based on various existing and emerging classical inhibitors.

Modulation of Expression and Activity of ABC Transporters by the Phytoestrogen Genistein. Impact on Drug Disposition

ATP binding cassette (ABC) transporters are involved in drug absorption, distribution and elimination. They also mediate multidrug resistance in cancer cells. Isoflavones, such as genistein (GNT), belong to a class of naturally-occurring compounds found at high concentrations in commonly consumed soya based-foods and dietary supplements. GNT and its metabolites interact with ABC transporters as substrates, inhibitors and/or modulators of their expression. This review compiles information about regulation of ABC transporters by GNT with special emphasis on the three major groups of ABC transporters involved in excretion of endo- and xenobiotics as follows: Pglycoprotein (MDR1, ABCB1), a group of multidrug resistance associated proteins (MRPs, ABCC subfamily) and ABCG2 (BCRP), an ABC half-transporter. The impact of these regulations on potential GNT-drug interactions is further considered.

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.

Phosphorylation Processes Controlling Aromatase Activity in Br east Cancer: An Update

Local estrogen production from aromatase-mediated conversion of androgens is an important mechanism of autocrine growth stimulation in hormone-dependent breast cancers. The control mechanism of aromatase enzymatic activity in recent years has been demonstrated to be more complex than previously identified. Indeed, it is well known that aromatase expression is regulated at the transcriptional level through the alternative use of tissue-specific promoters, whereas it has become clear that the activity of this enzyme is also controlled by post-transcriptional modifications, such as phosphorylation processes. This paper presents a selective review of the novel findings in this area showing phosphorylation/dephosphorylation of aromatase as a switch to rapidly modulate its enzymatic activity. Particularly, we describe studies conducted in our laboratories, focusing on the role of estrogens in modulating aromatase activity in estrogen-dependent breast cancer cells. Two separate mechanisms are described. First, 17β-estradiol (E₂), through c-Src kinase, is able to enhance tyrosine phosphorylation levels of aromatase protein and increases its enzymatic activity and estrogen biosynthesis. Secondly, E₂, through the activation of PI3K/Akt pathway, impairs the ability of the tyrosine phosphatase PTP1B to dephosphorylate aromatase, resulting in a consequent enhanced phosphorylation and activity of the aromatase protein itself. These new controls of aromatase function provide insights into the mechanisms through which local estrogen production can be altered in breast cancer tissues. They also offer a vast array of possibilities for identifying different cell signalings that should be targeted in novel therapeutic strategies for breast cancer treatment.

Impact of Axis of GHRH and GHRH Receptor on Cell Viability and Apoptosis of the Placental Choriocarcinoma Cell Line

Although GHRH and GHRH-R are recognized as key factors in placental development, little is known about the mechanism(s) of the regulation in trophoblastic cells during placental development. The objective of this study is to determine the potential relationship between the expression levels of GHRH-R and the placental and JEG-3 cell function. Furthermore, we aim to investigate the downstream pathways of GHRH/GHRH-R axis in the control of the JEG-3 cell viability and apoptosis. In this study, we detected the expression pattern of GHRH-R in human chorionic villous tissues and JEG-3 cell. Then, we evaluated the effects of GHRH/GHRH-R and the downstream pathways by using GHRH antagonist (JMR-132) on JEG-3 cell. Our present study found the expressions of GHRH-R in placental villous tissues and JEG-3 cell, and the expression levels of GHRH-R was significantly lower in villous tissues of early pregnancy loss when compared to normal controls. JMR-132 inhibited cellular viability and induced apoptosis in JEG-3 cell in a time and dosedependent manners through activation of caspase-3, p38, and p53, as well as inhibition of phosphorylation of Akt. Interestingly, ER stress markers such as GRP78, ubiquitinated proteins and phospho-eIF2α were significantly increased in JEG-3 cell after being treated with JMR-132. Conversely, pretreated with salubrinal (a selective inhibition of protein phosphatase 1-mediated eIF2α dephosphorylation), JEG-3 cells were rescued from JMR-132-mediated cell growth inhibition, and abolished JMR-132-induced cleaved caspase-3, CHOP, phospho-p53, and ubiquitinated proteins accumulation. Knockdown of endogenous GHRH-R significantly abolished the JMR-132-induced cleaved caspase-3 and activation of p38. In conclusion, our results, for the first time, demonstrated the expression levels of GHRH-R were closely related to the placental function. Inhibition of GHRH-R by using GHRH antagonist in JEG-3 cell may reduce cell viability and induce apoptosis through inactivation of Akt and ER stress via phosphorylation of eIF2α. These observations have enriched our understanding on the function of GHRH/GHRH-R axis and the downstream pathways in the control of the placental development.

The Most Important Aspect of the Paper: Our present study for the first time provided evidences that GHRH and GHRH-R loops involve in JEG-3 cell viability and apoptosis through Akt and eIF2α pathways.

Drug Design Targeting the CXCR4/CXCR7/CXCL12 Pathway

Under physiological conditions, CXCL12 modulates cell proliferation, survival, angiogenesis, and migration mainly through CXCR4. Interestingly, the newly discovered receptor CXCR7 for CXCL12 is highly expressed in many tumor cells as well as tumor-associated blood vessels, although the level of CXCR7 in normal blood cells is low. Recently, many studies have suggested that CXCR7 promotes cell growth and metastasis in various cancers, including lymphoma and leukemia, hepatocecullar, ovarian, colorectal, breast and lung cancer. Compared to CXCR4, CXCR7 is a non-classical GPCR that is unable to activate G proteins. The function of CXCR7 is generally considered to be mediated by: (a) recruiting β-arrestin-2; (b) heterodimerizing with CXCR4; and (c) acting as a “scavenger” of CXCL12, thus lowering the level of CXCL12 to weaken the activity of CXCR4. However, the crosstalk between CXCL12/CXCR7/CXCR4 and other signaling pathways (such as the p38 MAPK pathway, the PI3K/mTOR pathway, the STAT3 signaling, and metalloproteinases MMP-9 and MMP-2) is more complicated. The function of CXCR7 is also involved in modulating tumor microenvironment, tumor cell migration and apoptosis. Understanding these complex interactions will provide insight in drug design targeting the CXCR7 as potential anticancer therapy.

Melatonin in Pregnancy: Effects on Brain Development and CNS Programming Disorders

Melatonin is an important neuroprotective factor and its receptors are expressed in the fetal brain. During normal pregnancy, maternal melatonin level increases progressively until term and is highly transferred to the fetus, with an important role in brain formation and differentiation. Maternal melatonin provides the first circadian signal to the fetus. This indolamine is also produced de novo and plays a protective role in the human placenta. In pregnancy disorders, both maternal and placental melatonin levels are decreased. Alteration in maternal melatonin level has been associated with disrupted brain programming with long-term effects. Melatonin has strong antioxidant protective effects directly and indirectly via the activation of its receptors. The fetal brain is highly susceptible to oxygenation variation and oxidative stress that can lead to neuronal development disruption. Based on that, several approaches have been tested as a treatment in case of pregnancy disorders and melatonin, through its neuroprotective effect, has been recently accepted against fetal brain injury. This review provides an overview about the protective effects of melatonin during pregnancy and on fetal brain development.

Organ Preference of Cancer Metastasis and Metastasis-Related Cell Adhesion Molecules Including Carbohydrates

This review starts on one of our special interests, the organ preference of metastasis. We examined data on 1,117 autopsy cases and found that the organ distribution of metastasis of cancers of the lung, pancreas, stomach, colon, rectum, uterine cervix, liver, bile duct, and esophagus involved the lung, liver, adrenal gland, bone/bone marrow, lymph node, and pleura/peritoneum. Cancers of the kidney, thyroid, ovary, choriocarcinoma, and breast, however, manifested different metastatic patterns. The distribution of leukemia and lymphoma metastases was quite different from that of epithelial cancers. On the basis of experimental studies, we believe that the anatomical-mechanical hypothesis should be replaced by the microinjury hypothesis, which suggests that tissue microinjury induced by temporal tumor cell embolization is crucial for successful metastasis. This hypothesis may actually reflect the so-called inflammatory oncotaxis concept. To clarify the mechanisms underlying metastasis, we developed an experimental model system of a rat hepatoma AH7974 that embraced substrate adhesiveness. This model did not prove a relationship between substrateadhesion potential and metastatic lung-colonizing potential of tumor cells, but metastatic potential was correlated with the expression of the laminin carbohydrate that was recognized by Griffonia (Bandeiraea) simplicifolia isolectin G4. Therefore, we investigated the relationship between carbohydrate expression profiles and metastasis and prognosis. We indeed found an intimate relationship between the carbohydrate expression of cancer cells and the progression of malignant tumors, organ preference of metastasis, metastatic potential of tumor cells, and prognosis of patients.

Heat Shock Factor 1-Regulated miRNAs Can Target Huntingtin and Suppress Aggregates of Mutant Huntingtin

Background: Heat shock factor 1 (HSF1) is the master regulator of chaperone network in mammalian cells and can protect cells from adverse effects of misfolded proteins by rapidly inducing expression of multiple heat shock proteins (HSPs) and other cytoprotective proteins. HSF1 also regulates transcription of microRNAs (miRNAs) in heat shock-dependent manner and these miRNAs are likely to regulate diverse cellular processes by acting as downstream effectors of HSF1. Methods: The study was aimed at understanding the effect of HSF1-regulated miRNAs on huntingtin expression and Huntington’s Disease (HD) pathogenesis, if any. The cumulative effect of all HSF1-regulated miRNAs on huntingtin expression was measured by quantitative real-time PCR and luciferase reporter assay and effect of miRNAs on mutant huntingtin aggregates was determined by aggregate counting assay. Results: Our study reveals that HSF1-regulated miRNAs cumulatively target huntingtin and reduce its expression in HD cell model. We also identify 4 huntingtin-targeting miRNAs viz. miR-125b, miR-146a, miR-150 and miR-214 as candidate miRNAs responsible for observed inhibitory effect of HSF1 on huntingtin expression. We further demonstrate that HSF1-regulated miRNAs together can suppress aggregates of mutant huntingtin in cell model of HD. Conclusion: We conclude that the protective effect of HSF1 in the context of HD is a consequence of synergistic induction of HSPs and HSF1-regulated huntingtin-targeting miRNAs. Moreover, the suppressive effect of HSF1-regulated miRNAs on mutant huntingtin aggregates indicates their potential as therapeutic agents for the treatment of HD.

Drug-Loaded Nanocarriers in Tumor Targeted Drug Delivery

Background: Cancer cells are more susceptible than normal cells to the effect of chemotherapeutic agents and most of the anticancer drugs can cause harm to the normal cells. Optimum dose and frequency are both important factors in the persistence of cancer cells during cancer chemotherapy. Now attempts have been focusing on efforts to kill cancer cells by more specific targeting while sparing the normal cells by drug loaded nanocarriers.

Methods: We review technical papers and other articles related to nanoparticles, which have been developed as effective target specific strategies for cancer treatment, acting as nanocarriers and also as active agents.

Results: This review will allow to gain a more general view of the various drug loaded nanocarriers which offers a predominantly unique set of chemical, physical and photonic properties for better drug delivery to the tumor tissues based on morphological and functional differences between normal and tumor tissues.

Conclusion: Nanoparticulate delivery systems in cancer therapies provide better penetration of therapeutic and diagnostic substances with the cancerous tissue in comparison to conventional cancer therapies. Thus nanocarriers can be used for strategic development of novel drug delivery systems and reformulating existing drugs to enhance effectiveness.

Management of Ovarian Cancer In Younger Women

Background: Ovarian Cancer is a broad spectrum of diseases comprising several subtypes. Three major categories in younger women are germ cell tumor, sex cord stromal tumor and epithelial ovarian neoplasia.

Objective: literature search was for an update on management of ovarian cancer in young women.

Context: Germ cell tumor is suspected in young girls presenting with solid ovarian neoplasm as abdominal mass, discomfort, dyspnea or pain abdomen. Preoperative evaluation should include thorough clinical examination with biochemical profile tumor markers and imaging techniques. When prepubertal girls present with precocious puberty, clitoromegaly, development of secondary sexual character, one should suspect juvenile granulosa theca cell tumor. Often serum beta inhibin is elevated in these cases. Young women are not immune to other tumors. Surgery should be fertility sparing, salphingo -oopherectomy, omentectomy, peritoneal cytology, retro peritoneal lymphadenectomy whenever indicated. Except Stage I A puredysgerminoma, Stage IA grade 1 immature teratoma, Stage IA /B grade 1 epithelial ovarian carcinoma, all other histopathological types irrespective of the stage of the disease require adjuvant chemotherapy.

Conclusion: Girls, young women can have ovarian cancer conservative therapy. However treatment needs to be individualized. Except stage IA disease all other patient require adjuvant chemotherapy apart from fertility sparing surgery.

Management of Gestational Trophoblastic Diseases-An Update

Introduction: Gestational trophoblastic disease is a spectrum of neoplastic abnormalities arising from fetal trophoblastic tissue. The range of the diseases in this group varies from relatively benign Hydatidifom mole (complete and partial mole) to highly malignant choriocarcinoma.

Methods: We have reviewed the available literature and discussed the management and follow up based on the current understanding of the natural history, extent and the prognosis of the disease.

Key observations: Depending on the underlying pathology the disease can subside, progress or even metastasize and lead to death, if left untreated. The treatment of the disease is relatively simple and the disease is highly curable by single or multi agent chemotherapy. Appropriate and timely treatment not only saves the women from morbidity and death but also can help preserve their fertility.

Conclusions: Management of Gestational disease should ideally be done in a specialized multi-disciplinary environment and the outcome of treatment in majority of the cases is very satisfactory.

Angiogenesis Markers in Gynecological Tumors and Patents for Anti- Angiogenic Approach: Review

The formation of a tumor-associated vascular network is an important step in understanding the stages of tumor progression. This review aims to highlight the main markers of induction, proliferation and inhibition of angiogenesis, as well as the quantification of microvessel density, correlated with preclinical and clinical research in gynecologic cancers and also discussed related patents. Studies show that in the most advanced cases of gynecological cancers, biomarkers such as VEGF (Vascular Endothelial Growth Factor), MMP (Matrix Metalloproteinase), CD105 (Endoglin), TIMP (tissue inhibitors of metalloproteinases) and VASH (Vasohibin) are more expressed compared to healthy individuals. Continuous evaluation of these biomarkers in cancer cases could serve in the future as a basis for development of new therapeutic approaches, leading to a good response to cancer treatment, and thus increase survival of cancer patients.