Wilms' Tumour

Wilms Tumor and Consanguinity: A Case Report

Introduction: Wilms tumor, the second most common malignancy in childhood, is associated with hypertension in half the cases, but associated consanguinity rarely comes across, and no direct association between the incidence of nephroblastoma and consanguinity has been noted in current literature.

Case Presentation: We present a rare case of Wilms tumor in a patient with consanguineous parents. The patient is a 4-year-old female that presented with colicky abdominal pain associated with an abdominal mass, fever over one month and hypertension. There were no congenital anomalies or urinary symptoms. Both parents are first-degree relatives. The patient underwent surgery, and histopathology confirmed a diagnosis of Wilms tumor. The postoperative course was uneventful, and chemotherapeutic treatment was initiated.

Conclusion: The findings in our case highlight a possible causal relationship between Wilms Tumor and consanguinity. There is little published about this, and Wilms's relative risk in consanguineous marriage is unknown. This relationship warrants further research.

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

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

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

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

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

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

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

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

A Prognostic Nomogram for Predicting Overall Survival in Pediatric Wilms Tumor Based on an Autophagy-related Gene Signature

Background: Wilms Tumor (WT) is the most common primary renal malignancy in children. Autophagy plays dual roles in the promotion and suppression of various cancers.

Objective: The goal of our study was to develop a novel autophagy-related gene (ARG) prognostic nomogram for WT.

Methods: The Cancer Genome Atlas (TCGA) database was used. We screened the expression profiles of ARGs in 136 WT patients. The differentially expressed prognostic ARGs were evaluated by multivariate Cox regression analysis and survival analysis. A novel prognostic nomogram based on the ARGs and clinical characteristics was established using multivariate Cox regression analysis.

Results: First, 69 differentially expressed ARGs were identified in WT patients. Then, multivariate Cox regression analysis was used to determine 4 key prognostic ARGs (CC3CL1, ERBB2, HIF-α and CXCR4) in WT. According to their ARG expression levels, the patients were clustered into high- and low-risk groups. Next, survival analysis indicated that high-risk patients had significantly poorer overall survival than low-risk patients. The results of functional enrichment analysis suggested that autophagy may play a tumor-suppressive role in the initiation of WT. Finally, a prognostic nomogram with a Harrell's concordance index (C-index) of 0.841 was used to predict the survival probability of WT patients by integrating clinical characteristics and the 4-ARG signature. The calibration curve indicated its excellent predictive performance.

Conclusion: In summary, the ARG signature could be a promising biomarker for monitoring the outcomes of WT. We established a novel nomogram based on the ARG signature, which accurately predicts the overall survival of WT patients.

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.

Alport Syndrome: A Comprehensive Review on Genetics, Pathophysiology, Histology, Clinical and Therapeutic Perspectives

Background: Alport syndrome (AS) is a disease caused by mutations in COL4A3, COL4A4 or COL4A5, the genes that encode distinct chains of type IV collagen. The vast majority of cases present as an inherited disorder, although de novo mutations are present in around 10% of the cases.

Methods: This non-systematic review summarizes recent evidence on AS. We discuss the genetic and pathophysiology of AS, clinical manifestations, histopathology, diagnostic protocols, conventional treatment and prognostic markers of the disease. In addition, we summarize experimental findings with novel therapeutic perspectives for AS.

Results: The deficient synthesis of collagen heterotrimers throughout the organism leads to impaired basement membranes (BM) in several organs. As a result, the disease manifests in a wide range of conditions, particularly renal, ocular and auricular alterations. Moreover, leiomyomatosis and vascular abnormalities may also be present as atypical presentations. In this framework, diagnosis can be performed based on clinical evaluation, skin or renal biopsy and genetic screening, the latter being the gold standard. There are no formally approved treatments for AS, even though therapeutic options have been described to delay disease progression and increase life expectancy. Novel therapeutic targets under pre-clinical investigation included paricalcitol, sodium-glucose co-transporter- 2 inhibitors, bardoxolone methyl, anti-microRNA-21 oligonucleotides, recombinant human pentraxin-2, lysyl oxidase-like-2 blockers, hydroxypropyl-b-cyclodextrin, sodium 4-phenylbutyrate and stem cell therapy.

Conclusion: AS is still a greatly under and misdiagnosed disorder. The pathophysiology is still not fully understood and genetics of the disease also have some gaps. Up to know, there is no specific and effective treatment for AS. Further studies are necessary to establish novel and effective therapeutic protocols.

The Clinical Characteristics and Survival Profiles of Wilms Tumor in the United Arab Emirates: A Single-center Retrospective Analysis

Background: Wilms Tumor (WT) is the most common pediatric kidney tumor, yet the disease has variable clinical characteristics and prognostic outcomes across different populations.

Objective: This study aims to review the clinical characteristics and survival outcomes of children with WT who have received treatment at Dubai Hospital, UAE.

Methods: A retrospective study was conducted involving the medical records of confirmed WT children (aged < 14 years) who had received treatment between 2013 and 2018. Diagnosis should have been established based on the histopathological examination of operable tumors and needle biopsy for inoperable tumors. The Société Internationale d’Oncologie Pédiatrique (SIOP) WT 2001 protocol was used for patient management, and the UMBRELLA SIOP–RTSG 2016 Wilms tumor pathology and molecular biology protocol was used for histopathologic classification and clinical staging. The presenting sign and symptoms, the findings of diagnostic imaging techniques, histological grading, the received treatments, and follow-up outcomes were collected and analyzed. Kaplan-Meier survival analysis was used to carry out the survival analysis.

Results: Ten children were diagnosed with WT (median age of 3.40 years, 60% males). All patients presented with abdominal masses without prominent pain. Synchronous bilateral lesions were found at diagnosis in one patient and metastatic lesions in three patients. Four children were discharged against medical advice; five received treatment according to the SIOP WT 2001 regimen, while the remaining patient was managed in the United States according to the National Wilms Tumor Study Group (NWTSG) protocol. The overall 6-year and relapse-free survival rates were 90% and 80%, respectively.

Conclusion: The clinical characteristics and managemental outcomes of children presenting with WT are promising, possibly owing to adopting the SIOP protocol. Considering the small sample size, more large-scale, nation-wide studies are warranted.

Epigenetic Modifications in Acute Lymphoblastic Leukemia: From Cellular Mechanisms to Therapeutics

Background: Epigenetic modification pattern is considered as a characteristic feature in blood malignancies. Modifications in the DNA methylation modulators are recurrent in lymphoma and leukemia, so that the distinct methylation pattern defines different types of leukemia. Generally, the role of epigenetics is less understood, and most investigations are focused on genetic abnormalities and cytogenic studies to develop novel treatments for patients with hematologic disorders. Recently, understanding the underlying mechanism of acute lymphoblastic leukemia (ALL), especially epigenetic alterations as a driving force in the development of ALL opens a new era of investigation for developing promising strategy, beyond available conventional therapy.

Objective: This review will focus on a better understanding of the epigenetic mechanisms in cancer development and progression, with an emphasis on epigenetic alterations in ALL including, DNA methylation, histone modification, and microRNA alterations. Other topics that will be discussed include the use of epigenetic alterations as a promising therapeutic target in order to develop novel, well-suited approaches against ALL.

Conclusion: According to the literature review, leukemogenesis of ALL is extensively influenced by epigenetic modifications, particularly DNA hyper-methylation, histone modification, and miRNA alteration.

Delivery Systems for RNA Interference Therapy: Current Technologies and Limitations

In recent years, RNA interference technology has been extensively studied for its therapeutic potential against a wide variety of diseases. It aims to silence the expression of undesired genes associated with the target disease by the administration of RNA interference agents. However, these agents (nucleic acids) are unstable in the circulatory system and lack target specificity. Drug delivery systems are, therefore, crucial for the successful practice of the technique. A wide array of delivery systems has been developed to conquer these challenges, such as viral vectors, inorganic drug carriers, polymeric carriers and lipid-based carriers, with, however, significant limitations. In addition to the existing technologies, novel, innovative drug delivery systems, such as the configurable xenobot, are emerging at a rapid pace and have the potential to take the realm of biomedicine to the next level. This review summarizes technical difficulties in the development of drug delivery systems and current technologies developed for delivering RNAi agents with a discussion on their limitations.

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.

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.

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.

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.

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.

Influence of Aldo-keto Reductase 1C3 in Prostate Cancer - A Mini Review

Background: Aldo-keto reductase 1C3 (AKR1C3) is an important oxidoreductase with multiple substrates, that are involved in producing extra-testicular androgens. Its activity is influenced by environmental exposures, as well as by genetic variants. These genetic variants could therefore produce variable testosterone levels and subsequent androgen receptor (AR) activation. This could lead to differential downstream production of the prostate-specific antigen (PSA). As PSA level is used for clinical evaluation of the prostate, these variations could impact prostate cancer (PC) diagnosis, as well as PC management outcomes. This review brings together information with regards to key functions of this enzyme, its relevance in PC, its transcriptional regulation, clinical aspects associated with genetics, differential regulation in cancer and cancer progression, and the types of AKR1C3 inhibitors with future therapeutic value.

Conclusion: Based on these discussions, hypotheses are forwarded for future applicability of this enzyme and its genetic variants in transformational medical practices in PC. Options for the use of personalised AKR1C3 inhibitor drugs for late stage PC are also discussed.

Exploring Mechanisms of MicroRNA Downregulation in Cancer

MicroRNAs (miRNAs) are short, non-coding RNAs that regulate gene expression at a posttranscriptional level. Each miRNA controls the expression of multiple messenger RNAs (mRNAs) and their dysregulation has been implicated in multiple cancer phenotypes. While some miRNAs are upregulated, global downregulation of miRNA expression is often the rule in cancer. A multitude of potential mechanisms drive aberrant miRNA expression in cancer; miRNA coding regions can harbour genomic defects including mutations, amplifications or deletions, and some miRNAs are broadly repressed by transcription factors such as Myc or have epigenetic modifications to their promoter regions such as hypermethylation of CpG islands. Additionally, the suppression of components of the miRNA processing machinery has been shown to reduce mature miRNA expression and contribute to the malignant phenotype. Understanding the mechanisms driving miRNA downregulation is important in uncovering the critical and complex role of miRNAs in cancer biology. This review will outline the multiple mechanisms by which cancer cells suppress miRNA expression.

Intrinsic Disorder in Male Sex Determination: Disorderedness of Proteins from the Sry Transcriptional Network

Sex differentiation is a complex process where sexually indifferent embryo progressively acquires male or female characteristics via tightly controlled, perfectly timed, and sophisticatedly intertwined chain of events. This process is controlled and regulated by a set of specific proteins, with one of the first steps in sex differentiation being the activation of the Y-chromosomal Sry gene (sexdetermining region Y) in males that acts as a switch from undifferentiated gonad somatic cells to testis development. There are several key players in this process, which constitute the Sry transcriptional network, and collective action of which governs testis determination. Although it is accepted now that many proteins engaged in signal transduction as well as regulation and control of various biological processes are intrinsically disordered (i.e., do not have unique structure and remain unstructured, or incompletely structured, under physiological conditions), the roles and profusion of intrinsic disorder in proteins involved in the male sex determination have not been accessed as of yet. The goal of this study is to cover this gap by analyzing some key players of the Sry transcriptional network. To this end, we employed a broad set of computational tools for intrinsic disorder analysis and conducted intensive literature search in order to gain information on the structural peculiarities of the Sry networkrelated proteins, their intrinsic disorder predispositions, and the roles of intrinsic disorder in their functions.

Epi-Drugs and Epi-miRs: Moving Beyond Current Cancer Therapies

Epigenetic modifications determine phenotypic characteristics in a reversible, stable and genotype-independent manner. Epigenetic modifications mainly encompass CpG island methylation and histone modifications, both being important in the pathogenesis of malignancies. The reversibility of epigenetic phenomenon provides a suitable therapeutic option that is reactivation of epigenetically silenced tumor-suppressor genes. Inhibition of DNA methyltransferase, histone deacetylase and Aurora B kinase, individually or collectively, could feasibly prevent or reverse the impact of epigenetic silencing. MicroRNAs [miRNAs] are an important layer of epigenetic controlling of gene expression, and serve as diagnostic and prognostic biomarkers as well as treatment targets for several types of cancer. miRNAs are involved inepigenetically silencing or activation of genes, tumor suppressor genes and oncogenes, and their modulation opens new horizons for designing novel cancer therapeutic agents.

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.

Structural and Functional Characterization of the Proteins Responsible for N⁶-Methyladenosine Modification and Recognition

RNA modification, involving in a wide variety of cellular processes, has been identified over 100 types since 1950s. N⁶-methyladenosine (m6A), as one of the most abundant RNA modifications, is found in several RNA species and predominantly located in the stop codons, long internal exons as well as 3’UTR. It was reported that m6A modification preferentially appears after G in the conserved motif RRm6ACH (R = A/G and H = A/C/U). There are two families of enzymes responsible for maintaining the balance of m6A modification: m6A methyltransferases and demethylases, which add and remove methyl marks for adenosine of RNA, respectively. METTL3 complex, the m6A methyltransferases, and two kinds of demethylases including Fat mass and obesity-associated protein (FTO) and alkylation protein AlkB homolog 5 (ALKBH5) are characterized thus far. Besides the “writers” and “erasers”, m6A specific recognizing proteins, such as the YTH (YT521-B homology) domain family proteins, also have attracted significant attention. Herein, we focus on the recent progress in understanding the biological/biochemical functions and structures of proteins responsible for the m6A modification and recognition. Detailed analyses of these important proteins are essential for the further study of their biological function and will also guide us in designing more potent and specific small-molecule chemical inhibitors for these targets.

Melatonin Regulates Angiogenic Factors under Hypoxia in Breast Cancer Cell Lines

Angiogenesis is the process of new blood vessel formation, regulated by a number of pro- and antiangiogenic factors and usually begins in response to hypoxia. Exogenous administration of melatonin has shown numerous anti-tumor effects and appears to inhibit tumor angiogenesis. However, many factors involved in the anti-angiogenic effect of melatonin are still under investigation. Here, we evaluate the effects of melatonin on cell viability and expression of angiogenic factors in MCF-7 and MDA-MB-231 breast cancer cells under hypoxic conditions. Cell viability was investigated by MTT and gene and protein expression of the hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF-A) were verified by qPCR and immunocytochemistry after melatonin treatment (1 mM) under hypoxic conditions. Additionally, a protein array with 20 different cytokines/factors was performed on tumor cell lysates. The results showed that 1 mM of melatonin reduced the viability of MCF-7 and MDA-MB-231 cells (p < .05). This treatment also decreased both gene and protein expression of HIF-1α and VEGF-A under hypoxic conditions (p < .05). Among the proteins evaluated by protein array, melatonin treatment during hypoxia reduced VEGF-C, VEGFR receptors (VEGFR2 and VEGFR3), matrix metalloproteinase 9 (MMP9) and Angiogenin in MCF-7 cells. In MDA-MB-231 cells, a significant decrease was observed in VEGFR2, epidermal growth factor receptor (EGFR) and Angiogenin (p < .05). Taken together, these results showed that melatonin acts in the regulation of angiogenic factors in breast tumor cells and suggests an anti-angiogenic activity, particularly under hypoxic conditions.

Contextualizing the Genes Altered in Bladder Neoplasms in Pediatric and Teen Patients Allows Identifying Two Main Classes of Biological Processes Involved and New Potential Therapeutic Targets

Research on bladder neoplasms in pediatric and teen patients (BNPTP) has described 21 genes, which are variously involved in this disease and are mostly responsible for deregulated cell proliferation. However, due to the limited number of publications on this subject, it is still unclear what type of relationships there are among these genes and which are the chances that, while having different molecular functions, they i) act as downstream effector genes of well-known pro- or anti- proliferative stimuli and/or interplay with biochemical pathways having oncological relevance or ii) are specific and, possibly, early biomarkers of these pathologies. A Gene Ontology (GO)-based analysis showed that these 21 genes are involved in biological processes, which can be split into two main classes: cell regulation-based and differentiation/development-based. In order to understand the involvement/ overlapping with main cancer-related pathways, we performed a meta-analysis dependent on the 189 oncogenic signatures of the Molecular Signatures Database (OSMSD) curated by the Broad Institute. We generated a binary matrix with 53 gene signatures having at least one hit; this analysis i) suggests that some genes of the original list show inconsistencies and might need to be experimentally re- assessed or evaluated as biomarkers (in particular, ACTA2) and ii) allows hypothesizing that important (proto)oncogenes (E2F3, ERBB2/HER2, CCND1, WNT1, and YAP1) and (putative) tumor suppressors (BRCA1, RBBP8/CTIP, and RB1-RBL2/p130) may participate in the onset of this disease or worsen the observed phenotype, thus expanding the list of possible molecular targets for the treatment of BNPTP.

The Past, Present and Future Subclassification of Patients with Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is characterized as a heterogeneous disease where the patients are sub grouped according to several classification systems and mutational analyses. Diagnosis of AML is based on identification of the specific myeloid cell initiating the disease, quantification of immature blasts in bone marrow and peripheral blood, as well as detection of mutations and translocations. The heterogeneity of AML is caused by a block in differentiation that may occur in any of the different myeloid cell populations. These undifferentiated cells also harbor an increased proliferation potential that leads to accumulation of immature leukemic cells. The current development of more sensitive and less labor intensive analysis methods has led classification of patients from being a system based on morphology of the leukemic cells to being more sophisticated, detecting translocations and small mutations found in the whole leukemic clone or in a minor subclone. This review aims to describe the most common classification systems of AML, including frequently occurring translocations, mutations and epigenetic alterations, as well as describe traditional and novel methods for diagnosis and analysis of these patients.

Novel Drug Therapies for Fertility Preservation in Men Undergoing Chemotherapy: Clinical Relevance of Protector Agents

Cancer has been affecting a growing number of children, adolescents and adult males in reproductive age. Male reproductive potential is adversely affected by chemotherapeutic drugs and patients are at risk for prolonged infertility. Fertility recovery is related to the chemotherapeutic agent and dosage used, being thus difficult to predict. As a result, there is a strong need to identify a natural or synthetic compound that is able to preserve male fertility without interfering with the efficacy of the chemotherapeutic regimen. New procedures, as well as several drugs, are being investigated to assess their efficiency in protecting male reproductive functions from the chemotherapy side-effects. This review provides an overview of the wide range of chemotherapeutic drugs regularly used in cancer treatment and their detrimental effects on male fertility. In addition, it also assesses the existing protector agents for male fertility and their usefulness in preserving and protecting male reproductive functions exposed to chemotherapeutics. Several protector agents for male fertility are being studied, and results are promising. Nonetheless, further research must be implemented to identify a supplemental therapy that addresses the multiple side effects of chemotherapy on male reproductive function. Until such therapy is discovered, it is fundamental that all fertility preservation options are discussed with patients, before treatment is initiated, to assure parenthood.

Interventional Radiology in Paediatrics

As in adult practice, there is a growing role for paediatric interventional radiology expertise in the management of paediatric pathologies. This review is targeted for clinicians who may refer their patients to paediatric interventional radiology services, or who are responsible for patients who are undergoing paediatric interventional radiology procedures. The article includes a brief overview of the indications for intervention, techniques involved and the commonest complications. Although some of the procedures described are most commonly performed in a tertiary paediatric centre, many are performed in most Children’s hospitals.

microRNAs: Promising Biomarkers and Therapeutic Targets of Acute Myocardial Ischemia

microRNAs (miRNAs), small non-coding RNA molecules that act as negative regulators of gene expression, are involved in a wide range of biological functions and control several cellular processes. This review illustrates miRNA regulation and function in tissue response to acute ischemia, focusing on miRNA role in acute myocardial infarction and describing a subset of miRNAs de-regulated upon cardiac ischemia. These miRNAs may represent “master ischemic” miRNAs, playing a pathogenetic role in one of the different components of tissue response to ischemia. Moreover, circulating miRNAs correlated to myocardial infarction and examples of miRNA involvement in ischemic diseases different from cardiac ischemia are also discussed. The identification of specific miRNAs as key regulators of cell biology has opened new clinical avenues, and may allow new diagnostic and/or prognostic tools development, as much as innovative therapeutic strategies. Two paradigmatic reports, in which miRNAs have been targeted to improve cardiac function in pre-clinical models of myocardial infarction, are described in detail and confirmed the efficacy of these strategies.

Mesothelioma - Update on Management

Mesothelioma is an often fatal cancer arising from the lining of pleura, peritoneum, pericardium and tunica vaginalis (of the testis). In the past decade, investigators have met with limited or minimal success in demonstrating improvements in survival compared to supportive care or observation. Radical surgery such as extrapulmonary pleurectomy is associated with perioperative mortality rates of 6-30% by different institutions, compared to 3% with extended pleurectomy and decortication. Talc pleurodesis is preferred over video-assisted thorascopic partial pleurectomy in the setting of pleural effusion due to fewer complications and shorter hospital stay. To spare normal tissues, radiotherapy with IMRT (intensity-modulated radiation therapy) technique should be used in all cases. Reirradiation with proton particles for recurrent disease is being investigated. The ongoing PIT (Prophylactic Irradiation of Tracts) study will explore the effectiveness of radiotherapy to prevent or delay recurrent nodules on the chest wall following invasive chest wall intervention. The literature on this question is varied and inconclusive. Pemetrexed-cisplatin is currently the standard as first line therapy for malignant pleural mesothelioma in accordance with a phase III study showing improved quality of life and survival. In 2012, a new promising biomarker, fibulin-3 was reported in all mesothelioma sites. Fibulin-3 is a superior prognosticator compared with mesothelin and can be used to monitor tumor response. Mesothelin, the cell-surface glycoprotein, has become the primary target for immunotherapy. SS1P is a recombinant antimesothelin immunotoxin which induces a durable response in all mesotheliomas.

Therapeutic Agents Based on DNA Sequence Specific Binding

DNA interactive agents have been used in the clinical setting for the treatment of cancer since the beginning of modern-era chemotherapy. Despite a shift of focus towards molecular targeted therapy, DNA remains a critical macromolecular target for anti-cancer intervention and the next generation of agents must conform to the optimum combination of increased therapeutic activity and reduced off-target toxicity. We evaluate the potential of non-covalent DNA binding small molecules as “gene-control” agents, exploiting inherent or engineered sequence selectivity, to target critical genomic sequences. In addition we review examples of natural products and synthetic derivatives that exert their activity through sequence specific DNA-covalent modification.

Editorial from Guest Editor (DNA Methylation: A Target for Current and Future Therapies?)

T Cell Tuning for Tumour Therapy: Enhancing Effector Function and Memory Potential of Therapeutic T cells

The genetic engineering of T cells can lead to enhanced immune-mediated tumour destruction and harbors a great potential for the treatment of cancer. Recent efforts have centered on the design of receptors to re-direct the specificity of T cells towards tumour antigens by means of viral gene transfer. This strategy has shown great success in a number of phase one clinical trials. However, there are still challenges to overcome. On the one hand, T cell function can be further improved to optimize the therapeutic outcome. On the other hand, so called safety switches are required to deal with possible on and off target toxicities. In this review, we will give a brief summary of the success and risks of T cell gene therapy before discussing in detail current strategies to enhance effector function, persistence and safety of adoptively transferred T cells.

Neonatal Hypertension: An Underdiagnosed Condition, A Review Article

Advances in neonatology and intensive monitoring has increased our ability to identify and measure blood pressure in sick premature and term infants and this has contributed to an increased awareness of hypertension in the NICU. A few recent studies done by Zubrow and others have offered many new information on blood pressure values over the first month after birth and on other many intrinsic and extrinsic factors that can cause effects on the blood pressure in the neonatal period. There are no definite cut off for labelling hypertension in newborn period and also doubts are there on the pharmacological treatment. This is a field in neonatology which is least studied hence requires further inquiry. This review article will cover several aspects of neonatal hypertension like definition, normotensive data, etiology, clinical characteristics, diagnostic modalities, treatment choices and long term effect of these newborns.

A Systematic Review of Selected Musculoskeletal Late Effects in Survivors of Childhood Cancer

Survivors of childhood cancer are at risk for treatment-related musculoskeletal late effects. Early detection and orthopedic intervention can help ameliorate musculoskeletal late effects and prevent subsequent complications. This systematic review summarizes the literature describing associations between cancer, its treatment, and musculoskeletal late effects. We searched PubMed and Web of Science for English language articles published between January 1970 and December 2012. The search was limited to investigations with at least 15 participants and conducted at least 2 years after completion of therapy for childhood, adolescent, or young adult cancer. Some late skeletal effects, including low bone mineral density, osteonecrosis, slipped capital femoral epiphyses, oncogenic rickets, and hormonerelated growth disturbances have been previously reviewed and were excluded, as were outcomes following amputation and limb-salvage procedures. Of 2347 references identified, 30 met inclusion criteria and were retained. An additional 54 studies that met inclusion criteria were found in reference lists of retained studies. Of 84 studies, 60 focused on associations between radiotherapy, six between chemotherapy, and 18 between surgery and musculoskeletal late effects. We found that younger age, higher radiation dosage, and asymmetric or partial bone radiation volume influences the effects of radiation on the musculoskeletal system. Methotrexate and vincristine are associated with long-term muscular strength and flexibility deficits. Laminectomy and chest wall resection are associated with spinal malalignment, and enucleation is associated with orbital deformities among survivors. Radiotherapy, chemotherapy, and surgery are associated with musculoskeletal late effects independently and additively. Associations are additionally influenced by host and treatment characteristics.

Myocardial Ischemia/Reperfusion Injury: Potential of TRPV1 Agonists as Cardioprotective Agents

Myocardial Ischemia/Reperfusion (I/R) induced injury has widespread detrimental effects partially negating the benefits obtained from early revascularization in Acute Myocardial Infarction. Various complex mechanisms contribute to I/R injury and different agents targeting those specific mechanisms are being studied. Despite continued research and widespread interest, none of them have become incorporated into everyday practice. The TRPV1 (transient receptor potential vanilloid 1) channel is a non selective cation channel predominantly expressed in sensory neurons with the nerve fibers innervating the heart and blood vessels. Multiple studies have demonstrated the importance of the activation of TRPV1 and subsequent release of sensory neurotransmitters in cardioprotection. This review focuses on the role of TRPV1 in prevention of cardiac I/R injury, the work that has been done so far and future implications for TRPV1 agonists as cardioprotective agents.

Clear Cell Renal Cell Cancer Tumor-Propagating Cells: Molecular Characteristics

The present article highlights diverse roles of stem cells in healthy state, oncology and regenerative medicine in comparison to the Clear Cell Renal Cell Carcinoma (ccRCC) “stem cells”. Furthermore, we support the notion of urgent need to change the terminology of “cancer stem cells” into tumor-propagating cells (TPCs), and to diversify terms of kidney stem and kidney progenitor cell. We present the role of normal stem and progenitor cells in kidney development and regeneration in comparison to their markers. Moreover, we would like to introduce a hypothesis about the TPCs origin, and the role epithelial to mesenchymal transition in metastasis. We described current knowledge about various approaches to identification of renal TPCs. Finally, we present future perspectives in respect to current studies.

Renal Cell Carcinoma Cancer Stem Cells as Therapeutic Targets

Although early stage disease detection and treatment options for clear cell renal cell cancer (ccRCC) improved in recent years, prognosis of patients with late stage ccRCC remains poor, mostly due to development of tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors resistance followed by disease progression. Cancer stem cells (ccRCC-CSC) model has focused a significant attention in recent years as a potential explanation for the tumor heterogeneity, drug resistance, disease recurrence and metastasis of ccRCC and other cancers. Cancer stem cells have been proposed to be responsible for tumor initiation, repopulation and growth that cause patients to succumb to renal cancer. Precise identification of ccRCC-CSC populations and definition of hierarchy of cells within ccRCC tumor including tumor initiating cells and tumor progenitor cells will facilitate accurate characterization of drug targets and ultimately contribute to more personalized and effective care. This mini-review discusses the potential strategies to inhibit the signaling pathways underlying stemness in an effort to treat renal cancer. Mechanism that could be exploited as a therapeutic target against drug resistant ccRCC-CSCs is summarized.

Lifestyle Factors and MicroRNAs: A New Paradigm in Cancer Chemoprevention

MicroRNAs (miRNAs) are characterized as small RNA molecules that modulate gene transcription in a posttranslational manner. Functionally, miRNAs play important roles in a diverse number of biological processes, including cell development, differentiation, proliferation, and apoptosis. Consequently, changes in the expression pattern of miRNAs have been associated with multiple human pathologies, including cancer. Based on these alterations, distinct miRNAs can be utilized as markers for cancer risk evaluation or used in tumour detection. Recent evidence has indicated that lifestyle factors, such as nutrition, physical activity, and glycemic control provide health benefits through regulation of miRNA expression. In this review, we provide a concise overview of miRNA regulation, biosynthesis, and their expression patterns in normal and malignant tissue. We then summarize the emerging knowledge of how lifestyle factors, including nutrients, exercise, and hypoglycemic agents modify miRNAs and are involved in cancer prevention. Finally, we conclude by providing recommendation for future investigations into novel agents that can modulate miRNAs and act as chemotherapeutic agents against cancer.

Use of Single Nucleotide Polymorphism Array Technology to Improve the Identification of Chromosomal Lesions in Leukemia

Acute leukemias are characterized by recurring chromosomal and genetic abnormalities that disrupt normal development and drive aberrant cell proliferation and survival. Identification of these abnormalities plays important role in diagnosis, risk assessment and patient classification. Until the last decade methods to detect these aberrations have included genome wide approaches, such as conventional cytogenetics, but with a low sensitivity (5-10%), or gene candidate approaches, such as fluorescent in situ hybridization, having a greater sensitivity but being limited to only known regions of the genome. Single nucleotide polymorphism (SNP) technology is a screening method that has revolutionized our way to find genetic alterations, enabling linkage and association studies between SNP genotype and disease as well as the identification of alterations in DNA content on a whole genome scale. The adoption of this approach for the study of lymphoid and myeloid leukemias contributed to the identification of novel genetic alterations, such as losses/gains/uniparental disomy not visible by cytogenetics and implicated in pathogenesis, improving risk assessment and patient classification and in some cases working as targets for tailored therapies. In this review, we reported recent advances obtained in the knowledge of the genomic complexity of chronic myeloid leukemia and acute leukemias thanks to the use of high-throughput technologies, such as SNP array.

Advances in Immunotherapy of Chronic Myeloid Leukemia CML

Tyrosine kinase inhibitors induce sustained disease remissions in chronic myeloid leukemia by exploiting the addiction of this type of leukemia to the activity of the fusion oncogene BCR-ABL. However, these agents fail to eradicate CML stem cells which are ultimately responsible for disease relapses upon treatment discontinuation. Evidence that the immune system can effectively reject CML stem cells potentially leading to patient cure is provided by the experience with patients receiving allogeneic bone marrow transplantations. Compelling evidence indicates that more modern, antigen-specific immunotherapeutic approaches are also feasible and hold strong potential to be clinically effective. Amongst these, particularly promising is the use of autologous dendritic cells pulsed with antigens or direct application of in vitro transcribed RNA encoding for leukemia-associated antigens, since this approach allows to circumvent HLA-restriction of the leukemia-associated T cell epitopes that have been eventually identified. Combining these strategies with monoclonal antibodies, such as anti-CTLA-4 or anti-PD-1, may help to obtain even stronger immune responses and better clinical results. This narrative review addresses this topic by focusing in particular on the cell-based immunotherapeutic strategies for CML and on the issue of the leukemia-associated antigens to be selected for targeting.

Alternative Splicing in Chronic Myeloid Leukemia (CML): A Novel Therapeutic Target?

Although the imatinib based therapy of chronic myeloid leukemia (CML) represents a triumph of medicine, not all patients with CML benefit from this drug due to the development of resistance and intolerance. The interruption of imatinib treatment is often followed by clinical relapse, suggesting a failure in the killing of residual leukaemic stem cells. There is need to identify alternative selective molecular targets for this disease and develop more effective therapeutic approaches. Alternative pre-mRNA splicing (AS) is an epigenetic process that greatly diversifies the repertoire of the transcriptome. AS orchestrates interactions between various types of proteins and between proteins and nucleic acids. Changes caused by individual splicing events in the cells are small, however, “splicing programs” typically react to these individual changes with considerable effects in cell proliferation, cell survival, and apoptosis. Current evidence suggests a pivotal role of AS in leukemias, particularly in myelodisplastic syndrome (MDS) and chronic lymphocyte leukemia (CLL). From these studies and studies in other malignances, it is clear that splicing abnormalities play a significant role in malignant transformation. Evaluation of AS events in CML can be used to identify novel disease markers and drugsensitive targets to overcome the limits of the small molecule inhibitors currently used for treating patients with CML. The use of aberrant splice variants as disease markers has been reported, however, little is known about the use of splicing abnormalities as drug targets in CML. Herein we discuss potential therapeutic approaches that can be used to target splicing abnormalities in CML.

HtrA Protease Family as Therapeutic Targets

The HtrA proteases degrade damaged proteins and thus control the quality of proteins and protect cells against the consequences of various stresses; they also recognize specific protein substrates and in this way participate in regulation of many pathways. In many pathogenic bacteria strains lacking the HtrA function lose virulence or their virulence is decreased. This is due to an increased vulnerability of bacteria to stresses or to a decrease in secretion of virulence factors. In some cases HtrA is secreted outside the cell, where it promotes the pathogen’s invasiveness. Thus, the HtrA proteases of bacterial pathogens are attractive targets for new therapeutic approaches aimed at inhibiting their proteolytic activity. The exported HtrAs are considered as especially promising targets for chemical inhibitors. In this review, we characterize the model prokaryotic HtrAs and HtrAs of pathogenic bacteria, focusing on their role in virulence.

In humans HtrA1, HtrA2(Omi) and HtrA3 are best characterized. We describe their role in promoting cell death in stress conditions and present evidence indicating that HtrA1 and HtrA2 function as tumor suppressors, while HtrA2 stimulates cancer cell death induced by chemotherapeutic agents. We characterize the HtrA2 involvement in pathogenesis of Parkinson’s and Alzheimer’s diseases, and briefly describe the involvement of human HtrAs in other diseases. We hypothesize that stimulation of the HtrA’s proteolytic activity might be beneficial in therapies of cancer and neurodegenerative disorders, and discuss the possibilities of modulating HtrA proteolytic activity considering the present knowledge about their structure and regulation.

Cardiovascular Risk Factors, Metabolic Complications, & the Natural Course of CKD in Children

The survival rates of children with advanced chronic kidney disease (CKD) are significantly lower when compared with general pediatric population. As in adults, cardiovascular disease, infectious risks, uremia-related complications, and metabolic derangements contribute to increased morbidity and mortality. The last 30 years have brought significant advances in our understanding of pediatric chronic kidney disease. However, many approaches to management are still based upon findings described in the adult population. In order to optimize our approach to management and treatment, it is necessary to recognize pediatric CKD as an entity separate from adult CKD in its etiology, pathophysiology, and long-term consequences.

Apoptotic Potency of Angiostatic Compounds in the Treatment of Cancer

When tumours outgrow their vascular supply, they become hypoxic because of nutrient deficiency. This increases the expression and secretion of proangiogenic factors, like vascular endothelial growth factor (VEGF), leading to the activation of endothelial cells. The activated endothelial cells migrate, proliferate and form new blood vessels, resulting in increased tumour growth. This process is called tumour angiogenesis. Inhibiting tumour angiogenesis and therefore tumour growth is a well known concept in the treatment of cancer, such as hepatocellular carcinoma (HCC). This can be done by endogenous angiogenesis inhibitors, like angiostatin and its derivates. These are known to affect endothelial cell functions including the induction of apoptosis. The impact of these angiostatic factors on the cell is manifold. This also applies for so called small molecules, which affect tyrosine kinases such as receptors or intracellular signal transduction proteins. Other approaches, like monoclonal antibodies, target a single molecule, mainly VEGF, to inhibit receptorbinding and downstream signal transduction. Gene silencing, mainly via RNA interference (RNAi) intervenes on RNAlevel, leading to reduced gene expression and protein secretion. Due to intense research in this field, there is rising evidence that also tumour cells themselves are influenced by angiostatic treatment approaches and the underlying molecular mechanisms are more and more revealed. Here we give a (short) review regarding the pro-apoptotic potency of antiangiogenic compounds like angiostatic molecules, sequestering antibodies, small molecules and RNAi approaches targeting endothelial and tumour cell survival to inhibit angiogenesis and tumour growth.

Apoptosis Modulated by Oxidative Stress and Inflammation During Obstructive Nephropathy

Kidney apoptosis and fibrosis are an inevitable outcome of progressive chronic kidney diseases where congenital obstructive nephropathy is the primary cause of the end-stage renal disease in children, and is also a major cause of renal failure in adults. The injured tubular cells linked to interstitial macrophages, and myofibroblasts produce cytokines and growth factors that promote an inflammatory state in the kidney, induce tubular cell apoptosis, and facilitate the accumulation of extracellular matrix. Angiotensin II plays a central role in the renal fibrogenesis at a very early stage leading to a rapid progression in chronic kidney disease. The increasing levels of angiotensin II induce pro-inflammatory cytokines, NF-κB activation, adhesion molecules, chemokines, growth factors, and oxidative stress. Furthermore, growing evidence reports that angiotensin II (a pro-inflammatory hormone) increases the mitochondrial oxidative stress regulating apoptosis induction. This review summarizes our understanding about possible mechanisms that contribute to apoptosis modulated by inflammation and/or oxidative stress during obstructive nephropathy. The new concept of antiinflammatory tools regulating mitochondrial oxidative stress will directly affect the inflammatory process and apoptosis. This idea could have attractive consequences in the treatment of renal and other inflammatory pathologies.

Identification of IL7RA Risk Alleles for Rapid Progression During HIV-1 Infection: A Comprehensive Study in the GRIV Cohort

Interleukin 7 (IL7) is a critical factor for lymphocyte homeostasis. A dysfunction of the IL7/IL7R pathway has previously been described in HIV-1 infection, and promising results were observed in recent analyses of IL7 for therapeutic use in HIV infected individuals. However, further investigations are still warranted to understand the possible roles of this cytokine. Here, we explored whether the IL7 and IL7RA genetic polymorphisms were associated with the progression of HIV infection. We extensively genotyped the IL7 and IL7RA genes in the GRIV (Genomics of Resistance to Immunodeficiency Virus) cohort, composed of patients with extreme progression profiles - long-term non (LTNP) and rapid (RP) progressors -, and in a healthy control group (CTR). Statistical case-control analyses were performed using the Fisher’s exact test, comparing either LTNP vs CTR or RP vs CTR. Three IL7RA SNPs (single nucleotide polymorphisms - rs7701176, rs987106 and rs10491434), but no IL7 SNPs, were significantly associated with rapid disease progression (P<0.01). In a multi-marker analysis focusing on functional variants, a strong association between an IL7RA haplotype and rapid progression was observed (P=5.59x10-3). In summary, our comprehensive genetic study revealed three SNPs and a risk of haplotype associated with rapid progression to AIDS in the IL7RA gene. Interestingly, the haplotype is composed of SNPs previously identified in other inflammatory diseases (e.g., multiple sclerosis) by GWAS and by functional studies. Our results contribute to the growing understanding of the role of IL7/IL7R in HIV disease progression, and more widely, in CD4+ T cell homeostasis.

Opposing Functions for the Wilms Tumor Protein 1 (WT1) in Tumorigenesis

The Wilms tumor 1 (WT1) gene encodes a transcription factor that was among the first tumor suppressor genes to be identified. Dependent on the splice variant, some WT1 isoforms can function as transcriptional regulators, whereas other WT1 proteins are presumably involved in RNA processing. The mechanisms by which WT1 regulates transcription and the identification of bona fide target genes have been difficult to study, which is partially due to the complex nature of the gene and its context specific functions. While the role of WT1 as a tumor suppressor in Wilms tumor is widely accepted, considerable evidence points to an oncogenic function in other tumors. Recent studies have provided new insights into the underlying mechanisms that lead to the development of Wilms tumor. In addition, a conditional Wt1 knockout mouse model and RNAi-mediated screening approaches have uncovered new functions for WT1 in development and tumorigenesis.

Inhibition of Apoptosis in Pediatric Cancer by Survivin

An estimated 17.6 per 100,000 new cases of childhood cancer are diagnosed each year in the United States. The major subtypes of childhood cancer include leukemia, central nervous system tumors, lymphoma, neuroblastoma, rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, Wilms tumor, Germ cell tumors, and other rare tumors. Despite improvements in the diagnosis and treatment of these tumors over the last 30 years, subsets of children still have poor outcomes and many others have significant morbidity. Dysregulation of apoptotic pathways has been shown to contribute to tumor formation as well as resistance to therapy in both pediatric and adult malignancies. Survivin, the smallest member of the inhibitor of apoptosis protein (IAP) family, is highly expressed in diverse cancers and correlates with decreased patient survival. Here, we review the current literature on Survivin expression in pediatric cancer, its relationship to clinical outcome and potential therapeutic options to target this protein in pediatric cancer.

Epigenetic and Genetic Mechanisms of Abnormal 11p15 Genomic Imprinting in Silver-Russell and Beckwith-Wiedemann Syndromes

Fetal growth is a complex process depending on the genetics of the fetus, the availability of nutrients to the fetus, maternal nutrition and various growth factors and hormones of maternal, fetal and placental origin. The IGF system, and more particularly IGF2, is one of the most important endocrine and paracrine growth systems regulating fetal and placental growth (reviewed in [1]). The IGF2 gene is regulated by genomic imprinting and is expressed only from the paternally-inherited allele in most tissues during fetal development and after birth.

Imprinted genes are tightly regulated and are therefore particularly susceptible to changes, including environmental and nutritional changes. Dysregulation of a cluster of imprinted genes, including the IGF2 gene within the 11p15 region, results in two fetal growth disorders (Silver-Russell and Beckwith-Wiedemann syndromes) with opposite growth phenotypes. Those two syndromes are model imprinting disorders to decipher the regulation of genomic imprinting.

Immunotherapy for Myeloproliferative Neoplasms (MPN)

The four major entities that form the group of myeloproliferative neoplasms (MPN) are BCR-ABL positive chronic myeloid leukaemia (CML), chronic idiopathic myelofibrosis (CIMF), essential thrombocythemia (ET) and polycythemia vera (PV). All four are clonal diseases of the haematopoietic stem or precursor cell, they are of a chronic nature and potentially aggravate to myelofibrosis or transform into acute leukaemia. Several strategies are pursued in the treatment of MPN. On the one hand, targeted therapies such as tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib) and JAK2-inhibitors are adopted in MPN as well as rather unspecific treatment with interferon-alpha and with the newer group of immunomodulatory drugs (IMIDs). On the other hand, cellular immunotherapeutical options as allogeneic haematopoietic stem cell transplantation (HSCT) and donor lymphocyte infusion (DLI) are exerted in patients with MPN. Evidence resulting from graft-versus-leukaemia (GvL) effect was the key to develop more specific immunotherapies for patients with haematologic malignancies. In this context, CML is a model for immunotherapeutic approaches, and therefore, vaccination trials using peptides derived from leukaemia-associated antigens (LAA) to stimulate specific T cells are currently under investigation. But also in BCR-ABL-negative MPN, antigens have been identified and immunomodulatory treatment strategies have been performed. All of the current immunotherapeutical options in patients with MPN will be discussed throughout this review.

Production of Retroviral Vectors: Review

Retroviral vectors are presently amongst the most widely used vectors in gene therapy clinical trials to target pathologies of different origins, such as cancers, genetic diseases or neurological disorders. This review provides an overview on the evolution of retroviral vector design and production for gene therapy applications, including state of the art developments in flexible producer cells and safe vectors. In addition, production and purification processes will be addressed, with a particular focus on the improvements undertaken to increase vector productivity and to reduce the rapid loss of infectivity, which presently represent the main challenges in retroviral vectors production for gene therapy.

Anti-Angiogenic Therapies for Children with Cancer

Tumor angiogenesis, i.e. the development of neovascularisation in and around solid tumors, plays a key role in the local and distant growth of cancer and anti-angiogenic treatments are now established strategies to treat cancer patients. Specific inhibitors of angiogenesis such as bevacizumab or receptor tyrosine kinase inhibitors targeting VEGFR or PDGFR are now in clinical trials and are being increasingly validated for the treatment of poor prognostic cancers. Other anti-angiogenic strategies such as cilengitide or metronomic chemotherapy (low-dose anti-angiogenic chemotherapy) have been developed to treat certain types of adult cancer. In children, the clinical potential of anti-angiogenic approach is still in an early stage of investigation. This review will focus on the role of angiogenesis in pediatric solid tumors and will describe the pre-clinical and clinical experience with several anti-angiogenic compounds as a potential treatment for children with cancer.

Controlled Somatic and Germline Copy Number Variation in the Mouse Model

Changes in the number of chromosomes, but also variations in the copy number of chromosomal regions have been described in various pathological conditions, such as cancer and aneuploidy, but also in normal physiological condition. Our classical view of DNA replication and mitotic preservation of the chromosomal integrity is now challenged as new technologies allow us to observe such mosaic somatic changes in copy number affecting regions of chromosomes with various sizes. In order to go further in the understanding of copy number influence in normal condition we could take advantage of the novel strategy called Targeted Asymmetric Sister Chromatin Event of Recombination (TASCER) to induce recombination during the G2 phase so that we can generate deletions and duplications of regions of interest prior to mitosis. Using this approach in the mouse we could address the effects of copy number variation and segmental aneuploidy in daughter cells and allow us to explore somatic mosaics for large region of interest in the mouse.

Discovering Tumor Suppressor Genes Through Genome-Wide Copy Number Analysis

Classical tumor suppressor gene discovery has largely involved linkage analysis and loss-of-heterozygosity (LOH) screens, followed by detailed mapping of relatively large chromosomal regions. Subsequent efforts made use of genome-wide PCR-based methods to detect rare homozygous deletions. More recently, high-resolution genomic arrays have been applied to cancer gene discovery. However, accurate characterization of regions of genomic loss is particularly challenging due to sample heterogeneity, the small size of deleted regions and the high frequency of germline copy number polymorphisms. Here, we review the application of genome-wide copy number analysis to the specific problem of identifying tumor suppressor genes.

Telomere Maintenance as Therapeutic Target in Embryonal Tumours

Embryonal tumours most commonly occur in the first few years of life and account for approximately 30% of childhood malignancies. Knowledge of these tumours genetics has already impacted on their clinical management and further knowledge of their cellular immortalization will hopefully result in novel therapies. The ends of human chromosomes are capped and protected by telomeres; cellular replication, however, causes their loss. A critical length of telomere repeats is required to ensure proper telomere function and avoid the activation of DNA damage pathways that result in senescence and cell death. To proliferate beyond the senescence checkpoint, cells must restore their telomere length. Hence stabilization of telomere is an important step in cell immortalization and carcinogenesis. Telomere maintenance is evident in virtually all types of malignant cells, including embryonal tumours, where either a telomerase-dependent or alternative lengthening of telomeres (ALT) mechanism is employed in order to ensure their limitless replicative potential. For this reason effective strategies targeting telomere maintenance in cancer cells require a combination of telomerase and ALT inhibitors. In this review, we are giving an overview about telomere maintenance in childhood tumours and discussing its potential as a new therapeutic target.

Use of Cell Lines in the Investigation of Pharmacogenetic Loci

Drug response and toxicity, complex traits that are often highly varied among individuals, likely involve multiple genetic and non-genetic factors. Pharmacogenomic research aims to individualize therapy in an effort to maximize efficacy and minimize toxicity for each patient. Cell lines can be used as a model system for cellular pharmacologic effects, which include, but are not limited to, drug-induced cytotoxicity or apoptosis, biochemical effects and enzymatic reactions. Because severe toxicities may be associated with drugs such as chemotherapeutics, cell lines derived from healthy individuals or patients provide a convenient model to study how human genetic variation alters response to these drugs that would be unsafe or unethical to administer to human volunteers. In addition to the traditional candidate gene approaches that focus on well-understood candidate genes and pathways, the availability of extensive genotypic and phenotypic data on some cell line models has begun to allow genome-wide association (GWA) studies to simultaneously test the entire human genome for associations with drug response and toxicity. Though with some important limitations, the use of these cell lines in pharmacogenomic discovery demonstrates the promise of constructing a more comprehensive model that may ultimately integrate both genetic and non-genetic factors to predict individual response and toxicity to anticancer drugs.

Effect of β-Blockers on Perioperative Myocardial Ischemia in Patients Undergoing Noncardiac Surgery

Background: Myocardial ischemia remains a major cause of morbidity in patients undergoing noncardiac surgery. The purpose of the paper was to review the evidence of the use of perioperative β-blockers for the reduction of myocardial ischemia in patients having noncardiac surgery. Method: Pubmed was searched for articles that included β-blockers and perioperative myocardial ischemia. Randomized controlled trials that assessed the effect of β-blockers on myocardial ischemia in patients undergoing noncardiac surgery were included in this review and a meta-analysis was performed. Results: Sixteen randomized controlled trials including 2230 patients were included. The study methodologies and results were summarized and meta-analysis performed. Ten trials used β-blockers in the postoperative period; 954 patients received β-blockers and 924 patients were in the control group. Of the six trials that used β-blocker for premedication, there were 207 patients in the β-blocker and 145 patients in the control group. For the cohort when β-blockers were used postoperatively, myocardial ischemia was reduced significantly with the use of β-blockers (OR 0.42; 95% CI 0.27-0.65; P=0.0001; I2=0%). A similar beneficial effect was observed in trials that used β-blocker for premedication (OR 0.16; 95% CI 0.07-0.35; P < 0.00001; I2=40%). Conclusion: The meta-analysis shows that the use of β-blockers, both as premedication and postoperatively, in noncardiac surgery is associated with a significant reduction in perioperative myocardial ischemia.

Increased Paternal Age and Child Health and Development

The large number of adverse health outcomes associated with advanced paternal age is not widely recognized by the pediatric community. An exploration of the clinical and public health implications of this issue is required so as to develop appropriate policies. Included in this review are the clinically relevant conditions and diseases currently known to be associated with increasing paternal age, including diminutions in child IQ and social function [1], increased rates of low birth weight, certain childhood cancers, autistic spectrum disorders, schizophrenia, achondroplasia, Apert syndrome, Crouzon syndrome, and Multiple Endocrine Neoplasia (MEN). Other conditions for which there may be increased rates, but for which the data are still inconclusive, also are discussed. As men delay childbearing in the developed world, there is a need for pediatricians to be aware of the potential consequences. This paper provides pediatricians with a reference for conditions in children that are related to advanced paternal age, assisting them in maintaining a high index of suspicion, and for use in responding to questions from parents about this issue.

Toll-Like Receptors and Myocardial Ischemia/Reperfusion, Inflammation, and Injury

Cardiac ischemia/reperfusion (I/R) injury occurs in several important clinical contexts including percutaneous coronary interventions for acute myocardial ischemia, cardiac surgery in the setting of cardiopulmonary bypass, and cardiac transplantation. While the pathogenesis of I/R injury in these settings is multifactorial, it is clear that activation of the innate immune system and the resultant inflammatory response are important components of I/R injury. Toll-like receptor 4 (TLR4), originally identified as the sensor for bacterial lipopolysaccharide (LPS), has also been shown to serve as a sensor for endogenous molecules released from damaged or ischemic tissues. Accordingly, recent findings have demonstrated that TLR4 not only plays a central role as a mediator of cardiac dysfunction in sepsis, but also serves as a key mediator of myocardial injury and inflammation in the setting of I/R. Furthermore, TLR4 may play a role in the development of atherosclerotic lesions. Other studies have implicated TLR4 in the adverse remodeling that may occur after ischemic myocardial injury. This emerging body of literature, which is reviewed here, has provided new insight into the early molecular events that mediate myocardial injury and dysfunction in the setting of I/R injury.

Molecular Pathology of Sarcomas

Bone and soft tissue sarcomas are an infrequent group of tumours with a prevalence of 4 in 100000 people/ year. Sarcomas, such as synovial sarcoma, Ewings sarcoma and osteosarcoma, are more usual in adolescents or in young adults. Neoplasias such as leiomyosarcoma or liposarcoma are more frequent in patients over 55 years. One relevant topic is related to sarcomagenesis elucidation, a key for discovering the early molecular mechanisms involved in the development of sarcomas as well as the identification of reliable molecular markers and possible therapeutic targets. Today, it is known that the cellular context contributes to the phenotype. Analysis of gene expression profiling of human sarcomas revealed tightly clustered groups and could denote the existence of common signalling pathways for each branch. From the molecular point of view, these neoplasias are grouped into two main types: (a) sarcomas showing specific genetic alterations and relatively simple karyotypes, and translocations which originate gene fusions (e.g., EWS-FLI1 in Ewings sarcoma); or specific genetic mutations (e.g., c-kit in the gastrointestinal stromal tumour), and (b) sarcomas showing unspecific gene alterations and very complex karyotypes, and very numerous gains and losses. This review points out the clinical projection of sarcomagenesis elucidation and knowledge of diverse types of molecular alterations.

Renin Angiotensin System as a Regulator of Cell Volume. Implications to Myocardial Ischemia

It is known that long lasting changes in cell volume are incompatible with cellular functions. In the present review, I discussed the role of cell volume on gene expression and protein synthesis as well as the importance of the renin angiotensin system on the regulation of cell volume in the failing heart. Moreover, the relationship between mechanical stretch, cell volume and the renin angiotensin system as well some translational studies are also described and their relevance to the prevention or reduction of cardiac damage during myocardial ischemia is emphasized.

Marine Metabolites Overcoming or Circumventing Multidrug Resistance Mediated by ATP-Dependent Transporters: A New Hope for Patient with Tumors Resistant to Conventional Chemotherapy

The treatment of chemoresistant tumors represents an important challenge in the field of oncology. Primary or acquired overexpression of ATP-dependent transporters, in particular P-glycoprotein (Pgp, MDR1 protein), is a major cause of multidrug resistance and reduced patient survival. Sustained efforts have thereby been undertaken to find agents overcoming this resistance. This review provides a chemical and biological overview on bioactive metabolites from the marine field (natural molecules and analogues) that can overcome or circumvent resistance to ATP-dependent efflux pumps, their mechanisms of action and their structure-activity relationships. Their clinical relevance and status are presented. Active compounds (often microtubule-interacting agents) have been isolated from sponges and ascidians and, in lesser extent from cnidarians, and molluscs. The toxicity and the reversal activity can be uncoupled but, marine metabolites usually maintain high toxicity in multiresistant cancer cells. Certain display synergistic effects with clinically important anticancer drugs. The marine drug recently approved for cancer therapy [Trabectedin (Yondelis®)] and those entered into clinical trials act on multiple targets and, circumvent or overcome chemoresistance through very unusual mechanisms of action. Pharmacological and clinical data suggest that metabolites from the marine field could provide new therapeutic options for patients with tumors resistant to conventional therapy.

Epigenetic Aberrations and Targeted Epigenetic Therapy of Esophageal Cancer

Squamous cell carcinoma of the esophagus is one of the ten most frequent malignancies worldwide, characterized by a striking geographic variation in incidence. In North America and Europe, there has recently been a marked change in the epidemiology of this disease, where incidence rates for primary esophageal adenocarcinoma have increased in excess of any other human solid tumor. Although the reasons for this are largely unknown, several molecular genetic alterations have been associated with esophageal tumor progression. In recent years, epigenetic aberrations have been increasingly recognized as an important alternative mechanism of carcinogenesis and it is anticipated that substantial progress in the treatment of esophageal malignancy will likely only be made with a clearer understanding of esophageal tumor biology. Whereas genetic mutations, deletions, or allelic losses are fixed and irreversible, epigenetic abnormalities can potentially be corrected without interfering with the fundamental sequence of the target gene. Our current understanding of epigenetics in esophageal cancer, and the potential for targeted epigenetic therapy, will be the subject of this review.

Cardiac Metabolism in Myocardial Ischemia

Myocardial ischemia occurs for a mismatch between blood flow and metabolic requirements, when the rate of oxygen and metabolic substrates delivery to the myocardium is insufficient to meet the myocardial energy requirements for a given myocardial workload. During ischemia, substantial changes occur in cardiac energy metabolism, as a consequence of the reduced oxygen availability. Some of these metabolic changes are beneficial and may help the heart adapt to the ischemic condition. However, most of the changes are maladaptive and contribute to the severity of the ischemic injury leading stunned or hibernating myocardium, cell death and ultimately to contractile disfuction. Dramatic changes in cardiac metabolism and contractile function, also occur during myocardial reperfusion as a consequence of the generation of oxygen free radicals, loss of cation homeostasis, depletion of energy stores, and changes in subcellular activities. The reperfusion injury may cause in the death of cardiac myocytes that were still viable immediately before myocardial reperfusion. This form of myocardial injury, by itself can induce cardiomyocyte death and increase infarct size. During acute ischemia the relative substrate concentration is the prime factor defining preference and utilization rate. Allosteric enzyme regulation and protein phosphorylation cascades, partially controlled by hormones such as insulin, modulate the concentration effect; together they provide short-term adjustments of cardiac energy metabolism. The expression of metabolic genes is also dynamically regulated in response to developmental and (patho)physiological conditions, leading to long-term adjustments. Specific nuclear receptor transcription factors and co-activators regulate the expression of these genes. Understanding the functional role of these changes is critical for developing the concept of metabolic intervention for heart disease. The paper will review the alterations in energy metabolism that occur during acute and chronic ischemia.

Modulation of Cardiac Metabolism During Myocardial Ischemia

Metabolic modulation during myocardial ischemia is possible by the use of specific drugs, which may induce a shift from free fatty acid towards predominantly glucose utilization by the myocardium to increase ATP generation per unit oxygen consumption. Three agents (trimetazidine, ranolazine, and perhexiline) have well-documented anti-ischaemic effects. However, perhexiline, the most potent agent currently available, requires plasma-level monitoring to avoid hepatoneuro- toxicity. Besides, the long-term safety of trimetazidine and ranolazine has yet to be established. In addition to their effect in ischemia, the potential use of these drugs in chronic heart failure is gaining recognition as clinical and experimental data are showing the improvement of myocardial function following treatment with several of them, even in the absence of ischemia. Future applications for this line of treatment is promising and deserves additional research. In particular, large, randomised, controlled trials investigating the effects of these agents on mortality and hospitalization rates due to coronary artery disease are needed.

Targeting Vesicle Trafficking: An Important Approach to Cancer Chemotherapy

Cancer is a common disease in Western society that can affect any organ system. It has a high morbidity and mortality despite advances in treatment over the last hundred years. There is a clear need for new approaches to cancer chemotherapy including the possibility of reducing systemic adverse effects associated with current treatments. Vesicle trafficking is an essential cellular process that is perhaps not fully recognized. There is mounting evidence that vesicle trafficking, including the release of extracellular microvesicles, is a highly important process in tumourigenesis. Diverse aspects of tumourigenesis including invasion, metastasis, cell cycle regulation, angiogenesis, tumour immune privilege, neoplastic coagulopathy and multidrug resistance can be explained by altered vesicle trafficking in cancer cells. This paper reviews the evidence in the scientific and patent literature for the role of vesicle trafficking in tumourigenesis and suggests a number of targets and strategies that may be important for cancer therapeutics.

Bridging Innate Immunity and Myocardial Ischemia/Reperfusion Injury: The Search for Therapeutic Targets

Myocardial infarction necessitates new therapeutic interventions, since it still results in high morbidity and mortality worldwide. Reperfusion therapy itself results in (acceleration of) apoptosis, called myocardial ischemia/reperfusion (I/R) injury. For several decades it is known that the inflammatory response during reperfusion is the major cause of myocardial I/R injury. Therapeutic options are limited by lack of (detailed) understanding of intra- and intercellular mechanisms between inflammatory cells and cardiomyocytes. Furthermore, clinical trials generally fail to reproduce experimental successes, because essential factors are not taken into account in animal studies: risk factor for coronary artery disease, duration of ischemia and reperfusion, time of intervention. Above all, there is no specific therapeutic target for inhibiting the inflammatory response, in which cardiomyocytes are involved. The identification of Toll-like receptors (TLRs) on cardiomyocytes, has given rise to, not only new insights on the inflammatory response initiated by cardiomyocytes themselves, but also provided potential targets to reduce myocardial I/R injury. Experimental and clinical studies show that inflammatory responses are also involved in tissue repair responses. Since certain TLRs are expressed on inflammatory cells and cardiomyocytes, it ensures specific targeting of either detrimental effects or tissue repair responses in the inflammatory response during reperfusion. Which TLRs are involved in the ‘good’ and which in the ‘bad’ effects of the inflammatory response remains to be addressed. This review will discuss both experimental and clinical research on inflammatory reactions that occur after myocardial ischemia/ reperfusion (I/R). Data and conclusions concerning potential therapeutic targets in both experimental as clinical research settings will be reviewed.

Testosterone and Cardioprotection Against Myocardial Ischemia

Male gender is a risk factor for cardiovascular diseases. Testosterone being the main male sex hormone is therefore believed to be responsible for the deleterious effect of the male. However, there are recent studies showing that testosterone level is lower in patients with ischemic heart diseases, and testosterone treatment alleviates the symptoms. Earlier studies showed that functional androgen receptors are present in the heart and that testosterone acts directly at the myocardium. There is increasing evidence to suggest testosterone confers cardioprotection by direct action on the myocardium. Here, we review the recent literature on association between testosterone and myocardial ischemia in males, and the signal transduction mechanisms that mediate the action of testosterone in the heart. The studies reviewed in this article provide evidence that testosterone may confer protection via a varieties of mechanisms, which may be both genomic and non-genomic. Further studies are warranted to further delineate the integration of signaling mechanisms and to explore the possibility of using testosterone in the aging male population with ischemic heart diseases.

Histone Deacetylase Inhibitors: Molecular and Biological Activity as a Premise to Clinical Application

Epigenetic modifications are reversible chromatin rearrangements that in normal cells modulate gene expression, without changing DNA sequence. Alterations of this equilibrium, mainly affecting the two interdependent mechanisms of DNA methylation and histone acetylation, are frequently involved in the genesis of cancer. The histone code, regulating gene expression, is constituted by the combination of different acetylated lysine residues of histones. In neoplastic cells, the abundance of deacetylated histones is usually associated with DNA hypermethylation and gene silencing. Several compounds, known to have in vitro antineoplastic activity, have been eventually shown to act as histone deacetylase inhibitors. Thus, HDAC inhibitors have been successfully introduced in clinical trials as antitumour agents. They are classified according to their chemical structures and are endowed with different specificity and affinity for the HDACs of classes 1, 2, 4. Among HDAC inhibitors, the most potent are the hydroxamic acid derivatives, like SAHA, which has been recently approved for therapy of cutaneous T-cell lymphomas. Other classes of HDAC inhibitors are short chain fatty acids (SCFA), benzamides, epoxyketone and non-epoxyketone containing cyclic tetrapeptides, and hybrid molecules. SCFA, although widely used (especially valproic acid) and clinically efficacious, have weak HDAC inhibition constants. Benzamides, like MS-275, and cyclic peptides, like depsipeptide, have been studied in numerous clinical trials and demonstrated low toxicity and activity in solid and haematological neoplasms. HDAC inhibitors are also potent radiation sensitizers. Their future in oncology may thus be based on their activity as single agents and on their synergy with the hypomethylating drugs and with chemo- and radiotherapeutics.

Podophyllotoxin: Current Perspectives

Podophyllotoxin is a naturally occurring lignan with important antineoplastic and antiviral properties and supported by detailed understanding of their mechanism of action, and facilitated by chemical manipulations that have amplified their bioactivity, the podophyllotoxin analogues have advanced to the forefront of several areas of therapeutic and developmental chemotherapy. Additive and synergistic laboratory interactions with other cytotoxic drugs have been exploited to allow development of podophyllotoxin-based multidrug regimens, which are showing important activity in several malignancies, and many of its related analogues will complement conventional pharmaceuticals in treatment, prevention and diaganosis of disease, while at the same time adding value to agriculture. Additive and synergistic laboratory interactions with other cytotoxic drugs have been exploited to allow development of etoposide-based multidrug regimens, which are showing important activity in several malignancies. Extensive structural modifications of podophyllotoxin have been performed in order to obtain more potent and less toxic antitumour agents, which resulted in the widespread clinical introduction of two semisynthetic glucoconjugate analogues of etoposide and teniposide and newer agents with promising preclinical activity are in various stages of clinical assessment. As knowledge of molecular and biochemical mechanisms of action and resistance continues to expand, newer and better podophyllotoxin-based strategies for treatment of malignant disease are likely to evolve. This review provides a detailed discussion of research advances in the synthetic and medicinal chemistry of podophyllotoxin, and addresses the short history and pharmacological action of these compounds and further outlines the preclinical development and clinical trials of drugs in the pipeline and marketing approval. Finally, a systemic evaluation of novel and important analogues of podophyllotoxin and their contribution to the current structure-activity profile are considered. It is hoped that this review will be able to address the contributions of podophyllotoxin-related research to overall drug discovery and development and the role that this field will play in future.

BXT-51072 and the Prevention of Myocardial Ischemia-Reperfusion Injury

Oxidative stress is responsible for myocardial injury occurring after ischemia and reperfusion (IR) and has been shown to be modulated by the Haptoglobin (Hp) genotype. In this manuscript we demonstrate that the antioxidant BXT -51072, a glutathione peroxidase synthetic mimic, provides protection against IR injury in a Hp genotype dependent fashion.

Myocardial Ischemia and Reperfusion Injury: Studies Using Transgenic and Knockout Mice

Transgenic and knockout mice are created and used for a large variety of research objectives. This overview describes the (genetically modified) mouse models that have been used to study the development of myocardial ischemia and reperfusion injury. The role of cytokines, chemokines, leukocytes, reactive oxygen species, anti-oxidants, NO, complement system, coagulation system, heat shock proteins, apoptosis and necrosis, and acute phase reactants are presented.

DNA and RNA Aptamers as Modulators of Protein Function

The SELEX technique (systematic evolution of ligands by exponential enrichment) is a combinatorial library approach in which DNA or RNA molecules are selected by their ability to bind their protein targets with high affinity and specificity. The isolated molecules are referred to as aptamers (from aptus = Latin “to fit”). First, RNA and DNA aptamers were identified that bind to proteins naturally interacting with nucleic acids, or to small organic molecules such as ATP. In the following years, the use of the SELEX technique was extended to isolate oligonucleotide ligands for a wide range of proteins of importance for therapy, and diagnostics. Since these RNA and DNA molecules bind their targets with similar affinities as antibodies, and are able to distinguish between isotypes of an enzyme, aptamers have been also called synthetic antibodies. Recently, the use of in vitro selection methods to isolate protein inhibitors has been extended to complex targets, such as receptors that are only functional in their membrane-bound form, cells, and trypanosomes. RNA aptamers have been expressed in living cells where they inhibit a protein implicated in intracellular signal transduction. The utility of aptamers for in vivo experiments, and diagnostic and therapeutic purposes, is considerably enhanced by introducing chemical modifications into the oligonucleotides to provide resistance against enzymatic degradation in body fluids. Recently, such inhibitors have been evolved for a great variety of targets, including receptors, growth factors, and adhesion molecules implicated in disease. Furthermore, some results were already obtained in animal models and clinical trials.

The Role of the Chemokines in Myocardial Ischemia and Reperfusion

Chemokines critically regulate basal and inflammatory leukocyte trafficking and may play a role in angiogenesis. This review summarizes our current understanding of the regulation and potential role of the chemokines in myocardial ischemia and reperfusion. Reperfused myocardial infarction is associated with an inflammatory response leading to leukocyte recruitment, healing and scar formation. Neutrophil chemoattractants, such as the CXC chemokine CXCL8 / Interleukin (IL)-8, are upregulated in the infarcted area inducing polymorphonuclear leukocyte infiltration. In addition, mononuclear cell chemoattractants, such as the CC chemokine CCL2 / Monocyte Chemoattractant Protein (MCP)-1, are expressed, leading to monocyte and lymphocyte recruitment in the ischemic area. However, chemokines may have additional effects in healing infarcts beyond their leukotactic properties. We have recently described a marked transient induction of the angiostatic CXC chemokine CXCL10 / Interferon-γ inducible Protein (IP)- 10 in the infarct. Upregulation of angiostatic factors, such as IP- 10, in the first few hours following injury may inhibit premature angiogenesis, until the infarct is debrided and appropriate supportive matrix is formed. Suppression of IP-10 synthesis during the healing phase may allow formation of the wound neovessels, a critical process for infarct healing. Chemokine expression is also noted after a single brief ischemic insult in the absence of myocardial infarction, suggesting a potential role for a chemokine-induced inflammatory response in noninfarctive ischemic cardiomyopathy. Unlike cytokines, which have pleiotropic effects, chemokines have more specific cellular targets. Understanding of their role in myocardial infarction may allow us to design specific therapeutic strategies aiming at optimizing cardiac repair and preventing ventricular remodeling.

Alterations of Sex Differentiation in Males: From Candidate Genes to Diagnosis and Treatments

Sex, that is, whether one is physically male or female, is the basic dichotomy of life. Sex is important not only for reproductive role, but also for physical attributes, personal identity and disease susceptibility. Sex determination is genetically controlled, with the key event in males being the transmission of a Y chromosome from father to offspring. The sex-determining gene on the Y chromosome, SRY, triggers the expression of a repertoire of other genes that cause the undifferentiated gonad to develop as a testis. Hormones secreted by the developing testis cause the internal and external genitalia to masculinize. Testicular development is disrupted by de novo or inherited genetic alterations leading to gonadal dysgenesis. Decreased hormone production from dysgenetic testes disrupts the normal development of the internal and external genitalia. Incomplete masculinization of the genitalia also occurs from hormonal biosynthetic defects or decreased response to hormones from inherited receptor defects. Treatment is tailored to the individual diagnosis and may include removal of dysgenetic gonads, surgical correction of incompletely masculinized genitalia, replacement of deficient hormones, and, in some instances, gender reassignment.

Therapeutic Angiogenesis by Gene Transfer in Critical Limb and Myocardial Ischemia

Cardiovascular atherosclerotic diseases remain leading causes of morbidity and mortality in the world. Despite the significant progress that has been made in the management of these diseases using medical, surgical and percutaneous therapies over the last three decades, there remains a significant population of patients who are not optimal candidates for surgical or percutaneous revascularization. Substantial research has focused on the administration of angiogenic growth factors, either as recombinant protein or by gene transfer, to promote the development of supplemental collateral blood vessels that will constitute endogenous bypass conduits around occluded native arteries, a strategy termed “therapeutic angiogenesis”. While many cytokines have angiogenic activity, the best studied both in animal models and clinical trials are vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). This review will discuss gene transfer strategies for therapeutic angiogenesis in critical limb and myocardial ischemia.