High-dose cimetidine for the treatment of metastatic renal cell carcinoma. A Hoosier Oncology Group study.

The Hoosier Oncology Group evaluated cimetidine in 42 patients with metastatic renal cell carcinoma. There were two complete remissions that lasted for 26 and 33+ months in 38 evaluable patients. There were no partial remissions. Toxicity was minimal. Patients with renal cell carcinoma can occasionally respond to cimetidine with long-term remission.     

From chlorpromazine to clozapine--antipsychotic adverse effects and the clinician's dilemma.

The pharmacotherapy of schizophrenia remains an ongoing challenge for researchers and clinicians alike. Current medications remain suboptimal to effectively treat this illness despite the recent surge of what are considered to be better antipsychotics: the atypicals. The atypicals cause fewer extrapyramidal symptoms and tardive dyskinesia, but there is growing concern regarding the significant long-term metabolic and cardiac adverse effects of these novel antipsychotics. There are differences among the atypicals in their propensity to produce these adverse effects, and clinicians should weigh the risk-benefit ratio for each drug with each individual patient. Diabetes, heart disease, obesity, and unhealthy lifestyle choices are on the rise in the general population, and individuals with chronic schizophrenia are even more at risk. The dilemma clinicians face in trying to avoid the neurological morbidity of the typicals (extrapyramidal side effects and tardive dyskinesia) is the risk of consequently exposing patients to both the morbidity and potential mortality of the atypicals (cardiovascular, endocrine, and metabolic adverse effects). The importance of baseline investigations and monitoring at regular intervals as well as identification of patients at risk for obesity, diabetes, and cardiovascular morbidity has become crucial. Informed decision making is essential for successful antipsychotic pharmacotherapy. For a condition, which often necessitates long-term pharmacotherapy, the importance of prevention and (or) minimization of morbidity and mortality related to adverse effects of such pharmacotherapy cannot be understated.     

A sandwich-ELISA for the diagnosis of Peste des petits ruminants (PPR) infection in small ruminants using anti-nucleocapsid protein monoclonal antibody

Summary. A sandwich ELISA test using PPR specific monoclonal antibody (clone 4G6) to an epitope of nucleocapsid protein has been developed. The test uses polyclonal sera to capture the antigen from clinical samples (swabs and tissues). Captured antigens from clinical samples are detected using PPR specific monoclonal antibody. The test is specific to PPR as it failed to detect rinderpest vaccine virus (RBOK strain). Varieties of clinical samples originating from laboratory experiments (n=231) and from field (n=259) were employed to test the efficacy of sandwich-ELISA test. The test compared very well with an internationally accepted commercial Immune-capture ELISA kit, which uses biotinylated monoclonal antibody against the nucleocapsid protein. On a parallel testing using 490 clinical samples, 4G6 MAb based sandwich ELISA had an overall relative diagnostic specificity of 92.8% and diagnostic sensitivity of 88.9% compared to the commercial kit. The newly developed test is free from prozone phenomenon. PPR outbreaks from various parts of India have been confirmed using the test. Findings suggested that the newly developed ELISA is suitable for PPR diagnosis under field conditions.     

Pro-inflammatory cytokines and chemokines initiate multiple prostate cancer biologic pathways of cellular proliferation,heterogeneity and metastasis in a racially diverse population and underlie the genetic/biologic mechanism of racial disparity: Update

Pro-inflammatory cytokine and chemokines genes drive prostate cancer progression and metastasis: molecular mechanism update and the science that underlies racial disparity. comprehensive review article.Isaac J. Powell, S. Chinni, S.S. Reddy, Alexander Zaslavsky, Navnath Gavande Introduction: In 2013 we reported that with the use of bioinformatics and ingenuity pathway network analysis we were able to identify functional driver genes that were differentially expressed among a large population of African American men (AAM) and European American men (EAM). Pro-inflammatory cytokine genes were found to be more interactive and more expressed among AAM and have been found to be functional drivers of aggressive prostate cancer (CaP) and aggressiveness in other solid tumors. We examined these genes and biological pathways initiated by these cytokines in primary CaP tissue.Method We unravel the gene network and identified biologic pathways that impacted activation of the androgen receptor, mesenchymal epithelial transition (invasion) and chemokines associated with metastasis in the CaP tissue from 639 radical prostatectomy specimens.Results Biologic pathways identified by unraveling pro-inflammatory genes from our network, more expressed among AAM compared to EAM, were tumor necrosis factor (TNF), IL1b, IL6, and IL8. IL6 and IL8 are downstream of TNF activity and are known activators of androgen receptor and through mediators promote CaP cell proliferation. TNF and IL1b mediate tumor cell invasiveness through the activation of MMP (matrix metalloproteinase) which down regulates E-Cadherin to initiate epithelial mesenchymal transition which allows cells to become invasive in the microenvironment. Ultimately our network analysis indicates that TNF and IL1b activate CXCR4 receptor on CaP cells, which facilitates metastatic progression reportedly by binding to CXCL12 on lipid rafts and tumor implantation in the bone marrow.Conclusion Our retrospective biologic mechanistic model reveals a set of pro-inflammatory cytokines and chemokines that drive CaP aggressiveness, tumor heterogeneity, progression and metastasis. A prospective multi-institutional study needs to be conducted for clinical validation as well consideration of targeted therapy.     

Is visfatin an adipokine or myokine? Evidence for greater visfatin expression in skeletal muscle than visceral fat in chickens

Visfatin, an adipokine hormone produced primarily by visceral adipose tissue in mammals, has been implicated in the immune system, cellular aging, and glucose metabolism. Increased visceral adiposity and hyperglycemia have been correlated with elevated plasma visfatin levels in humans. The present study investigated visfatin cDNA and protein expression as well as plasma visfatin levels in chickens that are selected for rapid growth and are naturally hyperglycemic relative to mammals. By RT-PCR, we detected visfatin cDNA in multiple tissues in the chicken. The deduced amino acid sequence of full-length chicken visfatin was 92-93% homologous to mammalian visfatin. Using real-time quantitative PCR and Western blotting, chicken skeletal muscle was found to contain 5- and 3-fold greater quantities of visfatin mRNA and protein than abdominal fat pad, respectively. Visfatin mRNA and protein quantities were not significantly different among sc and visceral adipose tissue depots. Skeletal muscle visfatin mRNA and protein quantities as well as plasma visfatin levels determined by enzyme immunoassay were significantly higher in 8-wk-old compared with 4-wk-old chickens, possibly due to rapid skeletal muscle growth and visceral fat accretion occurring in broiler chickens during this period. However, fasting and refeeding did not affect plasma visfatin levels in the chicken. Collectively, our results provide novel evidence that skeletal muscle, not the visceral adipose tissue, is the primary source of visfatin in chickens, thereby raising the possibility that visfatin may be acting as a myokine affecting skeletal muscle growth and metabolism.     

Targeting the intestinal lymphatic system: a versatile path for enhanced oral bioavailability of drugs

Introduction: The major challenge of first pass metabolism in oral drug delivery can be surmounted by directing delivery toward intestinal lymphatic system (ILS). ILS circumvents the liver and transports drug directly into systemic circulation via thoracic duct. Lipid and polymeric nanoparticles are transported into ILS through lacteal and Peyer’s patches. Moreover, surface modification of nanoparticles with ligand which is specific for Peyer’s patches enhances the uptake of drugs into ILS. Bioavailability enhancement by lymphatic uptake is an advantageous approach adopted by scientists today. Therefore, it is important to understand clear insight of ILS in targeted drug delivery and challenges involved in it.

Areas covered: Current review includes an overview of ILS, factors governing lymphatic transport of nanoparticles and absorption mechanism of lipid and polymeric nanoparticles into ILS. Various ligands used to target Peyer’s patch and their conjugation strategies to nanoparticles are explained in detail. In vitro and in vivo models used to assess intestinal lymphatic transport of molecules are discussed further.

Expert opinion: Although ILS offers a versatile pathway for nanotechnology based targeted drug delivery, extensive investigations on validation of the lymphatic transport models and on the strategies for gastric protection of targeted nanocarriers have to be perceived in for excellent performance of ILS in oral drug delivery.     

Epac-Rap Signaling Reduces Oxidative Stress in the Tubular Epithelium

Activation of Rap1 by exchange protein activated by cAMP (Epac) promotes cell adhesion and actin cytoskeletal polarization. Pharmacologic activation of Epac-Rap signaling by the Epac-selective cAMP analog 8-pCPT-2′-O-Me-cAMP during ischemia-reperfusion (IR) injury reduces renal failure and application of 8-pCPT-2′-O-Me-cAMP promotes renal cell survival during exposure to the nephrotoxicant cisplatin. Here, we found that activation of Epac by 8-pCPT-2′-O-Me-cAMP reduced production of reactive oxygen species during reoxygenation after hypoxia by decreasing mitochondrial superoxide production. Epac activation prevented disruption of tubular morphology during diethyl maleate–induced oxidative stress in an organotypic three-dimensional culture assay. In vivo renal targeting of 8-pCPT-2′-O-Me-cAMP to proximal tubules using a kidney-selective drug carrier approach resulted in prolonged activation of Rap1 compared with nonconjugated 8-pCPT-2′-O-Me-cAMP. Activation of Epac reduced antioxidant signaling during IR injury and prevented tubular epithelial injury, apoptosis, and renal failure. Our data suggest that Epac1 decreases reactive oxygen species production by preventing mitochondrial superoxide formation during IR injury, thus limiting the degree of oxidative stress. These findings indicate a new role for activation of Epac as a therapeutic application in renal injury associated with oxidative stress.Renal ischemia-reperfusion (IR) injury is an important cause of AKI¹ and a significant risk factor for the development of renal dysfunction after kidney transplantation.² During IR injury, morphologic and functional alterations of the proximal tubular epithelium occur that are linked to the development of renal failure and activation of immune cells via release of proinflammatory cytokines.³Exchange protein activated by cAMP (Epac) is a guanine nucleotide exchange factor for the small GTPase Rap1.⁴ Activation of Epac by cAMP or by the Epac-selective cAMP analog 8-pCPT-2′-O-Me-cAMP (also referred to as 007) induces functional activation of Rap1.⁵ Initial studies showed that Epac-Rap signaling enhances cell adhesion by supporting maturation of cell-cell junctions^6,7 and promoting integrin-mediated cell-matrix adhesion.^8,9 In line with these studies, we recently demonstrated that selective activation of Epac reduces proximal tubular epithelial cell (PTEC) detachment during IR injury using in vitro and in vivo models.¹⁰ Activation of Epac-Rap was associated with reduced expression of markers for cellular stress in PTECs. In addition, in vitro cisplatin-induced apoptosis of PTECs could be significantly reduced by activation of Epac and this was also associated with improved adhesion of cells.¹¹ On the basis of these findings, we hypothesized that activation of Epac-Rap signaling may protect against a common cytotoxic event in these injury models.Unbalanced and uncontrolled production of reactive oxygen species (ROS) is an important mediator of cell injury and occurs during cisplatin nephrotoxicity,¹² IR injury,¹³ and renal fibrosis.¹⁴ In renal pathology, intracellular ROS can be produced enzymatically such as by NADPH oxidase (NOX) complexes or derive from dysfunctional mitochondrial activity. Mitochondrial ROS production appears to be the driving force behind hypoxia-reoxygenation cell injury¹⁵ and cisplatin cytotoxicity.¹⁶Here we studied the role of specific proximal tubular activation of Epac and how this protects against renal injury in both in vitro and in vivo models for IR injury. We found that ROS production during reoxygenation after hypoxia was decreased by activation of Epac. Selective proximal tubular activation of Epac by renal targeting of 8-pCPT-2′-O-Me-cAMP conjugated to lysozyme (LZM-007) reduced oxidative stress in an in vivo model for IR injury and significantly decreased IR injury–associated renal failure and tubular damage. Our data show that Epac activation reduces ROS-mediated cellular injury in renal disease and may be a therapeutic strategy for modulation of oxidative stress.