Chronic pancreatitis,pancreatic adenocarcinoma and the black box in-between

Pancreatic cancer is a challenging disease for patients,doctors and researchers who for decades have searched for a cure for this deadly malignancy.Although existing mouse models of pancreatic cancer have shed light on the mecha-nistic basis of the neoplastic conversion of the pancreas,their impact in terms of offering new diagnostics and therapeu-tic modalities remains limited.Chronic pancreatitis is an inflammatory disease of the pancreas that is associated with a gradual damage of the organ and an increased risk of developing neoplastic lesions.In this review,we propose that detailed studies of chronic inflammatory processes in the pancreas will provide insights into the evolution of pancreatic cancer.This information may prove useful in the design of effective therapeutic strategies to battle the disease.

Short-term antioxidant diet prevents hyperfiltration in young male rat kidney subjected to ischemia/reperfusion injury

Objectives: The process of transplantation is associated with exposure to both long and short cold and warm ischemic times that result in ischemia/reperfusion injury. Oxidative stress contributes to tissue fibrosis, renal dysfunction, and/or rejection. Treatments that scavenge oxygen free radicals and have antioxidant properties can ameliorate the damaging results in renal grafts following ischemia/reperfusion injury. The present study tests the hypothesis that an antioxidant-fortified diet given to rats before and after renal ischemia/reperfusion injury will reduce the kidney damage that results and improve renal function. Endothelial and inducible nitric oxide synthases may change with tissue injury, including ischemia/ reperfusion. Materials and Methods: Male Wistar rats were subjected to ischemia/reperfusion injury at 7 or 19 weeks of age with or without dietary antioxidant supplementation. One week later, glomerular filtration rate, mean arterial pressure and urinary nitric oxide were measured, and renal endothelial and inducible nitric oxide synthases examined. Results: The glomerular filtration rate was elevated more than two-fold above the normal range? at 8 weeks in animals on the regular diet exposed to ischemia/reperfu- sion, while in the 8 week antioxidant-fortified diet group the glomerular filtration rate was normal. Also, in 8 week rats, levels of endothelial nitric oxide synthase protein in cortex were higher on the regular than on the antioxidant-fortified diet. Conclusion: Early after ischemia/reperfusion injury renal endothelial nitric oxide synthase levels rise, possibly contributing to vascular dilation and hyperperfusion, and an antioxidant-fortified diet can ameliorate these changes in the younger age group.

CD4+T cells memorize obesity and promote weight regain

Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown.In this study,we report that immune cells,especially CD4+T cells,mediate the‘memory’of previous obese status.In a weight gain-loss-regain model,we found that C57BL/6J mice with an obesity history showed a much faster rate of body weight regain.This obesity memory could last for at least 2 months after previously obese mice were kept at the same body weight as non-obese mice.Surprisingly,such obesity memory was abrogated by dexamethasone treatment,whereas immunodeficient Rag1−/−and H2A−/−mice failed to establish such memory.Rag1−/−mice repossessed the obesity memory when immune cells or CD4+T cells isolated from previously obese mice were transferred.Furthermore,depletion of CD4+T cells led to obesity memory ablation.Taken together,we conclude that CD4+T cells mediate obesity memory and promote weight regain.

Drug resistance and combating drug resistance in cancer

Cancer is the second leading cause of death in the US.Current major treatments for cancer management include surgery,cytotoxic chemotherapy,targeted therapy,radiation therapy,endocrine therapy and immunotherapy.Despite the endeavors and achievements made in treating cancers during the past decades,resistance to classical chemotherapeutic agents and/or novel targeted drugs continues to be a major problem in cancer therapies.Drug resistance,either existing before treatment(intrinsic)or generated after therapy(acquired),is responsible for most relapses of cancer,one of the major causes of death of the disease.Heterogeneity among patients and tumors,and the versatility of cancer to circumvent therapies make drug resistance more challenging to deal with.Better understanding the mechanisms of drug resistance is required to provide guidance to future cancer treatment and achieve better outcomes.In this review,intrinsic and acquired resistance will be discussed.In addition,new discoveries in mechanisms of drug resistance will be reviewed.Particularly,we will highlight roles of ATP in drug resistance by discussing recent findings of exceptionally high levels of intratumoral extracellular ATP as well as intracellular ATP internalized from extracellular environment.The complexity of drug resistance development suggests that combinational and personalized therapies,which should take ATP into consideration,might provide better strategies and improved efficacy for fighting drug resistance in cancer.

Cancer stem cells,epithelial-mesenchymal transition,ATP and their roles in drug resistance in cancer

The cancer stem cell(CSC)state and epithelial-mesenchymal transition(EMT)activation are tightly interconnected.Cancer cells that acquire the EMT/CSC phenotype are equipped with adaptive metabolic changes to maintain low reactive oxygen species levels and stemness,enhanced drug transporters,anti-apoptotic machinery and DNA repair system.Factors present in the tumor microenvironment such as hypoxia and the communication with non-cancer stromal cells also promote cancer cells to enter the EMT/CSC state and display related resistance.ATP,particularly the high levels of intratumoral extracellular ATP functioning through both signaling pathways and ATP internalization,induces and regulates EMT and CSC.The three of them work together to enhance drug resistance.New findings in each of these factors will help us explore deeper into mechanisms of drug resistance and suggest new resistance-associated markers and therapeutic targets.

Notch signaling and its emerging role in autoimmunity

Studies of notch signaling in immune cells have uncovered critical roles for this pathway both during the differentiation and effector function phases of immune responses. Cells of the myeloid lineage, including macrophages and dendritic cells, function as key components of innate immune defense against infection and, by acting as antigen presenting cells, can instruct cells of the adaptive immune response, specifically CD4 and CD8 T cells. Tight regulation of this functional interaction is needed to ensure a well-balanced immune response and its dysregulation may indirectly or directly cause the tissue damage characteristic of autoimmune diseases. In this review, the focus will be placed on those recent findings which support a role for notch signaling in inflammatory responses mediated by macrophages and other myeloid lineage cells, as well as peripheral T cells, and their relevance to inflammatory and autoimmne diseases.

Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons

Alternative splicing of the pyruvate kinase M gene(PK-M)can generate the M2 isoform and promote aerobic glycolysis and tumor growth.However,the cancer-specific alternative splicing regulation of PK-M is not completely understood.Here,we demonstrate that PK-M is regulated by reciprocal effects on the mutually exclusive exons 9 and 10,such that exon 9 is repressed and exon 10 is activated in cancer cells.Strikingly,exonic,rather than intronic,cis-elements are key determinants of PK-M splicing isoform ratios.Using a systematic sub-exonic duplication approach,we identify a potent exonic splicing enhancer in exon 10,which differs from its homologous counterpart in exon 9 by only two nucleotides.We identify SRSF3 as one of the cognate factors,and show that this serine/arginine-rich protein activates exon 10 and mediates changes in glucose metabolism.These findings provide mechanistic insights into the complex regulation of alternative splicing of a key regulator of the Warburg effect,and also have implications for other genes with a similar pattern of alternative splicing.

Thymic-specific regulation of TCR signaling by Tespa1

Double-positive(DP)thymocytes undergo positive selection to become mature single-positive CD4+and CD8+T cells in response to T cell receptor(TCR)signaling.Unlike mature T cells,DP cells must respond to low-affinity self-peptide-MHC ligands before full upregulation of their surface TCR expression can occur.Thus,DP thymocytes must be more sensitive to ligands than mature T cells.A number of molecules have been found that are able to enhance the strength of the TCR signal to facilitate positive selection.However,almost all of these molecules are also active in mature T cells.Themis(thymocyte expressed molecule involved in selection)and Tespa1(thymocyte expressed positive selection associated 1)are two recently discovered molecules essential for optimal TCR signaling and thymocyte development.A deficiency in both molecules leads to defects in positive selection.Here,we compared the relative contributions of Themis and Tespa1 to positive selection in thymocytes.We show that Tespa1 deficiency led to more limited and specific gene expression profile changes in cells undergoing positive selection.In mixed bone marrow transfer experiments,Tespa1^(−/−)cells showed more severe defects in thymocyte development than Themis^(−/−)cells.However,Tespa1^(−/−)cells showed a substantial degree of homeostatic expansion and became predominant in the peripheral lymphoid organs,suggesting that Tespa1 is a thymic-specific TCR signaling regulator.This hypothesis is further supported by our observations in Tespa1 conditional knockout mice,as Tespa1 deletion in peripheral T cells did not affect TCR signaling or cell proliferation.The different regulatory effects of Tespa1 and Themis are in accordance with their nonredundant roles in thymocyte selection,during which Tespa1 and Themis double knockouts showed additive defects.

The epigenetics of CHARGE syndrome

In biology, we continue to appreciate the fact that the DNA sequence alone falls short when attempting to explain the intricate inheritance patterns for complex traits. This is particularly true for human disorders that appear to have simple genetic causes. The study of epigenetics, and the increased access to the epigenetic profiles of different tissues has begun to shed light on the genetic complexity of many basic biological processes, both physiological and pathological. Epigenetics refers to heritable changes in gene expression that are not due to alterations in the DNA sequence. Various mechanisms of epigenetic regulation exist, including DNA methylation and histone modification. The identification, and increased understanding of key players and mechanisms of epigenetic regulation have begun to provide significant insight into the underlying origins of various human genetic disorders. One such disorder is CHARGE syndrome （OMIM #214800）, which is a leading cause of deaf-blindness worldwide. A majority of CHARGE syndrome cases are caused by haploinsufficiency for the CHD7 gene, which encodes an ATP-dependent chromatin remodeling protein involved in the epigenetic regulation of gene expression. The CHD7 protein has been highly conserved throughout evolution, and research into the function of CHD7 homologs in multiple model systems has increased our understanding of this family of proteins, and epigenetic mechanisms in general. Here we provide a review of CHARGE syndrome, and discuss the epigenetic functions of CHD7 in humans and CHD7 homologs in model organisms.