Dual coding with STDP in a spiking recurrent neural network model of the hippocampus.

The firing rate of single neurons in the mammalian hippocampus has been demonstrated to encode for a range of spatial and non-spatial stimuli. It has also been demonstrated that phase of firing, with respect to the theta oscillation that dominates the hippocampal EEG during stereotype learning behaviour, correlates with an animal's spatial location. These findings have led to the hypothesis that the hippocampus operates using a dual (rate and temporal) coding system. To investigate the phenomenon of dual coding in the hippocampus, we examine a spiking recurrent network model with theta coded neural dynamics and an STDP rule that mediates rate-coded Hebbian learning when pre- and post-synaptic firing is stochastic. We demonstrate that this plasticity rule can generate both symmetric and asymmetric connections between neurons that fire at concurrent or successive theta phase, respectively, and subsequently produce both pattern completion and sequence prediction from partial cues. This unifies previously disparate auto- and hetero-associative network models of hippocampal function and provides them with a firmer basis in modern neurobiology. Furthermore, the encoding and reactivation of activity in mutually exciting Hebbian cell assemblies demonstrated here is believed to represent a fundamental mechanism of cognitive processing in the brain

Case reports and the fight against cancer

Some of the earliest case reports describing individual patients afflicted with cancer can be traced all the way back to the papyrus records of Ancient Egyptian medicine of approximately 1600 B.C.. Throughout the centuries physicians have continued the practice of writing case reports. Case reporting has provided significant advances in the knowledge of cancer on several fronts. It is without question that case reports do not replace well designed randomized clinical trials in advancing medical knowledge about cancerous diseases. However, case reports have their unique role in evidence-based medicine and often constitute the first line of evidence. This editorial reviews the many useful aspects of case reports and describes specific reports known to have revolutionized cancer management. Journal of Medical Case Reports is committed to publish well written case reports from around the world and be a source of inspiration for clinicians and scientists about newer research directions

Helicobacter pylori-induced gastric pathology: insights from in vivo and ex vivo models

Gastric colonization with Helicobacter pylori induces diverse human pathological conditions, including superficial gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma and its precursors. The treatment of these conditions often relies on the eradication of H. pylori, an intervention that is increasingly difficult to achieve and that does not prevent disease progression in some contexts. There is, therefore, a pressing need to develop new experimental models of H. pylori-associated gastric pathology to support novel drug development in this field. Here, we review the current status of in vivo and ex vivo models of gastric H. pylori colonization, and of Helicobacter-induced gastric pathology, focusing on models of gastric pathology induced by H. pylori, Helicobacter felis and Helicobacter suis in rodents and large animals. We also discuss the more recent development of gastric organoid cultures from murine and human gastric tissue, as well as from human pluripotent stem cells, and the outcomes of H. pylori infection in these systems

Netazepide inhibits expression of Pappalysin 2 in type-1 gastric neuroendocrine tumors

Background & Aims: In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling. Methods: We obtained serum samples and gastric corpus biopsy specimens from 8 patients with hypergastrinemia and type 1 gNETs enrolled in a phase 2 trial of netazepide. Control samples were obtained from 10 patients without gastric cancer. We used amplified and biotinylated sense-strand DNA targets from total RNA and Affymetrix (Thermofisher Scientific, UK) Human Gene 2.0 ST microarrays to identify differentially expressed genes in stomach tissues from patients with type 1 gNETs before, during, and after netazepide treatment. Findings were validated in a human AGS GR gastric adenocarcinoma cell line that stably expresses human CCK2R, primary mouse gastroids, transgenic hypergastrinemic INS-GAS mice, and patient samples. Results: Levels of pappalysin 2 (PAPPA2) messenger RNA were reduced significantly in gNET tissues from patients receiving netazepide therapy compared with tissues collected before therapy. PAPPA2 is a metalloproteinase that increases the bioavailability of insulin-like growth factor (IGF) by cleaving IGF binding proteins (IGFBPs). PAPPA2 expression was increased in the gastric corpus of patients with type 1 gNETs, and immunohistochemistry showed localization in the same vicinity as CCK2R-expressing enterochromaffin-like cells. Up-regulation of PAPPA2 also was found in the stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner in gastric AGS GR cells and mouse gastroids by activating CCK2R. Knockdown of PAPPA2 in AGS GR cells with small interfering RNAs significantly decreased their migratory response and tissue remodeling in response to gastrin. Gastrin altered the expression and cleavage of IGFBP3 and IGFBP5. Conclusions: In an analysis of human gNETS and mice, we found that gastrin up-regulates the expression of gastric PAPPA2. Increased PAPPA2 alters IGF bioavailability, cell migration, and tissue remodeling, which are involved in type 1 gNET development. These effects are inhibited by netazepide

Importance of the alternative NF-κB activation pathway in inflammation-associated gastrointestinal carcinogenesis

Chronic inflammation is a common factor in the development of many gastrointestinal malignancies. Examples include inflammatory bowel disease predisposing to colorectal cancer, Barrett's esophagus as a precursor of esophageal adenocarcinoma, and Helicobacter pylori-induced gastric cancer. The classical activation pathway of NF-κB signaling has been identified as regulating several sporadic and inflammation-associated gastrointestinal tract malignancies. Emerging evidence suggests that the alternative NF-κB signaling pathway also exerts a distinct influence on these processes. This review brings together current knowledge of the role of the alternative NF-κB signaling pathway in the gastrointestinal tract, with a particular emphasis on inflammation-associated cancer development. members of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) family were initially described as transcription factors in B lymphocytes in 1986 (68). Since then, they have been shown to be widely expressed and are conserved across both vertebrates and invertebrates (5, 27). The conventional model of NF-κB signaling proposes two main arms of the pathway. These share similar features but are triggered independently and activate different target genes (76). The classical (canonical) NF-κB activation pathway is triggered by Th1 cytokines and is typified by the action of reticuloendotheliosis viral oncogene homolog A (RelA) (p65)-NF-κB1(p50) heterodimers, whereas the alternative (noncanonical) activation pathway signals through the adaptor protein NF-κB-inducing kinase (NIK). Activation of this mechanism leads to nuclear translocation of transcriptionally active v-rel avian reticuloendotheliosis viral oncogene homolog B (RelB)-NF-κB2(p52) heterodimers. Signaling through either pathway can influence multiple different cellular functions and can exert effects that may appear contradictory. For example, both pro- and anti-apoptotic effects, as well as proliferation (18) and senescence (70) signals, have been attributed to the classical activation pathway of NF-κB signaling. Because of the wide variation in outcomes following pathway activation, it is difficult to extrapolate the effects of NF-κB signaling from one context to another. Classical pathway NF-κB signaling has been identified as a key regulator of inflammation-associated carcinogenesis in several tissues since the early 2000s when Greten et al. demonstrated increased sensitivity to colitis-associated carcinogenesis in mice lacking IKK-β in intestinal epithelial cells (31), and, almost simultaneously Pikarsky et al. identified a similar increase in tumor burden in Mdr2 mice lacking IKK-β in hepatocytes (60). More recent evidence has established that alternative activation pathway NF-κB signaling is also important during the development of several gastrointestinal pathologies in mouse and humans. This article seeks to review this evidence and to establish questions for future research

Inter-kingdom relationships in Crohn’s disease explored using a multi-omics approach

The etiology of Crohn’s disease (CD) is multifactorial. Bacterial and fungal microbiota are involved in the onset and/or progression of the disease. A bacterial dysbiosis in CD patients is accepted; however, less is known about the mycobiome and the relationships between the two communities. We investigated the interkingdom relationships, their metabolic consequences, and the changes in the fungal community during relapse and remission in CD. Two cohorts were evaluated: a British cohort (n = 63) comprising CD and ulcerative colitis patients, and controls. The fungal and bacterial communities of biopsy and fecal samples were analyzed, with the fecal volatiles; datasets were also integrated; and a Dutch cohort (n = 41) comprising CD patients and healthy controls was analyzed for stability of the gut mycobiome. A dysbiosis of the bacterial community was observed in biopsies and stool. Results suggest Bacteroides is likely key in CD and may modulate Candida colonization. A dysbiosis of the fungal community was observed only in the Dutch cohort; Malassezia and Candida were increased in patients taking immunosuppressants. Longitudinal analysis showed an increase in Cyberlindnera in relapse. Saccharomyces was dominant in all fecal samples, but not in biopsies, some of which did not yield fungal reads; amino acid degradation was the main metabolic change associated with CD and both bacteria and fungi might be implicated. We have shown that Bacteroides and yeasts may play a role in CD; understanding their role and relationship in the disease would shed new light on the development and treatment of CD

Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease

ObjectiveInflammatory bowel diseases cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect. This study aimed to identify drugs which alter NF-κB signalling and may be repositioned for use in inflammatory bowel disease.DesignThe SysmedIBD consortium established a novel drug-repurposing pipeline based on a combination of in-silico drug discovery and biological assays targeted at demonstrating an impact on NF-kappaB signalling, and a murine model of IBD.ResultsThe drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic Clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions. Clarithromycin's effects were validated in several experiments: it influenced NF-κB mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-κB protein shuttling in murine reporter enteroids; it suppressed NF-κB (p65) DNA binding in the small intestine of mice exposed to LPS, and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-κB (p65) nuclear translocation in human intestinal enteroids.ConclusionsThese findings demonstrate that in-silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of inflammatory bowel disease; and that further clinical assessment of clarithromycin in the management of inflammatory bowel disease is required

Comparative analysis of novel and conventional Hsp90 inhibitors on HIF activity and angiogenic potential in clear cell renal cell carcinoma: implications for clinical evaluation

<p>Abstract</p> <p>Background</p> <p>Perturbing Hsp90 chaperone function targets hypoxia inducible factor (HIF) function in a von Hippel-Lindau (VHL) independent manner, and represents an approach to combat the contribution of HIF to cell renal carcinoma (CCRCC) progression. However, clinical trials with the prototypic Hsp90 inhibitor 17-AAG have been unsuccessful in halting the progression of advanced CCRCC.</p> <p>Methods</p> <p>Here we evaluated a novel next generation small molecule Hsp90 inhibitor, EC154, against HIF isoforms and HIF-driven molecular and functional endpoints. The effects of EC154 were compared to those of the prototypic Hsp90 inhibitor 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589.</p> <p>Results</p> <p>The findings indicate that EC154 is a potent inhibitor of HIF, effective at doses 10-fold lower than 17-AAG. While EC154, 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589 impaired HIF transcriptional activity, CCRCC cell motility, and angiogenesis; these effects did not correlate with their ability to diminish HIF protein expression. Further, our results illustrate the complexity of HIF targeting, in that although these agents suppressed HIF transcripts with differential dynamics, these effects were not predictive of drug efficacy in other relevant assays.</p> <p>Conclusions</p> <p>We provide evidence for EC154 targeting of HIF in CCRCC and for LBH589 acting as a suppressor of both HIF-1 and HIF-2 activity. We also demonstrate that 17-AAG and EC154, but not LBH589, can restore endothelial barrier function, highlighting a potentially new clinical application for Hsp90 inhibitors. Finally, given the discordance between HIF activity and protein expression, we conclude that HIF expression is not a reliable surrogate for HIF activity. Taken together, our findings emphasize the need to incorporate an integrated approach in evaluating Hsp90 inhibitors within the context of HIF suppression.</p

The risky womb and the unthinkability of the pregnant man: addressing trans masculine hysterectomy

In April 2017, the European Court of Human Rights ruled that requiring trans people to undergo sterilisation in order to grant legal gender recognition was a breach of human rights. In the UK, sterilisation has never been a legal requirement for trans people. However, hysterectomy and salpingo-oopherectomy have been strongly encouraged for trans masculine people on medical grounds, although the clinical evidence for current recommendations is weak. Within this article I analyse the issue from a feminist perspective and argue that current presumptions in favour of surgical intervention are influenced by the history of medical interventions to “fix” bodies perceived as female, coupled with a strong social taboo against the pregnant man. As a consequence, medical and legal frameworks are not necessarily facilitating optimal outcomes for the individual. I suggest that practices in this regard should be critically examined, with a view to developing more tailored, person-centred practices and facilitating informed choice