Taheri, Negar

Neurointestinal diseases result from dysregulated interactions between the nervous system and the gastrointestinal (GI) tract, leading to conditions such as Hirschsprung’s disease and irritable bowel syndrome. These disorders affect many people, significantly diminishing their quality of life and overall health. Central to GI motility are the interstitial cells of Cajal (ICC), which play a key role in muscle contractions and neuromuscular transmission. This review highlights the role of ICC in neurointestinal diseases, revealing their association with various GI ailments. Understanding the functions of the ICC could lead to innovative perspectives on the modulation of GI motility and introduce new therapeutic paradigms. These insights have the potential to enhance efforts to combat neurointestinal diseases and may lead to interventions that could alleviate or even reverse these conditions.

Context Recent molecular discoveries have led to improved understanding of tumor biology and the development of new diagnostic assays. Objective To review primarily 3 examples of liver tumors and to briefly illustrate how recent molecular discoveries have altered clinical liver pathology practice. Data Sources First, we will discuss fibrolamellar carcinoma, which will be the main focus of discussion, as an example for new diagnostic tests that have been developed as a result of molecular discoveries. Additional information on the role of molecular diagnostics in hepatocellular adenoma and hepatocellular carcinoma will be provided. Second, we will use the example of epithelioid hemangioendothelioma as an example of how new diagnostic tools, based on molecular discoveries, may support improved prognostication. Finally, we will use the example of intrahepatic cholangiocarcinoma as an example of a liver tumor where new molecular discoveries have identified tractable therapeutic targets and led to new effective therapies. This portion of the manuscript will also include a description of the anatomic and molecular differences between intrahepatic, hilar, and extrahepatic cholangiocarcinoma. Conclusions Fueled by molecular discoveries, new and better diagnostic tests and therapeutic targets have improved clinical care in patients affected by liver tumors.

Due to modern medical advancements, greater proportions of the population will continue to age with longer life spans. Increased life span, however, does not always correlate with improved health span, and may result in an increase in aging-related diseases and disorders. These diseases are often attributed to cellular senescence, in which cells become disengaged from the cell cycle and inert to cell death. These cells are characterized by a proinflammatory secretome. The proinflammatory senescence-associated secretory phenotype, although part of a natural function intended to prevent further DNA damage, creates a microenvironment suited to tumor progression. This microenvironment is most evident in the gastrointestinal tract (GI), where a combination of bacterial infections, senescent cells, and inflammatory proteins can lead to oncogenesis. Thus, it is important to find potential senescence biomarkers as targets of novel therapies for GI diseases and disorders including cancers. However, finding therapeutic targets in the GI microenvironment to reduce the risk of GI tumor onset may also be of value. This review summarizes the effects of cellular senescence on GI aging, inflammation, and cancers, and aims to improve our understanding of these processes with a goal of enhancing future therapy.

Objective Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC. Design We used in vitro and in vivo models of resistant PDAC and integrated epigenomic, transcriptomic, nascent RNA and chromatin topology data. We identified a JunD-driven subgroup of enhancers, called interactive hubs (iHUBs), which mediate transcriptional reprogramming and chemoresistance in PDAC. Results iHUBs display characteristics typical for active enhancers (H3K27ac enrichment) in both therapy sensitive and resistant states but exhibit increased interactions and production of enhancer RNA (eRNA) in the resistant state. Notably, deletion of individual iHUBs was sufficient to decrease transcription of target genes and sensitise resistant cells to chemotherapy. Overlapping motif analysis and transcriptional profiling identified the activator protein 1 (AP1) transcription factor JunD as a master transcription factor of these enhancers. JunD depletion decreased iHUB interaction frequency and transcription of target genes. Moreover, targeting either eRNA production or signaling pathways upstream of iHUB activation using clinically tested small molecule inhibitors decreased eRNA production and interaction frequency, and restored chemotherapy responsiveness in vitro and in vivo. Representative iHUB target genes were found to be more expressed in patients with poor response to chemotherapy compared with responsive patients. Conclusion Our findings identify an important role for a subgroup of highly connected enhancers (iHUBs) in regulating chemotherapy response and demonstrate targetability in sensitisation to chemotherapy.

Wnt signaling involves multiple pathways that contribute to organ development, cell fate, inflammation, and normal stem cell renewal and maintenance. Although the homeostasis of stem cells in the gastrointestinal (GI) tract highly depends on the Wnt signaling pathway, this regulation is impaired in cancers and in aging. Overactive (uncontrolled) Wnt signaling can induce GI epithelial cancers such as colon and gastric cancer. Overactive Wnt signaling can also contribute to the initiation and progression of gastrointestinal stromal tumor, which is the most common human sarcoma occurring in the walls of the digestive organs, mainly the stomach and small intestine. Wnt expression is positively associated not only with the progression of oncogenesis but also with resistance to chemotherapy and radiotherapy. Of note, recent reports show that decreased Wnt signaling is related to intestinal stem cell aging and that overactivated Wnt signaling leads to gastric pacemaker stem cell aging in tunica muscularis. These findings indicate that Wnt signaling has different crucial aspects of cell fate determination with age in GI tunica mucosa and muscularis. In this review, we summarize the most recent advances in our understanding of Wnt signaling pathways and their role in regulating key aspects during development, carcinogenesis, inflammation, and aging, with the ultimate goal of identifying novel therapies.

AbstractBackgroundAging is a complex biological process and associated with a progressive decline in functions of most organs including the gastrointestinal (GI) tract. Age‐related GI motor disorders/dysfunctions include esophageal reflux, dysphagia, constipation, fecal incontinence, reduced compliance, and accommodation. Although the incidence and severity of these diseases and conditions increase with age, they are often underestimated due in part to nonspecific and variable symptoms and lack of sufficient medical attention. They negatively affect quality of life and predispose the elderly to other diseases, sarcopenia, and frailty. The mechanisms underlying aging‐associated GI dysfunctions remain unclear, and there is limited data examining the effect of aging on GI motor functions. Many studies on aging‐associated changes to cells within the tunica muscularis including enteric neurons, smooth muscles, and interstitial cells have proposed that cell loss and/or molecular changes may be involved in the pathogenesis of age‐related GI motor disorders/dysfunctions. There is also evidence that the aging contributes to phenotypic changes in innate immune cells, which are physically and functionally linked to other cells in the tunica muscularis and can alter GI (patho) physiology. However, various patterns of changes have been reported, some of which are contradictory, indicating a need for additional work in this area.PurposeAlthough GI infection due to intestinal bacterial overgrowth, bleeding, and cancers are also important and common problems in the elderly patients, this mini‐review focuses on data obtained from enteric neuromuscular aging research with the goal of better understanding the cellular and molecular mechanisms of enteric neuromuscular aging to enhance future therapy.