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Summary: The rapid decrease in infectious diseases globally has coincided with an increase in the prevalence of obesity and other components of metabolic syndrome. Insulin resistance is a common feature of metabolic syndrome and can be influenced by genetic and non‐genetic/environmental factors. The emergence of metabolic syndrome epidemics over only a few decades suggests a more prominent role of the latter. Changes in our environment and lifestyle have indeed paralleled the rise in metabolic syndrome. Gastrointestinal tract microbiota, the composition of which plays a significant role in host physiology, including metabolism and energy homeostasis, are distinctly different within the context of metabolic syndrome. Among humans, recent lifestyle‐related changes could be linked to changes in diversity and composition of 'ancient' microbiota. Given the co‐adaptation and co‐evolution of microbiota with the immune system over a long period of time, it is plausible that such lifestyle‐related microbiota changes could trigger aberrant immune responses, thereby predisposing an individual to a variety of diseases. Here, we review current evidence supporting a role for gut microbiota in the ongoing rise of metabolic syndrome. We conclude that population‐level shifts in microbiota can play a mediatory role between lifestyle factors and pathogenesis of insulin resistance and metabolic syndrome. [ABSTRACT FROM AUTHOR]

Abstract Background Achalasia is a well-characterized esophageal motor disorder but the rarity of the disease limits performing large studies on its demographic and clinical features. Methods Prospectively, 213 achalasia patients (110 men and 103 women) were enrolled in the study. The diagnosis established by clinical, radiographic, and endoscopic as well as manometry criteria. All patients underwent a pre-designed clinical evaluation before and within 6 months after the treatment. Results Solid dysphagia was the most common clinical symptom in men and women. Chest pain was the only symptom which was significantly different between two groups and was more complained by women than men (70.9% vs. 54.5% P value= 0.03). Although the occurrence of chest pain significantly reduced after treatment in both groups (P < 0.001), it was still higher among women (32% vs. 20.9% P value= 0.04). In both sexes, chest pain did not relate to the symptom duration, LES pressure and type of treatment patients received. Also no significant relation was found between chest pain and other symptoms expressed by men and women before and after treatment. Chest pain was less frequently reported by patients over 56 yrs of age in comparison to those less than 56 yrs (p < 0.05). Conclusion It seems that chest pain is the distinct symptom of achalasia which is affected by sex as well as age and does not relate to the duration of illness, LESP and the type of treatment achalasia patients receive.

Abstract Background Previous reports show a high proportion of young CRC patients in Iran. In this study we aim to look for the clustering of colorectal cancer in families of a series of CRC patients from Iran. Methods The family history of cancer is traced in 449 CRC patients of which 112 were 45 yrs or younger and 337 were older than 45 yrs at time of diagnosis. The patients were admitted in two hospitals in Tehran, during a 4-year period. Results Clinical diagnosis of HNPCC was established in 21 (4.7%) probands. Family history of CRC was more frequently reported by early-onset than by late-onset patients (29.5% vs. 12.8%, p < 0.001). Distribution of tumor site differed significantly between those with and without family history of CRC. Right colon cancer was the most frequent site (23/45, 35.4%) observed in patients with positive family history of colorectal cancer. Conclusion The relatively high frequency of CRC clustering along with HNPCC in our patients should be further confirmed with larger sample size population-based and genetic studies to establish a cost effective molecular screening for the future.

Purpose: Colorectal cancer (CRC) is linked to lifestyle exposures. However, changes in the CRC rates among younger populations remain poorly understood and suggest the existence of yet unidentified factor(s) that may contribute to colon carcinogenesis. Here, we investigated the potential role of time of eating in the risk of pre-cancerous colonic neoplasms (tubular adenoma: TA)., Methods: We enrolled 663 participants undergoing screening colonoscopies. Data on food timing, dietary intake, sleep/wake patterns, and chronotype were collected through structured questionnaires. Late eating was defined as the consumption of food or snack within a 3-hour window of sleep onset for at least four days a week. Pathology reports confirmed the histology of colonic polyps, and adenomas were further classified into risk categories., Results: A total of 644 patients met criteria for our study. There were 270 (42.2%) participants classified as late eaters. Compared to non-late eaters, the odds of TA were higher in late eaters (OR = 1.46, 95% CI = 1.05-2.03, p = 0.023), an association which was strengthened after adjusting for multiple confounders (OR 1.98, 95% CI 1.19-3.28, p = 0.008). Late eating remained an independent risk factor for high-risk as well as multiple TAs., Conclusion: This study proposes late eating as a risk factor for colon tubular adenomas and underscores the potential role of less studied forms of circadian disruption imposed by time of eating in the development of colon neoplastic formation., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Alcohol use disorder accounts for a growing worldwide health system concern. Alcohol causes damages to various organs, including intestine and liver, primarily involved in its absorption and metabolism. However, alcohol-related organ damage risk varies significantly among individuals, even when they report consuming comparable dosages of alcohol. Factor(s) that may modulate the risk of organ injuries from alcohol consumption could be responsible for inter-individual variations in susceptibility to alcohol-related organ damages. Accumulating evidence suggests disruptions in circadian rhythm can exacerbate alcohol-related organ damages. Here we investigated the interplay between alcohol, circadian rhythm, and key tissue cellular processes at baseline, after a regular and a shift in the light/dark cycle (LCD) in mice. Central/peripheral clock expression of core clock genes (CoClGs) was analyzed. We also studied circadian homeostasis of tissue cellular processes that are involved in damages from alcohol. These experiments reveal that alcohol affects the expression of CoClGs causing a central-peripheral dyssynchrony, amplified by shift in LCD. The observed circadian clock dyssynchrony was linked to circadian disorganization of key processes involved in the alcohol-related damages, particularly when alcohol was combined with LCD. These results offer insights into the mechanisms by which alcohol interacts with circadian rhythm disruption to promote organ injury., (© 2024 Wiley‐VCH GmbH.)

Patient-derived organoids (PDOs) developed ex vivo and in vitro are increasingly used for therapeutic screening. They provide a more physiologically relevant model for drug discovery and development compared to traditional cell lines. However, several challenges remain to be addressed to fully realize the potential of PDOs in therapeutic screening. This paper summarizes recent advancements in PDO development and the enhancement of PDO culture models. This is achieved by leveraging materials engineering and microfabrication technologies, including organs-on-a-chip and droplet microfluidics. Additionally, this work discusses the application of PDOs in therapy screening to meet diverse requirements and overcome bottlenecks in cancer treatment. Furthermore, this work introduces tools for data processing and analysis of organoids, along with their microenvironment. These tools aim to achieve enhanced readouts. Finally, this work explores the challenges and future perspectives of using PDOs in drug development and personalized screening for cancer patients., (© 2024 Wiley‐VCH GmbH.)

Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer characterized by a poor outcome and an increasing incidence. A significant majority (>80%) of newly diagnosed cases are deemed unresectable, leaving chemotherapy as the sole viable option, though with only moderate success. This necessitates the identification of improved therapeutic options for PDA. We hypothesized that there are temporal variations in cancer-relevant processes within PDA tumors, offering insights into the optimal timing of drug administration - a concept termed chronotherapy. In this study, we explored the presence of the circadian transcriptome in PDA using patient-derived organoids and validated these findings by comparing PDA data from The Cancer Genome Atlas with noncancerous healthy pancreas data from GTEx. Several PDA-associated pathways (cell cycle, stress response, Rho GTPase signaling) and cancer driver hub genes (EGFR and JUN) exhibited a cancer-specific rhythmic pattern intricately linked to the circadian clock. Through the integration of multiple functional measurements for rhythmic cancer driver genes, we identified top chronotherapy targets and validated key findings in molecularly divergent pancreatic cancer cell lines. Testing the chemotherapeutic efficacy of clinically relevant drugs further revealed temporal variations that correlated with drug-target cycling. Collectively, our study unravels the PDA circadian transcriptome and highlights a potential approach for optimizing chrono-chemotherapeutic efficacy.

Introduction: Aging studies in humans and mice have played a key role in understanding the intestinal microbiome and an increased abundance of "inflammaging" Gram-negative (Gn) bacteria. The mechanisms underlying this inflammatory profile in the aging microbiome are unknown. We tested the hypothesis that an aging-related decrease in colonic crypt epithelial cell anti-microbial peptide (AMP) gene expression could promote colonic microbiome inflammatory Gn dysbiosis and inflammaging. Methods: As a model of aging, C57BL/6J mice fecal (colonic) microbiota (16S) and isolated colonic crypt epithelial cell gene expression (RNA-seq) were assessed at 2 months (mth) (human: 18 years old; yo), 15 mth (human: 50 yo), and 25 mth (human: 84 yo). Informatics examined aging-related microbial compositions, differential colonic crypt epithelial cell gene expressions, and correlations between colonic bacteria and colonic crypt epithelial cell gene expressions. Results: Fecal microbiota exhibited significantly increased relative abundances of pro-inflammatory Gn bacteria with aging. Colonic crypt epithelial cell gene expression analysis showed significant age-related downregulation of key AMP genes that repress the growth of Gn bacteria. The aging-related decrease in AMP gene expressions is significantly correlated with an increased abundance in Gn bacteria (dysbiosis), loss of colonic barrier gene expression, and senescence- and inflammation-related gene expression. Conclusion: This study supports the proposed model that aging-related loss of colonic crypt epithelial cell AMP gene expression promotes increased relative abundances of Gn inflammaging-associated bacteria and gene expression markers of colonic inflammaging. These data may support new targets for aging-related therapies based on intestinal genes and microbiomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Forsyth, Shaikh, Engen, Preuss, Naqib, Palmen, Green, Zhang, Bogin, Lawrence, Sharma, Swanson, Bishehsari, Voigt and Keshavarzian.)

The incidence rate of colorectal cancer in younger adults has been rising in developed countries. This trend may be attributed to environmental exposures as a result of lifestyle changes. Many of the lifestyle factors that promote colorectal cancer can also affect the gut microbiome, which may be associated with colorectal cancer risks. The role of the microbiome in the ongoing rise of early-onset colorectal cancer is unknown. Here, we aimed to investigate age-related differences in the gut microbiome of patients with colorectal cancer and healthy individuals by examining both the fecal and tumor microbiomes. We utilized the publicly accessible data on fecal shotgun metagenomics from CuratedMetagenomeData and TCGA via the GDC Data Portal. Comparison of 701 colorectal cancer and 693 controls revealed that microbial features were age dependent, with a significant difference in species enrichment between early-onset (<50 years) and late-onset (>65 years) patients with colorectal cancer. Analysis of the tumor-associated microbiome in a separate dataset of 85 patients with colorectal cancer verified age-specific differences in taxon abundance between early- and late-onset patients with colorectal cancer. Finally, using host gene expression data, we found a stronger microbe-host interaction in early- vs. late-onset colorectal cancers. Altogether, these findings indicate that microbial features were age-dependent with stronger microbial-host interactions at the tumor site in early-onset colorectal cancers, suggesting a direct role of microbes in tumorigenesis via interaction with cancer-related pathways in this age group., Prevention Relevance: Early-onset colorectal cancer is on the rise, presumably because of changes in environmental exposures. Lifestyle changes may contribute to colorectal cancer via alterations in gut microbes. Here, we show that microbial association with colorectal cancer is age-dependent, and microbe interactions with tumor pathways are stronger in young versus older colorectal cancers., (©2023 American Association for Cancer Research.)

Colorectal cancer (CRC) is one of the most common and fatal types of cancer. Inflammation promotes CRC development, however, the underlying etiological factors are unknown. Human cytomegalovirus (HCMV), a virus that induces inflammation and other cancer hallmarks, has been detected in several types of malignancy, including CRC. The present study investigated whether HCMV infection was associated with expression of the pro‑inflammatory enzymes 5‑lipoxygenase (5‑LO) and cyclooxygenase‑2 (COX‑2) and other molecular, genetic and clinicopathological CRC features. The present study assessed 146 individual paraffin‑embedded CRC tissue microarray (TMA) cores already characterized for TP53 and KRAS mutations, microsatellite instability (MSI) status, Ki‑67 index and EGFR by immunohistochemistry (IHC). The cores were further analyzed by IHC for the expression of two HCMV proteins (Immediate Early, IE and pp65) and the inflammatory markers 5‑LO and COX‑2. The CRC cell lines Caco‑2 and LS‑174T were infected with HCMV strain VR1814, treated with antiviral drug ganciclovir (GCV) and/or anti‑inflammatory drug celecoxib (CCX) and analyzed by reverse transcription‑quantitative PCR and immunofluorescence for 5‑LO, COX‑2, IE and pp65 transcripts and proteins. HCMV IE and pp65 proteins were detected in ~90% of the CRC cases tested; this was correlated with COX‑2, 5‑LO and KI‑67 expression, but not with EGFR immunostaining, TP53 and KRAS mutations or MSI status. In vitro , HCMV infection upregulated 5‑LO and COX‑2 transcript and proteins in both Caco‑2 and LS‑174T cells and enhanced cell proliferation as determined by MTT assay. Treatment with GCV and CCX significantly decreased the transcript levels of COX‑2, 5‑LO, HCMV IE and pp65 in infected cells. HCMV was widely expressed in CRC and may promote inflammation and serve as a potential new target for CRC therapy.

The epidemy of metabolic syndrome (MetS) is typically preceded by adoption of a "risky" lifestyle (e.g., dietary habit) among populations. Evidence shows that those with low socioeconomic status (SES) are at an increased risk for MetS. To investigate this, we recruited 123 obese subjects (body mass index [BMI] ≥ 30) from Chicago. Multi-omic data were collected to interrogate fecal microbiota, systemic markers of inflammation and immune activation, plasma metabolites, and plasma glycans. Intestinal permeability was measured using the sugar permeability testing. Our results suggest a heterogenous metabolic dysregulation among obese populations who are at risk of MetS. Systemic inflammation, linked to poor diet, intestinal microbiome dysbiosis, and gut barrier dysfunction may explain the development of MetS in these individuals. Our analysis revealed 37 key features associated with increased numbers of MetS features. These features were used to construct a composite metabolic-inflammatory (MI) score that was able to predict progression of MetS among at-risk individuals. The MI score was correlated with several markers of poor diet quality as well as lower levels of gut microbial diversity and abnormalities in several species of bacteria. This study reveals novel targets to reduce the burden of MetS and suggests access to healthy food options as a practical intervention., (© 2023 Wiley-VCH GmbH.)

The evolutionarily conserved circadian system allows organisms to synchronize internal processes with 24-h cycling environmental timing cues, ensuring optimal adaptation. Like other organs, the pancreas function is under circadian control. Recent evidence suggests that aging by itself is associated with altered circadian homeostasis in different tissues which could affect the organ's resiliency to aging-related pathologies. Pancreas pathologies of either endocrine or exocrine components are age-related. Whether pancreas circadian transcriptome output is affected by age is still unknown. To address this, here we profiled the impact of age on the pancreatic transcriptome over a full circadian cycle and elucidated a circadian transcriptome reorganization of pancreas by aging. Our study highlights gain of rhythms in the extrinsic cellular pathways in the aged pancreas and extends a potential role to fibroblast-associated mechanisms.

Introduction: Chronotherapy is the timing of medication according to biological rhythms of the host to optimize drug efficacy and minimize toxicity. Efficacy and myelosuppression of azathioprine/6-mercaptopurine (AZA/6-MP) are correlated with the metabolite 6-thioguanine, while the metabolite 6-methylmercaptopurine correlates with hepatotoxicity., Methods: This was a single-center, 10-week prospective crossover trial involving 26 participants with inactive inflammatory bowel disease (IBD) on a stable dose and time of AZA or 6-MP therapy. Participants were switched to the opposite delivery time (morning or evening) for 10 weeks, and metabolite measurements were at both time points., Results: In the morning vs evening dosing, 6-thioguanine levels were 225.7 ± 155.1 vs 175.0 ± 106.9 ( P < 0.01), and 6-methylmercaptopurine levels were 825.1 ± 1,023.3 vs 2,395.3 ± 2,880.3 ( P < 0.01), with 69% (18 out of 26) of participants had better metabolite profiles in the morning. Participants with optimal dosing in the morning had an earlier chronotype by corrected midpoint of sleep., Discussion: In the first study on a potential role of chronotherapy in IBD, we found (i) morning dosing of AZA or 6-MP resulted in more optimal metabolite profiles and (ii) host chronotype could help identify one-third of patients who would benefit from evening dosing. Circadian regulation of metabolic enzymes of AZA/6-MP activity in the liver is the likely cause of these differences. This pilot study confirms the need to incorporate chronotherapy in future multicenter clinical trials on IBD disease., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

In Dec. 2019-January 2020, a pneumonia illness originating in Wuhan, China, designated as coronavirus disease 2019 (COVID-19) was shown to be caused by a novel RNA coronavirus designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). People with advanced age, male sex, and/or underlying health conditions (obesity, type 2 diabetes, cardiovascular disease, hypertension, chronic kidney disease, and chronic lung disease) are especially vulnerable to severe COVID-19 symptoms and death. These risk factors impact the immune system and are also associated with poor health, chronic illness, and shortened longevity. However, a large percent of patients without these known risk factors also develops severe COVID-19 disease that can result in death. Thus, there must exist risk factors that promote exaggerated inflammatory and immune response to the SARS-CoV-2 virus leading to death. One such risk factor may be alcohol misuse and alcohol use disorder because these can exacerbate viral lung infections like SARS, influenza, and pneumonia. Thus, it is highly plausible that alcohol misuse is a risk factor for either increased infection rate when individuals are exposed to SARS-CoV-2 virus and/or more severe COVID-19 in infected patients. Alcohol use is a well-known risk factor for lung diseases and ARDS in SARS patients. We propose that alcohol has three key pathogenic elements in common with other COVID-19 severity risk factors: namely, inflammatory microbiota dysbiosis, leaky gut, and systemic activation of the NLRP3 inflammasome. We also propose that these three elements represent targets for therapy for severe COVID-19., (© 2022 Research Society on Alcoholism.)

There is a growing interest to understand if and how the gut microbiome is causally linked to the pathogenesis and/or progression of diseases. While in vitro cell line models are commonly used for studying specific aspects of the host-microbe interaction, gnotobiotic murine models are considered the preferred platform for studying causality in microbiome research. Nevertheless, findings from animal studies provide limited opportunity for delineating various areas of interest to the human gut microbiome research. Gut-on-chips are biomimetics recapitulating intestinal physiology which enable investigation of bidirectional effects of the host and microbiome. We posit that they could advance causal and ecological gut microbiome research in three major areas: (i) diet-microbiome and drug-microbiome interaction; (ii) microbiome-targeted therapeutics pharmacoecology; and (iii) mechanistic studies of gut microbiome and microbiome-targeted intervention in extraintestinal pathologies., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The main composition of intestinal microbiota in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) patients has not yet been elucidated. In this, case-control study, we identified differences of intestinal microbiota in male patients with NAFLD, presumed NASH, and healthy controls., Materials and Methods: We compared gut microbial composition of 25 patients with NAFLD, 13 patients with presumed NASH, and 12 healthy controls. Demographic information as well as clinical, nutritional, and physical activity data was gathered. Stool and blood samples were collected to perform the laboratory analysis. The taxonomic composition of gut microbiota was assessed using V4 regions of microbial small subunit ribosomal Ribonucleic acid genes sequencing of stool samples., Results: Firmicutes, Actinobacteria, and Bacteroidetes were the most frequently phyla in all groups. Our results revealed that Veillonella was the only genus with significantly different amounts in presumed NASH patients compared with patients with NAFLD ( P = 2.76 × 10 -6 , q = 2.07 × 10 -4 , logFC = 5.52)., Conclusion: This pilot study was the first study to compare gut microbial composition in patients with NAFLD and presumed NASH in the Middle East. Given the potential effects of gut microbiota on the management and prevention of NAFLD, larger, prospective studies are recommended to confirm this study's findings., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Research in Medical Sciences.)

Opioids are the most popular drugs for both acute and chronic pain management. The G protein-coupled mu-opioid receptor (MOR) is the therapeutic target for most clinically used opioids, including morphine. A mounting number of publications suggest a relationship between the MOR and possible cancer progression and recurrence extending to managing chronic cancer pain. In this study, we studied the possible link between opioid use and pancreatic cancer (PC) progression. We found increased MOR expression in murine and human PC cell lines, human PC-derived organoids, and in the undifferentiated or poorly differentiated areas of surgically resected PC tissues. Direct stimulation of MOR by morphine (MOR agonist) caused a significant dose-dependent increase in proliferation, invasion, and levels of stemness markers in PC cells. In a co-culture system, MOR stimulation of macrophages also resulted in increased proliferation of PC cells. MOR overexpression increased proliferation and cancer stemness, whereas knock-down of MOR followed opposite results in the PC cells. Morphine induced chemoresistance to conventional chemotherapeutic agents used for PC treatment. Overall, our results suggest that MOR is expressed in pancreatic cancer and may be involved in tumor progression and chemoresistance., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Metabolic dysfunction and obesity rates are on the rise. Although the central modes of circadian disruption has been studied in relation to the risk of obesity, the role of eating time has remained unclear. Here, we aimed to assess circadian behavioral phenotypes and their association with the risk of elevated body mass index (BMI)., Methods: This was a prospective cross-sectional study of individuals presenting for colorectal cancer screening colonoscopy. Participants completed demographic questionnaires, The Munich ChronoType Questionnaire (MCTQ), and Food Timing Screener (FTS). The primary outcome of the study was the association between circadian phenotypes and elevated BMI., Results: A total of 488 individuals completed the survey, with a mean (SD) age of 57.5 (10.8) years. The mean body mass index (BMI) was 28.8 (6.1) kg/m 2 , with 72.3% of individuals met criteria for elevated BMI. Four circadian behavioral phenotypes were generated: early chronotype with regular food timing (ER) (34.7%), early chronotype with irregular food timing (EI) (11.7%), intermediate/late chronotype with regular food timing (LR) (33.9%), and intermediate/late chronotype with irregular food timing (LI) (19.7%). In a multivariable regression analysis, LI phenotype had 2.9 times higher odds of elevated BMI as compared to ER phenotype (OR 2.9, 95% CI 1.3-6.7, P = 0.01)., Conclusion: The combination of late chronotype and irregular food timing, representative of a behavioral circadian rhythm disruption, is associated with higher rates of elevated BMI. The majority of individuals with this abnormal circadian phenotype were younger than 60 years old. This observation is especially relevant because of the ongoing rise in the obesity rates among young adults., Level Iii: Evidence obtained from well-designed cohort or case-control analytic studies., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Disruptions in sleep related to mealtime may contribute to gut microbial imbalances, and put individuals at higher risk for metabolic diseases. The aim of this pilot study was to investigate the relationships between late-night eating habits and sleep quality and duration, with gut microbiota (GM) profiles., Methods: In this cross-sectional study, 36 men referred to a clinic were enrolled. In addition to demographic information, each participant completed questionnaires regarding medical history, physical activity, late-night eating habits, sleep quality and sleep duration. The scores from these questionnaires were used to categorize study participants into the following groups: sleep quality (good or poor), late-night eating (yes or no) and sleep duration (<7 or ≥7 hours). Five grams of stool was also obtained from each participant for GM profiling analysis by sequencing., Results: The mean age of the study population was 42.1 ± 1.6 years. Firmicutes and Actinobacteria were the two dominant phyla present in all participant samples. Differences in the relative abundance of GM at each taxonomic rank between study groups were insignificant. Only Erysipelotrichales at the order level were found to be significantly different between individuals who had late-night eating habits and those who did not ( P & q < 0.05). No other parameter demonstrated a significant difference in GM profiles of participants., Conclusion: In this pilot study, we found Erysipelotrichales to be more abundant in individuals with late-night eating habits. Studies with higher sample sizes are warranted to better delineate the possible effects of time of eating on microbial composition., (© 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

The patient population suffering from pancreatic ductal adenocarcinoma (PDAC) presents, as a whole, with a high degree of molecular tumor heterogeneity. The heterogeneity of PDAC tumor composition has complicated treatment and stalled success in clinical trials. Current in vitro techniques insufficiently replicate the intricate stromal components of PDAC tumor microenvironments (TMEs) and fail to model a given tumor's unique genetic phenotype. The development of patient-derived organoids (PDOs) has opened the door for improved personalized medicine since PDOs are derived directly from patient tumors, thus preserving the tumors' unique behaviors and genetic phenotypes. This study developed a tumor-chip device engineered to mimic the PDAC TME by incorporating PDOs and stromal cells, specifically pancreatic stellate cells and macrophages. Establishing PDOs in a multicellular microfluidic chip device prolongs cellular function and longevity and successfully establishes a complex organotypic tumor environment that incorporates desmoplastic stroma and immune cells. When primary cancer cells in monoculture were subjected to stroma-depleting agents, there was no effect on cancer cell viability. However, targeting stroma in our tumor-chip model resulted in a significant increase in the chemotherapy effect on cancer cells, thus validating the use of this tumor-chip device for drug testing., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2022.)

Background and Aims: Fatty infiltration of the pancreas has been shown to be associated with both precancerous pancreatic lesions and pancreatic ductal adenocarcinoma. We aim to determine predictors of fatty infiltration of the pancreas in United States adults., Methods: In this retrospective cohort study conducted at a large academic hospital in Chicago, Illinois, we calculated the relative fatty infiltration of the pancreas (corrected to spleen) of 265 cancer-free individuals based on their cross-sectional imaging. Demographic data and relevant laboratory results were obtained from medical records., Results: We found that age was the strongest predictor of fatty infiltration of the pancreas in our series ( P < .01). Fatty infiltration of the pancreas was also significantly associated with body mass index ( P < .01) and hyperlipidemia ( P < .05). In women, in addition to age ( P < .05), elevated body mass index ( P  = .023), hyperlipidemia ( P  = .013), and fatty liver ( P  = .017) were predictors of fat in pancreas. We found a sex-dependent association between pancreatic fat and metabolic syndrome including fatty liver ( P  = .002)., Conclusion: Fatty infiltration of the pancreas increases by age and components of metabolic syndrome. These assertions could be sex-dependent., (© 2022 The Authors.)

Recently, we described a phenomenon whereby apoptotic cells generate and release CrkI-containing microvesicles, which stimulate proliferation in surrounding cells upon contact to compensate for their own demise. We termed these microvesicles "ACPSVs" for Apoptotic Compensatory Proliferation Signaling microvesicles. As immune cells and a majority of current cancer therapeutics destroy tumor cells primarily by apoptosis, we conducted a small pilot study to assess the possibility that ACPSVs may also be generated in squamous cell carcinomas. We first evaluated a primary and a metastatic squamous cell carcinoma cancer cell lines for their ability to produce ACPSVs under normal and apoptotic conditions. We next conducted a pilot study to assess the occurrence of ACPSVs in solid tumors extracted from 20 cancer patients with squamous cell carcinomas. Both cancer cell lines produced copious amounts of ACPSVs under apoptotic conditions. Interestingly, the metastatic squamous cell carcinoma cancer cell line also produced high levels of ACPSVs under healthy condition, suggesting that the ability to generate ACPSVs may be hijacked by these cells. Importantly, ACPSVs were also abundant in the solid tumors of all squamous cell carcinoma cancer patients. Detection of ACPSVs in cancer has potentially important ramifications in tumor biology and cancer therapeutics which warrants further investigation., (© 2022. The Author(s).)

Coronavirus disease 2019 (COVID-19) has taken hundreds of thousands of lives globally. Besides the respiratory tract, the virus can affect the gastrointestinal (GI) tract. Data regarding the significance of GI symptoms in the COVID-19 course are limited. In this largest US study to date, the authors reviewed electronic encounters of 1003 consecutive patients who were tested positive for the virus between March 12 and April 3, 2020. Initial GI symptoms were present in up to 22.4% of patients and were associated with worse outcomes after adjustment for demographics, comorbidities, and other clinical symptoms. COVID-19 with GI involvement may define a more severe phenotype., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Obesity is characterized by an accumulation of redundant body fat linked to metabolic dysregulation and low-grade systemic inflammation. Lifestyle choices are imperative determining factors of obesity. The contemporary lifestyle is associated with behaviors that disrupt circadian rhythms, impacting metabolic homeostasis. Our animal and human studies suggest that circadian phenotypes could be related to the risk of metabolic dysregulation and obesity. The purpose of this study is to examine the role of inconsistent eating habits on body weight in adults. Individuals who presented for colon cancer screening were enrolled. Subjects received structured questionnaires to capture 7-day eating and sleeping times in a week prospectively. Bodyweight and height were extracted from medical records, and Body Mass Index (BMI) was calculated. Inconsistent eating times were defined as an average difference of >2 hours between the largest meal on weekdays and weekends. Forty-nine of the 61 (80.3 %) individuals enrolled in the study completed the questionnaires. The mean age and standard deviation (SD) were 60.8 (7.9), and 27 (55.1 %) were male. Subjects with inconsistent eating times had a significantly higher BMI (33.8 ± 3.6 SD, n = 9) than subjects who did not (27.5 ± 6.5 SD, n = 40; p = 0.001). The highest BMI was observed in subjects who ate inconsistently and late (35.8 ± 4.6 SD). In this cross-sectional study, time of eating habits was associated with BMI. Controlled cohort studies are needed to determine the potential link between eating time and the risk of obesity in the long term., (Copyright © 2022 Adnan et al.)

Background: Circadian rhythms coordinate multiple biological processes, and time of eating is an important entrainer of peripheral circadian clocks, including those in the gastrointestinal tract and liver. Whereas time of eating can be assessed through valid and reliable tools designed to measure nutrient intake (24-h recalls), currently there is no easily administered, valid, and reliable tool designed to specifically assess both time of food intake and sleep., Objectives: The objective of this study was to test the validity and reliability of 2 questionnaires developed to measure food and sleep-wake timing, the Food Timing Questionnaire (FTQ) and Food Timing Screener (FTS), and the agreement between these 2 tools., Methods: The content validity of these tools was assessed by an expert panel of 10 registered dietitian nutritionists. Adult volunteers ( n  = 61) completed both tools to assess internal consistency and test-retest reliability. Criterion-related validity was determined through the association of FTQ and FTS with 2 valid instruments, the Automated Self-Administered 24-hour recall (ASA24 ® ) Dietary Assessment tool and the Munich Chronotype Questionnaire. Agreement between the FTQ and FTS was tested by calculating the Pearson's correlations for both food and sleep-wake timing., Results: The content validity indexes for both tools were >0.80, and internal consistency and test-retest reliability coefficients were >0.50 for all meals and sleep-wake times. Correlation coefficients were >0.40 between both tools and criterion measures of food intake and sleep except for snacks. Correlations between the FTQ and FTS for all eating events and sleep were >0.60 except for snack 1., Conclusions: Both the FTQ and FTS are valid and reliable instruments for meal timing and sleep. However, further psychometric testing in a more expansive and diverse sample will improve the ability of these tools to accurately assess food timing and sleep and their impact on health outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Pancreatic Ductal Adenocarcinoma (PDAC) is an expeditiously fatal malignancy with a five-year survival rate of 6-8%. Conventional chemotherapeutics fail in many cases due to inadequate primary response and rapidly developing resistance. This treatment failure is particularly challenging in pancreatic cancer because of the high molecular heterogeneity across tumors. Additionally, a rich fibro-inflammatory component within the tumor microenvironment (TME) limits the delivery and effectiveness of anticancer drugs, further contributing to the lack of response or developing resistance to conventional approaches in this cancer. As a result, there is an urgent need to model pancreatic cancer ex vivo to discover effective drug regimens, including those targeting the components of the TME on an individualized basis. Patient-derived three-dimensional (3D) organoid technology has provided a unique opportunity to study patient-specific cancerous epithelium. Patient-derived organoids cultured with the TME components can more accurately reflect the in vivo tumor environment. Here we present the advances in organoid technology and multicellular platforms that could allow for the development of "organ-on-a-chip" approaches to recapitulate the complex cellular interactions in PDAC tumors. We highlight the current advances of the organ-on-a-chip-based cancer models and discuss their potential for the preclinical selection of individualized treatment in PDAC.

Pancreatic ductal adenocarcinoma (PDA) is an extremely lethal malignancy arising from the pancreas. The treatment of PDA is complicated by ineffective treatments and a lack of biomarkers predictive of treatment success. We have designed a patient-derived organoid (PDO) based high-throughput drug screening assay to model treatment response to a variety of conventional and investigational treatments for PDA. Consecutive patients undergoing endoscopic ultrasound-guided fine-needle biopsy for tissue diagnosis of PDA at Rush University Medical Center were offered to participate in the study. Biopsies were immediately processed to develop organoids. Fifteen PDOs were screened for sensitivity to 18 compounds, including conventional PDA chemotherapies and FDA-approved investigational targeted therapies in cancer using Cell-titer GLO 3D (Promega) cell viability assay. The area under the curve (AUC) was calculated and normalized to the maximum area under the curve to generate a normalized AUC between 0 and 1. Molecular profiling of PDOs was conducted using RNA-seq. Human PDA transcriptomic was extracted from The Cancer Genome Atlas (TCGA). The drug response curves were reproducible. We observed variation in response to conventional therapies overall as well as among individual patients. There were distinct transcriptome signatures associated with response to the conventional chemotherapeutics in PDA. The transcriptomic profile of overall resistance to conventional therapies in our study was associated with poor survival in PDA patients in TCGA. Our pathway analysis for targeted drugs revealed a number of predictors of response associated with the mechanism of action of the tested drug. The multiplex organoid-based drug assay could be used in preclinical to inform patient stratification and therapeutic selection in PDA. When combined with omics data, ex vivo response to treatment could help identify gene signatures associated with response to novel therapies.

Background: Physiological circadian rhythms (CRs) are complex processes with 24-hour oscillations that regulate diverse biological functions. Chronic weekly light/dark (LD) shifting (CR disruption; CRD) in mice results in colonic hyperpermeability. However, the mechanisms behind this phenomenon are incompletely understood. One potential innovative in vitro method to study colonic CRs are colon organoids. The goals of this study were to utilize circadian clock gene Per2 luciferase reporter (Per2::Luc) mice to measure the effects of chronic LD shifting on colonic tissue circadian rhythmicity ex vivo and to determine if organoids made from shifted mice colons recapitulate the in vivo phenotype., Methods: Non-shifted (NS) and shifted (S) BL6 Per2::Luc mice were compared after a 22-week experiment. NS mice had a standard 12h light/12h dark LD cycle throughout. S mice alternated 12h LD patterns weekly, with light from 6am-6pm one week followed by shifting light to 6pm-6am the next week for 22 weeks. Mice were tested for intestinal permeability while colon tissue and organoids were examined for CRs of bioluminescence and proteins of barrier function and cell fate., Results: There was no absolute difference in NS vs. S 24h circadian period or phase. However, chronic LD shifting caused Per2::Luc S mice colon tissue to exhibit significantly greater variability in both the period and phase of Per2::Luc rhythms than NS mice colon tissue and organoids. Chronic LD shifting also resulted in increased colonic permeability of the Per2::Luc mice as well as decreased protein markers of intestinal permeability in colonic tissue and organoids from shifted Per2:Luc mice., Conclusions: Our studies support a model in which chronic central circadian disruption by LD shifting alters the circadian phenotype of the colon tissue and results in colon leakiness and loss of colonic barrier function. These CRD-related changes are stably expressed in colon stem cell derived organoids from CRD mice., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Conventional adenomas (tubular adenoma [TA] or tubulovillous adenoma) and sessile serrated lesions (SSLs) are neoplastic precancerous lesions frequently detected in patients undergoing average risk screening colonoscopy and polyp surveillance. Metachronous risk stratification of adenomas is currently limited to histologic features and size of polyps. We report long interspersed nucleotide element-1 (LINE-1) methylation levels in SSL in comparison to TA and the impact of TA size and presence of high-grade dysplasia (HGD) on LINE-1 methylation., Methods: LINE-1 methylation was assessed by pyrosequencing of bisulfite-converted DNA. We compared LINE-1 methylation between TA and SSL, among varying sizes of TA, and between TA with HGD and low-grade dysplasia (LGD)., Results: LINE-1 methylation declined with increasing polyp size in TA when comparing those <5 mm (72.31 ± 6.11), 5 to <10 mm (67.50 ± 7.00), and ≥10 mm (66.75 ± 11.89). There were lower LINE-1 methylation levels in TA with LGD (n = 119) compared with SSLs (n = 29) (69.11 ± 8.62 vs 81.41 ± 2.43, P < 0.001). TA containing HGD (n = 26) had lower LINE-1 methylation levels than those with LGD (n = 119) (59.86 ± 7.93 vs 69.11 ± 8.62, P < 0.001)., Discussion: HGD and increasing size of TA/tubulovillous adenoma were associated with lower LINE-1 methylation. This supports a hypothesis that LINE-1 hypomethylation in TAs indicates advancement along the CRC tumorigenesis pathway. Lower LINE-1 methylation and greater variance of global DNA methylation was seen in TA compared with SSL. LINE-1 methylation in adenomas correlates with polyp size and degree of dysplasia and deserves further study as a predictor of metachronous colorectal cancer risk., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Obesity has become a common rising health care problem, especially in "modern" societies. Obesity is considered a low-grade systemic inflammation, partly linked to leaky gut. Circadian rhythm disruption, a common habit in modern life, has been reported to cause gut barrier impairment. Abnormal time of eating, defined by eating close to or during rest time, is shown to cause circadian rhythm disruption. Here, using a non-obesogenic diet, we found that abnormal feeding time facilitated weight gain and induced metabolic dysregulation in mice. The effect of abnormal time of eating was associated with increased gut permeability, estimated by sucralose and/or lactulose ratio and disrupted intestinal barrier marker. Analysis of gut microbiota and their metabolites, as important regulators of barrier homeostasis, revealed that abnormal food timing reduced relative abundance of butyrate-producing bacteria, and the colonic butyrate level. Overall, our data supported that dysbiosis was characterized by increased intestinal permeability and decreased beneficial barrier butyrate-producing bacteria and/or metabolite to mechanistically link the time of eating to obesity. This data provides basis for noninvasive microbial-targeted interventions to improve intestinal barrier function as new opportunities for combating circadian rhythm disruption induced metabolic dysfunction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Pancreatic cancer (PC) rate is increasing in the U.S. The use of prescription and illicit opioids has continued to rise nationally in recent years as well. Opioids have been shown to have a deleterious effect on multiple types of cancer with recent data suggesting opium use as a risk factor for PC. Using national databases, we tested whether opioid usage pattern over time could explain the state and national-based variations in PC rates in the U.S. Opioid death rate (as a surrogate for prescription and illicit opioid use) was extracted from the CDCs Wonder online data through the Vital Statistics Cooperative Program. Incidence of pancreatic cancer was retrieved from the online CDCs data base gathered from the U.S. Cancer Statistics Working Group. Prevalence of obesity, tobacco and alcohol use was collected from Behavioral risk factor surveillance system. Mixed-effects regression models were used to test the association between levels of PC rate and opioid death/use rates during the years 1999-2016. A rise in PC was seen over time at the national and state levels. Similarly, the opioid death rates increased over time. Among other potential PC risk factors, only obesity prevalence showed an increase during the study period. A state's opioid death rate at 4 years prior significantly predicted initial incidence of PC (β = 0.1848, p<0.0001) and had a significant effect on the estimated annual change in the rate of PC (β = -.0193,p<0.0001). Opioid use may be an un-identified risk factor contributing to the increasing incidence of PC in the U.S. These novel findings need to be verified by population-based studies., Competing Interests: The authors have declared that no competing interests exist.

The metabolic syndrome is prevalent in developed nations and accounts for the largest burden of non-communicable diseases worldwide. The metabolic syndrome has direct effects on health and increases the risk of developing cancer. Lifestyle factors that are known to promote the metabolic syndrome generally cause pro-inflammatory alterations in microbiota communities in the intestine. Indeed, alterations to the structure and function of intestinal microbiota are sufficient to promote the metabolic syndrome, inflammation and cancer. Among the lifestyle factors that are associated with the metabolic syndrome, disruption of the circadian system, known as circadian dysrhythmia, is increasingly common. Disruption of the circadian system can alter microbiome communities and can perturb host metabolism, energy homeostasis and inflammatory pathways, which leads to the metabolic syndrome. This Perspective discusses the role of intestinal microbiota and microbial metabolites in mediating the effects of disruption of circadian rhythms on human health.

On November 15, 2019, the 24th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held as a satellite conference during the annual Society for Leukocyte Biology meeting in Boston, Massachusetts. The 2019 meeting focused on alcohol, immunity, and organ damage, and included two plenary sessions. The first session highlighted new research exploring the mechanisms of alcohol-induced inflammation and liver disease, including effects on lipidomics and lipophagy, regulatory T cells, epigenetics, epithelial cells, and age-related changes in the gut. The second session covered alcohol-induced injury of other organs, encompassing diverse areas of research ranging from neurodegeneration, to lung barrier function, to colon carcinogenesis, to effects on viral infection. The discussions also highlighted current laboratory and clinical research used to identify biomarkers of alcohol use and disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)