Micro(nano)plastics and Their Potential Impact on Human Gut Health: A Narrative Review.

Microplastics and nanoplastics (MNPs) are becoming an increasingly severe global problem due to their widespread distribution and complex impact on living organisms. Apart from their environmental impact, the effects of MNPs on living organisms have also continued to attract attention. The harmful impact of MNPs has been extensively documented in marine invertebrates and larger marine vertebrates like fish. However, the research on the toxicity of these particles on mammals is still limited, and their possible effects on humans are poorly understood. Considering that MNPs are commonly found in food or food packaging, humans are primarily exposed to them through ingestion. It would be valuable to investigate the potential harmful effects of these particles on gut health. This review focuses on recent research exploring the toxicological impacts of micro- and nanoplastics on the gut, as observed in human cell lines and mammalian models. Available data from various studies indicate that the accumulation of MNPs in mammalian models and human cells may result in adverse consequences, in terms of epithelial toxicity, immune toxicity, and the disruption of the gut microbiota. The paper also discusses the current research limitations and prospects in this field, aiming to provide a scientific basis and reference for further studies on the toxic mechanisms of micro- and nanoplastics.

Development of a Novel Comprehensive Hepatocellular Carcinoma Outcome Prognostic Scoring System With Integration of Imaging Features.

BACKGROUND: Accurate prognostic stratification of hepatocellular carcinoma (HCC) is vital for clinical trial enrollment and treatment allocation. Multiple scoring systems have been created to predict patient survival, but no standardized scoring systems account for radiologic tumor features. We sought to create a generalizable scoring system for HCC which incorporates standardized radiologic tumor features and more accurately predicts overall survival (OS) than established systems. METHODS: Clinicopathologic parameters were collected from a prospectively collected cohort of patients with HCC treated at a single institution. Imaging studies were evaluated for tumor characteristics. Patients were randomly divided into a training set for identification of covariates that impacted OS and a validation set. Cox models were used to determine the association of various factors with OS and a scoring system was created. RESULTS: We identified 383 patients with HCC with imaging and survival outcomes, n = 255 in the training set and 128 in the validation cohort. Factors associated with OS on multivariate analysis included: tumor margin appearance on CT or MRI (hazard ratio [HR] 1.37, 95% CI, 1.01-1.88) with infiltrative margins portending worse outcomes than encapsulated margins, massive tumor morphology (HR 1.64, 95% CI, 1.06-2.54); >2 lesions (HR 2.06, 95% CI, 1.46-2.88), Child-Turcotte-Pugh class C (HR 3.7, 95% CI, 2.23-6.16), and portal vein thrombus (HR 2.41, 95% CI, 1.71-3.39). A new scoring system was developed and more predictive of OS than other well-established systems. CONCLUSIONS: Incorporation of standardized imaging characteristics to established clinical and lab predictors of outcome resulted in an improved predictive scoring system for patients with HCC.

Unravelling the role of intratumoral bacteria in digestive system cancers: current insights and future perspectives.

Recently, research on the human microbiome, especially concerning the bacteria within the digestive system, has substantially advanced. This exploration has unveiled a complex interplay between microbiota and health, particularly in the context of disease. Evidence suggests that the gut microbiome plays vital roles in digestion, immunity and the synthesis of vitamins and neurotransmitters, highlighting its significance in maintaining overall health. Conversely, disruptions in these microbial communities, termed dysbiosis, have been linked to the pathogenesis of various diseases, including digestive system cancers. These bacteria can influence cancer progression through mechanisms such as DNA damage, modulation of the tumour microenvironment, and effects on the host's immune response. Changes in the composition and function within the tumours can also impact inflammation, immune response and cancer therapy effectiveness. These findings offer promising avenues for the clinical application of intratumoral bacteria for digestive system cancer treatment, including the potential use of microbial markers for early cancer detection, prognostication and the development of microbiome-targeted therapies to enhance treatment outcomes. This review aims to provide a comprehensive overview of the pivotal roles played by gut microbiome bacteria in the development of digestive system cancers. Additionally, we delve into the specific contributions of intratumoral bacteria to digestive system cancer development, elucidating potential mechanisms and clinical implications. Ultimately, this review underscores the intricate interplay between intratumoral bacteria and digestive system cancers, underscoring the pivotal role of microbiome research in transforming diagnostic, prognostic and therapeutic paradigms for digestive system cancers.

Advancements in NMN biotherapy and research updates in the field of digestive system diseases.

Nicotinamide mononucleotide (NMN), a crucial intermediate in NAD + synthesis, can rapidly transform into NAD + within the body after ingestion. NMN plays a pivotal role in several important biological processes, including energy metabolism, cellular aging, circadian rhythm regulation, DNA repair, chromatin remodeling, immunity, and inflammation. NMN has emerged as a key focus of research in the fields of biomedicine, health care, and food science. Recent years have witnessed extensive preclinical studies on NMN, offering valuable insights into the pathogenesis of age- and aging-related diseases. Given the sustained global research interest in NMN and the substantial market expectations for the future, here, we comprehensively review the milestones in research on NMN biotherapy over the past 10 years. Additionally, we highlight the current research on NMN in the field of digestive system diseases, identifying existing problems and challenges in the field of NMN research. The overarching aim of this review is to provide references and insights for the further exploration of NMN within the spectrum of digestive system diseases.

Morphology and ultrastructure of digestive system in pre-zoea and zoea I larvae of red king crab, Paralithodes camtschaticus (Tilesius, 1815).

The digestive system structure in pre-zoea and zoea I larvae of the red king crab Paralithodes camtschaticus has been examined. During this development period, the digestive system consists of an esophagus, a stomach, a midgut (where the hepatopancreas ducts open), and a hindgut. The esophagus begins from the oral slit on the animal's ventral side and extends vertically up to the junction with the cardiac stomach. The latter is followed by the pyloric stomach. At the stages under study, crabs have a cardiac-pyloric valve and a pyloric filter in the stomach already developed. The midgut begins with an expansion in the cephalothorax, enters the pleon, grows narrower there, and extends to somite 3 of pleon. The hepatopancreas is represented by a symmetrical paired gland which occupies almost the entire cephalothorax space and opens with its ducts at the junction of the pyloric stomach with the midgut. The hepatopancreas is divided into the anterior and posterior lobes. At the pre-zoea stage, the anterior lobes are large and filled with yolk. At the zoea I stage, the anterior lobes are smaller relative to the entire hepatopancreas, and the posterior lobes increase and form tubular outgrowths. It has been shown that during the transition from pre-zoea to zoea I, the number of mitochondria in enterocytes increases and a peritrophic membrane forms in the midgut. These changes are probably associated with the transition to independent living and feeding.

Correlation between inflammatory cytokines and the likelihood of developing multiple types of digestive system cancers: A Mendelian randomization study.

OBJECTIVE: Inflammatory cytokines have been linked to digestive system cancers, yet their exact causal connection remains uncertain. Consequently, we conducted a Mendelian randomization (MR) analysis to gauge how inflammatory cytokines are linked to the risk of five prevalent digestive system cancers (DSCs). METHODS: We collected genetic variation data for 41 inflammatory cytokines from genome-wide association studies (GWAS), and the results data for five common diseases from the Finnish database. Our primary analytical approach involved employing the inverse-variance weighted, residual sum (IVW) method, complemented by the MR-Egger method, the weighted median method, simple mode analysis, and weighted mode analysis as supplementary analytical techniques. Furthermore, we conducted multiple sensitivity analyses. RESULTS: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), macrophage colony-stimulating factor (M-CSF), and interleukin (IL)-18 showed a negative association with the risk of hepatocellular carcinoma. Conversely, TRAIL was inversely linked to the risk of gastric cancer, while IL-16 exhibited a positive correlation with gastric cancer risk. Stem cell factor (SCF) acted as a protective factor against pancreatic cancer. For colorectal cancer, IL-7, IL-9, IL-13, and vascular endothelial growth factor (VEGF) were identified as risk factors. Notably, our results did not indicate a significant correlation between inflammatory cytokines and the risk of esophageal cancer. CONCLUSION: Our research unveils potential connections between 41 inflammatory cytokines and the risk of five common DSCs through a MR analysis. These associations offer valuable insights that could aid in the development of diagnostic biomarkers and the identification of novel therapeutic targets for DSCs.

The relationship and clinical significance of lactylation modification in digestive system tumors.

Lactylation, an emerging post-translational modification, plays a pivotal role in the initiation and progression of digestive system tumors. This study presents a comprehensive review of lactylation in digestive system tumors, underscoring its critical involvement in tumor development and progression. By focusing on metabolic reprogramming, modulation of the tumor microenvironment, and the molecular mechanisms regulating tumor progression, the potential of targeting lactylation as a therapeutic strategy is highlighted. The research reveals that lactylation participates in gene expression regulation and cell signaling by affecting the post-translational states of histones and non-histone proteins, thereby influencing metabolic pathways and immune evasion mechanisms in tumor cells. Furthermore, this study assesses the feasibility of lactylation as a therapeutic target, providing insights for clinical treatment of gastrointestinal cancers. Future research should concentrate on elucidating the mechanisms of lactylation, developing efficient lactylation inhibitors, and validating their therapeutic efficacy in clinical trials, which could transform current cancer treatment and immunotherapy approaches. In summary, this review emphasizes the crucial role of lactylation in tumorigenesis and progression through a detailed analysis of its molecular mechanisms and clinical significance.

Intratumoral microorganisms in tumors of the digestive system.

Tumors of the digestive system pose a significant threat to human health and longevity. These tumors are associated with high morbidity and mortality rates, leading to a heavy economic burden on healthcare systems. Several intratumoral microorganisms are present in digestive system tumors, and their sources and abundance display significant heterogeneity depending on the specific tumor subtype. These microbes have a complex and precise function in the neoplasm. They can facilitate tumor growth through various mechanisms, such as inducing DNA damage, influencing the antitumor immune response, and promoting the degradation of chemotherapy drugs. Therefore, these microorganisms can be targeted to inhibit tumor progression for improving overall patient prognosis. This review focuses on the current research progress on microorganisms present in the digestive system tumors and how they influence the initiation, progression, and prognosis of tumors. Furthermore, the primary sources and constituents of tumor microbiome are delineated. Finally, we summarize the application potential of intratumoral microbes in the diagnosis, treatment, and prognosis prediction of digestive system tumors. Video Abstract.

Incidental detection of upper gastrointestinal epithelial neoplasia by screening endoscopy prior to endoscopic ultrasonography in patients with pancreaticobiliary disease.

BACKGROUND: Screening esophagogastroduodenoscopy plays an important role in the early detection of upper gastrointestinal cancer. To provide more opportunities for patients with pancreaticobiliary disease to undergo this screening, we have performed esophagogastroduodenoscopy prior to endoscopic ultrasonography. However, the usefulness of this protocol is not elucidated. This study aimed to investigate the utility of screening esophagogastroduodenoscopy in this protocol in the detection of upper gastrointestinal epithelial neoplasms. METHODS: The outcomes of screening esophagogastroduodenoscopy performed prior to endoscopic ultrasonography in patients with pancreaticobiliary disease at our hospital between April 2020 and September 2022 were investigated. A logistic regression model was used to identify factors affecting the detection of epithelial neoplasms. Additionally, we compared the detection rate of gastric epithelial neoplasms between screening esophagogastroduodenoscopy performed prior to endoscopic ultrasonography and that performed at our medical checkup center. RESULTS: A total of 615 screening esophagogastroduodenoscopies prior to endoscopic ultrasonography were performed, and 12 (2.0%) epithelial neoplasms were detected, including esophageal lesions (n = 2) and gastric lesions (n = 10). Of these lesions, 75% (9/12) underwent curative endoscopic resection. A multivariate analysis showed that open-type gastric mucosal atrophy (odds ratio, 7.7; 95% confidence interval, 1.5-38.4; p = 0.01) and the use of magnification endoscopy (odds ratio, 7.3; 95% confidence interval, 1.9-27.9; p < 0.01) independently affected the detection of epithelial neoplasms. The detection rate of gastric epithelial neoplasms was significantly higher using this protocol than that in our medical checkup center (1.6% versus 0.2%, p < 0.01). CONCLUSIONS: A protocol of screening esophagogastroduodenoscopy prior to endoscopic ultrasonography may be recommended because epithelial neoplasms could be detected at a non-negligible rate.

Association between green tea intake and digestive system cancer risk in European and East Asian populations: a Mendelian randomization study.

PURPOSE: Previous observational studies have shown that green tea consumption is associated with a reduced incidence of digestive system cancers (DSCs). However, the observed association could be due to confounding factors. Therefore, we used a two-sample Mendelian randomization (MR) approach to assess the causal effect of green tea intake on the risk of five common DSCs. METHODS: Independent genetic variants strongly associated with green tea consumption in European and East Asian populations were selected as instrumental variables in genome-wide association studies involving up to 64,949 European individuals and 152,653 East Asian individuals, respectively. The associations between genetic variants and DSCs were extracted from the FinnGen study and the Japan Biobank. The primary analysis was performed using random-effects inverse variance weighting (IVW). Other MR analyses, including weighted mode-based estimate, weighted-median, MR-Egger regression, Mendelian Randomization-Pleiotropy Residual Sum and Outlier (MR-PRESSO) analysis, were used for sensitivity analyses. In addition, a multivariate MR design was performed to adjust for smoking and alcohol consumption. RESULTS: The IVW results showed no causal relationship between tea intake and DSCs risk in European population (esophagus cancer: odds ratio (OR) = 1.044, 95% confidence interval (CI) 0.992-1.099, p = 0.096; stomach cancer: OR = 0.988, 95% CI 0.963-1.014, p = 0.368; colorectal cancer: OR = 1.003, 95% CI 0.992-1.015, p = 0.588; liver cancer: OR = 0.996, 95% CI 0.960-1.032, p = 0.808; pancreatic cancer: OR = 0.990, 95% CI 0.965-1.015, p = 0.432). The MR-Egger regression, MR-PRESSO analysis and other methods also confirmed the reliability of the conclusion. Similarly, no significant association was found between green tea consumption and the incidence of DSCs among East Asians. This relationship is not significant even after adjusting for smoking and alcohol consumption (P > 0.05). CONCLUSION: Our study provides evidence that genetically predicted green tea intake is not causally associated with the development of DSCs in the European and East Asian population.

Endoscopic assessment of failed fundoplications differs between endoscopists.

BACKGROUND: Despite excellent long-term outcomes, a small proportion of patients who undergo fundoplication with hiatal hernia repair (laparoscopic antireflux surgery [ARS]) for treatment of gastroesophageal reflux disease (GERD) may require reoperation. Esophagogastroduodenoscopy (EGD) assessment in patients presenting with symptom recurrence plays a critical role in surgical planning of redo-ARS by confirming failure of the fundoplication and revealing the pattern of failure. We aimed to compare the findings documented by external endoscopists (i.e., outside physicians) to those documented by internal endoscopists (i.e., operating foregut or thoracic surgeons) before redo-ARS. METHODS: After IRB approval, we conducted a retrospective chart review of patients who underwent redo-ARS at a tertiary surgical center between November 2016 and March 2023. Patients with both external and internal EGD reports were included, and findings from the two reports were compared. RESULTS: Of 197 patients who underwent redo-ARS, both preoperative EGD reports were available for 181 (136 [75.1%] women; median age, 61 years [IQR 53-69]; median BMI, 27.9 kg/m2 [IQR 24.9-31.3]). The median time between primary and redo-ARS was 89 months (IQR 38-153), and the median time between external and internal endoscopic evaluation was 5 months (IQR 2-12). Only 38.9% of external reports mentioned a prior fundoplication. Compared to the operating surgeons, external physicians reported a significantly lower proportion of Barrett's esophagus (52.4%, p < .001), slipped fundoplications (28.8%, p < .001), paraesophageal hernias (20.5%, p < .001), disrupted fundoplications (20%, p < .001), intrathoracic fundoplications (0%, p < .001), and twisted fundoplications (0%, p < .001). CONCLUSIONS: External endoscopists' reports of failed fundoplications are often incomplete and lack relevant details. Discrepancies between nonsurgical endoscopists and experienced surgeons are likely explained by a lack of training and experience to discern and document fundoplication changes accurately. To reduce this gap, we strongly recommend the adoption of standard definitions describing post-fundoplication endoscopic changes and the inclusion of relevant training within educational programs.

Bowel function, quality of life, and mental health of patients with high-grade intraepithelial neoplasia or T1 colorectal cancer after organ-preserving versus organ-resection surgeries: a cross-sectional study at a Chinese tertiary care center.

BACKGROUND: This study aimed to determine the postoperative intestinal functioning, quality of life (QoL), and psychological well-being of patients treated either with organ-preserving surgery (OPS) or organ-resection surgery (ORS) for high-grade intraepithelial neoplasia (HIN) or T1 colorectal cancer (CRC). METHODS: This cross-sectional study was conducted at a single tertiary care center. In total, 175 eligible individuals with T1 CRC or HIN were divided into the OPS (n = 103) or ORS (n = 72) group based on whether the relevant segment of the intestine was preserved or resected. Intestinal function was evaluated using low anterior resection syndrome (LARS) scores. QoL was evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ)-C30 and EORTC-QLQ-CR29. Psychological status was evaluated using the Fear of Progression Questionnaire-Short Form and the Self-rating Anxiety and Depression scales. Propensity score matching (PSM) was used to minimize the influence of potential confounders. RESULTS: Overall, 130 of 175 patients (74.29%) responded to the questionnaires; 56 and 74 were in the ORS and OPS groups, respectively. Thirty-five patient pairs were successfully matched through PSM. The mild and severe LARS rates were significantly higher in the ORS group than in the OPS group (P < 0.001). The EORTC-QLQ-C30 and EORTC-QLQ-CR29 scores revealed significantly better physical, role, and emotional functioning and an overall improved state of health (with multiple reduced symptom scores) in the OPS group than in the ORS group (P < 0.05). Significantly more patients were depressed in the ORS group than in the OPS group (P = 0.034), whereas anxiety or fear of disease progression did not differ significantly between the groups. CONCLUSIONS: OPS for the treatment of HIN or T1 CRC was found to be more advantageous for patients in terms of improved intestinal function, QoL, and psychological status than was ORS.

Position statement of the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) on APC I1307K and cancer risk.

While constitutional pathogenic variants in the APC gene cause familial adenomatous polyposis, APC c.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate increased risk of colorectal cancer (CRC), particularly in individuals of Ashkenazi Jewish descent. However, published data include relatively small sample sizes, generating inconclusive results regarding cancer risk, particularly in non-Ashkenazi populations. This has led to different country/continental-specific guidelines regarding genetic testing, clinical management and surveillance recommendations for I1307K. A multidisciplinary international expert group endorsed by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT), has generated a position statement on the APC I1307K allele and its association with cancer predisposition. Based on a systematic review and meta-analysis of the evidence published, the aim of this document is to summarise the prevalence of the APC I1307K allele and analysed the evidence of the associated cancer risk in different populations. Here we provide recommendations on the laboratory classification of the variant, define the role of predictive testing for I1307K, suggest recommendations for cancer screening in I1307K heterozygous and homozygous individuals and identify knowledge gaps to be addressed in future research studies. Briefly, I1307K, classified as pathogenic, low penetrance, is a risk factor for CRC in individuals of Ashkenazi Jewish origin and should be tested in this population, offering carriers specific clinical surveillance. There is not enough evidence to support an increased risk of cancer in other populations/subpopulations. Therefore, until/unless future evidence indicates otherwise, individuals of non-Ashkenazi Jewish descent harbouring I1307K should be enrolled in national CRC screening programmes for average-risk individuals.

Germline mutations in WNK2 could be associated with serrated polyposis syndrome.

BACKGROUND: Patients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts. METHODS: After a previous whole-exome sequencing in 39 SPS patients from 16 families (discovery cohort), we sequenced specific genes in an independent validation cohort of 211 unrelated SPS cases. Additional external replication was also available in 297 SPS cases. The WNK2 gene was disrupted in HT-29 cells by gene editing, and WNK2 variants were transfected using a lentiviral delivery system. Cells were analysed by immunoblots, real-time PCR and functional assays monitoring the mitogen-activated protein kinase (MAPK) pathway, cell cycle progression, survival and adhesion. RESULTS: We identified 2 rare germline variants in the WNK2 gene in the discovery cohort, 3 additional variants in the validation cohort and 10 other variants in the external cohorts. Variants c.2105C>T (p.Pro702Leu), c.4820C>T (p.Ala1607Val) and c.6157G>A (p.Val2053Ile) were functionally characterised, displaying higher levels of phospho-PAK1/2, phospho-ERK1/2, CCND1, clonogenic capacity and MMP2. CONCLUSION: After whole-exome sequencing in SPS cases with familial aggregation and replication of results in additional cohorts, we identified rare germline variants in the WNK2 gene. Functional studies suggested germline WNK2 variants affect protein function in the context of the MAPK pathway, a molecular hallmark in this disease.

Decision-making and regret in patients with germline CDH1 variants undergoing prophylactic total gastrectomy.

INTRODUCTION: Prophylactic total gastrectomy (PTG) can eliminate gastric cancer risk and is recommended in carriers of a germline CDH1 pathogenic variant. PTG has established risks and potential life-long morbidity. Decision-making regarding PTG is complex and not well-understood. METHODS: Individuals with germline CDH1 pathogenic or likely pathogenic variants who underwent surveillance endoscopy and recommended for PTG were evaluated. Factors associated with decision to pursue PTG (PTGpos) or not (PTGneg) were queried. A decision-regret survey was administered to patients who elected PTG. RESULTS: Decision-making was assessed in 120 patients. PTGpos patients (63%, 76/120) were younger than PTGneg (median 45 vs 58 years) and more often had a strong family history of gastric cancer (80.3% vs 34.1%). PTGpos patients reported decision-making based on family history more often and decided soon after diagnosis (8 vs 27 months) compared with PTGneg. Negative endoscopic surveillance results were more common among PTGneg patients. Age >60 years, male sex and longer time to decision were associated with deferring PTG. Strong family history, a family member who died of gastric cancer and carcinoma on endoscopic biopsies were associated with decision to pursue PTG. In the PTGpos group, 30 patients (43%) reported regret which was associated with occurrence of a postoperative complication and no carcinoma detected on final pathology. CONCLUSION: The decision to undergo PTG is influenced by family cancer history and surveillance endoscopy results. Regret is associated with surgical complications and pathological absence of cancer. Individual cancer-risk assessment is necessary to improve pre-operative counselling and inform the decision-making process. TRIAL REGISTRATION NUMBER: NCT03030404.

Ability of a polygenic risk score to refine colorectal cancer risk in Lynch syndrome.

BACKGROUND: Polygenic risk scores (PRSs) have been used to stratify colorectal cancer (CRC) risk in the general population, whereas its role in Lynch syndrome (LS), the most common type of hereditary CRC, is still conflicting. We aimed to assess the ability of PRS to refine CRC risk prediction in European-descendant individuals with LS. METHODS: 1465 individuals with LS (557 MLH1, 517 MSH2/EPCAM, 299 MSH6 and 92 PMS2) and 5656 CRC-free population-based controls from two independent cohorts were included. A 91-SNP PRS was applied. A Cox proportional hazard regression model with 'family' as a random effect and a logistic regression analysis, followed by a meta-analysis combining both cohorts were conducted. RESULTS: Overall, we did not observe a statistically significant association between PRS and CRC risk in the entire cohort. Nevertheless, PRS was significantly associated with a slightly increased risk of CRC or advanced adenoma (AA), in those with CRC diagnosed <50 years and in individuals with multiple CRCs or AAs diagnosed <60 years. CONCLUSION: The PRS may slightly influence CRC risk in individuals with LS in particular in more extreme phenotypes such as early-onset disease. However, the study design and recruitment strategy strongly influence the results of PRS studies. A separate analysis by genes and its combination with other genetic and non-genetic risk factors will help refine its role as a risk modifier in LS.

X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.

BACKGROUND: SHROOM4 is thought to play an important role in cytoskeletal modification and development of the early nervous system. Previously, single-nucleotide variants (SNVs) or copy number variations (CNVs) in SHROOM4 have been associated with the neurodevelopmental disorder Stocco dos Santos syndrome, but not with congenital anomalies of the urinary tract and the visceral or the cardiovascular system. METHODS: Here, exome sequencing and CNV analyses besides expression studies in zebrafish and mouse and knockdown (KD) experiments using a splice blocking morpholino in zebrafish were performed to study the role of SHROOM4 during embryonic development. RESULTS: In this study, we identified putative disease-causing SNVs and CNVs in SHROOM4 in six individuals from four families with congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems (CNS). Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls. These phenotypes could be rescued by co-injection of human wild-type SHROOM4 mRNA and morpholino. CONCLUSION: The identified SNVs and CNVs in affected individuals with congenital anomalies of the urinary tract, the anorectal, the cardiovascular and the central nervous systems, and subsequent embryonic mouse and zebrafish studies suggest SHROOM4 as a developmental gene for different organ systems.

Deciphering the lipid-cancer nexus: comprehensive Mendelian randomization analysis of the associations between lipid profiles and digestive system cancer susceptibility.

BACKGROUND: Digestive system cancers represent a significant global health challenge and are attributed to a combination of demographic and lifestyle changes. Lipidomics has emerged as a pivotal area in cancer research, suggesting that alterations in lipid metabolism are closely linked to cancer development. However, the causal relationship between specific lipid profiles and digestive system cancer risk remains unclear. METHODS: Using a two-sample Mendelian randomization (MR) approach, we elucidated the causal relationships between lipidomic profiles and the risk of five types of digestive system cancer: stomach, liver, esophageal, pancreatic, and colorectal cancers. The aim of this study was to investigate the effect impact of developing lipid profiles on the risk of digestive system cancers utilizing data from public databases such as the GWAS Catalog and the UK Biobank. The inverse‒variance weighted (IVW) method and other strict MR methods were used to evaluate the potential causal links. In addition, we performed sensitivity analyses and reverse MR analyses to ensure the robustness of the results. RESULTS: Significant causal relationships were identified between certain lipidomic traits and the risk of developing digestive system cancers. Elevated sphingomyelin (d40:1) levels were associated with a reduced risk of developing gastric cancer (odds ratio (OR) = 0.68, P < 0.001), while elevated levels of phosphatidylcholine (16:1_20:4) increased the risk of developing esophageal cancer (OR = 1.31, P = 0.02). Conversely, phosphatidylcholine (18:2_0:0) had a protective effect against colorectal cancer (OR = 0.86, P = 0.036). The bidirectional analysis did not suggest reverse causality between cancer risk and lipid levels. Strict MR methods demonstrated the robustness of the above causal relationships. CONCLUSION: Our findings underscore the significant causal relationships between specific lipidomic traits and the risk of developing various digestive system cancers, highlighting the potential of lipid profiles in informing cancer prevention and treatment strategies. These results reinforce the value of MR in unraveling complex lipid-cancer interactions, offering new avenues for research and clinical application.

Appraising associations between signature lipidomic biomarkers and digestive system cancer risk: novel evidences from a prospective cohort study of UK Biobank and Mendelian randomization analyses.

BACKGROUND: The roles of serum lipids on digestive system cancer (DSC) risk were still inconclusive. In this study, we systematically assessed indicative effects of signature lipidomic biomarkers (high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG)) on DSC (oesophagus, stomach, colorectal, liver, gallbladder, and pancreas cancers) risk. METHODS: HDL-C, LDL-C, and TG concentration measurements were respectively analyzed with enzyme immunoinhibition, enzymatic selective protection, and GPO-POD methods in AU5800 supplied from Beckman Coulter. The diagnoses of DSCs were coded using International Classification of Diseases, Tenth Revision (ICD-10) codes updated until October 2022 in the UK Biobank (UKB). In this study, we assessed phenotypic association patterns between signature lipidomic biomarkers and DSC risk using restricted cubic splines (RCSs) in multivariable-adjusted Cox proportional hazards regression models. Moreover, linear and nonlinear causal association patterns of signature lipidomic biomarkers with DSC risk were determined by linear and nonlinear Mendelian randomization (MR) analyses. RESULTS: A median follow-up time of 11.8 years was recorded for 319,568 participants including 6916 DSC cases. A suggestive independent nonlinear phenotypic association was observed between LDL-C concentration and stomach cancer risk (Pnonlinearity < 0.05, Poverall < 0.05). Meanwhile, a remarkable independent linear negative phenotypic association was demonstrated between HDL-C concentration and stomach cancer risk (Pnonlinearity > 0.05, Poverall < 0.008 (0.05/6 outcomes, Bonferroni-adjusted P)), and suggestive independent linear positive associations were observed between HDL-C concentration and colorectal cancer risk, and between TG concentration and gallbladder cancer risk (Pnonlinearity > 0.05, Poverall < 0.05). Furthermore, based on nonlinear and linear MR-based evidences, we observed an suggestive independent negative causal association (hazard ratio (HR) per 1 mmol/L increase: 0.340 (0.137-0.843), P = 0.020) between LDL-C and stomach cancer risk without a nonlinear pattern (Quadratic P = 0.901, Cochran Q P = 0.434). Meanwhile, subgroup and stratified MR analyses both supported the category of LDL-C ≥ 4.1 mmol/L was suggestively protective against stomach cancer risk, especially among female participants (HR: 0.789 (0.637-0.977), P = 0.030) and participants aged 60 years or older (HR: 0.786 (0.638-0.969), P = 0.024), and the category of TG ≥ 2.2 mmol/L concluded to be a suggestive risk factor for gallbladder cancer risk in male participants (HR: 1.447 (1.020-2.052), P = 0.038) and participants aged 60 years or older (HR: 1.264 (1.003-1.593), P = 0.047). CONCLUSIONS: Our findings confirmed indicative roles of signature lipidomic biomarkers on DSC risk, notably detecting suggestive evidences for a protective effect of high LDL-C concentration on stomach cancer risk, and a detrimental effect of high TG concentration on gallbladder cancer risk among given participants.

Effectiveness of G-CSF in chemotherapy for digestive system tumors: a systematic review of the Clinical Practice Guidelines for the Use of G-CSF 2022 delineated by the Japan Society of Clinical Oncology.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) reportedly reduces the risk of neutropenia and subsequent infections caused by cancer chemotherapy. Although several guidelines recommend using G-CSF in primary prophylaxis according to the incidence rate of chemotherapy-induced febrile neutropenia (FN), the effectiveness of G-CSF in digestive system tumor chemotherapy remains unclear. To address these clinical questions, we conducted a systematic review as part of revising the Clinical Practice Guidelines for the Use of G-CSF 2022 published by the Japan Society of Clinical Oncology. METHODS: This systematic review addressed two main clinical questions (CQ): CQ1: "Is primary prophylaxis with G-CSF effective in chemotherapy?", and CQ2: "Is increasing the intensity of chemotherapy with G-CSF effective?" We reviewed different types of digestive system tumors, including esophageal, gastric, pancreatic, biliary tract, colorectal, and neuroendocrine carcinomas. PubMed, Cochrane Library, and Ichushi-Web databases were searched for information sources. Independent systematic reviewers conducted two rounds of screening and selected relevant records for each CQ. Finally, the working group members synthesized the strength of evidence and recommendations. RESULTS: After two rounds of screening, 5/0/3/0/2/0 records were extracted for CQ1 of esophageal/gastric/pancreatic/biliary tract/colorectal/ and neuroendocrine carcinoma, respectively. Additionally, a total of 2/6/1 records were extracted for CQ2 of esophageal/pancreatic/colorectal cancer, respectively. The strength of evidence and recommendations were evaluated for CQ1 of colorectal cancer; however, we could not synthesize recommendations for other CQs owing to the lack of records. CONCLUSION: The use of G-CSF for primary prophylaxis in chemotherapy for colorectal cancer is inappropriate.