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Background: Laparoscopic gastrectomy lacks hand-direct tactile sense and has a limited surgical field compared to laparotomy. Apart from textbook classification, there are anatomical variations in the gastric arteries. Laparoscopic gastrectomy presents technical difficulties and necessitates a more comprehensive comprehension of regional anatomy than open surgical procedures. We aimed to compare efficacy and safety of preoperative computed tomography angiography (CTA) associated with surgical decision-making for laparoscopic gastrectomy., Methods: The GISSG 20-01 study was a multicenter, open-label, randomized clinical trial. The enrollment criteria mainly included histologically confirmed gastric cancer patients with BMI ≥ 25 kg/m 2 . Eligible patients were randomly assigned to the CTA group or the non-CTA group in a 1:1 ratio. The primary endpoint was the volume of intraoperative blood loss., Results: Between November 2020 and December 2021, 382 patients were enrolled and randomly assigned. After exclusion of 25 patients, 357 patients were included in the modified intention-to-treat population (179 in the CTA group and 178 in the non-CTA group). The mean intraoperative blood loss (CTA vs non-CTA; 74.2 vs 95.0 mL, P = 0.005) and operation time (215.4 vs 231.2 min, P = 0.004) was significantly lower in the CTA group. Total number of retrieved lymph nodes was similar in two groups (32.2 vs 30.2, P = 0.070). The CTA group had a significantly lower surgery task load index sore than the non-CTA group (36.6 vs 41.7, P < 0.001). There was no significant difference in postoperative complications rate of 14.5% in the CTA group and 22.5% in the non-CTA group (difference, - 8.0% [95% CI, - 16.0 to 0.1]; P = 0.053)., Conclusion: Preoperative CTA associated with surgical decision-making could relieve surgery burden and lead to a better surgical performance compared with non-CTA support, which including decreased blood loss volume, vessel damage and operation time., Trial Registration: NCT04636099., Competing Interests: Declarations. Conflict of interest: We declare no competing interests., (© 2025. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Subject-specific knee joint models are widely used to predict joint contact mechanics for individuals but may not capture the variance in knee joint geometry across a population. Statistical shape modeling uses the dataset of a cohort to encapsulate population-wide variability. The present study aimed to develop a shape modeling procedure for poromechanical finite element models of knee joint to account for population diversity in the creep response of knees. Shape models of right knee joints were created from MRI of 31 healthy male subjects using principal component analysis. Creep analysis was performed for 13 shape models in total, i.e., the average model, plus six models for both the first and second principal modes. For a given loading, the contact and fluid pressures varied substantially within these mathematically produced models but compared reasonably well to that of three subject-specific models that were constructed from individual knees, representing approximately the smallest, median and largest knees of the 31 right knees. While the joint size variation, generally represented by the first principal component, predominantly influenced the magnitudes of contact and fluid pressures, the joint shape variation characterized by the second principal component further affected the pressure distribution, and load sharing between the lateral and medial compartments. The present study evaluated a workflow for the statistical shape modeling of poromechanical behavior of knee joints with sample results based on a small population. However, the workflow can be readily used for a large population to address the challenge of interpatient variability in joint contact mechanics, particularly in contact and fluid pressures in articular cartilage, and variable creep behaviors of the joint associated with individual anatomical variations., Competing Interests: Declarations. Conflict of interest: The authors have no conflict of interest to declare., (© 2024. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Aim: To analyze sex differences in age trajectories of supine positional obstructive sleep apnea (POSA)., Methods: We conducted retrospective analysis of polysomnography studies from 13,144 individuals aged from 2 to 103 years with at least 30 min of both supine and lateral sleep. We used generalized linear mixed-effects models to estimate position-specific mean apnea-hypopnea index (AHI) values and logistic regression to estimate the proportion with POSA or with exclusive POSA among individuals with obstructive sleep apnea (OSA). Predictors included sex, 5-y age group, sleep position, and their interactions., Results: Supine AHI was higher than lateral AHI regardless of age or sex except under age 5 y. The ratio of supine AHI to lateral AHI reliably exceeded 2 after age 30-35 in males and age 50-55 in females. For both sexes, the proportion with POSA among individuals with OSA increased rapidly with age until 30-35 and then stabilized. The proportion with POSA among individuals with OSA was significantly higher in males than females for each age group between 40 and 75 (p < 0.03). Among individuals with OSA in those 20 and older, the proportion with POSA was 64.6% (95% CI: 62.7%, 66.5%) in males and 55.8% (95% CI: 53.6%, 57.8%) in females. The proportion of individuals showing exclusive POSA also increased with age and peaked near 41% at age 15-20 in males and at age 20-25 in females., Conclusion: POSA becomes more common with age in both sexes; in women, its prevalence is generally lower but continues to increase after age 65., Competing Interests: Declarations. Ethical approval: This retrospective review of in-laboratory sleep PSG data was approved by the Institutional Review Board of the University of North Carolina at Chapel Hill (UNC-CH) (IRB #21-1984). Informed consent: For this study, based on deidentified patient records, the Institutional Review Board waived informed consent. Conflict of interest: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The site-specific tissue properties of knee cartilage may play an essential role in knee joint mechanical function, and mitigate joint injury and cartilage degeneration. The present study aimed to determine the significance of tissue inhomogeneity in knee joint contact mechanics using a porcine model., Methods: Finite element models were developed for a porcine knee with intact and total meniscectomy conditions to simulate whole-joint compression-relaxation tests under a 1.2-mm ramp-compression at 0.01, 0.1, or 1 mm/s. Two reference benchmarks were introduced for the implementation of poromechanical material properties of fibril-reinforced cartilage: Benchmark II consisted of 17 sets of cartilage properties, each for a region in the knee, representing site-specific inhomogeneity averaged from cartilage indentation maps of 14 porcine knees. Benchmark I was comprised of a single set of properties by taking the average properties of 17 regions in Benchmark II, assuming tissue homogeneity. To validate the modeling method, the reference benchmarks were used to produce results against whole-joint compression test data., Results: Both benchmarks were able to approximate experimental force-compression data obtained from the same knee with intact menisci and total meniscectomy, provided that the average properties from 14 knees were appropriately scaled to account for individual joint differences. Noticeable differences in stress and pressure distributions were observed between the benchmarks. For instance, benchmark I generated higher peak contact and fluid pressures in the medial tibial cartilage, but benchmark II produced the higher ones in the lateral tibial cartilage. The load sharing asymmetry between the lateral and medial compartments was reduced in benchmark II which was more pronounced for higher compression rates. On the other hand, benchmark II produced a more uniform stress distribution or lower maxima. Meniscectomy caused a slight shift of the contact centers in the tibial plateaus as compared to the intact joint., Conclusion: The modeling results demonstrated substantial differences in loading distributions in the joint between the homogeneous and nonhomogeneous models represented by the two benchmarks, indicating the role of tissue inhomogeneity in the joint contact mechanics. Region-dependent tissue properties may need to be implemented in joint mechanical modeling to evaluate the site of cartilage prone to injury or degeneration., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable: the porcine knee experimental data used in this model study were obtained in previously published studies. Consent for publication: Not applicable. Competing interests: Li is a senior editorial board member of this journal., (© 2025. The Author(s).)

Background: Transfer RNA-derived small RNAs (tsRNAs), including tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs), constitute a novel class of small noncoding RNAs (sncRNAs). tsRNAs have been linked to tumorigenesis and the progression of carcinogenesis; however, the precise molecular mechanism through which tRFs act in gastric cancer (GC) remains unknown., Methods: tRF-Tyr is a potential GC tumor suppressor that was identified through high-throughput sequencing technology. The expression and subcellular localization of tRF-Tyr in GC were detected by via qRT‒PCR and FISH. RNA pull-down, mass spectrometry, RNA immunoprecipitation (RIP), dual-luciferase reporter and rescue assays were performed to explore the regulatory mechanisms through which tRF-Tyr acts in GC., Results: tRF-Tyr was significantly downregulated and the downregulation of its mainly concentrated in the nuclei of GC cells. Functionally, tRF-Tyr inhibited the proliferation, invasiveness and migration of GC cells and promoted GC cells apoptosis in vitro; meanwhile, tRF-Tyr inhibited tumor growth in vivo. Mechanistically, tRF-Tyr bound directly to the hnRNPD protein and competitively inhibited the binding of hnRNPD to the c-Myc 3'UTR, thereby, regulating the c-Myc/Bcl2/Bax pathway and ultimately inhibiting the progression of GC., Conclusions: This study focused on a novel GC suppressor, tRF-Tyr, and revealed a previously undiscovered mechanism that tRF-Tyr inhibits tumor progression by targeting hnRNPD. These findings provide new insight into the involvement of tRFs in GC and suggest a novel target for GC treatment., Competing Interests: Declarations. Ethics approval and consent to participate: All patients were informed consent, and the study was performed in accordance with the Declaration of Helsinki and approved by the Biomedical Research Ethic Committee of Shandong Provincial Hospital (No. SWYX2024-340). All animal experiments were approved by Animal Experimental Ethics Committee of Shandong Provincial Hospital (No. 2024-048). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: The multicentre RESOLVE trial examined the efficacy of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in gastric or gastro-oesophageal junction cancer. Initial analyses did not encompass overall survival owing to the immature data. This paper provides an updated analysis of the survival data from the RESOLVE trial., Methods: In this randomised, open-label, phase 3 study, participants aged 18 years or older with cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma who were feasible for D2 lymphadenectomy and had a Karnofsky performance score of 70 or higher were enrolled. Participants were randomly assigned in a 1:1:1 ratio via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m 2 on day 1 of each 21-day cycle plus oral capecitabine 1000 mg/m 2 twice a day on days 1-14, adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m 2 on day 1 of each 21-day cycle plus oral S-1 40-60 mg twice a day on days 1-14), or perioperative SOX (intravenous oxaliplatin 130 mg/m 2 on day 1 of each 21-day cycle plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy. The primary endpoint, assessed in the modified intention-to-treat population, was 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-CapOx and the non-inferiority (hazard ratio [HR] non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx, and has been reported previously. This final report focuses on the secondary endpoint of 5-year overall survival, also assessed in the modified intention-to-treat population. Other secondary endpoints-R0 resection rate and safety-were not updated in this analysis. The study is registered at ClinicalTrials.gov, NCT01534546, and is complete., Findings: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were enrolled and randomly assigned, of whom 1022 participants were included in the modified intention-to-treat population: 345 (259 male, 86 female) in the adjuvant-CapOx group, 340 (238 male, 102 female) in the adjuvant-SOX group, and 337 (271 male, 66 female) in the perioperative-SOX group. As of April 7, 2022, the median duration of follow-up was 62·8 months (IQR 52·0-75·1). The 5-year overall survival rates were 52·1% (95% CI 46·3-57·5) for the adjuvant-CapOx group, 61·0% (55·3-66·2) for the adjuvant-SOX group, and 60·0% (54·2-65·3), for the perioperative-SOX group. Overall survival was significantly prolonged with perioperative-SOX (HR 0·79; 95% CI 0·62-1·00, p=0·049) and adjuvant-SOX (HR 0·77, 0·61-0·98, p=0·033), compared with adjuvant-CapOx., Interpretation: Consistent with the initial analysis of 3-year disease-free survival, the extended 5-year overall survival analysis from the RESOLVE trial confirmed the survival advantage of perioperative-SOX and adjuvant-SOX compared with the standard adjuvant-CapOx regimen. The SOX regimen, given perioperatively or as an adjuvant treatment, emerges as a potential standard treatment modality for locally advanced gastric or gastro-oesophageal junction cancer management in Asian patients., Funding: The National Key Research and Development Program of China, the National Natural Science Foundation of China, the Capital's Funds for Health Improvement and Research, the Beijing Natural Science Foundation, National Natural Science Foundation of China, the Beijing Natural Science Foundation, Taiho, Hengrui Pharmaceutical and Sanofi-Aventis., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests All authors declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Aging is an inevitable physiological process in organisms, and the development of tumors is closely associated with cellular senescence. This article initially examines the role of cellular senescence in tumorigenesis, emphasizing the correlation between telomere length-a marker of cellular senescence-and tumor risk. Concurrently, the study explores the expression levels of senescence-associated markers, such as p16, p53, and mTOR, in the context of tumor development. Additionally, the study investigates the impact of tumors on cellular and organismal senescence, including the effects on immune system function and metabolic processes. Ultimately, the discussion explores the potential application of anti-aging strategies in tumor therapy and considers the possibility of utilizing senescence mechanisms as a novel therapeutic approach for tumors. This research provides novel insights into the complex interplay between senescence and tumor development, suggesting potential strategies for future preventative measures and therapeutic interventions., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: While p53 mutations occur early in Barrett's oesophagus (BE) progression to oesophageal adenocarcinoma (EAC), their role in gastric cardia stem cells remains unclear., Objective: This study investigates the impact of p53 mutation on the fate and function of cardia progenitor cells in BE to EAC progression, particularly under the duress of chronic injury., Design: We used a BE mouse model (L2-IL1β) harbouring a Trp53 mutation (R172H) to study the effects of p53 on Cck2r + cardia progenitor cells. We employed lineage tracing, pathological analysis, organoid cultures, single-cell RNA sequencing (scRNA-seq) and computational analyses to investigate changes in progenitor cell behaviour, differentiation patterns and tumour progression. Additionally, we performed orthotopic transplantation of sorted metaplastic and mutant progenitor cells to assess their tumourigenic potential in vivo., Results: The p53 mutation acts as a switch to expand progenitor cells and inhibit their differentiation towards metaplasia, but only amidst chronic injury. In L2-IL1β mice, p53 mutation increased progenitors expansion and lineage-tracing with a shift from metaplasia to dysplasia. scRNA-seq revealed dysplastic cells arise directly from mutant progenitors rather than progressing through metaplasia. In vitro, p53 mutation enhanced BE progenitors' organoid-forming efficiency, growth, DNA damage resistance and progression to aneuploidy. Sorted metaplastic cells grew poorly with no progression to dysplasia, while mutant progenitors gave rise to dysplasia in orthotopic transplantation. Computational analyses indicated that p53 mutation inhibited stem cell differentiation through Notch activation., Conclusions: p53 mutation contributes to BE progression by increasing expansion and fitness of undifferentiated cardia progenitors and preventing their differentiation towards metaplasia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Sleep spindles may be implicated in sensing and regulation of peripheral glucose. Whether spindle density in patients with type 2 diabetes mellitus (T2DM) differs from that of healthy subjects is unknown., Methods: Our retrospective analysis of polysomnography (PSG) studies identified 952 patients with T2DM and 952 sex-, age- and BMI-matched control subjects. We extracted spindles from PSG electroencephalograms and used rank-based statistical methods to test for differences between subjects with and without diabetes. We also explored potential modifiers of spindle density differences. We replicated our analysis on independent data from the Sleep Heart Health Study., Results: We found that patients with T2DM exhibited about half the spindle density during sleep as matched controls (P < 0.0001). The replication dataset showed similar trends. The patient-minus-control paired difference in spindle density for pairs where the patient had major complications were larger than corresponding paired differences in pairs where the patient lacked major complications, despite both patient groups having significantly lower spindle density compared to their respective control subjects. Patients with a prescription for a glucagon-like peptide 1 receptor agonist had significantly higher spindle density than those without one (P ≤ 0.03). Spindle density in patients with T2DM monotonically decreased as their highest recorded HbA1C level increased (P ≤ 0.003)., Conclusions: T2DM patients had significantly lower spindle density than control subjects; the size of that difference was correlated with markers of disease severity (complications and glycemic control). These findings expand our understanding of the relationships between sleep and glucose regulation., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Published by Elsevier Ltd.)

The gut microbiota is a complex and dynamic ecosystem that plays a crucial role in human health and disease, including obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, inflammatory bowel disease, and cancer. Chronic inflammation is a common feature of these diseases and is closely related to angiogenesis (the process of forming new blood vessels), which is often dysregulated in pathological conditions. Inflammation potentially acts as a central mediator. This abstract aims to elucidate the connection between the gut microbiota and angiogenesis in various diseases. The gut microbiota influences angiogenesis through various mechanisms, including the production of metabolites that directly or indirectly affect vascularization. For example, short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate are known to regulate immune responses and inflammation, thereby affecting angiogenesis. In the context of cardiovascular diseases, the gut microbiota promotes atherosclerosis and vascular dysfunction by producing trimethylamine N-oxide (TMAO) and other metabolites that promote inflammation and endothelial dysfunction. Similarly, in neurodegenerative diseases, the gut microbiota may influence neuroinflammation and the integrity of the blood-brain barrier, thereby affecting angiogenesis. In cases of fractures and wound healing, the gut microbiota promotes angiogenesis by activating inflammatory responses and immune effects, facilitating the healing of tissue damage. In cancer, the gut microbiota can either inhibit or promote tumor growth and angiogenesis, depending on the specific bacterial composition and their metabolites. For instance, some bacteria can activate inflammasomes, leading to the production of inflammatory factors that alter the tumor immune microenvironment and activate angiogenesis-related signaling pathways, affecting tumor angiogenesis and metastasis. Some bacteria can directly interact with tumor cells, activating angiogenesis-related signaling pathways. Diet, as a modifiable factor, significantly influences angiogenesis through diet-derived microbial metabolites. Diet can rapidly alter the composition of the microbiota and its metabolic activity, thereby changing the concentration of microbial-derived metabolites and profoundly affecting the host's immune response and angiogenesis. For example, a high animal protein diet promotes the production of pro-atherogenic metabolites like TMAO, activating inflammatory pathways and interfering with platelet function, which is associated with the severity of coronary artery plaques, peripheral artery disease, and cardiovascular diseases. A diet rich in dietary fiber promotes the production of SCFAs, which act as ligands for cell surface or intracellular receptors, regulating various biological processes, including inflammation, tissue homeostasis, and immune responses, thereby influencing angiogenesis. In summary, the role of the gut microbiota in angiogenesis is multifaceted, playing an important role in disease progression by affecting various biological processes such as inflammation, immune responses, and multiple signaling pathways. Diet-derived microbial metabolites play a crucial role in linking the gut microbiota and angiogenesis. Understanding the complex interactions between diet, the gut microbiota, and angiogenesis has the potential to uncover novel therapeutic targets for managing these conditions. Therefore, interventions targeting the gut microbiota and its metabolites, such as through fecal microbiota transplantation (FMT) and the application of probiotics to alter the composition of the gut microbiota and enhance the production of beneficial metabolites, present a promising therapeutic strategy., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Poly-ADP-ribose-polymerase 1/2 (PARP1/2) inhibitors have been approved for cancers with homologous recombination deficiency (HRD). However, their narrow therapeutic indexes largely due to hematologic toxicities have limited their clinical usefulness. Developing selective PARP1 inhibitors has emerged as an attractive strategy to achieve equivalent antitumor activity while alleviating the hematological toxicity caused by PARP2 inhibition. Herein, we report the discovery of pyrazolo[1,5,4-de]quinoxalin-2(3 H )-one 30 as a novel selective PARP1 inhibitor. 30 formed tighter PARP1-DNA trapping than AZD9574, leading to better potency in inhibiting cancer cell proliferation. 30 achieved tumor regression in the BRCA1-mutated MDA-MB-436 xenograft model and showed synergistic efficacy in combination with carboplatin in the SUM149PT xenograft model. In the rat hematological toxicity study, 30 exhibited minimal impact on hematological parameters at 25 mg/kg, while AZD5305 at 1 mg/kg caused 56.5% reduction of reticulocyte. Taken together, we discovered compound 30 with a therapeutic index superior to that of PARP1 inhibitors AZD5305 and AZD9574 in the preclinical setting.

Objectives: The efficacy of enhanced recovery after surgery (ERAS) to improve the prognosis of patients who undergo laparoscopic distal gastrectomy (LDG) for gastric cancer is uncertain. This randomized study compared oncological outcomes in LDG after ERAS or conventional care., Background: At present, randomized controlled trials have confirmed that ERAS can improve the short-term clinical outcomes of patients undergoing LDG, but whether it improves survival has not been reported yet., Methods: A multicenter, randomized, controlled trial was performed to compare oncological outcomes of ERAS versus conventional care in LDG. Between April 4, 2019, and March 18, 2020, 527 patients with locally advanced lower gastric adenocarcinoma were recruited from 13 centers in China. The primary endpoints were 3-year overall survival (OS) and disease-free survival (DFS). The secondary endpoints were complications, mortality, recovery, time of receiving adjuvant chemotherapy and medical expenses., Results: The full analysis set included 186 cases in the ERAS group and 184 in conventional group, well balanced with respect to patient demographics and baseline characteristics (published before). Postoperative hospital stay and the interval before adjuvant chemotherapy were obviously shorter in the ERAS group compared to conventional group as reported previously and with lower medical expenses. Compared with the conventional group, ERAS group had fewer overall complications (21.0% vs. 30.4%, respectively; P=0.037). The median (IQR) follow-up for all cases was 42.17 (range, 3.12-48.50) months. The 3-year OS and DFS in the ERAS group and conventional group were 86.56% and 80.11% (log-rank P=0.025), 79.57% and 69.57% (log-rank P=0.027), respectively. In a subgroup analysis of stage I and II disease patients, 3-year OS and DFS were similar between the groups (P=0.901; P=0.859 for stage I and P=0.421; P=0.459 for stage II). However, in the stage III disease, the ERAS group exhibited longer 3-year OS and DFS than the conventional group (79.41% vs. 64.47% for OS, log-rank P=0.046; 70.59% vs. 53.95% for DFS, log-rank P=0.046)., Conclusions: Patients undergoing ERAS LDG had fewer overall complications, shorter hospital stay, decreased medical expenses, and improved 3-year OS and DFS rates, particularly in cases with stage III gastric cancer., Competing Interests: Financial Disclosure: There are no financial conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) is the dominant hydrolase of 2',3'-cyclic GMP-AMP (cGAMP). Inhibition of ENPP1 contributes to increased cGAMP concentration and stimulator of interferon gene (STING) activation, with the potential to boost immune response against cancer. ENPP1 is a promising therapeutic target in tumor immunotherapy. To date, orally bioavailable ENPP1 inhibitors with highly potent activity under physiological conditions have been rarely reported. Herein, we report our effort in the design and synthesis of two different series of ENPP1 inhibitors, and in the identification of a highly potent ENPP1 inhibitor 27 (IC 50  = 1.2 nM at pH 7.5), which significantly enhanced the cGAMP-mediated STING activity in THP-1 cells. Phosphonate compound 27 has good preclinical pharmacokinetic profiles with low plasma clearance rate in mouse, rat, and dog. It has been developed as bis-POM prodrug 36 which successfully improves the oral bioavailability of 27. In the Pan02 syngeneic mouse model of pancreatic cancer, orally administered 36 showed synergistic effect in combination with radiotherapy., Competing Interests: Declaration of competing interest The authors are all employees of Haihe Biopharma. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: There is a scarcity of large randomized clinical trials on the efficacy and safety of high-dose amino acid supplementation (AAS) in patients with gastrointestinal tumors undergoing surgical treatment., Methods: This pragmatic, randomized, controlled, single-center, open-label, parallel-group AMIGITS trial was performed in a tertiary care teaching hospital. Patients with gastrointestinal tumors were randomly assigned to receive either AAS or standard care (SC). Amino acid targets were 2.0 g/kg per day in the AAS group and 1.2 g/kg per day in the SC group. The AAS group received additional amino acids intravenously, while the SC group received an iso-energetic 5% glucose intravenously., Results: Overall, 407 patients (AAS group, 204; SC group, 203) were included in this study. During the intervention, the actual mean daily energy intake did not differ significantly between the AAS and SC groups (25.53 vs. 25.16 kcal/kg per day, P =0.493). However, the actual mean daily amino acid intake was significantly higher in the AAS group than that in the SC group (1.81 vs. 0.94 g/kg per day, P <0.001). The infection incidence during hospitalization and within 30 days of surgery was significantly lower in the AAS group than that in the SC group ( P =0.031 and P= 0.024, respectively). The 30-day postoperative incidence of amino acid treatment-related adverse events and other complications did not significantly differ between the two groups. The postoperative hospital stay was significantly different between the two groups ( P< 0.001)., Conclusions: AAS was associated with a reduced infection incidence within 30 days of major surgery in patients with gastrointestinal tumors and can be a promising strategy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Polysomnography (PSG) measures brain activity during sleep via electroencephalography (EEG) using six leads. Artifacts caused by movement or loose leads distort EEG measurements. We developed a method to automatically identify such artifacts in a PSG EEG trace. After preprocessing, we extracted power levels at frequencies of 0.5-32.5 Hz with multitaper spectral analysis using 4 s windows with 3 s overlap. For each resulting 1 s segment, we computed segment-specific correlations between power levels for all pairs of leads. We then averaged all pairwise correlation coefficients involving each lead, creating a time series of segment-specific average correlations for each lead. Our algorithm scans each averaged time series separately for "bad" segments using a local moving window. In a second pass, any segment whose averaged correlation is less than a global threshold among all remaining good segments is declared an outlier. We mark all segments between two outlier segments fewer than 300 s apart as artifact regions. This process is repeated, removing a channel with excessive outliers in each iteration. We compared artifact regions discovered by our algorithm to expert-assessed ground truth, achieving sensitivity and specificity of 80% and 91%, respectively. Our algorithm is an open-source tool, either as a Python package or a Docker., Competing Interests: Conflicts of Interest: The authors declare no conflicts of interest.

Electroencephalograms can capture brain oscillatory activities during sleep as a form of electrophysiological signals. We analysed electroencephalogram recordings from full-night in-laboratory polysomnography from 100 patients with Down syndrome, and 100 age- and sex-matched controls. The ages of patients with Down syndrome spanned 1 month to 31 years (median 4.4 years); 84 were younger than 12 years, and 54 were male. From each electroencephalogram, we extracted relative power in six frequency bands or rhythms (delta, theta, alpha, slow sigma, fast sigma, and beta) from six channels (frontal F3 and F4, central C3 and C4, and occipital O1 and O2) during five sleep stages (N3, N2, N1, R and W)-180 features in all. We examined differences in relative power between Down syndrome and control electroencephalograms for each feature separately. During wake and N1 sleep stages, alpha rhythms (8.0-10.5 Hz) had significantly lower power in patients with Down syndrome than controls. Moreover, the rate of increase in alpha power with age during rapid eye movement sleep was significantly slower in Down syndrome than control subjects. During wake and N1 sleep, delta rhythms (0.25-4.5 Hz) had higher power in patients with Down syndrome than controls. During N2 sleep, slow sigma rhythms (10.5-12.5 Hz) had lower power in patients with DS than controls. These findings extend previous research from routine electroencephalogram studies demonstrating that patients with Down syndrome had reduced circadian amplitude-the difference between wake alpha power and deep sleep delta power was smaller in Down syndrome than control subjects. We envision that these brain oscillatory activities may be used as surrogate markers for clinical trials for patients with Down syndrome., (© 2024 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

The separation and utilization of cellulose, hemicellulose, and lignin in lignocellulosic biorefineries present significant challenges. This study proposes a pretreatment method for biomass refining by combining acid and kraft pulping. Firstly, the biomass was pretreated by malic acid, resulting in the isolation of xylo-oligosaccharides (XOS) with a yield of 86.26 % with optimized conditions of 180 °C, 1 wt% concentration, 40 min. Secondly, a mixture of 12.98 wt% NaOH and 1.043 wt% Na 2 S is employed to achieve lignin removal efficiency up to 63.42 %. Physical refinement techniques are then applied to enhance the enzyme digestion efficiency of cellulose, resulting in an increase from 55.03 % to 91.4 % for efficient cellulose conversion. The reacted samples exhibit a lignin composition rich in β-O-4 ether bonds, facilitating their high-value utilization. The results indicated that the combined pretreatment approach demonstrates high efficiency in separating cellulose, hemicellulose, and lignin while obtaining XOS, highly active lignin, and enzyme-digested substrates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Study Objectives: Randomized controlled trials have shown that combining norepinephrine reuptake inhibitors and antimuscarinics can ameliorate the severity of obstructive sleep apnea. This article explores whether the effectiveness and safety of combining norepinephrine reuptake inhibitors with antimuscarinic agents surpass monotherapy for treating obstructive sleep apnea., Methods: We searched randomized controlled trials including adult patients with obstructive sleep apnea who received combination therapy and monotherapy in 8 databases from inception until April 5, 2023 and evaluated the studies' quality and conducted a meta-analysis and systematic review. The primary outcome was the apnea-hypopnea index. Secondary outcome measures included loop gain, hypoxic burden, oxygen desaturation index, and ventilation at low ventilatory drive, among other indicators. We assessed the quality of the studies using Cochrane Methods criteria., Results: We identified 4 randomized controlled trials for systematic review and 2 for meta-analysis. The results of the meta-analysis showed that norepinephrine reuptake inhibitors combined with antimuscarinic agents in patients with obstructive sleep apnea prolonged total sleep time by a mean of 28.20 minutes [95% confidence interval (5.78, 50.61), P = .01] and increased sleep efficiency by 4.73% [95% confidence interval (0.50, 8.97), P = .03] compared with norepinephrine reuptake inhibitors alone. Other indices and adverse events were of no statistical significance. The systematic reviews revealed that norepinephrine reuptake inhibitors combined with antimuscarinics may be superior to monotherapy in improving apnea-hypopnea index and endotypic traits., Conclusions: This evaluation demonstrated the potential advantages of combining norepinephrine reuptake inhibitors plus antimuscarinics for treating OSA compared with norepinephrine reuptake inhibitors alone and revealed no statistically significant difference in drug safety., Citation: Wang J, Ye Y, Shang Z, et al. Effect of norepinephrine reuptake inhibitors combined with antimuscarinic agents vs monotherapy for OSA: a systematic review and meta-analysis. J Clin Sleep Med . 2024;20(8):1363-1372., (© 2024 American Academy of Sleep Medicine.)

Sleep apnea is a common sleep disorder. The availability of an easy-to-use sleep apnea predictor would provide a public health benefit by promoting early diagnosis and treatment. Our goal was to develop a prediction tool that used commonly available variables and was accessible to the public through a web site. Using data from polysomnography (PSG) studies that measured the apnea-hypopnea index (AHI), we built a machine learning tool to predict the presence of moderate to severe obstructive sleep apnea (OSA) (defined as AHI ≥15). Our tool employs only seven widely available predictor variables: age, sex, weight, height, pulse oxygen saturation, heart rate and respiratory rate. As a preliminary step, we used 16,958 PSG studies to examine eight machine learning algorithms via five-fold cross validation and determined that XGBoost exhibited superior predictive performance. We then refined the XGBoost predictor by randomly partitioning the data into a training and a test set (13,566 and 3392 PSGs, respectively) and repeatedly subsampling from the training set to construct 1000 training subsets. We evaluated each of the resulting 1000 XGBoost models on the single set-aside test set. The resulting classification tool correctly identified 72.5 % of those with moderate to severe OSA as having the condition (sensitivity) and 62.8 % of those without moderate to-severe OSA as not having it (specificity); overall accuracy was 66 %. We developed a user-friendly publicly available website (https://manticore.niehs.nih.gov/OSApredictor). We hope that our easy-to-use tool will serve as a screening vehicle that enables more patients to be clinically diagnosed and treated for OSA., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Published by Elsevier Ltd.)

Metabolic reprogramming dictates tumor molecular attributes and therapeutic potentials. However, the comprehensive metabolic characteristics in gastric cancer (GC) remain obscure. Here, metabolic signature-based clustering analysis identifies three subtypes with distinct molecular and clinical features: MSC1 showed better prognosis and upregulation of the tricarboxylic acid (TCA) cycle and lipid metabolism, combined with frequent TP53 and RHOA mutation; MSC2 had moderate prognosis and elevated nucleotide and amino acid metabolism, enriched by intestinal histology and mismatch repair deficient (dMMR); and MSC3 exhibited poor prognosis and enhanced glycan and energy metabolism, accompanied by diffuse histology and frequent CDH1 mutation. The Shandong Provincial Hospital (SDPH) in-house dataset with matched transcriptomic, metabolomic, and spatial-metabolomic analysis also validated these findings. Further, we constructed the metabolic subtype-related prognosis gene (MSPG) scoring model to quantify the activity of individual tumors and found a positive correlation with cuproptosis signaling. In conclusion, comprehensive recognition of the metabolite signature can enhance the understanding of diversity and heterogeneity in GC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

SOS1, a guanine nucleotide exchange factor (GEF), plays a critical role in catalyzing the conversion of KRAS from its GDP- to GTP-bound form, regardless of KRAS mutation status, and represents a promising new drug target to treat all KRAS-driven tumors. Herein, we employed a scaffold hopping strategy to design, synthesize, and optimize a series of novel binary ring derivatives as SOS1 inhibitors. Among them, compound 10f (HH0043) displayed potent activities in both biochemical and cellular assays and favorable pharmacokinetic profiles. Oral administration of HH0043 resulted in a significant tumor inhibitory effect in a subcutaneous KRAS G12C -mutated NCI-H358 (human lung cancer cell line) xenograft mouse model, and the tumor inhibitory effect of HH0043 was superior to that of BI-3406 at the same dose (total growth inhibition, TGI: 76% vs 49%). On the basis of these results, HH0043, with a novel 1,7-naphthyridine scaffold that is distinct from currently reported SOS1 inhibitors, is nominated as the lead compound for this discovery project., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Background and Objective: With advances in gut microbiome research, it has been recognized that the gut microbiome has an important and far-reaching impact on many human diseases, including cancer. Therefore, more and more researchers are focusing on the treatment of gut flora in tumors. In this article, we present a review of the mechanisms of gut microbes in tumor immunotherapy and related studies to provide reference for further research and insights into the clinical application of gut microbes., Methods: Between April 25, 2023, and November 25, 2023, we searched for articles published only in English between 1984 and 2023 using the databases PubMed, American Medical Association and Elsevier ScienceDirect using the keywords "gut microbiology" and "tumor" or "immunotherapy"., Key Content and Findings: The gastrointestinal tract contains the largest number of microorganisms in the human body. Microorganisms are involved in regulating many physiological activities of the body. Studies have shown that gut microbes and their derivatives are involved in the occurrence and development of a variety of inflammations and tumors, and changes in their abundance and proportion affect the degree of cancer progression and sensitivity to immunotherapy. Gut microbiota-based drug research is ongoing, and some anti-tumor studies have entered the clinical trial stage., Conclusions: The abundance and proportion of intestinal microorganisms influence the susceptibility of tumors to tumor immunotherapy. This article reviewed the effects and mechanisms of gut microbes on tumor immunotherapy to further explore the medical value of gut microbes in tumor immunotherapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-316/coif). The authors have no conflicts of interest to declare., (2024 Translational Cancer Research. All rights reserved.)

Background: Brain waves during sleep are involved in sensing and regulating peripheral glucose level. Whether brain waves in patients with diabetes differ from those of healthy subjects is unknown. We examined the hypothesis that patients with diabetes have reduced sleep spindle waves, a form of brain wave implicated in periphery glucose regulation during sleep., Methods: From a retrospective analysis of polysomnography (PSG) studies on patients who underwent sleep apnea evaluation, we identified 1,214 studies of patients with diabetes mellitus (>66% type 2) and included a sex- and age-matched control subject for each within the scope of our analysis. We similarly identified 376 patients with prediabetes and their matched controls. We extracted spindle characteristics from artifact-removed PSG electroencephalograms and other patient data from records. We used rank-based statistical methods to test hypotheses. We validated our finding on an external PSG dataset., Results: Patients with diabetes mellitus exhibited on average about half the spindle density (median=0.38 spindles/min) during sleep as their matched control subjects (median=0.70 spindles/min) ( P <2.2e-16). Compared to controls, spindle loss was more pronounced in female patients than in male patients in the frontal regions of the brain ( P= 0.04). Patients with prediabetes also exhibited signs of lower spindle density compared to matched controls ( P= 0.01-0.04)., Conclusions: Patients with diabetes have fewer spindle waves that are implicated in glucose regulation than matched controls during sleep. Besides offering a possible explanation for neurological complications from diabetes, our findings open the possibility that reversing/reducing spindle loss could improve the overall health of patients with diabetes mellitus., Competing Interests: Conflict of Interest. The authors declare no competing interests.

Recent studies have highlighted the biological significance of cuproptosis in disease occurrence and development. However, it remains unclear whether cuproptosis signaling also has potential impacts on tumor initiation and prognosis of gastric cancer (GC). In this study, 16 cuproptosis-related genes (CRGs) transcriptional profiles were harnessed to perform the regularized latent variable model-based clustering in GC. A cuproptosis signature risk scoring (CSRS) scheme, based on a weighted sum of principle components of the CRGs, was used to evaluate the prognosis and risk of individual tumors of GC. Four distinct cuproptosis signature-based clusters, characterized by differential expression patterns of CRGs, were identified among 1136 GC samples across three independent databases. The four clusters were also associated with different clinical outcomes and tumor immune contexture. Based on the CSRS, GC patients can be divided into CSRS-High and CSRS-Low subtypes. We found that DBT, MTF1 , and ATP7A were significantly elevated in the CSRS-High subtype, while SLC31A1, GCSH, LIAS, DLAT, FDX1, DLD , and PDHA1 were increased in the CSRS-Low subtype. Patients with CSRS-Low score were characterized by prolonged survival time. Further analysis indicated that CSRS-Low score also correlated with greater tumor mutation burden (TMB) and higher mutation rates of significantly mutated genes (SMG) in GC. In addition, the CSRS-High subtype harbored more significantly amplified focal regions related to tumorigenesis ( 3q27.1, 12p12.1, 11q13.3 , etc.) than the CSRS-Low tumors. Drug sensitivity analyses revealed the potential compounds for the treatment of gastric cancer with CSRS-High score, which were experimentally validated using GC cells. This study highlights that cuproptosis signature-based subtyping is significantly associated with different clinical features and molecular landscape of GC. Quantitative evaluation of the CSRS of individual tumors will strengthen our understanding of the occurrence and development of cuproptosis and the treatment progress of GC., Competing Interests: The authors declare no competing interests., (© 2024 The Authors. iMeta published by John Wiley & Sons Australia, Ltd on behalf of iMeta Science.)

Competing Interests: Conflict of interest The authors declare that they have no conflict of interest.

Malignant tumours of the digestive system cover a wide range of diseases that affect the health of people to a large extent. Angiogenesis is indispensable in the development, and metastasis of tumours, mainly in two ways: occupation or formation. Vessels can provide nutrients, oxygen, and growth factors for tumours to encourage growth and metastasis, so cancer progression depends on simultaneous angiogenesis. Recently, exosomes have been proven to participate in the angiogenesis of tumours. They influence angiogenesis by binding to tyrosine kinase receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 with different affinities, regulating Yap-VEGF pathway, Akt pathway or other signaling pathway. Additionally, exosomes are potential therapeutic vectors that can deliver many types of cargoes to different cells. In this review, we summarize the roles of exosomes in the angiogenesis of digestive system tumours and highlight the clinical application prospects, directly used as targers or delivery vehicles, in antiangiogenic therapy., (© 2024. The Author(s).)

Background: For gastric cancer with total gastrectomy, the usual laparoscopic surgical approaches are totally laparoscopic total gastrectomy (TLTG) and laparoscopic-assisted total gastrectomy (LATG). Due to its difficult anastomotic technique, the adoption of TLTG is limited. Therefore, surgeons prefer using LATG, which also led to TLTG being somewhat overlooked, so there is no clear conclusion today as to which surgical procedure is more favorable to the patient's recovery. This article aimed to compare the safety and short-term outcomes of the two surgical approaches., Materials and Methods: Studies comparing TLTG and LATG, published up to December 2022, were searched in PubMed, Web of Science, and Embase databases. The study outcomes, including operative time, blood loss, anastomosis time, number of retrieved lymph nodes, proximal and distal resection margins, time to first fluid and soft diet, hospitalization duration, time to first flatus, and postsurgical and anastomotic complications, were compared between these two different surgical procedures. Statistics were analyzed with RevMan 5.4 and Stata 13.1., Results: Fifteen publications were included in this study. The total sample included 3023 cases. The meta-analysis revealed no significant difference in overall postoperative complications between the two surgical approaches ( P >0.05). Compared with LATG, TLTG led to reduced intraoperative blood loss ( P <0.0001), an increased number of lymphatic node dissections ( P <0.0001), and decreased hospitalization duration ( P =0.002). However, operative time, anastomosis time, pulmonary infection, resection margins, time to first fluid and soft diet, time to first flatus and anastomosis-related complications were no significant difference between TLTG and LATG groups ( P >0.05)., Conclusion: TLTG did not lead to an increase in overall postoperative complications, which is a reliable surgical approach for treatment of gastric cancer. Moreover, it may reduce harm to patients and enable them to obtain better surgical outcomes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Tumor mutational load (TML) has emerged as a potential biomarker for multiple solid tumors. However, data on its prognostic impact on upper gastrointestinal (UGI) cancer are limited. Therefore, the aim of this systematic review and meta-analysis was to assess the prognostic value of TML for the survival of patients with UGI cancer., Method: A comprehensive search of the PubMed, Embase, Cochrane Library, and Web of Science databases was conducted up to February 13, 2023. Eleven studies met our inclusion criteria. Hazard ratios (HRs) for progression-free survival and overall survival and their 95% confidence intervals (CIs) were calculated. Subsequently, the combined HR and its 95% CI were calculated for UGI tract cancers in the high and low TML groups. I 2 statistics and p-values were used to evaluate heterogeneity. Publication bias, sensitivity, and subgroup analyses were performed to determine sources of heterogeneity., Results: In total, 932 patients with UGI tract cancer from 11 publications were included. The high TML group treated with immunotherapy showed significantly improved overall survival (HR = 0.68; 95% CI: 0.53, 0.86; p = .001) and progression-free survival (HR = 0.74; 95% CI: 0.58, 0.95; p = .020) compared with the low TML group., Conclusion: Our study demonstrated that patients with UGI tumors and higher TML have a better prognosis with immunotherapy, suggesting that TML is a promising predictive biomarker for immunotherapy., Registration: The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO Registration No: CRD42023405596)., (© 2024 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) has recently emerged as a novel tumor suppressor. Researchers have observed that LHPP plays a crucial role in inhibiting proliferation, growth, migration, invasion, and cell metabolism across various cancers. Nevertheless, the specific functions and underlying mechanisms of LHPP as a tumor suppressor in gastric cancer (GC) require further exploration. The expression of LHPP was assessed in human GC specimens and cell lines. Various assays were employed to evaluate the impact of LHPP on GC cells. RNA sequencing and Gene Set Enrichment Analysis were conducted to unravel the mechanism through which LHPP regulates GC cell behavior. Additionally, xenograft nude mouse models were utilized to investigate the in vivo effects of LHPP. The findings indicate that LHPP, functioning as a tumor suppressor, is downregulated in both GC tissues and cells. LHPP emerges as an independent risk factor for GC patients, and its expression level exhibits a positive correlation with patient prognosis. LHPP exerts inhibitory effects on the adhesion and proliferation of GC cells by suppressing the expression of insulin-like growth factor 1 receptor (IGF1R) and modulating downstream signaling pathways. Consequently, LHPP holds potential as a biomarker for targeted therapy involving IGF1R inhibition in GC patients., Competing Interests: The authors declare that they have no conflict of interests., (© 2024 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Monoubiquitination of FANCD2 is a central step in the activation of the Fanconi anemia (FA) pathway after DNA damage. Defects in the FA pathway centered around FANCD2 not only lead to genomic instability but also induce tumorigenesis. At present, few studies have investigated FANCD2 in tumors, and no pan-cancer research on FANCD2 has been conducted. We conducted a comprehensive analysis of the role of FANCD2 in cancer using public databases and other published studies. Moreover, we evaluated the role of FANCD2 in the proliferation, migration and invasion of lung adenocarcinoma cells through in vitro and in vivo experiments, and explored the role of FANCD2 in cisplatin chemoresistance. We investigated the regulatory effect of FANCD2 on the cell cycle of lung adenocarcinoma cells by flow cytometry, and verified this effect by western blotting. FANCD2 expression is elevated in most TCGA tumors and shows a strong positive correlation with poor prognosis in tumor patients. In addition, FANCD2 expression shows strong correlations with immune infiltration, immune checkpoints, the tumor mutation burden (TMB), and microsatellite instability (MSI), which are immune-related features, suggesting that it may be a potential target of tumor immunotherapy. We further found that FANCD2 significantly promotes the proliferation, invasion, and migration abilities of lung adenocarcinoma cells and that its ability to promote cancer cell proliferation may be achieved by modulating the cell cycle. The findings indicate that FANCD2 is a potential biomarker and therapeutic target in cancer treatment by analyzing the oncogenic role of FANCD2 in different tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Studies show that patients with obstructive sleep apnea (OSA) are more likely than the general population to have psychological disorders such as depression. However, it is less clear how OSA treatment affects this association. This meta-analysis aimed to assess whether or not continuous positive airway pressure (CPAP) and mandibular advancement devices (MADs) reduce depression symptoms in patients with OSA., Methods: We searched Pubmed, Embase, Web of Science, and Cochrane Library from creating the databases until November 2022. Our analysis included RCTs that examined CPAP and MAD treatment effectiveness for depression in patients with OSA., Results: We identified 17 CPAP studies comprising 1,931 patients for inclusion in the meta-analysis. The results of the meta-analysis using a fixed effects model found that CPAP improved depressed mood in patients with OSA relative to controls (SMD = 0.27;95% CI:0.18,0.36), with small heterogeneity among trials (I 2  = 8.1% < 50%, P = 0.359). We performed subgroup analyses on three factors: the length of trial follow-up, patient adherence data, and depression assessment scales. The meta-analysis also identified six MAD studies involving 315 patients. According to this analysis, there was no heterogeneity between studies (I 2  = 0%, P = 0.748). MADs did not significantly improve depression symptoms compared to controls, indicating a combined effect of SMD = 0.07 (95% CI: - 0.15,0.29), P > 0.05., Conclusion: The present findings confirm that CPAP may improve depressive symptoms in patients with OSA. However, the review results suggest that MADs have no significant effect on depressive symptoms in patients with OSA, a finding that is different from the results of previous meta-analyses., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Gastric cancer (GC) diagnosed in the elderly population has become a serious public health problem worldwide. Given the combined effects of frailty and the consequences of cancer treatment, older individuals with GC are more likely than young patients to suffer from postoperative complications and poor clinical outcomes. Nutrition, functional capacity and psychological state-based multimodal prehabilitation, which is dominated by Enhanced Recovery After Surgery (ERAS) pathway management, has been shown to reduce postoperative complications, promote functional recovery and decrease hospitalisation time in certain malignancies. However, no previous studies have investigated the clinical application of multimodal prehabilitation in frail older patients with GC., Methods and Analysis: The study is a prospective, multicentre randomised controlled trial in which a total of 368 participants who meet the inclusion criteria will be randomised into either a prehabilitation group or an ERAS group. The prehabilitation group will receive multimodal prehabilitation combined with ERAS at least 2 weeks before the gastrectomy is performed, including physical and respiratory training, nutritional support, and therapy and psychosocial treatment. The ERAS group patients will be treated according to the ERAS pathway. All interventions will be supervised by family members. The primary outcome measures are the incidence and severity of postoperative complications. Secondary outcomes include survival, functional capacity and other short-term postoperative outcomes. Overall, the multimodal prehabilitation protocol may improve functional capacity, reduce the surgical stress response and concomitant systemic inflammation, and potentially modulate the tumour microenvironment to improve short-term and long-term clinical outcomes and patients' quality of life., Ethics and Dissemination: All procedures and participating centres of this study were approved by their respective ethics committees (QYFYKYLL 916111920). The final study results will be published separately in peer-reviewed journals., Trial Registration Number: NCT05352802., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The vast majority of severe (Type 0) spinal muscular atrophy (SMA) cases are caused by homozygous deletions of survival motor neuron 1 ( SMN1 ). We report a case in which the patient has two copies of SMN1 but clinically presents as Type 0 SMA. The patient is an African American male carrying a homozygous maternally inherited missense variant (c.796T>C) in a cis -oriented SMN1 duplication on one chromosome and an SMN1 deletion on the other chromosome (genotype: 2*+0). Initial extensive genetic workups including exome sequencing were negative. Deletion analysis used in the initial testing for SMA also failed to detect SMA as the patient has two copies of SMN1 . Because of high clinical suspicion, SMA diagnosis was finally confirmed based on full-length SMN1 sequencing. The patient was initially treated with risdiplam and later gene therapy with onasemnogene abeparvovec at 5 months without complications. The patient's muscular weakness has stabilized with mild improvement. The patient is now 28 months old and remains stable and diffusely weak, with stable respiratory ventilatory support. This case highlights challenges in the diagnosis of SMA with a non-deletion genotype and provides a clinical example demonstrating that disruption of functional SMN protein polymerization through an amino acid change in the YG-box domain represents a little known but important pathogenic mechanism for SMA. Clinicians need to be mindful about the limitations of the current diagnostic approach for SMA in detecting non-deletion genotypes., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Li, Perera, Varghese, Shiloh-Malawsky, Hunter, Sneddon, Powell, Matera and Fan.)

DNASE1L3, an enzyme highly expressed in DCs, is functionally important for regulating autoimmune responses to self-DNA and chromatin. Deficiency of DNASE1L3 leads to development of autoimmune diseases in both humans and mice. However, despite the well-established causal relationship between DNASE1L3 and immunity, little is known about the involvement of DNASE1L3 in regulation of antitumor immunity, the foundation of modern antitumor immunotherapy. In this study, we identify DNASE1L3 as a potentially new regulator of antitumor immunity and a tumor suppressor in colon cancer. In humans, DNASE1L3 is downregulated in tumor-infiltrating DCs, and this downregulation is associated with poor patient prognosis and reduced tumor immune cell infiltration in many cancer types. In mice, Dnase1l3 deficiency in the tumor microenvironment enhances tumor formation and growth in several colon cancer models. Notably, the increased tumor formation and growth in Dnase1l3-deficient mice are associated with impaired antitumor immunity, as evidenced by a substantial reduction of cytotoxic T cells and a unique subset of DCs. Consistently, Dnase1l3-deficient DCs directly modulate cytotoxic T cells in vitro. To our knowledge, our study unveils a previously unknown link between DNASE1L3 and antitumor immunity and further suggests that restoration of DNASE1L3 activity may represent a potential therapeutic approach for anticancer therapy.

Organoids are established through in vitro 3D culture, and they can mimic the structure and physiological functions of organs or tissues in vivo. Organoids have attracted much attention in recent years. They can provide a reliable technology platform for cancer research and treatment and are a valuable preclinical model for academic research and personalized medicine. A number of studies have confirmed that organoids have great application prospects in new drug development, drug screening, tumour mechanism research, and precision medicine. In this review, we mainly focus on recent advances in the application of organoids in cancer research. We also discussed the opportunities and challenges facing organoids, hoping to indicate directions for the development of organoids in the future., (© 2023. YUMED Inc. and BioMed Central Ltd.)

Purpose: Radical gastrectomy with D2 lymphadenectomy can trigger a high incidence of postoperative pancreatic fistula (POPF), which produces a poor clinical prognosis. We sought to evaluate the effect of somatostatin analogs (SSA) on POPF and clinical prognosis after radical gastrectomy., Methods: A total of 123 patients with a high risk of POPF after radical gastrectomy (drainage fluid amylase concentration on a postoperative day [POD] 1 > 3 times the upper limit of normal serum amylase value) were randomly divided into the SSA group (n = 61) and the control group (n = 62). The former received continuous intravenous SSA (0.3 mg/8 h) for 3 days from POD1, and the latter normal saline. The primary outcome was the incidence of POPF., Results: The incidence of POPFs in the SSA group was significantly lower than that in the control group (3.3% vs. 14.5%, P = 0.029). The incidence of short-term postoperative complications was significantly lower in the SSA group than in the control group (9.8% vs. 24.2%, P = 0.034). The median white blood cell counts, neutrophil counts, and the percentage of neutrophils on POD4 were significantly lower in the SSA group than in the control group (all P < 0.05). The SSA group had a shorter mean time to the first liquid diet (87.33 ± 17.92 h vs. 93.97 ± 17.29 h, P = 0.039). And the SSA group had less median daily drainage volume (96.33 mL vs. 119.67 mL, P = 0.025) and shorter drainage duration (7.0 days vs. 10.0 days, P = 0.013)., Conclusion: Postoperative treatment with a somatostatin analog reduced the incidence of POPF and short-term complications after radical gastrectomy. (TRN: ChiCTR2200056201, Reg. Date: 2022/2/1)., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Lung adenocarcinoma (LUAD) is the most common type of lung cancer. LRP1B was initially identified as a cancer suppressor in several cancers. However, the potential biological phenotypes and molecular mechanisms of LRP1B in LUAD have not been fully investigated. In our study, we showed that the expression of LRP1B in LUAD tissues was lower than that in normal tissues. Knockdown of LRP1B markedly enhanced malignancy of LUAD cells. Genomic analysis indicated that the population expressing low-levels of LRP1B had higher genomic instability, which accounted for a larger proportion of aneuploidy and inflammation subtyping. Enrichment analysis of bulk and cell-line transcriptomic data both showed that the low expression of LRP1B could induce the activation of IL-6-JAK-STAT3, chemokine, cytokine, and other inflammation signaling pathways. Moreover, our findings revealed that knockdown LRP1B enhanced the secretion of IL-6 and IL-8, as confirmed by ELISA assays. Further validation using PCR and WB confirmed that downregulation of LRP1B mRNA significantly upregulated the activity of the IL-6-JAK-STAT3 pathway. Collectively, this study highlights LRP1B as a tumor suppressor gene and reveals that LRP1B knockdown promotes malignant progression in LUAD by inducing inflammation through the IL-6-JAK-STAT3 pathway., Competing Interests: None., (AJCR Copyright © 2023.)

Gut microbiota is closely related to human health and disease because, together with their metabolites, gut microbiota maintain normal intestinal peristalsis. The use of antibiotics or opioid anesthetics, or both, during surgical procedures can lead to dysbiosis and affect intestinal motility; however, the underlying mechanisms are not fully known. This review aims to discuss the effect of gut microbiota and their metabolites on postoperative intestinal motility, focusing on regulating the enteric nervous system, 5-hydroxytryptamine neurotransmitter, and aryl hydrocarbon receptor., (© 2023. The Author(s).)

Semaphorin 4D (SEMA4D) is considered a new antitumor target closely related to immune cells. However, understanding the role of SEMA4D in the tumor microenvironment (TME) is limited. In this study, we explored the expression and immune cell infiltration patterns of SEMA4D using multiple bioinformatics datasets and analyzed the relationship between SEMA4D expression with immune checkpoints, tumor mutational load (TMB), microsatellite instability (MSI) and immune function. We detected that SEMA4D is overexpressed in many tumors types, widely enriched in immune cells, and closely associated with TILs, MSI, TMB, as well as T-cell exhaustion-associated immune checkpoints, and thus can broadly affect the immune microenvironment. We further verified the overexpression of SEMA4D in tumor and its distribution in TME by immunohistochemistry, RT-qPCR and flow cytometry, and confirmed that decreased expression of SEMA4D can lead to recovery of T cell exhaustion. In conlusion, this study provides a more comprehensive perspective of SEMA4D regulation of tumor immunity, which provide a new option for cancer immunotherapy., 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 © 2023 Zeng, Zhang, Ye, Wang, Jing and Li.)

Hepatectomy is an effective surgical method for the treatment of liver diseases, but intraoperative bleeding and postoperative liver function recovery are still key issues. This study aims to develop a composite hydrogel dressing with excellent hemostatic properties, biocompatibility, and ability to promote liver cell regeneration. The modified gelatin matrix (GelMA, 10%) was mixed with equal volumes of sodium alginate-dopamine (Alg-DA) at concentrations of 0.5%, 1%, and 2%. Then a cross-linking agent (0.1%) was added to prepare different composite hydrogels under UV light, named GelMA/Alg-DA-0.5, GelMA/Alg-DA-1 and GelMA/Alg-DA-2, respectively. All the prepared hydrogel has a porous structure with a porosity greater than 65%, and could be stabilized in a gel state after being cross-linked by ultraviolet light. Physicochemical characterization showed that the elastic modulus, water absorption, adhesion, and compressibility of the composite hydrogels were improved with increasing Alg-DA content. Furthermore, the prepared hydrogel exhibits in vitro degradability, excellent biocompatibility, and good hemostatic function. Among all tested groups, the group of GelMA/Alg-DA-1 hydrogel performed the best. To further enhance its application potential in the field of liver regeneration, adipose-derived mesenchymal stem cell exosomes (AD-MSC-Exo) were loaded into GelMA/Alg-DA-1 hydrogel. Under the same conditions, GelMA/Alg-DA-1/Exo promoted cell proliferation and migration more effectively than hydrogels without extracellular vesicles. In conclusion, the prepared GelMA/Alg-DA-1 composite hydrogel loaded with AD-MSC-Exo has great application potential in liver wound hemostasis and liver regeneration., 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 © 2023 Xia, Lai, Li, Zeng, Sun, Zhang, Zhu, Li and Wu.)

Background and Objective: As a surgical tool, indocyanine green (ICG) is increasingly used in surgery, especially in gastric and colorectal surgery. The use of ICG fluorescence imaging can improve the accuracy of tumor resection and potentially improve surgical outcomes for cancer patients. However, there are still different opinions or controversies on the application of ICG in the literature and the administration of ICG is still not uniform. In this review, we summarize the current status of its application and ICG administration methods in gastrointestinal cancer and discuss its existing limitations and future research directions., Methods: Literature published in the PubMed database from 1969 to 2022 was searched for using the keywords "Indocyanine green or near-infrared imaging or ICG", "gastric cancer", "gastroesophageal junction cancer", and "colorectal cancer" to summarize the main applications of ICG in gastrointestinal cancers., Key Content and Findings: ICG guidance can rapidly determine tumor location and save operative time, and can also visualize lymph nodes (LNs) in real-time, helping surgeons to retrieve more LNs for better postoperative staging, but its use in identifying sentinel lymph node (SLN) in gastric cancer (GC) remains controversial due to false negatives. ICG fluorescent angiography has great potential in preventing colorectal anastomotic leakage, but there is a dearth of high-caliber research evidence. In addition, ICG has unique advantages in detecting colorectal liver micrometastasis. Notably, there is still no uniform administration method and dose of ICG., Conclusions: In this review, we summarize the current status of ICG application in gastrointestinal cancer, and the current literature suggests that it is safe and effective and has the potential to change the clinical outcome of patients. Therefore, ICG should be routinely used in gastrointestinal cancers to improve the surgical outcomes of patients. In addition, this review summarizes the ICG administration in the literature, and we expect future guidelines to unitize and standardize the administration of ICG., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-230/coif). The authors have no conflicts of interest to declare., (2023 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: Protective loop ileostomy is commonly performed in laparoscopic low anterior rectal resection to prevent the serious complications of anastomotic fistula. It is usually created at the right lower quadrant of the abdomen and another wound is required for stoma. The study aimed to evaluate the outcomes of ileostomy at the specimen extraction site (SES) and another site (AS) beside the auxiliary incision., Methods: A retrospective analysis was conducted on 101 eligible patients with pathologically diagnosed adenocarcinoma of the rectum from January 2020 to December 2021 in the study center. According to whether the ileostomy was at the specimen extraction site, patients were divided into SES group (40 patients) and AS group (61 patients). Clinicopathological characteristics, the intraoperative details, and postoperative outcomes of the two groups were measured., Results: Univariate analysis showed that the operative time was significantly shorter and the blood loss was significantly less in the SES group than in the AS group during laparoscopic low anterior rectal resection, the time to first flatus was significantly shorter, and the pain was significantly less in the SES group than in the AS group during ileostomy closure. The postoperative complications were similar in both groups. Multivariable analysis showed that ileostomy at the specimen extraction site was a significant factor influencing the operative time and blood loss of rectal resection, and influencing the pain and the time to first flatus during ileostomy closure., Conclusion: Compared to ileostomy at AS, protective loop ileostomy at SES was time-saving and less bleeding during laparoscopic low anterior rectal resection, and more quick to first flatus and less pain during stoma closure, and did not lead to more postoperative complications. The median incision of the lower abdomen and the left lower abdominal incision were both good sites for ileostomy., (© 2023. The Author(s).)

Background: The characteristics of and relationship between sleep apnoea and hypoventilation in patients with muscular dystrophy (MD) remain to be fully understood., Methods: We analysed 104 in-laboratory sleep studies of 73 patients with MD with five common types (DMD-Duchenne, Becker MD, CMD-congenital, LGMD-limb-girdle and DM-myotonic dystrophy). We used generalised estimating equations to examine differences among these types for outcomes., Results: Patients in all five types had high risk of sleep apnoea with 53 of the 73 patients (73%) meeting the diagnostic criteria in at least one study. Patients with DM had higher risk of sleep apnoea compared with patients with LGMD (OR=5.15, 95% CI 1.47 to 18.0; p=0.003). Forty-three per cent of patients had hypoventilation with observed prevalence higher in CMD (67%), DMD (48%) and DM (44%). Hypoventilation and sleep apnoea were associated in those patients (unadjusted OR=2.75, 95% CI 1.15 to 6.60; p=0.03), but the association weakened after adjustment (OR=2.32, 95% CI 0.92 to 5.81; p=0.08). In-sleep average heart rate was about 10 beats/min higher in patients with CMD and DMD compared with patients with DM (p=0.0006 and p=0.02, respectively, adjusted for multiple testing)., Conclusion: Sleep-disordered breathing is common in patients with MD but each type has its unique features. Hypoventilation was only weakly associated with sleep apnoea; thus, high clinical suspicion is needed for diagnosing hypoventilation. Identifying the window when respiratory muscle weakness begins to cause hypoventilation is important for patients with MD; it enables early intervention with non-invasive ventilation-a therapy that should both lengthen the expected life of these patients and improve its quality.Cite Now., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Diffuse type gastric cancer was identified with relatively worse prognosis than other Lauren's histological classification. Integrin β1 (ITGB1) was a member of integrin family which played a markedly important role in tumorigenesis and progression. However, the influence of ITGB1 in diffuse gastric cancer (DGC) remains uncertain. Here, we leveraged the transcriptomic and proteomic data to explore the association between ITGB1 expression and clinicopathologic information and biological process in DGC. Cell phenotype experiments combined with quantitative-PCR (q-PCR) and western blotting were utilized to identify the potential molecular mechanism underling ITGB1.Transcriptomics and proteomics both revealed that the higher ITGB1 expression was significantly associated with worse prognosis in DGC, but not in intestinal GC. Genomic analysis indicated that the mutation frequency of significantly mutated genes of ARID1A and COL11A1, and mutational signatures of SBS6 and SBS15 were markedly increased in the ITGB1 low expression subgroup. The enrichment analysis revealed diverse pathways related to dysregulation of ITGB1 in DGC, especially in cell adhesion, proliferation, metabolism reprogramming, and immune regulation alterations. Elevated activities of kinase-ROCK1, PKACA/PRKACA and AKT1 were observed in the ITGB1 high-expression subgroup. The ssGSEA analysis also found that ITGB1 low-expression had a higher cuproptosis score and was negatively correlated with key regulators of cuproptosis, including FDX1, DLAT, and DLST. We further observed that the upregulated expression of mitochondrial tricarboxylic acid (TCA) cycle in the ITGB1 low-expression group. Reduced expression of ITGB1 inhibited the ability of cell proliferation and motility and also potentiated the cell sensitive to copper ionophores via western blotting assay. Overall, this study revealed that ITGB1 was a protumorigenic gene and regulated tumor metabolism and cuproptosis in DGC., 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 © 2023 Zhu, Chen, Li, Ren, Ye, Xu, Liu, Du, Zhang, Liu, Xie, Wang, Ma, Chong, Shang and Li.)

Aim: To investigate the effect of intravenous dexamethasone administration on postoperative enteral nutrition tolerance in patients following gastrointestinal surgery., Methods: Based on the previous results of a randomized controlled study to explore whether intravenous administration of dexamethasone recovered gastrointestinal function after gastrointestinal surgery, we used the existing research data from 1 to 5 days post operation in patients with enteral nutrition tolerance and nutrition-related analyses of the changes in serum indices, and further analyzed the factors affecting resistance to enteral nutrition., Result: The average daily enteral caloric intake was significantly higher in patients receiving intravenous administration of dexamethasone during anesthesia induction than in controls (8.80 ± 0.92 kcal/kg/d vs. 8.23 ± 1.13 kcal/kg/d, P = 0.002). Additionally, intravenous administration of 8 mg dexamethasone during anesthesia induction can reduce the changes in postoperative day (POD) 3, POD5, and preoperative values of serological indices, including ΔPA, ΔALB, and ΔRBP ( P < 0.05). In the subgroup analysis, dexamethasone significantly increased the average daily enteral nutrition caloric intake in patients undergoing enterotomy (8.98 ± 0.87 vs. 8.37 ± 1.17 kcal/kg/d, P = 0.010) or in female patients (8.94 ± 0.98 vs. 8.10 ± 1.24 kcal/kg/d, P = 0.019). The changes of serological indexes (ΔPA, ΔALB, and ΔRBP) in the dexamethasone group were also significantly different on POD3 and POD5 ( P < 0.05). In addition, multivariate analysis showed that dexamethasone use, surgical site, and age might influence enteral nutrition caloric tolerance., Conclusion: Postoperative enteral nutrition tolerance was significantly improved in patients receiving intravenous administration of dexamethasone during anesthesia induction, especially in patients following enterotomy surgery, with significant improvements in average daily enteral caloric intake, PA levels, ALB levels, and RBP levels., Clinical Trial Registration: http://www.chictr.org.cn, identifier: ChiCTR1900024000., 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 © 2023 Tian, Zhou, Wang, Wang, Shang, Li, Jing and Chen.)

Background: Patients with tumors generally present with accompanying activation of the coagulation system, which may be related to tumor stage. To our knowledge, few studies have examined the activation of the coagulation system in reference to lymph node metastasis within gastric cancer. This study aimed to investigate the correlation between multiple coagulation-related factors and lymph node metastasis in patients with gastric cancer after excluding the influence of tumor T stage., Materials and Methods: We retrospectively evaluated the relationship between lymph node metastasis and coagulation-related factors in 516 patients with T4a stage gastric cancer. We further analyzed influencing factors for lymph node metastasis and verified the predictive value of maximum amplitude (MA, a parameter of thromboelastography which is widely used to assess the strength of platelet-fibrinogen interaction in forming clots) in reference to lymph node metastasis., Results: Platelet counts (P=0.011), fibrinogen levels (P=0.002) and MA values (P=0.006) were statistically significantly higher in patients with T4a stage gastric cancer presenting with lymph node metastasis than in those without lymph node metastasis. Moreover, tumor N stage was statistically significantly and positively correlated with platelet count (P<0.001), fibrinogen level (P=0.003), MA value (P<0.001), and D-dimer level (P=0.010). The MA value was an independent factor for lymph node metastasis (β=0.098, 95% CI: 1.020-1.193, P=0.014) and tumor N stage (β=0.059, 95% CI: 0.015-0.104, P=0.009), and could be used to predict the presence of lymph node metastasis in patients with gastric cancer (sensitivity 0.477, specificity 0.783, P=0.006). The independent influencing factors for MA value mainly included platelet levels, fibrinogen levels, D-dimer and hemoglobin levels; we found no statistically significant correlations with tumor diameter, tumor area, and other evaluated factors., Conclusion: We conclude that MA value is an independent influencing factor for lymph node metastasis and tumor N stage in patients with T4a stage gastric cancer. The MA value has important value in predicting the presence or absence of lymph node metastasis in patients with gastric cancer., Clinical Trial Registration: http://www.chictr.org.cn, identifier ChiCTR2200064936., 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 © 2023 Qiao, Sha, Song, Chen, Lian, Wang, Zhou, Peng, Li, Tian and Jing.)

Background: To develop a CT-based radiomics nomogram for the high-precision preoperative differentiation of gastric hepatoid adenocarcinoma (GHAC) patients from gastric adenocarcinoma (GAC) patients., Research Design and Methods: 108 patients with GHAC from 6 centers and 108 GAC patients matched by age, sex and T stage undergoing pathological examination were retrospectively reviewed. Patients from 5 centers were divided into two cohorts (training and internal validation) at a 7:3 ratio, the remaining patients were external test cohort. Venous-phase CT images were retrieved for tumor segmentation and feature extraction. A radiomics model was developed by the least absolute shrinkage and selection operator method. The nomogram was developed by clinical factors and the radiomics score., Results: 1409 features were extracted and a radiomics model consisting of 19 features was developed, which showed a favorable performance in discriminating GHAC from GAC (AUC training cohort  = 0.998, AUC internal validation set  = 0.942, AUC external test cohort  = 0.731). The radiomics nomogram, including the radiomics score, AFP, and CA72&#95;4, achieved good calibration and discrimination (AUC training cohort  = 0.998, AUC internal validation set  = 0.954, AUC external test cohort  = 0.909)., Conclusions: The noninvasive CT-based nomogram, including radiomics score, AFP, and CA72&#95;4, showed favorable predictive efficacy for differentiating GHAC from GAC and might be useful for clinical decision-making.

Mutations in the GJA1 gene that encodes connexin43 (Cx43) cause several rare genetic disorders, including diseases affecting the epidermis. Here, we examined the in vitro functional consequences of a Cx43 mutation, Cx43-G38E, linked to a novel human phenotype of hypotrichosis, follicular keratosis and hyperostosis. We found that Cx43-G38E was efficiently translated in Xenopus oocytes and localized to gap junction plaques in transfected HeLa cells. Cx43-G38E formed functional gap junction channels with the same efficiency as wild-type Cx43 in Xenopus oocytes, although voltage gating of the gap junction channels was altered. Notably, Cx43-G38E significantly increased membrane current flow through the formation of active hemichannels when compared to wild-type Cx43. These data demonstrate the association of increased hemichannel activity to a connexin mutation linked to a skeletal-cutaneous phenotype, suggesting that augmented hemichannel activity could play a role in skin and skeletal disorders caused by human Cx43 mutations.