Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8+ T cell effector functions.

Concentrations of the secondary bile acid, deoxycholic acid (DCA), are aberrantly elevated in colorectal cancer (CRC) patients, but the consequences remain poorly understood. Here, we screened a library of gut microbiota-derived metabolites and identified DCA as a negative regulator for CD8+ T cell effector function. Mechanistically, DCA suppressed CD8+ T cell responses by targeting plasma membrane Ca2+ ATPase (PMCA) to inhibit Ca2+-nuclear factor of activated T cells (NFAT)2 signaling. In CRC patients, CD8+ T cell effector function negatively correlated with both DCA concentration and expression of a bacterial DCA biosynthetic gene. Bacteria harboring DCA biosynthetic genes suppressed CD8+ T cells effector function and promoted tumor growth in mice. This effect was abolished by disrupting bile acid metabolism via bile acid chelation, genetic ablation of bacterial DCA biosynthetic pathway, or specific bacteriophage. Our study demonstrated causation between microbial DCA metabolism and anti-tumor CD8+ T cell response in CRC, suggesting potential directions for anti-tumor therapy.

Engineering contact curved interface with high-electronic-state active sites for high-performance potassium-ion batteries.

Potassium-ion batteries (PIBs) have attracted ever-increasing interest due to the abundant potassium resources and low cost, which are considered a sustainable energy storage technology. However, the graphite anodes employed in PIBs suffer from low capacity and sluggish reaction kinetics caused by the large radius of potassium ions. Herein, we report nitrogen-doped, defect-rich hollow carbon nanospheres with contact curved interfaces (CCIs) on carbon nanotubes (CNTs), namely CCI-CNS/CNT, to boost both electron transfer and potassium-ion adsorption. Density functional theory calculations validate that engineering CCIs significantly augments the electronic state near the Fermi level, thus promoting electron transfer. In addition, the CCIs exhibit a pronounced affinity for potassium ions, promoting their adsorption and subsequently benefiting potassium storage. As a result, the rationally designed CCI-CNS/CNT anode shows remarkable cyclic stability and rate capability. This work provides a strategy for enhancing the potassium storage performance of carbonaceous materials through CCI engineering, which can be further extended to other battery systems.

The triangular relationship between traditional Chinese medicines, intestinal flora, and colorectal cancer.

Over the past decade, colorectal cancer has reported a higher incidence in younger adults and a lower mortality rate. Recently, the influence of the intestinal flora in the initiation, progression, and treatment of colorectal cancer has been extensively studied, as well as their positive therapeutic impact on inflammation and the cancer microenvironment. Historically, traditional Chinese medicine (TCM) has been widely used in the treatment of colorectal cancer via promoted cancer cell apoptosis, inhibited cancer metastasis, and reduced drug resistance and side effects. The present research is more on the effect of either herbal medicine or intestinal flora on colorectal cancer. The interactions between TCM and intestinal flora are bidirectional and the combined impacts of TCM and gut microbiota in the treatment of colon cancer should not be neglected. Therefore, this review discusses the role of intestinal bacteria in the progression and treatment of colorectal cancer by inhibiting carcinogenesis, participating in therapy, and assisting in healing. Then the complex anticolon cancer effects of different kinds of TCM monomers, TCM drug pairs, and traditional Chinese prescriptions embodied in apoptosis, metastasis, immune suppression, and drug resistance are summarized separately. In addition, the interaction between TCM and intestinal flora and the combined effect on cancer treatment were analyzed. This review provides a mechanistic reference for the application of TCM and intestinal flora in the clinical treatment of colorectal cancer and paves the way for the combined development and application of microbiome and TCM.

Uncovering the cellular and omics characteristics of natural killer cells in the bone marrow microenvironment of patients with acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy and the most frequently acute leukemia of stem cell precursors and the myeloid derivatives in adult. Longitudinal studies have indicated the therapeutic landscape and drug resistance for patients with AML are still intractable, which largely attribute to the deficiency of detailed information upon the pathogenesis. METHODS: In this study, we compared the cellular phenotype of resident NK cells (rAML-NKs, rHD-NKs) and expanded NK cells (eAML-NKs, eHD-NKs) from bone marrow of AML patients (AML) and healthy donors (HD). Then, we took advantage of the co-culture strategy for the evaluation of the in vitro cytotoxicity of NK cells upon diverse tumor cell lines (e.g., K562, Nalm6, U937). With the aid of RNA-sequencing (RNA-SEQ) and bioinformatics analyses (e.g., GOBP analysis, KEGG analysis, GSEA, volcano plot), we verified the similarities and differences of the omics features between eAML-NKs and eHD-NKs. RESULTS: Herein, we verified the sharp decline in the content of total resident NK cells (CD3-CD56+) in rAML-NKs compared to rHD-NKs. Differ from the expanded eHD-NKs, eAML-NKs revealed decline in diverse NK cell subsets (NKG2D+, CD25+, NKp44+, NKp46+) and alterations in cellular vitality but conservations in cytotoxicity. According to transcriptomic analysis, AML-NKs and HD-NKs showed multifaceted distinctions in gene expression profiling and genetic variations. CONCLUSIONS: Collectively, our data revealed the variations in the cytobiological and transcriptomic features between AML-NKs and HD-NKs in bone marrow environment. Our findings would benefit the further development of novel biomarkers for AML diagnosis and NK cell-based cytotherapy in future.

One-day versus three-day low-residue diet bowel preparation regimens before colonoscopy: a meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Although studies have shown that the quality of bowel preparation with low-residue diet (LRD) is as effective as that of clear fluid diet (CLD), there is currently no consensus on how long an LRD should last. The aim of this study was to compare a 1-day versus 3-day LRD on bowel preparation before colonoscopy. METHODS: A systematic review search was conducted in MEDLINE/PubMed, EMBASE, Web of Science, and Cochrane database from inception to April 2023. We identified randomized controlled trials (RCTs) that compared 1-day with 3-day LRD bowel cleansing regiments for patients undergoing colonoscopy. The rate of adequate bowel preparation, polyp detection rate, adenoma detection rate, tolerability, willingness to repeat preparation, and adverse events were estimated using odds ratios (OR) and 95% confidence interval (CI). We also performed meta-analysis to identify risk factors and predictors of inadequate preparation. RESULTS: Four studies published between 2019 and 2023 with 1927 participants were included. The present meta-analysis suggested that 1-day LRD was comparable with 3-day LRD for adequate bowel preparation (OR 0.89; 95% CI, 0.65-1.21; P = 0.45; I2 = 0%; P = 0.52). The polyp detection rate (OR 0.94; 95% CI, 0.77-1.14; P = 0.52; I2 = 23%; P = 0.27) and adenoma detection rate (OR 0.87; 95% CI, 0.71-1.08; P = 0.21; I2 = 0%; P = 0.52) were similar between the groups. There were significantly higher odds of tolerability in patients consuming 1-day LRD compared with 3-day LRD (OR 1.64; 95% CI, 1.13-2.39; P < 0.01; I2 = 47%; P = 0.15). In addition, constipation was identified as the independent predictor of inadequate preparation (OR 1.98; 95% CI, 1.27-3.11; P < 0.01; I2 = 0%; P = 0.46). CONCLUSION: The present study demonstrated that a 1-day LRD was as effective as a 3-day CLD in the quality of bowel preparation before colonoscopy and significantly improved tolerability of patients. In addition, constipation is an independent risk factor of poor bowel preparation, and the duration of LRD in patients with constipation still needs further clinical trials.

The Abca7V1613M variant reduces Aß generation, plaque load, and neuronal damage.

BACKGROUND: Variants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD). METHODS: CRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed. RESULTS: Abca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aß) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aß-associated inflammation, gliosis, and neuronal damage. DISCUSSION: Overall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aß pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology. HIGHLIGHTS: ABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.

BIN1K358R suppresses glial response to plaques in mouse model of Alzheimer's disease.

INTRODUCTION: The BIN1 coding variant rs138047593 (K358R) is linked to Late-Onset Alzheimer's Disease (LOAD) via targeted exome sequencing. METHODS: To elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1K358R knock-in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology. RESULTS: The presence of the BIN1K358R variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild-type and 5xFAD backgrounds homozygous for the BIN1K358R variant. DISCUSSION: The BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities. HIGHLIGHTS: BIN1 rs138047593 (K358R) coding variant is associated with increased risk of LOAD. BIN1 K358R variant increases amyloid plaque load in 12-month-old 5xFAD mice. BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques. BIN1 K358R variant decreases neuronal damage in 5xFAD mice. BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.

Reduced Adenoma Miss Rate With 9-Minute vs 6-Minute Withdrawal Times for Screening Colonoscopy: A Multicenter Randomized Tandem Trial.

INTRODUCTION: Although the 9-minute mean withdrawal time (m-WT) is often reported to be associated with the optimal adenoma detection rate (ADR), no randomized trials of screening colonoscopy have confirmed the impact of a 9-minute m-WT on adenoma miss rate (AMR) and ADR. METHODS: A multicenter tandem trial was conducted in 11 centers. Seven hundred thirty-three asymptomatic participants were randomized to receive segmental tandem screening colonoscopy with a 9-minute withdrawal, followed by a 6-minute withdrawal (9-minute-first group, 9MF, n = 366) or vice versa (6-minute-first group, 6MF, n = 367). The primary outcome was the lesion-level AMR. RESULTS: The intention-to-treat analysis revealed that 9MF significantly reduced the lesion-level (14.5% vs 36.6%, P < 0.001) and participant-level AMR (10.9% vs 25.9%, P < 0.001), advanced adenoma miss rate (AAMR, 5.3% vs 46.9%, P = 0.002), multiple adenomas miss rate (20.7% vs 56.5%, P = 0.01), and high-risk adenomas miss rate (14.6% vs 39.5%, P = 0.01) of 6MF without compromising detection efficiency ( P = 0.79). In addition, a lower false-negative rate for adenomas ( P = 0.002) and high-risk adenomas ( P < 0.05), and a lower rate of shortening surveillance schedule ( P < 0.001) were also found in 9MF, accompanying with an improved ADR in the 9-minute vs 6-minute m-WT (42.3% vs 33.5%, P = 0.02). The independent inverse association between m-WT and AMR remained significant even after adjusting ADR, and meanwhile, 9-minute m-WT was identified as an independent protector for AMR and AAMR. DISCUSSION: In addition to increasing ADR, 9-minute m-WT also significantly reduces the AMR and AAMR of screening colonoscopy without compromising detection efficiency.

The gut-lung axis in critical illness: microbiome composition as a predictor of mortality at day 28 in mechanically ventilated patients.

BACKGROUND: Microbial communities are of critical importance in the human host. The lung and gut microbial communities represent the most essential microbiota within the human body, collectively referred to as the gut-lung axis. However, the differentiation between these communities and their influence on clinical outcomes in critically ill patients remains uncertain. METHODS: An observational cohort study was obtained in the intensive care unit (ICU) of an affiliated university hospital. Sequential samples were procured from two distinct anatomical sites, namely the respiratory and intestinal tracts, at two precisely defined time intervals: within 48 h and on day 7 following intubation. Subsequently, these samples underwent a comprehensive analysis to characterize microbial communities using 16S ribosomal RNA (rRNA) gene sequencing and to quantify concentrations of fecal short-chain fatty acids (SCFAs). The primary predictors in this investigation included lung and gut microbial diversity, along with indicator species. The primary outcome of interest was the survival status at 28 days following mechanical ventilation. RESULTS: Sixty-two mechanically ventilated critically ill patients were included in this study. Compared to the survivors, the diversity of microorganisms was significantly lower in the deceased, with a significant contribution from the gut-originated fraction of lung microorganisms. Lower concentrations of fecal SCFAs were detected in the deceased. Multivariate Cox regression analysis revealed that not only lung microbial diversity but also the abundance of Enterococcaceae from the gut were correlated with day 28 mortality. CONCLUSION: Critically ill patients exhibited lung and gut microbial dysbiosis after mechanical ventilation, as evidenced by a significant decrease in lung microbial diversity and the proliferation of Enterococcaceae in the gut. Levels of fecal SCFAs in the deceased served as a marker of imbalance between commensal and pathogenic flora in the gut. These findings emphasize the clinical significance of microbial profiling in predicting the prognosis of ICU patients.

Emerging advances in engineered macrophages for tumor immunotherapy.

Macrophages are versatile antigen-presenting cells. Recent studies suggest that engineered modifications of macrophages may confer better tumor therapy. Genetic engineering of macrophages with specific chimeric antigen receptors offers new possibilities for treatment of solid tumors and has received significant attention. In vitro gene editing of macrophages and infusion into the body can inhibit the immunosuppressive effect of the tumor microenvironment in solid tumors. This strategy is flexible and can be applied to all stages of cancer treatment. In contrast, nongenetic engineering tools are used to block relevant signaling pathways in immunosuppressive responses. In addition, macrophages can be loaded with drugs and engineered into cellular drug delivery systems. Here, we analyze the effect of the chimeric antigen receptor platform on macrophages and other existing engineering modifications of macrophages, highlighting their status, challenges and future perspectives. Indeed, our analyses show that new approaches in the treatment of solid tumors will likely exploit macrophages, an innate immune cell.

The hsa_circ_0000276-ceRNA regulatory network and immune infiltration in cervical cancer.

BACKGROUND: Our previous studies have confirmed that miR-154-5p can regulate pRb expression, and thus, play a tumor suppressor role in HPV16 E7-induced cervical cancer. However, its upstream molecules have not been elucidated in the progression of cervical cancer. This study aimed to explore the role of the miR-154-5p upstream molecule, hsa_circ_0000276 in cervical cancer development and its possible mechanisms of action. METHODS: We detected differences in whole transcriptome expression profiles of cervical squamous carcinoma and tissues adjacent to cervical cancer tissues from patients using microarray technology to predict circular RNAs (circRNAs) with binding sites to miR-154-5p. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of hsa_circ_0000276 (which had the strongest binding capacity to miR-154 and was selected as the target molecule) in cervical cancer tissues, followed by in vitro functional assays. Downstream microRNAs (miRNAs) and mRNAs of hsa_circ_0000276 were identified using transcriptome microarray data and databases, while the protein-protein interaction networks were obtained using STRING. A competing endogenous RNA (ceRNA) network centered on hsa_circ_0000276 was constructed using Cytoscape and GO and KEGG databases. Abnormal expression and prognosis of critical downstream molecules were analyzed using gene databases and molecular experiments. qRT-PCR and western blot analysis was performed to verify the expression of candidate genes. RESULTS: We identified 4,001 differentially expressed circRNAs between HPV16-positive cervical squamous carcinoma and benign cervical tissues and 760 circRNAs targeting miR-154-5p, including hsa_circ_0000276. hsa_circ_0000276 and miR-154-5p directly bound, and hsa_circ_0000276 was upregulated, in cervical precancerous lesions and cervical cancer tissues and cells. Silencing hsa_circ_0000276 inhibited G1/S transition and cell proliferation and promoted apoptosis in SiHa and CaSki cells. Bioinformatics analysis showed that the hsa_circ_0000276 ceRNA network included 17 miRNAs and seven mRNAs, and downstream molecules of hsa_circ_0000276 were upregulated in cervical cancer tissues. These downstream molecules were associated with a poor prognosis and affected cervical cancer-associated immune infiltration. Of these, expression of CD47, LDHA, PDIA3, and SLC16A1 was downregulated in sh_hsa_circ_0000276 cells. CONCLUSIONS: Our findings show that hsa_circ_0000276 exerts cancer-promoting effects in cervical cancer and is an underlying biomarker for cervical squamous cell carcinoma.

Comparison of the efficacy and safety of an oral sulfate solution and 3-L polyethylene glycol on bowel preparation before colonoscopy: a phase III multicenter randomized controlled trial.

BACKGROUND AND AIMS: Adequate bowel preparation is crucial for clear mucosal visualization during colonoscopy. We aimed to comprehensively compare oral sulfate solution (OSS) and 3-L split-dose polyethylene glycol (PEG) for bowel preparation before colonoscopy. METHODS: This randomized, active-controlled, noninferiority study was performed in 10 medical centers. Eligible subjects were enrolled to receive OSS or 3-L PEG in a split-dose regimen. The quality of bowel preparation, adverse reactions, and acceptability were evaluated. The quality of bowel preparation was evaluated using the Boston Bowel Preparation Scale. Safety was evaluated by adverse reactions. The study population was divided into the full analysis set (FAS), the safety set, the modified FAS (mFAS), and the per-protocol set (PPS). RESULTS: Three hundred forty-eight potentially eligible subjects were enrolled. Three hundred forty-four subjects were included in the FAS and safety set, 340 subjects were included in the mFAS, and 328 subjects were included in the PPS. Adequate bowel preparation of the OSS was not inferior to 3-L PEG in the mFAS (98.22% vs 97.66%) and the PPS (98.17% vs 98.78%). There was no significant difference in acceptability between the 2 groups (94.74% vs 94.80%, P = .9798). Overall adverse reactions were similar (50.88% vs 44.51%, P = .2370) between the 2 groups. CONCLUSIONS: The split-dose OSS regimen was not inferior to the split-dose 3-L PEG regimen for the quality of bowel preparation in a Chinese adult population. The safety and acceptability of the 2 groups were similar. (Clinical trial registration number: NCT05465889.).

A preliminary study on degenerate characteristics of lumbar and abdominal muscles in middle-aged and elderly people with varying bone mass.

BACKGROUND: With the wide application of QCT in the clinical assessment of osteoporosis and sarcopenia, the characteristics of musculoskeletal degeneration in middle-aged and elderly people need to be further revealed. We aimed to investigate the degenerate characteristics of lumbar and abdominal muscles in middle-aged and elderly people with varying bone mass. METHODS: A total of 430 patients aged 40-88 years were divided into normal, osteopenia, and osteoporosis groups according to quantitative computed tomography (QCT) criteria. The skeletal muscular mass indexes (SMIs) of five muscles [abdominal wall muscles (AWM), rectus abdominis (RA), psoas major muscle (PMM), posterior vertebral muscles (PVM), and paravertebral muscles (PM)] included in lumbar and abdominal muscles were measured by QCT. Differences in SMIs among three groups, as well as the correlation between SMIs and volumetric bone mineral density (vBMD) were analyzed. The areas under the curves (AUCs) for SMIs for prediction of low bone mass and osteoporosis were calculated. RESULTS: In male group, SMIs of RA and PM in osteopenia group were significantly lower than those in the normal group (P = 0.001 and 0.023, respectively). In female group, only SMI of RA in osteopenia group was significantly lower than that in the normal group (P = 0.007). SMI of RA was positively correlated with vBMD with the highest coefficients in male and female groups (r = 0.309 and 0.444, respectively). SMIs of AWM and RA had higher AUCs varying from 0.613 to 0.737 for prediction of low bone mass and osteoporosis in both genders. CONCLUSIONS: The changes of SMIs of the lumbar and abdominal muscles in patients with varying bone mass are asynchronous. SMI of RA is expected to be a promising imaging marker for predicting abnormal bone mass. TRIAL REGISTRATION: ChiCTR1900024511 (Registered 13-07-2019).

The Reliability and Quality of Short Videos as a Source of Dietary Guidance for Inflammatory Bowel Disease: Cross-sectional Study.

BACKGROUND: Dietary management is considered a potential adjunctive treatment for inflammatory bowel disease (IBD). Short-video sharing platforms have enabled patients to obtain dietary advice more conveniently. However, accessing useful resources while avoiding misinformation is not an easy task for most patients. OBJECTIVE: This study aimed to evaluate the quality of the information in IBD diet-related videos on Chinese short-video sharing platforms. METHODS: We collected and extracted information from a total of 125 video samples related to the IBD diet on the 3 Chinese short-video sharing platforms with the most users: TikTok, Bilibili, and Kwai. Two independent physicians evaluated each video in terms of content comprehensiveness, quality (rated by Global Quality Score), and reliability (rated by a modified DISCERN tool). Finally, comparative analyses of the videos from different sources were conducted. RESULTS: The videos were classified into 6 groups based on the identity of the uploaders, which included 3 kinds of medical professionals (ie, gastroenterologists, nongastroenterologists, and clinical nutritionists) and 3 types of non-medical professionals (ie, nonprofit organizations, individual science communicators, and IBD patients). The overall quality of the videos was poor. Further group comparisons demonstrated that videos from medical professionals were more instructive in terms of content comprehensiveness, quality, and reliability than those from non-medical professionals. Moreover, IBD diet-related recommendations from clinical nutritionists and gastroenterologists were of better quality than those from nongastroenterologists, while recommendations from nonprofit organizations did not seem to be superior to other groups of uploaders. CONCLUSIONS: The overall quality of the information in IBD diet-related videos is unsatisfactory and varies significantly depending on the source. Videos from medical professionals, especially clinical nutritionists and gastroenterologists, may provide dietary guidance with higher quality for IBD patients.

Prokinetic effects of Citrus reticulata and Citrus aurantium extract with/without Bupleurum chinense using multistress-induced delayed gastric emptying models.

CONTEXT: Citrus aurantium L (Rutaceae) (Au) and Citrus reticulata Blanco (Rutaceae) (Ci) are commonly used as couplet prokinetics and Bupleurum chinense DC. (Umbelliferae) (Bup) is an herbal antidepressant in traditional Chinese medicine. OBJECTIVE: This study evaluates the synergistic prokinetic effects of Bup with Au and Ci in mice suffering from multistress-induced delayed gastric emptying (DGE). MATERIALS AND METHODS: Kunming mice were divided into four groups: control, DGE, AuCi and AuCiBup. Mice were gavaged with AuCi (14.25 g/kg) or AuCiBup (22.13 g/kg) extract for 12 days. Gastric reminder rate, intestinal driving ratio, sucrose preference and open field test were examined, and serotonin (5-HT), motilin (MTL), substance P (SP), 5-HT4R and c-kit were assayed. Intracellular Ca2+ levels in primary cultured gastric smooth muscle cells (GSMCs) were determined. RESULTS: Both AuCi and AuCiBup treatment significantly reduced gastric residual rate (39.5% and 67.7%, p < 0.01). Higher serum levels of 5-HT, MTL and SP were observed in treatment groups (AuCi: 0.060 mg/L, AuCiBup: 0.089 mg/L, DGE: 0.025 mg/L, p < 0.01). The expression of 5-HT4R and c-kit in the antrum and duodenum was upregulated after treatment (AuCi and AuCiBup, 4.3-times, 2.8-times to DGE, p < 0.01). Medicated serums of AuCi and AuCiBup effectively increased the influx of Ca2+ into GSMCs in vitro (1.8-times, p < 0.01). In terms of 5-HT4R expression, circulatory contents of 5-HT and SP and Ca2+ influx, AuCiBup demonstrated better prokinetic effects than AuCi. CONCLUSIONS: These findings indicate the potential for developing combination therapy with antidepressants and prokinetics in gastrointestinal dysmotility management.

Impact of 9-Minute Withdrawal Time on the Adenoma Detection Rate: A Multicenter Randomized Controlled Trial.

BACKGROUND & AIMS: Although current quality indicators of colonoscopy recommend 6 minutes as the minimum standard for withdrawal time (WT), the impact of a WT longer than 6 minutes on neoplasia detection is unclear. METHODS: A multicenter randomized controlled trial involving 1027 patients was conducted from January 2018 to July 2019. Participants were randomly divided into a 9-minute (n = 514) and 6-minute (n = 513) WT group, and a timer was used to adjust the withdrawal speed. The primary outcome was the adenoma detection rate (ADR). RESULTS: Intention-to-treat analysis showed a significantly higher ADR in the 9-minute versus 6-minute WT group (36.6% vs. 27.1%, P = .001). Prolonging WT from 6 to 9 minutes significantly increased ADR of the proximal colon (21.4% vs. 11.9%, P < .001) as well as of the less experienced colonoscopists (36.8% vs. 23.5%, P = .001). Improvements were also observed in the polyp detection rate (58.0% vs. 47.8%, P < .001), and mean number of polyps and adenomas detected per colonoscopy (1.1 vs. 0.9, P = .002; 0.5 vs. 0.4, P = .008, respectively). The higher ADRs in 9-minute WT were also confirmed by the per-protocol (PP) analysis and subgroup analyses, with an increased rate of sessile serrated lesion detection in the 9-minute WT by PP analysis (4.0% vs. 1.3%, P = .04). Multivariate logistic regression demonstrated that the 9-minute WT was independently associated with increased ADR (P = .005). CONCLUSIONS: Prolonging WT from 6 to 9 minutes significantly improved ADR, especially in the proximal colon and for less experienced colonoscopists. A 9-minute WT benchmark should be considered as one of the quality indicators of colonoscopy. ClinicalTrials.gov (identifier, NCT03399045).

Alleviative effects of foraging exercise on depressive-like behaviors in chronic mild stress-induced ischemic rat model.

BACKGROUND: Poststroke depression (PSD) is a common complication that seriously affects the functional recovery and prognosis of an individual. As some patients with PSD fail to respond to drug therapy, it is urgent to find a viable alternative treatment. METHODS: An active exercise program known as foraging exercise (FE), using food as bait, was designed. First, focal ischemia and chronic unpredictable mild stress (CUMS) were used to establish a PSD model in rats. FE was then performed for 4 weeks. Body weight and behavioral assessments were conducted at the end of the 4th and 8th weeks. RESULTS: After 8 weeks, the results revealed that, compared with the PSD group, the behavioral scores of the rats in the PSD/FE group were significantly improved, the expression of Iba-1 in the affected frontal lobe and striatum was decreased, and serum levels of IL-6 and the IL-6/IL-10 ratio were downregulated. However, the ratio of residual brain volume in rats that had experienced CUMS was significantly less than that in the stroke group. CONCLUSION: FE can alleviate the behavioral scores of PSD rats, and its mechanism may be related to a modulation of the immune-inflammation response of microglia. Furthermore, chronic, persistent stress may increase the volume of cerebral infarction after stroke.

The presence of retraction clefts correlates with lymphovascular invasion and lymph node metastasis and predicts poor outcome: Analysis of 2497 breast cancer patients.

Some invasive breast carcinomas are surrounded by a clear space that separate the tumor cells from the adjacent stroma, similar to invasive micropapillary carcinoma (IMPC), but lack the thin strands of connective tissue that separate the cells and characteristic "inside-out" growth pattern of IMPC on immunohistochemical stain for EMA. We consider the presence of the retraction clefts a common phenomenon that may present as a precursor stage of IMPC (PSIMPC). In this study, a total of 2497 cases of invasive breast carcinomas were prospectively collected. Among 2497 cases of breast cancer, 949 (38.0 %) cases were PSIMPC, 200 (8.0 %) cases were IMPC and 1348 (54.0 %) cases were IBC-NST. LVI was seen in128 of 200 (64 %) IMPC and 364 of 948 (38.0 %) PSIMPC, in contrast to 246 of 1341 (18 %) IBC-NST (P < 0.001). Lymph node metastasis was seen in 147 of 200 (73.4 %) IMPC and 551 of 949 (58 %) PSIMPC, in contrast to 563 of 1345 (42 %) IBC-NST (P < 0.001). The 5-year disease-free survival (DFS) and overall survival (OS) of PSIMPC were 76.8 % and 87.6 %, compared to 63.2 % and 85.9 % in IMPC, 86.2 % and 93.7 % in IBC-NST. PSIMPC demonstrated a more favorable DFS and OS compared to IMPC, but worse DFS and OS compared to IBC-NST. Cox and logistic regression analysis showed that PSIMPC was an independent predictor of DFS and OS. Our findings suggest that the presence of retraction clefts is a precursor state of IMPC, exhibiting IMPC-like features, such as higher incidence of lymphovascular invasion, lymph node metastasis and more aggressive clinical behavior.

Oral presentation assessment and image reading behaviour on brain computed tomography reading in novice clinical learners: an eye-tracking study.

BACKGROUND: To study whether oral presentation (OP) assessment could reflect the novice learners' interpretation skills and reading behaviour on brain computed tomography (CT) reading. METHODS: Eighty fifth-year medical students were recruited, received a 2-hour interactive workshop on how to read brain CT, and were assigned to read two brain CT images before and after instruction. We evaluated their image reading behaviour in terms of overall OP post-test rating, the lesion identification, and competency in systematic image reading after instruction. Students' reading behaviour in searching for the target lesions were recorded by the eye-tracking technique and were used to validate the accuracy of lesion reports. Statistical analyses, including lag sequential analysis (LSA), linear mixed models, and transition entropy (TE) were conducted to reveal temporal relations and spatial complexity of systematic image reading from the eye movement perspective. RESULTS: The overall OP ratings [pre-test vs. post-test: 0 vs. 1 in case 1, 0 vs. 1 in case 2, p < 0.001] improved after instruction. Both the scores of systematic OP ratings [0 vs.1 in both cases, p < 0.001] and eye-tracking studies (Case 1: 3.42 ± 0.62 and 3.67 ± 0.37 in TE, p = 0.001; Case 2: 3.42 ± 0.76 and 3.75 ± 0.37 in TE, p = 0.002) showed that the image reading behaviour changed before and after instruction. The results of linear mixed models suggested a significant interaction between instruction and area of interests for case 1 (p < 0.001) and case 2 (p = 0.004). Visual attention to the target lesions in the case 1 assessed by dwell time were 506.50 ± 509.06 and 374.38 ± 464.68 milliseconds before and after instruction (p = 0.02). However, the dwell times in the case 2, the fixation counts and the frequencies of accurate lesion diagnoses in both cases did not change after instruction. CONCLUSION: Our results showed OP performance may change concurrently with the medical students' reading behaviour on brain CT after a structured instruction.

Emerging Advances of Detection Strategies for Tumor-Derived Exosomes.

Exosomes derived from tumor cells contain various molecular components, such as proteins, RNA, DNA, lipids, and carbohydrates. These components play a crucial role in all stages of tumorigenesis and development. Moreover, they reflect the physiological and pathological status of parental tumor cells. Recently, tumor-derived exosomes have become popular biomarkers for non-invasive liquid biopsy and the diagnosis of numerous cancers. The interdisciplinary significance of exosomes research has also attracted growing enthusiasm. However, the intrinsic nature of tumor-derived exosomes requires advanced methods to detect and evaluate the complex biofluid. This review analyzes the relationship between exosomes and tumors. It also summarizes the exosomal biological origin, composition, and application of molecular markers in clinical cancer diagnosis. Remarkably, this paper constitutes a comprehensive summary of the innovative research on numerous detection strategies for tumor-derived exosomes with the intent of providing a theoretical basis and reference for early diagnosis and clinical treatment of cancer.