7-Dehydrocholesterol dictates ferroptosis sensitivity.

Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, degenerative disorders4 and organ ischaemia-reperfusion injury (IRI)5,6. Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.

The person-to-person transmission landscape of the gut and oral microbiomes.

The human microbiome is an integral component of the human body and a co-determinant of several health conditions1,2. However, the extent to which interpersonal relations shape the individual genetic makeup of the microbiome and its transmission within and across populations remains largely unknown3,4. Here, capitalizing on more than 9,700 human metagenomes and computational strain-level profiling, we detected extensive bacterial strain sharing across individuals (more than 10 million instances) with distinct mother-to-infant, intra-household and intra-population transmission patterns. Mother-to-infant gut microbiome transmission was considerable and stable during infancy (around 50% of the same strains among shared species (strain-sharing rate)) and remained detectable at older ages. By contrast, the transmission of the oral microbiome occurred largely horizontally and was enhanced by the duration of cohabitation. There was substantial strain sharing among cohabiting individuals, with 12% and 32% median strain-sharing rates for the gut and oral microbiomes, and time since cohabitation affected strain sharing more than age or genetics did. Bacterial strain sharing additionally recapitulated host population structures better than species-level profiles did. Finally, distinct taxa appeared as efficient spreaders across transmission modes and were associated with different predicted bacterial phenotypes linked with out-of-host survival capabilities. The extent of microorganism transmission that we describe underscores its relevance in human microbiome studies5, especially those on non-infectious, microbiome-associated diseases.

Immune surveillance of brain metastatic cancer cells is mediated by IFITM1.

Brain metastasis, most commonly originating from lung cancer, increases cancer morbidity and mortality. Although metastatic colonization is the rate-limiting and most complex step of the metastatic cascade, the underlying mechanisms are poorly understood. Here, in vivo genome-wide CRISPR-Cas9 screening revealed that loss of interferon-induced transmembrane protein 1 (IFITM1) promotes brain colonization of human lung cancer cells. Incipient brain metastatic cancer cells with high expression of IFITM1 secrete microglia-activating complement component 3 and enhance the cytolytic activity of CD8+ T cells by increasing the expression and membrane localization of major histocompatibility complex class I. After activation, microglia (of the innate immune system) and cytotoxic CD8+ T lymphocytes (of the adaptive immune system) were found to jointly eliminate cancer cells by releasing interferon-gamma and inducing phagocytosis and T-cell-mediated killing. In human cancer clinical trials, immune checkpoint blockade therapy response was significantly correlated with IFITM1 expression, and IFITM1 enhanced the brain metastasis suppression efficacy of PD-1 blockade in mice. Our results exemplify a novel mechanism through which metastatic cancer cells overcome the innate and adaptive immune responses to colonize the brain, and suggest that a combination therapy increasing IFITM1 expression in metastatic cells with PD-1 blockade may be a promising strategy to reduce metastasis.

Salmonella Biomimetic Nanoparticles for Photothermal-Chemotherapy of Colorectal Cancer.

Nanomedicines have been widely used in colorectal cancer treatment, but their suboptimal targeting and deficient penetration capabilities remain obstacles in the delivery of therapeutics. In this study, inspired by the natural tumor tropism and intestinal invasion of Salmonella, we engineered highly biomimetic nanoparticles (SM-AuNRs) utilizing a Salmonella membrane to coat bacilliform Au nanorods. The engineered SM-AuNRs were able to mimic the germ's morphology and biological surface. SM-AuNRs containing the specific proteins inherited from the Salmonella membrane facilitated specific targeting and internalization into tumor cells. Meanwhile, SM-AuNRs with the rod-shaped morphology effectively traversed mucus barriers and tumor stroma. Due to the superior biological barrier penetrating and tumor targeting capabilities, doxorubicin-loaded SM-AuNRs with near-infrared laser irradiation displayed remarkable photothermal-chemotherapeutic antitumor effects in mouse orthotopic colorectal cancer models. Our findings pave the way for the design of bacteria-mimicking nanoparticles, presenting a promising avenue for the targeting and efficient treatment of colorectal cancer.

MnOOH-Catalyzed Autoxidation of Glutathione for Reactive Oxygen Species Production and Nanocatalytic Tumor Innate Immunotherapy.

The antioxidant system, signed with reduced glutathione (GSH) overexpression, is the key weapon for tumor to resist the attack by reactive oxygen species (ROS). Counteracting the ROS depletion by GSH is an effective strategy to guarantee the antitumor efficacy of nanocatalytic therapy. However, simply reducing the concentration of GSH does not sufficiently improve tumor response to nanocatalytic therapy intervention. Herein, a well-dispersed MnOOH nanocatalyst is developed to catalyze GSH autoxidation and peroxidase-like reaction concurrently and respectively to promote GSH depletion and H2O2 decomposition to produce abundant ROS such as hydroxyl radical (·OH), thereby generating a highly effective superadditive catalytic therapeutic efficacy. Such a therapeutic strategy that transforms endogenous "antioxidant" into "oxidant" may open a new avenue for the development of antitumor nanocatalytic medicine. Moreover, the released Mn2+ can activate and sensitize the cGAS-STING pathway to the damaged intratumoral DNA double-strands induced by the produced ROS to further promote macrophage maturation and M1-polarization, which will boost the innate immunotherapeutic efficacy. Resultantly, the developed simple MnOOH nanocatalytic medicine capable of simultaneously catalyzing GSH depletion and ROS generation, and mediating innate immune activation, holds great potential in the treatment of malignant tumors.

Integrated Analysis of Colorectal Cancer Reveals Cross-Cohort Gut Microbial Signatures and Associated Serum Metabolites.

BACKGROUND & AIMS: Studies have reported abnormal gut microbiota or circulating metabolome associated with colorectal cancer (CRC), but it remains a challenge to capture the CRC-relevant features consistent across geographic regions. This is particularly the problem for metabolic traits of CRC because the analyses generally use different platforms and laboratory methods, which poses a barrier to cross-dataset examination. In light of this, we sought to elucidate the microbial and metabolic signatures of CRC with broad population relevance. METHODS: In this integrated metagenomic (healthy controls [HC], n = 91; colorectal adenoma [CRA], n = 63; CRC, n = 71) and metabolomic (HC, n = 34; CRA, n = 31; CRC, n = 35) analysis, CRC-associated features and microbe-metabolite correlations were first identified from a Shanghai cohort. A gut microbial panel was trained in the in-house cohort and cross-validated in 7 published metagenomic datasets of CRC. The in-house metabolic connections to the cross-cohort microbial signatures were used as evidence to infer serum metabolites with potentially external relevance. In addition, a combined microbe-metabolite panel was produced for diagnosing CRC or adenoma. RESULTS: CRC-associated alterations were identified in the gut microbiome and serum metabolome. A composite microbe-metabolite diagnostic panel was developed and yielded an area under the curve of 0.912 for adenoma and 0.994 for CRC. We showed that many CRC-associated metabolites were linked to cross-cohort gut microbiome signatures of the disease, including CRC-enriched leucylalanine, serotonin, and imidazole propionate; and CRC-depleted perfluorooctane sulfonate, 2-linoleoylglycerol (18:2), and sphingadienine. CONCLUSIONS: We generated cross-cohort metagenomic signatures of CRC, some of which linked to in-house CRC-associated serum metabolites. The microbial and metabolic shifts may have wide population relevance.

Enzyme-catalyzed synthesis of selenium-doped manganese phosphate for synergistic therapy of drug-resistant colorectal cancer.

BACKGROUND: The development of multidrug resistance (MDR) during postoperative chemotherapy for colorectal cancer substantially reduces therapeutic efficacy. Nanostructured drug delivery systems (NDDSs) with modifiable chemical properties are considered promising candidates as therapies for reversing MDR in colorectal cancer cells. Selenium-doped manganese phosphate (Se-MnP) nanoparticles (NPs) that can reverse drug resistance through sustained release of selenium have the potential to improve the chemotherapy effect of colorectal cancer. RESULTS: Se-MnP NPs had an organic-inorganic hybrid composition and were assembled from smaller-scale nanoclusters. Se-MnP NPs induced excessive ROS production via Se-mediated activation of the STAT3/JNK pathway and a Fenton-like reaction due to the presence of manganese ions (Mn2+). Moreover, in vitro and in vivo studies demonstrated Se-MnP NPs were effective drug carriers of oxaliplatin (OX) and reversed multidrug resistance and induced caspase-mediated apoptosis in colorectal cancer cells. OX@Se-MnP NPs reversed MDR in colorectal cancer by down-regulating the expression of MDR-related ABC (ATP binding cassette) transporters proteins (e.g., ABCB1, ABCC1 and ABCG2). Finally, in vivo studies demonstrated that OX-loaded Se-MnP NPs significantly inhibited proliferation of OX-resistant HCT116 (HCT116/DR) tumor cells in nude mice. CONCLUSIONS: OX@Se-MnP NPs with simple preparation and biomimetic chemical properties represent promising candidates for the treatment of colorectal cancer with MDR.

Effect of Probiotic Supplementation on the Gut Microbiota Composition of Infants Delivered by Cesarean Section: An Exploratory, Randomized, Open-label, Parallel-controlled Trial.

BACKGROUND: Infants born via cesarean section (CS) are at an increased risk of immune-related diseases later in life, potentially due to altered gut microbiota. Recent research has focused on the administration of probiotics in the prevention of gut microbiota dysbiosis in neonates delivered by CS. This study was performed to investigate the effects of probiotic supplementation on the gut microbiota of CS-delivered infants. METHODS: Thirty full-term neonates delivered by CS were randomized into the intervention (supplemented orally with a probiotic containing Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis for 2 weeks) and control groups. Stool samples were collected at birth and 2 weeks and 42 days after birth. The composition of the gut microbiota was analyzed using 16S rRNA sequencing technology. RESULTS: The applied bacterial strains were abundant in the CS-delivered infants supplemented with probiotics. Probiotics increased the abundance of some beneficial bacteria, such as Bacteroides, Acinetobacter, Veillonella, and Faecalibacterium. Low colonization of Klebsiella, a potentially pathogenic bacterium, was observed in the intervention group. CONCLUSIONS: Our results showed that probiotics supplemented immediately after CS enriched the gut microbiota composition and altered the pattern of early gut colonization. TRIAL REGISTRATION: registration number NCT05086458.

Low Colorectal Tumor Removal by E-Cadherin Destruction-Enabled Tumor Cell Dissociation.

Treatments for low colorectal cancer (CRC) remain a great challenge due to the heavy physical and psychological burdens of colostomy, strong drug toxicity in chemotherapy, and myelosuppression-/chemoradiation-related gastrointestinal symptoms. In this study, a highly biosafe and effective tumor cell dissociation-based low CRC treatment modality has been verified on both PDOs in vitro and colorectal tumor models in vivo. Notably, controllable EDTA release at the tumor sites was achieved by the LDH degradation in response to a slightly acidic microenvironment of low CRC tumors. Resultantly, the intratumoral E-cadherin for intercellular junctions of low CRC tumors was effectively destroyed via Ca2+ depletion by released EDTA from the interlayers, initiating remarkable tumor cell dissociation and resultant tumor disaggregation/removal via defecation. Dissociated tumor cells were prevailingly enveloped by LDH/EDTA, which prevented them from readhering to adjacent tissues, providing an unprecedented, efficient and safe therapeutic modality for low CRC, which will benefit patients suffering low CRC.

Efficacy of the Oral Administration of Maltodextrin Fructose Before Major Abdominal Surgery: A Prospective, Multicenter Clinical Study.

BACKGROUND: To study the efficacy of the oral administration of maltodextrin and fructose before major abdominal surgery (MAS). METHODS: This prospective, multicenter, parallel-controlled, double-blind study included patients aged 45-70 years who underwent elective gastrectomy, colorectal resection, or duodenopancreatectomy. The intervention group (IG) was given 800 mL and 400 mL of a maltodextrin and fructose beverage at 10 h and 2 h before MAS, respectively, and the control group (CG) received water under the same experimental conditions. The primary endpoint was insulin resistance index (IRI), and the secondary endpoints were fasting blood glucose, fasting insulin, insulin secretion index, insulin sensitivity index, intraoperative blood glucose, subjective comfort score, and clinical outcome indicators. RESULTS: A total of 240 cases were screened, of which 231 cases were randomly divided into two groups: 114 in the IG and 117 in the CG. No time-treatment effect was detected for any endpoint. The IRI and fasting insulin were significantly lower in the IG than CG after MAS (p = 0.02 & P = 0.03). The scores for anxiety, appetite, and nausea were significantly lower in the IG than CG at 1 h before MAS. Compared with baseline, the scores for appetite and nausea decreased in the IG but increased in the CG. CONCLUSION: The oral administration of maltodextrin and fructose before MAS can improve preoperative subjective well-being and reduce postoperative insulin resistance without increasing the risk of gastrointestinal discomfort.

The Obesity Paradox in Elderly Patients Undergoing Emergency Surgery: A Nationwide Analysis.

BACKGROUND: Obesity has long been considered a risk factor for postoperative adverse events in surgery. We sought to study the impact of body mass index (BMI) on the clinical outcomes of the high-risk emergency general surgery (EGS) elderly patients. METHODS: All EGS ≥65 years old patients in the 2007-2016 ACS-NSQIP database, identified using the variables 'emergency' and 'surgspec,' were included. Patients were classified into five groups: normal weight: BMI <25 kg/m2, overweight: BMI ≥25 kg/m2 and <30 kg/m2, Class I: BMI ≥30 kg/m2 and <35 kg/m2, Class II: BMI ≥35 kg/m2 and <40 kg/m2, and Class III: BMI ≥40 kg/m2. Patients with BMI<18.5 kg/m2 were excluded. Multivariable logistic regression models were built to assess the relationship between obesity and 30-day postoperative mortality, overall morbidity, and individual postoperative complications after adjusting for demographics (e.g., age, gender), comorbidities (e.g., diabetes mellitus, heart failure), laboratory tests (e.g., white blood cell count, albumin), and operative complexity (e.g., ASA classification). RESULTS: A total of 78,704 patients were included, of which 26,011 were overweight (33.1%), 13,897 (17.6%) had Class I obesity, 5904 (7.5%) had Class II obesity, and 4490 (5.7%) had Class III obesity. On multivariable analyses, compared to the nonobese, patients who are overweight or with Class I-III obesity paradoxically had a lower risk of mortality, bleeding requiring transfusion, pneumonia, stroke and myocardial infarction (MI). Additionally, the incidence of MI and stroke decreased in a stepwise fashion as BMI progressed from overweight to severely obese (MI: OR: 0.84 [0.73-0.95], OR: 0.73 [0.62-0.86], OR: 0.66 [0.52-0.83], OR: 0.51 [0.38-0.68]; stroke: OR: 0.80 [0.65-0.99], OR: 0.79 [0.62-1.02], OR: 0.71 [0.50-1.00], OR: 0.43 [0.28-0.68]). CONCLUSION: In our study of elderly EGS patients, overweight and obese patients had a lower risk of mortality, bleeding requiring transfusion, pneumonia, reintubation, stroke, and MI. Further studies are needed to confirm and investigate the obesity paradox in this patient population.

Analysis of Gut Microbiome and Metabolite Characteristics in Patients with Slow Transit Constipation.

BACKGROUND: Slow transit constipation (STC) is a type of functional constipation in which colon transit time is extended as a result of a reduction in the high amplitude of colon contraction activity. The utility of gut microbiome and metabolite characteristics in patients with STC is rarely studied. Short-chain fatty acids (SCFAs) enhance colonic fluid and sodium absorption and thus may aggravate the symptoms of STC. However, the content and role of SCFAs in constipation patients are not clear. We speculate that gut microbiome and SCFAs in the colon of STC patients may be abnormal and linked to the underlying mechanism of STC. METHODS: This observational study is registered at ClinicalTrials.gov (NCT02984969). The high-throughput sequencing was used to analyze the diversity and composition of fecal microbial communities. Gas chromatography-mass spectrometry (GC-MS) was used to determine the properties and concentrations of the SCFAs in the two groups. RESULTS: The Shannon diversity and Simpson diversity of the gut microbiome were significantly greater in the STC group than the control group. The two groups also showed significant differences in the species composition of the gut microbiome at different classification levels. The results of GC-MS showed that the acetate concentrations in the STC group were significantly reduced compared with the control group, but the other five types of SCFAs and total SCFAs showed no significant difference between groups. ROC curve analyses revealed that the AUC of Acetate (AUC = 0.758) was higher than Propionate (AUC = 0.660). The largest AUC of gut microbiome for predicting STC was Prevotella (AUC = 0.807). Correlation analysis showed a positive correlation between the concentration of Ruminococcus and Disease history (rs = 0.519). Meanwhile, a positive correlation between the concentration of Roseburia and Acetate (rs = 0.606) or Butyrate (rs = 0.543) was found. CONCLUSION: We found significant differences between the STC and control groups in the main components of the gut microbiome, with greater diversity in the STC group and differences between the groups in species composition at different classification levels. These different microbiome and metabolite may be valuable biomarkers for STC.

General Versus Neuraxial Anesthesia for Appendectomy: A Multicenter International Study.

BACKGROUND: In resource-limited countries, open appendectomy is still performed under general anesthesia (GA) or neuraxial anesthesia (NA). We sought to compare the postoperative outcomes of appendectomy under NA versus GA. METHODS: We conducted a post hoc analysis of the International Patterns of Opioid Prescribing (iPOP) multicenter study. All patients ≥ 16 years-old who underwent an open appendectomy between October 2016 and March 2017 in one of the 14 participating hospitals were included. Patients were stratified into two groups: NA-defined as spinal or epidural-and GA. All-cause morbidity, hospital length of stay (LOS), and pain severity were assessed using univariate analysis followed by multivariable logistic regression adjusting for the following preoperative characteristics: age, gender, body mass index (BMI), smoking, history of opioid use, emergency status, and country. RESULTS: A total of 655 patients were included, 353 of which were in the NA group and 302 in the GA group. The countries operating under NA were Colombia (39%), Thailand (31%), China (23%), and Brazil (7%). Overall, NA patients were younger (mean age (SD): 34.5 (14.4) vs. 40.7 (17.9), p-value < 0.001) and had a lower BMI (mean (SD): 23.5 (3.8) vs. 24.3 (5.2), p-value = 0.040) than GA patients. On multivariable analysis, NA was independently associated with less postoperative complications (OR, 95% CI: 0.30 [0.10-0.94]) and shorter hospital LOS (LOS > 3 days, OR, 95% CI: 0.47 [0.32-0.68]) compared to GA. There was no difference in postoperative pain severity between the two techniques. CONCLUSIONS: Open appendectomy performed under NA is associated with improved outcomes compared to that performed under GA. Further randomized controlled studies should examine the safety and value of NA in lower abdominal surgery.

Opioids After Surgery in the United States Versus the Rest of the World: The International Patterns of Opioid Prescribing (iPOP) Multicenter Study.

OBJECTIVE: The International Patterns of Opioid Prescribing study compares postoperative opioid prescribing patterns in the United States (US) versus the rest of the world. SUMMARY OF BACKGROUND DATA: The US is in the middle of an unprecedented opioid epidemic. Diversion of unused opioids contributes to the opioid epidemic. METHODS: Patients ≥16 years old undergoing appendectomy, cholecystectomy, or inguinal hernia repair in 14 hospitals from 8 countries during a 6-month period were included. Medical records were systematically reviewed to identify: (1) preoperative, intraoperative, and postoperative characteristics, (2) opioid intake within 3 months preoperatively, (3) opioid prescription upon discharge, and (4) opioid refills within 3 months postoperatively. The median/range and mean/standard deviation of number of pills and OME were compared between the US and non-US patients. RESULTS: A total of 4690 patients were included. The mean age was 49 years, 47% were female, and 4% had opioid use history. Ninety-one percent of US patients were prescribed opioids, compared to 5% of non-US patients (P < 0.001). The median number of opioid pills and OME prescribed were 20 (0-135) and 150 (0-1680) mg for US versus 0 (0-50) and 0 (0-600) mg for non-US patients, respectively (both P < 0.001). The mean number of opioid pills and OME prescribed were 23.1 ±â€Š13.9 in US and 183.5 ±â€Š133.7 mg versus 0.8 ±â€Š3.9 and 4.6 ±â€Š27.7 mg in non-US patients, respectively (both P < 0.001). Opioid refill rates were 4.7% for US and 1.0% non-US patients (P < 0.001). CONCLUSIONS: US physicians prescribe alarmingly high amounts of opioid medications postoperatively. Further efforts should focus on limiting opioid prescribing and emphasize non-opioid alternatives in the US.

Gut microbiota dysbiosis signature is associated with the colorectal carcinogenesis sequence and improves the diagnosis of colorectal lesions.

BACKGROUND AND AIM: The gut microbiota is associated with colorectal lesions in cases of precancer and colorectal cancer (CRC). However, there are apparent differences in studies on the gut microbiota in the pathogenic sequence from precancer to cancer. Here, we characterize the gut microbiota signatures of colorectal precancer and cancer and test their utility in detecting colorectal lesions in two independent Chinese cohorts. METHODS: Stool samples collected from patients with precancer and CRC were subjected to 16S ribosomal RNA gene sequencing and metagenomic shotgun sequencing analyses, which revealed the microbial signatures of the two disease stages. RESULTS: In comparison with healthy controls, lower microbial richness and diversity were observed in precancer and intensive interbacterial associations were found in CRC. We identified 41 bacteria that showed gradual increases while 12 bacteria showed gradual decreases at the genus level gradually during the development of CRC. Novel CRC-associated pathogenetic species were identified. Species units that contributed to altered microbial functions were identified in CRC patients and healthy controls. The microbial panel showed a comparable ability to fecal immunochemical test (FIT) in detecting CRC. However, the combination of microbes and FIT significantly improved the detection ability and sensitivity of colon lesions based on 18 genera. Microbial network analysis revealed a significant positive correlation among beneficial microbes and a negative correlation in detrimental phenotypes. CONCLUSIONS: Microbial dysbiosis was revealed in colorectal lesions. The combination of microbial markers and FIT improved the CRC detection ability, which might assist in the early diagnosis of CRC.

Dynamic signatures of gut microbiota and influences of delivery and feeding modes during the first 6 months of life.

The gut microbiota of infants changes over time and is affected by various factors during early life. However, rarely have studies explored the gut microbiota development and affecting factors in the Chinese infant population. We enrolled 102 infants and collected stool samples from them at birth, 42 days, 3 mo, and 6 mo after delivery to characterize the microbiota signatures and the effects of different factors that modulate the gut microbiota diversity, composition, and function over time. DNA extracted from the bacteria in the stool samples was subjected to high-throughput sequencing and bioinformatics analysis. Microbial richness and diversity increased significantly during the first 6 mo of life. Beneficial microbes such as Bifidobacterium, Lactobacillus, and Blautia were found to be increased in the infant's gut at 6 mo, while pathological bacteria such as Escherichia-Shigella, Enterobacter, Staphylococcus, and Klebsiella decreased over time. The changes in the infant delivery mode and infant-feeding mode only produced changes in the microbial composition, whereas changes in bacterial richness, diversity and effects sizes on the microbial architecture were all time dependent. A comparison of infant delivery modes conveyed a decrease in abundance of Bacteroidetes over time in the gut of infants born via C-section, while the Bifidobacterium was the most dominant genus in the vaginal delivery group. The gut microbiota of infants changed extensively during the first 6 mo of life. Delivery and feeding modes were strong factors that significantly affected microbial architecture and functions.

c-Myb promotes growth and metastasis of colorectal cancer through c-fos-induced epithelial-mesenchymal transition.

c-Myb is a crucial transcription factor that participates in various biological functions; however, its role in colorectal cancer (CRC) remains poorly investigated. We first analyzed the expression and clinical significance of c-Myb in a retrospective cohort enrolling 132 CRC patients. Then, the CRISPR/Cas9 technique was used to establish c-Myb gene KO CRC cell lines. Cellular functional assays in vitro and in vivo were used to evaluate the impact of c-Myb KO in CRC cells. Finally, RNA sequencing was used to investigate the potential oncogenic mechanisms regulated by c-Myb in CRC progression and related cellular validations were accordingly carried out. As a result, c-Myb is significantly overexpressed in CRC tissues as compared with adjacent normal tissues. High expression of c-Myb is positively correlated with lymph node metastasis and poor prognosis. Univariate analysis and multivariate analysis further identify c-Myb as an independent unfavorable prognostic factor for CRC patients. c-Myb KO inhibits the proliferation, apoptosis resistance, invasion, metastasis, colony formation and in vivo tumorigenesis of CRC cells. Also, the mechanism investigation indicates that c-Myb may promote CRC progression by regulating c-fos. c-fos overexpression can rescue the inhibitory effect of c-Myb KO on the malignant characteristics of CRC cells. Finally, we find that c-Myb KO inhibits the epithelial-mesenchymal transition (EMT) molecular phenotype in CRC cells, whereas c-fos overexpression can rescue this inhibitory effect. This study suggests that c-Myb promotes the malignant progression of CRC through c-fos-induced EMT and has the potential to be a promising prognostic biomarker and therapeutic target.

Dysbiosis signatures of gut microbiota in coronary artery disease.

Gut microbiota dysbiosis has been considered to be an important risk factor that contributes to coronary artery disease (CAD), but limited evidence exists about the involvement of gut microbiota in the disease. Our study aimed to characterize the dysbiosis signatures of gut microbiota in coronary artery disease. The gut microbiota represented in stool samples were collected from 70 patients with coronary artery disease and 98 healthy controls. 16S rRNA sequencing was applied, and bioinformatics methods were used to decipher taxon signatures and function alteration, as well as the microbial network and diagnostic model of gut microbiota in coronary artery disease. Gut microbiota showed decreased diversity and richness in patients with coronary artery disease. The composition of the microbial community changed; Escherichia-Shigella [false discovery rate (FDR = 7.5*10-5] and Enterococcus (FDR = 2.08*10-7) were significant enriched, while Faecalibacterium (FDR = 6.19*10-10), Subdoligranulum (FDR = 1.63*10-6), Roseburia (FDR = 1.95*10-9), and Eubacterium rectale (FDR = 2.35*10-4) were significant depleted in the CAD group. Consistent with the taxon changes, functions such as amino acid metabolism, phosphotransferase system, propanoate metabolism, lipopolysaccharide biosynthesis, and protein and tryptophan metabolism were found to be enhanced in CAD patients. The microbial network revealed that Faecalibacterium and Escherichia-Shigella were the microbiotas that dominated in the healthy control and CAD groups, respectively. The microbial diagnostic model based on random forest also showed probability in identifying those who suffered from CAD. Our study successfully identifies the dysbiosis signature, dysfunctions, and comprehensive networks of gut microbiota in CAD patients. Thus, modulation targeting the gut microbiota may be a novel strategy for CAD treatment.

Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer.

BACKGROUND: Emerging evidence suggests that PIWI-interacting RNAs (piRNAs) may be important epigenetic regulators of gene expression in human cancers; however, their functional and clinical significance in colorectal cancer (CRC) remains unknown. METHODS: We performed piRNA expression profiling in paired cancer and normal tissues through small RNA-sequencing. The clinical significance of candidate piRNAs was investigated, and independently validated in 771 CRC patients from three independent cohorts. The biological function of piRNAs was characterized in cell lines, followed by identification and validation of downstream target genes in CRC tissues. RESULTS: We identified piR-1245 as a novel and frequently overexpressed noncoding RNA in CRC, and its expression significantly correlated with advanced and metastatic disease. Patients with high piR-1245 expression experienced significantly shorter overall survival, and multivariate analysis identified its expression to serve as an independent prognostic biomarker in CRC. Functionally, piR-1245 acts as an oncogene and promotes tumor progression, and gene expression profiling results identified a panel of downstream target-genes involved in regulating cell survival pathway. Based upon piRNA:mRNA sequence complementarity, we identified a panel of tumor suppressor genes (ATF3, BTG1, DUSP1, FAS,NFKBIA, UPP1, SESN2, TP53INP1 and MDX1) as direct targets of piR-1245, and successfully validated an inverse correlation between their expression and piR-1245 in CRC. CONCLUSIONS: We for the first time have identified the role for a PIWI-interacting noncoding RNA, piR-1245, as a novel oncogene and a potential prognostic biomarker in colorectal cancer.