Pentapeptide PYRAE triggers ER stress-mediated apoptosis of breast cancer cells in mice by targeting RHBDF1-BiP interaction.

Reinforced cellular responses to endoplasmic reticulum (ER) stress are caused by a variety of pathological conditions including cancers. Human rhomboid family-1 protein (RHBDF1), a multiple transmembrane protein located mainly on the ER, has been shown to promote cancer development, while the binding immunoglobulin protein (BiP) is a key regulator of cellular unfolded protein response (UPR) for the maintenance of ER protein homeostasis. In this study, we investigated the role of RHBDF1 in maintaining ER protein homeostasis in breast cancer cells. We showed that deleting or silencing RHBDF1 in breast cancer cell lines MCF-7 and MDA-MB-231 caused marked aggregation of unfolded proteins in proximity to the ER. We demonstrated that RHBDF1 directly interacted with BiP, and this interaction had a stabilizing effect on the BiP protein. Based on the primary structural motifs of RHBDF1 involved in BiP binding, we found a pentapeptide (PE5) targeted BiP and inhibited BiP ATPase activity. SPR assay revealed a binding affinity of PE5 toward BiP (Kd = 57.7 µM). PE5 (50, 100, 200 µM) dose-dependently promoted ER protein aggregation and ER stress-mediated cell apoptosis in MCF-7 and MDA-MB-231 cells. In mouse 4T1 breast cancer xenograft model, injection of PE5 (10 mg/kg, s.c., every 2 days for 2 weeks) significantly inhibited the tumor growth with markedly increased ER stress and apoptosis-related proteins in tumor tissues. Our results suggest that the ability of RHBDF1 to maintain BiP protein stability is critical to ER protein homeostasis in breast cancer cells, and that the pentapeptide PE5 may serve as a scaffold for the development of a new class of anti-BiP inhibitors.

Coupled Aerobic Methane Oxidation and Arsenate Reduction Contributes to Soil-Arsenic Mobilization in Agricultural Fields.

Microbial oxidation of organic compounds can promote arsenic release by reducing soil-associated arsenate to the more mobile form arsenite. While anaerobic oxidation of methane has been demonstrated to reduce arsenate, it remains elusive whether and to what extent aerobic methane oxidation (aeMO) can contribute to reductive arsenic mobilization. To fill this knowledge gap, we performed incubations of both microbial laboratory cultures and soil samples from arsenic-contaminated agricultural fields in China. Incubations with laboratory cultures showed that aeMO could couple to arsenate reduction, wherein the former bioprocess was carried out by aerobic methanotrophs and the latter by a non-methanotrophic bacterium belonging to a novel and uncultivated representative of Burkholderiaceae. Metagenomic analyses combined with metabolite measurements suggested that formate served as the interspecies electron carrier linking aeMO to arsenate reduction. Such coupled bioprocesses also take place in the real world, supported by a similar stoichiometry and gene activity in the incubations with natural paddy soils, and contribute up to 76.2% of soil-arsenic mobilization into pore waters in the top layer of the soils where oxygen was present. Overall, this study reveals a previously overlooked yet significant contribution of aeMO to reductive arsenic mobilization.

[Dual-specificity Phosphatase 1 Suppresses Vascular Smooth Muscle Cell Calcification by Optical Atrophy 1-related Pathway].

Objective To investigate the effect of dual-specificity phosphatase 1/optical atrophy 1 (DUSP1/OPA1) signaling pathway on vascular smooth muscle cell (VSMC) calcification.Methods An in vitro model of VSMC calcification was induced by exposure to ß-glycerophosphate and calcium chloride.VSMC calcification was assessed by Alizarin Red S staining and calcium content by ELISA.Apoptosis was detected by TUNEL.Western blotting was employed to determine the protein levels of DUSP1,OPA1,Runt-related transcription factor 2 (Runx-2),bone morphogenetic protein 2 (BMP-2),and cysteinyl aspartate-specific proteinase-3 (Caspase-3).The effects of DUSP1 overexpression and OPA1 knockdown on cell calcification were investigated.Results Calcium chloride and ß-glycerolphosphate induced VSMC calcification and down-regulated the expression levels of DUSP1 (t=11.951,P<0.001) and OPA1 (t=8.487,P<0.001).DUSP1 overexpression promoted OPA1 expression (t=-8.921,P<0.001),attenuated VSMC calcification,reduced calcium content and apoptosis rate,and down-regulated the expression of Runx-2,BMP-2,and active Caspase-3 (all P<0.001).OPA1 knockdown increased calcium content and apoptosis rate,up-regulated the expression of Runx-2,BMP-2,and active Caspase-3,and promoted VSMC calcification (all P<0.001).Conclusion DUSP1 may inhibit the VSMC calcification through the OPA1 signaling pathway.

Detection of RAS gene mutation and its clinical significance in children with acute lymphoblastic leukemia. / å„¿ç«¥æ€¥æ€§æ·‹å·´ç»†èƒžç™½è¡€ç— ä¸­RASåŸºå› çªå˜çš„æ£€æµ‹åŠå ¶ä¸´åºŠæ„ä¹‰.

OBJECTIVES: To investigate the mutation rate of the RAS gene and its clinical significance in children with acute lymphoblastic leukemia. METHODS: A retrospective analysis was performed on the medical data of 120 children with newly diagnosed acute lymphoblastic leukemia, who were admitted to the Third Affiliated Hospital of Zhengzhou University from January 2015 to January 2020 and underwent next-generation sequencing. The clinical and molecular features were analyzed. The impact of RAS gene mutation on the overall survival rate was evaluated in these children. RESULTS: Among the 120 children, 35 (29.2%) had RAS gene mutation, 30 (25.0%) had KRAS gene mutation, and 5 (4.2%) had both NRAS and KRAS gene mutations. All NRAS mutations and 71% (25/35) of KRAS mutations were located at the 12th and 13th codons. RAS gene mutation was detected in 35 (33.3%) out of 105 children with B-lineage acute lymphoblastic leukemia, but it was not detected in those with acute T lymphocyte leukemia. Of all the children, 11 (9.2%) were lost to follow-up, and among the 109 children followed up, 16 (14.7%) died. The children with RAS gene mutation had a significantly lower 2-year overall survival rate than those without RAS gene mutation (P<0.05). The prognosis of children with RAS gene mutation combined with WT1 overexpression and WBC>50×109/L at diagnosis was worse (P<0.05). CONCLUSIONS: RAS gene mutation is commonly observed in children with B-lineage acute lymphoblastic leukemia and may have an adverse effect on prognosis.

Comparison of various insulin resistance surrogates on prognostic prediction and stratification following percutaneous coronary intervention in patients with and without type 2 diabetes mellitus.

BACKGROUND: Insulin resistance (IR), evaluation of which is difficult and complex, is closely associated with cardiovascular disease. Recently, various IR surrogates have been proposed and proved to be highly correlated with IR assessed by the gold standard. It remains indistinct whether different IR surrogates perform equivalently on prognostic prediction and stratification following percutaneous coronary intervention (PCI) in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients with and without type 2 diabetes mellitus (T2DM). METHODS: The present study recruited patients who were diagnosed with NSTE-ACS and successfully underwent PCI. IR surrogates evaluated in the current study included triglyceride-glucose (TyG) index, visceral adiposity index, Chinese visceral adiposity index, lipid accumulation product, and triglyceride-to-high density lipoprotein cholesterol ratio, calculations of which were conformed to previous studies. The observational endpoint was defined as the major adverse cardiovascular and cerebrovascular events (MACCE), including cardiac death, non-fatal myocardial infarction, and non-fatal ischemic stroke. RESULTS: 2107 patients (60.02 ± 9.03 years, 28.0% female) were ultimately enrolled in the present study. A total of 187 (8.9%) MACCEs were documented during the 24-month follow-up. Despite regarding the lower median as reference [hazard ratio (HR) 3.805, 95% confidence interval (CI) 2.581-5.608, P < 0.001] or evaluating 1 normalized unit increase (HR 1.847, 95% CI 1.564-2.181, P < 0.001), the TyG index remained the strongest risk predictor for MACCE, independent of confounding factors. The TyG index showed the most powerful diagnostic value for MACCE with the highest area under the receiver operating characteristic curve of 0.715. The addition of the TyG index, compared with other IR surrogates, exhibited the maximum enhancement on risk stratification for MACCE on the basis of a baseline model (Harrell's C-index: 0.708 for baseline model vs. 0.758 for baseline model + TyG index, P < 0.001; continuous net reclassification improvement: 0.255, P < 0.001; integrated discrimination improvement: 0.033, P < 0.001). The results were consistent in subgroup analysis where similar analyses were performed in patients with and without T2DM, respectively. CONCLUSION: The TyG index, which is most strongly associated with the risk of MACCE, can be served as the most valuable IR surrogate for risk prediction and stratification in NSTE-ACS patients receiving PCI, with and without T2DM.

Neo-adjuvant radiation therapy provides a survival advantage in T3-T4 nodal positive gastric and gastroesophageal junction adenocarcinoma: a SEER database analysis.

BACKGROUND: Due to negative results in clinical trials of postoperative chemoradiation for gastric cancer, at present, there is a tendency to move chemoradiation therapy forward in gastric and gastroesophageal junction (GEJ) adenocarcinoma. Several randomized controlled trials (RCTs) are currently recruiting subjects to investigate the effect of neo-adjuvant radiotherapy (NRT) in gastric and GEJ cancer. Large retrospective studies may be beneficial in clarifying the potential benefit of NRT, providing implications for RCTs. METHODS: We retrieved the clinicopathological and treatment data of gastric and GEJ adenocarcinoma patients who underwent surgical resection and chemotherapy between 2004 and 2015 from Surveillance, Epidemiology, and End Results (SEER) database. We compared survival between NRT and non-NRT patients among four clinical subgroups (T1-2N-, T1-2N+, T3-4N-, and T3-4N+). RESULTS: Overall, 5272 patients were identified, among which 1984 patients received NRT. After adjusting confounding variables, significantly improved survival between patients with and without NRT was only observed in T3-4N+ subgroup [hazard ratio (HR) 0.79, 95% confidence interval (CI): 0.66-0.95; P = 0.01]. Besides, Kaplan-Meier plots showed significant cause-specific survival advantage of NRT in intestinal type (P <  0.001), but not in diffuse type (P = 0.11) for T3-4N+ patients. In the multivariate competing risk model, NRT still showed survival advantage only in T3-4 N+ patients (subdistribution HR: 0.77; 95% CI: 0.64-0.93; P = 0.006), but not in other subgroups. CONCLUSIONS: NRT might benefit resectable gastric and GEJ cancer patients of T3-4 stages with positive lymph nodes, particularly for intestinal-type. Nevertheless, these results should be interpreted with caution, and more data from ongoing RCTs are warranted.

Stroke of antiplatelet and anticoagulant therapy in patients with coronary artery disease: a meta-analysis of randomized controlled trials.

BACKGROUND: We performed a meta-analysis sought to investigate the risk of stroke with antiplatelet and anticoagulant therapies among patients with coronary artery disease (CAD). METHODS: We searched PubMed, EMBASE, and Cochrane Library for randomized controlled trials from January 1995 to March 2020. Studies were retrieved if they reported data of stroke for patients with CAD and were randomized to receive intensive versus conservative antithrombotic therapies, including antiplatelet and oral anticoagulant (OAC). Analyses were pooled by random-effects modeling. A total of 42 studies with 301,547subjects were enrolled in this analysis. RESULTS: Intensive antithrombotic therapy significantly reduced risk of all stroke (RR 0.86, 95% CI 0.80-0.94) and ischemic stroke (RR 0.80, 95% CI 0.71-0.91), but increased risk of hemorrhagic stroke (RR 1.36, 95% CI 1.00-1.86) and intracranial hemorrhage (RR 1.46, 95% CI 1.17-1.81). Subgroup analyses indicated that OAC yields more benefit to all stroke than antiplatelet therapy (OAC: RR 0.73, 95% CI 0.58-0.92; Antiplatelet: RR 0.90, 95% CI 0.83-0.97; Between-group heterogeneity P value = 0.030). The benefit of antiplatelet therapy on all stroke and ischemic stroke were mainly driven by the studies comparing longer versus shorter duration of dual antiplatelet therapy (All stroke: RR 0.86, 95% CI 0.78-0.95; ischemic stroke: RR 0.84, 95% CI 0.75-0.94). CONCLUSIONS: Among CAD patients who have already received antiplatelet therapy, either strengthening antiplatelet or anticoagulant treatments significantly reduced all stroke, mainly due to the reduction of ischemic stroke, although it increased the risk of hemorrhagic stroke and intracranial hemorrhage. OAC yields more benefit to all stroke than antiplatelet therapy.

Melatonin attenuates vascular calcification by activating autophagy via an AMPK/mTOR/ULK1 signaling pathway.

Melatonin has been demonstrated to protect against calcification in cyclosporine nephrotoxicity. Autophagy may affect vascular calcification by inhibiting apoptosis and the transdifferentiation process. This study sought to explore whether melatonin attenuates vascular calcification by regulating autophagy via the AMP-activated protein kinase/mammalian target of rapamycin/Unc-51-like kinase 1 (AMPK/mTOR/ULK1) signaling pathway. The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualised by Alizarin red staining, while calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure expression of runt-related transcription factor 2 (Runx2, an osteogenic transcription factor), light chain 3 (LC3) II/I, and cleaved caspase 3. Melatonin markedly reduced calcium deposition and ALP activity. Runx2 and cleaved caspase 3 were downregulated, whereas LC3 II/I was increased in response to melatonin, and was accompanied by decreased apoptosis. An immunofluorescence assay revealed that melatonin treatment markedly decreased Runx2 expression and upregulated LC3 expression. Treatment with the autophagy inhibitor 3-methyladenine reversed this phenomenon. Melatonin significantly increased expression of p-AMPK and p-ULK1, and decreased mTOR expression. Treatment with compound C (an inhibitor of AMPK) or MHY1485 (an agonist of mTOR) ablated the observed benefits of melatonin treatment. Melatonin protects VSMCs against calcification by activating autophagy via the AMPK/mTOR/ULK1 pathway.

Association between positivity of serum autoantibodies and liver disease severity in patients with biopsy-proven NAFLD.

BACKGROUND AND AIMS: Some previous studies reported serum autoantibody positivity in patients with nonalcoholic fatty liver disease (NAFLD). The clinical significance of these findings remains uncertain. We aimed to investigate the association between the presence of serum autoantibodies and liver disease severity in NAFLD. METHODS AND RESULTS: A total of 388 consecutive patients with biopsy-proven NAFLD were included in the study. Various serum autoantibodies (including also anti-nuclear antibodies [ANA]) were detected by indirect immunofluorescent or immunoblotting assays. Overall, 84 (21.6%) patients with biopsy-confirmed NAFLD had positivity for at least one of the measured serum autoantibodies. ANA positivity was present in 50 (12.9%) patients, whereas anti-U1RNP or pANCA antibodies were detectable in 9 (2.3%) and 6 (1.5%) patients, respectively. Multivariate logistic regression analysis showed that ANA positivity (adjusted-odds ratio: 4.51, 95%CI: 1.77-11.5; P = 0.002) or positivity of any serum autoantibodies (adjusted-odds ratio: 3.14, 95%CI: 1.30-7.62; P = 0.01) were independently associated with advanced liver fibrosis (stages F3-F4). In serum autoantibody/ANA-positive patients, the proportion of those with advanced fibrosis was also greater among carriers of PNPLA3 rs738409 GG or CG than among those carrying PNPLA3 rs738409 CC genotype. CONCLUSIONS: Serum autoantibody positivity was independently associated with advanced liver fibrosis in patients with biopsy-proven NAFLD. The presence of serum autoantibodies in patients with advanced fibrosis occurred more frequently amongst those carrying PNPLA3 rs738409 GG or CG genotypes.

Effect of alirocumab on coronary plaque in patients with coronary artery disease assessed by optical coherence tomography.

BACKGROUND: Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors have been demonstrated to produce significantly greater reduction in LDL cholesterol levels and cardiovascular events than standard statin therapy. However, evidence on the impact of PCSK9 inhibitors on coronary plaque composition and morphology is limited. METHODS: In this open-label randomized study, eligible patients with intermediate coronary lesions and elevated LDL cholesterol values were randomized to either alirocumab 75 mg Q2W plus statin (atorvastatin 20 mg/day or rosuvastatin 10 mg/day) therapy or standard care. Optical coherence tomography (OCT) assessments for target lesions were obtained at baseline and at 36 weeks of follow-up. RESULTS: LDL cholesterol levels were significantly decreased in both the alirocumab and standard care arms, whereas the absolute reduction in LDL cholesterol was significantly greater in patients treated with alirocumab (1.72 ± 0.51 vs. 0.96 ± 0.59, P < 0.0001). Compared with standard care, the addition of alirocumab to statins was associated with significantly greater increases in minimum fibrous cap thickness (18.0 [10.8-29.2] µm vs 13.2 [7.4-18.6] µm; P = 0.029), greater increases in minimum lumen area (0.20[0.10-0.33] mm2 vs 0.13 [0.12-0.24] mm2; P = 0.006) and a greater diminution in maximum lipid arc (15.1̊ [7.8-24.5] vs. 8.4̊ [2.0-10.5]; P = 0.008). CONCLUSIONS: The addition of alirocumab to statins can not only provide additional LDL cholesterol lowering effects but also have a potential role in promoting a more stable plaque phenotype. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04851769 . Registered 2 Mar 2019.

B cell activating factor regulates periodontitis development by suppressing inflammatory responses in macrophages.

BACKGROUND: B cell activating factor (BAFF) is a member of the tumor necrosis factor (TNF) superfamily with immunomodulatory effects on both innate and adaptive immune responses. Periodontitis is an inflammatory disease characterized by periodontal soft tissue inflammation and the progressive loss of periodontal ligament and alveolar bone. Macrophages are closely related to periodontitis progression. However, the role of BAFF in periodontitis development and macrophage polarization and the underlying mechanism remain unknown. METHODS: In vivo, a ligation-induced mouse model of periodontitis for BAFF blockade was established to investigate the expression of inducible nitric oxide synthase (iNOS) through real-time PCR (RT-PCR) and immunohistochemistry. In addition, the level of TNF-α in the periodontium, the number of osteoclasts, and alveolar bone resorption were observed. In vitro, RAW 264.7 macrophage cells were treated with 100 ng/mL Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS) in either the presence or absence of 50 nM small interfering RNA (siRNA) targeting BAFF, followed by further incubation for 24 h. These cells and supernatants were collected and stored for RT-PCR, enzyme-linked immunosorbent assay, western blotting and immunofluorescence microscopy. RESULTS: In vivo, BAFF blockade decreased the levels of TNF-α in the periodontium in a ligature-induced mouse periodontitis model. Reduced osteoclast formation and lower alveolar bone loss were also observed. In addition, BAFF blockade was related to the expression of polarization signature molecules in macrophages. In vitro, BAFF knockdown notably suppressed the production of TNF-α in RAW 264.7 cells stimulated by P. gingivalis LPS. Moreover, BAFF knockdown attenuated the polarization of RAW 264.7 cells into classically activated macrophages (M1), with reduced expression of iNOS. CONCLUSIONS: Based on our limited evidence, we showed BAFF blockade exhibits potent anti-inflammatory properties in mice experimental periodontitis in vivo and in P. gingivalis LPS-treated RAW 264.7 cells in vitro, and macrophage polarization may be responsible for this effect.

Melatonin attenuates vascular calcification by inhibiting mitochondria fission via an AMPK/Drp1 signalling pathway.

Mitochondrial fission plays a role in cardiovascular calcification. Melatonin has previously been shown to protect against cardiovascular disease, so this study sought to explore whether it attenuates vascular calcification by regulating mitochondrial fission via the AMP-activated protein kinase/dynamin-related protein 1 (AMPK/Drp1) signalling pathway. The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualized by Alizarin red staining, while calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure the expression of runt-related transcription factor 2 (Runx2), Drp1 and cleaved caspase 3. Melatonin markedly reduced calcium deposition and ALP activity. Runx2 and cleaved caspase 3 were down-regulated, Drp1 was reduced in response to melatonin, and this was accompanied by decreased apoptosis. Melatonin also reduced levels of mitochondrial superoxide, reversed ß-glycerophosphate (ß-GP)-induced ΔΨm dissipation and decreased mitochondrial fragmentation. The effects of melatonin in ß-GP-treated VSMCs were similar to those of mitochondrial division inhibitor 1. Melatonin significantly activated the expression of AMPK and decreased Drp1 expression. Treatment with compound C ablated the observed benefits of melatonin treatment. These findings indicate that melatonin protects VSMCs against calcification by inhibiting mitochondrial fission via the AMPK/Drp1 pathway.

Identification and validation of tumour microenvironment-based immune molecular subgroups for gastric cancer: immunotherapeutic implications.

BACKGROUND: Immunotherapy could trigger durable response in advanced gastric cancer, but it only benefits a minority of patients. We aimed to propose a robust molecular classification of gastric cancer microenvironment to identify ideal candidates for tailoring effective immunotherapy. METHODS: A training cohort of 375 gastric cancer samples with RNA sequencing data was analysed. We virtually microdissected tumour, stromal, and immune cell gene expression patterns employing a non-negative matrix factorization algorithm. These expression patterns were annotated using immune- and stromal-related gene signatures. Validation of immunogenomic classification was performed across six microarray datasets of 1406 samples. RESULTS: We found approximately half of gastric cancer samples to have higher immune cell infiltrates, PD-L1 expression, markers of cytolytic activity, and fewer copy number aberrations (all P < 0.05). We termed this group of tumours the Immune Class, which incorporated two components, namely Immune Activation and Immunosuppressive Subtype, according to immunosuppressive or activated microenvironment. Immune Activation Subtype was associated with improved survival in multivariate survival analysis and shared similar genomic characteristics with responders of anti-PD-1 therapy. Immunosuppressive Subtype featured high immune infiltration, stromal enrichment, and transforming growth factor (TGF)-ß signalling pathway activation and correlated with non-responsiveness signature of checkpoint blockade therapy, which might be suitable for anti-PD-L1 and anti-TGF-ß combined therapy. CONCLUSIONS: We proposed and independently validated three reproducible immune molecular subtypes of gastric cancer, which may provide implications for patient selection of immunotherapy.

Impacts of triglyceride-glucose index on prognosis of patients with type 2 diabetes mellitus and non-ST-segment elevation acute coronary syndrome: results from an observational cohort study in China.

BACKGROUND: The relationship between triglyceride-glucose index (TyG index) and the prevalence and prognosis of cardiovascular disease has been confirmed by former studies. However, it remains uncertain whether TyG index has a prognostic impact in patients with type 2 diabetes mellitus (T2DM) and non-ST-segment elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). METHODS: The study retrospectively enrolled 798 patients (mean age: 60.9 ± 8.3 years; 68.3% men) with T2DM and NSTE-ACS who underwent PCI at Beijing Anzhen Hospital from January to December 2015. TyG index was calculated as previously reported: ln [fasting TGs (mg/dL) * FBG (mg/dL)/2]. The primary endpoint was a composite of adverse events as follows: all-cause death, non-fatal myocardial infarction (MI) and ischemia-driven revascularization. RESULTS: TyG index was significantly higher in patients with a primary endpoint event compared with those without. Multivariate Cox proportional hazards analysis showed that 1-unit increase of TyG index was independently associated with higher risk of primary endpoint, independent of other risk factors [hazard ratio (HR) 3.208 per 1-unit increase, 95% confidence interval (CI) 2.400-4.289, P < 0.001]. The addition of TyG index to a baseline risk model had an incremental effect on the predictive value for adverse prognosis [AUC: baseline risk model, 0.800 vs. baseline risk model + TyG index, 0.856, P for comparison < 0.001; category-free net reclassification improvement (NRI) 0.346, P < 0.001; integrated discrimination improvement (IDI) 0.087, P < 0.001]. CONCLUSIONS: Increased TyG index is a significant predictor of adverse prognosis in patients with T2DM and NSTE-ACS undergoing PCI. Further studies need to be performed to determine whether interventions for TyG index have a positive impact on improving clinical prognosis.

Novel Bacillus strains from the human gut exert anticancer effects on a broad range of malignancy types.

Cancer is one of the leading causes of death worldwide, but effective therapies remain the topic of many research activities. Many recent studies have thus focused on particular gut microbiota due to their important roles in treating cancers, but very few microbes of therapeutic value have been reported. In this study, we isolated four bacterial strains, BY38, BY40, BY43 and BY45, from the fecal specimens of healthy individuals and cancer patients. The treatment of cancer cells with the products of these cultured bacteria induced significant inhibitory effects on the proliferation of ovarian cancer cells and colorectal cancer cells in a dose-dependent manner. A phylogenetic analysis showed that the four anticancer strains belong to the genus Bacillus, and flow cytometry assays indicated that the inhibitory effects might be achieved through the induction of cell apoptosis. These results suggest that these bacteria could be novel and promising anticancer agents against cancers.

Metabolic-associated fatty liver disease is associated with severity of COVID-19.

The Corona Virus Disease 2019 (COVID-19) pandemic has attracted increasing worldwide attention. While metabolic-associated fatty liver disease (MAFLD) affects a quarter of world population, its impact on COVID-19 severity has not been characterized. We identified 55 MAFLD patients with COVID-19, who were 1:1 matched by age, sex and obesity status to non-aged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients without MAFLD. Our results demonstrate that in patients aged less than 60 years with COVID-19, MAFLD is associated with an approximately fourfold increase (adjusted odds ratio 4.07, 95% confidence interval 1.20-13.79, P = .02) in the probability for severe disease, after adjusting for confounders. Healthcare professionals caring for patients with COVID-19 need to be aware that there is a positive association between MAFLD and severe illness with COVID-19.

Marital status, an independent predictor for survival of gastric neuroendocrine neoplasm patients: a SEER database analysis.

BACKGROUND: Marital status proves to be an independent prognostic factor in a variety of cancers. However, its prognostic impact on gastric neuroendocrine neoplasms (G-NEN) has not been investigated. METHODS: We identified 3947 G-NEN patients from the Surveillance, Epidemiology, and End Results (SEER) database. Meanwhile, propensity scores for marital status were used to match 506 unmarried patients with 506 married patients. We used Kaplan-Meier method and multivariate Cox regression to analyse the association between marital status and the overall survival (OS) and G-NEN cause-specific survival (CSS) before matching and after matching. RESULTS: Married patients enjoyed better OS and CSS, compared with divorced/separated, single, and widowed patients. Multivariate Cox regression analysis indicated that unmarried status was associated with higher mortality hazards for both OS and CSS among G-NEN patients. Additionally, widowed individuals had the highest risks of overall (adjusted hazard ratio (HR): 1.56, 95% confidence interval (CI): 1.35-1.81, P < 0.001) and cancer-specific mortality (adjusted HR: 1.33, 95% CI: 1.05-1.68, P = 0.02) compared to other unmarried groups in both males and females. Furthermore, unmarried status remained an independent prognostic and risk factor for both OS (HR 1.51, 95% CI 1.19-1.90, P = 0.001) and CSS (HR 1.50, 95% CI 1.10-2.05, P = 0.01) in 1:1 propensity score-matched analysis. CONCLUSION: Marital status was an independent prognostic factor for G-NEN. Meanwhile, widowed patients with G-NEN had the highest risk of death compared with single, married, and divorced/separated patients.

The Prognostic Significance of Different Bleeding Classifications in off-pump coronary artery bypass grafting.

BACKGROUND: Perioperative bleeding during cardiac surgery are known to make patients susceptible to adverse outcomes and several bleeding classifications have been developed to stratify the severity of bleeding events. Further validation of different classifications was needed. The aim of present study was to validate and explore the prognostic value of different bleeding classifications in patients undergoing off-pump coronary artery bypass grafting (OPCAB). METHODS: Data on baseline and operative characteristics of 3988 patients who underwent OPCAB in Beijing Anzhen Hospital from February 2008 to December 2014 were available. The primary endpoint was a composite of in-hospital death and nonfatal postoperative myocardial infarction (MI). The secondary endpoint was postoperative acute kidney injury (AKI). We explored the association of major bleeding defined by the European registry of Coronary Artery Bypass Grafting (E-CABG), Universal Definition of Perioperative Bleeding (UDPB), Bleeding Academic Research Consortium (BARC) classification and Study of Platelet Inhibition and Patient Outcomes (PLATO) with primary endpoints by multivariable logistic regression analysis and investigated their significance of adverse event prediction using goodness-of-fit tests of - 2 log likelihood. RESULTS: In-hospital mortality was 1.23% (n = 49) and postoperative MI was observed in 4.76% (n = 190) of patients, AKI in 24.69% (n = 985). The incidence of the primary outcome was 5.99% (n = 239). Multivariable logistic regression analysis showed that BARC type 4 (OR = 2.64, 95% CI: 1.66-4.19, P < 0.001), UDPB class 4 (OR = 3.52, 95% CI: 2.05-6.02, P < 0.001) and E-CABG class 2-3 (class 2: OR = 2.24, 95% CI: 1.36-3.70, P = 0.001; class 3: OR = 12.65, 95% CI: 2.74-18.43, P = 0.002) bleeding but not PLATO bleeding were associated with an increased risk of in-hospital death and postoperative MI. Major bleeding defined by all the four classifications mentioned above was an independent risk factor of AKI after surgery. Inclusion of major bleeding defined by these four classifications improved the predictive performance of the multivariable model with baseline characteristics. CONCLUSIONS: Bleeding assessed by BARC, E-CABG and UDPB classifications were significantly associated with poorer immediate outcomes. These classifications seemed to be valuable tool in the assessment of prognostic effect of perioperative bleeding.

Impacts of geriatric nutritional risk index on prognosis of patients with non-ST-segment elevation acute coronary syndrome: Results from an observational cohort study in China.

BACKGROUND AND AIMS: It is recognized that malnutrition increases risk of worse prognosis in patients with various diseases. The present study investigated if poor nutritional status predicts adverse outcomes in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: The study enrolled 2299 patients (mean age: 60.01 ± 8.95 years; 71.8% male) with NSTE-ACS who underwent PCI at Beijing Anzhen Hospital from January to December 2015. The entire cohort was divided into training set (n = 1519) and testing set (n = 780) at a ratio of approximate 2 : 1. Nutritional status was assessed by geriatric nutritional risk index (GNRI). The primary endpoint was a composite of adverse events as follows: all-cause death, non-fatal myocardial infarction (MI) and any revascularization. Multivariate Cox analysis showed that GNRI significantly associated with primary endpoint, independent of other risk factors [hazard ratio (HR) 1.159 per 1-point decrease of GNRI, 95% confidence interval (CI) 1.130-1.189, p < 0.001]. The addition of GNRI to a baseline model had an incremental effect on the predictive value for adverse prognosis in training set [AUC: from 0.821 to 0.873, p < 0.001; category-free net reclassification improvement (NRI): 0.313, p < 0.001; integrated discrimination improvement (IDI): 0.108, p < 0.001]. The incremental effect of GNRI was further validated and confirmed in testing set. CONCLUSION: Lower GNRI is a significant predictor of adverse prognosis in patients with NSTE-ACS undergoing PCI. Further studies need to be performed to determine whether nutritional interventions have a positive impact on improving clinical prognosis.

Prognostic impact of estimated remnant-like particle cholesterol in patients with differing glycometabolic status: an observational cohort study from China.

BACKGROUND: It is uncertain whether estimated remnant-like particle cholesterol (RLP-C) could predict residual risk in patients with different glycometabolic status. This study aimed to evaluate the relationship between estimated RLP-C and adverse prognosis in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) treated with percutaneous coronary intervention (PCI) and to identify the potential impact of glycometabolism on the predictive value of estimated RLP-C. METHODS: The study assessed 2419 participants with NSTE-ACS undergoing PCI at Beijing Anzhen Hospital from January to December 2015. Estimated RLP-C was calculated as follows: total cholesterol (TC) minus low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). The adverse events included all-cause death, non-fatal myocardial infarction (MI), and ischemia-driven revascularization. RESULTS: Estimated RLP-C was prominently associated with adverse prognosis in the total population [hazard ratio (HR) 1.291 per 1-SD increase, 95% confidence interval (CI) 1.119-1.490, P <  0.001], independent of confounding risk factors. However, subgroup analysis showed that increasing estimated RLP-C was related to a higher risk of adverse events in the diabetic population only [HR 1.385 per 1-SD increase, 95% CI 1.183-1.620, P <  0.001]. Estimated RLP-C failed to be a significant determinant of adverse prognosis in non-diabetic and pre-diabetic subgroups. The addition of estimated RLP-C to a baseline model including traditional risk factors enhanced the predictive performance both in total and diabetic populations. CONCLUSIONS: High estimated RLP-C level is a significant predictor for recurrent adverse events in patients with diabetes and NSTE-ACS treated with PCI.