Prediction of lymph node metastasis in T1 colorectal cancer based on combination of body composition and vascular invasion.

OBJECTIVES: Lymph node metastasis (LNM) in colorectal cancer (CRC) patients is not only associated with the tumor's local pathological characteristics but also with systemic factors. This study aims to assess the feasibility of using body composition and pathological features to predict LNM in early stage colorectal cancer (eCRC) patients. METHODS: A total of 192 patients with T1 CRC who underwent CT scans and surgical resection were retrospectively included in the study. The cross-sectional areas of skeletal muscle, subcutaneous fat, and visceral fat at the L3 vertebral body level in CT scans were measured using Image J software. Logistic regression analysis were conducted to identify the risk factors for LNM. The predictive accuracy and discriminative ability of the indicators were evaluated using receiver operating characteristic (ROC) curves. Delong test was applied to compare area under different ROC curves. RESULTS: LNM was observed in 32 out of 192 (16.7%) patients with eCRC. Multivariate analysis revealed that the ratio of skeletal muscle area to visceral fat area (SMA/VFA) (OR = 0.021, p = 0.007) and pathological indicators of vascular invasion (OR = 4.074, p = 0.020) were independent risk factors for LNM in eCRC patients. The AUROC for SMA/VFA was determined to be 0.740 (p < 0.001), while for vascular invasion, it was 0.641 (p = 0.012). Integrating both factors into a proposed predictive model resulted in an AUROC of 0.789 (p < 0.001), indicating a substantial improvement in predictive performance compared to relying on a single pathological indicator. CONCLUSION: The combination of the SMA/VFA ratio and vascular invasion provides better prediction of LNM in eCRC.

Preoperative controlling nutritional status as an optimal prognostic nutritional index to predict the outcome for colorectal cancer.

BACKGROUND: The controlling nutritional status (CONUT) score effectively reflects a patient's nutritional status, which is closely related to cancer prognosis. This study investigated the relationship between the CONUT score and prognosis after radical surgery for colorectal cancer, and compared the predictive ability of the CONUT score with other indexes. AIM: To analyze the predictive performance of the CONUT score for the survival rate of colorectal cancer patients who underwent potentially curative resection. METHODS: This retrospective analysis included 217 patients with newly diagnosed colorectal. The CONUT score was calculated based on the serum albumin level, total lymphocyte count, and total cholesterol level. The cutoff value of the CONUT score for predicting prognosis was 4 according to the Youden Index by the receiver operating characteristic curve. The associations between the CONUT score and the prognosis were performed using Kaplan-Meier curves and Cox regression analysis. RESULTS: Using the cutoff value of the CONUT score, patients were stratified into CONUT low (n = 189) and CONUT high groups (n = 28). The CONUT high group had worse overall survival (OS) (P = 0.013) and relapse-free survival (RFS) (P = 0.015). The predictive performance of CONUT was superior to the modified Glasgow prognostic score, the prognostic nutritional index, and the neutrophil-to-lymphocyte ratio. Meanwhile, the predictive performances of CONUT + tumor node metastasis (TNM) stage for 3-year OS [area under the receiver operating characteristics curve (AUC) = 0.803] and 3-year RFS (AUC = 0.752) were no less than skeletal muscle mass index (SMI) + TNM stage. The CONUT score was negatively correlated with SMI (P < 0.01). CONCLUSION: As a nutritional indicator, the CONUT score could predict long-term outcomes after radical surgery for colorectal cancer, and its predictive ability was superior to other indexes. The correlation between the CONUT score and skeletal muscle may be one of the factors that play a predictive role.

circSKA3 promotes colorectal cancer metastases through miR-1238 and methylation.

Colorectal cancer (CRC) is becoming one of the most common cancers overworld, which causes a high rate of death in patients. circRNAs are non-coding RNAs(ncRNAs), which have been reported to be involved in the development of many cancers, including CRC. However, the exact mechanism that how circRNAs function through in CRC remains unclear. In this study, we firstly used GEO database and bioinformatic methods to identify the significant changed circRNAs, with circSKA3 being the most significantly upregulated circRNAs in CRC tissues. PCR results further confirmed higher expression of circSKA3 in CRC patients. CCK-8, scratch, and transwell assays indicated that circSKA3 could promote the proliferation, migration, and invasion of CRC cell lines for cell detection. Dual-luciferase assays were carried out to detect the downstream targets of circSKA3, and a binding site between circSKA3 and miR-1238 was identified and miR-1238 could also combine with YTHDF2. Overexpression of YTHDF2 rescued the decreased cell proliferation, migration, and invasion caused by miR-1238 overexpression. RIP assay further indicated that YTHDF2 could decrease the methylation of STAT5A. In summary, our study found that circSKA3 was upregulated in CRC tissues comparing with normal tissues. circSKA3 could increase the expression ofYTHDF2 through sponging miR-1238 to decrease the methylation of STAT5A, which could provide a novel target for CRC treatment.

Cross-talk between gastric cancer and hepatic stellate cells promotes invadopodia formation during liver metastasis.

In gastric cancer (GC), the liver is a common organ for distant metastasis, and patients with gastric cancer with liver metastasis (GCLM) generally have poor prognosis. The mechanism of GCLM is unclear. Invadopodia are special membrane protrusions formed by tumor cells that can degrade the basement membrane and ECM. Herein, we investigated the role of invadopodia in GCLM. We found that the levels of invadopodia-associated proteins were significantly higher in liver metastasis than in the primary tumors of patients with GCLM. Furthermore, GC cells could activate hepatic stellate cells (HSCs) within the tumor microenvironment of liver metastases through the secretion of platelet-derived growth factor subunit B (PDGFB). Activated HSCs secreted hepatocyte growth factor (HGF), which activated the MET proto-oncogene, MET receptor of GC cells, thereby promoting invadopodia formation through the PI3K/AKT pathway and subsequently enhancing the invasion and metastasis of GC cells. Therefore, cross-talk between GC cells and HSCs by PDGFB/platelet derived growth factor receptor beta (PDGFRß) and the HGF/MET axis might represent potential therapeutic targets to treat GCLM.

Is total neoadjuvant treatment beneficial for locally advanced rectal cancer? a meta-analysis of randomized controlled trials.

BACKGROUND: Total neoadjuvant therapy (TNT) is a new strategy combining neoadjuvant therapy and chemotherapy to enhance tumor shrinkage and systemic control. Its effectiveness remains debated. OBJECTIVES: This study conducts a meta-analysis of randomized controlled trials (RCTs) to assess TNT's impact and provide high-quality evidence for rectal cancer treatment decisions. METHOD: We searched China National Knowledge Infrastructure, VIP Database, Wanfang Database, China biomedical literature database, PubMed database, Embase database, and The Cochrane Library for RCTs comparing TNT with neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer. The included trials were screened and assessed for quality based on inclusion and exclusion criteria, and meta-analysis was performed using RevMan 5.3 software. RESULTS: A total of 11 RCTs reported in 14 articles, with 1624 cases in the TNT group and 1541 cases in the CRT group. The results of the meta-analysis showed that compared with the CRT group, the TNT group had a higher pathological complete response rate (RR=1.65, 95% CI [1.40, 1.94], P<0.00001), higher T0 downstaging rate (RR=1.51, 95% CI [1.29, 1.77], P<0.00001), higher 3-year overall survival (HR=0.81, 95% CI [0.67, 0.98], P=0.03), and higher 3-year disease-free survival (HR=0.82, 95% CI [0.70, 0.95], P=0.008). However, there was no statistically significant difference between the two groups in terms of R0 resection rate (RR=1.02, 95% CI [0.99, 1.05], P=0.14), sphincter preservation rate (RR=0.94, 95% CI [0.88, 1.01], P=0.12), anastomotic leakage rate (RR=1.42, 95% CI [0.85, 2.38], P=0.18), and grade 3 or higher adverse events (RR=1.21, 95% CI [0.95, 1.54], P=0.13). CONCLUSIONS: In the treatment of locally advanced rectal cancer, TNT offers greater survival benefits compared to neoadjuvant CRT and does not significantly increase the incidence of adverse events. However, further data and studies with long-term outcomes are still required.

Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.

The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN-pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1-pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions. Prolonged hypoxia promotes the activation of RIPK1 kinase by modulating its proline hydroxylation, independent of the TNFα-TNFR1 pathway. As such, inhibiting proline hydroxylation of RIPK1 promotes RIPK1 activation to trigger cell death and inflammation. Hepatocyte-specific Vhl deficiency promoted RIPK1-dependent apoptosis to mediate liver pathology. Our findings illustrate a key role of the EGLN-pVHL pathway in suppressing RIPK1 activation under normoxic conditions to promote cell survival and a model by which hypoxia promotes RIPK1 activation through modulating its proline hydroxylation to mediate cell death and inflammation in human diseases, independent of TNFR1.

Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.

Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser415 to suppress energy stress-induced cell death. Inhibiting pS415-RIPK1 by Ampk deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid Ampkα1-deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.

Fructose aggravates copper-deficiency-induced non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), is the most common cause of chronic liver disease, affecting 24% of the global population. Accumulating evidence demonstrates that copper deficiency (CuD) is implicated in the development of NAFLD, besides, high fructose consumption by promoting inflammation contributes to NAFLD. However, how CuD and/or fructose (Fru) causes NAFLD is not clearly delineated. The present study aims to investigate the role of CuD and/or fructose supplement on hepatic steatosis and hepatic injury. We established a CuD rat model by feeding weaning male Sprague-Dawley rats for 4 weeks with CuD diet. Fructose was supplemented in drinking water. We found the promoting role of CuD or Fructose (Fru) in the progress of NAFLD, which was aggravated by combination of the two. Furthermore, we presented the alteration of hepatic lipid profiles (including content, composition, and saturation), especially ceramide (Cer), cardiolipin (CL), phosphatidylcholine (PC) and phosphatidylethanolamine (PE) was closely associated with CuD and/or Fru fed induced-NAFLD in rat models. In conclusion, insufficient copper intake or excessive fructose supplement resulted in adverse effects on the hepatic lipid profile, and fructose supplement causes a further hepatic injury in CuD-induced NAFLD, which illuminated a better understanding of NAFLD.

Incidence, risk factors, and predictive modeling of stoma site incisional hernia after enterostomy closure: a multicenter retrospective cohort study.

PURPOSE: Stoma site incisional hernia (SSIH) is a common complication, but its incidence and risk factors are not well known. The objective of this study is to explore the incidence and risk factors of SSIH and build a predictive model. METHODS: We performed a multicenter retrospective analysis on the patients who underwent enterostomy closure from January 2018 to August 2020. Patient's general condition, perioperative, intraoperative, and follow-up information was collected. The patients were divided into control group (no occurrence) and observation group (occurrence) according to whether SSIH occurred. Univariate and multivariate analysis were used to evaluate the risk factors of SSIH, following which we constructed a nomogram for SSIH prediction. RESULTS: One hundred fifty-six patients were enrolled in the study. The incidence of SSIH was 24.4% (38 cases), of which 14 were treated with hernia mesh repair, and the others were treated with conservative treatment. Univariate and multivariate analysis showed that age ≥ 68 years (OR 1.045, 95% CI 1.002 ~ 1.089, P = 0.038), colostomy (OR 2.913, 95% CI 1.035 ~ 8.202, P = 0.043), BMI ≥ 25 kg/m2 (OR 1.181, 95% CI 1.010 ~ 1.382, P = 0.037), malignant tumor (OR 4.838, 95% CI 1.508 ~ 15.517, P = 0.008) and emergency surgery (OR 5.327, 95% CI 1.996 ~ 14.434, P = 0.001) are the independent risk factors for SSIH. CONCLUSIONS: Based on the results, a predictive model for the occurrence of SSIH was constructed to screen high-risk groups of SSIH. For patients at high risk for SSIH, how to deal with the follow-up and prevent the occurrence of SSIH is worth further exploration.

Prediction values of tertiary lymphoid structures in the prognosis of patients with left- and right-sided colon cancer: a multicenter propensity score-matched study.

BACKGROUND: Tertiary lymphoid structures (TLS) are the lymphocyte aggregates that play a key role in the vast majority of solid tumors including colon cancer, displaying an antitumor effect under most circumstances. The heterogeneity between left- and right-sided colon cancer (LCC and RCC) encompasses various aspects, such as clinical manifestations, pathological features, and immune responses. However, the function and prognostic significance of TLS within LCC and RCC have yet to be fully understood. METHODS: A retrospective analysis was performed on 2612 patients who underwent radical resection for LCC or RCC without distant metastasis in multiple medical centers. Utilizing propensity score matching, 121 patients with LCC and 121 patients with RCC were selected for the training set. An external validation set including 64 patients with LCC and 64 patients with RCC were also employed. Hematoxylin-eosin and immunohistochemical staining were used to assess TLS and the proportion of various immune cells. Clinical characteristics and prognostic values of TLS in patients with LCC and RCC were analyzed. Nomograms were constructed for LCC and RCC to predict 3-year and 5-year overall survival (OS), respectively. RESULTS: For LCC and RCC patients, TLS was located in the interstitial region or outside the tumor tissue and mainly consisted of B cells and T cells. The TLS quantity and density in RCC were higher than those of LCC. In multivariate Cox regression analysis, TLS density ( P =0.014), vascular invasion ( P =0.019), and AJCC stage ( P =0.026) were independent prognostic factors for 5-year OS of RCC. For LCC patients, AJCC stage ( P =0.024), tumor differentiation ( P =0.001), and tumor budding ( P =0.040) emerged as independent prognostic factors for 5-year OS. Similar results were obtained in the external verification set. Separate nomograms for RCC and LCC were developed, displaying improved prediction performance compared to the AJCC 8th edition TNM staging system. CONCLUSIONS: Differences in TLS quantity and density were observed between LCC and RCC, suggesting that a nomogram based on TLS density could more effectively predict survival for RCC patients. Furthermore, a nomogram based on tumor budding was recommended for better prediction of LCC patient survival. Taken together, these results suggested that the immune and clinical characteristics of colon cancer at left and right side were substantially different, which may lead to the use of different prediction model and the development of individual treatment strategy.

Gastric microbiota: an emerging player in gastric cancer.

Gastric cancer (GC) is a common cancer worldwide with a high mortality rate. Many microbial factors influence GC, of which the most widely accepted one is Helicobacter pylori (H. pylori) infection. H. pylori causes inflammation, immune reactions and activation of multiple signaling pathways, leading to acid deficiency, epithelial atrophy, dysplasia and ultimately GC. It has been proved that complex microbial populations exist in the human stomach. H. pylori can affect the abundance and diversity of other bacteria. The interactions among gastric microbiota are collectively implicated in the onset of GC. Certain intervention strategies may regulate gastric homeostasis and mitigate gastric disorders. Probiotics, dietary fiber, and microbiota transplantation can potentially restore healthy microbiota. In this review, we elucidate the specific role of the gastric microbiota in GC and hope these data can facilitate the development of effective prevention and therapeutic approaches for GC.

Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex.

Copper deficiency has emerged to be associated with various lipid metabolism diseases, including non-alcoholic fatty liver disease (NAFLD). However, the mechanisms that dictate the association between copper deficiency and metabolic diseases remain obscure. Here, we reveal that copper restoration caused by hepatic ceruloplasmin (Cp) ablation enhances lipid catabolism by promoting the assembly of copper-load SCO1-LKB1-AMPK complex. Overnutrition-mediated Cp elevation results in hepatic copper loss, whereas Cp ablation restores copper content to the normal level without eliciting detectable hepatotoxicity and ameliorates NAFLD in mice. Mechanistically, SCO1 constitutively interacts with LKB1 even in the absence of copper, and copper-loaded SCO1 directly tethers LKB1 to AMPK, thereby activating AMPK and consequently promoting mitochondrial biogenesis and fatty acid oxidation. Therefore, this study reveals a mechanism by which copper, as a signaling molecule, improves hepatic lipid catabolism, and it indicates that targeting copper-SCO1-AMPK signaling pathway ameliorates NAFLD development by modulating AMPK activity.

Two-step thermotropic phase transition and dielectric relaxation in 1D supramolecular lead iodide perovskite [NH4@18-crown ether]PbI3.

The supramolecular lead iodide perovskite crystals, {[NH4(18-crown-6)]PbI3}∞ (1), (18-crown-6 = 1,4,7,10,13,16-hexaoxacyclooctadecane), was successfully achieved by a facile solvent evaporation strategy using a DMF solution containing equal molar quantities of PbI2, NH4I and 18-crown-6. The supramolecular perovskite was characterized by microanalysis for C, H and N elements, thermogravimetric (TG) analysis, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and single crystal X-ray diffraction techniques. DSC measurements demonstrated that 1 experiences a two-step thermotropic phase transition around 333 K and 383 K, respectively. The phase transition is relevant to the disorder-order transformation of the 18-crown-6 molecule at ∼333 K, while both breaking-symmetry and ordered-disordered transformation of the 18-crown-6 molecule occurred at ∼383 K. In addition, the sharp change of the PbI6 coordination octahedron distortion degree plays a synergistic role in the two-step phase transition. The dielectric relaxation occurs above 243 K in 1 and is mainly attributed to the displacement of the NH4+ ions relative to the ring of the 18-crown-6 molecule and {PbI3}∞ chain induced by an AC electrical field.

Molecular Landscape of ERBB2 Alterations in 14,956 Solid Tumors.

ERBB2 abnormalities frequently occur and serve as rationale therapeutic targets in cancer. In this study, clinical and next-generation sequencing data from 14,956 patients across more than 20 tumor types were collected. A total of 406 (2.7%) patients were identified with ERBB2 amplifications, and 303 (2.0%) patients with pathogenic somatic ERBB2 mutations. ERBB2 amplifications fell most frequently in breast (15.9%) and stomach (8.3%) cancers. Somatic ERBB2 SNVs/indels occurred most common in bladder/urinary tract (7.3%) and intestine (6.1%) cancers. The top mutated ERBB2 SNVs/indels were p.Y772_A775dup (25.5%) and p.S310F/Y (19.9%). Significantly higher rates of ERBB2 SNV/indels were found in women compared to men (2.8% vs. 1.5%, p < 0.0001). CDK12 was the most common co-amplification gene with ERBB2 in cancers with a high frequency of ERBB2 amplifications. Patients with ERBB2 amplifications or mutations had higher TMB compared with patients with non-ERBB2 alterations. The study provided the landscape of ERBB2 alterations across a variety of solid tumors that may benefit from anti-HER2 agents.

Molecular and cellular mechanisms underlying postoperative paralytic ileus by various immune cell types.

Postoperative ileus (POI) is a well-known complication following gut manipulation or surgical trauma, leading to an impaired gut motility and prolonged postoperative recovery time. Few current therapeutic strategies can prevent POI, and this disorder remains to be a major clinical challenge for patients undergoing surgery. Comprehensive understanding of cellular and molecular mechanisms related to the pathogenesis of POI stimulates the discovery of more promising targets for treatment. POI is closely associated with a series of inflammatory events within the bowel wall, and as key components of inflammatory mechanisms, different types of immune cells, including macrophages, dendritic cells, and T lymphocytes, play significant roles during the development of POI. A variety of immune cells are recruited into the manipulation sites after surgery, contributing to early inflammatory events or impaired gut motility. Our review intends to summarize the specific relationship between different immune cells and POI, mainly focusing on the relevant mechanisms underlying this disorder.

Accuracy of Oxygen Saturation Measurements in Patients with Obesity Undergoing Bariatric Surgery.

BACKGROUND: We aimed to determine the magnitude, direction, and influencing factors of the concordance between arterial oxygen saturation (SaO2) and peripheral capillary oxygen saturation (SpO2) in patients with obesity undergoing bariatric surgery, supporting the measurement of SaO2 and SpO2 in key populations. METHODS: Patients with obesity undergoing bariatric surgery from 2017 to 2020 were included. Preoperative SpO2 and SaO2 were collected. Linear correlation and multiple linear regression analyses were performed to characterize the relationships between body mass index (BMI), age, and sex with pulse oximetry and arterial blood gas (ABG) parameters. Bland-Altman analysis was applied to determine the concordance between SpO2 and SaO2 and the limits of this concordance. RESULTS: A total of 134 patients with obesity undergoing bariatric surgery were enrolled. SaO2 was negatively associated with BMI (p < 0.0001) and age (p = 0.006), and SpO2 was negatively associated with BMI (p = 0.021) but not with age. SpO2 overestimated SaO2 in 91% of patients with a bias of 2.05%. This bias increased by 203% in hypoxemic patients compared with nonhypoxemic patients (p < 0.0001). The bias was 1.3-fold higher (p = 0.023) in patients with a high obesity surgery mortality risk score (OS-MRS) than in those with low or intermediate scores. CONCLUSION: Compared with SpO2, preoperative SaO2 can more accurately reflect the real oxygen saturation in patients with obesity undergoing bariatric surgery, especially for those with BMI ≥ 40 kg/m2, age ≥ 40 years, and high OS-MRS. ABG analysis can provide a more reliable basis for accurate and timely monitoring, ensuring the perioperative safety of susceptible patients.

Salt-Sensitive Ileal Microbiota Plays a Role in Atrial Natriuretic Peptide Deficiency-Induced Cardiac Injury.

Atrial natriuretic peptide (ANP) activity deficiency contributes to salt-sensitive hypertension in humans and mice. However, the role of ileal microbiota in salt sensitivity in ANP deficiency-related cardiac injury has not been investigated yet. This study used ANP-/- mice to analyze the role of the salt-sensitive ileal microbiome on cardiac injury. ANP-/- mice showed an increase in blood pressure (BP), the heart weight/body weight (HW/BW) ratio, and cardiac hypertrophy compared with wild-type (WT) mice. ANP deficiency did not impact the histological structure but reduced occludin expression in the ileum. Antibiotics significantly relieved BP and cardiac hypertrophy in ANP-/- mice. A high-salt diet (HSD) increased BP, the HW/BW ratio, and cardiac hypertrophy/fibrosis in WT and ANP-/- mice, and an HSD treatment in ANP-/- mice exacerbated these cardiac parameters. The HSD markedly decreased muscularis layer thickening, villus length, and numbers of Paneth and goblet cells in the ileum of WT and ANP-/- mice. Furthermore, the HSD increased the level of TLR4 and IL-1ß in ANP-/- mice ileum compared with WT mice. Antibiotics reduced the HW/BW ratio, cardiac hypertrophy/fibrosis, and the level of TLR4 and IL-1ß in the ileum, and rescued the muscularis layer thickening, villus length, and numbers of Paneth and goblet cells in the ileum of HSD-ANP-/- mice. Importantly, ANP deficiency induced the colonization of Burkholderiales bacterium YL45, Lactobacillus johnsonii, and Lactobacillus reuteri in the ileum on the NSD diet, which was only observed in HSD-induced WT mice but not in WT mice on the NSD. Besides, the HSD significantly enhanced the sum of the percentage of the colonization of Burkholderiales bacterium YL45, Lactobacillus johnsonii, and Lactobacillus reuteri in the ileum of ANP-/- mice. Ileal microbiota transfer (IMT) from ANP-/- mice to healthy C57BL/6J mice drove Lactobacillus johnsonii and Lactobacillus reuteri colonization in the ileum, which manifested an increase in BP, the HW/BW ratio, cardiac hypertrophy, and ileal pathology compared with IMT from WT mice. The HSD in C57BL/6J mice with IMT from ANP-/- mice drove the colonization of Burkholderiales bacterium YL45, Lactobacillus johnsonii, and Lactobacillus reuteri in the ileum and further exacerbated the cardiac and ileal pathology. Our results suggest that salt-sensitive ileal microbiota is probably related to ANP deficiency-induced cardiac injury.

Characterization of the Estrogen Response Helps to Predict Prognosis and Identify Potential Therapeutic Targets in Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is an aggressive malignancy originating from the epithelium of the bile duct. The prognosis of patients is poor regardless of radical resection and chemoradiotherapy. The current classification and prognostic model of CCA are unable to satisfy the requirements for predicting the clinical outcome and exploring therapeutic targets. Estrogen signaling is involved in diverse cancer types, and it has long been established that CCA could be regulated by estrogen. In our study, estrogen response was identified to be significantly and stably correlated with poor prognosis in CCA. Employing several algorithms, CCA was classified into ES cluster A and B. ES cluster B was mainly composed of patients with fluke infection and overlapped with CCA cluster 1/2, and ES cluster A was mainly composed of patients without fluke infection and overlapped with CCA cluster 3/4. COMT and HSD17B1 were identified to be responsible for the differential estrogen response between ES clusters A and B, and the estrogen response may be correlated with the differentiation and cancer stemness of CCA at the single-cell level. Complement activation and the expression of C3 and C5, which are mainly expressed by CCA cells, were significantly downregulated in ES cluster B. An estrogen response risk score (ESRS) model was constructed to predict the prognosis of CCA, followed by a nomogram integrating ESRS and clinical features. Finally, altered pathways, applicable drugs and sensitivity to chemical drugs were analyzed specific to the estrogen response. In summary, our results provide insights into the role of the estrogen response in CCA progression as well as applicable drugs and potential therapeutic targets in estrogen metabolism, the complement system and ESRS-related pathways.

An Emerging Role of Defective Copper Metabolism in Heart Disease.

Copper is an essential trace metal element that significantly affects human physiology and pathology by regulating various important biological processes, including mitochondrial oxidative phosphorylation, iron mobilization, connective tissue crosslinking, antioxidant defense, melanin synthesis, blood clotting, and neuron peptide maturation. Increasing lines of evidence obtained from studies of cell culture, animals, and human genetics have demonstrated that dysregulation of copper metabolism causes heart disease, which is the leading cause of mortality in the US. Defects of copper homeostasis caused by perturbed regulation of copper chaperones or copper transporters or by copper deficiency resulted in various types of heart disease, including cardiac hypertrophy, heart failure, ischemic heart disease, and diabetes mellitus cardiomyopathy. This review aims to provide a timely summary of the effects of defective copper homeostasis on heart disease and discuss potential underlying molecular mechanisms.