Altered mucosal bacteria and metabolomics in patients with Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare genetic disorder characterized by the development of pigmented spots, gastrointestinal polyps and increased susceptibility to cancers. Currently, most studies have investigated intestinal microbiota through fecal microbiota, and there are few reports about mucosa-associated microbiota. It remains valuable to search for the key intestinal microbiota or abnormal metabolic pathways linked to PJS. AIM: This study aimed to assess the structure and composition of mucosa-associated microbiota in patients with PJS and to explore the potential influence of intestinal microbiota disorders and metabolite changes on PJS. METHODS: The bacterial composition was analyzed in 13 PJS patients and 12 controls using 16S rRNA gene sequencing (Illumina MiSeq) for bacteria. Differential analyses of the intestinal microbiota were performed from the phylum to species level. Liquid chromatography-tandem mass spectrometry (LC‒MS) was used to detect the differentially abundant metabolites of PJS patients and controls to identify different metabolites and metabolic biomarkers of small intestinal mucosa samples. RESULTS: High-throughput sequencing confirmed the special characteristics and biodiversity of the mucosa microflora in patients with PJS. They had lower bacterial biodiversity than controls. The abundance of intestinal mucosal microflora was significantly lower than that of fecal microflora. In addition, lipid metabolism, amino acid metabolism, carbohydrate metabolism, nucleotide metabolism and other pathways were significantly different from those of controls, which were associated with the development of the enteric nervous system, intestinal inflammation and development of tumors. CONCLUSION: This is the first report on the mucosa-associated microbiota and metabolite profile of subjects with PJS, which may be meaningful to provide a structural basis for further research on intestinal microecology in PJS.

Corrigendum: The prognosis value of CONUT and SIS score for recurrent or metastatic esophageal squamous cell carcinoma patients treated with second-line immunotherapy.

[This corrects the article DOI: 10.3389/fonc.2023.1167625.].

Immune checkpoint inhibitors combined with or without radio(chemo)therapy for locally advanced or recurrent/metastatic esophageal squamous cell carcinoma.

OBJECTIVE: This study was designed to investigate the efficacy and prognostic factors for immune checkpoint inhibitors (ICIs) combined with or without radio(chemo)therapy and to evaluate their toxicity in patients with locally advanced or recurrent/metastatic esophageal squamous cell carcinoma (LA/RM ESCC). METHODS: In this study, 198 patients with locally advanced or recurrent/metastatic (LA/RM) ESCC who received ICIs combined with or without radiotherapy/chemotherapy in the Department of Radiotherapy of the Fourth Hospital of Hebei Medical University were retrospectively analyzed. Univariate and multivariate analyses were performed to determine the prognostic factors for overall survival (OS) and progression free survival (PFS). The factors affecting treatment response and the occurrences of treatment-related adverse events (trAEs) were analyzed. RESULTS: The median OS and PFS were 30.4 months (95% confidence interval [CI] 15.1-45.7 months) and 15.3 months (95% CI 12.8-17.8 months), respectively. Univariate and multivariate analysis showed that the number of ICI cycles, the intervention of radiotherapy and dysphagia were independent factors affecting OS (Hazard ratio [HR] = 0.39, 2.043 and 0.365, respectively; P = 0.018, 0.001 and 0.032, respectively). The intervention of radiotherapy was an independent factor for PFS (hazard ratio [HR] = 18.149, P = 0.013). The median OS and PFS for patients who had complete response and partial response (Objective response, ORR) were 50.8 months (95% CI 25.8-75.7 months) and 20.5 months (95% CI 14.1-27.0), respectively, which were significantly higher than those in the non-ORR group (OSnon-ORR:17.5 months, 95% CI 14.0-21.0; χ2 = 13.881, P < 0.001; PFSnon-ORR: 12.1 months, 95% CI 10.1-14.1, χ2 = 10.676, P = 0.001). The intervention of radiotherapy could improve treatment response (χ2 = 47.725, P = 0.000). In entire study population, 83 patients (41.9%) had ≥ grade 2 trAEs. CONCLUSIONS: ICIs combined with radiotherapy/chemotherapy are safe and effective in LA/RM ESCC patients. Intervention of radiotherapy, the number of immunotherapy cycles and occurrence of dysphagia affecting the overall survival of LR/RM ESCC patients. Intervention of radiotherapy was an independent prognosis factor for OS and PFS and associated with better treatment response.

The prognosis value of CONUT and SIS score for recurrent or metastatic esophageal squamous cell carcinoma patients treated with second-line immunotherapy.

Objective: To investigate the predictive value of Controlling Nutritional Status (CONUT) score and systemic inflammation (SIS) score in the prognosis, short-term efficacy, and immune-related side effects of patient with recurrent or metastatic esophageal squamous cell carcinoma (R/M ESCC) receiving immunotherapy as second line therapy combined with or without radiotherapy. Methods: Forty-eight patients with R/M ESCC who received second-line therapy with Camrelizumab were retrospectively studied. They were divided into the high and low score groups according to the CONUT and SIS score. Univariate and multivariate analyses were used to analyze factors that might affect patient prognosis and the effects of different CONUT score and SIS on the short-term efficacy and immune-related toxic and side effects of patients. Results: The 1- and 2-year overall survival (OS) and progression-free survival (PFS) rates were 42.9% and 22.5%, and 29.0% and 5.8%, respectively. The CONUT score ranged from 0 to 6 (3.31 ± 1.43), whereas the SIS score ranged from 0 to 2 (1.19 ± 0.73). Multivariate analysis showed that treatment related toxicity, number of cycles of Camrelizumab used, short-term effect and SIS score were independent prognostic factors for OS (P=0.044, 0.021, 0.021, 0.030, respectively), whereas SIS and CONUT scores were independent prognostic factors for PFS (P=0.005, 0.047, respectively). Patients with low CONUT/SIS score had a low incidence rate of immune-related adverse reactions (X2 = 9.735, 5.693; P=0.002, 0.017) and better short-term efficacy (X2 = 4.427, 7.438; P=0.035, 0.006). Conclusion: R/M ESCC patients with low CONUT/SIS score have better prognosis, higher objective response rate, lower incidence of immune-related toxic and side effects after receiving immunotherapy as second-line therapy. CONUT scores and SIS scores may be reliable prognostic indicators for patient receiving immunotherapy as second-line therapy for R/M ESCC.

Comprehensive analysis of the PTPN13 expression and its clinical implication in breast cancer.

Protein tyrosine phosphatases non-receptor 13 (PTPN13) could be a potential biomarker in breast cancer (BRCA), but its genetic variation and biological significance in BRCA remain undefined. Hereon, we comprehensively investigated the clinical implication of PTPN13 expression/gene mutation in BRCA. In our study, a total of 14 cases of triple-negative breast cancers (TNBC) treated with neoadjuvant therapy were enrolled, and post-operation TNBC tissues were collected for next-generation sequencing (NGS) analysis (422 genes including PTPN13). According to the disease-free survival (DFS) time, 14 TNBC patients were divided into Group A (long-DFS) and Group B (short-DFS). The NGS data displayed that the overall mutation rate of PTPN13 was 28.57% as the third highest mutated gene, and PTPN13 mutations appeared only in Group B with short-DFS. In addition, The Cancer Genome Atlas (TCGA) database demonstrated that PTPN13 was lower expressed in BRCA than in normal breast tissues. However, PTPN13 high expression was identified to be related to a favorable prognosis in BRCA using data from the Kaplan-Meier plotter. Moreover, Gene Set Enrichment Analysis (GSEA) revealed that PTPN13 is potentially involved in interferon signaling, JAK/STAT signaling, Wnt/ß-catenin signaling, PTEN pathway, and MAPK6/MAPK4 signaling in BRCA. This study provided evidence that PTPN13 might be a tumor suppressor gene and a potential molecular target for BRCA, and genetic mutation and/or low expression of PTPN13 predicted an unfavorable prognosis in BRCA. The anticancer effect and molecular mechanism of PTPN13 in BRCA may be associated with some tumor-related signaling pathways.

Relationship between postoperative nodal skip metastasis of mid-thoracic esophageal squamous cell carcinoma and patient prognosis and its value in guiding postoperative adjuvant treatment.

Objective: To evaluate the predictive role of nodal skip metastasis (NSM) in the prognosis of lymph node-positive mid-thoracic esophageal squamous cell carcinoma, and to evaluate the significance of postoperative adjuvant treatment in patients with different sites of metastatic nodes. Methods: A retrospective analysis was performed on clinical data of 321 lymph node-positive mid-thoracic esophageal squamous cell carcinoma patients who underwent surgery in the Fourth Hospital of Hebei Medical University. Based on the site and condition of lymph node metastasis by postoperative pathology, the patients were divided into two groups: NSM group and non-NSM (NNSM) group. The propensity score matching (PSM) method was employed to match the two groups. The prognostic factors of patients before and after PSM as well as the effect of different adjuvant treatment modes on the prognosis of patients before and after PSM were analyzed. SPSS 29.0 statistical software was used for analysis. Results: PSM in a 1 : 1 matching ratio was performed, 103 patients were assigned to NSM group and NNSM group respectively. Significant differences were found in the 3- and 5-year OS and DFS between the two groups before PSM, the 3- and 5-year OS also showed a significant difference after PSM (P < 0.05). Multivariate analysis illustrated that gender, postoperative adjuvant treatment mode, N stage and lymph node metastasis were independent risk factors for OS and DFS after PSM (P < 0.05); for NSM patients, postoperative adjuvant chemotherapy and radiotherapy significantly prolonged OS and DFS before and after PSM (P < 0.05). But no significant difference was found in OS and DFS for NNSM patients after PSM (P > 0.05). Conclusion: Postoperative NSM is a good prognostic factor for patients with mid-thoracic esophageal squamous cell carcinoma, postoperative adjuvant chemoradiotherapy was recommended for those group, thereby gaining survival benefits.

Comparison of the effect of postoperative radiotherapy with surgery alone for esophagus squamous cell carcinoma patients: A meta-analysis.

BACKGROUND: This meta-analysis was conducted to evaluate the effect of postoperative radiotherapy for patients having esophagus squamous cell carcinoma after radical surgery. METHODS: A comprehensive research was performed in Pubmed, Embase and Cochrane Library electronic databases from inception until December 10, 2017. We collected all published full articles about comparison of surgery plus postoperative radiotherapy with surgery alone. RESULTS: Four randomized-controlled trials (RCTs) with 1050 participants and 8 non-randomized-controlled trials with 3248 participants were included and evaluated separately. The risk ratio rate and its 95% confidence interval (CI) were calculated. Both RCTs and non-randomized-controlled trials (NRCTs) groups showed a significant increase in 3-year overall survival (OS) rate (RRRCT = 0.89, 95% CI: 0.80-0.99; RRNRCT = 0.82, 95% CI: 0.76-0.88) and decrease locoregional recurrence rate (RRRCT = 0.53, 95% CI: 0.43-0.66; RRNRCT = 0.47, 95% CI: 0.32-0.69) after postoperative radiotherapy compared with surgery alone. The 5-year OS rate in the group of NRCTs was markedly enhanced (RR = 0.87, 95% CI: 0.82-0.92), while that of the RCTs group was not enhanced in a significant way (RR = 0.84, 95% CI: 0.70-1.02). Subgroup analysis based on pathological lymph node status revealed that postoperative radiotherapy could improve OS regardless of pathological lymph node status (pathological lymph node positive patients: RR5-year os-RCT = 0.81, 95% CI: 0.70-0.93; RR5-year os-NRCT = 0.87, 95% CI: 0.80-0.94; Pathological lymph node negative patients: RR3-year os-RCT = 0.76, 95% CI: 0.59-0.96; RR3-year os-NRCT = 0.52, 95% CI: 0.30-0.89). No effect on distant recurrence rate was detected. Adverse effects induced by postoperative radiotherapy were comparatively modest and tolerable. CONCLUSION: Polled results yielded that postoperative radiotherapy was promising in improving OS and reducing the locoregional recurrence rate. More large-scale up-to-date RCTs are needed to further validate the use of postoperative radiotherapy in modern practice.

Efficacy and safety of Tripterygium wilfordii Hook F for CKD in Mainland China: A systematic review and meta-analysis.

Tripterygium wilfordii Hook F (TwHF) is a promising Chinese traditional medicine used to significantly reduce proteinuria and improve renal function. However, its efficacy and safety in treatment of chronic kidney disease need to be further explored in order to promote its application in clinics. This review compared the efficacy and safety of TwHF with the placebo, conventional Western medicine and other immunosuppressive medicine in a range of kidney disorders. One hundred three randomized controlled trials were included. TwHF therapy decreased 24-hr proteinuria by 0.59 g/day (95% confidence interval [CI; -0.68, -0.50]), serum creatinine level by 1.93 µmol/L (95% CI [-3.69, -0.17]), and blood urea nitrogen level by 0.24 mmol/L (95% CI [-0.41, -0.07]); increased the total effective rate by 27% (95% CI [1.24, 1.30]); and decreased the incidence of adverse reactions by 19% (95% CI [0.68, 0.96]) overall. Meta regression results showed that the duration of therapy and mean age of participants were the major sources of high heterogeneity. Sensitivity analysis demonstrated that our statistic results were relatively stable and credible. The present findings suggested that TwHF possibly has nephroprotective effects by decreasing proteinuria, serum creatinine level, and blood urea nitrogen level and no more adverse reactions compared with control group in most kidney disorders. However, these findings still need to be further confirmed by high-quality trials.

Curcumin combined with oxaliplatin effectively suppress colorectal carcinoma in vivo through inducing apoptosis.

Studies have shown chemopreventive and/or chemotherapeutic effects of several curcumin-based combinatorial treatments on colorectal cancer cells. However, their in vivo effects remain unclear. This study has demonstrated the therapeutic effect of curcumin and oxaliplatin, alone or in combination, on subcutaneously xenografted LoVo human colorectal cancer cells in immunodeficient (nu/nu) mice in vivo. Combinatorial administration of curcumin and oxaliplatin evidently inhibited the growth of colorectal cancer in nude mice, which was significantly more effective than either agent alone. Curcumin combined with oxaliplatin treatment induced apoptosis, accompanied by ultrastructural changes and cell cycle arrest in S and G2/M phases. Further mechanism analysis indicated that while the number of apoptotic tumor cells and the expression of Bax, caspase-3, and poly (ADP-ribose) polymerase (PARP) increased significantly, the expression of Bcl-2, survivin, HSP70, pro-caspase-3, and pro-PARP were dramatically suppressed in tumor cells after the treatment with combinatorial curcumin and oxaliplatin for 22 days. Taken together, the present study has demonstrated that administration of combined curcumin and oxaliplatin effectively suppressed colorectal carcinoma in vivo through inducing apoptosis and thus may provide an effective treatment for colorectal carcinoma.

Force activates smooth muscle alpha-actin promoter activity through the Rho signaling pathway.

In pressure or volume overload, hypertrophic growth of the myocardium is associated with myofibroblast differentiation, a process in which cardiac fibroblasts express smooth muscle alpha-actin (SMA). The signaling mechanisms that mediate force-induced myofibroblast differentiation and SMA expression are not defined. We examined the role of the Rho-Rho-kinase pathway in force-induced SMA expression in fibroblasts using an in vitro model system that applies static tensile forces (0.65 pN/microm(2)) to integrins via collagen-coated magnetite beads. Force maximally induced RhoA activation at 10 minutes that was localized to force application sites and required intact actin filaments. Force application induced phosphorylation of LIM kinase (5-10 minutes) and an early dephosphorylation of cofilin (5 minutes) that was followed by prolonged cofilin phosphorylation. These responses were blocked by Y27632, an inhibitor of Rho kinase. Force promoted actin filament assembly at force application sites (10-20 minutes), a process that required Rho kinase and cofilin. Force application induced nuclear translocation of the transcriptional co-activator MRTF-A but not MRTF-B. Nuclear translocation of MRTF-A required Rho kinase and intact actin filaments. Force caused 3.5-fold increases of SMA promoter activity that were completely blocked by transfection of cells with dominant-negative MRTF-A or by inhibition of Rho kinase or by actin filament disassembly. These data indicate that mechanical forces mediate actin assembly through the Rho-Rho-kinase-LIMK cofilin pathway. Force-mediated actin filament assembly promotes nuclear translocation of MRTF and subsequent activation of the SMA promoter to enhance SMA expression.

Mechanical force activates eIF-2alpha phospho-kinases in fibroblast.

Mechanical forces can induce differentiation of fibroblasts into myofibroblasts, a process which requires activation of the MAP kinase p38. Currently, the identification of other phospho-kinases involved in myofibroblast differentiation has not been explored. We applied static tensile forces to rat cardiac fibroblasts via collagen-coated magnetite beads and examined activation of protein phospho-kinases by the Kinexus phospho-antibody screening system. Of 75 candidate protein kinases screened, 39 were detected and, of these, 31 phospho-kinases were analyzed. Following force application, 12 out of 31 phospho-kinases exhibited increases of phosphorylation including PKR (>4-fold), MKK3 (3-fold), MKK6 ( approximately 2-fold), and p38 ( approximately 2-fold). In several types of mechanically sensitive, contractile fibroblasts including rat cardiac, human gingival, and Rat-2 fibroblasts, tensile forces increased eIF-2alpha phosphorylation, a downstream effector of PKR. We conclude that phospho-antibody screening is an efficient method for discovery of novel mechanical force-induced phospho-kinases and force can activate eIF-2alpha phospho-kinases in fibroblasts.

The removal of extracellular calcium: a novel mechanism underlying the recruitment of N-methyl-D-aspartate (NMDA) receptors in neurotoxicity.

The involvement of NMDA-type glutamate receptor in neuronal injury established in experimental stroke and neurotrauma models has been recently challenged by failures in treatment of stroke/neurotrauma patients with NMDA receptor antagonists. NMDA receptor activity is known to be essential for mediating a multitude of physiological functions. However, how NMDA receptors are recruited to cause neuronal injury remains unclear. Here we report that the time period during which initial NMDA receptor up-regulation occurs is critical for the recruitment of NMDA receptors causing neuronal injury during extracellular calcium (Ca2+) reperfusion in cultured hippocampal neurons, and represents the key period for neuronal protection by NMDA receptor antagonists. Furthermore, we identified that via intracellular sodium (Na+), extracellular Ca2+ depletion induces the up-regulation of NMDA receptor gating. Taken together, our study provides direct experimental evidence suggesting that determination of when and how NMDA receptors are recruited to cause neurotoxicity is essential for guiding treatment via antagonism of NMDA receptor functions.

A functional interaction of sodium and calcium in the regulation of NMDA receptor activity by remote NMDA receptors.

The NMDA receptor is an important subtype glutamate receptor that acts as a nonselective cation channel highly permeable to both calcium (Ca2+) and sodium (Na+). The activation of NMDA receptors produces prolonged increases of intracellular Ca2+ concentration ([Ca2+]i) and thereby triggers downstream signaling pathways involved in the regulation of many physiological and pathophysiological processes. Previous studies have focused on how Ca2+ or Na+ affects NMDA receptor activity in isolation. Specifically, [Ca2+]i increase may downregulate NMDA channels and thus is considered an important negative feedback mechanism controlling NMDA receptor activity, whereas an increase in intracellular Na+ concentration ([Na+]i) may upregulate NMDA channel activity. Thus so that the activity-dependent regulation of NMDA receptors and neuroplasticity may be further understood, a critical question that has to be answered is how an individual NMDA receptor may be regulated when both of these ionic species flow into neurons during the same time period via neighboring activated NMDA receptors. Here we report that the gating of a NMDA channel is regulated by the activation of remote NMDA receptors via a functional Na+-Ca2+ interaction and that during the activation of NMDA receptors Na+ influx potentiates Ca2+ influx on one hand and overcomes Ca2+-induced inhibition of NMDA channel gating on the other hand. Furthermore, we have identified that a critical increase (5 +/- 1 mM) in [Na+]i is required to mask the effects of Ca2+ on NMDA channel gating in cultured hippocampal neurons. Thus cross talk between NMDA receptors mediated by a functional Na+-Ca2+ interaction is a novel mechanism regulating NMDA receptor activity.