Comparison of SOX and CAPOX in patients with advanced gastric cancer after laparoscopic D2 gastrectomy: A randomized controlled trial.

BACKGROUND: Optimal adjuvant chemotherapy after laparoscopic surgery in gastric cancer (GC) patients is still undefined. We aimed to evaluate the efficacy of S-1 plus oxaliplatin (SOX) and capecitabine plus oxaliplatin (CAPOX) in patients with GC after laparoscopic gastrectomy. METHODS: A non-inferiority randomized controlled clinical trial was performed in China. Patients with advanced GC who underwent laparoscopic D2 gastrectomy were randomly assigned to receive SOX and CAPOX regimens. RESULTS: In total, 191 patients were screened between May 2018 and June 2019, and 140 (73.3%) were included in the modified intent-to-treat analysis (mITT), of whom 69 and 71 were assigned to the SOX and CAPOX groups, respectively. The SOX group had similar 3-year overall survival (OS) and disease-free survival to the CAPOX group. Subgroup analysis revealed significantly better OS in the SOX group for male patients ([HR] = 0.395; 95% [CI], 0.153-1.019; p = 0.045), age >60 (HR = 0.219; 95% [CI], 0.064-0.753; p = 0.016), tumors in the gastric antrum (HR = 0.273; 95% [CI], 0.076-0.981; p = 0.047), and moderately differentiated tumors (HR = 0.338; 95% [CI], 0.110-1.041; p = 0.041). There were no significant differences observed in terms of adverse events and recurrence patterns between the two groups. CONCLUSION: Adjuvant SOX was non-inferior to CAPOX treatments for patients with GC who underwent curative laparoscopic D2 gastrectomy. For male patients, aged >60 years, tumors in the gastric antrum, and moderately differentiated tumors, adjuvant SOX may achieve an improvement compared with CAPOX.

Evaluating intra-fractional tumor motion in lung stereotactic radiotherapy with deep inspiration breath-hold.

PURPOSE: To evaluate the intra-fractional tumor motion in lung stereotactic body radiotherapy (SBRT) with deep inspiration breath-hold (DIBH), and to investigate the adequacy of the current planning target volume (PTV) margins. METHODS: Twenty-eight lung SBRT patients with DIBH were selected in this study. Among the lesions, twenty-three were at right or left lower lobe, two at right middle lobe, and three at right or left upper lobe. Post-treatment gated cone-beam computed tomography (CBCT) was acquired to quantify the intra-fractional tumor shift at each treatment. These obtained shifts were then used to calculate the required PTV margin, which was compared with the current applied margin of 5 mm margin in anterior-posterior (AP) and right-left (RL) directions and 8 mm in superior-inferior (SI) direction. The beam delivery time was prolonged with DIBH. The actual beam delivery time with DIBH (Tbeam_DIBH) was compared with the beam delivery time without DIBH (Tbeam_wo_DIBH) for the corresponding SBRT plan. RESULTS: A total of 113 treatments were analyzed. At six treatments (5.3%), the shifts exceeded the tolerance defined by the current PTV margin. The average shifts were 0.0 ± 1.9 mm, 0.1±1.5 mm, and -0.5 ± 3.7 mm in AP, RL, and SI directions, respectively. The required PTV margins were determined to be 4.5, 3.9, and 7.4 mm in AP, RL, and SI directions, respectively. The average Tbeam_wo_DIBH and Tbeam_DIBH were 2.4 ± 0.4 min and 3.6 ± 1.5 min, respectively. The average treatment slot for lung SBRT with DIBH was 25.3 ± 7.9 min. CONCLUSION: Intra-fractional tumor motion is the predominant source of treatment uncertainties in CBCT-guided lung SBRT with DIBH. The required PTV margin should be determined based on data specific to each institute, considering different techniques and populations. Our data indicate that our current applied PTV margin is adequate, and it is possible to reduce further in the RL direction. The time increase of Tbeam_DIBH, relative to the treatment slot, is not clinically significant.

Clinical outcome and prognostic factors of T4N0M0 colon cancer after R0 resection: A retrospective study.

BACKGROUND: Paradoxically, patients with T4N0M0 (stage II, no lymph node metastasis) colon cancer have a worse prognosis than those with T2N1-2M0 (stage III). However, no previous report has addressed this issue. AIM: To screen prognostic risk factors for T4N0M0 colon cancer and construct a prognostic nomogram model for these patients. METHODS: Two hundred patients with T4N0M0 colon cancer were treated at Tianjin Medical University General Hospital between January 2017 and December 2021, of which 112 patients were assigned to the training cohort, and the remaining 88 patients were assigned to the validation cohort. Differences between the training and validation groups were analyzed. The training cohort was subjected to multivariate analysis to select prognostic risk factors for T4N0M0 colon cancer, followed by the construction of a nomogram model. RESULTS: The 3-year overall survival (OS) rates were 86.2% and 74.4% for the training and validation cohorts, respectively. Enterostomy (P = 0.000), T stage (P = 0.001), right hemicolon (P = 0.025), irregular review (P = 0.040), and carbohydrate antigen 199 (CA199) (P = 0.011) were independent risk factors of OS in patients with T4N0M0 colon cancer. A nomogram model with good concordance and accuracy was constructed. CONCLUSION: Enterostomy, T stage, right hemicolon, irregular review, and CA199 were independent risk factors for OS in patients with T4N0M0 colon cancer. The nomogram model exhibited good agreement and accuracy.

Minimizing normal tissue low dose bath for left breast Volumetric Modulated Arc Therapy (VMAT) using jaw offset.

PURPOSE: With proper beam setup and optimization constraints in the treatment planning system, volumetric modulated arc therapy (VMAT) can improve target dose coverage and conformity while reducing doses to adjacent structures for whole breast radiation therapy. However, the low-dose bath effect on critical structures, especially the heart and the ipsilateral lung, remains a concern. In this study, we present a VMAT technique with the jaw offset VMAT (JO-VMAT) to reduce the leakage and scatter doses to critical structures for whole breast radiation therapy. MATERIALS AND METHODS: The data of 10 left breast cancer patients were retrospectively used for this study. CT images were acquired on a CT scanner (GE, Discovery) with the deep-inspiration breath hold (DIBH) technique. The planning target volumes (PTVs) and the normal structures (the lungs, the heart, and the contralateral breast) were contoured on the DIBH scan. A 3D field-in-field plan (3D-FiF), a tangential VMAT (tVMAT) plan, and a JO-VMAT plan were created with the Eclipse treatment planning system. An arc treatment field with the x-jaw closed across the central axis creates a donut-shaped high-dose distribution and a cylinder-shaped low-dose volume along the central axis of gantry rotation. Applying this setup with proper multi-leaf collimator (MLC) modulation, the optimized plan potentially can provide sufficient target coverage and reduce unnecessary irradiation to critical structures. The JO-VMAT plans involve 5-6 tangential arcs (3 clockwise arcs and 2-3 counterclockwise arcs) with jaw offsets. The plans were optimized with objective functions specified to achieve PTV dose coverage and homogeneity; For organs at risk (OARs), objective functions were specified individually for each patient to accomplish the best achievable treatment plan. For tVMAT plans, optimization constraints were kept the same except that the jaw offset was removed from the initial beam setup. The dose volume histogram (DVH) parameters were generated for dosimetric evaluation of PTV and OARs. RESULTS: The D95% to the PTV was greater than the prescription dose of 42.56 Gy for all the plans. With both VMAT techniques, the PTV conformity index (CI) was statistically improved from 0.62 (3D-FiF) to 0.83 for tVMAT and 0.84 for JO-VMAT plans. The difference in the homogeneity index (HI) was not significant. The Dmax to the heart was reduced from 12.15 Gy for 3D-FiF to 8.26 Gy for tVMAT and 7.20 Gy for JO-VMAT plans. However, a low-dose bath effect was observed with tVMAT plans to all the critical structures including the lungs, the heart, and the contralateral breast. With JO-VMAT, the V5Gy and V2Gy of the heart were reduced by 32.7% and 15.4% compared to 3D-FiF plans. Significantly, the ipsilateral lung showed a reduction in mean dose (4.65-3.44 Gy) and low dose parameters (23.4% reduction for V5Gy and 10.7% reduction for V2Gy) for JO-VMAT plans compared to the 3D-FiF plans. The V2Gy dose to the contralateral lung and breast was minimal with JO-VMAT techniques. CONCLUSION: A JO-VMAT technique was evaluated in this study and compared with 3D-FiF and tVMAT techniques. Our results showed that the JO-VMAT technique can achieve clinically comparable coverage and homogeneity and significantly improve dose conformity within PTV. Additionally, JO-VMAT eliminated the low-dose bath effect at all OARs evaluation metrics including the ipsilateral/contralateral lung, the heart, and the contralateral breast compared to 3D-FiF and tVMAT. This technique is feasible for the whole breast radiation therapy of left breast cancers.

Role of extracellular vesicles in castration-resistant prostate cancer.

Prostate cancer (PCa) is a common health threat to men worldwide, and castration-resistant PCa (CRPC) is the leading cause of PCa-related deaths. Extracellular vesicles (EVs) are lipid bilayer compartments secreted by living cells that are important mediators of intercellular communication. EVs regulate the biological processes of recipient cells by transmitting heterogeneous cargoes, contributing to CRPC occurrence, progression, and drug resistance. These EVs originate not only from malignant cells, but also from various cell types within the tumor microenvironment. EVs are widely dispersed throughout diverse biological fluids and are attractive biomarkers derived from noninvasive liquid biopsy techniques. EV quantities and cargoes have been tested as potential biomarkers for CRPC diagnosis, progression, drug resistance, and prognosis; however, technical barriers to their clinical application continue to exist. Furthermore, exogenous EVs may provide tools for new therapies for CRPC. This review summarizes the current evidence on the role of EVs in CRPC.

Evaluation of different scoring systems in the prediction of complications, morbidity, and mortality after laparoscopic radical gastrectomy.

BACKGROUND: This retrospective study aimed to assess the suitability of POSSUM and its modified versions, E-PASS and its modified score, SRS, and SORT scores for predicting postoperative complications and mortality in patients undergoing laparoscopic radical gastrectomy for gastric cancer. MATERIALS AND METHODS: Data analysis was performed on 349 patients who underwent laparoscopic radical gastrectomy at Tianjin Medical University General Hospital between January 2016 and December 2021. The discriminative ability of the scoring systems was evaluated using the area under the receiver operating characteristic curve (AUC). The primary endpoint focused on the prediction of postoperative complications, while the secondary endpoint assessed the prediction of postoperative mortality. RESULTS: Among the scoring systems evaluated, the modified E-PASS (mE-PASS) score exhibited the highest AUC (0.846) and demonstrated the highest sensitivity (81%) and specificity (79%) for predicting postoperative complications. All other scores, except for POSSUM, showed moderate discriminative ability in predicting complications. In terms of predicting postoperative mortality, the E-PASS score had the highest AUC (0.978), while the mE-PASS score displayed the highest sensitivity (76%) and specificity (90%). Notably, both E-PASS and mE-PASS scores exhibited excellent discriminative ability. CONCLUSIONS: The P-POSSUM, O-POSSUM, E-PASS, mE-PASS, SRS, and SORT scoring systems are useful tools for predicting postoperative outcomes in laparoscopic radical gastrectomy. Among them, the mE-PASS score demonstrated the best predictive power. However, the POSSUM system could only be applicable to predict postoperative mortality.

Multi-objective optimization of cortical bone grinding parameters based on particle swarm optimization.

Grinding is a fundamental operation in craniotomy. Suitable grinding parameters will not only reduce force damage, but also ensure grinding efficiency. In this study, the regression equations of material removal rate and grinding force were obtained based on the theory of cortical bone grinding and full factorial test results, a multi-objective optimization based on the particle swarm algorithm was proposed for optimizing the grinding parameters: spindle speed, feed speed, and grinding depth in the grinding process. Two conflicting objectives, minimum grinding force and maximum material removal rate, were optimized simultaneously. The results revealed that the optimal grinding parameter combination and optimization results were as follows: spindle speed of 5000 rpm, feed rate of 60 mm/min, grinding depth of 0.6 mm, grinding force of 15.1 N, and material removal rate of 113.8 mm3/min. The parameter optimization result can provide theoretical guidance for selecting cortical bone grinding parameters in actual craniotomy.

Resection of sigmoid cancer with bladder invasion using laparoscopic combined with a cystoscopic holmium laser: an innovative surgical procedure.

The aim of this study was to introduce a new surgical procedure for the resection of sigmoid colon tumours invading the bladder by combining laparoscopy and cystoscopy, and the feasibility and safety of the method were verified. The data of 6 patients with sigmoid colon cancer invading the bladder in a tertiary hospital in Chongqing from January 2020 to October 2022 were collected, sigmoid colon tumour resection was performed by this procedure, and the data related to the surgery were recorded. All six patients successfully underwent sigmoid colon tumour resection, and all sigmoid colon and bladder resections had negative margins. The mean total operative time was 211.66 ± 27.33 min, and the mean resection time of the bladder tumour was 22.16 ± 4.63 min. The median blood loss was 100 ml, and the mean number of retrieved lymph nodes was nineteen. There were no serious intraoperative complications in any of the cases. After operation, the first flatus and defecation were 4 and 4.5 days, respectively. The mean time of drainage tube retention and the time of bladder flushing were 3 and 1.5 days, respectively. The mean time of urinary tube retention was 7.5 days. There were no intestinal obstructions, dysuria, or other complications. For patients with sigmoid colon tumours invading the bladder, this method can effectively resect sigmoid colon tumours and minimize the loss of bladder tissue at the same time, which helps to prolong the survival of these patients. The surgical method is safe, reliable, and feasible.

Different Methods of Minimally Invasive Esophagojejunostomy After Total Gastrectomy for Gastric Cancer: Outcomes from Two Experienced Centers.

BACKGROUND: Esophagojejunostomy after minimally invasive total gastrectomy (MITG) for gastric cancer (GC) is technically challenging. Failure of the esophagojejunal anastomosis can lead to significant morbidity, leading to short- and long-term quality of life (QoL) impairment or mortality. The optimal reconstruction method following MITG remains controversial. We evaluated outcomes of minimally invasive esophagojejunostomy after laparoscopic or robotic total gastrectomies. METHODS: We retrospectively reviewed MITG patients between 2015 and 2020 at two high-volume centers in China and the United States. Eligible patients were divided into groups by different reconstruction methods. We compared clinicopathologic characteristics, postoperative outcomes, including complication rates, overall survival rate (OS), disease-free survival rate (DFS), and patient-reported QoL. RESULTS: GC patients (n = 105) were divided into intracorporeal esophagojejunostomy (IEJ, n = 60) and extracorporeal esophagojejunostomy (EEJ, n = 45) groups. EEJ had higher incidence of wound infection (8.3% vs 13.3%, P = 0.044) and pneumonia (21.7% vs 40.0%, P = 0.042) than IEJ. The linear stapler (LS) group was inferior to the circular stapler (CS) group in reflux [50.0 (11.1-77.8) vs 44.4 (0.0-66.7), P = 0.041] and diarrhea [33.3 (0.0-66.7) vs 0.0 (0.0-66.7), P = 0.045] while LS was better than CS for dysphagia [22.2 (0.0-33.3) vs 11.1 (0.0-33.3), P = 0.049] and eating restrictions [33.3 (16.7-58.3) vs 41.7 (16.7-66.7), P = 0.029] at 1 year. OS and DFS did not differ significantly between LS and CS. CONCLUSIONS: IEJ anastomosis generated better results than EEJ. LS was associated with a better patient eating experience, but more diarrhea and reflux compared with CS. Clinical and patient-reported outcomes show the superiority of IEJ with the LS reconstruction method in MITG for GC.

Optimal postoperative surveillance strategies for cancer survivors with gastric neuroendocrine carcinoma based on individual risk: a multicenter real-world cohort study.

BACKGROUND: The best follow-up strategy for cancer survivors after treatment should balance the effectiveness and cost of disease detection while detecting recurrence as early as possible. Due to the low incidence of gastric neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma [G-(MA)NEC], high-level evidence-based follow-up strategies is limited. Currently, there is a lack of consensus among clinical practice guidelines regarding the appropriate follow-up strategies for patients with resectable G-(MA)NEC. MATERIALS AND METHODS: The study included patients diagnosed with G-(MA)NEC from 21 centers in China. The random forest survival model simulated the monthly probability of recurrence to establish an optimal surveillance schedule maximizing the power of detecting recurrence at each follow-up. The power and cost-effectiveness were compared with the National Comprehensive Cancer Network, European Neuroendocrine Tumor Society, and European Society for Medical Oncology Guidelines. RESULTS: A total of 801 patients with G-(MA)NEC were included. The patients were stratified into four distinct risk groups utilizing the modified TNM staging system. The study cohort comprised 106 (13.2%), 120 (15.0%), 379 (47.3%), and 196 cases (24.5%) for modified groups IIA, IIB, IIIA, and IIIB, respectively. Based on the monthly probability of disease recurrence, the authors established four distinct follow-up strategies for each risk group. The total number of follow-ups 5 years after surgery in the four groups was 12, 12, 13, and 13 times, respectively. The risk-based follow-up strategies demonstrated improved detection efficiency compared to existing clinical guidelines. Further Markov decision-analytic models verified that the risk-based follow-up strategies were better and more cost-effective than the control strategy recommended by the guidelines. CONCLUSIONS: This study developed four different monitoring strategies based on individualized risks for patients with G-(MA)NEC, which may improve the detection power at each visit and were more economical, effective. Even though our results are limited by the biases related to the retrospective study design, we believe that, in the absence of a randomized clinical trial, our findings should be considered when recommending follow-up strategies for G-(MA)NEC.

Dual-modality and Noninvasive Diagnostic of MNP-PEG-Mn Nanoprobe for Renal Fibrosis Based on Photoacoustic and Magnetic Resonance Imaging.

To date, imaging-guided multimodality therapy is important to improve the accuracy of the diagnosis of renal fibrosis, and nanoplatforms for imaging-guided multimodality diagnosis are gaining more and more attention. There are many limitations and deficiencies in clinical use for early-stage diagnosis of renal fibrosis, and multimodal imaging can contribute more thoroughly and provide in-detail information for effective clinical diagnosis. Melanin is an endogenous biomaterial, and we developed an ultrasmall particle size melanin nanoprobe (MNP-PEG-Mn) based on photoacoustic (PA) and magnetic resonance (MR) dual-modal imaging. MNP-PEG-Mn nanoprobe, with the average diameter about 2.7 nm, can be passively targeted for accumulation in the kidney, and it has excellent free radical scavenging and antioxidant abilities without further exacerbating renal fibrosis. Using the normal group signal as a control, the dual-modal imaging results showed that the MR imaging (MAI) and PA imaging (PAI) signals reached the strongest at 6 h when MNP-PEG-Mn entered the 7 day renal fibrosis group via the left vein of the tail end of the mice; however, the strength of the dual-modal imaging signal and the gradient of signal change were significantly weaker in the 28 day renal fibrosis group than in the 7 day renal fibrosis group and normal group. The phenomenon preliminarily indicates that as a PAI/MRI dual-modality contrast medium candidate, MNP-PEG-Mn has outstanding ability in clinical application potential.

Melanin theranostic nanoplatform as an efficient drug delivery system for imaging-guided renal fibrosis therapy.

As renal fibrosis nanotherapeutics, the endogenous biomaterial melanin not only has natural biocompatibility and biodegradability but also has inherent photoacoustic imaging ability and certain anti-inflammatory effects. These properties determine that melanin can not only as a carrier of medication but also track the biodistribution and renal uptake of drugs in vivo by photoacoustic imaging in real-time. Curcumin is a natural compound with biological activity, which has excellent ROS scavenging ability and good anti-inflammatory property. These materials appear more advantages in the development of nanoscale diagnostic and therapeutic platforms for future clinical translation. Herein, this study developed curcumin-loaded melanin nanoparticles (MNP-PEG-CUR NPs) as an efficient medication delivery system for photoacoustic imaging guidance renal fibrosis treatment. The nanoparticles are about 10 nm in size, exhibit good renal clearance efficiency, excellent photoacoustic imaging ability, and good in vitro and in vivo biocompatibility. These preliminary results indicated that MNP-PEG-CUR have clinically applicable potential as a therapeutic nanoplatform for renal fibrosis.

Stromal Interaction Molecule 1 (STIM1) is a Potential Prognostic Biomarker and Correlates with Immune Infiltrates in Solid Tumors.

Increasing evidence has shown that stromal interaction molecule 1 (STIM1), a key subunit of store-operated Ca2+ entry (SOCE), is closely associated with tumor growth, development, and metastasis. However, there is no report of a comprehensive assessment of STIM1 in pan-cancer. This study aimed to perform a general analysis of STIM1 in human tumors, including its molecular characteristics, functional mechanisms, clinical significance, and immune infiltrates correlation based on pan-cancer data from The Cancer Genome Atlas (TCGA). Gene expression analysis was investigated using TCGA RNA-seq data, the Tumor Immune Estimation Resource (TIMER). Phosphorylation analysis was undertaken using the Clinical Proteomic Tumor Analysis Consortium (CP-TAC) and the PhosphoNET database. Genetic alterations of STIM1 were analyzed using cBioPortal. Prognostic analysis was via the R package "survival" function and the Kaplan-Meier plotter. Functional enrichment analysis was via by the R package "cluster Profiler" function. The association between STIM1 and tumor-infiltrating immune cells and immune markers was by the R package "GSVA" function and TIMER. STIM1 was differentially expressed and associated with distinct clinical stages in multiple tumors. The phosphorylation of STIM1 at S673 is highly expressed in clear cell renal carcinoma and lung adenocarcinoma tumors compared to normal tissues. STIM1 genetic alterations correlate with poor prognosis in several tumors, including ovarian cancer and lung squamous cell carcinomas. High STIM1 expression is associated with good or poor prognosis across diverse tumors. Overall survival (OS) analysis indicated that STIM1 is a favorable prognostic factor for patients with BRCA, KIRC, LIHC, LUAD, OV, SARC, and UCEC, and is a risk prognostic factor for BLCA, KIRP, STAD, and UVM. There is a close correlation between STIM1 expression and immune cell infiltration, immune-regulated genes, chemokines, and immune checkpoints in a variety of tumors. STIM1 functions differently in diverse tumors, playing an oncogenic or antitumor role. Moreover, It may serve as a prognostic biomarker and an immunotherapy target across multiple tumors.

Wettability and biological responses of titanium surface's biomimetic hexagonal microstructure.

In this research, an experiment was conducted on how the surface wettability and biocompatibility of staplers' titanium nails impact the healing of gastrointestinal tissue. Firstly, the bionic hexagonal structure was prepared on the surface of Ti metal by laser processing technology, and the laser textured titanium samples were observed by scanning electron microscope. Then, the liquid-solid contact angle-measuring instrument was used to characterize the wettability of titanium samples. Finally, cells were cultured on the surface of different titanium samples, CCK8 assay and qRT-PCR were carried out to investigate cell adhesion and collagen secretion on the surface of different samples. The results showed that the bionic hexagonal surface increased the surface roughness, reduced the liquid-solid contact angle, and promoted the adhesion and collagen secretion of fibroblasts. The increased wettability provided a better growth environment for cell growth. Microtexture is an important factor affecting the behavior of cells and its size parameters regulate cell gene expression, which is worthy of further study.

Alteration of the gut microbiota profile in children with autism spectrum disorder in China.

Background: Autism spectrum disorder (ASD) is associated with alterations in the gut microbiome. However, there are few studies on gut microbiota of children with ASD in China, and there is a lack of consensus on the changes of bacterial species. Purpose: Autism spectrum disorder (ASD) is associated with alterations in the gut microbiome. However, there are few studies on gut microbiota of children with ASD in China, and there is a lack of consensus on the changes of bacterial species. Methods: We used 16S rRNA sequencing to analyze ASD children (2 to 12 years), HC (2 to 12 years). Results: Our findings showed that the α-diversity, composition, and relative abundance of gut microbiota in the ASD group were significantly different from those in the HC groups. Compared with the HC group, the α-diversity in the ASD group was significantly decreased. At the genus level, the relative abundance of g_Faecalibacterium, g_Blautia, g_Eubacterium_eligens_group, g_Parasutterella, g_Lachnospiraceae_NK4A136_group and g_Veillonella in ASD group was significantly increased than that in HC groups, while the relative abundance of g_Prevotella 9 and g_Agathobacter was significantly decreased than that in HC groups. In addition, KEGG pathway analysis showed that the microbial functional abnormalities in ASD patients were mainly concentrated in metabolic pathways related to fatty acid, amino acid metabolism and aromatic compound metabolism, and were partially involved in neurotransmitter metabolism. Conclusion: This study revealed the characteristics of gut microbiota of Chinese children with ASD and provided further evidence of gut microbial dysbiosis in ASD.

Chronic alcohol-induced dysbiosis of the gut microbiota and gut metabolites impairs sperm quality in mice.

Studies have indicated that the ethanol exposure impairs the gut microbiota, At the same time, high levels of alcohol exposure damage sperm in mice. However, whether the gut microbiota is involved in mediating the effects of alcohol on sperm quality remains unclear. This study aimed to assess the effect of chronic alcohol consumption on intestinal microbiota in mice and analyze the potential pathophysiological effect of altered intestinal microbiota on sperm quality. We established a mouse model of chronic alcohol consumption by allowing male C57 mice to freely ingest 10% ethanol for 10 weeks, and collected the fecal microbiota of the male mice in the chronic drinking group (alcohol) and the control group (control) and transplanted the specimens into the transplant groups (the alcohol-fecal microbiota transplantation [FMT] group and the control-FMT group). Sperm quality was significantly decreased in the alcohol-FMT group compared with the control-FMT group. Gut microbiota analysis revealed that the abundance of 11 operational taxonomic units (OTUs) was altered in the alcohol-FMT group. Nontargeted metabolomics identified 105 differentially altered metabolites, which were mainly annotated to amino acids, lipids, glycerophosphoethanolamine, organic oxygenic compounds, organic acids and their derivatives, steroids, and flavonoids. In particular, the oxidative phosphorylation pathway, which is the key to spermatogenesis, was significantly enriched in the alcohol-FMT group. Moreover, compared with the control-FMT group, the alcohol-FMT group presented significantly higher serum endotoxin and inflammatory cytokine levels, with more pronounced T cell and macrophage infiltration in the intestinal lamina propria and elevated levels of testicular inflammatory cytokines. In addition, RNA sequencing showed significant differences in the expression of testis-related genes between the alcohol-FMT group and the control-FMT group. In particular, the expression of genes involved in gamete meiosis, testicular mitochondrial function, and the cell division cycle was significantly reduced in alcohol-FMT mice. In conclusion, these findings indicated that intestinal dysbiosis induced by chronic alcohol consumption may be an important factor contributing to impaired sperm quality. Chronic alcohol consumption induces intestinal dysbiosis, which then leads to metabolic disorders, elevated serum endotoxin and inflammatory cytokine levels, testicular inflammation, abnormal expression of related genes, and ultimately, impaired sperm quality. These findings are potentially useful for the treatment of male infertility.

A pan-cancer analysis reveals the genetic alterations and immunotherapy of Piezo2 in human cancer.

Background: Piezo2 is a transmembrane-spanning ion channel protein implicated in multiple physiological processes, including cell proliferation and angiogenesis in many cell types. However, Piezo2 was recognized as representing a double-edged sword in terms of tumor growth. The prognostic and immunotherapeutic roles of Piezo2 in pan-cancer have not been reported. Methods: In this study, several databases available including the UCSC Xena database, HPA, TIDE, GSEA, and cBioportal were used to investigate the expression, alterations, associations with immune indicators, and prognostic roles of Piezo2 across pan-cancer. R software and Perl scripts were used to process the raw data acquired from the UCSC Xena database. Results: Based on processed data, our results suggested that Piezo2 expression levels were tissue-dependent in different tumor tissues. Meanwhile, the survival analysis reflected that patients suffering from KIRC, LUAD, and USC with high Piezo2 expression had good OS, while those suffering from KIRP and SARC with high Piezo2 expression had poor OS. In addition, our results showed that Piezo2 expression was associated with the infiltration of CD4+ T memory cells, mast cells, and dendritic cells. These results suggested that Piezo2 may involve tumor progression by influencing immune infiltration or regulating immune cell function. Further analysis indicated that Piezo2 could influence TME by regulating T-cell dysfunction. We also found that gene mutation was the most common genetic alteration of Piezo2. The GSEA analysis revealed that Piezo2 was associated with calcium ion transport, the activation of the immune response, antigen processing and presentation pathways. Conclusion: Our study showed the expression and prognostic features of Piezo2 and highlighted its associations with genetic alterations and immune signatures in pan-cancer. Moreover, we provided several novel insights for further research on the therapeutic potential of Piezo2.

CD40×HER2 bispecific antibody overcomes the CCL2-induced trastuzumab resistance in HER2-positive gastric cancer.

BACKGROUND: There was much hard work to study the trastuzumab resistance in HER2-positive gastric cancer (GC), but the information which would reveal this abstruse mechanism is little. In this study, we aimed to investigate the roles of tumor cell-derived CCL2 on trastuzumab resistance and overcome the resistance by treatment with the anti-CD40-scFv-linked anti-HER2 (CD40 ×HER2) bispecific antibody (bsAb). METHODS: We measured the levels of CCL2 expression in HER2-positive GC tissues, and revealed biological functions of tumor cell-derived CCL2 on tumor-associated macrophages (TAMs) and the trastuzumab resistance. Then, we developed CD40 ×HER2 bsAb, and examined the targeting roles on HER2 and CD40, to overcome the trastuzumab resistance without systemic toxicity. RESULTS: We found the level of CCL2 expression in HER2-postive GC was correlated with infiltration of TAMs, polarization status of infiltrated TAMs, trastuzumab resistance and survival outcomes of GC patients. On exposure to CCL2, TAMs decreased the M1-like phenotype, thereby eliciting the trastuzumab resistance. CCL2 activated the transcription of ZC3H12A, which increased K63-linked deubiquitination and K48-linked auto-ubiquitination of TRAF6/3 to inactivate NF-κB signaling in TAMs. CD40 ×HER2 bsAb, which targeted the CD40 to restore the ubiquitination level of TRAF6/3, increased the M1-like phenotypic transformation of TAMs, and overcame trastuzumab resistance without immune-related adversary effects (irAEs). CONCLUSIONS: We revealed a novel mechanism of trastuzumab resistance in HER2-positive GC via the CCL2-ZC3H12A-TRAF6/3 signaling axis, and presented a CD40 ×HER2 bsAb which showed great antitumor efficacy with few irAEs.

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.