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Neoadjuvant short-course radiotherapy combined with chemotherapy as total neoadjuvant therapy increases the pathological complete response rate for patients with locally advanced rectal cancer. The potential synergistic effects of combining radiotherapy and immunotherapy might benefit patients with locally advanced rectal cancer. We aimed to compare the efficacy and safety of short-course radiotherapy followed by capecitabine–oxaliplatin chemotherapy with or without immunotherapy as total neoadjuvant therapy in patients with locally advanced rectal cancer. SPRING-01 was a single-centre, open-label, phase 2, randomised controlled trial done at the Shandong Provincial Hospital, China. Patients were aged 18–85 years with an Eastern Cooperative Oncology Group performance status of 0–1 and had biopsy-confirmed, newly diagnosed, treatment-naive, primary, locally advanced rectal adenocarcinoma with at least one of the following features: clinical tumour stage T3–4 or greater, clinical nodal stage N1 or higher, extramural vascular invasion, mesorectal fascia involvement, or lateral lymph node metastasis. Participants were randomly assigned (1:1) to receive either sintilimab plus capecitabine–oxaliplatin or capecitabine–oxaliplatin alone. The randomisation sequence was generated using computer-generated random numbers with SAS software version 9.4, using a simple randomisation method without stratification or blocking, and allocation was concealed using opaque, sealed envelopes. Neither patients nor clinical staff were masked to treatment allocation; however, pathological assessments and data analyses were conducted in a blinded manner. Patients received short-course radiotherapy (5 × 5 Gy over 5 days) followed by six cycles of intravenous capecitabine–oxaliplatin chemotherapy (intravenous oxaliplatin 130 mg/m2 over 2 h on day 1, and oral capecitabine 1000 mg/m2 twice daily on days 1–14 of each 3-week cycle) with or without intravenous sintilimab (200 mg/m2 on day 1 of each 3-week cycle), starting 1 week after completion of radiotherapy. Total mesorectal excision surgery, was done 2–3 weeks after the completion of total neoadjuvant therapy. The primary endpoint was the pathological complete response rate in the intention-to-treat population. The trial was registered with the Chinese Clinical Trial Registry (ChiCTR2100052288). Between Oct 8, 2021, and Sept 26, 2023, 116 patients with locally advanced rectal cancer were screened, of whom 98 eligible patients were randomly assigned to the sintilimab plus capecitabine–oxaliplatin group (n=49) or the capecitabine–oxaliplatin group (n=49). 68 (69%) of 98 patients were male and 30 (31%) were female; all patients were Asian. Median follow-up was 25 months (IQR 20–32). The pathological complete response rate was significantly higher in the sintilimab plus capecitabine–oxaliplatin group than in the capecitabine–oxaliplatin group (29 [59·2%, 95% CI 45·4–72·9] vs 16 [32·7%, 19·5–45·8]; p=0·015). Postoperative complications occurred in 11 (24% [95% CI 12–37]) of 45 patients in the sintilimab plus capecitabine–oxaliplatin group and in five (11% [2–21]) of 44 in the capecitabine–oxaliplatin group. Treatment-related adverse events during neoadjuvant therapy occurred in 45 (92%) of 49 patients in the sintilimab plus capecitabine–oxaliplatin group and in 44 (90%) of 49 patients in the capecitabine–oxaliplatin group. The most common treatment-related adverse events in the sintilimab plus capecitabine–oxaliplatin group and the capecitabine–oxaliplatin group were thrombocytopenia (18 [37%] vs 26 [53%]), leukopenia (19 [39%] vs 26 [53%]), anaemia (27 [55%] vs 33 [67%]), nausea or vomiting (25 [51%] vs 27 [55%]), and diarrhoea (21 [43%] vs 24 [49%]). Grade 3–4 treatment-related adverse events were observed in 16 (33%) patients in the sintilimab plus capecitabine–oxaliplatin group and 17 (35%) patients in the capecitabine–oxaliplatin group. The most common grade 3–4 adverse event was thrombocytopenia, reported in six (12%) patients in the sintilimab plus capecitabine–oxaliplatin group and in 11 (22%) patients in the capecitabine–oxaliplatin group. Serious adverse events occurred in 15 (31%) of 49 patients in the sintilimab plus capecitabine–oxaliplatin group and in nine (18%) of 49 patients in the capecitabine–oxaliplatin group. The most common serious adverse event in both treatment groups was thrombocytopenia. One (2%) patient in the capecitabine–oxaliplatin group died from septic shock due to acute ileus. No treatment-related deaths occurred in the sintilimab plus capecitabine–oxaliplatin group. In patients with locally advanced rectal cancer, short-course radiotherapy combined with sintilimab and capecitabine–oxaliplatin as a total neoadjuvant treatment significantly increased the pathological complete response rate while maintaining manageable safety profile. These findings suggest that this regimen might be a promising neoadjuvant treatment approach for locally advanced rectal cancer. The National Natural Science Foundation of China; The Special Foundation for Taishan Scholars Program of Shandong Province; The Key Research and Development Program of Shandong Province; The Natural Science Foundation of Shandong Province; The China Postdoctoral Science Foundation; and Innovent Biologics. For the Chinese translation of the abstract see Supplementary Materials section.

BackgroundThe cholecystokinin-2/gastrin receptor (Cck2r) is expressed in corpus isthmus progenitor, enterochromaffin-like and parietal cells, regulating acid secretion and cell turnover. However, the role of gastrin on Cck2r progenitors during mucosal regeneration remains unexplored.ObjectiveTo study the role of gastrin-Cck2r axis and corpus progenitors during gastric injury and regeneration.DesignWe generated Cck2r-CreERT2; Gastrin-DTR-p2A-TdTomato; Rosa26-ZsGreen mice to trace corpus Cck2r+ progenitors during homeostasis and injury, under conditions of hypogastrinaemia and hypergastrinaemia. Injury models included acute ulceration, chronic H. pylori gastritis and N-Nitroso-N-Methylurea (MNU) exposure.ResultsHypergastrinaemia significantly expanded Cck2r+ isthmus progenitors, whereas hypogastrinaemia reduced them. Gastric ulceration induced a twofold elevation in plasma gastrin by day 14, antral G-cell expansion and complete ulcer healing by day 28. Gastrin infusion or proton pump inhibitor (PPI) treatment further elevated gastrin and promoted complete ulcer healing by day 14, whereas G-cell ablation minimised gastrin, impaired healing and abrogated the benefits of PPI (p<0.05). The vagus nerve, through the muscarinic receptor 3, mediated both gastrin elevations and Cck2r+ progenitor expansion during ulcer healing. G-cell ablation in H. pylori-infected mice increased colonisation and exacerbated inflammation, atrophy, metaplasia and dysplasia (p<0.05), while hypergastrinaemia was protective. Similarly, in the MNU model, G-cell ablation worsened gastric pathology while hypergastrinaemia mitigated it.ConclusionsWe report a novel role for G-cell-derived gastrin in ulcer healing. Hypogastrinaemia is a risk factor for poor ulcer healing, corpus atrophy and potentially cancer, while physiological gastrin responses are protective. PPI-induced hypergastrinaemia plays a key role in ulcer healing, and gastrin signalling may prevent gastric preneoplasia.

Pyroptosis is a form of programmed cell death driven by inflammatory caspases (caspase-1/4/5/11). Distinct from apoptosis, pyroptosis is characterized by the formation of membrane pores, cell swelling followed by rupture, and the release of cellular contents, along with the secretion of a wide range of pro-inflammatory cytokines. Pyroptosis can be activated through two primary pathways: the canonical pathway (caspase-1-dependent) and the non-canonical pathway (caspase-4/5/11-dependent). In recent years, the role of pyroptosis in tumor initiation, progression, and therapy has drawn significant attention, revealing its dual regulatory effects—both anti-tumor and tumor-promoting—highlighting its potential as a novel therapeutic target. Given its pivotal role in modulating anti-tumor immunity, the induction of pyroptosis emerges as a promising strategy to enhance the effectiveness of immunotherapy. To date, an increasing number of studies have explored the synergistic potential of combining pyroptosis-inducing strategies with immunotherapy, particularly immune checkpoint blockade, in cancer treatment.This review explores the molecular mechanisms underlying pyroptosis, and systematically summarizes the emerging evidence supporting pyroptosis as an immunogenic form of cell death that enhances immune checkpoint blockade efficacy and offers promising prospects for combination cancer therapies.

Obesity is a widespread metabolic disorder linked to various conditions, including type 2 diabetes, hypertension, fatty liver disease, sleep apnea, and hyperuricemia. It significantly impacts quality of life and economic productivity. Traditional methods like diet and lifestyle changes often fail to produce substantial weight loss. Consequently, emerging treatments such as anti-obesity medications, bariatric surgery, and fecal microbiota transplantation are becoming more prominent. Recent research emphasizes the role of hormones that communicate with the hypothalamus through the gut-brain axis, affecting appetite, insulin secretion, and body weight via specific signaling pathways. This review explores the role of key gastrointestinal hormones (GLP-1, PYY, ghrelin, CCK, GIP, leptin, and bile acids) and their signaling pathways in metabolic regulation. The present research systematically evaluates the impact of bariatric surgery on appetite modulation and certain metabolic functions through key signaling pathways, including GLP-1R, GHS-R1a, and FXR/TGR5.

Insulin resistance (IR) is the most common pathophysiological change in patients with type 2 diabetes mellitus (T2DM). Several recent studies have suggested that the gut microbiome and microbial metabolites are involved in the pathogenesis of IR. Bariatric surgery, as an effective treatment for T2DM, can markedly alleviate IR through mechanisms that have not been elucidated. In this review, we summarize the current evidence on the changes in the gut microbiome and microbial metabolites (including lipopolysaccharide, short-chain fatty acids, branched-chain amino acids, aromatic amino acids, bile acids, methylamines, and indole derivatives) after bariatric surgery. Additionally, we discuss the mechanisms that correlate the changes in microbial metabolites with the postoperative alleviation of IR. Furthermore, we discuss the prospect of bariatric surgery as a treatment for T2DM.

Background The platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP) level are markers that have been reported to predict the histological type of various tumors, and here, we evaluated their utility in predicting colorectal polyp histological types. Methods We retrospectively reviewed 172 patients with colorectal polyps who underwent endoscopic polypectomy. The associations between histological type and clinicopathologic parameters were assessed by multivariate analysis. Results The optimal PLR and CRP cut-off values were 113.32 and 0.39, respectively. The PLR ( P  = 0.002) and CRP ( P  = 0.009) values were associated with the histological type according to the univariate analysis, whereas low PLR ( P  ≤ 0.001) and CRP ( P  = 0.017) values were independent risk factors in the multivariate analysis together with maximum tumor diameter ( P  ≤ 0.001) and tumor number ( P  = 0.0014). Conclusions Preoperative PLR and CRP are correlated with the colorectal polyp histological type.

BackgroundSepsis is a life-threatening condition with high mortality. A few studies have emerged utilizing single-cell RNA sequencing (scRNA-seq) to analyze gene expression at the single-cell resolution in sepsis, but a comprehensive high-resolution analysis of blood antigen-presenting cells has not been conducted.MethodsAll published human scRNA-seq data were downloaded from the single cell portal database. After manually curating the dataset, we extracted all antigen-presenting cells, including dendritic cells (DCs) and monocytes, for identification of cell subpopulations and their gene profiling and intercellular interactions between septic patients and healthy controls. Finally, we further validated the findings by performing deconvolution analysis on bulk RNA sequencing (RNA-seq) data and flow cytometry.ResultsWithin the traditional DC populations, we discovered novel anergic DC subtypes characterized by low major histocompatibility complex class II expression. Notably, these anergic DC subtypes showed a significant increase in septic patients. Additionally, we found that a previously reported immunosuppressive monocyte subtype, Mono1, exhibited a similar gene expression profile to these anergic DCs. The consistency of our findings was confirmed through validation using bulk RNA-seq and flow cytometry, ensuring accurate identification of cell subtypes and gene expression patterns.ConclusionsThis study represents the first comprehensive single-cell analysis of antigen-presenting cells in human sepsis, revealing novel disease-associated anergic DC subtypes. These findings provide new insights into the cellular mechanisms of immune dysregulation in bacterial sepsis.

Purpose Malignant mesothelioma is a rare, aggressive cancer. Although the World Health Organization (WHO) histologic subtypes–epithelioid (best prognosis), biphasic, and sarcomatoid (worst prognosis)—provide baseline stratification, architectural and molecular features (e.g., aneuploidy, immune infiltration) introduce heterogeneity not fully captured by histotype alone. Methods Using The Cancer Genome Atlas (TCGA) data and an independent validation cohort, we found that TNM stage was not independently prognostic after multivariable adjustment. We therefore developed a clinicomolecular model integrating transcriptomic and clinicopathological variables. Differential expression analysis of TCGA tumors identified 1,055 genes associated with poor prognosis (FDR < 0.05, |log2FC| > 1). Least absolute shrinkage and selection operator (LASSO) followed by multivariate Cox regression yielded five independent predictors: pathological subtype, receipt of pharmaceutical (systemic) therapy, and tumor expression of SPAG5, CORO1C, and SGCE. The final score was: RiskScore = 1.590 × (pathological type) − 2.258 × (pharmaceutical therapy) + 3.048 × SPAG5 + 1.652 × CORO1C + 0.908 × SGCE. Results In the TCGA cohort, high-risk patients had significantly shorter overall survival (log-rank p  < 0.001), and time-dependent ROC AUCs exceeded 0.70 at 1–5 years. In the validation cohort, the RiskScore significantly stratified overall survival (log-rank p  < 0.001) and demonstrated superior predictive accuracy over both TNM staging and the established European Organization for Research and Treatment of Cancer (EORTC) prognostic score. Conclusion This clinicomolecular model provides prognostic discrimination superior to TNM stage and EORTC score, offering a robust tool for risk-stratified management of mesothelioma.

Background Harmonic ACE +7 Shears with Advanced Hemostasis is an upgraded ultrasonic device, an ultrasonic surgical and electrosurgical system (USES). The study aimed to evaluate the economic and clinical effectiveness of the USES compared with the conventional ultrasonic scalpel (CUS) in gastrectomy. Methods We conducted a single-center, retrospective cohort study using the electronic medical records in China. We collected intraoperative and postoperative data from gastric cancer patients who underwent the endoscope-assisted distal gastrectomy from 2018 to June 30, 2019. Procedure-related costs were estimated. We used linear regression by controlling a set of covariates to assess the effect of USES on outcomes. Result Out of 87 eligible patients, the USES group (40 patients) and CUS group (47 patients) were comparable in terms of age, medical history and stages of cancer. Compared with the CUS, the USES saved 4.27 hemoclips per person (95% CI 0.57–7.97, p < 0.05) and 34.18 ml intraoperative blood per person (95% CI 8.74–59.62 ml, p < 0.05), respectively. Postoperative length of stay (LOS) was shorter in the USES group (7.90 ± 1.95 vs. 9.26 ± 2.81 days) but the difference was not statistically significant (p = 0.05). Conclusions The USES group was associated with fewer hemoclips use and intraoperative blood loss in patients undergoing laparoscopic gastrectomy at comparable costs.

Preeclampsia is a multi-system disorder involved in pregnancy without an effective treatment except delivery. The precise pathogenesis of this complicated disorder is still not completely understood. The objective of this study is to evaluate the alterations of protein expression and phosphorylations that are important in regulating placental cell function in preterm and term preeclampsia. Using the Protein Pathway Array, 38 proteins in placental tissues were found to be differentially expressed between preterm preeclampsia and gestational age matched control, while 25 proteins were found to be expressed differentially between term preeclampsia and matched controls. Among these proteins, 16 proteins and their associated signaling pathways overlapped between preterm and term preeclampsia, suggesting the common pathogenesis of two subsets of disease. On the other hand, many proteins are uniquely altered in either preterm or term preeclampsia and correlated with severity of clinical symptoms and outcomes, therefore, providing molecular basis for these two subsets of preeclampsia. Furthermore, the expression levels of some of these proteins correlated with neonatal small for gestational age (PAI-1 and PAPP-A) and adverse outcomes (Flt-1) in women with preterm preeclampsia. These proteins could potentially be used as candidate biomarkers for predicting outcomes of preeclampsia.