Mutation characteristics and molecular evolution of ovarian metastasis from gastric cancer and potential biomarkers for paclitaxel treatment.

Ovarian metastasis is one of the major causes of treatment failure in patients with gastric cancer (GC). However, the genomic characteristics of ovarian metastasis in GC remain poorly understood. In this study, we enroll 74 GC patients with ovarian metastasis, with 64 having matched primary and metastatic samples. Here, we show a characterization of the mutation landscape of this disease, alongside an investigation into the molecular heterogeneity and pathway mutation enrichments between synchronous and metachronous metastasis. We classify patients into distinct clonal evolution patterns based on the distribution of mutations in paired samples. Notably, the parallel evolution group exhibits the most favorable prognosis. Additionally, by analyzing the differential response to chemotherapy, we identify potential biomarkers, including SALL4, CCDC105, and CLDN18, for predicting the efficacy of paclitaxel treatment. Furthermore, we validate that CLDN18 fusion mutations improve tumor response to paclitaxel treatment in GC with ovarian metastasis in vitro and vivo.

Congener-specific fate and impact of microcystins in the soil-earthworm system.

Microcystins (MCs) have a significant influence on aquatic ecosystems, but little is known about their terrestrial fate and impact. Here, we investigated the fate of two MCs (MC-LR and MC-RR) in the soil-earthworm system, with consideration of their congener-specific impact on earthworm health, soil bacteria, and soil metabolome. Although MCs had little acute lethal effect on earthworms, they caused obvious growth inhibition and setae rupture. Relative to MC-RR, MC-LR exhibited higher bioaccumulation and the resulting dermal lesions and deformation of longitudinal muscles. While the incorporation of both MCs into soils stimulated pathogenic bacteria and depressed oxidative stress tolerant bacteria, the response among soil nitrification and glutathione metabolism differed between the two congeners. The dissipation kinetics of MCs obeyed the first-order model. Earthworms stimulated soil N-cycling enzyme activities, increased the abundance of MC-degrading bacteria, and promoted bacterial metabolic functions related to glutathione metabolism, xenobiotics biodegradation, and metabolism of amino acids that comprise MCs, which accelerated the dissipation of MC-LR and MC-RR by 227% and 82%, respectively. These results provide evidence of significant congener differences in the terrestrial fate and impact of MCs, which will enable a better understanding of their role in mediating soil functions and ecosystem services.

Novel selective agents for the degradation of AR/AR-V7 to treat advanced prostate cancer.

The androgen receptor AR antagonists, such as enzalutamide and apalutamide, are efficient therapeutics for the treatment of prostate cancer (PCa). Even though they are effective at first, resistance to both drugs occurs frequently. Resistance is mainly driven by aberrations of the AR signaling pathway including AR gene amplification and the expression of AR splice variants (e.g. AR-V7). This highlights the urgent need for alternative therapeutic strategies. Here, a total of 24 compounds were synthesized and biologically evaluated to disclose compound 20i, exhibiting potent AR antagonistic activities (IC50 = 172.85 ± 21.33 nM), promising AR/AR-V7 protein degradation potency, and dual targeting site of probably AR (ligand-binding domain, LBD and N-terminal domain, NTD). It potently inhibits cell growth with IC50 values of 4.87 ± 0.52 and 2.07 ± 0.34 µM in the LNCaP and 22RV1 cell lines, respectively, and exhibited effective tumor growth inhibition (TGI = 50.9 %) in the 22RV1 xenograft study. These data suggest that 20i has the potential for development as an AR/AR-V7 inhibitor with degradation ability to treat advanced prostate cancer.

Proton pump inhibitors enhance macropinocytosis-mediated extracellular vesicle endocytosis by inducing membrane v-ATPase assembly.

Besides participating in diverse pathological and physiological processes, extracellular vesicles (EVs) are also excellent drug-delivery vehicles. However, clinical drugs modulating EV levels are still lacking. Here, we show that proton pump inhibitors (PPIs) reduce EVs by enhancing macropinocytosis-mediated EV uptake. PPIs accelerate intestinal cell endocytosis of autocrine immunosuppressive EVs through macropinocytosis, thereby aggravating inflammatory bowel disease. PPI-induced macropinocytosis facilitates the clearance of immunosuppressive EVs from tumour cells, improving antitumor immunity. PPI-induced macropinocytosis also increases doxorubicin and antisense oligonucleotides of microRNA-155 delivery efficiency by EVs, leading to enhanced therapeutic effects of drug-loaded EVs on tumours and acute liver failure. Mechanistically, PPIs reduce cytosolic pH, promote ATP6V1A (v-ATPase subunit) disassembly from the vacuolar membrane and enhance the assembly of plasma membrane v-ATPases, thereby inducing macropinocytosis. Altogether, our results reveal a mechanism for macropinocytic regulation and PPIs as potential modulators of EV levels, thus regulating their functions.

Study on Flowability Regulation of Vacuum Gas-Atomized Fe-Cr-Ni-W-B Spherical Powder.

High-quality Fe-Cr-Ni-W-B spherical powder is crucial for the powder metallurgy preparation of high-strength and tough Fe-Cr-Ni-W-B alloys. In this study, the controlled preparation of high-quality Fe-Cr-Ni-W-B spherical powder was achieved using the vacuum gas atomization method. The effects and mechanisms of atomization gas pressure, the melt nozzle inner diameter, and heat treatment temperature on the microstructure and flowability of Fe-Cr-Ni-W-B spherical powder were systematically investigated. By optimizing process parameters, spherical Fe-Cr-Ni-W-B powder with a sphericity of 95.1% and a flowability of 15.88 s/50 g was obtained, laying the foundation for the powder metallurgy preparation of high-strength and tough Fe-Cr-Ni-W-B alloys.

Genomic and immune microenvironment features influencing chemoimmunotherapy response in gastric cancer with peritoneal metastasis: a retrospective cohort study.

BACKGROUND: Patients with peritoneal metastasis (PM) from gastric cancer (GC) exhibit poor prognosis. Chemoimmunotherapy offers promising clinical benefits; however, its efficacy and predictive biomarkers in a conversion therapy setting remain unclear. The authors aimed to retrospectively evaluate chemoimmunotherapy efficacy in a conversion therapy setting for GC patients with PM and establish a prediction model for assessing clinical benefits. MATERIALS AND METHODS: A retrospective evaluation of clinical outcomes encompassed 55 GC patients with PM who underwent chemoimmunotherapy in a conversion therapy setting. Baseline PM specimens were collected for genomic and transcriptomic profiling. Clinicopathological factors, gene signatures, and tumor immune microenvironment were evaluated to identify predictive markers and develop a prediction model. RESULTS: Chemoimmunotherapy achieved a 41.8% objective response rate and 72.4% R0 resection rate in GC patients with PM. Patients with conversion surgery showed better overall survival (OS) than those without the surgery (median OS: not reached vs 7.82 m, P<0.0001). Responders to chemoimmunotherapy showed higher ERBB2 and ERBB3 mutation frequencies, CTLA4 and HLA-DQB1 expression, and CD8+ T cell infiltration, but lower CDH1 mutation and naïve CD4+ T cell infiltration, compared to nonresponders. A prediction model was established integrating CDH1 and ERBB3 mutations, HLA-DQB1 expression, and naïve CD4+ T cell infiltration (AUC=0.918), which were further tested using an independent external cohort (AUC=0.785). CONCLUSION: This exploratory study comprehensively evaluated clinicopathological, genomic, and immune features and developed a novel prediction model, providing a rational basis for the selection of GC patients with PM for chemoimmunotherapy-involved conversion therapy.

Catheter-guided anvil insertion for circular stapler esophagojejunal anastomosis: a novel technique in laparoscopic total gastrectomy.

OBJECTIVE: This study evaluates feasibility, safety, and short-term outcomes of employing the catheter-guided stapler anvil insertion technique for esophagojejunal anastomosis using a circular stapler during laparoscopic total gastrectomy (LTG). MATERIALS AND METHODS: From September 2021 to April 2023, the catheter-guided stapler anvil insertion technique was employed in 80 patients undergoing laparoscopic total gastrectomy (LTG) for esophagojejunal anastomosis. A modified D2 dissection, according to the en bloc technique, was performed in the patients. Subsequently, a longitudinal incision, approximately 2 cm in length, was made on the anterior wall of the esophagus, about 2 cm above the tumor. The transection line was pre-marked with blue dye along the esophagus's minor axis, and the tail of the anvil was capped with a 10-cm length of catheter (F14 d4.7 mm). The surgeon secures the head of anvil and carefully inserts it into the esophagus, ensuring that only a 5-cm segment of the catheter remains outside the esophagus. A linear cutter was employed to transect and seal the lower end of the esophagus. Subsequently, esophagojejunostomy was performed under laparoscopic guidance using a circular stapler. RESULTS: Among patients undergoing esophagojejunal anastomosis with the new technique, postoperative complications included pneumonia or pleural effusion in 14 patients (17.5%), anastomotic stenosis in 3 patients (3.75%), abdominal infection in 2 patients (2.5%), and intestinal obstruction in 1 patient (1.25%). No instances of anastomotic leakage, anastomotic bleeding, or deaths were recorded. All patients experiencing complications improved with conservative treatment, without the need for secondary surgery. CONCLUSION: The catheter-guided stapler anvil insertion technique is demonstrated to be a safe and effective method for esophagojejunostomy, potentially reducing the occurrence of anastomotic leakage.

Clinicopathological characteristics of gastric neuroendocrine neoplasms: A comprehensive analysis.

OBJECTIVE: This study aimed to explore the clinicopathological characteristics and prognostic implications of gastric neuroendocrine neoplasms (g-NENs). METHODS: A retrospective enrollment of 142 patients diagnosed with g-NENs was conducted at Zhejiang Cancer Hospital between January 1, 2007 and December 31, 2021. The study compared essential clinicopathological features and survival rates. Additionally, the prognosis of gastric neuroendocrine carcinomas/mixed neuroendocrine-non-neuroendocrine neoplasms (g-NEC/MiNEN) were contrasted with those of gastric adenocarcinoma (GAC) and signet ring cell carcinoma (SRCC). RESULTS: The study comprised a total of 142 g-NENs cases, with a male-to-female ratio of approximately 2:1. The 5-year survival rates for g-NEC and g-MiNEN were 26.7% and 35.2%, respectively. Corresponding 5-year survival rates for G1 and G2 were observed at 100% and 80.0%, respectively. g-NEC/MiNEN showed a significantly worse prognosis compared to g-NET (p < 0.001). g-NEC/MiNEN exhibited a poor prognosis compared to GAC (p < 0.001), and within poorly differentiated GAC, g-NEC/MiNEN demonstrated a worse prognosis (p = 0.007). Additionally, patients receiving postoperative adjuvant therapy exhibited notably prolonged overall survival (OS) in the case of g-NEC/MiNEN (p = 0.010). CONCLUSION: In short, the prognosis of g-NEC/MiNEN was worse than that of g-NET, GAC and poorly differentiated GAC, but this group benefit from postoperative adjuvant therapy.

Sinapine thiocyanate alleviates intervertebral disc degeneration by not regulating JAK1/STAT3/NLRP3 signal pathway.

BACKGROUND: Intervertebral disc degeneration (IDD) is a major cause of low back pain. Sinapine thiocyanate (ST) has been reported to have a wide range of biological activities. However, the treatment of IDD with ST has not been studied. OBJECTIVES: To explore the role and mechanism of ST treatment in IDD. MATERIAL AND METHODS: Nucleus pulposus cells (NPCs) were induced using lipopolysaccharide (LPS), which was used as an in vitro model of IDD. Cell activity, oxidative stress-related indicators and protein expression were detected using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, enzyme-linked immunosorbent assay (ELISA) and western blot. Pyroptosis was evaluated with propidium iodide (PI)/Hoechst double staining and immunofluorescence for NOD-like receptor protein 3 (NLRP3), and pyroptosis-related proteins and inflammatory factors were measured with western blot and ELISA. The pathological changes of IDD were assessed with hematoxylin & eosin (H&E) and safranin-O staining. RESULTS: Our results showed that ST alleviated LPS-induced degeneration of NPCs, as evidenced by reducing reactive oxygen species (ROS), malondialdehyde (MDA), matrix metalloproteinase-13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), and increasing collagen II and aggrecan expression. Moreover, ST repressed LPS-induced pyroptosis by inhibiting NLRP3, caspase-1 p20, interleukin (IL)-1ß and IL-18. Further studies showed that ST did not restrain the activation of the JAK1/STAT3 signaling pathway induced by colivelin, or of the enhanced pyroptosis induced by polyphyllin VI. Sinapine thiocyanate alleviated IDD in vivo and suppressed NLRP3-mediated pyroptosis and the JAK1/STAT3 signaling pathway. CONCLUSIONS: Sinapine thiocyanate could alleviate IDD, although this did not include a reduction in NLRP3-mediated pyroptosis and inactivation of the JAK1/STAT3 signaling pathway, thus potentially being a candidate drug for IDD treatment.

Chinese expert consensus on cone-beam CT-guided diagnosis, localization and treatment for pulmonary nodules.

Cone-beam computed tomography (CBCT) system can provide real-time 3D images and fluoroscopy images of the region of interest during the operation. Some systems can even offer augmented fluoroscopy and puncture guidance. The use of CBCT for interventional pulmonary procedures has grown significantly in recent years, and numerous clinical studies have confirmed the technology's efficacy and safety in the diagnosis, localization, and treatment of pulmonary nodules. In order to optimize and standardize the technical specifications of CBCT and guide its application in clinical practice, the consensus statement has been organized and written in a collaborative effort by the Professional Committee on Interventional Pulmonology of China Association for Promotion of Health Science and Technology.

RALDH1 Inhibition Shows Immunotherapeutic Efficacy in Hepatocellular Carcinoma.

Globally, hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related death. We previously identified an immune evasion pathway whereby tumor cells produce retinoic acid (RA) to promote differentiation of intratumoral monocytes into protumor macrophages. Retinaldehyde dehydrogenase 1 (RALDH1), RALDH2, and RALDH3 are the three isozymes that catalyze RA biosynthesis. In this study, we have identified RALDH1 as the key driver of RA production in HCC and demonstrated the efficacy of RALDH1-selective inhibitors (Raldh1-INH) in suppressing RA production by HCC cells. Raldh1-INH restrained tumor growth in multiple mouse models of HCC by reducing the number and tumor-supporting functions of intratumoral macrophages as well as increasing T-cell infiltration and activation within tumors. Raldh1-INH also displayed favorable pharmacokinetic, pharmacodynamic, and toxicity profiles in mice thereby establishing them as promising new drug candidates for HCC immunotherapy.

A novel scaffold long-acting selective estrogen receptor antagonist and degrader with superior preclinical profile against ER+ breast cancer.

Breast cancer is one of the most common malignant tumors in women worldwide, with the majority of cases showing expression of estrogen receptors (ERs). Although drugs targeting ER have significantly improved survival rates in ER-positive patients, drug resistance remains an unmet clinical need. Fulvestrant, which overcomes selective estrogen receptor modulator (SERM) and AI (aromatase inhibitor) resistance, is currently the only long-acting selective estrogen receptor degrader (SERD) approved for both first and second-line settings. However, it fails to achieve satisfactory efficacy due to its poor solubility. Therefore, we designed and synthesized a series of novel scaffold (THC) derivatives, identifying their activities as ER antagonists and degraders. G-5b, the optimal compound, exhibited binding, antagonistic, degradation or anti-proliferative activities comparable to fulvestrant in ER+ wild type and mutants breast cancer cells. Notably, G-5b showed considerably improved stability and solubility. Research into the underlying mechanism indicated that G-5b engaged the proteasome pathway to degrade ER, subsequently inhibiting the ER signaling pathway and leading to the induction of apoptosis and cell cycle arrest events. Furthermore, G-5b displayed superior in vivo pharmacokinetics and pharmacodynamics properties, coupled with a favorable safety profile in the MCF-7 tamoxifen-resistant (MCF-7/TR) tumor xenograft model. Collectively, G-5b has emerged as a highly promising lead compound, offering potent antagonistic and degradation activities, positioning it as a novel long-acting SERD worthy of further refinement and optimization.

Variability of somatosensory evoked potential and motor evoked potential change criteria in thoracic spinal decompression surgery based on preoperative motor status.

BACKGROUND CONTEXT: Combined somatosensory- and motor-evoked potential (SSEP and MEP) changes for predicting prognosis in thoracic spinal surgery have been variably reported. PURPOSE: We aimed to explore the validity of combined SSEP and MEP for predicting postoperative motor deficits (PMDs) in thoracic spinal decompression surgery (TSDS) and identify a relatively optimal neurophysiological predictor of PMDs in patients based on preoperative motor status. STUDY SETTING: Retrospective study. PATIENT SAMPLE: A total of 475 patients were analyzed. OUTCOME MEASURES: A reduction in muscle strength by more than or equal to one manual muscle testing (MMT) grade postoperatively compared with the preoperative MMT grade was identified as PMDs. Postoperative motor deficits were detected by comparing the preoperative and postoperative physical examination findings in short- and long-term follow-up visits. METHODS: All patients were divided into two subgroups according to preoperative motor status. The following data were collected: (1) demographic data; (2) IONM (intraoperative neuromonitoring) data; and (3) postoperative motor outcomes. Binary logistic regression analysis was performed to assess the efficacy of IONM change to predict PMDs. A receiver operating characteristic curve (ROC) was used to establish optimal IONM warning criteria. RESULTS: Ninety-eight patients had severe preoperative motor deficits (Group S), and 377 patients did not (Group N). MEP and SSEP change was effective for predicting PMDs in the short term (p<.01) and long term (p<.01) for TSDS patients. In Group N, the cutoff values for predicting PMDs in the short term were a decrease of 65% in SSEP amplitude and 89.5% in MEP amplitude of the baseline value. Furthermore, the cutoff values for predicting PMDs in the short term were durations of change of 24.5 minutes for SSEP and 32.5 minutes for MEP. In Group S, however, the cutoff values for predicting PMDs in the short term were a decrease of 36.5% in SSEP amplitude and 59.5% in MEP amplitude of the baseline value. Moreover, the critical values for predicting short-term PMDs were durations of change of 16.5 minutes for SSEP and 17.5 minutes for MEP. CONCLUSIONS: The optimal IONM changes for prediction vary depending on preoperative motor status. Combined SSEP and MEP are excellent for predicting PMDs in TSDS.

A recurrence-predictive model based on eight genes and tumor mutational burden/microsatellite instability status in Stage II/III colorectal cancer.

BACKGROUND: Although adjuvant chemotherapy (ACT) is widely used to treat patients with Stage II/III colorectal cancer (CRC), administering ACT to specific patients remains a challenge. The decision to ACT requires an accurate assessment of recurrence risk and absolute treatment benefit. However, the traditional TNM staging system does not accurately assess a patient's individual risk of recurrence. METHODS: To identify recurrence risk-related genetic factors for Stage II/III CRC patients after radical surgery, we conducted an analysis of whole-exome sequencing of 47 patients with Stage II/III CRC who underwent radical surgery at five institutions. Patients were grouped into non-recurrence group (NR, n = 24, recurrence-free survival [RFS] > 5 years) and recurrence group (R, n = 23, RFS <2 years). The TCGA-COAD/READ cohort was employed as the validation dataset. RESULTS: A recurrence-predictive model (G8plus score) based on eight gene (CUL9, PCDHA12, HECTD3, DCX, SMARCA2, FAM193A, AATK, and SORCS2) mutations and tumor mutation burden/microsatellite instability (TMB/MSI) status was constructed, with 97.87% accuracy in our data and 100% negative predictive value in the TCGA-COAD/READ cohort. For the TCGA-COAD/READ cohort, the G8plus-high group had better RFS (HR = 0.22, p = 0.024); the G8plus-high tumors had significantly more infiltrated immune cell types, higher tertiary lymphoid structure signature scores, and higher immunological signature scores. The G8plus score was also a predict biomarker for immunotherapeutic in advanced CRC in the PUCH cohort. CONCLUSIONS: In conclusion, the G8plus score is a powerful biomarker for predicting the risk of recurrence in patients with stage II/III CRC. It can be used to stratify patients who benefit from ACT and immunotherapy.

Analysis of clinicopathological features and prognostic factors of breast cancer brain metastasis.

BACKGROUND: Breast cancer (BC) has become the most common malignancy in women. The incidence and detection rates of BC brain metastasis (BCBM) have increased with the progress of imaging, multidisciplinary treatment techniques and the extension of survival time of BC patients. BM seriously affects the quality of life and sur-vival prognosis of BC patients. Therefore, clinical research on the clinicopathological features and prognostic factors of BCBM is valuable. By analyzing the clinicopathological parameters of BCBM patients, and assessing the risk factors and prognostic indicators, we can perform hierarchical diagnosis and treatment on the high-risk population of BCBM, and achieve clinical benefits of early diagnosis and treatment. AIM: To explore the clinicopathological features and prognostic factors of BCBM, and provide references for diagnosis, treatment and management of BCBM. METHODS: The clinicopathological data of 68 BCBM patients admitted to the Air Force Medical Center, Chinese People's Liberation Army (formerly Air Force General Hospital) from 2000 to 2022 were collected. Another 136 BC patients without BM were matched at a ratio of 1:2 based on the age and site of onset for retrospective analysis. Categorical data were subjected to χ2 test or Fisher's exact probability test, and the variables with P < 0.05 in the univariate Cox proportional hazards model were incorporated into the multivariate model to identify high-risk factors and independent prognostic factors of BCBM, with a hazard ratio (HR) > 1 suggesting poor prognostic factors. The survival time of patients was estimated by the Kaplan-Meier method, and overall survival was compared between groups by log-rank test. RESULTS: Multivariate Cox regression analysis showed that patients with stage III/IV tumor at initial diagnosis [HR: 5.58, 95% confidence interval (CI): 1.99-15.68], lung metastasis (HR: 24.18, 95%CI: 6.40-91.43), human epidermal growth factor receptor 2 (HER2)-overexpressing BC and triple-negative BC were more prone to BM. As can be seen from the prognostic data, 52 of the 68 BCBM patients had died by the end of follow-up, and the median time from diagnosis of BC to the occurrence of BM and from the occurrence of BM to death or last follow-up was 33.5 and 14 mo, respectively. It was confirmed by multivariate Cox regression analysis that patients with neurological symptoms (HR: 1.923, 95%CI: 1.005-3.680), with bone metastasis (HR: 2.011, 95%CI: 1.056-3.831), and BM of HER2-overexpressing and triple-negative BC had shorter survival time. CONCLUSION: HER2-overexpressing, triple-negative BC, late tumor stage and lung metastasis are risk factors of BM. The presence of neurological symptoms, bone metastasis, and molecular type are influencing prognosis factors of BCBM.

Plant Protein-Derived Active Peptides: A Comprehensive Review.

Active peptides are a class of physiologically active protein fragments, which can be prepared from different sources. In the past few decades, the production of peptides with various effects from different plant proteins continues to receive academic attention. With advances in extraction, purification, and characterization techniques, plant protein-derived active peptides continue to be discovered. They have been proven to have various functional activities such as antioxidant, antihypertensive, immunomodulatory, antimicrobial, anti-inflammatory, antidiabetic, antithrombotic, and so on. In this review, we searched Web of Science and China National Knowledge Infrastructure for relevant articles published in recent years. There are 184 articles included in this manuscript. The current status of plant protein-derived active peptides is systematically introduced, including their sources, preparation, purification and identification methods, physiological activities, and applications in the food industry. Special emphasis has been placed on the problems of active peptide exploration and the future trend. Based on these, it is expected to provide theoretical reference for the further exploitation of plant protein-derived active peptides, and promote the healthy and rapid development of active peptide industry.

Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment.

The initiation and progression of cancer are intricately linked to the tumor microenvironment (TME). Understanding the function of specific cancer-TME interactions poses a major challenge due in part to the complexity of the in vivo microenvironment. Here we predict cancer-TME interactions from single cell transcriptomic maps of both human colorectal cancers (CRCs) and mouse CRC models, ask how these interactions are altered in human tumor organoid (tumoroid) cultures, and functionally recapitulate human myeloid-carcinoma interactions in vitro. Tumoroid cultures suppress gene expression programs involved in inflammation and immune cell migration, providing a reductive platform for re-establishing carcinoma-immune cell interactions in vitro. Introduction of human monocyte-derived macrophages into tumoroid cultures instructs macrophages to acquire immunosuppressive and pro-tumorigenic gene expression programs similar to those observed in vivo. This includes hallmark induction of SPP1, encoding Osteopontin, an extracellular CD44 ligand with established oncogenic effects. Taken together, these findings offer a framework for understanding CRC-TME interactions and provide a reductionist tool for modeling specific aspects of these interactions.

SOX combined with sintilimab versus SOX alone in the perioperative management of locally advanced gastric cancer: a propensity score-matched analysis.

OBJECTIVES: To evaluate the efficacy of SOX combined with a programmed cell death protein-1 (PD-1) inhibitor compared with SOX alone in the perioperative management of locally advanced gastric cancer and to explore biomarkers that may predict response to anti-PD-1 therapy. METHODS: Data of patients with clinical stage T3-4aN0-3M0 (IIb-III) gastric cancer were reviewed to create a primary database. Patients treated with perioperative SOX combined with sintilimab were included in Group A, while those treated with SOX alone were included in Group B. After one-to-one propensity score matching, pathological response and short-term survival outcomes were compared between the two groups. In addition, potential efficacy-related biomarkers were analyzed. RESULTS: Between January 2018 and December 2022, a total of 150 patients were included in the analysis, with 75 patients in each group. The rates of pathological complete response (21.3% vs. 4.0%; P = 0.001) and major pathological response (45.3% vs. 22.7%; P = 0.003) in Group A were statistically higher than those in Group B. There was no significant difference in 1-year overall survival (92.8% vs. 92.0%; P = 0.392) and disease-free survival (88.9% vs. 88.0%; P = 0.357) between the two groups. Subgroup analysis of Group A showed that the pathological complete response (40.6% vs. 8.6%; P = 0.002) and major pathological response (65.6% vs. 28.6%; P = 0.002) rates were significantly higher in programmed death ligand-1-positive patients with a combined positive score of ≥ 5. A pathological complete response was achieved in 42.9% patients (3/7) with mismatch repair deficiency. For the two patients confirmed as Epstein-Barr virus-positive, one patient achieved a pathological complete response and the other achieved a major pathological response. CONCLUSIONS: The adoption of SOX combined with a PD-1 inhibitor may improve the pathological response rate of patients with locally advanced gastric cancer, especially those with programmed death ligand-1 combined positive score ≥ 5, Epstein-Barr virus-positivity and mismatch repair deficiency. However, further prospective studies are still warranted to confirm the long-term survival benefit.

A pan-cancer analysis of potassium channel tetramerization domain containing 12 in human cancer.

Abnormal expression of the potassium channel tetramerization domain containing 12 (KCTD12) is closely related to the occurrence and development of various tumors, but a pan-cancer analysis of KCTD12 has not yet been conducted. We explored the association between KCTD12 and more than 30 human malignancies using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. First, the mRNA and protein levels of KCTD12 were examined and their correlations with tumor stage and survival were explored. Second, we analyzed the infiltration of CD8+ and CD4+ T cells and cancer-associated fibroblasts in tumors and explored the correlation between KCTD12 expression and tumor cell stemness, genomic heterogeneity, and diagnostic specificity. Finally, we explored the molecular mechanisms associated with KCTD12 using KEGG/GO analysis. The results showed that KCTD12 mRNA and protein expression levels decreased in most tumors was significantly associated with the prognosis of tumor patients, and the phosphorylation level of KCTD12 decreased in several tumors, such as S200 and T196, pancreatic adenocarcinoma (PAAD), lung adenocarcinoma (LUAD), and breast invasive cancer (BRCA). The expression of KCTD12 was positively correlated with the degree of cancer-associated fibroblasts infiltration in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), PAAD, and stomach adenocarcinoma (STAD). The relationship between KCTD12 expression and CD8+ and CD4+ T cell infiltration was also clarified. KCTD12 showed high diagnostic sensitivity for various types of tumors and may be involved in tumor cell biology by affecting tumor cell stemness, tumor burden, and other characteristics. Finally, we analyzed the molecular functions of KCTD12 and possible KEGG/GO signaling pathways. In this study, we developed a biological marker for diagnosis, prognosis, and immune infiltration of the pan-cancers.