Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers.

BACKGROUND: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H). METHODS: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable. RESULTS: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease. CONCLUSION: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Genomic Alterations and Clinical Characterization in Chinese Patients with Metastatic Colorectal Cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) is increasingly characterized by myriad genomic alterations beyond the well-known factors such as RAS, BRAF, and microsatellite instability (MSI). Novel genomic changes, including ERBB2 amplifications, mutations, and gene fusions, are now recognized as potential targets for precision therapy. This study aims to explore the genomic landscape of a Chinese cohort with mCRC to identify potentially targetable genetic alterations for personalized treatment strategies. METHODS: A total of 500 mCRC patients in China were enrolled, based on which genomic profiling was performed using capture-based targeted sequencing across a panel of 520 genes on tumor tissues to identify prevalent genomic alterations. The mutations were analyzed by optimized proprietary algorithms. MSI and mismatch repair deficiency status were analyzed using the read-count-distribution approach. Besides, the overall survival (OS) related to these molecular changes was estimated. RESULTS: The cohort's genomic profiling revealed TP53 mutations in 78%, APC in 60%, and KRAS in 47% of the patients. MSI-High status was confirmed in 5.8% of cases via a next-generation sequencing (NGS)-based algorithm. ERBB2/HER2 amplifications were found in 12% (60/500) of patients, with potential therapeutic implications for those without concurrent KRAS mutations. A subset of patients (1.2%; 6/500) showed fusions and DNA damage response (DDR) gene mutations (except TP53) that could be targeted therapeutically. The KRAS (G12C) variant was detected in 14 patients (2.8%), and 61 (12.2%) had a BRAF V600E mutation. Notably, survival analysis showed no significant differences in OS between KRAS mutant loci and NRAS mutations (p = 0.436). However, BRAF V600E mutations were associated with a poorer prognosis than BRAF wild-type and non-V600E mutations (16.3 months vs. 29.5 and 31.1 months, respectively; p < 0.001). CONCLUSIONS: This study validates the feasibility of using NGS to detect prognostic and therapeutically actionable genetic variants in Chinese mCRC patients, contributing to understanding the genomic variation within this population and highlighting the potential for personalized medicine in managing mCRC.

Regio- and Diaseteroselective Synthesis of Polysubstituted Piperidines Enabled by Boronyl Radical-Catalyzed (4+2) Cycloaddition.

Piperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines are highly desirable. This work presents a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5-positions that are not readily accessible by known methods. Using commercially available diboron(4) compounds and 4-phenylpyridine as the catalyst precursors, the boronyl radical-catalyzed cycloaddition between 3-aroyl azetidines and various alkenes, including previously unreactive 1,2-di-, tri-, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal-free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations. A plausible mechanism, with the ring-opening of azetidine as the rate-limiting step, has been proposed based on the experimental and computational results.

Garsorasib in patients with KRASG12C-mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 2 trial.

BACKGROUND: Garsorasib (D-1553; InventisBio, Shangai, China), a potent KRASG12C inhibitor, has shown promising antitumour activity in patients with KRASG12C-mutated (ie, Gly12Cys) non-small-cell lung cancer (NSCLC) in a phase 1 study. We report results from a phase 2 study conducted to evaluate the efficacy and safety of garsorasib in patients with locally advanced or metastatic KRASG12C-mutated NSCLC. METHODS: This open-label, multicentre, single-arm, phase 2 trial enrolled adult patients with KRASG12C-mutated NSCLC who had previously been treated with platinum-based chemotherapy and immune checkpoint inhibitors from 43 hospitals in China. Participants received 600 mg garsorasib orally twice per day. Tumour assessments were performed at baseline, at the end of every two cycles (of 21 days) for the first eight cycles, and at the end of every three cycles thereafter. The primary endpoint was objective response rate (ORR) as assessed by an independent review committee (IRC) following the guidelines in Response Evaluation Criteria in Solid Tumours, version 1.1. Efficacy and safety were assessed in all patients who received at least one dose of garsorasib. This trial is registered at ClinicalTrials.gov, NCT05383898, and is active but no longer recruiting. FINDINGS: From June 17, 2022, to May 17, 2023, of 225 patients screened for eligibility, 123 patients were enrolled and treated with garsorasib. Of these 123 participants, the median age was 64 years (IQR 59-68), 108 (88%) were male and 15 (12%) were female. At data cutoff (Nov 17, 2023), the median follow-up duration was 7·9 months (IQR 6·3-10·4), and 82 (67%) of 123 patients had discontinued treatment. The IRC-confirmed ORR was 50% (61 of 123 patients; 95% CI 41-59). 117 (95%) of 123 patients reported treatment-related adverse events, with 61 (50%) experiencing grade 3 or higher events. The most common types of adverse events of grade 3 or higher associated with garsorasib were hepatic and gastrointestinal events, including increased liver enzymes, such as aspartate aminotransferase (21 [17%] of 123 participants), alanine aminotransferase (19 [15%] of 123 participants), and gamma-glutamyltransferase (28 [23%] of 123 participants); nausea (2 [2%] of 123 participants); and vomiting (2 [2%] of 123 participants). No new safety signals were identified, and most of the adverse events were well managed. INTERPRETATION: The results show that garsorasib has a high response rate, long duration of response, and an acceptable and manageable safety profile in patients with previously treated KRASG12C-mutated NSCLC. Garsorasib potentially provides a promising treatment option for this patient population. FUNDING: InventisBio.

Efficacy and Safety of Taletrectinib in Chinese Patients With ROS1+ Non-Small Cell Lung Cancer: The Phase II TRUST-I Study.

PURPOSE: Taletrectinib, a highly potent, CNS-active, ROS1 tyrosine kinase inhibitor (TKI), has demonstrated high and durable response rates, high intracranial objective response rate (ORR), prolonged progression-free survival (PFS), and activity against G2032R with a favorable safety profile. We report outcomes from the pivotal TRUST-I study (ClinicalTrials.gov identifier: NCT04395677) of taletrectinib for ROS1+ non-small cell lung cancer in China. METHODS: TRUST-I evaluated TKI-naїve and crizotinib-pretreated patients. The primary end point was confirmed ORR (cORR) by independent review committee; key secondary end points included duration of response (DOR), PFS, and safety. RESULTS: As of November 2023, 173 patients were enrolled (median age, 55 years; 58% female; 73% never smoked; TKI naїve: n = 106; crizotinib pretreated: n = 67). In TKI-naїve patients, cORR and intracranial cORR were 91% and 88%, respectively, and 52% and 73% in crizotinib-pretreated patients. In TKI-naїve patients, median DOR and median PFS were not reached (NR) with 22.1-month and 23.5-month follow-up, respectively. In crizotinib-pretreated patients, the median DOR was 10.6 months (95% CI, 6.3 months to NR; 8.4-month follow-up), and the median PFS was 7.6 months (95% CI, 5.5 to 12.0 months; 9.7-month follow-up). Eight of 12 patients (67%) with G2032R mutations responded. The most frequent treatment-emergent adverse events (TEAEs) were increased AST (76%), diarrhea (70%), and increased ALT (68%), most of which were grade 1-2. Incidences of neurologic TEAEs were low (dizziness: 23%; dysgeusia: 10%) and mostly grade 1. Discontinuations (5%) and dose reductions (19%) due to TEAEs were low. CONCLUSION: Taletrectinib continues to show high and durable overall responses, prolonged PFS, robust activity against intracranial lesions and acquired resistance mutations including G2032R, and a favorable safety profile with a low incidence of neurologic TEAEs.

Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results.

Claudin18.2 (CLDN18.2) is highly expressed with the development of various malignant tumors, especially gastrointestinal cancers, and is emerging as a new target for cancer treatment. Satricabtagene autoleucel (satri-cel)/CT041 is an autologous chimeric antigen receptor (CAR) T cell targeting CLDN18.2, and the interim results of the CT041-CG4006 trial were reported in June 2022. Here we present the final results of this single-arm, open-label, phase 1 trial, which evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced gastrointestinal cancers. This trial included a dose-escalation stage (n = 15) and a dose-expansion stage in four different cohorts (total n = 83): cohort 1, satri-cel monotherapy in 61 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 2, satri-cel plus anti-PD-1 therapy in 15 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 3, satri-cel as sequential treatment after first-line therapy in five patients with gastrointestinal cancers; and cohort 4, satri-cel monotherapy in two patients with anti-CLDN18.2 monoclonal antibody-refractory gastric cancer. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics and immunogenicity. A total of 98 patients received satri-cel infusion, among whom 89 were dosed with 2.5 × 108, six with 3.75 × 108 and three with 5.0 × 108 CAR T cells. Median follow-up was 32.4 months (95% confidence interval (CI): 27.3, 36.5) since apheresis. No dose-limiting toxicities, treatment-related deaths or immune effector cell-associated neurotoxicity syndrome were reported. Cytokine release syndrome occurred in 96.9% of patients, all classified as grade 1-2. Gastric mucosal injuries were identified in eight (8.2%) patients. The overall response rate and disease control rate in all 98 patients were 38.8% and 91.8%, respectively, and the median progression-free survival and overall survival were 4.4 months (95% CI: 3.7, 6.6) and 8.8 months (95% CI: 7.1, 10.2), respectively. Satri-cel demonstrates therapeutic potential with a manageable safety profile in patients with CLDN18.2-positive advanced gastrointestinal cancer. ClinicalTrials.gov identifier: NCT03874897 .

Enhancement of the function of mesenchymal stem cells by using a GMP-grade three-dimensional hypoxic large-scale production system.

Background: Efficiently increasing the production of clinical-grade mesenchymal stem cells (MSCs) is crucial for clinical applications. Challenges with the current planar culture methods include scalability issues, labour intensity, concerns related to cell senescence, and heterogeneous responses. This study aimed to establish a large-scale production system for MSC generation. In addition, a comparative analysis of the biological differences between MSCs cultured under various conditions was conducted. Methods and materials: We developed a GMP-grade three-dimensional hypoxic large-scale production (TDHLSP) system for MSCs using self-fabricated glass microcarriers and a multifunctional bioreactor. Different parameters, including cell viability, cell diameter, immunophenotype, morphology, karyotype, and tumourigenicity were assessed in MSCs cultured using different methods. Single-cell RNA sequencing (scRNA-seq) revealed pathways and genes associated with the enhanced functionality of MSCs cultured in three dimensions under hypoxic conditions (3D_Hypo MSCs). Moreover, CD142 knockdown in 3D_Hypo MSCs confirmed its in vitro functions. Results: Inoculating 2 × 108 MSCs into a 2.6 L bioreactor in the TDHLSP system resulted in a final scale of 4.6 × 109 3D_Hypo MSCs by day 10. The 3D_Hypo MSCs retained characteristics of the 2D MSCs, demonstrating their genomic stability and non-tumourigenicity. Interestingly, the subpopulations of 3D_Hypo MSCs exhibited a more uniform distribution and a closer relationship than those of 2D MSCs. The heterogeneity of MSCs was strongly correlated with 'cell cycle' and 'stroma/mesenchyme', with 3D_Hypo MSCs expressing higher levels of activated stroma genes. Compared to 2D MSCs, 3D_Hypo MSCs demonstrated enhanced capabilities in blood vessel formation, TGF-ß1 secretion, and inhibition of BV2 proliferation, with maintenance of Senescence-Associated ß-Galactosidase (SA-ß-gal) negativity. However, the enhanced functions of 3D_Hypo MSCs decreased upon the downregulation of CD142 expression. Conclusion: The TDHLSP system led to a high overall production of MSCs and promoted uniform distribution of MSC clusters. This cultivation method also enhanced key cellular properties, such as angiogenesis, immunosuppression, and anti-aging. These functionally improved and uniform MSC subpopulations provide a solid basis for the clinical application of stem cell therapies.

Exploring the mechanism of Scleromitrion diffusum (Willd.) in treating lung cancer based on network pharmacology and experimental validation.

This study aims to elucidate the mechanisms by which the effective components of Scleromitrion diffusum (Willd.) (SDW) treat lung cancer, using network pharmacology, in vitro cell experiments, and molecular docking methods. Network pharmacology techniques were employed to construct a network of SDW components, lung cancer targets, and signaling pathways. A proteinprotein interaction (P P I) network was built for target genes, identifying core gene targets. Signaling pathway and biological process analyses were conducted. MT T assays measured cell viability, and Western blot analysis assessed the impact of core protein targets and key pathway proteins on the stemness of three lung cancer cell lines. Molecular docking was performed to link SDW components with core proteins and key pathway targets related to lung cancer. SDW was found to target 88 genes and 5 active components (2-methoxy-3-methyl-9-10-anthraquinone, stigmasterol, beta-sitosterol, quercetin, and poriferasterol) relevant to lung cancer treatment. The P I3K/Akt and MEK/ERK pathways were identified as major signaling pathways. Extracts from SDW roots significantly inhibited the proliferation of three lung cancer cell lines (A549, HCC827, and NCIH-1395), primarily via P I3K/Akt and MEK/ERK pathways, significantly reducing the expression of p-Akt and p-Erk1/2 and slightly inhibiting caspase-9, p-P I3K, and EGFR expression. Molecular docking confirmed the strong binding activities of SDW components with lung cancer-related core proteins and key pathway targets. SDW may regulate apoptosis and proliferation in lung cancer treatment through P I3K-Akt and MAP K/ERK signaling pathways. The combination of network pharmacology, molecular docking, and experimental validation provides valuable insights into the molecular mechanisms of SDW in lung cancer therapy.

Camrelizumab plus famitinib in previously chemo-immunotherapy treated patients with advanced NSCLC: results from an open-label multicenter phase 2 basket study.

BACKGROUND: The combination of immune checkpoint inhibitors and antiangiogenic agents has been effective in treating multiple cancers. This was further explored in an open-label, multicenter phase 2 basket study (NCT04346381), which evaluated the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients with advanced solid tumors. We herein report the findings from the cohort of advanced NSCLC patients who progressed after treatment with platinum-doublet chemotherapy and immunotherapy. METHODS: Eligible patients were enrolled and treated with camrelizumab (200 mg once every 3 weeks via intravenous infusion) and oral famitinib (20 mg once daily). The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled in this cohort, with a median follow-up duration of 11.5 months. Three patients (7.5%) achieved a partial response, and 29 patients (72.5%) achieved stable disease. The ORR and DCR with this combination regimen were 7.5% (95% CI, 1.6-20.4) and 80.0% (95% CI, 64.4-90.9), respectively. The median DoR was 12.1 months (95% CI, 10.3-not reached). The median PFS was 5.4 months (95% CI, 4.1-7.5), and the median OS was 12.1 months (95% CI, 9.1-16.7). The estimated 12-month OS rate was 51.5% (95% CI, 34.9-65.9). The most frequent grade 3 or higher treatment-related adverse events occurring in more than 5% of patients included hypertension (27.5%), palmar-plantar erythrodysesthesia syndrome (10%), decreased neutrophil count (10%), and proteinuria (7.5%). CONCLUSION: Camrelizumab plus famitinib demonstrated favorable benefits in PFS and OS, along with manageable safety profiles, in patients with advanced NSCLC who progressed after platinum-doublet chemotherapy and immunotherapy. This finding warrants further exploration.

Luminescence center modulation for the synthesis of a narrow-band green phosphor: mechanism and backlighting display application.

A highly efficient and stable green phosphor with a narrow emission-band in a hexagonal aluminate was synthesized based on the energy transfer between Eu2+ and Mn2+ luminescence centers. The related mechanism was elucidated from the viewpoints of the crystal structure and energy level, providing insights for designing novel phosphors with high performance.

Safety and Efficacy of CT041 in Patients With Refractory Metastatic Pancreatic Cancer: A Pooled Analysis of Two Early-Phase Trials.

PURPOSE: CT041 is a chimeric antigen receptor (CAR)-modified T-cell therapy that specifically targets claudin18.2 in solid tumors. Here, we report the pooled analysis results of two exploratory clinical trials to evaluate CT041 in patients with previously treated pancreatic cancer (PC). PATIENTS AND METHODS: These two multicenter, open-label phase I/Ib trials (CT041-CG4006, CT041-ST-01) have a similar target population and evaluation schedule. The primary objective was to assess the safety and tolerability of CT041, whereas secondary objectives included efficacy, pharmacokinetics, and immunogenicity. RESULTS: The combined cohort comprised 24 patients with advanced PC. Among them, five patients (20.8%) had previously received one line of therapy, whereas 19 (79.2%) received ≥2 lines of therapy. The most common treatment-emergent adverse events of grade 3 or more were preconditioning-related hematologic toxicities. Cytokine release syndrome (CRS) and GI disorders were most reported grade 1 or 2 adverse events. The overall response rate and disease control rate were 16.7% and 70.8%. The median progression-free survival (mPFS) after infusion was 3.3 months (95% CI, 1.8 to 6.2), and the median overall survival (mOS) was 10.0 months (95% CI, 5.5 to 17.6). The median duration of response (mDoR)was 9.5 months (95% CI, 2.6 to Not reached), with a DoR rate at 12 months of 50% (95% CI, 5.8 to 84.5). The mPFS (6.0 v 1.0 months, P < .001) and mOS (17.6 v 4.0 months, P < .001) were prolonged in patients achieving partial response/stable disease than the progressive disease group. CA19-9 levels had reduced by at least 30% in 17 (70.8%) patients. CONCLUSION: In patients with metastatic PC after progression on previous therapy, CT041 demonstrated a tolerable safety profile and encouraging anticancer efficacy signals. Response benefit observed here needs to be ascertained in the future.

Drug resistance­related gene targets and molecular mechanisms in the A2780/Taxol­resistant epithelial ovarian cancer cell line.

Epithelial ovarian cancer (EOC) is a fatal gynecological malignant tumor with a low 5-year survival rate. The use of the first-line chemotherapeutic drug, paclitaxel, for the treatment of EOC is associated with resistance, often leading to treatment failure. The present study investigated the gene targets in an A2780 paclitaxel-resistant EOC cell line (A2780/Taxol), and the potential underlying mechanisms using transcriptome sequencing technology and bioinformatics analysis. The transcriptome of the A2780/Taxol cell line was sequenced, and 498 differentially expressed genes were obtained contained in the Gene Expression Omnibus dataset. Further bioinformatics analysis revealed that matrix metalloproteinase 1 (MMP1), zyxin (ZYX) and Unc-5 netrin receptor C (UNC5C) may be gene targets related to paclitaxel resistance. Moreover, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that a potential mechanism associated with paclitaxel resistance was related to cell migration. Furthermore, the expression levels of MMP1, ZYX and UNC5C were verified using western blotting, immunofluorescence and immunohistochemistry in vitro. The results revealed that the expression levels of MMP1 and ZYX were significantly increased in A2780/Taxol cells, while UNC5C expression was significantly decreased, which was consistent with the results of the transcriptome sequencing. The present study demonstrated that MMP1, ZYX and UNC5C may be the gene targets associated with paclitaxel resistance in EOC. These genes have potential to be used as molecular markers for EOC drug therapy, targeted elimination of drug resistance, and evaluation of treatment efficacy and patient prognosis.

A p21-ATD mouse model for monitoring and eliminating senescent cells and its application in liver regeneration post injury.

Cellular senescence associates with pathological aging and tissue dysfunctions. Studies utilizing mouse models for cell lineage tracings have emphasized the importance of senescence heterogeneity in different organs and cell types. Here, we constructed a p21- (Akaluc - tdTomato - Diphtheria Toxin Receptor [DTR]) (ATD) mouse model to specifically study the undefined mechanism for p21-expressing senescent cells in the aged and liver injury animals. The successful expressions of these genes enabled in vitro flow cytometric sorting, in vivo tracing, and elimination of p21-expressing senescent cells. During the natural aging process, p21-expressing cells were found in various tissues of p21-ATD mice. Eliminating p21-expressing cells in the aged p21-ATD mice recovered their multiple biological functions. p21-ATD/Fah-/- mice, bred from p21-ATD mice and fumarylacetoacetate hydrolase (Fah)-/- mice of liver injury, showed that the majority of their senescent hepatocytes were the phenotype of p21+ rather than p16+. Furthermore, eliminating the p21-expressing hepatocytes significantly promoted the engraftment of grafted hepatocytes and facilitated liver repopulation, resulting in significant recovery from liver injury. Our p21-ATD mouse model serves as an optimal model for studying the pattern and function of p21-expressing senescent cells under the physical and pathological conditions during aging.

A division-of-labor mode contributes to the cardioprotective potential of mesenchymal stem/stromal cells in heart failure post myocardial infarction.

Background: Treatment of heart failure post myocardial infarction (post-MI HF) with mesenchymal stem/stromal cells (MSCs) holds great promise. Nevertheless, 2-dimensional (2D) GMP-grade MSCs from different labs and donor sources have different therapeutic efficacy and still in a low yield. Therefore, it is crucial to increase the production and find novel ways to assess the therapeutic efficacy of MSCs. Materials and methods: hUC-MSCs were cultured in 3-dimensional (3D) expansion system for obtaining enough cells for clinical use, named as 3D MSCs. A post-MI HF mouse model was employed to conduct in vivo and in vitro experiments. Single-cell and bulk RNA-seq analyses were performed on 3D MSCs. A total of 125 combination algorithms were leveraged to screen for core ligand genes. Shinyapp and shinycell workflows were used for deploying web-server. Result: 3D GMP-grade MSCs can significantly and stably reduce the extent of post-MI HF. To understand the stable potential cardioprotective mechanism, scRNA-seq revealed the heterogeneity and division-of-labor mode of 3D MSCs at the cellular level. Specifically, scissor phenotypic analysis identified a reported wound-healing CD142+ MSCs subpopulation that is also associated with cardiac protection ability and CD142- MSCs that is in proliferative state, contributing to the cardioprotective function and self-renewal, respectively. Differential expression analysis was conducted on CD142+ MSCs and CD142- MSCs and the differentially expressed ligand-related model was achieved by employing 125 combination algorithms. The present study developed a machine learning predictive model based on 13 ligands. Further analysis using CellChat demonstrated that CD142+ MSCs have a stronger secretion capacity compared to CD142- MSCs and Flow cytometry sorting of the CD142+ MSCs and qRT-PCR validation confirmed the significant upregulation of these 13 ligand factors in CD142+ MSCs. Conclusion: Clinical GMP-grade 3D MSCs could serve as a stable cardioprotective cell product. Using scissor analysis on scRNA-seq data, we have clarified the potential functional and proliferative subpopulation, which cooperatively contributed to self-renewal and functional maintenance for 3D MSCs, named as "division of labor" mode of MSCs. Moreover, a ligand model was robustly developed for predicting the secretory efficacy of MSCs. A user-friendly web-server and a predictive model were constructed and available (https://wangxc.shinyapps.io/3D_MSCs/).

Molecular features of gastroenteropancreatic neuroendocrine carcinoma: A comparative analysis with lung neuroendocrine carcinoma and digestive adenocarcinomas.

Objective: There is an ongoing debate about whether the management of gastroenteropancreatic (GEP) neuroendocrine carcinoma (NEC) should follow the guidelines of small-cell lung cancer (SCLC). We aim to identify the genetic differences of GEPNEC and its counterpart. Methods: We recruited GEPNEC patients as the main cohort, with lung NEC and digestive adenocarcinomas as comparative cohorts. All patients undergone next-generation sequencing (NGS). Different gene alterations were compared and analyzed between GEPNEC and lung NEC (LNEC), GEPNEC and adenocarcinoma to yield the remarkable genes. Results: We recruited 257 patients, including 99 GEPNEC, 57 LNEC, and 101 digestive adenocarcinomas. Among the mutations, KRAS, RB1, TERT, IL7R, and CTNNB1 were found to have different gene alterations between GEPNEC and LNEC samples. Specific genes for each site were revealed: gastric NEC ( TERT amplification), colorectal NEC ( KRAS mutation), and bile tract NEC ( ARID1A mutation). The gene disparities between small-cell NEC (SCNEC) and large-cell NEC (LCNEC) were KEAP1 and CDH1. Digestive adenocarcinoma was also compared with GEPNEC and suggested RB1, APC, and KRAS as significant genes. The TP53/ RB1 mutation pattern was associated with first-line effectiveness. Putative targetable genes and biomarkers in GEPNEC were identified in 22.2% of the patients, and they had longer progression-free survival (PFS) upon targetable treatment [12.5 months vs. 3.0 months, HR=0.40 (0.21-0.75), P=0.006]. Conclusions: This work demonstrated striking gene distinctions in GEPNEC compared with LNEC and adenocarcinoma and their clinical utility.

Influential upregulation of KCNE4: Propelling cancer associated fibroblasts-driven colorectal cancer progression.

BACKGROUND: Colorectal cancer (CRC) is a malignancy of remarkable heterogeneity and heightened morbidity. Cancer associated fibroblasts (CAFs) are abundant in CRC tissues and are essential for CRC growth. Here, we aimed to develop a CAF-related classifier for predicting the prognosis of CRC and identify critical pro-tumorigenic genes in CAFs. METHOD: The mRNA expression and clinical information of CRC samples were sourced from two comprehensive databases, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Using a weighted gene co-expression network analysis (WGCNA) approach, CAF-related genes were identified and a CAF risk signature was developed through the application of univariate analysis and the least absolute shrinkage and selection operator (LASSO) Cox regression model. EdU cell proliferation assay, and transwell assay were performed to detect the oncogenic role of KCNE4 in CAFs. RESULTS: We constructed a prognostic CAF model consisting of two genes (SFRP2 and KCNE4). CRC patients were classified into low- and high-CAF-risk groups using the median CAF risk score, and patients in the high-CAF-risk group had worse prognosis. Meanwhile, a higher risk score for CAFs was associated with greater stromal and CAF infiltrations, as well as higher expression of CAF markers. Furthermore, TIDE analysis indicated that patients with a high CAF risk score are less responsive to immunotherapy. Our further experiments had confirmed the strong correlation between KCNE4 and the malignant phenotypes of CAFs. Moreover, we had shown that KCNE4 could actively promote tumor-promoting phenotypes in CAFs, indicating its critical role in cancer progression. CONCLUSION: The two-gene prognostic CAF signature was constructed and could be reliable for predicting prognosis for CRC patients. Moreover, KCNE4 may be a promising strategy for the development of novel anti-cancer therapeutics specifically directed against CAFs.

Ultrasensitive and Multiple Biomarker Discrimination for Alzheimer's Disease via Plasmonic & Microfluidic Sensing Technologies.

As the population ages, the worldwide prevalence of Alzheimer's disease (AD) as the most common dementia in the elderly is increasing dramatically. However, a long-term challenge is to achieve rapid and accurate early diagnosis of AD by detecting hallmarks such as amyloid beta (Aß42). Here, a multi-channel microfluidic-based plasmonic fiber-optic biosensing platform is established for simultaneous detection and differentiation of multiple AD biomarkers. The platform is based on a gold-coated, highly-tilted fiber Bragg grating (TFBG) and a custom-developed microfluidics. TFBG excites a high-density, narrow-cladding-mode spectral comb that overlaps with the broad absorption of surface plasmons for high-precision interrogation, enabling ultrasensitive monitoring of analytes. In situ detection and in-parallel discrimination of different forms of Aß42 in cerebrospinal fluid (CSF) are successfully demonstrated with a detection of limit in the range of ≈30-170 pg mL-1, which is one order of magnitude below the clinical cut-off level in AD onset, providing high detection sensitivity for early diagnosis of AD. The integration of the TFBG sensor with multi-channel microfluidics enables simultaneous detection of multiple biomarkers using sub-µL sample volumes, as well as combining initial binding rate and real-time response time to differentiate between multiple biomarkers in terms of binding kinetics. With the advantages of multi-parameter, low consumption, and highly sensitive detection, the sensor represents an urgently needed potentials for large-scale diagnosis of diseases at early stage.

Helicobacter pylori and immunotherapy for gastrointestinal cancer.

Helicobacter pylori infection is associated with the risk of gastrointestinal (GI) cancers; however, its impact on immunotherapy for GI cancers remains uncertain. In this study, we included 10,122 patients who underwent 13C-urea breath tests. Among 636 patients with Epstein-Barr virus-negative microsatellite-stable gastric cancer (GC) who were treated with anti-PD-1/PD-L1 therapy, H. pylori-positive patients exhibited significantly longer immune-related progression-free survival (irPFS) compared with H. pylori-negative patients (6.97 months versus 5.03 months, p < 0.001, hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.62-0.95, p = 0.015). Moreover, the H. pylori-positive group demonstrated a trend of 4 months longer median immune-related overall survival (irOS) than the H. pylori-negative group. H. pylori-positive GC displayed higher densities of PD-L1+ cells and nonexhausted CD8+ T cells, indicative of a "hot" tumor microenvironment. Transcriptomic analysis revealed that H. pylori-positive GC shared molecular characteristics similar to those of immunotherapy-sensitive GC. However, H. pylori-positive patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal adenocarcinoma and esophageal squamous cell carcinoma (ESCC) had shorter irPFS compared with H. pylori-negative patients (16.13 months versus not reached, p = 0.042, HR 2.26, 95% CI 1.13-4.50, p = 0.021 and 5.57 months versus 6.97 months, p = 0.029, HR 1.59, 95% CI 1.14-2.23, p = 0.006, respectively). The difference in irOS between H. pylori-positive and -negative patients had the same trend as that between dMMR/MSI-H colorectal adenocarcinoma and ESCC patients. We also identified a trend of shorter irPFS and irOS in H. pylori-positive liver cancer and pancreatic cancer patients. In summary, our findings supported that H. pylori infection is a beneficial factor for GC immunotherapy by shaping hot tumor microenvironments. However, in dMMR/MSI-H colorectal adenocarcinoma and ESCC patients, H. pylori adversely affects the efficacy of immunotherapy.

Distinct clinical characteristics in stage III rectal cancer among different age groups and treatment outcomes after neoadjuvant chemoradiotherapy.

Background: There is a rapidly increasing incidence of early-onset colorectal cancer (EO-CRC) which threatens the survival of young people, while aging also represents a challenging clinical problem. Objectives: We aimed to investigate the differences in the clinical characteristics and prognosis in stage III rectal cancer (RC), to help optimize treatment strategies. Design and methods: This study included 757 patients with stage III RC, all of whom received neoadjuvant chemoradiotherapy and total mesorectal excision. The whole cohort was categorized as very early onset (VEO, ⩽30 years old), early onset (EO, >30 years old, ⩽50 years old), intermediate onset (IO, >50 years, ⩽70 years), or late onset (LO, >70 years old). Results: There were more female VEO patients than males, more mucinous adenocarcinoma, signet-ring cell carcinoma, pre-treatment cT4 stage, and higher pre-treatment serum carbohydrate antigen 19-9 compared with the other three groups. VEO patients had the worst survival with the highest RC-related mortality (34.5%), recurrence (13.8%), and metastasis (51.7%). LO patients had the highest non-RC-related mortality rate (16.6%). The Cox regression model showed VEO was a negative independent prognostic factor for disease-free survival [DFS, hazard ratio (HR): 2.830, 95% confidence interval (CI): 1.633-4.904, p < 0.001], distant metastasis-free survival (DMFS, HR: 2.969, 95% CI: 1.720-5.127, p < 0.001), overall survival (OS, HR: 2.164, 95% CI: 1.102-4.249, p = 0.025), and cancer-specific survival (CSS, HR: 2.321, 95% CI: 1.145-4.705, p = 0.020). LO was a negative independent factor on DFS (HR: 1.800, 95% CI: 1.113-2.911, p = 0.017), DMFS (HR: 1.903, 95% CI: 1.150-3.149, p = 0.012), OS (HR: 2.856, 95% CI: 1.745-4.583, p < 0.001), and CSS (HR: 2.248, 95% CI: 1.282-3.942, p = 0.005). VEO patients had better survival in the total neoadjuvant therapy-like (TNT-like) pattern on DFS (p = 0.039). IO patients receiving TNT-like patterns had better survival on DFS, OS, and CSS (p = 0.006, p = 0.018, p = 0.006, respectively). Conclusion: In stage III RC, VEO patients exhibited unique clinicopathological characteristics, with VEO a negative independent prognostic factor for DFS, DMFS, OS, and CSS. VEO and IO patients may benefit from a TNT-like treatment pattern.