The clinical outcome of minor changes in serum creatinine for patients after curative gastrectomy: a prospective study.

Introduction: Patients with renal insufficiency are more prone to postoperative complications (PCs). Studies have shown that minor changes in serum creatinine (SCr), immediately post-surgery, can aid in assessing patients' renal function. This study aimed to explore the relationship between the changes in SCr and PCs in patients with gastric cancer (GC). Materials and methods: We prospectively collected data regarding the SCr of 530 GC patients, within 2 weeks before surgery and within 24 hours after surgery in our hospital (2014-2016). The patients were divided into three groups according to the level of SCr change after surgery: reduced (<10%), normal (10%), and elevated (>10%) creatinine groups. Univariate and multivariate logistic analysis were performed to evaluate its correlation with short-term PCs in the patients. The R language was used to construct a nomogram. Results: 83, 217, and 230 patients were assigned to the elevated, reduced, and normal SCr groups, respectively. Multivariate analysis showed that the reduced and elevated SCr groups were independently associated with the occurrence of PCs and severe postoperative complications (SPCs), respectively. Additionally, postsurgical SCr change, age, hypoalbuminemia, total gastrectomy, combined resection, and laparoscopy, were independently related to PCs. Combining the above influential factors, the predictive model can distinguish patients with PCs more reliably (c-index is 0.715). Conclusion: Post-surgery, reduced SCr is a protective factor for PCs, while elevated serum creatinine is an independent risk factor for SPCs. Our nomogram can identify GC patients with high risks of PCs.

Identification of proliferative hepatocellular carcinoma using the SMARS score and implications for microwave ablation.

OBJECTIVE: To compare therapeutic outcomes of predicted proliferative and nonproliferative hepatocellular carcinoma (HCC) after microwave ablation (MWA) using a previously developed imaging-based predictive model, the SMARS score. METHODS: This multicenter retrospective study included consecutive 635 patients with unresectable HCC who underwent MWA between August 2013 and September 2020. Patients were stratified into predicted proliferative and nonproliferative phenotypes according to the SMARS score. Overall survival (OS) and recurrence-free survival (RFS) were compared between the predicted proliferative and nonproliferative HCCs before and after propensity score matching (PSM). OS and RFS were also compared between the two groups in subgroups of tumor size smaller than 30 mm and tumor size 30-50 mm. RESULTS: The SMARS score classified 127 and 508 patients into predicted proliferative and nonproliferative HCCs, respectively. The predicted proliferative HCCs exhibited worse RFS but equivalent OS when compared with nonproliferative HCCs before (p < 0.001 for RFS; p = 0.166 for OS) and after (p < 0.001 for RFS; p = 0.456 for OS) matching. Regarding subgroups of tumor size smaller than 30 mm (p = 0.098) and tumor size 30-50 mm (p = 0.680), the OSs were similar between the two groups. However, predicted proliferative HCCs had worse RFS compared to nonproliferative HCCs in the subgroup of tumor size 30-50 mm (p < 0.001), while the RFS did not differ in the subgroup of tumor size smaller than 30 mm (p = 0.141). CONCLUSION: Predicted proliferative HCCs have worse RFS than nonproliferative ones after MWA, especially in tumor size larger than 30 mm. However, the phenotype of the tumor may not affect the OS. CRITICAL RELEVANCE STATEMENT: Before performing microwave ablation for hepatocellular carcinoma, the tumor phenotype should be considered because it may affect the therapeutic outcome. KEY POINTS: Proliferative hepatocellular carcinoma (HCC) may be identified using the SMARS score, an imaging-based predictive model. SMARS predicted proliferative HCCs have worse recurrence-free and equivalent overall survival compared to nonproliferative HCC after microwave ablation. Tumor phenotype should be considered before performing microwave ablation.

Efficient Capture and Traceless Release of Functional CD8+ T Cells with a Microfluidic Chip for Enhanced In Vitro and In Vivo CD4-CAR Transduction.

The chimeric antigen receptor (CAR) T cells targeting CD4 expressed cells in acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) could reduce the risk of off target effects in normal tissues. However, the efficacy of adoptive cell therapy is predominantly attributed to CD8+ T cells, necessitating their purification before lentivirus transfection to enhance the production of CD4-CAR-T cells. In this study, we developed a microfluidic chip functionalized with an optimized CD8 aptamer, A3t-MU, to facilitate the enrichment and purification of CD8+ T cells. The presented chip showed efficient capture and seamless release of CD8+ T cells from cultured T cells and peripheral blood mononuclear cells (PBMCs). The purity of the released CD8+ T cells reached 98.1%, representing a 13% improvement over the conventional magnetic bead separation method. CD4-CAR was efficiently transduced into the purified CD8+ T cells to construct CAR-T cells. We evaluated the antitumor capability of the CD4-CAR transduced CD8+ T cells (anti-CD4 CD8-CAR T cells) both in vitro and in vivo. The anti-CD4 CD8-CAR T cells exhibited significant cancer-cell-killing capacity across multiple tumor cell lines, including CEM, Jurkat, and MV4-11. Meanwhile, anti-CD4 CD8-CAR T cells significantly inhibited tumor growth in vivo. In conclusion, the presented microfluidic chip offers a cost-effective and high-purity approach for CD8+ T cell separation, enhancing CD4-CAR transduction and achieving efficient antitumor capability both in vitro and in vivo.

Transcriptomic analyses reveals a diverse venom composition in Agelena limbata (Araneae: Agelenaidae).

Spider venom is a natural source of diverse biomolecules, but due to technical limitations, only a small fraction has been studied. With the advancement of omics technologies, research on spider venom has broadened, greatly promoting systematic studies of spider venom. Agelena limbata is a common spider found in vegetation, known for constructing funnel-shaped webs, and feeding on insects such as Diptera and Homoptera. However, due to its small size and the difficulty in obtaining venom, the composition of Agelena limbata venom has never been studied. In this study, a transcriptomics approach was used to analyze the toxin components in the venom of Agelena limbata, resulting in the identification of 28 novel toxin-like sequences and 24 peptidases. Based on sequence similarity and differences in cysteine motifs, the 28-novel toxin-like sequences were classified into 10 superfamilies. According to the results annotated in the database, the 24 peptidases were divided into six distinct families, with the serine protease family being the most common. A phylogenetic tree was constructed using the toxin-like sequences of Agelena limbata along with Psechrus triangulus and Hippasa lycosina. An analysis of the structural domains and motifs of Agelena limbata was also conducted. The results indicated that Agelena limbata is more distantly related to the other two species of funnel-web spiders, and that the toxin superfamily IX has a unique function compared to the other superfamilies. This study reveals the components of the Agelena limbata venom, deepening our understanding of it, and through bioinformatics analysis, has identified unique functions of the toxin superfamilies, providing a scientific basis for the development of bioactive drugs in the future.

Risk factors of HBV reactivation in leukemia patients with resolved HBV infection after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The hepatitis B surface antigen (HBsAg)-negative and antibody to hepatitis B core antigen (anti-HBc)-positive patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at risk of HBV reactivation (HBVr). METHODS: To analyze the risk factors for HBVr, a total of 1,042 leukemia patients(≥18years of age), who underwent allo-HSCT from January 2016 to April 2022 in The First Affiliated Hospital of Soochow University, were enrolled in the study. Finally, 193 leukemia patients with resolved HBV infection were included into the study. RESULTS: HBVr occurred in 22 patients (11.39 %), and the median time to HBVr was 24 months (with a range of 11-51months). Hepatitis flares developed in 22.73 % of patients with HBVr, and hepatic failure occurred in 1 patient. During the follow-up period, only 1(1.3 %) patient experienced HBVr among 79 patients with antiviral prophylaxis. While 21(18.42 %) patients experienced HBVr among 114 patients without antiviral prophylaxis. The cumulative incidence of HBV reactivation at 3 years was 44.4. % for anti-HBs-negative donors/recipients with a low anti-HBs titer (<100IU/L) and 7.1 % for anti-HBs-positive donors/recipients with a high anti-HBs titer (≥100IU/L) respectively. In addition, univariate and multivariate Cox regression analyses confirmed the use of rituximab as a risk factor for HBV reactivation. CONCLUSION: The univariate and multivariate analyses confirmed that the anti-HBs titer in both recipients and donors are protective indicators to prevent incidence of HBVr. In addition, antiviral prophylaxis can significantly reduce the incidence of HBVr.

Trafficking circuit of CD8+ T cells between the intestine and bone marrow governs antitumour immunity.

Immunotherapy elicits a systemic antitumour immune response in peripheral circulating T cells. However, the T cell trafficking circuit between organs and their contributions to antitumour immunity remain largely unknown. Here we show in multiple mouse leukaemia models that high infiltration of leukaemic cells in bone marrow (BM) stimulates the transition of CD8+CD44+CD62L+ central memory T cells into CD8+CD44-CD62L- T cells, designated as inter-organ migratory T cells (TIM cells). TIM cells move from the BM to the intestine by upregulating integrin ß7 and downregulating C-X-C motif chemokine receptor 3 during leukaemogenesis. Upon immunogenic chemotherapy, these BM-derived TIM cells return from the intestine to the BM through integrin α4-vascular cell adhesion molecule 1 interaction. Blocking C-X-C motif chemokine receptor 3 function boosts the immune response against leukaemia by enhancing T cell trafficking. This phenomenon can also be observed in patients with leukaemia. In summary, we identify an unrecognized intestine-BM trafficking circuit of T cells that contributes to the antitumour effects of immunogenic chemotherapy.

Genetic and clinical characteristics of acute B-cell lymphoblastic leukemia with MEF2D fusions and report of two novel MEF2D rearrangements.

The MEF2D rearrangement is a recurrent chromosomal abnormality detected in approximately 2.4-5.3% of patients with acute B-cell lymphoblastic leukemia (B-ALL). Currently, MEF2D-rearranged B-ALL is not classified as an independent subtype in the WHO classification. Consequently, the clinical significance of MEF2D rearrangement in B-ALL remains largely unexplored. In this study, we retrospectively screened 260 B-ALL patients with RNA sequencing data collected between November 2018 and December 2022. Among these, 10 patients were identified with MEF2D rearrangements (4 with MEF2D::HNRNPUL1, 3 with MEF2D::BCL9, 1 with MEF2D::ARID1B, 1 with MEF2D::DAZAP1 and 1 with MEF2D::HNRNPM). Notably, HNRNPM and ARID1B are reported as MEF2D fusion partners for the first time. The patient with the MEF2D::HNRNPM fusion was resistant to chemotherapy and chimeric antigen receptor T-cell therapy and relapsed early after allogenic stem cell transplantation. The patient with MEF2D::ARID1B experienced early extramedullary relapse after diagnosis. All 10 patients achieved complete remission after induction chemotherapy. However, 9/10 (90%) of whom experienced relapse. Three of the 9 patients relapsed with aberrant expression of myeloid antigens. The median overall survival of these patients was only 11 months. This small cohort showed a high incidence of early relapse and short survival in patients with MEF2D rearrangements.

Sesquilignans PD from Zanthoxylum nitidum var. tomentosum exerts antitumor effects via the ROS/MAPK pathway in liver cancer cells.

Sesquilignans PD is a natural phenylpropanoid compound that was isolated from Zanthoxylum nitidum var. tomentosum. In this study, we assessed the antitumor effect of PD on SK-Hep-1 and HepG2 cells and the underlying molecular mechanisms. The results revealed that PD markedly inhibited the proliferation and migration of both liver cancer cells. Moreover, PD induced apoptosis, autophagy, and reactive oxygen species (ROS) production in liver cancer cells. Notably, PD increased the protein levels of p-p38 MAPK and p-ERK1/2 in liver cancer cells. This is the first report on the anticancer effect of PD, which is mediated via increased ROS production and MAPK signaling activation.

Comparative transcriptomic and proteomic kinetic analysis of adeno-associated virus production systems.

Recombinant adeno-associated virus (rAAV) is a major gene delivery vehicle. We have constructed a stable rAAV producer cell line by integrating essential rAAV genome, viral and helper genes into the genome of HEK293 cell under the control of inducible promoters. Upon induction, the cell line produces transducing rAAV. To gain insight into enhancing rAAV productivity and vector quality, we performed a comparative transcriptomic and proteomic analysis of our synthetic cell line GX2 and two wild-type AAV (wtAAV) production systems, one by virus co-infection and the other by multi-plasmid transfection. The three systems had different kinetics in viral component synthesis but generated comparable copies of AAV genomes; however, the capsid titer of GX2 was an order of magnitude lower compared to those two wtAAV systems, indicating that its capsid production may be insufficient. The genome packaging efficiency was also lower in GX2 despite it produced higher levels of Rep52 proteins than either wtAAV systems, suggesting that Rep52 protein expression may not limit genome packaging. In the two wtAAV systems, VP were the most abundant AAV proteins and their levels continued to increase, while GX2 had high level of wasteful cargo gene expression. Furthermore, upregulated inflammation, innate immune responses, and MAPK signaling, as well as downregulated mitochondrial functions, were commonly observed in either rAAV or wtAAV systems. Overall, this comparative multi-omics study provided rich insights into host cell and viral factors that are potential targets for genetic and process intervention to enhance the productivity of synthetic rAAV producer cell lines. KEY POINTS: • wtAAV infection was more efficient in producing full viral particles than the synthetic cell GX2. • Capsid protein synthesis, genome replication, and packaging may limit rAAV production in GX2. • wtAAV infection and rAAV production in GX2 elicited similar host cell responses.

Squamous cell carcinoma of ear and temporal bone: A retrospective study on clinicopathological predictors.

BACKGROUND: Ear and temporal bone squamous cell carcinoma (ETBSCC) is a rare and aggressive malignant tumor with minimal clinicopathological studies. The object of this study was to retrospectively evaluate the predictive effect of clinicopathological variables on the 5-year overall survival (OS) rate of ETBSCC patients in a single tertiary medical center in Tianjin, China. METHODS: A cohort of 44 patients with diagnosed ETBSCC from December 2012 to August 2022 were retrospectively studied. Univariate and multivariate analysis were, respectively, performed for the assessment of clinicopathological predictors, including sex, age, history of chronic suppurative otitis media (CSOM), lesion side, diameter, the choice of surgical approach, parotidectomy, neck dissection, adjuvant therapies, T stage, lymph node metastasis, tumor grade, margin, perineural invasion (PNI), and Ki-67 index. RESULTS: Seventeen females and 27 males were included, with the mean age of 65 years old, ranging from 36 to 89 years. The 5-year OS rate was 43% (mean 51 months, 95% confidence interval [CI] = 39-64). Significant prediction of a worse prognosis for 5-year OS rate was observed under univariate analysis for advanced T stage, positive margin, identified PNI, and higher Ki-67 index, respectively. Advanced T stage was confirmed to be an independent prognostic factor strongly affecting 5-year OS rate among this cohort of patients using a multivariate cox proportional hazard model. CONCLUSION: We found that clinicopathological parameters, especially postoperative pathological parameters, play a critical role in predicting the prognosis of ETBSCC patients.

HAX1-Overexpression Augments Cardioprotective Efficacy of Stem Cell-Based Therapy Through Mediating Hippo-Yap Signaling.

Although stem/progenitor cell therapy shows potential for myocardial infarction repair, enhancing the therapeutic efficacy could be achieved through additional genetic modifications. HCLS1-associated protein X-1 (HAX1) has been identified as a versatile modulator responsible for cardio-protective signaling, while its role in regulating stem cell survival and functionality remains unknown. In this study, we investigated whether HAX1 can augment the protective potential of Sca1+ cardiac stromal cells (CSCs) for myocardial injury. The overexpression of HAX1 significantly increased cell proliferation and conferred enhanced resistance to hypoxia-induced cell death in CSCs. Mechanistically, HAX1 can interact with Mst1 (a prominent conductor of Hippo signal transduction) and inhibit its kinase activity for protein phosphorylation. This inhibition led to enhanced nuclear translocation of Yes-associated protein (YAP) and activation of downstream therapeutic-related genes. Notably, HAX1 overexpression significantly increased the pro-angiogenic potential of CSCs, as demonstrated by elevated expression of vascular endothelial growth factors. Importantly, implantation of HAX1-overexpressing CSCs promoted neovascularization, protected against functional deterioration, and ameliorated cardiac fibrosis in ischemic mouse hearts. In conclusion, HAX1 emerges as a valuable and efficient inducer for enhancing the effectiveness of cardiac stem or progenitor cell therapeutics.

Correlation Between Basal Metabolic Rate and Clinical Outcomes in Gastric Cancer Patients: A Retrospective Study.

OBJECTIVES: Hypermetabolism is associated with clinical prognosis of cancer patients. The aim of this study was to explore the association between basal metabolic rate (BMR) and postoperative clinical outcomes in gastric cancer patients. METHODS: We collected data of 958 gastric cancer patients admitted at our center from June 2014 to December 2018. The optimal cutoff value of BMR (BMR ≤1149 kcal/day) was obtained using the X-tile plot. Logistic and Cox regression analyses were then performed to evaluate the relevant influencing factors of clinical outcomes. Finally, R software was utilized to construct the nomogram. RESULTS: A total of 213 patients were defined as having a lower basal metabolic rate (LBMR). Univariate and multivariate analyses showed that gastric cancer patients with LBMR were more prone to postoperative complications and had poor long-term overall survival (OS). The established nomogram had good predictive power to assess the risk of OS in gastric cancer patients after radical gastrectomy (c-index was 0.764). CONCLUSIONS: Overall, LBMR on admission is associated with the occurrence of postoperative complications in gastric cancer patients, and this population has a poorer long-term survival. Therefore, there should be more focus on the perioperative management of patients with this risk factor before surgery.

Interleukin-27 Promotes the Generation of Myeloid-derived Suppressor Cells to Alleviate Graft-versus-host Disease.

BACKGROUND: Stimulation of myeloid-derived suppressor cell (MDSC) formation represents a potential curative therapeutic approach for graft-versus-host disease (GVHD), which significantly impacts the prognosis of allogeneic hematopoietic stem cell transplantation. However, the lack of an effective strategy for inducing MDSC production in vivo has hindered their clinical application. In our previous study, MDSC expansion was observed in interleukin (IL)-27-treated mice. METHODS: In this study, we overexpressed exogenous IL-27 in mice using a recombinant adeno-associated virus vector to investigate its therapeutic and exacerbating effects in murine GVHD models. RESULTS: In our study, we demonstrated that exogenous administration of IL-27 significantly suppressed GVHD development in a mouse model. We found that IL-27 treatment indirectly inhibited the proliferation and activation of donor T cells by rapidly expanding recipient and donor myeloid cells, which act as MDSCs after irradiation or under inflammatory conditions, rather than through regulatory T-cell expansion. Additionally, IL-27 stimulated MDSC expansion by enhancing granulocyte-monocyte progenitor generation. Notably, we verified that IL-27 signaling in donor T cells exerted an antagonistic effect on GVHD prevention and treatment. Further investigation revealed that combination therapy involving IL-27 and T-cell depletion exhibited remarkable preventive effects on GVHD in both mouse and xenogeneic GVHD models. CONCLUSIONS: Collectively, these findings suggest that IL-27 promotes MDSC generation to reduce the incidence of GVHD, whereas targeted activation of IL-27 signaling in myeloid progenitors or its combination with T-cell depletion represents a potential strategy for GVHD therapy.

Construction of Switch Modules for CAR-T Cell Treatment Using a Site-Specific Conjugation System.

Chimeric antigen receptor T-cell (CAR-T cell) therapy has become a promising treatment option for B-cell hematological tumors. However, few optional target antigens and disease relapse due to loss of target antigens limit the broad clinical applicability of CAR-T cells. Here, we conjugated an antibody (Ab) fusion protein, consisting of an Ab domain and a SpyCatcher domain, with the FITC-SpyTag (FITC-ST) peptide to form a bispecific safety switch module using a site-specific conjugation system. We applied the safety switch module to target CD19, PDL1, or Her2-expressing tumor cells by constructing FMC63 (anti-CD19), antiPDL1, or ZHER (anti-Her2)-FITC-ST, respectively. Those switch modules significantly improved the cytotoxic effects of anti-FITC CAR-T cells on tumor cells. Additionally, we obtained the purified CD8+ T cells by optimizing a shorter version of the CD8-binding aptamer to generate anti-FITC CD8-CAR-T cells, which combined with the CD4-FITC-ST switch module (anti-CD4) to eliminate the CD4-positive tumor cells in vitro and in vivo. Overall, we established a novel safety switch module by site-specific conjugation to enhance the antitumor function of universal CAR-T cells, thereby expanding the application scope of CAR-T therapy and improving its safety and efficacy.

The efficiency and safety of low-dose apatinib combined with oral vinorelbine in pretreated HER2-negative metastatic breast cancer.

BACKGROUND: Apatinib is an oral small-molecule tyrosine kinase inhibitor that blocks vascular endothelial growth factor receptor-2. Oral vinorelbine is a semisynthetic chemotherapeutic agent of vinorelbine alkaloids. Apatinib and oral vinorelbine have been proved to be effective in the treatment of metastatic breast cancer (mBC). At present, several small sample clinical trials have explored the efficacy of apatinib combined with oral vinorelbine in the treatment of mBC. METHODS: This retrospective study included 100 human epidermal growth factor receptor-2 (HER2)-negative mBC patients who received low-dose apatinib (250 mg orally per day) plus oral vinorelbine until disease progression or intolerance during February 2017 and March 2023. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), and safety were analyzed by SPSS 26.0 software and GraphPad Prism 8 software. Cox proportional hazards regression model for univariate and multivariate was used to identify factors significantly related to PFS and OS. RESULTS: The median follow-up time for this study was 38.1 months. Among 100 patients with HER2-negative mBC, 66 were hormone receptor (HR)-positive/HER2-negative and 34 were triple-negative breast cancer (TNBC). The median PFS and OS were 6.0 months (95% CI, 5.2-6.8 months) and 23.0 months (95% CI, 19.9-26.1 months). There were no statistical differences in PFS (p = 0.239) and OS (p = 0.762) between the HR-positive /HER2-negative and TNBC subgroups. The ORR, CBR, and DCR were 21.0%, 58.0%, and 78.0%, respectively. Ninety-five patients (95.0%) experienced varying grades of adverse events (AEs) and 38.0% of patients for Grades 3-4. The most common Grades 3-4 AEs that we observed were neutropenia (30.0%) and leukopenia (25.0%). CONCLUSION: Low-dose apatinib combined with oral vinorelbine demonstrates potential efficacy and well tolerated for pretreated HER2-negative mBC.

Monocytic myeloid-derived suppressor cells as an immune indicator of early diagnosis and prognosis in patients with sepsis.

BACKGROUND: Immunosuppression is a leading cause of septic death. Therefore, it is necessary to search for biomarkers that can evaluate the immune status of patients with sepsis. We assessed the diagnostic and prognostic value of low-density neutrophils (LDNs) and myeloid-derived suppressor cells (MDSCs) subsets in the peripheral blood mononuclear cells (PBMCs) of patients with sepsis. METHODS: LDNs and MDSC subsets were compared among 52 inpatients with sepsis, 33 inpatients with infection, and 32 healthy controls to investigate their potential as immune indicators of sepsis. The percentages of LDNs, monocytic MDSCs (M-MDSCs), and polymorphonuclear MDSCs (PMN-MDSCs) in PBMCs were analyzed. Sequential organ failure assessment (SOFA) scores, C-reactive protein (CRP), and procalcitonin (PCT) levels were measured concurrently. RESULTS: The percentages of LDNs and MDSC subsets were significantly increased in infection and sepsis as compared to control. MDSCs performed similarly to CRP and PCT in diagnosing infection or sepsis. LDNs and MDSC subsets positively correlated with PCT and CRP levels and showed an upward trend with the number of dysfunctional organs and SOFA score. Non-survivors had elevated M-MDSCs compared with that of patients who survived sepsis within 28 days after enrollment. CONCLUSIONS: MDSCs show potential as a diagnostic biomarker comparable to CRP and PCT, in infection and sepsis, even in distinguishing sepsis from infection. M-MDSCs show potential as a prognostic biomarker of sepsis and may be useful to predict 28-day hospital mortality in patients with sepsis.

Effectiveness and tolerability of programmed cell death protein-1 inhibitor + chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers.

BACKGROUND: The combination of programmed cell death protein-1 (PD-1) inhibitor and chemotherapy is approved as a standard first- or second-line treatment in patients with advanced oesophageal or gastric cancer. However, it is unclear whether this combination is superior to chemotherapy alone. AIM: To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, or oesophageal carcinoma. METHODS: We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer. We employed either random or fixed models to analyze the outcomes of each clinical trial, encompassing data on overall survival (OS), progression-free survival (PFS), objective response rate, and adverse events (AEs). RESULTS: Nine phase 3 clinical trials (7016 advanced oesophageal and gastric cancer patients) met the inclusion criteria. Our meta-analysis demonstrated that the pooled PD-1 inhibitor + chemotherapy group had a significantly longer OS than the chemotherapy-alone group [hazard ratio (HR) = 0.76, 95% confidence interval (CI): 0.71-0.81]; the pooled PFS result was consistent with that of OS (HR = 0.67, 95%CI: 0.61-0.74). The count of patients achieving an objective response in the PD-1 inhibitor + chemotherapy group surpassed that of the chemotherapy-alone group [odds ratio (OR) = 1.86, 95%CI: 1.59-2.18]. AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group, regardless of whether ≥ grade 3 only (OR = 1.30, 95%CI: 1.07-1.57) or all AE grades (OR = 1.88, 95%CI: 1.39-2.54) were examined. We performed a subgroup analysis based on the programmed death-ligand 1 (PD-L1) combined positive score (CPS) and noted extended OS and PFS durations within the CPS ≥ 1, CPS ≥ 5, and CPS ≥ 10 subgroups of the PD-1 inhibitor + chemotherapy group. CONCLUSION: In contrast to chemotherapy alone, the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer, GEJ tumor, or oesophageal cancer. This holds true particularly for individuals with PD-L1 CPS scores of ≥ 5 and ≥ 10.

In-orbit dark count rate performance and radiation damage high-temperature annealing of silicon avalanche photodiode single-photon detectors of the Micius satellite.

Silicon avalanche photodiode (APD) single-photon detectors in space are continuously affected by radiation, which gradually degrades their dark count performance. From August 2016 to June 2023, we conducted approximately seven years (2507 days) of in-orbit monitoring of the dark count performance of APD single-photon detectors on the Micius Quantum Science Experimental Satellite. The results showed that due to radiation effects, the dark count growth rate was approximately 6.79 cps/day @ -24 °C and 0.37 cps/day @ -55 °C, with a significant suppression effect on radiation-induced dark counts at lower operating temperature. Based on the proposed radiation damage induced dark count annealing model, simulations were conducted for the in-orbit dark counts of the detector, the simulation results are consistent with in-orbit test data. In May 2022, four of these detectors underwent a cumulative 5.7 hours high-temperature annealing test at 76 °C, dark count rate shows no measurable changes, consistent with annealing model. As of now, these ten APD single-photon detectors on the Micius Quantum Science Experimental Satellite have been in operation for approximately 2507 days and are still functioning properly, providing valuable experience for the future long-term space applications of silicon APD single-photon detectors.

Tuning capsid formation dynamics in recombinant adeno-associated virus producing synthetic cell lines to enhance full particle productivity.

Recombinant adeno-associated virus (rAAV) is widely used as an in vivo delivery vector for gene therapy. It is used in a very large dose, and the large quantities required for broad applications present manufacturing challenges. We have developed a synthetic biology platform of constructing cell lines integrated with essential viral genes which can be induced to produce rAAV without plasmid transfection or virus transduction. Through iterative design-construct-characterization cycles, we have showcased the potential of this synthetic cell production system. Systems characterization of the dynamics of viral transcripts and proteins as well as virus assembly and packaging revealed that the expression level and balance of viral genome and capsid protein are keys to not only the productivity but also the full particle content, an important product quality attribute. Boosting cap gene expression by sequential transfection and integration of multiple copies of the cap gene elevated the rAAV titer to levels on a par with traditional plasmid transfection and virus infection. However, overexpression of the cap gene shifted the balance and kinetics of the genome and capsid. We independently tuned the dynamics of genome amplification and capsid protein synthesis by modulating the induction concentration as well as the time profile, and significantly enhanced full particle content while maintaining a high productivity. This strategy of constructing an inducible stable producer cell line is readily adaptable to rAAV vectors of different serotypes and payloads. It can greatly facilitate scalable production of gene therapy vectors.

Construction of a versatile fusion protein for targeted therapy and immunotherapy.

Antibody (Ab)-based drugs have been widely used in targeted therapies and immunotherapies, leading to significant improvements in tumor therapy. However, the failure of Ab therapy due to the loss of target antigens or Ab modifications that affect its function limits its application. In this study, we expanded the application of antibodies (Abs) by constructing a fusion protein as a versatile tool for Ab-based target cell detection, delivery, and therapy. We first constructed a SpaC Catcher (SpaCC for short) fusion protein that included the C domains of Staphylococcal protein A (SpaC) and the SpyCatcher. SpaCC conjugated with SpyTag-X (S-X) to form the SpaCC-S-X complex, which binds non-covalently to an Ab to form the Ab-SpaCC-S-X protein complex. The "X" can be a variety of small molecules such as fluoresceins, cell-penetrating peptide TAT, Monomethyl auristatin E (MMAE), and DNA. We found that Ab-SpaCC-S-FITC(-TAT) could be used for target cell detection and delivery. Besides, we synthesized the Ab-SpaCC-SN3-MMAE complex by linking Ab with MMAE by SpaCC, which improved the cytotoxicity of small molecule toxins. Moreover, we constructed an Ab-DNA complex by conjugating SpaCC with the aptamer (Ap) and found that Ab-SpaCC-SN3-Ap boosted the tumor-killing function of T-cells by retargeting tumor cells. Thus, we developed a multifunctional tool that could be used for targeted therapies and immunotherapies, providing a cheap and convenient novel drug development strategy.