Combinational zimberelimab plus lenvatinib and chemotherapy for alpha-fetoprotein elevated, advanced gastric cancer patients (AFPGC): a phase 1 dose-escalation study.

BACKGROUND: Alpha-fetoprotein elevated gastric cancer (AFPGC) got growing interests for its aggressive nature and unfavorable prognosis. Here, a phase 1 dose escalation study was conducted to evaluate safety and efficacy of zimberelimab (GLS-010, anti-PD-1) plus lenvatinib and chemotherapy (XELOX) as the first-line treatment for AFPGC. METHODS: Histologically confirmed HER2-negative, advanced GC patients with elevated serum AFP level (≥ 20 ng/ml) were screened. Using a 3 + 3 dose escalation design, patients were administered varying doses of lenvatinib (12, 16, 20 mg) with GLS-010 and XELOX. The primary endpoints were safety and determination of recommended phase II dose (RP2D). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and disease control rate. RESULTS: Nine patients were enrolled with no dose-limiting toxicities observed. Most frequent treatment-related AEs were fatigue (55.6%), hand-foot syndrome (55.6%) and rash (55.6%), and no grade ≥ 4 AEs were reported. All patients exhibited disease control with ORR reaching 33.3%. The median PFS and OS reached 7.67 months (95% CI 4.07-11.27) and 13.17 months (95% CI 2.78-23.56), respectively. Serum AFP level was found correlated with therapeutic responses. Further 16s rRNA sequencing analysis demonstrated altered gut microbiota with elevated abundance of Lachnospiraceae bacterium-GAM79 and Roseburia hominis A2-183. CONCLUSIONS: GLS-010 plus lenvatinib and XELOX demonstrated a manageable safety profile with promising efficacy for AFPGC. With RP2D of lenvatinib determined as 16 mg, further expansion cohort is now ongoing. Translational investigation suggested that serum AFP can be indictive for therapeutic responses and certain microbiota species indicating favorable responses to immunotherapy was elevated after the combinational treatment.

Erratum: Hypoxia induced exosomal circRNA promotes metastasis of Colorectal Cancer via targeting GEF-H1/RhoA axis: Erratum.

[This corrects the article DOI: 10.7150/thno.44419.].

Bi-Interlayer Strategy for Modulating NiCoP-Based Heterostructure toward High-Performance Aqueous Energy Storage Devices.

Nickel-cobalt (NiCo) phosphides (NCPs) possess high electrochemical activity, which makes them promising candidates for electrode materials in aqueous energy storage devices, such as supercapacitors and zinc (Zn) batteries. However, the actual specific capacitance and rate capability of NCPs require further improvement, which can be achieved through reasonable heterostructural design and loading conditions of active materials on substrates. Herein, novel hierarchical Bi-NCP heterogeneous structures with built-in electric fields consisting of bismuth (Bi) interlayers (electrodeposited on carbon cloth (CC)) are designed and fabricated to ensure the formation of uniform high-load layered active materials for efficient charge and ion transport. The resulting CC/Bi-NCP electrodes show a uniform, continuous, and high mass loading (>3.5 mg) with a superior capacitance reaching 1200 F g-1 at 1 A g-1 and 4129 mF cm-2 at 1 mA cm-2 combined with high-rate capability and durable cyclic stability. Moreover, assembled hybrid supercapacitors (HSCs), supercapatteries, and alkaline Zn-ion (AZBs) batteries constructed using these electrodes deliver high energy densities of 64.4, 81.8, and 319.1 Wh kg-1, respectively. Overall, the constructed NCPs with excellent aqueous energy storage performance have the potential for the development of novel transition metal-based heterostructure electrodes for advanced energy devices.

Genome-wide CNV analysis reveals candidate genes associated with milk production traits in water buffalo (Bubalus bubalis).

Buffaloes are vital contributors to the global dairy industry. Understanding the genetic basis of milk production traits in buffalo populations is essential for breeding programs and improving productivity. In this study, we conducted whole-genome resequencing on 387 buffalo genomes from 29 diverse Asian breeds, including 132 river buffaloes, 129 swamp buffaloes, and 126 crossbred buffaloes. We identified 36,548 copy number variant (CNVs) spanning 133.29 Mb of the buffalo genome, resulting in 2,100 copy number variant regions (CNVRs), with 1,993 shared CNVRs being found within the studied buffalo types. Analyzing CNVRs highlighted distinct genetic differentiation between river and swamp buffalo subspecies, verified by evolutionary tree and principal component analyses. Admixture analysis grouped buffaloes into river and swamp categories, with crossbred buffaloes displaying mixed ancestry. To identify candidate genes associated with milk production traits, we employed 3 approaches. First, we used Vst-based population differentiation, revealing 11 genes within CNVRs that exhibited significant divergence between different buffalo breeds, including genes linked to milk production traits. Second, expression quantitative loci (eQTL) analysis revealed differential expression of CNVR-driven genes (DECGs) associated with milk production traits. Notably, known milk production-related genes were among these DECGs, validating their relevance. Last, a genome-wide association study (GWAS) identified 3 CNVRs significantly linked to peak milk yield. Our study provides comprehensive genomic insights into buffalo populations and identifies candidate genes associated with milk production traits. These findings facilitate genetic breeding programs aimed at increasing milk yield and improving quality in this economically important livestock species.

Adverse Reactions in Relapsed/Refractory B-Cell Lymphoma Administered with Chimeric Antigen Receptor T Cell Alone or in Combination with Autologous Stem Cell Transplantation.

(1) Background: The combination of CAR-T with ASCT has been observed to enhance the efficacy of CAR-T cell therapy. However, the impact of this combination on adverse reactions is still uncertain. (2) Methods: Between January 2019 and February 2023, 292 patients diagnosed with r/r B-cell lymphoma received either CAR-T therapy alone or in combination with ASCT at our institution. We evaluated the incidence of CRS and CRES and utilized a logistic regression model to identify factors contributing to severe CRS (grade 3-4) and CRES (grade 3-4). (3) Results: The overall incidence of CRS and CRES was 78.9% and 8.2% in 147 patients receiving CAR-T alone, and 95.9% and 15.2% in 145 patients receiving CAR-T combined with ASCT, respectively. The incidence of overall CRS (p < 0.0001) and mild CRS (grade 1-2) (p = 0.021) was elevated in the ASCT combined with CAR-T group. No significant difference was observed in severe CRS and CRES between the groups. Among the 26 cases of lymphoma involving the central nervous system (CNS), 96.2% (25/26) developed CRS (15.4% grade 3-4), and 34.6% (9/26) manifested CRES (7.7% grade 3-4). Female patients had a lower incidence of severe CRS but a higher incidence of severe CRES. Lymphomas with CNS involvement demonstrated a higher risk of CRES compared to those without central involvement. (4) Conclusions: The combination of ASCT with CAR-T demonstrated a preferable option in r/r B-cell lymphoma without an increased incidence of severe CRS and CRES.

Anti-PD-L1 antibody TQB2450 combined with tyrosine kinase receptor inhibitor AL2846 for immunotherapy-refractory advanced hepatocellular carcinoma and esophageal squamous cell carcinoma: A prospective phase 1b cohort study.

BACKGROUND: Effective systemic therapy remains limited for advanced esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma (HCC), particularly after prior failed treatment with immune checkpoint inhibitors (ICIs). Theoretically, a combination of tyrosine kinase inhibitors (TKIs) with ICIs may restore immunotherapy sensitivity. METHODS: In this phase 1b study, patients received AL2846, an antiangiogenic TKI with multiple targets (c-MET, VEGFR1, c-KIT, Axl, RET, KDR, and VEGFR3), in combination with an anti-PD-L1 antibody (TQB2450) until disease progression, intolerable toxicity, death, or discontinuation for any cause. The primary end points included overall response rate (ORR) and safety, with secondary end points encompassing progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response. RESULTS: Between November 2021 and September 2022, 18 patients with ESCC and 15 patients with HCC, whose ORR was 11.1% (95% confidence interval [CI], 3.1%-32.8%) and 0%, respectively, were enrolled. Adverse events (AEs) of any grade and treatment-related AEs were documented in 32 patients (97.0%) and 31 patients (93.9%), respectively. Grade 3 or higher AEs were observed in 10 patients (30.3%), with vomiting (6.1%) and infectious pneumonia (9.1%) being the most prevalent. Median PFS and OS values were 3.22 months (95% CI, 1.35-5.68 months) and 5.98 months (95% CI, 3.71-8.87 months), respectively, in patients with ESCC, and 5.55 months (95% CI, 2.66 months to not evaluable [NE]) and 16.72 months (95% CI, 4.86 months to NE), respectively, in patients with HCC. The DCRs were 66.7% (95% CI, 43.75%-83.72%) in patients with ESCC and 73.3% (95% CI, 48.05%-89.10%) in patients with HCC. CONCLUSIONS: Combined TQB2450 and AL2846 therapy exhibited a favorable safety profile in immunotherapy-refractory patients with advanced ESCC and HCC.

Porous Aromatic Frameworks Enabling Polyiodide Confinement toward High Capacity and Long Lifespan Zinc-Iodine Batteries.

Aqueous zinc-iodine batteries (AZIBs) are attracting increasing attention because of their high safety and abundance of resources. However, the performance of AZIBs is compromised by inadequate confinement of soluble polyiodides, the undesired shuttle effect, and slow reaction kinetics. In this study, a porous aromatic framework (PAF) with abundant benzene motifs and a well-organized pore structure is adopted as the iodine host, which exhibits high iodine adsorption capacity and robust polyiodide confinement. Both experimental characterizations and theoretical simulations indicate that the interactions between iodine species and the PAF-1 facilitate the redox reaction by coupling the electronic structures of the active species in the framework. A comparison of PAF-1, PAF-5, and PAF-11 also emphasizes the structural advantages of the high surface area and interconnected three-dimensional channels of PAF-1. Consequently, the I2@PAF-1 cathode can deliver a high capacity of 328 mAh g-1 at 0.5 C, outstanding rate performance, and a stable cycling life of 20 000 cycles (86 % retention at 10 C). The robust polyiodide confinement and superb electrochemical performance of Zn-I2@PAF-1 provide insights into the practical application of PAFs as excellent electrode materials for AZIBs.

Azimuthal polarized quasi-bound states in the continuum based on rotational symmetry breaking.

Bound states in the continuum (BICs) allow to obtain an ultrahigh-quality-factor optical cavity. Nevertheless, BICs must be extended in one or more directions, substantially increasing the device footprint. Although super-cavity mode quasi-BICs supported by single nanopillars have been demonstrated recently, their low-quality factor and localized electromagnetic field inside the dielectric nanopillar are insufficient for high-sensitivity refractive index sensing applications. We propose a ring structure rotated by a dielectric sectorial nanostructure, which can achieve a high quality factor by breaking the rotational symmetry of the ring structure with a footprint as small as 3 µm2. As a straightforward application, we demonstrate high performance local refractive index and nanoscale film thickness sensing based on rotational symmetry breaking induced BICs. These BICs reach quality factor and sensitivity of one order of magnitude better than those of conventional super-cavity mode BICs. The proposed method provides insights into the design of compact high quality factor photonic devices, opening up new possibilities for applications in refractive index and nanoscale film thickness sensing.

Social isolation induces intestinal barrier disorder and imbalances gut microbiota in mice.

Social isolation, a known stressor, can have detrimental effects on both physical and mental health. Recent scientific attention has been drawn to the gut-brain axis, a bidirectional communication system between the central nervous system and gut microbiota, suggesting that gut microbes may influence brain function. This study aimed to explore the impact of social isolation on the intestinal barrier and gut microbiota. 40 male BALB/c mice were either individually housed or kept in groups for 8 and 15 weeks. Socially isolated mice exhibited increased anxiety-like behavior, with significant differences between the 8-week and 15-week isolation groups (P < 0.05). After 8 weeks of isolation, there was a reduction in tight junction protein expression in the intestinal mechanical barrier. Furthermore, after 15 weeks of isolation, both tight junction protein and mucin expression, key components of the intestinal chemical barrier, decreased. This was accompanied by a substantial increase in inflammatory cytokines (IL-6 mRNA, IL-10, and TNF-α) in colon tissue in the 15-week isolated group (P < 0.05). Additionally, Illumina MiSequencing revealed significant alterations in the gut microbiota of socially isolated mice, including reduced Firmicutes and Bacteroides compared to the control group. Lactobacillus levels also decreased in the socially isolated mice.

A real-world observation on thrombopoietic agents for patients with cancer treatment-induced thrombocytopenia in China: A multicenter, cross-sectional study.

BACKGROUND: Studies on various thrombopoietic agents for cancer treatment-induced thrombocytopenia (CTIT) in China are lacking. This study aimed to provide detailed clinical profiles to understand the outcomes and safety of different CTIT treatment regimens. METHODS: In this retrospective, cross-sectional study, 1664 questionnaires were collected from 33 hospitals between March 1 and July 1, 2021. Patients aged >18 years were enrolled who were diagnosed with CTIT and treated with recombinant interleukin 11 (rhIL-11), recombinant thrombopoietin (rhTPO), or a thrombopoietin receptor agonist (TPO-RA). The outcomes, compliance, and safety of different treatments were analyzed. RESULTS: Among the 1437 analyzable cases, most patients were treated with either rhTPO alone (49.3%) or rhIL-11 alone (27.0%). The most common combination regimen used was rhTPO and rhIL-11 (10.9%). Platelet transfusions were received by 117 cases (8.1%). In multivariate analysis, rhTPO was associated with a significantly lower proportion of platelet recovery, platelet transfusion, and hospitalization due to chemotherapy-induced thrombocytopenia (CIT) than rhIL-11 alone. No significant difference was observed in the time taken to achieve a platelet count of >100 × 109/L and chemotherapy dose reduction due to CIT among the different thrombopoietic agents. The outcomes of thrombocytopenia in 170 patients who received targeted therapy and/or immunotherapy are also summarized. The results show that the proportion of platelet recovery was similar among the different thrombopoietic agents. No new safety signals related to thrombopoietic agents were observed in this study. A higher proportion of physicians preferred to continue treatment with TPO-RA alone than with rhTPO and rhIL-11. CONCLUSIONS: This survey provides an overview of CTIT and the application of various thrombopoietic agents throughout China. Comparison of monotherapy with rhIL-11, rhTPO, and TPO-RA requires further randomized clinical trials. The appropriate application for thrombopoietic agents should depend on the pretreatment of platelets, treatment variables, and risk of bleeding. PLAIN LANGUAGE SUMMARY: To provide an overview of the outcome of cancer treatment-induced thrombocytopenia in China, our cross-sectional study analyzed 1437 cases treated with different thrombopoietic agents. Most of the patients were treated with recombinant interleukin 11 (rhIL-11) and recombinant thrombopoietin (rhTPO). rhTPO was associated with a significantly lower proportion of platelet recovery and platelet transfusion compared with rhIL-11.

A Bibliometric and Visual Analysis of the Current Status and Trends of Forensic Mixed Stain Research.

OBJECTIVES: To explore the context and hotspot changes of forensic mixed stain research through bibliometric approach. METHODS: The literature of forensic mixed stain included in the core collection of Web of Science database from 2011 to 2022 were collected as the study object, and the annual publication number, countrie (region), institution, journal, keywords, etc. were bibliometrically and visually analyzed using the R-based Bibliometrix 1.1.6 package and VOSviewer 1.6.18 software. RESULTS: A total of 732 articles on forensic mixed stain were included from 2011 to 2022, with the annual number of articles published and the annual citation frequency showing a steady increase year by year. Among the 59 countries (regions) with the most published articles, the United States ranked first with 246 articles, followed by China with 153 articles. The literature came from 104 journals, and the total number of articles published in the top 10 journals was 633. FORENSIC SCI INT GENET ranked first with 307 articles. Visual analysis using VOSviewer software showed that keywords could be divided into four research clusters, namely the genetic marker development group (blue), the mixed stain typing analysis theory group (red), the sequencing analysis group (yellow), and the case sample research group (green). It can be divided into four development stages in terms of different time periods: early development (2011-2013), middle development (2014-2016), rapid development (2017-2020) and latest development (2021-2022). CONCLUSIONS: The number of publications by domestic and foreign scholars in the study of mixed stain in forensic science is showing a relatively stable trend. Machine learning, next generation sequencing and other research have been the hottest topics that have attracted the most attention in recent years, which is expected to further develop the theory of mixed stain typing and sequencing analysis in forensic mixed stain research.

SIRT5 promote malignant advancement of chordoma by regulating the desuccinylation of c-myc.

Chordoma is a relatively rare and locally aggressive malignant tumor. Sirtuin (SIRT)5 plays pivotal roles in various tumors, but the role of SIRT5 in chordoma has not been found. This study was performed to investigate the regulatory effects of SIRT5 on cell proliferation, migration, and invasion and the underlying mechanism in chordoma. A xenograft tumor mouse model was established to assess tumor growth. Reverse transcription-quantitative polymerase chain reaction was used to analyze the mRNA levels of SIRT5 and c-myc. The effects of SIRT5 and c-myc on cell proliferation, migration, and invasion of chordoma cells were detected by cell counting kit-8, colony formation, and Transwell assays. The interaction between SIRT5 and c-myc was evaluated by co-immunoprecipitation (IP) assay. The succinylation of c-myc was analyzed by IP and Western blot. The results showed that SIRT5 expression was upregulated in chordoma tissues and cells. SIRT5 interacted with c-myc to inhibit the succinylation of c-myc at K369 site in human embryonic kidney (HEK)-293T cells. Silencing of SIRT5 suppressed the cell proliferation, migration, and invasion of chordoma cells, while the results were reversed after c-myc overexpression. Moreover, silencing SIRT5 suppressed tumor growth in mice. These findings suggested that SIRT5 promoted the malignant advancement of chordoma by regulating the desuccinylation of c-myc.

Development of surface-enhanced Raman scattering-sensing Method by combining novel Ag@Au core/shell nanoparticle-based SERS probe with hybridization chain reaction for high-sensitive detection of hepatitis C virus nucleic acid.

The ultrasensitive detection of hepatitis C virus (HCV) nucleic acid is crucial for the early diagnosis of hepatitis C. In this study, by combining Ag@Au core/shell nanoparticle (Ag@AuNP)-based surface-enhanced Raman scattering (SERS) tag with hybridization chain reaction (HCR), a novel SERS-sensing method was developed for the ultrasensitive detection of HCV nucleic acid. This SERS-sensing system comprised two different SERS tags, which were constructed by modifying Ag@AuNP with a Raman reporter molecule of 4-ethynylbezaldehyde, two different hairpin-structured HCR sequences (H1 or H2), and a detection plate prepared by immobilizing a capture DNA sequence onto the Ag@AuNP layer surface of the detection wells. When the target nucleic acid was present, the two SERS tags were captured on the surface of the Ag@AuNP-coated detection well to generate many "hot spots" through HCR, forming a strong SERS signal and realizing the ultrasensitive detection of the target HCV nucleic acid. The limit of detection of the SERS-sensing method for HCV nucleic acid was 0.47 fM, and the linear range was from 1 to 105 fM.

A single-centre, real-world study of BTK inhibitors for the initial treatment of MYD88mut /CD79Bmut diffuse large B-cell lymphoma.

BACKGROUND: MCD (MYD88L265P /CD79Bmut ) diffuse large B-cell lymphoma has a poor prognosis. There is no published clinical research conclusion regarding zanubrutinib or orelabrutinib for the initial treatment of MCD DLBCL. AIMS: This study aimed to analyse the efficacy and safety of Bruton's tyrosine kinase inhibitor (BTKi) (zanubrutinib or orelabrutinib) therapy for newly diagnosed DLBCL patients with MYD88mut and/or CD79Bmut . MATERIALS AND METHODS: Twenty-three newly diagnosed DLBCL patients with MYD88mut and/or CD79Bmut from June 2020 to June 2022 received BTKi combined with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or rituximab + lenalidomide (R2 ). A control group of 17 patients with MYD88mut and/or CD79Bmut DLBCL who received the standard R-CHOP therapy was also assessed. We retrospectively analysed clinical characteristics, safety, overall response rate (ORR), complete response (CR) rate and progression-free survival (PFS) of the two groups. RESULTS: The main clinical features were a high International Prognostic Index (IPI) score (≥3, 22/40, 55%) and a high rate of extranodal involvement (27/40,67.5%). Among the 23 DLBCL patients, 18 received BTKi + R-CHOP, and five elderly DLBCL patients were treated with BTKi + R2 . Compared with those in the control group (ORR 70.6%, CRR 52.9%, 1-year PFS rate 41.2%), improved ORR, CRR and PFS results were observed in the BTKi + R-CHOP group (100%, 94.4% and 88.9%, p = 0.019, 0.007, and 0.0001). In subgroup analyses based on genetic subtypes, cell origin, dual expression or IPI score, patients in the BTKi + R-CHOP group had better PFS than patients in the control group. In the BTKi + R-CHOP group, no significant difference was found in ORR, CRR and PFS based on subtype analysis, while BTKi-type subgroups exhibited statistically significant differences in 1-year PFS (p = 0.028). There were no significant differences in grade 3-4 haematological toxicity (p = 1) and grade 3-4 non-haematological toxicity (p = 0.49) between the BTKi + R-CHOP and R-CHOP treatment groups. In the BTKi + R2 group, the ORR was 100%, the CRR was 80%, and the 1-year PFS rate was 80%. The incidences of grade 3-4 haematologic toxicity and non-haematological toxicity were both 40%. No bleeding or cardiovascular events of grade 3 or higher occurred in any patients. DISCUSSION: The efficacy of BTKi combined with R-CHOP was similar to previous reports, which was significantly better than R-CHOP alone. It is necessary to fully consider that 14 patients in the BTKi + R-CHOP group received a BTKi as maintenance therapy when evaluating efficacy. Meanwhile, the addition of a BTKi may improve the prognosis of non-GCB, DEL or high-IPI-score DLBCL patients with MYD88mut and/or CD79Bmut . In our study, five elderly DLBCL patients with MYD88mut and/or CD79Bmut were achieved better ORR, CRR, PFS than the historical data of R-miniCHOP treatment and Ibrutinib + R2 treatment. However, the efficacy and benefit of BTKis for this type of DLBCL need to be further analysed using a larger sample size. CONCLUSION: This study suggests that newly diagnosed DLBCL patients with MYD88mut and/or CD79Bmut may benefit from BTKis according to real-world clinical data.

Chemotherapy re-use versus anti-angiogenic monotherapy as the third-line treatment of patients with metastatic colorectal cancer: a real-world cohort study.

BACKGROUND: There are various recommendations for third-line treatment in mCRC, however, there is no consensus on who is more suitable for particular strategy. Chemotherapy re-use in third-line setting is a common option in clinical practice. This study aimed to investigate the efficacy of third-line chemotherapy re-use by the comparison with that of anti-angiogenic monotherapy, and further find the population more suitable for third-line chemotherapy. METHODS: Using electronic medical records of patients with mCRC, a retrospective cohort study was conducted. A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting as control group were retrospectively collected. Baseline characteristics were analyzed using the χ² test or the Fisher's exact test. ROC curve and surv_cutpoint function of 'survminer' package in R software were used to calculate the cut-off value. Survival curves were plotted with the Kaplan-Meier method and were compared using the log-rank test. The Cox proportional hazard regression model was used to analyze the potential risk factors. RESULTS: A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting were retrospectively collected. Chemotherapy rechallenge was recorded in 93 patients (93/143, 65.0%), and the remaining patients chose new chemotherapeutic drugs that had not been previously used, including irinotecan-based (22/50), oxaliplatin-based (9/50), raltitrexed (9/50), gemcitabine (5/50) and other agents (5/50). The ORR and DCR of third-line chemotherapy reached 8.8%, 61.3%, respectively (anti-angiogenic monotherapy group: ORR 2.6%, DCR 47.4%). The mPFS and mOS of patients receiving chemotherapy were 4.9 and 12.0 m, respectively (anti-angiogenic monotherapy group: mPFS 2.7 m, mOS 5.2 m). Subgroup analyses found that patients with RAS/RAF mutation, longer PFS (greater than 10.6 m) in front-line treatment or larger tumor burden had better prognosis with third-line chemotherapy rather than anti-angiogenic monotherapy. CONCLUSIONS: Third-line chemotherapy re-use was effective in mCRC. Those with more aggressive characteristics (RAS/RAF mutant, larger tumor burden) or better efficacy of previous chemotherapy (longer PFS) were more appropriate for third-line chemotherapy, rather than anti-angiogenic monotherapy.

First-line sugemalimab with chemotherapy for advanced esophageal squamous cell carcinoma: a randomized phase 3 study.

Although antiprogrammed death 1 antibody plus chemotherapy has recently been approved for first-line esophageal squamous cell carcinoma (ESCC), antiprogrammed death-ligand 1 antibody may offer another combination option in this setting. In this multicenter, randomized, double-blinded phase 3 trial a total of 540 adults (aged 18-75 years) with unresectable, locally advanced, recurrent or metastatic ESCC and who had not received systemic treatment were enrolled. All patients were randomized at 2:1 to receive either sugemalimab (an anti-PD-L1 antibody; 1,200 mg) or placebo every 3 weeks for up to 24 months, plus chemotherapy (cisplatin 80 mg m-2 on day 1 plus 5-fluorouracil 800 mg m-2 day-1 on days 1-4) every 3 weeks for up to six cycles. At the prespecified interim analysis this study had met dual primary endpoints. With a median follow-up of 15.2 months, the prolongation of progression-free survival was statistically significant with sugemalimab plus chemotherapy compared with placebo plus chemotherapy (median 6.2 versus 5.4 months, hazard ratio 0.67 (95% confidence interval 0.54-0.82), P = 0.0002) as assessed by blinded independent central review. Overall survival was also superior with sugemalimab chemotherapy (median 15.3 versus 11.5 months, hazard ratio 0.70 (95% confidence interval 0.55-0.90, P = 0.0076). A significantly higher objective response rate (60.1 versus 45.2%) as assessed by blinded independent central review was observed with sugemalimab chemotherapy. The incidence of grade 3 or above treatment-related adverse events (51.3 versus 48.4%) was comparable between the two groups. Sugemalimab plus chemotherapy significantly prolonged progression-free survival and overall survival in treatment-naïve patients with advanced ESCC, with no unexpected safety signal. The ClinicalTrials.gov identifier is NCT04187352 .

Gastric cancer secreted miR-214-3p inhibits the anti-angiogenesis effect of apatinib by suppressing ferroptosis in vascular endothelial cells.

Different from necrosis, apoptosis, autophagy and other forms of cell death, ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated fatty acids under the action of iron divalent or lipoxygenase, leading to cell death. Apatinib is currently used in the third-line standard treatment of advanced gastric cancer, targeting the anti-angiogenesis pathway. However, Apatinib-mediated ferroptosis in vascular endothelial cells has not been reported yet. Tumor-secreted exosomes can be taken up into target cells to regulate tumor development, but the mechanism related to vascular endothelial cell ferroptosis has not yet been discovered. Here, we show that exosomes secreted by gastric cancer cells carry miR-214-3p into vascular endothelial cells and directly target zinc finger protein A20 to negatively regulate ACSL4, a key enzyme of lipid peroxidation during ferroptosis, thereby inhibiting ferroptosis in vascular endothelial cells and reducing the efficiency of Apatinib. In conclusion, inhibition of miR-214-3p can increase the sensitivity of vascular endothelial cells to Apatinib, thereby promoting the antiangiogenic effect of Apatinib, suggesting a potential combination therapy for advanced gastric cancer.

The effect of incentive spirometry in perioperative patients with lung cancer-a systematic review and meta-analysis.

BACKGROUND: Incentive spirometry (IS) as a routine respiratory therapy during the perioperative period has been widely used in clinical practice. However, the impact of IS on patients with perioperative lung cancer remains controversial. This review aimed to evaluate the efficacy of IS in perioperative pulmonary rehabilitation for patients with lung cancer. METHODS: Cochrane Library, PubMed, Web of Science, Ovid, CINAHL, Chinese National Knowledge Infrastructure, Weipu, and Wanfang Databases were searched from inception to 30 November 2023. Only randomized controlled trials were included in this systematic review. The PRISMA checklist served as the guidance for conducting this review. The quality assessment of the included studies was assessed by the Cochrane risk-of-bias tool. The meta-analysis was carried out utilizing Review Manager 5.4. Furthermore, sensitivity analysis and subgroup analysis were also performed. RESULTS: Nine studies recruited 1209 patients met our inclusion criteria. IS combined with other respiratory therapy techniques was observed to reduce the incidence of postoperative pulmonary complications, enhance pulmonary function, curtail the length of hospital stay, and lower the Borg score. Nevertheless, no improvements were found in the six-minute walk distance or quality of life score. CONCLUSIONS: Although IS demonstrates benefits as a component of comprehensive intervention measures for perioperative patients with lung cancer, it proves challenging to determine the precise impact of IS as a standalone component within the comprehensive intervention measures. Therefore, further researches are required to better understand the effectiveness of IS isolation and its interactions when integrated with additional respiratory therapies for these patients. CLINICAL TRIAL REGISTRATION: PROSPERO, https://www.crd.york.ac.uk/prospero/ , registry number: CRD42022321044.

Combined score based on plasma fibrinogen and platelet-lymphocyte ratio as a prognostic biomarker in esophageal squamous cell carcinoma.

BACKGROUND: Increasing evidence has showed that inflammatory biomarkers, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and fibrinogen can be used as predictors in the prognosis of esophageal squamous cell carcinoma (ESCC). The aim of this study was to explore prognostic value of these biomarkers and evaluate the clinicopathological and prognostic significance of combined score based on plasma fibrinogen and platelet-lymphocyte ratio (F-PLR score). METHODS: A total of 506 patients with ESCC were enrolled in this study. Harrell's concordance index (c-index) was used to determine the optimal cut-off values of these markers and evaluate their prognostic significance. The relationship between factors with survival rates (including overall survival [OS] and disease-free survival [DFS]) was explored by Kaplan-Meier curve, univariate analysis and multivariate cox hazard analysis. RESULTS: Our result indicated that high F-PLR score was significantly associated with longer tumor length and deeper depth of tumor invasion (p < 0.01). The result of Cox multivariable analysis showed that F-PLR score was an independent prognostic factor for OS (p = 0.002) and DFS (p = 0.003). In addition, F-PLR score presented the greater c-index values for OS and DFS compared with NLR, PLR and fibrinogen level. Our result also showed that the c-index values for OS and DFS were both greater in TNM + F-PLR than those in TNM stage alone. CONCLUSIONS: In conclusion, F-PLR score is a predictive biomarker for prognosis in patients with ESCC.

Pharmacological and mechanistic aspects of quercetin in osteoporosis.

Osteoporosis (OP) is a bone disease associated with increasing age. Currently, the most common medications used to treat OP are anabolic agents, anti-resorptive agents, and medications with other mechanisms of action. However, many of these medications have unfavorable adverse effects or are not intended for long-term use, potentially exerting a severe negative impact on a patient's life and career and placing a heavy burden on families and society. There is an urgent need to find new drugs that can replace these and have fewer adverse effects. Quercetin (Que) is a common flavonol in nature. Numerous studies have examined the therapeutic applications of Que. However, a comprehensive review of the anti-osteoporotic effects of Que has not yet been conducted. This review aimed to describe the recent studies on the anti-osteoporotic effects of Que, including its biological, pharmacological, pharmacokinetic, and toxicological properties. The outcomes demonstrated that Que could enhance OP by increasing osteoblast differentiation and activity and reducing osteoclast differentiation and activity via the pathways of Wnt/ß-catenin, BMP/SMAD/RUNX2, OPG/RANKL/RANK, ERK/JNK, oxidative stress, apoptosis, and transcription factors. Thus, Que is a promising novel drug for the treatment of OP.