Dual CTLA-4 and PD-1 checkpoint blockade using CS1002 and CS1003 (nofazinlimab) in patients with advanced solid tumors: A first-in-human, dose-escalation, and dose-expansion study.

BACKGROUND: This study investigated the safety and efficacy of an anti-CTLA-4 monoclonal antibody (CS1002) as monotherapy and in combination with an anti-PD-1 monoclonal antibody (CS1003) in patients with advanced/metastatic solid tumors. METHODS: The phase 1 study involved phase 1a monotherapy dose-escalation (part 1) and phase 1b combination therapy dose escalation (part 2) and expansion (part 3). Various dosing schedules of CS1002 (0.3, 1, or 3 mg/kg every 3 weeks, or 3 mg/kg every 9 weeks) were evaluated with 200 mg CS1003 every 3 weeks in part 3. RESULTS: Parts 1, 2, and 3 included a total of 13, 18, and 61 patients, respectively. No dose-limiting toxicities or maximum tolerated doses were observed. Treatment-related adverse events (TRAEs) were reported in 30.8%, 83.3%, and 75.0% of patients in parts 1, 2, and 3, respectively. Grade ≥3 TRAEs were experienced by 15.4%, 50.0%, and 18.3% of patients in each part. Of 61 patients evaluable for efficacy, 23 (37.7%) achieved objective responses in multiple tumor types. Higher objective response rates were observed with conventional and high-dose CS1002 regimens (1 mg/kg every 3 weeks or 3 mg/kg every 9 weeks) compared to low-dose CS1002 (0.3 mg/kg every 3 weeks) in microsatellite instability-high/mismatch repair-deficient tumors, melanoma, and hepatocellular carcinoma (50.0% vs. 58.8%, 14.3% vs. 42.9%, and 0% vs. 16.7%). CONCLUSION: CS1002, as monotherapy, and in combination with CS1003, had a manageable safety profile across a broad dosing range. Promising antitumor activities were observed in patients with immune oncology (IO)-naive and IO-refractory tumors across CS1002 dose levels when combined with CS1003, supporting further evaluation of this treatment combination for solid tumors. PLAIN LANGUAGE SUMMARY: CS1002 is a human immunoglobulin (Ig) G1 monoclonal antibody that blocks the interaction of CTLA-4 with its ligands and increases T-cell activation/proliferation. CS1003, now named nofazinlimab, is a humanized, recombinant IgG4 monoclonal antibody that blocks the interaction between human PD-1 and its ligands. In this original article, we determined the safety profile of CS1002 as monotherapy and in combination with CS1003. Furthermore, we explored the antitumor activity of the combination in anti-programmed cell death protein (ligand)-1 (PD-[L]1)-naive microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) pan tumors, and anti-PD-(L)1-refractory melanoma and hepatocellular carcinoma (HCC). CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising antitumor activities across CS1002 dose levels when combined with CS1003. This supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.

Bimodal DNA self-origami material with nucleic acid function enhancement.

BACKGROUND: The design of DNA materials with specific nanostructures for biomedical tissue engineering applications remains a challenge. High-dimensional DNA nanomaterials are difficult to prepare and are unstable; moreover, their synthesis relies on heavy metal ions. Herein, we developed a bimodal DNA self-origami material with good biocompatibility and differing functions using a simple synthesis method. We simulated and characterized this material using a combination of oxDNA, freeze-fracture electron microscopy, and atomic force microscopy. Subsequently, we optimized the synthesis procedure to fix the morphology of this material. RESULTS: Using molecular dynamics simulation, we found that the bimodal DNA self-origami material exhibited properties of spontaneous stretching and curling and could be fixed in a single morphology via synthesis control. The application of different functional nucleic acids enabled the achievement of various biological functions, and the performance of functional nucleic acids was significantly enhanced in the material. Consequently, leveraging the various functional nucleic acids enhanced by this material will facilitate the attainment of diverse biological functions. CONCLUSION: The developed design can comprehensively reveal the morphology and dynamics of DNA materials. We thus report a novel strategy for the construction of high-dimensional DNA materials and the application of functional nucleic acid-enhancing materials.

Acupuncture for functional dyspepsia: Bayesian meta-analysis.

BACKGROUND: Acupuncture stands out as a prominent complementary and alternative medicine therapy employed for functional dyspepsia (FD). We conducted a Bayesian meta-analysis to ascertain both the relative effectiveness and safety of various acupuncture methods in the treatment of functional dyspepsia. METHODS: We systematically searched eight electronic databases, spanning from their inception to April 2023. The eligibility criteria included randomized controlled trials investigating acupuncture treatments for FD. Study appraisal was conducted using the Cochrane risk of bias tool. Pairwise and network meta-analyses were conducted using RevMan 5.3 and ADDIS V.1.16.6 software. Bayesian network meta-analysis was performed to compare and rank the efficacy of different acupuncture therapies for FD symptoms. RESULTS: This study found that combining different acupuncture methods or using acupuncture in conjunction with Western medicine is more effective in improving symptoms of functional dyspepsia compared to using Western medicine alone. According to the comprehensive analysis results, notably, the combination of Western medicine and acupuncture exhibited superior efficacy in alleviating early satiation and postprandial fullness symptoms. For ameliorating epigastric pain, acupuncture combined with moxibustion proved to be the most effective treatment, while moxibustion emerged as the optimal choice for addressing burning sensations. Warming needle was identified as the preferred method for promoting motilin levels. CONCLUSION: The findings of this study demonstrate that acupuncture, both independently and in conjunction with other modalities, emerged as a secure and effective treatment option for patients with functional dyspepsia.

The clinical value of acupuncture for women with premature ovarian insufficiency: a systematic review and meta-analysis of randomized controlled trials.

Objective: The aim of this study was to evaluate the therapeutic implications of acupuncture on improving ovarian function in women diagnosed with premature ovarian insufficiency (POI) through the implementation of randomized clinical trials (RCTs). Methods: A comprehensive search of eight databases was conducted to identify RCTs up until 5 October 2023. The outcomes included the levels of sex hormones, antral follicle count (AFC), Kupperman score, and total effective rate. The risk of bias (RoB) tool was utilized to evaluate the quality of the included studies. In order to guarantee the robustness and reliability of the findings, subgroup and sensitivity analyses were performed to investigate potential sources of heterogeneity. Results: A total of 13 RCTs comprising 775 patients were included in the study. Acupuncture demonstrated significant efficacy in reducing follicle-stimulating hormone (FSH) [SMD = 0.83, 95% CI (0.27, 1.39), I 2 = 92%, p = 0.004], enhancing estradiol levels (E2) [SMD = 0.50, 95% CI (0.07, 0.93), p = 0.02, I 2 = 87%], and increasing anti-Müllerian hormone (AMH) [SMD = 0.24, 95% CI (0.05, 0.44), p = 0.01, I 2 = 8%], as well as improving the overall effective rate [RR = 1.22, 95% CI (1.10, 1.35), p < 0.01, I 2 = 14%]. Subgroup analysis revealed that compared with non-acupuncture therapy, the acupuncture with Chinese herbal medicine (CHM) and hormone replacement therapy (HRT) group exhibited a substantial reduction in FSH levels [SMD = 1.02, 95% CI (0.52, 1.51), I 2 = 60%, p < 0.01]. Furthermore, the acupuncture with CHM group also exhibited a substantial reduction [SMD = 4.59, 95% CI (1.53, 7.65), I 2 = 98%, p < 0.01]. However, only the acupuncture with CHM and HRT group demonstrated a significant increase in E2 levels [SMD = 0.55, 95% CI (0.23, 0.87), I 2 = 12%, p < 0.01]. Conclusion: Acupuncture has demonstrated superiority over non-acupuncture in diminishing serum FSH levels and increasing serum E2, AMH, and the overall efficacy rate in women diagnosed with POI. These research findings suggest the necessity for broader-scale research with meticulous designs to fully demonstrate the efficacy and safety of acupuncture in the treatment of women with POI. Systematic review registration: https://www.crd.york.ac.uk, identifier CRD42023467751.

RIP1 kinase inactivation protects against LPS-induced acute respiratory distress syndrome in mice.

Acute respiratory distress syndrome (ARDS) is characterized by lung tissue oedema and inflammatory cell infiltration, with limited therapeutic interventions available. Receptor-interacting protein kinase 1 (RIPK1), a critical regulator of cell death and inflammation implicated in many diseases, is not fully understood in the context of ARDS. In this study, we employed RIP1 kinase-inactivated (Rip1K45A/K45A) mice and two distinct RIPK1 inhibitors to investigate the contributions of RIP1 kinase activity in lipopolysaccharide (LPS)-induced ARDS pathology. Our results indicated that RIPK1 kinase inactivation, achieved through both genetic and chemical approaches, significantly attenuated LPS-induced ARDS pathology, as demonstrated by reduced polymorphonuclear neutrophil percentage (PMN%) in alveolar lavage fluid, expression of inflammatory and fibrosis-related factors in lung tissues, as well as histological examination. Results by tunnel staining and qRT-PCR analysis indicated that RIPK1 kinase activity played a role in regulating cell apoptosis and inflammation induced by LPS administration in lung tissue. In summary, employing both pharmacological and genetic approaches, this study demonstrated that targeted RIPK1 kinase inactivation attenuates the pathological phenotype induced by LPS inhalation in an ARDS mouse model. This study enhances our understanding of the therapeutic potential of RIPK1 kinase modulation in ARDS, providing insights for the pathogenesis of ARDS.

Three-birds-with-one-stone: An eco-friendly and renewable humic acid-derived material application strategy for macrolide antibiotic detection and multifunctional composite film preparation.

This research proposes a simple and novel strategy for the green detection of antibiotics along with the reduction of microplastic and humic acid (HA) hazards. The entire process is based on a single-step solvent-sieving method to separate HA into insoluble (IHA) and soluble (SHA) components, subsequently recombining and designing the application according to the original characteristics of selected fractions in accordance with the zero-waste principle. IHA was applied as a dispersive solid phase extraction (DSPE) sorbent without chemical modification for the enrichment of trace MACs in complex biological matrices. The recovery of MACs was 74.06-100.84 % in the range of 2.5-1000 µg∙kg-1. Furthermore, SHA could be combined with biodegradable polyvinyl alcohol (PVA) to prepare multifunctional composite films. SHA endows the PVA film with favorable mechanical properties, excellent UV shielding as well as oxidation resistance performance. Compared with pure PVA, the tensile strength, toughness, antioxidant and UV-protection properties were increased to 157.3 Mpa, 258.6 MJ·m-3, 78.6 % and 60 % respectively. This study achieved a green and economically valuable utilization of all components of waste HA, introduced a novel approach for monitoring and controlling harmful substances and reducing white pollution. This has significant implications for promoting sustainable development and recovering valuable resources.

Humoral immune responses primed by the alteration of gut microbiota were associated with galactose-deficient IgA1 production in IgA nephropathy.

Introduction: Galactose-deficient IgA1 (GdIgA1) is critical in the formation of immunodeposits in IgA nephropathy (IgAN), whereas the origin of GdIgA1 is unknown. We focused on the immune response to fecal microbiota in patients with IgAN. Methods: By running 16S ribosomal RNA gene sequencing, we compared IgAN samples to the control samples from household-matched or non-related individuals. Levels of plasma GdIgA1 and poly-IgA complexes were measured, and candidate microbes that can either incite IgA-directed antibody response or degrade IgA through specific IgA protease activities were identified. Results: The IgAN group showed a distinct composition of fecal microbiota as compared to healthy controls. Particularly, high abundance of Escherichia-Shigella was associated with the disease group based on analyses using receiver operating characteristic (area under curve, 0.837; 95% CI, 0.738-0.914), principle coordinates, and the linear discriminant analysis effect size algorithm (linear discriminant analysis score, 4.56; p < 0.001). Accordingly, the bacterial levels directly correlated with high titers of plasma GdIgA1(r = 0.36, p < 0.001), and patients had higher IgA1 against stx2(2.88 ± 0.46 IU/mL vs. 1.34 ± 0.35 IU/mL, p = 0.03), the main antigen of Escherichia-Shigella. Conversely, the healthy controls showed relatively higher abundance of the commensal bacteria that produce IgA-degrading proteases. Particularly, the abundance of some intestinal bacteria expressing IgA proteases showed an inverse correlation with the levels of plasma GdIgA1 in IgAN. Conclusion: Our data suggest that mucosal IgA production, including those of GdIgA1, is potentially linked to the humoral response to gut Escherichia-Shigella as one of the sources of plasma GdIgA1. Conversely, the IgA protease-producing microbiota in the gut are suppressed in patients with IgAN.