Epoxy-based multifunctional re-bondable polymer with self-healing, shape memory and superb bonding properties.

Thermoset epoxy resin-based materials are widely used, but their permanent cross-linked network limits their processability and reusability, which can lead to environmental burdens. In this work, by exploiting the weak reactivity of aniline to design appropriate reaction ratios, we achieved a linear link between the epoxy resin and the curing agent. This linear link, along with the crosslinking points provided by the flexibly branched polyurethanes, avoids the inherent brittleness associated with the highly crosslinked network of conventional epoxy resins. As a result, the adhesive exhibits extraordinary improvements in extensibility and toughness. The lap shear strength, tensile strength and elongation at break reach 11.9 MPa, 14.4 MPa and 607 %, respectively. The fracture toughness is as high as 109.6 kJ/m2, far beyond the existing epoxy adhesives. The synergistic effect of disulfide bonds and hydrogen bonds confers the adhesive with self-healing and repeatable bonding characteristics. The multi-level hydrogen bonding and appropriate phase separation structure are key to optimizing toughness, resulting in excellent comprehensive performance. The introduction of polyurethane not only improves toughness but also enhances the interfacial bonding force between the adhesive and the substrate, broadening the scope of applications. The prepared high-performance polymers provide new insights into reusable epoxy adhesives.

Efficacy and Safety of Chlortalidone and Hydrochlorothiazide in Prevention of Cardiovascular Diseases.

Background: The variance between guideline recommendations and real-world usage might stem from the perception that chlorthalidone poses a higher risk of adverse effects, although there is no clear evidence of disparities in cardiovascular outcomes. It is crucial to assess both the clinical cardiovascular effects and adverse reactions of both drugs for clinical guidance. In this study, we present a comprehensive and updated analysis comparing the efficacy and safety of chlorthalidone (CHLOR) versus hydrochlorothiazide (HCTZ) for the prevention of cardiovascular diseases through lower the blood pressure. Methods: We conducted a systematic literature search using reputable databases including PubMed, Embase, Cochrane, and Web of Science up to April 2023, to identify studies that compared the efficacy and safety of CHLOR versus HCTZ for the long term prognosis of cardiovascular disease. This analysis represents the most up-to-date and systematic evidence on the comparative efficacy and safety of CHLOR and HCTZ for cardiovascular diseases. Results: Our review included a total of 6 eligible articles with a cohort of 368,066 patients, of which 36,999 were treated with CHLOR and 331,067 were treated with HCTZ. The primary diagnosis studied in six articles was hypertension. Initial features between the two different groups were comparable across every possible outcome. These papers followed patients using the two drugs over a long period of time to compare the differences in the occurrence of cardiovascular disease, and the results were as follows, the confidence interval is described in square brackets, followed by the p-value: We measured the outcomes of myocardial infarction with an odds ratio (OR) of 0.80 [0.56, 1.14], p = 0.41, heart failure with an OR of 0.86 [0.64, 1.14], p = 0.05, cardiovascular events with an OR of 1.85 [0.53, 6.44], p = 0.34, non-cancer-related death with an OR of 1.02 [0.56, 1.85], p = 0.45, death from any cause with an OR of 1.95 [0.52, 7.28], p = 0.32, complication rate, stroke with an OR of 0.94 [0.80, 1.10], p = 0.45, hospitalization for acute kidney injury with an OR of 1.38 [0.40, 4.78], p = 0.61 and hypokalemia with an OR of 2.10 [1.15, 3.84], p = 0.01. Pooled analyses of the data revealed that CHLOR was associated with a higher incidence of hypokalemia compared to HCTZ and the results were statistically significant. Conclusions: CHLOR and HCTZ are comparable in efficacy for prevention cardiovascular diseases, with the only difference being a higher incidence of hypokalemia in patients using CHLOR compared to those using HCTZ. Considering the potential heterogeneity and bias in the analytical studies, these results should be interpreted with caution.

A phase II study of anlotinib plus whole brain radiation therapy for patients with NSCLC with multiple brain metastases.

BACKGROUND: Whole brain radiotherapy (WBRT) is the mainstay of treatment for patients with non-small cell lung cancer (NSCLC) with multiple brain metastases (BMs); however, the BRAIN study showed that the efficacy of WBRT is unsatisfactory. This prospective phase II study aimed to evaluate the efficacy and safety of WBRT combined with anlotinib, a novel anti-angiogenic multi-target tyrosine kinase inhibitor (TKI), in patients with multiple BMs (>3) from advanced NSCLC. METHODS: Patients with advanced NSCLC with multiple BMs who had received two or more lines of treatment were eligible for enrolment into this study. All patients were treated with anlotinib (8-12 mg, QD, on days 1-14 of a 21-day cycle) combined with WBRT (DT 30 Gy/12 F), followed by maintenance therapy with anlotinib until disease progression or treatment intolerance. The primary endpoint of this study was the intracranial progression-free survival (iPFS). The secondary endpoints were intracranial objective response rate (iORR), intracranial disease control rate (iDCR), overall survival (OS) and treatment safety. RESULTS: Between May 2019 and January 2021, 28 patients were enrolled, all of whom were evaluable for efficacy and safety. The median age was 57.7 years, and 46.4% were male. Twenty-five patients had adenocarcinoma (89.3%), six had EGFR mutations (21.4%) and two had ALK mutations (7.1%). The median iPFS was 11.1 months (95% confidence interval (CI): 5.4-16.8 months) and the median OS was 13.4 months (95% CI: 5.2-21.6 months). The iORR was 71.4% (six complete responses + 14 partial responses). The most frequently observed adverse events (AEs) were hypertension (71.4%), fatigue (64.3%), anorexia (46.4%), and foot and hand skin reactions (25.0%). No patients developed ≥ grade 4 AEs. No intracranial haemorrhages occurred during treatment. Dose adjustment due to AEs occurred in 17.9% of patients. CONCLUSIONS: Anlotinib combined with WBRT is effective and well-tolerated in patients with NSCLC with multiple BMs.

Hyaluronic acid modified prussian blue analogs/TiO2 janus nanostructures through efficient charge separation to enhance photocatalytic-driven dual gas for achieve multimodal treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the abnormal proliferation of fibroblast-like synoviocytes and changes in the joint synovium, including elevated reactive oxygen species, decreased pH, and reduced oxygen content. In this study, we synthesized a novel nanocomposite material, namely HA-PBA-TiO2 Janus nanocomposite, by in situ etching in prussian blue analogs doped with Co and Ni, followed by the growth of TiO2 nano-flowers and encapsulation in hyaluronic acid. When these janus nanoparticles diffused to the inflammatory sites of RA, they exhibited outstanding photocatalytic water-splitting ability under 660 nm laser irradiation, generating H2 and O2. This capability helps ameliorate the hypoxic microenvironment at RA inflammatory sites by eliminating reactive oxygen species (ROS) and enhancing antioxidation and oxygenation. Furthermore, owing to the doping of Co and Ni, HA-PBA-TiO2 exhibits photothermal conversion capability, which significant damage to FLS upon exposure to 660 nm laser irradiation, thereby controlling their aberrant proliferation. Through a series of in vitro and in vivo experiments, we validated the significant therapeutic efficacy of HA-PBA-TiO2 in treating RA, highlighting its broad prospects for application.

Effect of Polygonatum sibiricum on biological toxicity of zinc oxide nanoparticles during respiratory exposure.

Although zinc oxide nanoparticles (ZnO NPs) with distinct physicochemical properties have attracted great attention, the application of ZnO NPs is still limited due to their potential biotoxicity. In this work, ZnO-Polygonatum sibiricum (PS) NPs are synthesized to overcome this challenge. The ZnO NPs stably combine with PS according to microstructural observation, particle size distribution, zeta potential results and Fourier transform infrared spectroscopy analysis. The cytotoxicity of ZnO NPs is alleviated by combining them with PS as a consequence of the diminished generation of reactive oxygen species and reinforced superoxide dismutase activity. Furthermore, the respiratory index and histopathologic results of mice exposed to NPs manifest that the pulmonary dysfunction caused by ZnO NPs is avoided in the ZnO-PS NPs group. This study provides the foundations for the amelioration and universal utilization of ZnO NPs and emphasizes the potential of ZnO-PS NPs in biomedical applications.

Rnf111 has a pivotal role in regulating development of definitive hematopoietic stem and progenitor cells through the Smad2/3-Gcsfr/NO axis in zebrafish.

The ubiquitination or SUMOylation of hematopoietic related factors plays pivotal roles in hematopoiesis. RNF111, known as a ubiquitin ligase (Ubl), is a newly discovered SUMO-targeted ubiquitin ligase (STUbl) involved in multiple signaling pathways mediated by TGF-ß family members. However, its role in hematopoiesis remains unclear. Herein, a heritable Rnf111 mutant zebrafish line was generated by CRISPR/Cas9-mediated genome editing. Impaired hematopoietic stem and progenitor cells (HSPC) of definitive hematopoiesis was found in Rnf111 deficient mutants. Ablation of Rnf111 resulted in decreased phosphorylation of Smad2/3 in HSPC. Definitive endoderm 2 inducer (IDE2), which specifically activates TGF-ß signaling and downstream Smad2 phosphorylation, can restore the definitive hematopoiesis in Rnf111-deficient embryos. Further molecular mechanism studies revealed that Gcsfr/NO signaling was an important target pathway of Smad2/3 involved in Rnf111-mediated HSPC development. In conclusion, our study demonstrated that Rnf111 contributes to the development of HSPC by maintaining Smad2/3 phosphorylation and the Gcsfr/NO signaling pathway activation. Keywords: Rnf111, Ubiquitin ligase (UbL), HSPC, Smad2/3, Gcsfr/NO.

Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Recombinant Neorudin, a New Anticoagulant Drug in Patients With Acute Coronary Syndrome.

This study evaluated the safety, tolerability, pharmacodynamics, and pharmacokinetics of recombinant neorudin (EPR-hirudin [EH]) in patients with acute coronary syndrome (ACS), providing a basis for further therapeutic research. This open-label, single-center, nonrandomized, nonblinded, and noncontrolled trial categorized 24 patients with nonprogressive ACS who met the screening criteria into 3 groups. They received an intravenous injection of neorudin (0.4 mg/kg), followed by an intravenous drip at doses of 0.15, 0.30, and 0.45 mg/kg/h for 3 days in the low-, medium-, and high-dose groups, respectively. The safety, tolerability, pharmacodynamics, and pharmacokinetics of EH were assessed after treatment, indicating that neorudin was safe and well tolerated in nonprogressive ACS. No serious adverse events or clinical composite end points were observed. The activated partial thromboplastin time and thrombin time increased significantly and dose dependently following EH administration across all groups compared to pretreatment values. Conversely, thrombin activity significantly decreased after drug administration but returned to baseline levels shortly after drug withdrawal. Within the administered dose range, neorudin exposure increased with the dose, and its half-life was approximately 2 hours. Neorudin was found to be safe and tolerable for treating patients with nonprogressive ACS, demonstrating therapeutic efficacy at doses up to 0.45 mg/kg/h over a 3-day period.

MicroRNA-Triggered Programmable DNA-Encoded Pre-PROTACs for Cell-Selective and Controlled Protein Degradation.

Proteolysis-targeting chimeras (PROTACs) have accelerated drug development; however, some challenges still exist owing to their lack of tumor selectivity and on-demand protein degradation. Here, we developed a miRNA-initiated assembled pre-PROTAC (miRiaTAC) platform that enables the on-demand activation and termination of target degradation in a cell type-specific manner. Using miRNA-21 as a model, we engineered DNA hairpins labeled with JQ-1 and pomalidomide and facilitated the modular assembly of DNA-encoded pre-PROTACs through a hybridization chain reaction. This configuration promoted the selective polyubiquitination and degradation of BRD4 upon miR-21 initiation, highlighting significant tumor selectivity and minimal systemic toxicity. Furthermore, the platform incorporates photolabile groups, enabling the precise optical control of pre-PROTACs during DNA assembly/disassembly, mitigating the risk of excessive protein degradation. Additionally, by introducing a secondary ligand targeting CDK6, these pre-PROTACs were used as a modular scaffold for the programmable assembly of active miRiaTACs containing two different warheads in exact stoichiometry, enabling orthogonal multitarget degradation. The integration of near-infrared light-mediated photodynamic therapy through an upconversion nanosystem further enhanced the efficacy of the platform with potent in vivo anticancer activity. We anticipate that miRiaTAC represents a significant intersection between dynamic DNA nanotechnology and PROTAC, potentially expanding the versatility of PROTAC toolkit for cancer therapy.

Benign polymorphisms in the BRCA genes with linkage disequilibrium is associated with cancer characteristics.

Germline pathogenic mutation of the BRCA gene increases the prevalence of breast cancer. Reports on the benign variants of BRCA genes are limited. However, the definition of these variants might be altered with the accumulation of clinical evidence. Therefore, in the present study, we focused on benign single nucleotide polymorphisms (SNPs) of BRCA genes. Linkage disequilibrium was calculated from whole genome sequencing of the BRCA genes obtained from 500 healthy controls and 49 breast cancer patients. Sanger sequencing was used to confirm the mutation. The linkage disequilibrium was noted for seven and three SNPs in the BRCA1 and BRCA2 genes, respectively. Breast cancer with BRCA1/2 linkage disequilibrium was not correlated with a personal history of benign diseases or family history of cancer. Nevertheless, breast cancer with BRCA1 linkage disequilibrium was correlated with high tumor-infiltrating lymphocytes and positive extensive intraductal components. The patients with BRCA1 linkage disequilibrium tended to have worse disease-specific survival. Cancers with BRCA2 linkage disequilibrium are associated with a lower ratio of grade III cancer. Moreover, patients with BRCA2 linkage disequilibrium tended to have better overall survival. In conclusion, linkage disequilibrium from benign SNPs of the BRCA genes potentially affects cancer characteristics.

Optimizing the combination of chemotherapeutic drugs along with radiotherapy for extranodal NK/T-cell lymphoma.

Background: Extranodal natural killer/T-cell lymphoma (ENKTCL) has a unique treatment principle. However, the optimal combination of drugs along with radiotherapy (RT) is unknown. Design: Retrospective cohort study. Objectives: We screened multiple drug combinations to identify the most efficacious therapeutic combinations. Methods: We reviewed 3105 patients who received 40 chemotherapy regimens with different combinations of 9 drug classes and/or RT. Least absolute shrinkage and selection operator and multivariable Cox regression analyses were used to screen efficacious single drugs and identify optimal combinations for overall survival (OS). Inverse probability of treatment weighting (IPTW) and multivariable analyses were used to compare survival between treatment regimens. Results: Screening and validation revealed RT, asparaginase (ASP), and gemcitabine (GEM) to be the most efficacious single modality/drug. RT remained an important component of first-line treatment, whereas ASP was a fundamental drug of non-anthracycline (ANT)-based regimens. Addition of RT to non-ANT-based or ASP/GEM-based regimens, or addition of an ASP-drug into ANT-based or GEM/platinum-based regimens, improved 5-year OS significantly. Use of ASP/GEM-based regimens was associated with significantly higher 5-year OS (79.9%) compared with ASP/ANT-based (69.2%, p = 0.001), ASP/methotrexate-based (63.5%, p = 0.011), or ASP/not otherwise specified-based (63.2%, p < 0.001) regimens. The survival benefit of ASP/GEM-based regimens over other ASP-based regimens was substantial across risk-stratified and advanced-stage subgroups. The survival benefits of a combination of RT, ASP, and GEM were consistent after adjustment for confounding factors by IPTW. Conclusion: These results suggest that combining ASP/GEM with RT for ENKTCL is an efficacious and feasible therapeutic option and provides a rationale and strategy for developing combination therapies.

The Tetratricopeptide repeat protein TaTPR-B1 regulates spike compactness in bread wheat.

Spike compactness (SC) is strongly associated with wheat (Triticum aestivum L.) grain yield. In this study, we conducted a quantitative trait locus (QTL) analysis using a doubled haploid (DH) population derived from a cross between two common wheat varieties with contrasting spike morphology, revealing 16 stable QTLs associated with SC. The effect of a major QTL, QSc.cau-6B.1, was validated in 231 F7 recombinant inbred lines (RILs) derived from the same cross as the DH population. Using two residual heterozygous lines (RHLs), we delimited QSc.cau-6B.1 to an approximately 0.5-Mbp physical interval containing four high-confidence genes. The tetratricopeptide repeat-TraesCS6B03G1214400 (TaTPR-B1) was the priority candidate gene according to sequence and expression variations between near-isogenic lines. Accordingly, TaTPR-B1 knockout in the common wheat variety 'CB037' significantly increased SC compared to the wild type (WT). Conversely, TaTPR-B1 overexpression in the common wheat variety 'Fielder' significantly decreased SC compared to the WT. Moreover, we developed a PCR-based marker targeting the 32-bp insertion/deletion (InDel) between the two TaTPR-B1 alleles, which could be practical and valuable in modern wheat breeding programs for diagnostic purposes. Collectively, these findings provide insight into the genetic basis of SC in common wheat and present a valuable target with a breeder-friendly diagnostic marker for gene pyramid breeding.

Impact of HIV-1 tat protein on methamphetamine-induced inhibition of vesicular monoamine transporter2-mediated dopamine transport and methamphetamine conditioned place preference in HIV-1 tat transgenic mice.

Perturbation of dopamine transmission has been implicated as a contributing factor in HIV-1 associated neurocognitive disorders with concurrent methamphetamine (METH) abuse. We have demonstrated that the HIV-1 protein, transactivator of transcription (Tat), decreases dopamine transport through inhibition of vesicular monoamine transporter2 (VMAT2). This study determined the effects of Tat protein on METH-inhibited VMAT2 function and METH-conditioned place preference (CPP). In vitro exposure of isolated mouse whole brain vesicles to recombinant Tat1-86 or METH displayed a concentration-dependent inhibition of the vesicular [3H]Dopamine uptake, in which a combination of Tat and METH induced a greater reduction of dopamine uptake compared to Tat or METH alone. In vivo, the maximal velocity (Vmax) of vesicular [3H]Dopamine uptake was decreased in inducible Tat transgenic (iTat-tg) mice harvested after treatment with either 21-day doxycycline (Dox) or 14-day METH (3 mg/kg, i.p., daily), whereas these mice treated with both Dox and METH displayed an additive reduction of the Vmax compared to either Tat or METH alone. Moreover, Dox-induced Tat expression increased METH-CPP in an exposure-dependent manner, with iTat-tg mice demonstrating a 2.3-fold potentiation of METH-CPP compared with Tat null control mice upon administration of Dox for 14 days. Furthermore, a 7-day administration of Dox reinstated extinguished METH-CPP. Collectively, these results suggest a synergistic effect of Tat protein and METH on inhibition of VMAT2-mediated DA transport, potentially contributing to potentiation of METH-CPP in iTat-tg mice.

Long-term rice-crayfish farming alters soil dissolved organic carbon quality and biodegradability by regulating microbial metabolism and iron oxidation.

The biodegradability of dissolved organic carbon (DOC) is a crucial process in the migration and transformation of soil organic carbon (SOC), and play a vital role in the global soil carbon (C) cycle. Although the significance of DOC in SOC transportation and microbial utilization is widely acknowledged, the impact of long-term rice-crayfish (RC) farming on the content, quality, and biodegradability of DOC in paddy soils, as well as regulatory mechanisms involved, remains unclear. To address this gap, a space-for-time method was employed to investigate the effects of different RC farming durations (1-, 5-, 10-, 15-, and 20- years) on the quality and biodegradability of DOC, as well as their relationship with soil microbial metabolism and minerals in this study. The results revealed that continuous RC farming increased the soil DOC content, but reduced DOC biodegradability. Specifically, after 20 years of continuous RC farming, the DOC content increased by 52.7% compared to the initial year, whereas the DOC biodegradability decreased by 63.4%. Analysis using three-dimensional fluorescence and ultraviolet spectroscopy demonstrated that continuous RC farming resulted in a decrease in the relative abundance of humus-like fractions, humification, and aromaticity indexes in DOC, but increased the relative abundance of protein-like fractions, biological, and fluorescence index, indicating that long-term RC farming promoted the simple depolymerization of the molecular structure of DOC. Continuous RC farming increased the activity of hydrolase involved in soil nitrogen (N) and phosphorus (P) cycles and oxidase, but decreasing the hydrolase C/N and C/P acquisition ratios; moreover, it also stimulated an increase in soil iron oxides and exchangeable calcium content. Structural equation modeling suggests that soil hydrolases and iron oxides are the primary drivers of DOC quality change, with DOC biodegradability being driven solely by soil iron oxides and not regulated by DOC quality. In conclusion, long-term RC farming promotes the catalytic decomposition of DOC aromatic substances and the production of DOC protein-like components by increasing soil oxidase activity and decreasing the hydrolase C/N acquisition ratio; these processes collectively contribute to the simple depolymerization of DOC molecular structure. Additionally, long-term RC farming induced legacy effects of soil iron oxides and enhanced chemical protection role leading to reduced DOC biodegradability. These findings suggested that long-term RC farming may reduce the rapid turnover and loss of DOC, providing a negative feedback on climate warming.

The role of uric acid in the risk of hypertension developed from prehypertension: a five-year Chinese urban cohort study.

BACKGROUND: Uric acid as a prominent causal factor in the pathogenesis of hypertension is well recognized. Nevertheless, the influence of uric acid on the transition from prehypertension to hypertension within the Chinese population remains understudied. METHODS: A cohort of 1,516 prehypertensive individuals, aged 35 to 84 years, underwent recruitment following a comprehensive health assessment in 2017 and subsequent re-evaluation in 2022. Baseline characteristics and relevant clinical data were collected. The analytical approach encompassed multiple logistic regression and propensity score matching. RESULTS: Over 5 years, the cumulative incidence of hypertension amounted to 35.1%, with 33.9% in males and 37.3% in females, respectively. Notably, prehypertensive subjects concomitant with hyperuricemia exhibited a higher cumulative incidence of hypertension in comparison to the non-hyperuricemic counterparts (40.7% vs. 34.0%, p = 0.041). Multiple logistic regression unveiled a significant association between hyperuricemia and heightened hypertension risk (adjusted odds ratio [OR] = 1.44; 95% confidence interval [CI], 1.05-1.98; p = 0.022). Nonetheless, this association did not reach statistical significance when examining female subjects (adjusted OR = 1.10; 95% CI, 0.58-2.09; p = 0.781) or participants aged ≥ 60 years (adjusted OR = 1.07; 95% CI, 0.61-1.88; p = 0.814). Further validation through propensity score matching affirmed that subjects afflicted by hyperuricemia experienced a substantially elevated risk of transitioning from prehypertension to hypertension over the course of five years compared with the non-hyperuricemic counterparts (41.3% vs. 32.3%, p = 0.045), after adjusting for 12 covariates including age and gender. Hyperuricemia emerged as an independent risk factor predisposing individuals to the development of hypertension from a prehypertensive state. CONCLUSION: This observation prompted the formulation of a hypothesis suggesting that ameliorating elevated uric acid levels may potentially mitigate the progression from prehypertension to hypertension.

Lipidomics in forensic science: a comprehensive review of applications in drugs, alcohol, latent fingermarks, fire debris, and seafood authentication.

Forensic science, an interdisciplinary field encompassing the collection, examination, and presentation of evidence in legal proceedings, has recently embraced lipidomics as a valuable tool. Lipidomics, a subfield of metabolomics, specializes in the analysis of lipid structures and functions, offering insights into biological processes that can aid forensic investigations. While not a substitute for DNA analysis in personal identification, lipidomics complements this technique by focusing on small biological molecules, with distinct sample requirements. This review comprehensively explores the current applications of lipidomics in forensic science. The review commences with an introduction to the concept and historical background of lipidomics, subsequently delving into its utilization in diverse areas such as drug analysis, ethyl alcohol and substitute assessment, latent fingermark detection, fire debris analysis, and seafood authentication. By showcasing the various biological materials and methods employed, this review underscores the potential of lipidomics as a powerful adjunct in forensic investigations.

Comparison of zuberitamab plus CHOP versus rituximab plus CHOP for the treatment of drug-naïve patients diagnosed with CD20-positive diffuse large B-cell lymphoma: a phase 3 trial.

BACKGROUND: In patients with untreated CD20-positive diffuse large B-cell lymphoma (DLBCL), a phase 3 trial was carried out to evaluate the efficacy and safety of zuberitamab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; Hi-CHOP) versus rituximab plus CHOP (R-CHOP) treatment regimens. METHODS: In a 2:1 ratio, eligible patients were assigned randomly to receive treatment of six cycles of either 375 mg/m2 zuberitamab or rituximab together with conventional CHOP chemotherapy. The objective response rate (ORR) at C6D50 served as the primary endpoint, and a non-inferiority margin of 10% was established. The secondary endpoints included the complete response (CR) rate at C6D50, duration of response (DOR), progression-free survival (PFS) and event-free survival (EFS) judged by blinded-independent review committee (BIRC), overall survival (OS) and safety outcomes. RESULTS: Of the 487 randomized patients, 423 patients including 287 in the Hi-CHOP and 136 in the R-CHOP groups completed the C6D50 assessment. For the full analysis set (FAS) and per-protocol set (PPS), BIRC-assessed ORR at C6D50 for the Hi-CHOP and R-CHOP groups were 83.5% versus 81.4% and 95.3% versus 93.7%, respectively. The non-inferiority was confirmed as the lower limit of the two-sided 95% CI for the intergroup differences of -5.2% and -3.3%; both were >-10% in the FAS and PPS. The BIRC-assessed CR rate of Hi-CHOP was significantly higher in PPS (85.7% vs 77.3%, p=0.038), but comparable in FAS (75.2% vs 67.9%, p=0.092). After a median follow-up of 29.6 months, patients in the Hi-CHOP group had a slight advantage with regard to the DOR (HR 0.74, p=0.173), PFS (HR 0.67, p=0.057), EFS (HR 0.90, p=0.517) and OS (HR 0.60, p=0.059). Patients with the germinal-center B cell-like subtype who received Hi-CHOP exhibited statistically significant improvements in ORR (p=0.034) and CR rate (p=0.038) at C6D50, EFS (p=0.046) and OS (p=0.014). Treatment-emergent adverse event occurrence rates were comparable across groups (all p>0.05). Infusion-related responses occurred more often in the Hi-CHOP group (32.1% vs 19.9%, p=0.006), all of grade 1-3 severity. CONCLUSIONS: Zuberitamab (375 mg/m2) plus CHOP was non-inferior to R-CHOP regarding ORR but exhibited a higher CR rate and was well tolerated in CD20-positive, previously untreated Chinese patients with DLBCL. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry, ChiCTR2000040602, retrospectively registered.

HLX07 alone or combined with serplulimab, cisplatin and 5-fluorouracil for advanced esophageal squamous cell carcinoma: A phase 2 study.

BACKGROUND: The combination of anti-PD-1 antibody serplulimab and chemotherapy is considered standard first-line therapy for advanced esophageal squamous cell carcinoma (ESCC), but few later-line treatments are available. Here we evaluated the therapeutic efficacy of the recombinant, humanized anti-EGFR antibody HLX07 when used alone or together with serplulimab and chemotherapy against advanced ESCC. METHODS: This open-label, non-randomized, two-cohort, phase 2 trial involved patients 18-75 years old with histologically or cytologically confirmed locally advanced, unresectable, or metastatic ESCC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients who had failed first-line immuno-chemotherapy or at least two lines of other systemic therapy received HLX07 monotherapy intravenously at a dose of 1,000 mg once every 2 weeks (Q2W). Patients with no prior systemic therapy received HLX07 (1,000 mg, day 1) and serplulimab (200 mg, day 1) intravenously Q2W for up to 2 years, concurrently with cisplatin (50 mg/m2, day 1) for up to 8 cycles and 5-fluorouracil (1,200 mg/m2, days 1-2) for up to 12 cycles intravenously Q2W. The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). RESULTS: Overall, 50 patients were enrolled. In the HLX07 monotherapy group, ORR was 15.0% (3/20), and the median PFS was 1.5 months (95% confidence interval [CI], 1.3 to 3.7). The median duration of response was not reached, and the rate of patients showing an objective response lasting at least 6 months was 66.7% (95% CI, 5.4 to 94.5). Two (10.0%, 2/20) patients experienced grade 3-4 treatment-related adverse events (TRAEs), including hypomagnesemia, hypocalcemia, and fatigue. No patient experienced grade 5 TRAEs. In the HLX07 combination group, the ORR was 60.0% (18/30), and the median PFS was 7.8 months (95% CI, 3.3 to 9.1). Fourteen (46.7%, 14/30) patients experienced grade 3-4 TRAEs, and one (3.3%, 1/30) patient died due to serplulimab-related pneumonitis. CONCLUSIONS: HLX07 monotherapy and its combination with serplulimab and chemotherapy showed manageable toxicity and promising antitumor activity in patients with recurrent or metastatic ESCC. Randomized controlled trials are warranted to further establish the safety and efficacy of HLX07 against ESCC. TRIAL REGISTRATION: This trial was registered at Clinicaltrials.gov (NCT05221658).

Effects of the co-exposure of microplastic/nanoplastic and heavy metal on plants: Using CiteSpace, meta-analysis, and machine learning.

Micro/nanoplastics (MNPs) and heavy metals (HMs) coexist worldwide. Existing studies have reported different or even contradictory toxic effects of co-exposure to MNPs and HMs on plants, which may be related to various influencing factors. In this study, existing publications were searched and analyzed using CiteSpace, meta-analysis, and machine learning. CiteSpace analysis showed that this research field was still in the nascent stage, and hotspots in this field included accumulation, cadmium (Cd), growth, and combined toxicity. Meta-analysis revealed the differential association of seven influencing factors (MNP size, pollutant treatment duration, cultivation media, plant species, MNP type, HM concentration, and MNP concentration) and 8 physiological parameters receiving the most attention. Co-exposure of the two contaminants had stronger toxic effects than HM treatment alone, and phytotoxicity was generally enhanced with increasing concentrations and longer exposure durations, especially when using nanoparticles, hydroponic medium, dicotyledons producing stronger toxic effects than microplastics, soil-based medium, and monocotyledons. Dry and fresh weight analysis showed that co-exposure to MNPs and Cd resulted in significant phytotoxicity in all classifications. Concerning the MNP types, polyolefins partially attenuated plant toxicity, but both modified polystyrene (PS) and biodegradable polymers exacerbated joint phytotoxicity. Finally, machine learning was used to fit and predict plant HM concentrations, showing five classifications with an accuracy over 80 %, implying that the polynomial regression model could be used to predict HM content in plants under complex pollution conditions. Overall, this study identifies current knowledge gaps and provides guidance for future research.

Annonaceous acetogenins mimic AA005 targets mitochondrial trifunctional enzyme alpha subunit to treat obesity in male mice.

Obesity and related diseases pose a major health risk, yet current anti-obesity drugs inadequately addressing clinical needs. Here we show AA005, an annonaceous acetogenin mimic, resists obesity induced by high-fat diets and leptin mutations at non-toxic doses, with the alpha subunit of the mitochondrial trifunctional protein (HADHA) as a target identified through proteomics and in vitro validation. Pharmacokinetic analysis shows AA005 enriches in adipose tissue, prompting the creation of adipose-specific Hadha-deficient mice. These mice significantly mitigate diet-induced obesity, echoing AA005's anti-obesity effects. AA005 treatment and Hadha deletion in adipose tissues increase body temperature and energy expenditure in high-fat diet-fed mice. The beneficial impact of AA005 on obesity mitigation is ineffective without uncoupling protein 1 (UCP1), essential for thermogenesis regulation. Our investigation shows the interaction between AA005 and HADHA in mitochondria, activating the UCP1-mediated thermogenic pathway. This substantiates AA005 as a promising compound for obesity treatment, targeting HADHA specifically.