A novel technique of percutaneous transhepatic treatment of biliary-enteric anastomotic occlusive strictures with compliant balloon-occluded distal cholangiography and large-bore catheter: a retrospective case series.

Background: Endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic biliary balloon dilatation (PTBD) is a challenge in resolving biliary-enteric anastomotic occlusive strictures (BEAOS) and/or coexisting stones. The biliary-enteric anastomosis (BEA) often cannot be seen because of the surgically altered gastrointestinal anatomy. Here, a technique that combined percutaneous compliant-occluded distal cholangiography and the maintenance of a large-bore catheter is described to resolve this issue. Methods: A retrospective review of 10 patients who presented with BEAOS with/without coexisting stones who were treated with percutaneous compliant balloon-occluded distal cholangiography, bile duct stone removal, and the maintenance of a large-bore catheter between February 2017 and January 2021 was performed. Treatment response, laboratory examinations, including hepatic function tests, routine blood tests, and blood electrolytes, complications, and imaging data were evaluated. Paired t-tests were used to investigate the difference of laboratory examinations before and after the procedure. Results: All 10 cases were technically successful. A total of 9 stones in 6 patients were successfully removed by the compliant balloon. All catheters were removed after the patency of the stricture was confirmed by percutaneous transhepatic cholangiography (PTHC) 6 months later. No severe adverse events occurred during the perioperative period. There were 2 patients who experienced episodes of cholangitis during the follow-up period (mean, 17 months; range, 4-24 months), and neither BEAOS nor bile duct stones recurred within 2 years after the procedure. White blood cells (WBC), total bilirubin (TB), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were (6.0±1.4)×109/L and (6.0±1.6)×109/L (P=0.91), 31.4±15.7 and 29.6±10.3 µmol/L (P=0.74), 50.8±20.0 and 85.8±67.0 U/L (P=0.16), and 42.6±15.2 and 71.8±44.9 U/L (P=0.09) pre and postintervention, respectively. Conclusions: Percutaneous transhepatic compliant balloon-occluded distal cholangiography and the maintenance of a large-bore catheter probably provide an effective and safe alternative method for resolving BEAOS and/or coexisting stones.

Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial.

Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg-1 every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6-62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79-19.12), 8.18 months (95% CI = 6.67-10.48) and 17.48 months (95% CI = 12.35-26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67-not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63-31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027.

P300 intention recognition based on phase lag index (PLI)-rich-club brain functional network.

Brain-computer interface (BCI) technology based on P300 signals has a broad application prospect in the assessment and diagnosis of clinical diseases and game control. The paper of selecting key electrodes to realize a wearable intention recognition system has become a hotspot for scholars at home and abroad. In this paper, based on the rich-club phenomenon that exists in the process of intention generation, a phase lag index (PLI)-rich-club-based intention recognition method for P300 is proposed. The rich-club structure is a network consisting of electrodes that are highly connected with other electrodes in the process of P300 generation. To construct the rich-club network, this paper uses PLI to construct the brain functional network, calculates rich-club coefficients of the network in the range of k degrees, initially identifies rich-club nodes based on the feature of node degree, and then performs a descending order of betweenness centrality and identifies the nodes with larger betweenness centrality as the specific rich-club nodes, extracts the non-linear features and frequency domain features of Rich-club nodes, and finally uses support vector machine for classification. The experimental results show that the range of rich-club coefficients is smaller with intent compared to that without intent. Validation was performed on the BCI Competition III dataset by reducing the number of channels to 17 and 16 for subject A and subject B, with recognition quasi-departure rates of 96.93% and 94.93%, respectively, and on the BCI Competition II dataset by reducing the number of channels to 17 for subjects, with a recognition accuracy of 95.50%.

Accelerated sarcopenia precedes learning and memory impairments in the P301S mouse model of tauopathies and Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) impairs cognitive functions and peripheral systems, including skeletal muscles. The PS19 mouse, expressing the human tau P301S mutation, shows cognitive and muscular pathologies, reflecting the central and peripheral atrophy seen in AD. METHODS: We analysed skeletal muscle morphology and neuromuscular junction (NMJ) through immunohistochemistry and advanced image quantification. A factorial Analysis of Variance assessed muscle weight, NCAM expression, NMJ, myofibre type distribution, cross-sectional areas, expression of single or multiple myosin heavy-chain isoforms, and myofibre grouping in PS19 and wild type (WT) mice over their lifespan (1-12 months). RESULTS: Significant weight differences in extensor digitorum longus (EDL) and soleus muscles between WT and PS19 mice were noted by 7-8 months. For EDL muscle in females, WT weighed 0.0113 ± 0.0005 compared with PS19's 0.0071 ± 0.0008 (P < 0.05), and in males, WT was 0.0137 ± 0.0001 versus PS19's 0.0069 ± 0.0006 (P < 0.005). Similarly, soleus muscle showed significant differences; females (WT: 0.0084 ± 0.0004; PS19: 0.0057 ± 0.0005, P < 0.005) and males (WT: 0.0088 ± 0.0003; PS19: 0.0047 ± 0.0004, P < 0.0001). Analysis of the NMJ in PS19 mice revealed a marked reduction in myofibre innervation at 5 months, with further decline by 10 months. NMJ pre-terminals in PS19 mice became shorter and simpler by 5 months, showing a steep decline by 10 months. Genotype and age strongly influenced muscle NCAM immunoreactivity, denoting denervation as early as 5-6 months in EDL muscle Type II fibres, with earlier effects in soleus muscle Type I and II fibres at 3-4 months. Muscle denervation and subsequent myofibre atrophy were linked to a reduction in Type IIB fibres in the EDL muscle and Type IIA fibres in the soleus muscle, accompanied by an increase in hybrid fibres. The EDL muscle showed Type IIB fibre atrophy with WT females at 1505 ± 110 µm2 versus PS19's 1208 ± 94 µm2, and WT males at 1731 ± 185 µm2 versus PS19's 1227 ± 116 µm2. Similarly, the soleus muscle demonstrated Type IIA fibre atrophy from 5 to 6 months, with WT females at 1194 ± 52 µm2 versus PS19's 858 ± 62 µm2, and WT males at 1257 ± 43 µm2 versus PS19's 1030 ± 55 µm2. Atrophy also affected Type IIX, I + IIA, and IIA + IIX fibres in both muscles. The timeline for both myofibre and overall muscle atrophy in PS19 mice was consistent, indicating a simultaneous decline. CONCLUSIONS: Progressive and accelerated neurogenic sarcopenia may precede and potentially predict cognitive deficits observed in AD.

Hydrangea-like TiO2/Bi2MoO6 porous nanoflowers triggering highly sensitive electrochemical immunosensing to tumor marker.

Rapid and sensitive detection of carcinoembryonic antigen (CEA) is of great significance for cancer patients. Here, molybdenum (Mo) was doped into bismuth oxide (Bi2O3) by one-pot hydrothermal method forming porous tremella Bi2MoO6 nanocomposites with a larger specific surface area than the spherical structure. Then, a new kind of hydrangea-like TiO2/Bi2MoO6 porous nanoflowers (NFs) was prepared by doping titanium into Bi2MoO6, where titanium dioxide (TiO2) grew in situ on the surface of Bi2MoO6 nanoparticles (NPs). The hydrangea-like structure provides larger specific surface area, higher electron transfer ability and biocompatibility as well as more active sites conducive to the attachment of anti-carcinoembryonic antigen (anti-CEA) to TiO2/Bi2MoO6 NFs. A novel label-free electrochemical immunosensor was then constructed for the quantitative detection of CEA using TiO2/Bi2MoO6 NFs as sensing platform, showing a good linear relationship with CEA in the concentration range 1.0 pg/mL ~ 1.0 mg/mL and a detection limit of 0.125 pg/mL (S/N = 3). The results achieved with the designed immunosensor are comparable with many existing immunosensors used for the detection of CEA in real samples.

Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors.

BACKGROUND: Studies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a first-in-class, humanized tetravalent bispecific antibody targeting PD-1 and VEGF-A simultaneously. Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors. METHODS: Patients with advanced solid tumors were treated with ivonescimab 0.3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks using a 3+3+3 dose escalation design. Dose expansion occurred at 10 and 20 mg/kg in selected tumor types. The primary objective was to assess the safety and tolerability, and to determine the maximum tolerated dose (MTD). The secondary objectives included pharmacokinetics, pharmacodynamics and preliminary antitumor activity based on Response Evaluation Criteria in Solid Tumors V.1.1. RESULTS: Between October 2, 2019 and January 14, 2021, a total of 51 patients were enrolled and received ivonescimab. Two dose-limiting toxicities were reported at 30 mg/kg. The MTD of ivonescimab was 20 mg/kg every 2 weeks. Grade≥3 treatment-related adverse events (TRAEs) occurred in 14 patients (27.5%). The most common TRAEs of any grade were rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), diarrhea (15.7%) and pruritus (11.8%). The most common grade≥3 TRAEs were hypertension (7/51, 13.7%), alanine aminotransferase increased (3/51, 5.2%), aspartate aminotransferase increased (2/51, 3.9%) and colitis (2/51, 3.9%). Of 47 patients who had at least one postbaseline assessment, the confirmed objective response rate was 25.5% (12/47) and disease control rate was 63.8% (30/47). Among 19 patients with platinum-resistant ovarian cancer, 5 patients (26.3%) achieved partial response (PR). Efficacy signals were also observed in patients with mismatch repair proficient (pMMR) colorectal cancer, non-small cell lung cancer, and both MMR deficient and pMMR endometrial cancer. CONCLUSIONS: Ivonescimab demonstrated manageable safety profiles and promising efficacy signals in multiple solid tumors. Exploration of alternative dosing regimens of ivonescimab monotherapy and combination therapies is warranted. TRIAL REGISTRATION NUMBER: NCT04047290.

Synthesis and Characterization of Superhydrophobic Epoxy Resin Coating with SiO2@CuO/HDTMS for Enhanced Self-Cleaning, Photocatalytic, and Corrosion-Resistant Properties.

The exceptional corrosion resistance and combined physical and chemical self-cleaning capabilities of superhydrophobic photocatalytic coatings have sparked significant interest among researchers. In this paper, we propose an economical and eco-friendly superhydrophobic epoxy resin coating that incorporates SiO2@CuO/HDTMS nanoparticles modified with Hexadecyltrimethoxysilane (HDTMS). The application of superhydrophobic coatings effectively reduces the contact area between the metal surface and corrosive media, leading to a decreased corrosion rate. Additionally, the incorporation of nanomaterials, exemplified by SiO2@CuO core-shell nanoparticles, improves the adhesion and durability of the coatings on aluminum alloy substrates. Experimental data from Tafel curve analysis and electrochemical impedance spectroscopy (EIS) confirm the superior corrosion resistance of the superhydrophobic modified aluminum alloy surface compared to untreated surfaces. Estimations indicate a significant reduction in corrosion rate after superhydrophobic treatment. Furthermore, an optical absorption spectra analysis of the core-shell nanoparticles demonstrates their suitability for photocatalytic applications, showcasing their potential contribution to enhancing the overall performance of the coated surfaces. This research underscores the promising approach of combining superhydrophobic properties with photocatalytic capabilities to develop advanced surface modification techniques for enhanced corrosion resistance and functional properties in diverse industrial settings.

Dysregulation and antimetastatic function of circLRIG1 modulated by miR-214-3p/LRIG1 axis in bladder carcinoma.

CircLRIG1, a newly discovered circRNA, has yet to have its potential function and biological processes reported. This study explored the role of circLRIG1 in the development and progression of bladder carcinoma and its potential molecular mechanisms. Techniques such as qRT-PCR, Western blot, various cellular assays, and in vivo models were used to investigate mRNA and protein levels, cell behavior, molecular interactions, and tumor growth. The results showed that both circLRIG1 and LRIG1 were significantly reduced in bladder carcinoma tissues and cell lines. Low circLRIG1 expression was associated with poor patient prognosis. Overexpressing circLRIG1 inhibited bladder carcinoma cell growth, migration, and invasion, promoted apoptosis, and decreased tumor growth and metastasis in vivo. Importantly, circLRIG1 was found to sponge miR-214-3p, enhancing LRIG1 expression, and its overexpression also modulated protein levels of E-cadherin, N-cadherin, Vimentin, and LRIG1. Similar effects were observed with LRIG1 overexpression. Notably, a positive correlation was found between circLRIG1 and LRIG1 expression in bladder carcinoma tissues. Additionally, the tumor-suppressing effect of circLRIG1 was reversed by overexpressing miR-214-3p or silencing LRIG1. The study concludes that circLRIG1 suppresses bladder carcinoma progression by enhancing LRIG1 expression via sponging miR-214-3p, providing a potential strategy for early diagnosis and treatment of bladder carcinoma.

Influence of Zr Addition on the Microstructure and Hydrogenation Kinetics of Ti50-xV25Cr25Zrx (x = 0, 5, 7, and 9) Alloys.

Due to the poor activation performance and kinetics of Ti50V25Cr25 alloys, the element Zr was added to improve the phase structure of the alloy and achieve a high-performance hydrogen storage alloy. The Ti50-xV25Cr25Zrx (x = 0, 5, 7, and 9) system alloys were prepared by arc melting. The alloys were analyzed using an X-ray diffractometer (XRD), scanning electron microscope (SEM), and differential scanning calorimeter (DSC). The hydrogen storage capabilities of the alloys were also obtained by the Sievert volumetric method. The results indicated that the alloy with Zr added had a combination of the C15 Laves phase and the BCC phase, whereas the Zr-free alloy had a BCC single phase. The partial replacement of Zr with Ti resulted in an increase in the lattice parameters of the main phase. The hydrogen storage kinetic performance and activation of the alloys both significantly improved with an increasing Zr concentration. The time to reach 90% of the maximum hydrogen storage capacity decreased to 2946 s, 230 s, and 120 s, respectively, with the increases in Zr concentration. The initial hydrogen absorption content of the alloys increased and then decreased after the addition of the element Zr. The second phase expanded with an increasing Zr concentration, which in turn decreased the abundance of the BCC main phase. The Ti43V25Cr25Zr7 alloy showed good cycle stability and hydrogen-desorption performance, and it could absorb 90% of the maximum hydrogen storage capacity in around 230 s. The maximum hydrogen-absorption capacity of the alloy was 2.7 wt%. The diffusion activation energy of hydrogen desorption dropped from 102.67 kJ/mol to 92.62 kJ/mol.

Sex differences in single neuron function and proteomics profiles examined by patch-clamp and mass spectrometry in the locus coeruleus of the adult mouse.

AIMS: This study aimed to characterize the properties of locus coeruleus (LC) noradrenergic neurons in male and female mice. We also sought to investigate sex-specific differences in membrane properties, action potential generation, and protein expression profiles to understand the mechanisms underlying neuronal excitability variations. METHODS: Utilizing a genetic mouse model by crossing Dbhcre knock-in mice with tdTomato Ai14 transgenic mice, LC neurons were identified using fluorescence microscopy. Neuronal functional properties were assessed using patch-clamp recordings. Proteomic analyses of individual LC neuron soma was conducted using mass spectrometry to discern protein expression profiles. Data are available via ProteomeXchange with identifier PXD045844. RESULTS: Female LC noradrenergic neurons displayed greater membrane capacitance than those in male mice. Male LC neurons demonstrated greater spontaneous and evoked action potential generation compared to females. Male LC neurons exhibited a lower rheobase and achieved higher peak frequencies with similar current injections. Proteomic analysis revealed differences in protein expression profiles between sexes, with male mice displaying a notably larger unique protein set compared to females. Notably, pathways pertinent to protein synthesis, degradation, and recycling, such as EIF2 and glucocorticoid receptor signaling, showed reduced expression in females. CONCLUSIONS: Male LC noradrenergic neurons exhibit higher intrinsic excitability compared to those from females. The discernible sex-based differences in excitability could be ascribed to varying protein expression profiles, especially within pathways that regulate protein synthesis and degradation. This study lays the groundwork for future studies focusing on the interplay between proteomics and neuronal function examined in individual cells.

A spherical adsorbent produced from a bagasse biochar chitosan assembly for selective adsorption of platinum-group metals from wastewater.

This study addresses the challenge of platinum-group metal scarcity by exploring the adsorption of these metals from industrial wastewater. An inexpensive adsorbent with selective platinum-group metal adsorption capacity, named chitosan/citric acid@diatomaceous earth-sugarcane bagasse (CTS/CA@DE-SBS), was newly synthesized. The material features a double coating of chitosan and diatomite on bagasse biochar, and it exhibits an excellent adsorption performance for platinum-group metals due to the synergistic effects of the biochar and chitosan-diatomaceous earth intercross-linked coatings. CTS/CA@DE-SBS achieved an 81 % adsorption efficiency and a static saturated adsorption capacity of 217 mg/g for Pt (IV) in water. Notably, the material exhibited selective adsorption properties for platinum-group metals dissolved in diverse aqueous solutions. The potential for the secondary recovery of platinum-group metals in complex aqueous bodies further underscores the significance of this adsorbent. In conclusion, this research introduces a promising solution for platinum-group metal shortages, offering a cost-effective and selective adsorbent with potential applications in the secondary recovery of these metals from industrial wastewater.

Cadonilimab Combined with Chemotherapy with or without Bevacizumab as First-Line Treatment in Recurrent or Metastatic Cervical Cancer (COMPASSION-13): A Phase 2 Study.

PURPOSE: Immune checkpoint inhibitors (ICI) have been a potential treatment option for patients with cervical cancer in several clinical studies. We investigated the safety and efficacy of cadonilimab, a bispecific antibody targeting PD-1 and CTLA-4, plus standard therapy for the first-line treatment of R/M CC (recurrent and/or metastatic cervical cancer). PATIENTS AND METHODS: Eligible patients were assigned to 3 cohorts: cohort A-15 (cadonilimab 15 mg/kg every 3 weeks (Q3W) plus chemotherapy), cohort A-10 (cadonilimb 10 mg/kg Q3W plus chemotherapy), and cohort B-10 (cadonilimab 10 mg/kg Q3W plus chemotherapy and bevacizumab). They received the corresponding treatments until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision. The primary objective was safety; the secondary endpoints included objective overall response (ORR), duration of response, disease control rate, progression-free survival, and overall survival. This study is registered with ClinicalTrials.gov (NCT04868708). RESULTS: As of February 13, 2023, treatment-related adverse events (TRAE) occurred in 45 (100.0%) patients. Grade ≥3 TRAEs were reported in 33 (73.3%) patients. Immune-related adverse events (irAE) occurred in 29 (64.4%) patients and grade ≥3 irAEs were observed in 9 (20.0%) patients. Seven (15.6%) of 45 patients permanently discontinued cadonilimab treatment due to TRAEs. One death due to hemorrhagic shock occurred in cohort B-10. Among 44 patients who underwent at least one post-baseline tumor assessment, the ORR was 66.7% in cohort A-15, 68.8% in cohort A-10, 92.3% in cohort B-10, and 79.3% in cohorts A-10 and B-10 combined. CONCLUSIONS: Cadonilimab combined with standard therapy was acceptable, with encouraging antitumor activity in patients with R/M CC.

Multifunctional self-assembled adsorption microspheres based on waste bamboo shoot shells for multi-pollutant water purification.

In this study, multilayer self-assembled multifunctional bamboo shoot shell biochar microspheres (BSSBM) were prepared, in which bamboo shoot shell biochar was used as the carrier, titanium dioxide as the intermediate medium, and chitosan as the adhesion layer. The adsorption behavior of BSSBM on heavy metals Ag(I) and Pd(II), antibiotics, and dye wastewater was systematically analyzed. BSSBM shows a wide range of adsorption capacity. BSSBM is a promising candidate for the purification of real polluted water, not only for metal ions, but also for Tetracycline (TC) and Methylene Blue (MB). The maximum adsorption amounts of BSSBM on Pd(II), Ag(I), TC and MB were 417.3 mg/g, 222.5 mg/g, 97.2 mg/g and 42.9 mg/g, respectively.The adsorption of BSSBM on Pd(II), MB and TC conformed to the quasi-first kinetic model, and the adsorption on Ag(I) conformed to the quasi-second kinetic model. BSSBM showed remarkable selective adsorption capacity for Ag(I) and Pd(II) in a multi-ion coexistence system. BSSBM not only realized the high value-added utilization of waste, but also had the advantages of low cost, renewable and selective adsorption. BSSBM demonstrated its potential as a new generation of multifunctional adsorbent, contributing to the recovery of rare/precious metals and the treatment of multi-polluted water.

Efficacy and safety of cadonilimab in previously treated recurrent or metastatic nasopharyngeal carcinoma(COMPASSION-06): A phase II multicenter study.

OBJECTIVE: This study was designed to assess the efficacy and safety of cadonilimab monotherapy, a first-in-class, bi-specific PD-1/CTLA-4 antibody, in patients with previously treated recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). PATIENTS AND METHODS: This multicenter, open-label, single-arm, phase II clinical trial enrolled patients with R/M-NPC who had failed first-line platinum-based chemotherapy and second-line single agent or combined chemotherapy, and immunotherapy-naive. Patients received cadonilimab for 6 mg/kg once every 2 weeks (Q2W). The primary endpoint was objective response rate (ORR) in full analysis set (FAS) assessed by investigators according to RECIST v.1.1. The secondary endpoint included progression-free survival (PFS), overall survival (OS), duration of response (DoR), time to response (TTR) and safety. RESULTS: A total of 23 patients were assessed. The median time from first dose to data cutoff was 16.56 (range, 0.8-25.2) months. ORR was 26.1 % (95 %CI:10.2-48.4). The ORR were 44.4 % (95 %CI: 13.7-78.8) and 14.3 % (95 %CI:1.8-42.8) in patients with tumor PD-L1 expression ≥50 % and <50 %, respectively. ORR was achieved in 40.0 % (95 %CI:12.2-73.8) of patients with EBV-DNA level <4000 IU/ml (n = 10) and 15.4 % (95 %CI:1.9-45.4) of those with ≥4000 IU/ml. The median PFS was 3.71 months (95 %CI: 1.84-9.30). respectively. Median OS was not reached, and the 12-month OS rate was 79.7 % (95 % CI:54.5-91.9). Only two patients (8.3 %) experienced Grade ≥3 treatment-related adverse events (TRAEs) with hypothyroidism (30.4 %), rash (21.7 %) and pruritus (21.7 %) being the most prevalent TRAEs. CONCLUSION: Cadonilimab monotherapy demonstrated a promising efficacy and manageable toxicity in patients with previously treated R-M/NPC and provide an efficacious salvage treatment option.

CD74 is associated with inflamed tumor immune microenvironment and predicts responsiveness to PD-1/CTLA-4 bispecific antibody in patients with solid tumors.

INTRODUCTION: Cadonilimab (AK104) is a first-in-class tetravalent bispecific antibody that targets both PD-1 and CTLA-4, showing a manageable safety profile and favorable clinical benefits. This study aimed to identify the biomarkers of clinical response and explore the immune response within the tumor microenvironment upon the AK104 therapy in advanced solid tumors. MATERIAL AND METHODS: Gene expression profiles of paired pre- and post-treatment tumor tissues from twenty-one patients were analyzed. The association of gene expression levels with either clinical efficacy or prognosis was evaluated and subsequently validated with published datasets using log-rank for Kaplan-Meier estimates. Comparative immune profile analyses of tumor microenvironment before and after AK104 treatment were conducted. The visualization of tumor-infiltrating lymphocytes was performed using multiplex immunohistochemistry. The predictive value of CD74 was further validated with protein expression by immunohistochemistry. RESULTS: Baseline CD74 gene expression was associated with favorable patient outcomes (overall survival [OS], HR = 0.33, 95% CI 0.11-1.03, p = 0.0463), which was further confirmed with the published datasets. Tumors with high CD74 gene expression at baseline were more likely to exhibit an immune-inflamed microenvironment. AK104 efficiently enhanced the infiltration of immune cells in the tumor microenvironment. Additionally, high CD74 protein expression (≥ 10% of the tumor area occupied by CD74 stained immune cells) at baseline was associated with better progressive-free survival (HR = 0.21, 95% CI 0.06-0.68, p = 0.0065) and OS (HR = 0.35, 95% CI 0.12-1.08, p = 0.0615). CONCLUSIONS: Our findings demonstrate that CD74 is a promising predictive biomarker for AK104 therapeutic response in advanced solid tumors. Trial registration number NCT03261011.

Selection of endovascular treatment strategies and analysis of the efficacy of different locations and types of splenic artery aneurysms.

PURPOSE: To analyze the selection of endovascular treatment strategies and the efficacy of various locations and types of splenic artery aneurysms (SAAs). METHODS: Sixty-three cases of patients diagnosed with SAA from January 2016 to October 2021 were collected, and their clinical data and follow-up results were analyzed. RESULTS: Among the 63 patients, 55 had true SAAs, and 8 had false SAAs. The average diameter of the true SAAs was 2.0 ± 0.8 cm. There were 10 cases of intra-aneurysm embolization, 24 cases of intra-aneurysm and aneurysm-bearing artery embolization, 10 cases of bare stent-assisted coil embolization, and 11 cases of stent grafts. The false SAAs had an average diameter of 2.3 ± 1.1 cm. Aneurysm-bearing artery embolization was applied in 5 cases, and stent grafts were applied in 3 cases. The incidence of complications after embolization of the aneurysm-bearing artery was higher (P < 0.01). Postembolization syndrome occurred in 10 patients; 7 patients developed splenic infarction to varying degrees, 1 patient had mildly elevated blood amylase, and 1 patient developed splenic necrosis with abscess formation, all of which improved after active treatment. The average length of hospital stay was 5.5 ± 3.2 days. The average follow-up time was 17.2 ± 16.1 months, and the aneurysm cavity of all patients was completely thrombotic. CONCLUSION: Endovascular treatments of SAAs are safe and effective. For various locations and types of SAAs, adequate selection of treatment is necessary. Stent grafts are recommended for their safety, economy, practicality, and preservation of the physiological functions of the human body.

Pelvic floor muscle strength and influencing factors based on vaginal manometry among healthy women at different life stages: A multicentre cross-sectional study.

OBJECTIVE: To assess pelvic floor muscle (PFM) strength and influencing factors among healthy women at different life stages. DESIGN: Multicentre cross-sectional study. SETTING: Fourteen hospitals in China. POPULATION: A total of 5040 healthy women allocated to the following groups (with 1680 women per group): premenopausal nulliparous, premenopausal parous and postmenopausal. METHODS: The PFM strength was evaluated by vaginal manometry. Multivariate logistic regression was used to determine the influencing factors for low PFM strength. MAIN OUTCOME MEASURES: Maximum voluntary contraction pressure (MVCP). RESULTS: The median MVCP values were 36, 35 and 35 cmH2O in premenopausal nulliparous (aged 19-51 years), premenopausal parous (aged 22-61 years), and postmenopausal (aged 40-86 years) women, respectively. In the premenopausal nulliparous group, physical work (odds ratio, OR 2.05) was the risk factor for low PFM strength, which may be related to the chronic increased abdominal pressure caused by physical work. In the premenopausal parous group, the number of vaginal deliveries (OR 1.28) and diabetes (OR 2.70) were risk factors for low PFM strength, whereas sexual intercourse (<2 times per week vs. none, OR 0.55; ≥2 times per week vs. none, OR 0.56) and PFM exercise (OR 0.50) may have protective effects. In the postmenopausal group, the number of vaginal deliveries (OR 1.32) and family history of pelvic organ prolapse (POP) (OR 1.83) were risk factors for low PFM strength. CONCLUSIONS: Physical work, vaginal delivery, diabetes and a family history of POP are all risk factors for low PFM strength, whereas PFM exercises and sexual life can have a protective effect. The importance of these factors varies at different stages of a woman's life.

Highly Stretchable, Biodegradable, and Recyclable Green Electronic Substrates.

As a steady stream of electronic devices being discarded, a vast amount of electronic substrate waste of petroleum-based nondegradable polymers is generated, raising endless concerns about resource depletion and environmental pollution. With coupled reagent (CR)-grafted artificial marble waste (AMW@CR) as functional fillers, polylactic acid (PLA)-based highly stretchable biodegradable green composite (AMW@CR-SBGC) is prepared, with elongation at break up to more than 250%. The degradation mechanism of AMW@CR-SBGC is deeply revealed. AMW@CR not only contributed to the photodegradation of AMW@CR-SBGC but also significantly promoted the water degradation of AMW@CR-SBGC. More importantly, AMW@CR-SBGC showed great potential as sustainable green electronic substrates and AMW@CR-SBGC-based electronic skin can simulate the perception of human skin to strain signals. The outstanding programmable degradability, recyclability, and reusability of AMW@CR-SBGC enabled its application in transient electronics. As the first demonstration of artificial marble waste in electronic substrates, AMW@CR-SBGC killed three birds with one stone in terms of waste resourcing, e-waste reduction, and saving nonrenewable petroleum resources, opening up vast new opportunities for green electronics applications in areas such as health monitoring, artificial intelligence, and security.

Investigation of gut microbiota changes and allergic inflammation of mice with milk protein-induced allergic enteritis.

This study aimed to investigate the changes of gut microbiota and allergic inflammation in mice with allergic enteritis caused by milk protein. In this study, female BALB\C mice in the whey protein (WP-sensitized) group were gavaged with WP and normal saline, the sham-sensitized group was given normal saline once a week for 5 weeks. One week later, the WP-sensitized mice were administered 60 mg ß-lactoglobulin (BLG). The results showed that mice's body weight decreased, feces with loose and bloody, and systemic allergic reactions and ear swelling increased in the WP-sensitized group. The levels of WP-specific Ig, mMCP-1, calprotectin of feces, and inflammation-related factors in the WP-sensitized group were increased. WP-sensitized group intestine tissues were damaged severely and the expressions of ZO-1, Claudin-1, and Occludin reduced. The results of 16S rRNA sequencing showed that there were differences in operational taxonomic units (OUT) levels of gut microbes between the two groups, o_Clostridiales, c_Clostridia, and f_Lachnospiraceae were more abundant in the WP-sensitized group. In conclusion, the WP sensitization can induce the allergic inflammation, intestinal injury and intestinal barrier dysfunction in mice, and the gut microbes were also changed, which provided a reference for the treatment of WP-sensitized mice.

A Phase 1b Study of Ivonescimab, a Programmed Cell Death Protein-1 and Vascular Endothelial Growth Factor Bispecific Antibody, as First- or Second-Line Therapy for Advanced or Metastatic Immunotherapy-Naive NSCLC.

INTRODUCTION: This study (HARMONi-5) aimed to evaluate the safety and efficacy of ivonescimab (a bispecific antibody against programmed cell death protein 1 and vascular endothelial growth factor) as first- or second-line monotherapy in patients with advanced immunotherapy-naive NSCLC. METHODS: Eligible patients received intravenous ivonescimab 10 mg/kg every 3 weeks (Q3W), 20 mg/kg every 2 weeks (Q2W), 20 mg/kg Q3W, or 30 mg/kg Q3W. The primary end points were safety and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: At data cutoff (October 5, 2022), 108 patients were enrolled and received ivonescimab. Programmed death ligand-1 tumor proportion score (TPS) was greater than or equal to 1% in 74 patients (68.5%), including 35 (32.4%) with TPS greater than or equal to 50%. The median follow-up was 10.4 months (range: 8.4-10.9 mo). For all patients, ORR and disease control rate were 39.8% and 86.1%, respectively. ORR by TPS was 14.7%, 51.4%, and 57.1% in patients with TPS less than 1%, greater than or equal to 1%, and greater than or equal to 50%, respectively. In the 67 programmed death ligand-1-positive patients receiving first-line ivonescimab, the ORR was 33.3%, 52.6%, 60.0%, and 75.0% at the doses of 10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W, and 30 mg/kg Q3W, respectively. Grade greater than or equal to 3 treatment-related adverse events (TRAEs) were observed in 24 patients (22.2%). TRAEs leading to treatment discontinuation occurred in one patient (0.9%). TRAEs leading to death occurred in three patients (2.8%) with squamous NSCLC. The occurrence of grade greater than or equal to 3 TRAEs and grade greater than or equal to 3 bleeding events in squamous versus nonsquamous NSCLC patients was 25.5% versus 18.9% and 0.0% versus 1.9%, respectively. CONCLUSIONS: Ivonescimab monotherapy was well tolerated and found to have a promising efficacy in patients with advanced or metastatic NSCLC. CLINICALTRIALS: gov identifier: NCT04900363.