[In vitro and in vivo validation of cytotoxicity of targeting human epidermal growth factor receptor-2 chimeric antigen receptor T (HER2-CAR-T) cells].

Objective To evaluate the toxicology of targeting human epidermal growth factor receptor-2 chimeric antigen receptor T (HER2-CAR-T) cells and to provide a safety basis for the clinical evaluation of HER2-CAR-T cell therapy. Methods The recombinant lentiviral vector was used to generate HER2-CAR-T cells. Soft agar colony formation assay was used to observe the colony formation of HER2-CAR-T cells, and the colony formation rate was statistically analyzed. The HER2-CAR-T cell suspension was co-incubated with rabbit red blood cell suspension, and the hemolysis of red blood cells was evaluated by direct observation and microplate reader detection. The HER2-CAR-T cell preparation was injected into the ear vein of male New Zealand rabbits, and the stimulating effect of HER2-CAR-T cells on the blood vessels of the animals was observed by staining of tissue sections. The vesicular stomatitis virus envelope glycoprotein (VSV-G) gene of pMD 2.G vector was used as the target sequence, and the safety of the lentiviral vector was verified by real-time fluorescence quantitative PCR. The heart, liver, lung, and kidney of mice receiving HER2-CAR-T cell infusion were collected, and the lesions were observed by HE staining. Results The HER2-CAR-T cells were successfully prepared. These cells did not exhibit soft agar colony formation ability in vitro, and the HER2-CAR-T cell preparation did not cause hemolysis in New Zealand rabbit red blood cells. After the infusion of HER2-CAR-T cells into the ear vein of New Zealand rabbits, no obvious vascular stimulation response was found, and no specific amplification of VSV-G was detected. No obvious lesions were found in the heart, liver, lung and kidney tissues of the treatment group. Conclusion The prepared HER2-CAR-T cells have reliable safety.

Ultrasound-guided quantitative fluorescence molecular endoscopy for monitoring response in patients with esophageal cancer following neoadjuvant chemoradiotherapy.

PURPOSE: The ability to identify residual tumor tissues in patients with locally advanced esophageal cancer (EC) following neoadjuvant chemoradiotherapy (nCRT) is essential for monitoring the treatment response. Using the fluorescent tracer bevacizumab-800CW, we evaluated whether ultrasound-guided quantitative fluorescent molecular endoscopy (US-qFME), which combines quantitative fluorescence molecular endoscopy (qFME) with ultrasound-guided needle biopsy/single-fiber fluorescence (USNB/SFF), can be used to identify residual tumor tissues in patients following nCRT. PATIENTS AND METHODS: Eighteen patients received an additional endoscopy procedure the day before surgery. qFME was performed at the primary tumor site (PTS) and in healthy tissue to first establish the optimal tracer dose. USNB/SFF was then used to measure intrinsic fluorescence in the deeper PTS layers and in lymph nodes (LN) suspected for metastasis. Finally, the intrinsic fluorescence and the tissue optical properties, the absorption and the reduced scattering coefficient, were combined into a new parameter: omega. RESULTS: First, a dose of 25 mg bevacizumab-800CW allowed for clear differentiation between the PTS and healthy tissue, with a target-to-background ratio (TBR) of 2.98 (IQR: 1.86-3.03). Moreover, we found a clear difference between both the deeper esophageal PTS layers and suspected LN compared to healthy tissues, with TBR values of 2.18 and 2.17, respectively. Finally, our new parameter, omega, further improved the ability to differentiate between the PTS and healthy tissue. CONCLUSIONS: Combining bevacizumab-800CW with US-qFME may serve as a viable strategy for monitoring the response to nCRT in EC and may help stratify patients with respect to active surveillance versus surgery.

Synthesis and application of bismuth nanoparticle-loaded longan porous carbon for simultaneous electrochemical determination of Pb(II) and cd(II) in seafoods.

The discarded longan shell-derived porous carbon material (LPC) served as a scaffold for synthesizing bismuth nanoparticle-loaded longan porous carbon nanocomposite (BiNPs@LPC) via a hydrothermal method. Then BiNPs@LPC was utilized to modify screen-printed carbon electrodes (SPCE) for simultaneous detection of Pb(II) and Cd(II) by square wave anodic stripping voltammetry (SWASV). The material was thoroughly characterized by scanning electron microscopy, X-ray diffraction, Raman spectra, Brunauer-Emmett-Teller analysis, electrochemical impedance spectroscopy and cyclic voltammetry. BiNPs@LPC exhibited abundant porous structures, high surface area, and numerous active sites, which could improve significantly response sensitivity. Under optimal conditions, the peak currents of Pb(II) and Cd(II) exhibited favorable linear relationships with the concentration within a range of 0.1-150 µg L-1, with detection limits (S/N = 3) of 0.02 µg L-1 and 0.03 µg L-1, respectively. BiNPs@LPC/SPCE demonstrated remarkable selectivity, stability and repeatability. The proposed method was successfully applied for the detection of Pb(II) and Cd(II) in seafoods achieving satisfying recovery of 97.8%-108.3% and 96.7%-106.4%. These excellent test properties were coupled with convenience for batch preparation of the modified electrodes, highlighting its potential for practical applications in heavy metal detection of real samples.

[Application and Effect of Patient Portal System in the Remote Management of Chronic Diseases for Older Adults With Coronary Heart Disease]. / æ‚£è€ é—¨æˆ·ç³»ç»Ÿåœ¨è€å¹´å† å¿ƒç— æ ¢ç— è¿œç¨‹ç®¡ç†ä¸­çš„åº”ç”¨åŠæ•ˆæžœ.

Objective: To investigate the application of personal health record (PHR) and chronic disease management platform established on the basis of patient portal system (PPS) in managing older adults with coronary heart disease and to examine the effect on patients' self-care ability, coping mode, and quality of life. Methods: A total of 532 elderly patients with coronary heart disease were included in the study. All the participants enrolled were admitted to a tertiary-care hospital between January 2019 and June 2021. They were randomly assigned to the study group (269 cases) and the control group (263 cases). Patients in the control group were discharged with the routine discharge procedures and received the routine follow-up care. On the other hand, patients in the study group were discharged and followed up through the PHR and chronic disease management platform established on the basis of PPS. After 6 months, 12 months, and 18 months of patient management, the Exercise of Self-Care Agency (ESCA) Scale, Medical Coping Modes Questionnaire (MCMQ) and Seattle Angina Questionnaire (SAQ) were used to evaluate the patients' self-care ability, coping mode, and quality of life, respectively. The patient management effects of the two groups were analyzed. Results: Before the management programs started, there was no statistically significant difference in the scores for the scales between the two groups of patients. After 6 months, 12 months, and 18 months of patient management, the ESCA scores of both groups were higher than those before patient management started (P<0.05). Facing scores in the MCMQ of both groups were higher than those before patient management started (P<0.05), while the scores for avoidance and yielding were lower than those before patient management started (P<0.05). The SAQ scores of both groups were higher than those before patient management started (P<0.05). After 6 months, 12 months and 18 months of patient management, the ESCA scores of the study group were always higher compared with those of the control group (P<0.05). The facing score of the study group was higher, while the scores for avoidance and yielding were lower compared with those of the control group (P<0.05). The SAQ scores of the study group were higher compared with those of the control group (P<0.05). The medication compliance rate in the study group (83.27%) was higher than that in the control group (69.96%) (P<0.05). The incidence of adverse cardiovascular events in the study group (4.09%) was lower than that in the control group (10.27%) (P<0.05). The average times of emergency treatment and readmission in the study group were lower compared with those of the control group (P<0.05). The patient satisfaction score of the study group was higher compared with that of the control group (P<0.05). Conclusion: The PHR and chronic disease management platform established on the basis of PPS can increase the convenient access to medical care among elderly patients with coronary heart disease, which is conducive to improving their self-care ability, coping mode, and quality of life. In addition, the patient management effect is good.

Diagnostic value of high-frequency ultrasound combined with fine needle aspiration cytology and BRAF gene for papillary thyroid microcarcinoma.

We attempted to evaluate clinical application value of high-frequency ultrasound (HFUS), fine needle aspiration cytology (FNAC), BRAF gene, and combination of HFUS, FNAC, and BRAF gene in diagnosing papillary thyroid microcarcinoma (PTMC). The 150 patients with thyroid minimal lesions who underwent HFUS, FNAC and BRAF gene testing before surgery in our hospital from June 2020 to December 2021 were selected as research subjects. Patients were divided into two groups based on postoperative pathological results. The consistency of diagnostic results of HFUS, FNAC, and BRAF gene and their combination with those of pathological examination, diagnostic efficacy of HFUS, FNAC and BRAF gene combined detection and individual detection for PTMC lymph node metastasis, and diagnostic value of HFUS, FNAC and BRAF gene combined detection and individual detection for PTMC lymph node metastasis received analysis and comparison. The consistency of diagnostic results of combined detection with pathological examination exhibited elevation relative to that of HFUS, FNAC and BRAF gene detection alone (P < 0.05). The negative predictive value, sensitivity and accuracy of combined detection exhibited elevation relative to individual detection (P < 0.05). The AUC of combined detection in diagnosing PTMC lymph node metastasis exhibited elevation relative to that of HFUS and BRAF gene alone (P < 0.05). HFUS combined with FNAC and BRAF genes possesses high diagnostic value, with high diagnostic sensitivity, specificity, and accuracy. Thus, combined detection for PTMC before surgery can accurately determine whether lymph node metastasis occurs, reduce occurrence of missed diagnosis and misdiagnosis, and thus improve diagnostic precision.

Evaluation of hepatic functional reserve of hepatocellular carcinoma (≤ 5 cm) by liver shear wave velocity combined with multiple parameters.

Background: Normal hepatic functional reserve is the key to avoiding liver failure after liver surgery. This study investigated the assessment of hepatic functional reserve using liver shear wave velocity (LSWV) combined with biochemical indicators, tumor volume, and portal vein diameter. Methods: In this single-center prospective study, a total of 123 patients with hepatocellular carcinoma (HCC) were divided into a test group (n=92) and a validation group (n=31). All patients were Child-Pugh grade A. The indocyanine green retention rate at 15 min (ICG-R15), liver shear wave velocity (LSWV), portal vein diameter (Dpv), alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GGT), albumin (ALB), prothrombin time (PT), and also liver tumor volume (maximum diameter ≤5 cm) were measured. In the test group, multiple parameters were used to evaluate hepatic functional reserve, and the multiparametric model was established. Receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic performance of the multiparametric model. In the validation group, the predictive effectiveness of the multiparametric model was analyzed using consistency tests. Results: It was revealed that LSWV, ALB, and PT were statistically significant in evaluation of the hepatic functional reserve (P<0.05). The multiparametric model was formulated as follows: Y= -18.954 + 9.726*LSWV-0.397*ALB+2.063*PT. The value of the area under the curve (AUC) for the multiparametric model was 0.913 (95% confidence interval (CI): 0.835-0.962, P< 0.01), with a cutoff value of 16.656 (sensitivity, 0.763; specificity, 0.926). The Kappa value of consistency testing was 0.655 (P<0.01). Conclusion: LSWV combined with ALB and PT exhibited a high predictive effectiveness for the assessment of hepatic functional reserve, assisting the clinical diagnosis and management of liver diseases.

Efficacy and Mechanism of Highly Active Umbilical Cord Mesenchymal Stem Cells in the Treatment of Osteoporosis in Rats.

Background: Osteoporosis increases bone brittleness and the risk of fracture. Umbilical cord mesenchymal stem cell (UCMSC) treatment is effective, but how to improve the biological activity and clinical efficacy of UCMSCs has not been determined. METHODS: A rat model of osteoporosis was induced with dexamethasone sodium phosphate. Highly active umbilical cord mesenchymal stem cells (HA-UCMSCs) and UCMSCs were isolated, cultured, identified, and infused intravenously once at a dose of 2.29 × 106 cells/kg. In the 4th week of treatment, bone mineral density (BMD) was evaluated via cross-micro-CT, tibial structure was observed via HE staining, osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs) was examined via alizarin red staining, and carboxy-terminal cross-linked telopeptide (CTX), nuclear factor-κß ligand (RANKL), procollagen type 1 N-terminal propeptide (PINP) and osteoprotegerin (OPG) levels were investigated via enzyme-linked immunosorbent assays (ELISAs). BMMSCs were treated with 10-6 mol/L dexamethasone and cocultured with HA-UCMSCs and UCMSCs in transwells. The osteogenic and adipogenic differentiation of BMMSCs was subsequently examined through directional induction culture. The protein expression levels of WNT, ß-catenin, RUNX2, IFN-γ and IL-17 in the bone tissue were measured via Western blotting. RESULTS: The BMD in the healthy group was higher than that in the model group. Both UCMSCs and HA-UCMSCs exhibited a fusiform morphology; swirling growth; high expression of CD73, CD90 and CD105; and low expression of CD34 and CD45 and could differentiate into adipocytes, osteoblasts and chondrocytes, while HA-UCMSCs were smaller in size; had a higher nuclear percentage; and higher differentiation efficiency. Compared with those in the model group, the BMD increased, the bone structure improved, the trabecular area, number, and perimeter increased, the osteogenic differentiation of BMMSCs increased, RANKL expression decreased, and PINP expression increased after UCMSC and HA-UCMSC treatment for 4 weeks. Furthermore, the BMD, trabecular area, number and perimeter, calcareous nodule counts, and OPG/RANKL ratio were higher in the HA-UCMSC treatment group than in the UCMSC treatment group. The osteogenic and adipogenic differentiation of dexamethasone-treated BMMSCs was enhanced after the coculture of UCMSCs and HA-UCMSCs, and the HA-UCMSC group exhibited better effects than the UCMSC coculture group. The protein expression of WNT, ß-catenin, and runx2 was upregulated, and IFN-γ and IL-17 expression was downregulated after UCMSC and HA-UCMSC treatment. CONCLUSION: HA-UCMSCs have a stronger therapeutic effect on osteoporosis compared with that of UCMSCs. These effects include an improved bone structure, increased BMD, an increased number and perimeter of trabeculae, and enhanced osteogenic differentiation of BMMSCs via activation of the WNT/ß-catenin pathway and inhibition of inflammation.

An age classification model based on DNA methylation biomarkers of aging in human peripheral blood using random forest and artificial neural network.

Recent epigenetic studies have revealed a strong association between DNA methylation and aging and lifespan, which changes (increases or decreases) with age. Based on these, the construction of age prediction models associated with DNA methylation levels can be used to infer biological ages closer to the functional state of the organism. We downloaded methylation data from the Gene Expression Omnibus (GEO) public database for normal peripheral blood samples from people of different ages. We grouped the samples according to age (18-35 years and >50 years), screened the methylation sites that differed between the two groups, identified 44 differentially methylated sites, and subsequently obtained 11 age-related characteristic methylation sites using the random forest method. Then, we constructed an age classification model with these 11 characteristic methylation sites using an artificial neural network and evaluated its efficacy. The age classification model was constructed by an artificial neural network and its efficacy was evaluated. The model predicted an area under the curve (AUC) of 0.97 in the validation set and accurately distinguished between those aged 18-35 and >50 years. Furthermore, the levels of these 11 characteristic methylation sites also differed significantly between the two sets of samples in the validation set, including six newly identified age-related methylation sites (P<0.001). Finally, we constructed a multifactor regulatory network based on the corresponding genes of age-related methylation sites to reveal the transcriptional and post-transcriptional regulation patterns. As a result of the increasing problem of aging, the age classification model we constructed allows us to accurately distinguish different age groups at the molecular level, which will be more predictive than chronological age for assessing individual aging and future health status.

Comparison of postoperative complications in mediastinal lymph node dissection versus mediastinal lymph node sampling for early stage non-small cell lung cancer: Protocol for a systematic review and meta-analysis.

INTRODUCTION: Lung cancer is the primary cause of cancer-related deaths worldwide, with high rates of morbidity and mortality. The most effective treatment for early stage (I-II) non-small cell lung cancer (NSCLC) is surgical resection. However, the extent of mediastinal lymph nodes removal required and the impact of their removal remains controversial. This systematic review and meta-analysis aimed to evaluate the postoperative complications in patients with stage I-II NSCLC who received mediastinal lymph node dissection (MLND) or mediastinal lymph node sampling (MLNS). METHODS AND ANALYSIS: According to the predefined inclusion criteria, we will conduct a comprehensive search for randomized controlled trials (RCTs) and observational studies examining the postoperative complications of MLND compared to MLNS in patients with stage I-II NSCLC. The search will be performed across multiple databases including PubMed, Embase, the Cochrane Library, CNKI, WanFang, Sinomed, VIP, Duxiu, and Web of Science from inception to February 2024. Additionally, relevant literature references will be retrieved and hand searching of pertinent journals will be conducted. Screening, data extraction, and quality assessment will be performed by two independent reviewers. Review Manager 5.4 will be applied in analyzing and synthesizing. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) will be used to assess the quality of evidence for the whole RCTs and used Newcastle-Ottawa scale to assess the methodologic quality of observational studies. ETHICS AND DISSEMINATION: This study did not include personal information. Ethical approval was not required for this study. This study is based on a secondary analysis of the literature, so ethical review approval is not required. The final report will be published in a peer-reviewed journal. CONCLUSION: This systematic review will contribute to compare the safety and survival benefits of these two surgical techniques for the treatment of early stage NSCLC, to further guide the selection of surgical approaches. TRIAL REGISTRATION: The protocol of the systematic review has been registered on Open Science Framework, with a registration number of DOI https://doi.org/10.17605/OSF.IO/N2Y5D.

SMAD7 expression in CAR-T cells improves persistence and safety for solid tumors.

Despite the tremendous progress of chimeric antigen receptor T (CAR-T) cell therapy in hematological malignancies, their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment (TME) and systemic toxicity caused by excessive cytokine release. As a key regulator of the immunosuppressive TME, TGF-ß promotes cytokine synthesis via the NF-κB pathway. Here, we coexpressed SMAD7, a suppressor of TGF-ß signaling, with a HER2-targeted CAR in engineered T cells. These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-ß-triggered exhaustion, which enabled sustained tumoricidal capacity after continuous antigen exposure. Moreover, SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells. Mechanistically, SMAD7 downregulated TGF-ß receptor I and abrogated the interplay between the TGF-ß and NF-κB pathways in CAR-T cells. As a result, these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-ß. SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids. Therefore, our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.

Boosted hydrogen evolution kinetics of heteroatom-doped carbons with isolated Zn as an accelerant.

Carbon-based single-atom catalysts, a promising candidate in electrocatalysis, offer insights into electron-donating effects of metal center on adjacent atoms. Herein, we present a practical strategy to rationally design a model catalyst with a single zinc (Zn) atom coordinated with nitrogen and sulfur atoms in a multilevel carbon matrix. The Zn site exhibits an atomic interface configuration of ZnN4S1, where Zn's electron injection effect enables thermal-neutral hydrogen adsorption on neighboring atoms, pushing the activity boundaries of carbon electrocatalysts toward electrochemical hydrogen evolution to an unprecedented level. Experimental and theoretical analyses confirm the low-barrier Volmer-Tafel mechanism of proton reduction, while the multishell hollow structures facilitate the hydrogen evolution even at high current intensities. This work provides insights for understanding the actual active species during hydrogen evolution reaction and paves the way for designing high-performance electrocatalysts.

A rechargeable Ca/Cl2 battery.

Rechargeable calcium (Ca) metal batteries are promising candidates for sustainable energy storage due to the abundance of Ca in Earth's crust and the advantageous theoretical capacity and voltage of these batteries. However, the development of practical Ca metal batteries has been severely hampered by the current cathode chemistries, which limit the available energy and power densities, as well as their insufficient capacity retention and low-temperature capability. Here, we describe the rechargeable Ca/Cl2 battery based on a reversible cathode redox reaction between CaCl2 and Cl2, which is enabled by the use of lithium difluoro(oxalate)borate as a key electrolyte mediator to facilitate the dissociation and distribution of Cl-based species and Ca2+. Our rechargeable Ca/Cl2 battery can deliver discharge voltages of 3 V and exhibits remarkable specific capacity (1000 mAh g-1) and rate capability (500 mA g-1). In addition, the excellent capacity retention (96.5% after 30 days) and low-temperature capability (down to 0 °C) allow us to overcome the long-standing bottleneck of rechargeable Ca metal batteries.

Highly sensitive and selective SERS detection of caspase-3 during cell apoptosis based on the target-induced hotspot effect.

Caspase-3 is an important biomarker for the process of apoptosis, which is a key target for cancer treatment. Due to its low concentration in single cells and the structural similarity of caspase family proteins, it is exceedingly challenging to accurately determine the intracellular caspase-3 during apoptosis in situ. Herein, a biosensing strategy based on the target-induced SERS "hot spot" formation has been developed for the simultaneous highly sensitive and selective detection of intracellular caspase-3 level. The nanosensor is composed of gold nanoparticles modified with the probe molecule 4-mercaptophenylboronic acid (4-MPBA) and a peptide chain. The well-designed peptide chain contains two distinct functional domains, one with a sulfhydryl group for bonding to the gold nanoparticles and the other a fragment specifically recognized by caspase-3. When caspase-3 is present, the negatively charged segment (NH2-Asp-Asp-Asp-Glu-Val-Asp-OH) of the peptide chain is specifically hydrolyzed, leaving a positively charged fragment coated on the surface of the gold nanoparticles. At this time, the golden nanoparticles undergo significant coupling aggregation due to the electrostatic interaction, resulting in a large number of SERS "hot spot" formation. The SERS signal of the 4-MPBA located at the nano-gap is significantly boosted because of the local plasma enhancement effect. The highly sensitive determination of caspase-3 can be achieved according to the altered SERS signal intensity of 4-MPBA. The turn-on of the SERS signal-induced target contributes to the excellent selectivity and the formation of the SERS "hot spot" effect that further improves the sensitivity of caspase-3 detection. The advantages of this biosensing technique allow for the precise in situ monitoring of the dynamic changes in caspase-3 levels during apoptosis. In addition, the differences in caspase-3 levels during the apoptosis of various cell types were compared. Monitoring the caspase-3 levels can be used to track the cellular apoptosis process, evaluate the effect of drugs on cancer cells in real time, and provide guidance for the selection of the appropriate drug dosage.

A Systematic Review and Meta-analysis of Renin-angiotensin System Inhibitors and Angiotensin Receptor Neprilysin Inhibitors in Preventing Recurrence After Atrial Fibrillation Ablation.

ABSTRACT: To systematically evaluate the efficacy and safety of renin-angiotensin system inhibitors (RASIs) and angiotensin receptor neprilysin inhibitors in preventing the recurrence of atrial fibrillation after atrial fibrillation ablation, we have written this meta-analysis. We systematically searched randomized controlled trials or cohort studies on RASIs and angiotensin receptor neprilysin inhibitor-sacubitril/valsartan (SV) in preventing the recurrence of atrial fibrillation. Two researchers independently screened the literature, extracted the data, and assessed the risk of bias in the included studies. Afterward, the meta-analysis was performed using RevMan 5.3 software. This meta-analysis results showed that the recurrence rate of atrial fibrillation after ablation in subjects using RASIs was lower than that in subjects not using them [relative risk = 0.85, 95% confidence interval (CI) (0.72-0.99), P = 0.03]; the recurrence rate in subjects using SV was lower than that in subjects using RASIs [RR= 0.50, 95% CI (0.37-0.68), P < 0.00001]. These results show that both the use of RASIs and SV can prevent the recurrence of after atrial fibrillation ablation, among which the use of SV is more effective.

Correlation of Folic Acid Metabolic Gene Polymorphisms, Homocysteine, Vitamin B12, and Red Blood Cell Folate with Adverse Pregnancy Outcomes.

Objective: This study aims to investigate the relationship between folic acid (FA) metabolic gene polymorphisms, homocysteine (Hcy), vitamin B12 (Vit B12), and red blood cell folate (RBCF) with adverse pregnancy. The findings of this study can help in the prevention and treatment of adverse pregnancy in the future. Methods: 118 pregnant women admitted to Qingdao Central Hospital between August 2020 and October 2022 were selected for retrospective analysis, including 62 cases of normal delivery (control group, CG) and 56 cases of adverse pregnancy (research group, RG). The single nucleotide polymorphisms of MTHFR C677T, MTHFR A1298C, and MTRR A66G gene loci were tested in both cohorts. Besides, differences in Hcy, Vit B12, and RBCF levels were observed, as well as Hcy, Vit B12, and RBCF alterations in different genotype carriers in the research group. Results: An elevated proportion of MTHFR 677TT-type gene and MTRR 66GG-type gene carriers and a lower proportion of MTRR 66GG-type gene carriers were found in the research group (χ2 = 4.458, 4.238, 4.206, P = .035, .040, .040). As indicated by the Logistic regression analysis, carriers of MTHFR 677TT and MTRR 66GG gene had an increased risk of adverse pregnancy outcomes (95%CI=2.881-5.942, 1.427-3.809, P < .001), while MTRR 66AG carriers had a decreased risk (95%CI=0.124-1.849, P < .001). Finally, Hcy levels of MTHFR 677TT and MTRR 66GG gene carriers increased, while Vit B12 and RBCF decreased; the opposite was true for MTRR 66AG gene carriers (P < .001). Conclusions: FA metabolic gene polymorphisms, Hcy, Vit B12, and RBCF are closely related to adverse pregnancy outcomes, which is of great significance for future clinical evaluation of adverse pregnancy.

Humanized single-domain antibody targeting HER2 enhances function of chimeric antigen receptor T cells.

Introduction: Chimeric antigen receptors (CARs) can redirect T cells against antigen-expressing tumors, and each component plays an important role in the function and anti-tumor efficacy. It has been reported that using human sequences or a low affinity of CAR single-chain variable fragments (scFvs) in the CAR binding domains is a potential way to enhance the function of CAR-T cells. However, it remains largely unknown how a lower affinity of CARs using humanized scFvs affects the function of CAR-T cells until recently. Methods: We used different humanized anti-HER2 antibodies as the extracellular domain of CARs and further constructed a series of the CAR-T cells with different affinity. Results: We have observed that moderately reducing the affinity of CARs (light chain variable domain (VL)-based CAR-T) could maintain the anti-tumor efficacy, and improved the safety of CAR therapy both in vitro and in vivo compared with high-affinity CAR-T cells. Moreover, T cells expressing the VL domain only antibody exhibited long-lasting tumor elimination capability after multiple challenges in vitro, longer persistence and lower cytokine levels in vivo. Discussion: Our findings provide an alternative option for CAR-T optimization with the potential to widen the use of CAR T cells.

Comparative assessment of efficacy and safety of approved oral therapies for overactive bladder: a systematic review and network meta-analysis

ABSTRACT Purpose: To compare the effectiveness and safety of marketed oral drugs for overactive bladder based on a systematic review and network meta-analysis approach. Methods: Pubmed, Embase, Web of Science, and the Cochrane Register of Clinical Trials databases were systematically searched. The search time frame was from database creation to June 2, 2022. Randomized controlled double-blind trials of oral medication for overactive bladder were screened against the protocol's entry criteria. Trials were evaluated for quality using the Cochrane Risk of Bias Assessment Tool, and data were statistically analyzed using Stata 16.0 software. Result: A total of 60 randomized controlled double-blind clinical trials were included involving 50,333 subjects. Solifenacin 10mg was the most effective in mean daily micturitions and incontinence episodes, solifenacin 5/10mg in mean daily urinary urgency episodes and nocturia episodes, fesoterodine 8mg in urgency incontinence episodes/d and oxybutynin 5mg in voided volume/micturition. In terms of safety, solifenacin 5mg, ER-tolterodine 4mg, mirabegron, vibegron and ER-oxybutynin 10mg all showed a better incidence of dry mouth, fesoterodine 4mg, ER-oxybutynin 10mg, tolterodine 2mg, and vibegron in the incidence of constipation. Compared to placebo, imidafenacin 0.1mg showed a significantly increased incidence in hypertension, solifenacin 10mg in urinary tract infection, fesoterodine 4/8mg and darifenacin 15mg in headache. Conclusion: Solifenacin showed better efficacy. For safety, most anticholinergic drugs were more likely to cause dry mouth and constipation, lower doses were better tolerated. The choice of drugs should be tailored to the patient's specific situation to find the best balance between efficacy and safety.

Self-Assembly of Multiwalled Carbon Nanotubes on a Silicone Rubber Foam Skeleton for Durable Piezoresistive Sensors.

Conductive nanomaterial/flexible polymer composite foams are of great interest in the field of flexible and wearable piezoresistive pressure sensors. However, the existing composite foam sensors are faced with stability issues from conductive nanomaterials, which tends to decrease their long-term durability. Herein, we developed a solvent evaporation-induced self-assembly strategy, which could significantly improve the stability of multiwalled carbon nanotubes (MWCNTs) on a silicone rubber foam skeleton. The process for self-assembly of MWCNTs was straightforward. Aqueous MWCNT dispersion droplets were first hierarchically enclosed in silicone rubber via water-in-oil (W/O) Pickering high internal phase emulsions (HIPEs). Then, the high pressure generated by fast evaporation of the solvent from the droplets could break the thinnest pore walls to form interconnected pores. As a result, very dense and firm MWCNT layers were self-assembled on the pore wall surface. Due to the excellent stability of MWCNTs and tetramodal interconnected porosity, our MWCNTs/silicone rubber composite foam showed the following "super" properties: low density of 0.26 g/mL, high porosity of 76%, and excellent mechanical strength (the maximum stress loss of 8.3% at 80% strain after 100 compression cycles). In addition, excellent piezoresistive performance, including superior discernibility for different amplitudes of compressive strain (up to 80%), rapid response time (150 ms), and high sensitivity (gauge factor of 1.44), was demonstrated for such foams, together with prominent durability (39,000 compression cycles at 60% strain in air) and excellent stability of resistance response in water and organic solvents (5000 compression cycles at 30% strain in water and ethanol). Regarding its application, a wearable piezoresistive sensor, which was assembled from the as-prepared conductive silicone rubber composite foam, could capture various movements from tiptoeing and finger bending to small deformations resulting from human pulse.

Reversely Trapping Isolated Atoms in High Oxidation State for Accelerating the Oxygen Evolution Reaction Kinetics.

Developing efficient electrocatalysts for the oxygen evolution reaction (OER) is paramount to the energy conversion and storage devices. However, the structural complexity of heterogeneous electrocatalysts makes it a great challenge to elucidate the dynamic structural evolution and OER mechanisms. Here, we develop a controllable atom-trapping strategy to extract isolated Mo atom from the amorphous MoOx -decorated CoSe2 (a-MoOx @CoSe2 ) pre-catalyst into Co-based oxyhydroxide (Mo-CoOOH) through an ultra-fast self-reconstruction process during the OER process. This conceptual advance has been validated by operando characterizations, which reveals that the initially rapid Mo leaching can expedite the dynamic reconstruction of pre-catalyst, and simultaneously trap Mo species in high oxidation state into the lattice of in situ generated CoOOH support. Impressively, the OER kinetics of CoOOH has been greatly accelerated after the reverse decoration of Mo species, in which the Mo-CoOOH affords a markedly decreased overpotential of 297 mV at the current density of 100 mA cm-2 . Density functional theory (DFT) calculations demonstrate that the Co species have been greatly activated via the effective electron coupling with Mo species in high oxidation state. These findings open new avenues toward directly synthesizing atomically dispersed electrocatalysts for high-efficiency water splitting.

Intermittent energy restriction changes the regional homogeneity of the obese human brain.

Background: Intermittent energy restriction (IER) is an effective weight loss strategy. However, the accompanying changes in spontaneous neural activity are unclear, and the relationship among anthropometric measurements, biochemical indicators, and adipokines remains ambiguous. Methods: Thirty-five obese adults were recruited and received a 2-month IER intervention. Data were collected from anthropometric measurements, blood samples, and resting-state functional magnetic resonance imaging at four time points. The regional homogeneity (ReHo) method was used to explore the effects of the IER intervention. The relationships between the ReHo values of altered brain regions and changes in anthropometric measurements, biochemical indicators, and adipokines (leptin and adiponectin) were analyzed. Results: Results showed that IER significantly improved anthropometric measurements, biochemical indicators, and adipokine levels in the successful weight loss group. The IER intervention for weight loss was associated with a significant increase in ReHo in the bilateral lingual gyrus, left calcarine, and left postcentral gyrus and a significant decrease in the right middle temporal gyrus and right cerebellum (VIII). Follow-up analyses showed that the increase in ReHo values in the right LG had a significant positive correlation with a reduction in Three-factor Eating Questionnaire (TFEQ)-disinhibition and a significant negative correlation with an increase in TFEQ-cognitive control. Furthermore, the increase in ReHo values in the left calcarine had a significant positive correlation with the reduction in TFEQ-disinhibition. However, no significant difference in ReHo was observed in the failed weight loss group. Conclusion: Our study provides objective evidence that the IER intervention reshaped the ReHo of some brain regions in obese individuals, accompanied with improved anthropometric measurements, biochemical indicators, and adipokines. These results illustrated that the IER intervention for weight loss may act by decreasing the motivational drive to eat, reducing reward responses to food cues, and repairing damaged food-related self-control processes. These findings enhance our understanding of the neurobiological basis of IER for weight loss in obesity.