Safety and biological outcomes following a phase 1 trial of GD2-specific CAR-T cells in patients with GD2-positive metastatic melanoma and other solid cancers.

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation antigen have become an approved standard of care worldwide for relapsed and refractory B-cell malignancies. If CAR-T cell therapy for non-hematological malignancies is to achieve the same stage of clinical development, then iterative early-phase clinical testing can add value to the clinical development process for evaluating CAR-T cell products containing different CAR designs and manufactured under differing conditions. METHODS: We conducted a phase 1 trial of third-generation GD2-specific CAR-T cell therapy, which has previously been tested in neuroblastoma patients. In this study, the GD2-CAR-T therapy was evaluated for the first time in metastatic melanoma patients in combination with BRAF/MEK inhibitor therapy, and as a monotherapy in patients with colorectal cancer and a patient with fibromyxoid sarcoma. Feasibility and safety were determined and persistence studies, multiplex cytokine arrays on sera and detailed immune phenotyping of the original CAR-T products, the circulating CAR-T cells, and, in select patients, the tumor-infiltrating CAR-T cells were performed. RESULTS: We demonstrate the feasibility of manufacturing CAR-T products at point of care for patients with solid cancer and show that a single intravenous infusion was well tolerated with no dose-limiting toxicities or severe adverse events. In addition, we note significant improvements in CAR-T cell immune phenotype, and expansion when a modified manufacturing procedure was adopted for the latter 6 patients recruited to this 12-patient trial. We also show evidence of CAR-T cell-mediated immune activity and in some patients expanded subsets of circulating myeloid cells after CAR-T cell therapy. CONCLUSIONS: This is the first report of third-generation GD2-targeting CAR-T cells in patients with metastatic melanoma and other solid cancers such as colorectal cancer, showing feasibility, safety and immune activity, but limited clinical effect. TRIAL REGISTRATION NUMBER: ACTRN12613000198729.

Bidirectional regulation of levodopa-induced dyskinesia by a specific neural ensemble in globus pallidus external segment.

Levodopa-induced dyskinesia (LID) is an intractable motor complication arising in Parkinson's disease with the progression of disease and chronic treatment of levodopa. However, the specific cell assemblies mediating dyskinesia have not been fully elucidated. Here, we utilize the activity-dependent tool to identify three brain regions (globus pallidus external segment [GPe], parafascicular thalamic nucleus, and subthalamic nucleus) that specifically contain dyskinesia-activated ensembles. An intensity-dependent hyperactivity in the dyskinesia-activated subpopulation in GPe (GPeTRAPed in LID) is observed during dyskinesia. Optogenetic inhibition of GPeTRAPed in LID significantly ameliorates LID, whereas reactivation of GPeTRAPed in LID evokes dyskinetic behavior in the levodopa-off state. Simultaneous chemogenetic reactivation of GPeTRAPed in LID and another previously reported ensemble in striatum fully reproduces the dyskinesia induced by high-dose levodopa. Finally, we characterize GPeTRAPed in LID as a subset of prototypic neurons in GPe. These findings provide theoretical foundations for precision medication and modulation of LID in the future.

Surgical choice for the treatment of partial intestinal ischemic necrosis caused by acute type a aortic dissection combined with malperfusion of superior mesenteric artery.

Acute type A aortic dissection is a severe cardiovascular disease characterized by rapid onset and high mortality. Traditionally, urgent open aortic repair is performed after admission to prevent aortic rupture and death. However, when combined with malperfusion syndrome, the low perfusion of the superior mesenteric artery can further lead to intestinal necrosis, significantly impacting the surgery's prognosis and potentially resulting in adverse consequences, bringing. This presents great significant challenges in treatment. Based on recent domestic and international research literature, this paper reviews the mechanism, current treatment approaches, and selection of surgical methods for poor organ perfusion caused by acute type A aortic dissection. The literature review findings suggest that central aortic repair can be employed for the treatment of acute type A aortic dissection with inadequate perfusion of the superior mesenteric artery. The superior mesenteric artery can be windowed and (/or) stented, followed by delayed aortic repair. Priority should be given to revascularization of the superior mesenteric artery, followed by central aortic repair. During central aortic repair, direct blood perfusion should be performed on the distal true lumen of the superior mesenteric artery, leading to resulting in favorable therapeutic outcomes. The research results indicate that even after surgical aortic repair, intestinal ischemic necrosis may still occur. In such cases, prompt laparotomy and necessary necrotic bowel resection are crucial for saving the patient's life.

Study on risk factors and treatment strategies of hypoxemia after acute type a aortic dissection surgery.

Acute type A aortic dissection is a life-threatening cardiovascular disease characterized by rapid onset and high mortality. Emergency surgery is the preferred and reliable treatment option. However, postoperative complications significantly impact patient prognosis. Hypoxemia, a common complication, poses challenges in clinical treatment, negatively affecting patient outcomes and increasing the risk of mortality. Therefore, it is crucial to study and comprehend the risk factors and treatment strategies for hypoxemia following acute type A aortic dissection to facilitate early intervention.

Shared insights for heat health risk adaptation in metropolitan areas of developing countries.

Global warming has led to a surge in heat health risks (HHRs), the impacts of which are particularly pronounced in metropolitan areas of developing countries. In the current study, six metropolitan areas - Beijing, China; Cairo, Egypt; Jakarta, Indonesia; Mumbai, India; Rio de Janeiro, Brazil; and Tehran, Iran - were selected as the study area to further differentiate the built-up landscapes by utilizing the concept of local climate zones. Moreover, we assessed the similarities and differences in HHR associated with the landscape. Results revealed a 30.67% higher HHR in compact built-up landscapes than in the open built-up type. Urban green spaces played an effective but differentiated role in mitigating HHR. That is, low vegetation in urbanized areas and trees in suburban areas significantly mitigated HHR. Collectively, our findings emphasize the role of effective planning and management in addressing HHR and provide empirical support for implementing HHR mitigation and adaptation strategies.

Visualization of water transfer channel in sludge dewatering conditioned with skeleton builders by X-ray micro-computed tomography.

Skeleton builders were normally deemed to improve the high porosity and newly-generated permeability of sludge cakes by building water transfer channel during high pressure filtration, thus enhancing sludge dewaterability. However, currently a direct visualization proof of water transfer channel was still lacking. This study provided the direct proof for visualizing water transfer channel in dewatered sludge cakes conditioned with a typical skeleton builder (i.e., phosphogypsum (PG)) by X-ray micro-computed tomography (micro-CT) for the first time. After the addition of PG, the pixel value and image luminance increased significantly, indicating the presence of high density substances from both two-dimensional (2D) cross section and three-dimensional (3D) reconstruction CT images. Moreover, the CT numbers showed strong and negative correlations with specific resistance to filtration (SRF) (R = - 0.99, p < 0.05), capillary suction time (CST) (regression coefficient (R) = - 0.87, probability (p) < 0.05), and water content of the dewatered sludge cake (R = - 0.99, p < 0.05), respectively. These results indicated that the X-ray micro-CT could be a potential technique for analyzing the water distribution in sludge samples conditioned with skeleton builders.

Mitochondrial Morphology and Function Abnormality in Ovarian Granulosa Cells of Patients with Diminished Ovarian Reserve.

In this study, we examined the changes in the mitochondrial structure and function in cumulus granulosa cells of patients with diminished ovarian reserve (DOR) to explore the causes and mechanisms of decreased mitochondrial quality. The mitochondrial ultrastructure was observed by transmission electron microscope, and the function was determined by detecting the ATP content, reactive oxygen species (ROS) levels, the number of mitochondria, and the mitochondrial membrane potential. The expression of ATP synthases in relation to mitochondrial function was analyzed. Additionally, protein immunoblotting was used to compare the expression levels of mitochondrial kinetic protein, the related channel protein in the two groups. Patients with DOR had abnormal granulosa cell morphology, increased mitochondrial abnormalities, decreased mitochondrial function, and disturbed mitochondrial dynamics. Additionally, the silent information regulator 1 (SIRT1)/phospho-AMP-activated protein kinase (P-AMPK)-peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) pathway expression was decreased, which was speculated to be associated with the decreased mitochondrial mass in the DOR group. The mitochondrial mass was decreased in granulosa cells of patients in the DOR group. The mitochondrial dysfunction observed in granulosa cells of patients in the DOR group may be associated with dysregulation of the SIRT1/P-AMPK-PGC-1α-mitochondrial transcription factor A (TFAM) pathway.

Carba PBP: a novel penicillin-binding protein-based lateral flow assay for rapid phenotypic detection of carbapenemase-producing Enterobacterales.

Rapid phenotypic detection assays, including Carba NP and its variants, are widely applied for clinical diagnosis of carbapenemase-producing Enterobacterales (CPE). However, these tests are based on the acidification of the pH indicator during carbapenem hydrolysis, which limits test sensitivity and speed, especially for the detection of CPE producing low-activity carbapenem (e.g., OXA-48 variants). Herein, we developed a novel rapid and sensitive CPE detection method (Carba PBP) that could measure substrate (meropenem) consumption based on penicillin-binding protein (PBP). Meropenem-specific PBP was used to develop a competitive lateral flow assay (LFA) for meropenem identification. For the detection of carbapenemase activity, meropenem concentration was optimized using a checkerboard assay. The performance of Carba PBP was evaluated and compared with that of Carba NP using a panel of 94 clinical strains characterized by whole-genome sequencing and carbapenem susceptibility test. The limit of detection of PBP-based LFA for meropenem identification was 7 ng mL-1. Using 10 ng mL-1 meropenem as the substrate, Carba PBP and Carba NP could detect 10 ng mL-1 carbapenemase within 25 min and 1,280 ng mL-1 CPE in 2 h, respectively. The sensitivity and specificity were 100% (75/75) and 100% (19/19) for Carba PBP and 85.3% (64/75) and 100% (19/19) for Carba NP, respectively. When compared with Carba NP, Carba PBP showed superior performance in detecting all the tested CPE strains (including OXA-48-like variants) within 25 min and presented two orders of magnitude higher analytical sensitivity, demonstrating potential for clinical diagnosis of CPE. IMPORTANCE This study successfully achieved the goal of carbapenemase activity detection with both high sensitivity and convenience, offering a convenient lateral flow assay for clinical diagnosis of carbapenemase-producing Enterobacterales.

ZnT 9 Involvement in Estradiol-Modulated Zinc Homeostasis of the Human Follicular Microenvironment.

Female subfertility has been a growing concern for reproductive health. Assisted reproductive technologies make pregnancy possible, but the outcome rate is still suboptimal. Zinc is an essential factor for fertility and development. Zinc levels in follicular fluids were measured by electrochemical method, and we found that zinc in the follicular fluids was related to high-quality embryo rate (R = 0.39, p = 0.01). Basal estradiol levels and estradiol levels on the day of HCG injection were negatively correlated with zinc concentrations in the follicular fluid (R = - 0.53, p < 0.001; R = - 0.32, p < 0.05), and estradiol promoted ZnT 9 protein expression in cumulus granulosa cells in vitro and in vivo. When the zinc level was at 3.63-3.85 µg/mL, follicular fluid samples had the highest SOD activity. Therefore, zinc played an important role in improving oocyte development by increasing antioxidant capacity. Our results suggested that estradiol affected zinc homeostasis in follicles by controlling the expression of ZnT 9, which in turn influenced the potential of oocytes to develop into good-quality embryos. This study to provide tangible improvements to patient outcomes will make it a focus of both scientific and translational efforts in the future.

Modified aortic root anastomosis and the frozen elephant trunk technique using an integrated tetra-furcate graft to repair type A aortic dissection.

BACKGROUND: Surgery is the preferred treatment for acute Stanford type A aortic dissection (STAAD); however, due to the complexity of the procedure, cardiac ischaemia and cardiopulmonary bypass (CPB) time are longer than general heart surgery, leading to complications. In this present study, we used an integrated tetra-furcate graft for both modified aortic root and distal arch anastomoses (frozen elephant trunk technique, [FET]), and investigated postoperative outcomes associated with this technique in patients with STAAD. METHODS: We included a total of 140 patients who underwent total arch replacement and FET between January 2019 and June 2022 in the present study, 41 patients who underwent the modified technique, and 99 who underwent the graft eversion technique. We subsequently analyzed the perioperative outcomes to compare the differences between the two techniques. RESULTS: There were no statistically significant differences between the two groups in regards to the preoperative characteristics; however, the intraoperative CPB, cardiac ischaemia, and operation times of the modified technique group were significantly shorter than those of the eversion technique group (P = 0.02, P = 0.01, and P = 0.04, respectively), as were postoperative hypoxaemia, intensive care unit (ICU) stay, and ventilation times (P = 0.04, P = 0.03, and P = 0.04, respectively). Additionally, the degree of postoperative bilirubin elevation was milder in the modified technique group (P = 0.002 for direct bilirubin and P = 0.01 for indirect bilirubin). CONCLUSIONS: The modified anastomosis technique can significantly shorten CPB, cardiac ischemia, and operation times, and reduce the intraoperative FFP transfusion and postoperative hypoxemia times. This modified technique, therefore, is worth utilizing for patients with STAAD.

Mitochondrial abnormality in ovarian granulosa cells of patients with polycystic ovary syndrome.

The quality of oocytes in patients with polycystic ovary syndrome (PCOS) decreases, which is closely related to the function of oocytes' mitochondria. If mitochondrial dysfunction is involved in PCOS, it is likely to affect the function of cumulus cells. However, the mechanism of mitochondrial dysfunction remains unclear. In the present study, granulosa cells were collected from women attending the Hebei Reproductive Health Hospital and were divided into the normal ovarian reserve group (CON group) and the PCOS group. The mitochondrial ultrastructure was observed by transmission electron microscope, and the mitochondrial function was determined by detecting the ATP content, reactive oxygen species levels, the number of mitochondria and the mitochondrial membrane potential. Additionally, western blotting was used to compare the expression levels of mitochondrial kinetic protein, the related channel protein, between the two groups. In the present study, it was found that patients with PCOS had abnormal granulosa cell morphology, increased mitochondrial abnormalities, decreased mitochondrial function and disturbed mitochondrial dynamics. In addition, the silent information regulator 1/phosphorylated­AMP­activated protein kinase/peroxisome proliferator­activated receptor­Î³ coactivator 1α pathway expression was decreased, and it was hypothesized that the decreased mitochondrial mass in the PCOS group was associated with it.

Prevalence of high blood pressure and its associated factors among students in Shenyang, China: A cross-sectional study.

There is growing evidence that the prevalence of high blood pressure is increasing, and it may have serious consequences. However, research on the prevalence and influencing factors of high blood pressure among primary and secondary school students is still relatively scarce. This study aims to investigate the prevalence and influencing factors of high blood pressure among primary and secondary school students in Shenyang, in order to provide scientific evidence for the prevention and management of this disease. From April to May 2020, 4892 students aged 7 to 17 years were selected as the survey subjects, and on-site physical measurements and questionnaire surveys were conducted. The prevalence of high blood pressure was described. Restricted cubic spline was used to analyze the dose-response relationship between sleep duration, BMI and the risk of high blood pressure. Logistic regression was used to analyze the risk factors. Multiplicative and additive models were used to analyze the interaction between sleep duration and BMI. The results showed that the overall prevalence of high blood pressure among students aged 7 to 17 years in Shenyang was 9.9%, with a higher prevalence in females than males (12.1% vs 7.9%) and in urban areas than suburban areas (11.8% vs 7.7%). The prevalence was lowest in students with normal weight (8.3%) and highest in those who were obese (12.5%). The prevalence fluctuated to some extent among different age groups, but overall, it increased with age, with the lowest prevalence in primary school students (7.0%), 11.4% in mild school students, and the highest prevalence of 14.3% in high school students. Multivariable analysis showed that the risk of high blood pressure in female students was 1.90 times higher than that in male students (95% CI: 1.54-2.35), and the risk in suburban areas was 0.65 times lower than that in urban areas (95% CI: 0.52-0.81). Students with a BMI ≥ 21 kg/m2 had a 1.58 times higher risk than those with a BMI < 21 kg/m2(95% CI: 1.28-1.96), while those with a sleep time ≥ 8 hours had a 0.80 times lower risk than those with a sleep time < 8 hours (95% CI: 0.65-0.99). Exercise can significantly reduce the risk of high blood pressure, while using electronic devices for more than 0.5 hours significantly increases the risk of high blood pressure. BMI and sleep duration have no interaction effect on the risk of high blood pressure. To reduce the prevalence of high blood pressure, students should reduce the use of electronic devices, ensure adequate exercise, maintain a reasonable weight, and ensure sufficient sleep.

An attentional residual feature fusion mechanism for sheep face recognition.

In the era of globalization and digitization of livestock markets, sheep are considered an essential source of food production worldwide. However, sheep behavior monitoring, disease prevention, and precise management pose urgent challenges in the development of smart ranches. To address these problems, individual identification of sheep has become an increasingly viable solution. Despite the benefits of traditional sheep individual identification methods, such as accurate tracking and record-keeping, they are labor-intensive and inefficient. Popular convolutional neural networks (CNNs) are unable to extract features for specific problems, further complicating the issue. To overcome these limitations, an Attention Residual Module (ARM) is proposed to aggregate the feature mapping between different layers of the CNN. This approach enables the general model of the CNN to be more adaptable to task-specific feature extraction. Additionally, a targeted sheep face recognition dataset containing 4490 images of 38 individual sheep has been constructed. Furthermore, the experimental data was expanded using image enhancement techniques such as rotation and panning. The results of the experiments indicate that the accuracy of the VGG16, GoogLeNet, and ResNet50 networks with the ARM improved by 10.2%, 6.65%, and 4.38%, respectively, compared to these recognition networks without the ARM. Therefore, the proposed method for specific sheep face recognition tasks has been proven effective.

Numerical simulation to optimize passive aeration strategy for semi-aerobic landfill.

Passive aeration has been proven to be efficient for oxygen supply in landfill. The combination of passive aeration and semi-aerobic landfill offers a cost-effective and energy-efficient approach to solid waste (SW) treatment. However, determining the optimal strategy for this combination has remained unclear. This study aimed to investigate the strategy of passive aeration in a semi-aerobic landfill using numerical simulation methods. A model coupled hydrodynamic model and compartment model for degradation of SW was implemented. The accuracy was well validated by comparing measured and simulated results in a pilot-scale landfill. Compared with natural convection, passive aeration by funnel caps could increase air input by 20 %. By simulating volumetric fraction distribution of CO2, CH4 and O2 in landfill, an orthogonal experiment including 4 factors was designed to identify that the diameter of tubes (DT), the spacing between tubes (ST) and the landfill depth (LD) have substantial impacts on aerobic zone ratio (AZR) of landfill. But the diameter of gas ports (DGP) has an indiscernible effect. The optimized factors were determined to be as follows: DT = 0.3 m, ST = 15.0 m, DGP = 0.05 m, and LD = 4.0 m, under which the semi-aerobic landfill could enhance SW degradation. Large diameter and spacing of tubes are favorable to improve the AZR at the top of the landfill, and the aerobic zone mainly exists near the ventilation tubes. These findings contribute to the development of more efficient and sustainable solid waste treatment strategies in semi-aerobic landfill.

Dendritic Cell-Mediated Cross-Priming by a Bispecific Neutralizing Antibody Boosts Cytotoxic T Cell Responses and Protects Mice against SARS-CoV-2.

Administration of neutralizing antibodies (nAbs) has proved to be effective by providing immediate protection against SARS-CoV-2. However, dual strategies combining virus neutralization and immune response stimulation to enhance specific cytotoxic T cell responses, such as dendritic cell (DC) cross-priming, represent a promising field but have not yet been explored. Here, a broadly nAb, TNT , are first generated by grafting an anti-RBD biparatopic tandem nanobody onto a trimerbody scaffold. Cryo-EM data show that the TNT structure allows simultaneous binding to all six RBD epitopes, demonstrating a high-avidity neutralizing interaction. Then, by C-terminal fusion of an anti-DNGR-1 scFv to TNT , the bispecific trimerbody TNT DNGR-1 is generated to target neutralized virions to type 1 conventional DCs (cDC1s) and promote T cell cross-priming. Therapeutic administration of TNT DNGR-1, but not TNT , protects K18-hACE2 mice from a lethal SARS-CoV-2 infection, boosting virus-specific humoral responses and CD8+ T cell responses. These results further strengthen the central role of interactions with immune cells in the virus-neutralizing antibody activity and demonstrate the therapeutic potential of the Fc-free strategy that can be used advantageously to provide both immediate and long-term protection against SARS-CoV-2 and other viral infections.

Effect of minimally invasive versus conventional aortic root replacement on transfusion and postoperative wound complications in patients: A meta-analysis.

We examined whether small incision aortic root replacement could reduce the amount of blood transfusion during operation and the risk of postoperative complications. An extensive e-review of the 4 main databases (PubMed, Cochrane, Web of Science and EMBASE) was carried out to determine all the published trials by July 2023. The search terms used were associated with partial versus full sternotomy and aortic root. This analysis only included the study articles that compared partial and full sternotomy. After excluding articles based on titles or abstracts, selected full-text articles had reference lists searched for any potential further articles. We analysed a total of 2167 subjects from 10 comparable trials. The minimally invasive aortic root graft in breastbone decreased the duration of hospitalization (MD, -2.58; 95% CI, -3.15, -2.01, p < 0.0001) and intraoperative red blood cell transfusion (MD, -1.27; 95% CI, -2.34, -0.19, p = 0.02). However, there were no significant differences in wound infection (OR, 0.88; 95% CI, 0.16, 4.93, p = 0.88), re-exploration for bleeding (OR, 0.96; 95% CI, 0.60, 1.53, p = 0.86), intraoperative blood loss (MD, -259.19; 95% CI, -615.11, 96.73, p = 0.15) and operative time (MD, -7.39; 95% CI, -19.10, 4.32, p = 0.22); the results showed that the microsternotomy did not differ significantly from that of the routine approach. Small sternotomy may be an effective and safe substitute for the treatment of the aorta root. Nevertheless, the wide variety of data indicates that larger, well-designed studies are required to back up the current limited literature evidence showing a benefit in terms of complications like postoperative wound infections or the volume of intraoperative red blood cell transfusion.

Anti-Colorectal Cancer Activity of Solasonin from Solanum nigrum L. via Histone Deacetylases-Mediated p53 Acetylation Pathway.

(1) Background: Solanum nigrum L. is a plant of the genus Solanum in the family Solanaceae and is commonly used to treat tumors. Solasonin (SS) is a steroidal alkaloid extracted from Solanum nigrum L. that has anti-colorectal cancer (CRC) activity. (2) Methods: Column chromatography, semi-preparative HPLC and cellular activity screening were used to isolate potential anti-CRC active compounds in Solanum nigrum L., and structure identification using 1H-NMR and 13C-NMR techniques. Expression levels of HDAC in CRC were mined in the UALCAN database. The in vitro effects of SS on SW620 cell line and its mechanism were examined via Western blot, EdU staining, flow cytometry and immunofluorescence. CRC xenograft model and IHC staining were mainly used to evaluate the role of SS in vivo. (3) Results: The results showed that SS was the most potent anti-CRC component in Solanum nigrum L., which induced apoptosis and cell cycle arrest in the SW620 cell line. HDAC was highly expressed in CRC. The treatment of SW620 cell line with SS resulted in a significant downregulation of HDAC, an increase in the level of P53 acetylation and a subsequent increase in the level of P21. The in vivo validation results showed that SS could effectively inhibit CRC growth, which was associated with the downregulation of HDAC. (4) Conclusions: SS treatment for CRC mainly works through the induction of apoptosis and cycle arrest, and its mechanism of action is mainly related to HDAC-induced P53 acetylation, and the HDAC/P53 signaling pathway may be a potential pathway for the treatment of CRC.