Preclinical evaluation of a novel CAR-T therapy utilizing a scFv antibody highly specific to MAGE-A4p230-239/HLA-A∗02:01 complex.

Despite the revolutionary success of chimeric antigen receptor (CAR)-T therapy for hematological malignancies, successful CAR-T therapies for solid tumors remain limited. One major obstacle is the scarcity of tumor-specific cell-surface molecules. One potential solution to overcome this barrier is to utilize antibodies that recognize peptide/major histocompatibility complex (MHCs) in a T cell receptor (TCR)-like fashion, allowing CAR-T cells to recognize intracellular tumor antigens. This study reports a highly specific single-chain variable fragment (scFv) antibody against the MAGE-A4p230-239/human leukocyte antigen (HLA)-A∗02:01 complex (MAGE-A4 pMHC), screened from a human scFv phage display library. Indeed, retroviral vectors encoding CAR, utilizing this scFv antibody as a recognition component, efficiently recognized and lysed MAGA-A4+ tumor cells in an HLA-A∗02:01-restricted manner. Additionally, the adoptive transfer of T cells modified by the CAR-containing glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related receptor (GITR) intracellular domain (ICD), but not CD28 or 4-1BB ICD, significantly suppressed the growth of MAGE-A4+ HLA-A∗02:01+ tumors in an immunocompromised mouse model. Of note, a comprehensive analysis revealed that a broad range of amino acid sequences of the MAGE-A4p230-239 peptide were critical for the recognition of MAGE-A4 pMHC by these CAR-T cells, and no cross-reactivity to analogous peptides was observed. Thus, MAGE-A4-targeted CAR-T therapy using this scFv antibody may be a promising and safe treatment for solid tumors.

Effects of Dexmedetomidine on Systemic Inflammation and Postoperative Complications in Laparoscopic Pancreaticoduodenectomy: A Double-blind Randomized Controlled Trial.

BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD) may induce intense inflammatory response which might be related to the patient's outcomes. Clinical dexmedetomidine (DEX) has been widely used for opioid-sparing anesthesia and satisfactory sedation. The objective of this study was to investigate the influence of DEX on inflammatory response and postoperative complications in LPD. METHODS: Ninety-nine patients undergoing LPD were randomly assigned to two groups: normal saline (NS) and DEX. The primary outcome was the neutrophil-to-lymphocyte ratio (NLR) differences postoperatively within 48 h. Secondary outcomes were postoperative complications, the length of postoperative hospital stay and the incidence of ICU admission. Other outcomes included anesthetics consumption and intraoperative vital signs. RESULTS: NLR at postoperative day 2 to baseline ratio decreased significantly in the DEX group (P = 0.032). Less major complications were observed in the DEX group such as pancreatic fistula, delayed gastric emptying and intra-abdominal infection (NS vs. DEX, 21.7% vs. 13.6%, P = 0.315; 10.9% vs. 2.3%, P = 0.226; 17.4% vs. 11.4%, P = 0.416, respectively) though there were no statistical differences. Three patients were transferred to the ICU after surgery in the NS group, while there was none in the DEX group (P = 0.242). The median postoperative hospital stay between groups were similar (P = 0.313). Both intraoperative propofol and opioids were less in the DEX group (P < 0.05). CONCLUSIONS: Intraoperative DEX reduced the early postoperative inflammatory response in LPD. It also reduced the use of narcotics that may related to reduced major complications, which need additional research further.

CAR-Modified Vγ9Vδ2 T Cells Propagated Using a Novel Bisphosphonate Prodrug for Allogeneic Adoptive Immunotherapy.

The benefits of CAR-T therapy could be expanded to the treatment of solid tumors through the use of derived autologous αß T cell, but clinical trials of CAR-T therapy for patients with solid tumors have so far been disappointing. CAR-T therapy also faces hurdles due to the time and cost intensive preparation of CAR-T cell products derived from patients as such CAR-T cells are often poor in quality and low in quantity. These inadequacies may be mitigated through the use of third-party donor derived CAR-T cell products which have a potent anti-tumor function but a constrained GVHD property. Vγ9Vδ2 TCR have been shown to exhibit potent antitumor activity but not alloreactivity. Therefore, in this study, CAR-T cells were prepared from Vγ9Vδ2 T (CAR-γδ T) cells which were expanded by using a novel prodrug PTA. CAR-γδ T cells suppressed tumor growth in an antigen specific manner but only during a limited time window. Provision of GITR co-stimulation enhanced anti-tumor function of CAR-γδ T cells. Our present results indicate that, while further optimization of CAR-γδ T cells is necessary, the present results demonstrate that Vγ9Vδ2 T cells are potential source of 'off-the-shelf' CAR-T cell products for successful allogeneic adoptive immunotherapy.

Research Misconduct Investigations in China's Science Funding System.

As stewards of public money, government funding agencies have the obligation and responsibility to uphold the integrity of funded research. Despite an increasing amount of empirical studies examining research-related misconduct, a majority of these studies focus on retracted publications. How agencies spot funding-relevant wrongdoing and what sanctions the offenders face remain largely unexplored. This is particularly true for public funding agencies in emerging science powers. To amend this oversight, we retrieved and analyzed all publicized investigation results from China's largest basic research funding agency over the period from 2005 to 2021. Our findings reveal that both the "police patrol" and "fire alarm" approaches are used to identify misconduct and deter funding-related fraud in China. The principal triggers for investigations are journal article retractions, whistleblowing, and plagiarism detection software. Among the six funding-related misconduct types publicized and punished, the top three are: (1) fraudulent papers, (2) information fabrication and/or falsification in the research proposal, and (3) proposal plagiarism. The most common administrative sanctions are debarment and reclamation of grants. This article argues that more systematic research and cooperation among stakeholders is needed to cultivate research integrity in emerging science powers like China. Specific training and education should be provided for young scientists to help them avoid the pitfall of academic misconduct.

AIB3IIC3IIIQ8VI: A New Family for the Design of Infrared Nonlinear Optical Materials by Coupling Octahedra and Tetrahedra Units.

Large second-harmonic generation (SHG) response and broad band gap are two important and competitive parameters. It is difficult to balance them out in one material. In this work, by coupling alkali earth metal (AEM) octahedra with large highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) gap and nonlinear optical (NLO)-active tetrahedra units, nine noncentrosymmetric (NCS) compounds, belonging to a new quaternary chalcogenide family AIB3IIC3IIIQ8VI with unique windmill-like [Mg3M3IIIQ24] (MIII = Al, Ga; Q = S, Se) units constructed by alternated [MgQ6] octahedra and [MIIIQ4] tetrahedra, are rationally designed and fabricated. The compounds show a stable structural framework but adjustable optical properties. Among them, NaMg3Ga3Se8 shows a large SHG response (∼1 × AgGaS2 (AGS)), wide band gap (in selenide) (2.77 eV), high laser-induced damage threshold (LIDT) (∼2.3 × AGS), and suitable birefringence (0.079@546 nm). It should be a potential candidate for infrared (IR) nonlinear optical (NLO) materials. The results enrich the chemical diversity of chalcogenides and open an avenue for the development of new IR NLO materials through the octahedra and tetrahedra coupled strategy.

Comparison of anther transcriptomes in response to cold stress at the reproductive stage between susceptible and resistant Japonica rice varieties.

BACKGROUND: Rice is one of the most important cereal crops in the world but is susceptible to cold stress (CS). In this study, we carried out parallel transcriptomic analysis at the reproductive stage on the anthers of two Japonica rice varieties with contrasting CS resistance: cold susceptible Longjing11 (LJ11) and cold resistant Longjing25 (LJ25). RESULTS: According to the obtained results, a total of 16,762 differentially expressed genes (DEGs) were identified under CS, including 7,050 and 14,531 DEGs in LJ25 and LJ11, respectively. Examining gene ontology (GO) enrichment identified 35 up- and 39 down-regulated biological process BP GO terms were significantly enriched in the two varieties, with 'response to heat' and 'response to cold' being the most enriched. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified 33 significantly enriched pathways. Only the carbon metabolism and amino acid biosynthesis pathways with down-regulated DEGs were enriched considerably in LJ11, while the plant hormone signal transduction pathway (containing 153 DEGs) was dramatically improved. Eight kinds of plant hormones were detected in the pathway, while auxin, abscisic acid (ABA), salicylic acid (SA), and ethylene (ETH) signaling pathways were found to be the top four pathways with the most DEGs. Furthermore, the protein-protein interaction (PPI) network analysis identified ten hub genes (co-expressed gene number ≥ 30), including six ABA-related genes. Various DEGs (such as OsDREB1A, OsICE1, OsMYB2, OsABF1, OsbZIP23, OsCATC, and so on) revealed distinct expression patterns among rice types when the DEGs between LJ11 and LJ25 were compared, indicating that they are likely responsible for CS resistance of rice in cold region. CONCLUSION: Collectively, our findings provide comprehensive insights into complex molecular mechanisms of CS response and can aid in CS resistant molecular breeding of rice in cold regions.

Effects of lidocaine administration via the perforated outer cuff of a dual-cuff endotracheal tube and remifentanil administration on recovery from general anaesthesia for female patients undergoing thyroidectomy: a single centre, double-blind, randomised study.

BACKGROUND: Cough caused by endotracheal tube (ETT) placement is ubiquitous and correlates with adverse outcomes. Remifentanil administration via target-controlled infusion (TCI) is one of the cough prevention measures used during recovery. In a pilot study, lidocaine administered via the perforated outer cuff of a dual-cuff endotracheal tube was also found to prevent cough due to ETT placement. We therefore compared these two cough prevention approaches during recovery after thyroidectomy in a single-centre, double-blind, randomised study conducted in China during the period from 09/10/2020 to 30/04/2021. METHODS: Ninety-eight female patients aged 18-65 years with American Society of Anaesthesiologists Physical Status scores of I and II were scheduled to undergo thyroidectomy. The ETT contained an internal cuff covered by a perforated outer cuff to allow for lidocaine delivery. Patients were randomised to receive either 4 ml of saline solution (Group R, n = 49) or 4 ml of 2% lidocaine in the outer cuff (Group L, n = 49) at the beginning of skin suturing. Remifentanil (2 ng/ml) was maintained in Group R until extubation, while remifentanil was maintained in Group L until the end of skin suturing. The primary outcome was cough during patient transfer, at 1 min before extubation, and at extubation. The secondary outcomes were haemodynamics and other recovery parameters. RESULTS: Primary outcomes were compared between remifentanil vs. lidocaine application, namely, the incidence of cough during patient transfer (0% in Group R vs. 0% in Group L), at 1 min before extubation (22.45% in Group R vs. 4.08% in Group L; P = 0.015), and at extubation (61.22% in Group R vs. 20.41% in Group L; P < 0.001). Compared with remifentanil, lidocaine more effectively decreased heart rate elevation and hypoxemia at 5 min after extubation, the spontaneous respiration recovery time, the extubation time, the duration of post-anaesthesia care unit (PACU) stay, Richmond Agitation-Sedation Scale scores in the agitated range and Critical-Care Pain Observation Tool scores. CONCLUSION: Lidocaine administered via the perforated outer cuff of the ETT significantly improved recovery from general anaesthesia compared to remifentanil in female patients after thyroidectomy. TRIAL REGISTRATION: Chinese Clinical Trial Registry (No. ChiCTR2000038653), registered on 27/09/2020.

Safety and antibody immune response of CHP-NY-ESO-1 vaccine combined with poly-ICLC in advanced or recurrent esophageal cancer patients.

The nanoparticle complex of cholesteryl pullulan (CHP) and NY-ESO-1 antigen protein (CHP-NY-ESO-1) presents multiple epitope peptides to MHC class I and II pathways, leading to CD8+ and CD4+ T cell responses. Poly-ICLC is a synthetic, double-stranded RNA, an agonist of toll-like receptor (TLR)-3, and a cytoplasmic receptor of melanoma differentiation-associated gene (MDA)-5. It should be a suitable immune adjuvant of cancer vaccine to overcome the inhibitory tumor microenvironment. We conducted a phase 1 clinical trial of CHP-NY-ESO-1 with poly-ICLC in patients with advanced or recurrent esophageal cancer. CHP-NY-ESO-1/poly-ICLC (µg/mg) was administered at a dose of 200/0.5 or 200/1.0 (cohorts 1 and 2, respectively) every 2 weeks for a total of six doses. The primary endpoints were safety and immune response. The secondary endpoint was tumor response. In total, 16 patients were enrolled, and six patients in each cohort completed the trial. The most common adverse event (AE) was injection site skin reaction (86.7%). No grade 3 or higher drug-related AEs were observed. No tumor responses were observed, and three patients (30%) had stable disease. The immune response was comparable between the two cohorts, and all patients (100%) achieved antibody responses with a median of 2.5 vaccinations. Comparing CHP-NY-ESO-1 alone to the poly-ICLC combination, all patients in both groups exhibited antibody responses, but the titers were higher in the combination group. In a mouse model, adding anti-PD-1 antibody to the combination of CHP-NY-ESO-1/poly-ICLC suppressed the growth of NY-ESO-1-expressing tumors. Combining the vaccine with PD-1 blockade holds promise in human trials.

Determinants of China's health expenditure growth: based on Baumol's cost disease theory.

BACKGROUND: During the past four decades, China's total health expenditure and health expenditure per capita have both experienced a dramatic increase in growth rate. This study aims to explore the determinants of health expenditure growth and the influencing mechanism of these determinants, with considering the productivity efficiency represented by Baumol's cost disease. METHODS: Based on the longitudinal data of 30 provincial-level administrative regions in China, from 2010 to 2017, multi-variates regression models were constructed to assess the determinants, including demography, income, Baumol's cost disease, technology, their effects on per capital total health expenditure growth and the three financing sources: government, society and out-of-pocket health expenditure. Moreover, the Spatial Durbin Model was used to analyze the influence mechanism of determinants on the increase of health expenditure across provinces. RESULTS: Among 210 province-year growth rate observations, all of the average growth rate of total health expenditure (12.78%) was much higher than the growth rate of per capita GDP (8.06%). According to the statistical analysis, we found that:(1) Income and Baumol's cost disease have a significant positive impact on health expenditure growth(P < 0.01). The impact of technical factors on government health expenditure is significantly positive. (2) The determinants affected the growth of health costs in different regions variably; the eastern region is mainly driven by Baumol's cost disease and technical factors, while the central and western regions are mainly affected by income factors and Baumol's cost disease. (3) There is a significant spatial spillover effect on the health expenditure growth between regions. The income factor and Baumol's cost disease have a positive impact on the health expenditure growth in its own region as well as in other regions. CONCLUSIONS: Income and Baumol's cost disease significantly contributed to China health expenditure growth. The health expenditure determinants showed spatial varies effect and space spillover effect on the neighborhood areas. Which indicates that a reasonable salary system should be contrasted to meet the changeling from the Baumol's cost disease, and the necessity of equity in health resource allocation among provinces in China.

Medium- and long-term projection for health expenditure with the implementation of Healthy Shanghai Initiative: The influence of chronic disease prevention and control plan. / 《健康上海行动》计划背景下卫生费用的中长期预测­­éžä¼ æŸ“æ€§æ ¢æ€§ç–¾ç— é˜²æ²»è®¡åˆ’çš„å½±å“.

OBJECTIVES: The rapid growth of health expenditure has always been the focus of health policy. This study aims to project health expenditure in Shanghai and to carry out policy simulations on the impact of chronic disease prevention programs on health costs in the Healthy Shanghai Initiative. METHODS: Based on the Shanghai health accounts, component-based model was used to project Shanghai total health expenditure of 2020-2035, and the policy stimulation was implemented. RESULTS: In 2020-2035, Shanghai's health expenditure is expected to grow continually, the proportion of total health expenditure in GDP will exceed 8.00% in 2023, reach 9.00% in 2025, and 10.03% in 2035. The proportion of current health expenditure in GDP will exceed 8.00% in 2024 and reach 9.55% in 2035. The chronic disease prevention plan help saving the medical expenditure of respiratory diseases,endocrine system diseases, and circulatory system diseases, accounting 3.28% to 10.58% of total health expenditure. CONCLUSIONS: The sustainability of health financing in Shanghai is facing challenges under the new normal of economy. It is necessary to promote the prevention and control of chronic diseases and strengthen cost control from both the supply and demand sides.