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JOURNAL/nrgr/04.03/01300535-202419110-00030/figure1/v/2024-03-08T184507Z/r/image-tiff The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury. Ruxolitinib, a JAK-STAT inhibitor, exhibits effectiveness in autoimmune diseases, arthritis, and managing inflammatory cytokine storms. Although studies have shown the neuroprotective potential of ruxolitinib in neurological trauma, the exact mechanism by which it enhances functional recovery after spinal cord injury, particularly its effect on astrocytes, remains unclear. To address this gap, we established a mouse model of T10 spinal cord contusion and found that ruxolitinib effectively improved hindlimb motor function and reduced the area of spinal cord injury. Transcriptome sequencing analysis showed that ruxolitinib alleviated inflammation and immune response after spinal cord injury, restored EAAT2 expression, reduced glutamate levels, and alleviated excitatory toxicity. Furthermore, ruxolitinib inhibited the phosphorylation of JAK2 and STAT3 in the injured spinal cord and decreased the phosphorylation level of nuclear factor kappa-B and the expression of inflammatory factors interleukin-1β, interleukin-6, and tumor necrosis factor-α. Additionally, in glutamate-induced excitotoxicity astrocytes, ruxolitinib restored EAAT2 expression and increased glutamate uptake by inhibiting the activation of STAT3, thereby reducing glutamate-induced neurotoxicity, calcium influx, oxidative stress, and cell apoptosis, and increasing the complexity of dendritic branching. Collectively, these results indicate that ruxolitinib restores glutamate homeostasis by rescuing the expression of EAAT2 in astrocytes, reduces neurotoxicity, and effectively alleviates inflammatory and immune responses after spinal cord injury, thereby promoting functional recovery after spinal cord injury., (Copyright © 2024 Copyright: © 2024 Neural Regeneration Research.)

Background: Midazolam is a short-acting benzodiazepine frequently used in the perioperative setting. This study aimed to investigate the potential impact of intraoperative midazolam on postoperative delirium (POD) in older patients undergoing non-cardiac surgery., Methods: This study included patients aged ≥ 65 years who received general anaesthesia between April 2020 and April 2022 in multiple hospitals across China. POD occurring within 7 days was assessed using the 3-minute Diagnostic Interview for Confusion Assessment Method (3D-CAM). Univariable and multivariable logistic regression models based on the random effects were used to determine the association between midazolam administration and the occurrence of POD, presented as risk ratio (RR) and 95% confidence intervals (CI). Kaplan-Meier cumulative incidence curve was plotted to compare the distribution of time to POD onset between patients who received midazolam and those who did not. Subgroup analyses based on specific populations were performed to explore the relationship between midazolam and POD., Results: In all, 5,663 patients were included, of whom 723 (12.8%) developed POD. Univariate and multivariable logistic regression analyses based on random effects of different hospitals showed no significant association between midazolam medication and POD among older population (unadjusted RR=0.96, 95% CI: 0.90-1.30, P=0.38; adjusted RR=1.09, 95% CI: 0.91-1.33, P=0.35). Kaplan-Meier curve showed no difference in the distribution of time to POD onset (Hazard ratio [HR]=1.02, 95%CI: 0.88-1.18, P=0.82). The results of subgroup analyses found that intraoperative midazolam treatment was not associated with POD in the specific subgroups of patients., Conclusions: Intraoperative administration of midazolam may not be associated with an increased risk of POD in older patients undergoing non-cardiac surgery., Competing Interests: Conflicts of Interest: The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

Background: Paraplegia after spinal cord ischemia is a devastating condition in the clinic. Here, we develop an awake rabbit model of spinal cord ischemia with delayed paraplegia and explore the influence of ambient temperature on the outcomes after injury., Methods: A total of 47 male rabbits were involved in the present study. Transient spinal cord ischemia was induced by occluding the infrarenal abdominal aorta of awake rabbits at different ambient temperatures. To find the optimal conditions for developing delayed paraplegia, hindlimb motor function after ischemia was evaluated between experiments., Results: The onset and magnitude of ischemic injury varied with the ambient temperature maintained during the peri-ischemia period. More serious spinal cord injury occurred when ischemia was induced at higher temperatures. At 18°C, 25-minute ischemia resulted in 74% of rabbits developing delayed paraplegia. At a temperature of 28°C or higher, most of the animals developed acute paraplegia immediately. While at 13°C, rabbits usually regained normal motor function without paraplegia., Conclusion: This awake rabbit model is highly reproducible and will be helpful in future studies of delayed paraplegia after spinal cord ischemia. The ambient temperature must be considered while using this model during investigation of therapeutic interventions., (© 2023 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Left atrial appendage (LAA) closure can prevent stroke in high-risk patients with atrial fibrillation.A bioabsorbable LAA occluder made of degradable polymer materials, such as polydioxanone (PDO) and poly-L-lactic acid (PLA), and nitinol wire was used. Occluders were successfully implanted in 18 Chinese rural dogs, 2 of which died within 48 hours after operation due to pericardial tamponade and hemorrhage, respectively. Follow-up observation was performed after transcatheter LAA closure. New tissue was found on the surface of the occluder 2 months after operation. No adjacent structures such as the mitral valve and the left superior pulmonary vein were affected by the occluder discs. Hematoxylin and eosin (HE) staining was performed at 3 months after operation, which showed intact intimal structure on the occluder surface, and unabsorbed PDO and PLA were observed. Scanning electron microscopy showed irregular arrangement of endothelial cells. New endothelial tissue was observed to completely cover the occluder at 6 months after operation. Most PDOs were replaced by fibrous connective tissue, and scanning electron microscopy showed regularly arranged endothelial cells. Pathological examination at 12 months showed only a small remnant of PDO. The gross specimens of the liver, spleen, and kidneys and pathological examination did not indicate thromboembolism.The bioabsorbable LAA occluder made of PDO, PLA, and nitinol wire was safe and effective for the occlusion of LAA in dogs. The surface of the occluder was endothelialized half a year after operation. The absorbable materials of the occluder were degraded after 1 year.

The influence of chimeric antigen receptor T (CAR-T) cell therapy on platelet function in relapsed/refractory (R/R) multiple myeloma (MM) has not been thoroughly investigated. Our cohort comprised fifty MM patients treated with CAR-T cells. The mean platelet closure time (PCT) induced by collagen/adenosine diphosphate (CADP) in peripheral blood was significantly prolonged before lymphodepletion (195.24 ± 11.740 s) and notably reduced post-CAR-T cell therapy (128.02 ± 5.60 s), with a statistically significant improvement (67.22, 95% CI 46.91-87.53, P < 0.001). This post-treatment PCT was not significantly different from that of healthy controls (10.64, 95% CI 1.11-22.40, P > 0.05). Furthermore, a pronounced enhancement in PCT was observed in patients with a response greater than partial remission (PR) following CAR-T cell infusion compared to pre-treatment values (P < 0.001). An extended PCT was also associated with a less favorable remission status. In patients with cytokine release syndrome (CRS) grades 0-2, those with a PCT over 240.5 s exhibited a shorter progression-free survival (PFS), with median PFS times of 10.2 months for the PCT > 240.5 s group versus 22.0 months for the PCT ≤ 240.5 s group. Multivariate analysis revealed that a PCT value exceeding 240.5 s is an independent prognostic factor for overall survival (OS) in R/R MM patients after CAR-T cell therapy. The study demonstrates that CAR-T cell therapy enhances platelet function in R/R MM patients, and PCT emerges as a potential prognostic biomarker for the efficacy of CAR-T cell therapy., (© 2024. The Author(s).)

The current CAR-T cell therapy products have been hampered in their druggability due to the personalized preparation required, unclear pharmacokinetic characteristics, and unpredictable adverse reactions. Enabling standardized manufacturing and having clear efficacy and pharmacokinetic characteristics are prerequisites for ensuring the effective practicality of CAR-T cell therapy drugs. This review provides a broad overview of the different approaches for controlling behaviors of CAR-T cells in vivo. The utilization of genetically modified vectors enables in vivo production of CAR-T cells, thereby abbreviating or skipping the lengthy in vitro expansion process. By equipping CAR-T cells with intricately designed control elements, using molecule switches or small-molecule inhibitors, the control of CAR-T cell activity can be achieved. Moreover, the on-off control of CAR-T cell activity would yield potential gains in phenotypic remodeling. These methods provide beneficial references for the future development of safe, controllable, convenient, and suitable for standardized production of CAR-T cell therapy products., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Peripheral T-cell lymphomas (PTCL) are an aggressive group of mature T-cell neoplasms, often associated with poor outcomes, in part, due to frequent relapsed/refractory disease. The objective of this study was to assess the prognostic impact of disease progression within 24 months (POD24) on overall survival (OS) for patients diagnosed with PTCL., Methods: A retrospective analysis was conducted on a cohort of patients with newly diagnosed PTCL who underwent chemotherapy at the Affiliated Hospital of Xuzhou Medical University between January 2010 and September 2021. Prognostic assessment was limited to patients who were evaluable for POD24., Results: Records were reviewed for 106 patients with PTCL, of whom 66 patients experienced POD24 (referred to as the POD24 group) and 40 patients did not experience POD24 (referred to as the no POD24 group). Significant differences were observed between the POD24 group and the no POD24 group in regard to clinical stage, Eastern Cooperative Oncology Group (ECOG) performance status (PS), International Prognostic Index (IPI) score, lactate dehydrogenase (LDH) levels, β2-microglobulin (β2-MG) levels, prealbumin and albumin levels. Patients in the POD24 group had a significant shorter median OS compared to the no POD24 group (11.9 months vs not reached, respectively; P  < 0.001). Non response (NR) to treatment and POD24 were identified as independent negative prognostic factors for survival in patients with PTCL., Conclusion: POD24 is a prognostic factor associated with unfavorable outcomes in patients with PTCL and can be used to identify high-risk patients and guide treatment decisions.

Relapsed/refractory multiple myeloma patients with extramedullary disease (EMD) have unfavorable prognosis and lack effective therapy. Chimeric antigen receptor (CAR) T-cell activities in EMD have yet to be determined; how EMD-specific microenvironment influences the clinical outcomes of CAR T-cell therapy remains of great interest. In this prospective cohort study, patients with histologically confirmed extra-osseous EMD were enrolled and treated with combined anti-BCMA and anti-CD19 CAR T-cell therapy from May 2017 to September 2023. Thirty-one patients were included in the study. Overall response occurred in 90.3% of medullary disease and 64.5% of EMD (p = .031). Discrepancies in treatment response were noted between medullary and extramedullary diseases, with EMD exhibiting suboptimal and delayed response, as well as shortened response duration. With a median follow-up of 25.3 months, the median progression-free and overall survival were 5.0 and 9.7 months, respectively. Landmark analysis demonstrated that progression within 6 months post-infusion is strongly associated with an increased risk of death (HR = 4.58; p = .029). Compared with non-EMD patients, patients with EMD showed inferior survival outcomes. Unique CAR-associated local toxicities at EMD were seen in 22.6% patients and correlated with the occurrence and severity of systemic cytokine release syndrome. To the cutoff date, 65% treated patients experienced EMD progression, primarily in the form of BCMA + progression. The pretherapy EMD immunosuppressive microenvironment, characterized by infiltration of exhausted CD8 + T cells, was associated with inferior clinical outcomes. CAR T cells have therapeutic activity in relapsed/refractory EMD, but the long-term survival benefits may be limited. EMD-specific microenvironment potentially impacts treatment. Further efforts are needed to extend EMD remission and improve long-term outcomes., (© 2024 Wiley Periodicals LLC.)

Background: Many studies have demonstrated the effectiveness of chimeric antigen receptor-T (CAR-T) cell therapy for relapsed or refractory multiple myeloma (RRMM), but the hematologic toxicity has not been well characterized., Methods: A total of 111 adults with RRMM who received BCMA CAR-T cells, BCMA + CD19 CAR-T cells or tandem BCMA/CD19 dual-target (BC19) CAR-T cells infusion were enrolled. We characterized cytopenia and hematologic recovery at different time points after CAR-T-cell therapy, analyzed the effect of cytopenia on prognosis and identified the risk factors., Results: Patients had a high probability of cytopenia, with anemia, neutropenia and thrombocytopenia occurring in 92%, 95% and 73%, respectively. There were 60 (54%) patients had prolonged hematologic toxicity (PHT) after D28. The median hemoglobin and platelet count were significantly lower at D28 post-CAR-T cell therapy than at baseline. Hemoglobin increased to above baseline at D90. The median absolute neutrophil count was lower than baseline at D0 and D28, and it recovered to baseline at D180. The baseline level of lactate dehydrogenase was associated with thrombocytopenia. Extramedullary involvement was associated with hemoglobin recovery, while the baseline level of albumin and types of CAR-T were related to platelet recovery. Patients with anemia at baseline and at D0, D180 and D360 had shorter progression-free survival (PFS), while anemia at D0, D60, D180 and D360 was associated with shorter overall survival (OS). Neutropenia at D0 was associated with shorter PFS and patients with neutropenia at D90 or D180 had shorter OS. Patients with thrombocytopenia at any time had shorter PFS and OS. Compared to patients without PHT, patients with PHT had shorter PFS and OS., Conclusions: The majority of RRMM patients treated with CAR-T cells experienced cytopenia. Cytopenia occurred at specific time points was associated with a poorer prognosis., Competing Interests: Declaration of Competing Interest All authors declare no competing financial interests., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

T-cell immunoglobulin and mucin domain 3 (TIM3) is an immune checkpoint protein expressed on various types of immune cells in two forms, namely membrane TIM3 (mTIM3) and soluble TIM3 (sTIM3). mTIM3 and sTIM3 share the same ligands, but less is known about functions and mechanisms of sTIM3 compared to those of mTlM3. Abnormal levels of plasma sTIM3 have been observed in patients with many diseases including cancer. Current research mainly focuses on the potential of sTIM3 as a biomarker for the diagnosis and treatment of cancer. However, there are limited investigations on sTIM3 as a target for immunotherapy. This paper provides a literature review on the recent research progress of the production and biological functions of sTIM3 and its clinical significance in cancer immunotherapy.

Background: Tocilizumab is commonly used for the management of chimeric antigen receptor (CAR) T-cell therapy-associated cytokine release syndrome (CRS). However, it remains unknown whether tocilizumab or its dosage affects the efficacy and safety of CAR T-cell therapy. The objective of this multicenter retrospective study was to explore the impact of tocilizumab on CAR T-cell therapy., Methods: In total, 93 patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving humanized anti-CD19 CAR T cells were recruited from May 2016 to November 2022. Forty-five patients received tocilizumab (tocilizumab group), whereas 48 patients did not (nontocilizumab group). Thirteen patients received >1 dose of tocilizumab. The primary end point was the effect of tocilizumab on the efficacy and safety of CAR T cells. Additionally, proliferation, killing, and cytokine assays of CAR T cells were performed in vitro in the presence of tocilizumab., Results: The median age of the patients was 33 years, with 47 males and 46 females. Patients in the tocilizumab group showed similar complete response (CR) rate, overall survival (OS), and event-free survival (EFS) compared with the nontocilizumab group. Compared with patients who received ≤1 dose of tocilizumab, receiving >1 dose of tocilizumab did not affect their CR rate, OS, or EFS. In the tocilizumab group, all patients experienced CRS and 26.7% experienced immune effector cell-associated neurotoxicity syndrome (ICANS). In the nontocilizumab group, 64.6% of patients experienced CRS and 8.3% experienced ICANS. Up to 75% of ICANS and 87.5% of grade ≥3 ICANS occurred in the tocilizumab group. In vitro, tocilizumab did not impair the proliferation and killing effects of CAR T cells., Conclusions: Tocilizumab does not affect the efficacy of CAR T cells but may increase the likelihood of ICANS., (© 2024 American Cancer Society.)

Semiconducting carbon nanotubes (CNTs) are considered as the most promising channel material to construct ultrascaled field-effect transistors, but the perfect sp 2 C─C structure makes stable doping difficult, which limits the electrical designability of CNT devices. Here, an inner doping method is developed by filling CNTs with 1D halide perovskites to form a coaxial heterojunction, which enables a stable n-type field-effect transistor for constructing complementary metal-oxide-semiconductor electronics. Most importantly, a quasi-broken-gap (BG) heterojunction tunnel field-effect transistor (TFET) is first demonstrated based on an individual partial-filling CsPbBr 3 /CNT and exhibits a subthreshold swing of 35 mV dec -1 with a high on-state current of up to 4.9 µA per tube and an on/off current ratio of up to 10 5 at room temperature. The quasi-BG TFET based on the CsPbBr 3 /CNT coaxial heterojunction paves the way for constructing high-performance and ultralow power consumption integrated circuits., (© 2024 Wiley‐VCH GmbH.)

Background Aims: Chimeric antigen receptor-T (CAR-T) cells have exhibited remarkable efficacy in treating refractory or relapsed multiple myeloma (R/R MM). Although obesity has a favorable value in enhancing the response to immunotherapy, less is known about its predictive value regarding the efficacy and prognosis of CAR-T cell immunotherapy., Methods: We conducted a retrospective study of 111 patients with R/R MM who underwent CAR-T cell treatment. Using the body mass index (BMI) classification, the patients were divided into a normal-weight group (73/111) and an overweight group (38/111). We investigated the effect of BMI on CAR-T cell therapy outcomes in patients with R/R MM., Results: The objective remission rates after CAR-T cell infusion were 94.7% and 89.0% in the overweight and normal-weight groups, respectively. The duration of response and overall survival were not significant difference between BMI groups. Compared to normal-weight patients, overweight patients had an improved median progression-free survival. There was no significant difference in cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome between the subgroups. In terms of hematological toxicity, the erythrocyte, hemoglobin, platelet, leukocyte and neutrophil recovery was accelerated in the overweight group. Fewer patients in the overweight group displayed moderate percent CD4 and CD4/CD8 ratios compared to the normal-weight group. Furthermore, the percent CD4 ratios were positively correlated with the levels of cytokines [interleukin-2 (IL-2) (day 14), interferon gamma (IFN-γ) (day 7) and tumor necrosis factor alpha (TNF-α) (days 14 and 21)] after cells infusion. On the other hand, BMI was positively associated with the levels of IFN-γ (day 7) and TNF-α (days 14 and 21) after CAR-T cells infusion., Conclusions: Overall, this study highlights the potential beneficial effect of a higher BMI on CAR-T cell therapy outcomes., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Developing low-power FETs holds significant importance in advancing logic circuits, especially as the feature size of MOSFETs approaches sub-10 nanometers. However, this has been restricted by the thermionic limitation of SS, which is limited to 60 mV per decade at room temperature. Herein, we proposed a strategy that utilizes 2D semiconductors with an isolated-band feature as channels to realize sub-thermionic SS in MOSFETs. Through high-throughput calculations, we established a guiding principle that combines the atomic structure and orbital interaction to identify their sub-thermionic transport potential. This guides us to screen 192 candidates from the 2D material database comprising 1608 systems. Additionally, the physical relationship between the sub-thermionic transport performances and electronic structures is further revealed, which enables us to predict 15 systems with promising device performances for low-power applications with supply voltage below 0.5 V. This work opens a new way for the low-power electronics based on 2D materials and would inspire extensive interests in the experimental exploration of intrinsic steep-slope MOSFETs., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)

Semiconductor devices at the nanoscale with low-dimensional materials as channels exhibit quantum transport characteristics, thereby their electrical simulation relies on the self-consistent solution of the Schrödinger-Poisson equations. While the non-equilibrium Green's function (NEGF) method is widely used for solving this quantum many-body problem, its high computational cost and convergence challenges with the Poisson equation significantly limit its applicability. In this study, we investigate the stability of the NEGF method coupled with various forms of the Poisson equation, encompassing linear, analytical nonlinear, and numerical nonlinear forms Our focus lies on simulating carbon nanotube field-effect transistors (CNTFETs) under two distinct doping scenarios: electrostatic doping and ion implantation doping. The numerical experiments reveal that nonlinear formulas outperform linear counterpart. The numerical one demonstrates superior stability, particularly evident under high bias and ion implantation doping conditions. Additionally, we investigate different approaches for presolving potential, leveraging solutions from the Laplace equation and a piecewise guessing method tailored to each doping mode. These methods effectively reduce the number of iterations required for convergence., (© 2024 IOP Publishing Ltd.)

Background: Postoperative delirium is a common complication in older patients, with poor long-term outcomes. This study aimed to investigate risk factors and develop a predictive model for postoperative delirium in older patients after major abdominal surgery., Methods: This study retrospectively recruited 7577 patients aged ≥ 65 years who underwent major abdominal surgery between January 2014 and December 2018 in a single hospital in Beijing, China. Patients were divided into a training cohort (n = 5303) and a validation cohort (n = 2224) for univariate and multivariate logistic regression analyses and to build a nomogram. Data were collected for 43 perioperative variables, including demographics, medical history, preoperative laboratory results, imaging, and anesthesia information., Results: Age, chronic obstructive pulmonary disease, white blood cell count, glucose, total protein, creatinine, emergency surgery, and anesthesia time were associated with postoperative delirium in multivariate analysis. We developed a nomogram based on the above 8 variables. The nomogram achieved areas under the curve of 0.731 and 0.735 for the training and validation cohorts, respectively. The discriminatory ability of the nomogram was further assessed by dividing the cases into three risk groups (low-risk, nomogram score < 175; medium-risk, nomogram score 175~199; high-risk, nomogram score > 199; P < 0.001). Decision curve analysis revealed that the nomogram provided a good net clinical benefit., Conclusions: We developed a nomogram that could predict postoperative delirium with high accuracy and stability in older patients after major abdominal surgery., (© 2024. The Author(s).)

Purpose: Previous studies have suggested a potential association between gut microbiota and neurological and psychiatric disorders. However, the causal relationship between gut microbiota and cognitive performance remains uncertain., Methods: A two-sample Mendelian randomization (MR) study used SNPs linked to gut microbiota (n = 18,340) and cognitive performance (n = 257,841) from recent GWAS data. Inverse-variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode were employed. Heterogeneity was assessed via Cochran's Q test for IVW. Results were shown with funnel plots. Outliers were detected through leave-one-out method. MR-PRESSO and MR-Egger intercept tests were conducted to address horizontal pleiotropy influence., Limitations: Limited to European populations, generic level, and potential confounding factors., Results: IVW analysis revealed detrimental effects on cognitive perfmance associated with the presence of genus Blautia (P = 0.013, 0.966[0.940-0.993]), Catenibacterium (P = 0.035, 0.977[0.956-0.998]), Oxalobacter (P = 0.043, 0.979[0.960-0.999]). Roseburia (P < 0.001, 0.935[0.906-0.965]), in particular, remained strongly negatively associated with cognitive performance after Bonferroni correction. Conversely, families including Bacteroidaceae (P = 0.043, 1.040[1.001-1.081]), Rikenellaceae (P = 0.047, 1.026[1.000-1.053]), along with genera including Paraprevotella (P = 0.044, 1.020[1.001-1.039]), Ruminococcus torques group (P = 0.016, 1.062[1.011-1.115]), Bacteroides (P = 0.043, 1.040[1.001-1.081]), Dialister (P = 0.027, 1.039[1.004-1.074]), Paraprevotella (P = 0.044, 1.020[1.001-1.039]) and Ruminococcaceae UCG003 (P = 0.007, 1.040[1.011-1.070]) had a protective effect on cognitive performance., Conclusions: Our results suggest that interventions targeting specific gut microbiota may offer a promising avenue for improving cognitive function in diseased populations. The practical application of these findings has the potential to enhance cognitive performance, thereby improving overall quality of life., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Cerebral blood flow and vascular structures serve as the fundamental components of brain metabolism and circulation. Acupuncture, an alternative and complementary medical approach, has demonstrated efficacy in treating cerebral ischemic stroke (CIS). Nevertheless, the mechanisms underlying the impact of acupuncture on vascular smooth muscle cell (VSMC) function remain uncertain. The objective of this systematic review and meta-analysis is to assess the alterations in VSMC function following acupuncture stimulation in CIS models., Methods: The databases PubMed, Web of Science, SCOPUS, and EMBASE were queried until November 2022 using a predetermined search strategy. The FORMAT BY SYRCLE guidelines were adhered to, and the risk of bias of the included studies was evaluated using the Risk of Bias tool developed by the Systematic Review Centre for Laboratory Animal Experimentation. The random-effects model was employed to estimate the standardized mean difference (SMD)., Results: Eighteen articles are included in this review. Acupuncture showed significant positive effects on the region cerebral blood flow (SMD=8.15 [95% CI, 4.52 to 11.78]) and neurological deficiency (SMD=-3.75 [95% CI, -5.54 to -1.97]). Descriptive analysis showed a probable mechanism of acupuncture stimulation in CIS rats related to VSMC function. Limitations and publication bias were presented in the studies., Conclusion: In this systematic review and meta-analysis, our findings indicate that acupuncture stimulation has the potential to improve regional cerebral blood flow and alleviate neurological deficits, possibly by regulating VSMC function. However, it is important to exercise caution when interpreting these results due to the limitations of animal experimental design and methodological quality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Cao et al.)

Aims: Left atrial appendage electrical isolation (LAAEI) has demonstrated a significant enhancement in the success rate of atrial fibrillation (AF) ablation. Nevertheless, concerns persist about the safety of LAAEI, particularly regarding alterations in left atrial appendage (LAA) flow velocity and the potential risks of thrombus. This study aimed to assess the efficacy and safety of LAAEI, investigating changes in LAA flow velocity in canines., Methods and Results: The study comprised a total of 10 canines. The LAAEI procedure used by a 23 mm cryoballoon of the second generation was conducted at least 180 s. Intracardiac ultrasonography (ICE) was employed to quantify the velocity flow of the LAA both prior to and following LAAEI. Following a 3-month period, subsequent evaluations were performed to assess the LAA velocity flow and the potential reconnection. Histopathological examination was conducted. Left atrial appendage electrical isolation was effectively accomplished in all canines, resulting in a 100% acute success rate (10/10). The flow velocity in the LAA showed a notable reduction during LAAEI as compared with the values before the ablation procedure (53.12 ± 5.89 vs. 42.01 ± 9.22 cm/s, P = 0.007). After the follow-up, reconnection was observed in four canines, leading to a success rate of LAAEI of 60% (6/10). The flow velocity in the LAA was consistently lower (53.12 ± 5.89 vs. 44.33 ± 10.49 cm/s, P = 0.006), and no blood clot development was observed. The histopathological study indicated that there was consistent and complete injury to the LAA, affecting all layers of its wall. The injured tissue was subsequently replaced by fibrous tissue., Conclusion: The feasibility of using cryoballoon ablation for LAAEI was confirmed in canines, leading to a significant reduction of LAA flow velocity after ablation. Some restoration of LAA flow velocity after ablation may be linked to the passive movement of the LAA and potential reconnecting. However, this conclusion is limited to animal study; more clinical data are needed to further illustrate the safety and accessibility of LAAEI in humans., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Despite the high therapeutic response achieved with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory multiple myeloma (R/R MM), primary resistance and relapse exist with single-target immunotherapy. Here, we design bispecific BC19 CAR T cells targeting BCMA/CD19 and evaluate antimyeloma activity in vitro and in vivo. Preclinical results indicate that BC19 CAR specifically recognize target antigens, and BC19 CAR T cells mediate selective killing of BCMA or CD19-positive cancer cells. BC19 CAR T cells also exhibit potent antigen-specific anti-tumor activity in xenograft mouse models. We conduct an open-label, single-arm, phase I/II study of BC19 CAR T cells in 50 patients with R/R MM (ChiCTR2000033567). The primary endpoint was safety. BC19 CAR T cells are well tolerated with grade 3 or higher cytokine release syndrome in 8% of patients and grade 1 neurotoxic events in 4% of patients, which meet the pre-specified primary endpoint. Secondary endpoints include overall response rate (92%), median progression-free survival (19.7 months), median overall survival (19.7 months) and median duration of response (not reached). Our study demonstrates that bispecific BC19 CAR T cells are feasible, safe and effective in treating patients with R/R MM., (© 2024. The Author(s).)

Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We present a retrospective study of 67 patients with R/R B-ALL who received anti-CD19 CAR T-cell therapy, 41 (61.2%) patients received G-CSF (G-CSF group), while 26 (38.8%) did not (non-G-CSF group). Patients had similar duration of grade 3-4 neutropenia between the two groups. The incidences of CRS and NEs were higher in G-CSF group, while no differences in severity were found. Further stratified analysis showed that the incidence and severity of CRS were not associated with G-CSF administration in patients with low bone marrow (BM) tumor burden. None of the patients with low BM tumor burden developed NEs. However, there was a significant increase in the incidence of CRS after G-CSF administration in patients with high BM tumor burden. The duration of CRS in patients who used G-CSF was longer. There were no significant differences in response rates at 1 and 3 months after CAR T-cell infusion, as well as overall survival (OS) between the two groups. In conclusion, our results showed that G-CSF administration was not associated with the incidence or severity of CRS in patients with low BM tumor burden, but the incidence of CRS was higher after G-CSF administration in patients with high BM tumor burden. The duration of CRS was prolonged in G-CSF group. G-CSF administration was not associated with the efficacy of CAR T-cell therapy., (© 2024. The Author(s).)

Background: In agricultural production, fungal diseases significantly impact the yield and quality of cotton (Gossypium spp.) with Verticillium wilt posing a particularly severe threat., Results: This study is focused on investigating the effectiveness of endophytic microbial communities present in the seeds of disease-resistant cotton genotypes in the control of cotton Verticillium wilt. The technique of 16S ribosomal RNA (16S rRNA) amplicon sequencing identified a significant enrichment of the Bacillus genus in the resistant genotype Xinluzao 78, which differed from the endophytic bacterial community structure in the susceptible genotype Xinluzao 63. Specific enriched strains were isolated and screened from the seeds of Xinluzao 78 to further explore the biological functions of seed endophytes. A synthetic microbial community (SynCom) was constructed using the broken-rod model, and seeds of the susceptible genotype Xinluzao 63 in this community that had been soaked with the SynCom were found to significantly control the occurrence of Verticillium wilt and regulate the growth of cotton plants. Antibiotic screening techniques were used to preliminarily identify the colonization of strains in the community. These techniques revealed that the strains can colonize plant tissues and occupy ecological niches in cotton tissues through a priority effect, which prevents infection by pathogens., Conclusion: This study highlights the key role of seed endophytes in driving plant disease defense and provides a theoretical basis for the future application of SynComs in agriculture., (© 2024. The Author(s).)

CRISPR-based screens have discovered novel functional genes involving in diverse tumor biology and elucidated the mechanisms of the cancer pathological states. Recently, with its randomness and unbiasedness, CRISPR screens have been used to discover effector genes with previously unknown roles for AML. Those novel targets are related to AML survival resembled cellular pathways mediating epigenetics, synthetic lethality, transcriptional regulation, mitochondrial and energy metabolism. Other genes that are crucial for pharmaceutical targeting and drug resistance have also been identified. With the rapid development of novel strategies, such as barcodes and multiplexed mosaic CRISPR perturbation, more potential therapeutic targets and mechanism in AML will be discovered. In this review, we present an overview of recent progresses in the development of CRISPR-based screens for the mechanism and target identification in AML and discuss the challenges and possible solutions in this rapidly growing field., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

The present research focused on identifying necroptosis-related differentially expressed genes (NRDEGs) in spinal cord injury (SCI) to highlight potential therapeutic and prognostic target genes in clinical SCI. Three SCI-related datasets were downloaded, including GSE151371, GSE5296 and GSE47681. MSigDB and KEGG datasets were searched for necroptosis-related genes (NRGs). Differentially expressed genes (DEGs) and NRGs were intersected to obtain NRDEGs. The MCC algorithm was employed to select the first 10 genes as hub genes. A protein-protein interaction (PPI) network related to NRDEGs was developed utilizing STRING. Several databases were searched to predict interactions between hub genes and miRNAs, transcription factors, potential drugs, and small molecules. Immunoassays were performed to identify DEGs using CIBERSORTx. Additionally, qRT-PCR was carried out to verify NRDEGs in an animal model of SCI. Combined analysis of all datasets identified 15 co-expressed DEGs and NRGs. GO and KEGG pathway analyses highlighted DEGs mostly belonged to pathways associated with necroptosis and apoptosis. Hub gene expression analysis showed high accuracy in SCI diagnosis was associated with the expression of CHMP7 and FADD. A total of two hub genes, i.e. CHMP7, FADD, were considered potential targets for SCI therapy., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Sleep disturbances in the peri-operative period have been associated with adverse outcomes, including postoperative delirium (POD). However, research on sleep quality during the immediate postoperative period is limited., Objectives: This study aimed to investigate the association between sleep quality on the night of the operative day assessed using the Sleep Quality Numeric Rating Scale (SQ-NRS), and the incidence of POD in a large cohort of surgical patients., Design: A prospective cohort study., Setting: A tertiary hospital in China., Patients: This study enrolled patients aged 65 years or older undergoing elective surgery under general anaesthesia. The participants were categorised into the sleep disturbance and no sleep disturbance groups according to their operative night SQ-NRS., Main Outcome Measures: The primary outcome was delirium incidence, whereas the secondary outcomes included acute kidney injury, stroke, pulmonary infection, cardiovascular complications and all-cause mortality within 1 year postoperatively., Results: In total, 3072 patients were included in the analysis of this study. Among them, 791 (25.72%) experienced sleep disturbances on the night of operative day. Patients in the sleep disturbance group had a significantly higher risk of developing POD (adjusted OR 1.43, 95% CI 1.11 to 1.82, P  = 0.005). Subgroup analysis revealed that age 65-75 years; male sex; ASA III and IV; haemoglobin more than 12 g l -1 ; intra-operative hypotension; surgical duration more than 120 min; and education 9 years or less were significantly associated with POD. No interaction was observed between the subgroups. No significant differences were observed in the secondary outcomes, such as acute kidney injury, stroke, pulmonary infection, cardiovascular complications and all-cause mortality within 1 year postoperatively., Conclusions: The poor subjective sleep quality on the night of operative day was independently associated with increased POD risk, especially in certain subpopulations. Optimising peri-operative sleep may reduce POD. Further research should investigate potential mechanisms and causal relationships., Trial Registry: chictr.org.cn: ChiCTR1900028545., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society of Anaesthesiology and Intensive Care.)

Background: The combination of left atrial appendage closure (LAAC) and catheter ablation (CA) in a single procedure is a safe and effective form of treatment for atrial fibrillation (AF). However, several findings have argued that LAAC might increase the risk of AF recurring. Therefore, this study investigated the impact of insufficient ablation on AF recurrence after the hybrid procedures of CA and LAAC., Methods: We reviewed 107 consecutive patients with AF who received the CA and LAAC hybrid procedures (combined group). In the case-control study, another 107 patients who underwent only CA (ablation group) were successfully matched using propensity score matching. After correcting the insufficient ablation, 107 consecutive patients were enrolled prospectively. During the follow-up period, postprocedural 24-hour monitor recordings and a portable electrocardiogram (ECG) monitoring device were used to detect AF recurrence. Transesophageal echocardiography was used to evaluate LAAC., Results: The combined group showed an increase in the risk of AF recurrence after 539.2 ± 304.4 days of follow-up (29.9% vs. 15.9%, p < 0.05). Interestingly, the duration of the procedure was not significantly prolonged when LAAC was added after CA in the combined group, while there was a higher number of ablating attempts, duration of ablation, and additional ablation in the ablation group for both radiofrequency and cryoballoon ablation. After correcting for the insufficient ablation, the corrected group showed a significant decrease in AF recurrence after 420.4 ± 204.8 days of follow-up., Conclusions: Insufficient ablation is common when combining CA and LAAC and may lead to the recurrence of atrial fibrillation. It should be corrected intentionally by sufficient ablation of the pulmonary vein antrum and additional ablation., Clinical Trial Registration: The prospective study is a sub-study of our CAGEDAF study that has already been registered (ChiCTR2000039746)., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Background: Identifying the risk factors associated with perioperative mortality is crucial, particularly in older patients. Predicting 6-month mortality risk in older patients based on large datasets can assist patients and surgeons in perioperative clinical decision-making. This study aimed to develop a risk prediction model of mortality within 6 months after noncardiac surgery using the clinical data from 11 894 older patients in China., Materials and Methods: A multicentre, retrospective cohort study was conducted in 20 tertiary hospitals. The authors retrospectively included 11 894 patients (aged ≥65 years) who underwent noncardiac surgery between April 2020 and April 2022. The least absolute shrinkage and selection operator model based on linear regression was used to analyse and select risk factors, and various machine learning methods were used to build predictive models of 6-month mortality., Results: The authors predicted 12 preoperative risk factors associated with 6-month mortality in older patients after noncardiac surgery. Including laboratory-associated risk factors such as mononuclear cell ratio and total blood cholesterol level, etc. Also including medical history associated risk factors such as stroke, history of chronic diseases, etc. By using a random forest model, the authors constructed a predictive model with a satisfactory accuracy (area under the receiver operating characteristic curve=0.97)., Conclusion: The authors identified 12 preoperative risk factors associated with 6-month mortality in noncardiac surgery older patients. These preoperative risk factors may provide evidence for a comprehensive preoperative anaesthesia assessment as well as necessary information for clinical decision-making by anaesthesiologists., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Prognostic nutritional index (PNI) is an indicator to evaluate the nutritional immune status of patients. This study aimed to assess whether preoperative PNI could predict the occurrence of postoperative POD in aged patients undergoing non-neurosurgery and non-cardiac surgery., Method: The aged patients undergoing non-neurosurgery and non-cardiac surgery between January 2014 and August 2019 were included in the retrospective cohort study. The correlation between POD and PNI was investigated by univariate and multivariable logistic regression analysis, propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and subgroup analysis., Results: In the cohort (n = 29,814), the cutoff value of PNI was 46.01 determined by the receiver operating characteristic (ROC) curve. In univariate and three multivariable regression analysis, the ORs of PNI ≤ 46.01 was 2.573(95% CI:2.261-2.929, P < 0.001),1.802 (95% CI:1.567-2.071, P < 0.001),1.463(95% CI:1.246-1.718, P < 0.001),1.370(95% CI:1.165-1.611, P < 0.001). In the PSM model and IPTW model, the ORs of PNI ≤ 46.01 were 1.424(95% CI:1.172-1.734, P < 0.001) and 1.356(95% CI:1.223-1.505, P < 0.001)., Conclusion: The PNI was found to have a predictive value for POD in patients undergoing non-neurosurgery and non-cardiac surgery. Improving preoperative nutritional status may be beneficial in preventing POD for aged patients., Competing Interests: Declaration of Competing Interest Preliminary findings of this study were submitted as a poster to global experts meet on neurology, neuroscience, and brain disorder in Paris, France, April 2023. The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Background: The COVID-19 pandemic has a heavy impact on the mental health of elderly surgical patients worldwide. In particular, the elderly patients faced considerable psychological stress due to various environmental and medical factors during the outbreak. This study aims to examine changes in mental health trends among non-cardiac surgical patients aged 65 and above in China during the COVID-19 pandemic., Methods: This multi-center, convenient sampling, longitudinal observational study was conducted from April 1, 2020 to April 30, 2022. Primary outcome was the prevalence of postoperative depression. Secondary outcome was the prevalence of postoperative anxiety. Follow-up was conducted separately at 7 days and 30 days after surgery. Depression symptoms were assessed using the Patient Health Questionnaire 9 (PHQ-9) scale. Anxiety symptoms were assessed using Generalized Anxiety Disorder-7 (GAD-7) scale, with scores of ≥5 defining positive depression or anxiety symptoms. Multivariate logistic regression analysis was used to investigate risk factors of mental health status in more elderly patients undergoing non-cardiac surgery., Results: A total of 4639 patients were included, of whom 2279 (46.0 %) were male, 752 (15.2 %) were over the age of 75, and 4346 (93.7 %) were married. The monthly prevalence trends demonstrated that compared to the outbreak period, a significant reduction in the prevalence of depression and anxiety symptoms in elderly patients who underwent surgery during the post-pandemic period. In post-pandemic period, a statistically significant decrease in the prevalence of all severity depression and anxiety patients was noted at the 7-day follow-up, but no significant decrease was observed for severe depression and anxiety in the 30-day follow-up. In COVID-19 low-risk area, a significant overall decrease in prevalence of mental health was observed during the post-pandemic period compared to the outbreak period, including 7-day depression, 7-day anxiety, 30-day depression, and 30-day anxiety (all with P < 0.001). Female and patients with ≥2 comorbidities appeared to be more susceptible to postoperative depression and anxiety during the pandemic., Limitation: The absence of data from the early days of the COVID-19 outbreak., Conclusions: This study analyzed the prevalence of depression and anxiety in elderly non-cardiac patients during and after the COVID-19 pandemic, focusing on dimensions such as severity, risk-areas, gender, and comorbidity. Our findings revealed a significant decrease in the prevalence of depression and anxiety in elderly surgery patients during the post-pandemic period., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

The aim of this study was to investigate the effect of C-reactive protein (CRP) on the prognosis of adult patients with Immune thrombocytopenia purpura (ITP). A retrospective study of 628 adult ITP patients, as well as 100 healthy and 100 infected patients, attending the Affiliated Hospital of Xuzhou Medical University from January 2017 to June 2022 was performed. The ITP patients were grouped according to their CRP levels, and the differences in clinical characteristics of each group and the influencing factors of efficacy in newly diagnosed ITP patients were analyzed. CRP levels were significantly higher in the ITP and infected groups compared with healthy controls (P < 0.001), and platelet counts were significantly lower in the ITP group (P < 0.001). Between the CRP normal and elevated group, their age, white blood cell count, neutrophil count, lymphocyte count, red blood cell count, hemoglobin, platelet count, complement C3 and C4, PAIgG, bleeding score, proportion of severe ITP, and proportion of refractory ITP were significantly different (P < 0.05). Patients of severe ITP (P < 0.001), refractory ITP (P = 0.002), and with active bleeding (P < 0.001) had significantly higher CRP levels. Patients with no response after treatment had significantly higher CRP levels than those who achieved CR or R (P < 0.001). Platelet counts (r = - 0.261, P < 0.001) in newly diagnosed ITP patients and treatment outcomes (r = - 0.221, P < 0.001) were negatively correlated with CRP levels, and bleeding score was positively correlated with CRP levels (r = 0.207, P < 0.001). Treatment outcome was positively correlated with decrease in CRP levels (r = 0.313, P = 0.027). A multifactorial regression analysis of the influencing factors of treatment outcomes on newly diagnosed patients found that CRP was an independent risk factor of the prognosis (P = 0.011). In conclusion, CRP can help assess the severity and predict the prognosis of ITP patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To investigate the safety and efficacy of novel CD19-KIRS2/Dap12-BB chimeric antigen receptor T cells (CAR-T cells) in the treatment of relapsed/refractory B-cell malignancy (R/R BCM)., Methods: Three patients with R/R BCM treated with novel CD19-KIRS2/Dap12-BB CAR-T cells from June 2020 to November 2020 were enrolled, including 1 case of B-cell acute lymphoblastic leukaemia (B-ALL) and 2 cases of non-Hodgkin's lymphoma (NHL), and the efficacy and adverse reactions were observed., Results: After CAR-T cells infusion, patient with B-ALL achieved complete remission (CR) and minimal residual disease (MRD) turned negative, and 2 patients with NHL achieved partial remission (PR). Grade 2 cytokine release syndrome (CRS) occurred in B-ALL patient, grade 1 CRS occurred in 2 NHL patients, and grade II to IV hematologic adverse reactions occurred in 3 patients, all of which were controllable and reversible. The progression-free survival (PFS) of the 3 patients was 143, 199, and 91 days, and overall survival (OS) was 282, 430, and 338 days, respectively., Conclusion: The novel CD19-KIRS2/Dap12-BB CAR-T cells in treatment of 3 patients with R/R BCM have significant short-term efficacy and controllable adverse reactions, but the long-term efficacy needs to be further improved.

Foodborne illness caused by Staphylococcus aureus (S. aureus) has posed a significant threat to human health. Herein, an integrated multifunctional nanoplatform was developed for fluorescence detection and inactivation of S. aureus based on cascade signal amplification coupled with single strand DNA-template copper nanoparticles (ssDNA-Cu NPs). Benefiting from reasonable design, one-step cascade signal amplification was achieved through strand displacement amplification combined with rolling circle amplification, followed by in-situ generation of copper nanoparticles. S. aureus detection could be performed through naked eye observation and microplate reader measurement of the red fluorescence signal. The multifunctional nanoplatform had satisfactory specificity and sensitivity, achieving 5.2 CFU mL -1 detection limit and successful detection of 7.3 CFU of S. aureus in spiked egg after < 5 h of enrichment. Moreover, ssDNA-Cu NPs could eliminate S. aureus to avoid secondary bacterial contamination without further treatment. Therefore, this multifunctional nanoplatform has potential application in food safety dtection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Chimeric antigen receptor T (CAR-T) cell therapy exhibits remarkable efficacy against refractory or relapsed multiple myeloma (RRMM); however, the immune deficiency following CAR-Ts infusion has not been well studied. In this study, 126 patients who achieved remission post-CAR-Ts infusion were evaluated for cellular immunity. Following lymphodepletion (LD) chemotherapy, the absolute lymphocyte count (ALC) and absolute counts of lymphocyte subsets were significantly lower than baseline at D0. Grade ≥ 3 lymphopenia occurred in 99% of patients within the first 30 days, with most being resolved by 180 days. The median CD4 + T-cell count was consistently below baseline and the lower limit of normal (LLN) levels at follow-up. Conversely, the median CD8 + T-cell count returned to the baseline and LLN levels by D30. The median B-cell count remained lower than baseline level at D60 and returned to baseline and LLN levels at D180. In the first 30 days, 27 (21.4%) patients had 29 infections, with the majority being mild to moderate in severity (21/29; 72.4%). After day 30, 44 (34.9%) patients had 56 infections, including 20 severe infections. One patient died from bacteremia at 3.8 months post-CAR-Ts infusion. In conclusion, most patients with RRMM experienced cellular immune deficiency caused by LD chemotherapy and CAR-Ts infusion. The ALC and most lymphocyte subsets gradually recovered after day 30 of CAR-Ts infusion, except for CD4 + T cells. Some patients experience prolonged CD4 + T-cell immunosuppression without severe infection., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The current study aims to ascertain the anatomical feasibility of transferring the contralateral S1 ventral root (VR) to the ipsilateral L5 VR for treating unilateral spastic lower limb paralysis. Six formalin-fixed (three males and three females) cadavers were used. The VR of the contralateral S1 was transferred to the VR of the ipsilateral L5. The sural nerve was selected as a bridge between the donor and recipient nerve. The number of axons, the cross-sectional areas and the pertinent distances between the donor and recipient nerves were measured. The extradural S1 VR and L5 VR could be separated based on anatomical markers of the dorsal root ganglion. The gross distance between the S1 nerve root and L5 nerve root was 31.31 (± 3.23) mm in the six cadavers, while that on the diffusion tensor imaging was 47.51 (± 3.23) mm in 60 patients without spinal diseases, and both distances were seperately greater than that between the outlet of S1 from the spinal cord and the ganglion. The numbers of axons in the S1 VRs and L5 VRs were 13414.20 (± 2890.30) and 10613.20 (± 2135.58), respectively. The cross-sectional areas of the S1 VR and L5 VR were 1.68 (± 0.26) mm 2 and 1.08 (± 0.26) mm 2 , respectively. In conclusion, transfer of the contralateral S1 VR to the ipsilateral L5 VR may be an anatomically feasible treatment option for unilateral spastic lower limb paralysis.

The over production of reactive oxygen species (ROS) plays a critical role in the progression of chronic kidney disease (CKD). Organic ROS scavengers currently used for CKD treatment do not satisfy low dosage and high efficiency requirements. Ceria nanomaterials featured with renewable ROS scavenging activity are potential candidates for CKD treatment. Herein, a method for the synthesis of ceria nanoclusters (NCs) featured with small size of ≈1.2 nm is reported. The synthesized NCs are modified by three hydrophilic ligands with different molecular weights, including succinic acid (SA), polyethylene glycol diacid 600 (PEG600), and polyethylene glycol diacid 2000 (PEG2000). The surface modified NCs exhibit excellent ROS scavenging activity due to the high Ce 3+ /Ce 4+ ratio in their crystal structures. Compared with bigger-sized ceria nanoparticles (NPs) (≈45 nm), NCs demonstrate smoother blood concentration-time curve, lower organ accumulation, and faster metabolic rate superiorities. The administration of NCs to CKD mice, especially PEG600 and PEG2000 modified NCs, can effectively inhibit oxidative stress, inflammation, renal fibrosis, and apoptosis in their kidneys. Due to these benefits, the constructed NCs can ameliorate the progression of CKD. These findings suggest that NCs is a potential redox nanomedicine for future clinical treatment of CKD., (© 2023 Wiley-VCH GmbH.)

Objective: To investigate the effect of hemoglobin (Hb) on the efficacy of chimeric antigen receptor T cell therapy (CAR-T) in patients with multiple myeloma (MM)., Methods: From June 2017 to December 2020, 76 MM patients who received CAR-T therapy in the Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, with complete clinical data and evaluable efficacy, were selected as the research objects. According to the receiver operating characteristic (ROC) curve, the best cut-off value was obtained. The patients were divided into groups on the basis of Hb 105.5 g/L as the cut-off value. The age, sex, serum calcium, β 2 -microglobulin, serum creatinine, lactate dehydrogenase (LDH), and the influencing factors of CAR-T treatment efficacy in MM patients were analyzed., Results: Hb was an influencing factor of efficacy. Univariate analysis showed that Hb, LDH, and albumin affected the efficacy of CAR-T therapy. Multivariate analysis showed that Hb ( OR =1.039, 95% CI : 1.002-1.078) and LDH ( OR =1.014, 95% CI : 1.000-1.027) were the influencing factors for the efficacy of CAR-T therapy., Conclusion: The efficacy of CAR-T therapy in MM patients with low Hb is poor, and Hb is a factor affecting the efficacy of CAR-T therapy.

Ferroptosis, an iron-dependent lipid peroxidation-driven programmed cell death, is closely related to cancer therapy. The development of druggable ferroptosis inducers and their rational application in cancer therapy are critical. Here, we identified Tubastatin A, an HDAC6 inhibitor as a novel druggable ferroptosis inducer through large-scale drug screening. Tubastatin A directly bonded to GPX4 and inhibited GPX4 enzymatic activity through biotin-linked Tubastatin A putdown and LC/MS analysis, which is independent of its inhibition of HDAC6. In addition, our results showed that radiotherapy not only activated Nrf2-mediated GPX4 transcription but also inhibited lysosome-mediated GPX4 degradation, subsequently inducing ferroptosis tolerance and radioresistance in cancer cells. Tubastatin A overcame ferroptosis resistance and radioresistance of cancer cells by inhibiting GPX4 enzymatic activity. More importantly, Tubastatin A has excellent bioavailability, as demonstrated by its ability to significantly promote radiotherapy-induced lipid peroxidation and tumour suppression in a mouse xenograft model. Our findings identify a novel druggable ferroptosis inducer, Tubastatin A, which enhances radiotherapy-mediated antitumor effects. This work provides a compelling rationale for the clinical evaluation of Tubastatin A, especially in combination with radiotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background Aims: Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) multiple myeloma (MM). We present a retrospective study performed on 113 patients with R/R MM who received single anti-BCMA CAR T-cell, combined with anti-CD19 CAR T-cell or anti-CD138 CAR T-cell therapy., Methods: Eight patients were given G-CSF after successful management of CRS, and no CRS re-occurred thereafter. Of the remaining 105 patients that were finally analyzed, 72 (68.6%) received G-CSF (G-CSF group), and 33 (31.4%) did not (non G-CSF group). We mainly analyzed the incidence and severity of CRS or NEs in two groups of patients, as well as the associations of G-CSF timing, cumulative dose and cumulative time with CRS, NEs and efficacy of CAR T-cell therapy., Results: Both groups of patients had similar duration of grade 3-4 neutropenia, and the incidence and severity of CRS or NEs.There were also no differences in the incidence and severity of CRS or NEs between patients with the timing of G-CSF administration ≤3 days and those >3 days after CAR T-cell infusion. The incidence of CRS was greater in patients receiving cumulative doses of G-CSF >1500 μg or cumulative time of G-CSF administration >5 days. Among patients with CRS, there was no difference in the severity of CRS between patients who used G-CSF and those who did not. The duration of CRS in anti-BCMA and anti-CD19 CAR T-cell-treated patients was prolonged after G-CSF administration. There were no significant differences in the overall response rate at 1 and 3 months between the G-CSF group and the non-G-CSF group., Conclusions: Our results showed that low-dose or short-time use of G-CSF was not associated with the incidence or severity of CRS or NEs, and G-CSF administration did not influence the antitumor activity of CAR T-cell therapy., Competing Interests: Declaration of Competing Interests The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: G protein-coupled receptor, class C group 5 member D (GPRC5D) is considered to be a promising surface target for multiple myeloma (MM) immunotherapy. Here, we report the efficacy and safety of anti-GPRC5D chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory (R/R) MM., Methods: This phase Ⅱ, single-arm study enrolled patients (18-70 years) with R/R MM. Lymphodepletion was performed before patients received 2 × 10 6 /kg anti-GPRC5D CAR T cells. The primary end point was the proportion of patients who achieved an overall response. Safety was also evaluated in eligible patients., Results: From September 1, 2021, to March 23, 2022, 33 patients were infused with anti-GPRC5D CAR T cells. At a median follow-up of 5.2 months (range, 3.2-8.9), the overall response rate was 91% (95% CI, 76 to 98; 30 of 33 patients), including 11 (33%) stringent complete responses, 10 (30%) complete responses, four (12%) very good partial responses, and five (15%) partial responses. Partial responses or better were observed in nine (100%) of nine patients with previous anti-B-cell maturation antigen (BCMA) CAR T-cell therapy, including two patients who had received repeated anti-BCMA CAR T-cell infusions with no responses at the last time. Grade 3 or higher hematologic toxicities were neutropenia (33 [100%]), anemia (17 [52%]), and thrombocytopenia (15 [45%]). Cytokine release syndrome occurred in 25 (76%) of 33 patients (all were grade 1 or 2), and neurotoxicities in three patients (one grade 2 and one grade 3 ICANSs and one grade 3 headache)., Conclusion: Anti-GPRC5D CAR T-cell therapy showed an encouraging clinical efficacy and manageable safety profile in patients with R/R MM. For patients with MM that progressed after anti-BCMA CAR T-cell therapy or that is refractory to anti-BCMA CAR T cell, anti-GPRC5D CAR T-cell therapy might be a potential alternative option.

Introduction: Chimeric antigen receptor (CAR) T cell therapy has achieved unprecedented efficacy recently. However, the factors related to responses and durable remission are elusive. This study was to investigate the impact of pre-lymphodepletion (pre-LD) absolute lymphocyte count (ALC) on CAR T cell therapy outcomes., Methods: We conducted a retrospective study of 84 patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who underwent CAR T cell treatment at the Affiliated Hospital of Xuzhou Medical University between March 1,2016 and December 31, 2021. The enrolled patients were divided into high group and low group according to the optimal cutoff value of pre-LD ALC. The Kaplan-Meier analyses was used to calculate survival curves. The Cox proportional hazards model was used for univariate and multivariate analysis to assess the prognostic factors., Results: The ROC showed that the optimal cutoff value of pre-LD ALC was 1.05 x 10 9 /L. The overall response (defined as partial response or complete response) rate was significantly higher in patients with a high pre-LD ALC (75% versus 52.08%; P=0.032). Patients with a low pre-LD ALC had significantly inferior overall survival (OS) and progression-free survival (PFS) compared with those having a high pre-LD ALC (median OS, 9.6 months versus 45.17 months [P=0.008]; median PFS, 4.07 months versus 45.17 months [P= 0.030]). Meanwhile, low pre-LD ALC is an independent risk factor for PFS and OS., Discussion: The data suggested that pre-LD ALC may serve as a helpful indicator to predict the outcomes of CAR T cell therapy in patients with R/R DLBCL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lu, Zhu, Liu, Wang, Sun, Cheng, Yan, Cao, Sang, Zhu, Li, Sun, Zheng, Xu and Li.)

Background: Chimeric antigen receptor - T (CAR-T) cell therapy has shown remarkable efficacy in patients with relapsed/refractory multiple myeloma (R/R MM). However, a subset of patients still experienced progression or relapse, and the predictors of prognosis are little known. We analyzed the inflammatory markers before CAR-T cell infusion, to clarify their correlation with survival and toxicity., Methods: This study involved 109 R/R MM patients who received CAR-T therapy between June 2017 and July 2021. Inflammatory markers, including ferritin, c-reactive protein (CRP), and interleukin-6 (IL-6) before CAR-T cell infusion were detected and then categorized by quartiles. Adverse events and clinical outcomes were compared between patients with upper quartile of inflammatory markers and patients with lower three quartiles of inflammatory markers. An inflammatory prognostic index (InPI) based on these three inflammatory markers was developed in this study. Patients were divided into 3 groups according to the InPI score, progression-free survival (PFS) and overall survival (OS) were compared among the groups. In addition, we explored the correlation between cytokine release syndrome (CRS) and pre-infusion inflammatory markers., Results: We found that the pre-infusion high ferritin (hazard ratio [HR], 3.382; 95% confidence interval [CI], 1.667 to 6.863; P = .0007), high CRP (HR, 2.043; 95% CI, 1.019 to 4.097; P = .044), and high IL-6 (HR, 3.298; 95% CI, 1.598 to 6.808; P = .0013) were significantly associated with inferior OS. The formula of the InPI score was based on the HR value of these 3 variables. Three risk groups were formed: (good, 0 to 0.5 point; intermediate, 1 to 1.5 points; poor, 2 to 2.5 points). Median OS for patients with good, intermediate, and poor InPI was not reached, 24 months, and 4 months, respectively, and median PFS was 19.1 months, 12.3 months, and 2.9 months, respectively. In the cox proportional hazards model, poor InPI remained an independent prognostic factor for PFS and OS. Pre-infusion ferritin was negatively associated with CAR T-cell expansion normalized to baseline tumor burden. Spearman correlation analysis showed that pre-infusion ferritin and IL-6 levels positively correlated with the grade of CRS ( P = .0369 and P = .0117, respectively). The incidence of severe CRS was higher in patients with high IL-6 compared with patients with low IL-6 (26% vs . 9%, P = .0405). Pre-infusion ferritin, CRP and IL-6 were positively correlated with each peak values within the first month after infusion., Conclusions: Our results suggest that patients with elevated inflammation markers before CAR-T cell infusion are more likely to have poor prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Jie, Nian, Wang, Wang, Ma, Jiang, Wu, Qiao, Chen, Cao, Yan, Shi, Cheng, Zhu, Sang, Li, Chen, Xu and Li.)

Risk-stratification of acute myeloid leukemia (AML) based on (cyto)genetic aberrations, including hotspot mutations, deletions and point mutations have evolved substantially in recent years. With the development of next-generation sequence technology, more and more novel mutations in the AML were identified. Thus, to unravel roles and mechanism of novel mutations would improve prognostic and predictive abilities. In this study, two novel germline JAK2 His608Tyr (H608Y) and His608Asn (H608N) mutations were identified and the molecular basis of these mutations in the leukemiagenesis of AML was elucidated. Our results indicated that JAK2 H608Y and H608N mutations disrupted the hydrogen bond between Q656 and H608 which reduced the JH2 domain's activity and abolished interactions between JH1 and JH2 domains, forced JAK2 into the active conformation, facilitated the entrance of substrates and thus caused JAK2 hyperactivation. Further studies suggested that JAK2 H608Y and H608N mutations enhanced the cell proliferation and inhibited the differentiation of Ba/F3 and MV4-11 cells via activating the JAK2-STAT5 signaling pathway. Moreover, rescue experiments demonstrated that mutations repaired the hydrogen bond between Q656 and H608 displayed opposite results. Thus, this study revealed the molecular basis of JAK2 H608Y and H608N mutations in the pathology of AML., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: Limited progress in terms of an effective treatment for spinal cord injury (SCI) emphasizes the urgent need for novel therapies. As a vital central nervous system component, the resident astrocytes play crucial roles in regulating recovery after SCI. In this study, recovery after SCI was compared following the transplantation of either A1 or A2 astrocytes. A1 astrocytes are harmful as they upregulate the neurotoxic classical complement cascade genes. Conversely, A2 astrocytes are characterized as neuroprotective as they upregulate the production of many neurotrophic factors., Methods: We used different supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4 to generate A1 and A2 astrocytes. We detected the influence of astrocytes on neurons by co-culturing A1 and A2 astrocytes with neurons. We transplanted astrocytes into the lesion site of the spinal cord and assessed lesion progression, neural restoration, glia formation and locomotor recovery., Results: Astrocytes were polarized into A1 and A2 phenotypes following culture in the supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4, respectively. Furthermore, co-culturing A2 astrocytes with neurons significantly suppressed glutamate-induced neuronal apoptosis and promoted the degree of neuron arborization. Transplantation of these A2 astrocytes into the lesion site of the spinal cord of mice significantly improved motor function recovery, preserved spared supraspinal pathways, decreased glia scar deposition, and increased neurofilament formation at the site of injury compared to the transplantation of A1 astrocytes. Additionally, enhanced A2 astrocytes with potentially beneficial A2-like genes were also detected in the A2 group. Moreover, luxol fast blue staining and electron microscopy indicated increased preservation of myelin with organized structure after transplantation of A2 astrocytes than of A1 astrocytes., Conclusions: A2 astrocyte transplantation could be a promising potential therapy for SCI. Video abstract., (© 2023. The Author(s).)

Objectives: Chimeric antigen receptor (CAR) T-cell therapy is a new and effective method in relapsed or refractory (R/R) multiple myeloma (MM). This study was aimed to explore the risk factors of infection events., Methods: We retrospectively analyzed 68 patients with R/R MM who received CAR T-cell therapy at the Affiliated Hospital of Xuzhou Medical University from June 2017 to June 2021.35 patients received anti-CD19 combined with anti-BCMA CAR T-cell therapy and 33 patients received anti-BCMA CAR T-cell therapy alone., Results: Infection events in patients who received ≥4 prior lines of treatment or with grade 3-5 cytokines released syndrome (CRS) mainly occurred within 4 months after CAR T-cell infusion(CTI). The duration of infection-free survival was positively correlated with progression-free survival of patients with R/R MM (R 2  = 0.962, p < 0.001) and the first infection event was closely accompanied by the disease relapse or progression. Treatment lines (p = 0.05), duration of ANC<500 cells/mm 3 after CTI (p = 0.036), CRS grade (p = 0.007) and treatment response (p < 0.001) were the independent risk factors associated with infection for a multivariable model. The infection incidence was higher in patients with dual CAR T-cell therapy than with mono CAR T-cell therapy18 months after CTI although no statistic differences were observed within 18 months., Conclusions: Infections after CTI were closely associated with more lines of prior treatment, longer duration of ANC<500 cells/mm 3 , higher grade CRS and poor treatment response. Infections tended to occur in the early stage after CTI in patients with more lines of prior treatment and higher grade CRS., Competing Interests: Declaration of competing interest The authors declared that they have no conflict of interest., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: This study aims to analyze the serotype distribution and drug resistance of Streptococcus pneumoniae isolated from children aged 8 days to 7 years in Urumqi, China, between 2014 to 2021, during which PCV13 was introduced in the private sector's immunization program and COVID-19 control was administrated in the last 2 years., Methods: Serotypes of S. pneumoniae isolates were determined by Quellung reaction, and their susceptibility against 14 antimicrobials were tested. According to the start year of PCV13 administration (2017) and COVID-19 control (2020), the study period was divided into three stages: 2014-2015, 2018-2019, and 2020-2021., Results: A total of 317 isolates were involved in this study. The most common serotypes were type 19F (34.4%), followed by 19A (15.8%), 23F (11.7%), 6B (11.4%), and 6A(5.0%). The coverage rate of both PCV13 and PCV15 was 83.0%. The coverage of PCV20 was a little higher at 85.2%. The resistance rate against penicillin was 28.6% according to the breakpoints of oral penicillin, which would reach up to 91.8% based on the breakpoints of parenteral penicillin for meningitis. The resistance rates to erythromycin, clindamycin, tetracycline, and sulfamethoxazole-trimethoprim were 95.9%, 90.2%, 88.9%, and 78.8%, respectively. The PCV13 isolate was more resistant to penicillin than the non-PCV13 ones. There was not any significant change found in the serotype distribution since the PCV13 introduction and the COVID-19 control. The resistance rate against oral penicillin slightly elevated to 34.5% in 2018-2019 from 30.7% in 2014-2015 and then decreased significantly to 18.1% in 2020-2021 ( χ 2 = 7.716, P < 0.05), while the resistance rate to ceftriaxone (non-meningitis) continuously declined from 16.0% in 2014-2015 to 1.4% in 2018-2019 and 0% in 2020-2021 (Fisher = 24.463, P < 0.01)., Conclusion: The common serotypes of S. pneumoniae isolated from children in Urumqi were types 19F, 19A, 23F, 6B, and 6A, which we found to have no marked change since the PCV13 introduction and the COVID-19 control However, the resistance rate to oral penicillin and ceftriaxone significantly declined in the COVID-19 control stage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Guo, Shi, Gao, Tian, Yuan, Yang, Wumaier, Cao, Abulimiti, Zhang and Yao.)