Autologous CD7 CAR-T cells generated without T cell pre-selection in pediatric patients with relapsed/refractory T-ALL: A phase I trial.

Chimeric antigen receptor (CAR)-T cell therapy showed preliminary activity in patients with refractory or relapsed T cell acute lymphoblastic leukemia (r/r T-ALL). However, many obstacles remain, including manufacturing difficulties and risk of infections. This phase I study (NCT04840875) evaluated autologous CD7 CAR-T cells manufactured without pre-selection of healthy T cells in r/r T-ALL. Thirty patients (29 children and one adult) with a median of two lines of prior therapy but without detectable peripheral leukemia were enrolled. Excluding three cases of manufacturing failures, a total of 27 (90%) patients received infusions after products were confirmed free of leukemia contamination, including 16 (59%) meeting planned target doses. Common adverse events within 30 days included grade 3-4 cytopenias (100%), grade 1-2 (70%) and 3-4 (7%, including one dose-limiting toxicity) cytokine release syndrome, grade 1 neurotoxicity (7%), grade 2 infection (4%), and grade 2 graft-versus-host disease (4%). Two patients developed grade 2 infections after day 30. At day 30, 96% responded and 85% achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi). Seventy-four percent underwent transplantation. Twelve-month progression-free survival with and without censoring transplantation was 22% (95% confidence interval 4%-100%) and 57% (41%-81%), respectively. These results support that autologous CD7 CAR-T therapy without T cell pre-selection is feasible in patients with r/r T-ALL.

Histological chorioamnionitis and pathological stages on very preterm infant outcomes.

AIMS: Histological chorioamnionitis (HCA) is a condition linked to preterm birth and neonatal infection and its relationship with various pathological stages in extremely preterm neonates, and with their associated short- and long-term consequences, remains a subject of research. This study investigated the connection between different pathological stages of HCA and both short-term complications and long-term outcomes in preterm infants born at or before 32 weeks of gestational age. METHODS: Preterm infants born at ≤ 32 weeks of gestation who underwent placental pathology evaluation and were followed-up at 18-24 months of corrected age were included. Neonates were classified based on their exposure to HCA and were further subdivided into different groups according to maternal inflammatory responses (MIR) and fetal inflammatory responses (FIR) stages. We compared short-term complications during their hospital stay between the HCA-exposed and -unexposed groups and examined the influence of HCA stages on long-term outcomes. RESULTS: The HCA group exhibited distinct characteristics such as higher rates of premature rupture of membranes > 18 h, reduced amniotic fluid, early-onset sepsis, bronchopulmonary dysplasia and intraventricular haemorrhage (IVH) grades III-IV (P < 0.05). The moderate-severe HCA group displayed lower gestational age, lower birth weight and higher incidence of IVH (grades III-IV) and preterm sepsis compared with the mild HCA group (P < 0.05). After adjusting for confounders, the MIR stages 2-3 group showed associations with cognitive impairment and cerebral palsy (P < 0.05), and the FIR stages 2-3 group also showed poor long-term outcomes and cognitive impairment (P < 0.05). CONCLUSIONS: Moderate-severe HCA was associated with increased early-onset sepsis, severe IVH and poor long-term outcomes, including cognitive impairment and cerebral palsy. Vigilant prevention strategies are warranted for severe HCA cases in order to mitigate poorer clinical outcomes.

Exploring the mechanism of enterotoxicity mediated by the microbiome-butyrate-PPAR axis in podophyllotoxin through the toxicological evidence chain (TEC) concept.

Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The underlying mechanisms by which PPT exerts its action remain largely elusive. This study aimed to evaluate the molecular mechanisms underlying PPT-induced enterotoxicity utilizing the concept of toxicological evidence chain. Changes in body weight, behavior, and histopathological and biochemical markers in rats were observed. Additionally, microbiome, metabolome, and transcriptome analyses were integrated to identify potential microorganisms, metabolic markers, and major pathways using a co-occurrence network. Our findings suggested that PPT induced pathological changes in rats, including weight loss, diarrhea, and inflammation accompanied by increased levels of IFN-γ, IL-5, IL-6, GRO/KC, and IL-12p70. The decrease in butyrate levels in the PPT group may be related to the enrichment of Firmicutes. The reduction of butyrate levels may impair the expression of PPARγ, subsequently promoting Escherichia-Shigella proliferation. Additionally, the suppression of PPARs pathway may result in the increased production of inflammatory factors, contributing to enterotoxicity. This study offers a novel understanding of the molecular mechanisms underlying PPT-induced enterotoxicity, making a significant contribution to developing strategies to mitigate PPT toxicity and prevent associated diseases.

Sequential CD19 and CD22 chimeric antigen receptor T-cell therapy for childhood refractory or relapsed B-cell acute lymphocytic leukaemia: a single-arm, phase 2 study.

BACKGROUND: Relapses frequently occur following CD19-directed chimeric antigen receptor (CAR) T-cell treatment for relapsed or refractory B-cell acute lymphocytic leukaemia in children. We aimed to assess the activity and safety of sequential CD19-directed and CD22-directed CAR T-cell treatments. METHODS: This single-centre, single-arm, phase 2 trial, done at Beijing GoBroad Boren Hospital, Beijing, China, included patients aged 1-18 years who had relapsed or refractory B-cell acute lymphocytic leukaemia with CD19 and CD22 positivity greater than 95% and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were initially infused with CD19-directed CAR T cells intravenously, followed by CD22-directed CAR T-cell infusion after minimal residual disease-negative complete remission (or complete remission with incomplete haematological recovery) was reached and all adverse events (except haematological adverse events) were grade 2 or better. The target dose for each infusion was 0·5 × 106 to 5·0 × 106 cells per kg. The primary endpoint was objective response rate at 3 months after the first infusion. Secondary endpoints were duration of remission, event-free survival, disease-free survival, overall survival, safety, pharmacokinetics, and B-cell quantification. The prespecified activity analysis included patients who received the target dose and the safety analysis included all treated patients. This study is registered with ClinicalTrials.gov, NCT04340154, and enrolment has ended. FINDINGS: Between May 28, 2020, and Aug 16, 2022, 81 participants were enrolled, of whom 31 (38%) were female and 50 (62%) were male. Median age was 8 years (IQR 6-10), all patients were Asian. All 81 patients received the first infusion and 79 (98%) patients received sequential infusions, CD19-directed CAR T cells at a median dose of 2·7 × 106 per kg (IQR 1·1 × 106 to 3·7 × 106) and CD22-directed CAR T cells at a median dose of 2·2 × 106 per kg (1·1 × 106 to 3·7 × 106), with a median interval of 39 days (37-41) between the two infusions. 62 (77%) patients received the target dose, including two patients who did not receive CD22 CAR T cells. At 3 months, 60 (97%, 95% CI 89-100) of the 62 patients who received the target dose had an objective response. Median follow-up was 17·7 months (IQR 11·4-20·9). 18-month event-free survival for patients who received the target dose was 79% (95% CI 66-91), duration of remission was 80% (68-92), and disease-free survival was 80% (68-92) with transplantation censoring; overall survival was 96% (91-100). Common adverse events of grade 3 or 4 between CD19-directed CAR T-cell infusion and 30 days after CD22-directed CAR T-cell infusion included cytopenias (64 [79%] of 81 patients), cytokine release syndrome (15 [19%]), neurotoxicity (four [5%]), and infections (five [6%]). Non-haematological adverse events of grade 3 or worse more than 30 days after CD22-directed CAR T-cell infusion occurred in six (8%) of 79 patients. No treatment-related deaths occurred. CAR T-cell expansion was observed in all patients, with a median peak at 9 days (IQR 7-14) after CD19-directed and 12 days (10-15) after CD22-directed CAR T-cell infusion. At data cutoff, 35 (45%) of 77 evaluable patients had CAR transgenes and 59 (77%) had B-cell aplasia. INTERPRETATION: This sequential strategy induced deep and sustained responses with an acceptable toxicity profile, and thus potentially provides long-term benefits for children with this condition. FUNDING: The National Key Research & Development Program of China, the CAMS Innovation Fund for Medical Sciences (CIFMS), and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

The association among uric acid, microalbumin and estimated glomerular filtration rate in hypertensive patients: a case control study.

OBJECTIVE: To estimate the relationship among uric acid (UA), 24-h microalbumin (24 h-MAU) and estimated glomerular filtration rate (eGFR) in hypertensive patients. METHOD: The study enrolled adult patients hospitalized in TEDA International Cardiovascular Hospital. The study was used to explore the correlation among UA, 24 h-MAU and eGFR. Univariate analysis was used to compare continuous or categorical data groups according to data type. Multivariate analysis was used to explore the correlation among UA, Log 24 h-MAU and eGFR by linear regression, and the relationship among UA, 24 h-MAU ≥ 30 mg/24 h (increased 24 h-MAU) and eGFR < 90 ml·min-1·1.73 m-2 (mildly decreased eGFR) by logistic regression. Mediation effect analysis was used to explore the mediating effect of increased 24 h-MAU between UA and mildly decreased eGFR. Subgroup analysis was used to investigate the correlation among UA, 24 h-MAU and eGFR in different gender. RESULT: Seven hundred and thirty-three inpatients were enrolled in the study, including 257 patients with hyperuricemia. The level of UA was 377.8 ± 99.9 µmol/L in all patients enrolled, and it was about 50.1% higher in hyperuricemia group (482.3 ± 58.8 µmol/L vs. 321.4 ± 63.5 µmol/L, P < 0.001). The prevalence of hyperuricemia was 35.1% (95%CI 31.6-38.5%). The univariate regression analysis showed that UA was significant related to Log 24 h-MAU, increased 24 h-MAU, eGFR and mildly decreased eGFR. After adjusted confounding factors, UA was significant related to Log 24 h-MAU (ß = 0.163, P < 0.001), eGFR (ß = - 0.196, P < 0.001), increased 24 h-MAU (quantitative analysis: OR = 1.045, 95%CI 1.020-1.071, P < 0.001; qualitative analysis: OR = 2.245, 95%CI 1.410-3.572, P = 0.001), but had no significant relationship with mildly decreased eGFR. Mediating effect analysis showed that increased 24 h-MAU partially mediated the relationship between UA and mildly decreased eGFR (relative indirect effect: 25.0% and 20.3% in quantitative analysis and qualitative analysis respectively). In the subgroup analysis, the results were stable and similar to the analysis for entry patients. CONCLUSION: The prevalence of hyperuricemia was higher in hypertensive inpatients. UA was strongly associated with Log 24 h-MAU, eGFR and increased 24 h-MAU, while the correlation with mildly decreased eGFR was affected by multiple factors. And increased 24 h-MAU might be the intermediate factor between UA and mildly decreased eGFR.

The gut microbiome modulates gut-brain axis glycerophospholipid metabolism in a region-specific manner in a nonhuman primate model of depression.

Emerging research demonstrates that microbiota-gut-brain (MGB) axis changes are associated with depression onset, but the mechanisms underlying this observation remain largely unknown. The gut microbiome of nonhuman primates is highly similar to that of humans, and some subordinate monkeys naturally display depressive-like behaviors, making them an ideal model for studying these phenomena. Here, we characterized microbial composition and function, and gut-brain metabolic signatures, in female cynomolgus macaque (Macaca fascicularis) displaying naturally occurring depressive-like behaviors. We found that both microbial and metabolic signatures of depressive-like macaques were significantly different from those of controls. The depressive-like monkeys had characteristic disturbances of the phylum Firmicutes. In addition, the depressive-like macaques were characterized by changes in three microbial and four metabolic weighted gene correlation network analysis (WGCNA) clusters of the MGB axis, which were consistently enriched in fatty acyl, sphingolipid, and glycerophospholipid metabolism. These microbial and metabolic modules were significantly correlated with various depressive-like behaviors, thus reinforcing MGB axis perturbations as potential mediators of depression onset. These differential brain metabolites were mainly mapped into the hippocampal glycerophospholipid metabolism in a region-specific manner. Together, these findings provide new microbial and metabolic frameworks for understanding the MGB axis' role in depression, and suggesting that the gut microbiome may participate in the onset of depressive-like behaviors by modulating peripheral and central glycerophospholipid metabolism.

Ruxolitinib mitigates steroid-refractory CRS during CAR T therapy.

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and steroids, many patients can recover from severe CRS. However, some patients are refractory to steroids and develop life-threatening consequences. Ruxolitinib is an oral JAKs inhibitor and promising drug in inflammatory diseases. In this pilot study, we evaluate the efficacy of Ruxolitinib in CRS. Of 14 r/r B-ALL children who received CD19 or CD22 CAR T cell therapies, 4 patients developed severe (≥grade 3) CRS with symptoms that were not alleviated with high-dose steroids and thus received ruxolitinib. Rapid resolution of CRS symptoms was observed in 4 patients after ruxolitinib treatment. Serum cytokines significantly decreased after ruxolitinib intervention. All patients achieved complete remission on day 30 after infusion, and we could still detect CAR T expansion in vivo despite usage of ruxolitinib. There were no obvious adverse events related to ruxolitinib. In vitro assays revealed that ruxolitinib could dampen CAR T expansion and cytotoxicity, suggesting that the timing and dosage of ruxolitinib should be carefully considered to avoid dampening anti-leukaemia response. Our results suggest that ruxolitinib is active and well tolerated in steroid-refractory and even life-threatening CRS.

Toxicity and effectiveness of CD19 CAR T therapy in children with high-burden central nervous system refractory B-ALL.

INTRODUCTION: Although recent clinical trials have demonstrated the efficacy of CD19-directed chimeric antigen receptor (CAR) T-cell therapy for refractory or relapsed B acute lymphoblastic leukemia (r/r B-ALL), most trials exclude patients with high-burden CNS leukemia (CNSL) to avoid the risk of severe neurotoxicity. There were only sparse cases describing the effect of CAR T cells on low-burden CNSL, and the safety and effectiveness of CAR T cells in high-burden CNSL remains unknown. METHODS: Here, we retrospectively analyzed the results of CD19 CAR T-cell therapy in 12 pediatric patients that had low (Blasts < 20/µL in CSF) or high-burdens (Blasts or intracranial solid mass) of CNS B-ALL, that are enrolled in three clinical trials and one pilot study at Beijing Boren Hospital RESULTS: Eleven patients (91.7%) achieved complete remission (CR) on day 30, and one patient got CR on day 90 after infusion. Most patient experienced mild cytokine-release syndrome. However, of the five patients who retained > 5/µL blasts in CSF or a solid mass before CAR T-cell expansion, four developed severe (grade 3-4) neurotoxicity featured by persistent cerebral edema and seizure, and they fully recovered after intensive managements. Sustained remission was achieved in 9 of the 12 patients, resulted in a 6-month leukemia-free survival rate of 81.8% (95% CI 59.0-100). Only one patient has CNS relapse again. CONCLUSION: Our study demonstrates that CAR T cells are effective in clearing both low- and high-burden CNSL, but a high CNSL burden before CAR T-cell expansion may cause severe neurotoxicity requiring intense intervention.

MFGE8 mitigates brain injury in a rat model of SAH by maintaining vascular endothelial integrity via TIGß5/PI3K/CXCL12 signaling.

Leaked blood components, injured endothelial cells, local inflammatory response and vasospasm may converge to promote microthrombosis following subarachnoid hemorrhage (SAH). Previously, we showed that the milk fat globule-epidermal growth factor 8 (MFGE8) can mitigate SAH-induced microthrombosis. This present study was aimed to explore the molecular pathway participated in MFGE8-dependent protection on vascular endothelium. Immunofluorescence, immunoblot and behavioral tests were used to determine the molecular partner and signaling pathway mediating the effect of MFGE8 in vascular endothelium in rats with experimental SAH and controls, together with the applications of RNA silencing and pharmacological intervention methods. Relative to control, recombinant human MFGE8 (rhMFGE8) treatment increased 5-bromo-2'-deoxyuridine (BrdU) labeled new endothelial cells, reduced TUNUL-positive endothelial cells and elevated the expression of phosphatidylinositol 3-kinase (PI3K) and chemokine (C-X-C motif) ligand 12 (CXCL12), in the brains of SAH rats. These effects were reversed by MFGE8 RNA silencing, as well as following cilengitide and wortmannin intervention. These results suggest that MFGE8 promotes endothelial regeneration and mitigates endothelial DNA damage through the activation of the TIGß5/PI3K/CXCL12 signaling pathway.

The potential for metabolomics in the study and treatment of major depressive disorder and related conditions.

INTRODUCTION: Major depressive disorder (MDD) is a common mental disease, associated with a debilitating condition and high prevalence. Although the underlying mechanism of MDD remains to be elucidated, several factors, including social, biological, and psychological factors, have been associated with disease pathogenesis. Metabolomics can provide new insights into the prognosis, treatment response, and related biomarkers associated with MDD at the metabolic level. AREAS COVERED: In this review, we investigated the metabolic changes identified in different bio-samples from animal models of depression and MDD patients. Moreover, we summarized the metabolites associated with antidepressant treatment responses. Keywords used for the literature searches were 'depression' [MeSH] and 'metabolomics' [MeSH], in PubMed. EXPERT OPINION: Metabolomic evidence in humans has indicated that amino acid metabolism, energy metabolism, and lipid metabolism are the primary metabolic alterations that are observed in the etiology of MDD, and animal models serve as an important theoretical reference in this field. Metabolomics has shed new light on the pathogenic mechanisms and treatment responses during MDD; however, study results are not always consistent. The application of metabolomic results to clinical practice will require the integration of different biological samples and other omics studies, as well as the clinical validation of study findings.

Age-dependent acute interference with stem and progenitor cell proliferation in the hippocampus after exposure to 1800 MHz electromagnetic radiation.

To investigate the effects of exposure to an 1800 MHz electromagnetic field on cell death and cell proliferation in the developing brain, postnatal day 7 (P7) and P21 healthy Kunming mice were randomly assigned into the experimental and control groups. The experimental groups were exposed to an 1800 MHz electromagnetic field for 8 h daily for three consecutive days. The thymidine analog 5-bromo-2-deoxyuridine (BrdU) was injected intraperitoneally 1 h before each exposure session, and all animals were sacrificed 24 h after the last exposure. Cell death and proliferation markers were detected by immunohistochemistry in the dentate gyrus of the hippocampus. Electromagnetic exposure has no influence on cell death in the dentate gyrus of the hippocampus in P7 and P21 mice as indicated by active caspase-3 immunostaining and Fluoro-Jade labeling. The basal cell proliferation in the hippocampus was higher in P7 than in P21 mice as indicated by the number of cells labeled with BrdU and by immunohistochemical staining for phosphor-histone H3 (PHH3) and brain lipid-binding protein (BLBP). Electromagnetic exposure stimulated DNA synthesis in P7 neural stem and progenitor cells, but reduced cell division and the total number of stem cells in the hippocampus as indicated by increased BrdU labeling and reduced PHH3 and BLBP labeling compared to P7 control mice. There were no significant changes in cell proliferation in P21 mice after exposure to the electromagnetic field. These results indicate that interference with stem cell proliferation upon short-term exposure to an 1800 MHz electromagnetic field depends on the developmental stage of the brain.

Study on Oxymatrine-Based Research from 2001 to 2022: A Bibliometric Analysis.

Oxymatrine is a quinolizidine alkaloid mainly derived from Kushen; it possesses various therapeutic effects, such as organ- and tissue-protective, anticancer, and antiviral effects. The research directions for oxymatrine remain broad. In order to explore the overall status of oxymatrine-based research, we carried out a bibliometric analysis to summarize the oxymatrine-based, English-written studies published in the past 22 years. In total, 267 studies were included, most of which were original. The number of annual studies slowly increased with some fluctuations. Other than China, 11 different countries conducted studies on oxymatrine; the variety in the country of origin of these publications is presented as a recently increasing trend. Many affiliates and researchers have participated in oxymatrine-based research. Various treatment mechanisms involving different oxymatrine pathways have led to research in a wide range of fields, being published in numerous journals. Two particularly popular research fields related to oxymatrine involved anticancer and anti-inflammation. From this research, we concluded that with increasing and continuous in-depth studies, more therapeutic effects and mechanisms will be elucidated, and oxymatrine may present as a viable option for the treatment of additional diseases.

Podophyllotoxin via SIRT1/PPAR /NF-κB axis induced cardiac injury in rats based on the toxicological evidence chain (TEC) concept.

BACKGROUND: The study of cardiotoxicity of drugs has become an important part of clinical safety evaluation of drugs. It is commonly known that podophyllotoxin (PPT) and its many derivatives and congeners are broad-spectrum pharmacologically active substances. Clinical cardiotoxicity of PPT and its derivatives has been raised, basic research on the mechanism of cardiotoxicity remains insufficient. PURPOSE: In present study, our group's innovative concept of toxicological evidence chain (TEC) was applied to reveal the cardiac toxicity mechanism of PPT by targeted metabolomics, TMT-based quantitative proteomics and western blot. METHODS: The injury phenotype evidence (IPE) acquired from the toxicity manifestations, such as weight and behavior observation of Sprague-Dawley rat. The damage to rat hearts were assessed through histopathological examination and myocardial enzymes levels, which were defined as Adverse Outcomes Evidence (AOE). The damage to rat hearts was assessed through histopathological examination and myocardial enzyme levels, which were defined as evidence of adverse outcomes.Overall measurements of targeted metabolomics based on energy metabolism and TMT-based quantitative proteomics were obtained after exposure to PPT to acquire the Toxic Event Evidence (TEE). The mechanism of cardiac toxicity was speculated based on the integrated analysis of targeted metabolomics and TMT-based quantitative proteomics, which was verified by western blot. RESULTS: The results indicated that exposure to PPT could result in significant elevation of myocardial enzymes and pathological alterations in rat hearts. In addition, we found that PPT caused disorders in cardiac energy metabolism, characterized by a decrease in energy metabolism fuels. TMT-based quantitative proteomics revealed that the PPAR (Peroxisome proliferators-activated receptor) signaling pathway needs further study. It is worth noting that PPT may suppress the expression of SIRT1, subsequently inhibiting AMPK, decreasing the expression of PGC-1α, PPARα and PPARγ. This results in disorders of glucose oxidation, glycolysis and ketone body metabolism. Additionally, the increase in the expression of p-IKK and p-IκBα, leads to the nuclear translocation of NF-κB p65 from the cytosol, thus triggering inflammation. CONCLUSION: This study comprehensively evaluated cardiac toxicity of PPT and initially revealed the mechanism of cardiotoxicity,suggesting that PPT induced disorders of energy metabolism and inflammation via SIRT1/PPAR/NF-κB axis, potentially contributing to cardiac injury.

Activation of Piezo1 by intracranial hypertension induced neuronal apoptosis via activating hippo pathway.

AIM: Most of the subarachnoid hemorrhage (SAH) patients experienced the symptom of severe headache caused by intracranial hypertension. Piezo1 is a mechanosensitive ion channel protein. This study aimed to investigate the effect of Piezo1 on neurons in response to intracranial hypertension. METHODS: The SAH rat model was performed by the modified endovascular perforation method. Piezo1 inhibitor GsMTx4 was administered intraperitoneally after SAH induction. To investigate the underlying mechanism, the selective Piezo1 agonist Yoda1, Piezo1 shRNA, and MY-875 were administered via intracerebroventricular injection before SAH induction. In vitro, we designed a pressurizing device to exclusively explore the effect of Piezo1 activation on primary neurons. Neurons were pretreated with Piezo1 inhibition followed by intracranial hypertension treatment, and then apoptosis-related proteins were detected. RESULTS: Piezo1 inhibition significantly attenuated neuronal apoptosis and improved the outcome of neurological deficits in rats after SAH. The Hippo pathway agonist MY-875 reversed the anti-apoptotic effects of Piezo1 knockdown. In vitro, intracranial hypertension mimicked by the pressurizing device induced Piezo1 expression, resulting in Hippo pathway activation and neuronal apoptosis. The Hippo pathway inhibitor Xmu-mp-1 attenuated Yoda1-induced neuronal apoptosis. In addition, the combination of hypertension and oxyhemoglobin treatment exacerbated neuronal apoptosis. CONCLUSIONS: Intracranial hypertension induced Piezo1 expression, neuronal apoptosis, and the Hippo pathway activation; the Hippo signaling pathway is involved in Piezo1 activation-induced neuronal apoptosis in respond to intracranial hypertension. Primary neurons treated with intracranial hypertension and oxyhemoglobin together can better characterize the circumstance of SAH in vivo, which is contributed to construct an ideal in vitro SAH model.

A Novel and Green Method for Preparing Highly Conductive PEDOT:PSS Films for Thermoelectric Energy Harvesting.

As a π-conjugated conductive polymer, poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) is recognized as a promising environmentally friendly thermoelectric material. However, its low conductivity has limited applications in the thermoelectric field. Although thermoelectric efficiency can be significantly enhanced through post-treatment doping, these processes often involve environmentally harmful organic solvents or reagents. In this study, a novel and environmentally benign method using purified water (including room temperature water and subsequent warm water) to treat PEDOT:PSS film has been developed, resulting in improved thermoelectric performance. The morphology data, chemical composition, molecular structure, and thermoelectric performance of the films before and after treatment were characterized and analyzed using a scanning electron microscope (SEM), Raman spectrum, XRD pattern, X-ray photoelectron spectroscopy (XPS), and a thin film thermoelectric measurement system. The results demonstrate that the water treatment effectively removes nonconductive PSS from PEDOT:PSS composites, significantly enhancing their conductivity. Treated films exhibit improved thermoelectric properties, particularly those treated only 15 times with room temperature water, achieving a high electrical conductivity of 62.91 S/cm, a Seebeck coefficient of 14.53 µV K-1, and an optimal power factor of 1.3282 µW·m-1·K-2. In addition, the subsequent warm water treatment can further enhance the thermoelectric properties of the film sample. The underlying mechanism of these improvements is also discussed.

Allogeneic CD5-specific CAR-T therapy for relapsed/refractory T-ALL: a phase 1 trial.

Refractory or relapsed T cell acute lymphoblastic leukemia (r/r T-ALL) patients have poor prognoses, due to the lack of effective salvage therapies. Recently, CD7-targeting chimeric antigen receptor (CAR)-T therapies show efficacy in patients with r/r T-ALL, but relapse with CD7 loss is common. This study evaluates a CD5-gene-edited CAR-T cell therapy targeting CD5 in 19 r/r T-ALL patients, most of whom had previously failed CD7 CAR-T interventions. CAR-T products were derived from previous transplant donors (Cohort A) or newly matched donors (Cohort B). Primary endpoints were dose-limiting toxicity at 21 days and adverse events within 30 days. Secondary endpoints were responses, pharmacokinetics and severe adverse events after 30 days. A total of 16 received infusions, 10 at target dose of 1 × 106 kg-1. All encountered grade 3-4 cytopenias and one had a grade 3 infection within 30 days. All patients (100%) achieved complete remission or complete remission with incomplete blood count recovery by day 30. At a median follow-up of 14.3 months, four received transplantation; three were in remission and one died of infection. Of 12 untransplanted patients, 2 were in remission, 3 relapsed, 5 died of infection and 2 of thrombotic microangiopathy. CAR-T cells persisted and cleared CD5+ T cells. CD5- T cells, mostly CD5-gene-edited, increased but remained below normal levels. These results suggest this CD5-specific CAR-T intervention has a high remission rate for T-ALL patients. Evidence also suggests the risk of late-onset severe infection may be mitigated with consolidative transplantation. This study provides insights that could help to optimize this promising intervention. ClinicalTrials.gov registration: NCT05032599 .

C-JUN overexpressing CAR-T cells in acute myeloid leukemia: preclinical characterization and phase I trial.

Chimeric antigen receptor (CAR) T cells show suboptimal efficacy in acute myeloid leukemia (AML). We find that CAR T cells exposed to myeloid leukemia show impaired activation and cytolytic function, accompanied by impaired antigen receptor downstream calcium, ZAP70, ERK, and C-JUN signaling, compared to those exposed to B-cell leukemia. These defects are caused in part by the high expression of CD155 by AML. Overexpressing C-JUN, but not other antigen receptor downstream components, maximally restores anti-tumor function. C-JUN overexpression increases costimulatory molecules and cytokines through reinvigoration of ERK or transcriptional activation, independent of anti-exhaustion. We conduct an open-label, non-randomized, single-arm, phase I trial of C-JUN-overexpressing CAR-T in AML (NCT04835519) with safety and efficacy as primary and secondary endpoints, respectively. Of the four patients treated, one has grade 4 (dose-limiting toxicity) and three have grade 1-2 cytokine release syndrome. Two patients have no detectable bone marrow blasts and one patient has blast reduction after treatment. Thus, overexpressing C-JUN endows CAR-T efficacy in AML.

Global trends and hotspots of gastrointestinal microbiome and toxicity based on bibliometrics.

Background: Toxicity concerns persist in the fields of public health, environmental science, and pharmacology. The intricate and vital role of the gastrointestinal microbiome in influencing toxicity and overall human health has gained increasing recognition in recent years. This study presents a comprehensive bibliometric analysis to evaluate the global scientific output, emerging trends, and research focal points in the area of gastrointestinal microbiome and toxicity. Methods: The Web of Science Core Collection database was retrieved for publications on the gastrointestinal microbiome and toxicity from 1980 to 2022. Our analysis included scholarly research papers written in English and excluded duplicate publications. We used Biblioshiny and R to summarize the count and citation metrics of included articles, and visualized research trends and keywords. CiteSpace was used to identify reference literature, keywords, and citation bursts. VOSviewer was used to visualize the network of related countries, institutions, authors, co-cited authors, and keywords. Results: A total of 2,140 articles were included, allowing us to identify significant countries, institutions, authors, and research focal points. Our results indicate a growing trend in the field, with China and the United States leading the research. The most productive journal in this area is Science of the Total Environment. Key findings revealed that research hotspots have shifted from drugs to environmental pollutants, emphasizing microplastics. Important mechanisms studied include oxidative stress, metabolism, inflammation, and apoptosis, with target organs being the gastrointestinal tract, liver, and brain. Furthermore, we highlight the rising significance of the gut-brain axis and the usage of zebrafish as a model organism. Conclusion: Despite certain limitations, such as focusing solely on English-language publications and excluding unpublished literature, our findings provide valuable insights into the current state of research on toxicity and the gastrointestinal microbiome. In the future, modifications to the gastrointestinal microbiome could offer new directions for treating and mitigating toxicity. These discoveries provide a comprehensive perspective on the broader scope of this research field.

ASK1 inhibitor NQDI­1 decreases oxidative stress and neuroapoptosis via the ASK1/p38 and JNK signaling pathway in early brain injury after subarachnoid hemorrhage in rats.

Oxidative stress and neuroapoptosis are key pathological processes after subarachnoid hemorrhage (SAH). The present study evaluated the anti­oxidation and anti­apoptotic neuroprotective effects of the apoptosis signal­regulating kinase 1 (ASK1) inhibitor ethyl­2,7­dioxo­2,7­dihydro­3H­naphtho(1,2,3­de)quinoline­1­carboxylate (NQDI­1) in early brain injury (EBI) following SAH in a rat model. A total of 191 rats were used and the SAH model was induced using monofilament perforation. Western blotting was subsequently used to detect the endogenous expression levels of proteins. Immunofluorescence was then used to confirm the nerve cellular localization of ASK1. Short­term neurological function was assessed using the modified Garcia scores and the beam balance test 24 h after SAH, whereas long­term neurological function was assessed using the rotarod test and the Morris water maze test. Apoptosis of neurons was assessed by TUNEL staining and oxidative stress was assessed by dihydroethidium staining 24 h after SAH. The protein expression levels of phosphorylated (p­)ASK1 and ASK1 rose following SAH. NQDI­1 was intracerebroventricularly injected 1 h after SAH and demonstrated significant improvements in both short and long­term neurological function and significantly reduced oxidative stress and neuronal apoptosis. Injection of NQDI­1 caused a significant decrease in protein expression levels of p­ASK1, p­p38, p­JNK, 4 hydroxynonenal, and Bax and significantly increased the protein expression levels of heme oxygenase 1 and Bcl­2. The use of the p38 inhibitor BMS­582949 or the JNK inhibitor SP600125 led to significant decreases in the protein expression levels of p­p38 or p­JNK, respectively, and a significant reduction in oxidative stress and neuronal apoptosis; however, these inhibitors did not demonstrate an effect on p­ASK1 or ASK1 protein expression levels. In conclusion, treatment with NQDI­1 improved neurological function and decreased oxidative stress and neuronal apoptosis in EBI following SAH in rats, possibly via inhibition of ASK1 phosphorylation and the ASK1/p38 and JNK signaling pathway. NQDI­1 may be considered a potential agent for the treatment of patients with SAH.