CD19-CAR-DNT cells (RJMty19) in patients with relapsed or refractory large B-cell lymphoma: a phase 1, first-in-human study.

Background: Current approved chimeric antigen receptor (CAR) T-cell products are autologous cell therapies that are costly and poorly accessible to patients. We aimed to evaluate the safety and antitumor activity of a novel off-the-shelf anti-CD19 CAR-engineered allogeneic double-negative T cells (RJMty19) in patients with relapsed/refractory large B-cell lymphoma. We report the results from a first-in-human, open-label, single-dose, phase 1 study of allogeneic CD19-specific CAR double-negative T (CAR-DNT) cells. Methods: Eligibility criteria included the presence of measurable lesions, at least 2 lines of prior immunochemotherapy, and an ECOG score of 0-1. We evaluated four dose levels (DL) of RJMty19 in a 3 + 3 dose-escalation scheme: 1 × 106, 3 × 106, 9 × 106 and 2 × 107 CAR-DNT cells per kilogram of body weight. All patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide. The primary endpoints were dose-limiting toxicities (DLTs), incidence of adverse events (AEs), and clinically significant laboratory abnormalities. Secondary endpoints included evaluation of standard cellular pharmacokinetic parameters, immunogenicity, objective response rates (ORR), and disease control rate (DCR) per Lugano 2014 criteria. Findings: A total of 12 patients were enrolled between 22 July 2022 and 27 July 2023. Among these patients, 66% were classified as stage IV, 75% had an IPI score of 3 or higher, representing an intermediate risk or worse. The maximum tolerated dose was not reached because no DLT was observed. Four patient experienced grade 1 or 2 cytokine release syndrome and dizziness. The most common AEs were hematologic toxicities, including neutropenia (N = 12, 100%), leukopenia (N = 12, 100%), lymphopenia (N = 10, 83%), thrombocytopenia (N = 6, 50%), febrile neutropenia (N = 3, 25%), and anemia (N = 3, 25%). Seven subjects died till the cut-off date, five of them died of disease progression and two of them died of COVID 19. In all patients (N = 12), the ORR was 25% and CRR was 8.3%. DL1 and DL2 patients benefited less from the therapy (ORR: 17%, N = 1; DCR: 33%, N = 2). However, all DL3 patients achieved disease control (N = 3, 100%), and all DL4 patients achieved objective response (N = 3, 100%). Interpretation: Our results demonstrate that CD19-CAR-DNT cells appear to be well tolerated with promising antitumor activity in LBCL patients. Further study of this product with a larger sample size is warranted. This phase 1 study is registered on clinicaltrials.gov (NCT05453669). Funding: Wyze Biotech. Co., Ltd.

Targeted alleviation of ischemic stroke reperfusion via atorvastatin-ferritin Gd-layered double hydroxide.

In acute ischemic stroke therapy, potent neuroprotective agents are needed that prevent neural injuries caused by reactive oxygen species (ROS) during ischemic reperfusion. Herein, a novel 2D neuroprotective agent (AFGd-LDH) is reported, comprising Gd-containing layered double hydroxide nanosheets (Gd-LDH, as a drug nanocarrier/MRI contrast agent), atorvastatin (ATO, as a neuroprotective drug) and the ferritin heavy subunit (FTH, as a blood brain barrier transport agent). Experiments revealed AFGd-LDH to possess outstanding antioxidant activity, neuroprotective properties, blood‒brain barrier transit properties, and biocompatibility. In vitro studies demonstrated the ROS scavenging efficiency of AFGd‒LDH to be ∼90%, surpassing CeO2 (50%, a ROS scavenger) and edaravone (52%, a clinical neuroprotective drug). Ischemia‒reperfusion model studies in mice showed AFGd‒LDH could dramatically decrease apoptosis induced by reperfusion, reducing the infarct area by 67% and lowering the neurological deficit score from 3.2 to 0.9. AFGd-LDH also offered outstanding MRI performance, thus enabling simultaneous imaging and ischemia reperfusion therapy.

BSA-templated ultrasmall Ag/Gd2O3 as a self-enabled nanotheranostic for MR/CT/PA tri-modality imaging and photothermal therapy.

It is becoming more and more important to effectively integrate multiple complementary diagnostic imaging and synergistic therapies into a nano-platform, but it is still challenging. Here, we used bovine serum albumin (BSA) as a template to prepare ultra-small Ag/Gd2O3 (Ag/Gd@BSA) hybrid nanoparticles with high water dispersion by a biomineralization strategy for magnetic resonance (MR)/computed tomography (CT)/photoacoustic (PA) imaging-guided photothermal therapy (PTT). Compared with commercial MR and CT contrast agents, we showed that these well-characterized BSA-templated nanotheranostics possessed higher r1 relaxivity (5.84 mM-1 s-1) and HU values. In addition, these nanotheranostics have an excellent NIR absorption feature and outstanding photothermal conversion efficiency (47.4%) in the solution phase. The in vivo imaging experiment demonstrated that the Ag/Gd@BSA hybrid nanoparticles could serve as tri-modality imaging contrast agents to enable precise diagnosis of tumors. Meanwhile, it was also revealed that Ag/Gd@BSA had ability to be an ideal nanotherapeutic agent to achieve a satisfactory tumor treatment effect through PTT. Also, we showed the good biocompatibility of Ag/Gd@BSA nanoparticles. Overall, these results indicated that Ag/Gd@BSA was an effective nanotheranostic, which could accurately identify tumor sites and realize complete tumor elimination, having great potential in clinical transformation.

Effects of blood lipids and lipid-modifying drugs on intracranial aneurysms.

BACKGROUND AND PURPOSE: We used two-sample Mendelian randomization (MR) to examine the effects of blood lipids and lipid-modifying drugs on intracranial aneurysm (IA). METHODS: Genetic variants for the effects of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and triglycerides and targets for lipid-modifying drugs were selected from the genome-wide discovery analyses of the UK Biobank. Summary-level data on IAs were obtained from the International Stroke Genetics Consortium. Univariate and multivariate MR analyses were performed. RESULTS: Univariate MR analyses showed that the HDL-C was negatively correlated with IA (odds ratio [OR] = 0.816, 95% confidence interval [CI] = 0.715-0.932, p = 0.003) and ruptured IA (rIA; OR = 0.775, 95% CI = 0.663-0.906, p = 0.001). The multivariate MR-inverse variance weighted analysis showed that the HDL-C was negatively correlated with IA (OR = 0.655, 95% CI = 0.434-0.988, p = 0.043) and rIA (OR = 0.563, 95% CI = 0.347-0.913, p = 0.02), and the LDL-C was negatively correlated with IA (OR = 0.402, 95% CI = 0.191-0.848, p = 0.017) and rIA (OR = 0.376, 95% CI = 0.160-0.883, p = 0.025). Using genetic proxies of known lipid-modifying drugs, we found that the increased HDL-C with cholesterol ester transfer protein proxies was associated with a decreased risk of rIA (OR = 0.852, 95% CI = 0.747-0.973, p = 0.018), and the decreased LDL-C with 3-hydroxy-3-methylglutaryl-coenzyme A reductase proxies was associated with increased risk of IA (OR = 1.772, 95% CI = 1.080-2.908, p = 0.024) and rIA (OR = 1.856, 95% CI = 1.022-3.371, p = 0.042). CONCLUSIONS: Genetically determined HDL-C and LDL-C reduce the risk of IA and rIA. The effects of different lipid-modifying drugs on IA need to be further investigated.

MnCO3@BSA-ICG nanoparticles as a magnetic resonance/photoacoustic dual-modal contrast agent for functional imaging of acute ischemic stroke.

Timely and accurate diagnosis of acute ischemic stroke (AIS) and simultaneous functional imaging of cerebral oxygen saturation (sO2) are essential to improve the survival rate of stroke patients but remains challenging. Herein, we developed a pH-responsive manganese (Mn)-based nanoplatform as a magnetic resonance/photoacoustic (MR/PA) dual-modal contrast agent for AIS diagnosis. The Mn-based nanoplatform was prepared via a simple and green biomimetic method using bovine serum albumin (BSA) as a scaffold for fabrication of MnCO3 NPs as the T1 MR contrast agent and accommodation of indocyanine green (ICG) as the PA probe. The obtained MnCO3@BSA-ICG NPs were biocompatible and exhibited a pH-responsive longitudinal relaxation rate and a concentration-dependent PA signal. In vivo MR/PA dual-modal imaging demonstrated that MnCO3@BSA-ICG NPs quickly and efficiently led to the MR/PA contrast enhancements in the infarcted area while not in the normal region, allowing a timely and accurate diagnosis of AIS. Moreover, PA imaging could directly monitor the sO2 level, enabling a functional imaging of AIS. Therefore, MnCO3@BSA-ICG NPs could be applied as a potential MR/PA contrast agent for timely and functional imaging of AIS.

Design and validation of a recognition instrument-the stroke aid for emergency scale-to predict large vessel occlusion stroke.

BACKGROUND AND PURPOSE: Rapidly recognizing patients with large-vessel occlusion stroke (LVOS) and transferring them to a center offering recanalization therapy is crucial of maximizing the benefits of early treatment. We therefore aimed to design an easy-to-use recognition instrument for identifying LVOS. METHODS: Prospective data were collected from emergency departments of 12 stroke-center hospitals in China during a 17-month study period. The Stroke Aid for Emergency (SAFE) scale is based on consciousness commands, facial palsy, gaze, and arm motor ability. Receiver operating characteristic analysis was used to obtain the area under the curve for the SAFE scale and previously established scales to predict LVOS. RESULTS: The SAFE scale could accurately predict LVOS at an accuracy rate comparable to that of the National Institutes of Health Stroke Scale (c-statistics: 0.823 versus 0.831, p = 0.4798). The sensitivity, specificity, positive predictive value, and negative predictive value for the SAFE scale were 0.6875, 0.8577, 0.6937, and 0.8542, respectively, with a cutoff point of 4. The SAFE scale also performed well in a subgroup analysis based on the patients' ages, occluded vessel locations, and the onset-to-door times. CONCLUSIONS: The SAFE scale can accurately recognize LVOS at a rate comparable to those of other, similar scales.

Impact of ambient temperature exposure on newborns with low Apgar scores in northwest China.

In the context of global climate change, research efforts were focused on the association of ambient temperatures on maternal and neonatal health condition, but few have examined associations with low Apgar scores. From January 1, 2017, to December 31, 2018, all singleton deliveries of Ningxia Hui Autonomous Region were extracted from the Hospital Information System (N = 182,322). Daily temperature data were obtained from the official website of China Meteorological Administration. Low Apgar scores were defined as Apgar score ≤ 3 at 5 min in the present study. Logistic regression models were used to estimate the adjusted association between prenatal temperature exposure and low Apgar scores. Restricted cubic spline models were used to explore the dose-response relationship between temperature and low Apgar scores. The study population included 182,322 live singleton births, with 1575 (0.86%) cases of low Apgar scores. The elevated ambient temperature in different exposure timing windows in late pregnancy was associated with increased risk of low Apgar scores. As compared to moderate (10th-90th) temperature exposure, prenatal exposure to extreme hot (>90th) was associated with 13.9-47.0% increased risk of low Apgar scores, while non-significant relationship was found between extreme cold (<10th) exposure and low Apgar scores. The restricted cubic spline models showed a U-shaped relationship between prenatal temperature exposure and low Apgar scores (P for non-linearity < 0.05). Exposure to high ambient temperature during late pregnancy is associated with an increased risk of low Apgar scores in northwest China.

Physcion Protects Rats Against Cerebral Ischemia-Reperfusion Injury via Inhibition of TLR4/NF-kB Signaling Pathway.

BACKGROUND: Ischemic stroke (IS) is characterized by the rapid loss of brain function due to ischemia. Physcion has been found to have a neuroprotective effect against cerebral ischemia-reperfusion (I/R) injury. However, the mechanism by which physcion regulates cerebral I/R injury remains largely unknown. METHODS: An oxygen-glucose deprivation/reperfusion (OGD/R) model in SH-SY5Y cells and a rat cerebral ischemia-reperfusion (I/R) model were established, respectively. CCK-8 and flow cytometry assays were used to detect the viability and apoptosis of SH-SY5Y cells. Moreover, enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of SOD, MDA, GSH-Px, TNF-α, IL-1ß, IL-6 and IL-10 in the supernatant of SH-SY5Y cells. Meanwhile, Western blot assay was used to detect the expressions of TLR4, p-p65 and p-IκB in SH-SY5Y cells and I/R rats. RESULTS: In this study, physcion treatment significantly rescued OGD/R-induced neuronal injury. In addition, physcion decreased inflammatory response in SH-SY5Y cells after OGD/R insult, as shown by the decreased levels of the pro-inflammatory factors TNF-α, IL-1ß, IL-6 and IL-10. Moreover, physcion attenuated the oxidative stress in OGD/R-treated SY-SY5Y cells, as evidenced by the increased SOD and GSH levels and the decreased ROS and MDA levels. Meanwhile, physcion significantly reduced cerebral infarction, attenuated neuronal injury and apoptosis in I/R rats. Furthermore, physcion markedly decreased the expressions of TLR4, p-NF-κB p65 and p-IκB in the brain tissues of rats subjected to I/R and in SH-SY5Y cells exposed to OGD/R. CONCLUSION: In conclusion, our study indicated that physcion protected neuron cells against I/R injury in vitro and in vivo by inhibition of the TLR4/NF-kB pathway; thus, physcion might serve as a promising therapeutic candidate for IS.

Associations between haemodynamics and wall enhancement of intracranial aneurysm.

BACKGROUND AND PURPOSE: Previous studies have reported about inflammation processes (IPs) that play important roles in aneurysm formation and rupture, which could be driven by blood flow. IPs can be identified using aneurysmal wall enhancement (AWE) on high-resolution black-blood MRI (BB-MRI) and blood flow haemodynamics can be demonstrated by four-dimensional-flow MRI (4D-flow MRI). Thus, this study investigated the associations between AWE and haemodynamics in unruptured intracranial aneurysms (IA) by combining 4D-flow MRI and high-resolution BB-MRI. MATERIALS AND METHODS: Between April 2014 and October 2017, 48 patients with 49 unruptured IA who underwent both 4D-flow MRI and high-resolution BB-MRI were retrospectively included in this study. The haemodynamic parameters demonstrated using 4D-flow MRI were compared between different AWE patterns using the Kruskal-Wallis test and ordinal regression. RESULTS: The results of Kruskal-Wallis test showed that the average wall shear stress in the IA (WSSavg-IA), maximum through-plane velocity in the adjacent parent artery, inflow jet patterns and the average vorticity in IA (vorticityavg-IA) were significantly associated with the AWE patterns. Ordinal regression analysis identified WSSavg-IA (p=0.002) and vorticityavg-IA (p=0.033) as independent predictors of AWE patterns. CONCLUSION: A low WSS and low average vorticity were independently associated with a high AWE grade for IAs larger than 4 mm. Therefore, WSS and average vorticity could predict AWE and circumferential AWE.

Clinical application values of neutrophil-to-lymphocyte ratio in intracranial aneurysms.

Inflammation plays an important role in the pathogenesis and growth of intracranial aneurysms (IAs). We investigated the clinical value of the neutrophil-to-lymphocyte ratio (NLR) as a marker of systemic subclinical inflammation in patients with IAs. Consecutive patients with IAs who underwent endovascular treatment (EVT) were enrolled in the study. The evaluation indicators were aneurysm size and rupture, a poor outcome at 3 to 6 months, and delayed cerebral ischemia (DCI) during hospitalization. In total, 532 patients with IAs underwent EVT (mean age, 54.0 years; 62.4% female). Among patients with ruptured IAs, those with a higher NLR had an increased risk of a poor outcome at 3 to 6 months and DCI during hospitalization than those with a lower NLR. A higher NLR was significantly more strongly associated with the size of unruptured aneurysms and aneurysm rupture than a lower NLR. The NLR and C-reactive protein concentration showed similar predictive ability for aneurysm size and treatment prognosis. The NLR was lower at discharge than admission for patients with ruptured IAs and DCI. An elevated NLR was significantly associated with the size of unruptured IAs, an increased risk of a poor outcome, and DCI in patients with ruptured IAs.

Med23 serves as a gatekeeper of the myeloid potential of hematopoietic stem cells.

In response to myeloablative stresses, HSCs are rapidly activated to replenish myeloid progenitors, while maintaining full potential of self-renewal to ensure life-long hematopoiesis. However, the key factors that orchestrate HSC activities during physiological stresses remain largely unknown. Here we report that Med23 controls the myeloid potential of activated HSCs. Ablation of Med23 in hematopoietic system leads to lymphocytopenia. Med23-deficient HSCs undergo myeloid-biased differentiation and lose the self-renewal capacity. Interestingly, Med23-deficient HSCs are much easier to be activated in response to physiological stresses. Mechanistically, Med23 plays essential roles in maintaining stemness genes expression and suppressing myeloid lineage genes expression. Med23 is downregulated in HSCs and Med23 deletion results in better survival under myeloablative stress. Altogether, our findings identify Med23 as a gatekeeper of myeloid potential of HSCs, thus providing unique insights into the relationship among Med23-mediated transcriptional regulations, the myeloid potential of HSCs and HSC activation upon stresses.

The Prevalence of Sleep Disturbance and Its Socio-demographic and Clinical Correlates in First-episode Individuals With Schizophrenia in Rural China.

PURPOSE: This study aimed to determine the prevalence and the socio-demographic and clinical correlates of sleep disturbance in first-episode individuals with schizophrenia in rural China and the factors that impact sleep among individuals with schizophrenia. DESIGN AND METHODS: A total of 104 first-episode individuals with schizophrenia were randomly selected in rural areas in Ningxia, China, in 2015 as the study sample. FINDINGS: In first-episode individuals with schizophrenia, the prevalence of sleep disturbance was 78.8% (82/104). Sleep disturbance was significantly associated with economic status, living situation, educational level, depressive symptoms, and anxiety symptoms. PRACTICE IMPLICATIONS: Sleep disturbance is common in first-episode individuals with schizophrenia in rural China and more attention should be paid in clinical practice to improve the sleep quality for individuals with schizophrenia.

Uhrf1 controls the self-renewal versus differentiation of hematopoietic stem cells by epigenetically regulating the cell-division modes.

Hematopoietic stem cells (HSCs) are able to both self-renew and differentiate. However, how individual HSC makes the decision between self-renewal and differentiation remains largely unknown. Here we report that ablation of the key epigenetic regulator Uhrf1 in the hematopoietic system depletes the HSC pool, leading to hematopoietic failure and lethality. Uhrf1-deficient HSCs display normal survival and proliferation, yet undergo erythroid-biased differentiation at the expense of self-renewal capacity. Notably, Uhrf1 is required for the establishment of DNA methylation patterns of erythroid-specific genes during HSC division. The expression of these genes is enhanced in the absence of Uhrf1, which disrupts the HSC-division modes by promoting the symmetric differentiation and suppressing the symmetric self-renewal. Moreover, overexpression of one of the up-regulated genes, Gata1, in HSCs is sufficient to phenocopy Uhrf1-deficient HSCs, which show impaired HSC symmetric self-renewal and increased differentiation commitment. Taken together, our findings suggest that Uhrf1 controls the self-renewal versus differentiation of HSC through epigenetically regulating the cell-division modes, thus providing unique insights into the relationship among Uhrf1-mediated DNA methylation, cell-division mode, and HSC fate decision.

Disruption of the RAG2 zinc finger motif impairs protein stability and causes immunodeficiency.

Although the RAG2 core domain is the minimal region required for V(D)J recombination, the noncore region also plays important roles in the regulation of recombination, and mutations in this region are often related to severe combined immunodeficiency. A complete understanding of the functions of the RAG2 noncore region and the potential contributions of its individual residues has not yet been achieved. Here, we show that the zinc finger motif within the noncore region of RAG2 is indispensable for maintaining the stability of the RAG2 protein. The zinc finger motif in the noncore region of RAG2 is highly conserved from zebrafish to humans. Knock-in mice carrying a zinc finger mutation (C478Y) exhibit decreased V(D)J recombination efficiency and serious impairment in T/B-cell development due to RAG2 instability. Further studies also reveal the importance of the zinc finger motif for RAG2 stability. Moreover, mice harboring a RAG2 noncore region mutation (N474S), which is located near C478 but is not zinc-binding, exhibit no impairment in either RAG2 stability or T/B-cell development. Taken together, our findings contribute to defining critical functions of the RAG2 zinc finger motif and provide insights into the relationships between the mutations within this motif and immunodeficiency diseases.

Prognostic significance of IDH mutation in adult low-grade gliomas: a meta-analysis.

Mutations in the gene encoding isocitrate dehydrogenase (IDH) have been identified in approximately 65-90 % of low-grade gliomas (LGGs). Various studies examining the relationship between IDH mutation with the clinical outcome in patients with LGGs have yielded inconclusive results. The purpose of the present meta-analysis of literature is to determine this effect. We conducted a meta-analysis of 10 studies (937 patients) that evaluated the correlation between IDH mutation and overall survival (OS). For the quantitative aggregation of the survival results, the IDH mutation effect was measured by hazard ratio (HR). Overall, the pooled HR was 0.585 (95 % CI, 0.376-0.911, p = 0.025, random effect model) for patients with IDH mutation vs patients without IDH mutation. IDH mutation was associated with better overall survival of LGGs. At least this trend was observed in our analysis.