Search

Traditional cancer treatments use nonspecific drugs and monoclonal antibodies to target tumor cells. Chimeric antigen receptor (CAR)-T cell therapy, however, leverages the immune system's T-cells to recognize and attack tumor cells. T-cells are isolated from patients and modified to target tumor-associated antigens. CAR-T therapy has achieved FDA approval for treating blood cancers like B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma by targeting CD-19 and B-cell maturation antigens. Bi-specific chimeric antigen receptors may contribute to mitigating tumor antigen escape, but their efficacy could be limited in cases where certain tumor cells do not express the targeted antigens. Despite success in blood cancers, CAR-T technology faces challenges in solid tumors, including lack of reliable tumor-associated antigens, hypoxic cores, immunosuppressive tumor environments, enhanced reactive oxygen species, and decreased T-cell infiltration. To overcome these challenges, current research aims to identify reliable tumor-associated antigens and develop cost-effective, tumor microenvironment-specific CAR-T cells. This review covers the evolution of CAR-T therapy against various tumors, including hematological and solid tumors, highlights challenges faced by CAR-T cell therapy, and suggests strategies to overcome these obstacles, such as utilizing single-cell RNA sequencing and artificial intelligence to optimize clinical-grade CAR-T cells.

Abstract Aims Prognosis for ST‐segment elevation myocardial infarction (STEMI) is worse when heart failure is present on admission. Understanding clinical practice in different health systems can identify areas for quality improvement initiatives to improve outcomes. In the absence of international comparison studies, we aimed to compare treatments and in‐hospital outcomes of patients admitted with ST elevation myocardial infarction (STEMI) by heart failure status in two healthcare‐wide cohorts. Methods and results We used two nationwide databases to capture admissions with STEMI in the United Kingdom (Myocardial ischemia National Audit Project, MINAP) and Japan (Japanese Registry of All Cardiac and Vascular Diseases‐Diagnostic Procedure Combination, JROAD‐DPC) between 2012 and 2017. Participants were stratified using the HF Killip classification into three groups; Killip 1: no congestive heart failure, Killip 2–3: congestive heart failure, Killip 4: cardiogenic shock. We calculated crude rate and case mix standardized risk ratios (CSRR) for use of treatments and in‐hospital death. Patients were younger in the United Kingdom (65.4 [13.6] vs. 69.1 [13.0] years) and more likely to have co‐morbidities in the United Kingdom except for diabetes and hypertension. Japan had a higher percentage of heart failure and cardiogenic shock patients among STEMI during admission than that in the United Kingdom. Primary percutaneous coronary intervention (pPCI) rates were lower in the United Kingdom compared with Japan, especially for patients presenting with Killip 2–3 class heart failure (pPCI use in patients with Killip 1, 2–3, 4: Japan, 86.2%, 81.7%, 78.7%; United Kingdom, 79.6%, 58.2% and 79.9%). In contrast, beta‐blocker use was consistently lower in Japan than in the United Kingdom (61.4% vs. 90.2%) across Killip classifications and length of hospital stay longer (17.0 [9.7] vs. 5.0 [7.4] days). The crude rate of in‐hospital mortality increased with increasing Killip class group. Both the crude rate and CSRR was higher in the United Kingdom compared with Japan for Killip 2–3 (15.8% vs. 6.4%, CSRR 1.80 95% CI 1.73–1.87, P

CD19-directed immunotherapies are clinically effective for treating B cell malignancies but also cause a high incidence of neurotoxicity. A subset of patients treated with chimeric antigen receptor (CAR) T cells or bispecific T cell engager (BiTE) antibodies display severe neurotoxicity, including fatal cerebral edema associated with T cell infiltration into the brain. Here, we report that mural cells, which surround the endothelium and are critical for blood-brain-barrier integrity, express CD19. We identify CD19 expression in brain mural cells using single-cell RNA sequencing data and confirm perivascular staining at the protein level. CD19 expression in the brain begins early in development alongside the emergence of mural cell lineages and persists throughout adulthood across brain regions. Mouse mural cells demonstrate lower levels of Cd19 expression, suggesting limitations in preclinical animal models of neurotoxicity. These data suggest an on-target mechanism for neurotoxicity in CD19-directed therapies and highlight the utility of human single-cell atlases for designing immunotherapies.

INTRODUCTION: Regional glucose hypometabolism resulting in glutamate loss has been shown as one of the characteristics of Alzheimer's disease (AD). Because the impact of AD varies between the sexes, we utilized glutamate‐weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) for high‐resolution spatial mapping of cerebral glutamate and investigated subregional changes in a sex‐specific manner. METHODS: Eight‐month‐old male and female AD mice harboring mutant amyloid precursor protein (APPNL‐F/NL‐F: n = 36) and wild‐type (WT: n = 39) mice underwent GluCEST MRI, followed by proton magnetic resonance spectroscopy (1H‐MRS) in hippocampus and thalamus/hypothalamus using 9.4T preclinical MR scanner. RESULTS: GluCEST measurements revealed significant (p ≤ 0.02) glutamate loss in the entorhinal cortex (% change ± standard error: 8.73 ± 2.12%), hippocampus (11.29 ± 2.41%), and hippocampal fimbriae (19.15 ± 2.95%) of male AD mice. A similar loss of hippocampal glutamate in male AD mice (11.22 ± 2.33%; p = 0.01) was also observed in 1H‐MRS. DISCUSSIONS: GluCEST MRI detected glutamate reductions in the fimbria and entorhinal cortex of male AD mice, which was not reported previously. Resilience in female AD mice against these changes indicates an intact status of cerebral energy metabolism. Highlights: Glutamate levels were monitored in different brain regions of early‐stage Alzheimer's disease (AD) and wild‐type male and female mice using glutamate‐weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI). Male AD mice exhibited significant glutamate loss in the hippocampus, entorhinal cortex, and the fimbriae of the hippocampus. Interestingly, female AD mice did not have any glutamate loss in any brain region and should be investigated further to find the probable cause. These findings demonstrate previously unreported sex‐specific glutamate changes in hippocampal sub‐regions using high‐resolution GluCEST MRI. [ABSTRACT FROM AUTHOR]

Background and aimsMinimal hepatic encephalopathy (MHE) is the mildest form of hepatic encephalopathy (HE) and is characterized by deficits in neurocognitive performance without any clinical symptoms of HE. In the current study, we aim to evaluate and compare the neurocognitive, biochemical, and brain magnetic resonance (MR) imaging changes between patients with cirrhotic MHE and extrahepatic portal vein obstruction (EHPVO) MHE.MethodsThirty-three cirrhotic and 14 EHPVO patients were diagnosed with MHE and were included in the analysis along with 24 normal healthy volunteers. All subjects underwent MR imaging including diffusion tensor imaging and proton MR spectroscopy (1 H-MRS) followed by cognitive assessments, critical flicker frequency (CFF) measurements, quantification of blood ammonia, and serum proinflammatory cytokine levels.ResultsWe observed abnormal neurocognitive functions and CFF measurements in both cirrhotic MHE and EHPVO MHE patients as compared with controls. Significantly increased blood ammonia, serum proinflammatory cytokines (IL-6, TNF-α) level, mean diffusivity in multiple brain sites, 1 H-MRS derived glutamate/glutamine (Glx)/creatine (Cr), and significantly decreased 1 H-MRS derived myo-inositol/Cr were observed in both cirrhotic MHE and EHPVO MHE compared with those of controls. Choline/Cr level was significantly decreased in cirrhotic MHE as compared with controls and EHPVO MHE.ConclusionsCirrhotic MHE showed more severe changes on mean diffusivity in multiple brain sites and inflammation as compared with EHPVO MHE. This study confirms that there are significant difference in neurocognitive, biochemical, and MR profile between cirrhotic MHE and EHPVO MHE, which may help to understand the pathophysiologies of these two types of MHE and may contribute to improve their clinical managements.

Background Chronic kidney disease (CKD) is a major global health problem and its early identification would allow timely intervention to reduce complications. We performed a systematic review and meta-analysis of multivariable prediction models derived and/or validated in community-based electronic health records (EHRs) for the prediction of incident CKD in the community. Methods Ovid Medline and Ovid Embase were searched for records from 1947 to 31 January 2024. Measures of discrimination were extracted and pooled by Bayesian meta-analysis, with heterogeneity assessed through a 95% prediction interval (PI). Risk of bias was assessed using Prediction model Risk Of Bias ASsessment Tool (PROBAST) and certainty in effect estimates by Grading of Recommendations, Assessment, Development and Evaluation (GRADE). Results Seven studies met inclusion criteria, describing 12 prediction models, with two eligible for meta-analysis including 2 173 202 patients. The Chronic Kidney Disease Prognosis Consortium (CKD-PC) (summary c-statistic 0.847; 95% CI 0.827–0.867; 95% PI 0.780–0.905) and SCreening for Occult REnal Disease (SCORED) (summary c-statistic 0.811; 95% CI 0.691–0.926; 95% PI 0.514–0.992) models had good model discrimination performance. Risk of bias was high in 64% of models, and driven by the analysis domain. No model met eligibility for meta-analysis if studies at high risk of bias were excluded, and certainty of effect estimates was 'low'. No clinical utility analyses or clinical impact studies were found for any of the models. Conclusions Models derived and/or externally validated for prediction of incident CKD in community-based EHRs demonstrate good prediction performance, but assessment of clinical usefulness is limited by high risk of bias, low certainty of evidence and a lack of impact studies. [ABSTRACT FROM AUTHOR]

BackgroundAcute-on-chronic liver failure (ACLF) is a form of liver disease with high short-term mortality. ACLF offers considerable potential to affect the cortical areas by significant tissue injury due to loss of neurons and other supporting cells. We measured changes in cortical thickness and metabolites profile in ACLF patients following treatment, and compared it with those of age matched healthy volunteers.MethodsFor the cortical thickness analysis we performed whole brain high resolution T1-weighted magnetic resonance imaging (MRI) on 15 ACLF and 10 healthy volunteers at 3T clinical MR scanner. Proton MR Spectroscopy ((1)H MRS) was also performed to measure level of altered metabolites. Out of 15 ACLF patients 10 survived and underwent follow-up study after clinical recovery at 3 weeks. FreeSurfer program was used to quantify cortical thickness and LC- Model software was used to quantify absolute metabolites concentrations. Neuropsychological (NP) test was performed to assess the cognitive performance in follow-up ACLF patients compared to controls.ResultsSignificantly reduced cortical thicknesses in multiple brain sites, and significantly decreased N-acetyl aspartate (NAA), myo-inositol (mI) and significantly increased glutamate/glutamine (glx) metabolites were observed in ACLF compared to those of controls at baseline study. Follow-up patients showed significant recovery in cortical thickness and Glx level, while NAA and mI were partially recovered compared to baseline study. When compared to controls, follow-up patients still showed reduced cortical thickness and altered metabolites level. Follow-up patients had abnormal neuropsychological (NP) scores compared to controls.ConclusionsNeuronal loss as suggested by the reduced NAA, decreased cellular density due to increased cerebral hyperammonemia as supported by the increased glx level, and increased proinflammatory cytokines and free radicals may account for the reduced cortical thickness in ACLF patients. Presence of reduced cortical thickness, altered metabolites and abnormal NP test scores in post recovery subjects as compared to those of controls is associated with incomplete clinical recovery. The current imaging protocol can be easily implemented in clinical settings to evaluate and monitor brain tissue changes in patients with ACLF during the course of treatment.

The present study intends to explore the overall research performance/engagement of the faculty members on the ResearchGate from the Physics discipline working at Indian Central Universities. The analyzed data revealed that 473 faculty members were found, but only 361 (i.e., 76.32%) have their profile on ResearchGate. Further analyses include the distribution of RG metrices which indicated that 98.89% and 98.06% of the faculty members had added at least one research item and at least one full-text research item over the RG, respectively. The findings stated that Kriti Ranjan from the University of Delhi secured highest ranking across all metrices, except followers and followings. The mean value for the Reads and Citations were found to be 27525.59 (std. dev. = 163029.86) and 1555.2 (std. dev. = 5838.76), respectively. In addition, RI Score exhibits a strong positive correlation with other RG-based metrices excluding the ‘following’. This study can be considered the only ResearchGate analyses that has included the working researchers of the Physics discipline by analyzing their research engagement and active presence over it. [ABSTRACT FROM AUTHOR]

ATP derived from the conversion of phosphocreatine to creatine by creatine kinase provides an essential chemical energy source that governs myocardial contraction. Here, we demonstrate that the exchange of amine [...]

Glutamate, a major neurotransmitter in the brain, shows a pH-and concentration-dependent chemical exchange saturation transfer effect (GluCEST) between its amine group and bulk water, with potential for in vivo imaging [...]