Clinical efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapy for relapsed/refractory multiple myeloma: a systematic review and meta-analysis

BackgroundThe low rates of durable response against relapsed/refractory multiple myeloma (RRMM) in recent studies prompt that chimeric antigen receptor (CAR)-T cell therapies are yet to be optimized. The combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high clinical efficacy in several clinical trials for RRMM. We here conducted a meta-analysis to confirm its efficacy and safety.MethodsWe collected data from Embase, Web of Science, PubMed, CNKI, Wanfang and Cochrane databases up to April 2023. We extracted and evaluated data related to the efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapies in RRMM patients. The data was then analyzed using RevMan5.4 and StataSE-64 software. PROSPERO number was CRD42023455002.ResultsOur meta-analysis included 12 relevant clinical trials involving 347 RRMM patients who were treated with combined anti-BCMA and anti-CD19 CAR-T cell therapies. For efficacy assessment, the pooled overall response rate (ORR) was 94% (95% CI: 91%-98%), the complete response rate (CRR) was 50% (95% CI: 29%-71%), and the minimal residual disease (MRD) negativity rate within responders was 73% (95% CI: 66%-80%). In terms of safety, the pooled all-grade cytokine release syndrome (CRS) rate was 98% (95% CI: 97%-100%), grade≥3 CRS rate was 9% (95% CI: 4%-14%), and the incidence of neurotoxicity was 8% (95% CI: 4%-11%). Of hematologic toxicity, neutropenia was 82% (95% CI: 75%-89%), anemia was 71% (95% CI: 53%-90%), thrombocytopenia was 67% (95% CI: 40%-93%) and infection was 42% (95% CI: 9%-76%). The median progression-free survival (PFS) was 12.97 months (95% CI: 6.02-19.91), and the median overall survival (OS) was 26.63 months (95% CI: 8.14-45.11).ConclusionsAs a novel immunotherapy strategy with great potential, the combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high efficacy in RRMM, but its safety needs further improvement. This meta-analysis suggests possible optimization of combined CAR-T therapy.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023455002

Long-term effectiveness of a gambling intervention program among children in central Illinois.

Youth gambling is an increasing concern. As a response, the "Don't Gamble Away our Future (DGAOF)" program has been implemented among children in central Illinois. We aim to assess the long-term effectiveness of this school-based youth gambling prevention program in Illinois using the data from 2005 to 2009. The intervention included interactive PowerPoint presentations and prevention materials in parent packets. Students aged 8 to 18 years were eligible to participate in the intervention and the questionnaire pre-post knowledge tests (total score 0-9). Students in 5th grade and above also received a gambling behavior screen test using the Modified South Oaks Gambling Screening for Teens (MSOGST) for identifying probable gamblers. Multivariable generalized mixed models were conducted to detect the effects of a 5-year youth gambling prevention program as controlling potential confounders. A total of 16,262 and 16,421 students completed pre-post tests and MSOGST tests, respectively. Of 16,262, half were female, the majority (76.1%) were from senior high school, and 21.3% received the intervention at least twice. The median gap between interventions was 368 days. Students receiving multiple interventions had higher scores on the pre-test as compared to those receiving a single intervention (P<0.001 for all comparisons among groups), and they demonstrated an increasing trend of awareness about gambling over time (P<0.001 for multiple interventions; P = 0.538 for single intervention). The prevalence of problem gambling had decreased among students receiving the intervention twice as compared to receiving the intervention once (7.9% versus 9.4%; OR = 0.89, 95% CL: 0.82-0.97). However, this effect was not confirmed among students receiving the intervention three or more times. In conclusion, the DGAOF program has demonstrated a positive long-term impact on increasing gambling knowledge and partially reducing pathological gamblers through direct training. It suggests that multiple repeated interventions are important for youth gambling prevention

Expression of RhoC and its regulators RhoGDIbeta, RhoGDIgama and their clinical importance in lung squamous cell cancer and adenocarcinoma

Background and objective It has been proven that RhoC is known to be overexpressed in tumor. The activities of RhoC are negatively regulated by guanine nucleotide dissociation inhibitor beta,gama(GDIbeta,gama), but its role in cancer is quite limited. The purpose of the study is to investigate the expression of RhoC, RhoGDIbeta, RhoGDIgama and analyze the correlation between RhoC and RhoGDIbeta RhoGDIgama expression and clinic implication. Methods Western blot and RT-PCR were used to detect RhoC, RhoGDIbeta and RhoGDIgama protein and mRNA, respectively in 40 lung cancer tissues. Results The expression levels of RhoC, RhoGDIbeta and RhoGDIgama protein and mRNA were more remarkably higher in all tumor samples than those in the normal tissues. The expression levels of RhoC and RhoGDIgama positively correlated with clinical TNM staging, lymph node metastasis (r=0.659, P<0.05)(r=0.597, P<0.05), and the expression levels of RhoGDIβ negatively correlate with clinical TNM staging, lymph node metastasis (r=-0.621, P<0.05). Conclusion RhoC, RhoGDIbeta and RhoGDIgama are correlated with clinical TNM staging and may be correlated with lymph node metastasis of lung cancer

Long Non-Coding RNA MALAT1 Decreases the Sensitivity of Resistant Glioblastoma Cell Lines to Temozolomide

Background/Aim: Multidrug resistance (MDR) is largely responsible for the failure of chemotherapy. The long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript (MALAT1) has been reported to be closely related to tumor biology. In the present study, whether MALAT1 contributes to the resistance of glioblastoma cell lines to temozolomide (TMZ) was investigated. Methods: The glioblastoma cell lines U251 and U87 were exposed to increasing concentrations of TMZ to generate TMZ-resistant colonies (the U251/TMZ and U87/TMZ cell lines). The expression levels of MALAT1 and proteins related to epithelial-mesenchymal transition (EMT) were detected by real-time PCR and western blot, respectively. After the transfection of si-MALAT1 or pcDNA-MALAT1, cell viability, mRNA expression of MDR-associated proteins (MDR1, MRP5 and LRP1), and protein expression of EMT related proteins (ZEB1, Snail and SLUG) were evaluated. Results: The expression of MALAT1 was upregulated in the U251/TMZ and U87/TMZ cell lines compared to that in U251 and U87 cell lines, respectively. The treatment of si-MALAT1 decreased MDR1, MRP5, and LRP1 expression, enhanced cell sensitivity to TMZ, and downregulated ZEB1 protein expression, whereas pcDNA-MALAT1 had the opposite effects. However, the effects of si-MALAT1 on MDR -associated protein expression, cell viability, and EMT status were reversed by the transfection of pcDNA-ZEB1, and the effects of pcDNA-MALAT1 were reversed by the transfection of si-ZEB1. In vivo, MALAT1 overexpression enhanced tumors’ TMZ resistance and upregulated ZEB1 expression. Conclusion: MALAT1 decreased the sensitivity of resistant glioma cell lines to TMZ by regulating ZEB1

Image_1_Clinical efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapy for relapsed/refractory multiple myeloma: a systematic review and meta-analysis.tif

BackgroundThe low rates of durable response against relapsed/refractory multiple myeloma (RRMM) in recent studies prompt that chimeric antigen receptor (CAR)-T cell therapies are yet to be optimized. The combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high clinical efficacy in several clinical trials for RRMM. We here conducted a meta-analysis to confirm its efficacy and safety.MethodsWe collected data from Embase, Web of Science, PubMed, CNKI, Wanfang and Cochrane databases up to April 2023. We extracted and evaluated data related to the efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapies in RRMM patients. The data was then analyzed using RevMan5.4 and StataSE-64 software. PROSPERO number was CRD42023455002.ResultsOur meta-analysis included 12 relevant clinical trials involving 347 RRMM patients who were treated with combined anti-BCMA and anti-CD19 CAR-T cell therapies. For efficacy assessment, the pooled overall response rate (ORR) was 94% (95% CI: 91%-98%), the complete response rate (CRR) was 50% (95% CI: 29%-71%), and the minimal residual disease (MRD) negativity rate within responders was 73% (95% CI: 66%-80%). In terms of safety, the pooled all-grade cytokine release syndrome (CRS) rate was 98% (95% CI: 97%-100%), grade≥3 CRS rate was 9% (95% CI: 4%-14%), and the incidence of neurotoxicity was 8% (95% CI: 4%-11%). Of hematologic toxicity, neutropenia was 82% (95% CI: 75%-89%), anemia was 71% (95% CI: 53%-90%), thrombocytopenia was 67% (95% CI: 40%-93%) and infection was 42% (95% CI: 9%-76%). The median progression-free survival (PFS) was 12.97 months (95% CI: 6.02-19.91), and the median overall survival (OS) was 26.63 months (95% CI: 8.14-45.11).ConclusionsAs a novel immunotherapy strategy with great potential, the combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high efficacy in RRMM, but its safety needs further improvement. This meta-analysis suggests possible optimization of combined CAR-T therapy.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023455002.</p

Image_2_Clinical efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapy for relapsed/refractory multiple myeloma: a systematic review and meta-analysis.tif

BackgroundThe low rates of durable response against relapsed/refractory multiple myeloma (RRMM) in recent studies prompt that chimeric antigen receptor (CAR)-T cell therapies are yet to be optimized. The combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high clinical efficacy in several clinical trials for RRMM. We here conducted a meta-analysis to confirm its efficacy and safety.MethodsWe collected data from Embase, Web of Science, PubMed, CNKI, Wanfang and Cochrane databases up to April 2023. We extracted and evaluated data related to the efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapies in RRMM patients. The data was then analyzed using RevMan5.4 and StataSE-64 software. PROSPERO number was CRD42023455002.ResultsOur meta-analysis included 12 relevant clinical trials involving 347 RRMM patients who were treated with combined anti-BCMA and anti-CD19 CAR-T cell therapies. For efficacy assessment, the pooled overall response rate (ORR) was 94% (95% CI: 91%-98%), the complete response rate (CRR) was 50% (95% CI: 29%-71%), and the minimal residual disease (MRD) negativity rate within responders was 73% (95% CI: 66%-80%). In terms of safety, the pooled all-grade cytokine release syndrome (CRS) rate was 98% (95% CI: 97%-100%), grade≥3 CRS rate was 9% (95% CI: 4%-14%), and the incidence of neurotoxicity was 8% (95% CI: 4%-11%). Of hematologic toxicity, neutropenia was 82% (95% CI: 75%-89%), anemia was 71% (95% CI: 53%-90%), thrombocytopenia was 67% (95% CI: 40%-93%) and infection was 42% (95% CI: 9%-76%). The median progression-free survival (PFS) was 12.97 months (95% CI: 6.02-19.91), and the median overall survival (OS) was 26.63 months (95% CI: 8.14-45.11).ConclusionsAs a novel immunotherapy strategy with great potential, the combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high efficacy in RRMM, but its safety needs further improvement. This meta-analysis suggests possible optimization of combined CAR-T therapy.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023455002.</p

Image_3_Clinical efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapy for relapsed/refractory multiple myeloma: a systematic review and meta-analysis.tif

BackgroundThe low rates of durable response against relapsed/refractory multiple myeloma (RRMM) in recent studies prompt that chimeric antigen receptor (CAR)-T cell therapies are yet to be optimized. The combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high clinical efficacy in several clinical trials for RRMM. We here conducted a meta-analysis to confirm its efficacy and safety.MethodsWe collected data from Embase, Web of Science, PubMed, CNKI, Wanfang and Cochrane databases up to April 2023. We extracted and evaluated data related to the efficacy and safety of combined anti-BCMA and anti-CD19 CAR-T cell therapies in RRMM patients. The data was then analyzed using RevMan5.4 and StataSE-64 software. PROSPERO number was CRD42023455002.ResultsOur meta-analysis included 12 relevant clinical trials involving 347 RRMM patients who were treated with combined anti-BCMA and anti-CD19 CAR-T cell therapies. For efficacy assessment, the pooled overall response rate (ORR) was 94% (95% CI: 91%-98%), the complete response rate (CRR) was 50% (95% CI: 29%-71%), and the minimal residual disease (MRD) negativity rate within responders was 73% (95% CI: 66%-80%). In terms of safety, the pooled all-grade cytokine release syndrome (CRS) rate was 98% (95% CI: 97%-100%), grade≥3 CRS rate was 9% (95% CI: 4%-14%), and the incidence of neurotoxicity was 8% (95% CI: 4%-11%). Of hematologic toxicity, neutropenia was 82% (95% CI: 75%-89%), anemia was 71% (95% CI: 53%-90%), thrombocytopenia was 67% (95% CI: 40%-93%) and infection was 42% (95% CI: 9%-76%). The median progression-free survival (PFS) was 12.97 months (95% CI: 6.02-19.91), and the median overall survival (OS) was 26.63 months (95% CI: 8.14-45.11).ConclusionsAs a novel immunotherapy strategy with great potential, the combined anti-BCMA and anti-CD19 CAR-T cell therapy showed high efficacy in RRMM, but its safety needs further improvement. This meta-analysis suggests possible optimization of combined CAR-T therapy.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023455002.</p

A New Ursane-Type Nor-Triterpenoid from the Leaves of Eucommia ulmoides Oliv.

A new ursane-type nortriterpenoid, (11S,12S)-4-methyl-11,12-epoxy-2-hydroxy-3-oxoursa-1,4-dine-28-oic acid &amp;#947;-lactone (1), named ulmoidol A, together with ten known compounds: ulmoidol (2), corosolic acid (3), 2&amp;#945;,3&amp;#945;-dihydroxy-24-nor-4(23),12-oleanadien-28-oic acid (4), oleanolic acid (5), ursolic acid (6), cycloart-3&amp;#946;, 25-diol (7), foliasalacioside B1 (8), (6R,7E,9R)-9-hydroxy-4,7-megastigmadien-3-one-9-O-&amp;#945;-L-arabinopyranosyl-(1&amp;#8594;6)-&amp;#946;-D-glucopyranoside (9), (6R,7E,9R)-9-hydroxy-4,7-megastigma-dien-3-one-9-O-&amp;#946;-D-xylopyranosyl-(1&amp;#8594;6)-&amp;#946;-D-glucopyranoside (10), and quercetin 3-O-sambubioside (11) were isolated from the leaves of Eucommia ulmoides Oliv. The structure of compound 1 was determined by extensive spectroscopic analysis, and its absolute configuration was determined by CD experiments and a computational method. Compounds 3, 4, 7&amp;#8211;10 were isolated from this plant for the first time. Compounds 3 and 4 showed inhibition to PTPIB activities, with IC50 values of 0.69 and 3.98 &amp;#956;M, respectively