Treatment of multiple myeloma: What is the impact on T-cell function?

Treatment of multiple myeloma (MM) has evolved remarkably over the past few decades. Autologous stem cell transplantation, as well as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, has substantially improved the prognosis of patients with MM. Novel therapies, including chimeric antigen receptor-T cells, bispecific T-cell engagers, antibody-drug conjugates, histone deacetylase inhibitors, and nuclear export inhibitors, have provided more options. However, MM remains incurable. T cells are the principal weapons of antitumor immunity, but T cells display a broad spectrum of dysfunctional states during MM. The promising clinical results of T-cell-directed immunotherapies emphasize the significance of enhancing T-cell function in antimyeloma treatment. This review summarizes the potential effects of these antimyeloma agents on T-cell function and discusses possible optimized strategies for MM management by boosting T-cell immunity.

[Related factors and equity of health status among floating population in China based on geographic information system analysis].

OBJECTIVE: To understand the health status, influencing factors and spatial distribution of the Chinese floating population and to evaluate the health equity of the floating population. METHODS: All the data were collected from the 2017 Migrant Population Dynamic Monitoring Survey in China, binary Logistic regression was used to analyze the factors that might affect the health of the floating population, and the concentration index method was used to evaluate the health equity of the floating population. Spatial autocorrelation analyses the spatial aggregation of health status and health equity. RESULTS: The unhealthy rate of the floating population in China was 2.71%. Age and gender show a statistically significant impact on self-rated health; that is, as age increases, the self-rated health of the migrant population gradually deteriorates, and women are more likely to think that they are unhealthy. Fairness analysis shows that the concentration index of the floating population is 0.021 7, the urban household registration floating population is 0.021 6, and the rural household registration floating population is 0.021 9. It is shown that the fairness of the health status of the floating population is biased towards the high-income class, and the rural household registration floating population' s health unfairness is greater than that of the urban household registration migration population. Moreover, Moran' s i=0.211 for self-rated health and Moran' s i=0.291 for the unhealthy rate indicate that self-rated health has a spatial aggregation trend. Moran' s i=0.136 showed the characteristics of spatial clustering, and the two-week prevalence fairness of the floating population was mainly in the northern and southeastern coastal areas. CONCLUSION: In general, the health status of the floating population in China is relatively good. The main influencing factors of health included gender and age. The central tendency of health inequity is reflected in the southeast coastal and northern regions, which are characterized by poverty. Attention to spatial aggregation is not only helpful to analyze the reasons of floating population, but also to study the health differences between different regions and health-related factors, to improve the overall health level of the whole population.

Sex differences in diabetes­induced hepatic and renal damage.

Diabetes mellitus (DM) is a disease that affects millions of individuals worldwide and is characterized by abnormal glucose metabolism that can induce severe damage to numerous organs throughout the body. Sex differences have been demonstrated in a number of factors associated with diabetes and its complications, such as diabetic kidney disease and diabetic liver disease. To investigate the sex differences in DM further, the changes in the weight, food and water intake, and blood sugar of mice were recorded for 8 weeks in the present study. Hematoxylin and eosin staining, Masson's trichrome staining and transmission electron microscopy were used to observe the pathological changes of liver and kidney tissues. There is no significant difference in the water intake and blood glucose concentration between db/db female and male mice was observed. However, sex differences in liver and kidney damage including glomerular injury and hepatic fibrosis were found. In conclusion, the present study characterized the features of liver and kidney damage in db/db mice and indicated that sex differences should be taken into account in experiments using female and male experimental animals. Furthermore, sex differences should be taken into account in the selection of drug interventions in experiments and in clinical drug therapy.

Targeting autophagy overcomes cancer-intrinsic resistance to CAR-T immunotherapy in B-cell malignancies.

BACKGROUND: Chimeric antigen receptor T (CAR-T) therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignancies, but the cancer-intrinsic mechanisms underlying resistance to CAR-T cells remain yet to be fully understood. This study aims to explore the molecular determinants of cancer cell sensitivity to CAR-T cell-mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical efficacy. METHODS: The human whole-genome CRISPR/Cas9-based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR-T-cell-mediated killing. The in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR-T cells. In addition, the specific mechanisms influencing CAR-T cell-mediated cancer clearance were elucidated in mouse and cellular models. RESULTS: The CRISPR/Cas9-based knockout screening showed that the enrichment of autophagy-related genes (ATG3, BECN1, and RB1CC1) provided protection of cancer cells from CD19 CAR-T cell-mediated cytotoxicity. These findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of autophagy. Notably, higher expression of the three autophagy-related proteins in tumor samples was correlated with poorer responsiveness and worse survival in patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T therapy. Bulk RNA sequencing analysis of bone marrow samples from B-cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR-T cell therapy. Pharmacological inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR-T cell-mediated killing in mouse models of both B-cell leukemia and lymphoma. Moreover, our study revealed that cancer-intrinsic autophagy mediates evasion of CAR-T cells via the TNF-α-TNFR1 axis-mediated apoptosis and STAT1/IRF1-induced chemokine signaling activation. CONCLUSIONS: These findings confirm that autophagy signaling in B-cell malignancies is essential for the effective cytotoxic function of CAR-T cells and thereby pave the way for the development of autophagy-targeting strategies to improve the clinical efficacy of CAR-T cell immunotherapy.

Revealing genomic heterogeneity and commonality: A penalized integrative analysis approach accounting for the adjacency structure of measurements.

Advancements in high-throughput genomic technologies have revolutionized the field of disease biomarker identification by providing large-scale genomic data. There is an increasing focus on understanding the relationships among diverse patient groups with distinct disease subtypes and characteristics. Complex diseases exhibit both heterogeneity and shared genomic factors, making it essential to investigate these patterns to accurately detect markers and comprehensively understand the diseases. Integrative analysis has emerged as a promising approach to address this challenge. However, existing studies have been limited by ignoring the adjacency structure of genomic measurements, such as single nucleotide polymorphisms (SNPs) and DNA methylations. In this study, we propose a structured integrative analysis method that incorporates a spline type penalty to accommodate this adjacency structure. We utilize a fused lasso type penalty to identify both heterogeneity and commonality across the groups. Extensive simulations demonstrate its superiority compared to several direct competing methods. The analysis of The Cancer Genome Atlas melanoma data with DNA methylation measurements and GENEVA diabetes data with SNP measurements exhibit that the proposed analysis lead to meaningful findings with better prediction performance and higher selection stability.

A high-throughput droplet digital PCR system aiming eight DNA methylation targets for age prediction.

The droplet digital Polymerase Chain Reaction (ddPCR) has garnered recognition for its distinctive attribute of absolute quantification. And it has found practical utility in age prediction through DNA methylation profiles. However, a prevalent limitation in current ddPCR methodologies is the restricted capacity to detect only two targets concurrently in most instruments, leading to high costs, sample wastage, and labor-intensive procedures. To address the limitations, a novel high-throughput ddPCR system allowing for the simultaneous detection of eight targets was developed. Through the implementation of a new 8-plex ddPCR assay, coupled with comprehensive linear regression analyses involving primers and probes ratios, diverse inputs of single CpG sites with distinct primers and probes, and varying plex assay configurations, stable DNA methylation values for four CpGs and stable measurement precisions for distinct multiplex systems were consistently observed. These findings pave the way for advancing the field of chemistry science by enabling more efficient and cost-effective methods. Furthermore, the comparative validation of ddPCR and SNaPshot demonstrated a remarkable concordance in results, and the system also displayed well in the field of various aspects, including species specificity, DNA input, and aged samples. In this study, the recommended input of bisulfite-converted DNA was determined to be 10-50 ng due to the double-positive droplets. Notably, the Pearson correlation coefficient squared values of four CpGs were 0.4878 (ASPA), 0.4832 (IGSF1), 0.6881 (COL1A1), and 0.6475 (MEIS1-AS3). And the testing set exhibited a mean absolute error of 4.5923 years, indicating the robustness and accuracy of the age-predictive model.

Preparation of poly(caffeic acid)-coated epitope molecularly imprinted polymers and investigation of adsorption performance toward ovalbumin.

Food allergy can lead to severe allergic reactions that are potentially fatal for human, hence the detection of food allergens such as ovalbumin (OVA) is important. In this study, a poly(caffeic acid)-coated epitope molecularly imprinted polymer (EMIP) was prepared by chelation and autoxidation of caffeic acid with hexamethylenediamine. EMIP has not only imprinted cavities highly matched with OVA in size and spatial structure, but also externally abundant hydrophilic groups, resulting in few non-specific binding and good hydrophilicity. With high specificity, significant paramagnetism, and great reusability, EMIP can distinguish OVA from other proteins and selectively enrich OVA in egg white samples, which opens up a promising route to the determination of allergens in food products.

Bispecific CS1-BCMA CAR-T cells are clinically active in relapsed or refractory multiple myeloma.

Multiple myeloma (MM) bears heterogeneous cells that poses a challenge for single-target immunotherapies. Here we constructed bispecific CS1-BCMA CAR-T cells aiming to augment BCMA targeting with CS1. Sixteen patients with relapsed or refractory (RR) MM received CS1-BCMA CAR-T infusion. Six patients (38%) had cytokine release syndrome, which was of grade 1-2 in 31%. No neurological toxicities were observed. The most common severe adverse events were hematological, including leukopenia (100%), neutropenia (94%), lymphopenia (100%) and thrombocytopenia (31%). Three patients with solitary extramedullary disease (sEMD) did not respond. At a median follow-up of 246 days, 13 patients (81%) had an overall response and attained minimal residual disease-negativity, and six (38%) reached a stringent complete response (sCR). Among the 13 responders, 1-year overall survival and progression-free survival were 72.73% and 56.26%, respectively. Four patients maintained sCR with a median duration of 17 months. Four patients experienced BCMA+ and CS1+ relapse or progression. One patient responded after anti-BCMA CAR-T treatment failure. Lenalidomide maintenance after CAR-T infusion and the resistance mechanism of sEMD were preliminarily explored in three patients. CAR-T cells persisted at a median of 406 days. Soluble BCMA could serve as an ideal biomarker for efficacy monitoring. CS1-BCMA CAR-T cells were clinically active with good safety profiles in patients with RRMM. Clinical trial registration: This study was registered on ClinicalTrials.gov, number NCT04662099.

The crosstalk between enteric nervous system and immune system in intestinal development, homeostasis and diseases.

The gut is the largest digestive and absorptive organ, which is essential for induction of mucosal and systemic immune responses, and maintenance of metabolic-immune homeostasis. The intestinal components contain the epithelium, stromal cells, immune cells, and enteric nervous system (ENS), as well as the outers, such as gut microbiota, metabolites, and nutrients. The dyshomeostasis of intestinal microenvironment induces abnormal intestinal development and functions, even colon diseases including dysplasia, inflammation and tumor. Several recent studies have identified that ENS plays a crucial role in maintaining the immune homeostasis of gastrointestinal (GI) microenvironment. The crosstalk between ENS and immune cells, mainly macrophages, T cells, and innate lymphoid cells (ILCs), has been found to exert important regulatory roles in intestinal tissue programming, homeostasis, function, and inflammation. In this review, we mainly summarize the critical roles of the interactions between ENS and immune cells in intestinal homeostasis during intestinal development and diseases progression, to provide theoretical bases and ideas for the exploration of immunotherapy for gastrointestinal diseases with the ENS as potential novel targets.

Enhancing the Treatment of Uncontrolled Inflammation through the Targeted Delivery of TPCA-1-Loaded Nanoparticles.

Uncontrolled inflammation is a pathological state that underlies many diseases. Despite the development of numerous anti-inflammatory agents, the treatment of uncontrolled inflammation remains a challenging task. We developed a targeted delivery system for [5-(p-fluorophenyl)-2-ureido]thiophene-3-carboxamide (TPCA-1), a potent inhibitor of the NF-κB signaling pathway. The system comprises TPCA-1-loaded nanoparticles (NPs) functionalized with a monoclonal antibody (mAb) that specifically binds to the break point of the IgD6 region of the platelet/endothelial cell adhesion molecule-1 (PECAM-1) extracellular segment that is overexposed on the injured endothelium and activated macrophages during the pathogenesis of inflammation. In vitro binding and cellular uptake experiments revealed that the mAb modification on NPs could significantly enhance uptake by both Raw264.7 and HUVEC compared with unmodified NPs. In studies conducted at the cellular level focusing on anti-inflammatory and antioxidant effects, this formulation was found to effectively inhibit M1 polarization of macrophages, downregulate the secretion of pro-inflammatory cytokines, and reduce the production of reactive oxygen species (ROS) and nitric oxide (NO). In an animal model of vascular endothelial injury with acute inflammation, these NPs were capable of delivering TPCA-1 to inflammatory lesions in a targeted manner. Compared with the free agent-treated group, the NP-treated group exhibited reduced infiltration of inflammatory cells. In conclusion, our study demonstrates that this targeted delivery of TPCA-1-loaded NPs represents a promising strategy for improved mitigation of uncontrolled inflammation.

Factors affecting male-to-female ratio at birth in frozen-thawed embryo transfer cycles: a large retrospective cohort study.

Background: ICSI (intracytoplasmic sperm injection) leads to a reduced male-to-female ratio at birth, whereas blastocyst transfer results in an increased male-to-female ratio. However, limited knowledge exists regarding the impact of these factors on the live birth rate for each gender. This study aimed to investigate the influence of patient characteristics and treatment parameters on the live birth rate for each gender, as well as the ultimate male-to-female ratio at birth in frozen-thawed embryo transfer (FET) cycles. Method: This retrospective cohort study involved a total of 28,376 FET cycles and 9,217 subsequent deliveries, spanning from January 2003 to December 2015. The study consisted of two parts. First, logistic regression models were constructed to determine the factors influencing the male-to-female ratio among babies born after FET. Second, we aimed to investigate the mechanisms underlying this sex ratio imbalance by analyzing data from all transfer cycles. Generalized estimated equations were employed to assess the impact of risk factors on rates of male and female live births separately. Results: ICSI resulted in a lower proportion of male offspring compared to in vitro fertilization (IVF) (50.1% vs. 53.7%, aOR: 0.87, 95% CI: 0.80-0.96). Conversely, blastocyst transfer yielded a higher proportion of male offspring than cleavage-stage embryo transfer (58.7% vs. 51.6%, aOR: 1.32, 95% CI: 1.17-1.48). Analysis of all cycles indicated that ICSI resulted in a reduced likelihood of male live birth in comparison to IVF (19.8% vs. 21.6%, aOR: 0.90, 95% CI: 0.83-0.97). However, the transfer of blastocysts rather than cleavage-stage embryos not only increased the chance of male live birth (26.9% vs. 20.2%, aOR: 1.70, 95% CI:1.56-1.85) but also facilitated female live birth (20.3% vs. 19.3%, aOR: 1.26, 95% CI: 1.15-1.39). Conclusion: ICSI was associated with a reduction in the male-to-female sex ratio and a lower rate of male live births, while blastocyst transfer was associated with an increased male-to-female sex ratio at birth and a higher rate of male live births.

IL-10 plus the EASIX score predict bleeding events after anti-CD19 CAR T-cell therapy.

Chimeric antigen receptor (CAR) T-cell-associated coagulopathy can cause bleeding events. To explore risk factors for hemorrhage after CAR T-cell therapy, we retrospectively analyzed routine indicators in 56 patients with non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia who received anti-CD19 CAR T-cell therapy. Disturbance of coagulation occurred mainly within one month post infusion, especially on day 7 and 14. The cumulative incidence of bleeding events within one month was 32.8%, with the median onset of 7 (range, 0-28) days. All bleeding events were grade 1-3. Patients who experienced bleeding events within one month had longer prothrombin time, higher IL-6, higher IL-10, and lower platelets before lymphodepletion. There were also correlations among coagulation-, inflammatory-, and tumor burden-related markers. Multi-variate analysis showed IL-10 (> 7.98 pg/mL; adjusted odds ratio [OR], 13.84; 95% confidence interval [CI], 2.03-94.36; P = 0.007) and the endothelial activation and stress index (EASIX, defined as dehydrogenase [U/L] × creatinine [mg/dL] / platelets [×109 cells/L]; >7.65; adjusted OR, 7.06; 95% CI, 1.03-48.23; P = 0.046) were significant risk factors for bleeding events. IL-10 plus the EASIX defined three risk groups for bleeding events with cumulative incidence of 100% (hazard ratio [HR], 14.47; 95% CI, 2.78-75.29; P < 0.0001), 38.5% (HR, 3.68; 95% CI, 0.82-16.67; P = 0.089), and 11.8% (reference), respectively. Future studies are needed to verify the risk assessment models for bleeding events after CAR T-cell treatment in larger cohorts.

Prognostic Potential of Pulmonary Hypertension in Patients with Hematologic Malignancy.

INTRODUCTION: Cardiovascular diseases present a great burden for survivors of hematologic malignancy (HM). However, the effect of pulmonary hypertension (PH) on the clinical outcome of patients with HM remains unknown. This study aims to evaluate the prognostic potential of PH in patients with HM and explore the related clinical determinants. METHODS: This retrospective study included 220 patients with HM and PH and 220 controls without PH, the case-matching cohort analysis was performed based on age, sex, the year of diagnosis and disease type. The baseline characteristics and overall survival (OS) of the patients with HM with or without PH were compared. The cumulative overall survival was analyzed using the Kaplan-Meier curves and the log-rank test. Multivariate Cox proportional hazard models were conducted to identify the predictors of OS. RESULTS: PH was found in 11.98% (302/2520) of the patients with HM. The PH group had lower levels of hemoglobin, platelet, albumin, fibrinogen and B cell count; whereas the levels of lactate dehydrogenase, N terminal pro B type natriuretic peptide, D-dimer, fibrinogen degradation products and C-reactive protein were higher. Additionally, the PH group had a higher prevalence of atrial fibrillation. Survival analysis revealed that the PH group had an inferior OS compared to the non-PH group (16.9 vs. 37.6 months, p = 0.002). Further subgroup analysis revealed that the severe PH group had the worst OS, followed by the moderate and the mild PH groups (8.7 vs. 14.7 vs. 23.7 months, p < 0.001). Multivariate analysis showed that PH was an independent predictor for unfavorable clinical outcomes. CONCLUSIONS: Coexisting PH was associated with inferior clinical outcomes in patients with HM, and the severe PH group had the worst prognosis. The study may provide additional risk stratification for patients with HM.

Loss of Y chromosome in leukocytes can be regarded as a male-specific age predictor for age group estimation in forensic genetics.

Age prediction is an important field in forensic and aging research. Traditional methods used DNA methylation, telomere shortening, and mitochondrial DNA mutations to conduct age prediction models. Sex chromosomes, like the Y chromosome, have a significant role in aging as previously reported in hematopoietic disease and many non-reproductive cancers. Until now, there is no age predictor based on the percentage of loss of Y chromosome (LOY). LOY has been previously revealed to be correlated with Alzheimer's disease, short survival, and higher risk of cancer. The possible correlation of LOY between normal aging was not fully explored. In this study, we conducted age prediction by measuring LOY percentage by droplet digital PCR (ddPCR), based on 232 healthy male samples, including 171 blood samples, 49 saliva samples, 12 semen samples. The age group of samples ranges from 0 to 99 years, with two individuals in almost every single age. Pearson correlation method was performed to calculate the correlation index. The result indicated a correlation index of 0.21 (p = 0.0059) between age and LOY percentage in blood samples, with the regression formula being y = - 0.016823 + 0.001098x. The correlation between LOY percentage and age is obvious only when the individuals were divided into different age groups (R = 0.73, p = 0.016). In the studied saliva and semen samples, p-values of the correlation are 0.11 and 0.20, respectively, showing no significant association between age and LOY percentage in these two biological materials. For the first time, we investigated male-specific age predictor based on LOY. The study showed that LOY in leukocytes can be regarded as a male-specific age predictor for age group estimation in forensic genetics. This study might be indicative for forensic applications and aging research.

Therapeutic Effect of Polaprezinc on Reflux Esophagitis in the Rat Model.

BACKGROUND/AIMS: To explore the protective effects and therapeutic mechanism of Esomeprazole (PPI), polaprezinc granule (PZ), and PPI + PZ on reflux esophagitis (RE) in the rat model. METHODS: Wistar rats were randomly divided into 9 groups, which contain the control group, the acid cessation group (0.7% HCl, Q3D × 4), and the acid persistence group (0.7% HCl, Q3D × 11). PPI was administered by gavage at 8 mg·kg-1 body weight and PZ was administered by gavage at 120 mg·kg-1 body weight once a day for 15 days. The gastric cardia tissue of the feeding tube was observed under the light microscope, and the levels of interleukin-8 (IL-8) and prostaglandin E2 (PGE2) were measured by ELISA. The expression of EGFR, Akt, p-Akt, and p-mTOR was detected by Western blot. RESULTS: The ELISA results showed that the levels of IL-8 and PGE2 were significantly increased in the model group, but decreased in all groups after treatment. In the acid cessation group, PZ treatment had the most significant effect on reducing IL-8 levels and PPI + PZ treatment had the most significant effect on reducing PGE2 levels. In the acid persistence group, the PPI treatment had the most significant effect on reducing the levels of IL-8 and PGE2, and the PZ treatment could also significantly reduce their levels, close to the normal value. Western blot results showed that the expression of PI3K/Akt/mTOR pathway protein was increased in the model group, while its expression was decreased after treatment. CONCLUSIONS: Polaprezinc has a significant therapeutic effect on RE in rats, which can reduce the levels of IL-8 and PGE2 and downregulate the expression of PI3K/Akt/mTOR signal pathway protein. The efficacy of polaprezinc in the treatment of reflux esophagitis is comparable to that of PPI, and the combination of them is more effective in the reflux esophagitis treatment.

Effect of vitamin energy drinks on relieving exercise-induced fatigue in muscle group by ultrasonic bioimaging data analysis.

OBJECTIVE: This work was aimed to analyze the effect of vitamin energy drink on muscle fatigue by surface electromyography (SEMG) and ultrasonic bioimaging (USBI). METHODS: 20 healthy men were selected to do increasing load fatigue test. Surface electromyographic signals and ultrasonic biological images were collected based on wavelet threshold function with improved thresholds. Time domain and frequency domain characteristic integrated electromyography (IEMG), root mean square amplitude (RMS), average power frequency (MPF), and surface and deep muscle morphological changes were analyzed. Hemoglobin concentration (HB), red blood cell number (RBC), mean volume of red blood cell (MCV), blood lactic acid (BLA), malondialdehyde (MDA), and phosphocreatine kinase (CK) were measured. RESULTS: 1) the Accuracy (94.10%), Sensitivity (94.43%), Specificity (93.75%), and Precision (94.07%) of the long and short-term memory (LSTM) specificity for muscle fatigue recognition were higher than those of other models. 2) Compared with the control group, the levels of BLA, MDA, and CK in the experimental group were decreased and HB levels were increased after exercise (P < 0.05). 3) IEMG and RMS of the experimental group were higher than those of the control group, and increased with time (P < 0.05). 4) The mean amplitude of the response signal decreased with time. Compared with the control group, the surface muscle thickness, deep muscle thickness, total muscle thickness, contrast, and homogeneity (HOM) decreased in the experimental group; while the angular second moment (ASM) and contrast increased, showing great differences (P < 0.05). CONCLUSION: Surface electromyographic signal and ultrasonic biological image can be used as auxiliary monitoring techniques for muscle fatigue during exercise. Drinking vitamin energy drinks before exercise can relieve physical fatigue to a certain extent and promote the maintenance of muscle microstructure.

Dyslipidemia in Muscular Dystrophy: A Systematic Review and Meta-Analysis.

BACKGROUND: Muscular dystrophies (MDs) are characterized by chronic muscle wasting but also poorly understood metabolic co-morbidities. We have recently shown that Duchenne MD (DMD) patients, dogs and asymptomatic carriers are affected by a new form of dyslipidemia that may exacerbate muscle damage. OBJECTIVE: We aimed to perform a systematic review and meta-analysis for evidence that other types of MDs are associated with dyslipidemia compared to healthy controls. METHODS: Search was conducted using MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials for reports that compare plasma/serum lipids from MD patients and controls, and meta-analysis of cross-sectional studies quantifying total cholesterol, high-density lipoprotein, low density lipoprotein and triglycerides was performed. RESULTS: Out of 749 studies, 17 met our inclusion criteria for meta-analysis. 14 of the 17 studies (82%) included investigated myotonic dystrophy (DM); other studies were on pseudohypertrophic MD (PMD) or DMD. As a whole, MD individuals had significantly higher levels of circulating total cholesterol (Hedges' g with 95% confidence interval [CI], 0.80 [0.03 - 1.56]; p = 0.04) and triglycerides (Hedges' g with 95% confidence interval [CI], 2.28[0.63 - 3.92]; p = 0.01) compared to controls. Meta-regression analysis showed the percentage of male gender was significantly associated with the difference in total cholesterol (beta = 0.05; 95% CI, - 0.02 to 0.11; p = 0.043) and high-density lipoprotein (beta = - 9.38; 95% CI, - 16.26 to - 2.50; p = 0.028). CONCLUSIONS: MD is associated with significantly higher circulating levels of total cholesterol and triglycerides. However, caution on the interpretation of these findings is warranted and future longitudinal research is required to better understand this relationship.

Bruton tyrosine kinase inhibitors preserve anti-CD19 chimeric antigen receptor T-cell functionality and reprogram tumor micro-environment in B-cell lymphoma.

BACKGROUND AIMS: Combination therapy is being actively explored to improve the efficacy and safety of anti-CD19 chimeric antigen receptor T-cell (CART19) therapy, among which Bruton tyrosine kinase inhibitors (BTKIs) are highly expected. BTKIs may modulate T-cell function and remodel the tumor micro-environment (TME), but the exact mechanisms involved and the steps required to transform different BTKIs into clinical applications need further investigation. METHODS: We examined the impacts of BTKIs on T-cell and CART19 phenotype and functionality in vitro and further explored the mechanisms. We evaluated the efficacy and safety of CART19 concurrent with BTKIs in vitro and in vivo. Moreover, we investigated the effects of BTKIs on TME in a syngeneic lymphoma model. RESULTS: Here we identified that the three BTKIs, ibrutinib, zanubrutinib and orelabrutinib, attenuated CART19 exhaustion mediated by tonic signaling, T-cell receptor (TCR) activation and antigen stimulation. Mechanistically, BTKIs markedly suppressed CD3-ζ phosphorylation of both chimeric antigen receptor and TCR and downregulated the expression of genes associated with T-cell activation signaling pathways. Moreover, BTKIs decreased interleukin 6 and tumor necrosis factor alpha release in vitro and in vivo. In a syngeneic lymphoma model, BTKIs reprogrammed macrophages to the M1 subtype and polarized T helper (Th) cells toward the Th1 subtype. CONCLUSIONS: Our data revealed that BTKIs preserved T-cell and CART19 functionality under persistent antigen exposure and further demonstrated that BTKI administration was a potential strategy for mitigating cytokine release syndrome after CART19 treatment. Our study lays the experimental foundation for the rational application of BTKIs combined with CART19 in clinical practice.

Cerebellar ataxia with anti-mGluR1 auto-antibody in a pediatric patient: A case report.

Cerebellar ataxia (CA) related to anti-metabolic glutamate receptor 1 (mGluR1) is a rare autoimmune encephalitis, which is manifested as acute or subacute CA in most cases.To the best of our knowledge, only three cases of pediatric patients have been reported in the literature so far. This article reports the 4th case of mGluR1 related CA in a pediatric patient.