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.

Background: The 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. Methods: We 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. Results: Our 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). Conclusions: As 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 registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023455002.

Construction and validation of an 18F-FDG-PET/CT-based prognostic model to predict progression-free survival in newly diagnosed multiple myeloma patients.

OBJECTIVE: To investigate the relationship between 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) related parameters and the prognosis of multiple myeloma and to establish and validate a prediction model regarding the progression-free survival (PFS) of multiple myeloma. METHODS: A retrospective analysis of 126 newly diagnosed multiple myeloma patients who attended Nanjing Drum Tower Hospital from 2014-2021. All patients underwent PET/CT before treatment and were divided into a training cohort (n = 75) and a validation cohort (n = 51). Multivariate Cox proportional hazard regression analysis incorporated PET/CT-related parameters and clinical indicators. A nomogram was established to individually predict PFS in MM patients. The model was evaluated by calculating the C-index and calibration curve. RESULTS: Here, 4.2 was used as the cut-off value of SUVmax to divide patients into high and low groups. PFS significantly differed between patients in the high-SUVmax group and low-SUVmax group, and SUVmax was an independent predictor of PFS in newly diagnosed multiple myeloma (NDMM) patients. Univariate and multivariate cox regression analysis suggested that lactate dehydrogenase (LDH), bone marrow plasma cell (BMPC), and SUVmax affected PFS. These factors were incorporated to construct a nomogram model for predicting PFS at 1 and 2 years in NDMM patients. The C-index and calibration curves of the nomogram exhibited good accuracy and consistency, and the DCA curves suggested that the model had good clinical utility. CONCLUSION: The PET/CT parameter SUVmax is closely related to the prognosis of myeloma patients. The nomogram constructed in this study based on PET/CT-related parameters and clinical indicators individually predicts the PFS rate of NDMM patients and enables further risk stratification of NDMM patients.

Bifunctional iRGD-Exo-DOX crosses the blood-brain barrier to target central nervous system lymphoma.

Central nervous system lymphoma (CNSL) is a type of hematological tumor. Treatment of CNSL is difficult due to the existence of the blood-brain barrier (BBB). Here, we used exosomes (Exos), a type of extracellular vesicle, and iRGD to construct a new drug carrier system and use it to load doxorubicin (DOX). The results of in vitro and in vivo experiments showed that the iRGD-Exo-DOX system can efficiently and securely transport DOX through the BBB and target tumor cells. The results suggest that iRGD-Exo-DOX may cross the BBB through brain microvascular endothelial cell-mediated endocytosis. Together, our study indicates an impactful treatment of central nervous system tumors.

Identification of a novel fusion gene, RARA::ANKRD34C, in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia that is distinguished by the chromosomal translocation t(15;17)(q24;q21), which leads to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA). Recently, we identified a novel fusion gene in APL, RARA::ankyrin repeat domain 34C (ANKRD34C), identified its functions by morphological, cytogenetic, molecular biological and multiplex fluorescence in situ hybridization analyses, and demonstrated the potential therapeutic effect clinically and experimentally of all-trans retinoic acid (ATRA); the findings have important implications for the diagnosis and treatment of atypical APL.

Current Advances and Future Strategies for BCL-2 Inhibitors: Potent Weapons against Cancers.

Targeting the intrinsic apoptotic pathway regulated by B-cell lymphoma-2 (BCL-2) antiapoptotic proteins can overcome the evasion of apoptosis in cancer cells. BCL-2 inhibitors have evolved into an important means of treating cancers by inducing tumor cell apoptosis. As the most extensively investigated BCL-2 inhibitor, venetoclax is highly selective for BCL-2 and can effectively inhibit tumor survival. Its emergence and development have significantly influenced the therapeutic landscape of hematological malignancies, especially in chronic lymphocytic leukemia and acute myeloid leukemia, in which it has been clearly incorporated into the recommended treatment regimens. In addition, the considerable efficacy of venetoclax in combination with other agents has been demonstrated in relapsed and refractory multiple myeloma and certain lymphomas. Although venetoclax plays a prominent antitumor role in preclinical experiments and clinical trials, large individual differences in treatment outcomes have been characterized in real-world patient populations, and reduced drug sensitivity will lead to disease recurrence or progression. The therapeutic efficacy may vary widely in patients with different molecular characteristics, and key genetic mutations potentially result in differential sensitivities to venetoclax. The identification and validation of more novel biomarkers are required to accurately predict the effectiveness of BCL-2 inhibition therapy. Furthermore, we summarize the recent research progress relating to the use of BCL-2 inhibitors in solid tumor treatment and demonstrate that a wealth of preclinical models have shown promising results through combination therapies. The applications of venetoclax in solid tumors warrant further clinical investigation to define its prospects.

Semi-supervised enhanced discriminative local constraint preserving projection for dimensionality reduction of medical hyperspectral images.

Microscopic hyperspectral images has the advantage of containing rich spatial and spectral information. However, the large number of spectral bands provides a significant amount of spectral features, but also leads to data redundancy and noise, which seriously affect the recognition and classification performance of the images, as well as increasing the requirements for computation and storage. To address this issue, we propose a dimensionality reduction algorithm named enhanced discriminant local constraint preserving projection (EDLCPP). Specifically, the global spectral attention mechanism focuses on important bands, the high discriminability sample selection module measures the discriminability of samples using a modified average neighborhood margin, the graph construction module preserves the local geometric relationship and discriminant information, and the graph embedding module embeds the constructed graphs into a low-dimensional space to obtain the projection matrices. Experimental results on eight cholangiocarcinoma (CCA) hyperspectral images, Bloodcell1-3, and Bloodcell2-2 datasets have demonstrated the effectiveness of the proposed method.

Survival of 48866 cancer patients: results from Nantong area, China.

Objective: This study aimed to provide a realistic observation of survival by major site for 48,866 cancer patients treated at a tertiary cancer hospital in a rural area of China. Methods: Patients with cancer registered between 2007 and 2017 in the Nantong rural area were followed up. The starting date for survival calculation was the date of the first diagnosis of cancer at the Nantong Tumor Hospital, and the closing date was December 31, 2020. Observed survival (OS) was analyzed according to ICD-10 site, sex, age, region, and hospitalization period using the life table method and compared using the Wilcoxon (Gehan) statistic. Results: The overall 5-year OS rate was 40.48% for all 48,866 patients, 30.19% for males, and 51.90% for females. The top five cancer sites, accounting for 60.51% of the total cases, were the esophagus, lung, stomach, liver, and cervix, with 5-year OS rates of 33.72%, 18.64%, 32.10%, 19.04%, and 71.51%, respectively. The highest 5-year OS was observed in the thyroid (87.52%) and the lowest was in the pancreas (6.37%). Survival was significantly higher in younger patients than in older patients, with 5-year OSs of 69.26% and 19.84% in those aged 20-29 and 90-99 years, respectively. Five-year OSs improved significantly from 39.35% in 2007-2011 to 41.26% in 2012-2017. Conclusion: Overall survival improved over the years, although the improvement at some sites was not significant. The observed survival varies from region to region, reflecting differences in the patterns of major sites, disparities in proportions of hospitalization, and demographic characteristics.

A novel mesenchymal stem cell-based regimen for acute myeloid leukemia differentiation therapy.

Currently the main treatment of acute myeloid leukemia (AML) is chemotherapy combining hematopoietic stem cell transplantation. However, the unbearable side effect of chemotherapy and the high risk of life-threatening infections and disease relapse following hematopoietic stem cell transplantation restrict its application in clinical practice. Thus, there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse effects. Here, we revealed that umbilical cord-derived mesenchymal stem cells (UC-MSC) efficiently induced AML cell differentiation by shuttling the neutrophil elastase (NE)-packaged extracellular vesicles (EVs) into AML cells. Interestingly, the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor (VDR) activation in UC-MSC. Chemical activation of VDR by using its agonist 1α,25-dihydroxyvitamin D3 efficiently enhanced the pro-differentiation capacity of UC-MSC and then alleviated malignant burden in AML mouse model. Based on these discoveries, to evade the risk of hypercalcemia, we synthetized and identified sw-22, a novel non-steroidal VDR agonist, which exerted a synergistic pro-differentiation function with UC-MSC on mitigating the progress of AML. Collectively, our findings provided a non-gene editing MSC-based therapeutic regimen to overcome the differentiation blockade in AML.

Unsupervised dimensionality reduction of medical hyperspectral imagery in tensor space.

BACKGROUND AND OBJECTIVES: Compared with traditional RGB images, medical hyperspectral imagery (HSI) has numerous continuous narrow spectral bands, which can provide rich information for cancer diagnosis. However, the abundant spectral bands also contain a large amount of redundancy information and increase computational complexity. Thus, dimensionality reduction (DR) is essential in HSI analysis. All vector-based DR methods ignore the cubic nature of HSI resulting from vectorization. To overcome the disadvantage of vector-based DR methods, tensor-based techniques have been developed by employing multi-linear algebra. METHODS: To fully exploit the structure features of medical HSI and enhance computational efficiency, a novel method called unsupervised dimensionality reduction via tensor-based low-rank collaborative graph embedding (TLCGE) is proposed. TLCGE introduces entropy rate superpixel (ERS) segmentation algorithm to generate superpixels. Then, a low-rank collaborative graph weight matrix is constructed on each superpixel, greatly improving the efficiency and robustness of the proposed method. After that, TLCGE reduces dimensions in tensor space to well preserve intrinsic structure of HSI. RESULTS: The proposed TLCGE is tested on cholangiocarcinoma microscopic hyperspectral data sets. To further demonstrate the effectiveness of the proposed algorithm, other machine learning DR methods are used for comparison. Experimental results on cholangiocarcinoma microscopic hyperspectral data sets validate the effectiveness of the proposed TLCGE. CONCLUSIONS: The proposed TLCGE is a tensor-based DR method, which can maintain the intrinsic 3-D data structure of medical HSI. By imposing the low-rank and sparse constraints on the objective function, the proposed TLCGE can fully explore the local and global structures within each superpixel. The computational efficiency of the proposed TLCGE is better than other tensor-based DR methods, which can be used as a preprocessing step in real medical HSI classification or segmentation.

Two-dimensional substrate assisted SERS immunosensor for accurate detection of carcinoembryonic antigen.

Accurate and sensitive detection of carcinoembryonic antigen (CEA) is essential for the detection of various diseases in healthcare and the medical field. Currently, due to the high false negative rate of CEA assay in clinical setting and its use as a common indicator for early cancer screening, a novel CEA detection method with high sensitivity, increased specificity and the lower cost has become a clinical challenge. Here, a facile sandwich type immunosensor based on surface-enhanced Raman scattering (SERS) was presented including 4-mercaptobenzonitrile (4MBN) labeled gold core-silver shell nanoparticles (Au@4MBN@Ag NPs) as SERS tag and 4-mercaptophenylboronic acid (4-MPBA) functionalized two-dimensional (2D) silver nanoparticle film (Ag FM) as SERS capture substrate for CEA detection. A linearity of 10-9-10-14M was observed with high sensitivity and excellent selectivity for the detection of CEA. Additionally, the spiking experiment yielded 105.33-127.00% recovery with variation coefficients below 10% demonstrating high assay accuracy and precision. The immunosensor we proposed here is a promising approach to quantify CEA in liquid biopsy samples with high sensitivity, which could be further developed for early cancer screening.

The SMARCA4R1157W mutation facilitates chromatin remodeling and confers PRMT1/SMARCA4 inhibitors sensitivity in colorectal cancer.

Genomic studies have demonstrated a high frequency of genetic alterations in components of the SWI/SNF complex including the core subunit SMARCA4. However, the mechanisms of tumorigenesis driven by SMARCA4 mutations, particularly in colorectal cancer (CRC), remain largely unknown. In this study, we identified a specific, hotspot mutation in SMARCA4 (c. 3721C>T) which results in a conversion from arginine to tryptophan at residue 1157 (R1157W) in human CRC tissues associated with higher-grade tumors and controls CRC progression. Mechanistically, we found that the SMARCA4R1157W mutation facilitated its recruitment to PRMT1-mediated H4R3me2a (asymmetric dimethylation of Arg 3 in histone H4) and enhanced the ATPase activity of SWI/SNF complex to remodel chromatin in CRC cells. We further showed that the SMARCA4R1157W mutant reinforced the transcriptional expression of EGFR and TNS4 to promote the proliferation of CRC cells and patient-derived tumor organoids. Importantly, we demonstrated that SMARCA4R1157W CRC cells and mutant cell-derived xenografts were more sensitive to the combined inhibition of PRMT1 and SMARCA4 which act synergistically to suppress cell proliferation. Together, our findings show that SMARCA4-R1157W is a critical activating mutation, which accelerates CRC progression through facilitating chromatin recruitment and remodeling. Our results suggest a potential precision therapeutic strategy for the treatment of CRC patients carrying the SMARCA4R1157W mutation.

Surgical anatomy and clinical variation of the left colonic artery in laparoscopic anterior rectal resection.

Objectives: This study aims to investigate the surgical anatomy and clinical variation of the left colonic artery (LCA) during laparoscopic anterior rectal resection. Methods: We conducted a retrospective analysis of 87 patients diagnosed with colorectal cancer who underwent laparoscopic anterior rectal resection with preserved LCA at the Department of Gastroenterology, Sichuan Cancer Hospital, between March 2018 and April 2022, aiming to observe the emanation location, anatomical typing, and travel trajectory of the LCA, as well as its relationship with the inferior mesenteric vein (IMV). Results: In all observed cases, we observed that the LCA emanated from the left side of the inferior mesenteric artery (IMA), and the average distance from the root of the IMA to the emanation of the LCA was approximately 3.5 ± 1.1 cm. Specifically, 35 of these cases had the LCA branching from the IMA alone (Type I, 40.2%),16 cases had the LCA cotruncating with the sigmoid artery (SA) (Type II, 18.4%), 30 cases had the LCA cotruncating with the superior rectal artery (SRA) and SA (Type III, 34.5%), and six cases had the LCA cotruncating with four or more branches of the SRA and SA (Type IV, 6.9%). No LCA agenesis cases were found in this group. In addition, we also observed the occurrence of LCA alignment. Specifically, there were 25 cases where the LCA crossed the IMV in a diagonal upward direction (Type A, 28.7%), 36 cases where the LCA crossed the IMV in an upward arched manner (Type B, 41.4%), 18 cases where the LCA crossed the IMV in a vertical outward direction (Type C, 20.7%), and eight cases where the LCA crossed the IMV in a diagonal downward manner (Type D, 9.2%). Among them, two cases developed anastomotic fistula, one case had chyle leakage 1 week after surgery, and four cases experienced urinary retention; all of the patients successfully recovered and were discharged after receiving conservative treatment. Conclusion: The anatomy and variation of the LCA can be clearly and accurately observed during laparoscopic surgery. Understanding the type and variation of the LCA helps to dissect the vessels in the IMA region during surgery, particularly in cases when the LCA is preserved, and reduce the incidence of vascular injury and its complications.

Effect of School-Based Nutrition and Health Education for Rural Chinese Children.

The nutritional status of rural Chinese children has improved in recent years, but their nutritional knowledge is still relatively lacking. School-based nutrition and health education was conducted for children in three counties of China from 2018 to 2020. The students in the intervention schools were given two-year nutrition and health education courses, while the control schools did not receive any intervention. Students' nutrition knowledge, dietary intake, and dietary behaviors were collected using a questionnaire, and height and weight were measured uniformly. The nutrition knowledge score in the intervention group was increased by 1.01 and 0.64 points in the first and second years. A multilevel model was used to evaluate the intervention effects. Statistically significant interactions between groups and time were observed in nutrition knowledge, the frequency of eating breakfast, and dietary intake, including meat, eggs, milk, and vegetables (p < 0.05), but not in nutritional status. Therefore, the supplementation of school-based nutrition and health education had a positive impact on the nutrition knowledge and dietary intake of rural Chinese children.

Formosanin C induces autophagy-mediated apoptosis in multiple myeloma cells through the PI3K/AKT/mTOR signaling pathway.

OBJECTIVES: Multiple myeloma (MM) is an incurable plasma cell malignancy associated with poor survival. Novel therapeutic drugs are urgently needed to improve MM therapy and patient outcomes. This study aimed to investigate the effect of formosanin C (FC), a Chinese medicine monomer, on MM in vitro and disclose the underlying molecular mechanism. METHODS: The effect of FC on the viability, proliferation, apoptosis, and autophagy of MM cell lines (NCI-H929 and ARP1) was studied through CCK-8, colony formation, flow cytometry, GFP-LC3, and western blotting assays, respectively. A pharmacological approach and network pharmacology technology were implemented to explore the potential mechanisms of the action of FC on MM cells. RESULTS: FC efficiently suppressed the viability and colony-forming capacity, but promoted the number of autophagic vacuoles with GFP-LC3 localization and the percentage of apoptotic cells in MM cells. Additionally, FC significantly increased the levels of the autophagy-related proteins LC3-Ⅱ and Beclin 1, as well as the apoptosis-related proteins Bax and cleaved caspase-3, but blocked the expression of the proapoptotic protein Bcl-2 in the cells; these effects were reversed by an inhibitor of autophagy, 3-methyladenine. What's more, we found that the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway was involved in the FC-mediated inhibition of MM. Pharmacological inhibition of this pathway dramatically relieved FC-triggered excessive expression of autophagy-related proteins and rescued MM cells from FC-induced apoptosis. CONCLUSION: Our findings indicate that FC exhibits an anti-MM effect by activating cell autophagy through the PI3K/AKT/mTOR signaling pathway.

Screening T-Cell Activity via a Photodetachable DNA-Copolymer Nanocage and Its Therapeutic Application.

Screening T-cell activity and selecting active ones from large ex vivo-expanded populations before reinfusion is important for the success of T-cell therapy. Cytokine secretion is the evaluation criterion of cell immune activity. Cell membrane-anchored probes and microchamber-based techniques have been used to screen cytokine secretion at the single-cell level. However, they are either easily affected by nearby cells' secretion or lack of single-cell encapsulation efficiency. Here, we design a photodetachable DNA-copolymer nanocage on the cell membrane for screening the activities of ex vivo-expanded T cells by in-situ monitoring cytokine interferon-gamma (IFN-γ) secretion. The ones with good immune activity are selected for therapeutic application. DNA-copolymer nanocage is self-assembled on a cell membrane to encapsulate a single T cell. A self-quenched IFN-γ recognition aptamer is contained in the DNA-copolymer nanocage, which recovers fluorescence in response to IFN-γ secretion to indicate individual T-cell activity. The active T cells are collected after fluorescence-activated cell sorting, irradiated with 5 min UV light to detach nanocage from the cell membrane, and continuously cocultured with downstream cells. The selected Jurkat cells and CD19 CAR-T cells showed improved capabilities for downstream cell activation and cancer cell killing. The cell membrane-detachable DNA-copolymer nanocage-based T-cell activity screening and selection would have promising applications in T-cell therapy.

Socioeconomic status-based survival disparities and nomogram prediction for patients with multiple myeloma: Results from American and Chinese populations.

Objective: This study aimed to comprehensively investigate the relationship between the survival differences and socioeconomic status (SES) in patients with multiple myeloma (MM) and construct a predictive nomogram to assess clinical outcomes of MM patients. Methods: The Surveillance, Epidemiology, and End Results (SEER) census tract-level SES database provides two specialized attributes: SES index and rurality. Using this database, 37,819 patients diagnosed with MM between January 2007 and December 2016 were enrolled. We evaluated the effects of SES index on overall survival (OS) and myeloma-specific survival (MSS) using Kaplan-Meier curves and Cox regression analyses. Thereafter, we included 126 patients with MM from two independent medical centers in China and divided them into training (Center 1) and validation (Center 2) cohorts. Univariate and multivariate Cox analyses were used in the training cohort to construct a nomogram for predicting clinical outcomes. Nomogram performance was assessed using the area under the curve (AUC) and calibration curves. Results: In the SEER cohort, lower SES was significantly associated with worse OS rates and MSS rates (both P < 0.001). Multivariate analysis confirmed SES as an independent predictor of survival. Subgroup analysis indicated an increasing linear trend in survival benefits in non-Hispanic White, married, insured, and urban populations with increasing SES (all P < 0.001). In the training cohort, albumin, creatinine, rurality, and SES were confirmed as independent prognostic indicators. A nomogram for OS prediction was developed using these four factors, and it showed satisfactory discrimination and calibration. The 18- and 36-month AUC values of the nomogram were 0.79 and 0.82, respectively. Based on the total nomogram points, patients were categorized into two risk levels with good separation. Conclusion: SES strongly influences survival disparities in patients with MM. Our nomogram consisting of clinical and sociodemographic characteristics can potentially predict survival outcomes.

PDGFD switches on stem cell endothelial commitment.

The critical factors regulating stem cell endothelial commitment and renewal remain not well understood. Here, using loss- and gain-of-function assays together with bioinformatic analysis and multiple model systems, we show that PDGFD is an essential factor that switches on endothelial commitment of embryonic stem cells (ESCs). PDGFD genetic deletion or knockdown inhibits ESC differentiation into EC lineage and increases ESC self-renewal, and PDGFD overexpression activates ESC differentiation towards ECs. RNA sequencing reveals a critical requirement of PDGFD for the expression of vascular-differentiation related genes in ESCs. Importantly, PDGFD genetic deletion or knockdown increases ESC self-renewal and decreases blood vessel densities in both embryonic and neonatal mice and in teratomas. Mechanistically, we reveal that PDGFD fulfills this function via the MAPK/ERK pathway. Our findings provide new insight of PDGFD as a novel regulator of ESC fate determination, and suggest therapeutic implications of modulating PDGFD activity in stem cell therapy.