Early intervention with daratumumab improves survival for patients with high-risk smouldering myeloma
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Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes
In the MAIA study, daratumumab plus lenalidomide and dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). We report updated efficacy and safety from MAIA (median follow-up, 64.5 months), including a subgroup analysis by patient age (<70, ≥70 to <75, ≥75, and ≥80 years). Overall, 737 transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint, PFS, was improved with D-Rd versus Rd (median, 61.9 vs 34.4 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.45–0.67; P < 0.0001). Median OS was not reached in the D-Rd group versus 65.5 months in the Rd group (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003); estimated 60-month OS rates were 66.6% and 53.6%, respectively. D-Rd achieved higher rates of complete response or better (≥CR; 51.1% vs 30.1%), minimal residual disease (MRD) negativity (32.1% vs 11.1%), and sustained MRD negativity (≥18 months: 16.8% vs 3.3%) versus Rd (all P < 0.0001). D-Rd demonstrated clinically meaningful efficacy benefits across age groups. No new safety concerns were observed. Updated results (median follow-up, >5 years) continue to support frontline use of D-Rd in transplant-ineligible patients with NDMM.
Enhancing children’s numeracy and executive functions via their explicit integration
Executive functions (EF) are crucial to regulating learning and are predictors of emerging mathematics. However, interventions that leverage EF to improve mathematics remain poorly understood. 193 four-year-olds (mean age = 3 years; 11 months pre-intervention; 111 female, 69% White) were assessed 5 months apart, with 103 children randomised to an integrated EF and mathematics intervention. Our pre-registered hypotheses proposed that the intervention would improve mathematics more than practice as usual. Multi-level modelling and network analyses were applied to the data. The intervention group improved more than the control group in overall numeracy, even when controlling for differences across settings in EF and mathematics-enhancing practices. EF and mathematics measures showed greater interconnectedness post-intervention. In addition, disadvantaged children in the intervention group made greater gains than in the control group. Our findings emphasise the need to consider EFs in their integration with co-developing functions, and in their educational and socio-economic context.
Activated platelet-derived exosomal LRG1 promotes multiple myeloma cell growth
The hypercoagulable state is a hallmark for patients with multiple myeloma (MM) and is associated with disease progression. Activated platelets secrete exosomes and promote solid tumor growth. However, the role of platelet-derived exosomes in MM is not fully clear. We aim to study the underlying mechanism of how platelet-derived exosomes promote MM cell growth. Flow cytometry, Western blot, proteome analysis, co-immunoprecipitation, immunofluorescence staining, and NOD/SCID mouse subcutaneous transplantation model were performed to investigate the role of exosomal LRG1 on multiple myeloma cell growth. Peripheral blood platelets in MM patients were in a highly activated state, and platelet-rich plasma from MM patients significantly promoted cell proliferation and decreased apoptotic cells in U266 and RPMI8226 cells. Leucine-rich-alpha-2-glycoprotein 1 (LRG1) was significantly enriched in MM platelet-derived exosomes. Blocking LRG1 in recipient cells using LRG1 antibody could significantly eliminate the proliferation-promoting effect of platelet-derived exosomes on MM cells. And high exosomal LRG1 was associated with poor prognosis of patients with MM. Mechanistic studies revealed that LRG1 interacted with Olfactomedin 4 (OLFM4) to accelerate MM progression by activating the epithelial-to-mesenchymal transition (EMT) signaling pathway and promoting angiogenesis. Our results revealed that blocking LRG1 is a promising therapeutic strategy for the treatment of MM.
Breast cancer: pathogenesis and treatments
Breast cancer, characterized by unique epidemiological patterns and significant heterogeneity, remains one of the leading causes of malignancy-related deaths in women. The increasingly nuanced molecular subtypes of breast cancer have enhanced the comprehension and precision treatment of this disease. The mechanisms of tumorigenesis and progression of breast cancer have been central to scientific research, with investigations spanning various perspectives such as tumor stemness, intra-tumoral microbiota, and circadian rhythms. Technological advancements, particularly those integrated with artificial intelligence, have significantly improved the accuracy of breast cancer detection and diagnosis. The emergence of novel therapeutic concepts and drugs represents a paradigm shift towards personalized medicine. Evidence suggests that optimal diagnosis and treatment models tailored to individual patient risk and expected subtypes are crucial, supporting the era of precision oncology for breast cancer. Despite the rapid advancements in oncology and the increasing emphasis on the clinical precision treatment of breast cancer, a comprehensive update and summary of the panoramic knowledge related to this disease are needed. In this review, we provide a thorough overview of the global status of breast cancer, including its epidemiology, risk factors, pathophysiology, and molecular subtyping. Additionally, we elaborate on the latest research into mechanisms contributing to breast cancer progression, emerging treatment strategies, and long-term patient management. This review offers valuable insights into the latest advancements in Breast Cancer Research, thereby facilitating future progress in both basic research and clinical application.
CD38 in the pathobiology of cutaneous T-cell lymphoma and the potential for combination therapeutic intervention
Cutaneous T-Cell Lymphoma (CTCL) is a non-Hodgkin’s lymphoma involving malignant skin-homing T-cells, characterized by variable severity and limited treatment options. Our study shows that patient samples and derived cell lines express CD38 on CTCL cells, and αCD38 antibodies effectively target CD38 in a mouse model. In vivo αCD38 antibody treatment led to the loss of CD38 expression in residual tumor cells, highlighting the need for innovative strategies to improve CTCL outcomes despite the CD38 loss in residual tumor cells. To investigate the role of CD38 in CTCL pathology, we used CRISPR-Cas9 to create CD38-deficient (CD38KO) CTCL cells. These CD38KO cells showed higher expression of oncogenes B-catenin, TCF7, and BCL6, along with reduced migration. Elevated NAD+ levels in CD38KO cells increased cellular respiration after CD38 inhibition in CD38WT cells. In vivo, CD38KO cell transplants led to more aggressive tumors, likely due to elevated β-catenin, Bcl6, and Tcf-1 signaling. Prior research in multiple myeloma showed αCD38 antibody efficacy relies on CD38 expression. We discovered that panobinostat, a histone deacetylase inhibitor, increased surface CD38 expression in CTCL cells dose-dependently. Combining panobinostat with αCD38 antibody in a CTCL mouse model significantly improved survival compared to the antibody alone, underscoring CD38’s therapeutic potential in CTCL.
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