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T-ALL: the origin story
Awareness of disease extent and perceived palliative treatment goals among oncology patients: a multicenter study
Abstract In Egypt, approximately 134,000 new cancer cases and over 30,000 deaths are recorded annually. Unfortunately, a considerable proportion of patients present with an advanced stage. This patient population often faces a misconception that if they understand their disease stage and treatment goals, it will increase their anxiety. This study assessed Egyptian patients’ perceptions of their treatment objectives and the factors influencing their understanding. A survey-based study was conducted involving 487 Stage IV solid malignancy patients receiving palliative care at four Egyptian cancer centers. The survey assessed the patients’ awareness of their cancer diagnosis, stage, and treatment goals. Demographic data were collected. Responses were compared with medical records, and a total knowledge score (TKS) was calculated. A cutoff of ≥ 75% was set for satisfactory knowledge. Of the 487 patients, 46 (9.4%) denied having cancer and were excluded. Among the remaining 441 patients, despite 85.5% accurately knowing their tumor site, only 20.4% defined their exact tumor stage, and only 12% understood that the treatment was palliative rather than curative, while 28.9% thought that their tumors were benign. Collectively, 12% demonstrated a satisfactory knowledge level. The most significant factor that correlated positively with TKS was the education level (r s = 0.311, P < 0.001). Illiterate/primary-level education patients were 2.28 times more likely to have misconceptions. A substantial percentage of cancer patients demonstrated insufficient knowledge about their disease nature and treatment goals, especially those with lower education levels. These findings highlight the importance of improving patient education and physician-patient communication to help improve the process of shared decision-making.
BET inhibition blunts antibody production and macrophage-mediated fibrosis to restore lung function in murine cGVHD
Abstract Chronic graft-versus-host disease (cGVHD) significantly contributes to late mortality after allogeneic stem cell transplantation, with bronchiolitis obliterans syndrome (BOS) being a particularly lethal and treatment-resistant complication despite available therapies. Bromodomain and extraterminal (BET) proteins are epigenetic readers driving inflammatory transcriptional programs across multiple cell types. We hypothesized that BET inhibition would suppress inflammatory T and B cells and decrease macrophage polarization to a profibrotic phenotype, alleviating disease. In an established BOS cGVHD model, BET inhibition reduced germinal center (GC) formation and responses through a reduction of the CXCL13:CXCR5 axis and inflammatory T follicular helper/GC B cells in the spleen, along with a reduction in plasma cell infiltration within the lung. Mice with cGVHD had elevated pathogenic immunoglobulin G1 (IgG1) and IgM levels, both in circulation and deposited on lung tissue, which were attenuated under BET inhibition. Single-cell RNA-sequencing analysis revealed distinct cell states in the BOS lung vs control. In cGVHD mice, gene set enrichment analysis revealed the upregulation of profibrotic Arginase1 and Tgfb1 expression in alveolar macrophages (AM) and interstitial macrophages (IM), which was significantly reduced with BET inhibition. Furthermore, BET inhibition targeted lung-infiltrating M2 macrophages through the selective depletion of CD206+FcγR+ IM and AM, ultimately resulting in reduced collagen deposition and improved lung function. Our findings reveal a previously unrecognized mechanistic axis of BET regulation during cGVHD fibrosis and highlight BET inhibition as a promising therapeutic strategy.
Jupiter observations reveal a simple scaling law for particle acceleration
Effects of trehalose supplementation on bone healing, physical function, and pain in patients with pertrochanteric fractures: a randomized controlled trial
Shrouded in a starry sky: a case of AML-MRC with <i>KMT2A</i> amplification mimicking Burkitt-like morphology
Correction: Distinct social network structures and their cognitive and psychological correlates
Overcoming menin inhibitor resistance in AML cells with combinations including BET proteins and a dual BRG1/BRM inhibitor
Abstract Menin inhibitors (MI) disrupt the binding of menin to mixed-lineage leukemia 1 (MLL1), leading to the repression of MLL1 or MLL1-fusion protein target genes, including reduced levels of HOXA9 and MEIS1 in acute myeloid leukemia (AML) with mutant NPM1 (mtNPM1) or MLL1 rearrangement (MLL1-r). Although MI are relatively well tolerated and induce clinical remissions, they are often short-lived due to the development of resistance followed by AML relapse. Through repeated shocks with the MI SNDX-50469, a precursor tool compound to revumenib, followed by recovery, we developed MI-resistant (MITR) AML MV4-11 and OCI-AML3 cells. Present studies show that compared with MI-sensitive parental cells, MITR cells exhibit an altered epigenome, transcriptome, and proteome, without menin mutations. Through a CRISPR screen, novel druggable MI coenrichments were identified and targeted, including BRD4, SMARCA4, and CREBBP. Cotreatment with the MI and the SMARCA4/SMARCA2 (BRG1/BRM) inhibitor FHD-286 or the BET proteins inhibitor OTX015 (birabresib) synergistically induced in vitro lethality in MITR and MI-resistant AML cells expressing the mutant menin (M327I), as well as in patient-derived (PD) AML cells with MLL1-r or mtNPM1 that exhibited ex vivo resistance to MI. Compared with each drug alone, cotreatment with SNDX-5613 (revumenib) and FHD-286 or OTX015 and FHD-286 significantly reduced the in vivo AML burden and improved survival of the immune-depleted mice, without inducing significant toxicity, in the xenograft models of MITR and MI-resistant PD MLL1-r AML cells. These findings highlight novel, targeted, drug combinations that overcome MI resistance in AML cells with MLL1-r or mtNPM1.
The 1000 Chinese Pangenome empowers medical and population genetics
Isoflavonoids from Iris albicans as a carbon source to enhance the anti-aging potential of lactic acid bacteria-derived postbiotics
Abstract Dietary strategies that limit protein glycation can help slow aging and prevent age‑related diseases by reducing the accumulation of advanced glycation end products (AGEs). This study evaluated the antioxidant, antiglycation, and prebiotic potential of postbiotics produced by lactic acid bacteria using Iris albicans extract and its major isoflavonoids as carbon sources. Antioxidant activity (DPPH, ABTS, FRAP), prebiotic potential (A preb activity scores), and antiglycation effects were assessed via fructosamine formation, oxidative stress markers, protein aggregation, and AGE‑RAGE inhibition assays. Among all tested postbiotics, Limosilactobacillus reuteri MSD37 showed the highest antioxidant and antiglycation activities, especially when cultured with I. albicans extract or irilone. This postbiotic effectively preserved thiol groups, reduced protein oxidation, and inhibited AGE‑RAGE interactions. Moreover, L. reuteri MSD37 postbiotic enriched with I. albicans extract exhibited notably high prebiotic activity toward probiotic strains. Overall, I. albicans represents a promising carbon source for producing anti‑aging postbiotics, highlighting the potential of L. reuteri MSD37 as a gerobiotic candidate for promoting healthy aging.
Differential role of <i>CREBBP</i> missense and truncating mutations in germinal center development and lymphomagenesis
Abstract Truncating and missense mutations of the CREBBP gene are highly prevalent in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancies. These mutations are acquired early during tumor evolution by a common precursor cell (CPC) and lead to either complete protein loss or single amino acid substitutions in the lysine acetyltransferase (KAT) domain. As a result, CREBBP is impaired in its ability to acetylate enhancer histones and nonhistone proteins implicated in the germinal center (GC) reaction, the structure from which these tumors originate. However, whether truncating and KAT domain missense mutations are functionally equivalent in instructing the CPC remains unexplored. Using a conditional GC-specific knockin mouse model for the highly frequent CREBBP-R1446H amino acid change (CrebbpRH), we show that, compared with complete Crebbp loss, missense mutants impose distinct quantitative and qualitative effects on the GC response. CrebbpRH controls unique transcriptional programs leading to the preneoplastic expansion of GCs with abnormal architecture, increased percentage of T follicular helper cells, and a skewed immune response toward memory B-cell differentiation. The expression of CrebbpRH, but not Crebbp loss, was by itself sufficient to initiate malignant transformation, indicating a stronger tumor-promoting activity. Notably, lymphoma cells with CREBBPRH and CREBBP loss showed distinct sensitivity to CREBBP/p300 small-molecule inhibitors. Together with the differential distribution of missense and truncating mutations in FL and DLBCL, these findings have implications for the pathogenesis and therapeutic targeting of these cancers.
Exploring multiple minimal clinically important differences for the esophageal cancer scale QLICP-ES (V2.0) based on anchor-based and distribution-based methods
Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma: dynamics of MRD negativity in the IMROZ study
Abstract Quadruplet therapy with Isa-VRd (isatuximab, Velcade [bortezomib], Revlimid [lenalidomide], and dexamethasone) followed by Isa-Rd in the randomized phase 3 IMROZ study provided a significant progression-free survival benefit to transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). In the primary analysis, more Isa-VRd/Isa-Rd–treated patients achieved minimal residual disease (MRD) negativity and MRD-negative complete response (CR) at any time point than patients receiving VRd followed by Rd. Here, we report landmark analysis results of MRD negativity over time and its impact on clinical outcomes in IMROZ. Treatment with Isa-VRd/Isa-Rd led to deeper responses, with higher rates of MRD negativity and MRD-negative CR at the end of induction and during maintenance vs VRd/Rd, up to 60 months of follow-up. Benefit with Isa-VRd/Isa-Rd was observed across key patient subgroups, including older (&gt;70 years) and frail patients. Time to progression (TTP) was significantly prolonged with Isa-VRd/Isa-Rd vs VRd/Rd in patients who converted from MRD negative to MRD positive at any time point. In a landmark analysis of the time of conversion to MRD positivity, TTP in patients who converted from MRD negative at the end of induction to MRD positive also favored Isa-VRd/Isa-Rd. Evaluating MRD status of patients at &gt;1 time point may therefore be useful to support decisions on treatment selection and treatment continuation/discontinuation. Our findings on the degree of MRD negativity and MRD-negative CR benefit achieved during induction and maintenance by patients receiving Isa-VRd/Isa-Rd vs VRd/Rd extend the IMROZ primary analyses and further support Isa-VRd as standard of care for frontline treatment of transplant-ineligible patients with NDMM. This trial was registered at www.clinicaltrials.gov as #NCT03319667.
Multi-sensor observations and modeling of wave swash on a low-tide terrace beach
Tadagaki K, Tudor D, Gbahou F, et al. Human cytomegalovirus-encoded UL33 and UL78 heteromerize with host CCR5 and CXCR4 impairing their HIV coreceptor activity. <i>Blood</i> . 2012;119(21):4908-4918.
Dopaminergic mechanisms of dynamical social specialization
Active vibration suppression of a magnetic–ball bearing hybrid supported rotor system
Fibrinogen wags its disordered tail: α chain and thrombosis
Spatial justice and urban metabolism in arid cities: a comparative analysis with Amsterdam
Abstract Urban metabolism (UM) frameworks have traditionally prioritized technical efficiency metrics, often overlooking the socio-spatial distribution of metabolic benefits and burdens [1]. This gap is particularly significant in arid cities, where resource constraints amplify the consequences of inequitable green infrastructure (GI) distribution. This study examines the relationship between spatial justice (specifically regarding GI distribution) and urban metabolic patterns, centering on arid cities that face distinct metabolic challenges. The theoretical framework positions green infrastructure as a socio-ecological mediator within the urban metabolic system, connecting water, energy, and heat flows to lived environmental outcomes across socio-economic gradients. The study focuses on Amman and Cairo as representative arid cities varied in metabolic performance, by putting under comparative analysis with Amsterdam, a city recognized for integrated metabolic governance [2], we investigate how spatial equity patterns relate to broader urban metabolic characteristics by using a geospatial methodology integrating Normalized Difference Vegetation Index (NDVI) data with income-density stratification employed to analyze vegetation distribution across socio-economic gradients in all three cities. Our findings reveal pronounced disparities in relation to metabolic performance, with Disparity Ratios of 1.56 (Amman) and 2.68 (Cairo) compared to 1.10 in Amsterdam. These distribution patterns are examined in relation to each city’s documented metabolic context, governance approaches, and climatic constraints. The research positions us to understand how spatial inequality intersects with metabolic stress and demonstrates how the Disparity Ratio can function as an early-warning diagnostic of metabolic imbalance. By using a successful metabolic city, Amsterdam as an external reference point, the study identifies potential relationships between spatial equity and metabolic coherence that may inform more equitable planning approaches in resource-constrained urban contexts.