Browse Articles

The effect of prednisolone ingestion and acute exercise on lipocalin-2 and its variants in young men: a pilot randomised crossover study

Correction: Parity and post-reproductive mortality among U.S. Black and White women: Evidence from the Health and Retirement Study

The GATA-3–dependent transcriptome and tumor microenvironment are regulated by eIF4E and XPO1 in T-cell lymphomas

Abstract The transcription factor GATA-binding protein 3 (GATA-3) and the transcriptional program it regulates have emerged as oncogenic drivers across diverse T-cell lymphomas (TCLs), many of which are resistant to conventional chemotherapeutic agents and characterized by recurrent losses of key tumor suppressor genes, including TP53 and PTEN, both of which are clients of the nuclear export protein XPO1. Here, we demonstrated that XPO1 is highly expressed by malignant T cells expressing GATA-3 and by lymphoma-associated macrophages (LAMs) within their tumor microenvironment (TME). Using complementary genetically engineered mouse models, we demonstrated that TP53- and/or phosphate and tensin homolog (PTEN)-deficient TCLs, and LAMs within their TME, are sensitive to the selective exportin-1 (XPO1) antagonist selinexor. In an effort to identify TP53- and PTEN-independent mechanisms, we used complementary and orthogonal approaches to investigate the role of eIF4E and XPO1-dependent messenger RNA nuclear export in these TCLs. We identified a novel role for eIF4E/XPO1 in exporting GATA-3 and GATA-3–dependent transcripts from the nucleus in TCLs, and in the export of therapeutically relevant transcripts, including colony-stimulating factor-1 receptor, from LAMs. Therefore, XPO1 antagonism, by impairing oncogenic transcriptional programs in TCLs and depleting LAMs from their TME, is a novel approach to target 2 independent dependencies in a group of therapeutically challenging TCLs.

Publisher Correction: Antioxidant activity of Micractinium sp. (Chlorophyta) extracts against H2O2 induced oxidative stress in human breast adenocarcinoma cells

LazyAct: Lazy actor with dynamic state skip based on constrained MDP

Deep reinforcement learning has achieved significant success in complex decision-making tasks. However, the high computational cost of policies based on deep neural networks restricts their practical application. Specifically, each decision made by an agent requires a complete neural network computation, leading to a linear increase in computational cost with the number of interactions and agents. Inspired by human decision-making patterns, which involve reasoning only on critical states in continuous decision-making tasks without considering all states, we introduce the LazyAct algorithm. This algorithm significantly reduces the number of inferences while preserving the quality of the policy. Firstly, we incorporate a state skipping branch into the actor network to bypass states with minimal impact. Subsequently, we establish optimization objectives for single-agent and multi-agents inference, incorporating cost constraints based on the IMPALA and MAPPO frameworks, respectively. Finally, we utilize pre-training and fine-tuning techniques to train the policy network. Extensive experimental results indicate that LazyAct reduces the number of inferences by approximately 80% and 40% in single-agent and multi-agents scenarios, respectively, while sustaining comparable policy performance. The inferences reduction significantly decreases the time and FLOPs required by the LazyAct algorithm to complete tasks. Code is available here https://www.dropbox.com/scl/fo/wyoqo6q9gyt86zobfgbvx/h?\rlkey=0moyxsnoiisfs9y4h89hsou1l&dl=0.

Menin inhibitors in the treatment of acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the (oligo)clonal expansion of myeloid progenitor cells. Despite advances in treatment, AML remains challenging to cure, particularly in patients with specific genetic abnormalities. Menin inhibitors have emerged as a promising therapeutic approach, targeting key genetic drivers of AML, such as KMT2A (lysine methyl transferase 2A) rearrangements and NPM1 mutations. Here, we review the clinical value of menin inhibitors, highlighting their mechanism of action, efficacy, safety, and potential to transform AML treatment.

Author Correction: Lower urinary dysfunction as a long-term effect of childhood vincristine treatment, with potential influences by sex and dose

Long term cost-effectiveness analysis of IDegLira in the treatment of type 2 diabetes patients compared to GLP-1RA added to basal insulin after IDegLira entered the national reimbursement drug list in China

Background Degludec insulin liraglutide injection is the world’s first and only approved basal insulin GLP-1RA injection in China (GLP-1RA stands for Glucagon-Like Peptide-1 Receptor Agonist. This study aimed to evaluate the long-term cost-effectiveness of IDegLira versus GLP-1RA added to basal insulin regimen (combined regimen) for patients with type 2 diabetes in China. Methods Based on the perspective of the health system, the study adopts the Swedish Institute for Health Economics diabetes cohort model. The baseline and clinical efficacy data in the model are from the EXTRA study. The cost includes glucose-lowering medication, background treatment cost, and complication treatment costs. The prices of IDegLira and GLP-1RA are based on the national medical insurance payment standards. Insulin adopts the national volume-based procurement average price. Other cost and utility data are sourced from published literature. The health outcome indicator is quality-adjusted life years (QALYs). The simulation time horizon is 30 years. The discounting rate of cost and health outcomes is 5%. Results In clinical output, IDegLira could reduce the cumulative incidence of various chronic complications in patients compared to the combined regimen. The eye diseases (background, proliferative retinopathy, macular edema, and visual loss) decreased by 24.4%, 41.1%, 18.9%, and 12.2%, respectively. Neuropathy decreased by 17.3%. Proteinuria and end-stage renal disease decreased by 25.9% and 17.6% respectively. Ischemic heart disease, heart failure, and myocardial infarction (stroke) decreased by 0.8%, 1.1%, and 4.7%, respectively. In the base-case analysis, IDegLira compared to the combined regimen shows an incremental cost of -34,254 CNY and an incremental QALYs of 0.436. Under the threshold of 1 times the per capita GDP of China in 2022 (85,698 CNY), IDegLira is a dominant scheme with lower cost and better health outcome. In probabilistic sensitivity analysis, the probability of IDegLira being cost-effective is 100%, indicating that the base-case analysis results are robust. Conclusion Compared with the combined regimen, the use of IDegLira for Chinese patients with type 2 diabetes can improve long-term health output, save medical costs, and is a dominant scheme.

How I treat blastic plasmacytoid dendritic cell neoplasm

Abstract Historically, treatment options for blastic plasmacytoid dendritic cell neoplasm (BPDCN) were limited to conventional chemotherapy, adopted from regimens used to treat acute myeloid or acute lymphoblastic leukemias, or lymphomas. Nowadays, a novel therapy targeting CD123 is available to treat BPDCN. Yet, regardless of treatment choice, achieving a first complete remission represents the main goal of therapy, because it represents the best opportunity to prolong survival in BPDCN, if offered an allogeneic hematopoietic cell transplant (allo-HCT) as consolidative therapy. Although no specific conditioning regimen is considered standard of care in allo-HCT–eligible patients, recent data from 2 large registries reported a survival advantage when offering total body irradiation–based myeloablative conditioning (MAC) regimens. Unfortunately, applicability of MAC regimens is not feasible in patients who are older/unfit, which represents a considerable proportion of patients presenting worldwide. In such cases, reduced intensity conditioning regimens represent the next best option. Autologous HCT could be considered in patients who are older/unfit who did not have bone marrow involvement at initial presentation and at time of the procedure, albeit data supporting this option are less abundant. Future research is needed to decipher the interplay between clinical, genetic, and molecular features of the disease to personalize treatment accordingly, by enhancing efficacy and avoiding unnecessary toxicities.

A user-friendly software to accurately count and measure cysts from the parasitic nematode Heterodera glycines

Utilizing the subtractive proteomics approach to design ensemble vaccine against Candida lusitaniae for immune response stimulation; a bioinformatics study

Vaccines have always been one of the promising therapeutic sources against many pathogens including infectious fungi. Candida lusitaniae is also one of those fungi which is responsible for different infections in human beings including vaginitis, endocarditis, endophthalmitis and blood stream infections. There is thus, a need to adopt effective therapeutic strategies to tackle such infections. Vaccine is one of those efficient therapeutic agents which stimulates immune response and prevents a certain infection to get hazardous. Keeping in view this very important concept, we have designed in-silico vaccine against C. lusitaniae by following the subtractive proteomics approach. Initially, the screening of therapeutic targets was performed to identify potent vaccine candidates from the whole proteome of C. lusitaniae. Several significant factors were taken into account in this context, such as stability index, IFN status, allergenicity, and antigenicity. As a result, four distinct proteins that were both antigenic and non-allergenic, were selected from the whole proteome. Furthermore, physiochemical investigation revealed that these vaccine candidates were stable and that their IFN status was positive. Notably, each of these proteins was non-homologous to human beings. This particular attribute of the selected proteins i.e., to be non-homologous, was made in order to possess the ability to trigger an immunological response in host (humans). Furthermore, the whole proteome (WP) vaccine was constructed accordingly. The structural modelling of all the selected vaccine candidates was then performed to proceed them further for docking with the human toll-like receptor 2 (TLR2). Afterwards, the codon optimization was executed, followed by in-silico cloning of the final vaccine construct. The pet28A plasmid was incorporated for this purpose while, the SnapGene tool was utilized for this particular analysis. Ultimately, the immune simulations were executed to assess the immune response of the designed vaccine (WP). Upon final results, it was found that highest count of IgG and IgM was achieved i.e., up to 700000 between the days 8 to 13 and then slowly neutralized till the day 30. These results signified that the designed vaccine possessed the potential to stimulate the required immune response.

Antibodies to PF4 in severe COVID-19: same but different

Dysregulation of mTOR signalling is a converging mechanism in lissencephaly

Construction and validation of a predictive model for the risk of osteoporosis in patients with chronic kidney disease based on NHANES data

Background Chronic kidney disease (CKD) patients tend to exhibit a heightened susceptibility to osteoporosis owing to abnormalities in mineral and bone metabolism. The objective of this study was to develop and validate a nomogram for the prediction of osteoporosis risk in patients with CKD. Methods 1498 patients diagnosed with CKD were enrolled from the National Health and Nutrition Examination Survey (NHANES) data spanning 2005–2010, 2013–2014, and 2017–2018. The dataset was randomly divided into a training set and a validation set in a ratio of 7:3. Utilizing the least absolute shrinkage and selection operator (LASSO) regression technique for predictor identification, followed by employing multivariate logistic regression based on the selected predictors to construct a nomogram. The performance of the prediction model was assessed using various metrics, including the area under the receiver operating characteristic curve (AUC), calibration curve, the Hosmer-Lemeshow test, and decision curve analysis (DCA). Results The construction of the nomogram was based on five predictors, namely age, height, weight, alkaline phosphatase (ALP), and history of fracture. The AUC of 0.8511 in the training set and 0.8184 in the validation set demonstrates robust discriminability. Furthermore, the excellent calibration and clinical applicability of the model have been thoroughly validated. Conclusions Our study suggests a nomogram, providing nephrologists with a convenient and effective tool for identifying individuals at high risk of osteoporosis and avoiding adverse outcomes related to CKD.

Asciminib plus dasatinib and prednisone for Philadelphia chromosome–positive acute leukemia

Abstract Dasatinib is an effective treatment for Philadelphia chromosome–positive (Ph+) acute leukemia, but some patients develop resistance. Combination treatment with dasatinib and asciminib, an allosteric inhibitor of BCR::ABL1, may deepen responses and prevent the emergence of dasatinib-resistant clones. In this phase 1 study (NCT03595017), 24 adults with Ph+ acute lymphoblastic leukemia (ALL; n = 22; p190, n = 16; p210, n = 6) and chronic myeloid leukemia in lymphoid blast crisis (n = 2) were treated with escalating daily doses of asciminib in combination with dasatinib 140 mg daily plus prednisone 60 mg/m2 daily to determine the maximum tolerated dose. After a 28-day induction, dasatinib and asciminib were continued indefinitely or until hematopoietic stem cell transplant. The median age was 64.5 years (range, 33-85; 50% aged ≥65 years). The recommended phase 2 dose of asciminib was 80 mg daily in combination with dasatinib and prednisone. The dose limiting toxicity at 160 mg daily was asymptomatic grade 3 pancreatic enzyme elevation without symptomatic pancreatitis. There were no vaso-occlusive events. Among patients with de novo ALL, the complete hematologic remission rates at days 28 and 84 were 84% and 100%, respectively. At day 84, 100% of patients achieved complete cytogenetic remission, 89% achieved measurable residual disease negativity (<0.01%) by multicolor flow cytometry, and 74% and 26% achieved BCR::ABL1 reverse transcription quantitative polymerase chain reaction <0.1% and <0.01%, respectively. Dual BCR::ABL1 inhibition with dasatinib and asciminib is safe with encouraging activity in patients with de novo Ph+ ALL. This trial was registered at www.clinicaltrials.gov as #NCT02081378.

Characteristic analysis and surgical exploration for acetabular roof fractures: Multicenter retrospective cohort study

Background Acetabular roof was a crucial structure for maintaining the stability of hip joint; however, its important role was not especially emphasized in the Letournel-Judet classification system. Acetabular roof was segmented into the roof column and roof wall in Three-column classification and fracture in this area alone was defined as A3 injury. The purpose of this study was to explore the characteristics and surgical strategy of A3 injury. Methods Patients with roof column/wall fractures received surgical management from January 2015 to 2019 January at nine level-1 trauma centers were retrospectively analyzed. Fracture data, surgical incision, operation time, blood loss, fracture healing and relevant complications were recorded to explore fracture characteristics and appropriate surgical strategy. Reduction quality was assessed based on postoperative radiographic examination. Merle d’Aubigné score was used to assess the functional outcome during the follow-up. Results A total of 60 patients met the inclusion criteria in this study. Mean operation time was 112.83±21.77 min, and mean intraoperative blood loss was 396.67±182.00 ml. Satisfactory reduction quality was obtained in 49 cases (81.67%). All fractures healed well at an average mean of 3.07 months. Satisfactory outcomes were obtained in 46 cases (76.67%), and mean Merle d’Aubigné score was 15.53±1.33 points at the final follow-up. Reduction quality and functional outcome showed no statistical difference in three subtypes (P<0.05). Reduction quality and functional outcome presented positive correlation in three subtype fractures (P<0.05). The complication rate was 11.67% (7/60) in this study. Conclusion The injury mechanism of A3 injury was the direct impaction from femoral head on acetabular roof. Reduction and fixation of A3 injury were technique demanding, and poor prognosis may be accompanied even treated by experienced surgeons. Appropriate surgical strategies (Table 5) based on fracture characteristics in three subtypes of A3 injury were the premise of accepted prognosis.

Acute myeloid leukemia with <i>BCL6</i> and <i>KMT2A</i> dual rearrangements

Re-calibrating measurements of low-cost air quality monitors using PCR-GPR air quality forecasting models

As a key tool for real-time monitoring of air pollutant concentrations, the chemical sensor, the core component of the low-cost Air Quality Monitor (AQM), is susceptible to a variety of factors during the measurement process, leading to errors in the measurement data. To enhance the measurement accuracy of chemical sensors, this paper presents a calibration method based on the PCR-GPR model. This method not only effectively enhances the measurement accuracy of chemical sensors, but also combines the interpretability of traditional statistical models with the high-precision characteristics of Gaussian Process Regression (GPR) models. First, we perform Principal Component Analysis (PCA) on the measurement data of the AQM to solve the multicollinearity problem. Through PCA, we successfully extracted 8 principal components, which not only contained 95% of the information in the original data, but also effectively eliminated the correlation between the variables, providing a more robust data base for subsequent modeling. Subsequently, we established a Principal Component Regression (PCR) model using the concentration of pollutants measured by the national monitoring station as the dependent variable and the 8 principal components extracted above as the independent variables. The PCR model can effectively extract the linear relationship between the independent and dependent variables, providing a linear part of the explanation for the calibration process. However, there are often complex nonlinear relationships between pollutant concentrations and AQM measurements. To capture these nonlinear relationships, we further established a GPR model with the residuals of the PCR model as the dependent variable and the measurement data of the AQM as the independent variable. By combining the PCR model and the GPR model, we obtained the final PCR-GPR calibration model. It is worth mentioning that this study adopted the time series cross-validation method for data grouping, an innovative approach that is more aligned with real-world scenarios and adequately captures the seasonal variations in pollutant concentrations. The experimental results show that the model exhibits excellent performance on several evaluation metrics and can calibrate the chemical sensor well, improving its measurement accuracy by 16.94% ~ 82.01%.

β-Thalassemia minor is associated with high rates of worsening anemia in pregnancy

Abstract We identified 347 pregnancies in patients with β-thalassemia minor. Hemoglobin was &amp;lt;9 g/dL in 31% during third trimester and 7.6% at delivery. Postpartum hemorrhage occurred in 8.9%. Forty-six percent of IV iron administration was to iron-replete patients.

SCO6564, a novel 3-ketoacyl acyl carrier protein synthase III, contributes in fatty acid synthesis in Streptomyces coelicolor

The genus Streptomyces comprises gram-positive bacteria that produce large numbers of secondary metabolites, which have promising commercial applications and deserve extensive study. Most bacteria synthesize fatty acids using a type II fatty acid synthase, with each step catalyzed by a discrete protein. Fatty acid synthesis has been intensively studied in the model strain Streptomyces coelicolor, in which 3-ketoacyl-acyl carrier protein synthase III (KAS III, FabH) is essential for growth and fatty acid biosynthesis. In this study, the FabH homolog SCO6564 (named FabH2) was identified in the S. coelicolor genome by BLAST analysis. The expression of fabH2 restored the growth of Ralstonia solanacearum fabH mutant and made the mutant produce small amounts of branched-chain fatty acids. FabH2 could condense various substrates, including straight-chain and branched-chain acyl-CoAs, with malonyl-acyl carrier protein to initiate fatty acid synthesis in in vitro assays. The fabH2 deletion did not cause significant changes in the growth or fatty acid composition of S. coelicolor, indicating that fabH2 is nonessential for growth or fatty acid synthesis. However, fabH2 overexpression reduced the blue-pigmented actinorhodin production. Phylogenetic analysis of KAS III from different bacteria revealed that FabH2 belongs to a novel group of FabH-type, which is ubiquitous in Streptomyces spp.