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Design and optimization of a negative pressure rotary cutting safflower filaments harvesting device
Key process in sex-cell formation can finally be studied in vitro
Development of the Lee Symptom Scale–Skin Sclerosis for chronic GVHD–associated sclerosis
Abstract Sclerosis is a highly morbid manifestation of chronic graft-versus-host disease (cGVHD), associated with distressing symptoms and significant long-term disability. A patient-reported outcome (PRO) measure for cGVHD-associated sclerosis is essential to advance therapeutic trials. We aimed to develop a PRO for adults with cGVHD-associated sclerosis and evaluate and refine its content validity. Adults aged ≥18 years with cGVHD-associated sclerosis participated in semistructured interviews to identify salient symptoms and functions. Sclerosis-relevant symptoms and functions from existing PROs were also used to prompt discussion of topics not spontaneously mentioned. Symptoms and functions (subcodes) of importance were clustered and mapped to overarching domains (codes) using inductive analysis, and candidate items were developed. Cognitive interviews were used to evaluate content validity of the items, response options, recall period, and respondent instructions. Thirty-six open-ended interviews, conducted to saturation, revealed the breadth of the patient experience with cGVHD-associated sclerosis including 5 overarching domains: (1) skin changes, (2) symptoms, (3) emotional and social functioning, (4) mobility restrictions, and (5) activity limitations. A pool of 54 items was tested and iteratively refined through cognitive debriefing interviews (n = 25). Phrasing changes were made to improve relevance and comprehension. One item was removed, and 2 items were added to address respondent feedback, resulting in 55 items. Results support the relevance, comprehensibility, and comprehensiveness of the provisional Lee Symptom Scale–Skin Sclerosis. Concept elicitation and cognitive interviewing have informed the development of the Lee Symptom Scale–Skin Sclerosis. Psychometric testing and determination of minimal clinically important differences are underway in an external cohort to validate the PROs.
Elevated troponin levels in rhabdomyolysis as a predictor of mortality in patients with normal kidney and cardiac function
Megakaryocyte mitotic figures in de novo AML, myelodysplasia related, with STAG2, SRSF2, and ASXL1 comutations
The association of life’s essential 8 scores trajectory patterns with the risk of all cancer types
How the NIH dominates the world’s health research — in charts
An opponent striatal circuit for distributional reinforcement learning
How I use maintenance therapy in acute myeloid leukemia
Abstract Outcomes for acute myeloid leukemia (AML) have improved significantly in the past decade with the approval of novel therapeutics targeting diverse vulnerabilities of leukemic cells, expanded access to stem cell transplantation, and improved safety of transplantation. Although attainment of initial remission is now an expected outcome in most patients with AML receiving intensive or nonintensive induction regimens, maintaining long-term remission and decreasing the risk of relapse remain critical challenges. Maintenance approaches using assorted agents have yielded variable success and only recently have been integrated to the standard of care. We present 4 commonly encountered clinical scenarios that highlight challenges facing physicians as they care for patients with AML in remission and contemplate using postremission maintenance. Using published studies and emerging clinical data, we discuss our approach to maintenance treatment in AML, emphasizing that selection of a specific strategy is an individualized decision based on leukemia biology and risk stratification, presence of targetable mutations, initial treatment approach, performance status, and feasibility of allogeneic stem cell transplantation.
Experimental wavefront sensing techniques based on deep learning models using a Hartmann-Shack sensor for visual optics applications
Triplets: the bright and the dark side of the moon
Distributional outcomes of urban heat island reduction pathways under climate extremes
Zanubrutinib, venetoclax, and obinutuzumab in R/R CLL
Serum metabolomics indicates ferroptosis in patients with pantothenate kinase associated neurodegeneration
Abstract The core syndrome among NBIA disorders is pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder caused by mutations in the PANK2 gene. There is no therapy for PKAN; only symptomatic treatment is available. Our work aimed to identify the mechanisms induced by biochemical disturbances in the cell cycle and identify potential pharmacological targets to improve patient quality of life. Mass spectrometry (MS) (metals) and NMR spectroscopy (hydrophilic and hydrophobic compounds) were used for profile analyses of the sera of 12 PKAN patients and 12 controls to study the compounds involved in PKAN pathomechanisms. We performed ANOVA and multivariate analysis using orthogonal partial least squares discriminant analysis. We have shown for the first time that patients have 100–500-fold greater serum citrate levels than controls do, which may contribute to Fe transport and ferroptosis. Ferroptosis may be indicated by disturbances in the levels of many metals, oxidative stress, disturbances in energy production and neurotransmission or dysfunction of biological membranes. Our findings suggest that ferroptosis could be a primary cause of cell death in PKAN patients. This could be indicated by serum metabolomics.
‘Scientists will not be silenced’: thousands protest Trump research cuts
Population dynamics modeling reveals that myeloid bias involves both HSC differentiation and progenitor proliferation biases
Abstract Aging and chronic inflammation are associated with overabundant myeloid-primed multipotent progenitors (MPPs) among hematopoietic stem and progenitor cells (HSPCs). Although hematopoietic stem cell (HSC) differentiation bias has been considered a primary cause of myeloid bias, whether it is sufficient has not been quantitatively evaluated. Here, we analyzed bone marrow data from the IκB− (Nfkbia+/−Nfkbib−/−Nfkbie−/−) mouse model of inflammation with elevated NFκB activity, which reveals increased myeloid-biased MPPs. We interpreted these data with differential equation models of population dynamics to identify alterations of HSPC proliferation and differentiation rates. This analysis revealed that short-term HSC differentiation bias alone is likely insufficient to account for the increase in myeloid-biased MPPs. To explore additional mechanisms, we used single-cell RNA sequencing (scRNA-seq) measurements of IκB− and wild-type HSPCs to track the continuous differentiation trajectories from HSCs to erythrocyte/megakaryocyte, myeloid, and lymphoid primed progenitors. Fitting a partial differential equations model of population dynamics to these data revealed not only less lymphoid-fate specification among HSCs but also increased expansion of early myeloid-primed progenitors. Differentially expressed genes along the differentiation trajectories supported increased proliferation among these progenitors. These findings were conserved when wild-type HSPCs were transplanted into IκB− recipients, indicating that an inflamed bone marrow microenvironment is a sufficient driver. We then applied our analysis pipeline to scRNA-seq measurements of HSPCs isolated from aged mice and human patients with myeloid neoplasms. These analyses identified the same myeloid-primed progenitor expansion as in the IκB− models, suggesting that it is a common feature across different settings of myeloid bias.
Study of the vibration frequency characteristics of tectonic coal containing assemblages at different loading rates
Microsoft quantum computing ‘breakthrough’ faces fresh challenge
Human-correlated genetic models identify precision therapy for liver cancer
Abstract Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer-related mortality worldwide 1,2 . HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulate progressive driver mutations 3 , with hepatocytes the most likely cell of origin 2 . However, the landscape of driver mutations in HCC is broadly independent of the underlying aetiologies 4 . Despite an increasing range of systemic treatment options for advanced HCC, outcomes remain heterogeneous and typically poor. Emerging data suggest that drug efficacies depend on disease aetiology and genetic alterations 5,6 . Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC 7 . Here we generated a suite of genetically driven immunocompetent in vivo and matched in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance and metastasis. We integrated transcriptomic data from the mouse models with human HCC data and identified four common human–mouse subtype clusters. The subtype clusters had distinct transcriptomic characteristics that aligned with the human histopathology. In a proof-of-principle analysis, we verified response to standard-of-care treatment and used a linked in vitro–in vivo pipeline to identify a promising therapeutic candidate, cladribine, that has not previously been linked to HCC treatment. Cladribine acts in a highly effective subtype-specific manner in combination with standard-of-care therapy.