Miracle-dz/UniFAR-FTUs huggingface dataset:
Lymphoma cell VEGFR2 expression detected by immunohistochemistry predicts poor overall survival in diffuse large B cell lymphoma treated with immunochemotherapy (R‐CHOP)

Diffuse large B cell lymphoma (DLBCL) is clinically and biologically heterogeneous. In most cases of DLBCL, lymphoma cells co‐express vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2, suggesting autocrine in addition to angiogenic effects. We enumerated microvessel density and scored lymphoma cell expression of VEGF, VEGFR1, VEGFR2 and phosphorylated VEGFR2 in 162 de novo DLBCL patients treated with R‐CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone)‐like regimens. VEGFR2 expression correlated with shorter overall survival (OS) independent of International Prognostic Index (IPI) (P = 0·0028). Phosphorylated VEGFR2 (detected in 13% of cases) correlated with shorter progression‐free survival (PFS, P = 0·044) and trended toward shorter OS on univariate analysis. VEGFR1 was not predictive of survival on univariate analysis, but it did correlate with better OS on multivariate analysis with VEGF, VEGFR2 and IPI (P = 0·036); in patients with weak VEGFR2, lack of VEGFR1 coexpression was significantly correlated with poor OS independent of IPI (P = 0·01). These results are concordant with our prior finding of an association of VEGFR1 with longer OS in DLBCL treated with chemotherapy alone. We postulate that VEGFR1 may oppose autocrine VEGFR2 signalling in DLBCL by competing for VEGF binding. In contrast to our prior results with chemotherapy alone, microvessel density was not prognostic of PFS or OS with R‐CHOP‐like therapy.
Prognostic relevance of TLX3 (HOX11L2) expression in childhood T‐cell acute lymphoblastic leukaemia treated with Berlin–Frankfurt–Münster (BFM) protocols containing early and late re‐intensification elements

TLX3 expression (TLX3+) in childhood T‐cell acute lymphoblastic leukaemia (T‐ALL) seems to be associated with a poor prognosis when treated with regimens that lack early and/or late re‐intensification therapy elements. Because such elements are essential components of the ALL‐BFM (Berlin–Frankfurt–Münster) protocols, we evaluated whether TLX3+ T‐ALL patients benefit from this type of therapy. Thirty‐one/131 childhood T‐ALL cases (24%) enrolled into four population‐based Austrian ALL‐BFM therapy studies were TLX3+. The male to female ratio was 3·5:1 and median age and leucocyte count at diagnosis were 8·7 years and 58·9 × 109/l, respectively. Twenty‐four patients (77%) were good responders to prednisone. All were in complete remission after induction therapy. After a median observation time of 4·9 years (range 0·4–16·1 years) 28/31 TLX3+ cases remained in first complete remission after chemotherapy with one after additional stem cell transplantation. Although molecular disease was frequently present after a 4‐drug induction therapy, final treatment outcome was excellent indicating that TLX3+ T‐ALL cases may benefit from a BFM‐type of ALL therapy with early and late re‐intensification elements. Moreover, the fact that 2/3 relapses were also NUP214‐ABL1+ suggests that these cases might represent the particular risk‐prone TLX3+ subgroup that could benefit from a targeted tyrosine kinase inhibitor therapy.
Laboratory correlates for a phase II trial of romidepsin in cutaneous and peripheral T‐cell lymphoma

Romidepsin has shown promise in the treatment of T‐cell lymphomas, and so we evaluated molecular endpoints gathered from 61 patients enrolled on a phase II trial of romidepsin in cutaneous and peripheral T‐cell lymphoma at the National Institutes of Health. The endpoints included histone H3 acetylation and ABCB1 gene expression in peripheral blood mononuclear cells (PBMCs); ABCB1 gene expression in tumour biopsy samples; and blood fetal haemoglobin levels (HbF), all of which were increased following romidepsin treatment. The fold increase in histone acetylation in PBMCs at 24 h was weakly to moderately well correlated with the pharmacokinetic parameters Cmax and area under the curve (AUC)last (ρ = 0·37, P = 0·03 and ρ = 0·36, P = 0·03 respectively) and inversely associated with clearance (ρ = −0·44; P = 0·03). Histone acetylation in PBMCs at 24 h was associated with response (P = 0·026) as was the increase in fetal haemoglobin (P = 0·014); this latter association may be due to the longer on‐study duration for patients with disease response. Together, these results suggest that pharmacokinetics may be an important determinant of response to histone deacetylase inhibitors (HDIs) – the association with histone acetylation in PBMCs at 24 h is consistent with a hypothesis that potent HDIs are needed for a critical threshold of drug exposure and durable activity.
Urinary dedifferentiated podocytes as a non-invasive biomarker of lupus nephritis.

BACKGROUND Currently, renal biopsy remains the gold standard for the diagnosis and prognosis of lupus nephritis (LN). However, it is an invasive method, and new non-invasive laboratory tests are needed to identify renal involvement without renal biopsy. Podocyte damage plays an important role in the pathogenesis and progression of systemic lupus erythematosus (SLE). We characterize whether the phenotype of urinary podocytes (viability, apoptosis, mRNA and protein levels of the podocyte-associated molecules) is a novel marker of clinical and histological features in SLE patients with or without LN. METHODS We quantified in urinary sediments of 32 SLE patients and 20 controls, mRNA and protein levels of podocalyxin, synapotopodin, podocin, nephrin and WT-1 by quantitative real-time polymerase chain reaction and western blot analysis and correlated these with clinical and histological parameters. The viability of detached urine podocytes was analysed by flow cytometry with podocalyxin and annexin V/7-AAD double staining and immunofluorescence of urine podocyte cultures. RESULTS The degree of a poptotic podocytes from urine samples was significantly decreased in patients with LN, especially in the active state (33% compared with 75% in controls, P < 0.001), and the majority of the detached podocytes in the urine of patients with active LN were viable (70% grew in culture). Furthermore, urinary mRNA of podocyte-associated molecules was significantly lower in patients with active LN (P < 0.05) compared with healthy controls, and protein levels of podocyte markers were significantly increased in SLE patients, especially with LN compared with SLE without LN (P < 0.05) and the healthy control group (P < 0.01). Finally, urinary protein levels of podocyte-related markers were associated with proteinuria and histological features (P < 0.05 and P < 0.01), and receiver operating characteristics curves of protein levels discriminate between LN and healthy controls with an area under the curve (AUC) between 0.91 and 0.77 (P < 0.001). CONCLUSIONS Urinary dedifferentiated podocytes were shown in active LN, and their protein levels correlated with proteinuria and histological features in LN. These preliminary results suggest that it could be a potentially useful non-invasive marker for evaluating the progression of glomerular disease in SLE.
p53Ψ is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state

Significance p53 is one of the most intensively studied tumor-suppressor genes. We identified a naturally occurring p53 isoform, generated by an alternative-splicing event, that, although lacking transcriptional activity and canonical tumor suppressor functions, is able to reprogram cells toward the acquisition of metastatic features via a cyclophilin D interaction in the mitochondria matrix. Interestingly, this isoform is expressed on tissue injury and in tumors characterized by increased metastatic spread. In some of these tumors, p53-like isoforms are generated by intron 6 mutations. This suggests a possible physiological origin of certain p53 mutations and indicates that mutations resulting in the generation of truncated p53Ψ-like proteins do more than create a 53-null state. Although much is known about the underlying mechanisms of p53 activity and regulation, the factors that influence the diversity and duration of p53 responses are not well understood. Here we describe a unique mode of p53 regulation involving alternative splicing of the TP53 gene. We found that the use of an alternative 3′ splice site in intron 6 generates a unique p53 isoform, dubbed p53Ψ. At the molecular level, p53Ψ is unable to bind to DNA and does not transactivate canonical p53 target genes. However, like certain p53 gain-of-function mutants, p53Ψ attenuates the expression of E-cadherin, induces expression of markers of the epithelial-mesenchymal transition, and enhances the motility and invasive capacity of cells through a unique mechanism involving the regulation of cyclophilin D activity, a component of the mitochondrial inner pore permeability. Hence, we propose that p53Ψ encodes a separation-of-function isoform that, although lacking canonical p53 tumor suppressor/transcriptional activities, is able to induce a prometastatic program in a transcriptionally independent manner.
Multiscale observations of CO2, 13CO2, and pollutants at Four Corners for emission verification and attribution

Significance Climate change and air pollution caused by fossil-energy-related CO2 and NOx emissions is a capstone societal issue. A critical barrier to an international treaty aimed toward controlling emissions is the inability to verify inventories and reduction of emissions claimed by individual nations following implementation of new technologies. We demonstrate for the first time, to our knowledge, that simultaneous remote observations of CO2, NO2, and CO regional column enhancements can be made with high fidelity and frequency. These can then be used to identify emissions from power plants and to distinguish them from other sources. Our findings represent a significant advancement in remote sensing monitoring methodology and can be used to develop an enforceable, transparent, and equitable climate treaty. There is a pressing need to verify air pollutant and greenhouse gas emissions from anthropogenic fossil energy sources to enforce current and future regulations. We demonstrate the feasibility of using simultaneous remote sensing observations of column abundances of CO2, CO, and NO2 to inform and verify emission inventories. We report, to our knowledge, the first ever simultaneous column enhancements in CO2 (3–10 ppm) and NO2 (1–3 Dobson Units), and evidence of δ13CO2 depletion in an urban region with two large coal-fired power plants with distinct scrubbing technologies that have resulted in ∆NOx/∆CO2 emission ratios that differ by a factor of two. Ground-based total atmospheric column trace gas abundances change synchronously and correlate well with simultaneous in situ point measurements during plume interceptions. Emission ratios of ∆NOx/∆CO2 and ∆SO2/∆CO2 derived from in situ atmospheric observations agree with those reported by in-stack monitors. Forward simulations using in-stack emissions agree with remote column CO2 and NO2 plume observations after fine scale adjustments. Both observed and simulated column ∆NO2/∆CO2 ratios indicate that a large fraction (70–75%) of the region is polluted. We demonstrate that the column emission ratios of ∆NO2/∆CO2 can resolve changes from day-to-day variation in sources with distinct emission factors (clean and dirty power plants, urban, and fires). We apportion these sources by using NO2, SO2, and CO as signatures. Our high-frequency remote sensing observations of CO2 and coemitted pollutants offer promise for the verification of power plant emission factors and abatement technologies from ground and space.
Flexible n‐Type High‐Performance Thermoelectric Thin Films of Poly(nickel‐ethylenetetrathiolate) Prepared by an Electrochemical Method

Flexible thin films of poly(nickel-ethylenetetrathiolate) prepared by an electrochemical method display promising n-type thermoelectric properties with the highest ZT value up to 0.3 at room temperature. Coexistence of high electrical conductivity and high Seebeck coefficient in this coordination polymer is attributed to its degenerate narrow-bandgap semiconductor behavior.
Clinical predictors of severe malarial anaemia in a holoendemic Plasmodium falciparum transmission area

Severe malarial anaemia (SMA) is a common complication of Plasmodium falciparum infections, resulting in mortality rates that may exceed 30% in paediatric populations residing in holoendemic transmission areas. One strategy for reducing the morbidity and mortality associated with SMA is to identify clinical predictors that can be readily recognized by caregivers for prompt therapeutic interventions. To determine clinical predictors of SMA, Kenyan children (3–36 months, n = 671) presenting with acute illness at a rural hospital in Siaya District were recruited. Demographic, clinical, laboratory and haematological parameters were measured upon enrolment. As human immunodeficiency virus‐1 and bacteraemia promote reduced haemoglobin (Hb) concentrations, children with these infections were excluded from the analyses. Children with P. falciparum mono‐infections (n = 355) were stratified into three groups: uncomplicated malaria (Hb ≥ 110 g/l); non‐SMA (60 ≤ Hb < 109), and SMA (Hb < 60 g/l). SMA was characterized by a younger age, monocytosis, thrombocytopenia, reticulocytosis, reduced erythropoiesis, elevated pigment‐containing monocytes (PCM), respiratory distress, conjunctival and palmar pallor, splenomegaly, signs of malnutrition, and protracted fever and emesis. Logistic regression analysis demonstrated that age, reticulocyte count, presence of PCM and conjunctival and palmar pallor were significant predictors of SMA. Recognition of these clinical signs in children residing in resource‐poor settings may help to guide the identification and management of SMA.
The optimal use of steroids in paediatric acute lymphoblastic leukaemia: no easy answers

Glucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL), but usage differs between cooperative group protocols. All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone. Issues to consider in the choice of induction steroid include impact on event‐free and overall survival, acute morbidity such as infection risk, diabetes, and behavioural disturbances and long‐term complications such as avascular necrosis. It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase, but dosing schedules (intermittent versus continuous) vary. There is no consensus on the potential benefit of steroid administration during maintenance therapy. This review will summarize the current available data on steroid use in paediatric ALL, highlighting outcomes as well as major toxicities.
Structure, domain organization, and different conformational states of stem cell factor-induced intact KIT dimers

Significance Stem cell factor (SCF) mediates its cellular responses by binding to and activating KIT, a transmembrane receptor tyrosine kinase. Here we describe an electron microscopy (EM) 3D reconstruction of negatively stained preparations of SCF-stimulated full-length KIT dimers. Assessment of the EM structure in respect to X-ray crystal structures of KIT extracellular and tyrosine kinase domains reveals the relative positioning of the individual domains in the context of the entire SCF-KIT complex. Whereas the homotypic contacts between the two KIT protomers show a consistent twofold symmetry for the ectodomains, the cytoplasmic arrangement is asymmetric and is found in several discrete conformations. The observed asymmetric contacts between tyrosine kinases may represent molecular interactions occurring during trans autophosphorylation and kinase stimulation. Using electron microscopy and fitting of crystal structures, we present the 3D reconstruction of ligand-induced dimers of intact receptor tyrosine kinase, KIT. We observe that KIT protomers form close contacts throughout the entire structure of ligand-bound receptor dimers, and that the dimeric receptors adopt multiple, defined conformational states. Interestingly, the homotypic interactions in the membrane proximal Ig-like domain of the extracellular region differ from those observed in the crystal structure of the unconstrained extracellular regions. We observe two prevalent conformations in which the tyrosine kinase domains interact asymmetrically. The asymmetric arrangement of the cytoplasmic regions may represent snapshots of molecular interactions occurring during trans autophosphorylation. Moreover, the asymmetric arrangements may facilitate specific intermolecular interactions necessary for trans phosphorylation of different KIT autophosphorylation sites that are required for stimulation of kinase activity and recruitment of signaling proteins by activated KIT.
3D Freeze‐Casting of Cellular Graphene Films for Ultrahigh‐Power‐Density Supercapacitors

3D cellular graphene films with open porosity, high electrical conductivity, and good tensile strength, can be synthesized by a method combining freeze-casting and filtration. The resulting supercapacitors based on 3D porous reduced graphene oxide (RGO) film exhibit extremely high specific power densities and high energy densities. The fabrication process provides an effective means for controlling the pore size, electronic conductivity, and loading mass of the electrode materials, toward devices with high energy-storage performance.
Anti-thymocyte globulins in kidney transplantation: focus on current indications and long-term immunological side effects

Antithymocyte globulins (ATGs) are part of the immunosuppression arsenal currently used by clinicians to prevent or treat acute rejection in solid organ transplantation. ATG is a mixture of non-specific anti-lymphocyte immunoglobulins targeting not only T cell subsets but also several other immune and non-immune cells, rendering its precise immunoglobulin composition difficult to appreciate or to compare from one preparation to another. Furthermore, several mechanisms of action have been described. Taken together, this probably explains the efficacy and the side effects associated with this drug. Recent data suggest a long-term negative impact on allograft and patient outcomes, pointing out the need to better characterize the potential toxicity and the benefit-risk balance associated to this immunosuppressive therapy within large clinical trials.
Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

Significance The small, lipid-binding protein, α-synuclein (α-syn), is associated with neurodegenerative diseases. α-Syn exists in various splice isoforms, and isoform expression varies with disease, but how these isoforms affect protein function is unknown. Using a yeast model expressing α-syn splice variants, we show that inhibition of sterol synthesis differentially affects α-syn plasma membrane association, vesicular association, and cellular toxicity, depending on which α-syn isoform is expressed. This result suggests that higher membrane sterol concentrations may be protective of synucleinopathy progression. Given the common use of cholesterol-reducing statins and their potential effects on membrane-binding proteins, further investigation of how sterol concentration and α-syn splice isoforms affect vesicular trafficking in synucleinopathies is warranted. Synucleinopathies are neurodegenerative diseases associated with toxicity of the lipid-binding protein α-synuclein (α-syn). When expressed in yeast, α-syn associates with membranes at the endoplasmic reticulum and traffics with vesicles out to the plasma membrane. At higher levels it elicits a number of phenotypes, including blocking vesicle trafficking. The expression of α-syn splice isoforms varies with disease, but how these isoforms affect protein function is unknown. We investigated two of the most abundant isoforms, resulting in deletion of exon four (α-synΔ4) or exon six (α-synΔ6). α-SynΔ4, missing part of the lipid-binding domain, had reduced toxicity and membrane binding. α-SynΔ6, missing part of the protein–protein interaction domain, had reduced toxicity but no reduction in membrane binding. To compare the mechanism by which the splice isoforms exert toxicity, equally toxic strains were probed with genetic modifiers of α-syn–induced toxicity. Most modifiers equally altered the toxicity induced by the splice isoforms and full-length α-syn (α-synFL). However, the splice isoform strains responded differently to a sterol-binding protein, leading us to examine the effect of sterols on α-syn–induced toxicity. Upon inhibition of sterol synthesis, α-synFL and α-synΔ6, but not α-synΔ4, showed decreased plasma membrane association, increased vesicular association, and increased cellular toxicity. Thus, higher membrane sterol concentrations favor plasma membrane binding of α-synFL and α-synΔ6 and may be protective of synucleinopathy progression. Given the common use of cholesterol-reducing statins and these potential effects on membrane binding proteins, further investigation of how sterol concentration and α-syn splice isoforms affect vesicular trafficking in synucleinopathies is warranted.
Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation

Significance Osteoblast precursors residing in the bone marrow experience hypoxia, which leads to stabilization and increased activity of hypoxia-inducible factor 1α (HIF1α). However, whether an increase in HIF1α activity directly impacts bone formation is not known. Two well-known functions of HIF1α are to promote angiogenesis and to stimulate glycolysis in the cell. Here, we demonstrate that HIF1α stabilization in osteoblast precursors of postnatal mice markedly increases osteoblast number and bone mass. Furthermore, the greater bone mass was not secondary to increased angiogenesis but rather dependent on the up-regulation of glycolysis in osteoblast precursors. These results provide strong evidence that alterations in cellular metabolism directly influence cell differentiation. The bone marrow environment is among the most hypoxic in the body, but how hypoxia affects bone formation is not known. Because low oxygen tension stabilizes hypoxia-inducible factor alpha (HIFα) proteins, we have investigated the effect of expressing a stabilized form of HIF1α in osteoblast precursors. Brief stabilization of HIF1α in SP7-positive cells in postnatal mice dramatically stimulated cancellous bone formation via marked expansion of the osteoblast population. Remarkably, concomitant deletion of vascular endothelial growth factor A (VEGFA) in the mouse did not diminish bone accrual caused by HIF1α stabilization. Thus, HIF1α-driven bone formation is independent of VEGFA up-regulation and increased angiogenesis. On the other hand, HIF1α stabilization stimulated glycolysis in bone through up-regulation of key glycolytic enzymes including pyruvate dehydrogenase kinase 1 (PDK1). Pharmacological inhibition of PDK1 completely reversed HIF1α-driven bone formation in vivo. Thus, HIF1α stimulates osteoblast formation through direct activation of glycolysis, and alterations in cellular metabolism may be a broadly applicable mechanism for regulating cell differentiation.