Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic strategies for the treatment of sickle cell anaemia

Sickle cell anaemia is a severe inherited blood disorder for which there is presently no curative therapy other than allogeneic haematopoietic stem cell (HSC) transplantation. This therapeutic option, however, is not available to most patients because of the lack of a matched related donor. Different genetic strategies aiming to treat the anaemia and prevent sickling are under investigation. They include strategies to transfer a regulated globin gene in autologous HSCs–the most developed approach, which is about to undergo clinical evaluation–, and strategies to either restore endogenous HBG expression, repair or eliminate HBBS mutant transcripts, or correct the sickle mutation in HSCs or induced pluripotent stem cells. Their common ultimate goals are to afford therapeutic levels of HbA or HbF in the erythroid progeny of autologous HSCs (sufficient to prevent pathological sickling) and engraft the genetically modified HSCs with minimal short‐term toxicity (primarily caused by the conditioning regimen) and long‐term toxicity (primarily caused by genotoxicity). We discuss here the status of application of these technologies, outlining recent advances and the hurdles that lay ahead.
The differential effect of lenalidomide monotherapy in patients with relapsed or refractory transformed non‐Hodgkin lymphoma of distinct histological origin

Transformed lymphoma (TL) represents a heterogeneous group of lymphomas with an aggressive course and poor prognosis. We assessed the clinical benefit of single‐agent lenalidomide based on histological origin, including transformed follicular lymphoma (tFL) and transformed chronic lymphocytic leukaemia/small lymphocytic lymphoma (tCLL/SLL). Our analysis included 33 patients with TL. Patients received lenalidomide at a median dose of 25 mg/d. The overall response rate (ORR) was 46%, with a median response duration of 12·8 months after a median follow‐up of 5·6 months. Median progression‐free survival was 5·4 months. Among patients with tFL, ORR was 57%, with a median response duration of 12·8 months. None of the patients with tCLL/SLL responded to lenalidomide monotherapy. The most common grade 3/4 adverse events were reversible myelosuppression. Our results suggest that the original lymphoma histology (i.e. FL) in TL patients may potentially be associated with response to salvage lenalidomide monotherapy.
Heterogeneity in Health Care Computing Environments.

Abstract This paper discusses issues of heterogeneity in computer systems, networks, databases, and presentation techniques, and the problems it creates in developing integrated medical information systems. The need for institutional, comprehensive goals are emphasized. Using the Columbia-Presbyterian Medical Center's computing environment as the case study, various steps to solve the heterogeneity problem are presented.
Bacterial formate hydrogenlyase complex

Significance The isolation of an active formate hydrogenlyase is a breakthrough in understanding the molecular basis of bacterial hydrogen production. For over 100 years, Escherichia coli has been known to evolve H2 when cultured under fermentative conditions. Glucose is metabolized to formate, which is then oxidized to CO2 with the concomitant reduction of protons to H2 by a single complex called formate hydrogenlyase, which had been genetically, but never biochemically, characterized. In this study, innovative molecular biology and electrochemical experiments reveal a hydrogenase enzyme with the unique ability to sustain H2 production even under high partial pressures of H2. Harnessing bacterial H2 production offers the prospect of a source of fully renewable H2 energy, freed from any dependence on fossil fuel. Under anaerobic conditions, Escherichia coli can carry out a mixed-acid fermentation that ultimately produces molecular hydrogen. The enzyme directly responsible for hydrogen production is the membrane-bound formate hydrogenlyase (FHL) complex, which links formate oxidation to proton reduction and has evolutionary links to Complex I, the NADH:quinone oxidoreductase. Although the genetics, maturation, and some biochemistry of FHL are understood, the protein complex has never been isolated in an intact form to allow biochemical analysis. In this work, genetic tools are reported that allow the facile isolation of FHL in a single chromatographic step. The core complex is shown to comprise HycE (a [NiFe] hydrogenase component termed Hyd-3), FdhF (the molybdenum-dependent formate dehydrogenase-H), and three iron-sulfur proteins: HycB, HycF, and HycG. A proportion of this core complex remains associated with HycC and HycD, which are polytopic integral membrane proteins believed to anchor the core complex to the cytoplasmic side of the membrane. As isolated, the FHL complex retains formate hydrogenlyase activity in vitro. Protein film electrochemistry experiments on Hyd-3 demonstrate that it has a unique ability among [NiFe] hydrogenases to catalyze production of H2 even at high partial pressures of H2. Understanding and harnessing the activity of the FHL complex is critical to advancing future biohydrogen research efforts.
WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

Significance Genomic instability is a hallmark of human cancers. Common fragile sites (CFSs) pose nonrandom, preferential targets of genomic instability, such as chromosome breaks, in response to replicative stress. The tumor suppressor WW domain-containing oxidoreductase (WWOX) spans the CFS FRA16D and has been implicated in carcinogenesis by a currently unknown mechanism. In this study, we identify a direct role of WWOX in DNA damage response, which is a major antagonist of genomic instability. We show that WWOX maintains genomic stability and regulates DNA repair by modulating the activity of the DNA damage checkpoint kinase ataxia telangiectasia-mutated (ATM). Our findings provide evidence that a fragile gene product is directly involved in the response to DNA damage, suggesting a rationale for its preferential loss during carcinogenesis. Genomic instability is a hallmark of cancer. The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of γ-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells.
Regulation of fas/fas ligand‐mediated apoptosis by nuclear factor of activated T cells in megakaryocytes

Signal transduction pathways in megakaryocytes, a rare population of bone marrow cells, are poorly understood. We have previously shown that the calcineurin‐dependent transcription factor Nuclear Factor of Activated T cells (NFAT) is expressed in megakaryocytes and is required for the transcription of specific megakaryocytic genes. The biological role of NFAT in megakaryocytes, however, is unknown. Here we show that activation of the calcineurin/NFAT pathway in megakaryocytes forces the cells to go into apoptosis. Calcineurin/NFAT activation in megakaryocytes leads to membrane expression of Fas ligand (FASLG), a pro‐apoptotic member of the tumour necrosis factor superfamily. Expression of FASLG was augmented in cells stably overexpressing NFATC2 and suppressed in cells either pretreated with the calcineurin inhibitor ciclosporin A (CsA) or expressing the specific peptide inhibitor of NFAT, VIVIT. In cocultures with Fas‐expressing Jurkat T cells, the presence of activated megakaryocytic cells, but not of unstimulated cells or cells stimulated in the presence of CsA, significantly induced apoptosis in Jurkat cells in a Fas/FASLG‐ and NFAT‐dependent manner. These results represent the first evidence for a biological function of the calcineurin/NFAT pathway in megakaryocytes, and suggest that the biological role of megakaryocytes may include the induction of apoptosis in bystander cells.
Upper-tropospheric moistening in response to anthropogenic warming

Significance The fact that water vapor is the most dominant greenhouse gas underscores the need for an accurate understanding of the changes in its distribution over space and time. Although satellite observations have revealed a moistening trend in the upper troposphere, it has been unclear whether the observed moistening is a facet of natural variability or a direct result of human activities. Here, we use a set of coordinated model experiments to confirm that the satellite-observed increase in upper-tropospheric water vapor over the last three decades is primarily attributable to human activities. This attribution has significant implications for climate sciences because it corroborates the presence of the largest positive feedback in the climate system. Water vapor in the upper troposphere strongly regulates the strength of water-vapor feedback, which is the primary process for amplifying the response of the climate system to external radiative forcings. Monitoring changes in upper-tropospheric water vapor and scrutinizing the causes of such changes are therefore of great importance for establishing the credibility of model projections of past and future climates. Here, we use coupled ocean–atmosphere model simulations under different climate-forcing scenarios to investigate satellite-observed changes in global-mean upper-tropospheric water vapor. Our analysis demonstrates that the upper-tropospheric moistening observed over the period 1979–2005 cannot be explained by natural causes and results principally from an anthropogenic warming of the climate. By attributing the observed increase directly to human activities, this study verifies the presence of the largest known feedback mechanism for amplifying anthropogenic climate change.
Outcome and molecular characteristics of adolescent and young adult patients with newly diagnosed primary glioblastoma: a study of the Society of Austrian Neurooncology (SANO).

BACKGROUND Young age is a favorable prognostic factor for patients with glioblastoma multiforme (GBM). We reviewed the outcomes and molecular tumor characteristics of adolescent and young adult patients with GBM treated in 2 Austrian centers. PATIENTS AND METHODS Data on patients with histologically proven primary GBM diagnosed from 18 through 40 years of age were retrospectively analyzed. All patients were treated with standard first-line therapy. The primary end points were overall survival (OS) and time to progression (TTP). IDH1-R132H mutation status was analyzed using immunohistochemistry, and MGMT promoter methylation was assessed using methylation-specific polymerase chain reaction. RESULTS We included 70 patients (36 men and 34 women) with a median age of 33 years. IDH1-R132H mutations were detected in 22 (39.3%) of 56 cases and MGMT promoter methylation in 33 (61.1%) of 54 cases with available tissue samples. In patients with wild-type IDH, median TTP was 8.2 months and median OS was 24 months, compared with 18 months and 44 months, respectively, observed in patients with mutated IDH. Neither IDH1 nor MGMT status showed a statistically significant association with TTP or OS. Of note, the social and economical situation of the young patients with GBM was alarming, because only 17% succeeded in staying employed after receiving the diagnosis. CONCLUSIONS We found a high frequency of IDH1 mutations and MGMT promoter methylation among young adult patients with primary GBM that may contribute to the generally favorable outcome associated with young age. The social and economic coverage of patients with glioma remains an unsolved socio-ethical problem.
Inhibition of EZH2 suppresses self-renewal and induces radiation sensitivity in atypical rhabdoid teratoid tumor cells.

INTRODUCTION Overexpression of the Polycomb repressive complex 2 (PRC2) subunit Enhancer of Zeste 2 (EZH2) occurs in several malignancies, including prostate cancer, breast cancer, medulloblastoma, and glioblastoma multiforme. Recent evidence suggests that EZH2 may also have a role in rhabdoid tumors. Atypical teratoid/rhabdoid tumor (ATRT) is a rare, high-grade embryonal brain tumor that occurs most commonly in young children and carries a very poor prognosis. ATRTs are characterized by absence of the chromatin remodeling protein SMARCB1. Given the role of EZH2 in regulating epigenetic changes, we investigated the role of EZH2 in ATRT. METHODS Microarray analysis was used to evaluate expression of EZH2 in ATRT tumor samples. We used shRNA and a chemical inhibitor of EZH2 to examine the impact of EZH2 inhibition on cell growth, proliferation, and tumor cell self-renewal. RESULTS Here, we show that targeted disruption of EZH2 by RNAi or pharmacologic inhibition strongly impairs ATRT cell growth, suppresses tumor cell self-renewal, induces apoptosis, and potently sensitizes these cells to radiation. Using functional analysis of transcription factor activity, we found the cyclin D1-E2F axis to be repressed after EZH2 depletion in ATRT cells. CONCLUSIONS Our observations provide evidence that EZH2 disruption alters cell cycle progression and may be an important new therapeutic target, particularly in combination with radiation, in ATRT.
Anisotropic Slippery Surfaces: Electric‐Driven Smart Control of a Drop's Slide

Anisotropic slippery surfaces composed of directional, porous, conductive poly(3-hexylthiophene) (P3HT) fibers, and silicone oil exhibit excellent anisotropic sliding properties for several liquid droplets and the reversible control of conductive liquid droplets sliding on these surfaces under the application of voltage.
Malleable and Recyclable Poly(urea‐urethane) Thermosets bearing Hindered Urea Bonds

Poly(urea-urethane) thermosets containing the 1-tert-butylethylurea (TBEU) structure feature a reversible dissociation/association process of their covalent linkages under mild conditions. Unlike conventional thermosets, TBEU-based poly(urea-urethane) thermosets maintain their malleability after curing. Under high temperature (100 °C) and applied pressure (300 kPa), ground TBEU thermoset powder can be remolded to bulk after 20 min.
Prevention of chronic postoperative pain: Cellular and molecular insights for mechanisms-based treatment approaches.

Nearly every surgery can elicit a rather therapy-resistant chronic postoperative pain. Preventive medicine is therefore anticipated with hopeful eyes, but requires a better understanding of the neurobiological mechanisms underlying the transition from acute to chronic pain. Spinal mechanisms of pain amplification are regarded fundamental to pain chronification, but these mechanisms on their own are not at all likely to be sufficient. Indeed, not every surgical patient develops chronic postoperative pain. Progress in our neurobiological understanding of postoperative pain includes scientific discoveries of 'vulnerability factors', which substantially impact on the spinal cord, augmenting pain amplification mechanisms, perhaps to levels of no-return. In this review we elaborate on spinal pain amplification mechanisms in relation to pain chronification and the impact of vulnerability factors hereon. Moreover, these insights are incorporated within a clinical frame of treatment approaches currently used in surgical settings. As such, this review provides an integrated overview of mechanism-based treatment approaches in prevention of chronic postoperative pain.
Chemical Dealloying Derived 3D Porous Current Collector for Li Metal Anodes

A 3D porous Cu current collector is fabricated through chemical dealloying from a commerial Cu-Zn alloy tape. The interlinked porous framework naturally integrated can accommodate Li deposition, suppressing dendrite growth and alleviating the huge volume change during cycling. The Li metal anode combined with such a porous Cu collector demonstrates excellent performance and commerial potentials in Li-based secondary batteries.
Induced interleukin-33 expression enhances the tumorigenic activity of rat glioma cells.

BACKGROUND Glioma development is a multistep process associated with progressive genetic alterations but also regulated by cellular and noncellular components in a tumor-associated niche. METHODS Using 2 rat C6 glioma cell clones with different tumorigenesis, named C6-1 and C6-2, this study characterized genes associated with enhanced tumorigenic features of glioma cells by comparative cDNA microarray analysis combined with Q-PCR. Neurospehere formation and clonogenicity were examined to determine the growth of tumorigenic C6 glioma cells. The lentivirus-mediated gene knockdown approach was conducted to determine the role of interleukin-33 (IL-33) in glioma cell proliferation and migration. Transwell cell invasion assay was used to examine microglia migration induced by tumorigenic C6 cells. RESULTS The functional analysis of gene ontology (GO) biological processes shows that the upregulated genes found in tumorigenic C6 (C6-1) cells are closely related to cell proliferation. Tumorigenic C6 cells expressed cytokines and chemokines abundantly. Among these genes, IL-33 was profoundly induced in tumorigenic C6 cells with the expression of IL-33 receptor ST2. Furthermore, the growth rate and colony formation of tumorigenic C6 cells were attenuated by the inhibition of IL-33 and ST2 gene expression. Moreover, IL-33 was involved in tumorigenic glioma cell migration and regulation of the expression of several glioma-associated growth factors and chemokines in tumorigenic C6 cells. CONCLUSION Accordingly, we concluded that glioma cells with abundant production of IL-33 grow rapidly; moreover, the interactions of multiple cytokines/chemokines induced by glioma cells may develop a microenvironment that facilitates microglia/macrophage infiltration and fosters glioma growth in the brain.
Duration of anticoagulant therapy for venous thromboembolism: balancing benefits and harms on the long term

Venous thromboembolism (VTE) is effectively treated with anticoagulant therapy. After an initial treatment phase, extended treatment is effective to prevent recurrence after a first event but this is at the expense of a continued risk of bleeding. Ideally, patients at a high risk of recurrence and low risk of bleeding continue anticoagulant therapy, and for those at low risk of recurrence the duration of treatment can be limited. Identifying these patients, however, is difficult. Duration of treatment after a first VTE provoked by a transient risk factor should be limited to 3 months. Although guidelines suggest extended treatment for all patients after unprovoked VTE unless bleeding risk is high, we emphasize that the long‐term risks of recurrent VTE off anticoagulation are uncertain whereas the risk of bleeding associated with anticoagulant therapy increases with age. In the absence of evidence of replaced mortality or improved quality of life with extended anticoagulant treatment, we suggest a limited duration for most patients after a first VTE. Extended treatment can be considered, based mainly on patient preference.
Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

Significance Atherosclerosis, the major cause of death and illness in industrialized nations, develops in regions of arteries in which fluid flow patterns are disturbed and endothelial cells fail to align in the direction of flow. In contrast, regions of laminar flow in which cells are aligned are protected. The current work shows that the transmembrane proteoglycan syndecan 4 is required for endothelial cell alignment in the direction of flow and for the protective effect of high laminar flow, yet other flow responses are intact. The data therefore identify a role for syndecan 4 in flow direction sensing, show that sensing flow direction is separable from sensing flow magnitude, and provide new support for the key role of cell alignment in atheroprotection. Atherosclerotic plaque localization correlates with regions of disturbed flow in which endothelial cells (ECs) align poorly, whereas sustained laminar flow correlates with cell alignment in the direction of flow and resistance to atherosclerosis. We now report that in hypercholesterolemic mice, deletion of syndecan 4 (S4−/−) drastically increased atherosclerotic plaque burden with the appearance of plaque in normally resistant locations. Strikingly, ECs from the thoracic aortas of S4−/− mice were poorly aligned in the direction of the flow. Depletion of S4 in human umbilical vein endothelial cells (HUVECs) using shRNA also inhibited flow-induced alignment in vitro, which was rescued by re-expression of S4. This effect was highly specific, as flow activation of VEGF receptor 2 and NF-κB was normal. S4-depleted ECs aligned in cyclic stretch and even elongated under flow, although nondirectionally. EC alignment was previously found to have a causal role in modulating activation of inflammatory versus antiinflammatory pathways by flow. Consistent with these results, S4-depleted HUVECs in long-term laminar flow showed increased activation of proinflammatory NF-κB and decreased induction of antiinflammatory kruppel-like factor (KLF) 2 and KLF4. Thus, S4 plays a critical role in sensing flow direction to promote cell alignment and inhibit atherosclerosis.
A sharp T-cell antigen receptor signaling threshold for T-cell proliferation

Significance Biochemical signals triggered by the T-cell receptor (TCR) are required for stimulating T cells and can be initiated within seconds. However, a hallmark of T-cell activation, cell division, occurs hours after TCR signaling has begun, implying that T cells require a minimum duration and/or accumulate TCR signaling events to drive proliferation. To visualize the accumulated signaling experienced by T cells, we used a fluorescent reporter gene that is activated by TCR stimulation. This technique showed a threshold between dividing and nondividing T cells for TCR signaling that does not change with stronger or weaker TCR signaling or the presence of growth factor. Together these data may have implications for the development of T-cell–targeted therapies for autoimmunity. T-cell antigen receptor (TCR) signaling is essential for activation, proliferation, and effector function of T cells. Modulation of both intensity and duration of TCR signaling can regulate these events. However, it remains unclear how individual T cells integrate such signals over time to make critical cell-fate decisions. We have previously developed an engineered mutant allele of the critical T-cell kinase zeta-chain-associated protein kinase 70 kDa (Zap70) that is catalytically inhibited by a small molecule inhibitor, thereby blocking TCR signaling specifically and efficiently. We have also characterized a fluorescent reporter Nur77–eGFP transgenic mouse line in which T cells up-regulate GFP uniquely in response to TCR stimulation. The combination of these technologies unmasked a sharp TCR signaling threshold for commitment to cell division both in vitro and in vivo. Further, we demonstrate that this threshold is independent of both the magnitude of the TCR stimulus and Interleukin 2. Similarly, we identify a temporal threshold of TCR signaling that is required for commitment to proliferation, after which T cells are able to proliferate in a Zap70 kinase-independent manner. Taken together, our studies reveal a sharp threshold for the magnitude and duration of TCR signaling required for commitment of T cells to proliferation. These results have important implications for understanding T-cell responses to infection and optimizing strategies for immunomodulatory drug delivery.