Miracle-dz/UniFAR-FTUs huggingface dataset:
SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1♦

Sirtuins catalyze NAD+-dependent protein deacetylation and are critical regulators of transcription, apoptosis, metabolism, and aging. There are seven human sirtuins (SIRT1–7), and SIRT1 has been implicated as a key mediator of the pathways downstream of calorie restriction that have been shown to delay the onset and reduce the incidence of age-related diseases such as type 2 diabetes. Increasing SIRT1 activity, either by transgenic overexpression of the Sirt1 gene in mice or by pharmacological activation by small molecule activators resveratrol and SRT1720, has shown beneficial effects in rodent models of type 2 diabetes, indicating that SIRT1 may represent an attractive therapeutic target. Herein, we have assessed purported SIRT1 activators by employing biochemical assays utilizing native substrates, including a p53-derived peptide substrate lacking a fluorophore as well as the purified native full-length protein substrates p53 and acetyl-CoA synthetase1. SRT1720, its structurally related compounds SRT2183 and SRT1460, and resveratrol do not lead to apparent activation of SIRT1 with native peptide or full-length protein substrates, whereas they do activate SIRT1 with peptide substrate containing a covalently attached fluorophore. Employing NMR, surface plasmon resonance, and isothermal calorimetry techniques, we provide evidence that these compounds directly interact with fluorophore-containing peptide substrates. Furthermore, we demonstrate that SRT1720 neither lowers plasma glucose nor improves mitochondrial capacity in mice fed a high fat diet. SRT1720, SRT2183, SRT1460, and resveratrol exhibit multiple off-target activities against receptors, enzymes, transporters, and ion channels. Taken together, we conclude that SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.
2017 Clinical trials update in new treatments of β‐thalassemia

The underlying basis of β‐thalassemia pathology is the diminished β‐globin synthesis leading to α‐globin accumulation and premature apoptotic destruction of erythroblasts, causing oxidative stress‐induced ineffective erythropoiesis, bone marrow hyperplasia, splenomegaly, and increased intestinal iron absorption with progressive iron overload. Better understanding of the molecular mechanisms underlying this disease led to the recognition of new targets with potential therapeutic utility. Agents such as JAK2 inhibitors and TGF‐β ligand traps that reduce the ineffective erythropoiesis process are already being tested in clinical trials with promising results. Other agents that aim to reduce oxidative stress (activators of Foxo3, HRI‐eIF2aP, Prx2, Hsp70, and PK anti‐oxidant systems and inhibitors of HO‐1) and to decrease iron overload (hepcidin agonists, erythroferrone inhibitors and exogenous transferrin) are also under experimental investigation. Significant progress has also been made in the area of allogeneic hematopoietic stem cell transplantation with several ongoing clinical trials examining new condition regimens as well as different donor selection and stem cell source options. Gene therapy has reached a critical point and phase 1 clinical trials have recently been launched to examine the effectiveness and especially long term safety. Epigenetic manipulation and genomic editing of the γ‐ or β‐globin gene are novel and promising experimental gene therapy approaches for β‐thalassemia giving hope for cure for this chronic disease. This review outlines the key points of the molecular mechanisms underlying β‐thalassemia in relation to the development of new therapies and an update is given both at the pre‐clinical and clinical level. Am. J. Hematol. 91:1135–1145, 2016. © 2016 Wiley Periodicals, Inc.
The 90-kDa Heat Shock Protein Hsp90 Protects Tubulin against Thermal Denaturation*

Hsp90 and tubulin are among the most abundant proteins in the cytosol of eukaryotic cells. Although Hsp90 plays key roles in maintaining its client proteins in their active state, tubulin is essential for fundamental processes such as cell morphogenesis and division. Several studies have suggested a possible connection between Hsp90 and the microtubule cytoskeleton. Because tubulin is a labile protein in its soluble form, we investigated whether Hsp90 protects it against thermal denaturation. Both proteins were purified from porcine brain, and their interaction was characterized in vitro by using spectrophotometry, sedimentation assays, video-enhanced differential interference contrast light microscopy, and native polyacrylamide gel electrophoresis. Our results show that Hsp90 protects tubulin against thermal denaturation and keeps it in a state compatible with microtubule polymerization. We demonstrate that Hsp90 cannot resolve tubulin aggregates but that it likely binds early unfolding intermediates, preventing their aggregation. Protection was maximal at a stoichiometry of two molecules of Hsp90 for one of tubulin. This protection does not require ATP binding and hydrolysis by Hsp90, but it is counteracted by geldanamycin, a specific inhibitor of Hsp90.
Identification and Functional Characterization of a Novel Mitochondrial Carrier for Citrate and Oxoglutarate in Saccharomyces cerevisiae*

Mitochondrial carriers are a family of transport proteins that shuttle metabolites, nucleotides, and coenzymes across the mitochondrial membrane. The function of only a few of the 35 Saccharomyces cerevisiae mitochondrial carriers still remains to be uncovered. In this study, we have functionally defined and characterized the S. cerevisiae mitochondrial carrier Yhm2p. The YHM2 gene was overexpressed in S. cerevisiae, and its product was purified and reconstituted into liposomes. Its transport properties, kinetic parameters, and targeting to mitochondria show that Yhm2p is a mitochondrial transporter for citrate and oxoglutarate. Reconstituted Yhm2p also transported oxaloacetate, succinate, and fumarate to a lesser extent, but virtually not malate and isocitrate. Yhm2p catalyzed only a counter-exchange transport that was saturable and inhibited by sulfhydryl-blocking reagents but not by 1,2,3-benzenetricarboxylate (a powerful inhibitor of the citrate/malate carrier). The physiological role of Yhm2p is to increase the NADPH reducing power in the cytosol (required for biosynthetic and antioxidant reactions) and probably to act as a key component of the citrate-oxoglutarate NADPH redox shuttle between mitochondria and cytosol. This protein function is based on observations documenting a decrease in the NADPH/NADP+ and GSH/GSSG ratios in the cytosol of ΔYHM2 cells as well as an increase in the NADPH/NADP+ ratio in their mitochondria compared with wild-type cells. Our proposal is also supported by the growth defect displayed by the ΔYHM2 strain and more so by the ΔYHM2ΔZWF1 strain upon H2O2 exposure, implying that Yhm2p has an antioxidant function.
Newly diagnosed immune thrombocytopenia adults: Clinical epidemiology, exposure to treatments, and evolution. Results of the CARMEN multicenter prospective cohort

The clinical epidemiology of immune thrombocytopenia (ITP) is not well known in adults. This study was aimed at assessing the clinical epidemiology of incident ITP adults, the factors associated with chronicity and exposure to treatments. This study was conducted in the CARMEN registry, a multicentric prospective cohort aimed at including all newly diagnosed ITP adults in the French Midi‐Pyrénées region, South of France (3 million inhabitants) from June 2013. Descriptive analyses and multivariate logistic regression models were conducted. Out of 121 newly diagnosed ITP until December 2014, 113 patients were followed in the region and gave informed consent. Median age was 65 years. Half of the patients were female, 20.3% had a secondary ITP, 50.4% had a Charlson's score ≥1, median platelet count was 17 × 109/L; 50.9% had bleeding symptoms, including 2 severe gastrointestinal tract and 1 intracranial bleedings; 21.4% had another autoimmune disease and 20.3% experienced an infection within the six weeks before ITP onset. Persistency and chronicity rates were 68.2% and 58.7%, respectively. Antinuclear antibodies were associated with chronicity (OR: 2.89, 95% CI: 1.08‐7.74). Sixty‐eight (60.2%) patients were treated during the week following the diagnosis. Factors associated with the use of intravenous corticosteroids were secondary ITP and high bleeding score. Those associated with the use of intravenous immunoglobulin (IVIg) were a high bleeding score and low platelet count. In conclusion, severe bleeding is rare at ITP onset. Associated autoimmune diseases and recent infections were frequent. Antinuclear antibodies seem predictors of chronicity. Intravenous corticosteroids and IVIg were frequently used.
Factors predicting survival in chronic lymphocytic leukemia patients developing Richter syndrome transformation into Hodgkin lymphoma

We hereby report the clinical and biologic features of 33 of 4680 (0.7%) patients with chronic lymphocytic leukemia (CLL), managed at 10 Italian centers, who developed Hodgkin lymphoma (HL), a rare variant of Richter syndrome. The median age at CLL and at HL diagnosis were 61 years (range 41‐80) and 70 years (range 46‐82), respectively, with a median interval from CLL to the diagnosis of HL of 90 months (range 0‐258). In 3 cases, CLL and HL were diagnosed simultaneously. Hl was characterized by advanced stage in 79% of cases, International Prognostic Score (IPS) ≥4 in 50%, extranodal involvement in 39%, B symptoms in 70%. Prior treatment for CLL had been received by 82% of patients and included fludarabine in 67%. Coexistence of CLL and HL was detected in the same bioptic tissue in 87% of cases. The most common administered treatment was the ABVD regimen given to 22 patients (66.6%). The complete response (CR) rate after ABVD was 68%, and was influenced by the IPS (P = .03) and interval from the last CLL treatment (P = .057). Survival from HL was also influenced by the IPS (P = .006) and time from the last CLL treatment (P = .047). The achievement of CR with ABVD was the only significant and independent factor predicting survival (P = .037). Taken together, our results show that the IPS and the interval from the prior CLL treatment influence the likelihood of achieving CR after ABVD, which is the most important factor predicting survival of patients with CLL developing HL.
Adenosine A2A Receptor Is Involved in Cell Surface Expression of A2B Receptor*

The A2A and A2B adenosine receptors (A2AR and A2BR) are implicated in many physiological processes. However, the mechanisms of their intracellular maturation and trafficking are poorly understood. In comparative studies of A2AR versus A2BR expression in transfected cells, we noticed that the levels of cell surface expression of A2BR were significantly lower than those of A2AR. A large portion of the A2BR was degraded by the proteasome. Studies of cell surface expression of A2BR chimeric molecules in transfectants suggested that A2BR does not have the dominant forward transport signal for export from the endoplasmic reticulum to the cell surface. A2BR surface expression was increased in A2BR chimeras where the A2BR carboxyl terminus (CT) was replaced or fused with the A2AR CT. Co-transfection of A2AR with A2BR enhanced surface expression of A2BR though the F(X)6LL motif in the A2AR CT. The requirements of A2AR expression for better A2BR cell surface expression was not only established in transfectants but also confirmed by observations of much lower levels of A2BR-induced intracellular cAMP accumulation in response to A2BR-activating ligand in splenocytes from A2AR−/− mice than in wild type mice. The results of mechanistic studies suggested that poor A2BR expression at the cell surface might be accounted for mainly by the lack of a dominant forward transport signal from the endoplasmic reticulum to the plasma membrane; it is likely that A2BR forms a hetero-oligomer complex for better function.
Epidemiologi för hälsovetare : en introduktion

Boken ger en grundlaggande beskrivning av arbetssatt, teorier och metoder inom epidemiologin. Med utgangspunkt i rubrikerna Beskriva, Analysera och Atgarda forklaras begrepp och analysmetoder, olik .
Clinical role of flow cytometry in redefining bone marrow involvement in diffuse large B‐cell lymphoma (DLBCL) – a new perspective

Aims: The clinical role of flow cytometry in staging bone marrow in diffuse large B‐cell lymphoma (DLBCL), especially its impact on outcome, remains uncertain. The aim was to determine the contribution of flow cytometry to conventional staging, and to study the impact of this revised staging on survival.
Clinical outcomes in adult patients with aplastic anemia: A single institution experience

Newer treatment modalities are being investigated to improve upon historical outcomes with standard immunosuppressive therapy (IST) in aplastic anemia (AA). We analyzed outcomes of adult patients with AA treated with various combinatorial anti‐thymoglobulin‐based IST regimens in frontline and relapsed/refractory (R/R) settings. Pretreatment and on‐treatment clinical characteristics were analyzed for relationships to response and outcome. Among 126 patients reviewed, 95 were treatment‐naïve (TN) and 63, R/R (including 32 from the TN cohort); median ages were 49 and 50 years, respectively. Overall survival (OS) was superior in IST responders (P < .001). Partial response to IST was associated with shorter relapse‐free survival (RFS), as compared with complete response (P = .03). By multivariate analysis, baseline platelet and lymphocyte count predicted for IST response at 3 and 6 months, respectively. While additional growth factor interventions led to faster count recovery, there were no statistically significant differences in RFS or OS across the various frontline IST regimens (i.e., with/without G‐CSF or eltrombopag). While marrow cellularity did not correlate with peripheral‐blood counts at 3 months, cytomorphological assessment revealed dyspoietic changes in all nonresponders with hypercellular‐marrow indices. Covert dysplasia, identified through early bone marrow assessment, has implications on future therapy choices after IST failure. Salvage IST response depended upon prior response to ATG: prior responders (46%) vs. primary refractory (0%) (P < .01). In the R/R setting, there was no survival difference between IST and allogeneic stem cell transplant groups, with a trend toward superior OS in the former. Transplant benefits in the R/R setting may be underrealized due to transplant‐related mortality.
Interaction of the Human Prostacyclin Receptor with Rab11

The human prostacyclin receptor (hIP) undergoes agonist-induced internalization and subsequent recyclization in slowly recycling endosomes involving its direct physical interaction with Rab11a. Moreover, interaction with Rab11a localizes to a 22-residue putative Rab11 binding domain (RBD) within the carboxyl-terminal tail of the hIP, proximal to the transmembrane 7 (TM7) domain. Because the proposed RBD contains Cys308 and Cys311, in addition to Cys309, that are known to undergo palmitoylation, we sought to identify the structure/function determinants of the RBD, including the influence of palmitoylation, on agonist-induced trafficking of the hIP. Through complementary approaches in yeast and mammalian cells along with computational structural studies, the RBD was localized to a 14-residue domain, between Val299 and Leu312, and proposed to be organized into an eighth α-helical domain (α-helix 8), comprising Val299–Val307, adjacent to the palmitoylated residues at Cys308–Cys311. From mutational and [3H]palmitate metabolic labeling studies, it is proposed that palmitoylation at Cys311 in addition to agonist-regulated deacylation at Cys309 > Cys308 may dynamically position α-helix 8 in proximity to Rab11a, to regulate agonist-induced intracellular trafficking of the hIP. Moreover, Ala-scanning mutagenesis identified several hydrophobic residues within α-helix 8 as necessary for the interaction with Rab11a. Given the diverse membership of the G protein-coupled receptor superfamily, of which many members are also predicted to contain an α-helical 8 domain proximal to TM7 and, often, adjacent to palmitoylable cysteine(s), the identification of a functional role for α-helix 8, as exemplified as an RBD for the hIP, is likely to have broader significance for certain members of the superfamily.
Adultos e idosos com doenças crônicas : implicações para o cuidado de enfermagem

Chronic diseases are generally disabling and incurable. Nurses play an important role in educating patients on health problems, self-care, and harm reduction. A study group (GEPECADI Study and Research Group on Nursing and Care for Adults and Elderly Individuals) has been created to study care providing aspects of patients with chronic diseases receiving care at Hospital de Clínicas de Porto Alegre. In 2005, the group conducted a cross-sectional study for situational diagnosis. Medical records of 1,665 patients aged 60 years and older and hospitalized in clinical units were reviewed. Most frequent nursing diagnoses (self-care deficit: bathing/hygiene; imbalanced nutrition: less than body requirements; risk of infection; and ineffective breathing patterns) were identified and associated with prescribed care measures and time of hospital stay. Since many elderly patients have self-care deficits and malnutrition, which are risk factors for development of pressure ulcers, a protocol for prevention and treatment of pressure ulcers is being developed. It is based on the Braden Scale and will be used in clinical and surgical wards, emergency rooms and intensive care units. We believe that the group will contribute to the improvement of educative, research and health care measures that encourage healthy behaviors in adults and elderly individuals, as well as in their families and in the community.
MYC translocation and an increased copy number predict poor prognosis in adult diffuse large B‐cell lymphoma (DLBCL), especially in germinal centre‐like B cell (GCB) type

Aims: Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous disease with various genetic alterations. The aim was to investigate MYC, Bcl‐2 and Bcl‐6 translocations and copy number changes in adult DLBCLs to evaluate their clinicopathological features and prognostic implications.
A distinct immunophenotype identifies a subset of NPM1‐mutated AML with TET2 or IDH1/2 mutations and improved outcome

Recent work has identified distinct molecular subgroups of acute myeloid leukemia (AML) with implications for disease classification and prognosis. NPM1 is one of the most common recurrently mutated genes in AML. NPM1 mutations often co‐occur with FLT3‐ITDs and mutations in genes regulating DNA methylation, such as DNMT3A, TET2, and IDH1/2. It remains unclear whether these genetic alterations are associated with distinct immunophenotypic findings or affect prognosis. We identified 133 cases of NPM1‐mutated AML and correlated sequencing data with immunophenotypic and clinical findings. Of 84 cases (63%) that lacked monocytic differentiation (“myeloid AML”), 40 (48%) demonstrated an acute promyelocytic leukemia‐like (APL‐like) immunophenotype by flow cytometry, with absence of CD34 and HLA‐DR and strong myeloperoxidase expression, in the absence of a PML‐RARA translocation. Pathologic variants in TET2, IDH1, or IDH2 were identified in 39/40 APL‐like cases. This subset of NPM1‐mutated AML was associated with longer relapse‐free and overall survival, when compared with cases that were positive for CD34 and/or HLA‐DR. The combination of NPM1 and TET2 or IDH1/2 mutations along with an APL‐like immunophenotype identifies a distinct subtype of AML. Further studies addressing its biology and clinical significance may be especially relevant in the era of IDH inhibitors and recent work showing efficacy of ATRA therapy in NPM1 and IDH1‐mutated AML.
Järnbrist och järnbristanemi är globala hälsoproblem

Iron deficiency and iron deficiency anemia are global health problems leading to deterioration in patients' quality of life and more serious prognosis in patients with chronic diseases. The cause of iron deficiency and anemia is ususally a combination of increased loss and decreased intestinal absorption and delivery from iron stores due to inflammation. Oral iron is first line treatment, but often hampered by intolerance. Intravenous iron is safe, and the preferred treatment in patients with chronic inflammation and bowel diseases. The goal of treatment is normalisation of hemoglobin concentration and recovery of iron stores. It is important to follow up treatment to ensure that these objectives are met and also long-term in patients with chronic iron loss and/or inflammation to avoid recurrence of anemia. (Less)
Expression of the Anti-amyloidogenic Secretase ADAM10 Is Suppressed by Its 5′-Untranslated Region*

Proteolytic processing of the amyloid precursor protein by α-secretase prevents formation of the amyloid β-peptide (Aβ), which is the main constituent of amyloid plaques in brains of Alzheimer disease (AD) patients. α-Secretase activity is decreased in AD, and overexpression of the α-secretase ADAM10 (a disintegrin and metalloprotease 10) in an AD animal model prevents amyloid pathology. ADAM10 has a 444-nucleotide-long, very GC-rich 5′-untranslated region (5′-UTR) with two upstream open reading frames. Because similar properties of 5′-UTRs are found in transcripts of many genes, which are regulated by translational control mechanisms, we asked whether ADAM10 expression is translationally controlled by its 5′-UTR. We demonstrate that the 5′-UTR of ADAM10 represses the rate of ADAM10 translation. In the absence of the 5′-UTR, we observed a significant increase of ADAM10 protein levels in HEK293 cells, whereas mRNA levels were not changed. Moreover, the 5′-UTR of ADAM10 inhibits translation of a luciferase reporter in an in vitro transcription/translation assay. Successive deletion of the first half of the ADAM10 5′-UTR revealed a striking increase in ADAM10 protein expression in HEK293 cells, suggesting that this part of the 5′-UTR contains inhibitory elements for translation. Moreover, we detect an enhanced α-secretase activity and consequently reduced Aβ levels in the conditioned medium of HEK293 cells expressing both amyloid precursor protein and a 5′-UTR-ADAM10 deletion construct lacking the first half of the 5′-UTR. Thus, we provide evidence that the 5′-UTR of ADAM10 may have an important role for post-transcriptional regulation of ADAM10 expression and consequently Aβ production.
Commingling analysis of blood pressure in the Tecumseh community health study

A commingling analysis of the distribution of systolic and diastolic blood pressure was performed on measurements from 9,226 individuals living in Tecumseh, Michigan during 1962–1965. Even after correcting for skewness in the distributions, multiple normal distributions fit the data significantly better than a single normal one, suggesting some level of commingling. The exact nature of the components differed depending on the phenotype, and the number of components entertained, suggesting a possibly complex etiology, but with some definite qualitative effects. Segregation analysis under the mixed model is needed to address the nature of blood pressure in this community more definitively.