Miracle-dz/UniFAR-FTUs huggingface dataset:
FoxO Proteins Mediate Hypoxic Induction of Connective Tissue Growth Factor in Endothelial Cells*

Hypoxia, a driving force in neovascularization, promotes alterations in gene expression mediated by hypoxia-inducible factor (HIF)-1α. Connective tissue growth factor (CTGF, CCN2) is a modulator of endothelial cell growth and migration, but its regulation by hypoxia is poorly understood. Therefore, we analyzed signaling pathways involved in the regulation of CTGF by hypoxia in endothelial cells. Exposure to low oxygen tension or treatment with the hypoxia-mimetic dimethyloxalyl glycine (DMOG) stabilized HIF-1α and up-regulated CTGF in human umbilical vein endothelial cells and in a murine microvascular endothelial cell line. Induction of CTGF correlated with a HIF-dependent increase in protein and mRNA levels, and nuclear accumulation of the transcription factor FoxO3a. By contrast, gene expression and cellular localization of FoxO1 were not significantly altered by hypoxia. Expression of CTGF was strongly reduced by siRNA silencing of FoxO1 or FoxO3a. Furthermore, nuclear exclusion of FoxO1/3a transcription factors by inhibition of serine/threonine protein phosphatases by okadaic acid inhibited CTGF expression, providing evidence for both FoxO proteins as regulators of CTGF expression. The DMOG-stimulated induction of CTGF was further increased when endothelial cells were co-incubated with transforming growth factor-β, an activator of Smad signaling. Activation of RhoA-Rho kinase signaling by the microtubule-disrupting drug combretastatin A4 also enhanced the DMOG-induced CTGF expression, thus placing CTGF induction by hypoxia in a network of interacting signaling pathways. Our findings provide evidence that FoxO1, hypoxia-stimulated expression of FoxO3a and its nuclear accumulation are required for the induction of CTGF by hypoxia in endothelial cells.
Evaluation of desmopressin effects on haemostasis in children with congenital bleeding disorders

Summary. Desmopressin (DDAVP) affects haemostasis by the release of von Willebrand factor and coagulation factor VIII from endothelium. The aim of the study was to evaluate the results of DDAVP testing in paediatric patients with congenital bleeding disorders. Forty‐one patients consisting of children with von Willebrand’s disease (VWD, n = 26) and platelet function defects (PFD, n = 15) received DDAVP intravenously at a dosage of 0.3 μg/kg over 30 min. FVIII activity (FVIII), von Willebrand factor antigen (VWF:Ag), collagen‐binding activity (VWF:CB) and PFA 100® closure times (CT) were measured before, 60, 120 and 240 min after DDAVP. In VWD, the VWF:Ag increased threefold until 60 min and then it decreased continuously. Compared with baseline, VWF:Ag was significantly higher at 60 and 120 min but not at 240 min. In contrast, in PFD, the peak of VWF:Ag was reached after 120 min. Two hundred and forty minutes after DDAVP, the mean was still significantly elevated compared with baseline values. The course of VWF:CB corresponded to that of VWF:Ag. In patients with VWD and PFD, FVIII rose two‐ to threefold within 2 h after DDAVP. CT in patients with VWD shortened markedly within 120 min and then rose again. In all children with PFD, except one non‐responder, the CT shortened within 240 min after DDAVP. Two non‐responders with VWD were identified by the failed increase of VWF:Ag, VWF:CB and by prolonged CT. Haemostatic effects of DDAVP differ interindividually and dependent on the coagulation disorder. DDAVP was effective in most, but not in all patients. DDAVP testing is recommended to determine the individual haemostatic response.
Is the Company Man an Anachronism? Trends in Long Term Employment in the U.S. , 1973-2006

The wave of corporate downsizing in the 1990s focused attention on the role of long-term employment relationships in the United States. Given 1) the importance that these relationships have played historically, 2) the general view that long-term jobs are ? good jobs,? and 3) the suspicion that long-term employment relationships are becoming less common, I carry out a systematic investigation of the extent to which long-term employment relationships have, in fact, become less common. Specifically, I examine age-specific changes in the length of employment relationships for different birth cohorts from 1914-1981 using data from various supplements to the Current Population Survey (CPS) from 1973 through 2006. After controlling for demographic characteristics, I find that mean tenure and the fraction of workers reporting at least ten and at least twenty years of tenure have both fallen substantially. This decline is concentrated among men, while long-term employment relationships have became slightly more common among women. Mirroring this decline in tenure and long-term employment relationships, there has been an increase in ? churning? (defined as the proportion of workers in jobs with less than one year of tenure) for males as they enter their thirties and later. This pattern suggests that more recent cohorts are less likely than their parents to have a career characterized by a ? life-time? job with a single employer.
Survival outcomes with and without splenectomy in splenic marginal zone lymphoma

The optimal management of splenic marginal zone lymphoma (SMZL), a rare malignancy of the elderly, is not clearly defined. Splenectomy had been advocated in the past due to its palliative effect on abdominal discomfort, cytopenias, and prolonged remissions, even though most patients have disseminated disease in the bone marrow which subsequently relapses. No prospective studies compared outcomes after surgery or chemotherapy, so the choice of treatment is based on perception of individual benefits and risks. This study analyzed 1,251 cases of SMZL recorded in the Surveillance, Epidemiology, and End Results (SEER) database. Effects of splenectomy on survival outcomes were evaluated after balancing confounders with a propensity score (PS). While 52% of patients underwent spleen removal, no significant impact of the procedure on the risk of lymphoma-related death (LRD) (P 5 0.66)or overall survival was detectable. The results strengthen the notion that, with the availability of safe and effective alternatives, splenectomy should no longer be considered the treatment of choice in SMZL.
A pilot study on the effects of the transition of paediatric to adult health care in patients with haemophilia and in their parents: patient and parent worries, parental illness‐related distress and health‐related Quality of Life

Summary. The aim of this pilot study was to investigate the effects of the transition from paediatric to adult health care services in haemophilia patients and their parents. We compared pretransition children (n = 9) and their parents (n = 18) to posttransition patients (n = 8) and their parents (n = 21). Pre‐ and posttransition patients did not differ in self‐rated health‐related quality of life (QoL) or worries about the transition. Fathers of posttransition patients rated their son’s QoL as poorer than those of pretransition patients (P = 0.034) and indicated higher levels of illness‐related distress than fathers of pretransition patients (P = 0.034). The findings indicate that the transition affects parents more than patients. Moreover, we found gender differences in parental worries about the transition. The findings indicate that programmes designed to facilitate the transition in haemophilic patients should also address the patients’ parents.
Long‐term consequences of intracranial haemorrhage in children with haemophilia

Summary. Intracranial haemorrhages (ICH) in children with haemophilia are rare, and the outcome is variable, ranging from no apparent impairment to death. The aim of this investigation was to identify if children with haemophilia and ICH, have any long‐term problems with motor function, visual motor integration or strengths and difficulties compared with a control group. A review of the Haemophilia Database at Great Ormond Street Hospital for Children NHS Trust was undertaken to identify boys with haemophilia and a history of ICH, as well as a control group of peers with no such history. Boys were born between January 1994 and December 2002. All boys were assessed using the movement Assessment Battery for Children, the Developmental Test of Visual Motor Integration and The Strengths and Difficulties Questionnaire as standardized assessments of motor competence, visual motor integration and behavioural difficulties. Six boys with haemophilia and ICH and 11 controls (mean age: 7 years; range: 4–12 years) were assessed. Children with ICH were significantly more likely to have problems with motor function and visual motor integration (Fisher’s exact: P < 0.05). In addition, they had a tendency towards more problems with strengths and difficulties than their peer group (Fisher’s exact: P = 0.06). Five of the six boys who had sustained an ICH were in mainstream schools; four requiring assistance with their education. The results of this small study suggest that ICH may signify long‐term consequences for boys with haemophilia. The multidisciplinary team need to be aware of the rare but potentially important impact on motor function, visual motor integration and behaviour, which may inhibit the child from functioning optimally. An agreed comprehensive battery of assessments in collaboration with schools and healthcare workers is required to identify impairments to enable prompt interventions to be co‐ordinated.
The Scaffold Protein Shoc2/SUR-8 Accelerates the Interaction of Ras and Raf*

Shoc2/SUR-8 positively regulates Ras/ERK MAP kinase signaling by serving as a scaffold for Ras and Raf. Here, we examined the role of Shoc2 in the spatio-temporal regulation of Ras by using a fluorescence resonance energy transfer (FRET)-based biosensor, together with computational modeling. In epidermal growth factor-stimulated HeLa cells, RNA-mediated Shoc2 knockdown reduced the phosphorylation of MEK and ERK with half-maximal inhibition, but not the activation of Ras. For the live monitoring of Ras binding to Raf, we utilized a FRET biosensor wherein Ras and the Ras-binding domain of Raf were connected tandemly and sandwiched with acceptor and donor fluorescent proteins for the FRET measurement. With this biosensor, we found that Shoc2 was required for the rapid interaction of Ras with Raf upon epidermal growth factor stimulation. To decipher the molecular mechanisms underlying the kinetics, we developed two computational models that might account for the action of Shoc2 in the Ras-ERK signaling. One of these models, the Shoc2 accelerator model, provided a reasonable explanation of the experimental observations. In this Shoc2 accelerator model, Shoc2 accelerated both the association and dissociation of Ras-Raf interaction. We propose that Shoc2 regulates the spatio-temporal patterns of the Ras-ERK signaling pathway primarily by accelerating the Ras-Raf interaction.
Deferiprone (GPO‐L‐ONE®) monotherapy reduces iron overload in transfusion‐dependent thalassemias: 1‐year results from a multicenter prospective, single arm, open label, dose escalating phase III pediatric study (GPO‐L‐ONE; A001) from Thailand

Accessibility to iron chelators including deferoxamine and deferasirox remains obscured in many developing countries. To provide an alternative, the government pharmaceutical organization of Thailand (GPO) manufactured deferiprone which has similar bioequivalent to the standard product. Seventy‐three pediatric patients with severe β thalassemias, age range 3.2–19 years, were recruited to a 1‐year multicenter prospective, single arm, open label, dose escalating Phase III study of deferiprone to determine its clinical efficacy and safety. Sixty‐four patients (87.6%) completed the study with good compliance (>94%). Average deferiprone dose was 79.1±4.3 mg/kg/day. Overall, mean serum ferritin (SF) levels at 1 year were not significantly changed from baseline. However, 45% of patients (response group) had SF reduced >15% from baseline at 1 year with a median reduction of 1,065 ng ml−1. Baseline SF was the major factor that predicts clinical efficacy; patients with baseline SF>3,500 ng ml−1 had the most significant fall of SF at 1 year. A subgroup analysis by MRI‐T2* confirmed that the response group had higher baseline liver iron and deferiprone could significantly reduce liver iron overload and normalize levels of ALT at 1 year. Although, gastrointestinal irritation (20.5%) was the most common drug‐related adverse events (AEs) followed by transaminitis (16.4%) and neutropenia (6.8%), all patients were well tolerated. There was no mortality and agranulocytosis found in this trial. Monotherapy of deferiprone with appropriate dose adjustment and monitoring for adverse events appeared to be an effective chelation therapy in some patients with good compliance and acceptable safety profiles. Am. J. Hematol. 88:251–260, 2013. © 2013 Wiley Periodicals, Inc.
The health benefits of urban green spaces: a review of the evidence.

BACKGROUND Urban development projects can be costly and have health impacts. An evidence-based approach to urban planning is therefore essential. However, the evidence for physical and non-physical health benefits of urban green space is unclear. METHODS A literature search of academic and grey literature was conducted for studies and reviews of the health effects of green space. Articles found were appraised for their relevance, critically reviewed and graded accordingly. Their findings were then thematically categorized. RESULTS There is weak evidence for the links between physical, mental health and well-being, and urban green space. Environmental factors such as the quality and accessibility of green space affects its use for physical activity. User determinants, such as age, gender, ethnicity and the perception of safety, are also important. However, many studies were limited by poor study design, failure to exclude confounding, bias or reverse causality and weak statistical associations. CONCLUSION Most studies reported findings that generally supported the view that green space have a beneficial health effect. Establishing a causal relationship is difficult, as the relationship is complex. Simplistic urban interventions may therefore fail to address the underlying determinants of urban health that are not remediable by landscape redesign.
RUNX3 Modulates DNA Damage-mediated Phosphorylation of Tumor Suppressor p53 at Ser-15 and Acts as a Co-activator for p53*

Although it has been shown that the gastric tumor suppressor RUNX3 has a growth inhibitory activity, the precise molecular mechanisms behind RUNX3-mediated tumor suppression remained unclear. In this study, we found that RUNX3 is closely involved in DNA damage-dependent phosphorylation of tumor suppressor p53 at Ser-15 and acts as a co-activator for p53. The small interference RNA-mediated knockdown of RUNX3 inhibited adriamycin (ADR)-dependent apoptosis in p53-proficient cells but not in p53-deficient cells in association with a significant reduction of p53-target gene expression as well as phosphorylation of p53 at Ser-15. In response to ADR, RUNX3 was induced to accumulate in the cell nucleus and co-localized with p53. Immunoprecipitation experiments demonstrated that RUNX3 forms a complex with p53 in cells. In vitro pulldown assays revealed that the COOH-terminal portion of p53 is required for the interaction with RUNX3. Forced expression of RUNX3 enhanced p53-mediated transcriptional activation. Additionally, RUNX3 had an ability to induce the phosphorylation of p53 at Ser-15, thereby promoting p53-dependent apoptosis. Intriguingly, RUNX3 interacted with phosphorylated forms of ataxia telangiectasia-mutated in response to ADR; however, it did not affect the extent of DNA damage. From the clinical point of view, coordinated p53 mutation and decreased expression of RUNX3 in 105 human lung adenocarcinomas were significantly associated with the poor outcome of patients (p = 0.0203). Thus, our present results strongly suggest that RUNX3 acts as a novel co-activator for p53 through regulating its DNA damage-induced phosphorylation at Ser-15 and also provide a clue to understanding the molecular mechanisms underlying RUNX3-mediated tumor suppression.
Hypoxia-inducible Factor-1-mediated Regulation of Semaphorin 4D Affects Tumor Growth and Vascularity

Tumor progression and metastasis depend on the ability of cancer cells to initiate angiogenesis to ensure delivery of oxygen, nutrients, and growth factors to tumor cells and provide access to the systemic circulation. Hypoxia-inducible factor-1 (HIF-1) can activate expression of a broad range of genes that mediate many of the adaptive responses to decreased oxygen concentration, such as enhanced glucose uptake and formation of new blood vessels. Acting through Plexin-B1 on endothelial cells, Semaphorin 4D (Sema4D) has been shown to promote angiogenesis and enhance invasive growth and proliferation in some tumors. Here we show that the gene for Sema4D, the product of which is elevated in head and neck squamous cell carcinoma (HNSCC) cells, contains upstream hypoxia response elements (HRE) and is strongly induced in hypoxia in a HIF-1-dependent manner. Knocking down Sema4D expression with short hairpin (sh) RNA reduces in vitro endothelial cell migration and growth and vascularity of HNSCC xenografts expressing a degradation resistant HIF-1α subunit. We also demonstrate a correlation between HIF-1 activity and Sema4D expression in HNSCC specimens. These findings indicate that Sema4D is induced by hypoxia in a HIF-1-dependent manner and influences endothelial cell migration and tumor vascularity. Expression of Sema4D may be a strategy by which carcinomas promote angiogenesis and therefore could represent a therapeutic target for these malignancies.
Determinants of Vaginal Cleansing, Application, and Insertion in Tete Province, Mozambique, and Products Used

ABSTRACT Objective: In this article, we review insertion, application, and cleansing as they include the use of products other than water and have a number of harmful effects. Method: In 2007, a household survey of 919 women carried out in Tete Province, Mozambique, examined 8 vaginal practices. Results: Overall, 10% of the sexually active women reported regularly using these 3 vaginal practices concurrently. Of the women who practiced insertion, 65% used natural substances. A wider variety of products was used for applying substances on the external genitalia and for cleansing purposes. Conclusions: These findings have important implications for future HIV prevention, including in the use of microbicides.
Rituximab versus splenectomy in persistent or chronic adult primary immune thrombocytopenia: an adjusted comparison of mortality and morbidity

Splenectomy and rituximab are both recommended as second‐line treatment in immune thrombocytopenia (ITP), but they have never been directly compared. We compared their efficacy and serious adverse outcomes in a retrospective cohort of 105 adult primary ITP patients exposed to one or other of these treatments. Primary outcome was composite: death from hemorrhage or from infection and hospitalization for bleeding or for infection. Secondary outcomes were overall mortality, hospitalization for bleeding, hospitalization for infection, as well as response and complete response (international definitions). Analyses were adjusted on a propensity score. Patients treated with rituximab (n = 43) were older and had more comorbidities than the splenectomized patients (n = 62). Mean follow‐up was, respectively, 3 and 8.4 years. After adjustment on the propensity score, there was no difference between the two groups regarding the primary and other clinical outcomes. In the multivariate analysis, only a history of mucosal bleeding (HR 3.2 95% CI [1.2–8.5]) and a Charlson score ≥1 (HR 4.2 95% CI [1.8–9.6]) were associated with the primary outcome. These two factors were also associated with hospitalization for bleeding. As expected, response, complete response and maintenance rates were higher in the splenectomy group. Splenectomy compared with rituximab was independently associated with a response at 12 months (OR 4.4, 95% CI [1.7–11.8]). Then, adjusted analyses in this real‐life cohort confirmed the better results of splenectomy compared with rituximab. Am. J. Hematol. 89:41–46, 2014. © 2013 Wiley Periodicals, Inc.
Fitness and quality of life in children with haemophilia

Summary. Prior to the introduction of prophylactic clotting factor, children with haemophilia were discouraged from physical activity due to the risk of bleeds. Reports of children with haemophilia having lower levels of fitness and strength than their healthy peers were therefore well accepted. This study aimed to establish whether these deficits continued, and specifically, whether Australian boys with haemophilia and von Willebrand disorder had lower strength and aerobic capacity than their peers, despite widespread use of prophylaxis. Forty‐four boys aged 6.1–17.0 years (mean 10.9, SD 3.2) with haemophilia A and B and von Willebrand disorder participated in the study. Fitness, strength and body mass index (BMI) measures were compared with age‐ and gender‐matched data from a representative cohort of school children. Quality of Life was measured using the Haemo‐QoL to obtain baseline measures in an Australian population. There were no statistically significant or clinically important differences in aerobic fitness or BMI between the boys with haemophilia and controls in any age category. Boys with haemophilia in Years 4, 6 and 10 had greater strength than their peers. Australian boys with bleeding disorders do not have impaired aerobic capacity or strength compared with their peers. Quality of life in Australian boys with haemophilia is comparable to their European counterparts.
School Librarians as Ambassadors of Inclusive Information Access for Students with Disabilities.

Many scholarly studies investigating school library services provided to students with special needs primarily address aspects of collaboration with special education (SPED) teachers in an immersed school environment. Scarcely studied are ways that school library programs (SLPs) empower students in schools serving only students with a specific disability (vision impaired, autism, etc.), the challenges SLPs face in these schools, nor the specialized training made available to these librarians to ensure the delivery of efficient services. We formulated this study to determine: 1) the types of facilities, services, and resources SLPs provide to students with specific disabilities in these SPED schools; 2) the technologies that facilitate physical and intellectual access for these students within the school library; 3) the extent to which federal disability guidelines are implemented in the design and delivery of these SLPs; and 4) the specialized training that enables school librarians to better support students with special needs. Our findings suggest that, if adequate pre-service and in-service training is provided and pertinent support is received from outside and inside of school, school librarians, as ambassadors of accessibility, can and do play a highly influential role in empowering students and staff in SPED schools.