Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of cumulative bortezomib dose on survival in multiple myeloma patients receiving bortezomib‐melphalan‐prednisone in the phase III VISTA study

This analysis, using data from the bortezomib‐melphalan‐prednisone (VMP) arm of the Phase III VISTA study, investigated whether increased cumulative bortezomib dose could improve overall survival (OS) in transplant‐ineligible patients with previously untreated multiple myeloma. Median cumulative bortezomib dose received by the 340 patients was 39 mg/m2; this was selected as the cut‐off for defining the dose groups to be compared for OS. Patient characteristics were well balanced between dose groups except for age. OS was significantly longer in the higher (≥39 mg/m2) versus lower (<39 mg/m2) cumulative bortezomib dose group (median 66.3 vs. 46.2 months; hazard ratio (HR) 0.533, P < 0.0001; age‐adjusted HR 0.561, P = 0.0002). To overcome confounding effects of early discontinuations/deaths, which were more common in the lower cumulative dose group (27 vs. 4% of patients discontinued due to adverse events (AEs) in the lower and higher cumulative dose groups, respectively), a landmark analysis was conducted at 180 days, eliminating patients who died or discontinued before this time from the analysis. OS from this landmark remained significantly longer in the higher dose group (median 60.4 vs. 50.3 months; HR 0.709, P = 0.0372). Thus, higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, appears associated with improved OS. Approaches to achieve higher cumulative doses could include subcutaneous bortezomib administration, dose/schedule modifications, continuing therapy in responding patients, and proactive AE management. Am. J. Hematol. 90:314–319, 2015. © 2015 Wiley Periodicals, Inc.
Anti‐HLA antibody testing in hematology patients

Anti‐human leukocyte antigens (HLA) antibodies can adversely impact the care of hematology patients. In particular, HLA antibody testing provides important information for optimal stem cell and platelet donor selection in the management of stem cell recipients and platelet refractory patients. Current testing methods for HLA antibodies are briefly reviewed, with particular emphasis on laboratory and clinical issues associated with solid‐phase multiplex assays. Am. J. Hematol. 90:361–364, 2015. © 2015 Wiley Periodicals, Inc.
Functional Significance of FRH in Regulating the Phosphorylation and Stability of Neurospora Circadian Clock Protein FRQ*

FREQUENCY (FRQ) is the central component of the Neurospora circadian clock. All FRQ proteins form the FFC complex with FRH (FRQ-interacting RNA helicase) that acts as the negative element in the circadian negative feedback loop by repressing frq mRNA levels. To understand the function of the FRQ-FRH interaction, we mapped and identified the minimal FRQ region that is required for FRQ-FRH interaction. We demonstrated that the FRQ-FRH complex formation is required for the interaction between FRQ and the White Collar Complex (WCC) and clock function. On the other hand, in the FRQ-FRH complex, FRQ is also required for the FRH-WCC interaction. Disruption of FRQ-FRH interaction or down-regulation of FRH results in hypophosphorylation, rapid degradation of FRQ, as well as low levels of WHITE COLLAR-1 and WHITE COLLAR-2. Furthermore, we showed that the rapid FRQ degradation in the absence of FRH is independent of FWD-1, the ubiquitin E3 ligase of FRQ under normal conditions, thus uncovering an alternative pathway for FRQ degradation.
Formulasi Sediaan Gel Ekstrak Etanolik Buah Mahkota Dewa (Phaleria macrocarpa (Scheff) Boerl.) Dengan Basis Carbomer

Dampak negatif radikal bebas pada kulit akibat radiasi sinar ultraviolet telah banyak ditemukan. Senyawa antioksidan dalam buah mahkota dewa dapat berperan sebagai zat aktif dari bahan alam untuk formulasi sediaan gel produk kosmetika. Pembuatannya membutuhkan basis yang digunakan sebagai bahan pembentuk gel yaitu carbomer karena sifatnya yang stabil dalam penyimpanan. Tujuan penelitian untuk mengetahui dapatkah bahan alam ekstrak buah mahkota dewa diformulasikan dalam bentuk sediaan gel, pengaruh penyimpanan terhadap kestabilan gel tersebut dan pengaruh variasi konsentrasi basis terhadap sifat fisik gel. Jumlah sediaan gel yang dibuat secara keseluruhan sebanyak 8. Empat formula dengan ekstrak dan empat formula kontrol (tanpa ekstrak) dengan variasi konsentrasi basis carbomer berturut-turut 0,5%, 1%, 1,5% dan 2%. Sediaan gel diuji organoleptis, pH, homogenitas, viskositas, daya lekat, daya sebar. Data yang diperoleh masing-masing diuji statistik menggunakan anava satu jalan. Hasil uji organoleptis gel pada empat formula dengan ekstrak yaitu warna cokelat, kental dan bau khas mahkota dewa, sedangkan empat formula kontrol (tanpa ekstrak) yaitu warna bening, kental dan tidak berbau. Hasil penelitian menunjukkan semakin tinggi konsentrasi basis maka daya sebar semakin rendah tetapi viskositas dan daya lekat yang diperoleh semakin tinggi serta keseluruhan gel yang dibuat stabil dalam penyimpanan.
Vascular factors in dementia: prevention and pathology

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Physical Diagnosis: The History and Examination of the Patient

a few are careless about personal hygiene. The author gives a series of steps for investigating an outbreak of food poisoning together with a number of practical suggestions for ensuring that food-handlers will not be a source of food-poisoning organisms. Seven chapters are devoted to the inspection of foodstuffs where appropriate In the live state, but mainly as the foods are supplied or bought ready fOl" preparation. The instructions given are the standard ones; the presentation is concise and easily followed. Later chapters deal with storage and refrigeration, cooking and serving, constructton of food premises, washing up, refuse disposal. In one chapter a description is given of rats and thelr habits and another describes food pests. This is a comprehensive book covering the subject adequately and, as the author states, drawing the material from a number of sources. It should be a valuable guide to food-handlera and especially to their supervisors, whether in the services or in civilian life. It is the kind of book that should be in the nurses' Ilbrary of all hospitals, and is a useful summary for medical officers of health and food inspectors.
Systematic review of surveillance by social media platforms for illicit drug use

Background The use of social media (SM) as a surveillance tool of global illicit drug use is limited. To address this limitation, a systematic review of literature focused on the ability of SM to better recognize illicit drug use trends was addressed. Methods A search was conducted in databases: PubMed, CINAHL via Ebsco, PsychINFO via Ebsco, Medline via Ebsco, ERIC, Cochrane Library, Science Direct, ABI/INFORM Complete and Communication and Mass Media Complete. Included studies were original research published in peer‐reviewed journals between January 2005 and June 2015 that primarily focused on collecting data from SM platforms to track trends in illicit drug use. Excluded were studies focused on purchasing prescription drugs from illicit online pharmacies. Results Selected studies used a range of SM tools/applications, including message boards, Twitter and blog/forums/platform discussions. Limitations included relevance, a lack of standardized surveillance systems and a lack of efficient algorithms to isolate relevant items. Conclusion Illicit drug use is a worldwide problem, and the rise of global social networking sites has led to the evolution of a readily accessible surveillance tool. Systematic approaches need to be developed to efficiently extract and analyze illicit drug content from social networks to supplement effective prevention programs.
A systematic review of the management and outcomes of pregnancy in Glanzmann thrombasthenia

Summary. Glanzmann Thrombasthenia (GT) is a rare autosomal recessive disorder which usually manifests as severe mucocutaneous bleeding and is caused by deficiency of the platelet glycoprotein IIb‐IIIa. Pregnancy in women with GT presents particular challenges as there is increased risk of both maternal and foetal bleeding. To improve understanding and clarify the optimum management of pregnancy in this disorder, we performed a systematic review of the world literature of pregnancy and GT. This identified three single‐centre case series of patients with GT that included brief descriptions of women in pregnancy and 31 detailed case reports of 40 pregnancies in 35 women that resulted in 38 live births. Among the detailed case reports, ante‐natal bleeding was described in 50% of pregnancies but was usually mild and occurred at mucocutaneous sites. Primary postpartum haemorrhage (PPH) was reported in 34% of pregnancies and secondary PPH in 24%. PPH was frequently severe and occurred up to 20 days after delivery. There was a wide variation in approach to prevention and treatment of PPH but most women received platelet transfusion, sometimes with additional recombinant FVIIa and anti‐fibrinolytics. Maternal alloimmunization against platelet antigens was reported in 73% of pregnancies and was associated with four neonatal deaths. These data emphasize the need for multidisciplinary management of pregnancy in women with GT. Delivery plans should recognize the need for prevention and aggressive treatment of PPH and should minimize foetal bleeding risk in pregnancies complicated by alloimmunization.
Persistence to therapy and risk of fracture in patients treated with antiosteoporotic drugs: analysis of costs and consequences

Medication non-adherence is an important public health concern, affecting health outcomes and overall health care costs. Adherence is becoming a priority included in the political agenda of health care system. In 2012 was launched from EC the European Innovation Partnership on Active and Healthy Ageing (EIP-AHA). The EIP-AHA A1 Action Group is focused on prescription and adherence. Part of the results of this thesis have been made available to A1 Action Group as preliminary data that might be useful for the further focused interventions. This thesis aims to provide more evidence on relation between poor adherence and adverse outcomes and to define reason of poor adherence, by using drug-utilization approaches using different sources of health-related automated databases. The scope of the study is also to evaluate economic impact of enhancing adherence by using real-life approach. The case study is population exposure to anti-osteoporotic drugs: with ageing populations, the burden of osteoporotic fractures on society will increase in the coming years and the prevention of osteoporotic fractures is therefore a major public health issue. The results showed sub optimal level of persistence and drug regimen is one of the strong predictors of non-adherence. Gender influences adherence to therapy and this is an issue that could be taken in strong consideration in tailor intervention to improve adherence. Another aspect is comorbidity this highlighted that an approach centered on comorbidity/multimorbidity, could be more pertinent, in particular when address health issues concerning older people. The ICER , expressed in terms of cost/fracture avoided equals € 821. This value indicates the cost that the NHS should support each fracture avoided This thesis demonstrated the potential of the use of existing data sources to evaluate appropriateness of drug use. Drugs cost money to buy, but if we use them in an appropriate way we can also save costs in other areas. In particular enhancing adherence to medication may lead to reductions in the number of patients requiring hospitalization. This research only explored cost effectiveness of improve adherence in drug use for osteoporosis, but clearly many different pattern of drugs for chronic conditions could be assessed in a similar way.
t(9;22) as secondary alteration in core‐binding factor de novo acute myeloid leukemia

The presence of specific recurrent karyotype abnormalities is one of the most powerful prognostic predictors in acute myeloid leukemia (AML). AML with inv(16) is categorized by the World Health Organization in the group of core-binding factors (CBF) AML, and it is associated with a favorable prognosis. From the molecular standpoint, the inv(16) leads to the formation of the CBFB-MYH11 fusion gene, which has a role in the disruption of normal hematopoiesis and in the inactivation of tumor suppressor genes needed for neoplastic transformation. Clonal evolution is generally considered a sign of disease progression in AML, but additional chromosomal aberrations seems not to impact on prognosis in CBF AML.
Thrombin and Collagen Induce a Feedback Inhibitory Signaling Pathway in Platelets Involving Dissociation of the Catalytic Subunit of Protein Kinase A from an NFκB-IκB Complex*

Protein kinase A (PKA) activation by cAMP phosphorylates multiple target proteins in numerous platelet inhibitory pathways that have a very important role in maintaining circulating platelets in a resting state. Here we show that in thrombin- and collagen-stimulated platelets, PKA is activated by cAMP-independent mechanisms involving dissociation of the catalytic subunit of PKA (PKAc) from an NFκB-IκBα-PKAc complex. We demonstrate mRNA and protein expression for most of the NFκB family members in platelets. From resting platelets, PKAc was co-immunoprecipitated with IκBα, and conversely, IκBα was also co-immunoprecipitated with PKAc. This interaction was significantly reduced in thrombin- and collagen-stimulated platelets. Stimulation of platelets with thrombin- or collagen-activated IKK, at least partly by PI3 kinase-dependent pathways, leading to phosphorylation of IκBα, disruption of an IκBα-PKAc complex, and release of free, active PKAc, which phosphorylated VASP and other PKA substrates. IKK inhibitor inhibited thrombin-stimulated IkBα phosphorylation, PKA-IkBα dissociation, and VASP phosphorylation, and potentiated integrin αIIbβ3 activation and the early phase of platelet aggregation. We conclude that thrombin and collagen not only cause platelet activation but also appear to fine-tune this response by initiating downstream NFκB-dependent PKAc activation, as a novel feedback inhibitory signaling mechanism for preventing undesired platelet activation.
Nucleosome Formation Activity of Human Somatic Nuclear Autoantigenic Sperm Protein (sNASP)*

NASP (nuclear autoantigenic sperm protein) is a member of the N1/N2 family, which is widely conserved among eukaryotes. Human NASP reportedly prefers to bind to histones H3·H4 and the linker histone H1, as compared with H2A·H2B, and is anticipated to function as an H3·H4 chaperone for nucleosome assembly. However, the direct nucleosome assembly activity of human NASP has not been reported so far. In humans, two spliced isoforms, somatic and testicular NASPs (sNASP and tNASP, respectively) were identified. In the present study we purified human sNASP and found that sNASP efficiently promoted the assembly of nucleosomes containing the conventional H3.1, H3.2, H3.3, or centromere-specific CENP-A. On the other hand, sNASP inefficiently promoted nucleosome assembly with H3T, a testis-specific H3 variant. Mutational analyses revealed that the Met-71 residue of H3T is responsible for this inefficient nucleosome formation by sNASP. Tetrasomes, composed of the H3·H4 tetramer and DNA without H2A·H2B, were efficiently formed by the sNASP-mediated nucleosome-assembly reaction. A deletion analysis of sNASP revealed that the central region, amino acid residues 26–325, of sNASP is responsible for nucleosome assembly in vitro. These experiments are the first demonstration that human NASP directly promotes nucleosome assembly and provide compelling evidence that sNASP is a bona fide histone chaperone for H3·H4.
Generation of Human Induced Pluripotent Stem Cells from Umbilical Cord Matrix and Amniotic Membrane Mesenchymal Cells*

The umbilical cord and placenta are extra-embryonic tissues of particular interest for regenerative medicine. They share an early developmental origin and are a source of vast amounts of cells with multilineage differentiation potential that are poorly immunogenic and without controversy. Moreover, these cells are likely exempt from incorporated mutations when compared with juvenile or adult donor cells such as skin fibroblasts or keratinocytes. Here we report the efficient generation of induced pluripotent stem cells (iPSCs) from mesenchymal cells of the umbilical cord matrix (up to 0.4% of the cells became reprogrammed) and the placental amniotic membrane (up to 0.1%) using exogenous factors and a chemical mixture. iPSCs from these 2 tissues homogeneously showed human embryonic stem cell (hESC)-like characteristics including morphology, positive staining for alkaline phosphatase, normal karyotype, and expression of hESC-like markers including Nanog, Rex1, Oct4, TRA-1–60, TRA-1–80, SSEA-3, and SSEA-4. Selected clones also formed embryonic bodies and teratomas containing derivatives of the 3 germ layers, and could as well be readily differentiated into functional motor neurons. Among other things, our cell lines may prove useful for comparisons between iPSCs derived from multiple tissues regarding the extent of the epigenetic reprogramming, differentiation ability, stability of the resulting lineages, and the risk of associated abnormalities.
Cerclage cervical en urgence au deuxième trimestre de la grossesse. À propos de 18 cas à la maternité de Port-Royal

Le cerclage en urgence est realise devant des modifications cervicales evoquant une incompetence cervicale, au deuxieme trimestre de la grossesse. Face a cette pratique, il a paru interessant de savoir quels sont les resultats obtenus en termes de complications, issues de la grossesse, morbidite et mortalite perinatales. Une etude retrospective sur dossiers comprenant 18 femmes ayant eu un cerclage en urgence, entre 2005 et 2011, a ete menee a la maternite de Port-Royal. Un tiers des accouchements s'est deroule avant le terme de viabilite. La principale complication est la chorioamniotite qui s'associe systematiquement a des grossesses se soldant par un accouchement avant le terme de viabilite ou a des accouchements prematures. Par contre, la mortalite neonatale etait nulle, la morbidite neonatale n'etait liee qu'aux accouchements prematures puisqu'aucune infection materno-fœtale n'a ete retrouvee.
Immune regulatory gene polymorphisms as predisposing risk factors for the development of factor VIII inhibitors in Indian severe haemophilia A patients

Development of inhibitors to factor VIII, a serious complication of replacement therapy in haemophilia A patients, leads to increased bleeding, morbidity and mortality. There is no data on the risk factors for inhibitor development in Indian patients with severe haemophilia A. Our aim was to study the role of immune regulatory gene polymorphisms in the development of inhibitors. Fourteen immune regulatory gene polymorphisms (IL1β, IL4, IL10, TNFA and CTLA4) were analysed in 120 patients with severe haemophilia A, i.e. 50 inhibitor positive patients, and 70 inhibitor negative control patients, by PCR‐RFLP, DNA sequencing and allele‐specific PCRs. The IL10 promoter ‘GCC’ haplotypes overall (P: 0.002, OR: 3.452, 95% CI: 1.607–7.416), and ‘GCC/ATA’ (P: 0.011, OR: 3.492, 95% CI: 1.402–8.696) haplotype, associated with high and intermediate IL10 production, respectively, were significantly higher in inhibitor positive patients, whereas the ‘non‐GCC’ haplotypes overall (P: 0.002,OR: 0.290, 95% CI 0.135–0.622) and ‘ATA/ATA’ haplotype (P: 0.025, OR: 0.278, 95% CI: 0.096–0.802), associated with low IL10 synthesis, were significantly higher among inhibitor negative patients. The TNFA rs1799724 C/T heterozygote prevalence was significantly higher in the inhibitor positive group (P: 0.021, OR: 3.190, 95% CI: 1.273–7.990), whereas the other polymorphisms showed no statistically significant association with the presence of inhibitors. Different immune regulatory gene polymorphisms play a significant role as possible risk factors for the development of inhibitors in severe haemophilia A patients.
Transforming Growth Factor β Promotes Complexes between Smad Proteins and the CCCTC-binding Factor on the H19 Imprinting Control Region Chromatin*

Whether signal transduction pathways regulate epigenetic states in response to environmental cues remains poorly understood. We demonstrate here that Smad3, signaling downstream of transforming growth factor β, interacts with the zinc finger domain of CCCTC-binding factor (CTCF), a nuclear protein known to act as “the master weaver of the genome. ” This interaction occurs via the Mad homology 1 domain of Smad3. Although Smad2 and Smad4 fail to interact, an alternatively spliced form of Smad2 lacking exon 3 interacts with CTCF. CTCF does not perturb well established transforming growth factor β gene responses. However, Smads and CTCF co-localize to the H19 imprinting control region (ICR), which emerges as an insulator in cis and regulator of transcription and replication in trans via direct CTCF binding to the ICR. Smad recruitment to the ICR requires intact CTCF binding to this locus. Smad2/3 binding to the ICR requires Smad4, which potentially provides stability to the complex. Because the CTCF-Smad complex is not essential for the chromatin insulator function of the H19 ICR, we propose that it can play a role in chromatin cross-talk organized by the H19 ICR.
The NPH-II Helicase Displays Efficient DNA·RNA Helicase Activity and a Pronounced Purine Sequence Bias*

The superfamily 2 vaccinia viral helicase nucleoside triphosphate phosphohydrolase-II (NPH-II) exhibits robust RNA helicase activity but typically displays little activity on DNA substrates. NPH-II is thus believed to make primary contacts with backbone residues of an RNA substrate. We report an unusual nucleobase bias, previously unreported in any superfamily 1 or 2 helicase, whereby purines are heavily preferred as components of both RNA and DNA tracking strands. The observed sequence bias allows NPH-II to efficiently unwind a DNA·RNA hybrid containing a purine-rich DNA track derived from the 3′-untranslated region of an early vaccinia gene. These results provide insight into potential biological functions of NPH-II and the role of sequence in targeting NPH-II to appropriate substrates. Furthermore, they demonstrate that in addition to backbone contacts, nucleotide bases play an important role in modulating the behavior of NPH-II. They also establish that processive helicase enzymes can display sequence selectivity.