Miracle-dz/UniFAR-FTUs huggingface dataset:
Investigation of 305 patients with myelodysplastic syndromes and 20q deletion for associated cytogenetic and molecular genetic lesions and their prognostic impact

In patients with myelodysplastic syndromes (MDS), sole 20q deletion [del(20q)] is a recurrent favourable abnormality. We studied additional molecular and cytogenetic lesions and their prognostic impact in 305 MDS patients with del(20q) (229 males/76 females; 29–90 years). All patients were investigated by cytomorphology and chromosome banding analysis (CBA), subsets by fluorescence in situ hybridization, molecular mutation screening, and array comparative genomic hybridization (aCGH). By aCGH (n = 30), the minimal common deleted region (CDR) was flanked by PTPRT (20q13·11) and EYA2 (20q13·12). 210 (68·9%) patients had ‘early MDS’ without blast increase, 95 (31·1%) ‘advanced’ MDS with blast increase (5–19%). Additional chromosomal abnormalities (ACAs) were detected in 88/305 (28·9%) patients. Patients with advanced MDS more frequently had ACAs (P = 0·003) and had a higher mean number of ACAs (P = 0·020) and of molecular mutations (P = 0·060). Spliceosome mutations were frequent (U2AF1: n = 31/155; 20·0%; SRSF2: n = 31/159; 19·5%; SF3B1mut: n = 8/159; 5·0%). ASXL1mut (25/153; 16·3%) were associated with advanced MDS (P = 0·001). Presence of ≥3 ACAs (P = 0·003) and ASXL1mut (P = 0·002) were associated with worse 2‐year survival. In conclusion, the cytogenetic subgroup of MDS with del(20q) has a good prognosis but may be further subclassified by additional cytogenetic and molecular lesions. U2AF1mut is overrepresented in MDS with del(20q), and ASXL1mut is prognostically adverse.
A Generalized Proximal Point Algorithm for the Variational Inequality Problem in a Hilbert Space

We consider a generalized proximal point method for solving variational inequality problems with monotone operators in a Hilbert space. It differs from the classical proximal point method (as discussed by Rockafellar for the problem of finding zeroes of monotone operators) in the use of generalized distances, called Bregman distances, instead of the Euclidean one. These distances play not only a regularization role but also a penalization one, forcing the sequence generated by the method to remain in the interior of the feasible set so that the method becomes an interior point one. Under appropriate assumptions on the Bregman distance and the monotone operator we prove that the sequence converges (weakly) if and only if the problem has solutions, in which case the weak limit is a solution. If the problem does not have solutions, then the sequence is unbounded. We extend similar previous results for the proximal point method with Bregman distances which dealt only with the finite dimensional case and which applied only to convex optimization problems or to finding zeroes of monotone operators, which are particular cases of variational inequality problems.
Worsening of obesity and metabolic status yields similar molecular adaptations in human subcutaneous and visceral adipose tissue: decreased metabolism and increased immune response.

CONTEXT It is not known whether biological differences reported between sc adipose tissue (SAT) and visceral adipose tissue (VAT) depots underlie the pathogenicity of visceral fat. OBJECTIVE We compared SAT and VAT gene expression according to obesity, visceral fat accumulation, insulin resistance, and presence of the metabolic syndrome. DESIGN Subjects were assigned into four groups (lean, overweight, obese, and obese with metabolic syndrome). SETTING Subjects were recruited at a university hospital. PATIENTS Thirty-two women were included. MAIN OUTCOME MEASURES Anthropometric measurements, euglycemic-hyperinsulinemic clamps, blood analyses, and computed tomography scans were performed, and paired samples of SAT and VAT were obtained for DNA microarray-based gene expression profiling. RESULTS Considering the two fat depots together, 1125 genes were more and 1025 genes were less expressed in lean compared with metabolic syndrome subjects. Functional annotation clustering showed, from lean to metabolic syndrome subjects, progressive down-regulation of metabolic pathways including branched-chain amino acid, fatty acid, carbohydrate, and mitochondrial energy metabolism and up-regulation of immune response genes involved in toll-like receptor, TNF, nuclear factor-κB, and apoptosis pathways. Metabolism and immune response genes showed an opposite correlation with fat mass, fat distribution, or insulin resistance indices. These associations were similar in SAT and VAT, although about 1000 genes showed differential expression between SAT and VAT. CONCLUSIONS The increase in adiposity and the worsening of metabolic status are associated with a coordinated down-regulation of metabolism-related and up-regulation of immune response-related gene expression. Molecular adaptations in SAT prove as discriminating as those in VAT.
Sonoelastography in de Quervain thyroiditis.

Sonoelastography is a novel technique, providing an objective estimation of tissue elasticity by measuring the degree of distortion under the application of an external force (1). Recent studies demonstrated exceptional utility of sonoelastography in preoperative evaluation of thyroid nodules because neoplastic transformation is often associated with decreased elasticity of a lesion (1– 4). However, a sonoelastographic picture of de Quervain thyroiditis (dQT) has not yet been described. Herewithin we report cases of dQT in two women, ages 36 and 42 yr, presenting with malaise, pain in the neck, and temperature up to 38 C. Conventional ultrasonography revealed a picture typical for dQT in the first patient, but only minimal changes in the second patient, whereas sonoelastography in both demonstrated markedly decreased elasticity of the affected area (Figs. 1 and 2). Patients were euthyroid (TSH was 0.29 and 0.57 IU/ml, respectively) and had an increased erythrocyte sedimentation rate (48 and 61 mm/h, respectively). The cytological diagnosis of the specimen obtained by fine-needle biopsy was consistent with dQT. Patients were treated with ibuprofen and prednisone, which resulted in total remission. To conclude, obtained results suggest that inflammatory infiltration of thyroid parenchyma in dQT causes decreased thyroid tissue elasticity. Sonoelastography might be useful in diagnosing dQT, selecting regions for biopsy in patients with minimal changes on conventional ultrasonography, as well as in differential diagnosis with Hashimoto’s thyroiditis. Moreover, the coexistence of dQT may affect interpretation of elasticity of concomitant thyroid nodules. Studies on larger groups are required to further assess the usefulness of elastographic evaluation in dQT.
On Generic One-Parametric Semi-Infinite Optimization

We consider differentiable semi-infinite optimization problems depending on a real parameter. For generic one-parametric families we classify the corresponding set of generalized critical points into eight types. Five of these types also occur in problems with a finite number of inequality constraints, whereas the other three types are typical for the semi-infinite case. We discuss types 7 and 8 in detail. While at points of type 6, the singularity is due to the fact that in the associated lower level problem a Lagrange multiplier corresponding to an active inequality constraint vanishes, at points of type 7 and 8, the gradients of the active constraints in the lower level problem are linearly dependent. If the total number of active constraints in the lower level problem does not exceed the lower level dimension, the point is of type 7; otherwise, it is of type 8. Moreover, we distinguish between points of type 8a and 8b, where a point is of type 8a if the Mangasarian--Fromovitz constraint qualification holds in the lower level problem, and of type 8b otherwise. At points of type 8a, the set of generalized critical points is not smooth, but it does not exhibit a turning point. The linear and quadratic indices remain constant when passing along a point of type 8a. Points of type 7 and type 8b are (relative) boundary points of the set of generalized critical points.
Autorreporte de exposición a publicidad y promoción de tabaco en una cohorte de fumadores mexicanos

Objective. To determine in a population-based sample of smokers the level exposure to tobacco industry marketing through different channels before and after their restriction through the General Tobacco Control Law of 2008. Materials and methods. Data were analyzed from a cohort of adult smokers from four Mexican cities who were surveyed in 2007 and 2008. GEE models were estimated for each indicator of advertising and promotion exposure. Results. Increases were found in report of receiving free samples of tobacco (3.7-8.1%), branded clothing (3.6-6.4%), noticing tobacco industry sponsored events (1.9-4.7%) and noticing ads in bars (21.4-28%). Noticing outdoor advertising decreased over this time (54.7 a 47.2%). Conclusions. Our findings confirm tobacco industry shifting of marketing efforts when advertising and promotion bans are not comprehensive. There is a need to monitor compliance with marketing bans while working to make them comprehensive.
Bone mass in subjects with Klinefelter syndrome: role of testosterone levels and androgen receptor gene CAG polymorphism.

CONTEXT Klinefelter syndrome (KS) is a chromosomal alteration characterized by supernumerary X-chromosome(s), primary hypogonadism, decreased pubertal peak bone mineral density (BMD), and accelerated bone loss during adulthood. Decreased bone mass has been traditionally related to low testosterone levels. However, testosterone replacement therapy does not necessarily increase bone mass in these patients, and low BMD can be observed also in patients with normal testosterone levels. The androgen receptor (AR) gene CAG polymorphism seems to modulate the sensitivity to testosterone and previous studies have related it to some clinical aspects of KS, to include BMD, gynecomastia, testes and prostate volume, and hemoglobin concentration. OBJECTIVE To analyze the relation between bone mass, testosterone, and AR CAG polymorphism in men with KS. DESIGN Cross-sectional cohort study. SETTING University department. PATIENTS One hundred twelve consecutive treatment-naïve 47,XXY Klinefelter patients (mean age 33.5 ± 4.7 yr) and 51 age-matched normal male controls. MAIN OUTCOME MEASURES Dual-energy x-ray absorptiometry, CAG repeat length polymorphism, X-chromosome inactivation, and testosterone levels. RESULTS Forty-nine of 112 KS subjects (42.5%) had low bone mass (osteopenia or osteoporosis). Lumbar and/or femoral T-scores were lower in KS patients compared with controls. No significant relationship was observed between testosterone levels and bone parameters, and the prevalence of osteopenia/osteoporosis was similar in subjects with normal and low testosterone levels (43.7% and 40.5%, respectively). The mean CAG repeat length calculated after X-chromosome inactivation analysis showed no differences between patients with normal and low bone mass. CONCLUSIONS Testosterone levels and AR CAG polymorphism are not associated with bone mass phenotype in KS.
Milestones in understanding platelet production: a historical overview

The discovery of thrombopoietin (TPO, also termed THPO) in 1994 was a major achievement in understanding the regulation of platelet production. In prior decades, physiological studies had demonstrated that platelets were produced from bone marrow megakaryocytes and that the megakaryocytes responded to thrombocytopenia by increasing their number, size and DNA ploidy. In 1958, it was proposed that a ‘thrombopoietin’ must exist that regulated this interaction between the circulating platelet mass and the bone marrow megakaryocytes. After over three decades of effort, TPO was finally purified by five independent laboratories. TPO stimulated megakaryocyte colony‐forming cell growth and increased the number, size and ploidy of megakaryocytes. When the genes for TPO or TPO receptor were eliminated in mice, megakaryocytes grew and platelets were made, but at 15% of their normal number. A first generation of recombinant human (rh) TPO molecules [rhTPO and pegylated recombinant human megakaryocyte growth and development factor (PEG‐rhMGDF)] rapidly entered clinical trials in 1995 and increased platelet counts in humans undergoing non‐myeloablative chemotherapy but not in those undergoing stem cell transplantation. Antibodies developed against PEG‐rhMGDF and development of these recombinant thrombopoietins ended. A second generation of TPO receptor agonists (romiplostim and eltrombopag) was then developed. Neither of these TPO receptor agonists demonstrated any significant untoward effects and both are now licensed in many countries for the treatment of immune thrombocytopenia. This review describes the significant experiments that have surrounded the discovery of TPO and its clinical development.
Pharmacokinetics and Residual Studies of Florfenicol Following Multiple Dose Oral Administration in Poultry

Abstract Lohani, M. , Ahmad, A.H. , Singh, K.P. and Verma, S. 2010. Pharmacokinetics and residual studies of Florfenicol following multiple dose oral administration in poultry. J. Appl. Anim. Res., 38: 9–12. Pharmacokinetics o f Florfenicol was established in the plasma of poultry. Florfenicol was given as multiple dose 30 mg.kg−1 orally daily for 5 days in poultry. The mean values of half-life, body clearance (ClB) and mean volume of distribution (Vdarea) were 8.39 and 7.91 h; 0.5 and 0.29 l.h−1.kg−1 and 4.8 and 2.70 l.kg−1 after first and last dose, respectively. On the basis of depletion study for Florfenicol in poultry, a withdrawal time of 72 h was calculated.
High‐throughput sequencing for the identification of NOTCH1 mutations in early stage chronic lymphocytic leukaemia: biological and clinical implications

NOTCH1 mutations have recently emerged as new genetic lesions significantly correlated with survival in chronic lymphocytic leukaemia (CLL). We performed deep next generation sequencing of the NOTCH1 mutation hotspot in 384 cases at diagnosis, including 100 monoclonal B cell lymphocytosis (MBL) and 284 Binet stage A CLL cases, enrolled in the Gruppo Italiano Studio Linfomi O‐CLL1 multicentre trial. The NOTCH1 c. 7541_7542delCT dinucleotide deletion was detected and confirmed by an extremely sensitive polymerase chain reaction‐based approach in 11% of MBL and 13·4% of CLL patients. Remarkably, the NOTCH1 mutation was often observed at low clonal level, mainly in MBL patients. Sequential analyses in a fraction of cases showed that the NOTCH1 mutation generally does not occur during the disease course and that the mutational load in positive cases tends to be stable over time. NOTCH1‐mutated cases, even at low clonal level, displayed a significant reduction in median progression‐free survival, although NOTCH1 mutation lost its prognostic impact in a multivariate analysis including 11q and/or 17p deletion, IGHV mutational status, and MBL or CLL status. Our data highlight the importance of using highly sensitive methods to measure NOTCH1 mutations, in order to improve prognostic stratification and obtain useful information for potential therapeutic approaches.
An Algorithm for the Inequality-Constrained Discrete Min-Max Problem

In this paper we discuss an approach using an augmented Lagrangian formulation to directly solve the inequality constrained min--max problem. The algorithm involves a sequential quadratic programming subproblem, an adaptive penalty parameter selection rule, and a stepsize strategy, convergent to unit steps, that ensures progress toward optimality and feasibility of the inequality constraints. It is shown that the penalty parameter does not grow indefinitely. The convergence of the algorithm is established, and its numerical effectiveness is demonstrated with test examples.
Computation of Lyapunov-Type Numbers for Invariant Curves of Planar Maps

Invariant manifolds play an important role in the study of dynamical systems, and it is often crucial to know when they persist under small perturbations of the system. Sufficient conditions for persistence have been formulated in the literature in terms of so-called Lyapunov-type numbers, which measure and compare attractivity rates. The numerical evaluations of these numbers in a simple setting is the subject of this paper. We consider planar diffeomorphisms depending on a parameter; the diffeomorphisms have invariant curves which deform as the parameter changes. The Lyapunov-type numbers are then monitored as functions of parameter and are related to the dynamics on the invariant curves. As an example, we consider the delayed logistic map. We also describe how the invariant curves have been computed.
Open‐label, single‐arm, phase II study of enzastaurin in patients with follicular lymphoma

This open‐label, phase II study investigated whether enzastaurin, a protein kinase C‐beta (PKCβ) inhibitor, had activity in patients with grade 1 or 2 follicular lymphoma (FL). Adults with grade 1 or 2 FL who had no more than one prior treatment received oral enzastaurin continuously for up to 3 years. Of the 66 patients who received enzastaurin, 53 were evaluable for response. Overall response rate (ORR, primary efficacy endpoint) was 26·4% (3·8% complete response). Median (95% confidence interval) progression‐free survival, time to response, and duration of response were 18·1 (11·5–28·3), 4·9 (2·8–8·1), and 22·3 (8·8‐not applicable) months, respectively. In patients with tumour tissue available for biomarker analysis, ORRs in low versus high PKCβ2 expression groups were 41·7% and 8·3%, respectively (P = 0·041). The most common, mainly low‐grade drug‐related adverse events were fatigue (25·8%), diarrhoea (25·8%), nausea (18·2%), and chromaturia (18·2%). Four (6·1%) patients had Grade 3 toxicity and one (1·5%) patient had Grade 4 toxicity. Enzastaurin demonstrated limited clinical activity in grade 1 or 2 FL. Patients with low PKCβ2 expression in tumours had higher ORR than those with high PKCβ2 expression. Enzastaurin was well tolerated with mostly grade 1 or 2 toxicities. Further studies may be warranted in select patient populations.
Boundary Element Preconditioners for Problems Defined on Slender Domains

Within the framework of two-dimensional potential theory, we consider problems defined on slender domains. The boundary element matrices for such problems are poorly conditioned due to the presence of two disparate length scales. A new class of preconditioners is proposed to remedy this problem so that the preconditioned boundary element matrices become insensitive to the domain slenderness. The preconditioners are constructed using the spectral properties of the boundary integral operators defined on the elliptical domains.
Patients with Bardet-Biedl syndrome have hyperleptinemia suggestive of leptin resistance.

OBJECTIVE Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder of the primary cilium associated with obesity. In BBS mouse models, ciliary dysfunction leads to impaired leptin signaling and hyperleptinemia before obesity onset. To study the pathophysiology of obesity in BBS, we compared patients with BBS and body mass index Z-score (BMI-Z)-matched controls. DESIGN AND METHODS Fifty patients with BBS were matched 2:1 by age, sex, race, and BMI-Z with 100 controls. Patients with BBS and controls were compared for differences in body composition (dual-energy x-ray absorptiometry, abdominal magnetic resonance imaging), blood pressure Z-score (BP-Z; standardized for age, sex, and height), and fasting concentrations of leptin, lipids, insulin, and glucose. Patients with BBS were also compared by genotype. RESULTS Leptin, triglycerides, intraabdominal fat mass, and diastolic BP-Z were significantly greater in patients with BBS than in the controls. BBS1 (27%) and BBS10 (30%) mutations were the most prevalent. Patients with BBS10 mutations had significantly higher BMI-Z, greater visceral adiposity, and greater insulin resistance than those with BBS1 mutations. CONCLUSIONS Patients with BBS had higher leptin than expected for their degree of adiposity, consistent with the notion that ciliopathy-induced leptin signaling dysfunction is associated with leptin resistance. The preferential deposition of fat intraabdominally in patients with BBS may indicate a predisposition for metabolic complications, including hypertension and hypertriglyceridemia. The observation of disparate results in the BBS10 vs. BBS1 mutation groups is the first demonstration of physiological differences among patients with BBS caused by mutations in distinct genes. These results suggest that the obesity of BBS is distinct from nonsyndromic obesity.
Long‐term survival after allogeneic stem cell transplantation for advanced stage multiple myeloma

Despite the use of novel drugs and autologous stem cell transplantation (SCT), multiple myeloma (MM) is still considered to be an incurable disease. Both autologous and allogeneic SCT (allo-SCT) improve long-term survival. Allo-SCT can result in long-term disease control and remains a potentially curative therapeutic modality, related in part to the immune anti-myeloma effect of the allograft, but it is hampered by high transplant-related toxicities. Reduced intensity conditioning (RIC) allo-SCT has been developed in order to reduce transplant-related mortality while maintaining a graftversus-myeloma (GVM) effect. Few studies have reported long-term outcomes in MM after allo-SCT, with a median follow-up typically ranging from 2 to 5y ears. Recently, Sahebiet al (2013) reported an overall survival (OS) of 60%, progression-free survival (PFS) of 31% and relapse incidence of 59% at 7 years in 60 MM patients undergoing allo-SCT after RIC, with a median follow-up of 98 years. Very late relapses occurred in 10% of patients, even as late as 115 years after transplantation (Sahebi et al, 2013). We report on the long-term follow-up (median
Interaction between testosterone and growth hormone on whole-body protein anabolism occurs in the liver.

CONTEXT GH and testosterone both exert protein-anabolic effects and may act synergistically. Liver and muscle are major sites of protein metabolism. OBJECTIVE Our objective was to determine whether the site of GH and testosterone interaction on protein metabolism is primarily hepatic or extrahepatic. DESIGN In this open-label randomized crossover study, the impact on whole-body protein metabolism of oral (solely hepatic testosterone exposure) and transdermal (systemic testosterone exposure) testosterone replacement in the presence or absence of GH was compared. PATIENTS AND INTERVENTION Eleven hypopituitary men with GH and testosterone deficiency were randomized to 2-wk treatments with transdermal testosterone (10 mg) or oral testosterone (40 mg), with or without GH replacement (0.6 mg/d). The dose of testosterone administered orally achieves physiological portal testosterone concentrations without spillover into the systemic circulation. MAIN OUTCOME MEASURES Whole-body leucine turnover was measured, from which leucine rate of appearance (LRa), an index of protein breakdown, and leucine oxidation (Lox), a measure of irreversible protein loss, were estimated at the end of each treatment. RESULTS In the absence of GH, neither transdermal nor oral testosterone affected LRa or Lox. GH therapy significantly increased LRa, an effect equally reduced by transdermal and oral testosterone administration. GH replacement alone did not significantly change Lox, whereas addition of testosterone treatment reduced Lox, with the effect not significantly different between transdermal and oral testosterone. CONCLUSIONS In the doses used, testosterone stimulates protein anabolism by reducing protein breakdown and oxidation only in the presence of GH. Because the net effect on protein metabolism during GH therapy is not different between systemic and solely hepatic testosterone administration, we conclude that the liver is the primary site of this hormonal interaction.