Effectiveness of defibrotide in the prevention of hepatic venooclusive disease among adult patients receiving allogeneic hematopoietic cell transplantation: A retrospective single center experience

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is one of the most life-threatening early complications following hematopoietic cell transplantation (HCT). Due to the high mortality rate of severe VOD/SOS accompanied with multiorgan failure, there is a great interest in preventive strategies. The efficacy of defibrotide (DF) on the prevention of VOD/SOS has been clearly shown in high-risk pediatric patients, but evidence-based data on adults is scarce. In this report, we aimed to assess the impact of DF on the incidence of VOD/SOS in our center by posttransplant day 30 among patients who were treated with allogeneic HCT (allo-HCT). The study included a total of 56 patiens (28 males, 28 females). The median age of the study cohort was 43 (20-68). The daily dose of DF was 10 mg/kg and 25 mg/kg in 53 (94.6 %) and 3 (5.3 %) patients, respectively. Patients also recieved oral ursodeoxycolic acid (UDCA) 250 mg three-times daily started with conditioning until D + 90. Twenty-three (41.1 %) patients had at least one major EBMT-defined risk factor for development of VOD/SOS. One patient who belonged to a very high-risk group (with at least two major risk factors) developed very-severe VOD/SOS at posttransplant D + 20 and died as a result of multiorgan failure. The cumulative incidence of VOD/SOS at D + 30 was 1.9 %. Our findings indicate that 10 mg/kg daily intravenous DF combined with UDCA is quite effective in prevention of VOD/SOS in patients who underwent first allo-HSCT

Modeling mutant phenotypes and oscillatory dynamics in the Saccharomyces cerevisiae cAMP-PKA pathway

Background The cyclic AMP-Protein Kinase A (cAMP-PKA) pathway is an evolutionarily conserved signal transduction mechanism that regulates cellular growth and differentiation in animals and fungi. We present a mathematical model that recapitulates the short-term and long-term dynamics of this pathway in the budding yeast, Saccharomyces cerevisiae. Our model is aimed at recapitulating the dynamics of cAMP signaling for wild-type cells as well as single (pde1Δ and pde2Δ) and double (pde1Δpde2Δ) phosphodiesterase mutants. Results Our model focuses on PKA-mediated negative feedback on the activity of phosphodiesterases and the Ras branch of the cAMP-PKA pathway. We show that both of these types of negative feedback are required to reproduce the wild-type signaling behavior that occurs on both short and long time scales, as well as the the observed responses of phosphodiesterase mutants. A novel feature of our model is that, for a wide range of parameters, it predicts that intracellular cAMP concentrations should exhibit decaying oscillatory dynamics in their approach to steady state following glucose stimulation. Experimental measurements of cAMP levels in two genetic backgrounds of S. cerevisiae confirmed the presence of decaying cAMP oscillations as predicted by the model. Conclusions Our model of the cAMP-PKA pathway provides new insights into how yeast respond to alterations in their nutrient environment. Because the model has both predictive and explanatory power it will serve as a foundation for future mathematical and experimental studies of this important signaling network

Non-kutanöz Periferik T-hücreli Lenfomalarda Klinik Özellikler ve Tedavi Sonuçlarına ilişkin Gerçek Yaşam Deneyimi:Türk Hematoloji Araştırma ve Eğitim Grubunun Çok Merkezli Çalışması

Objective: Peripheral T-cell lymphomas (PTCLs) are an uncommon and quite heterogeneous group of disorders, representing only 10%-15% of all non-Hodgkin lymphomas. Although both molecular and clinical studies have increased in recent years, we still have little knowledge regarding real-life practice with PTCLs. In this study, we aimed to investigate the clinical characteristics and treatment outcomes of a large population-based cohort of patients presenting with systemic non-cutaneous PTCL. Materials and Methods: We conducted a multicenter retrospective analysis of 190 patients consecutively diagnosed and treated with non-cutaneous PTCLs between 2008 and 2016. Results: Considering all first-line treatment combinations, the overall response rate was 65.9% with 49.4% complete remission (n=81) and 16.5% partial response (n=27). The 5-year overall survival and event-free survival rates were significantly different between the transplant and non-transplant groups (p<0.01, and p=0.033, respectively). Conclusion: The retrospective analysis of a large volume of real-life data on the Turkish experience regarding non-cutaneous PTCL patients showed consistent results compared to other unselected PTCL cohorts with some minor differences in terms of survival and transplantation outcomes. The long-term outcome of patients who receive autologous hematopoietic cell transplantation as part of upfront consolidation or salvage therapy is favorable compared to patients who are unable to receive high-dose therapy. © 2022 by Turkish Society of Hematology Turkish Journal of Hematology, Published by Galenos Publishing House

T Helper 17 Cytokine profile in psoriatic arthritis and their relations with clinical findings

Tıpta Uzmanlık TeziSon dönemde interlökin-17 üreten, T helper-17 olarak adlandırılan yeni bir T hücre subgrubu olduğu ve otoimmun inflamatuvar hastalıkların gelişimindeki rolünün yanısıra kemik döngüsünde osteoklast aktivasyonunun güçlü bir uyaranı olduğu gösterilmiştir. İnterlökin-17'ye ek olarak interlökin-22 ve interlökin-23'te T helper-17 hücrelerinin sitokin profilinde önemli yer tutmaktadırlar. Bu çalışmada psöriatik artritte T helper-17 sitokin profilinin klinik bulgularla ilişkisi belirlenmeye çalışıldı. Ayrıca T helper-17 sitokinlerinin, bu hastalıktaki yeni kemik oluşumunu açıklaması bakımından değer taşıyacak olan, receptor aktivatör nükleer faktör kappa beta ligandı ve Wingless yolağı inhibitörü Dickkopf-1 ile de ilişkisinin belirlenmesi amaçlandı. Çalışmada psöriatik artritli hastaları sağlıklı kontrol grubu yanında pozitif kontrol grubu olarak sadece psöriazisi olan artriti olmayan hastalarla da karşılaştırdık. Psöriatik artritli ve psöriazisli hastaların klinik ve labaratuvar özellikleri kaydedildi. Tüm hastalarda ve kontrol grubunda Enzyme-linked immuno sorbent analiz yöntemi ile İnterlökin-17, İnterlökin-22, İnterlökin-23, Dickkopf-1 ve "soluble" reseptor aktivatör nükleer faktör kappa beta ligandı düzeyleri bakıldı. Çalışmamızda, interlökin-17, interlökin-22 ve interlökin-23 düzeylerinin psöriatik artrit grubunda psöriazis ve sağlıklı kontrol grubundan anlamlı düşük olduğunu saptadık. Bu bulgu başlangıçtaki beklentimize ters olarak T helper-17 grubu sitokinlerin, psöriatik artritte baskılandığını gösteren bir bulgudur. Çalışmamızda psöriatik artrit grubumuzda ?soluble? reseptor aktivatör nükleer faktör kappa beta ligandı düzeylerinin sağlıklı kontrol grubundan düşük olduğunu ayrıca psöriazis grubunda da "soluble" reseptor aktivatör nükleer faktör kappa beta ligandı düzeylerinin anlamlı düşük olduğunu saptadık. Psöriatik artrit grubunda oligoartiküler hasta grubunun fazla oluşu, bunlarda osteoliz bulguları ve dolayısıyla osteoklast aktivasyonunun düşük olması muhtemelen bu sonuca katkıda bulunmuş olabilir. Çalışmamızda psöriatik artrit grubunda Dickkopf-1 düzeylerinin hastalık patogenezi ile ilişkili olmadığını gösterir biçimde psöriazis ve sağlıklı kontrol grubundan düşük olduğunu ve farkın anlamlı olmadığını saptadık.AbstractLately, a new T cell subgroup named as T helper-17 which releases Interleukin-17 has been identified and demonstrated to play a role in the development of autoimmune inflammatory diseases as well as to stimulate the activation of osteoclasts within the bone cycle. Besides Interleukin-17, Interleukin-22 and Interleukin-23 are important components of T helper-17 cells cytokine profile. In this study, the relation of cytokine profile of T helper- 17 with the clinical findings are aimed to be determined in psoriatic arthritis. Also, the relation of T helper 17 cytokines with "soluble" receptor activator nuclear factor kappa beta ligand which is important in the new bone formation and the Wingless pathway inhibitor Dickkopf-1 are aimed to be evaluated. In this study, we compared the psoriatic arthritis patients with healthy controls as well as with positive control groups as psöriazis patients with or without arthritis. The clinical and laboratory findings of patients with psoriatic arthritis and psöriazis were recorded. The levels of Interleukin-17, Interleukin-22, Interleukin-23, Dickkopf-1 and "soluble" receptor activator of nuclear factor kappa beta ligand were determined with enzyme linked immune sorbent analysis method in all patients and control groups. In our study, the levels of Interleukin-17, Interleukin-22 and Interleukin-23 were observed to be significantly lower in psoriatic arthritis group than psöriazis and healthy control groups. This findings were controversial with our expectations in the beginning, suggesting that Thelper-17 group cytokines are suppressed in psoriatic arthritis. In our study, "soluble" receptor activator nuclear factor kappa beta ligand levels of psoriatic arthritis were observed to be lower than psöriazis and healthy control groups. The oligoarthritis group was larger in psoriatic arthritis which may probably contribute to this result since the findings of osteolysis and the osteoclast activation are observed to be lower in this group. In our study, we demonstrated that Dickkopf-1 levels in psoriatic arthritis group were lower than both psöriazis and healthy control groups without significant difference suggesting that Dickkopf-1 levels are not associated with disease pathogenesis

Defibrotide combined with triple therapy including posttransplant cyclophosphamide, low dose rabbit anti-t-lymphocyte globulin and cyclosporine is effective in prevention of graft versus host disease after allogeneic peripheral blood stem cell transplantation for hematologic malignancies

Endothelial dysfunction and damage play important roles in the pathophysiology of graft versus host disease (GvHD) and hepatic venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS). Preliminary evidence suggests that defibrotide (DF) may decrease the risk of GvHD. We speculated that DF prophylaxis may have a synergistic effect with other immunosupressive agents by decreasing the incidence of GvHD and retrospectively evaluated the impact of a DF prophylaxis on the development of GvHD. Thirty-eight adult patients with various hematological neoplasms who underwent peripheral blood allogeneic hematopoietic stem cell transplantation from all donor types were included. All patients received DF for prevention of VOD/SOS. GvHD prophylaxis included rabbit anti-T lymphocyte globulin (rATLG), posttransplant cyclophosphamide (PTCy) and cyclosporine (CsA). The median follow-up of the surviving patients was 484 (365?814) days. The cumulative incidence of grade III-IV acute GvHD and moderate/severe chronic GvHD requiring systemic immunosupression at 1 year were 20.6 % and 5.3 %, respectively. Non-relapse mortality, GvHD-relapse-free survival, and overall survival of the study cohort at 1-year were 21.1 %, 44.7 % and 57.9 %, respectively. Our preliminary results suggest that DF may act as a global endothelial protectant and decrease the risk of GvHD in combination with rATLG, PTCy and CsA. © 202

Individual Segregant Phenotype and Genotype Table

This file compiles phenotype and genotype data collected on individual segregants from the Bulk Segregant Analysis. Each row in the file contains data on a single segregant

Single vs. Double Dartos Interposition Flaps in Preventing Urethrocutaneous Fistula after Tubularized Incised Plate Urethroplasty in Primary Distal Hypospadias: A Prospective Randomized Study

WOS: 000270779400021PubMed: 19829040Introduction: This prospective study was designed to compare symmetrical overlapping double flaps with a single dartos flap in regard to fistula formation as an adjunct to tubularized incised plate urethroplasty (TIPU). Patients and Methods: 77 consecutive children with primary coronal or subcoronal hypospadias were randomized into 2 groups. A single layer dartos flap was used to cover the anastomotic site in the first group (37 patients). A wider dorsal dartos flap bisectioned in the midline was utilized in the second group of 40 patients. The complication rates were compared. Results: There was no difference between the 2 groups in terms of age, and meatal location. Postoperative median follow-up was 34 months. Urethrocutaneous fistula occurred in 3 patients (8.1%) of the monolayer group. No fistula developed in the second group with double flaps. Conclusions: The current study proposes that the use of double dorsal flaps, although statistically not significant, better prevents fistula formation compared to monolayer dartos flaps following TIPU operation. Copyright (C) 2009 S. Karger AG, Base

Data from: The genetic architecture of biofilm formation in a clinical isolate of Saccharomyces cerevisiae

Biofilms are microbial communities that form on surfaces. They are the primary form of microbial growth in nature and can have detrimental impacts on human health. Some strains of the budding yeast Saccharomyces cerevisiae form colony biofilms, and there is substantial variation in colony architecture between biofilm-forming strains. To identify the genetic basis of biofilm variation, we developed a novel version of quantitative trait locus mapping, which leverages cryptic variation in a clinical isolate of S. cerevisiae. We mapped 13 loci linked to heterogeneity in biofilm architecture and identified the gene most closely associated with each locus. Of these candidate genes, six are members of the cyclic AMP-protein kinase A pathway, an evolutionarily conserved cell signaling network. Principal among these is CYR1, which encodes the enzyme that catalyzes production of cAMP. Through a combination of gene expression measurements, cell signaling assays, and gene overexpression, we determined the functional effects of allelic variation at CYR1. We found that increased pathway activity resulting from protein coding and expression variation of CYR1 enhances the formation of colony biofilms. Four other candidate genes encode kinases and transcription factors that are targets of this pathway. The protein products of several of these genes together regulate expression of the sixth candidate, FLO11, which encodes a cell adhesion protein. Our results indicate that epistatic interactions between alleles with both positive and negative effects on cyclic AMP-protein kinase A signaling underlie much of the architectural variation we observe in colony biofilms. They are also among the first to demonstrate genetic variation acting at multiple levels of an integrated signaling and regulatory network. Based on these results, we propose a mechanistic model that relates genetic variation to gene network function and phenotypic outcomes

Bulk Genotype Table

This file contains the allele counts (number of occurrences of an allele in a sequencing read) for each heterozygous site found in YJM311 from the YJM311 (parental), simple, intermediate, and complex se- quencing runs, and the G-statistic values at each of these sites for the pairwise comparisons between the simple, intermediate, and complex pools. Note that heterozygous sites where neither allele matched the reference sequence are very rare, so were excluded from these results. Each row in the file contains data on a single heterozygous site identified in YJM311. The coordinates are based on Saccharomyces Genome Database (SGD) release r62, (release date: February 18, 2009)