tbuckley/cabot-search huggingface dataset:
High-Order Epistasis in Catalytic Power of Dihydrofolate Reductase Gives Rise to a Rugged Fitness Landscape in the Presence of Trimethoprim Selection
Authors: Yusuf Talha Tamer, Ilona K Gaszek, Haleh Abdizadeh, Tugce Altinusak Batur, Kimberly A Reynolds, Ali Rana Atilgan, Canan Atilgan, Erdal Toprak
Journal: Molecular Biology and Evolution (2019)

Evolutionary fitness landscapes of several antibiotic target proteins have been comprehensively mapped showing strong high-order epistasis between mutations, but understanding these effects at the biochemical and structural levels remained open. Here, we carried out an extensive experimental and computational study to quantitatively understand the evolutionary dynamics of Escherichia coli dihydrofolate reductase (DHFR) enzyme in the presence of trimethoprim-induced selection. To facilitate this, we developed a new in vitro assay for rapidly characterizing DHFR steady-state kinetics. Biochemical and structural characterization of resistance-conferring mutations targeting a total of ten residues spanning the substrate binding pocket of DHFR revealed distinct changes in the catalytic efficiencies of mutated DHFR enzymes. Next, we measured biochemical parameters (Km, Ki, and kcat) for a mutant library carrying all possible combinations of six resistance-conferring DHFR mutations and quantified epistatic interactions between them. We found that the high-order epistasis in catalytic power of DHFR (kcat and Km) creates a rugged fitness landscape under trimethoprim selection. Taken together, our data provide a concrete illustration of how epistatic coupling at the level of biochemical parameters can give rise to complex fitness landscapes, and suggest new strategies for developing mutant specific inhibitors.
Regulatory remodeling in the allo-tetraploid frog Xenopus laevis
Authors: Dei Elurbe, Sarita Paranjpe, Georgios Georgiou, Ila van Kruijsbergen, Ozren Bogdanovic, Romain Gibeaux, Rebecca Heald, Ryan Lister, Martijn A Huynen, Simon van Heeringen, Gert Jan C. Veenstra
Journal: Genome biology (2017)

Genome duplication has played a pivotal role in the evolution of many eukaryotic lineages, including the vertebrates. A relatively recent vertebrate genome duplication is that in Xenopus laevis, which resulted from the hybridization of two closely related species about 17 million years ago. However, little is known about the consequences of this duplication at the level of the genome, the epigenome, and gene expression. The X. laevis genome consists of two subgenomes, referred to as L (long chromosomes) and S (short chromosomes), that originated from distinct diploid progenitors. Of the parental subgenomes, S chromosomes have degraded faster than L chromosomes from the point of genome duplication until the present day. Deletions appear to have the largest effect on pseudogene formation and loss of regulatory regions. Deleted regions are enriched for long DNA repeats and the flanking regions have high alignment scores, suggesting that non-allelic homologous recombination has played a significant role in the loss of DNA. To assess innovations in the X. laevis subgenomes we examined p300-bound enhancer peaks that are unique to one subgenome and absent from X. tropicalis. A large majority of new enhancers comprise transposable elements. Finally, to dissect early and late events following interspecific hybridization, we examined the epigenome and the enhancer landscape in X. tropicalis × X. laevis hybrid embryos. Strikingly, young X. tropicalis DNA transposons are derepressed and recruit p300 in hybrid embryos. The results show that erosion of X. laevis genes and functional regulatory elements is associated with repeats and non-allelic homologous recombination and furthermore that young repeats have also contributed to the p300-bound regulatory landscape following hybridization and whole-genome duplication.
AB0590 A SINGLE CENTER RETROSPECTIVE ANALYSIS OF EFFICACY AND SAFETY BETWEEN LOW-DOSE VERSUS HIGH-DOSE RITUXIMAB AS REMISSION INDUCTION THERAPY IN JAPANESE PATIENTS WITH ANCA-ASSOCIATED VASCULITIS
Authors: Kei Hirose, Manami Hirata, Yuriko Yamamura, Akiko Ueno, Masahiro Yamamura
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Administration of four once-weekly doses of 375 mg/m<sup>2</sup> rituximab (RTX) has been indicated for ANCA-associated vasculitis (AAV) as remission induction therapy. However, randomized controlled trial for Japanese AAV patients have never been conducted, although Japanese AAV patients are characterized by the predominance of elderly patients with microscopic polyangiitis (MPA). <h3>Objectives:</h3> To compare the efficacy and safety between low-dose versus high-dose RTX therapy as remission induction therapy in Japanese patients with AAV. <h3>Methods:</h3> A single center retrospective analysis of 27 consecutive AAV patients with RTX therapy was performed. Clinical and laboratory variables at diagnosis, rates of complete remission (CR), defined as Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone &lt;7.5 mg/day, adverse effects, and vasculitis relapses following RTX use. <h3>Results:</h3> Twenty-five MPA patients and 2 GPA patients (14 males and 13 females) were included in the present study. Twenty-six patients were positive for MPO-ANCA. Their median age was 77 years (range: 40-85 years). Treatments were determined according to the discretion of the attending physician. As remission induction therapy, 18 patients were treated with once or twice (1/2) RTX infusions (375 mg/m<sup>2</sup>), while 9 patients with 3 or 4 times (3/4) RTX infusions. At 6 months, 55.6% of the 1/2 infusion group (10/18) and 44.4% of the 3/4 infusion group (4/9) reached CR. At 6 months, mean PSL levels were 7.8 mg/day in the 1/2 infusion group and 6.6 mg/day in the 3/4 infusion group. At 18 months, 88.9% of the 1/2 infusion group (16/18) and 77.8% of the 3/4 infusion group (7/9) were survived. 0% of the 1/2 infusion group (0/18) and 33.3% of the 3/4 infusion group (3/9) were relapsed. Severe adverse effects occurred in 38.9% of the 1/2 infusion group (7/18) and in 22.2% of the 3/4 infusion group (2/9). <h3>Conclusion:</h3> Our retrospective analysis indicated that cumulative CR rates and PSL tapering did not significantly differ between low-dose versus high-dose RTX as remission induction therapy in Japanese AAV patients, mostly elderly MPA patients, although there was no significant difference in severe adverse effects such as opportunistic infections between them. <h3>Disclosure of Interests:</h3> None declared
Plan S: the final cut—response from cOAlition S
Authors: Robert Kiley
Journal: The Lancet (2019)

On behalf of the cOAlition S Executive Steering Group, I commend the Editors of The Lancet for their positive support for Plan S and the ambition to make full and immediate open access a reality. Finding ways in which researchers can seek to publish in their preferred journals, while ensuring that the outputs of funded research can be accessed and used by all, is a key part of our strategy. It was especially pleasing to read that the Lancet group's hybrid journals will be fully compliant with Plan S. As the payment of article processing charges in hybrid journals will no longer be supported by Plan S funders, we welcome the stance the Lancet family of journals have adopted: researchers who have articles accepted for publication in these venues can self-archive the Author-Accepted Manuscript (at no cost) in a repository where it can be made publicly available at the time of publication (no embargo) under a CC BY Open Access license. This approach is in line with that of other publishers such as the Royal Society and the Microbiology Society, and we look forward to other publishers moving to a fully open access model. I also commend the Lancet group's work on global health and its campaigning for important values such as the right to health, health equity, and social justice. However, when cOAlition S says that it will not pay for “brand value”,1The Lancet GroupPlan S: the final cut.Lancet. 2019; 393: 2276Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar this is about not being willing to pay more for an equal quality of publication services in journals with perceived higher prestige. We value high-quality peer review that can improve the quality of research and will assess the research on its own merits, not based on where it is published. We also value transparency and call for more information on the prices of services the journals provide. I am Head of Open Research at the Wellcome Trust and interim cOAlition S Coordinator. Plan S: the final cutA consortium of research funders, Coalition S, has published its revised recommendations for accelerating the transition to open access for scientific publications. The fundamental principles of Plan S remain intact. No scholarly publication should be locked behind a paywall. Open access should be immediate, without embargoes. The preferred Creative Commons licence is CC BY. Funders will support open access fees at reasonable levels. Funders will not pay for publication in hybrid journals, unless they are part of transformative arrangements with clearly defined open access endpoints. Full-Text PDF
PB1707 APPLICATIONS OF A MATHEMATICAL MODEL IN ACUTE PROMYELOCYTIC LEUKEMIA IN CLINICAL PRACTICE AND PROSPECTIVE TRIALS DESIGN
Authors: G.H. Yoshinari, A.C. Fassoni, L.F. Mello, E.M. Rego
Journal: HemaSphere (2019)

Background: Acute Promyelocytic Leukemia (APL) is a rare condition, potentially lethal, in which risk-based therapy led to better outcomes. Due to its rarity and relatively high overall survival rate, prospective randomized trials to investigate alternative treatment schedules are challenging. Mathematical models may provide useful information in this matter. Aims: We aim to propose a mathematical model that accurately captures the dynamics of leucocytes in peripheral blood and to explore the potential of the information deriving from the model. Methods: We collected clinical and laboratory data during induction from 39 patients treated for APL under the International Consortium on Acute Leukemia (ICAL) protocol. We propose a mathematical model based on Ordinary Differential Equations (ODEs) that represents the dynamics of leucocytes in peripheral blood and the effect of induction protocol (based on All-trans retinoic acid and anthracyclines) on the disease's dynamics. The model was then adjusted to reproduce the disease behavior of patients from our cohort. Results: Our patients present demographic characteristics and clinical outcomes similar to other clinical trials on APL previously published. With a median follow-up of 41.8 months, relapse-free survival and overall survival at two years were both 78.7%. For patients with an adequate set of clinical data, the adjusted model solutions showed good fit. We were able to reproduce different clinical outcomes through computational simulations over the model and determinate that not only pretreatment conditions matter on the risk of relapse, but also the response to induction protocol. We also propose a metric to compare alternative chemotherapy protocols.Summary/Conclusion: Our model was able to reproduce the dynamical behavior found in APL patients, including the effects of induction treatment in this dynamics. Information provided by an adequate mathematical model can assist in decision making and improve clinical trial design.
Prognostic Stratification of Acute Myeloid Leukemia and Mylodysplastic Syndrome Patients on the Basis of Genetic Variations
Authors: Muhammad ALI, Sulman Basit, Muhammad tariq Masood, Yasar Mehmood Yousafzai, Asif Naseer, Sadeeq ur Rahman, Musharraf Jelani, Imran Khan, Yousaf Khan, Abid Jameel, Jawad Ahmed, Abid Sohail Taj
Journal: Blood (2016)
OP0107 HETEROZYGOUS MUTATIONS IN COPA ARE ASSOCIATED WITH ENHANCED TYPE I INTERFERON SIGNALLING
Authors: Marie-Louise Frémond, Alice Lepelley, Carolina Uggenti, Maria José Martin-Niclos, Marine Depp, Vincent Bondet, Darragh Duffy, Gillian I Rice, Mary Brennan, Caroline Thumerelle, Siham Boulisfane, Marie Legendre, Serge Amselem, Thierry Molina, Nadia Nathan, Yanick Crow
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Heterozygous mutations in <i>COPA</i>, encoding coatomer protein subunit alpha, cause an autosomal dominant inflammatory syndrome associating lung, joint and renal disease, showing some overlap with STING-associated vasculopathy with onset in infancy (SAVI). Mutations were originally described to cause endoplasmic reticulum (ER) stress and priming of a T helper 17 response. More recently, increased transcription of interferon (IFN)-stimulated genes (ISGs) was reported in blood circulating cells of affected individuals. However, the precise pathophysiology of this disease remains unclear. <h3>Objectives</h3> To better decipher the mechanism of COPA syndrome. <h3>Methods</h3> We studied 8 patients from 3 unrelated families, each segregating a heterozygous mutation in <i>COPA.</i> We assessed type I IFN status by IFNα ultra-sensitive digital quantification in plasma, STAT1 phosphorylation and RNA expression of ISGs in whole blood from patients. <i>In vitro</i> assays also were performed in HEK293T and THP-1 cells to study IFN signalling in the context of COPA mutations. <h3>Results</h3> We observed commonalities in the lung pathology between COPA and SAVI, as well as an IFN signature, raised levels of IFNα protein in the serum and phosphorylation of STAT1 in patient T cells. In a cellular model of HEK293T, phosphorylation of IRF3 and increased ISG expression were observed in cells co-transfected with wild type STING and mutant COPA plasmids. In THP-1 cells, short hairpin RNA knockdown of COPA induced IFN signalling that was abrogated in the absence of STING. <h3>Conclusion</h3> Our data suggest that mutations in <i>COPA</i> lead to constitutive activation of type I IFN signalling through STING. Based on these results, one patient has been treated with the JAK1/2 inhibitor ruxolitinib for the last 12 months. How COPA interacts with ER-resident STING remains to be investigated. <h3>References</h3> [1] Watkin et al, Nat Genet2015;47:654-60. [2] Volpi et al, Clin Immunol2018;187:33-36. <h3>Disclosure of Interests</h3> None declared
Abstract 16180: Prognostic Implications Of Circulating miRs As Biomarkers In Cardiovascular Primary Prevention - Results From The Population-based DETECT-study
Authors: David M Leistner, Jens Klotsche, Tino Roexe, Ariane Fischer, Lars Pieper, Gúnter K Stalla, Hendrik Lehnert, Sigmund Silber, Winfried Maerz, Hans-Ulrich Wittchen, Stefanie Dimmeler, Andreas M Zeiher
Journal: Circulation (2012)

Introduction: MicroRNA (miRs) are small non-coding RNAs that intracellularly control gene expression by binding target mRNAs. Circulating levels of miRs have been recently proposed as biomarkers fo...
PF299 EARLY RESPONSE OBSERVATION OF PEDIATRIC PATIENTS WITH BURKITT'S LYMPHOMA TREATED WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T‐CELLS
Authors: W.‐Q. Zhang, B. Hu, L. Jing, J. Yang, J. Du, S. Wang, Y.‐L. Ren, Y. Liu, Y.‐H. Zhang
Journal: HemaSphere (2019)

Background: Pediatric patients with relapsed or refractory Burkitt's lymphoma (BL) present as a major challenge due to their poor outcomes despite use of high‐intensity chemotherapy and rituximab. CAR‐T has shown efficacy in treating refractory or relapsed leukemia and non‐Hodgkin lymphoma (NHL) in adult patients. Aims: To assess the safety and efficacy of CAR‐T in the treatment of refractory or relapsed BL in pediatric patients. Methods: Our trial (ChiCTR18000144) enrolled and treated 5 patients with BL. The inclusion criteria includes: 1) The patient who didn’t get complete remission(CR)after at least 5 courses of standard chemotherapy plus CD20 mAb; and 2) The patient who didn’t get partial remission (PR) or showing progression after 2 courses of second‐line chemotherapy; and 3) High expression of at least one B cells markers (CD19/CD20/CD22) examined by immunohistochemistry. The highest expressed marker was chosen as first round CAR‐T target. The therapeutic doses of CAR‐T range from 1 ∗ 10^6 to 3 ∗ 10^6 per kilogram of body weight each course. The effects and adverse events of CART cells after infusion were observed. The change of CAR‐T cells and cytokines were measured weekly. Tumor response was evaluated at day 30 and day 60 post infusion and every two months afterwards. Results: Five patients aged 6 to 10 years with a median age of 8 years, were enrolled, including 4 male (80%) and 1 female (20%). St Jude staging at the time of diagnosis: 3 cases (60%) in stage III, 2 cases (40%) in stage IV, 1 case of CNS invasion (20%), 1 case of bone marrow invasion (20%) and none in stage I or stage II. Five patients were treated with 1 to 3 rounds of CAR‐T. The overall response rate (OR) was 100%. Three cases (60%) achieved CR by one round of CD19 CAR‐T cell therapy, while two cases (40%) achieved PR with CD19 CAR‐T treatment and achieved CR after subsequent treatment with CD22 or CD22 and CD20 CAR‐T. During the treatment, fever, gastro‐intestine discomfort, rash, capillary leak syndrome, Immunopneumonia, tremor, hypotension, Immunocytopenia abnormal coagulation, liver dysfunction, and other toxic effects occurred. One patient (20%) was diagnosed of cytokine‐release syndrome(CRS) grading I and the other four grading III. All cases recoverd fully after active symptomatic and supportive treatment (including application of glucocorticoids in CRS grading III). There were no death events. The last follow‐up was January 30, 2019. The longest follow‐up duration was 382 days, the shortest 62 days, and the median was 249 days. Currently, all patients were in event‐free survival. Summary/Conclusion: CD19/CD20/CD22‐CAR‐T therapy shows robust efficacy in pediatric patients with refractory and relapsed BL and the toxic and adverse effects are moderate and can be well controlled.
Debating Whether Checkups Are Time Wasted or Time Misused
Authors: Rita Rubin
Journal: JAMA (2019)

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PB2334 AUTOLOGOUS STEM CELL TRANSPLANT IN ADULT MULTIPLE SCLEROSIS PATIENTS: A STUDY FROM NORTH INDIA
Authors: A. Dayama, R. Bhargava, S. Raut, S. Jain, V. Dua
Journal: HemaSphere (2019)

Background: Autologous Stem Cell Transplant (ASCT) has been shown to provide long periods of progression free survival in Multiple Sclerosis (MS). Over the past many years many groups have done the procedure in various groups of patients with different types of MS and using different conditioning regimens. Aims: This is an observational study to demonstrate safety of ASCT in MS patients at a transplant centre in North India using a lymphoablative regimen. Methods: The study was conducted from January 2017 and December 2018. MS patients who were either referred by a neurologist or who came of their own volition were evaluated. Kurtzke Expanded Disability Status Scale (EDSS) score was calculated and those with a score of >7 were excluded. Patients <18 years were excluded. Informed written consent was taken. Mobilization was done with G-CSF (10 μg/kg/day) with prednisolone (1 mg/kg/day) to prevent disease flare-up. A minimum of 2 × 106 CD34 cells/kg were collected. Conditioning regimen consisted of Rabbit ATG 0.5 mg/kg on day -6 followed by 1 mg/kg on day -5 to -2 and Cyclophosphamide 50 mg/kg on day-5 to -2. Rituximab 375 mg/m2 was given on day-7 and day+30 to prevent EBV reactivation and disease relapse. Antibiotic prophylaxis was given with levofloxacin, fluconazole and valacyclovir. Any persistent change in the EDSS score ≥0.5 was considered significant. Results: A total of 34 patients were included in this study. Ten patients had positive urine cultures prior to transplant and were treated before starting any chemotherapy.Majority (73%) of the patients were women (25/34). There was one patient of PPMS, sixteen of RRMS, and remaining were SPMS(50%). The median EDSS score was 5.5. The median age of the study population was 32 years. Mobilization was easily achieved with G-CSF with no disease flare ups. The median CD34 cell harvest was 5.71 × 106 cells/kg. All patients developed febrile neutropenia which was managed as per department policy. There was no mortality during peri transplant up to day+100. One patient of SPMS died following intracerebral bleed on day +120 unrelated to transplant complications. Subjective symptoms improved in majority (30/34) patients. EDSS score improved in 11/34 patients (8/11 with RRMS) with disease progression in 3/34 patients at a median follow up duration of 562 days. Five out of nine RRMS patients with active disease on MRI had a response. Summary/Conclusion: The study shows that ASCT can be done safely for patients with relatively high EDSS scores with additional precautions for screening for infections. RRMS patients with active disease on MRI show the most improvement. SPMS patients may not show significant improvement in the short term.