tbuckley/cabot-search huggingface dataset:
Selection and Neutral Mutations Drive Pervasive Mutability Losses in Long-Lived Anti-HIV B-Cell Lineages
Authors: Marcos C Vieira, Daniel Zinder, Sarah Cobey
Journal: Molecular Biology and Evolution (2018)

High-affinity antibodies arise within weeks of infection from the evolution of B-cell receptors under selection to improve antigen recognition. This rapid adaptation is enabled by the distribution of highly mutable "hotspot" motifs in B-cell receptor genes. High mutability in antigen-binding regions (complementarity determining regions [CDRs]) creates variation in binding affinity, whereas low mutability in structurally important regions (framework regions [FRs]) may reduce the frequency of destabilizing mutations. During the response, loss of mutational hotspots and changes in their distribution across CDRs and FRs are predicted to compromise the adaptability of B-cell receptors, yet the contributions of different mechanisms to gains and losses of hotspots remain unclear. We reconstructed changes in anti-HIV B-cell receptor sequences and show that mutability losses were ∼56% more frequent than gains in both CDRs and FRs, with the higher relative mutability of CDRs maintained throughout the response. At least 21% of the total mutability loss was caused by synonymous mutations. However, nonsynonymous substitutions caused most (79%) of the mutability loss in CDRs. Because CDRs also show strong positive selection, this result suggests that selection for mutations that increase binding affinity contributed to loss of mutability in antigen-binding regions. Although recurrent adaptation to evolving viruses could indirectly select for high mutation rates, we found no evidence of indirect selection to increase or retain hotspots. Our results suggest mutability losses are intrinsic to both the neutral and adaptive evolution of B-cell populations and might constrain their adaptation to rapidly evolving pathogens such as HIV and influenza.
PB1912 EFFICACY AND SAFETY OF RITUXIMAB BIOSIMILAR TRUXIMA IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AND NON‐HODGKIN'S LYMPHOMAS
Authors: I. Micheva, S. Useir, L. Gercheva
Journal: HemaSphere (2019)

Background: Rituximab, an anti‐CD20 monoclonal antibody, is a key therapeutic in the treatment of B cell lymphomas and Chronic lymphocytic leukemia (CLL). Truxima TM is the first biosimilar of the medicine Rituximab to be approved for the treatment of patients non‐Hodgkin's lymphoma (NHL) and CLL, showing similar efficacy, pharmacokinetics, safety and immunogenicity profile. The use of biosimilars may reduce treatment costs andincrease patient access to Rtuximab. Aims: The aim of the study was to assess the efficacy and safety of Truxima TM treatment in combination with chemotherapy in patients NHL and CLL followed for 12 months. Methods: A total of fifty one patients, 28 men and 23 women, were treated with ruxima TM in the Clinic of Hematology at “Sveta Marina” University Hospital, Varna. Truxima TM was applied at a dose of 375 mg/m 2 every 3 weeks in combination with chemotherapy. Response was estimated at treatment completion. Results: Median age was 68,5 years. 22 patients were with CLL, one Richter,s syndrome, 16 with Diffuse large B cell lymphoma (DLBCL), 4 with Mantel cell lymphoma (MCL), 4 with Ssmall cell lymphoma (SCL), 4 with Marginal cell lymphoma (MZL). Truxima TM was combined with different chemotherapeutic regimens: CHOP in 11 patients, Bendamustin in 23, FC in 6, MINE in 3, ACVBP in 1, COP in 3, ICE in 1, and Leukeran in 1. In 34 patients Truxima TM was applied as a first line treatment, in 12 patients as a second line, in 5 cases as a third line. 30 patients have completed their treatment at the time of analysis. Complete response was achieved in 9 (30%) patients, partial response in 17 (56,7%) patients, stable disease in 4 (13,3%). Progressive disease was observed in 1 patient with DLBCL. Grade 3 or 4 hematological toxicity was registered in 5 patients (9,8%). Infusion related reactions were observed in 5,8% of the patientsat grade 1 and 2. Summary/Conclusion: Our experience with the biosimilar over the last year has revealed that Truxima TM is an effective treatment without unexpected side effects. Moreover, cost may be a factor for doctor's choice.
Increasing dietary rice bran consumption for colorectal cancer prevention and control.
Authors: Erica Borresen, Tiffany Weir, Kerry Doyle-Gundlach, Melissa Wdowik, Regina J. Brown, Robert Frederick Marschke, Erica Dickson, Joanne O'Malia, Marlon Bazan, Elizabeth Ryan
Journal: Journal of Clinical Oncology (2013)

1558 Background: Emerging evidence supports that dietary rice bran (RB) exhibits colorectal cancer (CRC) control and prevention activity, yet a significant knowledge gap exists for feasibility of increased RB intake in humans. BENEFIT (Bran Enriching Nutritional Eating For Intestinal health Trial), is a community-academic partnership for dietary chemoprevention research. Our main objectives were to pilot the feasibility of increased RB consumption in healthy adults, with and without a history of CRC, and to examine changes in gut microflora and fecal metabolite profiles following RB consumption. Methods: Seven meals and six snacks were developed for inclusion of dietary RB (30g/day). A total of 15 adults (7 non-cancer and 8 CRC survivors) completed the randomized-controlled, dietary intervention trial. Participants were blinded to their study group (placebo-control or RB) and consumed one study meal and snack daily for 28 days. Blood, urine, saliva and stool samples were collected at baseline, 2-week, and 4-week timepoints for metabolomic and microbiome analyses. Participants recorded weekly 3-day dietary food logs. Results: Adding RB (30g) into prepared foods provided 4-8% daily caloric intake with 95.5% intervention compliance. Inclusion of RB or control diet intervention in our non-cancer cohort did not result in a major shift of the fecal microbiome after 2- and 4-weeks. For CRC survivors, we observed that 19% of the total variation in the fecal microbiome was due to the rice bran intervention. At the genus level, we saw changes in Bacteroides, Bifidobacterium, and Ruminococcus. Principal Components Analyses of fecal metabolome detected using liquid-chromatography mass spectrometry revealed 16% variation between time points and 8% variation when comparing RB and control groups at 4 weeks. Candidate metabolites from ~50 features will be determined by spectral libraries and database matches. Conclusions: The accessibility, affordability, and availability of RB support the global public health impact potential for novel RB “phytochemical teamwork” based CRC control and prevention strategies. These findings warrant further evaluation of increased RB intake in a larger cohort for CRC control and prevention.
Sterol biosynthesis pathway is overexpressed in mammary tumorospheres
Authors: Florence Monville, Larderet Gaelle, Nathalie Cervera, Julien Wicinskij, Jeannine Geneix, Daniel Birnbaum, Emmanuelle Charafe-Jauffret
Journal: Cancer Research (2008)

2015  The existence of breast cancer stem cells has recently been demonstrated. These cells represent the ideal target cells in breast cancer therapy. They remain to be better characterized in order to find specific pathways to inhibit.  A method to isolate and propagate breast cancer stem cells (CSC) and progenitors is to grow epithelial cells in suspension and serum-free conditions as “tumorospheres” that can indefinitely self-renew forming secondary and latter spheres, with each time an enrichment in stem/progenitor content.  To characterize these CSC, we cultured 16 breast cancer cell lines in non adherent serum-free conditions to generate tumorospheres and profiled them on Affymetrix Microarrays U133 2.0 plus. Supervised analysis between cell lines cultured as secondary tumorospheres and corresponding cell lines cultured in standard adherent conditions identified a 146-genes signature. In this signature, adherent cell lines overexpressed proliferation-associated genes, suggesting that tumorospheres are less proliferative compared to adherent corresponding cell lines. Tumorospheres overexpressed genes coding for enzymes of sterol biosynthesis.  Ontoexpress analysis revealed that the entire mevalonate-dependant sterol biosynthesis pathway was represented, from HMGCR till CYP1A1, which is the first enzyme mediating cholesterol conversion into steroid hormones. Isoprenoids biosynthesis genes, especially farnesyl synthesis, downstream HMG CoA Reductase, were also overexpressed in this signature.  We treated breast cancer cell lines with Simvastatin, a potent inhibitor of HMG CoA Reductase, an upstream enzyme of mevalonate-dependant sterol biosynthesis pathway. Inhibition of this pathway leaded to an important decrease in tumorospheres formation.  These results suggest that sterol biosynthesis pathway is prominent in CSC growing/propagation and that inhibition of this pathway could be effective to target breast cancer stem cells.
AB0977 ULTRASOUND MEASUREMENT OF JOINT CARTILAGE THICKNESS IN HEALTHY ASIAN SCHOOL-AGED CHILDREN
Authors: Chun-chun Gau, Chao-Yi Wu
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Degeneration of the osteocartilaginous structures due to synovial inflammatory process is a feature of juvenile idiopathic arthritis (JIA)<sup>1</sup>. While anthropometry difference has been reported between Asian and Caucasian<sup>2,</sup> Asian specific age- and gender-related normal standard reference values should be established before ultrasound (US) measurement of cartilage thickness (Cth) becomes standard procedure in the clinic. <h3>Objectives</h3> The standard cartilage thickness in Asian children population <h3>Methods</h3> A cross-sectional study was performed in 100 healthy Asian children (including 48 girls and 52 boys, age between 5 to 12 years-old). Bilateral knees, ankles, wrists, second metacarpophalangeals (MCPs) and proximal interphalangeals (PIPs) were measured using US. Children's body weight and body height were also recorded for later adjustment. <h3>Results</h3> We observed no difference in the Cth between right and left knees, ankles and wrists but MCPs and PIPs. Cartilage thickness in the large joints such as ankles and knees differed between sexes (p&lt;0.001), and the boys had thicker cartilage than those of the girls. Cartilage thickness decreases with increasing age after weight, height and BMI adjustment. A formula for calculating sex-specific cartilage thickness at different ages in childhood is suggested. <h3>Conclusion</h3> Cartilage thickness measurement with US in small joints may be biased. A standard reference of Cth for Asians in the knee, ankle and wrist joints between age 5- to 12 have been proposed. <h3>References</h3> [1] Naredo, E. et al. Longitudinal power Doppler ultrasonographic assessment of joint inflammatory activity in early rheumatoid arthritis: predictive value in disease activity and radiologic progression. Arthritis Rheum57, 116-124, doi:10.1002/art.22461 (2007). [2] Yue, B. et al. Differences of knee anthropometry between Chinese and white men and women. J Arthroplasty26, 124-130, doi:10.1016/j.arth.2009.11.020 (2011). <h3>Disclosure of Interests</h3> None declared
A PHASE I STUDY OF THE BTK INHIBITOR ABIVERTINIB (AC0010) IN PATIENTS WITH RELAPSED OR REFRACTORY B-CELL LYMPHOMA
Authors: M. Yang, J. Qian, J. Huang, Y. Jiao, W. Tang, X. Xu, W. Xu, F. R. Luo, J. Jin
Journal: HemaSphere (2019)
Characterisation of serum total tau following paediatric traumatic brain injury: a case-control study
Authors: Sophie Stukas, Victoria Higgins, Helena Frndova, Jasmine Gill, Evyatar Hubara, Anne-Marie Guerguerian, Kathy Boutis, Miriam Beauchamp, Catherine Farrell, Franz E Babl, Carmel Delzoppo, Mardee Greenham, Amy A Wilkinson, Alison Crichton, Vicki Anderson, Khosrow Adeli, Jamie Hutchison, Cheryl Wellington
Journal: The Lancet Child & Adolescent Health (2019)
PB1873 PREDIAGNOSTIC TRAJECTORIES OF HEMOGLOBIN, LYMPHOCYTE AND PLATELET COUNT IN PATIENTS DEVELOPING CLL.
Authors: M. Andersen, M. Grand, V. Siersma, C. Andersen, C. Niemann
Journal: HemaSphere (2019)

Background: CLL is a slowly developing disease, but information about development in hemoglobin, platelet and lymnphocyte counts prior to CLL diagnosis is sparse and prediagnostic trajectories of such need exploring. A better understanding of disease progression will generate earlier treatment options and may even lead to preventive approaches. Despite general agreement that CLL patients have lymphocytosis in the years preceding a diagnosis, there is less certainty as to how why and when biomarkers develop. Therefore, we undertook a cohort study comparing hemoglobin, lymphocyte and platelet count trajectories in patients with CLL with unmutated IGHV (CLLunmut), mutated IGHV (CLLmut) compared with control individuals. Aims: To define how biomarker trajectories of patients with CLL differ from control individuals. Methods: All patients diagnosed with CLL in Greater Copenhagen between 2008 and 2016 were matched to 15 randomly selected control individuals matched on sex and age at diagnosis. We retrieved data on all CLL patients and their control individuals from the Copenhagen Primary Care Laboratory database, which contains results from all prediagnostic tests requested by general practitioners in Copenhagen from 2000 to 2015. We estimated the population‐averaged trajectories separately for each biomarker using generalized estimating equations. We included time to diagnosis, classification group (controls, IGHVunmut and IGHVmut), sex and age at diagnoses as covariates, along with an interaction between time to diagnosis and classification group. Results: Of the 778 patients who developed CLL, 437 were IGHVmut, 200 IGHVunmut and 141 patients had unknown IGHV status. We included 71.957 prediagnostic lymphocyte count measurements, 111.465 platelet count measurements, 107.029 CRP measurements and 111585 hemoglobin measurements. The lymphocyte‐count‐trajectories differed significantly between the IGHVmut and IGHVunmut subgroups. From 8 years prior to diagnosis, the IGHVmut subgroup had a slower increase from a higher starting point compared to the IGHVunmut subgroup, which increased closer to diagnosis with a steeper slope resulting in an overall higher lymphocyte count at time of diagnosis. Hemoglobin decreased linearly over time in all groups. In line with the findings for lymphocytosis, the platelet count decreased steadily from 8 years prior to diagnosis for patients with IGHVmut status, whereas the trajectories of IGHVunmut patients decreased dramatically 5 years prior to diagnosis for IGHVunmut patients. Summary/Conclusion: Here, we reveal that IGHVunmut patients develop lymphocytosis and thrombocytopenia within 5 years prior to diagnosis, much closer to diagnosis than IGHVmut patients do. By defining the time point of CLL development for these two disease entities, we identify the window of opportunity for population‐based studies to unravel the mechanisms of CLL progression, paving the road for personalized preventive interventions. image
The role of Na<sub>v</sub>1.7 and methylglyoxal-mediated activation of TRPA1 in itch and hypoalgesia in a murine model of type 1 diabetes
Authors: Ruo-Xiao Cheng, Yu Feng, Di Liu, Zhi-Hong Wang, Jiang-Tao Zhang, Li-Hua Chen, Cun-Jin Su, Bing Wang, Ya Huang, Ru-Rong Ji, Ji Hu, Tong Liu
Journal: Theranostics (2019)

Methylglyoxal (MGO), an endogenous reactive carbonyl compound, plays a key role in the pathogenesis of diabetic neuropathy.The aim of this study is to investigate the role of MGO in diabetic itch and hypoalgesia, two common symptoms associated with diabetic neuropathy.Methods: Scratching behavior, mechanical itch (alloknesis), and thermal hypoalgesia were quantified after intradermal (i.d.) injection of MGO in naïve mice or in diabetic mice induced by intraperitoneal (i.p.) injection of streptozotocin (STZ).Behavioral testing, patch-clamp recording, transgenic mice, and gene expression analysis were used to investigate the mechanisms underlying diabetic itch and hypoalgesia in mice.Results: I.d.injection of MGO evoked dose-dependent scratching in normal mice.Addition of MGO directly activated transient receptor potential ankyrin 1 (TRPA1) to induce inward currents and calcium influx in dorsal root ganglia (DRG) neurons or in TRPA1-expressing HEK293 cells.Mechanical itch, but not spontaneous itch was developed in STZ-induced diabetic mice.Genetic ablation of Trpa1 (Trpa1 -/-), pharmacological blockade of TRPA1 and Nav1.7, antioxidants, and mitogen-activated protein kinase kinase enzyme (MEK) inhibitor U0126 abrogated itch induced by MGO or in STZ-induced diabetic mice.Thermal hypoalgesia was induced by intrathecal (i.t.) injection of MGO or in STZ-induced diabetic mice, which was abolished by MGO scavengers, intrathecal injection of TRPA1 blockers, and in Trpa1 -/-mice. Conclusion:This study revealed that Nav1.7 and MGO-mediated activation of TRPA1 play key roles in itch and hypoalgesia in a murine model of type 1 diabetes.Thereby, we provide a novel potential therapeutic strategy for the treatment of itch and hypoalgesia induced by diabetic neuropathy.
Towards standardisation of naming novel prokaryotic taxa in the age of high-throughput microbiology
Authors: Falk Hildebrand, Mark J Pallen, Peer Bork
Journal: Gut (2019)

Towards standardisation of naming novel prokaryotic taxa in the age of high-throughput microbiologyWe thank Professor Oren for his interest in our work and for his constructive comments. 1In our recent article in Gut, we described the discovery of a new species that rose to high abundance in the human gut after treatment with ceftriaxone. 2We made the decision to propose taxonomic Latin names for this new species and for associated taxa because we wished to create a memorable, user-friendly, sustainable and transferable nomenclature that could be readily adopted by other researchers.Our
SP0010 INFECTIOUS RISK AND MANAGEMENT OF VACCINATION
Authors: Nico Wulffraat
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> O ver the years, awareness of vaccine-preventable infection in rheumatic diseases has increased. At the same time, the safety of vaccines is still a hot topic in the public arena. Large-scale registries with data on juvenile idiopathic arthritis or RA taking the combination of methotrexate and biologics have demonstrated an increased incidence of infections. EULAR recommendations for both vaccination in pediatric patients and adults with rheumatic diseases, provide evidence-based guidance based on data from published studies on safety and efficacy of vaccinations in adults and children with rheumatic conditions. Especially in children, few data exist on safety and efficacy of live-attenuated vaccines such as MMR. This is relevant given the decreasing vaccination coverage and occurrence of measles outbreakes <h3>Objectives:</h3> To provide an overview of vaccines used in patients groups with rheumatic conditions under medication such as MTX and or biologicals. Also we seek for evidence on adverse events, protection rates and persistence of protective antibody titers over time. From these studies general guidelines are proposed. <h3>Methods:</h3> Literature review of vaccination studies performed in adults and children. In addition the clinical practice of boostering of MMR in JIA patients under immunosuppressive therapy was investigated in several large academic pediatric centers across Europe. Thus 234 JIA patients were identified that received a MMR booster under MTX and or biologicals. <h3>Results:</h3> EULAR recommendations are updated for children and adults. For most vaccines it is adivised to follow the national vaccination guidelines. Non-live vaccines can be safely provided to AIIRD patients under immunomodulating treatments, whereas the administration of live attenuated vaccines should be avoided under immunomodulating treatment, with the possible exceptions of herpes zoster and MMR. In 234 children with JIA who received the MMR booster while using MTX and or a Biological only 7 of adverse events were reported. Adverse events reported were mild (skin reaction, mild fever, urinary tract infection. There was no relation between disease activity, disease type or duration, sex, age and outcome of vaccinations. Vaccination status of patients with rheumatic conditions should be assessed annually. Live attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. <h3>Conclusion:</h3> The EULAR recommendations of 2011 are currently updated and will provide an up-to-date guidance on the management of vaccinations in patients with inflammatory rheumatic conditions. There is still a scartity of data on safety and efficay of live attenuated vaccines under biologicals. The next challenge is the implementation into the clinical practice of health professionals across Europe. <h3>Disclosure of Interests:</h3> None declared
A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM).
Authors: Paul G. Richardson, Michel Attal, S. Vincent Rajkumar, Jesus San Miguel, Meral Beksac, Ivan Spicka, Xavier Leleu, Fredrik Schjesvold, Philippe Moreau, Meletios A. Dimopoulos, Jeffrey SY. Huang, Jiri Minarik, Michele Cavo, H. Miles Prince, Sandrine Macé, Kathryn Penkus Corzo, Frank Campana, Solenn Le-Guennec, Franck Dubin, Kenneth Carl Anderson
Journal: Journal of Clinical Oncology (2019)

8004 Background: The primary objective of this phase 3 trial was to demonstrate progression free survival (PFS) improvement of isatuximab (Isa), a novel anti-CD38 monoclonal antibody, combined with pomalidomide (P)/dexamethasone (d) versus (vs) Pd. Methods: Patients (pts) with RRMM who received ≥2 prior lines, including lenalidomide (len) and a proteasome inhibitor (PI), refractory to last therapy were enrolled. IsaPd arm received Isa 10 mg/kg IV weekly for first 4 weeks (wks), then every 2 wks. Both arms received approved schedules of pom and dex (4mg PO days 1-21; 40mg [20mg if &gt;75 yrs] PO or IV weekly) every 28 days until progression or unacceptable toxicity. Results: 307 pts (154 IsaPd, 153 Pd) were randomized and analyzed (ITT). Patient characteristics were well balanced across arms. Median age: 67 (36-86) yrs; median prior lines of therapy: 3 (2-11); estimated GFR: &lt;60ml/min in 33.9% pts; 92.5% refractory to len, 75.9% to PI; and 19.5% pts had high-risk cytogenetics. At median follow-up of 11.6 months (mos), median PFS was 11.5 mos IsaPd vs 6.5 mos Pd; HR 0.596 (95% CI 0.44-0.81), P=0.001. PFS benefit was consistent across all major subgroups. ORR (≥PR) was 60.4% IsaPd vs 35.3% Pd, P&lt;0.0001. VGPR rate or better was 31.8% IsaPd vs 8.5% Pd, and MRD negativity (NGS, 10 -5 ) was seen in 5.2% IsaPd pts vs 0% Pd. At analysis date, overall survival (OS) was immature (99 events) but a trend to OS improvement in IsaPd (vs Pd) was observed (HR 0.687; 95% CI 0.461-1.023). Median treatment duration was 41 wks IsaPd vs 24 wks Pd; median Isa infusion (inf.) duration was 3.3h at 1 st inf. and 2.8h at subsequent inf. Grade ≥3 AEs were observed in 86.8% IsaPd vs 70.5% Pd; 7.2% IsaPd and 12.8% Pd pts discontinued due to AEs; 7.9% IsaPd and 9.4% Pd pts died due to AEs. Inf. reactions were reported in 38.2% (2.6% grade 3-4) IsaPd. Grade ≥3 infections were seen in 42.8% IsaPd and 30.2% Pd, grade ≥3 neutropenia in 84.9% (febrile 11.8%) IsaPd and 70.1% (febrile 2.0%) Pd. Conclusions: IsaPd significantly improved PFS and ORR vs Pd, with a manageable safety profile. IsaPd is an important new treatment option for the management of RRMM. Clinical trial information: NCT02990338.