tbuckley/cabot-search huggingface dataset:
Population-based Screening for <i>BRAF</i>V600E in Metastatic Colorectal Cancer Reveals Increased Prevalence and Poor Prognosis
Authors: Jenny E. Chu, Benny Johnson, Laveniya Kugathasan, Van K. Morris, Kanwal Raghav, Lucas Swanson, Howard J. Lim, Daniel J. Renouf, Sharlene Gill, Robert Wolber, Aly Karsan, Scott Kopetz, David F. Schaeffer, Jonathan M. Loree
Journal: Clinical Cancer Research (2020)

BRAFV600E mutations portend poor prognosis in metastatic colorectal cancer (mCRC); however, the true prevalence and prognosis are unknown, as unwell patients may not undergo BRAF sequencing.We reviewed a population-based cohort of 1,898 patients with colorectal cancer that underwent reflexive IHC mismatch repair (MMR) and BRAFV600E testing. Outcomes among IHC-detected BRAFV600E mCRC (BRAFIHC) were compared with patients with next-generation sequencing (NGS)-identified BRAFV600E-mutated mCRC from two institutions (BRAFNGS) with patients spanning from 2004 to 2018.All-stage population prevalence of BRAFV600E was 12.5% (238/1,898) and did not differ between early and metastatic stages (P = 0.094). Prevalence among mCRC was 10.6% (61/575), of whom 51 (83.6%) were referred to oncology and 26 (42.6%) had NGS testing. BRAFIHC had worse median overall survival (mOS) than BRAFNGS [5.5 vs. 20.4 months; HR, 2.90; 95% confidence interval (CI), 1.89-4.45; P < 0.0001], which persisted in multivariate analysis (P < 0.0001). Across a combined NGS and IHC cohort, BRAFV600E tumors with deficient MMR showed worse mOS compared with MMR proficient tumors (8.9 vs. 17.2 months; HR, 1.46; 95% CI, 0.96-2.27; P = 0.043). In this combined cohort, first-line progression-free survival was 5.9 months, with minimal differences between regimens. Within the population-based cohort, attrition between treatment lines was high with only 60.7% receiving first-line chemotherapy and 26.2% receiving second line.Patients with BRAFV600E-mutated mCRC have a worse prognosis than previously suggested, potentially arising from referral bias for testing. High attrition between lines of therapy suggests efficacious therapies need to be prioritized early for patients to benefit.
instaGRAAL: chromosome-level quality scaffolding of genomes using a proximity ligation-based scaffolder
Authors: Lyam Baudry, Nadège Guiglielmoni, Hervé Marie-Nelly, Alexandre Cormier, Martial Marbouty, Komlan Avia, Yann Loe Mie, Olivier Godfroy, Lieven Sterck, J. Mark Cock, Christophe Zimmer, Susana M. Coelho, Romain Koszul
Journal: Genome biology (2020)

Abstract Hi-C exploits contact frequencies between pairs of loci to bridge and order contigs during genome assembly, resulting in chromosome-level assemblies. Because few robust programs are available for this type of data, we developed instaGRAAL, a complete overhaul of the GRAAL program, which has adapted the latter to allow efficient assembly of large genomes. instaGRAAL features a number of improvements over GRAAL, including a modular correction approach that optionally integrates independent data. We validate the program using data for two brown algae, and human, to generate near-complete assemblies with minimal human intervention.
AB0316 MULTIPLE SWITCH BETWEEN BIOSIMILARS DMARDs (BSDMARDS) IN PATIENTS WITH INFLAMMATORY ARTHRITIDES: EXPERIENCE OF A SINGLE ITALIAN CENTRE
Authors: M. Riva, V. Varisco, L. Riva, F. Rumi, M. R. Pozzi
Journal: Annals of the Rheumatic Diseases (2020)

Background: The availability of bsDMARDs since some years represents an opportunity to improve patient access to effective biologic therapy, to better accommodate restraints within healthcare budgets and to improve overall patient outcomes. Different policies are followed in different countries to implement the use of bsDMARDs. Although the latest position paper of AIFA (Agenzia Italiana del Farmaco) envisions the automatic sostitution between the originator and biosimilar, until now the prescriber decision and the patient consent are strongly advised. The question around biosimilar to biosimilar switching is overlooked. Nevertheless different rules are established at regional level and in our Hospital automatic switching between originator/biosimilar and biosimilar/biosimilar was applied. Objectives: To analyze the efficacy and safety of switch from originator to biosimilar (O/B) and/or biosimilar to biosimilar (B/B) in patients with RA, PsA and SpA. Methods: We retrospectively analyzed in 63 patients (30 F, mean age 58.3 yr, 21 RA, 26 PsA, 16 SpA), treated with Infliximab, Etanercept and Adalimumab, disease activity (DAS28 CRP for RA, Tender/Swollen joint count for PsA, BASDAI for SpA, CRP for all) and adverse events/infections (AE). The time points considered were 3 rd month before the switch and 3 rd and 6 th month after. Results: 45 patients underwent sigle switch (35 O/B, 9 B/B) and 18 (28.5%) double switch (O/B/B). 27 B/B switch were done. No differences in disease activity were observed before and after switch (8 RA patients: mDAS28 CRP 2.86&gt;3.23, 11 PsA patients: mTJ count 2.5 &gt; 3.43, 8 SpA patients: BASDAI 2.88 &gt; 2.84). The mean number of swollen joints was very low in PsA group and we decided to exclude this variable. The CRP level was low and stable along all period examined in the three groups. No increase in steroid daily dose, nor in concomitant DMARDs therapy was reported. In the Etanercept B/B switch (14 pts) the number of infections was the same before (3) and after (3). In Infliximab B/B switch (13 pts) 3 infections were reported only before the switch. The severity was mild/moderate with prevalence of respiratory infections (57%). No remarkable variation of transaminases and blood counts were observed. Conclusion: Althoug the population we examined was eterogeneous and quite small, we observed that the efficay and safety of Infliximab and Etanercept are maintained with biosimilar to biosimilar switch, also after double switch (originator&gt;biosimilar&gt;biosimilar). We also can confirm that the switch from originator to biosimilar Infliximab, Etanercept and Adalimumab is safe in our experience. Disclosure of Interests: None declared
Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial
Authors: Adriaan A. Voors, Jean‐François Tamby, John G. Cleland, Michael Koren, Leslie B. Forgosh, Dinesh Gupta, Lars H. Lund, Albert Camacho, Ravi Karra, Henk P. Swart, Pierpaolo Pellicori, Frank Wagner, Ray E. Hershberger, Narayana Prasad, Robert Anderson, Anu Anto, Kaylyn Bell, Jay M. Edelberg, Liang Fang, Marcus Henze, Cynthia Kelly, Gregory Kurio, Wanying Li, Kate Wells, Chun Yang, Sam L. Teichman, Carlos L. del Rio, Scott D. Solomon
Journal: European Journal of Heart Failure (2020)

Abstract Aims Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction. Methods and results We studied the effects of danicamtiv on LV and LA function in non‐clinical studies ( ex vivo : skinned muscle fibres and myofibrils; in vivo : dogs with heart failure) and in a randomized, double‐blind, single‐ and multiple‐dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50–100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P &lt; 0.05) and LA emptying fraction (+10.7%, P &lt; 0.05). In patients with HFrEF (mean age 60 years, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatment‐emergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations ≥2000 ng/mL) increased stroke volume (up to +7.8 mL, P &lt; 0.01), improved global longitudinal (up to −1.0%, P &lt; 0.05) and circumferential strain (up to −3.3%, P &lt; 0.01), decreased LA minimal volume index (up to −2.4 mL/m 2 , P &lt; 0.01) and increased LA function index (up to 6.1, P &lt; 0.01), when compared with placebo. Conclusions Danicamtiv was well tolerated and improved LV systolic function in patients with HFrEF. A marked improvement in LA volume and function was also observed in patients with HFrEF, consistent with pre‐clinical findings of direct activation of LA contractility.
PARP inhibitor resistance: the underlying mechanisms and clinical implications
Authors: He Li, Zhao-Yi Liu, Nayiyuan Wu, Yong-Chang Chen, Quan Cheng, Jing Wang
Journal: Molecular Cancer (2020)

Abstract Due to the DNA repair defect, BRCA1/2 deficient tumor cells are more sensitive to PARP inhibitors (PARPi) through the mechanism of synthetic lethality. At present, several PAPRi targeting poly (ADP-ribose) polymerase (PARP) have been approved for ovarian cancer and breast cancer indications. However, PARPi resistance is ubiquitous in clinic. More than 40% BRCA1/2-deficient patients fail to respond to PARPi. In addition, lots of patients acquire PARPi resistance with prolonged oral administration of PARPi. Homologous recombination repair deficient (HRD), as an essential prerequisite of synthetic lethality, plays a vital role in killing tumor cells. Therefore, Homologous recombination repair restoration (HRR) becomes the predominant reason of PARPi resistance. Recently, it was reported that DNA replication fork protection also contributed to PARPi resistance in BRCA1/2-deficient cells and patients. Moreover, various factors, such as reversion mutations, epigenetic modification, restoration of ADP-ribosylation (PARylation) and pharmacological alteration lead to PARPi resistance as well. In this review, we reviewed the underlying mechanisms of PARP inhibitor resistance in detail and summarized the potential strategies to overcome PARPi resistance and increase PARPi sensitivity.
AB0870 PAIN AND FUNCTIONAL OUTCOME OF PERIPHERAL BLOOD DERIVED STEM CELLS IN PRIMARY OSTEOARTHRITIS OF KNEE AT LOW RESOURCES SETTING: A PHASE II PILOT RCT
Authors: M. R. Khasru
Journal: Annals of the Rheumatic Diseases (2020)

Background: Osteoarthritis (OA) of the knee is one of the main causes of musculoskeletal disability. Osteoarthritis is now often considered as organ failure. Because of limitations in the effectiveness of conventional management options, alternative possibilities such as cell based therapies are approaching into vogue Objectives: To assess the effectiveness of peripheral bold derived stem cells (PBSCs) therapy for primary OA knee. Methods: This phase-II pilot RCT was conducted after the IRB ethical clearance. Patients attending PM&amp;R department of BSMMU having KL grade III osteoarthritis knee those fulfilled the selection criteria were considered as the sample. All respondents were divided to into two groups by using randomization technique. In control group, 15 respondents received standard care for Knee Osteoarthritis. In PBSCs group, 15 cases received with single dose autologous peripheral blood derived stem cells (PBSCs). Stem cells were harvested using G-CSF 30MU and CD34 stem cells were collected through apheresis. Quality was ensured measuring cell viability and surface antigen. All respondents were assessed before treatment and at week 4, week 12 and week 24 for pain reduction and for functional improvement using Visual Analogue Scale (VAS 0-10 cm) and validated Bengali WOMAC questionnaire. Joint sonography was done before treatment, at 12 week and 24 week after treatment commencement. Results: Female were 60% and 67% in control and PBSCs group respectively. The mean age was 56.3±6.7 and 55.8±7.3 year in control and PBSCs. After 12 weeks of stem cell therapy, pain reduction and functional significant improvement was observed in both groups. However, after 24 weeks further significant pain reduction, functional improvement was observed in PBSCs group. Moreover, the cartilage thickness measured by high frequency ultrasound and the mean cartilage thickness was increased by 0.14 mm from the baseline among PBSCs group. Conclusion: PBSCs is promising in patients with primary OA knee. Further large scale research is solicited. References: [1]Dubey, N., Mishra, V., Dubey, R., Syed-Abdul, S., Wang, J., Wang, P. and Deng, W. (2018). Combating Osteoarthritis through Stem Cell Therapies by Rejuvenating Cartilage: A Review. Stem Cells International, 2018, pp.1-13. [2]Jevotovsky, D., Alfonso, A., Einhorn, T. and Chiu, E. (2018). Osteoarthritis and stem cell therapy in humans: a systematic review. Osteoarthritis and Cartilage, 26(6), pp.711-729. [3]Wang, A., Feng, Y., Jia, H., Zhao, M. and Yu, H. (2019). Application of mesenchymal stem cell therapy for the treatment of osteoarthritis of the knee: A concise review. World Journal of Stem Cells, 11(4), pp.222-235. Acknowledgments: Department of Transfusion Medicine, BSMMU Disclosure of Interests: None declared
Emerging Technologies for Identifying Atrial Fibrillation
Authors: Eric Y. Ding, Gregory M. Marcus, David D. McManus
Journal: Circulation Research (2020)

Atrial fibrillation (AF) is a major cause of morbidity and mortality globally, and much of this is driven by challenges in its timely diagnosis and treatment. Existing and emerging mobile technologies have been used to successfully identify AF in a variety of clinical and community settings, and while these technologies offer great promise for revolutionizing AF detection and screening, several major barriers may impede their effectiveness. The unclear clinical significance of device-detected AF, potential challenges in integrating patient-generated data into existing healthcare systems and clinical workflows, harm resulting from potential false positives, and identifying the appropriate scope of population-based screening efforts are all potential concerns that warrant further investigation. It is crucial for stakeholders such as healthcare providers, researchers, funding agencies, insurers, and engineers to actively work together in fulfilling the tremendous potential of mobile technologies to improve AF identification and management on a population level.
Naturally occurring 5′ preS1 deletions markedly enhance replication and infectivity of HBV genotype B and genotype C
Authors: Jing Li, Jisu Li, Shiqi Chen, Quan Yuan, Jing Zhang, Jingwen Wu, Qirong Jiang, Qianru Wang, Ning-Shao Xia, Jiming Zhang, Shuping Tong
Journal: Gut (2020)

Deletion of 15-nucleotide or 18-nucleotide (nt) covering preS1 ATG frequently arises during chronic infection with HBV genotypes B and C. Since the second ATG is 33nt downstream, they truncate large (L) envelope protein by 11 residues like wild-type genotype D. This study characterised their functional consequences. HBV genomes with or without deletion were amplified from a patient with advanced liver fibrosis and assembled into replication competent 1.1mer construct. Deletion, insertion or point mutation was introduced to additional clones of different genotypes. Viral particles concentrated from transfected HepG2 cells were inoculated to sodium taurocholate cotransporting polypeptide (NTCP)-reconstituted HepG2 (HepG2/NTCP) cells or differentiated HepaRG cells, and HBV RNA, DNA, proteins were monitored. From transfected HepG2 cells, the 15-nt and 18-nt deletions increased HBV RNA, replicative DNA and extracellular virions. When same number of viral particles was inoculated to HepG2/NTCP cells, the deletion mutants showed higher infectivity. Conversely, HBV infectivity was diminished by putting back the 18nt into naturally occurring genotype C deletion mutants and by adding 33nt to genotype D. Infectivity of full-length genotype C clones was also enhanced by mutating the first ATG codon of the preS1 region but diminished by mutating the second in-frame ATG. Removing N-terminal 11 residues from preS1 peptide 2-59 of genotype C potentiated inhibition of HBV infection and enhanced binding to HepG2/NTCP cells. The 15-nt and 18-nt deletions somehow increase HBV RNA, replicative DNA and virion production. Shortened L protein is more efficient at mediating HBV infection.
Management of Immune-Related Adverse Events Affecting Outcome in Patients Treated With Checkpoint Inhibitors—Reply
Authors: Alexander M. M. Eggermont, Michal Kicinski, Stefan Suciu
Journal: JAMA Oncology (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Third‐Generation Anti–Cyclic Citrullinated Peptide Antibodies Improve Prediction of Clinical Arthritis in Individuals at Risk of Rheumatoid Arthritis
Authors: Andrea Di Matteo, Kulveer Mankia, Laurence Duquenne, Michael Mahler, Diane Corscadden, Katie Mbara, Leticia Garcia‐Montoya, Jacqueline L. Nam, Paul Emery
Journal: Arthritis & Rheumatology (2020)

To 1) determine the prevalence of anti-cyclic citrullinated peptide 3 (anti-CCP3) antibodies in anti-CCP2 antibody-positive (anti-CCP2+) at-risk individuals, and 2) explore the additional value of anti-CCP3 antibodies in anti-CCP2+ at-risk individuals for predicting progression to inflammatory arthritis.Stored serum samples obtained from 347 anti-CCP2+ (BioPlex 2200; Bio-Rad) at-risk individuals without clinical synovitis were tested for anti-CCP3 antibodies. Anti-CCP2 titers were categorized as low or high, and anti-CCP3 titers were categorized as negative, low, or strong. Progression to inflammatory arthritis was defined as the development of clinical synovitis in ≥1 joint. Only subjects with ≥1 follow-up visit were included in the progression analysis (n = 291).In the 347 samples included, anti-CCP3 antibody titers tended to be either negative (n = 138 [39.7%]) or strongly positive (n =189 [54.4%]), with very few subjects showing a low titer (n = 20 [5.7%]). In contrast, for anti-CCP2 antibodies, more low titers were observed (n = 103 [29.7%]). Eighty-eight of 291 subjects (30.2%) developed inflammatory arthritis. The rate of progression to inflammatory arthritis in the low-titer anti-CCP2 group and the high-titer anti-CCP2 group fell from 7.5% to 3.3% and from 38.9% to 9.8%, respectively, when anti-CCP3 was negative. Progression in the high-titer anti-CCP2 group increased from 38.9% to 48.4% when anti-CCP3 was strongly positive. The area under the curve was 0.72 for anti-CCP2 (95% confidence interval [95% CI] 0.66, 0.78) and 0.76 for anti-CCP3 (95% CI 0.70, 0.81) for assessment of progression. In the multivariable analysis, the odds ratio for the development of inflammatory arthritis in anti-CCP3+ subjects was 1.73 (95% CI 1.20, 2.51) (P < 0.01).Anti-CCP3 antibodies improve the prediction of inflammatory arthritis in anti-CCP2+ at-risk individuals. The impact of anti-CCP3 antibody status for the risk stratification of individuals with high-titer anti-CCP2 is particularly notable.
Anti–PD-1 Induces M1 Polarization in the Glioma Microenvironment and Exerts Therapeutic Efficacy in the Absence of CD8 Cytotoxic T Cells
Authors: Ganesh Rao, Khatri Latha, Martina Ott, Aria Sabbagh, Anantha Marisetty, Xiaoyang Ling, Daniel Zamler, Tiffany A. Doucette, Yuhui Yang, Ling-Yuan Kong, Jun Wei, Gregory N. Fuller, Fernando Benavides, Adam M. Sonabend, James Long, Shulin Li, Michael Curran, Amy B. Heimberger
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Anti-programmed cell death protein 1 (PD-1) therapy has demonstrated inconsistent therapeutic results in patients with glioblastoma (GBM) including those with profound impairments in CD8 T-cell effector responses. Experimental Design: We ablated the CD8α gene in BL6 mice and intercrossed them with Ntv-a mice to determine how CD8 T cells affect malignant progression in forming endogenous gliomas. Tumor-bearing mice were treated with PD-1 to determine the efficacy of this treatment in the absence of T cells. The tumor microenvironment of treated and control mice was analyzed by IHC and FACS. Results: We observed a survival benefit in immunocompetent mice with endogenously arising intracranial glioblastomas after intravenous administration of anti–PD-1. The therapeutic effect of PD-1 administration persisted in mice even after genetic ablation of the CD8 gene (CD8−/−). CD11b+ and Iba1+ monocytes and macrophages were enriched in the glioma microenvironment of the CD8−/− mice. The macrophages and microglia assumed a proinflammatory M1 response signature in the setting of anti–PD-1 blockade through the elimination of PD-1–expressing macrophages and microglia in the tumor microenvironment. Anti–PD-1 can inhibit the proliferation of and induce apoptosis of microglia through antibody-dependent cellular cytotoxicity, as fluorescently labeled anti–PD-1 was shown to gain direct access to the glioma microenvironment. Conclusions: Our results show that the therapeutic effect of anti–PD-1 blockade in GBM may be mediated by the innate immune system, rather than by CD8 T cells. Anti–PD-1 immunologically modulates innate immunity in the glioma microenvironment—likely a key mode of activity.
Collagen IV: a critical new starting point for engineering upper airways
Authors: Martina M. De Santis, Darcy E. Wagner
Journal: European Respiratory Journal (2020)

<b>Collagen IV and integrin alpha 2 engagement is critical for forming differentiated airway epithelium capable of mucociliary clearance <i>in vitro</i>, but pre-vascularised scaffolds transplanted under immunosuppresion fail to maintain differentiated epithelium</b>https://bit.ly/2wT9XK5
A Test of Diversity — What USMLE Pass/Fail Scoring Means for Medicine
Authors: Quentin R. Youmans, Utibe R. Essien, Quinn Capers
Journal: New England Journal of Medicine (2020)

Although the effect of a pass/fail USMLE Step 1 exam on trainees from underrepresented groups remains uncertain, the change may help diversify the medical profession, opening a world of possibilities for physicians and patients alike.
Data from the ERA-EDTA Registry were examined for trends in excess mortality in European adults on kidney replacement therapy
Authors: Rianne Boenink, Vianda S. Stel, Bård E. Waldum-Grevbo, Frederic Collart, Julia Kerschbaum, James G. Heaf, Johan de Meester, Patrik Finne, Sergio A. García-Marcos, Marie Evans, Patrice M. Ambühl, Mustafa Arici, Carole Ayav, Retha Steenkamp, Aleix Cases, Jamie P. Traynor, Runolfur Palsson, Carmine Zoccali, Ziad A. Massy, Kitty J. Jager, Anneke Kramer
Journal: Kidney International (2020)