tbuckley/cabot-search huggingface dataset:
Evaluation of Pharmacodynamic Responses to Cancer Therapeutic Agents Using DNA Damage Markers
Authors: Deborah F. Wilsker, Allison M. Barrett, Angie B. Dull, Scott M. Lawrence, Melinda G. Hollingshead, Alice Chen, Shivaani Kummar, Ralph E. Parchment, James H. Doroshow, Robert J. Kinders
Journal: Clinical Cancer Research (2019)

Abstract Purpose: We sought to examine the pharmacodynamic activation of the DNA damage response (DDR) pathway in tumors following anticancer treatment for confirmation of target engagement. Experimental Design: We evaluated the time course and spatial activation of 3 protein biomarkers of DNA damage recognition and repair (γH2AX, pS343-Nbs1, and Rad51) simultaneously in a quantitative multiplex immunofluorescence assay (IFA) to assess DDR pathway activation in tumor tissues following exposure to DNA-damaging agents. Results: Because of inherent biological variability, baseline DDR biomarker levels were evaluated in a colorectal cancer microarray to establish clinically relevant thresholds for pharmacodynamic activation. Xenograft-bearing mice and clinical colorectal tumor biopsies obtained from subjects exposed to DNA-damaging therapeutic regimens demonstrated marked intratumor heterogeneity in the timing and extent of DDR biomarker activation due, in part, to the cell-cycle dependency of DNA damage biomarker expression. Conclusions: We have demonstrated the clinical utility of this DDR multiplex IFA in preclinical models and clinical specimens following exposure to multiple classes of cytotoxic agents, DNA repair protein inhibitors, and molecularly targeted agents, in both homologous recombination–proficient and -deficient contexts. Levels exceeding 4% nuclear area positive (NAP) γH2AX, 4% NAP pS343-Nbs1, and 5% cells with ≥5 Rad51 nuclear foci indicate a DDR activation response to treatment in human colorectal cancer tissue. Determination of effect-level cutoffs allows for robust interpretation of biomarkers with significant interpatient and intratumor heterogeneity; simultaneous assessment of biomarkers induced at different phases of the DDR guards against the risk of false negatives due to an ill-timed biopsy.
P047 The plasma cell bone marrowniche in ACPA+ ra patients contain citrulline specific cells
Authors: R Thyagarajan, AH Hensvold, L Israelsson, J Steen, H Wähämaa, A van Vollenhoven, K Amara, AI Catrina, V Malmström, C Grönwall
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Post-doctoral fellow <h3>Introduction</h3> Anti-citrullinated antibodies (ACPA) in RA have been postulated to contribute to disease pathogenesis. This has been supported by studies of monoclonal APCA generated by cloning from single cell sorting of different B cell subsets from peripheral blood and synovial fluid. It has been debated if the bone marrow (BM) compartment of RA patients hosts long lived plasma cells producing ACPA or if ACPA are primarily coming from plasmablasts at the sites of inflammation, e.g. the synovium. <h3>Objectives</h3> The main objectives were to study primary lymphoid tissue from RA patients, the BM plasma cell IgG repertoire and further characterize recombinantly expressed antibodies from selected sequences to explore if ACPA producing long lived plasma cells reside in this niche. <h3>Methods</h3> For this study we collected bone marrow from proximal or distal femur of RA patients undergoing hip replacement surgery due to secondary osteoarthritis. BM samples were processed from four ACPA+RF+ and one ACPA-RF+ RA patients. Mononuclear cells were obtained by Ficoll separation and CD138+ plasma cells were single cell sorted by flow cytometry. Paired heavy and light chains were PCR amplified, sequenced and analyzed by V-Quest and IgBLAST towards the IMGT database to annotate variable gene usage. Selected sequences were cloned and expressed as IgG in Expi293 cells. <h3>Results</h3> Overall 465 paired IgG BM plasma cell sequences were obtained, 97 from the ACPA- patient and 368 (range 20–194) from ACPA+ patients. We observed statistically significant changes in heavy chain variable gene usage with lower VH-1 and higher VH-3 frequency in the ACPA+ sequences compared to ACPA- seqences. We also found statistically significant increase in VH N-glycosylation in ACPA+sequences (22.6% ACPA+ vs 12.4% ACPA-; p=0.03). There was however no difference in mutation numbers. From these, 34 clones were selected, based on mutation numbers and presence of Fab N-glycosylation sites, for subsequent mAb-expression. Among the 34 clones we found two CCP2+ and cit-peptide positive clones and one malondialdehyde-acetaldehyde (MAA) adduct reactive clone, originating from different APCA+ patients. <h3>Conclusions</h3> We could identify BM plasma cells producing autoantibodies to malondialdehyde-modified proteins and citrullinated peptides, isolated from RA patients. Hence, we show for the first time, that not just at the site of inflammation but also long-lived plasma cells in bone marrow do produce RA specific autoantibodies. <h3>Acknowledgements</h3> Orthopedic staff at Karolinska University Hospital. Danika Shepis, Louise Berg and Christina Gerstner for sorting help. <h3>Disclosure of Interest</h3> None declared
Optimal therapeutic activity of monoclonal antibodies against chikungunya virus requires Fc-FcγR interaction on monocytes
Authors: Julie M. Fox, Vicky Roy, Bronwyn M. Gunn, Ling Huang, Melissa A. Edeling, Matthias Mack, Daved H. Fremont, Benjamin J. Doranz, Syd Johnson, Galit Alter, Michael S. Diamond
Journal: Science Immunology (2019)

Anti–chikungunya virus antibodies require FcγR engagement but not complement activation for protection and viral clearance.
FCGR2B B2.4 Haplotype Predicts Increased Risk of Red Blood Cell Alloimmunization in Sickle Cell Disease Patients
Authors: Abel Costa Neto, Flávia Leite Santos, Ingrid Helena Ribeiro, Valeria Brito Oliveira, Marcia Regina Dezan, Simone Kashima, Dimas Tadeu Covas, Alexandre Costa Pereira, Guilherme Henrique Hencklain Fonseca, Frederico Moreira, José Eduardo Krieger, Sandra Fatima Menosi Gualandro, Vanderson Rocha, Alfredo Mendrone, Carla Luana Dinardo
Journal: Blood (2018)
The JAMA Peer Review Report for 2000
Authors: Elaine S. Williams
Journal: JAMA (2001)

WE HEREBY THANK THE3613PEER REVIEWERS WHO completed JAMA manuscript reviews in 2000 andwhosenamesappearonpages1078-1092. In 2000, it took an average of 44 calendar days from manuscript receipt to rejection; 117 days from receipt to acceptance; and 182 days from receipt to publication. A mean of 24 days was required for peer review; each reviewer handled an average of 2 manuscripts. Fifty-six percent of the 4366 manuscripts we received were sent for external peer review. Forty-two percent of manuscripts were rejected without external review. Two percent of accepted manuscripts (mostly invited editorials) did not have external review. The total acceptance rate for manuscripts in 2000 was 11%, and the acceptance rate for unsolicited manuscripts was 7%.
TMOD-40. INTRACRANIAL PATIENT-DERIVED XENOGRAFT FROM A PEDIATRIC GLIOBLASTOMA RETAINS MOLECULAR CHARACTERISTICS AND GROWTH PATHWAYS
Authors: Angela White, Shiva Kumar, Amanda Smith, Annmarie Ramkissoon, Nicole Oatman, Biplab Dasgupta, Erin Breese, Charles Stevenson, Christine Fuller, Maryam Fouladi, Mariko DeWire, Rachid Drissi, Lionel M L Chow
Journal: Neuro-Oncology (2017)

Pediatric glioblastomas (pGBM) are characterized by overlapping and unique molecular driver mutations compared to their adult counterparts. Primary cell cultures and patient-derived xenograft (PDX) models of pGBM are rare which may contribute to difficulty in advancing patient outcomes. We have established an orthotopic PDX mouse model from a pGBM resected from a 12 yo male with recurrent disease. The patient received focal radiation and several chemotherapy regimens prior to the recurrence leading to this tumor resection. The surgical tumor specimen was dissociated and directly implanted into the brains of immunocompromised (NSG) mice. DNA and immunohistochemical analyses of the patient tumor and PDX were performed. Multiple in vitro culture conditions were tested on the dissociated primary tumor cells and PDX tumor cells. Implantation of the patient tumor cells in mice resulted in tumor growth after 120-250 days. Tumors were serially transplanted successfully. Attempts to establish in vitro cell cultures from primary tumor and from established PDX tumors failed. DNA sequencing of the patient tumor sample and tumors from each PDX generation revealed the H3F3A G34R mutation characteristic of cortical pGBM, and mutations in the TP53, PTEN and PIK3CA genes, all of which were conserved in PDX tumors. Interestingly, the patient tumor showed evidence of telomerase activity and alternative lengthening of telomeres (ALT) as did the PDX tumors. The combined PTEN and PIK3CA mutations in this tumor resulted in activation of the PI3K-mTOR pathway. Treatment of tumor-bearing mice with an mTOR or PI3K inhibitor resulted in suppression of the pathway and reduced proliferation. This pGBM PDX model conserved key driver mutations and pathways from the patient tumor. In vitro culture of pGBM can be extremely challenging to establish and more difficult methods such as orthotopic PDX may be required to study these tumors.
Comprehensive genomic profiling of Chinese esophageal squamous cell carcinoma patients
Authors: Y. Ji, Y. Wu, W. Fu, L. Liu, Z. Tian, S. Wen, K. Zhang, M. Yao, A. Liu, Y. Zhou
Journal: Annals of Oncology (2019)

Background: Esophageal squamous cell carcinoma (ESCC) is the most important pathological type of esophageal cancer with high incidence and limited efficient therapies in China and worldwide. Understanding of ESCC genomic features is advantageous for exploring clinical therapeutic strategies. Methods: Deep sequencing targeting 450 cancer genes was performed on FFPE and matched blood samples collected from 90 Chinese ESCC patients(pts) with a median age of 60 years old. Genomic alterations (GAs) including single nucleotide variations, short and long indel, gene rearrangements and copy number variations were analyzed. Tumor mutation burden (TMB) was assessed in all samples by standard NGS algorithms. The expression of PD-L1 in 44 samples was evaluated by IHC (28-8 Ab). Results: The most commonly found GAs were mutations in TP53 (94.4%), FGF3 (43.3%), CCND1 (43.3%), FGF4 (42.2%), FGF19 (42.2 %), CDKN2A (36.7%), NOTCH1 (25.6%), PIK3CA (22.2%), and ERBB2 amp(2.2%).Compared with TCGA data, the frequency of TP53 and ERBB2 amp mutations was similar, while the frequency of NOTCH1 mutations was significantly higher (25.6% vs 11%) and the frequency of EGFR amp was lower (5.6% vs 19%) in Chinese cohort. In addition, 4 of 90 samples harbored germline mutations (SDHA, RAD51C, PALB2 and BCL2L11). Among these GAs, 73.3% mutations were in cell cycle (62.2%) and PI3K/AKT (42.2%) pathway. In Chinese ESCC pts, the median TMB was 7.0 muts/Mb, and some pts showed high TMB (33.3% pts≥10 muts/Mb,11.1% pts≥20 muts/Mb). 15.6% pts (TMB≥10 muts/Mb) harbored chromosome 11q13 (FGF3/4/19 and CCND1) amp, which may be related to immunotherapy hyper-progression. Based on the IHC analysis, 10 of 44 Chinese pts showed positive (TPS≥1%) PD-L1 expression, and 7 of them also showed high TMB (≥10 muts /Mb). However, no correlation was found between high TMB and PD-L1 expression. Conclusions: In this study, we found that the frequencies of GAs, such as EGFR and NOTCH1 alterations, were different between Chinese and western ESCC pts. Compared to Western ESCC pts, the positivity of PD-L1 expression was similar, while TMB was higher in Chinese ESCC pts. These findings suggested potential therapeutic targets for targeted and immunotherapies of Chinese ESCC pts. Legal entity responsible for the study: OrigiMed. Funding: Has not received any funding. Disclosure: M. Yao, A. Liu, Y. Zhou: Employee: OrigiMed. All other authors have declared no conflicts of interest.
PIWI proteins play oncogenic functions in pancreatic cancer
Authors: W. Li, J. Martinez Useros, M.J. Fernández-Aceñero, N. García Carbonero, J. García-Foncillas
Journal: Annals of Oncology (2019)

Background: Human homologues of PIWI proteins identified are PIWIL1, PIWIL2, PIWIL3 and PIWIL4 (Sasaki et al. 2003). Aberrant expression of these proteins has been associated with hallmarks of cancer, and have also a potential prognostic and diagnostic markers for different cancers (Suzuki et al. 2012). However, their functional and clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unknown. The purpose of this study was to dissect the role of PIWI proteins and their prognostic relevance. Methods: PIWI proteins expression were analyzed by western blot in human PDAC derived cell lines and one non-transformed pancreatic cell line. Functional experiments were performed with PIWIL3 and/or PIWIL4 downregulated PDAC derived cell lines and one non-transformed cell line. Immunohistochemistry was performed to evaluate expression of PIWI proteins in 124 PDAC samples from Fundacion Jimenez Diaz Hospital, and with 124 validation cohort from TGCA. Then, association between PIWI proteins expression and survival was assessed. Results: Only PIWIL3 and PIWIL4 showed differential expression in PDAC cell lines. Both wound-healing and transwell assay showed a decrease in migration ratio after PIWIL3 and/or PIWIL4 downregulation (P < 0.05). Furthermore, both PIWIL3 and/or PIWIL4 are necessary for the maintenance of undifferentiated phenotype highlighted by a reduction in size and number of pancreatic spheres after PIWIL3 and/or PIWIL4 downregulation (P < 0.05). On the other hand, PIWIL1 associated with shorter survival (P = 0.056), and this finding was validated in the TGCA cohort (P = 0.021). PIWIL2 associated significantly to shorter survival (P = 0.046) in our training set, and validation set exhibited a high trend toward significance (P = 0.051). Although PIWIL3 and PIWIL4 did not show association with survival in our training set, validation set revealed a statistically significant association of PIWIL4 with shorter overall survival (P = 0.027). Conclusions: The present study demonstrate that PIWIL3 and PIWIL4 regulates PDAC aggressiveness by inhibiting cell migration and regulate undifferentiated phenotype of cancer cells. Furthermore, PIWIL1, PIWIL2 and PIWIL4 are potential prognostic biomarkers in PDAC. Legal entity responsible for the study: Fundación Instituto de Investigación Sanitaria - Fundación Jiménez Díaz (G-85874949). Funding: Spanish Ministry of Economy and Competitiveness. Disclosure: All authors have declared no conflicts of interest.
Targeting the NF-κB signaling pathway in chronic tendon disease
Authors: Adam C. Abraham, Shivam A. Shah, Mikhail Golman, Lee Song, Xiaoning Li, Iden Kurtaliaj, Moeed Akbar, Neal L. Millar, Yousef Abu-Amer, Leesa M. Galatz, Stavros Thomopoulos
Journal: Science Translational Medicine (2019)

Tendon disorders represent the most common musculoskeletal complaint for which patients seek medical attention; inflammation drives tendon degeneration before tearing and impairs healing after repair. Clinical evidence has implicated the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway as a correlate of pain-free return to function after surgical repair. However, it is currently unknown whether this response is a reaction to or a driver of pathology. Therefore, we aimed to understand the clinically relevant involvement of the NF-κB pathway in tendinopathy, to determine its potential causative roles in tendon degeneration, and to test its potential as a therapeutic candidate. Transcriptional profiling of early rotator cuff tendinopathy identified increases in NF-κB signaling, including increased expression of the regulatory serine kinase subunit IKKβ, which plays an essential role in inflammation. Using cre-mediated overexpression of IKKβ in tendon fibroblasts, we observed degeneration of mouse rotator cuff tendons and the adjacent humeral head. These changes were associated with increases in proinflammatory cytokines and innate immune cells within the joint. Conversely, genetic deletion of IKKβ in tendon fibroblasts partially protected mice from chronic overuse-induced tendinopathy. Furthermore, conditional knockout of IKKβ improved outcomes after surgical repair, whereas overexpression impaired tendon healing. Accordingly, targeting of the IKKβ/NF-κB pathway in tendon stromal cells may offer previously unidentified therapeutic approaches in the management of human tendon disorders.
More power to their elbow
Authors: Fiona Godlee
Journal: BMJ (2019)

Bones and joints seem to be featuring more than usual in The BMJ ’s research and education sections. This is a good thing. They represent a large and growing part of the work of healthcare, as people live longer and, hopefully, more active lives. And the presence of these studies in The BMJ indicates that the field is on the up, with stronger research methodology and a greater willingness to answer questions and report on outcomes that matter to patients.

A couple of weeks ago we heard that subachromial decompression surgery offered no important improvements …
Data Coming out of the Human Inhibitor PUP Study (HIPS) Reveal 4 Subgroups of Patients with Distinct Antibody Signatures
Authors: Bagirath Gangadharan, Birgit M Reipert, Verena Berg, Friedrich Scheiflinger, Jan Blatny, K Fijnvandraat, Ralph A. Gruppo, Jenny Klintman, Christoph Male, Catherine E. McGuinn, Shannon L. Meeks, Vlad Calin Radulescu, Margaret V. Ragni, Michael Recht, Elena Santagostino, Amy Shapiro, Janice Staber, Hassan M. Yaish, Donald L Yee, Deborah Brown
Journal: Blood (2018)
Irritable Bowel Syndrome (Japanese Version)
Authors: Shahnaz Sultan, Ashish Malhotra
Journal: Annals of Internal Medicine (2017)

In the Clinic6 June 2017Irritable Bowel Syndrome (Japanese Version)Correction(s) for this article:CorrectionsNov 2022Correction: Japanese Translations of In the ClinicFREEShahnaz Sultan, MD, MHSc and Ashish Malhotra, MDShahnaz Sultan, MD, MHScFrom the University of Minnesota and Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota.Search for more papers by this author and Ashish Malhotra, MDFrom the University of Minnesota and Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/IsTranslatedFrom_AITC201706060_Japanese SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Editors' Note: This article (available in PDF format) is the translated Japanese version of In the Clinic: Irritable Bowel Syndrome (Sultan S, Malhotra A. Irritable Bowel Syndrome. Ann Intern Med. 2017;166:ITC81-ITC96. doi:10.7326/AITC201706060). Author, Article, and Disclosure InformationAffiliations: From the University of Minnesota and Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota.Correction: This article was updated on 1 November 2022 to remove the glossary of terms, which was not present on the original publication, and to indicate the translators of the article.Funding Source: American College of Physicians.Disclosures: Drs. Sultan and Malhotra, ACP Contributing Authors, report no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-0573.With the assistance of additional physician writers, the editors of Annals of Internal Medicine develop In the Clinic using MKSAP and other resources of the American College of Physicians.In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical guidelines, please go to https://www.acponline.org/clinical_information/guidelines/. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoIrritable Bowel Syndrome Shahnaz Sultan and Ashish Malhotra Correction: Japanese Translations of In the Clinic Metrics Cited byCorrection: Japanese Translations of In the Clinic 6 June 2017Volume 166, Issue 11Page: JITC81-JITC96 ePublished: 19 February 2019 Issue Published: 6 June 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Bilateral central retinal vein occlusion as the first manifestation in chronic myeloid leukaemia
Authors: Weidar Chen, Cih-En Huang, Chien-Hsiung Lai, Evelyn Jou Chen Huang
Journal: BMJ (2019)

A previously well 20 year old woman described bilateral acute onset blurred

vision for two weeks. Visual acuity was 20/400 (right eye) and 20/200 (left eye). Funduscopy (fig …
Early estimates of seasonal influenza vaccine effectiveness - United States, January 2013
Authors: Lisa Jackson, Michael L. Jackson, C. Hallie Phillips, Joyce Benoit, Edward A. Belongia, Deanna Cole, Sarah Kopitzke, Tamara A. Kronenwetter Koepel, Huong Q. McLean, Jennifer K. Meece, Sandra K. Strey, Maria E. Sundaram, Mary Vandermause, Manjusha Gaglani, Juhee Song, Lydia Clipper, Dean Kjar, Anne Robertson, Kempapura Murthy, Melinda Dunnahoo, Stephanie Oliver, Monica Weir, Hope Gonzales, Martha Zayed, Michael Reis, Cathleen Rivera, David Morgan, Pedro Piedra, Vasanthi Avadhanula, Arnold S. Monto, Suzanne E. Ohmit, Joshua G. Petrie, Emileigh Johnson, Rachel T. Cross, Casey Martens, Marcus Zervos, Lois Lamerato, Heather Eng, Mary Patricia Nowalk, Stephen R. Wisniewski, Richard K. Zimmerman, Charles R. Rinaldo, Arlene Bullotta, Joe Suyama, Evelyn Reis, Donald B. Middleton, Rachel Hess, Mark Thompson, Alicia M. Fry, Swathi N. Thaker, Sarah Spencer, Po Yung Cheng, David K. Shay, La Shondra Berman, Joseph Bresee, Erin Burns, Jerome Tokars, Nancy Cox
Journal: MMWR Morbidity and Mortality Weekly Report (2013)
Gestational Diabetes and Childhood Obesity
Authors: Jacob M. Bradshaw, Samuel J. A. Ensor, Harry A. L. Lorenz
Journal: JAMA (2019)

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