tbuckley/cabot-search huggingface dataset:
Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal
Authors: Doua Azzouz, Aidana Omarbekova, Adriana Heguy, Dominik Schwudke, Nicolas Gisch, Brad H Rovin, Roberto Caricchio, Jill P Buyon, Alexander V Alekseyenko, Gregg J Silverman
Journal: Annals of the Rheumatic Diseases (2019)

Background/Purpose To search for a transmissible agent involved in lupus pathogenesis, we investigated the faecal microbiota of patients with systemic lupus erythematosus (SLE) for candidate pathobiont(s) and evaluated them for special relationships with host immunity. Methods In a cross-sectional discovery cohort, matched blood and faecal samples from 61 female patients with SLE were obtained. Faecal 16 S rRNA analyses were performed, and sera profiled for antibacterial and autoantibody responses, with findings validated in two independent lupus cohorts. Results Compared with controls, the microbiome in patients with SLE showed decreased species richness diversity, with reductions in taxonomic complexity most pronounced in those with high SLE disease activity index (SLEDAI). Notably, patients with SLE had an overall 5-fold greater representation of Ruminococcus gnavus ( RG ) of the Lachnospiraceae family, and individual communities also displayed reciprocal contractions of a species with putative protective properties. Gut RG abundance correlated with serum antibodies to only 1/8 RG strains tested. Anti-RG antibodies correlated directly with SLEDAI score and antinative DNA levels, but inversely with C3 and C4. These antibodies were primarily against antigen(s) in an RG strain-restricted pool of cell wall lipoglycans. Novel structural features of these purified lipoglycans were characterised by mass spectrometry and NMR. Highest levels of serum anti- RG strain-restricted antibodies were detected in those with active nephritis (including Class III and IV) in the discovery cohort, with findings validated in two independent cohorts. Conclusion These findings suggest a novel paradigm in which specific strains of a gut commensal may contribute to the immune pathogenesis of lupus nephritis.
A potential explanation for self-radicalisation
Authors: Justin E. Lane, F. LeRon Shults, Wesley J. Wildman
Journal: Behavioral and Brain Sciences (2018)

Abstract We believe that Whitehouse's model could be extended in a way that can help us make sense of self-radicalised individuals who are not active in cliques. We believe that conceptual ties may be important to this process and present a brief analysis of a database collected by the national consortium for the Study of Terrorism and Responses to Terrorism (START), to suggest future research to complement Whitehouse's proposal.
ATRIAL FIBRILLATION IS ASSOCIATED WITH LOW CARDIOVASCULAR MORTALITY IN HYPERTROPHIC CARDIOMYOPATHY
Authors: Anais Hausvater, Ethan Rowin, Mark Link, Patrick Abt, William Gionfriddo, N.A. Mark Estes, Wendy Wang, Barry Maron, Martin Maron
Journal: Journal of the American College of Cardiology (2017)
Risk Factors in Food-induced Anaphylactic Shock: Which Matters Most, Food or Cofactor?
Authors: Rosa Munoz-Cano, Rocio Casas, Mariona Pascal, Giovanna Araujo, Silvia Quarta, Silvia A. Riggioni Viquez, Clara San Bartolome, Joan Bartra
Journal: Journal of Allergy and Clinical Immunology (2019)
Molecular and Materials Engineering for Delivery of Peptide Drugs to Treat Type 2 Diabetes
Authors: Anastasia K. Varanko, Ashutosh Chilkoti
Journal: Advanced Healthcare Materials (2019)

Abstract Type 2 diabetes is exploding globally. Despite numerous treatment options, nearly half of type 2 diabetics are unsuccessful at properly managing the disease, primarily due to a lack of patient compliance, driven by adverse side effects as well as complicated and frequent dosing schedules. Improving the delivery of type 2 diabetes drugs has the potential to increase patient compliance and thus, greatly enhance health outcomes and quality of life. This review focuses on molecular and materials engineering strategies that have been implemented to improve the delivery of peptide drugs to treat type 2 diabetes. Peptide drugs benefit from high potency and specificity but suffer from instability and short half‐lives that limit their utility as therapeutics and pose a significant delivery challenge. Several approaches have been developed to improve the availability and efficacy of antidiabetic peptides and proteins in vivo. These methods are reviewed herein and include devices, which sustain the release of peptides in long term, and molecular engineering strategies, which prolong circulation time and slow the release of therapeutic peptides. By optimizing the delivery of these peptides and proteins using these approaches, long‐term glucose control can be achieved in type 2 diabetes patients.
Efficacy and Safety of Pomalidomide in Combination with Prednisone in Patients with Myelofibrosis and Anemia — Final Results of a Prospective Phase 2 Study
Authors: Lucia Masarova, Naval G. Daver, Tapan M. Kadia, Naveen Pemmaraju, Elias J. Jabbour, Lingsha Zhou, Sherry A. Pierce, Jorge E. Cortes, Hagop M. Kantarjian, Srdan Verstovsek
Journal: Blood (2018)
Single Cell Analysis of Acquired Pomalidomide-Resistance in Multiple Myeloma Cell Lines Reveals Distinct Subclonal Cereblon Mutations and Gene Expression Heterogeneity
Authors: Sarah Gooding, Chad C. Bjorklund, Michael Amatangelo, Yan Ren, Mathieu Marella, Suzana Couto, Christopher Park, Sneh Lata, Reshma Nibhani, Fadi Towfic, Udo Oppermann, Karthik Ramasamy, William E. Pierceall, Paresh Vyas, Anjan Thakurta
Journal: Blood (2018)
Genomic alterations in breast cancer: level of evidence for actionability according to ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)
Authors: R. Condorelli, F. Mosele, B. Verret, T. Bachelot, P.L. Bedard, J. Cortes, D.M. Hyman, D. Juric, I. Krop, I. Bieche, C. Saura, C. Sotiriou, F. Cardoso, S. Loibl, F. Andre, N.C. Turner
Journal: Annals of Oncology (2019)

Better knowledge of the tumor genomic landscapes has helped to develop more effective targeted drugs. However, there is no tool to interpret targetability of genomic alterations assessed by next-generation sequencing in the context of clinical practice. Our aim is to rank the level of evidence of individual recurrent genomic alterations observed in breast cancer based on the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) in order to help the clinicians to prioritize treatment. Analyses of databases suggested that there are around 40 recurrent driver alterations in breast cancer. ERBB2 amplification, germline BRCA1/2 mutations, PIK3CA mutations were classified tier of evidence IA based on large randomized trials showing antitumor activity of targeted therapies in patients presenting the alterations. NTRK fusions and microsatellite instability (MSI) were ranked IC. ESR1 mutations and PTEN loss were ranked tier IIA, and ERBB2 mutations and AKT1 mutations tier IIB. Somatic BRCA 1/2 mutations, MDM2 amplifications and ERBB 3 mutations were ranked tier III. Seventeen genes were ranked tier IV based on preclinical evidence. Finally, FGFR1 and CCND1 were ranked tier X alterations because previous studies have shown lack of actionability.
Impact of antibiotic use on response to treatment with immune checkpoint inhibitors.
Authors: Uqba Khan, Cristian Peña, Julianna Brouwer, Katherine Hoffman, Arindam Roy Choudhury, Chao Zhang, Prashant Thakkar, Doron Betel, Sandipto Sarkar, Gregory Sonnenberg, Ashish Saxena, Manish A. Shah
Journal: Journal of Clinical Oncology (2019)

143 Background: There is an emerging evidence that the gut microbiome may influence anti-tumor immune response during treatment with checkpoint inhibitors (CPIs). A number of factors can cause gut microbiome dysbiosis including the use of antibiotics (ABX). We hypothesized that the use of ABX during immunotherapy can adversely affect the efficacy of CPIs. We explored the prevalence of ABX use amongst patients (pts) using CPIs, and whether the use of ABX influences the response to CPIs. Methods: We performed an institutional retrospective review of all the pts treated with CPIs from 2/2015-3/2018. A patient was considered to have used ABX if he or she was prescribed ABX within 6 months before or after, initiating CPIs. Statistical analysis was done using logistic regression with overall response rate (ORR) (CR, PR and SD) as the outcome. 9 separate analyses were done: one for each temporality (30 days, 60 days, 6 months) and use-order (before, after, neither) combination. Odds ratios for ORR as univariate analysis, and adjusted for age and sex; and adjusted for age, sex, and tumor type were calculated. Results: Out of 242 pts, 111 were lung, 36 bladder, 35 renal, 16 gastrointestinal and 44 other cancers. 50% (121) pts received nivolumab, 28% (68) pembrolizumab and 21% (52) atezolizumab. 75%, 46% and 32% of the pts received ABX within 6 months, 60 days and 30 days of starting CPIs. Only ABX use in the first 30- or 60-days following CPI initiation was associated with inferior ORR (OR 0.42 [95% CI:0.23,0.76] p = 0.005 for 60-days). ABX use prior to initiation of CPI at any time point, or ABX use in the first 6 months of CPI use did not impact CPI efficacy, Table 1. Conclusions: ABX use within the first 60 days of starting CPI therapy is prevalent (32%). This study suggests that the use of ABX within 60 days following initiation of CPIs significantly negatively impacts the ORR. Unnecessary usage of ABX should be avoided, especially during the early phase of starting CPIs. [Table: see text]
Rectal cancer treatment and outcomes in elderly patients treated with curative intent.
Authors: Sharlyn Kang, Kate Jessica Wilkinson, Daniel Brungs, Wei Chua, Weng Leong Ng, Ray Asghari, James Chen, Elias H. Nasser, Hiren A. Mandaliya, Sarah Maloney, Robert Winn, Soni Putnis, Cheok Soon Lee, Stephanie Hui-Su Lim
Journal: Journal of Clinical Oncology (2019)

678 Background: There is limited information on outcomes in elderly patients with rectal cancer as they are often excluded from clinical trials. This study aimed to assess treatment patterns and outcomes in these patients. Methods: We utilised data from electronic records to identify patients aged ≥ 70 years with a histological diagnosis of rectal cancer from 2006-2015, treated in the South Western Sydney and Illawarra Shoalhaven Local Health Districts, Australia. Treatment modalities, recurrence and survival data were analysed. Results: We identified 942 patients with rectal cancer, with median follow-up of 3.4 years. 393 patients (42%) were aged ≥ 70 years. Median age of this cohort was 77 years (range 70–96 years). Elderly patients were more likely to present with locoregional disease (stage I-III, 83% vs. 75%) and more likely to receive palliative treatment only (21% vs. 16%, p = 0.0005). Of 704 patients who received treatment with curative intent, 300 (43%) were ≥ 70 years. Although clinicopathological features were similar between elderly and young patients, patients ≥ 70 years were more likely to be treated with surgery alone (56% vs. 28%, p &lt; 0.0001), less likely to receive neoadjuvant (25% vs. 44%, p &lt; 0.0001) or adjuvant treatments (29% vs. 55%, p &lt; 0.0001), or be discussed in a multidisciplinary meeting (51% vs. 61%, p = 0.001). Compared to younger patients, elderly patients had a significantly poorer overall survival (HR 2.9, 95% CI 2.2 – 3.7, p &lt; 0.0001). There were no significant differences in cancer specific survival (HR 1.4, 95% CI 0.98 – 2.0, p = 0.06) or relapse free survival (HR 0.92, 95% CI 0.7 – 1.2, p = 0.60). Conclusions: Although more elderly patients were treated with palliative intent compared to younger patients, the majority of elderly rectal cancer patients were still treated with curative intent. Most had surgery alone. Uptake of neoadjuvant and adjuvant therapy, as well as multidisciplinary involvement, was lower. Elderly patients had similar cancer-specific outcomes compared to younger patients, supporting curative intent treatment in these patients. Further analyses are underway to identify subgroups in the elderly population who benefit from trimodality therapy, and potential differences in their disease biology.
Long-Term Durable Responses after Autologous Stem Cell Transplantation in POEMS Syndrome
Authors: Neeraj Y Saini, Romil Patel, Ankur Varma, Qaiser Bashir, Omar Hasan, Ruby Delgado, Gabriela Rondon, Akash Mukherjee, Uday Popat, Chitra Hosing, Yago Nieto, Partow Kebriaei, Donna M. Weber, Sheeba K. Thomas, Hans C. Lee, Elisabet E. Manasanch, Robert Z. Orlowski, Richard E Champlin, Muzaffar H. Qazilbash, Krina K. Patel
Journal: Blood (2018)
1315 IL28B AND PNPLA3 POLYMORPHISMS AFFECT HISTOLOGICAL LIVER DAMAGE IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE
Authors: S. Petta, S. Grimaudo, C. Camma, D. Cabibi, V. Di Marco, G. Licata, R.M. Pipitone, A. Craxi
Journal: Journal of Hepatology (2012)
Clinical research advancements shaping ‘best practice’
Authors: Aurelia Nattiv, Anna Waterbrook, Jonathon A Drezner
Journal: British Journal of Sports Medicine (2019)

We are excited to present this AMSSM-BJSM issue, emphasising the highest quality clinical research by members of the American Medical Society for Sports Medicine (AMSSM) to help shape ‘best practice’. This call for papers resulted in a record number of high-quality original research submissions, most within AMSSM priority research areas. Each paper submitted received the highest standard of peer review and consideration.

Original research papers in this issue include a multicentre randomised intervention trial by Stephanie Kliethermes and colleagues examining the impact of serial sports training risk assessment and counselling to reduce injury risk in young athletes ( see page 243 ); a randomised clinical trial by Kate Ackerman and colleagues on transdermal oestrogen replacement therapy in oligo-amenorrheic athletes to improve bone mineral density ( see page 229 ); and a multicentre study by Emily Kraus and colleagues using a modified female athlete triad cumulative risk assessment to predict bone stress injuries in male distance runners ( see page 237 ). Khodaee Morteza and colleagues also provide an important discussion piece addressing concerns related to portable intravenous fluids in sports ( see page 226 ).

The comprehensive AMSSM …
A Novel Form of 4-1BBL Prevents Cancer Development via Nonspecific Activation of CD4+ T and Natural Killer Cells
Authors: Hampartsoum B. Barsoumian, Lalit Batra, Pradeep Shrestha, William S. Bowen, Hong Zhao, Nejat K. Egilmez, Jorge G. Gomez-Gutierrez, Esma S. Yolcu, Haval Shirwan
Journal: Cancer Research (2019)

Costimulation through 4-1BB (CD137) receptor generates robust CD8+ T-effector and memory responses. The only known ligand, 4-1BBL, is a trimeric transmembrane protein that has no costimulatory activity as a soluble molecule. Thus, agonistic antibodies to the receptor have been used for cancer immunotherapy in preclinical models and are currently being evaluated in the clinic. Here, we report that treatment with an oligomeric form of the ligand, SA-4-1BBL, as a single agent is able to protect mice against subsequent tumor challenge irrespective of the tumor type. Protection was long-lasting (>8 weeks) and a bona fide property of SA-4-1BBL, as treatment with an agonistic antibody to the 4-1BB receptor was ineffective in generating immune protection against tumor challenge. Mechanistically, SA-4-1BBL significantly expanded IFNγ-expressing, preexisting memory-like CD44+CD4+ T cells and NK cells in naïve mice as compared with the agonistic antibody. In vivo blockade of IFNγ or depletion of CD4+ T or NK cells, but not CD8+ T or B cells, abrogated the immunopreventive effects of SA-4-1BBL against cancer. SA-4-1BBL as a single agent also exhibited robust efficacy in controlling postsurgical recurrences. This work highlights unexpected features of SA-4-1BBL as a novel immunomodulator with implications for cancer immunoprevention and therapy. SIGNIFICANCE: This study demonstrates the unique and unexpected immunomodulatory features of SA-4-1BBL that bridge innate and adaptive immune responses with both preventive and therapeutic efficacy against cancer.
Characterization Of Amoxicillin- And Clavulanic Acid-Specific T-Cells In Patients With Amoxicillin-Clavulanic Acid Hypersensitivity Reactions
Authors: Adriana Ariza, María Isabel Montañez, Monday O. Ogese, Arun Tailor, Tahia D. Fernandez, María J. Torres, Dean J. Naisbitt
Journal: Journal of Allergy and Clinical Immunology (2019)
Challenges and advances of CRISPR-Cas9 genome editing in therapeutics
Authors: Konstantinos Stellos, Kiran Musunuru
Journal: Cardiovascular Research (2018)

Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated 9 (Cas9) is a powerful multiplexed tool that enables the quick and easy editing of parts of the genome by deleting, adding, or rearranging DNA nucleotides.Recently, the specific characteristics of this gene-editing tool have shown a promising therapeutic potential to eliminate defective genes and treat genetic diseases.
Objective assessment of dermal fibrosis in cutaneous scarring, using optical coherence tomography, high‐frequency ultrasound and immunohistomorphometry of human skin
Authors: S. Ud‐Din, P. Foden, K. Stocking, M. Mazhari, S. Al‐Habba, M. Baguneid, D. McGeorge, A. Bayat
Journal: British Journal of Dermatology (2019)

Noninvasive quantitative assessment of dermal fibrosis remains a challenge. Optical coherence tomography (OCT) and high‐frequency ultrasound (HFUS) can accurately measure structural and physiological changes in skin. To perform quantitative analysis of cutaneous fibrosis. Sixty‐two healthy volunteers underwent multiple sequential skin biopsies (day 0 and 1–8 weekly thereafter), with OCT and HFUS measurements at each time point supported with immunohistomorphometry analysis. HFUS and OCT provided quantitative measurements of skin thickness, which increased from uninjured skin (1·18 and 1·2 mm, respectively) to week 1 (1·28 mm, P = 0·01; 1·27 mm, P = 0·02), and compared favourably with haematoxylin and eosin. Spearman correlation showed good agreement between techniques (P < 0·001). HFUS intensity corresponded to dermal density, with reduction from uninjured skin (42%) to week 8 (29%) (P = 0·02). The OCT attenuation coefficient linked with collagen density and was reduced at week 8 (1·43 mm, P < 0·001). Herovici analysis showed that mature collagen levels were highest in uninjured skin (72%) compared with week 8 (42%, P = 0·04). Fibronectin was greatest at week 4 (0·72 AU) and reduced at week 8 (0·56 AU); and α‐smooth muscle actin increased from uninjured skin (11·5%) to week 8 (67%, P = 0·003). Time‐matched comparison images between haematoxylin and eosin, OCT and HFUS demonstrated that epidermal and dermal structures were better distinguished by OCT. HFUS enabled deeper visualization of the dermis including the subcutaneous tissue. Choice of device was dependent on the depth of scar type, parameters to be measured and morphological detail required in order to provide better objective quantitative indices of the quality and extent of dermal fibrosis.
Design, mechanism, delivery and therapeutics of canonical and Dicer-substrate siRNA
Authors: Maria Abdul Ghafoor Raja, Haliza Katas, Muhammad Wahab Amjad
Journal: Asian Journal of Pharmaceutical Sciences (2019)

Upon the discovery of RNA interference (RNAi), canonical small interfering RNA (siRNA) has been recognized to trigger sequence-specific gene silencing. Despite the benefits of siRNAs as potential new drugs, there are obstacles still to be overcome, including off-target effects and immune stimulation. More recently, Dicer substrate siRNA (DsiRNA) has been introduced as an alternative to siRNA. Similarly, it also is proving to be potent and target-specific, while rendering less immune stimulation. DsiRNA is 25–30 nucleotides in length, and is further cleaved and processed by the Dicer enzyme. As with siRNA, it is crucial to design and develop a stable, safe, and efficient system for the delivery of DsiRNA into the cytoplasm of targeted cells. Several polymeric nanoparticle systems have been well established to load DsiRNA for in vitro and in vivo delivery, thereby overcoming a major hurdle in the therapeutic uses of DsiRNA. The present review focuses on a comparison of siRNA and DsiRNA on the basis of their design, mechanism, in vitro and in vivo delivery, and therapeutics.
Clinical Characterization of A Population of Patients With Positive Drug Provocation Test to Amoxicillin
Authors: Maria Salas, Inmaculada Doña, Francisca Gomez, Natalia Pérez-sanchez, Ibon Eguiluz-Gracia, Ana Prieto del Prado, M.D. Cañamero, Maria Auxiliadora Guerrero, Cristobalina Mayorga, Maria J. Torres
Journal: Journal of Allergy and Clinical Immunology (2019)
Symptom Subtypes of Obstructive Sleep Apnea Predict Incidence of Cardiovascular Outcomes
Authors: Diego R. Mazzotti, Brendan T. Keenan, Diane C. Lim, Daniel J. Gottlieb, Jinyoung Kim, Allan I. Pack
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Symptom subtypes have been described in clinical and population samples of patients with obstructive sleep apnea (OSA). It is unclear whether these subtypes have different cardiovascular consequences.
Two Birds with One Stone: Therapeutic Targeting of IL1α Signaling Pathways in Pancreatic Ductal Adenocarcinoma and the Cancer-Associated Fibroblasts
Authors: Jianhua Ling, Paul J. Chiao
Journal: Cancer Discovery (2019)

Abstract Summary: In this issue of Cancer Discovery, Biffi and colleagues report that IL1 signaling cascades resulted in JAK/STAT activation and promoted an inflammatory cancer-associated fibroblast (iCAF) state, which contributed to the establishment of distinct fibroblast niches in the pancreatic ductal adenocarcinoma (PDAC) microenvironment to support the growth of PDAC cells. Furthermore, the investigators demonstrated that TGFβ signaling inhibited IL1R1 expression, antagonized IL1α responses, and promoted differentiation of CAFs into myofibroblasts; thus, IL1α signaling is an important therapeutic target for both PDAC cells and the iCAFs in the tumor microenvironment. See related article by Biffi et al. p. 282.
Phenotypic Heterogeneity of the Endothelium
Authors: William C. Aird
Journal: Circulation Research (2007)

Endothelial cells, which form the inner cellular lining of blood vessels and lymphatics, display remarkable heterogeneity in structure and function. This is the first of a 2-part review focused on phenotypic heterogeneity of blood vessel endothelium. This review provides an historical perspective of our understanding of endothelial heterogeneity, discusses the scope of phenotypic diversity across the vascular tree, and addresses proximate and evolutionary mechanisms of endothelial cell heterogeneity. The overall goal is to underscore the importance of phenotypic heterogeneity as a core property of the endothelium.