tbuckley/cabot-search huggingface dataset:
Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer
Authors: Seock-Ah Im, Yen-Shen Lu, Aditya Bardia, Nadia Harbeck, Marco Colleoni, Fabio Franke, Louis Chow, Joohyuk Sohn, Keun-Seok Lee, Saul Campos-Gomez, Rafael Villanueva-Vazquez, Kyung-Hae Jung, Arunava Chakravartty, Gareth Hughes, Ioannis Gounaris, Karen Rodriguez-Lorenc, Tetiana Taran, Sara Hurvitz, Debu Tripathy
Journal: New England Journal of Medicine (2019)

An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater benefit with regard to progression-free survival than endocrine therapy alone in premenopausal or perimenopausal patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here we report the results of a protocol-specified interim analysis of the key secondary end point of overall survival.We randomly assigned patients to receive either ribociclib or placebo in addition to endocrine therapy (goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen). Overall survival was evaluated with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods.A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval [CI], 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P = 0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87).This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. (Funded by Novartis; MONALEESA-7 ClinicalTrials.gov number, NCT02278120.).
The Review of Systems, the Electronic Health Record, and Billing
Authors: Marissa A. Hendrickson, Genevieve B. Melton, Michael B. Pitt
Journal: JAMA (2019)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Deciphering Mechanisms of UVR-Induced Tumoral Immune Checkpoint Regulation against Melanoma
Authors: Ravi P. Sahu
Journal: Cancer Research (2019)

Abstract Exposure to solar ultraviolet radiation (UVR) impacts various cellular, genetic, and immunologic responses governing biological and pathophysiologic events including the development of skin cancers. The mechanistic insights into UVR-induced immune tolerance against skin cancers, particularly cutaneous melanoma, have been a great challenge, given the sophisticated regulation of immune checkpoint proteins. A study led by Wang and colleagues has elucidated novel mechanisms of UVR-induced immune suppression, implicated in melanoma immune evasion and progression mediated via upregulation of PD-L1, and reduced CD8+ T-cell–mediated cytotoxicity in HMGB1/TBK1/IRF3/NF-κB–dependent manner. These findings offer new mechanistic insights into UVR-induced melanoma immune evasion and progression. See related article by Wang et al., p. 2909
Effects of a Patient Activation Tool on Decision Making Between Surgery and Nonoperative Management for Pediatric Appendicitis
Authors: Peter C. Minneci, Jennifer N. Cooper, Karen Leonhart, Kristine Nacion, Jason Sulkowski, Kyle Porter, Lai Wei, Katherine J. Deans
Journal: JAMA Network Open (2019)

Strategies to activate and engage patients and caregivers in shared decision making in the acute care setting may result in improved outcomes.
Prevention of Opioid Overdose
Authors: Kavita M. Babu, Jeffrey Brent, David N. Juurlink
Journal: New England Journal of Medicine (2019)

In the time it takes to read this article, at least one person in the United States will have died from an opioid overdose. 1From 1999 through 2017, more than 700,000 U.S. residents died from a drug overdose; the majority of these events involved an opioid. 2 Among persons between the ages of 24 and 34 years, one in five deaths is now related to opioid use. 3 Every opioid-related death represents a missed opportunity for prevention.In this review, we focus on prescriber strategies for overdose prevention in three groups of patients: those who have not received previous opioid therapy, those receiving long-term opioid therapy, and those with an opioid use disorder. R educing Ov er dose R isk in Initi a l Opioid Ther a pyAll opioid overdoses share a common characteristic: a first opioid exposure.Although this exposure often occurs independent of a health care interaction (e.g., experimentation with a medication prescribed to a friend or relative), prescribers should strive "to keep opioid-naive patients opioid-naive." 4For mild or moderate acute pain, nonopioid regimens are the preferred first-line therapy.
Formulation and preclinical evaluation of a toll-like receptor 7/8 agonist as an anti-tumoral immunomodulator
Authors: Ruolin Lu, Chad Groer, Peter A. Kleindl, K. Ryan Moulder, Aric Huang, Jordan R. Hunt, Shuang Cai, Daniel J. Aires, Cory Berkland, M. Laird Forrest
Journal: Journal of Controlled Release (2019)

The toll-like receptor 7 and 8 (TLR7/8) agonist Resiquimod (R848) has been recognized as a promising immunostimulator for the treatment of cutaneous cancers in multiple clinical trials. However, systemic administration of R848 often results in strong immune-related toxicities while having limited therapeutic effects to the tumor. In the present study, a prodrug-based nanocarrier delivery system was developed that exhibited high therapeutic efficiency. R848 was conjugated to α-tocopherol to constitute an R848-Toco prodrug, followed by formulating with a tocopherol-modified hyaluronic acid (HA-Toco) as a polymeric nano-suspension. In vitro evaluation showed that the delivery system prolonged the release kinetics while maintaining TLR agonist activities. When administered subcutaneously, the nano-suspension formed a depot at the injection site, inducing localized immune responses without systemic expansion. This formulation also suppressed tumor growth and recruited immune cells to the tumor in a murine model of head and neck cancer. In a preclinical canine study of spontaneous mast cell tumors, the treatment led to a 67% response rate (three partial remissions and one complete remission).
Surface‐Engineered Monocyte Inhibits Atherosclerotic Plaque Destabilization via Graphene Quantum Dot‐Mediated MicroRNA Delivery
Authors: Feila Liu, Ning Ding, Da Huo, Guanyuan Yang, Keyu Wei, Ge Guan, Yanzhao Li, Jingyuan Yang, Tianran Wang, Yeqin Wang, Ju Tan, Wen Zeng, Chuhong Zhu
Journal: Advanced Healthcare Materials (2019)

Abstract Rupture‐prone atherosclerotic plaque is the cause of the high mortality and morbidity rates that accompany atherosclerosis‐associated diseases. MicroRNAs can regulate the expression of a variety of atherosclerotic inflammation‐related genes in macrophages. There are currently no definitive methods for delivering microRNAs into the interior of plaque. Monocytes typically possess a pathological feature that allows them to be recruited to atherosclerotic plaque resulting in rupture‐prone; however, whether monocytes can be modified to be gene carriers remains unclear. In this study, a novel monocyte surface‐engineered gene‐delivery system based on graphene quantum dots (GQDs) is developed. Briefly, GQDs‐microRNA223 linked by disulfide bonds are grafted onto the monocyte membrane via a carefully designed C18‐peptide (C18P) containing a hydrophobic end to afford the designed monocyte‐C18P‐GQDs‐miR223 architecture. The system can reach and enter the interior of the plaque and release the GQDs‐miRNA via C18P digestion. The released GQDs‐miRNA are taken up by the macrophages in atherosclerotic plaques, and the disulfide linkages between the GQDs and the miRNA are cleaved through γ‐interferon‐inducible lysosomal thiol reductase (GILT) in the lysosome. Under the protection of GQDs, miRNA cargos are transfected into the cytosol and subsequently undergo nuclear translocation, allowing a significantly reduced plaque burden by regulating inflammatory response in vivo.
Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury by Blockade of the <scp>CX</scp><sub>3</sub><scp>CL</scp>1/<scp>CX</scp><sub>3</sub><scp>CR</scp>1 Pathway in Experimental Mouse Models of Systemic Sclerosis
Authors: Vu H. Luong, Akira Utsunomiya, Takenao Chino, Le H. Doanh, Takashi Matsushita, Takashi Obara, Yoshikazu Kuboi, Naoto Ishii, Akihito Machinaga, Hideaki Ogasawara, Wataru Ikeda, Tetsu Kawano, Toshio Imai, Noritaka Oyama, Minoru Hasegawa
Journal: Arthritis & Rheumatology (2019)

Objective To assess the preclinical efficacy and mechanism of action of an anti‐ CX 3 CL 1 monoclonal antibody ( mA b) in systemic sclerosis ( SS c). Methods Cultured human dermal fibroblasts were used to evaluate the direct effect of anti‐ CX 3 CL 1 mA b on fibroblasts. In addition, bleomycin‐induced and growth factor–induced models of SS c were used to investigate the effect of anti‐ CX 3 CL 1 mA b on leukocyte infiltration, collagen deposition, and vascular damage in the skin. Results Anti‐ CX 3 CL 1 mA b treatment significantly inhibited Smad3 phosphorylation ( P &lt; 0.05) and expression of type I collagen and fibronectin 1 ( P &lt; 0.01) in dermal fibroblasts stimulated with transforming growth factor β1 ( TGF β1). In the bleomycin model, daily subcutaneous bleomycin injection increased serum CX 3 CL 1 levels ( P &lt; 0.05) and augmented lesional CX 3 CL 1 expression. Simultaneous administration of anti‐ CX 3 CL 1 mA b or CX 3 CR 1 deficiency significantly suppressed the dermal thickness, collagen content, and capillary loss caused by bleomycin ( P &lt; 0.05). Injection of bleomycin induced expression of pS mad3 and TGF β1 in the skin, which was inhibited by anti‐ CX 3 CL 1 mA b. Further, the dermal infiltration of CX 3 CR 1+ cells, macrophages (inflammatory and alternatively activated [M2‐like] subsets), and CD 3+ cells significantly decreased following anti‐ CX 3 CL 1 mA b therapy ( P &lt; 0.05), as did the enhanced skin expression of fibrogenic molecules, such as thymic stromal lymphopoietin and secreted phosphoprotein 1 ( P &lt; 0.05). However, the treatment did not significantly reduce established skin fibrosis. In the second model, simultaneous anti‐ mCX 3 CL 1 mA b therapy significantly diminished the skin fibrosis induced by serial subcutaneous injection of TGF β and connective tissue growth factor ( P &lt; 0.01). Conclusion Anti‐ CX 3 CL 1 mA b therapy may be a novel approach for treating early skin fibrosis in inflammation‐driven fibrotic skin disorders such as SS c.
External Beam, Brachytherapy, or Chemotherapy? Defining Adjuvant Therapy for Early-Stage and High- and High–Intermediate-Risk Endometrial Cancer
Authors: Joanne Wei-un Jang, Larissa Janeen Lee
Journal: Journal of Clinical Oncology (2019)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 54-year-old postmenopausal female with a history of stroke and carotid endarterectomy presented with 3 weeks of vaginal bleeding with passage of clots. Gynecologic exam revealed a 3-cm barrel-shaped cervix with friability at the os and no appreciable parametrial involvement. Cervical biopsy showed high-grade endometrioid adenocarcinoma. Pelvic magnetic resonance imaging demonstrated a 9.9-cm × 4.5-cm × 6.2-cm mass extending from the uterus to the cervix with greater than 50% myometrial invasion (MMI; Fig 1 ). Total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy revealed International Federation of Gynecology and Obstetrics (FIGO) stage II endometrial cancer: a 12-cm grade 3 endometrioid adenocarcinoma with 80% MMI and lymphovascular invasion (LVI) involving the outer half of the cervical stroma ( Fig 1 ), and without pelvic lymph node involvement.
Temporal Stability and Prognostic Biomarker Potential of the Prostate Cancer Urine miRNA Transcriptome
Authors: Jouhyun Jeon, Ekaterina Olkhov-Mitsel, Honglei Xie, Cindy Q Yao, Fang Zhao, Sahar Jahangiri, Carmelle Cuizon, Seville Scarcello, Renu Jeyapala, John D Watson, Michael Fraser, Jessica Ray, Kristina Commisso, Andrew Loblaw, Neil E Fleshner, Robert G Bristow, Michelle Downes, Danny Vesprini, Stanley Liu, Bharati Bapat, Paul C Boutros
Journal: JNCI Journal of the National Cancer Institute (2019)

The development of noninvasive tests for the early detection of aggressive prostate tumors is a major unmet clinical need. miRNAs are promising noninvasive biomarkers: they play essential roles in tumorigenesis, are stable under diverse analytical conditions, and can be detected in body fluids.We measured the longitudinal stability of 673 miRNAs by collecting serial urine samples from 10 patients with localized prostate cancer. We then measured temporally stable miRNAs in an independent training cohort (n = 99) and created a biomarker predictive of Gleason grade using machine-learning techniques. Finally, we validated this biomarker in an independent validation cohort (n = 40).We found that each individual has a specific urine miRNA fingerprint. These fingerprints are temporally stable and associated with specific biological functions. We identified seven miRNAs that were stable over time within individual patients and integrated them with machine-learning techniques to create a novel biomarker for prostate cancer that overcomes interindividual variability. Our urine biomarker robustly identified high-risk patients and achieved similar accuracy as tissue-based prognostic markers (area under the receiver operating characteristic = 0.72, 95% confidence interval = 0.69 to 0.76 in the training cohort, and area under the receiver operating characteristic curve = 0.74, 95% confidence interval = 0.55 to 0.92 in the validation cohort).These data highlight the importance of quantifying intra- and intertumoral heterogeneity in biomarker development. This noninvasive biomarker may usefully supplement invasive or expensive radiologic- and tissue-based assays.
Distribution of Self-reported Hidradenitis Suppurativa Age at Onset
Authors: Haley B. Naik, Maia Paul, Steven R. Cohen, Afsaneh Alavi, Mayte Suàrez-Fariñas, Michelle A. Lowes
Journal: JAMA Dermatology (2019)

Distribution of Self-reported Hidradenitis Suppurativa Age at OnsetAlthough hidradenitis suppurativa (HS) has a reported mean age at onset of 21.8 years, 1 we have observed initial onset of HS lesions in individuals older than 40 years more commonly than expected.In this retrospective study, we investigated age at HS onset and its distribution.
Abstract 14790: Endogenous Sex Hormone Levels and Risk for Incident Heart Failure Among Men and Post-Menopausal Women in the Atherosclerosis Risk in Communities Study
Authors: Vinita Subramanya, Di Zhao, Christie M Ballantyne, Pamela Ouyang, Wendy S Post, Wendy Ying, Dhananjay Vaidya, Chiadi E Ndumele, Ron C Hoogeveen, Erin D Michos
Journal: Circulation (2018)

Introduction: Men develop heart failure (HF) more frequently and at younger ages while women are more likely to develop HF with preserved ejection fraction with better survival. The underlying biol...
SIRT1 regulates metabolism and leukemogenic potential in CML stem cells
Authors: Ajay Abraham, Shaowei Qiu, Balu K. Chacko, Hui Li, Andrew Paterson, Jianbo He, Puneet Agarwal, Mansi Shah, Robert Welner, Victor M. Darley-Usmar, Ravi Bhatia
Journal: Journal of Clinical Investigation (2019)

Chronic myeloid leukemia (CML) results from hematopoietic stem cell transformation by the BCR-ABL kinase. Despite the success of BCR-ABL tyrosine kinase inhibitors (TKIs) in treating CML patients, leukemia stem cells (LSCs) resist elimination and persist as a major barrier to cure. Previous studies suggest that overexpression of the sirtuin 1 (SIRT1) deacetylase may contribute to LSC maintenance in CML. Here, by genetically deleting SIRT1 in transgenic CML mice, we definitively demonstrated an important role for SIRT1 in leukemia development. We identified a previously unrecognized role for SIRT1 in mediating increased mitochondrial oxidative phosphorylation in CML LSCs. We showed that mitochondrial alterations were kinase independent and that TKI treatment enhanced inhibition of CML hematopoiesis in SIRT1-deleted mice. We further showed that the SIRT1 substrate PGC-1α contributed to increased oxidative phosphorylation and TKI resistance in CML LSCs. These results reveal an important role for SIRT1 and downstream signaling mechanisms in altered mitochondrial respiration in CML LSCs.
How strong is the evidence that conservative treatment reduces pain and improves function in individuals with patellar tendinopathy? A systematic review of randomised controlled trials including GRADE recommendations
Authors: Luciana De Michelis Mendonça, Hércules R Leite, Johannes Zwerver, Nicholas Henschke, Guilherme Branco, Vinicius Cunha Oliveira
Journal: British Journal of Sports Medicine (2019)

Objective To determine the effectiveness of conservative treatment (CT) on pain and function in patients with patellar tendinopathy (PT) compared with minimal intervention (MI) or other invasive intervention, or in addition to decline eccentric squat. Methods Searches were performed in MEDLINE, Embase, Cochrane, PEDro, SPORTDiscus, CINAHL and AMED databases. All randomised trials that evaluated CT (any intervention not involving invasive procedures or medication) in individuals with PT were included. Two reviewers screened studies, extracted data and assessed risk of bias of all included studies. Where suitable, meta-analyses were conducted; we assessed certainty of the evidence using GRADE methodology. Results When compared with MI, CT did not improve pain (weighted mean difference (WMD) −2.6, 95% CI −6.5 to 1.2) or function (WMD 1.8, 95% CI −2.4 to 6.1) in the short-term (up to 3 months) follow-up. When compared with invasive intervention, CT did not improve pain (WMD 0.7, 95% CI −0.1 to 1.4) or function (WMD −6.6, 95% CI −13.3 to 0.2) in the short-term follow-up. No overall effects were found for combined CT (when a conservative intervention was added to decline eccentric squat) on pain (WMD −0.5, 95% CI −1.4 to 0.4) or function (WMD −2.3, 95 % –9.1 to 4.6) at short-term follow-up. Single studies showed an effect on pain with iontophoresis at short-term follow-up (d = 2.42) or dry needling at medium/long-term follow-up (d = 1.17) and function with exercise intervention at medium/long-term follow-up (over 3 months) (d = 0.83). Summary/Conclusion Our estimates of treatment effect have only low to very low certainty evidence to support them. This field of sports medicine/sports physiotherapy urgently needs larger, high-quality studies with pain and function among the potential primary outcomes.
Pulmonary environmental cues drive group 2 innate lymphoid cell dynamics in mice and humans
Authors: Franz Puttur, Laura Denney, Lisa G. Gregory, Juho Vuononvirta, Robert Oliver, Lewis J. Entwistle, Simone A. Walker, Mark B. Headley, Ewan J. McGhee, James E. Pease, Matthew F. Krummel, Leo M. Carlin, Clare M. Lloyd
Journal: Science Immunology (2019)

Collagen-I and CCL8-CCR8 axis control the motility of ILC2s in the inflamed lung.
Recapitulating bone development through engineered mesenchymal condensations and mechanical cues for tissue regeneration
Authors: Anna M. McDermott, Samuel Herberg, Devon E. Mason, Joseph M. Collins, Hope B. Pearson, James H. Dawahare, Rui Tang, Amit N. Patwa, Mark W. Grinstaff, Daniel J. Kelly, Eben Alsberg, Joel D. Boerckel
Journal: Science Translational Medicine (2019)

Mechanical loading regulates mesenchymal condensation–mediated endochondral bone regeneration.