tbuckley/cabot-search huggingface dataset:
Immune Checkpoint Inhibitor Therapy in Breast Cancer
Authors: Cesar A. Santa-Maria, Rita Nanda
Journal: Journal of the National Comprehensive Cancer Network (2018)

Initial studies investigating single-agent activity of immune checkpoint inhibitors (ICIs) serve as proof of principle that harnessing the immune system can have anticancer activity in a variety of human malignancies. Although breast cancer was historically believed to be immunogenically silent, early studies indicate overall response rates with ICIs are similar to those observed with many other solid malignancies. Overall response rates in advanced breast cancer are low, but the responses are remarkably durable. A deeper understanding of the biology of the interaction between cancer and immune cells is required to both develop biomarkers that more accurately predict response to therapy and identify effective immunotherapy-based combination strategies that can enhance the immunogenicity of biologically "cold" tumors. Breast cancer encompasses a variety of diseases defined by the presence or absence of central oncogenic drivers, and early data suggest that the distinct subtypes may have unique immune phenotypes. Breast cancer represents an ideal disease in which to investigate immunotherapeutic strategies given the prevalence of the disease, unique clinical trial design opportunities, and immunophenotypic diversity.
Tapering Janus kinase inhibitors in rheumatoid arthritis with low disease activity or remission: reality or dream?
Authors: Jasvinder A Singh
Journal: Annals of the Rheumatic Diseases (2018)

In this issue of the journal, Takeuchi et al presented results of a baricitinib long-term extension study of patients who received baricitinib 4 mg for ≥15 months and maintained a clinical disease activity index (CDAI) low disease activity (LDA; CDAI <10) or remission (CDAI ≤2.8) for ≥3 months.1 Patients with rheumatoid arthritis (RA) were randomised to baricitinib tapering to 2 mg daily dose versus continuing the baricitinib 4 mg daily.

Patients in this study had a mean (SD) age of 54 (12) years, 75% were female, 75% were anticyclic citrullinated protein antibody (ACPA) positive, 75% were rheumatoid factor positive, 46% on concomitant glucocorticoids, 82% were on concomitant methotrexate, one-third each had previously failed one or two traditional disease-modifying antirheumatic drugs (DMARDs), but only 13% previously failed a biologic. Patients had one swollen and one tender joint count, and the CDAI score was 3.6 (SD, 2.8), just before tapering.

The rates of LDA (67% vs 80%) and remission (33% vs 40%) at 48 weeks and non-serious infection rates (24.9 vs 30.6) were lower and relapse (CDAI score >10; 37% vs 23%) and rescue rates (18% vs 10%) higher in baricitinib 2 mg (tapering) vs 4 mg (continuing) daily dose groups. Among the rescued patients, most people who lost response (up to two-thirds) could regain the LDA or remission within 24 weeks after rescue to baricitinib 4 mg daily, 67% for the 2 mg group vs 54% for the 4 mg group. Compared with 4 mg daily dosing, baricitinib dose reductions to 2 mg daily were associated with statistically significant increase in CDAI, simplified disease activity, disease activity score (DAS) and earlier relapse. Among DMARD-incomplete responder (IR) patients who had achieved remission at step-down baseline, the majority maintained remission in both dose groups, 56% vs 68% …
<i>EIF1AX</i> and <i>RAS</i> Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC
Authors: Gnana P. Krishnamoorthy, Natalie R. Davidson, Steven D. Leach, Zhen Zhao, Scott W. Lowe, Gina Lee, Iňigo Landa, James Nagarajah, Mahesh Saqcena, Kamini Singh, Hans-Guido Wendel, Snjezana Dogan, Prasanna P. Tamarapu, John Blenis, Ronald A. Ghossein, Jeffrey A. Knauf, Gunnar Rätsch, James A. Fagin
Journal: Cancer Discovery (2018)

Abstract Translation initiation is orchestrated by the cap binding and 43S preinitiation complexes (PIC). Eukaryotic initiation factor 1A (EIF1A) is essential for recruitment of the ternary complex and for assembling the 43S PIC. Recurrent EIF1AX mutations in papillary thyroid cancers are mutually exclusive with other drivers, including RAS. EIF1AX mutations are enriched in advanced thyroid cancers, where they display a striking co-occurrence with RAS, which cooperates to induce tumorigenesis in mice and isogenic cell lines. The C-terminal EIF1AX-A113splice mutation is the most prevalent in advanced thyroid cancer. EIF1AX-A113splice variants stabilize the PIC and induce ATF4, a sensor of cellular stress, which is co-opted to suppress EIF2α phosphorylation, enabling a general increase in protein synthesis. RAS stabilizes c-MYC, an effect augmented by EIF1AX-A113splice. ATF4 and c-MYC induce expression of amino acid transporters and enhance sensitivity of mTOR to amino acid supply. These mutually reinforcing events generate therapeutic vulnerabilities to MEK, BRD4, and mTOR kinase inhibitors. Significance: Mutations of EIF1AX, a component of the translation PIC, co-occur with RAS in advanced thyroid cancers and promote tumorigenesis. EIF1AX-A113splice drives an ATF4-induced dephosphorylation of EIF2α, resulting in increased protein synthesis. ATF4 also cooperates with c-MYC to sensitize mTOR to amino acid supply, thus generating vulnerability to mTOR kinase inhibitors. This article is highlighted in the In This Issue feature, p. 151
Do Royal Marsden Hospital (RMH) and MD Anderson Cancer Center (MDACC) prognostic scoring systems predict survival in patients with bone sarcoma?
Authors: W. Alselwi, F. Azam, M.F. Latif, I.A.E.-H. Osman, W.A.H. Taha, K. Bawazir, A. Farooq, N. Bukhari, F. Ibnshamsah
Journal: Annals of Oncology (2018)
Reduced Nasal Viral Load and IFN Responses in Infants with Respiratory Syncytial Virus Bronchiolitis and Respiratory Failure
Authors: Ryan S. Thwaites, Matthew Coates, Kazuhiro Ito, Marwa Ghazaly, Calandra Feather, Farhana Abdulla, Tanushree Tunstall, Pooja Jain, Lindsey Cass, Garth Rapeport, Trevor T. Hansel, Simon Nadel, Peter Openshaw
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Respiratory syncytial virus (RSV) bronchiolitis is a major cause of morbidity and mortality in infancy. Severe disease is believed to result from uncontrolled viral replication, an excessive immune response, or both.To determine RSV load and immune mediator levels in nasal mucosal lining fluid by serial sampling of nasal fluids from cases of moderate and severe bronchiolitis over the course of infection.Infants with viral bronchiolitis necessitating admission (n = 55) were recruited from a pediatric center during 2016 and 2017. Of these, 30 were RSV infected (18 "moderate" and 12 mechanically ventilated "severe"). Nasal fluids were sampled frequently over time using nasosorption devices and nasopharyngeal aspiration. Hierarchical clustering of time-weighted averages was performed to investigate cytokine and chemokine levels, and gene expression profiling was conducted.Unexpectedly, cases with severe RSV bronchiolitis had lower nasal viral loads and reduced IFN-γ and C-C chemokine ligand 5/RANTES (regulated upon activation, normal T cell expressed and secreted) levels than those with moderate disease, especially when allowance was made for disease duration (all P < 0.05). Reduced cytokine/chemokine levels in severe disease were also seen in children with other viral infections. Gene expression analysis of nasopharyngeal aspiration samples (n = 43) confirmed reduced type-I IFN gene expression in severe bronchiolitis accompanied by enhanced expression of MUC5AC and IL17A.Infants with severe RSV bronchiolitis have lower nasal viral load, CXCL10 (C-X-C motif chemokine ligand 10)/IP-10, and type-I IFN levels than moderately ill children, but enhanced MUC5AC (mucin-5AC) and IL17A gene expression in nasal cells.
Abstract 20736: Ischemic Postconditioning Requires High-Quality CPR and Epinephrine to Improve Cardiac Mitochondrial Respiration After Prolonged Cardiac Arrest
Authors: Timothy R Matsuura, Jason A Bartos, Matthew D Olson, Adamantios Tsangaris, Kadambari Chandra Shekar, Stephen A George, Jennifer N Rees, Scott H McKnite, Matthias L Riess, Robert W Neumar, Martin Bienengraeber, Tom P Aufderheide, Demetris Yannopoulos
Journal: Circulation (2016)

Introduction: Ischemic postconditioning (IPC) has been shown to improve cardiac mitochondrial respiration during CPR and left ventricular ejection fraction post-ROSC in a porcine model of prolonged...
Profiling of transcription factor activation by androgen receptor in androgen dependent and androgen independent xenograft prostate tumors
Authors: Monica Davila, William E. Grizzle, Ratna Chakrabarti
Journal: Cancer Research (2005)

4517  Acquisition of resistance to androgen ablation therapy by prostate tumors during androgen deprivation remains a major obstacle to the effective treatment of prostate cancer. One of the reasons for development of androgen-independent prostate tumors following anti-androgen therapy is abnormal functioning of the androgen receptor (AR) as a nuclear receptor. The complexity of androgen-mediated regulation of gene transcription is developed from the ability of the AR to modulate transcription of a variety of genes through activation or inactivation of a number of transcription factors. To identify transcription factors that are activated or inactivated in response to androgen treatment or deprivation, we used human xenograft prostate tumors at different stages of androgen sensitivity or refractoriness. We used a novel protein-DNA interaction based method, TranSignal protein-DNA array, to profile activation status of transcription factors. We used crude nuclear extracts of five human prostate xenograft CWR22 tumors and a prostate cancer cell line to monitor the binding ability of transcription factors to specific response elements upon activation from a pool of 54 unique transcription factor binding sequences. Various CWR22 tumors include tumors from a) intact mice (Ctr), b) from castrated mice (Cstr), c) from castrated mice with androgen pellets implanted (CstrA), d) mice injected with androgen-independent human tumor cells (R), and e) mice exhibiting relapsed tumors after castration (RUI). We also used PC3AR cells, a stably transfected PC3 cell line capable of expressing androgen receptor and PSA, with or without treatment with DHT. Our studies using CWR22 human prostate cancer xenograft tumors showed differential activation of a number of transcription factors between tumors from castrated and androgen supplemented castrates. This includes AP-2 (1), CREB, E2F, GATA-1-binding protein, GRE, NF-1, NFATc, NF-E1, NF-E2, NFkB, Pit1, Sp1, TRDR4 and USF-1 transcription factors following androgen treatment. Direct binding of some of the transcription factors to their cognate response elements are validated by electrophoretic mobility shift assays. The overall pattern of the response element occupancy indicates a higher number of transcription factors are DNA-bound in Ctr, CstrA and RUI tumors compared to the Cstr tumor, which suggests possible induction of transcription of specific genes involved in progression of tumor growth in response to androgen. Increased activation of transcription factors in RUI tumors, whereas, reflects possible onset of an androgen-independent mechanism mediated by either AR or through an AR bypass mechanism.
Abstract 19012: Genetic Deletion of 12/15 Lipoxygenase Delays Vascular Remodeling, Limits Cardiorenal Dysfunction and Improves Survival After Pressure Overload
Authors: Kevin Ingle, Vasundhara Kain, Donald G Rokosh, Sumanth D Prabhu, Ganesh V Halade
Journal: Circulation (2016)

Introduction: The lipid metabolizing enzyme 12/15lipoxygenase (12/15LOX) induces pro-inflammatory responses that may increase cardiovascular and renal complications. Hypothesis: Deletion of 12/15LOX limits left ventricular (LV) hypertrophy associated perivascular inflammation and cardiorenal remodeling after pressure overload. Methods and Results: 8-12 week old male C57BL/6J wild-type (WT; n=23) and 12/15LOX–/– mice (n=21) were subject to transverse aortic constriction (TAC) and monitored for 7, 28 and 56 days (d) post-TAC. Compared to WT, 12/15LOX-/-mice exhibited less LV dysfunction (echocardiography) and improved survival rates post-TAC. 12/15LOX-/- mice post-TAC also exhibited less LV hypertrophy and decreased lung edema. At d7 post-TAC, 12/15LOX-/- mice showed increased cardiac gene expression of Arg-1 and the prostanoid receptors, EP2 and EP4. The EP4 receptor expression was consistently elevated from d7 till d56 in 12/15LOX-/- mice post-TAC when compared with WT controls. Post-TAC, wheat germ agglu...
Impact of BRCA status on outcomes and survival in high-risk early breast cancers
Authors: E. Klajer, S. Paget-Bailly, G. Meynard, A. Meurisse, F. Bazan, L. Chaigneau, E. Dobi, N. Meneveau, P. Montcuquet, C. Villanueva, A. Thiery-Vuillemin, E. Kalbacher, C. Populaire, M.-A. Collonge-Rame, J. Gligorov, E. Curtit, X. Pivot, L. Mansi
Journal: Annals of Oncology (2018)
A phase 1 study of MM-121 (a fully human monoclonal antibody targeting the epidermal growth factor receptor family member ErbB3) in combination with cetuximab and irinotecan in patients with advanced cancers.
Authors: James M. Cleary, Autumn Jackson McRee, Bert H. O'Neil, Sunil Sharma, Joseph Pearlberg, Sara Manoli, William Lloyd Kubasek, W. Michael Korn
Journal: Journal of Clinical Oncology (2014)

3076 Background: ErbB3-EGFR heterodimers have been implicated in resistance to targeted and conventional therapies across multiple malignancies. Methods: This phase 1 trial assessed the safety, tolerability, and pharmacokinetic (PK) properties of MM-121 in combination with cetuximab (Part 1) or with cetuximab and irinotecan (Part 2) in patients (pts) with advanced solid cancers. Pts were dosed in a "3+3" design with escalating doses of MM-121 and cetuximab without (Pat 1) or with (Part 2) biweekly irinotecan. Results: Part 1 enrolled 34 pts with a median age of 60. Common (>25%) adverse events (AE) of any grade were: fatigue (64.7%), dermatitis acneiform (47.1%), hypomagnesemia (47.1%), diarrhea (44.1%), decreased appetite (32.4%) and hypokalemia (26.5%). One DLT was observed in the first cohort of Part 1 (G3 lung infection) and dose escalation was able to continue to the highest recommended doses of MM121 and cetuximab. One pts (CRC) had a complete response (CR), and three pts (NCSLC (2), cholangiocarcinoma) had a partial response (PR). Twelve pts had a best response of stable disease (SD). Part 2 enrolled 14 pts with a median age of 58. Common (>25%) AEs of any grade were: diarrhea (92.9%), hypokalemia (57.1%), nausea (50%), fatigue (42.9%), hypomagnesemia (37.5%), decreased appetite (35.7%), dermatitis acneiform (28.6%), mucosal inflammation (28.6%), dehydration (28.6%), and weight decrease (28.6%). Three DLTs were observed in Part 2: one at the first dose level (G3 diarrhea), and two at the second dose level (G3 mucositis with G4 neutropenia and G3 UTI, dehydration, and diarrhea with G4 neutropenia and cardiac arrest and G5 respiratory failure) and an MTD was reached. One CRC pts who previously had developed acquired resistance to cetuximab had a PR, and one pts had a best response of SD in Part 2 of the study. Mandatory pre- and post-treatment biopsies are analyzed to assess the PD correlates of response and resistance to this combination. Conclusions: The HER3 antibody, MM121, can be combined with cetuximab +/- irinotecan and had modest activity in a population of refractory solid tumor pts. Clinical trial information: NCT01451632.
Effect of Prefrontal Cortex Stimulation on Regulation of Amygdala Response to Threat in Individuals With Trait Anxiety
Authors: Maria Ironside, Michael Browning, Tahereh L. Ansari, Christopher J. Harvey, Mama N. Sekyi-Djan, Sonia J. Bishop, Catherine J. Harmer, Jacinta O'Shea
Journal: JAMA Psychiatry (2018)

Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) is under clinical investigation as a treatment for major depressive disorder. However, the mechanisms of action are unclear, and there is a lack of neuroimaging evidence, particularly among individuals with affective dysfunction. Furthermore, there is no direct causal evidence among humans that the prefrontal-amygdala circuit functions as described in animal models (ie, that increasing activity in prefrontal cortical control regions inhibits amygdala response to threat).To determine whether stimulation of the prefrontal cortex reduces amygdala threat reactivity in individuals with trait anxiety.This community-based randomized clinical trial used a double-blind, within-participants design (2 imaging sessions per participant). Eighteen women with high trait anxiety (age range, 18-42 years) who scored greater than 45 on the trait measure of State-Trait Anxiety Inventory were randomized to receive active or sham tDCS of the DLPFC during the first session and the other intervention during the next session. Each intervention was followed immediately by a functional imaging scan during which participants performed an attentional task requiring them to ignore threatening face distractors. Data were collected from May 7 to October 6, 2015.Amygdala threat response, measured with functional magnetic resonance imaging.Data from 16 female participants (mean age, 23 years; range, 18-42 years), with 8 in each group, were analyzed. Compared with sham stimulation, active DLPFC stimulation significantly reduced bilateral amygdala threat reactivity (z = 3.30, P = .04) and simultaneously increased activity in cortical regions associated with attentional control (z = 3.28, P < .001). In confirmatory behavioral analyses, there was a mean improvement in task accuracy of 12.2% (95% CI, 0.30%-24.0%; mean [SD] difference in number of correct answers, 2.2 [4.5]; t15 = 1.94, P = .04) after active DLPFC stimulation.These results reveal a causal role for prefrontal regulation of amygdala function in attentional capture by threat in individuals with high trait anxiety. The finding that prefrontal stimulation acutely increases attentional control signals and reduces amygdala threat reactivity may indicate a neurocognitive mechanism that could contribute to tDCS treatment effects in affective disorders.isrctn.org Identifier: ISRCTN78638425.
A biobank of patient-derived pediatric brain tumor models
Authors: Sebastian Brabetz, Sarah E. S. Leary, Susanne N. Gröbner, Madison W. Nakamoto, Huriye Şeker-Cin, Emily J. Girard, Bonnie Cole, Andrew D. Strand, Karina L. Bloom, Volker Hovestadt, Norman L. Mack, Fiona Pakiam, Benjamin Schwalm, Andrey Korshunov, Gnana Prakash Balasubramanian, Paul A. Northcott, Kyle D. Pedro, Joyoti Dey, Stacey Hansen, Sally Ditzler, Peter Lichter, Lukas Chavez, David T. W. Jones, Jan Koster, Stefan M. Pfister, Marcel Kool, James M. Olson
Journal: Nature Medicine (2018)
Systemic Treatment of Metastatic Clear Cell Renal Cell Carcinoma in 2018: Current Paradigms, Use of Immunotherapy, and Future Directions
Authors: Aly-Khan A. Lalani, Bradley A. McGregor, Laurence Albiges, Toni K. Choueiri, Robert Motzer, Thomas Powles, Christopher Wood, Axel Bex
Journal: European Urology (2018)
Hyperpigmented Macule on the Palm and Diminished Sensation
Authors: Reda Awali, Pranatharthi H. Chandrasekar
Journal: JAMA (2018)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Can Stroke Complications Be Distinguished From Comorbid Stroke in Administrative Data?
Authors: Ken Uchino
Journal: JAMA Cardiology (2018)

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 Cardiology 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 Cardiology journal
Deep learning algorithms for detection of critical findings in head CT scans: a retrospective study
Authors: Sasank Chilamkurthy, Rohit Ghosh, Swetha Tanamala, Mustafa Biviji, Norbert G Campeau, Vasantha Kumar Venugopal, Vidur Mahajan, Pooja Rao, Prashant Warier
Journal: The Lancet (2018)
Population-level effectiveness of rapid, targeted, high-coverage roll-out of HIV pre-exposure prophylaxis in men who have sex with men: the EPIC-NSW prospective cohort study
Authors: Andrew E Grulich, Rebecca Guy, Janaki Amin, Fengyi Jin, Christine Selvey, Jo Holden, Heather-Marie A Schmidt, Iryna Zablotska, Karen Price, Bill Whittaker, Kerry Chant, Craig Cooper, Scott McGill, Barbara Telfer, Barbara Yeung, Gesalit Levitt, Erin E Ogilvie, Nila J Dharan, Mohamed A Hammoud, Stefanie Vaccher, Lucy Watchirs-Smith, Anna McNulty, David J Smith, Debra M Allen, David Baker, Mark Bloch, Rohan I Bopage, Katherine Brown, Andrew Carr, Christopher J Carmody, Kym L Collins, Robert Finlayson, Rosalind Foster, Eva Y Jackson, David A Lewis, Josephine Lusk, Catherine C O'Connor, Nathan Ryder, Emanuel Vlahakis, Phillip Read, David A Cooper, Don Smith, Catriona Ooi, Sarah Martin, Tuck Meng Soo, David Templeton, David Townson, Brad Forssman, Nick Doong, Gai Han Thai, Ben Anderson, Hugh MacLeod, Nicolas Parkhill
Journal: The Lancet HIV (2018)