tbuckley/cabot-search huggingface dataset:
Abstract PR14: Defining isoform-specific roles for AKTs in BRAFV600E-driven melanoma
Authors: Jaymes Farrell, Jodie Pietruska, Siobhan McRee, Philip Tsichlis, Philip Hinds
Journal: Cancer Research (2020)

Abstract The PI3K/AKT pathway is frequently dysregulated in cutaneous melanoma and impacts both tumor aggression and resistance to BRAFV600E/K inhibitors. While current clinical approaches to AKT inhibition are severely limited by the toxicity of pan-AKT inhibitors, selective inhibition of individual AKT isoforms (AKT1, AKT2, or AKT3) remains an attractive, if yet unattainable, approach. A critical gap in our understanding concerns how the three highly homologous yet functionally distinct AKT isoforms contribute to melanomagenesis and treatment response. To address this question, we are employing RNAi and gene editing approaches to interrogate the effect of selective suppression or CRISPR/Cas9-mediated deletion of each isoform in vitro, as well as the impact of AKT isoform loss on 1) the growth of melanoma xenografts and 2) the development of spontaneous tumors in a melanoma-prone mouse model. In addition, we are interrogating tumor-promoting functions of AKT isoform-selective substrates recently identified in a phospho-proteomic screen of mouse fibroblasts, a system that allows us to identify downstream actionable targets that may mediate the effects of AKT isoforms in tumorigenesis. Broadly, we are focusing on the importance of AKTs in tumor cell growth, metastasis, and response to inhibitors of BRAFV600E/K or CDK4/6. We find that loss of AKT1 impacts growth of BRAF mutant human melanoma cells both in vitro and in vivo. Additionally, AKT1 appears to play an isoform-specific role in response to pharmacologic CDK4/6 inhibition, impacting transcriptional and morphologic changes typically associated with permanent cell cycle arrest. In contrast, loss of AKT2 has a minimal impact on melanoma cell growth or response to CDK4/6 inhibition, but severely limits the development of metastatic disease, potentially through a combination of impaired seeding at the metastatic site and defects in glycolysis. While AKT3 loss does not appreciably impact the above-mentioned cellular phenotypes, the protumorigenic role of AKT3 may involve activation of broadly-acting neutral proteases previously implicated in cell cycle progression, cell migration, and CDK5 regulation. Taken together, we provide evidence for distinct roles for AKT isoforms in several aspects of the tumorigenic process as well as response to current therapies. Future studies will focus on identification and targeting of the relevant downstream mediators of these phenotypes. This abstract is also being presented as Poster A16. Citation Format: Jaymes Farrell, Jodie Pietruska, Siobhan McRee, Philip Tsichlis, Philip Hinds. Defining isoform-specific roles for AKTs in BRAFV600E-driven melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR14.
Blood-brain barrier leakage in systemic lupus erythematosus is associated with gray matter loss and cognitive impairment
Authors: Lyna Kamintsky, Steven D Beyea, John D Fisk, Javeria A Hashmi, Antonina Omisade, Cynthia Calkin, Tim Bardouille, Chris Bowen, Maher Quraan, Arnold Mitnitski, Kara Matheson, Alon Friedman, John G Hanly
Journal: Annals of the Rheumatic Diseases (2020)

To examine the association between blood-brain barrier (BBB) integrity, brain volume and cognitive dysfunction in adult patients with systemic lupus erythematosus (SLE).A total of 65 ambulatory patients with SLE and 9 healthy controls underwent dynamic contrast-enhanced MRI scanning, for quantitative assessment of BBB permeability. Volumetric data were extracted using the VolBrain pipeline. Global cognitive function was evaluated using a screening battery consisting of tasks falling into five broad cognitive domains, and was compared between patients with normal versus extensive BBB leakage.Patients with SLE had significantly higher levels of BBB leakage compared with controls (p=0.04). Extensive BBB leakage (affecting over >9% of brain volume) was identified only in patients with SLE (16/65; 24.6%), who also had smaller right and left cerebral grey matter volumes compared with controls (p=0.04). Extensive BBB leakage was associated with lower global cognitive scores (p=0.02), and with the presence of impairment on one or more cognitive tasks (p=0.01).Our findings provide evidence for a link between extensive BBB leakage and changes in both brain structure and cognitive function in patients with SLE. Future studies should investigate the mechanisms underlying BBB-mediated cognitive impairment, validate the diagnostic utility of BBB imaging, and determine the potential of targeting the BBB as a therapeutic strategy in patients with SLE.
Aftermath of torrential rains and covid-19 in Pakistan
Authors: Amjad Ali, Zhongren Ma, Jialin Bai
Journal: BMJ (2020)

Alongside covid-19, environmental challenges should be prioritised. 1Unfortunately, Pakistan is currently facing both types of disaster.Recent heavy rains across the country have left dozens dead (310, including 107 children), thousands affected, and swept away entire hamlets, 220 000 houses, livestock, and agricultural land, with water reservoirs now filled to capacity. 2 Damage includes a lack of shelter, drinking water, food, drugs, electricity, and communication means.A deluge in Karachi, the most affected area, claimed at least 19 lives in one day.
Hepatitis Hide and Seek
Authors: E Barnes, A Folgori, S Capone, L Swadling, S Aston, A Kurioka, J Meyer, R Huddart, K Smith, R Townsend, A Brown, R Antrobus, V Ammendola, M Naddeo, G O'Hara, C Willberg, A Harrison, F Grazioli, M L Esposito, L Siani, C Traboni, Y Oo, D Adams, A Hill, S Colloca, A Nicosia, R Cortese, P Klenerman
Journal: Science Translational Medicine (2012)
New Disease Cases, Deaths Related to Breast Implants
Authors: Rebecca Voelker
Journal: JAMA (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 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
Adjuvant-pulsed mRNA vaccine nanoparticle for immunoprophylactic and therapeutic tumor suppression in mice
Authors: Mohammad Ariful Islam, Jamie Rice, Emma Reesor, Harshal Zope, Wei Tao, Michael Lim, Jianxun Ding, Yunhan Chen, Dike Aduluso, Bruce R. Zetter, Omid C. Farokhzad, Jinjun Shi
Journal: Biomaterials (2020)
Therapy Response and Outcome Explained by Leukemia Cell of Origin
Authors: Zhimin Gu, Kathryn E. Dickerson, Jian Xu
Journal: Cancer Discovery (2020)

Abstract Summary: In this issue of Cancer Discovery, Cai and colleagues delineate a new mechanism that links cell of origin, the transcription factor EVI1, apoptotic priming, and therapeutic susceptibility in mixed lineage leukemia–rearranged acute myeloid leukemia. These findings establish a cell of origin–dependent program that may be leveraged by therapeutic combinations to overcome drug resistance in chemoresistant leukemias. See related article by Cai et al., p. 1500.
Profiling of Serum Oxylipins During the Earliest Stages of Rheumatoid Arthritis
Authors: Javier Rodríguez‐Carrio, Roxana Coras, Mercedes Alperi‐López, Patricia López, Catalina Ulloa, Francisco Javier Ballina‐García, Aaron M. Armando, Oswald Quehenberger, Mónica Guma, Ana Suárez
Journal: Arthritis & Rheumatology (2020)

Eicosanoids modulate inflammation via complex networks involving different pathways and downstream mediators, including oxylipins. Although altered eicosanoids are linked to rheumatoid arthritis (RA), suggesting that metabolization is enhanced, the role of oxylipins in disease stratification remains unexplored. This study was undertaken to characterize oxylipin networks during the earliest stages of RA and evaluate their associations with clinical features and treatment outcomes.In total, 60 patients with early RA (according to the American College of Rheumatology/European League Against Rheumatism 2010 criteria), 11 individuals with clinically suspect arthralgia (CSA), and 28 healthy control subjects were recruited. Serum samples were collected at the time of onset. In the early RA group, 50 patients who had not been exposed to disease-modifying antirheumatic drug (DMARD) or glucocorticoid treatment at the time of recruitment were prospectively followed up at 6 and 12 months after having received conventional synthetic DMARDs. A total of 75 oxylipins, mostly derived from arachidonic, eicosapentanoic, and linoleic acids, were identified in the serum by liquid chromatography tandem mass spectrometry.Univariate analyses demonstrated differences in expression patterns of 14 oxylipins across the RA, CSA, and healthy control groups, with each exhibiting a different trajectory. Network analyses revealed a strong grouping pattern of oxylipins in RA patients, whereas in individuals with CSA, a fuzzy network of oxylipins with higher degree and closeness was found. Partial least-squares discriminant analyses yielded variable important projection scores of >1 for 22 oxylipins, which allowed the identification of 2 clusters. Cluster usage differed among the groups (P = 0.003), and showed associations with disease severity and low rates of remission at 6 and 12 months in RA patients who were initially treatment-naive. Pathway enrichment analyses revealed different precursors and pathways between the groups, highlighting the relevance of the arachidonic acid pathway in individuals with CSA and the lipooxygenase pathway in patients with early RA. In applying distinct oxylipin signatures, subsets of seropositive and seronegative RA could be identified.Oxylipin networks differ across stages during the earliest phases of RA. These distinct oxylipin networks could potentially elucidate pathways with clinical relevance for disease progression, clinical heterogeneity, and treatment response.
Pharmaceutical Implications of Sex-Related RNA Divergence in Psychiatric Disorders
Authors: Alon Simchovitz-Gesher, Hermona Soreq
Journal: Trends in Pharmacological Sciences (2020)

Male-female differences have long been observed in the epidemiology and clinical presentation of psychiatric disorders. Current understanding is based on sex hormones and on transcription patterns governed by the sex chromosomes, and specific sexually dimorphic pathways were only recently identified. However, the underlying molecular mechanisms and pharmaceutical implications remain unclear. We highlight the importance of studying the sex-specific patterns of mental diseases at all levels from genomics to pharmaceutics. In particular, we discuss transcriptional level differences between the sexes in psychiatric disorders and outline the possible impact of such research on future pharmaceutical developments.
Characterization of asthma and risk factors for delayed SARS‐CoV‐2 clearance in adult COVID‐19 inpatients in Daegu
Authors: Sujeong Kim, Chang‐Gyu Jung, Ji Yeon Lee, Gunwoo Kim, Sae Won Choi, Hyun Jung Jin, Han‐Ki Park
Journal: Allergy (2020)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Response to: ‘Correspondence on ‘Long-term efficacy and safety of canakinumab in patients with colchicine-resistant familial Mediterranean fever: results from the randomised phase III CLUSTER trial’’ by Satis<i>et al</i>
Authors: Seza Ozen, Fabrizio De Benedetti
Journal: Annals of the Rheumatic Diseases (2020)

We thank Satis et al 1 for their interest in our article,2 and will try to address their queries. Our colleagues suggest that flares with musculoskeletal symptoms as predominant signs may not be remembered by the patients when they report them. We reported that in Epoch 4 of the CLUSTER study, >90% of the patients treated with canakinumab experienced no flares or one flare throughout the 72-week period, while a median of 17.5 flares per year was reported before baseline. As detailed in the methods section and according to the study protocol, during the trial patients were considered to experience a flare when they present with a physician global assessment (which includes the assessment of musculoskeletal symptoms) ≥2 and C-reactive protein (CRP) ≥30 mg/L. On the other hand, if the phenomenon that Satis et al 1 mentioned occurred when patients reported the number of flares before the trial, it could have potentially led to an underestimation of the number of flares …
Abstract PR01: A cancer cell program promotes T-cell exclusion and resistance to checkpoint blockade
Authors: Parin Shah, Michael Cuoco, Mei-Ju Su, Johannes Melms, Rachel Leeson, Abhay Kanodia, Shaolin Mei, Jia-Ren Lin, Shu Wang, Bokang Rabasha, David Liu, Alex K. Shalek, Itay Tirosh, Peter K. Sorger, Kai Wucherpfennig, Eliezer M. Van Allen, Dirk Schadendorf, Bruce E. Johnson, Asaf Rotem, Orit Rozenblatt-Rosen, Levi A. Garraway, Charles H. Yoon, Benjamin Izar, Aviv Regev, Livnat Jerby-Arnon
Journal: Cancer Research (2020)

Abstract Immune checkpoint inhibitors (ICI) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA-seq (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T-cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance. This study will be published on Nov. 1st in Cell (Jerby-Arnon et al., Cell 2018). This abstract is also being presented as Poster A25. Citation Format: Parin Shah, Michael Cuoco, Mei-Ju Su, Johannes Melms, Rachel Leeson, Abhay Kanodia, Shaolin Mei, Jia-Ren Lin, Shu Wang, Bokang Rabasha, David Liu, Alex K. Shalek, Itay Tirosh, Peter K. Sorger, Kai Wucherpfennig, Eliezer M. Van Allen, Dirk Schadendorf, Bruce E. Johnson, Asaf Rotem, Orit Rozenblatt-Rosen, Levi A. Garraway, Charles H. Yoon, Benjamin Izar, Aviv Regev, Livnat Jerby-Arnon. A cancer cell program promotes T-cell exclusion and resistance to checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR01.
Deciphering the Complexity of MEK Mutations in the Clinic
Authors: Christopher E. Whitehead, Judith S. Sebolt-Leopold
Journal: Cancer Research (2020)

Abstract Significant advances in tumor sequencing have led to an explosion in our knowledge of the genetic complexity of cancer. For many cancers, the selection of a targetable alteration is not readily apparent, especially when confronted with mutational variants of unknown significance. The complex clinical landscape of MEK mutations illustrates the need for improved methods to identify those patients, independent of tumor histology, who would benefit from treatment with a MAP kinase pathway inhibitor. In this issue of Cancer Research, Hanrahan and colleagues adopt an in silico platform to attempt to distinguish benign MEK mutations from those that are functional and, therefore, most likely to be therapeutically actionable. See related article by Hanrahan et al., p. 4233
Long-pulsed neodymium-doped yttrium-aluminum-garnet laser versus cryotherapy for the treatment of cutaneous warts: A randomized controlled trial
Authors: Jian-jun Liu, Hong-tian Li, Ying-yun Ren, Fan Yang, Zhi-hao Cheng, Tian-bao Xia, Jun-lian Liu, Xiao-jia Cao, Shi-chao Lu
Journal: Journal of the American Academy of Dermatology (2020)
American Radium Society Appropriate Use Criteria on Radiation Therapy for Extensive-Stage SCLC
Authors: Kristin A. Higgins, Charles B. Simone, Arya Amini, Indrin J. Chetty, Jessica Donington, Martin J. Edelman, Stephen G. Chun, Larry L. Kestin, Benjamin Movsas, George B. Rodrigues, Kenneth E. Rosenzweig, Ben J. Slotman, Igor I. Rybkin, Andrea Wolf, Joe Y. Chang
Journal: Journal of Thoracic Oncology (2020)
CCR2-targeted micelles for anti-cancer peptide delivery and immune stimulation
Authors: Noah Trac, Leng-Ying Chen, Ailin Zhang, Chun-Peng Liao, Christopher Poon, Jonathan Wang, Yuta Ando, Johan Joo, Carolina Garri, Keyue Shen, Kian Kani, Mitchell E. Gross, Eun Ji Chung
Journal: Journal of Controlled Release (2020)
Can artificial intelligence help to detect dysplasia in patients with ulcerative colitis?
Authors: Yasuharu Maeda, Shin-ei Kudo, Noriyuki Ogata, Masashi Misawa, Yuichi Mori, Kensaku Mori, Kazuo Ohtsuka
Journal: Endoscopy (2020)

A 72-year-old man with an 18-year history of pancolitis had been visiting our hospital regularly for 12 years. He was taking oral mesalamine and mercaptopurine to sustain clinical remission. Surveillance colonoscopy was performed using high-definition endoscopy (CF-HQ290ZI; Olympus, Tokyo, Japan) with an artificial intelligence (AI)-based detection system (EndoBRAIN-EYE; Cybernet Systems, Tokyo, Japan).
Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer
Journal: New England Journal of Medicine (2007)

43). Table 3 (page 2741)should have included a footnote for Grade 4 adverse events: "A total of 13 grade 4 adverse events occurred among 10 (6%) of the patients receiving lapatinib plus capecitabine, and 16 grade 4 adverse events occurred among 11 (7%) of the patients receiving capecitabine alone.These differences are not significant."The table has been corrected on the Journal's Web site at www.nejm.org.Synergistic Copathogens -HIV-1 and HSV-2 (February 22, 2007;356:854-6).The fourth sentence of the fourth paragraph (page 855) should have read "As Nagot et al. show with sampling every 2 weeks, 50% of patients who are coinfected with HSV-2 and HIV-1 shed HSV-2 virus asymptomatically" rather than "with once-weekly sampling."The text has been corrected on the Journal's Web site at www.nejm.org.
Ideas About Resourcing Health Care in the United States: Can Economic Evaluation Achieve Meaningful Use?
Authors: William V. Padula, Mark J. Sculpher
Journal: Annals of Internal Medicine (2020)

The United States is one of the few high-income countries not to apply economic evaluation routinely to health care decision making on a national level, yet it excels at spending least efficiently on health care. In the interest of continuing to develop new solutions to curb spending on health care and reduce waste in the United States, perhaps now is an important moment to reconsider the benefits of economic evaluation and the barriers that must be overcome to have it emerge as a solution for health care institutions and the patients they serve. This article offers several distinct considerations to make economic evaluation methods (such as cost-effectiveness analysis) an effective component of value-based decision making in the United States. These considerations include overcoming the barriers presented by opportunity costs, spending on health care services versus biomedical technologies, phasing out low-value care, using value of information to prioritize resources, and determining what to do with the quality-adjusted life-year. These issues need to be addressed to achieve a collective purpose for economic evaluation at state and national levels.
Giving oral medicines and supplements to children
Authors: Deonne Dersch-Mills, Bonnie J Kaplan
Journal: BMJ (2020)

### What you need to know

A 6 year old boy undergoing treatment for acute myelogenous leukaemia is discharged from hospital to continue treatment from home. He is unable to swallow tablets or capsules and so must use compounded liquid formulations, some of which have only seven day stability. His family live in a remote area, two hours’ drive to the nearest compounding pharmacy. They bring a cooler every week when they drive to obtain medication refills because the medications must be refrigerated at all times. The medications are unpalatable, and his parents are spending up to three hours three times a day, every day, trying to give him his medication. 

Giving medications to children who cannot yet swallow tablets or capsules (hereafter referred to collectively as “pills”) is a common problem without a universal solution. Frequently, parents, clinicians, and pharmacists attempt to crush tablets, empty capsules into food, search for alternative dosage forms, or find a different medicine altogether. Unfortunately, finding alternative formulations that children will accept can be challenging. Oral liquid formulations are sometimes a viable solution, but many oral liquid preparations are not commercially available, can be difficult to measure and dose correctly, or may …