tbuckley/cabot-search huggingface dataset:
Patient-Driven Discovery, Therapeutic Targeting, and Post-Clinical Validation of a Novel <i>AKT1</i> Fusion–Driven Cancer
Authors: Emily K. Slotkin, Daniel Diolaiti, Neerav N. Shukla, Filemon S. Dela Cruz, Jennifer J. Clark, Gunes Gundem, Venkata D. Yellapantula, Max F. Levine, Daoqi You, Peilin Ma, Sagarika Pachhal, Glorymar Ibanez Sanchez, Ryma Benayed, Achim A. Jungbluth, Lillian M. Smyth, Audrey Mauguen, Irena Gushterova, Hongxu Ding, Lee Spraggon, Robert Darnell, Andrea Califano, Marc Ladanyi, Elli Papaemmanuil, Andrew L. Kung, David M. Hyman, Stephen S. Roberts
Journal: Cancer Discovery (2019)

Despite the important role of the PI3K/AKT/mTOR axis in the pathogenesis of cancer, to date there have been few functional oncogenic fusions identified involving the AKT genes. A 12-year-old female with a histopathologically indeterminate epithelioid neoplasm was found to harbor a novel fusion between the LAMTOR1 and AKT1 genes. Through expanded use access, she became the first pediatric patient to be treated with the oral ATP-competitive pan-AKT inhibitor ipatasertib. Treatment resulted in dramatic tumor regression, demonstrating through patient-driven discovery that the fusion resulted in activation of AKT1, was an oncogenic driver, and could be therapeutically targeted with clinical benefit. Post-clinical validation using patient-derived model systems corroborated these findings, confirmed a membrane-bound and constitutively active fusion protein, and identified potential mechanisms of resistance to single-agent treatment with ipatasertib. SIGNIFICANCE: This study describes the patient-driven discovery of the first AKT1 fusion-driven cancer and its treatment with the AKT inhibitor ipatasertib. Patient-derived in vitro and in vivo model systems are used to confirm the LAMTOR1-AKT1 fusion as a tumorigenic driver and identify potential mechanisms of resistance to AKT inhibition.This article is highlighted in the In This Issue feature, p. 565.
Pembrolizumab in patients with advanced non-small-cell lung cancer (KEYNOTE-001): 3-year results from an open-label, phase 1 study
Authors: Natasha B Leighl, Matthew D Hellmann, Rina Hui, Enric Carcereny, Enriqueta Felip, Myung-Ju Ahn, Joseph Paul Eder, Ani S Balmanoukian, Charu Aggarwal, Leora Horn, Amita Patnaik, Matthew Gubens, Suresh S Ramalingam, Gregory M Lubiniecki, Jin Zhang, Bilal Piperdi, Edward B Garon
Journal: The Lancet Respiratory Medicine (2019)
Endoscopic sleeve gastroplasty versus intragastric balloon insertion: efficacy, durability, and safety
Authors: Lea Fayad, Lawrence J. Cheskin, Atif Adam, Dilhana S. Badurdeen, Christine Hill, Abhishek Agnihotri, Margo Dunlap, Cem Simsek, Mouen A. Khashab, Anthony N. Kalloo, Vivek Kumbhari
Journal: Endoscopy (2019)

Abstract Background Intragastric balloon (IGB) placement and endoscopic sleeve gastroplasty (ESG) are reported to be safe and effective endoscopic bariatric therapies. This study aimed to compare the patient demographics and therapeutic outcomes between the IGB and ESG procedures. Methods: This was a retrospective review of prospectively collected data from consecutive patients between December 2015 and October 2017 who underwent IGB or ESG at a single academic center. Fluid-filled IGBs implanted for a 6-month duration were used. IGB and ESG patients were subjected to identical post-procedure dietary instructions and follow-up protocols. Body weight was recorded at 1, 3, 6, and 12 months post-procedure. Results A total of 47 patients underwent IGB insertion and 58 underwent ESG. The IGB cohort had a lower baseline body mass index (BMI) than the ESG (34.5 vs. 41.5 kg/m2; P &lt; 0.001) and a significantly lower proportion of men (2.1 % vs. 41.4 %; P &lt; 0.001). IGB patients showed a mean (standard deviation [SD]) percentage total body weight loss (%TBWL) that was significantly lower than ESG patients at 1 month (6.6 % [2.6 %] vs. 9.9 % [2.4 %]; P &lt; 0.001), 3 months (11.1 % [4.4 %] vs. 14.3 % [4.6 %]; P = 0.004), 6 months (15.0 % [7.6 %] vs. 19.5 % [5.7 %]; P = 0.01), and 12 months (13.9 % [9.0 %] vs. 21.3 % [6.6 %]; P = 0.005). The IGB cohort also experienced significantly more adverse events compared with the ESG (17 % vs. 5.2 %; P = 0.048). Conclusions IGB placement and ESG result in clinically meaningful weight loss. However, ESG appears to provide clinically superior and more enduring weight loss with fewer adverse events compared with an IGB.
Can a Physiologic Insight “Resuscitate” Research in Cardiopulmonary Resuscitation?
Authors: Damon C. Scales, Brian P. Kavanagh
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

genetic and environmental factors that affect gene regulation affect disease risk, remains a major challenge.The discovery that a regulatory variant affecting MUC5B expression in distal airways is associated with a very large increase in risk of developing pulmonary fibrosis is a compelling early step toward this goal (12).It will also be critical to identify disease-associated changes in mucin gene expression in different regions of the lung and to understand how these affect mucus function.Recent studies show that differences in mucus composition are associated with dramatic differences in mucus organization and function.For example, MUC5B and MUC5AC are found within distinct domains of mucus plugs in fatal asthma, and the MUC5AC-rich domains play a unique role in mucostasis by tethering to the epithelium (13).In pigs, MUC5B from submucosal gland ducts formed strands composed of multiple MUC5B filaments, whereas MUC5AC emerged from superficial secretory cells as wispy threads or sheets, and it seems likely that these distinct structures contribute differently to mucociliary transport ( 14).Understanding how regional and disease-associated differences in mucins and other mucus components affect host defense and lung function is likely to be a long but rewarding journey.Okuda and colleagues have provided a map that will help us find our way.
Ketamine for sedation in acutely painful procedures in Kenya: findings after implementation of the Every Second Matters-Ketamine package
Authors: Moytrayee Guha, Sebastian Suarez, Moshood O Omotayo, Daniel I Sessler, Khama Rogo, Taha Yusufali, Thomas F Burke
Journal: The Lancet Global Health (2019)

BackgroundAdequate pain management for painful procedures improves the quality and safety of patient care and has become accepted as a basic human right. In low-resource settings, pain relief for painful procedures is scarce because of cultural, attitudinal, legal, and system-related reasons, as well as a scarcity of anaesthetists. A practice of "hold still", where patients are forcibly held down during painful procedures, remains common in Kenya and in other low-resource settings. In December, 2013, we launched the Every Second Matters-Ketamine (ESM-Ketamine) package in Kenya, for use during emergency surgery when no anaesthetist is available. Here, we aim to describe how non-anaesthetists who were trained in an ESM-Ketamine programme broadened use of their skills to provide procedural sedation for patients in need of painful procedures when an anaesthetist would not have been previously called.MethodsMedical officers, nurses, and clinical officers in Kenya undertook a 5-day ESM-Ketamine competency-based training programme for non-anaesthetists. We provided every facility in the ESM-Ketamine initiative with wall charts, checklists, and kits. Trained providers recorded patients' demographic data, pre-operative diagnoses, the procedure or procedures undertaken, medications administered, and ketamine-related adverse events. Partners Healthcare and Maseno University gave ethical approval for the programme.FindingsBetween Dec 1, 2013, and July 30, 2018, 62 ESM-Ketamine providers across 11 facilities administered ketamine to 512 patients undergoing painful procedures in non-training settings where an anaesthetist would previously not have been called. 273 patients (53·3%) were male and median age was 23 years (IQR 11–36 years). The five most common indications were: incision and drainage, debridement, or both (159 [31·1%]); fracture reduction (56 [10·9%]); circumcision (41 [8·0%]); wound repair (29 [5·7%]); and foreign body removal (26 [5·1%]). Median ketamine dose was 2·0 mg/kg (IQR 2·0 –3·0). Hallucinations or agitation treated with diazepam were reported in 45 patients [8·8%]; brief oxygen desaturation occurred in 22 (4·3%) patients. Prolonged (>30s) desaturations below 92% occurred in two patients (0·4%). The lowest desaturation was 85%. All patients recovered uneventfully. There were no deaths or injuries associated with ketamine use in the programme.InterpretationThe ESM-Ketamine package appears safe for use by trained providers in support of procedural sedation when previously an anaesthetist would not have been called. Scale-up of the ESM-Ketamine package may support the human rights imperative that every person deserves pain relief when undergoing a painful procedure.FundingNone.
The Oxygenscan: A Rapid and Reproducible Test to Determine Patient-Specific, Clinically Relevant Biomarkers of Disease Severity in Sickle Cell Anemia
Authors: Minke A.E, Rab, Celeste K Kanne, Brigitte A. van Oirschot, Jennifer F. Bos, Maite Elizabeth Houwing, Marjon H. Cnossen, Roger Schutgens, Gerard Pasterkamp, Richard van Wijk, Vivien A Sheehan, Eduard J. van Beers
Journal: Blood (2018)
Abstract 17352: Effects of Inhibition of p38 Mitogen-Activated Protein Kinase on Post-Resuscitation Myocardial Function in a Rat Model of Cardiopulmonary Resuscitation
Authors: Tianfeng Hua, Changqing Miao, Weiping Huang, Jin Yang, Hao Li, Xiaobo Wu, Jennifer Bradley, Mary Ann Peberdy, Joseph P Ornato, Wanchun Tang
Journal: Circulation (2017)

Introduction: The p38 mitogen-activated protein kinase (MAPK) is an intracellular kinase in the cardiovascular system. Activation of p38 MAPK contributes to endothelial dysfunction, increases infar...
Programming Stimuli-Responsive Behavior into Biomaterials
Authors: Barry A. Badeau, Cole A. DeForest
Journal: Annual Review of Biomedical Engineering (2019)

Stimuli-responsive materials undergo triggered changes when presented with specific environmental cues. These dynamic systems can leverage biological signals found locally within the body as well as exogenous cues administered with spatiotemporal control, providing powerful opportunities in next-generation diagnostics and personalized medicine. Here, we review the synthetic and strategic advances used to impart diverse responsiveness to a wide variety of biomaterials. Categorizing systems on the basis of material type, number of inputs, and response mechanism, we examine past and ongoing efforts toward endowing biomaterials with customizable sensitivity. We draw an analogy to computer science, whereby a stimuli-responsive biomaterial transduces a set of inputs into a functional output as governed by a user-specified logical operator. We discuss Boolean and non-Boolean operations, as well as the various chemical and physical modes of signal transduction. Finally, we examine current limitations and promising directions in the ongoing development of programmable stimuli-responsive biomaterials.
Abstract P341: Reduction of Insulin Resistance and Carotid Intima-Media Thickness in Older African American Women: A Randomized Comparison of Transcendental Meditation and Health Education
Authors: Robert Schneider, Kenneth Walton, Otelio Randall, Carolyn Gaylord-King, Charlie Harris, Sanford Nidich, Gregory Strayhorn, Maxwell Rainforth, John Salerno, Shichen Xu
Journal: Circulation (2019)

Background: High stress level is thought to be a factor in the disproportionate rates of mortality from CHD and stroke in African Americans. Stress-related CVD risk factors such as hyperglycemia, dyslipidemia, obesity, and high blood pressure tend to occur together, and their co-occurrence has been labeled the “insulin-resistance” or “metabolic” syndrome. The Transcendental Meditation (TM) program is reported to prevent or reverse effects of stress and may provide benefits complementary to lifestyle changes based on diet and exercise. Methods: A total of 200 older African American women (mean age 65.5, range 55-85 y) in Washington DC and Atlanta, GA were randomly allocated to two behavioral treatment groups—the TM program and a diet-exercise health education (HE) program. The following outcomes were tested before and after one-year: carotid intima-media thickness (CIMT), insulin resistance indicated by homeostatic model assessment (HOMA-IR), serum lipids, blood pressure, and overnight urinary cortisol excretion. Between group and within group changes were analyzed. CIMT change was compared with normative data using t-test for single means. Results: CIMT declined significantly in both the TM group [ T (1, 71) = - 2.25, p &lt; .03] and the HE group [ T (1, 63) = - 2.656, p = .03] compared to the yearly progression rate from a large normative database. In the TM group, insulin resistance indicated by HOMA-IR decreased compared to the HE group [ F (1, 138) = 4.72, p &lt; .03]. Urinary cortisol excretion (a measure of chronic stress) decreased (statistical trend, p &lt; 0.1) in each group. Conclusions: In this randomized trial, we found prevention of CIMT progression in both TM and HE groups compared to national norms. In the TM group, this may relate to the reduction in insulin resistance presented here and to the improved dyslipidemia presented previously. Both TM and HE groups tended to lower cortisol secretion, suggesting that the effects of both approaches may be due to lowered chronic stress, a probable contributor to CIMT and CVD.
Abstract P153: Depressive Symptoms and First Hospitalization for Heart Failure: Findings From the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: Yulia Khodneva, Parag Goyal, Emily Levitan, Elizabeth Jackson, Madeline Sterling, Andrea Cherrington, Raegan Durant, Monika Safford
Journal: Circulation (2019)

Introduction: Depressive symptoms are independently associated with cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke. It is unclear whether depressive symptoms are associated with first heart failure (HF) hospitalization and whether this relationship differs by ejection fraction (EF). We hypothesized that depressive symptoms are associated with increased risk of first HF hospitalization among community dwelling adults free of HF or coronary heart disease at baseline, and that this relationship would be similar by EF. Methods: We examined this relationship in the REGARDS study, a prospective longitudinal cohort of community dwelling adults aged ≥45 years (55% women, 41% black) from across the continental US, with oversampling of blacks and residents of the Southeast. Participants completed a baseline survey on medical history and health behaviors, and an in-home visit which collected physiologic parameters, blood and urine samples, ECG, and medication inventory. Participants are followed prospectively and hospital records are collected for CVD-related hospitalizations. Depressive symptoms were defined as score ≥4 on the 4-item Center for Epidemiologic Studies Depression scale (CES-D-4). HF hospitalizations were expert adjudicated and specified according to EF as preserved EF (EF &gt;40%) (HFpEF) or reduced EF (EF≤ 40%) (HFrEF). Results: Over a median [IQR] of 9.3 [6.4-11] years of follow-up, there were 614 first HF hospitalizations among 22,465 individuals (384 HFpEF, 230 HFrEF). Participants with depressive symptoms had less education and lower annual income. The age-adjusted first HF hospitalization incidence rates per 1000 person-years were 4.6 (95% CI, 3.2-4.0) for participants with depressive symptoms versus 2.6 (95% CI, 2.3-2.8) for non-depressed, p 0.0002. This elevated risk remained significant after controlling for a host CVD risk factors. When HFpEF was assessed separately, depressive symptoms were associated with increased risk of hospitalization after controlling for all covariates (hazard ratio [HR] 1.54, 95% CI 1.06-2.22). In contrast, depressive symptoms were not associated with first HFrEF hospitalization in both unadjusted and adjusted analyses. Conclusions: Depressive symptoms at baseline were independently associated with future risk of first hospitalization for HFpEF but not for HFrEF.
Psychosocial difficulties, demands for professional information about disease, and satisfaction with health care among cancer and hematological patients.
Authors: Anna Kieszkowska-Grudny, Monika Rucinska, Mateusz Szmit, Henryka Kubaj, Olga Wilk, Robert Ciesak
Journal: Journal of Clinical Oncology (2015)

e17551 Background: Most patients (pts) suffering from cancers (oncological-ONC and hematological-HMT) experience medical and psychosocial problems associated with disease and treatment. The aim of this study was to analyze psychosocial difficulties which occur during treatment and various approaching in seeking information and differences in satisfaction with healthcare taking into account type of cancer and pts age. Methods: ONC and HMT pts filled out a questionnaire prepared for this study including data: demographic, areas of perceived difficulties, needs for information and valuation of satisfaction with medical and non-medical services. The Positive and Negative Affect Schedule were completed to assess pts’ mood. Results: 219 pts were included to the study (111 ONC pts: 37-80±10,24y, mean 61, median 62 and 108 HMT pts: 20-85±17,86y, mean 55, median 59). 39 ONC and 30 HMT (32%) were over 64years. The most critical pts’ problems were: lack of possibility to work/learn (78%), limitation in daily activities (64%), fear of loss of independence and lifestyle (58%) and deterioration of financial situation (56%). In comparison with HMT, ONC pts perceived illness significantly more often (p < 0,05) as a catastrophe, but also as a challenge and exam for relatives. They felt often that their role as a partner, member of the family and employee has worsened. ONC were more concerned in receiving professional information from doctor/nurse, but being more satisfied with the information on their status received from employers/relatives. HMT had much more negative emotions than ONC. Older pts had less positive emotions, but assessed receiving information and support much better than younger, however they were less interested in active seeking in this kind of professional help. Conclusions: Depends on cancer type and age, pts need different information about their disease and various methods of support. Subjective pts’ expectations from social and healthcare system differ and should be taken into account when planning support for ONC and HMT pts.
Does tumor location affect prostate cancer prognosis?
Authors: Jun Akatsuka, Go Kimura, Kotaro Obayashi, Masayuki Sano, Masato Yanagi, Yuki Endo, Hayato Takeda, Tatsuro Hayashi, Ichiro Matsuzawa, Yasutomo Suzuki, Tsutomu Hamasaki, Yukihiro Kondo
Journal: Journal of Clinical Oncology (2019)

45 Background: Does tumor location affect prostate cancer prognosis? To clarify this question we conducted a retrospective study to characterize the incidence and prognostic significance of tumor location of prostate cancer. Methods: From 2000 to 2017, radical prostatectomy with no neoadjuvant therapy was performed in 916 cases in our hospital. Serial whole mount sections were reviewed to determine the incidence, clinicopathological features and prognostic significance of tumor location in the prostate gland. For the tumor location, we defined the subzones, which were made from subdivision of the McNeal’s zonal anatomy, are shown in Table 1 in detail. The peripheral zone (PZ) is composed of 8 subzones including A1, A2, A3 , M1, M2, M3, M4, M5. The transition zone (TZ) is composed of 5 subzones including T1, T2, T3, T4 and B1. The central zone (CZ) is composed of 3 subzones including M6, B2 and B3. Results: The median age was 67 and PSA was 8.6 ng/ml. The subzonal tumor incidence divided by all cases was the highest in A2, followed by M4, A1, M3, T2 in that order, while the lowest in B3, followed by M6, T4, T3, B1 in that order. The median follow-up time was 67 months. A 5-year PSA failure rate (5Y-PSAFR) was 23%. Among the subzones, the highest 5Y-PSAFR was seen in B3, followed by M6, B2, T4, A3, and the lowest was seen in M4, A2, T2, A1 in that order. A multivariate analysis for PSAF risk among subzones showed that B3 (HR 8.6, p &lt;0.0001) and M6 (HR 3.3, p = 0.03) were the independent high risk subzones. Conclusions: We demonstrated that the cancer incidence and prognosis varies according to the location within the prostate gland. The B3 and M6 around the ejaculatory duct showed the lowest incidence, while these locations also had the highest recurrence risk. [Table: see text]
North American clinical management guidelines for hidradenitis suppurativa: A publication from the United States and Canadian Hidradenitis Suppurativa Foundations
Authors: Ali Alikhan, Christopher Sayed, Afsaneh Alavi, Raed Alhusayen, Alain Brassard, Craig Burkhart, Karen Crowell, Daniel B. Eisen, Alice B. Gottlieb, Iltefat Hamzavi, Paul G. Hazen, Tara Jaleel, Alexa B. Kimball, Joslyn Kirby, Michelle A. Lowes, Robert Micheletti, Angela Miller, Haley B. Naik, Dennis Orgill, Yves Poulin
Journal: Journal of the American Academy of Dermatology (2019)
Abstract 008: Poor Lower Extremity Physical Function Increases Risk for Cardiovascular Disease Events in Older Women: The OPACH Study
Authors: John Bellettiere, Michael J LaMonte, Jonathan Unkart, Charles Kooperberg, Marcia L Stefanick, Chongzhi Di, Andrea Z LaCroix
Journal: Circulation (2019)

Background: Good lower extremity physical functioning is paramount to healthy aging as it prevents social isolation, enables civic engagement, and facilitates physical activity. Strong evidence links physical functioning with all-cause mortality, but little is known about its relationship to cardiovascular disease (CVD). Methods: Women (n=5043, mean age=79±7) with no history of myocardial infarction or stroke completed the Short Physical Performance Battery (SPPB) consisting of three timed tasks to assess standing balance, strength (5 chair stands), and gait (4m walk). Results were summarized using prespecified cutpoints yielding a score from 0 (worst) to 12 (best). Women were followed for CVD events for up to 6 years. Hazard ratios (HR) were estimated for women with poor, low, moderate, and high functioning (respective SPPB ranges for each group; 0-3, 4-6, 7-9, and 10-12) using Cox proportional hazard models adjusted for several covariates including accelerometer-measured moderate to vigorous physical activity (MVPA) and sedentary behavior. Effect modification of associations between SPPB and CVD by age, MVPA, Reynolds Risk Score, race-ethnicity, and self-rated health were tested by including multiplicative interaction terms in fully adjusted Cox models with statistical significance for interactions set to 0.10. Results: Covariate-adjusted HRs (95% CIs) for CVD [ 1.00 (ref.); 0.85 (0.62, 1.15); 0.69 (0.51, 0.93); 0.49 (0.35, 0.68)] and CVD mortality [ 1.00 (ref.); 0.72 (0.45, 1.15); 0.44 (0.27, 0.72); 0.35 (0.19, 0.62)] decreased across poor, low, moderate, and high SPPB subgroups, respectively (p-trend&lt;.001