tbuckley/cabot-search huggingface dataset:
Abstract 12996: Use of Premature Ventricular Extrastimuli During Supraventricular Tachycardia to Differentiate Atrioventricular Nodal Reentrant Tachycardia From Atrioventricular Reentrant Tachycardia
Authors: Hiroyuki Ito, Nitish Badhwar, Akash R Patel, Ronn E Tanel, Kurt S Hoffmayer, Cara N Pellegrini, Henry H Hsia, Vasanth Vedantham, Randall J Lee, Gregory M Marcus, Edward P Gerstenfeld, Melvin M Scheinman
Journal: Circulation (2016)

Introduction: Ventricular entrainment is useful to distinguish atrioventricular nodal reentrant tachycardia (AVNRT) from atrioventricular reentrant tachycardia (AVRT) by subtracting the ventriculoatrial (VA) interval during tachycardia from the interval between the last pacing stimulus and the last entrained atrial electrogram (SA). We tested the hypothesis whether induced right ventricular (RV) extrastimuli (V 2 ) resetting tachycardia would be equivalent or superior to ventricular entrainment to distinguish AVNRT from AVRT. Methods: Patients with either AVNRT or AVRT who underwent electrophysiological study in three institutions were investigated. The entire tachycardia cycle length (TCL) was scanned with V 2 delivered from the RV apex. SA-VA differences were calculated with V 2 clearly resetting the tachycardia even when it was delivered prior to His refractory period. The prematurity of V 2 was assessed the V 2 coupling interval (CI) divided by the TCL. Results: A total of 189 patients (age 37.0 ± 22.3 years; 104 male) were included. There were 92 AVNRT (including 5 atypical forms) and 97 AVRT including 7 AVRT with decremental accessory pathway (AP). SA-VA difference was more than 70 ms in all AVNRT and was less than 70 ms in all AVRT with right and septal AP except those with decremental AP. There was significant negative correlation between SA-VA and CI/TCL ratio in both AVNRT and AVRT without decremental AP. A SA-VA difference &lt;110 ms with CI/TCL less than 65% distinguished AVRT using left AP from AVNRT with sensitivity, specificity, positive and negative predictive values of 100%, 88%, 68%, and 100%, respectively. Ventricular entrainment resulted in tachycardia termination or AV dissociation in 31% compared with 16% using the V 2 technique (P = 0.0024). Conclusions: A SA-VA of 70 ms using the V 2 technique proved excellent for differentiation of AVNRT from AVRT using septal and right AP. There was overlap between AVNRT and AVRT with decremental AP or with left AP, but use of the V 2 technique with short CI (&lt;65% TCL) differentiated AVNRT from AVRT using left AP. This technique less frequently resulted in tachycardia termination than ventricular entrainment.
Activation of mTOR signaling and loss of negative feedback to IRS1 are early events in development of endometrial hyperplasia in Tsc2-deficient rats
Authors: Adrienne McCampbell, Cheryl Walker, Bhuvanesh Dave, Russell Broaddus
Journal: Cancer Research (2008)

3563  Progression from normal endometrium to endometrial carcinoma (EndoCa) occurs via the intermediate stage of endometrial hyperplasia (EH). We previously reported that EH in postmenopausal women is linked to overexpression of IGF-IR, loss of a negative regulator of the IGF-I pathway (PTEN), and subsequent activation of Akt and mTOR signaling (McCampbell et al., Clin Cancer Res 2006). Additionally, a transducer of IGF signaling, IRS1, is activated (as judged by tyrosine phosphorylation) in EH. The Tuberous Sclerosis (TS) complex, composed of TSC1 and TSC2, normally functions to inhibit mTOR. TSC2 is phosphorylated and inactivated by Akt phosphorylation. Heterozygozity at the TSC2 locus predisposes Eker rats to the development of uterine leiomyoma and renal carcinoma. Our objective was to determine whether deficiency of the TSC2 tumor suppressor promoted abnormal proliferation of the endometrium and whether the molecular mechanisms identified in human EH are also involved in this rat model. We examined uterine morphology microscopically, activation of the mTOR pathway component S6 (Ser235), and regulation of the IGF pathway (as judged by serine phosphorylation of IRS1 (Ser636/639) which prevents IRS1 interaction with IGF-IR) in Eker rat endometrium. Immunohistochemistry was used to precisely analyze S6 and IRS1 expression in normal and hyperplastic endometrial epithelium.  Heterozygosity at the TSC2 locus resulted in the development of EH in 100% of 16 month old Eker rats (n=10). Multiple hyperplastic foci were observed in all uteri (61 lesions/91 cross sections). Additionally, the development of hyperplastic lesions was accompanied by activation of mTOR (as judged by phosphorylation of S6) and concomitant loss of inhibitory serine phosphorylation of IRS1. Interestingly, focal areas of microscopically normal endometrial epithelium adjacent to areas of hyperplastic epithelium exhibited activation of mTOR signaling, consistent with loss of the wild-type allele of TSC2. However, the microscopically normal epithelium retained positive immunoreactivity for serine phosphorylation of IRS-1, indicative of intact negative feedback to IRS1 by the downstream mTOR effector S6K. Importantly, hyperplastic epithelium showed activation of mTOR accompanied by the absence of IRS1 serine phosphorylation, indicating that the hyperplastic lesions had lost negative feedback inhibition to IRS1.  These data support a central role for Akt/mTOR signaling in the development of both human and rat EH. Both global activation of Akt/mTOR signaling and abrogation of negative-feedback to IRS1 appear to be characteristic of hyperplasia, implicating for the first time loss of negative-feedback to IRS1 as an early event in the development of a preneoplastic lesion. We propose mTOR signaling is a good target for chemoprevention of endometrial carcinoma in high-risk women.
Comment on Itoh et al. Intensive Treat-to-Target Statin Therapy in High-Risk Japanese Patients With Hypercholesterolemia and Diabetic Retinopathy: Report of a Randomized Study. Diabetes Care 2018;41:1275–1284
Authors: Alberto Donzelli, Alessandro Schivalocchi, Giulia Giudicatti, Alessandro Battaggia
Journal: Diabetes Care (2018)

The commercially funded randomized study by Itoh et al. (1), comparing treat-to-target approaches in patients with diabetic retinopathy with hypercholesterolemia (baseline LDL cholesterol [LDL-C] ∼106 mg/dL), “found no significant decrease in CV [cardiovascular] events or CV-associated deaths with intensive therapy.” The authors speculated about a nonsignificant decrease “possibly because the between-group difference of LDL-C was lower than expected (27.7 mg/dL at 36 months of treatment).” The intensive statin therapy targeted LDL-C <70 mg/dL, while the standard one targeted 100–120 mg/dL.

The primary outcome, a composite of CV events, tended to occur less often in the intensive group: in 129 patients versus 153 in the standard group (hazard ratio [HR] 0.84, 95% CI 0.67–1.07). An exploratory finding also showed fewer cerebral events (HR 0.52, …
P3.09-06 The Link Between Tumor Promoting Fibrous Microenvironment and Immunosuppressive Microenvironment in Stage I Lung Adenocarcinoma
Authors: T. Sakai, K. Aokage, S. Neri, H. Nakamura, S. Okada, T. Miyoshi, K. Tane, M. Sugano, M. Kojima, S. Fujii, T. Kuwata, A. Ochiai, M. Tsuboi, G. Ishii
Journal: Journal of Thoracic Oncology (2018)
High response rate with T-VEC in early metastatic melanoma (stage IIIB/C-IVM1a)
Authors: V. Franke, D.M.S. Berger, W.M.C. Klop, B. van der Hiel, B.A. van de Wiel, S. Ter Meulen, M. Wouters, W. van Houdt, A.C.J. van Akkooi
Journal: Annals of Oncology (2018)
Analysis of Circulating Tumor DNA and Clinical Correlates in Patients with Esophageal, Gastroesophageal Junction, and Gastric Adenocarcinoma
Authors: Shumei Kato, Ryosuke Okamura, Joel M. Baumgartner, Hitendra Patel, Lawrence Leichman, Kaitlyn Kelly, Jason K. Sicklick, Paul T. Fanta, Scott M. Lippman, Razelle Kurzrock
Journal: Clinical Cancer Research (2018)

Esophageal, gastroesophageal junction, and gastric adenocarcinoma (herein gastroesophageal adenocarcinomas) are associated with poor prognosis and limited systemic treatment options. To further understand the genomic landscape of gastroesophageal cancers and its clinical correlations, circulating tumor DNA (ctDNA) from patients' plasma was evaluated using next-generation sequencing (NGS).We analyzed genomic alterations of 55 patients (mostly advanced disease; 9, surgically resectable) with gastroesophageal adenocarcinomas using clinical-grade NGS performed on plasma-derived ctDNA (54-73 gene panel). The test detects single-nucleotide variants, as well as copy number amplifications, fusions, and indels in selected genes.Seventy-six percent of patients (42/55) had ≥1 genomic alteration [including variants of unknown significance (VUS)] and 69.1% (38/55) had ≥1 characterized alteration (excluding VUSs). The median number of alterations per patient was 2 (range, 0-15). TP53 (50.9%, 28/55), PIK3CA (16.4%, 9/55), ERBB2 (14.5%, 8/55), and KRAS (14.5%, 8/55) genes were most frequently affected characterized alterations. Thirty-one patients also had tissue NGS. Concordance between tissue and ctDNA ranged from 61.3% (TP53 alterations) to 87.1% (KRAS alterations). ERBB2 alterations were significantly associated with poor overall survival (HR, 14.06; 95% confidence interval, 2.44-81.03; P = 0.003 multivariate analysis). Among patients with ≥1 alteration, no 2 patients had identical molecular portfolios. All patients with ≥1 characterized alteration had theoretically targetable alterations by an FDA-approved agent (on- or off-label). Illustrative case treated with cognate agent is presented.Evaluation of ctDNA by NGS among patients with gastroesophageal adenocarcinoma is feasible. Patients harbored heterogeneous patterns of genomics, with most having alterations that are potentially pharmacologically tractable.
Receipt of Overlapping Opioid and Benzodiazepine Prescriptions Among Veterans Dually Enrolled in Medicare Part D and the Department of Veterans Affairs
Authors: Ron Carico, Xinhua Zhao, Carolyn T. Thorpe, Joshua M. Thorpe, Florentina E. Sileanu, John P. Cashy, Jennifer A. Hale, Maria K. Mor, Thomas R. Radomski, Leslie R.M. Hausmann, Julie M. Donohue, Katie J. Suda, Kevin Stroupe, Joseph T. Hanlon, Chester B. Good, Michael J. Fine, Walid F. Gellad
Journal: Annals of Internal Medicine (2018)

Background: Overlapping use of opioids and benzodiazepines is associated with increased risk for overdose. Veterans receiving medications concurrently from the U.S. Department of Veterans Affairs (VA) and Medicare may be at higher risk for such overlap. Objective: To assess the association between dual use of VA and Medicare drug benefits and receipt of overlapping opioid and benzodiazepine prescriptions. Design: Cross-sectional. Setting: VA and Medicare. Participants: All veterans enrolled in VA and Medicare Part D who filled at least 2 opioid prescriptions in 2013 (n = 368 891). Measurements: Outcomes were the proportion of patients with a Pharmacy Quality Alliance (PQA) measure of opioid–benzodiazepine overlap (≥2 filled prescriptions for benzodiazepines with ≥30 days of overlap with opioids) and the proportion of patients with high-dose opioid–benzodiazepine overlap (≥30 days of overlap with a daily opioid dose >120 morphine milligram equivalents). Augmented inverse probability weighting regression was used to compare these measures by prescription drug source: VA only, Medicare only, or VA and Medicare (dual use). Results: Of 368 891 eligible veterans, 18.3% received prescriptions from the VA only, 30.3% from Medicare only, and 51.4% from both VA and Medicare. The proportion with PQA opioid–benzodiazepine overlap was larger for the dual-use group than the VA-only group (23.1% vs. 17.3%; adjusted risk ratio [aRR], 1.27 [95% CI, 1.24 to 1.30]) and Medicare-only group (23.1% vs. 16.5%; aRR, 1.12 [CI, 1.10 to 1.14]). The proportion with high-dose overlap was also larger for the dual-use group than the VA-only group (4.7% vs. 2.3%; aRR, 2.23 [CI, 2.10 to 2.36]) and Medicare-only group (4.7% vs. 2.9%; aRR, 1.06 [CI, 1.02 to 1.11]). Limitation: Data are from 2013 and cannot capture medications purchased without insurance; unmeasured confounding may remain in this cross-sectional study. Conclusion: Among a national cohort of veterans dually enrolled in VA and Medicare, receiving prescriptions from both sources was associated with greater risk for receiving potentially unsafe overlapping prescriptions for opioids and benzodiazepines. Primary Funding Source: U.S. Department of Veterans Affairs.
DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway
Authors: Liana Adam, F. Anthony San Lucas, Richard Fowler, Yao Yu, Wenhui Wu, Yulun Liu, Huamin Wang, David Menter, Michael T. Tetzlaff, Joe Ensor, Ganiraju Manyam, Stefan T. Arold, Chad Huff, Scott Kopetz, Paul Scheet, Michael J. Overman
Journal: Clinical Cancer Research (2018)

Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease.Experimental Design: Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations. Two SBA models with ERBB2 kinase activating mutations were tested for sensitivity to anti-ERBB2 agents in vivo and in vitro. Biochemical changes were measured by reverse-phase protein arrays.WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. Although APC mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%. ERBB2 mutations and amplifications were present in 23% of samples. Patients with alterations in the ERBB2 signaling cascade (64%) demonstrated worse clinical outcomes (median survival 70.3 months vs. 109 months; log-rank HR = 2.4, P = 0.03). Two ERBB2-mutated (V842I and Y803H) cell lines were generated from SBA patient samples. Both demonstrated high sensitivity to ERBB2 inhibitor dacomitinib (IC50 < 2.5 nmol/L). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, whereas it had no effect in an SBA wild-type ERBB2 model.The in vitro and in vivo models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating ERBB2 mutations in patients with SBA that harbor these alterations.
Measuring and Improving the Value of Hospital Care
Authors: Peter W. Groeneveld
Journal: JAMA Network Open (2018)

Nihar R. Desai, MD, MPH; Lesli S. Ott, MA; Elizabeth J. George, MPH; Xiao Xu, PhD; Nancy Kim, MD, PhD; Shengfan Zhou, MS; Angela Hsieh, PhD; Sudhakar V. Nuti, BA; Zhenqiu Lin, PhD; Susannah M. Bernheim, MD, MHS; Harlan M. Krumholz, MD, SM
A composite liquid biomarker for non-invasive diagnosis of resectable pancreatic ductal adenocarcinoma
Authors: A.W. Berger, T.J. Ettrich, D. Schwerdel, A. Reinacher-Schick, H. Algül, A.-O. König, E. Gallmeier, K. Wille, S. Daum, M. Geissler, A. Tannapfel, W. Uhl, T. Seufferlein
Journal: Annals of Oncology (2018)
Optimal interval from preceding radiotherapy (RT) to enhance efficacy of immune check point inhibitors (ICIs): Consecutive analysis of 294 patients with non-small cell lung cancer (NSCLC)
Authors: H. Horinouchi, Y. Matsumoto, S. Murakami, Y. Goto, S. Kanda, Y. Fujiwara, N. Yamamoto, Y. Nakayama, Y. Ohe
Journal: Annals of Oncology (2018)
Benzodiazepine Use and Long-Term Mortality in Real-Life Chronic Heart Failure Outpatients: A Cohort Analysis
Authors: Crisanto Diez-Quevedo, Josep Lupon, Marta de Antonio, Mar Domingo, Marta Martin-Subero, Teresa Rangil, Pedro Moliner, Elisabet Zamora, Salvador Altimir, Javier Santesmases, Maria Isabel Troya, Maria Boldo, Joan de Pablo, Antoni Bayes-Genis
Journal: Psychotherapy and Psychosomatics (2018)
A phase III study of INCB054828 as adjuvant therapy in patients (pts) with high-risk urothelial carcinoma (UC) harboring fibroblast growth factor receptor 3 (FGFR3) genomic alterations
Authors: A. Necchi, J.L. Pérez-Gracia, Y. Loriot, W. Witjes, F. Montorsi, A. Bjartell, S.F. Shariat
Journal: Annals of Oncology (2018)
Parsing Hippocampal Theta Oscillations by Nested Spectral Components during Spatial Exploration and Memory-Guided Behavior
Authors: Vítor Lopes-dos-Santos, Gido M. van de Ven, Alexander Morley, Stéphanie Trouche, Natalia Campo-Urriza, David Dupret
Journal: Neuron (2018)

Theta oscillations reflect rhythmic inputs that continuously converge to the hippocampus during exploratory and memory-guided behavior. The theta-nested operations that organize hippocampal spiking could either occur regularly from one cycle to the next or be tuned on a cycle-by-cycle basis. To resolve this, we identified spectral components nested in individual theta cycles recorded from the mouse CA1 hippocampus. Our single-cycle profiling revealed theta spectral components associated with different firing modulations and distinguishable ensembles of principal cells. Moreover, novel co-firing patterns of principal cells in theta cycles nesting mid-gamma oscillations were the most strongly reactivated in subsequent offline sharp-wave/ripple events. Finally, theta-nested spectral components were differentially altered by behavioral stages of a memory task; the 80-Hz mid-gamma component was strengthened during learning, whereas the 22-Hz beta, 35-Hz slow gamma, and 54-Hz mid-gamma components increased during retrieval. We conclude that cycle-to-cycle variability of theta-nested spectral components allows parsing of theta oscillations into transient operating modes with complementary mnemonic roles.
Abstract 12738: Elevated Sympathetic Activity, Impaired Endothelial Function, and Late Hypertension After Repair of Coarctation of the Aorta
Authors: Melissa G Lee, Jonathan P Mynard, Elisabeth Lambert, Michael M Cheung, Gavin Lambert, Yves d’Udekem
Journal: Circulation (2016)

Introduction: There is a high prevalence of hypertension late after repair of coarctation of the aorta but its exact mechanism is unknown. Elevated sympathetic tone may contribute to the development of late hypertension. This study aims to investigate the neural profile of coarctation patients including the use of muscle sympathetic nerve activity (MSNA) testing, a direct method of measuring sympathetic activity. Methods: Twenty-three patients aged ≥18 years with a coarctation repair underwent transthoracic echocardiography (TTE) and measurements of resting and 24-hour ambulatory blood pressures (BP), MSNA, sympathetic and cardiac baroreflex functions, digital endothelial function, and pulse wave velocity (PWV). Median age at repair was 1.2 months (interquartile range: 0-9 months). Patients were compared to 18 healthy controls matched for age, gender, weight, and waist/hip circumference ratio. Results: After a follow-up of 26 ± 5 years, 6% (1/18) and 44% (8/18) had clinic resting hypertension and prehypertension, respectively. On 24-hour BP monitoring, 15% (3/20) and 20% (4/20) had hypertension and prehypertension, respectively. Left ventricular hypertrophy on TTE was present in 43% (6/14), and was more prevalent in patients with prehypertension/hypertension on 24-hour BP monitoring compared to those with normal 24-hour BP (75% [3/4] vs. 30% [3/10], p=0.2). Coarctation patients had elevated MSNA compared with controls (50 ± 25 vs. 29 ± 14 bursts/100 heartbeats, p=0.01), decreased sympathetic baroreflex function (-2.2 ± 2.1 vs. -7.0 ± 5.6 bursts/100 heartbeats·mmHg -1 , p=0.007), normal cardiac baroreflex function (41.9 ± 30.4 vs. 35.7 ± 21.1 ms·mmHg -1 , p=0.6), decreased endothelial function (pulse amplitude tonometry ratio: 0.4 ± 0.3 vs. 0.8 ± 0.5, p=0.004), and normal PWV (5.8 ± 1.1 vs. 5.5 ± 0.4 m/s, p=0.7). Conclusions: After coarctation repair patients have increased MSNA, impaired sympathetic baroreflex response, and impaired endothelial function, all of which may contribute to the development of late hypertension. Agents targeting sympathetic activity and endothelial function may be the ideal antihypertensive therapies after coarctation repair. Regular monitoring for late hypertension after coarctation repair is warranted.
Primary systemic amyloidosis in patients with Waldenström macroglobulinemia
Authors: Saurabh Zanwar, Jithma P. Abeykoon, Stephen M. Ansell, Morie A. Gertz, Angela Dispenzieri, Eli Muchtar, Surbhi Sidana, Nidhi Tandon, S. Vincent Rajkumar, David Dingli, Ronald Go, Martha Q. Lacy, Taxiarchis Kourelis, Thomas E. Witzig, David Inwards, Francis Buadi, Wilson Gonsalves, Thomas Habermann, Patrick Johnston, Grzegorz Nowakowski, Robert A. Kyle, Shaji Kumar, Prashant Kapoor
Journal: Leukemia (2018)
Nested PCR for diagnosing scabies infestation
Authors: J.E. Hahm, C.W. Kim, S.S. Kim
Journal: British Journal of Dermatology (2018)

Scabies is a highly contagious, very itchy infestation on the skin of mites called Sarcoptes scabiei. Although it is more prevalent in developing countries, outbreaks in elderly care facilities are a growing problem for developed countries. Mineral oil examination, which involves gently scraping the patient's skin with mineral oil, transferring scales to a glass slide, and then identifying the mites or eggs with a microscope, is regarded as the gold standard in diagnosing scabies, but it is not always accurate. This study, from South Korea, aimed to enhance the accuracy of laboratory diagnosis of scabies. The authors tested a different way of detecting scabies, called nested polymerase chain reaction (PCR) and compared nested PCR results with those of conventional diagnostic method, to see which is more accurate. Nested PCR is a way of making many copies of a specific DNA region in a test tube, making it possible to look for DNA from the mites that cause scabies. Clinically suspected scabies patients underwent mineral oil examination. The diagnosis was positive for scabies when mites or eggs were found under the microscope, and patients were then designated as ‘microscopy‐positive’. Patients in the ‘microscopy‐negative’ group presented with negative microscopic results, meaning that mites or eggs had not been seen under a microscope. Skin scrapings were collected from both groups for PCR. Of the total 63 samples, 28 were microscopy‐positive and 35 were negative. All microscopically proven scabies cases were positive with nested PCR. Among microscopy‐negative ones, S. scabiei DNA was detected in 9 samples. This means that in 9 of the 35 cases where mites or eggs were not found under a microscope using the normal testing method, mites' DNA was indeed found using nested PCR. If sensitivity (accuracy) of nested PCR is considered 100%, then sensitivity of microscopy is 75.68%. Therefore, nested PCR can be successfully used as an alternative method for diagnosing suspected scabies cases. Furthermore, infection‐control measures and treatments can be initiated before it spreads too widely, minimizing the risk of outbreaks.