tbuckley/cabot-search huggingface dataset:
The Adrenal Gland as a Sanctuary Site of Metastases After Pembrolizumab Treatment: A Case Series
Authors: Michelle C. Nguyen, Manisha H. Shah, David A. Liebner, Floor J. Backes, John Phay, Lawrence A. Shirley
Journal: Journal of the National Comprehensive Cancer Network (2018)

Therapeutic agents targeting the PD-1/PD-L1 axis have shown durable clinical responses in patients with various cancer types. Although objective responses are common, intrapatient heterogeneous responses have been described, and the mechanism for the different organ responses remains unknown. We present a series of patients in whom a lack of response was noted solely in the adrenal glands. This is the first case series describing 3 patients with heterogeneous patterns of response to pembrolizumab with progression of adrenal metastatic disease despite objective response (complete or partial response) in all other sites of metastatic disease. Two patients, one with melanoma and one with uterine carcinosarcoma, underwent robotic adrenalectomy for enlarging adrenal metastases. An additional patient with melanoma underwent laparotomy with attempted resection, but infiltration of the adrenal tumor into the inferior vena cava prohibited safe excision. This report provides additional insight into the heterogeneous patterns of disease response to anti–PD-1 therapy, highlighting the adrenal gland as a potential sanctuary site for this immunotherapy. These cases display the potential benefit of early surgical resection in this scenario and the pitfalls of delaying referral to a surgeon for assessment of operative intervention.
The pro-metastasis effect of circANKS1B in breast cancer
Authors: Kaixuan Zeng, Bangshun He, Burton B. Yang, Tao Xu, Xiaoxiang Chen, Mu Xu, Xiangxiang Liu, Huiling Sun, Yuqin Pan, Shukui Wang
Journal: Molecular Cancer (2018)

Recent studies indicate that circular RNA (circRNA) plays a pivotal role in cancer progression. Here, we sought to investigate its role in breast cancer. CircANKS1B (a circRNA originated from exons 5 to 8 of the ANKS1B gene, hsa_circ_0007294) was identified by RNA-sequencing and validated by qRT-PCR and Sanger sequencing. Clinical breast cancer samples were used to evaluate the expression of circANKS1B and its associations with clinicopathological features and prognosis. Gain- and loss-of-function experiments in cell lines and mouse xenograft models were performed to support clinical findings and elucidate the function and underlying mechanisms of circANKS1B in breast cancer. CircANKS1B was significantly up-regulated in triple-negative breast cancer (TNBC) compared with non-TNBC tissues and cell lines. Increased circANKS1B expression was closely associated with lymph node metastasis and advanced clinical stage and served as an independent risk factor for overall survival of breast cancer patients. Functional studies revealed that circANKS1B promoted breast cancer invasion and metastasis both in vitro and in vivo by inducing epithelial-to-mesenchymal transition (EMT), while had no effect on breast cancer growth. Mechanistically, circANKS1B abundantly sponged miR-148a-3p and miR-152-3p to increase the expression of transcription factor USF1, which could transcriptionally up-regulate TGF-β1 expression, resulting in activating TGF-β1/Smad signaling to promote EMT. Moreover, we found that circANKS1B biogenesis in breast cancer was promoted by splicing factor ESRP1, whose expression was also regulated by USF1. Our data uncover an essential role of the novel circular RNA circANKS1B in the metastasis of breast cancer, which demonstrate that therapeutic targeting of circANKS1B may better prevent breast cancer metastasis.
GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts
Authors: Rosalie M. Sterner, Reona Sakemura, Michelle J. Cox, Nan Yang, Roman H. Khadka, Cynthia L. Forsman, Michael J. Hansen, Fang Jin, Katayoun Ayasoufi, Mehrdad Hefazi, Kendall J. Schick, Denise K. Walters, Omar Ahmed, Dale Chappell, Tarek Sahmoud, Cameron Durrant, Wendy K. Nevala, Mrinal M. Patnaik, Larry R. Pease, Karen E. Hedin, Neil E. Kay, Aaron J. Johnson, Saad S. Kenderian
Journal: Blood (2018)
Rating of perceived challenge as a measure of internal load for technical skill performance
Authors: Sharief Hendricks, Kevin Till, Jon L Oliver, Rich D Johnston, Matthew J Attwood, James Craig Brown, David Drake, Simon MacLeod, Stephen D Mellalieu, Ben Jones
Journal: British Journal of Sports Medicine (2018)

Whether we are developing young athletes, designing injury prevention programmes, preparing high-level athletes for competition or rehabilitating an athlete back to sport, the technical skill performance of the athlete(s) needs to be considered. Usually, technical skill performance is captured by training time (minutes), training frequency (number of sessions) or movement repetitions.1 However, this approach is limited by only assessing the external workload of the technical skill. Beyond the external workload, the athlete’s physiological and psychological response to the load can also be assessed (termed internal load).1 One commonly used internal load measurement is the rating of perceived exertion (RPE)—a 0–10 or 0–100 category ratio rating scale where the lower end represents rest and the upper end maximal effort. Typically, the RPE scale is used to capture the athlete’s global perceived experience of the physical work load. From a skill perspective however, this method provides little insight into the perceived technical demands of the movement(s). Weston and colleagues recognised this limitation and asked athletes to provide an RPE for the technical demand of matches and training (RPE-T).2 3 RPE scales, however, are proposed as general intensity scales.4 This characteristic, arguably, can be considered as both an advantage (can be used for various applications) or a disadvantage if …
Спектр жирних кислот сироватки крові пацієнтів із хронічними дифузними захворюваннями печінки залежно від етіології та морфологічних особливостей
Authors: Yu.M. Stepanov, V.I. Didenko, I.A. Klenina, V.A. Karachinova, N.Yu. Oshmianska
Journal: GASTROENTEROLOGY (2018)

У статті подано морфологічні особливості (за даними гістологічних методів дослідження, методу напівтонких зрізів та комп’ютерної морфометрії) розвитку та прогресування хронічних дифузних захворювань печінки, хронічного гепатиту, асоційованого з вірусом С, та алкогольної хвороби печінки. Показано, що залежно від етіологічного фактора важлива відмінність була виявлена за характером, ступенем стеатозу та локалізацією ліпідних крапель, що свідчить про розбіжність деяких біохімічних механізмів накопичення ліпідів у гепатоцитах. Розглянуто роль вільних жирних кислот сироватки крові при даних захворюваннях, виявлено підвищення їх вмісту у сироватці крові, встановлено дефіцит деяких фракцій, що може бути однією з причин формування неалкогольної жирової хвороби печінки та інших захворювань, пов’язаних з обміном речовин. Маркером запальних процесів можна вважати ленолеву (С18:3) й арахідонову (С20:0) вільні жирні кислоти. Запропоновано індекси співвідношення жирних кислот, що дозволяють охарактеризувати та встановити метаболічні шляхи розвитку та прогресування захворювання, що відіграє важливу роль у диференційованому підході при встановленні нозологічних форм захворювань печінки.
Developing a Mobile Application for Global Cardiovascular Education
Authors: Samit Bhatheja, Valentin Fuster, Surbhi Chamaria, Sarthak Kakkar, Rivelle Zlatopolsky, Jason Rogers, Emamuzo Otobo, Ashish Atreja, Samin K. Sharma, Annapoorna S. Kini
Journal: Journal of the American College of Cardiology (2018)
Cardiac CaV1.2 channels require β subunits for β-adrenergic–mediated modulation but not trafficking
Authors: Lin Yang, Alexander Katchman, Jared Kushner, Alexander Kushnir, Sergey I. Zakharov, Bi-xing Chen, Zunaira Shuja, Prakash Subramanyam, Guoxia Liu, Arianne Papa, Daniel Roybal, Geoffrey S. Pitt, Henry M. Colecraft, Steven O. Marx
Journal: Journal of Clinical Investigation (2018)

Ca2+ channel β-subunit interactions with pore-forming α-subunits are long-thought to be obligatory for channel trafficking to the cell surface and for tuning of basal biophysical properties in many tissues. Unexpectedly, we demonstrate that transgenic expression of mutant α1C subunits lacking capacity to bind CaVβ can traffic to the sarcolemma in adult cardiomyocytes in vivo and sustain normal excitation-contraction coupling. However, these β-less Ca2+ channels cannot be stimulated by β-adrenergic pathway agonists, and thus adrenergic augmentation of contractility is markedly impaired in isolated cardiomyocytes and in hearts. Similarly, viral-mediated expression of a β-subunit–sequestering peptide sharply curtailed β-adrenergic stimulation of WT Ca2+ channels, identifying an approach to specifically modulate β-adrenergic regulation of cardiac contractility. Our data demonstrate that β subunits are required for β-adrenergic regulation of CaV1.2 channels and positive inotropy in the heart, but are dispensable for CaV1.2 trafficking to the adult cardiomyocyte cell surface, and for basal function and excitation-contraction coupling.
OP0074 Association between brain-derived neurotrophic factor gene polymorphisms and fibromyalgia in a korean population: a multi-centre study
Authors: J.-H. Kang, K.-E. Lee, D.-J. Park, S.-H. Kim, S.-S. Nah, J.H. Lee, S.-K. Kim, Y.-A. Lee, S.-J. Hong, H.-S. Kim, H.-S. Lee, H.A. Kim, C.-I. Joung, S.-H. Kim, S.-S. Lee
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of fibromyalgia (FM) and studies have found that FM patients have altered serum and plasma BDNF levels. However, it is not known whether polymorphisms of the <i>BDNF</i> gene are associated with FM. In this study, we explored the association between polymorphisms of the <i>BDNF</i> gene with FM susceptibility and the severity of symptoms. <h3>Methods</h3> The study enrolled 409 patients with FM and 423 controls from 10 medical centres that participated in the Korean nationwide FM survey study. Alleles at 10 positions in the <i>BDNF</i> gene were genotyped: rs2883187 (C&gt;T), rs7103873 (G&gt;C), rs7103411(C&gt;T), rs10835210 (C&gt;A), rs11030104 (A&gt;G), rs12273539 (C&gt;T), rs11030102(C&gt;G), rs11030101 (A&gt;T), rs6265 (G&gt;A), and rs7124442(C&gt;T). <h3>Results</h3> The allele and genotype frequencies of <i>BDNF</i> rs11030104 differed significantly between the FM patients and controls (p=0.031). The GG genotype of rs11030104 had a protective role against FM (p=0.016) and the G allele of rs11030104 was negatively associated with the presence of FM compared with the A allele (p=0.013). In comparison, although the allele and genotype frequencies of <i>BDNF</i> rs12273539 did not differ between the FM patients and controls, the TT genotype of <i>BDNF</i> rs12273539 was associated with susceptibility to FM (p=0.038). Haplotype analyses suggested that some <i>BDNF</i> haplotypes have a protective role against FM. Finally, we found that that some genotypes and haplotypes of the <i>BDNF</i> gene contribute to the specific symptoms of FM. <h3>Conclusions</h3> This study is the first to evaluate the associations of <i>BDNF</i> gene polymorphisms with FM. Our results suggest that some <i>BDNF</i> single-nucleotide polymorphisms and haplotypes are associated with susceptibility to, and contribute to the symptoms of, FM. <h3>Disclosure of Interest</h3> None declared
NHS announces major overhaul of national cancer screening programmes in England
Authors: Gareth Iacobucci
Journal: BMJ (2018)

National cancer screening programmes in England are to undergo a major overhaul as part of the NHS’s upcoming long term plan.

A review led by the government’s former cancer tsar Mike Richards will focus on how to increase early detection by using advances in technology and new approaches to selecting people for screening.

Richards said, “There is no doubt that the screening programmes in England save …
Characterization of Novel Subtypes in B Progenitor Acute Lymphoblastic Leukemia
Authors: Zhaohui Gu, Michelle L. Churchman, Kathryn G. Roberts, Ian Moore, Xin Zhou, Joy Nakitandwe, Kohei Hagiwara, Stephane Pelletier, Sebastian Gingras, Hartmut Berns, Debbie Payne-Turner, Ashley Hill, Ilaria Iacobucci, Lei Shi, Stanley Pounds, Cheng Cheng, Deqing Pei, Chunxu Qu, Meenakshi Devidas, Yunfeng Dai, Shalini C. Reshmi, Julie Gastier Foster, Elizabeth A. Raetz, Michael J. Borowitz, Brent Wood, William L. Carroll, Patrick Zweider McKay, Karen R. Rabin, Leonard A. Mattano, Kelly W. Maloney, Alessandro Rambaldi, Orietta Spinelli, Jerald Radich, Mark D. Minden, Jacob M. Rowe, Selina Luger, Mark R. Litzow, Martin S. Tallman, Janis Recevskis, Yanming Zhang, Ravi Bhatia, Jessica Kohlschmidt, Krzysztof Mrózek, Clara D. Bloomfield, Wendy Stock, Steven M. Kornblau, Hagop M. Kantarjian, Marina Y. Konopleva, William E. Evans, Sima Jeha, Ching-Hon Pui, Jun J. Yang, Elisabeth M. Paietta, James R. Downing, Mary V Relling, Jinghui Zhang, Mignon L. Loh, Stephen P. Hunger, Charles G. Mullighan
Journal: Blood (2018)
Gastrointestinal hemorrhage caused by the direct invasion of a hepatocellular carcinoma successfully treated with polyglycolic acid sheet shielding
Authors: Tomohiko Mannami, Nobukiyo Fujiwara, Genyo Ikeda, Takahito Mishima, Taiga Kuroi, Takayuki Muraoka, Yasuyuki Ohtawa
Journal: Endoscopy (2018)

A 76-year-old man with a history of alcoholic liver cirrhosis presented with a 4-day history of melena. He had been diagnosed 30 months previously with hepatocellular carcinoma (HCC), but chose to not receive further evaluation or treatment. Laboratory findings revealed severe anemia (hemoglobin 4.9 g/dL) and liver dysfunction. A computed tomography (CT) scan demonstrated an enlarged HCC mass (10-cm diameter) located in the left lobe of the liver, compressing the stomach ([Fig. 1]). Esophagogastroduodenoscopy (EGD) detected a submucosal tumor with central ulceration in the lesser curvature of the stomach ([Fig. 2]).
Abstract P370: Association of Coronary Calcium on Non-gated 6mm Chest CT with Mortality
Authors: Arturo Dominguez, Matthew Allison, Christina L Wassel, Dena Rifkin, Cindy Morgan, Michael Wright, Michael Criqui, Joachim Ix
Journal: Circulation (2013)

Background: Coronary artery calcification (CAC) predicts cardiovascular disease (CVD), but imaging to measure CAC is not covered by most insurance providers. Standard 6mm non-gated chest computed tomography (CT) is commonly performed for other clinical indications. Our objective was to compare the association between CAC scores on 3mm ECG gated cardiac CT to standard 6mm non-gated chest CT with risk of death. Methods: Between 2000-03, 4,544 community-living individuals self-referred for “whole body” CT scans had both a 3mm gated cardiac CT and 6mm non-gated chest CT and were followed for mortality through 2009. In this nested case-control study, we selected 173 cases who died, and age and gender frequency matched controls. CAC was scored by the Agatston method on both scans. Unconditional logistic regression determined odds of mortality. Results: The mean age was 68 years and 37% (257 of 691) were women. Spearman correlation of CAC scores between 6mm non-gated chest CT and 3mm gated cardiac CT was 0.79 (p 300 compared to the 3mm gated cardiac CTs. Compared to those without CAC, those with CAC &gt;300 on 6mm non-gated CT scans were at 2.8-fold greater odds of mortality, while those with CAC &gt;300 on 3mm gated CT scans had 1.8-fold greater odds in adjusted models (Table). As a continuous predictor (per 1SD higher Ln[CAC+1]), each SD higher CAC score had 1.50-fold (95% CI 1.20, 1.88) greater odds of death on 6mm chest CT and 1.27 (1.04, 1.55) on 3mm cardiac CT. Conclusions: CAC scores on non-gated 6mm chest CT are strongly correlated with 3mm gated cardiac CT and provide similar information about mortality risk. If confirmed, the many chest CTs done for other clinical purposes may provide valuable information on CVD risk.
Duration of Pediatric Clinical Trials Submitted to the US Food and Drug Administration
Authors: Kanecia O. Zimmerman, P. Brian Smith, Ann W. McMahon, Jean Temeck, Debbie Avant, Dianne Murphy, Susan McCune
Journal: JAMA Pediatrics (2018)

<h3>Importance</h3> The increasing prevalence of pediatric chronic disease has resulted in increased exposure to long-term drug therapy in children. The duration of recently completed drug trials that support approval for drug therapy in children with chronic diseases has not been systematically evaluated. Such information is a vital first step in forming safety pharmacovigilance strategies for drugs used for long-term therapy in children. <h3>Objective</h3> To characterize the duration of clinical trials submitted to the US Food and Drug Administration (FDA) for pediatric drug approvals, with a focus on drugs used for long-term therapy. <h3>Design and Setting</h3> A review was performed of all safety and efficacy clinical trials conducted under the Best Pharmaceuticals for Children Act or the Pediatric Research Equity Act and submitted to the FDA from September 1, 2007, to December 31, 2014, to support the approval of drugs frequently used for long-term therapy in children. Statistical analysis was performed from July 1, 2015, to December 31, 2017. <h3>Main Outcomes and Measures</h3> Maximum duration of trials submitted to support FDA approval of drugs for children. <h3>Results</h3> A total of 306 trials supporting 86 drugs intended for long-term use in children were eligible for the primary analysis. The drugs most commonly evaluated were for treatment of neurologic (25 [29%]), pulmonary (16 [19%]), and anti-infective (14 [16%]) indications. The median maximum trial duration by drug was 44 weeks (minimum, 1.1 week; maximum, 364 weeks). For nearly two-thirds of the drugs (52 [61%]), the maximum trial duration was less than 52 weeks. For 10 of the drugs (12%), the maximum trial duration was 3 years or more. Maximum duration of trials did not vary by therapeutic category, minimum age of enrollment, calendar year, or legislative mandate. <h3>Conclusions and Relevance</h3> Pediatric clinical trials designed to sufficiently investigate drug safety and efficacy to support FDA approval are of relatively limited duration. Given the potential long-term exposure of patients to these drugs, the clinical community should consider whether new approaches are needed to better understand the safety associated with long-term use of these drugs.
Tumor-infiltrating lymphocytes and pathologic complete response among the patients with HER2 positive breast cancer receiving neoadjuvant docetaxel, carboplatin, trastuzumab and pertuzumab (TCHP): Single center experience
Authors: J. Ha, J.E. Kim, J.H. Jeong, J.-H. Ahn, K.H. Jung, H.J. Lee, G. Gong, E.Y. Chae, H.H. Kim, I.Y. Chung, B.S. Ko, S.-B. Kim
Journal: Annals of Oncology (2018)
Histologic similarities in children with eosinophilic esophagitis and proton pump inhibitor–responsive esophageal eosinophilia
Authors: Nathalie Nguyen, Anna Baumgarten, Benjamin L. Wright, Kelley E. Capocelli, Zhaoxing Pan, James J. Lee, Glenn T. Furuta, Joanne C. Masterson
Journal: Journal of Allergy and Clinical Immunology (2018)
Coronary Physiology Beyond Coronary Flow Reserve in Microvascular Angina
Authors: K. Lance Gould, Nils P. Johnson
Journal: Journal of the American College of Cardiology (2018)

Angina with no angiographic stenosis, commonly called “microvascular angina,” encompasses a wide continuum of coronary pathophysiology in conflicting published reports. Comprehensive quantitative myocardial perfusion offers new insights beyond overly simplistic coronary flow reserve. Integrating regional absolute stress flow, relative stress flow, coronary flow reserve, and qualitative subendocardial perfusion gradient on tomograms of relative images, provides correct diagnosis, quantitative physiological classification, and potential treatment. Angina without angiographic stenosis is associated with abnormal quantitative perfusion with rare, but instructive, exceptions. However, microvascular dysfunction without angina is common, particularly associated with risk factors. Reduced subendocardial/epicardial relative activity is common with diffuse coronary artery disease without focal stenosis with or without angina depending on the severity of reduced subendocardial perfusion. Precision quantitative myocardial perfusion in 5,900 cases objectively classifies angina with no angiographic stenosis into 4 categories: subendocardial ischemia due to diffuse coronary artery disease (most common), overlooked stenosis, diffuse microvascular dysfunction due to risk factors or specific microvasculopathies, and nonischemic cardiac pain mechanisms (rare), or some mix of these prototypes, of which 95% associate with risk factors, or subclinical or clinically manifest coronary atherosclerosis needing vigorous risk factor treatment.
M7824 (MSB0011359C), a bifunctional fusion protein targeting transforming growth factor β (TGF-β) and PD-L1, in Asian patients with pretreated biliary tract cancer (BTC): Efficacy by BTC subtype
Authors: C. Yoo, D.-Y. Oh, H.J. Choi, M. Kudo, M. Ueno, S. Kondo, L.-T. Chen, M. Osada, C. Helwig, I. Dussault, M. Ikeda
Journal: Annals of Oncology (2018)
NICE responds to surgical mesh article
Authors: Gillian Leng, Kevin Harris
Journal: BMJ (2018)

The life changing complications that affect some women after vaginal mesh procedures should prompt us all to reflect on how the health system should monitor and respond to potential harms from any intervention, medicine, or device.

The National Institute for Health and Care Excellence first made recommendations about the use of mesh in its interventional procedures guidance in 2005.1 This was cautious advice with …
TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy
Authors: Deepika Sharma, Ankit Malik, Clifford Guy, Peter Vogel, Thirumala-Devi Kanneganti
Journal: Journal of Clinical Investigation (2018)

Pyrin is an inflammasome sensor that promotes caspase-1–mediated pyroptotic cell death and maturation of proinflammatory cytokines IL-1β and IL-18. Familial Mediterranean fever (FMF), an autoinflammatory disorder, is associated with mutations in the gene encoding pyrin (MEFV). FMF-knockin (FMF-KI) mice that express chimeric pyrin protein with FMF mutation (MefvV726A/V726A) exhibit an autoinflammatory disorder mediated by autoactivation of the pyrin inflammasome. Increase in the levels of TNF are observed in FMF-KI mice, and many features of FMF overlap with the autoinflammatory disorder associated with TNF receptor signaling. In this study, we assessed the contribution of TNF signaling to pyrin inflammasome activation and its consequent role in distinct FMF pathologies. TNF signaling promoted the expression of pyrin in response to multiple stimuli and was required for inflammasome activation in response to canonical pyrin stimuli and in myeloid cells from FMF-KI mice. TNF signaling promoted systemic wasting, anemia, and neutrophilia in the FMF-KI mice. Further, TNF-induced pathology was induced specifically through the TNFR1 receptor, while TNFR2-mediated signaling was distinctly protective in colitis and ankle joint inflammation. Overall, our data show that TNF is a critical modulator of pyrin expression, inflammasome activation, and pyrin-inflammasomopathy. Further, specific blockade of TNFR1 or activation of TNFR2 could provide substantial protection against FMF pathologies.