tbuckley/cabot-search huggingface dataset:
Transbronchial cryobiopsy increases diagnostic confidence in interstitial lung disease: a prospective multicentre trial
Authors: Jürgen Hetzel, Athol U. Wells, Ulrich Costabel, Thomas V. Colby, Simon L.F. Walsh, Johny Verschakelen, Alberto Cavazza, Sara Tomassetti, Claudia Ravaglia, Michael Böckeler, Werner Spengler, Michael Kreuter, Ralf Eberhardt, Kaid Darwiche, Alfons Torrego, Virginia Pajares, Rainer Muche, Regina Musterle, Marius Horger, Falko Fend, Arne Warth, Claus Peter Heußel, Sara Piciucchi, Alessandra Dubini, Dirk Theegarten, Tomas Franquet, Enrique Lerma, Venerino Poletti, Maik Häntschel
Journal: European Respiratory Journal (2020)

The accurate diagnosis of individual interstitial lung diseases (ILD) is often challenging, but is a critical determinant of appropriate management. If a diagnosis cannot be made after multidisciplinary team discussion (MDTD), surgical lung biopsy is the current recommended tissue sampling technique according to the most recent guidelines. Transbronchial lung cryobiopsy (TBLC) has been proposed as an alternative to surgical lung biopsy.This prospective, multicentre, international study analysed the impact of TBLC on the diagnostic assessment of 128 patients with suspected idiopathic interstitial pneumonia by a central MDTD board (two clinicians, two radiologists, two pathologists). The level of confidence for the first-choice diagnoses were evaluated in four steps, as follows: 1) clinicoradiological data alone; 2) addition of bronchoalveolar lavage (BAL) findings; 3) addition of TBLC interpretation; and 4) surgical lung biopsy findings (if available). We evaluated the contribution of TBLC to the formulation of a confident first-choice MDTD diagnosis.TBLC led to a significant increase in the percentage of cases with confident diagnoses or provisional diagnoses with high confidence (likelihood ≥70%) from 60.2% to 81.2%. In 32 out of 52 patients nondiagnostic after BAL, TBLC provided a diagnosis with a likelihood ≥70%. The percentage of confident diagnoses (likelihood ≥90%) increased from 22.7% after BAL to 53.9% after TBLC. Pneumothoraces occurred in 16.4% of patients, and moderate or severe bleeding in 15.7% of patients. No deaths were observed within 30 days.TBLC increases diagnostic confidence in the majority of ILD patients with an uncertain noninvasive diagnosis, with manageable side-effects. These data support the integration of TBLC into the diagnostic algorithm for ILD.
The microtubule stabilizing agent discodermolide is also a powerful inducer of accelerated senescence
Authors: Laura E. Klein, Scott Freeze, Amos B. Smith, Susan B. Horwitz
Journal: Cancer Research (2004)

5608  Discodermolide, a small molecule isolated from a Caribbean sponge, inhibits cell growth, blocks cells in mitosis and stabilizes microtubules, as does Taxol. Presently in Phase I clinical trials, the drug has a greater aqueous solubility than Taxol, making it a poor substrate for P-glycoprotein. Since Taxol-resistant cell lines that do not express P-glycoprotein demonstrated no cross resistance to discodermolide, we wanted to explore differences between the mechanisms of action of these two agents. While attempting to isolate discodermolide resistant A549 non-small cell lung carcinoma cells, we found a single clone that proliferated in 8nM of the drug. Any further increase in the concentration resulted in a senescence phenotype, including a β-galactosidase activity that was functional at pH 6.0. After six days of growth the following was observed: 1) the senescence effects produced by discodermolide more closely resembled those of the powerful senescence inducing, DNA damaging agent doxorubicin, than of Taxol; and 2) the occurrence of both mitotic catastrophe (aberrant mitosis) and apoptosis resembled that produced by comparable concentrations of Taxol. These three mechanisms of growth inhibition are not mutually exclusive, as all combinations were observed with discodermolide. Senescence markers investigated include characteristic changes in the expression and activity of proteins involved in such diverse functions as tumor suppression, mitogenic signaling, and cell cycle and mitotic checkpoint regulation. The observed increase in levels of proteins, such as cyclin D-CDK4 and PCNA, that can sequester cyclin dependent kinase inhibitors, suggests mechanisms that allow the resistant clone to survive in 8nM discodermolide, and reasons why the cells cannot grow in higher concentrations of drug. Our findings provide interesting initial insights into this potentially important new anticancer agents mechanism of action, explaining previously reported observations that are difficult to understand within the realm of microtubule stabilization. One example is that despite discodermolides significantly enhanced affinity, in vitro, for the same or overlapping binding site used by Taxol, and its more impressive bundling of microtubules in cells at comparable concentrations to that of Taxol, the drug was found, by the methods used to assess cell proliferation, to be a less potent inhibitor of cell growth than Taxol. Another unexplained observation from our laboratory is the synergy observed between Taxol and discodermolide in cell growth inhibition. Our results also explain some of the difficulties encountered in isolating cell lines resistant to discodermolide. This is the first report of a microtubule stabilizing agent with a repertoire of tumor cell growth inhibitory mechanisms that includes a powerful induction of senescence.
Sleep disturbance in adults with chronic pruritic dermatoses is associated with increased C-reactive protein levels
Authors: Sagar P. Patel, Raveena Khanna, Justin Choi, Kyle A. Williams, Youkyung S. Roh, Michael S. Hong, Nishadh H. Sutaria, Thomas Pritchard, Madan M. Kwatra, Shawn G. Kwatra
Journal: Journal of the American Academy of Dermatology (2020)
Clinical course and factors associated with outcomes among 1904 patients hospitalized with COVID-19 in Germany: an observational study
Authors: Irit Nachtigall, Pavlina Lenga, Katarzyna Jóźwiak, Petra Thürmann, Andreas Meier-Hellmann, Ralf Kuhlen, Joerg Brederlau, Torsten Bauer, Juergen Tebbenjohanns, Karin Schwegmann, Michael Hauptmann, Julius Dengler
Journal: Clinical Microbiology and Infection (2020)

ObjectivesIn Germany the coronavirus disease 2019 (COVID-19) pandemic situation is unique among large European countries in that incidence and case fatality rate are distinctly lower. We describe the clinical course and examine factors associated with outcomes among patients hospitalized with COVID-19 in Germany.MethodsIn this retrospective cohort study we included patients with COVID-19 admitted to a national network of German hospitals between February 12 and June 12, 2020. We examined demographic characteristics, comorbidities and clinical outcomes.ResultsWe included 1904 patients with a median age of 73 years, 48.5% (924/1904) of whom were female. The mortality rate was 17% (317/1835; 95% confidence interval (95%CI) 16–19), the rate of admission to the intensive care unit (ICU) was 21% (399/1860; 95%CI 20–23), and the rate of invasive mechanical ventilation was 14% (250/1850: 95%CI 12–15). The most prominent risk factors for death were male sex (hazard ratio (HR) 1.45; 95%CI 1.15–1.83), pre-existing lung disease (HR 1.61; 95%CI 1.20–2.16), and increased patient age (HR 4.11 (95%CI 2.57–6.58) for age >79 years versus <60 years). Among patients admitted to the ICU, the mortality rate was 29% (109/374; 95%CI 25–34) and higher in ventilated (33% [77/235; 95%CI 27–39]) than in non-ventilated ICU patients (23%, 32/139; 95%CI 16–30; p < 0.05).ConclusionsIn this nationwide series of patients hospitalized with COVID-19 in Germany, in-hospital and ICU mortality rates were substantial. The most prominent risk factors for death were male sex, pre-existing lung disease, and greater patient age.
Cap is lifted on medical school places in England
Authors: Abi Rimmer
Journal: BMJ (2020)

The government has announced that it will lift the cap on the number of medical school places in England after changes to A level assessments resulted in successful candidates left without courses.

Earlier this month, education secretary Gavin Williamson announced that students in England would receive the A level grades that they had been predicted to achieve by their teachers, rather than those previously awarded to them which were based on an algorithm.1

Following this announcement, medical bodies lobbied the government to remove the cap on medical school places—which was set at approximately 7500 in England and 9500 in the UK—so that more eligible students could train to become doctors.

On 20 August, the government said that it would lift the cap on places and …
Challenging detection of hard-to-find gastric cancers with artificial intelligence-assisted endoscopy
Authors: Daisuke Murakami, Masayuki Yamato, Yuji Amano, Tomohiro Tada
Journal: Gut (2020)

We read with interest the article by van der Sommen et al ,1 and assert some important and relevant points of adopting artificial intelligence (AI)-assisted endoscopy in clinical practice. Computer-aided diagnosis systems have successfully applied to all segments of the GI tract, even the diagnosis of dysplasia in Barrett’s oesophagus which is the bane of expert endoscopists.2 Recently, colonoscopy with real-time computer-aided detection (CADe) systems achieved higher polyp detection as compared with the performance of expert endoscopists.3 However, in adopting CADe to conventional oesophagogastroduodenoscopy (OGD), related discussions for improving the detection of hard-to-find gastric cancers (GC) are inevitable.

The stomach has a wider, bent lumen, implicating more laborious gastric observations without a blind spot, compared with other GI tract anatomical features such as the oesophagus and colon. In routine OGD, the endoscopists have to distinguish gastric neoplasms from surrounding gastritis mucosa at more distant view, as opposed to detection of colorectal neoplasms and Barrett-related dysplasia by near-view images. In addition, early GCs usually show subtle elevation or depression and their irregular appearances easily hide in the coarse background gastritis caused by Helicobacter pylori infection. Therefore, it is sometimes difficult even for experts to discover early GCs, particularly smaller sizes. …
Abstract 12399: Increased Urinary Liver-Type Fatty Acid-Binding Protein Level Predicts Major Adverse Cardiovascular Events in Hypertensive Patients
Authors: Yousaku Okubo, Yukiko Nakano, Sho Okamura, Naoya Hironobe, Michitaka Amioka, Chikaaki Motoda, Takehito Tokuyama, Yasuki Kihara
Journal: Circulation (2018)

Introduction: Urinary liver-type fatty acid-binding protein (L-FABP) is known as a potential biomarker for acute kidney injury. Its predictive value for cardiovascular mortality has even been sugge...
Nlrp3 Inflammasome-Primed Neutrophils Amplify Granulopoiesis Following Myocardial Injury
Authors: Prabhakara R Nagareddy, Gopalkrishna Sreejit, Baskaran Athmanathan, Ashish Dhyani, Rahul Annabathula, Susan S Smyth, Enzo Porrello, Ahmed Abdel-Latif, Andrew J Murphy
Journal: Circulation (2018)
Venoarterial extracorporeal membrane oxygenation to rescue sepsis-induced cardiogenic shock: a retrospective, multicentre, international cohort study
Authors: Nicolas Bréchot, David Hajage, Antoine Kimmoun, Julien Demiselle, Cara Agerstrand, Santiago Montero, Matthieu Schmidt, Charles-Edouard Luyt, Guillaume Lebreton, Guillaume Hékimian, Erwan Flecher, Elie Zogheib, Bruno Levy, Arthur S Slutsky, Daniel Brodie, Pierre Asfar, Alain Combes
Journal: The Lancet (2020)
Teaching Hospitals
Authors: John K. Iglehart
Journal: New England Journal of Medicine (1993)

Teaching hospitals, which developed in response to changes in medical education in the early 20th century, have three missions that are critical to the maintenance of clinical excellence: graduate medical education, clinical and basic research, and the provision of a spectrum of patient care. The revenues that fund these interrelated activities derive largely from the care of patients and -- to a lesser extent -- grants, but they are dispersed in a complex web of cross-subsidies. Now, however, as managed-care plans proliferate and competition in prices becomes the watchword of reform, the commitment of third-party payers to finance the expensive . . .
Sex Differences in Compositional Plaque Volume Progression in Patients With Coronary Artery Disease
Authors: Sang-Eun Lee, Ji Min Sung, Daniele Andreini, Mouaz H. Al-Mallah, Matthew J. Budoff, Filippo Cademartiri, Kavitha Chinnaiyan, Jung Hyun Choi, Eun Ju Chun, Edoardo Conte, Ilan Gottlieb, Martin Hadamitzky, Yong Jin Kim, Byoung Kwon Lee, Jonathon A. Leipsic, Erica Maffei, Hugo Marques, Pedro de Araújo Gonçalves, Gianluca Pontone, Sanghoon Shin, Peter H. Stone, Habib Samady, Renu Virmani, Jagat Narula, Daniel S. Berman, Leslee J. Shaw, Jeroen J. Bax, Fay Y. Lin, James K. Min, Hyuk-Jae Chang
Journal: JACC. Cardiovascular imaging (2020)
Opioid Use Disorder and Overdose in Older Adults With Breast, Colorectal, or Prostate Cancer
Authors: Andrew W Roberts, Samantha Eiffert, Elizabeth M Wulff-Burchfield, Stacie B Dusetzina, Devon K Check
Journal: JNCI Journal of the National Cancer Institute (2020)

Despite high rates of opioid therapy, evidence about the risk of preventable opioid harms among cancer survivors is underdeveloped. Our objective was to estimate the odds of opioid use disorder (OUD) and overdose following breast, colorectal, or prostate cancer diagnosis among Medicare beneficiaries.We conducted a retrospective cohort study using 2007-2014 Surveillance, Epidemiology, and End Results-Medicare data for cancer survivors with a first cancer diagnosis of stage 0-III breast, colorectal, or prostate cancer at age 66-89 years between 2008 and 2013. Cancer survivors were matched to up to 2 noncancer controls on age, sex, and Surveillance, Epidemiology, and End Results region. Using Firth logistic regression, we estimated adjusted 1-year odds of OUD or nonfatal opioid overdose associated with a cancer diagnosis. We also estimated adjusted odds of OUD and overdose separately and by cancer stage, prior opioid use, and follow-up time.Among 69 889 cancer survivors and 125 007 controls, the unadjusted rates of OUD or nonfatal overdose were 25.2, 27.1, 38.9, and 12.4 events per 10 000 patients in the noncancer, breast, colorectal, and prostate samples, respectively. There was no association between cancer and OUD. Colorectal survivors had 2.3 times higher odds of opioid overdose compared with matched controls (adjusted odds ratio = 2.33, 95% confidence interval = 1.49 to 3.67). Additionally, overdose risk was greater in those with more advanced disease, no prior opioid use, and preexisting mental health conditions.Opioid overdose was a rare, but statistically significant, outcome following stage II-III colorectal cancer diagnosis, particularly among previously opioid-naïve patients. These patients may require heightened screening and intervention to prevent inadvertent adverse opioid harms.
ECG-Gated Cardiac FDG PET Acquisitions Significantly Improve Detectability of Infective Endocarditis
Authors: Caroline Boursier, Xavier Duval, Aurélie Bourdon, Laetitia Imbert, Besma Mahida, Elodie Chevalier, Marine Claudin, Bruno Hoen, François Goehringer, Christine Selton-Suty, Véronique Roch, Zohra Lamiral, Olivier Humbert, François Rouzet, Pierre-Yves Marie
Journal: JACC. Cardiovascular imaging (2020)
Epigenomic technologies for precision oncology
Authors: Dieter Weichenhan, Daniel B. Lipka, Pavlo Lutsik, Ashish Goyal, Christoph Plass
Journal: Seminars in Cancer Biology (2020)

Epigenetic patterns in a cell control the expression of genes and consequently determine the phenotype of a cell. Cancer cells possess altered epigenomes which include aberrant patterns of DNA methylation, histone tail modifications, nucleosome positioning and of the three-dimensional chromatin organization within a nucleus. These altered epigenetic patterns are potential useful biomarkers to detect cancer cells and to classify tumor types. In addition, the cancer epigenome dictates the response of a cancer cell to therapeutic intervention and, therefore its knowledge, will allow to predict response to different therapeutic approaches. Here we review the current state-of-the-art technologies that have been developed to decipher epigenetic patterns on the genomic level and discuss how these methods are potentially useful for precision oncology.
Abstract 5678: Novel glucocorticoid receptor degrading bifunctional molecules as therapeutics in castration-resistant prostate cancer
Authors: James T. Link, Nicholas Blazanin, Yonathan Lissanu Deribe
Journal: Cancer Research (2020)

Abstract While the majority of men with prostate cancer will experience modest morbidity, advanced castration-resistant prostate cancer (CRPC) remains a devastating disease with significant mortality and limited treatment options. Recently approved anti-androgen therapies such as enzalutamide have shown promising clinical responses. Unfortunately, patients frequently develop resistance to these therapies. Signaling through the glucocorticoid receptor (GR) has emerged as a primary mechanism of resistance to enzalutamide in CRPC suggesting that GR is an attractive therapeutic target. However, existing small molecule antagonists of GR suffer from partial agonist activity leading to activation of a subset of GR target genes which limits their anti-tumor efficacy. To overcome this problem, we have developed bifunctional small molecules or proteolysis targeting chimeras (PROTACs) that induce potent and specific degradation of GR. Using iterative structure-activity relationship (SAR) studies, we have developed a novel chemical linker that imparted superior properties to PROTACs. These novel GR PROTACs induce profound degradation of GR. Using proteomic analysis and quantification of more than 8000 proteins, we show that our GR PROTAC is highly selective for GR. GR PROTACs inhibited proliferation of enzalutamide-resistant prostate cancer cells, have favorable pharmacokinetic properties and are active in vivo. Importantly, GR PROTACs work synergistically with enzalutamide to inhibit growth of prostate cancer xenografts in a castration-resistant mouse model of prostate cancer. Mechanistically, we identified improved suppression of AR and GR target genes in the combination of GR PROTAC and enzalutamide. More importantly, the combination was able to suppress crucial developmental pathways implicated in prostate cancer resistance to therapy and tumor dormancy. Our novel GR PROTACs highlight the power of targeted protein degradation to deliver excellent chemical probes and potentially impactful cancer therapeutics. Citation Format: James T. Link, Nicholas Blazanin, Yonathan Lissanu Deribe. Novel glucocorticoid receptor degrading bifunctional molecules as therapeutics in castration-resistant prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5678.
The Public Health Standard in Action—Analysis of the US Food and Drug Administration’s IQOS Review
Authors: Micah L. Berman, Allison M. Glasser
Journal: JAMA Oncology (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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Abstract 6408: E3<i>scan</i>™ ligand binding assay platform for targeted protein degradation and PROTAC discovery
Authors: Ksenya Cohen Katsenelson, Luis Gonzalez, Gabriel Pallares, Alastair J. King, Daniel K. Treiber
Journal: Cancer Research (2020)

Abstract E3 ligases have emerged as pivotal targets for a next generation protein degradation-based drug discovery paradigm. This new paradigm includes both ligand binding-directed “reprogramming” of E3 substrate specificity approaches and a more directed approach, using small molecule proteolysis-targeting chimeras (PROTACs), to selectively degrade disease-driving proteins. As there are hundreds of diverse putative E3 ligases with differentiated tissue expression, this new paradigm may well define a next dimension of precision medicine defined by an axis of tissue-specific activity. While there have been some early successes, the E3 drug discovery field has a significant unmet need for a standardized biochemical ligand binding assay platform. A platform is required that: 1) Can measure ligand binding across the E3 family using a standardized method enabling “apples to apples” comparisons; 2), Is highly scalable and rapid; 3) Has an exquisite dynamic range for the measurement of accurate KD values as low as digit picomolar (pM). Eurofins DiscoverX herein presents its novel E3scan™ technology that addresses each of these unmet needs. E3scan, based upon well-established KINOMEscan® technology, has been successfully applied to diverse E3 ligases, including CRBN, VHL, MDM2, MDMX, cIAP1, cIAP2, and XIAP, with many other E3 assays in progress. We shall present assay validation data for these targets, including data for ligands with KD values in the low to mid pM range. In conclusion, we present Eurofins DiscoverX's novel E3scan platform that shall enable accelerated screening and SAR analysis in the E3 drug discovery field, with rapid turnaround times for discovery library screens (20 business day TAT) and weekly SAR (5 business day TAT) and the largest assay panel available on a single technology platform. Citation Format: Ksenya Cohen Katsenelson, Luis Gonzalez, Gabriel Pallares, Alastair J. King, Daniel K. Treiber. E3scan™ ligand binding assay platform for targeted protein degradation and PROTAC discovery [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6408.
Alteration of brain dopamine and serotonin levels in cocaine users: a preliminary report
Authors: K Y Little, U N Patel, T B Clark, J D Butts
Journal: American Journal of Psychiatry (1996)

This study tested the hypothesis that cocaine depletes dopamine levels in the brain.Levels of dopamine, serotonin, and their metabolites in the frontal cortex and striatum of nine cocaine users and nine matched control subjects who had never used cocaine were determined from postmortem autopsy material.The cocaine users had significantly lower dopamine levels and higher serotonin levels in the frontal cortex than the control subjects. Levels in other brain areas did not differ between the two groups.Alterations of dopamine and serotonin levels might contribute to symptoms of cocaine withdrawal and craving.