tbuckley/cabot-search huggingface dataset:
PRIMA-1 induces apoptosis in p53 mutant breast cancer cell lines by inhibiting the JNK cell survival pathway and promoting the activation of proapoptotic p53 targets Bax and PUMA
Authors: Tao Wang, Kyunghee Lee, Abdur Rehman, Yves Pommier, Sayed S. Daoud
Journal: Cancer Research (2006)

3051  The p53 protein plays a major role in the maintenance of genome stability in mammalian cells. Mutations of p53 occur in over 40% of breast cancers and are indicative of tumor resistant to chemotherapeutic agents. Recently, there has been a high degree of interest in pharmacological approaches to restore the normal function to mutant p53. The compound p53-dependent reactivation and induction of massive apoptosis (PRIMA-1) has been shown to induce cytotoxic effects and apoptosis in human tumor cells. We reported (Breast Cancer Res. 7: R765-774, 2005) that PRIMA-1 restores the p53-hsp90α interaction, enhances the translocation of this complex to the nucleus and reactivates p53 transcriptional activity in breast cancer cells. Here we studied the molecular mechanisms of apoptosis in breast cancer cells (MDA-231 and GI-101A) with various types of p53 mutations as compared to MCF-7 with wild-type p53 after treatment with PRIMA-1. We show that PRIMA-1 selectively induces apoptosis in MDA-231 and GI-101A compared to MCF-7 breast cancer cells as measured by the Annexin V assays. This effect was paralleled by an increase in the total levels of p53 and the induction of its phosphorylation at Ser15 as detected by Western blot analysis with the Odyssey™Infrared Imaging System. Using a chromatin immunoprecipitation (ChIP) assay, we show that PRIMA-1 restored the p53 DNA binding activity to the promoters of proapoptotic genes such as PUMA and Bax, but inhibited the binding activity to the promoters of the anti-apoptotic MAP4K4 gene. Hence, our data indicate that PRIMA-1 induces apoptosis in p53 mutant breast cancer cells by promoting the activation of proapoptotic signaling pathways and inhibiting the JNK cell survival pathway. (Supported by Susan G. Komen Breast Cancer Foundation grant BCTR0402398)
Identifying Crohn’s disease signal from variome analysis
Authors: Yanran Wang, Maximilian Miller, Yuri Astrakhan, Britt-Sabina Petersen, Stefan Schreiber, Andre Franke, Yana Bromberg
Journal: Genome Medicine (2019)

Abstract Background After years of concentrated research efforts, the exact cause of Crohn’s disease (CD) remains unknown. Its accurate diagnosis, however, helps in management and preventing the onset of disease. Genome-wide association studies have identified 241 CD loci, but these carry small log odds ratios and are thus diagnostically uninformative. Methods Here, we describe a machine learning method—AVA,Dx (Analysis of Variation for Association with Disease)—that uses exonic variants from whole exome or genome sequencing data to extract CD signal and predict CD status. Using the person-specific coding variation in genes from a panel of only 111 individuals, we built disease-prediction models informative of previously undiscovered disease genes. By additionally accounting for batch effects, we were able to accurately predict CD status for thousands of previously unseen individuals from other panels. Results AVA,Dx highlighted known CD genes including NOD2 and new potential CD genes. AVA,Dx identified 16% (at strict cutoff) of CD patients at 99% precision and 58% of the patients (at default cutoff) with 82% precision in over 3000 individuals from separately sequenced panels. Conclusions Larger training panels and additional features, including other types of genetic variants and environmental factors, e.g., human-associated microbiota, may improve model performance. However, the results presented here already position AVA,Dx as both an effective method for revealing pathogenesis pathways and as a CD risk analysis tool, which can improve clinical diagnostic time and accuracy. Links to the AVA,Dx Docker image and the BitBucket source code are at https://bromberglab.org/project/avadx/ .
Evaluating Pembrolizumab Interference with Monoclonal Protein Detection By Immunofixation and By MALDI-TOF Mass Spectrometry (MASS-FIX)
Authors: Taxiarchis Kourelis, David L. Murray, Angela Dispenzieri, Jody L. Frinack, Melea D. Hetrick, Maria Alice V. Willrich
Journal: Blood (2017)
TCT-635 Combined and Independent Impact of Diabetes Mellitus and Elevated C-Reactive Protein Levels on Risk for Death and MI Following PCI: Insights From a Large Single-Center Registry
Authors: Usman Baber, Roxana Mehran, Karthik Seetharam, Jason Kovacic, Asaad Khan, Joseph Sweeny, Parasuram Melarcode-Krishnamoorthy, Yuliya Vengrenyuk, George Dangas, Samin Sharma, Annapoorna Kini
Journal: Journal of the American College of Cardiology (2019)
TCT-673 Retrograde Chronic Total Occlusion Percutaneous Coronary Interventions via Saphenous Vein Grafts
Authors: Iosif Xenogiannis, Fotios Gkargkoulas, Dimitrios Karmpaliotis, Oleg Krestyaninov, Dmitrii Khelimskii, Farouc Amin Jaffer, Jaikirshan Khatri, David Kandzari, R. Michael Wyman, Anthony Doing, Catalin Toma, Robert Yeh, Hector Tamez, James Choi, Wissam Jaber, Habib Samady, Abdul Sheikh, Srini Potluri, Mitul Patel, Ehtisham Mahmud, Basem Elbaruni, Ioannis Tsiafoutis, Brian Jefferson, Taral Patel, Barry Uretsky, Jeffrey W. Moses, Nicholas Lembo, Manish Parikh, Ajay Jayant Kirtane, Ziad Ali, Michael Megaly, Evangelia Vemmou, Ilias Nikolakopoulos, Bavana Rangan, Pamela Morley, Bassel Bou Dargham, Shuaib Abdullah, Santiago Garcia, Subhash Banerjee, Emmanouil Brilakis, Khaldoon Alaswad
Journal: Journal of the American College of Cardiology (2019)
TCT-589 Role of the Position of the Pressure Guidewire Sensor Distal to the Coronary Artery Stenosis on Fractional Flow Reserve Measurements
Authors: Karl Isaaz, Sarah Balichard, Antoine Gerbay, Benjamain Haber, Gael Bouchou, Jérémy Terreaux, Alexis Cerisier, Antoine Da Costa
Journal: Journal of the American College of Cardiology (2019)
TCT-634 Trend Analysis of In-Hospital Outcomes for Patients With Chronic Total Coronary Occlusion With Diabetes Undergoing PCI vs. CABG
Authors: Birendra Amgai, Dhrubajyoti Bandyopadhyay, Sandipan Chakraborty, Neelkumar Patel, Soniya Koirala, Aneeta Kumari, Adrija Hajra, Vivek Amit Modi, Vardhmaan Jain, Raktim Ghosh, Wilbert Aronow, Eyal Herzog
Journal: Journal of the American College of Cardiology (2019)
Trends in Aggregate Use and Associated Expenditures of Antihyperglycemic Therapies Among US Medicare Beneficiaries Between 2012 and 2017
Authors: Andrew Sumarsono, Brendan M. Everett, Darren K. McGuire, Gregg C. Fonarow, Javed Butler, Ambarish Pandey, Muthiah Vaduganathan
Journal: JAMA Internal Medicine (2019)

A survey of internal medicine residents about their professional preferences, their perceptions of cardiology, and how these attitudes combine to inform career choices showed substantial sex differences. 5More women than men reported never considering cardiology, and women had different perceptions of cardiology than men.Women cardiologists are more likely than men to experience sex and parenting discrimination, be single, not have children, and report less satisfaction in family life, though overall career satisfaction remains high for both men and women. 6 A limitation of our study is the use of publicly available data that were aggregated with no individual identifiers.From 1991 to 2016, there have been increases in the percentage of women in 9 medical subspecialties but substantial differences between specialties remain.As compared with the other 8 subspecialties, cardiology had the lowest percentage of women, which is an important issue that the cardiology profession should continue to address.
The cancer-associated variants of DNA polymerase beta have impaired dRP lyase activity and show differences in sensitivity to chemotherapeutic drugs.
Authors: Shibani Dalal, Anna Chikova, Joachim Jaeger, Joann Sweasy
Journal: Cancer Research (2008)

5774  The purpose of this study is to determine if we can exploit the impaired activity of cancer-associated variants of DNA polymerase beta (pol β) in the use of chemotherapeutic drugs. Approximately 30% of human tumors characterized to date express pol β variant proteins. Pol β, a well-studied base excision repair protein, has two inherent catalytic activities, polymerase activity and dRP lyase activity. In our lab, we have previously shown that two of the pol β cancer-associated variants are polymerase active but act as sequence-specific mutators, and one of them binds to DNA but has no polymerase activity.  In our recent study, we have chosen two variants that map within the 8kD amino terminal domain of pol β. This domain catalyzes the removal of deoxyribose phosphate during short patch base excision repair. The Leu22Pro (L22P) and Tyr39Cys (Y39C) pol β variants were identified in a gastric carcinoma. The L22P cancer-associated pol β variant has very little dRP lyase activity but retains its polymerase activity. The L22P variant has reduced DNA binding affinity and is deficient in base excision repair. Molecular dynamics simulations suggest that alteration of Leu22 to Pro changes the local packing, and this in turn affects the shape of the binding pocket that is required for efficient dRP lyase catalysis. The Y39C pol β variant also has reduced dRP lyase activity compared to wild type (WT). Our in vivo data confirm that while expression of WT pol β in Pol β-deleted Mouse Embryonic Fibroblasts (MEFs) increases resistance to the alkylating agent, MMS, expression of cancer-associated dRP lyase deficient L22P and Y39C variants results in sensitivity, suggesting a loss of base excision repair activity in vivo. .  The chemotherapeutic drugs Cisplatin and Ara-C induce DNA damage in the cell. It has been shown in vitro that pol β effectively bypasses Cisplatin adducts and can incorporate the cytosine analog Ara-C into DNA. Therefore, we explored the possible influence of the expression of cancer associated dRP lyase deficient variants of pol β on cellular sensitivity to Cisplatin and Ara-C. Expression of L22P increases the sensitivity of cells to Cisplatin and Ara-C. Interestingly, the Y39C variant showed no differences compared to WT. We are now in the process of characterizing the drug sensitivity of several of the other pol β cancer- associated variants. Our initial findings suggest that the presence of different variants of pol β can result in differential sensitivity to cancer drugs. This indicates that repair deficiencies of tumors cells may be able to be exploited during chemotherapy.
Efficacy of Dexrazoxane in Preventing Anthracycline Cardiotoxicity in Breast Cancer
Authors: Ariane V.S. Macedo, Ludhmila A. Hajjar, Alexander R. Lyon, Bruno R. Nascimento, Alessandro Putzu, Lorenzo Rossi, Rafael B. Costa, Giovanni Landoni, Angélica Nogueira-Rodrigues, Antonio L.P. Ribeiro
Journal: JACC CardioOncology (2019)

The authors performed a systematic review and meta-analysis of randomized and nonrandomized trials on the efficacy of dexrazoxane in patients with breast cancer who were treated with anthracyclines with or without trastuzumab.Breast cancer treatment with anthracyclines and trastuzumab is associated with an increased risk of cardiotoxicity. Among the various strategies to reduce the risk of cardiotoxicity, dexrazoxane is an option for primary prevention, but it is seldom used in clinical practice.Online databases were searched from January 1990 up to March 1, 2019, for clinical trials on the use of dexrazoxane for the prevention of cardiotoxicity in patients with breast cancer receiving anthracyclines with or without trastuzumab. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model meta-analysis.Seven randomized trials and 2 retrospective trials with a total of 2,177 patients were included. Dexrazoxane reduced the risk of clinical heart failure (RR: 0.19; 95% CI: 0.09 to 0.40; p < 0.001) and cardiac events (RR: 0.36; 95% CI: 0.27 to 0.49; p < 0.001) irrespective of previous exposure to anthracyclines. The rate of a partial or complete oncological response, overall survival, and progression-free survival were not affected by dexrazoxane.Dexrazoxane reduced the risk of clinical heart failure and cardiac events in patients with breast cancer undergoing anthracycline chemotherapy with or without trastuzumab and did not significantly impact cancer outcomes. However, the quality of available evidence is low, and further randomized trials are warranted before the systematic implementation of this therapy in clinical practice.
TCT-231 Prognosis of Percutaneous Coronary Intervention Versus Optimal Medical Therapy in the Treatment of Chronic Total Coronary Occlusion: A Systematic Review and Meta-Analysis
Authors: Wasawat Vutthikraivit, Mohamed Elmassry, Pattara Rattanawong, Jakrin Kewcharoen, Natthapon Angsubhakorn, Saif El Nawaa, M Rubayat Rahman, Pablo Paz, Barbara Mantilla, Scott Shurmur, Mohammad Mehdi Ansari
Journal: Journal of the American College of Cardiology (2019)
Is Matt Hancock right to take credit for falling death rates?
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Earlier this month England’s health and social care secretary, Matt Hancock, tweeted about some “terrific news”—death rates were at their lowest level since records began, which he claimed was the result of record investment in the NHS and government policies.1

As part of its new Fact Check series The BMJ looks at the accuracy of the claim.

Hancock’s tweet linked to Office for National Statistics quarterly data on mortality in England for April to June 2019.2 He wrote, “Terrific news: UK mortality rates down to their lowest level since records began. Yet more evidence that our record NHS investment, prevention agenda and NHS long term plan are yielding real results for people’s health across the country.”

In April to June this year the age standardised mortality was 886 deaths per 100 000 population, which ONS said was statistically significantly lower than in the second quarter in …
TCT-412 Comparative Safety and Efficacy of Second-Generation P2Y12 Inhibitors Versus Clopidogrel in Combination With Oral Anticoagulation in Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis
Authors: Shaun Giancaterino, Florentino Lupercio, Pedro Villablanca, Frederick Han, Kurt Hoffmayer, Gordon Ho, Farshad Raissi, David Krummen, Ulrika Birgersdotter-Green, Gregory Feld, Ryan Reeves, Ehtisham Mahmud, Jonathan Hsu
Journal: Journal of the American College of Cardiology (2019)
Reply to: Magneto is ineffective in controlling electrical properties of cerebellar Purkinje cells, Assessing the utility of Magneto to control neuronal excitability in the somatosensory cortex and Revaluation of magnetic properties of Magneto
Authors: Michael A. Wheeler, Christopher D. Deppmann, Manoj K. Patel, Ali D. Güler
Journal: Nature Neuroscience (2019)
European drug agency approves cannabis-based medicine for severe forms of epilepsy
Authors: Jacqui Wise
Journal: BMJ (2019)

The European Medicines Agency (EMA) has approved the first cannabis based medicine to treat two rare and severe forms of childhood onset epilepsy, although hurdles remain before the drug becomes available on the NHS.

In August the National Institute for Health and Care Excellence (NICE) published draft guidance saying that on the current evidence it could not recommend cannabidiol as an effective use of NHS resources.1 However, it said it was working with the manufacturer GW Pharmaceuticals to tackle the problems highlighted by its independent appraisal committee. The committee is to meet on 26 September to consider the comments received during the public consultation and further draft guidance will be given three …
Delirium tremens in a nine-year-old child
Authors: D Sherwin, B Mead
Journal: American Journal of Psychiatry (1975)

The authors report a case of delirium tremens in a 9-year-old American Indian boy, who was later found to have been drinking steadily for 3 years prior to his emergency admission for agitation and delirium. The authors suggest that the use of alcohol by children is an activity that may be more common than most physicians realize.
TCT-593 Left Ventricular Unloading Preserves Energy Substrate Utilization in Preclinical Models of Acute Myocardial Infarction
Authors: Lija Swain, Xiaoying Qiao, Lara Reyelt, Aditya Chennojwala, Michael Chin, Corinne Thomas, Paige Crowley, Shreyas Bhave, Navin Kapur
Journal: Journal of the American College of Cardiology (2019)
Brief behaviour change strategies for distressed patients in primary care
Authors: Amber M Gum, Gary P Epstein-Lubow, Brandon A Gaudiano, Marsha Wittink, Carol Horvath
Journal: BMJ (2019)

### What you need to know

A middle aged woman, divorced many years, presents to her general practitioner for a routine follow-up visit with arthritis, weight gain, and intermittent migraines. She appears stressed and tired. Upon questioning, she reports strain, fatigue, poor sleep, and worry. She is caring for her mother, who lives with her and has Alzheimer’s disease, and she is adjusting to having her daughter’s family (husband and three young children) move in with her due to unemployment. 

Many patients present to primary care in emotional distress, simply referred to as “distress” hereafter. Brief behavioural interventions offered in primary care can reduce distress in the moment and may confer longer term benefits as well, potentially helping patients achieve personally meaningful goals, reduce distress, and improve physical outcomes. In doing so, providers also may experience benefits in their relationships with patients and job satisfaction.1

In this Practice Pointer, we present an approach for non-specialists to use in their consultation with patients in distress. Figure 1 presents an overview. These behavioural strategies can be used with distressed patients whether or not they are taking psychiatric medications.23 Most …
TCT-332 Pre-Op Diagnosis of Silent Coronary Ischemia Using CT-Derived Fractional Flow Reserve May Reduce Post-Op MI and Death in Patients Undergoing Peripheral Vascular Surgery
Authors: Dainis Krievins, Edgars Zellans, Andrejs Erglis, Ligita Zvaigzne, Indulis Kumsars, Gustavs Latkovskis, Roberts Rumba, Christopher Zarins
Journal: Journal of the American College of Cardiology (2019)
TCT-381 TAVR-Patients at High Risk for Bleeding: Value of LAAO in This Special Cohort
Authors: Felix Woitek, Stephan Haussig, Lisa Crusius, Sven Möbius-Winkler, Marcus Sandri, Nicolas Majunke, Michael Borger, Holger Thiele, Mohamed Abdel-Wahab, Norman Mangner, Axel Linke
Journal: Journal of the American College of Cardiology (2019)
Activity and survival benefit of second-line chemotherapy (2L-Ctx) in advanced pancreatic adenocarcinoma (APC): Pooled analysis of the literature.
Authors: MinYuen Teo, Raymond S. McDermott
Journal: Journal of Clinical Oncology (2013)

e15019 Background: Many clinicians adopt a nihilistic approach to the management of APC. Delivery of 2L-Ctx is relatively uncommon and no recognized standard exists. We sought to examine the published activity of chemotherapy in the 2 nd line setting, and the rate of 2L-Ctx delivery and its influence on reported overall survival in 1st line trials. Methods: 1 st and 2L-Ctx randomized trials published between 2000 and 2012 were identified from Pubmed, and manuscripts were obtained for data extraction. Pooled weighted objective response rates (ORR) and disease control rates (DCR) were calculated. For 1 st line studies, the percentage of patients who received 2L-Ctx were extracted and plotted against reported median overall survival (OS) and post-progression survival (PPS), defined as arithmetic difference between median OS and progression-free survival. Spearman correlation and linear regression were performed. Results: Sixty nine 2L Ctx studies (77 arms, n=2859) were identified. Majority received prior gemcitabine-based chemotherapy. Pooled ORR was 6.6% (95% CI 5.6 – 7.6%) and DCR was 36.7% (34.5 – 38.0%). When only prospective studies were evaluated (42 studies, 48 arms, n=1546), ORR was 5.0% (3.8 – 6.2%) and DCR was 33.9% (31.0 – 36.9%). Exploratory analysis suggested that intensification of gemcitabine-based therapy (ORR: 10.0%; DCR: 54.7%) might be marginally more active than fluoropyrimidine (7.6%; 32.2%) or taxane based 2L-Ctx (5.2%; 33.6%). 28/52 identified 1st line studies (54%) reported the percentage of patients treated with second-line chemotherapy (11 phase II, 28 arms, n=1450; 17 phase III, 33 arms, n=5051). Percentage of 2L-Ctx delivery ranged from 14 – 68% and correlated with OS (r=.49 [.26 – .67], p&lt;.01) and PPS (r=.57 [.36 – .72], p&lt;.01). When phase II studies were excluded, correlation was improved for OS (r=.63 [.35 – .81], p&lt;.01) and PPS (r=.79 [.59 – .89], p&lt;.01). Percentage of locally advanced disease did not correlate with OS/PPS nor affect prior analysis. Conclusions: Whilst awaiting further advancement in the 1 st line setting, increased delivery of 2L-Ctx to patients with APC and maintained performance status may offer a survival benefit.
NHS in England to offer prenatal repair for spina bifida “within weeks,” after NICE approval
Authors: Shivali Fulchand
Journal: BMJ (2019)

The National Institute for Health and Care Excellence (NICE) has recommended in draft guidance that babies at risk of spina bifida be operated on in the womb using an open repair technique in specialised NHS centres by clinical teams with specific training and experience.1

It concluded, however, that there was not enough evidence to recommend the prenatal keyhole technique for spina bifida and advised that this procedure should only be used in the context of research.

NHS England said that it would fund open repair for spina bifida for …
Noninvasive Stereotactic Radiotherapy for Renal Denervation in a Swine Model
Authors: Xingxing Cai, Yuli Yang, Yichen Shen, Wei Wang, Li Qian, Jing Cai, Runmin Chi, Yudong Fei, Shunxuan Yu, Le Wei, Jianwen Hou, Qian Wang, Jianguo Zhang, Dengbin Wang, Mawei Jiang, Yi-Gang Li
Journal: Journal of the American College of Cardiology (2019)
TCT-808 Transfemoral Transcatheter Aortic Valve Replacement Using Fascia Iliaca Block as an Alternative Approach to Conscious Sedation as Compare to General Anesthesia: Findings From a Single Center
Authors: Wei Lau, Francis Shannon, George Hanzel, Robert Safian, Amr Abbas, Marc Sakwa, Steven Almany, Ivan Hanson, Nai-Wei Chen, Randy Fayne
Journal: Journal of the American College of Cardiology (2019)