tbuckley/cabot-search huggingface dataset:
Piloting a surveillance system for HIV drug resistance in the European Union
Authors: Marita JW van de Laar, Arnold Bosman, Anastasia Pharris, Emmi Andersson, Lambert Assoumou, Eva Ay, Norbert Bannert, Barbara Bartmeyer, Melissa Brady, Marie-Laure Chaix, Diane Descamps, Kenny Dauwe, Jannik Fonager, Andrea Hauser, Maja Lunar, Maria Mezei, Martha Neary, Mario Poljak, Ard van Sighem, Chris Verhofstede, Andrew J Amato-Gauci, Eeva K Broberg
Journal: Eurosurveillance (2019)

BackgroundA steady increase in HIV drug resistance (HIVDR) has been demonstrated globally in individuals initiating first-line antiretroviral therapy (ART). To support effective use of ART and prevent spread of HIVDR, monitoring is essential.AimWe piloted a surveillance system for transmitted HIVDR to assess the feasibility of implementation at the European level.MethodAll 31 countries in the European Union and European Economic Area were invited to retrospectively submit data on individuals newly diagnosed with HIV in 2015 who were tested for antiviral susceptibility before ART, either as case-based or as aggregate data. We used the Stanford HIV database algorithm to translate genetic sequences into levels of drug resistance.ResultsNine countries participated, with six reporting case-based data on 1,680 individuals and four reporting aggregated data on 1,402 cases. Sequence data were available for 1,417 cases: 14.5% of individuals (n = 244) showed resistance to at least one antiretroviral drug. In case-based surveillance, the highest levels of transmitted HIVDR were observed for non-nucleoside reverse-transcriptase inhibitors (NNRTIs) with resistance detected in 8.6% (n = 145), followed by resistance to nucleoside reverse-transcriptase inhibitors (NRTI) (5.1%; n = 85) and protease inhibitors (2.0%; n = 34).ConclusionWe conclude that standard reporting of HIVDR data was feasible in the participating countries. Legal barriers for data sharing, consensus on definitions and standardisation of interpretation algorithms should be clarified in the process of enhancing European-wide HIV surveillance with drug resistance information.
Abstract 17153: Trends in Coronary Revascularization Among Cancer Patients in the United States, 2005-2014
Authors: Muni Rubens, Anshul Saxena, Peter McGranaghan, Venkataraghavan Ramamoorthy, Sankalp Das, Sandeep Appunni, Deborah Suarez, Brittany Puebla, Alexandra Guida, Emir Veledar
Journal: Circulation (2018)

Introduction: Although co-existing coronary artery disease (CAD) and cancers are increasing, trends of coronary revascularization in patients with cancer history is scarce. Hence, we examined trends, costs, hospital length of stay and in-hospital mortality among cancer patients who underwent percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) surgery in the United States. Methods: The current study was a retrospective analysis of the National Inpatient Sample, collected during the period 2005-2014. Coronary revascularizations were identified among patients ≥45 years by procedure codes 36.01-36.07, 36.09, or 00.66 for PCI, and 36.1x for CABG surgery. Cancer hospitalizations were identified if any of the CCS codes were 11-43. Results: A total of 8,428,811 weighted coronary revascularizations were done during the study period, and 636,819 (7.6%) were among cancer patients. Of this, 454,138 (71.3%) were PCI and 182,681 (28.7%) were CABG. About 35.0% were in the age group 65-74 years and 41.0% in the age group ≥70 years. Majority of patients had Medicare coverage (72.0%), followed by private insurance (22.15%). Among patients with history of cancer, coronary revascularizations increased significantly from 6.5% to 8.5% (relative increase, 30.8%; P trend &lt;0.001). PCI increased significantly from 4.7% to 6.0% (relative increase, 27.7%; P trend &lt;0.001) and CABG increased significantly from 1.8% to 2.5% (relative increase, 38.9%; P trend =0.056) during the study period. The median (interquartile range [IQR]) length of stay decreased significantly from 2.8 (0.86-6.3) to 3.2 (1.6-6.4) days (relative decrease, 14.3%; P trend =0.003) and overall in-hospital mortality rate increased significantly from 1.7% to 2.4% (relative decrease, 41.2%; P trend =0.031). Median cost of hospitalizations increased significantly from $51,206 to $87,935 (relative increase, 71.7%; P trend =0.047). Conclusion: Cancer patients had increasing number of coronary revascularization interventions and adverse hospital outcomes. Prevention and management of risk factors, early disease diagnosis, and advanced treatments should be implemented to improve CAD outcomes in this population.
Abstract B62: Intratumoral genetic heterogeneity in rectal cancer and response to neoadjuvant chemoradiotherapy
Authors: Cibele Masotti, Fabiana Bettoni, Bruna R. Correa, Angelita Habr-Gama, Joaquim Gama-Rodrigues, Maria Viana, Bruna B. Vailati, Guilherme P. Sao Juliao, Laura M. Fernandez, Pedro A. F. Galante, Rodrigo O. Perez, Anamaria A. Camargo
Journal: Clinical Cancer Research (2018)

Abstract Response to neoadjuvant chemoradiotherapy (nCRT) varies substantially among patients with locally advanced rectal cancer, but key determinants of treatment response are not fully understood. Intratumoral genetic heterogeneity (ITGH) is a common feature of solid tumors and has been proposed to drive disease progression and treatment response. Others and we have recently demonstrated that primary nontreated rectal tumors exhibit significant ITGH, but the effect of nCRT in shaping the clonal architecture of rectal cancer has not yet been addressed. In the present work, we further expanded the analysis of ITGH in rectal cancer by analyzing whole-exome sequencing (WES) and clinical data from 79 primary nontreated rectal cancers obtained from The Cancer Genome Atlas. We show that primary rectal tumors exhibit a remarkable variability in the degree of ITH. We also analyzed the effect of nCRT on ITGH and monitored tumor cell subpopulation dynamics after treatment through WES of paired tumor samples collected at diagnosis (pretreatment) and at surgery following nCRT (post-treatment) from seven patients. We show that treatment exposure does not introduce novel somatic mutations or significantly alter tissue genetic heterogeneity. Instead, nCRT acts as a potent selective pressure, shaping the mutational landscape of rectal tumors and allowing the selection and expansion of tumor cell subpopulations, which are more prone to resist nCRT. Our results shed light on the highly heterogeneous and dynamic mutational landscape of rectal tumors and indicate that ITGH may directly affect response to nCRT. Citation Format: Cibele Masotti, Fabiana Bettoni, Bruna R. Correa, Angelita Habr-Gama, Joaquim Gama-Rodrigues, Maria Viana, Bruna B. Vailati, Guilherme P. Sao Juliao, Laura M. Fernandez, Pedro A. F. Galante, Rodrigo O. Perez, Anamaria A. Camargo. Intratumoral genetic heterogeneity in rectal cancer and response to neoadjuvant chemoradiotherapy [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B62.
Drugs That Modify Cholesterol Metabolism Alter the p38/JNK-Mediated Targeted and Nontargeted Response to Alpha and Auger Radioimmunotherapy
Authors: Riad Ladjohounlou, Catherine Lozza, Alexandre Pichard, Julie Constanzo, Jihad Karam, Pierre Le Fur, Emmanuel Deshayes, Vincent Boudousq, Salomé Paillas, Muriel Busson, Marion Le Blay, Marta Jarlier, Sara Marcatili, Manuel Bardiès, Frank Bruchertseifer, Alfred Morgenstern, Julien Torgue, Isabelle Navarro-Teulon, Jean-Pierre Pouget
Journal: Clinical Cancer Research (2019)

For the development of new anticancer therapeutic radiopharmaceuticals, including alpha particle emitters, it is important to determine the contribution of targeted effects in irradiated cells, and also of nontargeted effects in nonirradiated neighboring cells, because they may affect the therapeutic efficacy and contribute to side effects.Here, we investigated the contribution of nontargeted cytotoxic and genotoxic effects in vitro and in vivo (in xenografted mice) during alpha (212Pb/212Bi, 213Bi) and Auger (125I) radioimmunotherapy (RIT).Between 67% and 94% (alpha RIT) and 8% and 15% (Auger RIT) of cancer cells were killed by targeted effects, whereas 7% to 36% (alpha RIT) and 27% to 29% (Auger RIT) of cells were killed by nontargeted effects. We then demonstrated that the nontargeted cell response to alpha and Auger RIT was partly driven by lipid raft-mediated activation of p38 kinase and JNK. Reactive oxygen species also played a significant role in these nontargeted effects, as demonstrated by NF-κB activation and the inhibitory effects of antioxidant enzymes and radical scavengers. Compared with RIT alone, the use of RIT with ASMase inhibitor (imipramine) or with a lipid raft disruptor (e.g., methyl-beta-cyclodextrin or filipin) led to an increase in clonogenic cell survival in vitro and to larger tumors and less tissue DNA damage in vivo. These results were supported by an inhibitory effect of pravastatin on Auger RIT.Cell membrane-mediated nontargeted effects play a significant role during Auger and alpha RIT, and drugs that modulate cholesterol level, such as statins, could interfere with RIT efficacy.
Focal Adhesion Kinase and β‐Catenin Cooperate to Induce Hepatocellular Carcinoma
Authors: Na Shang, Hao Wang, Thomas Bank, Aldeb Perera, Cara Joyce, Gina Kuffel, Michael J. Zilliox, Scott J. Cotler, Xianzhong Ding, Asha Dhanarajan, Peter Breslin, Wei Qiu
Journal: Hepatology (2019)

There is an urgent need to understand the molecular signaling pathways that drive or mediate the development of hepatocellular carcinoma (HCC). The focal adhesion kinase (FAK) gene protein tyrosine kinase 2 is amplified in 16.4% of The Cancer Genome Atlas HCC specimens, and its amplification leads to increased FAK mRNA expression. It is not known whether the overexpression of FAK alone is sufficient to induce HCC or whether it must cooperate in some ways with other oncogenes. In this study, we found that 34.8% of human HCC samples with FAK amplification also show β‐catenin mutations, suggesting a co‐occurrence of FAK overexpression and β‐catenin mutations in HCC. We overexpressed FAK alone, constitutively active forms of β‐catenin ( CAT ) alone, or a combination of FAK and CAT in the livers of C57/BL6 mice. We found that overexpression of both FAK and CAT , but neither FAK nor CAT alone, in mouse livers was sufficient to lead to tumorigenesis. We further demonstrated that FAK’s kinase activity is required for FAK/CAT‐induced tumorigenesis. Furthermore, we performed RNA‐sequencing analysis to identify the genes/signaling pathways regulated by FAK, CAT, or FAK/CAT. We found that FAK overexpression dramatically enhances binding of β‐catenin to the promoter of androgen receptor (AR), which leads to increased expression of AR in mouse livers. Moreover, ASC‐J9, an AR degradation enhancer, suppressed FAK/CAT‐induced HCC formation. Conclusion: FAK overexpression and β‐catenin mutations often co‐occur in human HCC tissues. Co‐overexpression of FAK and CAT leads to HCC formation in mice through increased expression of AR; this mouse model may be useful for further studies of the molecular mechanisms in the pathogenesis of HCC and could lead to the identification of therapeutic targets.
Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer’s disease
Authors: Tomoko Wakabayashi, Kazuki Yamaguchi, Kentaro Matsui, Toshiharu Sano, Tetsuya Kubota, Tadafumi Hashimoto, Ayako Mano, Kaoru Yamada, Yuko Matsuo, Naoto Kubota, Takashi Kadowaki, Takeshi Iwatsubo
Journal: Molecular Neurodegeneration (2019)

Based on epidemiological and experimental studies, type 2 diabetes mellitus (T2DM), especially insulin resistance that comprises the core mechanism of T2DM, has been recognized as a significant risk factor for Alzheimer's disease (AD). Studies in humans and diabetic AD model mice have indicated a correlation between insulin resistance and increased amyloid deposition in the brain. Paradoxically, mice with targeted disruption of genes involved in the insulin signaling pathway showed protective effects against the AD-related pathology. These conflicting observations raise an issue as to the relationship between dysregulation of insulin signaling and AD pathophysiology.To study the causal relations and molecular mechanisms underlying insulin resistance-induced exacerbation of amyloid pathology, we investigated the chronological changes in the development of insulin resistance and amyloid pathology in two independent insulin-resistant AD mouse models, i.e., long-term high-fat diet (HFD) feeding and genetic disruption of Irs2, in combination with dietary interventions. In addition to biochemical and histopathological analyses, we examined the in vivo dynamics of brain amyloid-β (Aβ) and insulin by microdialysis technique.HFD-fed diabetic AD model mice displayed a reduced brain response to peripheral insulin stimulation and a decreased brain to plasma ratio of insulin during the hyperinsulinemic clamp. Diet-induced defective insulin action in the brain was accompanied by a decreased clearance of the extracellular Aβ in vivo and an exacerbation of brain amyloid pathology. These noxious effects of the HFD both on insulin sensitivity and on Aβ deposition in brains were reversibly attenuated by dietary interventions. Importantly, HFD feeding accelerated Aβ deposition also in the brains of IRS-2-deficient AD mice.Our results suggested a causal and reversible association of brain Aβ metabolism and amyloid pathology by diet-dependent, but not genetically-induced, insulin-resistance. These observations raise the possibility that the causal factors of insulin resistance, e.g., metabolic stress or inflammation induced by HFD feeding, but not impaired insulin signaling per se, might be directly involved in the acceleration of amyloid pathology in the brain.
Most pregnancy related deaths in US are preventable, says CDC
Authors: Owen Dyer
Journal: BMJ (2019)

Three in every five deaths in the United States related to pregnancy are preventable, concludes a case by case review of deaths in 13 US states from 2013 to 2017, compiled by scientists from the US Centers for Disease Control (CDC).1

The researchers also analysed reported maternal deaths in all 50 states from 2011 to 2015 and found that the country’s mortality rate, the highest of any developed country, remains stubbornly high at 17.2 per 100 000 live births—about 700 deaths across the US each year.

That is twice the rate in the UK, which itself has twice the rate of other European countries such as Spain, Italy, Greece, Finland, Sweden, and Bulgaria. Since 1990, WHO data show, the world rate has halved, while the US rate has actually climbed.2

But the US rate is still only a 10th …
Abstract P6-20-05: Therapeutic targeting of <i>BRCA1</i> and <i>TP53</i> mutant breast cancer through mutant p53 reactivation
Authors: B Na, X Yu, T Wither, J Gilleran, M Yao, TK Foo, C Chen, D Moore, B Xia, Y Lin, D Kimball, S Ganesan, D Carpizo
Journal: Cancer Research (2019)

Abstract Triple negative breast cancer (TNBC) is an aggressive subset for which novel therapeutic approaches are needed. A significant proportion of TNBC patients harbor either germline or somatic mutations in BRCA1, or epigenetic silencing of BRCA1, which renders them deficient in DNA repair. Virtually all BRCA1 deficient breast cancers harbor mutations in TP53 suggesting that inactivation of p53 is a requirement for tumor progression in the setting of BRCA1 deficiency. Due to this dependency, we hypothesized that restoring wild type p53 function in BRCA1 deficient breast cancer would be therapeutic. The majority of TP53 mutations are missense, which generate a defective protein that potentially can be targeted with small molecules. Zinc Metallochaperones (ZMCs) are a new class of anti-cancer drugs that reactivate a class of zinc deficient mutant TP53 alleles by restoring zinc binding. Using ZMC1 in human breast cancer cell lines expressing the zinc deficient p53R175H, we demonstrate that loss of BRCA1 sensitizes cells to mutant p53 reactivation. Using genetically engineered murine mammary tumor models with Brca1 deficiency, we demonstrate that ZMC1 significantly improves survival in mice bearing tumors harboring the zinc deficient Trp53R172H allele but not the Trp53 null allele. We synthesized a novel formulation of ZMC1 (Zn-1), in which the drug is made in complex with zinc to improve zinc delivery, and demonstrate that Zn-1 has increased efficacy over ZMC1. Furthermore, we show that ZMC1 plus olaparib is a highly effective combination for tumors expressing the p53R172H mutant. In conclusion, we have validated preclinically a novel therapeutic approach for BRCA1 deficient breast cancer through reactivation of mutant p53. Citation Format: Na B, Yu X, Wither T, Gilleran J, Yao M, Foo TK, Chen C, Moore D, Xia B, Lin Y, Kimball D, Ganesan S, Carpizo D. Therapeutic targeting of BRCA1 and TP53 mutant breast cancer through mutant p53 reactivation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-05.
Abstract P3-12-19: Withdrawn
Authors: M Chowdhary, A Lee, S Gao, PN Barry, R Diaz, RH Decker, LD Wilson, SB Evans, MS Moran, CA Knowlton, KR Patel
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Chowdhary M, Lee A, Gao S, Barry PN, Diaz R, Decker RH, Wilson LD, Evans SB, Moran MS, Knowlton CA, Patel KR. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-12-19.
Making the hospital work for you: surviving a ward on call
Authors: James Smith, Francesca Flohr, Anusha Edwards
Journal: BMJ (2011)

The third in a series of articles takes you through what to bring with you and how to hand over Your first on call as a doctor is coming up, and thoughts are running through your head: “Am I ready?” “Do I know what I am doing?” and “Medical school hasn’t prepared me for this.” As part of the series “Making the hospital work for you” the aim of this article is to reassure medical students and junior doctors that with basic preparation and simple techniques, an on call shift will fly by and hopefully be an enjoyable experience. The thought of your first on call shift can be daunting. Try to relax the day before and avoid a late night. Being well rested and relaxed before your shift optimises rational thought and decision making. ### Basics of emergency medicine The on call doctor is often the first medic to review sick patients, and their initial assessment and management can be vital to overall prognosis. It is important that junior doctors have a basic understanding of emergency medicine before embarking on an on call shift. Basic requirements include the prescribing and understanding of the following: ### Equipment Although on call junior doctors are often seen struggling under the weight, they should carry the following essentials:
Abstract A36: Clinical and molecular characterization of oropharynx squamous cell carcinoma samples
Authors: Ana Carolina de Carvalho, Bruna Pereira Sorroche, Matias Eliseo Melendez, Cristina da Silva Sabato, Edenir Inez Palmero, Lidia Maria Rebolho Batista Arantes, Cristovam Scapulatempo Neto, André Lopes Carvalho
Journal: Clinical Cancer Research (2018)

Abstract Background: Oropharynx squamous cell carcinomas (OPSCC) associated with high-risk human papilloma virus (HR-HPV) infection represent a distinct clinical and epidemiologic entity, with differences in clinical presentation and treatment outcome when compared to tobacco-associated tumors. Objective: The aim of this study was to identify clinical and molecular factors that can differentiate OPSCC patients into subgroups according to their outcome. Materials and Methods: Twenty-five surgically treated OPSCC samples were included in this study. p16 protein expression was used as a surrogate marker for HR-HPV. The methylation status of 5 genes was evaluated by quantitative methylation-specific PCR (qMSP). Exons 4-8 of the P53 gene were evaluated by Sanger sequencing and p53 protein expression was evaluated by immunohistochemistry (clone DO-7). Results: The majority of patients (88%) were male, had advanced disease (80%), and were tobacco users (88%). Twenty percent of the cases were HR-HPV positive and 62.5% presented deleterious P53 mutations, which was moderately concordant with strong p53 protein expression (Kappa value = 0.467; p = 0.022). CCNA1, CDH8, DAPK, PCDH10, and TIMP3 promoter hypermethylation was observed in 16-36%, of the OPSCC evaluated. DAPK hypermethylation was associated with HPV status (p = 0.023), while CCNA1 methylation was inversely related to p53 mutations in primary tumors (p = 0.042) and associated with a better disease-free survival (22.3% vs. 100%; p = 0.028) and overall survival (8% vs. 100%; p = 0.012). Conclusions: Even though all samples analyzed were of the oropharynx, several differences regarding molecular and clinical characteristics were identified. More cases should be evaluated in order to assess whether the differences identified are able to classify these patients according to their outcome and help in a more thorough patient management. Citation Format: Ana Carolina de Carvalho, Bruna Pereira Sorroche, Matias Eliseo Melendez, Cristina da Silva Sabato, Edenir Inez Palmero, Lidia Maria Rebolho Batista Arantes, Cristovam Scapulatempo Neto, André Lopes Carvalho. Clinical and molecular characterization of oropharynx squamous cell carcinoma samples [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A36.