tbuckley/cabot-search huggingface dataset:
Abstract 5348: Single-cell analysis of mutational heterogeneity in acute myeloid leukemia tumors with high-throughput droplet microfluidics
Authors: Dennis J. Eastburn, Maurizio Pellegrino, Adam Sciambi, Sebastian Treusch, Liwen Xu, Robert Durruthy-Durruthy, Kaustubh Gokhale, Jose Jacob, Tina X. Chen, William Oldham, Jairo Matthews, Hagop Kantarjian, Andrew Futreal, Keyur Patel, Keith W. Jones, James L. Zehnder, Koichi Takahashi
Journal: Cancer Research (2018)

Abstract To make possible the routine characterization of genetic diversity within cancer cell populations, we developed a novel two-step microfluidic droplet workflow that enables efficient and massively-parallel single-cell PCR-based genomic barcoding for single-cell DNA sequencing applications. We demonstrate that the two-step microfluidic approach is required for robust DNA amplification on thousands of individual cells per run with high coverage uniformity and low allelic dropout of targeted genomic loci. To apply our single-cell sequencing technology to human tumor samples, we developed a targeted panel to partially sequence 26 genes frequently mutated in acute myeloid leukemia (AML) including TP53, DNMT3A, FLT3, NPM1, NRAS, IDH1 and IDH2. Using this panel, we were able to sensitively identify SNV and indel-defined clones within AML samples and assess their distribution at the time of diagnosis, remission and relapse. We also used single cell SNVs to monitor host and donor cell populations during bone marrow transplantation (BMT), which allowed us to accurately evaluate engraftment and disease relapse. Collectively, our single-cell data indicates that clonal populations inferred from VAFs obtained from bulk sequencing data may not fully resolve the heterogeneity within tumors; moreover, the single-cell nature of our approach enabled the unambiguous identification of multiple co-occurring mutations within subclones that is not possible with bulk measurements. Collectively, our results show a greater degree of heterogeneity in AML tumor samples than is commonly appreciated with traditional sequencing paradigms and demonstrate the value of single-cell analysis for AML. Citation Format: Dennis J. Eastburn, Maurizio Pellegrino, Adam Sciambi, Sebastian Treusch, Liwen Xu, Robert Durruthy-Durruthy, Kaustubh Gokhale, Jose Jacob, Tina X. Chen, William Oldham, Jairo Matthews, Hagop Kantarjian, Andrew Futreal, Keyur Patel, Keith W. Jones, James L. Zehnder, Koichi Takahashi. Single-cell analysis of mutational heterogeneity in acute myeloid leukemia tumors with high-throughput droplet microfluidics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5348.
Abstract 2697: Alterations in the HSP70 interactome are induced by overexpression of MUC1 in pancreatic cancer
Authors: . Nitika, Donald J. Wolfgeher, Pinku Mukherjee, Andrew W. Truman
Journal: Cancer Research (2018)

Abstract Heat Shock Protein 70 (HSP70) is an evolutionarily well-conserved molecular chaperone involved in several cellular processes such as folding of proteins, modulating protein-protein interactions and transport of proteins across membranes. HSP70 works synergistically with a series of chaperones, co-chaperones, adaptors, and folding enzymes known as the HSP70 “interactome”. Previous work has demonstrated that HSP70 interactome changes can be promoted by overexpression of oncoproteins. An important “client” of HSP70 is the oncoprotein MUC1. MUC1 is overexpressed and promotes drug resistance in pancreatic cancer. We applied quantitative affinity-purification mass spectrometry (AP-MS) to characterize the HSP70 interactome differences between PC3/NEO and PC3/MUC1 cell lines. 439 HSP70-interacting proteins were identified and quantified via LC-MS/MS. Interestingly while 53% of HSP70 interactions remained constant upon MUC1 overexpression, 29% significantly increased and 18% decreased. Many of the altered proteins were key co-chaperones that regulate and maintain HSP70 activity. High levels of MUC1 promoted HSP70 association with 15 co-chaperones (HSPA5, DNAJB1, STIP1, TXNDC5, HSPB1, CCT2, TCP1, P4HB, CCT6A, CCT8, PDIA3 and HSP90B). Conversely, MUC1 overexpression triggered the loss of HSP70 interaction with only 2 co-chaperones (PPIB and DNAJA2). We are currently validating these altered interactions using an array of biochemical techniques. Our hope is that by understanding these HSP70 interactome changes, we may be able to uncover novel ways to inhibit MUC1 function in pancreatic cancer. Citation Format: . Nitika, Donald J. Wolfgeher, Pinku Mukherjee, Andrew W. Truman. Alterations in the HSP70 interactome are induced by overexpression of MUC1 in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2697.
Abstract 5844: Targeting DNA repair in Philadelphia positive B-ALL
Authors: Danielle Johnson, Shwetha Tharkar, Simon Jones, Matt Jarpe, Mahesh Chandrasekharan, Srividya Bhaskara
Journal: Cancer Research (2018)

Abstract Introduction: The Philadelphia (Ph) chromosome was the first reported chromosomal rearrangement linked to a human malignancy. Ph-positive precursor B-cell acute lymphoblastic leukemic (Ph+Pre-B-ALL) expressing the BCR-ABL1 oncoprotein is a major subclass of ALL with poor prognosis and high relapse rates in adults. BCR-ABL1 drives an aberrantly hyperactive DNA repair that confers survival advantages to leukemic cells and serves as its ‘Achilles' heel'. We used HDAC1,2 selective inhibitor in isolation or in combination with doxorubicin (a chemotherapy regimen component used for treating pre-B-ALL) to combat the aberrant DSB repair processes. Experimental design: We used a combination of molecular and cell biology, proteomics and functional genomics-based approaches and primary patient-derived xenograft mouse models to understand the genome stability mechanisms targeted by HDAC1,2 inhibition to overcome oncogenic signals promoted by the BCR-ABL1 fusion protein. Results: Mass-spectrometry analysis and DNA repair assays showed that HDAC1,2 inhibition and doxorubicin treatments impact common as well as distinct DNA repair and genome maintenance networks including decreased chromatin association of Mre11-Rad51-DNA ligase 1, the central hub of DNA repair. Translating this mechanistic knowledge, we then showed that the HDAC1,2 inhibitor either alone or when combined with a low dose doxorubicin caused cytotoxicity in primary patient Ph+ Pre-B-ALL cells, and decreased leukemia burden without adverse side-effects in vivo in refractory Ph+ Pre-B-ALL PDX models that we created. We recently found that HDAC1,2 targets H4K91ac mark in Ph+Pre-B-ALL cells. H4K91ac occurs within the body of nucleosome core and thus directly controls nucleosome or chromatin integrity. Increased H4K91ac following HDAC1,2 inhibition occurs around DSB sites genome-wide could cause a delay in the rate at which DSBs are repaired in Ph+Pre-B-ALL cells as a result of defective nucleosome structure around DSB sites. Conclusion: Our comprehensive study using a multipronged approach showed that HDAC1,2 inhibition as a monotherapy or in combination with a low-dose doxorubicin can override DSB repair ‘addiction' in Ph+ Pre-B-ALL. We are currently using the genome-wide ChIP-seq approach and an homing endonuclease DSB reporter system to examine how HDAC1,2 inhibition changes the chromatin landscape in Ph+Pre-B-ALL cells. Citation Format: Danielle Johnson, Shwetha Tharkar, Simon Jones, Matt Jarpe, Mahesh Chandrasekharan, Srividya Bhaskara. Targeting DNA repair in Philadelphia positive B-ALL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5844.
Abstract 325: A functional homologous recombination assay predicts primary chemotherapy response and long-term survival in ovarian cancer patients
Authors: Manuela Tumiati, Sakari Hietanen, Johanna Hynninen, Elina Pietilä, Anniina Färkkilä, Katja Kaipio, Amjad Alkodsi, Minna Tuominen, Sampsa Hautaniemi, Olli Carpén, Liisa Kauppi
Journal: Cancer Research (2018)

Abstract Background: High-grade serous ovarian cancer (HGSOC) is the most common and aggressive type of ovarian cancer (OC) and the fifth most common malignancy occurring in women, meaning that 1 in 70 will develop OC during her lifetime. The current first-line treatment for HGSOC patients consists of cytoreductive surgery and platinum/taxanes-based chemotherapy. Homologous recombination deficiency (HRD) correlates with platinum sensitivity in OC patients, which clinically is the most useful predictor of sensitivity to PARPi. To date, there are no reliable diagnostic tools to anticipate response to platinum-based chemotherapy, thus we aimed to develop an ex vivo functional HRD detection test that could predict both platinum-sensitivity and patient eligibility to targeted drug treatments. Methods: We obtained a functional HR score by quantifying homologous recombination (HR) repair after ionizing radiation-induced DNA damage in primary ovarian cancer samples (n=24). Samples spontaneously clustered in 3 categories: HR-deficient, HR-low and HR-proficient. We analysed the HR score association with platinum sensitivity and treatment response, platinum-free interval (PFI) and overall survival (OS), and compared it with other clinical parameters (treatment strategy, FIGO stage, age). In parallel, we performed DNA sequencing of HR genes to assess if functional HRD can be predicted by currently offered genetic screening. Results: Low HR scores predicted primary platinum sensitivity with high statistical significance (p=0.001) and associated with longer PFI (HR-deficient vs HR-proficient: 531 vs 113 days). The HR score was the only factor that significantly correlated with improved OS (HR score &amp;lt;35 vs ≥35, hazard ratio=0.12, 95% CI=0.02 to 0.79, p=0.026). At the genomic level, we identified a few mutations of unclear significance in HR genes but, overall, DNA sequencing failed to predict functional HRD. Conclusions: We developed an ex vivo assay that detects tumor functional HRD and an HR score able to predict platinum sensitivity, which holds the clinically relevant potential to become the routine companion diagnostic in the management of ovarian cancer patients. Citation Format: Manuela Tumiati, Sakari Hietanen, Johanna Hynninen, Elina Pietilä, Anniina Färkkilä, Katja Kaipio, Amjad Alkodsi, Minna Tuominen, Sampsa Hautaniemi, Olli Carpén, Liisa Kauppi. A functional homologous recombination assay predicts primary chemotherapy response and long-term survival in ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 325.
Abstract P144: Red Meat Consumption and Risk of Nonfatal Acute Myocardial Infarction: Results From a Population-based Case-control Study in Costa Rica
Authors: DongqingWang, HanniaCampos, AnaBaylin
Journal: Circulation (2016)

Background: Red meat consumption has been found positively associated with cardiovascular disease (CVD) incidence and mortality in the United States and some European countries, but not in Asian countries where red meat consumption is low. The association is still unknown in Hispanic American populations which have relatively low red meat consumption but are undergoing nutrition transition towards Western dietary patterns. Objective: We aimed to estimate the association between total, processed, and unprocessed red meat consumption and nonfatal acute myocardial infarction (AMI) in the Costa Rican population. We also assessed potential mediators, effect modifiers, and the association of substituting other alternative healthy foods for red meat. Design: We recruited cases (n=1785) with a first nonfatal AMI and population-based controls (n=1785) living in Costa Rica, matched for age, sex, and area of residence. Dietary intake was assessed with a validated food frequency questionnaire. Odds ratios (ORs) and 9...
Abstract 11928: Cardiospecific Overexpression of Carnosine Synthase Attenuates Myocardial Ischemia Reperfusion Injury
Authors: ShahidBaba, Deqingzhang, DavidHoetker, YiruGuo, AruniBhatnagar
Journal: Circulation (2014)

Even though myocardial ischemia/reperfusion (I/R) remains the leading cause of death, the underlying mechanisms remain incompletely understood. Increased formation of reactive carbonyl has been shown to be a common biochemical feature of I/R injury. These carbonyls are generated from the oxidation of proteins and membrane lipids. Reactive carbonyls such as methylglyoxal are generated from increased glycolytic activity during ischemia. Previous work in our lab has shown that the endogenous dipeptide carnosine (β-alanine-histidine) quenches both protein and lipid derived carbonyls. It can also buffer changes in intracellular pH and chelate metals that catalyze ROS production. In the heart, carnosine is synthesized by the ATP grasp enzyme (ATPGD1). Hence, we examined whether overexpression of ATPGD1 could increase carnosine synthesis in the heart and attenuate I/R injury. To overexpress ATPGD1, we generated mice in which the expression of the transgene was driven by cardiospecific α-MHC promoter. Two differe...
Cardioprotective Effect of Angiotensin-Converting Enzyme Inhibition Against Hypoxia/Reoxygenation Injury in Cultured Rat Cardiac Myocytes
Authors: SatoakiMatoba, TetsuyaTatsumi, NatsuyaKeira, AkiraKawahara, KazukoAkashi, MiyukiKobara, JunAsayama, MasaoNakagawa
Journal: Circulation (1999)

Background—Although ACE inhibitors can protect myocardium against ischemia/reperfusion injury, the mechanisms of this effect have not yet been characterized at the cellular level. The present study was designed to examine whether an ACE inhibitor, cilazaprilat, directly protects cardiac myocytes against hypoxia/reoxygenation (H/R) injury. Methods and Results—Neonatal rat cardiac myocytes in primary culture were exposed to hypoxia for 5.5 hours and subsequently reoxygenated for 1 hour. Myocyte injury was determined by the release of creatine kinase (CK). Both cilazaprilat and bradykinin significantly inhibited CK release after H/R in a dose-dependent fashion and preserved myocyte ATP content during H/R, whereas CV-11974, an angiotensin II receptor antagonist, and angiotensin II did not. The protective effect of cilazaprilat was significantly inhibited by Hoe 140 (a bradykinin B2 receptor antagonist), NG-monomethyl-l-arginine monoacetate (L-NMMA) (an NO synthase inhibitor), and methylene blue (a soluble gua...
Abstract 13067: Depression and 5-Year Stroke Risk in Patients With Atrial Fibrillation
Authors: Bruno B Lima, Andrew D Althouse, Muhammad B Munir, Michael S Sharbaugh, Bruce L Rollman, Samir Saba
Journal: Circulation (2016)

Introduction: Stroke is a leading cause of death and permanent disability in patients with Atrial Fibrillation (AF). Depression is highly prevalent and previous studies have suggested that it is associated with a significantly increased risk of stroke morbidity and mortality in the general population. Here, we report the impact of depressive mood on the risk of stroke among patients with AF. Hypothesis: Depression increases the risk of stroke among patients with AF. Methods: We enrolled 5976 patients diagnosed with AF at the hospitals and clinics of the University of Pittsburgh Medical Center from January 2006 to November 2013. Depression status was determined by chart review of physicians’ diagnoses. Stroke incidence in each group is summarized with Kaplan-Meier curves; Cox proportional-hazards models were used to assess the relationship between depression and stroke risk when accounting for potential confounders. Results: Of the 5976 patients, 681 (11.4%) had diagnosis of depression. Patients were followed for a median of 39 months (range 1-60), during which there were 200 total strokes (35 in patients with depression). Risk of stroke was higher in patients with diagnosed depression (7.5% vs 4.7%, HR=1.70, 95% CI: 1.18-2.45, p=0.004, Figure). Even after controlling for several known stroke risk factors (age, sex, alcohol and tobacco use, congestive heart failure, previous stroke, diabetes, hypertension, vascular diseases, COPD and anticoagulant use), depressed patients had higher incidence of stroke (HR=1.45, 95% CI 0.99-2.11, p=0.054). Conclusion: Diagnosis of depression is associated with increased risk of ischemic stroke in patients with Atrial Fibrillation. Clinical trials remain necessary to establish whether screening AF patients for depression and then providing effective anti-depressive treatment can reduce the incidence of stroke and improve clinical outcomes.
HLA Class II Associations With Rheumatic Heart Disease Are More Evident and Consistent Among Clinically Homogeneous Patients
Authors: YajairaGuédez, AlyaaKotby, MahaEl-Demellawy, AshrafGalal, GlenysThomson, SalahZaher, SamirKassem, MalakKotb
Journal: Circulation (1999)

Background—Discrepancies in reported HLA class II associations with rheumatic heart disease (RHD) may have been due to inaccuracies of serological typing reagents and/or lack of defined clinical classification of patients analyzed. The molecular association between HLA and RHD was investigated in patients with defined clinical outcome. Methods and Results—Class II allele/haplotype distribution was determined in 2 groups of RHD patients (n=88) and a control group (n=59). Patients were divided into the mitral valve disease (MVD) category (ie, those with mitral regurgitation with or without mitral stenosis) and the multivalvular lesions (MVL) category, with impairment of aortic and/or tricuspid valves in addition to mitral valve damage. The MVD category (n=65) accounted for 74% of patients and included significantly fewer recurrent RF episodes compared with MVL patients (P=0.002). Conclusions—Significant increases in DRB1*0701 and DQA1*0201 alleles and DRB1*0701-DQA1*0201 haplotypes were found in patients. R...
Desert Hedgehog Promotes Ischemia-Induced Angiogenesis by Ensuring Peripheral Nerve Survival
Authors: Marie-AngeRenault, CandiceChapouly, QinyuYao, FrédéricLarrieu-Lahargue, SoizicVandierdonck, AnnabelReynaud, MyriamPetit, BéatriceJaspard-Vinassa, IsabelleBelloc, ElisabethTraiffort, MartialRuat, CécileDuplàa, ThierryCouffinhal, ClaudeDesgranges, Alain-PierreGadeau
Journal: Circulation Research (2013)

Rationale:Blood vessel growth and patterning have been shown to be regulated by nerve-derived signals. Desert hedgehog (Dhh), one of the Hedgehog family members, is expressed by Schwann cells of peripheral nerves. Objective:The purpose of this study was to investigate the contribution of Dhh to angiogenesis in the setting of ischemia. Methods and Results:We induced hindlimb ischemia in wild-type and Dhh–/– mice. First, we found that limb perfusion is significantly impaired in the absence of Dhh. This effect is associated with a significant decrease in capillary and artery density in Dhh–/–. By using mice in which the Hedgehog signaling pathway effector Smoothened was specifically invalidated in endothelial cells, we demonstrated that Dhh does not promote angiogenesis by a direct activation of endothelial cells. On the contrary, we found that Dhh promotes peripheral nerve survival in the ischemic muscle and, by doing so, maintains the pool of nerve-derived proangiogenic factors. Consistently, we found that...
Microtubules Modulate the Stiffness of Cardiomyocytes Against Shear Stress
Authors: SatoshiNishimura, ShinyaNagai, MasayoshiKatoh, HiroshiYamashita, YasutakeSaeki, Jun-ichiOkada, ToshiakiHisada, RyozoNagai, SeiryoSugiura
Journal: Circulation Research (2006)

Although microtubules are involved in various pathological conditions of the heart including hypertrophy and congestive heart failure, the mechanical role of microtubules in cardiomyocytes under such conditions is not well understood. In the present study, we measured multiple aspects of the mechanical properties of single cardiomyocytes, including tensile stiffness, transverse (indentation) stiffness, and shear stiffness in both transverse and longitudinal planes using carbon fiber–based systems and compared these parameters under control, microtubule depolymerized (colchicine treated), and microtubule hyperpolymerized (paclitaxel treated) conditions. From all of these measurements, we found that only the stiffness against shear in the longitudinal plane was modulated by the microtubule cytoskeleton. A simulation model of the myocyte in which microtubules serve as compression-resistant elements successfully reproduced the experimental results. In the complex strain field that living myocytes experience i...
Abstract 18340: Cytokine Profile is Associated With Rheumatic Mitral Valve Disease Severity
Authors: Adriana Soares, Lívia S Passos, Craig Sable, Andrea Beaton, Kenneth J Gollob, Walderez O Dutra, Maria do Carmo P Nunes
Journal: Circulation (2017)

Background: Rheumatic heart disease (RHD) remains a serious public health problem in developing countries. The pattern of immune response after exposure to streptococcus is one of the main determin...
Management of obstructive sleep apnoea in a primary care vs sleep unit setting: a randomised controlled trial
Authors: Nuria Tarraubella, Manuel Sánchez-de-la-Torre, Nuria Nadal, Jordi De Batlle, Iván Benítez, Anunciación Cortijo, Maria Cruz Urgelés, Virginia Sanchez, Iñigo Lorente, M Mercé Lavega, Araceli Fuentes, Joan Clotet, Laia Llort, Lidia Vilo, M Carmen Juni, Aurelia Juarez, Maribel Gracia, Anabel L Castro-Grattoni, Lydia Pascual, Olga Minguez, Juan F Masa, Ferran Barbé
Journal: Thorax (2018)

Objective To assess the effectiveness and cost-effectiveness of primary care (PC) and sleep unit (SU) models for the management of subjects with suspected obstructive sleep apnoea (OSA). Methods Multicentre, open-label, two-arm, parallel-group, non-inferiority randomised controlled trial. A total of 302 subjects with suspected OSA and/or resistant hypertension were consecutively enrolled, 149 were treated at 11 PC units and 153 patients at a SU. The primary outcomes were a 6-month change in the Epworth Sleepiness Scale (ESS) score and Health Utilities Index (HUI). The non-inferiority margin for the ESS score was −2.0. Results A total of 80.2% and 70.6% of the PC and SU patients were diagnosed with OSA, respectively, and 59.3% and 60.4% of those were treated with CPAP in PC and SU units, respectively. The Apnoea–Hypopnoea Index was similar between the groups (PC vs SU (median (IQR); 23.1 (26.8) events/h vs 21.8 (35.2) events/h), and the baseline ESS score was higher in the PC than in the SU group (10.3 (6.6) vs 9 (7.2)). After 6 months, the ESS score of the PC group decreased from a mean of 10.1 to 7.6 (−2.49; 95% CI −3.3 to −1.69), and that of the SU group decreased from 8.85 to 5.73 (−3.11; 95% CI −3.94 to 2.28). The adjusted difference between groups for the mean change in the ESS score was −1.25 (one-sided 95% CI −1.88; p=0.025), supporting the non-inferiority of PC management. We did not observe differences in the HUI between groups. The cost analysis showed a median savings of €558.14/patient for the PC setting compared with the SU setting. Conclusions Among patients with suspected OSA, the PC model did not result in a worse ESS score or HUI than the specialist model and generated savings in terms of management cost. Therefore, the PC model was more cost-efficient than the SU model. Trial registration Results; &gt;&gt; NCT02234765 , Clinical Trials.gov.