tbuckley/cabot-search huggingface dataset:
Abstract 2185: Multiple region whole-genome sequencing reveals intratumor heterogeneity and branching clonal architecture of non-clear-cell renal cell carcinoma
Authors: Bin Zhu*, Luana Poeta*, Manuela Costantini*, Tongwu Zhang*, Steno Sentinelli, Jianxin Shi, Kevin Brown, Xing Hua, Meredith Yeager, Mingyi Wang, Belynda Hicks, Stephen Chanock*, Michele Gallucci*, Vito Fazio*, Maria Teresa Landi*
Journal: Cancer Research (2018)

Abstract Limited knowledge about the intratumor heterogeneity (ITH) of non-clear-cell renal cell carcinoma (nccRCC) hinders therapeutic efficacy. We performed multi-region whole-genome sequencing, genome-wide methylation profiling and deep targeted sequencing of both primary and paired metastatic tumors in 124 samples from 29 subjects with papillary renal cell carcinoma type 1, papillary renal cell carcinoma type 2 and collecting duct kidney tumors. Samples were taken from the tumors' center to the periphery at ~1.5cm from each other. We conducted integrative ITH analysis of single nucleotide variants, somatic copy number alterations, structural variants, transposon element insertions, telomere length and DNA methylation, and inferred their respective evolutionary history. We also analyzed the concordance between physical and lineage phylogenetic evolution, and inferred the regions from which the metastases likely originated. ITH varied significantly across tumors and histological subtypes. For example, the average number of structural variants per tumor was 1.2 in papillary RCC type 1 vs. 23.6 in papillary RCC type 2. In papillary tumors, ITH was lowest for copy number alterations (~5% subclonal changes across all tumor types), intermediate for single nucleotide variants (~32%), and highest for structural variants (~60%), suggesting a tumor molecular evolution along these steps. Lineage trees commonly showed branching evolutions with a dominant subclone. Focal deletion of the CDKN2A gene characterized the collecting duct tumors. Methylation ITH was highest in the enhancer regions. Metastatic and primary tumors shared similar mutation signatures. Telomere length was generally longer in normal vs. tumor samples and was similar in physically adjacent samples. In summary, our study characterized ITH of nccRCC with unprecedented details for multiple types of somatic alterations, and delineated the branching architecture of clonal evolution, including the metastatic phase. Citation Format: Bin Zhu*, Luana Poeta*, Manuela Costantini*, Tongwu Zhang*, Steno Sentinelli, Jianxin Shi, Kevin Brown, Xing Hua, Meredith Yeager, Mingyi Wang, Belynda Hicks, Stephen Chanock*, Michele Gallucci*, Vito Fazio*, Maria Teresa Landi*. Multiple region whole-genome sequencing reveals intratumor heterogeneity and branching clonal architecture of non-clear-cell renal cell carcinoma [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 2185.
Abstract 17660: Prevalence and Prognosis of Early Ischemic Moderate to Severe Mitral Regurgitation After Primary Percutaneous Coronary Intervention
Authors: Jimmy MacHaalany, Olivier F Bertrand, Yoann Bataille, Kim O’Connor, Eltigani Abdelaal, Pierre Voisine, éric Charbonneau, Jean-Pierre Déry, Mario Sénéchal
Journal: Circulation (2013)

Background: Previously reported prevalence of ischemic mitral regurgitation (IMR) ranged from 15-64%, with 3-16% developing late moderate to severe IMR. However, most of these studies were performed in a heterogeneous population and prior to the routine use of PCI for STEMI. The objective of this study was to determine the prevalence and clinical prognostic implication of early IMR after primary PCI. Methods: Between January 2006 and July 2012, 174 consecutive patients referred to our tertiary care center for primary PCI, within 12 hours of symptoms onset, were included. Early post-MI (1-2 days) and late post-MI (244 days [85 - 533]) echocardiography data were analyzed. Patients were categorized according to their early post-MI IMR grading: no-MR group (≤ mild: n=155, 89%), MR group (≥ moderate: n=19, 11%). Results: Mean age was 63 ± 12 years, 79% were males and median follow-up was 366 days [34-582]. At the end of follow-up, IMR ≥ moderate was documented in 15% of our entire cohort. MR regression (≥ mode...
Abstract 2187: A rapid autopsy program for cancer research
Authors: Thomas G. Beach, Lucia I. Sue, Geidy E. Serrano, Anthony Intorcia, Jessica Walker, Michael Glass, Michael Callan
Journal: Cancer Research (2018)

Abstract Many new technologies, such as genomics, transcriptomics, proteomics and metabolomics, are directed at molecular-level analyses of high-quality human normal and diseased tissues. At present, however, the relative lack of suitable tissue for this work is a critical roadblock to the full utilization of these new methods. Tissue is traditionally collected at the time of therapeutic surgical interventions, such as biopsy, or at the time of death, by autopsy. Biopsy is only done on individuals with disease and therefore normal control tissues are only obtained by chance. Biopsy tissue is often completely used for diagnostic purposes or is insufficient in quantity to constitute a shared resource, or for studies of intra-tumoral heterogeneity. Metastatic tissue is often not biopsied, precluding analysis of its evolving molecular changes. Both diseased and normal control tissue could potentially be obtained at autopsy, but autopsy tissue is generally only suitable when it is rapidly obtained after death. The Brain and Body Donation Program (BBDP) in Sun City, Arizona, is a not-for-profit longitudinal clinicopathological study of aging and is the world's only consistently-rapid autopsy program (3 h median). Board-certified pathologists diagnose all tissue microscopically. Many cases have both primary and metastatic tumor tissue. Both fresh-frozen &amp; formalin-fixed samples are saved. All subjects are research volunteers with comprehensive clinical documentation. Our informed consent allows wide sharing of tissue and data, including with for-profit companies. More than 100 cancer autopsies have been done; fixed and frozen tissue is available from more than 25 cancer types, many of which have both primary and metastatic tumor tissue. Normal control tissue is available from more than 40 tissue types and RNA quality is high (Walker DG et al, Cell Tissue Bank 2016 17(3):361-75). The BBDP is listed on the NCI Specimen Resource Locator, and inquiries may be made directly to our website, www.brainandbodydonationprogram.org. Citation Format: Thomas G. Beach, Lucia I. Sue, Geidy E. Serrano, Anthony Intorcia, Jessica Walker, Michael Glass, Michael Callan. A rapid autopsy program for cancer research [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 2187.
A Multicenter Study Into Causes of Severe Acute Liver Injury
Authors: Anthony C. Breu, Vilas R. Patwardhan, Jennifer Nayor, Jalpan N. Ringwala, Zachary G. Devore, Rahul B. Ganatra, Kelly E. Hathorn, Laura Horton, Sentia Iriana, Elliot B. Tapper
Journal: Clinical Gastroenterology and Hepatology (2018)
Abstract 3830: Monoclonal and bispecific antibodies against human insulin-like growth factors in oncology
Authors: Qi Zhao
Journal: Cancer Research (2018)

Abstract The insulin-like growth factor (IGF) axis plays an important role in cell growth and differentiation. During the past decade, IGF type 1 receptor (IGF-1R) was deemed a promising target for cancer therapy. The major challenge is that abnormal activation of IGF-1R ligands (IGF-I and IGF-II) exists in series of cancers and contributes to the resistance in IGF-1R-targeted therapies. The IGF-I/II actions are mediated through the IGF receptor type 1 (IGF-1R) and the insulin receptor (IR), which are overexpressed in multiple types of tumors. Up to date, we have developed different antibody formats against IGF-II or IGF-I/II, including one fully human IgG m708.5 with picomolar affinity[1], two bispecific antibodies (BsAbs) m660 [2, 3] and m67 [4], and one small-size nanobody s7g1 (15 kDa) (unpublished data). BsAb m67 has exhibited in cynomolgus macaques and high stability in serum. Compared with large-size antibodies, nanobody s7g1 has distinct advantages because of greater and more rapid tissue accumulation. All antibodies can eliminate the efflux of IGFs from tumor tissues and circulating IGFs in the serum. The m708.5 shows dual-specific for IGF-I/IGF-II with the highest affinities. The m708.5 has shown satisfying preclinical activities against a broad spectrum of human cell lines. When tested in neuroblastoma cell lines, m708.5 showed strong antitumor activity alone and in combination with chemotherapeutic agents [5]. Therefore, the anti-IGF-I/II antibodies offers an alternative approach to target both the IGF-1R and IR-A signaling pathways through the inhibition of IGF-I/II. These results support the clinical development of anti-IGF antibodies for solid tumors with potential for synergy with chemotherapy. Acknowledgements: This work was supported by the Science and Technology Development Fund of Macau (FDCT/131/2016/A3). References: 1. Zhao, Q., et al.. Mol Cancer Ther, 2011. 10(9): p. 1677-85. 2. Chen, W., et al.. Mol Cancer Ther, 2012. 11(7): p. 1400-10. 3. Feng, Y., et al.. Mol Cancer Ther, 2009. 8(5): p. 1113-8. 4. Feng, Y., et al.. Exp Mol Pathol, 2014. 97(3): p. 359-67. 5. Zhao, Q., et al.. Int J Cancer, 2015. 137(9): p. 2243-52. Citation Format: Qi Zhao. Monoclonal and bispecific antibodies against human insulin-like growth factors in oncology [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 3830.
Improved Therapeutic Outcome in Children with Acute Lymphoblastic Leukemia in Croatia
Authors: J. Konja, L. Rajic, S. Culic, J. Roganovic, E. Bilic, R. Femenic, R. Lasan Trcic, D. Batinic, G. Jakovljevic, M. Anicic
Journal: Annals of Oncology (2012)
Body Weight, Cardiovascular Risk Factors, and Coronary Mortality
Authors: PekkaJousilahti, JaakkoTuomilehto, ErkkiVartiainen, JuhaPekkanen, PekkaPuska
Journal: Circulation (1996)

Background Body weight is closely related to several known cardiovascular risk factors, but it may also have an independent effect on the risk of coronary heart disease (CHD). In this study, we analyzed the association between body mass index (BMI) and smoking, serum cholesterol, and blood pressure at baseline, as well as how BMI and the other risk factors are related to CHD mortality. Methods and Results A total of 16 113 men and women aged 30 to 59 years were examined in eastern Finland in either 1972 or 1977. Serum cholesterol and blood pressure had a positive association and smoking had a negative association with BMI. During the 15-year prospective follow-up, mortality from CHD was positively associated with BMI. The BMI-associated risk ratio of CHD mortality, adjusted for age and study year, estimated from the Cox proportional hazards model was 1.04 (per kg/m2) (P<.001) among men. Inclusion of smoking in the model increased the risk ratio for BMI, whereas inclusion of serum cholesterol and blood pre...
Abstract SY35-01: Systematic approaches to identify cancer dependencies
Authors: William C. Hahn
Journal: Cancer Research (2018)

Abstract We now have a draft view of the genetic alterations that occur in human cancer, and molecular profiling of cancers provides the means to identify therapeutic agents for some patients. However, the number of mutations found at low frequency, the molecular heterogeneity of most cancers, and the lack of therapeutic agents specific for many cancer drivers limit the application of precision medicine in many patients. To complement genome characterization studies, we have used genome-scale gain- and loss-of-function approaches to identify genes required for cell survival and transformation. Specifically, we have performed systematic studies to interrogate rare alleles found altered in cancer genomes and used advances in synthetic gene synthesis to prospectively interrogate all possible alleles of known cancer genes. In parallel, we have performed both genome-scale RNAi and CRISRP-Cas9 screens in more than 800 cancer cell lines to identify differentially essential genes and the context that specifies gene dependency. These studies allow us to define a global cancer dependencies map, which will help further operationalize precision cancer medicine. Citation Format: William C. Hahn. Systematic approaches to identify cancer dependencies [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 SY35-01.
Abstract 2344: Identification and validation of synthetic lethal cancer pairs from genome-wide CRISPR screens
Authors: Benjamin Schwartz, Junping Jing, Euan Stronach, David Cooper, Boris Wilson, Sarah Middleton, Mugdha Khaladkar, Coco Dong, Usman Shabon, Yanhua Rao, Stefanie Riesenberg
Journal: Cancer Research (2018)

Abstract Although most canonical somatic cancer mutations have now been cataloged, only a fraction are amenable to drug discovery efforts. These are limited to targets with gain of function mutations and druggable protein domains. Examples include kinases such as FLT3 and metabolic enzymes such as IDH1/2. However, excluded from this list are undruggable protein targets with gain of function mutations, such as KRAS, or tumor suppressors which acquire loss of function mutations, such as APC. The concept of synthetic lethality is being used to address this gap in cancer discovery. Cells which carry these directly undruggable somatic mutations become susceptible to inhibition of secondary targets. This susceptibility is specific in context to cells carrying the cancer associated mutation, offering both a novel approach for establishing efficacy as well as a potential therapeutic window for normal cells. The successful development of PARP inhibitors for BRCA mutant ovarian and breast cancers has provided the first clinical validation of this idea. Pooled, genome-wide knock out experiments are being pursued to systematically discover more of these types of synthetic lethalities. Typically, a sgRNA library is used to transfect a CAS9 expressing cancer cell line, and sequencing of the guides over time identifies lethalities specific to the cell line. Once this experiment is repeated over hundreds of cell lines, one can use the genomic information of the cell lines, such as mutations or copy number aberrations, to identify potential new combinations of molecular lethality. We have analyzed pooled CRISPR knockout data in a large panel of cancer cell lines generated from two independent sources (Broad Institute and Open Targets) to identify these types of lethality. Besides identifying targets for prevalent cancer mutations, we have also identified lethal combinations based on genes aberrantly deleted/silenced in cancers, termed “collateral lethality.” These include pairs of paralogs, many of which code enzymes with redundant functions. In this presentation we will outline our analysis strategies and methods, and describe the development of a downstream experimental validation pipeline, using a specific target/predictor pair to exemplify our approach. Citation Format: Benjamin Schwartz, Junping Jing, Euan Stronach, David Cooper, Boris Wilson, Sarah Middleton, Mugdha Khaladkar, Coco Dong, Usman Shabon, Yanhua Rao, Stefanie Riesenberg. Identification and validation of synthetic lethal cancer pairs from genome-wide CRISPR screens [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 2344.
Abstract 14251: Nuclear Accumulation of Muscle LIM Protein is Regulated by Myocyte Contractility and Correlates With Cardiac Function in the Transition to Heart Failure
Authors: Anju Paudyal, Sukriti Dewan, Cindy Ikie, Pieter D de Tombe, Samuel Y Boateng
Journal: Circulation (2015)

Prolonged increases in hemodynamic load lead to a loss of mechanosensing and heart failure because myocytes are unable to adapt to alterations in mechanical stress. We have previously shown that a decreased ratio of cytoplasmic to nuclear Muscle LIM protein (the MLP ratio) is associated with a loss of mechanosensitivity in human heart failure. However, the type and duration of mechanical stress that leads to impaired mechanosensitivity is unknown. In this study, we tested whether passive or active stress/strain was more important in modulating the MLP ratio (a measure of mechanosensitivity) and determined whether this correlated with heart function during the transition to failure. To test this, we exposed cultured neonatal rat myocytes to 48 h of 10% cyclic mechanical stretch at 1 Hz to mimic the passive forces associated with changes in blood pressure and volume. To mimic the forces generated by crossbridge activity during systole, we electrically paced myocytes at 6.8 V (1Hz) for 48 hours. The MLP ratio decreased 50% (p&lt;0.05, n=4 cultures) only in response to electrical pacing, suggesting impaired mechanosensitivity. We then inhibited contractility by treating myocytes with 10μM blebbistatin which resulted in a 3 fold increase in the MLP ratio (n=8 cultures, p&lt;0.05). This indicates that myocyte contractility regulates MLP nuclear shuttling and mechanosensitivity. To examine how mechanosensitivity changes during the transition to heart failure, we examined a guinea pig model of angiotensin II infusion (400ng/kg/min). The hearts were examined at 4, 8 and 12 weeks post-operatively. Using subcellular fractionation we showed that the MLP ratio increased 88% (n=4, P=0.009) during compensated phase at 8 weeks, but decreased significantly during heart failure at 12 weeks (p=0.0003, n=4). Furthermore, the MLP ratio correlated significantly with the E/A ratio (r=0.71, p&lt;0.01 n=12), a clinical measure of diastolic function. This data indicate that impaired cardiac mechanosensitivity resulting in a reduced MLP ratio is regulated predominantly by myofilament crossbridge activity rather than passive strain. Increased mechanical stress within the contracting myofilaments contributes to the loss of mechanosensing during the transition to heart failure.
Abstract 4587: <i>ESR1</i> methylation in primary tumors and paired circulating tumor DNA of patients with high-grade serous ovarian cancer
Authors: Lydia Giannopoulou, Sofia Mastoraki, Areti Strati, Issam Chebouti, Kitty Pavlakis, Sabine Kasimir-Bauer, Evi Lianidou
Journal: Cancer Research (2018)

Abstract Background: The estrogen receptor is highly expressed in epithelial ovarian cancer and represents the main target for endocrine therapy. The ESR1 gene is frequently methylated in many types of gynecological malignancies and previous studies have shown an inverse correlation between ESR1 methylation and gene expression. Few studies attempted to investigate the role of ESR1 methylation in ovarian cancer so far, and the clinical significance of ESR1 methylation status is not as yet clear. Methods: The ESR1 methylation status was examined in primary tumors and corresponding circulating tumor DNA (ctDNA) samples of patients with high-grade serous ovarian cancer. For the detection of methylation we applied a novel highly specific and sensitive real-time methylation specific PCR (real-time MSP) assay. Two groups of primary tumor samples were recruited (training group, n=66 and validation group, n=61), along with the corresponding plasma samples (n=58) for the validation group. ESR1 methylation was also analyzed in a small group of 16 normal fallopian tube samples. Results: ESR1 was found methylated in both groups of primary tumor samples and in the corresponding plasma samples of the validation group. More specifically, ESR1 methylation was detected in 32/66 (48.5%) and 17/61 (27.9%) primary tumor samples of the training and the validation group, respectively, and in 23/58 (39.7%) corresponding plasma samples. A significant agreement between ESR1 methylation in primary tumors and paired ctDNA was observed in 40/56 (71.4%) samples of the validation group (P=0.004, k=0.360). Almost all normal fallopian tube samples (15/16) were found methylated. Interestingly, the presence of ESR1 methylation in the primary tumor samples of the validation group was nearly significantly correlated (P=0.057) with a better overall survival. Conclusions: We detected for the first time ESR1 methylation in ctDNA of patients with high-grade serous ovarian cancer. The agreement between ESR1 methylation in the primary tumors and paired ctDNA is statistically significant. Our results indicate a potential correlation between ESR1 methylation and better overall survival in high-grade serous ovarian cancer patients. Citation Format: Lydia Giannopoulou, Sofia Mastoraki, Areti Strati, Issam Chebouti, Kitty Pavlakis, Sabine Kasimir-Bauer, Evi Lianidou. ESR1 methylation in primary tumors and paired circulating tumor DNA of patients with high-grade serous ovarian 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 4587.
Engaging Patients in Value-Based Cancer Care
Authors: S. Yousuf Zafar, Blase N. Polite, Mark McClellan
Journal: JAMA Oncology (2018)

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
Involvement of Cardiotrophin-1 in Cardiac Myocyte-Nonmyocyte Interactions During Hypertrophy of Rat Cardiac Myocytes In Vitro
Authors: KoichiroKuwahara, YoshihikoSaito, MasakiHarada, MasahiroIshikawa, EmikoOgawa, YoshihiroMiyamoto, IchiroHamanaka, ShigekiKamitani, NoboruKajiyama, NobukiTakahashi, OsamuNakagawa, IzuruMasuda, KazuwaNakao
Journal: Circulation (1999)

Background—The mechanism responsible for cardiac hypertrophy is currently conceptualized as having 2 components, mediated by cardiac myocytes and nonmyocytes, respectively. The interaction between myocytes and nonmyocytes via growth factors and/or cytokines plays an important role in the development of cardiac hypertrophy. We found that cardiac myocytes showed hypertrophic changes when cocultured with cardiac nonmyocytes. Cardiotrophin-1 (CT-1), a new member of the interleukin-6 family of cytokines, was identified by its ability to induce hypertrophic response in cardiac myocytes. In this study, we used the in vitro coculture system to examine how CT-1 is involved in the interaction between cardiac myocytes and nonmyocytes during the hypertrophy process. Methods and Results—RNase protection assay revealed that CT-1 mRNA levels were 3.5 times higher in cultured cardiac nonmyocytes than in cultured cardiac myocytes. We developed anti–CT-1 antibodies and found that they significantly inhibited the increased ...