tbuckley/cabot-search huggingface dataset:
Abstract 5483: Investigating the role of the retinoblastoma protein in induction and maintenance of oncogene-induced cellular senescence in tumor suppression
Authors: Mohamad Harajly, Hasan Zalzali, Farah Ghamloush, Raya H. Saab
Journal: Cancer Research (2017)

Abstract Oncogene-induced cellular senescence is a tumor suppressor response resulting in irreversible cell cycle exit, and is dependent on the p53 and RB pathways. Loss of p53 has recently been shown to allow re-entry of senescent cells into the cell cycle. The role of the RB1 protein in maintenance of the senescent state is less well studied. We investigated whether RB1 is necessary for the induction as well as the maintenance of oncogene-induced senescence, and we also evaluated whether RB1 activation is sufficient to induce and/or maintain senesce in the absence of a functional p53 pathway. Inactivation of RB1 prior to onset of senescence led to failure of senescence induction, with impaired cell cycle exit and failure to induce senescence markers. On the other hand, loss of RB1 after cells had already entered oncogene-induced senescence was able to reverse some features of the senescence phenotype, but did not result in successful cell division and accumulation. Interestingly, in the absence of p53, constitutively active RB1 was sufficient for cells to undergo oncogene-induced senescence, and effectively prevented colony formation. Finally, while p53 inactivation was sufficient for senescent cells to re-enter the cell cycle, constitutive activation of RB1 prevented cell cycle re-entry, even in the absence of p53. Our findings show that RB1 is necessary for both the induction and maintenance of oncogene-induced senescence, and that active RB is sufficient for senescence induction as well as its maintenance, both in the presence and absence of p53. These results have direct implications on targeting RB activation as a senescence-inducing approach in both p53 wild type and p53-defective premalignant and malignant tumors. Note: This abstract was not presented at the meeting. Citation Format: Mohamad Harajly, Hasan Zalzali, Farah Ghamloush, Raya H. Saab. Investigating the role of the retinoblastoma protein in induction and maintenance of oncogene-induced cellular senescence in tumor suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5483. doi:10.1158/1538-7445.AM2017-5483
Abstract 1113: Inhibition of DNA repair by NR1D1 enhances chemosensitivity of breast cancer cells
Authors: Na-Lee Ka, Tae-Young Na, Hyelin Na, Mi-Ock Lee
Journal: Cancer Research (2017)

Abstract Most chemotherapeutic agents exert cytotoxic effects by inducing excessive DNA lesions in cancer cells. Therefore, regulating DNA repair networks is a critical factor that determines sensitivity of cancer cells to chemotherapeutic drugs. In this study, we identified the role of nuclear receptor NR1D1 in DNA repair, which enhanced chemosensitivity in breast cancer cells. NR1D1 inhibited recruitment of the DNA repair complex to damaged DNA sites, thereby impaired proper DNA repair upon doxorubicin treatment in breast cancer cells. Interaction with Poly(ADP-ribose) polymerase-1 and subsequent PARylation were critical steps that allow NR1D1 to translocate to DNA double-strand breaks. In agreement, depletion of NR1D1 in MCF-7 cells resulted in resistance to a chemotherapeutic drug, doxorubicin, in both in vitro and in vivo experiments. Further, NR1D1 expression level was correlated positively with clinical outcomes in breast cancer patients who received chemotherapy. Thus, NR1D1 and its ligands may provide better therapeutic options that could enhance the outcomes of adjuvant chemotherapy in breast cancer patients. Citation Format: Na-Lee Ka, Tae-Young Na, Hyelin Na, Mi-Ock Lee. Inhibition of DNA repair by NR1D1 enhances chemosensitivity of breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1113. doi:10.1158/1538-7445.AM2017-1113
<i>Bap1</i> and <i>Pbrm1:</i> Determinants of Tumor Grade and mTOR Activation in VHL-Deficient Mouse Models of Renal Cell Carcinoma
Authors: Janet Y. Leung, William Y. Kim
Journal: Cancer Discovery (2017)

Abstract Summary: Large genome sequencing efforts have identified frequent mutations in the histone-modifying and chromatin-remodeling genes BAP1 and PBRM1 in clear cell renal cell carcinoma (ccRCC). In this issue of Cancer Discovery, Gu and colleagues model these genetic events in mice and report that dual inactivation of Vhl with either Bap1 or Pbrm1 results in faithful genetically engineered murine models of ccRCC. Moreover, their work establishes that Bap1 and Pbrm1 are determinants of tumor grade and mTORC1 activation and provocatively suggests that the cell of origin of ccRCC may lie in PAX8-expressing Bowman capsule cells. Cancer Discov; 7(8); 802–4. ©2017 AACR. See related article by Gu et al., p. 900.
Profibrotic Infrapatellar Fat Pad Remodeling Without M1 Macrophage Polarization Precedes Knee Osteoarthritis in Mice With Diet‐Induced Obesity
Authors: Erika Barboza, Joanna Hudson, Wan‐Pin Chang, Susan Kovats, Rheal A. Towner, Robert Silasi‐Mansat, Florea Lupu, Collin Kent, Timothy M. Griffin
Journal: Arthritis & Rheumatology (2017)

Objective To test the hypothesis that high‐fat (HF) diet–induced obesity increases proinflammatory cytokine expression, macrophage infiltration, and M1 polarization in the infrapatellar fat pad (IFP) prior to knee cartilage degeneration. Methods We characterized the effect of HF feeding on knee OA pathology, body adiposity, and glucose intolerance in male C57BL/6J mice and identified a diet duration that induces metabolic dysfunction prior to cartilage degeneration. Magnetic resonance imaging and histomorphology were used to quantify changes in the epididymal, subcutaneous, and infrapatellar fat pads and in adipocyte sizes. Finally, we used targeted gene expression and protein arrays, immunohistochemistry, and flow cytometry to quantify differences in fat pad markers of inflammation and immune cell populations. Results Twenty weeks of feeding with an HF diet induced marked obesity, glucose intolerance, and early osteoarthritis (OA), including osteophytes and cartilage tidemark duplication. This duration of HF feeding increased the IFP volume. However, it did not increase IFP inflammation, macrophage infiltration, or M1 macrophage polarization as observed in epididymal fat. Furthermore, leptin protein levels were reduced. This protection from obesity‐induced inflammation corresponded to increased IFP fibrosis and the absence of adipocyte hypertrophy. Conclusion The IFP does not recapitulate classic abdominal adipose tissue inflammation during the early stages of knee OA in an HF diet–induced model of obesity. Consequently, these findings do not support the hypothesis that IFP inflammation is an initiating factor of obesity‐induced knee OA. Furthermore, the profibrotic and antihypertrophic responses of IFP adipocytes to HF feeding suggest that intraarticular adipocytes are subject to distinct spatiotemporal structural and metabolic regulation among fat pads.
ReMixT: clone-specific genomic structure estimation in cancer
Authors: Andrew W. McPherson, Andrew Roth, Gavin Ha, Cedric Chauve, Adi Steif, Camila P. E. de Souza, Peter Eirew, Alexandre Bouchard-Côté, Sam Aparicio, S. Cenk Sahinalp, Sohrab P. Shah
Journal: Genome biology (2017)

Somatic evolution of malignant cells produces tumors composed of multiple clonal populations, distinguished in part by rearrangements and copy number changes affecting chromosomal segments. Whole genome sequencing mixes the signals of sampled populations, diluting the signals of clone-specific aberrations, and complicating estimation of clone-specific genotypes. We introduce ReMixT, a method to unmix tumor and contaminating normal signals and jointly predict mixture proportions, clone-specific segment copy number, and clone specificity of breakpoints. ReMixT is free, open-source software and is available at http://bitbucket.org/dranew/remixt .
Abstract 4576: Targeted human cytolytic fusion proteins: an update
Authors: Stefan Barth
Journal: Cancer Research (2017)

Abstract Targeted immunotherapeutics, such as antibody drug conjugates (ADCs) or immunotoxins (ITs) represent promising agents for treatment of cancer. Despite their encouraging performance in clinical trials, both ADCs and ITs suffer from disadvantages like stoichiometrically undefined chemical linkage of the cytotoxic payload and potential immunogenicity of bacteria- or plant-derived toxins in humans, respectively. Therefore, in contrast to depleting B cell epitopes from bacterial toxins, we designed a number of targeted recombinant cytolytic fusion proteins, replacing bacterial toxins like Pseudomonas exotoxin A by human enzymes like proteases, kinases, RNases or microtubuli-associated proteins. Binding and biological activities were shown in vitro, ex vivo and in different in vivo models. This presentation will summarize the latest results on the hCFPs generated and demonstrate the efficacy of treatment of CD64-, CSPG4-, and EpCAM-targeting constructs in direct comparison to the corresponding Pseudomonas exotoxin-based immunotoxins. The presentation will conclude with an outlook on future perspective and applications of the next generation of targeted fully human recombinant cytolytic fusion proteins. Citation Format: Stefan Barth. Targeted human cytolytic fusion proteins: an update [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4576. doi:10.1158/1538-7445.AM2017-4576
Abstract 4650: Mutation detection by target sequence analyses using tissue-specific panels in esophageal squamous cell carcinoma
Authors: Takeshi Iwaya, Fumitaka Endo, Kohei Kume, Yasushi Sasaki, Takashi Tokino, Satoshi Nishizuka
Journal: Cancer Research (2017)

Abstract Whole-exome sequencing (WES) studies on esophageal squamous cell carcinoma (ESCC) have revealed that only a small number of frequently mutated genes, such as TP53, NOTCH1, NRF2, and ZNF750, are present in individual tumors, whereas hundreds of others less frequently mutated genes are accumulated. The mutation detection rate by target sequence analyses is an important factor for clinical sequence in the course of ESCC treatment. This study aimed to evaluate the mutation detection rates of several target sequence analyses for ESCC. Ten pairs of surgically or endoscopically acquired tumor tissues and corresponding peripheral blood mononuclear cells were obtained from ESCC patients. We used three types of target sequence panels for mutation screening in 10 ESCC patients as follows: 1) Cancer Hotspot Panel (CHPv2), targeting mutation hotspot regions in the most common 50 human cancer genes that are frequently mutated (panel size: 22,027 bp), for five patients; 2) TP53 Panel, covering all exons of TP53 (panel size: 2,359 bp), for five patients; and 3) ESCC Panel, originally designed to target 31 frequently mutated genes in ESCC (panel size: 210,570 bp), for seven patients. Four missense and two nonsense mutations in TP53 were detected in CHPv2 and the TP53 Panel. Furthermore, one missense mutation in FBXW7 and one intronic mutation in the vicinity of exon 8 in TP53 were also observed in CHPv2 and the TP53 Panel, respectively. In the ESCC Panel, 47 mutations in 17 genes were detected in seven patients. The mutation detection rates by the TP53 Panel, CHPv2, and ESCC Panel were 593.0/Mb, 63.5/Mb, and 30.4/Mb, respectively. These mutation detection rates were more than 20-fold higher than that of WES, which has been reported to be 3.1/Mb for ESCC. These results suggest that tissue-specific cancer-related gene panels are a highly effective approach for mutation detection in ESCC. Citation Format: Takeshi Iwaya, Fumitaka Endo, Kohei Kume, Yasushi Sasaki, Takashi Tokino, Satoshi Nishizuka. Mutation detection by target sequence analyses using tissue-specific panels in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4650. doi:10.1158/1538-7445.AM2017-4650
Abstract 5470: Reversibility of therapy-induced senescence in non-small cell lung cancer as a model of cancer recurrence
Authors: Tareq Saleh, Emmanuel K. Cudjoe, S Lauren Kyte, Scott C. Henderson, Lynne W. Elmore, David A. Gewirtz
Journal: Cancer Research (2017)

Abstract Disease recurrence at either primary or metastatic tumor sites arising from dormant tumors is largely responsible for the morbidity and mortality of many cancers. Although cellular quiescence has been proposed as a mechanism of dormancy, the nature of the growth arrest that allows tumor cells to re-emerge months or years after treatment has never been directly determined. The current work was designed to examine the hypothesis that the senescence induced by cancer chemotherapeutic drugs could be reversible, with implications for tumor dormancy and disease recurrence. Studies were performed using etoposide in models of non-small cell lung cancer (NSCLC). Exposure to etoposide at sublethal concentrations resulted in growth arrest accompanied by the induction of senescence and autophagy. Growth arrest was transient in that proliferative recovery was evident by day 7 post-etoposide exposure. Analysis of senescence based on β-galactosidase activity demonstrated that the restoration of proliferative capacity coincided with a decline in the extent of senescence. Real-time live microscopy demonstrated heterogeneous fates of senescent cells, where the bulk of the cell population remaining in a state of stasis, a subset of cells undergoing apoptosis, and a fraction of the large, flattened, and polyploid cells spontaneously entering into mitosis. Neither genetic nor pharmacological inhibition of autophagy influenced the senescence response to etoposide, the eventual proliferative recovery, or sensitivity to etoposide. These findings indicate that the induction and resolution of senescence is independent of the accompanying autophagy, and that the autophagy induced by etoposide is non-cytoprotective in function. These observations suggest that therapy-induced senescence may ultimately be a transient process in that at least a subpopulation of tumor cells can and will regain proliferative capacity. Consequently, therapy-induced senescence could potentially be studied as a model of tumor dormancy, and the reversibility of senescence as a model of disease recurrence. Citation Format: Tareq Saleh, Emmanuel K. Cudjoe, S Lauren Kyte, Scott C. Henderson, Lynne W. Elmore, David A. Gewirtz. Reversibility of therapy-induced senescence in non-small cell lung cancer as a model of cancer recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5470. doi:10.1158/1538-7445.AM2017-5470
Abstract LB-092: High impact of methylation accumulation on cancer risk: 5-year follow-up of a multicenter prospective cohort study
Authors: Masahiro Maeda, Takeshi Nakajima, Ichiro Oda, Taichi Shimazu, Nobutake Yamamichi, Takao Maekita, Kiyoshi Asada, Chizu Yokoi, Takayuki Ando, Takeichi Yoshida, Sohachi Nanjo, Mitsuhiro Fujishiro, Takuji Gotoda, Masao Ichinose, Toshikazu Ushijima
Journal: Cancer Research (2017)

Abstract Aberrant DNA methylation can be accumulated in normal-appearing tissues, and its degree can be correlated with cancer risk [Hattori, Genome Med, 8:10, 2016]. Such accumulation is especially prominent in inflammation-associated cancers, including gastric cancer. To bring the findings into cancer risk diagnosis, we conducted a multicenter prospective cohort study with 826 patients [Asada, Gut, 64:388, 2015]. Between 2008 and 2010, 826 patients after endoscopic treatment of gastric cancer and without current H. pylori infection were enrolled, and a gastric biopsy was collected. Methylation levels of pre-defined three marker genes (miR-124a-3, EMX1 and NKX6-1) were measured by quantitative methylation-specific PCR. Patients were classified into quartiles according to methylation levels of individual genes (Q1, the lowest; Q4, the highest). Among the 826 enrolled patients, 795 patients received annual follow-ups by endoscopy with a median period of 5.46 years (interquartile range: 3.95 - 6.09). By the end, 133 patients developed a metachronous gastric cancer, and 116 of them developed a cancer after 1 year of the enrollment (authentic metachronous cancer). Kaplan-Meier analysis showed that Q4 had a higher cumulative incidence of metachronous gastric cancer than Q1 with p-values of &amp;lt;0.001 to 0.004 (log-rank test). Multivariate analyses adjusted for hospital, gender and age, pepsinogen index, history of endoscopic treatment, smoking and green vegetable intake also showed that Q4 had significantly high HRs compared with Q1, being 3.0 (95%CI: 1.58 to 5.72, p=0.0017) for miR-124a-3 [Maeda, Gut, online]. The results clearly showed that accumulation levels of aberrant DNA methylation can be used for cancer risk diagnosis. Even among the patients who carried a high risk of metachronous gastric cancer, cancer risk stratification was achieved. The strong influence of methylation accumulation on gastric cancer risk indicated a large contribution of aberrant DNA methylation to H. pylori infection-induced gastric carcinogenesis. Epigenetic cancer risk diagnosis is now becoming real. Citation Format: Masahiro Maeda, Takeshi Nakajima, Ichiro Oda, Taichi Shimazu, Nobutake Yamamichi, Takao Maekita, Kiyoshi Asada, Chizu Yokoi, Takayuki Ando, Takeichi Yoshida, Sohachi Nanjo, Mitsuhiro Fujishiro, Takuji Gotoda, Masao Ichinose, Toshikazu Ushijima. High impact of methylation accumulation on cancer risk: 5-year follow-up of a multicenter prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-092. doi:10.1158/1538-7445.AM2017-LB-092
Abstract 4838: Optimization of prostate cancer organoid culture methods to grow PDX and human biopsy tissue
Authors: Mike L. Beshiri, Crystal Tran, Adam G. Sowalsky, Holly M. Nguyen, Supreet Agarwal, Caitlin M. Tice, Eva Corey, Kathy Kelly
Journal: Cancer Research (2017)

Abstract A major obstacle in the field of prostate cancer research is the limited capacity to culture prostate cancer-derived cells in vitro. There are relatively few established prostate cancer cell lines in use today. Those that are available are amenable to in vitro drug assays and mechanistic studies, but do not well-represent the genetic diversity of the disease, nor do they accurately predict in vivo response. Recently, organoid culture techniques have been developed for prostate cancer by the laboratories of Hans Clevers and Charles Sawyers that have increased our ability to grow metastatic tumor-derived prostate cancer cells in vitro. This represents a great step forward, but we are still restricted by the limited availability of biopsy tissue and the relatively low success rate (~20%) in establishing new organoid lines. The LuCaP series of patient-derived xenografts (PDXs) represents a well-characterized set of prostate cancer specimens that is genetically diverse, reflective of a range of treatment histories, and available to the research community. We have modified the organoid culture technique based upon systematic comparisons and analysis for organoid growth of the LuCaP PDXs. Our modified conditions represent an improvement upon the original growth conditions. We have successfully cultured 21 out of 24 LuCaPs attempted, for at least one generation, and 16 out of 24 are able to grow long-term over several generations. This includes 3 of the newest LuCaPs (167, 170.2, and 189.3) that we have genomically characterized. Comparison of the PDX and various organoid generations showed significant conservation of genomic changes ranging from 75-90% for nonsynonymous point mutations. The modified organoid culture method immediately and significantly increases the number of prostate cancer lines that are available by making the LuCaP PDXs accessible to in vitro culture. In addition to the PDXs, our method has improved the success for culturing metastatic samples grown from biopsies. We show here that 2 out of 3 patient-derived organoid lines that we have established, grow well in the modified conditions but poorly in the original culture conditions, the third grows equally well in both conditions. Citation Format: Mike L. Beshiri, Crystal Tran, Adam G. Sowalsky, Holly M. Nguyen, Supreet Agarwal, Caitlin M. Tice, Eva Corey, Kathy Kelly. Optimization of prostate cancer organoid culture methods to grow PDX and human biopsy tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4838. doi:10.1158/1538-7445.AM2017-4838
Use of Surveillance Mammography Among Older Breast Cancer Survivors by Life Expectancy
Authors: Rachel A. Freedman, Nancy L. Keating, Lydia E. Pace, Joyce Lii, Ellen P. McCarthy, Mara A. Schonberg
Journal: Journal of Clinical Oncology (2017)

Purpose The benefits of annual surveillance mammography in older breast cancer survivors with limited life expectancy are not known, and there are important risks; however, little is known about mammography use among these women. Materials and Methods We used National Health Interview Study data from 2000, 2005, 2008, 2010, 2013, and 2015 to examine surveillance mammography use among women age ≥ 65 years who reported a history of breast cancer. Using multivariable logistic regression, we assessed the probability of mammography within the last 12 months by 5- and 10-year life expectancy (using the validated Schonberg index), adjusting for survey year, region, age, marital status, insurance, educational attainment, and indicators of access to care. Results Of 1,040 respondents, 33.7% were age ≥ 80 years and 88.6% were white. Approximately 8.6% and 35.1% had an estimated life expectancy of ≤ 5 and ≤ 10 years, respectively. Overall, 78.9% reported having routine surveillance mammography in the last 12 months. Receipt of mammography decreased with decreasing life expectancy ( P < .001), although 56.7% and 65.9% of those with estimated ≤ 5-year and ≤ 10-year life expectancy, respectively, reported mammography in the last year. Conversely, 14.1% of those with life expectancy > 10 years did not report mammography. In adjusted analyses, lower ( v higher) life expectancy was significantly associated with lower odds of mammography (odds ratio, 0.4; 95% CI, 0.3 to 0.8 for ≤ 5-year life expectancy and OR, 0.4; 95% CI, 0.3 to 0.6 for ≤ 10-year life expectancy). Conclusion Many (57%) older breast cancer survivors with an estimated short life expectancy (< 5 years) receive annual surveillance mammography despite unknown benefits, whereas 14% with estimated life expectancy > 10 years did not report mammography. Practice guidelines are needed to optimize and tailor follow-up care for older patients.