tbuckley/cabot-search huggingface dataset:
Abstract 2060: Therapeutic approaches for CCNE1-amplified HR-proficient ovarian cancer
Authors: Shoumei Bai, Ronald J. Buckanovich
Journal: Cancer Research (2021)

Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors have shown great success in ovarian cancer patients that are homologous recombination deficient (HRD). However, approximately 50% of high grade serous ovarian cancer (HGSOC) are HR-proficient. HR-proficient Cancer cells evade lethal DNA damage by triggering HR pathways at the cost of genome stability and evolving of more aggressive cancer cells. Cyclin E1 (CCNE1) amplification is a major subset of known HR-proficient HGSOC. This subset of cancer responds poorly to essentially all available ovarian cancer therapies including PARP inhibitors. Our study showed that the mTOR, HR, and checkpoint pathways were enriched in CCNE1-amplifed ovarian cancer patients. Interactome mapping demonstrated that many of the interactive proteins in the mTOR pathway were also components of HR and DNA checkpoint pathways. mTOR inhibition resulted in downregulation of HR and DNA checkpoint proteins. Downregulation of ATR partly mirrored mTOR inhibition. mTOR inhibitors and ATR inhibitors synergized with PARP inhibitors in vitro and in vivo in CCNE1-amplified HGSOC tumors. This was associated with decrease in cancer stem-like cancer cells and loss of polyploid tumor cells, which are vital for evolving of more aggressive, therapy-resistant cancer cells. These studies will have potential impact on further preclinical validation and clinical applications to cure CCNE1-amplifed HRP ovarian cancer. Citation Format: Shoumei Bai, Ronald J. Buckanovich. Therapeutic approaches for CCNE1-amplified HR-proficient ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2060.
Abstract 1962: Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models
Authors: Sandra E. Wiley, Yongwei Su, Yubin Ge
Journal: Cancer Research (2021)

Abstract Mutations in KRAS at G12, G13, and Q61 are oncogenic drivers in many cancers, including lung, colorectal, pancreatic, multiple myeloma, and uterine carcinomas. KRAS mutations are frequently accompanied by stabilization of the MYC oncoprotein through increased MYC transcription and decreased protein degradation that is mediated by phosphorylation of MYC on Ser 62 by ERK and CDK9 kinases. Voruciclib is a novel oral inhibitor of CDKs 9, 4, 6, and 1 that is currently being tested in Phase 1B clinical trials for B-cell malignancies and acute myeloid leukemia. Voruciclib inhibition of CDK9 leads to decreased expression of transcriptional targets of RNA Pol II, such as Mcl1 and MYC. To test whether voruciclib could be effective in cancers driven by dysregulated KRAS-MYC signaling, ~20 cancer cell lines with KRAS mutations (G12A, G12C, G12D, G12S, G12V, G13C, G13D, Q61H) were treated in preclinical studies with voruciclib. MTS and Cell Titer Glo assays were used to monitor growth in vitro. Voruciclib decreased viability in all cell lines tested. To investigate MYC protein stability, MIA PACA-2 (G12C) cells were treated with 4 µM voruciclib for 5-240 min, followed by SDS-PAGE and Western Blotting analysis with α-MYC and α-pSer62-MYC antibodies. Voruciclib treatment resulted in a reduction in phosphorylation of MYC on Ser 62. A 60% decrease in pSer62 was observed after 5 min that reached 80% by 60 min. In contrast, there was no decrease in total MYC protein at either 5 or 15 min. A 10% reduction in total MYC was observed at 60 min that reached 50% at 240 min. The ability of voruciclib to inhibit tumor growth in vivo was also tested in murine xenograft models. KRAS mutant human cancer cells HCT-116 (CRC, KRAS G13D), SW-480 (CRC, KRAS G12V), and H-460 (NSCLC, KRAS Q61H) were injected subcutaneously into SCID mice. Once tumors reached 5-10 mm in diameter, voruciclib or vehicle were administered orally at 50, 100, or 200 mg/kg OD for 11-14 days. Tumors were measured every 2-3 days, and growth inhibition relative to control was calculated. Significant tumor growth inhibition (&amp;gt;50%) was observed at all doses of voruciclib tested. Collectively, these data demonstrate that voruciclib inhibition of CDK9 leads to reduced phosphorylation of MYC on Ser 62 followed by a decrease in total MYC protein in MIA PACA-2 cells and inhibition of growth in multiple KRAS mutant cancer cell lines in vivo and in vitro. This suggests that voruciclib could be an attractive therapeutic option for cancers driven by KRAS-MYC. Citation Format: Sandra E. Wiley, Yongwei Su, Yubin Ge. Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1962.
The evolving gene regulatory landscape—a tinkerer of complex creatures
Authors: Geoffrey J. Faulkner
Journal: Genome biology (2021)

Our genome is littered with DNA of no clear function.Yet, as shown recurrently by this Special Issue on Regulatory Elements, sequences outside of protein-coding exons are responsible for many, if not most, of the phenotypic differences observed amongst species and individuals.Over the course of evolution, these noncoding regions can provide the raw materials to Jacob's tinkerer [1], yielding new regulatory switches that shift the spatiotemporal specificity of gene expression.As reviewed by Panigrahi and O'Malley [2], exquisite resolution of genome organisation, accessibility, transcription factor binding, and DNA modifications, now allows the discovery and characterisation of enhancers, promoters, silencers, and other regulatory elements en masse.Tracing the evolutionary origins of these elements in different species provides a window into their often similar histories, as well as their present functions.By consequence, this Special Issue of Genome Biology is of exceptionally broad biological scope.It presents molecular and computational analyses of diverse experimental systems.The works contained within are however unified by their intent to simplify and better understand the complex relationships between regulatory elements and protein-coding genes.Transposable elements (TEs) occupy a large proportion of most eukaryotic genomes and, as first shown by McClintock [3], are a major source of gene regulatory innovation.Judd et al. [4] report that the circadian transcriptional network in mouse liver incorporates a number of circadian-responsive TE enhancers contributed by members of the immobile murine RSINE1 family.Focusing on another class of TEs, Troskie et al. [5] use PacBio long-read sequencing to survey the transcriptome of human pseudogenes and identify alternative promoters for various protein-coding genes, such as RB1, that are embedded in upstream pseudogenes.A theme of these TE studies, and one shared by the analysis of duplicated gene (ohnolog) regulation in several fish species by Gillard et al. [6], is that TEs spread tissue-specific regulatory elements encoding novel transcription factor binding sites.Another common thread of this Special Issue is the measurement of proteincoding gene transcription as a readout of regulatory element activity.For instance,
Abstract 3108: Human telomerase reverse transcriptase regulates stemness of pancreatic cancer
Authors: Juanjuan Ye, Keiko Yamakawa, Yuko Narusawa, Yoko Matsuda
Journal: Cancer Research (2021)

Abstract Backgrounds: Human telomerase reverse transcriptase (hTERT) plays a key role on immortalization of cancer cells. In the present study, we clarified the effect of small interfering RNA (siRNA) targeting hTERT in pancreatic cancer cell lines. Methods: Two sequences of siRNA targeting hTERT and negative control siRNA were transfected into PANC-1 and MIA PaCa-2 human pancreatic cancer cell lines. Cell proliferation (WST-8 cell counting assay), stemness (sphere formation) and migration (scratch assay) were analyzed using hTERT-siRNA transfected cells and control-siRNA transfected cells. The expression levels of CDK1, SOX9 and nestin were analyzed by real time PCR. Results: As compared to control-siRNA, hTERT-siRNA suppressed cell proliferation and stemness of pancreatic cancer cell lines. Cell migration did not show any difference between hTERT-siRNA and control-siRNA transfected cells. The expression levels of CDK1, SOX9 and nestin in hTERT-siRNA transfected cells were lower than those in control-siRNA transfected cells. Conclusion: The present study indicates that inhibition of hTERT in pancreatic cancer cells suppressed stemness via alteration of the expression levels of CDK1, SOX9 and nestin. Citation Format: Juanjuan Ye, Keiko Yamakawa, Yuko Narusawa, Yoko Matsuda. Human telomerase reverse transcriptase regulates stemness of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3108.
Paired Tumor-Normal Sequencing Provides Insights Into the <i>TP53</i>-Related Cancer Spectrum in Patients With Li-Fraumeni Syndrome
Authors: Ozge Ceyhan-Birsoy, Pier Selenica, M Herman Chui, Gowtham Jayakumaran, Ryan Ptashkin, Maksym Misyura, Umut Aypar, Sowmya Jairam, Ciyu Yang, Yirong Li, Nikita Mehta, Yelena Kemel, Erin Salo-Mullen, Anna Maio, Margaret Sheehan, Ahmet Zehir, Maria Carlo, Alicia Latham, Zsofia Stadler, Mark Robson, Kenneth Offit, Marc Ladanyi, Michael Walsh, Jorge S Reis-Filho, Diana Mandelker
Journal: JNCI Journal of the National Cancer Institute (2021)

Genetic testing for Li-Fraumeni syndrome (LFS) is performed by using blood specimens from patients selected based on phenotype-dependent guidelines. This approach is problematic for understanding the LFS clinical spectrum because patients with nonclassical presentations are missed, clonal hematopoiesis-related somatic blood alterations cannot be distinguished from germline variants, and unrelated tumors cannot be differentiated from those driven by germline TP53 defects.To provide insights into the LFS-related cancer spectrum, we analyzed paired tumor-blood DNA sequencing results in 17 922 patients with cancer and distinguished clonal hematopoiesis-related, mosaic, and germline TP53 variants. Loss of heterozygosity and TP53 mutational status were assessed in tumors, followed by immunohistochemistry for p53 expression on a subset to identify those lacking biallelic TP53 inactivation.Pathogenic/likely pathogenic TP53 variants were identified in 50 patients, 12 (24.0%) of which were clonal hematopoiesis related and 4 (8.0%) of which were mosaic. Twelve (35.3%) of 34 patients with germline TP53 variants did not meet LFS testing criteria. Loss of heterozygosity of germline TP53 variant was observed in 96.0% (95% confidence interval [CI] = 79.7% to 99.9%) of core LFS spectrum-type tumors vs 45.5% (95% CI = 16.8% to 76.6%) of other tumors and 91.3% (95% CI = 72.0% to 98.9%) of tumors from patients who met LFS testing criteria vs 61.5% (95% CI = 31.6% to 86.1%) of tumors from patients who did not. Tumors retaining the wild-type TP53 allele exhibited wild-type p53 expression.Our results indicate that some TP53 variants identified in blood-only sequencing are not germline and a substantial proportion of patients with LFS are missed based on current testing guidelines. Additionally, a subset of tumors from patients with LFS do not have biallelic TP53 inactivation and may represent cancers unrelated to their germline TP53 defect.
Conservative management of grade 4 and 5 renal injuries
Authors: C. Fragkoulis, I. Glykas, D. Moschotzopoulos, S. Lamprou, A. Kaoullas, A. Leventi, M. Gravanis, G. Karydas, G. Stathouros, G. Papadopoulos, K. Ntoumas
Journal: European Urology (2021)
Clinical subphenotypes in COVID-19: derivation, validation, prediction, temporal patterns, and interaction with social determinants of health
Authors: Chang Su, Yongkang Zhang, James H. Flory, Mark G. Weiner, Rainu Kaushal, Edward J. Schenck, Fei Wang
Journal: npj Digital Medicine (2021)

The coronavirus disease 2019 (COVID-19) is heterogeneous and our understanding of the biological mechanisms of host response to the viral infection remains limited. Identification of meaningful clinical subphenotypes may benefit pathophysiological study, clinical practice, and clinical trials. Here, our aim was to derive and validate COVID-19 subphenotypes using machine learning and routinely collected clinical data, assess temporal patterns of these subphenotypes during the pandemic course, and examine their interaction with social determinants of health (SDoH). We retrospectively analyzed 14418 COVID-19 patients in five major medical centers in New York City (NYC), between March 1 and June 12, 2020. Using clustering analysis, 4 biologically distinct subphenotypes were derived in the development cohort (N = 8199). Importantly, the identified subphenotypes were highly predictive of clinical outcomes (especially 60-day mortality). Sensitivity analyses in the development cohort, and rederivation and prediction in the internal (N = 3519) and external (N = 3519) validation cohorts confirmed the reproducibility and usability of the subphenotypes. Further analyses showed varying subphenotype prevalence across the peak of the outbreak in NYC. We also found that SDoH specifically influenced mortality outcome in Subphenotype IV, which is associated with older age, worse clinical manifestation, and high comorbidity burden. Our findings may lead to a better understanding of how COVID-19 causes disease in different populations and potentially benefit clinical trial development. The temporal patterns and SDoH implications of the subphenotypes may add insights to health policy to reduce social disparity in the pandemic.
Outcomes of 10 years’ experience of percutaneous cryoablation for the treatment of cT1 renal tumour presented according to RENAL, PADUA and ABLATE nephrometry systems
Authors: A. Piasentin, M. Rizzo, G. Rebez, F. Claps, L. Ongaro, P. Cabas, R. Ciabattoni, G. Visalli, C. Marrocchio, F. Giudici, S. Cernic, M. Bertolotto, M.A. Cova, C. Trombetta, G. Liguori
Journal: European Urology (2021)
Abstract 2378: Circulating microRNAs and cytokines as prognostic biomarkers for doxorubicin-induced cardiac injury and for evaluating the beneficial effects of exercise
Authors: Prince Jeyabal, Eugenie S. Kleinerman
Journal: Cancer Research (2021)

Abstract Introduction: Cardiotoxicity and late cardiomyopathies compromise survival in &amp;gt;50% of childhood cancer survivors treated doxorubicin (Dox). Early intervention is important for initiating therapy to preserve heart function. There are no accepted biomarkers identifying which patients are at risk for developing cardiac problems and no interventions to inhibit the cardiac damage. Troponin has not proved useful for predicting Dox-induced cardiotoxicity and patient outcome. We developed a pediatric mouse cardiotoxicity model to define early biomarkers of Dox-induced cardiac injury, investigate the efficacy of an exercise intervention, and whether these biomarkers can be used as a non-invasive method to monitor exercise effectiveness. Hypothesis: Circulating micro-RNAs are increased during Dox but not Dox + exercise therapy which correlate with cardiac damage. These can be used to monitor intervention effectiveness. Methods: Mice were treat with Dox (2.5mg/kg 2x/wk for 2 wks), Dox + exercise (walking 45 min/day at 12 meter/min) or PBS. Cardiac function was evaluated by echocardiography 24 hrs after therapy. Blood was collect before and 6 and 24 hrs after therapy. Plasma cytokine levels, troponin and miRNAs (miRNA 1, 29b, 499) were quantified. We also obtained plasma samples from Dox-treated osteosarcoma patients. Results: Decreased ejection fraction and fractional shortening were seen in Dox but not Dox + exercise-treated mice. There was an increase in miR-1 and miR-499 and the pro-inflammatory cytokines IL-1α, IL-1β and IL-6, in Dox-treated but not Dox + exercise-treated mice compared with PBS controls. Troponin levels were not elevated until 24 hrs following therapy. Increased miRNAs and cytokines in the Dox-treated patient plasma samples 24 hrs after therapy mimicked the results observed in mice. Conclusion: These data indicate that miRNA499, miRNA1, IL-1α, IL-1β and IL-6 are early biomarkers of Dox-induced cardiac injury which predict cardiac functional changes and can be used to evaluate intervention efficacy during combined therapy. Following these biomarkers may also assist in identifying patients at risk for cardiac late effects and also enable intervention modification as needed. Citation Format: Prince Jeyabal, Eugenie S. Kleinerman. Circulating microRNAs and cytokines as prognostic biomarkers for doxorubicin-induced cardiac injury and for evaluating the beneficial effects of exercise [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2378.
Low-Dose Interleukin-2 Restores Human Regulatory T Cell Function, in Vitro, As a Potential in the Handle of Graft Versus Host Disease (GvHD)
Authors: Tzeon-Jye Chiou, Hsiu-Hsia Lin, Wei-Hao Wu, Jhih-Yun Jian, Sin-Tak Chu, Woan-Fang Tzeng
Journal: Blood (2017)
Site Specific Knock-In Genome Editing in Human HSCs Using Baboon Envelope gp Pseudotypedviral Derived “Nanoblades” Loaded with Cas9/sgRNA Combined with Donor Encoding AAV-6
Authors: Alejandra Gutierrez, Maria Jimena Abrey Recalde, Philippe E. Mangeot, Caroline Costa, Ornellie Bernandin, Floriane Fusil, Gisèle Froment, Francisco Martin, Karim Bellabdelah, Emiliano P. Ricci, Eduard Ayuso, François loic Cosset, Els Verhoeyen
Journal: Molecular Therapy (2019)
Public Preferences for Social Distancing Policy Measures to Mitigate the Spread of COVID-19 in Missouri
Authors: Ingrid Eshun-Wilson, Aaloke Mody, Virginia McKay, Matifadza Hlatshwayo, Cory Bradley, Vetta Thompson, David V. Glidden, Elvin H. Geng
Journal: JAMA Network Open (2021)

Policies to promote social distancing can minimize COVID-19 transmission but come with substantial social and economic costs. Quantifying relative preferences among the public for such practices can inform locally relevant policy prioritization and optimize uptake.To evaluate relative utilities (ie, preferences) for COVID-19 pandemic social distancing strategies against the hypothetical risk of acquiring COVID-19 and anticipated income loss.This survey study recruited individuals living in the Missouri area from May to June 2020 via randomly distributed unincentivized social media advertisements and local recruitment platforms for members of minority racial and ethnic groups. Participants answered 6 questions that asked them to choose between 2 hypothetical counties where business closures, social distancing policy duration, COVID-19 infection risk, and income loss varied.Reweighted population-level relative preferences (utilities) for social distancing policies, subgroups, and latent classes.The survey had a 3% response rate (3045 of 90 320). Of the 2428 respondents who completed the survey, 1669 (75%) were 35 years and older, 1536 (69%) were women, and 1973 (89%) were White. After reweighting to match Missouri population demographic characteristics, the strongest preference was for the prohibition of large gatherings (mean preference, -1.43; 95% CI, -1.67 to -1.18), with relative indifference to the closure of social and lifestyle venues (mean preference, 0.05; 95% CI, -0.08 to 0.17). There were weak preferences to keep outdoor venues (mean preference, 0.50; 95% CI, 0.39 to 0.61) and schools (mean preference, 0.18; 95% CI, 0.05 to 0.30) open. Latent class analysis revealed 4 distinct preference phenotypes in the population: risk averse (48.9%), conflicted (22.5%), prosocial (14.9%), and back to normal (13.7%), with men twice as likely as women to belong to the back to normal group than the risk averse group (relative risk ratio, 2.19; 95% CI, 1.54 to 3.12).In this survey study using a discrete choice experiment, public health policies that prohibited large gatherings, as well as those that closed social and lifestyle venues, appeared to be acceptable to the public. During policy implementation, these activities should be prioritized for first-phase closures. These findings suggest that policy messages that address preference heterogeneity (eg, focusing on specific preference subgroups or targeting men) could improve adherence to social distancing measures for COVID-19 and future pandemics.
Impact of the COVID-19 Pandemic on Breast Cancer Mortality in the US: Estimates From Collaborative Simulation Modeling
Authors: Oguzhan Alagoz, Kathryn P Lowry, Allison W Kurian, Jeanne S Mandelblatt, Mehmet A Ergun, Hui Huang, Sandra J Lee, Clyde B Schechter, Anna N A Tosteson, Diana L Miglioretti, Amy Trentham-Dietz, Sarah J Nyante, Karla Kerlikowske, Brian L Sprague, Natasha K Stout
Journal: JNCI Journal of the National Cancer Institute (2021)

The coronavirus disease 2019 (COVID-19) pandemic has disrupted breast cancer control through short-term declines in screening and delays in diagnosis and treatments. We projected the impact of COVID-19 on future breast cancer mortality between 2020 and 2030.Three established Cancer Intervention and Surveillance Modeling Network breast cancer models modeled reductions in mammography screening use, delays in symptomatic cancer diagnosis, and reduced use of chemotherapy for women with early-stage disease for the first 6 months of the pandemic with return to prepandemic patterns after that time. Sensitivity analyses were performed to determine the effect of key model parameters, including the duration of the pandemic impact.By 2030, the models project 950 (model range = 860-1297) cumulative excess breast cancer deaths related to reduced screening, 1314 (model range = 266-1325) associated with delayed diagnosis of symptomatic cases, and 151 (model range = 146-207) associated with reduced chemotherapy use in women with hormone positive, early-stage cancer. Jointly, 2487 (model range = 1713-2575) excess breast cancer deaths were estimated, representing a 0.52% (model range = 0.36%-0.56%) cumulative increase over breast cancer deaths expected by 2030 in the absence of the pandemic's disruptions. Sensitivity analyses indicated that the breast cancer mortality impact would be approximately double if the modeled pandemic effects on screening, symptomatic diagnosis, and chemotherapy extended for 12 months.Initial pandemic-related disruptions in breast cancer care will have a small long-term cumulative impact on breast cancer mortality. Continued efforts to ensure prompt return to screening and minimize delays in evaluation of symptomatic women can largely mitigate the effects of the initial pandemic-associated disruptions.
Why are there so few (or so many) circulating coronaviruses?
Authors: Benjamin L. Rice, Daniel C. Douek, Adrian B. McDermott, Bryan T. Grenfell, C. Jessica E. Metcalf
Journal: Trends in Immunology (2021)

Despite vast diversity in non-human hosts and conspicuous recent spillover events, only a small number of coronaviruses have been observed to persist in human populations. This puzzling mismatch suggests substantial barriers to establishment. We detail hypotheses that might contribute to explain the low numbers of endemic coronaviruses, despite their considerable evolutionary and emergence potential. We assess possible explanations ranging from issues of ascertainment, historically lower opportunities for spillover, aspects of human demographic changes, and features of pathogen biology and pre-existing adaptive immunity to related viruses. We describe how successful emergent viral species must triangulate transmission, virulence, and host immunity to maintain circulation. Characterizing the factors that might shape the limits of viral persistence can delineate promising research directions to better understand the combinations of pathogens and contexts that are most likely to lead to spillover.