tbuckley/cabot-search huggingface dataset:
Abstract I25: Understanding and exploiting natural barriers to pancreatic tumorigenesis
Authors: Scott W. Lowe
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an extraordinarily aggressive cancer that arises in the context of a unique tumor microenvironment. Molecularly, PDAC involves a combination of undruggable cancer drivers, including activating mutations in the KRAS oncogene and disruption of tumor suppressors such a TP53, SMAD4, and CDKN2A together with poorly characterized epigenetic changes that correlate with metastatic progression. Histologically, PDAC arises within a heterogeneous tissue microenviroment characterized by dense fibroinflammatory stroma that influences disease progression and limits therapy response. Our laboratory has developed genetically engineered mouse models based on ES cells (GEMMESCs) of pancreas cancer, where chimeric mice are produced directly from multiallelic ES cells harboring a latent KrasG12D oncogene together with all the genetic elements needed for Kras activation in the together with those needed for tetracycline-inducible (and reversible) regulation of short hairpin RNAs targeting capable of suppressing any gene of interest at any time after pancreas cancer initiation. Using this system, we have probed the epigenetic requirements for pancreas cancer initiation and compare them to those required for pancreatic regeneration following tissue damage; in addition, we have explored the metabolic programs needed for p53 to suppress tumorigenesis. Our studies have identified elements of cellular plasticity that act at multiple points that suppress pancreas cancer progression and identify actionable intervention points required for these transitions. Citation Format: Scott W. Lowe. Understanding and exploiting natural barriers to pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I25.
Feasibility of aorta after endarterectomy as middle hepatic vein reconstruction in living donor liver transplantation
Authors: Jae Hyun Kwon, Dong-hwan Jung, Shin Hwang, Ki-hun Kim, Chul-soo Ahn, Deok-bog Moon, Gi-won Song, Gil-chun Park, Young-in Yoon, Hwui-dong Cho, Sung-gyu Lee
Journal: International Journal of Surgery (2020)
Abstract PD6-5: The association between radiotherapy and contralateral breast cancer risk in young <i>BRCA1/2</i>-associated breast cancer patients
Authors: Mark van Barele, Delal Akdeniz, Bernadette AM Heemskerk-Gerritsen, Margreet HA Baaijens, Margriet GA Sattler, Marjanka K Schmidt, Agnes Jager, Maartje J Hooning
Journal: Cancer Research (2020)

Abstract Background: Long-term side-effects of cancer treatment are becoming more important as survival improves. Secondary cancer is a concern after radiotherapy, especially for patients treated at a young age. Since the BRCA1/2 genes play an essential role in DNA-repair, carriers of BRCA1/2 mutations are possibly more susceptible to the harmful side-effects of radiotherapy. Aim: To investigate whether breast cancer (BC) patients with a BRCA1/2 mutation are at increased risk of developing contralateral breast cancer (CBC) after treatment with adjuvant radiotherapy at a young age. Methods: BRCA1/2 mutation carriers previously diagnosed with BC were selected from the Dutch national HEBON study. We used a left-truncated Cox proportional hazards model to estimate the association between radiotherapy (yes/no) and CBC risk, stratifying for age (&amp;lt;40 vs ≥40) and censoring for contralateral prophylactic mastectomy. Results: Median follow-up was 10.1 years for the radiotherapy group (n=901), and 9.3 years for the non-radiotherapy group (n=609) (p=0.072). Median age at BC diagnosis and the distribution of BRCA1 and BRCA2 carriers was similar for both groups. Radiotherapy overall was not significantly associated with a higher risk of CBC (adjusted hazard ratio (HR) 1.31; 95%CI 0.91-1.89, n=1510). Six-hundred and forty patients were less than 40 years of age at BC diagnosis. Those treated with radiotherapy (n=366) had a higher stage and less often underwent mastectomy and prophylactic contralateral mastectomy. Stratifying by age at diagnosis yielded a HR of 1.66 (95%CI 0.93-2.95) for age&amp;lt;40 and a HR of 1.01 (95%CI 0.64-1.61) for age≥ 40. Conclusion: BRCA1/2 mutation carriers irradiated for primary BC under the age of 40 may have an increased risk of developing CBC. Citation Format: Mark van Barele, Delal Akdeniz, Bernadette AM Heemskerk-Gerritsen, Margreet HA Baaijens, Margriet GA Sattler, Marjanka K Schmidt, Agnes Jager, Maartje J Hooning, HEBON collaborators. The association between radiotherapy and contralateral breast cancer risk in young BRCA1/2-associated breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD6-5.
Covid-19: Over 300 Italian doctors and scientists call for more testing
Authors: Marta Paterlini
Journal: BMJ (2020)

More than 300 Italian doctors and scientists have called on the prime minister, Giuseppe Conte, and local authorities to use their skills and facilities to ramp up RNA testing to identify mild and asymptomatic cases of covid-19, which they have said account for 80% of all cases and are helping to spread the contagion.

“Given the dramatic emergency in which our country finds itself, we consider it our civic duty to intervene as scientists equipped with technical skills,” they said in an open letter to the heads of national and regional government. “In many other countries (including China, France, Austria, and Germany) academic laboratories with high level skills have been co-opted in order to provide equipment and staff for the extension of diagnostic tests,” they said. “In Italy there is an …
Interferon gamma replacement as salvage therapy in chronic pulmonary aspergillosis: effects on frequency of acute exacerbation and all-cause hospital admission
Authors: Edward J M Monk, Chris Harris, Rainer Döffinger, Gemma Hayes, David W Denning, Chris Kosmidis
Journal: Thorax (2020)

Chronic pulmonary aspergillosis (CPA) is often poorly responsive to antifungal treatment; secondary infections increase morbidity/mortality, particularly in progressive cases. Interferon gamma (IFNγ) has been implicated in not only Aspergillus control but also bacterial clearance. Clinical notes of patients with CPA treated with IFNγ (2011–2018) were retrospectively hand-searched. In patients treated for &gt;12 months (n=20), the frequency of acute exacerbation reduced from 3.1 to 1.4 episodes/year (p=0.006) in the 12 months after treatment initiation compared with the 12 months before. A significant reduction in the frequency of hospital admissions/year was also observed (0.8 to 0.3, p=0.04). These findings support further prospective studies.
Abstract BS1-1: RNA Methylation in human cancer
Authors: C He
Journal: Cancer Research (2020)

Abstract Over 150 types of post-transcriptional RNA modifications have been identified in all kingdoms of life. We have discovered the first two RNA demethylases, FTO and ALKBH5, which catalyze oxidative demethylation of the most prevalent modifications of mammalian messenger RNA (mRNA) and other nuclear RNA, N6-methyladenosine (m6A). These findings indicate that reversible RNA modification could impact biological regulation analogous to the well-known reversible DNA and histone chemical modifications. We have also characterized proteins that selectively recognize m6A-modified mRNA and affect the translation status and lifetime of the target mRNA, as well as molecular machines that deposit the m6A methylation on mRNA. Functional studies reveal m6A methylation as a critical mechanism to synchronize groups of transcripts for coordinated metabolism, translation, and decay, allowing timely and coordinated protein synthesis and transcriptome switching during cell differentiation and development. Misregulations of these processes lead to embryo lethality and human diseases such as cancer. I will focus on our discoveries of how aberrant expressions of m6A regulators could contribute to human cancer. I will also present effects of m6A regulation on immune response related to cancer progression. Citation Format: C He. RNA Methylation in human cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr BS1-1.
Abstract P1-03-09: The role of E2F5 in breast cancer progression and metastasis
Authors: Briana To, Eran Robert Andrechek
Journal: Cancer Research (2020)

Abstract Advances in cancer genomics and transcriptomics have provided a better understanding of the diverse genetic landscape driving breast cancer pathogenesis. Despite these advances, the molecular drivers of triple negative breast cancer, an aggressive and heterogenous disease, remains highly elusive. Utilizing a genomic approach, we examined genetic differences across mouse models of breast cancer and identified a gene that was consistently deleted in basal-like mouse models, the predominant intrinsic subtype of triple negative breast cancer. Specifically, we identified a consistent deletion in the transcription factor E2F5. In human breast cancer, E2F5 activity and expression is associated with better overall survival and relapse free survival. To further study the role of E2F5 in breast cancer, E2F5 was deleted in the mammary gland of FVB mice (E2F5cKO) through the use of a cre-lox system driven by the MMTV promoter. E2F5cKO mouse demonstrated a delay a mammary outgrowth, suggesting a potential role in mammary gland development. E2F5cKO mice were aged and observed for tumor development. This revealed mammary tumor formation after an extended latency of 19 months. The resulting mammary tumors demonstrated diverse histological patterns. E2F5cKO tumors also demonstrate high metastatic potential with 70% of tumor bearing mice developing metastasis to the lung. In addition, E2F5cKO tumors have a propensity to metastasize to axillary lymph nodes when transplanted into MMTV-Cre mice, a unique feature that is not commonly observed in other mouse models of breast cancer. To begin to understand the mechanism of tumor progression in E2F5cKO mice, differential gene expression was performed on gene expression data derived from E2F5 or GFP overexpression Human Mammary Epithelial Cells. The resulting differentially expressed genes were further filtered based on fold change, established role in cancer, potential E2F binding site and gene ontology. One of the leading candidates that arose from this analysis was KRas, an oncogene that is highly implicated in tumorigenesis. KRas expression negatively correlated with E2F5 expression. Using a bioinformatic approach, we demonstrated that this inverse relationship between KRas and E2F5 appears to be conserved in human breast cancer. Given this inverse relationship between E2F5 and KRas, we postulate that E2F5 deletion in the mammary gland of mice leads to increased KRas activity. Consistent with our hypothesis, western blot analysis revealed high activity in two major KRas signaling pathways, Akt and Erk, in the majority of E2F5cKO tumors. Together, this preliminary data suggest that E2F5 may behave as a tumor suppressor by negatively regulating the oncogene KRas. Citation Format: Briana To, Eran Robert Andrechek. The role of E2F5 in breast cancer progression and metastasis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-03-09.
The Frequency of Ras Mutations in Cancer
Authors: Ian A. Prior, Fiona E. Hood, James L. Hartley
Journal: Cancer Research (2020)

Ras is frequently mutated in cancer, however, there is a lack of consensus in the literature regarding the cancer mutation frequency of Ras, with quoted values varying from 10%-30%. This variability is at least in part due to the selective aggregation of data from different databases and the dominant influence of particular cancer types and particular Ras isoforms within these datasets. To provide a more definitive figure for Ras mutation frequency in cancer, we cross-referenced the data in all major publicly accessible cancer mutation databases to determine reliable mutation frequency values for each Ras isoform in all major cancer types. These percentages were then applied to current U.S. cancer incidence statistics to estimate the number of new patients each year that have Ras-mutant cancers. We find that approximately 19% of patients with cancer harbor Ras mutations, equivalent to approximately 3.4 million new cases per year worldwide. We discuss the Ras isoform and mutation-specific trends evident within the datasets that are relevant to current Ras-targeted therapies.
Abstract P6-03-19: Oridonalogs reverse chemoresistance in breast cancer cells by targeting STAT3
Authors: Xi Liu, Yefei Wen, Hyejin Kim, Pingyuan Wang, Haiying Chen, Mingdao Hu, Ye Ding, Jia Zhou, Qiang Shen
Journal: Cancer Research (2020)

Abstract Chemotherapy remains the mainstream treatment option for invasive and metastatic breast cancer. Adriamycin (ADR) is one of the most frequently used and an effective chemotherapeutic agent for treating patients with breast cancer. However, the resistance towards ADR becomes a major obstacle to achieve efficacy and favorable outcomes in breast cancer patients with chemotherapy. We recently developed a serial oridonalogs that may possess the ability to overcome chemoresistance in cancer cells, whereas whether these novel anti-cancer agents reverse ADR resistance in resistant breast cancer cells are not adequately explored and further the mechanism of action has not been studied. In this study, oridonalogs, YD0514, CYD0618, and CYD0686, were used to determine their effects on the proliferation of the ADR-resistant breast cancer cells. We found significant inhibition of proliferation of wild-type breast cancer cell line MCF-7 and ADR-resistant MCF-7/ADR cells, time- and dose-dependently. Among the tested compounds, CYD0618 and CYD0686 were more effective in inducing apoptosis in wild-type and resistant breast cancer cells than YD0514, in comparison to the natural product and lead compound oridonin. In addition, total STAT3 level was found higher in ADR-resistant breast cancer cells, while phospho-STAT3 was higher in resistant cells. CYD0618 inhibited STAT3 activation in ADR-resistant cells. Our findings suggest that STAT3 activation may be critically involved in the development of acquired resistance to ADR, while oridonalogs such as CYD0618 may open the avenue to reverse and overcome ADR resistance in breast cancer by targeting STAT3. Further mechanistic explorations are currently underway. Citation Format: Xi Liu, Yefei Wen, Hyejin Kim, Pingyuan Wang, Haiying Chen, Mingdao Hu, Ye Ding, Jia Zhou, Qiang Shen. Oridonalogs reverse chemoresistance in breast cancer cells by targeting STAT3 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-19.
Covid-19: New York City deaths pass 1000 as Trump tells Americans to distance for 30 days
Authors: Janice Hopkins Tanne
Journal: BMJ (2020)

<h3>Abstract</h3> Although many studies have focused on abnormal patterns of brain functional connectivity in Autism spectrum disorder (ASD), one important factor, the developmental effect of brain networks was largely overlooked. To clarify the abnormal developmental trajectory of brain functional connectivity in ASD, we focused on the age-related changes in three “core” neurocognitive networks: default mode network (DMN), salience network (SN) and central executive network (CEN, also divided into left and right CEN, i.e., lCEN and rCEN). The development of intrinsic functional connectivity (iFC) within and between these networks were analyzed in 107 Chinese participants, including children, adolescents, and adults (54 patients with ASD and 53 typically developed (TD) participants; ages 6-30 years). We found that diagnosis-related distinctions in age-related changes suggest three maturation patterns in networks’ or nodes’ iFC: delayed (iFC between SN and rCEN), ectopic (iFC between SN and DMN, and iFC between posterior cingulate cortex (PCC) and right anterior insula/dorsal anterior cingulate cortex (dACC)), and failure maturation (iFC between dACC and ventral medial prefrontal cortex). Compared with age-matched TD participants, ASD patients in children and adolescents exhibited hypo-connectivity, while that in adults showed hyper-connectivity. In addition, an independent verification based on Autism Brain Imaging Data Exchange (ABIDE) datasets confirmed our findings of developmental trajectories in ASD group, which also showed unchanged functional connectivity with age between DMN and SN and increasing iFC between rCEN and SN. The conspicuous differences in the development of three “core” networks in ASD were demonstrated, which may lead a nuanced understanding towards the abnormal brain network maturation trajectory of autism.
Clinical Significance of HER2 Overexpression in Gastric and Gastroesophageal Junction Cancers
Authors: M. Baykara, M. Benekli, O. Ekinci, U. Coskun, E.P. Eser, O. Polat, U. Demirci, A. Uner, A. Ozet, S. Buyukberber
Journal: Annals of Oncology (2012)
Abstract PS17-49: Investigating CDK4/6 inhibition in triple negative breast cancer
Authors: Qiuchen Guo, Gregory J Goreczny, Milos Spasic, Adam Maynard, Sandra S McAllister
Journal: Cancer Research (2021)

Abstract The purpose of our study is to evaluate the immunological effects of CDK4/6 inhibitors in pre-clinical models of triple negative breast cancer (TNBC). CDK4/6 inhibitors, including abemaciclib, are currently approved to treat patients with metastatic hormone receptor-positive (HR+), Her2-negative breast cancer. We previously reported in our Her2+ model that CDK4/6 inhibitors promote anti-tumor immunity through inducing tumor cell antigen presentation via activating tumor endogenous retroviral elements, which induce type III interferon production and MHC-I upregulation (Goel, DeCristo, et al., Nature, 2017). We also uncovered important anti-tumor effects on the immune system: CDK4/6 inhibitors decrease T regulatory cell proliferation without affecting cytotoxic CD8 T cell numbers. TNBC has been considered a poor candidate for CDK4/6 inhibitor therapy, as tumors often lose retinoblastoma (Rb) protein expression/function, which is critical for CDK4/6 inhibitor-induced cell cycle arrest. However, Rb mutation or loss occurs in only ~20% of TNBC cases and we found Rb expressing murine and human TNBC cell lines decreased proliferation in vitro in response to abemaciclib. In our preclinical model of TNBC, abemaciclib induced tumor regression. Consistent with previous findings, TNBC tumor cells upregulated MHC-I upon abemaciclib treatment, suggesting increased antigen presentation. Tumor cell-surface PD-L1 was also increased with abemaciclib both in vitro and in vivo, as assessed by flow cytometry and RT-qPCR. These results are encouraging, given that αPD-L1 therapy (Atezolizumab) in combination with chemotherapy (nab-paclitaxel) has recently been approved as standard care for metastatic TNBC and the IMpassion130 trial reported enhanced progression-free and overall survival in patients with PD-L1+ tumors. We also found that abemaciclib increased CD8+ and CD4+ T cells and decreased PD1+ CD8 and CD4 cells in the spleen. Furthermore, total numbers of naïve CD8+ and CD4+ T cells increased with abemaciclib treatment, suggesting a favorable anti-tumor systemic immunological effect. Our data suggest the potential efficacy of CDK4/6 inhibitors in combination with αPD-L1 in the treatment of Rb+ TNBC. Deeper analysis of the mechanisms involved in regulating PD-L1 and enhancing naïve T cells should enable us to evaluate combination therapies using CDK4/6 inhibitors for this particularly deadly breast cancer subtype. Citation Format: Qiuchen Guo, Gregory J Goreczny, Milos Spasic, Adam Maynard, Sandra S McAllister. Investigating CDK4/6 inhibition in triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-49.
The relationship between anesthetic technique and thirty-day mortality in patients undergoing noncardiac- and nonneurosurgery: A retrospective, propensity score-matched cohort study
Authors: Xueying Luo, Baoer Liu, Feng Li, Sujing Zheng, Ya Li, Liping Yang, Rui Gao, Qiu yi Guo, Haodong Chen, Kanghua Huang, Haofei Hu, Jinsong He
Journal: International Journal of Surgery (2020)
Global, regional, and national burden of neck pain in the general population, 1990-2017: systematic analysis of the Global Burden of Disease Study 2017
Authors: Saeid Safiri, Ali-Asghar Kolahi, Damian Hoy, Rachelle Buchbinder, Mohammad Ali Mansournia, Deepti Bettampadi, Ahad Ashrafi-Asgarabad, Amir Almasi-Hashiani, Emma Smith, Mahdi Sepidarkish, Marita Cross, Mostafa Qorbani, Maziar Moradi-Lakeh, Anthony D Woolf, Lyn March, Gary Collins, Manuela L Ferreira
Journal: BMJ (2020)

Abstract Objective To use data from the Global Burden of Disease Study between 1990 and 2017 to report the rates and trends of point prevalence, annual incidence, and years lived with disability for neck pain in the general population of 195 countries. Design Systematic analysis. Data source Global Burden of Diseases, Injuries, and Risk Factors Study 2017. Main outcome measures Numbers and age standardised rates per 100 000 population of neck pain point prevalence, annual incidence, and years lived with disability were compared across regions and countries by age, sex, and sociodemographic index. Estimates were reported with uncertainty intervals. Results Globally in 2017 the age standardised rates for point prevalence of neck pain per 100 000 population was 3551.1 (95% uncertainty interval 3139.5 to 3977.9), for incidence of neck pain per 100 000 population was 806.6 (713.7 to 912.5), and for years lived with disability from neck pain per 100 000 population was 352.0 (245.6 to 493.3). These estimates did not change significantly between 1990 and 2017. The global point prevalence of neck pain in 2017 was higher in females compared with males, although this was not significant at the 0.05 level. Prevalence increased with age up to 70-74 years and then decreased. Norway (6151.2 (95% uncertainty interval 5382.3 to 6959.8)), Finland (5750.3 (5058.4 to 6518.3)), and Denmark (5316 (4674 to 6030.1)) had the three highest age standardised point prevalence estimates in 2017. The largest increases in age standardised point prevalence estimates from 1990 to 2017 were in the United Kingdom (14.6% (10.6% to 18.8%)), Sweden (10.4% (6.0% to 15.4%)), and Kuwait (2.6% (2.0% to 3.2%)). In general, positive associations, but with fluctuations, were found between age standardised years lived with disability for neck pain and sociodemographic index at the global level and for all Global Burden of Disease regions, suggesting the burden is higher at higher sociodemographic indices. Conclusions Neck pain is a serious public health problem in the general population, with the highest burden in Norway, Finland, and Denmark. Increasing population awareness about risk factors and preventive strategies for neck pain is warranted to reduce the future burden of this condition.