tbuckley/cabot-search huggingface dataset:
Abstract #2946: Anti-cancer activity of a new non-steroidal anti-angiogenic microtubule disruptor in breast cancer
Authors: Chloe Stengel, Simon Newman, Paul Foster, Mathew Leese, Eric Ferrandis, Sandra Regis-Lydi, Barry Potter, Michael Reed, Atul Purohit
Journal: Cancer Research (2009)

Drugs that inhibit the growth of tumors and their blood supply could have considerable therapeutic potential. However, to date, there are few small molecules as clinically successful agents that meet these criteria. In this study, we examined the effects of STX2484, a polycyclic non-steroidal sulfamate ester, on the proliferation of MCF-7WT (ER+) and MCF-7DOX (ER+, P-gly+, taxane resistant) breast cancer cells, its ability to inhibit carbonic anhydrase II (CAII), which is involved in the transport of sulfamate drugs, and its efficacy in vivo in a MDA-MBA-231 (ER-) xenograft tumor model in nude mice. Its ability to inhibit the proliferation of human umbilical endothelial cells (HUVECs) was also assessed as an in vitro marker of its anti-angiogenic potential. Proliferation was quantified in vitro using the Alamar blue reagent and the CAII assays were performed with CAII from human red blood cells, using p-nitrophenol acetate as the substrate. Effects of STX2484 on microtubule dynamics were investigated by monitoring paclitaxel-stimulated tubulin polymerisation in vitro, in the presence of STX2484. These studies demonstrated that STX2484 is a microtubule disruptor and inhibits MCF-7WT and MCF-7DOX cell proliferation with IC50 values of 270 nM and 160 nM, respectively. The IC50 value for CAII inhibition is 680 nM. STX2484 is a potent inhibitor of HUVEC proliferation (IC50 value = 170 nM), and is also active in an another model of in vitro angiogenesis in which HUVECs are co-cultured with dermal fibroblasts. These promising in vitro data were translated in vivo. To assess efficacy, nude mice bearing MDA-MB-231 xenografts (80-100 mm3) were treated for 28 days and tumor measurements taken weekly. Oral dosing of STX2484 (20 mg/kg, 5 days per week) completely blocked MDA-MB-231 tumor growth with no weight loss being observed. In this study we have characterised a novel non-steroid based microtubule disruptor which combines both anti-tumor and anti-angiogenic properties in one orally bioavailable molecule. STX2484 acts by disrupting microtubule dynamics and after absorption it is likely transported through the liver without undergoing metabolic inactivation by being sequestered in red blood cells via binding to CAII as demonstrated previously for other sulfamate-based drugs. Furthermore, STX2484 inhibits the proliferation of the multi-drug resistant MCF-7DOX breast cancer cell line, indicating that it is not a substrate for the P-glycoprotein pump and may be used to treat taxane resistant tumors and therefore worthy of further development as a cancer therapy.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2946.
Diagnostic and therapeutic pitfalls in NPM1-mutated AML: notes from the field
Authors: Brunangelo Falini, Sofia Sciabolacci, Lorenza Falini, Lorenzo Brunetti, Maria Paola Martelli
Journal: Leukemia (2021)

Abstract Mutations of Nucleophosmin ( NPM1 ) are the most common genetic abnormalities in adult acute myeloid leukaemia (AML), accounting for about 30% of cases. NPM1 -mutated AML has been recognized as distinct entity in the 2017 World Health Organization (WHO) classification of lympho-haematopoietic neoplasms. WHO criteria allow recognition of this leukaemia entity and its distinction from AML with myelodysplasia-related changes, AML with BCR-ABL1 rearrangement and AML with RUNX1 mutations. Nevertheless, controversial issues include the percentage of blasts required for the diagnosis of NPM1 -mutated AML and whether cases of NPM1 -mutated myelodysplasia and chronic myelomonocytic leukaemia do exist. Evaluation of NPM1 and FLT3 status represents a major pillar of the European LeukemiaNet (ELN) genetic-based risk stratification model. Moreover, NPM1 mutations are particularly suitable for assessing measurable residual disease (MRD) since they are frequent, stable at relapse and do not drive clonal haematopoiesis. Ideally, combining monitoring of MRD with the ELN prognostication model can help to guide therapeutic decisions. Here, we provide examples of instructive cases of NPM1 -mutated AML, in order to provide criteria for the appropriate diagnosis and therapy of this frequent leukaemia entity.
Associations of Type 2 Diabetes Onset Age With Cardiovascular Disease and Mortality: The Kailuan Study
Authors: Maoxiang Zhao, Lulu Song, Lan Sun, Miao Wang, Chi Wang, Siyu Yao, Yao Li, Cuijuan Yun, Sijin Zhang, Yizhen Sun, Ziwei Hou, Shouling Wu, Hao Xue
Journal: Diabetes Care (2021)

OBJECTIVE We aimed to explore the associations between type 2 diabetes onset age and cardiovascular disease (CVD) and all-cause mortality in the Chinese population. RESEARCH DESIGN AND METHODS This study included 101,080 participants free of prevalent diabetes and CVD at baseline from the Kailuan Study. All participants were monitored biennially until 31 December 2017. During follow-up, 11,384 participants were diagnosed as having type 2 diabetes. For each case subject, one control subject was randomly selected, matched for age (± 1 years) and sex. The final analysis comprised 10,777 case-control pairs. Weighted Cox regression models were used to evaluate the average hazard ratios (AHRs) and 95% CIs of incident CVD and all-cause mortality among patients with new-onset type 2 diabetes versus control subjects across age-groups. Results During a median follow-up of 5.57 years, 1,794 incident events (907 CVD events, of which there were 725 strokes and 887 deaths) occurred. After adjustment for potential confounders, participants with type 2 diabetes diagnosed at age &amp;lt;45 years had the highest relative risks of CVD and all-cause mortality relative to the matched control subjects, with AHRs of 3.21 (95% CI 1.18–8.72) for CVD, 2.99 (95% CI 1.01–9.17) for stroke, and 4.79 (95% CI 1.95–11.76) for all-cause mortality. The risks gradually attenuated with each decade increase in type 2 diabetes onset age. CONCLUSIONS The relative risks of CVD and all-cause mortality differed across type 2 diabetes onset age-groups, and the associations were more evident in younger-onset type 2 diabetes.
Abstract 16145: Risk Factors Associated With New-Onset Heart Failure in Patients Undergoing Orthopedic Surgery
Authors: Alexandra M Sanchez, Rushabh M Vakharia, Matthew R Lozier, Martin W Roche, Joshua Larned
Journal: Circulation (2019)

Introduction: There is a paucity in the literature regarding risk factors associated with new-onset congestive heart failure (CHF) exacerbation in patients undergoing primary total knee arthroplast...
Abstract IA-017: Chromatin and gene transcription in hypoxia
Authors: Michael Batie, Julianty Frost, Sonia Rocha
Journal: Clinical Cancer Research (2021)

Abstract Oxygen is essential for the life of most multicellular organism and changes in oxygen availability have implications in physiological and pathophysiological conditions. In response to hypoxia (low oxygen availability) transcriptional changes are induced. The transcriptional response to hypoxia is mediated primarily by the Hypoxia Inducible Factor (HIF) family of transcription factors. HIFs are activated in hypoxia via inhibition of prolyl hydroxylases (PHDs), a group of molecular dioxygenases, which require oxygen for their activity. Whilst the role of HIFs in the transcriptional response to hypoxia is well characterized, little is known with regards to chromatin structure in low oxygen stress and how this coordinates the transcriptional response. It was recently shown that chromatin is sensitive to oxygen levels, with hypoxia altering histone methylation at hypoxia responsive genes via inhibition of specific JmjC histone demethylases. To further investigate chromatin structure and its role in hypoxia induced gene transcription, we have performed ATAC-seq and RNA-seq in human cancer cell lines in acute and prolonged hypoxia. We find that acute hypoxia leads to increased promoter accessibility at a subset of hypoxia inducible genes, and this mostly precedes changes in mRNA expression, with further changes in chromatin structure after prolonged hypoxia. In addition, ChIP-seq data on histone methylation marks (H3K4me and H3K36me3), revealed similar earlier patterns of genomic distribution. Furthermore, we dissected the impact of HIF in the observed changes using a chemical probe and specific HIF1beta depletion analysis of ATAC-seq. This work gives insights into the role of chromatin dynamics in regulating the transcriptional response to hypoxia and elucidating the mechanisms behind these changes may lead to targeted therapies for hypoxia driven diseases. Citation Format: Michael Batie, Julianty Frost, Sonia Rocha. Chromatin and gene transcription in hypoxia [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-017.
Comparative regulomics supports pervasive selection on gene dosage following whole genome duplication
Authors: Gareth B. Gillard, Lars Grønvold, Line L. Røsæg, Matilde Mengkrog Holen, Øystein Monsen, Ben F. Koop, Eric B. Rondeau, Manu Kumar Gundappa, John Mendoza, Daniel J. Macqueen, Rori V. Rohlfs, Simen R. Sandve, Torgeir R. Hvidsten
Journal: Genome biology (2021)

Abstract Background Whole genome duplication (WGD) events have played a major role in eukaryotic genome evolution, but the consequence of these extreme events in adaptive genome evolution is still not well understood. To address this knowledge gap, we used a comparative phylogenetic model and transcriptomic data from seven species to infer selection on gene expression in duplicated genes (ohnologs) following the salmonid WGD 80–100 million years ago. Results We find rare cases of tissue-specific expression evolution but pervasive expression evolution affecting many tissues, reflecting strong selection on maintenance of genome stability following genome doubling. Ohnolog expression levels have evolved mostly asymmetrically, by diverting one ohnolog copy down a path towards lower expression and possible pseudogenization. Loss of expression in one ohnolog is significantly associated with transposable element insertions in promoters and likely driven by selection on gene dosage including selection on stoichiometric balance. We also find symmetric expression shifts, and these are associated with genes under strong evolutionary constraints such as ribosome subunit genes. This possibly reflects selection operating to achieve a gene dose reduction while avoiding accumulation of “toxic mutations”. Mechanistically, ohnolog regulatory divergence is dictated by the number of bound transcription factors in promoters, with transposable elements being one likely source of novel binding sites driving tissue-specific gains in expression. Conclusions Our results imply pervasive adaptive expression evolution following WGD to overcome the immediate challenges posed by genome doubling and to exploit the long-term genetic opportunities for novel phenotype evolution.
Abstract 15578: Cacao Bean Polyphenols Inhibits Cardiac Hypertrophy and Dysfunction in Pressure Overload-Induced Heart Failure Model
Authors: Yasufumi Katanasaka, Yusuke Miyazaki, Yoichi Sunagawa, Hiromichi Wada, Koji Hasegawa, Tatsuya Morimoto
Journal: Circulation (2018)

Introduction: Pathological stress such as pressure overload and myocardial infarction induces cardiac hypertrophy, which increases the risk of heart failure (HF). Since cocoa products are among the...
Abstract PO-021: Single-cell DNA sequencing as a means to directly examine the size and frequency of radiation-induced mutations - An exploratory study
Authors: Felix Mathew, Jonathan Yeo, Luc Galarneau, Norma Ybarra, Patricia Tonin, Yu Chang Wang, Ioannis Ragoussis, John Kildea
Journal: Clinical Cancer Research (2021)

Abstract This study examines if single-cell DNA sequencing may be used to study the mutational effects of ionizing radiation. As the action of ionizing radiation is a stochastic process, each cell in an irradiated sample experiences its own unique radiation-induced DNA damage. As a result, conventional sequencing methods such as bulk cell sequencing cannot be used to identify individual mutations. In this work, Epstein-Barr virus (EBV) transformed B-lymphoblastoid cells were irradiated with 6 MV X-ray radiation using a medical linear accelerator. Four samples of cells from the same population (400,000 cells/ml) were exposed to sham irradiation (0 Gray [Gy]; control), 0.5 Gy, 1.5 Gy and 3.0 Gy respectively at a common dose rate of about 600 cGy/min. Irradiated samples were incubated for 24 hrs and subsequently underwent single-cell whole-genome DNA sequencing to characterize the radiation impact. Mutational profiles of approximately 500 cells, randomly selected from each sample, were individually analyzed and compared to identify the variation of several mutational parameters as a function of dose. We quantified the copy number variations (CNV) for each cell in our samples. Additionally, we segregated insertion CNVs and deletion CNVs and independently analyzed their dose dependences. We found that the total number of CNVs (insertion and deletion combined) increased with dose, and the number of deletion CNVs consistently increased most. We have repeated the experiment and a new round of single-cell DNA sequencing is underway. If confirmed, our results will demonstrate that the mutational effects of ionizing radiation may be examined directly using single-cell sequencing. Citation Format: Felix Mathew, Jonathan Yeo, Luc Galarneau, Norma Ybarra, Patricia Tonin, Yu Chang Wang, Ioannis Ragoussis, John Kildea. Single-cell DNA sequencing as a means to directly examine the size and frequency of radiation-induced mutations - An exploratory study [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-021.
Abstract 12660: Cuff Measured Blood Pressures Inaccurately Estimate Intra-Aortic Pressures - Time for A Paradigm Shift?
Authors: Azra Mahmud, Ali Al Ghamdi, Mohammad Balghith, Kamal Ayoub, Mohammad Fayaz Khan, Sameer Al Chaghouri, Fawaz Al Mutairi, Muayed Al Zaibag
Journal: Circulation (2018)

Introduction: Hypertension (HTN) is the leading cause of cardiovascular mortality and morbidity. Invasive intra-aortic pressures are the gold standard for accurate blood pressure (BP) measurement a...
Perceptions, priorities, and project delivery problems in women's and environmental health in Peru: a qualitative study
Authors: Laura J Brown, Elaine C Flores
Journal: The Lancet Planetary Health (2021)

BackgroundWomen living in low-income and-middle-income countries experience increased exposure and worse effects of environmental threats and climate change. Peru is especially susceptible to a range of environmental exposures, including high levels of pollutants, contamination associated with extractive industries, and flooding exacerbated by the ongoing climate emergency. International policies and movements are increasingly calling for a gendered approach to planetary health. However, little research has been done explicitly examining environmental threats to women's health in Peru. We aimed to understand the current Peruvian research, advocacy, and policy landscape at the environment-gender health nexus.MethodsWe did in-depth semi-structured interviews in Spanish via online Zoom video conferencing (audio only) with key informants from the Peruvian Government, academia, and non-governmental organisations to explore their perception of environmental health threats and priorities, population vulnerability factors, awareness of projects and collaborations on these topics, and the role of gender in their work. We used thematic analysis to compare priorities, gender sensitivity, and barriers and facilitators to delivering successful women's environmental health projects in the country.FindingsSince July 14, 2020, we have interviewed 16 people, with four further interviews planned to take place before the end of May, 2021. Several interviewees mentioned the detrimental role of weak institutions, multilevel corruption, and the absence of interdisciplinarity and intersectorality across programmes and research. Barriers to successful collaboration across organisations and sectors were clearly identified, including funding scandals related to extractive economies, high staff turnovers impairing long-term programme implementation, and machismo culture in both organisations and communities. By contrast, some interviewees highlighted that successful collaborations were instead built on direct relationships, reputation, trust, and transparency. Women's empowerment was also described as important for successful programme delivery, especially in female-led associations. Some interviewees emphasised the so-called invisibilisation of vulnerable groups, such as girls, teenagers, pregnant women, victims of gender-based violence, and LGBTQI people. Existing health inequalities varied by setting and cultural context and were deeply and silently exacerbated by the COVID-19 pandemic.InterpretationThese qualitative findings highlight the multiple and inter-related contextual issues faced by environmentally threatened communities in Peru, and how macrostructural barriers contribute to a paucity of sustainable, gender-oriented, environmental health projects.FundingPartially funded by the UK's Economic and Social Research Council.
A plasma membrane transporter coordinates phosphate reallocation and grain filling in cereals
Authors: Bin Ma, Lin Zhang, Qifei Gao, Junmin Wang, Xiaoyuan Li, Hu Wang, Yu Liu, Hui Lin, Jiyun Liu, Xin Wang, Qun Li, Yiwen Deng, Weihua Tang, Sheng Luan, Zuhua He
Journal: Nature Genetics (2021)
Neurotrauma Biomarker Levels and Adverse Symptoms Among Military and Law Enforcement Personnel Exposed to Occupational Overpressure Without Diagnosed Traumatic Brain Injury
Authors: Angela M. Boutté, Bharani Thangavelu, Jeffrey Nemes, Christina R. LaValle, Mike Egnoto, Walter Carr, Gary H. Kamimori
Journal: JAMA Network Open (2021)

<h3>Importance</h3> There is a scientific and operational need to define objective measures of exposure to low-level overpressure (LLOP) and concussion-like symptoms among persons with specialized occupations. <h3>Objective</h3> To evaluate serum levels of neurotrauma biomarkers and their association with concussion-like symptoms reported by LLOP-exposed military and law enforcement personnel who are outwardly healthy and cleared to perform duties. <h3>Design, Setting, and Participants</h3> This retrospective cohort study, conducted from January 23, 2017, to October 21, 2019, used serum samples and survey data collected from healthy, male, active-duty military and law enforcement personnel assigned to operational training at 4 US Department of Defense and civilian law enforcement training sites. Personnel aged 18 years or older with prior LLOP exposure but no diagnosed traumatic brain injury or with acute blast exposure during sampling participated in the study. Serum samples from 30 control individuals were obtained from a commercial vendor. <h3>Main Outcomes and Measures</h3> Serum levels of glial fibrillary acidic protein, ubiquitin carboxyl hydrolase (UCH)-L1, neurofilament light chain, tau, amyloid β (Aβ)-40, and Aβ-42 from a random sample (30 participants) of the LLOP-exposed cohort were compared with those of 30 age-matched controls. Associations between biomarker levels and self-reported symptoms or operational demographics in the remainder of the study cohort (76 participants) were assessed using generalized linear modeling or Spearman correlations with age as a covariate. <h3>Results</h3> Among the 30 randomly sampled participants (mean [SD] age, 32 [7.75] years), serum levels of UCH-L1 (mean difference, 4.92; 95% CI, 0.71-9.14), tau (mean difference, 0.16; 95% CI, −0.06 to 0.39), Aβ-40 (mean difference, 138.44; 95% CI, 116.32-160.56), and Aβ-42 (mean difference, 4.97; 95% CI, 4.10-5.83) were elevated compared with those in controls. Among the remaining cohort of 76 participants (mean [SD] age, 34 [7.43] years), ear ringing was reported by 44 (58%) and memory or sleep problems were reported by 24 (32%) and 20 (26%), respectively. A total of 26 participants (34%) reported prior concussion. Amyloid β-42 levels were associated with ear ringing (<i>F</i><sub>1,72</sub> = 7.40;<i>P</i> = .008) and memory problems (<i>F</i><sub>1,72</sub> = 9.20;<i>P</i> = .003). <h3>Conclusions and Relevance</h3> The findings suggest that long-term LLOP exposure acquired during occupational training may be associated with serum levels of neurotrauma biomarkers. Assessment of biomarkers and concussion-like symptoms among personnel considered healthy at the time of sampling may be useful for military occupational medicine risk management.
Targeting Adenosine with Adenosine Deaminase 2 to Inhibit Growth of Solid Tumors
Authors: Lin Wang, Luz M. Londono, Jessica Cowell, Ozge Saatci, Mertkaya Aras, Pelin G. Ersan, Sara Serra, Hong Pei, Renee Clift, Qiping Zhao, Kim B. Phan, Lei Huang, Michael J. LaBarre, Xiaoming Li, H. Michael Shepard, Silvia Deaglio, Joel Linden, Christopher D. Thanos, Ozgur Sahin, Caglar Cekic
Journal: Cancer Research (2021)

Abstract Extracellular adenosine in tumors can suppress immune responses and promote tumor growth. Adenosine deaminase 2 (ADA2) converts adenosine into inosine. The role of ADA2 in cancer and whether it can target adenosine for cancer therapy has not been investigated. Here we show that increased ADA2 expression is associated with increased patient survival and enrichment of adaptive immune response pathways in several solid tumor types. Several ADA2 variants were created to improve catalytic efficiency, and PEGylation was used to prolong systemic exposure. In mice, PEGylated ADA2 (PEGADA2) inhibited tumor growth by targeting adenosine in an enzyme activity–dependent manner and thereby modulating immune responses. These findings introduce endogenous ADA2 expression as a prognostic factor and PEGADA2 as a novel immunotherapy for cancer. Significance: This study identifies ADA2 as a prognostic factor associated with prolonged cancer patient survival and introduces the potential of enzymatic removal of adenosine with engineered ADA2 for cancer immunotherapy.