tbuckley/cabot-search huggingface dataset:
CDYL promotes the chemoresistance of small cell lung cancer by regulating H3K27 trimethylation at the CDKN1C promoter
Authors: Zhengang Qiu, Weiliang Zhu, Hui Meng, Lihua Tong, Xi Li, Peng Luo, Lilan Yi, Xiaoli Zhang, Linlang Guo, Ting Wei, Jian Zhang
Journal: Theranostics (2019)

Rationale: Chemoresistance frequently occurs in patients with small cell lung cancer (SCLC) and leads to a dismal prognosis.However, the mechanisms underlying this process remain largely unclear. Methods:The effects of chromodomain Y-like (CDYL) on chemoresistance in SCLC were determined using Western blotting, immunohistochemistry, cell counting kit-8 assays, flow cytometry, and tumorigenicity experiments, and the underlying mechanisms were investigated using mRNA sequencing, chromatin immunoprecipitation-qPCR, electrophoretic mobility shift assays, co-immunoprecipitation, GST pull down assays, bisulfite sequencing PCR, ELISA, and bioinformatics analyses.Results: CDYL is expressed at high levels in chemoresistant SCLC tissues from patients, and elevated CDYL levels correlate with an advanced clinical stage and a poor prognosis.Furthermore, CDYL expression is significantly upregulated in chemoresistant SCLC cells.Using gain-and loss-of-function methods, we show that CDYL promotes chemoresistance in SCLC in vitro and in vivo.Mechanistically, CDYL promotes SCLC chemoresistance by silencing its downstream mediator cyclin-dependent kinase inhibitor 1C (CDKN1C).Further mechanistic investigations showed that CDYL recruits the enhancer of zeste homolog 2 (EZH2) to regulate trimethylation of lysine 27 in histone 3 (H3K27me3) at the CDKN1C promoter region and promotes transcriptional silencing.Accordingly, the EZH2 inhibitor GSK126 de-represses CDKN1C and decreases CDYL-induced chemoresistance in SCLC.Principal conclusions: Based on these results, the CDYL/EZH2/CDKN1C axis promotes chemoresistance in SCLC, and these markers represent promising therapeutic targets for overcoming chemoresistance in patients with SCLC.
Epidemiology of oral cancers referred for NACT, the demographics, clinical profile, and organ functions.
Authors: Sushmita Rath, Vijay Maruti Patil, Vanita Noronha, Amit Joshi, Bharatsinha Baburao Bhosale, Snehal Punatar, Bhavesh Poladia, Arvind Sahu, S Juvekar, Pankaj Chaturvedi, Anil K D'cruz, Kumar Prabhash
Journal: Journal of Clinical Oncology (2013)

e12520 Background: The use of neoadjuvant chemotherapy(NACT) in head &amp; neck cancers is not well defined. Very few publications on this topic deal with the epidemiology ,clinical &amp; biochemical profile. These factors have an important say in deciding the choice of regimen. Methods: An prospective analysis of oral cavity cancer patients ,who were referred for NACT at our center, was done. The analysis focussed on the demographics, clinical &amp; biochemical parameters of these patients at presentation . Results: From 2010-2012 , 528 patients of oral cavity cancers were referred for NACT from the multidisciplinary clinic. The median age of patients was 45 years (22-78 years) ; 10.4% were above the age of 60 years and 83.7% were males. Only 16.5% of patients were from the city in which the hospital was located. 69.1% were tobacco users, 53.8% were smokers , 37.5% were alcoholic &amp; 81.5% had in addition other local tobacco containing chewable preparations. Only 2.65% denied any addictions. Amongst the symptoms pain, facical swelling,oral ulcer , oral bleeding, foul smell, trismus &amp; weight loss were present in 41.9%, 72.5%, 57.6% , 72.5% , 77.1%, 41.4% &amp; 49.4% respectively. The ECOG performance status were 0,1,2 in 8.3%, 84.7%, 2.7% patients respectively. The subsite of the disease were buccal mucosa,tongue, floor of mouth, alveolus, hard palate in 67.8%, 24.4% ,4.7% , 0.9% ,1.1% respectively. 65.3% &amp; 16.7% patients were in T4a and T4b stage. N2b(42%) and N2c (31.4% )were the most common N stage seen. All patients had stage IV disease. Comorbidites like diabetes mellitus, hypertension and cardiac disease were seen in 22.3%, 18.9% &amp; 13.3%. The median BMI was 21.45 Kg/m2 &amp; 24.3% had BMI below 18.5 Kg/m2 (severly malnourished). The need for NACT was mainly due to extensive disease ,edema reaching upto zygoma and edema upto hyoid bone .The regimens administered were TPF in 6.6% and Taxane with Platinum in rest others. The major reasons for not selecting TPF were logistics (75%) &amp; malnourished status (25%). Conclusions: Patients referred for NACT at our center had locally advanced disease,nearly all were addicts, one fourth had severe malnourishment &amp; current standard TPF could be administered in only a few of them.
Abstract 19465: Cardiopulmonary BestAbstract Award: 17β-estradiol and Estrogen Receptor α Modulate BMPR2 and Apelin to Promote Protective Effects on Right Ventricular (RV) Function in Pulmonary Hypertension (PH)
Authors: Andrea L Frump, Margie Albrecht, Bakhtiyor Yakubov, Sandra Breuils-Bonnet, Steeve Provencher, Sébastien Bonnet, Tim Lahm
Journal: Circulation (2017)

Introduction: Women with PAH exhibit better RV function and survival than men. However, the underlying mechanisms are unknown. Hypothesis: E2, through ERα, attenuates PH-induced RV dysfunction by u...
Survival trends among patients with acute myeloid leukemia in the United States.
Authors: Dipesh Uprety, Krishna Bilas Ghimire, Barsha Nepal, Binay Kumar Shah
Journal: Journal of Clinical Oncology (2013)

e17598 Background: The chemotherapy regimen for acute myeloid leukemia (AML) has not changed significantly over the last two decades. Better patient care may have improved survival in AML patients. This study was conducted to evaluate the relative survival rates in AML patients over two decades in the United States. Methods: Adult patients (age≥20 years) diagnosed with AML were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Several cohorts categorized by race (Caucasians &amp; African-Americans (AA)), gender &amp; age (20-59, ≥60 years) were compared to see survival differences from 1992-2000 &amp; 2001-2009. We used SEER Stat software to calculate 1- and 5-year relative survival rates (RS). The survival rates accompany standard errors. Results: The database comprised of 28,217 patients. The relative survival rates of AML improved significantly during 2001-2009 compared to 1992-2000 1-year 39.2±0.4 vs 33.7±0.5,( Z score 9.079, p&lt;0.0005); 5- year 20.1±0.4 vs 15.3±0.4, (Z score 10.357, p&lt;0.0005). The 1-and 5-year RS for men during 1992-2000 vs 2001-2009 were 32.3±0.7% vs 39.2±0.5% (Zscore=8.392, p&lt;0.0005) &amp; 13.9±0.5% vs 18.7±0.5% (Zscore= 8.710, p&lt;0.0005) respectively. For women, the survival rates during 1992-2000 vs 2001-2009 were 35.3±0.7% vs 39.1±0.5% (Zscore=4.318, p&lt;0.0005) at 1-year &amp; 16.9±0.6% vs 21.7±0.5% (Z score=5.917, p&lt;0.0005) at 5-years. For younger patients (&lt;60 years), relative survival rates at during 1992-2000 and 2001-2009 were: 1- year: 56.7±0.9 vs 63.5±0.6, (Z score=6.462, p&lt;0.0005); 5- year: 33.0±0.8 vs 40.6±0.7, (Z score= 7.070, p &lt;0.0005). Similarly, the survival rates were significantly better for older patients and for all ethnic groups during 2001-2009 compared to 1992-2000. Conclusions: The relative survival in AML has increased significantly during 2001-2009 compared to 1992-2000. This may be secondary to improvement in supportive care.
Mitochondrial General Control of Amino Acid Synthesis 5 Like 1 Regulates Glutaminolysis, Mammalian Target of Rapamycin Complex 1 Activity, and Murine Liver Regeneration
Authors: Lingdi Wang, Lu Zhu, Kaiyuan Wu, Yong Chen, Duck‐Yeon Lee, Marjan Gucek, Michael N. Sack
Journal: Hepatology (2019)

The regenerative capacity of the liver plays a protective role against hepatotoxins and impaired regeneration exacerbates liver dysfunction in nonalcoholic fatty liver disease (NAFLD). Mitochondrial bioenergetic and -synthetic functions are important contributory factors in hepatic regeneration, and the control of mitochondrial protein acetylation is implicated in the mitochondrial susceptibility to liver stressors. Here, we evaluated the role of general control of amino acid synthesis 5 like 1 (GCN5L1), a mediator of mitochondrial metabolism and acetylation, in modulating murine liver regeneration (LR) in response to acute CCl4 -induced hepatotoxicity.Initial metabolomic screening found that liver GCN5L1 knockout (LKO) mice have augmented glutaminolysis. Absence of GCN5L1 modified enzyme activity of liver-enriched glutaminase enzyme (glutaminase 2; GLS2), and GCN5L1 levels modulated GLS2 oligomerization and acetylation. This metabolic remodeling resulted in the elevation of α-ketoglutarate levels, which are known to activate mammalian target of rapamycin complex 1 (mTORC1). This signaling pathway was induced with increased phosphorylation of S6 kinase in LKO hepatocytes, and inhibition of glutaminolysis reversed aberrant mTORC1 signaling. At the same time, glutaminolysis, activity of GLS2, and activation of mTORC1 signaling were reversed by the genetic reintroduction of the mitochondrial isoform of GCN5L1 into LKO primary hepatocytes. Finally, LKO mice had a more robust regenerative capacity in response to CCl4 hepatoxicity, and this response was blunted by both the mTORC1 inhibitor, rapamycin, and by pharmacological blunting of glutaminolysis.These data point to a central role of glutaminolysis in modulating the regenerative capacity in the liver. Furthermore, inhibition of mitochondrial GCN5L1 to augment LR may be a useful strategy in disease states linked to hepatotoxicity.
Abstract 13454: The Impact of Prior Stroke on the Outcome of Patients With Severe Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement
Authors: Romain Didier, Edward Koifman, Sarkis Kiramijyan, Smita Negi, Ricardo Escarcega, Nevin Baker, Gai Jiaxing, Rebecca Torguson, Petros Okubagzi, Itsik Ben-Dor, Lowell Satler, Augusto Pichard, Ron Waksman
Journal: Circulation (2015)

Introduction: Prior stroke has been identified as an independent correlate for post-procedure cerebrovascular events (CVE) in aortic stenosis (AS) patients undergoing surgical aortic valve replacement (SAVR). The present study aimed to evaluate the impact of prior cerebrovascular events on outcome in AS patients undergoing TAVR. Methods: Patients with severe AS undergoing TAVR between May 2007-March 2015 were included and categorized to patients with and without prior CVE defined as stroke and transit ischemic attack. Baseline, procedural characteristics, in-hospital outcomes, 1-month and 1-year mortality were compared, in accordance with the VARC-2 consensus. Results: A cohort of 662 consecutive patients with severe AS undergoing TAVR was included in the analysis. Of these, 120 patients had prior CVE, and 542 without. Balloon expandable valve was used in 70.7% and self-expandable valve in 29.3% of the patients. Trans-femoral access was used in 78% (571), and pre-TAVR balloon aortic valvuloplasty was performed in 87% (574). Patients with prior CVE had a higher mean STS score compared to those without prior CVE (10.1% versus 8.8%, respectively; p=0,006) and demonstrated higher rates of atherosclerotic disease involving the coronary, peripheral and carotid arteries. In-hospital minor stroke occurred more often in patients with prior CVE vs. those without CVE (3.3% vs. 0.7%; p=0.04). However, similar mortality rates were recorded at 1, 6, and 12 months (figure 1), and there were no significant differences in major stroke, bleeding, or post-procedure hospital stay between both groups. Conclusions: Prior history of CVE infers a higher risk for in-hospital minor stroke, yet no impact on other outcomes post TAVR. Patients with and without a history of prior CVE with severe aortic stenosis will similarly benefit from TAVR. Therefore, a history of CVE should not be considered an exclusion criterion.
Abstract P052: Circulating Natural Killer Cells and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Nancy S Jenny, Nels C Olson, Alicia M Ellis, Margaret F Doyle, Sally A Huber, Richard A Kronmal, Bruce M Psaty, Russell P Tracy
Journal: Circulation (2018)

Introduction: Clinically, natural killer (NK) cells are important in inflammatory and autoimmune diseases. As part of innate immunity, NK cells produce chemokines and inflammatory cytokines, potentially linking them to cardiovascular disease (CVD) development and progression as well. However, their role in human CVD is not clear. Hypothesis: NK cells are proatherogenic in humans and are associated with CVD risk factors and subclinical CVD measures. Methods: We examined cross-sectional associations of circulating NK cell levels with CVD risk factors, subclinical CVD measures and coronary artery calcium (CAC) in 891 White, Black, Chinese and Hispanic men and women (mean age 66 y) in the Multi-Ethnic Study of Atherosclerosis (MESA) at Exam 4 (2005-07). NK cell percent, percent of circulating lymphocytes that were CD3 - CD56 + CD16 + , was measured in whole blood by flow cytometry. CAC presence was defined as Agatston score &gt; 0. Results: Mean (standard deviation) NK percent differed by race/ethnicity; 8.2% (4.7) in Whites, 11.3% (7.5) in Chinese (p&lt;0.001 compared to Whites), 7.1 (4.2) in Blacks (p=0.007) and 8.4 (5.2) in Hispanics (p=0.6). NK cell percent was positively associated with age (p&lt;0.001) and systolic blood pressure (P=0.003) in the full group. However, NK cell percent was lower in current smokers than in never smokers (p=0.002). Adjusting for age, sex, race/ethnicity, smoking, body mass index, systolic blood pressure, diabetes and dyslipidemia, NK cell percent was negatively associated with common carotid intima media thickness (IMT; β coefficient -0.01; 95% confidence interval -0.03, -0.003) but was not associated with internal carotid IMT (-0.002; -0.037, 0.033). Likewise, NK cell percent was not associated with the presence of CAC (compared those with no detectable CAC; relative risk 1.02; 95% confidence interval 0.96, 1.08) or continuous Agatston score in those with a positive score (β coefficient 0.16, 95% confidence interval -0.003, 0.32) in the full group (models adjusted as above). Results were similar across race/ethnic groups. Conclusions: Of clinical interest, CD3 - CD56 + CD16 + NK cell percent varied significantly by race/ethnicity in these men and women from MESA. However, NK cell percent was inconsistently associated with CVD risk factors; positively with age and systolic blood pressure, and negatively with smoking. NK cell percent was also negatively associated with common carotid IMT. Larger sample sizes and longitudinal analyses will be required to clarify the potential relationship between NK cells and atherosclerosis in humans.
Advance of sporadic Alzheimer's disease animal models
Authors: Lili Zhang, Chen Chen, Marvin SH Mak, Junfeng Lu, Zeqing Wu, Qiuhe Chen, Yifan Han, Yuefeng Li, Rongbiao Pi
Journal: Medicinal Research Reviews (2019)

Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disease. In the past decades, numbers of promising drug candidates showed significant anti-AD effects in preclinical studies but failed in clinical trials. One of the major reasons might be the limitation of appropriate animal models for evaluating anti-AD drugs. More than 95% of AD cases are sporadic AD (sAD). However, the anti-AD drug candidates were mainly tested in the familial AD (fAD) animal models. The diversity between the sAD and fAD might lead to a high failure rate during the development of anti-AD drugs. Therefore, an ideal sAD animal model is urgently needed for the development of anti-AD drugs. Here, we summarized the available sAD animal models, including their methodology, pathologic features, and potential underlying mechanisms. The limitations of these sAD animal models and future trends in the field were also discussed.
Gene expression profile and the biology of squamous cell carcinomas of the head and neck
Authors: Anna Colo, Andre Carvalho, Ana Simoes, Lucas Fahham, Eduardo Neves, Luiz Reis, Alex Carvalho
Journal: Cancer Research (2008)

4263   Head and Neck Squamous Cell Carcinomas (HNSCC) are histologically similar, arising from epithelial cells within the mucosa lining of the upper aerodigestive tract. However, in spite of common therapeutic regimes, HNSCC from different subsites have clear differences in their biology, with diverse growth patterns, metastatic rates and prognosis. To address these differences at the molecular level, 121 HNSCC samples (7 from nasal cavity (NAS), 55 from oral cavity (ORA), 35 from oropharynx (ORO), 6 from hipopharynx (HIP), 18 from larynx (LAR)), treated with surgery or surgery followed by radiotherapy were assayed through microarray technology. Differentially expressed genes were defined by a non-parametric Wilcox test and correction by False Discovery Rate (5%). Statistically significant differences were found only among ORA and ORO, totalizing 6 genes with p
Sodium Glucose Cotransporter 2 Inhibition and the Visualization of Kidney Hemodynamics
Authors: Christoph Wanner
Journal: Circulation (2019)

Article, see p 303 For the majority of practitioners, renal physiology, tubuloglomerular feedback, and glomerular hemodynamics are, at worst, long since forgotten and, at best, hazy concepts with only a cloudy recollection of the finer details.Until recently, this would not pose any significant impediment to clinical practice.However, the type 2 diabetes mellitus epidemic and the growing body of evidence of the significant impact of the sodium glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular and renal outcomes in high-risk individuals, with type 2 diabetes mellitus, forces a rethink.As a direct result of their proven benefits, SGLT2 inhibitors are being used increasingly, not just by diabetologists, but also by cardiologists, nephrologists, and general practitioners.SGLT2 inhibitors influence glucose, salt, and water handling and blood pressure within the kidney in addition to systemic effects, and the time has come for all clinicians to brush up on the mechanism of action of this class of medication. 1 In diabetes mellitus, single-nephron hyperfiltration occurs secondary to an imbalance between vasoactive factors modulating the tone of the afferent and the efferent arterioles of the glomerulus.Consequently, there is increased glomerular filtration pressure and glomerular filtration rate (GFR) on activation of the reninangiotensin system affecting the majority of individuals with type 1 and type 2 diabetes mellitus.Blockade of angiotensin receptors dilates the constricted vas efferens of the glomerulus, decreasing intraglomerular pressure and GFR.Despite an initial decline in GFR, long-term renal benefits are apparent with a relative risk reduction of ≈25% in hard renal end points (ie, doubling of serum creatinine or end-stage kidney disease). 2imilarly, GFR declines in response to SGLT2 inhibition in individuals with type 1 and type 2 diabetes mellitus; this is presumably a consequence of diminished nephron hyperfiltration.The causal mechanism behind this decline in kidney function provokes much intense discussion but remains unclear, despite detailed study.What is clear, however, is that, long term, this initial dip in renal function with SGLT2 inhibition does not have a negative impact on renal outcomes; quite the opposite, in fact.4][5] The initial decline in estimated GFR is in the range of 3 to 5 mL•min -1 •1.73 m -2 and is seen with all currently marketed SGLT2 inhibitors.To the surprise of most clinicians, and in addition to treatment with angiotensin-convert-
Final results of a single-arm phase II study of bevacizumab and temozolomide following radiochemotherapy in newly dignosed adult glioblastoma patients.
Authors: Martin Kelly Nicholas, Rimas Vincas Lukas, Christine Amidei, Nicholas Vick, Nina Paleologos, Mark Gordon Malkin, Hendrikus Krouwer, Larry Junck, Jean Arzbaecher, Albert Lai, Ryan Merrell
Journal: Journal of Clinical Oncology (2013)

2076 Background: This study evaluated efficacy and safety of bevacizumab (BEV) added to the post-radiation treatment phase for patients with newly diagnosed glioblastoma (GBM). Methods: Sixty-two participants with newly diagnosed GBM were enrolled between May 2007 and June 2010. Participants received standard radiation therapy (RT) within 6 weeks of surgery, and concomitant administration of temozolomide (TMZ). Four weeks after radiation, treatment with TMZ (Days 1-5 of a 28 day cycle) with BEV, (days 1 and 15 of a 28 day cycle) was started, and continued until disease progressed or adverse effects indicated need to stop treatment. Analyses were completed for all participants by intention to treat (ITT), with progression-free survival (PFS) and overall survival (OS) serving as primary and secondary endpoints respectively. Results: Subbjects completed a mean of 7.7 (range 0-29) cycles of post-RT with BEV and TMZ. Twenty participants (32%) were unable to proceed to the post-RT phase. The forty-two participants who did proceed to the post-RT phase completed a mean of 11.5 cycles of treatment. Thirty-eight participants (61%) stopped the study due to disease progression; 6 participants (14%) voluntarily discontinued treatment after 24 cycles with at least stable disease. At a median follow-up time of 24 months, median progression-free survival (PFS) for all participants was 8.8 months while median overall survival (OS) was 16.5 months for all participants. Ly with These results also compare favorably with recently reported results from the AVAglio study (PFS = 10.6 mo.). The toxicity profile was consistent with that reported in similar studies. MGMT promoter methtion.ylation status is under investiga Conclusions: Participants in this study demonstrated a median 1.9 month PFS benefit as compared to the 6.9 median OS reported by Stupp, et al. (2005) and a median 1.9 month OS benefit as compared to the 14.6 month median OS reported by Stupp, et al. (2005). Results suggest that the addition of bevacizumab to the post-RT phase of treatment improves both PFS and OS for persons with GBM despite the high percentage of participants being unable to progress to post-radiation treatment. Clinical trial information: NCT005906.