tbuckley/cabot-search huggingface dataset:
Prevalence of Subclinical Coronary Artery Disease in Masters Endurance Athletes With a Low Atherosclerotic Risk Profile
Authors: Ahmed Merghani, Viviana Maestrini, Stefania Rosmini, Andrew T. Cox, Harshil Dhutia, Rachel Bastiaenan, Sarojini David, Tee Joo Yeo, Rajay Narain, Aneil Malhotra, Michael Papadakis, Mathew G. Wilson, Maite Tome, Khaled AlFakih, James C. Moon, Sanjay Sharma
Journal: Circulation (2017)

Background: Studies in middle-age and older (masters) athletes with atherosclerotic risk factors for coronary artery disease report higher coronary artery calcium (CAC) scores compared with sedentary individuals. Few studies have assessed the prevalence of coronary artery disease in masters athletes with a low atherosclerotic risk profile. Methods: We assessed 152 masters athletes 54.4±8.5 years of age (70% male) and 92 controls of similar age, sex, and low Framingham 10-year coronary artery disease risk scores with an echocardiogram, exercise stress test, computerized tomographic coronary angiogram, and cardiovascular magnetic resonance imaging with late gadolinium enhancement and a 24-hour Holter. Athletes had participated in endurance exercise for an average of 31±12.6 years. The majority (77%) were runners, with a median of 13 marathon runs per athlete. Results: Most athletes (60%) and controls (63%) had a normal CAC score. Male athletes had a higher prevalence of atherosclerotic plaques of any luminal irregularity (44.3% versus 22.2%; P =0.009) compared with sedentary males, and only male athletes showed a CAC ≥300 Agatston units (11.3%) and a luminal stenosis ≥50% (7.5%). Male athletes demonstrated predominantly calcific plaques (72.7%), whereas sedentary males showed predominantly mixed morphology plaques (61.5%). The number of years of training was the only independent variable associated with increased risk of CAC &gt;70th percentile for age or luminal stenosis ≥50% in male athletes (odds ratio, 1.08; 95% confidence interval, 1.01–1.15; P =0.016); 15 (14%) male athletes but none of the controls revealed late gadolinium enhancement on cardiovascular magnetic resonance imaging. Of these athletes, 7 had a pattern consistent with previous myocardial infarction, including 3(42%) with a luminal stenosis ≥50% in the corresponding artery. Conclusions: Most lifelong masters endurance athletes with a low atherosclerotic risk profile have normal CAC scores. Male athletes are more likely to have a CAC score &gt;300 Agatston units or coronary plaques compared with sedentary males with a similar risk profile. The significance of these observations is uncertain, but the predominantly calcific morphology of the plaques in athletes indicates potentially different pathophysiological mechanisms for plaque formation in athletic versus sedentary men. Coronary plaques are more abundant in athletes, whereas their stable nature could mitigate the risk of plaque rupture and acute myocardial infarction.
A Meta-Analysis and Meta-Regression of the Efficacy of Front-Line Treatment Combinations with Ponatinib Versus 1st- and 2nd-Generation Tyrosine Kinase Inhibitors for Ph+ Acute Lymphoblastic Leukemia
Authors: Elias J. Jabbour, Maral DerSarkissian, Mei Sheng Duh, Nora McCormick, Wendy Y. Cheng, Lisa J. McGarry, Ariadne Souroutzidis, Hui Huang, Hagop M. Kantarjian
Journal: Blood (2016)
High Serum PCSK9 Is Associated With Increased Risk of New-Onset Diabetes After Transplantation in Renal Transplant Recipients
Authors: Michele F. Eisenga, Dorien M. Zelle, John H. Sloan, Carlo A.J.M. Gaillard, Stephan J.L. Bakker, Robin P.F. Dullaart
Journal: Diabetes Care (2017)

New-onset diabetes after transplantation (NODAT) is a major complication in renal transplant recipients (RTRs). Cholesterol metabolism has been linked to diabetes development. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is crucial in LDL receptor regulation. Its association with NODAT is unknown. We prospectively determined the association between serum PCSK9 levels and NODAT development and then with all-cause mortality, cardiovascular mortality, and renal graft failure.In a university setting, nondiabetic RTRs recruited between 2001 and 2003 with a functional graft for ≥1 year were eligible. Serum PCSK9 was measured by ELISA. Cox proportional hazards analysis was used to assess the association of PCSK9 with the development of NODAT, all-cause mortality, cardiovascular mortality, and graft failure.In 453 RTRs (age 51 ± 12 years, 56% male; 6.1 [2.7-11.7] years after transplantation), serum PCSK9 was 107.1 ± 43.4 μg/L. During a median follow-up of 10 years, 70 RTRs developed NODAT, 123 died, and 59 developed graft failure. NODAT occurred more frequently in the upper PCSK9 tertile (23%) versus the lowest two PCSK9 tertiles (12%; P < 0.001). In crude Cox regression analyses, PCSK9 was significantly associated with development of NODAT (hazard ratio 1.34 [95% CI 1.10-1.63]) per SD change (P = 0.004). This association remained independent of adjustment for potential confounders, including statin use. PCSK9 was not associated with all-cause mortality, cardiovascular mortality, or graft failure.Circulating PCSK9 is associated with NODAT in RTRs. The PCSK9 pathway may contribute to the pathogenesis of NODAT.
Global Elimination of Hepatitis C Virus
Authors: Rachael L. Fleurence, Harvey J. Alter, Francis S. Collins, John W. Ward
Journal: Annual Review of Medicine (2024)

Hepatitis C virus (HCV) is predominantly transmitted through parenteral exposures to infectious blood or body fluids. In 2019, approximately 58 million people worldwide were still infected with HCV, and 290,000 deaths occurred due to hepatitis C-related conditions, despite hepatitis C being curable. There are substantial barriers to elimination, including the lack of widespread point-of-care diagnostics, cost of treatment, stigma associated with hepatitis C, and challenges in reaching marginalized populations, such as people who inject drugs. The World Health Organization (WHO) has set goals to eliminate hepatitis C by 2030. Several countries, including Australia, Egypt, Georgia, and Rwanda, have made remarkable progress toward hepatitis C elimination. In the United States, the Biden-Harris administration recently issued a plan for the national elimination of hepatitis C. Global progress has been uneven, however, and will need to accelerate considerably to reach the WHO's 2030 goals. Nevertheless, the global elimination of hepatitis C is within reach and should remain a high public health priority.
CHARACTERISTICS OF ANKLE MUSCLE ACTIVITY DURING TILTING MOVEMENTS ON A WOBBLE BOARD
Authors: Miho Morita, Yukio Urabe, Eri Fujii, Nobuaki Moriyama, Takahiko Yamamoto, Takuya Takeuchi, Shogo Tsutsumi, Shuhei Numano, Yuta Suzuki, Noriaki Maeda
Journal: British Journal of Sports Medicine (2017)

Background Balance training is a common component of rehabilitation after ankle sprains. A relatively high activity of the peroneus longus (PL) to the activity of the tibialis anterior (TA) (a low TA/PL ratio) is reported as an effective muscle activity pattern during balance training to prevent inversion ankle sprains. To date, no research has investigated ankle muscle activity during tilting movements on a wobble board. Objective To assess the magnitude of muscle activity of the ankle while inversion and eversion movements of the ankle joint are performed on a wobble board. Design Single-session randomized repeated-measures study design. Setting University laboratory. Participants Seventeen young adults (11 females and 6 males) with no history of ankle injury. Interventions Participants performed tilting movements on a wobble board in a medial and lateral direction while balancing on their non-dominant leg. The frequency of the movement was set at 40 bpm. Muscle activity of the TA and the PL during five cycles of inversion-eversion movements were collected and stored for analysis. Main Outcome Measurements Normalized RMS EMG values (percentage of each participant's maximum voluntary isometric contraction; %MVIC) of the TA and PL, along with TA/PL ration in the inversion (wobble board tilted in the lateral direction) and eversion (wobble board tilted in the medial direction) phase. Results There was a significant difference in muscle activity of the PL (inversion phase; 41.6±15.3%MVIC, eversion phase; 59.2±21.5% MVIC, p&lt;0.01) and TA/PL ratio (inversion phase; 52.6±22.3%, eversion phase; 34.1±16.3%, p&lt;0.01). There was no significant difference in muscle activity of the TA (p&gt;0.05). Conclusions The results of the present study indicate that tilting movements on a wobble board in the medial direction (eversion of the ankle joint) may be favorable as an exercise modality after inversion ankle sprains as a high PL activity and a low TA/PL ratio was acquired.
Physiology of Angina and Its Alleviation With Nitroglycerin
Authors: Kaleab N. Asrress, Rupert Williams, Timothy Lockie, Muhammed Z. Khawaja, Kalpa De Silva, Matthew Lumley, Tiffany Patterson, Satpal Arri, Sana Ihsan, Howard Ellis, Antoine Guilcher, Brian Clapp, Philip J. Chowienczyk, Sven Plein, Divaka Perera, Michael S. Marber, Simon R. Redwood
Journal: Circulation (2017)

The mechanisms governing exercise-induced angina and its alleviation by the most commonly used antianginal drug, nitroglycerin, are incompletely understood. The purpose of this study was to develop a method by which the effects of antianginal drugs could be evaluated invasively during physiological exercise to gain further understanding of the clinical impact of angina and nitroglycerin.Forty patients (mean age, 65.2±7.6 years) with exertional angina and coronary artery disease underwent cardiac catheterization via radial access and performed incremental exercise using a supine cycle ergometer. As they developed limiting angina, sublingual nitroglycerin was administered to half the patients, and all patients continued to exercise for 2 minutes at the same workload. Throughout exercise, distal coronary pressure and flow velocity and central aortic pressure were recorded with sensor wires.Patients continued to exercise after nitroglycerin administration with less ST-segment depression (P=0.003) and therefore myocardial ischemia. Significant reductions in afterload (aortic pressure, P=0.030) and myocardial oxygen demand were seen (tension-time index, P=0.024; rate-pressure product, P=0.046), as well as an increase in myocardial oxygen supply (Buckberg index, P=0.017). Exercise reduced peripheral arterial wave reflection (P<0.05), which was not further augmented by the administration of nitroglycerin (P=0.648). The observed increases in coronary pressure gradient, stenosis resistance, and flow velocity did not reach statistical significance; however, the diastolic velocity-pressure gradient relation was consistent with a significant increase in relative stenosis severity (k coefficient, P<0.0001), in keeping with exercise-induced vasoconstriction of stenosed epicardial segments and dilatation of normal segments, with trends toward reversal with nitroglycerin.The catheterization laboratory protocol provides a model to study myocardial ischemia and the actions of novel and established antianginal drugs. Administration of nitroglycerin causes changes in the systemic and coronary circulation that combine to reduce myocardial oxygen demand and to increase supply, thereby attenuating exercise-induced ischemia. Designing antianginal therapies that exploit these mechanisms may provide new therapeutic strategies.
Margaret McCartney: Can’t we take mental illness seriously without Prince Harry?
Authors: Margaret McCartney
Journal: BMJ (2017)

For over 400 years, monarchs such as Henry VII touched the face or neck of people with scrofula. This disease—tuberculous cervical lymphadenitis—was also known as “the King’s evil.” It often improved anyway, giving the impression that unquestioned authority and ritual could do miracles.1

George I ended the practice, and royal touches now involve flashes of media magic. Prince Harry scored global headlines by stating that he sought counselling after his mother’s death.

This has been broadly viewed as brilliant advocacy for de-stigmatising mental distress and encouraging people to talk. Such is Harry’s reach that Simon Wessely, president of the Royal College of Psychiatrists, thinks that “in just 25 minutes he has achieved more good than I have in 25 years.”2

Who …
Genome-wide association scan detected candidate polymorphisms associated with overall survival (OS) in advanced non-small cell lung cancer (NSCLC) treated with carboplatin (CBDCA) and paclitaxel (PTX)
Authors: Y. Sato, N. Yamamoto, H. Kunitoh, Y. Ohe, N. Katori, J. Sawada, H. Sakamoto, N. Saijo, T. Yoshida, T. Tamura
Journal: Journal of Clinical Oncology (2009)

8031 Background: The combination of CBDCA and PTX is one of the standard chemotherapy for patients with advanced NSCLC. Genome-wide association studies (GWAS) are a powerful tool for identifying genes for biomarkers of common diseases. This prospective study was investigated whether candidate polymorphisms in GWAS could influence OS in advanced NSCLC patients treated with CBDCA and PTX. Methods: Chemotherapy naïve stage IIIB or IV NSCLC patients, treated with CBDCA (AUC=6mg/ml/min) and PTX (200mg/m 2 , 3-hour), were eligible in this study. The DNA samples were extracted from peripheral blood mononuclear cells before treatment and 110,000 SNPs were obtained by Illuimna's Sentrix Human-1 Genotyping BeadChip. Statistical analyses were performed by the log-rank test and Cox proportional hazards model in consideration of the linkage disequilibrium. Results: From July 2002 to May 2004, 117 patients (male/female: 85/32, PS 0/1/2: 22/92/3, stage IIIB/IV: 50/67), aged 29–80 (median: 61) years, received a total of 387 cycles of treatment. The median survival time (MST) of 117 patients was 17.1 months. In the GWAS, four SNPs were associated significantly with shortened OS: rs1656402 in the EIF4E2 Gene (MST for AG [n = 54] + AA [n = 44] and GG [n = 19] were 18.2 and 7.7 months, respectively; p = 4.2× 10 -7 , HR = 3.58 [2.1–6.1]), rs1209950 in the ETS2 gene (MST for AA [n = 105] and AG [n = 12] + GG [n = 0] were 17.7 and 7.0 months, respectively. p = 9.2×10 -8 , HR = 4.95 [2.6–9.5]), rs10074374 (MST for CC [n = 114] and CT [n = 3] + TT [n = 0] were 17.1 and 2.2 months, respectively. p = 2.2×10 -6 , HR = 23.2 [6.3–85.1]) and rs2063681 (MST for CT [n = 45] + CC [n = 61] and TT [n = 11] were 17.8 and 6.6 months, respectively. p = 5.2×10 -8 , HR = 5.47 [2.8–10.9]). These four SNPs were statistically significant even after multiple comparison adjustment. Conclusions: GWAS is a powerful tool to search for new prognostic biomarkers for patients with stage IIIB or IV NSCLC who receive CBDCA and PTX as the first-line chemotherapy and may unveil an unexplored molecular pathways correlated with the drug response. [Table: see text]
Abstract #903: Glycopeptide antibodies used to characterize human P-glycoprotein differential glycosylation in mulitdrug resistant uterine sarcoma cells, MES-SA/Dx5
Authors: Stan Ivey, Nicole Jackson, Mastingor Desir, Tianshu Li
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Human P-glycoprotein (Pgp) is a large, heavily N-link glycosylated membrane protein that can be involved in multidrug resistance during chemotherapy treatments. Pgp runs as a large smear in electrophoretic gels due to its extensive glycosylation, ranging from 170-190 kDa. When normal Pgp is overexpressed, its glycan complement changes. It is thought this is due to glycosylation errors in the rapidly exiting Pgp, as it is posttranslationally processed intracellularly. In our previous study, we used lectins to characterize these aberrant glycans and found that they contained at least two different complex N-glycans, one high mannose tree and one branched, hybrid oligosaccharide capped with terminal sialic acids. DSA, a lectin specific for biantennary oligosaccharides, possessing beta (1-4)-N-acetyl-D-glucosamine residues, also recognized the blotted Pgp and probably detected the core Galbeta (1-4)-GlcNAc(x) component found in other Pgps. There are 3 N-linked glycosylated sites on human Pgps and, interestingly, they all occur on a short extracellular stretch of about 16 amino acids near the N-terminus. Polyclonal antibodies were raised against this extracellular loop: a 16-mer synthetic peptide without the glycans (S N IT N RSDI N DTGFFM, sequence 89-105, ABR-Affinity Bioreagents, Project# A553001). We are currently using these glycopeptide antibodies to study the differential glycosylation of overexpressed Pgp to determine if there is a specific glycome pattern in cancer cells overexpressing Pgp or a random mis-glycosylation. To this end, we are shaving MES-SA/Dx5 cells using proteinase K, along with trypsin, to release the glycosylated extracellular loop, without killing the cells. Once released, the Pgp-specific glycopeptide pAbs are being used in affinity columns to isolate the Pgp glycopeptides. We are using ELISA competition assays, Western blots, and Mass Spec analysis to determine if overexpressed Pgp glycans can be useful as biomarkers or unique targets to shut down the aberrant Pgps. Supported by an NIH-INBRE minigrant and a grant from The Cancer Federation (SI).

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 903.
Estimation of drug cost avoidance (DCA) and pathology cost avoidance (PCA) through participation in NCIC clinical trials group (NCIC-CTG) phase III clinical trials in Canada.
Authors: Patricia A. Tang, Annette E. Hay, Christopher J. O'Callaghan, Nicole Mittmann, Carole Chambers, Joseph L Pater, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2014)

6560 Background: Cost avoidance (CA) occurs when, due to the provision of a drug therapy (DCA) or a pathology test (PCA) via trial participation, payment for standard treatment or testing is not required. The aim of this study was to estimate the total DCA and PCA for Canadian patients (pts) enrolled in NCIC-CTG conducted phase 3 trials. Methods: Phase 3 trials that had completed accrual and resulted in DCA or PCA were identified. PCA was calculated based on the number of pts screened and test cost. DCA was estimated based on pts randomized, protocol dosing regimen, drug cost, median dose intensity and median duration of therapy. If this information was incomplete, assumptions were made based on published literature. Costs for Canadian pts accrued are presented in Canadian dollars. No adjustment was made for inflation. Results: From 1999-2011, 4 trials resulted in PCA (1,479 pts) and 17 trials resulted in DCA (3195 pts). Total PCA was estimated at $4,194,849, which included testing for KRAS ($141,058), microsatellite instability ($18,600), and 21-gene recurrence score ($4,035,191). Total DCA was estimated at $27,935,957, of which targeted therapy comprised 42.6% of DCA (5 trials). The combined PCA and DCA was $32,130,806. Conclusions: Over the time period studied, these NCIC-CTG trials resulted in total CA (PCA and DCA) of approximately $7514/pt. Although not all trials lead to CA, these savings should be taken account when considering the financial impact of conducting clinical research. Trial (drug with CA) Mean DCA per pt ($) Total DCA for trial ($) CO.13 (irinotecan) 10,565 1,595,249 CO.20 (cetuximab) 22,588 7,544,519 CRC.2 (oxaliplatin) 13,665 3,689,425 CRC.5 (bevacizumab) 17,430 1,115,520 PA.2 (5FUFA) 93 3,993 MA.27 (exemestane, anastrazole) 9,034 9,519,856 MA.31 (trastuzumab) 31,784 1,239,595 MAC.1 (CMF/AC) 535 6,959 MAC.4 (tamoxifen) 639 21,000 MAC.5 (tamoxifen) 639 39,319 MAC.7 (anastrazole) 2,005 88,209 REC.1 (interferon) 4,290 68,643 OV.16 (paclitaxel) 3,011 710,586 OV.17 (paclitaxel) 4,996 169,858 HN.6 (cisplatin) 90 14,391 LY.12 (rituximab, cytarabine) 6,660 2,104,412 BRC.3 (etoposide) 1,106 4,423
Can Memory T Cell Monitoring Using Flow Cytometry Predict Survival in Haploidentical Hematopoietic Stem Cell Transplantation?
Authors: Bohyun Kim, Seongsoo Jang, Yu-Jin Lee, Young-Uk Cho, Chan-Jeoung Park, Eun-Seok Choi, Kyung-Nam Koh, Ho Joon Im, Jong Jin Seo
Journal: Blood (2016)
Lung Cancer-Targeting Peptides with Multi-subtype Indication for Combinational Drug Delivery and Molecular Imaging
Authors: Yi-Hsuan Chi, Jong-Kai Hsiao, Ming-Huang Lin, Chen Chang, Chun-Hsin Lan, Han-Chung Wu
Journal: Theranostics (2017)

Lung cancer is the leading cause of cancer-related death worldwide. Most targeted drugs approved for lung cancer treatment are tyrosine kinase inhibitors (TKIs) directed against EGFR or ALK, and are used mainly for adenocarcinoma. At present, there is no effective or tailored targeting agent for large cell carcinoma (LCC) or small cell lung cancer (SCLC). Therefore, we aimed to identify targeting peptides with diagnostic and therapeutic utility that possess broad subtype specificity for SCLC and non-small cell lung cancer (NSCLC). We performed phage display biopanning of H460 LCC cells to select broad-spectrum lung cancer-binding peptides, since LCC has recently been categorized as an undifferentiated tumor type within other histological subcategories of lung cancer. Three targeting phages (HPC1, HPC2, and HPC4) and their respective displayed peptides (HSP1, HSP2, and HSP4) were able to bind to both SCLC and NSCLC cell lines, as well as clinical specimens, but not to normal pneumonic tissues. In vivo optical imaging of phage homing and magnetic resonance imaging (MRI) of peptide-SPIONs revealed that HSP1 was the most favorable probe for multimodal molecular imaging. Using HSP1-SPION, the T2-weighted MR signal of H460 xenografts was decreased up to 42%. In contrast to the tight binding of HSP1 to cancer cell surfaces, HSP4 was preferentially endocytosed and intracellular drug delivery was thereby effected, significantly improving the therapeutic index of liposomal drug in vivo. Liposomal doxorubicin (LD) conjugated to HSP1, HSP2, or HSP4 had significantly greater therapeutic efficacy than non-targeting liposomal drugs in NSCLC (H460 and H1993) animal models. Combined therapy with an HSP4-conjugated stable formulation of liposomal vinorelbine (sLV) further improved median overall survival (131 vs. 84 days; P = 0.0248), even in aggressive A549 orthotopic models. Overall, these peptides have the potential to guide a wide variety of tailored theranostic agents for targeting therapeutics, non-invasive imaging, or clinical detection of SCLC and NSCLC.