tbuckley/cabot-search huggingface dataset:
Pharmacokinetic and ADME study of nanoparticle albumin-bound 17AAG (nab-17AAG) in mice
Authors: Vuong Trieu, Jon Cordia, Andrew Yang, Bridget Beals, Sherry Ci, Leslie Louie, Neil Desai
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

5747 

Background: Nab technology enhances tumor penetration of insoluble drugs by a novel mechanism of albumin receptor-mediated (gp60) endothelial trancytosis and improves drug accumulation in tumors via albumin-mediated binding to SPARC. The Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17AAG), is a better tolerated anti-cancer agent than its natural-product predecessor, geldanamycin. Rodent IV administration of nab-17AAG was performed to investigate: (i) the pharmacokinetic (PK) properties of 17AAG and its major metabolite, 17-amino geldanamycin (17AG) and, (ii) the absorption, distribution, metabolism, and excretion (ADME) profile of nab-17AAG.    Methods: For PK evaluation, bolus tail-vein injections of nab-17AAG were administered in CD1 mice, at dose levels of 50, 100, and, 150 mg/kg. Blood samples (up to 0.6 mL) for PK analysis were obtained at the following target times: predose and at 0.0167, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 4, 8, 24, 36 and 48 hrs postdose. Mouse sera were analyzed for 17AAG and 17AG using a LC/MS analytical method. Noncompartmental PK parameters were estimated using WinNonlin software. For ADME studies, ICR mice received a single IV administration of nab-3H-17AAG at 150 mg/kg. Urine and fecal specimens were collected across 5 days at 4, 12, or 24 hr postdose intervals for analysis of nab-3H-17AAG-derived radioactivity.    Results: Tmax for the parent, 17AAG, occurred at the first blood collection at all 3 dose levels, without dose-dependent trends. The max serum concentration of 17AAG increased with increasing dose but at a less than dose-proportional ratio for the different dose levels. Systemic exposure to 17AAG increased with increasing dosage and was dose proportional at the mid and high doses. Terminal elimination half-lives (HL) were similar for 17AAG & 17AG, ranging from 0.357 to 0.652 hrs with no consistent dose-dependent trends. Vz and Vss values for 17AAG were variable, but slightly greater in the high-dose group. Metabolic conversion of 17AAG to 17AG reached max concentration within 1 hr postdose and was greater at the higher dose levels. 17AG had a slightly longer HL (30 to 60 mins), a later Tmax (30 to 60 mins), a 3-fold lower exposure, and at least a 10-fold lower Cmax than 17AAG. ADME studies showed that nab-3H-17AAG was primarily excreted in feces (≥ 64%) and urine (≥ 17%) with no preferential tissue site for accumulation. Of three 3H-17AAG urine metabolites detected, less than 6% were related to17AAG.    Conclusions: Application of nab technology to 17AAG resulted in a formulation of 17AAG with the expected characteristics of albumin-bound nanoparticles, inclusive of a linear PK profile with respect to dose and large volume of distribution. ADME studies showed that nab-3H-17AAG was primarily excreted in feces and urine with no preferential site for tissue accumulation.
Abstract 13763: Circulating Endothelial Progenitor Cell Phenotypes are Weakly Associated With Select Biomarkers of Inflammation
Authors: Joao Daniel T Fontes, Susan Cheng, Elizabeth L McCabe, Shih-Jen Hwang, Ramachandran S Vasan, Stanley Y Shaw, Kenneth S Cohen, Martin G Larson, Emelia J Benjamin, Thomas J Wang
Journal: Circulation (2011)

Introduction: Depletion of circulating endothelial progenitor cell phenotypes, conventionally termed ‘EPCs’, has been associated with higher cardiovascular disease (CVD) risk. Although systemic inf...
Medical fiction
Authors: J. Collee
Journal: BMJ (1999)

Papers pp 972, 978 

The best works of fiction operate on several levels at once. They contain simple characters and messages which a child can understand, but they also contain deeper meanings, which may only become obvious after frequent retelling. Thus the great tales of antiquity—the Mahabharata , the Odyssey , the Epic of Gilgamesh —can operate both as soap operas and as profound meditations on the great imponderables of life.

It is no accident that these stories are often obscure or ambiguous; indeed, this feature partly accounts for their success. If things are too obvious there is no drama in them. If there's no drama, the story doesn't engage us emotionally, and without emotional engagement the story is unmemorable. Much health advertising fails for this reason: its very clarity makes it uninteresting and forgettable. By contrast, tobacco …
Gated imaging for left ventricular volume measurement.
Authors: J A Bianco
Journal: Circulation (1980)

EDITORmaintaining stable blood levels.In addition, at least one patient the procainamide group (H.L 1.) was documented to have low blood levels because of poor compliance, rather than because of kinetics of the drug.The questions raised in Dr. Kletzkin's letter are interesting and provocative, but we do not believe that retrospective analysis justifies declaring the superiority of either of two drugs.The major differences cross a boundary of significance by the observations only one patient because of the limited number of patients.In addi- tion, some of the differences lose their significance when analyzed by a two-tail test, rather than a one-tail test.The question raised is worthy of further investigation by appropriate randomization crossover techniques and larger numbers of observations.
Abstract 9868: Coronary Artery Calcium Predicts Coronary Heart Disease Events Even at the Extremes of Age: The Multi-Ethnic Study of Atherosclerosis
Authors: Rajesh Tota-Maharaj, Michael J Blaha, Ron Blankstein, Leslee J Shaw, Roger S Blumenthal, Matthew J Budoff, Khurram Nasir
Journal: Circulation (2011)

CAC testing to refine risk prediction is utilized in intermediate-risk asymptomatic patients, largely excluding elderly and young patients who are typically classified as high- or low-risk due to the influence of age in risk-scoring algorithms. The clinical utility of CAC in predicting coronary heart disease (CHD) events in patients at extremes of age remains to be explored. Methods: The MESA cohort was followed up for a median of 5.8 years. The primary endpoint of CHD events was assessed in the following age groups: 45-54, 55-64, 65-74, and 75-84 years. Cox regression analysis was employed to determine the interplay of CAC and aging in predicting CHD events after adjusting for demographic factors, traditional risk factors, and medication use. Results: Of 6,809 participants, 278 (4%) CHD events were noted. The prevalence of CAC=0 was 75% in the 45-54 age group, decreasing progressively with increasing age (75-84 yr=19%, p&lt;0.0001). Conversely, CAC &gt;100 increased from 6% in the 45-54 age group to 51% in the elderly. After adjusting for age, demographic and cardiovascular risk factors, CAC&gt;100 predicted a significantly increased CHD event rate compared to CAC=0 in both the young and elderly (45-54: HR 8.29 [95% CI 2.84-24.16], 75-84: HR 8.34 [95% CI 2.11-36.92]). Increasing age group was associated with a statistically significant increased risk of CHD events, compared to the 45-54 year old group, even after adjusting for risk factors and CAC (HR [95% CI], 55-64 yr: 1.71[1.06-2.74], 65-74 yr: 1.75 [1.10-2.79], 75-84 yr: 1.95 [1.17-3.25]). Conclusions: Greater CAC burden was associated with increased CHD events in all age groups, adding incremental prognostic value in both young and elderly patients. Young individuals with CAC&gt;100 had a higher CHD event rate compared to older individuals with no CAC. Increasing age was independently associated with higher event rates, confirming that atherosclerotic burden cannot completely explain the association of aging with CHD events.
P0282 : The long non coding RNA UC.158 modulates growth of Wnt/β;-catenin driven hepatocellular carcinoma (HCC)
Authors: I.H. Cheong, A. Lampis, M. Fassan, V. Paulus-Hock, C. Vicentini, J. Hahne, L. Cascione, L. Quagliata, T. Jamieson, D. Athineos, A. Veronese, R. Visone, C. Murgia, G. Ferrari, T.R. Evans, G.J. Feng, T. Dale, L. Boulter, R. Guest, S. Forbes, M. Negrini, L. Terracciano, A. Scarpa, T. Patel, P. Workman, O. Sansom, N. Valeri, C. Braconi
Journal: Journal of Hepatology (2015)
Reduction in Recurrent Cardiovascular Events With Intensive Lipid-Lowering Statin Therapy Compared With Moderate Lipid-Lowering Statin Therapy After Acute Coronary Syndromes
Authors: Sabina A. Murphy, Christopher P. Cannon, Stephen D. Wiviott, Carolyn H. McCabe, Eugene Braunwald
Journal: Journal of the American College of Cardiology (2009)
Human kallikrein 2 (KLK2) inhibiting peptides
Authors: Can Hekim, Hannu Koistinen, Miikka Pakkala, Ale NA¤rvA¤nen, Ulf-HA kan Stenman
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

3092 

Background and aims: Human Kallikrein 2 (KLK2), a prostate specific serine protease, is overexpressed in prostate cancer. It is thought to promote tumour growth and metastasis by degrading extracellular matrix. Thus, inhibition of KLK2 is potentially useful way of preventing prostate cancer growth and metastasis. KLK2 is also emerging as a new biomarker for prostate cancer detection. We aimed to develop peptides that inhibit KLK2 activity towards natural substrates.

Methods: Phage display libraries were used to identify peptide ligands that specifically inhibit KLK2. The motifs required for inhibition were characterized by alanine scanning and amino acid deletion analyses. The enzymatic activity of KLK2 was measured with a peptide substrate and natural substrates like IGFBP-3 and proPSA. To increase plasma stability, the linear peptides were cyclized by peptide bonding in a head-to-tail fashion.

Results: Three linear peptides that specifically inhibited the enzymatic activity of KLK2 were identified. Amino acid deletion and substitution analyses showed that motifs of 6 amino acids were essential for inhibition. The peptides also inhibited KLK2 activity towards proPSA and IGFBP-3. The linear peptides were rapidly degraded in plasma but head-to-tail cyclized peptides were stable for more than 24 hours and retained their inhibitory activity.

Conclusions: We have identified specific peptides that inhibit KLK2 activity towards both peptide and natural substrates, such as proPSA and IGFBP-3, which may be involved in prostate cancer growth and metastasis. The peptides were characterized and modified to improve plasma stability for in vivo applications. These novel peptides are potentially useful for treatment and diagnosis of prostate cancer.
Stem Cell Mobilization by Granulocyte Colony-Stimulating Factor for Myocardial Recovery After Acute Myocardial Infarction
Authors: Dietlind Zohlnhöfer, Alban Dibra, Tobias Koppara, Antoinette de Waha, Rasmus Sejersten Ripa, Jens Kastrup, Marco Valgimigli, Albert Schömig, Adnan Kastrati
Journal: Journal of the American College of Cardiology (2008)
Abstract 15926: Usefullness of Peak Mitral Regurgitation Velocity to Left Ventricular Outflow Tract Time Velocity Integral Ratio as a New Prognostic Marker in Failing Heart
Authors: Mehmet S Cetin, Elif H Ozcan Cetin, Ugur Canpolat, Selahattin Aydin, Yesim Akin Guray, Dursun Aras, Ahmet Temizhan, Sinan Aydogdu
Journal: Circulation (2014)

Introduction: Systemic vascular resistance (SVR), a neglected hemodynamic parameter, provides a precious tool for risk estimation and therapy guidance in advanced heart failure (HF). Routine right heart catheterization for this purpose is an invasive technique with potential procedural risks. So, noninvasive techniques by using Doppler may be more practical for estimation of SVR. The ratio of peak mitral regurgitation velocity (MRV) to left ventricular outflow tract time-velocity integral (LVOT TVI) was showed a good correlation with SVR obtained by right heart catheterization. Herein, we aimed to assess the predictive role of MRV/LVOT TVI ratio for follow-up all-cause mortality in HF .

Methods: A total of 80 patients with HF (LVEF <30%) and age- and gender-matched 20 healthy control subjects were enrolled. All participants underwent transthoracic echocardiography.

Results: MRV/LVOT TVI ratio was higher in HF group compared to the control group (0.48±0.16 vs. 0.25±0.04, p<0.001). Among HF patients, MRV/LVOT TVI ratio was the highest in NYHA class 4 group (p<0.001), and it was positively correlated with functional status (β=0.590, p<0.001). MRV/LVOT TVI ratio was positively correlated with troponin I (β=0.357, p<0.001), serum BNP level (β=0.343, p=0.016), uric acid level (β=0.282, p=0.009) and negatively correlated with peak VO2 (β=-0.60, p<0.001), SEATTLE score derived life expectancy (β=-0.297, p=0.007). In multivariate Cox regression analysis, MRV/LVOT TVI ratio (HR=15,52 95% CI: 2.814-85.602 p=0.002) was found as the significant predictor for all cause mortality in HF patients, independent from other risk factors. In ROC analyis, a cut of value 0.46 for MRV/LVOTTVI ratio 68.8% sensitivity and 70.5% specifity for prediction of one-year mortality (AUC=0.755 p=0.001).

Conclusion: Our study revealed that MRV/LVOT TVI ratio as a reflector of SVR, was an independent predictor of all-cause mortality in HF patients. This simple, available and non-invasive parameter may guide practitioners for risk stratification and more aggressive management of HF patients.
Abstract 5915: Clinical and Neurohormonal Correlates and Prognostic Value of Serum Prolactin Levels in Patients with Chronic Heart Failure
Authors: John Parissis, Dimitrios Farmakis, Maria Nikolaou, Vassiliki Bistola, Antonios Rigas, Dionysia Birmpa, Koula Venetsanou, Ioannis A Paraskevaidis, Gerasimos Filippatos, Dimitrios T Kremastinos
Journal: Circulation (2008)
Hospital survey of residents' practice and patterns: End-of-life care.
Authors: G. O. Akogbe, C. A. Ezigbo, N. Anumenechi, B. B. Abdulazeez
Journal: Journal of Clinical Oncology (2010)

e19663 Background: End of life care is an essential part of cancer management. It improves the quality of life for patients and families of terminally ill cancer patients. It provides relief from pain and other distressing symptoms, affirms life and regards dying as a normal process. Intends neither to hasten nor postpone death, integrates the psychological aspect of patients care, offer support system to help family cope and uses a team approach to address the needs of patients and their families. Residents are very important in giving this all important care to patients. The purpose of this survey is to determine the knowledge, attitude and practice of “end of life care” among residents. Methods: Questionnaires were completed by randomly selected residents from the major clinical oncology departments of the Ahmadu Bello University Teaching Hospital, Zaria, Nigeria. The questionnaire addressed these domain;awareness, ability to give this care, frequency of encounter with patients requiring this care, attitude towards the care and encounter with patients with do not resuscitate (DNR) instruction. Results: Of the 100 questionnaires distributed, a total of 76 residents completed and returned the questionnaires: yielding 76% response rate. 84% of the respondent were aware of WHO guidelines on “end of life care.” Only 33% of the respondent were able to give this care in their various unit, while 64% were not due to various constraint. Logistic is the most cited constraint (43%), while, financial constraint (21%), lack of knowledge/awareness on what to do (15%), and patients refusal (5%) were the other difficulties encountered. Only 11% of the respondent encountered patients with do not resuscitate (DNR) instruction. Conclusions: Majority of patients were not receiving sufficient “end of life care” due to logistic problems, financial constraints and unfavorable attitude of residents to this all important care. Future research will focus on developing curricula and interventions for the residents and other health workers to improve the practice of “end of life care” in this part of the world. No significant financial relationships to disclose.
Mistrafficking of primary granule proteins (pgps) in leukemia simultaneously promotes pgp cross-priming and increases susceptibility to ctl killing
Authors: Gheath Alatrash, Yoko Ono, Anna Sergeeva, Sijie Lu, Changqing Wang, Eric Wieder, Jeffrey Molldrem
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

1034 

We have identified PR1, a nonomeric HLA-A2-restricted peptide (VLQELNVTV), as a leukemia-associated antigen (LAA) derived from the myeloid-restricted serine proteases neutrophil elastase (ELA2) and proteinase-3 (PRTN3), recognized PGPs overexpressed in many leukemias. PR1-specific cytotoxic T lymphocytes (PR1-CTL) have been shown to preferentially recognize and kill myeloid leukemia cells. Vaccination with PR1 peptide leads to immune and clinical responses in some patients with myeloid leukemia. However, not all leukemia that is susceptible to PR-1 CTL killing overexpresses PGPs. Therefore, we hypothesized that aberrant protein expression in target leukemia causes LAA presentation by MHC-I and therefore predisposes leukemia to CTL killing. To study the subcellular localization of PGPs, the cytoplasmic, nuclear, membrane, and golgi/ER fractions were obtained from apheresis products from patients with AML and CML and compared to healthy donors. In contrast to normal granulocytes, leukemia showed significantly higher PRTN3 and ELA2 distribution to cytoplasmic, nuclear and membrane organelles, in addition to primary granules, as confirmed by western blot (WB) and confocal microscopy (CM). Similarly, PRTN3 and ELA2 were 5- to 20-fold higher in sera from AML and CML patients (n=20), compared to healthy controls (n=5). This increased serum expression might favor antigen uptake by antigen presenting cells (APC). To test this, we studied whether fresh B cells and the HLA-A2+ HMy.CIR B-cell line could cross-present soluble PRTN3 and ELA2 when co-incubated at concentrations similar to those of leukemia patients. PRTN3 and ELA2 localized to LAMP-2+ lysosomes 2 hours after co-incubation with B-cells or HMy.CIR, assessed by CM and WB. Priming of naive CTL with PRTN3- and ELA2-pulsed B cells could be shown in vitro and cross-presentation to PR1 CTL was dependent on proteasomal cleavage since treatment of APC with lactacystin blocked PR1-CTL proliferation using BrdU labeling. Together, these results demonstrate that in leukemia ELA2 and PRTN3 are aberrantly localized to gogli/ER and the cytoplasm, rather than azurophil granules, which are often absent or deficient in myeloid leukemia. This abnormal expression may confer preferential susceptibility to PR1-CTL killing since both proteins are readily available for MHC-I presentation, unlike in normal granulocytes where they are sequestered from this pathway in membrane-bound granules. Finally, increased serum expression of PRTN3 and ELA2 favors cross-presentation of both proteins to PR1-CTL by B cells. Thus, mistrafficking of PGPs can simultaneously shape host T-cell immunity and trigger target cell susceptibility, mechanisms that might be broadly applicable to other cancers.
Invasive Cancer Incidence and Survival — United States, 2013
Authors: S. Jane Henley, Simple D. Singh, Jessica King, Reda J. Wilson, Mary Elizabeth O’Neil, A. Blythe Ryerson
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Although cancer represents many heterogeneous diseases, some cancer types share common risk factors. For example, conclusive evidence links cancer at multiple sites with tobacco use, alcohol use, human papillomavirus (HPV) infection, excess body weight, and physical inactivity (1,2). To monitor changes in cancer incidence and assess progress toward achieving Healthy People 2020 objectives,* CDC analyzed data from the U.S. Cancer Statistics (USCS) data set for 2013, the most recent year for which incidence and survival data are available. In 2013, a total of 1,559,130 invasive cancers were reported to cancer registries in the United States (excluding Nevada), for an annual age-adjusted incidence rate of 439 cases per 100,000 persons. Cancer incidence rates were higher among males (479) than females (413), highest among blacks (444), and ranged by state from 364 (New Mexico) to 512 (Kentucky) per 100,000 persons (359 in Puerto Rico). The proportion of persons with cancer who survived ≥5 years after diagnosis was 67%. This proportion was the same for males and females (67%), but lower among blacks (62%) than among whites (67%). Cancer surveillance data are key to cancer epidemiologic and clinical outcomes research, program planning and monitoring, resource allocation, and state and federal appropriations accountability.
Phase II multicenter sequential study of oxaliplatin (O) and capecitabine (C) followed by irinotecan (I) and capecitabine (C) in first line advanced colorectal cancer (CRC)
Authors: J. Cassinello, J. V. Álvarez, M. J. García-López, E. Pujol, A. Colmenarejo, F. de Segovia, F. Marcos, E. Filipovich
Journal: Journal of Clinical Oncology (2005)

3544 Background: In phase II trials, XELOX and XELIRI were highly active and well tolerated in first-line MCRC. The aim of this study is to explore the efficacy and safety of XELOX followed by XELIRI as first-line treatment in MCRC. Specifically, we wanted to evaluate the impact of sequential scheduling on the dose-limiting neurotoxicity associated with oxaliplatin accumulation. Methods: Eligible pts had histologically or cytologically confirmed MCRC, ECOG PS ≤2 and adequate bone marrow, renal and hepatic function. Prior chemotherapy for MCRC was not allowed. Pts received 4 cycles of XELOX (capecitabine 1000mg/m2 orally bid d1–14 + oxaliplatin 130mg/m2 i.v. d1, q3w) followed by 4 cycles of XELIRI (capecitabine 1000mg/m2 bid d1–14 + irinotecan 240mg/m2 i.v. d1, q3w). This sequential schedule was repeated until unacceptable toxicity or disease progression. Results: Of the 29 pts enrolled to date: M/F (72%/28%); median age 69.6 years (range 41.2–78.8); ECOG PS 0–1 (93%). Previous treatment included surgery (83%), adjuvant chemotherapy (38%), and radiotherapy (14%). 146 cycles (median 4, range 1–16) have been administered. 28 pts received XELOX (88 cycles, median 4), and 11 pts received XELIRI (42 cycles, median 4) during the first sequential schedule. 3 pts received XELOX (9 cycles, median 4) and 2 pts received XELIRI (7 cycles, median 3.5) in the second sequential schedule. Median relative dose intensity was 94% for capecitabine, 100% for oxaliplatin and 97% for irinotecan. In 15 efficacy evaluable pts, the ORR was 47% (95% CI, 22–72%). 13 pts are not evaluable due to adverse events (n=4), ongoing treatment (n=8), or withdrawal of consent (n=1). There were no grade 4 events. Conclusions: Preliminary results show that this sequential schedule is active and well tolerated in first-line MCRC. The low rate of grade 3 neurotoxicity/paresthesia is also promising. No significant financial relationships to disclose.
The Surgical Significance of Acute Abdominal Pain
Authors: J. William Hinton
Journal: New England Journal of Medicine (1950)

IN REVIEWING case records in two of the larger hospitals of New York over a period of twenty-seven years, I have been disturbed by the frequency with which patients suffering from acute abdominal pain are subjected to laparotomy with resulting negative pathological findings. Even more distressing is the opinion expressed by many surgeons that exploration with negative findings is preferable to unrecognized acute appendicitis, which may develop into peritonitis with a fatal termination. One cannot but question this attitude in view of the present minimal mortality rate from acute appendicitis, including cases with abscesses and general peritonitis.A review of . . .
Abstract 12333: Do the Patients With Inertia Force of Late Systolic Aortic Flow Have Less Incidence of Heart Failure?
Authors: Toshihiko Goto, Kazuaki Wakami, Takafumi Kato, Hachiya Kenta, Hiroshi Fujita, Tomomitsu Tani, Nobuyuki Ohte
Journal: Circulation (2013)

Inertia force of late systolic aortic flow (IF) is observed in the left ventricles (LV) with good systolic function. A lack of IF provokes isolated LV diastolic dysfunction and may be related to th...