tbuckley/cabot-search huggingface dataset:
eGFR in changing drug regimens
Authors: Jeffrey K Aronson
Journal: BMJ (2007)

Giles and Fitzmaurice did not discuss another use of estimated renal function—to guide changes in the dosage regimens of drugs that are eliminated unchanged by the kidneys, that have active metabolites that are eliminated by the kidneys, or whose pharmacodynamic effects are affected by renal insufficiency.1 This is particularly important for drugs that have a low therapeutic index.

Recommendations about drug dosage regimens given in manufacturers' summaries of product characteristics …
Clinical properness of poker schedule weekly alternating 5-fluorouracil, irinotecan, bevacizumab, and oxaliplatin (FIr-B/FOx) in young-elderly metastatic colorectal cancer (MCRC).
Authors: G. Bruera, A. Santomaggio, K. Cannita, P. Lanfiuti Baldi, M. Tudini, F. De Galitiis, P. Marchetti, A. Antonucci, C. Ficorella, E. Ricevuto
Journal: Journal of Clinical Oncology (2010)

e14093 Background: Phase II study evaluating efficacy and toxicity of poker combination of 5-fluorouracil (5-FU), irinotecan (CPT-11), oxaliplatin (OHP) and bevacizumab (BEV) as first line in MCRC, particularly in young-elderly. Methods: End-points: objective responses (OR), progression-free survival (PFS), toxicity, overall survival (OS). Statistical plan: Simon two-step, p0 50%, p1 70%, power 80%, α 5%, β 20%. Schedule: weekly 12h-TFI/5-FU 900 mg/m2/d 1-2, 8-9, 15-16 and 22-23 alternating to CPT-11 160 mg/m2 plus BEV 5 mg/kg days 1 and 15, or OHP, q4 weeks. Results: Fifty consecutive patients (pts) enrolled; median follow-up 18m. Median age 63 (range 40-73), young-elderly (yE) 24 (48%). Liver metastases (LM): 33 (66%), yE 15 (63%); exclusive LM 21 (42%), yE 8 (33%). OR: intent-to-treat (49 pts) 40 (82%), yE (24 pts) 19 (79%); as-treated (43 pts) 36 (84%), 16 (80%). Median PFS: 12 m (31 events), yE 11 m (17 events). Median OS: 28 m (23 events), yE 21 m (13 events). Liver metastasectomies performed in 13 pts (26%), yE 3 pts (12.5%): in pts with LM 39%, yE 20%. Median number of cycles 5 (range 2-9); administered 247. Median received dose intensity (rDI) per cycle for each drug ≥ 80% and in yE: 5-FU 80% (1,420 mg/m2/w); CPT-11 76% (61 mg/m2/w); OHP 79% (31.5 mg/m2/w); BEV 80% (2 mg/kg/w). Cumulative G3-4 toxicities: diarrhea 28%, yE 25%; stomatitis/mucositis 6%, yE 12.5%; asthenia 6%, yE 12.5%; hypertension 2%, yE none; neutropenia 10%, yE 12.5%. Limiting toxicity syndromes (LTS) were observed in 22 pts (44%), yE 11 pts (46%). Multiple vs single sites LTS in 12 pts (24%) vs. 10 pts (20%); in yE 9 pts (37.5%) vs. 2 pts (8%). Conclusions: In young-elderly pts the high efficacy of Poker combination, rDIs and cumulative toxicities are equivalent to overall pts, with a trend toward increased LTS in multiple sites. No significant financial relationships to disclose.
Cost-Effectiveness of Transcatheter Aortic Valve Replacement Compared With Surgical Aortic Valve Replacement in High-Risk Patients With Severe Aortic Stenosis
Authors: Matthew R. Reynolds, Elizabeth A. Magnuson, Yang Lei, Kaijun Wang, Katherine Vilain, Haiyan Li, Joshua Walczak, Duane S. Pinto, Vinod H. Thourani, Lars G. Svensson, Michael J. Mack, D. Craig Miller, Lowell E. Satler, Joseph Bavaria, Craig R. Smith, Martin B. Leon, David J. Cohen
Journal: Journal of the American College of Cardiology (2012)
Abstract 891: FGF21 prevents high fat diet-induced pancreatic cancer in mice expressing oncogenic Kras
Authors: Weiqin Lu, Yaying Yang, Xiaojie Wang, Yan Liu, Yongde Luo, Robert A. Wolff, James L. Abbruzzese, Craig D. Logsdon
Journal: Cancer Research (2015)

Abstract The genetic landscape of pancreatic cancer shows nearly ubiquitous mutations of Kras. However, expression of mutant Kras alone is not sufficient to drive pancreatic ductal adenocarcinoma (PDAC) in adult mice. Obesity is a metabolic disorder and is a risk factor for PDAC. One of the main factors that contributes to the development of obesity is high-fat consumption. Recent studies have demonstrated that High-Fat-Diet (HFD) can promote oncogenic Kras mediated development of pancreatic intraepithelial neoplasia and PDAC. However, it is not clear why mice with oncogenic KrasG12D expression are predisposed to HFD mediated pancreatic carcinogenesis. Here, we report that Ras activity dramatically reduces the expression of fibroblast growth factor 21 (FGF21). FGF21 is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF21 lower serum free fatty acids and lead to weight loss in obese mice. FGF21 is highly expressed in pancreatic acinar cells and is a potential autocrine factor. High levels expression of FGFR1 and β-Klotho, key components for specific sites of FGF21 action, were observed on normal control mouse pancreatic acinar cells using both qRT-PCR and immunohistochemistry technics. FGF21 levels were dramatically reduced (∼6-fold) by Cre-mediated knock-in of oncogenic KrasG12D within one week and further decreased by more than 100-fold within 7 months. This effect of KrasG12D may have been mediated by decreased expression of pancreatic transcription factor Mist1, which was also observed. To dissect obesity and oncogenic KrasG12D mediated PDAC, we fed adult KrasG12D expressing mice with HFD or HFD+FGF21. We observed that KrasG12D expressing mice fed with HFD+FGF21 for 9 weeks significantly lower body weight and pancreatic triglyceride, as well as dramatically fewer PanIN lesions and tumor, compared with KrasG12D mice on a HFD without FGF21. FGF21 treatment extended survival of KrasG12D expressing mice on a HFD. Our results suggest that pancreas-derived FGF21 is an important metabolic regulator which is silenced by oncogenic KrasG12D expression and plays an important role in preventing HFD induced PDAC in KrasG12D expressing mice. Citation Format: Weiqin Lu, Yaying Yang, Xiaojie Wang, Yan Liu, Yongde Luo, Robert A. Wolff, James L. Abbruzzese, Craig D. Logsdon. FGF21 prevents high fat diet-induced pancreatic cancer in mice expressing oncogenic Kras. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 891. doi:10.1158/1538-7445.AM2015-891
Statistic Notes: Regression towards the mean
Authors: J M Bland, D G Altman
Journal: BMJ (1994)

The statistical term “regression,” from a Latin root meaning “going back,” was first used by Francis Galton in his paper “Regression towards Mediocrity in Hereditary Stature.”1 Galton related the heights of children to the average height of their parents, which he called the mid- parent height (figure). Children and parents had the same mean height of 68.2 inches. The ranges differed, however, because the mid-parent height was an average of two …
Soundings: Executing Timothy McVeigh
Authors: George Dunea
Journal: BMJ (2001)

Even many of the most vociferous opponents of capital punishment were subdued in their protests when Timothy McVeigh, the Oklahoma bomber, was put to death in the early hours of 11 June in Terre Haute, Indiana. The execution, which was the first federal application of the death penalty in the United States for 38 years, was carried out painlessly and aseptically with an injection of sodium thiopental, pancuronium, and potassium chloride. It was the culmination of a drawn out process that cost more than $15m (£10.7m) in legal fees and received the maximum amount of media coverage and hype. Videotaping the execution was forbidden, but some survivors or relatives of the victims watched in person or on closed circuit television.

Although many people oppose capital punishment, repeated polls indicate that at least 65% of Americans are in favour of it. There was even greater support for the execution of Timothy McVeigh. The Chicago Tribune, among others, argued that such execution was neither vengeance nor deterrence, but punishment plain and simple, society's justifiable response to a small number of extraordinarily vicious crimes, such as genocide, mass murder, or terrorism.

State medical societies and the American Medical Association have issued clear guidelines on what doctors may or may not do (BMJ 1998;316:1394). More recently the World Medical Association went further by ruling that doctors should take no part whatsoever in executions, not even certifying death, and it was hoped that doctors would exert pressure on governments to outlaw capital punishment.

Yet in a survey of 482 American doctors last year, 74% felt that it was acceptable for doctors to certify death and 43% saw nothing wrong with injecting the drugs. The author of the survey, a doctor, was surprised and troubled by results indicating that while medical societies opposed participation in executions, individual doctors paradoxically seemed to condone it.

Also, paradoxically, the same doctors were evenly split about physician assisted suicide, with 20% unsure and many more prepared to deny their patients with painful terminal metastatic disease the same painless exit accorded to the slayer of 168 men, women, and children.
Abstract 20627: Modulation of Cardiac Sodium Channel by Palmitoylation and Its Association With Cardiac Disease Mutations
Authors: Zifan Pei, Andy Hudmon, Theodore R Cummins
Journal: Circulation (2014)

Cardiac sodium channel (Nav1.5) is responsible for the generation and propagation of the cardiac action potential, which underlies cardiac excitability. It can be modified by a variety of post-translational modifications. Palmitoylation is one of the most common post-translational lipid modifications that can dynamically regulate protein life cycle and functional activity. In our study, we identified palmitoylation on Nav1.5 and its alteration in channel biophysical properties. Nav1.5 palmitoylation was identified in both HEK 293 cells stably expressing Nav1.5 and cardiac tissues using acyl-biotin exchange assay. Nav1.5 palmitoylation was inhibited by pre-incubating the cells with the inhibitor 2-Br-Palmitate (2BP, 25uM, 24hrs). Biophysically, 2BP treatment drastically shifted the channel steady-state inactivation to more hyperpolarized voltages, suggesting palmitoylation altering channel functional activity. In addition, four predicted endogenous palmitoylation sites were identified using CSS-Palm 3.0. Site-directed mutagenesis method was used to generate a cysteine removing background of wt Nav1.5 to study the role of predicted sites. Patch clamp analysis of wt and cysteine-removed Nav1.5 revealed a significant change in channel biophysics. 2BP treatment significantly shifted steady-state inactivation of wt Nav1.5 while not affecting cysteine-removed Nav1.5 significantly, indicating the important role of these four cysteine sites in modulating channel palmitoylation. Moreover, several LQT disease mutations were identified to potentially add or remove palmitoylation sites. Further analysis of these disease mutations revealed a significant shift in channel steady-state inactivation and this alteration cannot be seen with the substitution of other residues on the same site, suggesting the specific role of cysteine residue in causing the functional alteration. For the LQT mutation that removes potential palmitoylation site, 2BP treatment did not affect channel biophysical properties, indicating the essential role of this cysteine in channel palmitoylation. These results suggest that palmitoylation on Nav1.5 regulates channel functional activity and its modulation may contribute to new cardiac channelopathies.
Safety and Efficacy of Mitomycin C Trabeculectomy in Southern India
Authors: R. Ramakrishnan, John Michon, Alan L. Robin, R. Krishnadas
Journal: Ophthalmology (1993)

Glaucoma is a major cause of blindness in developing nations. Medical and laser therapy have limitations in this environment. Filtration surgery alone often fails in young, darkly pigmented, individuals. The authors, therefore, evaluated the safety and efficacy of filtration surgery, using topical mitomycin C, in patients undergoing trabeculectomy in India.A short-term pilot study used mitomycin C at the time of trabeculectomy in a population of southern Indians with various forms of glaucoma. A single 5-minute intraoperative application of 0.4 mg/ml mitomycin C was given to 76 consecutive patients requiring filtration surgery for the control of intraocular pressure (IOP). All patients were admitted for 6 days and were seen at 6-week intervals for a minimum of 18 weeks.The mean preoperative IOP was 35.3 +/- 9.6 mmHg. Postoperative IOP control was attained in 93.4% of patients as defined by an IOP of 20 mmHg or less without additional glaucoma medications (or an IOP reduction > 25% if the preoperative IOP was < or = 20 mmHg). No corneal epithelial defects or wound leaks were seen. The major complications were cataract formation and a decreased visual acuity in ten (13%) eyes.Mitomycin C-aided trabeculectomy was highly successful in controlling IOP in this darkly pigmented population and may become an important adjunct in the treatment of glaucoma in developing countries.
Abnormal patency of the eustachian tube.
Authors: Allen Gw
Journal: JAMA (1967)

Some women who are pregnant or on oral contraceptives develop an abnormal patency of the eustachian tube as a complicating factor.  This annoying condition which is benign is characterized by a hollow sound of ones own voice and a feeling of tension upon the ear drum.  It is frequently misdiagnosed as mild obstruction of the eustachian tube.  This condition is believed to occur as the result of pituitary suppression resulting from the reaction of the steroids.  Withdrawal from the drug will result in the disappearance of symptoms.
Stress and breast cancer
Authors: T. Brady
Journal: BMJ (2002)

Editor—One of the main findings of the paper by Graham et al was that women who had had one or more severely stressful life experiences in the five years after diagnosis had a lower risk of recurrence than those who didn't (hazard ratio 0.52).1 Using information collected after baseline (diagnosis in this study) in a survival model is fraught with difficulty because collection of that information may not be possible after the event of interest has occurred. Careful interpretation of the results of any such analysis is therefore recommended.

It seems that a mistake in interpretation has occurred in this paper. Women who had a recurrence were not interviewed again more than eight weeks after their recurrence. So, for example, a woman in whom cancer recurred after 12 months would have nearly four years of missing data for the variable “severely stressful life experiences.” It follows that the investigators were more likely to detect stressful life experiences in women who had recurrences later on in the study or not at all. The finding that stressful life experiences were associated with a decreased incidence of recurrence is probably due to this ascertainment bias rather than any real effect.
Exploring the intra-patient PIK3CA mutational heterogeneity of circulating tumour cells by massive parallel sequencing in patients with metastatic hormone receptor-positive breast cancer
Authors: B. De Laere, D. Peeters, R.F. Salgado, P. Vermeulen, P. van Dam, L.Y. Dirix, S. Van Laere
Journal: Annals of Oncology (2015)
Abstract 94: Melatonin inhibits stemness of glioblastoma cancer stem-like cells via regulation of histone methylation
Authors: Hyemin Lee, Ji Hoon Jung, Hyun Joo Lee, Myoung Seok Jeong, Deok-Beom Jung, Hee Young Kwon, Sung-Hoon Kim
Journal: Cancer Research (2015)

Abstract The pineal gland hormone melatonin (N-acetyl-5-methoxytryptamine) is well known as an anticancer effector. Recently, a variety of studies have shown that melatonin induces apoptosis in various cancer cell types such as colon cancer, Ewing sarcoma, hepatic cancer, prostate cancer and breast cancer cells. Glioblastoma cancer stem-like cells (GCSLC) are the most common and aggressive primary brain tumor in adults. In the present study, we found that melatonin significantly decreased the sphere formation of GCSLC, and attenuated the expression of c-Myc genes. Furthermore, melatonin suppressed expression of H3K4me3 and H3K79me3 around c-Myc promoter region by Western blotting and Chip assay. Of note, melatonin suppressed the expression of several stemness markers including nestin in GCSLC. Overall, our findings suggest melatonin as a potent anticancer stem cell agent for GCSLC. Citation Format: Hyemin Lee, Ji Hoon Jung, Hyun Joo Lee, Myoung Seok Jeong, Deok-Beom Jung, Hee Young Kwon, Sung-Hoon Kim. Melatonin inhibits stemness of glioblastoma cancer stem-like cells via regulation of histone methylation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 94. doi:10.1158/1538-7445.AM2015-94
Serum levels of molecules that are markers of B cell activation are elevated prior to the development of acquired immunodeficiency syndrome-associated non-Hodgkin's B cell lymphoma
Authors: Elizabeth Crabb Breen, Larry Magpantay, Zheng Hu, Lisa Jacobson, Roger Detels, Charles Rabkin, Richard Kaslow, Richard Ambinder, Otoniel Martinez-Maza
Journal: Cancer Research (2006)

694   Persons with human immunodeficiency virus (HIV) infection are at increased risk of acquired immunodeficiency syndrome-associated non-Hodgkin9s B cell lymphoma (AIDS-NHL). AIDS-NHL is heterogeneous, with tumors arising in both relatively immunocompetent and severely immunodeficient persons, and may be the result of inappropriate and/or chronic B cell activation, as well as loss of functional immunity to Epstein-Barr virus (EBV). In a nested case-control study utilizing samples from participants in the Multicenter AIDS Cohort Study, we assessed pre-AIDS-NHL serum levels of several B cell stimulatory cytokines and molecules associated with B cell activation by enzyme-linked immunosorbent assay. Levels of interleukin (IL) 6, IL10, soluble CD23 (sCD23), sCD27, sCD30, C’-reactive protein (CRP), and total IgE were quantified in longitudinal serum samples collected at up to three time points prior to lymphoma diagnosis (3-5 years, 1-3 years, and
An Alternatively Spliced Form of CD79b Gene May Account for Altered B-Cell Receptor Expression in B-Chronic Lymphocytic Leukemia
Authors: A. Alfarano, S. Indraccolo, P. Circosta, S. Minuzzo, A. Vallario, R. Zamarchi, A. Fregonese, F. Calderazzo, A. Faldella, M. Aragno, C. Camaschella, A. Amadori, F. Caligaris-Cappio
Journal: Blood (1999)
Abstract 5955: Role of Bradykinin and Chymase in Cardiorenal Function Under Long-Term ACE Inhibition in Heart Failure
Authors: Atsuyuki Wada, Takehiro Matsumoto, Masato Ohnishi, Masanori Fujii, Takayoshi Tsutamoto, Minoru Horie
Journal: Circulation (2008)

Renal insufficiency is relatively common in patients with heart failure (HF) and patients with chronic kidney disease are known to have a significant increase in cardiovascular morbidity and mortality. Angiotensin (Ang) II plays an important role in water and sodium (Na) balance and renal injury. Although ACE inhibitors (ACEIs) suppress the formation of Ang II and are useful in the treatment of HF, the agents also prevent the breakdown of bradykinin (BK), which exerts its vasodilative action through BK type 2 (B2) receptors. On the other hand, over 50% of renal Ang II formation in HF is mediated by ACE independent chymase pathway. The roles of BK and chymase in the cardiorenal function under chronic treatment of ACEI has not been fully elucidated as yet. We therefore evaluated the cardiorenal effects of a specific B2 receptor antagonist, FR173657 (FR, 0.3mg/kg/day) or a specific chymase inhibitor, (ChyI, 100mg/kg/day) with an ACEI, enalapril (1mg/kg/day) compared to those of enalapril alone in dogs with tachycardia induced HF (22days). Cardiac contractile function markedly deteriorated and body fluid retention and impaired renal function accompanied with upregulation of renal ACE and chymase mRNA levels after the induction of severe HF. However, enalapril significantly improved the ejection fraction (vehicle 19% vs. enalapril 36%, p&lt;0.01) and increased urine excretion (vehicle 0.36 vs. enalapril 0.55 ml/min, p&lt;0.05) associated with increases in the glomerular filtration rate (GFR) and renal plasma flow (RPF) (vehicle 24 vs. enalapril 60 ml/min, and 74 vs. 169 ml/min, respectively p&lt;0.05) in HF. There were no differences observed in blood pressure and LV ejection fraction among three treatment groups. FR did not statistically affect urinary Na excretion, GFR and RPF compared to the ACE inhibition alone, however, the chymase inhibition has more significantly increased water and Na excretion rate (0.70 vs. 0.55 ml/min and 56 vs. 26 μEq/min, respectively p&lt;0.05) and GFR (70 vs. 59 ml/min, p&lt;0.05) compared to the ACE inhibition alone. In conclusion, endogenous BK does not likely contributes to the renoprotective effects of ACEI, however, combining ACE and chymase inhibition has greater therapeutic potential in the amelioration of renal function in HF.
Abstract 14281: Door-To-Balloon Time Decreases With Pre-Hospital Wireless Electrocardiogram Transmission in Patients with ST-Segment Elevation Myocardial Infarction
Authors: Andrea Mignatti, Brian Greet, Sripal Bangalore, Robert O Roswell
Journal: Circulation (2011)

Background: Current ACC/AHA guidelines recommend a door-to-balloon time (D2B) of < 90 minutes in patients with ST-segment elevation myocardial infarction (STEMI). In April 2010, the Fire Department...
Abstract P133: Effects of Physical Activity and Sedentary Behaviors on Risk of Heart Failure
Authors: Deborah R Young, Kristi Reynolds, Margo A Sidell, Somjot S Brar, Nirupa R Ghai, Barbara Sternfeld, Steven J Jacobsen, Jeff Slezak, Bette J Caan, Virginia P Quinn
Journal: Circulation (2013)

Background: Heart failure (HF) is a major cardiovascular disease, affecting an estimated 5.7 million American adults with more than 600,000 incident cases occurring each year. It is well known that...
Abstract 9305: Integrating Palliative Care into the Outpatient Heart Failure Disease Management Setting: A Feasibility Study
Authors: Dawn Lombardo, L orraine S Evangelista, Shaista Malik, Jennifer Ballard-Hernandez, Marjan Motie, Solomon Liao
Journal: Circulation (2012)

BACKGROUND: There is limited research on the effectiveness of palliative care (PC) programs on symptom distress and quality of life (QOL) in patients with advanced heart failure (HF). PURPOSE: We conducted this prospective, comparative study to determine whether a shared care model that integrates PC with standard HF care in an outpatient setting versus standard HF care alone impacts symptom burden, depression, anxiety, and QOL (physical, emotional, overall). METHODS: Thirty-six patients (mean age 53.9 ± 68.0; predominantly male [72%]; White [61%]; married [69%]; New York Heart Association class II [69%]) were referred for an outpatient PC consultation in conjunction with their post-discharge follow-up visit with their HF provider. Changes in symptom burden, depression, anxiety and QOL at three months were compared to 36 patients with advanced HF matched on age, gender, race, and NYHA functional class. RESULTS: Significant improvements were observed in symptom burden (P &lt; .001), depression (P = .002), emotional QOL (P = .001) and overall QOL (P &lt; .001) in both groups over time; anxiety and physical QOL improved for patients receiving PC but worsened for patients in the comparison group (Table 1). A multivariate model that included PC accounted for 57%, 23%, 75%, 37% and 50% of variance in symptom burden, depression, physical, emotional, and overall QOL, respectively. CONCLUSIONS: Our findings support the interpretation that participation in a PC intervention may reduce symptom burden and depression and enhance QOL in patients hospitalized with acute HF exacerbation. Larger scale, prospective, randomized clinical trials sufficiently powered to assess clinical outcomes, are warranted to assess the efficacy of a shared care model that integrates PC with standard HF care in outpatient settings on symptom distress, psychological outcomes, and QOL in patients with advanced HF.