tbuckley/cabot-search huggingface dataset:
Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors.
Authors: R. Kefford, H. Arkenau, M. P. Brown, M. Millward, J. R. Infante, G. V. Long, D. Ouellet, M. Curtis, P. F. Lebowitz, G. S. Falchook
Journal: Journal of Clinical Oncology (2010)

8503 Background: GSK2118436 is a highly potent and selective ATP competitive BRAF inhibitor with > 100-fold selectivity for mutant (mut) BRAF over wild type (wt) in cell lines. It displays dose-dependent inhibition of MEK and ERK phosphorylation in mut BRAF cell lines and tumor regression in xenograft models. Methods: This is a first-time in human, dose escalation study to identify the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in cohorts of 1 to 20 patients (pts). Pts were treated with oral GSK2118436 once to three times daily. Once safety was established in cohorts of 3 to 4 pts, cohorts were expanded to determine the optimal dose based on efficacy and tolerability. Results: 61 pts (52 mut BRAF melanoma) received 12–400 mg daily. Plasma concentrations were dose-proportional and exceeded the minimal therapeutic target at doses > 35 mg BID. 1 pt reported dose-limiting toxicity of syncope (200 mg BID) and resumed reduced dosing. AEs included skin changes (23 pts, 1 gr 3), low grade cutaneous SCC (2 pts), headache (12 pts, 1 gr 3), nausea (11 gr 1), fatigue (9 gr 1), and vomiting (8 pts, 4 gr 2). MTD has not yet been determined. Concentration-dependent pERK inhibition was seen in tumor (max 93% inhibition) at GSK2118436 concentration of 140 ng/mL. In pts with mut BRAF melanoma: exposure-related decrease in FDG-PET metabolic uptake was noted with 11/14 (79%) pts showing a decrease from baseline (range −5 to −100%). In pts with mut BRAF melanoma (without brain mets) 18/ 30 (60%) pts have a > 20% tumor decrease by RECIST at first restaging (8–9 wks). Conclusions: MTD has not yet been reached. Clinical activity with minimal toxicity was observed at multiple dose levels in mut BRAF tumors. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
Development of a quality of life instrument for children with bronchopulmonary dysplasia
Authors: Lysbert Schaap, Bertine M.J. Flokstra-de Blok, Jet van der Hulst, Anthony E.J. Dubois, Elianne J.L.E. Vrijlandt
Journal: European Respiratory Journal (2012)

Background. Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. It is associated with prolonged hospitalization, long-term pulmonary morbidity and an increased risk for adverse neurodevelopmental outcome. The impact of these complications on health-related quality of life (HRQL) is not known because there is no disease-specific instrument to measure HRQL available.  Aim. To develop a disease-specific questionnaire to measure HRQL in children with BPD aged 4 to 8 years old.  Methods. Participants: children aged 4 to 8 years old with BPD. The first steps in the development of a HRQL instrument are item generation and item reduction. Sources for item generation were literature, expert opinion and parents of participants. For item reduction, parents indicated how much the items affected the HRQL of their child. The clinical impact method and item analysis were used to reduce items.  Results. 51 children participated in the study; 20 in item generation and 31 in item reduction. 130 items were identified. With the clinical impact method 53 items with an overall importance (OI) >1.00 were selected. Three items with highest OI were 9easily distracted9 (2.52), 9having a cold for longer period of time9 (2.42) and 9coughing9 (2.39). After item analysis, 47 items remained in the questionnaire. Items were linked to a variety of subjects such as pulmonary problems, growth/nutrition, exercise, school, behavior, social and emotional functioning.  Conclusion. This is the first time the development of a disease-specific instrument to measure HRQL in BPD has been undertaken. The items in the developed questionnaire have clinical impact. The next step will be to determine validity of these items.
Iron therapy for the treatment of iron deficiency in chronic heart failure: intravenous or oral?
Authors: Theresa McDonagh, Iain C. Macdougall
Journal: European Journal of Heart Failure (2015)

This article considers the use and modality of iron therapy to treat iron deficiency in patients with heart failure, an aspect of care which has received relatively little attention compared with the wider topic of anaemia management. Iron deficiency affects up to 50% of heart failure patients, and is associated with poor quality of life, impaired exercise tolerance, and mortality independent of haematopoietic effects in this patient population. The European Society of Cardiology Guidelines for heart failure 2012 recommend a diagnostic work‐up for iron deficiency in patients with suspected heart failure. Iron absorption from oral iron preparations is generally poor, with slow and often inefficient iron repletion; moreover, up to 60% of patients experience gastrointestinal side effects. These problems may be exacerbated in heart failure due to decreased gastrointestinal absorption and poor compliance due to pill burden. Evidence for clinical benefits using oral iron is lacking. I.v. iron sucrose has consistently been shown to improve exercise capacity, cardiac function, symptom severity, and quality of life. Similar findings were observed recently for i.v. ferric carboxymaltose in patients with systolic heart failure and impaired LVEF in the double‐blind, placebo‐controlled FAIR‐HF and CONFIRM‐HF trials. I.v. iron therapy may be better tolerated than oral iron, although confirmation in longer clinical trials is awaited. Routine diagnosis and management of iron deficiency in patients with symptomatic heart failure regardless of anaemia status is advisable, and, based on current evidence, prompt intervention using i.v. iron therapy should now be considered.
Abstract 15692: Low Blood Pressure And Defective Vasoconstriction In Tie2-cre/grk2fl/fl mice
Authors: Michele Ciccarelli, Antonietta Franco, Daniela Sorriento, Carmine Del Giudice, Gerald W Dorn, Bruno Trimarco, Guido Iaccarino
Journal: Circulation (2011)

GRK2 regulates eNOS activity through Akt binding and inhibition in endothelial cells derived from liver sinusoidal capillaries. However, the role of GRK2 in regulation of systemic vascular tone has...
Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer.
Authors: M Mackean, A Planting, C Twelves, J Schellens, D Allman, B Osterwalder, B Reigner, T Griffin, S Kaye, J Verweij
Journal: Journal of Clinical Oncology (1998)

PURPOSE Capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes that results in the preferential release of 5-FU at the tumor site. PATIENTS AND METHODS In this phase I study, capecitabine was administered twice daily as outpatient therapy, each cycle administered for 2 weeks followed by 1 week of rest. Thirty-four patients with solid tumors, all of whom except three patients were pretreated, were treated at dose levels from 502 to 3,514 mg/m2 daily. RESULTS The median treatment duration was four cycles (85 days; range, 14 to 833+ days). Two patients continue on treatment at 686 and 833+ days. Capecitabine 3,000 mg/m2 daily was not tolerable, with dose-limiting toxicities of diarrhea with hypotension, abdominal pain, and leukopenia. Palmar-plantar erythrodysesthesia (PPE) became evident at higher dose levels after prolonged treatment. Evidence of objective tumor response was reported in four patients at 2,510 mg/m2 daily and greater (one complete response [CR] and three partial responses [PRs]) with subjective minor tumor responses in a further seven patients. Pharmacokinetic studies showed rapid gastrointestinal absorption of capecitabine, followed by extensive conversion into 5'-deoxy-5-fluorouridine (5'-DFUR), with only low systemic 5-FU levels. CONCLUSION Capecitabine is a tolerable oral outpatient therapy that shows promising clinical activity in a variety of cancers. The recommended phase II dose is 2,510 mg/m2 daily administered by this intermittent schedule.
Attempts to modulate chemoresistance in older patients with AML using PSC-833 - Results of the LRF AML14 trial
Authors: Alan Kenneth Burnett, Robert Kerrin Hills, A. H. Goldstone, A. Prentice, D. Milligan, M. Pallis, N. Russell, L. N. Truran, K. Wheatley
Journal: Blood (2003)
Abstract 3955: 53BP1 facilitates the ATM-dependent phosphorylation of APLF in the DNA damage response
Authors: Amanda L. Fenton, Diana Tran, Christine Anne Koch
Journal: Cancer Research (2014)

Abstract Aprataxin and polynucleotide kinase-like factor (APLF) is a DNA repair factor which facilitates DNA repair in part through interactions with its forkhead-associated (FHA) domain. The APLF FHA domain mediates interactions with specific threonine phosphorylated epitopes via a functionally conserved and essential arginine residue (Arg-27). In the context of DNA double-strand break (DSB) repair, substitution of APLF amino acid residue Arg-27 to alanine abolishes interactions with the DSB repair scaffold protein XRCC4, and impairs DSB repair. APLF is also a component of the ATM-dependent DNA damage response (DDR), which also includes 53BP1, and undergoes ionizing-radiation induced phosphorylation at Ser-116 facilitating its role in DSB repair. Here we demonstrate that the APLF FHA domain is essential for Ser-116 phosphorylation and for the association with 53BP1, which collectively enhance the accumulation of APLF at sites of DNA damage. The level of 53BP1 expression, but not XRCC4, was found to correlate with the phosphorylation of APLF by ATM, and disruption of the APLF-53BP1 interaction was associated with impaired cell survival following DNA damage. These results suggest that the APLF FHA domain directs interactions with multiple partners in the DNA damage response, and that 53BP1 facilitates the ATM-dependent phosphorylation of APLF. Citation Format: Amanda L. Fenton, Diana Tran, Christine Anne Koch. 53BP1 facilitates the ATM-dependent phosphorylation of APLF in the DNA damage response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3955. doi:10.1158/1538-7445.AM2014-3955
M2 macrophages produce less type I and III IFNs upon human rhinovirus (HRV) infection and have a higher viral load than M1 macrophages
Authors: Alexandra Nikonova, Stephanie Traub, Eugene Faizuloev, Sebastian Johnston, Musa Khaitov, Luminita Stanciu
Journal: European Respiratory Journal (2011)

Background:  Macrophages (MΦ) are innate immune cells that play a key role in lung antiviral immune responses. A model of two major MΦ types has been developed: M1 (classically activated) and M2 (alternatively activated) MΦ. M2 MΦ are believed to be increased in asthma.   Objective:  We hypothesized that upon HRV infection, M2 MΦ produce less type I and III interferon (IFN) and consequently have a higher viral load than M1 and un-polarized MΦ.   Methods:  Monocyte-derived MΦ (MDM) obtained from peripheral blood mononuclear cells of healthy donors were polarized to M1 or M2 by treatment with IFN-γ and TNF-α or IL-4, respectively. Un-polarized MDM (uMDM) were treated with media alone. M1, M2 and uMDM were infected with major group HRV16 at MOI 1 and cultured for 72h. Cytokines were measured in the supernatants by ELISA and gene expression in cell lysates by real-time PCR. Supernatants of M1, M2 and uMDM were titrated on Hela-Ohio cells to obtain the HRV16 titre.   Result:  HRV16 infection of M1 MΦ induced increased levels IFN-α, β, λ1 and λ2/3 in comparison with HRV16 infection of M2 MΦ and uMDM (for genes – at 8h, 24h, p   Conclusion:  Our data suggest that in response to HRV infection, M2 MΦ produce decreased levels of antiviral proteins such as IFN-α, β, λ1 and λ2/3. This may explain the enhanced susceptibility to viral infections in asthmatic patients.  Dr. A. Nikonova is a recipient of an EAACI & GA2LEN Exchange Research Fellowship 2009 and European Respiratory Society Fellowship (Number 682).
Lipid metabolism in human platelets
Authors: Nancy Lewis, Philip W. Majerus
Journal: Journal of Clinical Investigation (1969)

Washed human platelets were incubated with radioactive glycerol; the platelets were able to synthesize de novo the major phosphoglycerides including phosphatidic acid, phosphatidylinositol, phosphatidyl choline, phosphatidyl ethanolamine, and phosphatidyl serine. The specific activities of the phosphoglycerides obtained after glycerol incorporation indicate that phosphatidic acid, phosphatidylinositol, and phosphatidyl choline are metabolically active relative to phosphatidyl ethanolamine and that formation of phosphatidyl serine occurs to a much more limited extent. When platelets were incubated with bovine thrombin, 1 U/ml, the pattern of glycerol incorporation into phospholipid was changed. There was a 3-fold decrease in the total incorporation into lipid in 30 min with a relative 5-fold decreased incorporation into phosphatidyl choline and phosphatidyl ethanolamine and a 5-fold increased incorporation into phosphatidyl serine. The increased incorporation into phosphatidyl serine. The increased incorporation into phosphatidyl serine was maximal within the first 2 min but was transient, since within 20 minutes, the rate returned to that seen in platelets incubated with glycerol alone. Purified human thrombin also produced this same effect on phospholipid synthesis in platelets. Trypsin produced effects on phosphoglyceride formation similar to those seen with thrombin, and the trypsin-induced effect was inhibited by prior incubation of trypsin with soybean trypsin inhibitor, suggesting that proteolysis may be required for the observed effects on phospholipid synthesis.
Detection of human papillomavirus mRNA and cervical cancer cells in peripheral blood of cervical cancer patients with metastasis.
Authors: C C Pao, J J Hor, F P Yang, C Y Lin, C J Tseng
Journal: Journal of Clinical Oncology (1997)

PURPOSE To determine the presence of cervical cancer cells in circulating peripheral blood of stage IVb cervical cancer patients with metastasis to distant organs. PATIENTS AND METHODS Cervical cancer tissue from 15 stage IVb cervical cancer patients with metastasis were analyzed for the presence of human papillomavirus (HPV) type 16 DNA by nested polymerase chain reaction (PCR). The presence of transcriptional products of the HPV type 16 E6-transforming gene in the peripheral blood of the same 15 cancer patients was analyzed by reverse transcription and PCR. Cervical tissues and peripheral-blood specimens from 12 normal healthy individuals served as controls. RESULTS Thirteen of 15 (86.7%) cervical cancer tissues from same number of patients were found to contain HPV type 16 DNA. Peripheral-blood specimens from 12 of 13 (92.3%) cervical HPV DNA-positive patients were found to contain HPV-specific mRNA detectable by reverse transcription (RT) and PCR. Cervical tissues from all 12 normal controls were HPV-free. None of the peripheral-blood specimens from two cervical HPV-negative cancer patients and 12 normal controls contained detectable amounts of mRNA of HPV type 16 E6-transforming gene. CONCLUSION The most likely source of the HPV-specific mRNA detected in the peripheral blood of cervical cancer patients with metastasis is the cervical cancer cells derived from or shed from the cervix. The presence of HPV E6 mRNAs in peripheral blood may be a sensitive indicator of circulating cervical cancer cells. If PCR positivity is proven to be able to predict disease progression reliably, these findings may have clinical applications in the treatment of cervical and many other cancers.
Comorbidities in COPD patients are not associated to higher disease severity
Authors: Laura Caram, Renata Ferrari, Cristiane Naves, Suzana Tanni, Liana Coelho, Simone do Vale, Irma Godoy
Journal: European Respiratory Journal (2011)

The influence of disease severity on the prevalence of comorbidities in COPD patients is unclear. The aim of this study was to assess the prevalence of comorbidities in 25 mild/moderate COPD patients (68% male gender, age= 65±8 years, FEV1= 73±15%) and 25 severity/very severity CPOD patients (56% male gender, age= 69±9 years, FEV1= 40±18%). Comordities were registered based on medical charts diagnoses, on Charlson comorbidity index and on Hospital Anxiety and Depression Scale. Of the 50 patients evaluated, 70% had diagnosis of comorbidities, and 42% of these were cardiovascular diseases (40% hypertension, 10% coronary artery disease and 6% heart failure grade I). Depression was present in 20% of patients, dyslipidemia in 14% and diabetes mellitus in 14%. The prevalence of dyslipidemia (p=0.02), depression (0.008) and alcoholism (p=0.06) were higher in patients with mild to moderate disease. Charlson comorbidity index, systemic arterial blood pressure, diabetes mellitus, ischemic heart disease and chronic cardiac failure and the scores of the Hospital Anxiety and Depression Scale were similar between both groups. The majority of patients with diagnostic of dyslipidemia had concentrations of lipids (total cholesterol, HDL, LDL and triglycerides) within normal values and the lipid profile were similar between groups. In conclusion, comorbidities are highly prevalevent in COPD patients regardless of the disease severity. Some diseases such as dyslipidemia, depression and alcoholism are even more prevalente in mild/moderate patients.  Research supported by FAPESP (2010/10312-1)
Human Immunodeficiency Virus-1 Entry Into Purified Blood Dendritic Cells Through CC and CXC Chemokine Coreceptors
Authors: Seyoum Ayehunie, Eduardo A. Garcia-Zepeda, James A. Hoxie, Richard Horuk, Thomas S. Kupper, Andrew D. Luster, Ruth M. Ruprecht
Journal: Blood (1997)
Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition
Authors: Nathalie Jacque, Anne Marie Ronchetti, Clément Larrue, Godelieve Meunier, Rudy Birsen, Lise Willems, Estelle Saland, Justine Decroocq, Thiago Trovati Maciel, Mireille Lambert, Laury Poulain, Marie Anne Hospital, Pierre Sujobert, Laure Joseph, Nicolas Chapuis, Catherine Lacombe, Ivan Cruz Moura, Susan Demo, Jean Emmanuel Sarry, Christian Recher, Patrick Mayeux, Jérôme Tamburini, Didier Bouscary
Journal: Blood (2015)
Sleep Disturbances and Glucose Metabolism in Older Adults: The Cardiovascular Health Study
Authors: Linn Beate Strand, Mercedes Carnethon, Mary Lou Biggs, Luc Djoussé, Robert C. Kaplan, David S. Siscovick, John A. Robbins, Susan Redline, Sanjay R. Patel, Imre Janszky, Kenneth J. Mukamal
Journal: Diabetes Care (2015)

OBJECTIVE We examined the associations of symptoms of sleep-disordered breathing (SDB), which was defined as loud snoring, stopping breathing for a while during sleep, and daytime sleepiness, and insomnia with glucose metabolism and incident type 2 diabetes in older adults. RESEARCH DESIGN AND METHODS Between 1989 and 1993, the Cardiovascular Health Study recruited 5,888 participants ≥65 years of age from four U.S. communities. Participants reported SDB and insomnia symptoms yearly through 1989–1994. In 1989–1990, participants underwent an oral glucose tolerance test, from which insulin secretion and insulin sensitivity were estimated. Fasting glucose levels were measured in 1989–1990 and again in 1992–1993, 1994–1995, 1996–1997, and 1998–1999, and medication use was ascertained yearly. We determined the cross-sectional associations of sleep symptoms with fasting glucose levels, 2-h glucose levels, insulin sensitivity, and insulin secretion using generalized estimated equations and linear regression models. We determined the associations of updated and averaged sleep symptoms with incident diabetes in Cox proportional hazards models. We adjusted for sociodemographics, lifestyle factors, and medical history. RESULTS Observed apnea, snoring, and daytime sleepiness were associated with higher fasting glucose levels, higher 2-h glucose levels, lower insulin sensitivity, and higher insulin secretion. The risk of the development of type 2 diabetes was positively associated with observed apnea (hazard ratio [HR] 1.84 [95% CI 1.19–2.86]), snoring (HR 1.27 [95% CI 0.95–1.71]), and daytime sleepiness (HR 1.54 [95% CI 1.13–2.12]). In contrast, we did not find consistent associations between insomnia symptoms and glucose metabolism or incident type 2 diabetes. CONCLUSIONS Easily collected symptoms of SDB are strongly associated with insulin resistance and the incidence of type 2 diabetes in older adults. Monitoring glucose metabolism in such patients may prove useful in identifying candidates for lifestyle or pharmacological therapy. Further studies are needed to determine whether insomnia symptoms affect the risk of diabetes in younger adults.
CAPS: An Automated Evaluation System
Authors: RICHARD C. EVENSON, IVAN W. SLETTEN, JAMES L. HEDLUND, DAVID M. FAINTICH
Journal: American Journal of Psychiatry (1974)

The Community Adjustment Profile System (CAPS) compares a patient's community adjustment prior to treatment with his adjustment after treatment, using a statewide computerized information system. Ten areas of community adjustment are measured by 60 items on a questionnaire completed by a community correspondent, usually a relative who lives with the patient. The data from the questionnaire are keypunched into a central computer and a CAPS report is printed out at the admitting hospital. Data obtained at the time of admission are compared with data obtained 90 days after the patient has left the hospital. The profile shows graphically whether a patient's outcome was better or worse than the statewide average. CAPS currently has an 80 percent return rate and 400 reports are processed monthly.
Hip fracture audit may have saved 1000 lives since 2007:
Authors: Jacqui Wise
Journal: BMJ (2015)

The care and survival of older people with hip fracture in England have substantially improved since the launch of a national, clinician led audit initiative, an independent evaluation has found.1

The UK National Hip Fracture Database was launched in 2007 as a collaboration between the British Orthopaedic Association and the British Geriatrics Society. The initiative published six national clinical standards for hip fracture care, including early surgery and access to acute geriatric care. Hospital clinical teams monitor their performance against these standards to …