tbuckley/cabot-search huggingface dataset:
Pharmacodynamic Biomarkers: Falling Short of the Mark?
Authors: Justin F. Gainor, Dan L. Longo, Bruce A. Chabner
Journal: Clinical Cancer Research (2014)

Abstract In recent years, the clinical development of targeted therapies has been advanced by a greater understanding of tumor biology and genomics. Nonetheless, drug development remains a slow and costly process. An additional challenge is that targeted therapies may benefit only a subset of patients treated—typically those patients whose tumors are dependent on the target of interest. Thus, there is a growing need for the incorporation of both predictive and pharmacodynamic (PD) biomarkers in drug development. Predictive biomarkers are important to help guide patient selection, while PD biomarkers can provide information on the pharmacologic effects of a drug on its target. PD studies may provide insights into proof of mechanism (i.e., Does the agent hit its intended target?) and proof of concept (i.e., Does hitting the drug target result in the desired biologic effect?). PD studies may also provide information on the optimal biologic dosing or scheduling of a targeted agent. Herein, we review PD endpoints in the context of targeted drug development in non–small cell lung cancer, highlighting some of the key challenges encountered to date. In doing so, we discuss recent experiences with repeat tumor biopsies, surrogate tissue analysis, alternative clinical trial designs (e.g., window-of-opportunity trials), circulating biomarkers, and mechanism-based toxicity assessments. The application of such technologies and biomarkers in early clinical trials may facilitate rational drug development, while enhancing our understanding of why certain targeted therapies succeed or fail. See all articles in this CCR Focus section, “Progress in Pharmacodynamic Endpoints.” Clin Cancer Res; 20(10); 2587–94. ©2014 AACR.
Extended Family History of Type 1 Diabetes and Phenotype and Genotype of Newly Diagnosed Children
Authors: Anna Parkkola, Taina Härkönen, Samppa J. Ryhänen, Jorma Ilonen, Mikael Knip
Journal: Diabetes Care (2012)

To determine the frequency of newly diagnosed diabetic children with first- and second-degree relatives affected by type 1 diabetes and to characterize the effects of this positive family history on clinical markers, signs of β-cell autoimmunity, and HLA genotype in the index case.Children (n = 1,488) with type 1 diabetes diagnosed under 15 years of age were included in a cross-sectional study from the Finnish Pediatric Diabetes Register. Data on family history of diabetes and metabolic decompensation at diagnosis were collected using a questionnaire. Antibodies to β-cell autoantigens (islet cell antibodies, insulin autoantibodies, GAD antibodies, and antibodies to the islet antigen 2 molecule) and HLA genotypes were analyzed.A total of 12.2% of the subjects had a first-degree relative with type 1 diabetes (father 6.2%, mother 3.2%, and sibling 4.8%) and 11.9% had an affected second-degree relative. Children without affected relatives had lower pH (P < 0.001), higher plasma glucose (P < 0.001) and β-hydroxybutyrate concentrations (P < 0.001), a higher rate of impaired consciousness (P = 0.02), and greater weight loss (P < 0.001). There were no differences in signs of β-cell autoimmunity. The familial cases carried the HLA DR4-DQ8 haplotype more frequently than sporadic cases (74.0 vs. 67.0%, P = 0.02).When the extended family history of type 1 diabetes is considered, the proportion of sporadic diabetes cases may be reduced to <80%. A positive family history for type 1 diabetes associates with a less severe metabolic decompensation at diagnosis, even when only second-degree relatives are affected. Autoantibody profiles are similar in familial and sporadic type 1 diabetes, suggesting similar pathogenetic mechanisms.
A Phase I Study with Neratinib (HKI-272), an Irreversible Pan ErbB Receptor Tyrosine Kinase Inhibitor, in Patients with Solid Tumors
Authors: Kwok-K. Wong, Paula M. Fracasso, Ronald M. Bukowski, Thomas J. Lynch, Pamela N. Munster, Geoffrey I. Shapiro, Pasi A. Jänne, Joseph P. Eder, Michael J. Naughton, Matthew J. Ellis, Suzanne F. Jones, Tarek Mekhail, Charles Zacharchuk, Jennifer Vermette, Richat Abbas, Susan Quinn, Christine Powell, Howard A. Burris
Journal: Clinical Cancer Research (2009)

The dose-limiting toxicities, maximum tolerated dose, pharmacokinetic profile, and preliminary antitumor activity of neratinib (HKI-272), an irreversible pan ErbB inhibitor, were determined in patients with advanced solid tumors.Neratinib was administered orally as a single dose, followed by a 1-week observation period, and then once daily continuously. Planned dose escalation was 40, 80, 120, 180, 240, 320, 400, and 500 mg. For pharmacokinetic analysis, timed blood samples were collected after administration of the single dose and after the first 14 days of continuous daily administration.Dose-limiting toxicity was grade 3 diarrhea, which occurred in one patient treated with 180 mg and in four patients treated with 400 mg neratinib; hence, the maximum tolerated dose was determined to be 320 mg. Other common neratinib-related toxicities included nausea, vomiting, fatigue, and anorexia. Exposure to neratinib was dose dependent, and the pharmacokinetic profile of neratinib supports a once-a-day dosing regimen. Partial response was observed for 8 (32%) of the 25 evaluable patients with breast cancer. Stable disease >or=24 weeks was observed in one evaluable breast cancer patient and 6 (43%) of the 14 evaluable non-small cell lung cancer patients.The maximum tolerated dose of once-daily oral neratinib is 320 mg. The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 immunohistochemical staining intensity of 2+ or 3+. The antitumor activity, tolerable toxicity profile, and pharmacokinetic properties of neratinib warrant its further evaluation.
Heart Malformation
Authors: Joseph T.C. Shieh, Deepak Srivastava
Journal: Circulation (2009)

C ongenital heart disease (CHD) is the most common human birth defect worldwide, 1 taking a tremendous toll on affected families, caregivers, and healthcare systems.Approximately 40 000 children are born each year in the United States with a heart malformation, and at least another 40 000 are born annually with subclinical malformations that result in heart disease later in adulthood.Significant advances in cardiac care and surgery have lowered mortality, and there are now Ͼ1 million survivors of CHD in the United States.As a result, the economic effects of CHD are substantial, particularly when lifetime costs of management are considered.
Loss of Retinal Cadherin Facilitates Mammary Tumor Progression and Metastasis
Authors: Georgia Agiostratidou, Maomi Li, Kimita Suyama, Ines Badano, Rinat Keren, Su Chung, Amy Anzovino, James Hulit, Binzhi Qian, Boumediene Bouzahzah, Eliseo Eugenin, Olivier Loudig, Greg R. Phillips, Joseph Locker, Rachel B. Hazan
Journal: Cancer Research (2009)

The mammary epithelium is thought to be stabilized by cell-cell adhesion mediated mainly by E-cadherin (E-cad). Here, we show that another cadherin, retinal cadherin (R-cad), is critical for maintenance of the epithelial phenotype. R-cad is expressed in nontransformed mammary epithelium but absent from tumorigenic cell lines. In vivo, R-cad was prominently expressed in the epithelium of both ducts and lobules. In human breast cancer, R-cad was down-regulated with tumor progression, with high expression in ductal carcinoma in situ and reduced expression in invasive duct carcinomas. By comparison, E-cad expression persisted in invasive breast tumors and cell lines where R-cad was lost. Consistent with these findings, R-cad knockdown in normal mammary epithelium stimulated invasiveness and disrupted formation of acini despite continued E-cad expression. Conversely, R-cad overexpression in aggressive cell lines induced glandular morphogenesis and inhibited invasiveness, tumor formation, and lung colonization. R-cad also suppressed the matrix metalloproteinase 1 (MMP1), MMP2, and cyclooxygenase 2 gene expression associated with pulmonary metastasis. The data suggest that R-cad is an adhesion molecule of the mammary epithelium, which acts as a critical regulator of the normal phenotype. As a result, R-cad loss contributes to epithelial suppression and metastatic progression.
Effect of Intensive Versus Standard Lipid-Lowering Treatment With Atorvastatin on the Progression of Calcified Coronary Atherosclerosis Over 12 Months
Authors: Axel Schmermund, Stephan Achenbach, Thomas Budde, Yuri Buziashvili, Andreas Förster, Guy Friedrich, Michael Henein, Gert Kerkhoff, Friedrich Knollmann, Valery Kukharchuk, Avijit Lahiri, Roman Leischik, Werner Moshage, Michael Schartl, Winfried Siffert, Elisabeth Steinhagen-Thiessen, Valentin Sinitsyn, Anja Vogt, Burkhard Wiedeking, Raimund Erbel
Journal: Circulation (2006)

Recent clinical trials have suggested that intensive versus standard lipid-lowering therapy provides for additional benefit. Electron-beam computed tomography provides the opportunity to quantify the progression of coronary artery calcification (CAC) in serial measurements.In a multicenter, randomized, double-blind trial, 471 patients (age 61+/-8 years) who had no history of coronary artery disease and no evidence of high-grade coronary stenoses (>50% diameter reduction) were randomized if they had > or =2 cardiovascular risk factors and moderate calcified coronary atherosclerosis as evidenced by a CAC score > or =30. Patients were assigned to receive 80 mg or 10 mg of atorvastatin per day over 12 months. Progression of CAC volume scores could be analyzed in 366 patients. After pretreatment with 10 mg of atorvastatin for 4 weeks, 12 months of study medication reduced LDL cholesterol from 106+/-22 to 87+/-33 mg/dL in the group randomized to receive 80 mg of atorvastatin (P<0.001), whereas levels remained stable in the group randomized to receive 10 mg (108+/-23 at baseline, 109+/-28 mg/dL at the end of the study, P=NS). The mean progression of CAC volume scores, corrected for the baseline CAC volume score, was 27% (95% CI 20.8% to 33.1%) in the 80-mg atorvastatin group and 25% (95% CI 19.1% to 30.8%) in the 10-mg atorvastatin group (P=0.65). CAC progression showed no relationship with on-treatment LDL cholesterol levels.We did not observe a relationship between on-treatment LDL cholesterol levels and the progression of calcified coronary atherosclerosis. Over a period of 12 months, intensive atorvastatin therapy was unable to attenuate CAC progression compared with standard atorvastatin therapy. The possibility remains that the time window was too short to demonstrate an effect.
Extreme chromosomal instability forecasts improved outcome in ER-negative breast cancer: a prospective validation cohort study from the TACT trial
Authors: M. Jamal-Hanjani, R. A'Hern, N.J. Birkbak, P. Gorman, E. Grönroos, S. Ngang, P. Nicola, L. Rahman, E. Thanopoulou, G. Kelly, P. Ellis, P. Barrett-Lee, S.R.D. Johnston, J. Bliss, R. Roylance, C. Swanton
Journal: Annals of Oncology (2015)
Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells
Authors: Bo Song, Yuan Wang, Matthew A. Titmus, Galina Botchkina, Andrea Formentini, Marko Kornmann, Jingfang Ju
Journal: Molecular Cancer (2010)

Translational control mediated by non-coding microRNAs (miRNAs) plays a key role in the mechanism of cellular resistance to anti-cancer drug treatment. Dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS, TS) are two of the most important targets for antifolate- and fluoropyrimidine-based chemotherapies in the past 50 years. In this study, we investigated the roles of miR-215 in the chemoresistance to DHFR inhibitor methotrexate (MTX) and TS inhibitor Tomudex (TDX).The protein levels of both DHFR and TS were suppressed by miR-215 without the alteration of the target mRNA transcript levels. Interestingly, despite the down-regulation of DHFR and TS proteins, ectopic expression of miR-215 resulted in a decreased sensitivity to MTX and TDX. Paradoxically, gene-specific small-interfering RNAs (siRNAs) against DHFR or TS had the opposite effect, increasing sensitivity to MTX and TDX. Further studies revealed that over-expression of miR-215 inhibited cell proliferation and triggered cell cycle arrest at G2 phase, and that this effect was accompanied by a p53-dependent up-regulation of p21. The inhibitory effect on cell proliferation was more pronounced in cell lines containing wild-type p53, but was not seen in cells transfected with siRNAs against DHFR or TS. Moreover, denticleless protein homolog (DTL), a cell cycle-regulated nuclear and centrosome protein, was confirmed to be one of the critical targets of miR-215, and knock-down of DTL by siRNA resulted in enhanced G2-arrest, p53 and p21 induction, and reduced cell proliferation. Additionally, cells subjected to siRNA against DTL exhibited increased chemoresistance to MTX and TDX. Endogenous miR-215 was elevated about 3-fold in CD133+HI/CD44+HI colon cancer stem cells that exhibit slow proliferating rate and chemoresistance compared to control bulk CD133+/CD44+ colon cancer cells.Taken together, our results indicate that miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX. The findings of this study suggest that miR-215 may play a significant role in the mechanism of tumor chemoresistance and it may have a unique potential as a novel biomarker candidate.
When Doors of Perception Close: Bottom-up Models of Disrupted Cognition in Schizophrenia
Authors: Daniel C. Javitt
Journal: Annual Review of Clinical Psychology (2009)

Schizophrenia is a major mental disorder that affects approximately 1% of the population worldwide. Cognitive deficits are a key feature of schizophrenia and a primary cause of long-term disability. Current neurophysiological models of schizophrenia focus on distributed brain dysfunction with bottom-up as well as top-down components. Bottom-up deficits in cognitive processing are driven by impairments in basic perceptual processes that localize to primary sensory brain regions. Within the auditory system, deficits are apparent in elemental sensory processing, such as tone matching following brief delay. Such deficits lead to impairments in higher-order processes such as phonological processing and auditory emotion recognition. Within the visual system, deficits are apparent in functioning of the magnocellular visual pathway, leading to higher-order deficits in processes such as perceptual closure, object recognition, and reading. In both auditory and visual systems, patterns of deficit are consistent with underlying impairment of brain N-methyl-d-aspartate receptor systems.
Solid organ transplant recipients: clinical considerations in the application of exercise
Authors: K-J L McKenzie, D C McKenzie, E M Yoshida
Journal: British Journal of Sports Medicine (2014)

Over 100 000 solid organ transplants are performed worldwide each year and this has a significant impact on physical function and quality of life. However, the capacity for exercise in solid-organ recipients is reduced. Regular physical activity improves most of the indices of fitness in these patients but, with few exceptions, they do not reach the values seen in healthy controls. The reason for the 40–60% reduction in maximal exercise capacity is not clear; the disease process, need for life long immunosuppression and sedentary lifestyle all contribute. The interaction between exercise and immunosuppressing medication merits research as does the specifics of the exercise prescription for these patients. This paper reviews important features of this rapidly expanding group of patients and suggests clinical considerations in the application of exercise in this population.
Inhibition of Virus Attachment to CD4+ Target Cells Is a Major Mechanism of T Cell Line–adapted HIV-1 Neutralization
Authors: Sophie Ugolini, Isabelle Mondor, Paul W.H.I. Parren, Dennis R. Burton, Shermaine A. Tilley, Per Johan Klasse, Quentin J. Sattentau
Journal: The Journal of Experimental Medicine (1997)

Antibody-mediated neutralization of human immunodeficiency virus type–1 (HIV-1) is thought to function by at least two distinct mechanisms: inhibition of virus–receptor binding, and interference with events after binding, such as virus–cell membrane fusion. Here we show, by the use of a novel virus–cell binding assay, that soluble CD4 and monoclonal antibodies to all confirmed glycoprotein (gp)120 neutralizing epitopes, including the CD4 binding site and the V2 and V3 loops, inhibit the adsorption of two T cell line–adapted HIV-1 viruses to CD4+ cells. A correlation between the inhibition of virus binding and virus neutralization was observed for soluble CD4 and all anti-gp120 antibodies, indicating that this is a major mechanism of HIV neutralization. By contrast, antibodies specific for regions of gp120 other than the CD4 binding site showed little or no inhibition of either soluble gp120 binding to CD4+ cells or soluble CD4 binding to HIV-infected cells, implying that this effect is specific to the virion–cell interaction. However, inhibition of HIV-1 attachment to cells is not a universal mechanism of neutralization, since an anti-gp41 antibody did not inhibit virus–cell binding at neutralizing concentrations, implying activity after virus–cell binding.
Hunt acknowledges need to make emergency medicine and general practice more attractive
Authors: A. O'Dowd
Journal: BMJ (2013)

The government plans to make emergency medicine and general practice more attractive to doctors, MPs have been told, as a way to tackle shortages in both specialties in England.

The health secretary, Jeremy Hunt, appearing before the parliamentary health select committee on 2 July for its inquiry into implementation of the Health and Social Care Act, said that these parts of the workforce needed to be boosted and made more attractive to new doctors.

MPs asked about a claim made by the College of Emergency Medicine that only 17% of emergency departments provided consultant cover for 16 hours each day on Mondays to Fridays and that 50% of trainee vacancies in this specialty were unfilled. …
Neural respiratory drive, pulmonary mechanics and breathlessness in patients with cystic fibrosis
Authors: C. C. Reilly, K. Ward, C. J. Jolley, A. C. Lunt, J. Steier, C. Elston, M. I. Polkey, G. F. Rafferty, J. Moxham
Journal: Thorax (2011)

<h3>Background</h3> Neural respiratory drive (NRD) measured from the diaphragm electromyogram (EMGdi) reflects the load/capacity balance of the respiratory muscle pump and is a marker of lung disease severity. EMGdi measurement is invasive, but recording the EMG from the parasternal intercostal muscles using surface electrodes (sEMGpara) could provide a non-invasive method of assessing NRD and disease severity. <h3>Objectives</h3> To test the hypothesis that NRD measured by sEMGpara correlates with EMGdi, to provide an index of disease severity in cystic fibrosis (CF) and to relate to exercise-induced breathlessness. <h3>Methods</h3> 15 patients with CF (mean forced expiratory volume in 1 s (FEV<sub>1</sub>) 53.5% predicted) and 15 age-matched healthy controls were studied. sEMGpara and EMGdi were recorded at rest and during exercise. sEMGpara was recorded using surface electrodes and EMGdi using a multipair oesophageal electrode catheter. Signals were normalised using the peak EMG recorded during maximum respiratory manoeuvres and expressed as EMG%max. The respiratory pattern, metabolic data, oesophageal and gastric pressures and Borg scores were also recorded. <h3>Results</h3> Mean (SD) resting sEMGpara%max and EMGdi%max were higher in patients with CF than in controls (13.1 (7)% and 18.5 (7.5)% vs 5.8 (3)% and 7.5 (2)%, respectively, p&lt;0.001). In the patients with CF, resting sEMGpara%max and EMGdi%max were related to the degree of airways obstruction (FEV<sub>1</sub>) (r=−0.91 and r=−0.82, both p&lt;0.001), hyperinflation (r=0.63 and r=0.56, both p&lt;0.001) and dynamic lung compliance (r=−0.53 and r=−0.59, both p&lt;0.001). During exercise, sEMGpara%max and EMGdi%max were strongly correlated with breathlessness in the patients with CF before (r=0.906, p&lt;0.001) and after (r=0.975, p&lt;0.001) the onset of neuromechanical dissociation. <h3>Conclusion</h3> sEMGpara%max provides a non-invasive marker of neural drive, which reflects disease severity and exercise-induced breathlessness in CF.
Emphasis on Carbohydrates May Negatively Influence Dietary Patterns in Youth With Type 1 Diabetes
Authors: Sanjeev N. Mehta, Denise L. Haynie, Laurie A. Higgins, Natalie N. Bucey, Alisha J. Rovner, Lisa K. Volkening, Tonja R. Nansel, Lori M.B. Laffel
Journal: Diabetes Care (2009)

OBJECTIVE To assess perceptions of healthful eating and the influence of diabetes management on dietary behaviors among youth with type 1 diabetes and parents. RESEARCH DESIGN AND METHODS Youth with type 1 diabetes (n = 35), ages 8–21 years, and parents participated in focus groups. Focus group recordings were transcribed and coded into themes. Clinical data were abstracted from the electronic medical record. RESULTS Central topics were perceptions of healthful eating and the impact of diabetes management on diet. An emphasis on limiting postprandial glycemic excursions occasionally contradicted the traditional perception of healthful eating, which emphasized consumption of nutrient-dense whole foods in favor of prepackaged choices. Whereas fixed regimens required more rigid diets, basal-bolus regimens provided more opportunities for unhealthful eating. Most youth perceived “refined” grains as more healthful grains. CONCLUSIONS For youth with type 1 diabetes and parents, an emphasis on carbohydrate quantity over quality may distort beliefs and behaviors regarding healthful eating.
Association of CKD and Cancer Risk in Older People
Authors: Germaine Wong, Andrew Hayen, Jeremy R. Chapman, Angela C. Webster, Jie Jin Wang, Paul Mitchell, Jonathan C. Craig
Journal: Journal of the American Society of Nephrology (2009)

People with ESRD are at increased risk for cancer, but it is uncertain when this increased risk begins in the spectrum of chronic kidney disease (CKD). The aim of our study was to determine whether moderate CKD increases the risk for cancer among older people. We linked the Blue Mountains Eye Study, a prospective population-based cohort study of 3654 residents aged 49 to 97 yr, and the New South Wales Cancer Registry. During a mean follow-up of 10.1 yr, 711 (19.5%) cancers occurred in 3654 participants. Men but not women with at least stage 3 CKD had a significantly increased risk for cancer (test of interaction for gender P = 0.004). For men, the excess risk began at an estimated GFR (eGFR) of 55 ml/min per 1.73 m2 (adjusted hazard ratio [HR] 1.39; 95% confidence interval [CI] 1.00 to 1.92) and increased linearly as GFR declined. For every 10-ml/min decrement in eGFR, the risk for cancer increased by 29% (adjusted HR 1.29; 95% CI 1.10 to 1.53), with the greatest risk at an eGFR <40 ml/min per 1.73 m2 (adjusted HR 3.01; 95% CI 1.72 to 5.27). The risk for lung and urinary tract cancers but not prostate was higher among men with CKD. In conclusion, moderate CKD (stage 3) may be an independent risk factor for the development of cancer among older men but not women, and the effect of CKD on risk may vary for different types of cancer.
Haemorrhagic pleural effusion several months after inhalation of a foreign body
Authors: I Steffensen, P Faurschou
Journal: European Respiratory Journal (1993)

We present the case of a 50 yr old female with chronic obstructive lung disease, who, secondary to inhalation of a foreign body, developed recurrent pneumonia and a haemorrhagic pleural effusion (HPE). The foreign body (vegetable matter) was removed by rigid bronchoscopy and the patient recovered.