tbuckley/cabot-search huggingface dataset:
Cognitive Decline in a Colombian Kindred With Autosomal Dominant Alzheimer Disease
Authors: Daniel C. Aguirre-Acevedo, Francisco Lopera, Eliana Henao, Victoria Tirado, Claudia Muñoz, Margarita Giraldo, Shrikant I. Bangdiwala, Eric M. Reiman, Pierre N. Tariot, Jessica B. Langbaum, Yakeel T. Quiroz, Fabian Jaimes
Journal: JAMA Neurology (2016)

Data from an autosomal dominant Alzheimer disease (ADAD) kindred were used to track the longitudinal trajectory of cognitive decline associated with preclinical ADAD and explore factors that may modify the rate of cognitive decline.To evaluate the onset and rate of cognitive decline during preclinical ADAD and the effect of socioeconomic, vascular, and genetic factors on the cognitive decline.We performed a retrospective cohort study from January 1, 1995, through June 31, 2012, of individuals from Antioquia, Colombia, who tested positive for the ADAD-associated PSEN1 E280A mutation. Data analysis was performed from August 20, 2014, through November 30, 2015. A mixed-effects model was used to estimate annual rates of change in cognitive test scores and to mark the onset of cognitive decline.Memory, language, praxis, and total scores from the Consortium to Establish a Registry for Alzheimer Disease test battery. Chronologic age was used as a time scale in the models. We explore the effects of sex; educational level; socioeconomic status; residence area; occupation type; marital status; history of hypertension, diabetes mellitus, and dyslipidemia; tobacco and alcohol use; and APOE ε4 on the rates of cognitive decline.A total of 493 carriers met the inclusion criteria and were analyzed. A total of 256 carriers had 2 or more assessments. At the time of the initial assessment, participants had a mean (SD) age of 33.4 (11.7) years and a mean (SD) educational level of 7.2 (4.2) years. They were predominantly female (270 [54.8%]), married (293 [59.4%]), and of low socioeconomic status (322 [65.3%]). Word list recall scores provided the earliest indicator of preclinical cognitive decline at 32 years of age, 12 and 17 years before the kindred's respective median ages at mild cognitive impairment and dementia onset. After the change point, carriers had a statistically significant cognitive decline with a loss of 0.24 (95% CI, -0.26 to -0.22) points per year for the word list recall test and 2.13 (95% CI, -2.29 to -1.96) points per year for total scores. Carriers with high educational levels had an increase of approximately 36% in the rate of cognitive decline after the change point when compared with those with low educational levels (-2.89 vs -2.13 points per year, respectively). Onset of cognitive decline was delayed by 3 years in individuals with higher educational levels compared with those with lower educational levels. Those with higher educational level, middle/high socioeconomic status, history of diabetes and hypertension, and tobacco and alcohol use had a steeper cognitive decline after onset.Preclinical cognitive decline was evident in PSEN1 E280A mutation carriers 12 years before the onset of clinical impairment. Educational level may be a protective factor against the onset of cognitive impairment.
Phase II study of erlotinib (OSI 774) in women with recurrent or metastatic endometrial cancer: NCIC CTG IND-148
Authors: K. V. Jasas, A. Fyles, L. Elit, P. J. Hoskins, J. Biagi, J. Dubuc-Lissoir, S. Matthews, J. Dancey, E. Eisenhauer, A. M. Oza
Journal: Journal of Clinical Oncology (2004)

5019 Background: EGFR over expression is seen in 60–80% of endometrial cancers(EC) and may have a major role in tumour growth and progression. Erlotinib is an orally active, selective inhibitor of EGFR tyrosine kinase activity. Methods: A 2 stage phase II study was performed to evaluate single agent activity of erlotinib in EC. Multinomial endpoints incorporating response and stable disease were used. Women with recurrent or metastatic EC, with measurable disease, chemotherapy naïve and up to 1 line of prior hormonal therapy were eligible to participate. Patients (pts) received single agent erlotinib at a daily dose of 150 mg continuously. A cycle was defined as 4 weeks of therapy, with response assessment every 2 cycles. Results: Twenty seven pts have been entered to date, with 25 evaluable for toxicity and 23 for response (1 cancelled before starting, 1 had only 5 days of trial drug, additional 2 pts too early for assessment). Treatment was well tolerated with 60% of pts receiving 90% of planned dose intensity. Seven had dose reductions (3 for skin toxicity; 3 diarrhea and 1 keratitis/conjuctivitis). The most common drug related toxicity was rash (2 grade(gr)3, 10 gr2 and 10 gr1). Drug related severe toxicity was infrequent with the only gr4 toxicity being an elevation of transaminases (SGOT). Grade-3 toxicities included 3 pts with diarrhea, 1 rash and pruritis, 1 non-neutropenic infection and dyspnea, plus single reports of fatigue, arthralgia, keratitis/conjunctivitis, rash, puritis and an elevation of bilirubin. There were no grade 3 or 4 hematologic toxicities. To date there is 1 confirmed partial response (PR) of disease in the mesentery and lungs lasting 10.4 mo. 12 pts have had stable disease (SD), with median duration of 3.4 mo (1.5–7.6). EGFR status using primary archival tumor tissue has been analyzed on 12 pts to date; 7 were positive, 5 were negative. Of the 7 pts who were EGFR positive, 1 had a PR, 3 SD and 3 progressive disease(PD). Of 5 who were EGFR negative, 2 had SD and 3 PD. Conclusion: Erlotinib in endometrial cancer is well tolerated. The study has fulfilled criteria to proceed stage II, with planned accrual of 30 evaluable patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI Pharmaceuticals
The involucrin gene of Old-World monkeys and other higher primates: synapomorphies and parallelisms resulting from the same gene-altering mechanism.
Authors: P Djian, H Green
Journal: Molecular Biology and Evolution (1992)

The involucrin gene of platyrrhines and hominoids contains a segment of 10-codon repeats which were added vectorially at the same site in the coding region. We have now cloned and sequenced the involucrin gene of four cercopithecoid monkeys--two macaques (mulatta and fascicularis) and two Cercopithecus monkeys (aethiops and hamlyni). Each gene contains a similar segment of short repeats; some of these were added in a common anthropoid lineage, others were added in a common catarrhine lineage, and still others were added in a common macaque or Cercopithecus lineage. Repeats added before a lineage diverges become synapomorphies in the sister taxa resulting from the divergence. Repeats added independently in different diverged lineages become parallelisms. The synapomorphies are the result of the action of a targeted duplication mechanism acting in a common ancestral lineage, but the parallelisms are the result of the same duplication mechanism transmitted to successively divergent sublineages and acting independently in each.
Modeling of early PSA kinetics in intermediate risk prostate cancer
Authors: G. Delouya, D. Taussky, T. Nguyen, M. Jolicoeur, C. Lambert, M. Fortin, J. Bahary, S. Gauthier-Bizier, P. Després
Journal: Journal of Clinical Oncology (2008)

16080 Background: Absolute changes in prostate specific antigen (PSA) values within the first year after radiotherapy can predict biochemical outcome on later follow up years. Other robust indicators of outcome might be present in analyzing the behavior of the early PSA kinetics. We investigated this hypothesis by modeling the PSA response in patients treated with external-beam radiotherapy for intermediate risk prostate cancer. Methods: We analyzed the PSA history of 74 patients from our institution with intermediate risk prostate cancer ( Gleason 6 + PSA values of 10–20 or Gleason 7 + PSA values <10). Patients were treated with either 70.2 Gy in 39 fractions or 79.2 Gy in 44 fractions. Patients had a follow up of at least 1 year (mean112 ± 48 weeks) and were objectively selected on the basis of their PSA curves. Patients exhibiting a mathematically sound exponential decay in their PSA values, determined by a non-linear fitting procedure, were retained for further analysis. Spearman’s coefficients were then computed to assess the correlation between pre- radiotherapy factors, treatment arms and parameters describing the exponential decay fits. The PSA fits were characterized by their half-life and their coefficient of determination, taken here as a measure of the goodness of fit (R2). Results: We found that 68% (n=50) of the patients exhibited a mathematically sound exponential decay in their PSA values. The mean half-life of PSA-decay was 15.5 ± 7.7 weeks. There was a statistically significant correlation (p<0.01) between the half-life of the decays and the coefficient of determination of fits to the data. It was observed that shorter half-lives corresponded to PSA curves closer to mathematically ideal exponential decay. Radiotherapy dose had no influence on the PSA decay half-life nor on the coefficient of determination of the fits. Conclusion: We have determined that rapid decrease of PSA values after radiotherapy is associated with mathematically ideal decays. Although it is yet too soon to say if it would correlate with a lower probability of biochemical recurrence, these observations nonetheless suggest a promising link with theoretical cell killing models. We plan to integrate these findings in a prognostic model for patient with intermediate risk prostate cancer. No significant financial relationships to disclose.
A phase II trial of motexafin gadolinium (MGd) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum-based chemotherapy: Preliminary results of stage 1
Authors: G. Nicholas, R. B. Natale, F. Greco, R. Govindan, P. Chabot, K. Pandya, L. Eubank, M. F. Renschler
Journal: Journal of Clinical Oncology (2007)

18001 Background: Motexafin gadolinium (MGd) is a tumor-selective antineoplastic agent that disrupts redox dependent pathways by targeting oxidative stress-related proteins such as thioredoxin reductase (TRX). TRX often is overexpressed in NSCLC and is associated with a poor prognosis. Inhibition of TRX reverses tumor phenotype in lung carcinoma cells in vitro and in vivo. This randomized 2-stage phase II trial investigated tumor response and survival with 2 regimens of single agent MGd for the 2nd line treatment of advanced NSCLC. Methods: Patients with locally advanced or metastatic NSCLC ± brain metastases, ECOG PS 0–1, who had received one prior platinum-based chemotherapy regimen ± kinase inhibitor were randomized to intravenous MGd (10 mg/kg/week - Group A) or MGd (15 mg/kg/q 3 weeks - Group B) given in 21 day cycles. The sample size was 30 per arm in stage 1, and 24 per arm in stage 2. Response was evaluated by RECIST every 6 weeks. Results: 51 evaluable patients, median age of 62 years (range 41–85), with locally advanced (14%) or metastatic (86%) adenocarcinoma (47%), squamous cell carcinoma (14%), large cell carcinoma (10%), bronchoalveolar carcinoma (2%) or other NSCLC (27%) were randomized to group A (N=22) or group B (N=29). 37% had not responded to first line chemotherapy. MGd treatment was well tolerated, with 1–12 cycles (median 2, mean 3) administered. The most common grade 3+ adverse events were hypophosphatemia (15.7%), fatigue (13.7%), dyspnea (9.8%), hypoxia (7.8%), and finger blisters (5.9%). 48 patients were evaluable for response, with a confirmed response rate of 4.2% (2 PR). Median time to progression was 7 weeks in each group, with 26% and 15% free from progression at 4 and 6 months, respectively. Median survival of 51 evaluable patients was 10.2 months (95% CI: 6.7 months - not reached), 9.2 months for group A and not reached at &gt; 1 year for group B. Conclusions: MGd appears active as a single agent for second line treatment of NSCLC patients with advanced or metastatic NSCLC who have failed prior platinum-based chemotherapy, with a modest response rate and promising survival. The trial has met the criteria for continuation into stage 2 for each treatment group. No significant financial relationships to disclose.
Human Lymphoblastoid Cell Lines. II. Cytogenetic Studies
Authors: C. M. Steel, S. McBeath, M. L. O'Riordan
Journal: JNCI Journal of the National Cancer Institute (1971)

Cytogenetic studies were undertaken on 14 human lymphoblastoid cell lines. Four were eneupleld, all from elderly patients with malignant disease, and eight from young patients with infectious mono-nucleosis were diploid. It is uncertain whether the age or the diagnosis of the donor is the important factor in determining the karyotype of an established line. The evidence suggests that aneuploidy usually arises in vitro from an inoculum of diploid cells. The modal karyotype of a mass culture changes by the emergence of a clone growing more rapidly than the parent line. The “marker C” chromosomes, described by ethers, was not found in any of 12 lines initiated in the authors' laboratory but was present in 89% of divisions in a line obtained from another center. There is no good evidence for the recurrence of any other specific chromosome aberration in different cell lines.
Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali: a single-blind, dose-ranging, adaptive randomised phase 2 trial
Authors: Alassane Dicko, Joelle M Brown, Halimatou Diawara, Ibrahima Baber, Almahamoudou Mahamar, Harouna M Soumare, Koualy Sanogo, Fanta Koita, Sekouba Keita, Sekou F Traore, Ingrid Chen, Eugenie Poirot, Jimee Hwang, Charles McCulloch, Kjerstin Lanke, Helmi Pett, Mikko Niemi, François Nosten, Teun Bousema, Roly Gosling
Journal: The Lancet Infectious Diseases (2016)
LSC 2014 abstract - RORγ t-specific RNAi decreases allergic airway inflammation and airway hyperresponsiveness in a mouse model of neutrophilic asthma
Authors: Sina Webering, Lars Lunding, Heinz Fehrenbach, Michael Wegmann
Journal: European Respiratory Journal (2014)

Introduction:  Recent studies suggest T helper 17 (Th17) cells as important players in the progression of asthma towards a severe phenotype. Regulated by the transcription factor Retinoic acid-related Orphan Receptor gamma (RORγ) t, which is essential for the differentiation of these cells, Th17 cells appear to act as general promoters of chronic inflammatory responses. Thus, it is conceivable to make use of this transcription factor as a prime target for therapeutic intervention.Therefore, the aim of this study was to diminish RORγ t expression by usingsmall interfering RNAs(siRNAs) and to characterize its effects on Th17 cell activity in-vitro and in-vivo.   Methods:  Th17 cells were generated in-vitro and transfected with several siRNA candidates targeting RORγ t. Afterwards, the in-vivo relevance of siRNA-mediated downregulation of RORγ t was characterized in a mouse model of neutrophilic asthma.   Results:  SiRNA-transfected Th17 cells revealed not only reduced expression of RORγ t but also of proinflammatory cytokines such as IL-17A. Intratracheal application of the most active siRNA in a mouse model of neutrophilic asthma inhibited the development of airway hyperresponsiveness to methacholine. In addition, application of the RORγ t-specific siRNA prevented airway inflammation characterized by a significantly reduced number of neutrophils and decreased bronchoalveolar lavage IL17A, TNF-α and KC levels.   Conclusion:  Our data show that knockdown of RORγ t by gene silencing improved airway inflammation in a mouse model of experimental asthma and may have therapeutic potential for the treatment of neutrophilic asthma.
Development of ultra-sensitive single molecule immunoassays for the intracellular kinases Akt1/pAkt1 and Erk2/pErk2 for small tissue studies
Authors: J. Todd, D. Held, B. K. Klein, E. Macy, S. J. Agee, Q. A. Lu, R. Puskas
Journal: Journal of Clinical Oncology (2009)

e22068 Background: The Ras/Raf/MEK/ERK and PI3K/PTEN/AKT kinase cascades are critical pathways in malignant transformation, tumor progression and multi-drug resistance (MDR) in human cancers. Expression and genetic studies have contributed much to our understanding of this role, but further clinical investigations at the post-transcriptional level are necessary. Towards this end, Singulex has developed single molecule immunoassays for total Akt1, pAkt1, total Erk2 and pErk2 utilizing the Erenna Immunoassay System for use in small tissue studies and clinical trials. Methods: Analytical sensitivity, inter- assay precision, linearity and specificity were determined and compared to corresponding ELISA assays. Novel assays were tested on lysates from a variety of commonly utilized cell lines in cancer studies: MCF-7, PBMC, Jurkat, HeLa, and NIH3T3 cells. Results: All four novel assays were significantly more sensitive than the ELISA assay method based upon sample endpoint dilutions. Acceptable precision (&lt;20%CV) was demonstrated for the Akt1/pAkt1 assays in PBMC lysates and for the Erk2/pErk2 assays in MCF-7, HeLa and NIH3T3 lysates. The LLoQ of the Akt1/pAkt1 assay in Jurkat lysates was sufficient to quantify Akt1/pAkt1 from as few as 10–20 cells. Based upon a typical 1mm needle biopsy, this is sufficient to quantify Akt1/pAkt1 from less than 1/1000 th of that biopsy. Conclusions: We show that the Singulex Akt1, pAkt1, Erk2 and pErk2 assays are over 50 fold more sensitive than currently available ELISA assays, and specifically quantify analyte in a variety of cell lysates. We have further demonstrated that the Akt1/pAkt1 assay can quantify from as little as 1/1000th of a typical needle biopsy. Thus, these novel assays greatly improve upon pre- existing technology, providing a new tool for clinical trials investigating Ras/Raf/MEK/ERK and PI3K/PTEN/AKT pathways previously limited by ELISA sensitivity. [Table: see text]
Testing a model of caregiver satisfaction with hospice care in the cancer population.
Authors: Meredith A. MacKenzie, Harleah G. Buck, Salimah H. Meghani, Barbara Riegel
Journal: Journal of Clinical Oncology (2014)

107 Background: Caregiver satisfaction with hospice care is a quality measure for hospice organizations and predicts caregiver and patient health, mortality and resource use. Yet contributing factors to caregiver satisfaction are poorly understood and there are no tested models of caregiver satisfaction in the literature to date. To fill this gap, our aim was to develop and test a model of caregiver satisfaction with hospice care in the cancer population. Methods: This was a retrospective cohort study of national data collected by the National Hospice and Palliative Care Organization (NHPCO) using the Family Evaluation of Hospice Care (FEHC) survey in 2011. We utilized a random sample of 1000 cancer caregivers (70,782 available). An initial theoretical model was developed which posited a relationship between demand (as measured by reported patient symptoms) and satisfaction, modified by caregiver internal and external resources. Structural equation modeling was used to test the model and adjustments made to improve model fit. Results: The final model fit the data well (LR=189.08, df=78; RMSEA=0.04; CFI=0.91; SRMR=0.03). Caregiver satisfaction was predicted by demand – higher perception of demand (more patient symptoms) reduces caregiver satisfaction. Patient age, caregiver race, education, relationship to the patient and length of hospice stay modify this relationship directly – black, non-spousal and more highly educated caregivers are less satisfied, along with caregivers of younger patients and those with shorter lengths of stay. Patient and caregiver age, caregiver sex and length of stay influence this relationship by altering caregiver perception of demand. Younger caregiver and patient age, being a female caregiver and longer length of stay increases caregiver demand, decreasing satisfaction. Note that length of stay works both for and against satisfaction. Conclusions: Caregiver satisfaction is a complex perception that depends on caregiver and patient characteristics, as well as hospice care received. Hospice care providers should consider screening caregiver-patient dyads for “high-risk” characteristics and providing additional supportive measures.
Ongoing clinical development of lapatinib in HER2-positive (HER2+) metastatic breast cancer (MBC): An innovative approach to recruit patients in clinical studies.
Authors: S. R. D. Johnston, K. A. Gelmon, X. B. Pivot, W. J. Gradishar, A. Conner, D. Kothari, P. Legenne, M. Leigh, L. O'Rourke, R. Parikh
Journal: Journal of Clinical Oncology (2011)

TPS105 Background: HER2 gene product is overexpressed in ~20% of breast cancer and is associated with an aggressive phenotype and poor prognosis. Finding suitable patients with HER2+ MBC who adhere to strict protocol criteria, coupled with various competitive clinical trials presents recruitment challenges. A 3-trial approach that enrolls patients in different HER2+ MBC settings with nonoverlapping inclusion criteria may boost recruitment at each center. Methods: Three ongoing global phase III trials are examining the clinical profile of lapatinib (Table). COMPLETE (EGF108919; NCT00667251) is a study of taxane-based chemotherapy with lapatinib or trastuzumab, followed by lapatinib or trastuzumab monotherapy, as first-line therapy for HER2+ MBC patients. The primary endpoint is progression-free survival (PFS); secondary endpoints include overall survival (OS), time to CNS metastases at first progression, and incidence of CNS metastases at progression. EGF114299 (NCT01160211) tests an aromatase inhibitor (AI) in combination with lapatinib, trastuzumab, or both in HR+, HER2+ postmenopausal MBC patients. The primary endpoint compares OS in the lapatinib/trastuzumab/AI arm vs trastuzumab/AI arm. Secondary endpoints include OS in the lapatinib/AI vs trastuzumab/AI arms and lapatinib/trastuzumab/AI vs lapatinib/AI arms, PFS, and biomarker evaluation. CEREBEL (EGF111438; NCT00820222) examines the incidence of CNS metastasis as site of first relapse on lapatinib+capecitabine vs trastuzumab+capecitabine in HER2+ MBC patients previously treated with anthracyclines or taxanes and with an independently reviewed baseline MRI scan confirming no CNS metastases. Secondary endpoints include PFS, time to first CNS metastasis, and OS. Each study is open to accrual and will further elucidate the role of lapatinib in multiple settings of HER2+ MBC. Patient population Line of therapy Trial HER2+ MBC without CNS metastases First line HR- or HR+ not suitable for endocrine therapy HR+ and suitable for endocrine therapy Not suitable for COMPLETE or EGF114299 COMPLETE (EGF108919) EGF114299 CEREBEL (EGF111438) Second line and beyond CEREBEL (EGF111438)