tbuckley/cabot-search huggingface dataset:
Dasatinib pharmacokinetics and exposure-response (E-R): Relationship to safety and efficacy in patients (pts) with chronic myeloid leukemia (CML)
Authors: X. Wang, A. Hochhaus, H. M. Kantarjian, S. Agrawal, A. Roy, M. Pfister, T. Chen, E. Bleickardt, C. Nicaise, N. Shah
Journal: Journal of Clinical Oncology (2008)

3590 Background: Dasatinib is 325-fold more potent than imatinib and 16-fold more potent than nilotinib against BCR-ABL in vitro. In the randomized, dose optimization Study CA180–034 of pts with chronic phase CML, the 100 mg once daily dose was associated with similar efficacy but less frequent pleural effusion (pl eff), cytopenia, dose reduction, and interruption than the other three dosing schedules. Methods: The clinical study design has been previously described. Here we present population pharmacokinetic (PPK) and E-R analyses. Exposure measures examined included: mean steady-state (ss) concentration (Cavg), ss trough concentration (Cmin), and ss peak concentration (Cmax). E-R was characterized using a Cox proportional-hazards model. Covariates examined included: age, gender, body weight (PPK only), and history of cardiac disease (E-R only). Results: Of the 670 pts randomized, samples from 567 were evaluated for PK. Of these, 94 had a pl eff, 271 required dose reduction and 376 dose interruption. PPK analysis showed that exposure to dasatinib did not depend upon age, gender, or body weight, but was highly dependent on the dosing schedule. E-R analysis showed that the risk of pl eff was greater with increasing Cmin (2.33-fold for each doubling of Cmin, p<0.001) and increasing age (1.93-fold for each decade of life, p<0.001). Cmax and Cavg were not statistically significant predictors of pl eff. Cmin was also correlated with dose reduction and interruption, but not with efficacy. Conclusion: Cmin appears to correlate strongly with dasatinib toxicity but not with efficacy. The lowest Cmin was achieved with the 100 mg once-daily dose regimen, which has been shown to have the optimal therapeutic index among the regimens tested. Mean (CV%) ng/mL 100 mg QD 50 mg BID 140 mg QD 70 mg BID Cmin 2.69 (26) 5.13 (24) 3.86 (28) 6.9 (24) Cmax 66.85 (56) 37.6 (48) 94.09 (55) 53.71 (46) Cavg 14.16 (20) 14.32 (18) 19.96 (18) 20.34 (17) Cmin <2.5 Cmin 2.5-<5.0 Cmin >5.0 Pleural effusion (%) 4 14 25 Dose reduction (%) 26 45 59 Dose interruption (%) 51 64 75 Major cytogenetic response (%) 69 63 62 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb, Novartis Bristol-Myers Squibb, Innovive, Merck, Novartis, Wyeth
Laser Treatment of Nongenital Verrucae
Authors: Jannett Nguyen, Dorota Z. Korta, Lance W. Chapman, Kristen M. Kelly
Journal: JAMA Dermatology (2016)

<h3>Importance</h3> Although cutaneous warts are common lesions, full remission is not always achieved with conventional therapies. Laser modalities including carbon dioxide (CO<sub>2</sub>), erbium:yttrium-aluminum-garnet (Er:YAG), pulsed dye (PDL), and Nd:YAG have been investigated as alternative treatments for warts. <h3>Objective</h3> To review the use and efficacy of lasers for treating nongenital cutaneous warts. <h3>Evidence Review</h3> Published randomized clinical trials (RCTs), cohort studies, case series, and case reports involving laser treatment of nongenital warts were retrieved by searching PubMed with no date limits. Quality ratings of studies were based on a modified version of the Oxford Centre for Evidence-Based Medicine scheme for rating individual studies. A higher emphasis was placed on RCTs and prospective cohort studies with large sample sizes and detailed methodology. <h3>Findings</h3> There were 35 studies published between 1989 and 2015 that comprised an aggregate of 2149 patients. Simple and recalcitrant nongenital warts treated with lasers show variable response rates (CO<sub>2</sub>laser, 50%-100%; Er:YAG laser, 72%-100%; PDL, 47%-100%; and Nd:YAG laser, 46%-100%). Current RCTs suggest that PDL is equivalent to conventional therapies such as cryotherapy and cantharidin. Combination therapies with lasers and other agents including bleomycin, salicylic acid, and light-emitting diode have shown some success. <h3>Conclusions and Relevance</h3> Lasers can be an effective treatment option for both simple and recalcitrant warts. The lasers most studied for this purpose are CO<sub>2</sub>, PDL, and Nd:YAG, and of these, PDL has the fewest adverse effects. Currently, use of lasers for wart treatment is limited by lack of established treatment guidelines. Future studies are needed to compare laser modalities with each other and with nonlaser treatment options, and to establish optimal treatment protocols.
Preliminary Observations on the Effect of Human Leukocyte Interferon in Non-Hodgkin's Lymphoma
Authors: Thomas C. Merigan, Karol Sikora, James H. Breeden, Ronald Levy, Saul A. Rosenberg
Journal: New England Journal of Medicine (1978)

IN laboratory animals both endogenously induced and passively administered interferon have inhibitory effects on a wide variety of tumors, including those caused by oncogenic viruses.1 2 3 4 Such effects are most striking when the interferon is administered prophylactically, but interferon has occasionally been observed to have therapeutic effects. In the latter situation, its continued administration appears required for maintenance of the beneficial effect. Studies by Strander and his associates at the Karolinska Hospital in a variety of solid tumors, particularly osteogenic sarcoma,5 have suggested that human leukocyte interferon may have beneficial effects in man.In recent years it has also been recognized . . .
Control of Lung Metastasis Progression in Mice: Role of Growth Kinetics of 3LL Lewis Lung Carcinoma and Host Immune Reactivity&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;, &lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: E Gorelik, S Segal, M Feldman
Journal: JNCI Journal of the National Cancer Institute (1980)

Studies were made of the growth of metastases of the 3LL Lewis lung carcinoma in tumor-bearing and tumor-excised C57BL/6 mice after intrafootpad inoculation of different cell doses to the intact or immunosuppressed host. The total metastatic volume was higher in tumor-bearing mice given transplants of low doses of 3LL cells (3 X 10(4)- 1 X 10(5)) than in mice receiving high doses of cells (1 X 10(6)-5 X 10(6)). The growth of postoperative lung metastases depends on the size of the removal of local tumors and the rate of their development. Surgical removal of small, medium, or large local tumors, respectively, resulted in the development of smaller, similar, or larger volumes of pulmonary metastases compared to the metastases in tumor-bearing mice not having surgery. Accelerated growth of postoperative metastases in mice inoculated with low doses of 3LL cells was observed following removal of the local tumors of more than 310 mm3. The same effect was observed on mice given transplants of high doses of 3LL cells only when the removed local tumors had reached a volume of more than 550 mm3. In immunologically suppressed tumor-bearing mice, acceleration of the metastatic growth in the lungs was observed independently of the inoculum size. Even in the immunosuppressed mice, the growth of metastases was not optimal, and an additional stimulus for their growth was achieved following the removal of local tumors. This finding suggested that immunologic and nonimmunologic mechanisms were involved in the control of the metastatic growth of 3LL tumors in mice.
Validation Of a Multi-Diagnostic Approach Including Flow Cytometry To Identify Specific Risk Categories Within Low and Intermediate-1 Risk Myelodysplastic Syndromes Within a Prospective Clinical Trial: A Study On Behalf Of The HOVON89 Study Group
Authors: Eline M.P. Cremers, Theresia M. Westers, Canan Alhan, Claudia Cali, Heleen A. Visser-Wisselaar, Dana A Chitu, Marian J.P.L. Stevens-Kroef, Pedro Silva Coelho, Edo Vellenga, Saskia K. Klein, Pierre W. Wijermans, Georgine E. de Greef, Martijn R. Schaafsma, M Marwijk Kooy, Petra Muus, Gert J. Ossenkoppele, Joop H. Jansen, Arjan A. van de Loosdrecht
Journal: Blood (2013)
Abstract 191: Ras GTPase-activating Protein SH3 Domain Binding Protein 1 (G3BP1) Regulates The Induction Of Stress Granules During Cardiac Hypertrophy
Authors: Danish Sayed
Journal: Circulation Research (2014)

Stress granules (SGs) are dynamic, microscopically visible, cytoplasmic bodies that play a major role in mRNA metabolism (e.g. sorting, storage, decay) and induced in cells during stress conditions like starvation, oxidative strain or growth. With substantial role in cancer and neurodegenerative diseases, these granules have never been studied during cardiac hypertrophy, or in the heart in general. Several studies have identified independent proteins, mostly mRNA binding proteins that are part of these granules, some of which are sufficient to nucleate the assembly in quiescent cells even without stress. One such mRNA binding protein is Ras GTPase-activating protein SH3 domain binding protein 1 (G3BP1), which increases during cardiac hypertrophy via posttranscriptional regulation. Thus, we hypothesized that G3BP1 might be involved in the induction of SGs during hypertrophy and hence in regulating mRNA processing and gene expression. Our aim was to investigate, 1) if these SGs appear in hypertrophied hearts and 2) if G3BP1 is necessary and sufficient to induce them during hypertrophic stimuli. In vivo staining of TIA-1/TIAR (SG marker) in mouse hearts subjected to sham or transaortic coarctation (TAC) surgeries showed accumulation of these granules with cardiac hypertrophy. Similar induction was seen in isolated, cultured, rat neonatal cardiac myocytes with hypertrophic stimulation (Endothelin1) or overexpression of G3BP1 alone (&gt;60% of myocytes stained for SG). Conversely, switch to growth-inhibited conditions or knockdown of G3BP1 in hypertrophying myocytes was sufficient to prevent the assembly of these structures. Co-staining with other components of these granules like TIA-1/TIAR or proteins specific to P bodies, like decapping enzyme 1 validated these structures as SGs in cardiac myocytes. Interestingly, a long non-coding RNA, Gas5 (Growth Arrest Specific 5) that is validated binding partner of G3BP1 sequestered to perinuclear focal locations in myocytes stimulated with ET1, suggesting growth-induced recruitment to SGs. While we are still in process of examining G3BP1 targets that are recruited to SGs and their role in hypertrophy development, we have concluded that G3BP1 is required for the induction of SGs during cardiac hypertrophy
Pharmacogenetics of tamoxifen in relation to disease-free survival in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial.
Authors: V. O. Dezentje, R. H. Van Schaik, J. M. Vletter-Bogaartz, J. A. Wessels, E. T. Hille, C. Seynaeve, C. J. Van De Velde, J. W. Nortier, H. Gelderblom, H. Guchelaar
Journal: Journal of Clinical Oncology (2010)

510 Background: Retrospective studies on the relationship between CYP2D6 genotype and tamoxifen efficacy show conflicting results (Dezentje et al., Clin Cancer Res 2009:15;15-21). Negative studies have been criticized because of heterogeneous populations, lack of controlling for possible confounders and of systematic documentation of treatment adherence and outcome measures. Well documented studies on homogeneous populations with a more comprehensive pathway approach are imperative. Methods: 747 Dutch patients who were randomized to receive tamoxifen followed by exemestane after 2.5 to 3 years within the TEAM Trial were genotyped for 29 germline genetic variants in 12 candidate genes encoding enzymes that are involved in the metabolic and pharmacodynamic pathway of tamoxifen. These variants were related to disease free survival (DFS) during tamoxifen use (censored at the time of switch to exemestane). A multivariable Cox regression was used to adjust for clinically relevant factors. Results: The clinical characteristics of the genotyped patients were similar to the entire Dutch TEAM cohort randomized to tamoxifen (n = 1,379). DFS was associated with UGT2B15*2 [Vt/Vt + Wt/Vt vs. Wt/Wt: HR = 0.51 (0.27-0.95); p = 0.034] and the estrogen receptor-1 polymorphism ESR1 PvuII [gene-dose effect: HR = 1.72 (1.10-2.69); p = 0.017]. In the univariable analysis CYP2C19*2 was associated with DFS [Vt/Vt vs Wt/Vt + Wt/Wt: HR = 3.85 (1.64-9.05); p = 0.002]. However, this association lost significance when adjusted for the ESR1 PvuII polymorphism. No association was found between the CYP2D6 genotypes and DFS. Conclusions: This translational study suggests that common and therefore relevant polymorphisms in UGT2B15 and the estrogen receptor-1 impact DFS in breast cancer patients treated with adjuvant tamoxifen. The previously reported association between CYP2D6 genotype and tamoxifen efficacy was not confirmed in our study. No significant financial relationships to disclose.
Pre-Procedural 6-Min Walk Test as a Mortality Predictor in Patients Undergoing Transcatheter Mitral Valve Repair
Authors: Mike Saji, Gorav Ailawadi, Timothy S. Welch, Emily Downs, Damien J. LaPar, Ravi Ghanta, Jamie L.W. Kennedy, Mohammad Abuannadi, Andrew J. Buda, James D. Bergin, John A. Kern, John M. Dent, Michael Ragosta, D. Scott Lim
Journal: Journal of the American College of Cardiology (2016)
TCTAP A-072 Early Results of Percutaneous Closure of the Atrial Septal Defects with Occlutech Figulla Devices: A Single Center Experience
Authors: Hye Won Kwon, Hyo Bin Lim, Seong-Ho Kim, Sang Yun Lee, So Ick Jang, Su-Jin Park, Mi Kyoung Song
Journal: Journal of the American College of Cardiology (2016)
Association of Psoriasis With the Risk for Type 2 Diabetes Mellitus and Obesity
Authors: Ann Sophie Lønnberg, Lone Skov, Axel Skytthe, Kirsten Ohm Kyvik, Ole Birger Pedersen, Simon Francis Thomsen
Journal: JAMA Dermatology (2016)

<h3>Importance</h3> Psoriasis has been shown to be associated with overweight and type 2 diabetes mellitus. The genetic association is unclear. <h3>Objective</h3> To examine the association among psoriasis, type 2 diabetes mellitus, and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) in twins. <h3>Design, Setting, and Participants</h3> This cross-sectional, population-based twin study included 34 781 Danish twins, 20 to 71 years of age. Data from a questionnaire on psoriasis was validated against hospital discharge diagnoses of psoriasis and compared with hospital discharge diagnoses of type 2 diabetes mellitus and self-reported BMI. Data were collected in the spring of 2002. Data were analyzed from January 1 to October 31, 2014. <h3>Main Outcomes and Measures</h3> Crude and adjusted odds ratios (ORs) were calculated for psoriasis in relation to type 2 diabetes mellitus, increasing BMI, and obesity in the whole population of twins and in 449 psoriasis-discordant twins. Variance component analysis was used to measure genetic and nongenetic effects on the associations. <h3>Results</h3> Among the 34 781 questionnaire respondents, 33 588 with complete data were included in the study (15 443 men [46.0%]; 18 145 women [54.0%]; mean [SD] age, 44.5 [7.6] years). After multivariable adjustment, a significant association was found between psoriasis and type 2 diabetes mellitus (odds ratio [OR], 1.53; 95% CI, 1.03-2.27;<i>P</i> = .04) and between psoriasis and increasing BMI (OR, 1.81; 95% CI, 1.28-2.55;<i>P</i> = .001 in individuals with a BMI&gt;35.0). Among psoriasis-discordant twin pairs, the association between psoriasis and obesity was diluted in monozygotic twins (OR, 1.43; 95% CI, 0.50-4.07;<i>P</i> = .50) relative to dizygotic twins (OR, 2.13; 95% CI, 1.03-4.39;<i>P</i> = .04). Variance decomposition showed that additive genetic factors accounted for 68% (95% CI, 60%-75%) of the variance in the susceptibility to psoriasis, for 73% (95% CI, 58%-83%) of the variance in susceptibility to type 2 diabetes mellitus, and for 74% (95% CI, 72%-76%) of the variance in BMI. The genetic correlation between psoriasis and type 2 diabetes mellitus was 0.13 (−0.06 to 0.31;<i>P</i> = .17); between psoriasis and BMI, 0.12 (0.08 to 0.19;<i>P</i> &lt; .001). The environmental correlation between psoriasis and type 2 diabetes mellitus was 0.10 (−0.71 to 0.17;<i>P</i> = .63); between psoriasis and BMI, −0.05 (−0.14 to 0.04;<i>P</i> = .44). <h3>Conclusions and Relevance</h3> This study determines the contribution of genetic and environmental factors to the interaction between obesity, type 2 diabetes mellitus, and psoriasis. Psoriasis, type 2 diabetes mellitus, and obesity are also strongly associated in adults after taking key confounding factors, such as sex, age, and smoking, into account. Results indicate a common genetic etiology for psoriasis and obesity.
Intrauterine Inflammation and Maternal Exposure to Ambient PM <sub>2.5</sub> during Preconception and Specific Periods of Pregnancy: The Boston Birth Cohort
Authors: Rebecca Massa Nachman, Guangyun Mao, Xingyou Zhang, Xiumei Hong, Zhu Chen, Claire Sampankanpanich Soria, Huan He, Guoying Wang, Deanna Caruso, Colleen Pearson, Shyam Biswal, Barry Zuckerman, Marsha Wills-Karp, Xiaobin Wang
Journal: Environmental Health Perspectives (2016)

Background:Prenatal exposure to ambient PM2.5, (i.e., fine particulate matter, aerodynamic diameter ≤ 2.5 μm) has been associated with preterm birth and low birth weight. The association between prenatal PM2.5 exposure and intrauterine inflammation (IUI), an important risk factor for preterm birth and neurodevelopmental outcomes, has not been evaluated.Objectives:We aimed to investigate the association between maternal exposure to PM2.5 and IUI in the Boston Birth Cohort, a predominantly urban low-income minority population.Methods:This analysis included 5,059 mother–infant pairs in the Boston Birth Cohort. IUI was assessed based on intrapartum fever and placenta pathology. PM2.5 exposure was assigned using data from the U.S. EPA's Air Quality System. Odds ratios (OR) and 95% confidence intervals (CI) quantified the association of maternal PM2.5 exposure during preconception and various periods of pregnancy with IUI.Results:Comparing the highest with the lowest PM2.5 exposure quartiles, the multi-adjusted association with IUI was significant for all exposure periods considered, including 3 months before conception (OR = 1.52; 95% CI: 1.22, 1.89), first trimester (OR = 1.93; 95% CI: 1.55, 2.40), second trimester (OR = 1.67; 95% CI: 1.35, 2.08), third trimester (OR = 1.53; 95% CI: 1.24, 1.90), and whole pregnancy (OR = 1.92; 95% CI: 1.55, 2.37).Conclusions:Despite relatively low exposures, our results suggest a monotonic positive relationship between PM2.5 exposure during preconception and pregnancy and IUI. IUI may be a sensitive biomarker for assessing early biological effect of PM2.5 exposure on the developing fetus.Citation:Nachman RM, Mao G, Zhang X, Hong X, Chen Z, Soria CS, He H, Wang G, Caruso D, Pearson C, Biswal S, Zuckerman B, Wills-Karp M, Wang X. 2016. Intrauterine inflammation and maternal exposure to ambient PM2.5 during preconception and specific periods of pregnancy: the Boston Birth Cohort. Environ Health Perspect 124:1608–1615; http://dx.doi.org/10.1289/EHP243
Abstract P003: Comparison of Ideal Cardiovascular Health Status Across National Representative Cohorts: A Systematic Review
Authors: Adnan Younus, Rehan Malik, Rameez Ahmad, Shozab Ali, Muhammad Aziz, Syed MS. Bukhari, Oluseye Ogunmoroti, Chukwuemeka Osondu, Muhammad Amir Younus, Lara Roberson, Muhammad A. Latif, Choudhry Humayun, Emir Veledar, Khurram Nasir
Journal: Circulation (2016)

Introduction: In 2010, the American Heart Association set 2020 national goals for promoting cardiovascular health (CVH), emphasizing measurement of reproducible health behaviors and health factors and attaining ideal CVH status. In recent years, significant emphasis has been placed on adopting these metrics globally to monitor strategies to improve CVH. In this study, we synthesize available data to compare distribution of CVH metric metrics detailed in national representative cohorts a focus on presence of ideal CVH (ICVH). Method: A MEDLINE database search was conducted using relevant free text terms such as “life’s simple 7”, “AHA 2020”, “American Heart Association 2020” and “Ideal cardiovascular health”. Ideal CVH was defined as 6-7 ideal factors; conversely poor ICVH was considered as 0-1 ideal factors. Results: The pooled data comprised of 7 cross-national cohorts with a total of 152289 participants from India, United States, China, Spain, Korea, Luxembourg and Republic of Srpska. Significant variations in individual ideal CVH metrics were noted. Across population cohorts, diet metric consistently appeared suboptimal apart from Korea in which 55% participants reported ideal diet status. Overall majority population in each of the 7 cross-national cohorts lied in the range having 2-5 ideal CV health metrics (79-88%). A very small percentage of each population had 0-1 METRICS, with Spain, USA and Republic of Srpska having the highest percentage (18%) of reported poor ICVH. On the other hand, only representative cohorts from China and Korea reported ideal CVH status in more than 10% population. Conclusion: Overall suboptimal proportion of national representative cohorts have reported ideal CVH status. Significant efforts are needed to streamline current policies for enhancing CVH and sharpening focus interventions that will yield the greatest sustainable improvement in population CVH status.
Idiopathic Cardiac Hypertrophy
Authors: Richard A. Serbin, Bernard Chojnacki
Journal: New England Journal of Medicine (1955)

IN most cases of cardiac hypertrophy an antecedent cause, such as hypertension, valvular disease or coronary arteriosclerosis, is easily demonstrable. Hypertrophy in certain patients with congestive heart failure exists without evidence of any of the known causes of heart disease.The first recorded case of so-called idiopathic hypertrophy of the heart was described in 1901 by Josserand and Gallavardin.1 In 1944 Levy and Von Glahn2 collected 14 cases from the literature and added 10 of their own. Other contributors3 4 5 6 7 8 9 10 11 12 13 14 15 16 have brought the total number of cases in the literature to 46. Three more cases are presented below.Case ReportsCASE . . .
Tissue in Cube: In Vitro 3D Culturing Platform with Hybrid Gel Cubes for Multidirectional Observations
Authors: Masaya Hagiwara, Tomohiro Kawahara, Rina Nobata
Journal: Advanced Healthcare Materials (2016)

An in vitro 3D culturing platform enabling multidirectional observations of 3D biosamples is presented. The 3D structure of biosamples can be recognized without fluorescence. The cubic platform employs two types of hydrogels that are compatible with conventional culture dishes or well plates, facilitating growth in culture, ease of handling, and viewing at multiple angles. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.