tbuckley/cabot-search huggingface dataset:
Gefitinib (’Iressa’, ZD1839) is a BCRP and MDR1 inhibitor.
Authors: Markos Leggas, John D. Schuetz, John C. Panetta, Brad Johnston, Feng Bai, Sheng Zhou, Brian Sorrentino, Christopher M. Waters, Peter J. Houghton, Clinton F. Stewart
Journal: Cancer Research (2004)

2454   Gefitinib (‘Iressa’, ZD1839) is an orally active EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor). However, recent data suggest that gefitinib and other 4-anilinoquinazoline (4-AQ) derivatives have additional functions that may influence their clinical use (Erlichman, CR, 2001; Schuetz, AACR proc., 2002). We have shown previously that gefitinib strongly increases the otherwise poor and variable oral bioavailability of the cytotoxic camptothecin (CMT) analogs topotecan and irinotecan. It was hypothesized that gefitinib increases oral absorption by inhibiting intestinal efflux transporters such as the ABC transporter breast cancer resistance protein (BCRP), which is known to transport these CMT analogs. The objectives of this study were to determine how gefitinib affects the function of BCRP and evaluate whether gefitinib affects other transporters  in vivo . Bcrp1 deficient mice had higher topotecan bioavailability and decreased systemic clearance indicating that this protein plays a major role in the disposition of topotecan in mice. Treatment of Bcrp1 null mice with topotecan and gefitinib further increased topotecan oral absorption. Transport of topotecan by other transporters was confirmed as Mdr1a/b null mice had higher bioavailability than wild type mice treated with topotecan. Moreover,  in vitro  assays revealed that gefitinib inhibited efflux of Hoechst-33342 from cells engineered to express BCRP, and Calcein-AM efflux from MDR1 transfected cells. Importantly, gefitinib inhibited BCRP and MDR1 function at clinically attainable concentrations (eg 1-5 μM). Gefitinib accumulation in BCRP transfected and vector only transfected Saos-2 cells was not dramatically different at these concentrations, suggesting that gefitinib was functioning as an inhibitor. In conclusion, these studies illustrate the broad implications for the therapeutic combination of gefitinib or other 4-AQ derivatives with agents that are BCRP and MDR1 substrates. Gefitinib may offer a means to normalize variations in oral drug absorption and reverse tumor drug resistance. ‘Iressa’ is a trademark of the AstraZeneca group of companies
Abstract 17099: Additional LDL-C Reduction Achieved With Alirocumab Dose Increase on Background Statin
Authors: John J Kastelein, Dean J Kereiakes, Christopher P Cannon, Harold E Bays, Pascal Minini, L. Veronica Lee, Jaman Maroni, Michel Farnier
Journal: Circulation (2015)

Background: The majority of ODYSSEY Phase 3 clinical trials of the PCSK9 inhibitor alirocumab (ALI) utilized a dose increase strategy designed to individualize LDL-C lowering therapy. Objective: To describe dose response in patients on background statin whose ALI dose was increased from 75 to 150 mg every 2 wks (Q2W) at wk 12. Methods: This analysis included 6 Phase 3, randomized, double-blind, double-dummy trials of 24-104 wks duration (N=1291): ALI vs placebo (COMBO I, FH I+II) or vs ezetimibe 10 mg/day (COMBO II, OPTIONS I+II). Patients on background statin with an initial dose of ALI 75 mg Q2W had dose increase to 150 mg SQ Q2W at wk 12, if at wk 8 LDL-C was ≥70 mg/dL (or &gt;100 mg/dl in OPTIONS studies for patients without prior CHD but other risk factors). LDL-C % reductions from baseline were compared at wk 12 (before dose increase) vs wk 24, including only patients receiving study treatment (on-treatment analysis). Results: Majority of FH and high-risk patients (73.7%) achieved LDL-C &lt;70 or &lt;100 mg/dL (depending on CV risk) with the 75 mg Q2W dose on background statin. ALI dose was increased in 340 (26.3%) patients at wk 12 (Table). Overall, following dose increase at wk 12, an additional 14.2% reduction in LDL-C was seen at wk 24. Across the Phase 3 program, comparable AE rates were seen in patients who received dose increase vs those who did not: 65.8% vs 66.2% in placebo-controlled trials and 54.5% vs 55.9% in ezetimibe-controlled trials; injection site reactions were reported by 3.9% vs 4.9% in placebo-controlled trials and 0.9% vs 0.8% in ezetimibe-controlled trials. Conclusions: The 75 mg Q2W dose is sufficient for most patients to achieve risk-specific LDL-C goals. Increasing ALI dose from 75 to 150 mg Q2W at wk 12 was associated with a 14.2% additional reduction in LDL-C at wk 24, more than double the additional LDL-C reduction achieved by doubling a statin dose. The flexible dosing strategy allows the majority of patients to get to LDL-C goals without affecting the safety profile.
Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors
Authors: Fabio Conforti, Xu Zhang, Guanhua Rao, Tommaso De Pas, Yoko Yonemori, Jose Antonio Rodriguez, Justine N McCutcheon, Raneen Rahhal, Anna T Alberobello, Yisong Wang, Yu-Wen Zhang, Udayan Guha, Giuseppe Giaccone
Journal: Cancer Research (2017)

Exportin 1 (XPO1) mediates nuclear export of many cellular factors known to play critical roles in malignant processes, and selinexor (KPT-330) is the first XPO1-selective inhibitor of nuclear export compound in advanced clinical development phase for cancer treatment. We demonstrated here that inhibition of XPO1 drives nuclear accumulation of important cargo tumor suppressor proteins, including transcription factor FOXO3a and p53 in thymic epithelial tumor (TET) cells, and induces p53-dependent and -independent antitumor activity in vitro Selinexor suppressed the growth of TET xenograft tumors in athymic nude mice via inhibition of cell proliferation and induction of apoptosis. Loss of p53 activity or amplification of XPO1 may contribute to resistance to XPO1 inhibitor in TET. Using mass spectrometry-based proteomics analysis, we identified a number of proteins whose abundances in the nucleus and cytoplasm shifted significantly following selinexor treatment in the TET cells. Furthermore, we found that XPO1 was highly expressed in aggressive histotypes and advanced stages of human TET, and high XPO1 expression was associated with poorer patient survival. These results underscore an important role of XPO1 in the pathogenesis of TET and support clinical development of the XPO1 inhibitor for the treatment of patients with this type of tumors. Cancer Res; 77(20); 5614-27. ©2017 AACR.
ヒト脂肪由来幹細胞/間質細胞増殖のための動的培養プラットフォームとしての脱細胞化した脂肪組織マイクロキャリア【Powered by NICT】
Authors: Yu Claire, Kornmuller Anna, Brown Cody, Hoare Todd, E Flynn Lauren
Journal: Biomaterials (2017)
Reoccurrence of botulinum neurotoxin subtype A3 inducing food-borne botulism, Slovakia, 2015
Authors: Lucia Mad’arová, Brigitte G Dorner, Lars Schaade, Vladimír Donáth, Mária Avdičová, Milota Fatkulinová, Jozef Strhársky, Ivana Sedliačiková, Cyril Klement, Martin B Dorner
Journal: Eurosurveillance (2017)

A case of food-borne botulism occurred in Slovakia in 2015. Clostridium botulinum type A was isolated from three nearly empty commercial hummus tubes. The product, which was sold in Slovakia and the Czech Republic, was withdrawn from the market and a warning was issued immediately through the European Commission’s Rapid Alert System for Food and Feed (RASFF). Further investigation revealed the presence of botulinum neurotoxin (BoNT) subtype BoNT/A3, a very rare subtype implicated in only one previous outbreak (Loch Maree in Scotland, 1922). It is the most divergent subtype of BoNT/A with 15.4% difference at the amino acid level compared with the prototype BoNT/A1. This makes it more prone to evading immunological and PCR-based detection. It is recommended that testing laboratories are advised that this subtype has been associated with food-borne botulism for the second time since the first outbreak almost 100 years ago, and to validate their immunological or PCR-based methods against this divergent subtype.
Composite Primary End Points in Cardiovascular Outcomes Trials Involving Type 2 Diabetes Patients: Should Unstable Angina Be Included in the Primary End Point?
Authors: Nikolaus Marx, Darren K. McGuire, Vlado Perkovic, Hans-Juergen Woerle, Uli C. Broedl, Maximilian von Eynatten, Jyothis T. George, Julio Rosenstock
Journal: Diabetes Care (2017)

Reductions in cardiovascular (CV) outcomes in recently reported trials, along with the recent approval by the U.S. Food and Drug Administration of an additional indication for empagliflozin to reduce the risk of CV death in type 2 diabetes patients with evidence of CV disease, have renewed interest in CV outcome trials (CVOTs) of glucose-lowering drugs. Composite end points are a pragmatic necessity in CVOTs to ensure that sample size and duration of follow-up remain reasonable. Combining clinical outcomes into a composite end point increases the numbers of events ascertained and thus statistical power and precision. Historically, composite CV end points in diabetes trials have included a larger number of components, while more recent CVOTs almost exclusively use a composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke-the so-called three-point major adverse CV event (3P-MACE) composite-or add hospitalization for unstable angina (HUA) to these three outcomes (4P-MACE). The inclusion of HUA increases the number of events for analysis, but noteworthy disadvantages include clinical subjectivity in ascertainment of HUA and its lower prognostic relevance compared with CV death, MI, or stroke. Furthermore, results from recent CVOTs indicate that glucose-lowering agents seem to have minimal impact on HUA. Its inclusion therefore potentially favors a shift of the hazard ratio (HR) toward the null, which is especially problematic in trials designed to demonstrate noninferiority. The primary outcome of 3P-MACE may offer a better balance than 4P-MACE between statistical efficiency, operational complexity, the likelihood of diagnostic precision (and therefore clinical relevance) for each of the component outcomes, clinical importance, and the aim to adequately capture any potential treatment effect of the intervention. Nevertheless, as individual medications may mechanistically differ in their impact on CV outcomes, no particular individual or composite end point can be seen as a "gold standard" for CVOTs of all glucose-lowering drugs.
<i>MITF</i>-High and <i>MITF</i>-Low Cells and a Novel Subpopulation Expressing Genes of Both Cell States Contribute to Intra- and Intertumoral Heterogeneity of Primary Melanoma
Authors: Marie Ennen, Céline Keime, Giovanni Gambi, Alice Kieny, Sebastien Coassolo, Christelle Thibault-Carpentier, Fanny Margerin-Schaller, Guillaume Davidson, Constance Vagne, Dan Lipsker, Irwin Davidson
Journal: Clinical Cancer Research (2017)

Purpose: Understanding tumor heterogeneity is an important challenge in current cancer research. Transcription and epigenetic profiling of cultured melanoma cells have defined at least two distinct cell phenotypes characterized by distinctive gene expression signatures associated with high or low/absent expression of microphthalmia-associated transcription factor (MITF). Nevertheless, heterogeneity of cell populations and gene expression in primary human tumors is much less well characterized.Experimental Design: We performed single-cell gene expression analyses on 472 cells isolated from needle biopsies of 5 primary human melanomas, 4 superficial spreading, and one acral melanoma. The expression of MITF-high and MITF-low signature genes was assessed and compared to investigate intra- and intertumoral heterogeneity and correlated gene expression profiles.Results: Single-cell gene expression analyses revealed varying degrees of intra- and intertumor heterogeneity conferred by the variable expression of distinct sets of genes in different tumors. Expression of MITF partially correlated with that of its known target genes, while SOX10 expression correlated best with PAX3 and ZEB2 Nevertheless, cells simultaneously expressing MITF-high and MITF-low signature genes were observed both by single-cell analyses and RNAscope.Conclusions: Single-cell analyses can be performed on limiting numbers of cells from primary human melanomas revealing their heterogeneity. Although tumors comprised variable proportions of cells with the MITF-high and MITF-low gene expression signatures characteristic of melanoma cultures, primary tumors also comprised cells expressing markers of both signatures defining a novel cell state in tumors in vivoClin Cancer Res; 23(22); 7097-107. ©2017 AACR.
RUNX3 antagonizes the effect of the Notch signalling pathway in the development and maintenance of the intestinal epithelium
Authors: Tun Ko, Linda Chuang, Kosei Ito, Yoshiaki Ito
Journal: Clinical Cancer Research (2007)

B2   RUNX3 is a tumor suppressor where the loss of its expression and the mislocalization of its protein have been linked to the pathogenesis of increasing number of cancers. Recent studies have shown that the Notch signalling pathway plays an important role in regulating the intestinal epithelium development. Mice harbouring the constitutively active Notch Intracellular Domain (NICD), a known oncogene, as a transgene display increased populations of proliferating intestinal epithelial precursor cells. Interestingly, our RUNX3 null mice also show a similar phenotype. We, therefore, hypothesize that RUNX3 antagonizes the effect of the Notch signalling pathway in the development and maintenance of the intestinal epithelium. Our data show that the intestinal epithelia of Runx3 null mice, when compared to those of wildtype mice, exhibit upregulation in the gene expression of Hes1 which is a well-known gene target of the Notch signaling pathway. The gene expression of Hes1 is activated by a transcription activation complex containing NICD, RBP-Jk and Mastermind-like 1 (MAML1). We are able to show that RUNX3 associates with RBP-Jk, MAML1 and NICD. Furthermore, such associations result in RUNX3 inhibiting Hes1 gene expression. Finally, we will be examining the possibility that RUNX3 functions as a tumor suppressor in human colorectal cancer by inhibiting the Notch-dependent proliferative effect on human colorectal cancer cell lines.
Prevalence of Pubic Hair Grooming–Related Injuries and Identification of High-Risk Individuals in the United States
Authors: Matthew D. Truesdale, E. Charles Osterberg, Thomas W. Gaither, Mohannad A. Awad, Molly A. Elmer-DeWitt, Siobhan Sutcliffe, Isabel Allen, Benjamin N. Breyer
Journal: JAMA Dermatology (2017)

<h3>Importance</h3> Pubic hair grooming is a common practice that can lead to injury and morbidity. <h3>Objective</h3> To identify demographic and behavioral risk factors associated with pubic hair grooming–related injuries to characterize individuals with high risk of injury and develop recommendations for safe grooming practices. <h3>Design, Setting, and Participants</h3> This cross-sectional study conducted a national survey of noninstitutionalized US adults (aged 18-65 years). The web-based survey was conducted through a probability-based web panel designed to be representative of the US population. Data were collected in January 2014 and analyzed from August 1, 2016, through February 1, 2017. <h3>Main Outcomes and Measures</h3> Grooming-related injury history (yes or no), high-frequency injuries (&gt;5 lifetime injuries), and injury requiring medical attention. <h3>Results</h3> Among the 7570 participants who completed the survey (4198 men [55.5%] and 3372 women [44.5%]; mean (SD) age, 41.9 [18.9] years), 5674 of 7456 (76.1%) reported a history of grooming (66.5% of men and 85.3% of women [weighted percentages]). Grooming-related injury was reported by 1430 groomers (weighted prevalence, 25.6%), with more women sustaining an injury than men (868 [27.1%] vs 562 [23.7%];<i>P</i> = .01). Laceration was the most common injury sustained (818 [61.2%]), followed by burn (307 [23.0%]) and rashes (163 [12.2%]). Common areas for grooming-related injury for men were the scrotum (378 [67.2%]), penis (196 [34.8%]), and pubis (162 [28.9%]); for women, the pubis (445 [51.3%]), inner thigh (340 [44.9%]), labia majora (369 [42.5%]), and perineum (115 [13.2%]). After adjustment for age, duration of grooming, hairiness, instrument used, and grooming frequency, men who removed all their pubic hair 11 times or more during their lifespan had an increased risk for grooming injury (adjusted odds ratio [AOR], 1.97; 95% CI, 1.28-3.01;<i>P</i> = .002) and were prone to repeated high-frequency injuries (AOR, 3.89; 95% CI, 2.01-7.52;<i>P</i> &lt; .001) compared with groomers who did not remove all their pubic hair. Women who removed all their pubic hair 11 times or more had increased odds of injury (AOR, 2.21; 95% CI, 1.53-3.19;<i>P</i> &lt; .001) and high-frequency injuries (AOR, 2.98; 95% CI, 1.78-5.01;<i>P</i> &lt; .001) compared with groomers who do not remove all their pubic hair. In women, waxing decreased the odds of high-frequency injuries (AOR, 0.11; 95% CI, 0.03-0.43;<i>P</i> = .001) compared with nonelectric blades. In total, 79 injuries among 5674 groomers (1.4%) required medical attention. <h3>Conclusions and Relevance</h3> Grooming frequency and degree of grooming (ie, removing all pubic hair) are independent risk factors for injury. The present data may help identify injury-prone groomers and lead to safer grooming practices.
Abstract 11436: Empagliflozin Early Reverses Metabolic and Cardiovascular Overload in Type-2 Diabetics With Chronic Heart Failure
Authors: Tatsuaki Murakami, Kazuo Ohsato
Journal: Circulation (2016)

Introduction: Diabetes mellitus is thought to be highly involved in complex metabolic and cardiovascular disturbances, however the effective therapies in patients with diabetes mellitus and chronic heart failure have not been established. Hypothesis: We assessed hypothesis that empagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, a recently developed antidiabetic agent, promptly reverses complex metabolic and cardiac disturbances in patients with type-2 diabetes mellitus and chronic heart failure. Methods: Type-2 diabetic patients with chronic heart failure were randomized to group-E where they received antidiabetic therapy with empagliflozin for 2 weeks, or to group-C where they received enhanced therapies with conventional antidiabetic agents without an SGLT2 inhibitor. We evaluated practical metabolic and cardiovascular variables including NT-proBNP and ultrasonic quantified diameter of inferior vena cava (IVCD). Changes in practical metabolic and cardiovascular variables were compared between the 2 groups. Results: The patients in group-E (n=22) manifested improvements in metabolic and cardiovascular variables represented by blood glucose (-35.3±18.2 mg/dL, p=0.02), systolic blood pressure (-7.4±1.5 mmHg, p=0.01), body weight (-1.5±0.7 kg, p=0.01), and NT-proBNP (pg/mL; from 636.3±612.8 to 433.4±437.7, p=0.03), while those in group-C (n=11) showed no improvement except for blood glucose. Heart rate remained unchanged in both groups. The changes in body weight was characterized by those in water weight as well as those in fat weight, but not by those in muscle weight. Respiratory variation in IVCD increased in group-E (%; from 50.4±7.1 to 64.2±8.8, p=0.03), while it remained unchanged in group-C. Changes of respiratory variation in IVCD or NT-proBNP in group-E did not correlate to those of blood glucose (IVCD: r=0.09, p=0.88, NT-proBNP: r=0.14, p=0.68). Conclusions: These results indicate that empagliflozin in diabetic patients with chronic heart failure early reverses metabolic and cardiovascular overload independent of glucose lowering, which may provide novel potential benefit for management of progressive metabolic and cardiovascular disturbances in type-2 diabetics with chronic heart failure.
Abstract #1154: IL-6 induces IL-10 expression and promotes cancer progression after activation of STAT3 in human colon carcinoma cells
Authors: Kamohara Hidenobu, Shunji Suzuki, Seiji Mita, Takatoshi Ishiko, Yukiharu Hiyoshi, Hideo Baba
Journal: Cancer Research (2009)

Introduction: Cytokines are produced by various immunnocompetent cells, as well as cancer cells. Some studies have been demonstrated IL-6 and IL-10 play an important role in evading host immune surveillance in tumor microenvironment, but interactions of both cytokines has not been fully understood. Therefore, the aim of this study is to reveal two mechanisms by IL-6 in human colon carcinoma cells. One is the system of IL-10 regulation by IL-6 and IFN\#947;, another is the biological function of IL-6 after activation of STAT3 in colon carcinoma cells. Methods and Results: Firstly, we examined the effect of proinflammatory cytokines on IL-10 expression in human colon carcinoma cells (COLO205). COLO205 cells were stimulated with or without cytokines. Northern blotting and ELISA revealed TNF\#945;, IL-1\#946;, or IL-6 upregulated IL-10 mRNA and protein expression. Especially, IL-6 was a potent inducer of IL-10. IL-6 induced IL-10 production in a dose dependent manner by ELISA. IL-10 was enhanced after co-stimulation with IL-6 and either TNF\#945;, IL-1\#946; or IL-8. By contrast, IFN\#947; inhibited IL-6 induced production of IL-10. IFN\#947; downregulated IL-6 receptor \#945; mRNA expression by Northern blotting. These results indicated IFN\#947; could suppress signal transduction by IL-6. Nextly, we evaluated the biological role of IL-6 in COLO205 cells. IL-6 does-dependently significantly promoted cell proliferation after 60 hr incubation by WTS-1 assay. IL-6 significantly promoted chemoinvasion by using matrigel coated insert well system. NIH3T3 cell supernatants were added in a lower chamber as a chemoattratant. Western-Immunoprecipitation analysis identified IL-6 does-dependently activated phosphorylation of STAT3. Its maximum effect was observed in 20-30 min after the stimulation with 10-100 ng/ml concentration of IL-6. Conclusion: Induction of tumor-derived IL-10 by IL-6 could act on host immune cells, resulting in immune suppression through a TH1/TH2 cytokines balance in tumor microenvironment. Secreted IL-6 from various cells surrounding tumor tissues would contribute to colon cancer progression after activation of STAT3. IL-6 and IL-10 would be one of therapeutic molecular targets in future colon cancer treatment.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1154.
Do systematic reviews still exclude studies with “no relevant outcome data”?
Authors: Kerry M Dwan, Paula R Williamson, Jamie J Kirkham
Journal: BMJ (2017)

The BMJ published an investigation into the prevalence and impact of outcome reporting bias in randomised controlled trials included in Cochrane systematic reviews in 2010.1 It concluded that studies should not be excluded from reviews on the basis that there was “no relevant outcome data” (NROD) as failure to report review outcomes does not mean that the outcomes were not measured. Moreover, this recommendation is an expected methodological standard for Cochrane intervention reviews.2 Quality assurance screening of reviews by the Cochrane Editorial Unit has found that reviews still exclude studies on the basis of NROD. We investigated the proportion of Cochrane reviews excluding studies on the basis of NROD and whether the proportion …
Mechanisms of resistance to the BCR-ABL1 allosteric inhibitor asciminib
Authors: W Qiang, O Antelope, M S Zabriskie, A D Pomicter, N A Vellore, P Szankasi, D Rea, J M Cayuela, T W Kelley, M W Deininger, T O’Hare
Journal: Leukemia (2017)