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https://www.readbyqxmd.com/read/29317226/oral-delivery-of-highly-lipophilic-poorly-water-soluble-drugs-self-emulsifying-drug-delivery-systems-sedds-to-improve-oral-absorption-and-enable-high-dose-toxicology-studies-of-a-cetp-inhibitor-in-preclinical-species
#1
Xue-Qing Chen, Theresa Ziemba, Christine Huang, Ming Chang, Carrie Xu, Jennifer X Qiao, Tammy C Wang, Heather J Finlay, Mark E Salvati, Leonard P Adam, Olafur Gudmundsson, Michael J Hageman
BMS-A is a highly lipophilic compound (clogP 10.5) with poor aqueous solubility (< 0.0001 mg/mL at pH 6.5). The compound exhibits low oral exposure when dosed as cosolvent solution formulations. The purpose of this study was to evaluate lipid-based formulations for enabling high-dose toxicology studies and enhancing toxicology margins of BMS-A in pre-GLP studies in non-rodent species. The solubility of BMS-A was screened in lipid and cosolvent/surfactant excipients and prototype formulations were developed...
January 6, 2018: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29316444/force-generation-via-%C3%AE-cardiac-myosin-titin-and-%C3%AE-actinin-drives-cardiac-sarcomere-assembly-from-cell-matrix-adhesions
#2
Anant Chopra, Matthew L Kutys, Kehan Zhang, William J Polacheck, Calvin C Sheng, Rebeccah J Luu, Jeroen Eyckmans, J Travis Hinson, Jonathan G Seidman, Christine E Seidman, Christopher S Chen
Truncating mutations in the sarcomere protein titin cause dilated cardiomyopathy due to sarcomere insufficiency. However, it remains mechanistically unclear how these mutations decrease sarcomere content in cardiomyocytes. Utilizing human induced pluripotent stem cell-derived cardiomyocytes, CRISPR/Cas9, and live microscopy, we characterize the fundamental mechanisms of human cardiac sarcomere formation. We observe that sarcomerogenesis initiates at protocostameres, sites of cell-extracellular matrix adhesion, where nucleation and centripetal assembly of α-actinin-2-containing fibers provide a template for the fusion of Z-disk precursors, Z bodies, and subsequent striation...
January 8, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29296748/immune-signatures-associated-with-improved-progression-free-and-overall-survival-for-myeloma-patients-treated-with-ahsct
#3
Christine M Ho, Philip L McCarthy, Paul K Wallace, Yali Zhang, Ahmad Fora, Patrick Mellors, Joseph D Tario, Benjamin L S McCarthy, George L Chen, Sarah A Holstein, Sophia R Balderman, Xuefang Cao, Bruno Paiva, Theresa Hahn
Multiple therapeutic options exist for multiple myeloma (MM), including autologous hematopoietic stem cell transplantation (AHSCT). Measurement of minimal residual disease (MRD) and immune reconstitution is rapidly becoming an integral part of the care of MM patients. We investigated comprehensive immune profiling (IP) associated with progression-free survival (PFS) and overall survival (OS). From August 2007 to January 2014, 101 consecutive MM patients underwent peripheral blood IP and marrow MRD testing before and approximately 100 days after AHSCT...
June 27, 2017: Blood Advances
https://www.readbyqxmd.com/read/29280043/cardiac-biomarkers-for-early-detection-and-prediction-of-trastuzumab-and-or-lapatinib-induced-cardiotoxicity-in-patients-with-her2-positive-early-stage-breast-cancer-a-neoaltto-sub-study-big-1-06
#4
Noam Ponde, Ian Bradbury, Matteo Lambertini, Michael Ewer, Christine Campbell, Helene Ameels, Dimitrios Zardavas, Serena Di Cosimo, José Baselga, Jens Huober, Miguel Izquierdo, Debora Fumagalli, Ivana Bozovic-Spasojevic, Marion Maetens, Nadia Harbeck, Lajos Pusztai, Michael Berghorn, Young-Hyuck Im, Manuel Ruiz Borrego, Dar-Ren Chen, Richard Rodeheffer, Martine Piccart, Thomas Suter, Evandro de Azambuja
BACKGROUND: Biomarkers of cardiac damages, such as troponin T (TnT) and the amino-terminal fragment of brain natriuretic peptide (NT-proBNP), may be useful as early predictors of cardiac dysfunction. The role of these biomarkers in patients receiving lapatinib and/or trastuzumab before anthracyclines is unknown. This study explores TnT and NT-proBNP as predictors of early cardiac toxicity in neoadjuvant breast cancer patients. METHODS: This sub-study of the NEOALTTO trial tested if changes in the levels of TnT and NT-proBNP occurred after 2 weeks of anti-HER2 therapy (lapatinib, trastuzumab or their combination) alone and/or after 18 weeks of anti-HER2 therapy plus weekly paclitaxel...
December 27, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29278617/genome-wide-meta-analyses-identifies-novel-taxane-induced-peripheral-neuropathy-associated-loci
#5
Lara E Sucheston-Campbell, Alyssa I Clay-Gilmour, William E Barlow, G Thomas Budd, Daniel O Stram, Christopher A Haiman, Xin Sheng, Li Yan, Gary Zirpoli, Song Yao, Chen Jiang, Kouros Owzar, Dawn Hershman, Kathy S Albain, Daniel F Hayes, Halle C Moore, Timothy J Hobday, James A Stewart, Abbas Rizvi, Claudine Isaacs, Muhammad Salim, Jule R Gralow, Gabriel N Hortobagyi, Robert B Livingston, Deanna L Kroetz, Christine B Ambrosone
OBJECTIVE: Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN. PATIENTS AND METHODS: Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans...
February 2018: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/29273792/timing-and-pacing-of-the-late-devonian-mass-extinction-event-regulated-by-eccentricity-and-obliquity
#6
David De Vleeschouwer, Anne-Christine Da Silva, Matthias Sinnesael, Daizhao Chen, James E Day, Michael T Whalen, Zenghui Guo, Philippe Claeys
The Late Devonian envelops one of Earth's big five mass extinction events at the Frasnian-Famennian boundary (374 Ma). Environmental change across the extinction severely affected Devonian reef-builders, besides many other forms of marine life. Yet, cause-and-effect chains leading to the extinction remain poorly constrained as Late Devonian stratigraphy is poorly resolved, compared to younger cataclysmic intervals. In this study we present a global orbitally calibrated chronology across this momentous interval, applying cyclostratigraphic techniques...
December 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/29246261/content-validation-of-an-interprofessional-learning-video-peer-assessment-tool
#7
Gillian Nisbet, Christine Jorm, Chris Roberts, Christopher J Gordon, Timothy F Chen
BACKGROUND: Large scale models of interprofessional learning (IPL) where outcomes are assessed are rare within health professional curricula. To date, there is sparse research describing robust assessment strategies to support such activities. We describe the development of an IPL assessment task based on peer rating of a student generated video evidencing collaborative interprofessional practice. We provide content validation evidence of an assessment rubric in the context of large scale IPL...
December 16, 2017: BMC Medical Education
https://www.readbyqxmd.com/read/29214652/pharmacology-in-translation-the-preclinical-and-early-clinical-profile-of-the-novel-%C3%AE-2-3-functionally-selective-gabaa-receptor-positive-allosteric-modulator-pf-06372865
#8
Sarah A Nickolls, Rachel Gurrell, Guido van Amerongen, Juha Kammonen, Lishuang Cao, Adam R Brown, Clara Stead, Andy Mead, Christine Watson, Cathleen Hsu, Robert M Owen, Andy Pike, Rebecca L Fish, Laigao Chen, Ruolun Qiu, Evan D Morris, Gang Feng, Mark Whitlock, Donal Gorman, Joop van Gerven, David S Reynolds, Pinky Dua, Richard P Butt
BACKGROUND AND PURPOSE: Benzodiazepines (BZDs), non-selective positive allosteric modulators (PAMs) of GABAA receptors, have significant side-effects that limit their clinical utility. As many of these side-effects are mediated by the α1 subunit there has been a concerted effort to develop α2/3 subtype-selective PAMs. EXPERIMENTAL APPROACH: In vitro screening assays were used to identify molecules with functional selectivity for receptors containing α2/3 subunits over those containing α1 subunits...
December 7, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29203585/safety-and-efficacy-of-selinexor-in-relapsed-or-refractory-multiple-myeloma-and-waldenstrom-s-macroglobulinemia
#9
Christine Chen, David Siegel, Martin Gutierrez, Meagan Jacoby, Craig C Hofmeister, Nashat Gabrail, Rachid Baz, Morten Mau-Sorensen, Jesus G Berdeja, Michael Savona, Lynn Savoie, Suzanne Trudel, Nuchanan Areethamsirikul, T J Unger, Tami Rashal, Tim Hanke, Michael Kauffman, Sharon Shacham, Donna Reece
Novel therapies are needed for patients with relapsed or refractory multiple myeloma (MM). We conducted a multicenter, phase 1 study in advanced hematological malignancies to assess the safety, efficacy and recommended phase 2 dose (RP2D) of oral selinexor, a selective inhibitor of the nuclear export protein XPO1. In the dose-escalation phase, 25 patients with heavily pretreated MM (22) or Waldenstrom's macroglobulinemia (3) were administered selinexor (3-60 mg/m2) in 8 or 10 doses per 28-day cycle. In the dose-expansion phase, 59 patients with MM received selinexor at 45 or 60 mg/m2 with 20 mg dexamethasone, twice-weekly in 28-day cycles, or selinexor (40 or 60mg flat dose) without corticosteroids in 21 day cycles...
December 4, 2017: Blood
https://www.readbyqxmd.com/read/29196080/outcomes-after-allogeneic-stem-cell-transplantation-in-patients-with-double-hit-and-double-expressor-lymphoma
#10
Alex F Herrera, Scott J Rodig, Joo Y Song, Young Kim, Gabriel K Griffin, Dongyun Yang, Liana Nikolaenko, Matthew Mei, Victoria Bedell, Paola Dal Cin, Christine Pak, Edwin P Alyea, Elizabeth Budde, Robert Chen, Yi-Bin Chen, Wing C Chan, Corey S Cutler, Vincent T Ho, John Koreth, Amrita Krishnan, Joyce L Murata-Collins, Sarah Nikiforow, Joycelynne Palmer, German A Pihan, Raju Pillai, Leslie Popplewell, Steven T Rosen, Tanya Siddiqi, Aliyah R Sohani, Jasmine Zain, Larry W Kwak, Dennis D Weisenburger, David M Weinstock, Robert J Soiffer, Joseph H Antin, Stephen J Forman, Auayporn P Nademanee, Philippe Armand
Double-hit lymphomas (DHL) and double-expressor lymphomas (DEL) are associated with resistance to frontline and salvage immunochemotherapy, as well as autologous stem cell transplantation (SCT). We hypothesized that allogeneic SCT (alloSCT) could overcome the chemoresistance associated with DEL/DHL. We retrospectively studied the impact of DEL/DHL status in a multicenter cohort of patients who underwent alloSCT for relapsed/refractory (rel/ref) aggressive B-cell non-Hodgkin lymphoma (B-NHL). 78 patients transplanted at 3 centers in whom tumor tissue was available for immunohistochemistry and FISH were enrolled; 47% had DEL and 13% had DHL...
November 28, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29177603/impact-of-multi-gene-mutational-profiling-on-clinical-trial-outcomes-in-metastatic-breast-cancer
#11
Rossanna C Pezo, Tom W Chen, Hal K Berman, Anna M Mulligan, Albiruni A Razak, Lillian L Siu, David W Cescon, Eitan Amir, Christine Elser, David G Warr, Srikala S Sridhar, Celeste Yu, Lisa Wang, Tracy L Stockley, Suzanne Kamel-Reid, Philippe L Bedard
PURPOSE: Next-generation sequencing (NGS) has identified recurrent genomic alterations in metastatic breast cancer (MBC); however, the clinical utility of incorporating routine sequencing to guide treatment decisions in this setting is unclear. We examine the frequency of genomic alterations in MBC patients from academic and community hospitals and correlate with clinical outcomes. METHODS: MBC patients with good performance status were prospectively recruited at the Princess Margaret Cancer Centre (PM) in Canada...
November 24, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29167235/cortisol-limits-selected-actions-of-synthetic-glucocorticoids-in-the-airway-epithelium
#12
Danica Prodanovic, Christine R Keenan, Shenna Langenbach, Meina Li, Qianyu Chen, Michael J Lew, Alastair G Stewart
Cortisol, a physiologic glucocorticoid (GC), is essential for growth and differentiation of the airway epithelium. Epithelial function influences inflammation in chronic respiratory diseases. Synthetic GCs, including inhaled corticosteroids, exert anti-inflammatory effects in airway epithelium by transactivation of genes and by inhibition of proinflammatory cytokine release. We examined the effect of cortisol on the actions of synthetic GCs in the airway epithelium, demonstrating that cortisol acts like a partial agonist at the GC receptor (GR), limiting GC-induced GR-dependent transcription in the BEAS-2B human bronchial epithelial cell line...
November 22, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29160304/il11-is-a-crucial-determinant-of-cardiovascular-fibrosis
#13
Sebastian Schafer, Sivakumar Viswanathan, Anissa A Widjaja, Wei-Wen Lim, Aida Moreno-Moral, Daniel M DeLaughter, Benjamin Ng, Giannino Patone, Kingsley Chow, Ester Khin, Jessie Tan, Sonia P Chothani, Lei Ye, Owen J L Rackham, Nicole S J Ko, Norliza E Sahib, Chee Jian Pua, Nicole T G Zhen, Chen Xie, Mao Wang, Henrike Maatz, Shiqi Lim, Kathrin Saar, Susanne Blachut, Enrico Petretto, Sabine Schmidt, Tracy Putoczki, Nuno Guimarães-Camboa, Hiroko Wakimoto, Sebastiaan van Heesch, Kristmundur Sigmundsson, See L Lim, Jia L Soon, Victor T T Chao, Yeow L Chua, Teing E Tan, Sylvia M Evans, Yee J Loh, Muhammad H Jamal, Kim K Ong, Kim C Chua, Boon-Hean Ong, Mathew J Chakaramakkil, Jonathan G Seidman, Christine E Seidman, Norbert Hubner, Kenny Y K Sin, Stuart A Cook
Fibrosis is a final common pathology in cardiovascular disease(1). In the heart, fibrosis causes mechanical and electrical dysfunction(1,2) and in the kidney, it predicts the onset of renal failure(3). Transforming growth factor β1 (TGFB1) is the principal pro-fibrotic factor(4,5) but its inhibition is associated with side effects due to its pleiotropic roles(6,7). We hypothesised that downstream effectors of TGFB1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicities. Using integrated imaging-genomics analyses of primary human fibroblasts, we found that Interleukin 11 (IL11) upregulation is the dominant transcriptional response to TGFB1 exposure and required for its profibrotic effect...
November 13, 2017: Nature
https://www.readbyqxmd.com/read/29150601/decoding-critical-long-non-coding-rna-in-ovarian-cancer-epithelial-to-mesenchymal-transition
#14
Ramkrishna Mitra, Xi Chen, Evan J Greenawalt, Ujjwal Maulik, Wei Jiang, Zhongming Zhao, Christine M Eischen
Long non-coding RNA (lncRNA) are emerging as contributors to malignancies. Little is understood about the contribution of lncRNA to epithelial-to-mesenchymal transition (EMT), which correlates with metastasis. Ovarian cancer is usually diagnosed after metastasis. Here we report an integrated analysis of >700 ovarian cancer molecular profiles, including genomic data sets, from four patient cohorts identifying lncRNA DNM3OS, MEG3, and MIAT overexpression and their reproducible gene regulation in ovarian cancer EMT...
November 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/29150421/final-analysis-of-survival-outcomes-in-the-randomized-phase-3-first-trial
#15
Thierry Facon, Meletios A Dimopoulos, Angela Dispenzieri, John V Catalano, Andrew Belch, Michele Cavo, Antonello Pinto, Katja Weisel, Heinz Ludwig, Nizar J Bahlis, Anne Banos, Mourad Tiab, Michel Delforge, Jamie D Cavenagh, Catarina Geraldes, Je-Jung Lee, Christine Chen, Albert Oriol, Javier De La Rubia, Darell White, Daniel Binder, Jin Lu, Kenneth C Anderson, Philippe Moreau, Michel Attal, Aurore Perrot, Bertrand Arnulf, Lugui Qiu, Murielle Roussel, Eileen Boyle, Salomon Manier, Mohamad Mohty, Herve Avet-Loiseau, Xavier Leleu, Annette Ervin-Haynes, Guang Chen, Vanessa Houck, Lotfi Benboubker, Cyrille Hulin
This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥ 60 months' follow-up)...
November 17, 2017: Blood
https://www.readbyqxmd.com/read/29146776/light-signaling-dependent-regulation-of-photoinhibition-and-photoprotection-in-tomato
#16
Feng Wang, Nan Wu, Luyue Zhang, Golam Jalal Ahammed, Xiaoxiao Chen, Xun Xiang, Jie Zhou, Xiaojian Xia, Kai Shi, Jingquan Yu, Christine H Foyer, Yanhong Zhou
Photoreceptor-mediated light signaling plays a critical role in plant growth, development, and stress responses but its contribution to the spatial regulation of photoinhibition and photoprotection within the canopy remains unclear. Here, we show that low red/far-red (L-R/FR) ratio light conditions significantly alleviate PSII and PSI photoinhibition in the shade leaves of tomato plants. This protection is accompanied by a phytochrome A (phyA)-dependent induction of LONG HYPOCOTYL 5 (HY5). HY5 binds to the promoter of ABA INSENSITIVE 5 (ABI5), triggering RESPIRATORY BURST OXIDASE HOMOLOG1 (RBOH1)-dependent H2O2 production in the apoplast...
November 16, 2017: Plant Physiology
https://www.readbyqxmd.com/read/29140263/access-to-guideline-recommended-pharmacogenomic-tests-for-cancer-treatments-experience-of-providers-and-patients
#17
Ann Chen Wu, Kathleen M Mazor, Rachel Ceccarelli, Stephanie Loomer, Christine Y Lu
Genomic tests are the fastest growing sector in medicine and medical science, yet there remains a dearth of research on access to pharmacogenomic tests and medications. The objective of this study is to explore providers' and patients' experiences and views on test access as well as strategies used for gaining access. We interviewed clinicians who prescribed medications that should be guided by pharmacogenomic testing and patients who received those prescriptions. We organized the themes into the four dimensions suggested by the World Health Organization framework on access to medications and health technologies...
November 15, 2017: Journal of Personalized Medicine
https://www.readbyqxmd.com/read/29133888/neuronal-hyperactivity-due-to-loss-of-inhibitory-tone-in-apoe4-mice-lacking-alzheimer-s-disease-like-pathology
#18
Tal Nuriel, Sergio L Angulo, Usman Khan, Archana Ashok, Qiuying Chen, Helen Y Figueroa, Sheina Emrani, Li Liu, Mathieu Herman, Geoffrey Barrett, Valerie Savage, Luna Buitrago, Efrain Cepeda-Prado, Christine Fung, Eliana Goldberg, Steven S Gross, S Abid Hussaini, Herman Moreno, Scott A Small, Karen E Duff
The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques-fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics-with the most prominent hyperactivity occurring in the entorhinal cortex...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29128266/molecular-profiling-of-patients-with-advanced-colorectal-cancer-princess-margaret-cancer-centre-experience
#19
Joanne W Chiu, Monika K Krzyzanowska, Stefano Serra, Jennifer J Knox, Neesha C Dhani, Helen Mackay, David Hedley, Malcolm Moore, Geoffrey Liu, Ronald L Burkes, Christine Brezden-Masley, Michael H Roehrl, Kenneth J Craddock, Ming-Sound Tsao, Tong Zhang, Celeste Yu, Suzanne Kamel-Reid, Lillian L Siu, Philippe L Bedard, Eric X Chen
BACKGROUND: Molecular aberrations in KRAS, NRAS, BRAF, and PIK3CA have been well-described in advanced colorectal cancer. The incidences of other mutations are less known. We report results of molecular profiling of advanced colorectal cancer in an academic cancer center. PATIENTS AND METHODS: Patients with advanced colorectal were enrolled in an institution-wide molecular profiling program. Profiling was performed on formalin-fixed paraffin embedded archival tissues using a customized MassArray panel (23 genes, 279 mutations) or the Illumina MiSeq TruSeq Cancer Panel (48 genes, 212 amplicons, ≥ 500× coverage) in a Clinical Laboratory Improvement Amendments-certified laboratory...
October 23, 2017: Clinical Colorectal Cancer
https://www.readbyqxmd.com/read/29117459/receptor-homodimerization-plays-a-critical-role-in-a-novel-dominant-negative-p2ry12-variant-identified-in-a-family-with-severe-bleeding
#20
Stuart J Mundell, David Rabbolini, Sara Gabrielli, Qiang Chen, Riyaad Aungraheeta, James L Hutchinson, Tatjana Kilo, Joel Mackay, Christopher M Ward, William Stevenson, Marie-Christine Morel-Kopp
BACKGROUND: Although inherited platelet disorders are still underdiagnosed worldwide, advances in molecular techniques are improving disease diagnosis and patient management. OBJECTIVE: To identify and characterize the mechanism underlying the bleeding phenotype in a Caucasian family with an autosomal dominant P2RY12 variant. METHODS: Full blood count, platelet aggregometry, flow cytometry and western-blotting were performed before NGS. Detailed molecular analysis of the identified P2Y12R receptor's variant was subsequently performed in mammalian cells over-expressing receptor constructs...
November 8, 2017: Journal of Thrombosis and Haemostasis: JTH
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