tbuckley/cabot-search huggingface dataset:
Abstract P275: Time-of-Day--Dependent Variation in Myocardial Ischemia/Reperfusion Injury Is Lost in Mice Lacking the Regulator of Calcineurin 1 Gene
Authors: D B Grinsfelder, David Rotter, Nita Sachan, Beverly A Rothermel
Journal: Circulation Research (2011)

Many important components of the cardiovascular system display circadian rhythmicity. In humans, the incidence of myocardial infarction peaks in the morning. Furthermore, studies in mouse models have demonstrated that damage from ischemia/reperfusion (I/R) occurring during the transition to waking is greater than at the end of the active period. In the hearts of wild type mice we have observed large circadian oscillations in the transcript and protein levels of the exon 4 isoform of the calcineurin regulatory protein ( Rcan1.4 ). This 15 to 20-fold oscillation peaks around circadian time 0 (CT:0) when mice enter a period of rest. Using an in vivo murine model of myocardial I/R injury we subjected wild type and Rcan1 KO mice to 45 minutes of myocardial ischemia followed by reperfusion for 24 hrs. Mice were housed in hermetic light boxes with opposing light cycles such that the surgeon was blinded as to the light entrainment of individual mice. I/R was performed at the beginning (CT:0 to CT:2) and the end (CT:10 to CT:12) of the mouse's light entrainment cycle. Twenty-four hours after reperfusion Evan's Blue and 2,3,5-Triphenyltetrazolium chloride staining were used to quantify the area-at-risk per left ventricle (AAR/LV) and the extent of myocardial infarction per area-at-risk (INF/AAR). Serum troponin-I levels were quantified as an indication of muscle damage. AAR/LV was the same in all animals, however, I/R injury in wild-type mice at CT:12 was 30% higher than in mice subjected to I/R at CT:0. Plasma troponin-I levels were also higher. Remarkably, there was no circadian difference in the extent of I/R injury or troponin-I levels in the Rcan1 KO mice. Damage in the Rcan1 KO mice at both time points was comparable to the level of damage observed in wild type mice at CT:12, when Rcan1.4 expression is low. Importantly, expression of all central clock genes remained circadian in the hearts of Rcan1 KO mice suggesting that circadian changes in the vulnerability of the myocardium to I/R damage is directly dependent upon Rcan1 function.
The Relapsed - Memorial Sloan - Kettering Cancer Center (R-MSKCC) Prognostic Score Is a Risk-Stratification Model for the Central Nervous System (CNS) Involvement at Relapse in Patients with Diffuse Large B Cell Lymphoma (DLBCL) in the Rituximab Era
Authors: Noriko Nishimura, Yasuhito Terui, Kengo Takeuchi, Naoko Tsuyama, Anna Takahashi, Norihito Inoue, Hirofumi Yamauchi, Yoshiharu Kusano, Yuko Mishima, Masahiro Yokoyama, Kiyohiko Hatake
Journal: Blood (2016)
Postoperative Venous Thromboembolism in Children Is Increased in Setting of Cancer or Infection
Authors: Harold J. Leraas, Jina Kim, Zhifei Sun, Uttara P. Nag, Brian D. Ezekian, Reed W. Kamyszek, Brian C. Gulack, Henry E. Rice, Obinna O. Adibe, Alexandra J. Borst, Jennifer A Rothman, Elisabeth T. Tracy
Journal: Blood (2016)
Preliminary results of a phase 1A/1B study of BGB-A317, an anti-PD-1 monoclonal antibody (mAb), in patients with advanced hepatocellular carcinoma (HCC)
Authors: Chia-Jui Yen, Benjamin Markman, Yee Chao, Andrew Hill, Jinyu Kang, Lai Wang, Kang Li, Qinzhou Qi, Zhong Wu, Hui Gan
Journal: Annals of Oncology (2017)
Triplet plus molecular-targeted drug for chemotherapy-naïve metastatic colorectal cancer: Multicenter-analysis
Authors: Masahito Kotaka, Hironaga Satake, Hisateru Yasui, Yukimasa Hatachi, Takatsugu Ogata, Yoshihiro Okita, Takeshi Kato, Akihito Tsuji
Journal: Annals of Oncology (2017)
Skeletal Muscle Microvascular-Linked Improvements in Glycemic Control From Resistance Training in Individuals With Type 2 Diabetes
Authors: Ryan D. Russell, Donghua Hu, Timothy Greenaway, Sarah J. Blackwood, Renee M. Dwyer, James E. Sharman, Graeme Jones, Kathryn A. Squibb, Aascha A. Brown, Petr Otahal, Meg Boman, Hayder Al-Aubaidy, Dino Premilovac, Christian K. Roberts, Samuel Hitchins, Stephen M. Richards, Stephen Rattigan, Michelle A. Keske
Journal: Diabetes Care (2017)

OBJECTIVE Insulin increases glucose disposal in part by enhancing microvascular blood flow (MBF) and substrate delivery to myocytes. Insulin’s microvascular action is impaired with insulin resistance and type 2 diabetes. Resistance training (RT) improves glycemic control and insulin sensitivity, but whether this improvement is linked to augmented skeletal muscle microvascular responses in type 2 diabetes is unknown. RESEARCH DESIGN AND METHODS Seventeen (11 male and 6 female; 52 ± 2 years old) sedentary patients with type 2 diabetes underwent 6 weeks of whole-body RT. Before and after RT, participants who fasted overnight had clinical chemistries measured (lipids, glucose, HbA1c, insulin, and advanced glycation end products) and underwent an oral glucose challenge (OGC) (50 g × 2 h). Forearm muscle MBF was assessed by contrast-enhanced ultrasound, skin MBF by laser Doppler flowmetry, and brachial artery flow by Doppler ultrasound at baseline and 60 min post-OGC. A whole-body DEXA scan before and after RT assessed body composition. RESULTS After RT, muscle MBF response to the OGC increased, while skin microvascular responses were unchanged. These microvascular adaptations were accompanied by improved glycemic control (fasting blood glucose, HbA1c, and glucose area under the curve [AUC] during OGC) and increased lean body mass and reductions in fasting plasma triglyceride, total cholesterol, advanced glycation end products, and total body fat. Changes in muscle MBF response after RT significantly correlated with reductions in fasting blood glucose, HbA1c, and OGC AUC with adjustment for age, sex, % body fat, and % lean mass. CONCLUSIONS RT improves OGC-stimulated muscle MBF and glycemic control concomitantly, suggesting that MBF plays a role in improved glycemic control from RT.
Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial
Authors: Peter G Gibson, Ian A Yang, John W Upham, Paul N Reynolds, Sandra Hodge, Alan L James, Christine Jenkins, Matthew J Peters, Guy B Marks, Melissa Baraket, Heather Powell, Steven L Taylor, Lex E X Leong, Geraint B Rogers, Jodie L Simpson
Journal: The Lancet (2017)
Activity of oral VT-464, a selective CYP17-lyase inhibitor, in the LNCaP prostate cancer xenograft.
Authors: William Douglas Figg, Shawn D. Spencer, Stephen T Pisle, Heather M Pressler, Sarah M Troutman, Joel Robert Eisner, Stephen W Rafferty, Robert J Schotzinger, William R Moore
Journal: Journal of Clinical Oncology (2012)

4671 Background: With the FDA approval of abiraterone acetate, inhibition of CYP17 (17α hydroxylase/C17, 20-lyase) is now a validated approach to the treatment of castration-resistant prostate cancer. VT-464 is a novel, selective CYP17-lyase inhibitor with decreased activity against CYP17 hydroxylase (less mineralcocorticoid and glucocorticoid effects). The study objectives were to observe the effects of VT-464 in a prostate cancer xenograft model and to compare its activity to abiraterone acetate and surgical castration. Methods: SCID mice were implanted subcutaneously with LNCaP cells. When tumors reached 100 mm 3 , mice were randomized to receive vehicle (0.5% CMC in saline, 5 mL/kg), VT-464 at 15, 50, or 100 mg/kg p.o. b.i.d. A second cohort of LNCaP tumor-bearing mice received vehicle, surgical castration, or VT-464, or abiraterone acetate at 100 mg/kg p.o. b.i.d. for 28 days. Terminal blood and tumor concentrations were analyzed on day 28, four hours after the last dose. Results: In the first LNCaP xenograft cohort, percent growth inhibition (± S.E.) of 9.6 (±15.6), 38.5 (±12.4), and 73.9 (±13.2) was observed on day 21 of treatment for VT-464 doses of 15, 50, and 100 mg/kg, respectively. Growth reduction at 100 mg/kg was statistically significant compared to vehicle control from day 7 to 28. VT-464 was well tolerated with insignificant weight loss at all doses. In the second cohort, VT-464-treated (100 mg/kg) mice had significantly reduced tumor volumes on day 28 compared to control and abiraterone acetate (p&lt;0.05, p&lt;0.01, respectively). Reduction in tumor volumes were similar between VT-464-treated (100 mg/kg) and castrate animals. Plasma and tumor analyses revealed much greater plasma and tumor exposure of VT-464 compared to abiraterone acetate. Conclusions: VT-464 exhibited dose-dependent growth inhibition with significantly reduced tumor volumes at the highest dose compared to abiraterone acetate. The activity in VT-464-treated animals was similar to that of castrate animals. These preclinical results show promising activity of VT-464 in the treatment of prostate cancer.
Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study
Authors: Hagop M Kantarjian, Daniel J DeAngelo, Anjali S Advani, Matthias Stelljes, Partow Kebriaei, Ryan D Cassaday, Akil A Merchant, Naohito Fujishima, Toshiki Uchida, Maria Calbacho, Anna A Ejduk, Susan M O'Brien, Elias J Jabbour, Hui Zhang, Barbara J Sleight, Erik R Vandendries, David I Marks
Journal: The Lancet Haematology (2017)
Presentation of Colorectal Cancer (Crc) At a District Regional Hospital
Authors: M Hamed, M McClintock, G McCormack
Journal: Endoscopy (2006)

Results: We identified 145 patients (77 males, 68 females) diagnosed with CRC in the years 2002 to 2004. One Hundred and Eight patients (74%) were more than 60 years old. Eleven (8%) had T1 disease, 38 (26%) had T2 disease, 40 (28%) had T3 disease and 11 (8%) had T4 disease. T stage was not available for 45 patients (31%). Regional node metastases were present in 39 (27%), absent in 55 (38%) and nodes could not be assessed in 35%. Distant metastases were present in18 (12%). The common reasons for presentation in the group were iron deficiency anaemia, abdominal pain and altered bowel habit.
Endoscopic ultrasonography-guided freestyle rendezvous recanalization of a complete postoperative rectosigmoid anastomotic obstruction with a lumen-apposing metal stent
Authors: Omid Sanaei, Saowanee Ngamruengphong, Yen-I Chen, Majidah Bukhari, Olaya Brewer Gutierrez, Vivek Kumbhari, Mouen Khashab
Journal: Endoscopy (2017)

A 44-year-old woman with a large symptomatic uterine leiomyoma underwent radical pelvic mass resection, bilateral salpingo-oophorectomy, and modified pelvic exenteration with rectosigmoid resection and creation of a diverting ileostomy. A sigmoidoscopy performed 2 months later followed by a water-soluble contrast enema showed complete obstruction of the rectosigmoid anastomosis. An endoscopic ultrasonography (EUS)-guided recanalization of the obstruction was planned.
Not all <i>RAS</i> mutations created equal: Functional and clinical characterization of 80 different <i>KRAS</i> and <i>NRAS</i> mutations.
Authors: Jonathan M. Loree, Ben Miron, Vijaykumar Holla, Michael J. Overman, Allan Andresson Lima Pereira, Michael Lam, Van Karlyle Morris, Kanwal Pratap Singh Raghav, Mark Routbort, Kenna Rael Shaw, Nitza Burck, Revital Sharivkin, Oded Edelheit, Funda Meric-Bernstam, Michael Vidne, Gabi Tarcic, Scott Kopetz
Journal: Journal of Clinical Oncology (2017)

3589 Background: Mutations (mts) in RAS predict lack of response to anti-EGFR therapy in colorectal cancer. Outside the “typical RAS” mts ( KRAS/NRAS Codons 12, 13, 59, 61, 117, 146) cited in guidelines and anti-EGFR labeling, clinical impact of other “atypical RAS” mts is uncertain. Methods: Available literature and databases were surveyed to identify 80 KRAS/NRAS mts. We used the NovellusDx Functional Annotation for Cancer Treatment (FACT) to transfect these RAS mts (repeated a mean of 5.5 times/mt) in a cell-based assay that quantifies nuclear ERK localization as a measure of MAPK pathway activation, and normalized to wild type (WT) transfection. In 963 metastatic colorectal cancer patients (pts) with BRAF WT/ KRAS mutant tumors, overall survival (OS) was evaluated by level of RAS signaling activity. Results: Of the surveyed mutations,96% (45/47) of typical mts and 39% (13/33) of atypical mts increased MAPK pathway activation above WT (range: 107%-211% of WT activity). Within the typical RAS mts, mts in NRAS or exon 3, 4 of KRAS had higher activity than mts in exon 2 (codons 12/13) of KRAS, reaffirming the biologic relevance of expanded RAS testing (median activity of 130% vs 178%, P &lt; 0.001). The median activity of atypical RAS mts was lower than typical RAS mts (110% vs 159%, P &lt; 0.001). Several notable exceptions in atypical RAS mts with high activity levels were KRAS V14I, Q22K, D33E, N116S, and F156L (all &gt; 165% of WT activity). Conversely, within the typical RAS mts in the guidelines, KRAS G13C and K117R were not shown to increase activity significantly above WT. Pts with any RAS mt with MAPK activity above the median of typical mts had a worse OS compared to pts below the median in univariate (HR 1.45, 95% CI 1.04-2.32, P = 0.033) and multivariate models (HR 1.96, 95% CI 1.13-3.42, P = 0.017) that controlled for age, gender, sidedness, and synchronous vs metachronous presentation. Conclusions: Functional characterization confirmed activity of RAS mts in the current guidelines, but also suggested that a subset of atypical RAS mutations have similar levels of activation of the MAPK pathway. Within the subset of pts with RAS mts, those mts resulting in high MAPK activity are associated with notably shorter OS.
PulseNet International: Vision for the implementation of whole genome sequencing (WGS) for global food-borne disease surveillance
Authors: Celine Nadon, Ivo Van Walle, Peter Gerner-Smidt, Josefina Campos, Isabel Chinen, Jeniffer Concepcion-Acevedo, Brent Gilpin, Anthony M. Smith, Kai Man Kam, Enrique Perez, Eija Trees, Kristy Kubota, Johanna Takkinen, Eva Møller Nielsen, Heather Carleton
Journal: Eurosurveillance (2017)

PulseNet International is a global network dedicated to laboratory-based surveillance for food-borne diseases. The network comprises the national and regional laboratory networks of Africa, Asia Pacific, Canada, Europe, Latin America and the Caribbean, the Middle East, and the United States. The PulseNet International vision is the standardised use of whole genome sequencing (WGS) to identify and subtype food-borne bacterial pathogens worldwide, replacing traditional methods to strengthen preparedness and response, reduce global social and economic disease burden, and save lives. To meet the needs of real-time surveillance, the PulseNet International network will standardise subtyping via WGS using whole genome multilocus sequence typing (wgMLST), which delivers sufficiently high resolution and epidemiological concordance, plus unambiguous nomenclature for the purposes of surveillance. Standardised protocols, validation studies, quality control programmes, database and nomenclature development, and training should support the implementation and decentralisation of WGS. Ideally, WGS data collected for surveillance purposes should be publicly available, in real time where possible, respecting data protection policies. WGS data are suitable for surveillance and outbreak purposes and for answering scientific questions pertaining to source attribution, antimicrobial resistance, transmission patterns, and virulence, which will further enable the protection and improvement of public health with respect to food-borne disease.
Cyclin D1 as a biomarker of response to fulvestrant (F) in hormone receptor-positive (HR+) breast cancer (BC).
Authors: Krystal Pauline Cascetta, Doris Germain, Amy Tiersten
Journal: Journal of Clinical Oncology (2015)

582 Background: Overexpression of cyclin D1 (CD1) occurs in up to 45% of BCs. High cyclin D1 expression (HCD1) has been shown to significantly increase overall survival yet the opposite is observed in HR+ BC patients (pts) with HCD1 who receive tamoxifen (TAM). TAM is the drug of choice for premenopausal pts with ER+ BC. Numerous studies report an association btwn CD1 overexpression & TAM resistance. Thus, a large fraction of pts who receive TAM may not benefit from it. F may serve as an alternative approach for these pts. We hypothesized that pts with HCD1 will have a better duration of response to F compared to those with low expression. In order to address the above, we retrospectively analyzed CD1 expression in HR+ metastatic BC (MBC) pts treated with F at our institution. Methods: 20 primary BCs were stained for CD1 expression. IHC was scored based on intensity as 0 (negative), 1+, 2+, 3+ & extent as 0 ( < 10%), 1 (11-25%), 2 (26-50%), 3 (51-75%), 4 (76-90%) & 5 ( > 90%). A total score was subgrouped as low (0 to 4) or high (5 to 8). A retrospective chart review extracted clinical data. The primary endpoint was duration of response to F as it relates to CD1 expression in HR+ MBC. Results: Of the 20 pts (median age 54 years), 40% had low cyclin D1 (LCD1) expression (n = 8) vs. 60% with HCD1 (n = 12). All but 1 pt in the LCD1 cohort had poorly differentiated (PD) invasive ductal carcinoma (IDC) (87.5%). The remaining pt had moderately differentiated (MD) invasive ductal & lobular carcinoma (mixed). 50% of HCD1 pts had PD tumors while 16.7% were MD. In the HCD1 cohort, 41.7% were IDC, 33% ILC and 25% mixed. Four pts were HER2-neu+, 2 in the LCD1 group & 2 in the HCD1 group. 75% in the LCD1 group were postmenopausal vs. 58% in the HCD1 cohort. TAM exposure was higher in the HCD1 group compared to the LCD1 group (58% vs. 25%). LN positivity was higher in the HCD1 group compared to the LCD1 group (58% vs. 37.5%). Median time to progression (TTP) with F was significantly increased in tumors with HCD1 expression compared to those with LCD1 (1149 days vs. 133 days, respectively; p = 0.027). Conclusions: TTP on F is significantly increased for HR+ HCD1 expressing BC compared to HR+ BC with LCD1 expression. Clinical trials exploring the use of F in BCs with HCD1 expression may be warranted.
Clinical utility of circulating DNA analysis for rapid detection of actionable mutations to select metastatic colorectal patients for anti-EGFR treatment
Authors: A.R. Thierry, S. El Messaoudi, C. Mollevi, J.L. Raoul, R. Guimbaud, D. Pezet, P. Artru, E. Assenat, C. Borg, M. Mathonnet, C. De La Fouchardière, O. Bouché, C. Gavoille, C. Fiess, B. Auzemery, R. Meddeb, E. Lopez-Crapez, C. Sanchez, B. Pastor, M. Ychou
Journal: Annals of Oncology (2017)
Enrico Mihich, MD: In Memoriam (1928–2016)
Authors: Margaret Foti, Youcef M. Rustum
Journal: Cancer Research (2017)

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Enrico “Henry” Mihich, MD, scientist, educator, administrator, cosmopolitan, American Association for Cancer Research (AACR) past president, and Fellow of the AACR Academy, died December 29, 2016, at the age of 88, after an impressive career in cancer research that spanned
Survival Outcome for Hepatocellular Carcinoma Following Liver Transplantation
Authors: A Qasim, S Bakhiet, T Tajjudin, B Zaman, D Maguire, J Geoghegan, O Traynor, J Hegarty, N Nolan, A McCormick
Journal: Endoscopy (2006)

Methods: Patients who underwent liver transplantation (Milan & UCSF criteria) for HCC were included for survival analysis. Patient and disease characteristics were compared to determine primary outcomes (retransplantation rate and survival outcome) at 3 months, 1- and 5- years post transplantation.
Genome-wide association study (GWAS) of cisplatin-related hearing loss in testicular cancer survivors (TCS) to reveal associated variant in Wolfram syndrome 1 (WFS1) gene.
Authors: Heather E. Wheeler, Robert D. Frisina, Eric R Gamazon, Omar El Charif, Darren R. Feldman, Robert James Hamilton, David J. Vaughn, Clair Beard, Chunkit Fung, Lawrence H. Einhorn, Taisei Mushiroda, Michiaki Kubo, Nancy Cox, M. Eileen Dolan, Lois B. Travis
Journal: Journal of Clinical Oncology (2016)

10015 Background: Cisplatin is widely used and highly ototoxic; we sought to identify genetic variants that modulate cisplatin-related hearing loss. Methods: We performed a GWAS for cisplatin-related hearing loss in 512 patients of European genetic ancestry enrolled in an ongoing multi-center North American clinical study of TCS. The geometric mean of air conduction thresholds measured at 4, 6, 8, 10 and 12 kHz was the quantitative phenotype used in the GWAS. SNPs were genotyped on the Illumina HumanOmniExpressExome chip and imputed using the 1000 Genomes reference panel, with 5.1 million SNPs passing quality control for GWAS inclusion. Covariates included in the GWAS were age at audiometry, cumulative cisplatin dose, and 10 genotypic principal components. Results: One SNP, rs62283056, in the first intron of WFS1 met genome-wide significance for association with cisplatin-associated hearing loss (P = 4.8 x 10-9). Mutations in this gene can cause autosomal dominant deafness and Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). The minor allele of rs62283056 (frequency 0.21 in the GWAS cohort) associates with increased hearing loss and decreased expression of WFS1 (cis-eQTL) in several human tissues from the GTEx Project, including cerebellar hemisphere, tibial nerve and thyroid. WFS1 is differentially expressed in the human inner ear (cochlea vs. vestibule, Padj = 0.032, Schrauwen et al. Hear Res 2015). We found a significant interaction between rs62283056 genotype and cumulative cisplatin dose (P = 0.029), indicating higher dose may exacerbate the hearing loss effect in patients carrying the minor allele. When hearing loss is dichotomized as a geometric mean > 20 dB (n = 242 affected), the allelic OR for hearing loss risk is 1.9 [95% CI: 1.3 – 2.8]. Conclusions: The WFS1 SNP is the first report of a genome-wide significant association with cisplatin-related hearing loss in adults. Expression data and known gene function corroborate its potential involvement in hearing loss. Future studies will focus on replicating and extending the genetic and mechanistic findings discovered here.