tbuckley/cabot-search huggingface dataset:
A phase 1/2 open-label study of safety and antitumor activity of EPI-506, a novel AR N-terminal domain inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC) with progression after enzalutamide or abiraterone.
Authors: Robert B. Montgomery, Emmanuel S. Antonarakis, Maha Hussain, Karim Fizazi, Anthony M. Joshua, Gerhardt Attard, Marianne Sadar, Frank Perabo, Kim N. Chi
Journal: Journal of Clinical Oncology (2015)

TPS5072 Background: EPI-506 is a first-in-class, highly specific small molecule inhibitor of the androgen receptor (AR) N-terminal domain (NTD). In vitro and in vivo studies have shown activity against full length AR and constitutively active AR splice variants, including AR-V7 (associated with resistance to abiraterone and enzalutamide). EPI-506 is expected to be effective in mCRPC driven by both canonical and aberrant AR signaling by targeting the NTD common to full length and splice variant AR. Initial clinical development of EPI-506 will target mCRPC with progression after prior enzalutamide and abiraterone. Methods: This open-label, single-arm, phase 1/2 study will evaluate the benefit of 12 week once-daily dosing with EPI-506, after establishing the safety, pharmacokinetics (PK), and optimal dose of EPI-506 in single- and multiple-dose escalations. The study will involve ~20 investigational sites in the US and Canada, and is expected to launch in Q2 2015. The planned enrollment is 150 patients. Inclusion criteria include mCRPC with progression after one or more lines of hormonal therapy or chemotherapy, and progression on enzalutamide or abiraterone. Exclusion criteria include hematologic, hepatic or renal insufficiency. The phase 2 portion of the study will evaluate activity in 3 patient populations: post-enzalutamide mCRPC, post-abiraterone mCRPC, and enzalutamide/abiraterone naïve mCRPC. Primary endpoints include PSA response at week 12, defined as a ≥ 50% PSA decrease from baseline. Secondary endpoints include: PK, objective RECIST response, time to PSA progression, radiographic progression-free survival, and safety/tolerability. Exploratory endpoints include evaluation of AR splice variants and AR mutations from CTC-based and ctDNA-based methodologies, as well as molecular characterization of optional tissue biopsies. This trial will be the first to evaluate the novel NTD inhibitor EPI-506 in men with enzalutamide- and/or abiraterone-failure mCRPC, and is the first agent with the potential to inhibit both canonical and variant-mediated AR signaling.
Comparison of the clinical course of Clostridium difficile infection in glutamate dehydrogenase-positive toxin-negative patients diagnosed by PCR to those with a positive toxin test
Authors: J. Origüen, L. Corbella, M.Á. Orellana, M. Fernández-Ruiz, F. López-Medrano, R. San Juan, M. Lizasoain, T. Ruiz-Merlo, A. Morales-Cartagena, G. Maestro, P. Parra, J. Villa, R. Delgado, J.M. Aguado
Journal: Clinical Microbiology and Infection (2017)
癌イメージングと治療における有効性を増強するGRP78結合ペプチドの構造に基づく最適化【Powered by NICT】
Authors: Wang Sheng-Hung, Lee Andy Chi-Lung, Chen I-Ju, Chang Nai-Chuan, Wu Han-Chung, Yu Hui-Ming, Chang Ya-Jen, Lee Te-Wei, Yu Jyh-Cherng, L Yu Alice, Yu John
Journal: Biomaterials (2016)
Theory of mind: A foundational component of human general intelligence
Authors: David Estes, Karen Bartsch
Journal: Behavioral and Brain Sciences (2017)

Abstract To understand the evolution of general intelligence, Burkart et al. endorse a “cultural intelligence approach,” which emphasizes the critical importance of social interaction. We argue that theory of mind provides an essential foundation and shared perspective for the efficient ontogenetic transmission of crucial knowledge and skills during human development and, together with language, can account for superior human general intelligence.
in vivoおよびin vitroでの間葉系間質細胞上の粒状物および分離した金属上金属股関節人工骨頭置換術摩耗の影響【Powered by NICT】
Authors: Rakow Anastasia, Schoon Janosch, Dienelt Anke, John Thilo, Textor Martin, Duda Georg, Perka Carsten, Schulze Frank, Ode Andrea
Journal: Biomaterials (2016)
Brief Report: Functional Interaction of Endoplasmic Reticulum Aminopeptidase 2 and HLA–B27 Activates the Unfolded Protein Response
Authors: Zhenbo Zhang, Francesco Ciccia, Fanxing Zeng, Giuliana Guggino, Kirby Yee, Hasan Abdullah, Mark S. Silverberg, Riccardo Alessandro, Giovanni Triolo, Nigil Haroon
Journal: Arthritis & Rheumatology (2016)

The basic mechanisms underlying the pathogenesis of ankylosing spondylitis (AS) remain unresolved. We previously reported an association of the single-nucleotide polymorphism (SNP) rs2549782 in the endoplasmic reticulum aminopeptidase 2 gene (ERAP2) with AS. It is known that patients homozygous for the G allele (GG) of another ERAP2 SNP, rs2248374, lack expression of ERAP2 (ERAP2 null). The present study utilized this information to study the impact of ERAP2 deficiency on HLA-B27 expression in patients with AS, specifically focusing on the functional interaction of ERAP2 and HLA-B27 in peripheral blood mononuclear cells (PBMCs) from patients with AS and assessing the effects in vitro in specific cell lines.Expression of intact peptide HLA-B27 (pB27) or the major histocompatibility complex class I free heavy chains (FHCs) was assessed in PBMCs isolated from HLA-B27-positive patients with AS. ERAP2-suppressed, stable B27-expressing C1R cells (C1R-B27) were tested for the expression levels of pB27 and FHCs, as well as for markers of the unfolded protein response (UPR). Distribution of the ERAP2 SNPs rs2549782 and rs2248374 in patients with AS and in patients with Crohn's disease was assessed.PBMCs from AS patients lacking ERAP2 expressed higher levels of FHCs than did PBMCs from patients positive for ERAP2. This finding was replicated in C1R-B27 cells after suppression of ERAP2. In addition, ERAP2 suppression led to increased levels of the UPR markers BiP, CCAAT/enhancer binding protein homologous protein 10, and X-box binding protein 1 [spliced] as compared to that in short hairpin RNA-treated control cells. There was strong linkage disequilibrium in the ERAP2 locus. All patients with the rs2549782 T allele (which reportedly increases the function of the ERAP-2 protein) were homozygous for the G allele of rs2248374, leading to absence of ERAP2.ERAP2 deficiency causes increased FHC expression and up-regulation of the UPR pathway.
Anal cancer in Oncólogos del Occidente from Colombia, South America 1997-2012.
Authors: Carlos Raul Villegas Mejia, Jose Arnoby Chacon Cardona, Tomas Sanchez Villegas
Journal: Journal of Clinical Oncology (2013)

e15189 Background: This work describes epidemiologic characteristics in anal cancer, in the United States is 1% to 2% of bowel cancers and 3.9% of anorectal carcinomas. Statistics for anal cancer are unknown in our specific Colombia region. Methods: We performed a descriptive preliminary retrospective analysis of 50% of our total patients from Oncologos del Occidente like a private treatment cancer center from January of 1997 to June 2012. Results: 10,000 records were reviewed with 663 colorectoanal cancer and 47 were anal cancer; median age 60.064 (range 32-88. SD. 12.595), 64% female and 96% urban areas; Clinical stage II 32%, stage IIIA 14%, stage IIIB 30%, and 23% were unknown stage; Squamous cell carcinoma including basaloid 79%, adenocarcinoma 17%; Well differentiated 32%, moderately 19% and poorly 19%; 6% had Radical perineal surgery, 81% received chemoradiation (QT/RT), 13% without treatment and 2% were treated with sequential QT+RT; 19% relapsed and 70% of them were local with 87% without any treatment. Gap of RT was 1 to 14 days (11%), 15 to 30 days (23%), 31 to 106 days (15%). No gap (0 days) 51%, Gap mean 13.085 (Range 0-106 SD. 19.534); The initial QT Regimen was 5FU/mitomycin 60%, 5 FU/cisplatinum 4%, capecitabine / mitomycin C in 11%; General survival to 5 years 60% Stage II and 38% Stage III, median survival for Stage III 35%; Mean follow up 43.10 months (range 0 - 178. SD. 45.5), Gap Survival to 5 years was 36% without rest with a median of 20 months, Gap of 1 to 14 days with a median of 35 months and 40% of survival to 5 years; and 55% from 15-30 days of survival to 5 years (p&gt; 0.05). Conclusions: These results reflect the occurrence pattern of anal cancer in a specific area of Colombia, and the importance of a multidisciplinary treatment group.
BMA laments “disappointing” pace of increase in GP numbers
Authors: Abi Rimmer
Journal: BMJ (2017)

The number of full time equivalent GPs in England increased by less than 1% in the past three months, show new figures the BMA has described as “disappointing.”

The figures, from NHS Digital, show that there were 34 242 full time equivalent GPs in England as at 30 June 2017, an increase of 321 (0.9%) from 33 921 in March 2017.1

Excluding locum GPs, the number of full time equivalent GPs increased by 263 (0.8%) to 33 235 in June from 32 972 in March.

But from March 2016 to March 2017 the number of full time GPs, excluding locums, fell by 1252 …
Relationship between Helicobacter pylori infection and glaucoma11The authors have no commercial interests in the products or devices mention herein.
Authors: Jannis Kountouras, Nikolaos Mylopoulos, Panagiota Boura, Christos Bessas, Dimitrios Chatzopoulos, John Venizelos, Christos Zavos
Journal: Ophthalmology (2001)
Effect of an Intensive Lifestyle Intervention on Glycemic Control in Patients With Type 2 Diabetes
Authors: Mette Yun Johansen, Christopher Scott MacDonald, Katrine Bagge Hansen, Kristian Karstoft, Robin Christensen, Maria Pedersen, Louise Seier Hansen, Morten Zacho, Anne-Sophie Wedell-Neergaard, Signe Tellerup Nielsen, Ulrik Wining Iepsen, Henning Langberg, Allan Arthur Vaag, Bente Klarlund Pedersen, Mathias Ried-Larsen
Journal: JAMA (2017)

It is unclear whether a lifestyle intervention can maintain glycemic control in patients with type 2 diabetes.To test whether an intensive lifestyle intervention results in equivalent glycemic control compared with standard care and, secondarily, leads to a reduction in glucose-lowering medication in participants with type 2 diabetes.Randomized, assessor-blinded, single-center study within Region Zealand and the Capital Region of Denmark (April 2015-August 2016). Ninety-eight adult participants with non-insulin-dependent type 2 diabetes who were diagnosed for less than 10 years were included. Participants were randomly assigned (2:1; stratified by sex) to the lifestyle group (n = 64) or the standard care group (n = 34).All participants received standard care with individual counseling and standardized, blinded, target-driven medical therapy. Additionally, the lifestyle intervention included 5 to 6 weekly aerobic training sessions (duration 30-60 minutes), of which 2 to 3 sessions were combined with resistance training. The lifestyle participants received dietary plans aiming for a body mass index of 25 or less. Participants were followed up for 12 months.Primary outcome was change in hemoglobin A1c (HbA1c) from baseline to 12-month follow-up, and equivalence was prespecified by a CI margin of ±0.4% based on the intention-to-treat population. Superiority analysis was performed on the secondary outcome reductions in glucose-lowering medication.Among 98 randomized participants (mean age, 54.6 years [SD, 8.9]; women, 47 [48%]; mean baseline HbA1c, 6.7%), 93 participants completed the trial. From baseline to 12-month follow-up, the mean HbA1c level changed from 6.65% to 6.34% in the lifestyle group and from 6.74% to 6.66% in the standard care group (mean between-group difference in change of -0.26% [95% CI, -0.52% to -0.01%]), not meeting the criteria for equivalence (P = .15). Reduction in glucose-lowering medications occurred in 47 participants (73.5%) in the lifestyle group and 9 participants (26.4%) in the standard care group (difference, 47.1 percentage points [95% CI, 28.6-65.3]). There were 32 adverse events (most commonly musculoskeletal pain or discomfort and mild hypoglycemia) in the lifestyle group and 5 in the standard care group.Among adults with type 2 diabetes diagnosed for less than 10 years, a lifestyle intervention compared with standard care resulted in a change in glycemic control that did not reach the criterion for equivalence, but was in a direction consistent with benefit. Further research is needed to assess superiority, as well as generalizability and durability of findings.clinicaltrials.gov Identifier: NCT02417012.
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Therapy—Breakthrough in Low-Density Lipoprotein Cholesterol Lowering, Breakdown in Value
Authors: Daniel B. Mark, Ilana Richman, Mark A. Hlatky
Journal: JAMA Cardiology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
2週(または4週)間隔の光干渉断層法:Xienceエベロリムス溶出ステント留置後の新生内膜被覆完成の画像的根拠
Authors: Yano Hideki, Horinaka Shigeo, Ishikawa Toshihiko, Ishimitsu Toshihiko
Journal: Circulation (2016)
Erratum to: Insights into the design and interpretation of iCLIP experiments
Authors: Nejc Haberman, Ina Huppertz, Jan Attig, Julian König, Zhen Wang, Christian Hauer, Matthias W. Hentze, Andreas E. Kulozik, Hervé Le Hir, Tomaž Curk, Christopher R. Sibley, Kathi Zarnack, Jernej Ule
Journal: Genome biology (2017)
Urologist Practice Affiliation and Intensity-modulated Radiation Therapy for Prostate Cancer in the Elderly
Authors: Brent K. Hollenbeck, Samuel R. Kaufman, Phyllis Yan, Lindsey A. Herrel, Tudor Borza, Florian R. Schroeck, Bruce L. Jacobs, Ted A. Skolarus, Vahakn B. Shahinian
Journal: European Urology (2017)
LONG-TERM OUTCOMES OF DILATED CARDIOMYOPATHY PRESENTING DURING CHILDHOOD: RESULTS FROM A NATIONAL POPULATION-BASED STUDY OF CHILDHOOD CARDIOMYOPATHY
Authors: Peta M.a. Alexander, Katherine Lee, Piers Daubeney, Christian Turner, Terry Robertson, Alan Nugent, Andrew Davis, James Ramsay, Robert Justo, Tara Bharucha, Ingrid King, Robert G. Weintraub
Journal: Journal of the American College of Cardiology (2010)
AbMiner: A relational database of validated antibodies and corresponding gene identifiers
Authors: Sylvia M. Major, Satoshi Nishizuka, Rick Rowland, Uma Shankavaram, Frank Washburn, Dan Asin, Hosein Kouros-Mehr, John N. Weinstein
Journal: Cancer Research (2004)

4802  We have developed AbMiner, a publicly available relational database of information on commercially available antibodies and their corresponding genomic annotations. The development of AbMiner was motivated by our own group’s need to compile and search such information on hundreds of antibodies used for quantitation of proteins in a proteomic profiling study. We subsequently realized that the compendium would be very useful to the wider biomedical research community for applications in proteomics, immunology, and many other fields. Hence, AbMiner was further developed as a user-friendly program package for wide distribution. One type of information it contains comes from Western blots done for quality control in the context of proteomic profiling of the 60 human cancer cell lines (the NCI-60) used by the NCI’s Developmental therapeutics Program to screen for potential anticancer agents. Included are melanoma and leukemias as well as cancer cell types of ovarian, renal, breast, prostate, lung, colon, and central nervous system origin. Building on the work of Paweletz et al. (Oncogene, 20: 1981, 2001), we developed a higher density version of ‘reverse-phase’ protein lysate microarrays (lysate arrays) and then used them to profile the NCI-60 (Nishizuka, et al., Cancer Res., 63: 5243, 2003 and Nishizuka et al., PNAS, in press). To decide which antibodies would be useful on for detection on those arrays, we created a protein lysate pool consisting of equal amounts of all 60 cell lines and used it for Western blots. Antibodies that gave only a single predominant band at the expected molecular weight were accepted for use on the arrays. AbMiner includes the results of this testing process as well as the array results for a subset of the antibodies. Out of 441 completed antibody screenings, 70% showed a single predominant band. Using MatchMiner (Bussey, et al., Genome Biol., 4: R27, 2003), a web-based program we developed for batch translation of gene and protein identifiers, we matched each antibody’s name with its antigen’s gene symbol. The corresponding gene name, UniGene cluster ID, LocusLink ID, and RefSeq identifiers were then obtained using MatchMiner and other tools (HUGO Gene Nomenclature Committee, LocusLink). Users can browse and search antibodies in AbMiner by screening results or other pertinent information on the antibodies or by gene identifier. AbMiner is available via the web at http://discover.nci.nih.gov/. As an illustration of its utility, we present here the correlations between protein expression levels for 52 proteins from lysate arrays and the corresponding transcript levels as measured using four different microarray platforms.
Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.
Authors: Caroline Robert, Antoni Ribas, Omid Hamid, Adil Daud, Jedd D. Wolchok, Anthony M. Joshua, Wen-Jen Hwu, Jeffrey S. Weber, Tara C. Gangadhar, Richard Wayne Joseph, Roxana Stefania Dronca, Amita Patnaik, Hassane M. Zarour, Richard Kefford, Peter Hersey, Xiaoyun Li, Scott J. Diede, Scot Ebbinghaus, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2016)

9503 Background: The anti–PD-1 antibody pembro (pembro; MK-3475) prevents PD-1 from binding to its ligands, PD-L1 and PD-L2, and is approved for treating advanced melanoma at a dose of 2 mg/kg every 3 wk (Q3W). Pembro demonstrated superior PFS over chemotherapy for ipilimumab (ipi)-refractory melanoma (KEYNOTE-002) and superior OS and PFS over ipi for advanced melanoma (KEYNOTE-006). We present 3-year OS data for all patients (pts) with melanoma enrolled in the phase 1b KEYNOTE-001 study (NCT01295827). Methods: Pts were enrolled in ipi-naive and ipi-treated cohorts and received pembro 2 or 10 mg/kg Q3W or 10 mg/kg Q2W until intolerable toxicity, progression, or investigator decision. Clinically stable pts with radiographic progression could remain on pembro until progression was confirmed. Response was assessed by RECIST v1.1 every 12 wk. After pembro discontinuation, pts were contacted to assess survival every 3 mo. OS was estimated using the Kaplan-Meier method. Results: Of the 655 pts enrolled, 24% had BRAFV600mutation, 78% had stage M1c disease, 38% had elevated LDH, 75% had ≥1 prior therapy, and 52% had prior ipi. As of the Sep 18, 2015, data cutoff date, median follow-up duration was 32 mo (range 24-46) and 358 (55%) pts had died. The 36-mo OS rate was 40% and median OS was 23.8 mo (95% CI, 20.2-29.0), with similar results for each dose (Table). 36-mo OS rates were 41% in both ipi-treated and ipi-naive pts and 45% in treatment-naive pts (Table). Examination of the OS curve suggests a long-term OS benefit for a fraction of pts treated with pembro. Additional data, including PFS, ORR, duration of response, and safety, will be available for presentation. Conclusions: Pembro provides long-term survival benefit in pts with ipi-naive and ipi-treated advanced melanoma, with 40% of pts alive at 3 years. These data support the use of pembrolizumab in pts with advanced melanoma regardless of prior treatment. Clinical trial information: NCT01295827. N Median OS (95% CI), mo 24-mo OS Rate, % 36-mo OS Rate, % Pembro 2 Q3W 162 23.5 (18.3-35.0) 49 38 Pembro 10 Q3W 313 22.9 (18.5-31.1) 49 39 Pembro 10 Q2W 180 25.9 (18.9-41.8) 52 43 Ipi treated 342 20.0 (17.8-27.1) 46 41 Ipi naive 313 28.8 (23.1-32.2) 54 41 Treatment naive* 149 32.0 (27.1-NR) 60 45 *Excludes pts with mucosal melanoma.
P-glycoprotein (P-gp1) as direct modulator of collateral sensitivity in multidrug resistant tumor cells.
Authors: Remi-Martin Laberge, Jing Lian, Elias Georges
Journal: Cancer Research (2007)

2285   Resistance to multiple anti-cancer drugs is a major obstacle in cancer treatment. Such multidrug resistance (MDR), often to chemically unrelated compounds is mediated by the action of several membrane transport proteins or ABC transporters. P-glycoprotein (P-gp1) is the most studied MDR-causative protein. P-gp1 mediates the active efflux of drugs in tumor cell lines with a ratio of ATP molecules to drug of 2:1. The P-gp1 ATPase activity modulator verapamil, has been shown to induce collateral sensitivity. In a previous report (Karwatsky, et. al. Biochemistry, 2003) we demonstrated that verapamil and other collateral sensitivity agents cause apoptosis in MDR cells that over-express P-gp1 in a p53 independent manner, through increased reactive oxygen species resulting from hyper-activation of P-gp1 ATPase. Moreover, inhibitors of P-gp1 ATPases (e.g. PSC833 or Ivermectin) reverse Verapamil-induced collateral sensitivity. Collectively, our earlier results provided a strong correlation between P-gp1 and Verapamil induced collateral sensitivity. In this report, using a siRNA approach, we demonstrate a direct link between P-gp1 expression and verapamil induced collateral sensitivity. Our results demonstrate for the first time that down regulation of P-gp1 expression reverses P-gp1 induced collateral sensitivity to verapamil and other collateral sensitivity-inducing agents or drugs. Moreover, and consistent with the molecular mechanism of verapamil-induced collateral sensitivity with respect to the role of P-gp1 and reactive oxygen species, we show a direct synergy between verapamil and inhibitors of electron-transport chain, (eg. Rotenone & Antimycin A). Taken together, these results resolve a very important and outstanding mechanism relating to the role of P-gp1 in collateral sensitivity. In addition, these findings open up the possibility of developing highly specific anti-cancer drugs to MDR tumors.