tbuckley/cabot-search huggingface dataset:
MM-121: a human monoclonal antibody ErbB3 antagonist
Authors: Birgit Schoeberl, Kip West, Magdalena Leszczyniecka, Lin Nie, Olga Burenkova, Bryan Linggi, Aaron Fulgham, Art Kudla, Joe Toth, Violette Paragas, Lihui Xu, Viara Grantcharova, Raghida Bukhalid, Washington Alves, Matt Wallace, Jose Varghese, Mike Feldhaus, Aparna Kumar, Jonathan Fitzgerald, Emily Pace, William Slichenmyer, Ulrik Nielsen
Journal: Cancer Research (2008)

3974   The role of the EGFR family in cancer is well documented. To date most of the attention has been focused on EGFR and ErbB2. We have taken a systems approach to understanding ErbB signaling and built a comprehensive computational model of the pathway. Simulations revealed ErbB3 as an ultra-sensitive node in the ErbB pathway and suggested it as a better target for therapeutic intervention. Historically, ErbB3 has not been considered as an attractive target because of its impaired kinase activity and low expression in tumors although recent publications suggest a key role in promoting resistance to EGFR and ErbB2 targeted therapeutics.  Human monoclonal IgG2 antibodies against ErbB3 were then developed and tested in multiple orthogonal assays for the ability to modulate ErbB3 activity and one candidate, MM-121, was chosen to move forward into pre-clinical testing. MM-121 demonstrated potent inhibition of heregulin-induced signaling events in human cancer cell lines.  When MM-121 efficacy was assessed in vivo, MM-121 showed a dose-dependent ability to inhibit tumor growth in multiple xenograft models of human cancer, including ovarian, renal cell, pancreatic and prostate cancer. Pharmacodynamic analysis of samples from these studies showed that chronic MM-121 administration resulted in inhibition of ErbB3 activity which correlated with efficacy.  In vitro antibody binding studies suggested that MM-121 binds to ErbB3 receptors from mouse, rat, cynomolgus monkey and human with a similar affinity. In order to design an efficacious and safe dosing regimen, pre-clinical studies were carried out in mouse, rat and cynomolgus monkey. These studies suggest that MM-121 can safely be administered at serum levels that produce in good inhibition of ErbB signaling and efficacy in xenograft models of cancer.  Cumulatively, these data support that MM-121 could have significant clinical benefit for the treatment of cancer and warrant proceeding forward into phase 1 clinical trials.
Effect of Chemically Defined Medium NCTC 109 Supplemented With Methocel and of Silicone Coating the Flasks on Strain 2071 Cells in Suspension Cultures&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Jay C. Bryant, Virginia J. Evans, Edward L. Schilling, Wilton R. Earle
Journal: JNCI Journal of the National Cancer Institute (1961)

In earlier studies with rapidly agitated fluid-suspension cultures, cells of all strains tested on protein-free, chemically defined medium NCTC 109 had undergone rapid and complete disintegration. In the present study, this medium, supplemented with a methylcellulose, supported slow, logarithmic proliferation of cells of strain 2071 in such cultures, provided the inner walls of the flasks were coated with a silicone. Rates of increase ranging from 2.7 to 9.5 days were directly correlated with size of inoculum. Maximum populations attained at the end of the logarithmic phase in different experiments were about 1.1 × 106 cells/ml. Glucose was utilized at relatively low rates, 0.20 to 0.35 mg/106 cells/day. Methocel supplement in silicone-coated flasks was uniformly effective as a protective agent within the low viscosity grades and the wide range of concentrations tested. The roles of Methocel and of silicone are discussed, but explanation of their action must await further research.
Physiological parameters regulating circulating levels of the IGFBP-4/Stanniocalcin-2/PAPP-A axis
Authors: Grigorios Panagiotou, Athanasios D. Anastasilakis, Georgios Kynigopoulos, Elpida C. Skouvaklidou, Zacharias G. Saridakis, Jagriti Upadhyay, Eirini Pagkalidou, Aggeliki Apostolou, Thomai Karagiozoglou-Lampoudi, Christos S. Mantzoros
Journal: Metabolism (2017)
Abstract 11057: Treatment Decisions for Coronary Artery Disease After Cardiac Catheterization
Authors: Brian R Englum, Phillip Schulte, Brian Gulack, Manesh R Patel, John H Alexander, Peter K Smith
Journal: Circulation (2013)

Introduction:  Treatment for CAD can be divided into 3 strategies: medical therapy (MT), PCI, and CABG. Previous research has focused on outcomes for these strategies; however, studies have not examined the factors driving these decisions, or how these decisions have changed over time.   Methods:  Using institutional data, we evaluated 22,537 patients undergoing catheterization from 1986 to 2012 who had significant CAD (≥1 coronary artery with ≥75% stenosis). Logistic regression models examined the association of patient baseline characteristics with the decision for revascularization vs. MT and for CABG vs. PCI. Models were developed in 3 different eras (Balloon angioplasty, 1986-1995; BMS, 1996-2003; DES, 2004-2012). In addition, we developed a combined model using all 3 eras to evaluate changes in decision making over time.   Results:  During the study interval, the percent of patients having PCI increased dramatically, while CABG and MT rates fell (Figure 1). Significant factors influencing the decision to revascularize included STEMI, CAD severity, LV EF, and age. Increasingly complex CAD favored CABG over PCI, but this relationship has not changed over the study interval. Comorbidities, including diabetes and decreasing LV EF, appeared to have little influence on this decision (Figure 2).   Conclusion:  Cardiac factors appear to dominate decisions about revascularization. Trends in treatment may be partly due to increased use of primary PCI for STEMI. Despite evidence of the benefits of CAGB in cohorts with DM and CHF, these factors appear to have had little influence on decision making regarding the method of revascularization.
Identifying <i>HER2</i> mutation, amplification, and HER2 protein overexpression as therapeutic targets in lung cancers.
Authors: Bob T. Li, Tao Zheng, Ai Ni, Matthew David Hellmann, Emmet Jordan, David Barron, Lillian Mary Smyth, David B. Solit, Ahmet Zehir, Dara S. Ross, Michael F. Berger, Marc Ladanyi, Charles M. Rudin, Mark G. Kris, Maria E. Arcila
Journal: Journal of Clinical Oncology (2016)

e20666 Background: We have previously shown that human epidermal growth factor receptor 2 (HER2, ERBB2) mutation and amplification represent distinct molecular entities in lung cancers (Li J Thorac Oncol 2015). The optimal method for assessing HER2 status in lung cancers for targeted therapy remains undefined. Methods: Prospective next generation sequencing (NGS) was performed on lung adenocarcinoma specimens by Memorial Sloan Kettering-Integrated Mutation Profiling for Actionable Cancer Targets (MSK-IMPACT) for potentially actionable drivers across 410 cancer related genes in 2014-2015 encompassing HER2 mutation (indels and point mutations) and amplification (fold change ≥ 1.5). Specimens found to have HER2 mutations or amplification were further assessed by fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC). HER2 IQFISH pharmDx, Dako probe was used for FISH with HER2/CEP17 ratio ≥ 2.0 defined as positive. The 4B5 Ventana antibody was used for HER2 protein overexpression by IHC. Results of the various HER2 testing were compared. Results: A total of 776 lung adenocarcinomas underwent NGS and found 21 cases (3%) of HER2 mutation and 20 cases (3%) of HER2 amplification; only one case showed concurrent mutation and amplification (S310F, fold change 11.7). 12 mutant cases (57%) harbored an identical 12bp insertion in exon 20 (p.A775_G776insYVMA). FISH analysis of 34 samples (18 mutant, 14 amplified) was positive in 1 of 18 mutant and 14 of 14 NGS amplified cases. IHC analysis of 18 mutant cases ranged from 0 to 2+, and analysis of 12 amplified cases showed high correlation with IHC 3+. All cases of HER2 amplification by FISH or high level HER protein overexpression (IHC 3+) were captured by NGS. Conclusions: This independent study confirmed that HER2 mutation and HER2 amplification are distinct molecular targets in lung cancers. IHC and FISH are suitable methods for identifying HER2 amplification but are not surrogates for assessing HER2 mutation. NGS identified HER2 mutation and all cases of HER2 amplification or high level HER2 overexpression, and constitutes an ideal method of upfront screening for all HER2 alterations for selecting patients for HER2 targeted therapy.
Abstract P218: PKCε Regulates PI3K/mTOR Complex-2-Dependent AKT Activation Independent of c-Raf/MEK/ERK Pathway
Authors: Phillip Moschella, John McKillop, Rebecca Harston, Dhandapani Kuppuswamy
Journal: Circulation Research (2011)

Mammalian target of rapamycin (mTOR) has been shown to influence hypertrophic growth of the myocardium through two unique complexes, mTOR complexed with Raptor (mTORC1) and mTOR complexed to Rictor (mTORC2) with downstream activation of S6K1 and AKT respectively. Previously, we characterized the role of novel PKC isoforms (epsilon and delta) on mTORC1-dependent activation of S6K1 downstream of both PI3K-dependent and independent pathways in adult cardiomyocytes. PKC epsilon (PKCε) has been implicated in AKT activation during ischemia-reperfusion injury and has been co-immunoprecipitated in transgenic PKCε overexpressing murine myocardium. In the present study, we explored the role of PKCε on PI3K-dependent AKT S473 phosphorylation. As such, insulin stimulated pAKT S473 was significantly reduced by pretreatment with wortmannin, a selective PI3K inhibitor. However, insulin stimulated activation of AKT was not reduced by pretreatment with either Gö6976 blockade of the classical PKC isoforms (PKC alpha/beta) or U0126 blockade of MEK. Thus, insulin stimulated activation of AKT is mediated primarily through a PI3K-dependent pathway independent of the classical PKC isoforms. To begin to evaluate the role of the novel PKCs, we utilized adenoviral expression of dominant negative PKCε (dnPKCε). After 48 hours of expression of dnPKCε, insulin stimulated pAKT S473 was significantly reduced as compared to B-gal infection controls. Next we identified for the first time in isolated cardiomyocytes a direct link between PKCε and AKT through immunoprecipitation of a unique signaling complex comprised of PKCε bound to mTORC2 and pAKT (S473) only during insulin stimulation. These data establish for the first time in adult isolated cardiomyocytes: i) the necessity of PKCε during insulin stimulated PI3K-dependent AKT activation and ii) a signaling complex containing mTOR, Rictor, PKCε, and pAKT that forms during insulin stimulation. Given the importance of AKT in physiologic growth and survival, these studies indicate that PKCε plays a pivotal role during AKT activation and for the first time displays a direct link between PKCε, pAKT and mTORC2 in isolated cardiomyocytes.
Paediatrician jailed for downloading child porn is struck off
Authors: Clare Dyer
Journal: BMJ (2017)

A consultant paediatrician who was sentenced to three years in prison last March for downloading images and videos of child sexual abuse has been struck off by a medical practitioners tribunal in Manchester.

Jonathan Walsh, 47, who is in Dartmoor Prison, did not ask to attend the hearing or request an adjournment. This, argued a lawyer for the General Medical Council, suggested that Walsh regarded the outcome as inevitable.

Guidelines for medical practitioners tribunals state that, in convictions involving child pornography, it is “highly likely that . . . the only proportionate sanction will be erasure” and …
Relative Carcinogenic Activity of Monomethyl Derivatives of Benz[&lt;italic&gt;a&lt;/italic&gt;]anthracene in Fischer Line 344 Rats&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: W. F. Dunning, M. R. Curtis
Journal: JNCI Journal of the National Cancer Institute (1960)

All 12 monomethyl derivatives of benz [a]anthracene were tested for carcinogenic potency by bilateral subcutaneous injection of 2 mg. in 0.2 cc. of paraffin in each of 60 Fischer line 344 rats. Four of the compounds (10-, 4-, 5-, 9-methyl benz[a]anthracene) were highly carcinogenic. Five of the derivatives (7-, 6-, 4′-, 3-, and 1′-methyl benz[a]anthracene) were weakly active and the remaining 3 (3′-, 2′-, and 8-methyl benz[a]anthracene) were inactive. The induced neoplasms were observed with almost equal frequency and in approximately the same average latent period in males and females. Ninety percent of the 248 induced neoplasms were classified as fibrosarcomas or sarcomas of myogenic origin. These were the most frequent types induced by each of the active compounds.
Verification of biomarkers in predicting drug sensitivity with in vitro 3D drug sensitivity test in non-small cell lung cancer.
Authors: Dage Liu, Nariyasu Nakashima, Yoshuke Kita, Yoshimasa Tokunaga, Kazuhito Nii, Natsumi Matsuura, Jun Nakano, Shintaro Tarumi, Masaya Okuda, Tetsuhiko Go, Xia Zhang, Yoshiyuki Kakehi, Hiroyasu Yokomise
Journal: Journal of Clinical Oncology (2016)

11602 Background: Various molecules have been reported to participate in the sensitivity of chemotherapy and their expression in tumor was used as biomarkers in predicting the response to chemotherapy clinically. Biomarkers have been applied to anti-cancer agent selecting and show a promising usefulness for individualized treatment. However, the utility of biomarkers was usually inspected by the clinical survival rate or the rate of reduction in tumors, direct correlation to the anti-cancer drug sensitivity has not been well proved. Collagen gel droplet embedded culture-drug sensitivity test (CD-DST) is a newly developed in vitro chemosensitivity test that has several advantages over the conventional ones. The predictive value of biomarkers to the anti-cancer agent sensitivity was invested using CD-DST test in non-small cell lung cancer (NSCLC) tumor. Methods: Eighteen patients with primary NSCLC were recruited in this study. For CD-DST test, viable cells were collected from fresh surgical specimen and embed into the collagen gel droplets in 3D condition. Tumor cells were exposed to 5-FU or docetaxel (DOC) for 24 hours and further incubated with serum-free culture medium for 7 days. The in vitro sensitivity was expressed as the percentage T/C ratio, where T was the total volume of the treated group and C was the total volume of the control group. Expression of thymindylate synthase (TS) (biomarker for 5-FU) and beta III-tubulin (biomarker for DOC) was assessed by immunohistochemistry. Results: 1): Anti-cancer drug sensitivity: The sensitivity for 5F-U (T/C%) was 77.1 ± 18.1, and the sensitivity for DOC was 74.9 ± 22.8. 2): Expression of biomarkers: TS expression was 47.4 ± 32.8, and beta III tubulin expression was 42.2 ± 26.2. 3): Correlation: The expression of TS and beta III tubulin significantly correlated with drug sensitivity for 5-FU and DOC respectively (r = 0.635, p = 0.0046; r = 0.503, p = 0.0033). Higher expression of biomarkers indicated worse anti-cancer drug sensitivity. Conclusions: The significant correlation between the biomarkers and sensitivity to anti-cancer agent was proved in NSCLC tumors. CD-DST may become a useful tool in inspecting the usefulness of biomarkers.
A phase 1 first-in-human (FIH) dose-escalation (DE) study of the oral dual PI3K/mTOR inhibitor PQR309 in patients (pts) with advanced solid tumors: Final DE results.
Authors: Rebecca Sophie Kristeleit, Nicholas F. Brown, Dagmar Hess, Markus Joerger, Roger Von Moos, Jordi Rodón, Cinta Hierro, Alexa Childs, Anastasios Stathis, Sasa Dimitrijevic, Michael Stumm, Richard Herrmann, Cristiana Sessa, Vincent Bize, Viviane Hess, Andreas Wicki
Journal: Journal of Clinical Oncology (2015)

2592 Background: PQR309 is a novel, orally bioavailable, balanced pan-PI3K, mTORC1 and mTORC2 inhibitor. Methods: An accelerated 3+3 DE, open label Phase 1 trial of continuous once daily (OD) PQR309 to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD) in pts with advanced solid tumours was performed. Pts had no standard therapeutic options. An expansion cohort at maximum tolerated dose (MTD) is planned. The starting dose of PQR309 was 10mg OD. The dose limiting toxicity (DLT) period was the first cycle of treatment, 21 days (d). Paired tumour biopsies (PTB) were collected. Results: 25 pts (18F:7M) were enrolled as of January 2015 and treated at 11 doses ranging from 10-150mg. Common adverse events (AE) ( ≥ 30% pts) included fatigue, hyperglycaemia, nausea, diarrhea, constipation, rash, anorexia and vomiting. Grade (G) 3/4 drug-related AE were seen in 11 and 3 pts respectively. The most common drug-related AE ≥ G3 was hyperglycaemia observed in 7 pts. DLT occurred in 2/6 pts at 100mg OD associated with sequential AE G2-4; one patient (pt) with > 14d interruption in PQR309 due to G2-4 rash, hyperbilirubinaemia, suicide attempt and one pt with dose reduction to 80 mg due to G2-3 fatigue, diarrhea, transaminitis, both during cycle 1. Preliminary PK shows fast absorption (Tmax 1-2h), dose proportionality for Cmax and AUC and an estimated T1/2 of around 20 hours, consistent with PQR309 in vivo models. Preliminary PD analysis of 16 phosphoproteins (PP) involved in PI3K/mTOR/MAPK signalling in PTB shows marked decrease of p-Akt, pS6 and p4EPB from 40mg OD with moderate inhibition of p-Erk. A partial response (PR) in a pt with metastatic thymus cancer (ca) and RICTOR gene amplification, 24% disease volume reduction in a pt with sinonasal ca and PIK3CA E545K mutation and stable disease for over 16 weeks in a pt with clear cell Bartholin’s gland ca have been observed. Conclusions: The MTD and recommended phase-2 dose of PQR309 is 80mg OD. PD shows PI3K pathway PP downregulation in PTB and PK is dose-proportional. Clinical activity including a PR has been observed in pts with known PI3K pathway dysregulation. Recruitment in the 80mg and planned expansion cohort is ongoing. Clinical trial information: NCT01940133.
Induction of Hepatic Lesions, Hepatomas, Pulmonary Tumors, and Hemangio-Endotheliomas in Mice With &lt;italic&gt;o&lt;/italic&gt;-Aminoazotoluene
Authors: Howard B. Andervont, Hugh G. Grady, Jesse E. Edwards
Journal: JNCI Journal of the National Cancer Institute (1942)

Journal Article Induction of Hepatic Lesions, Hepatomas, Pulmonary Tumors, and Hemangio-Endotheliomas in Mice With o-Aminoazotoluene Get access Howard B. Andervont, Howard B. Andervont principal biologist Search for other works by this author on: Oxford Academic PubMed Google Scholar Hugh G. Grady, Hugh G. Grady acting assistant surgeon Search for other works by this author on: Oxford Academic PubMed Google Scholar Jesse E. Edwards Jesse E. Edwards research fellow National Cancer Institute, National Institute of Health, United States Public Health Service. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 3, Issue 2, October 1942, Pages 131–153, https://doi.org/10.1093/jnci/3.2.131 Published: 01 October 1942
Novel Latency Reversal Agents for HIV-1 Cure
Authors: Adam M. Spivak, Vicente Planelles
Journal: Annual Review of Medicine (2017)

Antiretroviral therapy (ART) has rendered HIV-1 infection a treatable illness; however, ART is not curative owing to the persistence of replication-competent, latent proviruses in long-lived resting T cells. Strategies that target these latently infected cells and allow immune recognition and clearance of this reservoir will be necessary to eradicate HIV-1 in infected individuals. This review describes current pharmacologic approaches to reactivate the latent reservoir so that infected cells can be recognized and targeted, with the ultimate goal of achieving an HIV-1 cure.
Prenatal environmental tobacco smoke exposure and children's respiratory health
Authors: Lyudmila Jelenina, Olga Lavrova, Maria Petrova
Journal: European Respiratory Journal (2011)

Background: Exposure to environmental tobacco smoke (ETS) is associated with respiratory symptoms.

Prenatal ETS exposure is associated with impaired lung function and wheezing illnesses, particularly in preschool children. Although negative impact of prenatal ETS exposure on children is evident, ETS impact on respiratory system of infants is still poorly explored.

Purpose: To assess the possible effects of ETS exposure in utero on lower respiratory disease in children from infants up to seven years of age.

Methods: We evaluated the health impact of ETS in 117 infants born from asthmatic mothers. We also analyzed the onset of wheeze & asthma by the age of 7 with regard to the impact of ETS.

Results: The prevalence of wheeze during the first year of life was 4.7 times higher in infants who were prenatally exposed to ETS (OR-4.69 [CI:1.63-13.52]) compared to children without ETS exposure. However, no differences in allergic asthma prevalence by 7 years of age were found between the patient groups.

Conclusions: The research results provide strong evidence linking prenatal ETS to impairments in infants' respiratory system.
Accuracy of Cuff-Measured Blood Pressure
Authors: Dean S. Picone, Martin G. Schultz, Petr Otahal, Svend Aakhus, Ahmed M. Al-Jumaily, J. Andrew Black, Willem J. Bos, John B. Chambers, Chen-Huan Chen, Hao-Min Cheng, Antoine Cremer, Justin E. Davies, Nathan Dwyer, Brian A. Gould, Alun D. Hughes, Peter S. Lacy, Esben Laugesen, Fuyou Liang, Roman Melamed, Sandy Muecke, Nobuyuki Ohte, Sho Okada, Stefano Omboni, Christian Ott, Xiaoqing Peng, Telmo Pereira, Giacomo Pucci, Ronak Rajani, Philip Roberts-Thomson, Niklas B. Rossen, Daisuke Sueta, Manish D. Sinha, Roland E. Schmieder, Harold Smulyan, Velandai K. Srikanth, Ralph Stewart, George A. Stouffer, Kenji Takazawa, Jiguang Wang, Berend E. Westerhof, Franz Weber, Thomas Weber, Bryan Williams, Hirotsugu Yamada, Eiichiro Yamamoto, James E. Sharman
Journal: Journal of the American College of Cardiology (2017)
Re: Jaffe et al.: Injectable fluocinolone acetonide long-acting implant for noninfectious intermediate uveitis, posterior uveitis, and panuveitis: 2-year results ( Ophthalmology . 2016;123:1940-1948)
Authors: Ankita Shrivastav, Rahul Mayor, Manisha Agarwal, Ramesh Venkatesh, Shalini Singh
Journal: Ophthalmology (2017)
TRP Channels as Potential Drug Targets
Authors: Magdalene M. Moran
Journal: The Annual Review of Pharmacology and Toxicology (2017)

The transient receptor potential (TRP) superfamily of channels comprises a diverse group of cation channels. Four TRP channel subunits coassemble to form functional homo- or heterotetramers that pass sodium, calcium, or both in the inward direction. Modulating TRP channel activity provides an important way to impact cellular function by regulating both membrane excitability and intracellular calcium levels. The import of these channels is underscored by the number of genetic diseases caused when they are mutated: Skeletal, skin, sensory, ocular, cardiac, and neuronal disturbances all arise from aberrant TRP function. Not surprisingly, there has been significant pharmaceutical interest in targeting these fascinating channels. Compounds that modulate TRP vanilloid 1 (TRPV1), TRPV3, TRPV4, TRP ankyrin 1 (TRPA1), and TRP melastatin 8 (TRPM8) have all entered clinical trials. The goal of this review is to familiarize the readers with the rationale behind the pursuit of these channels in drug discovery and the status of those efforts.