tbuckley/cabot-search huggingface dataset:
Folate receptor targeted anti-tumor activity of EC-0225, a folate-targeted dual drug conjugate
Authors: Joseph A. Reddy, Hari K. Santhapuram, Elaine Westrick, Marilynn Vetzel, Alicia Dawson, Ryan Dorton, Terri Smith, Iontcho Vlahov, Christopher P. Leamon
Journal: Cancer Research (2006)

568  The membrane-bound folate receptor (FR) is overexpressed on a wide range of primary and metastatic human cancers, such as those originating in ovary, lung, breast, endometrium, kidney and brain. Since folate-linked conjugates are known to be efficiently bound and internalized by FR-expressing cells, similar to the free vitamin, we have explored the possibility of using a single folate ligand to simultaneously target two small molecule chemotherapeutic drugs to the same FR. Herein we report the in vitro and in vivo evaluation of EC-0225, a novel folate conjugate of two drugs- one a potent microtubule inhibiting agent, and the second a DNA alkylating drug. When tested on cells in culture, EC-0225 was found to provide specific dose-dependent potency. Thus, EC-0225 inhibited the growth of FR-positive KB cells with an IC50 of ∼ 1 nM. The cytotoxic activity was greatly reduced in the presence of a large excess of folic acid. In addition, EC-0225 displayed no activity on FR-negative cells, thereby demonstrating this compound9s specificity. EC-02259s activity was next evaluated against FR-positive tumors in mice. Thus, Balb/c mice bearing subcutaneous M109 tumors (syngeneic lung carcinoma) were treated intravenously with EC-0225, and this brief therapy caused complete remissions (CRs) in 4 of 5 animals. Furthermore, the activity occurred in the absence of weight loss or major organ tissue degeneration. In contrast, greatly reduced anti-tumor activity (0/5 CRs) was observed in EC-0225-treated animals that were co-dosed with a non-drug containing folate. EC-02259s potency was also confirmed in a second cancer model, human KB xenografts growing in nu/nu mice. Here, EC-0225 therapy again displayed remarkable anti-tumor activity (5/5 CRs), and this activity also occurred in the absence of weight loss or major organ tissue degeneration. In contrast, combination therapy at various doses of the two free drugs proved to be very toxic when administered at equivalent levels, and this regimen was not effective at lower non-toxic dose levels. The ability of EC-0225 therapy to inhibit the growth of large (250, 500 and 750 mm3) tumors was also tested and found to be extremely active against all tumor sizes. Importantly, this is the first presentation demonstrating that a FR-targeted chemotherapeutic drug can effect regression of such large established tumors in an animal model. Taken together, the above results indicate that EC-0225 is a highly promising chemotherapeutic agent which can be selectively delivered to advanced FR-positive tumors without causing overt toxicity.
Personalizing Risk Stratification for Sudden Death in Dilated Cardiomyopathy
Authors: Brian P. Halliday, John G.F. Cleland, Jeffrey J. Goldberger, Sanjay K. Prasad
Journal: Circulation (2017)

Results from the DANISH Study (Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heat Failure on Mortality) suggest that for many patients with dilated cardiomyopathy (DCM), implantable cardioverter-defibrillators do not increase longevity. Accurate identification of patients who are more likely to die of an arrhythmia and less likely to die of other causes is required to ensure improvement in outcomes and wise use of resources. Until now, left ventricular ejection fraction has been used as a key criterion for selecting patients with DCM for an implantable cardioverter-defibrillator for primary prevention purposes. However, registry data suggest that many patients with DCM and an out-of-hospital cardiac arrest do not have a markedly reduced left ventricular ejection fraction. In addition, many patients with reduced left ventricular ejection fraction die of nonsudden causes of death. Methods to predict a higher or lower risk of sudden death include the detection of myocardial fibrosis (a substrate for ventricular arrhythmia), microvolt T-wave alternans (a marker of electrophysiological vulnerability), and genetic testing. Midwall fibrosis is identified by late gadolinium enhancement cardiovascular magnetic resonance imaging in ≈30% of patients and provides incremental value in addition to left ventricular ejection fraction for the prediction of sudden cardiac death events. Microvolt T-wave alternans represents another promising predictor, supported by large meta-analyses that have highlighted the negative predictive value of this test. However, neither of these strategies have been routinely adopted for risk stratification in clinical practice. More convincing data from randomized trials are required to inform the management of patients with these features. Understanding of the genetics of DCM and how specific mutations affect arrhythmic risk is also rapidly increasing. The finding of a mutation in lamin A/C, the cause of ≈6% of idiopathic DCM, commonly underpins more aggressive management because of the malignant nature of the associated phenotype. With the expansion of genetic sequencing, the identification of further high-risk mutations appears likely, leading to better-informed clinical decision making and providing insight into disease mechanisms. Over the next 5 to 10 years, we expect these techniques to be integrated into the existing algorithm to form a more sensitive, specific, and cost-effective approach to the selection of patients with DCM for implantable cardioverter-defibrillator implantation.
Large Variation in the Ratio of Mitochondrial to Nuclear Mutation Rate across Animals: Implications for Genetic Diversity and the Use of Mitochondrial DNA as a Molecular Marker
Authors: Remi Allio, Stefano Donega, Nicolas Galtier, Benoit Nabholz
Journal: Molecular Biology and Evolution (2017)

It is commonly assumed that mitochondrial DNA (mtDNA) evolves at a faster rate than nuclear DNA (nuDNA) in animals. This has contributed to the popularity of mtDNA as a molecular marker in evolutionary studies. Analyzing 121 multilocus data sets and four phylogenomic data sets encompassing 4,676 species of animals, we demonstrate that the ratio of mitochondrial over nuclear mutation rate is highly variable among animal taxa. In nonvertebrates, such as insects and arachnids, the ratio of mtDNA over nuDNA mutation rate varies between 2 and 6, whereas it is above 20, on average, in vertebrates such as scaled reptiles and birds. Interestingly, this variation is sufficient to explain the previous report of a similar level of mitochondrial polymorphism, on average, between vertebrates and nonvertebrates, which was originally interpreted as reflecting the effect of pervasive positive selection. Our analysis rather indicates that the among-phyla homogeneity in within-species mtDNA diversity is due to a negative correlation between mtDNA per-generation mutation rate and effective population size, irrespective of the action of natural selection. Finally, we explore the variation in the absolute per-year mutation rate of both mtDNA and nuDNA using a reduced data set for which fossil calibration is available, and discuss the potential determinants of mutation rate variation across genomes and taxa. This study has important implications regarding DNA-based identification methods in predicting that mtDNA barcoding should be less reliable in nonvertebrates than in vertebrates.
STARVE-PC: Biomarker-driven phase 2 study of ipilimumab plus nivolumab for AR-V7-expressing metastatic castration-resistant prostate cancer (mCRPC).
Authors: Karim Boudadi, Daniel L. Suzman, Brandon Luber, Hao Wang, John L. Silberstein, Maritza N. Taylor, Rana Sullivan, Donna Dowling, Rana Harb, Ryan Vance Dittamore, Alan Meeker, Jun Luo, Charles G. Drake, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2016)

TPS5089 Background: AR-V7 is an AR splice variant present in ~20% of men with mCRPC, and is associated with poor responses to abiraterone and enzalutamide. Developing effective treatments for AR-V7+ mCRPC is an unmet medical need, and combined immune checkpoint blockade may be a fruitful approach in such pts. Previous studies have shown benefits using ipilimumab in a subset of mCRPC pts. Given that treatment of prostate cancer cells with potent anti-androgens may induce PD-L1 expression, and given that the AR-V7+ phenotype may be associated with DNA repair defects (mismatch repair, homologous recombination), we hypothesize that the addition of nivolumab in AR-V7+ mCRPC men will improve the response rates seen with ipilimumab, and that the combination will be safe and tolerable. We also hypothesize that successful treatment with this combination may correlate with conversion of AR-V7 from positive to negative, and with baseline PD-L1 expression in CTCs and tumor biopsies. Methods: STARVE-PC is a single-arm open-label phase 2 trial (NCT02601014) of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 wks x 4 doses, followed by nivolumab 3 mg/kg every 2 wks. Treatment will continue until wk 48, radiologic progression, or unmanageable toxicity. The target population (N = 15) is men with mCRPC and detectable AR-V7 using our CTC-enriched RT-PCR–based assay performed in a CLIA lab. CTCs will be collected for AR-V7 analysis at baseline, at wk 12, and at progression, to allow dynamic evaluation of AR-V7 status. The primary endpoint is PSA50 response rate; the trial will meet its endpoint if ≥ 3/15 men achieve a PSA50 response. Additional clinical endpoints include PSA progression free survival (PSA-PFS), clinical/radiologic PFS, objective responses, overall survival, and frequency/intensity of adverse events. We will prospectively assess baseline PD-L1 status in CTCs and metastatic tumor biopsies, and DNA repair defects will also be examined in an exploratory fashion. If this study shows preliminary evidence of clinical activity and reasonable safety, our future goal will be to compare the efficacy of combined checkpoint blockade versus taxane chemotherapy in AR-V7+ mCRPC. Clinical trial information: NCT02601014.
Effect of Supplementary Methionine or Choline Plus Cystine on the Incidence of &lt;italic&gt;p&lt;/italic&gt;-Dimethylaminoazobenzene-induced Hepatic Tumors in the Rat
Authors: Julius White, Jesse E. Edwards
Journal: JNCI Journal of the National Cancer Institute (1942)

Effect of Supplementary Methionine or Choline Plus Cystine on the Incidence of p-Dimethylaminoazobenzene-induced Hepatic Tumors in the Rat Get access Julius White, Julius White senior biochemist 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 1, August 1942, Pages 43–59, https://doi.org/10.1093/jnci/3.1.43 Published: 01 August 1942
Targeted Next Generation Sequencing Identifies Novel Genetic Mutations in Patients with Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma or IgM-Monoclonal Gammopathies of Undetermined Significance
Authors: Marzia Varettoni, Silvia Zibellini, Ettore Rizzo, Luca Malcovati, Virginia Valeria Ferretti, Matteo Giovanni Della Porta, Anna Gallì, Luca Arcaini, Irene Defrancesco, Mario Cazzola
Journal: Blood (2016)
The impact of insurance status on racial disparities in cancer outcomes for nonelderly adults: A population based analysis.
Authors: Hubert Pan, Gary V. Walker, Pamela Allen, Stephen Grant, Beverly Ashleigh Guadagnolo, Benjamin D. Smith, Matthew Koshy, Chad G Rusthoven, Usama Mahmood
Journal: Journal of Clinical Oncology (2016)

e18068 Background: Previous studies have repeatedly demonstrated racial disparities in cancer outcomes. The objective of this study was to determine the relationship between these disparities and type of insurance. Methods: Patients 18 to 64 years old diagnosed with one of the 5 most deadly cancers (lung, breast, prostate, colorectal, and pancreas) in the Surveillance Epidemiology and End Results (SEER) database from 2007 to 2012 were analyzed. A Cox proportional hazards model for cancer specific survival (CSS) was constructed using known prognostic factors (age, race, gender, marital status, extent of disease, county poverty level, insurance type, residence type, receipt of cancer-directed surgery or radiation, and disease site) as covariates. Interaction between race and insurance was assessed by adding an interaction term to the Cox model. The cohort was then separated by insurance type; within each subset, racial variation in CSS was estimated by Kaplan Meier and the prior Cox model was applied to determine racial disparity after adjustment for the above factors. Results: Of the 479,028 patients in this cohort, 83% had non-Medicaid insurance, 12% had Medicaid insurance, and 5% were uninsured. The racial breakdown of the group was 66% White, 15% Black, 10% Hispanic, 7% Asian, and 1% Native American. On multivariable analysis, there was a significant interaction between race and insurance status (Interaction-P < 0.001). At a median follow up of 25 months, the range of 2-year CSS among different races was 16%, 17%, and 6% for uninsured, Medicaid, and non-Medicaid patients, respectively. Variation in hazard ratios (HR) for CSS by race was greatest for uninsured patients (HR for Black = 1.40, P < 0.001; HR for White = 1.43, P < 0.001), intermediate for Medicaid patients (HR for Black = 1.29, P < 0.001; HR for White = 1.27, P < 0.001), and least for non-Medicaid insurance patients (HR for Black = 1.19, P < 0.001; HR White = 1.05, P < 0.001) (all HR with Hispanic as reference). Conclusions: Among patients diagnosed with the 5 most deadly cancers, racial variation in CSS was greatest for patients without insurance. Expanding insurance coverage may help decrease racial variation in cancer outcomes.
Effects of the 2009 Medical Cannabinoid Legalization Policy on Hospital Use for Cannabinoid Dependency and Persistent Vomiting
Authors: Mustafa Al-Shammari, Karina Herrera, Xibei Liu, Brandon Gisi, Takashi Yamashita, Kyu-Tae Han, Mohamed Azab, Harmeet Mashiana, Muthena Maklad, Muhammad Talha Farooqui, Ranjit Makar, Ji Won Yoo
Journal: Clinical Gastroenterology and Hepatology (2017)
Scrapped training programme was helping to increase GP numbers, review finds
Authors: Abi Rimmer
Journal: BMJ (2017)

A broad based training programme that was scrapped in 2015 was encouraging more trainees into general practice, including those who were not of a “generalist disposition,” a review of the programme has concluded.1

The Academy of Medical Royal Colleges introduced a two year broad based training programme in 2013. It gave trainees experience in general practice, psychiatry, paediatrics, and general medicine. In 2015, however, Health Education England decided to end recruitment to the programme,2 although the programme is still available in Scotland and Wales.

A review of the training programme, conducted by Cardiff University, has found that most of the trainees who took part chose to enter GP training.1 …
RHOA-ROCK signalling is necessary for lateralization and differentiation of the developing sinoatrial node
Authors: Rebecca Vicente-Steijn, Tim P. Kelder, Leon G. Tertoolen, Lambertus J. Wisse, Daniël A. Pijnappels, Robert E. Poelmann, Martin J. Schalij, Marco C. deRuiter, Adriana C. Gittenberger-de Groot, Monique R.M. Jongbloed
Journal: Cardiovascular Research (2017)

RHOA-ROCK signalling regulates cell migration, proliferation, differentiation, and transcription. RHOA is expressed in the developing cardiac conduction system in chicken and mice. In early development, the entire sinus venosus myocardium, including both the transient left-sided and the definitive sinoatrial node (SAN), has pacemaker potential. Later, pacemaker potential is restricted to the right-sided SAN. Disruption of RHOA expression in adult mice causes arrhythmias including bradycardia and atrial fibrillation, the mechanism of which is unknown but presumed to affect the SAN. The aim of this study is to assess the role of RHOA-ROCK signalling in SAN development in the chicken heart.ROCK signalling was inhibited chemically in embryonic chicken hearts using Y-27632. This prolonged the immature state of the sinus venosus myocardium, evidenced by up-regulation of the transcription factor ISL1, wide distribution of pacemaker potential, and significantly reduced heart rate. Furthermore ROCK inhibition caused aberrant expression of typical SAN genes: ROCK1, ROCK2, SHOX2, TBX3, TBX5, ISL1, HCN4, CX40, CAV3.1, and NKX2.5 and left-right asymmetry genes: PITX2C and NODAL. Anatomical abnormalities in pulmonary vein development were also observed. Patch clamp electrophysiology confirmed the immature phenotype of the SAN cells and a residual left-sided sinus venosus myocardium pacemaker-like potential.RHOA-ROCK signalling is involved in establishing the right-sided SAN as the definitive pacemaker of the heart and restricts typical pacemaker gene expression to the right side of the sinus venosus myocardium.
Chains of magnetosomes with controlled endotoxin release and partial tumor occupation induce full destruction of intracranial U87-Luc glioma in mice under the application of an alternating magnetic field
Authors: Edouard Alphandéry, Ahmed Idbaih, Clovis Adam, Jean-Yves Delattre, Charlotte Schmitt, François Guyot, Imène Chebbi
Journal: Journal of Controlled Release (2017)
Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers
Authors: Jungsun Kim, William R. Bamlet, Ann L. Oberg, Kari G. Chaffee, Greg Donahue, Xing-Jun Cao, Suresh Chari, Benjamin A. Garcia, Gloria M. Petersen, Kenneth S. Zaret
Journal: Science Translational Medicine (2017)

THBS2 and CA19-9 markers in human blood improve detection of pancreatic ductal adenocarcinoma.
Intimal Hyperplasia, Stenosis, and Arteriovenous Fistula Maturation Failure in the Hemodialysis Fistula Maturation Study
Authors: Alfred K. Cheung, Peter B. Imrey, Charles E. Alpers, Michelle L. Robbin, Milena Radeva, Brett Larive, Yan-Ting Shiu, Michael Allon, Laura M. Dember, Tom Greene, Jonathan Himmelfarb, Prabir Roy-Chaudhury, Christi M. Terry, Miguel A. Vazquez, John W. Kusek, Harold I. Feldman
Journal: Journal of the American Society of Nephrology (2017)

Intimal hyperplasia and stenosis are often cited as causes of arteriovenous fistula maturation failure, but definitive evidence is lacking. We examined the associations among preexisting venous intimal hyperplasia, fistula venous stenosis after creation, and clinical maturation failure. The Hemodialysis Fistula Maturation Study prospectively observed 602 men and women through arteriovenous fistula creation surgery and their postoperative course. A segment of the vein used to create the fistula was collected intraoperatively for histomorphometric examination. On ultrasounds performed 1 day and 2 and 6 weeks after fistula creation, we assessed fistula venous stenosis using pre-specified criteria on the basis of ratios of luminal diameters and peak blood flow velocities at certain locations along the vessel. We determined fistula clinical maturation using criteria for usability during dialysis. Preexisting venous intimal hyperplasia, expressed per 10% increase in a hyperplasia index (range of 0%–100%), modestly associated with lower fistula blood flow rate (relative change, −2.5%; 95% confidence interval [95% CI], −4.6% to −0.4%; P =0.02) at 6 weeks but did not significantly associate with stenosis (odds ratio [OR], 1.07; 95% CI, 1.00 to 1.16; P =0.07) at 6 weeks or failure to mature clinically without procedural assistance (OR, 1.07; 95% CI, 0.99 to 1.15; P =0.07). Fistula venous stenosis at 6 weeks associated with maturation failure (OR, 1.98; 95% CI, 1.25 to 3.12; P =0.004) after controlling for case mix factors, dialysis status, and fistula location. These findings suggest that postoperative fistula venous stenosis associates with fistula maturation failure. Preoperative venous hyperplasia may associate with maturation failure but if so, only modestly.
Ketamine for the Treatment of Depression—Reply
Authors: Gerard Sanacora
Journal: JAMA Psychiatry (2017)

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Tyk2 as a target for immune regulation in human viral/bacterial pneumonia
Authors: Johanna Berg, Katja Zscheppang, Diana Fatykhova, Mario Tönnies, Torsten T. Bauer, Paul Schneider, Jens Neudecker, Jens C. Rückert, Stephan Eggeling, Maria Schimek, Achim D. Gruber, Norbert Suttorp, Stefan Hippenstiel, Andreas C. Hocke
Journal: European Respiratory Journal (2017)

The severity and lethality of influenza A virus (IAV) infections is frequently aggravated by secondary bacterial pneumonia. However, the mechanisms in human lung tissue that provoke this increase in fatality are unknown and therapeutic immune modulatory options are lacking.We established a human lung ex vivo co-infection model to investigate innate immune related mechanisms contributing to the susceptibility of secondary pneumococcal pneumonia.We revealed that type I and III interferon (IFN) inhibits Streptococcus pneumoniae-induced interleukin (IL)-1β release. The lack of IL-1β resulted in the repression of bacterially induced granulocyte-macrophage colony-stimulating factor (GM-CSF) liberation. Specific inhibition of IFN receptor I and III-associated tyrosine kinase 2 (Tyk2) completely restored the S. pneumoniae-induced IL-1β-GM-CSF axis, leading to a reduction of bacterial growth. A preceding IAV infection of the human alveolus leads to a type I and III IFN-dependent blockade of the early cytokines IL-1β and GM-CSF, which are key for orchestrating an adequate innate immune response against bacteria. Their virally induced suppression may result in impaired bacterial clearance and alveolar repair.Pharmacological inhibition of Tyk2 might be a new treatment option to sustain beneficial endogenous GM-CSF levels in IAV-associated secondary bacterial pneumonia.