tbuckley/cabot-search huggingface dataset:
Higher IQ in childhood is linked to a longer life
Authors: Daniel Falkstedt, Anton C J Lager
Journal: BMJ (2017)

The association between intelligence level (IQ) measured during childhood or adolescence and longevity has been observed in many studies.It is clear that, on average, individuals with higher IQs have tended to live a little longer than those with lower IQs.A limitation in the evidence base so far, however, has been an over-reliance on studies of male conscripts followed up only to middle adulthood.
Abstract 265: CITED4 Induces Physiologic Hypertrophy and Improves Cardiac Remodeling After Ischemic Injury
Authors: Vassilios J Bezzerides, Colin Platt, Kaavya Paruchuri, Loren Oh, Chunyang Xiao, Nina Mann, Anthony Rosenzweig
Journal: Circulation Research (2015)

Cardiac hypertrophy is an adaptive response to increased hemodynamic stresses, which can be either physiologic, as with exercise, or pathologic, as with valvular heart disease. Recent data suggest that physiologic hypertrophy secondary to exercise may be mediated by the transcription factor CEBPβ and the p300-interacting protein CITED4. We sought to investigate the cardiovascular effects of CITED4 expression in vivo. Using a cardiac-specific and inducible transgenic mouse (Tg) model, we determined the effects of CITED4 expression on cardiac parameters including heart weight, cell size, cardiac function and gene expression. Expression of CITED4 for 3 weeks induced increases in heart weight (22% in HW/TL, p &lt; 0.01) and cardiomyocyte (CM) size (24.5% in cell area, p &lt; 0.001) with normal systolic function and without evidence of fibrosis. Gene profiling demonstrated increased expression of cardiac troponin, a favorable αMHC/βMHC ratio and a reduction in BNP consistent with physiologic hypertrophy. Genome-wide expression profiling of neonatal rat ventricular myocytes (NRVMs) over-expressing CITED4 demonstrated the activation of a unique set of genes including BCL2, ATP12a, Efemp1, Ifi204 and Tcf19. To further examine the potential beneficial role of CITED4, we induced ischemia by transient occlusion of the left anterior descending (LAD) coronary (30 min) followed by reperfusion for 24 hours, 6 days or 4 weeks. At 24 hrs after ischemia-reperfusion injury (IRI), neither cardiac dysfunction on echo nor infarct sizes were different between CITED4 Tg and controls. However, CITED4 Tgs showed substantial recovery of cardiac function at 4 weeks (FS: CITED4 Tg 51%, Control 34%, p &lt; 0.01) and a 3.4-fold reduction in fibrosis (p &lt; 0.005). Analysis of possible cellular responses responsible for the functional recovery demonstrated enhanced autophagic flux with reduced accumulation of LC3II (down 71%, p&lt;0.05) and p62 (down 54%, p&lt;0.005). Further examination of the involved signaling pathway revealed direct activation of mTORC1 and its effectors consistent with a growth phenotype. We conclude that CITED4 expression is sufficient to induce physiologic cardiac hypertrophy and improves cardiac remodeling after ischemic injury likely through activation of mTORC1.
Abstract 260: Cardiosphere Derived Cells Generated from the Human Atria Exhibit Superior Potency Compared to the Left Ventricle
Authors: David L Simpson, Agnieszka Blusztajn, Ileana Valle, Michelle Kreke, Linda Marban, Rachel R Smith
Journal: Circulation Research (2013)

Currently, allogeneic cardiosphere-derived cells (CDCs) are being tested in a phase I/II clinical trial. Our manufacturing process utilizes the atria and other regions of the heart to build a master cell bank, but leaves the left ventricle (LV) intact thus eliminating a potential source to build our clinical stocks. In an effort to increase CDC yield per heart, we compared CDCs generated from the atria to the left ventricle (LV). To investigate this hypothesis we characterized CDCs by flow cytometry, growth kinetics and in vivo potency. The surface marker profiles for atrial CDCs and LV CDCs were very similar. Of the 17 markers used to characterize CDCs (c-kit, MDR-1, Sca-1, Abcg2, CD133, CD31, CD34, CD45, CD105, CD29, CD44, CD73, CD166, CD140b, CD90, DDR2 and α-SMA) only one demonstrated substantial differential expression in LV versus atria. PDGFR-β (CD140b) was upregulated in CDCs derived from the LV compared to the atria. Consistent with this finding, GEO2R analysis of DNA microarray data revealed increased PDGFR-β and PDGF-B expression in normal human LV tissue compared to atrial tissue. We have also observed that CDC expression of PDGFR-β negatively correlates with in vivo potency (R=0.899) suggesting that the high expression of this marker in CDCs derived from the LV may limit its regenerative performance. Indeed when calculated growth rates were compared, tissue samples from the atria yielded 4 to 6-fold more CDCs compared to the LV (atria=26±10 versus LV=5±5 Million CDCs/g/day). Also, CDCs derived from the atria and LV led to differential improvements in ejection fraction (EF) over three weeks. CDCs from the atria significantly outperformed the control group (atrial CDCs=Δ+12.6±10.8%, control=Δ-15.3±13.6%), while CDCs from the LV showed minimal treatment effects and failed to meet our minimal potency requirement (LV CDCs=Δ+0.0±6.2%). In conclusion, LV CDCs display limited potential for clinical use. This observation provides a unique opportunity to explore the mechanisms that govern functional potency and assist in understanding the basic processes involved in CDC mediated repair.
Syphilis surveillance in France, 2000-2003
Authors: E Couturier, A Michel, M Janier, N Dupin, C Semaille
Journal: Eurosurveillance (2004)

This article describes syphilis trends, characteristics of patients from 2000 to 2003 in France and trends of the benzylpenicillin benzathine 2.4 million UI sales from 2001 to 2003. The ongoing surveillance system for syphilis case reporting since 2001 has been set up in volunteer settings, mostly public settings where STI treatment is offered. Clinical case reporting is complemented by sexual behavioural data based on a self-administered questionnaire. From 2000 to 2003, 1089 syphilis cases were reported in France, increasing from 37 cases in 2000 to 428 in 2003. Overall, 96% of syphilis cases were in men with a mean age of 36.5 years and 70% of whom were born in France. The proportion of syphilis cases with HIV co-infection decreased over time from 60% in 2000 to 33% in 2003. The most affected area by the syphilis epidemic is the Ile-de-France region, mainly the city of Paris. The greatest proportion of syphilis cases diagnosed in men who have sex with men (MSM) were in the Ile-de-France region, where they made up 87% of cases, compared with 75% in other regions. Among the patients who completed the self-administered questionnaire on sexual behaviour, 83% reported having casual sex partners in the 3 months prior to their syphilis diagnosis. Trends in the sales of benzylpenicillin benzathine 2.4 million UI in private pharmacies are similar to those observed in the surveillance system, and increased between 2001 and 2003. In conclusion, syphilis transmission is still ongoing in France in 2003 and the role of unprotected oral sex in the transmission of syphilis should be emphasised.
The oncologic burden of hepatitis C virus infection: A clinical perspective
Authors: Harrys A. Torres, Terri Lynn Shigle, Nassim Hammoudi, James T. Link, Felipe Samaniego, Ahmed Kaseb, Vincent Mallet
Journal: CA A Cancer Journal for Clinicians (2017)

ABSTRACT Answer questions and earn CME/CNE Chronic hepatitis C virus (HCV) infection affects millions of people worldwide and is associated with cancer. Direct‐acting antivirals (DAAs) have changed HCV treatment paradigms, but little is known about the management of HCV infection in patients with cancer. The substantial burden of HCV infection and the inconclusive evidence regarding its detection and management in patients with cancer prompted the authors to review the literature and formulate recommendations. Patients for whom HCV screening is recommended included all patients with hematologic malignancies, hematopoietic cell transplantation candidates, and patients with liver cancer. There is a lack of consensus‐based recommendations for the identification of HCV‐infected patients with other types of cancer, but physicians may at least consider screening patients who belong to groups at heightened risk of HCV infection, including those born during 1945 through 1965 and those at high risk for infection. Patients with evidence of HCV infection should be assessed by an expert to evaluate liver disease severity, comorbidities associated with HCV infection, and treatment opportunities. DAA therapy should be tailored on the basis of patient prognosis, type of cancer, cancer treatment plan, and hepatic and virologic parameters. HCV‐infected patients with cancer who have cirrhosis (or even advanced fibrosis) and those at risk for liver disease progression, especially patients with HCV‐associated comorbidities, should have ongoing follow‐up, regardless of whether there is a sustained virologic response, to ensure timely detection and treatment of hepatocellular carcinoma. HCV infection and its treatment should not be considered contraindications to cancer treatment and should not delay the initiation of an urgent cancer therapy. CA Cancer J Clin 2017. © 2017 American Cancer Society. CA Cancer J Clin 2017;67:411–431. © 2017 American Cancer Society.
Infections associated with the addition of pertuzumab to trastuzumab-based chemotherapy.
Authors: Joanne E. Mortimer, Yuan Yuan, Jae J Jung, Daphne B. Stewart, Samuel Chung, Stephen Koehler, Jill Cooper, Laura Kruper, Louise Wong, Sanjeet Dadwal
Journal: Journal of Clinical Oncology (2017)

e12524 Background: We observed an increased incidence of severe skin and nail infections in HER2 positive patients whose treatment regimens included pertuzumab to trastuzumab-based chemotherapy; a previously unrecognized toxicity. Methods: We developed a registry for patients (pts.) who were identified by their treating physician to have severe skin/nail infections attributed to this dual HER2-directed treatment. A single infectious disease specialist (SD) oversaw the attribution of infection to drug or non-drug. Physicians were encouraged to assess quantitative immunoglobulins. Results: To date, 44 women were identified to have 62 individual episodes of infection, often at more than one site. Treatment was given as neoadjuvant therapy -24, as adjuvant therapy - 6, and for metastatic disease -14. The median age was 57 (Range 25-73); 24 received pertuzumab, trastuzumab, carboplatin, and docetaxel (PTCH); 22 pertuzumab, trastuzumab, and a taxane; 2 were on pertuzumab and trastuzumab alone. Folliculitis of the scalp, abdomen, chest wall and/or buttocks was observed in 31 patients; abscesses developed in 15;6 required surgical interventions. Paronychial infections involving one to 16 digits were observed in 6, 3 of whom required surgical intervention. With the exception of 2 pts, all had adequate WBCs. Cultures were obtained in 20 pts., and identified MSSA in 8, MRSA in 5, and Streptococcal species in 3. Two pts. with cellulitis had negative cultures; 1 pt. was cultured after initiation of antibiotics, and 1 pt. died of gram positive cocci sepsis on cycle 2 day 7 of PTCH. Her WBC on day 1 was 13.0, and she received pegfilgrastim on day 2. Immunoglobulins were found to be low in 16 of 29 (41%) women tested. In the absence of culture data, infections were managed with cephalexin, doxycycline, or topical antibiotics. The majority of patients continued on chemotherapy, but pertuzumab was deleted from the regimen in 2 pts. Conclusions: We continue to see a significant increase in gram positive invasive skin and nail infections in women with HER2 positive breast cancer treated with pertuzumab and trastuzumab-based regimens. Low levels of quantitative immunoglobulin in select patients suggest a possible mechanism.
NIDOGEN1 as a novel regulator of endothelial control over breast cancer invasion and metastasis.
Authors: Martin Buess, Daniela A. Ferraro, Francesca Patella, Sara Zanivan, Gerhard Christofori
Journal: Journal of Clinical Oncology (2017)

e23005 Background: The microenvironment is a central regulator of cancer biology. While the contribution of fibroblasts has been largely studied, the role of endothelial cells as regulators of cancer cell behavior is still poorly understood. As in a diverse spectrum of physiological processes in normal tissue, endothelial cells may exert a similar regulatory control in cancer progression and metastasis. Methods: To characterize the functional effects of endothelial-cancer interaction we focused on an in vitro co-culture model. Results: Co-culturing human umbilical venous endothelial cells (HUVEC) with SKBR-3 breast cancer cells induced morphological changes with epithelial-mesenchymal transition traits (EMT) and a significantly increased migratory and invasive potential. This activity leading to an elongated phenotype, expression of mesenchymal markers and pro-migratory gene sets in SKBR-3 was contained in HUVEC conditioned medium. The pro-migratory effect on SKBR-3 was significantly more pronounced when the supernatant was obtained from a sub-confluent and highly proliferative endothelial cell culture than from a confluent and resting endothelial cell layer. To identify the secreted regulatory molecules, we analyzed the supernatant of sub-confluent and confluent endothelial cells by quantitative MS proteomics (SILAC analysis). Eight candidate proteins significantly more secreted in conditioned medium from confluent HUVEC represented potential inhibitors of migration. Among them NIDOGEN1 was found to be necessary and sufficient for the inhibition of EMT and migration in SKBR-3. Stimulation of SKBR-3 with supernatant from sub-confluent HUVEC increased p-STAT3 levels in SKBR-3. Silencing nidogen1 in confluent HUVEC re-activated phosphorylation of STAT3 indicating that NIDOGEN1 inhibits the promigratory STAT3 pathway. The STAT3 pathway and migration were also inhibited by overexpression of nidogen1 in MDA-MB-231 LM2 cells.When injected in the mammary fat pad of nude mice these cells formed significantly less lung metastases than controls (p &lt; 0.01). Conclusions: We identified NIDOGEN1 as a novel regulator of endothelial control over cancer cell migration, invasion and metastasis.
Hepatitis C virus reactivation in patients receiving cancer treatment: A prospective observational study
Authors: Harrys A. Torres, Jeff Hosry, Parag Mahale, Minas P. Economides, Ying Jiang, Anna S. Lok
Journal: Hepatology (2017)

Hepatitis C virus (HCV) reactivation in patients receiving cancer treatment has been reported in retrospective studies. We sought to determine prospectively the incidence, predictors, and clinical significance of HCV reactivation during cancer treatment. HCV-infected patients receiving cancer treatment at our institution between November 2012 and July 2016 were studied. Reactivation was defined as an increase in HCV-RNA ≥1 log10 IU/mL over baseline and hepatitis flare as an increase in alanine aminotransferase to ≥3 times the upper limit of normal. One hundred patients were studied, 50 with hematologic malignancies and 50 with solid tumors. Reactivation occurred in 23 (23%) patients, including 18 (36%) patients with hematologic malignancies and 5 (10%) patients with solid tumors. In univariate analysis, patients with reactivation were more likely than those without reactivation to have prolonged lymphopenia (median, 95 versus 22 days; P = 0.01) and to have received rituximab (44% versus 9%; P < 0.0001), bendamustine (22% versus 0%; P < 0.001), high-dose steroids (57% versus 21%; P = 0.001), or purine analogs (22% versus 5%; P = 0.02). Rituximab (odds ratio = 9.52; P = 0.001), and high-dose steroids (odds ratio = 5.05; P = 0.01) retained significance in multivariable analysis. Of the 23 patients with reactivation, 10 (43%) had hepatitis flare. No patient with reactivation experienced liver failure or liver-related death within 36 weeks after initiation of cancer treatment. Fourteen patients with hepatitis flare, six of whom had reactivation, required discontinuation or dose reduction of cancer treatment.HCV reactivation occurred in 23% of HCV-infected patients receiving cancer treatment, and most had an unremarkable clinical course. However, reactivation can affect the cancer treatment plan. Our findings suggest that HCV infection should not contraindicate cancer therapy and infected patients should have access to multiple cancer treatments with close monitoring while receiving regimens associated with HCV reactivation. (Hepatology 2018;67:36-47).
Evolution of NPM1-negative therapy-related myelodysplastic syndromes following curative treatment of NPM1-mutant AML
Authors: S Herold, K Sockel, C Sayehli, R Herbst, U Dührsen, U Oelschlägel, A Böttner, H Hindahl, J Kullmer, S Helas, M Sauer, B Mohr, A Mies, M Bornhäuser, G Ehninger, C Röllig, C Thiede, U Platzbecker
Journal: Leukemia (2017)
Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells
Authors: Mohammad Rashidian, Jessica R. Ingram, Michael Dougan, Anushka Dongre, Katherine A. Whang, Camille LeGall, Juan J. Cragnolini, Brian Bierie, Monica Gostissa, James Gorman, Gijsbert M. Grotenbreg, Atul Bhan, Robert A. Weinberg, Hidde L. Ploegh
Journal: The Journal of Experimental Medicine (2017)

Immunotherapy using checkpoint-blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non-small cell lung cancer in a subset of patients. The presence of CD8 T cells in the tumor correlates with improved survival. We show that immuno-positron emission tomography (immuno-PET) can visualize tumors by detecting infiltrating lymphocytes and, through longitudinal observation of individual animals, distinguish responding tumors from those that do not respond to therapy. We used 89Zr-labeled PEGylated single-domain antibody fragments (VHHs) specific for CD8 to track the presence of intratumoral CD8+ T cells in the immunotherapy-susceptible B16 melanoma model in response to checkpoint blockade. A 89Zr-labeled PEGylated anti-CD8 VHH detected thymus and secondary lymphoid structures as well as intratumoral CD8 T cells. Animals that responded to CTLA-4 therapy showed a homogeneous distribution of the anti-CD8 PET signal throughout the tumor, whereas more heterogeneous infiltration of CD8 T cells correlated with faster tumor growth and worse responses. To support the validity of these observations, we used two different transplantable breast cancer models, yielding results that conformed with predictions based on the antimelanoma response. It may thus be possible to use immuno-PET and monitor antitumor immune responses as a prognostic tool to predict patient responses to checkpoint therapies.
Appropriateness of Antiepileptic Drug Level Monitoring
Authors: Raymond Gambino
Journal: JAMA (1996)

<h3>To the Editor.</h3> —The article by Dr Schoenenberger and colleagues<sup>1</sup>reports that only 27% of antiepileptic drug level determinations had an appropriate indication. That is a misleading conclusion. Most test requests considered inappropriate were so classified because the blood sample was not drawn at the appropriate time. In my opinion, that is not inappropriate ordering, but rather represents an absence of systems at their institution to ensure that drug levels are drawn at the correct time. The article also failed to address an equally important question: How many patients in their medical complex were receiving drugs that should be monitored but were not monitored? Such information is essential to ensure that all appropriate actions are taken. Daily ordering of phenobarbital levels is clearly inappropriate, but failure to order a phenobarbital level periodically to ensure patient compliance or adequate drug absorption is also inappropriate. At the Columbia-Presbyterian Medical Center in
Abstract P215: β3-Adrenergic Receptor Mediated NOS Signaling in Cardiomyocytes
Authors: Vabren L Watts, Xiaolin Niu, Karen L Miller, Lili A Barouch
Journal: Circulation Research (2011)

Beta3 -adrenergic receptors play a pivotal role in modulating cardiac function, though their precise role in the heart remains controversial. We have recently demonstrated alterations in Ca 2+ -dependent NOS isoforms and decreased NOS activity in left ventricular tissue of beta3 -/- mice after pressure overload. However, the exact manner in which beta3-AR signaling regulates these isoforms to stimulate NOS activity at the cardiomyocyte level is not well understood. In this study we used a specific beta3-AR agonist, BRL37344 (BRL), to assess the role of beta3-AR in eNOS and nNOS regulation in hypertrophied isolated neonatal rat ventricular cardiomyocytes (NRVM). To induce hypertrophy we pretreated cells with norepinephrine for 72 hours, which resulted in a 70% increase in cell size and a 25% increase in beta3-AR mRNA expression as compared with non-hypertrophied cells, analyzed by immunocytochemistry and real-time PCR. In hypertrophied cardiomyocytes, BRL administration lead to a time-dependent 5-fold increase in NOS activity, measured by the arginine-to-citrulline conversion assay. beta3-activation also caused a 1.5-fold increase in nNOS phosphorylation at positive regulatory site Ser1416, and dephosphorylation of negative regulatory site Ser847 as compared with unstimulated control. NOS activity and nNOS phosphorylation overlapped in time. In addition BRL induced phosphorylation eNOS-Ser114, which indicates eNOS deactivation. Pretreatment with pertussis toxin (PTX) suppressed BRL-induced nNOS-Ser1416 phosphorylation, nNOS-Ser847 dephosphorylation, and NOS activity, suggesting G i/o dependency. Taken together, our data suggest that BRL regulates NOS signaling in ventricular cardiomyocytes via phosphorylation regulation of nNOS. To our knowledge this is first study to demonstrate a role for nNOS phosphorylation as a key factor in beta3-AR signaling. These results contribute significantly to our understanding the negative inotropic properties of myocardial beta3-AR at cellular levels during cardiac sympathetic overstimulation, and will ultimately aid in drug discoveries that target the molecular mechanisms associated heart failure.