tbuckley/cabot-search huggingface dataset:
Lactate Influx through the Endothelial Cell Monocarboxylate Transporter MCT1 Supports an NF-κB/IL-8 Pathway that Drives Tumor Angiogenesis
Authors: Frédérique Végran, Romain Boidot, Carine Michiels, Pierre Sonveaux, Olivier Feron
Journal: Cancer Research (2011)

Lactate generated from pyruvate fuels production of intracellular NAD(+) as an end result of the glycolytic process in tumors. Elevated lactate concentration represents a good indicator of the metabolic adaptation of tumors and is actually correlated to clinical outcome in a variety of human cancers. In this study, we investigated whether lactate could directly modulate the endothelial phenotype and thereby tumor vascular morphogenesis and perfusion. We found that lactate could enter endothelial cells through the monocarboxylate transporter MCT-1, trigger the phosphorylation/degradation of IκBα, and then stimulate an autocrine NF-κB/IL-8 (CXCL8) pathway driving cell migration and tube formation. These effects were prevented by 2-oxoglutarate and reactive oxygen species (ROS) inhibitors, pointing to a role for prolyl-hydroxylase and ROS in the integration of lactate signaling in endothelial cells. PHD2 silencing in endothelial cells recapitulated the proangiogenic effects of lactate, whereas a blocking IL-8 antibody or IL-8-targeting siRNA prevented them. Finally, we documented in mouse xenograft models of human colorectal and breast cancer that lactate release from tumor cells through the MCT4 (and not MCT1) transporter is sufficient to stimulate IL-8-dependent angiogenesis and tumor growth. In conclusion, our findings establish a signaling role for lactate in endothelial cells and they identify the lactate/NF-κB/IL-8 pathway as an important link between tumor metabolism and angiogenesis.
Differential regulation of myeloid leukemias by the bone marrow microenvironment
Authors: Daniela S Krause, Keertik Fulzele, André Catic, Chia Chi Sun, David Dombkowski, Michael P Hurley, Sanon Lezeau, Eyal Attar, Joy Y Wu, Herbert Y Lin, Paola Divieti-Pajevic, Robert P Hasserjian, Ernestina Schipani, Richard A Van Etten, David T Scadden
Journal: Nature Medicine (2013)
Association of XPD and CDA polymorphisms with clinical outcome in non-small cell lung cancer in a Chinese population
Authors: Min Zhou, Yongjie Ding, Huanyin Wan
Journal: European Respiratory Journal (2012)

XPD plays a key role in the repair of DNA and platinum resistance lesions. Cytidine deaminase genes decide the velocity of catalyze gemcitabine. This study aims at investigating the relationship between the XPD, CDA genotypes and the outcome in NSCLC patients. We used RFLP to evaluate genetic polymorphism of the XPD Asp312Asn, XPD Lys751Gln, CDA Lys27Gln and CDA Ala70Thr in 93 NSCLC patients treated with cisplatin-gemcitabine regimen. 44% of patients carrying the XPD 312Asp/Asp had progression of disease, whereas 55.56% with heterozygous XPD 312Asp/Asn had progression of disease as well. There were no significant correlation between XPD Asp312Asn and clinical benefit (P=0.502). 53.95% of patients with wild-type had clinical benefit (PR and SD), 52.94% of patients carrying XPD 751Lys/Gln responded to therapy. There was no difference between different genotype (P=0.517). But the difference of OS between XPD 312Asp/ Asp and XPD 312Asp/Asn was very significant (20.0 months vs 12.4 months, P=0.04). TTP had no difference between the patients with wide-type genotype (10.7 months) and those carrying XPD 751Lys/Gln (7.0 months); However, the OS of patients with wide-type genotype (20.5 months) was longer than that (11.5 months) of patients carrying XPD 751Lys/Gln. No significant differences in TTP or OS were observed in patients carrying different genotype of CDA Lys27Gln. This investigation provides suggestive evidence of a favorable effect about the XPD 312Asp/Asp and XPD 751Lys/Lys genotype on survival in platinum-treated NSCLC. But CDA 27 polymorphism does not affect the efficacy of gemcitabine.
Further Exploration of the Relationship Between Insulin Glargine and Incident Cancer
Authors: Nancy E. Morden, Stephen K. Liu, Jeremy Smith, Todd A. Mackenzie, Jonathan Skinner, Murray Korc
Journal: Diabetes Care (2011)

In vitro evidence suggests insulin glargine promotes tumors; observational human studies are conflicting. We aimed to expand understanding of this potential treatment risk.This retrospective cohort study of type 2 diabetic patients >68 years old used Medicare inpatient, outpatient (2003-2008), and prescription data (2006-2008). Adjusting for patient characteristics, dose, and metformin use, Cox models yielded hazard ratios (HRs) for incident cancer (breast, prostate, pancreas, colon, any site) associated with three forms of insulin: nonglargine, glargine, or glargine plus nonglargine (combination).Overall, 81,681 patients were followed for a mean of 23.1 months. Mean age was 77.4 years. Treatment group distribution was 20.7% glargine, 60.5% nonglargine, 18.7% combination insulin. We observed 5,466 incident cancers; crude rates did not vary by treatment group. In fully adjusted models, nonglargine use was the referent; glargine was not associated with significant increased risk of any cancer measure. In secondary analyses including only the top quartile of daily insulin dose patients, glargine was not associated with any cancer risk difference; combination insulin was associated with higher breast cancer risk (HR 1.75 [95% CI 1.10-2.78]) and lower colon cancer risk (0.33 [0.13-0.80]). In age-stratified analyses of highest-dose users, combination insulin conferred a higher risk of breast cancer in those ≤75 years old (2.87 [1.45-1.59]).The general lack of association between glargine-only use and cancer is reassuring. Breast cancer risk associated with high-dose combination insulin in secondary analyses could result from multiple comparisons, residual confounding, or true association; further research is warranted.
Cardiac natriuretic peptides during exercise and training after heart transplantation
Authors: B Geny
Journal: Cardiovascular Research (2001)

Time for primary review 30 days. 

The cardiac natriuretic system, composed of atrial and brain natriuretic peptides (ANP and BNP), plays a major role in blood pressure and fluid homeostasis, protecting the organism from volume and pressure overloads. Accordingly, the cardiac hormones have been shown to delay the occurrence of overt heart failure through their diuretic, natriuretric and vasodilatory properties [1–3]. Adrenomedullin, mainly produced by vascular smooth muscle cells and by vascular endothelial cells, is also secreted by the failing human heart. This potent vasorelaxing and natriuretic peptide can thus be considered as a third cardiac hormone, involved in circulation control [4,5].

Short term survival is no longer the pivotal issue for most heart-transplant recipients (Htx) because of enhancement in organ preservation, surgical and medical therapies. Consequently, improving quality of life after heart transplantation arises as an important goal, which might be reached through exercise and training programs [6–8]. Since cardiac natriuretic peptides greatly participate in cardiovascular adaptations, it appeared interesting to focus this review on ANP, BNP and adrenomedullin (ADM) responses to exercise and training after heart transplantation.

Relative rather than absolute work load will be used to compare groups since it is generally considered to be a better indicator of the magnitude of fluid-regulating hormone changes, both in normal subjects and in Htx [9]. After discussing why circulating ANP, BNP and ADM are elevated in Htx, we will investigate the stimuli of their secretion during exercise and present the few data available concerning their response to exercise training after heart transplantation.

After successful cardiac transplantation, normalization of filling pressures, as well as normalization of the renin–angiotensin–aldosterone and the sympathetic systems, generally occur, explaining why persistent elevation of circulating ANP and BNP was unexpected [10–13]. In fact, replacing the failing heart by a so-called … 

* Corresponding author. Tel.: +33-390-243-439; fax: +33-390-243-444 bernard.geny{at}physio-ulp.u-strasbg.fr
IMPROVED EXERCISE CAPACITY IN HFNEF CORRELATES WITH IMPROVED DIASTOLIC FUNCTION, BUT UNCHANGED CHRONOTROPIC COMPETENCE
Authors: Rolf Wachter, Hans-Dirk Düngen, Gö;tz Gelbrich, Silja Schwarz, Markus Lö;ffler, Gerd Hasenfuß, Martin Halle, Burkert Pieske, Frank Edelmann
Journal: Journal of the American College of Cardiology (2010)
Meta-Analysis of Methicillin-Resistant Staphylococcus aureus Colonization and Risk of Infection in Dialysis Patients
Authors: Ioannis M. Zacharioudakis, Fainareti N. Zervou, Panayiotis D. Ziakas, Eleftherios Mylonakis
Journal: Journal of the American Society of Nephrology (2014)

Patients undergoing dialysis are particularly vulnerable to methicillin-resistant Staphylococcus aureus (MRSA) infections. We performed a meta-analysis of published studies to estimate the prevalence of MRSA colonization in dialysis patients, time trends, and long-term risk of subsequent MRSA infections. Our search of the PubMed and Embase databases returned 5743 nonduplicate citations, from which we identified 38 relevant studies that included data on 5596 dialysis patients. The estimated prevalence of MRSA colonization was 6.2% (95% confidence interval [95% CI], 4.2% to 8.5%). The prevalence increased over time but remained stable after 2000. Stratification of patients according to dialysis modality and setting revealed that 7.2% (95% CI, 4.9% to 9.9%) of patients on hemodialysis were colonized with MRSA compared with 1.3% (95% CI, 0.5% to 2.4%) of patients on peritoneal dialysis (P=0.01), and that a statistically significant difference existed in the percentage of colonized inpatients and outpatients (14.2% [95% CI, 8.0% to 21.8%] versus 5.4% [95% CI, 3.5% to 7.7%], respectively; P=0.04). Notably, the risk of developing MRSA infections increased among colonized hemodialysis patients compared with noncolonized patients (relative risk, 11.5 [95% CI, 4.7 to 28.0]). The long-term (6–20 months) probability of developing a MRSA infection was 19% among colonized hemodialysis patients compared with only 2% among noncolonized patients. In summary, 6.2% of dialysis patients are MRSA colonized, and the average prevalence of colonization has remained stable since 2000. Colonization in hemodialysis patients is associated with increased risk of MRSA infection.
Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo
Authors: Guang-Biao Zhou, Hui Kang, Lan Wang, Li Gao, Ping Liu, Jun Xie, Feng-Xiang Zhang, Xiang-Qin Weng, Zhi-Xiang Shen, Jue Chen, Long-Jun Gu, Ming Yan, Dong-Er Zhang, Sai-Juan Chen, Zhen-Yi Wang, Zhu Chen
Journal: Blood (2006)
The Impact of the Privacy Rule on Cancer Research: Variations in Attitudes and Application of Regulatory Standards
Authors: Elizabeth Goss, Michael P. Link, Suanna S. Bruinooge, Theodore S. Lawrence, Joel E. Tepper, Carolyn D. Runowicz, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2009)

The American Society of Clinical Oncology (ASCO) Cancer Research Committee designed a qualitative research project to assess the attitudes of cancer researchers and compliance officials regarding compliance with the US Privacy Rule and to identify potential strategies for eliminating perceived or real barriers to achieving compliance.A team of three interviewers asked 27 individuals (13 investigators and 14 compliance officials) from 13 institutions to describe the anticipated approach of their institutions to Privacy Rule compliance in three hypothetical research studies.The interviews revealed that although researchers and compliance officials share the view that patients' cancer diagnoses should enjoy a high level of privacy protection, there are significant tensions between the two groups related to the proper standards for compliance necessary to protect patients. The disagreements are seen most clearly with regard to the appropriate definition of a "future research use" of protected health information in biospecimen and data repositories and the standards for a waiver of authorization for disclosure and use of such data.ASCO believes that disagreements related to compliance and the resulting delays in certain projects and abandonment of others might be eased by additional institutional training programs and consultation on Privacy Rule issues during study design. ASCO also proposes the development of best practices documents to guide 1) creation of data repositories, 2) disclosure and use of data from such repositories, and 3) the design of survivorship and genetics studies.
THE PROVOCATION OF LATENT LYMPHOCYTIC CHORIOMENINGITIS VIRUS INFECTIONS IN MICE BY TREATMENT WITH ANTILYMPHOCYTIC SERUM
Authors: Mogens Volkert, Claus Lundstedt
Journal: The Journal of Experimental Medicine (1968)

The hypothesis that treatment with antilymphocytic serum (ALS) can provoke latent virus infections has been investigated. In adult mice infections with sublethal doses of LCM virus usually result in the development of immunity to the virus and at the same time to a prolonged latent infection. In the experiments described an intensive treatment with large doses of ALS was given to mice which had recovered from LCM virus infection. At the beginning of the treatment the mice had high titers of complement-fixing antibodies in their blood and no detectable virus. The data presented show that in spite of the immunity the ALS treatment provoked the occult virus and led to the development of viremia in all the treated mice. In some, very high virus titers were demonstrable. When the ALS treatment was discontinued the viremia disappeard again. In most of the mice the ALS did not suppress the complement-fixing antibody titers and in some there was even a considerable increase in titer. In such cases the increases in virus titers and in antibody titers were closely related to one another. These results demonstrate once again that the complement-fixing antibodies to the LCM virus in mice probably do not influence the virus.
The determination of rhodopsin structure may require alternative approaches
Authors: Arlene D. Albert, Philip L. Yeagle
Journal: Behavioral and Brain Sciences (1995)

Abstract The structure of rhodopsin is a subject of intense interest. Solving the structure by traditional methods has proved exceedingly challenging. It may therefore be useful to confront the problem by a combination of alternate techniques. These include FTIR (Fourier transform infrared spectroscopy) and AFM (atomic force microscopy) on the intact protein. Furthermore, additional insights may be gained through structural investigations of discrete rhodopsin domains.
Is it time for home treatment of pulmonary embolism?
Authors: Mareike Lankeit, Stavros Konstantinides
Journal: European Respiratory Journal (2012)

Acute pulmonary embolism (PE) is a frequent cause of death, but not all patients are at high risk of an adverse early outcome. It has been proposed that selected patients may be considered for early discharge and home treatment, but it was only recently that improved risk assessment strategies permitted advances in the identification of low-risk PE. Clinical prediction rules, such as the Pulmonary Embolism Severity Index (PESI), and laboratory biomarkers, particularly natriuretic peptides and cardiac troponins, appeared capable of excluding severe PE and serious comorbidity. Recently, two randomised trials and two prospective cohort studies investigated the feasibility and safety of outpatient treatment. All excluded patients with haemodynamic instability and serious comorbidity, but only one trial used a validated clinical score (PESI) for patient inclusion, and only one cohort study employed a biomarker test. Overall, 90-day outcome was favourable and the results appear promising. To optimise patient selection, future trials will need to test simplified clinical scores combined with high-sensitivity biomarker assays, and it will have to be determined whether echocardiography and/or compression ultrasonography are also required before discharge. Furthermore, ongoing trials will show whether new oral anticoagulants are a safe and cost-effective option for managing patients out of hospital.
Humanized Anti-Interleukin-6 Receptor Antibody Suppresses Tumor Angiogenesis and <i>In vivo</i> Growth of Human Oral Squamous Cell Carcinoma
Authors: Satoru Shinriki, Hirofumi Jono, Kazutoshi Ota, Mitsuharu Ueda, Mareina Kudo, Tomoko Ota, Yuichi Oike, Motoyoshi Endo, Mutsuko Ibusuki, Akimitsu Hiraki, Hideki Nakayama, Yoshihiro Yoshitake, Masanori Shinohara, Yukio Ando
Journal: Clinical Cancer Research (2009)

The biological effect of interleukin-6 (IL-6) signaling in oral squamous cell carcinoma (OSCC) and whether IL-6 receptor (IL-6R)-mediated signaling can be a therapeutic target for OSCC are unclear. The aim of this study was to investigate the effects of inhibition of IL-6R-mediated signaling on OSCC progression and to evaluate the availability of tocilizumab, a humanized antihuman IL-6R antibody, as a therapeutic agent for OSCC.We evaluated expression levels of IL-6 and IL-6R in 58 OSCC tissues and 4 OSCC cell lines by real-time quantitative reverse transcription-PCR and/or immunohistochemstry. We investigated the effects of tocilizumab on OSCC growth in vitro and in xenografts. Xenografts were analyzed by immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 (pSTAT3), Ki-67, and CD31, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was done.Expression levels of IL-6 at both mRNA and protein levels in OSCC tissues were significantly higher than those in normal mucosal tissues. In addition, OSCC cell lines expressed higher levels of both IL-6 and IL-6R mRNA than did HaCaT keratinocytes. Tocilizumab significantly reduced in vivo growth of SAS cells with a drastic reduction of STAT3 phosphorylation in tumor cells in mice. Inhibition of IL-6 signaling significantly decreased vascular endothelial growth factor mRNA expression in SAS, and microvessel density and vessel diameter in SAS tumors in tocilizumab-treated mice.Therapeutic approaches targeting IL-6R by tocilizumab may be effective for OSCC treatment by at least inhibiting angiogenesis.
Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: Results of a prospective, nonrandomized study
Authors: Rolando Ortega, Pere Ginès, Juan Uriz, Andrés Cárdenas, Blas Calahorra, Dara De Las Heras, Mónica Guevara, Ramón Bataller, Wladimiro Jiménez, Vicente Arroyo, Juan Rodés
Journal: Hepatology (2002)

Vasopressin analogues associated with albumin improve renal function in hepatorenal syndrome (HRS). The current study was aimed at assessing the efficacy of the treatment, predictive factors of response, recurrence of HRS, and survival after therapy. Twenty-one consecutive patients with HRS (16 with type 1 HRS, 5 with type 2 HRS) received terlipressin (0.5-2 mg/4 hours intravenously) until complete response was achieved (serum creatinine level &lt; 1.5 mg/dL) or for 15 days; 13 patients received intravenous albumin together with terlipressin. Twelve of the 21 patients (57%) showed complete response. Albumin administration was the only predictive factor of complete response (77% in patients receiving terlipressin and albumin vs. 25% in those receiving terlipressin alone, P = .03). Treatment with terlipressin and albumin was associated with a remarkable decrease in serum creatinine level, increase in arterial pressure, and suppression of the renin-aldosterone system. By contrast, no significant changes in these parameters were found in patients treated with terlipressin alone. Only 1 patient showed ischemic adverse effects. Recurrence of HRS occurred in 17% of patients with complete response. The occurrence of complete response was associated with an improved survival. In conclusion, terlipressin therapy reverses HRS in a high proportion of patients. Recurrence rate after treatment withdrawal is uncommon. Albumin appears to improve markedly the beneficial effects of terlipressin.
Carbonic Anhydrase Activity Monitored <i>In Vivo</i> by Hyperpolarized 13C-Magnetic Resonance Spectroscopy Demonstrates Its Importance for pH Regulation in Tumors
Authors: Ferdia A. Gallagher, Helen Sladen, Mikko I. Kettunen, Eva M. Serrao, Tiago B. Rodrigues, Alan Wright, Andrew B. Gill, Sarah McGuire, Thomas C. Booth, Joan Boren, Alan McIntyre, Jodi L. Miller, Shen-Han Lee, Davina Honess, Sam E. Day, De-En Hu, William J. Howat, Adrian L. Harris, Kevin M. Brindle
Journal: Cancer Research (2015)

Abstract Carbonic anhydrase buffers tissue pH by catalyzing the rapid interconversion of carbon dioxide (CO2) and bicarbonate (HCO3−). We assessed the functional activity of CAIX in two colorectal tumor models, expressing different levels of the enzyme, by measuring the rate of exchange of hyperpolarized 13C label between bicarbonate (H13CO3−) and carbon dioxide (13CO2), following injection of hyperpolarized H13CO3−, using 13C-magnetic resonance spectroscopy (13C-MRS) magnetization transfer measurements. 31P-MRS measurements of the chemical shift of the pH probe, 3-aminopropylphosphonate, and 13C-MRS measurements of the H13CO3−/13CO2 peak intensity ratio showed that CAIX overexpression lowered extracellular pH in these tumors. However, the 13C measurements overestimated pH due to incomplete equilibration of the hyperpolarized 13C label between the H13CO3− and 13CO2 pools. Paradoxically, tumors overexpressing CAIX showed lower enzyme activity using magnetization transfer measurements, which can be explained by the more acidic extracellular pH in these tumors and the decreased activity of the enzyme at low pH. This explanation was confirmed by administration of bicarbonate in the drinking water, which elevated tumor extracellular pH and restored enzyme activity to control levels. These results suggest that CAIX expression is increased in hypoxia to compensate for the decrease in its activity produced by a low extracellular pH and supports the hypothesis that a major function of CAIX is to lower the extracellular pH. Cancer Res; 75(19); 4109–18. ©2015 AACR.
Reduced Nuclear Genomes Maintain High Gene Transcription Levels
Authors: Goro Tanifuji, Naoko T. Onodera, Christa E. Moore, John M. Archibald
Journal: Molecular Biology and Evolution (2013)

Reductive genome evolution is seen in organisms living in close association with each other, such as in endosymbiosis, symbiosis, and parasitism. The reduced genomes of endosymbionts and parasites often exhibit similar features such as high gene densities and A+T compositional bias. Little is known about how the regulation of gene expression has been affected in organisms with highly compacted genomes. We studied gene transcription patterns in "nucleomorph" genomes, which are relic nuclear genomes of algal endosymbionts found in cryptophytes and chlorarachniophytes. We examined nuclear and nucleomorph gene transcription patterns using RNA-Seq transcriptome and genome mapping analyses in representatives of both lineages. In all four examined genomes, the most highly transcribed nucleomorph gene category was found to be plastid-associated genes. Remarkably, only 0.49-3.37% of the nucleomorph genomes of these organisms did not have any mRNA counterpart in our RNA-Seq data sets, and nucleomorph genes show equal or higher levels of transcription than their counterparts in the nuclear genomes. We hypothesize that elevated levels of nucleomorph gene transcription may serve to counteract the degradation or modification of protein function due to the loss of interacting proteins in the nucleomorph and nucleomorph-associated subcellular compartments.