tbuckley/cabot-search huggingface dataset:
Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia
Authors: O H Ng, Y Erbilgin, S Firtina, T Celkan, Z Karakas, G Aydogan, E Turkkan, Y Yildirmak, C Timur, E Zengin, J J M van Dongen, F J T Staal, U Ozbek, M Sayitoglu
Journal: Blood Cancer Journal (2014)

WNT signaling has been implicated in the regulation of hematopoietic stem cells and plays an important role during T-cell development in thymus. Here we investigated WNT pathway activation in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients. To evaluate the potential role of WNT signaling in T-cell leukomogenesis, we performed expression analysis of key components of WNT pathway. More than 85% of the childhood T-ALL patients showed upregulated β-catenin expression at the protein level compared with normal human thymocytes. The impact of this upregulation was reflected in high expression of known target genes (AXIN2, c-MYC, TCF1 and LEF). Especially AXIN2, the universal target gene of WNT pathway, was upregulated at both mRNA and protein levels in ∼40% of the patients. When β-CATENIN gene was silenced by small interfering RNA, the cancer cells showed higher rates of apoptosis. These results demonstrate that abnormal WNT signaling activation occurs in a significant fraction of human T-ALL cases independent of known T-ALL risk factors. We conclude that deregulated WNT signaling is a novel oncogenic event in childhood T-ALL.
What is the impact of chronic systemic inflammation such as rheumatoid arthritis on mortality following cancer?
Authors: J F Simard, S Ekberg, A L V Johansson, J Askling
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Emerging evidence links inflammation and immune competence to cancer progression and outcome. Few studies addressing cancer survival in the context of rheumatoid arthritis (RA) have reported reduced survival without accounting for the underlying mortality risk in RA. Whether this increased mortality is a cancer-specific phenomenon, an effect of the decreased lifespan in RA or a combination of both remains unknown. <h3>Methods</h3> Using Swedish register data (2001–2009), we performed a cohort study of individuals with RA (N=34 930), matched to general population comparators (N=169 740), incident cancers (N=12 676) and deaths (N=14 291). Using stratified Cox models, we estimated HRs of death associated with RA in the presence and absence of cancer, by stage and time since cancer diagnosis, for all cancers and specific sites. <h3>Results</h3> In the absence of cancer, RA was associated with a doubled mortality rate (HR=2.1, 95% CI 2.0 to 2.2). In the presence of cancer, the relative effect of RA on mortality was varied by stage. For cancer (tumour, node, metastases) stages I and II at diagnosis, the relative effect of RA on mortality was the same as in the absence of cancer. For cancers diagnosed at advanced stages with absolute higher mortality, the effect decreased (HR=1.2, 95% CI 1.1 to 1.3). These associations remained across time since cancer diagnosis and were reasonably similar across cancer sites. <h3>Conclusions</h3> Much of the increase in mortality in patients with RA diagnosed with cancer seems to reside with effects of RA independently of the cancer.
Development of Therapeutic Combinations Targeting Major Cancer Signaling Pathways
Authors: Timothy A. Yap, Aurelius Omlin, Johann S. de Bono
Journal: Journal of Clinical Oncology (2013)

Signaling networks play key homeostatic processes in living organisms but are commonly hijacked in oncogenesis. Prominent examples include genetically altered receptor tyrosine kinases and dysregulated intracellular signaling molecules. The discovery and development of targeted therapies against such oncogenic proteins has imparted clinical benefit. Nevertheless, concerns remain about the limited single-agent efficacy and narrow therapeutic indices of many of these antitumor agents. Moreover, it is apparent that oncogenic proteins comprise complex signaling networks that interact through crosstalk and feedback loops, which modify therapeutic vulnerability. These complexities mandate the study of drug combinations, which will also become necessary to reverse tumor drug resistance. Here, we outline the challenges associated with rational drug codevelopment strategies, with a focus on the importance of analytically validated biomarkers for patient selection and pharmacokinetic-pharmacodynamic (PK-PD) studies. Overall, the most informative clinical studies of novel combinations will have the following characteristics: robust scientific hypotheses leading to their selection; supportive preclinical data from contextually appropriate preclinical model systems; sufficient preclinical PK data to inform on the risk of drug-drug interactions; and detailed PD studies to determine the biologically active dose range for each agent. Toward this end, several novel clinical trial designs may be envisioned to accelerate successful drug combination development while minimizing the risk of late drug combination attrition. Although considerable challenges remain, these efforts may enable important steps to be taken toward more durable therapeutic control of many cancers.
Iron-Sensing Proteins that Regulate Hepcidin and Enteric Iron Absorption
Authors: Mitchell D. Knutson
Journal: Annual Review of Nutrition (2010)

The human body cannot actively excrete excess iron. As a consequence, iron absorption must be strictly regulated to ensure adequate iron uptake and prevent toxic iron accumulation. Iron absorption is controlled chiefly by hepcidin, the iron-regulatory hormone. Produced by the liver and secreted into the circulation, hepcidin regulates iron metabolism by inhibiting iron release from cells, including duodenal enterocytes, which mediate the absorption of dietary iron. Hepcidin production increases in response to iron loading and decreases in iron deficiency. Such regulation of hepcidin expression serves to modulate iron absorption to meet body iron demand. This review discusses the proteins that orchestrate hepatic hepcidin production and iron absorption by the intestine. Emphasis is placed on the proteins that directly sense iron and how they coordinate and fine-tune the molecular, cellular, and physiologic responses to iron deficiency and overload.
Effects of bile and bile salts on growth and membrane lipid uptake by Giardia lamblia. Possible implications for pathogenesis of intestinal disease.
Authors: M J Farthing, G T Keusch, M C Carey
Journal: Journal of Clinical Investigation (1985)

We have shown previously that ox and pig bile accelerate in vitro growth of Giardia lamblia. We have now investigated the possible mechanisms by which mammalian biles promote parasite growth. Growth effects of (a) ox, pig, guinea pig, and human biles, (b) pure bile salts, and (c) egg and soybean lecithins were studied in the presence of a lecithin-containing growth medium. Individually, dilute native bile and pure sodium taurocholate (TC), glycocholate (GC), and taurodeoxycholate (TDC) promoted parasite growth; growth was most marked with biles of high phospholipid content, with biles enriched in more hydrophobic bile salts (ox approximately equal to human greater than pig greater than guinea pig) and with micellar concentrations of GC and submicellar concentrations of TC and TDC. By measuring uptake of radiolabeled biliary lipids from bile and bile salt-supplemented growth medium, we showed that the parasite consumed bile lipids, with the rank order lecithin greater than bile salts. Apparent net uptake of cholesterol was considered to be due to exchange, since net loss of cholesterol from the growth medium was not detected. Although bile and bile salt-stimulated parasite growth was associated with enhanced lecithin uptake, reduction in generation time was observed at low bile and bile salt concentrations when lecithin uptake was similar to bile free controls. Thus, bile salts may stimulate Giardia growth initially by a mechanism independent of enhanced membrane phospholipid uptake. However, since Giardia has no capacity to synthesize membrane lipid, biliary lecithin may be a major source of phospholipid for growth of this parasite.
Generalized Hailey-Hailey disease
Authors: WOLFGANG CH. MARSCH, GUNTER STUTTGEN
Journal: British Journal of Dermatology (1978)

Journal Article Generalized Hailey‐Hailey disease Get access WOLFGANG CH. MARSCH, WOLFGANG CH. MARSCH Department of Dermatology, Free University of Berlin, Rudolf‐Virchow‐Hospital, Berlin, Germany Search for other works by this author on: Oxford Academic Google Scholar GÜNTER STÜTTGEN GÜNTER STÜTTGEN Department of Dermatology, Free University of Berlin, Rudolf‐Virchow‐Hospital, Berlin, Germany Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 99, Issue 5, 1 November 1978, Pages 553–560, https://doi.org/10.1111/j.1365-2133.1978.tb02024.x Published: 01 November 1978
Prevention Conference VI: Diabetes and Cardiovascular Disease
Authors: Barbara V. Howard, Beatriz L. Rodriguez, Peter H. Bennett, Maureen I. Harris, Richard Hamman, Lewis H. Kuller, Thomas A. Pearson, Judith Wylie-Rosett
Journal: Circulation (2002)

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional,
Characterization of Prostanoid Receptors in Podocytes
Authors: MARTIN BEK, ROLF NU[Combining Diaeresis]SING, PASCAL KOWARK, ANNA HENGER, PETER MUNDEL, HERMANN PAVENSTA[Combining Diaeresis]DT
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Prostaglandins participate in the regulation of important glomerular functions and are involved in the pathogenesis of glomerular diseases. This study investigates the influence of prostaglandins on membrane voltage, ion conductances, cAMP accumulation, and cytosolic calcium activity ([Ca2+]i) in differentiated podocytes. Prostaglandin E2 (PGE2) caused a concentration-dependent depolarization and an increase of the whole cell conductance in podocytes (EC50 ≈ 50 nM). Compared with PGE2, the EP2/EP3/EP4 receptor agonist 11-deoxy-PGE1 caused an equipotent depolarization, whereas the DP receptor agonist BW 245 C, the EP1/EP3 receptor agonist sulprostone, and the IP receptor agonist iloprost were at least 100 to 1000 times less potent than PGE2. The EP2 receptor agonist butaprost did not change membrane voltage of podocytes. The depolarizing effect of PGE2 was increased in an extracellular solution with a reduced Cl- concentration (from 145 to 32 mM). PGE2 and the prostaglandin agonists, but not the IP receptor agonist iloprost and the EP2 receptor agonist butaprost, induced a time- and concentration-dependent cAMP accumulation in podocytes. In fura-2 fluorescence experiments, PGE2, sulprostone, PGF2α, fluprostenol (a potent FP agonist), and U-46619 (a selective thromboxane A2 agonist) induced a biphasic increase of [Ca2+]i in 60 to 80% of podocytes. In reverse transcription-PCR studies, podocyte mRNA for the EP1, EP4, FP, and TP receptor could be amplified. These data indicate that in podocytes, PGE2 regulates distinct cellular functions via the EP1 and EP4 receptor, thereby increasing [Ca2+]i and cAMP, respectively. Furthermore, PGF2α and U-46619 increase [Ca2+]i via their specific receptors.
Anomalous Origin of the Right Coronary Artery From the Left Sinus of Valsalva in an Elderly Man
Authors: Yoshihisa Naruse, Akira Sato, Yuki Kakefuda, Tomoya Hoshi, Akito Imai, Chiho Tokunaga, Yuzuru Sakakibara, Kazutaka Aonuma
Journal: Circulation (2012)
Independent Metabolic Syndrome Variants Predict New-Onset Coronary Artery Disease
Authors: Dhananjay Vaidya, Rasika A. Mathias, Brian G. Kral, Lisa R. Yanek, Lewis C. Becker, Diane M. Becker
Journal: Diabetes Care (2010)

OBJECTIVE Any combination of metabolic abnormalities may constitute the metabolic syndrome (MetS), conferring coronary artery disease (CAD) risk, but the independent effect of different combinations on CAD onset remains unknown. RESEARCH DESIGN AND METHODS Healthy adult siblings (n = 987) of premature CAD (&amp;lt;60 years) case subjects were followed for 9.8 ± 3.8 years. Baseline MetS variables (insulin sensitivity index, waist circumference, systolic blood pressure, HDL cholesterol, and triglycerides) were recombined into five principal components (PC1–5), and risk factor–adjusted proportional hazards for CAD onset of median-dichotomized PCs were estimated. RESULTS The significant hazard ratios were as follows: for PC1 (all abnormalities except blood pressure) 1.66 (P = 0.036), PC2 (high blood pressure levels, high HDL cholesterol) 1.71 (P = 0.016), and PC4 (low HDL cholesterol, high insulin sensitivity, low triglycerides) 2.0 (P = 0.001). Traditionally defined MetS had a hazard ratio of 1.32 (P = 0.18). CONCLUSIONS Independent MetS variants identified by PC analysis may explain metabolic mechanisms that increase CAD risk better than the presence of traditional MetS.
Nanoparticle drug loading as a design parameter to improve docetaxel pharmacokinetics and efficacy
Authors: Kevin S. Chu, Allison N. Schorzman, Mathew C. Finniss, Charles J. Bowerman, Lei Peng, James C. Luft, Andrew J. Madden, Andrew Z. Wang, William C. Zamboni, Joseph M. DeSimone
Journal: Biomaterials (2013)
Inhibition of bradykinin vasodilation and potentiation of norepinephrine and angiotensin vasoconstriction by inhibitors of prostaglandin synthesis in skeletal muscle of the rat.
Authors: E J Messina, R Weiner, G Kaley
Journal: Circulation Research (1975)

Recent reports have indicated that vascular responsiveness can be altered by exogenously administered or endogenously released prostaglandins. Furthermore, in certain tissues inhibitors of prostaglandin synthesis have been shown to limit the increase in blood flow in response to bradykinin and to enhance the reduction in blood flow in response to angiotensin and norepinephrine. These findings suggest an important local circulatory role for prostaglandins. We attempted to implicate further prostaglandins in local blood flow regulation by examining the effects of indomethacin (IND) and 5,8,11,14-eicosatetraynoic acid (ETA), inhibitors of prostaglandin synthesis, on microvascular arteriolar responses to bradykinin, prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), histamine, norepinephrine, and angiotensin. Male Wistar rats were anesthetized with sodium pentobarbital, and their cremaster muscle was exteriorized and prepared for in vivo microscopic observation of microvessels. Changes in arteriolar luminal diameters in response to topical administration of vasoactive agents were quantified with an image-shearing measuring eyepiece in conjunction with a television microscope and recorder. Local administration of IND or ETA significantly reduced the arteriolar dilation elicited by bradykinin, whereas the responses to PGE1 and PGE2 remained unaltered. Responses to histamine, although somewhat reduced, were not significantly different from control. Vasoconstrictor responses of arterioles elicited by norepinephrine and angiotensin were potentiated by IND or ETA administration. These results indicate that prostaglandins synthetized in skeletal muscle microcirculation in situ (1) mediate, in part, vasodilator responses to bradykinin and (2) modulate vasoconstrictor responses to angiotensin and norepinephrine. Thus, these findings support the hypothesis that prostaglandins are local regulators of microvascular responsiveness.
Motivational Brochures Increase the Number of Medicare-Eligible Persons With Diabetes Making Therapeutic Footwear Claims
Authors: Joseph W. LeMaster, Jonathan R. Sugarman, Greg Baumgardner, Gayle E. Reiber
Journal: Diabetes Care (2003)

OBJECTIVE—This study tests the hypothesis that Medicare beneficiaries at high risk of foot complications who are mailed a motivational brochure describing the Medicare diabetes-related therapeutic footwear benefit will increase their therapeutic footwear–related Medicare claims. RESEARCH DESIGN AND METHODS—In this quasi-experimental study, a motivational brochure was mailed in the summer of 1997 to 5,872 Medicare beneficiaries in Washington, Alaska, and Idaho who were identified as being at high risk for foot-related claims on the basis of their prior Medicare claims history. Beneficiaries were identified through footwear claims made in these states—and also in three comparison states (Oregon, Montana, and Wyoming)—during the 18 months before and after the mailing. Linear regression was used to compare the number of persons making claims in the intervention states with the comparison states before, at the time of, and after the mailing. RESULTS—Before the intervention, the number of persons making claims was increasing in the nonintervention states and decreasing in the intervention states. During the first month after the intervention mailing, the number of persons making claims remained nearly the same in nonintervention states, but increased 13 persons per month in intervention states (95% CI 3.5–11 persons/month). After the intervention, the number of persons making claims continued to increase similarly in both intervention and nonintervention states. CONCLUSIONS—Mailed motivational brochures were associated with an increase in the number of persons making therapeutic footwear claims. Randomized trials should confirm these findings.
A survey of phenotype II in familial Mediterranean fever
Authors: Melike Melikoğlu, Huri Özdoğan, Cengiz Korkmaz, Özgür Kasapçopur, Nil Arısoy, Semra Akkuş, I˙zzet Fresko, Hasan Yazıcı
Journal: Annals of the Rheumatic Diseases (2000)

Phenotype II in familial Mediterranean fever (FMF) is the onset of amyloidosis before the onset of FMF with its typical attacks, or as an isolated finding in a member of an FMF family. Its presence was investigated by looking for proteinuria among the asymptomatic relatives of patients with FMF complicated by amyloidosis and among the asymptomatic relatives of patients with juvenile chronic arthritis (JCA) complicated by amyloidosis, used as controls.The relatives of the index patients (13 with FMF and amyloidosis) and controls (6 with JCA and amyloidosis) were screened for proteinuria. Rectal biopsies were performed when proteinuria was significant (>/=300 mg/d).461 relatives were screened in the FMF group and 269 among the controls. Two of the FMF relatives and one JCA relative had no symptoms of FMF but had significant proteinuria. Rectal biopsy for amyloidosis was negative in all instances of significant proteinuria.Phenotype II is uncommon among the relatives of patients with FMF and amyloidosis.
Induction of Renal Tumorigenesis with Elevated Levels of Somatic Loss of Heterozygosity in <i>Tsc1</i>+/- Mice on a <i>Blm</i>-Deficient Background
Authors: Catherine Wilson, Shelley Idziaszczyk, James Colley, Vikki Humphreys, Carol Guy, Julie Maynard, Julian R. Sampson, Jeremy P. Cheadle
Journal: Cancer Research (2005)

Abstract A Bloom's deficient mouse model (Blmm3/m3) has been shown to induce colorectal tumorigenesis when crossed with Apc+/Min mice. Here, we investigated whether the Blmm3/m3 genotype could induce tumorigenesis in extracolonic tissues in tuberous sclerosis 1–deficient (Tsc1+/−) mice that are predisposed to renal cystadenomas and carcinomas. Genotyping of offspring from Tsc1+/− Blm+/m3 intercrosses showed that a ∼24% excess of Tsc1+/− over Tsc1+/+ mice died before weaning (P = 0.016), although Blm deficiency had no cumulative effect on Tsc1+/− survival. Tsc1+/− Blmm3/m3 mice had significantly more macroscopic and microscopic renal lesions at 3 to 6 months compared with Tsc1+/− Blm+/m3 mice (P =0.0003 and 0.0203, respectively), and their tumors showed significantly increased levels of somatic loss of heterozygosity (LOH) of the wild-type Tsc1 (Tsc1wt) allele compared with those from Tsc1+/− Blm+/+ mice (P &amp;lt; 0.0001). Tsc1+/− Blm+/m3 mice did not show significantly more renal lesions compared with Tsc1+/− Blm+/+ animals; however, their lesions still showed significantly increased levels of somatic LOH of the Tsc1wt allele (P = 0.03). Ninety-five percent (19 of 20) of lesions from Tsc1+/− Blm+/m3 mice retained the wild-type Blm (Blmwt) allele, indicating that the increased somatic LOH at Tsc1 was mediated by Blm haploinsufficiency. Renal lesions from a Blm-deficient background stained positively with anti-phospho-S6 ribosomal protein (Ser240/244), suggesting that these lesions develop through the normal pathway of Tsc-associated tumorigenesis. This work shows the use of the Blmm3/m3 mice for inducing renal tumorigenesis, and the high levels (∼87%) of LOH in the resultant tumors will help facilitate mapping of loci involved in tumor progression.
Pharmacogenomics of chemotherapeutic susceptibility and toxicity
Authors: Erika L Moen, Lucy A Godley, Wei Zhang, M Eileen Dolan
Journal: Genome Medicine (2012)

The goal of personalized medicine is to tailor a patient's treatment strategy on the basis of his or her unique genetic make-up. The field of oncology is beginning to incorporate many of the strategies of personalized medicine, especially within the realm of pharmacogenomics, which is the study of how inter-individual genetic variation determines drug response or toxicity. A main objective of pharmacogenomics is to facilitate physician decision-making regarding optimal drug selection, dose and treatment duration on a patient-by-patient basis. Recent advances in genome-wide genotyping and sequencing technologies have supported the discoveries of a number of pharmacogenetic markers that predict response to chemotherapy. However, effectively implementing these pharmacogenetic markers in the clinic remains a major challenge. This review focuses on the contribution of germline genetic variation to chemotherapeutic toxicity and response, and discusses the utility of genome-wide association studies and use of lymphoblastoid cell lines (LCLs) in pharmacogenomic studies. Furthermore, we highlight several recent examples of genetic variants associated with chemotherapeutic toxicity or response in both patient cohorts and LCLs, and discuss the challenges and future directions of pharmacogenomic discovery for cancer treatment.
Surprised by Hope
Authors: Prudence A. Francis
Journal: Journal of Clinical Oncology (2008)

Providing and maintaining hope for patients with incurable cancer is something that medical oncologists recognize as important. Yet the fine line that we frequently tread between giving a realistic prognosis to facilitate informed decision making, while not taking away hope, can prove challenging. Sometimes during a subsequent consultation, an oncologist may discern a significant mismatch between the prognostic information they have previously tried to convey and the patient’s view of their future, which may present a dilemma. Physician estimation of how long a patient with advanced cancer might survive if they receive systemic therapy, versus their actual survival, may be substantially mismatched in some cases.