tbuckley/cabot-search huggingface dataset:
Risk of Asynchronous Contralateral Breast Cancer in Noncarriers of <i>BRCA1</i> and <i>BRCA2</i> Mutations With a Family History of Breast Cancer: A Report From the Women's Environmental Cancer and Radiation Epidemiology Study
Authors: Anne S. Reiner, Esther M. John, Jennifer D. Brooks, Charles F. Lynch, Leslie Bernstein, Lene Mellemkjær, Kathleen E. Malone, Julia A. Knight, Marinela Capanu, Sharon N. Teraoka, Patrick Concannon, Xiaolin Liang, Jane C. Figueiredo, Susan A. Smith, Marilyn Stovall, Malcolm C. Pike, Robert W. Haile, Duncan C. Thomas, Colin B. Begg, Jonine L. Bernstein
Journal: Journal of Clinical Oncology (2012)

To fully characterize the risk of contralateral breast cancer (CBC) in patients with breast cancer with a family history who test negative for BRCA1 and BRCA2 mutations.From our population-based case-control study comparing women with CBC to women with unilateral breast cancer (UBC), we selected women who tested negative for BRCA1 and BRCA2 mutations (594 patients with CBC/1,119 control patients with UBC). Rate ratios (RRs) and 95% CIs were estimated to examine the association between family history of breast cancer and risk of asynchronous CBC. Age- and family history-specific 10-year cumulative absolute risks of CBC were estimated.Family history of breast cancer was associated with increased CBC risk; risk was highest among young women (< 45 years) with first-degree relatives affected at young ages (< 45 years; RR, 2.5; 95% CI, 1.1 to 5.3) or women with first-degree relatives with bilateral disease (RR, 3.6; 95% CI, 2.0 to 6.4). Women diagnosed with UBC before age 55 years with a first-degree family history of CBC had a 10-year risk of CBC of 15.6%.Young women with breast cancer who have a family history of breast cancer and who test negative for deleterious mutations in BRCA1 and BRCA2 are at significantly greater risk of CBC than other breast cancer survivors. This risk varies with diagnosis age, family history of CBC, and degree of relationship to an affected relative. Women with a first-degree family history of bilateral disease have risks of CBC similar to mutation carriers. This has important implications for the clinical management of patients with breast cancer with family history of the disease.
What are the new milestones in the pathogenesis of systemic sclerosis?
Authors: N Hunzelmann, J Brinckmann
Journal: Annals of the Rheumatic Diseases (2009)

Systemic sclerosis (SSc) is a chronic inflammatory autoimmune disease involving the connective tissue of the skin and various internal organs. In recent years research on SSc has evolved to provide a better understanding of the interdependence of the three major systems involved—namely, the vascular system, the immune system and the connective tissue. Hypoxia is increasingly recognised as a decisive factor in modulating the inflammatory process in SSc, activating fibroblasts and changing their phenotype. In addition, several mediators synthesised by immune cells, including cytokines such as transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF), cooperate in inducing the activation of fibroblasts and their differentiation into myofibroblasts. Therefore, a variety of intracellular and extracellular strategies to inhibit the activity of TGFβ and PDGF are currently receiving intense investigation. To further improve our therapeutic strategies for this paradigmatic fibrotic disease, an improved understanding of connective tissue remodelling as it takes place in the different stages of SSc will be imperative.
Mutation-Independent Anaplastic Lymphoma Kinase Overexpression in Poor Prognosis Neuroblastoma Patients
Authors: Lorena Passoni, Luca Longo, Paola Collini, Addolorata Maria Luce Coluccia, Fabio Bozzi, Marta Podda, Andrea Gregorio, Claudio Gambini, Alberto Garaventa, Vito Pistoia, Federica Del Grosso, Gian Paolo Tonini, Mangeng Cheng, Carlo Gambacorti-Passerini, Andrea Anichini, Franca Fossati-Bellani, Massimo Di Nicola, Roberto Luksch
Journal: Cancer Research (2009)

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase predominantly expressed in the developing nervous system. Recently, mutated ALK has been identified as a major oncogene associated with familial and sporadic neuroblastomas (NBL). Yet, a direct correlation between endogenous expression level of the ALK protein, oncogenic potential, and clinical outcome has not been established. We investigated ALK genetic mutations, protein expression/phosphorylation, and functional inhibition both in NBL-derived cell lines and in 34 localized and 48 advanced/metastatic NBL patients. ALK constitutive phosphorylation/activation was observed in high-ALK expressing cells, harboring either a mutated or a wild-type receptor. No activation was found in cell lines with low expression of wild-type ALK. After 72 hours of treatments, small molecule ALK inhibitor CEP-14083 (60 nmol/L) induced growth arrest and cell death in NBL cells overexpressing wild-type (viability: ALK(high) 12.8%, ALK(low) 73%, P = 0.0035; cell death: ALK(high) 56.4%, ALK(low) 16.2%, P = 0.0001) or mutated ALK. ALK protein expression was significantly up-regulated in advanced/metastatic compared with localized NBLs (ALK overexpressing patients: stage 1-2, 23.5%; stage 3-4, 77%; P < 0.0001). Interestingly, protein levels did not always correlate with ALK genetic alterations and/or mRNA abundance. Both mutated and wild-type ALK receptor can exert oncogenic activity in NBL cells. However, wild-type ALK receptor requires a critical threshold of expression to achieve oncogenic activation. Overexpression of either mutated or wild-type ALK defines poor prognosis patients. Alternative mechanisms other than direct mutations and/or gene amplification regulate the ALK level of expression in NBL cells. Wild-type ALK is a potential therapeutic target for advanced/metastatic NBLs.
VARIATIONS IN SKIN SURFACE LIPID COMPOSITION WITH DIFFERENT SAMPLING TECHNIQUES-I*
Authors: W. J. CUNLIFFE, J. A. COTTERILL, B. WILLIAMSON
Journal: British Journal of Dermatology (2006)

SUMMARY.— The effect of 3 different sampling techniques on forehead surface lipid biochemistry was investigated. Samples obtained by either a sponge method or by ether washings contained significantly more free fatty acid and cholesterol and less triglyceride, wax ester and squalene than did samples collected by absorbent papers. The reasons for these differences are discussed and it is suggested that more careful attention to detail is necessary in the sampling and handling of surface lipids before biochemical analysis.
Mechanical and structural correlates of canine pericardium.
Authors: A W Wiegner, O H Bing, T K Borg, J B Caulfield
Journal: Circulation Research (1981)

We have assessed viscoelastic properties of pericardium within the physiological range of stresses and related mechanical behavior to fiber direction as defined by scanning electron microscopy. Stiffness, stress relaxation, and creep were measured in samples taken from the anterior surface of 14 canine pericardia. Stress-strain relations generally were not exponential; stiffness at a stress of 1 g/mm2 ranged from 12.9 to 239 g/mm2 during stretch and varied both from pericardium to pericardium and with the orientation of the strip within the sample (anisotropy). The strips exhibited hysteretic behavior which was not promotional to rate of strain. Following a rapid increase in stress, creep averaged less than 1% and stress relaxation, 34% in a 30-minute test period. The orientation of the strip with the greatest stiffness was consistent from pericardium to pericardium, and correlated with a layer of collagen fibers oriented along the major axis of te strip.
Protective Role of Interleukin-10 in Atherosclerosis
Authors: Ziad Mallat, Sandrine Besnard, Micheline Duriez, Virginie Deleuze, Florence Emmanuel, Michel F. Bureau, Fabienne Soubrier, Bruno Esposito, Hélène Duez, Catherine Fievet, Bart Staels, Nicolas Duverger, Daniel Scherman, Alain Tedgui
Journal: Circulation Research (1999)

Abstract —The potential role of anti-inflammatory cytokines in the modulation of the atherosclerotic process remains unknown. Interleukin (IL)-10 has potent deactivating properties in macrophages and T cells and modulates many cellular processes that may interfere with the development and stability of the atherosclerotic plaque. IL-10 is expressed in human atherosclerosis and is associated with decreased signs of inflammation. In the present study, we show that IL-10–deficient C57BL/6J mice fed an atherogenic diet and raised under specific pathogen-free conditions exhibit a significant 3-fold increase in lipid accumulation compared with wild-type mice. Interestingly, the susceptibility of IL-10–deficient mice to atherosclerosis was exceedingly high (30-fold increase) when the mice were housed under conventional conditions. Atherosclerotic lesions of IL-10–deficient mice showed increased T-cell infiltration, abundant interferon-γ expression, and decreased collagen content. In vivo, transfer of murine IL-10 achieved 60% reduction in lesion size. These results underscore the critical roles of IL-10 in both atherosclerotic lesion formation and stability. Moreover, IL-10 appears to be crucial as a protective factor against the effect of environmental pathogens on atherosclerosis. The full text of this article is available at http://www.circresaha.org.
New substrates for Achilles tendinopathy: substantial plantaris tendon or Substance P?
Authors: Johannes L Tol
Journal: British Journal of Sports Medicine (2011)

An interesting debate on the exact aetiology of pain in Achilles tendinopathy is ongoing. Contrary to an intratendinous degenerative origin of the pain, a new theory focuses on the role of the plantaris tendon. This new theory reflects a paratendinous origin of the pain with ingrowth of sensory and sympathetic nerves and release of nociceptive substances.1 Alfredson2 presents convincing evidence for the role of the plantaris tendon ( see pages 1023 and 1026 ) which is thickened and is in close relation or invaginated to the medial Achilles tendon in 80% of the symptomatic tendons.

Inspired by the Scandinavian pioneers, I note an exponential increase of basic and clinical research with a strong focus on clarifying the mechanism of degeneration and reversion to regenerative processes. This increased attention raises our hopes that chronic tendon injuries could finally be treated …
Stereological measurement of porto-central gradients in gene expression in mouse liver
Authors: Jan M. Ruijter, Roben G. Gieling, Marry M. Markman, Jaco Hagoort, Wouter H. Lamers
Journal: Hepatology (2004)

The liver is thought to consist of lobules, numerous repeating, randomly oriented units. Within these lobules, genes are expressed in gradients along the porto-central axis, which spans the distance between portal and central veins. We have developed a robust stereological method to map all points in an image to their position on this porto-central axis. This approach is based on the distribution of well-characterized periportal and pericentral enzymes, which are visualized on sections preceding and following the section of interest. Because expression of the model genes phosphoenolpyruvate carboxykinase and ornithine aminotransferase declines gradually with increasing distance from the portal vein and central vein, respectively, these genes can be used to prepare images with topographical information without any assumption about the shape of the hepatic unit, or about the direction or shape of the gradient to be determined. The "relative distance" image is a 2-dimensional image that accurately maps the relative position of hepatocytes on the porto-central axis in 3-dimensional space. It is superimposed on the serial section under investigation to relate local staining density to position on the porto-central axis and obtain the gene expression gradient. The method was used to determine the expression gradient of 2 periportal and 2 pericentral enzymes and their response to fasting. The "total distance" image was used to measure the length of the porto-central axis, which was approximately 210 microm in mice and found to decrease 13% after 1 day of starvation. The method can be applied to any tissue component that can be stained quantitatively.
The metabolism of 3alpha, 7alpha, 12alpha-trihydorxy-5beta-cholestan-26-oic acid in two siblings with cholestasis due to intrahepatic bile duct anomalies. An apparent inborn error of cholic acid synthesis.
Authors: R F Hanson, J N Isenberg, G C Williams, D Hachey, P Szczepanik, P D Klein, H L Sharp
Journal: Journal of Clinical Investigation (1975)

Studies were carried out in a family in which two children with cholestasis due to intrahepatic bile duct anomalies were shown to have increased amounts of the cholic acid precursor, 3alpha, 7alpha, 12alpha-trihydorxy-5beta-cholestan-26-oic acid (THCA). The metabolism of THCA was studied in one of these patients after an intravenous injection of (3H)THCA, and the cause of the increased amounts of THCA in this condition was found to be due to a metabolic defect in the conversion of this compound into cholic acid. A small amount of (3H)cholic acid was also identified after (3H)THCA administration, confirming that this metabolic defect was incomplete. Varanic acid (3alpha, 7alpha, 12alpha, 24xi-tetrahydorxy-5beta-cholestan-26-oic acid), a metabolite of THCA, could not be identified in either of these patients. By assuming that this compound would be conjugated and excreted if the metabolic block occurred after the formation of varanic acid, the defect in these patients appears to be due to a deficiency of a 24-hydroxylating enzyme system required to convert THCA into varanic acid. This condition appears to be transmitted in an autosomal recessive fashion, because the two affected patients were of opposite sex, and neither a normal sibling nor the two parents have increased amount of THCA in their bile.
Could Plugging the Oxidation-Mediated Ca <sup>2+</sup> Leak Stem the Tide of the Atrial Fibrillation Epidemic?
Authors: Peter H. Backx
Journal: Circulation Research (2012)

A s the most common sustained arrhythmia, atrial fibril- lation (AF) afflicts Ͼ2 million patients in the United States alone, and this number is predicted to double by the year 2050. 1 Although AF is not life-threatening, it is linked to a 2-fold increase in mortality when present as a comorbidity in heart disease patients. 2,3AF can have devastating consequences, such as stroke, impaired cardiac performance, and promotion of cardiomyopathy.The treatment of AF can also produce life-threatening side effects, such as ventricular arrhythmias and hemorrhage.AF patients are generally classified as paroxysmal (episodes lasting Ͻ7 days), persistent (lasting Ͼ7 days but treated to restore sinus rhythm), or permanent (no attempt to restore sinus rhythm). 2,3AF is usually secondary to other conditions such as hypertension, heart failure, valvular disease, sleep apnea, hyperthyroidism, and diabetes.Most of these AF-inducing conditions are associated with elevated atrial pressure and atrial stretch, as well as increased oxidative stress and inflammation, which lead to structural and electric changes (remodeling) that create a substrate for supporting AF induction and maintenance. 4,
Plasma Protein Aspartyl Damage Is Increased in Hemodialysis Patients
Authors: Alessandra F. Perna, Diego Ingrosso, Ersilia Satta, Cinzia Lombardi, Patrizia Galletti, Antimo D’Aniello, Natale G. De Santo
Journal: Journal of the American Society of Nephrology (2004)

Plasma proteins in hemodialysis patients display a significant increase in deamidated/isomerized Asx (asparagine and aspartic acid) content, a marker of protein fatigue damage. This has been linked to the toxic effects of hyperhomocysteinemia in uremic erythrocytes; however, treatment aimed at abating homocysteine levels did not lead to significant reductions in plasma protein damage. The hypothesis that lack of reduction in protein damage could be due to protein increased intrinsic instability, as result of interference with the uremic milieu rather than to hyperhomocysteinemia, was put forward. The deamidated/isomerized Asx content of normal plasma incubated with several uremic toxins for 24 h, 72 h, and 7 d was measured, identifying a group of toxins that were able to elicit this kind of damage. Uremic toxins were also incubated with purified human albumin, and dose-response experiments with the two most toxic agents in terms of protein damage (guanidine and guanidinopropionic acid) were carried out. The effect of the hemodialysis procedure on protein damage was evaluated. For investigating also the consequences of these alterations, human albumin was treated <i>in vitro</i> to produce an increase in deamidated/isomerized Asx residues, and the effects of albumin deamidation on protein binding were evaluated. Among the uremic toxins that are able to elicit protein damage, guanidine produced a dose-dependent increase in protein damage. No difference was found after a hemodialysis session. Deamidated albumin shows normal binding capacity to warfarin, salicylic acid, or diazepam but reduced binding to homocysteine. In conclusion, uremic toxins, especially guanidine, display an ability to induce significant protein damage, which can in turn have functional consequences.
The world as an inside working memory
Authors: Naoyuki Osaka
Journal: Behavioral and Brain Sciences (2004)

O'Regan &amp; Noë's (O&amp;N's) theoretical framework for studying visual perception and awareness is intriguing. This framework, based on sensorimotor contingency, can be examined in recent visual brain theories using neuroimaging methodologies. Here, I consider how a working memory (WM) system explains the sensorimotor account of visual consciousness. I believe WM inside the brain provides at least partial support for O&amp;N's theory.
Preservation of complete anal sphincteric proprioception in restorative proctocolectomy: the inhibitory reflex and fine control of continence need not be impaired.
Authors: W G Lewis, M E Williamson, A S Miller, P M Sagar, P J Holdsworth, D Johnston
Journal: Gut (1995)

This study evaluates whether reflux function of the anal sphincter remains unchanged after restorative proctocolectomy, provided that the sphincter remaining is kept intact, without mucosal stripping or endo-anal anastomosis. Paired tests of anorectal function were performed before, and a median of 6 (range 2-12) months after restorative proctocolectomy with stapled, end to end pouch-anal anastomosis. Beforehand, distension of the rectum with 50 ml of air produced a median (interquartile range) increase in pressure within the rectum of 22 (15-29) cm H2O and reflex inhibition of the anal sphincter from a pressure of 76 (62-106) cm H2O to a pressure of 34 (15-52) cm H2O. After the procedure, distension of the ileal pouch with 50 ml of air produced an increase in pressure within the pouch of only 5 (4-8) cm H2O (p < 0.001 compared with beforehand) and reflex inhibition of the anal sphincter from a pressure of 62 (25-79) cm H2O to 37 (17-68) cm H2O. Maximal reflex inhibition of the upper third if the anal sphincter to a pressure of 26 (15-48) cm H2O was observed when pressure within the pouch increased by 16 (11-22) cm H2O. After restorative proctocolectomy, all patients were continent (two experienced minor nocturnal leakage of mucus) and 25 could discriminate between flatus and faeces. Thus, reflux function was preserved in response to changes in pressure, ensuring that the subtler aspects of anal continence were preserved.
Neoadjuvant Chemotherapy for Metastatic Colon Cancer: A Cautionary Note
Authors: Anton J. Bilchik, Graeme Poston, Steven A. Curley, Steven Strasberg, Leonard Saltz, Rene Adam, Bernard Nordlinger, Philippe Rougier, Lee S. Rosen
Journal: Journal of Clinical Oncology (2005)

Anton J. Bilchik, John Wayne Cancer Institute at St John’s Health Center, Santa Monica, CA Graeme Poston, Royal Liverpool and Aintree University Hospitals, Liverpool, UK Steven A. Curley, The University of Texas M.D. Anderson Cancer Center, Houston, TX Steven Strasberg, Siteman Cancer Center at Washington University in St Louis, St Louis, MO Leonard Saltz, Memorial Sloan Kettering Cancer Center, New York, NY Rene Adam, Paul Brousse Hospital, Paris, France Bernard Nordlinger and Philippe Rougier, Paul Brousse Hospital, Paris, France Lee S. Rosen, John Wayne Cancer Institute at St John’s Health Center, Santa Monica, CA
Desensitization of Soluble Guanylate Cyclase in Renal Cortex during Endotoxemia in Mice
Authors: MLADEN KNOTEK, MATTHEW ESSON, PATRICIA GENGARO, CHARLES L. EDELSTEIN, ROBERT W. SCHRIER
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Acute endotoxemic renal failure involves renal vasoconstriction, which presumably occurs despite increased nitric oxide (NO) generation by inducible NO synthase in the kidney. The present study examined the hypothesis that the renal vasoconstriction during endotoxemia occurs in part because of desensitization of soluble guanylate cyclase (sGC). Endotoxic shock was induced in male B6/129F2/J mice by an intraperitoneal injection of Escherichia coli lipopolysaccharide. The endotoxemia resulted in shock and renal failure as evidenced by a decrease in mean arterial pressure and an increase in serum creatinine and urea nitrogen. Serum NO increased in a time-dependent manner, reaching the highest levels at 24 h, in parallel with induction of inducible NO synthase protein in the renal cortex. In renal cortical slices obtained from endotoxemic mice, cyclic guanosine monophosphate (cGMP) increased significantly at 6 h and 15 h as compared with control but normalized at 24 h after injection of lipopolysaccharide. Incubation of renal cortical slices in the presence of a phosphodiesterase inhibitor isobutylmethylxantine did not alter the pattern of changes in cGMP. Incubation of renal cortical slices with 2 mM sodium nitroprusside resulted in a similar accumulation of cGMP in slices taken from control and endotoxemic mice at 6 h and 15 h. However, in slices from 24-h endotoxemic mice, accumulation of cGMP in response to sodium nitroprusside was significantly lower. This lower stimulability of sGC was not paralleled by a decrease in its abundance in renal cortex on immunoblot. Taken together, these results demonstrate a desensitization of sGC in renal cortex during endotoxemia, which may contribute to the associated renal vasoconstriction.
Reward doctors for early diagnosis of dementia, says think tank
Authors: K. Chinthapalli
Journal: BMJ (2012)

Doctors and commissioners should be financially rewarded for diagnosing dementia, the economics think tank the Social Market Foundation has said.

Nigel Keohane, its deputy director and a coauthor of its report on dementia, said, “While there is no cure for dementia, early diagnosis means that patients can access treatment and support, allowing them and their families to prepare for the future progress of the condition. Costs to the state can be reduced if diagnosis happens earlier. That’s why incentives for GPs, clinical commissioning groups, and directors of public health should be directly linked to increased diagnosis rates and [why] practitioners should be …