tbuckley/cabot-search huggingface dataset:
PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers
Authors: Susan Wee, Zainab Jagani, Kay Xiaoqin Xiang, Alice Loo, Marion Dorsch, Yung-Mae Yao, William R. Sellers, Christoph Lengauer, Frank Stegmeier
Journal: Cancer Research (2009)

Abstract The RAS pathway is one of the most frequently deregulated pathways in cancer. RAS signals through multiple effector pathways, including the RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK MAPK and phosphatidylinositol 3-kinase (PI3K)-AKT signaling cascades. The oncogenic potential of these effector pathways is illustrated by the frequent occurrence of activating mutations in BRAF and PIK3CA as well as loss-of-function mutations in the tumor suppressor PTEN, a negative regulator of PI3K. Previous studies have found that whereas BRAF mutant cancers are highly sensitive to MEK inhibition, RAS mutant cancers exhibit a more variable response. The molecular mechanisms responsible for this heterogeneous response remain unclear. In this study, we show that PI3K pathway activation strongly influences the sensitivity of RAS mutant cells to MEK inhibitors. Activating mutations in PIK3CA reduce the sensitivity to MEK inhibition, whereas PTEN mutations seem to cause complete resistance. We further show that down-regulation of PIK3CA resensitizes cells with co-occurring KRAS and PIK3CA mutations to MEK inhibition. At the molecular level, the dual inhibition of both pathways seems to be required for complete inhibition of the downstream mammalian target of rapamycin effector pathway and results in the induction of cell death. Finally, we show that whereas inactivation of either the MEK or PI3K pathway leads to partial tumor growth inhibition, targeted inhibition of both pathways is required to achieve tumor stasis. Our study provides molecular insights that help explain the heterogeneous response of KRAS mutant cancers to MEK pathway inhibition and presents a strong rationale for the clinical testing of combination MEK and PI3K targeted therapies. [Cancer Res 2009;69(10):4286–93]
SMAD4 mutation and the combined syndrome of juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia
Authors: N. K. Iyer, C. A. Burke, B. H. Leach, J. G. Parambil
Journal: Thorax (2010)

Juvenile polyposis syndrome (JPS) and hereditary haemorrhagic telangiectasia (HHT) are autosomal dominant disorders with characteristic clinical phenotypes. Recently, reports of the combined syndrome of JPS and HHT have been described in individuals with mutations in the <i>SMAD4</i> gene, whose product—SMAD4—is a critical intracellular effector in the signalling pathway of transforming growth factor β (TGFβ). This report describes a 24-year-old man who presented to the Respiratory Institute after colectomy for JPS with a <i>SMAD4</i> mutation and who was subsequently diagnosed to have HHT with asymptomatic cerebral and pulmonary arteriovenous malformations (AVMs). Patients with JPS due to a <i>SMAD4</i> mutation should be screened for the vascular lesions associated with HHT, especially occult AVMs in visceral organs, which may potentially present catastrophically with serious medical consequences.
REDUCED-SIZE HEPATIC ALLOGRAFTS
Authors: M. Malagó, M.D, X. Rogiers, M.D, C.E. Broelsch, M.D., Ph.D
Journal: Annual Review of Medicine (1995)

▪ Abstract Reduced-size hepatic transplantation (RSHT) was developed to alleviate the mortality resulting from the scarcity of suitable cadaveric grafts. RSHT consists of various techniques that reduce a full liver to a smaller size. These techniques include reduced-size cadaveric liver transplantation (RLT), split liver transplantation (SLT), and living-related liver transplantation (LRLT). RLT utilizes part of a liver, while the rest is discarded; in SLT, the whole liver is used for two recipients after bipartition; and in LRLT, a portion of the liver retrieved from a living donor is transplanted. Whereas RLT only redistributes the pool of organs to the advantage of pediatric recipients, both SLT and LRLT increase the availability of grafts for transplantation. RSHT yields results comparable to full-liver allografting and drastically reduces the mortality of patients waiting for transplantation. The procedures involved are technically demanding and should be restricted to experienced liver centers.
Sp100 as a Potent Tumor Suppressor: Accelerated Senescence and Rapid Malignant Transformation of Human Fibroblasts through Modulation of an Embryonic Stem Cell Program
Authors: Dmitri G. Negorev, Olga V. Vladimirova, Andrew V. Kossenkov, Elena V. Nikonova, Renee M. Demarest, Anthony J. Capobianco, Michael K. Showe, Frank J. Rauscher, Louise C. Showe, Gerd G. Maul
Journal: Cancer Research (2010)

Abstract Identifying the functions of proteins, which associate with specific subnuclear structures, is critical to understanding eukaryotic nuclear dynamics. Sp100 is a prototypical protein of ND10/PML nuclear bodies, which colocalizes with Daxx and the proto-oncogenic PML. Sp100 isoforms contain SAND, PHD, Bromo, and HMG domains and are highly sumoylated, all characteristics suggestive of a role in chromatin-mediated gene regulation. A role for Sp100 in oncogenesis has not been defined previously. Using selective Sp100 isoform-knockdown approaches, we show that normal human diploid fibroblasts with reduced Sp100 levels rapidly senesce. Subsequently, small rapidly dividing Sp100 minus cells emerge from the senescing fibroblasts and are found to be highly tumorigenic in nude mice. The derivation of these tumorigenic cells from the parental fibroblasts is confirmed by microsatellite analysis. The small rapidly dividing Sp100 minus cells now also lack ND10/PML bodies, and exhibit genomic instability and p53 cytoplasmic sequestration. They have also activated MYC, RAS, and TERT pathways and express mesenchymal to epithelial transdifferentiation (MET) markers. Reintroduction of expression of only the Sp100A isoform is sufficient to maintain senescence and to inhibit emergence of the highly tumorigenic cells. Global transcriptome studies, quantitative PCR, and protein studies, as well as immunolocalization studies during the course of the transformation, reveal that a transient expression of stem cell markers precedes the malignant transformation. These results identify a role for Sp100 as a tumor suppressor in addition to its role in maintaining ND10/PML bodies and in the epigenetic regulation of gene expression. Cancer Res; 70(23); 9991–10001. ©2010 AACR.
Highly restricted expression of a stromal cell determinant in mouse bone marrow in vivo.
Authors: K Jacobsen, K Miyake, P W Kincade, D G Osmond
Journal: The Journal of Experimental Medicine (1992)

B lymphocyte precursor cells in mouse bone marrow develop in close association with stromal cells which provide essential growth signals. To identify molecules that may normally play a role in this interaction we have examined the in vivo binding of a new monoclonal antibody (mAb) (KMI6) that recognizes a determinant on a bone marrow stromal cell line (BMS2) in vitro. Flow cytometric and radioautographic evaluations revealed that the antigen recognized by KMI6 is represented on the surface of an extremely small number of cells in bone marrow cell suspensions from adult mice. An apparent molecular mass of 110 kD was obtained by surface labeling of a stromal cell clone and immunoprecipitation. Purified mAb KMI6 labeled with 125I was then given intravenously to young C3H/HeJ mice. Unbound mAb was washed out by cardiac perfusion and femoral bone marrow was examined by light and electron microscope radioautography. KMI6 labeling was heavy on the plasma membrane of many stromal cells, especially those located towards the outer subosteal region. The KMI6-labeled stromal cells were usually associated with cells of lymphoid morphology which they often completely surrounded. The labeling was restricted to areas of stromal cell plasma membranes in contact with lymphoid cells. The lymphoid cells themselves, as well as macrophages and other hemopoietic cells, failed to bind mAb KMI6 significantly. Stromal cells in bone marrow depleted of hemopoietic cells by gamma-irradiation (9,5 Gy) bound mAb KMI6 at reduced intensity. The results demonstrate that the KMI6 determinant, a 110-kD protein, is expressed on bone marrow stromal cells in vivo. Its restriction to areas of interaction with lymphoid cells suggests a role in forming microenvironmental niches of B lymphopoiesis. The surface membrane of individual stromal cells may thus be functionally polarized towards interacting B cell precursors and other hemopoietic cells.
Mild Renal Dysfunction and Cardiovascular Risk in Hypertensive Patients
Authors: Giovanna Leoncini, Francesca Viazzi, Denise Parodi, Elena Ratto, Simone Vettoretti, Valentina Vaccaro, Maura Ravera, Giacomo Deferrari, Roberto Pontremoli
Journal: Journal of the American Society of Nephrology (2004)

Mild renal dysfunction, defined as GFR <60 to 70 ml/min and/or the presence of increased urinary albumin excretion, is associated with higher cardiovascular morbidity and mortality in primary hypertension. The aim of the present study was to investigate the relationship between renal dysfunction and target organ damage (TOD), namely left ventricular hypertrophy (LVH), retinal vascular changes, and carotid atherosclerosis, in a large cohort of unselected middle-aged hypertensive patients with normal serum creatinine. A group of 934 untreated patients with primary hypertension (543 men, 391 women; mean age 50 +/- 11 yr) was studied. Renal function was estimated by the creatinine clearance using the Cockcroft-Gault formula and by the presence of albuminuria, measured as the albumin to creatinine ratio (A/C) in first morning urine samples. LVH was determined according to electrocardiographic criteria, and retinal vascular changes were evaluated by direct ophthalmoscopy in all patients. In a subgroup of patients (n = 340; 208 men, 132 women; mean age 47 +/- 9), the presence and extent of cardiac and vascular organ damage was also assessed by ultrasound techniques. Creatinine clearance was on the average 82 +/- 20 ml/min. The overall prevalence of ECG-detected LVH and retinopathy was 12 and 49%, respectively. Creatinine clearance was inversely related to duration of disease, systolic BP, serum glucose, total cholesterol, LDL cholesterol, and early signs of TOD, namely retinal vascular changes and LVH. Patients in the bottom quintile of creatinine clearance showed higher prevalence of both ECG-determined LVH (P = 0.04) and retinal vascular changes (P = 0.02). In the subgroup of patients who underwent ultrasound evaluation of cardiovascular structures, the prevalence of mild renal dysfunction was 18%, whereas the prevalence of LVH and carotid plaque was 49 and 26%, respectively. Patients with mild renal dysfunction showed higher left ventricular mass and increased intima-media thickness (P < 0.0001), as well as higher prevalence of LVH and carotid plaque as compared with those with normal renal function. Controlling for duration of hypertension and mean BP, the risk of TOD in our cohort increased by 20% for each 10 ml/min decrease in creatinine clearance and by 30% for each 0.2 mg/mmol increase in Log A/C. In conclusion, mild renal dysfunction is associated with preclinical end-organ damage in patients with primary hypertension. These data may help to explain the observed increase in cardiovascular mortality reported in these patients. The evaluation of creatinine clearance and urinary albumin excretion could be useful for identifying patients who are at higher cardiovascular risk.
Heparin cofactor II inhibits arterial thrombosis after endothelial injury
Authors: Li He, Cristina P. Vicente, Randal J. Westrick, Daniel T. Eitzman, Douglas M. Tollefsen
Journal: Journal of Clinical Investigation (2002)

Heparin cofactor II (HCII) is a plasma protein that inhibits thrombin rapidly in the presence of dermatan sulfate, heparan sulfate, or heparin. HCII has been proposed to regulate coagulation or to participate in processes such as inflammation, atherosclerosis, and wound repair. To investigate the physiologic function of HCII, about 2 kb of the mouse HCII gene, encoding the N-terminal half of the protein, was deleted by homologous recombination in embryonic stem cells. Crosses of F1HCII+/– animals produced HCII–/– offspring at the expected mendelian frequency. Biochemical assays confirmed the absence of dermatan sulfate–dependent thrombin inhibition in the plasma of HCII–/– animals. Crosses of HCII–/– animals produced litters similar in size to those obtained from heterozygous matings. At 1 year of age, HCII-deficient animals were grossly indistinguishable from their wild-type littermates in weight and survival, and they did not appear to have spontaneous thrombosis or other morphologic abnormalities. In comparison with wild-type animals, however, they demonstrated a significantly shorter time to thrombotic occlusion of the carotid artery after photochemically induced endothelial cell injury. This abnormality was corrected by infusion of purified HCII but not ovalbumin. These observations suggest that HCII might inhibit thrombosis in the arterial circulation.
Pyridoxine in atopic dermatitis
Authors: D.C. MABIN, S. HOLLIS, J. LOCKWOOD, T.J. DAVID
Journal: British Journal of Dermatology (2006)

Summary A previous study has reported benefit when pyridoxine hydrochloride was given to patients with atopic dermatitis. To investigate this in children, we performed a randomized, double-blind, parallel-group, placebo-controlled trial. Forty-eight children with moderate or severe atopic dermatitis were recruited and, of those who completed the study, 19 received pyridoxine hydrochloride 50 mg once daily for 4 weeks and 22 received placebo. Disease activity was monitored by clinical severity scores measuring the extent and degrees of erythema recorded by the investigator and symptom scores (daytime itch and nocturnal sleep disturbance) recorded by parents. There was no statistically significant difference between the two groups at the end of treatment. We have been unable to demonstrate clinical benefit from pyridoxine supplementation in children with atopic dermatitis.
The Microbiome in Infectious Disease and Inflammation
Authors: Kenya Honda, Dan R. Littman
Journal: Annual Review of Immunology (2012)

The mammalian alimentary tract harbors hundreds of species of commensal microorganisms (microbiota) that intimately interact with the host and provide it with genetic, metabolic, and immunological attributes. Recent reports have indicated that the microbiota composition and its collective genomes (microbiome) are major factors in predetermining the type and robustness of mucosal immune responses. In this review, we discuss the recent advances in our understanding of host-microbiota interactions and their effect on the health and disease susceptibility of the host.
Increased serum concentration of urinary trypsin inhibitor with asthma exacerbation
Authors: K. Yasui, H. Kanda, T. Iwanami, A. Komiyama
Journal: European Respiratory Journal (2003)

The aim of the study was to determine whether the amount of urinary trypsin inhibitor (UTI) in serum, a degenerate induced by neutrophil elastase (NE), reflects the degree of bronchial inflammation in children with acute asthma exacerbation. The involvement of neutrophil-mediated inflammation plays as important a role as eosinophil-mediated inflammation in the pathogenesis of acute asthma exacerbation. However, no measurable marker is sensitive enough to assess neutrophil-mediated inflammation in the airways. The pre‐α‐/inter‐α‐trypsin inhibitors are assumed to be precursors of UTI. NE degrades pre‐α‐/inter‐α‐trypsin inhibitors to liberate UTI. UTI concentrations in 25 childhood patients admitted with asthma exacerbation and 15 control subjects were measured by means of one-step sandwich-type enzyme immunoassay. Serum UTI concentrations in the patients at admission were significantly higher than control values (10.597±0.649 and 6.136±0.303 U·mL −1 , respectively (mean±sem)). These levels returned to baseline values with improvement in the asthmatic symptoms. However, serum NE and α 1 antitrypsin concentrations were not significantly different between patients and controls, even during acute exacerbation in the former. The findings suggest that neutrophil-mediated inflammatory events are involved in exacerbation of childhood asthma. The monitoring of urinary trypsin inhibitor concentrations might be useful for evaluating the neutrophil-mediated inflammation in childhood asthma attack.
Ventricular Afterload and Ventricular Work in Fontan Circulation
Authors: Hideaki Senzaki, Satoshi Masutani, Jun Kobayashi, Toshiki Kobayashi, Nozomu Sasaki, Haruhiko Asano, Shunei Kyo, Yuji Yokote, Akira Ishizawa
Journal: Circulation (2002)

Background — Recent studies have indicated that there are inherent limitations associated with Fontan physiology. However, there have been no quantitative analyses of the effects of right heart bypass on ventricular afterload, hydraulic power, and resultant overall hemodynamics. Methods and Results — During routine cardiac catheterization, aortic impedance and ventricular hydraulic power were determined, both at rest and under increased ventricular work induced by dobutamine, in 17 patients with Fontan circulation, 15 patients with a single ventricle whose pulmonary circulation was maintained only by Blalock-Taussig shunts, and 13 patients who had normal 2-ventricle circulation. Both vascular resistance (nonpulsatile load on the ventricle) and pulsatile components of ventricular afterload (represented by low-frequency impedance) were significantly higher in the Fontan group than in the other groups ( P &lt;0.01), and this was associated with decreased cardiac output in the Fontan patients. In addition, hydraulic power cost per unit forward flow was 40% lower in the 2-ventricle circulation than in the single-ventricle circulation, suggesting lower ventricular efficiency in single-ventricle circulation attributable to the lack of a pulmonary ventricle. Furthermore, in the Fontan group, β-adrenergic reserve was markedly decreased because of a limited preload reserve. Conclusions — Fontan physiology is associated with disadvantageous ventricular power and afterload profiles and has limited ventricular reserve capacity. Thus, to improve the long-term prognosis of patients after Fontan surgery, future research should be conducted into medical interventions that can overcome these limitations inherent in Fontan circulation.
Cataracts Following Chronic Headbanging: A Report of Two Cases
Authors: J. R. BEMPORAD, J. A. SOURS, H. F. SPALTER
Journal: American Journal of Psychiatry (1968)

In order to assess the relationship between severe cataracts and violent headbanging, ophthalmologic examinations were performed on a random group of institutionalized headbangers; it was found that the majority had cataracts of varying maturity. The authors describe two patients, eight and ten years old, with cataracts subsequent to chronic headbanging and review recent theories attempting to explain it.
Humanization of autoantigen
Authors: Wataru Nishie, Daisuke Sawamura, Maki Goto, Kei Ito, Akihiko Shibaki, James R McMillan, Kaori Sakai, Hideki Nakamura, Edit Olasz, Kim B Yancey, Masashi Akiyama, Hiroshi Shimizu
Journal: Nature Medicine (2007)
Competing interests in epidemiology
Authors: C. L. Soskolne
Journal: BMJ (2015)

We congratulate The BMJ for being among the first medical journals to implement a policy on declaring financial competing interests. The journal is a pioneer in recognising that transparency through such declarations is not a panacea but requires policy adjustments.

The adjustments made relate specifically to articles commissioned by The BMJ and apply to medical education articles that will, in future, be …
Modulation of Fc receptors of mononuclear phagocytes by immobilized antigen-antibody complexes. Quantitative analysis of the relationship between ligand number and Fc receptor response.
Authors: J Michl, J C Unkeless, M M Pieczonka, S C Silverstein
Journal: The Journal of Experimental Medicine (1983)

Macrophages plated on surfaces coated with antigen-IgG complexes lose the capacity to bind and ingest IgG-coated particles via their Fc receptors (FcR). Macrophages plated on surfaces containing a similar number of IgG molecules that are not complexed to antigen show little or no decrease in FcR activity. Using a rat monoclonal antibody (2.4G2 IgG) directed against the trypsin-resistant FcR (FcRII) of mouse macrophages we show that the decrease in receptor activity induced by substrate-adherent immune complexes is caused by the physical removal of 60 and 75% of FcRII from the nonadherent membrane surfaces of resident and thioglycollate broth-induced macrophages, respectively. Macrophages maintained on antigen-IgG-coated surfaces for up to 44 h show no recovery in FcRII activity or number, while macrophages on control surfaces exhibit two and threefold increases, respectively, in these parameters. Macrophages maintained for 72 h on antigen-IgG-coated surfaces show a small recovery in FcRII activity, and in the number of FcRII that is accessible to bind 125I-2.4G2 IgG. FcRII modulation, as measured by the binding of 125I-labeled 2.4G2 IgG, is initiated when the number of IgG molecules bound to the substrate is approximately equal to the total number of FcRII on the plasma membranes of all the macrophages on the substrate. FcRII activity and number decrease linearly as the number of substrate-bound IgG molecules increases exponentially, and are maximally reduced when the number of IgG molecules on the substrate is 20-fold greater than the total number of all FcRII on the surfaces of all the macrophages in the culture. Thus there is a stoichiometric relationship between the number of IgG molecules on the substrate and the extent of FcRII modulation.
A Longitudinal Study of Hippocampal Volume, Cortisol Levels, and Cognition in Older Depressed Subjects
Authors: J. T. O'Brien
Journal: American Journal of Psychiatry (2004)

This study determined whether cognitive impairments and structural brain changes in older depressed subjects, especially in the hippocampus, are related to hypercortisolemia.Sixty-one depressed subjects over age 60 who met DSM-IV criteria for major depression and 40 healthy comparison subjects underwent structural magnetic resonance imaging, neuropsychological testing, apolipoprotein E (APOE) genotyping, and salivary cortisol assessment (over 3 days) with follow-up 6 months later. Hippocampal volume was measured by manual segmentation that was blind to diagnosis. Average area under the curve for salivary cortisol over the 3 days was calculated. Cognitive function was assessed by using a combined memory z score.Depressed subjects showed multiple impairments in attention, working memory, visual memory, verbal memory, new learning, and executive function in relation to comparison subjects. They had hypercortisolemia (53% increase in area under the curve) and a reduction in right hippocampal volume (6% decrease). Hippocampal volume reduction was not associated with increased cortisol levels but was significantly correlated with continuing memory deficits at 6 months. Persisting "mild cognitive impairment" was seen in 20 (41%) of 49 subjects at 6 months and was associated with reduced hippocampal volume but not severity of depression, cortisol levels, or APOE genotype.Older depressed subjects have persisting cognitive impairments associated with hippocampal volume reduction, but the results do not support cortisol-mediated hippocampal neurotoxicity as the major etiological mechanism. Neuropathological studies are required to investigate the basis for hippocampal changes, while follow-up will determine whether hippocampal atrophy is a risk factor for cognitive decline.