tbuckley/cabot-search huggingface dataset:
MEK plus PI3K/mTORC1/2 Therapeutic Efficacy Is Impacted by<i>TP53</i>Mutation in Preclinical Models of Colorectal Cancer
Authors: Celina García-García, Martín A. Rivas, Yasir H. Ibrahim, María Teresa Calvo, Albert Gris-Oliver, Olga Rodríguez, Judit Grueso, Pilar Antón, Marta Guzmán, Claudia Aura, Paolo Nuciforo, Katti Jessen, Guillem Argilés, Rodrigo Dienstmann, Andrea Bertotti, Livio Trusolino, Judit Matito, Ana Vivancos, Irene Chicote, Héctor G. Palmer, Josep Tabernero, Maurizio Scaltriti, José Baselga, Violeta Serra
Journal: Clinical Cancer Research (2015)

PI3K pathway activation occurs in concomitance with RAS/BRAF mutations in colorectal cancer, limiting the sensitivity to targeted therapies. Several clinical studies are being conducted to test the tolerability and clinical activity of dual MEK and PI3K pathway blockade in solid tumors.In the present study, we explored the efficacy of dual pathway blockade in colorectal cancer preclinical models harboring concomitant activation of the ERK and PI3K pathways. Moreover, we investigated if TP53 mutation affects the response to this therapy.Dual MEK and mTORC1/2 blockade resulted in synergistic antiproliferative effects in cell lines bearing alterations in KRAS/BRAF and PIK3CA/PTEN. Although the on-treatment cell-cycle effects were not affected by the TP53 status, a marked proapoptotic response to therapy was observed exclusively in wild-type TP53 colorectal cancer models. We further interrogated two independent panels of KRAS/BRAF- and PIK3CA/PTEN-altered cell line- and patient-derived tumor xenografts for the antitumor response toward this combination of agents. A combination response that resulted in substantial antitumor activity was exclusively observed among the wild-type TP53 models (two out of five, 40%), but there was no such response across the eight mutant TP53 models (0%). Interestingly, within a cohort of 14 patients with colorectal cancer treated with these agents for their metastatic disease, two patients with long-lasting responses (32 weeks) had TP53 wild-type tumors.Our data support that, in wild-type TP53 colorectal cancer cells with ERK and PI3K pathway alterations, MEK blockade results in potent p21 induction, preventing apoptosis to occur. In turn, mTORC1/2 inhibition blocks MEK inhibitor-mediated p21 induction, unleashing apoptosis. Clin Cancer Res; 21(24); 5499-510. ©2015 AACR.
Dietary Supplements and Cancer Prevention: Balancing Potential Benefits Against Proven Harms
Authors: M. E. Martinez, E. T. Jacobs, J. A. Baron, J. R. Marshall, T. Byers
Journal: JNCI Journal of the National Cancer Institute (2012)

Nutritional supplementation is now a multibillion-dollar industry, and about half of all US adults take supplements. Supplement use is fueled in part by the belief that nutritional supplements can ward off chronic disease, including cancer, although several expert committees and organizations have concluded that there is little to no scientific evidence that supplements reduce cancer risk. To the contrary, there is now evidence that high doses of some supplements increase cancer risk. Despite this evidence, marketing claims by the supplement industry continue to imply anticancer benefits. Insufficient government regulation of the marketing of dietary supplement products may continue to result in unsound advice to consumers. Both the scientific community and government regulators need to provide clear guidance to the public about the use of dietary supplements to lower cancer risk.
She's been forgetting
Authors: Richard Donze
Journal: Annals of Internal Medicine (2015)

Ad Libitum15 September 2015She's been forgettingRichard Donze, DO, MPHRichard Donze, DO, MPHFrom West Chester, PennsylvaniaSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M15-0912 Audio Reading - “She's been forgetting” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "She's been forgetting," by R. Donze. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail her meds just lookat those ankles withno diuretics for Godknows how long andoverall not as clearof late either so maybeit's finally time forassisted living saythe kids waiting atthe house pushingme and 65 and 70themselves but the"finally" is for everytime I've said howsharp she seemsand if you wannasee severe not-so-clear I canshow you thoughsometimes I wonderwhat I'm trying toprotect or forestall asif I can keep her go-ing in the old houselong enough to passthere watched bytiger maple armoirewalnut spinet cherrybreakfront all thatchina that silver soI almost don't wantto start asking theday year and presi-dent questions butafter she ... Author, Article, and Disclosure InformationAffiliations: From West Chester, PennsylvaniaCurrent Author Address: Richard Donze, DO, MPH; e-mail, [email protected]net. PreviousarticleNextarticle Advertisement Audio Reading - “She's been forgetting” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "She's been forgetting," by R. Donze. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 15 September 2015Volume 163, Issue 6Page: 451KeywordsAnklesDiuretics ePublished: 15 September 2015 Issue Published: 15 September 2015 Copyright & PermissionsCopyright © 2015 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Cholinergic Markers in Elderly Patients With Early Signs of Alzheimer Disease
Authors: Kenneth L. Davis
Journal: JAMA (1999)

Context A central tenet of Alzheimer disease (AD) is the loss of cortical cholinergic function and cholinergic markers in postmortem brain specimens.Whether these profound deficits in cholinergic markers found in end-stage patients are also found in patients with much earlier disease is not known.Objective To determine whether cholinergic deficits in AD precede, follow, or occur in synchrony with the earliest signs of cognitive deterioration. Design, Setting, and PatientsPostmortem study of nursing home residents with Clinical Dementia Rating (CDR) Scale scores of 0.0 to 2.0 and 4.0 to 5.0 who underwent autopsy between 1986 and 1997, comparing the activity of the cholinergic marker enzymes in the cortices of 66 elderly subjects with no (CDR score = 0.0; n = 18), questionable (CDR score = 0.5; n = 11), mild (CDR score = 1.0; n = 22), or moderate (CDR score = 2.0; n = 15) dementia vs subjects with severe dementia (CDR score = 4.0-5.0;n = 15). Main Outcome MeasuresActivity of the cholinergic marker enzymes choline acetyltransferase and acetylcholinesterase in 9 neocortical brain regions. ResultsThe activity of choline acetyltransferase and acetylcholinesterase in 9 neocortical brain regions did not differ significantly in subjects with CDR scores of 0.0 to 2.0, but was significantly lower in subjects with severe dementia (CDR score = 4.0-5.0).Choline acetyltransferase levels were significantly correlated with severity of neuropathological lesions of AD, as measured by density of neuritic plaques and neurofibrillary tangles. ConclusionsAlthough neocortical cholinergic deficits are characteristic of severely demented AD patients, in this study, cholinergic deficits were not apparent in individuals with mild AD and were not present until relatively late in the course of the disease.These results suggest that patients with more severe disease should be a target for cholinergic treatment.
Depression and functional bowel disorders in gastrointestinal outpatients.
Authors: J D Rose, A H Troughton, J S Harvey, P M Smith
Journal: Gut (1986)

Although depression has been linked with both the irritable bowel syndrome and non-organic abdominal pain, which are common in gastrointestinal outpatients, the prevalence of depression in most surveys of outpatient practice has been low. Use of the Beck Depression Inventory to screen new referrals to a general medical and gastrointestinal clinic and to a minor surgical clinic showed that 50 of 100 medical patients were rated as having some degree of depression, compared with 14 of 75 (19%) of the surgical patients in whom abdominal pain and bowel dysfunction were rare (X2 = 9.6, p less than 0.01). In the medical clinic no organic disorder was detected in 64% of the depressed patients, the majority of whom presented with abdominal pain or irritable bowel syndrome. Depression was significantly commoner in this group of patients than in those with other conditions, (X2 = 6.63, p = 0.01). That depression is common in gastrointestinal outpatients is not always appreciated and its symptoms should be sought in all patients with bowel dysfunction and chronic abdominal pain.
Neuron Specific Enolase, A Clinically Useful Marker for Neurons and Neuroendocrine Cells
Authors: P J Marangos, D E Schmechel
Journal: Annual Review of Neuroscience (1987)

The rationale for studying cell specific proteins is rooted in the realization that proteins strictly localized or even greatly enriched in a given cell type are likely to be involved in biochemical events that are either specific to that cell type or performed in a different manner by that particular cell. This concept is further strengthened if the cell specific protein has an ontogenetic appearance that parallels that of the differentiation of the cell. The biochemical characterization of the proteins, actin, myosin, and troponin, in muscle as well as hemoglobin in red cells and tubulin in nerve cells constitutes examples illustrating the usefulness of this approach. In all these cases the structural and functional charactcrization of a given protein provided key insights regarding the function of specific cell types. The elucidation and characterization of nervous system specific proteins
Interstitial Fluid Pressure: III. Its Effect on Resistance to Tissue Fluid Mobility
Authors: ARTHUR C. GUYTON, KONRAD SCHEEL, DENNIS MURPHREE
Journal: Circulation Research (1966)

The resistance to fluid mobility in the interstitial fluid spaces has been measured between perforated catheters inserted into the subcutaneous abdominal tissues of the dog and between perforated capsules implanted in the tissues 1 month previously. When the pressures in the catheters or perforated capsules were less than atmospheric pressure, the resistance to fluid movement was almost infinite, but when the pressures were increased almost to or above atmospheric pressure the resistance usually decreased more than 100,000-fold, indicating a suddenly increased size of the tissue spaces. The shape of the pressure-volume curve relating (a) interstitial fluid pressure to (b) volume of mobile interstitial fluid was calculated from pressure-conductance curves recorded in these experiments. On comparing this pressure-volume curve with a previously measured pressure-volume curve of the entire interstitial fluid compartment, two important points were observed: first, both curves exhibit a sudden increase in volume when the interstitial fluid pressure rises above atmospheric pressure. Second, the mobile interstitial fluid volume approaches zero when the interstitial fluid pressure falls below atmospheric pressure while the measured volume is still very great. It is postulated that this difference is caused by entrapment of large amounts of water in a relatively immobile state in the gelatinous matrix of the ground substance filling the interstitial spaces.
A patient with ankylosing spondylitis and recurrent haemoptysis
Authors: T. Franquet, N.L. Müller, J.D. Flint
Journal: European Respiratory Journal (2004)

Case historyA 54-yr-old male presented with a history of recurrent episodes of haemoptysis over the previous 2 yrs.The patient also complained of back pain and stiffness for 15 yrs due to ankylosing spondylitis.Over the previous 2 weeks, he had been complaining of progressively increasing dyspnoea, malaise and fever.The fever persisted despite antibiotics and the patient showed acute severe haemoptysis.He drank little alcohol and had ceased smoking a few cigarettes daily 20 yrs previously.He had no previous history of pulmonary tuberculosis.On admission, he was pale and complained of nonproductive cough.His temperature was 37.6uC, pulse rate 98 beats?min -1 , respiratory frequency 30 breaths?min -1 and blood pressure 160/90 mmHg.On physical examination, the patient was a thin male, who appeared comfortable at rest, without respiratory stridor.No lymphadenopathy was evident.The head and neck were normal.
The health of children in refuges for women victims of domestic violence: cross sectional descriptive survey
Authors: E. Webb, J. Shankleman, M. R Evans, R. Brooks
Journal: BMJ (2001)

To describe the health and developmental status of children living in refugees for women victims of domestic violence and to investigate their access to primary healthcare services.Cross sectional survey.Women's refugees in Cardiff.148 resident children aged under 16 years and their mothers.Completeness of records on the child health system (register of all children that includes data on the child's health) for named health visitor, named general practitioner, and immunisation uptake; satisfactory completion of child health surveillance; Denver test results for developmental status; Rutter test scores for behavioural and emotional problems; reports of maternal concerns.148/257 (58%) children living in refugee between April 1999 and January 2000 were assessed. Child health system data were incorrect (general practitioner and/or address) or unavailable for 85/148 (57%) children. Uptake of all assessments and immunisations was low. 13/68 (19%) children aged <5 years had delayed or questionable development on the Denver test, and 49/101 (49%) children aged 3-15 years had a Rutter score of >10 (indicating probable mental health problems). Concerns were expressed by mothers of 113/148 (76%) children. After leaving the refuge, 22 children were untraceable and 36 returned home to the perpetrator from whom the families had fled.The children had a high level of need, as well as poor access to services. Time spent in a refuge provides a window of opportunity to review health and developmental status. Specialist health visitors could facilitate and provide support, liaison, and follow up.
Duodenal mucosal reductase in wild-type and Hfe knockout mice on iron adequate, iron deficient, and iron rich feeding
Authors: R J Simpson
Journal: Gut (2003)

Genetic haemochromatosis is a common hereditary iron loading disorder in humans. The disease is associated with loss of function mutations in the HFE gene. This is thought to change iron stores via increased iron absorption.In this study we investigated how adaptation of mucosal reductase activity is engaged in this process and how the changes compare with adaptation seen when an iron deficient diet is fed.Duodenal mucosal surface reductase was measured with nitroblue tetrazolium in age matched groups of male Hfe knockout mice (Hfe) and wild- type mice fed a purified diet containing normal (iron adequate), high (iron rich), or low (iron deficient) iron concentrations.Reductase activity increased when mice were fed an iron deficient diet and decreased when they were fed an iron rich diet. Total villus activity, as measured by the average area under the activity curve along the crypt-villus axis, was increased 2.8-2.9-fold by iron deficiency in both genotypes. Approximately half of this difference was attributable to the significantly increased length of the villi in mice on an iron deficient diet (p<0.05). Hfe knockout did not affect villus length but increased mucosal reductase activity near the villus tips. Similar increases (1.3-1.6-fold) were seen on all diets but the increase was significant for iron deficient and iron loaded diets only (p<0.05).Hfe gene product and dietary iron downregulate villus reductase activity in mice.
Primary prevention with lipid lowering drugs and long term risk of vascular events in older people: population based cohort study
Authors: A. Alperovitch, T. Kurth, M. Bertrand, M.-L. Ancelin, C. Helmer, S. Debette, C. Tzourio
Journal: BMJ (2015)

<b>Objective</b> To determine the association between use of lipid lowering drugs (statin or fibrate) in older people with no known history of vascular events and long term risk of coronary heart disease and stroke <b>Design</b> Ongoing prospective population based cohort study recruited in 1999-2000, with five face-to-face examinations. <b>Setting</b> Random sample of community dwelling population aged 65 years and over, living in three French cities (Bordeaux, Dijon, Montpellier). <b>Participants</b> 7484 men and women (63%) with mean age 73.9 years and no known history of vascular events at entry. Mean follow-up was 9.1 years. <b>Main outcome measures</b> Adjusted hazard ratios of coronary heart disease and stroke in baseline lipid lowering drug users compared with non-users, calculated using multivariable Cox proportional hazard models adjusted for numerous potential confounding factors. Hazard ratios were estimated for use of any lipid lowering drug and for statin and fibrate separately. <b>Results</b> Lipid lowering drug users were at decreased risk of stroke compared with non-users (hazard ratio 0.66, 95% confidence interval 0.49 to 0.90); hazard ratios for stroke were similar for statin (0.68, 0.45 to1.01) and fibrate (0.66, 0.44 to 0.98). No association was found between lipid lowering drug use and coronary heart disease (hazard ratio 1.12, 0.90 to 1.40). Analyses stratified by age, sex, body mass index, hypertension, systolic blood pressure, triglyceride concentrations, and propensity score did not show any effect modification by these variables, either for stroke or for coronary heart disease. <b>Conclusion</b> In a population based cohort of older people with no history of vascular events, use of statins or fibrates was associated with a 30% decrease in the incidence of stroke.
Pathogenesis of Hepatic Coma
Authors: L Zieve, D M Nicoloff
Journal: Annual Review of Medicine (1975)

Hepatic coma is a complex pathophysiologic state that is multifactorial in origin. Incomplete and uncontrolled but significant observations in patients have offered clues for experimental study. Unfortunately the body of solid experimental data is small, and the amount of uninhibited speculation excessive. To compound this problem there has been confusion between correlation and causation. Hepatic en­ cephalopathy has many associated alterations, some of which are noncausal corre­ lated changes and some consequences of the encephalopathy. Seen after the fact, these two types of alterations cannot be differentiated from causal factors. This has often been forgotten in this field where everyone is primarily interested in etiology, and claims have been made that do not withstand careful inspection. Several previous reviews offer broad perspectives on the whole subject (1-3). In 1966 we (4) reviewed the subject of pathogenesis in detail, and we will assume acquaintance with that material for purposes of the present review. In addition to the known metabolic abnormalities, which will again be summarized and brought up to date, that article provided a brief discussion of the clinical picture, the role of precipitating factors, and the contribution of electrolyte and acid-base abnormali­ ties. Since then Zimmon (5, 6) has shown that the well-known shift to the right in the in vivo oxyhemoglobin dissociation curve, when more than minimal, is asso­ ciated with the presence of hepatic encephalopathy and is due to an unidentified small molecular weight acidic plasma factor. When the hepatic encephalopathy disappears, the shift to the right is reversed. Such reversal has been observed following suppression of gut bacteria.
Influence of hypoxia in inflammatory synovitis
Authors: T Bodamyali, C R Stevens, M E J Billingham, S Ohta, D R Blake
Journal: Annals of the Rheumatic Diseases (1998)

HypothesisPersistent synovitis results from a hypoxia driven progressive transition to glycolytic metabolism that promotes transcriptional changes permissive to unresolved inflammation as the disease progresses.Erosion of cartilage and bone may involve gene expression characteristic to the "anoxic response system" of wound repair.
Ipilimumab in patients with melanoma and autoimmune disease
Authors: Chrisann Kyi, Richard D Carvajal, Jedd D Wolchok, Michael A Postow
Journal: Journal for ImmunoTherapy of Cancer (2014)

Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), an immune-checkpoint receptor and regulator of T-cell activation, has become an important therapeutic target for immunotherapy in cancer and autoimmune diseases. To date, clinical trials involving cancer immunotherapies, such checkpoint blocking antibodies directed at CTLA-4 (ipilimumab), have excluded patients with underlying autoimmune disease given concern for potential triggering of autoimmune exacerbations. We present the first known cases to our knowledge of two patients with active autoimmune diseases who received ipilimumab. In this limited clinical experience, no serious exacerbations of underlying autoimmunity have yet been observed, and one patient benefited from ipilimumab. These cases advocate for further investigation of the safety of cancer immunotherapies in cancer patients with underlying autoimmune conditions in carefully designed clinical trials with cautious monitoring.
Human Monoclonal Antibodies to Sialyl-Lewisa (CA19.9) with Potent CDC, ADCC, and Antitumor Activity
Authors: Ritsuko Sawada, Shu-Man Sun, Xiaohong Wu, Feng Hong, Govind Ragupathi, Philip O. Livingston, Wolfgang W. Scholz
Journal: Clinical Cancer Research (2011)

Abstract Purpose: The carbohydrate antigen sialyl-Lewisa (sLea), also known as CA19.9, is widely expressed on epithelial tumors of the gastrointestinal tract and breast and on small-cell lung cancers. Since overexpression of sLea appears to be a key event in invasion and metastasis of many tumors and results in susceptibility to antibody-mediated lysis, sLea is an attractive molecular target for tumor therapy. Experimental Design: We generated and characterized fully human monoclonal antibodies (mAb) from blood lymphocytes from individuals immunized with a sLea–KLH vaccine. Results: Several mAbs were selected based on ELISA and FACS including two mAbs with high affinity for sLea (5B1 and 7E3, binding affinities 0.14 and 0.04 nmol/L, respectively) and further characterized. Both antibodies were specific for Neu5Acα2–3Galβ1–3(Fucα1–4)GlcNAcβ as determined by glycan array analysis. Complement-dependent cytotoxicity against DMS-79 cells was higher (EC50 0.1 μg/mL vs. 1.7 μg/mL) for r7E3 (IgM) than for r5B1 (IgG1). In addition, r5B1 antibodies showed high level of antibody-dependent cell-mediated cytotoxicity activity on DMS-79 cells with human NK cells or peripheral blood mononuclear cells. To evaluate in vivo efficacy, the antibodies were tested in a xenograft model with Colo205 tumor cells engrafted into SCID (severe combined immunodeficient mice) mice. Treatment during the first 21 days with four doses of r5B1 (100 μg per dose) doubled the median survival time to 207 days, and three of five animals survived with six doses. Conclusion: On the basis of the potential of sLea as a target for immune attack and their affinity, specificity, and effector functions, 5B1and 7E3 may have clinical utility. Clin Cancer Res; 17(5); 1024–32. ©2011 AACR.