tbuckley/cabot-search huggingface dataset:
Secretases: potential and roadblocks on the way to therapy
Authors: Bart De Strooper
Journal: Molecular Neurodegeneration (2013)

Over the last decade important progress has been made towards the understanding of the molecular pathobiology of Alzheimer’s Disease. One of the major breakthroughs was the identification of presenilin and its crucial role in the gamma-Secretase processing of APP and Notch. Ever since, it has been a major aim to block gamma-Secretase in a safe way. Recent results of trials, in particular the semagacestat trial of Ely-Lilly, indicate that blocking gamma-Secretase in Alzheimer patients can cause important side effects. Significantly, the cognitive condition of patients under semagacestat treatment worsened, suggesting an important role of one of the gamma-Secretase substrates in cognition. The outcome of this trial raises the question whether it will be possible to identify a therapeutic window for gamma-Secretase inhibition in AD. We will show in the current presentation that our knowledge on gamma-Secretase function and regulation has dramatically progressed in the last years. We will explain how different gamma-Secretase complexes have different biological roles, and that selectively targeting them could provide safer drugs. Also increasing insights into structure and function could lead to safer drugs, such as gamma-secretase modulators, but also drugs that specifically interfere with docking of specific substrates to the different gamma-Secretases. Finally insight into the regulation of the gamma-Secretase complex only starts to emerge, which also could open new opportunities for safer drugs.
Grief and major depression
Authors: R. Pies
Journal: BMJ (2014)

The anti–epidermal growth factor receptor (anti-EGFR) antibody cetuximab is clinically approved for the treatment of EGFR-expressing metastatic colorectal cancer and advanced head and neck cancer. Overexpression of EGFR has also been found in more than 70% of carcinomas of the cervix. The overall goal of this study was to determine whether <sup>64</sup>Cu-1,4,7,10-tetraazacyclododecane-<i>N,N′,N″,N′″-</i>tetraacetic acid (DOTA)-cetuximab has potential as an agent for measuring EGFR concentration by PET imaging in cervical cancer tumors. <b>Methods:</b> Cetuximab was conjugated to the bifunctional chelator DOTA and labeled with <sup>64</sup>Cu. EGFR messenger RNA (mRNA) expression was correlated with EGFR densities on the cell surface of 5 different cervical cancer cell lines and with receptor function, measured by internalization of <sup>64</sup>Cu-DOTA-cetuximab. Imaging in tumor-bearing mice with small-animal PET was performed using the highest-expressing cervical cancer cell line. <b>Results:</b> The affinity of <sup>64</sup>Cu-DOTA-cetuximab binding for the EGFR was similar in 4 EGFR-positive lines, varying from 0.1 to 0.7 nM. The mRNA expression corresponded well with EGFR densities and levels of internalization, with responses decreasing in the order of CaSki &gt; ME-180 &gt; DoTc2 4510 &gt; HeLa &gt; C-33A. Biodistribution and small-animal PET studies with <sup>64</sup>Cu-DOTA-cetuximab in CaSki tumor-bearing nude mice showed relatively high tumor uptake at 24 h after injection (13.2 ± 1.2 percentage of injected activity per gram), although there was also significant retention of activity in the blood and liver accumulation. <b>Conclusion:</b><sup>64</sup>Cu-DOTA-cetuximab was successfully used to detect and quantify EGFR expression in cervical cancer tumors, and small-animal PET/CT of EGFR-expressing CaSki tumors suggests potential for PET/CT of EGFR-positive tumors.
On the mechanism of barium induced diastolic depolarisation in isolated ventricular myocytes
Authors: F. VALENZUELA, M. VASSALLE
Journal: Cardiovascular Research (1989)

Barium can induce spontaneous activity in cardiac non-pacemaker cells. The mechanism of barium induced diastolic depolarisation was studied in isolated ventricular myocytes, using a microelectrode technique. Barium (0.05–0.2 mmol·litre−1) decreased resting potential and caused the membrane potential at the end of the action potential to undershoot the diminished resting value temporarily, thereby inducing diastolic depolarisation. Resting membrane resistance was increased by Ba but at the end of phase 3 repolarisation the resistance temporarily decreased below its steady state diastolic value. In presence of Ba, hyperpolarisation abolished or reversed diastolic depolarisation. At the end of phase 3 repolarisation, membrane resistance was decreased, whether diastolic depolarisation was present, absent or reversed. A high [K]o (15.4 mmol·litre−1) decreased Ba effects on action potential, membrane resistance and diastolic depolarisation. Caesium decreased the Ba induced diastolic depolarisation and the associated increase in membrane resistance, but had little effect on spontaneous activity at depolarised levels. Barium induced an oscillatory potential, with increased membrane resistance. Noradrenaline plus low [Ba]o, and high [Ba]o alone (1–5 mmol·litre−1), can induce spontaneous activity. Thus, in myocardial cells barium induces diastolic depolarisation at polarised levels by a voltage and time dependent block of potassium conductance, which is modulated by action potential voltage changes. However, as [Ba]o is increased, spontaneous activity at a depolarised level may be related to the decay of potassium currents and to oscillatory potentials.
Optimal methods for measuring eligibility for liver transplant in hepatocellular carcinoma patients undergoing transarterial chemoembolization
Authors: Hyung-Don Kim, Ju Hyun Shim, Gi-Ae Kim, Yong Moon Shin, Eunsil Yu, Sung-Gyu Lee, Danbi Lee, Kang Mo Kim, Young-Suk Lim, Han Chu Lee, Young-Hwa Chung, Yung Sang Lee
Journal: Journal of Hepatology (2014)
Levels of Beta-Microseminoprotein in Blood and Risk of Prostate Cancer in Multiple Populations
Authors: Christopher A. Haiman, Daniel O. Stram, Andrew J. Vickers, Lynne R. Wilkens, Katharina Braun, Camilla Valtonen-André, Mari Peltola, Kim Pettersson, Kevin M. Waters, Loic Le Marchand, Laurence N. Kolonel, Brian E. Henderson, Hans Lilja
Journal: JNCI Journal of the National Cancer Institute (2012)

A common genetic variant (rs10993994) in the 5' region of the gene encoding β-microseminoprotein (MSP) is associated with circulating levels of MSP and prostate cancer risk. Whether MSP levels are predictive of prostate cancer risk has not been evaluated.We investigated the prospective relationship between circulating plasma levels of MSP and prostate cancer risk in a nested case-control study of 1503 case subjects and 1503 control subjects among black, Latino, Japanese, Native Hawaiian, and white men from the Multiethnic Cohort study. We also examined the ability of MSP to serve as a biomarker for discriminating prostate cancer case subjects from control subjects. All statistical tests are two-sided.In all racial and ethnic groups, men with lower MSP levels were at greater risk of developing prostate cancer (odds ratio = 1.02 per one unit decrease in MSP, P < .001 in the prostate-specific antigen [PSA]-adjusted analysis). Compared with men in the highest decile of MSP, the multivariable PSA-adjusted odds ratio was 3.64 (95% confidence interval = 2.41 to 5.49) for men in the lowest decile. The positive association with lower MSP levels was observed consistently across racial and ethnic populations, by disease stage and Gleason score, for men with both high and low levels of PSA and across all genotype classes of rs10993994. However, we did not detect strong evidence of MSP levels in improving prostate cancer prediction beyond that of PSA.Regardless of race and ethnicity or rs10993994 genotype, men with low blood levels of MSP have increased risk of prostate cancer.
Complex roles of cyclo-oxygenase 2 in hepatitis
Authors: A. P Holt, D. H Adams
Journal: Gut (2007)

There is currently insufficient evidence to support the use of COX-2 inhibitors in treating chronic hepatitis or in preventing liver fibrosis

    There is a bark of an English tree, which I have found to be a powerful astringent, very efficacious in curing agues and intermitting disorders.1 

So wrote the Reverend Edmund Stone in 1763 in a letter to the Royal Society wherein he described his success in treating patients with fever with an extract of powdered willow bark. Although willow extract was used in many ancient cultures as an antipyretic, the active component, salicylic acid, was not identified until the 19th century. The discovery of the chemical structure of salicylate by Herman Kolbe paved the way for the synthesis of acetylsalicylic acid by Bayer in the late 19th century. The mechanism by which it exerted its anti-inflammatory effects remained a mystery until John Vane revealed in the 1970s that aspirin and the newly developed non-steroidal anti-inflammatory drugs (NSAIDs) are non-selective inhibitors of cyclo-oxygenase (COX), the enzyme that catalyses the formation of prostaglandins from arachidonic acid. The enzyme contains two active sites, a cyclo-oxygenase which converts arachidonic acid to prostaglandin G2 (PGG2), and a haem with peroxidase activity which reduces PGG2 to the type-2 prostanoid precursor PGH2, which is subsequently converted into biologically active molecules including the classical prostaglandins (PGE2, PGD2 and PGJ2), prostacyclin and thromboxane-A2.

Three COX isoenzymes have been described, COX1, COX2 and COX3, a splice variant of COX1. COX1 and COX2 display 60% homology at the amino acid level and are both membrane proteins located primarily in the endoplasmic reticulum (COX1) and perinuclear envelope (COX2). COX1 is constitutively expressed in most tissues and is responsible for many cytoprotective and physiological functions. COX2 expression is negligible in …
Musculoskeletal manifestations in polymyalgia rheumatica and temporal arteritis
Authors: J Narvaez
Journal: Annals of the Rheumatic Diseases (2001)

To evaluate the incidence and characteristics of musculoskeletal manifestations in polymyalgia rheumatica (PMR) and temporal arteritis (TA).The records of 163 cases of PMR or TA diagnosed over a 15 year period in one area of Spain were reviewed for the presence and type of musculoskeletal manifestations.Of 163 patients, 90 had isolated PMR and 73 had TA. Eighteen of the 90 patients (20%) with isolated PMR developed distal peripheral arthritis either at diagnosis or during the course of the disease. When it occurred, synovitis was mild, monoarticular or pauci-articular, asymmetrical, transient, and not destructive. Other distal manifestations observed in these patients were carpal tunnel syndrome and distal extremity swelling with pitting oedema. In all cases these manifestations occurred in conjunction with active PMR. As expected, PMR was the most frequent musculoskeletal manifestation in patients with TA, occurring in 56% of cases. On the contrary, only 11% of patients with TA developed peripheral arthritis. An important finding was that peripheral arthritis in these patients appears to be linked only temporally to the presence of simultaneous PMR and is not observed in its absence. Distal extremity swelling or defined polyarthritis were not observed.The spectrum of distal musculoskeletal manifestations of PMR in our series is similar to that reported in other populations. By contrast, distal musculoskeletal symptoms are uncommon in TA. The almost complete absence of distal musculoskeletal manifestations in patients with pure TA suggests different mechanisms of disease in PMR and TA, supporting the view of two separate conditions or one common disease in which host susceptibility influences the clinical expression.
230 Usefulness of the measurement of critical flicker frequency in the diagnosis of minimal hepatic encephalopathy (MHE)
Authors: M. Romero-Gomez, J. Cordoba, R. Jover, J.A. Del-Olmo, M. Ramírez, M. Flavia, L. Compañy, D. Nuñez, J.M. Rodrigo, V. Felipo
Journal: Journal of Hepatology (2006)
Digoxin Use and the Risk of Breast Cancer in Women
Authors: Robert J. Biggar, Jan Wohlfahrt, Anna Oudin, Thomas Hjuler, Mads Melbye
Journal: Journal of Clinical Oncology (2011)

Digoxin resembles estrogen chemically and may have estrogenic effect. We hypothesized that digoxin use might increase breast cancer incidence and examined if use might be associated with risk of breast cancer, categorized by estrogen receptor (ER) status. To determine if being under care for heart disease biased the findings, rate ratios in users of angina drugs were similarly evaluated as a control exposure group.Women using digoxin and angina drugs were identified in the nationwide Danish Prescription Database, available between 1995 and 2008. Incident breast cancers were identified in the Danish Cancer Registry and further classifying by ER status. Relative risks (RR) were compared to nonusers using age- and period-adjusted incidence rate ratios.Two thousand one hundred forty-four of 104,648 women using digoxin developed breast cancer. Current digoxin users were at increased risk of breast cancer (RR, 1.39; 95% CI, 1.32 to 1.46), but risk was not increased in former users (RR, 0.91; 95% CI, 0.83 to 1.00). The increased risks in digoxin users were marginally higher for ER-positive breast cancers (RR, 1.35; 95% CI, 1.26 to 1.45) and ER unknown breast cancers (RR, 1.51; 95% CI, 1.38 to 1.64) than for ER-negative breast cancers (RR, 1.20; 95% CI, 1.03 to 1.40). Among 137,493 women exposed to angina drugs only (a comparison group with cardiovascular disease; n = 2,658 breast cancers), incidence was not increased in current or former users.Women currently using digoxin had a significantly increased risk of breast cancer. Risk normalized when digoxin was stopped. No risk increases were observed in women using angina drugs only. The higher risk of developing ER-positive breast cancers supports an estrogen-mimicking mechanism.
Activation of β-Catenin by Hypoxia in Hepatocellular Carcinoma Contributes to Enhanced Metastatic Potential and Poor Prognosis
Authors: Liang Liu, Xiao-Dong Zhu, Wen-Quan Wang, Yuan Shen, Yi Qin, Zheng-Gang Ren, Hui-Chuan Sun, Zhao-You Tang
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Aberrant activation of β-catenin contributes to the malignant phenotype in hepatocellular carcinoma (HCC). Hypoxia is also known to promote HCC invasion and metastasis. However, the association between β-catenin and the proinvasive role of hypoxia remains unclear. We investigated the role of β-catenin in the proinvasive consequences of hypoxia in HCC. Experimental Design: We established in vitro and in vivo hypoxic models to investigate the expression of β-catenin in hypoxic HCC cells and its role in hypoxia-induced aggressiveness. The clinical significance of β-catenin and/or hypoxia-induced factor-1α (HIF-1α) was evaluated using HCC tissue microarrays. Results: Hypoxia induced β-catenin overexpression and/or intracellular accumulation in four HCC cell lines through downregulating the endogenous degradation machinery, and promoted in vitro invasion and in vivo metastasis of MHCC97 and Hep3B cells. Besides morphologic changes, hypoxic MHCC97 and Hep3B cells exhibited molecular alterations consistent with epithelial-mesenchymal transition, characterized by the loss of epithelial cell markers (E-cadherin and plakoglobin) and upregulation of mesenchymal markers (vimentin and N-cadherin), as well as the increase of matrix metalloproteinase 2. However, silencing β-catenin in these hypoxic cells reversed epithelial-mesenchymal transition and repressed metastatic potential. Positive expression of β-catenin in HCC tissue microarray was associated with the expression of HIF-1α (P = 0.034), and coexpression of β-catenin and HIF-1α in HCC was correlated with shorter overall survival and time to recurrence. Conclusion: β-Catenin in HCC is activated by hypoxia and contributes to hypoxia-induced metastatic potential. Clin Cancer Res; 16(10); 2740–50. ©2010 AACR.
Transatlantic ideas on the philosophy of therapeutics in the middle of the 19th century
Authors: Edward J Huth
Journal: Journal of the Royal Society of Medicine (2009)

Early in the 19th century the move toward seeking numerical evidence in support of judgments on the efficacy of treatments advanced sharply with Pierre-Charles-Alexandre Louis' advocacy of la methode numerique (the numerical method) through his case studies of blood-letting as a treatment.1 This movement had begun prominently in the preceding century with Jurin's collection of numerical data on mortality from smallpox inoculation,2 Lind's trial on the treatment of scurvy3 and various British calls for numerical evidence on treatments.4 But Louis' strong advocacy provoked passionate debates in the Academie des Sciences in Paris, which had their own important consequences. Among these was the publication in 1840 of Principes Generaux de Statistique Medicale by Jules Gavarret.5
E3/19K from adenovirus 2 is an immunosubversive protein that binds to a structural motif regulating the intracellular transport of major histocompatibility complex class I proteins.
Authors: W A Jefferies, H G Burgert
Journal: The Journal of Experimental Medicine (1990)

We have previously expressed in transgenic mice a chimeric H-2Kd/Kk protein called C31, which contains the extracellular alpha 1 domain of Kd, whereas the rest of the molecule is of Kk origin. This molecule functions as a restriction element for alloreactive and influenza A-specific cytotoxic T lymphocytes (CTL) but is only weakly expressed at the cell surface of splenocytes. Here, we show that the low cell surface expression is the result of slow intracellular transport and processing of the C31 protein. A set of hybrid molecules between Kd and Kk were used to localize the regions in major histocompatibility complex (MHC) molecules that are important for their intracellular transport and to further localize the structures responsible for binding to the adenovirus 2 E3/19K protein. This protein appears to be an important mediator of adenovirus persistence. It acts by binding to the immaturely glycosylated forms of MHC class I proteins in the endoplasmic reticulum (ER), preventing their passage to the cell surface and thereby reducing the recognition of infected cells by virus-specific T cells. We find the surprising result that intracellular transport and E3/19K binding are controlled primarily by the first half of the second domain of Kd, thus localizing these phenomena to the five polymorphic residues in this region of the Kd protein. This result implies that the E3/19K protein may act by inhibiting peptide binding or by disrupting the oligomerization of MHC class I molecules required for transport out of the ER. Alternatively, the E3/19K protein may inhibit the function of a positively acting transport molecule necessary for cell surface expression of MHC class I molecules.
DNA/RNA Content and Proliferative Fractions of Colorectal Carcinomas: A Five-Year Prospective Study Relating Flow Cytometry to Survival
Authors: W. E. Enker, M. Kimmel, E. S. Cibas, M. L. Cranor, M. R. Melamed
Journal: JNCI Journal of the National Cancer Institute (1991)

Journal Article DNA/RNA Content and Proliferative Fractions of Colorectal Carcinomas: A Five-Year Prospective Study Relating Flow Cytometry to Survival Get access Warren E. Enker, Warren E. Enker * Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer CenterNew York, NY *Correspondence to: Warren E. Enker, MD, Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021. Search for other works by this author on: Oxford Academic PubMed Google Scholar Marek Kimmel, Marek Kimmel Laboratory of Investigative Cytology, Department of Pathology, Memorial Sloan-Kettering Cancer CenterNew York, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar Edmund S. Cibas, Edmund S. Cibas Laboratory of Investigative Cytology, Department of Pathology, Memorial Sloan-Kettering Cancer CenterNew York, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar Milicent L. Cranor, Milicent L. Cranor Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer CenterNew York, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar Myron R. Melamed Myron R. Melamed Laboratory of Investigative Cytology, Department of Pathology, Memorial Sloan-Kettering Cancer CenterNew York, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 83, Issue 10, 15 May 1991, Pages 701–707, https://doi.org/10.1093/jnci/83.10.701 Published: 15 May 1991 Article history Received: 08 January 1991 Accepted: 01 March 1991 Published: 15 May 1991
Integrating Patient-Reported Outcomes Into Cancer Symptom Management Clinical Trials Supported by the National Cancer Institute–Sponsored Clinical Trials Networks
Authors: Jeff A. Sloan, Lawrence Berk, Joseph Roscoe, Michael J. Fisch, Edward G. Shaw, Gwen Wyatt, Gary R. Morrow, Amylou C. Dueck
Journal: Journal of Clinical Oncology (2007)

Patient-reported outcomes (PROs) are often the primary end point in symptom management trials. The scientific field of PROs is evolving, as evidenced by the US Food and Drug Administration's February 2007 release of a draft guidance for using PROs in effectiveness claims for drug labeling. This article presents issues encountered during use of PROs in National Cancer Institute-sponsored symptom management trials. Selected trials are presented that exemplify the challenges often seen in symptom management trials, and solutions are described. The examples presented include defining the appropriate end point, selecting and validating assessments, and answering the research questions through statistical analysis and interpretation. Progress has been made in addressing some of the unique challenges of PRO-based symptom management research. Many challenges still remain, but a foundational body of work now exists for more consistent and rigorous application of PROs into symptom management trials. There remains a need for more research in several methodologic aspects of design, analysis, and interpretation of symptom management trials.
Delta-Like Ligand 4–Notch Blockade and Tumor Radiation Response
Authors: Stanley K. Liu, Saif A. S. Bham, Emmanouil Fokas, John Beech, Jaehong Im, Song Cho, Adrian L. Harris, Ruth J. Muschel
Journal: JNCI Journal of the National Cancer Institute (2011)

The microenvironment plays an important role in regulating tumor response to radiotherapy. Ionizing radiation can disrupt tumor vasculature, and Notch pathway inhibition can interfere with functional angiogenesis. We explored the potential cooperativity between Notch inhibition and ionizing radiation in delaying tumor growth.