tbuckley/cabot-search huggingface dataset:
Organ-Specific Modulation of Steady-State mdr Gene Expression and Drug Resistance in Murine Colon Cancer Cells
Authors: Z. Dong, R. Radinsky, D. Fan, R. Tsan, C. D. Bucana, C. Wilmanns, I. J. Fidler
Journal: JNCI Journal of the National Cancer Institute (1994)

Background: The major cause of death from cancer is metastases that are resistant to conventional therapies. The resistance of metastatic tumor cells to chemotherapy can be caused by their intrinsic properties, such as increased expression of the mdr genes. Purpose: The purpose of our present study was to determine some of the mechanisms by which the organ microenvironment influences the response of tumor cells to chemotherapy. Methods: Murine CT-26 colon cancer cells growing in continuous culture (parental cells) were harvested and injected subcutaneously into the lateral flank (to produce subcutaneous tumors) or the lateral tail vein (to produce experimental lung metastases) of 10 8-week-old syngeneic male BALB/c mice. Seven days after tumor-cell injection, the mice were given intravenous injections of either doxorubicin (10 mg/kg) or 0.9% NaCl (controls). This in vivo injection was repeated 7 days later. Mice with subcutaneous tumors and lung metastases were killed by cervical dislocation on day 21, and tumor samples from control mice were harvested and adapted to culture. The sensitivity of the cultured cells to doxorubicin and fluorouracil (5-FU) was determined at multiple time points. Levels of mdr-1 DNA were measured by slot-blot and Southern-blot analyses, mdr mRNA expression levels were measured by Northern-blot analysis using mdr-1- and mdr-3-specific hybridization probes, and P-glycoprotein level was determined by fluorescence-activated cell sorting using different monoclonal antibodies. Results: Treatment with doxorubicin produced 80% growth inhibition of CT-26 subcutaneous tumors but had little effect on the number (and size) of experimental lung metastases. Collectively, the results suggest that the multidrug-resistant phenotype developed in CT-26 cells growing in the lung environment. Cultures established from lung metastases were initially resistant to doxorubicin (but not to 5-FU) and showed elevated expression of mdr-1 mRNA transcripts and P-glycoprotein. This resistance could be overcome by verapamil and disappeared after 21 days in culture. No mdr gene amplification was detected. The expression level of mdr-specific mRNA (predominance of mdr-1) and P-glycoprotein was directly associated with resistance to doxorubicin. Conclusions: Results of this study have demonstrated that the in vivo sensitivity of murine CT-26 colon carcinoma cells to doxorubicin depends on the organ environment. The organ environment can influence the P-glycoprotein-mediated multidrug-resistant phenotype in tumor cells, and the increased expression of P-glycoprotein is transient; once removed from the environment (lung), the cell's resistance reverts to that of the sensitive parent cells. [J NatI Cancer Inst 86:913–920, 1994]
-Difluoromethylornithine and Polyamine Levels in the Human Prostate: Results of a Phase IIa Trial
Authors: A. R. Simoneau, E. W. Gerner, M. Phung, C. E. McLaren, F. L. Meyskens
Journal: JNCI Journal of the National Cancer Institute (2001)

α-Diuoromethylornithine and Polyamine Levels in the Human Prostate: Results of a Phase IIa Trial Anne R. Simoneau  ; Eugene W. Gerner; Mai Phung; Christine E. McLaren; Frank L. Meyskens, Jr. JNCI J Natl Cancer Inst (2001) 93 (1): 57-59. DOI: https://doi.org/10.1093/jnci/93.1.57 Published: 03 January 2001 Article history   Views  Cite  Share  Tools Topic: polyamines , prostate , difluoromethylornithine Issue Section: Brief Communication Prostate cancer is the most commonly diagnosed malignancy in men and the second leading cause of male cancer deaths in the United States (1). As such, the prevention of prostate cancer is of national medical concern. One approach to prevention of prostate cancer is to suppress the polyamine levels in the prostate, an avenue suggested by studies indicating that ornithine decarboxylase (ODC), the ~rst enzyme in the polyamine pathway, is overexpressed in human prostate cancer tissue (2) and is the target enzyme for α-diuoromethylornithine (DFMO). This inhibitor suppresses tissue contents of polyamines, which are required for optimal cell proliferation and di{erentiation. Elevated levels of polyamine are associated with several malignant or premalignant lesions (3–5). Prostate cancer seems a logical organ system for DFMO chemoprevention, since ODC activity and polyamine content are higher in prostatic tissue than in other mammalian tissues (6). Also, investigators (7–10) have demonstrated marked polyamine suppression by DFMO in rodent prostates and prostate cell lines. Mohan et al. (2) measured ODC activity in benign and malignant Skip to Main from Content tissues the same patient and found the cancerous portion to have levels almost
The Department of Internal Medicine: Hub of the Academic Health Center Response to the Aging Imperative
Authors: William R. Hazzard
Journal: Annals of Internal Medicine (2000)

In the 21st century, geriatrics will increasingly dominate U.S. health care as the median age of the population progressively increases. Academic departments of geriatrics have been created in nations that have already experienced this shift. As an alternative strategy that builds on traditional strengths of academic medicine in the United States, departments of internal medicine should lead a multidepartmental, pan-institutional response to the aging imperative. Recognition of gerontology and geriatric medicine as central to the missions of internal medicine in clinical care, education, and research must be increased. In the process, academic departments of internal medicine will develop a high level of geriatric expertise and will launch many programs that address this challenge. Successful development of geriatric programs will serve as a catalyst to strengthen the integration among and between generalists and subspecialists. This will entail developing optimal sites and systems of geriatric care—at different levels of care and over time—that can enhance the geriatric education of medical students, residents, fellows, and practicing physicians. The study of aging and geriatric health care will also become an integral part of departmental research, in its subspecialty divisions as well as its divisions of general internal medicine and geriatrics. This strategy is urgently recommended as both a challenge and an opportunity for all departments of internal medicine.
A Phase I Clinical Trial of Thoracic Radiotherapy and Concurrent Celecoxib for Patients with Unfavorable Performance Status Inoperable/Unresectable Non–Small Cell Lung Cancer
Authors: Zhongxing Liao, Ritsuko Komaki, Luka Milas, Chen Yuan, Merrill Kies, Joe Y. Chang, Melenda Jeter, Thomas Guerrero, George Blumenschien, Cheryl M. Smith, Frank Fossella, Barry Brown, James D. Cox
Journal: Clinical Cancer Research (2005)

Abstract Objectives: Preclinical observations that selective cyclooxygenase-2 inhibitors enhance in vitro cell radiosensitivity and in vivo tumor radioresponse led to clinical trials testing therapeutic efficacy of these agents. Our study was designed to determine whether the COX-2 inhibitor celecoxib could be safely administered in doses within those approved by the Food and Drug Administration when used concurrently with thoracic radiotherapy in patients with poor prognosis non–small cell lung cancer (NSCLC). Patients and Methods: The trial consisted of three cohorts of patients: (a) locally advanced NSCLC with obstructive pneumonia, hemoptysis, and/or minimal metastatic disease treated with 45 Gy in 15 fractions; (b) medically inoperable early-stage NSCLC treated with definitive radiation of 66 Gy in 33 fractions; and (c) patients who received induction chemotherapy but who were not eligible for concurrent chemoradiotherapy trials. These patients received 63 Gy in 35 fractions. Celecoxib was administered p.o. on a daily basis 5 days before and throughout the course of radiotherapy. Celecoxib doses were escalated from 200, 400, 600, to 800 mg/d given in two equally divided doses. Two to eight patients of each cohort were assigned to each dose level of celecoxib. Results: Forty-seven patients were enrolled in this protocol (19 in cohort I, 22 in cohort II, and 6 in cohort III). The main toxicities were grades 1 and 2 nausea and esophagitis, and they were independent of the dose of celecoxib or radiotherapy schedule. Only two patients in group II developed grade 3 pneumonitis 1 month after treatment, one on 200 mg, and the other on 400 mg celecoxib. Celecoxib-related toxicity developed in 3 of 47 patients: an uncontrolled hypertension in one patient on 800 mg celecoxib and hemorrhagic episodes in 2 patients (shoulder hematoma in one and hemoptysis in the other) on 200 mg celecoxib who were on warfarin for other medical reasons. Of 37 patients evaluable for tumor response, 14 had complete response, 13 partial responses, and 10 stable or progressive disease. The actuarial local progression-free survival was 66.0% at 1 year and 42.2% at 2 years following initiation of radiotherapy. Conclusions: These results show that celecoxib can be safely administered concurrently with thoracic radiotherapy when given up to the highest Food and Drug Administration–approved dose of 800 mg/d, which we used. A maximal tolerated dose was not reached in this study. The treatment resulted in actuarial local progression-free survival of 66.0% at 1 year and 42.2% at 2 years, an encouraging outcome that warrants further assessment in a phase II/III trial.
TERT Promoter Mutation Status as an Independent Prognostic Factor in Cutaneous Melanoma
Authors: Klaus G. Griewank, Rajmohan Murali, Joan Anton Puig-Butille, Bastian Schilling, Elisabeth Livingstone, Miriam Potrony, Cristina Carrera, Tobias Schimming, Inga Möller, Marion Schwamborn, Antje Sucker, Uwe Hillen, Celia Badenas, Josep Malvehy, Lisa Zimmer, André Scherag, Susana Puig, Dirk Schadendorf
Journal: JNCI Journal of the National Cancer Institute (2014)

Recently, TERT promoter mutations were identified at high frequencies in cutaneous melanoma tumor samples and cell lines. The mutations were found to have a UV-signature and to lead to increased TERT gene expression. We analyzed a large cohort of melanoma patients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics.410 melanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations. An analysis of associations between mutation status and various clinical and pathologic variables was performed.TERT promoter mutations were identified in 154 (43%) of 362 successfully sequenced melanomas. Mutation frequencies varied between melanoma subtype, being most frequent in melanomas arising in nonacral skin (48%) and melanomas with occult primary (50%), and less frequent in mucosal (23%), and acral (19%) melanomas. Mutations carried a UV signature (C>T or CC>TT). The presence of TERT promoter mutations was associated with factors such as BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001). TERT promoter mutation was independently associated with poorer overall survival in patients with nonacral cutaneous melanomas (median survival 80 months vs 291 months for wild-type; hazard ratio corrected for other covariates 2.47; 95% confidence interval [CI] = 1.29 to 4.74; P = .006).UV-induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma, with frequencies varying depending on melanoma subtype. In nonacral cutaneous melanomas, presence of TERT promoter mutations is independently associated with poor prognosis.
The physiological effects of cycling on tandem and single bicycles * Commentary * Commentary
Authors: J G Seifert, D W Bacharach, E R Burke
Journal: British Journal of Sports Medicine (2003)

The purpose of this field study was to compare the physiological responses from cycling on a tandem road bicycle to those from cycling on a single road bicycle.Nine pairs of experienced, recreational tandem cyclists rode a tandem or their single bicycle for 5 min at each velocity of 19.3, 22.5, 25.8, and 29.0 kph on a flat, paved surface. Heart rate (HR), rating of perceived exertion (RPE), and lactic acid (LA) data were collected after each interval.Riding a tandem resulted in lower HR, RPE, and LA mean values across the four velocities compared to the single bicycle. Mean (SD) HR, RPE, and LA for tandem and single bicycles were 126 (20.7) v 142 (20.1) bpm, 10.1 (1.7) v 11.3 (2.6), and 1.46 (1.0) mM/L v 2.36 (1.7) mM/L, respectively. No position differences were observed between the captain and stoker (front and rear positions) when both were on the tandem. Stokers had significantly lower HR, LA, and RPE values when they rode a tandem compared to a single bicycle. No statistical differences were observed between bicycles for the captains. When on the single bicycle, captains exhibited significantly lower HR, RPE, and LA values than stokers.Cycling on a tandem resulted in lower physiological stress than when cycling at the same velocity on a single bicycle. Cyclists were able to ride from 4.8-8.0 kph faster on a tandem than on a single bicycle at similar physiological stress. Apparently, stokers can add to power output on a tandem without adding significantly to wind resistance.
Endothelial-to-mesenchymal transition contributes to cardiac fibrosis
Authors: Elisabeth M Zeisberg, Oleg Tarnavski, Michael Zeisberg, Adam L Dorfman, Julie R McMullen, Erika Gustafsson, Anil Chandraker, Xueli Yuan, William T Pu, Anita B Roberts, Eric G Neilson, Mohamed H Sayegh, Seigo Izumo, Raghu Kalluri
Journal: Nature Medicine (2007)
Immunoglobulin E–dependent Active Fatal Anaphylaxis in Mast Cell–deficient Mice
Authors: Il Hwan Choi, Young Min Shin, Jae Seung Park, Moo Sam Lee, Eue Hyeog Han, Ok Hee Chai, Shun Young Im, Tai  You Ha, Hern-Ku Lee
Journal: The Journal of Experimental Medicine (1998)

Mast cells have long been believed to be the central effector cells in the development of immunoglobulin (Ig)E-dependent anaphylaxis. In this study, we investigated the role of mast cells in IgE-dependent hapten-induced active fatal anaphylaxis using mast cell–deficient WBB6F1- W/Wv (W/Wv) and congenic normal (+/+) mice. Although a 5-min delay in shock signs and death were observed in W/Wv mice, 100% fatal reactions to penicillin V (Pen V) occurred in both +/+ and W/Wv mice. Administration of monoclonal anti–IL-4 antibody completely prevented the fatal reactions, and the effect of anti–IL-4 was associated with its suppressive activity on Pen V–specific serum levels of IgE, but not IgG. The platelet-activating factor (PAF) antagonist, BN 50739, completely prevented the fatal reactions in both strains of mice. Our kinetic study revealed, in contrast to no elevation of plasma histamine level in W/Wv mice, high levels of PAF in the circulation after challenge in both +/+ and W/Wv mice, albeit to a lesser degree in the latter case. These data indicate that cells other than mast cells are sufficient to induce an IgE-dependent active fatal anaphylaxis by elaborating PAF, which is the critical mediator for fatal murine anaphylaxis.
Genes that modify the hemochromatosis phenotype in mice
Authors: Joanne E. Levy, Lynne K. Montross, Nancy C. Andrews
Journal: Journal of Clinical Investigation (2000)

Hereditary hemochromatosis (HH) is a prevalent human disease caused by a mutation in HFE, which encodes an atypical HLA class I protein involved in regulation of intestinal iron absorption. To gain insight into the pathogenesis of hemochromatosis, we have bred Hfe knockout mice to strains carrying other mutations that impair normal iron metabolism. Compound mutant mice lacking both Hfe and its interacting protein, beta-2 microglobulin (B2m), deposit more tissue iron than mice lacking Hfe only, suggesting that another B2m-interacting protein may be involved in iron regulation. Hfe knockout mice carrying mutations in the iron transporter DMT1 fail to load iron, indicating that hemochromatosis involves iron flux through DMT1. Similarly, compound mutants deficient in both Hfe and hephaestin (Heph) show less iron loading than do Hfe knockout mice, indicating that iron absorption in hemochromatosis involves the function of Heph as well. Finally, compound mutants lacking Hfe and the transferrin receptor accumulate more tissue iron than do mice lacking Hfe alone, consistent with the idea that interaction between these two proteins contributes to the control of normal iron absorption. In addition to providing insight into the pathogenesis of HH, our results suggest that each of these genes might be a candidate modifier of the human hemochromatosis phenotype.
Closing the digital divide
Authors: R. Smith
Journal: BMJ (2003)

As recently as September 2000 a scientist from the World Health Organization wrote that global inequity in access to the internet was greater than any other inequity.1 Less than three years later more than 100 health institutions in the developing world have free electronic access to over 2000 journals—access that is equal, and sometimes better, than in institutions in New York, London, and Paris. This week access is being extended beyond the 68 countries with incomes of less than $1000 (£612; €922) a head to 42 countries with incomes between $1000 and $3000 a head.

Until very recently health institutions in low income countries had almost no access to international journals, and the few textbooks available were often years out of date. 2 3 These institutions simply couldn't afford the journals. Many small organisations worked hard to try to provide information, but international organisations such as …
Helminths and harmony
Authors: J V Weinstock
Journal: Gut (2003)

Mounting evidence suggests that helminths help regulate mucosal inflammation

The frequency of Crohn’s disease (CD) has increased substantially over the last 50 years. It is most prevalent in highly industrialised temperate regions. CD and ulcerative colitis (UC) are rare in less developed countries. This suggests that critical environmental factors affect the worldwide distribution of inflammatory bowel disease (IBD). The “IBD hygiene hypothesis” states that raising children in extremely hygienic environments negatively affects immune development which predisposes them to immunological diseases such as IBD.1 It is also postulated that the modern day lack of exposure to helminths due to our hygienic practices is an important environmental factor contributing to IBD. Until modern times, nearly all children and most adults harboured intestinal helminths. Helminths and the immune system of Homo sapiens co-evolved in close proximity over many 1000s of years. Helminths regulate their host’s immune system and prevent excessive inflammatory responses, which could underlie the mechanism of protection. Moreels and colleague2 now lend further support for this hypothesis by reporting in this issue of Gut that infection with the helminth Schistosoma mansoni protects rats from trinitrobenzene sulphonic acid (TNBS) induced colitis [see page 99] .

Approximately two million people in the USA and Europe have CD or UC, which usually begins during the second to third decade of life. IBD probably results from an inappropriately vigorous immune response to contents of the intestinal lumen. Evidence supporting this contention includes the effectiveness of immune suppressants at controlling the disease and experimental data derived from mice prone to IBD because of defects in immune regulation.3 In most of these murine models, the inflammation is driven by T helper 1 (Th1) circuitry and by substances in the intestinal lumen.

UC and CD are disorders of complex derivation caused by the interplay …
Validation and Important Differences for the Sarcoidosis Assessment Tool. A New Patient-reported Outcome Measure
Authors: Marc A. Judson, Michael Mack, Jennifer L. Beaumont, Rosemary Watt, Elliot S. Barnathan, David E. Victorson
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Patient-reported outcome (PRO) measures have been developed to measure symptoms and other aspects of health-related quality of life.The Sarcoidosis Assessment Tool (SAT), a sarcoidosis-specific PRO, was administered in a lung and skin sarcoidosis treatment trial. We explored SAT performance characteristics and correlation with standard clinical measurements to validate it as a useful clinical sarcoidosis-specific PRO.The SAT analyses focused on baseline and Week 16 assessments. Besides the SAT, participants underwent clinical and physician assessments plus additional PROs that were used as anchor variables and were compared with the SAT. Reliability was evaluated by using Cronbach α coefficient. Spearman correlation coefficients were used to evaluate the association between SAT scores with clinical and other PRO measures. Changes between assessments in the clinical and PRO "anchor" variables were classified as improved, stable, or worsened. Mean differences between adjacent categories of the known groups and mean changes from the ability to detect change analyses were reviewed for appropriate clinically important difference estimates.Results from 173 patients were analyzed. Each SAT module reflected appropriate anchor variables at baseline and in terms of change. The Cronbach α for each of these modules was at least 0.87. In addition, we successfully established a clinically important difference range for each SAT module.We demonstrated that the SAT is a reliable and consistent sarcoidosis-specific PRO. It has excellent internal consistency and reliability. A range of clinically important differences has been established for the SAT modules. Clinical trial registered with www.clinicaltrials.gov (NCT 00955279).
<i>In Vivo</i>and<i>In Vitro</i>Effects of Macrolide Antibiotics on Mucus Secretion in Airway Epithelial Cells
Authors: Takeshi Shimizu, Shino Shimizu, Reiko Hattori, Esteban C. Gabazza, Yuichi Majima
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

To examine the in vivo effects of macrolide antibiotics on mucus hypersecretion, we induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal instillation of ovalbumin (OVA) in OVA-sensitized rats and by intranasal LPS instillation. Oral administration of clarithromycin (CAM) (5-10 mg/kg) significantly inhibited OVA- and LPS-induced mucus production and neutrophil infiltration, whereas josamycin and ampicillin showed no effect. In vitro effects of macrolide antibiotics on airway epithelial cells were examined using NCI-H292 cells and human nasal epithelial cells cultured in air-liquid interface. Mucus secretion was evaluated by ELISA using anti-mucin monoclonal antibodies (anti-MUC5AC and HCS18). CAM and erythromycin significantly inhibited spontaneous and tumor necrosis factor-alpha (20 ng/ml)-induced mucus secretion from NCI-H292 cells at 10-6 to 10-7 M and from human nasal epithelial cells at 10-4 to 10-5 M. MUC5AC messenger RNA expression was also significantly inhibited. These results indicate that the 14-member macrolide antibiotics, CAM and erythromycin, exert direct inhibitory effects on mucus secretion from airway epithelial cells and that they may be useful for the treatment of mucus hypersecretion caused by allergic inflammation and LPS stimulation.