tbuckley/cabot-search huggingface dataset:
The Future of Clinical Research
Authors: Robert J. Levine
Journal: New England Journal of Medicine (1979)

From June 5 to 7, 1979, I attended a conference entitled "Clinical Research: Elements for a prognosis" at the University of Chicago Center for Policy Study. Conferences on the relation between public policy and medical practice, pedagogy, or research are so common these days that one might wonder why this one is singled out for special notice. I should like to call special attention to the manner in which this conference was planned (by Richard L. Landau, Daniel X. Freedman, and Leon I. Goldberg). Since this conference was much more productive than most, I commend the organizers' style to others . . .
Stem Cells for Myocardial Regeneration
Authors: Donald Orlic, Jonathan M. Hill, Andrew E. Arai
Journal: Circulation Research (2002)

Stem cells are being investigated for their potential use in regenerative medicine. A series of remarkable studies suggested that adult stem cells undergo novel patterns of development by a process referred to as transdifferentiation or plasticity. These observations fueled an exciting period of discovery and high expectations followed by controversy that emerged from data suggesting cell-cell fusion as an alternate interpretation for transdifferentiation. However, data supporting stem cell plasticity are extensive and cannot be easily dismissed. Myocardial regeneration is perhaps the most widely studied and debated example of stem cell plasticity. Early reports from animal and clinical investigations disagree on the extent of myocardial renewal in adults, but evidence indicates that cardiomyocytes are generated in what was previously considered a postmitotic organ. On the basis of postmortem microscopic analysis, it is proposed that renewal is achieved by stem cells that infiltrate normal and infarcted myocardium. To further understand the role of stem cells in regeneration, it is incumbent on us to develop instrumentation and technologies to monitor myocardial repair over time in large animal models. This may be achieved by tracking labeled stem cells as they migrate into myocardial infarctions. In addition, we must begin to identify the environmental cues that are needed for stem cell trafficking and we must define the genetic and cellular mechanisms that initiate transdifferentiation. Only then will we be able to regulate this process and begin to realize the full potential of stem cells in regenerative medicine.
GENETIC FACTORS INFLUENCING C-TYPE RNA VIRUS INDUCTION
Authors: John R. Stephenson, Stuart A. Aaronson
Journal: The Journal of Experimental Medicine (1972)

Genetic factors were studied which affect the inducibility of C-type RNA viruses from embyro cultures of mouse strains with high and low incidence of spontaneous leukemia. Virus was inducible by chemical treatment from secondary embryo cultures of several inbred strains. Both virus inducibility and the capacity of the virus to persist in cells from which it was activated were found to be inherited as dominant genetic characteristics. The results show that the factors controlling virus activation and persistence in culture also play an important role in spontaneous virus expression in the animal.
A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma
Authors: Manfred Westphal, Dana C. Hilt, Enoch Bortey, Patrick Delavault, Robert Olivares, Peter C. Warnke, Ian R. Whittle, Juha Jääskeläinen, Zvi Ram
Journal: Neuro-Oncology (2003)

A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme. A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers. Because of the small number of patients in that trial, a larger phase 3 trial was performed to confirm these results. Two hundred forty patients were randomized to receive either BCNU or placebo wafers at the time of primary surgical resection; both groups were treated with external beam radiation postoperatively. The two groups were similar for age, sex, Karnofsky performance status (KPS), and tumor histology. Median survival in the intent-to-treat group was 13.9 months for the BCNU wafer-treated group and 11.6 months for the placebo-treated group (log-rank P-value stratified by country = 0.03), with a 29% reduction in the risk of death in the treatment group. When adjusted for factors affecting survival, the treatment effect remained positive with a risk reduction of 28% (P = 0.03). Time to decline in KPS and in 10/11 neuroperformance measures was statistically significantly prolonged in the BCNU wafer-treated group (P ≤ 0.05). Adverse events were comparable for the 2 groups, except for CSF leak (5% in the BCNU wafer-treated group vs. 0.8% in the placebo-treated group) and intracranial hypertension (9.1% in the BCNU wafer-treated group vs. 1.7% in the placebo group). This study confirms that local chemotherapy with BCNU wafers is well tolerated and offers a survival benefit to patients with newly diagnosed malignant glioma.
Nonspecific Interstitial Pneumonitis: A Common Cause of Pulmonary Disease in the Acquired Immunodeficiency Syndrome
Authors: ANTHONY F. SUFFREDINI
Journal: Annals of Internal Medicine (1987)

During a 4.4-year period, nonspecific interstitial pneumonitis was seen in 41 of 110 (38%) patients with the acquired immunodeficiency syndrome and accounted for 32% (48/152) of all episodes of clinical pneumonitis. Diffuse alveolar damage was typically a feature of nonspecific interstitial pneumonitis, but neither lung biopsy nor bronchoalveolar lavage detected a pathogen. Of these 41 patients, 13 had no associated pulmonary tumor and had not been exposed to pulmonary toxins, whereas 28 patients had either concurrent pulmonary Kaposi sarcoma, previous experimental therapies, or a history of pneumocystis pneumonia or drug abuse. Of these 41, 23 had normal chest radiographs. The clinical features of patients with nonspecific interstitial pneumonitis were similar to those of patients with pneumocystis pneumonia, although histologic findings showed less severe alveolar damage in patients with nonspecific interstitial pneumonitis (p less than 0.001). Pathologic evaluation and clinical follow-up suggest that many clinical episodes of pneumonitis in patients with the acquired immunodeficiency syndrome are due to nonspecific interstitial pneumonitis of unknown cause.
METABOLIC PROCESSES IN SKIN.
Authors: C. N. D. CRUICKSHANK
Journal: British Journal of Dermatology (1965)

Journal Article METABOLIC PROCESSES IN SKIN. Get access C. N. D. CRUICKSHANK, M.D., M.C.Path., D.I.H. C. N. D. CRUICKSHANK, M.D., M.C.Path., D.I.H. Medical Research Council, Unit for Research on the Experimental Pathology of the Skin, Medical School, University of Birmingham, Birmingham 15 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 77, Issue 12, 1 December 1965, Pages 603–609, https://doi.org/10.1111/j.1365-2133.1965.tb14590.x Published: 01 December 1965
Effectiveness of Adjuvant Fluorouracil in Clinical Practice: A Population-Based Cohort Study of Elderly Patients With Stage III Colon Cancer
Authors: Theodore J. Iwashyna, Elizabeth B. Lamont
Journal: Journal of Clinical Oncology (2002)

Although randomized controlled trials (RCTs) consistently show that adjuvant fluorouracil (5-FU) extends the survival of patients with stage III colon cancer, it is not yet known whether this benefit exists in populations underrepresented on clinical trials, particularly the elderly with medical comorbidity treated in the community. In this study, we ask the following: (1) What is the hazard of death associated with adjuvant 5-FU in the general population of elderly stage III colon cancer patients? (2) Does the hazard vary with patient age?In this prospective, nonrandomized, population-based cohort study of 3,357 elderly Medicare beneficiaries who had undergone resection of stage III colon cancer according to the Surveillance, Epidemiology, and End-Results registries, we use propensity score matching to compare the all-cause mortality of patients who received 5-FU to matched untreated patients.5-FU reduces the hazard of death by 27% (hazard ratio, 0.73; 95% confidence interval [CI], 0.65 to 0.82) across the 6 years of our data in a Cox model. At 5 years, 52.7% (95% CI, 49.6% to 55.6%) of the treated and 40.7% (95% CI, 38.1% to 43.4%) of the matched untreated are still alive. We find that these effects do not diminish with advancing patient age.The survival benefit of adjuvant 5-FU that has been demonstrated in participants of RCTs is also evident in a population sample of elderly Medicare beneficiaries with stage III colon cancer treated in the community. Furthermore, this survival benefit does not appear to diminish with patient age. These findings support the continued use of adjuvant 5-FU in the general population of elderly patients with stage III colon cancer and suggest that oncologists in the community are practicing at a high level of effectiveness.
Gene expression profiling identifies significant differences between the molecular phenotypes of bone marrow–derived and circulating human CD34+ hematopoietic stem cells
Authors: Ulrich Steidl, Ralf Kronenwett, Ulrich-Peter Rohr, Roland Fenk, Slawomir Kliszewski, Christian Maercker, Peter Neubert, Manuel Aivado, Judith Koch, Olga Modlich, Hans Bojar, Norbert Gattermann, Rainer Haas
Journal: Blood (2002)
Multimodality Comparison of Quantitative Volumetric Analysis of the Right Ventricle
Authors: Lissa Sugeng, Victor Mor-Avi, Lynn Weinert, Johannes Niel, Christian Ebner, Regina Steringer-Mascherbauer, Ralf Bartolles, Rolf Baumann, Georg Schummers, Roberto M. Lang, Hans-Joachim Nesser
Journal: JACC. Cardiovascular imaging (2010)
Transiently Entrapped Circulating Tumor Cells Interact with Neutrophils to Facilitate Lung Metastasis Development
Authors: Sung Jin Huh, Shile Liang, Arati Sharma, Cheng Dong, Gavin P. Robertson
Journal: Cancer Research (2010)

It is unknown why only a minority of circulating tumor cells trapped in lung capillaries form metastases and involvement of immune cells remains uncertain. A novel model has been developed in this study showing that neutrophils regulate lung metastasis development through physical interaction and anchoring of circulating tumor cells to endothelium. Human melanoma cells were i.v. injected into nude mice leading to the entrapment of many cancer cells; however, 24 hours later, very few remained in the lungs. In contrast, injection of human neutrophils an hour after tumor cell injection increased cancer cell retention by approximately 3-fold. Entrapped melanoma cells produced and secreted high levels of a cytokine called interleukin-8 (IL-8), attracting neutrophils and increasing tethering beta(2) integrin expression by 75% to 100%. Intercellular adhesion molecule-1 on melanoma cells and beta(2) integrin on neutrophils interacted, promoting anchoring to vascular endothelium. Decreasing IL-8 secretion from melanoma cells lowered extracellular levels by 20% to 50%, decreased beta(2) integrin on neutrophils by approximately 50%, and reduced neutrophil-mediated extravasation by 25% to 60%, resulting in approximately 50% fewer melanoma cells being tethered to endothelium and retained in lungs. Thus, transendothelial migration and lung metastasis development decreased by approximately 50%, showing that targeting IL-8 in melanoma cells has the potential to decrease metastasis development by disrupting interaction with neutrophils.
Mechanical Analysis of Tumor Growth Regression by the Cyclooxygenase-2 Inhibitor, DFU, in a Walker256 Rat Tumor Model: Importance of Monocyte Chemoattractant Protein-1 Modulation
Authors: Mariko Muta, Gaku Matsumoto, Emi Nakashima, Masakazu Toi
Journal: Clinical Cancer Research (2006)

Abstract Cyclooxygenase (COX)-2 inhibition results in tumor regression; however, little is known about the mechanism. In the present study, using a Walker256 tumor model and a rat bone marrow–derived endothelial cell line TR-BME-2, we analyzed the effects of a new selective COX-2 inhibitor, 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2-(5H)-furanone (DFU), on the production of chemokines and growth factors and on the neovascularization. The oral administration of DFU (5 mg/kg/d) significantly suppressed the tumor growth with decreasing microvessel density in vivo, although it showed no direct inhibition of Walker256 cell proliferation in vitro. It was newly found that the recruitment of systemically injected TR-BME-2 cells into the tumor site was significantly inhibited by DFU treatment. In addition, we found that DFU significantly reduced the production of monocyte chemoattractant protein-1 (MCP-1) both in tumor tissues and in the systemic circulation (P &amp;lt; 0.001 and P &amp;lt; 0.001, respectively). Such reduction was not observed in other chemotactic factors, vascular endothelial growth factor and stromal cell–derived factor-1. The induced chemotaxis of TR-BME-2 by serum of tumor-bearing rats was significantly reduced in DFU-treated rat serum, although DFU showed no direct inhibition for TR-BME-2 cells, either cell growth or chemotaxis. Treatment with neutralizing antibodies to soluble mediators, including MCP-1, significantly suppressed the chemotaxis. Regarding the down-regulation machinery of MCP-1 production in vivo, tumor-associated macrophages seem to play crucial roles, because DFU eliminated MCP-1 production in the activated macrophages remarkably but not in Walker256 tumor cells in vitro. In conclusion, COX-2 inhibitor DFU exerts tumor regression activity in a Walker256 tumor model by suppressing MCP-1 production in tumor tissues and in the circulation.
Modulation of human cardiac transient outward potassium current by EGFR tyrosine kinase and Src-family kinases
Authors: Yan-Hui Zhang, Wei Wu, Hai-Ying Sun, Xiu-Ling Deng, Lik-Cheung Cheng, Xin Li, Hung-Fat Tse, Chu-Pak Lau, Gui-Rong Li
Journal: Cardiovascular Research (2011)

The human cardiac transient outward K+ current Ito (encoded by Kv4.3 or KCND3) plays an important role in phase 1 rapid repolarization of cardiac action potentials in the heart. However, modulation of Ito by intracellular signal transduction is not fully understood. The present study was therefore designed to determine whether/how human atrial Ito and hKv4.3 channels stably expressed in HEK 293 cells are regulated by protein tyrosine kinases (PTKs). Whole-cell patch voltage-clamp, immunoprecipitation, western blotting, and site-directed mutagenesis approaches were employed in the present study. We found that human atrial Ito was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2. The inhibitory effect was countered by the protein tyrosine phosphatase inhibitor orthovanadate. In HEK 293 cells stably expressing human KCND3, genistein, AG556, and PP2 significantly reduced the hKv4.3 current, and the reduction was antagonized by orthovanadate. Interestingly, orthovanadate also reversed the reduced tyrosine phosphorylation level of hKv4.3 channels by genistein, AG556, or PP2. Mutagenesis revealed that the hKv4.3 mutant Y136F lost the inhibitory response to AG556, while Y108F lost response to PP2. The double-mutant Y108F–Y136F hKv4.3 channels showed no response to either AG556 or PP2. Our results demonstrate that human atrial Ito and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue; tyrosine phosphorylation of the channel may be involved in regulating cardiac electrophysiology.
Inhibition of Akt/Protein Kinase B Signaling by Naltrindole in Small Cell Lung Cancer Cells
Authors: Yulong L. Chen, P. Y. Law, Horace H. Loh
Journal: Cancer Research (2004)

Abstract The phosphatidylinositol 3-kinase-Akt/protein kinase B (PKB) survival signaling is very important for cancer cell survival and growth. Constitutively active phosphatidylinositol 3-kinase-Akt/PKB signaling in small cell lung cancer (SCLC) is a major factor for the survival of SCLC cells. Inhibitors of this signaling pathway would be potential antitumor agents, particularly for SCLC. Here we report that naltrindole, which has been used as a classic δ opioid antagonist, inhibited growth and induced apoptosis in the three characteristic SCLC cell lines, NCI-H69, NCI-H345, and NCI-H510. Naltrindole treatment reduced constitutive phosphorylation of Akt/PKB on serine 473 and threonine 308 in cells. We found that the levels of constitutive phosphorylation of Akt/PKB on serine 473 correlate with the sensitivity of the three cell lines to naltrindole treatment. Furthermore, naltrindole treatment not only reduced the phosphorylation of the Akt/PKB upstream kinase phosphoinositide-dependent kinase-1, but also its downstream effectors glycogen synthase kinase-3β and the Forkhead transcription factors AFX and FKHR. DNA array analysis of 205 apoptosis-related genes indicated that some Akt/PKB-dependent genes were either up- or down-regulated by naltrindole. Flow cytometric and microscopic analyses clearly showed that naltrindole induced apoptosis in SCLC cells. RNA interference experiments confirmed that naltrindole-induced cell death was associated with the Akt/PKB survival pathway. Together, these results show that naltrindole is a new inhibitor of the Akt/PKB signaling pathway, suggesting that naltrindole could be a potential lead for the development of a new type of inhibitors that target the constitutively active Akt/PKB signaling-dependent SCLC cells.
Helicobacter pylori and oesophageal cancer--not always protective
Authors: K. E L McColl
Journal: Gut (2007)

partly in helping individual units construct patient information and consent forms.It will be useful in creating audit standards for units, for individual trainees and established endoscopists.I would like the report to be used in a highly constructive manner to help improve the quality assurance of endoscopy.The JAG has quality assured .250endoscopy units for training and this has been credible as JAG represents all the relevant stakeholders (the Royal Colleges, Specialist Societies, nurses, etc).It is now appropriate to widen the JAG remit beyond training standards to one of quality assurance for the endoscopy service.This has already effectively happened for units undertaking colon cancer screening colonoscopy in England where a successful JAG accreditation visit is a mandatory requirement.The JAG is in the ideal quality assurance body for all endoscopy units, irrespective of whether or not they contribute to the screening programme.Quality assurance needs auditable standards and ''complications of endoscopy'' is an excellent text from which to develop safety standards.Working party reports like this one, are powerful tools in our quest to maintain and improve quality, we should use them to their greatest potential.
Safety, Tolerability, and Efficacy Of Hizentra® In Japanese Patients With Primary Immunodeficiency Over 48 Weeks
Authors: Kohsuke Imai, Hirokazu Kanegane, Masafumi Yamada, Hidetoshi Takada, Tadashi Ariga, Midori Kobayashi, Mikhail Rojavin, Martin Bexon, Shigeaki Nonoyama, Toshiro Hara, Toshio Miyawaki
Journal: Journal of Allergy and Clinical Immunology (2014)
Regional Brain Morphometry in Patients With Schizophrenia or Bipolar Disorder and Their Unaffected Relatives
Authors: Colm McDonald, Nicolette Marshall, Pak C. Sham, Edward T. Bullmore, Katja Schulze, Ben Chapple, Elvira Bramon, Francesca Filbey, Seema Quraishi, Muriel Walshe, Robin M. Murray
Journal: American Journal of Psychiatry (2006)

OBJECTIVE: Schizophrenia and psychotic bipolar disorder have a number of overlapping symptoms and risk factors, but it is not yet clear if the disorders are characterized by similar deviations in brain morphometry or whether any such deviations reflect the impact of shared susceptibility genes on brain structure. The authors used region-of-interest morphometry to volumetrically assess brain structures frequently implicated in psychotic illness in families affected with schizophrenia or psychotic bipolar disorder. METHOD: Magnetic resonance imaging brain scans were obtained from 243 subjects, comprising 42 patients with schizophrenia or schizoaffective disorder, 57 of their unaffected first-degree relatives, 38 patients with psychotic bipolar disorder, 52 of their unaffected first-degree relatives, and 54 healthy comparison subjects. Most of the families affected with schizophrenia and all of the families affected with bipolar disorder were multiply affected with the illness. Volumetric measurements of the cerebrum, lateral ventricles, third ventricle, and hippocampus were completed with stereological methods. RESULTS: Patients with schizophrenia had increased volume of the lateral and third ventricles and reduced hippocampal volume. None of these volumetric abnormalities was present in psychotic bipolar disorder. Unaffected relatives of patients with schizophrenia from multiply affected families had enlarged lateral ventricles but no other volumetric deviations. Unaffected relatives of patients with bipolar disorder showed preservation of ventricular and hippocampal volume. CONCLUSIONS: Schizophrenia and psychotic bipolar disorder are characterized by morphometric distinctions in ventricular and hippocampal regions. Lateral ventricular enlargement represents a potential morphometric endophenotype for schizophrenia.
REGULATION OF GENE TRANSCRIPTION BY BOTANICALS: Novel Regulatory Mechanisms
Authors: Neil F. Shay, William J. Banz
Journal: Annual Review of Nutrition (2005)

▪ Abstract Early investigations of gene regulation revealed that nutrients could modulate gene expression, an example being the discovery of metal-regulated gene transcription ( 11 , 19 , 44 ). Only more recently have we focused on the ability of non-nutritional botanicals or functional food components to affect gene expression at the transcriptional level. Significant findings include the discovery that hyperforin is an active ingredient of the herbal remedy St. John's wort, and activates gene transcription of cytochrome p450-3A4, causing significant botanical-drug interactions. Recently, the lipid-regulating peroxisome proliferator-activated receptors have been studied as receptors activated by soy isoflavones, perhaps explaining the lipid-lowering effect of soy intake. Epigallocatechin gallate has been shown to be an inhibitor of the protealytic activity of the proteasome; this inhibition has a significant implication for cell proliferation and the stability of transcription factors in the nucleus. Very recently, the effects of botanicals have been studied as activators of sirtuins, important deacetylation enzymes that have been shown to enhance lifespan in a variety of organisms. Sirtuins have been implicated in the lifespan-enhancing effect of caloric restriction. Originally presumed to act mainly on compaction or accessibility of DNA, recent evidence shows important activity of sirtuins as controllers of transcriptional coactivator availability. This review focuses on novel mechanisms by which botanical products regulate cell function via gene transcription. Investigating these newly appreciated mechanisms will assist with the characterization and clarification of specific effects of botanicals on gene expression.