tbuckley/cabot-search huggingface dataset:
Identification of a Novel &lt;emph type="ital"&gt;TP53&lt;/emph&gt; Cancer Susceptibility Mutation Through Whole-Genome Sequencing of a Patient With Therapy-Related AML
Authors: Daniel C. Link
Journal: JAMA (2011)

The identification of patients with inherited cancer susceptibility syndromes facilitates early diagnosis, prevention, and treatment. However, in many cases of suspected cancer susceptibility, the family history is unclear and genetic testing of common cancer susceptibility genes is unrevealing.To apply whole-genome sequencing to a patient without any significant family history of cancer but with suspected increased cancer susceptibility because of multiple primary tumors to identify rare or novel germline variants in cancer susceptibility genes. DESIGN, SETTING, AND PARTICIPANT: Skin (normal) and bone marrow (leukemia) DNA were obtained from a patient with early-onset breast and ovarian cancer (negative for BRCA1 and BRCA2 mutations) and therapy-related acute myeloid leukemia (t-AML) and analyzed with the following: whole-genome sequencing using paired-end reads, single-nucleotide polymorphism (SNP) genotyping, RNA expression profiling, and spectral karyotyping.Structural variants, copy number alterations, single-nucleotide variants, and small insertions and deletions (indels) were detected and validated using the described platforms. RESULTS; Whole-genome sequencing revealed a novel, heterozygous 3-kilobase deletion removing exons 7-9 of TP53 in the patient's normal skin DNA, which was homozygous in the leukemia DNA as a result of uniparental disomy. In addition, a total of 28 validated somatic single-nucleotide variations or indels in coding genes, 8 somatic structural variants, and 12 somatic copy number alterations were detected in the patient's leukemia genome.Whole-genome sequencing can identify novel, cryptic variants in cancer susceptibility genes in addition to providing unbiased information on the spectrum of mutations in a cancer genome.
Direct-to-Consumer Genetic Testing: Perceptions, Problems, and Policy Responses
Authors: Timothy Caulfield, Amy L. McGuire
Journal: Annual Review of Medicine (2011)

Direct-to-consumer (DTC) genetic testing has attracted a great amount of attention from policy makers, the scientific community, professional groups, and the media. Although it is unclear what the public demand is for these services, there does appear to be public interest in personal genetic risk information. As a result, many commentators have raised a variety of social, ethical, and regulatory issues associated with this emerging industry, including privacy issues, ensuring that DTC companies provide accurate information about the risks and limitations of their services, the possible adverse impact of DTC genetic testing on healthcare systems, and concern about how individuals may interpret and react to genetic risk information.
Long-Term Survival Associated With Complete Resection After Induction Chemotherapy in Stage IIIA (N2) and IIIB (T4N0-1) Non–Small-Cell Lung Cancer Patients: The Spanish Lung Cancer Group Trial 9901
Authors: Pilar Garrido, José Luis González-Larriba, Amelia Insa, Mariano Provencio, Antonio Torres, Dolores Isla, José Miguel Sanchez, Felipe Cardenal, Manuel Domine, Jose Ramon Barcelo, Vicente Tarrazona, Andres Varela, Rafael Aguilo, Julio Astudillo, Ignacio Muguruza, Angel Artal, Florentino Hernando-Trancho, Bartomeu Massuti, Maria Sanchez-Ronco, Rafael Rosell
Journal: Journal of Clinical Oncology (2007)

To assess the activity of induction chemotherapy followed by surgery in stage IIIA and selected stage IIIB non-small-cell lung cancer patients.Mediastinoscopy proof of either positive N2 (IIIA) or T4N0-1 (IIIB) disease was required. Induction therapy was three cycles of cisplatin/gemcitabine/docetaxel, followed by surgery.From December 1999 to March 2003, 136 patients were entered onto the study; the clinical response rate in 129 assessable patients was 56%. The overall complete resection rate was 68.9% of patients eligible for surgery (72% of stage IIIA patients and 66% of stage IIIB patients) and 48% of all assessable patients. Eight (12.9%) of 62 completely resected patients had a pathologic complete response. Seven patients (7.8%) died during the postoperative period. The median overall survival time was 15.9 months, 3-year survival rate was 36.8%, and 5-year survival rate was 21.1%, with no significant differences in survival between stage IIIA and stage IIIB patients. Median survival time was 48.5 months for 62 completely resected patients, 12.9 months for 13 incompletely resected patients, and 16.8 months for 15 nonresected patients (P = .005). Three- and 5-year survival rates were 60.1% and 41.4% for completely resected patients, 23.1% and 11.5% for incompletely resected patients, and 31.1% and 0% for nonresected patients, respectively. In the multivariate analysis, complete resection (hazard ratio [HR] = 0.35; P < .0001), clinical response (HR = 0.32; P < .0001), and age younger than 60 years (HR = 0.64; P = .027) were the most powerful prognostic factors.Induction chemotherapy followed by surgery is effective in stage IIIA and in selected stage IIIB patients attaining complete resection.
The Placebo Effect in Alternative Medicine: Can the Performance of a Healing Ritual Have Clinical Significance?
Authors: Ted J. Kaptchuk
Journal: Annals of Internal Medicine (2002)

In alternative medicine, the main question regarding placebo has been whether a given therapy has more than a placebo effect. Just as mainstream medicine ignores the clinical significance of its own placebo effect, the placebo effect of unconventional medicine is disregarded except for polemics. This essay looks at the placebo effect of alternative medicine as a distinct entity. This is done by reviewing current knowledge about the placebo effect and how it may pertain to alternative medicine. The term placebo effect is taken to mean not only the narrow effect of a dummy intervention but also the broad array of nonspecific effects in the patient–physician relationship, including attention; compassionate care; and the modulation of expectations, anxiety, and self-awareness. Five components of the placebo effect—patient, practitioner, patient-practitioner interaction, nature of the illness, and treatment and setting—are examined. Therapeutic patterns that heighten placebo effects are especially prominent in unconventional healing, and it seems possible that the unique drama of this realm may have "enhanced" placebo effects in particular conditions. Ultimately, only prospective trials directly comparing the placebo effects of unconventional and mainstream medicine can provide reliable evidence to support such claims. Nonetheless, the possibility of enhanced placebo effects raises complex conundrums. Can an alternative ritual with only nonspecific psychosocial effects have more positive health outcomes than a proven, specific conventional treatment? What makes therapy legitimate, positive clinical outcomes or culturally acceptable methods of attainment? Who decides?
Contemporary Management of Chronic Obstructive Pulmonary Disease
Authors: S. F. Paul Man, Finlay A. McAlister, Nick R. Anthonisen, Don D. Sin
Journal: JAMA (2003)

The presentation of chronic obstructive pulmonary disease (COPD) usually is insidious, and many patients are undiagnosed until the disease is far advanced. Therefore, the early use of spirometry is recommended for anyone who is suspected to have COPD. In the early stages of the disease, the patient is only mildly symptomatic (cough and sputum production). As COPD becomes more advanced, functional impairment in the form of chronic dyspnea occurs and acute exacerbations of symptoms become more frequent, contributing to overall morbidity and mortality. The single most important known causative factor of COPD is cigarette smoking. Smoking cessation remains, therefore, the mainstay of COPD therapy. In patients with advanced disease, symptomatic treatment with the regular use of either short- or long-acting sympathomimetic and/or anticholinergic bronchodilators, singly or in combination, should be added to smoking cessation and influenza and pneumococcal vaccination therapies. An inhaled corticosteroid, either alone or more commonly in combination with a long-acting bronchodilator, can further reduce exacerbations and improve the health status of these patients. Furthermore, patients with severe COPD, particularly those who are debilitated, should be considered for pulmonary rehabilitation because these programs have been proven useful in maintaining, or in some cases improving, health status for these patients. Finally, correction of resting arterial hypoxemia with oxygen therapy for more than 15 h/d prolongs survival of COPD patients for those with a resting PaO<sub>2</sub>lower than 55 to 60 mm Hg.
Nuclear genes involved in mitochondria-to-nucleus communication in breast cancer cells.
Authors: Robert Delsite, Sushant Kachhap, Ramaswamy Anbazhagan, Edward Gabrielson, Keshav K Singh
Journal: Molecular Cancer (2002)

The interaction of nuclear and mitochondrial genes is an essential feature in maintenance of normal cellular function. Of 82 structural subunits that make up the oxidative phosphorylation system in the mitochondria, mitochondrial DNA (mtDNA) encodes 13 subunits and rest of the subunits are encoded by nuclear DNA. Mutations in mitochondrial genes encoding the 13 subunits have been reported in a variety of cancers. However, little is known about the nuclear response to impairment of mitochondrial function in human cells. We isolated a Rho0 (devoid of mtDNA) derivative of a breast cancer cell line. Our study suggests that depletion of mtDNA results in oxidative stress, causing increased lipid peroxidation in breast cancer cells. Using a cDNA microarray we compared differences in the nuclear gene expression profile between a breast cancer cell line (parental Rho+) and its Rho0 derivative impaired in mitochondrial function. Expression of several nuclear genes involved in cell signaling, cell architecture, energy metabolism, cell growth, apoptosis including general transcription factor TFIIH, v-maf, AML1, was induced in Rho0 cells. Expression of several genes was also down regulated. These include phospholipase C, agouti related protein, PKC gamma, protein tyrosine phosphatase C, phosphodiestarase 1A (cell signaling), PIBF1, cytochrome p450, (metabolism) and cyclin dependent kinase inhibitor p19, and GAP43 (cell growth and differentiation). Mitochondrial impairment in breast cancer cells results in altered expression of nuclear genes involved in signaling, cellular architecture, metabolism, cell growth and differentiation, and apoptosis. These genes may mediate the cross talk between mitochondria and the nucleus.
Observations on the Therapeutic Action of Ultra-Violet Light upon the Eye
Authors: W. S. Duke-Elder
Journal: BMJ (1926)

OF late years, owing largely to the work of Leonard Hill and his co-workers, the treatment of general disease by ultra-violet light is being rapidly put on a scientific basis -but hithe,rto no-serious attempt has been made -in this co'untry to investigate how far it might'be utilized in the treatment of diseases of the eye.To this paper, which is a preliminiary report of theexperience gained at the ,Ultra-Violet-Clinic of the Royal London -Ophthalmic 'Hospital, I must prefix an acknowledgement of my in-'debtedness to the Me'dical Research Council for opportunitv and financial aid in this work, and to Professor Leonard Hill and Sir John H. Parsons for much stimulating help and .encouragement.'The preliminary nature of the paper must be emphasized.The metaod of treatment cannot as yet be said to be altogether out 'of 'the experimental stage, and sufficient experience has not yet been obtained to dogma,tize absolutely on its indications and limitations, or to 'assign to it its ultimate value in our therapeutic 'armamentarium.The present paper is basedon the 'treatmenlt *of seventy cases,' and it is hoped that later, when larger statistics have been gathered, fuller and more authoritative reports will be -published.At the present moment, however, it is felt that results 'of sufficient interest 'ha've accumulated to warrant publication, largely -in the hope that the knowledge of them may stimulate other-to supplement t'hem cut of their own experience.'0`2 "2'.-.--'T"972`61
Collagen and fibronectin expression in cardiac fibroblasts from hypertensive rats
Authors: N. Philips, R. I Bashey, S. A Jimenez
Journal: Cardiovascular Research (1994)

Objective: Left ventricular hypertrophy in spontaneously hypertensive rats (SHR) is accompanied by excessive accumulation of collagen in the myocardium. The objective of this work was to examine the role of myocardial fibroblasts in this phenomenon. Methods: Myocardial fibroblasts from SHR and control Wistar Kyoto rats (WKY) were incubated with l4C-proline: total l4C incorporation and l4C-collagen synthesis were determined by collagenase digestion assays. I4C containing proteins were further characterised by SDS gel electrophoresis. RNA was isolated from these cultures and used for northern blot hybridisation with rodent specific cDNAs for collagen types I and III and fibronectin. Results: Biosynthetic labelling of fibroblastic cell cultures with l4C-proline showed that l4C-proline incorporation into total protein expressed on a DNA basis was 30% higher in fibroblasts from hypertensive rats than in the corresponding sex and age matched normal rats. When the same set of cell cultures was examined for l4C-collagen synthesis there was a 50% increment in cell strains from hypertensive animals; these differences were highly significant. When the expression of collagen types I and III and fibronectin genes was analysed by northern blot analyses. 1.5- to 2-fold greater steady state levels of types I and III collagens and fibronectin transcripts were found in fibroblasts from hypertensive rats when compared to cells from normal rats. Conclusions: Myocardial fibroblast cultures from hypertensive rats produce increased amounts of collagen and fibronectin associated with increased expression of the genes for types I and III collagens and also for fibronectin. Myocardial fibroblasts may participate in the increased myocardial connective tissue deposition associated with genetic hypertension. Cardiovascular Research 1994;28:1342-1347
The Bradshaw Lecture ON THE PREVENTION OF ACUTE RHEUMATISM: Delivered at the Royal College of Physicians, London, November 4th, 1924
Authors: F. J. Poynton
Journal: BMJ (1924)

THE prevenitioII of acute rlheumatism is faced witlh many difficulties, and I think the more closely it is studied the more apparent these beconle.1.The first of these difficulties is nomenclature, for acute rheumatism may be the most insidious of maladies.Yet if we leave-out " acute " and use the term " rheumatism " we are at once overwhelmed by the various disorders with 'which we are confronted, and if we abanidon the term rheumiiatism " altogether we shall have great difficulty in finding a substitute.It is when the prevention of acute rheumatism is entertained upon a great scale that this weakness in the nomenclature becomiies of practical importance.2. The next difficulty is concerned with the etiology of acute rheumatism considered as an infective disease.This view of the causation has a most important bearing upon the possibilities of prevention, but is at present in a state of uncertaintv.Wlhen, in 1898, I first became associated with my faithful and valuable colleague
Asthma during pregnancy: mechanisms and treatment implications
Authors: V. E. Murphy, P. G. Gibson, R. Smith, V. L. Clifton
Journal: European Respiratory Journal (2005)

Asthma is becoming increasingly prevalent worldwide. Numerous historical and prospective cohort studies have investigated the effects of maternal asthma on pregnancy outcome; however, the data has been conflicting and many studies have not used standard classifications for asthma severity. Overall, the literature suggests that asthmatic females are more at risk of low birth weight neonates, pre-term delivery and complications such as pre-eclampsia, especially in the absence of actively managed asthma treated with inhaled corticosteroids. Pregnancy with a female foetus may particularly increase the risk of these outcomes. In addition, pregnancy has an effect on the course of asthma. The risk of an exacerbation requiring medical intervention may be as high as 50% in females with severe asthma and this may further increase the risk of poor outcomes, particularly low birth weight and pre-term delivery. The mechanisms responsible for changes in asthma with pregnancy, or alterations in pregnancy outcomes due to asthma have not been thoroughly explored. Maternal inflammatory pathways may contribute to reduced foetal growth through alterations in placental function. Asthma treatment, by reducing maternal inflammation and preventing exacerbations, is safe for use in pregnant females and contributes to improved outcomes for both mother and foetus.
Pseudogout Syndrome in Hospital Patients
Authors: J. Desmond O'Duffy
Journal: JAMA (1973)

From 1970 through 1971, 31 episodes of pseudogout occurred in 28 hospitalized patients. Twenty-three episodes occurred after surgery (21 operations, including 11 orthopedic procedures and 3 parathyroid adenectomies) at a median of three days. Five of the nine attacks in medical patients occurred after acute vascular illnesses (median, seven days). Knee involvement was most common (25 of 31 episodes); other large joints were sometimes affected, and nearly half of the patients had more than one joint inflamed. Ten of the patients were observed during their first episode. Joint aspiration with intra-articular steroid injection appears to be the best treatment. Because most attacks were noted during the early postoperative phase, hypocalcemia is postulated as one metabolic "trigger" for this form of crystal synovitis.
Pneumococcal conjugate vaccine is immunogenic in lung fluid of HIV-infected and immunocompetent adults
Authors: Stephen B. Gordon, Helena Kayhty, Malcolm E. Molyneux, Raili Haikala, Anu Nurkka, Janelisa Musaya, Eduard E. Zijlstra, Dennis Lindell, Neil French
Journal: Journal of Allergy and Clinical Immunology (2007)
Coexistence of localized Langerhans cell histiocytosis and cutaneous Rosai-Dorfman disease
Authors: K-H. Wang, C-J. Cheng, C-H. Hu, W-R. Lee
Journal: British Journal of Dermatology (2002)

Rosai-Dorfman disease (RDD; sinus histiocytosis with massive lymphadenopathy) and Langerhans cell histiocytosis (LCH) are two different yet pathogenetically related histiocytic disorders. While systemic and localized forms have been identified in both diseases, each has its own characteristic histological, immunohistochemical and ultrastructural profile. Rarely, either RDD or LCH can also occur in the context of certain malignant neoplasms. However, the coexistence of RDD and LCH has never been described. We report a case of cutaneous RDD in which a focus of LCH was found. Clinical and laboratory examinations revealed no evidence of extracutaneous involvement of RDD or LCH. We believe that this is the first report of such a coexistence, and the possible pathogenesis is discussed.
Mouse Strain-Related Differences in the Biologic and Immunologic Responses to a Murine Sarcoma Virus
Authors: A. F. Gazdar, E. K. Russell, R. B. Herberman
Journal: JNCI Journal of the National Cancer Institute (1973)

Important differences were present in the biologic and immunologic responses of 4-week-old BALB/c, C3H, and (NZW × NZB)F1 (B/W) mice to a murine sarcoma virus(Gz-MSV) isolated froma B/W mouse. Although the 3 strains rapidly developed large soft-tissue tumors at the virus inoculation site, the tumors regressed in C3H mice but grew progressively in BALB/c mice. These 2 strains showed excellent correlation among tumor regression, virus titers, and plasma levels of virus-neutralizing and cytotoxic antibodies. The biologic responses of B/W mice to the virus were complex and were not correlated with the humoral immune responses. Tumors in B/W mice persisted for long periods, despite histologic evidence of rejection and high levels of cytotoxic antibodies. Cellular immune responses to the tumor were relatively weak in all 3 strains. B/W mice developed massive splenomegaly, with extensive inflammatory fibrosis and vascular proliferation replacing the normal architecture. The biologic responses of NZB and B/W mice to Gz-MSV were similar. Splenectomy did not prevent the death of virus-inoculated BALB/c, NZB, and B/W mice but it prolonged the survival time of B/W mice.
TNF-α Promotes c-REL/ΔNp63α Interaction and TAp73 Dissociation from Key Genes That Mediate Growth Arrest and Apoptosis in Head and Neck Cancer
Authors: Hai Lu, Xinping Yang, Praveen Duggal, Clint T. Allen, Bin Yan, Jonah Cohen, Liesl Nottingham, Rose-Anne Romano, Satrajit Sinha, Kathryn E. King, Wendy C. Weinberg, Zhong Chen, Carter Van Waes
Journal: Cancer Research (2011)

Abstract Inflammation-induced activation of proto-oncogenic NF-κB/REL and dysfunction of tumor suppressor TP53/p63/p73 family transcription factors are key events in cancer progression. How inflammatory signaling coordinates dysregulation of these two transcription factor families during oncogenesis remains incompletely understood. Here, we observed that oncoprotein c-REL and tumor suppressor TAp73 are coexpressed and complex with ΔNp63α in the nucleus of a subset of head and neck squamous cell carcinoma (HNSCC) cell lines with mutant (mt)TP53. TNF-α, a proinflammatory cytokine, promoted c-REL nuclear translocation, c-REL/ΔNp63α interaction, and dissociation of TAp73 from ΔNp63α and the nucleus to the cytoplasm, whereas c-REL siRNA knockdown attenuated this effect. Overexpression of c-REL or a c-REL κB-site DNA-binding mutant enhanced protein interaction with ΔNp63α and TAp73 dissociation, implicating c-REL/ΔNp63α-specific interactions in these effects. We discovered that TNF-α or genetic alteration of c-REL expression inversely modulates ΔNp63α/TAp73 interactions on distinct p63 DNA-binding sites, including those for key growth arrest and apoptotic genes p21WAF1, NOXA, and PUMA. Functionally, c-REL repressed these genes and the antiproliferative effects of TNF-α or TAp73. Conversely, c-REL siRNA depletion enhanced TAp73 promoter interaction and expression of genes mediating growth arrest and apoptosis. Similar to TNF-α–treated HNSCC lines, human HNSCC tumors and hyperplastic squamous epithelia of transgenic mice overexpressing ΔNp63α that exhibit inflammation also show increased nuclear c-REL/ΔNp63α and cytoplasmic TAp73 localization. These findings unveil a novel and reversible dynamic mechanism whereby proinflammatory cytokine TNF-α–induced c-REL/ΔNp63α interactions inactivate tumor suppressor TAp73 function, promoting TNF-α resistance and cell survival in cancers with mtTP53. Cancer Res; 71(21); 6867–77. ©2011 AACR.