tbuckley/cabot-search huggingface dataset:
Risk-Adapted Treatment in Clinical Stage I Testicular Seminoma: The Third Spanish Germ Cell Cancer Group Study
Authors: Jorge Aparicio, Pablo Maroto, Xavier García del Muro, Josep Gumà, Alfonso Sánchez-Muñoz, Mireia Margelí, Montserrat Doménech, Romá Bastús, Antonio Fernández, Marta López-Brea, Josefa Terrassa, Andrés Meana, Purificación Martínez del Prado, Javier Sastre, Juan J. Satrústegui, Regina Gironés, Lidia Robert, José R. Germà
Journal: Journal of Clinical Oncology (2011)

Purpose To confirm the efficacy of a risk-adapted treatment approach for patients with clinical stage I seminoma. The aim was to reduce both the risk of relapse and the proportion of patients receiving adjuvant chemotherapy while maintaining a high cure rate. Patients and Methods From 2004 to 2008, 227 patients were included after orchiectomy in a multicenter study. Eighty-four patients (37%) presented no local risk factors, 44 patients (19%) had tumors larger than 4 cm, 25 patients (11%) had rete testis involvement, and 74 patients (33%) had both criteria. Only the latter group received two courses of adjuvant carboplatin, whereas the rest were managed by surveillance. Results After a median follow-up time of 34 months, 16 relapses (7%) have been documented (15 [9.8%] among patients on surveillance and one [1.4%] among those treated with carboplatin). All relapses occurred in retroperitoneal lymph nodes, except for one case in pelvic nodes. Median node size was 25 mm, and median time to recurrence was 14 months. All patients were rendered disease-free with chemotherapy. The actuarial 3-year disease-free survival rate was 88.1% (95% CI, 82.3% to 93.9%) for patients on surveillance and 98.0% (95% CI, 94.0% to 100%) for those treated with adjuvant chemotherapy. Overall 3-year survival was 100%. Conclusion With the limitations of the short follow-up duration, we confirm that a risk-adapted approach is effective for stage I seminoma. Adjuvant carboplatin seems adequate treatment for patients with 2 risk criteria, as is active surveillance for those with 0 to one risk factors. More reliable predictive factors are needed to improve the applicability of this model.
Circulating KL-6 levels in patients with drug induced pneumonitis
Authors: H Ohnishi
Journal: Thorax (2003)

<b>Background:</b> The circulating level of KL-6/MUC1 is a sensitive marker for various interstitial lung diseases. Previous case reports have suggested that KL-6 may also be increased in some patients with drug induced pneumonitis. A study was undertaken to determine whether serum KL-6 could be a marker for particular types of drug induced pneumonitis. <b>Methods:</b> The findings of high resolution computed tomographic (HRCT) chest scans of 30 patients with drug induced pneumonitis were reviewed separately by two independent observers. The pneumonitis was classified into four predominant patterns: widespread bilateral consolidation (diffuse alveolar damage, DAD; n=7), fibrosis with or without consolidation (chronic interstitial pneumonia, CIP; n=11), consolidation without fibrosis (bronchiolitis obliterans organising pneumonia or eosinophilic pneumonia, BOOP/EP; n=8), and diffuse ground glass opacities without fibrosis (hypersensitivity pneumonitis, HP; n=4). Serum KL-6 levels were measured by a sandwich enzyme linked immunosorbent assay. <b>Results:</b> The overall sensitivity of serum KL-6 in detecting drug induced lung disease was 53.3%, which was lower than its sensitivity in detecting other interstitial lung diseases. However, the KL-6 level was increased in most patients with a DAD or CIP pattern (16/18; 88.9%) and was closely correlated with their clinical course. In contrast, serum KL-6 levels were within the normal range in all patients with a BOOP/EP or HP pattern. <b>Conclusions:</b> Particular patterns detected by HRCT scanning, such as DAD and CIP but not the BOOP/EP or HP patterns, are associated with increased circulating KL-6 levels in drug induced pneumonitis. Serum KL-6 levels may reflect the clinical activity of the particular disorders.
The Hospital Staff, Community Medicine, and Continuing Education
Authors: Ward Darley
Journal: JAMA (1968)

The April 18, 1966, issue ofThe Journalcontains a paper in which I proposed that we use increasing knowledge and specialism and increasing efficiency in data processing and communication to the end that we increase our capacity to cope with increasing demands and costs of medical care and with increasing shortages of medical personnel. In my brief discussion of the organization necessary to accomplish all of this, I suggested that the day would come when the satisfactions of the health and medical professional might come more from being one of a group or team than from being an entrepreneur, that the effective functioning of the group or team might call for new categories in the constellation of specialism, and that the eventual role of the community hospital might call for both the centralization and decentralization of many of its functions. I indicated that organization should provide the common ground
<i>Nod2</i> regulates the host response towards microflora by modulating T cell function and epithelial permeability in mouse Peyer's patches
Authors: Frédérick Barreau, Chrystèle Madre, Ulrich Meinzer, Dominique Berrebi, Monique Dussaillant, Françoise Merlin, Lars Eckmann, Mickael Karin, Ghislaine Sterkers, Stéphane Bonacorsi, Thécla Lesuffleur, Jean-Pierre Hugot
Journal: Gut (2009)

Nucleotide oligomerisation domain 2 ( NOD2 ) mutations are associated with susceptibility to Crohn's disease and graft-versus-host disease, two human disorders related with dysfunctions of Peyer's patches (PPs). In Nod2 −/− mice transcellular permeability and bacterial translocation are increased in PPs. In this study, we show that both anti-CD4 + and anti-interferon γ (anti-IFN γ ) monoclonal antibodies abrogate this phenotype and reduce the expression of tumour necrosis factor (TNF) receptor 2 and the long isoform of myosin light chain kinase, thus demonstrating that immune T cells influence the epithelial functions. In turn, intraperitoneal injection of ML-7 (a myosin light chain kinase inhibitor) normalises the values of CD4 + T cells, IFN γ and TNF α . This reciprocal cross-talk is under the control of the gut microflora as shown by the normalisation of all parameters after antibiotic treatment. Toll-like receptor 2 (TLR2) and TLR4 expression were increased in Nod2 −/− mice under basal conditions and TLR2 and TLR4 agonists induced an increased transcellular permeability in Nod2 +/+ mice. Muramyldipeptide (a Nod2 agonist) or ML-7 was able to reverse this phenomenon. It thus appears that Nod2 modulates the cross-talk between CD4 + T cells and the epithelium recovering PP and that it downregulates the pro-inflammatory effect driven by the ileal microflora, likely by inhibiting the TLR pathways.
How women with a family history of breast cancer and their general practitioners act on genetic advice in general practice: prospective longitudinal study
Authors: G. H de Bock
Journal: BMJ (2001)

increase in older age groups from 1972 to 1994, which was particularly noticeable in Scottish children. 8lthough debate over the cut-off points will continue, this should not detract from the urgency of tackling the problem of obesity.Our data indicate that overweight and obesity on the basis of body mass index have increased noticeably since 1984.Most studies have shown poor prediction of adult obesity from child assessments but a consistent positive correlation between child and adult overweight and obesity. 10Rising trends in children will almost certainly be represented in later trends in adult overweight and obesity and probably in an increase in associated adult morbidity.We thank our colleagues in the study team, all parents, children, and helpers in the study areas, and Professor Tim Cole for supplying the international cut-off points in advance of their publication.
Ovarian Influence on Pulmonary Carcinogenesis by Hydrazine Sulfate in BALB/c/Cb/Se Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: C Biancifiori
Journal: JNCI Journal of the National Cancer Institute (1970)

Daily administration of hydrazine sulfate, 1.13 mg/mouse for 150 doses, to BALB/c/Cb/Se female mice in various hormonal states varied the incidence and the average number of pulmonary tumors per tumor-bearing mouse as follows: in intact virgins, 90.0% and 3; in breeders, 100% and 14; in gonadectomized mice, 60.0% and 5. Histologically, in intact virgins, 3.3% were carcinomas and 96.6% were adenomas; in breeders, 47.2% were carcinomas and 52.7% were adenomas; in gonadectomized mice, 4% were carcinomas and 96% were adenomas. Many pulmonary carcinomas induced in breeders infiltrated the thoracic wall and the mediastinal organs and metastasized to the adrenal glands and myocardium. The greater biologic and morphologic malignancy of the induced tumors observed in breeders, as compared to those in intact virgin and gonadectomized mice, was associated with an increased ovarian hormone production.
Is It Always Unethical to Use a Placebo in a Clinical Trial?
Authors: Andreas Stang, Hans-Werner Hense, Karl-Heinz Jöckel, Erick H Turner, Martin R Tramèr
Journal: PLoS Medicine (2005)

Placebos are used in trials to conceal whether a treatment is being given or not and hence to control for the psychosomatic effects of offering treatment. Placebo-controlled trials are controversial. Critics of such trials argue that if a proven effective therapy exists, a placebo should not be used. But proponents argue that placebo trials are still crucial to prove the efficacy and safety of many treatments.
ANTIGEN-INDUCED STIMULATION OF GLUCOSAMINE INCORPORATION BY GUINEA PIG PERITONEAL MACROPHAGES IN DELAYED HYPERSENSITIVITY
Authors: M. Elizabeth Hammond, Harold F. Dvorak
Journal: The Journal of Experimental Medicine (1972)

The interaction between sensitized lymphocytes and specific antigen occurring in delayed hypersensitivity causes bystander macrophages to undergo a variety of light-microscopic, ultrastructural, and biochemical changes, which are reflected in alterations in cell movement and intercellular contacts. Since such alterations involve functions of the cell periphery, we postulated that metabolic changes in this polysaccharide-rich zone would accompany the expression of delayed hypersensitivity. We here demonstrate that the incorporation of radioactive glucosamine by peritoneal macrophages into TCA-precipitable, membrane-associated material is regularly enhanced when these are cultured in the presence of specific antigen and nonadherent cells (lymphocytes) primed for delayed hypersensitivity. Lymphocytes from unsensitized animals, or from animals immunized so as to form antibody but not delayed hypersensitivity, do not stimulate such incorporation. Antigen-induced glucosamine incorporation is maximal at 2 or 3 days of culture and is not observed earlier; it may be elicited with as little as 0.1 microg/ml PPD, and affords an exceedingly reproducible and sensitive index of delayed hypersensitivity. Radioautographic studies indicate that nearly all plastic adherent cells (90% macrophages) incorporate glucosamine and that grains are concentrated in the regions of the perinuclear zone and cell membrane. Subcellular fractionation indicates that nearly 30% of counts and the highest specific activity are associated with the membrane-rich microsomal fraction; the microsomal distribution of counts increases in both absolute and relative terms when macrophages are cultured in the presence of specific antigen and sensitized lymphocytes. Taken together, these data indicate that a sizable fraction of incorporated glucosamine is localized to the vicinity of the cell periphery but lack sufficient resolution to determine whether this material is associated with the cell membrane itself or with the extramembranous cell coat. This last possibility is of particular interest since we have previously shown that macrophage cell coat material is lost or altered as a consequence of an interaction between sensitized lymphocytes and specific antigen.
Histone Methyltransferase EZH2 Induces Akt-Dependent Genomic Instability and BRCA1 Inhibition in Breast Cancer
Authors: Maria E. Gonzalez, Matthew L. DuPrie, Heather Krueger, Sofia D. Merajver, Alejandra C. Ventura, Kathy A. Toy, Celina G. Kleer
Journal: Cancer Research (2011)

Abstract Increased levels of EZH2, a critical regulator of cellular memory, signal the presence of metastasis and poor outcome in breast cancer patients. High levels of EZH2 are associated with nuclear pleomorphism, lack of estrogen receptor expression, and decreased nuclear levels of BRCA1 tumor suppressor protein in invasive breast carcinomas. The mechanism by which EZH2 overexpression promotes the growth of poorly differentiated invasive carcinomas remains to be defined. Here, we show that EZH2 controls the intracellular localization of BRCA1 protein. Conditional doxycycline-induced upregulation of EZH2 in benign mammary epithelial cells results in nuclear export of BRCA1 protein, aberrant mitoses with extra centrosomes, and genomic instability. EZH2 inhibition in CAL51 breast cancer cells induces BRCA1 nuclear localization and rescues defects in ploidy and mitosis. Mechanistically, EZH2 overexpression is sufficient for activation of the phosphoinositide 3-kinase/Akt (PI3K/Akt) pathway specifically through activation of Akt isoform 1. EZH2-induced BRCA1 nuclear export, aneuploidy, and mitotic defects were prevented by treatment with the PI3K inhibitors LY294002 or wortmannin. Targeted inhibition of Akt-1, Akt-2, and Akt-3 isoforms revealed that the EZH2-induced phenotype requires specific activation of Akt-1. The relevance of our studies to human breast cancer is highlighted by the finding that high EZH2 protein levels are associated with upregulated expression of phospho-Akt-1 (Ser473) and decreased nuclear expression of phospho-BRCA1 (Ser1423) in 39% of invasive breast carcinomas. These results enable us to pinpoint one mechanism by which EZH2 regulates BRCA1 expression and genomic stability mediated by the PI3K/Akt-1 pathway. Cancer Res; 71(6); 2360–70. ©2011 AACR.
Multimodality Approaches for the Curative Treatment of Esophageal Cancer
Authors: Raymond Jang, Gail Darling, Rebecca K S Wong
Journal: Journal of the National Comprehensive Cancer Network (2015)

Carcinoma of the esophagus and gastroesophageal junction tumors presenting with locoregional disease are potentially curable, although the cure rate is modest. Many different treatment approaches have been studied, with a multimodality approach associated with a 10% to 15% greater survival advantage compared with a single-modality approach. A systematic review was conducted to address 3 clinical questions: whether patients with resectable esophageal cancer should receive preoperative versus postoperative therapy, how to choose between these options, and whether surgery be avoided in patients who are candidates for both definitive chemoradiotherapy and definitive combined modality therapy. Recommendations from 3 recent treatment guidelines from Ontario, NCCN, and Belgium were consulted to address these questions.
Onychomycosis: current treatment and future challenges
Authors: D T Roberts
Journal: British Journal of Dermatology (1999)

Onychomycosis is a fungal infection of the nails, more often of the toenails. It is a common condition, with an estimated overall prevalence of 3–10% in European populations. Dermatophytes, especially Trichophyton rubrum and Trichophyton mentagrophytes, are the usual pathogens. Some 50% of infected patients fail to seek medical advice. Medically confirmed onychomycosis should be treated. This recommendation is based on several disease‐specific considerations: cosmetic and functional disability, lack of spontaneous remission, impairment of health and wellbeing in elderly patients and the need to reduce contamination in communal bathing places. Current treatments for onychomycosis include oral antifungal agents such as terbinafine (Lamisil®) and itraconazole (Sporanox®). They offer significantly improved rates of cure, shorter treatment regimens and a lower level of adverse events than was previously the case. Comparative studies have shown that terbinafine is more effective than griseofulvin, fluconazole or itraconazole in the treatment of this condition, providing a cure rate of 70–80% and an excellent tolerability profile. Terbinafine is also the most cost‐effective agent. However, several problems remain that will provide future challenges in the treatment of onychomycosis, not least the consistent treatment failure rate of 20%. In many of these cases, surgery may need to precede drug therapy in order to maximise the prospects of clinical and mycological cure. In addition, duration of treatment also needs to be more closely adjusted to the individual case by prior identification of severity and extent of toenail infection, and combined oral and topical therapy also requires further investigation.
Meta-Analysis: The Effect of Statins on Albuminuria
Authors: Kevin Douglas, Patrick G. O'Malley, Jeffrey L. Jackson
Journal: Annals of Internal Medicine (2006)

Background: Albuminuria is an independent risk factor for cardiovascular and renal disease with limited therapeutic options. Data on the effects of statins on albuminuria are conflicting. Purpose: To determine whether and to what degree statins affect albuminuria. Data Sources: English-language and non–English-language studies found in PubMed, MEDLINE, EMBASE, BIOSIS, SciSearch, PASCAL, and International Pharmaceutical Abstracts (IPA) databases and the Cochrane Central Register of Controlled Trials that were published between January 1974 and November 2005. Study Selection: Randomized, placebo-controlled trials of statins reporting baseline and follow-up measurements of albuminuria or proteinuria measured by 24-hour urine collection or the urinary albumin-to-creatinine ratio. Data Extraction: Two investigators independently abstracted study quality, characteristics, and outcomes. Data Synthesis: Fifteen studies involving a total of 1384 patients and averaging 24 weeks in duration were included. Meta-analysis of the proportional reduction in proteinuria showed that statins reduced albuminuria (11 studies) and proteinuria (4 studies) in 13 of 15 studies. The reduction in excretion was greater among studies with greater baseline albuminuria or proteinuria: change of 2% (95% CI, −32% to 35%) for those with excretion less than 30 mg/d, −48% (CI, −71% to −25%) for those with excretion of 30 to 300 mg/d, and −47% (CI, −67% to −26%) for those with excretion more than 300 mg/d. Statistical heterogeneity was evident only in the group with excretion greater than 300 mg/d (excretion < 30 mg/d, I2 = 23% [P = 0.27]; excretion of 30 to 299 mg/d, I2 = 0% [P = 0.64]; excretion ≥ 300 mg/d, I2 = 63% [P = 0.020]). Limitations: Published studies were not of high quality on average and varied markedly in effect size, as well as in characteristics of the cohorts. Unpublished studies showing no effect could impact these results. Conclusion: Statins may have a beneficial effect on pathologic albuminuria. The validity of this finding, and whether this effect translates into reduction of cardiovascular or end-stage renal disease, requires larger studies.
Bedaquiline: 10 years later, the drug susceptibility testing protocol is still pending
Authors: Max Salfinger, Giovanni Battista Migliori
Journal: European Respiratory Journal (2015)

With 9.0 million cases and 1.5 million deaths estimated in 2013, tuberculosis (TB) remains one of the world's deadliest communicable diseases; however, it is slowly declining each year and it is estimated that 37 million lives were saved between 2000 and 2013 through effective diagnosis and treatment [1]. Globally, 3.5% of new and 20.5% of previously treated TB cases (480 000 people) were estimated to have been multidrug-resistant (MDR)-TB in 2013, with 9.0% of them being affected by extensively drug-resistant (XDR)-TB. Although bedaquiline is already used to treat MDR-TB neither DST nor MIC protocols are yet available to guide its use <http://ow.ly/ESrRz>
Establishment and characterization of clinically relevant models of ependymoma: a true challenge for targeted therapy
Authors: S. Guan, R. Shen, T. Lafortune, N. Tiao, P. Houghton, W. K. A. Yung, D. Koul
Journal: Neuro-Oncology (2011)

The development of new therapies for ependymoma is dramatically limited by the absence of optimal in vivo and in vitro models. Successful ependymoma treatment requires a profound understanding of the disease's biological characteristics. This study focuses on the establishment and characterization of in vivo and in vitro models of ependymoma to study the molecular pathways necessary for growth and progression in ependymoma. In addition, this study also emphasizes the use of these models for therapeutic intervention of ependymomas. We established optimal conditions for the long-term growth of 2 tumor xenografts and cultures of 2 human ependymoma cell lines. This study also describes the establishment of in vivo models. Histopathologic features of tumors from both intracranial and subcutaneous sites in mice revealed perivascular pseudorosettes and ependymal rosettes, which are typical morphologic features of ependymoma similar to those observed in human specimens. The in vitro models revealed glial fibrillary acidic protein and vimentin expression, and ultrastructural studies demonstrated numerous microvilli, caveolae, and microfilaments commonly seen in human ependymoma. To study signaling pathway alterations in ependymoma, we profiled established ependymoma models with Western blot analysis that demonstrated aberrant activation mainly of the phosphoinositide 3-kinase and epidermal growth factor receptor signaling pathways. Targeting phosphoinositide 3-kinase and epidermal growth factor receptor signaling pathways with small molecule inhibitors showed growth inhibitory effects. These models can also be used to study the standard therapies used for ependymomas, as shown by some of the drugs used in this study. Therefore, the models developed will assist in the biological studies and preclinical drug screening for ependymomas.
Combined Ultrasmall Superparamagnetic Particles of Iron Oxide–Enhanced and Diffusion-Weighted Magnetic Resonance Imaging Reliably Detect Pelvic Lymph Node Metastases in Normal-Sized Nodes of Bladder and Prostate Cancer Patients
Authors: Harriet C. Thoeny, Maria Triantafyllou, Frederic D. Birkhaeuser, Johannes M. Froehlich, Dechen W. Tshering, Tobias Binser, Achim Fleischmann, Peter Vermathen, Urs E. Studer
Journal: European Urology (2009)
Hormonal and nutritional substrate control of cardiac lysosomal enzyme activities.
Authors: K Wildenthal
Journal: Circulation Research (1976)

Prolonged starvation is known to induce significant alterations in several cardiac lysosomal enzymes, particularly the acid proteinase cathepsin D. To determine what specific factors might mediate these changes, fetal mouse hearts in organ culture were maintained in media designed to simulate selected hormonal or nutritional substrate changes that accompany starvation. Reduced concentrations of glucose caused an increase in the activity of beta-acetylglucosaminidase but had no effect on cathepsin D or acid phosphatase activites (i.e., effects opposite from those of starvation). Also, high concentrations of free fatty acid, acetoacetate, and beta-OH-butyrate induced an increase in cathepsin D (+18%) and a simultaneous decrease in glucosaminidase (-19%), with little change in acid phosphatase. Furthermore, glucagon had no effect on any of the enzymes, whereas growth hormone caused a small (6%) increase in cathepsin D activity. In addition, insulin deprivation caused significant increases (7-25%) in the activities of all three enzymes. Insulin deprivation and excess ketones, but not the other interventions, increased the proportion of enzyme activity which was nonsedimentable. These results suggest the possibility that lysosomal alterations during starvation may be related in part to prolonged insulin deficiency and exposure to high concentrations of ketones and free fatty acids.