tbuckley/cabot-search huggingface dataset:
Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer
Authors: Anna Bill-Axelson, Lars Holmberg, Mirja Ruutu, Hans Garmo, Jennifer R. Stark, Christer Busch, Stig Nordling, Michael Häggman, Swen-Olof Andersson, Stefan Bratell, Anders Spångberg, Juni Palmgren, Gunnar Steineck, Hans-Olov Adami, Jan-Erik Johansson
Journal: New England Journal of Medicine (2011)

In 2008, we reported that radical prostatectomy, as compared with watchful waiting, reduces the rate of death from prostate cancer. After an additional 3 years of follow-up, we now report estimated 15-year results.From October 1989 through February 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy. Follow-up was complete through December 2009, with histopathological review of biopsy and radical-prostatectomy specimens and blinded evaluation of causes of death. Relative risks, with 95% confidence intervals, were estimated with the use of a Cox proportional-hazards model.During a median of 12.8 years, 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died (P=0.007). In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting, death was due to prostate cancer. This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6% and 20.7%, respectively (a difference of 6.1 percentage points; 95% confidence interval [CI], 0.2 to 12.0), and a relative risk with surgery of 0.62 (95% CI, 0.44 to 0.87; P=0.01). The survival benefit was similar before and after 9 years of follow-up, was observed also among men with low-risk prostate cancer, and was confined to men younger than 65 years of age. The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age. Among men who underwent radical prostatectomy, those with extracapsular tumor growth had a risk of death from prostate cancer that was 7 times that of men without extracapsular tumor growth (relative risk, 6.9; 95% CI, 2.6 to 18.4).Radical prostatectomy was associated with a reduction in the rate of death from prostate cancer. Men with extracapsular tumor growth may benefit from adjuvant local or systemic treatment. (Funded by the Swedish Cancer Society and the National Institutes of Health.).
Molecular evolution of the fungi: relationship of the Basidiomycetes, Ascomycetes, and Chytridiomycetes.
Authors: B H Bowman, J W Taylor, A G Brownlee, J Lee, S D Lu, T J White
Journal: Molecular Biology and Evolution (1992)

Establishing the phylogeny of fungi and protists often has proved difficult owing to the simple morphologies and convergent characters in these organisms. We used DNA sequences of nuclear small-subunit ribosomal RNA genes to determine phylogenetic relationships among three major classes of organisms considered to be fungi--Basidiomycetes, Ascomycetes and Chytridiomycetes--and to assess the taxonomic position of Neocallimastix, an economically important anaerobic rumen microorganism whose classification is controversial. The Basidiomycetes and Ascomycetes, two classes of nonflagellated fungi, are the most closely related taxa. Chytridiomycetes, though bearing flagella, group with these higher fungi rather than with the protists. Neocallimastix, a eukaryote lacking mitochondria and variously classified as a protist or as a fungus, shows closest molecular affinities with the Chytridiomycete fungi in the order Spizellomycetales.
Protein kinase D2 is a novel regulator of glioblastoma growth and tumor formation
Authors: Ninel Azoitei, Alexander Kleger, Nina Schoo, Dietmar Rudolf Thal, Cornelia Brunner, Ganesh Varma Pusapati, Alina Filatova, Felicitas Genze, Peter Möller, Til Acker, Rainer Kuefer, Johan Van Lint, Heinrich Baust, Guido Adler, Thomas Seufferlein
Journal: Neuro-Oncology (2011)

Glioblastoma multiforme, a highly aggressive tumor of the central nervous system, has a dismal prognosis that is due in part to its resistance to radio- and chemotherapy. The protein kinase C (PKC) family of serine threonine kinases has been implicated in the formation and proliferation of glioblastoma multiforme. Members of the protein kinase D (PKD) family, which consists of PKD1, -2 and, -3, are prominent downstream targets of PKCs and could play a major role in glioblastoma growth. PKD2 was highly expressed in both low-grade and high-grade human gliomas. The number of PKD2-positive tumor cells increased with glioma grading (P < .001). PKD2 was also expressed in CD133-positive glioblastoma stem cells and various glioblastoma cell lines in which the kinase was found to be constitutively active. Inhibition of PKDs by pharmacological inhibitors resulted in substantial inhibition of glioblastoma proliferation. Furthermore, specific depletion of PKD2 by siRNA resulted in a marked inhibition of anchorage-dependent and -independent proliferation and an accumulation of glioblastoma cells in G0/G1, accompanied by a down-regulation of cyclin D1 expression. In addition, PKD2-depleted glioblastoma cells exhibited substantially reduced tumor formation in vivo on chicken chorioallantoic membranes. These findings identify PKD2 as a novel mediator of glioblastoma cell growth in vitro and in vivo and thereby as a potential therapeutic target for this devastating disease.
Phase I Safety and Pharmacokinetic Study of Recombinant Human Anti-Vascular Endothelial Growth Factor in Patients With Advanced Cancer
Authors: M. S. Gordon, K. Margolin, M. Talpaz, G. W. Sledge, E. Holmgren, R. Benjamin, S. Stalter, S. Shak, D. C. Adelman
Journal: Journal of Clinical Oncology (2001)

PURPOSE: We investigated the safety and pharmacokinetics of a recombinant human monoclonal antibody to vascular endothelial growth factor (rhuMAb VEGF) in patients with cancer. PATIENTS AND METHODS: Cohorts of patients with metastatic cancer having failed prior therapy entered a phase I trial of rhuMAb VEGF administered by a 90-minute intravenous infusion at doses from 0.1 to 10.0 mg/kg on days 0, 28, 35, and 42. Patients underwent pharmacokinetic sampling on day 0 and had serum samples obtained during the subsequent 28 days. Response assessment was carried out on days 49 and 72. RESULTS: Twenty-five patients with a median Eastern Cooperative Oncology Group performance status of 0 were accrued. There were no grade III or IV adverse events definitely related to the antibody. There were three episodes of tumor-related bleeding. Infusions of rhuMAb VEGF were well tolerated without significant toxicity. Grades I and II adverse events possibly or probably related to study drug included asthenia, headache, and nausea. Pharmacokinetics revealed a linear profile with a half-life of 21 days. There were no objective responses, though 12 patients experienced stable disease over the duration of the study. CONCLUSION: rhuMAb VEGF was safely administered without dose-limiting toxicity at doses ranging up to 10 mg/kg. Multiple doses of rhuMAb VEGF were well tolerated, and pharmacokinetic studies indicate that doses of ≥ 0.3 mg/kg have a half-life similar to that of other humanized antibodies. Subsequent trials will explore rhuMAb VEGF alone and in combination chemotherapy.
Histone deacetylase turnover and recovery in sulforaphane-treated colon cancer cells: competing actions of 14-3-3 and Pin1 in HDAC3/SMRT corepressor complex dissociation/reassembly
Authors: Praveen Rajendran, Barbara Delage, W Mohaiza Dashwood, Tian-Wei Yu, Bradyn Wuth, David E Williams, Emily Ho, Roderick H Dashwood
Journal: Molecular Cancer (2011)

Abstract Background Histone deacetylase (HDAC) inhibitors are currently undergoing clinical evaluation as anti-cancer agents. Dietary constituents share certain properties of HDAC inhibitor drugs, including the ability to induce global histone acetylation, turn-on epigenetically-silenced genes, and trigger cell cycle arrest, apoptosis, or differentiation in cancer cells. One such example is sulforaphane (SFN), an isothiocyanate derived from the glucosinolate precursor glucoraphanin, which is abundant in broccoli. Here, we examined the time-course and reversibility of SFN-induced HDAC changes in human colon cancer cells. Results Cells underwent progressive G 2 /M arrest over the period 6-72 h after SFN treatment, during which time HDAC activity increased in the vehicle-treated controls but not in SFN-treated cells. There was a time-dependent loss of class I and selected class II HDAC proteins, with HDAC3 depletion detected ahead of other HDACs. Mechanism studies revealed no apparent effect of calpain, proteasome, protease or caspase inhibitors, but HDAC3 was rescued by cycloheximide or actinomycin D treatment. Among the protein partners implicated in the HDAC3 turnover mechanism, silencing mediator for retinoid and thyroid hormone receptors (SMRT) was phosphorylated in the nucleus within 6 h of SFN treatment, as was HDAC3 itself. Co-immunoprecipitation assays revealed SFN-induced dissociation of HDAC3/SMRT complexes coinciding with increased binding of HDAC3 to 14-3-3 and peptidyl-prolyl cis/trans isomerase 1 (Pin1). Pin1 knockdown blocked the SFN-induced loss of HDAC3. Finally, SFN treatment for 6 or 24 h followed by SFN removal from the culture media led to complete recovery of HDAC activity and HDAC protein expression, during which time cells were released from G 2 /M arrest. Conclusion The current investigation supports a model in which protein kinase CK2 phosphorylates SMRT and HDAC3 in the nucleus, resulting in dissociation of the corepressor complex and enhanced binding of HDAC3 to 14-3-3 or Pin1. In the cytoplasm, release of HDAC3 from 14-3-3 followed by nuclear import is postulated to compete with a Pin1 pathway that directs HDAC3 for degradation. The latter pathway predominates in colon cancer cells exposed continuously to SFN, whereas the former pathway is likely to be favored when SFN has been removed within 24 h, allowing recovery from cell cycle arrest.
An Operation for Haemorrhoids
Authors: W. T. Thomas
Journal: BMJ (1898)

resistance.Only once since last May has the patient had a fit, and while we do not exclude the possibility of a recurreince of thc cerebral growth which the solitaly convulsive seizure and a slight feeling of numbness on two occasioins experienced in the left hand rather suggest, the mian, enerally speaking, is in excellent health, has perfect use in his arm and feg, is quite freelftroim all subjective sensations such as giddiness, and is at present following his occupation, and has doue so for the last few months.Note by Dr. Oliver.-November 5th, i898.-Since the above was
Growth-Dependent Podocyte Failure Causes Glomerulosclerosis
Authors: Akihiro Fukuda, Mahboob A. Chowdhury, Madhusudan P. Venkatareddy, Su Q. Wang, Ryuzoh Nishizono, Tsukasa Suzuki, Larysa T. Wickman, Jocelyn E. Wiggins, Timothy Muchayi, Diane Fingar, Kerby A. Shedden, Ken Inoki, Roger C. Wiggins
Journal: Journal of the American Society of Nephrology (2012)

Podocyte depletion leads to glomerulosclerosis, but whether an impaired capacity of podocytes to respond to hypertrophic stress also causes glomerulosclerosis is unknown. We generated transgenic Fischer 344 rats that express a dominant negative AA-4E-BP1 transgene driven by the podocin promoter; a member of the mammalian target of rapamycin complex 1 (mTORC1) pathway, 4E-BP1 modulates cap-dependent translation, which is a key determinant of a cell’s hypertrophic response to nutrients and growth factors. AA-4E-BP1 rat podocytes expressed the transgene and had normal kidney histology and protein excretion at 100 g of body weight but developed ESRD by 12 months. Proteinuria and glomerulosclerosis were linearly related to both increasing body weight and transgene dose. Uni-nephrectomy reduced the body weight at which proteinuria first developed by 40%–50%. The initial histologic manifestation of disease was the appearance of bare areas of glomerular basement membrane from the pulling apart of podocyte foot processes, followed by adhesions to the Bowman capsule. Morphometric analysis confirmed the mismatch between glomerular tuft volume and total podocyte volume (number × size) per tuft in relation to weight gain and nephrectomy. Proteinuria and glomerulosclerosis did not develop if dietary calorie restriction prevented weight gain and glomerular enlargement. In summary, failure of podocytes to match glomerular tuft growth in response to growth signaling through the mTORC1 pathway can trigger proteinuria, glomerulosclerosis, and progression to ESRD. Reducing body weight and glomerular growth may be useful adjunctive therapies to slow or prevent progression to ESRD.
Role of bronchoalveolar lavage in immunocompromised patients with pneumonia treated with a broad spectrum antibiotic and antifungal regimen
Authors: I A Hohenadel, M Kiworr, R Genitsariotis, D Zeidler, J Lorenz
Journal: Thorax (2001)

In a retrospective study the value of bronchoalveolar lavage (BAL) in the diagnosis of pneumonia was investigated in 95 immunocompromised patients suffering from haematological disorders and receiving a regimen of broad spectrum antibiotics and antifungal agents (BSAR).With the exception of four afebrile patients, all had fever, raised C reactive protein (CRP) levels, and new infiltrates visible on chest radiography. All patients underwent BAL to identify the organism causing the pneumonia and surveillance cultures were performed regularly for pathogens at different sites. Following classification of the isolates, patients with positive cultures were subdivided into two groups, pathogenic or contaminated. We investigated whether relevant pathogens were cultured only from the BAL fluid and whether they were susceptible to BSAR.Although 77 of the 95 patients were thrombocytopenic, bleeding during BAL occurred in only 15% of all patients. Ten days after the procedure the fever improved in 88% of patients, radiographic findings improved in 71%, and CRP levels improved in 75% of patients; 22% of patients died within 28 days. Pathologically relevant isolates were found in 65% of all patients. Respiratory pathogens were detected only in the BAL fluid of 29 of the 95 patients (35% Gram positive species, 40% Gram negative species, 11% Mycobacterium, 11% fungi, and 3% cytomegalovirus). In 16 of these 29 patients (55%) the pathogens cultured only from the BAL fluid were resistant to treatment. Pathogens detected only in the BAL fluid were not susceptible to a standard broad spectrum antibiotic and antifungal regimen including teicoplanin, ceftriaxon, tobramycin, and amphotericin B in 12 of the 29 patients (41%).Our data suggest that 12 patients were treated with broad spectrum antimicrobial agents which were not directed at the appropriate organism on in vitro sensitivity tests without BAL. BAL is a relatively safe procedure in the diagnosis of pneumonia, supplying important information in immunocompromised patients as well as in immunocompromised patients receiving BSAR.
Interleukin-6 Contributes to Growth in Cholangiocarcinoma Cells by Aberrant Promoter Methylation and Gene Expression
Authors: Hania Wehbe, Roger Henson, Fanyin Meng, Janna Mize-Berge, Tushar Patel
Journal: Cancer Research (2006)

Abstract The association between chronic inflammation and the development and progression of malignancy is exemplified in the biliary tract where persistent inflammation strongly predisposes to cholangiocarcinoma. The inflammatory cytokine interleukin-6 (IL-6) enhances tumor growth in cholangiocarcinoma by altered gene expression via autocrine mechanisms. IL-6 can regulate the activity of DNA methyltransferases, and moreover, aberrant DNA methylation can contribute to carcinogenesis. We therefore investigated the effect of chronic exposure to IL-6 on methylation-dependent gene expression and transformed cell growth in human cholangiocarcinoma. The relationship between autocrine IL-6 pathways, DNA methylation, and transformed cell growth was assessed using malignant cholangiocytes stably transfected to overexpress IL-6. Treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine decreased cell proliferation, growth in soft agar, and methylcytosine content of malignant cholangiocytes. However, this effect was not observed in IL-6-overexpressing cells. IL-6 overexpression resulted in the altered expression and promoter methylation of several genes, including the epidermal growth factor receptor (EGFR). EGFR promoter methylation was decreased and gene and protein expression was increased by IL-6. Thus, epigenetic regulation of gene expression by IL-6 can contribute to tumor progression by altering promoter methylation and gene expression of growth-regulatory pathways, such as those involving EGFR. Moreover, enhanced IL-6 expression may decrease the sensitivity of tumor cells to therapeutic treatments using methylation inhibitors. These observations have important implications for cancer treatment and provide a mechanism by which persistent cytokine stimulation can promote tumor growth. (Cancer Res 2006; 66(21): 10517-24)
Positive expiratory pressure plateau breathing in spontaneously breathing patients with myocardial infarction and pulmonary dema
Authors: F. Kerr, D. J. Ewing, J. B. Irving, M. F. Sudlow, B. J. Kirby
Journal: Thorax (1974)

<b>Kerr, F., Ewing, D. J., Irving, J. B., Sudlow, M. F., and Kirby, B. J. (1974).</b><i>Thorax</i>, <b>29</b>, 690-694. <b>Positive expiratory pressure plateau breathing in spontaneously breathing patients with myocardial infarction and pulmonary oedema.</b> The respiratory effects of breathing with a positive expiratory pressure plateau (PEPP) was studied in 24 spontaneously breathing, alert, nonsedated patients with pulmonary oedema following myocardial infarction. When 20 patients breathed room air with PEPP a small rise in arterial oxygen tension (<i>P</i>ao<sub>2</sub>) with a fall in alveolar to arterial oxygen gradient (A—ado<sub>2</sub>) occurred. Arterial carbon dioxide tension did not change significantly. When PEPP was used in six patients after breathing 100% oxygen for 20 minutes there was no significant change in <i>P</i>ao<sub>2</sub>, A—ado<sub>2</sub> or anatomical shunt (Qs/Qt). Expired air collection in a further six of the patients demonstrated that although PEPP produced an increase in tidal volume (Vt), alveolar ventilation (Va) fell slightly as a result of a decrease in respiratory rate, and oxygen consumption (Vo<sub>2</sub>) did not change. In 10 normal subjects functional residual capacity (FRC), measured continuously in a whole-body volume displacement plethysmograph, decreased by a small amount when these subjects breathed with PEPP. Positive expiratory pressure plateau breathing in spontaneously breathing conscious patients with pulmonary oedema produced a small improvement in ventilation/perfusion matching not by an increase in FRC but by an increase in Vt. The increase in Vt probably altered the ventilation/perfusion relationships by a redistribution of inspired gas.
The effectiveness of leflunomide as a co-therapy of tumour necrosis factor inhibitors in rheumatoid arthritis: a population-based study
Authors: A Finckh, S Dehler, C Gabay
Journal: Annals of the Rheumatic Diseases (2008)

Background: Randomised trials have demonstrated that the efficacy of anti-tumour necrosis factor (TNF) agents is significantly increased by concomitant methotrexate (MTX) in rheumatoid arthritis (RA). In clinical routine, anti-TNF agents are commonly prescribed with other disease-modifying antirheumatic drugs (DMARDs) than MTX, however their effectiveness in combination with anti-TNF agents is not well established. Objective: To compare the effectiveness of leflunomide (LEF) and other conventional DMARDs with MTX as co-therapy to anti-TNF agents in RA. Methods: All patients on anti-TNF agents and conventional DMARDs within the Swiss Clinical Quality Management (SCQM)-RA database were included (n = 1218) and categorised according to the type of co-therapy into anti-TNF+MTX (n = 842), anti-TNF+LEF (n = 260) and anti-TNF+other DMARDs (n = 116). Drug discontinuation rates and incidence of toxic side effects were analysed using Cox proportional hazard models. Progression of radiographic damage, the evolution of functional disability and the improvement of RA disease activity were analysed using longitudinal regression models, adjusting for potential confounders. Results: The overall discontinuation rates of anti-TNF and conventional DMARD combination therapies were relatively high with a median survival of only 16 months (interquartile range (IQR): 10–37), but they did not differ between the three regimens (p = 0.69). The progression of radiographic damage (p = 0.77), functional disability (p = 0.09) and RA disease activity (p = 0.33) were also similar between the different regimen. In addition, no significant difference in the frequency of adverse events emerged. Conclusion: Overall these results suggest that LEF and potentially other conventional DMARDs offer an effective and safe alternative to MTX as co-therapy in combination with anti-TNF agents.
Gefitinib as a First-Line Therapy of Advanced or Metastatic Adenocarcinoma of the Lung in Never-Smokers
Authors: Dae Ho Lee, Ji-Youn Han, Hong Gi Lee, Jae Jin Lee, Eun Kyoung Lee, Hyae Young Kim, Hark Kyun Kim, Eun Kyung Hong, Jin Soo Lee
Journal: Clinical Cancer Research (2005)

Abstract Purpose: A subset of patients with adenocarcinoma of the lung who had never smoked cigarettes showed excellent tumor responses to gefitinib therapy. To evaluate the efficacy of gefitinib as a first-line therapy in this subgroup of patients, we conducted a phase II study. Experimental Design: Eligible patients had no smoking history, stage IIIB or IV adenocarcinoma, Eastern Cooperative Oncology Group performance status 0 to 2, and adequate organ functions. Treatment consisted of daily oral administration ofF 250 mg gefitinib for 28 days until disease progression. Responses were assessed after every two cycles of therapy. Results: Of 37 patients enrolled, 36 were assessed for response. Twenty-five patients (69%) had partial response, 4 (11%) had stable disease, and 7 (19%) had progressive disease. Of 10 patients with evaluable brain metastases, 7 had objective responses in both intracranial and extracranial lesions, 1 had stable disease in the brain and dramatic response in the extracranial lesions, and 2 had progressive disease in both sites. After a median follow-up of 48 weeks (range, 4-70 weeks), 26 patients had disease progression, with median progression-free survival of 33 weeks, and 9 patients died, all due to disease progression. The median survival time has not been reached yet but the estimated 1-year survival rate was 73%. Common toxicities were skin rash and mild diarrhea but there was no significant hematologic toxicity. Conclusions: Gefitinib showed very dramatic antitumor activity, even in the brain, with unprecedented survival outcome in never-smoker adenocarcinoma patients. These data support the use of gefitinib as a first-line therapy in this particular subgroup.