tbuckley/cabot-search huggingface dataset:
Proteasome inhibitor MG132 induces Death Receptor 5 through CHOP in prostate cancer cell
Authors: Tatsushi Yoshida, Takumi Shiraishi, Susumu Nakata, Miki Wakada, Yoichi Mizutani, Tsuneharu Miki, Toshiyuki Sakai
Journal: Cancer Research (2006)

2385  TNF-related apoptosis-inducing ligand (TRAIL) is one of promising candidates for cancer therapeutics due to its ability to induce apoptosis in cancer cells with little or no toxicity in normal cells. However, some tumor types exhibit resistance to TRAIL. Thus it is important to overcome this resistance. Combined treatment with a proteasome inhibitor and TRAIL is a promising strategy to overcome TRAIL resistance in cancer cells. Proteasome inhibitors induce the expression of Death Receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism of DR5 up-regulation has not been elucidated. In this study, we report that CHOP is a regulator of DR5 induction by proteasome inhibitor MG132. First, we show that the combination of MG132 and TRAIL effectively induced apoptosis even in hormone refractory prostate cancer DU145 cells. DU145 cells have a mutation of tumor suppressor p53 gene. Therefore our result suggests that the combination of MG132 and TRAIL is efficacious in malignant tumors carrying p53 mutation. MG132 induced DR5 expression at a protein and mRNA level in DU145 cells, indicating that the induction was also independent of p53. Furthermore, MG132 increased DR5 promoter activity. Using a series of deletion-mutant plasmids containing DR5 promoters of various sizes, we found that MG132 stimulated the promoter activity through the region of - 289 to - 253. This region contained a CHOP-binding site. Site-directed mutation of the site abrogated the promoter activity enhanced by MG132. An electrophoretic mobility shift assay demonstrated that CHOP directly bound to the MG132-responsive site on the DR5 promoter. Expression of the CHOP protein was increased with MG132 along with DR5 up-regulation. In addition, MG132 also increased CHOP mRNA and promoter activity. Furthermore, CHOP siRNA attenuated the DR5 up-regulation due to MG132. These results indicate that the proteasome inhibitor MG132 induces DR5 expression through CHOP up-regulation.
Radical cystectomy and continent diversion in patients with non organ-confined bladder cancer
Authors: K. Czeloth, P. De Geeter, H. Loehmer, N. Jost, P. Albers
Journal: Journal of Clinical Oncology (2008)

16072 Background: The aim of this study was to analyse the oncological and functional outcome of patients with non organ- confined bladder cancer undergoing cystectomy and to evaluate if this subgroup benefits from a continent urinary diversion. Methods: From 07/2003 to 06/2007, 197 patients underwent a radical cystectomy and urinary diversion for bladder cancer at our institution. 106 (53.8%) had a non organ-confined tumor (>pT3b and/or N+ and/or M+) and were consecutively analysed including QLQ-30 questionnaire. Results: With a median age of 68 years (35–89) 24% and 17% were older than 74 and 80 years, respectively. 60% of patients presented with local cancer-related symptoms. Preoperative weighted Charlson comorbidity index was 2–4, 5–7, 8–10 in 65%, 24%, and 10%, respectively. Charlson 10-year-survival-probability was 0–20%, 21–50% and >50% in 63%, 16%, and 22%, respectively. The mean follow-up currently is 11.5 months (0.5 to 46) and the actual overall survival time is 9.9 months (1- 40). 43 % of patients progressed. The mean progression free survival (PFS) is 6.5 months (1- 24) without significant stage-specific differences (16% pT3N0M0, 12% pT4N0M0, 45% pN+M0, 9% pN0M+, 18% pN+M+). A continent diversion received 41 (38.7%) patients (32 neobladders, 7 Mainz-pouch I, 2 Mainz-pouch II). 42% of patients (pT4, pN+) underwent an adjuvant chemotherapy, 25 with continent, 19 with incontinent urinary diversion. Overall, 9 patients (20%) had to discontinue chemotherapy because of major complications (CTCAE III/IV). 13 patients (12%) experienced a local tumor progression, 4 of these with a neobladder. 6 patients had temporarily a non-functional neobladder. The postoperative mean global health status of the QLQ-C30 questionnaire was 50% and 70,8% in patients with incontinent and continent diversions, respectively (not significant). Conclusions: Despite the limited time to tumor progression, patients with non organ-confined bladder cancer benefit from radical cystectomy due to a reduced local progression rate. Likewise, patients with locally advanced bladder cancer should be offered a continent urinary diversion if feasable. Adjuvant treatment options are not influenced by the choice of diversion. Improved preoperative staging and geriatric assessment is warranted. No significant financial relationships to disclose.
Midline Granuloma
Authors: GERALD S. SPEAR
Journal: Annals of Internal Medicine (1976)

Comments and Correction1 August 1976Midline GranulomaGERALD S. SPEAR, M.D.GERALD S. SPEAR, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-85-2-261_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: Fauci, Johnson, and Wolff state that patients with midline granuloma have no "systemic manifestations or involvement of other organ systems" (1). They say nearly the same in their recent paper, wherein also, in listing clinicopathologic criteria that distinguish midline granuloma from Wegener's granulomatosis, they do not mention that the cellular infiltrate in these two disorders may differ (2).That visceral lesions may be present in midline granuloma was emphasized in a case report in 1956, in which three previous histologically similar cases were also reviewed in detail (3). Skin involvement was particularly noteworthy. The differences in the...References1. FAUCIJOHNSONWOLFF ARS: Midline granuloma or Wegener's granulomatosis. Ann Intern Med 84:609-610, 1976 LinkGoogle Scholar2. FAUCIJOHNSONWOLFF ARS: Radiation therapy of midline granuloma. Ann Intern Med 84:140-147, 1976 LinkGoogle Scholar3. SPEARWALKER GW: Lethal midline granuloma (granuloma gangraenescens) at autopsy. Bull Johns Hopkins Hosp 99:313-332, 1956 MedlineGoogle Scholar1. FAUCIJOHNSONWOLFF ARS: Radiation therapy of midline granuloma. Ann Intern Med 84:140-147, 1976 LinkGoogle Scholar2. SPEARWALKER GW: Lethal midline granuloma (granuloma gangraenescens) at autopsy. Bull Johns Hopkins Hosp 99:313-332, 1956 MedlineGoogle Scholar3. FECHNERLAMPPIN RD: Midline malignant reticulosis. A clinicopathologic entity. Arch Otolaryngol 95:467-476, 1972 CrossrefMedlineGoogle Scholar4. SCOTTROBB-SMITH RA: Histiocytic medullary reticulosis. Lancet 2:194-198, 1939 Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 August 1976Volume 85, Issue 2Page: 261-262KeywordsGranulomasLesionsWegener granulomatosis ePublished: 1 December 2008 Issue Published: 1 August 1976 PDF downloadLoading ...
STUDIES ON VIRULENCE
Authors: Lloyd D. Felton, Katharine M. Dougherty
Journal: The Journal of Experimental Medicine (1924)

1. An automatic apparatus is described by which a new supply of food can be furnished actively growing organisms at any desired interval of time-an automatic transferring device. 2. A single strain of pneumococcus, Type I, Neufeld, which had become avirulent for mice, acquired virulence of maximal degree when grown in the described apparatus with skimmed milk sterilized in an Arnold sterilizer as the medium. Transfers were made at intervals of 2, 4, and 8 hours. It is difficult to determine the best interval of transfer, but the 8 hour interval apparently is most suitable, with the 4 and 2 hour following in preference in the order named. 3. Pasteurized skimmed milk from a single dairy, but obtained on different days, when used as medium at a 2 hour interval, varied in effect on the virulence of pneumococci, the results showing that the virulence might be either increased, decreased, or maintained. 4. Skimmed milk heated for varying lengths of time, 30 minutes at 17 pounds pressure, or 60 or 90 minutes at the same pressure, lost its suitability for maintaining virulence of a pneumococcus when transferred every 2 hours, the effect being in direct proportion to the length of time the milk was heated. 5. The H ion concentration of milk had slight effect on virulence. A virulent strain of pneumococcus was grown in milk adjusted to pH = 5, 6, 7, 8, and 9, transfers being made every 2 hours. Virulence was maintained to a like degree on milk titrated to pH = 5, 6, and 7, but when the organism was grown in milk of pH = 8 and 9, virulence decreased, more rapidly at pH = 9 than at pH = 8. 6. A pure line practically avirulent strain of pneumococcus picked by the Barber method, when grown in milk at a 4 hour interval of transfer, increased in virulence 10 million fold; that is to say, until one diplococcus would kill a mouse. Prior to this study, no record has been found in which the virulence of any microorganism has been increased to such a degree by an in vitro method.
Targeting p300 Addiction in<i>CBP</i>-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation of<i>MYC</i>Expression
Authors: Hideaki Ogiwara, Mariko Sasaki, Takafumi Mitachi, Takahiro Oike, Saito Higuchi, Yuichi Tominaga, Takashi Kohno
Journal: Cancer Discovery (2015)

Loss-of-function mutations in the CBP/CREBBP gene, which encodes a histone acetyltransferase (HAT), are present in a variety of human tumors, including lung, bladder, gastric, and hematopoietic cancers. Consequently, development of a molecular targeting method capable of specifically killing CBP-deficient cancer cells would greatly improve cancer therapy. Functional screening of synthetic-lethal genes in CBP-deficient cancers identified the CBP paralog p300/EP300 Ablation of p300 in CBP-knockout and CBP-deficient cancer cells induced G1-S cell-cycle arrest, followed by apoptosis. Genome-wide gene expression analysis revealed that MYC is a major factor responsible for the synthetic lethality. Indeed, p300 ablation in CBP-deficient cells caused downregulation of MYC expression via reduction of histone acetylation in its promoter, and this lethality was rescued by exogenous MYC expression. The p300-HAT inhibitor C646 specifically suppressed the growth of CBP-deficient lung and hematopoietic cancer cells in vitro and in vivo; thus p300 is a promising therapeutic target for treatment of CBP-deficient cancers.Targeting synthetic-lethal partners of genes mutated in cancer holds great promise for treating patients without activating driver gene alterations. Here, we propose a "synthetic lethal-based therapeutic strategy" for CBP-deficient cancers by inhibition of the p300 HAT activity. Patients with CBP-deficient cancers could benefit from therapy using p300-HAT inhibitors.
Consolidation Chemotherapy After Concurrent Chemoradiotherapy in Patients With Stage III Non–Small-Cell Lung Cancer
Authors: Young Hak Kim, Michiaki Mishima
Journal: Journal of Clinical Oncology (2016)

TO THE EDITOR: Ahn et al conducted a randomized phase III study to investigate the efficacy of consolidation chemotherapy with docetaxel and cisplatin after concurrent chemoradiotherapy (CCRT) with the same regimen in patients who had stage III non–small-cell lung cancer (NSCLC) and concluded that CCRTalone should remain the standard of care. However, in the study, patients were randomly assigned not after the completion of CCRT but before its initiation, and almost one third of the patients in the consolidation arm did not receive any consolidation chemotherapy. In addition, that 10% of the patients in the consolidation arm died during the CCRT phase suggests that CCRT with docetaxel and cisplatin may be too toxic. The reasons for early death in the consolidation arm should be elucidated, and the number of early deaths, if any, in the observation arm also should be disclosed. Regardless, this study did not answer the critical question: “My patient completed CCRT and is still in good health. As such, should I offer consolidation chemotherapy to this patient?” To answer this question, Tsujino et al recently conducted a pooled analysis and concluded that consolidation chemotherapy after CCRT did not have any survival advantages; however, as Curran clearly stated in the editorial of the same issue, the analysis included radiosensitizing regimens of low-dose weekly carboplatin-based chemotherapy as well as the full-dose cisplatin-based chemotherapy regimens. Prospectively, consolidation docetaxel or gefitinib has failed to show a survival benefit after full-dose cisplatin-etoposide chemotherapy. Although such a prospective study has never been conducted in patients who received radiosensitizing regimens, consolidation chemotherapy has been traditionally included in these regimens to compensate for the lack of systemic anticancer drug exposure. It is only to be applied after CCRTwith radiosensitizing regimens, but consolidation chemotherapy still has a role. Currently, we have many chemotherapy options to combine with thoracic radiotherapy; however, it is clear that traditional cytotoxic chemoradiotherapy has reached a plateau and that we need additional treatment strategies. In the near future, studies about chemoradiotherapy in combinationwith molecularly targeted agents or immunotherapy, such as immune checkpoint inhibitors, will be encouraging.
Abstract 16191: Incidence, Characteristics and Outcome of Sudden Cardiac Death During Sports in Women
Authors: Eloi Marijon, Wulfran Bougouin, David Celermajer, Marie-Cecile Perier, Nicole Karam, Muriel Tafflet, Nordine Benameur, Natalia Machado de Deus, Lionel Lamhaut, Jean Yves Le Heuzey, Florence Dumas, Hazrije Mustafic, Michel Desnos, Christian Spaulding, Alain Cariou, Jean Philippe Empana, Xavier Jouven
Journal: Circulation (2013)

Background: No specific data are available on sudden cardiac death (SCD) during sport activities among women in the general population. Hypothesis: There are significant differences in SCD during s...
BMA disagrees that 15 of 16 junior contract issues are resolved
Authors: Abi Rimmer
Journal: BMJ (2016)

The BMA has reiterated that it does not agree with the government’s statement that 15 of the 16 issues around the junior doctors’ contract have been resolved.

The Department of Health and NHS Employers have both stated that 15 of the 16 issues that it had agreed to discuss with the BMA, after conciliatory talks, had been resolved.1 2 However, a spokeswoman for the BMA said that the statement was disingenuous. “We simply do not recognise that figure—it is a misrepresentation of the talks,” she said.

The …
Quantitative measurement of soluble E-cadherin in sera of breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy and its predictive and prognostic value
Authors: G. Hofmann, N. Dandachi, M. Balic, W. Schippinger, K.-D. Wernecke, H. Samonigg, T. Bauernhofer
Journal: Journal of Clinical Oncology (2005)

768 Background: To date, no reliable predictive markers are available to assess response to or prognosis after neoadjuvant chemotherapy (NCT) in patients with breast cancer. It was demonstrated recently that different levels of soluble E-cadherin (sE-cadherin), a product of proteolytic cleavage of cell surface E-cadherin, were associated with metastatic disease and poor prognosis in various tumor types. Therefore, it was assumed that serum sE-cadherin levels measured before and after NCT and their changes may be correlated with relevant clinical variables, prognosis and response to NCT. Methods: In a retrospective analysis, sE-cadherin levels were measured in sera of 133 female patients with histologically proven breast cancer before and after NCT by using a commercially available quantitative sandwich enzyme immunoassay technique. All of the patients received median 4 (range 1–6) cycles of anthracyline-based chemotherapy. The median patient age was 50 (range 21–71) years. Tumor size was measured clinically in one dimension and translated into the TNM-system before start and before each further cycle of chemotherapy. In univariate and multivariate analyses using a commercially available statistic program, the relations of levels of sE-cadherin with clinical and pathological parameters as well as response and disease-free interval were calculated. Results: The sE-cadherin level before NCT (median 4148,4 ng/ml) showed a positive correlation with the pretherapeutic tumor size (p=0,008). The sE-cadherin level after NCT (median 3635,7 ng/ml) showed a positive correlation with the posttherapeutic tumor-size (p=0,001) and clinical response to NCT (p=0,006). Higher levels of sE-cadherin after NCT were significantly associated (p=0,007) with shorter disease-free interval as well. A borderline significant correlation (p=0,05) was observed between sE-cadherin levels before start of NCT and clinical response to NCT in the multivariate analysis. Conclusion: These findings warrant the evaluation of sE-cadherin as a predictive and prognostic marker for patients with breast cancer and NCT in a prospective trial. No significant financial relationships to disclose.
Expression of double-strand RNA activated protein kinase (PKR) and its prognostic significance in lymph node negative rectal cancer
Authors: H.-J. Kim, H.-C. Kwon, S. Y. Oh, S.-H. Kim, K. J. Park, J.-S. Kim, H. J. Choi, M. S. Roh, H. S. Lee, T. H. Hwang
Journal: Journal of Clinical Oncology (2005)

3545 Background: The interferon induced, dsRNA-activated, protein kinase (PKR) is a key regulator of translational initiation, and plays an important role in the regulation of cell proliferation, apoptosis, and transformation. The aim of this study was to evaluate the prognostic significance of PKR in rectal cancer. Methods: Forty-three patients with stage II rectal carcinoma who underwent potentially curative resection followed by postoperative adjuvant chemoradiation, and 5-fluorouracil based chemotherapy were investigated immunohistochemically using the monoclonal antibody TJ4C4. Overall scores for PKR expression were calculated based on staining intensity and immunoreactive tumor cell fraction. Clinical information, including tumor grade, carcinoembryonic antigen (CEA), disease-free survival (DFS), and overall survival (OS) was evaluated and compared with the degree of PKR expression. Results: The median follow-up duration was 53.2 months, and median patient age was 55 years (range 33–73). The mean PKR expression score was 6.7 ± 3.5. No relationships were found between the PKR score and age, sex, tumor grade, or CEA level, however smaller tumors (≤ 5cm) were associated with high PKR score (P = 0.025). When patients were subdivided into 2 groups based on the mean PKR expression score, the relapse rate was lower for those with a high PKR score (7.4% vs. 43.8%, P = 0.008), and a significant difference was found between these two groups in terms of 5-year DFS (92.6% vs. 55.6%, P = 0.0072), and 5-year OS (92.6% vs. 55.6%, P = 0.0459). Other clinicopathologic variables were not related to clinical outcome. Conclusions: PKR expression levels were associated with disease recurrence, DFS, and OS in lymph node negative rectal cancer patients. No significant financial relationships to disclose.
Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup
Authors: William Bruno, Lorenza Pastorino, Paola Ghiorzo, Virginia Andreotti, Claudia Martinuzzi, Chiara Menin, Lisa Elefanti, Camilla Stagni, Antonella Vecchiato, Monica Rodolfo, Andrea Maurichi, Siranoush Manoukian, Vincenzo De Giorgi, Imma Savarese, Francesca Gensini, Lorenzo Borgognoni, Alessandro Testori, Giuseppe Spadola, Mario Mandalà, Gianlorenzo Imberti, Paola Savoia, Chiara Astrua, Anna Maria Ronco, Alessandra Farnetti, Maria Grazia Tibiletti, Maurizio Lombardo, Giuseppe Palmieri, Fabrizio Ayala, Paolo Ascierto, Giovanni Ghigliotti, Marisa Muggianu, Francesco Spagnolo, Virginia Picasso, Enrica Teresa Tanda, Paola Queirolo, Giovanna Bianchi-Scarrà
Journal: Journal of the American Academy of Dermatology (2016)
Cardiovascular risks associated with clarithromycin
Authors: Geetha Iyer, G Caleb Alexander
Journal: BMJ (2016)

A growing literature suggests these risks are not negligible

Concerns about the cardiovascular risks of macrolide antibiotics surfaced in the 1980s, with case reports and clinical studies describing arrhythmias and QT prolongation with erythromycin.1 2 These concerns subsequently extended to azithromycin3 and clarithromycin,4 two other members of the macrolide class. For example, a large cohort study using Danish healthcare data showed, on average, a 76% higher risk of cardiovascular mortality with current use of clarithromycin compared with penicillin V among middle aged patients, translating into an adjusted absolute risk difference of 37 cardiac deaths per million courses.4 The authors acknowledged concerns about confounding by indication and residual confounding. However, in a randomised controlled trial without such problems, a two week course of clarithromycin increased the risk of cardiovascular death for three years, compared with placebo, among patients with stable coronary artery disease.5

The study by Wong and colleagues in this issue6 further characterises …
Circulating HIV-Specific Interleukin-21+CD4+ T Cells Represent Peripheral Tfh Cells with Antigen-Dependent Helper Functions
Authors: Bruce T. Schultz, Jeffrey E. Teigler, Franco Pissani, Alexander F. Oster, Gregory Kranias, Galit Alter, Mary Marovich, Michael A. Eller, Ulf Dittmer, Merlin L. Robb, Jerome H. Kim, Nelson L. Michael, Diane Bolton, Hendrik Streeck
Journal: Immunity (2016)
Ovarian cancer staging: time for a closer look?
Authors: D R Spriggs, S Makhija
Journal: Journal of Clinical Oncology (1998)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1998.16.8.2577 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 9704705 Ovarian cancer staging: time for a closer look? D R SpriggsxD R SpriggsSearch for articles by this author , S MakhijaxS MakhijaSearch for articles by this author https://doi.org/10.1200/JCO.1998.16.8.2577 PDF "Ovarian cancer staging: time for a closer look?." Journal of Clinical Oncology, 16(8), pp. 2577–2578© 1998 by American Society of Clinical Oncology
Elevated Neutrophil: Lymphocyte Ratio Does Not Predict Survival In Multiple Myeloma Patients
Authors: Jean Paul Atallah, Basem Azab, Abhirami Vivekanandarajah, Ali Naboush, Houssein Abdul Sater, Mohammad Farhan, Nileshkumar J Patel, Myriam Elkosseifi, Elias Fares, Christine Boumitri, Vera Zaraket, Marc Saad, Samer Hassan, Marcel Odaimi, Terenig Terjanian
Journal: Blood (2013)