tbuckley/cabot-search huggingface dataset:
Prediction of reclassification at repeat biopsy with [-2]proPSA during active surveillance for low-risk prostate cancer: Prospective longitudinal analysis of a Japanese multicenter study cohort.
Authors: Mikio Sugimoto, Hiromi Hirama, Kazuto Ito, Taizo Shiraishi, Yoshiyuki Kakehi
Journal: Journal of Clinical Oncology (2013)

e16054 Background: Biomarkers that predict aggressiveness and tumor burden of prostate cancer are needed for patients who undergo AS. One of such candidates is [-2]proPSA. It has been reported that expression of [-2]proPSA is specific to prostate cancer and associated with grade and stage. The aim of this research is to evaluate the predictive ability of [-2]proPSA and its related parameters for the biopsy reclassification during AS. Methods: 13 institutions participated in the multi-center Japanese AS study (a prospective one-arm cohort study). 134 patients were enrolled in this study between January 2002 and December 2003. Inclusion criteria are as follows; (1) stage T1cN0M0, (2) age from 50 to 80, (3) serum PSA = 20 ng/ ml or less, (4) one or two positive cores per 6 to 12 systematic biopsy cores, (5) Gleason score = 6 or less and (6) maximum cancer involvement in positive core = 50% or less. We prospectively collected blood samples from patients who opted AS as an initial treatment. The serum samples were stocked frozen until testing. The patients who remained on AS for 1-year were recommended to undergo repeat biopsy. Reclassification was judged by a central pathologist who was also involved in the initial diagnosis at inclusion. Results: 67 patients underwent repeat biopsy at 1-year after AS. Biopsy reclassification was histopathologically found in 25 of 67 patients (37.3%). Table shows the patients’ backgrounds and the cutoff values of predictive variables at 90% and 80% sensitivity and specificity. p2PSA, %p2PSA and phi; (p2PSA/fPSA) × √(tPSA) levels at baseline and p2PSA and phi at 1-year after AS were significantly higher in the reclassification group than those in the non-reclassification group. At 90% sensitivity, the cutoff values of p2PSA, %p2PSA and phi at baseline were 12.52, 1.51 and 37.91 with a specificity of 23.81%, 26.19% and 26.19%, respectively. In both 90% and 80% sensitivity, p2PSA and its related parameters have higher specificity than PSA and its related parameters. Conclusions: [-2]proPSA and its related parameters could predict pathological reclassification in repeat biopsy during AS.
Update on Genetic Testing in Gynecologic Cancer
Authors: Susan M. Domchek, Mark E. Robson
Journal: Journal of Clinical Oncology (2019)

Article Tools REVIEW ARTICLES Gynecologic Cancer Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.19.00363 Journal of Clinical Oncology - published online before print August 12, 2019 PMID: 31403865 Update on Genetic Testing in Gynecologic Cancer Susan M. Domchek, MD1xSusan M. DomchekSearch for articles by this author and Mark E. Robson, MD2xMark E. RobsonSearch for articles by this author Show More 1University of Pennsylvania, Philadelphia, PA2Memorial Sloan Kettering Cancer Center, New York, NY https://doi.org/10.1200/JCO.19.00363 First Page Full Text PDF Figures and Tables © 2019 by American Society of Clinical Oncology
The prognostic value of P53 in the nodal metastization of gastric cancer.
Authors: Luisa Quaresma, Antonio CALDEIRA Fradique, Fernanda Cabrita, Alexandra Pupo, Guedes DA Silva, Gualdino Silva, Jorge Esteves, Mateus Marques, Mario Oliveira, Filomena Pina, Ligia Bruno Da Costa
Journal: Journal of Clinical Oncology (2012)

e14673 Background: Lymph node Metastases play a major role as an independent prognostic factor in gastric cancer. Presence of distal lymph node metastases assumes a pejorative prognostic significance, and represents a problem in terms of therapeutic approach. For this reason it’s of major interest to find predictive markers of distal lymph node chain involvement. The P53 tumor suppressor gene, a product of the TP53 gene works normally as a brake on DNA replication, as suppressor of angiogenesis and triggering of apoptosis. The gene most frequently mutated in gastric cancer is the TP53, that is responsible for the production of P53 mutant protein, which forms inactive complex with the native protein, and manifest by the overexpression of p53 in immunocytochemistry. The overexpression of P53 gene has been considered a bad prognostic factor associated mainly with lymph node metastases. Methods: This study seeks to determine the relation between the expression of P53 and the presence of distal lymph node metastases as an indicator for an extended lymphadenectomy. A total of 50 patients undergoing surgery with D2 lymphadenectomy for gastric carcinoma with curative intent were enrolled in this work. Therefore it was evaluated in 1,786 lymph nodes the correlation between the P53 expression with tumor location, size, histological type, depth , number of nodes involved, number of distal lymph node metastases and the TNM stage. Results: In all parameters, mutant P53 protein related with indicators of poor prognosis. In particular has demonstrated a statistical significant correlation (p=0.019) with the presence of distal lymph node metastases. The main objective of this study which was finding a prognostic predictor of distal nodal metastases has been reached. Conclusions: Mutant P53 protein is a good prognostic indicator, for the presence of distal lymph node involvement in gastric carcinoma.
Comparative Proteomics and Functional Analysis of Red Blood Cell Membrane Proteins in the Rare in(Lu) Blood Type
Authors: Slim Azouzi, Mahmoud Mikdar, Sara El Hoss, Alexandra Willemetz, Emilie-fleur Gautier, Patrick Mayeux, Wassim El Nemer, Yves Colin, Caroline Le Van Kim, Thierry Peyrard
Journal: Blood (2017)
Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors
Authors: M. D. Galsky, D. D. Von Hoff, M. Neubauer, T. Anderson, M. Fleming, R. W. Sweetman, J. Mahoney, D. Midwinter, L. Vocila, T. Z. Zaks
Journal: Journal of Clinical Oncology (2009)

3541 Background: The current paradigm of histology-specific drug development may not be optimal in the era of targeted therapeutics. We sought to explore the activity of lapatinib, an oral tyrosine kinase inhibitor of HER2, with a trial design focused on the target rather than on tumor-type. Methods: Patients (pts) with HER2-amplified treatment-refractory metastatic gastro- esophageal (G/E), bladder (B), ovarian (O), or uterine (U) tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1500 mg PO daily (malignancies selected based on reported frequencies of HER2 amplification). The planned sample size was 250 HER2+ pts, with the goal of then randomizing 100 pts with SD at week (wk) 12 to either lapatinib or placebo until progressive disease (PD). Pts who responded at wk 12 (CR or PR) continued on lapatinib; those who progressed were discontinued from study. Primary objectives were response rate at 12 wks and percentage of pts who remain progression free at 24 wks. Secondary objectives were duration of response, progression free survival (PFS) after randomization, and determination of the incidence of HER2 amplification in multiple tumor types. Futility analyses were preplanned to ensure feasibility of screening and of randomization (i.e. a sufficient rate of non- progression at 12 wks). Results: A total of 145 pts were screened (G/E=47, B=35, O=58, U=5); 42 were HER2-amplified (G/E=16, B=13, O=13, U=0) and 32 (G/E=13, B=9, O=10) were enrolled. At wk 12, 1 (3%) patient had a CR, 10 (31%) had SD, 19 (59%) had PD, and 2 (6%) were unknown. Median time to progression during open-label lapatinib was 78 days, 95% CI (42, 92). Only 7 pts with SD underwent randomization. Two pts with esophageal cancer remain on study; one (CR at wk 12) remains a CR at wk 60 and the other (SD at wk 12) remains with SD at wk 36. Low response rate coupled with slow screening and enrollment led to early study closure. Conclusions: Basing trial eligibility on a target, versus histologic classification, is challenging. While HER2 amplifications appear to be prevalent in select non-breast tumors, lapatinib monotherapy in refractory disease is associated with a low level of objective responses. [Table: see text]
Small interfering RNA targeting survivin sensitizes lung cancer cell with mutant p53 to ionizing radiation
Authors: Masato Ikeda, Kenji Tamura, Kimio Yonesaka, Taroh Satoh, Takayasu Kurata, Toshiji Nogami, Kazuhiko Nakagawa, Masahiro Fukuoka
Journal: Cancer Research (2005)

3322  Survivin, a novel member of inhibitor of apoptosis (IAP) protein family, is aberrantly expressed in cancer but undetectable in normal tissue. Survivin expression predicts poor prognosis and shorter survival in human cancers, including lung, colon, pancreas, prostate and breast. Survivin gene expression is downregulated in G1 and upregulated in G2/M phase in a cell cycle-dependent manner. p53 is one of the tumor suppressor genes, frequently mutates in cancer tissues. p53 induction and check points control in response to DNA damage induce apoptosis and correlates with drug sensitivity. Generally, cancer tissues/cells with mutated p53 have a tendency to be resistant to anti-cancer drug. We have previously reported that wild type p53 downregulates survivin expression in lung cancer cell lines. We have also reported that survivin inhibition by siRNA induces apoptosis and increases sensitivity to adriamycin (Yonesaka et al. Abstr. No. 2933, 95th Annual Meeting of the American Association for Cancer Research, March, 2004, Orlando, Florida.). To investigate the possible regulation of survivin in response to ionizing radiation, we examined the survivin expression level in lung cancer cell line after the treatment of ionizing radiation. After irradiation, protein level of survivin in A549 with wild type p53, decreased following p53 inductions, although no reduction of survivin was observed in PC9 with mutated p53. To evaluate differences of sensitivity to ionizing radiation in cancer cells by inhibition of survivin, we have inhibited survivin by siRNA in PC9, which has mutated p53. After 48h siRNA administration to PC9, which has significantly inhibited the survivin expression, we replaced the medium and added to 30J/m2 of ionizing radiation. Additional 24h incubation after the ionizing radiation, the cell proliferation was significant repressed in the cell treated by siRNA targeting survivin, in comparison with in the cell treated by anti-scramble. We have also observed the several protein levels, which are upstream and downstream of survivin, including ATM, p53, Cdc25C, Cdc2, and caspase3 in order to clarify the possible cascade in response to ionizing radiation. These results suggested that survivin is downregulated by p53, and the siRNA targeting survivin increase sensitivity to ionizing radiation. The siRNA targeting survivin could be potential approach to increase sensitivity to radiation especially in lung cancer cells with mutated p53.
Implication of bax in apoptosis depends on microtubules network mobility
Authors: Michel Longuet, Raphael Serduc, Catherine M. Riva-Lavieille
Journal: Cancer Research (2004)

575  Paclitaxel and vincristine sulfate, two anti-microtubules agents are known to induce apoptosis. In this study, we tried to apprehend the relationship between the regulation of apoptotic proteins such as the Bcl2-family proteins and the cytoskeleton structure during apoptosis induction by these two drugs. Paclitaxel and vincristine sulfate were used for a 24 hr incubation and resulted in EC50s of 1μM and 1μg/ml, respectively. Under these conditions, paclitaxel treatment induced microtubules network polymerization, condensation of chromatin, characteristic features of early and late apoptosis as confirmed by orange acridine and ethydium bromide double staining. However, the shape of cells was not modified, while mitochondria changed their conformation from filamentous to aggregated corpuscles located around the nucleus. In addition, pro-apoptotic Bax protein remained in the cytoplasm, the β-tubulin polymerization induced phosphorylation and inactivation of anti-apoptotic Bcl-2 and/or BclX- proteins leading to intense mitochondria swelling and membrane disruption that are responsible for observed cytochrome c release and apoptotic proceeding. On the contrary, after vincristine sulfate treatment we observed morphological modifications such as cell shrinkage and nucleus condensation as the result of β-tubulin depolarization and disruption of microtubules. Bax protein was intensively translocated into mitochondria membrane, decreasing the proportion of Bax/Bcl-2 or Bax/ BclX-L heterodimers allowing the release cytochrome c from the mitochondria and apoptotic process. In conclusion, we demonstrated that the two anti-microtubule agents (paclitaxel and vincristine sulfate) induced apoptosis by two different pathways. However, mitochondrial dysfunction followed by cytochrome c release are the crucial events whatever the apoptotic signal, polymerization or disruption of β-tubulin.
Identification of GOUTC (a novel gene overexpressed in urinary tract carcinomas, DNA59712) that promotes proliferation, invasion and anchorage-independent growth of bladder cancer cells
Authors: Bu-Er Wang, Zemin Zhang, Hartmut Koeppen, Thomas Wu, Wei-Qiang Gao
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

3252 

Bladder cancer is the 4th and 8th most common cancer in men and women in the United sates, respectively. In an effort to identify genes upregulated in bladder tumors relative to normal bladder tissue, we have looked at Genelogic and GEPIS databases. Here we report a novel gene, named GOUTC, which is upregulated in urinary tract carcinomas and in bladder transitional cell carcinomas based on Genelogic database. The expression pattern of this gene is confirmed by real-time RT-PCR in clinical bladder tumor samples and bladder tumor cell lines. Overexpression of GOUTC in bladder cancer cell lines that express low level of GOUTC and grow relatively slowly, enhanced cell proliferation as evidenced by tritiated thymidine incorporation assay. The growth-promoting effects were not only seen in transient expressing cells, but also in stable transfectant cells. Furthermore, the cells stably expressing GOUTC promote anchorage-independent growth in soft agar assay. The stable cells formed not only more colonies but also larger colonies than the control cells. Using V5-tag, we found that the protein of GOUTC is in cytoplasm. Therefore, the GOUTC that we identified may represent a novel oncogenic molecule that promotes proliferation and anchorage-independent growth of bladder tumor cells or tumor progression.
Doctors should treat impetigo with antiseptics not antibiotics, says NICE
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Clinicians should treat non-bullous impetigo—a highly contagious bacterial infection of the skin—with a topical antiseptic rather than antibiotics, says new draft guidance from the National Institute for Health and Care Excellence (NICE).1

The recommendation follows a review by NICE and Public Health England (PHE) which found that a topical antiseptic, such as hydrogen peroxide 1% cream, …
CT Perfusion Versus Coronary CT Angiography in Patients With Suspected In-Stent Restenosis or CAD Progression
Authors: Daniele Andreini, Saima Mushtaq, Gianluca Pontone, Edoardo Conte, Carlos Collet, Jeroen Sonck, Andrea D’Errico, Luca Di Odoardo, Marco Guglielmo, Andrea Baggiano, Daniela Trabattoni, Paolo Ravagnani, Piero Montorsi, Giovanni Teruzzi, Paolo Olivares, Franco Fabbiocchi, Stefano De Martini, Giuseppe Calligaris, Andrea Annoni, Maria Elisabetta Mancini, Alberto Formenti, Marco Magatelli, Elisa Consiglio, Giuseppe Muscogiuri, Federico Lombardi, Cesare Fiorentini, Antonio L. Bartorelli, Mauro Pepi
Journal: JACC. Cardiovascular imaging (2019)
Characterization of novel germ line p53 mutations associated with pediatric adrenocortical cancer
Authors: Claudia B. Eichler-Jonsson, Josh Greenberg, David Malkin
Journal: Cancer Research (2004)

2525  Adrenocortical carcinoma (ACC) is a rare form of childhood cancer often associated with the Li-Fraumeni and Beckwith-Wiedemann syndromes. Our laboratory is interested in studying the functional properties of distinct ACC-associated p53 alterations. Five unique p53 point mutations (152L, 219S, 235D, 275ter, 337H) present in adrenocortical tumors were identified and, by means of site-directed mutagenesis, p53 sequences harboring these mutations were generated and have been analyzed in order to understand their biological properties and impact in adrenocortical cell transformation. Here we demonstrate that, with the exception of mutant p53-337H, whose activity seems to be pH-sensitive, each amino acid substitution conferred complete loss of wild-type function as shown by impaired transcriptional activity towards a p53-responsive promoter and absence of growth suppression when these p53 mutant sequences were ectopically expressed in two distinct cell lines. Moreover, three (152L, 219S, 235D) were able to act in a dominant-negative fashion abrogating p53-dependent transcriptional activity when co-transfected with wild-type p53. Currently we are exploring whether synthetic molecules including PRIMA-1, geldanamycin and others that stabilize the p53 core domain can rescue wild-type p53 function in adrenocortical cell lines. We hypothesize that the binding of chaperone molecules to these mutant proteins might be affected by these agents and understanding the mechanism by which these compounds can rescue p53 functionality may establish them as novel anticancer agents for these highly chemo-resistant tumors.
Why has positive inotropy failed in chronic heart failure? Lessons from prior inotrope trials
Authors: Tariq Ahmad, P. Elliott Miller, Megan McCullough, Nihar R. Desai, Ralph Riello, Mitchell Psotka, Michael Böhm, Larry A. Allen, John R. Teerlink, Giuseppe M.C. Rosano, Joann Lindenfeld
Journal: European Journal of Heart Failure (2019)

Current pharmacological therapies for heart failure with reduced ejection fraction are largely either repurposed anti‐hypertensives that blunt overactivation of the neurohormonal system or diuretics that decrease congestion. However, they do not address the symptoms of heart failure that result from reductions in cardiac output and reserve. Over the last few decades, numerous attempts have been made to develop and test positive cardiac inotropes that improve cardiac haemodynamics. However, definitive clinical trials have failed to show a survival benefit. As a result, no positive inotrope is currently approved for long‐term use in heart failure. The focus of this state‐of‐the‐art review is to revisit prior clinical trials and to understand the causes for their findings. Using the learnings from those experiences, we propose a framework for future trials of such agents that maximizes their potential for success. This includes enriching the trials with patients who are most likely to derive benefit, using biomarkers and imaging in trial design and execution, evaluating efficacy based on a wider range of intermediate phenotypes, and collecting detailed data on functional status and quality of life. With a rapidly growing population of patients with advanced heart failure, the epidemiologic insignificance of heart transplantation as a therapeutic intervention, and both the cost and morbidity associated with ventricular assist devices, there is an enormous potential for positive inotropic therapies to impact the outcomes that matter most to patients.
Dose Escalation Trial of the Wee1 Inhibitor Adavosertib (AZD1775) in Combination With Gemcitabine and Radiation for Patients With Locally Advanced Pancreatic Cancer
Authors: Kyle C. Cuneo, Meredith A. Morgan, Vaibhav Sahai, Matthew J. Schipper, Leslie A. Parsels, Joshua D. Parsels, Theresa Devasia, Mahmoud Al-Hawaray, Clifford S. Cho, Hari Nathan, Jonathan Maybaum, Mark M. Zalupski, Theodore S. Lawrence
Journal: Journal of Clinical Oncology (2019)

AZD1775 (adavosertib) is an inhibitor of the Wee1 kinase. In this study, we built on our preclinical studies to evaluate the safety and efficacy of AZD1775 in combination with gemcitabine and radiation in patients with newly diagnosed locally advanced pancreatic cancer.Thirty-four patients with locally advanced pancreatic cancer were enrolled with the intention to receive four 21-day cycles of gemcitabine (1,000 mg/m2 days 1 and 8) with AZD1775 (once daily on days 1, 2, 8, and 9). Cycles 2 and 3 were administered concurrently with radiation, and cycles 5 to 8 were optional. AZD1775 was dose escalated using a time-to-event continual reassessment method on the basis of the rate of dose-limiting toxicities within the first 15 weeks of therapy. The primary objective was to determine the maximum tolerated dose of AZD1775 given in conjunction with gemcitabine and radiation. Secondary objectives were to estimate overall and progression-free survival and determine pharmacodynamic activity of AZD1775 in surrogate tissues.The recommended phase II dose of AZD1775 was 150 mg/d. Eight patients (24%) experienced a dose-limiting toxicity, most commonly anorexia, nausea, or fatigue. The median overall survival for all patients was 21.7 months (90% CI, 16.7 to 24.8 months), and the median progression-free survival was 9.4 months (90% CI, 8.0 to 9.9 months). Hair follicle biopsy samples demonstrated evidence of Wee1 inhibition with decreased phosphorylation of cyclin-dependent kinase 1 staining by immunohistochemistry after AZD1775 administration at the recommended phase II dose.AZD1775 in combination with gemcitabine and radiation therapy was well tolerated at a dose that produced target engagement in a surrogate tissue. The overall survival is substantially higher than prior results combining gemcitabine with radiation therapy and warrants additional investigation.