tbuckley/cabot-search huggingface dataset:
Abstract 4880: Disruption of STAT3 signaling promotes K-Ras induced lung tumorigenesis
Authors: Beatrice Grabner, Daniel Schramek, Kristina M. Mueller, Ralf Harun Zwick, Josef Penninger, Valeria Poli, Richard Moriggl, Maria Sibilia, Helmut Popper, Robert Eferl, Emilio Casanova
Journal: Cancer Research (2012)

Abstract Lung cancer related and unrelated to smoking is still leading cause of cancer deaths worldwide with an overall survival rate of 15%. Several genetic alterations have been associated with lung cancer: loss of tumor suppressor genes such as p53, INK4a, LKB1 and mutations/amplifications in several oncogenes like K-Ras, EGFR, or c-Myc. Most frequent smoking-related mutations impair GTP hydrolysis in K-Ras, an oncogene downstream of the EGFR pathway, causing persistent cell growth and proliferation in 20-30% of lung adenocarcinomas. Another important downstream effector of EGFR signaling is the signal transducer and activator of transcription (STAT)-3. STAT-3 regulates important pathways in tumorigenesis, through upregulation of genes encoding apoptosis inhibitors (Bcl-XL, Bcl-2, Mcl-1, survivin). In patient samples and NSCLC cell lines nuclear, phosphorylated STAT3 is enhanced and correlates with subsequent suppression of apoptosis of NSCLC tumors. However, the role of STAT-3 in lung cancer in vivo has not yet been established. In order to investigate the role of STAT-3 in lung tumors, we have established a genetic mouse model that allows inducing K-RasG12D-dependent lung tumors and simultaneously genetically ablating STAT-3. Survival analysis of this model showed a significant advantage of K-RasG12D male mice harbouring STAT-3 compared to K-RasG12D mice lacking one or both alleles of Stat-3, indicating a hapoloinsufficient tumor suppressor role in oncogenic K-RasG12D tumor formation. Furthermore, animals with deleted STAT-3 and activated K-RasG12D have a significant increase in tumor burden and develop more adenomas and adenocarcinomas than age-matched animals, harbouring only oncogenic K-RasG12D. This data suggest that disruption of STAT-3 signaling promotes tumorigenesis in K-Ras induced tumors. We are currently investigating the molecular and cellular mechanisms responsible for this observation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4880. doi:1538-7445.AM2012-4880
Response to HRH
Authors: Richard Rawlins
Journal: Journal of the Royal Society of Medicine (2013)

Prince Charles’ Editorial1 is helpful in furthering our understanding of his advocacy, but more clarification is necessary if his wise words are not to result in the antipathy which greeted his speech to the BMA in 1982, and to which he makes reference.

He tells us ‘For many years I have advocated an integrated approach to medicine and health. By integrated medicine, I mean the kind of care that integrates the best of new technology and current knowledge with ancient wisdom. More specifically, perhaps, it is an approach to care of the patient which includes mind, body and spirit and which maximizes the potential of conventional, lifestyle and complementary approaches in the process of healing.’

The Prince should be invited to clarify to which ‘ancient wisdom’ he refers. That the sun goes round the earth? That illness is due to imbalance of four humours?

There is no question clinicians should be caring and demonstrate compassion. But that does not require progressive modern medicine to ‘integrate’ in any sense with alternative medical systems. ‘Complementary approaches’ such as homeopathy, Reiki and a variety of systems to activate ‘vital forces’ as spoken of by Prince Charles are not needed to complete conventional treatments. They are alternatives to evidence-based modern medicine. The best of ancient wisdom is already incorporated into ‘medicine’. To integrate medicine with systems for which there is no plausible evidence-base would do a disservice to patients – and to tax-payers expected to foot the bill.

No doubt patients feel better after a constructive therapeutic encounter with an empathic practitioner.

As Lord Darzi has emphasized in his commentary on evidence-based medicine evidence of effectiveness of all medical practice is expected to be robust, and withstand critical scrutiny.2 That is the way forward for medicine.
Abstract 3450: Functional characterization of a DNA damage response network in glioblastoma associated with long-term patient survival
Authors: Taewon Yoon, Danielle Loughlin, Shuqian Yu, Brijal Desai, Kevin Choe, Andy J. Minn
Journal: Cancer Research (2012)

Abstract Glioblastoma multiforme (GBM) is the most aggressive primary brain cancer in humans with a median survival of less than 14 months. However, a small minority of GBM patients have a median survival of over three years. In an effort to identify genetic and epigenetic events that might explain this relative long-term survival, an integrative genomic approach was utilized. We show that in contrast to most GBM patients, relative long-term survivors have tumors that lack a biological network that responds to DNA damage. This network is comprised of pro-inflammatory genes and genes normally regulated through interferon signaling. By overlaying the network with phenotype information, key genes and gene-gene interactions that strongly associate with patient survival were identified to facilitate the discovery of important genes and genetic dependencies in the network. One such gene is Interferon-Stimulated Gene 15 (ISG15), which is part of the interferon subnetwork and encodes for an ubiquitin-like protein. Targeted disruption of ISG15 in various GBM cell lines unmasked a DNA damage response as characterized by delayed S-phase entry and G2/M accumulation, increased γH2AX, and senescence. Various genes that displayed a predicted interaction with ISG15 were tested for evidence for a biological interaction. Functional validation confirmed that these predicted interactions with ISG15 were mirrored by genetic and regulatory interactions that resulted in rescue of the effects of ISG15 knockdown. We also investigated genes that control the pro-inflammatory subnetwork. Targeted disruption of one such gene, MYD88, resulted in decreased invasion and increased sensitivity to DNA damage. In summary, we have identified a biological network that responds to and regulates DNA damage. The absence of network genes results in susceptibility to DNA damage, senescence, and decreased invasion. GBM patients with tumors lacking the network are rare long-term survivors of an otherwise uniformly and rapidly fatal tumor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3450. doi:1538-7445.AM2012-3450
P17.19 * TO TREAT OR NOT TO TREAT: IMPACT OF AGE AND COMORBIDITIES IN GLIOBLASTOMA PATIENTS
Authors: A. R. Alitto, C. Mazzarella, S. Chiesa, B. Diletto, M. Ferro, S. Gaudino, C. Colosimo, C. Anile, G. Maira, M. Balducci
Journal: Neuro-Oncology (2014)

PURPOSE/OBJECTIVE: Age and comorbidities could influence compliance to adjuvant Radiochemotherapy. We evaluate compliance and outcomes in elderly patients (>65 years old) with Glioblastoma Multiforme (GBM) treated according to three prospective phase II trials using Temozolomide (TMZ) concurrently and sequential to radiotherapy. MATERIALS AND METHODS: Three prospective phase II trials were performed for patients with a histological diagnosis of GBM (≥ 18 yrs); radiotherapy was delivered on tumor bed +/- residual + margin of 1,5 cm (CTV1: 59.4 Gy) and tumor bed +/- residual + edema until March 2008 or + margin of 3 cm (CTV2: 45 Gy) subsequently. The timing of concurrent Temozolomide (TMZ) was different between the studies: TMZ was administrated in the first and the last week of RT until December 2003 and every five days for week successively excluding Saturday and Sunday; in the third study patients received concomitant or sequential Fractionated Stereotactic Conformal RT boost to increase dose (69.4 Gy). Adjuvant TMZ was administered to all patients: six cycles if disease was absent, or until disease progression or unbearable toxicity in the other cases. Overall co-morbidities were assessed using the Charlson Index of Co-morbidity (CCI). Toxicity was evaluated according to RTOG; survival analisys was calculated using Kaplan-Meier method. RESULTS: 72 patients were treated between October 2001 to December 2012. Median age was 69 yrs (range 65-80 yrs): 41 male and 31 female. 41 patients underwent a partial removal and 31 a complete surgery. A CC1≥ 1 was present in 41% of patients. 66 patients received a total dose of 60 Gy, while six 69.4 Gy. The compliance to the treatment was 98%. Acute toxicity was reversible in all patients. Neutropenia was observed in in 16.6% (G1-2 11,1% and G3-G4 5,5%); thrombocytopenia was reported in 30,6% (G1-2 15,3% and G3-G4 15,3%). Neurologic toxicity was present in 30,6% of the patients without difference between G1-2 and G3-4. With a median follow-up of 72 months (range 6-139 months), median progression-free-survival was 12 months. Median overall survival (OS) was 15 months, 2-yrs OS was 30%, no patient being alive at 5 years. A significant impact on OS was been represented from only complete surgery vs partial (p = 0.03) and a trend for radiation dose of 7000 vs 6000 cGy (p = 0.06). It was not observe any difference in OS after a stratification of elderly (two subsets ≥ and <70 yrs; three subsets <70, between 70 and 74, >75 yrs). In particular, at 2 years OS was: 10% for patients >75 years old, 21% for >70 and <74, 38% for < 70. CONCLUSIONS: This study suggests that radio-chemotherapy is feasible also in elderly with an improved OS for higher doses of RT. CCI ≤ 2 does not impact on compliance and outcomes. A prospective study is ongoing to confirm these findings.
PHENOTYPES OF MITRAL VALVE PROLAPSE AS A CAUSE OF SUDDEN DEATH: A CASE-CONTROL STUDY
Authors: Jerome Hourdain, Marie Annick Clavel, Jean Claude Deharo, Samuel Asirvatham, Michael Ackerman, Jean-Francois Avierinos, Maurice Sarano, CHU La Timone
Journal: Journal of the American College of Cardiology (2015)
Abstract 2161: Network-based inference of ALK oncogenic signaling in T-cell lymphoproliferative disorders
Authors: Roberto Piva, Elisa Pellegrino, Luca Agnelli, Daniela Cantarella, Cristina Ferreri, Manuela Ferracin, Giuditta Cuccuru, Claudia Voena, Paolo Provero, Massimo Negrini, Ferdinando Di Cunto, Antonino Neri, Enzo Medico, Giorgio Inghirami
Journal: Cancer Research (2010)

Abstract Anaplastic large cell lymphomas (ALCL) are a subset of T-cell Non-Hodgkin Lymphomas (T-NHL) in which the intracytoplasmic domain of the anaplastic lymphoma kinase (ALK) gene is frequently fused to nucleophosmin (NPM1). It has been previously shown that the transcription factor STAT3 is a major substrate of ALK enzymatic activity and it is strictly required for the growth and survival of ALK-transformed cells. With the aim to unravel the regulatory network underlying NPM-ALK-mediated transformation and tumor maintenance, we timely dissected the mRNA and miRNA expression signature of ALK-positive ALCL cell lines following ALK or STAT3 silencing. We observed that the majority of ALK-regulated genes were concordantly dependent on STAT3, including known and novel STAT3 target genes. Additional transcription factors (C/EBP beta, LEF1, and others) emerged as STAT3-dependent initiators and master regulators of ALK oncogenic properties in ALCL. However, STAT3 signaling was inconsistent and completely dispensable in non small cell cancer cell lines expressing EML4-ALK fusion proteins, suggesting a T-cell specific STAT3 regulatory network. Finally, we analyzed the gene expression profiling of 90 systemic peripheral T cell lymphomas, including a set of ALK positive and negative ALCL (n=36). We observed that ALK positive ALCL were significantly clustered in a separate subgroup, characterized by a relevant STAT3 signature. Using prediction analyses, we identified a set of genomic classifiers able to a clearly separate ALK positive and ALK negative ALCL from other T-NHL. In conclusion we proved that inference of ALK oncogenic transcriptional networks is a powerful tool to identify meaningful signaling molecules that regulate the transition into a pathologic cellular state. Our molecular classification suggests that ALCL may represent a unique entity discernible from other T-NHL, and that a restricted number of genes can be instrumental for clinical stratification and, possibly, to address the therapy of patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2161.
Abstract P6-04-03: Unique Recurrent Signature and Signaling Pathway of Asian Triple Negative Breast Cancer
Authors: WH Kuo, HL Chen, CK Hsiao, EY Chuang, KJ. Chang
Journal: Cancer Research (2010)

Abstract Background: Triple-negative (TN) breast cancer, a lack of understanding of the driving oncogenic mechanisms and thus therapeutic targets has left this an understudied ‘Cinderella’ in breast cancer phase III trials. No publication has been addressed on recurrent signature and pathway signaling of Asia TN breast cancer. The gene expression difference between Eastern and Western breast cancer is also unknown. Material and Methods: 185 represent breast cancer cases including 43 Luminal A, 31 Luminal B, 35 Her-2 type, 51 TN and remaining 25 unclassified were selected from our tissue bank. Using Agilent microarray chip, we explored gene expression profile of these patients. For direct western and eastern comparison, 195 Caucasian breast cancer gene expression profile using the same Agilent platform were downloaded wedsite. In TN breast cancers, excluding 3 cases with stage IV disease at diagnosis, 11 patients developed distant recurrence during follow up. For these 48 patients, recurrent model was established by two step Cox proportional hazard regression: in first step, 35 candidate recurrent genes were selected from 20173 genes with significant level less than 0.0005. Then, we randomly choose 4 genes from the 35 candidate genes to construct recurrent model to avoid overfitting. TN related signaling pathways were discovered using Ingenuity Pathway Analysis(IPA) and GSEA(Gene Set Enrichment Analysis). Results: Using non-supervised analysis, we found the eastern and western breast cancers have their own TN cancer clustering phenomenon, obviously in a different cluster. This represented the eastern and western breast cancer have fundamental differences. The model including PKRAG3, MORC2, GRB7, FAM43A showed the best recurrence prediction power in 52360 combination models(R Square 0.71). This model was cross-validated by Vector machine(SVM) with leave one out setting. The overall accuracy was 87.5%. The sensitivity and specificity were 72.7% and 91.9%. This model was failed to predict recurrence in Luminal or Her-2 Molecular type. With IPA, we found 9 TN related pathway. The top two were cAMP-mediated and Ephrin Receptor signaling. 10 pathways were found from GSEA. Nicotinate, Olfactory transduction and Axon guidance were on the top of the list. Further functional study is on going. Discussion: This is the first study to compare the gene expression between eastern and western breast cancer on the same gene expression platform. The gene expression profile is fundamentally different between eastern and western TN breast cancers. This phenomenon infers different biological behavior and drug sensitivity may exist among different ethnic groups. We established recurrent prediction model unique for Taiwanese TN breast cancer by four genes with high accuracy. We can develop commercial recurrent kit after further clinical validation. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-04-03.
Intravenous Nesiritide, a Natriuretic Peptide, in the Treatment of Decompensated Congestive Heart Failure
Authors: Wilson S. Colucci, Uri Elkayam, Darlene P. Horton, William T. Abraham, Robert C. Bourge, Allen D. Johnson, Lynne E. Wagoner, Michael M. Givertz, Chang-seng Liang, Matthew Neibaur, W. Herbert Haught, Thierry H. LeJemtel
Journal: New England Journal of Medicine (2000)

Intravenous infusion of nesiritide, a brain (B-type) natriuretic peptide, has beneficial hemodynamic effects in patients with decompensated congestive heart failure. We investigated the clinical use of nesiritide in such patients.
Seamless phase II/III trial design with survival and PRO endpoints for treatment selection: Case study of RTOG 1216.
Authors: David Ira Rosenthal, Qiang Zhang, Merrill S. Kies, Minh-Tam Truong, Richard Jordan, Paul M. Harari, Quynh-Thu Le
Journal: Journal of Clinical Oncology (2013)

TPS6099 Background: Clinical trial results from phase II trials to select an experimental treatment arm for separate phase III trial comparison can require years. Cancer clinical trials also now aim at both survival and PRO/functional outcomes, especially in head and neck (HN) studies. We developed a unique seamless phase II/III trial design to save on sample size and trial duration. The initial multi-arm phase II trial selects the most effective regimen among multiple experimental arms by first comparing each of the new treatments to a common control arm, using chosen endpoints, such as progression free survival. The winner will be tested for overall survival in the phase III study. Methods: We propose a phase II/III design to test the efficacy of experimental arms of postoperative radiation (RT) + docetaxel or RT + docetaxel + cetuximab in patients with HN squamous cancer. These are compared to the control arm of RT + cisplatin in the phase II part. Only one arm will be selected to go on to phase III depending on efficacy (PFS), PRO and safety outcomes. One experimental arm must be sufficiently better than the common control arm and the winner not having increased toxicity or functional cost to be selected for phase III inclusion. If not, the trial is halted for futility. Patients in the phase II selected arm and the control arm are included in phase III testing. Group sequential method is used to design each component. Separate interim efficacy and futility analyses are built in such that each endpoint can be monitored as in separate phase II, III trials. Once sample sizes are derived, operating characteristics for the seamless II/III design are evaluated through simulations under the null and various alternative hypotheses. Savings on sample size and time are compared to typical separate phase II and III designs and to the design testing only the arm of RT + docetaxel + cetuximab in phase II. Conclusion: The phase II/III RTOG 1216 HNC trial offers cost effectiveness, operational efficiency and scientific innovation.
Abstract 1849: Identification and functional analysis of <i>SHISA2</i> overexpressed in prostate cancer
Authors: Kenji Tamura, Mutsuo Furihata, Hirofumi Satake, Takashi Anchi, Maiko Kamei, Hideo Fukuhara, Tsutomu Shimamoto, Shingo Ashida, Takashi Karashima, Ichiro Yamasaki, Hiroshi Nishikawa, Masayuki Kamada, Masaharu Yasuda, Keiji Inoue, Taro Shuin
Journal: Cancer Research (2012)

Abstract Prostate cancer (PC) is usually androgen-dependent and responds well to androgen ablation therapy. However, at a certain stage some prostate cancers eventually acquire a castration-resistant phenotype. These cancer cells are originally high-grade and show very poor response to any anticancer therapies. To identify novel molecular cancer drug targets, we previously analyzed the gene expression profiles of high-grade PCs using a cDNA microarray combined with laser microbeam microdissection and found a number of genes that are transactivated in high-grade PC. Among them, we report the identification of a novel molecular target, SHISA2. We confirmed overexpression of SHISA2 in high-grade prostate cancer cells by semi-quantitative RT-PCR and immunohistochemical analysis. Knockdown of SHISA2 expression by siRNA in a prostate cancer cell line resulted in a drastic decrease of cell numbers. In contrast, SHISA2 overexpression in a prostate cancer cell line promoted cell proliferation. These findings suggest that SHISA2 could be involved in aggressive phenotype of prostate cancers, including castration-resistant prostate cancers, and that it should be a potential molecular target for development of new therapeutics and a diagnostic biomarker for aggressive prostate cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1849. doi:1538-7445.AM2012-1849
Improving community access for breast cancer screening.
Authors: JL Bell, KD Gray, PZ Huggler
Journal: Cancer Research (2009)

Abstract Abstract #5016 Background: The Breast Health Outreach Program (BHOP) at the University of Tennessee Medical Center's Cancer Institute began in 1996 delivery breast health education and mobile mammography to underserved areas in East Tennessee. Through grant funding, dedicated personnel and community support, the program is able to provide breast health services to 25 East Tennessee counties.&amp;#x2028; Study Design: The BHOP is designed to deliver culturally and educationally sensitive breast health education classes prior to onsite mobile mammography screening. Thirty-minute classes inform women of appropriate, best breast health practices, eliminate fears associated with mammography and encourage women to obtain annual screening. Once relationships are established, the BHOP is offered annually in churches, industrial work sites, and community centers.&amp;#x2028; &amp;#x2028; Results: Since 1996, the BHOP has educated over 13,500 women, delivered approximately 8,800 screening mammograms and diagnosed 20 cancers. As delivery processes improved, 6,851 screening mammograms were provided between 2002 and 2006 with 1,080 women receiving their first-ever mammogram. Fourteen breast cancers were diagnosed in this period. Further data analysis from this time period reveals increases in education, screenings, first-ever mammograms and diagnosed cancers.&amp;#x2028; Conclusions: Mobile mammography is becoming "standard" in rural communities of East Tennessee. Most of the women now participating in the program have had previous mammograms through the BHOP. Each year the BHOP has increased the number of women obtaining their first-ever mammogram by targeting new sites. Companies and communities are moving to support healthy living practices and providing healthier environments for employees and their families. As the BHOP has matured and become widely recognized, measures of program effectiveness have improved. Future areas for research will address longitudinal data tracking to assess mortality impact and early diagnosis trends. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5016.
Universal New York Health Care
Authors: Dan E. Beauchamp, Ronald L. Rouse
Journal: New England Journal of Medicine (1990)

Now that universal access to health care is back on the governmental agenda, elected officials are faced with the dilemma of expanding our present pluralistic system of numerous private and public payers, with its built-in administrative inefficiencies and inflationary pressures, or scrapping the present system of financing and moving to a tax-based scheme like the Canadian Medicare program, an option fraught with political difficulties.