tbuckley/cabot-search huggingface dataset:
Abstract POSTER-BIOL-1333: TRIP6 regulates p27KIP1 to promote ovarian tumorigenesis
Authors: Fang-Tsyr Lin, Victor T. G. Lin, Vivian Y. Lin, Yun-Ju Lai, Chen-Shan Chen, Kang Liu, Weei-Chin Lin
Journal: Clinical Cancer Research (2015)

Abstract Although the nuclear p27KIP1 functions as a negative regulator of G1/S cell cycle progression by binding to and inhibiting cyclin-CDK complexes, the cytosolic p27KIP1 has been shown to promote adhesion disassembly and tumor invasion. Loss of nuclear p27KIP1 and cytosolic mislocalization of p27KIP1 are frequently found during cancer progression, and these events correlate with poor clinical outcome in many types of cancers, including ovarian cancer. However, the mechanisms underlying this dysregulation are not yet fully understood. TRIP6 is an adaptor protein that is highly expressed in ovarian serous cystadenocarcinoma. It serves as a platform to recruit a number of molecules, such as NF-κB p65, c-Src, p130cas, Crk, LPA2 and Fas/CD95 receptors, to promote cell motility and antiapoptotic signaling. Using an ovarian cancer xenograft mouse model, we find that TRIP6 knockdown significantly reduces ovarian tumor proliferation. We determine that this effect is in part through the regulation of p27KIP1. Our data show that TRIP6 serves as a bridge to promote the recruitment of p27KIP1 to AKT in the cytosol. TRIP6 regulates the membrane translocation and activation of AKT, and facilitates AKT-mediated recognition and phosphorylation of p27KIP1 specifically at T157, thereby promoting the cytosolic mislocalization of p27KIP1. This is required for p27KIP1 to enhance LPA-induced ovarian cancer cell migration. TRIP6 also promotes serum-induced reduction of nuclear p27KIP1 expression through Skp2-dependent and -independent mechanisms. Consequently, knockdown of TRIP6 in ovarian cancer xenografts restores nuclear p27KIP1 expression and impairs tumor proliferation. Since the expression of TRIP6 and the activity of AKT are significantly higher in ovarian cancer, restoring the expression of nuclear p27KIP1 and inhibiting the migratory effect of phospho-T157-p27KIP1 by targeting TRIP6 may prove to be an effective approach to reduce ovarian cancer progression. Citation Format: Fang-Tsyr Lin, Victor T. G. Lin, Vivian Y. Lin, Yun-Ju Lai, Chen-Shan Chen, Kang Liu, Weei-Chin Lin. TRIP6 regulates p27KIP1 to promote ovarian tumorigenesis [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1333.
Abstract 4722: Inactivation of neogenin promotes castration resistance and bone metastasis in prostate cancer models
Authors: Goutam Chakraborty, Mayur Gadiya, Myriam Kossai, Dong Gao, Weijing Su, Hua Gao, Yu Chen, Howard I. Scher, Mark A. Rubin, Filippo Giancotti
Journal: Cancer Research (2015)

Abstract Increasing evidence suggests that exposure to new generation agents targeting the AR promotes the emergence of castration-resistant stem-like clones ultimately leading to treatment failure. In order to develop improved therapies for castration-resistant prostate cancer (CRPC), it is important to understand the origin and biology of these stem-like clones. We have observed significantly diminished levels of Neogenin (encoded by NEO1) in CRPC. Neogenin functions as a neuronal guidance receptor but has also been implicated in epithelial branching morphogenesis and is homologous to DCC, which functions as a suppressor of tumor progression in breast and colorectal cancer. We found that silencing of neogenin induces androgen receptor (AR) dependent prostate cancer cells to undergo an epithelial to mesenchymal transition (EMT) and acquire neuroendocrine (NE) differentiation features. In addition, the neogenin-silenced cells expressed high levels of the stem cell markers β4 integrin and CD44 and formed rapidly growing tumor spheres in vitro. Intriguingly, these cells had become castration resistant due to loss of AR expression and were able to efficiently colonize the bone upon intracardiac injection in immunodeficient mice. Genomic and molecular pathology studies indicated that NEO1 expression is lost in CRPC and NEPC. To examine the relationship between the acquisition of the castration resistant phenotype and loss of neogenin, we have generated a series of casodex- and enzalutamide-resistant clones from LNCaP cells. Interestingly, we observed that a significant fraction of these clones have lost expression of neogenin and acquired expression of the β4 integrin and are highly metastatic in immunodeficient mice, similar to the characteristics of CRPC observed in the clinic. To validate these results, we sought to identify a population of β4-positive cells in the peripheral blood of patients with CRPC. By using immunofluorescent staining and FACS analysis, we were able to identify β4-positive circulating tumor cells (CTCs) from the peripheral blood of CRPC patients. These cells were not detected in the blood of healthy normal donors but their numbers increased with disease progression. These findings identify a novel tumor progression pathway that is likely to operate in at least a fraction of CRPC cases. Citation Format: Goutam Chakraborty, Mayur Gadiya, Myriam Kossai, Dong Gao, Weijing Su, Hua Gao, Yu Chen, Howard I. Scher, Mark A. Rubin, Filippo Giancotti. Inactivation of neogenin promotes castration resistance and bone metastasis in prostate cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4722. doi:10.1158/1538-7445.AM2015-4722
HCV and diabetes: towards a ‘Sustained’ glycaemic improvement after treatment with DAAs? – Authors' reply
Authors: P. Pavone, T. Tieghi, G. d'Ettorre, M. Lichtner, R. Marocco, I. Mezzaroma, G. Passavanti, P. Vittozzi, C. Mastroianni, V. Vullo
Journal: Clinical Microbiology and Infection (2016)
Randomized multicenter phase II trial of irinotecan and bevacizumab as neoadjuvant and adjuvant to temozolomide-based chemoradiation versus chemoradiation for unresectable glioblastoma: Interim results of the TEMAVIR study from the ANOCEF group.
Authors: B. Chauffert, L. Feuvret, F. Bonnetain, L. Taillandier, H. Taillia, D. Frappaz, R. Schott, J. Honnorat, M. Fabbro, I. Tennevet, F. Ghiringhelli, J. S. Guillamo, X. Durando, D. Castera, M. Frenay, C. Campello, R. Guillevin, J. Skrzypski, T. S. Dabakuyo, O. L. Chinot
Journal: Journal of Clinical Oncology (2011)

2029^ Background: The prognosis of unresectable glioblastoma (GBM) remains poor despite temozolomide- based chemoradiation with a median of 6 month progression-free survival (PFS). Activity of bevacizumab/irinotecan has been reported in patients with relapsed GBM (Vredenburgh, 2007). The objective of this randomized phase II trial was to evaluate the efficacy and safety of irinotecan (IRI) and bevacizumab (BVZ) as neo-adjuvant and adjuvant treatment to chemoradiation with temozolomide (TMZ) and BVZ for naive unresectable glioblastoma. Control arm was TMZ as concomitant and adjuvant treatment to radiation. Methods: Pts with de novo unresectable GBM, aged 18-70, and KPS > 50, and EORTC RPA class 5 were eligible. Experimental arm (A) consisted of neo-adjuvant BVZ 10 mg/kg and IRI 125 mg/m2, every 2 wk for 4 cycles before radiotherapy 60 Gy in 30 fractions with concurrent TMZ 75 mg/m2/day and BVZ every 2 wk. Adjuvant BVZ and IRI were given every 2 wk for 6 month. The control arm (B) consisted of concomitant TMZ 75 mg/m2/d during radiotherapy and 150-200 mg/m2 for 5 d every 28 d for 6 month. Cross over were allowed for progression. The inclusion of 67 pts/arm was planned, using Fleming’s 2 steps design aiming at an increase of PFS at 6 month (PFS6) from 50 % to 66 %, with unilateral alpha 5% and 80% power. Results: Patients (134) were included from April 2009 to January 2011. Clinical factors were well balanced between arms. At interim analysis 6 month after inclusion of the first 30 pts in arm A, 17 were alive and free of progression (57%). In arm B, 13 patients were alive and free of progression (43%). Four deaths were related to treatment in arm A (3 cerebral haemorrhages, 1 peritonitis) and 0 in arm B. According to Fleming’s rules it was required to include 30 pts more in arm A for final analysis. Conclusions: Interim results suggest that experimental arm could reach efficacy hypotheses based on the favourable trend in PFS. The risk of severe cerebral haemorrhage due to BVZ appears as unusually high in this patient population. Updated results will be presented at the meeting.
Abstract SY12-03: Obesity, inflammation and breast cancer
Authors: Andrew J. Dannenberg
Journal: Cancer Research (2015)

Abstract Obesity is a risk factor for the development of hormone receptor-positive breast cancer in postmenopausal women. In addition to its impact on breast cancer risk, obesity has been recognized as a poor prognostic factor among breast cancer survivors. Obesity causes subclinical inflammation in visceral and subcutaneous white adipose tissue, characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures (CLS). Estrogen synthesis is catalyzed by aromatase, which is encoded by CYP19. Several pro-inflammatory mediators including PGE2 and TNF-alpha are known inducers of aromatase. Utilizing a combination of preclinical models and human breast tissue samples, we demonstrated that obesity was associated with increased numbers of CLS in the breast (CLS-B), activation of the NF-κB transcription factor, increased levels of pro-inflammatory mediators and elevated aromatase expression. These findings raise the possibility that the obesity-inflammation-aromatase axis is important for understanding the link between obesity and hormone receptor-positive breast cancer in postmenopausal women. To further explore the potential clinical significance of breast adipose inflammation, a retrospective study was carried out to investigate the relationship between CLS-B and breast cancer recurrence. The presence of CLS-B at the time of index mastectomy was associated with shortened recurrence free survival in women who develop recurrent breast cancer. Whether white adipose inflammation promotes the progression of breast cancer via local effects, systemic mechanisms, e.g., hyperinsulinemia or both is uncertain. Given the apparent significance of white adipose inflammation (CLS-B) in the pathogenesis of disease, a blood-based biomarker discovery effort has been initiated. Elevated levels of CRP, IL-6 and insulin as well as altered levels of numerous metabolites correlate with the presence of breast white adipose inflammation. Finally, the connection between obesity, adipose inflammation and cancer provides a strong rationale for attempting to develop effective anti-inflammatory interventions. This will be illustrated with findings from a recent preclinical study that utilized caloric restriction to reverse adipose inflammation and related molecular changes in the mammary glands of obese mice. Citation Format: Andrew J. Dannenberg. Obesity, inflammation and breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY12-03. doi:10.1158/1538-7445.AM2015-SY12-03
A Strong Immune Effect by Allogeneic Stem Cell Transplantation May Improve Survival in AML Patients with a High Ratio of the FLT3-ITD Mutation to the Wt-FLT3 Allele: Results from an Analysis of 257 Patients Treated in the SAL AML-2003 Trial
Authors: Gerhard Ehninger, Martin Bornhauser, Michael Kramer, Christoph Röllig, Hannes Wandt, Mathias Hanel, Hermann Einsele, Walter E. Aulitzky, Norbert Schmitz, Wolfgang E. Berdel, Matthias Stelljes, Joachim Kienast, Eckhard Thiel, Andreas Mackensen, Uwe Platzbecker, Markus Schaich, Johannes Schetelig, Jiri Mayer, Hubert Serve, Anthony D. Ho, Christian Thiede
Journal: Blood (2011)
The Comparison Between Long-Term and Short-Term Administration of Itraconazole for Primary Antifungal Prophylaxis in Recipients of Allogeneic Hematopoietic Stem Cell: A Multicenter, Randomized, Open-Label Trial (NCT01160952)
Authors: Ren Lin, Yonghua Li, Xiaojun Xu, Zhiping Fan, Qianli Jiang, Fen Huang, Hongsheng Zhou, Danian Nie, Chaoyang Song, Ziwen Guo, Jing Sun, Yang Xiao, Qifa Liu
Journal: Blood (2012)
The Prognostic Impact of the Revised IPSS Cytogenetic Scoring System for Patients with MDS Allows a Risk-Stratification for Patients with MDS-Derived Acute Myeloid Leukemia
Authors: Friedrich Stölzel, Michael Kramer, Brigitte Mohr, Martin Wermke, Martin Bornhäuser, Gerhard Ehninger, Markus Schaich, Uwe Platzbecker
Journal: Blood (2012)
Abstract 1657: The role of Noxa/MCL-1 axis in solid tumors treated with DNA damaging agents
Authors: Wataru Nakajima, Kanika Sharma, Mark A. Hicks, June Y. Lee, Nobuyuki Tanaka, Hisashi Harada
Journal: Cancer Research (2015)

Abstract DNA damaging agents, such as cisplatin and etoposide, are employed for the treatment of a wide array of solid tumors, but the prolonged use of chemotherapeutic drugs is limited by their toxicity and by the development of resistance. To overcome these major roadblocks to improved prognosis requires mechanism-based therapeutic strategies that maximize the antitumor effect of drugs while limiting their toxicities. These agents exert anticancer effects via multiple mechanisms, yet its most prominent mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of BCL-2 family-dependent mitochondrial apoptosis. Direct therapeutic targeting of the BCL-2 family in cancer is therefore conceptually appealing but has proved remarkably challenging. This is due, in part, to the difficulty in producing effective drugs and in achieving a satisfactory therapeutic index. Also important, but less appreciated in this regard, are the potentially complex, tissue-specific interactions among the BCL-2 family members observed in different tumor types. We have found that the expression of pro-apoptotic Noxa and anti-apoptotic MCL-1 proteins of the BCL-2 family is a critical determinant of the sensitivity to DNA-damaging agents in solid tumors; (1) MCL-1 is a labile protein and its stability is regulated by phosphorylation followed by ubiquitination and proteasome-mediated degradation; (2) Noxa specifically binds to and recruits MCL-1 from the cytosol to the mitochondria. Translocation of MCL-1 initiates its phosphorylation and subsequent ubiquitination, which triggers proteasome-mediated degradation; (3) The Noxa-dependent phosphorylation sites are regulated by CDK2 and are different from those phosphorylated by CDK1 in response to paclitaxel treatment; (4) Noxa is transcriptionally induced by cisplatin or etoposide. Downregulation of Noxa by shRNA strongly inhibits cisplatin-induced apoptosis. These results suggest that the Noxa/MCL-1 axis plays a critical role in apoptosis induced by DNA damaging agents and targeting Noxa/MCL-1 could be an alternative strategy to overcome the resistance to these agents. Citation Format: Wataru Nakajima, Kanika Sharma, Mark A. Hicks, June Y. Lee, Nobuyuki Tanaka, Hisashi Harada. The role of Noxa/MCL-1 axis in solid tumors treated with DNA damaging agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1657. doi:10.1158/1538-7445.AM2015-1657
Submucosal tunneling endoscopic resection of a symptomatic leiomyoma in the proximal esophagus
Authors: Nikhil Kumta, Ming-Ming Xu, Pawan Marfatia, Meredith Pittman, Karl Bednarek, Michel Kahaleh
Journal: Endoscopy (2016)

A 71-year-old woman with hypertension, dyslipidemia, and diverticulosis presented with a 1-year history of dysphagia and an unintentional weight loss of 6 lb (2.7 kg). An upper endoscopy was performed, which revealed a subepithelial lesion in the proximal esophagus. Endoscopic ultrasound demonstrated a 1.7 × 1-cm hypoechoic lesion in the muscularis propria layer, near the aorta ([Fig. 1]). The results of fine-needle aspiration were consistent with a leiomyoma. Given the presence of symptoms and the proximity of the leiomyoma to the aorta, resection of the tumor was pursued using a submucosal tunneling endoscopic resection technique.
Activation of the mTOR pathway in primary medullary thyroid carcinoma and lymph node metastases.
Authors: A. Tamburrino, A. A. Molinolo, P. Salerno, R. Chernock, M. Raffeld, L. Xi, J. S. Gutkind, J. F. Moley, S. A. Wells, M. Santoro
Journal: Journal of Clinical Oncology (2011)

10598 Background: Medullary thyroid carcinoma (MTC), a rare tumor arising from C-cells, is characterized by RET proto-oncogene activation in all familial and roughly half of sporadic cases. Conventional treatments have been ineffective in advanced MTC. Further understanding of the molecular pathogenesis of MTC may reveal novel therapeutic targets. Methods: We developed a tissue microarray to evaluate 55 primary MTC cases (14 hereditary, 38 sporadic, 3 unknown) and 23 matched lymph node metastases (LNM). Using immunohistochemistry (IHC) we investigated the phosphorylation status of proteins of the RAS/MEK/ERK and PI3K/mTOR pathways. In parallel, DNA from formalin-fixed paraffin embedded samples was pyrosequenced for RET mutations. We analyzed associations among RET mutational status, pathway activation, and clinico-pathological features by Fisher’s exact test or Spearman’s rank correlation. Results: Germline RET mutations were present in all hereditary MTC specimens and somatic RET mutations were present in 37% of sporadic MTC specimens. In IHC analysis for phospho-ERK 16/43 (37%) tissue samples showed cytoplasmic staining, which was focal in all cases (less than 25% of cells). There was activation (nuclear staining) of Akt (phospho-Ser473) in 23/44 (52%) specimens (50% of cells demonstrated staining). Activation of phospho-ribosomal protein S6 (pS6), a downstream target of mTOR, was evident in the cytoplasm of 35/51 (69%) specimens (staining ranged from 50% to 100% of cells). Activation of pS6 was detected also in specimens of C-cell hyperplasia (7/12; 58%), possibly representing an early event in MTC formation. pS6 intensity scores (0-4 scale) were higher (either 3 or 4) in LNM (19/21) compared to matched primary MTC (11/21; p= 0.015). pS6 activation was unrelated to RET mutational status. Conclusions: The AKT/mTOR/S6 pathway is activated in human MTC tissues and particularly in LNM. Cells exhibiting mTOR pathway activation may be selected during tumor development. These findings provide a rationale for further studies on the role of mTOR pathway activation, as targeting mTOR with rapamycin derivatives may benefit patients with advanced MTC.
The LSD1 Inhibitor RN-1 Recapitulates the Fetal Pattern of Hemoglobin Synthesis in Anemic and Normal, Non-Anemic Baboons
Authors: Angela Rivers, Kestis Vaitkus, Vinzon Ibanez, Maria Armila Ruiz, Ramaswamy Jagadeeswaran, Joseph DeSimone, Donald Lavelle
Journal: Blood (2015)
P19 Central airway obstruction in bronchogenic carcinoma
Authors: M Hindle, A Sibly, MG Aldik, A Marchbank, C Daneshvar
Journal: Thorax (2016)

<h3>Background</h3> Endobronchial compromise with central airways obstruction (CAO) is a life threatening complication of lung cancer. Endobronchial treatments provide immediate symptom relief, while allowing other treatment modalities to begin. Yet the prevalence of this condition is poorly defined. We set to identify the prevalence of CAO to inform the development of an interventional service. <h3>Method</h3> Between 11/2014–11/2015, we reviewed the index computer tomography (CT) scans of all patients diagnosed with a thoracic malignancy. Data collected included staging and the presence of endobronchial involvement. In patients with reported endobronchial involvement, images were reviewed for suitability of airway treatment. <h3>Results</h3> Over the study period 434 patients were diagnosed with a thoracic malignancy. In 51 non-primary bronchogenic malignancies were identified, including 41 mesotheliomas. Of the remaining 383 patients with lung cancer, 359 underwent an index CT scan. Staging by CT was reported in 291 (81.0%) patients. Of the 359 patients with CT imaging available, endobronchial disease was present in 111 (30.9% (95% confidence intervals (CI) 26.1–35.7%), with 29 (8.0%; 95% CI: 5.2–10.8%) patients having CAO. Of these, the commonest site was the bronchus intermedius (62.1%). The median degree of obstruction was 71.4% (interquartile range 50–100). Extrinsic compression was dominant in 8 (27.6%) patients. By cell type, squamous cell carcinoma, NSCLC-NOS, small cell lung carcinoma, and adenocarcinoma accounted for 9 (31.0%), 5 (17.2%), 4 (13.8%), and 4 (13.8%) cases respectively. In 9 (31.0%) no histology was available. Of those patients with CAO, 26 (89.7%) could be considered for airway treatments, however only 3 (12%) had a therapeutic procedure performed. Of 18 patients with follow up imaging, 8 (44%) developed obstructive complications. <h3>Conclusions</h3> CAO affects nearly 1 in 10 lung cancer patients at the time of diagnosis and services should be developed to evaluate and offer timely intervention. Further longitudinal data will help predict the risk of developing central airways obstruction.
Hodgkin Lymphoma: Current Status and Clinical Trial Recommendations
Authors: Catherine S Diefenbach, Joseph M Connors, Jonathan W Friedberg, John P Leonard, Brad S Kahl, Richard F Little, Lawrence Baizer, Andrew M Evens, Richard T Hoppe, Kara M Kelly, Daniel O Persky, Anas Younes, Lale Kostakaglu, Nancy L Bartlett
Journal: JNCI Journal of the National Cancer Institute (2016)

The National Clinical Trials Network lymphoid malignancies Clinical Trials Planning Meeting (CTPM) occurred in November of 2014. The scope of the CTPM was to prioritize across the lymphoid tumors clinically significant questions and to foster strategies leading to biologically informed and potentially practice changing clinical trials. This review from the Hodgkin lymphoma (HL) subcommittee of the CTPM discusses the ongoing clinical challenges in HL, outlines the current standard of care for HL patients from early to advanced stage, and surveys the current science with respect to biomarkers and the landscape of ongoing clinical trials. Finally, we suggest areas of unmet need in HL and elucidate promising therapeutic strategies to guide future HL clinical trials planning across the NCTN.
Clinical, Biochemical, and Histopathology Features of Patients With Glycogenic Hepatopathy
Authors: Saurabh Mukewar, Ayush Sharma, Kandace A. Lackore, Felicity T. Enders, Michael S. Torbenson, Patrick S. Kamath, Lewis R. Roberts, Yogish C. Kudva
Journal: Clinical Gastroenterology and Hepatology (2016)
Polycomb-Dependent Epigenetic Landscape in Adult T Cell Leukemia (ATL); Providing Proof of Concept for Targeting EZH1/2 to Selectively Eliminate the HTLV-1 Infected Population
Authors: Makoto Yamagishi, Dai Fujikawa, Daisuke Honma, Nobuaki Adachi, Shota Nakagawa, Makoto Hori, Naoya Kurokawa, Ai Soejima, Kazumi Nakano, Tadanori Yamochi, Makoto Nakashima, Seiichiro Kobayashi, Yuetsu Tanaka, Masako Iwanaga, Atae Utsunomiya, Kaoru Uchimaru, Kunihiro Tsukasaki, Kazushi Araki, Toshiki Watanabe
Journal: Blood (2015)
First Report of National Estimates of the Incidence of Myelodysplastic Syndromes and Chronic Myeloproliferative Disorders from the U.S. SEER Program.
Authors: Dana E. Rollison, Matthew Hayat, Martyn Smith, Sara S. Strom, William D. Merritt, Lynn Ries, Brenda K. Edwards, Alan F. List
Journal: Blood (2006)