Browsing by Subject "Adenocarcinoma"
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Item A complete map of the Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) signaling pathway(Springer, 2021-06) Najar, Mohd Altaf; Rex, D.A.B.; Modi, Prashant Kumar; Agarwal, Nupur; Dagamajalu, Shobha; Karthikkeyan, Gayathree; Vijayakumar, Manavalan; Chatterjee, Aditi; Sankar, Uma; Prasad, T.S. Keshava; Anatomy and Cell Biology, School of MedicineCalcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is a serine/threonine-protein kinase belonging to the Ca2+/calmodulin-dependent protein kinase subfamily. CAMKK2 has an autocatalytic site, which gets exposed when Ca2+/calmodulin (CAM) binds to it. This results in autophosphorylation and complete activation of CAMKK2. The three major known downstream targets of CAMKK2 are 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPKα), calcium/calmodulin-dependent protein kinase 1 (CAMK1) and calcium/calmodulin-dependent protein kinase 4 (CAMK4). Activation of these targets by CAMKK2 is important for the maintenance of different cellular and physiological processes within the cell. CAMKK2 is found to be important in neuronal development, bone remodeling, adipogenesis, and systemic glucose homeostasis, osteoclastgensis and postnatal myogensis. CAMKK2 is reported to be involved in pathologies like Duchenne muscular dystrophy, inflammation, osteoporosis and bone remodeling and is also reported to be overexpressed in prostate cancer, hepatic cancer, ovarian and gastric cancer. CAMKK2 is involved in increased cell proliferation and migration through CAMKK2/AMPK pathway in prostate cancer and activation of AKT in ovarian cancer. Although CAMKK2 is a molecule of great importance, a public resource of the CAMKK2 signaling pathway is currently lacking. Therefore, we carried out detailed data mining and documentation of the signaling events associated with CAMKK2 from published literature and developed an integrated reaction map of CAMKK2 signaling. This resulted in the cataloging of 285 reactions belonging to the CAMKK2 signaling pathway, which includes 33 protein-protein interactions, 74 post-translational modifications, 7 protein translocation events, and 22 activation/inhibition events. Besides, 124 gene regulation events and 25 activator/inhibitors involved in CAMKK2 activation were also cataloged. The CAMKK2 signaling pathway map data is made freely accessible through WikiPathway database ( https://www.wikipathways.org/index.php/Pathway:WP4874 ). We expect that data on a signaling map of CAMKK2 will provide the scientific community with an improved platform to facilitate further molecular as well as biomedical investigations on CAMKK2 and its utility in the development of biomarkers and therapeutic targets.Item Endoscopic papillectomy: risk factors for incomplete resection and recurrence during long-term follow-up(Elsevier, 2014-02) Ridtitid, Wiriyaporn; Tan, Damien; Schmidt, Suzette E.; Fogel, Evan L.; McHenry, Lee; Watkins, James L.; Lehman, Glen A.; Sherman, Stuart; Coté, Gregory A.; Department of Medicine, IU School of MedicineBackground Endoscopic papillectomy is increasingly used as an alternative to surgery for ampullary adenomas and other noninvasive ampullary lesions. Objective To measure short-term safety and efficacy of endoscopic papillectomy, define patient and lesion characteristics associated with incomplete endoscopic resection, and measure adenoma recurrence rates during long-term follow-up. Design Retrospective cohort study. Setting Tertiary-care academic medical center. Patients All patients who underwent endoscopic papillectomy for ampullary lesions between July 1995 and June 2012. Intervention Endoscopic papillectomy. Main Outcome Measurements Patient and lesion characteristics associated with incomplete endoscopic resection and ampullary adenoma-free survival analysis. Results We identified 182 patients who underwent endoscopic papillectomy, 134 (73.6%) having complete resection. Short-term adverse events occurred in 34 (18.7%). Risk factors for incomplete resection were jaundice at presentation (odds ratio [OR] 0.21, 95% confidence interval [CI] 0.07–0.69; P = .009), occult adenocarcinoma (OR 0.06, 95% CI, 0.01–0.36; P = .002), and intraductal involvement (OR 0.29, 95% CI, 0.11–0.75; P = .011). The en bloc resection technique was strongly associated with a higher rate of complete resection (OR 4.05, 95% CI, 1.71–9.59; P = .001). Among patients with ampullary adenoma who had complete resection (n = 107), 16 patients (15%) developed recurrence up to 65 months after resection. Limitations Retrospective analysis. Conclusion Jaundice at presentation, occult adenocarcinoma in the resected specimen, and intraductal involvement are associated with a lower rate of complete resection, whereas en bloc papillectomy increases the odds of complete endoscopic resection. Despite complete resection, recurrence was observed up to 5 years after papillectomy, confirming the need for long-term surveillance.Item Gastrointestinal carcinoma and sarcoma surgery(AME, 2019-06-05) Koniaris, Leonidas G.; Surgery, IU School of MedicineA number of advances in both earlier diagnostic imaging and better treatment options for patients with intra-abdominal malignancies have occurred. Frequently such newer therapies rely on the integration of established surgical and radiation approaches potentially with newer chemotherapies and immunomodulators. Unfortunately, with further study some newer therapies have proven less beneficial than initially suggested. Keeping up with the data supporting newer alternatives, and determining which therapies to provide patients can be a challenge. Nonetheless, integrating newer study data into beneficial therapeutic algorithms and understanding the molecular basis and rationale for new therapies remains a critically important role for treating physicians. To help provide busy clinicians and trainees with a current update for the management of intra-abdominal malignancies, this special issue of Translational Gastroenterology and Hepatology provides succinct reviews relevant to both diagnosis and treatment for patients with abdominal sarcoma or adenocarcinoma.Item Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group.(Springer, 2011-10) Yoon, H. H.; Catalano, P.; Gibson, M. K.; Skaar, T. C.; Philips, S.; Montgomery, E. A.; Hafez, M. J.; Powell, M.; Liu, G.; Forastiere, A. A.; Benson, A. B.; Kleinberg, L. R.; Murphy, K. M.PURPOSE: Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual. Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy. METHODS: In a multicenter clinical trial (E1201), 81 eligible treatment-naïve subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy, with planned subsequent surgical resection. Toxicity endpoints were defined as grade ≥3 radiation-related or myelosuppressive events probably or definitely related to therapy, occurring during or up to 6 weeks following the completion of radiochemotherapy. SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double stranded break repair, or platinum influx, efflux, or detoxification. RESULTS: Grade ≥3 radiation-related toxicity (mostly dysphagia) and myelosuppression occurred in 18 and 33% of subjects, respectively. The variant alleles of the XRCC2 5' flanking SNP (detected in 28% of subjects) and of GST-Pi Ile-105-Val (detected in 65% of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47% vs. 9%, and 31% vs. 0%, respectively; P = 0.005). No SNP was associated with myelosuppression. CONCLUSIONS: This novel finding in a well-characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity.Item IDO Immune Status after Chemoradiation May Predict Survival in Lung Cancer Patients(American Association for Cancer Research, 2018-02-01) Wang, Weili; Huang, Lei; Jin, Jian-Yue; Jolly, Shruti; Zang, Yong; Wu, Huanmei; Yan, Li; Pi, Wenhu; Li, Lang; Mellor, Andrew L.; Kong, Feng-Ming Spring; Radiation Oncology, School of MedicineHost immunity influences the impact of radiotherapy (RT) in cancer, but mechanistic connections remain obscure. In this study, we investigated the relationship of indoleamine 2,3-dioxygenase (IDO) systemic activity on clinical outcomes in RT-treated non-small cell lung cancer (NSCLC). IDO-mediated production of kynurenine and the kynurenine:tryptophan ratio in patient blood serum were determined for stage III NSCLC patients at times before, during, and after RT administration and then correlated to overall survival (OS), progression-free survival, and disease progression rate in patients. We found the impact of RT on these serum IDO markers to be heterogeneous in patients. On average, kynurenine:tryptophan ratios were reduced during RT but restored after RT. Notably, both baseline levels of kynurenine:tryptophan and changes in the levels of kynurenine after RT were significantly associated with OS. When combined, favorable change and favorable baseline corresponded with very long-term OS (median OS was not reached after 57 months of median follow-up). Favorable change combined with unfavorable baseline still corresponded with a lack of distant metastases. Our results suggest that RT alters IDO-mediated immune status in NSCLC patients and that changes in this serum biomarker may be useful to predict outcomes and perhaps personalize RT dosage to improve survival.Significance: Radiotherapy appears to influence systemic IDO activity and to exert a significant impact on metastatic risk and overall survival, with possible implications for defining a biomarker to optimize radiation dose in patients to improve outcomes. Cancer Res; 78(3); 809-16. ©2017 AACR.Item Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2(Oxford University Press, 2017-05-05) Plotnik, Joshua P.; Hollenhorst, Peter C.; Biology, School of ScienceAberrant activation of RAS/MAPK signaling is a driver of over one third of all human carcinomas. The homologous transcription factors ETS1 and ETS2 mediate activation of gene expression programs downstream of RAS/MAPK signaling. ETS1 is important for oncogenesis in many tumor types. However, ETS2 can act as an oncogene in some cellular backgrounds, and as a tumor suppressor in others, and the molecular mechanism responsible for this cell-type specific function remains unknown. Here, we show that ETS1 and ETS2 can regulate a cell migration gene expression program in opposite directions, and provide the first comparison of the ETS1 and ETS2 cistromes. This genomic data and an ETS1 deletion line reveal that the opposite function of ETS2 is a result of binding site competition and transcriptional attenuation due to weaker transcriptional activation by ETS2 compared to ETS1. This weaker activation was mapped to the ETS2 N-terminus and a specific interaction with the co-repressor ZMYND11 (BS69). Furthermore, ZMYND11 expression levels in patient tumors correlated with oncogenic versus tumor suppressive roles of ETS2. Therefore, these data indicate a novel and specific mechanism allowing ETS2 to switch between oncogenic and tumor suppressive functions in a cell-type specific manner.Item Locally advanced adenocarcinoma and adenosquamous carcinomas of the cervix compared to squamous cell carcinomas of the cervix in gynecologic oncology group trials of cisplatin-based chemoradiation(Elsevier, 2014-11) Rose, Peter G.; Java, James J.; Whitney, Charles W.; Stehman, Frederick B.; Lanciano, Rachelle; Thomas, Gillian M.; Department of Obstetrics and Gynecology, IU School of MedicineOBJECTIVE: Conflicting results have been reported for adeno- and adenosquamous carcinomas of the cervix with respect to their response to therapy and prognosis. The current study sought to evaluate impact of adeno- and adenosquamous histology in the randomized trials of primary cisplatin-based chemoradiation for locally advanced cervical cancer. METHODS: Patients with adeno- and adenosquamous cervical carcinomas were retrospectively studied and compared to squamous cell carcinomas in GOG trials of chemoradiation. RESULTS: Among 1671 enrolled in clinical trials of chemoradiation, 182 adeno- and adenosquamous carcinomas were identified (10.9%). A higher percentage of adeno- and adenosquamous carcinomas were stage IB2 (27.5% versus 20.0%) and fewer had stage IIIB (21.4% versus 28.6%). The mean tumor size was larger for squamous than adeno- and adenosquamous. Adeno- and adenosquamous carcinomas were more often poorly differentiated (46.2% versus 26.8%). When treated with radiation therapy alone, the 70 patients with adeno- and adenosquamous carcinoma of the cervix showed a statistically poorer overall survival (p=0.0499) compared to the 647 patients with squamous cell carcinoma of the cervix. However, when treated with radiation therapy with concurrent cisplatin-based chemotherapy, the 112 patients with adeno- and adenosquamous carcinomas had a similar overall survival (p=0.459) compared the 842 patients with squamous cell carcinoma. Adverse effects to treatment were similar across histologies. CONCLUSION: Adeno- and adenosquamous carcinomas of the cervix are associated with worse overall survival when treated with radiation alone but with similar progression-free and overall survival compared to squamous cell carcinomas of the cervix when treated with cisplatin based chemoradiation.Item Nestin Delineates Pancreatic Cancer Stem Cells in Metastatic Foci of NOD/Shi-scid IL2Rγnull (NOG) Mice(Elsevier B.V., 2014-03) Matsuda, Yoko; Yoshimura, Hisashi; Ueda, Junji; Naito, Zenya; Korc, Murray; Ishiwata, Toshiyuki; Department of Medicine, IU School of MedicinePancreatic ductal adenocarcinoma (PDAC) is associated with a high incidence of hepatic metastases, as well as occasional pulmonary metastases. To delineate the potential role of cancer stem cells (CSCs) in PDAC metastasis, human PDAC cells were injected into the spleen of mice. The characteristics and expression of markers associated with CSC and epithelial–mesenchymal transition (EMT) of metastatic cells that developed in the liver and lung were then compared with parental cells. The metastatic cells were polygonal, and larger than parental cells. Metastatic cells also exhibited decreased proliferation and increased adhesion to extracellular matrices, as well as enhanced migration and invasion in vitro and increased metastatic capacity in vivo. The CSC markers ALDH1A1, ABCG2, and nestin were expressed at high levels in metastatic cells and exhibited changes consistent with EMT (eg, decreased E-cadherin expression). Moreover, metastatic cells readily formed spheres in culture and exhibited an increased side population by flow analysis. Nestin and ABCG2 were also expressed at high levels in metastatic lesions from PDAC patients, and silencing nestin with shRNA in PDAC cells derived from lung metastases resulted in a marked decrease in the capacity of the cells to form spheres and to yield pulmonary or hepatic metastases. Thus, the metastatic potential of human PDAC cells correlates with CSCs and with EMT characteristics and is dependent on nestin expression.Item Quantitative Serum Glycomics of Esophageal Adenocarcinoma, and Other Esophageal Disease Onsets(American Chemical Society, 2009-06) Mechref, Yehia; Hussein, Ahmed; Bekesova, Slavka; Pungpapong, Vitara; Zhang, Min; Dobrolecki, Lacey E.; Hickey, Robert J.; Hammoud, Zane T.; Novotny, Milos V.; Department of Medicine, IU School of MedicineAberrant glycosylation has been implicated in various types of cancers and changes in glycosylation may be associated with signaling pathways during malignant transformation. Glycomic profiling of blood serum, in which cancer cell proteins or their fragments with altered glycosylation patterns are shed, could reveal the altered glycosylation. We performed glycomic profiling of serum from patients with no known disease (N=18), patients with high grade dysplasia (HGD, N=11) and Barrett’s (N=5), and patients with esophageal adenocarcinoma (EAC, N=50) in an attempt to delineate distinct differences in glycosylation between these groups. The relative intensities of 98 features were significantly different among the disease onsets; 26 of these correspond to known glycan structures. The changes in the relative intensities of three of the known glycan structures predicted esophageal adenocarcinoma with 94% sensitivity and better than 60% specificity as determined by receiver operating characteristic (ROC) analysis. We have demonstrated that comparative glycomic profiling of EAC reveals a subset of glycans that can be selected as candidate biomarkers. These markers can differentiate disease-free from HGD, disease-free from EAC, and HGD from EAC. The clinical utility of these glycan biomarkers requires further validation.Item A systematic review of the role of periadventitial dissection of the superior mesenteric artery in affecting margin status after pancreatoduodenectomy for pancreatic adenocarcinoma(Elsevier, 2016-04) Butler, James R.; Ahmad, Syed A.; Katz, Matthew H.; Cioffi, Jessica L.; Zyromski, Nicholas J.; Department of Surgery, IU School of MedicineBACKGROUND: Resectable pancreatic ductal adenocarcinoma continues to carry a poor prognosis. Of the controllable clinical variables known to affect outcome, margin status is paramount. Though the importance of a R0 resection is generally accepted, not all margins are easily managed. The superior mesenteric artery [SMA] in particular is the most challenging to clear. The aim of this study was to systematically review the literature with specific focus on the role of a SMA periadventitial dissection during PD and it's effect on margin status in pancreatic adenocarcinoma. STUDY DESIGN: The MEDLINE, EMBASE and Cochrane databases were searched for abstracts that addressed the effect of margin status on survival and recurrence following pancreaticoduodenectomy [PD]. Quantitative analysis was performed. RESULTS: The overall incidence of a R1 resection ranged from 16% to 79%. The margin that was most often positive following PD was the SMA margin, which was positive in 15-45% of resected specimens. Most studies suggested that a positive margin was associated with decreased survival. No consistent definition of R0 resection was observed. CONCLUSIONS: Margin positivity in resectable pancreatic adenocarcinoma is associated with poor survival. Inability to clear the SMA margin is the most common cause of incomplete resection. More complete and consistently reported data are needed to evaluate the potential effect of periadventitial SMA dissection on margin status, local recurrence, or survival.