Leo Jenkins Cancer Center
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Item Open Access Reducing Neurocognitive Impairment In Treating Limited Stage Small Cell Lung Cancer with Gamma Knife Radiosurgery(2023-07-31) Cunningham, Andrew; Behm, Hayley; Ju, Andrew; Peach, MatthewSmall Cell Lung Cancer (SCLC) represents 15% of lung cancer and is characterized by rapid growth with metastasis resulting in poor survival rates.1 SCLC with a limited stage defined as disease limited to the hemithorax with no evidence of current metastasis.2 The current gold standard includes chemoradiation and prophylactic cranial irradiation (PCI)3,4 which can result in acute adverse effects that do not improve over time.2 These include long-term toxicity with neurocognitive impairment, decrease short term memory and change in personality. An alternative treatment is the implementation of a watchful waiting strategy utilizing Gamma Knife Radiosurgery on a single or a few metastatic lesions as they appear. With Gamma Knife Radiosurgery, treating small lesions to a high dose with little irradiation to the rest of the brain does not result in cognitive side effects. Patients are subjected to close image surveillance of serial MRIs monthly to determine if Gamma Knife is necessary.Item Open Access Pembrolizumab Induced Tumor Shrinkage in Rare Osseous Metastasis of Basal Cell Carcinoma(2023-07-31) Cunningham, Andrew; Goetz, Amanda; Ju, Andrew; Peach, MatthewCutaneous basal cell carcinoma (BCC) is an increasingly common malignancy with a rising incidence over the past decade. 1 BCC seldom exhibits lymphatic or hematogenous metastasis with an incidence of only 0.0028% to 0.5%. 2 There are only around 400 combined reports of metastatic spread of basal cell carcinoma (mBCC) since the 1980s, with hematogenous cases constituting a small minority. Typically, those diagnosed with hematogenous mBCC have a median survival of 8-14 months compared to those diagnosed with lymphatic mBCC, whose survival average is reported to be 3.6 years. 3 This case report focuses on a patient who presented with a basal cell carcinoma on his left shoulder that had metastasized to the spine. Ultimately, a multimodal therapeutic approach was required to bring the patient’s metastatic disease under control, including surgical resection, radiation therapy, and systemic therapy with hedgehog inhibitors (vismodegib, sonidegib) and novel employment of immunotherapy agents including pembrolizumab. To the author’s knowledge and based on our included literature review, this is the first case where pembrolizumab was used to treat osseous mBCC.Item Open Access Real-World Performance of Blood-Based Proteomic Profiling in First-Line Immunotherapy Treatment in Advanced Stage Non-Small Cell Lung Cancer(2021) Walker, Paul R.; Rich, Patricia; Mitchell, R. Brian; Schaefer, Eric; Dubay, John W.; Boyd, Jason; Oubre, David; Page, Ray; Khalil, Mazen; Sinha, Suman; Boniol, Scott; Halawani, Hafez; Santos, Edgardo S.; Brenner, Warren; Orsini, James M.; Pauli, Emily; Goldberg, Jonathan; Veatch, Andrea; Haut, Mitchell; Ghabach, Bassam; Bidyasar, Savita; Quejada, Maria; Khan, Waseemullah; Huang, Kan; Traylor, Linda; Akerley, WallaceItem Open Access Metabolic Response as Assessed by 18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography Does Not Predict Outcome in Patients with Intermediate- or High-Risk Rhabdomyosarcoma: A Report from the Children's Oncology Group Soft Tissue Sarcoma Committee(2021) Harrison, Douglas J.; Chi, Yueh-Yun; Tian, Jing; Hingorani, Pooja; Mascarenhas, Leo; McCowage, Geoffrey B.; Weigel, Brenda J.; Venkatramani, Rajkumar; Wolden, Suzanne L.; Yock, Torunn I.; Rodeberg, David A.; Hayes-Jordan, Andrea A.; Teot, Lisa A.; Spunt, Sheri L.; Meyer, William H.; Hawkins, Douglas S.; Shulki, Barry L.; Parisi, Marguerite T.Item Open Access Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer(2013-1) Di, Li-Jun; Byun, Jung S.; Wong, Madeline M.; Wakano, Clay; Taylor, Tara; Bilke, Sven; Baek, Songjoon; Hunter, Kent; Yang, Howard; Lee, Maxwell; Zvosec, Celia; Khramtsova, Galina; Cheng, Fan; Perou, Charles M.; Miller, C. Ryan; Raab, Rachel; Olopade, Olufunmilayo I.; Gardner, KevinItem Open Access Race, insurance type, and stage of presentation among lung cancer patients(2014-12) Efird, Jimmy T.; Landrine, Hope; Shiue, Kristin Y.; O'Neal, Wesley T.; Podder, Tarun; Rosenman, Julian G.; Biswas, TithiItem Open Access The claudin family of proteins in human malignancy: a clinical perspective(2013) Ding, Lei; Lu, Zhe; Lu, Qun; Chen, Yan-HuaItem Open Access A non-tight junction function of claudin-7—Interaction with integrin signaling in suppressing lung cancer cell proliferation and detachment(2015-06-17) Lu, Zhe; Kim, Do Hyung; Fan, Junming; Lu, Qun; Verbanac, Kathryn; Ding, Lei; Renegar, Randall; Chen, Yan-HuaBackground Claudins are a family of tight junction (TJ) membrane proteins involved in a broad spectrum of human diseases including cancer. Claudin-7 is a unique TJ membrane protein in that it has a strong basolateral membrane distribution in epithelial cells and in tissues. Therefore, this study aims to investigate the functional significance of this non-TJ localization of claudin-7 in human lung cancer cells. Methods Claudin-7 expression was suppressed or deleted by lentivirus shRNA or by targeted-gene deletion. Cell cycle analysis and antibody blocking methods were employed to assay cell proliferation and cell attachment, respectively. Electron microscopy and transepthelial electrical resistance measurement were performed to examine the TJ ultrastructure and barrier function. Co-immunolocalization and co-immunoprecipitation was used to study claudin-7 interaction with integrin β1. Tumor growth in vivo were analyzed using athymic nude mice. Results Claudin-7 co-localizes and forms a stable complex with integrin β1. Both suppressing claudin-7 expression by lentivirus shRNA in human lung cancer cells (KD cells) and deletion of claudin-7 in mouse lungs lead to the reduction in integrin β1 and phospho-FAK levels. Suppressing claudin-7 expression increases cell growth and cell cycle progression. More significantly, claudin-7 KD cells have severe defects in cell-matrix interactions and adhere poorly to culture plates with a remarkably reduced integrin β1 expression. When cultured on uncoated glass coverslips, claudin-7 KD cells grow on top of each other and form spheroids while the control cells adhere well and grow as a monolayer. Reintroducing claudin-7 reduces cell proliferation, upregulates integrin β1 expression and increases cell-matrix adhesion. Integrin β1 transfection partially rescues the cell attachment defect. When inoculated into nude mice, claudin-7 KD cells produced significantly larger tumors than control cells. Conclusion In this study, we identified a previously unrecognized function of claudin-7 in regulating cell proliferation and maintaining epithelial cell attachment through engaging integrin β1.Item Open Access Epigenetic mechanisms of drug resistance: drug-induced DNA hypermethylation and drug resistance.(East Carolina University, 1993-04-01) Nyce, Jonathan W.; Leonard, Sherry Ann; Canupp, Dawn; Schulz, Stefan; Wong, SoIn a model system employing Chinese hamster V-79 cells, the DNA synthesis inhibitor 3'-azido-3'- deoxythymidine (BW A509U, AZT) was shown to induce genome-wide DNA hypermethylation, low-frequency silencing of thymidine kinase (TK; EC 2.7.1.21) gene expression, and resistance to AZT. Twenty-four hours of exposure of V-79 cells to 150 ,uM AZT led to >2-fold enhancement of genomic 5-methylcytosine levels and produced TK- epimutants at a rate -43-fold above background. Such AZT-induced TK- epimutants were shown to be severely reduced in their capacity to activate AZT to its proximate antiviral form, AZT 5'- monophosphate, as compared with the TK+ parental cell line from which they were derived. TK- clones isolated under these conditions were shown to be 9- to 24-fold more resistant to the cytotoxic effects of AZT than the parental TK+ cell line and showed collateral resistance to 5-fluoro-2'-deoxyuridine. Three of four TK- epimutants could be reactivated at very high frequency (8-73%) to the TK+ AZT-sensitive phenotype by 24 hr of exposure to the demethylating agent 5-azadeoxycytidine (5-azadC), implying that drug-induced DNA hypermethylation, rather than classical mutation, was involved in the original gene-silencing event in these three clones. These 5-azadC-induced TK+ revertants concomitantly regained the ability to metabolize AZT to its 5'-monophosphate. RNA slot blot analyses indicated that the four AZT-induced TK- clones expressed 8.9%, 15.6%, 17.8%, and 11.1% of the parental level ofTK mRNA. The three clones that were reactivatable by 5-azadC showed reexpression of TK mRNA to levels 84.4%, 51.1%, and 80.0% that of the TK+ parental cell line. These experiments show that one potential mechanism of drug resistance involves drug-induced DNA hypermethylation and resulting transcriptional inactivation of cellular genes whose products are required for drug activation. Originally published Proceedings of the National Academy of Science, Vol. 90, No. 7, Apr 1993Item Open Access American Ginseng Modifies 137Cs-Induced DNA Damage and Oxidative Stress in Human Lymphocytes(East Carolina University, 2009-01-01) Lee, Tung-Kwang; O'Brien, Kevin F.; Wang, Weidong; Sheng, Chao; Wang, Tao; Johnke, Roberta M.; Allison, Ron R.The multifold bioactive medicinal properties of ginseng have been closely linked to its antioxidative ability, which is related to its ginsenoside content. Since the key mechanism of radiation-induced cell death and tissue damage is the generation of reactive oxygen species (ROS) that attack cellular DNA, this study focuses on the impact of a standardized North American ginseng extract (NAGE) on 137Cs-induced oxidative stress in human peripheral lymphocytes (PBL) obtained from 10 healthy individuals (6M/4F), 42.7 ± 4.6 years of age. At two different time points (0 h and 24 h before irradiation), we applied NAGE (250 - 1000 µg ml-1) to mononuclear cell cultures for cytokinesisblock micronuclei (MN) assay and determination of the state of oxidative stress in PBL. We found that at both time points, NAGE significantly reduced the MN yields in PBL after irradiation (1 and 2 Gy) in a concentration-dependent manner (P<0.001). Compared with radiation alone, the maximum reduction rate of MN yield were 51.1% and 49.1% after 1 Gy and 2 Gy exposures, respectively. We also found that before irradiation the presence of NAGE in the culture medium resulted in a significant increased intracellular total antioxidant capacity (TAC) in PBL. At both time points, the increment of 137Cs-induced MN yields in PBL was positively correlated with the increment of intracellular ROS production (R = 0.6 - 0.7, P = 0.002), but negatively correlated with the reduction of TAC levels (R = -0.4 - 0.5, P = 0.02 - 0.004). However, the presence of NAGE in the culture medium significantly increased the TAC levels, while concomitantly decreasing both ROS production and MN yields in PBL (P<0.001). Our findings that NAGE is effective in protecting human PBL against radiation-induced oxidative stress should encourage further in vivo study of dietary supplementation with NAGE as an effective natural radiation countermeasure. Originally published Open Nuclear Medicine Journal Vol 1 No. 1, 2009.