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  1. Article ; Online: Pathologic Processing of Lung Cancer Resection Specimens After Neoadjuvant Therapy.

    Weissferdt, Annikka / Leung, Cheuk H / Lin, Heather / Sepesi, Boris / William, William N / Swisher, Stephen G / Cascone, Tina / Lee, J Jack / Pataer, Abujiang

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

    2023  Volume 37, Issue 1, Page(s) 100353

    Abstract: Neoadjuvant treatment of non-small cell lung cancer challenges the traditional processing of pathology specimens. Induction therapy before resection allows evaluation of the efficacy of neoadjuvant agents at the time of surgery. Many clinical trials use ... ...

    Abstract Neoadjuvant treatment of non-small cell lung cancer challenges the traditional processing of pathology specimens. Induction therapy before resection allows evaluation of the efficacy of neoadjuvant agents at the time of surgery. Many clinical trials use pathologic tumor response, measured as major pathologic response (MPR, ≤10% residual viable tumor [RVT]) or complete pathologic response (CPR, 0% RVT) as a surrogate of clinical efficacy. Consequently, accurate pathologic evaluation of RVT is crucial. However, pathologic assessment has not been uniform, which is particularly true for sampling of the primary tumor, which instead of the traditional processing, requires different tissue submission because the focus has shifted from tumor typing alone to RVT scoring. Using a simulation study, we analyzed the accuracy rates of %RVT, MPR, and CPR of 31 pretreated primary lung tumors using traditional grossing compared with the gold standard of submitting the entire residual primary tumor and identified the minimum number of tumor sections to be submitted to ensure the most accurate scoring of %RVT, MPR, and CPR. Accurate %RVT, MPR, and CPR calls were achieved in 52%, 87%, and 81% of cases, respectively, using the traditional grossing method. Accuracy rates of at least 90% for these parameters require either submission of all residual primary tumor or at least 20 tumor sections. Accurate %RVT, MPR, and CPR scores cannot be achieved with traditional tumor grossing. Submission of the entire primary tumor, up to a maximum of 20 sections, is required for the most accurate reads.
    MeSH term(s) Humans ; Lung Neoplasms/surgery ; Lung Neoplasms/drug therapy ; Carcinoma, Non-Small-Cell Lung/surgery ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Neoadjuvant Therapy/methods ; Lung/pathology ; Treatment Outcome
    Language English
    Publishing date 2023-10-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 645073-8
    ISSN 1530-0285 ; 0893-3952
    ISSN (online) 1530-0285
    ISSN 0893-3952
    DOI 10.1016/j.modpat.2023.100353
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  2. Article ; Online: Major Pathologic Response and Prognostic Score Predict Survival in Patients With Lung Cancer Receiving Neoadjuvant Chemotherapy.

    Pataer, Apar / Weissferdt, Annikka / Correa, Arlene M / Vaporciyan, Ara A / Sepesi, Boris / Heymach, John V / Berezowska, Sabina / Cascone, Tina / Swisher, Stephen G

    JTO clinical and research reports

    2022  Volume 3, Issue 11, Page(s) 100420

    Abstract: Introduction: Complete pathologic response (CPR) is an acceptable surrogate for survival in clinical trials but it occurs infrequently in patients with NSCLC receiving neoadjuvant chemotherapy (NCT). Therefore, we studied the impact of major pathologic ... ...

    Abstract Introduction: Complete pathologic response (CPR) is an acceptable surrogate for survival in clinical trials but it occurs infrequently in patients with NSCLC receiving neoadjuvant chemotherapy (NCT). Therefore, we studied the impact of major pathologic response (MPR) for predicting survival of patients with NSCLC receiving NCT. We also tested a newly reported scoring system-the prognostic score (PRSC)-which combines T category, lymph node status, and MPR status.
    Methods: We analyzed CPR and MPR, defined as 0% and less than or equal to 10% viable tumor cells, respectively, in 339 patients with NSCLC with various histologic types who had been treated with NCT followed by complete surgical resection. We evaluated the relationships between CPR, MPR, or PRSC and overall survival using the Kaplan-Meier method and Cox regression multivariate models, accounting for known prognostic factors, such as age, gender, histologic subtype, and pathologic stage.
    Results: Among all 339 patients, the Kaplan-Meier method revealed that patients with CPR and MPR had better survival. MPR identified a favorable group of patients who experienced survival similar to patients with CPR. Nevertheless, patients with no MPR had a significantly reduced probability of survival. Furthermore, univariate and multivariate Cox proportional hazards regression analysis revealed that MPR and PRSC were significantly associated with overall survival.
    Conclusions: Our data suggest that MPR can be used as an end point for overall survival in different histologic types for evaluation of therapeutic agents in clinical trials exploring NCT. We also confirmed that PRSC had a prognostic impact, differentiating patients into three prognostic groups, but not superior compared with MPR alone or the TNM8 systems.
    Language English
    Publishing date 2022-09-30
    Publishing country United States
    Document type Journal Article
    ISSN 2666-3643
    ISSN (online) 2666-3643
    DOI 10.1016/j.jtocrr.2022.100420
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  3. Article ; Online: Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer.

    Tan, Xiaochao / Wang, Shike / Xiao, Guan-Yu / Wu, Chao / Liu, Xin / Zhou, Biyao / Yu, Jiang / Duose, Dzifa Yawa / Xi, Yuanxin / Wang, Jing / Gupta, Kunika / Pataer, Apar / Roth, Jack A / Kim, Michael P / Chen, Fengju / Creighton, Chad J / Russell, William K / Kurie, Jonathan M

    The Journal of clinical investigation

    2024  

    Abstract: Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including ... ...

    Abstract Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase Secretory Pathway Ca2+ Transporting 1 (ATP2C1). We show that GOLIM4 recruits ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate calcium-dependent cargo loading and Golgi membrane bending and vesicle scission. GOLIM4 depletion disrupts the protein complex, resulting in a secretory blockade that inhibits the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintains intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiates the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibits the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupts pro-survival autocrine loops and attenuates pro-metastatic processes in the tumor microenvironment. Potentially underlying the selective activity of Mn against 3q-amplified malignancies, ATP2C1 co-amplification increases Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between co-amplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies.
    Language English
    Publishing date 2024-04-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI176355
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  4. Article ; Online: Controversies and challenges in the pathologic examination of lung resection specimens after neoadjuvant treatment.

    Weissferdt, Annikka / Pataer, Apar / Swisher, Stephen G / Heymach, John V / Gibbons, Don L / Cascone, Tina / Sepesi, Boris

    Lung cancer (Amsterdam, Netherlands)

    2021  Volume 154, Page(s) 76–83

    Abstract: New therapy approaches in the treatment of surgically resectable non-small cell lung cancer (NSCLC) challenge the traditional handling and examination of pathology specimens. The increasingly common use of neoadjuvant therapies before surgical resection, ...

    Abstract New therapy approaches in the treatment of surgically resectable non-small cell lung cancer (NSCLC) challenge the traditional handling and examination of pathology specimens. The increasingly common use of neoadjuvant therapies before surgical resection, due to advantages in novel drug administration, tolerance, and measurement of radiographic and pathologic response compared to adjuvant treatment, has the potential to alter the microscopic tumor appearance and its biology. Currently, many clinical trials use pathologic response as a surrogate endpoint of clinical efficacy, since the extent of residual viable tumor appears to correlate with outcome in patients treated with neoadjuvant chemotherapy. Consequently, pathologic assessment of the extent of residual viable tumor is of paramount importance. However, high level evidence-based guidelines on how to process and evaluate such specimens are lacking. Moreover, while pathologic response has been shown to be associated with survival after chemotherapy, its significance after immunotherapy remains to be determined. Additionally, many clinical trials do not routinely include pathologists in trial design, which may lead to non-standardized evaluation of pathologic response. Although recently, several algorithms have been proposed to address these issues, none of them represents evidence-based recommendations or is universally applied. Therefore, controversies and challenges continue to exist, raising concerns about the validity, reproducibility, and comparability of the results of many neoadjuvant clinical trials. Herein, we discuss the current difficulties in pathologic specimen evaluation following neoadjuvant therapy in NSCLC and propose potential approaches to overcome these challenges.
    MeSH term(s) Carcinoma, Non-Small-Cell Lung/drug therapy ; Chemotherapy, Adjuvant ; Humans ; Lung ; Lung Neoplasms/drug therapy ; Neoadjuvant Therapy ; Reproducibility of Results
    Language English
    Publishing date 2021-02-17
    Publishing country Ireland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 632771-0
    ISSN 1872-8332 ; 0169-5002
    ISSN (online) 1872-8332
    ISSN 0169-5002
    DOI 10.1016/j.lungcan.2021.02.014
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  5. Article ; Online: Membrane-Protected Molecularly Imprinted Polymer for the Microextraction of Indole-3-butyric Acid in Mung Bean Sprouts.

    Aihebaier, Sailemayi / Muhammad, Turghun / Wei, Aixia / Mamat, Anwar / Abuduaini, Munira / Pataer, Parezhati / Yigaimu, Aziguli / Yimit, Abliz

    ACS omega

    2019  Volume 4, Issue 16, Page(s) 16789–16793

    Abstract: Based on the hollow fiber protected molecularly imprinted polymer, a micro-solid-phase extraction (μ-SPE) method was developed and applied for the analysis of indole-3-butyric acid in mung bean sprouts by high-performance liquid chromatography. The ... ...

    Abstract Based on the hollow fiber protected molecularly imprinted polymer, a micro-solid-phase extraction (μ-SPE) method was developed and applied for the analysis of indole-3-butyric acid in mung bean sprouts by high-performance liquid chromatography. The extraction conditions of the μ-SPE method were optimized using L
    Language English
    Publishing date 2019-10-01
    Publishing country United States
    Document type Journal Article
    ISSN 2470-1343
    ISSN (online) 2470-1343
    DOI 10.1021/acsomega.9b01550
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  6. Article ; Online: Surgical outcomes after chemotherapy plus nivolumab and chemotherapy plus nivolumab and ipilimumab in patients with non-small cell lung cancer.

    Feldman, Hope / Sepesi, Boris / Leung, Cheuk H / Lin, Heather / Weissferdt, Annikka / Pataer, Apar / William, William N / Walsh, Garrett L / Rice, David C / Roth, Jack A / Mehran, Reza J / Hofstetter, Wayne L / Antonoff, Mara B / Rajaram, Ravi / Gibbons, Don L / Lee, J Jack / Heymach, John V / Vaporciyan, Ara A / Swisher, Stephen G /
    Cascone, Tina

    The Journal of thoracic and cardiovascular surgery

    2023  Volume 167, Issue 4, Page(s) 1444–1453.e4

    Abstract: Objective: Chemotherapy plus nivolumab is the standard of care neoadjuvant treatment for patients with resectable stage IB to IIIA non-small cell lung cancer. The influence of dual checkpoint blockade with chemotherapy on surgical outcomes remains ... ...

    Abstract Objective: Chemotherapy plus nivolumab is the standard of care neoadjuvant treatment for patients with resectable stage IB to IIIA non-small cell lung cancer. The influence of dual checkpoint blockade with chemotherapy on surgical outcomes remains unknown. We aimed to determine operative complexity and perioperative outcomes associated with neoadjuvant chemotherapy and nivolumab with or without ipilimumab.
    Methods: A total of 44 patients with stage IB (≥4 cm) to IIIA non-small cell lung cancer were treated on sequential platform arms of the NEOSTAR trial. A total of 22 patients were treated with nivolumab + chemotherapy, and 22 patients were treated with ipilimumab + nivolumab + chemotherapy. The safety of surgical resection after neoadjuvant therapy was estimated using 30-day complication rates. Operative reports and surgeons' narratives were evaluated to determine procedural complexity and operative conduct.
    Results: All 22 of 22 patients (100%) treated with nivolumab + chemotherapy underwent surgical resection: 20 R0 (90.9%), 17 (77.3%) lobectomies, 1 wedge resection, 2 segmentectomies, and 2 pneumonectomies. The majority, 21 of 22 (95%), were performed by thoracotomy. A total of 13 of 22 (59.1%) were rated as challenging resections. A total of 4 of 22 patients (18.2%) experienced grade 3 or greater Clavien-Dindo complication. A total of 20 of 22 patients (90.9%) treated with ipilimumab + nivolumab + chemotherapy underwent surgical resection: 19 R0 (95%), 18 (90%) lobectomies, 1 pneumonectomy, and 1 segmentectomy. A total of 16 of 20 (80%) resections were performed via thoracotomy, 3 of 20 (15%) via robotics, and 1 of 20 (5%) via thoracoscopy. A total of 9 of 20 (45%) resections were considered challenging. A total of 4 of 20 patients (20%) experienced grade 3 or greater Clavien-Dindo complication.
    Conclusions: Surgical resections are feasible and safe, with high rates of R0 after neoadjuvant chemotherapy and nivolumab with or without ipilimumab. Overall, approximately half of cases (22/42, 52.3%) were considered to be more challenging than a standard lobectomy.
    MeSH term(s) Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/surgery ; Nivolumab ; Ipilimumab/adverse effects ; Lung Neoplasms/drug therapy ; Lung Neoplasms/surgery ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Neoplasm Staging ; Neoadjuvant Therapy/adverse effects ; Treatment Outcome
    Chemical Substances Nivolumab (31YO63LBSN) ; Ipilimumab
    Language English
    Publishing date 2023-10-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3104-5
    ISSN 1097-685X ; 0022-5223
    ISSN (online) 1097-685X
    ISSN 0022-5223
    DOI 10.1016/j.jtcvs.2023.09.073
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  7. Article ; Online: Evaluation of Pathologic Response in Lymph Nodes of Patients With Lung Cancer Receiving Neoadjuvant Chemotherapy.

    Pataer, Apar / Weissferdt, Annikka / Vaporciyan, Ara A / Correa, Arlene M / Sepesi, Boris / Wistuba, Ignacio I / Heymach, John V / Cascone, Tina / Swisher, Stephen G

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

    2021  Volume 16, Issue 8, Page(s) 1289–1297

    Abstract: Introduction: Major pathologic response (MPR), defined as residual viable tumor of less than or equal to 10%, currently serves as a surrogate end point for survival for patients with resectable NSCLC after neoadjuvant chemotherapy. However, the ... ...

    Abstract Introduction: Major pathologic response (MPR), defined as residual viable tumor of less than or equal to 10%, currently serves as a surrogate end point for survival for patients with resectable NSCLC after neoadjuvant chemotherapy. However, the significance of pathologic response in lymph nodes harboring metastatic tumors in such patients remains uncertain. Therefore, we studied the effect of neoadjuvant chemotherapy on resected positive lymph nodes and determined if the degree of pathologic response in the lymph nodes alone (LN-MPR) or in combination with that of the primary tumor (PT-MPR) was able to predict the outcome.
    Methods: A total of 75 patients with NSCLC who underwent neoadjuvant chemotherapy and completed surgical resection were included in this study. Tissue specimens were retrospectively evaluated by two pathologists blinded to the patients' treatments and outcomes. Specimens were reviewed for the degree of pathologic response in the primary tumor and in any involved lymph nodes. The prognostic performance of LN-MPR alone or in combination with PT-MPR with respect to overall survival (OS) was evaluated using the Kaplan-Meier method and Cox regression model.
    Results: LN-MPR was significantly predictive of long-term OS after neoadjuvant chemotherapy. A combination of PT-MPR with LN-MPR was significantly associated with outcome and allowed stratification of patients into three prognostic groups (p = 0.001).
    Conclusions: LN-MPR in isolation is a reliable predictor of OS in patients with NSCLC receiving neoadjuvant chemotherapy. A combination of LN-MPR with PT-MPR seems to correlate well with the outcome and can be used to predict prognosis in this patient population.
    MeSH term(s) Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Humans ; Lung Neoplasms/drug therapy ; Lymph Nodes ; Neoadjuvant Therapy ; Prognosis ; Retrospective Studies
    Language English
    Publishing date 2021-04-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2432037-7
    ISSN 1556-1380 ; 1556-0864
    ISSN (online) 1556-1380
    ISSN 1556-0864
    DOI 10.1016/j.jtho.2021.03.029
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  8. Article ; Online: EF2-kinase targeted cobalt-ferrite siRNA-nanotherapy suppresses

    Asik, Elif / Akpinar, Yeliz / Caner, Ayse / Kahraman, Nermin / Guray, Tulin / Volkan, Murvet / Albarracin, Constance / Pataer, Apar / Arun, Banu / Ozpolat, Bulent

    Nanomedicine (London, England)

    2019  Volume 14, Issue 17, Page(s) 2315–2338

    Abstract: Aim: ...

    Abstract Aim:
    MeSH term(s) Animals ; BRCA1 Protein/genetics ; Breast Neoplasms/genetics ; Breast Neoplasms/therapy ; Cell Line, Tumor ; Cobalt/chemistry ; Elongation Factor 2 Kinase/genetics ; Female ; Ferric Compounds/chemistry ; Gene Expression Regulation, Neoplastic ; Gene Transfer Techniques ; Humans ; Mice, Nude ; Mutation ; Nanomedicine/methods ; Nanoparticles/chemistry ; RNA, Small Interfering/administration & dosage ; RNA, Small Interfering/therapeutic use ; RNAi Therapeutics/methods
    Chemical Substances BRCA1 Protein ; Ferric Compounds ; RNA, Small Interfering ; cobalt ferrite ; Cobalt (3G0H8C9362) ; Elongation Factor 2 Kinase (EC 2.7.11.20)
    Language English
    Publishing date 2019-08-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2277839-1
    ISSN 1748-6963 ; 1743-5889
    ISSN (online) 1748-6963
    ISSN 1743-5889
    DOI 10.2217/nnm-2019-0132
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  9. Article ; Online: Major pathologic response and RAD51 predict survival in lung cancer patients receiving neoadjuvant chemotherapy.

    Pataer, Apar / Shao, Ruping / Correa, Arlene M / Behrens, Carmen / Roth, Jack A / Vaporciyan, Ara A / Wistuba, Ignacio I / Swisher, Stephen G

    Cancer medicine

    2018  Volume 7, Issue 6, Page(s) 2405–2414

    Abstract: In a previous study, we determined that major pathologic response (MPR) as indicated by the percentage of residual viable tumor cells predicted overall survival (OS) in patients with non-small-cell lung cancer (NSCLC) who received neoadjuvant ... ...

    Abstract In a previous study, we determined that major pathologic response (MPR) as indicated by the percentage of residual viable tumor cells predicted overall survival (OS) in patients with non-small-cell lung cancer (NSCLC) who received neoadjuvant chemotherapy. In this study, we assessed whether two genes and five protein biomarkers could predict MPR and OS in 98 patients with NSCLC receiving neoadjuvant chemotherapy. We collected formalin-fixed, paraffin-embedded specimens of resected NSCLC tumors from 98 patients treated with neoadjuvant chemotherapy. We identified mutations in KRAS and EGFR genes using pyrosequencing and examined the expression of protein markers VEGFR2, EZH2, ERCC1, RAD51, and PKR using immunohistochemistry. We assessed whether gene mutation status or protein expression was associated with MPR or OS. We observed that KRAS mutation tended to be associated with OS (P = .06), but EGFR mutation was not associated with OS. We found that patients with high RAD51 expression levels had a poorer prognosis than did those with low RAD51 expression. We also observed that RAD51 expression was associated with MPR. MPR and RAD51 expression were associated with OS in univariate and multivariate analyses (P = .04 and P = .02, respectively). Combination of MPR with RAD51 is a significant predictor of prognosis in patients with NSCLC who received neoadjuvant chemotherapy. We demonstrated that MPR or RAD51 expression was associated with OS in patients with NSCLC receiving neoadjuvant chemotherapy. Prediction of a patient's prognosis could be improved by combined assessment of MPR and RAD51 expression.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/pathology ; Male ; Middle Aged ; Neoadjuvant Therapy/methods ; Rad51 Recombinase/genetics ; Survival Rate
    Chemical Substances RAD51 protein, human (EC 2.7.7.-) ; Rad51 Recombinase (EC 2.7.7.-)
    Language English
    Publishing date 2018-04-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2659751-2
    ISSN 2045-7634 ; 2045-7634
    ISSN (online) 2045-7634
    ISSN 2045-7634
    DOI 10.1002/cam4.1505
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  10. Article ; Online: Accumulation of RNA-dependent protein kinase (PKR) in the nuclei of lung cancer cells mediates radiation resistance.

    Hao, Chuncheng / Shao, Ruping / Raju, Uma / Fang, Bingliang / Swisher, Stephen G / Pataer, Apar

    Oncotarget

    2016  Volume 7, Issue 25, Page(s) 38235–38242

    Abstract: We have previously demonstrated that radiation induced cell death in PKR (-/-) deficient mouse embryo fibroblasts (MEFs) but not in PKR (+/+) wild type MEFs. Our study indicated that PKR can also be involved in survival pathways following radiation ... ...

    Abstract We have previously demonstrated that radiation induced cell death in PKR (-/-) deficient mouse embryo fibroblasts (MEFs) but not in PKR (+/+) wild type MEFs. Our study indicated that PKR can also be involved in survival pathways following radiation therapy through activation of the AKT survival pathways in these MEFs is mediated in part through PKR. The role of PKR on radiation sensitivity in cancer cells has not been evaluated. In this study, we demonstrated that radiation treatment causes nuclear translocation of PKR in human lung cancer cells. The transduction of lung cancer cells with a dominant negative adenoviral PKR vector blocks nuclear translocation of PKR and leads to the reversal of radiation resistance. Plasmid transduction of lung cancer cells with nuclear targeted wild type PKR vectors also increased radiation resistance. This effect is selectively abrogated by plasmid transduction of dominant negative PKR vectors which restore radiation sensitivity. These findings suggest a novel role for PKR in lung cancer cells as a mediator of radiation resistance possibly through translocation of the protein product to the nucleus.
    Language English
    Publishing date 2016-06-21
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.9428
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