Ganetespib overcomes resistance to PARP inhibitors in breast cancer by targeting core proteins in the DNA repair machinery.

DNA damage repair plays essential roles in drug resistance, especially resistance to Poly (ADP-ribose) polymerase (PARP) inhibitors in the clinic. A subset of DNA repair proteins such as Breast cancer gene 1 (BRCA1), BRCA2 and RecA homolog (RAD51) are client proteins of heat shock protein 90 (Hsp90). Clearance of these DNA repair proteins by inhibition of Hsp90 is a promising strategy for overcoming resistance to PARP inhibitors. Here we report the pharmacological analysis of the highly potent second-generation Hsp90 inhibitor, ganetespib. Methods Nuclear BRCA1, BRCA2, and RAD51 expression in breast cancer cells were detected by subcellular fractionation and western blot analysis. Formation of nuclear RAD51 and γ-H2AX foci was analyzed by immunofluorescent staining. The cytotoxicity of ganetespib and ABT-888 in breast cancer cells were evaluated by cell proliferation, colony survival, and apoptosis assay. To investigate the efficacy of this therapy in vivo, SCID mice bearing MCF7 xenografts were treated with ganetespib and ABT-888, both as single agents and in combination. Results Ganetespib significantly destabilized nuclear BRCA1, BRCA2, and RAD51, and efficiently disrupted homologous recombination-mediated DNA double-strand break repair in breast cancer cells. The synergistic antitumor effects of ganetespib and the PARP inhibitor, ABT-888 were observed, and concurrent treatment with both inhibitors synergistically inhibited xenograft tumor growth. Importantly, the combined treatment was well tolerated, without significant loss of body weight or major histological changes in the breast cancer xenograft model. Conclusion These data provide a novel strategy for the treatment of breast cancer with wild type BRCA1 using combination therapy targeting Hsp90 to overcome resistance to PARP inhibitors.

Development of a Rabbit Model of Radiation-Induced Sciatic Nerve Injury: In Vivo Evaluation Using T2 Relaxation Time Measurements.

OBJECTIVES: To develop a rabbit model of radiation-induced sciatic nerve injury (RISNI), using computed tomography (CT)-guided stereotactic radiosurgery, and assess the value of T2 measurements of injured nerves. MATERIALS AND METHODS: Twenty New Zealand rabbits were randomly divided into A (n = 5) and B (n = 15) groups. Group A rabbits underwent CT and magnetic resonance scan and were then killed for comparison of images and anatomy of sciatic nerves. One side of the sciatic nerve of group B rabbits received irradiation doses of 35, 50, or 70 Gy (n = 5 per group). Magnetic resonance imaging and functional assessments were performed before irradiation and 1, 2, 3, and 4 months thereafter. RESULT: The thigh section of the sciatic nerve outside the pelvis could be observed by CT and magnetic resonance imaging. T2 values of the irradiated nerve of the 35-Gy group increased gradually, peaking at 4 months; T2 values of the 50-Gy group increased faster, peaking at 3 months. Significant differences between the 35-Gy and control groups were found at 3 and 4 months, and between the 50-Gy and control groups at 2, 3, and 4 months. Functional scores of the 50-Gy group declined progressively, whereas the 35-Gy group scores reached a low point at 3 months posttreatment and then recovered. Functional scores of the irradiated limbs demonstrated a negative correlation with T2 values (r = -0.591 and -0.595, P < 0.05). Electron microscopy revealed progressive deformation and degeneration of the irradiated nerve in the 35- and 50-Gy groups, which were more severe in the 50-Gy group. CONCLUSIONS: A rabbit RISNI model can be produced using the midthigh segment of the sciatic nerve and single-fraction doses of 35 and 50 Gy. Although T2 values are useful for monitoring RISNI, they may not be sensitive enough to evaluate its severity.

Identifying FGA peptides as nasopharyngeal carcinoma-associated biomarkers by magnetic beads.

Early diagnosis and treatment is known to improve prognosis for nasopharyngeal carcinoma (NPC). The study determined the specific peptide profiles by comparing the serum differences between NPC patients and healthy controls, and provided the basis for the diagnostic model and identification of specific biomarkers of NPC. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) can be used to detect the molecular mass of peptides. Mass spectra of peptides were generated after extracting and purification of 40 NPC samples in the training set, 21 in the single center validation set and 99 in the multicenter validation set using weak cationic-exchanger magnetic beads. The spectra were analyzed statistically using FlexAnalysis™ and ClinProt™ bioinformatics software. The four most significant peaks were selected out to train a genetic algorithm model to diagnose NPC. The diagnostic sensitivity and specificity were 100% and 100% in the training set, 90.5% and 88.9% in the single center validation set, 91.9% and 83.3% in the multicenter validation set, and the false positive rate (FPR) and false negative rate (FNR) were obviously lower in the NPC group (FPR, 16.7%; FNR, 8.1%) than in the other cancer group (FPR, 39%; FNR, 61%), respectively. So, the diagnostic model including four peptides can be suitable for NPC but not for other cancers. FGA peptide fragments identified may serve as tumor-associated biomarkers for NPC.

Chinese literatures of radiation oncology covered by PubMed over the past five years.

BACKGROUND AND OBJECTIVE: PubMed is generally acknowledged for its scientificity in literature coverage and authority of literature retrieval . In recent years, many studies have been published in China about radiation oncology. We aimed to investigate the literatures about radiation oncology in China covered by PubMed over the past five years. METHODS: We collected primary data by searching the PubMed database using the related subject words. The collected data were analyzed and evaluated by bibliometric methods. RESULTS: In the past five years, 550 articles by Chinese authors related to radiotherapy were indexed in PubMed. These articles were published in 160 journals among 26 Chinese provinces/cities. These articles mainly focused on radiation dose and computer-aided radiation therapy. Sixty-four articles were published by Chinese Journal of Cancer , which ranked the top. Forty-four articles were published by the International Journal of Radiation Oncology Biology Physics (IF=4.29), with the largest number among SCI journals. One hundred and sixteen articles from Guangdong Province were covered, accounting for 21.09%. CONCLUSIONS: Over the past five years, the discipline of radiation oncology has been greatly developed. The literatures mainly focus on clinical radiation oncology and their regional distribution is uneven.

CT-diagnosed severe skull base bone destruction predicts distant bone metastasis in early N-stage nasopharyngeal carcinoma.

Bone metastasis is the most frequent type of distant metastasis in nasopharyngeal carcinoma (NPC). In this study, we investigated the correlation between the skull base bone destruction and the distant bone metastasis in patients with NPC. A total of 449 cases with NPC who were diagnosed and had definitive radiotherapy from 2001 to 2006 were enrolled in this study. The skull base bone destruction was diagnosed by computed tomography (CT) in all cases, and 191 patients also underwent magnetic resonance imaging scan. Kaplan-Meier method was adopted to perform the univariate analysis; Cox regression model was used to perform multivariate analysis to determine whether the skull base bone destruction when diagnosed by CT was an independent impact factor of the distant bone metastases. The group with skull base bone destruction had a distant bone metastases rate of 9.0% (14/155), whereas the group without skull base bone destruction had rate of 4.1% (12/294). The multivariate analysis showed that the skull base bone destruction, when diagnosed by CT, was an independent impact factor of the distant bone metastases-free survival in the early N-staging cases, but was not an independent impact factor when diagnosed by MRI. The skull base bone destruction diagnosed by CT in patients with NPC had predictive value for the distant bone metastases, especially for the early N-staging cases.

Glatiramer acetate reverses cognitive deficits from cranial-irradiated rat by inducing hippocampal neurogenesis.

Patients received cranial-irradiation can be affected with cognitive deficits and decreasing hippocampal neurogenesis. In this work, we characterized the cognitive ability and immune-induced neurogenesis of the pre- and post-treated cranial-irradiated rats with Glatiramer acetate (GA), known as a weak CNS auto-antigen. The GA-treated rats displayed better cognitive abilities in Morris water maze (MWM). The numbers of Iba-I-positive microglia, BrdU(+)/DCX(+) cells and BrdU(+)/NeuN(+) cells in hippocampus increased, which are accompanied with increased IFN-γ and decreased IL-6, IL-4. Furthermore, GA reverted the Th1/Th2 balance. GA treatment can reverse the cognitive deficits caused by cranial irradiation through a mechanism that likely involves immunomodulation.

A risk score model for the metastasis of level Ib lymph node based on the clinicopathological features of nasopharyngeal carcinoma in a large sample.

The aim of the present study was to develop a metastatic risk score model of neck level Ib lymph nodes in primary nasopharyngeal carcinoma (NPC) to guide the level Ib radiotherapy. There were a total of 1,557 patients enrolled in the study, and of these patients, 1,145 were included in the training set. Univariate χ2 analysis and multivariate logistic regression analyses were used to screen the independent risk factors to construct the risk score model. A total of 85 patients in the validating set underwent a pathology biopsy of level Ib lymph nodes to test the model. The remaining 327 patients from the prognostic-research set were used to evaluate the prognostic impact of level Ib irradiation in high- and low-risk groups. The independent risk factors in the model were carotid sheath involvement, the maximal diameter of the neck lymph nodes (≥20 mm) and the involvement of the level II/III/IV lymph nodes. The involvement of level IV was assigned score 2 and the other risk factors were assigned score 1. According to the total scores, the patients were divided into the low- (total score, 0-1; level Ib metastasis rate, 0.5%) and high-risk groups (total score, 2-4; level Ib metastasis rate, 8.5%). In the validating set, the metastatic rate of level Ib in 43 low-risk patients was 0%, and the rate was 31.0% (13/42) in 42 high-risk patients. In the prognostic-research set, the prognosis of 137 low-risk patients was not affected by level Ib irradiation. However, level Ib unirradiation was an independent prognostic factor for the locoregional recurrence in 190 high-risk patients. According to the data, the novel score model could help assess the metastatic risk of level Ib in primary NPC, and the radiotherapy on level Ib may impact the locoregional recurrence in high-risk patients.

Expression of GOLPH2 is associated with the progression of and poor prognosis in gastric cancer.

Golgi phosphoprotein 2 (GOLPH2) has been associated with the development and progression of various human cancers. The aims of this study were to investigate the relationship between GOLPH2 and gastric cancer (GC) progression and explore the clinical significance of GOLPH2 in GC. GOLPH2 expression was examined in four pairs of primary GC tissues and the adjacent non-cancerous tissues from the same patients, using immunohistochemistry (IHC), quantitative PCR and western blotting. Furthermore, GOLPH2 protein expression was analyzed in 10 normal gastric tissues and 385 clinicopathologically characterized cases of GC by IHC. Statistical analyses were performed to determine the prognostic and diagnostic associations. GOLPH2 mRNA and protein expression were both markedly upregulated in GC tissues, compared with the paired adjacent non-cancerous tissues. The Chi-square test and Spearman analysis revealed a significant correlation between GOLPH2 expression and clinical stage, T classification, lymph node metastasis, metastasis and venous invasion. Patients with a higher GOLPH2 expression had a shorter overall survival (OS), compared to patients with lower GOLPH2 expression. Notably, our results suggested that GOLPH2 is associated with the development and progression of GC. Therefore, additional studies focusing on the potential of GOLPH2 as a novel therapeutic target in GC are required.