Cross-talk between disulfidptosis and immune check point genes defines the tumor microenvironment for the prediction of prognosis and immunotherapies in glioblastoma.

Disulfidptosis is a condition where dysregulated NAPDH levels and abnormal accumulation of cystine and other disulfides occur in cells with high SLC7A11 expression under glucose deficiency. This disrupts normal formation of disulfide bonds among cytoskeletal proteins, leading to histone skeleton collapse and triggering cellular apoptosis. However, the correlation between disulfidptosis and immune responses in relation to glioblastoma survival rates and immunotherapy sensitivity remains understudied. Therefore, we utilized The Cancer Genome Atlas and The Chinese Glioma Genome Atlas to identify disulfidptosis-related immune checkpoint genes and established an overall survival (OS) prediction model comprising six genes: CD276, TNFRSF 14, TNFSF14, TNFSF4, CD40, and TNFRSF18, which could also be used for predicting immunotherapy sensitivity. We identified a cohort of glioblastoma patients classified as high-risk, which exhibited an upregulation of angiogenesis, extracellular matrix remodeling, and epithelial-mesenchymal transition as well as an immunosuppressive tumor microenvironment (TME) enriched with tumor associated macrophages, tumor associated neutrophils, CD8 + T-cell exhaustion. Immunohistochemical staining of CD276 in 144 cases further validated its negative correlation with OS in glioma. Disulfidptosis has the potential to induce chronic inflammation and an immunosuppressive TME in glioblastoma.

A New HPV score System Predicts the Survival of Patients With Cervical Cancers.

Persistent high-risk human papillomavirus (hrHPV) infection is confirmed as the major cause of cervical cancer. According to the HPV infection status, cervical cancer could be generalized as following three subgroups: HPV-negative, pure HPV-infection, and HPV-integration. Currently, the impact of HPV status on cervical cancer prognosis remains under dispute. Therefore, we explored the potential correlation between HPV status and the clinical outcome of cervical cancer, by establishing a robust prognostic predicting model based on a cervical cancer cohort using The Cancer Genome Atlas (TCGA) database. We performed an iCluster algorithm incorporating DNA copy number variation, SNP, DNA methylation, mRNA expression, and miRNA expression profile together and classified the cohort into three clusters. According to defined clusters, we established an HPV score system by weighing resultant gene alterations through random forest and COX models. This prediction tool could help to identify cervical cancer prognosis through evaluating individual HPV infection status and subsequent genetic modification, which might provide insights into HPV-related gene driven cervical cancer treatment strategies, yet its predictive power and robustness need to be further verified with independent cohorts.

Identification of Potential Driver Genes Based on Multi-Genomic Data in Cervical Cancer.

Background: Cervical cancer became the third most common cancer among women, and genome characterization of cervical cancer patients has revealed the extensive complexity of molecular alterations. However, identifying driver mutation and depicting molecular classification in cervical cancer remain a challenge. Methods: We performed an integrative multi-platform analysis of a cervical cancer cohort from The Cancer Genome Atlas (TCGA) based on 284 clinical cases and identified the driver genes and possible molecular classification of cervical cancer. Results: Multi-platform integration showed that cervical cancer exhibited a wide range of mutation. The top 10 mutated genes were TTN, PIK3CA, MUC4, KMT2C, MUC16, KMT2D, SYNE1, FLG, DST, and EP300, with a mutation rate from 12 to 33%. Applying GISTIC to detect copy number variation (CNV), the most frequent chromosome arm-level CNVs included losses in 4p, 11p, and 11q and gains in 20q, 3q, and 1q. Then, we performed unsupervised consensus clustering of tumor CNV profiles and methylation profiles and detected four statistically significant expression subtypes. Finally, by combining the multidimensional datasets, we identified 10 potential driver genes, including GPR107, CHRNA5, ZBTB20, Rb1, NCAPH2, SCA1, SLC25A5, RBPMS, DDX3X, and H2BFM. Conclusions: This comprehensive analysis described the genetic characteristic of cervical cancer and identified novel driver genes in cervical cancer. These results provide insight into developing precision treatment in cervical cancer.

Weekly versus triweekly cisplatin-alone adjuvant chemoradiotherapy after radical hysterectomy for stages IB-IIA cervical cancer with risk of recurrence.

Weekly and triweekly cisplatin-alone concomitant chemoradiotherapy regimens after radical surgery were compared in stages IB-IIA cervical cancer with intermediate- or high-risk factors to identify the better therapeutic regimen. We retrospectively analyzed patients with stages IB-IIA cervical cancer who received radical hysterectomy followed by concurrent adjuvant chemoradiotherapy to compare the efficiency between weekly and triweekly regimen groups. We evaluated between-group differences in survival, recurrence, compliance, and adverse effects. A total of 217 patients were included in this study (triweekly group vs. weekly group; 97 vs. 120). The mean follow-up was 47.2 months. The 5-year disease-free survival (DFS) was 84.4% or 76.5% for patients treated with triweekly cisplatin chemotherapy or the weekly regimen, respectively (P = 0.110). The 5-year overall survival (OS) was 82.4 and 78.6% for the same treatment groups, respectively (P = 0.540). The DFS of the patients with pelvic lymph node metastasis were marginally better in triweekly regimen group compared with the weekly group (P = 0.031). Grades 3-4 leukopenia was significantly more common in the triweekly group (P = 0.028). The weekly cisplatin chemotherapy group experienced the same therapeutic effect as the triweekly cisplatin-alone chemotherapy group but with less toxicity. However, triweekly cisplatin regimen reduced the recurrence in patients with pelvic lymph node metastasis.

LINC01305 inhibits malignant progression of cervical cancer via miR-129-5p/Sox4 axis.

BACKGROUND: The association between LINC01305, a newly discovered long non-coding RNA (lncRNA), and cervical cancer (CC) has been poorly analyzed. In the present study, we revealed high expression of LINC01305 in CC by the cancer genome atlas (TCGA) and Gene Expression Omnibus (GEO), and dissected the related mechanisms. METHODS: LINC01305, microRNA (miR) -129-5p and SRY-related high-mobility group box 4 (Sox4) mRNA levels were quantitated by quantitative reverse transcription-PCRy qRT-PCR). CC tissues and cell lines and corresponding controls were enrolled for the quantification of LINC01305 expression in CC. Effects of LINC01305 and miR-129-5p on cell proliferation, metastasis, and apoptosis were evaluated by MTT, colony formation, wound healing, Transwell and flow cytometry assays. Sox4 protein levels were tested by Western blot (WB). Bioinformatics analysis, RNA immunoprecipitation (RIP), RNA pull-down and dual-luciferase reporter (DLR) assay were performed to determine molecular mechanisms of LINC01305 in CC. Xenograft models of CC were constructed to evaluate the role of LINC01305 in vivo. RESULTS: The expression of LINC01305 was evidently elevated in CC tissues and cell lines than that in controls and associated with clinicopathological features. Downregulating LINC01305 suppressed malignant phenotypes (proliferation, migration, invasion) of Hela and SiHa cells. In addition, silencing miR-129-5p by its inhibitor eliminated the inhibition of growth and metastasis induced by LINC01305 siRNA. Sox4 might serve as a direct target for miR-129-5p and was negatively regulated by miR-129-5p and LINC01305. CONCLUSION: LINC01305 acts as a competitive endogenous RNA (ceRNA) and regulates Sox4 via sponging miR-129-5p, contributing to the diagnosis and treatment of CC.

Building radiation-resistant model in triple-negative breast cancer to screen radioresistance-related molecular markers.

BACKGROUND: To build the triple-negative breast cancer (TNBC) radiation resistance model in vitro and vivo, and screen the molecular markers that related to radiation resistance. METHODS: We used X-ray to irradiate MDA-MB-231 cells repeatedly to build radioresistant cell (231-RR), then select one gemcitabine-resistance of MDA-MB-231 cell (231-GEM). We screen differentially expressed genes of these cell lines. Then, we would select 2 genes of them associated with DNA damage repair or cell cycle, and build RNAi lentivirus vector to knock down related gene. We also used X-rays repeatedly exposure TNBC tumor xenograft to build tumor with radioresistance properties, and then verify previously screening differentially expressed genes using IHC. Finally, we used The Cancer Genome Atlas (TCGA) database to validate the relationships between radioresistance related genes and the prognosis of breast cancer. RESULTS: We got 161 up-regulated genes and 156 down-regulated genes from three cell lines. Cellular results show the 231-cell with knock-down CDKN1A or SOD2 gene, its radiation sensitivity was significantly enhanced. We successfully got the TNBC xenograft tumor with radioresistance properties. Immunohistochemical results show that the radioresistance of tumor tissue with higher p21 (CDKN1A encoding protein) and SOD2 expression (P<0.01). The prognosis of patients with low SOD2 expression is better than that of high expression, but have no statistical significance (P=0.119); patients with low CDKN1A expression is significantly better than high expression (P=0.000). Multivariate cox analysis manifest that CDKN1A gene expression level is an independent prognostic factor in breast cancer patient (P=0.008). CONCLUSIONS: Construction of radiation resistance cell and xenograft tumor with radio-resistant properties model for radiation biology research is feasible. High SOD2 and CDKN1A is associated with the poor prognosis in breast cancer patients. These two genes could be used as a predicted makers of breast cancer radiation sensitivity.

Weekly versus triweekly cisplatin-based concurrent chemoradiotherapy in the treatment of locally advanced cervical carcinoma: An updated meta-analysis based on randomized controlled trials.

BACKGROUND: Radiotherapy concurrent with cisplatin is the standard regimen used for treatment of locally advanced cervical carcinoma. In this meta-analysis, survival, recurrence, compliance, and acute adverse effects were compared between weekly and triweekly cisplatin-based concurrent chemoradiotherapy regimens for treatment of cervical cancer. METHODS: A systematic search for relevant studies was conducted using PubMed, Cochrane Library, EMBASE, and Medline databases. Fixed- or random-effects models were used for pooled analysis. The endpoints were overall survival, recurrence, compliance, and acute adverse effects reported as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Eight randomized controlled trials met the inclusion criteria. No significant differences were observed between the 2 arms with respect to recurrence, survival, and acute adverse effects (all P > .05). However, the triweekly cisplatin regimen was associated with significantly lower incidence of local recurrence (OR, 1.72; 95% CI, 1.07-2.78; P = .03), radiotherapy completion (OR, 2.08; 95% CI, 0.99-4.38; P = .05), and anemia (OR, 2.10; 95% CI, 1.01-4.37; P = .05), while a weekly cisplatin regimen was associated with a lower risk of leukopenia (OR, 0.57; 95% CI, 0.42-0.92; P = .00) and thrombocytopenia (OR, 0.55; 95% CI, 0.31-0.97; P = .04). CONCLUSIONS: Triweekly cisplatin-based chemotherapy significantly reduced local recurrence with tolerable toxicity and might be the optimal regimen in concurrent chemoradiotherapy for locally advanced cervical carcinoma.

The prognostic value of excission repair cross-complementation group one enzyme expression in locally advanced cervical carcinoma patients treated with cisplatin-based treatment: a meta-analysis.

BACKGROUND: Recently, several studies observed that locally advanced cervical carcinoma with negative excision repair crross-complementation group one enzyme expression has better outcomes in cisplatin-based chemotherapy or chemoradiotherapy than carcinoma with positive excission repair cross-complementation group one enzyme expression. In this meta-analysis, we quantitatively evaluated the prognostic value of excission repair cross-complementation group one enzyme expression in locally advanced cervical carcinoma patients receiving platinum-based chemotherapy or chemoradiotherapy. MATERIALS: A systematic search for relevant studies was conducted in the PubMed, Cochrane Library, EMBASE and Medline databases. Fixed- or random-effects models were used for pooled analysis. The endpoints were overall survival and disease-free survival () reported as ORs and 95% CIs. The effects of excission repair cross-complementation group one enzyme expression on the clinicopathological parameters were measured by the pooled ORs and their 95% CIs. RESULTS: Eight studies (612 patients in total) satisfied the inclusion criteria. Negative/low excission repair cross-complementation group one enzyme expression was significantly associated with better overall survival (OR, 1.92; 95% CI, 1.22 to 3.05; P = 0.005) and disease-free survival (OR, 5.77; 95% CI, 1.90 to 17.54; P = 0.002). Additionally, there were significant associations between excission repair cross-complementation group one enzyme expression and lymph node metastasis (OR, 2.57; 95% CI, 1.28 to 5.16; P = 0.008). CONCLUSIONS: This meta-analysis suggested that pretreatment excission repair cross-complementation group one enzyme expression might be a useful biomarker to predict prognoses for locally advanced cervical carcinoma patients receiving platinum-based chemotherapy or chemoradiotherapy.

Combined pretreatment with 18F-FDG PET/CT and Comet assay guides the concurrent chemoradiotherapy of locally advanced cervical cancer: study protocol for a randomized controlled trial.

BACKGROUND: Cisplatin-based chemoradiation is the standard of care for patients with locally advanced cervical cancer. Nevertheless, an increasing number of radio-resistant tumors still recur. METHODS AND DESIGN: Three hundred cervical cancer patients with FIGO stages IB2-IVA and no para-aortic lymphadenopathy (> 10 mm) will be enrolled. All patients will be randomly divided into four arms to receive either (1) intensity modulated radiation therapy (IMRT), (2) RapidArc, (3) positron emission tomography/computed tomography (PET/CT) with F-18 fluorodeoxyglucose (FDG), or (4) Comet assay-guided IMRT, PET/CT, and Comet assay-guided RapidArc. All patients will receive definitive radiotherapy consisting of external beam whole pelvic radiation therapy and high-dose rate intracavitary brachytherapy. Cisplatin 30 mg/m2 weekly will be administered concurrently for five courses. Two to four cycles of TP (Taxol 135 mg/m2, D1, and DDP 75 mg/m2, D1-3) sequential chemotherapy will be performed according to MRI or PET/CT after cisplatin-based chemoradiation. The primary outcome measure is progression-free survival, and the second outcome measures are overall survival and time to progression. DISCUSSION: RapidArc has an obvious advantage in improving the degree of target coverage, improving organs at risk, sparing healthy tissue, and significantly reducing the treatment time. FDG-PET/CT can increase the agreement between biopsies and delineated tumor volume and has the potential to positively impact the course of treatment. The Comet assay is attractive as a potential clinical test of tumor radiosensitivity. During radiotherapy, accurately defining disease areas is critical to avoid the unnecessary irradiation of normal tissue. Based on FDG-PET/CT and Comet assay, higher doses can be safely delivered to accurate tumor volumes, while the doses to the bladder and rectum are relatively low. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration and Results System Receipt Release Date: May 21, 2017 - Retrospectively registered. NCT03163979 .

Concurrent weekly single cisplatin vs triweekly cisplatin alone with radiotherapy for treatment of locally advanced cervical cancer: a meta-analysis.

Background: Radiotherapy (RT) concurrent with cisplatin (CDDP) is the standard regimen used for treatment of locally advanced cervical carcinoma. In this meta-analysis, we compared the weekly and triweekly single CDDP concomitant chemoradiation regimens for treatment of cervical cancer with respect to compliance, recurrence, survival, and acute adverse effects. Materials and methods: A systematic search for relevant studies was conducted in PubMed, Cochrane Library, EMBASE, and Medline databases. Fixed- or random-effects model was used for pooled analysis. The end points were overall survival, recurrence, compliance, and acute adverse effect reported as odds ratios (ORs) and 95% CIs. Results: Six randomized trials and two retrospective studies qualified the inclusion criteria. The regimen of triweekly CDDP alone concurrent with RT showed better compliance (OR, 0.49; 95% CI, 0.29-0.83; P=0.009). No significant difference was observed between the 2 arms with respect to recurrence, survival, and acute adverse effects (all P>0.05). However, triweekly CDDP regimen was associated with significantly lower incidence of local recurrence (OR, 1.83; 95% CI: 1.12-3.01; P=0.02), while weekly CDDP regimen was associated with a lower risk of leucopenia (OR, 0.30; 95% CI: 0.10-0.92; P=0.03). Conclusion: Triweekly single platinum chemotherapy plus concurrent RT was superior to weekly CDDP regimen with respect to local recurrence and treatment compliance in patients with locally advanced cervical carcinoma.

Estrogen Receptor Mediates the Radiosensitivity of Triple-Negative Breast Cancer Cells.

BACKGROUND This study aimed to evaluate differences in the radiosensitivities of triple-negative breast cancer (TNBC) and luminal-type breast cancer cells and to investigate the effects of estrogen receptor (ER) expression on the biological behaviors of the cells. MATERIAL AND METHODS Colony-forming assays were performed to detect differences in radiosensitivities in breast cancer cell lines. Gene transfection technology was used to introduce the expression of ERα in TNBC cells to compare the difference in radiosensitivity between the TNBC cells and ERα transfected cells. CCK-8 assays were used to observe changes in the proliferation of TNBC cells after ERα transfection. Immunofluorescence was used to detect the number of γH2AX foci in nuclei. Flow cytometry was used to detect changes in cell cycle distribution and apoptosis. Western blotting was used to detect changes in autophagy-associated proteins. RESULTS The radioresistance of the TNBC cell line MDA-MB-231 (231 cells) was greater than that of ERα-positive luminal-type breast cancer cell line MCF-7. Moreover, 231 cell proliferation and radioresistance decreased after ERα transfection. Interestingly, ERα-transfected 231 cells showed increased double-stranded breaks and delayed repair compared with 231 cells, and ERα-transfected 231 cells showed increased G2/M phase arrest and apoptosis after irradiation compared with those in 231 cells. ERα transfection in 231 cells reduced autophagy-related protein expression, suggesting that autophagy activity decreased in 231 ER-positive cells after irradiation. CONCLUSIONS TNBC cells were more resistant to radiation than luminal-type breast cancer cells. ERα expression may have major roles in modulating breast cancer cell radiosensitivity.

Early Local Recurrence Presents Adverse Effect on Outcomes of Primary Breast Sarcoma: A Retrospective Study From Single Institute in China.

Primary breast sarcomas (PBSs) are spectrum heterogeneous sarcomas in breast and the optimal treatment for them is still under discussion. Our study was to investigate clinical characteristics and identify potential prognostic factors for this rare malignancy. The authors retrospectively reviewed 38 patients with PBSs between October 2000 and February 2014 in FuDan University Shanghai Cancer Center. Local control rate and overall survival (OS) were determined by Kaplan-Meier actuarial method. Univariate analysis and Cox proportional hazards model were applied to identify potential prognostic factors. With median follow-up of 40.19 months, 14 patients (14/38) were found with local recurrence. Extensive operation like mastectomy was not superior to local resection (P = 0.167). Three-year recurrence-free survival and OS rate were 61.9% and 89%, respectively. Larger tumor size and local recurrence were indicated as unfavorable prognostic factors in univariate analysis. Cox model identified narrow interval of recurrence free survival as an unfavorable factor (P = 0.048). Surgery remains crucial treatment for PBSs. Mastectomy, however, is not routinely necessary if clear margin could be achieved by local excision. Early recurrence indicates a poor OS.

Significance of XRCC1 Codon399 polymorphisms in Chinese patients with locally advanced nasopharyngeal carcinoma treated with radiation therapy.

AIM: Little is known about the relationship between XRCC1 Codon399 polymorphisms and radiotherapy (RT) outcomes in patients with nasopharyngeal carcinoma (NPC). We aimed to investigate whether XRCC1 Codon399 polymorphisms were correlated to treatment efficacy and normal tissue toxicity in Chinese patients with locally advanced NPC after RT. METHODS: Sixty eligible patients with NPC stage III-IVa were recruited. Patients received definitive RT, 66-76 Gy. One cycle neoadjuvant chemotherapy with docetaxel and cisplatin regimen was used before RT, two or three cycles for concurrent chemo-RT followed by two to four cycles adjuvant chemotherapy with the same regimen. Before the treatment, XRCC1 Codon399 polymorphisms were determined by polymerase chain reaction based ligase detection reaction methods. RESULTS: Six of 60 NPC patients were homozygous for XRCC1 Codon399 Gln/Gln and 35% were heterozygous. The expressions of genotypes were unrelated to gender, age, clinical stage, T stage or N stage. Codon399 Gln/Gln allele correlated with a higher medium-term tumor regression ratio after RT for primary nasopharyngeal neoplasm and metastatic lymph nodes (>80% vs 40-60%, P < 0.01). Compared with other two genotypes, patients with XRCC1 Codon399 Gln/Gln allele were more likely to obtain complete remission of tumor (100% vs 76 and 67%, P > 0.05). No correlation between XRCC1 Codon399 polymorphisms and acute or late radiation-induced injury of normal tissues was observed. CONCLUSIONS: The XRCC1 Codon399 Gln/Gln allele may be associated with better tumor regression, and is suggested as a promising predictive factor for outcome for locally advanced NPC. Further study with larger samples and long-time follow-up is needed for accurate assessment.

Management experiences of primary angiosarcoma of breast: a retrospective study from single institute in the People's Republic of China.

BACKGROUND: Primary angiosarcoma of breast (PAOB) is a rare and highly aggressive malignancy. There is no general agreement on optimal treatments or prognostic factors for this orphan disease. The objective of this study was to investigate the clinicopathologic features and management experiences of PAOB. METHODS: We performed a retrospective review of medical and pathologic records of 17 consecutive patients diagnosed with PAOB between January 2000 and February 2014 at FuDan University Shanghai Cancer Center. We evaluated the clinical characteristics, multimodality treatments, and associated clinical outcomes. RESULTS: A total of 16 patients were included in this retrospective study (median age at PAOB presentation 33.5 years, range: 19-56 years). Palpable tumor with or without breast skin ecchymosis presented as the most common initial symptom. All patients underwent surgery with curative intent. Median disease-free survival and overall survival (OS) were 9 months and 13.6 months, respectively. One-year and 3-year disease-free survival rates were 43.8% and 6.3%, with OS rates of 93.8% and 78.1%, respectively. High histologic grade indicated poorer OS by univariate analysis (P=0.01). However, neither adjuvant chemotherapy nor radiotherapy contributed to clinical outcomes in our series. CONCLUSION: PAOB is considered as an infrequent breast neoplasm with aggressive characteristics. Histologic grade and early metastasis (within 12 months after diagnosis) are associated with poor prognosis. Regardless of grade, additional benefit was not observed with adjuvant therapy.