Overexpression of glycosyltransferase 8 domain containing 2 confers ovarian cancer to CDDP resistance by activating FGFR/PI3K signalling axis.

It has been reported that chemotherapy resistance mainly contributed to treatment failure and poor survival in patients with ovarian cancer. Therefore, clarifying the molecular mechanism and identifying effective strategies to overcome drug resistance may play an important clinical impact on this malignant tumor. In our study, we found that the expression of Glycosyltransferase 8 domain containing 2 (GLT8D2) was significantly upregulated in ovarian cancer samples with CDDP (Cis-dichlorodiammine-platinum) resistance. Biological experiment demonstrate that GLT8D2 overexpression confers CDDP resistance on ovarian cancer cells; however, inhibition of GLT8D2 sensitized ovarian cancer cell lines to CDDP cytotoxicity both in vitro and in vivo. By using affinity purification/mass spectrometry (IP/MS) and reciprocal co-immunoprecipitation (co-IP) analyses, we found that GLT8D2 interacts with fibroblast growth factor receptor 1(FGFR1) in ovarian cancer cells. Furthermore, overexpression of GLT8D2 activated FGFR/PI3K signaling axis and upregulated the phosphorylation levels of FRS2a and AKT (AKT serine/threonine kinase). Importantly, pharmacological inhibition of FGFR and PI3K (phosphatidylinositol 3-kinase) signaling pathway significantly counteracted GLT8D2-induced chemoresistance and enhanced platinum's therapeutic efficacy in ovarian cancer. Therefore, our findings suggest that GLT8D2 is a potential therapeutic target for the treatment of ovarian cancer; targeting GLT8D2/FGFR/PI3K/AKT signaling axis may represent a promising strategy to enhance platinum response in patients with chemoresistant ovarian cancer.

Effectiveness of Sequential Chemoradiation vs Concurrent Chemoradiation or Radiation Alone in Adjuvant Treatment After Hysterectomy for Cervical Cancer: The STARS Phase 3 Randomized Clinical Trial.

IMPORTANCE: There is no current consensus on the role of chemotherapy in addition to radiation for postoperative adjuvant treatment of patients with early-stage cervical cancer with adverse pathological factors. OBJECTIVE: To evaluate the clinical benefits of sequential chemoradiation (SCRT) and concurrent chemoradiation (CCRT) compared with radiation alone (RT) as a postoperative adjuvant treatment in early-stage cervical cancer. DESIGN, SETTING, AND PARTICIPANTS: After radical hysterectomy at 1 of 8 participating hospitals in China, patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB to IIA cervical cancer with adverse pathological factors were randomized 1:1:1 to receive adjuvant RT, CCRT, or SCRT. Data were collected from February 2008 to December 2018. INTERVENTIONS: Patients received adjuvant RT (total dose, 45-50 Gy), CCRT (weekly cisplatin, 30-40 mg/m2), or SCRT (cisplatin, 60-75 mg/m2, plus paclitaxel, 135-175 mg/m2) in a 21-day cycle, given 2 cycles before and 2 cycles after radiotherapy, respectively. MAIN OUTCOMES AND MEASURES: The primary end point was the rate of disease-free survival (DFS) at 3 years. RESULTS: A total of 1048 women (median [range] age, 48 [23-65] years) were included in the analysis (350 in the RT group, 345 in the CCRT group, and 353 in the SCRT group). Baseline demographic and disease characteristics were balanced among the treatment groups except that the rate of lymph node involvement was lowest in the RT group (18.3%). In the intention-to-treat population, SCRT was associated with a higher rate of DFS than RT (3-year rate, 90.0% vs 82.0%; hazard ratio [HR], 0.52; 95% CI, 0.35-0.76) and CCRT (90.0% vs 85.0%; HR, 0.65; 95% CI, 0.44-0.96). Treatment with SCRT also decreased cancer death risk compared with RT (5-year rate, 92.0% vs 88.0%; HR, 0.58; 95% CI, 0.35-0.95) after adjustment for lymph node involvement. However, neither DFS nor cancer death risk was different among patients treated with CCRT or RT. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, conducted in a postoperative adjuvant treatment setting, SCRT, rather than CCRT, resulted in a higher DFS and lower risk of cancer death than RT among women with early-stage cervical cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00806117.

Distinguishing Microvasculature Features of Vogt-Koyanagi-Harada in Patients in Acute and Convalescent Phases Using Optical Coherence Tomography Angiography.

Purpose: To evaluate retinal and choroidal microvascular features of VKH patients in acute and convalescent phases after treatment using OCTA.Methods: A prospective, observational study was conducted in patients with initial VKH at the acute stage (n = 15) and healthy participants (n = 15) served as controls. After 3-month systemic corticosteroid treatment, patients' vascular parameters were recorded by OCTA before and after treatment and compared with results observed in healthy participants.Results: Our findings first uncovered that there are two types of abnormalities in the choriocapillary layer of patients with VKH in the acute stage: one is characterized as multiple dark spots of choriocapillary flow void and the other involves highly reflective areas surrounded by light spots with an increased flow area. During the convalescent stage, all eyes showed multifocal dark spots in the choriocapillary layer, leading to a reduced choroidal flow area.Conclusions: OCTA provides a better display of the microvascular appearance of the choroid to noninvasively evaluate choriocapillaris abnormalities in VKH disease.

Quantitative Analysis of Retinal Microvascular Changes after Conbercept Therapy in Branch Retinal Vein Occlusion Using Optical Coherence Tomography Angiography.

PURPOSE: To quantitatively evaluate microvascular changes in eyes with macular oedema due to branch retinal vein occlusion (BRVO) using optical coherence tomography angiography (OCTA) before and after intravitreal conbercept injection and the correlation of such changes with best-corrected visual acuity (BCVA) and retinal thickness. METHODS: Twenty-eight eyes of 28 patients treated with a single intravitreal injection of conbercept for macular oedema due to BRVO were included in this study. The automatically measured values of the vessel density in the superficial (SCP) and deep retinal capillary plexus (DCP), the foveal avascular zone (FAZ) area, the FAZ perimeter, the vessel density within a 300 µm wide ring surrounding the FAZ (FD-300), the acircularity index (AI), the choriocapillaris flow area and the retinal thickness were obtained via OCTA before and at 1 month after initial injection and compared with those of age- and sex- matched healthy subjects. RESULTS: In BRVO eyes, the vascular density in the SCP and DCP, the FD-300 and the flow area of choriocapillaris were significantly lower than those in healthy eyes, while the AI and the retinal thickness were significantly increased. After treatment, the retinal thickness in eyes with BRVO was significantly decreased in all quadrants, and the mean BCVA dramatically increased from 20/162 to 20/78 (p = 0.0017). The mean flow area of choriocapillaris significantly improved after treatment. Moreover, negative correlations between the logMAR BCVA and the whole vascular density in the SCP and DCP as well as the flow area of choriocapillaris were observed. CONCLUSION: OCTA enables non-invasive, layer-specific and quantitative assessment of microvascular changes in eyes with BRVO before and after treatment, and it can be used as a valuable imaging tool for the evaluation of the follow-up in BRVO patients.

Microvascular changes after conbercept therapy in central retinal vein occlusion analyzed by optical coherence tomography angiography.

AIM: To investigate microvascular changes in eyes with central retinal vein occlusion (CRVO) complicated by macular edema before and after intravitreal conbercept injection and evaluate correlations between these changes and best-corrected visual acuity (BCVA) and retinal thickness. METHODS: Twenty-eight eyes of 28 patients with macular edema caused by CRVO were included in this retrospective study. All patients received a single intravitreal conbercept injection to treat macular edema. BCVA and the results of optical coherence tomography angiography (OCTA) automatic measurements of the vessel density in the superficial (SCP) and deep retinal capillary plexus (DCP), the foveal avascular zone (FAZ) area, the FAZ perimeter (PERIM), the vessel density within a 300-µm wide ring surrounding the FAZ (FD-300), the acircularity index (AI), the choriocapillaris flow area, and retinal thickness were recorded before and at one month after treatment and compared with the results observed in age- and sex-matched healthy subjects. RESULTS: The vessel density in the SCP and DCP, the FD-300, and the flow area of the choriocapillaris were all significantly lower in CRVO eyes than in healthy eyes, while the AI and retinal thickness were significantly higher (all P<0.05). After treatment, retinal thickness was significantly decreased, and the mean BCVA had markedly improved from 20/167 to 20/65 (P=0.0092). The flow area of the choriocapillaris was also significantly improved, which may result from the reduction of shadowing effect caused by the attenuation of macular edema. However, there were no significant changes in SCP and DCP vessel density after treatment. The flow area of the choriocapillaris at baseline was negatively correlated with retinal thickness. CONCLUSION: OCTA enables the non-invasive, layer-specific and quantitative assessment of microvascular changes both before and after treatment, and can therefore be used as a valuable imaging tool for the evaluation of the follow-up in CRVO patients.

Morphological Difference of Choroidal Vasculature Between Polypoidal Choroidal Vasculopathy and Neovascular AMD on OCT: From the Perspective of Pachychoroid.

BACKGROUND AND OBJECTIVE: To investigate the morphological difference of choroidal vasculature between polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD) on optical coherence tomography (OCT). PATIENTS AND METHODS: One hundred eighty-nine patients with macula-involved PCV (n = 107) or nAMD (n = 82) were retrospectively reviewed. The subfoveal choroidal thickness (SFCT) and thickness of the Haller's layer were determined on enhanced depth imaging optical coherence tomography (EDI-OCT). The mean diameters of subfoveal large choroidal vessels were also calculated. RESULTS: Both the SFCT (257.31 µm ± 100.50 µm vs. 209.95 µm ± 97.51 µm) (P < .01) and the thickness of the Haller's layer (213.68 µm ± 82.65 µm vs. 159.67 µm ± 79.86 µm) (P < .01) were greater in PCV patients than nAMD patients. The ratio of thickness of the Haller's layer to the SFCT was higher in the PCV group (0.83 ± 0.07) than the nAMD group (0.7 5± 0.11) (P < .01). The mean diameter of subfoveal large choroidal vessels was greater in PCV patients (163.55 µm ± 62.23 µm vs. 112.81 ± 58.87 µm) (P < .01). CONCLUSION: Choroidal thickening and dilation of large choroidal vessels were commonly seen in PCV patients, supporting that PCV belongs to the pachychoroid spectrum disorders and might be a different entity from nAMD. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e114-e121.].

Down-regulation of p16 and MGMT promotes the anti-proliferative and pro-apoptotic effects of 5-Aza-dC and radiation on cervical cancer cells.

Cervical cancer is one of the most common malignancies of the female reproductive system. Therefore, it is critical to investigate the molecular mechanisms involved in the development and progression of cervical cancer. In this study, we stimulated cervical cancer cells with 5-aza-2'-deoxycytidine (5-Aza-dC) and found that this treatment inhibited cell proliferation and induced apoptosis; additionally, methylation of p16 and O-6-methylguanine-DNA methyltransferase (MGMT) was reversed, although their expression was suppressed. 5-Aza-dC inhibited E6 and E7 expression and up-regulated p53, p21, and Rb expression. Cells transfected with siRNAs targeting p16 and MGMT as well as cells stimulated with 5-Aza-dC were arrested in S phase, and the expression of p53, p21, and Rb was up-regulated more significantly. However, when cells were stimulated with 5-Aza-dC after transfection with siRNAs targeting p16 and MGMT, proliferation decreased significantly, and the percentage of cells in the sub-G1 peak and in S phase was significantly increased, suggesting a marked increase in apoptosis. But E6 and E7 overexpression could rescue the observed effects in proliferation. Furthermore, X-ray radiation caused cells to arrest in G2/M phase, but cells transfected with p16- and MGMT-targeted siRNAs followed by X-ray radiation exhibited a significant decrease in proliferation and were shifted toward the sub-G1 peak, also indicating enhanced apoptosis. In addition, the effects of 5-Aza-dC and X-ray radiation were most pronounced when MGMT expression was down-regulated. Therefore, down-regulation of p16 and MGMT expression enhances the anti-proliferative effects of 5-Aza-dC and X-ray radiation. This discovery may provide novel ideas for the treatment of cervical cancer.