The poor prognosis of clear-cell renal cell carcinoma (ccRCC) patients is due to progression and targeted drug resistance, but the underlying molecular mechanisms need further elucidation. This study examined the biological function and related mechanisms of gankyrin in ccRCC based on the results of our previous study. To this end, in vitro functional experiments; in vivo models of subcutaneous tumor formation, lung metastasis, and orthotopic ccRCC; and antibody chip detection, co-IP, ChIP assays were performed to examine the biological role and molecular mechanisms of gankyrin in ccRCC. Two hundred fifty-six ccRCC patients were randomly divided into training and validation cohorts to examine the prognostic value of gankyrin and other markers through IHC and statistical analyses. We observed that the gankyrin-overexpressing ccRCC cell lines 786-O and 769-P exhibited increased proliferation, invasion, migration, tumorigenicity, and pazopanib resistance and decreased apoptosis, while gankyrin knockdown achieved the opposite results. Mechanistically, gankyrin recruited STAT3 via direct binding, and STAT3 binding to the CCL24 promoter promoted its expression. Reciprocally, an increase in autocrine CCL24 enhanced the expression of gankyrin and STAT3 activation via CCR3 in ccRCC, forming a positive autocrine-regulatory loop. Furthermore, in vivo experimental results revealed that blocking the positive loop through gankyrin knockdown or treatment with the CCR3 inhibitor SB328437 reversed the resistance to pazopanib and inhibited lung metastasis in ccRCC. Moreover, a positive correlation between gankyrin and STAT3 or CCL24 expression in ccRCC specimens was observed, and improved accuracy for ccRCC patient prognosis was achieved by combining gankyrin and STAT3 or CCL24 expression with existing clinical prognostic indicators, including the TNM stage and SSIGN score. In summary, targeting the gankyrin/STAT3/CCL24/CCR3 autocrine-regulatory loop may serve as a remedy for patients with advanced ccRCC, and combining gankyrin and STAT3 or CCL24 expression with the current clinical indicators better predicts ccRCC patient prognosis.

Optical coherence tomography angiography (Angio-OCT), mainly based on the temporal dynamics of OCT scattering signals, has found a range of potential applications in clinical and scientific research. Based on the model of random phasor sums, temporal statistics of the complex-valued OCT signals are mathematically described. Statistical distributions of the amplitude differential and complex differential Angio-OCT signals are derived. The theories are validated through the flow phantom and live animal experiments. Using the model developed, the origin of the motion contrast in Angio-OCT is mathematically explained, and the implications in the improvement of motion contrast are further discussed, including threshold determination and its residual classification error, averaging method, and scanning protocol. The proposed mathematical model of Angio-OCT signals can aid in the optimal design of the system and associated algorithms.

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BackgroundIn the clinic, how to stratify renal cell carcinoma (RCC) patients with different risks and to accurately predict their prognostic outcome remains a crucial issue. In this study, we assessed the expression and prognostic value of gankyrin in RCC patients.MethodsThe expression of gankyrin was examined in public databases and validated in specimens from two independent centers. The clinical practice and disease correlation of gankyrin in RCC were evaluated in RCC patients, various cell lines and an orthotopic RCC model.FindingsUpregulation of gankyrin expression in RCC was corroborated in two independent cohorts. High gankyrin expression positively associated with disease progression and metastasis of RCC patients. A positive correlation between gankyrin and sunitinib-resistance was also observed in RCC cell lines and in an orthotopic RCC model. Kaplan-Meier analysis revealed that patients with higher gankyrin expression presented worse prognosis of RCC patients in the two cohorts. Gankyrin served as an independent prognostic factor for RCC patients even after multivariable adjustment by clinical variables. Time-dependent AUC and Harrell's c-index analysis presented that the incorporation of the gankyrin classifier into the current clinical prognostic parameters such as TNM stage, Fuhrman nuclear grade or SSIGN score achieved a greater accuracy than without it in predicting prognosis of RCC patients. All results were confirmed in randomized training and validation sets from the two patient cohorts.InterpretationGankyrin can serve as a reliable biomarker for disease progression and for prognosis of RCC patients. Combining gankyrin with the current clinical parameters may help patient management.FundNational Natural Science Foundation of China (No. 81773154, 81772747 and 81301861), Medical Discipline Construction Project of Pudong New Area Commission of Health and Family Planning (PWYgf2018-03), the Shanghai Medical Guidance (Chinese and Western Medicine) Science and Technology Support Project (No. 17411960200), Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai (No. PWR12016-05)