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Objectives Currently, renal cell carcinoma (RCC) presenting with perisinus fat invasion (PSI) and/or perinephric fat invasion (PFI) is merged as one entity, pathological T3a (pT3a); however, the combination of PFI and PSI (PFI+PSI) may not be associated with equivalent prognosis compared with either PFI or PSI alone (PFI/PSI). Here, we analyzed the prognostic significance of PFI+PSI vs. PFI/PSI in pT3aN0-1M0-1 RCC. Method We identified 5,290 patients with pT3aN0-1M0-1 RCC, treated by nephrectomy, from the Surveillance, Epidemiology and End Results database, between 2010 and 2016. Cox proportional hazards regression and Fine and Gray competing risks regression were fitted to assess risks of survival outcomes, respectively. 11 propensity score method was used to minimize differences in the covariates' distributions. Results Among all patients, 746 patients (14.1%), 2,569 patients (48.5%) and 1,975 patients (37.3%) experienced PFI+SI, PFI, and PSI, respectively, and 3,952 patients (74.7%) without diseases of lymiseases of N1 and/or M1 (all p > 0.5). Conclusion Multiple invasion patterns (PFI+PSI) are associated with inferior survival relative to PFI/PSI alone in patients with pT3aN0M0 RCC; however, these effects are masked in patients with metastatic disease. These results warrant consideration in the development of the next edition of the tumor-node-metastasis staging system, to improve risk stratification. Copyright © 2020 Wang, Yu, Zhu, Feng, Liu, Liu, Wang and Zeng.The risk stratification of diffuse large B-cell lymphoma (DLBCL) is crucial. The International Prognostic Index, the most commonly used and the traditional risk stratification system, is composed of fixed and artificially dichotomized attributes. We aimed to develop a novel prognostic model that allows the incorporation of up-to-date attributes comprehensively without information loss. We analyzed 204 patients with primary DLBCL who were uniformly treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) from 2007 to 2012 at Asan Medical Center. Using the multivariable fractional polynomial (MFP) method and bootstrap resampling, we selected the variables of significance and the best fitted functional form in fractional polynomials. Age, serum β2-microglobulin, serum lactate dehydrogenase, and BCL2 expression were selected as significant variables in predicting overall survival (OS), while age was excluded in predicting 2-years event-free survival. The prognostic score calculated by the MFP model effectively classifies patients into four risk groups with 5-years OS of 89.91% (low risk), 81.21% (low-intermediate risk), 66.40% (high-intermediate risk), and 37.89% (high risk). We suggest a new prognostic model that is simple and flexible. By using the MFP method, we can incorporate various clinicopathologic factors into a risk stratification system without arbitrary dichotomization. Copyright © 2020 Roh, Jung, Lee, Kim, Pak, Lee, Lee, Cho, Cho, Yoon, Park, Huh, Oh and Park.Regardless of the promising results of certain immune checkpoint blockers, current immunotherapeutics have met a bottleneck concerning response rate, toxicity, and resistance in lung cancer patients. Accumulating evidence forecasts that the crosstalk between tumor and immune cells takes center stage in cancer development by modulating tumor malignancy, immune cell infiltration, and immune evasion in the tumor microenvironment (TME). Cytokines and chemokines secreted by this crosstalk play a major role in cancer development, progression, and therapeutic management. An increased infiltration of Tumor-associated macrophages (TAMs) was observed in most of the human cancers, including lung cancer. In this review, we emphasize the role of cytokines and chemokines in TAM-tumor cell crosstalk in the lung TME. Given the role of cytokines and chemokines in immunomodulation, we propose that TAM-derived cytokines and chemokines govern the cancer-promoting immune responses in the TME and offer a new immunotherapeutic option for lung cancer treatment. Copyright © 2020 Sarode, Schaefer, Grimminger, Seeger and Savai.Recent development of integrative therapy against melanoma combines surgery, radiotherapy, targeted therapy, and immunotherapy; however, the clinical outcomes of advanced stage and recurrent melanoma are poor. As a skin cancer, melanoma is generally resistant to radiotherapy. Hence, there is an urgent need for evaluation of the mechanisms of radioresistance. The present study identified miR-335 as one of the differential expression of miRNAs in recurrent melanoma biopsies post-radiotherapy. The expression of miR-335 declined in melanoma tissues compared to the adjacent tissues. Moreover, miR-335 expression correlated with advanced stages of melanoma negatively. Consistent with the prediction of STARBASE and miRDB database, miR-335 targeted ROCK1 via binding with 3'-UTR of ROCK1 directly, resulting in attenuation of proliferation, migration, and radioresistance of melanoma cells. The authors validated that overexpression of miR-335 enhanced X-ray-induced tumor regression by B16 mouse models. Briefly, the present findings gained insights into miR-335/ROCK1-mediated radiosensitivity and provided a promising therapeutic strategy for improving radiotherapy against melanoma. Copyright © 2020 Cheng and Shen.Colorectal cancer (CRC), a common tumor, is characterized by a high mortality rate. Long non-coding RNA maternally expressed gene 3 (MEG3) serves a regulatory role in the carcinogenesis and progression of several types of cancer; however, its role in CRC remains largely unknown. The aim of this study was to explore the regulatory role and mechanism(s) of MEG3 in CRC. The Warburg effect or aerobic glycolysis is characteristic of the metabolism of tumor cells. To determine the effect of MEG3 on glycolysis of CRC cells, we used an XF analyzer to perform glycolysis stress test assays and found that overexpression of MEG3 significantly inhibited glycolysis, glycolytic capacity, as well as lactate production in CRC cells, whereas knockdown of MEG3 produced the opposite effect. Mechanistically, overexpression of MEG3 induced ubiquitin-dependent degradation of c-Myc and inhibited c-Myc target genes involved in the glycolysis pathway such as lactate dehydrogenase A, pyruvate kinase muscle 2, and hexokinase 2. Moreover, we found that MEG3 can be activated by vitamin D and vitamin D receptor (VDR). Abexinostat Clinical data demonstrated that MEG3 was positively associated with serum vitamin D concentrations in patients with CRC. We found that 1,25(OH)2D3 treatment increased MEG3 expression, and knockdown of VDR abolished the effect of MEG3 on glycolysis. These results indicate that vitamin D-activated MEG3 suppresses aerobic glycolysis in CRC cells via degradation of c-Myc. Thus, vitamin D may have therapeutic value in the treatment of CRC. Copyright © 2020 Zuo, Wu, Wang and Yuan.Thioredoxin (Trx) is a pro-oncogenic molecule that underlies tumor initiation, progression and chemo-resistance. PX-12, a Trx inhibitor, has been used to treat certain tumors. Currently, factors predicting tumor sensitivity to PX-12 are unclear. Given that hydrogen sulfide (H2S), a gaseous bio-mediator, promotes Trx activity, we speculated that it might affect tumor response to PX-12. Here, we tested this possibility. Exposure of several different types of tumor cells to PX-12 caused cell death, which was reversely correlated with the levels of H2S-synthesizing enzyme CSE and endogenous H2S. Inhibition of CSE sensitized tumor cells to PX-12, whereas addition of exogenous H2S elevated PX-12 resistance. Further experiments showed that H2S abolished PX-12-mediated inhibition on Trx. Mechanistic analyses revealed that H2S stimulated Trx activity. It promoted Trx from the oxidized to the reduced state. In addition, H2S directly cleaved the disulfide bond in PX-12, causing PX-12 deactivation. Additional studies found that, besides Trx, PX-12 also interacted with the thiol residues of other proteins. Intriguingly, H2S-mediated cell resistance to PX-12 could also be achieved through promotion of the thiol activity of these proteins. Addition of H2S-modified protein into culture significantly enhanced cell resistance to PX-12, whereas blockade of extracellular sulfhydryl residues sensitized cells to PX-12. Collectively, our study revealed that H2S mediated tumor cell resistance to PX-12 through multiple mechanisms involving induction of thiol activity in multiple proteins and direct inactivation of PX-12. H2S could be used to predict tumor response to PX-12 and could be targeted to enhance the therapeutic efficacy of PX-12. Copyright © 2020 Mao, Yang, Mizutani, Huang, Zhang, Shinmori, Gao and Yao.Cervical cancer (CC) is the fourth most common type of cancer that affects women. Compared to other types of cancer, CC has a high mortality rate in women worldwide. Several factors contribute to the development of CC, but persistent high-risk human papillomavirus infection is the main etiologic agent associated with the development of CC. Moreover, several studies reported that alterations in the expression of transcription factors present in a small subpopulation of cells within tumors called cancer stem cells (CSCs), which contribute to the development of CC by promoting tumorigenicity and metastasis. These transcription factors affect self-renewal and maintenance of pluripotency and differentiation in stem cells. OCT3/4 belongs to the family of transcription factors with the POU domain. It consists of five exons and can be edited by alternative splicing into three main transcripts OCT3/4A, OCT3/4B, and OCT3/4B1. The OCT3/4 expression in CSCs promotes carcinogenesis and the development of malignant tumors, and the loss of expression leads to the loss of self-renewal and proliferation and favors apoptosis. This review describes the main roles of OCT3/4 in CC and its importance in several biological processes that contribute to the development of CC and may serve as molecular targets to improve prognosis of CC. Copyright © 2020 Clemente-Periván, Gómez-Gómez, Leyva-Vázquez, Lagunas-Martínez, Organista-Nava and Illades-Aguiar.Background Next-generation sequencing (NGS) needs to be validated and standardized to ensure that cancer patients are reliably selected for target treatments. In Italy, NGS is performed in several institutions and harmonization of wet and dry procedures is needed. To this end, a consortium of five different laboratories, covering the most part of the Italian peninsula, was constituted. A narrow gene panel (SiRe®) covering 568 clinically relevant mutations in six different genes (EGFR, KRAS, NRAS, BRAF, cKIT, and PDGFRα) with a predictive role for therapy selection in non-small cell lung cancer (NSCLC), gastrointestinal stromal tumor, colorectal carcinoma (CRC), and melanoma was evaluated in each participating laboratory. Methods To assess the NGS inter-laboratory concordance, the SiRe® panel, with a related kit and protocol for library preparation, was used in each center to analyze a common set of 20 NSCLC and CRC routine samples. Concordance rate, in terms of mutation detected and relative allelic frequencies, was assessed. Then, each institution prospectively analyzed an additional set of 40 routine samples (for a total of 160 specimens) to assess the reproducibility of the NGS run parameters in each institution. Results An inter-laboratory agreement of 100% was reached in analyzing the data obtained from the 20 common sample sets; the concordance rate of allelic frequencies distribution was 0.989. The prospective analysis of the run metric parameters obtained by each center locally showed that the analytical performance of the SiRe® panel in the different institutions was highly reproducible. Conclusions The SiRe® panel represents a robust diagnostic tool to harmonize the NGS procedure in different Italian laboratories. Copyright © 2020 Malapelle, Pepe, Pisapia, Sgariglia, Nacchio, De Luca, Lacalamita, Tommasi, Pinto, Palomba, Palmieri, Vacirca, Barberis, Bottillo, Grammatico, Grillo, Costa, Smeraglio, Bruzzese and Troncone.