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BACKGROUND: Inflammation plays a vital role in tumor growth and progression and can be affected by radiotherapy (RT) and chemotherapy. We sought to investigate the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), and their associations with dosimetric factors in locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: In this retrospective study, subjects consisted of 244 patients who had received definitive RT ± chemotherapy for LA-NSCLC between 2012 and 2016. Absolute lymphocyte count (ALC), NLR and PLR recorded at pretreatment, during RT and post-RT were analyzed. Multivariable analysis (MVA) was performed to correlate clinical factors and inflammatory biomarkers with progression-free survival (PFS) and overall survival (OS) using a Cox regression model. Relationships between NLR or PLR with OS and PFS were evaluated with Kaplan-Meier analysis and compared with log-rank test results. Multiple stepwise linear regression was used to assess the associations between dosimetric factors and NLR or PLR. RESULTS: The median PFS and OS for all patients were 8.6 and 15.8 months, respectively. On MVA for PFS and OS, higher 1-month post-RT start NLR [hazard ratio (HR) 1.049; 95% CI: 1.018–1.080; P=0.001] or higher 1-month post-RT start PLR (HR 1.001; 95% CI: 1.000–1.002; P

Additional file 1: Fig S1. The number of breast cancer incident cases, deaths and disability-adjusted life years (DALYs) by sex and location from1990 to 2019. (A-C) Both sexes; (D-F) Female; (G-I) Male. Fig S2. The ASIR, ASDR, and ASR of DALYs of breast cancer in China, Japan, South Korea,East Asia and Pacific and the world from 1990 to 2019. (A-C) Both sexes; (D-F) Female; (G-I) Male. ASIR: age-standardized incidence rate, ASDR: age-standardized death rate, ASR:age-standardized rate, DALYs: disability-adjusted life-years. Fig S3. The number of breast cancer incident case, deaths and disability-adjusted life years (DALYs) for both sexes by age group in China, Japan, South Korea, East Asia and the Pacific and the world in 2019. The error bar indicates 95% uncertainty interval of the number. Fig S4. The rates of breast cancer incidence, death and disability-adjusted life years (DALYs) for both sexes by age group in China, Japan, South Korea, East Asia and the Pacific and the world in 2019. The error bar indicates 95% uncertainty interval of the rates. Fig S5. The EAPCs of ASIR, ASDR and ASR of DALYs for breast cancer from 1990 to 2019 by sex in the China, Japan, South Korea, East Asia and the Pacific and the world. EAPC: estimated annual percentage change; ASIR: age-standardized incidence rate; ASDR: age-standardized death rate; ASR: age-standardized rate; DALYs: disability-adjusted life-years. The error bar indicates 95% confidence interval (CI) of the EAPCs. Fig S6. Temporal trends of percent of deaths for breast cancer attributable to risk factors in China(A), Japan (B) and South Korea (C), 1990-2019. Fig S7. Temporal trends of percent of DALYs for breast cancer attributable to risk factors in China(A), Japan (B) and South Korea (C), 1990-2019. DALYs: disability-adjusted life-years. Fig S8. Trends in ASIR and ASDR during 1990–2019 and predictions from 2020 to 2034 in China(A-B), Japan (C-D) and South Korea (E-F). ASIR: age-standardized incidence rate; ASDR: age-standardized death rate. Fig S9. The number of incident cases and deaths during 1990-2019 and projected from 2020 to 2034 in Japan. (A-B) Both sexes; (C-D) Female; (E-F) Male. The error bar indicates 95% confidence interval (CI) of the number. Fig S10. The number of incident cases and deaths during 1990-2019 and projected from 2020 to 2034 in Republic of Korea. (A-B) Both sexes; (C-D) Female; (E-F) Male. The error bar indicates 95% confidence interval (CI) of the number. Table S1. The RMSE in different models.Table S2. World population age standard. Table S3. The age-standardized rate of breast cancer case in the world, East Asia and Pacific, China, Japan and South Korea from 1990 to 2019. Table S4. EAPC of percent of DALYs and deaths for breast cancer attributable to risk factors in China, Japan and South Korea, 1990-2019. Table S5. Predicted number of breast cancer incident cases and deaths in China, Japan and South Korea, and changes between 2020 and 2034 stratified into changes due to risk and demographics by sex. Table S6. Number of population estimates (in millions) in 1990 and 2019 and population projections in 2020 and 2034 by country. Table S7. The death rates of breast cancer in China, Japan and South Korea by sex and age, during 1990-2019, and projected until 2034.

Background Cumulative preclinical and clinical evidences showed radiotherapy might augment systemic antitumoral responses to immunotherapy for metastatic non-small cell lung cancer, but the optimal timing of combination is still unclear. The overall infiltration and exhausted subpopulations of tumor-infiltrating CD8+ T cells might be a potential biomarker indicating the response to immune checkpoint inhibitors (ICI), the alteration of which is previously uncharacterized during peri-irradiation period, while dynamic monitoring is unavailable via repeated biopsies in clinical practice. Methods Basing on tumor-bearing mice model, we investigated the dynamics of overall infiltration and exhausted subpopulations of CD8+ T cells after ablative irradiation. With the understanding of distinct metabolic characteristics accompanied with T cell exhaustion, we developed a PET radiomics approach to identify and visualize T cell exhaustion status. Results CD8+ T cell infiltration increased from 3 to 14 days after ablative irradiation while terminally exhausted populations significantly predominated CD8+ T cells during late course of this infiltrating period, indicating that 3–7 days post-irradiation might be a potential appropriate window for delivering ICI treatment. A PET radiomics approach was established to differentiate T cell exhaustion status, which fitted well in both ICI and irradiation settings. We also visualized the underlying association of more heterogeneous texture on PET images with progressed T cell exhaustion. Conclusions We proposed a non-invasive imaging predictor which accurately assessed heterogeneous T cell exhaustion status relevant to ICI treatment and irradiation, and might serve as a promising solution to timely estimate immune-responsiveness of tumor microenvironment and the optimal timing of combined therapy.

There are numerous antibodies used for cancer therapy in clinic, but they are essentially less efficacy than expected. None of them has tumor-specific and broad-spectral properties. PIWIL2-like (PL2L) protein 60 (PL2L60) is a product of alienated activation of PIWIL2 gene, and has been found to be specifically and widely expressed in various types of cancers, including hematopoietic and solid ones. Current study aims to investigate whether a monoclonal antibody (mAb) to PL2L60 has both tumor-specific and broad-spectral properties, which can be used universally to treat various types of cancers. The expression of PL2L60 protein in the cell surface and cytoplasm were determined in a panel of human and mouse tumor cell lines by flow cytometry, immunofluorescent microscopy and Western Blotting. The apoptosis and the cell cycle arrest of the tumor cells treated with mAb KAO3 were evaluated by flow cytometry. The tumorigenesis of the mAb KAO3-pretreated tumor cells was determined by tumor incidence and tumor size, and the efficacy of mAb KAO3 treatment on tumor growth in tumors-bearing mice were kinetically evaluated. Complement-dependent cytotoxicity (CDC) assay was used to determine the capacity of mAb KAO3 to kill tumor cells. Treatment of human or mouse tumor cells from hematopoietic or solid tumors with mAb KAO3 at the time of inoculation efficiently inhibited tumorigenesis in the severe combined immunodeficient (SCID) mice. Moreover, injection of mAb KAO3 into established tumors significantly inhibited their growth, and prolonged survival of the tumor-bearing mice, including lymphoma, breast cancer, lung cancer and cervical cancer. The efficacy of mAb KAO3 treatment is likely associated with its binding to PL2L60 expressed on tumor cell surface, which may lead to cancer cell death through blocking cell cycling and/or activation of complement. In conclusion, we have identified a tumor-specific mAb to PL2L60 (KAO3), which may be used potentially to treat all the types of human cancers including from both hematopoietic and solid ones.

Background: PL2L60 is a PIWIL2-like (PL2L) protein that is specifically and widely expressed in various types of hematopoietic and solid tumors. However, it is unknown whether PL2L60 is an effective target for cancer immunotherapy. The current study aimed to investigate the efficacy of an monoclonal antibody (mAb) to PL2L60 (clone KAO3；IgM isotype) in treatment of the cancers either from human or mouse.Methods: The expression of PL2L60 protein in the cell surface and cytoplasm were determined in a panel of human and mouse tumor cell lines by flow cytometry, immunofluorescent staining and Western Blotting. The apoptosis and the cell cycle arrest of the tumor cells treated with mAb KAO3 were evaluated by flow cytometry. The tumorigenesis of the mAb KAO3-pretreated tumor cells was determined by tumor incidence and tumor size, and efficacy of mAb KAO3 treatment on tumor growth in tumors-bearing mice were kinetically evaluated. Complement-dependent cytotoxicity tests were utilized to determine the mechanism of mAb KAO3 killing tumor cells. Results: Treatment of human or mouse tumor cells with mAb KAO3 at the time of inoculation efficiently inhibited their tumorigenesis in the immunodeficient mice. Moreover, injection of mAb KAO3 into established tumors significantly inhibited their growth, and prolonged survival of the tumor-bearing mice, including lymphoma, breast cancer, lung cancer and cervical cancer. The inhibitory effects of mAb KAO3 were likely associated with its binding to the PL2L60 expressed on tumor cell surface, which may induce cell apoptosis through either activation of complement or blocking cell cycling. The cell cycling was arrested at G2/M phase and DNA synthesis may be inhibited.Conclusion: We have identified the PL2L60 as a novel tumor-specific and broad-spectral biomarker, which is recognized by the mAb KAO3 as an efficient target for immunotherapy of both solid and hematopoietic cancers.

Purpose To analyze patterns of failure in patients with LA-NSCLC who received definitive chemoradiotherapy (CRT) and to build a nomogram for predicting the failure patterns in this population of patients. Materials and methods Clinicopathological data of patients with LA-NSCLC who received definitive chemoradiotherapy and follow-up between 2013 and 2016 in our hospital were collected. The endpoint was the first failure after definitive chemoradiotherapy. With using elastic net regression and 5-fold nested cross-validation, the optimal model with better generalization ability was selected. Based on the selected model and corresponding features, a nomogram prediction model was built. This model was also validated by ROC curves, calibration curve and decision curve analysis (DCA). Results With a median follow-up of 28 months, 100 patients experienced failure. There were 46 and 54 patients who experience local failure and distant failure, respectively. Predictive model including 9 factors (smoking, pathology, location, EGFR mutation, age, tumor diameter, clinical N stage, consolidation chemotherapy and radiation dose) was finally built with the best performance. The average area under the ROC curve (AUC) with 5-fold nested cross-validation was 0.719, which was better than any factors alone. The calibration curve revealed a satisfactory consistency between the predicted distant failure rates and the actual observations. DCA showed most of the threshold probabilities in this model were with good net benefits. Conclusion Clinicopathological factors could collaboratively predict failure patterns in patients with LA-NSCLC who are receiving definitive chemoradiotherapy. A nomogram was built and validated based on these factors, showing a potential predictive value in clinical practice.

// Shan-Shan Liu 1, * , Ning Liu 1, * , Meng-Yao Liu 1 , Lei Sun 1 , Wu-Yan Xia 1 , Hong-Min Lu 1 , Yu-Jie Fu 1 , Guo-Liang Yang 2 , Juan-Jie Bo 2 , Xiao-Xing Liu 3 , Haizhong Feng 1 , Hailong Wu 1 , Lin-Feng Li 1 and Jian-Xin Gao 1 1 State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China 2 Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China 3 Department of Radiotherapy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China * These authors have contributed equally to this work Correspondence to: Jian-Xin Gao, email: jianxingao@sjtu.edu.cn , 15618820486@163.com Lin-Feng Li, email: lilinfeng219@126.com Keywords: PIWIL2, PL2L60, intragenic promoter, alienated gene activation, STAT3 Received: March 07, 2017 Accepted: March 28, 2017 Published: May 02, 2017 ABSTRACT PIWIL2-like (PL2L) protein 60 (PL2L60), a product of aberrantly activated PIWIL2 gene, is widely expressed in various types of tumors and may promote tumorigenesis. However, the mechanisms underlying the activation of expression of PL2L60 remain unknown. In this study, an intragenic promoter responsible for the activation of PL2L60 within the human PIWIL2 gene has been identified, cloned and characterized. The promoter of PL2L60 is located in the intron 10 of the host gene PIWIL2 . Bioinformatic and mutagenic analysis reveals that this intragenic promoter within the sequence of 50 nucleotides contains two closely arranged cis-acting elements specific for the hepatic leukemia factor (HLF) in the positive strand and signal transducer and activator of transcription 3 (STAT3) in the negative strand. Chromatin immunoprecipitation analysis demonstrates that both the HLF and polymerase II (Pol II), a hallmark of active promoters, directly bind to the sequence, although STAT3 does not. Knockdown of HLF and STAT3 alone or both by RNA interference significantly reduced both promoter activity and the PL2L60 protein expression, although there is no additive effect. The expression of PL2L60 proteins was enhanced when host gene Piwil2 was genetically disrupted in a murine cell model. Taken together, we have identified a PL2L60-specific intragenic promoter in the host gene of PIWIL2 , which is interdependently activated by HLF and STAT3 through steric interaction. This activation is dependent on cellular milieu rather than the integrity of host gene PIWIL 2, highlighting a novel, important mechanism for a cancer-causing gene to be activated during tumorigenesis.

Protein arginine methylation is a common posttranslational modification resulting in the generation of asymmetric dimethylarginine (aDMA) and symmetric dimethylarginine (sDMA). Currently, the regulation of aDMA or sDMA by hypoxia, nutrient stavation or cytokines in the tumor microenvironment remains largely unknown. Here we show that p90aDMA, p70aDMA and p90sDMA, endogenous proteins containing aDMA or sDMA with mass 70 or 90 kDa, were widely and dominantly expressed in breast cancer cell lines. Notably, it was p90aDMA rather than p90sDMA that accumulated in the nucleus upon stimulation of cancer cells with interleukin (IL)-2, IL-4, IL-6 but not IL-8. In addition, the p90aDMA accumulation could be inhibited after treatment with a global methyltrasferase inhibitor, adenosine-2',3'-dialdehyde (AdOx). It seemed that some endogenous proteins in cancer cells were asymmetrically arginine-methylated upon exposure to some cytokines.. Furthermore, endogenous proteins of aDMA, such as p90aDMA and p70aDMA, were degraded in response to hypoxia, nutrient starvation and rapamycin treatment in breast and cervical cancer cells. IL-2/4/6 slightly increased basal autophagy but slightly decreased the rapamycin‑induced autophagy in cancer cells, suggesting that IL-2/4/6 and autophagy inducers play distinct roles in the regulation of aDMA of proteins. Conversely, rapamycin accumulated p90sDMA in MDA-MB‑231 and MCF-7 cells. Taken together, our results add a new dimension to the complexity of arginine methylated regulation in response to various stimuli and provide the first evidence that aDMA serves as one specific degradation signal of selective autophagy.