Secondary central nervous system (SCNS) involvement is an infrequent but universally fatal event in diffused large B‐cell lymphoma. The occurrence rate of SCNS involvement is approximately 5% but comes with a poor prognosis ever after. However, existing risk models to predict the incidence and prognosis of these patients with SCNS involvement lack both efficiency and accuracy. Controversy has also been reported regarding which risk factor may best identify the population with a high CNS relapse rate. In this study, we retrospectively analyzed 831 patients with diffused large B‐cell lymphoma, diagnosed between March 2008 and June 2018 in Tianjin Medical University Cancer Institute and Hospital, Beijing Cancer Hospital, and Cancer Hospital of The University of Chinese Academy of Science. Risk factors and nomogram were identified and established based on Fine and Gray's competing risk analysis. Among these patients, 55 (6.6%) of them eventually developed SCNS involvement. The 1‐ and 2‐year incidence for SCNS involvement were 3.9% and 4.7%, respectively. The median time from de novo diagnosis to CNS relapse was 8 months, and the median overall survival of these patients was 28 months. Considering the competing mortality before SCNS involvement, Fine and Gray's competing risk model was performed to analyze the characteristics related to SCNS involvement, and identified risk factors as the multiple extranodal involvements, elevated LDH and AMC level, and the involvement of breast, adrenal gland/kidney, pulmonary and bone. Corresponding factors were integrated into the competing nomogram for SCNS involvement ( c ‐index = 0.778). In conclusion, we present the first predictive nomogram to evaluate the risk to develop SCNS involvement in de novo DLBCL patients, which may help in both prognostic evaluation and clinical decision for this subgroup.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief and Authors. Following concerns raised in the public domain, the authors contacted the journal to request the retraction of the article. Sections of panels from various figures appear similar to each other, particularly panels from Figs. 3G, 5B and 3G and 5F, 3F, S4D, S5D, S5C and S10C, as well as S10E.

Pancreatic cancer is a dismal malignancy with poor prognosis. In spite of progress in surgical technology, chemotherapy is still the cornerstone in the multi-disciplinary treatment. Albumin-bound paclitaxel is a first-line treatment for PDAC patients. Yet the response rate of the drug is far from satisfying. SOX8 is a member of the sex determining region Y-boxes family, which is potentially related to the chemoresistance of tumor. Patient with high expression of SOX8 were insensitive to albumin-bound paclitaxel. SOX8 reduced apoptosis and G2/M cell cycle arrest caused by albumin-bound paclitaxel. SOX8 transcriptionally regulated EZH2, which reduced expression of SPARC by promoting the methylation of SPARC, thereby reducing the transport of albumin-bound paclitaxel in pancreatic cancer cells. EZH2 inhibitor, UNC1999, can reverse the effect of SOX8 on chemo-resistance of albumin-bound paclitaxel. Collectively, our data revealed SOX8/EZH2/SPARC signaling induced primary chemo-resistance of albumin-bound paclitaxel in pancreatic ductal adenocarcinoma.

目的:探索免疫化疗时代基于多种肿瘤浸润免疫细胞建立弥漫性大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)预后模型并进行初步评价.方法:采用ImmuCellAI算法计算DLBCL肿瘤微环境中24种免疫细胞的丰度,通过(least absolute shrinkage and selection operator,LASSO)回归和Cox回归筛选预测变量并构建基于免疫细胞的风险评分模型(immune cells-based risk scores,IRS)模型.同时将IRS模型与患者临床因素相结合,构建IRSC模型.采用Kaplan-Meier法和ROC曲线评估该模型,采用列线图计算不同时间点的生存率.结果:IRS模型高风险组患者总生存时间(OS)明显低于低风险组[P=1e-15,HR=0.298(0.2176～0.4082)],基于患者1、3、5年生存情况的ROC曲线AUC值分别为0.728、0.711和0.615,且该模型风险评分与免疫检查点抑制剂(immune checkpoint inhibitors,ICPIs)疗效呈负相关.IRSC模型较IRS模型预测效果更佳:高风险组预后显著差于低风险组P<2e-16,HR=0.170(0.1143～0.253)],基于患者1、3、5年生存情况的ROC曲线AUC值分别为0.797、0.809和0.792.结论:IRS模型能很好的预测DLBCL患者的预后及对ICPIs的疗效,而IRSC模型预后价值更高.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief and Authors. Following concerns raised in the public domain, the authors contacted the journal to request the retraction of the article. Sections of panels from various figures appear similar to each other, particularly panels from Figures 3G and 5B, 3G and 5F, 3F, S4D, S5D, S5C and S10C, as well as S10E.

Interstitial pneumonia (IP) is one of the potentially fatal adverse events for lymphoma patients undergoing immunochemotherapy. However, the risk factors and predictive markers remain unclear for this complication. This retrospective study aims to explore whether the change of absolute monocyte count (AMC) during immunochemotherapy is correlated with IP occurrence and progression. A total of 500 lymphoma patients receiving immunochemotherapy from 2014 to 2016 were enrolled in this investigation. Interstitial pneumonia was generally diagnosed as diffused pulmonary interstitial infiltrates on computed tomography images in conjunction with respiratory symptoms or pulmonary function test, which is also adopted as a diagnosing tool of IP in this study. Among the total 500 participating patients, 40 patients were diagnosed as IP, which account for 8% of the total subjects. The median number of chemotherapy cycles for those patients prior to IP occurrence is 4. This research suggests that the increase of peripheral AMC over 0.565 x 10(9)/L after 2 cycles of immunochemotherapy is a great potential to develop IP. Using the method of multivariate analysis, lymphoma lung involvement and high AMC after 2 cycles of immunochemotherapy were identified as independent risk factors for IP. Most IP patients with sustained AMC elevation (>0.575 x 10(9)/L at IP onset) accompanied severe pulmonary symptoms, while those with AMC fall-back might tolerate subsequent immunochemotherapy. Thus, this study concludes that early increase of AMC during immunochemotherapy in lymphoma patients with lung involvement suggested a great potential to develop IP. Dynamic changes in AMC may serve as a predictive marker for IP severity and a guide for treatment adjustment for both tumor and pulmonary injuries.

Forkheadbox protein 3 (FOXP3), initially identified as a key transcription factor for regulatory T cells (Treg cells), was also expressed in many tumors including pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC progression remains elusive. In this study, we utilized 120 PDAC tissues after radical resection to detect cancer-FOXP3 and Treg cells by immunohistochemistry and evaluated clinical and pathological features of these patients. Cancer-FOXP3 was positively correlated with Treg cells accumulation in tumor tissues derived from PDAC patients. In addition, high cancer-FOXP3 expression was associated with increased tumor volumes and poor prognosis in PDAC especially combined with high levels of Treg cells. Overexpression of cancer-FOXP3 promoted the tumor growth in immunocompetent syngeneic mice but not in immunocompromised or Treg cell-depleted mice. Furthermore, CCL5 was directly trans-activated by cancer-FOXP3 and promoted the recruitment of Treg cells from peripheral blood to the tumor site in vitro and in vivo. This finding has been further reinforced by the evidence that Treg cells recruitment by cancer-FOXP3 was impaired by neutralization of CCL5, thereby inhibiting the growth of PDAC. In conclusion, cancer-FOXP3 serves as a prognostic biomarker and a crucial determinant of immunosuppressive microenvironment via recruiting Treg cells by directly trans-activating CCL5. Therefore, cancer-FOXP3 could be used to select patients with better response to CCL5/CCR5 blockade immunotherapy.

Hypoxia inducible factor 1 (HIF-1) is a transcription factor composed of two subunits, namely, HIF-1α and HIF-1β, in which HIF-1β is constitutively expressed. HIF-1 upregulates several hypoxia-responsive proteins, including angiogenesis factors, glycolysis solution enzymes, and cell survival proteins. HIF-1 is also associated with the degree of inflammation in the tumor region, but the exact mechanism remains unclear. This study aims to identify the molecular mechanism of recruiting monocytes/macrophages by HIF-1α in pancreatic ductal adenocarcinoma (PDAC) and the effects of macrophages on pancreatic stellate cells (PSCs). Immunohistochemistry (IHC) was performed for cluster of differentiation 68 (CD68), HIF-1α, and chemical chemokines 2 (CCL2). Western blot, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), chromatin immunoprecipitation assay, and The Cancer Genome Atlas (TCGA) were used to verify the correlation between HIF-1α and CCL2 at protein and nucleic acid levels. Monocytes/macrophages were co-cultured with PSCs to observe their interaction. Samples showed significant correlation between CD68 and HIF-1α (t-test, p < 0.05). HIF-1α recruited monocytes/macrophages by promoting CCL2 secretion. Moreover, macrophages could accelerate the activation of PSCs. HIF-1α might promote inflammation and fibrosis of PDAC through CCL2 secretion, which may provide a novel target to treat PDAC patients.

Arsenic trioxide (ATO) has been selected as a promising treatment not only in leukemia but also in solid tumors. Previous studies showed that the cytotoxicity of ATO mainly depends on the induction of reactive oxygen species. However, ATO has only achieved a modest effect in pancreatic ductal adenocarcinoma, suggesting that the existing radical scavenging proteins, such as hypoxia inducible factor-1, attenuate the effect. The goal of this study is to investigate the effect of combination treatment of ATO plus PX-478 (hypoxia-inducible factor-1 inhibitor) and its underlying mechanism. Here, we showed that PX-478 robustly strengthened the anti-growth and pro-apoptosis effect of ATO on Panc-1 and BxPC-3 pancreatic cancer cells in vitro. Meanwhile, in vivo mouse xenograft models also showed the synergistic effect of ATO plus PX-478 compared with any single agent. Further studies showed that the anti-tumor effect of ATO plus PX-478 was derived from the reactive oxygen species-induced apoptosis. We next confirmed that Hypoxia-inducible factor-1 cleared reactive oxygen species by its downstream target, forkhead box O transcription factors, and this effect may justify the strategy of ATO plus PX-478 in the treatment of pancreatic cancer.

Objective:To discuss the clinical feature, diagnosis, and treatment course of pancreatic acinar cell carcinoma (ACC) to guide clinical practice and improve prognosis of patients. Methods:Clinical data of 15 patients with pathologically confirmed pancreatic acinar cell carcinoma between December 1994 and March 2014 in Tianjin Medical University Cancer Institute and Hospital were retro-spectively studied. Results:The patients include eight males and seven females with a median age of 44. Tumors in these patients appeared in different parts of the pancreas. Eight patients had tumor in the head, six in the body and tail, and one in the uncinate process. The tumor size ranged from 3 cm to 18 cm, with an average diameter of 6.67 cm. The patients presented less jaundice and the tumor markers remained constant, specifically, no increase was reported. Six patients had metastasis before their operation. Twelve patients received radical resection, while the other three received palliative treatment. The preoperative and intraoperative diagnoses were not exact. The final diagnosis depended on pathologic confirmation after surgery or puncture. The immunohistochemical results of trypsin and chymotrypsin were positive in the patients who were examined. The postoperative chemotherapy was usually based on gemcitabine. The average survival time was 20.6 months. Conclusion:Pancreatic acinar cell carcinoma has special clinical features, and clinicians tend to regard it as low-grade malignancy. The attitude towards ACC should be positive.

Stem cell factor (SCF) and hypoxia-inducible factor-1α (HIF-1α) both have important functions in pancreatic ductal adenocarcinoma (PDAC). This study aims to analyze the expression and clinicopathological significance of SCF and HIF-1α in PDAC specimens and explore the molecular mechanism at PDAC cells in vitro and in vivo. We showed that the expression of SCF was significantly correlated with HIF-1α expression via Western blot, PCR, chromatin immunoprecipitation (ChIP) assay, and luciferase assay analysis. The SCF level was also correlated with lymph node metastasis and the pathological tumor node metastasis (pTNM) stage in PDAC samples. The SCF higher-expression group had significantly lower survival rates than the SCF lower-expression group (p<0.05). Hypoxia up-regulated the expression of SCF through the hypoxia-inducible factor (HIF)-1α in PDAC cells at the protein and RNA levels. When HIF-1α was knocked down by RNA interference, the SCF level decreased significantly. Additionally, ChIP and luciferase results demonstrated that HIF-1α can directly bind to the hypoxia response element (HRE) region of the SCF promoter and activate the SCF transcription under hypoxia. The results of colony formation, cell scratch, and transwell migration assay showed that SCF promoted the proliferation and invasion of PANC-1 cells under hypoxia. Furthermore, the down-regulated ability of cell proliferation and invasion following HIF-1α knockdown was rescued by adding exogenous SCF under hypoxia in vitro. Finally, when the HIF-1α expression was inhibited by digoxin, the tumor volume and the SCF level decreased, thereby proving the relationship between HIF-1α and SCF in vivo. In conclusion, SCF is an important factor for the growth of PDAC. In our experiments, we proved that SCF, a downstream gene of HIF-1α, can promote the development of PDAC under hypoxia. Thus, SCF might be a potential therapeutic target for PDAC.

Stem cell factor (SCF), a ligand of c-kit, is a hematopoietic growth factor. Uncontrolled activity of SCF/c-kit signaling pathway contributes to the formation of a variety of human malignancies. In this study, we determined whether SCF expression could risk-stratify patients with hepatocellular carcinoma (HCC) after curative resection. HCC tissues from 160 patients were collected during curative resection and stained with SCF and CD34, a marker for microvessel density (MVD), using immunohistochemistry. Two statistical analyses were performed: an independent continuous and a multivariate categorical analysis, with test/validation set-defined cut points, and Kaplan-Meier estimated outcome measures of overall survival (OS) and relapse-free survival (RFS). We found that higher levels of SCF confer worse OS (continuous P = 0.014; and categorical P = 0.009), and RFS (continuous P = 0.002; categorical P = 0.003) of patients with HCC. SCF varies independently from MVD-CD34, tumor node metastasis, histologic grade, age and gender, and retains prognostic significance when analysed as a categorical variable in a multivariate analysis . We confirmed that MVD-CD34 is also an independent prognostic marker for patients with HCC. The levels of SCF and CD34 showed a positive and significant correlation (P < 0.0001) and double low expression confers superior OS (median = 48 months) and RFS (median = 24 months), whereas double high expression confers shortest RFS (median = 10.5 months) compared with single measurements. The prognostic values of SCF and CD34 were independently determined in this study and we propose that both of them are independent prognostic markers for HCC.

目的 了解食盐加碘新标准实施前后天津市高校大学生碘营养水平的变化情况.方法 于2011和2013年在天津市两所高校采用随机抽样调查方式,采集在校用餐的122名学生晨尿样本,每校采集3份饮用水供水点水样品和3份食堂盐样品.采用过硫酸铵消化砷铈催化分光光度法测定尿碘及水碘,直接滴定法测定盐碘.同时向调查对象现场发放碘营养状况调查问卷.结果 两年度大学生样本的性别、饮水种类、饮酒、海产品食用情况、肉蛋类食用情况、高钙食品食用情况、吸烟及碘营养知识比较,差异均无统计学意义(P＞0.05).2013年总体尿碘中位数为203.89 μg/L,较2011年(M=289.14 μg/L)降低(P＜0.05).两年度所采集12份水样碘含量均在7.60～11.56μg/L之间,2013年平均为9.90 μg/L,2011年平均为8.36 μg/L.2013年6份盐样中1份为非碘盐;2011年均为合格碘盐.结论 本次调查的高校大学生2013年碘营养水平较2011年降低,但仍处于充足和可接受水平.应加强特殊人群碘盐供应的监督管理.

Objective To investigate the iodine nutrition among the college students in Tianjin and the main influencing factors.Methods Random sampling was used in this survey.Morning urines of 296 college students were collected from five universities in Tianjin.Three samples of water and two of salts were collected from each school.The iodine contents in urine and water were measured by As3+-Ce4+ catalytic spectrophotometry using the ammonium persulfate digestion.The iodine content in salt was measured by direct titration.Questionnaires were collected from the students on site for analyzing impact factors on iodine nutrition from Oct.,2010 to May,2011.Results The median of urine iodine contents in the total 296 observations was 211.20 μg/L.The median of urine iodine of the medical students was higher(263.86 μg/L) than that of the non-medical students(166.61 μg/L) with statistical significance(P0.05).The median of urine iodine of smokers,vegitarian and alcohol user had a reducing trend compared with those of the non-smokers,people who eat a little meat or frequently and who usually drank tea.Besides,drinking purified water or tap-water and gender did not seem to influence urine iodine levels.Meanwhile,students who had a better knowledge about iodine nutrition had a rising trend compared with those who did not.The iodine contents of the 15 water samples collected from the five universities were 7.60 μg/L to 10.67 μg/L.Four of 10 salt samples were non-iodized salt.Conclusion The iodine nutrition among college students in Tianjin is sufficient and acceptable.The iodine nutrition is affected by living habits and iodine nutrition knowledge.

Objective To evaluate the iodine nutritional status of university students in Tianjin and analyze influencing factors affecting urinary iodine levels.Methods Students of Tianjin Medical University,Tianjin Nankai University,Tianjin University of Finance and Economics and Tianjin University of Traditional Chinese Medicine were selected as survey subjects,and 50 - 100 morning urinary samples were collected from each university,respectively.Urinary iodine was measured by arsenic-cerium catalytic spectrophotometry.The students were surveyed with questionnaires,which included family information,age, sex, specialty, iodine nutrition knowledge,source of drinking water,smoking or not and dietary habits.Results A total of 269 urine samples were collected,and the median urinary iodine was 213.68 μg/L.Urinary iodine levels(263.86 μg/L) of medical students was significantly higher than that( 168.01 μg/L,x2 =12.144,P ＜ 0.01 ) of non-medical students.There was an increasing trend of the level of urinary iodine of students with iodine nutrition knowledge scores ＞ 5 points (223.70 μg/L) over that of ≤5 points( 185.56 μg/L),but the difference was not significantly different statistically (x2 =2.297,P ＞ 0.05).Different gender and water sources had no significant effect on urinary iodine level(x2 =0.002,0.687,respectively,all P ＞ 0.05).Smokers urinary iodine levels( 154.55 μg/L) decreased compared with non-smokers(215.38 μg/L),but the difference was not statistically significant (x2 =0.515,P＞ 0.05).Vegetarian urinary iodine levels were lower than that of non-vegetarians,but the difference was not statistically significant(x2 =0.594,P ＞ 0.05).Conclusions Iodine nutritional status of students in university of Tianjin are generally at an appropriate level,but professional knowledge,habits and other factors may affect the intake of iodine,so students should develop good dietary habits to ensure a normal iodine nutrition status.