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Dang SC, Qian XB, Jin W, Cui L, Chen JX, Gu M. Onco Targets Ther. 2019;12:785–794. We, the Editor and Publisher of the journal OncoTargets and Therapy have retracted the published article. Following publication of the article, concerns were raised about the duplication of images from Figure 5 with images from an unrelated article. Specifically, The image for Figure 5A, Blank, has been duplicated with images from Figure 2C, Migration, Blank and Invasion, PLL3.7, from Chen B, Zhu A, Tian L, et al. [Corrigendum] miR‑23a suppresses pancreatic cancer cell progression by inhibiting PLK‑1 expression. Molecular Medicine Reports. 2022;26:222. https://doi.org/10.3892/mmr.2022.12738. The corresponding author did respond to our queries and explained that some experiments were carried out by a third party. However, they were unable to provide details of the third party or provide a satisfactory explanation for how the images came to be duplicated or provide satisfactory original data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, the Publisher and Editor requested to retract the article and the corresponding author was notified of this decision. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Yuan Tian,1,* Wenbiao Jin,1,* Honghua Sun,1 Dehao Jin,2 Dongxu Kang,1 Zhiyu Li,1 Longzhen Piao1 1Department of Oncology, The Affiliated Hospital of Yanbian University, Yanji City, Jilin Province, People’s Republic of China; 2Department of Radiology, Yanbian Maternal and Child Health Hospital, Yanji, Jilin Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhiyu Li; Longzhen Piao, Department of Oncology, The Affiliated Hospital of Yanbian University, No. 1327 Juzi Street, Yanji City, Jilin Province, People’s Republic of China, Tel +86 15526771578 ; +86 15526771162, Fax +86 433 2513610, Email 15526771578@163.com; plz1978@126.comBackground: Advanced-stage hepatocellular carcinoma (HCC), especially huge HCC or portal vein tumour thrombus (PVTT), is difficult to treat, and the prognosis is poor. The advantages of hepatic artery infusion chemotherapy (HAIC) combined with targeted therapy and immunotherapy for this complex disease are gradually becoming apparent. However, HAIC still has some inevitable disadvantages, such as arterial perfusion therapy requiring a long time, which results in many patients having difficulty completing the procedure. Modified HAIC (mHAIC)-based oxaliplatin and S-1 is a new treatment option for huge HCC or PVTT that can reduce complications and improve patient compliance. We report two cases of huge HCC or PVTT that were successfully treated with mHAIC combined with lenvatinib and camrelizumab. The clinical presentations, treatment strategies, and outcomes of these cases are presented.Case Presentation: Case 1: A 52-year-old female was found to have a huge HCC with a size of 14× 11 cm. She was treated with one cycle of mHAIC combined with transcatheter arterial chemoembolization (TACE), lenvatinib and camrelizumab and 3 cycles of mHAIC in combination with lenvatinib and camrelizumab. The patient’s follow-up maintenance therapy with lenvatinib and camrelizumab has been evaluated for efficacy in achieving complete response (CR). Case 2: A 57-year-old man was diagnosed with advanced HCC in combination with PVTT. He achieved partial remission (PR) after four cycles of mHAIC combined with lenvatinib and camrelizumab. This was followed by treatment with lenvatinib and camrelizumab with an efficacy assessment for CR, and progression-free survival (PFS) was 7 months.Conclusion: For advanced HCC with a large mass or PVTT, mHAIC combined with lenvatinib and camrelizumab is a safe and effective treatment with good patient compliance.Keywords: huge HCC, PVTT, mHAIC, case report

Jinxia Li,1 Yiping Wang,2 Weiyang Jin,3 Li Shen4 1College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 2Key Laboratory of Digestive Pathophysiology of Zhejiang Province, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, People’s Republic of China; 3School of Life and Environmental Science, Hangzhou Normal University, Hangzhou, 311121, People’s Republic of China; 4Institute of Basic Theory of TCM, China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of ChinaCorrespondence: Li ShenInstitute of Basic Theory of TCM, China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of ChinaTel +86-158-5825-6870Email shenli1116@126.comObjective: To observe the efficacy of Actinidia eriantha polysaccharide (AEPS) combined with PD1 antibody therapy in colorectal cancer–xenograft mice.Methods: CT26 cells were inoculated into 80 C57BL/6 mice to establish the colorectal cancer xenograft–mouse model. Mice were divided evenly into a model group, AEPS group, anti-PD1 group, and combined group. AEPS 5mL/kg•day was given orally and 10 mg/kg anti-PD1 injected intravenously for 28 days. Tumor growth and mouse survival were observed. Tumor-cell proliferation and metastasis markers Ki67, N-cadherin, KLF4, and Oct4 were detected with immunochemistry and Western blotting, T-cell infiltration in spleens and tumors was detected with MTT and flow cytometry. IFNγ and TNFα were detected with ELISA.Results: Tumor growth was significantly retarded and survival prolonged in the AEPS, anti-PD1, and combined groups. Ki67 expression decreased in the anti-PD1 and combined groups, and N-cadherin, KLF4, and Oct4 expression decreased in the AEPS and combined groups. IFNγ and TNFα levels, T-cell infiltration in spleen, and tumor all increased distinctively in the AEPS and combined groups. The combined group showed better antitumor effects and life-extension effect than the other two groups.Conclusion: AEPS and PD1 antibody-combination therapy can suppresses tumor growth and prolong survival of colorectal cancer–xenograft mice by regulating immunofunction, and the combined therapy showed better therapeutic efficacy than the single treatment.Keywords: colorectal cancer, PD1 antibody, Actinidia eriantha polysaccharide, combined therapy

Miao Da,1 Hao Jiang,1 Yangyang Xie,2 Weili Jin,3 Shuwen Han4 1Department of Nursing, Huzhou Third Municipal Hospital, Huzhou, Zhejiang, People’s Republic of China; 2Key Laboratory of Diagnosis and Treatment of Digestive System Cancers of Zhejiang Province, Ningbo 315000, Zhejiang, People’s Republic of China; 3Department of Gastroenterology, Nanxun District People’s Hospital, Huzhou, Zhejiang 313009, People’s Republic of China; 4Department of Oncology, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, Huzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Shuwen HanDepartment of Oncology, Huzhou Central Hospital, Affiliated Central Hospital HuZhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, Zhejiang, People’s Republic of ChinaTel +86 5722555750Email shuwenhan985@163.comAbstract: Although it has many treatment strategies, cancer is still one of the most common causes of morbidity and mortality in the world. Exosomes are small extracellular vesicles (EVs) that can be secreted by almost all cells. Exosomes can encapsulate various types of molecules, including lipids, proteins, DNA, messenger RNAs, and non-coding RNAs [microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)]. Exosome release is a way of communication between cells. They act as powerful signaling molecules between cancer cells and the surrounding cells that make up the cancer microenvironment. lncRNAs are a class of non-coding P, with a length of more than 200 bp, which are differentially expressed in many cancers. lncRNAs have been widely regarded as a new medium for cancer behavior. The presence of lncRNAs in circulation can be acellular or encapsulated in exosomal bodies released by cancer cells. Exosomal lncRNAs are functional and can transmit different phenotypic patterns to neighboring cells. Here, we reviewed the molecular mechanism of exosomal lncRNAs in regulating cancer progression, angiogenesis, and chemotherapy resistance, as well as the prospective applications of exosomal lncRNAs in cancer diagnosis, treatment and prognosis. These findings potentially promote the current understanding of exosomal lncRNAs and provide a new research direction for exosomal lncRNAs in cancer prevention, diagnosis, and treatment.Keywords: exosome, long non-coding RNAs, cancer

Wei Jin,1,* Jian-Chun Duan,2,* Zhi-Jie Wang,2 Lin Lin,2 Hua Bai,2 Jie Wang,2 Li Feng1 1Department of Chinese Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People’s Republic of China; 2State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie WangState Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing 100021, People’s Republic of ChinaTel +86 139-1070-4669Email zlhuxi@163.comLi FengDepartment of Chinese Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing 100021, People’s Republic of ChinaTel +86 186-1814-7576Email fengli663@126.comAbstract: Immunotherapy provided with checkpoint inhibitors such as the programmed cell death-1 (PD-1) receptor or its ligand-1 (PD-L1) protein has been shown to be effective for treating several types of cancer, and was recently approved for use in treating malignant melanoma, advanced non-small cell lung cancer (NSCLC), urothelial carcinoma, head and neck squamous cell carcinoma, liver cancer, and additional forms of cancer. However, there is little evidence concerning its effectiveness in treating thymic squamous cell carcinoma (TSCC). Here, we report two cases of refractory TSCC that were treated with PD-1 single/combination therapy in a clinical setting. The patients exhibited variable responses to therapy without any serious adverse events. In summary, our findings show that immunotherapy provided with an immuno-checkpoint inhibitor in combination with chemotherapy/anti-angiogenesis therapy can improve the treatment response of patients with refractory TSCC. Anti-PD-1 single/combination therapy may be used as a strategy for treating advanced refractory TC.Keywords: thymic carcinoma, anti-PD-1, single/combination therapy

Chao Lu,1– 3 Weiwei Jin,1,2 Yiping Mou,1,2 Hongliang Shao,4 Xiaosan Wu,4 Shaodong Li,5 Biwu Xu,4 Yuanyu Wang,1,2 Qicong Zhu,1,2 Tao Xia,1,2 Yucheng Zhou1– 3 1Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang Province, People’s Republic of China; 2Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, Zhejiang Province, People’s Republic of China; 3School of Medicine, Soochow University, Suzhou, Jiangsu Province, People’s Republic of China; 4School of Medicine, Bengbu Medical College, Bengbu, Anhui Province, People’s Republic of China; 5School of Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Yucheng Zhou; Yiping MouDepartment of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang Province, People’s Republic of ChinaEmail drzhouyc@163.com; yipingmou@126.comBackground: Gastrointestinal stromal tumors (GIST) of the duodenum are rarely reported and optimal minimally invasive management has not been well proposed. Pancreaticoduodenectomy and different types of pancreas-sparing duodenectomy can be chosen; however, which to choose and its corresponding clinical outcomes and oncological concerns remain controversial.Patients and Methods: Patients diagnosed with GIST of duodenum underwent laparoscopic pancreaticoduodenectomy (L-PD) or pancreas-sparing duodenectomy (L-PSD) in Zhejiang Provincial People’s Hospital were enrolled. All prospectively maintained data were analyzed retrospectively. Patients were grouped into the L-PD group or the L-PSD group, and the clinical outcomes and oncological outcomes were analyzed.Results: Between June 2013 and March 2019, a total of 22 patients (11 males/11 females) underwent surgical management, including 13 L-PDs and 9 L-PSDs. The average age was 58.2± 9.5 year-old (median 60.5 year-old). The most common presentations were GI bleeding (54.5%) and abdominal discomfort (27.2%), and the dominant lesion located in the second portion of duodenum (59.1%). Compared with L-PD group, L-PSD group showed much shorter operation time (364.2± 58.7min vs. 230.0± 12.3min, P< 0.001), less blood loss (176.9± 85.7mL vs. 61.1± 18.2min, P< 0.001), faster recovery to off-bed (2.6± 1.3d vs. 1.1± 0.3d, P=0.003), anus flatus (4.5± 1.0d vs. 2.4± 0.5d, P< 0.001) and liquid intake (4.9± 1.3d vs. 2.3± 0.5d, P< 0.001). Lymph node retrieval was much less in L-PSD, but no lymph node metastasis was observed in any patients. L-PSD had much Lower morbidity of both minor (Grade I/II) and major (III/IV/V) complications than that of L-PD (11.1% vs. 61.6%, P=0.02), resulting in shorter hospital stays (10.9± 3.8d vs. 20.6± 11.1d, P=0.021) and less total cost (76,972.4± 11,614.8yuan vs 125,628.7± 46,356.8yuan, P=0.006). The median follow-up was 42 months (range from 12 to 82months) without loss. Only 1 L-PD patient suffered hepatic metastasis 36months after surgery, and given sunitinib to stabilize the disease, none of the rest observed recurrence or metastasis.Conclusion: For GIST located opposite the major papilla, L-PSD showed comparable safety and oncological benefits when compared to L-PD, with shorter operation time, less blood loss and much faster recovery time, resulting in much less total cost. L-PSD should be applied in selected patients with experienced hands.Keywords: GIST, duodenum, pancreaticoduodenectomy, pancreas-sparing duodenectomy

Lin Liu,1,* Dongyu Xie,2,3,* Haina Xie,4,* Wei Huang,1 Jingxian Zhang,5 Wenye Jin,5 Wenjing Jiang,1 Donghao Xie5,6 1Department of Pharmacy, Dahua Hospital, Shanghai, People’s Republic of China; 2Department of Spleen-Stomach, Zhenjiang Affiliated Hospital of Nanjing University of Chinese Medicine, Zhenjiang, People’s Republic of China; 3Department of Spleen-Stomach, Zhenjiang Hospital of Traditional Chinese Medicine, Zhenjiang, People’s Republic of China; 4School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 5Department of Pharmacy, Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, People’s Republic of China; 6School of Pharmacy, Jiangsu University, Zhenjiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Donghao XieDepartment of Pharmacy, Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, People’s Republic of ChinaTel +86- 18221220090Email xdhdh2012@126.comIntroduction: ARHGAP10 belongs to the ARHGAP family, which is downregulated in certain human tumors. However, the detailed function of ARHGAP10 remains unclear in human colon carcinoma (CRC). In the current study, we aimed to explore the role of ARHGAP10 in the growth and metastasis of CRC cells.Methods: ARHGAP10 was induced silencing and overexpression using RNA interference (RNAi) and lentiviral-vector in CRC cells. Quantitative real-time PCR (qRT-PCR) and Western blot were used to quantify the mRNA and protein contents of ARHGAP10. Cell proliferation was determined by using Cell counting kit-8 (CCK-8). Transwell assay was utilized to examine the role of ARHGAP10 in the migration and invasion of CRC cells.Results: Our results indicated that ARHGAP10 was downregulated in human CRC tissues and low expression of ARHGAP10 was associated with poor prognosis of patients with CRC. Moreover, ARHGAP10 overexpression significantly inhibited the proliferation and metastasis of CRC cells. Moreover, a PI3K/AKT inhibitor LY294002 was utilized to examine the connection between ARHGAP10 and AKT. Our findings demonstrated that the AKT inhibitor LY294002 could rescue the function of ARHGAP10 in CRC cells.Discussion: It was the first time to elucidate that AKT involved in the ARHGAP10 signaling pathway and ARHGAP10 negatively mediated the phosphorylation of AKT (p-AKT) and RhoA activity in CRC cells. Interestingly, the Rho/MRTF/SRF inhibitor CCG-1423 significantly inhibited the phosphorylation of AKT in ARHGAP10 siRNA transfected CRC cells. Much importantly, overexpression of ARHGAP10 deeply suppressed the metastasis of CRC cells in the lung in vivo. Taken together, our findings not only enhanced the understanding of the anti-cancer effect of ARHGAP10 in CRC cells but also indicated its underlying pathway in CRC.Keywords: ARHGAP10, AKT, RhoA activity, colon carcinoma

Wei Jin,1,* Jinsheng Shi,2,* Meiqin Liu11Department of Gastroenterology, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, People’s Republic of China; 2Department of Pathology, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, People’s Republic of China *These authors contributed equally to this workCorrespondence: Wei JinDepartment of Gastroenterology, Yidu Central Hospital of Weifang, No.4138, South Linglongshan Road, Shandong 262500, People’s Republic of ChinaTel +86 0 536 327 5615Fax +86 0 536 327 9421Email jinweiyidu0536@163.comPurpose: Colon cancer is one of the common malignancies worldwide, and many genes, including microRNAs (miRNAs), have been demonstrated that associated with progression of various diseases, including cancers. The aim of this study is to investigate the potential role of miR-671-5p in colon cancer.Patients and methods: Reverse transcription-quantitative polymerase chain reaction (qRT-PCR) was performed to detect the expression levels of miR-671-5p in 115 paired colon cancer tissues and adjacent normal tissues, as well as in colon cancer cells. Kaplan-Meier curve and Cox regression analyses were used to estimate the prognostic significance of miR-671-5p in colon cancer. CCK-8 assay, colony-formation assay, Transwell migration and invasion assays were used to evaluate the effects of miR-671-5p on cell proliferation, migration, and invasion in colon cancer.Results: We found that miR-671-5p expression was increased in colon cancer tissues and cell lines. Overexpression of miR-671-5p was found associated with lymph node metastasis, TNM stage, and poor overall survival of patients with colon cancer. By exploiting miR-671-5p mimics and inhibitors, miR-671-5p overexpression significantly increased cell proliferation, migration, and invasion, while downregulation of miR-671-5p inhibited proliferation, migration, and invasion of colon cancer cells.Conclusion: Taken together, miR-671-5p may act as an oncogene in colon cancer and promote proliferation, migration, and invasion of colon cancer cells by targeting TRIM67. And it may be a promising prognostic biomarker and therapeutic application for colon cancer treatment.Keywords: miR-671-5p, colon cancer, prognosis, proliferation, migration, invasion

Sheng-Chun Dang,1 Fei Wang,1 Xiao-Bao Qian,1 Malik Abdul,1 Qais-Ahmad Naseer,1 Wei Jin,2 Rong Hu,3 Qian Gu,3 Min Gu4 1Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province 212001, People’s Republic of China; 2Department of Obstetrics and Gynecology, The Changshu No. 2 People’s Hospital, Changshu, Jiangsu Province 215500, People’s Republic of China; 3Department of Geriatrics, Zhenjiang First People’s Hospital, Jiangsu Province 212001, People’s Republic of China; 4Department of Oncology, Zhenjiang Hospital of Traditional Chinese and Western Medicine, Zhenjiang, Jiangsu 212001, People’s Republic of China Purpose: The expression of microRNA-505 (miR-505) has been investigated in various cancers; however, its effect and mechanism in relation to gastric cancer (GC) are yet to be determined. Thus, the current evaluation aimed to examine the expression and potential role of miR-505 in GC. Materials and methods: Quantitative real-time PCR was carried out to analyze miR-505 expression in GC cells and tissues. We observed that miR-505 is differentially expressed in GC cells following transfection of its mimics or inhibitors. Changes in cell invasion, cell proliferation, and epithelial–mesenchymal transition markers were measured. Results: These findings indicated that miR-505 expression is downregulated in both GC cell lines and GC tissues. In addition, knockdown miR-505 induced the invasion and proliferation of GC cells. Transfection of miR-505 mimics led to an elevation in N-cadherin expression but a decrease in E-cadherin expression. Furthermore, we have shown that miR-505 binds to the 3'-UTR region of Polo-like kinase-1. Conclusion: Our results indicated that miR-505 suppresses GC cell proliferation and invasion; it may be a valuable candidate gene for seeking therapy strategy for GC. Keywords: MicroRNA-505, EMT, polo-like kinase-1, gastric cancer

Hao Su,1,* Weisen Jin,2,* Peng Wang,1 Mandula Bao,1 Xuewei Wang,1 Chuanduo Zhao,1 Xishan Wang,1 Zhixiang Zhou,1 Haitao Zhou1 1Department of Colorectal Surgery, National Cancer Center, National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Beijing 100021, People’s Republic of China; 2Department of Anorectal Diseases, General Hospital of Chinese Armed Police Forces, Haidian District, Beijing 100039, People’s Republic of China *These authors contributed equally to this work Purpose: Overlapped delta-shaped anastomosis is a newly developed intracorporeal procedure in totally laparoscopic surgery for colon cancer. We explored the safety and efficacy of three-dimensional (3D) totally laparoscopic surgery for colon cancer using overlapped anastomosis and compared its short-term outcomes with those of two-dimensional (2D) surgery.Materials and methods: From January 2016 to March 2018, 97 colon cancer patients were grouped into the 3D group (43 patients) and the 2D group (54 patients); they underwent totally laparoscopic surgery for colon cancer using overlapped anastomosis by 3D and 2D laparoscopy, respectively. Data regarding the clinical characteristics, surgical and pathological outcomes, postoperative recovery and complications were collected and compared.Results: These two groups were well balanced in terms of age, gender, body mass index, American Society of Anesthesiologists scores, previous abdominal operation history and preoperative chemotherapy (P>0.05). The overall operation time, intraoperative blood loss and removal method of the specimen were similar between groups (P>0.05), but the anastomosis time was significantly shorter in the 3D group than that in the 2D group (P=0.004). There were no differences in terms of pathological outcomes, postoperative recovery and the postoperative complication rates between the groups (P>0.05). Moreover, no mobility related to the anastomosis, such as anastomotic bleeding, stenosis or leakage, occurred in any patient.Conclusion: 3D totally laparoscopic surgery for colon cancer using overlapped delta-shaped anastomosis is safe and effective, with satisfactory short-term outcomes. In addition, it is less time-consuming than 2D surgery regarding the overlapped anastomosis procedure. Keywords: minimally invasive surgery, three-dimensional laparoscopy, intracorporeal anastomosis, colon neoplasms

Sheng-Chun Dang,1 Xiao-Bao Qian,1 Wei Jin,2 Lei Cui,1 Ji-Xiang Chen,1 Min Gu3 1Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, People’s Republic of China; 2Department of Obstetrics and Gynecology, ChangShu No. 2 People’s Hospital, Changshu, Jiangsu 215500, People’s Republic of China; 3Department of Oncology, Zhenjiang Hospital of Traditional Chinese and Western Medicine, Zhenjiang, Jiangsu 212001, People’s Republic of China Background: To investigate the expression and role of G-protein-signaling modulator 2 (GPSM2) in a CD133+ pancreatic stem cell subset. Materials and methods: Pancreatic cancer stem cells (PCSCs) from the cell line PANC-1 were sorted into CD133+ and CD133- subsets by flow cytometry. The tumorigenic potential of the subsets was assessed by subcutaneous tumor formation experiments in nude mice. Differential expression of GPSM2 was examined by real-time quantitative-PCR (qPCR) and Western blotting. To silence GPSM2 expression, a shRNA lentiviral vector targeting GPSM2 was constructed and stably transfected into CD133+ PCSCs. The inhibitory efficiency of the GPSM2 gene was verified by qPCR and Western blotting. The proliferation, colony formation, and migration abilities of the transfected CD133+ pancreatic cancer cells were assessed by MTT, soft agar colony formation, and Transwell assays. Results: CD133+ and CD133- cell subsets were successfully isolated from PANC-1 cells. The CD133+ subset subcutaneously formed tumors in nude mice that were significantly bigger (343.05±57.59 mm3 vs 176.86±32.58 mm3, P

Endong Chen,1 Qiaolin Wu,2 Yixiang Jin,1 Wenxu Jin,1 Yefeng Cai,1 Qingxuan Wang,1 Xiaohua Zhang,1 Ouchen Wang,1 Quan Li,1 Zhouci Zheng3 1Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Head and Neck Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China Objectives: Few studies on prognostic indicators for primary thyroid lymphoma (PTL) have been presented due to the uncommon nature of the tumor. This is the first study to explore the independent prognostic factors in the 2 PTL subtypes.Methods: We retrospectively reviewed 1,653 cases of PTL. The cases comprised 28 Chinese patients from a local cohort and 1,625 patients from the Surveillance, Epidemiology, and End Results database from 1973 to 2013. Statistical analysis was performed to determine the demographics and prognostic factors of PTL patients.Results: The disease-specific survival (DSS) and prognostic indicators were significantly different between patients with extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) and patients with diffuse large B-cell lymphoma (DLBCL). Patients with MALT lymphoma were younger (P=0.011) and had lower clinical stage (P=0.014) compared to patients with DLBCL. Cox regression analysis revealed that age, treatment modalities employed, clinical stage, and number of other types of cancer were independent prognostic factors for DLBCL patients.Conclusion: PTL demonstrates specific clinical features and is associated with a relatively good prognosis. Older age is associated with poor DSS in both MALT patients and DLBCL patients. Additionally, combination of different treatment modalities is associated with improved DSS in DLBCL patients. Keywords: primary thyroid lymphoma, SEER database, disease-specific survival, combined modality treatment, prognosis

Imaging-based monitoring of disease burden in glioma patients is frequently confounded by treatment effects. Circulating biomarkers could theoretically augment imaging-based response monitoring. This systematic review aimed to present and evaluate evidence for differential expression and diagnostic accuracy of circulating biomarkers with respect to outcomes of tumor response, progression, stable disease, and treatment effects (pseudoprogression, radionecrosis, pseudoresponse, and pseudolesions) in patients undergoing treatment for World Health Organization grades II–IV diffuse astrocytic and oligodendroglial tumors. MEDLINE, EMBASE, Web Of Science, and SCOPUS databases were searched until August 18, 2019, for observational or diagnostic studies on multiple circulating biomarker types: extracellular vesicles, circulating nucleic acids, circulating tumor cells, circulating proteins, and metabolites, angiogenesis related cells, immune cells, and other cell lines. Methodological quality of included studies was assessed using an adapted Quality Assessment of Diagnostic Accuracy Studies-2 tool, and level of evidence (IA–IVD) for individual biomarkers was evaluated using an adapted framework from the National Comprehensive Cancer Network guidelines on evaluating tumor marker utility. Of 13,202 unique records, 58 studies met the inclusion criteria. One hundred thirty-three distinct biomarkers were identified in a total of 1,853 patients across various treatment modalities. Fifteen markers for response, progression, or stable disease and five markers for pseudoprogression or radionecrosis reached level IB. No biomarkers reached level IA. Only five studies contained data for diagnostic accuracy measures. Overall methodological quality of included studies was low. While extensive data on biomarker dysregulation in varying response categories were reported, no biomarkers ready for clinical application were identified. Further assay refinement and evaluation in larger cohorts with diagnostic accuracy study designs are required.PROSPERO Registration: CRD42018110658.

Quan Li,* Wen-Xu Jin,* Yi-Xiang Jin, Zhou-Ci Zheng, Xiao-Fen Zhou, Qing-Xuan Wang, Dan-Rong Ye, Yi-Han Sun, Xiao-Hua Zhang, Ou-Chen Wang, En-Dong Chen, Ye-Feng Cai Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China *These authors contributed equally to this work Aim: To investigate the clinical effects of MUC1 on papillary thyroid cancer (PTC) and explore the relationship between MUC1 expression and BRAF mutation. Methods: The data of 69 patients subjected to fine-needle aspiration biopsy in our hospital and 486 patient data downloaded from The Cancer Genome Atlas (TCGA) database were used. Univariate and multivariate analyses were performed.Results: The results on the 486 patients recorded in the TCGA indicated that high MUC1 expression was independently related to BRAF mutation, lymph node metastasis (LNM), and unifocal type. In the 69 fine-needle aspiration biopsy patients with PTC, high MUC1 expression was significantly related to LNM and extrathyroid extension (ETE). The result of Pearson’s correlation coefficient showed that BRAF mutation and MUC1 expression were moderately correlated. Moreover, in the subgroup with low MUC1 expression, the patients with BRAF mutation had higher ETE frequency and LNM than those without BRAF mutation. In the subgroup with BRAF mutation, patients with high MUC1 expression exhibited higher ETE frequency than those with low MUC1 expression, and high MUC1 expression occurred in older patients. In the subgroup with BRAF wild-type mutation, patients with high MUC1 expression had a higher incidence of ETE and LNM than those with low expression.Conclusion: We demonstrated that the MUC1 is an important oncogene in PTC and may have great significance on therapeutic cancer vaccine development.Keywords: MUC1, BRAF mutation, papillary thyroid cancer, prognosis, lymph node metastasis, extrathyroid extension

Zexin Chen,1 Hui Liu,2 Wen Jin,2 Zheyuan Ding,2 Shuangshuang Zheng,2 Yunxian Yu2 1Department of Clinical Epidemiology and Biostatistics, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 2Department of Epidemiology & Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of ChinaObjective: MicroRNA-21 (miR-21) has been shown to play an important role in cancer prognosis. We performed a meta-analysis to evaluate the prognostic effect of miR-21 from tissues and serum on survival of the patients with colorectal cancer (CRC).Methods: Relevant studies were identified by searching PubMed, Embase, and Cochrane Library. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of total and subgroup analyses, for overall survival (OS) and disease-free survival (DFS), were calculated to investigate the association between miR-21 expression and CRC prognosis.Results: Our analysis included eleven studies (3,669 subjects). In addition, four studies explored the association between miR-21 and DFS, and ten studies focused on the prognostic value of miR-21 for OS. Our results indicated that increased miR-21 expression of tissues predicted both poor DFS and OS in patients with CRC (DFS: HR =1.59, 95% CI =1.20–2.10; OS: HR =1.53, 95% CI =1.23–1.90). Consistent results were observed among colon cancer and quantitative real-time polymerase chain reaction subgroups.Conclusion: Meta-analysis indicated that miR-21 predicted recurrence and poor survival in patients with CRC. miR-21 may be more suitable to predict cancer prognosis in colon cancer patients. Keywords: miR-21, prognostic value, colorectal cancer

Qiang Ma,* Zhuo Chen,* Guojin Jia, Xueqiang Lu, Xuefeng Xie, Wei Jin Department of Urology, Jinshan Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this workAims: Prostate cancer (PCa) is the most frequently diagnosed malignancy in men. However, the underlying mechanism is not fully understood. In this study, we aim to research the molecular mechanisms underlying the initiation and progression of PCa.Results: Plant homeodomain finger protein 8 (PHF8) is upregulated in human PCa tissues and cell lines. PHF8 knockdown attenuates growth and cellular transformation of PCa cells. PHF8 depletion induces PCa cell apoptosis by activating proapoptotic proteins and inactivating antiapoptotic proteins. Furthermore, miR-125b is a target of PHF8, and miR-125b seems to be essential for the hyper proliferation of PCa cells in the presence of PHF8.Conclusion: In conclusion, we identify the histone demethylase PHF8 as an oncogenic protein in human PCa. These findings indicate PHF8 as a potential candidate for clinical intervention. Keywords: PHF8, prostate cancer, apoptosis, miR-125b

Abstract BAP1, BRCA1-Associated Protein 1, serves as a novel tumor suppressor through the deubiquitination of monoubiquitination of H2A and subsequent gene transcriptional regulation. Regulated cell death like apoptosis or ferroptosis is considered an essential mechanism mediating tumor suppression. Previous reports, including ours, have demonstrated that BAP1 could promote apoptosis and ferroptosis to inhibit tumor development. Whether BAP1 regulated additional types of cell death remains unclear. Disulfidptosis is a recently identified novel cell death mode characterized by aberrant accumulation of intracellular disulfide (e.g., cystine) and depletion of NADPH. In this study, we first demonstrated that BAP1 could significantly protect disulfidptosis induced by glucose starvation, which is validated by various cell death inhibitors and the accumulation of disulfide bonds in the cytoskeleton proteins. BAP1 is known to inhibit SLC7A11 expression. We found that the protective effect of BAP1 against disulfidptosis was counteracted when overexpressing SLC7A11 or adding additional cystine. Conversely, BAP1-mediated suppression of disulfidptosis was largely abrogated when SLC7A11-mediated cystine uptake was inhibited by the knockout of SLC7A11 or erastin treatment. Besides, high BAP1 expression showed lower NADP+/NADPH levels, which might confer resistance to disulfidptosis. Consistent with these observations, the expression level of BAP1 was also positively correlated with NADPH-related genes in KIRC patients, though the underlying mechanism mediating NADPH regulation remains further investigation. In summary, our results revealed the role of BAP1 in the regulation disulfidptosis and provided new insights into the understanding of disulfidptosis in tumor development.

Abstract Background Ferroptosis, characterized by iron-dependent lipid peroxidation, emerges as a promising avenue for hepatocellular carcinoma (HCC) intervention due to its tumor susceptibility. RNA N6-methyladenosine (m6A) modification has been involved in several types of regulated cell death. However, the roles and molecular mechanisms of m6A-related regulators in HCC cell ferroptosis remain unclear. Methods By examining a series of m6A modification enzymes upon ferroptosis induction or inhibition, we identified METTL16 as a novel ferroptotic repressor in HCC cells. The roles of METTL16 on ferroptosis and HCC development were investigated in multiple cell lines, human HCC organoids, subcutaneous xenografts and MYC/Trp53−/− HCC model in hepatocyte-specific Mettl16 knockout and overexpression mice. The underlying mechanism was elucidated with MeRIP/RIP-qPCR, luciferase assay, Co-IP assay and Mass Spectrometry. The clinical significance and relevance were evaluated in human samples. Results High METTL16 expression confers ferroptosis resistance in HCC cells and mouse models, and promotes cell viability and tumor progression. Mechanistically, METTL16 collaborates with IGF2BP2 to modulate SENP3 mRNA stability in an m6A-dependent manner, and the latter impedes the proteasome-mediated ubiquitination degradation of Lactotransferrin (LTF) via de-SUMOylation. Elevated LTF expression facilitates the chelation of free iron and reduces liable iron pool level. SENP3 and LTF are implicated in METTL16-mediated HCC progression and anti-ferroptotic effects both in vivo and in vitro. Clinically, METTL16 and SENP3 expression were positively correlated, and high METTL16 and SENP3 expression predicts poor prognosis in human HCC samples. Conclusions Our study reveals a new METTL16-SENP3-LTF signaling axis regulating ferroptosis and driving HCC development. Targeting this axis is a promising strategy for sensitizing ferroptosis and against HCC.

Abstract Background Pancreatic cancer (PaCa) is one of the most intractable and fatal malignancies and is associated with the dysregulation of long noncoding RNAs (lncRNAs), which are a large class of noncoding RNAs larger than 200 nt that act as competing endogenous RNAs or sponges for miRNAs to induce tumour biological behaviours. However, their clinical value in treating pancreatic cancer has been poorly explained, but they are essential for improving the prognosis of PaCa patients. Methods We analysed the plasma-derived exosomal lncRNA profiles of PaCa patients by using whole-transcriptome sequencing analysis and identified significantly differentially expressed lncRNAs, including LINC01268, LINC02802, AC124854.1, and AL132657.1. In the current study, the expression levels of four plasma-derived exosomal lncRNAs in PaCa plasma were validated via quantitative real-time polymerase chain reaction (qRT‒PCR). The relationship between the expression of the four lncRNAs and the clinicopathological features of patients with PaCa was also evaluated. Results We demonstrated that exosomal LINC01268, LINC02802, AC124854.1 and AL132657.1 were highly expressed in PaCa plasma compared with those in normal controls; moreover, they were positively correlated with the serum expression of carbohydrate antigen 19–9 (CA19-9). The receiver operating characteristic curves (AUCs) of the four lncRNAs were 0.8421, 0.6544, 0.7190, and 0.6321, and the AUC value of the combination of the four exosomal lncRNAs increased to 0.8476, with a sensitivity of 0.72 and specificity of 0.89. These results suggested that the plasma-derived exosomal genes LINC01268, LINC02802, AC124854.1, and AL132657.1 may be novel diagnostic markers for PaCa. Conclusions Our research demonstrated that the plasma-derived exosomal lncRNAs of PaCa patients are novel blood-based biomarkers of disease.

Abstract Not all MET exon 14 skipping (METex14) NSCLC patients benefited from MET inhibitors. We hypothesized an inter-tumoral heterogeneity in METex14 NSCLC. Investigations at genomic and transcriptomic level were conducted in METex14 NSCLC samples from stage I-III and recurrent/metastatic patients as discovery and validation cohort. Four molecular subtypes were discovered. MET-Driven subtype, with the worst prognosis, displayed MET overexpression, enrichment of MET-related pathways, and higher infiltration of fibroblast and regulatory T cells. Immune-Activated subtype having the most idea long-term survival, had higher tertiary lymphoid structures, spatial co-option of PD-L1+ cancer cells, and GZMK+ CD8+ T cell. FGFR- and Bypass-Activated subtypes displayed FGFR2 overexpression and enrichments of multiple oncogenic pathways respectively. In the validation cohort, patients with MET-Driven subtype had better response to MET inhibitors than those with MET overexpression. Thus, molecular subtypes of METex14 NSCLC with distinct biological and clinical significance may indicate more precise therapeutic strategies for METex14 NSCLC patients.

Abstract Background Recent intravesical administration of adenoviral vectors, either as a single injection or in combination with immune checkpoint inhibitors, exemplified by cretostimogene grenadenorepvec and nadofaragene firadenovec, has demonstrated remarkable efficacy in clinical trials for non-muscle invasive bladder cancer. Despite their ability to induce an enhanced immune reaction within the lesion, the intracellular survival signaling of cancer cells has not been thoroughly addressed. Methods An analysis of the prognostic data revealed a high probability of therapeutic efficacy with simultaneous inhibition of mTOR and STAT3. Considering the challenges of limited pharmaco-accessibility to the bladder due to its pathophysiological structure and the partially undruggable nature of target molecules, we designed a dual siRNA system targeting both mRNAs. Subsequently, this dual siRNA system was encoded into the adenovirus 5/3 (Ad 5/3) to enhance in vivo delivery efficiency. Results Gene-targeting efficacy was assessed using cells isolated from xenografted tumors using a single-cell analysis system. Our strategy demonstrated a balanced downregulation of mTOR and STAT3 at the single-cell resolution, both in vitro and in vivo. This approach reduced tumor growth in bladder cancer xenograft and orthotopic animal experiments. In addition, increased infiltration of CD8+ T cells was observed in a humanized mouse model. We provided helpful and safe tissue distribution data for intravesical therapy of siRNAs coding adenoviruses. Conclusions The bi-specific siRNA strategy, encapsulated in an adenovirus, could be a promising tool to augment cancer treatment efficacy and overcome conventional therapy limitations associated with “undruggability.” Hence, we propose that dual targeting of mTOR and STAT3 is an advantageous strategy for intravesical therapy using adenoviruses. Graphical Abstract The current investigation introduces an innovative conceptualization of bispecific short hairpin RNA (bs_shRNA) tailored for the equilibrated modulation of dual genes within a singular cellular context. This novel bs_shRNA was loaded into the genome of an oncolytic adenovirus to augment the therapeutic efficacy of oncolytic viral interventions via the targeted inhibition of mTOR and STAT3 pathways. In addition, the administration of BSV significantly reduced the volume of bladder cancer tumors, concomitantly facilitating an enhanced recruitment of CD8+T lymphocytes in vivo.

Abstract Nuclear condensates have been shown to regulate cell fate control, but its role in oncogenic transformation remains largely unknown. Here we show acquisition of oncogenic potential by nuclear condensate remodeling. The proto-oncogene SS18 and its oncogenic fusion SS18-SSX1 can both form condensates, but with drastically different properties and impact on 3D genome architecture. The oncogenic condensates, not wild type ones, readily exclude HDAC1 and 2 complexes, thus, allowing aberrant accumulation of H3K27ac on chromatin loci, leading to oncogenic expression of key target genes. These results provide the first case for condensate remodeling as a transforming event to generate oncogene and such condensates can be targeted for therapy. One sentence summary: Expulsion of HDACs complexes leads to oncogenic transformation.

Abstract Background Bladder cancer (BCa) stands out as a prevalent and highly lethal malignancy worldwide. Chemoresistance significantly contributes to cancer recurrence and progression. Traditional Tumor Node Metastasis (TNM) stage and molecular subtypes often fail to promptly identify treatment preferences based on sensitivity. Methods In this study, we developed a prognostic signature for BCa with uni-Cox + LASSO + multi-Cox survival analysis in multiple independent cohorts. Six machine learning algorithms were adopted to screen out the hub gene, RAC3. IHC staining was used to validate the expression of RAC3 in BCa tumor tissue. RT-qPCR and Western blot were performed to detect and quantify the mRNA and protein levels of RAC3. CCK8, colony formation, wound healing, and flow cytometry analysis of apoptosis were employed to determine cell proliferation, migration, and apoptosis. Molecular docking was used to find small target drugs, PIK-75. 3D cell viability assay was applied to evaluate the ATP viability of bladder cancer organoids before and after PIK-75 treated. Results The established clinical prognostic model, GIRS, comprises 13 genes associated with gemcitabine resistance and immunology. This model has demonstrated robust predictive capabilities for survival outcomes across various independent public cohorts. Additionally, the GIRS signature shows significant correlations with responses to both immunotherapy and chemotherapy. Leveraging machine learning algorithms, the hub gene, RAC3, was identified, and potential upstream transcription factors were screened through database analysis. IHC results showed that RAC3 was higher expressed in GEM-resistant BCa patients. Employing molecular docking, the small molecule drug PIK-75, as binding to RAC3, was identified. Experiments on cell lines, organoids and animals validated the biological effects of PIK-75 in bladder cancer. Conclusions The GIRS signature offers a valuable complement to the conventional anatomic TNM staging system and molecular subtype stratification in bladder cancer. The hub gene, RAC3, plays a crucial role in BCa and is significantly associated with resistance to gemcitabine. The small molecular drug, PIK-75 having the potential as a therapeutic agent in the context of gemcitabine-resistant and immune-related pathways.

Introduction: Atezolizumab plus bevacizumab is a commonly used first-line regimen for advanced hepatocellular carcinoma (HCC) treatment owing to its superior outcomes compared to sorafenib. However, optimal subsequent treatment options for patients with HCC who progressed on first-line atezolizumab plus bevacizumab remain unclear. Methods: This multinational, multi-institutional, retrospective study included patients with HCC from 22 centers in five Asia-Pacific countries who were treated with first-line atezolizumab plus bevacizumab, which was discontinued for any reason. The endpoints included progression-free survival (PFS) and overall survival (OS) according to patient characteristics and second-line regimens. Results: Between June 2016 and May 2023, 1141 patients were treated with first-line atezolizumab plus bevacizumab, of whom 629 (55.1%) received subsequent treatment. Sorafenib and lenvatinib were the most commonly administered second-line regimens (53.9% and 25.6%, respectively). Overall, the median PFS and OS were of 2.9 and 8.0 months, respectively. Lenvatinib had longer PFS (4.0 vs 2.3 months) and OS (8.0 vs 6.3 months) than sorafenib. Patients treated with tyrosine kinase inhibitor (TKI) plus immune checkpoint inhibitor (ICI) (n=50, 8.3%) showed PFS and OS of 5.4 and 12.6 months, respectively. Lower tumor burden and lenvatinib or TKI plus ICI use were associated with longer second-line PFS. Preserved liver function was associated with improved OS. Conclusions: In patients with HCC who progressed on first-line atezolizumab plus bevacizumab, sorafenib and lenvatinib were the most commonly used second-line regimens in Asia-Pacific countries, with lenvatinib resulting in longer OS than sorafenib. The second-line TKI plus ICI combination exhibited promising efficacy, suggesting the potential role of continuing ICIs beyond disease progression.

Abstract Objectives Stereotactic body radiotherapy (SBRT) is a treatment option for patients with early-stage non-small cell lung cancer (NSCLC) who are unfit for surgery. Some patients may experience distant metastasis. This study aimed to develop and validate a radiomics model for predicting distant metastasis in patients with early-stage NSCLC treated with SBRT. Methods Patients at five institutions were enrolled in this study. Radiomics features were extracted based on the PET/CT images. After feature selection in the training set (from Tianjin), CT-based and PET-based radiomics signatures were built. Models based on CT and PET signatures were built and validated using external datasets (from Zhejiang, Zhengzhou, Shandong, and Shanghai). An integrated model that included CT and PET radiomic signatures was developed. The performance of the proposed model was evaluated in terms of its discrimination, calibration, and clinical utility. Multivariate logistic regression was used to calculate the probability of distant metastases. The cutoff value was obtained using the receiver operator characteristic curve (ROC), and the patients were divided into high- and low-risk groups. Kaplan-Meier analysis was used to evaluate the distant metastasis-free survival (DMFS) of different risk groups. Results In total, 228 patients were enrolled. The median follow-up time was 31.4 (2.0-111.4) months. The model based on CT radiomics signatures had an area under the curve (AUC) of 0.819 in the training set (n = 139) and 0.786 in the external dataset (n = 89). The PET radiomics model had an AUC of 0.763 for the training set and 0.804 for the external dataset. The model combining CT and PET radiomics had an AUC of 0.835 for the training set and 0.819 for the external dataset. The combined model showed a moderate calibration and a positive net benefit. When the probability of distant metastasis was greater than 0.19, the patient was considered to be at high risk. The DMFS of patients with high- and low-risk was significantly stratified (P

BackgroundImatinib is the most widely used tyrosine kinase inhibitor (TKI) in patients with newly diagnosed chronic-phase chronic myeloid leukemia(CML-CP). However, failure to achieve optimal response after imatinib administration, and subsequent switch to second-generation TKI therapy results in poor efficacy and induces drug resistance. In the present study, we developed and validated a nomogram to predict the efficacy of imatinib in the treatment of patients newly diagnosed with CML-CP in order to help clinicians truly select patients who need 2nd generation TKI during initial therapy and to supplement the risk score system.MethodsWe retrospectively analyzed 156 patients newly diagnosed with CML-CP who met the inclusion criteria and were treated with imatinib at the Second Affiliated Hospital of Xi’an Jiao Tong University from January 2012 to June 2022. The patients were divided into a poor-response cohort (N = 60)and an optimal-response cohort (N = 43) based on whether they achieved major molecular remission (MMR) after 12 months of imatinib treatment. Using univariate and multivariate logistic regression analyses, we developed a chronic myeloid leukemia imatinib-poor treatment (CML-IMP) prognostic model using a nomogram considering characteristics like age, sex, HBG, splenic size, and ALP. The CML-IMP model was internally validated and compared with Sokal, Euro, EUTOS, and ELTS scores.ResultsThe area under the curve of the receiver operator characteristic curve (AUC)of 0.851 (95% CI 0.778–0.925) indicated satisfactory discriminatory ability of the nomogram. The calibration plot shows good consistency between the predicted and actual observations. The net reclassification index (NRI), continuous NRI value, and the integrated discrimination improvement (IDI) showed that the nomogram exhibited superior predictive performance compared to the Sokal, EUTOS, Euro, and ELTS scores (P < 0.05). In addition, the clinical decision curve analysis (DCA) showed that the nomogram was useful for clinical decision-making. In predicting treatment response, only Sokal and CML-IMP risk stratification can effectively predict the cumulative acquisition rates of CCyR, MMR, and DMR (P

Abstract Circulating tumor DNA (ctDNA) has been widely used as a minimally invasive biomarker in clinical routine. However, a number of factors such as panel design, sample quality, patients' disease stages are known to influence ctDNA detection sensitivity. In this study, we systematically evaluated common factors associated with the variability of ctDNA detection in plasma and investigated ctDNA abundance in bronchoalveolar lavage (BAL). Whole exome profiling was conducted on 61 tumor tissue samples to identify tumor‐specific variants, which were then used to design personalized assay MarRyDa® for ctDNA detection. DNA extracted from BAL fluid and plasma were genotyped using MarRyDa® platform. Our analysis showed that histological subtypes and disease stages had significant differences in ctDNA detection rate. Furthermore, we found that DNA purified from BAL supernatants contains the highest levels of ctDNA compared with BAL precipitates and plasma; therefore, utilizing BAL supernatants for tumor detection might provide additional benefits. Finally, we demonstrated that tumor cellularity played significant roles in the design of personalized ctDNA panel which eventually impacts ctDNA detection sensitivity. We suggest setting a flexible criteria for sample quality control and utilization of BAL might benefit more patients in clinics.

Abstract Objectives The recommended treatment for limited‐stage small‐cell lung cancer (LS‐SCLC) is a combination of thoracic radiotherapy (TRT) and etoposide plus cisplatin (EP) chemotherapy, typically administered over 4–6 cycles. Nonetheless, the optimal duration of chemotherapy is still not determined. This study aimed to compare the outcomes of patients with LS‐SCLC who received either 6 cycles or 4–5 cycles of EP chemotherapy combined with TRT. Materials and Methods In this retrospective analysis, we utilized data from our prior prospective trial to analyze the outcomes of 265 LS‐SCLC patients who received 4–6 courses of EP combined with concurrent accelerated hyperfractionated TRT between 2002 and 2017. Patients were categorized into two groups depending on their number of chemotherapy cycles: 6 or 4–5 cycles. To assess overall survival (OS) and progression‐free survival (PFS), we employed the Kaplan–Meier method after conducting propensity score matching (PSM). Results Among the 265 LS‐SCLC patients, 60 (22.6%) received 6 cycles of EP chemotherapy, while 205 (77.4%) underwent 4–5 cycles. Following PSM (53 patients for each group), the patients in the 6 cycles group exhibited a significant improvement in OS and PFS in comparison to those in the 4–5 cycles group [median OS: 29.8 months (95% confidence interval [CI], 23.6–53.1 months) vs. 22.7 months (95% CI, 20.8–29.1 months), respectively, p = 0.019; median PFS: 17.9 months (95% CI, 13.7–30.5 months) vs. 12.0 months (95% CI, 9.8–14.2 months), respectively, p = 0.006]. The two‐year and five‐year OS rates were 60.38% and 29.87% in the 6 cycles group, whereas 47.17% and 15.72% in the 4–5 cycles group, respectively. Conclusion Patients diagnosed with LS‐SCLC who were treated with EP regimen chemotherapy combined with TRT exhibited notably enhanced survival when administered 6 cycles of chemotherapy, as compared to those who underwent only 4–5 cycles.

Background Despite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects and dysfunctions of CAR-T cells have limited the efficacy and clinical application of this promising approach.Methods In this study, we incorporated a short hairpin RNA cassette targeting PD-1 into a BCMA-CAR with an OX-40 costimulatory domain. The transduced PD-1KD BCMA CAR-T cells were evaluated for surface CAR expression, T-cell proliferation, cytotoxicity, cytokine production, and subsets when they were exposed to a single or repetitive antigen stimulation. Safety and efficacy were initially observed in a phase I clinical trial for RRMM patients.Results Compared with parental BCMA CAR-T cells, PD-1KD BCMA CAR-T cell therapy showed reduced T-cell exhaustion and increased percentage of memory T cells in vitro. Better antitumor activity in vivo was also observed in PD-1KD BCMA CAR-T group. In the phase I clinical trial of the CAR-T cell therapy for seven RRMM patients, safety and efficacy were initially observed in all seven patients, including four patients (4/7, 57.1%) with at least one extramedullary site and four patients (4/7, 57.1%) with high-risk cytogenetics. The overall response rate was 85.7% (6/7). Four patients had a stringent complete response (sCR), one patient had a CR, one patient had a partial response, and one patient had stable disease. Safety profile was also observed in these patients, with an incidence of manageable mild to moderate cytokine release syndrome and without the occurrence of neurological toxicity.Conclusions Our study demonstrates a design concept of CAR-T cells independent of antigen specificity and provides an alternative approach for improving the efficacy of CAR-T cell therapy.

Abstract Background The outcomes of patients with tumors of the thoracolumbar spine treated with en bloc resection (EBR) using three-dimensional (3D)-printed endoprostheses are underreported. Methods We retrospectively evaluated patients with thoracolumbar tumors who underwent surgery at our institution. Logistic regression analysis was performed to identify the potential risk factors for surgical complications. Nomograms to predict complications were constructed and validated. Results A total of 53 patients with spinal tumors underwent EBR at our hospital; of these, 2 were lost to follow-up, 45 underwent total en bloc spondylectomy, and 6 were treated with sagittal en bloc spondylectomy. The anterior reconstruction materials included a customized 3D-printed artificial vertebral body (AVB) in 10 cases and an off-the-shelf 3D-printed AVB in 41 cases, and prosthesis mismatch occurred in 2 patients reconstructed with the off-the-shelf 3D-printed AVB. The median follow-up period was 21 months (range, 7–57 months). Three patients experienced local recurrence, and 5 patients died at the final follow-up. A total of 50 perioperative complications were encountered in 29 patients, including 25 major and 25 minor complications. Instrumentation failure occurred in 1 patient, and no prosthesis subsidence was observed. Using a combined surgical approach was a dependent predictor of overall complications, while Karnofsky performance status score, lumbar spine lesion, and intraoperative blood loss ≥ 2000 mL were predictors of major complications. Nomograms for the overall and major complications were constructed using these factors, with C-indices of 0.850 and 0.891, respectively. Conclusions EBR is essential for the management of thoracolumbar tumors; however, EBR has a steep learning curve and a high complication rate. A 3D-printed AVB is an effective and feasible reconstruction option for patients treated with EBR.

Abstract Tumor-infiltrating lymphocytes (TIL) have been suggested as an important prognostic marker in colorectal cancer, but assessment usually requires additional tissue processing and interpretational efforts. The aim of this study is to assess the clinical significance of artificial intelligence (AI)-powered spatial TIL analysis using only a hematoxylin and eosin (H&E)-stained whole-slide image (WSI) for the prediction of prognosis in stage II–III colon cancer treated with surgery and adjuvant therapy. In this retrospective study, we used Lunit SCOPE IO, an AI-powered H&E WSI analyzer, to assess intratumoral TIL (iTIL) and tumor-related stromal TIL (sTIL) densities from WSIs of 289 patients. The patients with confirmed recurrences had significantly lower sTIL densities (mean sTIL density 630.2/mm2 in cases with confirmed recurrence vs. 1021.3/mm2 in no recurrence, p

BackgroundsThe value of circulating microRNA (miR)-155 for breast cancer (BC) diagnosis may differ in different studies. Therefore, we conducted this systematic review and meta-analysis to evaluate the potential application of circulating miR-155 in the diagnosis of BC.MethodsArticles published before December 2023 and in English were searched in these databases: PubMed, Web of Science, Medline, EMBASE and Google Scholar. A summary of sensitivity, specificity, positive likelihood ratios (PLR), negative likelihood ratios (NLR), and diagnostic odds ratio (DOR) were calculated from the true positive (TP), true negative (TN), false positive (FP) and false negative (FN) of each study. Additionally, the summary receive-operating characteristics (SROC) curve was constructed to summarize the TP and FP rates.ResultsThe pooled parameters calculated were as follows: sensitivity, 0.93 (95% CI: 0.83-0.97); specificity, 0.85 (95% CI: 0.74-0.92); PLR, 6.4 (95% CI: 3.4-11.9); NLR, 0.09 (95% CI: 0.04-0.20); and DOR, 74 (95% CI: 22-247). The analysis showed a significant heterogeneity (sensitivity, I2 = 95.19%, p < 0.001; specificity, I2 = 95.29%, p < 0.001; DOR, I2 = 92.9%, p < 0.001). The SROC curve was with an area under curve (AUC) of 0.95 (95% CI: 0.93-0.97).ConclusionCirculating miR-155 has a potential in the diagnosis of BC.

The dry root of the soybean plant Astragalus membranaceus (Fisch) Bge. var. mongholicus (Bge) Hsiao or A. membranaceus (Fisch) Bge, Astragali Radix (AR) has a long medicinal history. Astragalus polysaccharide (APS), the natural macromolecule that exhibits immune regulatory, anti-inflammatory, anti-tumor, and other pharmacological activities, is an important active ingredient extracted from AR. Recently, APS has been increasingly used in cancer therapy owing to its anti-tumor ability as it prevents the progression of prostate, liver, cervical, ovarian, and non-small-cell lung cancer by suppressing tumor cell growth and invasion and enhancing apoptosis. In addition, APS enhances the sensitivity of tumors to antineoplastic agents and improves the body’s immunity. This macromolecule has prospects for broad application in tumor therapy through various pathways. In this article, we present the latest progress in the research on the anti-tumor effects of APS and its underlying mechanisms, aiming to provide novel theoretical support and reference for its use in cancer therapy.

Abstract Lipid metabolic reprogramming is an emerging hallmark of cancer. In order to sustain uncontrolled proliferation and survive in unfavorable environments that lack oxygen and nutrients, tumor cells undergo metabolic transformations to exploit various ways of acquiring lipid and increasing lipid oxidation. In addition, stromal cells and immune cells in the tumor microenvironment also undergo lipid metabolic reprogramming, which further affects tumor functional phenotypes and immune responses. Given that lipid metabolism plays a critical role in supporting cancer progression and remodeling the tumor microenvironment, targeting the lipid metabolism pathway could provide a novel approach to cancer treatment. This review seeks to: (1) clarify the overall landscape and mechanisms of lipid metabolic reprogramming in cancer, (2) summarize the lipid metabolic landscapes within stromal cells and immune cells in the tumor microenvironment, and clarify their roles in tumor progression, and (3) summarize potential therapeutic targets for lipid metabolism, and highlight the potential for combining such approaches with other anti-tumor therapies to provide new therapeutic opportunities for cancer patients.

Abstract Background Patients with locally advanced, unresectable, non‐small cell lung cancer (NSCLC) receiving definitive concurrent chemoradiation therapy (CCRT) benefit from durvalumab consolidation therapy. However, predictive factors for early relapse during durvalumab maintenance have not yet been identified. Methods The present study included the lung cancer cohort of the Catholic Medical Centers at the Catholic University of Korea from January 2018 to December 2021. A total of 51 NSCLC patients treated with durvalumab consolidation therapy after definitive CCRT were included in the analysis. Early relapse was defined as patients experiencing relapse within 6 months of starting initial durvalumab therapy. Results Among the 51 patients, 15 (29.4%) relapsed during the study period. Median time from initial therapy of durvalumab to progression was 451.00 ± 220.87 days (95% confidence interval [CI]: 18.10–883.90) in overall patients. In multivariate analysis, younger age (adjusted odds ratio [aOR], 0.792; 95% CI: 0.642–0.977; p = 0.030), higher pack‐years (aOR, 1.315; 95% CI: 1.058–1.635; p = 0.014), non‐COPD (aOR, 0.004; 95% CI: 0.000–0.828; p = 0.004) and anemia (aOR, 234.30; 95% CI: 1.212–45280.24; p = 0.042), were independent predictive factors for early relapse during durvalumab consolidation therapy. Conclusion Younger age, higher number of pack‐years, non‐COPD, and anemia were independent predictive factors for early relapse during durvalumab consolidation therapy in patients with unresectable stage III NSCLC after definitive CCRT. Careful patient selection and clinical attention are needed for high‐risk individuals.

Abstract Background We aimed to assess the trends in urinary tract infections (UTIs) and prognosis of patients with prostate cancer after radical prostatectomy (RP) and radiation therapy (RT) as definitive treatment options. Methods The data of patients diagnosed with prostate cancer between 2007 and 2016 were collected from the National Health Insurance Service database. The incidence of UTIs was evaluated in patients treated with RT, open/laparoscopic RP, and robot-assisted RP. The proportional hazard assumption test was performed using the scaled Schoenfeld residuals based on a multivariable Cox proportional hazard model. Kaplan–Meier analysis were performed to assess survival. Results A total of 28,887 patients were treated with definitive treatment. In the acute phase ( 12 months), UTIs were more frequent in RT than in RP. In the early follow-up period, the risk of UTIs was higher in the open/laparoscopic RP group (aHR, 1.63; 95% CI, 1.44–1.83; p

Abstract Background Skin cutaneous melanoma (SKCM) is an extremely malignant tumor and accounts for the majority of skin cancer deaths. Aspartate beta-hydroxylase domain containing 1 (ASPHD1) may participate in cancer progression through controlling α-ketoglutarate-dependent dioxygenases. However, its role in skin cutaneous melanoma (SKCM) has not been well studied. Methods The gene expression data of ASPDH1 and differentially expressed genes (DEGs) from TCGA and GTEx were evaluated, and verified via the GEO database. Then, we performed GO/KEGG, GSEA, PPI network analysis to analyze the functional implications of the DEGs related to ASPHD1. Then, the association between the ASPHD1 expression and clinical parameters was investigated by Cox regression analysis. Subsequently, the survival time of SKCM patients was evaluated by plotting Kaplan-Meier curves. Moreover, we investigated the correlation between the ASPHD1 expression and lymphocytic infiltration by using the data from TISIDB and TIMER 2.0. Next, we explored the association between ASPHD1 expression and drug sensitivity. Finally, we validate the expression differences by analyzing the results of qPCR, Western blot from human normal epidermal melanocytes and melanoma cells, and immunohistochemistry (IHC) from non-tumor skin as well as melanoma tissues. Results The ASPHD1 expression level was significantly upregulated in several cancers, including SKCM especially SKCM-metastasis tissues, and patients with an increased ASPHD1 expression had longer overall survival time than low expression ones. The functional enrichment analysis of ASPHD1-related DEGs showed an association with cell development regulation and tumorigenic pathways. Furthermore, the increased ASPHD1 expression level was associated with the level of immunostimulors, immunoinhibitors, chemokines, and TILs, such as CD4+, CD8+ T cell, mast cell, Th2 cell, and dendritic cell. More interesting, we found that ASPHD1 expression was tightly associated with CTLA4 and CD276 which are immune checkpoint markers. Moreover, the upregulated expression of ASPHD1 exhibited higher IC50 values for 24 chemotherapy drugs, including doxorubicin, and masitinib. Finally, the differential expression of ASPHD1 in SKCM was validated by the results of qPCR, Western blot, and IHC. Conclusion The expression of ASPHD1 in SKCM patients is closely related to patient survival. ASPHD1 may participate in the regulation of tumor immune microenvironment. Additionally, it may serve as a prognostic biomarker for SKCM and future in-depth studies are necessary to explore its value.

Abstract Epithelium‐specific ETS transcription factor 1 (ESE1) has been implicated in epithelial homeostasis, inflammation, as well as tumorigenesis, and cancer progression. However, numerous studies have reported contradictory roles—as an oncogene or a tumor suppressor of ESE1 in different cancers, and its function in the development and progression of pancreatic ductal adenocarcinoma (PDAC) has remained largely unexplored. Herein, we report that ESE1 was found upregulated in primary PDAC compared to normal pancreatic tissue, but high expression of ESE1 correlated to better relapse‐free survival in patients with PDAC. Interestingly, ESE1 was found to exhibit dual roles in regulation of malignant properties of PDAC cells in that its overexpression promoted cell proliferation, whereas its downregulation enhanced epithelial‐mesenchymal transition (EMT) phenotype. In the context of TGF‐β‐induced EMT, ESE1 is markedly downregulated at post‐transcriptional level, and reconstituted ESE1 expression partially reversed TGF‐β‐induced EMT marker expression. Furthermore, we identify AGR2 as a novel transcriptional target of ESE1 that participates in TGF‐β‐induced EMT in PDAC. Collectively, our findings reveal an ESE1/AGR2 axis that interacts with TGF‐β signaling to modulate EMT phenotype in PDAC.

Abstract Purpose To evaluate the clinical efficacy and safety of apatinib combined with intensity‐modulated radiation therapy (IMRT) in patients with unresectable hepatocellular carcinoma (uHCC). Materials and methods Open‐label, single‐arm, exploratory clinical trial of apatinib combined with IMRT for uHCC patients. Patients aged 18–75 years with adequate hematological, liver, and renal functions and Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were enrolled in this study from March 2017 to September 2020. Patients were received IMRT (biological effective dose: 46–60 Gy) and continuous apatinib (250–500 mg/day) oral administration until HCC progression or unacceptable toxic effects. The endpoints included progression‐free survival (PFS), overall survival (OS), disease control rate (DCR), objective response rate (ORR), and safety. The trial registration number is ChiCTR‐OPC‐17011890. Results A total of 33 patients have taken part in the study. The median age was 58 years old (range 32–77), 27 (81.9%) patients were ECOG PS 0–1, and 28 (84.9%) patients were male. In addition, 25 (75.7%) patients suffered from hepatitis B, 32 cases (97.0%) were in Barcelona Clinic Liver Cancer (BCLC) Stages B–C, and eight (24.2%) had portal vein involvement. Moreover, 12 (36.4%) and 21 (63.6%) patients received apatinib as first‐line and second or later‐line therapy, respectively. The average follow‐up was 11.4 months, the median PFS was 7.8 months (95% confidence interval: 3.9–11.7). The OS rates at 6 and 12 months were 96.7% and 66.2%. The ORR and DCR were 15.1% and 81.8%, respectively. Hepatic toxicity was the most common treatment‐related adverse events in Grades 3–4 (12.1%). No radiation‐induced liver disease and Grade 5 toxicity were recorded. Conclusion Apatinib combined with IMRT is a safe and effective method to improve PFS and DCR and has good anti‐tumor activity in patients with uHCC.

Abstract Background Preclinical data have shown the immunomodulatory effects of metformin and dipeptidyl peptidase 4 (DPP4) inhibitors in patients with diabetes. However, its clinical impact remains unclear in lung cancer. Methods Between 2017 and 2021, 466 patients received ICI monotherapy. Patients were categorized into concurrent (MET; metformin or combination of metformin and DPP4 inhibitor) and without concomitant (NMET; nonmetformin/DPP4 inhibitors) administration of metformin and DPP4 inhibitors groups at least 8 weeks before and during ICI therapy. The primary objectives were the objective response rate (ORR) and progression‐free survival (PFS). The second objective was to evaluate the overall survival (OS) and the occurrence of immune‐related adverse events (irAEs). Results Among 466 patients, 89 (19.0%) and 377 (81%) were categorized into the MET and NMET groups, respectively. MET group had a significantly higher ORR (MET group: 24.7% vs. NMET group: 14.8%, p = 0.025) and longer PFS than those in the NMET group (MET group 5.1 month vs. NMET group 2.8 months, p = 0.018). After patients were stratified based on the prior line of therapy and PD L1 expression status, the PFS of the second‐line therapy and PD L1 ≥50 was significantly higher in the MET than in the NMET group. The proportion of patients experiencing all‐grade irAEs was numerically higher in the MET group (19.1%) than in the NMET group (14.3%), without statistical significance (p = 0.382). Conclusions Concurrent use of metformin and DPP4 inhibitors with ICIs significantly improved the clinical outcomes without increasing the incidence of irAEs in NSCLC.

No information is available regarding the influence of besifovir (BSV), a new nucleotide analogue, on the occurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study evaluated the reduced risk of HCC in patients undergoing BSV treatment. A total of 188 patients with CHB were treated with BSV for up to 8 years. We prospectively assessed the incidence of HCC compared with the risk from prediction models. During the follow-up, 5 patients developed HCC: 1 of 139 patients with non-cirrhotic CHB, and 4 of 49 patients with liver cirrhosis. We compared the HCC incidence in non-cirrhotic and cirrhotic patients with the predicted number derived from the REACH-B (risk estimation for HCC in CHB) model and GAG-HCC (guide with age, gender, HBV DNA, core promotor mutation, and cirrhosis) model, respectively. The standardized incidence ratio (SIR) was 0.128 (p = 0.039) at 7 years in non-cirrhotic CHB patients, and the SIR was 0.371 (p = 0.047) at 7.5 years in cirrhotic patients, suggesting a significantly decreased HCC incidence in both groups. HCC prediction was available for BSV-treated patients using existing models. In conclusion, BSV decreased the risk of HCC in patients with CHB, and prediction models were applicable. Clinical trial registry website and trial number: ClinicalTrials.gov no: NCT01937806.

Background Massive tumor-associated macrophage (TAM) infiltration is observed in many tumors, which usually display the immune-suppressive M2-like phenotype but can also be converted to an M1-like antitumor phenotype due to their high degree of plasticity. The macrophage polarization state is associated with changes in cell shape, macrophage morphology is associated with activation status. M1 macrophages appeared large and rounded, while M2 macrophages were stretched and elongated cells. Manipulating cell morphology has been shown to affect the polarization state of macrophages. The shape of the cell is largely dependent on cytoskeletal proteins, especially, microtubules. As a microtubule-targetting drug, vinblastine (VBL) has been used in chemotherapy. However, no study to date has explored the effect of VBL on TAM shape changes and its role in tumor immune response.Method We used fluorescent staining of the cytoskeleton and quantitative analysis to reveal the morphological differences between M0, M1, M2, TAM and VBL-treated TAM. Flow cytometry was used to confirm the polarization states of these macrophages using a cell surface marker-based classification. In vivo antibody depletion experiments in tumor mouse models were performed to test whether macrophages and CD8+ T cell populations were required for the antitumor effect of VBL. VBL and anti-PD-1 combination therapy was then investigated in comparison with monotherapy. RNA-seq of TAM of treated and untreated with VBL was performed to explore the changes in pathway activities. siRNA mediated knockdown experiments were performed to verify the target pathway that was affected by VBL treatment.Results Here, we showed that VBL, an antineoplastic agent that destabilizes microtubule, drove macrophage polarization into the M1-like phenotype both in vitro and in tumor models. The antitumor effect of VBL was attenuated in the absence of macrophages or CD8+ T cells. Mechanistically, VBL induces the activation of NF-κB and Cyba-dependent reactive oxygen species generation, thus polarizing TAMs to the M1 phenotype. In parallel, VBL promotes the nuclear translocation of transcription factor EB, inducing lysosome biogenesis and a dramatic increase in phagocytic activity in macrophages.Conclusions This study explored whether manipulating cellular morphology affects macrophage polarization and consequently induces an antitumor response. Our data reveal a previously unrecognized antitumor mechanism of VBL and suggest a drug repurposing strategy combining VBL with immune checkpoint inhibitors to improve malignant tumor immunotherapy.

BackgroundTranssphenoidal secondary operations are a minority but not a rare occurrence. How to viably prevent cerebral fluid (CSF)-related complications and confine surgery-caused injury in secondary surgery as minimally as possible is a huge challenge. This article shares our solution of recycling a prior Hadad-Bassagasteguy flap (HBF) along with a using small piece of free autologous mucosa to reconstruct the skull base.MethodsOf 69 patients, fitted criteria were assigned into 2 different groups: a recycled HBF incorporated with an autologous free mucosa and a recycled HBF incorporated with an artificial dura to rebuild the skull base in secondary transsphenoidal surgery. The postoperative morbidities of pseudomeningocele, CSF leakage and meningitis were recorded and analyzed.ResultsA recycled HBF incorporated with an autologous mucosa is capable of reducing CSF complications compared to that of the matched group, particularly decreasing the morbidity of meningitis in secondary transsphenoidal surgery. Diabetes mellitus, craniopharyngioma, chordoma and the utilization of artificial dura were independent risk factors for CSF complications in secondary transsphenoidal surgery through univariate and multivariate logistic regression. In addition, diabetes mellitus and artificial dura are more likely to induce CSF leakage and meningitis. Patients suffering from craniopharyngioma are more susceptible to meningitis. Chordoma indiscriminately increased the risk of each CSF complication.ConclusionA recycled HBF incorporated with an autologous mucosa is reliable for reconstructing the skull base in secondary transsphenoidal surgery, especially for patients simultaneously suffering from diabetes mellitus and central skull base tumors.

Abstract Rationale Lung cancer is the most prevalent form of cancer and has a high mortality rate, making it a global public health concern. The N6-methyladenosine (m6A) modification is a highly dynamic and reversible process that is involved in a variety of essential biological processes. Using in vitro, in vivo, and multi-omics bioinformatics, the present study aims to determine the function and regulatory mechanisms of the long non-coding (lnc)RNA zinc ribbon domain-containing 1-antisense 1 (ZNRD1-AS1). Methods The RNAs that were bound to the m6A ‘reader’ were identified using YTH domain-containing 2 (YTHDC2) RNA immunoprecipitation (RIP)-sequencing. Utilizing methylated RIP PCR/quantitative PCR, pull-down, and RNA stability assays, m6A modification and ZNRD1-AS1 regulation were analyzed. Using bioinformatics, the expression levels and clinical significance of ZNRD1-AS1 in lung cancer were evaluated. Using fluorescent in situ hybridization and quantitative PCR assays, the subcellular location of ZNRD1-AS1 was determined. Using cell migration, proliferation, and angiogenesis assays, the biological function of ZNRD1-AS1 in lung cancer was determined. In addition, the tumor suppressor effect of ZNRD1-AS1 in vivo was validated using a xenograft animal model. Through bioinformatics analysis and in vitro assays, the downstream microRNAs (miRs) and competing endogenous RNAs were also predicted and validated. Results This study provided evidence that m6A modification mediates YTHDC2-mediated downregulation of ZNRD1-AS1 in lung cancer and cigarette smoke-exposed cells. Low levels of ZNRD1-AS1 expression were linked to adverse clinicopathological characteristics, immune infiltration, and prognosis. ZNRD1-AS1 overexpression was shown to suppress lung cancer cell proliferation, migration, and angiogenesis in vitro and in vivo, and to reduce tumor growth in nude mice. ZNRD1-AS1 expression was shown to be controlled by treatment of cells with either the methylation inhibitor 3-Deazaadenosine or the demethylation inhibitor Meclofenamic. Furthermore, the miR-942/tensin 1 (TNS1) axis was demonstrated to be the downstream regulatory signaling pathway of ZNRD1-AS1. Conclusions ZNRD1-AS1 serves an important function and has clinical relevance in lung cancer. In addition, the findings suggested that m6A modification could mediate the regulation of the ZNRD1-AS1/miR-942/TNS1 axis via the m6A reader YTHDC2. Graphical Abstract

Abstract Background The phase III trial IMpower133 showed that platinum and etoposide plus atezolizumab was associated with improved overall survival (OS) and progression free‐survival (PFS) when compared to the placebo group in treatment‐naïve extensive stage (ES) small cell lung cancer (SCLC). Due to superiority in clinical outcomes, combination immunotherapy plus chemotherapy have become mainstay treatment modalities as first‐line treatment in ES‐SCLC. Nevertheless, real‐world data are still lacking and the search for potential biomarkers is essential. This study aimed to evaluate potential predictive biomarkers applicable in ES‐SCLC under combination therapy. Methods Patients with ES‐SCLC under etoposide‐platinum‐atezolizumab enrolled from seven university hospitals affiliated to the Catholic University of Korea were evaluated. Pretreatment clinical parameters were evaluated for association with OS and PFS. Adverse events (AEs) during induction and maintenance phases were also evaluated. p‐values below 0.05 were considered statistically significant. Results A total of 41 patients were evaluated. Six‐month survival was 68.6%. As best response to treatment, 26 (63.4%) showed partial response, nine (22.0%) showed stable disease, and four (9.8%) showed progressive disease. During the induction phase, grade I–II AEs occurred in 22 (53.7%) patients, and grade III–IV AEs occurred in 26 (63.4%) patients. During the maintenance phase, nine out of 25 (36.0%) patients experienced any grade AEs. In multivariate analysis for OS, lactate dehydrogenase (LDH), c‐reactive protein (CRP), and forced vital capacity (%) were significant factors. In multivariate analysis for PFS, sex, and LDH were significant. Conclusion In ES‐SCLC under etoposide‐platinum‐atezolizumab, pretreatment CRP, LDH and FVC (%) were independent predictive factors.

Abstract Background The tumor immune microenvironment (TIME) generated by cancer-infiltrating immune cells has a crucial role in promoting or suppressing breast cancer progression. However, whether the steroid receptor coactivator-3 (SRC-3) modulates TIME to progress breast cancer is unclear. Therefore, the present study evaluates whether SRC-3 generates a tumor-promoting TIME in breast tumors using a syngeneic immune-intact mouse model of breast cancer. Methods We employed E0771 and 4T1 breast cancer in immune-intact syngeneic female C57BL/6 and BALB/c mice, respectively. SI-2, a specific small-molecule inhibitor of SRC-3, was administered daily (2.5 mg/kg) to E0771 and 4T1 breast tumor-bearing immune-intact mice. In addition, SRC-3 knockdown (KD)-E0771 and SRC-3 KD-4T1 cells and their parental breast cancer cells were injected into their syngeneic immune-intact female mice versus immune-deficiency mice to validate that the host immune system is required for breast tumor suppression by SRC-3 KD in immune-intact mice. Furthermore, tumor-infiltrating immune cells (such as CD4+, CD8+, CD56+, and Foxp3+ cells) in E0771 and 4T1 breast cancers treated with SI-2 and in SRC-3 KD E0771 and 4T1 breast cancers were determined by immunohistochemistry. Additionally, cytokine levels in SI-2-treated and SRC-3 KD E0771 breast tumors and their control cancers were defined with a Mouse Cytokine Array. Results SRC-3 inhibition by SI-2 significantly suppressed the progression of breast cancer cells (E0771 and 4T1) into breast cancers in immune-intact syngeneic female mice. SRC-3 KD-E0771 and -4T1 breast cancer cells did not produce well-developed tumors in immune-intact syngeneic female mice compared to their parental cells, but SRC-3 KD breast cancers were well developed in immune-defective host mice. SRC-3 inhibition by SI-2 and SRC-3 KD effectively increased the numbers of cytotoxic immune cells, such as CD4+ and CD8+ T cells and CD56+ NK cells, and Interferon γ (Ifng) in breast cancers compared to vehicle. However, SI-2 treatment reduced the number of tumor-infiltrating CD4+/Foxp3+ regulatory T (Treg) cells compared to vehicle treatment. In addition, SRC-3 inhibition by SI-2 and SRC-3 KD increased C-X-C motif chemokine ligand 9 (Cxcl9) expression in breast cancer to recruit C-X-C motif chemokine receptor 3 (Cxcr3)-expressing cytotoxic immune cells into breast tumors. Conclusions SRC-3 is a critical immunomodulator in breast cancer, generating a protumor immune microenvironment. SRC-3 inhibition by SI-2 or SRC-3 KD activates the Cxcl9/Cxcr3 axis in breast tumors and enhances the antitumor immune microenvironment to suppress breast cancer progression.

Abstract Objectives Exosomes are essential mediators of intercellular communication as they transport proteins and RNAs between cells. Owing to their tumor‐targeting capacity, immune compatibility, low toxicity, and long half‐life, mesenchymal stem cell‐derived exosomes have great potential for the development of novel antitumor strategies. In this context, the role of exosomes produced by adipose‐derived mesenchymal stem cells (ADSCs) for the treatment of bladder cancer (BC) remains unclear. Here, we investigated the use of ADSCs as a source of therapeutic exosomes, as well as their efficacy in delivering the tumor suppressor miR‐138‐5p in BC. Methods ADSCs stably expressing miR‐138‐5p were established using Lentivirus infection, and ADSC‐derived miR‐138‐5p exosomes (Exo‐miR‐138‐5p) were isolated from the cell culture medium. The effect of Exo‐miR‐138‐5p on BC cell migration, invasion, and proliferation was evaluated in vitro using wound healing, transwell invasion, and proliferation assays. The in vivo effect of Exo‐miR‐138‐5p was investigated using a subcutaneous xenograft mouse model. Results Exo‐miR‐138‐5p prevented the migration, invasion, and proliferation of BC cells in vitro. Moreover, ADSC‐derived exosomes could penetrate tumor tissues and successfully deliver miR‐138‐5p to suppress the growth of xenograft tumors in vivo. Conclusions The present results reveal that ADSC‐derived exosomes are an effective delivery vehicle for small molecule drugs in vivo, and exosome‐delivered miR‐138‐5p is a promising therapeutic agent for BC treatment.