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Background Postoperative urinary retention (POUR) is a known complication in the postanesthesia care unit (PACU). The variations in catheterization thresholds contribute to unnecessary invasive procedures. Objective In the current study, we implemented an algorithm for a sterile intermittent catheterization (SIC) threshold of 800 ml with volume-dependent bladder scan intervals and compared the incidence of SIC with that of a matched patient cohort threshold of 400 ml. Design, setting, and participants This comparative study of two prospective historical cohorts represented two thresholds for POUR, set at 400 ml without a standardized bladder scan protocol and 800 ml with a volume-dependent bladder scan protocol. Outcome measurements and statistical analysis The primary outcome was the frequency of catheterization during the PACU stay. Secondary outcomes evaluated patient safety aspects in occurrence of thresholds above 400/800 ml. The study was set at the PACU under the Department of Anesthesia, Center for Cancer and Organ Diseases, Rigshospitalet, Denmark. Results and limitations In total, 741 patients were consecutively included, with 307 in the POUR-400 and 434 in the POUR-800 group, and with comparable group characteristics. Significantly fewer patients fulfilled the SIC/catheter a’ demeure (CAD) criteria in the POUR-800 (5.0%) versus POUR-400 (14.3%) group, equivalent to a 65.0% relative reduction in SIC. Conclusions Implementation of a standardized ultrasound-guided protocol with volume-dependent scan intervals and an evidence-based catheterization threshold of 800 ml decreases the need for SIC by >65%, without increasing the need for urinary catheterization at the wards. Patient summary In this study, we implemented an algorithm for a sterile intermittent catheterization threshold of 800 ml with volume-dependent bladder scan intervals. A marked reduction was seen in catheterization in the postanesthesia care unit, without increasing catheterization rates at the ward., Take Home Message An algorithm for an intermittent catheterization threshold of 800 ml, with volume-dependent bladder scan intervals during patients’ stay at the postanesthesia care unit, reduces the incidence of urinary bladder catheterization. Extensive patient-clinician communication on bladder symptomatology is a crucial prerequisite.

The uptake of contralateral prophylactic mastectomy (CPM) has increased steadily over the last twenty years in women of all age groups and breast cancer stages. Since contralateral breast cancer is relatively rare and the breast cancer guidelines only recommend CPM in a small subset of patients with breast cancer, the drivers of this trend are unknown. This review aims to evaluate the evidence for and acceptability of CPM, data on patient rationales for choosing CPM, and some of the factors that might impact patient preferences. Based on the evidence, future recommendations will be provided. First, data on contralateral breast cancer risk and CPM rates and trends are addressed. After that, the evidence is structured around four main patient rationales for CPM formulated as questions that patients might ask their surgeon: Will CPM reduce mortality risk? Will CPM reduce the risk of contralateral breast cancer? Can I avoid future screening with CPM? Will I have better breast symmetry after CPM? Also, three different guidelines regarding CPM will be reviewed. Studies indicate a large gap between patient preferences for radical risk reduction with CPM and the current approaches recommended by important guidelines. We suggest a strategy including shared decision-making to enhance surgeons’ communication with patients about contralateral breast cancer and treatment options, to empower patients in order to optimize the use of CPM incorporating accurate risk assessment and individual patient preferences., Highlights • Contralateral prophylactic mastectomy rates have increased over the last 20 years. • Patients may want CPM to reduce risk of contralateral breast cancer and mortality. • Patients do not always have the tools available to make a well-informed decision. • Patient and surgeon’s shared decision-making could optimize the use of CPM.

The protein disulphide isomerase (PDI) gene family is a large, diverse group of enzymes recognised for their roles in disulphide bond formation within the endoplasmic reticulum (ER). PDI therefore plays an important role in ER proteostasis, however, it also shows involvement in ER stress, a characteristic recognised in multiple disease states, including cancer. While the exact mechanisms by which PDI contributes to tumorigenesis are still not fully understood, PDI exhibits clear involvement in the unfolded protein response (UPR) pathway. The UPR acts to alleviate ER stress through the activation of ER chaperones, such as PDI, which act to refold misfolded proteins, promoting cell survival. PDI also acts as an upstream regulator of the UPR pathway, through redox regulation of UPR stress receptors. This demonstrates the pro‐protective roles of PDI and highlights PDI as a potential therapeutic target for cancer treatment. Recent research has explored the use of PDI inhibitors with PACMA 31 in particular, demonstrating promising anti‐cancer effects in ovarian cancer. This review discusses the properties and functions of PDI family members and focuses on their potential as a therapeutic target for cancer treatment., Protein disulphide isomerases (PDIs) play a vital role in folding proteins into their correct comformation. Inhibition of PDIs can cause ER‐stress leading to cellular apoptosis. In many cancers, PDI expression and activity is increased suggesting they are potential targets for novel therapies. Here we review the latest on PDI in cancer and highlight key PDI inhibitors that may be in the future used as cancer treatments.

RNA binding proteins (RBPs) are increasingly appreciated as being essential for normal hematopoiesis and have a critical role in the progression of hematological malignancies. However, their functional consequences and clinical significance in diffuse large B‐cell lymphoma (DLBCL) remain unknown. Here, we conducted a systematic analysis to identify RBP‐related genes affecting DLBCL prognosis based on the Gene Expression Omnibus database. By univariate and multivariate Cox proportional hazards regression (CPHR) methods, six RBPs‐related genes (CMSS1, MAEL, THOC5, PSIP1, SNIP1, and ZCCHC7) were identified closely related to the overall survival (OS) of DLBCL patients. The RBPs signature could efficiently distinguished low‐risk from high‐risk patients and could serve as an independent and reliable factor for predicting OS. Moreover, Gene Set Enrichment Analysis revealed 17 significantly enriched pathways between high‐ versus low‐risk group, including the regulation of autophagy, chronic myeloid leukemia, NOTCH signaling pathway, and B cell receptor signaling pathway. Then we developed an RBP‐based nomogram combining other clinical risk factors. The receiver operating characteristic curve analysis demonstrated high prognostic predictive efficiency of this model with the area under the curve values were 0.820 and 0.780, respectively, in the primary set and entire set. In summary, our RBP‐based model could be a novel prognostic predictor and had the potential for developing treatment targets for DLBCL., We found that six RNA binding proteins are significantly related to the overall survival of diffuse large B‐cell lymphoma (DLBCL) patients, which could potentially be served as prognostic biomarkers. Gene Set Enrichment Analysis provided insight into the underlying mechanisms in the occurrence and development of DLBCL, which laid the foundation for further basic studies.

Triple negative breast cancer (TNBC) is an aggressive disease with a 5-y relative survival rate of 11% after distant metastasis. To survive the metastatic cascade, tumor cells remodel their signaling pathways by regulating energy production and upregulating survival pathways. AMP-activated protein kinase (AMPK) and Akt regulate energy homeostasis and survival, however, the individual or synergistic role of AMPK and Akt isoforms during lung colonization by TNBC cells is unknown. The purpose of this study was to establish whether targeting Akt, AMPKα or both Akt and AMPKα isoforms in circulating cancer cells can suppress TNBC lung colonization. Transient silencing of Akt1 or Akt2 dramatically decreased metastatic colonization of lungs by inducing apoptosis or inhibiting invasion, respectively. Importantly, transient pharmacologic inhibition of Akt activity with MK-2206 or AZD5363 inhibitors did not prevent colonization of lung tissue by TNBC cells. Knockdown of AMPKα1, AMPKα2, or AMPKα1/2 also had no effect on metastatic colonization of lungs. Taken together, these findings demonstrate that transient decrease in AMPK isoforms expression alone or in combination with Akt1 in circulating tumor cells does not synergistically reduce TNBC metastatic lung colonization. Our results also provide evidence that Akt1 and Akt2 expression serve as a bottleneck that can challenge colonization of lungs by TNBC cells.

Nan Jiang,1,2,* Xiao-Lin Ge,2,* Zhao-Yue Zhang,2 Jia Liu,2 Pei-Pei Wang,2 Xin-Chen Sun,1,2 Min Yang1 1The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, 210000, People’s Republic of China; 2Department of Radiotherapy, Jiangsu Province Hospital, Nanjing, Jiangsu, 210000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Min YangThe First School of Clinical Medicine, Nanjing Medical University, No. 818 of Tianyuan Road, Jiangning District, Nanjing, Jiangsu, 210000, People’s Republic of ChinaTel +86 13701516659Email yangmin@jsinm.orgXin-Chen SunDepartment of Radiotherapy, Jiangsu Province Hospital, No. 300 of Guangzhou Road, Gulou District, Nanjing, Jiangsu, 210000, People’s Republic of ChinaTel +86 13770662828Email sunxinchen2012@163.comPurpose: Intensity-modulated radiotherapy (IMRT) can improve the prognosis of patients with esophageal cancer. This study aimed to evaluate clinical factors relevant to the prognosis of patients with esophageal cancer who received intensity-modulated radiotherapy (IMRT) alone.Patient and Methods: Data of 103 patients with pathologically confirmed esophageal cancer who were admitted to our hospital between October 2011 and November 2017 were retrospectively reviewed. All patients had squamous cell carcinoma. All patients received IMRT. Patients with stage I–IVA tumors were included to represent the real-world clinical practice. We performed univariate and multivariate analyses to identify prognostic factors for overall survival (OS) and progression-free survival (PFS). In univariate analyses, the Kaplan–Meier method was used to estimate OS and PFS for various subgroups. In multivariate analyses, hazard ratios were calculated.Results: Single-factor analysis revealed that T stage (P=0.019), N stage (P =0.047), and lesion length (P =0.000) were associated with the prognosis of esophageal cancer patients who received IMRT. Cox regression analysis revealed that T stage (odds ratio [OR] = 4.68; P < 0.05), N stage (OR = 0.28; P < 0.05), and lesion length (OR = 0.09; P < 0.05) were independent factors relevant to prognosis.Conclusion: T stage, N stage, and lesion length influenced the long-term curative effects of IMRT for esophageal cancer and were prognostic factors for patients with esophageal cancer receiving definitive radiotherapy alone. The higher the stage and the longer the tumor, the lower the survival rate.Keywords: esophageal neoplasms, prognosis, intensity-modulated radiotherapy, retrospective studies

Yichao Wang,1,* Qianyi Zhong,1,* Zhaoyun Li,1 Zhu Lin,2 Hanjun Chen,1 Pan Wang1 1Department of Clinical Laboratory Medicine, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, 318000, People’s Republic of China; 2Department of Ultrasound, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, 318000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pan WangDepartment of Clinical Laboratory Medicine, Taizhou Central Hospital (Taizhou University Hospital), No. 999 Donghai Road, Jiaojiang District, Taizhou, Zhejiang, 318000, People’s Republic of ChinaTel +86 13586106875Email wangp9113@tzzxyy.comIntroduction: Breast cancer is the main reason for cancer-related deaths in women and the most common malignant cancer among women. In recent years, immunosuppressive factors have become a new type of treatment for cancer. However, there are no effective biomarkers for breast cancer immunotherapy. Therefore, exploring immune-related biomarkers is presently an important topic in breast cancer.Methods: Gene expression profile data of breast cancer from The Cancer Genome Atlas (TCGA) was downloaded. Scale-free gene co-expression networks were built with weighted gene co-expression network analysis. The correlation of genes was performed with Pearson’s correlation values. The potential associations between clinical features and gene sets were studied, and the hub genes were screened out. Gene Ontology and gene set enrichment analysis were used to reveal the function of hub gene in breast cancer. The gene expression profiles of GSE15852, downloaded from the Gene Expression Omnibus database, were used for hub gene verification. In addition, candidate biomarkers expression in breast cancer was studied. Survival analysis was performed using Log rank test and Kaplan–Meier. Immunohistochemistry was used to analyze the expression of CCNA2.Results: A total of 6 modules related to immune cell infiltration were identified via the average linkage hierarchical clustering. According to the threshold criteria (module membership > 0.9 and gene significance > 0.35), a significant module consisting of 13 genes associated with immune cells infiltration were identified as candidate hub genes after performed with the human protein interaction network. And 3 genes with high correlation to clinical traits were identified as hub genes, which were negatively associated with the overall survival. Among them, the expression of CCNA2 was increased in metastatic breast cancer compare with non-metastatic breast cancer, who underwent immunotherapy. Immunohistochemistry results showed that CCNA2 expression in carcinoma tissues was elevated compared with normal control.Discussion: CCNA2 identified as a potential immune therapy marker in breast cancer, which were first reported here and deserved further research.Keywords: breast cancer, immune infiltration, molecular markers, immunotherapy

Edyta Paczkowska,1,2 Michał Janowski,2 Katarzyna Karpińska,3 Małgorzata Ryłów,2 Barbara Zdziarska,2 Wojciech Poncyljusz,4 Bogusław Machaliński1 1Department of General Pathology, Pomeranian Medical University, Szczecin, Poland; 2Department of Hematology with Bone Marrow Transplantation Unit, University Hospital No. 1 of Pomeranian Medical University, Szczecin, Poland; 3Department of Pathomorphology, Pomeranian Medical University, Szczecin, Poland; 4Department of Diagnostic Imaging and Interventional Radiology, Pomeranian Medical University, Szczecin, PolandCorrespondence: Edyta PaczkowskaDepartment of General Pathology, Pomeranian Medical University, Al. Powstańców Wlkp. 72, Szczecin, 70-111, PolandEmail edyta.paczkowska@pum.edu.plIntroduction: Incidences of chronic myeloid leukaemia (CML) after treatment of Hodgkin lymphoma (HL) are well described. Here, we report a case of secondary HL in a patient with CML treated with dasatinib as a third-line treatment.Patient Information: A 64-year-old male was diagnosed with CML and initially treated with imatinib and then with nilotinib due to resistance. Finally, the patient experienced cardiovascular complications, and dasatinib was introduced. After 19 months of treatment, the patient experienced enlargement of lymph nodes that formed packs on the neck.Interventions: Based on histopathological examination of the lymph nodes, a diagnosis of classical Hodgkin lymphoma – mixed cellularity was established. The patient was successfully treated with 4 cycles of AVD (adriamycin, vinblastine, dacarbazine) chemotherapy.Outcomes: Complete metabolic remission of Hodgkin lymphoma is currently sustained, and the molecular response to dasatinib at a reduced dose of 50 mg daily corresponds with a deep molecular response.Conclusion: In this report, we demonstrate the efficacy and safety of the combination of dasatinib and AVD regimens in coexisting CML and HL. This case report emphasizes the importance of insightful evaluation and differential diagnosis in cases of lymphadenopathy during CML treatment.Keywords: chronic myeloid leukemia, Hodgkin lymphoma, dasatinib, lymphadenopathy, tyrosine kinase inhibitors

Han Bai,1 Jianjun Yu,2 Shidong Jia,2 Xiaoran Liu,1 Xu Liang,1 Huiping Li1 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, People’s Republic of China; 2Huidu Shanghai Medical Sciences, Shanghai, 201499, People’s Republic of ChinaCorrespondence: Xu Liang; Huiping LiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, No. 52, Fucheng Road, Haidian District, Beijing, 100142, People’s Republic of ChinaTel/Fax +86-10-88196739Email liangxu15@outlook.com; huipingli2012@hotmail.comPurpose: The status of TP53 mutations was measured in cell-free DNA from patients with metastatic breast cancer (MBC) to investigate disease characteristics and the prognostic role of different locations of the TP53 mutation site.Patients and Methods: Blood samples were taken from a total of 187 patients diagnosed with MBC who were treated at the Department of Breast Oncology, Peking University Cancer Hospital between January 2013 and March 2020. Next-generation sequencing was used to investigate the TP53 mutation spectra of circulating free DNA in these blood samples.Results: Among the 187 MBC patients, TP53-mutated patients had a significantly shorter median disease-free survival (DFS) and overall survival (OS) compared with TP53 wild-type patients (P=0.001 and P=0.006, respectively). Additionally, in hormone receptor positive/HER2 negative (HR+/HER2-) and triple negative (TNBC) cohorts, TP53-mutated patients had a significantly shorter median DFS than TP53 wild-type patients (P=0.038 and P=0.023, respectively). The 79 patients with TP53 mutations carried 87 somatic TP53 mutations, of which most (77.0%) mapped to the DNA-binding domain (DBD) of the protein encoded by TP53 exons 5– 8. In patients with TP53 mutations, those occurring in the non-DBD had a significantly shorter median DFS and OS than TP53 wild type (P< 0.001 and P=0.001, respectively). Additionally, patients with non-missense mutations in the DBD had a significantly shorter median DFS and OS than TP53 wild-type patients (P=0.001 and P< 0.001, respectively). TP53-mutated patients had a significantly shorter DFS than TP53 wild-type patients in the adjuvant endocrine therapy sensitive group (P=0.008), but differences in the endocrine therapy resistant group were not significant.Conclusion: TP53-mutated MBC patients had a significantly worse outcome than TP53 wild-type patients especially those in HR+/HER2– and TNBC cohorts. Of TP53-mutated patients, those with non-missense mutations in the DBD had worse breast cancer-related survival. TP53 mutations were also associated with endocrine resistance.Keywords: advanced breast cancer, TP53 mutation, NGS, adjuvant endocrine therapy, DNA-binding domain

Newer, more effective and non-cytotoxic therapies are an unmet need for patients with diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies. Recently approved agents include polatuzumab with bendamustine and rituximab, selinexor, and tafasitamab plus lenalidomide. Three CAR-T cell products are currently approved by the FDA, with others in clinical trials. Additional agents in development include bispecific antibodies and antibody drug conjugates. Combinations of targeted therapies should lead to further improvement in the outcome of patients with B-cell malignancies.

Daniel Geh,1 Quentin M Anstee,2,3 Helen L Reeves2– 4 1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; 2Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; 3The Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK; 4Hepatopancreatobiliary Multidisciplinary Team, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UKCorrespondence: Helen L ReevesTranslational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UKTel +44 191 208 4423Fax +44 191 208 4301Email h.l.reeves@ncl.ac.ukAbstract: Due to an increase in the obesity-associated metabolic syndrome of epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of hepatocellular carcinoma (HCC) in western countries. This presents added challenges, as NAFLD-associated HCC tends to present at an advanced stage in older patients with co-morbidities. Their prognosis is generally poor with the benefits of standard therapies less certain. The pathogenesis of NAFLD-associated HCC is multifactorial and not well understood, although the risk of HCC developing undoubtedly increases as NAFLD progresses to steatohepatitis and cirrhosis. Recent advances in our understanding of the drivers of NAFLD and HCC will hopefully lead to the development of clinically relevant biomarkers, tools and strategies to aid the identification of high-risk patients, inform preventive measures, and introduction of better tolerated targeted therapies. Lifestyle modification and chemoprevention with drugs such as anti-platelets, statins and anti-diabetics are being evaluated for HCC prevention. The landmark IMBrave150 study introducing the combination of atezolizumab and bevacizumab has recently transformed the landscape of systemic therapies in HCC, with follow-up analyses and real-world data for patients with NAFLD-associated HCC eagerly anticipated. While responses may vary in ways not yet appreciated, the rate of discovery and progress suggests imminent change and opportunities.Keywords: hepatocellular carcinoma, HCC, nonalcoholic fatty liver disease, NAFLD, liver cirrhosis, biomarkers, prevention, systemic therapy, immunotherapy

Pan Hu,1,* Yu Ben,1,* Juan Liu,1 Weicheng Zheng,1 Xiyue Yan,1 Yaping Zhang,2 Wenyu Shi1,2 1Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of China; 2Department of Hematology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenyu ShiDepartment of Oncology and Hematology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of ChinaTel +86-513-81160502Fax +86-513-85519820Email shiwenyu@hotmail.comYaping ZhangDepartment of Hematology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of ChinaTel +86-513-81160502Fax +86-513-85519820Email zzyaping@163.comAbstract: Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) complicated with angioimmunoblastic T-cell lymphoma (AITL) is extremely rare and typically shows an aggressive clinical course and unsatisfactory prognosis. Here, we describe the case of a 77-year-old man who was referred to the hospital because of repeated fever, night sweats, and weight loss. He was finally diagnosed with a discordant lymphoma consisting of AITL and DLBCL, with significantly different maximum standardized uptake values on positron emission tomography/computed tomography. Based on his complex illness and poor performance status, the patient received six cycles of lenalidomide combined with R-miniCHOP regimen and achieved complete remission with tolerable and controlled toxicity. He subsequently received lenalidomide maintenance therapy and achieved sustained remission. We consider the possible causes of this discordance involved AITL and EBV-positive DLBCL, and the possible mechanism of lenalidomide action in both T-cell and B-cell non-Hodgkin lymphomas. Lenalidomide-combination therapy may be a preferable choice in patients with an EBV-associated discordant lymphoma.Keywords: Epstein–Barr virus, diffuse large B-cell lymphoma, angioimmunoblastic T-cell lymphoma, discordant lymphoma, lenalidomide, positron emission tomography/computed tomography

Background PIK3CA is the second most frequently mutated gene in cancers and is extensively studied for its role in promoting cancer cell resistance to chemotherapy or targeted therapy. However, PIK3CA functions have mostly been investigated at a lower-order genetic level, and therapeutic strategies targeting PIK3CA mutations have limited effects. Here, we explore crucial factors interacting with PIK3CA mutations to facilitate a significant marginal survival effect at the higher-order level and identify therapeutic strategies based on these marginal factors. Methods Mutations in stomach adenocarcinoma (STAD), breast adenocarcinoma (BRCA), and colon adenocarcinoma (COAD) samples from The Cancer Genome Atlas (TCGA) database were top-selected and combined for Cox proportional-hazards model analysis to calculate hazard ratios of mutation combinations according to overall survival data and define criteria to acquire mutation combinations with considerable marginal effects. We next analyzed the PIK3CA + HMCN1 + LRP1B mutation combination with marginal effects in STAD patients by Kaplan-Meier, transcriptomic differential, and KEGG integrated pathway enrichment analyses. Lastly, we adopted a connectivity map (CMap) to find potentially useful drugs specifically targeting LRP1B mutation in STAD patients. Results Factors interacting with PIK3CA mutations in a higher-order manner significantly influenced patient cohort survival curves (hazard ratio (HR) = 2.93, p-value = 2.63 × 10− 6). Moreover, PIK3CA mutations interacting with higher-order combination elements distinctly differentiated survival curves, with or without a marginal factor (HR = 0.26, p-value = 6.18 × 10− 8). Approximately 3238 PIK3CA-specific higher-order mutational combinations producing marginal survival effects were obtained. In STAD patients, PIK3CA + HMCN1 mutation yielded a substantial beneficial survival effect by interacting with LRP1B (HR = 3.78 × 10− 8, p-value = 0.0361) and AHNAK2 (HR = 3.86 × 10− 8, p-value = 0.0493) mutations. We next identified 208 differentially expressed genes (DEGs) induced by PIK3CA + HMCN1 compared with LRP1B mutation and mapped them to specific KEGG modules. Finally, small-molecule drugs such as geldanamycin (connectivity score = − 0.4011) and vemurafenib (connectivity score = − 0.4488) were selected as optimal therapeutic agents for targeting the STAD subtype with LRP1B mutation. Conclusions Overall, PIK3CA-induced marginal survival effects need to be analyzed. We established a framework to systematically identify crucial factors responsible for marginal survival effects, analyzed mechanisms underlying marginal effects, and identified related drugs.

Chuangkun Li,1,2,* Weiwen Liang,1,2,* Lili Chu,1,* Yingqi Wei,1,2 Xiusen Qin,1,2 Zifeng Yang,1,2 Wentai Guo,1,2 Hui Wang,1,2 Huaiming Wang,1,2 Rongkang Huang1,2 1Department of Colorectal Surgery, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510655, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510655, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huaiming WangDepartment of Colorectal Surgery, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510655, People’s Republic of ChinaEmail wanghm7@mail.sysu.edu.cnRongkang HuangDepartment of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of ChinaTel +86-134-8021-8647Email huangrk3@mail.sysu.edu.cnPurpose: Anastomotic leakage after rectal cancer surgery in elderly patients is a critical challenge. Many risk factors have been found and many interventions tried, but anastomotic leakage in elderly patients remains difficult to deal with. This study aimed to create a nomogram for predicting anastomotic leakage after rectal surgery in elderly rectal cancer patients with dysfunctional stomata.Methods: We collected data from 326 consecutive elderly patients with dysfunctional stomata after rectal cancer surgery at the Sixth Affiliated Hospital, Sun Yat-Sen University from January 2014 to December 2019. Risk factors of anastomotic leakage were identified with multivariate logistic regression and used to create a nomogram. Predictive performance was evaluated by the area under the receiver-operating characteristic (ROC) curve.Results: American Society of Anesthesiologists score ≥ 3, male sex, and neoadjuvant radiotherapy were identified as significantly associated factors that could be combined for accurate prediction of anastomotic leakage on multivariate logistic regression and development of a nomogram.The area under the ROC curve for this model was 0.645. The C-index value for this model was 0.645, indicating moderate predictive ability of the risk of anastomotic leakage.Conclusion: The nomogram showed good ability to predict anastomotic leakage in elderly patients with rectal cancer after surgery, and might be helpful in providing a reference point for selection of surgical procedures and perioperative treatment.Keywords: nomogram, rectal cancer, anastomotic leakage, elderly patients

Background The aim of this study was to discuss the safety and efficacy of administering reduced doses (3 mg) of pegylated recombinant human granulocyte‐colony stimulating factor (PEG‐rhG‐CSF) at approximately 24 h or up to three days following treatment with etoposide and cisplatin (EP). Methods A total of 104 cycles from 31 patients were divided into a PEG‐rhG‐CSF prophylaxis group (PP‐Group) and a control group (No‐PP‐Group). The PP‐Group received a reduced dose of 3 mg of PEG‐rhG‐CSF within a minimum of 15 h and a maximum of 72 h following EP chemotherapy, while the rest did not receive any G‐CSF prophylaxis (No‐PP‐Group). For both groups, complete blood counts, incidence of febrile neutropenia (FN), grade III or IV neutropenia, and the use of antibiotics to treat neutropenia were recorded. Results There was statistically no significant difference in the incidence of FN (0% vs. 1.4%, p = 1), antibiotic use due to neutropenia (0% vs. 2.7%, p = 0.881), estimated lowest mean marginal (EM) platelet (106.56 × 109/L vs. 127.70 × 109/L, p = 0.056) and hemoglobin (110.48 g/L vs. 110.14 g/L, p = 0.906) levels between the two groups. However, when compared with the No‐PP‐group, the white blood cell count in the PP‐group was significantly higher (EM means: 4.95 × 109/L vs. 2.80 × 109/L, p, Even though cisplatin is slowly metabolized by the body, the routine administration time of PEG‐rhG‐CSF following cisplatin was safe. A reduced dose (3 mg) of PEG‐rhG‐CSF was also effective in preventing grade III and IV neutropenia.

Jian Zheng,1 Xiaoxi Li,2 Cunwei Cai,3 Chengyu Hong,1 Bin Zhang4 1Department of Thoracic Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, Liaoning, 110042, People’s Republic of China; 2Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, Liaoning, 110042, People’s Republic of China; 3Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, Liaoning, 110042, People’s Republic of China; 4Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of ChinaCorrespondence: Jian ZhengDepartment of Thoracic Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, NO. 44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning, 110042, People’s Republic of ChinaTel/ Fax +86-24-31916363Email zhengjian_2020@163.comBackground: The roles of microRNA (miR)-32 and miR-548a in non-small cell lung cancer (NSCLC) have been studied. But their influences on NSCLC cells to cisplatin (DDP) resistance remain elusive. This study estimated the mechanisms of miR-32 and miR-548a in NSCLC cells to DDP.Methods: Differentially expressed miRs in DDP-sensitive and resistant tissues were screened out using a GSE56036 chip. Then the predictive efficacies of miR-32 and miR-548a on DDP resistance were analyzed in NSCLC patients. The target mRNAs of miR-548a and miR-32 were predicted. miR-548a and miR-32 were knocked down to assess the influences of miR-32 and miR-548a on NSCLC growth. DDP-resistant cells were constructed and miR-32 and miR-548a expression was detected in resistant cells. After miR-32 and miR-548a knockdown, the IC50 value of DDP was detected. Then, the activation level of Wnt/β-catenin pathway was detected. The roles of miR-32 and miR-548a in NSCLC growth in vivo were detected by tumorigenesis experiment.Results: miR-32 and miR-548a were poorly expressed in DDP-resistant NSCLC. miR-32 and miR-548a mimic enhanced the DDP sensitivity of NSCLC cells. Both miR-32 and miR-548a targeted ROBO1, and overexpression of ROBO1 inhibited the promotion of miR-32 and miR-548a mimic on DDP sensitivity. ROBO1 activated the Wnt/β-catenin pathway, thus enhancing the DDP resistance.Conclusion: miR-32 and miR-548a target ROBO1 and inhibit Wnt/β-catenin activation, thus promoting the drug sensitivity of NSCLC cells to DDP.Keywords: non-small cell lung cancer, miR-32, miR-548a, cisplatin resistance, ROBO1, Wnt/β-catenin pathway

Background The tumor microenvironment is associated with prognosis in advanced non‐small cell lung carcinoma (NSCLC). The aim of this study was to explore the relationship between blood T cell diversity and survival of patients treated with pemetrexed‐based chemotherapy for nonsquamous NSCLC. Methods This prospective clinical study enrolled 26 patients with advanced NSCLC treated with 4–6 cycles of first‐line pemetrexed combined with platinum‐based therapy. The complementarity‐determining region 3 (CDR3) located in the T cell receptor beta chain (TCR β chain) was captured and deeply sequenced using next‐generation sequencing (NGS) technology, and the correlation between TCR changes and efficacy after chemotherapy was analyzed. Results Patients with an inferior quarter diversity index showed a significantly shorter progression‐free survival (PFS) than the others (median, 5.0 months vs. 8.1 months, P = 0.014). After two cycles of chemotherapy, the TCR diversity was significantly higher than the baseline (P = 0.034). Just as with the baseline, patients with an inferior quarter diversity index at the endpoint of cycle 2 showed a shorter progression‐free survival (PFS) than the others (median, 5.0 months vs. 8.4 months, P = 0.024). Conclusions In advanced NSCLC patients treated with first‐line pemetrexed combined with platinum, the low level of blood TCR diversity at baseline with an endpoint of two cycles of chemotherapy was correlated with a poor prognosis., The aim of this study was to explore the relationship between blood T cell diversity and the survival of patients treated with pemetrexed‐based chemotherapy for nonsquamous non‐small cell lung cancer (NSCLC). In advanced NSCLC patients treated with first‐line pemetrexed combined with platinum, the low level of blood TCR diversity at baseline with an endpoint of two cycles of chemotherapy was correlated with a poor prognosis. The level of diversity after two cycles was the only independent prognostic factor among the multifactor analysis.

Background Numerous studies have reported the correlation between AXIN2 polymorphism and cancer risk, but the results seem not consistent. In order to get an overall, accurate and updated results about AXIN2 polymorphism and cancer risk, we conducted this study. Methods An updated analysis was performed to analyze the correlation between AXIN2 polymorphisms and cancer risk. Linkage disequilibrium (LD) analysis was also used to show the associations. Results Seventy-two case-control studies were involved in the study, including 22,087 cases and 18,846 controls. The overall results showed rs11079571 had significant association with cancer risk (allele contrast model: OR = 0.539, 95%CI = 0.478–0.609, PAdjust = 0.025; homozygote model: OR = 0.22, 95% CI = 0.164–0.295, PAdjustrs1133683 in homozygote and recessive models (PAdjustrs35285779 in heterozygote and dominant models (PAdjustrs7210356 and rs9915936 in the populations of CEU, CHB&CHS, ESN and JPT (CEU: r2 = 0.91; CHB&CHS: r2 = 0.74; ESN: r2 = 0.62, JPT: r2 = 0.57), and a significant correlation between rs9915936 and rs7224837 in the populations of CHB&CHS, ESN and JPT (r2>0.5), between rs7224837 and rs7210356 in the populations of CEU, CHB&CHS, JPT (r2>0.5), between rs35435678 and rs35285779 in the populations of CEU, CHB&CHS and JPT (r2>0.5). Conclusions AXIN2 rs11079571, rs1133683 and rs35285779 polymorphisms have significant correlations with overall cancer risk. What’s more, two or more polymorphisms such as rs7210356 and rs9915936, rs9915936 and rs7224837, rs7224837 and rs7210356, rs35435678 and rs35285779 have significant correlation with cancer susceptibility in different populations.

Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies. Barriers to effective CAR-T cell therapy include severe life-threatening toxicities, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration. In addition, the host and tumor microenvironment interactions with CAR-T cells critically alter CAR-T cell function. Furthermore, a complex workforce is required to develop and implement these treatments. In order to overcome these significant challenges, innovative strategies and approaches to engineer more powerful CAR-T cells with improved anti-tumor activity and decreased toxicity are necessary. In this review, we discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CAR-T cell therapy in both hematological malignancy and solid tumors.

BackgroundSuccessful breast cancer screening relies on timely follow-up of abnormal mammograms. Delayed or failure to follow-up abnormal mammograms undermines the potential benefits of screening and is associated with poorer outcomes. However, a comprehensive review of inadequate follow-up of abnormal mammograms in primary care has not previously been reported in the literature. This review could identify modifiable factors that influence follow-up, which if addressed, may lead to improved follow-up and patient outcomes.MethodsA systematic literature review to determine the extent of inadequate follow-up of abnormal screening mammograms in primary care and identify factors impacting on follow-up was conducted. Relevant studies published between 1 January, 1990 and 29 October, 2020 were identified by searching MEDLINE®, Embase, CINAHL® and Cochrane Library, including reference and citation checking. Joanna Briggs Institute Critical Appraisal Checklists were used to assess the risk of bias of included studies according to study design.ResultsEighteen publications reporting on 17 studies met inclusion criteria; 16 quantitative and two qualitative studies. All studies were conducted in the United States, except one study from the Netherlands. Failure to follow-up abnormal screening mammograms within 3 and at 6 months ranged from 7.2–33% and 27.3–71.6%, respectively. Women of ethnic minority and lower education attainment were more likely to have inadequate follow-up. Factors influencing follow-up included physician-patient miscommunication, information overload created by automated alerts, the absence of adequate retrieval systems to access patient’s results and a lack of coordination of patient records. Logistical barriers to follow-up included inconvenient clinic hours and inconsistent primary care providers. Patient navigation and case management with increased patient education and counselling by physicians was demonstrated to improve follow-up.ConclusionsFollow-up of abnormal mammograms in primary care is suboptimal. However, interventions addressing amendable factors that negatively impact on follow-up have the potential to improve follow-up, especially for populations of women at risk of inadequate follow-up.

Zongying Liang, Baoshan Zhao, Jishen Hou, Jingxiong Zheng, Guohua Xin Department of Thoracic Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, 067000, People’s Republic of ChinaCorrespondence: Guohua XinDepartment of Thoracic Surgery, The Affiliated Hospital of Chengde Medical University, No. 36, Nanyingzi Street, Shuangqiao District, Chengde, 067000, People’s Republic of ChinaEmail iqbqth@163.comBackground: Circular RNA hsa_circ_0003340 (circ-OGDH) has been uncovered to be involved in esophageal squamous cell carcinoma (ESCC) progression. However, the mechanism by which circ-OGDH regulates ESCC progression is unclear.Methods: Expression levels of circ-OGDH, microRNA (miR)-615-5p, and PDX1 (pancreatic and duodenal homeobox 1) mRNA were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, apoptosis, migration, invasion, and cell cycle progression of ESCC cells were analyzed by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide), colony formation, flow cytometry, and transwell assays. Measurement of glutamine consumption, α-KG (α-ketoglutarate) production, and ATP (Adenosine Triphosphate) content using corresponding kits. Protein levels were analyzed by Western blotting. The targeting relationship between circ-OGDH or PDX1 and miR-615-5p was verified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The function of circ-OGDH in ESCC was confirmed by animal experiments.Results: Circ-OGDH was upregulated in ESCC. Circ-OGDH inhibition reduced ESCC growth in vivo and accelerated cell apoptosis, cell cycle arrest, repressed cell proliferation, migration, invasion, and reduced cell glutamine metabolism in ESCC cells in vitro. MiR-615-5p was downregulated in ESCC, while PDX1 had an opposite result. Circ-OGDH sponged miR-615-5p to regulate PDX1 expression. MiR-615-5p inhibitor neutralized the repressive effect of circ-OGDH knockdown on malignancy and glutamine metabolism of ESCC cells. PDX1 overexpression counteracted the inhibitory impact of miR-615-5p mimic on malignancy and glutamine metabolism of ESCC cells.Conclusion: Circ-OGDH sponged miR-615-5p to elevate PDX1 expression, thus elevating glutamine metabolism and promoting tumor growth in ESCC. The study offered evidence to support circ-OGDH as a promising target for ESCC therapy.Keywords: ESCC, circ-OGDH, miR-615-5p, PDX1, glutamine

We prepared an anti-p21Ras scFv which could specifically bind with mutant and wild-type p21Ras. However, it cannot penetrate the cell membrane, which prevents it from binding to p21Ras in the cytoplasm. Here, the RGD4C peptide was used to mediate the scFv penetration into tumor cells and produce antitumor effects. RGD4C-EGFP and RGD4C-p21Ras-scFv recombinant expression plasmids were constructed to express fusion proteins in E. coli, then the fusion proteins were purified with HisPur Ni-NTA. RGD4C-EGFP was used as reporter to test the factors affecting RGD4C penetration into tumor cell. The immunoreactivity of RGD4C-p21Ras-scFv toward p21Ras was identified by ELISA and western blotting. The ability of RGD4C-p21Ras-scFv to penetrate SW480 cells and colocalization with Ras protein was detected by immunocytochemistry and immunofluorescence. The antitumor activity of the RGD4C-p21Ras-scFv was assessed with the MTT, TUNEL, colony formation and cell migration assays. Chloroquine (CQ) was used an endosomal escape enhancing agent to enhance endosomal escape of RGD4C-scFv. RGD4C-p21Ras-scFv fusion protein were successfully expressed and purified. We found that the RGD4C fusion protein could penetrate into tumor cells, but the tumor cell entry of was time and concentration dependent. Endocytosis inhibitors and a low temperature inhibited RGD4C fusion protein endocytosis into cells. The change of the cell membrane potential did not affect penetrability. RGD4C-p21Ras-scFv could penetrate SW480 cells, effectively inhibit the growth, proliferation and migration of SW480 cells and promote this cells apoptosis. In addition, chloroquine (CQ) could increase endosomal escape and improve antitumor activity of RGD4C-scFv in SW480 cells. The RGD4C peptide can mediate anti-p21Ras scFv entry into SW480 cells and produce an inhibitory effect, which indicates that RGD4C-p21Ras-scFv may be a potential therapeutic antibody for the treatment of ras-driven cancers.

Background The 37 kDa/67 kDa laminin receptor (LRP/LR) is involved in several tumourigenic-promoting processes including cellular viability maintenance and apoptotic evasion. Thus, the aim of this study was to assess the molecular mechanism of LRP/LR on apoptotic pathways in late stage (DLD-1) colorectal cancer cells upon siRNA-mediated down-regulation of LRP/LR. Methods siRNAs were used to down-regulate the expression of LRP/LR in DLD-1 cells which was assessed using western blotting and qPCR. To evaluate the mechanistic role of LRP/LR, proteomic analysis of pathways involved in proliferation and apoptosis were investigated. The data from the study was analysed using a one-way ANOVA, followed by a two-tailed student’s t-test with a confidence interval of 95%. Results Here we show that knock-down of LRP/LR led to significant changes in the proteome of DLD-1 cells, exposing new roles of the protein. Moreover, analysis showed that LRP/LR may alter components of the MAPK, p53-apoptotic and autophagic signalling pathways to aid colorectal cancer cells in continuous growth and survival. Knock-down of LRP/LR also resulted in significant decreases in telomerase activity and telomerase-related proteins in the DLD-1 cells. Conclusions These findings show that LRP/LR is critically implicated in apoptosis and cell viability maintenance and suggest that siRNA-mediated knock-down of LRP/LR may be a possible therapeutic strategy for the treatment of colorectal cancer.

© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)., Introduction: Innovations in 3D spatial technology and augmented reality imaging driven by digital high-tech industrial science have accelerated experimental advances in breast cancer imaging and the development of medical procedures aimed to reduce invasiveness. Presentation of case: A 57-year-old post-menopausal woman presented with screen-detected left-sided breast cancer. After undergoing all staging and pre-operative studies the patient was proposed for conservative breast surgery with tumor localization. During surgery, an experimental digital and non-invasive intra-operative localization method with augmented reality was compared with the standard pre-operative localization with carbon tattooing (institutional protocol). The breast surgeon wearing an augmented reality headset (Hololens) was able to visualize the tumor location projection inside the patient's left breast in the usual supine position. Discussion: This work describes, to our knowledge, the first experimental test with a digital non-invasive method for intra-operative breast cancer localization using augmented reality to guide breast conservative surgery. In this case, a successful overlap of the previous standard pre-operative marks with carbon tattooing and tumor visualization inside the patient's breast with augmented reality was obtained. Conclusion: Breast cancer conservative guided surgery with augmented reality can pave the way for a digital non-invasive method for intra-operative tumor localization.

Background Evidence‐based policy making for delivering affordable lung cancer care relies on the breadth, depth and quality of knowledge of its treatment costs. This study estimates the annual prevalence, medical service utilization and direct treatment costs of lung cancer in urban China. Materials and Methods Using claim data from China's urban basic medical insurance between 2013 and 2016, we constructed a nationally representative sample of lung cancer patients in urban China. Weighted descriptive analyses, Poisson regressions and generalized linear modelling were used to analyse lung cancer medical service utilization and costs and their associations with patient characteristics. Results In urban China, the annual prevalence of lung cancer was 87.65/100000, with nearly 0.65% of total health expenditures of urban residents spent on lung cancer treatments. Weighted average annual total medical costs of lung cancer was RMB33.78 (US$5.36) thousand, with annual out‐of‐pocket costs of RMB10.26 (US$1.63) thousand. The average yearly number of lung cancer‐related outpatient visits was 2.42 and inpatient admissions was 2.07, with an average cost of RMB0.75 (US$0.12) thousand for outpatients and RMB 15.67 (US$2.49) thousand for inpatients. Inpatient expenses were the major component (95%) of lung cancer medical costs, with roughly 67% of inpatient services occurring in high‐level tertiary hospitals. Medical care utilization and direct medical costs were associated with sex, age and insurance status. Western medicine costs were the major contributor (39.4%) to average lung cancer‐related medical costs. Conclusion Lung cancer imposed a significant economic burden on China's health system and a financial cost on lung cancer sufferers and their families. Specific policies are required to efficiently allocate health resources, contain health expenditure and decrease the individual financial burden of lung cancer., In urban China, the annual prevalence of lung cancer was 87.65/100000, with nearly 0.65% of total health expenditures of urban residents spent on lung cancer treatments. Inpatient expenses were the major component (95%) of lung cancer medical costs.Western medicine cost contributes 39.4% for lung cancer medical costs.

Wei-Dong Bao,1,* Qi Jia,2,* Tao Wang,2,3,* Yan Lou,2 Dong-Jie Jiang,2 Cheng Yang,2 Xinghai Yang,2 Quan Huang,2 Hai-Feng Wei,2 Jian-Ru Xiao1,2 1Department of Orthopedics, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People’s Republic of China; 2Department of Orthopedic Oncology, Spinal Tumor Center, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People’s Republic of China; 3Department of Orthopeadics, Second Affiliated Hospital of Anhui Medical University, Hefei, 230000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hai-Feng Wei; Jian-Ru XiaoDepartment of Orthopedic Oncology, Spine Tumor Center, Changzheng Hospital, Second Military Medical University, #415 Fengyang Road, Shanghai, 200003, People’s Republic of ChinaTel +86-21-81886843Email gkxjl999@163.com; spine925@126.comPurpose: To investigate risk factors for instrumentation failure (IF) in titanium (Ti) mesh reconstruction for thoracic and lumbar tumors.Patients and Methods: The clinical data of patients with thoracic or lumbar tumors who received Ti mesh reconstruction via the posterior approach in our hospital from 2013 to 2018 were analyzed retrospectively. The observation indexes included sex, age, BMI, the vertebra resection mode, the number of resected vertebral segments, application of bone cement, radiotherapy, chemotherapy, revision or primary surgery, and primary tumor metastasis. Correlations between these factors and IF were analyzed by Kaplan–Meier survival and logistics regression analyses.Results: The 178 patients included 108 males and 70 females with a mean age of 48.09± 16.21 (6– 78) years and a mean follow-up period of 51.18 (24– 90) months. The data showed that 17 patients (9.55%) were inflicted with IF, involving the thoracic vertebra in 11 cases, thoracolumbar vertebrae (T12–L1) in 2 cases, and lumbar vertebrae in 4 cases. The mean interval between surgery to IF was 35.18± 14.17 (14– 59) months. Univariate analysis showed that total vertebral body resection, the number of resected vertebral segments, radiotherapy and multiple tumor resection were potential factors for IF, while multivariate analysis showed that only total vertebral body resection, the number of resected vertebral segments and radiotherapy were independent factors.Conclusion: Total vertebra resection, the number of resected vertebral segments (≥ 2) and radiotherapy before and after operation were significant risk factors related to IF.Keywords: instrumentation failure, titanium mesh, thoracic and lumbar tumors

Background The aim of this study was to determine the specific side detection rate of the sentinel lymph node biopsy and the accuracy in predicting lymph node metastasis in early stage cervical cancer. Methods A systematic search of databases was performed from the inception of the databases to 27 June 2020. Studies of cervical cancer patients with FIGO stage FIGO ⅠA~ⅡB, evaluating the sentinel lymph node biopsy with blue dye, technetium 99, combined technique (blue dye with technetium 99) or indocyanine green with a reference standard of systematic pelvis lymph node dissection or clinical follow‐up were included. Stata12.0 and Meta‐Disc 1.4 were used for the meta‐analysis. Results Of 2825 articles found, 21 studies (2234 women) were eventually included. Out of 21 studies, 20 met the detection rate evaluation criteria and six were included for sensitivity meta‐analysis. Due to heterogeneity, it was inappropriate to pool all studies. The pooled specific side detection rates were 85% in tumors up to 2 cm, 67% in tumors over 2 cm, 75.2% for blue dye, 74.7% for technetium 99, 84% for combined technique, and 85.5% for indocyanine green. The sentinel lymph node biopsy had a pooled specific side sensitivity of 88%. Adverse effects of sentinel lymph node biopsy appear minimal for most patients and are mainly related to the injection of blue dye. Conclusions Sentinel lymph node biopsy using a tracer with a high detection rate and ultrastaging is highly accurate and reliable when limited to seriously selected patients, with satisfactory bilateral lymph node mapping and where enough cases for learning curve optimization exist. Indocyanine green sentinel lymph node mapping seems to be a superior sentinel lymph node mapping technique compared to other methods at present., Sentinel lymph node biopsy using a tracer with a high detection rate and ultrastaging is highly accurate and reliable when limited to seriously selected patients, with satisfactory bilateral lymph node mapping and where enough cases for learning curve optimization exist. Indocyanine green sentinel lymph node mapping seems to be a superior sentinel lymph node mapping technique compared to other methods at present.

This study describes technical implications and compares short-term outcomes after a dorsal versus ventral approach for double-face augmentation urethroplasty (DFAU) for treating a near-obliterated bulbar urethral stricture (BUS). This was a retrospective evaluation of a prospectively collected database of patients with BUS (

Ning Xie,1,2,* Yifei Pan,3,* Jian Wu,4 Yunfan Bai,3 Cailan Xiao,1,2 Xiaoliang Gao,4 Jinhai Wang,1,2 Na Liu1,2 1Department of Gastroenterology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Shaanxi Key Laboratory of Gastrointestinal Motility Disorders, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Japan; 4Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Na Liu; Jinhai Wang Email liuna1@xjtu.edu.cn; jinhaiwang@hotmail.comBackground: Our previous studies demonstrate that ARL4C is the most critical clinical biomarker for gastric cancer (GC) patients among ARL family members (ARLs) and functions as an oncogene in GC. However, its underlying mechanisms in GC need to be further illustrated. In this study, we aim to explore the upstream and downstream molecular mechanisms of ARL4C in GC cells.Methods: The genetic alteration of ARL4C in GC is analyzed by cBioPortal database. Potential ARL4C-targeted microRNAs (miRs) are predicted by three databases. The high-throughput RNA sequencing is performed to explore the underlying mechanisms of ARL4C in GC cells. The effects of predicted microRNAs on ARL4C, the RNA-sequencing results validation and the biological functions of ARL4C in GC cells are illustrated by in vitro experiments.Results: Genetic analyses indicate that ARL4C is significantly upregulated in GC, which is not caused by gene amplification. MicroRNAs prediction shows the high relevance between ARL4C and miR-302 members. Moreover, miR-302c or miR-302d transfection reduces ARL4C protein expression in GC cells. Based on the high-throughput RNA sequencing of ARL4C-knockdown cells, enrichment analyses demonstrate that ARL4C is closely related to cell growth and involved in p53 signaling. Moreover, there are strong gene–gene interactions between ARL4C and genes in p53 signaling, and ARL4C downregulation could inhibit the protein expression of MDM2, a critical gene in p53 pathway. Further functional experiments demonstrate that ARL4C silencing leads to cell cycle arrest and increased cell apoptosis in AGS and MKN45 cells.Conclusion: Our data suggest that miR-302c and miR-302d may function as the upstream regulators of ARL4C. And, ARL4C might promote GC cell cycle progression via regulating p53 signaling. Our findings provide novel insights into the key role of ARL4C and the underlying mechanisms in GC progression, thus facilitating the development of ARL4C-targeted therapy.Keywords: ARL4C, gastric cancer, miRNA-302s, p53, cell cycle, apoptosis

Zhenkun Yan,1 Sen Hong,2 Yumei Song,3 Miaomiao Bi4 1Department of Endoscopy Center, The Third Hospital of Jilin University, Changchun, Jilin, 130022, People’s Republic of China; 2Department of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130022, People’s Republic of China; 3Department of Thoracic Oncology, Tumor Hospital of Jilin Province, Changchun, Jilin, 130022, People’s Republic of China; 4Department of Ophthalmology, The Third Hospital of Jilin University, Changchun, Jilin, 130022, People’s Republic of ChinaCorrespondence: Sen HongDepartment of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130022, People’s Republic of ChinaEmail hongsen@jlu.edu.cnZhenkun YanDepartment of Endoscopy Center, The Third Hospital of Jilin University, Changchun, Jilin, 130022, People’s Republic of ChinaEmail yanzhenkun@jlu.edu.cnIntroduction: Dysregulation of microRNAs (miRNAs), which represented a critical level of gene expression modulation, regulated the development of colorectal cancer. However, the functions of numerous miRNAs remain unclear in colorectal cancer.Methods: The microarray data of GSE115513 were retrieved; subsequently, the differentially expressed miRNAs between 411 colon tumors and 381 normal colon mucosa were analyzed. Real-time PCR (RT-qPCR) and bioinformatic analysis were applied to examine the expression of miR-4449 in collected colorectal tumors and published microarray data. The activity of signal transducer and activator of transcription 3 (STAT3) signaling was detected by Western blotting and RT-qPCR. Dual-Luciferase assay and bioinformatic analysis were used to confirm the interaction between suppressor of cytokine signaling 3 (SOCS3) and miR-4449. Loss of function and rescue assays were performed to study the involvement of miR-4449 and SOCS3 in cell proliferation and apoptosis of colorectal cancer.Results: Herein, we identified miR-4449 as a novel upregulated miRNA in colorectal cancer. Our data suggested that miR-4449 downregulation blocked the proliferation of colorectal cancer cells accompanied with the elevation of cell apoptosis. Decreased expression of miR-4449 led to inactivation of STAT3 pathway as indicated by dephosphorylation of STAT3 and downregulation of STAT3 target genes, including vascular endothelial growth factor (VEGF), c-Myc, baculovirus inhibitor of apoptosis containing 5 (BIRC5). Furthermore, SOCS3, a negative regulator of STAT3 pathway, was found to be a target gene of miR-4449. The data also showed that the inactivation of STAT3 pathway by miR-4449 inhibitor was realized by targeting SOCS3. Moreover, the biological function of miR-4449 downregulation was reversed by SOCS3 knockdown in colorectal cancer cells.Conclusion: The current study revealed that miR-4449 promoted cell proliferation of colorectal cancer and was a promising potential therapeutic target for colorectal cancer.Keywords: STAT3, microR-4449, colorectal cancer, SOCS3

Xing Liu,1 Shuping Zheng,2 Yong Peng,3 Jinfu Zhuang,4 Yuanfeng Yang,4 Yunlu Xu,2 Guoxian Guan1 1Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China; 2Public Technology Service Center, Fujian Medical University, Fuzhou, People’s Republic of China; 3Department of General Surgery, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 4Department of Colorectal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of ChinaCorrespondence: Guoxian GuanDepartment of Colorectal Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, Fujian, People’s Republic of ChinaTel +86 591-83357896Email fjxhggx@163.comYunlu XuPublic Technology Service Center, Fujian Medical University, 1 Xuefubei Road, Fuzhou City, 350001, Fujian, People’s Republic of ChinaTel +86 591-22862408Email xuyunlu3578@fjmu.edu.cnPurpose: To assess the value of macrophage-related biomarkers (CD163, CD68, MCSF, and CCL2) for predicting the response to neo-chemoradiotherapy (NCRT) and the prognosis of locally advanced rectal cancer (LARC).Methods: We enrolled 191 patients who underwent neoadjuvant chemoradiotherapy and radical resection between 2011 and 2015. Tumor tissues were collected before NCRT with a colonoscope and post-surgery and were subjected to immunohistochemical analysis.Results: The expression levels of macrophage-related biomarkers (CD163, CD68, MCSF, and CCL2) were lower in the pathological complete response (pCR) group when compared with the non-pCR group (all P< 0.05). Based on X-tile plots, we divided the tumors in two groups and found that lower pre-NCRT/post-surgical CD163, CD68, MCSF, CCL2 scores correlated with improved DFS. Cox regression analysis demonstrated that pre-NCRT CD163 (HR=1.008, 95% CI 1.003– 1.013, P=0.003) and MCSF (HR=2.187, 95% CI 1.343– 3.564, P=0.002) scores were independent predictors of DFS. Based on Cox multivariate analysis, we constructed a risk score model with a powerful ability to predict pCR in LARC patients. Moreover, COX regression analysis was performed to explore the role of the risk score in LARC patients. The results demonstrated that tumor size (HR=1.291, P=0.041), worse pathological TNM stage (HR=1.789, P=0.005, and higher risk score (HR=1.084, P< 0.001) were significantly associated with impaired disease-free survival. Based on the above results, a nomogram and decision curve analysis were generated.Conclusion: The expression levels of macrophage-related biomarkers CD163, CD68, MCSF, and CCL2 were associated with chemoradiotherapy resistance and prognosis in LARC patients following NCRT. A risk score model was constructed which could be used to predict LARC outcome.Keywords: rectal cancer, neoadjuvant chemoradiotherapy, risk, prognosis

Despite advances in therapeutics, the progression of melanoma to metastasis still confers a poor outcome to patients. Nevertheless, there is a scarcity of biological models to understand cellular and molecular changes taking place along disease progression. Here, we characterized the transcriptome profiles of a multi-stage murine model of melanoma progression comprising a nontumorigenic melanocyte lineage (melan-a), premalignant melanocytes (4C), nonmetastatic (4C11-) and metastasis-prone (4C11+) melanoma cells. Clustering analyses have grouped the 4 cell lines according to their differentiated (melan-a and 4C11+) or undifferentiated/“mesenchymal-like” (4C and 4C11-) morphologies, suggesting dynamic gene expression patterns associated with the transition between these phenotypes. The cell plasticity observed in the murine melanoma progression model was corroborated by molecular markers described during stepwise human melanoma differentiation, as the differentiated cell lines in our model exhibit upregulation of transitory and melanocytic markers, whereas “mesenchymal-like” cells show increased expression of undifferentiated and neural crest-like markers. Sets of differentially expressed genes (DEGs) were detected at each transition step of tumor progression, and transcriptional signatures related to malignancy, metastasis and epithelial-to-mesenchymal transition were identified. Finally, DEGs were mapped to their human orthologs and evaluated in uni- and multivariate survival analyses using gene expression and clinical data of 703 drug-naïve primary melanoma patients, revealing several independent candidate prognostic markers. Altogether, these results provide novel insights into the molecular mechanisms underlying the phenotypic switch taking place during melanoma progression, reveal potential drug targets and prognostic biomarkers, and corroborate the translational relevance of this unique sequential model of melanoma progression.

Junhong Li, Xingwang Zhou, Yufan Xiang, Shuxin Zhang, Wentao Feng, Yunbo Yuan, Yanhui Liu, Senlin Yin Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, People’s Republic of ChinaCorrespondence: Senlin Yin Email enforest@gmail.comObjective: To explore the prognostic value of preoperative fibrinogen to albumin ratio (FAR) in patients with glioblastoma (GBM) and its association with clinical characteristics.Patients and Methods: A retrospective analysis was carried out on patients with newly diagnosed GBM who had undergone operation at the Department of Neurosurgery at West China Hospital between June 1st 2015 to June 31st 2018. Receiver operating characteristic (ROC) curves were performed to determine the optimal cut-off values for fibrinogen, albumin, neutrophil to lymphocyte ratio (NLR), and FAR by calculating the maximum Youden index. Kaplan–Meier curves and Cox regression analyses were applied to evaluate the prognostic value of FAR in GBM. Harrell concordance index (C-index) and Akaike information criterion (AIC) were calculated to compare different prognostic models.Results: A total of 206 GBM patients were included in this research. The optimal cut-off value for fibrinogen, albumin, NLR, and FAR were 2.57, 42.4, 2.28, and 0.068 respectively. High FAR was significantly related to older age, KPS≤ 80, IDH-1 wildtype, presence of preoperative seizures, higher NLR, and tumor location. In Cox regression analyses, high FAR was significantly associated with poor prognosis. Prognostic models including FAR had the largest C-index and lowest AIC.Conclusion: FAR was determined to be an independent risk factor of prognosis in patients with newly-diagnosed GBM. And the prognostic predictive ability of FAR is stronger than fibrinogen and albumin.Keywords: fibrinogen to albumin ratio, FAR, fibrinogen, albumin, glioblastoma, prognosis

BackgroundOsteosarcoma is an aggressive malignant tumor which has attracted worldwide attention. MEX3A may be associated with tumors while has not yet seen its coverage on osteosarcoma. Herein, this study was to investigate the correlation between MEX3A and the progression of osteosarcoma.MethodsFirstly, we determined that expression of MEX3A was significantly higher in osteosarcoma tissues than that in marginal bone by immunohistochemical staining. Additionally, MEX3A expression was downregulated by the RNAi‐mediated knockdown. The functions of MEX3A knockdown on proliferation, apoptosis, cell cycle, migration was assessed by MTT assay, flow cytometry, wound-healing assay and Transwell assay, respectively. Knockdown of MEX3A resulted in suppressing cell proliferation, increasing cell apoptosis, inducing the G2 phase cell cycle arrest, and attenuating cellular migration. Furthermore, mouse xenograft model confirmed inhibitory effects of MEX3A knockdown on osteosarcoma formation.ResultsThe preliminary exploration on the molecular mechanism of MEX3A in osteosarcoma cells showed that the induction of apoptosis needs the participation of a series of apoptosis- associated factors, such as upregulation of Caspase 3, Caspase 8 and HSP60, downregulation of HSP27 and XIAP.ConclusionsIn summary, these findings predicated that therapy directed at decreasing MEX3A expression is a potential osteosarcoma treatment.

This study aims to evaluate HR‐HPV viral load in the cervical lesion assessment and its diagnostic value on the triage of ASCUS. The three‐step protocol for cervical cancer screening was carried out in 5171 patients from June 2017 to August 2019, and 1620 histopathological results were obtained. The positive rate of HR‐HPV and TCT increased with the aggravation of pathological grades of cervical lesions. The sensitivity and specificity of HR‐HPV (DH3) to detect CIN II+ were 91.91% and 84.46%, respectively. In comparison, the corresponding results of the cytology test were 80.51% and 83.12%. HPV16/18 viral load was positively correlated with the grade of cervical lesions (p, This study which involves 5171 patients is focusing on high‐risk HPV viral load and cervical lesions. It is the first research on the diagnostic value of high‐risk HPV viral load by using DALTONbio hybrid capture 3. Our findings suggest that HPV16/18 viral load has good diagnostic efficacy and specificity in predicting CIN II + lesions. HR‐HPV viral load detection can be used to screen the high‐risk population with CIN II + lesion to the greatest extent.

Rongxue Wan,1– 3 Jianguo Feng,2,4 Liling Tang1 1Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, People’s Republic of China; 2National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 3Department of Human Anatomy, School of Basic Medical Sciences, Guangdong Medical University, Zhanjiang, Guangdong Province, People’s Republic of China; 4Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People’s Republic of ChinaCorrespondence: Jianguo Feng 1023-1063 Shatai South Road, Baiyun DistrictSouthern Medical University, Guangzhou, 510515, People’s Republic of ChinaTel +86-1820-835-7473Email ffengjianguo@163.comLiling Tang 83 Shabei Street, Shapingba DistrictChongqing University, Chongqing, 400044, People’s Republic of ChinaTel +86-1399-605-1730Email tangliling@cqu.edu.cnAbstract: SMAD4 is a typical tumor suppressor in the TGF-β signaling pathway. In human cancers, SMAD4 is frequently mutated and inactivated. In recent years, the consequences of mutations and inactivation of SMAD4 are gradually becoming clearer. Most of the mutations have negative consequences and reduce the chances of survival of their carriers. Loss of SMAD4 functions due to mutations or abnormal expression can suppress the inhibition of tumor growth and support the tumor progression. Functions of SMAD4 and its variants in T cells are being studied extensively, to better understand the SMAD4 functions in T cells. In this review, we mainly discuss the recently reported consequences of mutations and abnormal expression of SMAD4 in tumors, and the effects of loss, deficiency or mutation of SMAD4 and its T cells, to show the use of SMAD4 mutations in cancer diagnosis and therapeutic strategies.Keywords: SMAD4, mutation, abnormal expression, T cell, TGF-&beta

Ovarian clear cell carcinoma (OCCC) reportedly develops from endometriosis. However, the molecular mechanism underlying its malignant progression to OCCC remains elusive. This study aimed to identify an essential gene in the malignant transformation of endometriosis to OCCC. We performed RNA sequencing in formalin‐fixed, paraffin‐embedded (FFPE) tissues of endometriosis (n = 9), atypical endometriosis (AtyEm) (n = 18), adjacent endometriosis to OCCC (AdjEm) (n = 7), and OCCC (n = 17). We found that tetraspanin 1 (TSPAN1) mRNA level was significantly increased by 2.4‐ (DESeq2) and 3.4‐fold (edgeR) in AtyEm and by 80.7‐ (DESeq2) and 101‐fold (edgeR) in OCCC relative to endometriosis. We confirmed that TSPAN1 protein level was similarly overexpressed in OCCC tissues and cell lines. In immortalized endometriosis cell lines, TSPAN1 overexpression enhanced cell growth and invasion. Mechanistically, TSPAN1 triggered AMP‐activated protein kinase (AMPK) activity, promoting endometriosis and cell growth. Upregulated levels of TSPAN1 are considered an early event in the development of high‐risk endometriosis that could progress to ovarian cancer. Our study suggests the potential of TSPAN1 as a screening candidate for high‐risk endometriosis., Endometriosis can progress toward ovarian clear cell carcinoma (OCCC). While investigating genes involved in this process, we confirmed that TSPAN1 expression increases during progression from endometriosis to OCCC. TSPAN1 promoted endometriotic cell growth through AMPK activity. These results indicate altered TSPAN1 expression levels as an early marker of malignant transformation that may enable screening for high‐risk endometriosis.

Rui Sun,* Jinhui Liu,* Sipei Nie,* Siyue Li, Jing Yang, Yi Jiang, Wenjun Cheng Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenjun ChengDepartment of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, People’s Republic of ChinaEmail wenjunchengdoc@163.comIntroduction: This bioinformatic study confirmed a new miRNA-mRNA regulatory network and a prognostic signature in endometrial cancer (EC).Materials and Methods: We downloaded RNA-seq and miRNA-seq data of EC from the TCGA database, then used EdegR package to screen differentially expressed miRNAs and mRNAs (DE-miRNAs and DE-mRNAs). Then, we constructed a regulatory network of EC-associated miRNAs and hub genes by Cytoscape, and determined the expression of unexplored miRNAs in EC tissues and normal adjacent tissues by quantitative Real-Time PCR (qRT-PCR). A prognostic signature model and a predictive nomogram were constructed. Finally, we explored the association between the prognostic model and the immune cell infiltration.Results: A total of 11,531 DE-mRNAs and 236 DE-miRNAs, as well as 275 and 118 candidate DEGs for upregulated and downregulated DE-miRNAs were screened out. The miRNA-mRNA network included 5 downregulated and 13 upregulated DE-miRNAs. qRT-PCR proved that the expression levels of miRNA-18a-5p, miRNA-18b-5p, miRNA-449c-5p and miRNA-1224-5p and their target genes (NR3C1, CTGF, MYC, and TNS1) were consistent with our predictions. Univariate and multivariate Cox proportional hazards regression analyses of the hub genes revealed a significant prognostic value of NR3C1, EZH2, AND GATA4, and these genes were closely related to eight types of immune infiltration cells.Conclusion: We identified three genes as candidate biomarkers for EC, which may provide a theoretical basis for targeted therapy.Keywords: TCGA, endometrial cancer, miRNA-mRNA network, prognostic model, immune infiltration cell

Systematic analysis of tumor‐infiltrating lymphocytes is essential for the development of new cancer treatments and the prediction of clinical responses to immunotherapy. Immunomodulatory drugs are used for the treatment of oral squamous cell carcinoma (OSCC), depending on immune infiltration profiles of the tumor microenvironment. In this study, we isolated 11,866 single T cells from tumors and paired adjacent normal tissues of three patients with OSCC. Using single‐cell RNA sequencing, we identified 14 distinct T‐cell subpopulations within the tumors and 5 T‐cell subpopulations in the adjacent normal tissues and delineated their developmental trajectories. Exhausted CD8+ T cells and regulatory CD4+ T cells (CD4+ Tregs) were enriched in OSCC tumors, potentially linked to tumor immunosuppression. Programmed death protein 1 (PD‐1) and cytotoxic T lymphocyte‐associated protein 4 (CTLA4) were identified as marker genes in exhausted CD8+ T cells, whereas forkhead box P3 (FOXP3) and CTLA4 were identified as markers of CD4+ Tregs. Furthermore, our data revealed that thymocyte selection‐associated high‐mobility group box (TOX) may be a key regulator of T‐cell dysfunction in the OSCC microenvironment. Overexpression of TOX upregulated expression of genes related to T‐cell dysfunction. In vitro experiments demonstrated that cytotoxic activity and proliferation efficiency of CD8+ T cells overexpressing PD‐1 or TOX were reduced. Notable, the transcription factor PRDM1 was found to transactivate TOX expression via a binding motif in the TOX promoter. Our findings provide valuable insight into the functional states and heterogeneity of T‐cell populations in OSCC that could advance the development of novel therapeutic strategies., Using single‐cell RNA sequencing, we identified 14 distinct T‐cell subpopulations from 11,866 T cells in OSCC. Our data revealed that exhausted CD8+ T cells and CD4+ Tregs were enriched in OSCC and TOX may be a key regulator of T‐cell dysfunction. Notable, the transcription factor PRDM1 was found to transactivate TOX expression via a binding motif in the TOX promoter.

Siyao Deng,1 Wenjing Ye,1 Shichuan Zhang,2,3 Guiquan Zhu,4 Peng Zhang,2 Yanqiong Song,2 Fanglei Duan,3 Jinyi Lang,2,3 Shun Lu2,3 1School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 3Radiation Oncology Key Laboratory of Sichuan Province, Chengdu, People’s Republic of China; 4State Key Laboratory of Oral Diseases, National Clinical Research Centre for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Shun LuDepartment of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Renmin South Road 55#, Chengdu, 610041, People’s Republic of ChinaTel +86 28 85420897Fax +86 28 85420110Email lushun1982@live.cnPurpose: Fanconi anemia (FA) is a rare genetic disorder characterized by congenital anomalies, progressive bone marrow failure and high susceptibility to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Management of FA patients with head and neck cancer is a challenge due to increased risk of surgery, poor tolerance of chemotherapy, and severe myelotoxicity of radiotherapy.Patients and Methods: We present a case of a 33-year-old man with carcinoma of oral tongue (T1N2M0), who experienced prolonged and profound bone marrow failure as a consequence of concurrent cisplatin/radiation. The young patient who developed HNSCC without risk factors, the myelotoxicity after exposure to platinum-based agent cisplatin and the further evaluation of phenotypic characteristics raised suspicion of FA. Whole exome sequencing performed for the patient and parents ultimately established the diagnosis of FA.Results: Genetic testing in 23 FANC genes revealed two novel heterozygous mutations, c.367C>T and c.3971_3972delCGinsTT in FANCA gene of the patient, which were inherited from his father and mother, respectively. Radiotherapy with reduced dose has successfully alleviated the symptoms of tumor invasion and progression, and the radiation-related side effects were acceptable. Unfortunately, the patient eventually died of locoregional disease progression.Conclusion: This case highlights the importance of considering the diagnosis of FA in young patients who develop HNSCC in the absence of risk factors, thus permitting more effective oncological treatment strategies and improved outcomes. In conclusion, any decision on different modalities of management in such patients should be based on a balance between locoregional control and therapeutic toxicity.Keywords: fanconi anemia, radiotherapy, cisplatin, head and neck squamous cell carcinoma, toxicity

Context The detection of low‐level persistent or relapsed B‐cell neoplasms, particularly post‐therapy, can be challenging, often requiring multiple testing modalities. Objective Here we investigate the utility of CD19‐based selection of neoplastic B‐cells (CD19S) as an enrichment strategy to improve the detection rate of cytogenetic abnormalities in post‐therapy samples of B‐cell neoplasms, especially those with low‐level disease. Design In a cohort largely comprised of post‐therapy B‐ALL and CLL samples, we performed fluorescence in situ hybridization (FISH) analysis on CD19‐selected cells (CD19S FISH) in 128 specimens from 88 patients, and on non‐selected cells (NS FISH) in a subset of cases. The FISH findings were compared with the concurrent flow cytometry (FC) results in all samples and molecular analysis in a subset. Results CD19S FISH was able to detect cytogenetic aberrations in 86.0% of post‐therapy samples with evidence of disease as determined by routine or MRD FC, compared to 59.1% of samples by NS FISH. CD19S FISH detected significantly higher percentages of positive cells compared to NS FISH (p, A systematic comparison of CD19‐selected (CD19S) FISH versus non‐selected FISH analysis establishes superiority (qualitative and quantitative) of the former modality in detecting post‐therapy persistence or relapse of B‐cell neoplasms. CD19S FISH can complement flow cytometric evaluation for the detection of low‐level involvement in B‐cell neoplasms and particularly in the detection of post‐therapy recurrent/emerging small subclones. Flow cytometry detection of

Huocong He,1,*,* Lurong Zhang,1,* Keyu Lin,1,* Zhengrong Huang,2 Yan Zhou,3 Shaojun Lin,4 Ying Su,1 Jianru Pan5 1Laboratory of Radiation Biology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350014, People’s Republic of China; 2Department of Integrative Medicine, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350014, People’s Republic of China; 3Department of Epidemiology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350014, People’s Republic of China; 4Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University, Fuzhou, Fujian, 350014, People’s Republic of China; 5College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian, 350002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huocong HeLaboratory of Radiation Biology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350014, People’s Republic of ChinaEmail hconghe@163.comJianru PanCollege of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian, 350002, People’s Republic of ChinaEmail panjr@fzu.edu.cnBackground: Paraspeckle component 1 (PSPC1) is overexpressed in various cancer and correlated with poor survival in the patients. However, little is known about its expression and role in the progression of nasopharyngeal carcinomas (NPC). The purpose of this study is to examine PSPC1 expression in NPC and explore its role in clinical prognosis of radiation therapy.Methods: The association of PSPC1 expression with clinicopathological features of 109 NPC patients was examined using partial correlation analysis. Cancer tissues were obtained prior to clinical treatment. All cases were diagnosed and pathologically confirmed to be poorly differentiated or undifferentiated NPC without distant metastasis. The patients were then treated with radiation and followed-up. Survival analysis was performed.Results: Partial correlation analysis revealed that the PSPC1 expression in NPC was correlated with N classification, recurrence, prognosis and radiosensitivity in NPC patients, but not with the gender, age, pathohistological pattern, clinical stage, and T classification. The overexpression of PSPC1 was detected in 64 samples (58.72%). Kaplan–Meier survival analysis revealed that the overall survival (OS) was longer in NPC patients with PSPC1 low expression than that in those with PSPC1 high expression. Moreover, patients with the overexpression of PSPC1 had a low progression-free survival and distant metastasis-free survival rate, compared to those who had a low expression of PSPC1. Although not statistically significant, patients with high expression of PSPC1 had a lower locoregional recurrence-free survival rate than those with low expression, and the curves between the two groups was well separated.Conclusion: PSPC1 overexpression was associated with poor prognosis for NPC, which might be a novel useful biomarker to predict the response of NPC to radiation therapy and its clinical outcome.Keywords: nasopharyngeal carcinoma, paraspeckle component 1, PSPC1, clinical prognosis, radiation, overexpression

Methylation biomarkers are promising tools for diagnosis and disease prevention. The S5 classifier is aimed at the prevention of cervical cancer by the early detection of cervical intraepithelial neoplasia (CIN). S5 is based on pyrosequencing a promoter region of EPB41L3 and five late regions of HPV types 16, 18, 31, and 33 following bisulfite conversion of DNA. Good biomarkers should perform well in a variety of sample types such as exfoliated cells, fresh frozen or formalin‐fixed paraffin‐embedded (FFPE) materials. Here, we tested the performance of S5 on 315 FFPE biopsies with paired exfoliated cervical samples using four different conversion kits (Epitect Bisulfite, Epitect Fast Bisulfite, EZ DNA Methylation, and EZ DNA Methylation‐Lightning). The S5 values from FFPE biopsies for all kits were significantly correlated with those obtained from their paired exfoliated cells. For the EZ DNA Methylation kit, we observed an average increased methylation of 4.4% in FFPE. This was due to incomplete conversion of DNA (73% for FFPE vs. 95% for cells). The other kits had a DNA conversion rate in FFPE similar to the cells (95%–97%). S5 performed well at discriminating, The S5 Classifier is a DNA methylation‐based assay designed to detect pre‐cancerous cervical tissue. It was designed using a particular bisulfite conversion kit and optimized on fresh cells only. In this study, we establish that the S5 Classifier works to a similar level of sensitivity and specificity in FFPE tissue as it does in exfoliated samples and with three other bisulfite conversion kits. This validates its validity as an effective biomarker assay.

Background To reveal the function of deubiquitylating enzyme USP41 in lung adenocarcinoma. Methods The relationship between USP41 and lung cancer was determined by analyzing data from The Cancer Genome Atlas (TCGA). A549 and H1299 cell lines were transfected with short hairpin RNA against USP41 (shUSP41 group) or negative control (shCon group). Western blotting was used to verify the transfection efficacy and marker expression. Cell proliferation and apoptosis were analyzed by EdU assay, MTT assay, and flow cytometry after USP41 knockdown. Transwell assay was used to determine the effect of USP41 downregulation on cell migration. Results Analysis of lung cancer data from TCGA database indicated a higher level of USP41 expression in lung cancer tumor tissue compared with that in noncancerous tissue, and USP41 overexpression was correlated with poor overall survival of lung cancer patients (p, USP41 is overexpressed in lung cancer tissue and associated with poor prognosis of lung cancer. USP41 overexpression promotes cell proliferation and migration and inhibits apoptosis of lung cancer cells.

Xufeng Guo,1 Shan Tian,2 Pan Cao,3 Yishan Xie,1 Weiguo Dong2 1Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Department of Infectious Disease, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of ChinaCorrespondence: Weiguo DongDepartment of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhi-dong Road, Wuhan, 430060, People’s Republic of ChinaTel +86-027-88041911Email Ddongweiguo@163.comCorrespondence: Yishan XieDepartment of Oncology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhi-dong Road, Wuhan, 430060, People’s Republic of ChinaTel +86-027-88041911Email 18502753963@163.comPurpose: The effects of phosphatidylinositol glycan anchor biosynthesis, class C (PIGC), in the progression of liver cancer are unknown. In this study, we attempted to clarify the clinical significance and mechanism of PIGC in hepatocellular carcinoma (HCC).Patients and Methods: To explore the expression profiles, DNA methylation, mutation status, clinical relevance, and prognostic value of PIGC in patients with HCC, a series of bioinformatic databases and websites were searched. Moreover, numerous vitro experiments were performed to investigate the mechanism of PIGC in the regulation of cancerous liver cells.Results: Expression of PIGC mRNA and protein was upregulated in cancerous liver specimens compared with normal liver tissues. High expression of PIGC mRNA was related to higher tumor grade, lymphatic metastasis, advanced TNM stage, and TP53 mutation. High expression of PIGC mRNA predicted more unfavorable overall survival (OS) (HR=1.7, P=0.0028) and disease-free survival (DFS) (HR=1.5, P=0.0067) in patients with liver cancer. The mutation rate of PIGC was 10%, and amplification was the most common mutant type. Expression of PIGC mRNA was negatively regulated by its DNA methylation (r=− 0.398, P< 0.0001). Moreover, silencing of PIGC in HepG2 cell line inhibited the proliferation and migration and led to cell cycle arrest at G0/G1 stage by reducing cyclinD1, CDK2, CDK4, and CDK6 expression, while overexpression of PIGC in Hcclm3 cell line revealed the opposite effect.Conclusion: PIGC is related to aggressive clinical features, and overexpression of PIGC signifies worse survival in patients with HCC. PIGC promotes proliferation and migration of cancerous liver cells through the regulation of the cell cycle.Keywords: hepatocellular carcinoma, PIGC, gene mutation, survival, cell cycle

Background Flap endonuclease 1 (FEN1) is a structure-specific nuclease that plays a role in a variety of DNA metabolism processes. FEN1 is important for maintaining genomic stability and regulating cell growth and development. It is associated with the occurrence and development of several diseases, especially cancers. There is a lack of systematic bibliometric analyses focusing on research trends and knowledge structures related to FEN1. Purpose To analyze hotspots, the current state and research frontiers performed for FEN1 over the past 15 years. Methods Publications were retrieved from the Web of Science Core Collection (WoSCC) database, analyzing publication dates ranging from 2005 to 2019. VOSviewer1.6.15 and Citespace5.7 R1 were used to perform a bibliometric analysis in terms of countries, institutions, authors, journals and research areas related to FEN1. A total of 421 publications were included in this analysis. Results Our findings indicated that FEN1 has received more attention and interest from researchers in the past 15 years. Institutes in the United States, specifically the Beckman Research Institute of City of Hope published the most research related to FEN1. Shen BH, Zheng L and Bambara Ra were the most active researchers investigating this endonuclease and most of this research was published in the Journal of Biological Chemistry. The main scientific areas of FEN1 were related to biochemistry, molecular biology, cell biology, genetics and oncology. Research hotspots included biological activities, DNA metabolism mechanisms, protein-protein interactions and gene mutations. Research frontiers included oxidative stress, phosphorylation and tumor progression and treatment. Conclusion This bibliometric study may aid researchers in the understanding of the knowledge base and research frontiers associated with FEN1. In addition, emerging hotspots for research can be used as the subjects of future studies.

Purpose To analyze the rate of potentially avoidable needle biopsies in mammographically suspicious calcifications if supplementary Contrast-Enhanced MRI (CE-MRI) is negative. Methods Using predefined criteria, a systematic review was performed. Studies investigating the use of supplemental CE-MRI in the setting of mammographically suspicious calcifications undergoing stereotactic biopsy and published between 2000 and 2020 were eligible. Two reviewers extracted study characteristics and true positives (TP), false positives, true negatives and false negatives (FN). Specificity, in this setting equaling the number of avoidable biopsies and FN rates were calculated. The maximum pre-test probability at which post-test probabilities of a negative CE-MRI met with BI-RADS benchmarks was determined by a Fagan nomogram. Random-effects models, I2-statistics, Deek’s funnel plot testing and meta-regression were employed. P-values, Highlights • A negative breast MRI can downgrade up to 80.6% of suspicious microcalcifications, potentially avoiding vacuum-assisted breast biopsies. • Up to a pretest probability of 22% , a negative breast MRI result would not exceed the 2% cancer rate required for a BI-RADS 3 category assignment.

Highlights • Canagliflozin constrains cell proliferation in the absence of glucose. • Canagliflozin modulates mitochondrial respiration. • Canagliflozin impairs glutamine-mediated anaplerosis through the citric acid cycle. • Canagliflozin mediates antiproliferative response through inhibition of glutamine metabolism., Notwithstanding that high rates of glucose uptake and glycolysis are common in neoplasia, pharmacological efforts to inhibit glucose utilization for cancer treatment have not been successful. Recent evidence suggests that in addition to classical glucose transporters, sodium-glucose transporters (SGLTs) are expressed by cancers. We therefore investigated the possibility that SGLT inhibitors, which are used in treatment of type 2 diabetes, may exert antineoplastic activity by limiting glucose uptake. We show that the SGLT2 inhibitor canagliflozin inhibits proliferation of breast cancer cells. Surprisingly, the antiproliferative effects of canagliflozin are not affected by glucose availability nor by the level of expression of SGLT2. Canagliflozin reduces oxygen consumption and glutamine metabolism through the citric acid cycle. The antiproliferative effects of canagliflozin are linked to inhibition of glutamine metabolism that fuels respiration, which represents a previously unanticipated mechanism of its potential antineoplastic action.