Publications by authors named "Qi Mei"

129 Publications

Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

Lancet 2021 07 7;398(10297):303-313. Epub 2021 Jun 7.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China.

Background: Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options.

Methods: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18-65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III-IVA, excluding T3-4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12-16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111.

Findings: Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33-42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4-90·6]) than in the standard therapy group (75·7% [69·9-81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32-0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group.

Interpretation: The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma.

Funding: The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S0140-6736(21)01123-5DOI Listing
July 2021

Dispersion Property and Evolution of Second Harmonic Generation Pattern in Type-I and Type-II van der Waals Heterostructures.

ACS Appl Mater Interfaces 2021 Jun 7;13(23):27334-27342. Epub 2021 Jun 7.

Shaanxi Joint Lab of Graphene, International Collaborative Center on Photoelectric Technology and Nano Functional Materials, State Key Laboratory of Photon-Technology in Western China Energy, Institute of Photonics & Photon-Technology, Northwest University, Xi'an 710069, China.

Dispersion property and second harmonic generation (SHG) pattern of novel two-dimensional (2D) van der Waals heterostructures (vdWHs) is of great significance not only for the characterization of material symmetry but also for understanding nonlinear photophysical phenomena. Herein, we demonstrate the SHG response of 2D type-I (MoTe/WSe) and type-II (MoSe/WSe) band alignment of vdWHs. In the dispersion relation of the second-order nonlinear coefficient, the pronounced peaks of the element for both vdWHs are mainly contributed by resonance in the interband transition processes, whereas other elements are derived from the intraband transition processes because of the highly efficient charge transfer from WSe to MoTe in type-I vdWHs and the ultrafast charge separation between WSe and MoSe in type-II vdWHs, respectively. Besides, more nonzero nonlinear coefficient elements can participate in a nonlinear response at the oblique incidence, to which special attention needs paid. The polarization angle α-dependent SHG patterns display a rotational fourfold symmetry, whereas the azimuthal angle ϕ-dependent SHG patterns show sixfold symmetry for both type-I and type-II vdWHs at any wavelength under normal incidence. Under oblique incidence, the α-dependent (ϕ-dependent) SHG patterns will reduce to twofold (threefold) symmetry for both vdWHs. The results highlight the potential to deterministically engineer novel nonlinear optical properties for tunable anisotropic applications of nonlinear optoelectronic devices based on vdWHs.
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http://dx.doi.org/10.1021/acsami.1c07441DOI Listing
June 2021

Health Issues and Immunological Assessment Related to Wuhan's COVID-19 Survivors: A Multicenter Follow-Up Study.

Front Med (Lausanne) 2021 7;8:617689. Epub 2021 May 7.

Institute of Experimental Immunology, University Clinic of Rheinische Friedrich-Wilhelms-University, Bonn, Germany.

Currently, a large number of hospitalized coronavirus infectious disease-2019 (COVID-19) patients have met the clinical discharge criteria and have been discharged. Little is known about the sequelae and herd immunity, two important factors influencing the life quality and safety of COVID-19 survivors. Discharged COVID-19 patients from four medical facilities in Wuhan, China, were followed in order to record and investigate possible post-COVID-19 sequelae and herd immunity. After hospital discharge, patients reported to Fangcang shelter hospitals for an initial 14-day period of mandatory clinical monitoring. After release from these shelter hospitals, patients returned home for self-quarantine. Real-time quantitative PCR (RT-qPCR) was used for severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) detection. Colloidal gold-based immunochromatographic strip assay (ICGSA) was used for anti-SARS-CoV-2 immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody testing. The data for this study are derived from case reports, medical records, and self-reports. A total of 3,677 COVID-19 survivors [median age = 59 years, interquartile range (IQR) = 47-68, range = 10-98; 55.5% female] who were released from four hospitals in Wuhan, China, between January 18 and March 29, 2020 were followed for a median of 144 days (IQR = 135-157). During follow-up, 976 (26.5%) patients had at least one post-COVID-19 sequela. The incidence of post-COVID-19 sequelae among elderly COVID-19 survivors (age ≥60 years) was slightly increased compared to that of young COVID-19 survivors (age <60 years; relative risk = 1.05, 95% CI = 1.02-1.10, = 0.007). During follow-up, a dramatic reduction of anti-SARS-CoV-2 IgG (88.0%, 95% CI = 84.2-90.4) and IgM (93.2%, 95% CI = 88.5-96.4) antibodies was observed. Among these COVID-19 survivors, 1.2% ( = 45) retested positive for SARS-CoV-2 and 1.0% ( = 37) died during follow-up. Of those who died during follow-up, 70.3% were male and all were negative for both IgG and IgM, except for one person who was IgG-positive. Our study documents significant post-COVID-19 sequelae that impair functions of multiple organ systems in COVID-19 survivors, suggesting that the long-term effects of this disease will negatively impact survivors' quality of life, continue to strain health care systems, and result in extended periods of lost productivity. Furthermore, female gender and anti-SARS-CoV-2 immunity may play an essential role in the survival after COVID-19 infection.
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http://dx.doi.org/10.3389/fmed.2021.617689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138053PMC
May 2021

A survival analysis of surgically treated incidental low-grade glioma patients.

Sci Rep 2021 Apr 19;11(1):8522. Epub 2021 Apr 19.

Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.

To evaluate the surgical effect on survival in patients with incidental low-grade glioma (LGG) through comparison between asymptomatic and symptomatic patients. The medical records of surgically treated adult cerebral incidental LGG (iLGG) patients in our department between January 2008 and December 2015 were retrospectively reviewed. The survival of patients was calculated starting from the initial imaging diagnosis. Factors related to progression-free survival (PFS), overall survival (OS) and malignant progression-free survival (MPFS) were statistically analyzed. Seventy-five iLGG patients underwent surgery: 49 in the asymptomatic group, who underwent surgery in the asymptomatic period, and 26 in the symptomatic group, who underwent surgery after the tumor had grown and the patients had developed tumor-related symptoms. Significantly more tumors were initially located adjacent to the functional area in the symptomatic group than in the asymptomatic group (P < 0.05), but there was no significant difference in the total resection rate between the two groups. The incidence of postoperative complications (15.4%) and postoperative epilepsy (23.1%) was higher in the symptomatic group than in the asymptomatic group (4.1% and 10.2%, respectively). Multivariate analysis showed that surgical timing, namely, surgery performed before or after symptom occurrence, had no significant effect on PFS, OS or MPFS, while total resection significantly prolonged PFS, OS and MPFS, and the pathology of oligodendroglioma was positively correlated with PFS and OS (P < 0.05). Surgical timing for iLGGs should facilitate total resection. If total resection can be achieved, even after symptom occurrence, patients can achieve comparable survival benefits to those treated with surgery in the asymptomatic phase.
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http://dx.doi.org/10.1038/s41598-021-88023-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055980PMC
April 2021

Porous SiO -coated ultrasmall selenium particles nanospheres attenuate cerulein-induce acute pancreatitis in mice by downregulating oxidative stress.

J Dig Dis 2021 Jun 17;22(6):363-372. Epub 2021 May 17.

Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.

Objective: To investigate the potential therapeutic role of porous SiO -coated ultrasmall selenium particles nanospheres ([email protected] nanospheres) pretreatment in acute pancreatitis (AP) and to investigate the related mechanism.

Methods: C57BL/6 mice were randomized to the normal control (CON) group, the AP (induced by cerulein injection) (CAE) group, and AP pretreated with [email protected] nanocomposites at 1 and 2 mg/kg (CAE + 1 or 2 mg/kg [email protected] ) groups, respectively. Serum levels of amylase and lipase, inflammatory cytokines (interleukin [IL]-6, IL-1β and tumor necrosis factor [TNF]-α), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine (Cr) were measured, and histopathology was performed to examine the tissue samples of the pancreas, lungs, kidneys and liver. Immunofluorescence assay of reactive oxygen species (ROS), myeloperoxidase (MPO) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling were conducted, and levels of MPO, malondialdehyde, superoxide dismutase and glutathione were evaluated. Finally, Western blot analysis was used to evaluate protein expressions of Nrf2, HO-1, NQO1, TLR4, MyD88 and p-p65 in pancreatic tissue.

Results: [email protected] nanospheres alleviated pathological damage to the pancreas, and reduced pancreatic enzymes and inflammatory cytokines. Injury to other organs such as the liver, lungs and kidneys was also alleviated, as indicated by decreased ALT, AST, BUN, and Cr levels as well as improved histopathology. Moreover, [email protected] nanospheres reduced oxidative stress, and ultimately inhibited TLR4/ MyD88/p-p65 pathway and increased the protein expressions of NQO1, Nrf2, and HO-1.

Conclusion: [email protected] nanospheres may alleviate AP by relieving oxidative stress and targeting the TLR4/Myd88/p-p65 and NQO1/Nrf2/HO-1 pathways.
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http://dx.doi.org/10.1111/1751-2980.12989DOI Listing
June 2021

Irradiation-Induced Activated Microglia Affect Brain Metastatic Colonization of NSCLC Cells via miR-9/ Axis.

Onco Targets Ther 2021 16;14:1911-1922. Epub 2021 Mar 16.

Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China.

Background And Purpose: Brain metastasis is among the leading causes of death in patients with non-small-cell lung cancer (NSCLC). Through yet unknown mechanisms, prophylactic cranial irradiation (PCI) can significantly decrease the incidence of brain metastases. Given that PCI probably exerts indirect anti-tumoral effects by turning cerebral "soil" unfavorable for the colonization of metastatic tumor "seeds". This study aims to reveal how PCI regulates the brain microenvironment conducing to a reduction in brain metastases.

Materials And Methods: Key markers of M1/M2 microglia types and mesenchymal-to-epithelial transition (MET) were analyzed by qRT-PCR and Western Blot in vitro. The target miR-9 was obtained by miRNA array analysis and confirmed by qRT-PCR in microglia. We used miRTarBase and TargetScan to analyze the target genes of miR-9 and confirmed by luciferase activity assay. Anti-metastatic effects of irradiation on the brain were evaluated by intravital imaging using a brain metastatic A549-F3 cell line in a nude mouse model.

Results: Irradiation induced M1 microglia activation, which inhibited the MET process of A549 cell lines. Furthermore, levels of miR-9 secreted by irradiated M1 microglia significantly increased and played a vital role in the inhibition of the A549 MET process by directly targeting , concurrently decreasing cell capacity for localization in the brain, thus reducing brain metastases.

Conclusion: We demonstrated that miR-9 secreted by irradiated M1-type microglia played an important role in modulating A549 cell lines into mesenchymal phenotype and further decreased their localization capabilities in the brain. Our findings signify the modulating effect of irradiation on metastatic soil and the cross-talk between tumour cells and the metastatic microenvironment; importantly, they provide new opportunities for effective anti-metastasis therapies, especially for brain metastasis patients.
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http://dx.doi.org/10.2147/OTT.S301412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981147PMC
March 2021

Survival Factors and Metabolic Pathogenesis in Elderly Patients (≥65) With COVID-19: A Multi-Center Study.

Front Med (Lausanne) 2020 7;7:595503. Epub 2021 Jan 7.

Institute of Experimental Immunology, University Clinic of Rheinische Friedrich-Wilhelms-University, Bonn, Germany.

Elderly patients infected with COVID-19 are reported to be facing a substantially increased risk of mortality. Clinical characteristics, treatment options, and potential survival factors remain under investigation. This study aimed to fill this gap and provide clinically relevant factors associated with survival of elderly patients with COVID-19. In this multi-center study, elderly patients (age ≥65 years old) with laboratory-confirmed COVID-19 from 4 Wuhan hospitals were included. The clinical end point was hospital discharge or deceased with last date of follow-up on Jul. 08, 2020. Clinical, demographic, and laboratory data were collected. Univariate and multivariate analysis were performed to analyze survival and risk factors. A metabolic flux analysis using a large-scale molecular model was applied to investigate the pathogenesis of SARS-CoV-2 with regard to metabolism pathways. A total of 223 elderly patients infected with COVID-19 were included, 91 (40.8%) were discharged and 132 (59.2%) deceased. Acute respiratory distress syndrome (ARDS) developed in 140 (62.8%) patients, 23 (25.3%) of these patients survived. Multivariate analysis showed that potential risk factors for mortality were elevated D-Dimer (odds ratio: 1.13 [95% CI 1.04 - 1.22], = 0.005), high immune-related metabolic index (6.42 [95% CI 2.66-15.48], < 0.001), and increased neutrophil-to-lymphocyte ratio (1.08 [95% 1.03-1.13], < 0.001). Elderly patients receiving interferon atmotherapy showed an increased probability of survival (0.29 [95% CI 0.17-0.51], < 0.001). Based on these factors, an algorithm (AlgSurv) was developed to predict survival for elderly patients. The metabolic flux analysis showed that 12 metabolic pathways including phenylalanine (odds ratio: 28.27 [95% CI 10.56-75.72], < 0.001), fatty acid (15.61 [95% CI 6.66-36.6], < 0.001), and pyruvate (12.86 [95% CI 5.85-28.28], < 0.001) showed a consistently lower flux in the survivors vs. the deceased subgroup. This may reflect a key pathogenic mechanism of COVID-19 infection. Several factors such as interferon atmotherapy and recreased activity of specific metabolic pathways were found to be associated with survival of elderly patients. Based on these findings, a survival algorithm (AlgSurv) was developed to assist the clinical stratification for elderly patients. Dysregulation of the metabolic pathways revealed in this study may aid in the drug and vaccine development against COVID-19.
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http://dx.doi.org/10.3389/fmed.2020.595503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873923PMC
January 2021

Mental health problems among COVID-19 survivors in Wuhan, China.

World Psychiatry 2021 Feb;20(1):139-140

Institute of Experimental Immunology, University Clinic of Rheinische Friedrich-Wilhelms-University, Bonn, Germany.

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http://dx.doi.org/10.1002/wps.20829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801855PMC
February 2021

Development and validation of prognostic model for predicting mortality of COVID-19 patients in Wuhan, China.

Sci Rep 2020 12 31;10(1):22451. Epub 2020 Dec 31.

Institute of Experimental Immunology, University Clinic of Rheinische Friedrich-Wilhelms-University, Bonn, Germany.

Novel coronavirus 2019 (COVID-19) infection is a global public health issue, that has now affected more than 200 countries worldwide and caused a second wave of pandemic. Severe adult respiratory syndrome-CoV-2 (SARS-CoV-2) pneumonia is associated with a high risk of mortality. However, prognostic factors predicting poor clinical outcomes of individual patients with SARS-CoV-2 pneumonia remain under intensive investigation. We conducted a retrospective, multicenter study of patients with SARS-CoV-2 who were admitted to four hospitals in Wuhan, China from December 2019 to February 2020. Mortality at the end of the follow up period was the primary outcome. Factors predicting mortality were also assessed and a prognostic model was developed, calibrated and validated. The study included 492 patients with SARS-CoV-2 who were divided into three cohorts: the training cohort (n = 237), the validation cohort 1 (n = 120), and the validation cohort 2 (n = 135). Multivariate analysis showed that five clinical parameters were predictive of mortality at the end of follow up period, including advanced age [odds ratio (OR), 1.1/years increase (p < 0.001)], increased neutrophil-to-lymphocyte ratio [(NLR) OR, 1.14/increase (p < 0.001)], elevated body temperature on admission [OR, 1.53/°C increase (p = 0.005)], increased aspartate transaminase [OR, 2.47 (p = 0.019)], and decreased total protein [OR, 1.69 (p = 0.018)]. Furthermore, the prognostic model drawn from the training cohort was validated with validation cohorts 1 and 2 with comparable area under curves (AUC) at 0.912, 0.928, and 0.883, respectively. While individual survival probabilities were assessed, the model yielded a Harrell's C index of 0.758 for the training cohort, 0.762 for the validation cohort 1, and 0.711 for the validation cohort 2, which were comparable among each other. A validated prognostic model was developed to assist in determining the clinical prognosis for SARS-CoV-2 pneumonia. Using this established model, individual patients categorized in the high risk group were associated with an increased risk of mortality, whereas patients predicted to be in the low risk group had a higher probability of survival.
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http://dx.doi.org/10.1038/s41598-020-78870-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775455PMC
December 2020

BTF3 promotes stemness and inhibits TypeⅠInterferon signaling pathway in triple-negative breast cancer.

Biochem Biophys Res Commun 2021 01 28;537:22-28. Epub 2020 Dec 28.

The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, Shandong University, School of Basic Medical Sciences, 250012, Jinan, China; Department of Pathology, Shandong University Qilu Hospital, 250012, Jinan, China. Electronic address:

Triple-negative breast cancer (TNBC) is a major challenge in clinical practice due to its aggressiveness and lack of targeted treatment. Cancer stem-like traits contribute to tumorigenesis and immune privilege of TNBC. However, the relationship of stemness and immunosurveillance remains unclear. Here, we demonstrate that BTF3 expression is related with stem-like properties in TNBC cells. BTF3 modulates stemness, migration and proliferation of TNBC in vitro. Bioinformatics analysis revealed that interferon signaling pathways and IRF7, both of which participate in the immune escape of TNBC, are closely related to BTF3 in TNBC cells. Knockdown of BTF3 activates IRF7 expression through increased degradation of BMI1, a protein that can represses IRF7 transcription by directly binding to its promotor region. BTF3 links stem-like traits and the interferon signaling pathway, revealing the potential connection of stemness and immunomodulation in TNBC. Clinically, we suggest that BTF3 is predictive of poor prognosis in patients with TNBC. Together, our findings highlight an important role of BTF3 in regulating the progression of TNBC cells.
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http://dx.doi.org/10.1016/j.bbrc.2020.12.060DOI Listing
January 2021

Pestalotiopsis trachicarpicola, a novel pathogen causes twig blight of Pinus bungeana (Pinaceae: Pinoideae) in China.

Antonie Van Leeuwenhoek 2021 Jan 27;114(1):1-9. Epub 2020 Nov 27.

College of Forestry, Northwest A&F University, Yangling, 712100, Shaanxi Province, China.

Pinus bungeana is one of indigenous trees in China and widely distributed in poor and arid regions for vegetation and industrial woody use. However, since a high-incidence disease threatens the growth of mature P. bungeana tree in the garden and in the plantation every year, the overwintering shoots were infected and died in the next spring with a ratio over 70%, but the cause was beyond understood. A total of 120 fungal isolates were separated from symptomatic twigs by histological isolation methods, including Pestalotiopsis spp., Fusarium spp., Trichothecium spp., Penicillium and some unknown fungal species. Pestalotiopsis spp. was dominant, accounting for 85%. Morphological observation under microcopy showed all Pestalotiopsis species are identical, and six isolations among them were randomly selected for pathogenicity tests. Fulfilling Koch's postulates showed that all six isolates of Pestalotiopsis spp. were pathogens of twig blight, causing the same symptoms as observed in the field, while other non-Pestalotiopsis isolates were avirulent to P. bungeana twigs. Multi-gene (ITS, tub2 and TEF1) analysis and morphological observation revealed that all the six Pestalotiopsis isolates belonged to P. trachicarpicola. To our knowledge, this is the first study reporting P. trachicarpicola as the pathogens responsible for P. bungeana twig blight in China.
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http://dx.doi.org/10.1007/s10482-020-01500-8DOI Listing
January 2021

Clinical challenges in cancer patients with COVID-19: Aging, immunosuppression, and comorbidities.

Aging (Albany NY) 2020 11 24;12(23):24462-24474. Epub 2020 Nov 24.

Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 has developed into a global pandemic. COVID-19 poses a huge threat to health care, and the shortage of medical resources caused by COVID-19 brought serious secondary disasters to elderly cancer patients who are particularly dependent on medical resources. The clinical challenges of cancer management, including aging, immunosuppression, and comorbidities, make cancer patients more vulnerable to COVID-19 with different clinical manifestations, disease severity, and outcomes. The review comprehensively analyzed the characteristics of the cancer patients under the pandemic and concluded that cancer patients were more susceptible to COVID-19, and also concluded that they were more likely to develop poor outcomes and the severe form of the disease. Three basic management strategies have been proposed to protect susceptible elderly cancer patients, find reliable indicators to monitor the course of disease, and implement effective prevention measures.
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http://dx.doi.org/10.18632/aging.104205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762454PMC
November 2020

Does chemotherapy reactivate SARS-CoV-2 in cancer patients recovered from prior COVID-19 infection?

Eur Respir J 2020 10 22;56(4). Epub 2020 Oct 22.

Institute of Medical Information, Biometry, and Epidemiology, Ludwig-Maximilian-University Munich, Munich, Germany.

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http://dx.doi.org/10.1183/13993003.02672-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474148PMC
October 2020

Assessment of patients who tested positive for COVID-19 after recovery.

Lancet Infect Dis 2020 09 6;20(9):1004-1005. Epub 2020 Jul 6.

Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University Munich, Munich, Germany.

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http://dx.doi.org/10.1016/S1473-3099(20)30433-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338012PMC
September 2020

Accumulation of AGO2 Facilitates Tumorigenesis of Human Hepatocellular Carcinoma.

Authors:
Yang Yang Qi Mei

Biomed Res Int 2020 30;2020:1631843. Epub 2020 Apr 30.

Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jie Fang Avenue, Wuhan, China.

AGO2 (Argonaute RISC Catalytic Component 2) plays an important role in small RNA-guided gene silencing processes. It has been implied in tumorigenesis of different types of tumors. In this study, we found that AGO2 expression was remarkably increased in human hepatocellular carcinoma (HCC) tissues when compared with adjacent noncancerous tissues. High expression of AGO2 was associated with poor prognosis in HCC patients. The CRISPR/Cas9-mediated knockout of AGO2 in SMMC-7721 cells inhibited cell proliferation and induced significant G1 phase arrest of cell cycle. Inhibition of cell migration was also observed in SMMC-7721 cells. experiments showed that tumors grew slower in nude mice transplanted with cells than in SMMC-7721 cell-derived xenograft mice. Microarray analysis and western blot analysis revealed that AGO2 depletion decreased expression of Survivin, Vimentin, and Snail. Overexpression of AGO2 in SMMC-7721 and Huh-7 cells could reverse the knockout-induced inhibition effects on either cell behaviors or expression of Survivin, Vimentin, and Snail Therefore, our data demonstrated that AGO2 might facilitate HCC tumorigenesis and metastasis through modulating expression of Survivin, Vimentin, and Snail.
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http://dx.doi.org/10.1155/2020/1631843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210519PMC
February 2021

Podoplanin is a useful prognostic marker and indicates better differentiation in lung squamous cell cancer patients? A systematic review and meta-analysis.

BMC Cancer 2020 May 14;20(1):424. Epub 2020 May 14.

Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, Hubei, China.

Background: The CSC (cancer stem cell) markers often indicate poor prognosis and more cell invasion or migration of cancer patients. Podoplanin was assumed as a candidate CSC marker and predict poor prognosis among squamous cancers. Whereas, the prognostic value of podoplanin among lung squamous cancer (LUSC) patients remains controversial.

Methods: A search of databases including PubMed, Embase and Web of Science was performed. Eligible articles studying the prognostic significance of podoplanin were selected. Odds ratio and HR (hazard ratio) were used to assess the relationships between podoplanin and clinical characteristics, as well as to quantify its prognostic role. The heterogeneity was estimated by I Statistic and P values from sensitivity analysis. Begg's funnel plots were used to estimate possible publication bias.

Results: 8 eligible studies containing 725 I-IV LUSC patients were included. Podoplanin expression showed no significant correlations with TNM stage, vascular invasion, lymphatic invasion, lymph node metastasis, pleural metastasis of tumor and gender of patients. However, podoplanin showed significant associations with better differentiation (pooled OR = 2.64, 95% CI 1.53-4.56, P = 0.0005, fixed effect) and better overall survival (HR = 2.14, 95% CI 1.45-3.15, P = 0.0001, fixed effect) and progression-free survival (HR = 1.73, 95% CI: 1.01-2.98, P = 0.05, fixed effect) of LUSC. Funnel plots illustrated no evidence of publication bias in our results.

Conclusions: Podoplanin could be a useful prognostic marker and indicates better differentiation for LUSC patients, and the value of PDPN expression as a marker for cancer stem cells in LUSC should be critically evaluated in future studies.
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http://dx.doi.org/10.1186/s12885-020-06936-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227255PMC
May 2020

Radiation-Induced DNMT3B Promotes Radioresistance in Nasopharyngeal Carcinoma through Methylation of p53 and p21.

Mol Ther Oncolytics 2020 Jun 21;17:306-319. Epub 2020 Apr 21.

Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, People's Republic of China.

Radiotherapy with or without concurrent chemotherapy is the standard treatment for nasopharyngeal carcinoma (NPC) patients, whose efficacy is limited partly by intrinsic and acquired radioresistance. DNA methyltransferase 3B (DNMT3B) has been reported to participate in tumorigenesis via DNA methylation, but its role in mediating progression and radioresistance of NPC remains unclear. Therefore, we conducted the following studies to explore the relationship between DNMT3B and NPC. Here, we found that DNMT3B was elevated in NPC tissues and predicted the poor prognosis of NPC patients. We demonstrated for the first time that ionizing radiation could induce DNMT3B, which might be one of the reasons for radioresistance. Silencing of DNMT3B inhibited migration and invasion via suppressing epithelial-mesenchymal transition (EMT) in NPC cells. Furthermore, silencing DNMT3B restored and activated p53 and p21 via DNA demethylation, which led to cell cycle arrest and apoptosis, resulting in increased radiosensitivity of NPC both and . DNMT3B functions as a novel oncogene in the radioresistance of NPC through regulating EMT, cell cycle, and apoptosis. Therefore, DNMT3B could be a potential target for NPC treatment.
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http://dx.doi.org/10.1016/j.omto.2020.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200625PMC
June 2020

miR-30a inhibits androgen-independent growth of prostate cancer via targeting MYBL2, FOXD1, and SOX4.

Prostate 2020 06 15;80(9):674-686. Epub 2020 Apr 15.

The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, China.

Background: Castrate-resistant prostate cancer (CRPC) is an aggressive and lethal disease. The pathogenesis of CRPC is not fully understood and novel therapeutic targets need to be identified to improve the patients' prognosis. MicroRNA-30a (miR-30a) has been demonstrated to be a tumor suppressor in many types of solid malignancies. However, its role in androgen-independent (AI) growth of prostate cancer (PCa) received limited attention as yet.

Methods: The clinical association of miR-30a and its potential targets with AI growth was characterized by bioinformatics analyses. Regulation of cell proliferation and colony formation rates by miR-30a were tested using PCa cell models. Xenograft models were used to measure the regulation of prostate tumor growth by miR-30a. The real-time quantitative polymerase chain reaction was used to validate whether miR-30a and its targets regulate cell cycle control genes and androgen receptor (AR)-dependent transcription. Bioinformatics tools, Western blot, and luciferase reporter assays were utilized to identify miR-30a targets.

Results: Bioinformatic analysis showed that low expression of miR-30a is associated with castration resistance of PCa patients and poor outcomes. Transfection of miR-30a mimics inhibited the AI growth of PCa cells in vitro and in vivo. Upregulation of miR-30a in 22RV1 cells altered the expression of cell cycle control genes and AR-mediated transcription, while downregulation of miR-30a in LNCaP cells had the opposite effects to AR-mediated transcription. MYBL2, FOXD1, and SOX4 were identified as miR-30a targets. Downregulation of MYBL2, FOXD1, and SOX4 affected the expression of cell cycle control genes and AR-mediated transcription and suppressed the AI growth of 22RV1 cells.

Conclusions: Our results suggest that miR-30a inhibits AI growth of PCa by targeting MYBL2, FOXD1, and SOX4. They provide novel insights into developing new treatment strategies for CRPC.
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http://dx.doi.org/10.1002/pros.23979DOI Listing
June 2020

The long-term survival of patients with III-IVb stage nasopharyngeal carcinoma treated with IMRT with or without Nimotuzumab: a propensity score-matched analysis.

BMC Cancer 2019 Nov 19;19(1):1122. Epub 2019 Nov 19.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Background: To assess the efficacy of Nimotuzumab in combination with first-line chemoradiotherapy treatment in Chinese patients with primary III-IVb stage nasopharyngeal carcinoma.

Methods: Patients with primary locoregionally advanced nasopharyngeal carcinoma who were treated with intensity-modulated radiotherapy (IMRT) and concurrent cisplatin-based chemotherapy between January 2008 and December 2013 at a single institution were retrospectively reviewed. Group A received at least 6 doses of Nimotuzumab, while Group B did not receive Nimotuzumab. A propensity score matching method was used to match patients from each group in a 1:3 ratio.

Results: In total, 730 eligible patients were propensity matched, with 184 patients in Group A and 546 patients in Group B. Significant differences were not observed in the patient and tumor characteristics between Group A and Group B. At a median follow-up of 74.78 months (range 3.53-117.83 months), locoregional recurrence, distant failure and death were observed in 10.68, 11.10 and 16.03% of all patients, respectively. The estimated 5-year locoregional relapse-free survival, distant metastasis-free survival, progression-free survival and overall survival in the Group A versus Group B were 85.34% versus 89.79% (P = 0.156), 93.09% versus 85.61% (P = 0.012), 79.96% versus 77.99% (P = 0.117) and 88.91% versus 78.30% (P = 0.006), respectively.

Conclusions: This nimotuzumab-containing regimen resulted in improved long-term survival of III-IVb stage NPC patients and warrants further prospective evaluation.
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http://dx.doi.org/10.1186/s12885-019-6156-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862826PMC
November 2019

Prognostic significance of the presence of intraductal carcinoma of the prostate and bone metastasis in needle biopsy for prostate carcinoma patients with Grade Group 5.

Pathol Res Pract 2020 Jan 31;216(1):152693. Epub 2019 Oct 31.

Department of Pharmacy, Shandong Provincial Hospital Affiliated To Shandong University, Jinan, China. Electronic address:

Intraductal carcinoma of the prostate (IDC-P) and bone metastasis have been both identified to associate with unfavorable clinical outcome of the prostate carcinoma (PCa). Our objective is to examine whether IDC-P or bone metastasis at diagnostic biopsies was associated with each other and whether they were linked with overall survival (OS) and cancer specific survival (CSS) of Grade Group 5 patients. We retrospectively selected the prostate biopsy specimens of 120 PCa patients with Grade Group 5 from Qilu Hospital of Shandong University between 2012 and 2016. There were 12 patients with IDC-P only, 52 patients with bone metastasis only and 10 patients with both IDC-P and bone metastasis. Overall, there was a significant correlation between the presences of the IDC-P and bone metastasis (P = 0.003). Kaplan-Meier survival analysis demonstrated that the presence of IDC-P and bone metastasis in diagnostic needle biopsy both conferred unfavorable CSS of Grade Group 5 patients. In addition, the presence of bone metastasis was a poor predictor of OS. Univariate and multivariate analysis revealed that bone metastasis was an independent prognostic factor for OS of Grade Group 5 patients, but IDC-P failed to be significant for either OS or CSS. Collectively, our study suggested that bone metastasis is an important prognostic factor and superior than the presence of the IDC-P for PCa patients with Grade Group 5.
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http://dx.doi.org/10.1016/j.prp.2019.152693DOI Listing
January 2020

SOX4 is activated by C-MYC in prostate cancer.

Med Oncol 2019 Sep 27;36(11):92. Epub 2019 Sep 27.

The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China.

Although MYC proto-oncogene (C-MYC) amplification has been consistently reported to be a potential marker for prostate cancer (PCa) progression and prognosis, the clinicopathological and prognostic significance of C-MYC protein expression remains controversial. Overexpression of SOX4 has been shown to play important roles in multiple cancers including PCa. However, the link between these two critical genetic aberrations is unclear. In the current study, we showed that C-MYC was overexpressed in 16.2% (17/105) of Chinese patients with localized PCa. Overexpression of C-MYC was significantly associated with high Gleason scores (P = 0.012) and high Ki67 labeling index (P = 0.005). C-MYC overexpression was correlated with cancer-related mortality and suggested to be an unfavorable prognostic factor in Chinese PCa patients (P = 0.018). Overexpression of C-MYC is associated with SOX4 overexpression in PCa tissues. Notably, SOX4 is a direct target gene of C-MYC; C-MYC activates SOX4 expression via binding to its promoter. In addition, Co-IP analysis demonstrated a physical interaction between C-MYC and SOX4 protein in PCa cells. Clinically, C-MYC+/SOX4+ characterized poor prognosis in a subset of PCa patients. In total, C-MYC overexpression may contribute to PCa progression by activating SOX4. Our findings highlight an important role of C-MYC/SOX4 in PCa progression in a subset of PCa patients.
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http://dx.doi.org/10.1007/s12032-019-1317-6DOI Listing
September 2019

Enhancer of zeste 2 polycomb repressive complex 2 subunit promotes sorafenib resistance of hepatocellular carcinoma though insulin-like growth factor 1 receptor.

Anticancer Drugs 2019 08;30(7):e0746

Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University QiLu Medical College.

Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) is the core component of polycomb repressive complex 2 and is overexpressed in several types of solid malignancies. It has been reported that EZH2 contributes to sorafenib resistance of hepatocellular carcinoma (HCC). However, its underlying molecular mechanisms remain unknown. In this study, we demonstrated that EZH2 induced sorafenib resistance of HCC cells in vitro. Mechanistically, EZH2 was a potent regulator of insulin-like growth factor 1 receptor (IGF1R) and EZH2-modulated IGF1R expression by directly transcriptionally repressing a set of microRNAs (miRNAs) including miR-101, miR-122, miR-125b, and miR-139. These miRNAs were required for EZH2-mediated sorafenib resistance by promoting IGF1R expression. Surprisingly, IGF1R inhibitors significantly reversed EZH2-induced sorafenib resistance. Collectively, we proposed a novel model for an EZH2 - miRNAs - IGF1R regulatory axis, which might provide insights into how EZH2 contributes to sorafenib resistance in HCC.
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http://dx.doi.org/10.1097/CAD.0000000000000746DOI Listing
August 2019

The SOX4/miR-17-92/RB1 Axis Promotes Prostate Cancer Progression.

Neoplasia 2019 08 22;21(8):765-776. Epub 2019 Jun 22.

The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, Shandong University, School of Basic Medical Sciences, Jinan, 250012, China; Department of Pathology, Shandong University Qilu Hospital, Jinan, 250012, China. Electronic address:

Although androgen-deprivation treatment (ADT) is the main treatment for advanced prostate cancer (PCa), it eventually fails. This failure invariably leads to castration-resistant prostate cancer (CRPC) and the development of the neuroendocrine (NE) phenotype. The molecular basis for PCa progression remains unclear. Previously, we and others have demonstrated that the sex-determining region Y-box 4 (SOX4) gene, a critical developmental transcription factor, is overexpressed and associated with poor prognosis in PCa patients. In this study, we show that SOX4 expression is associated with PCa progression and the development of the NE phenotype in androgen deprivation conditions. High-throughput microRNA profiling and bioinformatics analyses suggest that SOX4 may target the miR-17-92 cluster. SOX4 transcriptionally upregulates miR-17-92 cluster expression in PCa cells. SOX4-induced PCa cell proliferation, migration, and invasion are also mediated by miR-17-92 cluster members. Furthermore, RB1 is a target gene of miR-17-92 cluster. We found that SOX4 downregulates RB1 protein expression by upregulating the miR-17-92 expression. In addition, SOX4-knockdown restrains NE phenotype and PCa cell proliferation. Clinically, the overexpression of miR-17-92 members is shown to be positively correlated with SOX4 expression in PCa patients, whereas RB1 expression is negatively correlated with SOX4 expression in patients with the aggressive PCa phenotype. Collectively, we propose a novel model of a SOX4/miR-17-92/RB1 axis that may exist to promote PCa progression.
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http://dx.doi.org/10.1016/j.neo.2019.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593351PMC
August 2019

BTF3 sustains cancer stem-like phenotype of prostate cancer via stabilization of BMI1.

J Exp Clin Cancer Res 2019 May 28;38(1):227. Epub 2019 May 28.

The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China.

Background: Cancer stem-like traits contribute to prostate cancer (PCa) progression and metastasis. Deciphering the novel molecular mechanisms underlying stem-like traits may provide important insight for developing novel therapeutics.

Methods: Immunohistochemistry and immunofluorescence assays in prostatic tissues; gain- and loss-of-function analyses using ectopic overexpression and shRNAs in PCa cell lines; measurements of tumorigenic and stemness properties, and transcription in vitro and in vivo; transcriptional analysis in public databases.

Results: We identified that overexpression of BTF3 in PCa tissues and BTF3 expression highly correlates to stem-like traits. Cancer stem-like characteristics in PCa including self-renewal and metastatic potential were impaired by BTF3 loss and promoted by BTF3 overexpression. Mechanistically, BTF3 could stabilize BMI1, which is a crucial regulator of prostate stem cell self-renewal. More importantly, our data revealed that BTF3 is highly predictive of poor prognosis and may help in risk stratification of PCa patients.

Conclusions: BTF3 promotes PCa progression though modeling stem-like traits in PCa. BTF3 represents a stratification marker in PCa progression and outcomes.
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http://dx.doi.org/10.1186/s13046-019-1222-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540453PMC
May 2019

Prognostic significance of serum lactate dehydrogenase in patients with breast cancer: a meta-analysis.

Cancer Manag Res 2019 26;11:3611-3619. Epub 2019 Apr 26.

Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China.

Multiple studies have assessed the prognostic significance of serum lactate dehydrogenase (LDH) in patients with breast cancer, but their results remain controversial. This study aimed to evaluate the prognostic value of LDH in breast cancer by meta-analysis. Electronic searches for relevant articles were conducted in PubMed, Embase and Web of Science databases. The HR and their 95% CI were used to assess the prognostic value of serum LDH. Stata Statistical Software 12.0 was applied for statistical analysis. A total of 11 studies involving 6,102 patients were subjected to final analysis. Our results showed that higher serum LDH had significant effect on poor overall survival (HR, 1.88; 95% CI, 1.68-2.11) and progression-free survival (HR, 1.98; 95% CI, 1.46-2.68). Moreover, the results of subgroup analyses were consistent with that of overall outcomes. No significant heterogeneity and publication bias were found in this study. Serum LDH could act as a prognostic factor for patients with breast cancer. Future data are needed to validate and update our results.
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http://dx.doi.org/10.2147/CMAR.S199260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497911PMC
April 2019

CUL4B regulates cancer stem-like traits of prostate cancer cells by targeting BMI1 via miR200b/c.

Prostate 2019 08 21;79(11):1294-1303. Epub 2019 May 21.

The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, China.

Background: Cancer stem-like traits contribute to prostate cancer (PCa) progression and metastasis. Cullin 4B (CUL4B) is a member of the ubiquitin E3 ligase family and overexpressed in several solid malignancies including PCa. CUL4B has been suggested to be an oncogene through epigenetic repression of tumor suppressors. However, the link between CUL4B expression and cancer stem-like phenotype remains unclear.

Methods: Western blot analysis, sphere formation, and colony formation assays were used to examine the effect of CUL4B on cancer stem-like traits in PCa cells. Mechanically, bioinformatic analysis was utilized to evaluate whether BMI1 was a target of CUL4B. Moreover, real-time polymerase chain reaction, chromatin immunoprecipitation, and luciferase reporter assays were performed to identify microRNAs regulated by CUL4B. Finally, Western blot assay was used to validate the regulation of CUL4B, miR200b, and miR200c (miR200b/c) on the stem-like characteristics of PCa cells.

Results: CUL4B promotes PCa pluripotency-associated markers expression, sphere formation, and anchorage-independent growth ability in vitro. Mechanically, CUL4B upregulates BMI1 expression via epigenetically repressing miR200b/c expression. In addition, miR200b/c could partially reverse CUL4B-induced BMI1 and pluripotency-associated marker expression.

Conclusions: Our study revealed that CUL4B regulates cancer stem-like traits of prostate cancer cells by targeting BMI1 via miR200b/c, which might give novel insight into how CUL4B promotes PCa progression through regulating cancer stem-like traits.
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http://dx.doi.org/10.1002/pros.23835DOI Listing
August 2019

SALL4 induces radioresistance in nasopharyngeal carcinoma via the ATM/Chk2/p53 pathway.

Cancer Med 2019 04 24;8(4):1779-1792. Epub 2019 Mar 24.

Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.

Radiotherapy is the mainstay and primary curative treatment modality in nasopharyngeal carcinoma (NPC), whose efficacy is limited by the development of intrinsic and acquired radioresistance. Thus, deciphering new molecular targets and pathways is essential for enhancing the radiosensitivity of NPC. SALL4 is a vital factor in the development and prognosis of various cancers, but its role in radioresistance remains elusive. This study aimed to explore the association of SALL4 expression with radioresistance of NPC. It was revealed that SALL4 expression was closely correlated with advanced T classification of NPC patients. Inhibition of SALL4 reduced proliferation and sensitized cells to radiation both in vitro and in vivo. Furthermore, SALL4 silencing increased radiation-induced DNA damage, apoptosis, and G2/M arrest in CNE2 and CNE2R cells. Moreover, knockdown of SALL4 impaired the expression of p-ATM, p-Chk2, p-p53, and anti-apoptosis protein Bcl-2, while pro-apoptosis protein was upregulated. These findings indicate that SALL4 could induce radioresistance via ATM/Chk2/p53 pathway and its downstream proteins related to apoptosis. Targeting SALL4 might be a promising approach for the development of novel radiosensitizing therapeutic agents for radioresistant NPC patients.
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http://dx.doi.org/10.1002/cam4.2056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488116PMC
April 2019

CUL4B promotes prostate cancer progression by forming positive feedback loop with SOX4.

Oncogenesis 2019 Mar 14;8(3):23. Epub 2019 Mar 14.

The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, Shandong University, School of Basic Medical Sciences, 250012, Jinan, China.

How to distinguish indolent from aggressive disease remains a great challenge in prostate cancer (PCa) management. Cullin 4B (CUL4B) is a scaffold protein and exhibits oncogenic activity in a variety of human malignancies. In this study, we utilized PCa tissue specimens, cell lines and xenograft models to determine whether CUL4B contributes to PCa progression and metastasis. Here, we show that CUL4B expression highly correlates with the aggressiveness of PCa. CUL4B expression promotes proliferation, epithelial-mesenchymal transition, and metastatic potential of PCa cells, whereas CUL4B knockdown inhibits. Mechanically, CUL4B positively regulates SOX4, a key regulator in PCa, through epigenetic silencing of miR-204. In turn, SOX4 upregulates CUL4B expression through transcriptional activation, thereby fulfilling a positive feedback loop. Clinically, CUL4B+/SOX4+ defines a subset of PCa patients with poor prognosis. Bioinformatics analysis further reveals that Wnt/ß-catenin activation signature is enriched in CUL4B+/SOX4+ patient subgroup. Intriguingly, Wnt inhibitors significantly attenuates oncogenic capacities of CUL4B in vitro and in vivo. Together, our study identifies CUL4B as a key modulator of aggressive PCa by a positive feedback loop that interacts with SOX4. This regulatory circuit may have a crucial role in PCa progression.
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http://dx.doi.org/10.1038/s41389-019-0131-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418142PMC
March 2019

Differential response to neoadjuvant hormonal therapy in prostate cancer: Predictive morphological parameters and molecular markers.

Prostate 2019 05 2;79(7):709-719. Epub 2019 Mar 2.

The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, Shandong University, School of Basic Medical Sciences, Jinan, China.

Objectives: The predictive value of the histological parameters and molecular markers for neoadjuvant hormonal therapy (NHT) in prostate cancer (PCa) has not been well established. The aim of this study is to determine pathological variables that can predict differences in response to NHT in PCa.

Methods: A total of 85 locally high risk PCa patients with matched preoperative needle biopsies and radical prostatectomy (RP) specimens were included. All patients were treated with NHT for at least 3 months. We quantified the response to NHT using a new proposed pathological grading system. The system classified tumors into five groups (grades 0-4) according to the severity of histological response. We then categorized the PCa patients into drug-sensitive (DS) group (Grades 2-4) and drug-resistant (DR) group (Grades 0-1). Two pathologists assessed each pretreated tumors for presence or absence of nine morphological features. The expression of androgen receptor (AR), ERG, and PTEN were evaluated by immunohistochemistry (IHC) as well. Statistical analysis was performed to identify significant associations between differentially histological response to NHT and morphological features as well as molecular aberrations. We evaluated different prediction models using receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) analysis.

Results: 73% (n = 62/85) of tumors in our cohort belonged to DS group, whereas 27% (n = 23/85) of tumors were DR. Univariate logistic analysis suggested four pathological variables, cribriform growth pattern, macronucleoli, ductal adenocarcinoma differentiation, and PTEN loss in needle biopsies were significantly associated with DR effect, all with P-value < 0.05. Multivariate logistic regression analysis revealed that the three parameters as significant predictive factors for predicting DR effect. These were macronucleoli (RR = 4.008, P = 0.002), ductal adenocarcinoma differentiation (RR = 11.659, P = 0.009) and PTEN loss expression (RR = 7.275, P = 0.015). The AUC of three integrated indicators model was 0.781.

Conclusions: Our study suggested that the presence of tumor cribriform growth pattern, macronucleoli, ductal adenocarcinoma differentiation, and PTEN loss in needle biopsies are of value in predicting tumor response to NHT regimen. Multivariate logistic regression analysis revealed the performance of combined pathological indicators in predicting DR response was better than that of model based on individual factor alone.
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http://dx.doi.org/10.1002/pros.23777DOI Listing
May 2019

Genistein inhibits human papillary thyroid cancer cell detachment, invasion and metastasis.

J Cancer 2019 1;10(3):737-748. Epub 2019 Jan 1.

Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.

Papillary thyroid carcinoma (PTC) is the most commonly diagnosed endocrine cancer, and those with mutation have high recurrence rate and less favorable clinical behavior. Genistein having anti-carcinoma effects in various types of carcinomas as an estrogen analog, but the mechanism of Genistein in the progression of PTC remains unknown. Genistein significantly inhibits the proliferation and the invasion (P < 0.01), and the apoptosis (P < 0.001) of all tumor cell lines, which was probably due to the inducing of the arrest in G2/M phase of the cell cycle (P < 0.001). The anti-proliferation and apoptosis inducing effects are more obvious in BCPAP, IHH4 cell lines harboring mutation. Genistein significantly decreased the invasion of PTC cell lines and partially reverses epithelial mesenchymal transition in PTC cell lines. Functional study indicated that small interfering RNA (siRNA) knockdown of β-catenin significantly reverses the effect of genistein on EMT at protein levels. In conclusion, for the first time, our study suggested that genistein has anticarcinoma effect for PTC patients in the range of 2.5 and 80 μg/ml in thyroid carcinoma cells, which was probably through cytoplasmic translocation of β-catenin. Further study will be needed to determine whether genistein could be used in clinical trial of high-risk PTC.
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http://dx.doi.org/10.7150/jca.28111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360420PMC
January 2019
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