Publications by authors named "Dongsheng Huang"

160 Publications

Effect of the Hypoxia Inducible Factor on Sorafenib Resistance of Hepatocellular Carcinoma.

Front Oncol 2021 7;11:641522. Epub 2021 Jul 7.

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China.

Sorafenib a multi-target tyrosine kinase inhibitor, is the first-line drug for treating advanced hepatocellular carcinoma (HCC). Mechanistically, it suppresses tumor angiogenesis, cell proliferation and promotes apoptosis. Although sorafenib effectively prolongs median survival rates of patients with advanced HCC, its efficacy is limited by drug resistance in some patients. In HCC, this resistance is attributed to multiple complex mechanisms. Previous clinical data has shown that HIFs expression is a predictor of poor prognosis, with further evidence demonstrating that a combination of sorafenib and HIFs-targeted therapy or HIFs inhibitors can overcome HCC sorafenib resistance. Here, we describe the molecular mechanism underlying sorafenib resistance in HCC patients, and highlight the impact of hypoxia microenvironment on sorafenib resistance.
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http://dx.doi.org/10.3389/fonc.2021.641522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292964PMC
July 2021

Clinical features and imaging manifestations of retinoblastoma with hepatic metastasis.

Pediatr Blood Cancer 2021 Jul 22:e28959. Epub 2021 Jul 22.

Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

Clinical data of five patients with hepatic metastases of retinoblastoma were analyzed retrospectively (two had bilateral tumors three had unilateral intraocular tumors). On computed tomography, multiple and single low-density foci were observed. Four patients had tumor remission, and one showed no response after chemotherapy. Three patients who underwent enucleation were at high risk for extensive choroidal invasion. Central nervous system and bone metastases occurred in all five patients. Neuron-specific enolase and lactate dehydrogenase levels were significantly elevated in all patients. Two patients died (not from hepatic metastasis). Three patients (one with tumor progression and two with shorter courses) are continuing treatment.
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http://dx.doi.org/10.1002/pbc.28959DOI Listing
July 2021

Erratum: Long noncoding RNA LINC01123 promotes the proliferation and invasion of hepatocellular carcinoma cells by modulating the miR-34a-5p/TUFT1 axis: Erratum.

Int J Biol Sci 2021 8;17(9):2336-2337. Epub 2021 Jun 8.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.

[This corrects the article DOI: 10.7150/ijbs.45457.].
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http://dx.doi.org/10.7150/ijbs.61069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241735PMC
June 2021

Case Analysis of 14 Children with Malignant Rhabdoid Tumor of the Kidney.

Cancer Manag Res 2021 21;13:4865-4872. Epub 2021 Jun 21.

Department of Pediatrics, Beijing Tongren Hospital of China Capital Medical University, Beijing, 100176, People's Republic of China.

Objective: This study aims to summarize the clinical features and prognoses of the malignant rhabdoid tumor of the kidney (MRTK) in children. It further aims to analyze the high-risk factors affecting MRTK prognosis.

Methods: Clinical data from 14 children with MRTK treated in Paediatrics of Beijing Tongren Hospital from January 2010 to December 2019, along with the high-risk factors affecting prognosis, were retrospectively analyzed.

Results: There were 14 children with MRTK included in the study, with a median onset age of 13 (3-46) months. Thirteen patients had distant metastases, the most common site for metastases being inside the lung. A comprehensive treatment protocol combined with chemotherapy was mainly applied during the surgery. A surgical resection of primary tumors was performed on 13 (13/14) patients, and all 14 children received chemotherapy with ifosfamide + carboplatin + etoposide, ifosfamide + etoposide, and vincristine + pirarubicin + cyclophosphamide regimens, alternately. Three patients received radiotherapy and two received oral targeted drugs after partial response. The median follow-up was after 16.5 months (3-53 months) and the four-year overall survival (OS) was 41.8%. In children aged ≤24 months and children aged >24 months, the two-year OS was 67.2% and 100% (χ = 108.998, P<0.05), respectively. In children with Ki 67 > 70% and children with Ki 67 < 70%, the two-year OS was 52.6% and 86.9% (χ = 8.544, P = 0.003), respectively. In children with distant metastases and children without distant metastasis, the two-year OS was 70% and 100% (χ = 14.239, P<0.05), respectively.

Conclusion: The most common MRTK distant metastasis site is the lung. Risk factors for poor MRTK prognoses include an age of <24 months, Ki 67 > 70%, and distant metastases.
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http://dx.doi.org/10.2147/CMAR.S309274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232862PMC
June 2021

HIF-1α-activated TM4SF1-AS1 promotes the proliferation, migration, and invasion of hepatocellular carcinoma cells by enhancing TM4SF1 expression.

Biochem Biophys Res Commun 2021 Aug 10;566:80-86. Epub 2021 Jun 10.

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China. Electronic address:

Long non-coding RNAs (lncRNAs) are essential drivers or suppressors in human hepatocellular carcinoma (HCC) by participating in controlling transcription, translation, mRNA stability, and protein degradation protein-protein interaction. TM4SF1-AS1 is recently identified as a tumor-promoting factor in lung cancer. Nevertheless, its function in HCC and related molecular mechanisms remain unknown. Here, our data indicated that either hypoxia or hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (DMOG) induced the upregulation of TM4SF1-AS1 in HCC cells. HIF-1α knockdown rather than HIF-2α silencing remarkably abrogated hypoxia-upregulated TM4SF1-AS1 expression. Furthermore, we confirmed the elevated expression of TM4SF1-AS1 in HCC tissue samples and cell lines. The silencing of TM4SF1-AS1 prominently inhibited the proliferative, migratory, and invasive abilities of HCC cells. TM4SF1-AS1 depletion significantly blocked hypoxia-enhanced Hep3B cell proliferation and mobility. Interfering TM4SF1-AS1 remarkably reduced TM4SF1 mRNA and protein levels in HCC cells. But TM4SF1-AS1 knockdown did not impact the stability of TM4SF1 mRNA. Hypoxia enhanced the expression of TM4SF1 mRNA, which was subsequently decreased by TM4SF1-AS1 knockdown in HCC cells. We confirmed the positive correlation between TM4SF1 mRNA and TM4SF1-AS1 expression in HCC specimens. Finally, TM4SF1 prominently reversed the inhibitory role of TM4SF1-AS1 depletion in Hep3B cells. In summary, hypoxia-responsive TM4SF1-AS1 was overexpressed in human HCC and contributed to the malignant behaviors of tumor cells by enhancing TM4SF1-AS1 expression.
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http://dx.doi.org/10.1016/j.bbrc.2021.06.011DOI Listing
August 2021

Erratum: Long noncoding RNA LINC01123 promotes the proliferation and invasion of hepatocellular carcinoma cells by modulating the miR-34a-5p/TUFT1 axis: Erratum.

Int J Biol Sci 2021 20;17(7):1742-1743. Epub 2021 Apr 20.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.

[This corrects the article DOI: 10.7150/ijbs.45457.].
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http://dx.doi.org/10.7150/ijbs.61130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120462PMC
April 2021

Clinical Characteristics and Prognosis Analysis of Infantile Hepatoblastoma-A 15-Year Retrospective Single-Center Study.

Cancer Manag Res 2021 13;13:3201-3208. Epub 2021 Apr 13.

Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, 100176, People's Republic of China.

Objective: The present study aimed to summarize the clinical data of hepatoblastoma (HB) in infants under one year of age and to analyze the factors that affected the prognoses.

Methods: The clinical data of 132 pediatric patients with a pathologically confirmed HB, aged less than one year and who had visited the Pediatric Single Center of Beijing Tongren Hospital from May 2005 to May 2019, were retrospectively analyzed to summarize the clinical outcomes and prognoses.

Results: The male/female ratio was 1.27 and the median age was 8.40 months. The onset of HB was usually characterized by abdominal bulging (75.0%). The median level of AFP at the first visit was 154.7µg/mL, and the average platelet count was (405±166)×10/L. The epithelial type (57.6%) was the predominant pathological type, and stage III (54.5%) was the main PRETEXT staging. Distant metastases occurred in 45 cases, with pulmonary metastases (86.7%) being the most common site. At the time of visit, 24 cases (18.2%) had either portal vein, hepatic vein, or vena cava infiltration. Five cases (3.8%) had a hemorrhage of the ruptured tumor, and 26 cases (19.7%) had multiple intrahepatic foci. At the follow-up in May 2020, the overall survival (OS) rate at one, three, and five years of age was 94.3%, 88.8%, and 80.1%, respectively, and the event-free survival rate was 91.8%, 86.9%, and 77.5%, respectively, by the Kaplan-Meier survival analysis. According to the Log rank test, pediatric patients with an AFP <100ng/mL, a PRETEXT stage IV, presence of distant metastases and multiple foci of the primary tumor at the initial diagnosis had poorer prognoses (P<0.05).

Conclusion: The prognosis of HB in infancy is relatively good, but is still vulnerable to multiple factors, such as tumor features leading to different AFP levels, PRETEXT stage, presence of distant metastases, and multiple intrahepatic foci.
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http://dx.doi.org/10.2147/CMAR.S302078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053710PMC
April 2021

Update in clinical management for gallbladder neuroendocrine carcinoma.

Medicine (Baltimore) 2021 Apr;100(14):e25449

Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou.

Background: Gallbladder neuroendocrine carcinoma (GB-NEC) is rare and there are few reports at present. We sought to review the current knowledge of GB-NEC and provide recommendations for clinical management.

Methods: A systemic literature research was conducted in the websites of Pubmed, Medline, Web of Science, CNKI, Wanfang Data using the keywords including gallbladder combined with neuroendocrine carcinoma or neuroendocrine tumor or neuroendocrine neoplasm. Two reviewers independently screened the articles by reading the title, abstract and full-text.

Results: In computed tomography (CT) and magnetic resonance imaging (MRI) examination, a well-defined margin, gallbladder replacing type with larger hepatic and lymphatic metastases could be helpful for differential diagnosis of GB-NEC and gallbladder adenocarcinoma (GB-ADC). Older age, unmarried status, large tumor size (>5 cm), positive margins, and distant Surveillance, Epidemiology and End result (SEER) stage are independently associated with poor survival. Surgical resection remains as the preferred and primary treatment. The potential survival benefit of lymphadenectomy for patients remains controversial. Platinum-based postoperative adjuvant chemotherapy may improve the survival. The efficacy of other treatments including immunotherapy, targeted therapy and somatostatin analogue needs further investigation.

Conclusion: Typical imaging features could be helpful for preoperative diagnosis. Age, margin status, tumor size, marital status, histopathologic subtype and SEER stage may be independent predictors for the survival. Remarkable advances regarding the treatment for GB-NEC have been achieved in recent years. Further studies are needed to investigate the survival benefit of lymphadenectomy for patients with GB-NEC.
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http://dx.doi.org/10.1097/MD.0000000000025449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036038PMC
April 2021

"Without the need for a second visit" initiative improves patient satisfaction with updated services of outpatient clinics in China.

BMC Health Serv Res 2021 Mar 23;21(1):267. Epub 2021 Mar 23.

Department of Medical Administration, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, No.158 Shangtang Road, Zhejiang, Hangzhou, China.

Background: To implement the "without the need for a second visit" (WNASV) initiative in our hospital by optimizing the outpatient clinic services via an upgraded information system, in order to increase the quality of outpatient medical services and improve patients' satisfaction.

Methods: An Internet-based care delivery approach was developed and applied to improve the delivery of health care services, simplify the treatment process, and reduce patient waiting time. The patient waiting time and consultation time in the outpatient clinics of our hospital during the peak service intervals and the proportions of various payment methods for outpatient services during the period from May 2017 to September 2019 were retrospectively analyzed. Also, the patients' satisfaction with the outpatient process was surveyed.

Results: The waiting time for consultation was shortened from 32.25 min to 28.42 min; the consultation time was shortened from 6.52 min to 3.15 min; and the waiting time for payment decreased from 7.40 min to 4.31 min. The proportion of payment via a counter was reduced from 86.80 to 21.79%, the proportion of self-service payment increased from 9.99 to 16.05%, and the proportion of payment during a consultation increased from 3.21 to 61.91%. The scores of the patients' satisfaction with the outpatient services increased from an average of 89.10 points in 2017 to an average of 90.26 points in 2019.

Conclusion: The continuous improvement of the service process markedly increases the efficiency of the outpatient services, and effectively improves patient's satisfaction with the outpatient process, this initiative thus deserves further application.
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http://dx.doi.org/10.1186/s12913-021-06260-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986498PMC
March 2021

Melatonin promotes bone marrow mesenchymal stem cell osteogenic differentiation and prevents osteoporosis development through modulating circ_0003865 that sponges miR-3653-3p.

Stem Cell Res Ther 2021 02 25;12(1):150. Epub 2021 Feb 25.

Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, #107 West Yan Jiang Road, Guangzhou, Guangdong, 510120, China.

Background: Little is known about the implications of circRNAs in the effects of melatonin (MEL) on bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation and osteoporosis (OP) progression. The aim of our study was to investigate circRNAs in MEL-regulated BMSC differentiation and OP progression.

Methods: BMSC osteogenic differentiation was measured by qRT-PCR, western blot (WB), Alizarin Red, and alkaline phosphatase (ALP) staining. Differential circRNA and mRNA profiles of BMSCs treated by MEL were characterized by deep sequencing, followed by validation using RT-PCR, Sanger sequencing, and qRT-PCR. Silencing and overexpression of circ_0003865 were conducted for functional investigations. The sponged microRNAs and targeted mRNAs were predicted by bioinformatics and validated by qRT-PCR, RNA pull-down, and dual-luciferase reporter assay. The function of miR-3653-3p and circ_0003865/miR-3653-3p/growth arrest-specific gene 1 (GAS1) cascade was validated for the osteogenic differentiation of BMSCs by CCK-8, qRT-PCR, WB, Alizarin Red, and ALP staining. The effects of circ_0003865 on OP development were tested in murine OP model.

Results: MEL promoted osteogenic differentiation of BMSCs. RNA sequencing revealed significant alterations in circRNA and mRNA profiles associated with multiple biological processes and signaling pathways. Circ_0003865 expression in BMSCs was significantly decreased by MEL treatment. Silencing of circ_0003865 had no effect on proliferation while promoted osteogenic differentiation of BMSCs. Overexpression of circ_0003865 abrogated the promotion of BMSC osteogenic differentiation induced by MEL, but proliferation of BMSCs induced by MEL had no change whether circ_0003865 was overexpression or not. Furthermore, circ_0003865 sponged miR-3653-3p to promote GAS1 expression in BMSCs. BMSC osteogenic differentiation was enhanced by miR-3653-3p overexpression while BMSC proliferation was not affected. By contrast, miR-3653-3p silencing mitigated the promoted BMSC osteogenic differentiation caused by circ_0003865 silencing, but had no effect on proliferation. Finally, circ_0003865 silencing repressed OP development in mouse model.

Conclusion: MEL promotes BMSC osteogenic differentiation and inhibits OP pathogenesis by suppressing the expression of circ_0003865, which regulates GAS1 gene expression via sponging miR-3653-3p.
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http://dx.doi.org/10.1186/s13287-021-02224-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908669PMC
February 2021

Case report: Delayed retinoblastoma relapse in a lymph node after 9 years of complete remission.

Curr Probl Cancer 2021 Jan 8:100703. Epub 2021 Jan 8.

Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

Retinoblastoma (RB) is the most common primary intraocular malignancy of childhood. Recurrence of RB often occurs within 6 months to 1 year after the end of treatment. Orbital tissue is the most common site of recurrence in children who have undergone enucleation; other sites include the central nervous system, bone, bone marrow, lymph nodes, and other organs. Here, we describe an adolescent girl who presented with RB recurrence and metastasis in a distant lymph node after 9 years of complete remission. The tumor was an incidental finding during a routine examination and was misdiagnosed as lymphadenitis. After histopathologic examination of an aspiration biopsy sample, the correct diagnosis of recurrent metastatic RB was made. Systemic chemotherapy and surgical excision were provided; the patient remained tumor-free during the 6-month follow-up period. RB often relapses within 1 year after treatment; orbital tissue is the most common site of recurrence. However, our patient's case was unique in terms of delayed relapse and the presence of a single metastatic site; these findings may provide new insights into the behavior of RB. Furthermore, this case report indicates the need for lifelong follow-up of children with RB. Oncologists should be vigilant when treating patients with a history of RB, because complete remission does not mean complete safety; long-term recurrence and metastasis may occur. Lifelong follow-up is necessary for children with RB. Complete remission might be achieved after active and standardized treatment.
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http://dx.doi.org/10.1016/j.currproblcancer.2020.100703DOI Listing
January 2021

Adrenocortical Carcinoma in Eight Children: A Report and Literature Review.

Cancer Manag Res 2021 11;13:1307-1314. Epub 2021 Feb 11.

Department of Pediatrics, Beijing Tongren Hospital of China Capital Medical University, Beijing, 100176, People's Republic of China.

Objective: This study aimed to summarize the clinical characteristics, comprehensive treatment, and prognosis of adrenocortical carcinoma (ACC) in children.

Methods: The clinical data of eight children with definite diagnoses of ACC were retrospectively analyzed, and statistical methods were used to analyze the clinical characteristics, comprehensive treatment mode, and prognosis of these patients.

Results: (1) Clinical characteristics: two were males and six were females with the median age of onset was six-years old were involved. Four patients had a rash and precocious puberty as the symptoms of onset. European Network for the Study of Adrenal Tumors (ENSAT) staging: stage II, two patients; stage IV, six patients. (2) Comprehensive treatment: all eight patients underwent surgical treatment and received six cycles of chemotherapy: the regimen was "etoposide + pirarubicin + cisplatin + mitotane." (3) Prognosis analysis: among these eight patients, two patients died, two patients achieved complete remission, the disease was stable in four patients, and the overall five-year survival rate was 75%. Prognosis analyzed according to ENSAT staging (stage II versus stage IV) revealed that two-year survival rates of the two groups were 100% versus 65%, respectively, without statistical significant ( = 1.066, P = 0.302). Prognosis analyzed according to Weiss score (Weiss score was <6, five patients;≥6, three patients) revealed That survival time of the two groups was 50±9.52 months versus 6±1.70 months, the two-year survival rates of the two groups were 100% versus 35%, and the difference in survival rates between these two groups was statistically significant (χ = 4.091, P = 0.043).

Conclusion: The Weiss score is an important prognostic factor for ACC. The chemotherapy regimen "mitotane + etoposide + adriamycin + cisplatin" is recommended.
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http://dx.doi.org/10.2147/CMAR.S289191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884932PMC
February 2021

Biological features and clinical outcome in infant neuroblastoma: a multicenter experience in Beijing.

Eur J Pediatr 2021 Jul 13;180(7):2055-2063. Epub 2021 Feb 13.

Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Ministry of Education, Key Laboratory of Major Diseases in Children, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, with 37% of patients diagnosed during infancy. This study is aimed at evaluating the survival outcome in infants diagnosed with neuroblastoma. This was a retrospective cohort study including patients under the age of 12 months with neuroblastoma from four tertiary referral centers in Beijing, China (Beijing Children's Hospital, Beijing Tongren Hospital, Peking University First Hospital, and Capital Institute of Pediatrics). Two hundred and forty-seven infants with neuroblastoma were included (male = 132 and female = 115). 91.1% (n = 225) patients were classified as having low-risk or intermediate-risk disease and 8.9% (n = 22) as having high-risk disease. The most common metastatic site is distant lymph node (n=89, 36.0%), followed by liver (n=57, 23.1%), bone (n=42, 17.0%), bone marrow (n=37, 15.0%), soft tissue (n=25, 10%), and central nervous system (n=4, 1.6%). MYCN amplification was present in 9.9% of tumor samples, chromosome 1p or 11q aberration in 14%. Treatment involved surgery alone in 9.7% of patients (n=24, all with low-risk disease), surgery followed by adjuvant chemotherapy in 50.2% (n=124), neoadjuvant chemotherapy followed by surgery in 40.1% (n=97), and chemotherapy alone in 0.8% (n=2). 4.9% (n=12) patients died, and the major cause of death is disease progression. Three-year event-free and overall survival were 91.6%±2.1% and 97.4%±1.1%, respectively, in patients with low- or intermediate-risk disease, and 58.7%±11.5% and 63.6%±11.2%, respectively, in those with high-risk disease.Conclusions: Infants with neuroblastoma achieve a reasonable clinical outcome when treated with surgery with or without chemotherapy using a risk-stratified approach in China. Such information will facilitate counseling, therapeutic decision-making, and development of adapted standard-of-care guidelines for future patients in the country. What is Known: • NB is a disease of infancy; 37% of patients are diagnosed as infants. • Most children younger than 12 months of age have a good prognosis even in the presence of metastatic disease. What is New: • Infants with neuroblastoma achieve reasonable clinical outcome when treated with surgery with or without chemotherapy using a risk-stratified approach in China. • CNS metastasis in infants with neuroblastoma is very rare at diagnosis and had a worse prognosis than those without metastasis.
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http://dx.doi.org/10.1007/s00431-021-03989-1DOI Listing
July 2021

Hypoxia-Inducible Ubiquitin Specific Peptidase 13 Contributes to Tumor Growth and Metastasis via Enhancing the Toll-Like Receptor 4/Myeloid Differentiation Primary Response Gene 88/Nuclear Factor-κB Pathway in Hepatocellular Carcinoma.

Front Cell Dev Biol 2020 19;8:587389. Epub 2020 Oct 19.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. The activation of the toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB (TLR4/MyD88/NF-κB) pathway contributes to the development and progression of HCC. The ubiquitin-proteasome system regulates TLR4 expression. However, whether ubiquitin specific peptidase 13 (USP13) stabilizes TLR4 and facilitates HCC progression remains unclear. Here, quantitative real-time PCR (qRT-PCR) and immunohistochemistry analysis revealed that USP13 expression in HCC tissues was higher than in non-tumor liver tissues. Moreover, the elevated expression of USP13 was detected in HCC cells (SK-HEP-1, HepG2, Huh7, and Hep3B) compared to LO2 cells. Interestingly, the positive staining of USP13 was closely correlated with tumor size ≥ 5 cm and advanced tumor stage and conferred to significantly lower survival of HCC patients. Next, USP13 knockdown prominently reduced the proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion of Hep3B and Huh7 cells, while USP13 overexpression enhanced these biological behaviors of HepG2 and LO2 cells. The silencing of USP13 significantly restrained the growth and lung metastasis of HCC cells . Mechanistically, the USP13 depletion markedly inhibited the TLR4/MyD88/NF-κB pathway in HCC cells. USP13 interacted with TLR4 and inhibited the ubiquitin-mediated degradation of TLR4. Significantly, TLR4 re-expression remarkably reversed the effects of USP13 knockdown on HCC cells. USP13 expression was markedly upregulated in HCC cells under hypoxia conditions. Notably, USP13 knockdown repressed hypoxia-induced activation of the TLR4/MyD88/NF-κB pathway in HCC cells. In conclusion, our study uncovered that hypoxia-induced USP13 facilitated HCC progression via enhancing TLR4 deubiquitination and subsequently activating the TLR4/MyD88/NF-κB pathway.
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http://dx.doi.org/10.3389/fcell.2020.587389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604352PMC
October 2020

Diagnosis and treatment of infantile malignant solid tumors in beijing, China: A multicenter 10-year retrospective study.

Pediatr Investig 2020 Sep 27;4(3):178-185. Epub 2020 Sep 27.

Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing China.

Importance: Cancer is the main cause of death by disease in children. Children experience the highest incidence of cancer in the first year of life. However, there is no comprehensive registration system for children with tumors in China.

Objective: To summarize the diagnosis and treatment of infant cancer and analyze the status of standardized diagnosis and management among several treatment centers in Beijing, China, thereby providing evidence to guide further clinical research.

Methods: From January 1, 2010 to December 31, 2019, patients with newly diagnosed infantile malignant solid tumors were admitted to six large tertiary pediatric solid tumor diagnosis and treatment centers in Beijing. The epidemiology, clinical features, and therapeutic effects of tumors in these patients were analyzed retrospectively. All patients were followed up until March 31, 2020.

Results: In total, 938 patients were enrolled in this study. There were 530 boys (56.5%) and 408 girls (43.5%); the median age was 6.0 months (range, 0-12.0 months). The three most common tumors were retinoblastoma in 366 patients (39.0%), neuroblastoma in 266 patients (28.4%), hepatoblastoma in 133 patients (14.2%), and central nervous system tumors in 52 patients (5.5%). The estimated 5-year overall survival rate was 81.3% ± 1.8%, and the 5-year event-free survival rate was 71.8% ± 2.9%. The 5-year overall survival rates of non-rhabdomyosarcoma soft tissue sarcoma, neuroblastoma, and retinoblastoma were 100%, 88% ± 2.2%, and 86.9% ±2.1%, respectively. The 5-year event-free survival rates were 81.1% ± 2.7% for neuroblastoma, 81.6% ± 9.8% for non-rhabdomyosarcoma soft tissue sarcoma, and 72.7% ± 14.1% for extracranial malignant germ cell tumors.

Interpretation: The three most common infantile malignant solid tumors were retinoblastoma, neuroblastoma, and hepatoblastoma. Multidisciplinary combined diagnosis and treatment is needed for infantile tumors.
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http://dx.doi.org/10.1002/ped4.12213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520105PMC
September 2020

ANXA6 suppresses the tumorigenesis of cervical cancer through autophagy induction.

Clin Transl Med 2020 Oct;10(6):e208

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, People's Hospital of Hangzhou Medical College, Clinical Research Institute, Hangzhou, China.

Background: Autophagy is an intracellular degradation pathway conserved in eukaryotes. ANXA6 (annexin A6) belongs to a family of calcium-dependent membrane and phospholipid-binding proteins. Here, we identify ANXA6 as a newly synthesized protein in starvation-induced autophagy and validate it as a novel autophagy modulator that regulates autophagosome formation.

Results: ANXA6 knockdown attenuates starvation-induced autophagy, while restoration of its expression enhances autophagy. GO (gene ontology) analysis of ANXA6 targets showed that ANXA6 interacts with many RAB GTPases and targets endocytosis and phagocytosis pathways, indicating that ANXA6 exerts its function through protein trafficking. ATG9A (autophagy-related 9A) is the sole multispanning transmembrane protein and its trafficking through recycling endosomes is an essential step for autophagosome formation. Our results showed that ANXA6 enables appropriate ATG9A vesicle trafficking from endosomes to autophagosomes through RAB proteins or F-actin. In addition, restoration of ANXA6 expression suppresses mTOR (mammalian target of rapamycin) activity through the inhibition of the PI3K (phosphoinositide 3-kinase)-AKT and ERK (extracellular signal-regulated kinase) signaling pathways, which is a negative regulator of autophagy. Functionally, ANXA6 expression is correlated with LC3 (microtubule-associated protein 1 light chain 3) expression in cervical cancer, and ANXA6 inhibits tumorigenesis through autophagy induction.

Conclusions: Our results reveal an important mechanism for ANXA6 in tumor suppression and autophagy regulation.
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http://dx.doi.org/10.1002/ctm2.208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571625PMC
October 2020

Conversion Therapy for Advanced Pancreatic Cancer: The Case Series and Literature Review.

Front Pharmacol 2020 6;11:579239. Epub 2020 Oct 6.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.

Background: Pancreatic cancer has a high incidence and mortality. Most patients are in an advanced stage at the time of initial diagnosis and cannot be cured by a single surgery. The ASCO clinical practice guideline emphasized the overall management and multidisciplinary comprehensive treatment which put forward the concept of conversion therapy. In this paper, the real-world observation and study were carried out to explore the conversion effect of chemotherapy in patients with advanced pancreatic cancer and their long-term survival.

Methods: The subjects of this study are advanced pancreatic cancer patients who visited the oncology department of Zhejiang Provincial People's Hospital from 2015 to 2019. Collected and summarized the cases, and selected 5 representative patients for analysis, all of them received standard treatment (FOLFIRINOX, AS, AG, or GS). The progress, clinical evaluation, adverse reactions, and prognosis of these patients after conversion therapy were analyzed and discussed in conjunction with relevant literature.

Results: Five patients with advanced pancreatic cancer received conversion therapy with an average survival time of 29.8 months, two of them received surgical treatment, and postoperative evaluations were pathological complete response (pCR). The tolerance of chemotherapy was good in five patients, and no serious adverse reactions of grade 3 or 4 occurred.

Conclusion: Conversion therapy for patients with advanced pancreatic cancer strives for surgical opportunities of radical resection, prolongs survival and improves quality of life.
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http://dx.doi.org/10.3389/fphar.2020.579239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573973PMC
October 2020

Loganetin and 5-fluorouracil synergistically inhibit the carcinogenesis of gastric cancer cells via down-regulation of the Wnt/β-catenin pathway.

J Cell Mol Med 2020 12 24;24(23):13715-13726. Epub 2020 Oct 24.

Department of Medical Oncology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.

Although most gastrointestinal tumours are sensitive to 5-fluorouracil (5FU), drug resistance is commonly occurred after 5FU therapy in gastric cancer (GC). Loganetin is the primary active compound in Cornus officinali. However, the synergetic effects of loganetin and 5FU on GC remain unknown. Here, we investigated the synergetic effects and the underlying mechanism of loganetin and 5FU on proliferation, stem-like properties, migration, and invasion of GC both in vitro and in vivo. We found that loganetin alone inhibited the proliferation, stem-like properties, migration and invasion of GC cells in vitro. Importantly, the loganetin remarkably enhanced the anti-cancer effect of 5FU on GC cells and the Wnt/β-catenin pathway might be involved in this process. Animal experiments further confirmed the synergistic effects of 5FU and loganetin on inhibiting cell growth and metastasis of GC. These results suggested that loganetin could synergistically increase the effect of 5FU against GC, which sheds light on effective combinational drug strategies for GC treatment.
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http://dx.doi.org/10.1111/jcmm.15932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754039PMC
December 2020

Prognostic analysis for children with hepatoblastoma with lung metastasis: A single-center analysis of 98 cases.

Asia Pac J Clin Oncol 2020 Sep 13. Epub 2020 Sep 13.

Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, P.R. China.

Aims: To analyze the factors affecting the prognosis of hepatoblastoma (HB) with lung metastasis in children.

Methods: The HB patients with lung metastases admitted to Beijing Tongren Hospital, Capital Medical University were collected. The clinical data, overall results, and prognostic factors were analyzed. Multivariate analysis was done by the Cox proportional hazards model for patients' prognosis.

Results: Finally, 98 HB patients (64 boys and 34 girls) with lung metastasis met the inclusion criteria, in which 64 patients had lung metastases at diagnosis (median age, 22.3 months) and 34 patients developed lung metastases while on treatment (median time, 6.5 months). The survival time and 5-year survival rate of patients with standard treatment were significantly longer than that of without standard treatment (P < .001). The survival time and 3-year survival rate had no difference between patients underwent lung metastasectomy and without lung metastasectomy (P = .099), between different diagnosis time of lung metastasis in HB patients (P = .37), between each histology type (P = .313), and different PRETEXT stage (P = .353). While the survival time and 3-year survival rate of patients with lung metastasis alone were significantly longer than that of patients with extrapulmonary involvement (P = .007). Multivariate Cox proportional hazards model revealed that the lung metastasis accompanied with extrapulmonary involvement was a risk factor affecting prognosis (HR = 0.460, 95% CI 0.239-0.888).

Conclusions: For HB children with lung metastatic, extrapulmonary involvement might be a high-risk factor of prognosis and standardized treatment with lung metastasectomy might prolong the survival time of them.
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http://dx.doi.org/10.1111/ajco.13421DOI Listing
September 2020

Gallbladder neuroendocrine carcinoma: A single center experience.

Medicine (Baltimore) 2020 Sep;99(36):e21912

Hepatobiliary and Pancreatic Surgery.

Gallbladder neuroendocrine carcinoma (GB-NEC) is a group of rare and heterogeneous neoplasms and there are few reports at present.We analyzed the clinical and pathological features of 7 patients with GB-NEC who were admitted to Zhejiang Provincial People's Hospital from January 2011 to October 2019.The median age of 7 patients was 58 years with male to female ratio of 1:2.5. Right upper quadrant discomfort was the main complaint and no patients presented carcinoid syndrome-related symptoms. In contrast-enhanced computed tomography (CT) examination, 5 of 6 patients showed well-defined margin and continuous thin line-like contrast enhancement on the mucosa. Among the patients with liver metastases before surgery, 66.7% of patients were cancer antigen 125 (CA-125) positive, and among the patients presented with liver metastases during follow-up period, all patients were CA-125 positive. All patients with elevated CA-125 did not have ascites, ovarian carcinoma, peritoneal carcinoma, and endometrial carcinoma. According to postoperative pathological report, 1 patient was stage IIIA, and the other 6 patients were stage IVB. Six patients underwent surgery, and 1 patient just underwent liver biopsy. Two patients underwent laparoscopic radical cholecystectomy, and neither of them encountered serious complications after surgery with the overall survival time of 4.6 and 16.8 months, respectively. Compared with the patients without chemotherapy, 3 patients postoperatively treated with chemotherapy lived longer. The median survival of all 7 patients was 4.6 months and the 1-, 2-year survival rates were 14.29%, 0%.Surgical resection, including laparoscopic radical cholecystectomy, is feasible for the treatment of advanced GB-NEC in selected patients and has the advantages of prolonging survival in combination with chemotherapy. The elevation of CA-125 can be utilized as an important predictor of poor prognosis, while more investigations are necessary to confirm it.
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http://dx.doi.org/10.1097/MD.0000000000021912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478469PMC
September 2020

Circulating Tumor DNA as a Potential Marker to Detect Minimal Residual Disease and Predict Recurrence in Pancreatic Cancer.

Front Oncol 2020 30;10:1220. Epub 2020 Jul 30.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Department of Medical Oncology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death, partly due to the high recurrence rates for patients with PDAC. Current postoperative surveillance methods, including monitoring of clinical symptoms, tumor markers, and CT imaging, lack sensitivity and specificity for minimal residual disease (MRD). We investigated whether the detection of circulating tumor DNA (ctDNA) could identify MRD and predict relapse in postoperative patients with PDAC. In this study, we performed panel-captured sequencing to detect somatic mutations. Matched tissue samples were obtained to verify mutation. A total of 27 patients and 65 plasma samples were included. Among the somatic mutations, KRAS and TP53 were the most recurrent genes in both tissue and plasma samples. The detectable rate of ctDNA increased with the stage of PDAC. The maximal variant allele fraction (VAF) of ctDNA had a positive correlation with tumor largest diameter ( = 0.0101). Patients with ctDNA-positive status postoperatively had a markedly reduced disease-free survival (DFS) compared to those with ctDNA-negative status (HR, 5.20; = 0.019). Positive vascular invasion significantly influenced disease-free survival (DFS) ( = 0.036), and positive postoperative ctDNA status was an independent prognostic factor for DFS (HR = 3.60; 95% CI, 1.15-11.28; = 0.028). Postoperative ctDNA detection provides strong evidence of MRD and identifies patients with a high risk of relapse. ctDNA detection is a promising approach for personalized patient management during postoperative follow-up.
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http://dx.doi.org/10.3389/fonc.2020.01220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406781PMC
July 2020

Transcriptome profiling analysis reveals that ATP6V0E2 is involved in the lysosomal activation by anlotinib.

Cell Death Dis 2020 08 24;11(8):702. Epub 2020 Aug 24.

Department of Oncology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.

Anlotinib is a receptor tyrosine kinase inhibitor with potential anti-neoplastic and anti-angiogenic activities. It has been approved for the treatment of non-small-cell lung cancer. Lysosomes are acidic organelles and have been implicated in various mechanisms of cancer therapeutics. However, the effect of anlotinib on lysosomal function has not been investigated. In the present study, anlotinib induces apoptosis in human colon cancer cells. Through transcriptome sequencing, we found for the first time that anlotinib treatment upregulates ATP6V0E2 (ATPase H Transporting V0 Subunit E2) and other lysosome-related genes expression in human colon cancer. In human colon cancer, we validated that anlotinib activates lysosomal function and enhances the fusion of autophagosomes and lysosomes. Moreover, anlotinib treatment is shown to inhibit mTOR (mammalian target of rapamycin) signaling and the activation of lysosomal function by anlotinib is mTOR dependent. Furthermore, anlotinib treatment activates TFEB, a key nuclear transcription factor that controls lysosome biogenesis and function. We found that anlotinib treatment promotes TFEB nuclear translocation and enhances its transcriptional activity. When TFEB or ATP6V0E2 are knocked down, the enhanced lysosomal function and autophagy by anlotinib are attenuated. Finally, inhibition of lysosomal function enhances anlotinib-induced cell death and tumor suppression, which may be attributed to high levels of ROS (reactive oxygen species). These findings suggest that the activation of lysosomal function protects against anlotinib-mediated cell apoptosis via regulating the cellular redox status. Taken together, our results provide novel insights into the regulatory mechanisms of anlotinib on lysosomes, and this information could facilitate the development of potential novel cancer therapeutic agents that inhibit lysosomal function.
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http://dx.doi.org/10.1038/s41419-020-02904-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445181PMC
August 2020

Long noncoding RNA LINC01123 promotes the proliferation and invasion of hepatocellular carcinoma cells by modulating the miR-34a-5p/TUFT1 axis.

Int J Biol Sci 2020 5;16(13):2296-2305. Epub 2020 Jun 5.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.

Hepatocellular carcinoma (HCC), one of the main causes of cancer-related deaths globally, is characterized by rapid growth and high invasiveness. Accumulating evidence demonstrates that long noncoding RNAs (lncRNAs) play critical roles in the growth and metastasis of HCC. Recently, lncRNA LINC01123 has been found to contribute to cell proliferation and aerobic glycolysis in lung cancer. However, the function of LINC01123 in HCC, as well as the underlying mechanism of its action, remain unclear. Here, we found that the expression of LINC01123 was clearly upregulated in HCC tissues compared to nontumor tissues. Furthermore, expression of LINC01123 in HCC cells was significantly higher than in LO2 cells. Importantly, the upregulated level of LINC01123 was related to unfavorable clinical features and poor prognosis of HCC. Next, we demonstrated that LINC01123 knockdown suppressed the proliferation, migration and invasion of HCC cells . Depletion of LINC01123 inhibited HCC xenograft growth . Conversely, ectopic expression of LINC01123 facilitated HCC cell proliferation and invasion. Mechanistically, LINC01123 acted as a molecular sponge for miR-34a-5p in HCC cells. Tuftelin1 (TUFT1) was identified as the target gene of miR-34a-5p. LINC01123 positively regulated TUFT1 level by targeting of miR-34a-5p in HCC cells. Notably, TUFT1 restoration can abolish miR-34a-5p-induced inhibitory effects on HCC cell proliferation, migration and invasion. In conclusion, LINC01123 was overexpressed in HCC and accelerated cancer cell proliferation and invasion by regulating the miR-34a-5p/TUFT1 axis.
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http://dx.doi.org/10.7150/ijbs.45457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378647PMC
June 2020

Application of nomogram containing log odds of metastatic lymph node in gallbladder cancer patients.

Ann Transl Med 2020 May;8(10):655

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China.

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http://dx.doi.org/10.21037/atm-2020-91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290604PMC
May 2020

TGFβ2 is a prognostic-related biomarker and correlated with immune infiltrates in gastric cancer.

J Cell Mol Med 2020 07 12;24(13):7151-7162. Epub 2020 Jun 12.

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China.

TGFβ2 is an essential regulator of immune cell functionality, but the mechanisms whereby it drives immune infiltration in gastric cancer remain uncertain. The Oncomine and Tumor Immunoassay Resource (TIMER) databases were used for assessing the expression of TGFβ2, after which TIMER was used to explore the relationship between TGFβ2 and tumour immune infiltration. Finally, we assessed how TGFβ2 expression correlated with the expression of a set of marker genes associated with immune infiltration using TIMER and GEPIA. We determined TGFβ2 expression to be significantly correlated with outcome in multiple types of cancer in the Cancer Genome Atlas (TCGA), with the effect being particularly pronounced in gastric cancer. Furthermore, elevated TGFβ2 expression was found to be significantly correlated with gastric cancer N staging, and with the expression of a variety of immune markers associated with particular immune cell subsets. These results indicate that TGFΒ2 is associated with patient outcome and tumour immune cell infiltration in multiple cancer types. This suggests that TGFβ2 is a key factor which governs immune cell recruitment to gastric cancer tumours, potentially playing a vital role in governing immune cell infiltration and thus representing a valuable prognostic biomarker in gastric cancer patients.
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http://dx.doi.org/10.1111/jcmm.15164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339175PMC
July 2020

Radiation therapy is an important factor to improve survival in pediatric patients with head and neck rhabdomyosarcoma by enhancing local control: a historical cohort study from a single center.

BMC Pediatr 2020 05 29;20(1):265. Epub 2020 May 29.

Pediatric Department of Beijing Tongren Hospital, Capital Medical University, 100730, 1# Dong Jiao Min Xiang, Dongcheng District, Beijing, China.

Background: The purpose of this study is to analyze the influence of radiation therapy on survival in a historical cohort of 56 pediatric patients with head and neck rhabdomyosarcoma.

Methods: A historical cohort of 56 pediatric patients with head and neck rhabdomyosarcoma from June 1st, 2013 to June 30th, 2019 was chosen. Clinical data and follow up results were collected including all diagnosis, treatment and prognosis information. Overall survival (OS) and event free survival (EFS) as time-to-event distributions were estimated with Kaplan-Meier method, and univariate analysis was performed with log rank test to detect differences between groups. Multivariate analysis was performed to explore the risk factors for survival with Cox proportional hazard model.

Results: The media follow up time of all 56 patients was 31.8 months (range 3.5-74.6 months). There were 26 events during follow up, including 14 disease progressions and 12 relapses. The estimated 5-year OS of all patients was 69.9%, and the estimated 5-year EFS was 48.8%. Patients with radiation therapy as a component of the initial treatment plan had better 5-year OS and EFS compared with those without radiation therapy (OS 80.3% vs. 49.7%, p = 0.003 and EFS 63.9% vs. 21.9%, p < 0.001). In patients with events, those who received salvage radiation therapy had better 5-year OS compared with those who didn't (OS 66.0% vs. 31.2%, p = 0.033). On multivariate analysis, tumor size > 5 cm and non-initial radiation therapy were independent risk factors for OS in all patients, non-initial radiation therapy was an independent risk factor for EFS in all patients, and tumor size > 5 cm was an independent risk factor for OS in patients with events.

Conclusions: Radiation therapy as a component of initial treatment can improve the OS and EFS in pediatric head and neck rhabdomyosarcoma patients by enhancing local control, and non-initial radiation therapy is an independent risk factor for OS and EFS. Salvage radiation therapy still can improve OS in patients with disease progression and relapse. Tumor size > 5 cm is an independent risk factor for OS in pediatric HNRMS patients with or without disease progression/relapse.
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http://dx.doi.org/10.1186/s12887-020-02165-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260775PMC
May 2020

The genetic association between type 2 diabetic and hepatocellular carcinomas.

Ann Transl Med 2020 Mar;8(6):380

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China.

Background: Type 2 diabetes mellitus (T2DM) and hepatocellular carcinoma (HCC) are both major health problems throughout the world. It has been reported that T2DM is an independent risk factor for HCC, although the pathophysiology is still unclear.

Methods: In order to identify differentially expressed genes (DEGs) in T2DM and HCC, gene expression datasets for T2DM (GSE15653), HCC (GSE60502) and metformin-treated cells (GSE69850) were obtained from the Gene Expression Omnibus database repository. Protein-protein interaction (PPI) networks for the DEGs were constructed and gene clusters selected for functional enrichment analysis. Ten genes with the highest degree of connectivity were selected as hub genes and prognostic analysis together with analysis of gene expression and protein distribution were performed for these genes. Lastly, we investigated associations between the hub genes and genes associated with metformin treatment in hepatocarcinoma cells.

Results: In total, 256 common DEGs, including 155 up-regulated genes and 101 down-regulated genes, were identified. Enrichment analyses showed that the genes of the major module were largely associated with the cell cycle. All of the 10 hub genes ( and ) have a strong association with lower overall survival in liver cancer patients and four genes ( and ) have reduced expression in metformin-treated samples.

Conclusions: This study identified a number of genes that may play important roles in the association of T2DM and HCC, including four genes which may be the target of metformin treatment for diabetes and HCC. The specific mechanisms involved remain to be identified.
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http://dx.doi.org/10.21037/atm.2020.02.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186634PMC
March 2020

Application of star poly(ethylene glycol) derivatives in drug delivery and controlled release.

J Control Release 2020 07 25;323:565-577. Epub 2020 Apr 25.

Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China; Center for Cancer Biology and Innovative Therapeutics, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, China; School of Basic Medical Sciences, Zhejiang University, Hangzhou, China. Electronic address:

Multi-arm star poly(ethylene glycol) (PEG) polymers have a number of advantages over linear PEG polymers when used as carriers for drug delivery and controlled release. For instance, they have more terminals that can be modified to form multi-functional delivery systems with significantly increased drug loading. They can form micelles with higher stability and lower critical micelle concentration (CMC), which helps to improve the blood circulation and reduce the unfavorable burst drug release. Moreover, star PEG polymers can form three-dimensional hydrogels with controllable size and adjustable functions through cross-linking. Indeed, these unique advantages of star PEG polymers have promoted investigations on star PEG-based drug delivery systems. Herein, for the first time, we carefully reviewed the advances on the research and development of star PEG polymers, especially the 4-, 6- and 8-armed star PEG polymers, in delivery and controlled release of a series of bioactive agents, including both small molecules and biomacromolecules. Opportunities and challenges for successful translation of star PEG-based drug formulations into clinical use were also discussed.
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http://dx.doi.org/10.1016/j.jconrel.2020.04.039DOI Listing
July 2020

Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-ß-catenin.

Elife 2020 03 18;9. Epub 2020 Mar 18.

Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Stem Cell Institute, Boston, United States.

Mechanical forces are fundamental regulators of cell behaviors. However, molecular regulation of mechanotransduction remain poorly understood. Here, we identified the mechanosensitive channels Piezo1 and Piezo2 as key force sensors required for bone development and osteoblast differentiation. Loss of Piezo1, or more severely Piezo1/2, in mesenchymal or osteoblast progenitor cells, led to multiple spontaneous bone fractures in newborn mice due to inhibition of osteoblast differentiation and increased bone resorption. In addition, loss of Piezo1/2 rendered resistant to further bone loss caused by unloading in both bone development and homeostasis. Mechanistically, Piezo1/2 relayed fluid shear stress and extracellular matrix stiffness signals to activate Ca influx to stimulate Calcineurin, which promotes concerted activation of NFATc1, YAP1 and ß-catenin transcription factors by inducing their dephosphorylation as well as NFAT/YAP1/ß-catenin complex formation. Yap1 and ß-catenin activities were reduced in the Piezo1 and Piezo1/2 mutant bones and such defects were partially rescued by enhanced ß-catenin activities.
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http://dx.doi.org/10.7554/eLife.52779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112954PMC
March 2020

Regulatory loop between lncRNA FAS-AS1 and DNMT3b controls FAS expression in hydroquinone-treated TK6 cells and benzene-exposed workers.

Environ Pollut 2020 Jun 11;261:114147. Epub 2020 Feb 11.

Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, 523808, PR China; Department of Environmental and Occupational Health, School of Public Health, Guangdong Medical University, Dongguan, 523808, PR China. Electronic address:

Hydroquinone (HQ), one of the main metabolites of benzene, is a well-known human leukemogen. However, the specific mechanism of how benzene or HQ contributes to the development of leukemia is unknown. In a previous study, we demonstrated the upregulation of DNA methyltransferase (DNMT) expression in HQ-induced malignant transformed TK6 (HQ-TK6) cells. Here, we investigated whether a regulatory loop between the long noncoding RNA FAS-AS1 and DNMT3b exists in HQ-TK6 cells and benzene-exposed workers. We found that the expression of FAS-AS1 was downregulated in HQ-TK6 cells and workers exposed to benzene longer than 1.5 years via histone acetylation, and FAS-AS1 expression was negatively correlated with the time of benzene exposure. Restoration of FAS-AS1 in HQ-TK6 cells promoted apoptosis and inhibited tumorigenicity in female nude mice. Interestingly, treatment with a DNMT inhibitor (5-aza-2-deoxycytidine), histone deacetylase inhibitor (trichostatin A), or DNMT3b knockout led to increased FAS-AS1 through increased H3K27ac protein expression in HQ-TK6 cells, and DNMT3b knockout decreased H3K27ac and DNMT3b enrichment to the FAS-AS1 promoter region, which suggested that DNMT3b and/or histone acetylation involve FAS-AS1 expression. Importantly, restoration of FAS-AS1 resulted in reduced expression of DNMT3b and SIRT1 and increased expression of FAS in both HQ-TK6 cells and xenograft tissues. Moreover, the average DNMT3b expression in 17 paired workers exposed to benzene within 1.5 years was decreased, but that of the remaining 103 paired workers with longer exposure times was increased. Conversely, DNMT3b was negatively correlated with FAS-AS1 expression. Both FAS-AS1 and DNMT3b influenced the enrichment of H3K27ac in the FAS promoter region by regulating the expression of SIRT1, consequently upregulating FAS expression. Taken together, these observations demonstrate crosstalk between FAS-AS1 and DNMT3b via a mutual inhibition loop and indicate a new mechanism by which FAS-AS1 regulates the expression of FAS in benzene-related carcinogenesis.
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http://dx.doi.org/10.1016/j.envpol.2020.114147DOI Listing
June 2020
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