Publications by authors named "Xiaodong Zhu"

385 Publications

LncRNA KASRT Serves as a Potential Treatment Target by Regulating SRSF1-Related KLF6 Alternative Splicing and the P21/CCND1 Pathway in Osteosarcoma: An and Study.

Front Oncol 2021 9;11:700963. Epub 2021 Sep 9.

Department of Spine Surgery, Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.

Purpose: Long non-coding RNA KLF6 alternative splicing regulating transcript (lnc-KASRT) locates within the intronic region of SRSF1, possessing the potential to regulate KLF6 alternative splicing to promote carcinogenicity. Then, the current and study aimed to investigate the effect of lnc-KASRT on regulating tumor malignant behaviors, and the implication of its interaction with KLF6 alternative splicing in osteosarcoma.

Methods: Lnc-KASRT overexpression or knockdown plasmid was transfected into U-2OS and Saos-2 cells. Then, KLF6-SV1 knockdown plasmid with or without lnc-KASRT overexpression plasmid was transfected into these cells for compensative experiments. , lnc-KASRT overexpression or knockdown Saos-2 cells were injected in mice for tumor xenograft construction.

Results: Lnc-KASRT expression was increased in most osteosarcoma cell lines compared to control cell line. Lnc-KASRT overexpression promoted cell viability, mobility, and anti-apoptotic marker expression, while reducing apoptosis rate and pro-apoptotic marker expression; meanwhile, it regulated SRSF1, KLF6 alternative splicing (increased KLF6-splice variant 1 (KLF6-SV1), decreased KLF6-wild type (KLF6-WT)), and followed P21/CCND1 pathway in U-2OS/Saos-2 cells. The lnc-KASRT knockdown exhibited opposite trends. Subsequent compensative experiments disclosed that KLF6-SV1 knockdown attenuated most of the tumor-promoting effects of lnc-KASRT overexpression in U-2OS/Saos-2 cells. experiments further validated that lnc-KASRT enhanced tumor growth and reduced tumor apoptosis; meanwhile, it also increased tumor KLF6-SV1, MMP-1, and MMP-9 expressions but decreased tumor SRSF1 and KLF6-WT expressions in xenograft mice.

Conclusion: Lnc-KASRT serves as a potential treatment target regulating SRSF1-related KLF6 alternative splicing and following P21/CCND1 pathway in osteosarcoma.
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http://dx.doi.org/10.3389/fonc.2021.700963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458968PMC
September 2021

A Novel Tool for the Risk Assessment and Personalized Chemo-/Immunotherapy Response Prediction of Adenocarcinoma and Squamous Cell Carcinoma Lung Cancer.

Int J Gen Med 2021 16;14:5771-5785. Epub 2021 Sep 16.

Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China.

Background: The prevalence and cancer-specific death rate of lung cancer (LC) have risen in recent decades. A universally applicable prognostic signature for both adenocarcinoma LC (LUAD) and squamous cell carcinoma LC (LUSC) is still lacking.

Methods: A total of 453 patients from The Cancer Genome Atlas (TCGA)-LUAD cohort and 452 patients from TCGA-LUSC cohort were enrolled, and a prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) regression analysis based on the consensus prognostic genes in both cohorts. The newly defined pan-lung cancer risk count (PLCRC) of each patient was calculated via the summation formula.

Results: A total of 23 genes were selected for the calculation of the PLCRC. The PLCRC showed a moderate prognostic value in the entire (p < 0.001, HR: 2.75, AUC: 0.643), LUAD (p < 0.001, HR: 2.51, AUC: 0.636) and LUSC (p < 0.001, HR: 2.89, AUC: 0.656) cohorts. The PLCRC was an independent prognostic factor after adjusting the clinical features. The PLCRC was also effective in nine external validation cohorts and in patients with different clinical features. Activation of extracellular matrix pathways and infiltration of immunocytes promoted the tumorigenesis and development of both LUAD and LUSC. We generated a universally applicable prognostic signature, the PLCRC, which could dichotomize patients with significantly different clinical outcomes and guide the clinical treatment of LC patients. Chemotherapy is more suitable for patients with a low PLCRC, while anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy is more suitable for patients with a high PLCRC.

Conclusion: We established and validated a newly defined prognostic signature, the PLCRC, for both LUAD and LUSC patients and provided clinical strategies for patients from different risk subgroups.
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http://dx.doi.org/10.2147/IJGM.S327641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455901PMC
September 2021

Phosphorylated PAMAM dendrimers: an analog of dentin non-collagenous proteins, enhancing the osteo/odontogenic differentiation of dental pulp stem cells.

Clin Oral Investig 2021 Sep 13. Epub 2021 Sep 13.

Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.

Objectives: Polyamidoamine (PAMAM) dendrimers have well-defined structures, with monodispersity and easily modified surface groups, and they have broad applications in biomedicine. In this study, phosphorylated PAMAM (P-PAMAM) dendrimers were synthesized based on the idea of mimicking the phosphorylated proteins of dentin non-collagenous proteins (DNCP). Then, proliferation and osteo/odontogenic differentiation effects of P-PAMAM on dental pulp stem cells (DPSCs) were investigated and were compared with DNCP.

Materials And Methods: P-PAMAM was synthesized via the Mannich-type reaction. DNCP were extracted directly from human dentin with ethylenediaminetetraacetic acid (EDTA) solution. Then, the conditioned medium of P-PAMAM and DNCP were prepared respectively and applied to DPSCs. Proliferation of P-PAMAM was investigated with CCK-8, flow cytometry, and EdU test. Osteo/odontogenic differentiation of P-PAMAM was analyzed using alkaline phosphatase activity and staining, RT-PCR, western blot, alizarin red staining, and immunofluorescence staining.

Results: Fourier transform infrared spectroscopy and H nuclear magnetic resonance revealed that PAMAM were successfully phosphorylated. Western blot verified that the extracted DNCP contained dentin-related proteins DSPP, OPN, and BMP2. In cell proliferation, there was no apparent difference between P-PAMAM, DNCP, and Control groups (P > 0.05). P-PAMAM and DNCP upregulated related genes and proteins expression (DSPP/DSPP, COL-1/COL-1, ALP/ALP, RUNX2/RUNX2, OSX/OSX, OCN/OCN) and matrix mineralization. Still, the potential was lower than that of DNCP (P < 0.05).

Conclusions: P-PAMAM dendrimers, as a biomimetic analog of DNCP, promote osteo/odontogenic differentiation of DPSCs without influencing their proliferation at a low concentration.

Clinical Relevance: This preliminary study about P-PAMAM dendrimers is expected to provide a more convenient bioactive macromolecular material for the regeneration of the pulp-dentin complex.
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http://dx.doi.org/10.1007/s00784-021-04149-3DOI Listing
September 2021

Prognostic Role of EGFR/p-EGFR in Patients With Nasopharyngeal Carcinoma: A Meta-Analysis.

Front Oncol 2021 19;11:697369. Epub 2021 Aug 19.

Department of Oncology, Wuming Hospital of Guangxi Medical University, Nanning, China.

Background: The prognostic value of epidermal growth factor receptor (EGFR)/phosphorylated EGFR (p-EGFR) expression in nasopharyngeal carcinoma remains controversial. A meta-analysis was performed to investigate prognostic significance of EGFR/p-EGFR expression in patients with nasopharyngeal carcinoma.

Methods: Literatures published before November 2020 were systematically searched in relevant databases, including PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wan fang databases. STATA 13 statistical software was used to analyze the pooled hazard ratio (HR) and 95% confidence interval (CI). Heterogeneity of the studies was examined by I. Sensitivity and subgroup analysis were performed to explore sources of heterogeneity. The potential publication bias was assessed using both Egger's and Begg's tests.

Results: A total of 20 literatures with 1545 patients were included for the meta-analysis. The meta-analysis results suggested that high expression of EGFR was significantly associated with poor overall survival (OS) (HR = 1.70, 95% CI: 1.24-3.15, P = 0.001) and disease-free survival (DFS) (HR = 2.58, 95% CI: 1.87-3.56, P = 0.000). However, it was not significantly associated with progression-free survival (PFS) (HR = 1.85, 95% CI: 0.90-3.82, P = 0.09) and distant metastasis-free survival (DMFS) (HR = 1.39, 95% CI: 0.73-2.67, P = 0.319). The subgroup analysis indicated that patients with EGFR high expression in studies of higher TNM stage (III-IV) ratio had significantly poor OS (HR = 2.27, 95% CI: 1.09-4.73, P = 0.03), but heterogeneity existed in studies (I  =  95.1%, P = 0.000). Sensitivity analyses revealed that EGFR expression did not significantly affect OS by an individual study solely, indicating there was inherent heterogeneity in OS cohorts. There was no significant heterogeneity among eight studies in the DFS cohorts (I = 0%, P = 0.606). There was significant heterogeneity between EGFR expression and DMFS (I = 82.8%, P = 0.000). Sub-group analysis in differentiated carcinoma demonstrated a smaller heterogeneity (I = 33.2%). In addition, p-EGFR high expression had no significant correlation with OS (HR = 1.00, 95% CI: 0.88-1.14, P = 0.982) and DMFS (HR = 1.21, 95% CI: 0.96-1.52, P = 0.112). The heterogeneity among p-EGFR and OS studies was small (I = 21%, P = 0.26). There was no significant heterogeneity in the DMFS cohorts (I = 0%, P = 0.497).

Conclusion: EGFR high-expression was significantly associated with poor OS and DFS, which may serve as a prognostic predictor for nasopharyngeal cancer.

Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO], identifier [number CRD42021258457].
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http://dx.doi.org/10.3389/fonc.2021.697369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417403PMC
August 2021

Silencing c-Jun inhibits autophagy and abrogates radioresistance in nasopharyngeal carcinoma by activating the PI3K/AKT/mTOR pathway.

Ann Transl Med 2021 Jul;9(13):1085

Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, China.

Background: Radioresistance plays an important role in the failure of radiotherapy (RT) for nasopharyngeal carcinoma (NPC), leading to poor prognosis. The purpose of this study was to explore the relationship between the expression of the c-Jun oncogene and the prognosis of NPC. In addition, we investigated the potential mechanisms of c-Jun in the regulation of tumor growth and radioresistance in NPC.

Methods: c-Jun expression in NPC tissues and nasopharyngeal mucosa tissues was evaluated using immunochemistry. c-Jun and its downstream targets were verified by dual-luciferase reporter assays. Inhibitors or activators were used to interfere with the PI3K/AKT/mTOR pathway. Protein expression was analyzed by western blotting. NPC nude mouse xenograft models were used to investigate the potential effects of c-Jun and ionizing radiation .

Results: The expression of c-Jun in NPC tissues was significantly higher than that in normal nasopharyngeal mucosa (NNM) tissues, and Cox regression analysis revealed that c-Jun overexpression was an independent risk factor for poor prognosis in NPC patients. Both and experiments verified that c-Jun targeted PI3K/AKT signaling. We also performed an study showing that c-Jun knockdown effectively suppressed NPC growth in a xenograft tumor model by autophagy inhibition, and these effects were accompanied by the upregulation of p-PI3K p-AKT, p-mTOR, and P62 and downregulation of LC3-II expression.

Conclusions: High expression of c-Jun was correlated with poor prognosis in NPC patients. c-Jun knockdown increased cell sensitivity to radiation by inhibiting autophagy activation via the PI3K/AKT/mTOR signaling pathway. The present study provides a theoretical basis for a promising treatment for radioresistant NPC by inhibiting c-Jun expression.
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http://dx.doi.org/10.21037/atm-21-2563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339856PMC
July 2021

First-line treatment with chemotherapy plus cetuximab in Chinese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Efficacy and safety results of the randomised, phase III CHANGE-2 trial.

Eur J Cancer 2021 Oct 18;156:35-45. Epub 2021 Aug 18.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China. Electronic address:

Background: The EXTREME regimen (chemotherapy [CT; cisplatin/carboplatin and 5-fluorouracil]) plus cetuximab is a standard-of-care first-line (1L) treatment for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), as supported by international guidelines. The phase III CHANGE-2 trial assessed the efficacy and safety of a modified CT regimen (with a reduced dose of both components) and cetuximab versus CT for the 1L treatment of Chinese patients with R/M SCCHN.

Methods: Patients were randomised to receive up to six cycles of CT plus cetuximab followed by cetuximab maintenance until progressive disease or CT alone. The primary end-point was the progression-free survival (PFS) time assessed by the independent review committee (IRC).

Results: Overall, 243 patients were randomised (164 to CT plus cetuximab; 79 to CT). The hazard ratios for PFS by IRC and overall survival (OS) were 0.57 (95% CI: 0.40-0.80; median: 5.5 versus 4.2 months) and 0.69 (95% CI: 0.50-0.93; median: 11.1 versus 8.9 months), respectively, in favour of CT plus cetuximab. The objective response rates (ORR) by IRC were 50.0% and 26.6% with CT plus cetuximab and CT treatment, respectively. Treatment-emergent adverse events of maximum grade 3 or 4 occurred in 61.3% (CT plus cetuximab) and 48.7% (CT) of patients.

Conclusions: CHANGE-2 showed an improved median PFS, median OS and ORR with the addition of cetuximab to a modified platinum/5-fluorouracil regimen, with no new or unexpected safety findings, thereby confirming CT plus cetuximab as an effective and safe 1L treatment for Chinese patients with R/M SCCHN.

Clinical Trial Registration Number: NCT02383966.
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http://dx.doi.org/10.1016/j.ejca.2021.06.039DOI Listing
October 2021

Associations of immunological features with COVID-19 severity: a systematic review and meta-analysis.

BMC Infect Dis 2021 Aug 3;21(1):738. Epub 2021 Aug 3.

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

Background: COVID-19 has spread widely worldwide, causing millions of deaths. We aim to explore the association of immunological features with COVID-19 severity.

Methods: We conducted a meta-analysis to estimate mean difference (MD) of immune cells and cytokines levels with COVID-19 severity in PubMed, Web of Science, Scopus, the Cochrane Library and the grey literature.

Results: A total of 21 studies with 2033 COVID-19 patients were included. Compared with mild cases, severe cases showed significantly lower levels of immune cells including CD3 T cell (× 10, MD, - 413.87; 95%CI, - 611.39 to - 216.34), CD4 T cell (× 10, MD, - 203.56; 95%CI, - 277.94 to - 129.18), CD8 T cell (× 10, MD, - 128.88; 95%CI, - 163.97 to - 93.79), B cell (× 10/L; MD, - 23.87; 95%CI, - 43.97 to - 3.78) and NK cell (× 10/L; MD, - 57.12; 95%CI, - 81.18 to - 33.06), and significantly higher levels of cytokines including TNF-α (pg/ml; MD, 0.34; 95%CI, 0.09 to 0.59), IL-5 (pg/ml; MD, 14.2; 95%CI, 3.99 to 24.4), IL-6 (pg/ml; MD, 13.07; 95%CI, 9.80 to 16.35), and IL-10 (pg/ml; MD, 2.04; 95%CI, 1.32 to 2.75), and significantly higher levels of chemokines as MCP-1 (SMD, 3.41; 95%CI, 2.42 to 4.40), IP-10 (SMD, 2.82; 95%CI, 1.20 to 4.45) and eotaxin (SMD, 1.55; 95%CI, 0.05 to 3.05). However, no significant difference was found in other indicators such as Treg cell (× 10, MD, - 0.13; 95%CI, - 1.40 to 1.14), CD4/CD8 ratio (MD, 0.26; 95%CI, - 0.02 to 0.55), IFN-γ (pg/ml; MD, 0.26; 95%CI, - 0.05 to 0.56), IL-2 (pg/ml; MD, 0.05; 95%CI, - 0.49 to 0.60), IL-4 (pg/ml; MD, - 0.03; 95%CI, - 0.68 to 0.62), GM-CSF (SMD, 0.44; 95%CI, - 0.46 to 1.35), and RANTES (SMD, 0.94; 95%CI, - 2.88 to 4.75).

Conclusion: Our meta-analysis revealed significantly lower levels of immune cells (CD3 T, CD4 T, CD8 T, B and NK cells), higher levels of cytokines (TNF-α, IL-5, IL-6 and IL-10) and higher levels of chemokines (MCP-1, IP-10 and eotaxin) in severe cases in comparison to mild cases of COVID-19. Measurement of immunological features could help assess disease severity for effective triage of COVID-19 patients.
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http://dx.doi.org/10.1186/s12879-021-06457-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329624PMC
August 2021

DEPDC1B regulates the progression of human chordoma through UBE2T-mediated ubiquitination of BIRC5.

Cell Death Dis 2021 Jul 30;12(8):753. Epub 2021 Jul 30.

Department of Orthopaedic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 2000 Jiangyue Road, Shanghai, 200127, China.

Chordoma is a rare bone malignancy with a high rate of local recurrence and distant metastasis. Although DEP domain-containing protein 1B (DEPDC1B) is implicated in a variety of malignancies, its relationship with chordoma is unclear. In this study, the biological role and molecular mechanism of DEPDC1B in chordoma were explored. The function of DEPDC1B in chordoma cells was clarified through loss-of-function assays in vitro and in vivo. Furthermore, molecular mechanism of DEPDC1B in chordoma cells was recognized by RNA sequencing and Co-Immunoprecipitation (Co-IP) assay. The malignant behaviors of DEPDC1B knockdown chordoma cells was significantly inhibited, which was characterized by reduced proliferation, enhanced apoptosis, and hindered migration. Consistently, decreased expression of DEPDC1B suppressed tumor growth in xenograft mice. Mechanically, DEPDC1B affected the ubiquitination of baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) through ubiquitin-conjugating enzyme E2T (UBE2T). Simultaneous downregulation of BIRC5 and DEPDC1B may exacerbate the inhibitory effects of chordoma. Moreover, BIRC5 overexpression reduced the inhibitory effects of DEPDC1B knockdown in chordoma cells. In conclusion, DEPDC1B regulates the progression of human chordoma through UBE2T-mediated ubiquitination of BIRC5, suggesting that it may be a promising candidate target with potential therapeutic value.
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http://dx.doi.org/10.1038/s41419-021-04026-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324777PMC
July 2021

Circular RNA circ_0046264 Suppresses Osteosarcoma Progression via microRNA-940/Secreted Frizzled Related Protein 1 Axis.

Tohoku J Exp Med 2021 07;254(3):189-197

Department of Foot and Ankle Surgery, Affiliated Hospital of Binzhou Medical University.

Circular RNAs (circRNAs) feature prominently in regulating tumor progression. The study aims to investigate the role and mechanism of circ_0046264 in osteosarcoma. In this study, dysregulated circRNAs in osteosarcoma tissues and adjacent tissues were screened out by analyzing circRNA microarray (GSE140256). The expressions of circ_0046264 in 58 osteosarcoma tissues and 4 osteosarcoma cell lines were detected by quantitative real-time polymerase chain reaction. Subsequently, the relationship of circ_0046264 expression level and clinical features were analyzed. Ethyldeoxyuridine assay and Transwell assay were employed to detect cell viability, migration and invasion. Dual-luciferase reporter assay was adopted to confirm the targeting relationships between circ_0046264 and microRNA-940 (miR-940), as well as miR-940 and secreted frizzled related protein 1 (SFRP1). SFRP1 expression was determined by western blot. Here, we demonstrated that circ_0046264 was greatly down-regulated in osteosarcoma and was inversely related to tumor size and Ki67 expression. Functional assays validated that circ_0046264 could restrain the proliferation, migration and invasion. Mechanistically, circ_0046264 could adsorb miR-940 and indirectly modulate SFRP1 expression. Furthermore, the transfection of miR-940 mimics or SFRP1 small interfering RNA could reverse the impact of circ_0046264 overexpression on the growth, migration and invasion of osteosarcoma cells. Taken together, circ_0046264 is a tumor suppressor to inhibit the osteosarcoma progression via modulating the miR-940 / SFRP1 axis.
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http://dx.doi.org/10.1620/tjem.254.189DOI Listing
July 2021

Microtubules and Gαo-signaling modulate the preferential secretion of young insulin secretory granules in islet β cells via independent pathways.

PLoS One 2021 22;16(7):e0241939. Epub 2021 Jul 22.

Department of Cell and Developmental Biology, The Program of Developmental Biology and the Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, United States of America.

For sustainable function, each pancreatic islet β cell maintains thousands of insulin secretory granules (SGs) at all times. Glucose stimulation induces the secretion of a small portion of these SGs and simultaneously boosts SG biosynthesis to sustain this stock. The failure of these processes, often induced by sustained high-insulin output, results in type 2 diabetes. Intriguingly, young insulin SGs are more likely secreted during glucose-stimulated insulin secretion (GSIS) for unknown reasons, while older SGs tend to lose releasability and be degraded. Here, we examine the roles of microtubule (MT) and Gαo-signaling in regulating the preferential secretion of young versus old SGs. We show that both MT-destabilization and Gαo inactivation results in more SGs localization near plasma membrane (PM) despite higher levels of GSIS and reduced SG biosynthesis. Intriguingly, MT-destabilization or Gαo-inactivation results in higher secretion probabilities of older SGs, while combining both having additive effects on boosting GSIS. Lastly, Gαo inactivation does not detectably destabilize the β-cell MT network. These findings suggest that Gαo and MT can modulate the preferential release of younger insulin SGs via largely parallel pathways.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241939PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297875PMC
July 2021

Mild Hypoxia Enhances the Expression of HIF and VEGF and Triggers the Response to Injury in Rat Kidneys.

Front Physiol 2021 25;12:690496. Epub 2021 Jun 25.

Department of Pediatric Critical Care Medicine, Xinhua Hospital, Affiliated to the Medical School of Shanghai Jiao Tong University, Shanghai, China.

Background: Hypoxia contributes to a cascade of inflammatory response mechanisms in kidneys that result in the development of renal interstitial fibrosis and subsequent chronic renal failure. Nonetheless, the kidney possesses a self-protection mechanism under a certain degree of hypoxia and this mechanism its adaptation to hypoxia. As the hypoxia-inducible factor (HIF)-vascular endothelial growth factor (VEGF) axis is a key pathway for neovascularization, the activation of this axis is a target for renal hypoxia therapies.

Methods: Sprague-Dawley rats were exposed to normobaric hypoxia and subdivided into three groups, namely group A (21% O), group B (10% O), and group C (7% O). Renal tissue samples were processed and analyzed to determine pathological morphological changes, the expression of HIF, VEGF, inflammation factor and vascular density.

Results: We found that as the duration of hypoxia increased, destructive changes in the kidney tissues became more severe in group C (7% O). In contrast, the increased duration of hypoxia did not exacerbate kidney damage in group B (10% O). As the hypoxia was prolonged and the degree of hypoxia increased, the expression of HIF-1α increased gradually. As hypoxia time increased, the expression of VEGF increased gradually, but VEGF expression in group B (10% O) was the highest. Group C (7% O) had higher levels of IL-6, IL-10, and TNF-alpha. Additionally, the highest vascular density was observed in group B.

Conclusion: These findings suggest that activating the HIF-VEGF signaling pathway to regulate angiogenesis after infliction of hypoxic kidney injury may provide clues for the development of novel CKD treatments.
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http://dx.doi.org/10.3389/fphys.2021.690496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267573PMC
June 2021

Early post-operative PCO/CO predicts subsequent acute kidney injury after complete repair of tetralogy of Fallot.

Cardiol Young 2021 Jul 2:1-6. Epub 2021 Jul 2.

Department of Pediatric Critical Care Medicine, Xinhua Hospital, Affiliated to the Medical School of Shanghai Jiaotong University, 1665 Kongjiang Road, Yangpu District, Shanghai 200092, China.

Background: Acute kidney injury is a severe complication following complete repair of tetralogy of Fallot. Anaerobic metabolism is believed to contribute to the development of acute kidney injury. The ratio of central venous to arterial carbon dioxide tension to arterio-venous oxygen content (PV-ACO2/CA-VO2) has been proposed as a surrogate for respiratory quotient and an indicator of tissue oxygenation. We hypothesised that a small increase of PV-ACO2/CA-VO2 might have superior discrimination ability in subsequent acute kidney injury prediction.

Methods: This study is retrospective and single-centre design study. The study population consisted of 61 children with tetralogy of Fallot that underwent a complete surgical repair between July 2017 and January 2021. Baseline characteristics and intra-operative parameters were collected through a retrospective chart review. PV-ACO2/CA-VO2 was collected within 12 hours of surgical completion. Acute kidney injury was defined according to the criteria established by the Kidney Disease: Improving Global Outcomes group. Univariate and logistic regression analyses were performed to determine risk factors for acute kidney injury.

Results: Of the 61 patients, 20 (32.8%) developed acute kidney injury. Multivariate logistic analyses showed that age, height, haematocrit, and Pv-aCO2/Ca-vO2 were independently associated with the development of acute kidney injury. The addition of Pv-aCO2/Ca-vO2 to the model significantly increased model discrimination [AUROC 0.939 (95% CI 0.894-0.984) and AUROC 0.922 (95% CI 0.869-0.975), respectively].

Conclusions: The increase of PV-ACO2/CA-VO2 could improve the predictive ability for subsequent development of acute kidney injury in children with tetralogy of Fallot.
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http://dx.doi.org/10.1017/S1047951121002559DOI Listing
July 2021

Cross-platform binary code similarity detection based on NMT and graph embedding.

Math Biosci Eng 2021 05;18(4):4528-4551

National Key Laboratory of Science and Technology on Blind Signal Processing, Chengdu, 610000, China.

Cross-platform binary code similarity detection is determining whether a pair of binary functions coming from different platforms are similar, and plays an important role in many areas. Traditional methods focus on using platform-independent characteristic strands intersecting or control flow graph (CFG) matching to compute the similarity and have shortages in terms of efficiency and scalability. The existing deep-learning-based methods improve the efficiency but have a low accuracy and still using manually constructed features. Aiming at these problems, a cross-platform binary code similarity detection method based on neural machine translation (NMT) and graph embedding is proposed in this manuscript. We train an NMT model and a graph embedding model to automatically extract two parts of semantics of the binary code and represent it as a high-dimension vector, named an embedding. Then the similarity of two binary functions can be measured by the distance between their corresponding embeddings. We implement a prototype named SimInspector. Our comparative experiment result shows that SimInspector outperforms the state-of-the-art approach, Gemini, by about 6% with respect to similarity detection accuracy, and maintains a good efficiency.
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http://dx.doi.org/10.3934/mbe.2021230DOI Listing
May 2021

Generation and Characterization of Mouse Models of C3 Glomerulonephritis With CFI D288G and P467S Mutations.

Front Physiol 2021 3;12:649801. Epub 2021 Jun 3.

National Clinical Research Center for Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.

C3 glomerulopathy (C3GP) is a disease entity caused by abnormality of the complement alternative pathway (AP) and characterized by C3 deposition in glomeruli. Many variations or mutations of complement factors are believed to underlie the susceptibility to C3GP, but there is a lack of experimental evidence. We have recently reported a patient with C3 glomerulonephritis (C3GN) and compound heterozygosity of two novel variations in the complement factor (CFI). Here, we generated a mouse model to mimic the CFI variations for studying pathogenicity of CFI variations in C3GN development. We used the CRISPR/Cas9 system to make mutant mouse lines that carried D288G and P467S mutations in CFI, respectively, and crossed them to generate mice with compound heterozygosity of CFI D288G and P467S. The mice were all normal in either SPF (specific pathogen free) or regular environment. When treated with lipopolysaccharides (LPS), a bacterial endotoxin that mimics infection and sepsis, the mice developed albuminuria, kidney function impairment, and C3 glomerular deposition at levels comparable with the wild-type mice. The mice with other genotypes concerning CFI D288G and P467S were also tested in parallel. Unexpectedly, we found that the D288G homozygotes all developed severe mesangial deposition of C3 in the LPS model, indicating that CFI D288G variation was involved in the C3 deposition, a key feature of C3GN. The mouse lines generated in the present study can be used to further study the role of CFI variations in C3GN development; in addition, they may be used to screen and test infections and environmental factors capable of triggering C3GN.
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http://dx.doi.org/10.3389/fphys.2021.649801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209374PMC
June 2021

Blocking siglec-10 tumor-associated macrophages improves anti-tumor immunity and enhances immunotherapy for hepatocellular carcinoma.

Exp Hematol Oncol 2021 Jun 10;10(1):36. Epub 2021 Jun 10.

Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

Background: Tumor-associated macrophages (TAMs) promote key processes in the modulation of tumor microenvironment (TME). However, the clinical significance of heterogeneous subpopulations of TAMs in hepatocellular carcinoma (HCC) remains unknown.

Methods: HCC tissues from Zhongshan Hospital and data from The Cancer Genome Atlas were obtained and analyzed. Immunohistochemistry and flow cytometry were performed to detect the characteristics of sialic acid-binding immunoglobulin-like lectin 10 (Siglec-10) TAMs and explore their impact on the TME of HCC. The effect of Siglec-10 blockade was evaluated in vitro based on fresh human tumor tissues.

Results: Our data revealed that Siglec-10 was abundant in a large proportion of HCC specimens and prominently distributed on macrophages. Kaplan-Meier curves and Cox regression analysis showed that intratumoral Siglec-10 cell enrichment was associated with unfavorable prognosis in patients with HCC. Notably, multiple anti-inflammatory cytokines and inhibitory receptors were enriched in Siglec-10 TAMs. RNA sequencing data also revealed that numerous M2-like signaling pathways were significantly upregulated in Siglec-10 TAMs. High infiltration of Siglec-10 TAMs was associated with impaired CD8 T cell function in HCC. Of note, blocking Siglec-10 with the competitive binding antibody Siglec-10 Fc led to decreased expression of immunosuppressive molecules and increased the cytotoxic effects of CD8 T cells against HCC cells. Moreover, blocking Siglec-10 promoted the anti-tumor efficacy of the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab.

Conclusions: Siglec-10 TAMs are associated with immune suppression in the TME, and indicate poor prognosis in patients with HCC. Targeting Siglec-10 TAMs may serve as a promising immunotherapy approach for HCC.
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http://dx.doi.org/10.1186/s40164-021-00230-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191104PMC
June 2021

CD74 macrophages are associated with favorable prognosis and immune contexture in hepatocellular carcinoma.

Cancer Immunol Immunother 2021 May 19. Epub 2021 May 19.

Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

CD74 was initially thought to participate mainly in antigen presentation as an MHC class II chaperone. Recent studies have shown that CD74 plays an important role within the cell and throughout the immune system in a wide spectrum of neoplasms. However, the role of CD74 in hepatocellular carcinoma (HCC) remains elusive. In this study, HCC tissues from Zhongshan Hospital and data from The Cancer Genome Atlas (TCGA) were obtained and analyzed. Immunohistochemistry, flow cytometry, and single-cell RNA sequencing (scRNA-seq) were performed to detect the characteristics of CD74 cells and explore their impact on the tumor microenvironment (TME) of HCC. Our data revealed that stromal CD74 cell enrichment was associated with favorable prognosis in patients with HCC. CD74 was abundant in a large portion of HCC specimens and prominently distributed on stromal macrophages. scRNA-seq data also indicated that the pathways related to immune response were significantly upregulated in CD74 macrophages. High infiltration of CD74 macrophages was associated with increased infiltration of CD8 cytotoxic T lymphocytes (CTLs) with enhanced effector functions in HCC. Besides, blocking CD74 weakened the antitumor activity and proliferation ability of CD8 CTLs in HCC. Our findings highlight the critical role of CD74 in HCC. New drugs and antibodies targeting CD74 may be effective strategies for HCC therapy.
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http://dx.doi.org/10.1007/s00262-021-02962-zDOI Listing
May 2021

Finite element analysis of cutting balloon expansion in a calcified artery model of circular angle 180°: Effects of balloon-to-diameter ratio and number of blades facing calcification on potential calcification fracturing and perforation reduction.

PLoS One 2021 13;16(5):e0251404. Epub 2021 May 13.

Department of Modern Mechanical Engineering, School of Creative Science and Engineering, Waseda University, Shinjuku, Tokyo, Japan.

Calcified artery lesions cause stent under-expansion and increase the risk of in-stent restenosis and stent thrombosis. Cutting balloons facilitate the fracturing of calcification prior to stent implantation, although vessel dissection and perforation are potential issues. In clinical practice, calcifications having maximum calcium angles ≤ 180° are rarely fractured during conventional balloon angioplasty. We hypothesize that the lesion/device diameter ratio and the number of blades facing a non-circular calcified lesion may be crucial for fracturing the calcification while avoiding vessel injury. The geometries of the cutting balloons were constructed and their finite-element models were generated by folding and wrapping the balloon model. Numerical simulations were performed for balloons with five different diameters and two types of blade directions in a 180° calcification model. The calcification expansion ability was distinctly higher when two blades faced the calcification than when one blade did. Moreover, when two blades faced the calcification model, larger maximum principal stresses were generated in the calcification even when using undersized balloons with diameters reduced by 0.25 or 0.5 mm from the reference diameter, when compared with the case where one blade faced the calcified model and a balloon of diameter equal to the reference diameter was used. When two blades faced the calcification, smaller stresses were generated in the artery adjacent to the calcification; further, the maximum stress generated in the artery model adjacent to the calcification under the rated pressure of 12 atm when employing undersized balloons was smaller than that when only one blade faced the calcification and when lesion-identical balloon diameters were used under a nominal pressure of 6 atm. Our study suggested that undersized balloons of diameters 0.25 or 0.5 mm less than the reference diameter might be effective in not only expanding the calcified lesion but also reducing the risk of dissection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251404PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118280PMC
May 2021

Efficiency and Clinical Outcomes of Moses Technology with Flexible Ureteroscopic Laser Lithotripsy for Treatment of Renal Calculus.

Urol Int 2021 5;105(7-8):587-593. Epub 2021 May 5.

Department of Urology, Beijing Electric Power Hospital, SGCC (State Gird Corporation of China), Beijing, China.

Objective: The aim of the study was to compare the efficiency and clinical outcomes of Moses contact mode (MCM) and regular dusting mode (RDM) during flexible ureteroscopic lithotripsy (FURL) for treatment of renal calculus.

Methods: This retrospective analysis examined 216 patients with renal calculus who underwent FURL with MCM or RDM between March 2015 and January 2020. Stone characteristics, including size, volume, and density, were collected. Laser parameters, including laser type, laser working time, laser pause time, and foot-pedal use, were automatically recorded by the lithotripter work panel. The percentages of laser working time and laser pause time, stone fragmentation efficiency (SFE; volume/laser working time), postoperative complications, including fever and acute renal failure (ARF), stone-free rate (SFR), and the need for auxiliary procedures were determined.

Results: There were no significant differences in preoperative demographic and stone characteristics between the MCM group and the RDM group. The MCM group had a shorter laser working time (4.99 ± 1.06 vs. 5.94 ± 0.96 min, p < 0.001) and a greater SFE (137.86 [163.78-114.38] versus 114.94 [132.06-101.34] mm3/min, p < 0.001), which shortened the overall operative time (18.39 ± 5.13 vs. 21.17 ± 6.78 min, p = 0.001). There were no differences in postoperative complications, including fever and ARF, SFR (86.8 vs. 85.3%, p = 0.743), and auxiliary procedures between the 2 groups.

Conclusions: Using Moses laser technology with FURL significantly reduced laser working time and increased SFE, which shortened overall operative time. Urologists should consider this new instrument for the clinical management of renal calculus.
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http://dx.doi.org/10.1159/000512054DOI Listing
May 2021

BFAR coordinates TGFβ signaling to modulate Th9-mediated cancer immunotherapy.

J Exp Med 2021 Jul;218(7)

Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

TGFβ is essential for the generation of anti-tumor Th9 cells; on the other hand, it causes resistance against anti-tumor immunity. Despite recent progress, the underlying mechanism reconciling the double-edged effect of TGFβ signaling in Th9-mediated cancer immunotherapy remains elusive. Here, we find that TGFβ-induced down-regulation of bifunctional apoptosis regulator (BFAR) represents the key mechanism preventing the sustained activation of TGFβ signaling and thus impairing Th9 inducibility. Mechanistically, BFAR mediates K63-linked ubiquitination of TGFβR1 at K268, which is critical to activate TGFβ signaling. Thus, BFAR deficiency or K268R knock-in mutation suppresses TGFβR1 ubiquitination and Th9 differentiation, thereby inhibiting Th9-mediated cancer immunotherapy. More interestingly, BFAR-overexpressed Th9 cells exhibit promising therapeutic efficacy to curtail tumor growth and metastasis and promote the sensitivity of anti-PD-1-mediated checkpoint immunotherapy. Thus, our findings establish BFAR as a key TGFβ-regulated gene to fine-tune TGFβ signaling that causes Th9 induction insensitivity, and they highlight the translational potential of BFAR in promoting Th9-mediated cancer immunotherapy.
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http://dx.doi.org/10.1084/jem.20202144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091105PMC
July 2021

Clinical Factors Influencing End-of-Life Care in a Chinese Pediatric Intensive Care Unit: A Retrospective, Study.

Front Pediatr 2021 7;9:601782. Epub 2021 Apr 7.

Department of Pediatric Critical Care Medicine, Xinhua Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.

End-of-life(EOL) care decision-making for infants and children is a painful experience. The study aimed to explore the clinical factors influencing the EOL care to withhold/withdraw life-sustaining treatment (WLST) in Chinese pediatric intensive care unit (PICU). A 14-year retrospective study (2006-2019) for pediatric patients who died in PICU was conducted. Based on the mode of death, patients were classified into WLST group (death after WLST) and fCPR group (death after full intervention, including cardiopulmonary resuscitation). Intergroup differences in the epidemiological and clinical factors were determined. There were 715 patients enrolled in this study. Of these patients, 442 (61.8%) died after WLST and 273 (38.2%) died after fCPR. Patients with previous hospitalizations or those who had been transferred from other hospitals more frequently chose WLST than fCPR (both < 0.01), and the mean PICU stay duration was significantly longer in the WLST group ( < 0.05). WLST patients were more frequently complicated with chronic underlying disease, especially tumor ( < 0.01). Sepsis, diarrhea, and cardiac attack (all < 0.05) were more frequent causes of death in the fCPR group, whereas tumor as a direct cause of death was more frequently seen in the WLST group. Logistic regression analysis demonstrated that previous hospitalization and underlying diseases diagnosed before admission were strongly associated with EOL care with WLST decision (OR: 1.6; < 0.05 and OR: 1.6; < 0.01, respectively). Pediatric patients with previous hospitalization and underlying diseases diagnosed before admission were associated with the EOL care to WLST.
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http://dx.doi.org/10.3389/fped.2021.601782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058173PMC
April 2021

Efficacy and Safety of Pramipexole Sustained Release versus Immediate Release Formulation for Nocturnal Symptoms in Chinese Patients with Advanced Parkinson's Disease: A Pilot Study.

Parkinsons Dis 2021 3;2021:8834950. Epub 2021 Mar 3.

Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Objective: To explore the efficacy and safety of pramipexole sustained release (SR) versus pramipexole immediate release (IR) in treating nocturnal symptoms in levodopa-treated Chinese patients with advanced Parkinson's disease (PD) and sleep disturbances.

Method: SUSTAIN was an open-label, randomised, active-controlled parallel group exploratory pilot study (NCT03521635). A total of 98 patients were randomly allocated (1 : 1) to either pramipexole SR ( = 49) or pramipexole IR ( = 49) groups. The primary endpoint was a change from baseline in PD Sleep Scale 2 version (PDSS-2) total score at 18 weeks. A reduction in score represents improvement. Secondary endpoints included Nocturnal Hypokinesia Questionnaire, Scales for Outcomes in PD Sleep Scale, Early Morning Off (EMO), Epworth Sleepiness Scale, PD Questionnaire-8, and responder rates as measured by PDSS-2 total score (<18), EMO scores (≥1 point change), Clinical Global Impression Improvement scale, and Patient Global Impression-Improvement scale. Other endpoints included motor complications (MDS-UPDRS part IV) score. Adverse events were evaluated for each group.

Results: The mean pramipexole dose for both groups was 1.5 mg/day at week 18, and the mean changes in PDSS-2 total score for pramipexole SR and IR were -13.7 (95% CI -16.0 to -11.4) and -14.4 (-16.8 to -12.0) (difference of 0.7; =0.688). Change from baseline for both groups achieved the minimal clinical important difference threshold (MCID = -3.44). No significant difference was observed in change from baseline for other measures of sleep-related disturbances or responder rates. For motor complications, a greater improvement in MDS-UPDRS part IV score was observed in pramipexole SR over IR (-3.4 vs -2.3; treatment group difference: -1.1; =0.036). Both groups had comparable safety profiles.

Conclusion: In Chinese patients with advanced PD and sleep disturbances, pramipexole SR and IR have similar benefits in the treatment of nocturnal symptoms and safety, and an improvement from baseline in nocturnal symptoms was observed regardless of pramipexole formulation.
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http://dx.doi.org/10.1155/2021/8834950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946461PMC
March 2021

Finite Element Analysis of the Cutting Balloon With an Adequate Balloon-to-Artery Ratio for Fracturing Calcification While Preventing Perforation.

Circ Rep 2020 Dec 18;3(1):1-8. Epub 2020 Dec 18.

Department of Modern Mechanical Engineering, School of Creative Science and Engineering, Waseda University Tokyo Japan.

The appropriate balloon-to-artery ratio (BAR) for cutting balloons (CBs), to expand calcified lesions without increasing the risk of coronary artery perforation is unknown. This study investigated the effects of BAR on stress levels in the calcification and at the borders of the coronary artery adjacent to the calcification to determine an appropriate BAR. A custom-designed folding process of the CB model was developed. The CB models were deployed in a coronary artery model with a reference diameter of 3.0 mm, length of 24 mm, and wall thickness of 0.8 mm equipped with a 50% diameter stenotic, 360° concentric, 400-µm, and 5-mm-long calcification. Finite element analysis of the expansion of CBs with diameters increasing from 2.0 to 3.0 mm in 0.25-mm increments, corresponding to BARs from 0.67 : 1 to 1 : 1, was conducted with pressures up to 12 atm. Decreasing the CB by 0.25 and 0.5 mm (relative to the reference diameter of 3 mm) preserved maximum principal tensile stress levels comparable to that of a CB with a BAR of 1 : 1 while distinctly reducing the stress at the border of the artery adjacent and calcification. Selecting a CB that is 0.25 or 0.5 mm lower than the 3-mm reference diameter may be the first choice to effectively fracture calcifications without increasing the risk of severe artery dissection and perforation.
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http://dx.doi.org/10.1253/circrep.CR-20-0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939788PMC
December 2020

Pretreatment Plasma EBV-DNA Load Guides Induction Chemotherapy Followed by Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Cancer: A Meta-Analysis.

Front Oncol 2020 16;10:610787. Epub 2021 Feb 16.

Department of Radiotherapy, Guangxi Medical University Cancer Hospital, Nanning, China.

Background: The efficacy of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal cancer (LA-NPC) is controversial. In this paper, we conduct a meta-analysis based on relevant studies to provide strong evidence for clinical strategies.

Materials And Methods: We searched the MEDLINE, Embase, Cochrane, PubMed, and Web of Science databases for studies that stratified patients based on a high or low plasma Epstein-Barr virus deoxyribonucleic acid (EBV-DNA) load before treatment and compared the clinical efficacy of IC+CCRT vs. CCRT alone in LA-NPC. We tested for heterogeneity of studies and conducted sensitivity analysis. Subgroup analysis was performed for overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS).

Results: Seven studies with a total of 5289 cases were finally included in the meta-analysis. The heterogeneity test revealed the homogeneity of OS ( = 0.0%, =0.794), PFS ( = 0.0%, =0.778), DMFS ( = 0.0%, =0.997), and LRFS ( = 0.0%, =0.697) in patients with EBV-DNA loads of ≥4000 copies/ml in both the IC+CCRT and CCRT groups. The results reveal that IC+CCRT significantly extended the OS (HR 0.70 [95% CI 0.58-0.83], =0.000), PFS (HR 0.83 [95% CI 0.70-0.99], =0.033), and DMFS (HR 0.79 [95% CI 0.69-0.9], =0.000) of patients compared with the CCRT group, but there were no beneficial effects on LRFS (HR 1.07 [95% CI 0.80-1.42], =0.647). The heterogeneity test found that there was no significant heterogeneity of PFS ( = 0.0%, =0.564), DMFS ( = 0.0%, =0.648), LRFS ( = 22.3%, =0.257), and OS ( = 44.6%, =0.164) in patients with EBV-DNA loads of <4000 copies/ml. The results show that IC+CCRT prolonged DMFS (HR 0.57 [95% CI 0.39-0.85], =0.006) of patients without significant improvements in OS (HR 0.88 [95% CI 0.55-1.26], =0.240), PFS (HR 0.98 [95% CI 0.74-1.31], =0.908), and LRFS (HR 0.98 [95% CI 0.54-1.77], =0.943).

Conclusions: Pretreatment plasma EBV-DNA can be considered a promising effective marker for the use of IC in LA-NPC patients. The addition of IC could improve the OS and PFS of patients with EBV-DNA load ≥4000 copies/ml, but we saw no efficacy in patients with EBV-DNA load <4000 copies/ml. Moreover, regardless of the EBV-DNA load, IC could improve DMFS, but there was no effect on LRFS.
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http://dx.doi.org/10.3389/fonc.2020.610787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921716PMC
February 2021

Highly Efficient and Super Stable Full-Color Quantum Dots Light-Emitting Diodes with Solution-Processed All-Inorganic Charge Transport Layers.

Small 2021 Mar 3;17(12):e2007363. Epub 2021 Mar 3.

Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.

High performance and super stable all-inorganic full-color quantum dot light-emitting diodes (QLEDs) are constructed by adopting solution-processed Mg-doped NiO (Mg-NiO ) nanoparticles as hole transport layer (HTL) and Al-doped ZnO (AZO) as electron transport layer (ETL). Mg-NiO nanoparticles possess the advantages of low-temperature solution processability, intrinsic stability, and controllable electronic properties. UV-ozone (UVO) treatment is applied to the Mg-NiO film to modulate its surface composition. By carefully controlling the UVO treating time, favorable energy levels can be achieved to minimize the energy barrier for hole injection. At the cathode side, Al-doping can reduce the conductivity of ZnO ETL and decrease the interface charge transfer, effectively, thus leading to more balanced charge injection and consequent high luminance and efficiency. The maximum luminance and EQE can reach as high as 38 444 cd m and 5.09% for R-QLEDs, 177 825 cd m and 10.1% for G-QLEDs, and 3103 cd m and 2.19% for B-QLEDs. The luminance values are the highest ever reported for all-inorganic QLEDs. Furthermore, the all-inorganic devices show much better resistance to water and oxygen existing in air. The results show that the ion-doped NiO and AZO nanoparticles would facilitate the design and development of highly efficient and super stable QLEDs.
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http://dx.doi.org/10.1002/smll.202007363DOI Listing
March 2021

Using digital whole-slide images to evaluate renal amyloid deposition and its association with clinical features and outcomes of AL amyloidosis.

J Nephrol 2021 Mar 2. Epub 2021 Mar 2.

National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu, China.

Background: Few data are available quantifying the proportion of amyloid deposition in renal biopsy specimens. The aim of the study is to investigate the correlation between the proportion of amyloid deposition in renal biopsy and clinical characteristics of Chinese patients with immunoglobulin light-chain amyloidosis (AL amyloidosis).

Methods: 259 patients diagnosed with renal AL amyloidosis between 2003 and 2015 were studied retrospectively. We developed a digital, automated quantification method to evaluate amyloid deposits in glomeruli, vessels and interstitium on digital whole-slide images (WSIs). The associations between the proportion of amyloid-positive area in the renal biopsy and clinical manifestations were analyzed.

Results: The proportion (%) of amyloid-positive area in glomeruli, vessels, interstitium and the whole renal tissue were 11.81 ± 11.38, 14.14 ± 14.05, 3.34 ± 5.36 and 4.25 ± 5.77, respectively. The proportion of amyloid deposition in glomeruli, vessels and interstitium was positively correlated with serum creatinine (Scr), estimated glomerular filtration rate (eGFR) and urinary retinol binding protein (RBP). The proportion of glomerular amyloid deposition, age, urinary N-acetyl-b-D-glucosaminidase (NAG) and urinary RBP could independently predict the risk for overall death. The proportion (%) of amyloid-positive area in blood vessels, interstitium and the whole renal tissue, Scr, and urinary RBP were independent risk factors associated with renal survival.

Conclusion: A novel digital analysis algorithm was firstly developed to quantify the proportion of amyloid deposits in renal tissues based on digital WSIs. The degree and localization of amyloid deposits in the kidney evaluated by digital WSIs may have predictive value in assessing risk of outcome of AL amyloidosis.
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http://dx.doi.org/10.1007/s40620-020-00948-1DOI Listing
March 2021

Development and application of sensitive, specific, and rapid CRISPR-Cas13-based diagnosis.

J Med Virol 2021 Jul 25;93(7):4198-4204. Epub 2021 Mar 25.

Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Nucleic acid detection is a necessary part of medical treatment and fieldwork. However, the current detection technologies are far from ideal. A lack of timely and accessible testing for identifying cases and close contacts has allowed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative virus of the ongoing coronavirus disease-2019 (COVID-19) pandemic, to spread uncontrollably. The slow and expensive detection of mutations-predictors for chronic diseases such as cancer-form a barrier to personalized treatment. A recently developed diagnostic assay is ideal and field-ready-it relies on CRISPR-Cas13. CRISPR-Cas13 works similarly to other CRISPR systems: Cas13 is guided by a crRNA to cleave next to a specific RNA target sequence. Additionally, Cas13 boasts a unique collateral cleavage activity; collateral cleavage of a fluorescent reporter detects the presence of the target sequence in sample RNA. This system forms the basis of CRISPR-Cas13 diagnostic assays. CRISPR-Cas13 assays have >95% sensitivity and >99% specificity. Detection is rapid (<2 h), inexpensive ($0.05 per test), and portable-a test using lateral flow strips is akin to a pregnancy test. The recent adaptation of micro-well chips facilitates high-level multiplexing and is high-throughput. In this review, we cover the development of CRISPR-Cas13 assays for medical diagnosis, discuss the advantages of CRISPR-Cas13-based diagnosis over the traditional reverse transcription polymerase chain reaction (RT-PCR), and present examples of detection from real patient samples.
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http://dx.doi.org/10.1002/jmv.26889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014745PMC
July 2021

A prospective phase II study of raltitrexed combined with S-1 as salvage treatment for patients with refractory metastatic colorectal cancer.

Asia Pac J Clin Oncol 2021 Feb 10. Epub 2021 Feb 10.

Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

Aim: A third-line chemotherapy regimen for metastatic colorectal cancer (mCRC) is not available in China. Studies have shown that raltitrexed or S-1 has no complete cross-resistance with fluorouracil (5-FU). In this phase II study, we prospectively analyzed the efficacy and safety of raltitrexed combined with S-1 (RS regimen) in the treatment of mCRC after the failure of conventional chemotherapy.

Methods: A total of 105 patients with mCRC with progression following treatment with 5-FU, oxaliplatin, and irinotecan were enrolled between November 2015 and May 2019. Patients received intravenous infusion of raltitrexed (3 mg/m from day 1 every 3 weeks) and oral S-1 (80-120 mg for 14 days every 3 weeks). Tumor evaluations were performed every two cycles according to the RECIST 1.1 guidelines.

Results: In the intention-to-treat patients, the objective response and disease control rates were 7.62% and 48.57%, respectively. The median progression-free survival and median overall survival were 2.5 and 8.0 months, respectively. Common adverse events included neutropenia, anemia, thrombocytopenia, and nausea, while neutropenia, anemia, thrombocytopenia nausea, diarrhea, skin eruption, and oral ulceration had grade 3 or higher adverse events. Subgroup analysis revealed that primary site or gene mutation status had little influence on the RS regimen efficacy, while the baseline albumin level, 5-FU administration in second-line therapy, and number of previous treatment regimens affected the efficacy.

Conclusion: The RS regimen demonstrated favorable effects in patients with mCRC following failure of standard chemotherapy, and could be a new choice for third-line treatment, and must be verified in future randomized clinical trials (Clinical trial: NCT02618356).
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http://dx.doi.org/10.1111/ajco.13511DOI Listing
February 2021

A STING-related prognostic score predicts high-risk patients of colorectal cancer and provides insights into immunotherapy.

Ann Transl Med 2021 Jan;9(1):14

Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China.

Background: Targeted therapeutic strategies for advanced colorectal cancer (CRC) have been limited. STING is crucial to the antitumor immunotherapy, for it stimulates IFN signaling to mediate the crosstalk between innate and adaptive immune responses. Emerging evidence suggests that STING also contributes to the prognosis of CRC. However, prognostic models relating to STING have not yet been explored.

Methods: A total of 431 CRC samples from the TCGA database were analyzed to explore the prognostic value of STING-related genes. We trained prognostic models using the multivariate Cox regression. A STING-related prognostic score (SPS) was calculated as the gene expression multiplied by the corresponding coefficients of the final model. A backward stepAIC strategy was adopted to select the optimal model. A nomogram was used to personalize medical decisions for CRC.

Results: The expression level of STING was upregulated in the CMS1 subtype (P=0.036). Among STING-related genes, DHX9 (HR =0.72, P=0.01), IRF2 (HR =1.34, P=0.022), and POLR1D (HR =1.23, P=0.038) showed significant prognostic value. The SPS was proven to be an independent risk factor (training: HR =2.9, P=0.00013; validation: HR =3.02, P=0.01), and outperformed random classifiers in identifying high-risk CRC. The high SPS group was characterized by less genomic aberrations, upregulated IL6-JAK-STAT3 and IL2-STAT5 signaling pathways, increased expression of TIM-3, increased infiltration of regulatory T (Treg) cells and T helper 17 (Th17) cells, and decreased infiltration of M0 macrophages. Finally, the nomogram based on the SPS and clinical factors showed good performance in CRC.

Conclusions: SPS is an independent risk factor that could identify high-risk CRC. While ICBs may benefit patients of the CMS1 subtype, for the CMS2, CMS3, and CMS4 subtypes in the high SPS group, STING agonists and immunotherapies targeting the Th17 axis may be beneficial. Finally, the SPS-based nomogram could help advance personalized medical decisions for CRC.
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http://dx.doi.org/10.21037/atm-20-2430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859804PMC
January 2021

LncRNA H19 regulates macrophage polarization and promotes Freund's complete adjuvant-induced arthritis by upregulating KDM6A.

Int Immunopharmacol 2021 Apr 1;93:107402. Epub 2021 Feb 1.

Department of Immunology, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, China. Electronic address:

Aberrant expression of long non-coding RNA (lncRNA) H19 is tightly linked to multiple steps of tumorigenesis via the modulation of cell proliferation and apoptosis; however, the pathological significance and regulatory mechanisms of lncRNA H19 in macrophages remain obscure. To investigate whether lncRNA H19 modulates macrophage activation in rheumatoid arthritis (RA), lncRNA H19 levels in PMA-induced PBMC from patients with RA and healthy volunteers were assessed. In addition, the distribution of macrophage subsets, macrophage phenotypic characteristics, and pro-inflammatory gene expression were examined in lncRNA H19 smart silencer- or pcDNA 3.1- H19-transfected macrophages and AAV8-mediated H19 overexpression in a Freund' s complete adjuvant-induced arthritis mouse model. The level of lncRNA H19 was higher in RA patients than in healthy volunteers. Silencing of lncRNA H19 altered lipopolysaccharide plus interferon-induced M1 macrophage polarization and decreased IL-6, CD80, CCL8, and CXCL10 expression in macrophages of RA patients. LncRNA H19 overexpression markedly induced IL-6, CD80, HLA-DR, KDM6A, STAT1, IRF5, CCL8, CXCL9, CXCL10, and CXCL11 expression in macrophages and promoted macrophage migration. AAV8-mediated H19 overexpression aggravated arthritis in mice by promoting M1 macrophage polarization along with iNOS, IL-6, CCL8, CXCL9, CXCL10, CXCL11, MMP3, MMP13 and COX-2 expression in mononuclear cells isolated from the swollen ankle. GSK-J4, an inhibitor of KDM6A, suppressed the activity of lncRNA H19 in macrophages and ameliorated lncRNA H19-aggravated arthritis. In summary, the current study demonstrated that lncRNA H19 is upregulated in RA patients and arthritic mice. LncRNA H19 promotes M1 macrophage polarization and aggravates arthritis by upregulating KDM6A expression.
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http://dx.doi.org/10.1016/j.intimp.2021.107402DOI Listing
April 2021

Cell Cycle Regulation of the Pdx1 Transcription Factor in Developing Pancreas and Insulin-Producing β-Cells.

Diabetes 2021 04 1;70(4):903-916. Epub 2021 Feb 1.

Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN

Current evidence indicates that proliferating β-cells express lower levels of some functional cell identity genes, suggesting that proliferating cells are not optimally functional. Pdx1 is important for β-cell specification, function, and proliferation and is mutated in monogenic forms of diabetes. However, its regulation during the cell cycle is unknown. Here we examined Pdx1 protein expression in immortalized β-cells, maternal mouse islets during pregnancy, and mouse embryonic pancreas. We demonstrate that Pdx1 localization and protein levels are highly dynamic. In nonmitotic cells, Pdx1 is not observed in constitutive heterochromatin, nucleoli, or most areas containing repressive epigenetic marks. At prophase, Pdx1 is enriched around the chromosomes before Ki67 coating of the chromosome surface. Pdx1 uniformly localizes in the cytoplasm at prometaphase and becomes enriched around the chromosomes again at the end of cell division, before nuclear envelope formation. Cells in S phase have lower Pdx1 levels than cells at earlier cell cycle stages, and overexpression of Pdx1 in INS-1 cells prevents progression toward G2, suggesting that cell cycle-dependent regulation of Pdx1 is required for completion of mitosis. Together, we find that Pdx1 localization and protein levels are tightly regulated throughout the cell cycle. This dynamic regulation has implications for the dichotomous role of Pdx1 in β-cell function and proliferation.
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http://dx.doi.org/10.2337/db20-0599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980191PMC
April 2021
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