Publications by authors named "Ye Hu"

246 Publications

A potential role for metastasis-associated in colon cancer 1 () as a pan-cancer prognostic and immunological biomarker.

Math Biosci Eng 2021 Sep;18(6):8331-8353

Department of Oncology & Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian 116023, China.

Background: Metastasis-Associated in Colon Cancer 1(MACC1) is a validated biomarker for metastasis and is linked to survival. Although extensive experimental evidence indicates an association between MACC1 and diverse cancers, no pan-cancer analyses have yet been performed for this marker, and the role of MACC1 in immunology remains unknown.

Material And Methods: In our study, we performed the analysis of MACC1 expression and its influence on prognosis using multiple databases, including TIMER2, GEPIA2, Kaplan-Meier plotter. MACC1 promoter methylation levels were evaluated using the UALCAN database. Based on the TCGA database, we explored the relationship between MACC1 and tumor mutational burden (TMB), microsatellite instability (MSI), immune checkpoints using the R programming language. We evaluated the association between MACC1 and immune infiltration via TIMER and UALCAN.

Results: Our results revealed that abnormal DNA methylation may be an important cause for the different expression of MACC1 across cancer types. Meanwhile, we explored the potential oncogenic roles of MACC1 and found significant prognostic value. MACC1 may be related to T-cell function and the polarization of tumor-associated macrophages, especially in STAD and LGG. Its expression was associated with immune infiltration and was found to be closely related to immune checkpoint-associated genes, especially CD274 and SIGLEC15, indicating that MACC1 may be a potential immune therapeutic target for several malignancies. Our paper reveals for the first time the relationship between MACC1 and cancer immunology.

Conclusions: MACC1 might act as a predictor for the immune response in cancer patients, and could also represent a new potential immunotherapeutic target.
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http://dx.doi.org/10.3934/mbe.2021413DOI Listing
September 2021

SIRT7 interacts with TEK (TIE2) to promote adriamycin induced metastasis in breast cancer.

Cell Oncol (Dordr) 2021 Nov 19. Epub 2021 Nov 19.

Biobank, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, 518035, People's Republic of China.

Purpose: Emerging evidence suggests that cytotoxic therapy may promote drug resistance and metastasis while inhibiting the growth of primary tumors. As yet, however, the underlying mechanisms remain unclear. Here, we aimed to investigate the pro-metastatic effects of adriamycin (ADR) therapy on breast cancer cells and to investigate the mechanisms underlying these effects.

Methods: Differentially expressed genes between MCF-7 and ADR-resistant MCF-7 breast cancer cells were identified using high-throughput RNA-seq and differential gene expression analyses. In vitro transwell and scratch wound-healing assays, and an in vivo spontaneous metastasis model were used to study the metastatic potential of the breast cancer cells. The relationship between SIRT7 and TEK expression was studied using promoter activity, electrophoretic mobility shift (EMSA), CHIP-qPCR and Co-IP assays.

Results: Using transcriptome sequencing, we identified two key genes (SIRT7 and TEK) that might contribute to the pro-metastatic effect of ADR on breast cancer cells. SIRT7 acted as a negative regulator for TEK by inducing deacetylation of H3K18 at the TEK promoter. Through transcription factor prediction and double fluorescence experiments, we found that EST-1 could bind to the TEK promoter. Knockdown of EST-1 removed the transcriptional inhibition of TEK that was mediated by up-regulation of SIRT7. Co-IP showed that SIRT7 interacts directly with EST-1 in breast cancer cells, indicating that SIRT7 may induce H3K18 deacetylation at the TEK promoter region by directly binding to EST-1. In vitro and in vivo results showed that overexpression of SIRT7 or inhibition of TIE2 significantly reduced ADR-dependent breast cancer cell invasion/metastasis.

Conclusion: Our findings suggest that ADR therapy may accelerate breast cancer metastasis in a SIRT7/TEK(TIE2) dependent manner.
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http://dx.doi.org/10.1007/s13402-021-00649-2DOI Listing
November 2021

Nomogram to predict contralateral breast cancer risk in breast cancer survivors: A SEER-based study.

Medicine (Baltimore) 2021 Nov;100(46):e27595

Department of Oncology & Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, China.

Abstract: The main purpose of this study was to build a prediction model for patients with contralateral breast cancer (CBC) using competing risks methodology. The aim is to help clinicians predict the probability of CBC in breast cancer (BC) survivors.We reviewed data from the Surveillance, Epidemiology, and End Results database of 434,065 patients with BC. Eligible patients were used to quantify the association between the development of CBC and multiple characteristics of BC patients using competing risk models. A nomogram was also created to facilitate clinical visualization and analysis. Finally, the stability of the model was verified using concordance index and calibration plots, and decision curve analysis was used to evaluate the clinical utility of the model by calculating the net benefit.Four hundred thirty-four thousand sixty-five patients were identified, of whom 6944 (1.6%) developed CBC in the 10 years follow-up. The 10-year cumulative risk of developing CBC was 2.69%. According to a multivariate competing risk model, older patients with invasive lobular carcinoma who had undergone unilateral BC surgery, and whose tumor was better differentiated, of smaller size and ER-negative/PR-positive, had a higher risk of CBC. The calibration plots illustrated an acceptable correlation between the prediction by nomogram and actual observation, as the calibration curve was closed to the 45° diagonal line. The concordance index for the nomogram was 0.65, which indicated it was well calibrated for individual risk of CBC. Decision curve analysis produced a wide range of risk thresholds under which the model we built would yield a net benefit.BC survivors remain at high risk of developing CBC. Patients with CBC have a worse clinical prognosis compared to those with unilateral BC. We built a predictive model for the risk of developing CBC based on a large data cohort to help clinicians identify patients at high risk, which can then help them plan individualized surveillance and treatment.
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http://dx.doi.org/10.1097/MD.0000000000027595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601336PMC
November 2021

TMEM116 is required for lung cancer cell motility and metastasis through PDK1 signaling pathway.

Cell Death Dis 2021 Nov 16;12(12):1086. Epub 2021 Nov 16.

State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, P. R. China.

Transmembrane protein (TMEM) is a family of protein that spans cytoplasmic membranes and allows cell-cell and cell-environment communication. Dysregulation of TMEMs has been observed in multiple cancers. However, little is known about TMEM116 in cancer development. In this study, we demonstrate that TMEM116 is highly expressed in non-small-cell lung cancer (NSCLC) tissues and cell lines. Inactivation of TMEM116 reduced cell proliferation, migration and invasiveness of human cancer cells and suppressed A549 induced tumor metastasis in mouse lungs. In addition, TMEM116 deficiency inhibited PDK1-AKT-FOXO3A signaling pathway, resulting in accumulation of TAp63, while activation of PDK1 largely reversed the TMEM116 deficiency induced defects in cancer cell motility, migration and invasive. Together, these results demonstrate that TMEM116 is a critical integrator of oncogenic signaling in cancer metastasis.
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http://dx.doi.org/10.1038/s41419-021-04369-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599864PMC
November 2021

LPS-induced macrophage HMGB1-loaded extracellular vesicles trigger hepatocyte pyroptosis by activating the NLRP3 inflammasome.

Cell Death Discov 2021 Nov 6;7(1):337. Epub 2021 Nov 6.

Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.

Extracellular vesicles (EVs) have emerged as important vectors of intercellular dialogue. High mobility group box protein 1 (HMGB1) is a typical damage-associated molecular pattern (DAMP) molecule, which is cytotoxic and leads to cell death and tissue injury. Whether EVs are involved in the release of HMGB1 in lipopolysaccharide (LPS)-induced acute liver injuries need more investigation. EVs were identified by transmission electron microscopy, nanoparticle tracking analysis (NTA), and western blotting. The co-localization of HMGB1, RAGE (receptor for advanced glycation end-products), EEA1, Rab5, Rab7, Lamp1 and transferrin were detected by confocal microscopy. The interaction of HMGB1 and RAGE were investigated by co-immunoprecipitation. EVs were labeled with the PKH67 and used for uptake experiments. The pyroptotic cell death was determined by FLICA 660-YVAD-FMK. The expression of NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasomes were analyzed by western-blot or immunohistochemistry. Serum HMGB1, ALT (alanine aminotransferase), AST (aspartate aminotransferase), LDH (lactate dehydrogenase) and MPO (myeloperoxidase) were measured using a commercial kit. The extracellular vesicle HMGB1 was detected in the serums of sepsis patients. Macrophages were found to contribute to HMGB1 release through the EVs. HMGB1-RAGE interactions participated in the loading of HMGB1 into the EVs. These EVs shuttled HMGB1 to target cells by transferrin-mediated endocytosis leading to hepatocyte pyroptosis by the activation of NLRP3 inflammasomes. Moreover, a positive correlation was verified between the sepsis serum EVs-HMGB1 level and clinical liver damage. This finding provides insights for the development of novel diagnostic and therapeutic strategies for acute liver injuries.
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http://dx.doi.org/10.1038/s41420-021-00729-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572226PMC
November 2021

An Efficient Closed Form Solution to the Absolute Orientation Problem for Camera with Unknown Focal Length.

Sensors (Basel) 2021 Sep 28;21(19). Epub 2021 Sep 28.

Northwest Institute of Nuclear Technology, Xi'an 710024, China.

In this paper we propose an efficient closed form solution to the absolute orientation problem for cameras with an unknown focal length, from two 2D-3D point correspondences and the camera position. The problem can be decomposed into two simple sub-problems and can be solved with angle constraints. A polynomial equation of one variable is solved to determine the focal length, and then a geometric approach is used to determine the absolute orientation. The geometric derivations are easy to understand and significantly improve performance. Rewriting the camera model with the known camera position leads to a simpler and more efficient closed form solution, and this gives a single solution, without the multi-solution phenomena of perspective-three-point (P3P) solvers. Experimental results demonstrated that our proposed method has a better performance in terms of numerical stability, noise sensitivity, and computational speed, with synthetic data and real images.
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http://dx.doi.org/10.3390/s21196480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8512203PMC
September 2021

Novel Role of miR-18a-5p and Galanin in Rat Lung Ischemia Reperfusion-Mediated Response.

Oxid Med Cell Longev 2021 14;2021:6621921. Epub 2021 Aug 14.

Center of Pulmonary & Critical Care Medicine, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.

Lung ischemia reperfusion (IR) is known to occur after lung transplantation or cardiac bypass. IR leads to tissue inflammation and damage and is also associated with increased morbidity and mortality. Various receptors are known to partake in activation of the innate immune system, but the downstream mechanism of tissue damage and inflammation is yet unknown. MicroRNAs (miRNAs) are in the forefront in regulating ischemia reperfusion injury and are involved in inflammatory response. Here, we have identified by high-throughput approach and evaluated a distinct set of miRNAs that may play a role in response to IR in rat lung tissue. The top three differentially expressed miRNAs were validated through quantitative PCRs in the IR rat lung model and an model of IR of hypoxia and reoxygenation exposed type II alveolar cells. Among the miRNAs, miR-18a-5p showed consistent downregulation in both the model systems on IR. Cellular and molecular analysis brought to light a crucial role of this miRNA in ischemia reperfusion. miR-18a-5p plays a role in IR-mediated apoptosis and ROS production and regulates the expression of neuropeptide Galanin. It also influences the nuclear localization of transcription factor: nuclear factor-erythroid 2-related factor (Nrf2) which in turn may regulate the expression of the miR-18a gene. Thus, we have not only established a rat model for lung IR and enumerated the important miRNAs involved in IR but have also extensively characterized the role of miR-18a-5p. This study will have important clinical and therapeutic implications for and during transplantation procedures.
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http://dx.doi.org/10.1155/2021/6621921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420977PMC
August 2021

Isolation, characterization and HepG-2 inhibition of a novel proteoglycan from Flammulina velutipes.

Int J Biol Macromol 2021 Oct 16;189:11-17. Epub 2021 Aug 16.

Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University, Beijing 100048, China; Key Laboratory of Grains and Oils Quality Control and Processing, Collaborative Innovation Center for Modern Grain Circulation and Safety, College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing 210023, China. Electronic address:

Flammulina velutipes has anti-inflammatory, immunomodulatory, antioxidant and many bioactive properties with high contents of carbohydrate, proteins and fibers. In this study, a novel proteoglycan with polysaccharide complexes and protein chain, named PGD1-1, was isolated from F. velutipes. The structural characteristics of PGD1-1 were then determined, and its anti-proliferation and pro-apoptotic activities against HepG-2 cells were demonstrated in vitro. Results proved that the average molecular weight of PGD1-1 was 32.71 kDa, and the carbohydrate and protein contents were 93.35 and 2.33%, respectively. The protein moiety was bonded to a polysaccharide chain via O-glycosidic linkage. The monosaccharides consisted of d-glucose, D-galactose and D-xylose in a molar ratio of 21.90:2.84:1.00. PGD1-1 significantly inhibited the proliferation of HepG-2 cells by affecting cell lipid peroxidation and nitric oxide production. In addition, PGD1-1 promoted the apoptosis of HepG-2 cells, especially the early apoptosis. These findings proved that PGD1-1 was a novel potent ingredient against the proliferation of HepG-2, which will provide a theoretical basis for the development and utilization of the functional ingredients of the F. velutipes.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.08.086DOI Listing
October 2021

Chromatin remodeler ARID1A binds IRF3 to selectively induce antiviral interferon production in macrophages.

Cell Death Dis 2021 07 27;12(8):743. Epub 2021 Jul 27.

Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Transcription factor IRF3 is critical for the induction of antiviral type I interferon (IFN-I). The epigenetic regulation of IFN-I production in antiviral innate immunity needs to be further identified. Here, we reported that epigenetic remodeler ARID1A, a critical component of the mSWI/SNF complex, could bind IRF3 and then was recruited to the Ifn-I promoter by IRF3, thus selectively promoting IFN-I but not TNF-α, IL-6 production in macrophages upon viral infection. Myeloid cell-specific deficiency of Arid1a rendered mice more susceptible to viral infection, accompanied with less IFN-I production. Mechanistically, ARID1A facilitates chromatin accessibility of IRF3 at the Ifn-I promoters by interacting with histone methyltransferase NSD2, which methylates H3K4 and H3K36 of the promoter regions. Our findings demonstrated the new roles of ARID1A and NSD2 in innate immunity, providing insight into the crosstalks of chromatin remodeling, histone modification, and transcription factors in the epigenetic regulation of antiviral innate immunity.
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http://dx.doi.org/10.1038/s41419-021-04032-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316351PMC
July 2021

Imbalance Model of Heart Rate Variability and Pulse Wave Velocity in Psychotic and Nonpsychotic Disorders.

Schizophr Bull 2021 Jul 27. Epub 2021 Jul 27.

Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.

Objectives: Patients with psychiatric disorders have an increased risk of cardiovascular pathologies. A bidirectional feedback model between the brain and heart exists widely in both psychotic and nonpsychotic disorders. The aim of this study was to compare heart rate variability (HRV) and pulse wave velocity (PWV) functions between patients with psychotic and nonpsychotic disorders and to investigate whether subgroups defined by HRV and PWV features improve the transdiagnostic psychopathology of psychiatric classification.

Methods: In total, 3448 consecutive patients who visited psychiatric or psychological health services with psychotic (N = 1839) and nonpsychotic disorders (N = 1609) and were drug-free for at least 2 weeks were selected. HRV and PWV indicators were measured via finger photoplethysmography during a 5-minute period of rest. Canonical variates were generated through HRV and PWV indicators by canonical correlation analysis (CCA).

Results: All HRV indicators but none of the PWV indicators were significantly reduced in the psychotic group relative to those in the nonpsychotic group. After adjusting for age, gender, and body mass index, many indices of HRV were significantly reduced in the psychotic group compared with those in the nonpsychotic group. CCA analysis revealed 2 subgroups defined by distinct and relatively homogeneous patterns along HRV and PWV dimensions and comprising 19.0% (subgroup 1, n = 655) and 80.9% (subgroup 2, n = 2781) of the sample, each with distinctive features of HRV and PWV functions.

Conclusions: HRV functions are significantly impaired among psychiatric patients, especially in those with psychosis. Our results highlight important subgroups of psychiatric patients that have distinct features of HRV and PWV which transcend current diagnostic boundaries.
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http://dx.doi.org/10.1093/schbul/sbab080DOI Listing
July 2021

Potential Prospect of CDK4/6 Inhibitors in Triple-Negative Breast Cancer.

Cancer Manag Res 2021 1;13:5223-5237. Epub 2021 Jul 1.

Department of Oncology & Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, People's Republic of China.

Triple-negative breast cancer (TNBC) is an aggressive, difficult-to-treat subtype of cancer with a poor prognosis; there is an urgent need for effective, targeted molecular therapies. The cyclin D/cyclin-dependent kinase (CDK)4/6-retinoblastoma protein (Rb) pathway plays a critical role in regulating cell cycle checkpoints, a process which is often disrupted in cancer cells. Selective CDK4/6 inhibitors can prevent retinoblastoma protein phosphorylation by invoking cell cycle arrest in the first growth phase (G1), and may therefore represent an effective treatment option. In this article, we review the molecular mechanisms and therapeutic efficacy of CDK4/6 inhibitors in combination with other targeted therapies for the treatment of triple-negative breast cancer. Three selective CDK4/6 inhibitors have so far received the approval of the Food and Drug Administration (FDA) for patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2) breast cancer. Trilaciclib, a small molecule short-acting inhibitor of CDK4/6, has also been approved recently for people with small cell lung cancer, and is also expected to be clinically effective against breast cancer. Although the efficacy of CDK4/6 inhibitors in patients with triple-negative breast cancer remains uncertain, their use in conjunction with other targeted therapies may improve outcomes and is therefore currently being explored. Identifying biomarkers for response or resistance to CDK4/6 inhibitor treatment may optimize the personalization of treatment strategies for this disease. Ongoing and future clinical trials and biomarker studies will shed further light on these topics, and help to realize the full potential of CDK4/6 inhibitor treatment in triple-negative breast cancer.
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http://dx.doi.org/10.2147/CMAR.S310649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257068PMC
July 2021

Accuracy of New Deep Learning Model-Based Segmentation and Key-Point Multi-Detection Method for Ultrasonographic Developmental Dysplasia of the Hip (DDH) Screening.

Diagnostics (Basel) 2021 Jun 28;11(7). Epub 2021 Jun 28.

Department of Anatomy, Dongsan Medical Center, School of Medicine, Keimyung University, Daegu 42601, Korea.

Hip joint ultrasonographic (US) imaging is the golden standard for developmental dysplasia of the hip (DDH) screening. However, the effectiveness of this technique is subject to interoperator and intraobserver variability. Thus, a multi-detection deep learning artificial intelligence (AI)-based computer-aided diagnosis (CAD) system was developed and evaluated. The deep learning model used a two-stage training process to segment the four key anatomical structures and extract their respective key points. In addition, the check angle of the ilium body balancing level was set to evaluate the system's cognitive ability. Hence, only images with visible key anatomical points and a check angle within ±5° were used in the analysis. Of the original 921 images, 320 (34.7%) were deemed appropriate for screening by both the system and human observer. Moderate agreement (80.9%) was seen in the check angles of the appropriate group (Cohen's κ = 0.525). Similarly, there was excellent agreement in the intraclass correlation coefficient (ICC) value between the measurers of the alpha angle (ICC = 0.764) and a good agreement in beta angle (ICC = 0.743). The developed system performed similarly to experienced medical experts; thus, it could further aid the effectiveness and speed of DDH diagnosis.
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http://dx.doi.org/10.3390/diagnostics11071174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303134PMC
June 2021

[The relationships between different surgical approaches for maxillary sinus augmentation and implant failure and complications: a retrospective cohort study].

Shanghai Kou Qiang Yi Xue 2021 Apr;30(2):214-218

Department of Oral and Maxillofacial Surgery, Hefei Stomatology Hospital. Hefei 230001, Anhui Province, China.

Purpose: To investigate the 5-year survival and complication rates of implants placed in grafted sinuses with different surgical approaches and analyze the causes for failure.

Methods: This study retrospectively observed the prognosis of patients who underwent maxillary sinus augmentation by means of lateral window technique(LWT) or transalveolar osteotomy technique (TOT) and simultaneously installed implants performed, in Hefei Stomatological Hospital. The primary predictor variables were surgical approaches, including LWT and TOT. The primary outcome measurement was the 5-year implant survival rate, complication rates and failure causes. Potential confounders included diabetes, age at surgery, gender, smoking habit, oral hygiene, tooth position, length and diameter of implants and type of prosthesis. Chi-square test and logistic regression analysis were performed with SPSS 21.0 software package.

Results: Fifty-nine patients (31 males and 28 females), installed with 93 implants, with a mean age of (61.3±10.1) years old, were enrolled. Over (5±1.2) years of follow-up, five implants failed, with a total survival rate of 94.6%. In detail, there were 3 failed implants in the LWT group and 2 failed implants in the TOT group, for a survival rate of 85.7% and 97.2%, respectively. Chi-square test showed that smoking habit (P=0.010), oral hygiene(P=0.037) as well as operative approach(P=0.040) were significantly associated with the final survival rates, multivariate logistic regression analysis displayed that smoking habit (OR=0.030, 95%CI: 0.002-0.493, P=0.014) was still associated with the finial survival rates. Surgical approach(P=0.025) was markedly related to causes for the failed implants. Of which, three (100%) failed implants in the LWT group was due to poor osseointegration and implant mobility 3 months after sinus augmentation, and 2(100%) in the TOT group was because of persistent peri-implantitis and loss of the graft or alveolar bone 4 years after sinus augmentation. Smoking habit was also significantly relevant to complication rates(P=0.014), and the occurrence incidence of controllable peri-implantitis in patient having a smoking habit was relatively higher, accounting for 6.8%(6/88), compared with patients without smoking habit. Significant relationship between surgical approaches and implant complications was not observed(P=0.051).

Conclusions: Different surgical approaches for maxillary sinus augmentation do not significantly correlate with implant survival rates and implant complications. However, surgical approach is markedly related to the causes of failed implants. Smoking will lead to a decreased implant survival rate and controllable peri-implantitis.
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April 2021

SCUBE3 serves as an independent poor prognostic factor in breast cancer.

Cancer Cell Int 2021 May 18;21(1):268. Epub 2021 May 18.

Biobank, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China.

Background: Accumulating evidences indicate that the signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) plays a key role in the development and progression of many human cancers. However, the underlying mechanism and prognosis value of SCUBE3 in breast cancer are still unclear.

Methods: The clinical data of 137 patients with breast cancer who underwent surgical resection in Taizhou Hospital of Zhejiang Province were retrospectively analyzed. We first conducted a comprehensive study on the expression pattern of SCUBE3 using the Tumor Immune Estimation Resource (TIMER) and UALCAN databases. In addition, the expression of SCUBE3 in breast tumor tissues was confirmed by immunohistochemistry. The protein-protein interaction analysis and functional enrichment analysis of SCUBE3 were analyzed using the STRING and Enrichr databases. Moreover, tissue microarray (TMA) was used to analyze the relationship between SCUBE3 expression levels and clinical-pathological parameters, such as histological type, grade, the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). We further supplemented and identified the above results using the UALCAN and bc-GenExMiner v4.4 databases from TCGA data. The correlation between the expression of SCUBE3 and survival was calculated by multivariate Cox regression analysis to investigate whether SCUBE3 expression may be an independent prognostic factor of breast cancer.

Results: We found that the expression level of SCUBE3 was significantly upregulated in breast cancer tissue compared with adjacent normal tissues. The results showed that the distribution of breast cancer patients in the high expression group and the low expression group was significantly different in ER, PR, HER2, E-cadherin, and survival state (p < 0.05), but there was no significant difference in histologic grade, histologic type, tumor size, lymph node metastasis, TMN stage, subtypes, or recurrence (p > 0.05). In addition, the high expression of SCUBE3 was associated with relatively poor prognosis of ER- (p = 0.012), PR- (p = 0.029), HER2 + (p = 0.007). The multivariate Cox regression analysis showed that the hazard ratio (HR) was 2.80 (95% CI 1.20-6.51, p = 0.0168) in individuals with high SCUBE3 expression, and HR was increased by 1.86 (95% CI 1.06-3.25, p = 0.0300) for per 1-point increase of SCUBE3 expression.

Conclusions: These findings demonstrate that the high expression of SCUBE3 indicates poor prognosis in breast cancer. SCUBE3 expression may serve as a potential diagnostic indicator of breast cancer.
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http://dx.doi.org/10.1186/s12935-021-01947-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130162PMC
May 2021

Antineoplastic Effects and Mechanisms of a New RGD Chimeric Peptide from Bullfrog Skin on the Proliferation and Apoptosis of B16F10 Cells.

Protein J 2021 10 20;40(5):709-720. Epub 2021 Apr 20.

Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin, 300384, China.

Malignant melanoma, an increasingly common form of skin cancer, poses a significant threat to public health, especially when the disease progresses past skin lesions to the stage of advanced metastasis. In this work, a new anti-tumor peptide, temporin La (T-La), was selected from a cDNA library generated from bullfrog skin. Two new derivative antitumor peptides, T-La (S) and T-La (FS), were designed by bioinformatics analysis and coupled with the RGD small molecule peptide to create chimeric RGD peptides, (RGD-T-La [S] and RGD-T-La [FS]). Preliminary experiments showed that the new antitumor peptides had significant antitumor effects. After coupling to the chimeric RGD peptide, the targeted treatment of mouse melanoma was significantly improved. Our data demonstrate that the 4 peptides tested herein significantly inhibited the proliferation, migration, and invasion of B16F10 cells; with an increase in polypeptide concentration, the proportion of melanoma cells in the G0/G1 phase decreased or increased significantly, respectively, the reactive oxygen species (ROS) content increased significantly, the mitochondrial membrane potential decreased significantly, and the expression of pro-apoptotic Bax, Caspase-3, and Caspase-9 increased, and anti-apoptotic Bcl-2 decreased significantly. Tyr and MITF genes were significantly downregulated. In conclusion, the use of these new anti-tumor peptides, when combined with a chimeric RGD peptide, may increase ROS levels and decrease mitochondrial membrane potential by inhibiting the activity of mitochondria, thus releasing apoptosis-promoting factors in B16F10 cells. The present study describes a new potential strategy for the application of promising peptides in the treatment of various cancers.
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http://dx.doi.org/10.1007/s10930-021-09980-xDOI Listing
October 2021

The value of the Demetics ultrasound-assisted diagnosis system in the differential diagnosis of benign from malignant thyroid nodules and analysis of the influencing factors.

Eur Radiol 2021 Oct 15;31(10):7936-7944. Epub 2021 Apr 15.

Department of Ultrasound, Institute of Ultrasound in Musculoskeletal Sports Medicine, Guangdong Second Provincial General Hospital, Guangzhou, 510317, Guangdong, People's Republic of China.

Objectives: To evaluate the value of Demetics and to explore whether Demetics can help radiologists with varying years of experience in the differential diagnosis of benign from malignant thyroid nodules.

Methods: The clinical application value of Demetics was assessed by comparing the diagnostic accuracy of radiologists before and after applying Demetics. This retrospective analysis included 284 thyroid nodules that underwent pathological examinations. Two different combined methods were applied. Using method 1: the original TI-RADS classification was forcibly upgraded or downgraded by one level when Demetics classified the thyroid nodules as malignant or benign. Using method 2: the TI-RADS and benign or malignant classification of the thyroid nodules were flexibly adjusted after the physician learned the Demetics' results.

Results: Demetics exhibited a higher sensitivity than did junior radiologist 1 (p = 0.029) and was similar in sensitivity to the two senior radiologists. Demetics had a higher AUC than both junior radiologists (p = 0.042, p = 0.038) and an AUC similar to that of the senior radiologists. The sensitivity (p = 0.035) and AUC (p = 0.031) of junior radiologist 1 and the specificity (p < 0.001) and AUC (p = 0.026) of junior radiologist 2 improved with combined method 1. The AUC of junior radiologist 2 improved with combined method 2 (p = 0.045). The factors influencing the diagnostic results of Demetics include sonographic signs (echogenicity and echogenic foci), contrast of the image, and nodule size.

Conclusion: Demetics exhibited high sensitivity and accuracy in the differential diagnosis of benign from malignant thyroid nodules. Demetics could improve the diagnostic accuracy of junior radiologists.

Key Points: • Demetics exhibited a high sensitivity and accuracy in the differential diagnosis of benign from malignant thyroid nodules. • Demetics could improve the diagnostic accuracy of junior radiologists in the differential diagnosis of benign from malignant thyroid nodules. • Factors influencing the diagnostic results of Demetics include the sonographic signs (echogenicity and echogenic foci), contrast of the image, and nodule size.
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http://dx.doi.org/10.1007/s00330-021-07884-zDOI Listing
October 2021

Cervical cytology screening facilitated by an artificial intelligence microscope: A preliminary study.

Cancer Cytopathol 2021 Sep 7;129(9):693-700. Epub 2021 Apr 7.

AI Lab, Tencent, Shenzhen, China.

Background: Cervical cytology screening is usually laborious with a heavy workload and poor diagnostic consistency. The authors have developed an artificial intelligence (AI) microscope that can provide onsite diagnostic assistance for cervical cytology screening in real time.

Methods: A total of 2167 cervical cytology slides were selected from a cohort of 10,601 cases from Shenzhen Maternity and Child Healthcare Hospital, and the training data set consisted of 42,073 abnormal cervical epithelial cells. The recognition results of an AI technique were presented in a microscope eyepiece by an augmented reality technique. Potentially abnormal cells were highlighted with binary classification results in a 10× field of view (FOV) and with multiclassification results according to the Bethesda system in 20× and 40× FOVs. In addition, 486 slides were selected for the reader study to evaluate the performance of the AI microscope.

Results: In the reader study, which compared manual reading with AI assistance, the sensitivities for the detection of low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions were significantly improved from 0.837 to 0.923 (P < .001) and from 0.830 to 0.917 (P < .01), respectively; the κ score for atypical squamous cells of undetermined significance (ASCUS) was improved from 0.581 to 0.637; the averaged pairwise κ of consistency for multiclassification was improved from 0.649 to 0.706; the averaged pairwise κ of consistency for binary classification was improved from 0.720 to 0.798; and the averaged pairwise κ of ASCUS was improved from 0.557 to 0.639.

Conclusions: The results of this study show that an AI microscope can provide real-time assistance for cervical cytology screening and improve the efficiency and accuracy of cervical cytology diagnosis.
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http://dx.doi.org/10.1002/cncy.22425DOI Listing
September 2021

Tumour-Targeted and Redox-Responsive Mesoporous Silica Nanoparticles for Controlled Release of Doxorubicin and an siRNA Against Metastatic Breast Cancer.

Int J Nanomedicine 2021 8;16:1961-1976. Epub 2021 Mar 8.

Biobank, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, People's Republic of China.

Introduction: Metastatic breast cancer seriously harms women's health and is currently the tumour type with the highest mortality rate in women. Recently, the combinatorial therapeutic approaches that integrate anti-cancer drugs and genetic agents is an attractive and promising strategy for the treatment of metastatic breast cancer. Moreover, such a combination strategy requires better drug carriers that can effectively deliver the cargo to the breast cancer cells and achieve controlled release in the cells to achieve better therapeutic effects.

Methods: The tumour-targeted and redox-responsive mesoporous silica nanoparticles (MSNs) functionalised with DNA aptamers (AS1411) as a co-delivery system was developed and investigated for the potential against metastatic breast cancer. Doxorubicin (Dox) was loaded onto the MSNs, while AS1411 and a small interfering RNA (siTIE2) were employed as gatekeepers via attachment to the MSNs with redox-sensitive disulfide bonds.

Results: The controlled release of Dox and siTIE2 was associated with intracellular glutathione. AS1411 mediated the targeted delivery of Dox by increasing its cellular uptake in metastatic breast cancer, ultimately resulting in a lower IC50 in MDA-MB-231 cells (human breast cancer cell line with high metastatic potency), improved biodistribution in tumour-bearing mice, and enhanced in vivo anti-tumour effects. The in vitro cell migration/invasion assay and in vivo anti-metastatic study revealed synergism in the co-delivery system that suppresses cancer cell metastasis.

Conclusion: The tumour-targeted and redox-responsive MSN prepared in this study are promising for the effective delivery and controlled release of Dox and siTIE2 for improved treatment of metastatic breast cancer.
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http://dx.doi.org/10.2147/IJN.S278724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954039PMC
March 2021

Identification of Infertility-Associated Topologically Important Genes Using Weighted Co-expression Network Analysis.

Front Genet 2021 3;12:580190. Epub 2021 Feb 3.

Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Endometriosis has been associated with a high risk of infertility. However, the underlying molecular mechanism of infertility in endometriosis remains poorly understood. In our study, we aimed to discover topologically important genes related to infertility in endometriosis, based on the structure network mining. We used microarray data from the Gene Expression Omnibus (GEO) database to construct a weighted gene co-expression network for fertile and infertile women with endometriosis and to identify gene modules highly correlated with clinical features of infertility in endometriosis. Additionally, the protein-protein interaction network analysis was used to identify the potential 20 hub messenger RNAs (mRNAs) while the network topological analysis was used to identify nine candidate long non-coding RNAs (lncRNAs). Functional annotations of clinically significant modules and lncRNAs revealed that hub genes might be involved in infertility in endometriosis by regulating G protein-coupled receptor signaling (GPCR) activity. Gene Set Enrichment Analysis showed that the phospholipase C-activating GPCR signaling pathway is correlated with infertility in patients with endometriosis. Taken together, our analysis has identified 29 hub genes which might lead to infertility in endometriosis through the regulation of the GPCR network.
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http://dx.doi.org/10.3389/fgene.2021.580190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887323PMC
February 2021

Activation of MAT2A-RIP1 signaling axis reprograms monocytes in gastric cancer.

J Immunother Cancer 2021 02;9(2)

Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution (Wannan Medical College), Wuhu, China

Background: The activation of tumor-associated macrophages (TAMs) facilitates the progression of gastric cancer (GC). Cell metabolism reprogramming has been shown to play a vital role in the polarization of TAMs. However, the role of methionine metabolism in function of TAMs remains to be explored.

Methods: Monocytes/macrophages were isolated from peripheral blood, tumor tissues or normal tissues from healthy donors or patients with GC. The role of methionine metabolism in the activation of TAMs was evaluated with both in vivo analyses and in vitro experiments. Pharmacological inhibition of the methionine cycle and modulation of key metabolic genes was employed, where molecular and biological analyses were performed.

Results: TAMs have increased methionine cycle activity that are mainly attributed to elevated methionine adenosyltransferase II alpha (MAT2A) levels. MAT2A modulates the activation and maintenance of the phenotype of TAMs and mediates the upregulation of RIP1 by increasing the histone H3K4 methylation (H3K4me3) at its promoter regions.

Conclusions: Our data cast light on a novel mechanism by which methionine metabolism regulates the anti-inflammatory functions of monocytes in GC. MAT2A might be a potential therapeutic target for cancer cells as well as TAMs in GC.
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http://dx.doi.org/10.1136/jitc-2020-001364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888314PMC
February 2021

A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients.

NPJ Precis Oncol 2021 Feb 12;5(1). Epub 2021 Feb 12.

State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Studies have shown that tumor microenvironment (TME) might affect drug sensitivity and the classification of colorectal cancer (CRC). Using TME-specific gene signature to identify CRC subtypes with distinctive clinical relevance has not yet been tested. A total of 18 "bulk" RNA-seq datasets (total n = 2269) and four single-cell RNA-seq datasets were included in this study. We constructed a "Signature associated with FOLFIRI resistant and Microenvironment" (SFM) that could discriminate both TME and drug sensitivity. Further, SFM subtypes were identified using K-means clustering and verified in three independent cohorts. Nearest template prediction algorithm was used to predict drug response. TME estimation was performed by CIBERSORT and microenvironment cell populations-counter (MCP-counter) methods. We identified six SFM subtypes based on SFM signature that discriminated both TME and drug sensitivity. The SFM subtypes were associated with distinct clinicopathological, molecular and phenotypic characteristics, specific enrichments of gene signatures, signaling pathways, prognosis, gut microbiome patterns, and tumor lymphocytes infiltration. Among them, SFM-C and -F were immune suppressive. SFM-F had higher stromal fraction with epithelial-to-mesenchymal transition phenotype, while SFM-C was characterized as microsatellite instability phenotype which was responsive to immunotherapy. SFM-D, -E, and -F were sensitive to FOLFIRI and FOLFOX, while SFM-A, -B, and -C were responsive to EGFR inhibitors. Finally, SFM subtypes had strong prognostic value in which SFM-E and -F had worse survival than other subtypes. SFM subtypes enable the stratification of CRC with potential chemotherapy response thereby providing more precise therapeutic options for these patients.
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http://dx.doi.org/10.1038/s41698-021-00142-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881244PMC
February 2021

[Different concentration of lidocaine used for an exodontia of the impacted mandibular third molar].

Shanghai Kou Qiang Yi Xue 2020 Oct;29(5):499-503

Department of Oral and Maxillofacial Surgery, Hefei Stomatology Hospital. Hefei 230001, Anhui Province, China.

Purpose: To investigate the anesthesia outcomes of 1% lidocaine with 1∶100 000 epinephrine (EPI) for inferior alveolar nerve, lingual nerve and buccal nerve block, compared with 2% lidocaine with 1∶100 000 EPI.

Methods: A study with a cross-over design, with each patient also serving as their own control, was implemented to estimate the clinical outcomes. Predictor variable was 1% lidocaine with 1∶100 000 EPI versus 2% lidocaine with 1∶100 000 EPI. Outcome variables were patients' responses to pain on injection, onset time of anesthetizing, efficacy of anesthesia, and the time to sensation return for the lower lip and tongue. Patients reported pain level at every experimental stage with a 10-point Numerical Rating Scale(NRS). Three weeks later, the patients were tested with the alternate drug combinations. The same outcomes were assessed. A verification of treatment difference was performed using SPSS 17.0 software package.

Results: Twenty-one patients were recruited and completed the study protocol. Sixty-two percent of the patients were women and 38% were men with a median age of 24 years [interquartile range (IQR), 20-30 yr]. Patients reported significantly lower pain scores with 1% lidocaine (1.09,95%CI,0.77-1.41) on injection, compared with 2% lidocaine (1.66, 95%CI, 1.33-1.99) (P=0.010). Patients undergoing 1% lidocaine with 1∶100 000 EPI (52-63 s) had a markedly quicker onset time of anesthetizing than those using 2% lidocaine with 1∶100 000 EPI (259-335 s, P=0.000). The efficacy of anesthesia between 2 groups was not significantly different (P=0.751). Among the patients with the pain values of 1~3, there were 9 patients(100%) perceiving slight pain when splitting teeth was performed in 1% lidocaine group, while 4 patients(57%) felt slight pain when elevating soft flaps was performed and 3 patients(43%) perceived mild pain when splitting teeth was performed in 2% lidocaine group (P=0.019). The time to sensation return for the lower lip and tongue was significantly different between the 2 drug formulations (P=0.000), with an extended period of average 61 min (52-69 min) in 2% lidocaine group.

Conclusions: 1% lidocaine with EPI plays a similar role in clinical outcomes for inferior alveolar nerve, lingual nerve and buccal nerve block as 2% lidocaine with EPI, which produces lower pain on injection as well as a relatively short time to sensation return. The reasons for slight pain during surgical operation are a relative lower efficacy of anesthesia on the inferior alveolar nerve in 1% lidocaine group, and on the buccal nerve anesthesia in 2% lidocaine group.
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October 2020

Molecular design and anti-melanoma activity of a novel bullfrog antibacterial peptide RGD-chimera.

Oncol Lett 2021 Feb 15;21(2):115. Epub 2020 Dec 15.

Tianjin Key Laboratory of Agricultural Animal Breeding and Healthy Husbandry, College of Animal Science and Veterinary Medicine, Tianjin Agricultural University, Tianjin 300384, P.R. China.

Melanoma is a common malignant skin tumor, which is the only fatal skin tumor at present. Melanoma has a high degree of malignancy and metastasis. The activity of modified Temporin-La (T-La) peptides from bullfrog skin were evaluated for antitumor activity and improved targeting in melanoma cells. The amino acid sequence of T-La was modified, resulting in the antitumor peptide, T-La (FS). T-La and T-La (FS) were coupled to the RGD small molecule polypeptide to form the chimeric peptides RGD-T-La and RGD-T-La (FS), respectively. The secondary structures for the peptides, evaluated using circular dichroism, were found to be α-helical. The structure of T-La was evaluated using bioinformatics. In addition, the antitumor effects of the modified peptide and the targeting of RGD chimeric peptide to the tumor and were analyzed. Antitumor activity was measured using the MTT assay. Tumor cells with high integrin αvβ3 expression were detected using flow cytometry, and tumor cells were screened for sensitivity to RGD-T-La (FS) to establish a tumor model in nude mice. The effects of the peptides on tumor cells were measured using laser confocal microscopy in real-time. The mechanism of the peptide antitumor activity in tumor cells was evaluated with scanning electron microscopy. B16 melanoma cells were the most sensitive to the peptides, for which the cell survival rate was 24.65% for 10 g/ml RGD-T-La (FS). RGD-La (FS) had a rapid effect on tumor cells. RGD chimeric polypeptides exhibited site-targeting cytotoxic effects in tumor cells. In the B16 melanoma mouse model, the peptides exhibited antitumor effects against early melanoma development and induced tumor apoptosis, possibly by inhibiting VEGF and promoting caspase-3 expression. Overall, the present study provides a scientific basis for the application of small molecule antimicrobial peptides as targeted antitumor agents and lays the foundation for the clinical application of these peptides as antitumor drugs.
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http://dx.doi.org/10.3892/ol.2020.12376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751474PMC
February 2021

Predictive value of protease-activated receptor-2 (PAR ) in cervical cancer metastasis.

J Cell Mol Med 2021 02 23;25(3):1415-1424. Epub 2020 Dec 23.

Biobank of Shenzhen Second People's Hospital, Health Science Center, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.

Metastasis is the primary cause of an unfavourable prognosis in patients with malignant cancer. Over the last decade, the role of proteinases in the tumour microenvironment has attracted increasing attention. As a sensor of proteinases, proteinase-activated receptor 2 (PAR ) plays crucial roles in the metastatic progression of cervical cancer. In the present study, the expression of PAR in multiple types of cancer was analysed by Gene Expression Profiling Interactive Analysis (GEPIA). Kaplan-Meier plotter was used to calculate the correlation between survival and the levels of PAR , Grb-associated binding protein 2(Gab2) and miR-125b. Immunohistochemistry (IHC) was performed to examine PAR expression in a tissue microarray (TMA) of CESCs. Empower Stats was used to assess the predictive value of PAR in the metastatic potential of CESC. We found that PAR up-regulation was observed in multiple types of cancer. Moreover, PAR expression was positively correlated with the clinicopathologic characteristics of CESC. miR-125b and its target Gab2, which are strongly associated with PAR -induced cell migration, are well-characterized as predictors of the prognostic value of CESC. Most importantly, the Cancer Genome Atlas (TCGA) data set analysis showed that the area under the curve (AUC) of the PAR model was significantly greater than that of the traditional model (0.833 vs 0.790, P < .05), demonstrating the predictive value of PAR in CESC metastasis. Our results suggest that PAR may serve as a prognostic factor for metastasis in CESC patients.
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http://dx.doi.org/10.1111/jcmm.16227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875903PMC
February 2021

Affecting Factors and Correction Ratio in Genu Valgum or Varum Treated with Percutaneous Epiphysiodesis Using Transphyseal Screws.

J Clin Med 2020 Dec 18;9(12). Epub 2020 Dec 18.

Department of Orthopedic Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, 1035 Dalgubeol-daero, Dalseo-gu, Daegu 42601, Korea.

This study evaluated the correction rates of idiopathic genu valgum or varum after percutaneous epiphysiodesis using transphyseal screws (PETS) and analyzed the affecting factors. A total of 35 children without underlying diseases were enrolled containing 64 physes (44 distal femoral (DT), 20 proximal tibial (PT)). Anatomic tibiofemoral angle (aTFA) and the mechanical axis deviation (MAD) were taken from teleroentgenograms before PETS surgery and screw removal. The correction rates of the valgus and varus deformities for patients treated with PETS were 1.146°/month and 0.639°/month using aTFA while using MAD showed rates of 4.884%/month and 3.094%/month. After aTFA ( < 0.001) and MAD ( < 0.001) analyses, the correction rate of DF was significantly faster than that of PT. Under multivariable analysis, the aTFA correction rate was significantly faster in younger patients ( < 0.001), in males ( < 0.001), in patients with lower weights ( < 0.001), and in the group that was screwed at DF ( < 0.001). Meanwhile, the MAD correction rate was significantly faster in patients with lower heights ( = 0.003). PETS is an effective treatment method for valgus and varus deformities in growing children and clinical characters should be considered to estimate the correction rate.
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http://dx.doi.org/10.3390/jcm9124093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766970PMC
December 2020

Multi-AGV dispatching and routing problem based on a three-stage decomposition method.

Math Biosci Eng 2020 07;17(5):5150-5172

College of Logistics Engineering, Shanghai Maritime University, Shanghai, 201306, China.

Automatic guided vehicle (AGV) is a device for horizontal transportation between quay cranes and yard cranes in an automated container terminal. In which dispatching and routing problem (DRP) of the AGV system is a vital as well as basic issue. In the application of the actual AGV system, several practical factors including avoiding conflicts, path smoothness, difficulty in adjusting routes and anti-interference must be considered. The present study establishes the model with the goal of minimizing AGV travel distance, reducing operation time and response time. Furthermore, a three-stage decomposition solution to the problem was proposed by combining the advantages of pre-planning algorithm and real-time planning algorithm, which combines A algorithm with the principle of time window to plan the path of each AGV in time order. Finally, the effectiveness of this method in path search and time optimization is illustrated and the system efficiency is improved by comparing and analyzing the calculation examples of different scales.
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http://dx.doi.org/10.3934/mbe.2020279DOI Listing
July 2020

Identification and rescue of a novel TUBB8 mutation that causes the first mitotic division defects and infertility.

J Assist Reprod Genet 2020 Nov 18;37(11):2713-2722. Epub 2020 Sep 18.

Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Purpose: Tubulin beta eight class VIII (TUBB8) is essential for oogenesis, fertilization, and pre-implantation embryo development in human. Although TUBB8 mutations were recently discovered in meiosis-arrested oocytes of infertile females, there is no effective therapy for this gene mutation caused infertility. Our study aims to further reveal the infertility-causing gene mutations in the patient's family and to explore whether the infertility could be rescued by optimizing the conditions of embryo culture and finally achieve the purpose of making the patient pregnant.

Methods: Whole-exome sequence analysis and Sanger sequencing were performed on patients' family members to screen and identify candidate mutant genes. Construction of plasmids, in vitro transcription, microinjection of disease-causing gene cRNA, and immunofluorescence staining were used to recapitulate the infertility phenotype observed in patients and to understand the pathogenic principles. Simultaneously, overexpression of mutant and wild-type cRNA of the candidate gene in mouse oocytes at either germinal vesicle (GV) or metaphase II (MII) stage was performed in the rescue experiment.

Results: We first identified a novel heritable TUBB8 mutation (c.1041C>A: p.N347K) in the coding region which specifically affects the first mitosis and causes the developmental arrest of early embryos in a three-generation family. We further demonstrated that TUBB8 mutation could lead to abnormal spindle assemble. And moreover, additional expression of wild-type TUBB8 cRNA in the mouse oocytes in which the mutant TUBB8 were expressed can successfully rescue the developmental defects of resulting embryo and produce full-term offspring.

Conclusions: Our study not only defines a novel mutation of TUBB8 causing the early cleavage arrest of embryos, but also provides an important basis for treating such female infertility in the future.
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http://dx.doi.org/10.1007/s10815-020-01945-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642063PMC
November 2020

Are Epithelial Ovarian Cancers of the Mesenchymal Subtype Actually Intraperitoneal Metastases to the Ovary?

Front Cell Dev Biol 2020 17;8:647. Epub 2020 Jul 17.

Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Primary ovarian high-grade serous carcinoma (HGSC) has been classified into 4 molecular subtypes: Immunoreactive, Proliferative, Differentiated, and Mesenchymal (Mes), of which the Mes subtype (Mes-HGSC) is associated with the worst clinical outcomes. We propose that Mes-HGSC comprise clusters of cancer and associated stromal cells that detached from tumors in the upper abdomen/omentum and disseminated in the peritoneal cavity, including to the ovary. Using comparative analyses of multiple transcriptomic data sets, we provide the following evidence that the phenotype of Mes-HGSC matches the phenotype of tumors in the upper abdomen/omentum: (1) irrespective of the primary ovarian HGSC molecular subtype, matched upper abdominal/omental metastases were typically of the Mes subtype, (2) the Mes subtype was present at the ovarian site only in patients with concurrent upper abdominal/omental metastases and not in those with HGSC confined to the ovary, and (3) ovarian Mes-HGSC had an expression profile characteristic of stromal cells in the upper abdominal/omental metastases. We suggest that ovarian Mes-HGSC signifies advanced intraperitoneal tumor dissemination to the ovary rather than a subtype of primary ovarian HGSC. This is consistent with the presence of upper abdominal/omental disease, suboptimal debulking, and worst survival previously reported in patients with ovarian Mes-HGSC compared to other molecular subtypes.
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http://dx.doi.org/10.3389/fcell.2020.00647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380132PMC
July 2020
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