Publications by authors named "Wenyan Jiang"

76 Publications

MRI-based peritumoral radiomics analysis for preoperative prediction of lymph node metastasis in early-stage cervical cancer: A multi-center study.

Magn Reson Imaging 2021 Dec 27. Epub 2021 Dec 27.

Department of Biomedical Engineering, School of Intelligent Medicine, China Medical University, Shenyang 110122, PR China. Electronic address:

Purpose: To evaluate intra- and preitumoral radiomics on the contrast-enhanced T1-weighted (CE-T1) and T2-weighted (T2W) MRI for predicting the LNM, and develop a nomogram for potential clinical uses.

Methods: We enrolled 169 cervical cancer cases who underwent CE-T1 and T2W MR scans from two hospitals between Dec. 2015 and Sep. 2021. Intra- and peritumoral features were extracted separately and selected by the least absolute shrinkage and selection operator (LASSO) regression. Radiomics signatures were built using the selected features from different regions. Clinical parameters were evaluated by statistical analysis. The nomogram was developed combining the multi-regional radiomics signature and the most predictive clinical parameters.

Results: Five radiomics features were finally selected from the peritumoral regions with 1 and 3 mm distances in the CE-T1 and T2W MRI, respectively. The nomogram incorporating multi-regional combined radiomics signature, MR-reported LN status and tumor diameter achieved the highest AUCs in the training (nomogram vs. combined radiomics signature vs. clinical model, 0.891 vs. 0.830 vs. 0.812), internal validation (nomogram vs. combined radiomics signature vs. clinical model, 0.863 vs. 0.853 vs. 0.816) and external validation (nomogram vs. combined radiomics signature vs. clinical model, 0.804 vs. 0.701 vs. 0.787) cohort. DCA suggested good clinical usefulness of our developed models.

Conclusion: The current work suggested clinical potential for intra- and peritumoral radiomics with multi-modal MRI for preoperative predicting LNM.
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http://dx.doi.org/10.1016/j.mri.2021.12.008DOI Listing
December 2021

Intratumoral analysis of digital breast tomosynthesis for predicting the Ki-67 level in breast cancer: A multi-center radiomics study.

Med Phys 2022 Jan 13;49(1):219-230. Epub 2021 Dec 13.

School of Intelligent Medicine, China Medical University, Shenyang, P.R. China.

Purpose: To non-invasively evaluate the Ki-67 level in digital breast tomosynthesis (DBT) images of breast cancer (BC) patients based on subregional radiomics.

Methods: A total of 266 patients who underwent DBT scans were consecutively enrolled at two centers, between September 2017 and September 2021. The whole tumor region was partitioned into various intratumoral subregions, based on individual- and population-level clustering. Handcrafted radiomics and deep learning-based features were extracted from the subregions and from the whole tumor region, and were selected by least absolute shrinkage and selection operator (LASSO) regression, yielding radiomics signatures (RSs). The area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity were calculated to assess the developed RSs.

Results: Each breast tumor region was partitioned into an inner subregion (S1) and a marginal subregion (S2). The RSs derived from S1 always generated higher AUCs compared with those from S2 or from the whole tumor region (W), for the external validation cohort (AUCs, S1 vs. W, handcrafted RSs: 0.583 [95% CI, 0.429-0.727] vs. 0.559 [95% CI, 0.405-0.705], p-value: 0.920; deep RSs: 0.670 [95% CI, 0.516-0.802] vs. 0.551 [95% CI, 0.397-0.698], p-value: 0.776). The fusion RSs, combining handcrafted and deep learning-based features derived from S1, yielded the highest AUCs of 0.820 (95% CI, 0.714-0.900) and 0.792 (95% CI, 0.647-0.897) for the internal and external validation cohorts, respectively.

Conclusions: The subregional radiomics approach can accurately predict the Ki-67 level based on DBT data; thus, it may be used as a potential non-invasive tool for preoperative treatment planning in BC.
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http://dx.doi.org/10.1002/mp.15392DOI Listing
January 2022

Key Regulators of Autophagosome Closure.

Cells 2021 10 20;10(11). Epub 2021 Oct 20.

Center of Excellence for Environmental Safety and Biological Effects, Faculty of Environment and Life Sciences, Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Beijing University of Technology, 100 Ping Le Yuan, Chaoyang District, Beijing 100124, China.

Autophagy is an evolutionarily conserved pathway, in which cytoplasmic components are sequestered within double-membrane vesicles called autophagosomes and then transported into lysosomes or vacuoles for degradation. Over 40 conserved autophagy-related (ATG) genes define the core machinery for the five processes of autophagy: initiation, nucleation, elongation, closure, and fusion. In this review, we focus on one of the least well-characterized events in autophagy, namely the closure of the isolation membrane/phagophore to form the sealed autophagosome. This process is tightly regulated by ESCRT machinery, ATG proteins, Rab GTPase and Rab-related proteins, SNAREs, sphingomyelin, and calcium. We summarize recent progress in the regulation of autophagosome closure and discuss the key questions remaining to be addressed.
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http://dx.doi.org/10.3390/cells10112814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616111PMC
October 2021

Abnormal Network Homogeneity in the Right Superior Medial Frontal Gyrus in Cervical Dystonia.

Front Neurol 2021 5;12:729068. Epub 2021 Nov 5.

Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.

Increasing evidence from modern neuroimaging has confirmed that cervical dystonia (CD) is caused by network abnormalities. Specific brain networks are known to be crucial in patients suffering from CD. However, changes in network homogeneity (NH) in CD patients have not been characterized. Therefore, the purpose of this study was to investigate the NH of patients with CD. An automated NH method was used to analyze resting-state functional magnetic resonance (fMRI) data from 19 patients with CD and 21 gender- and age-matched healthy controls (HC). Correlation analysis were conducted between NH, illness duration and symptom severity measured by the Tsui scale. Compared with the HC group, CD patients showed a lower NH in the right superior medial frontal gyrus. No significant correlations were found between abnormal NH values and illness duration or symptom severity. Our findings suggest the existence of abnormal NH in the default mode network (DMN) of CD patients, and thereby highlight the importance of the DMN in the pathophysiology of CD.
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http://dx.doi.org/10.3389/fneur.2021.729068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602349PMC
November 2021

Comparing Brain Functional Activities in Patients With Blepharospasm and Dry Eye Disease Measured With Resting-State fMRI.

Front Neurol 2021 27;12:607476. Epub 2021 Oct 27.

Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.

Blepharospasm (BSP) and dry eye disease (DED) are clinically common diseases characterized by an increased blinking rate. A sustained eyelid muscle activity may alter the cortical sensorimotor concordance and lead to secondary functional changes. This study aimed to explore the central mechanism of BSP by assessing brain functional differences between the two groups and comparing them with healthy controls. In this study, 25 patients with BSP, 22 patients with DED, and 23 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) scan. The amplitude of low-frequency fluctuations (ALFF) was applied to analyze the imaging data. Analysis of covariance (ANCOVA) revealed widespread differences in ALFF across the three groups. In comparison with healthy controls, patients with BSP showed abnormal ALFF in the sensorimotor integration related-brain regions, including the bilateral supplementary motor area (SMA), left cerebellar Crus I, left fusiform gyrus, bilateral superior medial prefrontal cortex (MPFC), and right superior frontal gyrus (SFG). In comparison with patients with DED, patients with BSP exhibited a significantly increased ALFF in the left cerebellar Crus I and left SMA. ALFF in the left fusiform gyrus/cerebellar Crus I was positively correlated with symptomatic severity of BSP. Our results reveal that the distinctive changes in the brain function in patients with BSP are different from those in patients with DED and healthy controls. The results further emphasize the primary role of sensorimotor integration in the pathophysiology of BSP.
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http://dx.doi.org/10.3389/fneur.2021.607476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578056PMC
October 2021

Intra- and peritumoral radiomics on assessment of breast cancer molecular subtypes based on mammography and MRI.

J Cancer Res Clin Oncol 2022 Jan 8;148(1):97-106. Epub 2021 Oct 8.

Department of Biomedical Engineering, School of Intelligent Medicine, China Medical University, Shenyang, 110122, People's Republic of China.

Purpose: This study aimed to investigate the efficacy of digital mammography (DM), digital breast tomosynthesis (DBT), diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI separately and combined in the prediction of molecular subtypes of breast cancer.

Methods: A total of 241 patients were enrolled and underwent breast MD, DBT, DW and DCE scans. Radiomics features were calculated from intra- and peritumoral regions, and selected with least absolute shrinkage and selection operator (LASSO) regression to develop radiomics signatures (RSs). Prediction performance of intra- and peritumoral regions in the four modalities were evaluated and compared with area under the receiver-operating characteristic (ROC) curve (AUC), specificity and sensitivity as comparison metrics.

Results: The RSs derived from combined intra- and peritumoral regions improved prediction AUCs compared with those from intra- or peritumoral regions alone. DM plus DBT generated better AUCs than the DW plus DCE on predicting Luminal A and Luminal B in the training (Luminal A: 0.859 and 0.805; Luminal B: 0.773 and 0.747) and validation (Luminal A: 0.906 and 0.853; Luminal B: 0.807 and 0.784) cohort. For the prediction of HER2-enriched and TN, the DW plus DCE yielded better AUCs than the DM plus DBT in the training (HER2-enriched: 0.954 and 0.857; TN: 0.877 and 0.802) and validation (HER2-enriched: 0.974 and 0.907; TN: 0.938 and 0.874) cohort.

Conclusions: Peritumoral regions can provide complementary information to intratumoral regions for the prediction of molecular subtypes. Compared with MRI, the mammography showed higher AUCs for the prediction of Luminal A and B, but lower AUCs for the prediction of HER2-enriched and TN.
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http://dx.doi.org/10.1007/s00432-021-03822-0DOI Listing
January 2022

First Report of Apiospora mold on sugarcane in China caused by ().

Plant Dis 2021 Sep 21. Epub 2021 Sep 21.

Guangxi Academy of Agricultural Science, 125388, Nanning, Guangxi, China;

Sugarcane ( L. cv. Badila) is a chewing cane cultivar in southern China. Since the first case of poisoning caused by the consumption of moldy sugarcane was confirmed in northern China in 1972, cases have occurred almost every year. It has been confirmed that is the pathogen that primarily occurs during improper postharvest storage (Liu xingjie, 1984). In 2019, ten moldy sugarcane stems (cv. Badila) were collected from Tang County, Baoding City, Hebei Province, China. The sugarcane flesh turned dark and was grayish-white, red, or reddish-brown. Some of them smelled musty. Symptomatic stems were surface disinfected using 75% ethanol and peeled aseptically. Small sections (3 mm) were placed on potato dextrose agar amended with 0.01% chloramphenicol and incubated at 26 ± 2°C. Six fungal isolates were obtained from three sugarcane stems, a positive sample rate of 30%, and identified as the same fungus on the basis of morphological features owing to their formation of flat colonies that were initially white and later turned grayish white with moderate amounts of aerial mycelia. The mycelia consisted of smooth, hyaline, branched, and septate hyphae. The conidiophores were hyaline or pale brown and produced conidiogenous cells. The conidiogenous cells were pale brown, smooth, ampulliform, and 5.5 to 11.2 μm long (n=50). The conidia were brown, smooth, ellipsoidal to spherical, spherical in surface view, 4.5 to 7.4 μm in diameter, and 3.3 to 4.4 μm wide with a pale equatorial slit (n=50). The morphological characteristics of the one representative isolate, named LX1918, were identical to those of (Corda) Dyko & B. Sutton ( (Corda) Pintos & P. Alvarado) (Crous and Groenwald, 2013, Pintos and P. Alvarado, 2021). Genomic DNA was extracted from the mycelia to further identify the isolate. The internal transcribed spacer region (ITS rDNA), the translation elongation factor 1-alpha gene (TEF1) and the ß-tubulin gene (TUB2) were amplified using the primers ITS1/ITS4, EF1-728F/ EF-2 and T1/ Bt2b (White et al., 1990, O'Donnell et al. 1998, O'Donnell et al. 1997), respectively. BLASTn analysis of the ITS (556 bp, GenBank accession no. MW534386), TEF (434 bp, MW584370) and TUB2 (775 bp, MZ090019) sequences of isolate LX1918 showed that they were 99.43%, 99.52% and 99.74% similar to the published sequences of isolate CBS 106.12 (KF144883, KF145015 and KF144973), respectively. To confirm Koch's postulates, pathogenicity tests were conducted in triplicate by inoculating the aseptic wounds with a conidial suspension (10/ml) of the isolate in healthy sugarcane stems. The controls were inoculated with sterile water. The sugarcane stems were incubated at 26 ± 2 °C and 86 % relative humidity in the dark. Obvious moldy symptoms appeared several days after the sugarcane stems had been inoculated. The sugarcane flesh turned reddish brown. In contrast, the control stems were asymptomatic. (Ar. arundinis) was reisolated from the inoculated and moldy sugarcane. In addition, 3-nitropropionic acid could be detected using HPLC-MS after the fungus had been cultured on potato yeast sucrose agar for 14 days. Previous studies had confirmed that 3-nitropropionic acid produced by , and is the causal agent of poisoning caused by the consumption of moldy sugarcane (Hu wenjuan, 1986, Liu xingjie,1987). To our knowledge, this is the first report of () as the causal agent of infected sugarcane and its production of 3-nitropropionic acid, which is toxic to humans. Therefore, the confirmation that () infects sugarcane will expand our understanding of this pathogen and provide fundamental knowledge about the control of Apiospora mold to decrease the incidents of 3-nitropropionic acid poisoning.
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http://dx.doi.org/10.1094/PDIS-02-21-0386-PDNDOI Listing
September 2021

Role of whole-body diffusion-weighted imaging in evaluation of multiple myeloma.

Medicine (Baltimore) 2021 Sep;100(35):e27131

Department of Cardiovascular Center, First Hospital of Jilin University, Changchun, China.

Abstract: The evaluation of bone disease in multiple myeloma (MM) is an important topic in imaging. This study retrospectively investigated whole-body diffusion-weighted imaging (WB-DWI) in the evaluation of bone marrow infiltration and treatment response in MM.A total of 126 patients with MM who underwent WB-DWI between January 2016 and December 2020 were enrolled. All the patients received 4-course induction chemotherapy. WB-DWI was performed before and after chemotherapy to measure the apparent diffusion coefficient (ADC) values. According to gender and Revised International Staging System (RISS) staging groups, the relationship between ADC value and bone marrow plasma cell infiltration ratio before treatment were explored using Spearman and Pearson correlation coefficients. Comparison of ADC values before and after treatment according to different chemotherapy regimens and treatment response was performed by 2-independent samples non-parametric tests and t test.There was a negative correlation between the ADC value and the degree of bone marrow infiltration and this was statistically significant (r = -0.843, P < .001). In different gender and RISS groups, ADC value before treatment was negatively correlated with the proportion of plasma cell infiltration (male, r = -0.849; female, r = -0.836; Stage I, r = -0.659; Stage II, r = -0.870; Stage III, r = -0.745; all P < .001). The ADC values of all subjects increased to varying degrees after 4-course induction chemotherapy, including different chemotherapy regimens and treatment responses (all P < .05 except for progressive disease group).The ADC value was negatively correlated with the degree of bone marrow infiltration in different gender and RISS stages. The ADC value increased after treatment, but it was not consistent with progressive disease group. The increase of ADC value may indicate the disease burden and outcome of MM induced chemotherapy.
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http://dx.doi.org/10.1097/MD.0000000000027131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415940PMC
September 2021

Redox-responsive magnetic nanovectors self-assembled from amphiphilic polymer and iron oxide nanoparticles for a remotely targeted delivery of paclitaxel.

J Mater Chem B 2021 08;9(30):6037-6043

Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Chongqing University, Chongqing 400044, China.

To reduce the side effect of paclitaxel and enhance accumulation at the tumor site, a novel redox-responsive nanovector with excellent biocompatibility based on disulfide-linked amphiphilic polymer and magnetic nanoparticle was prepared. The system would realize PTX release due to breakage of the disulfide bond when being targeted to the tumor site by the external magnetic field. The nanovector significantly improved endocytosis and enhanced accumulation at the tumor site, with an effective inhibition of tumor cells in vitro and in vivo.
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http://dx.doi.org/10.1039/d1tb00991eDOI Listing
August 2021

Myocardial Infarction-Associated Extracellular Vesicle-Delivered miR-208b Affects the Growth of Human Umbilical Vein Endothelial Cells via Regulating CDKN1A.

Biomed Res Int 2021 5;2021:9965639. Epub 2021 Jun 5.

Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.

This study was aimed at investigating the effects of myocardial infarction- (MI-) associated extracellular vesicle- (EV-) delivered miR-208b on human umbilical vein endothelial cells (HUVECs). EVs were isolated and subsequently stained with PHK67. A dual-luciferase reporter gene assay was used to determine the target of miR-208b. Afterwards, HUVECs were transfected with either MI-associated EVs or miR-208b mimics, and cell viability, migration, and apoptosis were subsequently measured. Real-time quantitative polymerase chain reaction (RT-qPCR) was applied to determine the expressions of the tested genes. NanoSight, transmission electron microscopy, and western blotting showed that EVs were successfully isolated. Among the potential microRNA biomarkers for MI, miR-208b was chosen for subsequent experiments. We found that MI-associated EVs could be taken up by HUVECs and confirmed that was a direct target of miR-208b. Additionally, miR-208b mimics and MI-associated EVs significantly inhibited the viability and migration of HUVECs ( < 0.05) and promoted cell apoptosis, as well as reduced S phase and increased G2/M phase cell distribution. RT-qPCR revealed that both miR-208b mimics and MI-associated EVs upregulated the expressions of , , , , and but downregulated the expression of and reduced the / ratio. Our study concludes that MI-associated EVs delivered miR-208b to HUVECs, and EV-delivered miR-208b could affect the growth of HUVECs by regulating the miR-208b/CDKN1A pathway; thus, miR-208b can be therefore served as important therapeutic targets for MI treatment.
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http://dx.doi.org/10.1155/2021/9965639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203352PMC
October 2021

Effect of Preeclampsia on Ultrastructure of Thyroid Gland, Hepatic Type 1 Iodothyronine Deiodinase, and Thyroid Hormone Levels in Rats.

Biomed Res Int 2021 20;2021:6681491. Epub 2021 Apr 20.

School of Rehabilitation and Health Preservation, Chengdu University of Traditional Chinese Medicine, Chengdu 610032, China.

Background: Although hypothyroidism during pregnancy may develop grave outcomes for both mothers and offspring, management of which is still a challenge due to the insufficient understanding of this disease. The close correlation between hypothyroidism and preeclampsia is well documented, suggesting that preeclampsia is a potential risk factor for the development of maternal hypothyroidism. However, the exact role of preeclampsia in gestational hypothyroidism is still obscure.

Objective: In this study, we explored the possible mechanisms of the effect of preeclampsia on thyroid function of maternal rats.

Methods: Thirty pregnant rats were randomly divided into normal pregnancy control (NOP), preeclampsia (PE), and preeclampsia supplemented with amlodipine besylate (PEAml). NG-Nitro-L-arginine-methyl ester was used to induce preeclamptic symptoms. On gestational day 21, rats were sacrificed, and then, the ultrastructure of the thyroid gland, type 1 iodothyronine deiodinase (Dio1) expression, and serum-free thyroxine (FT), free triiodothyronine (FT), and thyroid stimulation hormones (TSH) were assessed.

Results: Compared to NOP rats, results of PE rats showed that thyroid follicular cells' ultrastructure was damaged; both hepatic Dio1 mRNA and protein levels were decreased. Interestingly, these changes were ameliorated in PEAml rats. Additionally, FT, FT, and TSH levels have no significant differences among groups.

Conclusion: These findings indicated that preeclampsia could disrupt synthesis, secretion, and metabolism function of thyroid hormones by damaging thyroid follicular cells and interfering Dio1 expression.
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http://dx.doi.org/10.1155/2021/6681491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183104PMC
October 2021

Personalized medicine modality based on patient-derived xenografts from a malignant transformed GCTB harboring H3F3A G34W mutation.

J Orthop Translat 2021 Jul 1;29:106-112. Epub 2021 Jun 1.

Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.

Background: The function of H3F3A G43W mutation, which has been observed in almost all GCTB, remains poorly characterized. Breakthrough in malignant GCTB has been trapped by the lack of clinical available drugs, limited canonical patient samples and paucity of fidelity preclinical models.

Methods: Tumor samples obtained from a malignant GCTB was implanted in immunodeficient mice for the generation of PDX. Histological examination and short tandem repeat (STR) were used for inherited features analyses. An epigenetic/transcriptional targeted compound library was selected for drug screening. The in vivo effects of selected drug were validated in PDX model.

Results: We established the PDX model with recurrent malignant GCTB specimens, histological examination and STR analyses revealed that PDX and their corresponding parental patients shared the same STRs and histologic features, suggesting common origins. ITF-2357 was the most significant compound with an IC50 lower than 0.1 uM. The results of the drug screening and in vivo PDX validation demonstrated that ITF-2357 might be a promising drug targeted H3F3A G34W mutation MGCTBs.

Conclusion: Our study demonstrates that PDX model maintained the same histologic and genetic features as those in the original patient. targeting HDAC through ITF-2357 effectively overcomes malignant GCTB progression in vitro and in vivo.

Translational Potential Statement: As PDX retain the principal histologic and genetic characteristics of the primary tumors, mad it a valuable research tool in predictive clinical efficacy. In this study, we first established a malignant GCTB PDX model, which might further accelerate the progress of drug development in malignant GCTB.
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http://dx.doi.org/10.1016/j.jot.2021.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173097PMC
July 2021

Suppression of CD13 Enhances the Cytotoxic Effect of Chemotherapeutic Drugs in Hepatocellular Carcinoma Cells.

Front Pharmacol 2021 11;12:660377. Epub 2021 May 11.

School of Pharmacy, Weifang Medical University, Weifang, China.

Multidrug resistance (MDR) of hepatocellular carcinoma (HCC) is a serious problem that directly hinders the effect of chemotherapeutics. In this study, we mainly explore the molecular mechanism of ROS-induced CD13 expression using hepatocarcinoma cells as the research object. We show that the drug of fluorouracil (5FU), epirubicin (EPI) and gemcitabine (GEM) can induce ROS generation, activate Ets2 and promote CD13 expression. Meanwhile, CD13 can activate NRF1 and up-regulate ROS scavenging genes transcription, such as SOD1, GPX1, GPX2 and GPX3, leading to down-regulation of intracellular ROS level and reducing the sensitivity of cells to chemotherapy agent. We also detected the anti-tumor effect of the combination therapy, CD13 inhibitor ubenimex and a variety of conventional anti-cancer drugs, such as 5FU, EPI, GEM, pemetrexed (Pem) and paclitaxel (PTX) were employed in combination. Ubenimex enhances the sensitivity of different chemotherapeutic agents and cooperates with chemotherapeutic agents to suppress tumor growth and . In general, overexpression of CD13 can lead to chemotherapy resistance, and CD13 inhibitor can reverse this effect. Combination of chemotherapy agent and ubenimex will become a potential treatment strategy for liver cancer resistance.
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http://dx.doi.org/10.3389/fphar.2021.660377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144446PMC
May 2021

Inhibition of the FACT Complex Targets Aberrant Hedgehog Signaling and Overcomes Resistance to Smoothened Antagonists.

Cancer Res 2021 06 14;81(11):3105-3120. Epub 2021 Apr 14.

Research Center of Translational Medicine, Shanghai Children's Hospital, State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.

Hedgehog signaling is aberrantly activated in hematologic malignancies and solid tumors, and targeting it is a promising therapeutic strategy against these cancers. Resistance to clinically available hedgehog-targeted Smoothened inhibitor (SMOi) drugs has become a critical issue in hedgehog-driven cancer treatment. Our previous studies identified inhibition of BET and CDK7 as two epigenetic/transcriptional-targeted therapeutic strategies for overcoming SMOi resistance, providing a promising direction for anti-hedgehog drug development. To uncover additional strategies for inhibiting aberrant hedgehog activity, here we performed CRISPR-Cas9 screening with an single-guide RNA library targeting epigenetic and transcriptional modulators in hedgehog-driven medulloblastoma cells, combined with tumor dataset analyses. Structure specific recognition protein 1 (SSRP1), a subunit of facilitates chromatin transcription (FACT) complex, was identified as a hedgehog-induced essential oncogene and therapeutic target in hedgehog-driven cancer. The FACT inhibitor CBL0137, which has entered clinical trials for cancer, effectively suppressed and growth of multiple SMOi-responsive and SMOi-resistant hedgehog-driven cancer models. Mechanistically, CBL0137 exerted anti-hedgehog activity by targeting transcription of and , which are core transcription factors of the hedgehog pathway. SSRP1 bound the promoter regions of and , while CBL0137 treatment substantially disrupted these interactions. Moreover, CBL0137 synergized with BET or CDK7 inhibitors to antagonize aberrant hedgehog pathway and growth of hedgehog-driven cancer models. Taken together, these results identify FACT inhibition as a promising epigenetic/transcriptional-targeted therapeutic strategy for treating hedgehog-driven cancers and overcoming SMOi resistance. SIGNIFICANCE: This study identifies FACT inhibition as an anti-hedgehog therapeutic strategy for overcoming resistance to Smoothened inhibitors and provides preclinical support for initiating clinical trials of FACT-targeted drug CBL0137 against hedgehog-driven cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3186DOI Listing
June 2021

miR-455-5p regulates atrial fibrillation by targeting suppressor of cytokines signaling 3.

J Physiol Biochem 2021 Aug 1;77(3):481-490. Epub 2021 Apr 1.

Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.

Atrial fibrillation (AF) is a condition that heart beats quaveringly or irregularly, which causes blood clots, heart failure, stroke, and other heart-related complications. Therefore, early diagnosis and timely preventions are necessary for AF treatment. Compelling evidence indicated that microRNAs (miRNAs) become emerging biomarkers of AF; thus, we aimed to investigate the possibility of miR-455-5p as an AF marker to provide a new strategy for early diagnosis of AF. A minipump containing angiotensin II was implanted into mice to induce AF, and adeno-associated virus (AAV) carrying anti-miR-negative control (NC) or anti-miR-455-5p was injected into the pericardial space of mice respectively. Next, myocytes isolated from wild-type newborn mice were stimulated with angiotensin II and anti-miR-NC or anti-miR-455-5p mimic. The results showed that the expression of miR-455-5p was positively correlated with the severity of AF, and miR-455-5p mimic accelerated the progression of AF by directly binding to its target gene suppressor of cytokines signaling 3 (SOCS3), leading to the activation of signal transducer and activator of transcription 3 (STAT3) signaling pathway. On the contrary, inhibition of miR-455-5p expression effectively ameliorated AF. In conclusion, miR-455-5p might serve as a biomarker of AF.
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http://dx.doi.org/10.1007/s13105-021-00808-xDOI Listing
August 2021

Effects of Atrial Fibrillation-Derived Exosome Delivery of miR-107 to Human Umbilical Vein Endothelial Cells.

DNA Cell Biol 2021 Apr 2;40(4):568-579. Epub 2021 Mar 2.

Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.

The aim of this study was to explore the effects of atrial fibrillation (AF)-derived exosome delivery of miR-107 to human umbilical vein endothelial cells (HUVECs) and its related mechanisms. Exosomes were isolated from the plasma of patients with AF and healthy controls, followed by characterization. The expression levels of miR-320d, miR-103a-3p, and miR-107 were measured using real-time quantitative PCR (RT-qPCR). The dual-luciferase reporter gene was used to verify the downstream target of miR-107. Afterward, HUVECs were treated with AF-derived exosomes or transfected with miR-107 mimics. After cell culture, Cell Counting Kit-8, Transwell, and flow cytometry were used to determine cell viability, migration, and apoptosis and cell cycle phase. Finally, RT-qPCR was performed to examine the expression of related genes. NanoSight, transmission electron microscopy, and western blotting showed that exosomes were successfully isolated, and that AF-derived exosomes could be taken up by HUVECs. The expression of miR-107 was significantly higher in AF-derived exosomes than in normal exosomes ( < 0.05). was shown to be the direct target of miR-107. In addition, miR-107 mimics and AF-derived exosomes significantly suppressed cell viability and migration ( < 0.05) and enhanced cell apoptosis; they also increased G0/G1-phase cells and reduced S-phase cells. RT-qPCR showed that exosomal miR-107 overexpression significantly downregulated the expression of and ( < 0.05), whereas it markedly upregulated the expression of , and ( < 0.05). AF-derived exosomes can deliver miR-107 to HUVECs, and exosomal miR-107 may regulate cell viability, migration, and apoptosis and cell cycle progression by mediating the miR-107/USP14 pathway.
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http://dx.doi.org/10.1089/dna.2020.6356DOI Listing
April 2021

Abnormal regional homogeneity and its relationship with symptom severity in cervical dystonia: a rest state fMRI study.

BMC Neurol 2021 Feb 5;21(1):55. Epub 2021 Feb 5.

Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China.

Background: Although several brain networks play important roles in cervical dystonia (CD) patients, regional homogeneity (ReHo) changes in CD patients have not been clarified. We investigated to explore ReHo in CD patients at rest and analyzed its correlations with symptom severity as measured by Tsui scale.

Methods: A total of 19 CD patients and 21 gender-, age-, and education-matched healthy controls underwent fMRI scans at rest state. Data were analyzed by ReHo method.

Results: Patients showed increased ReHo in the right cerebellum crus I and decreased ReHo in the right superior medial prefrontal cortex (MPFC). Moreover, the right precentral gyrus, right insula, and bilateral middle cingulate gyrus also showed increased ReHo values. A significantly positive correlation was observed between ReHo value in the right cerebellum crus I and symptom severity (p < 0.05).

Conclusions: Our investigation suggested abnormal ReHo existed in brain regions of the "pain matrix" and salience network (the right insula and bilateral middle cingulate gyrus), the motor network (the right precentral gyrus), the cerebellum and MPFC and further highlighted the significance of these networks in the pathology of CD.
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http://dx.doi.org/10.1186/s12883-021-02079-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863325PMC
February 2021

Voxel-Wise Brain-Wide Functional Connectivity Abnormalities in Patients with Primary Blepharospasm at Rest.

Neural Plast 2021 6;2021:6611703. Epub 2021 Jan 6.

Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China.

Background: Primary blepharospasm (BSP) is one of the most common focal dystonia and its pathophysiological mechanism remains unclear. An unbiased method was used in patients with BSP at rest to observe voxel-wise brain-wide functional connectivity (FC) changes.

Method: A total of 48 subjects, including 24 untreated patients with BSP and 24 healthy controls, were recruited to undergo functional magnetic resonance imaging (fMRI). The method of global-brain FC (GFC) was adopted to analyze the resting-state fMRI data. We designed the support vector machine (SVM) method to determine whether GFC abnormalities could be utilized to distinguish the patients from the controls.

Results: Relative to healthy controls, patients with BSP showed significantly decreased GFC in the bilateral superior medial prefrontal cortex/anterior cingulate cortex (MPFC/ACC) and increased GFC in the right postcentral gyrus/precentral gyrus/paracentral lobule, right superior frontal gyrus (SFG), and left paracentral lobule/supplement motor area (SMA), which were included in the default mode network (DMN) and sensorimotor network. SVM analysis showed that increased GFC values in the right postcentral gyrus/precentral gyrus/paracentral lobule could discriminate patients from controls with optimal accuracy, specificity, and sensitivity of 83.33%, 83.33%, and 83.33%, respectively.

Conclusion: This study suggested that abnormal GFC in the brain areas associated with sensorimotor network and DMN might underlie the pathophysiology of BSP, which provided a new perspective to understand BSP. GFC in the right postcentral gyrus/precentral gyrus/paracentral lobule might be utilized as a latent biomarker to differentiate patients with BSP from controls.
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http://dx.doi.org/10.1155/2021/6611703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808842PMC
October 2021

Reduced Global-Brain Functional Connectivity of the Cerebello-Thalamo-Cortical Network in Patients With Dry Eye Disease.

Front Hum Neurosci 2020 25;14:572693. Epub 2020 Sep 25.

Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.

The pathophysiology of patients with dry eye disease (DED) is associated with abnormal functional connectivity (FC). The present study aims to probe alterations of voxel-wise brain-wide FC in patient with DED at rest in an unbiased way. A total of 20 patients with DED and 23 controls matched by age, sex, and years of education underwent resting-state functional magnetic resonance imaging scans. Global-brain FC (GFC) was adopted to analyze the images. Support vector machine (SVM) was utilized to differentiate the patients from the controls. Compared with the controls, patients with DED exhibited decreased GFC in the right cerebellum lobule VIII/inferior semi-lunar lobule and left thalamus that belonged to the cerebello-thalamo-cortical network. The GFC values in the left thalamus were positively correlated to the illness duration ( = 0.589, = 0.006) in the patients. Decreased GFC values in the left thalamus could be used to discriminate the patients from the controls with optimal accuracy, sensitivity and specificity (88.37, 85.00, and 91.30%). Our findings indicate that decreased GFC in the brain regions associated with cerebello-thalamo-cortical network may provide a new insight for understanding the pathological changes of FC in DED. GFC values in the left thalamus may be utilized as a potential biomarker to identify the patients from the controls.
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http://dx.doi.org/10.3389/fnhum.2020.572693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546321PMC
September 2020

Recent advances in n-butanol and butyrate production using engineered Clostridium tyrobutyricum.

World J Microbiol Biotechnol 2020 Aug 14;36(9):138. Epub 2020 Aug 14.

Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, 43210, USA.

Acidogenic clostridia naturally producing acetic and butyric acids has attracted high interest as a novel host for butyrate and n-butanol production. Among them, Clostridium tyrobutyricum is a hyper butyrate-producing bacterium, which re-assimilates acetate for butyrate biosynthesis by butyryl-CoA/acetate CoA transferase (CoAT), rather than the phosphotransbutyrylase-butyrate kinase (PTB-BK) pathway widely found in clostridia and other microbial species. To date, C. tyrobutyricum has been engineered to overexpress a heterologous alcohol/aldehyde dehydrogenase, which converts butyryl-CoA to n-butanol. Compared to conventional solventogenic clostridia, which produce acetone, ethanol, and butanol in a biphasic fermentation process, the engineered C. tyrobutyricum with a high metabolic flux toward butyryl-CoA produced n-butanol at a high yield of > 0.30 g/g and titer of > 20 g/L in glucose fermentation. With no acetone production and a high C4/C2 ratio, butanol was the only major fermentation product by the recombinant C. tyrobutyricum, allowing simplified downstream processing for product purification. In this review, novel metabolic engineering strategies to improve n-butanol and butyrate production by C. tyrobutyricum from various substrates, including glucose, xylose, galactose, sucrose, and cellulosic hydrolysates containing the mixture of glucose and xylose, are discussed. Compared to other recombinant hosts such as Clostridium acetobutylicum and Escherichia coli, the engineered C. tyrobutyricum strains with higher butyrate and butanol titers, yields and productivities are the most promising hosts for potential industrial applications.
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http://dx.doi.org/10.1007/s11274-020-02914-2DOI Listing
August 2020

Erratum to CDK14 involvement in proliferation migration and invasion of esophageal cancer.

Ann Transl Med 2020 Apr;8(8):559

Department of Medical Oncology, Affiliated Hospital of Nantong University, Nantong 226001, China.

[This corrects the article DOI: 10.21037/atm.2019.11.105.].
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http://dx.doi.org/10.21037/atm.2020.04.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347780PMC
April 2020

miR-19a/19b-loaded exosomes in combination with mesenchymal stem cell transplantation in a preclinical model of myocardial infarction.

Regen Med 2020 06 10;15(6):1749-1759. Epub 2020 Aug 10.

Department of 4 Wards of Cardiovascular Internal Medicine, Shijiazhuang First Hospital, No. 9 Fangbei Road, Shijiazhuang 050011, Hebei, China.

We aimed to investigate the protection of exogenous miR-19a/19b with bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation on cardiac function and inhibition of fibrosis in myocardial infarction (MI). BM-MSC-derived exosomes were used to deliver miR-19a/19b (exo/miR-19a/19b) to the cultured cardiac HL-1 cells, and the apoptosis of cells were evaluated. Exo/miR-19a/19b and BM-MSCs were also transplanted to an MI mouse model. The recovery of cardiac function was assessed and the level of cardiac fibrosis was determined. Exo/miR-19a/19b and MSCs reduced the area of cardiac fibrosis in the heart tissue in the mouse MI model. Using BM-MSC-derived exosomes as a vehicle, miR-19a/19b significantly suppressed the apoptosis of cardiac HL-1 cells. The combination of Exo/miR-19a/19b and MSC transplantation significantly enhanced the recovery of cardiac function and reduced cardiac fibrosis in the MI model. Our study provides an effective regenerative intervention strategy to attenuate the damage of MI.
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http://dx.doi.org/10.2217/rme-2019-0136DOI Listing
June 2020

Vimentin plays an important role in the promotion of breast cancer cell migration and invasion by leucine aminopeptidase 3.

Cytotechnology 2020 Oct 22;72(5):639-647. Epub 2020 Jun 22.

School of Pharmacy, Weifang Medical University, Weifang, China.

Breast cancer is a common type of cancer in females. Our previous studies indicated that leucine aminopeptidase 3 (LAP3) promotes migration and invasion of breast cancer cells. Vimentin is a mesenchymal marker, and its upregulation represents the promotion of epithelial-mesenchymal transition. In this study, we found that LAP3 and vimentin were highly expressed in breast cancer tissues, and the overexpression of LAP3 in breast cancer cells promoted the expression of vimentin. Western blot analysis indicated that the overexpression of LAP3 upregulated the phosphorylation of Erk1/2. MEK inhibitor PD98059 downregulated the expression of vimentin, matrix metalloproteinase-2/9 (MMP-2/9), and fascin through the inhibition of Erk1/2 activity. We hypothesized that LAP3 promoted tumor migration and invasion by upregulating vimentin. The knockdown of vimentin resulted in the inhibited migration and invasion of MDA-MB-231 and MDA-MB-468 cells. The expression of MMP-2/9 and fascin could also be downregulated. In conclusion, vimentin might play an important role in the promotion of breast cancer metastasis by LAP3.
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http://dx.doi.org/10.1007/s10616-020-00402-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548013PMC
October 2020

CD13 Induces Autophagy to Promote Hepatocellular Carcinoma Cell Chemoresistance Through the P38/Hsp27/CREB/ATG7 Pathway.

J Pharmacol Exp Ther 2020 09 22;374(3):512-520. Epub 2020 Jun 22.

School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)

The chemoresistance of hepatocellular carcinoma (HCC) is a serious problem that directly hinders the effect of chemotherapeutic agents. We previously reported that Aminopeptidase N (CD13) inhibition can enhance the cytotoxic efficacy of chemotherapy agents. In the present study, we use liver cancer cells to explore the molecular mechanism accounting for the relationship between CD13 and chemoresistance. We demonstrate that CD13 overexpression activates the P38/heat shock protein 27/cAMP response element-binding protein (CREB) signaling pathway to limit the efficacy of cytotoxic agents. Moreover, blockade of P38 or CREB sensitizes HCC cells to 5-fluorouracil. Then we reveal that CREB binds to the autophagy related 7 () promoter to induce autophagy and promote HCC cell chemoresistance. CD13 inhibition also downregulates the expression of ATG7, autophagy, and tumor cell growth in vivo. Overall, the combination a CD13 inhibitor and chemotherapeutic agents may be a potential strategy for overcoming drug resistance in HCC. SIGNIFICANCE STATEMENT: Our study demonstrates that Aminopeptidase N (CD13) promotes hepatocellular carcinoma (HCC) cell chemoresistance via the P38/heat shock protein 27/cAMP response element-binding protein (CREB) pathway. CREB regulates autophagy related 7 transcription and expression to induce autophagy. Our results collectively suggest that CD13 may serve as a potential target for overcoming HCC resistance.
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http://dx.doi.org/10.1124/jpet.120.265637DOI Listing
September 2020

Meta-analysis of the diagnostic performance of diffusion magnetic resonance imaging with apparent diffusion coefficient measurements for differentiating glioma recurrence from pseudoprogression.

Medicine (Baltimore) 2020 Jun;99(23):e20270

Department of Radiology.

Objective: The accurate differentiation of glioma recurrence from pseudoprogression (PSP) after therapy remains a considerable clinical challenge. Several studies have shown that diffusion magnetic resonance imaging (MRI) has potential value in distinguishing these 2 outcomes. The current meta-analysis examined the diagnostic accuracy of diffusion MRI with the apparent diffusion coefficient (ADC) in the differentiation of glioma recurrence from PSP.

Method: PubMed, Embase, Cochrane Library, and Chinese Biomedical databases were reviewed to identify studies that fulfilled our inclusion/exclusion criteria and were published on or before May 5, 2019. Threshold effects; heterogeneity; pooled sensitivity (SENS), specificity, positive likelihood ratio, and negative likelihood ratio; and diagnostic odds ratio were calculated. The overall diagnostic usefulness of diffusion MRI-derived ADC values was assessed by calculating the area under the curve (AUC) following summary receiver operating characteristic (SROC) analysis.

Results: Six eligible studies examined a total of 214 patients. Calculation of pooled values indicated the SENS was 0.95 (95% confidence interval [CI] = 0.89-0.98), specificity was 0.83 (95% CI = 0.72-0.91), positive likelihood ratio was 4.82 (95% CI = 2.93-7.93), negative likelihood ratio was 0.08 (95% CI = 0.04-0.17), and diagnostic odds ratio was 59.63 (95% CI = 22.63-157.37). The SROC AUC was 0.9322. Publication bias was not significant, and SENS analysis indicated the results were relatively stable.

Conclusions: Our meta-analysis indicated that diffusion MRI with quantitative ADC is an effective approach for differentiation of glioma recurrence from PSP, and can be used as an auxiliary tool to diagnose glioma progression.
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http://dx.doi.org/10.1097/MD.0000000000020270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306328PMC
June 2020

Prokaryotic single-cell RNA sequencing by in situ combinatorial indexing.

Nat Microbiol 2020 10 25;5(10):1192-1201. Epub 2020 May 25.

Department of Biological Sciences, Columbia University, New York City, NY, USA.

Despite longstanding appreciation of gene expression heterogeneity in isogenic bacterial populations, affordable and scalable technologies for studying single bacterial cells have been limited. Although single-cell RNA sequencing (scRNA-seq) has revolutionized studies of transcriptional heterogeneity in diverse eukaryotic systems, the application of scRNA-seq to prokaryotes has been hindered by their extremely low mRNA abundance, lack of mRNA polyadenylation and thick cell walls. Here, we present prokaryotic expression profiling by tagging RNA in situ and sequencing (PETRI-seq)-a low-cost, high-throughput prokaryotic scRNA-seq pipeline that overcomes these technical obstacles. PETRI-seq uses in situ combinatorial indexing to barcode transcripts from tens of thousands of cells in a single experiment. PETRI-seq captures single-cell transcriptomes of Gram-negative and Gram-positive bacteria with high purity and low bias, with median capture rates of more than 200 mRNAs per cell for exponentially growing Escherichia coli. These characteristics enable robust discrimination of cell states corresponding to different phases of growth. When applied to wild-type Staphylococcus aureus, PETRI-seq revealed a rare subpopulation of cells undergoing prophage induction. We anticipate that PETRI-seq will have broad utility in defining single-cell states and their dynamics in complex microbial communities.
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http://dx.doi.org/10.1038/s41564-020-0729-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330242PMC
October 2020

Multi-Habitat Based Radiomics for the Prediction of Treatment Response to Concurrent Chemotherapy and Radiation Therapy in Locally Advanced Cervical Cancer.

Front Oncol 2020 5;10:563. Epub 2020 May 5.

CAS Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, China.

To develop a radiomic model based on multiparametric magnetic resonance imaging (MRI) for predicting treatment response prior to commencing concurrent chemotherapy and radiation therapy (CCRT) for locally advanced cervical cancer. The retrospective study enrolled 120 patients (allocated to a training or a test set) with locally advanced cervical cancer who underwent CCRT between December 2014 and June 2017. All patients enrolled underwent MRI with nine sequences before treatment and again at the end of the fourth week of treatment. Responses were evaluated by MRI according to RECIST standards, and patients were divided into a responder group or non-responder group. For every MRI sequence, a total of 114 radiomic features were extracted from the outlined tumor habitat. On the training set, the least absolute shrinkage and selection operator method was used to select key features and to construct nine habitat signatures. Then, three kinds of machine learning models were compared and applied to integrate these predictive signatures and the clinical characteristics into a radiomic model. The discrimination ability, reliability, and calibration of our radiomic model were evaluated. The radiomic model, which consisted of three habitat signatures from sagittal T2 image, axial T1 enhanced-MRI image, and ADC image, respectively, has shown good predictive performance, with area under the curve of 0.820 (95% CI: 0.713-0.927) in the training set and 0.798 (95% CI: 0.678-0.917) in the test set. Meanwhile, the model proved to perform better than each single signature or clinical characteristic. A radiomic model employing features from multiple tumor habitats held the ability for predicting treatment response in patients with locally advanced cervical cancer before commencing CCRT. These results illustrated a potential new tool for improving medical decision-making and therapeutic strategies.
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http://dx.doi.org/10.3389/fonc.2020.00563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214615PMC
May 2020

Comprehensive Genome-wide Perturbations via CRISPR Adaptation Reveal Complex Genetics of Antibiotic Sensitivity.

Cell 2020 03 27;180(5):1002-1017.e31. Epub 2020 Feb 27.

Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. Electronic address:

Genome-wide CRISPR screens enable systematic interrogation of gene function. However, guide RNA libraries are costly to synthesize, and their limited diversity compromises the sensitivity of CRISPR screens. Using the Streptococcus pyogenes CRISPR-Cas adaptation machinery, we developed CRISPR adaptation-mediated library manufacturing (CALM), which turns bacterial cells into "factories" for generating hundreds of thousands of crRNAs covering 95% of all targetable genomic sites. With an average gene targeted by more than 100 distinct crRNAs, these highly comprehensive CRISPRi libraries produced varying degrees of transcriptional repression critical for uncovering novel antibiotic resistance determinants. Furthermore, by iterating CRISPR adaptation, we rapidly generated dual-crRNA libraries representing more than 100,000 dual-gene perturbations. The polarized nature of spacer adaptation revealed the historical contingency in the stepwise acquisition of genetic perturbations leading to increasing antibiotic resistance. CALM circumvents the expense, labor, and time required for synthesis and cloning of gRNAs, allowing generation of CRISPRi libraries in wild-type bacteria refractory to routine genetic manipulation.
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http://dx.doi.org/10.1016/j.cell.2020.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169367PMC
March 2020

MicroRNA-135a promotes proliferation, migration, invasion and induces chemoresistance of endometrial cancer cells.

Eur J Obstet Gynecol Reprod Biol X 2020 Jan 15;5:100103. Epub 2019 Nov 15.

Department of Pathology, the First Hospital, Jilin University, 130021, China.

Aims: MicroRNAs play essential roles in tumorigenesis and progression in various cancers including endometrial cancer. Here we assessed the role of miR-135a on proliferation, chemosensitivity, migration and invasion of endometrial cancer cells.

Methods: WST-1 assay was performed to examine the proliferation of HEC-1-B and ISHIKAWA endometrial cancer cells with altered expression of miR-135a, with or without cisplatin treatment. Transwell migration and matrigel invasion assays were used to assess the migration and invasion of endometrial cancer cells. The Caspase-Glo3/7 assay was used to examine the effect of miR-135a on cisplatin-induced apoptosis of endometrial cancer cells. The dual-luciferase reporter assay was conducted to validate the putative binding site.

Results: Upregulation of miR-135a improved the proliferation, and promoted migration and invasion of endometrial cancer cells. Furthermore, miR-135a decreased the sensitivity of HEC-1-B and ISHIKAWA cells after cisplatin treatment. The cisplatin-induced apoptosis in endometrial cancer cells was inhibited by miR-135a by regulation of BAX and Bcl-2 expression. Meanwhile, miR-135a could regulate epithelial to mesenchymal transition (EMT) by altering the expression of E-cadherin, N-cadherin, snail and Vimentin in endometrial cancer cells. Further study showed that the expression levels of PTEN and p-AKT in endometrial cancer cells were changed after aberrant expression of miR-135a.

Conclusion: MiR-135a played important roles in tumorigenesis and disease progression of endometrial cancer by regulating proliferation and chemosensitivy of endometrial cancer cells by targeting AKT signaling pathway. Our study indicates that miR-135a might act as a potential biomarker to predict chemotherapy response and prognosis in endometrial cancer.
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http://dx.doi.org/10.1016/j.eurox.2019.100103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994408PMC
January 2020

Reduced Global-Brain Functional Connectivity and Its Relationship With Symptomatic Severity in Cervical Dystonia.

Front Neurol 2019 10;10:1358. Epub 2020 Jan 10.

Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.

Altered functional connectivity (FC) is related to pathophysiology of patients with cervical dystonia (CD). However, inconsistent results may be obtained due to different selected regions of interest. We explored voxel-wise brain-wide FC changes in patients with CD at rest in an unbiased manner and analyzed their correlations with symptomatic severity using the Tsui scale. A total of 19 patients with CD and 21 sex- and age-matched healthy controls underwent resting-state functional magnetic resonance imaging scans. Global-brain FC (GFC) was applied to analyze the images. Support vector machine was used to distinguish the patients from the controls. Patients with CD exhibited decreased GFC in the right precentral gyrus and right supplementary motor area (SMA) that belonged to the M1-SMA motor network. Significantly negative correlation was observed between GFC values in the right precentral gyrus and symptomatic severity in the patients ( = -0.476, = 0.039, uncorrected). Decreased GFC values in these two brain regions could be utilized to differentiate the patients from the controls with good accuracies, sensitivities and specificities (83.33, 85.71, and 80.95% in the right precentral gyrus; and 87.59, 89.49, and 85.71% in the right SMA). Our investigation suggests that patients with CD show reduced GFC in brain regions of the M1-SMA motor network and provides further insights into the pathophysiology of CD. GFC values in the right precentral gyrus and right SMA may be used as potential biomarkers to recognize the patients from the controls.
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http://dx.doi.org/10.3389/fneur.2019.01358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965314PMC
January 2020
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