Publications by authors named "Nan Song"

258 Publications

Smoothened is a therapeutic target for reducing glutamate toxicity in ischemic stroke.

Sci Transl Med 2021 Sep 8;13(610):eaba3444. Epub 2021 Sep 8.

The Brain Science Center, Beijing Institute of Basic Medical Sciences, 100850 Beijing, China.

[Figure: see text].
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http://dx.doi.org/10.1126/scitranslmed.aba3444DOI Listing
September 2021

Modified Maximal Levator Palpebrae Superioris Shortening in Correcting Congenital Severe Ptosis in Children.

Ann Plast Surg 2021 Aug 28. Epub 2021 Aug 28.

From the Department of Facial Plastic and Reconstructive Surgery, Eye and ENT Hospital of Fudan University, Shanghai 200031, China.

Objective: This study aims to evaluate the clinical effect of modified maximal levator palpebrae superioris shortening method for severe congenital ptosis.

Methods: A retrospective case series was performed including 66 eyes from 62 patients who underwent modified maximal levator palpebrae superioris shortening surgery to treat severe congenital ptosis between February 2015 and November 2018. Preoperative and postoperative margin reflex distance 1 and levator muscle function were recorded. The surgical results were graded as good, satisfied, and poor for functional and cosmetic improvement of the eyelids, and the incidence of complications was also documented.

Results: The mean patient age at the time of surgery was 4.6 ± 1.8 years (2-9 years), and the mean follow-up time was 36.3 ± 14.1 (12-55 months). A mean significant improvement in margin reflex distance 1 and levator function after operation was noted (P < 0.01). The eyelid height and symmetry were satisfied in 59 patients, with success rate of 95.2%. For the patients in the levator function (≤2 mm) group, the success rate was 87.5%. Moreover, the levator function (≤2 mm) group had a higher rate of poor results than levator function (2-4 mm) group (12.5% vs 2.2%). Overcorrection (6.5%) and eyelid fold deformity (11.3%) were the most frequent postoperative complications.

Conclusion: Modified maximal levator palpebrae superioris shortening was effective and endurable in the treatment of severe congenital ptosis with poor levator function, including in patients whose levator function was less than 2 mm.
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http://dx.doi.org/10.1097/SAP.0000000000002867DOI Listing
August 2021

Polygenic Risk Score Improves Risk Stratification and Prediction of Subsequent Thyroid Cancer after Childhood Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Aug 31. Epub 2021 Aug 31.

St. Jude Children's Research Hospital

Background: Subsequent thyroid cancer (STC) is one of the most common malignancies in childhood cancer survivors. We aimed to evaluate the polygenic contributions to STC risk and potential utility in improving risk prediction.

Methods: A polygenic risk score (PRS) was calculated from 12 independent single-nucleotide polymorphisms associated with thyroid cancer risk in the general population. Associations between PRS and STC risk were evaluated among survivors from St. Jude Lifetime Cohort (SJLIFE) and were replicated in survivors from Childhood Cancer Survivor Study (CCSS). A risk prediction model integrating the PRS and clinical factors, initially developed in SJLIFE, and its performance were validated in CCSS.

Results: Among 2,370 SJLIFE survivors with a median follow-up of 28.8 (interquartile range [IQR]=21.9-36.1) years, 65 (2.7%) developed STC. Among them, the standardized PRS was associated with an increased rate of STC (relative rate [RR]=1.57, 95% CI=1.24-1.98, p<0.001). Similar associations were replicated in 6,416 CCSS survivors among whom 121 (1.9%) developed STC during median follow-up of 28.9 (IQR=22.6-34.6) years (RR=1.52, 95% CI=1.25-1.83, p<0.001). A risk prediction model integrating the PRS with clinical factors showed better performance than the model considering only clinical factors in SJLIFE (p=0.004, AUC=83.2% vs. 82.1%, at age 40), which was further validated in CCSS (p=0.010, AUC=72.9% vs. 70.6%).

Conclusions: Integration of the PRS with clinical factors provided a statistically significant improvement in risk prediction of STC, although the magnitude of improvement was modest.

Impact: PRS improves risk stratification and prediction of STC, suggesting its potential utility for optimizing screening strategies in survivorship care.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0448DOI Listing
August 2021

Radial endobronchial ultrasound-assisted transbronchial needle aspiration for pulmonary peripheral lesions in the segmental bronchi adjacent to the central airway.

Transl Lung Cancer Res 2021 Jun;10(6):2625-2632

School of Medicine, Tongji University, Shanghai, China.

Background: Tissue samples from lesions located in the 3rd to 5th segmental bronchi are challenging to obtain. In this retrospective study, we aimed to evaluate the diagnostic rate of pulmonary peripheral lesions located in the 3rd to 5th segmental bronchi, near the inner field of lung on the computed tomography (CT) image and outside the bronchus, using radial endobronchial ultrasound (REBUS) followed by transbronchial needle aspiration (TBNA).

Methods: This retrospective study enrolled patients whose preoperative CT examinations showed a lesion located in the segmental bronchi (3rd to 5th), yet adjacent to the inner field of lung on the CT image. REBUS followed by TBNA was used to acquire tissue samples from these lesions. A bronchoscope was used to reach the bronchi surrounding the lesion, and an ultrasound probe was used to determine the lesion's location. Then, the ultrasound probe was withdrawn, and puncture was performed at the location that was determined by ultrasound. The tissue specimens obtained were subjected to pathological examination.

Results: Nineteen patients were enrolled in this study including 15 males and 4 females with an average age of 55 years old. Of the enrollees, 8 patients (42.1%) were successfully diagnosed with samples obtained through TBNA, including 6 cases of lung cancer, 1 case of non-specific inflammation, and 1 case of cryptococcal infection. The diagnostic rate was 42.1%. No post-procedural complications were observed among the patients. There was no significant difference in nodule diameter between patients with a diagnostic sample and those in whom TBNA failed to provide a diagnosis (2.99±0.96 2.26±1.27 cm, P=0.20).

Conclusions: With the assistance of REBUS, TBNA can acquire sufficient samples to achieve a reasonably diagnostic rate for parenchymal lung lesions located near the inner field of lung on the CT image without intrabronchial invasion.
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http://dx.doi.org/10.21037/tlcr-21-490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264313PMC
June 2021

Mini-Incision Eyelidplasty in Single Eye to Correct Congenital Upper Eyelid Crease Asymmetry.

J Craniofac Surg 2021 Jun 28. Epub 2021 Jun 28.

Department of Facial Plastic and Reconstructive Surgery, Eye and ENT Hospital of Fudan University, Shanghai, China.

Objective: This study aims to evaluate the clinical effect of mini-incision double eyelidplasty in single eye for correcting congenital upper eyelid crease asymmetry.

Methods: Mini-incision double eyelidplasty was performed on 24 patients in single eye to treat congenital upper eyelid crease asymmetry between May 2016 and September 2018. The postoperative surgical results were classified as "excellent," "fair," and "poor." The subjective satisfaction and incidence of complications were documented.

Results: The mean patient age at the time of surgery was 24.6 ± 3.1 years (21-28 years), and the mean follow-up time was 15.4 ± 8.7 (12-34 months). All patients showed "excellent" surgical outcomes according to symmetry of upper eyelid creases. All patients are "very satisfied" with the cosmetic outcomes. There were no cases of recurrence or other complications.

Conclusions: Mini-incision double eyelidplasty method in single eye was effective and endurable in the treatment of congenital upper eyelid crease asymmetry. The recovery rate was fast, and no cases of upper eyelid crease disappearance were observed in this study.
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http://dx.doi.org/10.1097/SCS.0000000000007734DOI Listing
June 2021

Aberrant expression of HDL-bound microRNA induced by a high-fat diet in a pig model: implications in the pathogenesis of dyslipidaemia.

BMC Cardiovasc Disord 2021 06 6;21(1):280. Epub 2021 Jun 6.

Key Laboratory of Ministry of Education for Traditional Chinese Medicine Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People's Republic of China.

Background: A high-fat diet can affect lipid metabolism and trigger cardiovascular diseases. A growing body of studies has revealed the HDL-bound miRNA profiles in familial hypercholesterolaemia; in sharp contrast, relevant studies on high-fat diet-induced dyslipidaemia are lacking. In the current study, HDL-bound miRNAs altered by a high-fat diet were explored to offer some clues for elucidating their effects on the pathogenesis of dyslipidaemia.

Methods: Six pigs were randomly divided into two groups of three pigs each, namely, the high-fat diet and the balanced diet groups, which were fed a high-fat diet and balanced diet separately for six months. HDL was separated from plasma, which was followed by dissociation of the miRNA bound to HDL. miRNA sequencing of the isolated miRNA was performed to identify the differential expression profiles between the two groups, which was validated by real-time PCR. TargetScan, miRDB, and miRWalk were used for the prediction of genes targeted by the differential miRNAs.

Results: Compared with the balanced diet group, the high-fat diet group had significantly higher levels of TG, TC, LDL-C and HDL-C at six months. miRNA sequencing revealed 6 upregulated and 14 downregulated HDL-bound miRNAs in the high-fat diet group compared to the balanced diet group, which was validated by real-time PCR. GO enrichment analysis showed that dysregulated miRNAs in the high-fat diet group were associated with the positive regulation of lipid metabolic processes, positive regulation of lipid biosynthetic processes, and positive regulation of Ras protein signal transduction. Insulin resistance and the Ras signalling pathway were enriched in the KEGG pathway enrichment analysis.

Conclusions: Twenty HDL-bound miRNAs are significantly dysregulated in high-fat diet-induced dyslipidaemia. This study presents an analysis of a new set of HDL-bound miRNAs that are altered by a high-fat diet and offers some valuable clues for novel mechanistic insights into high-fat diet-induced dyslipidaemia. Further functional verification study using a larger sample size will be required.
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http://dx.doi.org/10.1186/s12872-021-02084-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180175PMC
June 2021

Differential expression and alternative splicing of transcripts in orbital adipose/connective tissue of thyroid-associated ophthalmopathy.

Exp Biol Med (Maywood) 2021 Sep 2;246(18):1990-2006. Epub 2021 Jun 2.

Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China.

Thyroid-associated ophthalmopathy is a typical autoimmune disease of orbital tissues. Alternative splicing significantly influences many diseases progression, including cancer, age-related macular degeneration, and multiple sclerosis, by modulating the expression of transcripts. However, its role in thyroid-associated ophthalmopathy is still unclear. In this study, differential expression transcripts and differential alternative splicing genes in orbital adipose/connective tissues of thyroid-associated ophthalmopathy patients were detected using RNA sequencing, Cuffdiff, and replicate multivariate analysis of transcript splicing. Three thousand ninety six differential expression transcripts and 2355 differential alternative splicing genes were screened out, while functional enrichment analysis indicated that differential expression transcript and differential alternative splicing genes were associated with immune modulation, extracellular matrix remodeling, and adipogenesis. The expression of the , , , and gene transcripts was verified by qRT-PCR. In conclusion, prevalent alternative splicing is involved in the disease development in thyroid-associated ophthalmopathy. More attention should be paid to the mechanism of alternative splicing to explore more potential therapeutic targets in thyroid-associated ophthalmopathy.
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http://dx.doi.org/10.1177/15353702211017292DOI Listing
September 2021

Molecular Engineering of High-Performance Aggregation-Induced Emission Photosensitizers to Boost Cancer Theranostics Mediated by Acid-Triggered Nucleus-Targeted Nanovectors.

ACS Nano 2021 06 2;15(6):10689-10699. Epub 2021 Jun 2.

Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077, P.R. China.

Phototheranostics involving both fluorescence imaging and photodynamic therapy has been recognized to be potentially powerful for cancer treatment by virtue of various intrinsic advantages. However, the state-of-the-art materials in this area are still far from ideal toward practical applications, ascribed to their respective and collective drawbacks, such as inefficient imaging quality, inferior reactive oxygen species (ROS) production, the lack of subcellular-targeting capability, and dissatisfactory delivery. In this paper, these shortcomings are successfully addressed through the integration of finely engineered photosensitizers with aggregation-induced emission (AIE) features and well tailored nanocarrier systems. The yielded AIE NPs simultaneously exhibit broad absorption in the visible-light region, bright near-infrared fluorescence emission, high ROS generation, as well as tumor lysosomal acidity-activated and nucleus-targeted delivery functions, making them promising for precise and efficient phototheranostics. Both and evaluations show that the presented nanotheranostic systems bearing good photostability and appreciable biosecurity perform well in fluorescence imaging-guided photodynamic cancer therapy. This study thus not only extends the application scopes of AIE nanomaterials but also offers useful insights into constructing advanced cancer phototheranostics.
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http://dx.doi.org/10.1021/acsnano.1c03700DOI Listing
June 2021

Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

Cancers (Basel) 2021 May 14;13(10). Epub 2021 May 14.

Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark.

In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (-2df = 1.2 × 10). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (-2df = 1.1 × 10). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
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http://dx.doi.org/10.3390/cancers13102370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156547PMC
May 2021

Mini-incision Blepharoplasty with Pretarsal Fasciectomy for Double-Eyelid Surgery.

Aesthetic Plast Surg 2021 May 25. Epub 2021 May 25.

Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, No.83 Fen-Yang Road, Shanghai, 200031, China.

Background: Double-eyelid surgery has been one of the most popular aesthetic surgeries in oriental populations. The objective of this study was to introduce a simple procedure for double-eyelid surgery.

Methods: The mini-incision blepharoplasty with pretarsal fasciectomy technique is described and illustrated. Blepharoplasty cases in our practice from June 2018 to December 2019 were retrospectively reviewed. Patients who underwent mini-incision blepharoplasty with pretarsal fasciectomy were followed up for at least 6 months.

Results: Of 280 blepharoplasty cases, 32 patients underwent mini-incision blepharoplasty with pretarsal fasciectomy on both upper eyelids. Nineteen patients experienced resolve of swelling within 5 days postoperatively. No loss of fold was observed during follow-up. The satisfaction rate was 93.8%.

Conclusions: The mini-incision blepharoplasty with pretarsal fasciectomy is ideal for selected patients requesting double-eyelid surgery. It provides stable, natural, scarless result with minimum complication and rapid recovery.

Level Of Evidence: IV.
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http://dx.doi.org/10.1007/s00266-021-02349-6DOI Listing
May 2021

Tanshinone IIA Combined With Cyclosporine A Alleviates Lung Apoptosis Induced by Renal Ischemia-Reperfusion in Obese Rats.

Front Med (Lausanne) 2021 3;8:617393. Epub 2021 May 3.

Key Laboratory of Ministry of Education for Traditional Chinese Medicine Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, China.

Acute lung injury (ALI), which is induced by renal ischemia-reperfusion (IR), is one of the leading causes of acute renal IR-related death. Obesity raises the frequency and severity of acute kidney injury (AKI) and ALI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) was employed to lessen the lung apoptosis led by renal IR and to evaluate whether TIIA combined with CsA could alleviate lung apoptosis by regulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats. Hematoxylin-eosin (HE) staining was used to assess the histology of the lung injury. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) was used to assess apoptosis of the lung. Electron microscopy was used to assess mitochondrial morphology in lung cells. Arterial blood gas and pulmonary function were used to assess the external respiratory function. Mitochondrial function was used to assess the internal respiratory function and mitochondrial dynamics and biogenesis. Western blot (WB) was used to examine the PI3K/Akt/Bad pathway-related proteins. TIIA combined with CsA can alleviate lung apoptosis by regulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.
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http://dx.doi.org/10.3389/fmed.2021.617393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126627PMC
May 2021

PHF8-promoted TOPBP1 demethylation drives ATR activation and preserves genome stability.

Sci Adv 2021 05 5;7(19). Epub 2021 May 5.

State Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.

The checkpoint kinase ATR [ATM (ataxia-telangiectasia mutated) and rad3-related] is a master regulator of DNA damage response. Yet, how ATR activity is regulated remains to be investigated. We report here that histone demethylase PHF8 (plant homeodomain finger protein 8) plays a key role in ATR activation and replication stress response. Mechanistically, PHF8 interacts with and demethylates TOPBP1 (DNA topoisomerase 2-binding protein 1), an essential allosteric activator of ATR, under unperturbed conditions, but replication stress results in PHF8 phosphorylation and dissociation from TOPBP1. Consequently, hypomethylated TOPBP1 facilitates RAD9 (RADiation sensitive 9) binding and chromatin loading of the TOPBP1-RAD9 complex to fully activate ATR and thus safeguard the genome and protect cells against replication stress. Our study uncovers a demethylation and phosphorylation code that controls the assembly of TOPBP1-scaffolded protein complex, and provides molecular insight into non-histone methylation switch in ATR activation.
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http://dx.doi.org/10.1126/sciadv.abf7684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099190PMC
May 2021

Skin redraping for correction of lower eyelid epiblepharon combined with medial epicanthal fold: a retrospective analysis of 286 Asian children.

Eye (Lond) 2021 Apr 29. Epub 2021 Apr 29.

Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital of Fudan University, Shanghai, China.

Objective: This study was performed to evaluate the clinical effect of skin redraping on lower eyelid epiblepharon accompanied by a medial epicanthal fold.

Methods: This retrospective case series involved 572 eyes of 286 patients who underwent skin redraping surgery to treat lower eyelid epiblepharon accompanied by a medial epicanthal fold from January 2015 to May 2019. The postoperative surgical results were classified as "good", "fair" and "poor". The incision scars were assessed using the Vancouver scar scale. The patients' subjective satisfaction and incidence of complications were also documented.

Results: The mean patient age at the time of surgery was 6.9 ± 3.6 years (3-12 years), and the mean follow-up time was 32.6 ± 13.5 months (6-58 months). The clinical symptoms and severity of keratopathy were improved postoperatively. "Good" surgical outcomes were obtained in all patients, the mean Vancouver scar scale score was 1.1 ± 0.3, and hypertrophic scar formation did not occur. A total of 272 patients and their guardians were "very satisfied" with the cosmetic outcomes.

Conclusion: Skin redraping was effective and endurable in the treatment of lower eyelid epiblepharon accompanied by a medial epicanthal fold. The postoperative scars were slight and nearly invisible, and no cases of recurrence were observed in this study.
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http://dx.doi.org/10.1038/s41433-021-01550-wDOI Listing
April 2021

Serotonergic Modulation of Persistent Inward Currents in Serotonergic Neurons of Medulla in ePet-EYFP Mice.

Front Neural Circuits 2021 6;15:657445. Epub 2021 Apr 6.

Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, School of Physical Education and Health Care, East China Normal University, Shanghai, China.

Serotonergic (5-HT) neurons in the medulla play multiple functional roles associated with many symptoms and motor activities. The descending serotonergic pathway from medulla is essential for initiating locomotion. However, the ionic properties of 5-HT neurons in the medulla remain unclear. Using whole-cell patch-clamp technique, we studied the biophysical and modulatory properties of persistent inward currents (PICs) in 5-HT neurons of medulla in ePet-EYFP transgenic mice (P3-P6). PICs were recorded by a family of voltage bi-ramps (10-s duration, 40-mV peak step), and the ascending and descending PICs were mirrored to analyze the PIC hysteresis. PICs were found in 77% of 5-HT neurons (198/258) with no significant difference between parapyramidal region ( = 107) and midline raphe nuclei (MRN) ( = 91) in either PIC onset (-47.4 ± 10 mV and -48.7 ± 7 mV; = 0.44) or PIC amplitude (226.9 ± 138 pA and 259.2 ± 141 pA; = 0.29). Ninety-six percentage (191/198) of the 5-HT neurons displayed counterclockwise hysteresis and four percentage (7/198) exhibited the clockwise hysteresis. The composite PICs could be differentiated as calcium component (Ca_PIC) by bath application of nimodipine (25 μM), sodium component (Na_PIC) by tetrodotoxin (TTX, 2 μM), and TTX- and dihydropyridine-resistance component (TDR_PIC) by TTX and nimodipine. Ca_PIC, Na_PIC and TDR_PIC all contributed to upregulation of excitability of 5-HT neurons. 5-HT (15 μM) enhanced the PICs, including a 26% increase in amplitude of the compound currents of Ca_PIC and TDR_PIC ( < 0.001, = 9), 3.6 ± 5 mV hyperpolarization of Na_PIC and TDR_PIC onset ( < 0.05, = 12), 30% increase in amplitude of TDR_PIC ( < 0.01), and 2.0 ± 3 mV hyperpolarization of TDR_PIC onset ( < 0.05, = 18). 5-HT also facilitated repetitive firing of 5-HT neurons through modulation of composite PIC, Na_PIC and TDR_PIC, and Ca_PIC and TDR_PIC, respectively. In particular, the high voltage-activated TDR_PIC facilitated the repetitive firing in higher membrane potential, and this facilitation could be amplified by 5-HT. Morphological data analysis indicated that the dendrites of 5-HT neurons possessed dense spherical varicosities intensively crossing 5-HT neurons in medulla. We characterized the PICs in 5-HT neurons and unveiled the mechanism underlying upregulation of excitability of 5-HT neurons through serotonergic modulation of PICs. This study provided insight into channel mechanisms responsible for the serotonergic modulation of serotonergic neurons in brainstem.
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http://dx.doi.org/10.3389/fncir.2021.657445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055846PMC
April 2021

Clinical T1aN0M0 lung cancer: differences in clinicopathological patterns and oncological outcomes based on the findings on high-resolution computed tomography.

Eur Radiol 2021 Oct 15;31(10):7353-7362. Epub 2021 Apr 15.

Department of Radiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zheng Min Road, Shanghai, 200433, China.

Objectives: To elucidate the clinicopathological characteristics and oncological outcomes of clinical T1aN0M0 (c-T1N0M0) lung cancer based on the newest 8th TNM classification.

Methods: A total of 257 patients with c-T1aN0M0 lung cancer were retrospectively included in this study. According to the solid component size manifesting on the high-resolution computed tomography (HRCT), all lesions were classified as the pure ground-glass nodule (pure-GGN) with a diameter > 3 cm (n = 19), part-solid (n = 174), and pure-solid (n = 64) groups. We evaluated the prognostic impact of clinicopathologic variables including radiological presentations by establishing Cox proportional hazards model.

Results: When we evaluated the prognostic impact based on the radiological subtypes, the 5-year recurrence-free survival (RFS) and overall survival (OS) were significantly different among pure-GGN, part-solid, and pure-solid groups (RFS: 100% versus 95.4% versus 76.6%, p < 0.0001; OS: 100% versus 98.9% versus 87.5%, p < 0.0001). Cox regression analysis revealed the preoperative carcinoembryonic antigen (CEA) level and consolidation tumor ratio (CTR) were independently significant prognosticators related to RFS and OS. Furthermore, a receiver operating characteristic (ROC) verified the CTR (area under ROC [AUC] 0.784, 95%CI 0.697-0.869) was equipped with good performance to predict the postoperative recurrence with a cutoff point at 0.5. Lung cancer with higher CTR tended to be associated with lower survival in the c-T1aN0M0 stage.

Conclusions: For the c-T1aN0M0 lung cancer, pulmonary nodules manifested as the pure-GGN and part-solid subtypes had an excellent prognosis and may be considered as the "early-stage" cancer, whereas those with pure-solid appearance were associated with the high risk of recurrence despite the sub-centimeter size.

Key Points: • Radiological subtypes could further stratify the risk of lung cancer in cT1a. • Sub-solid nodule has a favorable survival in c-T1a lung cancer, whereas pure-solid nodule is not always "early-stage" lung cancer and is relatively prone to postoperative recurrence despite the sub-centimeter size. • The preoperative CEA level and CTR are valuable prognosticators to predict the recurrence in c-T1a lung cancer.
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http://dx.doi.org/10.1007/s00330-021-07865-2DOI Listing
October 2021

Improvement of pathological staging system for neuroendocrine tumors of the lung.

Ann Transl Med 2021 Mar;9(6):447

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.

Background: Currently, the tumor, node, and metastasis (TNM) staging system has a limited value in prognostic stratification for neuroendocrine tumors of the lung (NETL). A specific pathological staging system was therefore explored.

Methods: Two cohorts were assessed: the training cohort was composed of surgically treated patients from the Surveillance, Epidemiologic, and End Results (SEER) database [2004-2015]; the Shanghai cohort included Shanghai resident patients treated at Shanghai Pulmonary Hospital [2009-2018]. Multivariable Cox regression analysis was performed to identify factors associated with overall survival. A new staging system was proposed based on survival tree, and was further compared with the 8 edition of the TNM staging system.

Results: In the training set (n=3,204), multivariate Cox analysis showed that tumor histotype and nodal status were independently associated with survival, but not T stage. Therefore, by incorporating NETL histotype (G1, low-grade typical pulmonary carcinoids; G2, intermediate-grade atypical pulmonary carcinoids; G3, high-grade large-cell neuroendocrine carcinomas) and N stage, a new staging system was developed: IA, G1N0; IB, G1N1 or G2N0; II, G1N2, G2N1-2, or G3N0; III, G3N1-2. Five-year survival rates were 91.2%, 81.3%, 50.2% and 27.6% for the new stages IA to III in the validation set (n=3,204), respectively (P<0.001). Additionally, the new staging system had significantly better predictive ability than the TNM staging system, in both the SEER [C-index, 0.75 0.62; net reclassification improvement (NRI), 0.62; integrated discrimination improvement (IDI), 20%] and Shanghai (IDI, 8%) cohorts. Based on the new staging system, adjuvant chemotherapy conferred a significantly better survival in stage-III NETL cases (HR =0.34, 95% CI, 0.25-0.45).

Conclusions: The new pathological staging system can better predict NETL prognosis than the 8 edition of the TNM staging system, with the potential to guide postoperative treatment.
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http://dx.doi.org/10.21037/atm-20-5910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039668PMC
March 2021

Dexmedetomidine Attenuates Ischemia/Reperfusion-Induced Myocardial Inflammation and Apoptosis Through Inhibiting Endoplasmic Reticulum Stress Signaling.

J Inflamm Res 2021 31;14:1217-1233. Epub 2021 Mar 31.

Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People's Republic of China.

Background: Endoplasmic reticulum stress (ERS)-mediated myocardial inflammation and apoptosis plays an important role in myocardial ischemia/reperfusion (I/R) injury. Dexmedetomidine has been used clinically with sedative, analgesic, and anti-inflammatory properties. This study aimed to determine the effects of dexmedetomidine pretreatment on inflammation, apoptosis, and the expression of ERS signaling during myocardial I/R injury.

Methods: Rats underwent myocardial ischemia for 30 min and reperfusion for 6 h, and H9c2 cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury (OGD for 12 h and reoxygenation for 3 h). Dexmedetomidine was administered prior to myocardial ischemia in rats or ODG in cardiomyocytes. In addition, the α2-adrenergic receptor antagonist (yohimbine) or the PERK activator (CCT020312) was given prior to dexmedetomidine treatment.

Results: Dexmedetomidine pretreatment decreased serum levels of cardiac troponin I, reduced myocardial infarct size, alleviated histological structure damage, and improved left ventricular function following myocardial I/R injury in rats. In addition, dexmedetomidine pretreatment increased cell viability and reduced cytotoxicity following OGD/R injury in cardiomyocytes. Mechanistically, the cardioprotection offered by dexmedetomidine was mediated via the inhibition of inflammation and apoptosis through downregulating the expression of the ERS signaling pathway, including glucose-regulated protein 78 (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), C/EBP homologous protein (CHOP), inositol-requiring protein 1 (IRE1), and activating transcription factor 6 (ATF6). Conversely, the protective effects of dexmedetomidine were diminished by blocking the α2 adrenergic receptors with yohimbine or promoting PERK phosphorylation with CCT020312.

Conclusion: Dexmedetomidine pretreatment protects the hearts against I/R injury via inhibiting inflammation and apoptosis through downregulation of the ERS signaling pathway. Future clinical studies are needed to confirm the cardioprotective effects of dexmedetomidine in patients at risk of myocardial I/R injury.
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http://dx.doi.org/10.2147/JIR.S292263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020464PMC
March 2021

Persistent variations of blood DNA methylation associated with treatment exposures and risk for cardiometabolic outcomes in long-term survivors of childhood cancer in the St. Jude Lifetime Cohort.

Genome Med 2021 04 6;13(1):53. Epub 2021 Apr 6.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 735, Memphis, TN, 38105, USA.

Background: It is well-established that cancer treatment substantially increases the risk of long-term adverse health outcomes among childhood cancer survivors. However, there is limited research on the underlying mechanisms. To elucidate the pathophysiology and a possible causal pathway from treatment exposures to cardiometabolic conditions, we conducted epigenome-wide association studies (EWAS) to identify the DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions.

Methods: We included 2052 survivors (median age 33.7 years) of European ancestry from the St. Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Cumulative doses of chemotherapy and region-specific radiation were abstracted from medical records. Seven cardiometabolic conditions were clinically assessed. DNAm profile was measured using MethylationEPIC BeadChip with blood-derived DNA.

Results: By performing multiple treatment-specific EWAS, we identified 935 5'-cytosine-phosphate-guanine-3' (CpG) sites mapped to 538 genes/regions associated with one or more cancer treatments at the epigenome-wide significance level (p < 9 × 10). Among the treatment-associated CpGs, 8 were associated with obesity, 63 with hypercholesterolemia, and 17 with hypertriglyceridemia (false discovery rate-adjusted p < 0.05). We observed substantial mediation by methylation at four independent CpGs (cg06963130, cg21922478, cg22976567, cg07403981) for the association between abdominal field radiotherapy (abdominal-RT) and risk of hypercholesterolemia (70.3%) and by methylation at three CpGs (cg19634849, cg13552692, cg09853238) for the association between abdominal-RT and hypertriglyceridemia (54.6%). In addition, three CpGs (cg26572901, cg12715065, cg21163477) partially mediated the association between brain-RT and obesity with a 32.9% mediation effect, and two CpGs mediated the association between corticosteroids and obesity (cg22351187, 14.2%) and between brain-RT and hypertriglyceridemia (cg13360224, 10.5%). Notably, several mediator CpGs reside in the proximity of well-established dyslipidemia genes: cg21922478 (ITGA1) and cg22976567 (LMNA).

Conclusions: In childhood cancer survivors, cancer treatment exposures are associated with DNAm patterns present decades following the exposure. Treatment-associated DNAm sites may mediate the causal pathway from specific treatment exposures to certain cardiometabolic conditions, suggesting the utility of DNAm sites as risk predictors and potential mechanistic targets for future intervention studies.
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http://dx.doi.org/10.1186/s13073-021-00875-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025387PMC
April 2021

Tanshinone IIA combined with CsA inhibit myocardial cell apoptosis induced by renal ischemia-reperfusion injury in obese rats.

BMC Complement Med Ther 2021 Mar 22;21(1):100. Epub 2021 Mar 22.

Key Laboratory of Ministry of Education for Traditional Chinese Medicine Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, China.

Background: Acute myocardial injury (AMI), which is induced by renal ischemia-reperfusion (IR), is a significant cause of acute kidney injury (AKI)-related associated death. Obesity increases the severity and frequency of AMI and AKI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) pretreatment was used to alleviate myocardial cell apoptosis induced by renal IR, and to determine whether TIIA combined with CsA would attenuate myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.

Methods: Male rates were fed a high fat diet for 8 weeks to generate obesity. AKI was induced by 30 min of kidney ischemia followed 24 h of reperfusion. Obese rats were given TIIA (10 mg/kg·d) for 2 weeks and CsA (5 mg/kg) 30 min before renal IR. After 24 h of reperfusion, the rats were anaesthetized, the blood were fetched from the abdominal aorta and kidney were fetched from abdominal cavity, then related indicators were examined.

Results: TIIA combined with CsA can alleviate the pathohistological injury and apoptosis induced by renal IR in myocardial cells. TIIA combined with CsA improved cardiac function after renal ischemia (30 min)-reperfusion (24 h) in obese rats. At the same time, TIIA combined with CsA improved mitochondrial function. Abnormal function of mitochondria was supported by decreases in respiration controlling rate (RCR), intracellular adenosine triphosphate (ATP), oxygen consumption rate, and mitochondrial membrane potential (MMP), and increases in mitochondrial reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA damage, and mitochondrial respiratory chain complex enzymes. The injury of mitochondrial dynamic function was assessed by decrease in dynamin-related protein 1 (Drp1), and increases in mitofusin1/2 (Mfn1/2), and mitochondrial biogenesis injury was assessed by decreases in PPARγ coactivator-1-α (PGC-1), nucleo respiratory factor1 (Nrf1), and transcription factor A of mitochondrial (TFam).

Conclusion: We used isolated mitochondria from rat myocardial tissues to demonstrate that myocardial mitochondrial dysfunction occurred along with renal IR to induce myocardial cell apoptosis; obesity aggravated apoptosis. TIIA combined with CsA attenuated myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.
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http://dx.doi.org/10.1186/s12906-021-03270-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986523PMC
March 2021

Efficacy of immune-checkpoint inhibitors in PD-L1 selected or unselected patients vs. control group in patients with advanced or metastatic urothelial carcinoma.

Oncoimmunology 2021 03 5;10(1):1887551. Epub 2021 Mar 5.

Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.

Most patients with advanced or metastatic urothelial carcinoma do not benefit significantly from Immune checkpoint inhibitors (ICIs) use. A systematic review and meta-analysis of randomized controlled trials to assess the efficacy and activity of ICIs, in terms of Overall Survival (OS), Progression-free survival (PFS), and Objective Response Rate (ORR). We systematically searched for articles from PubMed, Cochrane Library, Embase, and Web of science from their inception to December 1, 2020 with no language restrictions. The search was performed to identify all clinical trials (phase I, phase II, phase III) of ICIs for treating urothelial carcinoma. The endpoints of the meta-analysis were OS, PFS, and ORR, compared unselected patients and in the subgroup of patients characterized by high expression of PD-L1 (PD-L1 selected patients). Sixteen studies comprising 5559 patients were identified, of which data for OS comparison were available from 4 RCTs (2342 patients), two studies for PFS (649 patients), and four RCTs were eligible for ORR analysis (2921 patients). Both pembrolizumab and atezolizumab have showed to improve OS compared to chemotherapy in unselected patients (HR 0.86, 95% CI 0.80-0.93, = .0001, I = 60%), while the difference was not significant in PD-L1 selected patients (HR 0.91, 95% CI 0.77-1.07, = .23, I = 0%). PFS difference was not observed in neither unselected population nor PD-L1 selected patients, the pooled HR of PFS for immunotherapy compared to control treatment was 1.05 (95% CI 0.74-1.49, = .79, I = 85%) and 0.84 (95% CI 0.68-1.03, = .09, I = 0%, respectively. Similar result was observed in ORR, the pooled HR of ORR for immunotherapy compared to control treatment was 1.45 (95% CI 0.53-3.98, = .47, I = 95%) and 2.19 (95% CI 0.79-6.08, = .13, I = 83%), respectively. Immunotherapy could significantly improve survival advantage in unselected patients but not in PD-L1 selected population, indicating that PD-L1 expression may not be a reliable marker in previously platinum-treated patients.
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http://dx.doi.org/10.1080/2162402X.2021.1887551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939561PMC
March 2021

Comprehensive multiomics analysis of the effect of ginsenoside Rb1 on hyperlipidemia.

Aging (Albany NY) 2021 03 19;13(7):9732-9747. Epub 2021 Mar 19.

Key Laboratory of Ministry of Education for Traditional Chinese Medicine Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People's Republic of China.

We analyzed the effects of ginsenoside Rb1 on hyperlipidemic in model mice. Using stool, plasma and hepatic tissue samples, we observed that the genera and were increased and was decrease in Rb1-treated mice as compared to untreated model mice. Ether lipid metabolism, glycerolipid metabolism, and glyoxylate and dicarboxylate metabolism were differentially enriched between the Rb1 and model groups. Lipidomics revealed 169 metabolites differentially expressed between the model and Rb1 groups in a positive ion model and 58 in a negative ion model. These metabolites mainly participate in glycerophospholipid, linoleic acid, and alpha-linolenic acid metabolism. The main metabolites enriched in these three pathways were phosphatidylcholine, diacylglycerol and ceramide, respectively. In a transcriptome analysis, 766 transcripts were differentially expressed between the Rb1 and model groups. KEGG analysis revealed lysine degradation, inositol phosphate metabolism, and glycerophospholipid metabolism to be the main enriched pathways. Multiomics analysis revealed glycerophospholipid metabolism to be a common pathway and phosphatidylcholine the main metabolite differentially enriched between the Rb1 and model groups. Results from fecal transplanted germ-free mice suggest that to suppress hyperlipidemia, Rb1 regulates gut microbiota by regulating the synthesis and decomposition of phosphatidylcholine in glycerophospholipid metabolism, which in turn decreases serum total cholesterol.
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http://dx.doi.org/10.18632/aging.202728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064217PMC
March 2021

Microlens array snapshot hyperspectral microscopy system for the biomedical domain.

Appl Opt 2021 Mar;60(7):1896-1902

We propose a microlens array-type snapshot hyperspectral microscope system that can provide spatial spectrum sampling according to detector frame rates for the biomedical domain. The system uses a shared optical path design. One path is used to perform direct microscopic imaging with high spatial resolution, while the other is used to collect microscopic images through a microlens array; the images are then spatially cut and reimaged such that they are spaced simultaneously by the prism-grating type hyperspectral imager's dispersion. Rapid acquisition of a three-dimensional data cube measuring 28×14×180 (××) can be performed at the detector's frame rate. The system has a spatial resolution of 2.5 µm and can achieve 180-channel sampling of a 100 nm spectrum in the 400-800 nm spectral range with spectral resolution of approximately 0.56 nm. Spectral imaging results from biological samples show that the microlens array-type snapshot hyperspectral microscope system may potentially be applied in real-time biological spectral imaging.
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http://dx.doi.org/10.1364/AO.417952DOI Listing
March 2021

Higher-level phylogenetic relationships of rove beetles (Coleoptera, Staphylinidae) inferred from mitochondrial genome sequences.

Mitochondrial DNA A DNA Mapp Seq Anal 2021 04 11;32(3):98-105. Epub 2021 Feb 11.

Tibet Academy of Agricultural and Animal Husbandry Science, Lhasa, China.

Rove beetles (Staphylinidae) and allied families constitute a huge radiation of Coleoptera, but basal relationships in this group remain controversial. In this study, we newly sequenced eight mitogenomes of representatives of Staphylinidae by using next-generation sequencing method. Together with 99 existing mitogenomes of Staphyliniformia, (sub)family relationships were investigated with ML and Bayesian searches under various substitution models and data recoding schemes. The results consistently supported Scydmaenidae and Silphidae to be subordinate groups of Staphylinidae. Within the monophyletic Staphylinidae (including Scydmaenidae and Silphidae), the hypothesis of four major subfamily groups cannot be confirmed. Bayesian inferences under the site-heterogeneous mixture model generally supported the basal position of major clades corresponding to the Omaliine group. At the subfamily level, the monophyly of Pselaphinae, Oxytelinae, Scaphidiinae, Steninae and Staphylininae was supported. However, the subfamilies Omaliinae, Tachyporinae, Aleocharinae and Paederinae were each non-monophyletic.
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http://dx.doi.org/10.1080/24701394.2021.1882444DOI Listing
April 2021

Association between gallstones and the risk of biliary tract cancer: a systematic review and meta-analysis.

Epidemiol Health 2021 3;43:e2021011. Epub 2021 Feb 3.

Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.

Objectives: Biliary tract cancers (BTCs) are rare but highly fatal. Although the etiology of BTC is poorly understood, gallstones are proposed to be a major risk factor. We conducted a systematic review and meta-analysis to examine the associations between gallstone characteristics and BTC risk.

Methods: We searched the MEDLINE, Embase, and Cochrane Central databases and systematically reviewed cohort and case-control studies published before April 9, 2018. All the included studies reported appropriate risk estimates and confidence intervals (CIs) for associations between the presence, size, number, or duration of gallstones and the risk of BTC, including gallbladder cancer (GBC), extrahepatic bile duct cancer (EBDC), and ampulla of Vater cancer (AOVC). Summary odds ratios (ORs) and their 95% CIs were calculated using a random-effects model in the meta-analysis. Subgroup analyses were conducted to inspect sources of potential heterogeneity, and the Egger test was performed to assess publication bias.

Results: Seven cohort studies and 23 case-control studies in Asian, European, and American populations were included. The presence of gallstones was associated with an increased risk of BTC (OR, 4.38; 95% CI, 3.23 to 5.93; I2=91.2%), GBC (OR, 7.26; 95% CI, 4.33 to 12.18), EBDC (OR, 3.17; 95% CI, 2.24 to 4.50), and AOVC (OR, 3.28; 95% CI, 1.33 to 8.11). Gallstone size (>1 vs. <1 cm; OR, 1.88; 95% CI, 1.10 to 3.22) was significantly associated with the risk of GBC.

Conclusions: Gallstone characteristics, such as presence, size, and number, are associated with an increased risk of BTC. However, significantly high heterogeneity in the meta-analyses is a limitation of this study.
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http://dx.doi.org/10.4178/epih.e2021011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060519PMC
April 2021

Genome-wide dissection reveals diverse pathogenic roles of bacterial Tc toxins.

PLoS Pathog 2021 02 4;17(2):e1009102. Epub 2021 Feb 4.

Beijing Institute of Tropical Medicine, Beijing, China.

Tc toxins were originally identified in entomopathogenic bacteria, which are important as biological pest control agents. Tc toxins are heteromeric exotoxins composed of three subunit types, TcA, TcB, and TcC. The C-terminal portion of the TcC protein encodes the actual toxic domain, which is translocated into host cells by an injectosome nanomachine comprising the other subunits. Currently the pathogenic roles and distribution of Tc toxins among different bacterial genera remain unclear. Here we have performed a comprehensive genome-wide analysis, and established a database that includes 1,608 identified Tc loci containing 2,528 TcC proteins in 1,421 Gram-negative and positive bacterial genomes. Our findings indicate that TcCs conform to the architecture of typical polymorphic toxins, with C-terminal hypervariable regions (HVR) encoding more than 100 different classes of putative toxic domains, most of which have not been previously recognized. Based on further analysis of Tc loci in the genomes of all Salmonella and Yersinia strains in EnteroBase, a "two-level" evolutionary dynamics scenario is proposed for TcC homologues. This scenario implies that the conserved TcC RHS core domain plays a critical role in the taxonomical specific distribution of TcC HVRs. This study provides an extensive resource for the future development of Tc toxins as valuable agrochemical tools. It furthermore implies that Tc proteins, which are encoded by a wide range of pathogens, represent an important versatile toxin superfamily with diverse pathogenic mechanisms.
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http://dx.doi.org/10.1371/journal.ppat.1009102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861908PMC
February 2021

N-Glycans and sulfated glycosaminoglycans contribute to the action of diverse Tc toxins on mammalian cells.

PLoS Pathog 2021 02 4;17(2):e1009244. Epub 2021 Feb 4.

Beijing Institute of Tropical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Tc toxin is an exotoxin composed of three subunits named TcA, TcB and TcC. Structural analysis revealed that TcA can form homopentamer that mediates the cellular recognition and delivery processes, thus contributing to the host tropism of Tc toxin. N-glycans and heparan sulfates have been shown to act as receptors for several Tc toxins. Here, we performed two independent genome-wide CRISPR-Cas9 screens, and have validated glycans and sulfated glycosaminoglycans (sGAGs) as Tc toxin receptors also for previously uncharacterized Tc toxins. We found that TcdA1 form Photorhabdus luminescens W14 (TcdA1W14) can recognize N-glycans via the RBD-D domain, corroborating previous findings. Knockout of N-glycan processing enzymes specifically blocks the intoxication of TcdA1W14-assembled Tc toxin. On the other hand, our results showed that sGAG biosynthesis pathway is involved in the cell surface binding of TcdA2TT01 (TcdA2 from P. luminescens TT01). Competition assays and biolayer interferometry demonstrated that the sulfation group in sGAGs is required for the binding of TcdA2TT01. Finally, based on the conserved domains of representative TcA proteins, we have identified 1,189 putative TcAs from 1,039 bacterial genomes. These TcAs are categorized into five subfamilies. Each subfamily shows a good correlation with both genetic organization of the TcA protein(s) and taxonomic origin of the genomes, suggesting these subfamilies may utilize different mechanisms for cellular recognition. Taken together, our results support the previously described two different binding modalities of Tc toxins, leading to unique host targeting properties. We also present the bioinformatics data and receptor screening strategies for TcA proteins, provide new insights into understanding host specificity and biomedical applications of Tc toxins.
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http://dx.doi.org/10.1371/journal.ppat.1009244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861375PMC
February 2021

OIP5-AS1 specifies p53-driven POX transcription regulated by TRPC6 in glioma.

J Mol Cell Biol 2021 Sep;13(6):409-421

The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.

Transcription factors (TFs) control an array of expressed genes. However, the specifics of how a gene is expressed in time and space as controlled by a TF remain largely unknown. Here, in TRPC6-regulated proline oxidase 1 (POX) transcription in human glioma, we report that OIP5-AS1, a long noncoding RNA, determines the specificity of p53-driven POX expression. The OIP5-AS1/p53 complex via its 24 nucleotides binds to the POX promoter and is necessary for POX expression but not for p21 transcription. An O-site in the POX promoter to which OIP5-AS1 binds was identified that is required for OIP5-AS1/p53 binding and POX transcription. Blocking OIP5-AS1 binding to the O-site inhibits POX transcription and promotes glioma development. Thus, the OIP5-AS1/O-site module decides p53-controlled POX expression as regulated by TRPC6 and affects glioma development.
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http://dx.doi.org/10.1093/jmcb/mjab001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436707PMC
September 2021

Identification of differentially expressed circular RNAs in keloid and normal skin tissue by high-throughput sequencing.

Dermatol Ther 2021 03 17;34(2):e14745. Epub 2021 Jan 17.

Departments of Facial Plastic Surgery, Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, China.

Keloid is a kind of pathological skin scar with unclear molecular pathology. Circular RNAs (circRNAs) are involved in the occurrence and development of many diseases; however, their relationship with keloid is not well understood. To investigate the involvement of dysregulated circRNAs in keloid. Thirty-seven keloids and 37 normal skin tissues were collected, and the changes of circRNAs, microRNAs (miRNAs) and mRNAs in 3 keloids and 3 normal samples by high-throughput sequencing were detected first. Based on the circRNA-miRNA-mRNA interaction network construction, gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis combining several signaling pathways associated with keloid formation and progression, the circRNAs required further verification were screened out. The expression levels of the selected circRNAs were verified in 37 keloids and 37 normal skin tissues using quantitative real-time polymerase chain reaction (QPCR). The interaction of candidate circRNA and its predicted binding miRNA was tested by dual-luciferase reporter gene experiment. Compared with normal controls, there was an average of 120 and 12 circRNAs, 44 and 63 miRNAs, 656 and 156 mRNAs were upregulated and downregulated, respectively, in keloids. According to the analysis of bioinformation, six circRNAs were picked out. The QPCR validation results of two upregulated circRNAs (hsa_circ_0001320 and circCOL5A1) were consistent with previous sequencing results. The interaction between hsa_circ_0001320 and miR-574-5p was confirmed. This study makes it clear that the abnormal expression of circRNAs may be related to the pathological process of keloid.
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http://dx.doi.org/10.1111/dth.14745DOI Listing
March 2021

Epitranscriptome of the ventral tegmental area in a deep brain-stimulated chronic unpredictable mild stress mouse model.

Transl Neurosci 2020 3;11(1):402-418. Epub 2020 Nov 3.

Center of Military Brain Science, Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences (AMMS), The Academy of Military Sciences, No. 27 Taiping Road, Haidian District, Beijing, China, 100850.

Deep brain stimulation (DBS) applied to the nucleus accumbens (NAc) alleviates the depressive symptoms of major depressive disorders. We investigated the mechanism of this effect by assessing gene expression and RNA methylation changes in the ventral tegmental area (VTA) following NAc-DBS in a chronic unpredictable mild stress (CUMS) mouse model of depression. Gene expression and -methyladenosine (mA) levels in the VTA were measured in mice subjected to CUMS and then DBS, and transcriptome-wide mA changes were profiled using immunoprecipitated methylated RNAs with microarrays, prior to gene ontology analysis. The expression levels of genes linked to neurotransmitter receptors, transporters, transcription factors, neuronal activities, synaptic functions, and mitogen-activated protein kinase and dopamine signaling were upregulated in the VTA upon NAc-DBS. Furthermore, mA modifications included both hypermethylation and hypomethylation, and changes were positively correlated with the upregulation of some genes. Moreover, the effects of CUMS on gene expression and mA-mRNA modification were reversed by DBS for some genes. Interestingly, while the expression of certain genes was not changed by DBS, long-term stimulation did alter their mA modifications. NAc-DBS-induced modifications are correlated largely with upregulation but sometimes downregulation of genes in CUMS mice. Our findings improve the current understanding of the molecular mechanisms underlying DBS effects on depression.
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http://dx.doi.org/10.1515/tnsci-2020-0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724003PMC
November 2020

Validation of the NSABP/NRG Oncology 8-Gene Trastuzumab-benefit Signature in Alliance/NCCTG N9831.

JNCI Cancer Spectr 2020 Oct 7;4(5):pkaa058. Epub 2020 Sep 7.

Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL, USA.

Our objective was to validate the NSABP 8-gene trastuzumab-benefit signature, developed and initially validated in NRG Oncology/NSABP B-31 in Alliance/NCCTG N9831. The B-31 and N9831 trials demonstrated the benefit of adding trastuzumab to chemotherapy in the adjuvant setting for HER2+ breast cancer patients. NSABP investigators utilized gene expression profiles of N9831 patients (N = 892) to blindly assign patients to large-, moderate-, or no-trastuzumab benefit groups and then NCCTG investigators assessed the degree of trastuzumab benefit using Cox models adjusted for age, nodes, estrogen receptor/progesterone receptor status, tumor size, and grade. Hazard ratios and 2-sided values for recurrence-free survival of the predicted large- (n = 387), moderate- (n = 401), and no-benefit (n = 104) groups, based on the 8-gene signature were 0.47 (95% CI = 0.31 to 0.73, < .001), 0.60 (95% CI = 0.39 to 0.92, = .02), and 1.54 (95% CI = 0.59 to 4.02, = .38), respectively (   .02), providing validation of the 8-gene signature in an independent study.
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http://dx.doi.org/10.1093/jncics/pkaa058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674704PMC
October 2020
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