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1.
Neuroimage ; : 118115, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33933599

RESUMO

Humans have a remarkable ability to infer the mind of others. This mentalizing skill relies on a distributed network of brain regions but how these regions connect and interact is not well understood. Here we leveraged large-scale multimodal neuroimaging data to elucidate the brain-wide organization and mechanisms of mentalizing processing. Key connectomic features of the mentalizing network (MTN) have been delineated in exquisite detail. We found the structural architecture of MTN is organized by two parallel subsystems and constructed redundantly by local and long-range white matter fibers. We uncovered an intrinsic functional architecture that is synchronized according to the degree of mentalizing, and its hierarchy reflects the inherent information integration order. We also examined the correspondence between the structural and functional connectivity in the network and revealed their differences in network topology, individual variance, spatial specificity, and functional specificity. Finally, we scrutinized the connectome resemblance between the default mode network and MTN and elaborated their inherent differences in dynamic patterns, laterality, and homogeneity. Overall, our study demonstrates that mentalizing processing unfolds across functionally heterogeneous regions with highly structured fiber tracts and unique hierarchical functional architecture, which make it distinguishable from the default mode network and other vicinity brain networks supporting autobiographical memory, semantic memory, self-referential, moral reasoning, and mental time travel.

2.
Clin Cancer Res ; 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947693

RESUMO

PURPOSE: Intratumoral hepatitis B virus (HBV) integrations and mutations are related to hepatocellular carcinoma (HCC) progression. Circulating cell-free DNA (cfDNA) has shown itself as a powerful non-invasive biomarker for cancer. However, the HBV integration and mutation landscape on cfDNA remains unclear. EXPERIMENTAL DESIGN: A cSMART (Circulating Single-Molecule Amplification and Resequencing Technology)-based method (SIM) was developed to simultaneously investigate HBV integration and mutation landscapes on cfDNA with HBV-specific primers covering the whole HBV genome. 481 HCC and 517 liver cirrhosis (LC) patients were recruited in the study. RESULTS: A total of 6,861 integration breakpoints including TERT and KMT2B were discovered in HCC cfDNA, more than in LC. The concentration of circulating tumor DNA (ctDNA) was positively correlated with the detection rate of these integration hotspots and total HBV integration events in cfDNA. To track the origin of HBV integrations in cfDNA, whole-genome sequencing (WGS) was performed on their paired tumor tissues. The paired comparison of WGS data from tumor tissues and SIM data from cfDNA confirmed most recurrent integration events in cfDNA originated from tumor tissue. The mutational landscape across the whole HBV genome was firstly generated for both HBV genotype C and B. A region from nt1100 to nt1500 containing multiple HCC risk mutation sites (OR>1) was identified as a potential HCC-related mutational hot-zone. CONCLUSIONS: Our study provides an in-depth delineation of HBV integration/mutation landscapes at cfDNA level and did a comparative analysis with their paired tissues. These findings shed light on the possibilities of non-invasive detection of virus insertion/mutation.

3.
Cardiovasc J Afr ; 32: 1-7, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33950066

RESUMO

OBJECTIVES: Left atrial appendage (LAA) morphology is a powerful predictor of thrombogenesis of the left atrium (LA) in patients with non-valvular atrial fibrillation (NVAF). However, it remains unknown whether LAA morphology is useful for stroke risk stratification in patients with NVAF. METHODS: A total of 555 atrial fibrillation patients were divided into thrombus and non-thrombus groups according to transoesophageal echocardiography. We analysed the correlation between LAA morphology and the CHADS2 score. We determined the L2CHADS2 score and compared the ability to predict LA/LAA thrombosis of the CHADS2, L2CHADS2 and CHA2DS2-VASc scores from the area under the curve (AUC). RESULTS: The odds ratio of non-chicken wing LAA morphology was 11.48. Non-chicken wing LAA morphology was significantly correlated with LA/LAA thrombosis. We incorporated LAA morphology into the CHADS2 score and named it the L2CHADS2 score. The AUC of the L2CHADS2 score (0.767) in predicting LA/LAA thrombosis was significantly higher than that of the CHADS2 (0.558) or CHA2DS2-VASc scores (0.557). The positive and negative predictive values of the L2CHADS2 score (13.1 and 98.7%) were higher than those of the CHADS2 (8.7 and 94.2%) and CHA2DS2-VASc scores (6.9 and 6.9%). CONCLUSIONS: Non-chicken wing LAA morphology was a powerful predictor of LA/LAA thrombosis in NVAF patients. The AUC, sensitivity and specificity of the L2 CHADS2 score were higher than those of the CHADS2 and CHA2 DS2 -VASc scores.

4.
Eur J Clin Nutr ; 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790398

RESUMO

BACKGROUND/OBJECTIVE: To investigate impacts of early postnatal macronutrient intakes on growth and body composition of preterm infants within the first 6 months. SUBJECTS/METHODS: One hundred and thirty-three very preterm (VPT) and/or very low birth weight (VLBW) infants were consecutively included. Enteral and parenteral macronutrient intakes during the first 28 days were recorded and average daily intakes were calculated. Growth was measured at birth, term age, and 6 months of corrected age (CA). Body composition was examined by air displacement plethysmograph at term age and 6 months of CA. Associations of nutrient intakes with growth and body composition over time were analyzed using generalized estimating equation. RESULTS: After adjusting for covariates, higher daily protein, lipid, and energy intake during the first 28 days was associated with higher weight at term age for every 1 g/kg/day increment of protein and lipid intake, and every 10 kcal/kg/day increment of energy intake was associated with 0.50 (95% CI 0.04, 0.96), 0.29 (95% CI 0.07, 0.51), and 0.27 (95% CI 0.10, 0.44) higher weight z-score, respectively. Higher protein intake was associated with lower z-score of fat mass (FM, ß = -1.88, 95% CI -3.53, -0.23) and percentage of body fat (PBF, ß = -2.18, 95% CI -3.98, -0.39) at 6 months of CA, but higher lipid and carbohydrate intake was associated with higher FM and PBF z-scores at 6 months of CA. CONCLUSIONS: Macronutrient intakes during the first month of life have impacts on growth and body composition before 6 months of age. Higher daily protein intake is associated with a better growth and healthier body composition for VPT/VLBW infants.

5.
Proc Natl Acad Sci U S A ; 118(15)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33827929

RESUMO

We previously determined that several diets used to rear Aedes aegypti and other mosquito species support the development of larvae with a gut microbiota but do not support the development of axenic larvae. In contrast, axenic larvae have been shown to develop when fed other diets. To understand the mechanisms underlying this dichotomy, we developed a defined diet that could be manipulated in concert with microbiota composition and environmental conditions. Initial studies showed that axenic larvae could not grow under standard rearing conditions (27 °C, 16-h light: 8-h dark photoperiod) when fed a defined diet but could develop when maintained in darkness. Downstream assays identified riboflavin decay to lumichrome as the key factor that prevented axenic larvae from growing under standard conditions, while gut community members like Escherichia coli rescued development by being able to synthesize riboflavin. Earlier results showed that conventional and gnotobiotic but not axenic larvae exhibit midgut hypoxia under standard rearing conditions, which correlated with activation of several pathways with essential growth functions. In this study, axenic larvae in darkness also exhibited midgut hypoxia and activation of growth signaling but rapidly shifted to midgut normoxia and arrested growth in light, which indicated that gut hypoxia was not due to aerobic respiration by the gut microbiota but did depend on riboflavin that only resident microbes could provide under standard conditions. Overall, our results identify riboflavin provisioning as an essential function for the gut microbiota under most conditions A. aegypti larvae experience in the laboratory and field.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33846132

RESUMO

The Qnr pentapeptide repeat proteins interact with DNA gyrase and protect it from quinolone inhibition. The two external loops, particularly the larger loop B, of Qnr proteins are essential for quinolone protection of DNA gyrase. The specific QnrB1 interaction sites on DNA gyrase are not known. In this study, we investigated the interaction between GyrA and QnrB1 using site-specific photo crosslinking of QnrB1 loop B combined with mass spectrometry. We found that amino acid residues 286-298 on the Tower domain of GyrA interact with QnrB1 and play a key role in QnrB1 protection of gyrase from quinolone inhibition. Alanine replacement of arginine at residue 293 and a small deletion of amino acids 286-289 of GyrA resulted in a decrease in the QnrB1-mediated increase in quinolone MICs and also abolished the QnrB1 protection of purified DNA gyrase from ciprofloxacin inhibition.

7.
Virol J ; 18(1): 74, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849568

RESUMO

BACKGROUND: Liver cancer has become one of the most common cancers and has a high mortality rate. Hepatocellular carcinoma is one of the most common liver cancers, and its occurrence and development process are associated with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Main body The serious consequences of chronic hepatitis virus infections are related to the viral invasion strategy. Furthermore, the viral escape mechanism has evolved during long-term struggles with the host. Studies have increasingly shown that suppressor of cytokine signaling (SOCS) proteins participate in the viral escape process. SOCS proteins play an important role in regulating cytokine signaling, particularly the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Cytokines stimulate the expression of SOCS proteins, in turn, SOCS proteins inhibit cytokine signaling by blocking the JAK-STAT signaling pathway, thereby achieving homeostasis. By utilizing SOCS proteins, chronic hepatitis virus infection may destroy the host's antiviral responses to achieve persistent infection. CONCLUSIONS: This review provides recent knowledge regarding the role of SOCS proteins during chronic hepatitis virus infection and provides some new ideas for the future treatment of chronic hepatitis.

8.
Transbound Emerg Dis ; 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33837669

RESUMO

This study reports the development of multiplex real-time PCR assays for differential detection of capripoxvirus (CaPV), parapoxvirus (PaPV) and foot-and-mouth disease virus (FMDV) in sheep, goats and cattle. Three multiplex assays were developed, a capripox (CaP) rule-out assay for simultaneous detection and differentiation of CaPV and PaPV, a FMD rule-out assay for simultaneous detection and differentiation of FMDV and PaPV, and a FMD/CaP rule-out assay for simultaneous detection and differentiation of CaPV, PaPV and FMDV. All multiplex assays included ß-actin gene ACTB as an internal positive control to monitor PCR inhibition and accuracy of nucleic acid extractions. The optimized assays were highly specific to the target viruses (CaPV, PaPV and FMDV) with no cross-reactivity against other viruses that cause similar clinical signs. Using positive control plasmids as template, the limit of detection (LOD) of the multiplex assays were estimated as 2 CaPV, 7 PaPV and 15 FMDV copies per assay. The amplification efficiency (AE) and correlation coefficient (R2 ), estimated from the standard curves (Ct vs. log10 template dilution), were 94%-106% and >0.99, respectively, for CaP and FMD rule-out assays, 96%-116% (AE) and >0.98 (R2 ), respectively, for CaP/FMD rule-out assays and 91%-102% and >0.99, respectively, for the corresponding singleplex assays. The diagnostic sensitivity (DSe) of the multiplex assays was assessed on 35 CaPV and 39 FMDV clinical specimens from experimentally infected (CS-E) animals, and 29 CaPV (LSDV), 28 FMDV and 36 PaPV clinical specimens from naturally infected (CS-N) animals; all tested positive (DSe 100%) except two CS-E FMDV specimens that were tested negative by FMD rule-out and the corresponding singleplex (FMDV) assays (37/39; DSe 95%). The newly developed multiplex assays offer a valuable tool for differential detection of clinically indistinguishable CaPV, PaPV and FMDV in suspected animals and animals with mixed infections.

10.
BMC Musculoskelet Disord ; 22(1): 379, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33892699

RESUMO

BACKGROUNDS: Theaim of this study was to assess the efficacy of a modified intrafocal pinningtechnique with three-dimensional (3D) planning to facilitate volar plating in dorsally comminuted intra-articular distal radius fractures. METHODS: Intotal 35 AO/OTA type C2 and C3 fractures were finally included.The 3D digital model of the fracture was reconstructed based on preoperative computedtomographic (CT) images, with the displacement of the comminuted dorsalfragment and the intra-articular fragment analyzed for preoperative planning. During operation, amodified intrafocal pinning technique was applied percutaneously from thedorsal aspect of the radius to reduce the collapsed intra-articular fragmentfollowing volar plating. Adequate reduction was confirmed in all of patientsconsidering radial height, radial inclination and volar tilt in postoperativeradiographs. RESULTS: No significant fracture re-displacement wasobserved in most of the cases during a mean follow-up period of 17.4 months, exceptfor two patients withthe C3 fracture. All of the patients achieved adequate clinicalROMs at 12 months postoperatively, with a mean DASH score of 12.0. Most of the patients achievedan excellent (n = 21) or good (n = 12) Gartland and Werley wrist score. CONCLUSIONS: Ourmodified intrafocal pinning technique with 3D planning contributes to a satisfactoryclinical and radiological outcome in dorsally comminuted intra-articular distalradius fractures fixed with a volar locking plate. TRIALREGISTRATION: Notapplicable because the design of the study is retrospective.

11.
Ital J Pediatr ; 47(1): 101, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33892756

RESUMO

BACKGROUND: Allergen immunotherapy (AIT) is the only causal therapy for IgE-mediated allergy. There is less evidence about the safety and efficacy of AIT especially subcutaneous immunotherapy (SCIT) in children under 5 years old. We aimed to investigate the side effects and associated risk factors of house dust mite (HDM) SCIT in preschool children with respiratory allergic diseases. METHODS: The preschool children who had HDM-related allergic rhinitis with/without asthma were enrolled and undergone standardized HDM SCIT in our department from June 2013 to December 2019. Local reactions (LRs) and systemic reactions (SRs) were recorded and categorized according to World Allergy Organization recommendations. Demographic data and other therapeutic-related parameters were also recorded to investigate potential risk factors for these side effects. RESULTS: A total of 91 children (60 boys, 65.93%; 31 girls, 34.07%; mean age 4.13 years old) were included in the study. Among the 91 patients, 3109 SCIT injections were recorded, 62/91 (68.13%) experienced 186 immediate LRs, 4 /91(4.40%) experienced 6 delayed LRs, 11/91 (12.09%) children experienced 44 immediate SRs, 21/44 (47.73%) were grade 1 SRs, 21/44 (47.73%) were grade 2, 2/44 (4.55%) were grade 3, no grade 4 or 5 SRs occurred. Furthermore, 1/91 (1.10%) experienced 1 delayed SRs, manifested by urticaria 2 days later after allergen injection. 9/91 (9.89%) experienced 2 or more times SRs. Multivariable logistic regression analysis showed BMI (OR 1.506; 95%CI 1.091 to 2.079; p < 0.05) and sIgE against HDM (OR 1.497; 95%CI 1.082 to 2.071; p < 0.05) were risk factors for LRs. No variable was found to correlate with SRs (all p > 0.05). CONCLUSIONS: HDM subcutaneous immunotherapy is considered to be safe in preschool children with respiratory allergic diseases. Higher BMI and HDM sIgE level in children are risk factors for developing LRs. The incidence of SRs and the rate of severe SRs are low in preschool children.

12.
Gastric Cancer ; 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33929613

RESUMO

BACKGROUND AND AIMS: Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is the most common EBV-associated cancer and accounts for ~ 10% of all gastric cancers (GC). Epstein-Barr virus nuclear antigen 1 (EBNA1), which is critical for the replication and maintenance of the EBV latent genome, is consistently expressed in all EBVaGC tumors. We previously developed small molecule inhibitors of EBNA1. In this study, we investigated the efficacy and selectivity of an EBNA1 inhibitor in cell-based and animal xenograft models of EBV-positive and EBV-negative gastric carcinoma. METHODS: We tested the potency of an EBNA1 inhibitor, VK-1727, in vitro and in xenograft studies, using EBV-positive (SNU719 and YCCEL1) and EBV-negative (AGS and MKN74) GC cell lines. After treatment, we analyzed cell viability, proliferation, and RNA expression of EBV genes by RT-qPCR. RESULTS: Treatment with VK-1727 selectively inhibits cell cycle progression and proliferation in vitro. In animal studies, treatment with an EBNA1 inhibitor resulted in a significant dose-dependent decrease in tumor growth in EBVaGC xenograft models, but not in EBV-negative GC xenograft studies. Gene expression analysis revealed that short term treatment in cell culture tended towards viral gene activation, while long-term treatment in animal xenografts showed a significant decrease in viral gene expression. CONCLUSIONS: EBNA1 inhibitors are potent and selective inhibitors of cell growth in tissue culture and animal models of EBV-positive GC. Long-term treatment with EBNA1 inhibitors may lead to loss of EBV in mouse xenografts. These results suggest that pharmacological targeting of EBNA1 may be an effective strategy to treat patients with EBVaGC.

13.
Curr Microbiol ; 78(5): 1871-1881, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33830318

RESUMO

Prometryne is a widely used herbicide in China to control annual grasses and broadleaf weeds. However, the stability of prometryne makes it difficult to be degraded, which poses a threat to human health. This study presents a bacterial strain isolated from soil samples with a prometryne application history, designated strain DY-1. Strain DY-1, identified as Pseudomonas sp., is capable of utilizing prometryne as a sole carbon source for growth and degrading 100% of prometryne within 48 h from an initial concentration of 50 mg L-1. To further optimize the degradation of prometryne, the prometryne concentration, temperature, pH, and salt concentration were examined. The optimal conditions for degradation of prometryne by strain DY-1 were an initial prometryne concentration of 50 mg L-1, 30 °C, pH 7-8, and NaCl concentration of 200 mg L-1. The same strain also degraded other s-triazine herbicides, including simetryne, ametryne, desmetryne, and metribuzin, under the same conditions. The biodegradation pathway of prometryne was established by isolating sulfoxide prometryne as the first metabolite and by the identification of sulfone prometryne and 2-hydroxy prometryne by liquid chromatography-mass spectrometry (LC-MS/MS). The results illustrated that strain DY-1 achieved the removal of prometryne by gradually oxidizing and hydrolyzing the methylthio groups. A bioremediation trial with contaminated soil and pot experiments showed that after treating the prometryne-contaminated soil with strain DY-1, the content of prometryne was significantly reduced (P < 0.05). This study provides an efficient bacterial strain and approach that could be potentially useful for detoxification and bioremediation of prometryne analogs.

14.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925272

RESUMO

The development of an ideal model plant located at a key phylogenetic node is critically important to advance functional and regulatory studies of key regulatory genes in the evolutionary developmental (evo-devo) biology field. In this study, we selected Chirita pumila in the family Gesneriaceae, a basal group in Lamiales, as a model plant to optimize its genetic transformation system established previously by us through investigating a series of factors and further conduct functional test of the CYC-like floral symmetry gene CpCYC. By transforming a RNAi:CpCYC vector, we successfully achieved the desired phenotypes of upright actinomorphic flowers, which suggest that CpCYC actually determines the establishment of floral zygomorphy and the horizontal orientation of flowers in C. pumila. We also confirmed the activities of CpCYC promoter in dorsal petals, dorsal/lateral staminodes, as well as the pedicel by transferring a CpCYC promoter:GUS vector into C. pumila. Furthermore, we testified the availability of a transient gene expression system using C. pumila mesophyll protoplasts. The improved transformation system together with the inherent biological features would make C. pumila an attractive new model in functional and regulatory studies for a broad range of evo-devo issues.

15.
Sci Rep ; 11(1): 9219, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33911148

RESUMO

Tumor suppressive microRNAs (miRNAs) are increasingly implicated in the development of anti-tumor therapy by reprogramming gene network that are aberrantly regulated in cancer cells. This study aimed to determine the therapeutic potential of putative tumor suppressive miRNA, miR-138, against glioblastoma (GBM). Whole transcriptome and miRNA expression profiling analyses on human GBM patient tissues identified miR-138 as one of the significantly downregulated miRNAs with an inverse correlation with CD44 expression. Transient overexpression of miR-138 in GBM cells inhibited cell proliferation, cell cycle, migration, and wound healing capability. We unveiled that miR-138 negatively regulates the expression of CD44 by directly binding to the 3' UTR of CD44. CD44 inhibition by miR-138 resulted in an inhibition of glioblastoma cell proliferation in vitro through cell cycle arrest as evidenced by a significant induction of p27 and its translocation into nucleus. Ectopic expression of miR-138 also increased survival rates in mice that had an intracranial xenograft tumor derived from human patient-derived primary GBM cells. In conclusion, we demonstrated a therapeutic potential of tumor suppressive miR-138 through direct downregulation of CD44 for the treatment of primary GBM.

16.
Zhongguo Zhen Jiu ; 41(4): 424-8, 2021 Apr 12.
Artigo em Chinês | MEDLINE | ID: mdl-33909365

RESUMO

The clinical experience of professor WANG Yin in the treatment of primary ovarian insufficiency are summarized. Regarding acupoints selection, the sancai, named "heaven-earth-human being" method is adopted, focusing on the regulation of the middle jiao and shen (mind/spirit). Regarding needling technique, the elongated needle is used in preference. Besides, the bloodletting and cupping method with filiform-fire needle are innovated to achieve both the reinforcing and the reducing purposes as well as to eliminate stasis. The periodic therapy is applied to comply with the changes in the physiological cycle of gynecology. Acupuncture, Chinese herbal medicine, or the combination of them is selected in consideration of the concrete individual cases of primary ovarian insufficiency.


Assuntos
Terapia por Acupuntura , Acupuntura , Insuficiência Ovariana Primária , Pontos de Acupuntura , Medicamentos de Ervas Chinesas , Feminino , Humanos , Insuficiência Ovariana Primária/terapia
17.
Ann Thorac Surg ; 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33667456

RESUMO

BACKGROUND: The optimal prosthesis for aortic valve replacement (AVR) with concomitant coronary artery bypass graft (CABG) is controversial. We aim to investigate postoperative outcomes in these patients with a bioprosthetic or mechanical prosthesis. METHODS: A retrospective cohort analysis of 2485 patients aged 50-69 years who underwent AVR+CABG in Hubei province hospitals from 2002-2018. The Median follow-up duration was 6.5 years (0-15.8 years). Propensity score matching for 18 baseline characteristics yielded 346 patient pairs between bioprosthetic and mechanical prosthetic groups. Endpoints were mortality, stroke, major bleeding event, and reoperation. RESULTS: No differences in survival, stroke, or overall reoperation rates were observed between the bioprosthetic and mechanical valve group. The 15-year cumulative incidence of reoperation due to prosthesis failure/dysfunction was higher in the bioprosthetic group (HR, 2.72 [95% CI, 1.26-5.88], P =0.011), whereas the 15-year cumulative incidence of reoperation due to CAD progression/bypass failure was similar between two groups (HR, 0.76 [95% CI, 0.37-1.57], P =0.459). Mechanical valves were associated with a higher 15-year cumulative incidence of the major bleeding events compared with bioprosthesis (HR, 1.92 [95% CI, 1.16-3.19], P =0.012). CONCLUSIONS: Long-term survival, overall reoperation, or stroke incidence was comparable among the two groups, while patients with a mechanical valve showed a greater likelihood of major bleeding events. Regarding the limited durability of bioprostheses, a larger sample size followed for 15 or more years will be necessary to determine the optimal aortic valve prosthesis for patients aged 50 to 69 years undergoing concurrent AVR and CABG.

18.
J Exp Clin Cancer Res ; 40(1): 87, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648530

RESUMO

BACKGROUND: Irradiation has emerged as a valid tool for nasopharyngeal carcinoma (NPC) in situ treatment; however, NPC derived from tissues treated with irradiation is a main cause cancer-related death. The purpose of this study is to uncover the underlying mechanism regarding tumor growth after irradiation and provided potential therapeutic strategy. METHODS: Fibroblasts were extracted from fresh NPC tissue and normal nasopharyngeal mucosa. Immunohistochemistry was conducted to measure the expression of α-SMA and FAP. Cytokines were detected by protein array chip and identified by real-time PCR. CCK-8 assay was used to detect cell proliferation. Radiation-resistant (IRR) 5-8F cell line was established and colony assay was performed to evaluate tumor cell growth after irradiation. Signaling pathways were acquired via gene set enrichment analysis (GSEA). Comet assay and γ-H2AX foci assay were used to measure DNA damage level. Protein expression was detected by western blot assay. In vivo experiment was performed subcutaneously. RESULTS: We found that radiation-resistant NPC tissues were constantly infiltrated with a greater number of cancer-associated fibroblasts (CAFs) compared to radiosensitive NPC tissues. Further research revealed that CAFs induced the formation of radioresistance and promoted NPC cell survival following irradiation via the IL-8/NF-κB pathway to reduce irradiation-induced DNA damage. Treatment with Tranilast, a CAF inhibitor, restricted the survival of CAF-induced NPC cells and attenuated the of radioresistance properties. CONCLUSIONS: Together, these data demonstrate that CAFs can promote the survival of irradiated NPC cells via the NF-κB pathway and induce radioresistance that can be interrupted by Tranilast, suggesting the potential value of Tranilast in sensitizing NPC cells to irradiation.

19.
Theranostics ; 11(10): 4599-4615, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754016

RESUMO

HBO1 (KAT7 or MYST2) is a histone acetyltransferase that acetylates H3 and H4 histones. Methods: HBO1 expression was tested in human OS tissues and cells. Genetic strategies, including shRNA, CRISPR/Cas9 and overexpression constructs, were applied to exogenously alter HBO1 expression in OS cells. The HBO1 inhibitor WM-3835 was utilized to block HBO1 activation. Results: HBO1 mRNA and protein expression is significantly elevated in OS tissues and cells. In established (MG63/U2OS lines) and primary human OS cells, shRNA-mediated HBO1 silencing and CRISPR/Cas9-induced HBO1 knockout were able to potently inhibit cell viability, growth, proliferation, as well as cell migration and invasion. Significant increase of apoptosis was detected in HBO1-silenced/knockout OS cells. Conversely, ectopic HBO1 overexpression promoted OS cell proliferation and migration. We identified ZNF384 (zinc finger protein 384) as a potential transcription factor of HBO1. Increased binding between ZNF384 and HBO1 promoter was detected in OS cell and tissues, whereas ZNF384 silencing via shRNA downregulated HBO1 and produced significant anti-OS cell activity. In vivo, intratumoral injection of HBO1 shRNA lentivirus silenced HBO1 and inhibited OS xenograft growth in mice. Furthermore, growth of HBO1-knockout OS xenografts was significantly slower than the control xenografts. WM-3835, a novel and high-specific small molecule HBO1 inhibitor, was able to potently suppressed OS cell proliferation and migration, and led to apoptosis activation. Furthermore, intraperitoneal injection of a single dose of WM-3835 potently inhibited OS xenograft growth in SCID mice. Conclusion: HBO1 overexpression promotes OS cell growth in vitro and in vivo.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33687882

RESUMO

BACKGROUND: A major challenge in cervical cancer radiotherapy is to tailor the radiation doses efficiently to both eliminate malignant cells and to reduce the side effects to normal tissue. Oncolytic adenoviral drug H101 is recently tested and approved for topical adjuvant treatment of several malignancies. OBJECTIVE: This study is to evaluate the potential neoadjuvant radiotherapy benefits of H101 by testing the inhibitory function of H101 combined with radiation in different cervical cancer cells. METHODS: Human cervical cancer cells C33a, SiHa, CaSki, and Hela were treated with varying concentrations of H101 alone or combined with radiation (2Gy or 4Gy). Cell viability and apoptosis were measured at indicated time intervals. HPV16 E6 and cellular p53 mRNA expression alteration were measured by qRT-PCR. RNA scope in-situ detect HPV E6 status. P53 protein alteration are detected by Western blot. RESULTS: Cell viability and apoptosis show the combination of a high dose of H101 (MOI=1000, 10000) with radiation yielded a synergistic anti-cancer effect in all tested cervical cancer cell lines (P<0.05), with the greatest effect achieved in HPV negative C33a cells (P<0.05). Low HPV16 viral load SiHa cell was more sensitive to combination therapy than high HPV16 viral load CaSki cell (P<0.05). The combined treatment could reduce HPV16 E6 expression and increase cellular P53 level compared to radiation alone in SiHa and CaSki (P<0.05). CONCLUSIONS: Oncolytic adenoviral H101 effectively enhances the antitumor efficacy of radiation in cervical cancer cells and may serve as a novel combination therapy for cervical cancer.

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