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1.
Mult Scler Relat Disord ; 51: 102870, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33819724

RESUMO

OBJECTIVE: Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervous system. Glial fibrillary acidic protein (GFAP) is a monomeric intermediate filament protein. A systematic review and meta-analysis was performed regarding a candidate biomarker for astrocytic damage of cerebrospinal fluid (CSF) and blood GFAP levels in differentiating multiple sclerosis and its subtypes. METHODS: Relevant studies published prior to October 2020 were retrieved from the PubMed, Web of Science, Cochrane Library and clinicaltrials.gov databases using the following keywords: 'Multiple sclerosis' or 'MS' and 'Glial Fibrillary Acidic Protein' or 'GFAP'. Two authors independently selected the articles and extracted the data. Of the 31 full articles screened, 11 were included in the qualitative analysis and meta-analysis. Differences in the mean CSF and blood GFAP levels were used as the main efficacy measures, and the meta-analysis was performed using Review Manager version 5.3 software. RESULTS: Eleven clinical trials comprising 960 patients were selected. CSF GFAP levels were higher in 503 MS patients than in 252 (healthy and disease) controls, with a moderate effect size of 0.72 (p < 0.00001). Mean CSF GFAP levels were significantly higher in 325 MS patients with relapsing disease than in 140 MS patients with progressive disease (SMD=-0.47; 95% CI=-0.80 to -0.15; P = 0.005). CSF GFAP levels in 161 MS patients in relapse (irrespective of MS subtype) were significantly higher than those in 180 MS patients in remission (MD=103.83; 95% CI=68.09 to139.57; P<0.001). The performances of GFAP in blood for differentiating patients with MS from controls were also significant. Blood GFAP was higher in 245 MS patients than in 53 (healthy and disease) controls, with a moderate effect size of 37.25 (p < 0.00001). CONCLUSION: The level of CSF-GFAP is correlated with MS and its different subtypes, reflecting the different degrees of damage to astrocytes in different subtypes of MS. In addition, progressive MS is more closely related to the increase in cerebrospinal fluid GFAP level than relapsing-remitting MS, and GFAP may be a useful marker of disease progression. Moreover, the GFAP level in the blood of MS patients is higher than that in the control group, and the sample size needs to be further expanded for verification in the future..

2.
FASEB J ; 35(5): e21535, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33817835

RESUMO

Thymic epithelial cells (TECs) are indispensable for T cell development, T cell receptor (TCR) repertoire selection, and specific lineage differentiation. Medullary thymic epithelial cells (mTECs), which account for the majority of TECs in adults, are critical for thymocyte selection and self-tolerance. CD74 is a nonpolymorphic transmembrane glycoprotein of major histocompatibility complex class II (MHCII) that is expressed in TECs. However, the exact role of CD74 in regulating the development of mTEC is poorly defined. In this research, we found that loss of CD74 resulted in a significant diminution in the medulla, a selective reduction in the cell number of mature mTECs expressing CD80 molecules, which eventually led to impaired thymic CD4+ T cell development. Moreover, RNA-sequence analysis showed that CD74 deficiency obviously downregulated the canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in mTECs. Our results suggest that CD74 positively controls mTEC cellularity and maturation partially by activating the canonical NF-κB signaling pathway.

3.
Vet Microbiol ; 255: 109022, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33711567

RESUMO

Herpesvirus based multivalent vaccines have been extensively studied, whereas few of them have been successfully used in clinic and animal husbandry industry due to the low expression of foreign immunogens in herpesvirus. In this study, we developed a new strategy to construct herpesvirus based bivalent vaccine with high-level expression of foreign immunogen, by which the ORF2 gene encoding the major antigen protein Cap of porcine circovirus type 2 (PCV2), was highly expressed in pseudorabies virus (PRV). To obtain the high expression of PCV2 immunogen, tandem repeats of PCV2 ORF2 gene were firstly linked by protein quantitation ratioing (PQR) linker to reach equal expression of each ORF2 gene. Then, the multiple copies of ORF2 gene were respectively inserted into the gE and gG sites of PRV using CRISPR/Cas9 system, in which the expression of ORF2 gene was driven by endogenous strong promoters of PRV. Through this way, the highest yield of Cap protein was achieved in two copies of quadruple ORF2 gene insertion. Finally, in mice and pigs immunized with the bivalent vaccine candidate, we detected high titer of specific antibodies for PRV and neutralized antibodies for PCV2, and observed protective effect of the bivalent vaccine candidate against PRV challenge in immunized pigs, suggesting a potential clinical application of the bivalent vaccine candidate we constructed. Together, our strategy could be extensively applied to the generation of other multivalent vaccines, and will pave the way to construct herpesvirus based multivalent vaccines to effectively reduce the cost of vaccine.

4.
Sci Total Environ ; 772: 145059, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-33770883

RESUMO

Oxygenation of the reduced species has been regarded as the major source for hydroxyl radical (HO) generation in aquatic environments. Yet, the O2-induced formation of HO in lake sediments during the flooding/drought transformation process remained largely unexplored. In this study, two types of sediments from Wucheng (WC) and Nanji (NJ) area in Lake Poyang, China, were collected, respectively, with the burst of HO derived by flooding/drought transformation process exploring via the incubation experiments. Results showed that no obvious HO can be detected for the two sediments during the flooding period, while the concentrations of HO increased rapidly for the flooding/drought transformation process due to the enhanced dissolved oxygen contents. The highest concentrations of HO in the surface sediment were 2.45 ± 0.19 µmol kg-1 for WC sediment and 0.69 ± 0.25 µmol kg-1 for NJ sediment, showing higher burst potential of HO for the former. The contents of Fe(II) in the surface sediments for WC area (589.3 ± 37.29 mg kg-1) were about two times higher than those for NJ area (308.4 ± 94.01 mg kg-1) during the flooding period. Oxygenation of the surface Fe(II) contributed significantly to the burst of HO in the flooding/drought transformation process. Moreover, the higher percentage of humic-like substances in WC sediment indicated that the dissolved humic fraction exhibited also important role in the HO formation due to electrons transfer under redox conditions. This study highlighted the importance of reactive reduced species in manipulating the burst of HO in lake sediment, which is essential for understanding the geochemical cycling of several major and trace elements as well as the behavior and fate of the contaminants in aquatic ecosystems.

5.
Proc Natl Acad Sci U S A ; 118(8)2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33602823

RESUMO

Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity.

6.
Food Chem ; 351: 129226, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-33639430

RESUMO

The effect of three drying methods (hot air, freeze and spray drying) on the solubility and amphiphilicity of gelatin were investigated and compared. Results showed spray drying gelatin (SDG) and hot air drying gelatin (HDG) showed the lowest and best solubility, respectively. This phenomenon was attributed to the degree of subunits degradation and hydrophobicity. The HDG showed an obvious degradation during the hot air drying and displayed the strongest hydrophilicity, while SDG showed a slight degradation and strongest hydrophobicity. The results of wettability showed that SDG had a better amphiphilicity (92.48°) in comparison with HDG (57.7°) and freeze drying gelatin (VDG, 77.53°), which can effectively reduce the interfacial tension of gelatin, thus significantly improving the stability of foam and emulsion (p < 0.05). These results suggested the drying methods can adjust the amphiphilicity of gelatin, and the SDG displayed a better amphiphilicity, showing good potential applications in foam and emulsion.


Assuntos
Dessecação/métodos , Congelamento , Gelatina/química , Gelatina/isolamento & purificação , Interações Hidrofóbicas e Hidrofílicas , Micro-Ondas , Solubilidade , Fatores de Tempo , Molhabilidade
7.
Cancer Biol Med ; 18(1): 74-87, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33628586

RESUMO

Objective: The newly defined cancer-testis (CT) gene, MEIOB, was previously found to play key roles in DNA double-strand break (DSB) repair. In this study, we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers (TNBCs). Methods: The Cancer Genome Atlas database was used to quantify the expression of MEIOB. Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC. The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro. Patient-derived xenograft (PDX) models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors. Results: We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors, especially TNBCs. Its activation was significantly associated with poor survival in breast cancer patients [overall, hazard ratio (HR) = 1.90 (1.16-2.06); TNBCs: HR = 7.05 (1.16-41.80)]. In addition, we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells. Further analysis showed that MEIOB participated in DSB repair in TNBCs. However, in contrast to its function in meiosis, it mediated homologous recombination deficiency (HRD) through the activation of polyADP-ribose polymerase (PARP)1 by interacting with YBX1. Furthermore, activated MEIOB was shown to confer sensitivity to PARP inhibitors, which was confirmed in PDX models. Conclusions: MEIOB played an oncogenic role in TNBC through its involvement in HRD. In addition, dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors, so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.

8.
Acta Cir Bras ; 36(1): e360105, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33605308

RESUMO

PURPOSE: To investigate the relationship between atherosclerotic abdominal aortic aneurysm (AAA) and CXC chemokine receptor type 2 (CXCR2). METHODS: Mouse AAA model was established by embedding angiotensin-II pump (1000 ng/kg/min) in ApoE-/- mice. Mice were received SB225002, a selective CXCR2 antagonist, for treatment. Blood pressure was recorded, and CXCR2+ macrophages were examined by flow cytometry analysis. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining was performed to detect cell apoptosis of abdominal aortic aneurysms. Macrophages were isolated from ApoE-/- mice and treated with Ang II and/or SB225002. Dihydroethidium staining was carried out to determine reactive oxygen species (ROS) activity. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the production of IL-1ß and TNF-α. The corresponding gene expressions were measured using real-time polymerase chain reaction (PCR), western blot, and immunohistochemistry staining. RESULTS: We found that Ang II activated the expression of CXCR2 in monocytes during the formation of AAA. Inhibition of CXCR2 significantly reduced the size of AAA, attenuated inflammation and phenotypic changes in blood vessels. Ang II-induced macrophages exhibited elevated ROS activity, and elevated levels of 1ß and TNF-α, which were then partly abolished by SB225002. CONCLUSIONS: CXCR2 plays an important role in AAA, suggesting that inhibiting CXCR2 may be a new treatment for AAA.


Assuntos
Aneurisma da Aorta Abdominal , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/prevenção & controle , Apolipoproteínas E/genética , Modelos Animais de Doenças , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-8B
9.
Clin Res Hepatol Gastroenterol ; : 101648, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33588099

RESUMO

BACKGROUND: Long non-coding RNA 01559 (LINC01559) has been found to be associated with the tumorigenesis of malignant tumors. However, the expression pattern and the potential molecular mechanism of LINC01559 in hepatocellular carcinoma (HCC) progression remain unclear. METHODS: Expression profile and clinical data of patients with HCC were retrieved from The Cancer Genome Atlas database. The quantitative real-time PCR (qRT-PCR) and western blot assays were used to detect the mRNA and protein levels of indicated molecules. Loss-of-function of LINC01559 and microRNA-511 (miR-511) assays were implemented to validate their roles in regulating proliferation, invasion and migration of HCC HepG2 and Huh7 cells. Bioinformatics and luciferase reporter assays were used to determine the possible interactions between LINC01559, miR-511 and solute carrier family 38 member 1 (SLC38A1). RESULTS: LINC01559 was highly expressed, and related to poor prognosis in HCC patients. LINC01559-knockdown restrained the proliferation and growth of HepG2 and Huh7 cells. Furthermore, LINC01559 can function as a sponge for miR-511, which was downregulated in HCC patients. Downregulation of miR-511 significantly increased the cell viability, invasive and migratory capacities, and could abolish the suppressive effect of LINC01559-knockdown on these HCC cells. Moreover, SLC38A1 was a target of miR-511 and upregulated in HCC. Knockdown of LINC01559 significantly reduced while miR-511 inhibitor notably elevated the mRNA and protein levels of SLC38A1, which were abrogated by downregulation of LINC01559 and miR-511 simultaneously. CONCLUSIONS: LINC01559 functioned as a competitive endogenous RNA mediating the malignant phenotypes of HCC cells via sponging miR-511, and may be a considerable therapeutic bio-target in HCC.

10.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(1): 67-72, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33441230

RESUMO

Objective To screen the sequence of nanobodies against human CD20, and obtain anti-CD20-human IgG Fc nanobodies with high affinity and specificity. Methods Based on the naive phage display library, 4 rounds of liquid affinity screening were performed using biotinylated CD20 antigen as the target, and positive clones were identified by ELISA. Prokaryotic expression vector CD20-IgG Fc/pCZN1 was constructed and transformed into E.coli Arctic Express, and the expression of the recombinant protein was induced by IPTG at low temperature and purified by Ni column. The purified product was identified by ELISA and Western blot analysis. Results The specific CD20 nanobody showed good repeatability and hydrophilicity. The purity of anti-CD20-human IgG Fc nanobodies was higher than 85%. ELISA indicated that anti-CD20-human IgG Fc nanobodies had high affinity with CD20 antigen, and Western blot analysis demonstrated they could specifically recognize CD20 antigen. Conclusion The sequence of anti-CD20 nanobody was successfully obtained using the naive phage nanobody library. The purified anti-CD20-human IgG Fc nanobody has high affinity and specificity.


Assuntos
Bacteriófagos , Anticorpos de Domínio Único , Antígenos CD20 , Ensaio de Imunoadsorção Enzimática , Biblioteca Gênica , Humanos , Anticorpos de Domínio Único/genética
11.
Int J Biol Macromol ; 171: 1-9, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33412193

RESUMO

In this study, the microwave irradiation as a green approach was applied to improve the properties (mainly solubility and interface properties) of pigskin gelatin. The results showed that the solubility of pigskin gelatin was improved obviously at room temperature (25 °C) due to the destruction of polymer subunits. Furthermore, the exposure of more hydrophobic groups in microwave-irradiated gelatin increased its hydrophobicity, consequently improving the amphiphilic property and the interfacial properties of gelatin. The results of interface behavior showed that the interfacial tension of microwave-irradiated gelatin was reduced obviously with the extension of irradiation time (0-30 min), which is more beneficial to adsorption of gelatin molecules at the interface, thus resulting in a significant increase of adsorption rate (AP) from 56.13% (0 min) to 91.87% (30 min). Correspondingly, the foaming and emulsifying properties of gelatin were also improved significantly (p < 0.05). This study would promote the development of food-grade foam and emulsion based on pigskin gelatin by adjusting solubility and interface properties.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33400489

RESUMO

The practical applications of Li metal batteries (LMBs) have long been limited by the obstacles of low Coulombic efficiency (CE) and formation of dendrites on Li metal electrode. Herein, we demonstrated the synthesis of a novel three-dimensional (3D) nanostructured skeleton substrate composed of nitrogen-doped hollow carbon fiber/carbon nanosheets/ZnO (NHCF/CN/ZnO) using 2-methylimidazole (2-MIZ)-coated 3D cloth as a scaffold. The mechanism of formation of this novel hierarchical structure was investigated. The multilayered hierarchical structure and abundant lithiophilic nucleation sites of the substrate provide a stable environment for the deposition and stripping of lithium metal, thus preventing the generation of lithium dendrites. Consequently, the lithium anode based on the NHCF/CN/ZnO current collector demonstrated an excellent Coulombic efficiency of 96.47% after 400 cycles at 0.5 mA cm-2. The prepared NHCF/CN/ZnO/Li electrode also showed outstanding cycling performance of over 800 h and an ultralow voltage hysteresis of less than 30 mV in a symmetric cell at 5 mA cm-2 and 5 mAh cm-2. Even at a high loading of the cathode with 10.4 mg cm-2, the full cell of NHCF/CN/ZnO/Li anode with LiFePO4 can also work very well. Our work offers a path toward the facial preparation of 3D hierarchical structure for high-performance lithium metal batteries.

13.
BMC Plant Biol ; 21(1): 9, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407138

RESUMO

BACKGROUND: Tissue culture is an effective method for the rapid breeding of seedlings and improving production efficiency, but explant browning is a key limiting factor of walnut tissue culture. Specifically, the polymerization of PPO-derived quinones that cause explant browning of walnut is not well understood. This study investigated explants of 'Zanmei' walnut shoot apices cultured in agar (A) or vermiculite (V) media, and the survival percentage, changes in phenolic content, POD and PPO activity, and JrPPO expression in explants were studied to determine the role of PPO in the browning of walnut explants. RESULTS: The results showed that the V media greatly reduced the death rate of explants, and 89.9 and 38.7% of the explants cultured in V media and A media survived, respectively. Compared with that of explants at 0 h, the PPO of explants cultured in A was highly active throughout the culture, but activity in those cultured in V remained low. The phenolic level of explants cultured in A increased significantly at 72 h but subsequently declined, and the content in the explants cultured in V increased to a high level only at 144 h. The POD in explants cultured in V showed high activity that did not cause browning. Gene expression assays showed that the expression of JrPPO1 was downregulated in explants cultured in both A and V. However, the expression of JrPPO2 was upregulated in explants cultured in A throughout the culture and upregulated in V at 144 h. JrPPO expression analyses in different tissues showed that JrPPO1 was highly expressed in stems, young leaves, mature leaves, catkins, pistils, and hulls, and JrPPO2 was highly expressed in mature leaves and pistils. Moreover, browning assays showed that both explants in A and leaf tissue exhibited high JrPPO2 activity. CONCLUSION: The rapid increase in phenolic content caused the browning and death of explants. V media delayed the rapid accumulation of phenolic compounds in walnut explants in the short term, which significantly decreased explants mortality. The results suggest that JrPPO2 plays a key role in the oxidation of phenols in explants after branch injury.

14.
Artigo em Inglês | MEDLINE | ID: mdl-33470096

RESUMO

A stable and efficient carrier transfer is a prerequisite for high-performance perovskite solar cells. With optimized additives, a significantly improved charge carrier transfer can be achieved at the interface of perovskite/2,2',7,7'-tetrakis-(N,N-di-4-methoxyphenylamino)-9,90-spirobifluorene (Spiro-OMeTAD) with significantly boosted photostability. Using time-dependent spectroscopic techniques, we investigated charge carrier and mobile-ion dynamics at the perovskite/Spiro-OMeTAD interface, where the Spiro-OMeTAD contains different bis(trifluoromethanesulfonyl)imide (TFSI) salts additives (Li-TFSI, Mg-TFSI2, Ca-TFSI2). The pristine response and the dynamic changes under continuous illuminations are presented, which is correlated to the different behaviors of mobile-ion accumulations at the perovskite/Spiro interface and ascribed to the improved hole mobilities in Spiro-OMeTAD, ultimately contributing to the favorable behaviors in solar cells. It is demonstrated that the hole mobility and conductivity of hole transport layers play an important role in suppressing mobile-ion accumulation at the interfaces of solar cells. With the engineering of mixed-cation mixed-halide perovskite, optimal engineering of additives in hole transport materials is an efficient strategy. Therefore, it should be emphasized for accelerating perovskite photovoltaic commercialization.

15.
Cardiovasc J Afr ; 32: 1-3, 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33496722

RESUMO

Critical patients with coronavirus disease 2019 (COVID-19) suffer from severe illness and have a high mortality rate. Lung transplantation may be the final option for a subset of these patients. Herein we report the important role of peri-operative echocardiography in a COVID-19 patient who underwent bilateral lung transplantation because of severe respiratory failure. The precise evaluation provided by echocardiography enabled the prevention of anastomotic complications and the successful management of haemodynamic instability. Echocardiographers should be familiar with the complications of lung transplantation and the haemodynamics under extracorporeal membrane oxygenation support to achieve a more accurate interpretation of cardiac parameters.

16.
J Hematol Oncol ; 14(1): 18, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33461583

RESUMO

Accurate interpretation of BRCA1/2 variants is critical for risk assessment and precise treatment of breast cancer (BC). Hence, the establishment of an ethnicity-based BRCA1/2 variant database of the Chinese population is of paramount importance. In this study, panel-based sequencing served to detect BRCA1/2 variants in a Chinese multicenter cohort of 21,216 BC patients and 6434 healthy controls. Overall, the percentage of subjects carrying pathogenic variants was 5.5% (1174/21,216) in BC patients and 1.1% (71/6434) in healthy controls. We identified 13 pathogenic variants as high-frequency variants that had a frequency of > 0.45‰ in BC patients (≥ 10 in 21,216 patients), none of which has been reported in Caucasians. Pathogenic BRCA1/2 variants correlated with younger onset age, higher frequencies of bilateral and triple-negative BC (TNBC), invasive carcinomas, high histological grades, and family history of BC and other cancers. Furthermore, the percentage of the subjects carrying VUS was 9.8% (2071/21,216) in BC patients and 6.9% (446/6434) in healthy controls. Based on our cohort study, we unambiguously reclassified 7 out of the 858 VUS resulting in lower VUS ratio in patients (from 9.8 to 7.9%) as well as in healthy control (from 6.9 to 5.3%). We also re-analyzed the 100 variants in 13 exons (2-5 and 15-23) of the BRCA1 genes using a functional assay (saturation genome editing; SGE). 55 of the 59 VUS had distinct status in the SGE study: 24 (43.6%) were pathogenic, and 31 (56.4%) were benign. Strong ethnicity-specific occurrences of pathogenic BRCA1/2 variants were identified in the Chinese population. Hence, the findings provide rationale and sequencing information for the implementation of BRCA1/2 variants tailored to the Chinese population into clinical risk assessment.

17.
Cancer Cell ; 39(3): 423-437.e7, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33450198

RESUMO

Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization in lungs. Here, we show that tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung metastasis by regulating recruitment of neutrophils and formation of neutrophil extracellular traps (NETs). CTSC enzymatically activates neutrophil membrane-bound proteinase 3 (PR3) to facilitate interleukin-1ß (IL-1ß) processing and nuclear factor κB activation, thus upregulating IL-6 and CCL3 for neutrophil recruitment. In addition, the CTSC-PR3-IL-1ß axis induces neutrophil reactive oxygen species production and formation of NETs, which degrade thrombospondin-1 and support metastatic growth of cancer cells in the lungs. CTSC expression and secretion are associated with NET formation and lung metastasis in human breast tumors. Importantly, targeting CTSC with compound AZD7986 effectively suppresses lung metastasis of breast cancer in a mouse model. Overall, our findings reveal a mechanism of how tumor cells regulate neutrophils in metastatic niches and support CTSC-targeting approaches for cancer treatment.

18.
NeuroRehabilitation ; 48(1): 83-96, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33361618

RESUMO

BACKGROUND: The treatment for patients suffering from motor dysfunction following stroke using continuous repetitive transcranial magnetic stimulation (rTMS) has the potential to be beneficial for recovery. However, the impact of explicit results on the coupling of various rTMS protocols on motor treatment in patients following acute cerebral infarction remain unexplored. OBJECTIVE: The current study aims to design a sham-controlled randomized report to explore the capability of consecutive suppressive-facilitatory rTMS method to increase the motor results following acute stroke. METHODS: A hundred ischemic stroke patients suffering from motor disorder were randomly assigned to obtain 4 week sessions of (1)10 Hz over the ipsilesional primary motor cortex (M1) and next 1 Hz over the contralesional M1; (2) contralesional sham stimulation and next ipsilesional real 10 Hz; (3) contralesional real 1 Hz rTMS and next ipsilesional sham stimulation; or (4) bilateral sham-control procedures. At 24 hours before and after the intervention, we obtained cortical excitability data from study subjects. At baseline, after treatment and 3 months follow up, we additionally evaluated patients with the clinical assessments. RESULTS: At post-intervention, group A showed greater motor improvements in FMA, FMA-UL, NIHSS, ADL and mRS values than group B, group C and group D, that were continued for at least 3 months after the completion of the treatment time. Specifically, it is shown in the cortical excitability study that the motor-evoked potential (MEP) amplitude and resting motor threshold (rMT) more significantly improved in group A than other groups. The improvement in motor function and change in motor cortex excitability exhibit a significant correlation in the affected hemisphere. The combined 1 Hz and 10 Hz stimulation treatment showed a synergistic effect. CONCLUSIONS: Facilitatory rTMS and coupling inhibitory produced extra satisfactory results in facilitating the motor's recovery in the subacute and acute phase following stroke compared to that acquired from alone single-course modulation.

19.
Toxicology ; 449: 152663, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33359577

RESUMO

Perfluorooctane sulfonate (PFOS), a stable end-product of perfluorinated compounds (PFCs), is associated with male reproductive disorders, but its underlying mechanisms are still unclear. We used in vivo and in vitro models to investigate the effects of PFOS on testosterone biosynthesis and related mechanisms. First, male ICR mice were orally administered PFOS (0-10 mg/kg/bw) for 4 weeks. Bodyweight, sperm count, reproductive hormones, mRNA expression of the genes related to testosterone biosynthesis, and the protein expression of protein kinase A (PKA), p38 mitogen-activated protein kinase (MAPK), cAMP-response element binding protein (CREB), CREB regulated transcription coactivator 2 (CRTC2) and steroidogenic acute regulatory protein (StAR) were evaluated. Furthermore, mouse primary Leydig cells were used to delineate the molecular mechanisms that mediate the effects of PFOS on testosterone biosynthesis. Our results demonstrated that PFOS dose-dependently decreased sperm count, testosterone level, CRTC2/StAR expression, and damaged testicular interstitium morphology, paralleled by increase in phosphorylated PKA, CREB and p38 in testes. Additionally, similar to the in vivo results, PFOS significantly decreased testosterone secretion, CRTC2/StAR expression, interaction between CREB and CRTC2 and binding of CREB/CRTC2 to StAR promoter region, paralleled by increase in phosphorylated-p38, PKA, and CREB expression. Meanwhile, inhibition of p38 by SB203580, or inhibition of PKA by H89 can significantly alleviate the above PFOS-induced effects. As such, the present study highlights a role of the CREB/CRTC2/StAR signaling pathway in PFOS-induced suppression of testosterone biosynthesis, advancing our understanding of molecular mechanisms for PFOS-induced male reproductive disorders.

20.
Child Care Health Dev ; 47(2): 281-289, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33314201

RESUMO

BACKGROUND: Parental phubbing and its effects on adolescents have recently begun to attract concern. Previous studies have shown that parental phubbing was associated with emotional and behavioral problems among adolescents. However, much less is known about the association between parental phubbing and youth life satisfaction, let alone the mediating and moderating mechanisms. METHODS: Self-reports of parental phubbing, satisfaction with the parent-adolescent relationship, life satisfaction, and attachment style were assessed in a sample of 303 Chinese teenagers (155 girls and 148 boys, Mage = 14.00, SDage = 0.86). Multiple regressions were applied to investigate the association between parental phubbing and adolescents' life satisfaction, the mediating role of adolescents' relationship satisfaction, and the moderating role of adolescents' attachment styles. RESULTS: Parental phubbing had a negative effect on adolescents' life satisfaction, yet this association was completely mediated by adolescents' relationship satisfaction. Besides, the association between parental phubbing and adolescents' relationship satisfaction was moderated by adolescents' attachment styles. Overall, the conditional effect of parental phubbing on adolescents' life satisfaction was significant among the preoccupied teens and the fearful teens but not significant among the secure teens and the dismissing teens. CONCLUSION: Although parental phubbing has the potential to undermine youth well-being, the actual consequences for adolescents are variable, depending on their attachment orientations.

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