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1.
Stem Cells Dev ; 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35018826

RESUMO

Induced pluripotent stem cells (iPSCs) are a new potential cure for diabetes, characterised by a capacity for self-renewal and differentiation to pancreatic islet beta cells, which secrete insulin and rebuild blood glucose balance. The safety and validity of iPSC-derived cell therapy for diabetes remain controversial. Teratoma formation arising from undifferentiated stem cells is a serious risk, but clinical reports of this phenomenon are rare. Here, we report a distinctive case of immature teratoma after the patient underwent iPSC-derived cell therapy for diabetes in another hospital, and he wastreated in our soft tissue sarcoma centre. The patient received islet beta cell injection, in which the cells were differentiated from autologous iPSCs, into the deltoid muscle. Two months later, a mass located in the injection area was detected and presented with enlarged axillary lymph nodes. Here, we present the clinical, radiological, and pathological features of this immature teratoma. Distinct from typical immature teratomas, this tumour was characterised by rapid growth and local lymph node metastasis. The tumour did not respond to typical chemotherapy regimens for immature teratomas. Magnetic resonance imaging (MRI) showed heterogeneous enhancement and a rich blood supply to the tumour. Histopathology revealed immature endoderm, mesoderm, and ectoderm tissues composed of osseous, cartilaginous, vascular, and adenoid tissues, which have more cellular atypia than typical teratomas. Staining for both OCT4 and SOX2 was positive in the tumour cell nucleus as revealed by immunofluorescence assay; however, insulin staining was negative. Next-generation sequencing showed many missense mutations, but abnormal gene rearrangement, defects, or changes in copy numbers were not observed. In conclusion, more attention should be given to teratoma formation after iPSC-derived cell therapy for diabetes, because these tumours are more aggressive than typical teratomas. The safety and validity of iPSC-derived cell therapy for diabetes should be explored further in standardised clinical trials.

2.
Nat Commun ; 13(1): 311, 2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35031608

RESUMO

Peptide modification methods that do not rely on the cysteine residue are underdeveloped, and their development could greatly expand the current toolbox for peptide chemistry. During the course of preliminary investigations into the classical ortho-phthalaldehyde (OPA)-amine-thiol condensation reaction, we found that in the absence of thiol, OPA readily condenses with two primary alkyl amines to form a class of underexplored isoindolin-1-imine compounds under mild aqueous conditions. From the intramolecular version of this OPA-2amines reaction, an efficient and selective methodology using mild reaction conditions has been developed for stapling unprotected peptides via crosslinking of two amino groups in both an end-to-side and side-to-side fashion. The stapling method is superfast and broadly applicable for various peptide substrates with the reacting amino groups separated by a wide range of different amino acid units. The macrocyclization reactions of selected substrates are completed within 10 seconds at 5 mM concentration and within 2 minutes at 50 µM concentration. Importantly, the resulting cyclized peptides with an isoindolinimine linkage can be extended in a one-pot sequential addition manner with several different electron-deficient π electrophiles, thereby generating more complex structures.

3.
Bioengineered ; 13(1): 856-862, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34967266

RESUMO

Polycystic ovary syndrome (PCOS) is a type of hormonal disorder that affects about 5-20% of females at their reproductive age worldwide. MicorRNA-19a (miR-19a) is a well-characterized miRNA in cancer biology and its function is mainly mediated by targeting tumor necrosis factor α (TNF-α), which plays critical roles in PCOS. Our preliminary analysis predicted the potential interaction between miR-19a and long non-coding RNA (lncRNA) placenta­specific protein 2 (PLAC2). Therefore, this study aimed to explore the role of PLAC2 in PCOS. Ovarian tissues were collected from 62 PCOS patients and 62 healthy females. Granulosa-like tumor cells (KGN) was prepared, and transient transfections was conducted. Dual-luciferase activity assay was used to investigate the interaction between PLAC2 and miR-19a. qPCR assays were performed for the expression analysis of miR-19a/TNF-α. In addition, Western blot analysis and cell apoptosis assay were conducted. The results showed that PLAC2 was upregulated in PCOS. PLAC2 and miR-19a showed a direct interaction, while overexpression of PLAC2 and miR-19a did not affect the expression of each other in KGN cells. Instead, overexpression of PLAC2 led to upregulated TNF-α, which is a target of miR-19a. Cell apoptosis analysis showed that PLAC2 and TNF-α promoted the apoptosis of KGN cells. Overexpression of miR-19a played an opposite role. In addition, the overexpression of PLAC2 reduced the effects of overexpression of miR-19a. Therefore, PLAC2 may regulate miR-19a/TNF-α to participate in PCOS.

4.
Lancet Oncol ; 23(1): 77-90, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34914889

RESUMO

BACKGROUND: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. METHODS: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. FINDINGS: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. INTERPRETATION: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks. FUNDING: Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

5.
Neural Regen Res ; 17(7): 1526-1534, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34916438

RESUMO

5-Bromo-2'-deoxyuridine (BrdU) is a halogenated pyrimidine that can be incorporated into newly synthesized DNA during the S phase of the cell cycle. BrdU is widely used in fate-mapping studies of embryonic and adult neurogenesis to identify newborn neurons, however side effects on neural stem cells and their progeny have been reported. In vivo astrocyte-to-neuron (AtN) conversion is a new approach for generating newborn neurons by directly converting endogenous astrocytes into neurons. The BrdU-labeling strategy has been used to trace astrocyte-converted neurons, but whether BrdU has any effect on the AtN conversion is unknown. Here, while conducting a NeuroD1-mediated AtN conversion study using BrdU to label dividing reactive astrocytes following ischemic injury, we accidentally discovered that BrdU inhibited AtN conversion. We initially found a gradual reduction in BrdU-labeled astrocytes during NeuroD1-mediated AtN conversion in the mouse cortex. Although most NeuroD1-infected astrocytes were converted into neurons, the number of BrdU-labeled neurons was surprisingly low. To exclude the possibility that this BrdU inhibition was caused by the ischemic injury, we conducted an in vitro AtN conversion study by overexpressing NeuroD1 in cultured cortical astrocytes in the presence or absence of BrdU. Surprisingly, we also found a significantly lower conversion rate and a smaller number of converted neurons in the BrdU-treated group compared with the untreated group. These results revealed an unexpected inhibitory effect of BrdU on AtN conversion, suggesting more caution is needed when using BrdU in AtN conversion studies and in data interpretation.

6.
Prog Neurobiol ; 208: 102198, 2021 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-34852273

RESUMO

Temporal lobe epilepsy (TLE) is a common drug-resistant epilepsy associated with abundant cell death in the hippocampus. Here, we develop a novel gene therapy-mediated cell therapy that regenerates GABAergic neurons using internal hippocampal astrocytes to suppress seizure activity in a rat TLE model. We discovered that TLE-induced reactive astrocytes in the hippocampal CA1 region can be efficiently converted into GABAergic neurons after overexpressing a neural transcription factor NeuroD1. The astrocyte-converted neurons showed typical markers of GABAergic interneurons, fired action potentials, and formed functional synaptic connections with other neurons. Following NeuroD1-mediated astrocyte-to-neuron conversion, the number of hippocampal interneurons was significantly increased, and the spontaneous recurrent seizure (SRS) activity was significantly decreased. Moreover, NeuroD1 gene therapy treatment rescued total neuronal loss in the CA1 region and ameliorated the cognitive and mood dysfunctions in the TLE rat model. These results suggest that regeneration of GABAergic interneurons through gene therapy approach may provide a novel therapeutic intervention to treat drug-resistant TLE.

7.
Front Cell Infect Microbiol ; 11: 790036, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34869083

RESUMO

Interferon gamma-inducible protein 16 (IFI16) is a DNA sensor protein, which triggers interferon-beta (IFN-ß) production. However, the role of IFI16 in the innate immunity against hepatitis B virus (HBV) remains controversial. Peripheral blood mononuclear cells (PBMCs) and serum specimens were collected from 20 patients with chronic hepatitis B (CHB) receiving Peg-IFN-α2b therapy. IFI16 mRNA/protein of PBMCs and serum IFI16 at baseline and changes during Peg-IFN-α2b treatment were detected. The interaction between IFI16 and HBV DNA in the PBMCs was analyzed using chromatin immunoprecipitation assay. Leukemic T cell line CEM-C7 and HBV-replicating HepG2.2.15 cells were used to test the effects of interferon treatment and HBV replication on IFI16 expression. Compared with healthy controls, lower levels of IFI16 mRNA but more significant expression of IFI16 protein with heterogeneous degradation were detected in PBMCs of CHB patients. Early changes in IFI16 mRNA, but not IFNB mRNA of PBMCs or serum IFI16, were correlated to HBeAg seroconversion of Peg-IFN-α2b therapy. An interaction between IFI16 and HBV DNA was detected in the PBMCs. In the cultured HepG2.2.15 and CEM-C7 cells, interferons resulted in the translocalization of IFI16 from the cytoplasm to the nucleus and inhibited IFI16 degradation. IFI16 of PBMCs may play a role in sensing HBV infection, and early change in IFI16 mRNA of PBMCs is valuable to predict HBeAg seroconversion in Peg-IFN-α2b treatment. The influences on IFI16 degradation and subcellular location may present a molecular mechanism of antiviral activity of interferon.

8.
J Oncol ; 2021: 9398661, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858500

RESUMO

Background: T cell-mediated antitumor immune response is the basis of colorectal cancer (CRC) immunotherapy. Cholesterol plays an important role in T cell signal transduction and function. Apolipoprotein E (APOE) plays a major role in cholesterol metabolism. Objective: To screen and analyze key markers involved in the anticolon cancer response of CD8+ T cells through the regulation of cholesterol metabolism. Methods: Based on the median cutoff of the expression value of APOE according to the data downloaded from The Cancer Genome Atlas and Gene Expression Omnibus database, patients were grouped into low and high expression groups. Differences in clinical factors were assessed, and survival analysis was performed. Differentially expressed genes (DEGs) in the high and low expression groups were screened, followed by the analysis of differences in tumor-infiltrating immune cells and weighted gene coexpression network analysis results. The closely related genes to APOE were identified, followed by enrichment analysis, protein-protein interaction (PPI) network analysis, and differential expression analysis. Immunohistochemical staining (IHC) was used to detect the expression of CD8 in CRC tissues. Results: There were significant differences in prognosis and pathologic_N between the APOE low and high expression groups. A total of 2,349 DEGs between the high and low expression groups were selected. A total of 967 genes were obtained from the blue and brown modules. The probability of distribution of CD8+ T cells differed significantly between the two groups, and 320 closely related DEGs of APOE were screened. Genes including the HLA gene family, B2M, IRF4, and STAT5A had a higher degree in the PPI network. GEO datasets verified the prognosis and the related DEGs of APOE. IHC staining verified the relationship between the distribution of CD8+ T cells and APOE expression. Conclusion: Genes including the HLA gene family, B2M, IRF4, and STAT5A might be the key genes involved in the anticolon cancer response of CD8+ T cells through the regulation of cholesterol metabolism.

9.
Front Pediatr ; 9: 751204, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858903

RESUMO

Aims: Cholangitis in biliary atresia (BA), which accelerates liver fibrosis progression, is among the most common serious complications after Kasai surgery; however, its etiology remains elusive. Gut microbiome migration may contribute to post-Kasai cholangitis. Further, there is no appropriate model of BA post-Kasai cholangitis for use in investigation of its pathogenesis. Methods: We explored the characteristics of gut microbiome in patients with BA before and after Kasai procedure based on 16S rDNA sequencing. We isolated the dominant strain from patient stool samples and established an in vitro model by infecting patient-derived liver organoids. Bulk RNA-seq was performed, and we conducted qPCR, ELISA, and western blot to explore the mechanism of fibrosis. Results: Gut microbiome diversity was lower in patients after, relative to before, Kasai procedure, while the relative abundance of Klebsiella was higher. Patients who developed cholangitis within 1 month after discharge tended to have simpler gut microbiome composition, dominated by Klebsiella. Klebsiella pneumoniae (KPN) was isolated and used for modeling. RNA-seq showed that BA liver organoids expressed markers of hepatic progenitor cells (KRT19, KRT7, EPCAM, etc.) and that organoids were more stable and less heterogeneous among individuals than liver tissues. After infection with KPN, gene expression patterns in BA liver organoids were enriched in pathways related to infection, apoptosis, and fibrosis. Preliminary experiments indicated the presence of IL-13/TGF-ß1-mediated fibrosis in post-Kasai cholangitis. Conclusions: Our findings using a newly-developed model, demonstrate a key role for Klebsiella, and a potential mechanism underlying fibrosis in post-Kasai cholangitis, mediated by the IL-13/TGF-ß1 pathway.

11.
Oxid Med Cell Longev ; 2021: 4729465, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34900085

RESUMO

The underlying mechanisms of cerebral ischemia/reperfusion (I/R) injury are unclear. Within this study, we aimed to explore whether p53 inhibition exerts protective effects via the p53/PRAS40/mTOR pathway after stroke and its potential mechanism. Both an in vitro oxygen-glucose deprivation (OGD) model with a primary neuronal culture and in vivo stroke models (dMCAO or MCAO) were used. We found that the infarction size, neuronal apoptosis, and autophagy were less severe in p53 KO mice and p53 KO neurons after cerebral I/R or OGD/R injury. By activating the mTOR pathway, p53 knockdown alleviated cerebral I/R injury both in vitro and in vivo. When PRAS40 was knocked out, the regulatory effects of p53 overexpression or knockdown against stroke disappeared. PRAS40 knockdown could inhibit the activities of the mTOR pathway; moreover, neuronal autophagy and apoptosis were exacerbated by PRAS40 knockdown. To sum up, in this study, we showed p53 inhibition protects against neuronal I/R injury after stroke via the p53/PRAS40/mTOR pathway, which is a novel and pivotal cerebral ischemic injury signaling pathway. The induction of neuronal autophagy and apoptosis by the p53/PRAS40/mTOR pathway may be the potential mechanism of this protective effect.

12.
BMJ Open ; 11(12): e049354, 2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34903536

RESUMO

OBJECTIVES: Biliary atresia (BA) is regarded as a serious neonatal hepatobiliary disease, and its aetiology and pathogenesis remain unclear. Epidemiological studies are limited, especially for the data from China. This study aims to explore risk factors of BA and provide new evidence to improve understanding of its aetiology. DESIGN: This is a case-control study from 1 January 2015 to 31 December 2016. SETTING: Cases were consecutively recruited from an urban tertiary care academic children's hospital in Shanghai, China, while the controls were recruited from a community hospital in Shanghai through a random sampling system. PARTICIPANTS: 721 patients suspected for BA who planned to take the diagnostic surgery were enrolled preoperatively. 613 were diagnosed with BA and recruited into the case group. Meanwhile, 688 infants without any observed major congenital anomalies or jaundice were enrolled. Finally, 594 valid questionnaires from the case group and 681 from the control group were obtained. PRIMARY AND SECONDARY OUTCOME MEASURES: Standardised questionnaires were used for data collection. Multivariate logistic regression analysis was performed to evaluate associations reported as ORs and precision, by adjusting covariates. RESULTS: Anxiety or stress during pregnancy was strongly associated with increased risk of BA (OR 8.36 (95% CI: 4.08 to 17.15); p<0.001), respectively. Lower birth weight, fathers from ethnic minorities of China, older age of fathers, lower income of parents, and exposure to infection, diseases and medication during pregnancy all made differences. CONCLUSIONS: Social factors including the educational and economic background and its related anxiety and stress during pregnancy might be noticed in the occurrence of BA. Maternal infections during pregnancy in the prevalence of BA were demonstrated. TRIAL REGISTRATION NUMBER: ChiCTR-IPR-15005885.

13.
Urology ; 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34774932

RESUMO

OBJECTIVE: To share the cases of pelvic fracture urethral distraction defect (PFUDD) in preschool boys and evaluate the transperineal anastomotic urethroplasty strategy for the treatment of these cases. MATERIALS AND METHODS: Between January 2010 and May 2021, 8 preschool boys (<6 years) with PFUDD underwent the transperineal anastomotic urethroplasty in our center were retrospectively reviewed. Etiology was traumatic pelvic fracture in all boys. The type of trauma included: fall injury in 1 and vehicle crush injury in 7. Urethroplasty was performed at least 3 months after initial trauma or the last failed intervention. One of them suffered from PFUDD associated with urethrorectal fistula received urethroplasty combined with fistula repair. A successful urethroplasty was defined as restoring the patency and continuity of urethra and no further interventions were needed. RESULTS: Follow-up was obtained in all the 8 preschool boys for 3-135 (median: 65) months. The average age was 4.1 years old (range 1-5). After operation, the final success rate was 100%. Neither stenosis recurrence nor urinary fistulas were reported during follow-up. Of the 8 boys, 1 developed urinary incontinence, only occurring after high-intensity exercise such as running. Potency state could not be evaluated for all boys due to the young age. One boy reported having normal morning erection after a follow-up of 135 months. CONCLUSION: PFUDD in preschool boys is a challenge for both the urologist and parent. Our study preliminarily confirmed that the progressive anastomotic urethroplasty strategy can ensure a high success rate.

14.
Mediators Inflamm ; 2021: 1629783, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34725544

RESUMO

Diabetic retinopathy (DR) is a type of diabetes complication, which can result in loss of vision in adults worldwide. Increasing evidence has revealed that microRNAs (miRs) can regulate DR progression. Thus, the present study was aimed at assessing the possible mechanism of miR-139-5p in high glucose- (HG-) incubated retinal pigment epithelial (ARPE-19) cells. The present results demonstrated that miR-139-5p expression was notably reduced in the serum samples of patients with DR, as well as in ARPE-19 cells treated with HG in a time-dependent manner. Moreover, miR-139-5p was markedly overexpressed by transfection of miR-139-5p mimics into ARPE-19 cells. Overexpression of miR-139-5p markedly induced cell viability and repressed HG-triggered apoptosis. Furthermore, overexpression of miR-139-5p relived HG-enhanced oxidative stress injury. It was found that HG induced malondialdehyde levels but decreased superoxide dismutase and glutathione peroxidase activities in ARPE-19 cells. In addition, overexpression of miR-139-5p could markedly decrease intracellular stress. The results demonstrated that overexpression of miR-139-5p effectively repressed HG-activated inflammation, as indicated by the upregulation of inflammation cytokines, including TNF-α, IL-6, and Cox-2, in ARPE-19 cells. Subsequently, it was identified that LIM-only factor 4 (LMO4) could act as a downstream target for miR-139-5p. LMO4 expression was significantly increased in patients with DR and HG-treated ARPE-19 cells. Mechanistically, knockdown of LMO4 reversed the biological role of miR-139-5p in proliferation, apoptosis, oxidative stress, and release of inflammation factors in vitro. Collectively, these results suggested that miR-139-5p significantly decreased ARPE-19 cell injury caused by HG by inducing proliferation and suppressing cell apoptosis, oxidant stress, and inflammation by modulating LMO4.

15.
J Healthc Eng ; 2021: 6124346, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630990

RESUMO

In this article, dexmedetomidine (Dex) was used to prevent neurological disorders in patients anesthetized with sevoflurane and the effect was analyzed using ultrasound images based on the restoration algorithm of the linear system model. Children injected with Dex were in the experimental group, while children injected with normal saline were in the control group. The mean arterial pressure (MAP), arterial oxygen saturation (SpO2), heart rate (HR), Pediatric anesthesia agitation scale (PAED) score, Face, Legs, Activity, Cry, Consolability (FLACC) score, and adverse drug event (ADE) in the two groups were compared before the injection (T1), at 5 min (T2), 10 min (T3), and 20 min (T4) after the injection, and when the patient came to himself (T5). It was found that in contrast with the control group, the MAP in the experimental group at T2, T3, and T4 periods was lower, while it was higher at T5 period and its HR at T2, T3, T4, and T5 periods was higher (P < 0.05); the PAED and FLACC scores were lower (P < 0.05), and the incidence of ADE (10.53%) was lower than that in the control group (31.58%) (P < 0.05). However, SpO2 at different periods showed no obvious differences between the two groups (P > 0.05). In conclusion, the restoration algorithm-based ultrasound images had high quality, and they demonstrated good application value in evaluating the effect of Dex to prevent neurological disorders in patients anesthetized by sevoflurane.

16.
Sci Rep ; 11(1): 19883, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615940

RESUMO

To investigate the mechanism of 25 hydroxyvitamin D (25(OH)D) deficiency in children with biliary atresia (BA) and its effect on liver fibrosis. The serum vitamin D and 25(OH)D, and expression of 25 hydroxylase (CYP2R1 and CYP27A1) in the liver of BA patients were detected and compared with those in the control group. We investigated the effect of differential expression of CYP2R1 in hepatocytes on the expression of genes related to liver fibrosis in primary hepatic stellate cells (HSCs) of BA and animal models of cholestasis. The ratio of 25(OH)D/vitamin D in the BA group was significantly lower than that in the control group. The mRNA and protein expression of CYP2R1 and CYP27A1 in liver tissue of the BA group was significantly lower than that in the control group. Exogenous active vitamin D (calcitriol) inhibited the proliferation and migration of primary HSCs isolated from BA patients, and reduced the expression of fibrosis-related genes in vitro. Downregulation of expression of CYP2R1 in hepatocytes increased expression of transforming growth factor (TGF)-ß1, collagen (Col)-1α1 and tissue inhibitor of metalloproteinase (TIMP)-1, and decreased the expression of matrix metalloproteinase (MMP)-2 in cocultured primary HSCs of BA. Upregulation of expression of CYP2R1 in mice with bile duct ligation significantly increased the level of 25(OH)D, decreased the expression of TGF-ß1, Col-1α1 and TIMP-1, and increased the expression of MMP-2. Children with BA have impaired vitamin D activation due to CYP2R1 deficiency. The dysactivation of vitamin D can promote the proliferation and activation of HSCs and participate in the development of hepatic fibrosis in BA.

17.
Environ Sci Technol ; 55(20): 14204-14214, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34623146

RESUMO

MnO2 nanorods with exposed (110), (100), or (310) facets were prepared and investigated for catalytic oxidation of chlorobenzene, then the (110)-exposed MnO2 nanorod was screened as the candidate parent and further modified by Pt and/or Mo with different contents. The loading of Pt enhanced activity and versatility of the pristine MnO2, but the polychlorinated byproducts and Cl2 were promoted, conversely, as the decoration of Mo inhibited the polychlorinated byproducts and improved durability. Determination of structure and properties suggested that Pt facilitated the formation of more oxygen vacancies/Mn3+ and surface adsorbed oxygen weakened the bonds of surface lattice oxygen, while Mo stabilized surface lattice oxygen and increased acid sites, especially Brønsted acid sites. Expectedly, Pt and Mo bifunctionally modified MnO2 presented a preferable activity, selectivity, and durability along with the super resistance to H2O, high-temperature, and HCl, and no prominent deactivation was observed within 30 h at 300 °C under dry and humid conditions, even at high-temperature aging at 600 °C and HCl-pretreatment (7 h). In this work, the optimized Mo and Pt codecorated MnO2 was considered a promising catalyst toward practical applications for catalytic oxidation of actual Cl-VOCs emissions.


Assuntos
Compostos de Manganês , Nanotubos , Catálise , Clorobenzenos , Óxidos
18.
Front Pharmacol ; 12: 715721, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34594218

RESUMO

Background: The MSI/MSS status does not fully explain cancer immunotherapy response in colorectal cancer. Thus, we developed a colorectal cancer-specific method that predicts cancer immunotherapy response. Methods: We used gene expression data of 454 samples (MSI = 131, MSI-L = 23, MSS = 284, and Unknown = 16) and developed a TMEPRE method that models signatures of CD8+ T-cell infiltration and CD8+ T-cell exhaustion states in the tumor microenvironment of colorectal cancer. TMEPRE model was validated on three RNAseq datasets of melanoma patients who received pembrolizumab or nivolumab and one RNAseq dataset of purified CD8+ T cells in different exhaustion states. Results: TMEPRE showed predictive power in three datasets of anti-PD1-treated patients (p = 0.056, 0.115, 0.003). CD8+ T-cell exhaustion component of TMEPRE model correlates with anti-PD1 responding progenitor exhausted CD8+ T cells in both tumor and viral infection (p = 0.048, 0.001). The global pattern of TMEPRE on 454 colorectal cancer samples indicated that 10.6% of MSS patients and 67.2% of MSI patients show biological characteristics that can potentially benefit from anti-PD1 treatment. Within MSI nonresponders, approximately 50% showed insufficient tumor-infiltrating CD8+ T cells and 50% showed terminal exhaustion of CD8+ T cells. These terminally exhausted CD8+ T cells coexisted with signatures of myeloid-derived suppressor cells in colorectal cancer. Conclusion: TMEPRE is a colorectal cancer-specific method. It captures characteristics of CD8+ T-cell infiltration and CD8+ T-cell exhaustion state and predicts cancer immunotherapy response. A subset of MSS patients could potentially benefit from anti-PD1 treatment. Anti-PD1 resistance MSI patients with insufficient infiltration of CD8+ T cells or terminal exhaustion of CD8+ T cells need different treatment strategies.

19.
20.
China CDC Wkly ; 3(40): 837-841, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34659864

RESUMO

What is already known on this topic?: Prior studies found that fall events were associated with a higher level of depressive symptoms and a lower level of social functioning and social participation. In addition, social participation has also been significantly associated with better conditions of depressive symptoms. What is added by this report?: This article implemented the literature in three ways. First, it examined the mechanisms of social participation in the association between fall injuries and depressive symptoms among older adults in China. Second, it specified the fall-injured older adults group from those who merely experienced fall events. Third, it compared the results between rural and urban China and discussed policy implications for both groups. What are the implications for public health practice?: Based on the findings of this study, future policies could consider boosting social participation at both the household and community level while taking into account the challenges of mobilities and social capabilities after fall injuries. Meanwhile, it is essential to accelerate the construction of aging-friendly communities to improve the accessibility of social participation and broaden social services to health management and monitoring.

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