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1.
Nanoscale Res Lett ; 15(1): 194, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001319

RESUMO

Two-dimensional (2D) organic-inorganic perovskites as one of the most important photovoltaic material used in solar cells have attracted remarkable attention. These 2D perovskites exhibit superior environmental stability and wide tunability of their optoelectronic properties. However, their photovoltaic performance is far behind those of traditional three-dimensional (3D) perovskites. In this work, we demonstrate the power conversion efficiency (PCE) of 2D perovskite solar cells (PVSCs) is greatly improved from 3.01% for initial to 12.19% by the incorporation of PbBr2. The enhanced efficiency is attributed to superior surface quality, enhanced crystallinity, and the resulting reduced trap-state density. Furthermore, PbBr2 incorporated devices without encapsulation show excellent humidity stability, illumination stability, and thermal stability. This work provides a universal and viable avenue toward efficient and stable 2D PVSCs.

2.
Org Lett ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33021797

RESUMO

A pair of new macrocyclic spermidine alkaloids, (+)-(S)-scocycamide and (-)-(R)-scocycamide, were isolated from the roots of Scopolia tangutica. Their structures were established by extensive spectroscopic data, electronic circular dichroism analyses, and chemical synthesis. They featured a unique 6/18 fused bicyclic framework with spermidine and catechol units, representing a new subtype of natural spermidine alkaloids. A plausible biosynthetic pathway was also proposed. They inhibited butyrylcholinesterase and exhibited antioxidant capacity, suggesting beneficial constituents against Alzheimer's disease and oxidation.

3.
Drug Res (Stuttg) ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33022720

RESUMO

Glucagon-like peptide-2 (GLP-2) is a peptide hormone that belongs to the glucagon-derived peptide family. We have previously shown that analogues of the sister hormone Glucagon-like peptide-1 (GLP-1) showed neuroprotective effects. Here we investigated the effect of a GLP-2 agonist in a cell model of Parkinson's disease (PD) created by treating SH-SY5Y or Neuro-2a cells with 1-Methyl-4-phenyl-pyridine ion (MPP+). Cell viability and cell cytotoxicity was detected by MTT and LDH assays, respectively. The protein expression levels of mitochondrial, autophagy and apoptotic biomarkers including PGC-1α, Mfn2, IRE1, ATG7, LC3B, Beclin1 and Bcl-2 were detected by western blot. Mitochondrial superoxide was detected by MitoSOX Red. In addition, mitochondrial morphology, autophagosome and apoptotic corpuscles were observed by transmission electron microscope (TEM). We found that the GLP-1 and the GLP-2 agonists both protect cells against mitochondrial damage, autophagy impairments and apoptosis induced by MPP+both in SH-SY5Y and Neuro-2a cells. Cell signaling for mitogenesis was enhanced, and oxidative stress levels much reduced by the drugs. This demonstrates for the first time the neuroprotective effects of a GLP-2 analogue in PD cellular models, in which oxidative stress, autophagy and apoptosis play crucial roles. The protective effects were comparable to those seen with the GLP-1 analogue liraglutide. The results suggest that not only GLP-1, but also GLP-2 has neuroprotective properties and may be useful as a novel treatment of PD.

4.
J Mater Chem B ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33026402

RESUMO

Nitric oxide (NO) is an important signaling molecule involved in various physiological and pathological processes. The effects of NO depend on its concentration, and the spatial and temporal constraints of the cell microenvironment. Meanwhile, NO can react with some biomolecules such as biothiols, leading to a short biological lifetime. Thus, it is very crucial to establish a real-time visualization method for monitoring NO levels. In this work, we have developed a fluorescent probe, RBA, for NO, with a 3-extended BODIPY as a fluorophore and a secondary amine as the active site. The probe RBA can quickly sense NO (∼10 s) in aerobic solutions to generate a fluorescent N-nitrosamine (RBA-NO, Φf = 0.87) due to blocking of the photoinduced electron transfer (PET) process from the secondary amine to the BODIPY core. This sensing reaction displays high sensitivity (LOD = 10 nM) and high selectivity for NO over relevant analytes except some reducing reagents including biothiols, and a remarkable interference effect is observed ascribed to a competitive reaction with biothiols. Furthermore, the exo- and endogenous detection of NO in live cells and zebra fish was achieved, and it was demonstrated that glutathione (GSH) weakens drastically the fluorescence response by cell-imaging experiments. These results imply that the colorimetric and fluorescence response of the chemosensor for NO depends on the levels of both NO and GSH in environments.

5.
Front Immunol ; 11: 1723, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013824

RESUMO

Liver transplantation (LT) has become the best chance and a routine practice for patients with end-stage liver disease and small hepatocellular carcinoma. However, life-long immunosuppressive regimens could lead to many post-LT complications, including cancer recurrence, infections, dysmetabolic syndrome, and renal injury. Impeccable management of immunosuppressive regimens is indispensable to ensure the best long-term prognosis for LT recipients. This is challenging for these patients, who probably have a post-LT graft survival of more than 10 or even 20 years. Approximately 20% of patients after LT could develop spontaneous operational tolerance. They could maintain normal graft function and histology without any immunosuppressive regimens. Operational tolerance after transplantation has been an attractive and ultimate goal in transplant immunology. The liver, as an immunoregulatory organ, generates an immune hyporesponsive microenvironment under physiological conditions. In this regard, LT recipients may be ideal candidates for studies focusing on operative tolerance. Cell-based strategies are one of the most promising methods for immune tolerance induction, including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory T cells, regulatory dendritic cells, regulatory macrophages, regulatory B cells, and mesenchymal stromal cells. The safety and the efficacy of many cell products have been evaluated by prospective clinical trials. In this review, we will summarize the latest perspectives on the clinical application of cell-based strategies in LT and will address a number of concerns and future directions regarding these cell products.

6.
J Am Chem Soc ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33021373

RESUMO

This work describes a strategy to produce circularly polarized thermally activated delayed fluorescence (CP-TADF). A set of two structurally similar organic emitters SFST and SFOT are constructed, whose spiro architectures containing asymmetric donors result in chirality. Upon grafting within the spiro frameworks, the donor and acceptor are fixed proximally in a face-to-face manner. This orientation allows intramolecular through-space charge transfer (TSCT) to occur in both emitters, leading to TADF properties. The donor units in SFST and SFOT have a sulfur and oxygen atom, respectively; such a subtle difference has great impacts on their photophysical, chiroptical, and electroluminescence (EL) properties. SFOT exhibits greatly enhanced EL performance in doped organic light-emitting diodes, with external quantum efficiency (EQE) up to 23.1%, owing to the concurrent manipulation of highly photoluminescent quantum efficiency (PLQY, ∼90%) and high exciton utilization. As a comparison, the relatively larger sulfur atom in SFST introduces heavy atom effects and leads to distortion of the molecular backbone that lengthens the donor-acceptor distance. SFST thus has lower PLQY and faster nonradiative decay rate. The collective consequence is that the EQE value of SFST, i.e., 12.5%, is much lower than that of SFOT. The chirality of these two spiro emitters results in circularly polarized luminescence. Because SFST has a more distorted molecular architecture than SFOT, the luminescence dissymmetry factor (|glum|) of circularly polarized luminescence of one enantiomer of the former, namely, either (S)-SFST or (R)-SFST, is almost twice that of (S)-SFOT/(R)-SFOT. Moreover, the CP organic light-emitting diodes (CP-OLEDs) show obvious circularly polarized electroluminescence (CPEL) signals with gEL of 1.30 × 10-3 and 1.0 × 10-3 for (S)-SFST and (S)-SFOT, respectively.

7.
Aliment Pharmacol Ther ; 52(7): 1259-1260, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33016550
8.
Artigo em Inglês | MEDLINE | ID: mdl-33038193

RESUMO

STUDY DESIGN: Questionnaire translation and validation. OBJECTIVE: The aim of this study was to translate the Early-Onset Scoliosis 24-Item Questionnaire (EOSQ-24) into simplified Chinese and to evaluate the reliability and validity of this questionnaire in children with early-onset scoliosis (EOS) in mainland China. SUMMARY OF BACKGROUND DATA: The EOSQ-24 is a validated quality of life questionnaire in children with EOS and has been translated into multiple languages and used worldwide. However, there is currently no simplified Chinese version available for use in mainland China. METHODS: The English version of the EOSQ-24 questionnaire was translated into simplified Chinese based on the recommendations of the International Quality of Life Assessment (IQoLA) group. The reliability of the scale was evaluated using test-retest reliability and internal consistency, and construct validity was examined through factor analysis. Hundred childrenwith EOS were enrolled in the study. To assess the test-retest reliability of the scale, the parents or caregivers of 38 of participants repeated the questionnaire after 2 weeks. RESULTS: Test-retest reliability was excellent overall (intraclass correlation coefficient [ICC] = 0.935) and ranged from moderate to excellent for each domain (ICC = 0.681-0.945). The overall internal consistency was excellent (Cronbach α = 0.893) and had a variable range for each domain (Cronbach α = 0.560-0.889). Factor analysis was performed, and seven principal components were extracted that accounted for 70.1% of the variance. CONCLUSION: The simplified Chinese version of the EOSQ-24 scale has acceptable reliability and construct validity, and it can be used for the assessment of health-related quality of life (HRQL), caretaker burden, and satisfaction for children with EOS in mainland China. LEVEL OF EVIDENCE: 3.

9.
Clin Infect Dis ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33048116

RESUMO

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) experience a wide clinical spectrum, with over 2% developing fatal outcome. The prognostic factors for fatal outcome remain sparsely investigated. METHODS: A retrospective cohort study was performed in a cohort of patients with confirmed COVID-19 in one designated hospital in Wuhan, China, from 17 January-5 March 2020. The laboratory parameters and a panel of cytokines were consecutively evaluated until patients' discharge or death. The laboratory features that could be used to predict fatal outcome were identified. RESULTS: Consecutively collected data on 55 laboratory parameters and cytokines from 642 patients with COVID-19 were profiled along the entire disease course, based on which 3 clinical stages (acute stage, days 1-9; critical stage, days 10-15; and convalescence stage, day 15 to observation end) were determined. Laboratory findings based on 75 deceased and 357 discharged patients revealed that, at the acute stage, fatality could be predicted by older age and abnormal lactate dehydrogenase (LDH), urea, lymphocyte count, and procalcitonin (PCT) level. At the critical stage, the fatal outcome could be predicted by age and abnormal PCT, LDH, cholinesterase, lymphocyte count, and monocyte percentage. Interleukin 6 (IL-6) was remarkably elevated, with fatal cases having a more robust production than discharged cases across the whole observation period. LDH, PCT, lymphocytes, and IL-6 were considered highly important prognostic factors for COVID-19-related death. CONCLUSIONS: The identification of predictors that were routinely tested might allow early identification of patients at high risk of death for early aggressive intervention.

10.
Oncol Rep ; 44(5): 2185-2197, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33000250

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of cancer­related morbidity and mortality globally. Despite the remarkable improvements in comprehensive HCC treatment, the underlying mechanistic details of HCC remain elusive. We screened HCC patients for differentially expressed genes (DEGs) using the Gene Expression Omnibus (GSE113850) and The Cancer Genome Atlas (TCGA) datasets. LINC01554 expression in 40 paired samples was determined by quantitative reverse transcription polymerase chain reaction (RT­qPCR), and its clinical significance was assessed. LINC01554 was found to have a gain­of­function role in HCC in vitro. Additionally, the bioinformatics analysis of the genes co­expressed with LINC01554 was performed using the Co­LncRNA website, and potential molecular mechanisms were investigated using the Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes resources and validated by in vitro experiments. A total of 229 DEGs were identified from the GSE113850 dataset. Among the identified DEGs, three long non­coding RNAs (lncRNAs) (DIO3OS, LINC01554, and LINC01093) with |logFC| ≥2 and P<0.05 were screened. A total of 148 lncRNAs with |logFC| ≥1 and P<0.05 were identified from TCGA dataset. Low LINC01554 expression levels were significantly correlated with overall survival, pathological stage, hepatitis B infection, tumour size, portal vein tumour thrombus, and TNM stage. Using gain­of­function assays, we further showed that LINC01554 inhibited the proliferation, migration, and invasion of the HCCLM9 and SK­Hep1 cells and promoted G0/G1 arrest, but it did not significantly affect apoptosis. Western blotting revealed that LINC01554 overexpression resulted in increased ZO­1 and E­cadherin expression levels, but decreased N­cadherin and vimentin expression levels. Moreover, LINC01554 overexpression inhibited Akt, p­Akt, ß­catenin, and p­Gsk3ß expression. Our results showed that LINC01554 repressed HCC cell invasiveness and epithelial­to­mesenchymal transition partly by inhibiting Wnt and PI3K­Akt signalling in vitro. Taken together, our findings provide new insights into the molecular mechanisms underlying HCC tumourigenesis and implicate LINC01554 as a potential target for HCC therapy.

11.
Org Lett ; 22(20): 8127-8131, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33026812

RESUMO

We developed an approach for direct selective hydroxylation of heterobenzylic methylenes to secondary alcohols avoiding overoxidation to ketones by using a KOBu-t/DMSO/air system. Most reactions could reach completion in several minutes to give hydroxylated products in 41-76% yields. Using DMSO-d6, this protocol resulted in difunctionalization of heterobenzylic methylenes to afford α-deuterated secondary alcohols (>93% incorporation). By employing this method, active pharmaceutical ingredients carbinoxamine and doxylamine were synthesized in two steps in moderate yields.

12.
J Immunother Cancer ; 8(2)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33055204

RESUMO

BACKGROUND: Tertiary lymphoid structures (TLS) are associated with favorable survival and play a critical role in most solid tumors. However, investigations of TLS are lacking in patients with grade 1 or grade 2 (G1/G2) non-functional pancreatic neuroendocrine tumors (NF-PanNETs). This study aimed to investigate the presence, cellular composition, association with tumor-infiltrating immune cells, and prognostic value of TLS in G1/G2 NF-PanNETs. METHODS: Tumor tissues from a 182-patient Fudan cohort and a 125-patient external validation set were assessed by H&E staining, immunohistochemistry, and/or multispectral fluorescent immunohistochemistry. RESULTS: TLS were identified in more than one-third of patients with G1/G2 NF-PanNETs and were located peritumorally, either just outside the tumor tissue or in the stromal area. TLS were mainly composed of B-cell follicles with germinal centers and T-cell zones with dendritic cells. Kaplan-Meier analyses showed that the presence of TLS correlated with both longer recurrence-free survival (RFS, p<0.001) and overall survival (OS, p=0.001), but the number of TLS had no prognostic significance. Multivariate Cox-regression analyses demonstrated that the presence of TLS, WHO classification, and 8th edition American Joint Committee on Cancer (AJCC8th) tumor-node-metastasis (TNM) stage were independent prognostic factors for RFS (p=0.004, p=0.001, and p<0.001, respectively) and OS (p=0.009, p=0.008, and p=0.019, respectively). These results were confirmed using an external validation set. Finally, a nomogram incorporating the presence of TLS was constructed to predict the probability of 5-year RFS of resected G1/G2 NF-PanNETs, which improved on the current WHO classification and AJCC8th TNM stage. CONCLUSIONS: The presence of TLS is an independent and favorable predictor of resected G1/G2 NF-PanNETs, which may play a role in cancer immunobiology.

13.
Neurology ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33055274

RESUMO

OBJECTIVE: We initiated a multicenter, prospective cohort study to test the hypothesis that aspirin is safe for patients with ischemic cerebrovascular disease (ICVD) harboring unruptured intracranial aneurysms (UIAs) <7 mm. METHODS: This prospective, multicenter cohort study consecutively enrolled 1866 eligible patients with ICVD harboring UIAs <7 mm in diameter from 4 hospitals between January 2016 and August 2019. Baseline and follow-up patient information, including the use of aspirin, were recorded. The primary endpoint was aneurysm rupture. RESULTS: After a total of 4,411.4 person-years, 643 (37.2%) patients continuously received aspirin treatment. Of all included patients, rupture occurred in 12 (0.7%). The incidence rate for rupture (IRR) was 0.27 (95% CI 0.15-0.48) per 100 person-years. The IRRs were 0.39 (95% CI 0.21-0.72) and 0.06 (95% CI 0.010-0.45) per 100 person-years for the nonaspirin and aspirin groups, respectively. In the multivariate analysis, uncontrolled hypertension and UIAs 5 to <7 mm were associated with a high rate of aneurysm rupture, whereas, aspirin use was associated with a low rate of aneurysm rupture. Compared with other groups, the high-risk group (UIAs 5 to <7 mm with concurrent uncontrolled hypertension) without aspirin had higher IRRs. CONCLUSION: Aspirin is a safe treatment for patients with concurrent small UIAs and ICVD. Patients that are not taking aspirin in the high-risk group warrant intensive surveillance. CLINICALTRIALSGOV IDENTIFIER: NCT02846259. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients harboring UIAs <7 mm with ICVD, aspirin does not increase the risk of aneurysm rupture.

14.
Clin Infect Dis ; 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33068430

RESUMO

BACKGROUND: The growing epidemics of severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne disease in East Asia, and its high case fatality rate have raised serious public health concerns. METHODS: Surveillance data on laboratory-confirmed SFTS cases in China were collected. The spatiotemporal dynamics and epidemiological features were explored. The socioeconomic and environmental drivers were identified for SFTS diffusion using survival analysis and for SFTS persistence using a two-stage generalized boosted regression tree model. RESULTS: During 2010‒2018, a total of 7,721 laboratory-confirmed SFTS cases were reported in China, with an overall CFR of 10.5%. The average annual incidence increased >20 times and endemic areas expanded from 27 to 1,574 townships, whereas the CFR declined from 19% to 10% during this period. Four geographical clusters, the Changbai Mountain area, the Jiaodong Peninsula, the Taishan Mountain area and the Huaiyangshan Mountain area, were identified. Diffusion and persistence of the disease were both driven by elevation, high coverages of woods, crops and shrub, and the vicinity of habitats of migratory birds, but had different meteorological drivers. Residents ≥60 years old in rural areas with crop fields and tea farms were at increased risk to SFTS. CONCLUSIONS: Surveillance of SFTS and intervention programs need to be targeted at areas with ecologically suitability for vector ticks and in the vicinity of migratory birds to curb the growing epidemic.

15.
BMC Psychiatry ; 20(1): 488, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023515

RESUMO

BACKGROUND: Bipolar disorder (BPD) is a common mood disorder that is often goes misdiagnosed or undiagnosed. Recently, machine learning techniques have been combined with neuroimaging methods to aid in the diagnosis of BPD. However, most studies have focused on the construction of classifiers based on single-modality MRI. Hence, in this study, we aimed to construct a support vector machine (SVM) model using a combination of structural and functional MRI, which could be used to accurately identify patients with BPD. METHODS: In total, 44 patients with BPD and 36 healthy controls were enrolled in the study. Clinical evaluation and MRI scans were performed for each subject. Next, image pre-processing, VBM and ReHo analyses were performed. The ReHo values of each subject in the clusters showing significant differences were extracted. Further, LASSO approach was recruited to screen features. Based on selected features, the SVM model was established, and discriminant analysis was performed. RESULTS: After using the two-sample t-test with multiple comparisons, a total of 8 clusters were extracted from the data (VBM = 6; ReHo = 2). Next, we used both VBM and ReHo data to construct the new SVM classifier, which could effectively identify patients with BPD at an accuracy of 87.5% (95%CI: 72.5-95.3%), sensitivity of 86.4% (95%CI: 64.0-96.4%), and specificity of 88.9% (95%CI: 63.9-98.0%) in the test data (p = 0.0022). CONCLUSIONS: A combination of structural and functional MRI can be of added value in the construction of SVM classifiers to aid in the accurate identification of BPD in the clinic.

16.
Stem Cell Res Ther ; 11(1): 433, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023631

RESUMO

BACKGROUND: Current strategies for craniofacial defect are faced with unmet outcome. Combining 3D-printing with safe, noninvasive magnetic therapy could be a promising breakthrough. METHODS: In this study, polylactic acid/hydroxyapatite (PLA/HA) composite scaffold was fabricated. After seeding rat bone marrow mesenchymal stem cells (BMSCs) on scaffolds, the effects of electromagnetic fields (EMF) on the proliferation and osteogenic differentiation capacity of BMSCs were investigated. Additionally, 6-mm critical-sized calvarial defect was created in rats. BMSC-laden scaffolds were implanted into the defects with or without EMF treatment. RESULTS: Our results showed that PLA/HA composite scaffolds exhibited uniform porous structure, high porosity (~ 70%), suitable compression strength (31.18 ± 4.86 MPa), modulus of elasticity (10.12 ± 1.24 GPa), and excellent cyto-compatibility. The proliferation and osteogenic differentiation capacity of BMSCs cultured on the scaffolds were enhanced with EMF treatment. Mechanistically, EMF exposure functioned partly by activating mitogen-activated protein kinase (MAPK) or MAPK-associated ERK and JNK pathways. In vivo, significantly higher new bone formation and vascularization were observed in groups involving scaffold, BMSCs, and EMF treatment, compared to scaffold alone. Furthermore, after 12 weeks of implanting, craniums in groups including scaffold, BMSCs, and EMF exposure showed the greatest biomechanical properties. CONCLUSION: In conclusion, EMF treatment combined with 3D-printed scaffold has great potential applications in craniofacial regeneration.

17.
BMJ ; 371: m3683, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037002
18.
J Phys Chem Lett ; : 9110-9116, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33049137

RESUMO

State coupling certainly determines the topologic features of the molecular potential energy surface (PES) and potentially diversifies chemical reaction pathways. Here we report the new PESs of BrCN- in the low-lying electronic states that are distinctly different from the previous predictions in the short Br-CN bond region but validated by the high-resolution ion velocity imaging measurements of low-energy dissociative electron attachment (DEA) to BrCN. Besides the vibrating CN- ions produced in the fast Br-CN bond stretching motions, we confirm that the ro-vibrating CN- ions with a nearly isotropic angular distribution are produced by receiving a torque in the combinational motion of Br-CN bond bending and stretching. The latter process is closely related to the potential well of BrCN- at the first excited state A2Π3/2 that arises from the Π-Σ state couplings. Our findings not only suggest that the PESs of other anionic cyanogen halides are in dire need of reexamination but also show that ion velocity imaging of the DEA process is a powerful experimental method for evaluating the theoretical PESs of molecular anions.

19.
Theranostics ; 10(25): 11507-11519, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33052229

RESUMO

Rationale: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with few therapeutic targets and rare effective treatments. Over 90% of PDAC tumors bear a Kras mutation, and the single-site mutation G12D (KrasG12D) is most prevalent. Methods: Here, we applied the CRISPR-CasRx system to silence the mutant KrasG12D transcript in PDAC cells. We also used a capsid-optimized adenovirus-associated virus 8 vector (AAV8) to deliver the CRISPR-CasRx system into PDAC orthotopic tumors and patient-derived tumor xenografts (PDX). Results: Our data showed that guided by a KrasG12D-specific gRNA, CasRx is able to precisely and efficiently silence the mutant KrasG12D expression in PDAC cells. The knockdown of mutant KrasG12D by CasRx abolishes the aberrant activation of downstream signaling induced by mutant KrasG12D and subsequently suppresses the tumor growth and improves the sensitivity of gemcitabine in PDAC. Additionally, delivering CasRx-gRNA via AAV8 into the orthotopic KrasG12D PDAC tumors substantially improves the survival of mice without obvious toxicity. Furthermore, targeting KrasG12D through CasRx suppresses the growth of PDAC PDXs. In conclusion, our study provides a proof-of-concept that CRISPR-CasRx can be utilized to target and silence mutant KrasG12D transcripts and therefore inhibit PDAC malignancy.

20.
Int Urol Nephrol ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33052518

RESUMO

PURPOSE: Patients with testicular non-seminomatous germ cell tumors in the modern cisplatin-based chemotherapy era show favorable outcomes, yielding survivors exposed to increased risk of second malignant neoplasms. The carcinogenic effects of cisplatin were well established, and its side effects had shown close connections with the urinary system. The study aimed to evaluate how the characteristics of the primary testicular nonseminoma are associated with urological second malignant neoplasms and survival outcomes. METHODS: Using the Surveillance, Epidemiology and End Results database, standardized incidence ratios (SIR) for three major urological tumors including kidney, bladder, and prostate cancer were calculated for 10,734 patients with testicular nonseminoma from 1975 to 2016. The survival analyses were performed using the Kaplan-Meier method and log-rank test, risk factors for overall survival were determined by Cox regression. RESULTS: We identified a total of 197 patients with secondary urological neoplasms. Patients with previous testicular nonseminoma had elevated risk of kidney cancer (SIR 2.13, 95% CI 1.59-2.79), bladder cancer (SIR 1.47, 95% CI 1.07-1.59), and decreased risks of prostate cancer (SIR 0.75, 95% CI 0.61-0.91) compared with the general population. Patients diagnosed with testicular nonseminoma had favorable prognosis with 10-year overall survival reaching 91.8%, and patients with urological second malignant neoplasms showed better prognoses than patients with other second malignant neoplasms (log-rank P < 0.001). CONCLUSION: Testicular nonseminoma survivors showed higher risks of kidney and bladder cancer associated with chemotherapy and decreased risk of prostate cancer. The prognosis of urological second neoplasms was better than other tumor origins.

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