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1.
Biomed Pharmacother ; : 109437, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31590992

RESUMO

Immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cell therapy are two main promising methods of immunotherapy, which have become increasingly important in cancer treatment. After the wider application of these medicine in clinic, a range of immune related adverse events (irAEs) covering almost any system arouse the concern for being randomness and unpredictability. Even if most adverse events are mild and controllable after thoughtful management, the occurrence of life-threatening toxicities should not be ignored because of the insidious and atypical symptoms, which makes the early diagnosis even more challenging. In this review, a brief introduction of immunotherapy and mechanisms underlying irAEs is involved. We mainly focus on the early diagnostic method and recommended management of toxicities of different systems separately, and consequently maximized effectiveness of immunotherapy can be achieved.

2.
J Cell Physiol ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31596511

RESUMO

To explore the prognosis of tumor mutation burden (TMB) and underlying relationships with tumor-infiltrating immune cells in bladder cancer (BLCA). Transcriptome profiles and somatic mutation data from The Cancer Genome Atlas database by the GDC tool. A total of 437 samples were included, consisted of 412 BLCA patients and matched 25 normal samples. Specific mutation information was summarized and illustrated in waterfall plot. Higher TMB levels revealed improved overall survival (OS) and lower tumor recurrence. We found 68 differentially expressed genes in two TMB groups and identified eight independent hub TMB-related signature. Pathway analysis suggested that differential TMB-related signature correlated with multiple cancer-related crosstalk, including cell cycle, DNA replication, cellular senescence, and p53 signaling pathway. Besides, the tumor mutation burden related signature (TMBRS) model based on eight signature possessed well predictive value with area under curve (AUC) = 0.753, and patients with higher TMBRS scores showed worse OS outcomes (p < .001). Moreover, we exhibited the inferred immune cell fractions in box plot and differential abundance of immune cells were shown in the heatmap. The Wilcoxon rank-sum test suggested that CD8+ T cell (p = .001) and memory activated CD4+ T cell (p = .004) showed higher infiltrating levels in high-TMB group, while the density of resting mast cells showed lower infiltrating level in high-TMB group (p = .016). Finally, it is significant to note that CD8+ T cell and memory activated CD4+ T cell subsets not only revealed higher infiltrating abundance in high-TMB group but correlated with prolonged OS and lower risk of tumor recurrence, respectively.

3.
Med Sci Monit ; 25: 7720-7727, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31611547

RESUMO

BACKGROUND Unbalanced standing and gait asymmetry are common in individuals with musculoskeletal disorders. Achieving symmetrical posture and gait is an important goal of rehabilitation. This study investigated the biomechanical differences in the lower extremities observed immediately after an insole was used and without the use of different one-sided insoles. MATERIAL AND METHODS Thirty young, healthy adult males received 3 different insole interventions: experimental group A had a customized 3-dimensional (3D)-printed single-sided lateral wedge insole (CLWI) inserted on the left side, and experimental group B had on the left side, a traditional single insert. The control had unilateral flat insoles; no insole inserted into the socks. Motion mechanics and gait parameters were collected at the 2-time points, after insertion of the insole and after 20 minutes of walking with the insole. RESULTS Asymmetric posture and gait appeared immediately after using the 2 insoles (lower joint moment, P<0.05). Compared with the control group, the abnormal posture and gait of experimental group B after wearing the traditional insole for 20 minutes were not obvious (P>0.05). However, the asymmetrical posture and gait remained in experimental group A after wearing the CLWI for 20 minutes (P<0.05). The center of pressure (COP) trajectory of the left foot of experimental group A was significantly higher than that of experimental group B and the control group at the 2-time points (P<0.05). CONCLUSIONS The asymmetry of posture and gait can be observed in a short time using a customized 3D-printed single-sided lateral wedge insole. This experiment provides guidance for the application of customized 3D-printed single-sided lateral wedge insoles for gait rehabilitation.

4.
Med Sci Monit ; 25: 7175-7181, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31549689

RESUMO

BACKGROUND 3D-printed insoles are widely used. This study was conducted to test a customized three-dimensional (3D)-printed heel support insole based on arch lift and to investigate whether the pressure distribution on the sole was improved while maintaining foot function. MATERIAL AND METHODS The design was based on a 3D plantar contour scanning modeling technique. Thirty healthy male participants walked along a 10-m track under 3 self-controlled interventions. A customized 3D-printed heel support insole based on arch lift was inserted into the socks for the experimental condition A. For condition B, a customized 3D-printed heel-supporting insole was inserted into the socks, and a standardized pre-made heel-supporting insole was inserted into the socks as a control (condition C). We used the Footscan® pressure plate to measure the plantar parameters in the forefoot contact and foot flange phases in each condition. RESULTS Compared with condition B and the control condition, the peak pressure under the heel was significantly lower in condition A (P<0.05), and the peak pressure in the midfoot region was not significantly increased (P>0.05). CONCLUSIONS The biomechanical properties of the customized 3D-printed heel support are better than those of the traditional heel support insole, especially when there is a need for an additional increase in heel height. Patients do not decrease midfoot motion function while using this customized insole.

5.
Medicine (Baltimore) ; 98(36): e16658, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490360

RESUMO

RATIONALE: Pelvic tumor had great impact on patients' quality of life. After tumor resection, how to accurately fill bone defect remained challenging for orthopedic surgeons. Due to lack of individual design, high incidence of prosthetic mismatching, and loosening were reported in pelvic reconstruction surgery with conventional modular prostheses. Nowadays, with rapid development of three-dimensional (3D) print technology, pelvic prostheses could be designed according to patients' own anatomy. The objective of this study was to describe the application of 3D printed customized hemi-pelvic prosthesis for patients with pelvic tumor. PATIENT CONCERNS: A 62-year-old female had developed severe right joint pain without obvious inducement from 5 months before she sought medical advice. Pain, swelling, and limited range of motion of right joint were founded during physical examination. DIAGNOSIS: The patients were diagnosed as "right acetabulum metastatic carcinoma" INTERVENTION:: 3D printed titanium alloy hemi-pelvic prosthesis was designed according the morphology of unaffected side hemi-pelvis and subsequently implanted in surgery to reconstruct the pelvis. 3D printed osteotomy guide and pelvic model were also manufactured and applied to improve accuracy of osteotomy and reduce operation time. X-Ray of pelvis, Harris score, musculoskeletal tumor society score (MSTS) and The MOS item short from health survey (SF-36) were recorded during the period of preoperation, 1, 3, 6, 12 months follow-up after operation. OUTCOMES: 3D printed hemi-pelvic prosthesis matched precisely with pelvis and implanted successfully. There was no sign of prosthetic loosening within 12 months' follow-up. No sign of peri-prosthetic infection from laboratory examination. Harris score, MSTS, and SF-36 were gradually increasing during follow-up period. LESSONS: Satisfactory effect of pelvic reconstruction could be achieved by 3D printed hemi-pelvic prostheses. It also provided a promising way to the treatment of pelvic tumor in similar cases.


Assuntos
Neoplasias Pélvicas/cirurgia , Impressão Tridimensional , Desenho de Prótese/métodos , Procedimentos Cirúrgicos Reconstrutivos/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pélvicas/patologia , Implantação de Prótese
6.
Medicine (Baltimore) ; 98(37): e17142, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517856

RESUMO

Morphological data of talus are important for the design of talar prostheses. The talar morphology of Chinese population has been rarely reported. This study adopted a three-dimensional (3D) measurement approach to provide accurate data for the anatomical morphology of talus in Northeast Chinese population and compared it with that of foreigners.One hundred forty-six healthy subjects form Northeast China underwent computed tomography (CT) arthrography. 3D digital talar model was reconstructed and thirteen morphological parameters were measured through Mimics and Magics software. Length and breadth indexes of total talus, trochlea, medial and lateral malleolus articular surface were mainly selected. Statistical analysis was conducted by independent-samples and paired-samples t test through SPSS software.All the indexes were normally distributed. No significant difference between left and right talus was identified in either males or females (P > .05). Most of the indexes showed significant sexual differences except the radian of lateral malleolus articular surface and the posterior breadth of trochlea (P < .05). The talar anatomy of Chinese subjects is different from the published data in other populations.The promising approach adopted in this study addresses some inconvenience with previous conventional methods on cadaver specimens. The geometric parameters of talus in Chinese population differ from those in other populations. The talar measurements and morphology analysis in this study suggest that population characteristics should be taken into account. This study will provide references for the design of talar prostheses in Chinese population.


Assuntos
Imagem Tridimensional , Ossos do Tarso/anatomia & histologia , Ossos do Tarso/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , China , Feminino , Humanos , Imagem Tridimensional/métodos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Tamanho do Órgão , Reprodutibilidade dos Testes , Caracteres Sexuais , Software , Tomografia Computadorizada por Raios X/métodos , Adulto Jovem
7.
Eur J Pharmacol ; 863: 172665, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31542479

RESUMO

Glioma is one of the most lethal malignancies and molecular regulators driving gliomagenesis are incompletely understood. Although temozolomide (TMZ) has been applied for malignant gliomas as a canonical chemotherapy, the treatment of glioma still remains limited due to frequently developed resistance to TMZ. Therefore, promising strategies that sensitize glioma cells to temozolomide are overwhelming to develop. Here we found that the expression of dihydrofolate reductase (DHFR) and thymidylate synthetase (TYMS), which played an essential role in folate metabolism and several types of tumors, were up-regulated in both human glioma tissues and cell lines, and overexpression of DHFR/TYMS promoted the proliferation of glioma cells. Notably, inhibition of DHFR/TYMS by pemetrexed exhibited synergistic anti-glioma activity with TMZ in both cell lines and U251 xenografts, which suggested potential combined chemotherapy for glioma. Mechanistically, the synergistic effect of inhibition of DHFR/TYMS with TMZ was due to activated AMPK and subsequently suppressed mTOR signaling pathway. Taken together, these findings identify an uncharacterized role of DHFR/TYMS in glioma growth and TMZ sensitivity mediated by AMPK-mTOR signal pathway, and provide a prospective approach for improving the anti-tumor activity of TMZ in glioma.

8.
Nanoscale ; 11(32): 15234-15244, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31385581

RESUMO

Thermally conductive polymer composites show attractive prospects as thermal management materials in many applications such as microelectronic devices. However, traditional approaches in the preparation of thermally conductive polymer composites usually have the disadvantages of complex processes. In this study, a facile method for highly thermally conductive silicone rubber composites is reported, based on 3D interconnected graphene sponges by using an inorganic salt as a sacrificial template. The composites exhibit a high thermal conductivity of 1.50 W m-1 k-1 and a thermal conductivity enhancement of 752% at a very low graphene loading of 1.46 wt%. More significantly, highly thermally conductive epoxy and styrene-butadiene rubber composites are also fabricated by the same method. The composites also show excellent electrical insulating properties (>1013 Ω cm). Thus, this effective method is proved to be widely used for the facile fabrication of polymer composites of both plastic and rubber matrices which are thermally conductive and have excellent electrical insulating properties.

9.
Mol Med Rep ; 20(3): 2426-2432, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31257540

RESUMO

Monitoring minimal residue disease (MRD) is an effective approach to evaluate the response to chemotherapy, and it is used to select the ideal therapeutic strategy and to predict the recurrence during therapy for hematological disorders. The Wilm's tumor 1 (WT1) gene, which is highly expressed in >80% of patients with acute myeloid leukemia (AML) and its increased expression level may cause poor clinical outcomes, is a potential MRD marker of hematological neoplasms. In the present study, the expression levels of WT1 and other molecular markers were retrospectively analyzed by reverse transcription­quantitative PCR in 195 patients with AML. The expression level of WT1 was significantly lower in patients with remission compared with patients with early­stage and recurrent AML. Moreover, WT1 expression was significantly decreased in patients with RUNX family transcription factor 1­RUNX1 translocation partner 1 fusion, but higher in patients with promyelocytic leukemia­retinoic acid receptor α fusion. WT1 expression was significantly reduced during remission. In patients with AML who underwent allogeneic hematopoietic stem cell transplantation (allo­HSCT), the mortality rate 2 years after allo­HSCT was significantly lower in patients with low expression level of WT1 compared with subjects presenting high expression level of WT1. Collectively, the upregulation of the expression level of WT1 in combination with the identification of other genetic abnormalities may be used as MRD markers of hematological neoplasms.

10.
Med Sci Monit ; 25: 4982-4991, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31276465

RESUMO

BACKGROUND Osteosarcoma (OS) is a common primary malignant bone tumor for which the molecular mechanisms remain unclear. Studies on coding and non-coding RNAs are needed to determine the molecular mechanism. MATERIAL AND METHODS To explore the potential roles of miRNAs and mRNA in OS, we determined the miRNA and mRNA expression profile of 3 pairs of OS and paracancerous tissues from patients with OS by sequencing and bioinformatics analysis. The expression levels of critical miRNAs and mRNAs were verified in 10 pairs of OS and paracancerous tissues. An miRNA inhibitor and mimics were used to investigate the interactions between miRNAs and target genes. The cell counting kit-8 assay was performed to evaluate OS cell proliferation after miRNA interference. RESULTS A total of 184 miRNAs and 2501 mRNAs were identified (fold-change >2.0 or <2.0, P<0.05), with up-regulation of 82 miRNAs and 1320 mRNAs and down-regulation of 102 miRNAs and 1181 mRNAs in OS tissue. The protein protein interaction network revealed that UQCRC1 (ubiquinol-cytochrome c reductase core protein 1) is a critical gene and a potential target gene of miR-214-3p. Both UQCRC1 and miR-214-3p were significantly differentially expressed in OS tissue and cell lines (down and up-regulated, respectively). Down-regulated miR-214-3p expression increased UQCRC1 expression and suppressed OS cell proliferation. In contrast, overexpression of miR-214-3p decreased UQCRC1 expression and promoted OS cell proliferation. CONCLUSIONS High miR-214-3p expression may promote OS cell proliferation by targeting UQCRC1, providing insight into a potential therapeutic target for preventing and treating OS.

11.
Biomed Res Int ; 2019: 4696843, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341898

RESUMO

Background: The potential advantages of Jiedu granule (a compound Chinese herbal medicine) combined therapeutic strategies compared with non-Jiedu granule therapeutic strategies for hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) remain unclear. Thus, the purpose of the study was to investigate the safety and efficacy of Jiedu granule for HCC with PVTT. Methods: We retrospectively reviewed the clinical data of 190 patients (94 for non-Jiedu and 96 for Jiedu) with HCC and PVTT from March 2012 to October 2016. Patients were followed up by outpatient examination and telephone till November 2018. Results: It was statistically insignificant between the two groups in baseline characteristics. Procedure-related adverse events (AEs) were observed and compared and most of them were not serious which were easily controlled or subsided naturally. No AE-induced death happened. The median overall survival (OS) rates in the single TACE plus GKR and Jiedu granule combined group were 11.3 months (95% CI: 9.168-13.435) and 15.8 months (95% CI: 13.244-18.339), respectively (p = 0.00047). Conclusions: Jiedu granule combined with TACE plus GKR is safe in HCC patients with PVTT and this Chinese herbal medicine is worthy to be promoted because of better prognosis which needs further research.

12.
Medicine (Baltimore) ; 98(29): e16503, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335720

RESUMO

RATIONALE: Total knee arthroplasty (TKA) is a globally well-accepted surgery because of its good outcome and safety. Although TKA-associated arterial injuries occur, postoperative anterior tibial artery (ATA) occlusion has not been reported yet. Herein, we present a case of ATA occlusion after TKA. PATIENT CONCERNS: A 42-year-old man with a 6-year history of right knee pain after right patella fracture treated with open reduction was referred to our clinic. Valgus and contracture deformities were detected in the right knee. Severe osteoarthritis (OA) in the right knee and multiple osteochondromas were observed on radiography. DIAGNOSIS: On the basis of clinical and imaging findings, the patient was diagnosed with OA and multiple osteochondromas. INTERVENTIONS: TKA was performed in the right knee and the osteochondromas were resected. ATA occlusion was found postoperatively and was treated conservatively. OUTCOMES: Although the right ATA occlusion did not resolve, the patient recovered well postoperatively, with pain relief and recovery of right knee range of motion. LESSONS: The clinical outcome in a case of ATA occlusion after TKA demonstrates that conservative treatment could be appropriate in this context.


Assuntos
Arteriopatias Oclusivas/diagnóstico por imagem , Artroplastia do Joelho/efeitos adversos , Artérias da Tíbia/diagnóstico por imagem , Adulto , Anticoagulantes/uso terapêutico , Arteriopatias Oclusivas/tratamento farmacológico , Humanos , Masculino , Osteoartrite do Joelho/cirurgia , Osteocondrose/cirurgia , Complicações Pós-Operatórias/diagnóstico por imagem
13.
Langmuir ; 35(32): 10446-10452, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31298029

RESUMO

The present work investigated diffusion interactions between nanoparticles and polymers during freezing colloidal suspensions. The size effects of nanoporous media formed by packed nanoparticles on the diffusion instability of the polymer solution were explored. It is found that small particles under low pulling speeds will obstruct the diffusion of polymers and the corresponding morphology will be banded structures. The intrinsic reason is the inhibited tube-like motion of polymer chains in the nanoporous particle layer. The increased particle size or the decreased solute size will solve the diffusion problem. On the other hand, the small pulling speed constructs an increased length of the particle layer in front of the freezing interface, which presents a longer diffusion path to impede the polymer diffusion. Instead, an increased pulling speed shortens the length of the particle layer so that it is easy for polymers to go through a short porous media. Hence, the diffusion of polymers will control the freezing morphology of the suspension and create dendrites. These results imply that a relatively larger particle size and a moderately higher pulling speed are beneficial for well-developed microstructures in the production of porous ceramics with the freeze-casting method.

14.
Cancer Cell ; 35(6): 932-947.e8, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31130341

RESUMO

We performed genomic and transcriptomic sequencing of 133 combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC) cases, including separate, combined, and mixed subtypes. Integrative comparison of cHCC-ICC with hepatocellular carcinoma and intrahepatic cholangiocarcinoma revealed that combined and mixed type cHCC-ICCs are distinct subtypes with different clinical and molecular features. Integrating laser microdissection, cancer cell fraction analysis, and single nucleus sequencing, we revealed both mono- and multiclonal origins in the separate type cHCC-ICCs, whereas combined and mixed type cHCC-ICCs were all monoclonal origin. Notably, cHCC-ICCs showed significantly higher expression of Nestin, suggesting Nestin may serve as a biomarker for diagnosing cHCC-ICC. Our results provide important biological and clinical insights into cHCC-ICC.

15.
Artif Cells Nanomed Biotechnol ; 47(1): 2114-2122, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31140328

RESUMO

MicroRNAs (miRNAs) play essential functions in pathogenesis of Ewing sarcoma (ES). However, the molecular mechanisms responsible for ES occurrence and development through the regulation of miRNAs remain largely unknown. This study is aimed to explore the differential expressed miRNAs and mRNAs that play vital roles in ES. GSE80201 miRNA and GSE68776 mRNA microarray dataset were selected to carry out a series of bioinformatics analysis such as GEO 2R, gene ontology, pathway enrichment analysis, Venn analysis and PPI network construction to predict hub genes. Furthermore, using quantitative real-time PCR, RNA interference and luciferase reporter assay we demonstrated that activated leukocyte cell adhesion molecule (ALCAM/CD166) is a direct target of miR-21-3p in human ES cell lines. Our results suggest that the miR-21/CD166 axis has the potential to serve as both diagnostic markers and therapeutic targets for ES.

16.
Cell Death Differ ; 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097787

RESUMO

Insufficient pancreatic ß-cell mass or insulin-producing ß-cells are implicated in all forms of diabetes mellitus. However, the molecular mechanisms underlying ß-cell destruction are complex and not fully defined. Here we observed that activation of STAT3 is intensely and specifically inhibited in ß-cells under hyperglycemic conditions. By knocking out STAT3 specifically in mouse ß-cells, we found that the loss of STAT3 sensitized mice to three low doses of STZ stimulation resulting in hyperglycemia. Mechanistically, accumulating PTEN, induced by STAT3 deficiency, directly represses phosphorylation of AKT, which negatively modulates transcription factor activation, dysregulates ß-cell function, positively promotes apoptotic signaling, and finally induces ß-cell apoptosis. Notably, the defective secretion of insulin and ß-cells apoptosis was completely rescued by PTEN ablation in STAT3-null islets or PTEN inhibitor bpv(phen) treatment. Thus our data suggest that STAT3 is a vital modulator of ß-cell survival and function, highlighting a critical role for STAT3 in the negative regulation of PTEN-AKT signaling pathway associated with ß-cell dysfunction and apoptosis.

17.
Adv Healthc Mater ; 8(14): e1900312, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31094096

RESUMO

Ideal cartilage tissue engineering requires scaffolds featuring good biocompatibility, large pore structure, high mechanical strength, as well as minimal invasion procedure. Although significant progress has been made in the development of polymer scaffolds, the construction of smart systems with all the desired properties is still emerging as a challenge. The thermogels of stereocomplex 4-arm poly(ethylene glycol)-polylactide (PEG-PLA) (scPLAgel ) and stereocomplex cholesterol-modified 4-arm PEG-PLA (scPLA-Cholgel ) from the equimolar enantiomeric 4-arm PEG-PLA and 4-arm PEG-PLA-Chol, respectively, are fabricated as scaffolds for cartilage tissue engineering. scPLA-Cholgel shows lower critical gelation temperature, higher mechanical strength, larger pore size, better chondrocyte adhesion, and slower degradation compared to scPLAgel as the benefit of cholesterol modification, which is more appropriate for cartilage regeneration. Moreover, the preservation of morphology, biomechanical property, cartilaginous specific matrix, as well as cartilaginous gene expressions of engineered cartilage mediated by scPLA-Cholgel are proven superior to those by scPLAgel . scPLA-Cholgel serves as a promising chondrocyte carrier for cartilage tissue engineering and gives an alternative solution to clinical cartilage repair.

18.
Cell Stem Cell ; 24(5): 707-723.e8, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982771

RESUMO

The identity and degree of heterogeneity of glial progenitors and their contributions to brain tumor malignancy remain elusive. By applying lineage-targeted single-cell transcriptomics, we uncover an unanticipated diversity of glial progenitor pools with unique molecular identities in developing brain. Our analysis identifies distinct transitional intermediate states and their divergent developmental trajectories in astroglial and oligodendroglial lineages. Moreover, intersectional analysis uncovers analogous intermediate progenitors during brain tumorigenesis, wherein oligodendrocyte-progenitor intermediates are abundant, hyper-proliferative, and progressively reprogrammed toward a stem-like state susceptible to further malignant transformation. Similar actively cycling intermediate progenitors are prominent components in human gliomas with distinct driver mutations. We further unveil lineage-driving networks underlying glial fate specification and identify Zfp36l1 as necessary for oligodendrocyte-astrocyte lineage transition and glioma growth. Together, our results resolve the dynamic repertoire of common and divergent glial progenitors during development and tumorigenesis and highlight Zfp36l1 as a molecular nexus for balancing glial cell-fate decision and controlling gliomagenesis.

19.
J Med Chem ; 62(7): 3268-3285, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30856328

RESUMO

Multiple sclerosis (MS) is a disease of the autoimmune-mediated disorder in the central nervous system, for which no effective therapeutic agent is currently available. The regulation of macrophage polarization toward M2 is a general benefit for treating MS. The gene biomarker-based phenotypic screening approach was developed, and 3,4-disubstituted piperidine derivative S-28 was identified as a lead compound modulating macrophage M2 polarization. Further SAR studies resulted in the discovery of the most potent modulator D11 that showed good oral bioavailability and significant in vivo therapeutic effects. Mechanistic studies demonstrated that the M2 polarization macrophages modulated by D11 mainly functioned through inhibiting the proliferation of T-cells and activating the phosphorylation of Stat3 and Akt. Therefore, the gene biomarker-based phenotypic screening was demonstrated as a promising tool for the discovery of novel macrophage M2 polarization modulators. Compound D11 may serve as a promising starting point for the development of therapeutics to treat MS.

20.
Phys Rev E ; 99(1-1): 013302, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30780269

RESUMO

A computational method is developed for the study of mechanical response and fracture behavior of phase field crystals (PFC), to overcome a limitation of the PFC dynamics which lacks an effective mechanism for describing fast mechanical relaxation of the material system. The method is based on a simple interpolation scheme for PFC (IPFC) making use of a condition of the displacement field to satisfy local elastic equilibration, while preserving key characteristics of the original PFC model. We conduct a systematic study on the mechanical properties of a sample nanoribbon system with honeycomb lattice symmetry subjected to uniaxial tension, for numerical validation of the IPFC scheme and the comparison with the original PFC and modified PFC methods. Results of mechanical response, in both elasticity and fracture regimes, show the advantage and efficiency of the IPFC method across different system sizes and applied strain rates, due to its effective process of mechanical equilibration. A brittle fracture behavior is obtained in IPFC calculations, where effects of system temperature and chirality on the fracture strength and Young's modulus are also identified, with results agreeing with those found in previous atomistic simulations of graphene. The IPFC scheme developed here is generic and applicable to the mechanical studies using different types of PFC free-energy functionals designed for various material systems.

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