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1.
Int Orthop ; 2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-32114659

RESUMO

PURPOSE: The aim of this study was to evaluate the clinical and functional outcomes of patients with large post-traumatic tibial bone defects managed by double-level bone transport using the Ilizarov technique and compare it with one-level bone transport technique. METHODS: A retrospective cohort study was conducted on 26 patients with open tibial fracture from January 2010 to January 2017. All cases were Gustilo III. Depending on the site of osteotomy, the patients were divided into single-level (n = 13) and double-level groups (n = 13). The bone transport time, consolidation time of the distraction gap, docking site healing time, external fixation time, external fixation index, soft tissue defect area, soft tissue growth index, operating time, and surgical bleeding volume were recorded and compared between the two groups. Bone and functional results were evaluated according to the Association for the Study and Application of the Method of Ilizarov (ASAMI) criteria. RESULTS: The mean duration of follow-up was 28.5 ± 5.8 months (range 13-38 months) since the Orthofix fixator was removed, all patients achieved complete union in the docking site and consolidation in the regenerate bone; moreover, the wound was closed The mean bone defect length after debridement was 7.2 cm (range 5.8-9.0 cm) in single-level group vs. 10.7 cm (range 7.5-15.0 cm) in the double-level group (P < 0.05). The mean docking site healing time was 10.85 ± 1.52 months in the single-level group vs. 8.93 ± 2.29 months in the double-level group (P < 0.05); external frame time was 18.06 months (range 15-20 months) in single-level group vs. 12.71 months (range 9.5-16.0 months) in the double-level group (P < 0.05); external fixation index was 2.52 months/cm (range 2.15-2.94 months/cm) versus 1.22 months/cm (range 0.96-1.67 months/cm) in double-level group (P < 0.01); and soft tissue growth index was 0.29 months/cm2 (range 0.21-0.45 months/cm2) in the single-level group versus 0.62 months/cm2 (range 0.47-0.86 months/cm2) in the double-level group (P < 0.01). According to the ASAMI classification, the clinical and functional results in the double-level group were better than in the single-level group. CONCLUSION: The Ilizarov technique of double-level bone transport with Orthofix external fixator can be used successfully to repair and reconstruct the tibial bone loss and accompanying soft tissue defect.

2.
Nat Commun ; 11(1): 1395, 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170083

RESUMO

Oncolytic viruses offer an in situ vaccination approach to activate tumor-specific T cell responses. However, the upregulation of PD-L1 expression on tumor cells and immune cells leads to tumor resistance to oncolytic immunotherapy. In this study, we generate an engineered oncolytic virus that coexpresses a PD-L1 inhibitor and GM-CSF. We find that the oncolytic virus is able to secrete the PD-L1 inhibitor that systemically binds and inhibits PD-L1 on tumor cells and immune cells. Importantly, the intratumoral injection with the oncolytic virus overcomes PD-L1-mediated immunosuppression during both the priming and effector phases, provokes systemic T cell responses against dominant and subdominant neoantigen epitopes derived from mutations, and leads to an effective rejection of both virus-injected and distant tumors. In summary, this engineered oncolytic virus is able to activate tumor neoantigen-specific T cell responses, providing a potent, individual tumor-specific oncolytic immunotherapy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy.

3.
Br J Cancer ; 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32147668

RESUMO

BACKGROUND: Previous studies suggested that mdivi-1 (mitochondrial division inhibitor), a putative inhibitor of dynamin-related protein (DRP1), decreased cancer cell proliferation through inducing mitochondrial fusion and altering oxygen consumption. However, the metabolic reprogramming underlying the DRP1 inhibition is still unclear in cancer cells. METHODS: To better understand the metabolic effect of DRP1 inhibition, [U-13C]glucose isotope tracing was employed to assess mdivi-1 effects in several cancer cell lines, DRP1-WT (wild-type) and DRP1-KO (knockout) H460 lung cancer cells and mouse embryonic fibroblasts (MEFs). RESULTS: Mitochondrial staining confirmed that mdivi-1 treatment and DRP1 deficiency induced mitochondrial fusion. Surprisingly, metabolic isotope tracing found that mdivi-1 decreased mitochondrial oxidative metabolism in the lung cancer cell lines H460, A549 and the colon cancer cell line HCT116. [U-13C]glucose tracing studies also showed that the TCA cycle intermediates had significantly lower enrichment in mdivi-1-treated cells. In comparison, DRP1-WT and DRP1-KO H460 cells had similar oxidative metabolism, which was decreased by mdivi-1 treatment. Furthermore, mdivi-1-mediated effects on oxidative metabolism were independent of mitochondrial fusion. CONCLUSIONS: Our data suggest that, in cancer cells, mdivi-1, a putative inhibitor of DRP1, decreases oxidative metabolism to impair cell proliferation.

4.
Dalton Trans ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134066

RESUMO

Recently, we demonstrated that the in situ formation of a building block is an attractive synthesis strategy for creating novel clusters with controllable structures. Herein, we present the design and synthesis of the first tantaloselenite polyoxoanion [Se4(TaO2)6(OH)4O17]4- (1) and a series of lanthanide derivatives (RE3+ = Tb3+, Dy3+, Ho3+, Er3+, Tm3+, Yb3+). In total, we report seven clusters that vary in both composition and structure but which share the same {Se4(TaO2)6} building block. The compounds are fully characterized by single-crystal X-ray diffraction, IR spectra, TG, and PXRD and their decolorization properties for RhB have also been investigated. Compound 1 exhibits good photocatalytic activity for the decolorization of RhB while the introduction of lanthanide into the framework can also maintain this activity.

5.
Histochem Cell Biol ; 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32124010

RESUMO

The proliferation, migration, and cellular morphology of vascular smooth muscle cells (VSMCs) play important roles in the pathogenesis of atherosclerosis (AS). Homocysteine (Hcy) is a sulfur-containing amino acid, which is an intermediate product of methionine metabolism. Hcy can induce proliferation, migration, and phenotypic switch of VSMCs, but details of these mechanisms are still unclear. The phosphatidylinositol 3-kinase (PI3K/Akt/mTOR) signaling pathway is involved in a host of cellular functions. In this study, we sought to determine if this multifunctional pathway played a role in Hcy-induced proliferation, migration, and phenotypic transformation of VSMCs, which has not been previously reported. miR-145 has been previously reported to suppress the effects of Hcy in VSMCs. In our study, using qRT-PCR, we found that Hcy itself reduced the expression of miR-145 in VSMCs, while overexpression of miR-145 reduced the proliferation, migration, and phenotypic transformation of VSMCs caused by Hcy. Using Western blot analysis, we found that VSMCs exposed to Hcy exhibited significant increases in the levels of PI3K, Akt, and mTOR proteins. Additionally, overexpression of miR-145 dramatically decreased PI3K, Akt, and mTOR expression. Using qRT-PCR we found that miR-145 expression increased after blocking PI3K using an inhibitor. Inhibition of the PI3K signaling pathway also prevented Hcy-induced VSMC proliferation, migration, and phenotypic switch. Taken together, our results suggest that miR-145 could inhibit VSMC proliferation, migration, and phenotype switching by preventing activation of the PI3K/Akt/mTOR signaling pathway.

6.
Haematologica ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32165486

RESUMO

Venetoclax is a promising agent in the treatment of acute myeloid leukemia, though its antileukemic activity is limited to combination therapies. Mcl-1 downregulation, Bim upregulation, and DNA damage have been identified as potential ways to enhance venetoclax activity. In this study, we combine venetoclax with the dual PI3K and histone deacetylase inhibitor CUDC-907, which can downregulate Mcl-1, upregulate Bim, and induce DNA damage, as well as downregulate c-Myc. We establish that CUDC-907 and venetoclax synergistically induce apoptosis in acute myeloid leukemia cell lines and primary acute myeloid leukemia patient samples ex vivo. CUDC-907 downregulates CHK1, Wee1, RRM1, and c-Myc, which were found to play a role in venetoclax-induced apoptosis. Interestingly, we found that venetoclax treatment enhances CUDC-907-induced DNA damage potentially through inhibition of DNA repair. In vivo results show that CUDC-907 enhances venetoclax efficacy in an acute myeloid leukemia cell line derived xenograft mouse model, supporting the development of CUDC-907 in combination with venetoclax for the treatment of acute myeloid leukemia.

7.
Br J Sports Med ; 2020 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-32201388

RESUMO

Rapid advances in technologies in the field of genomics such as high throughput DNA sequencing, big data processing by machine learning algorithms and gene-editing techniques are expected to make precision medicine and gene-therapy a greater reality. However, this development will raise many important new issues, including ethical, moral, social and privacy issues. The field of exercise genomics has also advanced by incorporating these innovative technologies. There is therefore an urgent need for guiding references for sport and exercise genomics to allow the necessary advancements in this field of sport and exercise medicine, while protecting athletes from any invasion of privacy and misuse of their genomic information. Here, we update a previous consensus and develop a guiding reference for sport and exercise genomics based on a SWOT (Strengths, Weaknesses, Opportunities and Threats) analysis. This SWOT analysis and the developed guiding reference highlight the need for scientists/clinicians to be well-versed in ethics and data protection policy to advance sport and exercise genomics without compromising the privacy of athletes and the efforts of international sports federations. Conducting research based on the present guiding reference will mitigate to a great extent the risks brought about by inappropriate use of genomic information and allow further development of sport and exercise genomics in accordance with best ethical standards and international data protection principles and policies. This guiding reference should regularly be updated on the basis of new information emerging from the area of sport and exercise medicine as well as from the developments and challenges in genomics of health and disease in general in order to best protect the athletes, patients and all other relevant stakeholders.

8.
Int J Surg ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32173611

RESUMO

BACKGROUND: Microwave ablation (MWA) is an important method in the treatment of liver cancer. This systematic review compared MWA with liver resection (LR) for liver cancer treatment. In recent years, the MWA has been also reported to play an important role. Studies comparing MWA and LR are lacking. This study aims to compare the efficacy of MWA and LR in the treatment of hepatocellular carcinoma (HCC). METHODS: A systematic search of PubMed, Embase, Cochrane Library and Web of Science up to April 1, 2019 was conducted for relevant studies that compared the efficacy of MWA and LR in the treatment of HCC. The primary outcomes were local tumor recurrence (LTR) and overall survival (OS) of patients. The secondary outcomes included disease free survival (DFS), extrahepatic metastasis, intrahepatic de novo lesions, length of stay, complications, intraoperative blood loss and operative time. RESULTS: A total of 16 studies including 2622 patients were identified. Incidence of LTR was significantly higher in patients with MWA than LR, with a pooled OR of 2.69 (95% CI 1.33 ‒ 5.41; P = 0.006). No significant difference in 1-year OS was found. However, patients with MWA experienced higher 3- and 5-year OS, with pooled ORs of 1.40 (95% CI 1.07 ‒ 1.84; P = 0.01) and 1.41 (95% CI 1.10 ‒ 1.80; P = 0.007) respectively. In secondary measures, the 1- and 3-year DFS were significantly higher in patients with MWA. However, no significant difference of 5-year DFS was observed. In addition, lower incidence of complications, less intraoperative blood loss and shorter operative time and shorter length of stay were observed in MWA. CONCLUSIONS: Though MWA may lead to higher incidence of recurrence, it may be an effective and safe alternative in patients with HCC or liver metastases. MWA may have benefits in patients' survival and safety. Randomized studies should be performed to determine the target population that benefits most from MWA in the future.

9.
Acta Pharmacol Sin ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139897

RESUMO

Serum- and glucocorticoid-inducible kinease-1 (SGK1) is a serine/threonine kinase regulated by hypotonic stimuli, which is involved in regulation of cell cycle and apoptosis. Our previous study shows that activation of volume-regulated Cl- channels (VRCCs) protects rat basilar artery smooth muscle cells (BASMCs) against hydrogen peroxide (H2O2)-induced apoptosis. In the present study, we investigated whether SGK1 was involved in the protective effect of VRCCs in BASMCs. We showed that hypotonic challenge significantly reduced H2O2-induced apoptosis, and increased SGK1 phosphorylation, but did not affect SGK1 protein expression. The protective effect of hypotonic challenge against H2O2-induced apoptosis was mediated through inhibiting mitochondria-dependent apoptotic pathway, evidenced by increased Bcl-2/Bax ratio, stabilizing mitochondrial membrane potential (MMP), decreased cytochrome c release from the mitochondria to the cytoplasm, and inhibition of the activation of caspase-9 and caspase-3. These protective effects of hypotonic challenge against H2O2-induced apoptosis was diminished and enhanced, respectively, by SGK1 knockdown and overexpression. We further revealed that SGK1 activation significantly increased forkhead box O3a (FOXO3a) phosphorylation, and then inhibited the translocation of FOXO3a into nucleus and the subsequent expression of Bcl-2 interacting mediator of cell death (Bim). In conclusion, SGK1 mediates the protective effect of VRCCs against H2O2-induced apoptosis in BASMCs via inhibiting FOXO3a/Bim signaling pathway. Our results provide compelling evidences that SGK1 is a critical link between VRCCs and apoptosis, and shed a new light on the treatment of vascular apoptosis-associated diseases, such as vascular remodeling, angiogenesis, and atherosclerosis.

10.
Brain Res Bull ; 158: 20-30, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32109527

RESUMO

Streptococcus pneumoniae is responsible for pneumococcal meningitis, with significant mortality and morbidity worldwide. Microglial inflammation plays a vital role in meningitis. The peptidoglycan sensor NOD2 (nucleotide-binding oligomerization domain 2) has been identified to promote microglia activation, but the role in autophagy following pneumococcal meningitis remains unclear. In the present study, we investigated the role of NOD2 in microglial inflammation and autophagy, as well as related signaling pathways, during S. pneumonia infection. NOD2 expression was knocked down by the injection of lentivirus-mediated short-hairpin RNA (shRNA). Our results revealed that NOD2 promotes microglial inflammation by increasing inflammatory mediators. We also showed that the TAK1-NF-κB pathway is involved in this process. In addition, NOD2 increased the expression of autophagy-related proteins and induced autophagosome formation. Rapamycin and 3-MA were utilized to assess the role of autophagy in microglial inflammation induced by S. pneumonia. We demonstrated that autophagy serves as a cellular defense mechanism to reduce inflammatory mediators. Similar to the in vitro results, NOD2 induced inflammation and autophagy in the brain in a mouse meningitis model. Moreover, NOD2 silencing significantly reduced brain edema and improved the neurological function of pneumococcal meningitis mice. Taken together, these data demonstrate that NOD2 promotes microglial inflammation and autophagy in murine pneumococcal meningitis, and the TAK1-NF-κB pathway is involved in microglial activation.

11.
J Med Virol ; 92(5): 468-472, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32048741
12.
Nanoscale ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32064483

RESUMO

One-dimensional (1D) inorganic-organic metal halide hybrids at the molecular level, which can be considered as arrays of nanochains isolated by organic components, have shown remarkable optical and electric properties. This review summarizes their reported structural types and shows how to modify their band gaps and optical and electric properties.

14.
Cell Host Microbe ; 27(2): 213-224.e7, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32023487

RESUMO

The gut is a first point of contact with ingested xenobiotics, where chemicals are metabolized directly by the host or microbiota. Atrazine is a widely used pesticide, but the role of the microbiome metabolism of this xenobiotic and the impact on host responses is unclear. We exposed successive generations of the wasp Nasonia vitripennis to subtoxic levels of atrazine and observed changes in the structure and function of the gut microbiome that conveyed atrazine resistance. This microbiome-mediated resistance was maternally inherited and increased over successive generations, while also heightening the rate of host genome selection. The rare gut bacteria Serratia marcescens and Pseudomonas protegens contributed to atrazine metabolism. Both of these bacteria contain genes that are linked to atrazine degradation and were sufficient to confer resistance in experimental wasp populations. Thus, pesticide exposure causes functional, inherited changes in the microbiome that should be considered when assessing xenobiotic exposure and as potential countermeasures to toxicity.

15.
J Med Chem ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32078308

RESUMO

ERK1 and ERK5 are proposed to have pivotal roles in several types of cancer. Under some circumstance, ERK5 may provide a common bypass route, which rescues proliferation upon abrogation of ERK1 signaling. Thus, we accurately classified the tumor types from The Cancer Genome Atlas (TCGA) based on the expression levels of ERK1 and ERK5. We proposed a novel therapeutic strategy to overcome the above-mentioned compensatory mechanism in specific tumor types by co-targeting both ERK1 and ERK5. On the basis of the idea of overcoming ERK5 compensation mechanism, 22ac (ADTL-EI1712) as the first selective dual-target inhibitor of ERK1 and ERK5 was discovered to have potent antitumor effects in vitro and in vivo. Interestingly, this compound was found to induce regulated cell death accompanied by autophagy in MKN-74 cells. Taken together, our results warrant the potential of this dual-target inhibitor as a new candidate drug that conquers compensatory mechanism in certain tumor types.

16.
Proc Natl Acad Sci U S A ; 117(5): 2462-2472, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31953260

RESUMO

Preadipocytes can give rise to either white adipocytes or beige adipocytes. Owing to their distinct abilities in nutrient storage and energy expenditure, strategies that specifically promote "beiging" of adipocytes hold great promise for counterbalancing obesity and metabolic diseases. Yet, factors dictating the differentiation fate of adipocyte progenitors remain to be elucidated. We found that stearoyl-coenzyme A desaturase 1 (Scd1)-deficient mice, which resist metabolic stress, possess augmentation in beige adipocytes under basal conditions. Deletion of Scd1 in mature adipocytes expressing Fabp4 or Ucp1 did not affect thermogenesis in mice. Rather, Scd1 deficiency shifted the differentiation fate of preadipocytes from white adipogenesis to beige adipogenesis. Such effects are dependent on succinate accumulation in adipocyte progenitors, which fuels mitochondrial complex II activity. Suppression of mitochondrial complex II by Atpenin A5 or oxaloacetic acid reverted the differentiation potential of Scd1-deficient preadipocytes to white adipocytes. Furthermore, supplementation of succinate was found to increase beige adipocyte differentiation both in vitro and in vivo. Our data reveal an unappreciated role of Scd1 in determining the cell fate of adipocyte progenitors through succinate-dependent regulation of mitochondrial complex II.

17.
Org Lett ; 22(3): 929-933, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31916776

RESUMO

Crokonoid A (1), a highly rearranged diterpenoid featuring a dual-bridged tricyclo[4.4.1.11,4]dodecane-2,11-dione ring system and its two possible ent-kaurene diterpenoid precursors (2 and 3), was isolated and structurally characterized by solid data from Croton kongensis. Compound 1 exhibited significant cytotoxicity against HL-60 and A-549 cell lines with IC50 values of 1.24 ± 0.56 and 1.92 ± 0.60 µM, respectively.

18.
Nat Commun ; 11(1): 261, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937787

RESUMO

Engineering the band gap chemically by organic molecules is a powerful tool with which to optimize the properties of inorganic 2D materials. The obtained materials are however still limited by inhomogeneous compositions and properties at nanoscale and small adjustable band gap ranges. To overcome these problems in the traditional exfoliation and then organic modification strategy, an organic modification and then exfoliation strategy was explored in this work for preparing 2D organic metal chalcogenides (OMCs). Unlike the reported organically modified 2D materials, the inorganic layers of OMCs are fully covered by long-range ordered organic functional groups. By changing the electron-donating ability of the organic functional groups and the electronegativity of the metals, the band gaps of OMCs were varied by 0.83 eV and their conductivities were modulated by 9 orders of magnitude, which are 2 and 107 times higher than the highest values observed in the reported chemical methods, respectively.

19.
Mol Oncol ; 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31981446

RESUMO

Although circulating tumor cells (CTCs) have shown promise as potential biomarkers for diagnostic and prognostic assessment in gastric cancer (GC), determining the predictive and prognostic value of programmed death-ligand 1 (PD-L1)-positive CTCs in patients with GC is a challenge. Here, we identified that the expression of total vimentin (VIM) protein was positively correlated with PD-L1 and inhibited CD8+ T-cell activation in patients with GC according to bioinformatics analysis. Notably, coexpression of PD-L1 and cell-surface VIM (CSV) was detected by immunofluorescence and immunohistochemistry assay in locally advanced GC tumor specimens and metastatic lymph nodes. Likewise, CSV expression level was significantly decreased after transiently knocking down PD-L1 in GC cell lines. Based on our established CTC detection platform, CTCs were isolated from peripheral blood samples collected from 70 patients (38 resectable and 32 unresectable) with GC using magnetic positive selection and a CSV-specific monoclonal antibody, 84-1. CSV+ PD-L1+ CTCs were observed in 50 of 70 (71%) GC patient samples, ranging from 0 to 261 mL-1 . A higher number of CSV+ PD-L1+ CTCs were significantly associated with a short survival duration and poor therapeutic response. This study demonstrated that detection of PD-L1+ CTCs using a CSV-enrichment method has promising value as a clinically relevant prognostic marker for GC.

20.
Top Curr Chem (Cham) ; 378(1): 10, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31894426

RESUMO

Single-nucleotide variants (SNVs) that are strongly associated with many genetic diseases and tumors are important both biologically and clinically. Detection of SNVs holds great potential for disease diagnosis and prognosis. Recent advances in DNA nanotechnology have offered numerous principles and strategies amenable to the detection and quantification of SNVs with high sensitivity, specificity, and programmability. In this review, we will focus our discussion on emerging techniques making use of DNA strand displacement, a basic building block in dynamic DNA nanotechnology. Based on their operation principles, we classify current SNV detection methods into three main categories, including strategies using toehold-mediated strand displacement reactions, toehold-exchange reactions, and enzyme-mediated strand displacement reactions. These detection methods discriminate SNVs from their wild-type counterparts through subtle differences in thermodynamics, kinetics, or response to enzymatic manipulation. The remarkable programmability of dynamic DNA nanotechnology also allows the predictable design and flexible operation of diverse strand displacement probes and/or primers. Here, we offer a systematic survey of current strategies, with an emphasis on the molecular mechanisms and their applicability to in vitro diagnostics.


Assuntos
DNA/química , DNA/genética , Variação Genética , Nucleotídeos/genética , Humanos , Nanotecnologia , Hibridização de Ácido Nucleico , Sondas de Ácido Nucleico/genética , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase
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