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1.
Neural Regen Res ; 16(1): 93-98, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32788452

RESUMO

Peripheral nerve injury (PNI) is common and, unlike damage to the central nervous system injured nerves can effectively regenerate depending on the location and severity of injury. Peripheral myelinating glia, Schwann cells (SCs), interact with various cells in and around the injury site and are important for debris elimination, repair, and nerve regeneration. Following PNI, Wallerian degeneration of the distal stump is rapidly initiated by degeneration of damaged axons followed by morphologic changes in SCs and the recruitment of circulating macrophages. Interaction with fibroblasts from the injured nerve microenvironment also plays a role in nerve repair. The replication and migration of injury-induced dedifferentiated SCs are also important in repairing the nerve. In particular, SC migration stimulates axonal regeneration and subsequent myelination of regenerated nerve fibers. This mobility increases SC interactions with other cells in the nerve and the exogenous environment, which influence SC behavior post-injury. Following PNI, SCs directly and indirectly interact with other SCs, fibroblasts, and macrophages. In addition, the inter- and intracellular mechanisms that underlie morphological and functional changes in SCs following PNI still require further research to explain known phenomena and less understood cell-specific roles in the repair of the injured peripheral nerve. This review provides a basic assessment of SC function post-PNI, as well as a more comprehensive evaluation of the literature concerning the SC interactions with macrophages and fibroblasts that can influence SC behavior and, ultimately, repair of the injured nerve.

2.
Food Chem ; 336: 127683, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32771900

RESUMO

This study aimed to reveal amino acid deamination and decarboxylation activities of spoilage microbiota in chill-stored grass carp fillets. Results showed that microbial deamination activities of umami/sweet-taste amino acids were higher than that of bitter-taste amino acids. The total deamination activity of tested amino acids decreased during the late period of storage, which inhibited the increase of ammonia in fish flesh. Microbial decarboxylation activity of ornithine was much higher than lysine and histidine, which was consistent with the rapid increase of putrescine in fish fillets. Meanwhile, putrescine could be produced in large quantities through arginine deiminase pathway of spoilage bacteria. Glucose utilization by spoilage microbiota was active during the late period of storage, which was consistent with the rapid consumption of lactate and total sugar in fish flesh. Overall, results of this study could be beneficial for revealing fish spoilage mechanisms and providing theoretical guidance for developing fish preservation technologies.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33039590

RESUMO

PURPOSE: This study aimed to evaluate the efficacy and safety of intensity-modulated radiotherapy (IMRT) for pleural recurrence of thymoma that was not suitable for surgery and had progressed after chemotherapy. MATERIALS AND METHODS: From February 2012, consecutive patients with pleural recurrence of thymoma were prospectively enrolled. Due to dose restrictions to normal tissue (lung, liver, kidney), three different levels of radiation doses (30Gy, 40Gy, 50Gy) were prescribed for pleural lesions of different sizes and locations, with a daily fraction dose of 2Gy. The objective response rate (ORR), local control time (LCT), overall survival time (OS), and toxicity were recorded, respectively. RESULTS: By August 2016, 31 patients had completed the IMRT treatment. There were 21 male and 10 female patients, with a median age of 49 (range 22-70) years. B3 thymoma was the major (62%) tumor subtype observed. During the median follow-up of 48 (24-70) months, the ORR was 97%, and the median LCT was 49 (95% CI:40.4-58.1) months. However, there were 29 (93.5%) patients who developed out-of-field recurrence, among whom 10 (32%) patients (30Gy: n=7; 40Gy: n=3) developed both out-of-field and in-field recurrence. The median progression-free survival was 19 months, and no in-field recurrence occurred in the 50Gy group. Moreover, a higher dose was related to a longer LCT. No toxicities higher than a grade 4 occurred after IMRT within the normal-tissue dose limitation. The 5-year OS of the patients was 81%. CONCLUSIONS: IMRT for pleural recurrence may act as an alternative treatment when surgery is not feasible, with a higher dose resulting in a longer LCT. In this study, out-of-field recurrence was considerably common, but repeated IMRT for new recurrence should be cautiously carried out due to the high risk of radiation-induced pneumonitis.

4.
Int J Biol Macromol ; 165(Pt A): 625-634, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33010271

RESUMO

Kaempferol, quercetin and myricetin are typical flavonols that feature different number of hydroxyl substituents at B-ring. In this study, kaempferol, quercetin and myricetin were individually mixed with chitosan (CS) based film matrix to develop active packaging films. Results showed the incorporation of flavonols produced dense inner microstructure by establishing intermolecular hydrogen bonding interactions with film matrix. The addition of flavonols reduced the water vapor permeability, oxygen permeability and UV-vis light transmittance of the films, whereas elevated the tensile strength, elongation at break, 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity and antimicrobial activity of the films. Among all the films, the film containing myricetin showed the highest water vapor and oxygen barrier abilities and mechanical properties. Notably, different films presented distinct flavonol release behaviors in fatty and aqueous food stimulants. Kaempferol was easily released into fatty food stimulant, while myricetin was easily released into aqueous food stimulant. The release behavior of flavonols in different food stimulants greatly affected the antioxidant activity of the films. Our results suggest the structure and functional properties of the films are closely related to the number of hydroxyl substituents at B-ring of flavonols.

5.
Cell Biochem Funct ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33047358

RESUMO

MiR-140-5p is high expressed in normal fracture healing, but its specific role and mechanism in tissue-to-bone healing are rarely reported. Therefore, this study investigated the effects of miR-140-5p on tissue-to-bone healing. Clone formation experiment, flow cytometry, Alizarin Red S Staining and Oil Red O Staining were performed to investigate the biological characteristics of mouse embryonic bone marrow mesenchymal stem cells C3H10T1/2. MiR-140-5p mimic was transfected into osteogenic medium (OS)-treated C3H10T1/2 cells to investigate the effects of miR-140-5p on osteogenic differentiation. MiR-140-5p transgenic mouse model and the transgenic fracture model were established, and the effects of miR-140-5p on osteogenic differentiation, bone mineral density (BMD) and bone mass of bone tissues were detected by haematoxylin and eosin staining and computed tomography scan. The expressions of osteocalcin, differentiation-related genes (Runx2, ALP, Spp1 and Bglap3) and miR-140-5p were determined by quantitative real-time polymerase chain reaction. C3H10T1/2 cells showed the abilities of forming cloned differentiation of osteogenesis, fat cells, and its phenotypes including CD44, CD90.1 and Sca-1 but excluding CD45 haematopoietic stem cell marker. Overexpression of miR-140-5p promoted the expressions of differentiation-related genes and calcium deposition of OS-treated C3H10T1/2 cells. MiR-140-5p increased the expression of osteocalcin, BMD and bone mass and promoted bone healing of miR-140-5p-transgenic mice with fracture. MiR-140-5p promoted osteogenic differentiation of mouse embryonic bone marrow mesenchymal stem cells and post-fracture healing in mice. SIGNIFICANCE OF THE STUDY: C3H10T1/2 cells showed the abilities of forming cloned differentiation of osteogenesis, fat cells and its phenotypes including CD44, CD90.1 and Sca-1 but excluding CD45 haematopoietic stem cell marker. Overexpression of miR-140-5p promoted the expressions of differentiation-related genes and calcium deposition of osteogenic medium-treated C3H10T1/2 cells. MiR-140-5p increased the expression of osteocalcin and bone mineral density and bone mass and promoted bone healing of miR-140-5p-transgenic mice with fracture. Our results showed that miR-140-5p promoted osteogenic differentiation of mouse embryonic bone marrow mesenchymal stem cells and post-fracture healing in mice, which may be a therapeutic target for treating fractures and promoting bone healing.

6.
J Am Acad Dermatol ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33031838

RESUMO

BACKGROUND: Observational studies have shown promising therapeutic effects of long-pulsed neodymium-doped yttrium aluminum garnet (LP-Nd:YAG) laser on warts. OBJECTIVE: To evaluate whether LP-Nd:YAG laser was superior to cryotherapy for cutaneous warts. METHODS: In this study, 150 adult patients with warts were randomized equally to receive laser or cryotherapy every 3-4 weeks, a maximum of 4 sessions. The primary outcomes were cure rate at 16 weeks and 6 months; secondary outcomes included time to clearance of warts and treatment-related adverse effects. RESULTS: There was no difference in the cure rate for laser versus cryotherapy at 16 weeks (54.1% vs. 46.7%) and 6 months (59.5% vs. 57.3%). However, time to clearance of warts, up to 16 weeks and 6 months, tended to be shorter for laser versus cryotherapy ( P = .04 and .08, respectively). Post-hoc analyses showed a significantly higher cure rate for laser versus cryotherapy in 3 subgroups of HPV 2/27/57-induced recalcitrant warts, but not in their counterpart subgroups. Laser had more mild adverse effects. LIMITATIONS: Single-center. CONCLUSIONS: The overall therapeutic effects of LP-Nd:YAG laser were similar to cryotherapy, but laser may be more effective to relatively recalcitrant warts and may associate with shorter time to clearance of warts.

7.
Phys Med Biol ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33032267

RESUMO

The coronavirus disease 2019 (COVID-19) is now a global pandemic. Tens of millions of people have been confirmed infection, and more people are suspected. Chest computed tomography (CT) is recognized as an important tool for COVID-19 severity assessment. As the number of chest CT images increase rapidly, manual severity assessment becomes a labor-intensive task, delaying appropriate isolation and treatment. In this paper, a study of automatic severity assessment for COVID-19 is presented. Specifically, chest CT images of 118 patients (age 46.5±16.5 years, 64 male and 54 female) with confirmed COVID-19 infection are used, from which 63 quantitative features and 110 Radiomics features are derived. Besides the chest CT image features, 36 laboratory indices of each patient are also used, which can provide complementary information from a different view. A random forest (RF) model is trained to assess the severity (non-severe or severe) according to the chest CT image features and laboratory indices. Importance of each chest CT image feature and laboratory index, which reflects the correlation to the severity of COVID-19, is also calculated from the RF model. Using three-fold cross-validation, the RF model shows promising results: 0.910 (true positive ratio), 0.858 (true negative ratio) and 0.890 (accuracy), along with AUC of 0.98. Moreover, several chest CT image features and laboratory indices are found to be important to COVID-19 severity, which could be valuable for the clinical diagnosis of COVID-19.

8.
Plant Physiol ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037128

RESUMO

Seed dormancy is an adaptive trait that is crucial to plant survival. Abscisic acid (ABA) is the primary phytohormone that induces seed dormancy. However, little is known about how the level of ABA in seeds is determined. Here we show that the Arabidopsis thaliana H3K27me3 demethylase RELATIVE OF EARLY FLOWERING 6 (REF6) suppresses seed dormancy by inducing ABA catabolism in seeds. Seeds of the ref6 loss-of-function mutants displayed enhanced dormancy that was associated with increased endogenous ABA content. We further show that the transcripts of two genes key to ABA catabolism, CYP707A1 and CYP707A3, but not genes involved in ABA biosynthesis, were significantly reduced in ref6 mutants during seed development and germination. In developing siliques, REF6 bound directly to CYP707A1 and CYP707A3, and was responsible for reducing their H3K27me3 levels. Genetic analysis demonstrated that the enhanced seed dormancy and ABA concentration in ref6 depended mainly on the reduced expression of CYP707A1 and CYP707A3. Conversely, overexpression of CYP707A1 could offset the enhanced seed dormancy of ref6. Taken together, our results revealed an epigenetic regulation mechanism that is involved in the regulation of ABA content in seeds.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33058942

RESUMO

Mammalian cells contain an elaborate network of organelles and molecular machines that orchestrate essential cellular processes. Visualization of this network at a molecular level is vital for understanding these cellular processes. Here we present a model system based on nerve growth factor (NGF)-differentiated PC12 cells (PC12+) and suitable for high resolution imaging of organelles and molecular machines in situ. We detail an optimized imaging pipeline that effectively combines correlative light and electron microscopy (CLEM), cryo-focused ion beam (cryo-FIB), cryo-electron tomography (cryo-ET), and sub-tomogram averaging to produce three-dimensional and molecular resolution snapshots of organelles and molecular machines in near-native cellular environments. Our studies demonstrate that cryo-ET imaging of PC12+ systems provides an accessible and highly efficient avenue for dissecting specific cellular processes in mammalian cells at high resolution.

10.
J Hazard Mater ; 404(Pt A): 124121, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33011633

RESUMO

Microplastics (MPs) can be easily taken up by a wide range of aquatic animals and cause blockage of the digestive tract leading to starvation. Meanwhile, aquatic organisms are facing threats posed by food restriction in both wild and cultured environment. Little knowledge, however, exists on how MPs interact with food conditions to affect aquatic animals. Here, koi carp were exposed to polystyrene MPs (0, 100 or 1000 µg/L) under controlled feeding (satiated or starved) for 30 or 60 days. MPs reduced and interacted synergistically with food conditions on growth after 30 days but antagonistically after 60 days. MPs reduced crude lipid and carbohydrate but increased and antagonistically interacted with feeding conditions on crude protein. Food conditions interacted with MPs on C, N and P but stoichiometric responses were decoupled with macromolecules changes. Food conditions antagonistically interacted with MPs on δ13C after 60 days. Linear discriminant analysis revealed that C:P and N:P were the two most important measured parameters accounting for the response of koi towards MPs and food restriction, presenting an antagonistic interaction of MPs and food status with the prolonged exposure duration.

11.
Sci Total Environ ; 755(Pt 2): 142606, 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33049530

RESUMO

Urban rainwater runoff is considered to be an important way to transport microplastics into the freshwater. By analyzing the microplastics in rainwater pipelines in different land function areas in Hongshan District (Wuhan, China), the preliminary results of microplastics abundance and characteristics in rainwater pipelines and rainwater pipeline sediments were obtained. The microplastics abundance in water samples was 2.75 ± 0.76 to 19.04 ± 2.96 items/L, the abundance of microplastics in the sediment was 6.00 ± 1.63 to 27.33 ± 4.64 items/100 g. The highest abundance among the samples was in the business district and the lowest in the campus. The microplastics in water samples and sediment samples were mainly fragments, accounting for 44.7% and 57.1%, respectively. The proportion of particle size <1 mm was 75.0% and above. The color of microplastics was diversified, and colored particles occupied over 60.0%. The types of polymers detected were mainly polyethylene, polypropylene and polyester, which were related to the types of polymers widely used in life. This study shows that urban rainwater pipelines is one of the ways for land-based microplastics to migrate to freshwater, and the accumulation of microplastics in stormwater pipe sediments might be an important contributor to microplastics in freshwater area.

12.
Wei Sheng Yan Jiu ; 49(5): 705-710, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33070809

RESUMO

OBJECTIVE: To explore the effect of pre-pregnancy weight and gestational weight gain in Chongqing City on birth weight of newborns. METHODS: Pregnant women were volunteered for the cohort study in 6 Maternal and Child Centers in Chongqing from January 2016 to June 2017, who were planning to be pregnant in latest 3 months. The basic information included height and weight of prepregnancy, first trimester, mid-trimester and third trimester of pregnancy, and pregnancy outcome were collected. ANOVA, chi square test and multi factor unconditional logistic regression model were used to analyze the data. RESULTS: In pre-pregnancy the major BMI of women were <18. 5(46. 74%, 1119/2394) and 18. 5≤BMI≤29. 99(47. 12%, 1128/2394), in first trimester of pregnancy, the figures were <18. 5(34. 46%, 825/2394) and 18. 5≤BMI≤29. 99(57. 77%, 1383/2394). The distribution BMI in above stages were statistically different(χ~2=74. 95, P<0. 01). The incidence of the low birth weight and macrosomia were 4. 51%(108/2394) and 6. 89%(165/2394). The average of neonatal birth weight, the low birth weight and macrosomia were statistically different(F=24. 18, P<0. 01) and(χ~2=66. 44, P<0. 01) comparisons among all prepregnancy BMI groups. The average birth weight of newborns, the low birth weight of the newborn and macrosomia were statistically different(F=11. 27, P<0. 01), and(χ~2=89. 53, P<0. 01) comparisons among all IOM groups of three stages of pregnancy. Low weight in pregnancy is the risk factor for low birth weight infants(RR=1. 90(95%CI 1. 27-2. 86)), while excessive gestational weight gain is the protective factor(RR=0. 66(95%CI 0. 46-0. 96)). Prepregnancy obesity(RR=3. 06(95%CI 1. 77-5. 31)) and excessive weight gain during pregnancy(RR=3. 60(95%CI 2. 48-5. 22)) were the risk factors for macrosomia. The above two factors, prepregnancy obesity and excessive weight gain during pregnancy interacted multiply. CONCLUSION: The figures of pre-pregnancy BMI are not equal to the BMI in first trimester of pregnancy. Low weight in pre-pregnancy is the risk factor for low birth weight infants, while excessive weight gain during pregnancy is the protective factor. Prepregnancy obesity and excessive weight gain during pregnancy are the risk factors for macrosomia. Prepregnancy obesity and excessive weight gain during pregnancy interacted multiply.


Assuntos
Ganho de Peso na Gestação , Peso ao Nascer , Índice de Massa Corporal , Criança , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Gravidez , Estudos Prospectivos
13.
Nucleic Acids Res ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33079992

RESUMO

Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides with little or no protein coding potential. The expanding list of lncRNAs and accumulating evidence of their functions in plants have necessitated the creation of a comprehensive database for lncRNA research. However, currently available plant lncRNA databases have some deficiencies, including the lack of lncRNA data from some model plants, uneven annotation standards, a lack of visualization for expression patterns, and the absence of epigenetic information. To overcome these problems, we upgraded our Plant Long noncoding RNA Database (PLncDB, http://plncdb.tobaccodb.org/), which was based on a uniform annotation pipeline. PLncDB V2.0 currently contains 1 246 372 lncRNAs for 80 plant species based on 13 834 RNA-Seq datasets, integrating lncRNA information from four other resources including EVLncRNAs, RNAcentral and etc. Expression patterns and epigenetic signals can be visualized using multiple tools (JBrowse, eFP Browser and EPexplorer). Targets and regulatory networks for lncRNAs are also provided for function exploration. In addition, PLncDB V2.0 is hierarchical and user-friendly and has five built-in search engines. We believe PLncDB V2.0 is useful for the plant lncRNA community and data mining studies and provides a comprehensive resource for data-driven lncRNA research in plants.

14.
iScience ; 23(9): 101536, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-33083765

RESUMO

A major hurdle in the treatment of cancer is chemoresistance induced under hypoxia that is characteristic of tumor microenvironment. Triptolide, a potent inhibitor of eukaryotic transcription, possesses potent antitumor activity. However, its clinical potential has been limited by toxicity and water solubility. To address those limitations of triptolide, we designed and synthesized glucose-triptolide conjugates (glutriptolides) and demonstrated their antitumor activity in vitro and in vivo. Herein, we identified a lead, glutriptolide-2 with an altered linker structure. Glutriptolide-2 possessed improved stability in human serum, greater selectivity toward cancer over normal cells, and increased potency against cancer cells. Glutriptolide-2 exhibits sustained antitumor activity, prolonging survival in a prostate cancer metastasis animal model. Importantly, we found that glutriptolide-2 was more potent against cancer cells under hypoxia than normoxia. Together, this work provides an attractive glutriptolide drug lead and suggests a viable strategy to overcome chemoresistance through conjugation of cytotoxic agents to glucose.

15.
Clin Interv Aging ; 15: 1809-1820, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061331

RESUMO

Objective: Our study aimed to explore the association between trimethylamine N-oxide and frailty in older adults with cardiovascular disease. Patients and Methods: This cross-sectional study analyzed a total of 451 people aged 65 years or older who underwent comprehensive geriatric assessments. Frailty status was determined using a frailty index constructed with 48 variables according to the cumulative deficits model. Physical frailty and cognitive frailty were also assessed in detail. Fasting plasma TMAO was measured by mass spectrometry. Results: The proportion of frail subjects was 29.9% (135/451). Plasma TMAO levels were significantly higher in frail patients than in nonfrail individuals (4.04 [2.84-7.01] vs 3.21 [2.13-5.03] µM; p<0.001). Elevated plasma TMAO levels were independently associated with the likelihood of frailty (OR 2.12, 95% CI 1.01-4.38, p=0.046). Dose-response analysis revealed a linear association between the TMAO concentration and the OR for frailty. A 2-unit increase in TMAO was independently correlated with physical frailty (OR 1.23, 95% CI 1.08-1.41, p for trend 0.002) and cognitive frailty (OR 1.21, 95% CI 1.01-1.45, p for trend 0.04). Conclusion: Elevated circulating TMAO levels are independently associated with frailty among older adults with cardiovascular disease.

16.
Cell Death Dis ; 11(10): 870, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067426

RESUMO

Recent studies have demonstrated that gastric cancer stem cells (CSCs) are a rare sub-group of gastric cancer (GC) cells and have an important role in promoting the tumor growth and progression of GC. In the present study, we demonstrated that the glycolytic enzyme Enolase 1 (ENO1) was involved in the regulation of the stem cell-like characteristics of GC cells, as compared to the parental cell lines PAMC-82 and SNU16, the expression of ENO1 in spheroids markedly increased. We then observed that ENO1 could enhance stem cell-like characteristics, including self-renewal capacity, cell invasion and migration, chemoresistance, and even the tumorigenicity of GC cells. ENO1 is known as an enzyme that is involved in glycolysis, but our results showed that ENO1 could markedly promote the glycolytic activity of cells. Furthermore, inhibiting glycolysis activity using 2-deoxy-D-glucose treatment significantly reduced the stemness of GC cells. Therefore, ENO1 could improve the stemness of CSCs by enhancing the cells' glycolysis. Subsequently, to further confirm our results, we found that the inhibition of ENO1 using AP-III-a4 (ENOblock) could reduce the stemness of GC cells to a similar extent as the knockdown of ENO1 by shRNA. Finally, increased expression of ENO1 was related to poor prognosis in GC patients. Taken together, our results demonstrated that ENO1 is a significant biomarker associated with the stemness of GC cells.

17.
J Int Med Res ; 48(10): 300060520931625, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33081551

RESUMO

PURPOSE: Our meta-analysis was undertaken to evaluate the efficacy and safety of nebivolol compared with other second-generation ß blockers for hypertensive patients. METHODS: We searched PubMed, the Cochrane Library, EMBASE, and Clinical Trials.gov databases for randomized controlled trials (RCTs). The efficacy endpoints included systolic blood pressure (SBP), diastolic blood pressure (DBP), reduction of SBP and DBP, heart rate (HR), and adverse events (AEs). FINDINGS: Eight RCTs with 1514 patients met the inclusion criteria. HR was significantly lower in patients receiving other second-generation ß blockers compared with patients receiving nebivolol. There was no difference the reduction of blood pressure (SBP and DBP) or the reduction of SBP or DBP between the groups. The incidence of AEs was lower in patients taking nebivolol compared with patients taking other second-generation ß blockers. CONCLUSIONS: No significant difference was demonstrated between nebivolol and other second-generation ß blockers in the reduction of blood pressure, SBP, and DBP. The tolerability of nebivolol was significantly better compared with other second-generation ß blockers, and nebivolol was also associated with a stable HR and a lower risk of AEs compared with other second-generation ß blockers.

18.
Cell Metab ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33086033

RESUMO

Tissue stem cells undergo premature senescence under stress, promoting age-related diseases; however, the associated mechanisms remain unclear. Here, we report that in response to radiation, oxidative stress, or bleomycin, the E3 ubiquitin ligase FBW7 mediates cell senescence and tissue fibrosis through telomere uncapping. FBW7 binding to telomere protection protein 1 (TPP1) facilitates TPP1 multisite polyubiquitination and accelerates degradation, triggering telomere uncapping and DNA damage response. Overexpressing TPP1 or inhibiting FBW7 by genetic ablation, epigenetic interference, or peptidomimetic telomere dysfunction inhibitor (TELODIN) reduces telomere uncapping and shortening, expanding the pulmonary alveolar AEC2 stem cell population in mice. TELODIN, synthesized from the seventh ß strand blade of FBW7 WD40 propeller domain, increases TPP1 stability, lung respiratory function, and resistance to senescence and fibrosis in animals chronically exposed to environmental stress. Our findings elucidate a pivotal mechanism underlying stress-induced pulmonary epithelial stem cell senescence and fibrosis, providing a framework for aging-related disorder interventions.

19.
Ann Surg ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33086319

RESUMO

BACKGROUND: Ventral hernia repair(VHR) is one of the most commonly performed procedures in the United States, but studies assessing the long-term outcomes of VHR using biologic mesh are scarce. OBJECTIVE: We sought to determine the rates of hernia recurrence(HR) and surgical site occurrences(SSOs) in a large cohort of patients who underwent AWR with biologic mesh. METHODS: We conducted a retrospective cohort study of patients who underwent AWR using either porcine ADM(PADM) or bovine ADM(BADM) from 2005 to 2019. We analyzed the full cohort and a subset of our population with minimum long-term follow-up(LTF) of 5 years. The primary outcome measure was HR. Secondary outcomes were SSOs. RESULTS: We identified a total of 725 AWRs (49.5% PADM, 50.5% BADM). Mean age was 69 ±â€Š11.5 years and mean body mass index was 31 ±â€Š7 kg/m. Forty-two percent of the defects were clean at the time of AWR, 44% were clean-contaminated, and 14% were contaminated/infected. Mean defect size was 180 ±â€Š174 cm, mean mesh size was 414 ±â€Š203 cm. Hernia recurred in 93 patients(13%), with cumulative HR rates of 4.9%, 13.5%, 17.3%, and 18.8% at 1, 3, 5, and 7 years, respectively. There were no differences in HR(p = 0.83) and SSO(p = 0.87) between the two mesh types. SSOs were identified in 27% of patients. In our LTF group (n = 162), the HR rate was 16%. Obesity, bridged repair, and concurrent stoma presence/creation were independent predictors of HR; component separation was protective against HR. CONCLUSIONS: Despite its use in complex AWR, ADM provides durable long-term outcomes with relatively low recurrence rates.

20.
Stat Med ; 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33086432

RESUMO

In an infectious disease cohort study, individuals who have been infected with a pathogen are often recruited for follow up. The period between infection and the onset of symptomatic disease, referred to as the incubation period, is of interest because of its importance on disease surveillance and control. However, the incubation period is often difficult to ascertain due to the uncertainty associated with asymptomatic infection onset time. An additional complication is that the observed infected subjects are likely to have longer incubation periods due to the prevalent sampling. In this article, we demonstrate how to estimate the distribution of the incubation period with the uncertain infection onset, subject to left-truncation and right-censoring. We employ a family of sufficiently general parametric models, the generalized odds-rate class of regression models, for the underlying incubation period and its correlation with covariates. In simulation studies, we assess the finite sample performance of the model fitting and hazard function estimation. The proposed method is illustrated on data from the HIV/AIDS study on injection drug users admitted to a detoxification program in Badalona, Spain.

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