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2.
J Cell Mol Med ; 2020 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-32207235

RESUMEN

Chemoresistance is the main obstacle of treatment in patients with osteosarcoma. RNA-binding protein PTBP1 has been identified as an oncogene in various cancers. However, the role of PTBP1 in osteosarcoma, especially in chemoresistant osteosarcoma, and the underlying mechanism remain unclear. In this study, we aimed to explore the functions of PTBP1 in chemoresistance of osteosarcoma. We found that PTBP1 was significantly increased in chemotherapeutically insensitive osteosarcoma tissues and cisplatin-resistant osteosarcoma cell lines (MG-63CISR and U-2OSCISR ) as compared to chemotherapy-sensitive osteosarcoma tissues and cell lines. Knock-down of PTBP1 can enhance the anti-proliferation and apoptosis-induced effects of cisplatin in MG-63CISR and U-2OSCISR cells. Moreover, PTBP1 knock-down significantly up-regulated the expression of the copper transporter SLC31A1, as indicated by transcriptome sequencing. Through RNA immunoprecipitation, dual-luciferase reporter assay and RNA stability detection, we confirmed that PTBP1 binds to SLC31A1 mRNA and regulates the expression level of SLC31A1 by affecting mRNA stability. Additionally, SLC31A1 silencing abrogated the chemosensitizing effect of PTBP1 knock-down in MG-63CISR and U-2OSCISR cells. Using a nude mouse xenograft model, we further confirmed that PTBP1 knock-down enhanced chemoresistant osteosarcoma responsiveness to cisplatin treatment in vivo. Collectively, the present study suggests that PTBP1 is a crucial determinant of chemoresistance in osteosarcoma.

3.
Genomics ; 2020 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-32209379

RESUMEN

Acinetobacter haemolyticus (A. haemolyticus) is a significant Acinetobacter pathogen, and the resistance of A. haemolyticus continues to rise due to abuse of antibiotics and the frequent gene exchange between bacteria in hospital. In this study, we performed complete genome sequencing of two A. haemolyticus strains TJR01 and TJS01 to improve our understanding of pathogenic and resistance of A. haemolyticus. Both TJR01 and TJS01 contain one chromosome and two plasmids. Compared to TJS01, more virulence factors (VFs) associated pathogenicity and resistant genes were predicted in TJR01 due to T4SS and integron associated with combination and transport. Antimicrobial susceptibility results were consistent with sequencing. We suppose TJS01 was a susceptive strain and TJR01 was an acquired multidrug resistance strain due to plasmid-mediated horizontal gene transfer. We hope these findings may be helpful for clinical treatment of A. haemolyticus infection and reduce the risk of potential outbreak infection.

4.
Fitoterapia ; 143: 104546, 2020 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-32173423

RESUMEN

Eight new compounds (Entanutilins O-V; 1-8), including four limonoids, two steroids, one triterpenoid and one lignan were isolated from the stem barks of Entandrophragma utile. Their structures were determined by detailed spectroscopic analyses (HRESIMS and 1D/2D-NMR). Bioactivity screening indicated that compounds 1, 6 and 7 exhibited effective in reversing resistance in MCF-7/DOX cells at a nontoxic concentration of 30 µM with 18.18-, 7.43- and 7.94-fold enhancing effect, respectively, meanwhile, compounds 5 and 6 showed moderate NO inhibitory activities in LPS-activated RAW 264.7 macrophages.

6.
Orthop Surg ; 2020 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-32167673

RESUMEN

OBJECTIVE: To measure the factors that affect functional leg length of Crowe type IV Developmental dysplasia of the hip (DDH) patients and to review our own methods to balance leg length discrepancy (LLD) in Crowe type IV DDH patients. METHODS: This was a prospective observational study which started in June 2017 and ended in August 2019. Inclusion criteria included: (i) Crowe type I or Crowe type IV hip dysplasia patients who underwent total hip arthroplasty (THA) in the Department of Orthopaedics at our institution between July 2017 and June 2018; (ii) the patients were treated with our specific leg length balance strategy; and (iii) the related outcomes of patients were completely recorded. Finally, 18 consecutive Crowe type I patients (20 hips) and 14 consecutive Crowe type IV patients (18 hips) were selected and divided into two groups according to Crowe types. All patients received THA, and patients with a longer affected side and inferior anatomical acetabular positions in Crowe type IV group also received subtrochanteric osteotomy. During operation and after hip reduction, leg lengths were compared while two legs were in an extended position and the operative leg was on top of the non-operative one. Additional leg length adjustment was applied when leg length was considered to be unequal. Prior to surgery, subluxation height of the femoral head on the affected side, functional LLD, bony length of lower limbs, and distance from teardrops to the lowest point line of the sacroiliac joint were recorded. After surgery, cup sizes, functional LLD, and height of hip rotational centers were measured. Clinical evaluations, such as Harris Hip Score (HHS) and SF-12 scale, were also obtained before and after surgery for all patients. RESULTS: At the last follow-up, functional LLD and clinical measurements of both Crowe type IV group and Crowe type I group were significantly improved. Compared with Crowe type I patients, Crowe type IV patients had a significantly lower MCS, a significantly longer leg lengthening length and a significantly lower hip center height after surgery. Significant differences of tibia length, leg length, and teardrop position were found between affected side and healthy side of Crowe type IV patients. Only three of 14 Crowe type IV patients remained under 1 cm functional LLD. Five patients in the Crowe type IV group developed lower limb numbness immediately following surgery, and they all recovered within 6 months. The average follow-up period for either group was 14 months, and all patients were followed-up at 1, 3, 6, and 12 months then yearly after surgery until the final follow-up. CONCLUSION: After detailed leg length balance process, THA combined with transverse sub-trochanter osteotomy could be an effective method to achieve equal function leg length with most Crowe type IV patients.

7.
Biotechnol J ; : e1900430, 2020 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-32170989

RESUMEN

Cyclin D1 is a key regulatory factor of the G1 to S transition during cell cycle progression. Aberrant cyclin D gene amplification and abnormal protein expression have been linked to hepatocellular carcinoma (HCC) tumorigenesis, warranting evaluation of cyclin D1 as a therapeutic target. Intrabodies, effective anti-cancer therapies that specifically inhibit target protein function within all intracellular compartments, may block cyclin D1 function. Here, a single-chain variable fragment (scFv) antibody against cyclin D1 (ADκ) selected from a human semi-synthetic phage display scFv library was expressed in Escherichia coli as soluble ADκ. Purified ADκ specifically bound to recombinant and endogenous cyclin D1 with high affinity. To enable blocking of intracellular cyclin D1 activity, an endoplasmic reticulum (ER) retention signal sequence was added to the ADκ sequence to encode anti-cyclin D1 intrabody ER-ADκ. Transfection of HepG2 cells with expression vector encoding ER-ADκ elicited intracellular ER-ADκ expression leading to cyclin D1 binding, significant G1 phase arrest, and apoptosis that were mechanistically tied to decreased intracellular phosphorylated retinoblastoma protein (Rb) levels. Meanwhile, ER-ADκ dramatically inhibited subcutaneous human HCC xenografts growth in nude mice in vivo after injection of tumors with expression vector encoding ER-ADκ. These results demonstrate the potential of intrabody-based cyclin D1 targeting therapy as a promising treatment for HCC. This article is protected by copyright. All rights reserved.

9.
Cell Rep ; 30(11): 3717-3728.e6, 2020 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-32187544

RESUMEN

Understanding the mechanisms of activity-dependent gene transcription underlying adaptive behaviors is challenging at neuronal-subtype resolution. Using cell-type specific molecular analysis in agouti-related peptide (AgRP) neurons, we reveal that the profound hunger-induced transcriptional changes greatly depend on plant homeodomain finger protein 6 (PHF6), a transcriptional repressor enriched in AgRP neurons. Loss of PHF6 in the satiated mice results in a hunger-state-shifting transcriptional profile, while hunger fails to further induce a rapid and robust activity-dependent gene transcription in PHF6-deficient AgRP neurons. We reveal that PHF6 binds to the promoters of a subset of immediate-early genes (IEGs) and that this chromatin binding is dynamically regulated by hunger state. Depletion of PHF6 decreases hunger-driven feeding motivation and makes the mice resistant to body weight gain under repetitive fasting-refeeding conditions. Our work identifies a neuronal subtype-specific transcriptional repressor that modulates transcriptional profiles in different nutritional states and enables adaptive eating behavior.

10.
Neurol Sci ; 2020 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-32185625

RESUMEN

L-3,4-dihydroxyphenylalanine (L-DOPA) was introduced about half a century ago and is still the most effective medicine for the treatment of Parkinson's disease (PD). However, such chronic treatment eventually leads to L-DOPA-induced dyskinesia (LID) on the majority of PD patients. Besides L-DOPA, dopamine agonists are able to induce dyskinesia as well. So far no drug is yet claimed to effectively curb LID, and amantadine has only a modest benefit on LID patients. Thus, understanding the molecular mechanisms behind LID is urgently needed, and developing new antiparkinsonian medications with low dyskinesia potential is necessarily required. In the last decades, several animal models have been generated for these aims. 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-lesioned monkey models always considered as gold standard of PD studies are also applied well for the research of LID. Additionally, several rodent models were developed for such clinical needs. Of them, 6-hydroxydopamine (OHDA)-lesioned rats or mice exhibiting countable abnormal involuntary movements (AIMs) after L-DOPA treatments have becoming widely applicable tools for LID pathogenesis studies. Under investigating these models for years, multiple potential LID-associated genes and pathways have been innovatively identified, which largely advance the therapeutic and preventative strategies for the disease. In this review, we attempt to update the recent findings represented in LID animal models and trial studies, which may facilitate the mechanistic understanding, drug development, and clinical evaluation of this movement disorder.

14.
J Biol Chem ; 295(11): 3734-3745, 2020 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-32005667

RESUMEN

Most of Gram-positive bacteria anchor surface proteins to the peptidoglycan cell wall by sortase, a cysteine transpeptidase that targets proteins displaying a cell wall sorting signal. Unlike other bacteria, Clostridium difficile, the major human pathogen responsible for antibiotic-associated diarrhea, has only a single functional sortase (SrtB). Sortase's vital importance in bacterial virulence has been long recognized, and C. difficile sortase B (Cd-SrtB) has become an attractive therapeutic target for managing C. difficile infection. A better understanding of the molecular activity of Cd-SrtB may help spur the development of effective agents against C. difficile infection. In this study, using site-directed mutagenesis, biochemical and biophysical tools, LC-MS/MS, and crystallographic analyses, we identified key residues essential for Cd-SrtB catalysis and substrate recognition. To the best of our knowledge, we report the first evidence that a conserved serine residue near the active site participates in the catalytic activity of Cd-SrtB and also SrtB from Staphylococcus aureus The serine residue indispensable for SrtB activity may be involved in stabilizing a thioacyl-enzyme intermediate because it is neither a nucleophilic residue nor a substrate-interacting residue, based on the LC-MS/MS data and available structural models of SrtB-substrate complexes. Furthermore, we also demonstrated that residues 163-168 located on the ß6/ß7 loop of Cd-SrtB dominate specific recognition of the peptide substrate PPKTG. The results of this work reveal key residues with roles in catalysis and substrate specificity of Cd-SrtB.

15.
J Hazard Mater ; 391: 122205, 2020 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-32045805

RESUMEN

Up to now, the environmental damage by heavy metal is getting worse and worse as the development of industry. Meanwhile, hexavalent chromium (Cr(VI)) in wastewater get special attention as its acute toxicity and potential carcinogencity. To solve this problem, we introduce a simple and efficient way to prepare a photocatalyst, ZnIn2S4 grown on nitrogen-doped hollow carbon spheres (ZIS-NHC), which is an effective catalyst that can used to reduce aqueous Cr(VI). This photocatalyst prepared by a three-step strategy. Benefiting from the excellent electrical conductivity and high specific surface area of the NHC which is superior to other carbon material and the favorable band gap of ZnIn2S4 makes ZIS-NHC has superior light-driven photocatalytic efficiency. The ZIS-NHC exhibits an excellent rate of degradation of aqueous Cr(VI) at a concentration of 50 mg/L within 50 min. Moreover, the ZIS-NHC retained excellent stability after five rounds of cycling experiments which was also discussed.

16.
Sleep Med ; 69: 71-77, 2020 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-32058229

RESUMEN

OBJECTIVE: The association between sleep duration and general and abdominal obesity in adults, especially in the rural Chinese population, remains unclear. Therefore, we conducted this study to evaluate the association between sleep duration and general and abdominal obesity in rural Chinese adults. METHODS: We included 12,446 adults aged 18-75 years old who completed a baseline examination during 2007-2008 and follow-up during 2013-2014. We prospectively investigated the sleep-obesity association over an average of six-year follow-up. Multivariable logistic regression was performed to assess the probability of new-onset general and abdominal obesity, estimating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: As compared with sleep duration 6.5-7.5 h, short sleep duration (<6.5 h) was significantly associated with increased probability of abdominal obesity in men (OR = 1.60, 95% CI: 1.05-2.45) after controlling for multiple covariates. A similar association was found in men aged >60 years but not in women or in men ≤60 years. We found no significant association between sleep duration and general obesity. The results were consistent when restricting the analysis to participants without cardiovascular disease, type 2 diabetes mellitus or cancer at baseline. CONCLUSIONS: Short sleep duration was significantly associated with abdominal obesity in rural Chinese adults, and the association varied by sex and age.

17.
Phys Chem Chem Phys ; 22(12): 6528-6537, 2020 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-32091071

RESUMEN

α-Pinene, the most abundant monoterpene in the atmosphere, accounts for more than 50% of global monoterpene emission. Though its reaction with ozone has been generally perceived as a major source of secondary organic aerosols (SOAs), direct evidence of its reaction intermediates (RI) and their evolution remain lacking. Here we study the ozonolysis of α-pinene between 180 and 298 K using a long-path, temperature-variable aerosol cooling chamber coupled to a rapid-scan time-resolved Fourier transform infrared spectrometer. The spectroscopic signatures of large Criegee intermediates (CIs) and hydroperoxides (HPs) were found for the first time. The aerosol size evolution during the reaction was also measured. In contrast to a previous perception, we show that temperature plays a determinant role in the ozonolysis kinetics. Finally, we show that the formation of HPs is an energetically favorable pathway to dissipate CIs. This study provides new insights into the ozonolysis of α-pinene and its contribution to SOA formation.

18.
Sci Rep ; 10(1): 3032, 2020 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-32080235

RESUMEN

The vaccine elicitation of broadly neutralizing antibodies against HIV-1 is a long-sought goal. We previously reported the amino-terminal eight residues of the HIV-1-fusion peptide (FP8) - when conjugated to the carrier protein, keyhole limpet hemocyanin (KLH) - to be capable of inducing broadly neutralizing responses against HIV-1 in animal models. However, KLH is a multi-subunit particle derived from a natural source, and its manufacture as a clinical product remains a challenge. Here we report the preclinical development of recombinant tetanus toxoid heavy chain fragment (rTTHC) linked to FP8 (FP8-rTTHC) as a suitable FP-conjugate vaccine immunogen. We assessed 16 conjugates, made by coupling the 4 most prevalent FP8 sequences with 4 carrier proteins: the aforementioned KLH and rTTHC; the H. influenzae protein D (HiD); and the cross-reactive material from diphtheria toxin (CRM197). While each of the 16 FP8-carrier conjugates could elicit HIV-1-neutralizing responses, rTTHC conjugates induced higher FP-directed responses overall. A Sulfo-SIAB linker yielded superior results over an SM(PEG)2 linker but combinations of carriers, conjugation ratio of peptide to carrier, or choice of adjuvant (Adjuplex or Alum) did not significantly impact elicited FP-directed neutralizing responses in mice. Overall, SIAB-linked FP8-rTTHC appears to be a promising vaccine candidate for advancing to clinical assessment.

19.
J Orthop Translat ; 21: 81-90, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32110507

RESUMEN

Background: Biodegradable suture anchors are commonly used for repairing torn rotator cuffs, but these biodegradable materials still suffer from low mechanical strength, poor osteointegration, and the generation of acidic degradation byproducts. Method: The purpose of this study was to evaluate the long-term mechanical behavior and osteogenetic capabilities of a biocomposite anchor injection molded with 30% ß-tricalcium phosphate microparticles blended with 70% poly (L-lactide-co-glycolide) (85/15). This study investigated in vitro degradation and in vivo bone formation in a canine model. The initial mechanical behavior, mechanical strength retention with degradation time, and degradation features were investigated. Results: The results showed that the biocomposite anchor had sufficient initial mechanical stability confirmed by comparing the initial shear load on the anchor with the minimum shear load borne by an ankle fracture fixation screw, which is considered a worst-case implantation site for mechanical loading. The maximum shear load retention of the biocomposite anchor was 83% at 12 weeks, which is desirable, as it aligns with the rate of bone healing. The ß-tricalcium phosphate fillers were evenly dispersed in the polymeric matrix and acted to slow the degradation rate and improve the mechanical strength of the anchor. The interface characteristics between the ß-tricalcium phosphate particles and the polymeric matrix changed the degradation behavior of the biocomposite. Phosphate buffer saline was shown to diffuse through the interface into the biocomposite to inhibit the core accelerated degradation rate. In vivo, the addition of ß-tricalcium phosphate induced new bone formation. The biocomposite material developed in this study demonstrated improved osteogenesis in comparison to a plain poly (L-lactide-co-glycolide) material. Neither anchor produced adverse tissue reactions, indicating that the biocomposite had favorable biocompatibility following long-term implantation. Conclusion: In summary, the new biocomposite anchor presented in this study had favorable osteogenetic capability, mechanical property, and controlled degradation rate for bone fixation. Translational potential of this article: The new biocomposite anchor had sufficient initial and long-term fixation stability and bone formation capability in the canine model. It is indicated that the new biocomposite anchor has a â€‹potential for orthopedic application.

20.
Medicine (Baltimore) ; 99(7): e18763, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32049782

RESUMEN

RATIONALE: Warthin's tumor is the second most common tumor arising from the parotid gland, but it rarely occurs concomitantly with tuberculous granulomatous inflammation with only 13 documented case reports in the English literature. PATIENT CONCERNS: An 82-year-old woman had a left infraauricular mass for approximately 3 years that had significantly increased in size over the previous 1 month. DIAGNOSES: A diagnosis of Warthin's tumor was made by ultrasonography (US)-guided core needle biopsy. Pathological examinations of the specimen obtained by total extirpation confirmed that the tumor was superimposed with tuberculous granuloma. INTERVENTIONS: The core biopsy wound did not heal and there was formation of a skin fistula tract with persistent discharge. During the operation with en bloc resection of the necrotic parotid tumor, adhesion between the branches of the facial nerve was too tight to allow preservation. OUTCOMES: A diagnosis of necrotic Warthin's tumor superimposed with tuberculous granuloma was made. Due to the high-clinical suspicion of tuberculosis (TB) due to Mycobacterium tuberculosis infection, anti-TB chemotherapy was given. LESSONS: Poor wound healing from a core biopsy and formation of a skin fistulous tract with persistent discharge should raise concern regarding potential extrapulmonary tuberculous infection. Although very rare, tuberculous granuloma concomitant with Warthin's tumor should be considered in the differential diagnosis of a parotid mass lesion. Adhesion of branches of the facial nerve should be expected, and sacrifice of the nerve may be planned. This consideration can be explained to the patient in preoperative counseling and planning. Anti-TB chemotherapy should be given in cases with a definite pathological report associated with speculative clinical presentation.


Asunto(s)
Adenolinfoma/etiología , Biopsia con Aguja Gruesa/efectos adversos , Granuloma/diagnóstico , Neoplasias de la Parótida/cirugía , Tuberculoma/diagnóstico , Anciano de 80 o más Años , Antituberculosos/uso terapéutico , Nervio Facial , Femenino , Granuloma/tratamiento farmacológico , Granuloma/patología , Humanos , Neoplasias de la Parótida/etiología , Neoplasias de la Parótida/patología , Adherencias Tisulares , Resultado del Tratamiento , Tuberculoma/tratamiento farmacológico , Tuberculoma/patología , Ultrasonografía
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