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1.
Commun Biol ; 4(1): 484, 2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33875784

RESUMO

Genomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer. Here we outline a previously undescribed role of COMMD4 in maintaining genomic stability, by regulation of chromatin remodelling at sites of DNA double-strand breaks. At break-sites, COMMD4 binds to and protects histone H2B from monoubiquitination by RNF20/RNF40. DNA damage-induced phosphorylation of the H2A-H2B heterodimer disrupts the dimer allowing COMMD4 to preferentially bind H2A. Displacement of COMMD4 from H2B allows RNF20/40 to monoubiquitinate H2B and for remodelling of the break-site. Consistent with this critical function, COMMD4-deficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous-end-joining and homologous recombination. We present peptide-mapping and mutagenesis data for the potential molecular mechanisms governing COMMD4-mediated chromatin regulation at DNA double-strand breaks.

2.
Brain Res Bull ; 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33892085

RESUMO

CIP2A is an oncoprotein that is overexpressed in multiple solid tumours and some malignant haematologic disorders. However, its function in glioma is poorly understood. In this study, our results demonstrated that the expression of CIP2A was higher in glioma tissues than in normal tissues. Using tissue microarrays for immunohistochemistry, we found that the intensity of CIP2A expression was higher in high-grade gliomas (grade III-IV) than in low-grade gliomas (grade I-II). In addition, we found that depletion of CIP2A inhibited glioma cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in vitro. Taken together, our findings revealed that CIP2A was involved in glioma progression, indicating that CIP2A could be used as a potential therapeutic target in the future.

3.
Sci Rep ; 11(1): 7434, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795785

RESUMO

We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.

4.
World Neurosurg ; 149: e116-e127, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33631390

RESUMO

OBJECTIVE: No previous large population-based studies of traumatic spinal injury (TSI) rates, trends, and patterns exist. We aimed to fill this knowledge gap on TSI epidemiology using a population-based study of 13 million people. METHODS: This is a descriptive cross-sectional cohort study that analyzes a national, mandatory reporting database for all emergency departments and ambulatory care centers in Ontario over 15 years. Demographics of TSI, trends in the TSI rate, etiology, transfer, disposition, comorbidities, and associated traumatic brain injury or spinal cord injury were analyzed. RESULTS: There were 167,357 TSI-related emergency department visits resulting in 70,684 hospitalizations and 376 deaths. The overall rate of TSI significantly increased from 66.94 to 118.61 per 100,000. Female patients had greater rates of TSI. Older patients had greater rates of TSI, especially related to falls. Fall was found to be the commonest mechanism of TSI, whereas motor vehicle collisions scaled down to the third commonest mechanism of TSI. Sport-related TSI had the greatest percentage of increase in the rate over all mechanisms (221%, P < 0.001). TSI with associated traumatic brain injury comprised 6% of the cohort but had the greatest percentage increase (91%) in the rate compared to all other TSI forms. CONCLUSIONS: The rate of TSI continues to rise in Ontario as the population ages. The rise is primarily attributed to a shift in the epidemiology and etiology of TSI from a younger male population toward an older female population, with falls as the primary injury mechanism. Establishing preventive measures to address this shift is essential.

5.
Langmuir ; 37(6): 2187-2194, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33528259

RESUMO

Microfluidic technology has aroused wide applications, including analytical science, diagnostic technology, and micro-/nanofabrication. However, bubbles in microfluidic channels always bring out adverse impacts such as cell damage and device malfunction. To prevent bubble formation, numerical simulation and experiments were integrated to reveal the effect of the factors including the internal structure of the channel, internal wettability, and liquid flow rate. On one hand, the simulation results reveal that bubble formation can be prevented by these mentioned factors, the weight of which can be provided by a logistic regression model. In addition, the raised equilibrium equations can efficiently explain the influence of these factors on bubble prevention. On the other hand, the validity of the simulation was further verified by the prevention of bubbles in the water-flowing microchannels. Therefore, this work provides a promising strategy to prevent bubble formation in microchannels, which has wide applications in microfluidic systems.

6.
Clin Exp Rheumatol ; 39(2): 385-392, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33427622

RESUMO

OBJECTIVES: Predicting response to anti-tumour necrosis factor alpha (anti-TNFα) drugs at baseline remains an elusive goal in rheumatoid arthritis (RA) management. The purpose of this study was to determine if baseline genetic variants of PTPRC, AFF3, myD228, CHUK, MTHFR1, MTHFR2, CD226 and a number of KIR and HLA alleles could predict response to anti-TNF-α in rheumatoid arthritis patients. METHODS: Peripheral blood samples were collected from 238 RA patients treated with anti-TNFα drugs. Genotyping was performed using biochip array technology by Randox Laboratories Ltd. and sequence specific polymerase chain reaction. Linear regression analysis was performed to investigate the role of these genotypes in predicting response to treatment, as defined by European League Against Rheumatism (EULAR) response classification and absolute change in disease activity score (DAS28). RESULTS: Of 238 RA patients analysed, 50.4% received adalimumab, 29.7% received etanercept, 14.8% received infliximab, 3.4% certoluzimab and 1.7% golimumab. The MTHFR1 variant rs1801133 was significantly associated with the EULAR response, p=0.044. Patients with the HLA-DRB1*0404 allele displayed a significantly larger reduction in DAS28 compared to non-carriers (mean -2.22, -1.67 respectively, p=0.033). CD226 rs763361 was the only SNP variant significantly associated with ΔDAS28 (p=0.029). CONCLUSIONS: This study has investigated individual allele associations with reductions in DAS28 across a range of anti-TNFα treatments. A combined predictive model indicates that patients with the HLA-DRB1*0404 allele and without the CD226 rs763361 polymorphism exhibit the largest reduction in DAS28 after anti-TNF-α treatment.


Assuntos
Antirreumáticos , Artrite Reumatoide , Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Etanercepte/uso terapêutico , Cadeias HLA-DRB1/genética , Haplótipos , Humanos , Infliximab/uso terapêutico , Resultado do Tratamento , Fator de Necrose Tumoral alfa/genética
7.
Anal Chem ; 93(3): 1515-1522, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33356146

RESUMO

Trans-interfacial behaviors of multiple ionic species at the interface between two immiscible electrolyte solutions (ITIES) are of importance to biomembrane mimicking, chemical and biosensing, and interfacial molecular catalysis. Utilizing host-guest interaction to facilitate ion transfer is an effective and commonly used method to decrease the Gibbs energy of transfer of a target molecule. Herein, we investigated a facilitated ion transfer (FIT) process of poly(amidoamine)dendrimer (PAMAM, G0-G2) by dibenzo-18-crown-6 (DB18C6) at the microinterfaces between water and 1,2-dichloroethane (µ-W/DCE). Because of the host-guest interaction between a dendrimer and a ligand, negative shifts of the transfer potentials were observed using cyclic voltammetry or Osteryoung square wave voltammetry. From the FIT behavior of the dendrimer, we revealed that each DB18C6 could selectively coordinate with one amino group. We first evaluated the protonated status of the intermediate state (1:2) exactly under the conditions the dendrimer (G1) transfers across the interface using the electrochemical mass spectrometry (EC-MS)-hyphenated technique, which is much smaller than the protonated status in the water phase (1:8 to 14). Using the same methodology, we also studied the facilitated transfer behaviors of G0 and G2. Based on these results, we put forward the mechanism of the FIT process, which might involve a deprotonating process at the interface for higher-generation dendrimers.

8.
Asian J Surg ; 44(4): 641-648, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33341336

RESUMO

OBJECTIVE: To compare the operation complexity and prognosis of completely laparoscopic versus open radical nephrectomy and infrahepatic tumor thrombectomy. METHODS: We reviewed and analyzed the clinical data of 87 patients with infrahepatic tumor thrombus from January 2015 to April 2019 retrospectively. Completely laparoscopic infrahepatic tumor thrombectomy was completed in 41 cases, and open surgery was completed in 46 cases. RESULTS: All 41 patients successfully completed laparoscopic operation, and there were no cases of death during the operation. The completely laparoscopic group were older, had smaller renal tumor diameter, shorter median operation time, lower median intraoperative hemorrhage volume, and lower median transfusion volume of suspended red blood cells compared with open surgeries. The proportion of low-level tumor thrombus (Mayo I) in the completely laparoscopic group was higher (63.4%), while the proportion of low-level tumor thrombus in the open surgery group was lower (30.4%) (P = 0.002). The postoperative complications incidence of laparoscopic surgery was 19.5%, which was lower than that of open surgery (47.8%) (P = 0.004). The mean cancer-specific survival time of the laparoscopic surgery group was 36.6 ± 2.5 months, while that of the open surgery group was 32.3 ± 2.7 months (P = 0.277). There was no statistical difference between the two groups. CONCLUSION: Although completely laparoscopic radical nephrectomy and infrahepatic tumor thrombectomy is a challenging operation, it could be feasible and safely performed, especially in the hands of highly-experienced laparoscopic urologists for well selected cases.

9.
Sci Rep ; 10(1): 21089, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33273485

RESUMO

Rheumatoid arthritis (RA) is characterised by painful, stiff and swollen joints. RA features sporadic 'flares' or inflammatory episodes-mostly occurring outside clinics-where symptoms worsen and plasma C-reactive protein (CRP) becomes elevated. Poor control of inflammation results in higher rates of irreversible joint damage, increased disability, and poorer quality of life. Flares need to be accurately identified and managed. A method comparison study was designed to assess agreement between CRP values obtained by dried blood spot (DBS) versus conventional venepuncture sampling. The ability of a weekly DBS sampling and CRP test regime to detect flare outside the clinic was also assessed. Matched venepuncture and finger lancet DBS samples were collected from n = 100 RA patients with active disease at baseline and 6 weeks (NCT02809547). A subset of n = 30 RA patients submitted weekly DBS samples over the study period. Patient demographics, including self-reported flares were recorded. DBS sample CRP measurements were made by enzyme-linked immunosorbent assay, and venepuncture samples by a reference immunoturbometric assay. Data was compared between sample types by Bland-Altman and weighted Deming regression analyses. Flare detection sensitivity and specificity were compared between 'minimal' baseline and 6 week sample CRP data and the 'continuous' weekly CRP data. Baseline DBS ELISA assay CRP measures yielded a mean positive bias of 2.693 ± 8.640 (95% limits of agreement - 14.24 to 19.63%), when compared to reference assay data. Deming regression revealed good agreement between the DBS ELISA method and reference assay data, with baseline data slope of 0.978 and intercept -0.153. The specificity of 'continuous' area under the curve (AUC) CRP data (72.7%) to identify flares, was greater than 'minimal' AUC CRP data (54.5%). This study indicates reasonable agreement between DBS and the reference method, especially at low to mid-range CRP values. Importantly, longitudinal CRP measurement in RA patients helps to clearly identify flare and thus could assist in remote monitoring strategies and may facilitate timely therapeutic intervention.Trial registration: The Remote Arthritis Disease Activity MonitoR (RADAR) study was registered on 22/06/2016 at ClinicalTrials.gov Identifier: NCT02809547. https://clinicaltrials.gov/ct2/show/NCT02809547 .

10.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(12): 1313-1319, 2020 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-33328003

RESUMO

OBJECTIVE: To study the percentage of the measured values of the main pulmonary ventilation function parameters in their predicted values based on Zapletal equation among healthy children aged 5-14 years in Kunming, China, and to provide a basis for accurate judgment of pulmonary ventilation function in clinical practice. METHODS: A total of 702 healthy children aged 5-14 years (352 boys and 350 girls) from Kunming were enrolled. The Jaeger spirometer was used to measure the nine indices:forced vital capacity (FVC), forced expiratory volume in one second (FEV1), ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC), maximal mid-expiratory flow (MMEF), forced expiratory flow at 25% of forced vital capacity (FEF25), forced expiratory flow at 50% of forced vital capacity (FEF50), forced expiratory flow at 75% of forced vital capacity (FEF75), peak expiratory flow (PEF), and maximal voluntary ventilation (MVV). The values obtained from the Zapletal equation of predicted values provided by the spirometer were used as the predicted values of children, and the percentage of measured values in predicted values was calculated. RESULTS: In the 702 children, the percentages of the measured values of the main pulmonary ventilation function parameters PEF, FVC, FEV1, FEV1/FVC, and MVV in their predicted values fluctuated from 102% to 114%, 94% to 108%, 98% to 113%, 98% to 107%, and 141% to 183% respectively. As for the main airway velocity parameters, the percentages of the measured values of FEF25, FEF50, FEF75, and MMEF in their predicted values fluctuated from 98% to 116%, 85% to 102%, 71% to 98%, and 83% to 100% respectively. The percentages of the measured values of PEF, FVC, FEV1, FEV1/FVC, MVV, FEF25, FEF50, FEF75, and MMEF in their predicted values had the lower limits of normal of 88.2%, 88.4%, 92.0%, 94.4%, 118.5%, 82.9%, 70.0%, 62.1%, and 70.1% respectively. CONCLUSIONS: There are differences between pulmonary ventilation function parameter levels and normal values provided by Zapletal equation in healthy children aged 5-14 years in Kunming. As for the pulmonary ventilation function parameters of PEF, FVC, FEV, FEV1/FVC, MVV, FEF25, FEF50, FEF75, and MMEF in these children, the lower limits of normal of measured values in predicted values may be determined as 88.2%, 88.4%, 92.0%, 94.4%, 118.5%, 82.9%, 70.0%, 62.1%, and 70.1% respectively.


Assuntos
Pulmão/fisiologia , Ventilação Pulmonar , Adolescente , Criança , Pré-Escolar , China , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Valores de Referência , Capacidade Vital
11.
J Orthop Res ; 2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33382130

RESUMO

Receptor activator of nuclear factor kappa-B ligand (RANKL) is one of the key factors regulating the maturation of osteoclasts and an important target for osteoporosis treatment. A monoclonal antibody against RANKL showed effective therapeutic activity against osteoporosis by inhibiting bone resorption by osteoclasts. However, being an exogenous protein, its efficacy decreases after long-term use, and its discontinuation increases the risk of vertebral fractures. Here, we aimed to design an active immunotherapeutic agent to induce a T-cell dependent primary response. The agent, a mutant RANKL vaccine (mRv), was produced by cross-linking mutant RANKL, lacking the ability to stimulate osteoclast maturation, with the carrier protein keyhole limpet hemocyanin, a neo-antigen with a large molecular mass. Subcutaneous injection of mRv stimulated rats with ovariectomy-induced osteoporosis to produce high titers of anti-RANKL antibodies. The mutant RANKL vaccine decreased serum CTX-1 and BALP levels and inhibited the microstructural degeneration of trabecular bone in osteoporotic rats. mRv overcame immune system tolerance, stimulated rats to produce therapeutic antibodies, stabilized bone metabolism, and inhibited trabecular microstructural degeneration. These findings confirm the potential of the mutant RANKL vaccine to be developed into an effective preventive and therapeutic agent for osteoporosis.

12.
J Mater Chem B ; 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33226396

RESUMO

Pore-forming toxins (PFTs), the most common virulence proteins, are promising therapeutic keys in bacterial infections. CAL02, consisting of sphingomyelin (Sm) and containing a maximum ratio of cholesterol (Ch), has been applied to sequester PFTs. However, Sm, a saturated phospholipid, leads to structural rigidity of the liposome, which does not benefit PFT combination. Therefore, in order to decrease the membrane rigidity and improve the fluidity of liposomes, we have introduced an unsaturated phospholipid, phosphatidylcholine (Pc), to the saturated Sm. In this report, a soft nanoliposome (called CSPL), composed of Ch, Sm and Pc, was artificially prepared. In order to further improve its antibacterial effect, vancomycin (Van) was loaded into the hydrophilic core of CSPL, where Van can be released radically at the infectious site through transmembrane pores formed by the PFTs in CSPL. This soft Van@CSPL nanoliposome with detoxification/drug release was able to inhibit the possibility of antibiotic resistance and could play a better role in treating severe invasive infections in mice.

13.
Vaccine ; 38(49): 7842-7849, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33164806

RESUMO

The poultry red mite (PRM), Dermanyssus gallinae, is a hematophagous ectoparasite considered as the major pest in the egg-laying industry. Vaccination is feasible strategy for controlling the haematophagous PRMs. Cathepsin D (CatD), cathepsin L (CatL) and legumain (Lgm) are three endopeptidases participating in digestion of hemoglobin in ticks. The in vitro test and the on-hen feeding device have been used to evaluate the efficacy of vaccines against D. gallinae, however they lacked some of the natural feeding cues for mites, resulting in unreliable results. In the present study, a reliable in vivo rearing system which was nearly close to the natural infestation status of mites was applied to evaluate the efficacy of vaccines against D. gallinae. After vaccinations with rDg-CatD-1, rDg-CatL-1 or rDg-Lgm, chicks developed the antigen-specific IgY immune response to each antigen. The survival rates of D. gallinae in three groups decreased significantly after they fed on the immunized birds. And the oviposition rate and fecundity were significantly reduced by 13.18% and 49.90% in the rDg-CatD-1 immunized group, 5.49% and 38.55% in the rDg-CatL-1 immunized group, respectively. Moreover, immunization with rDg-CatD-1 or rDg-CatL-1 significantly decreased the blood digestion rate of D. gallinae. However, no statistically significant effects on reproduction performance and blood digestion rate of mite were observed in group immunized with rDg-Lgm. Our results demonstrated that immunization with rDg-CatD-1 or rDg-CatL-1 could prevent and control D. gallinae by reducing the survival, reproductive capacity and blood digestion of mite. Importantly, the evaluation system based on the in vivo rearing system was reliable and practical, and it can accurately evaluate the effects of immunization on D. gallinae for pre-screening of potential novel antigens.

14.
Neurosurg Focus ; 49(4): E20, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33002878

RESUMO

OBJECTIVE: The purpose of this study was to examine the population-based trends and factors associated with hospitalization of patients with traumatic brain injury (TBI) treated in the Emergency Department (ED) among those 65 years and older. The implications of these trends for neurosurgery and the broader society are discussed. METHOD: With a national, mandatory reporting system of ED visits, the authors used Poisson regression controlling for age and sex to analyze trends in fall-related TBI of those aged 65 years and older between 2002 and 2017. RESULTS: The overall rate of ED visits for TBI increased by 78%-from 689.51 per 100,000 (95% CI 676.5-702.8) to 1229 per 100,000 (95% CI 1215-1243) between 2002 and 2017. Females consistently experienced higher rates of fall-related TBI than did males. All age groups 65 years and older experienced significant increases in fall-related TBI rate over the study period; however, the highest rates occurred among the oldest individuals (90+ and 85-89 years). The hospital admission rate increased with age and Charlson Comorbidity Index. Males experienced both a higher admission rate and a greater percentage change in admission rate than females. CONCLUSIONS: Rates of ED visits for fall-related TBI, hospitalization, and in-ED mortality in those aged 65 years and older are increasing for both sexes. The increasing hospital admission rate is related to more advanced comorbidities, male sex, and increasing age. These findings have significant implications for neurosurgical resources; they emphasize that health professionals should work proactively with patients, families, and caregivers to clarify goals of care, and they also outline the need for more high-level and, preferably, randomized evidence to support outcomes-based decisions. Additionally, the findings highlight the urgent need for improved population-based measures for prevention in not only this age demographic but in younger ones, and the need for changes in the planning of health service delivery and long-term care.

15.
Comput Struct Biotechnol J ; 18: 2610-2620, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33033581

RESUMO

Gastric neuroendocrine carcinoma (GNEC) is rare cancer detected in the stomach. Previously, we demonstrated that the poorer prognosis of GNEC patients compared with gastric adenocarcinoma (GAC) patients was probably due to the lack of response to chemotherapy. Thus, it is crucial to study the specific GNEC gene expression pattern and investigate chemoresistance mechanism of GNEC. The transcriptome of GNEC patients was compared with that of GAC patients using RNA-seq. The KEGG analysis was employed to explore the specific differential expression gene function enrichment pattern. In addition, the transcriptomes of two GNEC cell lines, ECC10 and ECC12, were also compared with those of two GAC cell lines, MGC-803 and AGS, using RNA-seq. Comparing patient samples and cell lines transcriptome data, we try to uncover the potential targets and pathways which may affect the chemoresistance of GNEC. By combing all transcriptome data, we identified 22 key genes that were specifically up-regulated in GNEC. This panel of genes probably involves in the chemoresistance of GNEC. From our current experimental data, NeuroD1, one of the 22 genes, is associated with the prognosis of GNEC patients. Knockdown of NeuroD1 enhanced the sensitivity to irinotecan of GNEC cell lines. Our research sheds light in identifying a panel of novel therapeutic target specifically for GNEC clinical treatment which has not been reported before.

16.
Biomed Res Int ; 2020: 9530618, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33083491

RESUMO

Purpose: Developed a preoperative prediction model based on multimodality imaging to evaluate the probability of inferior vena cava (IVC) vascular wall invasion due to tumor infiltration. Materials and Methods: We retrospectively analyzed the clinical data of 110 patients with renal cell carcinoma (RCC) with level I-IV tumor thrombus who underwent radical nephrectomy and IVC thrombectomy between January 2014 and April 2019. The patients were categorized into two groups: 86 patients were used to establish the imaging model, and the data validation was conducted in 24 patients. We measured the imaging parameters and used logistic regression to evaluate the uni- and multivariable associations of the clinical and radiographic features of IVC resection and established an image prediction model to assess the probability of IVC vascular wall invasion. Results: In all of the patients, 46.5% (40/86) had IVC vascular wall invasion. The residual IVC blood flow (OR 0.170 [0.047-0.611]; P = 0.007), maximum coronal IVC diameter in mm (OR 1.203 [1.065-1.360]; P = 0.003), and presence of bland thrombus (OR 3.216 [0.870-11.887]; P = 0.080) were independent risk factors of IVC vascular wall invasion. We predicted vascular wall invasion if the probability was >42% as calculated by: {Ln [Pre/(1 - pre)] = 0.185 × maximum cornal IVC diameter + 1.168 × bland thrombus-1.770 × residual IVC blood flow-5.857}. To predict IVC vascular wall invasion, a rate of 76/86 (88.4%) was consistent with the actual treatment, and in the validation patients, 21/26 (80.8%) was consistent with the actual treatment. Conclusions: Our model of multimodal imaging associated with IVC vascular wall invasion may be used for preoperative evaluation and prediction of the probability of partial or segmental IVC resection.

17.
ALTEX ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33086383

RESUMO

One of the most challenging areas in regulatory science is assessment of the substances known as UVCB (Unknown or Variable composition, Complex reaction products and Biological materials). Because the inherent complexity and variability of UVCBs present considerable challenges for establishing sufficient substance similarity based on chemical characteristics or other data, we hypothesized that animal alternatives new approach methodologies (NAMs), including in vitro test-derived biological activity signatures to characterize substance similarity, can be used to support grouping of UVCBs. We tested 141 petroleum substances as representative UVCBs in a compendium of 15 human cell types representing a variety of tissues. Petroleum substances were assayed in dilution series to derive point of departure estimates for each cell type and phenotype. Extensive quality control measures were taken to ensure that only high-confidence in vitro data are used to determine whether current groupings of these petroleum substances, based largely on the manufacturing process and physico-chemical properties, are justifiable. We found that bioactivity data-based groupings of petroleum substances were generally consistent with the manufacturing class-based categories. We also showed that these data, especially bioactivity from human induced pluripotent stem cell (iPSC)-derived and primary cells, can be used to rank substances in a manner highly concordant with their expected in vivo hazard potential based on their chemical compositional profile. Overall, this study demonstrates that NAMs can be used to inform groupings of UVCBs, to assist in identification of representative substances in each group for testing when needed, and to fill data gaps by read-across.

18.
Sci Rep ; 10(1): 18605, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33122723

RESUMO

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor protein that has roles in key cellular processes including apoptosis and cellular proliferation. As these cellular processes are frequently disrupted in human tumours and little is known about the role of SASH1 in the pathogenesis of the disease, we analysed the prognostic value of SASH1 in non-small cell lung cancers using publicly available datasets. Here, we show that low SASH1 mRNA expression is associated with poor survival in adenocarcinoma. Supporting this, modulation of SASH1 levels in a panel of lung cancer cell lines mediated changes in cellular proliferation and sensitivity to cisplatin. The treatment of lung cancer cells with chloropyramine, a compound that increases SASH1 protein concentrations, reduced cellular proliferation and increased sensitivity to cisplatin in a SASH1-dependent manner. In summary, compounds that increase SASH1 protein levels could represent a novel approach to treat NSCLC and warrant further study.

19.
Chin Med J (Engl) ; 133(17): 2078-2083, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32898352

RESUMO

BACKGROUND: Renal cell carcinoma (RCC) has the propensity to lead to venous tumor thrombus (VTT). Nephrectomy with tumor thrombectomy is an effective treatment option but is a technically challenging surgical procedure that is accompanied by a high rate of complications. The aims of this study were to investigate pre-operative imaging parameters for the assessment of inferior vena cava (IVC) wall invasion due to a tumor thrombus in patients with RCC and to identify predictors from the intra-operative findings. METHODS: Clinical and imaging data were collected from 110 patients who underwent nephrectomy with IVC tumor thrombectomy (levels I-IV) for RCC and IVC tumor thrombus at the Peking University Third Hospital between May 2015 and March 2018. Univariable and multivariable logistic regression and receiver operating characteristic curves were used to assess the correlations between pre-operative imaging features and intra-operative macroscopic invasions of the IVC wall by tumor thrombus. RESULTS: Among the 110 patients, 41 underwent partial or segmental resection of IVC. There were univariate associations of pre-operative imaging parameters that could be used to predict the need for IVC resection, including those of the Mayo classification, maximum anterior-posterior (AP) diameter of the renal vein at the renal vein ostium (RVo), maximum AP diameter of the VTT at the RVo and IVC occlusion. For the multivariable analysis, the AP diameter of the VTT at the RVo and IVC occlusion were associated with a significantly increased risk of invasion of the IVC wall by tumor thrombus. The optimum imaging thresholds included an AP diameter of the VTT at the RVo larger than 17.0 mm and the presence of IVC occlusion, with which we predicted invasions of the IVC wall requiring IVC resection. The probabilities of intra-operative IVC resection for patients without both independent factors, with an AP diameter of the VTT at the RVo larger than 17.0 mm, with IVC occlusion, and with both concurrent factors were 5%, 23%, 56%, and 66%, respectively. CONCLUSION: An increase in the AP VTT diameter at the RVo and the presence of complete occlusion of the IVC are independent risk factors for a high probability of IVC wall invasion by tumor thrombus.

20.
Int J Clin Exp Pathol ; 13(7): 1873-1879, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32782717

RESUMO

γ-synuclein (SNCG) is highly expressed in bladder cancer tissues and associated with tumor recurrence. However, the functional effect of SNCG on the development of bladder cancer remains unknown. In the present study, the effects of SNCG down-regulation by RNA interference (RNAi) on the proliferation and invasiveness of human bladder cancer cell line 5637 were explored. Three pairs of SNCG-specific small interference RNA (siRNA) were designed and transfected into the 5637 cell lines, and then the SNCG expressions in the three siRNA were assessed using reverse transcription-polymerase chain reactions (RT-PCR) and Western blot, while the cell proliferation and invasiveness of the 5637 cells were evaluated using cell counting kit-8 (CCK-8) and transwell assays, respectively. In addition, the expressions of matrix metalloproteinase-2 and -9 (MMP-2/9) were analyzed using enzyme-linked immunosorbent assays after the down-regulation of SNCG. The results showed that compared with the negative and empty vector controls, all three SNCG siRNAs were observed to significantly inhibit the SNCG expressions at the mRNA and protein levels (P < 0.05), among which the lowest SNCG expression was measured in SNCG-siRNA-244. And the SNCG suppression mediated by RNAi successfully inhibited the proliferation and invasiveness of the 5637 cell lines (P < 0.05), as well as the down-regulation of MMP-2/9. In conclusion, the proliferation and invasiveness of bladder cancer cells can be decreased by specifically interfering with the SNCG expression. And SNCG siRNA deserves further study as a novel target for biomedical therapy in bladder cancer.

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