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1.
Artigo em Inglês | MEDLINE | ID: mdl-35521682

RESUMO

BACKGROUND: The pathogenesis of Cushing's disease (CD) is still not adequately understood despite the identification of somatic driver mutations in USP8, BRAF and USP48. In this multiomics study, we combined RNA sequencing (RNA-seq) with Sanger sequencing to depict transcriptional dysregulation under different gene mutation backgrounds. Furthermore, we evaluated the potential of achaete-scute complex homolog 1 (ASCL1), a pioneer transcription factor, as a novel therapeutic target for treatment of CD and its possible downstream pathway. METHODS: RNA-seq was adopted to investigate the gene expression profile of CD, and Sanger sequencing was adopted to detect gene mutations. Bioinformatics analysis was used to depict transcriptional dysregulation under different gene mutation backgrounds. The function of ASCL1 in hormone secretion, cell proliferation and apoptosis were studied in vitro. The effectiveness of a ASCL1 inhibitor was evaluated in primary CD cells, and the clinical relevance of ASCL1 was examined in 68 patients with CD. RNA-seq in AtT-20 cells upon Ascl1 knockdown combined with published ChIp-seq data and dual luciferase assays were used to explore downstream pathways. RESULTS: ASCL1 was exclusively overexpressed in USP8-mutant and wild type tumors. Ascl1 promoted adrenocorticotrophin hormone overproduction and tumorigenesis and directly regulated Pomc in AtT-20 cells. A ASCL1 inhibitor presented promising efficacy in both AtT-20 and primary CD cells. ASCL1 overexpression was associated with a larger tumor volume and higher adrenocorticotrophin secretion in patients with CD. CONCLUSION: Our findings help to clarify the pathogenesis of CD and suggest that ASCL1 is a potential therapeutic target for treatment of CD.

2.
Bioengineered ; 13(5): 11794-11809, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35546071

RESUMO

After spinal cord injury (SCI), a large number of blood-derived macrophages infiltrate the lesion site and phagocytose myelin debris to become foamy macrophages, which leads to chronic inflammation. The drug D-4F, an apolipoprotein A-I peptidomimetic made of D-amino acids, has been reported to promote the lipid metabolism of foamy macrophages in atherosclerosis. However, the role and mechanism of D-4F in SCI are still unclear. In this study, we found that D-4F can promote the removal of myelin debris, reduce the formation of foamy macrophages in the lesion core and promote neuroprotection and recovery of motor function after SCI. These beneficial functions of D-4F may be related to its ability to upregulate the expression of ATP-binding cassette transporter A1 (ABCA1), the main transporter that mediates lipid efflux in foamy macrophages because inhibiting the activity of ABCA1 can reverse the effect of D-4F in vitro. In conclusion, D-4F may be a promising candidate for treating SCI by promoting the clearance of myelin debris by foamy macrophages via the ABCA1 pathway.

3.
Cell Death Discov ; 8(1): 260, 2022 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-35568721

RESUMO

Glioblastoma (GBM) cell-derived extracellular vesicles (EVs) have been demonstrated to modulate tumor microenvironment. In the present study, we attempted to discuss the role of hsa-microRNA-27a-3p (miR-27a-3p) delivered by GBM-EVs in M2 macrophage polarization. The isolated GBM-EVs were co-cultured with macrophages. After co-culture under normoxia/hypoxia, the effect of EV-derived hsa-miR-27a-3p on GBM cell biological processes was analyzed. Additionally, the target genes of hsa-miR-27a-3p were predicted. Moreover, the binding of enhancer of zeste homologue 1 (EZH1) to lysine-specific demethylase 3A (KDM3A) promoter region and the interaction between KDM3A and connective tissue growth factor (CTGF) were analyzed. GBM mouse models were established to verify the functions of EV-derived hsa-miR-27a-3p in vivo. We found increased hsa-miR-27a-3p in GBM tissues as well as GBM-EVs, which induced M2 polarization, thus promoting proliferative, migrative and invasive potentials of GBM cells. hsa-miR-27a-3p targeted EZH1 and promoted KDM3A expression to elevate the CTGF expression. GBM-EV-delivered hsa-miR-27a-3p promoted the KDM3A-upregulated CTGF by downregulating EZH1, thereby promoting M2 macrophage polarization and development of GBM in vivo. We demonstrated that EV-derived hsa-miR-27a-3p may promote M2 macrophage polarization to induce GBM.

4.
Clin J Sport Med ; 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35447629

RESUMO

ABSTRACT: Saphenous entrapment neuropathy in the distal thigh most commonly occurs at Hunter's canal and is characterized by neurologic symptoms distal to the midthigh in the saphenous nerve distribution. Presented is a 23-year-old active duty female service member with left medial knee pain worse with knee flexion and extension. Evaluation raised suspicion for saphenous nerve entrapment at Hunter's canal, and ultrasound-guided subsartorius fascial plane hydrodissection was performed in addition to focused rehabilitation of the adductor and core musculature. No reports of this treatment have been published to date. This case introduces ultrasound-guided subsartorius fascial plane hydrodissection as novel treatment in Hunter's canal syndrome.

5.
Insights Imaging ; 13(1): 70, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35394225

RESUMO

OBJECTIVES: To evaluate the application value of diffusion kurtosis imaging (DKI) for monitoring renal function and interstitial fibrosis. METHODS: Forty-two patients suspected of having primary nephropathy, hypertension or diabetes with impaired renal function were examined with DKI. DKI metrics of renal cortex and medulla on both sides of each patient were measured, including mean kurtosis (MK), axial kurtosis (Ka), radial kurtosis (Kr), mean diffusivity (MD) and fractional anisotropy (FA). The differences in DKI metrics between stable and impaired estimated glomerular filtration rate (eGFR) patients as well as between mild and severe interstitial fibrosis patients were compared. Correlations of DKI metrics with clinical indicators and pathology were analyzed. Diagnostic performance of DKI to assess the degree of renal dysfunction was analyzed. RESULTS: Cortical MK, parenchymal Ka, MD and medullary FA were different in stable vs impaired eGFR patients and mild vs severe interstitial fibrosis patients (all p < .05). Negative correlation was found between Ka and eGFR (cortex: r = - 0.579; medulla: r = - 0.603), between MD and interstitial fibrosis (cortex: r = - 0.899; medulla: r = - 0.770), and positive correlation was found between MD and eGFR (cortex: r = 0.411; medulla: r = 0.344), between Ka and interstitial fibrosis (cortex: r = 0.871; medulla: r = 0.844) (all p < .05). DKI combined with mean arterial blood pressure (MAP) and urea showed good diagnostic power for assessing the degree of renal dysfunction (sensitivity: 90.5%; specificity: 89.5%). CONCLUSIONS: Noninvasive DKI has certain application value for monitoring renal function and interstitial fibrosis.

6.
Opt Express ; 30(9): 15777-15795, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35473291

RESUMO

Large optical flats play a remarkable role in advanced large-aperture optical systems and the testing of the surface shape error is indispensable for the fabrication. The widely adopted Ritchey-Common test for large optical flats will fail without the rigorous test configurations including a large F/# prerequisition and a flat-to-interferometer distance invariance. A virtual-real combination Ritchey-Common interferometry is proposed to avoid the large F/# prerequisition by accurately modelling the optical path in a virtual interferometer. Furthermore, a virtual-real combination iterative algorithm is proposed in this method to break the flat-to-interferometer distance invariance. Measurement experiments for 100 mm and 422 mm aperture flats were performed to demonstrate the feasibility of this method. Compared with a direct testing in a standard Zygo interferometer, the peak to valley (PV) and root mean square (RMS) errors were less than 0.1 λ and 0.01 λ (λ=632.8 nm), respectively, in different Ritchey angles and flat-to-interferometer distances. Further numerical simulations demonstrate that RMS errors for various Zernike aberrations in arbitrary F/# are less than 0.01 λ. This method can break the distance invariance restriction and achieve high accuracy with an arbitrary F/#, thus providing substantial freedom in the design of test configurations to accommodate various test scenarios.

7.
Biomed Pharmacother ; 149: 112847, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35364376

RESUMO

OBJECTIVE: Cantleyoside (CA) is a kind of iridoid glycosides in Pterocephalus hookeri (C. B. Clarke) Höeck. The purpose of this study was to investigate the effects of CA on human rheumatoid arthritis fibroblast synovial cells (HFLS-RA). METHODS: Cell proliferation of HFLS-RA was assessed by CCK-8. ELISA was used to detect cytokines NO, TNF-α, IL-1ß/6, MCP-1, MMP-1/3/9 and metabolism-related ATPase activities and ATP levels. JC-1, DCFH-DA, Fluo-3 AM and Calcein AM probes were used to detect mitochondrial membrane potential (MMP), reactive oxygen species (ROS), Ca2+ and mitochondrial permeability conversion pore (MPTP), respectively. Isolated mitochondria assay was used to detect mitochondrial swelling. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and real-time ATP production were measured using a Seahorse analyzer. Apoptosis was detected by TUNEL and Hoechst staining. Western blot was used to detect the expressions of AMPK/p-AMPK, Sirt 1, IκBα, NF-κB p65/p-NF-κB p65, Bcl-2 and Bax. Cytoplasmic nuclear isolation was also performed to detect the translocation of NF-κB. RESULTS: CA significantly suppressed cell proliferation and the levels of NO, TNF-α, IL-1ß/6, MCP-1 and MMP-1/3/9 in HFLS-RA. In addition, CA promoted the apoptosis of HFLS-RA by increasing TUNEL and Hoechst positive cells and the ratio of Bax/Bcl-2. Inhibition of energy metabolism in HFLS-RA by CA reduced OCR, ECAR and real-time ATP generation rate. Importantly, CA promoted p-AMPK and Sirt 1 expression, inhibited IκBα degradation to reduce p-NF-κB and translocation. CONCLUSION: The results suggest that CA activates the AMPK/Sirt 1/NF-κB pathway by promoting mitochondrial dysfunction, thereby exerting anti-inflammatory and pro-apoptotic effects.


Assuntos
Artrite Reumatoide , Sirtuínas , Proteínas Quinases Ativadas por AMP/metabolismo , Trifosfato de Adenosina/metabolismo , Apoptose , Artrite Reumatoide/metabolismo , Linhagem Celular , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Metaloproteinase 1 da Matriz/metabolismo , Mitocôndrias/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Sirtuínas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo
8.
Biomater Sci ; 10(9): 2358-2369, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35383789

RESUMO

Employing hypoxia-activated prodrugs is an appealing oncotherapy strategy, but limited by insufficient tumor hypoxia. Moreover, a standalone prodrug fails to treat tumors satisfactorily due to tumor complexity. Herein, a nanosystem (TPZ@FeMSN-GOX) was established for triple synergetic cancer starvation therapy, hypoxia-activated chemotherapy and chemodynamic therapy (CDT). TPZ@FeMSN-GOX was prepared by synthesizing iron-doped mesoporous silica nanoparticles (FeMSNs) followed by surface conjugation with glucose oxidase (GOX), and then loading with hypoxia-activated prodrug tirapazamine (TPZ). When TPZ@FeMSN-GOX entered the tumor cells, GOX could not only exhaust glucose to starve cancer cells and concomitantly produce H2O2, but also consume O2 to aggravate the hypoxia environment and amplify TPZ-mediated chemotherapy. Meanwhile, the released Fe3+ was reduced to reactive Fe2+ by endogenous glutathione, which ultimately decomposed the produced H2O2 and endogenous H2O2 into highly toxic ˙OH, guaranteeing highly efficient CDT. Together, TPZ@FeMSN-GOX could effectively kill cancer cells and significantly inhibit tumor growth, providing a good paradigm for effective tumor treatment.


Assuntos
Nanopartículas , Neoplasias , Pró-Fármacos , Linhagem Celular Tumoral , Glucose , Glucose Oxidase , Humanos , Peróxido de Hidrogênio , Hipóxia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Tirapazamina/farmacologia
9.
Environ Technol ; : 1-11, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35441572

RESUMO

Bioremediation of sediment organic pollution has been intensely investigated, but the degradation of complex organic compounds, pesticide residues, and polychlorinated biphenyls (PCBs) remains poorly studied. In this study, sediments were collected from Zhanjiang Mangrove Reserve and inoculated in an inorganic salt medium using only biphenyl (BP) and PCBs as the carbon sources to obtain a PCB-degrading strain. A gram-negative bacterium that metabolized PCBs was isolated and identified as Klebsiella Lw3 by 16S rDNA phylogenetic analysis. Genomic sequencing showed that this bacterium possessed genes related to BP/PCB degradation, and its GC content was 58.2%; we identified 3326 cellular pathways. Gas chromatography-mass spectrometry was employed to test the PCB degrading ability; the results showed that the strain had a good degradation effect on PCB3 at concentrations of 5, 10, 20, 40, and 60 mg/L and that the final degradation rate was higher than 97% after 96 h. Interestingly, this strain showed good biodegradability of PCBs despite having no classical PCB degradation pathway, providing a new direction for Klebsiella research with practical significance for in situ bioremediation of PCB contamination. Overall, this study provides valuable insights into the genetic structure of PCB-degrading strains as well as eco-friendly and low-cost PCB degradation and lays a foundation for the discovery of new degradation pathways.

10.
Transl Psychiatry ; 12(1): 170, 2022 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-35461305

RESUMO

Patients with major depressive disorder (MDD) are at high risk of psychiatric readmission while the factors associated with such adverse illness trajectories and the impact of the same factor at different follow-up times remain unclear. Based on machine learning (ML) approaches and real-world electronic medical records (EMR), we aimed to predict individual psychiatric readmission within 30, 60, 90, 180, and 365 days of an initial major depression hospitalization. In addition, we examined to what extent our prediction model could be made interpretable by quantifying and visualizing the features that drive the predictions at different follow-up times. By identifying 13,177 individuals discharged from a hospital located in western China between 2009 and 2018 with a recorded diagnosis of MDD, we established five prediction-modeling cohorts with different follow-up times. Four different ML models were trained with features extracted from the EMR, and explainable methods (SHAP and Break Down) were utilized to analyze the contribution of each of the features at both population-level and individual-level. The model showed a performance on the holdout testing dataset that decreased over follow-up time after discharge: AUC 0.814 (0.758-0.87) within 30 days, AUC 0.780 (0.728-0.833) within 60 days, AUC 0.798 (0.75-0.846) within 90 days, AUC 0.740 (0.687-0.794) within 180 days, and AUC 0.711 (0.676-0.747) within 365 days. Results add evidence that markers of depression severity and symptoms (recurrence of the symptoms, combination of key symptoms, the number of core symptoms and physical symptoms), along with age, gender, type of payment, length of stay, comorbidity, treatment patterns such as the use of anxiolytics, antipsychotics, antidepressants (especially Fluoxetine, Clonazepam, Olanzapine, and Alprazolam), physiotherapy, and psychotherapy, and vital signs like pulse and SBP, may improve prediction of psychiatric readmission. Some features can drive the prediction towards readmission at one follow-up time and towards non-readmission at another. Using such a model for decision support gives the clinician dynamic information of the patient's risk of psychiatric readmission and the specific features pulling towards readmission. This finding points to the potential of establishing personalized interventions that change with follow-up time.


Assuntos
Transtorno Depressivo Maior , Readmissão do Paciente , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/terapia , Registros Eletrônicos de Saúde , Humanos , Aprendizado de Máquina , Estudos Retrospectivos , Fatores de Risco
11.
PLoS One ; 17(4): e0266006, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35363813

RESUMO

BACKGROUND: Patients with coronary heart disease (CHD) often experience anxiety, but the current studies on anxiety mostly focused on a certain point in time. Therefore, this study aimed to investigate the dynamic changes of peri-procedure anxiety, status of post-procedure quality of life, and cardiovascular readmission rates in patients with CHD who undergoing elective percutaneous coronary intervention (PCI), and to analyze the influence of peri-procedure anxiety on quality of life and readmission rate after PCI. METHODS: This prospective study was conducted at Changshu NO.1 People's Hospital. A total of 220 patients with CHD undergoing elective PCI were selected as study subjects. The general information, clinical data, anxiety, quality of life and readmission of patients were collected. Multivariate linear regression was used to examine the effect of peri-procedure anxiety on quality of life, and multivariate logistic regression was used to analyze the influence of peri-procedure anxiety on readmission rate. RESULTS: This study showed the anxiety scores at hospitalization appointment(T1), 3 days before procedure(T2), 1 day before procedure(T3), 1 day after procedure(T4) were 57(55,61),64(61,68),54(51.58), and 54(50,60), respectively. And, at 3 months and 6 months after PCI, the scores of Seattle Angina Questionnaire (SAQ) were 346.61(319.06,366.52) and 353.34(334.18,372.84) respectively. During 6 months follow-up, 54 cases were readmitted, with a readmission rate of 25.5%. Statistical analysis showed that T1 with anxiety (P = 0.002) and T2 with anxiety (P = 0.024) were independent risk factors for treatment satisfaction at 3 months after PCI. Anxiety in T4 (P = 0.005) was an independent risk factor on the angina frequency at 6 months after PCI. T2 with anxiety (B = 1.445, P = 0.010, 95%CI:1.409-12.773) and T4 without anxiety (B = -1.587, P = 0.042, 95%CI:-0.044-0.941) were risk factors affecting readmission for cardiovascular reasons within 6 months. CONCLUSION: Patient anxiety at T1 and T2 affects the treatment satisfaction dimension of the SAQ at 3 months after PCI, and anxiety at T4 affects the angina frequency dimension of the SAQ at 6 months after PCI. Anxiety at T2 and no anxiety at T4 increase short-term readmission rates. In the future, interventions should be strengthened at various time points in the peri-procedure period to improve post-procedure rehabilitation effect.


Assuntos
Doença das Coronárias , Intervenção Coronária Percutânea , Ansiedade , Doença das Coronárias/etiologia , Doença das Coronárias/cirurgia , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Estudos Prospectivos , Qualidade de Vida , Resultado do Tratamento
12.
Biomed Opt Express ; 13(3): 1581-1594, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35414977

RESUMO

Fourier ptychographic microscopy (FPM) is a recently developed computational imaging technique for wide-field, high-resolution microscopy with a high space-bandwidth product. It integrates the concepts of synthetic aperture and phase retrieval to surpass the resolution limit imposed by the employed objective lens. In the FPM framework, the position of each sub-spectrum needs to be accurately known to ensure the success of the phase retrieval process. Different from the conventional methods with mechanical adjustment or data-driven optimization strategies, here we report a physics-based defocusing strategy for correcting large-scale positional deviation of the LED illumination in FPM. Based on a subpixel image registration process with a defocused object, we can directly infer the illumination parameters including the lateral offsets of the light source, the in-plane rotation angle of the LED array, and the distance between the sample and the LED board. The feasibility and effectiveness of our method are validated with both simulations and experiments. We show that the reported strategy can obtain high-quality reconstructions of both the complex object and pupil function even the LED array is randomly placed under the sample with both unknown lateral offsets and rotations. As such, it enables the development of robust FPM systems by reducing the requirements on fine mechanical adjustment and data-driven correction in the construction process.

13.
J Exp Med ; 219(4)2022 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-35254403

RESUMO

Hepatitis B virus exposure in children usually develops into chronic hepatitis B (CHB). Although hepatitis B surface antigen (HBsAg)-specific CD8+ T cells contribute to resolve HBV infection, they are preferentially undetected in CHB patients. Moreover, the mechanism for this rarely detected HBsAg-specific CD8+ T cells remains unexplored. We herein found that the frequency of HBsAg-specific CD8+ T cells was inversely correlated with expansion of monocytic myeloid-derived suppressor cells (mMDSCs) in young rather than in adult CHB patients, and CCR9 was upregulated by HBsAg on mMDSCs via activation of ERK1/2 and IL-6. Sequentially, the interaction between CCL25 and CCR9 mediated thymic homing of mMDSCs, which caused the cross-presentation, transferring of peripheral HBsAg into the thymic medulla, and then promoted death of HBsAg-specific CD8+ thymocytes. In mice, adoptive transfer of mMDSCs selectively obliterated HBsAg-specific CD8+ T cells and facilitated persistence of HBV in a CCR9-dependent manner. Taken together, our results uncovered a novel mechanism for establishing specific CD8+ tolerance to HBsAg in chronic HBV infection.


Assuntos
Hepatite B Crônica , Células Supressoras Mieloides , Animais , Linfócitos T CD8-Positivos , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B , Humanos , Camundongos
14.
Am J Hum Genet ; 109(4): 669-679, 2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35263625

RESUMO

One mechanism by which genetic factors influence complex traits and diseases is altering gene expression. Direct measurement of gene expression in relevant tissues is rarely tenable; however, genetically regulated gene expression (GReX) can be estimated using prediction models derived from large multi-omic datasets. These approaches have led to the discovery of many gene-trait associations, but whether models derived from predominantly European ancestry (EA) reference panels can map novel associations in ancestrally diverse populations remains unclear. We applied PrediXcan to impute GReX in 51,520 ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) participants (35% African American, 45% Hispanic/Latino, 10% Asian, and 7% Hawaiian) across 25 key cardiometabolic traits and relevant tissues to identify 102 novel associations. We then compared associations in PAGE to those in a random subset of 50,000 White British participants from UK Biobank (UKBB50k) for height and body mass index (BMI). We identified 517 associations across 47 tissues in PAGE but not UKBB50k, demonstrating the importance of diverse samples in identifying trait-associated GReX. We observed that variants used in PrediXcan models were either more or less differentiated across continental-level populations than matched-control variants depending on the specific population reflecting sampling bias. Additionally, variants from identified genes specific to either PAGE or UKBB50k analyses were more ancestrally differentiated than those in genes detected in both analyses, underlining the value of population-specific discoveries. This suggests that while EA-derived transcriptome imputation models can identify new associations in non-EA populations, models derived from closely matched reference panels may yield further insights. Our findings call for more diversity in reference datasets of tissue-specific gene expression.


Assuntos
Doenças Cardiovasculares , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Humanos , Estilo de Vida , Polimorfismo de Nucleotídeo Único , Transcriptoma
15.
JAMA Netw Open ; 5(3): e220587, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35230439

RESUMO

IMPORTANCE: Anti-programmed cell death 1 (anti-PD-1) immunotherapy features a durable response and improved survival in a small subset of patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). The association between plasma Epstein-Barr virus (EBV) DNA titer dynamics and efficacy of anti-PD-1 monotherapy has been reported, while its value in predicting long-term outcomes and monitoring disease progression is unclear for patients with RM-NPC who are receiving anti-PD-1 monotherapy. OBJECTIVE: To evaluate the role of plasma EBV DNA titers in prognosis prediction and surveillance of disease progression for patients with RM-NPC who are receiving anti-PD-1 monotherapy. DESIGN, SETTING, AND PARTICIPANTS: Patients with RM-NPC from the POLARIS-02 prospective clinical trial, the largest cohort to receive anti-PD-1 monotherapy, were included in this study. From December 22, 2016, to February 19, 2019, 17 participating centers in China screened 279 patients with RM-NPC; 190 patients were enrolled and followed up until February 19, 2020. Plasma EBV DNA was detected before treatment and every 4 weeks until disease progression. MAIN OUTCOMES AND MEASURES: Plasma EBV DNA as a predictor for progression-free survival (PFS), overall survival (OS), durable clinical benefit (defined as PFS of ≥6 months), and disease progression. RESULTS: Of 179 patients with RM-NPC receiving anti-PD-1 therapy, 148 (82.7%) were men, and the median age was 46 years (range, 22-71 years). A higher baseline EBV DNA titer was associated with shorter median OS (hazard ratio, 1.88; 95% CI, 1.22-2.89; P = .004). Patients with a ratio of the EBV DNA titer at week 4 to that at baseline (W4 to baseline ratio) greater than 0.5 had shorter median OS (hazard ratio, 2.18; 95% CI, 1.30-3.65; P < .001) than those with a W4 to baseline ratio of 0.5 or less. Patients with higher baseline EBV DNA titers had a lower durable clinical benefit rate than those with lower baseline EBV DNA titers (19 of 97 [19.6%] vs 27 of 71 [38.0%]; P = .01). Similarly, patients with a W4 to baseline ratio greater than 0.5 had a lower durable clinical benefit rate than those with a W4 to baseline ratio of 0.5 or less (9 of 86 [10.5%] vs 32 of 54 [59.3%]; P < .001). In addition, a significant EBV DNA titer increase was present at a median of 2.6 months (IQR, 0.9-4.5 months) prior to radiographic progression. CONCLUSIONS AND RELEVANCE: This study of plasma EBV DNA in patients with RM-NPC who are receiving anti-PD-1 monotherapy suggests that plasma EBV DNA could be a useful biomarker for outcomes and monitoring disease progression.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Adulto , Idoso , DNA Viral , Progressão da Doença , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Feminino , Herpesvirus Humano 4/genética , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Recidiva Local de Neoplasia , Estudos Prospectivos , Adulto Jovem
16.
BMC Med ; 20(1): 94, 2022 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-35313867

RESUMO

BACKGROUND: To elucidate the influence of childhood asthma on adult height after consideration of genetic heterogeneity in height. METHODS: Based on the UK Biobank, we conducted a matched cohort study, including 13,602 European individuals with asthma diagnosed before 18 years old and 136,008 matched unexposed individuals without such an experience. Ascertainment of asthma was based on self-reported data (97.6%) or clinical diagnosis in healthcare registers (2.4%). We studied three height outcomes, including (1) the attained adult height (in centimeters), (2) the height deviation measured as the difference between a person's rank of genetically determined height (based on generated polygenetic risk score) and their rank of attained adult height in the study population (deviation in % of height order after standardization), and (3) the presence of height deficit comparing genetically determined and attained height (yes or no). We applied linear mixed-effect models to assess the associations of asthma diagnosed at different ages with attained adult height and height deviation, and conditional logistic regression models to estimate the associations of asthma with the risk of height deficit. RESULTS: 40.07% (59,944/149,610) of the study participants were born before 1950, and most of them were men (57.65%). After controlling for multiple covariates, childhood asthma was associated with shorter attained adult height, irrespective of age at asthma diagnosis. However, in the analysis of height deviation (deviation in %), we observed the greatest height deviation among individuals with asthma diagnosed before 4 years of age (- 2.57 [95% CI - 4.14 to - 1.00] and - 2.80 [95% CI - 4.06 to - 1.54] for the age of ≤ 2 and 3-4 years, respectively). The magnitude of height deviation in relation to asthma declined thereafter and became null after age 6. Similarly, there was a statistically significant height deficit in relation to an asthma diagnosis at ages ≤ 2 and 3-4 (odds ratios = 1.21, 95% CI 1.04 to 1.40, and 1.15, 95% CI 1.02 to 1.29) but not thereafter. The result pattern was similar when separately analyzing asthma with or without inhaled glucocorticoid (ICS) use, despite that the estimates were consistently stronger among asthma individuals who used ICS. CONCLUSIONS: Our results suggest a notable association of childhood asthma, primarily asthma diagnosed at an early age, with adult height, after consideration of genetic heterogeneity in height and use of ICS. This finding highlights the need for surveillance on the growth problems among children with asthma.


Assuntos
Antiasmáticos , Asma , Administração por Inalação , Adolescente , Corticosteroides/farmacologia , Corticosteroides/uso terapêutico , Adulto , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Asma/epidemiologia , Bancos de Espécimes Biológicos , Estatura , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Reino Unido/epidemiologia , Adulto Jovem
17.
Artigo em Inglês | MEDLINE | ID: mdl-35333923

RESUMO

BACKGROUND: Results of previous observational studies examining the risk of cancer among chronic kidney disease (CKD) patients are conflicting. We here explore the causal relationship between estimated glomerular filtration rate (eGFR) and albuminuria, two principal measurements of CKD, and 19 site-specific cancers using Mendelian randomization (MR) analysis. METHODS: Single nucleotide polymorphisms reported to be strongly correlated with eGFR and albuminuria in recent large genome-wide association studies were used as instrumental variables to investigate the causal relationship with cancer using summary-level statistics from several cancer-specific consortia, as well as data of 347,408 participants in the UK Biobank and 260,405 participants in the FinnGen. RESULTS: Our data showed that impaired kidney function was associated with higher odds of leukemia (odds ratio [OR] 1.23, 95% confidence interval [CI] 1.06-1.43, P = 0.007), cervical cancer (OR 1.22, 95% CI 1.04-1.43, P = 0.017) and female renal cell carcinoma (OR 1.4, 95% CI 1.12-1.77, P = 0.004), per 10% decrease in eGFR. The odds ratios were 1.21 (95% CI 1.07-1.36, P = 0.002) for colorectal cancer and 0.76 (95% CI 0.62-0.92, P = 0.006) for non-Hodgkin lymphoma, per doubling odds of albuminuria. In multivariable MR, effect sizes of eGFR-cervical cancer remained strong after adjusting for confounders. CONCLUSIONS: The current study indicates that progression of CKD contributes to carcinogenesis of renal cell carcinoma, leukemia, cervical and colorectal cancer. IMPACT: The potential association of kidney function and albuminuria with certain cancers warrants further investigation in order to provide appropriate recommendations regarding cancer screening among patients with CKD.

18.
Sheng Li Xue Bao ; 74(1): 93-109, 2022 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-35199130

RESUMO

Diabetic nephropathy is a microvascular complication of diabetes. Its etiology involves metabolic disorder-induced endothelial dysfunction. Endothelium-derived nitric oxide (NO) plays an important role in a number of physiological processes, including glomerular filtration and endothelial protection. NO dysregulation is an important pathogenic basis of diabetic nephropathy. Hyperglycemia and dyslipidemia can lead to oxidative stress, chronic inflammation and insulin resistance, thus affecting NO homeostasis regulated by endothelial nitric oxide synthase (eNOS) and a conglomerate of related proteins and factors. The reaction of NO and superoxide (O2.-) to form peroxynitrite (ONOO-) is the most important pathological NO pathway in diabetic nephropathy. ONOO- is a hyper-reactive oxidant and nitrating agent in vivo which can cause the uncoupling of eNOS. The uncoupled eNOS does not produce NO but produces superoxide. Thus, eNOS uncoupling is a critical contributor of NO dysregulation. Understanding the regulatory mechanism of NO and the effects of various pathological conditions on it could reveal the pathophysiology of diabetic nephropathy, potential drug targets and mechanisms of action. We believe that increasing the stability and activity of eNOS dimers, promoting NO synthesis and increasing NO/ONOO- ratio could guide the development of drugs to treat diabetic nephropathy. We will illustrate these actions with some clinically used drugs as examples in the present review.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Nefropatias Diabéticas/tratamento farmacológico , Endotélio Vascular , Humanos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico Sintase Tipo III/farmacologia , Óxido Nítrico Sintase Tipo III/uso terapêutico , Estresse Oxidativo , Ácido Peroxinitroso/metabolismo , Ácido Peroxinitroso/farmacologia , Ácido Peroxinitroso/uso terapêutico
19.
Exp Ther Med ; 23(3): 236, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35222713

RESUMO

Podocyte apoptosis and mitochondrial dysfunction serve a major role in diabetic nephropathy progression. The present study revealed a molecular mechanism regulating podocyte apoptosis and mitochondrial dysfunction. In vitro models were established using conditionally immortalized mouse podocyte clonal cells treated with high glucose (HG). Reverse quantitative-transcription PCR were used to detect gene expression, western blotting and immunofluorescence were used to detect protein expression, Cell Counting Kit-8 was used to detect cell viability and flow cytometry was used to detect cell apoptosis. HG treatment in the mouse podocyte clonal cells downregulated taurine-upregulated gene 1 (TUG1) expression and decreased viability in a dose-dependent manner. In addition, TUG1 knockdown (KD) increased HG-induced apoptosis, while TUG1 overexpression (OE) reduced HG-induced apoptosis in podocytes. HG-induced mitochondrial dysfunction was identified in podocytes, with increased reactive oxygen species levels, decreased complex I/III activity and decreased basal/maximal oxygen consumption rate. TUG1 KD worsened HG-induced mitochondrial dysfunction, and TUG1 OE reversed these effects. At the molecular level, TUG1 was revealed to promote sirtuin 1 (SIRT1) expression by sponging microRNA (miR)-9, and SIRT1 OE reversed the HG-induced apoptosis and mitochondrial dysfunction increased by TUG1 KD. The present data indicated that downregulation of TUG1 induced by HG was associated with HG-induced apoptosis and mitochondrial dysfunction in podocytes, and that TUG1 protected HG-induced podocytes by promoting SIRT1 expression via miR-9 inhibition.

20.
Eur J Prev Cardiol ; 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35104862

RESUMO

AIMS: To investigate associations of serum calcium, phosphate and vitamin D levels with the risk of developing aortic stenosis. METHODS AND RESULTS: We included 296,415 participants who were free of prior diagnosis of any valvular heart disease from the UK Biobank. Serum levels of phosphate, calcium and vitamin D were measured. Incidental of AS was determined by the records of hospital data. Cox regression was used to exam the association of serum mineral levels with incidental aortic stenosis after adjustment for potential confounders. The mean age was 56.4 years (SD 8.14) and 53.3% of participants were women. During an average follow-up of 8.1 years, 1232 individuals developed aortic stenosis. After adjustment, each 0.5-unit increase in serum phosphate level was associated with a 50% increase of aortic stenosis risk (HR 1.50, 95%CI 1.26 to 1.80). We observed no association of serum calcium and vitamin D levels with aortic stenosis. CONCLUSION: Increased serum phosphate level, but not calcium or vitamin D, was associated with a higher risk of incident aortic stenosis, this association did not differed substantially between patients with and without decreased kidney function. This finding implied that phosphate may be a potential interventional target for aortic stenosis.

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