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1.
Food Chem ; 403: 134331, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36162264

RESUMO

Tyrosinase plays a primary role in melanin biosynthesis and enzymatic browning of freshly cut fruits and vegetables. Herein, an on-line ultraperformance liquid chromatography diode array detector biochemical detection (UPLC-DAD-BCD) method was established to identify trace amount potent tyrosinase inhibitors and antibrowning agents in complex mixtures. The tyrosinase inhibition activities of some representative compounds were evaluated by using the established method and their chromatography-activity relationships were obtained. Then the proposed UPLC-DAD-BCD method was applied to screen tyrosinase inhibitors in edible herbal extracts and identified two tyrosinase inhibitors in green tea and three in cinnamon. The above active ingredients were determined by ultra-high-performance liquid chromatography linear ion trap/orbitrap high resolution mass spectrometry (UHPLC-FTMS). The on-line UPLC-DAD-BCD in combination with UHPLC-FTMS was confirmed to be a powerful technique to screen and elucidate the active ingredients in complex matrixes and could be applied to evaluate the integrated effects of multiple ingredients against corresponding targets.


Assuntos
Monofenol Mono-Oxigenase , Plantas Comestíveis , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Espectrometria de Massas/métodos , Extratos Vegetais/química
2.
Light Sci Appl ; 11(1): 324, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369148

RESUMO

Among 2D materials (Xenes) which are at the forefront of research activities, borophene, is an exciting new entry due to its uniquely varied optical, electronic, and chemical properties in many polymorphic forms with widely varying band gaps including the lightest 2D metallic phase. In this paper, we used a simple selective chemical etching to prepare borophene with a strong near IR light-induced photothermal effect. The photothermal efficiency is similar to plasmonic Au nanoparticles, with the added benefit of borophene being degradable due to electron deficiency of boron. We introduce this selective chemical etching process to obtain ultrathin and large borophene nanosheets (thickness of ~4 nm and lateral size up to ~600 nm) from the precursor of AlB2. We also report first-time observation of a selective Acid etching behavior showing HCl etching of Al to form a residual B lattice, while HF selectively etches B to yield an Al lattice. We demonstrate that through surface modification with polydopamine (PDA), a biocompatible smart delivery nanoplatform of B@PDA can respond to a tumor environment, exhibiting an enhanced cellular uptake efficiency. We demonstrate that borophene can be more suitable for safe photothermal theranostic of thick tumor using deep penetrating near IR light compared to gold nanoparticles which are not degradable, thus posing long-term toxicity concerns. With about 40 kinds of borides, we hope that our work will open door to more discoveries of this top-down selective etching approach for generating borophene structures with rich unexplored thermal, electronic, and optical properties for many other technological applications.

3.
Asian J Urol ; 9(4): 423-429, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36381601

RESUMO

Objective: Primary urethral carcinoma (PUC) is a rare malignant carcinoma but with limited therapeutic options. This review aims to provide an overview of the current strategies on this patient settings. Methods: Recent literature ranging from January 1987 and December 2021 was assessed through PubMed search to assess the diagnostic and therapeutic principles of PUC. Results: A complete of examination including cystoscopy, imaging, and biopsy should be conducted for these patients. Once diagnosed, the clinical decision of PUC should be made according to the tumor location, pathological pattern, and extent of the tumor. For patients with superficial and distal urethral lesions, organ sparing approaches or radical reconstructive procedures can be utilized. While for more advanced disease or nodal involvement, an optimal multimodal treatment strategy consisted of surgery and radiochemotherapy should be adopted. For patients with urothelial carcinoma of the prostate, the management including transurethral resection of the prostate followed by bacille Calmette-Guerin or radical cystoprostatectomy should depend on the infiltration depth of PUC. Conclusion: A complete of examination is important for the diagnosis of PUC. The management of PUC should be determined by the location, pathological pattern, and extent of the tumor. More multi-institutional collaborations should be held to investigate better treatment modalities for PUC.

4.
Front Oncol ; 12: 1012168, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36387191

RESUMO

Expression of DNA mismatch repair (MMR) protein (MLH1, PMS2, MSH2, and MSH6) in upper tract urothelial carcinoma (UTUC) has been explored in Western cohorts, but it is rarely reported in Eastern cohorts. We aimed to assess the loss of MMR protein expression among Chinese UTUC patients and study its clinicopathological implications. We enrolled 175 UTUC patients at our center and tested the expression of MMR proteins by immunohistochemistry. Then, we explored these patients' clinicopathological characteristics. We found loss of MMR proteins in 19 (10.9%) of 175 patients in our cohort (6 MSH2 and MSH6, 2 MSH6 alone, 6 MSH2 alone, 3 MLH1 and PMS2, and 2 PMS2 alone). Loss of MMR proteins was not a significant prognostic factor of relapse-free survival for these patients. In addition, patients with lower T stage or with bladder cancer history were more likely to have loss of MMR protein expression. At last, two metastatic patients (MSH2 and MSH6 loss; MSH2 loss) with loss of MMR protein experienced tumor recession after several cycles of anti-PD-1 immunotherapy. In conclusion, this is the largest Chinese UTUC cohort study to date that explores the loss of MMR protein expression. The rate of MMR loss observed was comparable to that in the Western UTUC cohort, supporting universal UTUC screening in China. Furthermore, a subset of advanced UTUCs with MMR protein loss are probably immunogenic, for whom single or combined immunotherapy may be potential therapeutic options in the future.

5.
J Cell Commun Signal ; 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36434320

RESUMO

Memo1 deletion in mice causes premature aging and an unbalanced metabolism partially resembling Fgf23 and Klotho loss-of-function animals. We report a role for Memo's redox function in renal FGF23-Klotho signaling using mice with postnatally induced Memo deficiency in the whole body (cKO). Memo cKO mice showed impaired FGF23-driven renal ERK phosphorylation and transcriptional responses. FGF23 actions involved activation of oxidation-sensitive protein phosphotyrosyl phosphatases in the kidney. Redox proteomics revealed excessive thiols of Rho-GDP dissociation inhibitor 1 (Rho-GDI1) in Memo cKO, and we detected a functional interaction between Memo's redox function and oxidation at Rho-GDI1 Cys79. In isolated cellular systems, Rho-GDI1 did not directly affect FGF23-driven cell signaling, but we detected disturbed Rho-GDI1 dependent small Rho-GTPase protein abundance and activity in the kidney of Memo cKO mice. Collectively, this study reveals previously unknown layers in the regulation of renal FGF23 signaling and connects Memo with the network of small Rho-GTPases.

6.
Front Genet ; 13: 968711, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36212128

RESUMO

Acupuncture is widely used to improve ovarian function. Previously, we demonstrated that acupuncture can improve oxidative stress in rats with tripterygium glycoside tablet suspension (TG)-induced diminished ovarian reserve (DOR). Herein, we aimed to explore the antioxidation mechanism of acupuncture for ameliorating the ovarian reserve in DOR rats. We performed microRNA sequencing and bioinformatics analysis to screen differentially expressed miRNAs (DE miRNAs) in ovarian tissues. In total, 1,172 miRNAs were identified by miRNA sequencing, of which 28 DE miRNAs were detected (including 14 upregulated and 14 downregulated) in ovarian tissues from the acupuncture group when compared with the DOR model rats. Based on functional enrichment analysis, the target genes of DE miRNAs were significantly enriched in GO-biological process (BP) terms associated with biological processes, positive regulation of transcription by RNA polymerase II, signal transduction, regulation of transcription, DNA-templated processes, and oxidation-reduction processes. In the Kyoto Encyclopedia of Genes and Genomes analysis, the main pathways were the MAPK signaling pathway, hepatitis B, proteoglycans in cancer, human cytomegalovirus infection, and the Ras signaling pathway. Finally, reverse transcription-quantitative PCR results confirmed that rno-miR-92b-3p, mdo-miR-26b-5p_R+1_1ss10TC, and bta-miR-7857-3p_R-1 were downregulated in the acupuncture group. The results revealed the impact of acupuncture on miRNA profiling of ovarian tissues from DOR rats, suggesting that rno-miR-92b-3p, mdo-miR-26b-5p_R+1_1ss10TC, and bta-miR-7857-3p_R-1 might provide relevant cues to relieve DOR-mediated oxidative stress.

7.
Vaccine ; 40(48): 6956-6962, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36283895

RESUMO

BACKGROUND: In recent years, the resurgence of pertussis has posed a public health challenge in many countries. This study aimed to evaluate the immunity levels against pertussis among populations of different ages in China. METHODS: We conducted a cross-sectional serological survey in Zhejiang Province, China in 2020. Serum IgG antibodies against pertussis toxin (anti-PT), filamentous hemagglutinin (anti-FHA), and pertactin (anti-PRN) were quantitatively measured. The geometric mean concentration (GMC) of three antibodies was calculated. An anti-PT level < 5 IU/mL was considered undetectable, ≥20 IU/mL as seropositive and ≥80 IU/mL as an indicator of recent infection. Mathematical models were fitted for anti-PT concentrations over time in children after four doses of the pertussis vaccination. RESULTS: A total of 4459 participants aged 0-59 years were included in the analyses. The overall positivity rate of anti-PT was 29.80% with the highest (81.44%) rate in the 1-2 years old and the lowest (4.72%) in 10-14 years old. The GMCs of anti-PT, anti-FHA and anti-PRN for the whole participants were 9.67 (95%CI: 9.25-10.10),18.93 (18.24-19.67), and 8.99 (8.61-9.38) IU/mL, respectively. Over 50% of subjects aged ≥ 7 years had undetectable anti-PT IgG antibodies (<5IU/mL). The proportions of the populations with anti-PT IgG ≥ 80 IU/mL were approximately 0.9%, 0.3% and 1.1% among the 10-14, 15-29, and 40-59 years old groups, respectively. The power regression equation of the attenuation model after last dose of pertussis vaccine was y = 41.088x-1.238 (R2 = 0.935, p < 0.001). The fitted anti-PT concentrations was only 5.60 IU/mL at 5 years following the last vaccination dose. CONCLUSION: The prevalence of pertussis decreased during the study period in the COVID-19 pandemic; however, there was still a certain proportion of adolescents and adults with evidence of recent infection. The decline in antibody levels after pertussis vaccination was observed, and booster doses are in urgent need in China.


Assuntos
COVID-19 , Coqueluche , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Lactente , Anticorpos Antibacterianos , China/epidemiologia , COVID-19/epidemiologia , Estudos Transversais , Imunoglobulina G , Pandemias , Toxina Pertussis , Vacina contra Coqueluche , Estudos Soroepidemiológicos , Coqueluche/epidemiologia , Coqueluche/prevenção & controle , Adulto Jovem , Pessoa de Meia-Idade
8.
IEEE Trans Image Process ; 31: 6487-6501, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36223353

RESUMO

Transferable adversarial attacks against Deep neural networks (DNNs) have received broad attention in recent years. An adversarial example can be crafted by a surrogate model and then attack the unknown target model successfully, which brings a severe threat to DNNs. The exact underlying reasons for the transferability are still not completely understood. Previous work mostly explores the causes from the model perspective, e.g., decision boundary, model architecture, and model capacity. Here, we investigate the transferability from the data distribution perspective and hypothesize that pushing the image away from its original distribution can enhance the adversarial transferability. To be specific, moving the image out of its original distribution makes different models hardly classify the image correctly, which benefits the untargeted attack, and dragging the image into the target distribution misleads the models to classify the image as the target class, which benefits the targeted attack. Towards this end, we propose a novel method that crafts adversarial examples by manipulating the distribution of the image. We conduct comprehensive transferable attacks against multiple DNNs to demonstrate the effectiveness of the proposed method. Our method can significantly improve the transferability of the crafted attacks and achieves state-of-the-art performance in both untargeted and targeted scenarios, surpassing the previous best method by up to 40% in some cases. In summary, our work provides new insight into studying adversarial transferability and provides a strong counterpart for future research on adversarial defense.


Assuntos
Redes Neurais de Computação
9.
Front Pediatr ; 10: 881064, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36299697

RESUMO

Objective: Primary warm-antibody autoimmune hemolytic anemia (w-AIHA) is prone to recurrence in children. In this study, we aimed to identify risk indicators for the early recurrence of primary w-AIHA and construct an effective recurrence risk assessment model. Methods: This was a retrospective cohort study. The clinical data of patients hospitalized with primary w-AIHA in the Department of Hematology and Oncology, Children's Hospital of Chongqing Medical University, between 1 January 2018 and 30 September 2021, were collected at the initial diagnosis. Univariate and multivariate logistic regression analyses were used to determine risk indicators for the early recurrence of primary w-AIHA in children, and ROC curve and Kaplan-Meier survival analyses were used for verification. Finally, a risk assessment model for early recurrence in children with primary w-AIHA was constructed using Cox regression and visualized using a nomogram. The model was also verified internally and externally. Results: This study included 62 children with primary w-AIHA. Of which, 18 experienced recurrence 1 year after the initial diagnosis. The univariate and multivariate logistic regression analyses showed that type O blood and the reticulocyte count (Ret) were risk indicators for the early recurrence of pediatric primary w-AIHA (P = 0.009, 0.047, respectively). The mean corpuscular hemoglobin concentration (MCHC) is a protective factor (P = 0.040). According to the ROC curve and Kaplan-Meier survival analyses, children with primary w-AIHA whose blood type was O or had an MCHC of <313.5 pg/fL or a Ret of ≥0.161×1012/L had a higher risk of early recurrence (HR = 2.640, 4.430 and 4.450, respectively, and P = 0.040, 0.015 and 0.018, respectively). The blood types (O), MCHCs, and Rets of 56 patients were incorporated into the Cox regression model, and the recurrence risk assessment model for children with primary w-AIHA was successfully constructed and visualized using a nomogram. The calibration curves and decision-curve analysis (DCA) suggested that the risk model has clinical applicability and effectiveness. Conclusion: Children with type O blood and an MCHC value of <313.5 pg/fL or a Ret value of ≥0.161×1012/L have a higher risk of early recurrence. The risk assessment model for the early recurrence of pediatric primary w-AIHA constructed in this study has good clinical applicability and effectiveness.

10.
Cells ; 11(19)2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36231077

RESUMO

Chronic obstructive pulmonary diseases (COPD) is a kind of age-related, airflow-obstruction disease mostly caused by cigarette smoke. However, the relationship between COPD and lung cellular senescence is still not fully understood. Here, we found silencing Pellino-1 could inhibit the protein level of P21. Then, through constructing cell lines expressed ubiquitin-HA, we found that the E3 ubiquitin ligase Pellino-1 could bind to senescence marker p21 and modify p21 by K63-site ubiquitination by co-IP assays. Furthermore, we found that p21-mediated lung cellular senescence could be inhibited by silencing Pellino-1 in a D-galactose senescence mice model. Moreover, by constructing a COPD mouse model with shPellino-1 adenovirus, we found that silencing Pellino-1 could inhibit COPD and inflammation via reduction of SASPs regulated by p21. Taken together, our study findings elucidated that silencing E3 ligase Pellino-1 exhibits therapeutic potential for treatment to attenuate the progression of lung cellular senescence and COPD.


Assuntos
Galactose , Proteínas Nucleares/metabolismo , Doença Pulmonar Obstrutiva Crônica , Ubiquitina-Proteína Ligases/metabolismo , Animais , Senescência Celular , Modelos Animais de Doenças , Pulmão/metabolismo , Camundongos , Proteínas Nucleares/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Ubiquitinas/metabolismo
11.
J Infect ; 85(5): 499-506, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36245138

RESUMO

OBJECTIVES: Escherichia coli is a common pathogen causing invasive bacterial infections in neonates. In recent years, clinical antimicrobial susceptibility testing has demonstrated an increased rate of drug-resistant E. coli infections. This study aimed to analyse the resistance characteristics of E. coli against common antimicrobial agents, and perform multilocus sequence typing (MLST) in clinical strains of E. coli collected from Chinese neonates. METHODS: Culture-positive specimens of E. coli were collected from neonates in seven class A tertiary hospitals located in seven cities across different provinces in China between November 2019 and October 2020. E. coli isolated from these specimens were subjected to antimicrobial susceptibility testing (by broth microdilution method), extended-spectrum ß-lactamase (ESBL) detection, and MLST. RESULTS: A total of 223 E. coli strains were isolated, with an overall resistance rate of 87.4%, an ESBL-positive rate of 48.0%, and a multidrug resistance rate of 42.2%. Among the 20 antimicrobial agents tested, E. coli strains showed the highest resistance rates against cefotaxime (59.2%), trimethoprim/sulfamethoxazole (56.5%), doxycycline (39.9%), ciprofloxacin (36.8%), and aztreonam (31.0%). The resistance rates of E. coli strains isolated from children's hospitals against piperacillin/tazobactam, cefotaxime, ciprofloxacin, trimethoprim/sulfamethoxazole, and carbapenems, were significantly higher than those of strains isolated from maternity and child health hospitals. The primary E. coli multilocus sequence types were ST1193, ST95, ST73, ST410, and ST131. The ESBL production rates and multidrug resistance rates of ST1193, ST410, and ST131 were significantly higher than those of ST95 and ST73. Significantly, more strains of E. coli ST1193 and ST410 were isolated from children's hospitals than from maternity and child health hospitals. CONCLUSIONS: The rates of antimicrobial agent resistance in E. coli isolates from hospitalised neonates in China were high. The increased number of strains of E. coli ST1193 and ST410 was the reason for higher resistance rates to multiple antimicrobial agents in E. coli from children's hospitals compared with those from maternal and child health hospitals.


Assuntos
Infecções por Escherichia coli , Escherichia coli , Antibacterianos/farmacologia , Aztreonam , Carbapenêmicos , Cefotaxima , Criança , Ciprofloxacina , Doxiciclina , Resistência a Medicamentos , Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/microbiologia , Feminino , Humanos , Recém-Nascido , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Piperacilina , Gravidez , Tazobactam , Centros de Atenção Terciária , Combinação Trimetoprima e Sulfametoxazol , beta-Lactamases
12.
Am J Transl Res ; 14(9): 5982-6010, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36247256

RESUMO

OBJECTIVE: We conducted an in-depth study of the immune system and ferroptosis to identify prognostic biomarkers and therapeutic targets for renal clear cell carcinoma. METHODS: Immune ferroptosis-related differentially expressed genes (IFR-DEGs) were selected from The Cancer Genome Atlas (TCGA). A lasso-Cox risk scoring model was established; its prognostic value was determined using prognostic analysis and single multivariate Cox analysis. Model genes were subjected to subcellular fluorescence localization, mRNA and protein expression analyses, and single-cell RNA sequencing localization analysis. Risk score was analyzed using the immune score, immune infiltrating cell correlation, immune checkpoint, TIDE, and drug sensitivity. RESULTS: A total of 103 IFR-DEGs were identified; a risk model comprising ACADSB, CHAC1, LURAP1L, and PLA2G6 was established. The survival curve, single multivariate Cox regression, and receiver operating characteristic (ROC) curve analysis showed that the model had good predictive ability (p < 0.05). It was also validated using the validation set and total cohort. Subcellular fluorescence localization revealed that ACADSB, CHAC1, and PLA2G6 were distributed in the cytoplasm and LURAP1L in the nucleus. The mRNA and protein expression trends were consistent. Single-cell RNA sequencing mapping revealed that ACADSB was enriched in distal tubule cell clusters. In the Kidney renal clear cell carcinoma (KIRC) mutation correlation analysis, 1.56% of the patients were found to have genetic alterations; The Spearman correlation analysis of model gene mutations showed that ACADSB was positively correlated with LURAP1L, which may have a synergistic effect; it was negatively correlated with CHAC1 and PLA2G6, and CHAC1 was negatively correlated with LURAP1L, which may have an antagonistic effect. Model and immune correlation analyses found that high-risk patients had significantly higher levels of CD8+ T cells, regulatory T cells (Tregs), immune checkpoints, immune scores, and immune escape than those in low-risk patients. High-risk patients had a higher susceptibility to small-molecule drugs. CONCLUSION: A novel prognostic model of immune ferroptosis-related genes (ACADSB, CHAC1, LURAP1L, and PLA2G6), which plays an important role in immune infiltration, microenvironment, and immune escape, was constructed. It effectively predicts the survival of patients with KIRC.

13.
Front Hum Neurosci ; 16: 1005425, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36310844

RESUMO

Introduction: Attention deficit and hyperactivity disorder (ADHD) is a common inherited disease of the nervous system whose cause(s) and pathogenesis remain unclear. Currently, the diagnosis of ADHD is mainly based on clinical experience and guidelines that have laid out some diagnostic standards. Our study aimed to apply a learning-based classification method to assist the ADHD diagnosis based on high-dimensional resting-state fMRI. Methods: Our study selected the ADHD-200 Peking dataset of resting-state fMRI, which has an ADHD patient (n = 142) group and a typically developing control (TDC) healthy control (n = 102) group. We first used Pearson and partial correlation coefficients to perform functional connectivity (FC) analysis between ROIs. Then, the Pearson and partial correlation coefficient matrices were concatenated into a dual-channel feature to build a dual data channel as input to the transfer learning neural network (TLNN) architecture. Finally, we transferred the pretrained model from the auxiliary domain to our target domain and fine-tuned it. Results: Based on the Pearson correlation coefficient, FC between ROIs was detected in 22 brain regions, including the fusiform gyrus, superior frontal gyrus, posterior superior temporal sulcus, inferior parietal lobule, anterior cingulate cortex, and parahippocampal gyrus. Based on the partial correlation coefficient, we found FC in the salient network, default network, sensory-motor network, dorsal attention network, and cerebellum network. With the TLNN architecture, we solved the problem of insufficient training data and improved the sensitivity of the classification method. When the VGG model (fine-tuned transfer strategy, 1,024 fully connected layers) was applied, the accuracy of TLNN classification ultimately reached 82%. Conclusion: Our study suggests that completing the training of the target domain by transferring the prior knowledge of the auxiliary domain is effective in solving the classification problem of small sample datasets. Based on prior knowledge of FC analysis, TLNN classification may assist ADHD diagnosis in a new way.

14.
Prostate Int ; 10(3): 142-147, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36225282

RESUMO

Background: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been approved for use in breast cancer susceptibility gene (BRCA)-mutated metastatic castration-resistant prostate cancer (mCPRC) patients. Our aim was to evaluate the adverse events (AEs) and efficacy of Olaparib in the treatment of mCRPC patients from the Chinese mainland. Methods: We retrospectively included mCPRC patients treated with Olaparib more than for 28 days. Patients with alterations in 15 homologous recombination repair (HRR) genes were defined as the HRRmt group, and the rest were defined as the HRRwt group. The efficacy was analyzed by prostate-specific antigen (PSA) decreased rate and PSA progression-free survival (PFS). The partial response, good response, and high response of PSA were defined as a reduction of between 0% and 50%, greater than 50%, and greater than 90% from baseline. Results: A total of 43 patients were enrolled in this study, including 26 HRRmt group patients and 17 HRRwt group patients. Two HRRwt patients received additional abiraterone therapy. A partial response, good response, and high response were achieved in 89% (23/26), 59% (15/26), and 15% (4/26) of HRRmt group patients, respectively. In HRRwt group, 59% (10/17), 35% (6/17), and 12% (2/17) of patients met the criteria of partial response, good response, and high response, respectively. Median PFS was 8.0 months in the HRRmt group and 3.0s months in the HRRwt group (HR, 0.61; 95% CI, 0.24-1.14; p = 0.148), respectively. All the 20 patients had AEs during Olaparib treatment. Ten episodes of grade 3 or 4 AEs were observed in four patients. The most common all-grade AEs were fatigue or asthenia (70%), anemia (65%), and decreased appetite (55%). Conclusions: Most of the AEs were tolerated, and Olaparib was effective in mCRPC patients with HRR deficiency. In addition, the underlying mechanism of the efficacy of Olaparib observed in HRRwt group patients remained explored.

15.
Mol Oncol ; 2022 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-36209367

RESUMO

The success of the PROfound, IPATential150, and TheraP trials promoted the transition from sequential treatment to therapeutic targets (TTs)-guided precision treatment in metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to evaluate the prevalence and prognostic value of TTs from these three trials. All included Chinese mCRPC patients underwent circulating tumor DNA (ctDNA) sequencing, PTEN status assessment, and dual-tracer [68 Ga-prostate-specific membrane antigen (PSMA) and 18 F-fluorodexyglucose (FDG)] positron emission tomography/computed tomography (PET/CT). Previous treatment with cabazitaxel, Lu-PSMA or olaparib was unallowed. Patients with known significant sarcomatoid or spindle cell or neuroendocrine small cell components were also excluded. TTs were defined as positive as follows: (a) high PSMA and no PSMA-/FDG+ disease on dual-tracer PET/CT scans; (b) defects in homologous recombination repair (HRR) genes in ctDNA; and (c) loss of PTEN immunohistochemistry staining in tumor tissue. The prevalence and prognostic value on progression-free survival (PFS) of TTs were evaluated. A total of 106 consecutive mCRPC patients were included. The prevalence of positive PET/CT, HRR defect, and PTEN loss was 30%, 29% and 16%, respectively. Sixty-three patients had at least one TT. Metastatic volume (odds ratio = 5.0; P = 0.017) was the only independent factor of positive TT in multivariate analysis. Seventy-four patients received abiraterone after TT screening. Patients with positive PET/CT (P = 0.011) and HRR defect (P = 0.002) had a significantly shorter PFS after receiving abiraterone than patients with negative TTs. However, PTEN status was unrelated to PFS, which may be due to a less number of patients with PTEN loss (P = 0.952). Overall, patients with any positive TTs had a significantly shorter PFS after abiraterone than patients with negative TTs (P = 0.009). Nearly 60% of Chinese patients with mCRPC who had a poor prognosis on abiraterone were candidates for precision treatments based on the specific criteria of TTs.

16.
J Am Chem Soc ; 144(41): 18778-18783, 2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36194507

RESUMO

We achieved a concise total synthesis of salimabromide by using a novel intramolecular radical cyclization to simultaneously construct the unique benzo-fused [4.3.1] carbon skeleton and the vicinal quaternary stereocenters. Other notable transformations include a tandem Michael/Mukaiyama aldol reaction to introduce most of the molecule's structural elements, along with hidden information for late-stage transformations, an intriguing tandem oxidative cyclization of a diene to form the bridged butyrolactone and enone moieties spontaneously, and a highly enantioselective hydrogenation of a cycloheptenone derivative (97% ee) that paved the way for the asymmetric synthesis of salimabromide.


Assuntos
Carbono , Compostos Heterocíclicos de 4 ou mais Anéis , Estereoisomerismo , Ciclização , Compostos Heterocíclicos de 4 ou mais Anéis/química
17.
Opt Lett ; 47(20): 5373-5376, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36240366

RESUMO

We present and demonstrate a method based on a periodic phase noise estimation in an optical frequency domain reflectometry (OFDR) capable of a beyond 107 range-resolution-1 product (RRP) for the first time, which corresponds to 2.5 × improvement compared with the state-of-the-art. The moving average filter is employed to suppress the amplification of noise in the derivation process. Further, with the help of a third-order Taylor expansion, this method provides a highly precise estimation of periodic phase noise, which is the main factor impacting the performance of OFDR systems with medium-to-long measurement range combined with a submillimeter spatial resolution. A spatial resolution within 535 µm over the measurement range of 8 km is obtained. The proposed method offers a promising technique for fiber network monitoring and sensing applications.

18.
PLoS Genet ; 18(9): e1010373, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36095024

RESUMO

Prostate cancer is the most inheritable cancer with approximately 42% of disease risk attributed to inherited factors by studies of twins, indicating the importance of additional genetic screening to identify predisposition variants. However, only DNA damage repair (DDR) genes have been investigated thoroughly in prostate cancer. To determine the comprehensive germline mutation landscape in Chinese prostate cancer patients, we performed whole exome sequencing in 100 Han Chinese patients with prostate cancer in Hong Kong and identified deleterious germline mutations. A total of 36 deleterious germline variants in 25 genes were identified in 29% patients. Variants were found in eight pathways, including DNA methylation, DDR, and tyrosine-protein kinase. These findings were validated in an independent Chinese cohort of 167 patients with prostate cancer in Shanghai. Seven common deleterious-variant-containing genes were found in discovery cohort (7/25, 28%) and validation cohort (7/28, 25%) with three genes not described before (LDLR, MYH7 and SUGCT) and four genes previously reported (FANCI, ITGA6, PABPC1 and RAD54B). When comparing with that of a cohort of East Asian healthy individuals, 12 non-DDR novel potential predisposition genes (ADGRG1, CHD4, DNMT3A, ERBB3, GRHL1, HMBS, LDLR, MYH7, MYO6, NT5C2, NUP98 and SUGCT) were identified using the discovery and validation cohorts, which have not been previously reported in prostate cancer patients in all ethnic groups. Taken together, this study reveals a comprehensive germline mutation landscape in Chinese prostate cancer patients and discovers 12 novel non-DDR predisposition genes to lay the groundwork for the optimization of genetic screening.


Assuntos
Mutação em Linhagem Germinativa , Neoplasias da Próstata , China , Predisposição Genética para Doença , Humanos , Masculino , Neoplasias da Próstata/genética , Proteínas Quinases/genética , Tirosina/genética , Sequenciamento Completo do Exoma
19.
J Ethnopharmacol ; 302(Pt A): 115700, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36126782

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Obesity is a critical threat to global health, and brown adipose tissue (BAT) is a potential target for the treatment of obesity and comorbidities. Xuezhikang Capsule (XZK), an extract of red yeast rice, has remarkable clinical efficacy and is widely used for the treatment of hyperlipidemia and coronary heart disease. However, its modulatory effect on BAT remains unknown. AIM OF THIS STUDY: The aim of this study was to investigate the protective mechanism of XZK in the obese spontaneously hypertensive rat (SHR) model by evaluating the regulatory effect of XZK on the BAT gene profile through transcriptome sequencing. MATERIALS AND METHODS: The SHRs were randomly divided into four groups: the standard chow diet (STD) group, the STD supplemented with 126 mg/kg of XZK group, the high-fat diet (HFD) group, and the HFD supplemented with 126 mg/kg of XZK group. All SHRs were fed for 18 weeks. The metabolic phenotypes, including body weight, fat mass, oral glucose tolerance test (OGTT), and serum glucose and lipid levels, was evaluated, and hematoxylin and eosin staining (H&E) staining was performed to evaluate the adipose tissue histopathological phenotype. Transcriptome sequencing was performed to determine the mechanism by which XZK improves the metabolic phenotype and the expression of key differential expression genes was verified by real-time quantitative polymerase chain reaction (qRT-PCR). RESULTS: XZK inhibited HFD-induced weight gain and adipose tissue remodeling in SHRs and prevented hypertrophy of epididymal adipocytes and maintained the brown fat phenotype. XZK intervention also improved glucose and lipid metabolism in SHRs, as suggested by a reduction in serum triglyceride (TG), low-density cholesterol (LDL-C), and fasting blood glucose (FBG) levels as well as increasing in serum high-density cholesterol (HDL-C) levels. Transcriptome sequencing analysis confirmed the regulatory effect of XZK on the gene expression profile of BAT, and the expression patterns of 45 genes were reversed by the XZK intervention. Additionally, the results of the transcriptome analysis of 10 genes that are important for brown fat function were in line with the results of qRT-PCR. CONCLUSIONS: XZK protected SHRs from HFD-induced obesity, inhibited fat accumulation and improved glucolipid metabolism. Additionally, the protective effect of XZK on the overall metabolism of obese SHRs might partly be related to its regulatory effect on the BAT gene expression profile. These findings might provide novel therapeutic strategies for obesity-related metabolic diseases in traditional Chinese medicine (TCM).

20.
Open Life Sci ; 17(1): 1104-1115, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36133421

RESUMO

Interleukin (IL)-17A plays a role in the development of atherosclerotic plaques; however, the mechanism remains unclear. In this study, apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat diet to induce atherosclerosis, followed by the treatment with exogenous recombinant IL-17A or the neutralizing antibody to confirm the impact of IL-17A on the established atherosclerotic plaques. We found that both the stimulation of IL-17A and blockage of endogenous IL-17 via antibody did not affect the size of the established plaques. However, IL-17A significantly increased the vulnerability of plaques characterized by the accumulation of lipids and T cells with a concurrent decrease in the number of smooth muscle cells. In addition, the blockage by IL-17 neutralizing antibody attenuated plaque vulnerability. Furthermore, we found that although IL-17A did not affect the efferocytosis of macrophages to apoptotic cells, it promoted the apoptosis of macrophages in the presence of oxidized low-density lipoprotein in vitro. Also, IL-17A upregulated chemokines MCP-1 and CXCL-10 expression in the plaques. Our data indicated that IL-17A controlled both SMC and macrophage accumulation and the apoptosis within the plaque, which may further weaken the aorta wall. This study suggests that IL-17A may be a potential therapeutic target for cardiovascular diseases.

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