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1.
J Colloid Interface Sci ; 606(Pt 2): 1882-1889, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34689044

RESUMO

Designing high-efficiency heterojunction photocatalysts for water splitting is an intriguing prospect in energy conversion. Herein, we successfully fabricated a CdS/ZIF-8 heterojunction system through a facile wet-chemically method, in which ZIF-8 nanoparticles were in-situ adhered on hollow CdS nanotubes. Due to the well-matched band structure and intimate interface contact in CdS/ZIF-8 hybrid structure, the interfacial charge separation in the established system was tremendously boosted. As a consequence, the established CdS/ZIF-8 heterojunction exhibited the optimal photocatalytic hydrogen production performance (2.10 mmol·g-1 L-1), which was 35 times higher than pristine CdS (0.06 mmol·g-1·L-1). We believe this strategy will endow new insights for the development of novel photocatalysts.

2.
Front Immunol ; 12: 743704, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721411

RESUMO

Objective: Anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody is a distinctive serology hallmark of dermatomyositis (DM). As an autoantigen, MDA5 is a cytoplasmic RNA recognition receptor. The aim of this study was to address the question of whether the RNA-containing immune complex (IC) formed by MDA5 and anti-MDA5 could activate type I interferon (IFN) response. Method: Patients with anti-MDA5+ DM (n = 217), anti-MDA5- DM (n = 68), anti-synthase syndrome (ASyS, n = 57), systemic lupus erythematosus (SLE, n = 245), rheumatoid arthritis (RA, n = 89), and systemic sclerosis (SSc, n = 30) and healthy donors (HD, n = 94) were enrolled in our studies. Anti-MDA5 antibody was detected by line blotting, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, and Western blotting. Cytokine profiling was determined by multiplex flow cytometry, and IFN-α was further measured by ELISA. Type I IFN-inducible genes were detected by quantitative PCR (qPCR). RNA-IC binding was analyzed by RNA immunoprecipitation. Plasmacytoid dendritic cells (pDCs) derived from healthy donors were cultivated and stimulated with MDA5 ICs with or without RNase and Toll-like receptor 7 (TLR-7) agonist. The interaction between MDA5 ICs and TLR7 was evaluated by immunoprecipitation and confocal microscopy. Results: According to our in-house ELISA, the presence of anti-MDA5 antibody in 76.1% of DM patients, along with 14.3% of SLE patients who had a lower titer yet positive anti-MDA5 antibody, was related to the high level of peripheral IFN-α. ICs formed by MDA5 and anti-MDA5 were potent inducers of IFN-α via TLR-7 in an RNA-dependent manner in vitro. Conclusion: Our data provided evidence of the mechanistic relevance between the anti-MDA5 antibody and type I IFN pathway.

3.
Emerg Microbes Infect ; : 1-34, 2021 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-34836485

RESUMO

The repeated emergence of highly pathogenic human coronaviruses as well as their evolving variants highlight the need to develop potent and broad-spectrum antiviral therapeutics and vaccines. By screening monoclonal antibodies (mAbs) isolated from COVID-19-convalescent patients, we found one mAb, 2-36, with cross-neutralizing activity against SARS-CoV. We solved the cryo-EM structure of 2-36 in complex with SARS-CoV-2 or SARS-CoV spike, revealing a highly conserved epitope in the receptor-binding domain (RBD). Antibody 2-36 neutralized not only all current circulating SARS-CoV-2 variants and SARS-COV, but also a panel of bat and pangolin sarbecoviruses that can use human angiotensin-converting enzyme 2 (ACE2) as a receptor. We selected 2-36-escape viruses in vitro and confirmed that K378 T in SARS-CoV-2 RBD led to viral resistance. Taken together, 2-36 represents a strategic reserve drug candidate for the prevention and treatment of possible diseases caused by pre-emergent SARS-related coronaviruses. Its epitope defines a promising target for the development of a pan-sarbecovirus vaccine.

4.
Org Lett ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34787420

RESUMO

Herein we report an enantioselective sulfenylation of cyclic imino esters with the efficient and versatile sulfenylation reagent S-alkyl 4-methylbenzenesulfonothioates. By utilizing the Cu/tBu-Phosferrox catalytic system, we can assemble diverse S-alkyl groups into the cyclic imino esters under mild conditions in good yields and with excellent enantioselectivities. Remarkably, this method demonstrates a high tolerance of diverse functional groups and proves to be applicable in the late-stage functionalization of pharmaceuticals.

5.
Front Med (Lausanne) ; 8: 746759, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34805216

RESUMO

Background: Current guidelines recommend that pregnancies with mother-to-child transmission (MTCT) prevention can cease antiviral treatment after delivery. We aimed to develop a nomogram for predicting non-rebound in HBV-infected pregnant women with MTCT prevention after post-partum nucleos(t)ide analogs (NAs) withdrawal based on parameters before treatment cessation. Methods: Pregnant women receiving antiviral therapy for MTCT prevention and who withdrew from taking NAs after delivery were included in this study. We used the least absolute shrinkage and selection operator (LASSO) logistics and a two-way stepwise regression to select prognostic factors for the risk model, and the concordance index (C-index) was used to assess its discrimination. Internal validation was performed through bootstrapping. Results: Of 92 included patients, 16 and 76 experienced non-rebound and virologic rebound within 48 weeks of post-partum NAs cessation, respectively. Platelet to lymphocyte ratio (PLR) at 34 ± 2 weeks of gestation, a reduction in hepatitis B surface antigen (HBsAg) from baseline to 34 ± 2 weeks of gestation, and hepatitis B virus (HBV) DNA declining from baseline to the end of treatment (EOT) were entered into the final risk model. Its C-index was 0.91 (95% CI, 0.82-0.99), and it reached as high as 0.88 after bootstrapping validation. The decision curve and decision tree were further developed to facilitate the application of this model. Conclusions: We developed a nomogram for predicting non-rebound in pregnant women with MTCT prevention after the withdrawal of antiviral agents, which facilitates physicians in making appropriate treatment recommendations.

6.
FEBS Open Bio ; 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34800087

RESUMO

Dermatomyositis and rheumatoid arthritis are inflammatory diseases which affect the skeletal muscles and joints, respectively. A common systemic complication of these diseases is interstitial lung disease (ILD) which leads to poor prognosis and increased mortality. However, the mechanism for initiation and development of ILD in patients with dermatomyositis is currently unknown. In this study, we used 16S rRNA high-throughput sequencing to profile the bacterial community composition of bronchoalveolar lavage fluid (BALF) of patients with dermatomyositis associated with ILD (DM-ILD, shortened to DM below), rheumatoid arthritis associated with ILD (RA-ILD, shortened to RA below) and healthy controls (N) to understand the differences in their lung microbiota and to predict gene function. We found that there were more operational taxonomic units (OTUs) in the lung microbiota of both RA and DM, compared to N, but there was no significant difference in the number of OTUs between RA and DM. Similarly, the diversity in alphaproteobacteria differed between RA and DM compared to N, but not between RA and DM. The lung microbiota of RA, DM, and N was mainly comprised of five phyla: Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, and Fusobacteria and 10 dominant genera. Despite the similarity in microbiota composition, we also identified 41 OTUs of lung microbiota that differed among RA, DM, and N. Additionally, linear discriminant analysis effect size (LEfSe) and linear discriminant analysis genus scores confirmed that 31 microbial biomarkers were clearly distinguished among RA, DM, and N. The functional and metabolic alterations of the lung microbiota among RA, DM, and N were predicted using PICRUSt, and differentially abundant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified. Research on the lung microbiota of patients with DM and RA may open new opportunities to develop biomarkers to identify high-risk patients.

7.
J Microbiol Methods ; : 106378, 2021 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-34818574

RESUMO

Listeria monocytogenes belongs to the category of facultative anaerobic bacteria, and is the pathogen of listeriosis, potentially lethal disease for humans. There are many similarities between L. monocytogenes and other non-pathogenic Listeria species, which causes great difficulties for their correct identification. The level of L. monocytogenes contamination in food remains high according to statistics from the Food and Drug Administration. This situation leads to food recall and destruction, which has caused huge economic losses to the food industry. Therefore, the identification of Listeria species is very important for clinical treatment and food safety. This work aims to explore an efficient classification algorithm which could easily and reliably distinguish Listeria species. We attempted to classify Listeria species by incorporating denoising autoencoder (DAE) and machine learning algorithms in matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). In addition, convolutional neural networks were used to map the high dimensional original mass spectrometry data to low dimensional core features. By analyzing MALDI-TOF MS data via incorporating DAE and support vector machine (SVM), the identification accuracy of Listeria species was 100%. The proposed classification algorithm is fast (range of seconds), easy to handle, and, more importantly, this method also allows for extending the identification scope of bacteria. The DAE model used in our research is an effective tool for the extraction of MALDI-TOF mass spectrometry features. Despite the fact that the MALDI-TOF MS dataset examined in our research had high dimensionality, the DAE + SVM algorithm was still able to exploit the hidden information embedded in the original MALDI-TOF mass spectra. The experimental results in our work demonstrated that MALDI-TOF mass spectrum combined with DAE + SVM could easily and reliably distinguish Listeria species.

8.
Org Biomol Chem ; 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34806739

RESUMO

A mild and simple method is reported for the construction of 3-difluoroarylmethylated coumarins using α,α-difluoroarylacetic acids as an easily handled difluoromethyl source in reaction with ester 3-arylpropiolates under the promotion of copper. The reaction involves a proposed radical-triggered domino decarboxylative aryldifluoromethylation/5-exo cyclization/ester migration process that directly forms Csp2-CF2Ar and C-C bonds with good functional group tolerance.

9.
Exp Ther Med ; 22(6): 1466, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34737806

RESUMO

Ageing often results in insulin resistance (IR) and chronic inflammation, and adipose is one of the tissues in which inflammation and IR occur earliest during this process. The present study investigated the effect and underlying mechanisms of ursolic acid (UA) on adipose IR and inflammation in ageing rats. Specific pathogen-free male Sprague-Dawley rats were randomly divided into 4 groups: i) Young normal (young); ii) untreated ageing (aged); and groups supplemented with UA either iii) low-UA 10 mg/kg (UA-L) or iv) high-50 mg/kg (UA-H). Animals in the UA-treated groups received 10 or 50 mg/kg UA (suspended in 5% Gum Arabic solution). The rats in the corresponding aged group and young groups received vehicle (5% Gum Arabic) alone. All rats were intragastrically treated once daily by oral gavage for 7 weeks. The day before the experiment terminated, overnight fasting blood (~700 µl) was collected and plasma was prepared to measure biochemical indicators; western blotting was performed to analyze the expression of insulin signaling proteins [(insulin receptor substrate 1 (IRS-1), phosphorylated (p)-IRS-1, PI3K, glucose transporter 4 (GLUT4), Akt and p-Akt)] and inflammatory factors (NF-κB, IL-6 and IL-1ß) in the epididymis white adipose tissue (eWAT). The results revealed that treatment with UA-H decreased eWAT weight, the ratio of eWAT weight/body weight, fasted insulin and triglyceride levels, the homeostasis model assessment of insulin resistance and adipose tissue insulin resistance index in ageing rats, indicating the amelioration of systemic and adipose tissue IR, compared with the aged group. Mechanistically, UA-H administration upregulated p-protein kinase B, the ratio of p-Akt to protein kinase B and total and cellular membrane GLUT4 protein levels in eWAT of ageing rats. Conversely, UA inhibited the increase in NF-κB expression and proinflammatory cytokines IL-6 and IL-1ß. However, these alterations were not observed in the rats of the aged group. Taken together, the findings of the present study indicated that UA may ameliorate adipose IR, which is associated with activation of the Akt-GLUT4 signaling pathway and inhibition of inflammation in ageing rats. These data provide a basis for the development of effective and safe drugs or functional substances, such as UA, for the prevention and treatment of metabolic diseases.

10.
Front Pharmacol ; 12: 708636, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603023

RESUMO

Background: The outbreak of coronavirus disease 2019 (COVID-19) has rapidly spread to become a global emergency since December 2019. Chinese herbal medicine plays an important role in the treatment of COVID-19. Chinese herbal medicine honeysuckle is an extremely used traditional edible and medicinal herb. Many trials suggest that honeysuckle has obtained a good curative effect for COVID-19; however, no systematic evaluation on the clinical efficacy of honeysuckle in the treatment of COVID-19 is reported. This study aimed to evaluate the efficacy and safety of Chinese herbal medicine honeysuckle in the treatment of COVID-19. Methods: Seven electronic databases (PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and China Biology Medicine) were searched to identify randomized controlled trials (RCTs) of honeysuckle for adult patients (aged ≥ 18 years) with COVID-19. The Cochrane Risk of Bias Tool was applied to assess the methodological quality of trials. Review Manager 5.3 software was used for data analysis. Results: Overall, nine RCTs involving 1,286 patients were enrolled. Our meta-analyses found that combination therapy of honeysuckle and conventional therapy was more effective than conventional therapy alone in lung computed tomography (CT) [relative risk (RR) = 1.24, 95% confidence interval (95%CI) (1.12, 1.37), P < 0.0001], clinical cure rate [RR = 1.21, 95%CI (1.12, 1.31), P < 0.00001], and rate of conversion to severe cases [RR = 0.50, 95%CI (0.33, 0.76), P = 0.001]. Besides, combination therapy can improve the symptom score of fever, cough reduction rate, symptom score of cough, and inflammatory biomarkers (white blood cell (WBC) count; C-reactive protein (CRP)) (P < 0.05). Conclusion: Honeysuckle combined with conventional therapy may be beneficial for the treatment of COVID-19 in improving lung CT, clinical cure rate, clinical symptoms, and laboratory indicators and reducing the rate of conversion to severe cases. Besides, combination therapy did not increase adverse drug events. More high-quality RCTs are needed in the future.

11.
Aesthetic Plast Surg ; 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34595598

RESUMO

OBJECTIVE: To evaluate the clinical efficacy and safety of the new autologous tissue filler derived from autologous skin and hairs for correction of nasolabial folds. MATERIALS AND METHODS: The new injectable soft tissue filler is prepared from autologous fibroblasts and keratin gel. A total of 40 patients were enrolled in this single-armed pilot study, all of them received the new filler injection treatment for correction nasolabial folds. Following up with the patients, collection of their clinical features, including photographs, satisfaction, and information on adverse events at the 1st, 3rd, 6th, 12th, and 24th months after injection. The clinical efficacy of each patient was evaluated by masked evaluators and independent expert panels, based on the Wrinkle Severity Rating Scale (WSRS) at different time points after the injection. RESULTS: Thirty-two patients completed the 24-months follow-up, obtaining at least 93.8% improvement, and 75% of them had significantly improved. Base on the self-satisfaction assessment (SSA) indicated that all of them were satisfied with the results. No adverse effects of filler injection treatment were observed during the follow-up. CONCLUSIONS: The combination of autologous keratin and fibroblasts as a new tissue engineering soft tissue filler has shown safety and long-term efficiency in correcting nasolabial folds, with high satisfaction and desirable result. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

12.
Plant Dis ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645309

RESUMO

Wheat pathogens, especially those causing powdery mildew and stripe rust, seriously threaten yield worldwide. Utilizing newly identified disease resistance genes from wheat relatives is an effective strategy to minimize disease damage. In this study, chromosome-specific molecular markers for the 3Sb and 7Sb chromosomes of Aegilops bicornis were developed using PCR-based landmark unique gene (PLUG) primers for screening wheat-Ae. bicornis progenies. Fluorescence in situ hybridization (FISH) was performed to further identify wheat-Ae. bicornis progenies using oligonucleotides probes Oligo-pSc119.2-1, Oligo-pTa535-1, and Oligo-(GAA)8. After establishing Ae. bicornis 3Sb and 7Sb chromosome-specific FISH markers, Holdfast (common wheat)-Ae. bicornis 3Sb addition, 7Sb addition, 3Sb(3A) substitution, 3Sb(3B) substitution, 3Sb(3D) substitution, 7Sb(7A) substitution, and 7Sb(7B) substitution lines were identified by the molecular and cytological markers. Stripe rust and powdery mildew resistance, along with agronomic traits were investigated to evaluate the breeding potential of these lines. Holdfast and Holdfast-Ae. bicornis progenies were all highly resistant to stripe rust, indicating that the stripe rust resistance might derive from Holdfast. However, Holdfast-Ae. bicornis 3Sb addition, 3Sb(3A) substitution, 3Sb(3B) substitution, and 3Sb(3D) substitution lines showed high resistance to powdery mildew while Holdfast was highly susceptible, indicating that chromosome 3Sb of Ae. bicornis carries previously unknown powdery mildew resistance gene(s). Additionally, the transfer of the 3Sb chromosome from Ae. bicornis to wheat significantly increased tiller number, but chromosome 7Sb has a negative effect on agronomic traits. Therefore, wheat germplasm containing Ae. bicornis chromosome 3Sb has potential to contribute to improving powdery mildew resistance and tiller number during wheat breeding.

13.
bioRxiv ; 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34671769

RESUMO

The repeated emergence of highly pathogenic human coronaviruses as well as their evolving variants highlight the need to develop potent and broad-spectrum antiviral therapeutics and vaccines. By screening monoclonal antibodies (mAbs) isolated from COVID-19-convalescent patients, we found one mAb, 2-36, with cross-neutralizing activity against SARS-CoV. We solved the cryo-EM structure of 2-36 in complex with SARS-CoV-2 or SARS-CoV spike, revealing a highly conserved epitope in the receptor-binding domain (RBD). Antibody 2-36 neutralized not only all current circulating SARS-CoV-2 variants and SARS-COV, but also a panel of bat and pangolin sarbecoviruses that can use human angiotensin-converting enzyme 2 (ACE2) as a receptor. We selected 2-36-escape viruses in vitro and confirmed that K378T in SARS-CoV-2 RBD led to viral resistance. Taken together, 2-36 represents a strategic reserve drug candidate for the prevention and treatment of possible diseases caused by pre-emergent SARS-related coronaviruses. Its epitope defines a promising target for the development of a pan-sarbecovirus vaccine.

14.
Clin Epigenetics ; 13(1): 185, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620221

RESUMO

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality. The alteration of DNA methylation plays a major role in the development of lung cancer. Methylation biomarkers become a possible method for lung cancer diagnosis. RESULTS: We identified eleven lung cancer-specific methylation markers (CDO1, GSHR, HOXA11, HOXB4-1, HOXB4-2, HOXB4-3, HOXB4-4, LHX9, MIR196A1, PTGER4-1, and PTGER4-2), which could differentiate benign and malignant pulmonary nodules. The methylation levels of these markers are significantly higher in malignant tissues. In bronchoalveolar lavage fluid (BALF) samples, the methylation signals maintain the same differential trend as in tissues. An optimal 5-marker model for pulmonary nodule diagnosis (malignant vs. benign) was developed from all possible combinations of the eleven markers. In the test set (57 tissue and 71 BALF samples), the area under curve (AUC) value achieves 0.93, and the overall sensitivity is 82% at the specificity of 91%. In an independent validation set (111 BALF samples), the AUC is 0.82 with a specificity of 82% and a sensitivity of 70%. CONCLUSIONS: This model can differentiate pulmonary adenocarcinoma and squamous carcinoma from benign diseases, especially for infection, inflammation, and tuberculosis. The model's performance is not affected by gender, age, smoking history, or the solid components of nodules.

15.
Front Immunol ; 12: 729602, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630407

RESUMO

Objectives: The aim of this study was to investigate anti-synthetase syndrome (ASyS) patients who presented with recurrent episodes of fever and systemic inflammation. Methods: A retrospective cohort of Chinese ASyS patients (n=126) in our center (between January 2013 and January 2020) was included. Patients presenting with concomitant autoimmune rheumatic diseases or malignancies were subsequently excluded. The number of non-infectious fever attacks and attack frequency were recorded and calculated. Patients with two or more attacks and within the upper three quartiles of attack frequency were defined as high-inflammation group. Univariate and multivariate analyses were carried out to characterize the high-inflammation subtype. Results: Out of 113 eligible patients with an average of 5 years follow up, 25 patients were defined as the high-inflammation group (16 for anti-Jo1, 9 for anti-PL7), with an average of 1.12 attack/patient-year. Compared to low-inflammation group (0-1 attack only and a frequency lower than 0.5 attack/patient-year), the high-inflammation group had higher occurrence of fever and rapid progressive interstitial lung disease (RPILD) as the first presentation (84% vs. 21% and 40% vs. 9%, respectively, both p<0.01). Anti-PL-7 was related to the more inflammatory phenotype (p=0.014). Cumulative disease-modifying agent exposures (>=3) were much higher in the high-inflammation group (60% vs. 26%), while biological agents, i.e., rituximab and tocilizumab, showed better "drug survival" for Jo-1+ and PL-7+ ASyS patients with high inflammation, respectively, in our cohort. Conclusions: ASyS with recurrent systemic inflammatory episodes reflects a subtype of more aggressive and refractory disease in the spectrum of ASyS. Increased awareness of this subtype might lead to more appropriate management.

16.
J Phys Chem Lett ; 12(43): 10622-10630, 2021 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-34699231

RESUMO

Multidimensional NMR spectroscopy provides a powerful tool for structure elucidation and dynamic analysis of complex samples, particularly for biological macromolecules. Multidimensional sparse sampling effectively accelerates NMR experiments while an efficient reconstruction method is generally required for unraveling spectra. Various reconstruction methods were proposed for pure Fourier NMR (only involving chemical shifts and J couplings detection). However, reconstruction concerned with Laplace-related NMR (i.e., involving relaxation or diffusion detection) is more challenging due to its ill-posed property. The existing Laplace-related NMR sparse sampling reconstruction methods suffer from poor resolution and possible artifacts in the resulting spectra owing to the pitfalls of the optimization algorithms. Herein, we propose a general approach for fast high-resolution reconstruction of multidimensional sparse sampling NMR, including pure Fourier, mixed Fourier-Laplace, and pure Laplace NMR, benefiting from the comprehensive sparse constraint and effective optimization algorithm and thus showing the promising prospects of multidimensional NMR.

17.
Blood Adv ; 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34547766

RESUMO

In childhood B-ALL, among the recently described subtypes were DUX4 and PAX5 altered (PAX5alt). Using whole transcriptome RNA sequencing (RNA-Seq) in 377 B-ALL children from MaSpore ALL 2003/2010 (MS2003/MS2010) studies, we found that, after hyperdiploid and ETV6-RUNX1, the third and fourth most common subtypes were DUX4 (n= 51; 14%) and PAX5alt (n= 36; 10%). DUX4 also formed the largest genetic subtype among patients with poor Day 33 MRD (n=12/44). But despite the poor MRD, outcome of DUX4 B-ALL was excellent (5-year cumulative risk of relapse (CIR) 8.9% [95% CI, 2.8% to 19.5%], 5-year OS 97.8% [95% CI, 85.3% to 99.7%]). In MS2003, 21% DUX4 B-ALL had poor peripheral blood (PB) response to prednisolone at day 8, higher than other subtypes (8%; P=0.03). In MS2010, with vincristine at day 1, no day 8 poor PB response was observed in DUX4 subtype (P=0.03). PAX5alt group had an intermediate risk of relapse (5-year CIR 18.1%) but when IKZF1 was not deleted, outcome was excellent with no relapse among 23 patients. Compared to MS2003, outcome of PAX5alt B-ALL with IKZF1 co-deletion was improved by treatment intensification in MS2010 (5-year CIR 80.0% vs 0%; P=0.05). In conclusion, despite its poor initial response, DUX4 B-ALL had a favorable overall outcome, and the prognosis of PAX5alt was strongly dependent on IKZF1 co-deletion.

18.
Front Med (Lausanne) ; 8: 701836, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34485337

RESUMO

Background: It is much valuable to evaluate the comparative effectiveness of the coronavirus disease 2019 (COVID-19) prevention and control in the non-pharmacological intervention phase of the pandemic across countries and identify useful experiences that could be generalized worldwide. Methods: In this study, we developed a susceptible-exposure-infectious-asymptomatic-removed (SEIAR) model to fit the daily reported COVID-19 cases in 160 countries. The time-varying reproduction number (R t ) that was estimated through fitting the mathematical model was adopted to quantify the transmissibility. We defined a synthetic index (I AC ) based on the value of R t to reflect the national capability to control COVID-19. Results: The goodness-of-fit tests showed that the SEIAR model fitted the data of the 160 countries well. At the beginning of the epidemic, the values of R t of countries in the European region were generally higher than those in other regions. Among the 160 countries included in the study, all European countries had the ability to control the COVID-19 epidemic. The Western Pacific Region did best in continuous control of the epidemic, with a total of 73.76% of countries that can continuously control the COVID-19 epidemic, while only 43.63% of the countries in the European Region continuously controlled the epidemic, followed by the Region of Americas with 52.53% of countries, the Southeast Asian Region with 48% of countries, the African Region with 46.81% of countries, and the Eastern Mediterranean Region with 40.48% of countries. Conclusion: Large variations in controlling the COVID-19 epidemic existed across countries. The world could benefit from the experience of some countries that demonstrated the highest containment capabilities.

19.
Cancer Lett ; 522: 80-92, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34536555

RESUMO

Plasmacytoid dendritic cells (pDCs) play immunosuppressive roles in the tumor microenvironment (TME). However, the molecular mechanisms underlying the recruitment and dysfunction of pDCs in the TME remain largely elusive, especially in hepatocellular carcinoma (HCC). In this study, we observed the accumulation of pDCs in the blood, tumor tissue, and ascitic fluid of HCC patients. A high density of tumor-infiltrating pDCs was correlated with poor prognosis in patients with HCC. Hypoxia-induced extracellular adenosine (eADO) significantly enhanced pDC recruitment into tumors via the adenosine A1 receptor (ADORA1). Mechanistically, hypoxia-inducible factor 1-alpha (HIF-1α) transcriptionally upregulated the expression of the ectonucleotidases CD39 and CD73 in HCC cells, both of which are essential for the generation of eADO. Moreover, eADO-stimulated pDCs promoted the induction of regulatory T cells and suppressed proliferation and cytotoxicity of CD8+ T cells. Depletion of pDCs using a monoclonal antibody or an ADORA1 antagonist significantly improved antitumor immunity and suppressed HCC growth in the immunocompetent HCC mouse model. Thus, targeting pDC recruitment may serve as a potential adjuvant strategy for immunotherapies in HCC.

20.
BMC Cancer ; 21(1): 1033, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530760

RESUMO

BACKGROUND: Standard therapy for human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC) is lacking. The clinical benefits with pan-HER inhibitors (afatinib, neratinib, and dacomitinib), anti-HER2 antibody drug conjugate (ADC) trastuzumab emtansine, and an emerging irreversible tyrosine kinase inhibitor (TKI) poziotinib were modest. Another new ADC trastuzumab deruxtecan showed encouraging outcomes, but only phase I study was completed. Pyrotinib, another emerging irreversible epidermal growth factor receptor (EGFR)/HER2 dual TKI, has been approved in HER2-positive breast cancer in 2018 in China. It has shown promising antitumor activity against HER2-mutant NSCLC in phase II trials, but pyrotinib-related diarrhea remains an issue. The antiangiogenic and immunomodulatory drug thalidomide is a cereblon-based molecular glue that can induce the degradation of the IKAROS family transcription factors IKZF1 and IKZF3. The use of thalidomide can also decrease gastrointestinal toxicity induced by anti-cancer therapy. METHODS: This is an open-label, single-arm phase II trial. A total of 39 advanced NSCLC patients with HER2 exon 20 insertions and ≤ 2 lines of prior chemotherapy will be recruited, including treatment-naïve patients who refuse chemotherapy. Patients are allowed to have prior therapy with immune checkpoint inhibitors and/or antiangiogenic agents. Those who have prior HER2-targeting therapy or other gene alterations with available targeted drugs are excluded. Eligible patients will receive oral pyrotinib 400 mg once daily and oral thalidomide 200 mg once daily until disease progression or intolerable toxicity. The primary endpoint is objective response rate. DISCUSSION: The addition of thalidomide to pyrotinib is expected to increase the clinical benefit in advanced NSCLC patients with HER2 exon 20 insertions, and reduce the incidence of pyrotinib-related diarrhea. We believe thalidomide is the stone that can hit two birds. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04382300 . Registered on May 11, 2020.


Assuntos
Acrilamidas/administração & dosagem , Aminoquinolinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptor ErbB-2/genética , Talidomida/administração & dosagem , Acrilamidas/efeitos adversos , Aminoquinolinas/efeitos adversos , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , China , Diarreia/induzido quimicamente , Esquema de Medicação , Éxons , Humanos , Fator de Transcrição Ikaros/efeitos dos fármacos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Receptor ErbB-2/antagonistas & inibidores
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