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1.
Neurosurgery ; 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36735283

RESUMO

BACKGROUND: Function recovery is related to cortical plasticity. The brain remodeling patterns induced by alterations in peripheral nerve pathways with different nerve reconstructions are unknown. OBJECTIVE: To explore brain remodeling patterns related to alterations in peripheral neural pathways after different nerve reconstruction surgeries. METHODS: Twenty-four female Sprague-Dawley rats underwent complete left brachial plexus nerve transection, together with the following interventions: no nerve repair (n = 8), grafted nerve repair (n = 8), and phrenic nerve transfer (n = 8). Resting-state functional MR images of brain were acquired at the end of seventh month postsurgery. Amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and functional connectivity (FC) were compared among 3 groups. Behavioral observation and electromyography assessed nerve regeneration. RESULTS: Compared with brachial plexus injury group, ALFF and ReHo of left entorhinal cortex decreased in nerve repair and nerve transfer groups. The nerve transfer group showed increased ALFF and ReHo than nerve repair group in left caudate putamen, right accumbens nucleus shell (AcbSh), and right somatosensory cortex. The FC between right somatosensory cortex and bilateral piriform cortices and bilateral somatosensory cortices increased in nerve repair group than brachial plexus injury and nerve transfer groups. The nerve transfer group showed increased FC between right somatosensory cortex and areas including left corpus callosum, left retrosplenial cortex, right parietal association cortex, and right dorsolateral thalamus than nerve repair group. CONCLUSION: Entorhinal cortex is a key brain area in recovery of limb function after nerve reconstruction. Nerve transfer related brain remodeling mainly involved contralateral sensorimotor areas, facilitating directional "shifting" of motor representation.

2.
J Hypertens ; 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36723459

RESUMO

OBJECTIVES: The aim of this study was to investigate the clinical characteristics of renal artery fibromuscular dysplasia (FMD) in patients in China and identify the cure rate of hypertension after angioplasty. METHODS: Consecutive hypertensive patients with renal artery stenosis caused by FMD who underwent catheter-based angiography, and were followed at two Chinese referral centres, were retrospectively analysed. All patients underwent a detailed investigation, including demographic characteristics, clinical characteristics, biochemical sampling, Doppler ultrasonography of carotid arteries, magnetic resonance angiography (MRA) of the intracranial artery, and CTA or MRA of the abdominal artery and catheter-based renal angiography. Patients were routinely followed up at 1 month, 6 months and every year after the procedure. RESULTS: Among 245 study participants, with a mean diagnosed age of 26.9 ±â€Š9.9 years, 137 (55.9%) were women, and 38 (15.5%) were children. All patients were diagnosed with hypertension at a mean age of 23.4 ±â€Š8.4 years. There were 73.5% focal and 15.2% multivessel cases. Aneurysms, arterial dissections and total occlusions were found in 21.6, 4.1 and 12.2% of patients, respectively. Patients with multifocal FMD were older (26.0 vs. 23.7 years, P = 0.021) and more often female (70.8 vs. 50.6%, P = 0.004). Among children with renal FMD, 55.2% were men, and 86.8% were focal. After a median follow-up of 7.0 years, multifocal FMD had a higher cure rate of hypertension than focal FMD after revascularization (71.7 vs. 55.8%, P = 0.032). CONCLUSION: In a cohort of mostly young Chinese patients, the prevalence of hypertension associated with renal FMD is similar in both sexes. Focal FMDs were more frequent than the multifocal ones and, after angioplasty, were associated with a worse blood pressure outcome.

3.
Mod Rheumatol ; 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36688590

RESUMO

OBJECTIVES: To investigate whether pSS patients with hyperglobulinemia have an increased risk of all-cause mortality. METHODS: Patients who registered in Chinese Rheumatism Data Centre from May 2016 to July 2021, and met the 2002 AECG criteria or 2016 ACR/EULAR classification criteria for SS were included. Hyperglobulinemia was defined as any elevated serum levels of IgG, IgA, or IgM. The primary outcome was all-cause death. Data for demographic and clinical characteristics, laboratory results, disease activity, damage scores, treatments were evaluated. RESULTS: A total of 9,527 pSS patients were included in the analysis, of whom 4,236 (44.5%) had at least one kind of elevated immunoglobulin level among IgG, IgA, and IgM. Patients with hyperglobulinemia had a significantly increased risk of death (crude HR 2.60; 95%CI 1.91-3.55; adjusted HR 1.90; 95%CI 1.20-3.01). Risk of death was positively correlated with IgG level (P trend <0.001). The 5-, 10-, and 15-year survival rates of patients with hyperglobulinemia were 96.9%, 92.3%, and 87.9%, respectively, and significantly lower than the corresponding rates of 98.8%, 97.9%, and 96.4% in patients without hyperglobulinemia. CONCLUSIONS: Hyperglobulinemia is an independent risk factor for increased all-cause mortality in pSS patients. Risk of death is positively correlated with IgG level.

4.
Int J Oncol ; 62(3)2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36704835

RESUMO

Currently, chemoresistance is a major challenge that directly affects the prognosis of patients with colorectal cancer (CRC). In addition, hypoxia is associated with poor prognosis and therapeutic resistance in patients with cancer. Accumulating evidence has shown that α­hederin has significant antitumour effects and that α­hederin can inhibit hypoxia­mediated drug resistance in CRC; however, the underlying mechanism remains unclear. In the present study, viability and proliferation assays were used to evaluate the effect of α­hederin on the drug resistance of CRC cells under hypoxia. Sequencing analysis and apoptosis assays were used to determine the effect of α­hederin on apoptosis under hypoxia. Western blot analysis and reverse transcription­quantitative PCR were used to measure apoptosis­related protein and mRNA expression levels. Furthermore, different mouse models were established to study the effect of α­hederin on hypoxia­mediated CRC drug resistance in vivo. In the present study, the high expression of Bcl2 in hypoxic CRC cells was revealed to be a key factor in their drug resistance, whereas α­hederin inhibited the expression of Bcl2 by reducing AKT phosphorylation in vitro and in vivo, and promoted the apoptosis of CRC cells under hypoxia. By contrast, overexpression of AKT reversed the effect of α­hederin on CRC cell apoptosis under hypoxia. Taken together, these results suggested that α­hederin may overcome hypoxia­mediated drug resistance in CRC by inhibiting the AKT/Bcl2 pathway. In the future, α­hederin may be used as a novel adjuvant for reversing drug resistance in CRC.


Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Colorretais/patologia , Proliferação de Células , Apoptose , Resistencia a Medicamentos Antineoplásicos/genética , Hipóxia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica
5.
Chemosphere ; 318: 137819, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36640988

RESUMO

Lack of knowledge on the destiny of organic micropollutants (OMPs) in the Tibetan Plateau region of China prevents the public from being aware of the need for protecting these unique aquatic ecosystems that are precious water resources and source areas of the Yellow River. To address this knowledge gap, this study systematically investigated the multi-residue analysis, distribution, and potential risks of six types of OMPs, namely, neonicotinoid pesticides (NEOs), fungicides, organophosphate esters (OPEs), organophosphorus pesticides (OPPs), psychoactive substances (PSs), and antidepressants (ADs), in surface waters of major cities in Qinghai. A total of 31 compounds, consisting of 8 NEOs, 1 fungicide, 12 OPEs, 2 OPPs, 5 PSs, and 3 ADs, were detected in >50% of the sites, showing their ubiquitous nature in the study area. Results showed that the total OMP concentration in surface water was 28.3-908 ng/L, and OPEs were the dominant composition (48.6%-97.4%). The risk quotient values of the detected diazinon and dursban regularly exceeded 1 for aquatic organisms at all sampling sites, indicating moderate-high chronic ecological risk. The joint probability curves showed that dursban and NEOs have higher risk levels than other OMPs. Although the results of the non-carcinogenic total hazard quotient of the OMPs in the surface water was less than 1 in all age groups and the carcinogenic risk was lower than the negligible risk level, the potential risks to children and infants were considerably greater and should not be underestimated. In addition to pollutant concentration and exposure duration, ingestion rate and body weight (BW) are also important factors affecting health risk, with BW having a negative effect. To the best of the authors' knowledge, this report is the first to describe OMP pollution in Qinghai, and the results provide new insight into the ecological security of the water resources of the Tibetan Plateau.

6.
mSystems ; : e0057622, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36602317

RESUMO

Shopping malls offer various niches for microbial populations, potentially serving as sources and reservoirs for the spread of microorganisms of public health concern. However, knowledge about the microbiome and the distribution of human pathogens in malls is largely unknown. Here, we examine the microbial community dynamics and genotypes of potential pathogens from floor and escalator surfaces in shopping malls and adjacent road dusts and greenbelt soils. The distribution pattern of microbial communities is driven primarily by habitats and seasons. A significant enrichment of human-associated microbiota in the indoor environment indicates that human interactions with surfaces might be another strong driver for mall microbiomes. Neutral community models suggest that the microbial community assembly is strongly driven by stochastic processes. Distinct performances of microbial taxonomic signatures for environmental classifications indicate the consistent differences of microbial communities of different seasons/habitats and the strong anthropogenic effect on homogenizing microbial communities of shopping malls. Indoor environments harbored higher concentrations of human pathogens than outdoor samples, also carrying a high proportion of antimicrobial resistance-associated multidrug efflux genes and virulence genes. These findings enhanced the understanding of the microbiome in the built environment and the interactions between humans and the built environment, providing a basis for tracking biothreats and communicable diseases and developing sophisticated early warning systems. IMPORTANCE Shopping malls are distinct microbial environments which can facilitate a constant transmission of microorganisms of public health concern between humans and the built environment or between human and human. Despite extensive investigation of the natural environmental microbiome, no comprehensive profile of microbial ecology has been reported in malls. Characterizing microbial distribution, potential pathogens, and antimicrobial resistance will enhance our understanding of how these microbial communities are formed, maintained, and transferred and help establish a baseline for biosurveillance of potential public health threats in malls.

8.
Food Sci Nutr ; 11(1): 344-349, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36655094

RESUMO

Liver fibrosis and cirrhosis are primarily caused by the activation of hepatic stellate cells (HSCs), regardless of their etiology. Collagen type I (collagen I) and connective tissue growth factor (CTGF) is produced more readily by activated HSCs. Consequently, identifying the molecular and cellular mechanisms responsible for HSCs activation is essential to better understand its mechanism of action and therapeutic potential. Cell death is caused by iron-dependent lipid peroxidation during ferroptosis. Ferroptosis plays an important role in the survival of activated HSCs and could contribute to the development of innovative prevention and treatment strategies for liver fibrosis. Danshensu (Dan) is a pure molecule extracted from the Salvia miltiorrhiza herb that protects against liver damage. However, Dan's effect on attenuating HSCs activation by regulating ferroptosis remains unclear. The results of this study indicated that lipopolysaccharide (LPS)-induced LX-2 and T6 cells activation occurs through the upregulation of collagen I, CTGF, Gpx4, and SLC7A11. Interestingly, Dan attenuated LPS-induced liver fibrosis in those cells by upregulating collagen I, CTGF, Gpx4, and SLC7A11 and by increasing lipid reactive oxygen species accumulation. Furthermore, the results also showed that the ferroptosis inhibitor liproxstatin attenuated the overproduction of lipid reactive oxygen species in LPS-activated LX-2 cells. We conclude that Dan attenuates LPS-induced HSC activation during liver fibrosis by regulating ferroptosis in LX-2 and T6 cells.

9.
Anal Methods ; 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36661345

RESUMO

More and more attention has been paid to the problem of pesticide residues, especially in plants and vegetables, due to their close relationship with human health and food safety. Compared to conventional detecting techniques, the fluorescence sensing method has achieved good results for pesticides detection. However, most of the reported fluorescent probes needed two or more steps to achieve the detection of pesticide residues, which greatly limited their application for in vivo imaging and in situ analysis of agricultural residues in plants and vegetables. In this paper, an Ag nanoclusters (AgNCs) based fluorescent probe is developed for one-step detection of pesticide residues. The novel nanoprobe displayed impressive advantages, such as a selective response to glyphosate pesticide, rapid response within 1 min and an ultralow detection limit of 21 nM. The sensing mechanism is attributed to the unique coordination interaction between AgNCs and glyphosate, which not only increased the size of AgNCs to form big Ag particles, but also caused the fluorescence quenching of AgNCs system. Due to its favorable properties, the probe has been successfully applied to imaging the organophosphorus pesticide of glyphosate in the leave tissues of Arabidopsis thaliana and the root tip cells of lettuce for the first time.

10.
J Am Chem Soc ; 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36661845

RESUMO

The synthesis of structurally diverse amines is of fundamental significance in the pharmaceutical industry due to the ubiquitous presence of amine motifs in biologically active molecules. Biocatalytic reductive amination for amine production has attracted great interest owing to its synthetic advantages. Herein, we report the direct synthesis of a wide range of sterically demanding secondary amines, including several important active pharmaceutical ingredients and pharmaceutical intermediates, via reductive amination of carbonyl substrates and bulky amine nucleophiles employing imine reductases. Key to success for this route is the identification of an imine reductase from Penicillium camemberti with unusual substrate specificity and its further engineering, which empowered the accommodation of a broad range of sterically demanding amine nucleophiles encompassing linear alkyl and (hetero)aromatic (oxy)alkyl substituents and the formation of final amine products with up to >99% conversion. The practical utility of the biocatalytic route has been demonstrated by its application in the preparative synthesis of the anti-hyperparathyroidism drug cinacalcet.

11.
Sensors (Basel) ; 23(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36679430

RESUMO

Artificial intelligence (AI) with deep learning models has been widely applied in numerous domains, including medical imaging and healthcare tasks. In the medical field, any judgment or decision is fraught with risk. A doctor will carefully judge whether a patient is sick before forming a reasonable explanation based on the patient's symptoms and/or an examination. Therefore, to be a viable and accepted tool, AI needs to mimic human judgment and interpretation skills. Specifically, explainable AI (XAI) aims to explain the information behind the black-box model of deep learning that reveals how the decisions are made. This paper provides a survey of the most recent XAI techniques used in healthcare and related medical imaging applications. We summarize and categorize the XAI types, and highlight the algorithms used to increase interpretability in medical imaging topics. In addition, we focus on the challenging XAI problems in medical applications and provide guidelines to develop better interpretations of deep learning models using XAI concepts in medical image and text analysis. Furthermore, this survey provides future directions to guide developers and researchers for future prospective investigations on clinical topics, particularly on applications with medical imaging.


Assuntos
Inteligência Artificial , Médicos , Humanos , Algoritmos , Julgamento , Pesquisadores
12.
Nat Commun ; 14(1): 324, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36658167

RESUMO

Organic field-effect transistors (OFETs) are of interest in unconventional form of electronics. However, high-performance OFETs are currently contact-limited, which represent a major challenge toward operation in the gigahertz regime. Here, we realize ultralow total contact resistance (Rc) down to 14.0 Ω âˆ™ cm in C10-DNTT OFETs by using transferred platinum (Pt) as contact. We observe evidence of Pt-catalyzed dehydrogenation of side alkyl chains which effectively reduces the metal-semiconductor van der Waals gap and promotes orbital hybridization. We report the ultrahigh performance OFETs, including hole mobility of 18 cm2 V-1 s-1, saturation current of 28.8 µA/µm, subthreshold swing of 60 mV/dec, and intrinsic cutoff frequency of 0.36 GHz. We further develop resist-free transfer and patterning strategies to fabricate large-area OFET arrays, showing 100% yield and excellent variability in the transistor metrics. As alkyl chains widely exist in conjugated molecules and polymers, our strategy can potentially enhance the performance of a broad range of organic optoelectronic devices.

13.
J Med Chem ; 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36695404

RESUMO

AXL kinase is heavily involved in tumorigenesis, metastasis, and drug resistance of many cancers, and several AXL inhibitors are in clinical investigations. Recent studies demonstrated that the N-terminal distal region of AXL plays more important roles in cell invasiveness than its C-terminal kinase domain. Therefore, degradation of AXL may present a novel superior therapeutic approach than the kinase inhibitor therapy. Herein, we report the discovery of a series of new AXL PROTAC degraders. One representative compound 6n potently depletes AXL with a DC50 value of 5 nM in MDA-MB-231 TNBC cells. It also demonstrates significantly improved potencies against the AXL signaling activation, cell proliferation, migration and invasion of TNBC cells comparing with the corresponding kinase inhibitor. Moreover, the compound exhibits promising therapeutic potential both in patient-derived organoids and a xenograft mouse model of MDA-MB-231 cells.

14.
Artigo em Inglês | MEDLINE | ID: mdl-36674180

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases which affects mainly middle-aged and older adults, resulting in a considerable disease burden. Evidence of concordance on NAFLD and lifestyle factors within older married couples in China is limited. This study aimed to evaluate spousal concordance regarding lifestyle factors and NAFLD among older Chinese couples. METHODS: We conducted a cross-sectional study using data from 58,122 married couples aged 65 years and over recruited from Shenzhen, China during 2018-2020. Logistic regression analyses were used to estimate the reciprocal associations in NAFLD within couples after incremental adjustment for potential confounders. RESULTS: There was a marked concordance regarding NAFLD among older married couples in our study. After adjustment for confounders, the odds of having NAFLD were significantly related to the person's spouse also having NAFLD (1.84 times higher in husbands and 1.79 times higher in wives). The spousal concordance of NAFLD was similar, irrespective of gender. Couples with both a higher educational level and abdominal obesity were more likely to have a concordance of NAFLD compared to couples with both a lower educational level and no abdominal obesity, respectively (p < 0.05). CONCLUSION: Our results indicated that health care professionals should bear in mind the marked spousal concordance with respect to risk factors and NAFLD for the prevention and early detection of the highly prevalent disease in older Chinese adults.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Pessoa de Meia-Idade , Humanos , Idoso , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Cônjuges , Estudos Transversais , Fatores de Risco , Obesidade/complicações , China/epidemiologia
15.
Int J Mol Sci ; 24(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36675279

RESUMO

α-Farnesene, an acyclic volatile sesquiterpene, plays important roles in aircraft fuel, food flavoring, agriculture, pharmaceutical and chemical industries. Here, by re-creating the NADPH and ATP biosynthetic pathways in Pichia pastoris, we increased the production of α-farnesene. First, the native oxiPPP was recreated by overexpressing its essential enzymes or by inactivating glucose-6-phosphate isomerase (PGI). This revealed that the combined over-expression of ZWF1 and SOL3 increases α-farnesene production by improving NADPH supply, whereas inactivating PGI did not do so because it caused a reduction in cell growth. The next step was to introduce heterologous cPOS5 at various expression levels into P. pastoris. It was discovered that a low intensity expression of cPOS5 aided in the production of α-farnesene. Finally, ATP was increased by the overexpression of APRT and inactivation of GPD1. The resultant strain P. pastoris X33-38 produced 3.09 ± 0.37 g/L of α-farnesene in shake flask fermentation, which was 41.7% higher than that of the parent strain. These findings open a new avenue for the development of an industrial-strength α-farnesene producer by rationally modifying the NADPH and ATP regeneration pathways in P. pastoris.


Assuntos
Pichia , Sesquiterpenos , NADP/metabolismo , Pichia/genética , Pichia/metabolismo , Sesquiterpenos/metabolismo , Trifosfato de Adenosina/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Engenharia Metabólica
16.
Crit Rev Biotechnol ; : 1-22, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36592988

RESUMO

Microorganisms play an important role in plant growth and development. In particular, endophytic fungi is one of the important kinds of microorganisms and has a mutually beneficial symbiotic relationship with host plants. Endophytic fungi have many substantial benefits to host plants, especially for woody plants, such as accelerating plant growth, enhancing stress resistance, promoting nutrient absorption, resisting pathogens and etc. However, the effects of endophytic fungi on the growth and development of woody plants have not been systematically summarized. In this review, the functions of endophytic fungi for the growth and development of woody plants have been mainly reviewed, including regulating plant growth (e.g., flowering, root elongation, etc.) by producing nutrients and plant hormones, and improving plant disease, insect resistance and heavy metal resistance by producing secondary metabolites. In addition, the diversity of endophytic fungi could improve the ability of woody plants to adapt to adverse environment. The components produced by endophytic fungi have excellent potential for the growth and development of woody plants. This review has systematically discussed the potential regulation mechanism of endophytic fungi regulating the growth and development of woody plants, it would be of great significance for the development and utilization of endophytic fungi resource from woody plants for the protection of forest resources.

17.
Ecotoxicol Environ Saf ; 251: 114520, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36640573

RESUMO

Increasing amounts of nanoplastics (NPs) in the environment are a great threat to human health, causing intestinal inflammation when consumed through seafood and water. There is, however, still a lack of understanding of the immunomodulatory role of NPs in immune cells, especially the early signal events behind inflammation resulting from NPs ingestion. In this study, we explored the dynamic internalization of polystyrene NPs and their carboxy and amino-functionalized products (PS, PS-COOH and PS-NH2) followed by activation of ROS-MAPK/NF-κB signaling pathways in macrophage RAW 264.7. The inflammatory and cytotoxic potentials of NPs were evaluated by ELISA and apoptosis assays. Results showed that PS-COOH accumulated most in cells and induced more pronounced ROS and apoptosis than PS, PS-NH2 and PS-µm. PS-COOH and PS-NH2 showed stronger MAPK/NF-κB activation potential to at a low concentration of 10 µg/mL than unmodified PS, followed by production of IL-6 and TNF-α cytokines. Furthermore, PS-COOH induced MAPK/NF-κB activation and cytokine secretion could be inhibited by NAC, indicating that ROS was responsible for signal dysregulation and immunogenicity of PS-COOH, but not for PS-NH2. The results suggested that the MAPK and NF-κB pathways were involved in NPs-induced macrophage inflammation, which was influenced by surface functionalization of NPs, with carboxylated PS NPs exhibiting a greater pro-inflammatory and cytotoxic potential.

18.
RMD Open ; 9(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36720560

RESUMO

OBJECTIVES: Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, were evaluated in a 6-month, double-blind, phase 3 study in Chinese patients with active (polyarthritic) psoriatic arthritis (PsA) and inadequate response to ≥1 conventional synthetic disease-modifying antirheumatic drug. METHODS: Patients were randomised (2:1) to tofacitinib 5 mg twice daily (N=136) or placebo (N=68); switched to tofacitinib 5 mg twice daily after month (M)3 (blinded). PRIMARY ENDPOINT: American College of Rheumatology (ACR50) response at M3. Secondary endpoints (through M6) included: ACR20/50/70 response; change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI); ≥75% improvement in Psoriasis Area and Severity Index (PASI75) response, and enthesitis and dactylitis resolution. Safety was assessed throughout. RESULTS: The primary endpoint was met (tofacitinib 5 mg twice daily, 38.2%; placebo, 5.9%; p<0.0001). M3 ACR20/ACR70/PASI75 responses, and enthesitis and dactylitis resolution rates, were higher and HAQ-DI reduction was greater for tofacitinib 5 mg twice daily versus placebo. Incidence of adverse events (AEs)/serious AEs (M0-3): 68.4%/0%, tofacitinib 5 mg twice daily; 75.0%/4.4%, placebo. One death was reported with placebo→tofacitinib 5 mg twice daily (due to accident). One serious infection, non-serious herpes zoster, and lung cancer case each were reported with tofacitinib 5 mg twice daily; four serious infections and one non-serious herpes zoster case were reported with placebo→tofacitinib 5 mg twice daily (M0-6). No non-melanoma skin cancer, major adverse cardiovascular or thromboembolism events were reported. CONCLUSION: In Chinese patients with PsA, tofacitinib efficacy was greater than placebo (primary and secondary endpoints). Tofacitinib was well tolerated; safety outcomes were consistent with the established safety profile in PsA and other indications. TRIAL REGISTRATION NUMBER: NCT03486457.


Assuntos
Artrite Psoriásica , Entesopatia , Herpes Zoster , Humanos , Artrite Psoriásica/tratamento farmacológico , Piperidinas/efeitos adversos
19.
bioRxiv ; 2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36712068

RESUMO

DNAAF5 is a dynein motor assembly factor associated with the autosomal heterogenic recessive condition of motile cilia, primary ciliary dyskinesia (PCD). The effects of allele heterozygosity on motile cilia function are unknown. We used CRISPR-Cas9 genome editing in mice to recreate a human missense variant identified in patients with mild PCD and a second, frameshift null deletion in Dnaaf5 . Litters with Dnaaf5 heteroallelic variants showed distinct missense and null gene dosage effects. Homozygosity for the null Dnaaf5 alleles was embryonic lethal. Compound heterozygous animals with the missense and null alleles showed severe disease manifesting as hydrocephalus and early lethality. However, animals homozygous for the missense mutation had improved survival, with partial preserved cilia function and motor assembly observed by ultrastructure analysis. Notably, the same variant alleles exhibited divergent cilia function across different multiciliated tissues. Proteomic analysis of isolated airway cilia from mutant mice revealed reduction in some axonemal regulatory and structural proteins not previously reported in DNAAF5 variants. While transcriptional analysis of mouse and human mutant cells showed increased expression of genes coding for axonemal proteins. Together, these findings suggest allele-specific and tissue-specific molecular requirements for cilia motor assembly that may affect disease phenotypes and clinical trajectory in motile ciliopathies. Brief Summary: A mouse model of human DNAAF5 primary ciliary dyskinesia variants reveals gene dosage effects of mutant alleles and tissue-specific molecular requirements for cilia motor assembly.

20.
J Endod ; 49(2): 162-168, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36592717

RESUMO

INTRODUCTION: Intracanal medicament is one of the essential steps for ensuring success in regenerative endodontic procedures. L-Chg10-teixobactin is a novel antimicrobial agent that exhibited potent antibacterial and antibiofilm effects against Enterococcusfaecalis at low concentrations compared with ampicillin. At the same time, its cytotoxicity on dental stem cells has not been studied. This study aimed to investigate the effects of L-Chg10-teixobactin on the viability, proliferation, migration, and osteo/odontogenic differentiation of stem cells from apical papilla (SCAPs). MATERIALS AND METHODS: SCAPs isolated from immature human third molars were treated with various concentrations of L-Chg10-teixobactin, calcium hydroxide, and dimethyl sulfoxide. The viability and proliferation of SCAPs were assessed using the LIVE/DEAD Viability/Cytotoxicity Kit and Cell Counting Kit-8. A scratch wound healing test was used to evaluate the lateral migration capacity of SCAPs. Alkaline phosphatase (ALP) activity, calcium mineralization ability tests -ie, ALP staining and alizarin red S staining, and quantitative real-time polymerase chain reaction were performed to assess the osteo /odontogenic differentiation of SCAPs. RESULTS: The tested concentrations of L-Chg10-teixobactin (0.01, 0.02, and 0.03 mg/mL), 1 mg/mL calcium hydroxide, and 0.03% dimethyl sulfoxide had no significant cytotoxic effect on SCAPs at any time point (P > .05). Besides, there were no significant differences between the control and experimental groups in SCAPs' viability, proliferation, and migration. L-Chg10-teixobactin upregulated the gene expression of osteo/odontogenic markers in SCAPs, while no significant difference was found in the ALP activity and alizarin red S staining. CONCLUSIONS: L-Chg10-teixobactin demonstrated excellent biocompatibility on SCAPs at concentrations from 0.01 to 0.03 mg/mL and potentially enhance the osteo/odontogenic differentiation of SCAPs; suggesting its promising role as root canal medicament for regenerative endodontic procedures.


Assuntos
Hidróxido de Cálcio , Dimetil Sulfóxido , Humanos , Hidróxido de Cálcio/farmacologia , Dimetil Sulfóxido/farmacologia , Proliferação de Células , Células Cultivadas , Diferenciação Celular , Células-Tronco , Osteogênese , Papila Dentária
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