A boy, aged 4 years and 6 months, had disease onset of fever, cough, pale complexion, and weakness, with hepatosplenomegaly, lymphadenectasis, and pancytopenia. He had been having repeated ...respiratory and digestive tract infections. Gene detection showed a pathogenic heterozygous mutation, c.C2147 > T(p.T716M), in the
gene. The boy was thus diagnosed with immune dysregulation syndrome. Anti-infective therapy and irregular corticosteroid therapy had an unsatisfactory effect in the early stage, but the symptoms improved after regular corticosteroid therapy. This article reported the case of immune dysregulation syndrome caused by
gene mutation and summarized the epidemiology, clinical features, diagnosis, and treatment of this disease, which can provide a reference for early diagnosis, treatment, and future studies of this disease.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with high mortality. The Food and Drug Administration-approved drugs, nintedanib and pirfenidone, could delay progressive fibrosis by ...inhibiting the overactivation of fibroblast, however, there was no significant improvement in patient survival due to low levels of drug accumulation and remodeling of honeycomb cyst and interstitium surrounding the alveoli. Herein, we constructed a dual drug (verteporfin and pirfenidone)-loaded nanoparticle (Lip@VP) with the function of inhibiting airway epithelium fluidization and fibroblast overactivation to prevent honeycomb cyst and interstitium remodeling. Specifically, Lip@VP extensively accumulated in lung tissues via atomized inhalation. Released verteporfin inhibited the fluidization of airway epithelium and the formation of honeycomb cyst, and pirfenidone inhibited fibroblast overactivation and reduced cytokine secretion that promoted the fluidization of airway epithelium. Our results indicated that Lip@VP successfully rescued lung function through inhibiting honeycomb cyst and interstitium remodeling. This study provided a promising strategy to improve the therapeutic efficacy for IPF.
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•Inhaled nanoparticles were fabricated to enhance drug lung delivery.•Verteporfin inhibited the formation of honeycomb cysts.•Pirfenidone inhibited the remodeling of alveoli interstitium.•This study provided a promising strategy to improve antifibrotic efficacy.
WEE1 is a tyrosine kinase that regulates G2/M cell cycle checkpoint and frequently overexpressed in various tumors. However, the expression and clinical significance of WEE1 in human laryngeal ...squamous cell carcinoma (LSCC) are still unknown. In this study, we found that WEE1 was highly expressed in LSCC tissues compared with adjacent normal tissues. Importantly, overexpression of WEE1 was correlated with T stages, lymph node metastasis, clinical stages and poor prognosis of LSCC patients. Furthermore, inhibition of WEE1 by MK-1775 induced cell growth inhibition, cell cycle arrest and apoptosis with the increased intracellular reactive oxygen species (ROS) levels in LSCC cells. Pretreatment with ROS scavenger
-acetyl-L-cysteine could reverse MK-1775-induced ROS accumulation and cell apoptosis in LSCC cells. MK-1775 also inhibited the growth of LSCC xenografts in nude mice. Altogether, these findings suggest that WEE1 is a potential therapeutic target in LSCC, and inhibition of WEE1 is the prospective strategy for LSCC therapy.
Accumulating evidence has indicated crucial roles for pseudogenes in human cancers. However, the roles played by pseudogenes in the pathogenesis of HCC, particularly HCC early recurrence, still ...incompletely elucidated. Herein, we identify a novel early recurrence related pseudogene RACGAP1P which was significantly upregulated in HCC and was associated with larger tumour size, advanced clinical stage, abnormal AFP level and shorter survival time. In vitro and in vivo experiments have shown that RACGAP1P is a prerequisite for the development of malignant characteristics of HCC cells, including cell growth and migration. Mechanistic investigations indicated that RACGAP1P elicits its oncogenic activity as a ceRNA to sequestrate miR-15-5p from its endogenous target RACGAP1, thereby leading to the upregulation of RACGAP1 and the activation of RhoA/ERK signalling. These results may provide new insights into the functional crosstalk of the pseudogene/miRNA/parent-gene genetic network during HCC early relapse and may contribute to improving the clinical intervention for this subset of HCC patients.
Enantiomers account for quite a large percentage of compounds in natural products. Our team is interested in the separation and biological activity of racemic compounds. In this report, four pairs of ...prenylated flavan enantiomers (±)-1–(±)-4, including five new compounds, were isolated from the stem and root bark of Daphne giraldii, and separated successfully by using chiral chromatographic column. Their planar structures and absolute configurations were established by comprehensive spectroscopic analyses as well as circular dichroism (CD) spectroscopy. The isolates had a selective cytotoxicity towards hepatic carcinoma cell lines. Among them, new compound (+)-4 showed a more potent inhibitory effect on Hep3B cells with an IC50 value of 30.3 μM, compared with its racemic mixture 4. Therefore, the action mechanism of (+)-4in vitro was subsequently investigated. The morphological observation and Western blot analysis demonstrated that (+)-4 could markedly induce apoptosis through intrinsic and extrinsic pathways, and also cause autophagy by increasing the phosphorylation of AMP-activated protein kinase (AMPK) in Hep3B cells. After treatment with the autophagic inhibitor bafilomycin A1 (Baf A1), (+)-4-induced apoptosis increased significantly, suggesting that the autophagy induced by (+)-4 performed a protective effect on apoptotic cell death.
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•Chiral separation of Daphne giraldii gave four pairs of enantiomers (±)-1–(±)-4.•(±)-1–(±)-4 had a selective effect on hepatic carcinoma cells, especially Hep3B.•New compound (+)-4 induced apoptosis through intrinsic and extrinsic pathways.•(+)-4 caused autophagy by increasing the phosphorylation of AMPK in Hep3B cells.•The autophagy induced by (+)-4 had a protective effect on apoptotic cell death.
Recognizing that physicians may struggle to achieve knowledge, skills, attitudes and or conduct at one or more stages during their training has highlighted the importance of the 'deliberate practice ...of improving performance through practising beyond one's comfort level under guidance'. However, variations in physician, program, contextual and healthcare and educational systems complicate efforts to create a consistent approach to remediation. Balancing the inevitable disparities in approaches and settings with the need for continuity and effective oversight of the remediation process, as well as the context and population specific nature of remediation, this review will scrutinise the remediation of physicians in training to better guide the design, structuring and oversight of new remediation programs.
Krishna's Systematic Evidence Based Approach is adopted to guide this Systematic Scoping Review (SSR in SEBA) to enhance the transparency and reproducibility of this review. A structured search for articles on remediation programs for licenced physicians who have completed their pre-registration postings and who are in training positions published between 1st January 1990 and 31st December 2021 in PubMed, Scopus, ERIC, Google Scholar, PsycINFO, ASSIA, HMIC, DARE and Web of Science databases was carried out. The included articles were concurrently thematically and content analysed using SEBA's Split Approach. Similarities in the identified themes and categories were combined in the Jigsaw Perspective and compared with the tabulated summaries of included articles in the Funnelling Process to create the domains that will guide discussions.
The research team retrieved 5512 abstracts, reviewed 304 full-text articles and included 101 articles. The domains identified were characteristics, indications, frameworks, domains, enablers and barriers and unique features of remediation in licenced physicians in training programs.
Building upon our findings and guided by Hauer et al. approach to remediation and Taylor and Hamdy's Multi-theories Model, we proffer a theoretically grounded 7-stage evidence-based remediation framework to enhance understanding of remediation in licenced physicians in training programs. We believe this framework can guide program design and reframe remediation's role as an integral part of training programs and a source of support and professional, academic, research, interprofessional and personal development.
Low drug loading and instability of liposomes are two main challenges in the clinic. Herein, a liposomal platform from alternative pyridine-appended disulfidephospholipid (Pyr-SS-PC) was developed ...for delivering camptothecin (CPT) with high loading and stability. These Pyr-SS-PC lipids with π-π stacking open a general gate in the delivery of aromatic ring-containing drugs.
Liposomal platform assembled from novel pyridine-appended disulfidephospholipids with exceptionally high drug loading and stability.
Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal human cancers, can be divided into head and body/tail cancers anatomically. We previously reported a prognostic relevance of tumour ...location in resectable PDAC. This study aimed to further explore the mechanism underlying the molecular diversity between the head and body/tail of PDACs. We detected tumour genomes in 154 resectable (surgery) and non‐resectable (biopsy) PDACs using a next‐generation sequencing panel. Wilcoxon's rank test or Fisher's exact test was used for evaluating associations between clinical characteristics, mutation frequency and survival probability between the two cohorts. Compared with pancreatic head cancers, pancreatic body/tail cancers showed significantly more enriched genomic alterations in KRAS (97.1% vs 82.4%, P = 0.004) and SMAD4 (42.0% vs 21.2%, P = 0.008). At early stages (I‐II), the SMAD4 mutation rate was significantly higher in pancreatic body/tail cancers than pancreatic head cancers (56.0% vs 26.5%, P = 0.021). At late stages (III‐IV), pancreatic body/tail cancers presented significantly higher KRAS mutation rate (100.0% vs 75.8%, P = 0.001), higher frequency of MAPK pathway mutation (100% vs 87.8%, P = 0.040) and lower rates of druggable genomic alterations (30.8% vs 57.6%, P = 0.030) than pancreatic head cancers. Our work points out that pancreatic body/tail cancer seems to be more malignant than pancreatic head cancer at late stages.
Acute kidney injury (AKI) is a potential complication for children with congenital heart disease (CHD) after cardiopulmonary bypass (CPB) surgery. This study was designed to investigate and compare ...the predictive values of urinary biomarkers for AKI after CPB surgery in infants and young children and to determine the optimal timing of testing and the cutoff value for each biomarker. The study prospectively enrolled 58 CHD children 3 years of age or younger who were undergoing CPB surgery. Urinary neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), microalbumin (MA), N-acetyl-ß-D-glucosaminidase (NAG), α1-microglobulin (α1-MG), and creatinine (UCr) were measured at baseline and at various time points after surgery. Children who experienced AKI had more complex cardiac surgical procedures as evaluated by Risk Adjustment for Congenital Heart Surgery 1 (RACHS-1), longer CPB and aortic clamping times, and worse clinical outcomes than those who did not. In the AKI group, all five urinary biomarkers increased substantially and peaked at 4 h after surgery. In contrast, in the non-AKI group, they increased slightly or had no significant changes during the first 24 h. All the biomarkers had the best predictive performances at 4 h after surgery. At this time point, NAG had the minimum area under the curve (AUC) (0.747), which was significantly lower than that of the others (AUC, 0.82–0.85;
P
< 0.05). The optimal cutoff value of each biomarker was 290 ng/mg UCr for NAGL, 1,477 pg/mg UCr for IL-18, 400 mg/g UCr for MA, 225 U/g UCr for NAG, and 290 mg/g UCr for α1-MG. In conclusion, urinary NGAL, IL-18, MA, and α1-MG had similar predictive performances for the early detection of AKI after CPB surgery in infants and young children.
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