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Background: Mucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification. Methods: The anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Dalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494–0.957) and 51.6% (95% CI, 0.307–0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue. Conclusions: Dalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration. Trial registration: ChiCTR2000031608. [ABSTRACT FROM AUTHOR]

Background: Metabolomics is a tool to study the pathogenesis of diseases and their associated metabolites, but there are still insufficient metabolomic studies on severe knee osteoarthritis.To investigate the differences in serum metabolites between healthy populations and knee osteoarthritis (KOA) patients in Southern China using widely targeted metabolomics, and to explore biomarkers and their metabolic pathways that could be associated with the severity of KOA. Methods: There were 10 healthy individuals in the control group and 32 patients with KOA. According to the Kellgren–Lawrence (KL) grading system, KOA was further divided into mild (n = 13, KL grade 1 and 2) and severe (n = 19, KL grade 3 and 4). Serum samples from all participants were collected and analyzed metabolomics based on ultra-performance liquid chromatography/electrospray ionization/tandem mass spectrometry. We screened for differential metabolites between patients and controls, and between mild and severe KOA. We explored the metabolic pathways involved in differential metabolism using the Kyoto Encyclopedia of Genes and Genomes database. Results: Sixty-one metabolites were differentially expressed in the sera of the patient group compared with the control group (45 upregulated and 16 downregulated). Analysis of the mild and severe KOA groups showed a total of 12 differential metabolites. Receiver operating characteristic curve analysis showed N-alpha-acetyl-L-asparagine was a good predictor of advanced osteoarthritis(OA).Differential metabolites are enriched in multiple pathways such as arachidonic acid metabolism. Conclusion: Widely targeted metabolomics found that upregulation of the amino acid metabolite N-α-acetyl-L-asparagine was significantly associated with severe KOA and could be a biomarker for predicting severity of KOA. Arachidonic acid metabolism may play an important role in patients with severe KOA. [ABSTRACT FROM AUTHOR]

Background: There is the ongoing debate over the effect of inspired oxygen fraction (FiO2) during mechanical ventilation on postoperative atelectasis. We aimed to compare the effects of low (30%) and moderate (60%) FiO2 on postoperative atelectasis. The hypothesis of the study was that 30% FiO2 during mechanical ventilation could reduce postoperative atelectasis volume compared with 60% FiO2. Methods: We performed a randomized controlled trial with 120 patients. Subjects were randomly assigned to receive 30% or 60% FiO2 during mechanical ventilation in a 1:1 ratio. The primary outcome was the percentage of postoperative atelectasis volume in the total lung measured using chest CT within 30 min after extubation. The secondary outcomes included different aeration region volumes, incidence of clinically significant atelectasis, and oxygenation index. Results: In total, 113 subjects completed the trial, including 55 and 58 subjects in the 30% and 60% FiO2 groups, respectively. The percentage of the postoperative atelectasis volume in the 30% FiO2 group did not differ from that in the 60% FiO2 group. Furthermore, there was no significant difference in the atelectasis volume between the two groups after the missing data were imputed by multiple imputation. Additionally, there were no significant differences in the volumes of the over-aeration, normal-aeration, and poor-aeration regions between the groups. No significant differences in the incidence of clinically significant atelectasis or oxygenation index at the end of surgery were observed between the groups. Conclusions: Compared with 60% FiO2, the use of 30% FiO2 during mechanical ventilation does not reduce the postoperative atelectasis volume. Trial registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn). Identifier: ChiCTR1900021635. Date: 2 March 2019. Principal invetigator: Weidong Gu. [ABSTRACT FROM AUTHOR]

Nanomaterials with enzyme‐like activities, termed as nanozymes, have found wide applications in various fields. It has been a long‐term aim to rationally design and synthesize highly active nanozymes and thus to further improve their application performance. Guided by the nanoconfinement effect, we confine cytochrome c (Cyt c) within a mesoporous metal–organic framework (MOF), PCN‐222 nanoparticle (NP), forming a protein/MOF hybrid nanozyme, termed as Cyt c@PCN‐222 NP. The confined Cyt c exhibits around 3–4‐fold higher peroxidase‐like activity than free Cyt c. Due to the increase in the activity of Cyt c, the Cyt c@PCN‐222 NPs exhibit a quite low limit of detection (≈0.13 μM) towards H2O2. Sonication‐induced H2O2 formation in water by using a lab‐quipped ultrasonic cleaner can be sensitively probed, which suggests that H2O2‐sensitive materials should be carefully handled during the utilization of ultrasonic equipment. We speculate that this nanoconfinement strategy can broaden our synthetic methodology for the rational design of nanozymes. [ABSTRACT FROM AUTHOR]

Thyroid cancer (TC) is the most common endocrine malignancy. Medullary thyroid carcinoma (MTC) is derived from parathyroid follicle cells (C cells) secrete calcitonin, accounting for approximately 5-10% of all thyroid cancers. The malignancy is between differentiated and undifferentiated thyroid cancer and undifferentiated thyroid cancer and has a relatively poor prognosis. In MTC tumor cells, RREB1 regulates the differentiation of parathyroid cells via RAS-Raf-1-ELK3 signaling and induce calcitonin secretion. Therefore, it is easy to induce parathyroid parafollicular cells canceration and medullary thyroid carcinoma. Here, we investigated the correlation between RREB1, RAS-Raf-1-ELK3 signaling pathway and medullary thyroid carcinoma with various phases. Our results suggest that RREB1 promotes parafollicular carcinoma through the Ras-Raf1-elk3 signaling pathway, providing a rationale to further investigate the role of RREB1 in parafollicular carcinoma. It provides theoretical guidance for the clinical treatment of medullary thyroid cancer. [ABSTRACT FROM AUTHOR]

Five pomelo cultivars (i.e., Citrus grandis cv. Shatianyou, Citrus grandis cv. Guanximiyou, Citrus grandis cv. Yuhuanyou, Citrus grandis cv. Duweiwendanyou and Citrus grandis cv. Liangpingyou) from different origins in China were selected to analyze their components by using supercritical CO2 fluid extraction coupled with ultra‐high‐performance liquid chromatography‐tandem mass spectrometry. A total of 45 compounds were identified in the supercritical CO2 fluid extracts of the pomelo peels from the five cultivars. These compounds included eight flavonoids, 18 coumarins, four organic acids, three aldehydes, and 12 other compounds, which were identified using the obtained MS data and by comparison with commercial standards, orbitrap Chinese Traditional Medicine Library, and previous literature. Twenty‐five of the identified compounds were detected for the first time in the pomelo peel extracts. Results suggested that the pomelo peels of C. grandis cv. Shatianyou contained the most natural chemical compositions. The pooled result may offer scientific evidence for further development and utilization of pomelo peels and a route for screening appropriate varieties for various demands. [ABSTRACT FROM AUTHOR]

Ultra‐high‐performance liquid chromatography–Q–Exactive Orbitrap–mass spectrometry (MS) and gas chromatography (GC)–MS were performed for the qualitative and quantitative analyses of Citri Sarcodactylis Fructus (CSF) from different origins. The contents of eight major CSF components, namely 5,7‐dimethoxycoumarin, scopoletin, hesperidin, tangeretin, nobiletin, limonin, nomilin, and stachydrine, were quantitatively analyzed. Clustering analysis and principal component analysis (PCA) were, respectively, performed to classify and compare the 10 CSF batches. One hundred and two volatile components were identified accordingly by comparing retention times, reference standards, parent peaks, fragment peaks, and findings from relevant literature. Moreover, high content of 5,7‐dimethoxycoumarin and stachydrine was detected in all the CSFs, especially in CSF‐Zhe. Therefore, the high content component coumarin "5,7‐dimethoxycoumarin" was suggested to be quality analysis component rather than hesperidin. Additionally, characteristic compounds were found to distinguish different CSFs. This work was a comprehensive study about the components of various CSF. It distinguished the basic differences in the compositions of CSF from different origins. Eventually, it provided experimental and systematic bases for the quality control analysis of CSF, which has potential application in the further research. [ABSTRACT FROM AUTHOR]

Patients with hepatitis B virus‐related acute‐on‐chronic liver failure (HBV‐ACLF) are characterized by immune paralysis and susceptibility to infections. Macrophages are important mediators of immune responses can be subclassified into two main phenotypes: classically activated and alternatively activated. However, few studies have investigated changes to macrophage polarization in HBV‐related liver diseases. Therefore, we investigated the functional status of monocyte‐derived macrophages (MDMs) from patients with mild chronic hepatitis B (n = 226), HBV‐related compensated cirrhosis (n = 36), HBV‐related decompensated cirrhosis (n = 40), HBV‐ACLF (n = 62) and healthy controls (n = 10), as well as Kupffer cells (KCs) from patients with HBV‐ACLF (n = 3). We found that during the progression of HBV‐related liver diseases, the percentage of CD163+CD206+ macrophages increased, while the percentage of CD80+human leukocyte antigen‐DR+ macrophages decreased significantly. MDMs and KCs mainly exhibited high CD163+CD206+ expression in patients with HBV‐ACLF, which predicted poor clinical outcome and higher liver transplantation rate. Transcriptome sequencing analysis revealed that chloride intracellular channel‐3 (CLIC3) was reduced in patients with HBV‐ACLF, indicating a poor prognosis. To further study the effect of CLIC3 on macrophage polarization, human monocytic THP‐1 cell‐derived macrophages were used. We found that classical and alternative macrophage activation occurred through nuclear factor kappa B (NF‐κB) and phosphoinositide 3‐kinase/protein kinase B pathways, respectively. CLIC3 suppression inhibited NF‐κB activation and promoted the alternative activation. In conclusion, macrophage polarization gradually changed from classically activated to alternatively activated as HBV‐related liver diseases progressed. Both CLIC3 suppression and increased alternatively activated macrophage percentage were potential indicators of the poor prognosis of patients with HBV‐ACLF. [ABSTRACT FROM AUTHOR]

The pericarp of Citrus reticulata "Chachi" (CRCP) is used as nutritional food and traditional medicine in China, usually harvested at three periods, namely, immature (CRCP‐G1), semi‐mature (CRCP‐G2), and fully mature (CRCP‐G3). Traditionally, if the CRCP is stored for a longer period, then the quality will be better. In this study, the dynamic variation of phytochemical and volatile compounds was profiled in the same batches of CRCP during 2 years of storage. Results illustrated that most of the phytochemical compounds showed a decreasing trend during storage, that is, total flavonoids, total phenolic acids, hesperidin, 3,5,6,7,8,3′,4′‐heptamethoxyflavone, 5‐hydroxy‐6,7,8,3′,4′‐pentamethoxyflavone, synephrine, and limonin. The ferulic acid increased significantly, whereas no significant changes were observed in the total polymethoxyflavones, nobiletin, and tangeretin after 2 years of storage. In addition, we found that the extraction yield of volatile oil decreased significantly in CRCP‐G1 during storage, and the herb odors were enhanced with the increase of phenols and esters. No significant difference in the extraction yield of volatile oil of CRCP‐G2 and CRCP‐G3 was found after 2 years of storage, but the citrus‐like notes were increased with the promoted generation of alkenes. In particular, the multivariate statistical analysis indicated that 7 volatiles showed a higher level after 1 year of storage, whereas 11 volatiles decreased and 4 volatiles increased after 2 years of storage, respectively. This study could show the early aging mechanism of CRCP harvested at different periods and provide a scientific guidance in the storage of CRCP. Practical Application: This study indicated a comprehensive method for rapid analysis of phytochemical and volatile compounds in pericarp of Citrus reticulata "Chachi" (Rutaceae) (CRCP) harvested at different periods during 2 years of storage. The results obtained from this study would be valuable for revealing the early aging mechanism and sustainable storage of CRCP. [ABSTRACT FROM AUTHOR]

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As a severe metabolic disease, type 2 diabetes mellitus (T2DM) has become a serious threat to human health in recent years. Gastrodin, as a primary chemical constituent in Gastrodia elata Blume, has antidiabetic effects. However, the possible mechanisms are unclear. The aim of the present study was to investigate the effects and possible mechanisms of gastrodin on the treatment of T2DM. In vivo , after treatment with gastrodin for 6 weeks, fasting blood glucose levels, blood lipid metabolism, and insulin sensitivity index values were remarkably reduced compared with those of the diabetic control group. The values of aspartate aminotransferase and alanine aminotransferase also showed that gastrodin alleviates liver toxicity caused by diabetes. Moreover, gastrodin relieved pathological damage to the pancreas in T2DM rats. In vitro , gastrodin alleviated insulin resistance by increasing glucose consumption, glucose uptake, and glycogen content in dexamethasone-induced HepG2 cells. The Western blotting results showed that gastrodin upregulated the expression of insulin receptors and ubiquitin-specific protease 4 (USP4) and increased the phosphorylation of GATA binding protein 1 (GATA1) and protein kinase B (AKT) in vivo and in vitro. Furthermore, gastrodin decreased the ubiquitin level of the insulin receptor via UPS4 and increased the binding of GATA1 to the USP4 promoter. Additionally, administration of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway inhibitors MK-2206 and LY294002 abolished the beneficial effects of gastrodin. Our results indicate that gastrodin promotes the phosphorylation of GATA1 via the PI3K/AKT pathway, enhances the transcriptional activity of GATA1, and then increases the expression level of USP4, thereby reducing the ubiquitination and degradation of insulin receptors and ultimately improving insulin resistance. Our study provides scientific evidence for the beneficial actions and underlying mechanism of gastrodin in the treatment of T2DM. [ABSTRACT FROM AUTHOR]

Maturation arrest (MA) is a subtype of non-obstructive azoospermia, and male infertility is a known risk factor for testicular tumors. However, the genetic basis for many affected individuals remains unknown. Here, we identified a deleterious hemizygous variant of X-linked retinoblastoma-binding protein 7 (RBBP7) as a potential key cause of MA, which was also found to be associated with the development of Leydig cell tumors. This mutation resulted in premature protein translation termination, affecting the sixth WD40 domain of the RBBP7 and the interaction of the mutated RBBP7 with histone H4. Decreased BRCA1 and increased yH2AX were observed in the proband. In mouse spermatogonial and pachytene spermatocyte-derived cells, deprivation of rbbp7led to cell cycle arrest and apoptosis. In Drosophila, knockdown of RBBP7/ Caf1-55 in germ cells resulted in complete absence of germ cells and reduced testis size, whereas knockdown of RBBP7/Caf1-55 in cyst cells resulted in hyperproliferative testicular cells. Interestingly, male infertility caused by Caf1-55 deficiency was rescued by ectopic expression of wild-type human RBBP7 but not mutant variants, suggesting the importance of RBBP7 in spermatogenesis. Our study provides insights into the mechanisms underlying the co-occurrence of MA and testicular tumors and may pave the way for innovative genetic diagnostics of these 2 diseases., Introduction Non-obstructive azoospermia (NOA), characterized by failure of spermatogenesis, is present in 10%-15% of male infertility cases. This covers hypospermatogenesis, maturation arrest (MA), and Sertoli cell-only syndrome (1). MA is [...]