LncNFYB promotes the proliferation of rheumatoid arthritis fibroblast-like synoviocytes via LncNFYB/ANXA2/ERK1/2 axis.

Long noncoding RNAs (lncRNAs) are specifically expressed in different diseases and regulate disease progression. To explore the functions of rheumatoid arthritis (RA)-specific lncRNA, we determined the lncRNA expression profile of fibroblast-like synoviocytes (FLS) obtained from patients with RA and osteoarthritis (OA) using a LncRNA microarray and identified up-regulated LncNFYB in RA as a potential therapeutic target. Using gain- and loss-of-function studies, LncNFYB was proven to promote FLS proliferation and cell cycle progress but not affect their invasion, migration, and apoptotic abilities. Further investigation discovered that LncRNA could combine with annexin A2 (ANXA2) and enhance the level of phospho-ANXA2 (Tyr24) in the plasma membrane area, which induced the activation of ERK1/2 to promote proliferation. These findings provide new insights into the biological functions of LncNFYB on modification of FLS, which may be exploited for the therapy of RA.

Direct measuring of single-heterogeneous bubble nucleation mediated by surface topology.

Heterogeneous bubble nucleation is one of the most fundamental interfacial processes ranging from nature to technology. There is excellent evidence that surface topology is important in directing heterogeneous nucleation; however, deep understanding of the energetics by which nanoscale architectures promote nucleation is still challenging. Herein, we report a direct and quantitative measurement of single-bubble nucleation on a single silica nanoparticle within a microsized droplet using scanning electrochemical cell microscopy. Local gas concentration at nucleation is determined from finite element simulation at the corresponding faradaic current of the peak-featured voltammogram. It is demonstrated that the criteria gas concentration for nucleation first drops and then rises with increasing nanoparticle radius. An optimum nanoparticle radius around 10 nm prominently expedites the nucleation by facilitating the special topological nanoconfinements that consequently catalyze the nucleation. Moreover, the experimental result is corroborated by our theoretical calculations of free energy change based on the classic nucleation theory. This study offers insights into the impact of surface topology on heterogenous nucleation that have not been previously observed.

A novel missense mutation in the MECOM gene in a Chinese boy with radioulnar synostosis with amegakaryocytic thrombocytopenia.

Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) type 2, caused by MDS1 and EVI1 complex locus (MECOM) gene mutations, is a rare inherited bone marrow failure syndrome (IBMFS) with skeletal anomalies, characterized by varying presentation of congenital thrombocytopenia (progressing to pancytopenia), bilateral proximal radioulnar synostosis, and other skeletal abnormalities. Due to limited knowledge and heterogenous manifestations, clinical diagnosis of the disease is challenging. Here we reported a novel MECOM mutation in a Chinese boy with typical clinical features for RUSAT-2. Trio-based whole exome sequencing of buccal swab revealed a novel heterozygous missense mutation in exon 11 of the MECOM gene (chr3:168818673; NM_001105078.3:c.2285G > A). The results strongly suggest that the variant was a germline mutation and disease-causing mutation. The patient received matched unrelated donor hematopoetic stem cell transplantation (HSCT). This finding was not only expanded the pathogenic mutation spectrum of MECOM gene, but also provided key information for clinical diagnosis and treatment of RUSAT-2.

Quantitative Analysis of Morphology and Function in the Fetal Heart with Severe Tricuspid Regurgitation by Speckle Tracking Imaging.

Morphology and function in a fetal heart with severe tricuspid regurgitation remains challenging. The aim of this study was to assess cardiac morphology and function in fetuses with severe tricuspid regurgitation by fetal heart quantification (HQ) and to assess the practical value of fetal HQ. Clinical information was analyzed for 63 pregnant women who underwent fetal cardiac ultrasonography. The women were divided into those who had a fetus with severe tricuspid regurgitation (n = 20) and those with a normal fetus (n = 40). The global sphericity index (GSI), fractional area change (FAC), and global longitudinal strain (GLS) of both ventricles and the sphericity index (SI) and fractional shortening (FS) of 24 segments were quantified by fetal HQ using speckle tracking imaging. Fetuses with severe tricuspid regurgitation had a significantly lower GSI (1.14 ± 0.10 vs. 1.26 ± 0.08, p < 0.001) and a higher GSI Z-score (-0.98 ± 1.01 vs. 0.25 ± 0.87, p < 0.001) as well as a significantly lower right ventricular FAC (36.50 ± 7.34% vs. 45.19 ± 3.39%, p < 0.001), FAC Z-score (-1.02 ± 1.41 vs. 0.49 ± 0.74, p < 0.001), and GLS (-21.01 ± 5.66% vs. 45.19 ± 3.49%, p < 0.001). The SI and SI Z-score were significantly lower in segments 1-18 of the right ventricle in fetuses with severe tricuspid regurgitation (p < 0.05); furthermore, FS of segments 1-12 and 19-24 and the FS Z-score of segments 18-24 were significantly lower in fetuses with severe tricuspid regurgitation (p < 0.05). Fetal HQ is useful for evaluation of cardiac morphology and function in fetuses with severe tricuspid regurgitation and can provide important reference information for both clinical diagnosis and treatment.

"Sandwich" protocol based on modified SMILE regimen for children with newly extranodal NK/T cell lymphoma, nasal type: a single-arm, single-center clinical study.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL), which is a rare form of mature T/NK cell lymphoma in children, currently lacks a standardized first-line treatment approach. However, a treatment protocol known as the "sandwich" regimen has been used in children newly diagnosed with ENKTL. This protocol combines the administration of methotrexate, ifosfamide, etoposide, pegaspargase, and dexamethasone (referred to as SMILE) with the addition of radiotherapy (RT). From September 2017 to December 2020, a total of five patients were included in the study, consisting of three males and two females. The median age of onset was 10.6 years (range, 9.8 to 14.0 years). Among the patients, four had nasal/nasopharyngeal disease at stage II, while one patient had extra nasal disease involving the skin at stage IV. The median EBV-DNA level in plasma was 1.68 × 103 copies/ml (range, 0.44 to 21.1 × 103copies/ml). All the patients had good overall response after 2 cycles of chemotherapy and radiotherapy, including 4 of the patients who had a complete response and 1 of the patients with partial remission. The patient with stage IV received allogeneic hematopoietic stem cell transplantation after the EBV-DNA level was elevated again during treatment. One patient in the low-risk group experienced grade 4 oral mucositis, while no other severe complications or treatment-related deaths were observed. The median follow-up period was 22 months (range, 5 to 57 months). All five patients successfully completed their treatment, with four patients achieving event-free survival, and one patient was lost to follow-up. The median OS time and EFS time was 33 months (range: 18-57 months) and 20 months (range: 5-47 months), respectively. The sandwich protocol has demonstrated a high response rate, good tolerance to chemotherapy, and no treatment-related fatalities. However, further confirmation is necessary through additional clinical studies involving larger sample sizes. Clinical trial registration number: Due to modified SMILE regimens with sandwiched radiotherapy yielded promising outcomes in children ENKTL, we have carried out a phase II multicenter clinical trial (ChiCTR220005954) for children ENKTL in China to further verify the efficacy and safety.

Association between serum uric acid level and systemic lupus erythematosus kidney outcome: An observational study in Southern Chinese population and a meta-analysis.

OBJECTIVE: The study aimed to explore the effect of serum uric acid (SUA) level on the progression of kidney function in systemic lupus erythematosus (SLE) patients. METHODS: A total of 123 biopsy-proven lupus nephritis (LN) patients were included in this retrospective observational study. Cox proportional hazard regression analyses as well as restricted cubic spline analyses were performed to identify predictors of renal outcome in LN patients. We also performed a systematic review and meta-analysis for SUA and overall kidney outcomes in SLE patients. RESULTS: Based on the laboratory tests at renal biopsy, 72 (58.5%) of the 123 patients had hyperuricemia. The median (IQR) follow-up duration was 3.67 years (1.79-6.63 years), and a total of 110 (89.4%) patients experienced progression of LN. Increased serum uric acid level, whether analyzed as continuous or categorical variable, was associated with higher risk of LN progression in Cox proportional hazard regression model (hazard ratio [HR]: 1.003, 95% confidence interval [CI]: 1.001-1.005; HR: 1.780, 95% CI: 1.201-2.639, respectively). This relationship maintained in women (HR: 1.947, 95% CI: 1.234-3.074) but not men (HR: 2.189, 95% CI: 0.802-5.977). The meta-analysis showed a similar result that both continuous and categorical SUA were positively associated with the risk of kidney function progression in LN (weighted mean difference [WMD]: 1.73, 95% CI: 0.97-2.49; odds ratio [OR]: 1.55, 95% CI: 1.20-2.01, respectively). CONCLUSIONS: Our study found overall and especially in women that higher SUA in LN patients were associated with increased risk of renal progression. Meta-analysis yielded consistent results. Future studies are required to establish if uric acid can be used as a biomarker for risk assessment and/or as a novel therapeutic target in SLE.

Cost-effectiveness analysis of imatinib versus dasatinib in the treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia when combined with conventional chemotherapy in China.

BACKGROUND: Tyrosine kinase inhibitors combined with conventional chemotherapy (CC) in treating Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) has achieved promising efficacy and safety outcomes. The study was conducted to compare the cost-effectiveness between imatinib (HANSOH Pharma, Jiangsu, China) and dasatinib (CHIATAI TIANQING Pharma, Jiangsu, China) in treating pediatric Ph-positive ALL when combined with CC from the perspective of the health system in China. METHODS: A Markov model was established to simulate a hypothetical cohort of pediatric Ph-positive ALL patients receiving imatinib or dasatinib, combined with CC. The model was designed using a 10-year horizon, a 3- month cycle, and a 5% discount rate. Three health states were included: alive with progression-free survival, progressed disease, and death. Patient characteristics and transition probabilities were estimated based on clinical trials. Other relevant data, such as direct treatment costs and health utility data were extracted from published literature and Sichuan Province's centralized procurement and supervision platform. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the results. The willingness-to-pay (WTP) was set as three times China's GDP per capita in 2021. RESULTS: In the base-case analysis, the total medical costs were $89,701 and $101,182, and the quality-adjusted life years (QALYs) gained were 1.99 and 2.70, for imatinib and dasatinib regimens, respectively. The incremental cost-effectiveness ratio for dasatinib versus imatinib was $16,170/QALY. The probabilistic sensitivity analysis indicated that treatment with dasatinib combined with CC achieved a 96.4% probability of cost-effectiveness at a WTP threshold of $37,765/QALY. CONCLUSIONS: Dasatinib combined with CC is likely to be a cost-effective strategy compared to imatinib combination therapy for pediatric Ph-positive ALL in China at a WTP threshold of $37,765/QALY.

Direct Probing of the Oxygen Evolution Reaction at Single NiFe2O4 Nanocrystal Superparticles with Tunable Structures.

Due to the precisely controllable size, shape, and composition, self-assembled nanocrystal superlattices exhibit unique collective properties and find wide applications in catalysis and energy conversion. Identifying their intrinsic electrocatalytic activity is challenging, as their averaged properties on ensembles can hardly be dissected from binders or additives. We here report the direct measurement of the oxygen evolution reaction at single superparticles self-assembled from ∼8 nm NiFe2O4 and/or ∼4 nm Au nanocrystals using scanning electrochemical cell microscopy. Combined with coordinated scanning electron microscopy, it is found that the turnover frequency (TOF) estimated from single NiFe2O4 superparticles at 1.92 V vs RHE ranges from 0.2 to 11 s-1 and is sensitive to size only when it is smaller than ∼800 nm in diameter. After the incorporation of Au nanocrystals, the TOF increases by ∼6-fold and levels off with further increasing Au content. Our study demonstrates the first direct single entity electrochemical study on individual nanocrystal superlattices with tunable structures and unravels the intrinsic structure-activity relationship that is not accessible by other methods.

Electrochemical Visualization of Gas Bubbles on Superaerophobic Electrodes Using Scanning Electrochemical Cell Microscopy.

Electrocatalytic gas evolution reactions, where gaseous molecules are electrogenerated by reduction or oxidation of a species, play a central role in many energy conversion systems. Superaerophobic electrodes, usually constructed by their surface microstructures, have demonstrated excellent performance for electrochemical gas evolution reactions due to their bubble-repellent properties. Understanding and quantification of the gas bubble behavior including nucleation and dynamics on such microstructured electrodes is an important but underexplored issue. In this study, we reported a scanning electrochemical cell microscopy (SECCM) investigation of individual gas bubble nucleation and dynamics on nanoscale electrodes. A classic Pt film and a nonconventional transition-metal dichalcogenide MoS2 film with different surface topologies were employed as model substrates for both H2 and N2 bubble electrochemical studies. Interestingly, the nanostructured catalyst surface exhibit significantly less supersaturation for gas bubble nucleation and a notable increase of bubble detachment compared to its flat counterpart. Electrochemical mapping results reveal that there is no clear correlation between bubble nucleation and hydrogen evolution reaction (HER) activity, regardless of local electrode surface microstructures. Our results also indicate that while the hydrophobicity of the nanostructured MoS2 surface promotes bubble nucleation, it has little effect on bubble dynamics. This work introduces a new method for nanobubble electrochemistry on broadly interesting catalysts and suggests that the deliberate microstructure on a catalyst surface is a promising strategy for improving electrocatalytic gas evolution both in terms of bubble nucleation and elimination.

Akkermansia muciniphila protects intestinal mucosa from damage caused by S. pullorum by initiating proliferation of intestinal epithelium.

Akkermansia muciniphila, a novel mucin-degrading bacterium, has been demonstrated to prevent the development of obesity and related complications. However, whether it can protect poultry from intestinal mucosal damage by enteropathogens has never been mentioned. In this study, we found that A. muciniphila colonized in the intestine and then relieved intestinal mucosal damage in chicks caused by S. pullorum, including anatomical and morphological damage, alleviation of body weight and intestinal inflammation. The repair process activated by A. muciniphila is accompanied by an increase in the number of goblet cells in the chick's intestine and an up-regulation of Mucin 2 and trefoil factor 2 (Tff2). In addition, we also demonstrate that A. muciniphila improved colon length, crypt depth, increased the proliferating cell nuclear antigen, with the accelerated proliferation of intestinal epithelium through Wnt/ß-catenin signaling pathway, thereby restoring the damaged intestinal mucosa. This study suggests that A. muciniphila activates the proliferation of intestinal cells protecting the intestinal barrier, thus relieving infection with S. pullorum in chickens.

Indwelling catheter can increase postoperative urinary tract infection and may not be required in total joint arthroplasty: a meta-analysis of randomized controlled trial.

BACKGROUND: The purpose of this study was to investigate whether patients undergoing total joint arthroplasty (TJA) require catheterization. METHODS: PubMed, EMBASE, Web of Science, Cochrane Library and China National Knowledge Infrastructure were systematically searched. All randomized controlled trials (RCTs) receiving either a urinary catheterization or no urinary catheterization were included. Meta-analysis results were assessed by RevMan 5.3 software. RESULTS: Seven independent RCTs were included, with a total sample size of 1533 patients, including 750 patients in the indwelling catheter group and 783 patients in the none-indwelling catheter group. Our pooled data analysis indicated that patients in the indwelling catheter group had a higher risk of urinary tract infection than patients in the none-indwelling catheter group (RR, 3.21; P = 0.0003). However, the meta-analysis indicated that there was no significant difference between the two groups in terms of urinary retention (RR, 0.67; P = 0.13), duration of the surgery (MD, - 0.37; P = 0.55), and length of hospital stay (MD, 0.15; P = 0.38). CONCLUSION: Based on the current evidence, this meta-analysis showed that urinary catheterization during TJA can increase the postoperative urinary tract infection, and it may not routinely be required for the patients undergoing TJA. LEVEL OF EVIDENCE: Level I, therapeutic study.

The 5'-AMP-Activated Protein Kinase Regulates the Function and Expression of Human Organic Anion Transporting Polypeptide 1A2.

The organic anion transporting polypeptides (OATPs) are important membrane proteins that mediate the cellular uptake of drugs and endogenous substances. OATP1A2 is widely distributed in many human tissues that are targeted in drug therapy; defective OATP1A2 leads to altered drug disposition influencing therapeutic outcomes. 5'-AMP-activated protein kinase (AMPK) signaling plays an important role in the pathogenesis of the metabolic syndrome characterized by an increased incidence of type II diabetes and nonalcoholic fatty liver disease. This study investigated the regulatory role of AMPK in OATP1A2 transport function and expression. We found that the treatment of AMPK-specific inhibitor compound C (dorsomorphin dihydrochloride) decreased OATP1A2-mediated uptake of estrone-3-sulfate in a concentration- and time-dependent manner. The impaired OATP1A2 function was associated with a reduced Vmax [154.6 ± 17.9 pmol × (µg × 4 minutes)-1 in compound C-treated cells vs. 413.6 ± 52.5 pmol × (µg × 4 minutes)-1 in controls]; the Km was unchanged. The cell-surface expression of OATP1A2 was decreased by compound C treatment, but total cellular expression was unchanged. The impaired cell-surface expression of OATP1A2 was associated with accelerated internalization and impaired targeting/recycling. Silencing of the AMPK α1-subunit using specific small interfering RNA corroborated the findings with compound C and revealed a role for AMPK in regulating OATP1A2 protein stability. Overall, this study implicated AMPK in the regulation of the function and expression of OATP1A2, which potentially impacts on the disposition of OATP1A2 drug substrates that may be used to treat patients with the metabolic syndrome and other diseases.

The inhibitory effects of five alkaloids on the substrate transport mediated through human organic anion and cation transporters.

1. Human solute carrier transporters (SLCs) are important membrane proteins mediate the cellular transport of many endogenous and exogenous substances. Organic anion/cation transporters (OATs/OCTs) and organic anion transporting polypeptides (OATPs) are essential SLCs involved in drug influx. Drug-drug/herb interactions through competing for specific SLCs often lead to unsatisfied therapeutic outcomes and/or unwanted side effects. In this study, we comprehensively investigated the inhibitory effects of five clinically relevant alkaloids (dendrobine, matrine, oxymatrine, tryptanthrin and chelerythrine) on the substrate transport through several OATs/OCTs and OATPs. 2. We performed transport functional assay and kinetic analysis on the HEK-293 cells over-expressing each SLC gene. 3. Our data showed tryptanthrin significantly inhibited the transport activity of OAT3 (IC50 = 0.93 ± 0.22 µM, Ki = 0.43 µM); chelerythrine acted as a potent inhibitor to the substrate transport mediated through OATP1A2 (IC50 = 0.63 ± 0.43 µM, Ki = 0.60 µM), OCT1 (IC50 = 13.60 ± 2.81 µM) and OCT2 (IC50 =10.80 ± 1.16 µM). 4. Our study suggested tryptanthrin and chelerythrine could potently impact on the drug transport via specific OATs/OCTs. Therefore, the co-administration of these alkaloids with drugs could have clinical consequences due to drug-drug/herb interactions. Precautions should be warranted in the multi-drug therapies involving these alkaloids.

Perioperative multiple low-dose Dexamethasones improves postoperative clinical outcomes after Total knee arthroplasty.

BACKGROUND: The purpose of this study was to investigate the efficacy and safety of multiple low-dose dexamethasones in primary total knee arthroplasty (TKA). METHODS: One hundred fifty patients were equally randomized into 3 groups: Group A (n = 50) received 2 doses of normal saline only; Group B (n = 50) received with 1 dose of intravenous dexamethasone and 1 dose of normal saline; Group C (n = 50) received with 2 doses of intravenous dexamethasone. The clinical outcomes and complications were assessed. RESULTS: The CRP and IL-6 were significantly lower in Group C and B than Group A at 24, 48, and 72 h postoperatively (P < 0.001 for all). The intensity of postoperative nausea and vomiting (PONV) in Group C was lower than Group A at 24 (P < 0.001, P = 0.002), 48 (P = 0.005, P = 0.041) and 72 h (P = 0.017, P = 0.031) postoperatively and Group B at 24 h (P = 0.027, P = 0.019) postoperatively. Pain were significantly less in Group C than Group A at 24 (P < 0.001), 48 h (P = 0.037) postoperatively and Group B 24 h (P = 0.030) postoperatively. Patients in Group C had better range of motion (ROM) and satisfaction than Group A (P < 0.001, P = 0.002) and B (P = 0.001, P = 0.043). No differences were found in complications. CONCLUSIONS: The administration of 10 mg dexamethasone 1 h before the surgery, and repeated at 6 h postoperatively can significantly reduce the level of postoperative CRP and IL-6 and the incidence of PONV, relieve pain, achieve an additional analgesic effect, and improve the early ROM compared with the other two groups in TKA. LEVEL OF EVIDENCE: Therapeutic Level I. TRIAL REGISTRATION: The Chinese Clinical Trial Registry ( ChiCTR1800017036 ). Registered on July 9, 2018.

Human oligopeptide transporter 2 (PEPT2) mediates cellular uptake of polymyxins.

OBJECTIVES: Polymyxins are a last-line therapy to treat MDR Gram-negative bacterial infections. Nephrotoxicity is the dose-limiting factor for polymyxins and recent studies demonstrated significant accumulation of polymyxins in renal tubular cells. However, little is known about the mechanism of polymyxin uptake into these cells. Oligopeptide transporter 2 (PEPT2) is a solute carrier transporter (SLC) expressed at the apical membrane of renal proximal tubular cells and facilitates drug reabsorption in the kidney. In this study, we examined the role of PEPT2 in polymyxin uptake into renal tubular cells. METHODS: We investigated the inhibitory effects of colistin and polymyxin B on the substrate uptake mediated through 15 essential SLCs in overexpressing HEK293 cells. The inhibitory potency of both polymyxins on PEPT2-mediated substrate uptake was measured. Fluorescence imaging was employed to investigate PEPT2-mediated uptake of the polymyxin fluorescent probe MIPS-9541 and a transport assay was conducted with MIPS-9541 and [(3)H]polymyxin B1. RESULTS: Colistin and polymyxin B potently inhibited PEPT2-mediated [(3)H]glycyl-sarcosine uptake (IC50 11.4 ± 3.1 and 18.3 ± 4.2 µM, respectively). In contrast, they had no or only mild inhibitory effects on the transport activity of the other 14 SLCs evaluated. MIPS-9541 potently inhibited PEPT2-mediated [(3)H]glycyl-sarcosine uptake (IC50 15.9 µM) and is also a substrate of PEPT2 (Km 74.9 µM). [(3)H]polymyxin B1 was also significantly taken up by PEPT2-expressing cells (Km 87.3 µM). CONCLUSIONS: Our study provides the first evidence of PEPT2-mediated uptake of polymyxins and contributes to a better understanding of the accumulation of polymyxins in renal tubular cells.

The Role of N-Glycosylation in Maintaining the Transporter Activity and Expression of Human Oligopeptide Transporter 1.

Human oligopeptide transporter 1 (hPepT1) mediates the absorption of dietary peptides and a range of clinically relevant drugs. According to the predicted topological structure, hPepT1 contains multiple asparagine residues in putative N-glycosylation sites. This study investigated the influence of the six putative N-glycosylation sites within the extracellular region between transmembrane domains 9 and 10 on hPepT1 transporter function and expression in HEK-293T cells. Our study confirmed that hPepT1 is N-glycosylated in HEK-293T cells with the glycosylated and fully deglycosylated isoforms exhibiting apparent molecular masses of ∼78 and ∼55 kDa, respectively. Transport uptake of Glycylsarcosine (Gly-sar) by the hPepT1-N562Q variant, but not by other single mutants, was moderately impaired. We also constructed multiple N-glycosylation mutants based on the hPepT1-N562Q mutant by mutagenizing the additional asparagine residues N404Q, N408Q, N439Q, N509Q, and N514Q. Transport function showed a graded decrease as the number of mutagenized residues increased and simultaneous removal of all six asparagine residues essentially abolished transport activity. Kinetic studies indicated that the Vmax values for Gly-sar transport by low activity mutants were decreased compared to those of wild-type, which suggested that the cell surface expression and/or turnover rate of hPepT1 mutants was impaired; Km values were unchanged in most cases. Using immunoblotting and immunofluorescence, the plasma membrane and total cellular expression of the mutant transporters were decreased in accordance with functional impairments. In summary, we provide the first molecular evidence that hPepT1 is modified by N-glycosylation and that all six asparagine residues in the large extracellular loop between transmembrane domains 9 and 10 are subject to N-glycosylation. This information enhances our understanding of the role of the large extracellular loop in hPepT1 regulation and could facilitate the development of new hPepT1 substrate drugs with improved bioavailability.

Casein Kinase 2 Is a Novel Regulator of the Human Organic Anion Transporting Polypeptide 1A2 (OATP1A2) Trafficking.

Human organic anion transporting polypeptides (OATPs) mediate the influx of many important drugs into cells. Casein kinase 2 (CK2) is a critical protein kinase that phosphorylates >300 protein substrates and is dysregulated in a number of disease states. Among the CK2 substrates are several transporters, although whether this includes human OATPs has not been evaluated. The current study was undertaken to evaluate the regulation of human OATP1A2 by CK2. HEK-239T cells in which OATP1A2 was overexpressed were treated with CK2 specific inhibitors or transfected with CK2 specific siRNA, and the activity, expression, and subcellular trafficking of OATP1A2 was evaluated. CK2 inhibition decreased the uptake of the prototypic OATP1A2 substrate estrone-3-sulfate (E3S). Kinetic studies revealed that this was due to a decrease in the maximum velocity (Vmax) of E3S uptake, while the Michaelis constant was unchanged. The cell surface expression, but not the total cellular expression of OATP1A2, was impaired by CK2 inhibition and knockdown of the catalytic α-subunits of CK2. CK2 inhibition decreased the internalization of OATP1A2 via a clathrin-dependent pathway, decreased OATP1A2 recycling, and likely impaired OATP1A2 targeting to the cell surface. Consistent with these findings, CK2 inhibition also disrupted the colocalization of OATP1A2 and Rab GTPase (Rab)4-, Rab8-, and Rab9-positive endosomal and secretory vesicles. Taken together, CK2 has emerged as a novel regulator of the subcellular trafficking and stability of OATP1A2. Because OATP1A2 transports many molecules of physiological and pharmacological importance, the present data may inform drug selection in patients with diseases in which CK2 and OATP1A2 are dysregulated.

[New methods to detect autophagic flux].

Autophagy is a crucial biological process of eukaryotes, which is involved in cell growth, survival and energy metabolism, while the premise of the autophagy function is activated autophagic flux. It has been confirmed that impaired autophagic flux promotes pathogenesis of many chronic inflammatory diseases, especially cancer, neurodegenerative disease and tissue fibrosis, therefore the analysis of autophagic flux state is important for revealing autophagy function and the mechanism of autophagy related diseases. Given that autophagy is a dynamic process with multiple steps, it is very hard to observe the real state of autophagic flux. Summarized here is the novel concept and current approach to detect autophagic flux. This knowledge is crucial for the researching of the biological function of autophagy, and may provide some strategies for developing autophagy-related drug.

Williams-Beuren syndrome in pediatric T-cell acute lymphoblastic leukemia: A rare case report and review of literature.

BACKGROUND: Williams-Beuren syndrome (WBS) is a rare genetic disorder caused by hemizygous microdeletion of contiguous genes on chromosome 7q11.23. Although the phenotype features extensive heterogeneity in severity and performance, WBS is not considered to be a predisposing factor for cancer development. Currently, hematologic cancers, mainly Burkitt lymphoma, are rarely reported in patients with WBS. Here in, we report a unique case of T-cell acute lymphoblastic leukemia in a male child with WBS. METHODS: This retrospective study analyzed the clinical data of this case receiving chemotherapy were analyzed. This is a retrospective study. RESULTS: The patient, who exhibited a typical WBS phenotype and presented with hemorrhagic spots. Chromosomal genome-wide chip analysis (CMA) revealed abnormalities on chromosomes 7 and 9. The fusion gene STIL-TAL1 and mutations in BCL11B, NOTCH1, and USP7 have also been found and all been associated with the occurrence of T-cell leukemia. The patient responded well to the chemotherapy. CONCLUSION: To the best of our knowledge, this is the first reported case of WBS in T-cell acute lymphoblastic leukemia. We want to emphasize that the occurrence of leukemia in this patient might be related to the loss of 7q11.23 and microdeletion of 9p21.3 (including 3 TSGs), but the relationship between WBS and malignancy remains unclear. Further studies are required to clarify the relationship between WBS and malignancy.

Nicotine destructs dental stem cell-based periodontal tissue regeneration.

Background/purpose: Nicotine is a widely known addictive and toxic substance in cigarette that exacerbates periodontitis. However, its deleterious effects on dental stem cells and subsequent implications in tissue regeneration remain unclear. This study aimed to explore the effects of nicotine on the regenerative capacity of human periodontal ligament stem cells (hPDLSCs) based on transcriptomics and proteomics, and determined possible targeted genes associated with smoking-related periodontitis. Materials and methods: hPDLSCs were treated with different concentrations of nicotine ranging from 10-3 to 10-8 M. Transcriptomics and proteomics were performed and confirmed employing Western blot, 5-ethynyl-2'-deoxyuridine (EdU), and alkaline phosphatase (ALP) staining. A ligature-induced periodontitis mouse model was established and administrated with nicotine (16.2 µg/10 µL) via gingival sulcus. The bone resorption was assessed by micro-computed tomography and histological staining. Key genes were identified using multi-omics analysis with verifications in hPDLSCs and human periodontal tissues. Results: Based on enrichments analysis, nicotine-treated hPDLSCs exhibited decreased proliferation and differentiation abilities. Local administration of nicotine in mouse model significantly aggravated bone resorption and undermined periodontal tissue regeneration by inhibiting the endogenous dental stem cells regenerative ability. HMGCS1, GPNMB, and CHRNA7 were hub-genes according to the network analysis and corelated with proliferation and differentiation capabilities, which were also verified in both cells and tissues. Conclusion: Our study investigated the destructive effects of nicotine on the regeneration of periodontal tissues from aspects of in vitro and in vivo with the supporting information from both transcriptome and proteome, providing novel targets into the molecular mechanisms of smoking-related periodontitis.