- Paeoniflorin exerts neuroprotective effects by modulating the M1/M2 subset polarization of microglia/macrophages in the hippocampal CA1 region of vascular dementia rats via cannabinoid receptor 2. [Journal Article]
- CMChin Med 2018; 13:14
- CONCLUSIONS: These findings demonstrated PF exerts its neuroprotective effect and shifts the inflammatory milieu toward resolution by modulation of microglia/macrophage polarization via CB2R activation.
- Agouti Signaling Protein and Its Receptors as Potential Molecular Markers for Intramuscular and Body Fat Deposition in Cattle. [Journal Article]
- FPFront Physiol 2018; 9:172
- Transcriptome analyses of bovine muscle tissue differing in intramuscular fat (IMF) content identified agouti signaling protein (ASIP) as a promising candidate gene for fat deposition. The protein is...
Transcriptome analyses of bovine muscle tissue differing in intramuscular fat (IMF) content identified agouti signaling protein (ASIP) as a promising candidate gene for fat deposition. The protein is secreted from adipocytes and may serve as a signaling molecule in cross-talk between adipocytes and muscle fibers or other cells. Known receptors for ASIP are the melanocortin receptors (e.g., MC4R) and attractin (ATRN). The present study was conducted to determine relationships between the expression ofASIPand its receptors in different bovine tissues with fat deposition. Adipose tissues, liver, and longissimus muscle tissue were collected from 246 F2-generation bulls (Charolais × Holstein cross) and gene expression was measured with RT-qPCR. During analysis of subcutaneous fat (SCF) of all bulls, 17 animals were identified with a transposon-derived transcript (Exon2C) inserted in theASIPgene and dramatically increasedASIPmRNA levels. Significant correlations between normalized mRNA values of SCF and phenotypic traits related to fat deposition were found in bulls without Exon2C. Three retrospectively assigned groups [Exon2C,n= 17; high carcass fat (HCF),n= 20; low carcass fat (LCF),n= 20] were further analyzed to verify expression differences and elucidate molecular reasons. Expression ofASIPcould be detected in isolated muscle fibers and adipocytes of Exon2C bulls in contrast to HCF and LCF bulls, indicating ectopicASIPexpression if the transposon is present. Among adipose tissues, highestASIPmRNA levels were measured in SCF with significantly higher values in HCF compared to LCF bulls (1.6-fold,P< 0.05). However, the protein abundance was below the detection limit in all bulls. Potential ASIP receptors were detected in most investigated tissues. The expression ofMC4Rwas higher and ofATRNwas lower in several tissues of LCF compared to HCF bulls, whereasMC1Rwas not differentially expressed. Bulls of the Exon2C group had lowerATRNmRNA values than HCF and LCF bulls in perirenal fat (PF), but higher (P< 0.05) values in muscle. Receptors were also expressed in tissues whereASIPmRNA was not detected. Consequently, those tissues could be targets for ASIP if it circulates.
- Evaluation of Drain Amylase Level after Pancreaticoduodenectomy with Special Reference to Delayed Pancreatic Fistula. [Journal Article]
- ASAm Surg 2018 Mar 01; 84(3):403-409
- Postoperative pancreatic fistula (PF) is a relatively frequent and occasionally fatal complication of pancreatoduodenectomy (PD). Several risk factors for PF have been reported, including high drain ...
Postoperative pancreatic fistula (PF) is a relatively frequent and occasionally fatal complication of pancreatoduodenectomy (PD). Several risk factors for PF have been reported, including high drain amylase level (D-AMY). Among the 140 consecutive patients who underwent PD, we analyzed 110 cases with D-AMY measurements over time after PD. According to the D-AMY change, we divided patients into five patterns and defined delayed PF cases. We analyzed clinical characteristics, including serum amylase and D-AMY, and examined the correlation between the period of drain insertion and PF grade. In 15 delayed PF cases, 12 cases were grade B or C, pancreatic cancer was less frequent, pancreatic ducts were smaller, and soft pancreas texture was more commonly observed. The D-AMY on postoperative day (POD) 1 was higher in cases of delayed PF compared with non-PF cases (P < 0.0001). In 28 cases with drain removal before POD 7, grade B or C PF was not observed afterward. The average D-AMY on POD 1 in cases with drain removal before POD 1 was significantly lower than in delayed PF cases. Although further studies are required to determine the most appropriate timing of drain removal, it is thought that intra-abdominal drains should be removed within seven days of PD in cases without signs of PF. On the other hand, delayed PF should be considered in cases of soft pancreas texture and/or high D-AMY on POD 1, even if D-AMY levels are low on POD 3 or decreasing on POD 5.
- Validation of Patient Reported Outcomes Measurement Information System (PROMIS) Computer Adaptive Tests (CATs) in the Surgical Treatment of Lumbar Spinal Stenosis. [Journal Article]
- SSpine (Phila Pa 1976) 2018 Mar 19
- CONCLUSIONS: PROMIS CATs demonstrate convergent validity, known groups validity, and responsiveness for surgically treated patients with lumbar stenosis to detect change over time and are more efficient than legacy instruments.
- New treatment options for inflammatory bowel diseases. [Review]
- JGJ Gastroenterol 2018 Mar 19
- The advent of anti-TNF agents has dramatically changed the treatment algorithms for IBD in the last 15 years, but primarily and more importantly secondary loss of response is often observed. Fortunat...
The advent of anti-TNF agents has dramatically changed the treatment algorithms for IBD in the last 15 years, but primarily and more importantly secondary loss of response is often observed. Fortunately , new treatment options have been actively explored and some have already entered our clinical practice. In the class of anti-cytokine agents, the anti-IL12/IL23 monoclonal antibodies (mAbs) have entered clinical practice with the anti-p40 mAb ustekinumab in Crohn's disease (CD). Also, more selective anti-IL23 agents (anti-p19) have shown efficacy and are being further developed, in contrast to agents inhibiting IL-17 downstream which have failed in clinical trials despite their clear efficacy in psoriasis (Verstockt et al. in Expert Opin Biol Ther 17(1):31-47, 2017; Verstockt et al. in Expert Opin Drug Saf 16(7):809-821, 2017). Following up on the efficacy of the anti-adhesion molecule vedolizumab, etrolizumab (anti-beta-7 integrin) and PF-00547659, an anti-MadCam mAb, are being developed (Lobaton et al. in Aliment Pharmacol Ther 39(6):579-594, 2014). Oral anti-trafficking agents, such as ozanimod, targeting the S1P receptor responsible for the efflux of T-cells from the lymph nodes, have also shown efficacy in patients with ulcerative colitis (UC) (Sandborn et al. in N Engl J Med 374(18):1754-1762, 2016). Oral agents inhibiting cell signaling have been explored successfully in IBD. Tofacitinib, a non-selective oral Janus kinase (JAK) inhibitor, is effective in patients with UC and several other more or less selective Jak1, 2 and 3 inhibitors are being developed for the treatment of CD and UC (Sandborn et al. in N Engl J Med 376(18):1723-1736, 2017; Vermeire et al. in Lancet 389(10066):266-275, 2017; De Vries et al. in J Crohns Colitis 11(7):885-93, 2017). Finally, despite initial disappointing results with systemic administration of mesenchymal stem cells, Alofisel, adipose tissue derived, allogeneic mesenchymal stem cells, locally injected in perianal fistula tracts, induce long-lasting beneficial effects and the drug has been approved in Europe (Panes et al. in Gastroenterology, 2017). In summary, the quest for new treatment options in IBD is very active and justified by the high medical need and unresolved problems patients are facing.
- Differential expression pattern of co-inhibitory molecules on CD4+T cells in uncomplicated versus complicated malaria. [Journal Article]
- SRSci Rep 2018 Mar 19; 8(1):4789
- The immune response of malaria patients is a main factor influencing the clinical severity of malaria. A tight regulation of the CD4+T cell response or the induction of tolerance have been proposed t...
The immune response of malaria patients is a main factor influencing the clinical severity of malaria. A tight regulation of the CD4+T cell response or the induction of tolerance have been proposed to contribute to protection from severe or clinical disease. We therefore compared the CD4+T cell phenotypes of Ghanaian children with complicated malaria, uncomplicated malaria, asymptomatic Plasmodium falciparum (Pf) infection or no infection. Using flow cytometric analysis and automated multivariate clustering, we characterized the expression of the co-inhibitory molecules CTLA-4, PD-1, Tim-3, and LAG-3 and other molecules implicated in regulatory function on CD4+T cells. Children with complicated malaria had higher frequencies of CTLA-4+or PD-1+CD4+T cells than children with uncomplicated malaria. Conversely, children with uncomplicated malaria showed a higher proportion of CD4+T cells expressing CD39 and Granzyme B, compared to children with complicated malaria. In contrast, asymptomatically infected children expressed only low levels of co-inhibitory molecules. Thus, different CD4+T cell phenotypes are associated with complicated versus uncomplicated malaria, suggesting a two-sided role of CD4+T cells in malaria pathogenesis and protection. Deciphering the signals that shape the CD4+T cell phenotype in malaria will be important for new treatment and immunization strategies.
- A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite. [Journal Article]
- NMedNat Med 2018 Mar 19
- Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antib...
Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antibodies directed against the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) from several subjects immunized with an attenuated Pf whole-sporozoite (SPZ) vaccine (Sanaria PfSPZ Vaccine). Passive transfer of one of these antibodies, monoclonal antibody CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique 'junctional' epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope's conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif. The demonstration that CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next-generation rational vaccine design.
- Quantitative analysis of the impact of a human pathogenic mutation on the CCT5 chaperonin subunit using a proxy archaeal ortholog. [Journal Article]
- BBBiochem Biophys Rep 2017; 12:66-71
- The human chaperonin complex is a ~ 1 MDa nanomachine composed of two octameric rings formed from eight similar but non-identical subunits called CCT. Here, we are elucidating the mechanism of a heri...
The human chaperonin complex is a ~ 1 MDa nanomachine composed of two octameric rings formed from eight similar but non-identical subunits called CCT. Here, we are elucidating the mechanism of a heritable CCT5 subunit mutation that causes profound neuropathy in humans. In previous work, we introduced an equivalent mutation in an archaeal chaperonin that assembles into two octameric rings like in humans but in which all subunits are identical. We reported that the hexadecamer formed by the mutant subunit is unstable with impaired chaperoning functions. This study quantifies the loss of structural stability in the hexadecamer due to the pathogenic mutation, using differential scanning calorimetry (DSC) and isothermal titration calorimetry (ITC). The disassembly of the wild type complex, which is tightly coupled with subunit denaturation, was decoupled by the mutation without affecting the stability of individual subunits. Our results verify the effectiveness of the homo-hexadecameric archaeal chaperonin as a proxy to assess the impact of subtle defects in heterologous systems with mutations in a single subunit.
- Synergistic antitumor activity of low-dose c-Met tyrosine kinase inhibitor and sorafenib on human non-small cell lung cancer cells. [Journal Article]
- OLOncol Lett 2018; 15(4):5081-5086
- Sorafenib is a multikinase inhibitor that is frequently used to treat various types of malignant tumors. However, it has been demonstrated that Sorafenib only has a moderate antitumor efficacy and is...
Sorafenib is a multikinase inhibitor that is frequently used to treat various types of malignant tumors. However, it has been demonstrated that Sorafenib only has a moderate antitumor efficacy and is associated with numerous side effects in non-small cell lung cancer (NSCLC), which greatly limits its clinical application. The present study aimed to examine the effects of a combination of Sorafenib and low-dose PF-2341066, a selective c-Met tyrosine kinase inhibitor, on the proliferation, apoptosis and migration of the NSCLC cell line NCI-H1993. The data indicated that treatment with a combination of Sorafenib and low-dose PF-2341066 was able to significantly inhibit the proliferation and migration as well as promote the apoptosis, of NCI-H1993 cells, compared with treatment with Sorafenib or low-dose PF-2341066 alone. Further experiments indicated that the levels of phosphorylated epidermal growth factor receptor and c-Met were significantly decreased following the combined treatment of Sorafenib and PF-2341066, compared with the treatment with Sorafenib or PF-2341066 alone. The findings of the present study indicated that using a low-dose c-Met inhibitor enhances the antitumor activity of Sorafenib in NSCLC and may provide a novel strategy for the treatment of NSCLC.
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- Psychometric proprieties of the Child Health Questionnaire in an Arabic-speaking context: A multi-trait and multi-sample study. [Journal Article]
- JCJ Child Health Care 2018 Jan 01; :1367493518761817
- Ongoing research on the assessment of children's health has led to the development of a large number of quantitative tools. The Child Health Questionnaire-Parent Form (CHQ-PF) is a set of questionnai...
Ongoing research on the assessment of children's health has led to the development of a large number of quantitative tools. The Child Health Questionnaire-Parent Form (CHQ-PF) is a set of questionnaires aimed at measuring different facets of children's health as perceived by their parents. The present multi-trait multi-sample study tested the validity and the reliability of the 50-item version of the CHQ with families ( N = 1095) living in contexts of low-intensity warfare. The validation procedures implemented (exploratory and confirmatory factor analysis, convergent validity, and reliability testing) yielded a new, shorter version of the questionnaire (CHQ-PF-25). We discuss the potential of using the CHQ-PF-25 in Arabic-speaking crisis contexts and the limitations of the present study.