Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central ...nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.
The presence of human papilloma virus in benign oral lesions has been studied by different techniques obtaining extremely variable results. The objective of this study was to determine the presence ...of human papillomavirus in 83 cases of benign hyperplastic epithelial oral lesions.
Eighty-three oral lesions with clinical or histopathological features suggestive of HPV infection were retrieved from the files of four oral pathology services. Demographic data were obtained from patient's medical charts. All cases had available clinical image, H&E preparations and paraffin blocks with enough tissue for HPV detection by in situ hybridization, and immunohistochemical reactions for Ki67.
Episomal positivity for wide spectrum HPV was observed in 24% of the cases; most of them (70%) HPV 6/11 positive. HPV 16/18 was not detected. Condyloma acuminatum was the most common lesion associated with HPV (75%), followed by verruca vulgaris (15%), squamous papilloma and multifocal epithelial hyperplasia, 5% each. Koilocytes were identified in all the HPV positive cases. Ki67 showed an abnormal proliferation pattern in 90% of the HPV positive cases; most of them (70%) showing groups of proliferating cells in focal superficial regions, and in 20% positivity was seen almost in the whole thickness of the epithelium. HPV negative cases showed Ki67 positive cells restricted to the basal layer.
Regarding oral lesions associated with HPV, condyloma is the most common lesion expressing low-risk subtypes. The etiology of squamous papilloma remains controversial as HPV was found in 1.9% of the cases. The identification of koilocytes and the pattern of expression of Ki67 reflect HPV infection and are helpful for classification. Papillary oral lesions not associated to HPV deserve further studies to better clarify its etiology.
Objective
To describe the clinical and genetic features of patients with cherubism.
Material and Methods
A descriptive analysis of 14 cases from nine different families was carried out. ...Clinicopathological, imaging, and follow‐up data were retrieved from patients’ medical files and correlated with the genetic profile of each patient. Genomic DNA isolated from buccal mucosa cells was subjected to direct sequencing analysis of the SH3BP2 gene.
Results
Females were more affected than males (8:6), and the mean age at diagnosis was 8.6 years (range 3–30 years). Eleven patients exhibited simultaneous bilateral involvement of the maxilla and mandible. Two patients did not have a familial history of cherubism. Progressive growth pattern was found in six patients and stable lesions were observed in other seven patients, whereas in one patient, complete spontaneous remission was documented during the follow‐up (31 years). Mutations were found in 13 cases and included the typical heterozygous missense mutations R415Q, P418T, and P418H at exon 9 of SH3BP2. No correlation between the mutations and the clinical manifestations was observed.
Conclusion
Three different point mutations in the SH3BP2 gene were detected with variable clinical involvement. Genotype–phenotype association studies in larger population with cherubism are necessary to provide important knowledge about molecular mechanisms related to the disease.
Abstract Interleukin-6 (IL-6) is a cytokine that can facilitate autoimmune phenomena, amplify acute inflammation and promote the evolution into a chronic inflammatory state. In addition, it is a ...major promoter of bone resorption in pathological conditions. In particular, IL-6 has a pivotal role in synovitis, bone erosions and in the systemic features of inflammation. This cytokine specifically binds to IL-6 receptor (IL-6R), forming the IL-6/IL-6R complex that binds to gp130, a membrane-bound protein, which is involved in non-ligand-binding signal transduction. Targeting IL-6R in both animal models of arthritis and in rheumatoid arthritis patients with a humanized anti IL-6R monoclonal antibody (tocilizumab) effectively controls local and systemic inflammatory manifestations and blocks cartilage and bone destruction. Given the pleiotropic function of IL-6 it can be anticipated that other inflammatory diseases and bone metabolic conditions might benefit from selective IL-6 signaling inhibition.
Little real-world evidence is available to describe the recent trends in treatment costs and outcomes for patients with multiple myeloma (MM). Using the Truven Health MarketScan Research Databases ...linked with social security administration death records, this study found that the percentage of MM patients using novel therapy continuously increased from 8.7% in 2000 to 61.3% in 2014. Compared with MM patients diagnosed in earlier years, those diagnosed after 2010 had higher rates of novel therapy use and better survival outcomes; patients diagnosed in 2012 were 1.25 times more likely to survive 2 years than those diagnosed in 2006. MM patients showed improved survival over the study period, with the 2-year survival gap between MM patients and matched controls decreasing at a rate of 3% per year. Total costs among MM patients have increased in all healthcare services over the years; however, the relative contribution of drug costs has remained fairly stable since 2009 despite new novel therapies coming to market. Findings from this study corroborate clinical data, suggesting a paradigm shift in MM treatment over the past decade that is associated with substantial survival gains. Future studies should focus on the impact on specific novel agents on patients' outcomes.
Tissue-infiltrating Ly6Chi monocytes play diverse roles in immunity, ranging from pathogen killing to immune regulation. How and where this diversity of function is imposed remains poorly understood. ...Here we show that during acute gastrointestinal infection, priming of monocytes for regulatory function preceded systemic inflammation and was initiated prior to bone marrow egress. Notably, natural killer (NK) cell-derived IFN-γ promoted a regulatory program in monocyte progenitors during development. Early bone marrow NK cell activation was controlled by systemic interleukin-12 (IL-12) produced by Batf3-dependent dendritic cells (DCs) in the mucosal-associated lymphoid tissue (MALT). This work challenges the paradigm that monocyte function is dominantly imposed by local signals after tissue recruitment, and instead proposes a sequential model of differentiation in which monocytes are pre-emptively educated during development in the bone marrow to promote their tissue-specific function.
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•Monocytes acquire regulatory properties in bone marrow early during gut infection•Infection-induced IFN-γ alters monocyte precursors in the bone marrow•Bone-marrow-resident NK cells prime monocytes for regulatory function•IL-12 produced in the gut activates bone marrow NK cells, instructing hematopoiesis
Ly6Chi monocytes play diverse roles in tissue immunity, but how this diversity of function is imposed remains poorly understood. Askenase and colleagues demonstrate that during infection, NK cells prime monocytes for regulatory function prior to bone marrow egress in response to systemic signals emanating from the infected tissue.
Unraveling the repertoire of venom toxins of Bothropoides pauloensis was assessed by snake venomics and venom gland transcriptomic surveys. Both approaches yielded converging overall figures, ...pointing to metalloproteinases (~37%), PLA2s (26–32%), and vasoactive (bradykinin-potentiating) peptides (12–17%) as the major toxin classes. The high occurrence of SVMPs, PLA2 molecules, vasoactive peptides, along with serine proteinases, explains the local and systemic effects observed in envenomations by B. pauloensis. Minor (<3%) C-type lectin, serine proteinase, l-amino acid oxidase, nerve growth factor, and CRISP molecules were also identified in the transcriptome and the proteome. Low abundance (0.3%) EST singletons coding for vascular endothelial growth factor (svVEGF), ohanin, hyaluronidase, and 5′ nucleotidase were found only in the venom gland cDNA library. At the molecular level, the transcriptomic and proteomic datasets display low compositional concordance. In particular, although there is good agreement between transcriptome and proteome in the identity of BPPs, PLA2 molecules and l-amino acid oxidase, both datasets strongly depart in their C-type lectin and SVMP complements. These data support the view that venom composition is influenced by transcriptional and translational mechanisms and emphasize the value of combining proteomic and transcriptomic approaches to acquire a more complete understanding of the toxinological profile and natural history of the snake venom.
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► The repertoire of venom toxins of B. pauloensis was assessed by venomic and transcriptomic surveys. ► Both approaches converge in their overall major toxin family profile but depart in the occurrence of minor components. ► The toxin profile explains the local and systemic effects observed in envenomations by B. pauloensis. ► B. pauloensis expresses the adult venom phenotype described in other Bothrops species.
Flavonoids are polyphenolic compounds found throughout the plant kingdom. They occur in every organ but are usually concentrated in leaves and flowers. During the last two decades, in vitro and in ...vivo studies demonstrated that flavonoids have inhibitory effects on human diseases through targeting of multiple cellular signaling components. Wnt/β-catenin signaling regulates proliferation, differentiation and fate specification in developmental stages and controls tissue homeostasis in adult life. For these reasons, this pathway has received great attention in the last years as potential pathway involved in distinct Human pathologies. In this review we discuss the emerging potential mechanisms for flavonoids on Wnt/β-catenin signaling in cancer and possible investigation strategies to understand flavonoids mode of action on this signaling pathway.
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