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  Multiple splicing factors whose protein but not mRNA levels affected by PFOA exposure were identified. The changes in protein abundance of the splicing factors was also reflected in altered splicing pattern of their target genes, which provided new insights on the previously unexplored mechanisms of PFOA-mediated hepatotoxicity and pathogenesis. V.PURPOSE Nodular basal cell carcinoma (nBCC) is mostly treated with surgical excision. Interest in minimally invasive treatment of these low-risk tumors is increasing. We assessed the effectiveness of nBCC treatment with curettage and imiquimod cream compared to surgical excision. METHODS Patients with nodular BCC included in this randomized controlled non-inferiority trial were randomly assigned to either curettage and imiquimod cream or surgical excision. Primary endpoint was the proportion of patients free from treatment failure one 1 year after the end of treatment. A pre-specified non-inferiority margin of 8% was used. A modified intention-to-treat and a per-protocol analysis was performed. Clinicaltrial.gov (NCT02242929). RESULTS 145 patients were randomized; 73 to curettage and imiquimod cream and 72 to surgical excision. Proportion of patients free of recurrence after 12 months was 86.3% for curettage and imiquimod (63/73) and 100% for excision (72/72). Difference in efficacy was -13.7% (95%-CI -21.6% to -5.8%, one-sided p=0.0004) favoring surgical excision. CONCLUSION Non-inferiority of curettage and imiquimod cream cannot be concluded. Given the still high efficacy of curettage and imiquimod cream, and indolent growth pattern of nBCC, curettage and imiquimod could still be a valuable treatment option with the possibility to prevent overuse of excisions. However, it cannot replace surgical excision. BACKGROUND Over the last five years, there has been a rapid growth in the number of clinical trials used to support an FDA approval for systemic therapies with labeled indications for plaque psoriasis. OBJECTIVE We aim to evaluate the fragility of clinical trial data used to support FDA-approval of therapies for psoriasis. METHODS We reviewed primary endpoints of the efficacy pivotal trials of all systemic medications with a labeled indication for plaque psoriasis available from Drugs@FDA. RESULTS 69 clinical trial primary endpoints met inclusion criteria and were assessed for robustness, yielding a median fragility index (MFI) of 72 and a median fragility quotient (MFQ) of 0.19. LIMITATIONS Efficacy and statistical analysis data for several approved medications were not available on the product label or on Drugs@FDA. CONCLUSIONS When compared to randomized controlled trials for FDA approval across various diseases, pivotal trials in psoriasis appear quite robust to changes in outcomes. The use of the humanized monoclonal anti-programmed cell death-1 antibodies pembrolizumab and nivolumab as potent anti-cancer therapies is rapidly increasing. However, since their approval numerous cases of cutaneous reactions have been reported. Cutaneous adverse reactions to these agents have yet to be fully characterized and range from non-specific eruptions to recognizable skin manifestations, which may be localized and vary from mild to life-threatening. This systematic review article provides an overview of the various adverse cutaneous reactions to pembrolizumab and nivolumab therapy and offers suggestions for their management. Though immunomodulation via cholinergic neurotransmitter acetylcholine (ACh), an important part of neuroendocrine-immune (NEI) regulatory network, has been well established in vertebrate species, the mechanisms remain poorly understood in invertebrates. In the present study, the immunomodulatory effect of ACh on haemocyte phagocytosis was investigated in an invertebrate bivalve species, Tegillarca granosa. Data obtained showed that in vitro ACh incubation suppressed phagocytic activity of haemocytes along with a significant elevation in intracellular Ca2+. In addition, the expressions of genes from Ca2+ signaling pathway were significantly induced whereas those from NF-κB signaling pathway were significantly down-regulated by ACh incubation. Furthermore, these adverse impacts of ACh were significantly relieved by the blocking of muscarinic acetylcholine receptors (mAChRs) or nicotinic acetylcholine receptors (nAChRs) using corresponding antagonists. Our study suggests that ACh suppresses phagocytosis via binding to both mAChRs and nAChRs, which disrupts intracellular Ca2+ homeostasis and subsequently interferes with downstream Ca2+ and NF-κB signaling pathways.  https://www.selleckchem.com/products/LBH-589.html  The IκB kinases (IKK) are large multiprotein complexes that regulate the activation of the transcription factor NF-κB and are involved in a diverse range of biological processes, including innate immunity, inflammation, and development.  https://www.selleckchem.com/products/LBH-589.html  To explore the potential roles of invertebrate IKKs on immunity, three IKK encoding genes have been identified from molluscan species disk abalone and designed as AbIKK1, AbIKK2 and AbIKK3 at the transcriptional level. Coding sequences of AbIKK1, AbIKK2 and AbIKK3 encode the peptides of 746, 751 and 713 amino acids with the predicted molecular mass of 86.16, 86.12 and 81.88 kDa respectively. All three AbIKKs were found to share conserved IKK family features including the kinase superfamily domain (KD), ubiquitin-like domain (ULD), and α-helical scaffold/dimerization domain (SDD), similar to their mammalian counterparts. Under normal physiological conditions, AbIKKs were ubiquitously detected in six different tissues, with the highest abundance in the digestive tract and gills. an evolutionarily conserved signaling mechanism for IKK mediated NF-κB activation in mollusks. Norfloxacin (NOR) is applied clinically to treat keratitis. However, NOR has brought severe side-effects for human corneal epithelium (HCEP) due to overdose and potential toxicity. In this study, two in vitro experimental models including monolayer HCEP cells and tissue-engineered human corneal epithelium (TE-HCEP) were used to explore the cytotoxicity and its related mechanisms. The HCEP cells treated with NOR at concentrations from 0.1875 to 3.0 mg/mL displayed abnormal morphology, declined viability, and increased plasma membrane permeability. Moreover, 0.75 mg/mL NOR induced chromatin condensation, S phase arrest, phosphatidylserine externalization, and formation of apoptotic body through activation of caspase-2/-8/-9/-3, downregulation of Bcl-2 and Bcl-xL, upregulation of Bad and Bax, mitochondrial transmembrane potential disruption and release of cytochrome c and apoptosis inducing factor into cytosol, whereas 1.5 mg/mL and 3.0 mg/mL NOR upregulated the expressions of receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like (MLKL) together with inactivation of caspase-2/-8.