Deletions of Chromosome 1p and 15q are Associated with Aggressiveness of Gastrointestinal Stromal Tumors

Background/PurposeSite-dependent profiles of chromosome imbalances (CIs) have been reported in gastrointestinal stromal tumors (GISTs). However, the role of specific CIs in association with metastasis is not clear.MethodsThirteen resected liver metastatic GISTs, including seven from the stomach and six from the small intestine, were analyzed using comparative genomic hybridization (CGH). The CIs associated with metastatic risk were assessed by comparing them with those identified in our previous study of 25 primary GISTs, including 14 from the stomach and 11 from the small intestine.ResultsSynchronous detection of liver metastasis was found more often in patients with intestinal than gastric GIST (5/6 vs. 2/7, p = 0.048). When compared with the primary tumors, the CI profile of liver metastases was similar in the intestinal group, but became more complex in the gastric group. Deletions of chromosomes 1p and 15q were very common (> 80%) in primary and metastatic tumors of the intestinal group, and exhibited a trend towards increase in the metastatic tumors of the gastric group. Both groups had a doubling in the frequency of 22q deletion in the liver metastases, which was not significantly different. Other CIs, including 9p deletion, increased significantly in the liver metastases of the gastric group, but not in the intestinal group.ConclusionOur results, together with clinical findings, indicated a CGH profile associated with the intrinsic aggressiveness of the GISTs. Deletion of 1p and 15q play a critical role in the acquisition of aggressiveness during early GIST development

Tumor-Associated Macrophage-Induced Invasion and Angiogenesis of Human Basal Cell Carcinoma Cells by Cyclooxygenase-2 Induction

Tumor-associated macrophages (TAMs) and cyclooxygenase-2 (COX-2) are associated with invasion, angiogenesis, and poor prognosis in many human cancers. However, the role of TAMs in human basal cell carcinoma (BCC) remains elusive. We found that the number of TAMs infiltrating the tumor is correlated with the depth of invasion, microvessel density, and COX-2 expression in human BCC cells. TAMs also aggregate near COX-2 expressing BCC tumor nests. We hypothesize that TAMs might activate COX-2 in BCC cells and subsequently increase their invasion and angiogenesis. TAMs are a kind of M2 macrophage derived from macrophages exposed to Th2 cytokines. M2-polarized macrophages derived from peripheral blood monocytes were cocultured with BCC cells without direct contact. Coculture with the M2 macrophages induced COX-2-dependent invasion and angiogenesis of BCC cells. Human THP-1 cell line cells, after treated with phorbol myristate acetate (PMA), differentiated to macrophages with M2 functional profiles. Coculture with PMA-treated THP-1 macrophages induced COX-2-dependent release of matrix metalloproteinase-9 and subsequent increased invasion of BCC cells. Macrophages also induced COX-2-dependent secretion of basic fibroblast growth factor and vascular endothelial growth factor-A, and increased angiogenesis in BCC cells

Reversible Cerebral Vasoconstriction Syndrome: A Comprehensive Systematic Review

OBJECTIVE: We aimed to analyze clinical characteristics, treatment patterns, and prognosis of patients with reversible cerebral vasoconstriction syndrome (RCVS). MATERIALS AND METHODS: Two investigators independently searched PubMed and EMBASE, and 191 cases were included in this study. Information regarding demographics, triggering factors, brain imaging findings, treatment modalities, recurrence, and clinical outcome was collected. RESULTS: The mean age of the patients was 39.9 years, and 155 (81.2%) were female. The most common triggering factor for RCVS was an exposure to vasoactive substances (41.4%), followed by pregnancy/postpartum (20.9%), and sexual intercourse (10.5%). Multifocal stenosis (84.0%) and beading shape (82.4%) were the leading abnormal findings on angiography, while cerebral ischemic lesions (47.6%) and cerebral hemorrhage (mainly subarachnoid hemorrhage) (35.1%) were the main findings on brain computed tomography (CT)/magnetic resonance imaging (MRI). Calcium channel blockers (nimodipine/verapamil) were the most commonly used medications (44.5%) in the treatment of RCVS. Multivariate analysis identified that RCVS was precipitated by trauma/surgery/procedure (hazard ratio (HR): 3.29, 95% confidence interval (CI) (1.21-8.88), p=0.019), and presence of aphasia/neglect/apraxia during the acute phase of the disease (HR: 3.83, 95% CI (1.33-11.05), p=0.013) were found to be the two independent risk factors for residual neurological deficit after RCVS. CONCLUSIONS: In our systematic review, vasoactive substances were the most frequent triggers for RCVS, which was most commonly accompanied by angiographic findings of multifocal stenotic lesions. Patients with RCVS precipitated by trauma or surgical procedures and those with focal cortical deficits had a higher risk of residual neurological deficits, and these patients should closely be monitored

Prevalence of BRAF and NRAS mutations in cutaneous melanoma patients in Taiwan

BRAF and NRAS mutations have been described in melanomas among Caucasians and some Asian populations. However, few large-scale studies have investigated the status and clinical significance of BRAF and NRAS mutations in a Taiwanese population. Methods: Melanoma samples (n = 119) were analyzed for mutations in exons 11 and 15 of the BRAF gene, and in exons 1 and 2 of the NRAS gene. The samples were studied in genomic DNA, using polymerase chain reaction amplification and Sanger sequencing. Mutations of the BRAF and NRAS genes were then correlated with clinicopathological features and patients' prognosis. Results: The incidence of somatic mutations within the BRAF and NRAS genes was 14.3% (17/119 patients) and 10.1% (12/119 patients), respectively. Among the 17 patients with BRAF mutations, 15 (88.2%) had V600E mutations. BRAF mutation was frequently detected in younger patients (p = 0.0035), in thin melanomas (p = 0.0181), and in melanomas with less ulceration (p = 0.0089). NRAS mutation was more often seen in patients with lymph node metastasis (p = 0.0332). Both BRAF and NRAS mutations were not significantly correlated with overall survival and disease-free survival. Conclusion: As BRAF and NRAS mutations are rare in Taiwan, BRAF- or NRAS-targeted therapies may be effective only for selected Taiwanese melanoma patients

A Promising Approach to Treat Psoriasis: Inhibiting Cytochrome P450 3A4 Metabolism to Enhance Desoximetasone Therapy

(1) Background: Human keratinocytes and murine skin express various cytochrome P450 enzymes. These include cytochrome P450 3A4, which may participate in the metabolism of cytochrome P450 3A4 substrate drugs. Desoximetasone, a topical corticosteroid and cytochrome P450 3A4 substrate, is used to treat skin conditions such as skin allergies, atopic dermatitis, and psoriasis. In this study, we aimed to investigate the anti-psoriatic effect of a low dose of desoximetasone by inhibiting cytochrome P450 3A4 metabolism in the epidermis. (2) Methods: Psoriasis-like skin was induced in BALB/c mice via the topical administration of imiquimod. The mice were then topically treated with 0.01–0.05% desoximetasone loaded into a cytochrome P450 3A4 enzyme inhibitor excipient base emollient microemulsion, 0.25% commercial desoximetasone ointment, or 0.5 mg/gm clobetasol ointment. (3) Results: The topical application of 0.05% desoximetasone loaded into a cytochrome P450 3A4 enzyme inhibitor excipient base emollient formulation restored the imiquimod-induced skin barrier disruption and resulted in fewer severe clinical and pathological features compared with the treatments with 0.25% commercial desoximetasone ointment and 0.5 mg/gm clobetasol ointment. (4) Conclusions: The cytochrome P450 3A4 enzyme inhibitor excipient base emollient formulation improved and prolonged the therapeutic effect of cytochrome P450 3A4 substrate drugs and may be a promising approach for psoriasis treatment

Salvianolic Acid B in Microemulsion Formulation Provided Sufficient Hydration for Dry Skin and Ameliorated the Severity of Imiquimod-induced Psoriasis-like Dermatitis in Mice

Psoriasis is a chronic inflammatory skin disorder with a pathogenesis involving the interleukin-23/interleukin-17 axis. Salvianolic acid B exerts several pharmacological effects, such as antioxidation, anti-inflammation, and antitumor effects. The anti-psoriatic effects of salvianolic acid B have not been reported. In this study, we aimed to determine the optimum vehicle for salvianolic acid B, investigate its therapeutic effect on psoriatic-like skin conditions, and explore its underlying mechanisms of action. BALB/c mice were administered topical imiquimod to induce psoriasis-like skin and were then randomly assigned to control, vehicle control, salvianolic acid B in vehicles, and 0.25% desoximetasone ointment treatment groups. Barrier function, cytokine expression, histology assessment, and disease severity were evaluated. The results showed that salvianolic acid B-containing microemulsion alleviated disease severity, reduced acanthosis, and inhibited interleukin-23/interleukin-17 (IL-23/IL-17) cytokines, epidermal proliferation, and increased skin hydration. Our study suggests that salvianolic acid B represents a possible new therapeutic drug for the treatment of psoriasis. In addition, such formulation could obtain high therapeutic efficacy in addition to providing sufficient hydration for dry skin

Insulin-Like Growth Factor II mRNA-Binding Protein 3 Expression Correlates with Poor Prognosis in Acral Lentiginous Melanoma

<div><p>Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3) is an RNA-binding protein expressed in multiple cancers, including melanomas. However, the expression of IMP-3 has not been investigated in acral lentiginous melanoma (ALM). This study sought to elucidate its prognostic value in ALMs. IMP-3 expression was studied in 93 patients diagnosed with ALM via immunohistochemistry. Univariate and multivariate analyses for survival were performed, according to clinical and histologic parameters, using the Cox proportional hazard model. Survival curves were graphed using the Kaplan-Meier method. IMP-3 was over-expressed in 70 out of 93 tumors (75.3%). IMP-3 expression correlated with thick and high-stage tumor and predicted poorer overall, melanoma-specific, recurrence-free and distant metastasis-free survivals (<i>P</i> = 0.002, 0.006, 0.008 and 0.012, respectively). Further analysis showed that patients with tumor thickness ≤ 4.0 mm and positive IMP-3 expression had a significantly worse melanoma-specific survival than those without IMP-3 expression (<i>P</i> = 0.048). IMP-3 (hazard ratio 3.67, 95% confidence intervals 1.35–9.97, <i>P</i> = 0.011) was confirmed to be an independent prognostic factor for melanoma-specific survival in multivariate survival analysis. Positive IMP-3 expression was an important prognostic factor for ALMs.</p></div

Plasma leptin concentrations are greater in type II diabetic patients and stimulate monocyte chemotactic peptide-1 synthesis via the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway

Background: Leptin is an adipokine that is recently reported to be a biomarker of systemic inflammation. Although atherosclerosis causes cardiovascular diseases, it is not clear whether leptin contributes to the acceleration of this process. In this study, we investigated whether alterations of plasma leptin levels were related to diabetic nephropathy and systemic inflammation. In addition, we examined the physiologic action of leptin in cultured vascular smooth muscle cells (VSMCs). Methods: A total of 126 type 2 diabetic participants and 37 healthy controls were studied. The diabetic participants were divided into three groups according to stage of nephropathy. We investigated whether leptin induced monocyte chemotactic peptide-1 (MCP-1) synthesis through the mitogen-activated protein kinase (MAPK) pathway using cultured VSMCs. Results: Plasma leptin concentrations were significantly higher in the diabetic group than in the controls. Plasma leptin levels were positively correlated with body mass index, fasting and postprandial blood glucose, hemoglobin A1c, total cholesterol, urinary albumin excretion, high-sensitivity C-reactive protein (hsCRP), and MCP-1 plasma levels, and negatively correlated with creatinine clearance values. In cultured VSMCs, leptin increased MCP-1 production in a dose-dependent manner, and this stimulating effect of leptin on MCP-1 expression was reversed by the MAPK (MEK) inhibitor PD98059. In addition, leptin stimulated the phosphorylation of MEK, extracellular signal–regulated kinase, and E26-like transcription factor, which are components of the MAPK pathway. Conclusions: Overall, these findings suggest that activation of leptin synthesis may promote MCP-1 activation in a diabetic environment via the MAPK pathway in VSMCs and that it possibly contributes to the acceleration of atherosclerosis