Melatonin promotes sorafenib‐induced apoptosis through synergistic activation of JNK/c‐jun pathway in human hepatocellular carcinoma

Melatonin has been shown to exert anticancer activity on hepatocellular carcinoma (HCC) through its antiproliferative and pro‐apoptotic effect in both experimental and clinical studies, and sorafenib is the only approved drug for the systemic treatment of HCC. Thus, this study was designed to investigate the combined effect of melatonin and sorafenib on proliferation, apoptosis, and its possible mechanism in human HCC. Here, we found that both melatonin and sorafenib resulted in a dose‐dependent growth inhibition of HuH‐7 cells after 48 hours treatment, and the combination of them enhanced the growth inhibition in a synergistic manner. Colony formation assay indicated that co‐treatment of HuH‐7 cells with melatonin and sorafenib significantly decreased the clonogenicity compared to the treatment with single agent. Furthermore, FACS and TUNEL assay confirmed that melatonin synergistically augmented the sorafenib‐induced apoptosis after 48 hours incubation, which was in accordance with the activation of caspase‐3 and the JNK/c‐jun pathway. Inhibition of JNK/c‐jun pathway with its inhibitor SP600125 reversed the phosphorylation of c‐jun and the activation of caspase‐3 induced by co‐treatment of HuH‐7 cells with melatonin and sorafenib in a dose‐dependent manner. Furthermore, SP600125 exhibited protective effect against apoptosis induced by the combination of melatonin and sorafenib. This study demonstrates that melatonin in combination with sorafenib synergistically inhibits proliferation and induces apoptosis in human HCC cells; therefore, supplementation of sorafenib with melatonin may serve as a potential therapeutic choice for advanced HCC.     

Correlates of psychological distress in study partners of older people with and without mild cognitive impairment (MCI) – the Sydney Memory and Ageing Study

Objectives: Psychological effects of supporting someone with mild cognitive impairment (MCI) are often overlooked. We aimed to establish correlates of psychological distress in study partners of individuals with and without nonclinical MCI.Methods: Demographic, psychosocial and health measures were obtained cross-sectionally from 714 participants (39% MCI) and study partners of a longitudinal community-based study on cognitive aging. Study partners (i.e. family members/friends) were categorized as providing support with instrumental everyday activities or not. Psychological distress was measured by the Kessler psychological distress scale. Multiple hierarchical regressions examined determinants of psychological distress within Pearlin's stress process model.Results: Psychological distress was generally low and not associated with MCI or whether study partners provided support or not. Instead, distress was greater if participants were male irrespective of study partners’ sex and if study partners reported negative reactions to participants’ behavioral symptoms, felt burdened by providing support and showed worse coping abilities; overall explaining 37% variance. Self-rated disability and aspects of health-related quality of life explained additional 7%.Conclusion: Objective impairment measures were not associated with distress in partners or supporters. However, study partners’ appraisals of functional and behavioral symptoms were linked to increased distress even in this very mildly affected community cohort.     

Malassezia yeasts activate the NLRP3 inflammasome in antigen‐presenting cells via Syk‐kinase signalling

Although being a normal part of the skin flora, yeasts of the genus Malassezia are associated with several common dermatologic conditions including pityriasis versicolour, seborrhoeic dermatitis (SD), folliculitis, atopic eczema/dermatitis (AE/AD) and dandruff. While Malassezia spp. are aetiological agents of pityriasis versicolour, a causal role of Malassezia spp. in AE/AD and SD remains to be established. Previous reports have shown that fungi such as Candida albicans and Aspergillus fumigatus are able to efficiently activate the NLRP3 inflammasome leading to robust secretion of the pro‐inflammatory cytokine IL‐1β. To date, innate immune responses to Malassezia spp. are not well characterized. Here, we show that different Malassezia species could induce NLRP3 inflammasome activation and subsequent IL‐1β secretion in human antigen‐presenting cells. In contrast, keratinocytes were not able to secrete IL‐1β when exposed to Malassezia spp. Moreover, we demonstrate that IL‐1β secretion in antigen‐presenting cells was dependent on Syk‐kinase signalling. Our results identify Malassezia spp. as potential strong inducers of pro‐inflammatory responses when taken up by antigen‐presenting cells and identify C‐type lectin receptors and the NLRP3 inflammasome as crucial actors in this process.     

Disseminated ulcerating lupus panniculitis emerging under interferon therapy of hairy cell leukemia: Treatment‐ or disease‐related?

We report a 43‐year‐old woman, who underwent therapy with interferon‐α for hairy cell leukemia. During interferon‐α therapy she developed multiple subcutaneous swellings, accompanied by fever and fatigue. A skin biopsy revealed lobular, T‐cell lymphocytic panniculitis. In conjunction with the clinical and immunological findings, the diagnosis of lupus panniculitis was made and interferon‐α therapy stopped. Initially, she responded well to oral prednisone and hydroxychloroquine, but after several months she became resistant to it. Her condition worsened, she developed skin ulcers in the inflamed regions. Only with the leukemia‐targeted therapy using cladribine and rituximab her skin condition could be controlled, suggesting hairy cell leukemia as an additional trigger of the lupus panniculitis. Our report is the first one to show induction of lupus panniculitis under interferon therapy of hairy cell leukemia and its presumable sustentation by the latter.     

Preoperative localization of hyperfunctioning parathyroid glands with 4D-CT

Primary hyperparathyroidism (pHPT) is almost exclusively the result of a solitary parathyroid adenoma. In most cases, the affected gland can be surgically removed, but precise preoperative imaging is essential for adenoma localization prior to surgical intervention. In this study, we evaluated the diagnostic value of four-dimensional computed tomography (4D-CT) as a preoperative imaging tool in relation to the localization of pathologic parathyroid glands in patients with pHPT and negative sestamibi scans. This study included 43 consecutive patients with pHPT referred for parathyroidectomy at the Department of Head and Neck Surgery of Copenhagen University Hospital Rigshospitalet in 2011 and 2012. All patients had a 4D-CT performed prior to parathyroidectomy. CT localization of the suspected adenoma was correlated to the actual surgical findings and subsequent histological diagnosis was also available as references for the accuracy of this imaging tool. Hyperfunctioning parathyroid glands were found in 40 patients. 4D-CT identified 32 solitary hyperfunctioning parathyroid glands located on the correct side of the neck (PPV 76 %) and 21 located within the correct quadrant (PPV 49 %). Unilateral resection was performed in 72 % of patients due to the localization findings of preoperative imaging. 4D-CT can, therefore, be considered an effective method for the preoperative localization of parathyroid adenomas and is an important tool in surgical intervention for patients referred to parathyroidectomy.     

The impact of langerin (CD207)+ dendritic cells and FOXP3+ Treg cells in the small bowel mucosa of children with celiac disease and atopic dermatitis in comparison to children with functional gastrointestinal disorders

In the present study we aimed to evaluate the impact of langerin (CD207)+ dendritic cells (DCs) and FOXP3+ Treg cells in the intestinal mucosa of children with celiac disease (CD) and atopic dermatitis (AD) in comparison to children with functional gastrointestinal disorders (FGD). Seventy‐five children (37 male, mean age 8.4 ± 4.8 years), who randomly underwent small bowel biopsy, were studied. The CD was diagnosed in 14 children, including five persons with concomitant AD (all positive for anti‐tissue transglutaminase IgA antibodies and with small bowel atrophy). Normal small bowel mucosa was found in eight patients with AD and in 53 patients with FGD. The sera of all patients were tested for total and specific IgE antibodies to food allergen panels. Staining for CD11c+, langerin (CD207+) DCs, CD4+, and FOXP3+ Treg cells was performed on paraffin‐embedded sections of bioptates using immunohistochemistry. The density of CD11c+ DCs, CD4+, and FOXP3+ Treg cells was higher in the CD patients compared to the AD and FGD patients (p = 0.02; p = 0.001). In AD, significantly higher density of CD11c+ DCs was detected in patients positive for specific IgE to food allergen panels (p = 0.02). The FGD patients with elevated total IgE had increased density of langerin (CD207)+ DCs compared to the patients with normal total IgE levels (p = 0.01). The increased density of FOXP3+ Treg cells, CD4+, cells and CD11c+ DCs was associated with CD but not with AD. The elevated level of total IgE or specific IgE to food allergens was associated with more pronounced expression of DCs, indicating a possible link between the presence of these cells in small bowel mucosa with elevated level of serum IgE.