Damage-associated molecular pattern (DAMP) activation in melanoma: investigation of the immunogenic activity of 15-deoxy, Δ12,14 prostamide J2

Metastatic melanoma is the most deadly skin neoplasm in the United States. Outcomes for this lethal disease have improved dramatically due to the use of both targeted and immunostimulatory drugs. Immunogenic cell death (ICD) has emerged as another approach for initiating antitumor immunity. ICD is triggered by tumor cells that display damage-associated molecular patterns (DAMPs). These DAMP molecules recruit and activate dendritic cells (DCs) that present tumor-specific antigens to T cells which eliminate neoplastic cells. Interestingly, the expression of DAMP molecules occurs in an endoplasmic reticulum (ER) stress-dependent manner. We have previously shown that ER stress was required for the cytotoxic activity of the endocannabinoid metabolite, 15-deoxy, Δ^12,14 prostamide J₂ (15dPMJ₂). As such, the current study investigates whether 15dPMJ₂ induces DAMP signaling in melanoma. In B16F10 cells, 15dPMJ₂ caused a significant increase in the cell surface expression of calreticulin (CRT), the release of ATP and the secretion of high-mobility group box 1 (HMGB1), three molecules that serve as surrogate markers of ICD. 15dPMJ₂ also stimulated the cell surface expression of the DAMP molecules, heat shock protein 70 (Hsp70) and Hsp90. In addition, the display of CRT and ATP was increased by 15dPMJ₂ to a greater extent in tumorigenic compared to non-tumorigenic melanocytes. Consistent with this finding, the activation of bone marrow-derived DCs was upregulated in co-cultures with 15dPMJ₂-treated tumor compared to non-tumor melanocytes. Moreover, 15dPMJ₂-mediated DAMP exposure and DC activation required the electrophilic cyclopentenone double bond within the structure of 15dPMJ₂ and the ER stress pathway. These results demonstrate that 15dPMJ₂ is a tumor-selective inducer of DAMP signaling in melanoma.     

Sensitive skin: correlation with skin surface microrelief appearance

BACKGROUND/PURPOSE: Sensitive skin is a condition associated with reduced tolerance to environmental factors and/or the application of topical products, such as cosmetics. Its pathophysiology has not been fully elucidated and few data are available on its prevalence. The aim of this study was to investigate possible correlation between objective sensitivity and skin surface microrelief. METHODS: During an epidemiological survey conducted for a campaign promoted by International Society of Plastic Dermatology in Italy, 243 adult healthy subjects of both sexes with no evident dermatological disorder but positive to the lactic acid stinging test, were submitted to cyanoacrylate stratum corneum stripping from the volar forearm for the determination of the irregularity of the skin surface microrelief (irregularity skin index (ISI)). RESULTS: A significant correlation was found between intensity of symptoms in stingers and ISI (r(s)=-0.47; P<0.001). CONCLUSION: Sensitive skin is common in the healthy population. ISI can contribute towards the identification of subjects with sensitive skin and the development of more specific skin treatments for this prevalent condition.     

Chronic-alcohol exposure alters IGF1 signaling in H9c2 cells via changes in PKC delta.

Previously, we have demonstrated that chronic-alcohol exposure alters insulin-like growth factor 1 (IGF1) signaling in adult rat heart cells. This report examines the effects of alcohol in vitro on the expression of protein kinase C (PKC) alpha, delta, and epsilon using the embryonic heart cell line, H9c2, and how this may be linked to changes in IGF1 signal transduction. Western blot analyses of H9c2 protein preparations demonstrate that there are significant increases in the total protein levels of PKC delta and epsilon after 4 days exposure to alcohol, and similar increases were found after 2 and 6 days exposure. In addition, there was a significant increase in PKC delta and epsilon in the membranal fractions and a decrease in the cytosolic fractions. No change was found in the expression or activity levels for PKC alpha. Chronic-alcohol exposure (100 mM, 4 days) increased the basal tyrosine kinase activity of the IGF1 receptor (IGF1R), and altered its rate of activation. Chronic-alcohol exposure also reduced the rate of Erk1/Erk2 activation by IGF1. Chronic alcohol blocked the proliferative effects of IGF1 on cell growth and reduced cell viability both in the presence and absence of IGF1, and this alcohol-induced reduction in cell viability was blocked using siRNA to inhibit PKC delta. In addition, a reduction in the amount of myosin light chain 2 was found in the alcohol-exposed cells. In conclusion, chronic alcohol alters PKC delta and epsilon expression and activity, and suppresses the IGF1 signaling pathway in embryonic heart cell culture. Blockage of PKC delta expression using siRNA inhibits the suppressive effects of alcohol on cell viability.     

The multiform and variable patterns of onset of orofacial granulomatosis

BACKGROUND: The recurrent chronic orofacial swelling caused by orofacial granulomatosis (OFG) can cause significant cosmetic and functional problems but can be prevented if the disease is diagnosed early and promptly treated. Although the enlargement of the lips is described to be the most common presenting complaint, the clinical onset of OFG may be characterized by minor associated mucosal and neurological manifestations, making early diagnosis very difficult or, sometimes, merely presumable. PATIENTS AND METHODS: We retrospectively analyzed the clinical manifestations of 19 patients with OFG, who were examined at our institution between 1998 and 2002, in order to determine their initial manifestations and presenting symptoms. RESULTS: A total of 10 patients showed classical recurrent enlargement of the lips (six lower; four upper) as presenting symptom. In the other nine patients, OFG onset was characterized by transient unilateral facial nerve palsy (two cases), intraoral manifestations (two cases), recurrent swelling of the periorbital area (two cases), of the chin (one case), of the zygomatic area (one case), and of the cheeks (one case). CONCLUSION: Our data underlined that OFG onset could be frequently characterized by widely variable, multiform, and temporary clinical findings. Involvement of atypical sites of the orofacial region and presence of single minor manifestations may occur as presenting symptoms, often preceding the development of traditional clinical findings.     

The Well-being Model: A New Drug Interaction Model for Positive and Negative Effects

Background: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account.

Methods: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs.

Results: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed.     

Complete maternal uniparental isodisomy of chromosome 4 in a subject with major depressive disorder detected by high density SNP genotyping arrays.

Uniparental isodisomy (iUPD) is a rare genetic condition caused by non-disjunction during meiosis that ultimately leads to a duplication of either the maternal or paternal chromosome in the affected individual. Two types of disorders can result, those due to imprinted genes and those due to homozygosity of recessive disease-causing mutations. Here, we describe the third known case of complete chromosome 4 iUPD of maternal origin. This condition became apparent during whole genome linkage studies of psychiatric disorders in the Portuguese population. The proband is an adult female with normal fertility and no major medical complaints, but a history of major depressive disorder and multiple suicide attempts. The proband's siblings and parents had normal chromosome 4 genotypes and no history of mood disturbance. A brief review of other studies lends support for the possibility that genes on chromosome 4 might confer risk for mood disorders. We conclude that chromosome 4 maternal uniparental disomy (UPD) is a rare disorder that may present with a major depressive phenotype. The lack of a common disease phenotype between this and two other cases of chromosome 4 iUPD [Lindenbaum et al. [1991] Am J Med Genet 49(Suppl 285):1582; Spena et al. [2004] Eur J Hum Genet 12:891-898) would suggest that there is no vital maternal gene imprinting on chromosome 4. However, since there is no reported case of paternal chromosome 4 UPD, paternal gene imprinting on chromosome 4 cannot be excluded.