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.     

High frequency of altered HLA class I phenotypes in invasive breast carcinomas

We studied 105 tumor samples obtained from patients diagnosed as having breast carcinomas for HLA class I and II (DR) antigen expression, using a panel of mAbs defining HLA-monomorphic, locus-specific and allele-specific determinants. Peripheral blood lymphocytes from patients were also typed for HLA alleles. The results indicated total HLA class I losses in 55 patients (52.3%), HLA-A locus losses in four patients (3.8%), HLA-B locus losses in eight patients (7.6%), and A, B, locus losses in 10 patients (9.5%). The remaining 28 patients whose tissues reacted positively with monomorphic- and locus-specific mAbs were tested for HLA allelic losses using several anti-HLA mAbs defining A2, A3, A9, B8, B12, etc. Of these 28 patients, 16 (57%) showed one or more losses of HLA reactivity. These results indicated that in 88.5% of patients we detected a particular HLA-altered tumor phenotype. The downregulation of HLA class I antigens in breast carcinomas may thus be more frequent than previously reported, and patients without HLA class I downregulation may be the exception rather than the rule. It cannot be ruled out that HLA alterations are present in some of the 12 patients with an apparently normal HLA phenotype, as some HLA alleles could not be studied because of the lack of appropriate mAbs. These HLA alterations could represent an important step associated with tumor invasion, conferring to the tumor cells the ability to escape from T-lymphocyte recognition.     

Premenstrual symptomatology: role of prior knowledge about premenstrual syndrome

OBJECTIVE: Most women have some premenstrual symptoms that may be influenced by diverse environmental factors. The aim of this study was to determine the influence of knowledge about premenstrual syndrome (PMS) in the reports of women and their symptoms. METHOD: We studied 86 healthy Mexican women whose highest level of education was sixth grade. Participants were assigned to one of two groups. The experimental group watched a videotape describing PMS and its negative consequences in daily life. The control group watched a videotape describing the menstrual cycle. The Menstrual Distress Questionnaire was administered to all women during the first week after menstruation, after which they were shown their designated videotape, and the questionnaire was administered again after the next menstruation. RESULTS: In the control group, there were no significant differences in premenstrual symptoms reported both before and after the women watched the videotape. However, women in the experimental group reported more severe premenstrual symptoms after watching the videotape. CONCLUSIONS: These results suggest that after observing the videotape, women's expectancies of negative symptoms in the premenstrual phase increased. Thus, the symptoms reported by these women were enhanced.     

Preferences for Conditional Economic Incentives to Improve Pre-exposure Prophylaxis Adherence: A Discrete Choice Experiment Among Male Sex Workers in Mexico

AIDS and Behavior - Pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV but requires sustained adherence. Conditional economic incentives (CEIs) can improve medication-taking...     

Self-perceived stress and the risk of peptic ulcer disease. A longitudinal study of US adults.

BACKGROUND--Although many physicians and laypersons believe that stress plays a role in the occurrence of peptic ulcer disease, the importance of stress in the pathogenesis of peptic ulcers remains controversial. METHODS--To investigate the relationship between perceived stress and peptic ulcer disease we used data from the National Health and Nutrition Examination Survey Epidemiologic Follow-up Study--a nationally representative cohort study of US adults. This analysis included 4511 persons who had not previously been diagnosed with peptic ulcer disease. RESULTS--At baseline, 68% of the cohort perceived themselves as stressed. During 13 years of follow-up, 208 persons developed ulcers; the cumulative incidence of ulcers was 7.2% for persons who were stressed and 4.0% for persons who were not. After we adjusted for age, sex, education, smoking status, and regular aspirin use, persons who perceived themselves as stressed were 1.8 times more likely to develop ulcers than those who did not (95% confidence interval, 1.3 to 2.5). We also found a graded relationship between the perceived amount of stress and the incidence of peptic ulcers; relative to nonstressed persons, the relative risk of developing an ulcer was 1.4, 1.9, 2.3, 2.4, and 2.9 at five increasing levels of stress. CONCLUSIONS--These findings suggest that persons who perceive their lives as stressful may be at increased risk for the development of peptic ulcer disease.     

A randomized trial comparing omeprazole, ranitidine, cisapride, or placebo in helicobacter pylori negative, primary care patients with dyspepsia: the CADET-HN Study

BACKGROUND: The management of Helicobacter pylori negative patients with dyspepsia in primary care has not been studied in placebo-controlled studies. METHODS: H. pylori negative patients with dyspepsia symptoms of at least moderate severity (> or =4 on a seven-point Likert scale) were recruited from 35 centers. Patients were randomized to a 4-wk treatment of omeprazole 20 mg od, ranitidine 150 mg bid, cisapride 20 mg bid, or placebo, followed by on-demand therapy for an additional 5 months. Treatment success was defined as no or minimal symptoms (score < or = 2 out of 7), and was assessed after 4 wk and at 6 months. RESULTS: Five hundred and twelve patients were randomized and included in the intention-to-treat (ITT) analysis. At 4 wk, success rates (95% CI) were: omeprazole 51% (69/135; 43-60%), ranitidine 36% (50/139, 28-44%), cisapride 31% (32/105, 22-39%), and placebo 23% (31/133, 16-31%). Omeprazole was significantly better than all other treatments (p < 0.05). The proportion of patients who were responders at 4 wk and at 6 months was significantly greater for those receiving omeprazole 31% (42/135, 23-39%) compared with cisapride 13% (14/105, 7-20%), and placebo 14% (18/133, 8-20%) (p= 0.001), but not ranitidine 21% (29/139, 14-27%) (p= 0.053). The mean number of on-demand study tablets consumed and rescue antacid used was comparable across groups. Economic analysis showed a trade-off between superior efficacy and increased cost between omeprazole and ranitidine. CONCLUSION: Treatment with omeprazole provides superior symptom relief compared to ranitidine, cisapride, and placebo in the treatment of H. pylori negative primary care dyspepsia patients.     

Inhibition of melanoma cell motility by the snake venom disintegrin eristostatin.

Eristostatin, an RGD-containing disintegrin isolated from the venom of Eristicophis macmahoni, inhibits lung or liver colonization of melanoma cells in a mouse model. In this study, transwell migration and in vitro wound closure assays were used to determine the effect of eristostatin on the migration of melanoma cells. Eristostatin significantly impaired the migration of five human melanoma cell lines. Furthermore, it specifically inhibited cell migration on fibronectin in a concentration-dependent manner, but not that on collagen IV or laminin. In contrast, eristostatin was found to have no effect on cell proliferation or angiogenesis. These results indicate that the interaction between eristostatin and melanoma cells may involve fibronectin-binding integrins that mediate cell migration. Mutations to alanine of seven residues within the RGD loop of eristostatin and four residues outside the RGD loop of eristostatin resulted in significantly less potency in both platelet aggregation and wound closure assays. For six of the mutations, however, decreased activity was found only in the latter assay. We conclude that a different mechanism and/or integrin is involved in these two cell activities.     

Detection of vulnerable plaque in a murine model of atherosclerosis with optical coherence tomography.

OBJECTIVES: The aim of this study was to evaluate the feasibility of optical coherence tomography (OCT) to identify the components of vulnerable plaques in a well-established murine model of human atherosclerosis. BACKGROUND: Although the pathologic features that predict plaque rupture at autopsy are well known, the development of a technology to identify these high risk features in vivo is lacking. OCT uses reflected light to provide histology-like images of plaque with higher resolution than competing imaging modalities. Whether OCT can reliably identify the features of an atherosclerotic plaque that define it as vulnerable-thin fibrous cap, large lipid core, and high percent of lipid in the artery-requires further study. METHODS: OCT images of the atherosclerotic innominate artery segments from the apolipoprotein E knockout (apoE(-/-)) mice were recorded and correlated with histology in both in vivo (n = 7) and well as in ex vivo experiments (n = 12). RESULTS: Excellent correlation between the OCT and histology measurements for fibrous cap thickness, lipid core size, and percentage lipid content was found. The fibrous cap thicknesses examined span those of human fibrous caps known to rupture (< 65 microm). Regions of greatest light reflection in OCT images were observed when calcium hydroxy-apatite was scattered in lipid, less in fibrous tissue, and least in lipid. CONCLUSIONS: These findings suggest that OCT holds promise for the identification of features defining vulnerable plaque including fibrous cap thickness, lipid core size, and the percentage of lipid content.