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.     

Metformina también como primera elección en pacientes con peso normal. ¿Se ha incrementado su uso?

ObjectiveTo assess whether the release of the new consensus algorithms in August 2006, along with the consensus recommendation of also using metformin as first choice in patients with normal weight, has led to an increase in the use of this drug in the period immediately after.DesignRetrospective longitudinal Study.SitesSantiago de Compostela Health District (A Coruña).ParticipantsUsers of the Galician health service in the Santiago de Compostela Health District.MethodsThe evolution of the monthly number of DHD (Daily Defined Doses/1000 inhabitants/day) of metformin from early 2003 until 12 months after the issuing of new algorithms was analysed graphically and using a multiple regression model.ResultsThe graphical representation of the DHD of metformin over time shows a linear growth for the period, but there is an increasing trend after the publication of the new consensus algorithm. The multiple regression showed that the increase is statistically significant.ConclusionsFollowing the publication of the new consensus algorithm an increasing trend in the use of metformin is observed in the short term.     

Cytokeratin expression in initial oral mucositis of head and neck irradiated patients.

OBJECTIVE: The aim of this work was to study cytokeratin (Ck) expression in initial radiation-induced oral mucositis. STUDY DESIGN: Eleven cases of initial radiomucositis of the buccal mucosa and 9 normal specimens were immunostained for Ck 1, 5, 6, 7, 8, 10, 14, 16, 18, and 19 by immunoperoxidase method. RESULTS: Expression of Ck 1, 6, 10, and 16 was stronger in mucositis than in normal mucosa. Ck 7, 8, and 18 were negative for both control and study groups. Ck 5, 13, and 14 were positive for both groups, nevertheless suprabasal staining for Ck 14 was more evident in mucositis than in the control group. Sporadic staining for Ck 19 was observed in 1 case of mucositis and in 2 controls. CONCLUSIONS: Increased Ck expression can be associated with the reactive proliferation of the epithelium and increasing resistance of the oral mucosa during the initial phases of radiotherapy.     

Daughters caregiving for hispanic and non-hispanic alzheimer patients: Does ethnicity make a difference?

This study assessed Cuban-American Hispanic and White non-Hispanic daughters who were major caregivers for their mothers suffering from Alzheimer's Disease. Although patients in both ethnic groups did not differ in their level of cognitive and functional impairment, Cuban-American Hispanic patients were significantly more likely to be living in their daughters' homes while the White non-Hispanic patients resided in institutional settings. Caregivers were equivalent in their knowledge and utilization of community services, but Cuban-American daughters were significantly more aware of financial aid resources. Cuban-American patients were significantly more depressed than their White non-Hispanic counterparts with daughters showing similar but nonsignificant trends. The impact of cultural factors on caregiving is discussed.     

Breast-feeding and mental and motor development at 51/2 years.

OBJECTIVE: Breast-feeding is associated with better child development outcomes, but uncertainty remains primarily due to the close relationship between breast-feeding and socioeconomic status. This study assesses the issue in a low socioeconomic status sample where breast-feeding was close to universal. METHODS: Seven hundred eighty-four Chilean children were followed longitudinally from infancy. All but four were initially breastfed, 40% nursed beyond 12 months, and infant growth was normal. Child development was assessed at 5(1/2) years by a cognitive, language, and motor test battery. The duration of breast-feeding as the sole milk source was analyzed as a continuous variable, adjusting for a comprehensive set of background factors. RESULTS: The relationship between breast-feeding and most 5(1/2)-year developmental outcomes was nonlinear, with poorer outcome for periods of breast-feeding as the sole milk source for <2 months or >8 months--statistically significant for language, motor, and one comprehensive cognitive test, with a suggestive trend for IQ. CONCLUSIONS: The observed nonlinear relationships showed that breast-feeding as the sole milk source for <2 months or >8 months, compared with 2-8 months, was associated with poorer development in this sample. The latter finding requires replication in other samples where long breast-feeding is common and socioeconomic status is relatively homogeneous.     

Results of a randomized study of early stage Hodgkin's disease using ABVD,EBVD, or MBVD

From January 1986 to December 1989, 157 previously untreated patients, with Hodgkin's disease stage I or II without bulky disease, were enrolled in a clinical comparative study. The objectives of the study were to compare the efficacy and safety of using epirubicine or mitoxantrone instead of adriamycin in the combination chemotherapy regimen ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine). The complete response rate was better in the patients treated with the ABVD or EBVD regimens compared to the MBVD arm. Also, differences in overall survival and relapse-free survival were better in the patients who received ABVD or EBVD compared to the MBVD regimen. Hematological, gastrointestinal and cardiac toxicity were similar in the three groups. Dose intensity, delays and complications were also similar in the three groups. The mitoxantrone-containing regimen was found to have less efficacy in comparison to the other regimens tested in the present study in patients with favorable stage I or II Hodgkin's disease. © 1995 Wi1ey-Liss Inc.     

Experimental infection of immunomodulated NOD/LtSz-SCID mice as a new model for Plasmodium falciparum erythrocytic stages

The main objective of this study was to determine whether a chemical immunomodulation protocol could reduce the resistance of NOD/LtSz-SCID mice to Plasmodium falciparum infection and provide an improved mouse model for screening the antimalarial activity of new compounds. This model was compared with the presently used immunodeficient Beige/Nude/Xid (BNX) mouse model, using the same protocol, in terms of percentage of infected mice, parasite development, leukocyte response and phagocytosis of P. falciparum infected cells in various organs. Our results show that the combination of the chemical immune modulation protocol with the genetic background of NOD/LtSz-SCID mice results in the development of long-lasting P. falciparum infection in a high percentage of mice. A comparison of the results obtained in the histological study for both mouse models suggests that the higher rate of success in NOD/LtSz-SCID mice could be related to the reduced macrophage recruitment developed in different tissues to remove the parasite from blood.