Increased Bone Marrow Uptake and Accumulation of Very-Late Antigen-4 Targeted Lipid Nanoparticles.

Lipid nanoparticles (LNPs) have evolved rapidly as promising delivery systems for oligonucleotides, including siRNAs. However, current clinical LNP formulations show high liver accumulation after systemic administration, which is unfavorable for the treatment of extrahepatic diseases, such as hematological disorders. Here we describe the specific targeting of LNPs to hematopoietic progenitor cells in the bone marrow. Functionalization of the LNPs with a modified Leu-Asp-Val tripeptide, a specific ligand for the very-late antigen 4 resulted in an improved uptake and functional siRNA delivery in patient-derived leukemia cells when compared to their non-targeted counterparts. Moreover, surface-modified LNPs displayed significantly improved bone-marrow accumulation and retention. These were associated with increased LNP uptake by immature hematopoietic progenitor cells, also suggesting similarly improved uptake by leukemic stem cells. In summary, we describe an LNP formulation that successfully targets the bone marrow including leukemic stem cells. Our results thereby support the further development of LNPs for targeted therapeutic interventions for leukemia and other hematological disorders.

Osteopontin binds ICOSL promoting tumor metastasis.

ICOSL/ICOS are costimulatory molecules pertaining to immune checkpoints; their binding transduces signals having anti-tumor activity. Osteopontin (OPN) is here identified as a ligand for ICOSL. OPN binds a different domain from that used by ICOS, and the binding induces a conformational change in OPN, exposing domains that are relevant for its functions. Here we show that in vitro, ICOSL triggering by OPN induces cell migration, while inhibiting anchorage-independent cell growth. The mouse 4T1 breast cancer model confirms these data. In vivo, OPN-triggering of ICOSL increases angiogenesis and tumor metastatization. The findings shed new light on ICOSL function and indicate that another partner beside ICOS may be involved; they also provide a rationale for developing alternative therapeutic approaches targeting this molecular trio.

Role of Anti-Osteopontin Antibodies in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.

Osteopontin (OPN) is highly expressed in demyelinating lesions in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). OPN is cleaved by thrombin into N- (OPN-N) and C-terminal (OPN-C) fragments with different ligands and functions. In EAE, administering recombinant OPN induces relapses, whereas treatment with anti-OPN antibodies ameliorates the disease. Anti-OPN autoantibodies (autoAbs) are spontaneously produced during EAE but have never been detected in MS. The aim of the study was to evaluate anti-OPN autoAbs in the serum of MS patients, correlate them with disease course, and recapitulate the human findings in EAE. We performed ELISA in the serum of 122 patients collected cross-sectionally, and 50 patients with relapsing-remitting (RR) disease collected at diagnosis and followed longitudinally for 10 years. In the cross-sectional patients, the autoAb levels were higher in the RR patients than in the primary- and secondary-progressive MS and healthy control groups, and they were highest in the initial stages of the disease. In the longitudinal group, the levels at diagnosis directly correlated with the number of relapses during the following 10 years. Moreover, in patients with active disease, who underwent disease-modifying treatments, autoAbs were higher than in untreated patients and were associated with low MS severity score. The autoAb displayed neutralizing activity and mainly recognized OPN-C rather than OPN-N. To confirm the clinical effect of these autoAbs in vivo, EAE was induced using myelin oligodendrocyte glycoprotein MOG35-55 in C57BL/6 mice pre-vaccinated with ovalbumin (OVA)-linked OPN or OVA alone. We then evaluated the titer of antibodies to OPN, the clinical scores and in vitro cytokine secretion by spleen lymphocytes. Vaccination significantly induced antibodies against OPN during EAE, decreased disease severity, and the protective effect was correlated with decreased T cell secretion of interleukin 17 and interferon-γ ex vivo. The best effect was obtained with OPN-C, which induced significantly faster and more complete remission than other OPN vaccines. In conclusion, these data suggest that production of anti-OPN autoAbs may favor remission in both MS and EAE. Novel strategies boosting their levels, such as vaccination or passive immunization, may be proposed as a future strategy in personalized MS therapy.

Decreased function of Fas and variations of the perforin gene in adult patients with primary immune thrombocytopenia.

A defective switching off of the immune response is involved in several autoimmune diseases. This switching off involves Fas-mediated apoptosis, perforin-mediated fratricide of activated lymphocytes, and the suppressive activity of regulatory T (Treg) cells. These mechanisms are altered in autoimmune lymphoproliferative syndrome that often displays autoimmune thrombocytopenia. The aim of this research was to evaluate these mechanisms in adult patients with primary immune thrombocytopenia (ITP), compared with healthy controls. The results show that a substantial subgroup of the ITP patients displayed a defective Fas function; most of them displayed decreased Fas expression in T cells activated in vitro. Moreover, ITP patients displayed an increased frequency of rare missense variations of the PRF1 gene and decreased levels of Treg. Immunological analysis showed that levels of Interleukin (IL)10 and IL17 were decreased and marginal zone B cells were increased. Moreover, myeloid and plasmacytoid dendritic cells were decreased in ITP patients. In conclusion, in adult ITP patients, several mechanisms involved in shutting off the immune response are defective and several immunological parameters are dysregulated; these alterations may play a role in the clinical heterogeneity of the disease.

ICOS-Ligand Triggering Impairs Osteoclast Differentiation and Function In Vitro and In Vivo.

Osteoblasts, osteocytes, and osteoclasts (OCs) are involved in the bone production and resorption, which are crucial in bone homeostasis. OC hyperactivation plays a role in the exaggerated bone resorption of diseases such as osteoporosis, rheumatoid arthritis, and osteolytic tumor metastases. This work stems from the finding that OCs can express B7h (ICOS-Ligand), which is the ligand of the ICOS T cell costimulatory molecule. Because recent reports have shown that, in endothelial, dendritic, and tumor cells, B7h triggering modulates several activities of these cells, we analyzed the effect of B7h triggering by recombinant ICOS-Fc on OC differentiation and function. The results showed that ICOS-Fc inhibits RANKL-mediated differentiation of human monocyte-derived OC-like cells (MDOCs) by inhibiting the acquirement of the OC morphology, the CD14- cathepsin K+ phenotype, and the expression of tartrate-resistant acid phosphatase, OSCAR, NFATc1, and DC-STAMP. Moreover, ICOS-Fc induces a reversible decrease in the sizes of cells and nuclei and cathepsin K expression in mature MDOCs. Finally, ICOS-Fc inhibits the osteolytic activities of MDOCs in vitro and the development of bone loss in ovariectomized or soluble RANKL-treated mice. These findings open a novel field in the pharmacological use of agonists and antagonists of the ICOS-B7h system.

GSH-targeted nanosponges increase doxorubicin-induced toxicity "in vitro" and "in vivo" in cancer cells with high antioxidant defenses.

Several reports indicate that chemo-resistant cancer cells become highly adapted to intrinsic oxidative stress by up-regulating their antioxidant systems, which causes an increase of intracellular GSH content. Doxorubicin is one of the most widely used drugs for tumor treatment, able to kill cancer cells through several mechanisms. However, doxorubicin use is limited by its toxicity and cancer resistance. Therefore, new therapeutic strategies able to reduce doses and to overcome chemo-resistance are needed. A new class of glutathione-responsive cyclodextrin nanosponges (GSH-NS), is able to release anticancer drugs preferentially in cells having high GSH content. Doxorubicin-loaded GSH-NS, in the cancer cells with high GSH content, inhibited clonogenic growth, cell viability, topoisomerase II activity and induced DNA damage with higher effectiveness than free drug. Moreover, GSH-NS reduced the development of human tumor in xenograft models more than free drug. These characteristics indicate that GSH-NS can be a suitable drug delivery carrier for future applications in cancer therapy.

IL-17 protects T cells from apoptosis and contributes to development of ALPS-like phenotypes.

In autoimmune/lymphoproliferative syndrome (ALPS), defective Fas death receptor function causes lymphadenomegaly/splenomegaly, the expansion of T-cell receptor αß(+) CD4/CD8 double-negative T cells, and frequent development of hematologic autoimmunity. Dianzani autoimmune lymphoproliferative disease (DALD) has a similar phenotype but lacks the expansion of double-negative T cells. This work shows that patients with ALPS and DALD have high serum levels of interleukin 17A (IL-17A), IL-17F, and IL-17AF, which are involved in several autoimmune diseases, and that their T cells show increased secretion of these cytokines upon activation in vitro. The following data indicate that these cytokines may contribute to ALPS and DALD: (1) recombinant IL-17A and IL-17F significantly inhibit Fas-induced cell death in Fas-sensitive T cells from healthy donors; (2) this inhibitory effect is also induced by the patients' serum and is reversed by anti-IL-17A antibodies; (3) IL-17A neutralization substantially increases Fas-induced cell death in T cells from ALPS and DALD patients in vitro; and (4) treatment with anti-IL-17A antibodies ameliorates the autoimmune manifestations and, at a lesser extent, the lymphoproliferative phenotype and prolongs survival in MRLlpr/lpr mice, which are an animal model of ALPS. These data suggest that IL-17A and IL-17F could be targeted therapeutically to improve Fas function in ALPS and DALD.

Síndrome de BOD / BOD syndrome

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Differential induction of IL-17, IL-10, and IL-9 in human T helper cells by B7h and B7.1.

ICOS and CD28 are expressed by T cells and are involved in costimulation of cytokine production in T helper (TH) cells. ICOS binds B7h expressed by several cell types, whereas CD28 binds B7.1 and B7.2 expressed by activated antigen presenting cells. This work investigated the role of B7h and B7.1 in TH17 and TH9 cell differentiation by assessing activity of recombinant B7h-Fc and B7.1-Fc on human naïve TH cells activated in the presence of different combinations of exogenous cytokines. In the presence of TGF-ß1 and IL-1ß (TH17 promoting condition), B7h-Fc was more effective than B7.1-Fc in inducing IL-17A and IL-10 secretion, whereas B7.1-Fc was more effective in inducing IL-17F. Dual costimulation with B7h-Fc and B7.1-Fc displayed an intermediate pattern with predominance of IL-17F over IL-17A, secretion of high levels of IL-10, and secretion of IL-9 levels lower than those induced by B7.1-Fc alone. In the presence of TGF-ß1 and IL-4 (TH9 promoting condition), B7h-Fc induced IL-17A only, whereas B7.1-Fc induced also IL-17F, IL-10, and high levels of IL-9. Experiments on memory TH cells showed that B7h-Fc mainly supported secretion of IL-17A and IL-10, whereas B7.1-Fc supported secretion of IL-17A, IL-17F, IL-10, and IL-9. These data indicate that B7h and B7.1 play different roles in modulation of TH17 and TH9 differentiation. This plasticity might be important in the immune response to pathogens and tumors, and in the development of autoimmune diseases, and should be taken in consideration in designing of immunotherapeutic protocols triggering ICOS or CD28.

Manejo clínico de la epidermolisis ampollosa distrófica hereditaria: a propósito de un caso / Clinical handling of hereditary dystrophic epidermolysis bullosa: a case report

Las epidermolisis ampollosas son enfermedades genéticamente determinadas, caracterizadas por una fragilidad excesiva de la piel a las fuerzas de fricción. Esto ocasiona erosiones y ampollas, espontáneamente o ante mínimos traumatismos. Todas ellas se producen por alteraciones, hoy conocidas, en las proteínas de la unión dermoepidérmica. Los pacientes afectados requieren una atención adecuada para mantener una buena calidad de vida, mediante un manejo clínico muy cuidadoso, que incluya la prevención y el tratamiento oportuno de las múltiples complicaciones asociadas, algunas de las cuales pueden llegar a condicionar su supervivencia. Presentamos un caso de epidermolisis ampollosa distrófica con inicio en el nacimiento, confirmada con estudios histológicos y ultraestructurales(AU)

The epidermolysis bullosa constitute a group of determined genetically illnesses characterized by an excessive fragility of the skin to the friction forces. All of them take place for protein alterations, today known, that intervene in the union of the epidermis with the dermis. This leads to the formation of erosion and blisters, spontaneously or before a minimal traumatism. The patients suffering from this type of pathologies need a very careful clinical handling, which propitiates them the attention adapted to support a good quality of life, as well as the prevention and opportune treatment of the multiple complications that they can present, some of which can go so far as to threaten their life. We present of dystrophic epidermolysis bullosa case at birth, confirmed throughout histological and ultrastructural studies(AU)

Hipoplasia ungueal bilateral y simétrica de las manos / Bilateral Symmetrical Nail Hypoplasia of the Hands

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Pitiriasis rosada: una presentación atípica / Pityriasis rosea: an atypical presentation

En este artículo mostramos una presentación atípica de pitiriasis rosada en una paciente diagnosticada inicialmente de tiña corporis. La pitiriasis rosada es una dermatosis papuloescamosa aguda y autolimitada que afecta fundamentalmente a niños y adultos jóvenes sin predominancia de sexo. Se postula una etiología infecciosa, fundamentalmente vírica, aunque no ha podido ser confirmada. Esta entidad puede manifestarse con formas atípicas que dificultan el diagnóstico, y además es una dermatosis que se irrita con extremada facilidad variando su aspecto clínico (AU)

In this article, we present an atypical presentation of pityriasis rosea in a patient initially diagnosed of tinea corporia. Pityriasis rosea is an acute and self-limited papulosquamous dermatosis that fundamentally affects children and young adults with no gender predominance. It is hypothesized that its etiology is infectious, basically viral, although this has not been confirmed. This condition may occur in atypical forms that hinder its diagnosis and is a dermatosis that becomes irritated very easily, varying its clinical aspect (AU)

Metástasis cutáneas de neoplasias internas / Cutaneous metastases of internal neoplasm

Las metástasis cutáneas son un evento raro en dermatología, hay que tener en cuenta que pueden ser el primer marcador de la enfermedad y que asímismo pueden ser la primera señal de progresión. Generalmente las cutánides tienen la misma distribución por sexos que los primarios, siendo lascutánides más frecuentes en mujeres las procedentes de la mama, y en el hombre las procedentes de pulmón.Es importante reconocer estas lesiones para no diferir un diagnóstico correcto y por sus implicaciones con respecto al tratamiento. En aquellos pacientescon antecedentes de neoplasias internas, las metástasis cutáneas siempre hay que tenerlas dentro del diagnóstico diferencial de las lesiones cutáneas (AU)

Cutaneous metastases are infrequent in dermatology; they may be the first sign of disease and the first signal of progression. Cutaneous metastasesusually have the same distribution by sex than primary neoplasms. Breast cutaneous metastases are the most frequent in women and lung cutaneousmetastases are the most frequent in men.It is important to recognize these lesions not to defer a correct diagnosis and because their implications with regard to the treatment. In patients whohave a history of an internal neoplasm, cutaneous metastases always must be taken in mind in the differential diagnosis of cutaneous pathologies (AU)

[Allergic contact dermatitis to cosmetics]. / Dermatitis alérgica de contacto por cosméticos.

INTRODUCTION: Contact dermatitis to cosmetics is a common problem in the general population, although its prevalence appears to be underestimated. We reviewed cases of allergic contact dermatitis to cosmetics diagnosed in our dermatology department over a 7-year period with a view to identifying the allergens responsible, the frequency of occurrence of these allergens, and the cosmetic products implicated. METHODS: Using the database of the skin allergy department, we undertook a search of all cases of allergic contact dermatitis to cosmetics diagnosed in our department from January 2000 through October 2007. RESULTS: In this period, patch tests were carried out on 2,485 patients, of whom 740 were diagnosed with allergic contact dermatitis and the cause was cosmetics in 202 of these patients (170 women and 32 men), who accounted for 27.3 % of all cases. A total of 315 positive results were found for 46 different allergens. Allergens most often responsible for contact dermatitis in a cosmetics user were methylisothiazolinone (19 %), paraphenylenediamine (15.2 %), and fragrance mixtures (7.8 %). Acrylates were the most common allergens in cases of occupational disease. Half of the positive results were obtained with the standard battery of the Spanish Group for Research Into Dermatitis and Skin Allergies (GEIDAC). The cosmetic products most often implicated among cosmetics users were hair dyes (18.5 %), gels/soaps (15.7 %), and moisturizers (12.7 %). CONCLUSION: Most patients affected were women. Preservatives, paraphenylenediamine, and fragrances were the most frequently detected cosmetic allergens, in line with previous reports in the literature. Finally, in order to detect new cosmetic allergens, cooperation between physicians and cosmetics producers is needed.

Dermatitis alérgica de contacto por cosméticos / Allergic Contact Dermatitis to Cosmetics

Introducción: La dermatitis de contacto por cosméticos es un problema frecuente entre la población general, sin embargo, parece ser que su prevalencia está infraestimada. Revisamos en este trabajo los casos de dermatitis de contacto alérgica por cosméticos diagnosticados en el Departamento de Dermatología en un periodo de 7 años con el objetivo de detectar los alergenos responsables, la frecuencia de los mismos, así como los productos cosméticos implicados. Métodos: Utilizando la base de datos de la sección de Alergia Cutánea se realiza una búsqueda de todos los casos de dermatitis de contacto alérgica por cosméticos diagnosticados en nuestro departamento entre enero de 2000 y octubre de 2007. Resultados: Durante este periodo se realizaron pruebas epicutáneas a 2.485 pacientes. De todos ellos, 740 fueron diagnosticados de una dermatitis de contacto alérgica, 202 pacientes (170 mujeres/32 varones), es decir, el 27,3 % lo fueron por cosméticos. Se detectaron un total de 315 parches positivos y 46 alergenos diferentes. Los alergenos que con más frecuencia produjeron una dermatitis de contacto en el usuario fueron las metilisotiazolinonas (19 %), la parafenilendiamina (15,2 %) y la mezcla de perfumes (7,8 %). Los acrilatos fueron los alergenos más frecuentes en aquellos casos que tenían un origen laboral. Con la batería estándar del Grupo Español en Investigación en Dermatitis y Alergia Cutánea (GEIDAC) se detectaron la mitad de las pruebas positivas. Los productos cosméticos implicados con mayor frecuencia en el usuario fueron los tintes capilares (18,5 %), los geles/jabones (15,7 %) y las cremas hidratantes (12,7 %). Conclusión: La mayoría de los pacientes afectados fueron mujeres. Los conservantes, la parafenilendiamina y los perfumes fueron los alergenos cosméticos más frecuentes, tal y como había sido publicado previamente en la literatura. Finalmente, con el objetivo de detectar nuevos alergenos cosméticos debe existir colaboración entre los facultativos y las casas comerciales (AU)

Introduction: Contact dermatitis to cosmetics is a common problem in the general population, although its prevalence appears to be underestimated. We reviewed cases of allergic contact dermatitis to cosmetics diagnosed in our dermatology department over a 7-year period with a view to identifying the allergens responsible, the frequency of occurrence of these allergens, and the cosmetic products implicated. Methods: Using the database of the skin allergy department, we undertook a search of all cases of allergic contact dermatitis to cosmetics diagnosed in our department from January 2000 through October 2007. Results: In this period, patch tests were carried out on 2485 patients, of whom 740 were diagnosed with allergic contact dermatitis and the cause was cosmetics in 202 of these patients (170 women and 32 men), who accounted for 27.3% of all cases. A total of 315 positive results were found for 46 different allergens. Allergens most often responsible for contact dermatitis in a cosmetics user were methylisothiazolinone (19%), paraphenylenediamine (15.2%), and fragrance mixtures (7.8%). Acrylates were the most common allergens in cases of occupational disease. Half of the positive results were obtained with the standard battery of the Spanish Group for Research Into Dermatitis and Skin Allergies (GEIDAC). The cosmetic products most often implicated among cosmetics users were hair dyes (18.5%), gels/soaps (15.7%), and moisturizing creams (12.7%). Conclusion: Most patients affected were women. Preservatives, paraphenylenediamine, and fragrances were the most frequently detected cosmetic allergens, in line with previous reports in the literature. Finally, in order to detect new cosmetic allergens, cooperation between physicians and cosmetics producers is needed (AU)

Pápulas hiperqueratósicas en las manos / Hyperkeratotic Papules on the Hands

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