Galectin-7 reprograms skin carcinogenesis by fostering innate immune evasive programs.

Non-melanoma skin cancer (NMSC) has risen dramatically as a result of chronic exposure to sunlight ultraviolet (UV) radiation, climatic changes and clinical conditions associated with immunosuppression. In spite of considerable progress, our understanding of the mechanisms that control NMSC development and their associated molecular and immunological landscapes is still limited. Here we demonstrated a critical role for galectin-7 (Gal-7), a ß-galactoside-binding protein preferentially expressed in skin tissue, during NMSC development. Transgenic mice (Tg46) overexpressing Gal-7 in keratinocytes showed higher number of papillomas compared to WT mice or mice lacking Gal-7 (Lgals7-/-) when subjected to a skin carcinogenesis protocol, in which tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA) and tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were sequentially administered. RNAseq analysis of Tg46 tumor lesions revealed a unique profile compatible with cells of the myelomonocytic lineage infiltrating these tumors, an effect that was substantiated by a higher number of CD11b+Gr1+ cells in tumor-draining lymph nodes. Heightened c-Met activation and Cxcl-1 expression in Tg46 lesions suggested a contribution of this pathway to the recruitment of these cells. Remarkably, Gal-7 bound to the surface of CD11b+Ly6ChiLy6Glo monocytic myeloid cells and enhanced their immunosuppressive activity, as evidenced by increased IL-10 and TGF-ß1 secretion, and higher T-cell inhibitory activity. In vivo, carcinogen-treated Lgals7-/- animals adoptively transferred with Gal-7-conditioned monocytic myeloid cells developed higher number of papillomas, whereas depletion of these cells in Tg46-treated mice led to reduction in the number of tumors. Finally, human NMSC biopsies showed increased LGALS7 mRNA and Gal-7 protein expression and displayed transcriptional profiles associated with myeloid programs, accompanied by elevated CXCL1 expression and c-Met activation. Thus, Gal-7 emerges as a critical mediator of skin carcinogenesis and a potential therapeutic target in human NMSC.

Histidine-Rich Glycoprotein Inhibits HIV-1 Infection in a pH-Dependent Manner.

Histidine-rich glycoprotein (HRG) is an abundant plasma protein with a multidomain structure, allowing its interaction with many ligands, including phospholipids, plasminogen, fibrinogen, IgG antibodies, and heparan sulfate. HRG has been shown to regulate different biological responses, such as angiogenesis, coagulation, and fibrinolysis. Here, we found that HRG almost completely abrogated the infection of Ghost cells, Jurkat cells, CD4+ T cells, and macrophages by HIV-1 at a low pH (range, 6.5 to 5.5) but not at a neutral pH. HRG was shown to interact with the heparan sulfate expressed by target cells, inhibiting an early postbinding step associated with HIV-1 infection. More importantly, by acting on the viral particle itself, HRG induced a deleterious effect, which reduces viral infectivity. Because cervicovaginal secretions in healthy women show low pH values, even after semen deposition, our observations suggest that HRG might represent a constitutive defense mechanism in the vaginal mucosa. Of note, low pH also enabled HRG to inhibit the infection of HEp-2 cells and Vero cells by respiratory syncytial virus (RSV) and herpes simplex virus 2 (HSV-2), respectively, suggesting that HRG might display broad antiviral activity under acidic conditions.IMPORTANCE Vaginal intercourse represents a high-risk route for HIV-1 transmission. The efficiency of male-to-female HIV-1 transmission has been estimated to be 1 in every 1,000 episodes of sexual intercourse, reflecting the high degree of protection conferred by the genital mucosa. However, the contribution of different host factors to the protection against HIV-1 at mucosal surfaces remains poorly defined. Here, we report for the first time that acidic values of pH enable the plasma protein histidine-rich glycoprotein (HRG) to strongly inhibit HIV-1 infection. Because cervicovaginal secretions usually show low pH values, our observations suggest that HRG might represent a constitutive antiviral mechanism in the vaginal mucosa. Interestingly, infection by other viruses, such as respiratory syncytial virus and herpes simplex virus 2, was also markedly inhibited by HRG at low pH values, suggesting that extracellular acidosis enables HRG to display broad antiviral activity.

Diagnóstico etiológico de la miocardiopatía en pacientes receptores de trasplante cardíaco: Concordancia entre el diagnóstico clínico pretrasplante y la anatomía patológica / Etiologic Diagnosis of Cardiomyopathy in Heart Transplant Recipients: Agreement Between Pre-transplant Clinical Diagnosis and Pathology

Introducción: El diagnóstico etiológico en pacientes con miocardiopatías en estadio avanzado puede ser un desafío. Un gran número de pacientes permanecen sin diagnóstico a pesar de una evaluación exhaustiva, por lo que quedan rotuladas como miocardiopatías dilatadas idiopáticas. Objetivos: Describir la etiología de la miocardiopatía en pacientes receptores de trasplante cardíaco según el diagnóstico clínico pretrasplante y su grado de concordancia con el diagnóstico anatomopatológico del corazón explantado. Material y métodos: Se realizó un análisis retrospectivo de pacientes consecutivos trasplantados en un hospital de alta complejidad de la Ciudad Autónoma de Buenos Aires desde 2003 hasta fines de 2013. Se efectuó un análisis de concordancia entre el diagnóstico clínico pretrasplante y el diagnóstico anatomopatológico del corazón explantado utilizando el coeficiente kappa. Resultados: Se analizaron 100 pacientes con una edad media en el momento del trasplante de 49,7 ± 12,5 años y una mediana de fracción de eyección del 26,6%. El diagnóstico clínico pretrasplante más frecuente fue el de miocardiopatía dilatada idiopática (37%), seguida por la miocardiopatía isquémico-necrótica (32%) y la miocardiopatía chagásica (10%). Entre los diagnósticos histopatológicos más frecuentes se encontraron el de miocardiopatía isquémico-necrótica (35%), de miocardiopatía hipertrófica (10%), de miocardiopatía chagásica (10%) y de miocarditis (8%); no se arribó a un diagnóstico causal en el 25% (miocardiopatía dilatada idiopática). El resultado del coeficiente kappa fue de 0,64 (IC 0,52-0,76). Conclusiones: Aproximadamente un tercio de los pacientes llegan al trasplante sin un diagnóstico etiológico. El análisis anatomopatológico permite identificar la causa en más de la mitad de estos pacientes. A pesar de que la concordancia entre el diagnóstico pretrasplante y la anatomía patológica fue estadísticamente buena, un porcentaje importante de pacientes podría beneficiarse con un diagnóstico etiológico más preciso, que podría tener implicaciones pronósticas, terapéuticas y/o en la evaluación de familiares.

Introduction: Etiologic diagnosis in patients with end-stage cardiomyopathy can be challenging. A large number of patients remain undiagnosed despite a thorough evaluation, so they are classified as idiopathic dilated cardiomyopathies. Objectives: To describe the etiology of cardiomyopathy in heart transplant recipients according to pretransplant clinical diagnosis and its degree of agreement with the anatomopathological diagnosis of the explanted heart. Methods: We performed a retrospective analysis of consecutively transplanted patients in a high complexity hospital of the Autonomous City of Buenos Aires from 2003 to the end of 2013. An agreement analysis between pretransplantation clinical diagnosis and anatomopathological diagnosis of the explanted heart was done using the kappa coefficient. Results: One-hundred patients with mean age of 49.7 ± 12.5 years at the time of transplantation and median ejection fraction of 26.6% were analyzed. The most common pretransplant clinical diagnosis was idiopathic dilated cardiomyopathy (37%), followed by ischemic-necrotic cardiomyopathy (32%) and Chagas cardiomyopathy (10%). The most common histopathological diagnoses were ischemic-necrotic cardiomyopathy (35%), hypertrophic cardiomyopathy (10%), Chagas cardiomyopathy (10%) and myocarditis (8%); a causal diagnosis was not reached in 25% of cases (idiopathic dilated cardiomyopathy). The kappa coefficient was 0.64 (CI 0.52-0.76). Conclusions: Approximately one third of patients reach transplantation without an etiologic diagnosis. Anatomopathological analysis allows identifying the cause in more than half of these patients. Although the correlation between pretransplant diagnosis and pathological anatomy was statistically adequate, a significant percentage of patients could benefit from a more specific etiologic diagnosis, which may have prognostic, therapeutic and/or family assessment implications.

Diagnóstico etiológico de la miocardiopatía en pacientes receptores de trasplante cardíaco: Concordancia entre el diagnóstico clínico pretrasplante y la anatomía patológica / Etiologic Diagnosis of Cardiomyopathy in Heart Transplant Recipients: Agreement Between Pre-transplant Clinical Diagnosis and Pathology

Introducción: El diagnóstico etiológico en pacientes con miocardiopatías en estadio avanzado puede ser un desafío. Un gran número de pacientes permanecen sin diagnóstico a pesar de una evaluación exhaustiva, por lo que quedan rotuladas como miocardiopatías dilatadas idiopáticas. Objetivos: Describir la etiología de la miocardiopatía en pacientes receptores de trasplante cardíaco según el diagnóstico clínico pretrasplante y su grado de concordancia con el diagnóstico anatomopatológico del corazón explantado. Material y métodos: Se realizó un análisis retrospectivo de pacientes consecutivos trasplantados en un hospital de alta complejidad de la Ciudad Autónoma de Buenos Aires desde 2003 hasta fines de 2013. Se efectuó un análisis de concordancia entre el diagnóstico clínico pretrasplante y el diagnóstico anatomopatológico del corazón explantado utilizando el coeficiente kappa. Resultados: Se analizaron 100 pacientes con una edad media en el momento del trasplante de 49,7 ± 12,5 años y una mediana de fracción de eyección del 26,6%. El diagnóstico clínico pretrasplante más frecuente fue el de miocardiopatía dilatada idiopática (37%), seguida por la miocardiopatía isquémico-necrótica (32%) y la miocardiopatía chagásica (10%). Entre los diagnósticos histopatológicos más frecuentes se encontraron el de miocardiopatía isquémico-necrótica (35%), de miocardiopatía hipertrófica (10%), de miocardiopatía chagásica (10%) y de miocarditis (8%); no se arribó a un diagnóstico causal en el 25% (miocardiopatía dilatada idiopática). El resultado del coeficiente kappa fue de 0,64 (IC 0,52-0,76). Conclusiones: Aproximadamente un tercio de los pacientes llegan al trasplante sin un diagnóstico etiológico. El análisis anatomopatológico permite identificar la causa en más de la mitad de estos pacientes. A pesar de que la concordancia entre el diagnóstico pretrasplante y la anatomía patológica fue estadísticamente buena, un porcentaje importante de pacientes podría beneficiarse con un diagnóstico etiológico más preciso, que podría tener implicaciones pronósticas, terapéuticas y/o en la evaluación de familiares.(AU)

Introduction: Etiologic diagnosis in patients with end-stage cardiomyopathy can be challenging. A large number of patients remain undiagnosed despite a thorough evaluation, so they are classified as idiopathic dilated cardiomyopathies. Objectives: To describe the etiology of cardiomyopathy in heart transplant recipients according to pretransplant clinical diagnosis and its degree of agreement with the anatomopathological diagnosis of the explanted heart. Methods: We performed a retrospective analysis of consecutively transplanted patients in a high complexity hospital of the Autonomous City of Buenos Aires from 2003 to the end of 2013. An agreement analysis between pretransplantation clinical diagnosis and anatomopathological diagnosis of the explanted heart was done using the kappa coefficient. Results: One-hundred patients with mean age of 49.7 ± 12.5 years at the time of transplantation and median ejection fraction of 26.6% were analyzed. The most common pretransplant clinical diagnosis was idiopathic dilated cardiomyopathy (37%), followed by ischemic-necrotic cardiomyopathy (32%) and Chagas cardiomyopathy (10%). The most common histopathological diagnoses were ischemic-necrotic cardiomyopathy (35%), hypertrophic cardiomyopathy (10%), Chagas cardiomyopathy (10%) and myocarditis (8%); a causal diagnosis was not reached in 25% of cases (idiopathic dilated cardiomyopathy). The kappa coefficient was 0.64 (CI 0.52-0.76). Conclusions: Approximately one third of patients reach transplantation without an etiologic diagnosis. Anatomopathological analysis allows identifying the cause in more than half of these patients. Although the correlation between pretransplant diagnosis and pathological anatomy was statistically adequate, a significant percentage of patients could benefit from a more specific etiologic diagnosis, which may have prognostic, therapeutic and/or family assessment implications.(AU)

Cardiomyocytes of chronically ischemic pig hearts express the MDR-1 gene-encoded P-glycoprotein.

The multidrug-resistant (MDR)-1 gene-encoded P-glycoprotein (Pgp-170) is not normally present in the cardiomyocyte. Given that in other tissues Pgp-170 is not found under normoxic conditions but is expressed during hypoxia, we searched for Pgp-170 in chronically ischemic porcine cardiomyocytes. Pgp-170 was detected and localized via immunohistochemistry in ischemic and nonischemic cardiomyocytes of eight adult pigs 8 weeks after placement of an Ameroid constrictor at the origin of the left circumflex artery (Cx). Regional myocardial ischemia in the Cx bed was documented with nuclear perfusion scans. Pgp-170 mass was quantified using Western blot analysis. In all pigs, Pgp-170 was consistently present in the sarcolemma and T invaginations of the cardiomyocytes of the ischemic zone. Pgp-170 expression decreased toward the border of the ischemic zone and was negative in nonischemic regions as well as in the myocardium of sham-operated animals. Western blot analysis yielded significantly higher Pgp-170 mass in ischemic than in nonischemic areas. We conclude that Pgp-170 is consistently expressed in the cardiomyocytes of chronically ischemic porcine myocardium. Its role in the ischemic heart as well as in conditions such as myocardial hibernation, stunning, and preconditioning may have potentially relevant clinical implications and merits further investigation.