M-CSF as a therapeutic target in BRAFV600E melanoma resistant to BRAF inhibitors.

BACKGROUND: Disseminated BRAFV600E melanoma responds to BRAF inhibitors (BRAFi) but easily develops resistance with poor prognosis. Secretome plays a pivotal role during tumour progression causing profound effects on therapeutic efficacy. Secreted M-CSF is involved in both cytotoxicity suppression and tumour progression in melanoma. We aimed to analyse the M-CSF contribution in resistant metastatic melanoma to BRAF-targeted therapies. METHODS: Conditioned media from melanoma cells were analysed by citoarray. Viability and migration/invasion assays were performed with paired melanoma cells and tumour growth in xenografted SCID mice. We evaluated the impact of M-CSF plasma levels with clinical prognosis from 35 metastatic BRAFV600E-mutant melanoma patients. RESULTS: BRAFi-resistant melanoma cells secretome is rich in pro-tumour cytokines. M-CSF secretion is essential to induce a Vemurafenib-resistant phenotype in melanoma cells. Further, we demonstrated that M-CSF mAb in combination with Vemurafenib and autophagy blockers synergistically induce apoptosis, impair migration and reduce tumour growth in BRAFi-resistant melanoma cells. Interestingly, lower M-CSF plasma levels are associated with better prognosis in metastatic melanoma patients. CONCLUSIONS: Secreted M-CSF induces a BRAFi-resistant phenotype and means worse prognosis in BRAFV600E metastatic melanoma patients. These results identify secreted M-CSF as a promising therapeutic target toward BRAFi-resistant melanomas.

Experimental sulphide inhibition calibration method in nitrification processes: A case-study.

Sulphide is one of the inhibitors in the nitrification process in WWTP in regions with sulphate rich soils. As little information is currently available on sulphide nitrification inhibition, the aim of this study was to develop a method based on a modification of the Successive Additions Method to calibrate the effect of sulphide on the activity of ammonia-oxidising bacteria (AOB) and nitrite-oxidising bacteria (NOB). The developed method was then applied to activated sludge samples from two WWTPs with different influent sulphide concentrations. In both cases, sulphide had a greater inhibitory effect on NOB than AOB activity. The sulphide inhibition was found to be lower in the activated sludge fed with sulphide-rich wastewater. The AOB and NOB activity measured at different sulphide concentrations could be accurately modelled with the Hill inhibition equation.

Berry fruits modulate kidney dysfunction and urine metabolome in Dahl salt-sensitive rats.

Berries are rich sources of (poly)phenols which have been associated with the prevention of cardiovascular diseases in animal models and in human clinical trials. Recently, a berry enriched diet was reported to decrease blood pressure and attenuate kidney disease progression on Dahl salt-sensitive rats. However, the relationship between kidney function, metabolism and (poly)phenols was not evaluated. We hypothesize that berries promote metabolic alterations concomitantly with an attenuation of the progression of renal disease. For that, kidney and urinary metabolomic changes induced by the berry enriched diet in hypertensive rats (Dahl salt-sensitive) were analyzed using liquid chromatography (UPLC-MS/MS) and 1H NMR techniques. Moreover, physiological and metabolic parameters, and kidney histopathological data were also collected. The severity of the kidney lesions promoted in Dahl rats by a high salt diet was significantly reduced by berries, namely a decrease in sclerotic glomeruli. In addition, was observed a high urinary excretion of metabolites that are indicators of alterations in glycolysis/gluconeogenesis, citrate cycle, and pyruvate metabolism in the salt induced-hypertensive rats, a metabolic profile counteracted by berries consumption. We also provide novel insights that relates (poly)phenols consumption with alterations in cysteine redox pools. Cysteine contribute to the redox signaling that is normally disrupted during kidney disease onset and progression. Our findings provide a vision about the metabolic responses of hypertensive rats to a (poly)phenol enriched diet, which may contribute to the understanding of the beneficial effects of (poly)phenols in salt-induced hypertension.

Immunohistochemical analysis of T-type calcium channels in acquired melanocytic naevi and melanoma.

BACKGROUND: Cutaneous malignant melanoma arises from transformed melanocytes de novo or from congenital or acquired melanocytic naevi. We have recently reported that T-type Ca2+ channels (TT-Cs) are upregulated in human melanoma and play an important role in cell proliferation. OBJECTIVES: To describe for the first time in formalin-fixed paraffin-embedded tissue the immunoexpression of TT-Cs in biopsies of normal skin, acquired melanocytic naevi and melanoma, in order to evaluate their role in melanomagenesis and/or tumour progression, their utility as prognostic markers and their possible use in targeted therapies. METHODS: Tissue samples from normal skin, melanocytic naevi and melanoma were subjected to immunohistochemistry for two TT-Cs (Cav3.1, Cav3.2); markers of proliferation (Ki67), the cell cycle (cyclin D1), hypoxia (Glut1), vascularization (CD31) and autophagy (LC3); BRAF V600E mutation (VE1) and phosphatase and tensin homologue (PTEN). Immunostaining was evaluated by histoscore. In silico analysis was used to assess the prognostic value of TT-C overexpression. RESULTS: TT-C immunoexpression increased gradually from normal skin to common naevi, dysplastic naevi and melanoma samples, but with differences in the distribution of both isoforms. Particularly, Cav3.2 expression was significantly higher in metastatic melanoma than in primary melanoma. Statistical correlation showed a linear interaction between PTEN loss/BRAF V600E/Cav3.1/LC3/ Ki67/cyclin D1/Cav3.2/Glut1. Disease-free survival (DFS) and overall survival correlated inversely with overexpression of Cav3.2. DFS also correlated inversely with overexpression of Cav3.1. CONCLUSIONS: TT-C immunoexpression on melanocytic neoplasms is consistent with our previous in vitro studies and appears to be related to tumour progression. TT-C upregulation can be considered as a prognostic marker using The Cancer Genome Atlas database. The high expression of Cav3.2 in metastatic melanoma encourages the investigation of the use of TT-C blockers in targeted therapies.

Droplets of Trapped Quantum Dipolar Bosons.

Strongly interacting systems of dipolar bosons in three dimensions confined by harmonic traps are analyzed using the exact path integral ground-state Monte Carlo method. By adding a repulsive two-body potential, we find a narrow window of interaction parameters leading to stable ground-state configurations of droplets in a crystalline arrangement. We find that this effect is entirely due to the interaction present in the Hamiltonian without resorting to additional stabilizing mechanisms or specific three-body forces. We analyze the number of droplets formed in terms of the Hamiltonian parameters, relate them to the corresponding s-wave scattering length, and discuss a simple scaling model for the density profiles. Our results are in qualitative agreement with recent experiments showing a quantum Rosensweig instability in trapped Dy atoms.

Corrigendum to "Calcium Channel Expression and Applicability as Targeted Therapies in Melanoma".

[This corrects the article DOI: 10.1155/2015/587135.].

Calcium channel expression and applicability as targeted therapies in melanoma.

The remodeling of Ca(2+) signaling is a common finding in cancer pathophysiology serving the purpose of facilitating proliferation, migration, or survival of cancer cells subjected to stressful conditions. One particular facet of these adaptive changes is the alteration of Ca(2+) fluxes through the plasma membrane, as described in several studies. In this review, we summarize the current knowledge about the expression of different Ca(2+) channels in the plasma membrane of melanoma cells and its impact on oncogenic Ca(2+) signaling. In the last few years, new molecular components of Ca(2+) influx pathways have been identified in melanoma cells. In addition, new links between Ca(2+) homeostasis and specific cell processes important in melanoma tumor progression have been unveiled. Thus, not only do Ca(2+) channels appear to have a potential as prognostic markers, but their pharmacological blockade or gene silencing is hinted as interesting therapeutic approaches.

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis.

Genes of the Sprouty family (Spry1-4) are feedback inhibitors of receptor tyrosine kinase (RTK) signaling. As such, they restrain proliferation of many cell types and have been proposed as tumor-suppressor genes. Although their most widely accepted target is the Extracellular-regulated kinases (ERK) pathway, the mechanisms by which Spry proteins inhibit RTK signaling are poorly understood. In the present work, we describe a novel mechanism by which Spry1 restricts proliferation, independently of the ERK pathway. In vivo analysis of thyroid glands from Spry1 knockout mice reveals that Spry1 induces a senescence-associated secretory phenotype via activation of the NFκB pathway. Consistently, thyroids from Spry1 knockout mice are bigger and exhibit decreased markers of senescence including Ki67 labeling and senescence-associated ß-galactosidase. Although such 'escape' from senescence is not sufficient to promote thyroid tumorigenesis in adult mice up to 5 months, the onset of Phosphatase and tensin homolog (Pten)-induced tumor formation is accelerated when Spry1 is concomitantly eliminated. Accordingly, we observe a reduction of SPRY1 levels in human thyroid malignancies when compared with non-tumoral tissue. We propose that Spry1 acts as a sensor of mitogenic activity that not only attenuates RTK signaling but also induces a cellular senescence response to avoid uncontrolled proliferation.

Excitations and stripe phase formation in a two-dimensional dipolar Bose gas with tilted polarization.

We present calculations of the ground state and excitations of an anisotropic dipolar Bose gas in two dimensions, realized by a nonperpendicular polarization with respect to the system plane. For sufficiently high density, an increase of the polarization angle leads to a density instability of the gas phase in the direction where the anisotropic interaction is strongest. Using a dynamic many-body theory, we calculate the dynamic structure function in the gas phase which shows the anisotropic dispersion of the excitations. We find that the energy of roton excitations in the strongly interacting direction decreases with increasing polarization angle and almost vanishes close to the instability. Exact path integral ground state Monte Carlo simulations show that this instability is indeed a quantum phase transition to a stripe phase, characterized by long-range order in the strongly interacting direction.

Sprouty1 is a candidate tumor-suppressor gene in medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a malignancy derived from the calcitonin-producing C-cells of the thyroid gland. Oncogenic mutations of the Ret proto-oncogene are found in all heritable forms of MTC and roughly one half of the sporadic cases. However, several lines of evidence argue for the existence of additional genetic lesions necessary for the development of MTC. Sprouty (Spry) family of genes is composed of four members in mammals (Spry1-4). Some Spry family members have been proposed as candidate tumor-suppressor genes in a variety of cancerous pathologies. In this work, we show that targeted deletion of Spry1 causes C-cell hyperplasia, a precancerous lesion preceding MTC, in young adult mice. Expression of Spry1 restrains proliferation of the MTC-derived cell line, TT. Finally, we found that the Spry1 promoter is frequently methylated in MTC and that Spry1 expression is consequently decreased. These findings identify Spry1 as a candidate tumor-suppressor gene in MTC.

Clínica de la acromegalia: presentación, cuadro clínico y comorbilidades / Clinical features of acromegaly: presentation, clinical picture and comorbidities

La acromegalia es un síndrome clínico producido por la secreción excesiva de hormona del crecimiento que afecta a prácticamente todo los órganos y tejidos. Se caracteriza por la desfiguración progresiva de los rasgos somáticos debido a las complicaciones metabólicas, endocrinas, cardiovasculares, respiratorias y articulares, así como por un aumento de la prevalencia de cáncer, sobre todo gastrointestinal. Conlleva una gran morbilidad y un aumento significativo de la mortalidad (AU)

Acromegaly is a clinical syndrome produced by excess growth hormone secretion affecting practically all organs and tissues. It is characterized by progressive enlargement of parts of the body due to metabolic, endocrine, respiratory and joint complications, as well as by an increase in the prevalence of cancer, especially gastrointestinal forms. This disorder produces high morbidity and a significant increase in mortality (AU)

Las vasculitis necrotizantes en lepra multibacilar

Los autores realizan un estudio retrospectivo sobre 9 pacientes de Lepra Multibacilar que presentaron episodios de vasculitis necrotizante. Destacan la gran frecuencia con que la aparición de la vasculitis determinó el diagnóstico de lepra sólo al internarse el paciente en un medio especializado. Observan la frecuencia con que la aparición del cuadro podría haber sido inducida por la administración de medicamentos no específicos para la lepra. Estiman que sería conveniente alertar a los médicos generalistas en el diagnóstico precoz de la enfermedad y a tener en cuenta a la lepra como diagnóstico diferencial en las vasculitis necrotizantes en zonas de endemia (AU)

Predictors of an unsatisfactory response to pentavalent antimony in the treatment of American visceral leishmaniasis

Although treatment of visceral leishmaniasis with pentavalent antimony is usually successful, some patients require second-line drug therapy, most commonly with amphotericin B. To identify the clinical characteristics that predict an inadequate response to pentavalent antimony, a case-control study was undertaken in Teresina, Piaui, Brazil. Over a two-year period, there were 19 cases of VL in which the staff physicians of a hospital prescribed second-line therapy with amphotericin B after determining that treatment with pentavalent antimony had failed. The control group consisted of 97 patients that were successfully treated with pentavalent antimony. A chart review using univariate and multivariate analysis was performed. The cure rate was 90 percent with amphotericin B. The odds ratio for the prescription of amphotericin B was 10.2 for children less than one year old, compared with individuals aged over 10 years. Patients who presented coinfection had an OR of 7.1 while those on antibiotics had an OR of 2.8. These data support either undertaking a longer course of therapy with pentavalent antimony for children or using amphotericin B as a first-line agent for children and individuals with coinfections. It also suggests that chemoprophylaxis directed toward bacterial coinfection in small children with VL may be indicated

Predictors of an unsatisfactory response to pentavalent antimony in the treatment of American visceral leishmaniasis.

Although treatment of visceral leishmaniasis with pentavalent antimony is usually successful, some patients require second-line drug therapy, most commonly with amphotericin B. To identify the clinical characteristics that predict an inadequate response to pentavalent antimony, a case-control study was undertaken in Teresina, Piaui, Brazil. Over a two-year period, there were 19 cases of VL in which the staff physicians of a hospital prescribed second-line therapy with amphotericin B after determining that treatment with pentavalent antimony had failed. The control group consisted of 97 patients that were successfully treated with pentavalent antimony. A chart review using univariate and multivariate analysis was performed. The cure rate was 90% with amphotericin B. The odds ratio for the prescription of amphotericin B was 10.2 for children less than one year old, compared with individuals aged over 10 years. Patients who presented coinfection had an OR of 7.1 while those on antibiotics had an OR of 2.8. These data support either undertaking a longer course of therapy with pentavalent antimony for children or using amphotericin B as a first-line agent for children and individuals with coinfections. It also suggests that chemoprophylaxis directed toward bacterial coinfection in small children with VL may be indicated.

Synthesis and structure determination of kahalalide F (1,2).

Kahalalide F, the only member of the family of peptides called kahalalides, isolated from the sacoglossan mollusc Elysia rufescens and the green alga Bryopsis sp., with important bioactivity, is in clinical trials for treatment of prostate cancer. An efficient solid-phase synthetic approach is reported. Kahalalide F presents several synthetic difficulties: (i) an ester bond between two beta-branched and sterically hindered amino acids; (ii) a didehydroamino acid; and (iii) a rather hydrophobic sequence with two fragments containing several beta-branched amino acids in a row, one of them terminated with a saturated aliphatic acid. The cornerstones of our strategy were (i) a quasiorthogonal protecting system with allyl, tert-butyl, fluorenyl, and trityl-based groups, (ii) azabenzotriazole coupling reagents, (iii) formation of the didehydroamino acid residue on the solid phase, and (iv) cyclization and final purification in solution. HPLC, high-field NMR, and biological activity studies showed that the correct stereochemistry of the natural product is that proposed by Rinehart et al. whereas the stereochemistry proposed by Scheuer et al. is that of a biologically less active diastereoisomer.

Ulceras de mikembro inferior: su importancia desde el punto de vista sanitario y social / Lower extremity ulcers: sanitary and social importance

Los autores estudian los cambios observados en las internacions de pacientes con UMI dutante el período 1995-1998 en el Hospital Carrasco, con especial referncia a egresos, tiempo de estadía, costos de internación y reinternaciones.Exponen protocolo de internacxión para estos pacientes, haciéndose referencia también a los problemas sociales que estas patologías determinan(AU)

Ulceras de mikembro inferior: su importancia desde el punto de vista sanitario y social / Lower extremity ulcers: sanitary and social importance

Los autores estudian los cambios observados en las internacions de pacientes con UMI dutante el período 1995-1998 en el Hospital Carrasco, con especial referncia a egresos, tiempo de estadía, costos de internación y reinternaciones.Exponen protocolo de internacxión para estos pacientes, haciéndose referencia también a los problemas sociales que estas patologías determinan

Evolución bacteriológica de la lepra lepromatosa según la presencia de episodios de eritema nudoso leproso

El ENL es una reacción frecuentemente observada en pacientes con lepra lepromatosa (LL), que parece desencadenarse poe le depósito de inmunocomplejos en la pared vascular y fenómenos de inmunidad celular, alguno de ellos específicos para el M. leprae. Para determinar si la presencia de ENL podía facilitar mejor evolución de la LL, evaluamos el tiempo de negativación bacteriológica (TNB) de pacientes LL según la aparición de episódios de ENL a lo largo del tratamiento. Se analisaron retrospectivamente las historias clínicas de 106 pacientes tratados mayormente con sulfas, 27 casos que nunca experimentaron episodios de ENL y 79 enfermos que lo habían desarrollado con distinta intensidad y frecuencia. Ambos grupos fueron similares en cuanto a edad, distribución por sexo, tipo de tratamiento y superficie corporal efectada, registrándose diferencias en la variedad clínica, más casos maculares en los LL sin ENL. Éstos tuvieron un TNB significativamente menos (3.1±0.4 años) al de los LL con ENL (6.1±0.3, media±es). Una subdivisión del último grupo según la magnitude y periodocidad de los episodios ENL tampoco reveló diferencias en el TNB, mostrando valores similares al registrado en el grupo original. La aparición de episódios de ENL no parece acelerar el tiempo de aclaramiento bacilar.