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.

Development and lifespan of Culicoides obsoletus s.s. (Meigen) and other livestock-associated species reared at different temperatures under laboratory conditions.

Culicoides Latreille (Diptera: Ceratopogonidae) transmit arboviruses affecting wild and domestic ruminants such as bluetongue (BTV) and Schmallenberg virus (SBV). The sub-adult development and lifespan of Culicoides obsoletus s.s. (Meigen), Culicoides circumscriptus Kieffer and Culicoides paolae Boorman were examined at three different temperatures under laboratory conditions. Insects were collected from field between spring and autumn 2015 in two livestock farms located in Majorca (Spain). Gravid females were held individually at 18, 25 or 30 °C. Low temperatures increased the adult lifespan, time to oviposit and rate of development, whereas high temperatures increased the number of eggs, successful pupation and adult emergence as well as the larvae growth rate. The results showed that C. obsoletus s.s. have optimum development at 18 °C, whereas the optimal rearing temperature for C. circumscriptus and C. paolae was under warmer conditions of 25-30 °C. Variations in temperature/humidity and assays with different materials and substrates for oviposition should be considered in future studies. Understanding the requirements of the different species of Culicoides optimizing the results should be of special interest for predicting environmental change effects on these species, in addition to determining the rearing conditions for candidate Culicoides vectors.

Determinants of the current and future distribution of the West Nile virus mosquito vector Culex pipiens in Spain.

Changes in environmental conditions, whether related or not to human activities, are continuously modifying the geographic distribution of vectors, which in turn affects the dynamics and distribution of vector-borne infectious diseases. Determining the main ecological drivers of vector distribution and how predicted changes in these drivers may alter their future distributions is therefore of major importance. However, the drivers of vector populations are largely specific to each vector species and region. Here, we identify the most important human-activity-related and bioclimatic predictors affecting the current distribution and habitat suitability of the mosquito Culex pipiens and potential future changes in its distribution in Spain. We determined the niche of occurrence (NOO) of the species, which considers only those areas lying within the range of suitable environmental conditions using presence data. Although almost ubiquitous, the distribution of Cx. pipiens is mostly explained by elevation and the degree of urbanization but also, to a lesser extent, by mean temperatures during the wettest season and temperature seasonality. The combination of these predictors highlights the existence of a heterogeneous pattern of habitat suitability, with most suitable areas located in the southern and northeastern coastal areas of Spain, and unsuitable areas located at higher altitude and in colder regions. Future climatic predictions indicate a net decrease in distribution of up to 29.55%, probably due to warming and greater temperature oscillations. Despite these predicted changes in vector distribution, their effects on the incidence of infectious diseases are, however, difficult to forecast since different processes such as local adaptation to temperature, vector-pathogen interactions, and human-derived changes in landscape may play important roles in shaping the future dynamics of pathogen transmission.

Descriptive study of naevus involution in a series of 74 patients with atypical naevus syndrome under SIAscopy digital follow-up.

BACKGROUND: Characterization of nevi involution could help to understand the biological behaviour of melanocytic neoplasms. OBJECTIVE: To describe the frequency and morphology of naevus involution in a series of patients with atypical naevus syndrome under digital follow-up with a SIAscopy program and, in a small sample of fading nevi, to analyse histopathological features and immunohistochemical biomarkers. METHODS: Seventy-four patients registered from April 2007 to July 2014 in the SIAscopy system of the Department of Dermatology of Hospital Arnau de Vilanova of Lleida, Spain, were reviewed. Fourteen naevus cases with fading features were prospectively excised during follow-up. Eleven already excised naevus controls were randomly selected from our archive. RESULTS: We observed that 81% of patients showed, at least, one involutive naevus and 25% of recorded nevi presented this phenomenon; the mean time of involution was 46.7 months. The predominant structural pattern was reticular (>70%), and the most frequently observed regression structures were vascular (33.8%). Histopathological significant higher intensity of inflammatory infiltrate in controls and higher presence of laminar and compact fibrosis and increase of vessels in cases were demonstrated. Regarding immunohistochemical biomarkers, only higher expression of cytoplasmic activated caspase 3 in controls was significant. CONCLUSIONS: Naevus involution is a common phenomenon in patients with dysplastic naevus syndrome. It is usually a slow process, more frequent in naevus with reticular pattern. SIAscopy regression structures are uncommon, with the exception of vascular ones. Histologically, fading involutive pattern is characterized by scarce inflammatory infiltrate and melanophages, delicate fibrosis and increase of vessels.

Water associated with residential areas and tourist resorts is the key predictor of Asian tiger mosquito presence on a Mediterranean island.

The Asian tiger mosquito, Aedes albopictus (Diptera: Culicidae), is a highly invasive species and a vector of several viruses of serious concern to public health. Investigating the habitat selection of this species at small to medium scales is essential to the planning of effective prevention and control campaigns. The present group considered detailed data for this species' presence/absence collected at 228 sites on Mallorca Island (Spain) in autumn 2015, 3 years after the first detection of the species on the island. Site occupancy models accounting for false negative detections and imperfect monitoring were used to evaluate the relationships between mosquito presence and habitat variables. In the study area, mosquito presence was negatively associated with altitude, probably as a result of greater human presence at low altitudes near the coast. Moreover, the presence of Ae. albopictus was positively associated with swimming pools as a result of associated gardens, plants and sources of fresh water. These two variables were combined to predict the presence of the species across the entire island.

Addition of N-terminal pro-B natriuretic peptide to soluble fms-like tyrosine kinase-1/placental growth factor ratio > 38 improves prediction of pre-eclampsia requiring delivery within 1 week: a longitudinal cohort study.

OBJECTIVE: Short-term prediction of pre-eclampsia (PE) using the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio is characterized by frequent false-positive results. As such, no treatment can be recommended to test-positive patients and multiple measurements are often required. The aim of this study was to evaluate the effectiveness of N-terminal pro-B natriuretic peptide (NT-proBNP), uric acid and the sFlt-1/PlGF ratio for prediction of delivery with PE within 1 week in singleton pregnancies with suspected PE and sFlt-1/PlGF ratio > 38. METHODS: This was a longitudinal prospective cohort study of singleton pregnancies presenting at 24 + 0 to 36 + 6 weeks of gestation with clinically suspected PE and sFlt-1/PlGF ratio > 38, enrolled between January 2015 and June 2017. Multiple samples per patient were allowed but were restricted to one sample per gestational week. From 495 enrolled patients, 270 blood samples from 134 patients were ultimately analyzed. By using generalized estimating equations (GEE), the best-fit model was selected for prediction of delivery with PE within 1 week. The predictive value of this model was then assessed using area under the paired-ROC curve (AUC) analysis. RESULTS: The best-fit model included the sFlt-1/PlGF ratio, NT-proBNP and the gestational week at the time of the measurement. This combined model was compared with the GEE model based on the sFlt-1/PlGF ratio and the gestational week at the time of the measurement (reduced model). The AUC for the combined model was 0.845 (95% CI, 0.787-0.896), which was significantly greater (P = 0.011) than that of the reduced model (0.786 (95% CI, 0.722-0.844)). CONCLUSION: The addition of NT-proBNP assessment improves the short-term prediction of delivery as a result of PE compared with sFlt-1/PlGF ratio alone, when the sFlt-1/PlGF ratio is > 38. This finding should be considered in future research on the assessment of short-term risk of delivery as a result of PE. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Bionomics of livestock-associated Culicoides (biting midge) bluetongue virus vectors under laboratory conditions.

This research contributes to knowledge of the basic bionomic parameters of vector and non-vector Culicoides species. Field-collected gravid C. imicola and Obsoletus complex showed the longest lifespans in laboratory conditions. Culicoides paolae and C. circumscriptus seemed to be the most suitable species for laboratory rearing in view of their high oviposition rates, short lifecycles, long adult lifespans and female-biased sex ratios.

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.

[Selection of candidates for prostate biopsy using multiparametric magnetic resonance imaging in patients with persistently raising PSA]. / Selección de pacientes candidatos a biopsia prostática mediante técnicas de resonancia magnética funcional en el seguimiento por elevación del PSA.

UNLABELLED: The current diagnosis of prostate cancer is based on randomized prostate biopsies to obtain histological material for study, without introducing any imaging technique in the diagnostic algorithm. OBJECTIVES: To conduct a literature review of the role of multiparametric MRI ( mMRI ) in the diagnosis of prostate cancer, and present preliminary data from our series of 233 patients undergoing mRMN and transrectal ultrasound (TRUS) prostate biopsy. MATERIAL AND METHODS: We performed a PubMed search for those articles that refer to the usefulness of mMRI in the follow-up and monitoring of patients with persistently elevated PSA without previous biopsies, and those with a previous negative biopsy, and assess the power of mRMN for detecting PCa in both the peripheral and the central gland. We present the preliminary results of our series, consisting of 233 patients selected between 2008 and 2011 undergoing mMRI and TRUS-guided prostatic biopsy because of elevated PSA levels or suspicious digital rectal examination. RESULTS: We discuss several articles published from 2003 to 2014. We compare our results with those from the literature. DISCUSSION: The diagnostic algorithm of prostate cancer to date does not include any imaging technique in the decision-making process. The mMRI is a functional imaging technique that provides increasing evidence in deciding which patients should be biopsied and which patients may avoid it despite persisting high levels of PSA. The advantage of this technique lies not only in its high detection rate in intermediate and high risk lesions, but also in its high specificity. It allows us to avoid diagnosing clinically insignificant tumors and thus, avoids overtreatment. CONCLUSION: The mRMN is a useful technique not yet incorporated in algorithms of prostate cancer diagnosis in urological societies. Its safety, effectiveness and efficiency are forcing to include its progressive use and with high probability will be soon incorporated into the decision-making charts.

Susceptibility of Culicoides species biting midges to deltamethrin-treated nets as determined under laboratory and field conditions in the Balearic Islands, Spain.

Culicoides Latreille (Diptera: Ceratopogonidae) are vectors of several arboviruses, including bluetongue virus (BTV) and African horse sickness virus (AHSV), which cause diseases in, respectively, sheep and cattle, and horses, and have economic repercussions mainly as a result of trade restrictions. Insecticides can be used to reduce vector populations and hence the spread of disease. Despite the economic importance of these diseases, relatively few studies have evaluated the efficacy of commercially available insecticides and the effectiveness of treated nets against Culicoides species. The aim of the present study was to evaluate the insecticidal effect of commercially available polyethylene nets (ZeroVector(®) ) treated with deltamethrin (4.4 g/kg ± 15%) on Culicoides species. Laboratory and field trials were conducted in Culicoides populations collected in Majorca in the Balearic Islands, Spain. The present study shows that deltamethrin-treated nets provoke high and rapid mortality (90-100%) in Culicoides midges under laboratory conditions and increase mortality by 13% when deployed in the field.

Sensitivity of Culicoides obsoletus (Meigen) (Diptera: Ceratopogonidae) to deltamethrin determined by an adapted WHO standard susceptibility test.

Bluetongue is a disease of major economic concern in Europe. Its causative agent, bluetongue virus (BTV), is transmitted by several Culicoides species (mainly Culicoides imicola and Culicoides obsoletus in Europe). The application of insecticides on animals may reduce transmission of BTV, however, no formulation is currently licensed specifically against Culicoides midges. The present study assesses the susceptibility of C. obsoletus to deltamethrin using an adapted World Health Organization (WHO) susceptibility test. Midges were exposed to different dosages of deltamethrin for 1 h, and mortality after 1 h and 24 h was recorded. Results indicated that deltamethrin is highly toxic to C. obsoletus since a dose of 1·33×10(-4)% was enough to kill 50% of the population (LD50) in 24 h. The deltamethrin concentration needed to kill 90% of the population (LD90) was 5·55×10(-4)%. The results obtained in the present work could help to create a system that can be used to assess insecticide resistance and susceptibility of Culicoides biting midges.

Detrimental effect of cypermethrin treated nets on Culicoides populations (Diptera; Ceratopogonidae) and non-targeted fauna in livestock farms.

Bluetongue (BT) is an important disease of ruminants which exhibits its most severe clinical signs on cattle and especially on certain breeds of sheep. The known vectors of BT are small insects of the genus Culicoides (Diptera; Ceratopogonidae). Two species from this genus - Culicoides imicola and Culicoides obsoletus - play the major role in the transmission of the disease in Europe. Several prophylactic methods are used to avoid transmission; however, an easy and cost-effective preventive technique would be very useful for the control of the Culicoides populations near the animals. In the present study, the insecticide effect of cypermethrin treated nets on a Culicoides population was evaluated. A polyethylene net sprayed with 1L cypermethrin solution (1%) surrounding a UV light suction trap was placed at a cattle farm in Majorca (Balearic Islands). Collections of Culicoides and other fauna from the trap and floor around the net were compared with a control. Results showed no significant differences in the collection of Culicoides midges between the insecticide-treated net and the control. However, significant differences were observed in the collection of the non-target fauna between the treated net and the control, indicating that the dose used in the present trial was enough to kill most of the arthropods that contacted the net. The reasons for these equivocal findings and means to improve this technique for the control of Culicoides midges are discussed.

Analogue transformations in physics and their application to acoustics.

Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an "analogue transformation acoustics" formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give explicit designs of a dynamic compressor, a spacetime cloak for acoustic waves and a carpet cloak for a moving aircraft.

Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells.

Drugs that target the chief mediator of nuclear export, chromosome region maintenance 1 protein (CRM1) have potential as therapeutics for leukemia, but existing CRM1 inhibitors show variable potencies and a broad range of cytotoxic effects. Here, we report the structural analysis and antileukemic activity of a new generation of small-molecule inhibitors of CRM1. Designated selective inhibitors of nuclear export (SINE), these compounds were developed using molecular modeling to screen a small virtual library of compounds against the nuclear export signal (NES) groove of CRM1. The 2.2-Å crystal structure of the CRM1-Ran-RanBP1 complex bound to KPT-251, a representative molecule of this class of inhibitors, shows that the drug occupies part of the groove in CRM1 that is usually occupied by the NES, but penetrates much deeper into the groove and blocks CRM1-directed protein export. SINE inhibitors exhibit potent antileukemic activity, inducing apoptosis at nanomolar concentrations in a panel of 14 human acute myeloid leukemia (AML) cell lines representing different molecular subtypes of the disease. When administered orally to immunodeficient mice engrafted with human AML cells, KPT-251 had potent antileukemic activity with negligible toxicity to normal hematopoietic cells. Thus, KPT-SINE CRM1 antagonists represent a novel class of drugs that warrant further testing in AML patients.

Control of postoperative pain with a wearable continuously operating pulsed radiofrequency energy device: a preliminary study.

BACKGROUND: Pulsed radiofrequency energy (PRFE) has long been reported to have a therapeutic effect on postoperative pain. In this study, a portable, wearable, low-energy-emitting PRFE therapy device was used to determine the control of postoperative pain after breast augmentation surgery. METHODS: The study enrolled 18 healthy women who underwent breast augmentation purely for aesthetic considerations. Postoperative pain after surgery was assessed with a 0- to 10-point visual analog scale (VAS). Baseline pain scores were taken at completion of the operation, and the patients were randomly assigned coded PRFE devices that were either active or placebo devices. For 7 days, VAS scores were recorded twice daily (a.m. and p.m.). Medication use also was logged for 7 days. The PRFE devices were left in place and in continuous operation for the 7 days of the study. RESULTS: All the patients tolerated the PRFE therapy well, and no side effects were reported. The VAS scores for the active group were significantly lower on postoperative day 1. By day 7, the baseline VAS remaining in the active group was 7.9% versus 38% in the placebo group. Together with lower VAS scores, narcotic pain medication use was lower in the patient group that received PRFE therapy. CONCLUSION: Postoperative pain is significantly lower with PRFE therapy. According to the findings, PRFE therapy in this form is an excellent, safe, drug-free method of postoperative pain control.

[Treatment of loculated parapneumonic empyema. Video assisted thoracoscopy or fibrinolytics?]. / Tratamiento del empiema paraneumónico tabicado: ¿videotoracoscopia o fibrinolíticos?

OBJECTIVE: There is no consensus regarding the ideal treatment of loculated parapneumonic empyema (PPE). The aim of this study is to compare the effectiveness of drainage plus urokinase (DF) with video-assisted thoracoscopy (VATS). MATERIAL AND METHODS: Retrospective review. Patients admitted with a PPE between January 2001 and July 2008. Loculated empyema was diagnosed by chest ultrasound and patients were treated with DF or VATS depending on the attending surgeon. Compared variables were: post-operative stay, total hospital stay, days of tube thoracostomy, post-operative fever and treatment failure. RESULTS: One hundred and twenty one patients were admitted with the diagnosis of PPE. Seventeen patients were excluded from analysis because of simple parapneumonic effusions. Of the 104 patients included in the study, 47 were treated with urokinase and 57 with videothoracoscopy. No statistically significant differences (P>.05) were found between the median values in the DF and VATS groups for hospital stay (median 12 vs 12 days) or post-operative stay (median 9 vs 9 days). There were differences in duration of tube thoracostomy (median DF group 5 days, VATS, 4 days, P<.05) and in the post-operative fever (median 3 vs 2 days, p<0,05).Twenty two per cent of children needed a second procedure (14 patients of DF and 9 of VATS group, P=.09). CONCLUSIONS: According to our experience, the results of DF and VATS for the treatment of loculated parapneumonic empyema are similar. Although there are no statistical differences, there seems to be a higher rate of failure, with the need of more procedures in the DF group. This difference does not affect the average total hospital stay.

[Evolution of the pelvis and hip throughout history: from primates to modern man]. / Évolution du bassin et de la hanche « à travers les âges ¼: des primates à l'homme moderne.

The evolution to a bipedal mode of locomotion was accompanied by a verticalization of the spine and a modification in the shape of the pelvis: horizontal curvature and sagittal rotation. Phylogenesis meets ontogenesis: flat bones in fetuses similar to the monkey, australopithecus features at birth and "human-like" features by 7 or 8years of age. These anatomical modifications explain the characteristics of human bipedalism: stable, economical, with hip and knee extension in the standing position with little lateral motion. Some pathologies induce a regression to a more archaic mode of bipedal locomotion.

[Endobronchial chondromesenchymal hamartoma]. / Hamartoma condromesenquimal endobronquial.

Primary lung tumours are uncommon in childhood. Among these tumours, endobronchial masses are even less common and, among benign tumours, inflammatory pseudotumours and hamartomas have the highest incidence in children. We present the case of a 2.5-year-old girl with a left endobronchial chondromesenchymal hamartoma with obstruction of 90% of the bronchial lumen. Complete resection of the endobronchial mass was performed by rigid bronchoscopy and application of topical mitomycin C. After tumour resection and a 12-month follow-up, the patient has shown a favourable outcome with immediate disappearance of respiratory symptoms. Successive fibreoptic bronchoscopies have shown no residual tumour.

[Interest of MR perfusion and MR spectroscopy for the diagnostic of atypical cerebral toxoplasmosis]. / Apport de l'IRM de perfusion et de la spectroscopie dans le diagnostic de toxoplasmose cérébrale atypique.

We report an atypical case of cerebral toxoplasmosis (CT) in a 70-year-old woman with a history of breast cancer. Contrast-enhanced computed tomography revealed a single ring-enhancing lesion in the pons with perifocal oedema and mass effect. Toxoplasma encephalitis was suggested by means of diffusion weighted imaging, MR perfusion and MR spectroscopy, leading to the discovery of HIV infection. The patient was put on antitoxoplasma therapy. Subsequent clinical and radiological improvements confirmed the diagnosis.

Aorto-enteric fistula after endovascular abdominal aortic aneurysm repair: case report and review.

OBJECTIVE: To report a case and to review previous publications regarding the rare complication of aorto-enteric fistula following endovascular aortic aneurysm repair. METHODS: We report the case of a stent-graft infection secondary to an aorto-enteric fistula 14 months after uncomplicated endovascular treatment of an infra-renal aortic aneurysm. RESULTS: The surgical treatment involved the removal of the infected graft and in situ aortic replacement by cryopreserved allograft. There have been no major complications noted during the 2-month follow-up after surgery. CONCLUSIONS: An aortojejunal fistula is a possible long-term complication of endovascular treatment of abdominal aortic aneurysm. An explantation of the infected graft and aortic replacement by a cryopreserved allograft is a valuable surgical treatment.