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Malignant melanoma (MM) is the most aggressive form of skin cancer, with increasing incidence worldwide. To date, there are no suitable clinical diagnostic, prognostic or predictive biomarkers for MM. Our data highlight the potential of metabolomic characterization of cancer stem cell‐ or serum‐derived exosomes using high‐resolution mass spectrometry for the discovery of clinically useful MM biomarkers. Malignant melanoma (MM) is the most aggressive and life‐threatening form of skin cancer. It is characterized by an extraordinary metastasis capacity and chemotherapy resistance, mainly due to melanoma cancer stem cells (CSCs). To date, there are no suitable clinical diagnostic, prognostic or predictive biomarkers for this neoplasia. Therefore, there is an urgent need for new MM biomarkers that enable early diagnosis and effective disease monitoring. Exosomes represent a novel source of biomarkers since they can be easily isolated from different body fluids. In this work, a primary patient‐derived MM cell line enriched in CSCs was characterized by assessing the expression of specific markers and their stem‐like properties. Exosomes derived from CSCs and serums from patients with MM were characterized, and their metabolomic profile was analysed by high‐resolution mass spectrometry (HRMS) following an untargeted approach and applying univariate and multivariate statistical analyses. The aim of this study was to search potential biomarkers for the diagnosis of this disease. Our results showed significant metabolomic differences in exosomes derived from MM CSCs compared with those from differentiated tumour cells and also in serum‐derived exosomes from patients with MM compared to those from healthy controls. Interestingly, we identified similarities between structural lipids differentially expressed in CSC‐derived exosomes and those derived from patients with MM such as the glycerophosphocholine PC 16:0/0:0. To our knowledge, this is the first metabolomic‐based study aimed at characterizing exosomes derived from melanoma CSCs and patients' serum in order to identify potential biomarkers for MM diagnosis. We conclude that metabolomic characterization of CSC‐derived exosomes sets an open door to the discovery of clinically useful biomarkers in this neoplasia.

Metastasis is the leading cause of cancer-related deaths and despite measurable progress in the field, underlying mechanisms are still not fully understood. Circulating tumor cells (CTCs) disseminate within the bloodstream, where most of them die due to the attack of the immune system. On the other hand, recent evidence shows active interactions between CTCs and platelets, myeloid cells, macrophages, neutrophils, and other hematopoietic cells that secrete immunosuppressive cytokines, which aid CTCs to evade the immune system and enable metastasis. Platelets, for instance, regulate inflammation, recruit neutrophils, and cause fibrin clots, which may protect CTCs from the attack of Natural Killer cells or macrophages and facilitate extravasation. Recently, a correlation between the commensal microbiota and the inflammatory/immune tone of the organism has been stablished. Thus, the microbiota may affect the development of cancer-promoting conditions. Furthermore, CTCs may suffer phenotypic changes, as those caused by the epithelial–mesenchymal transition, that also contribute to the immune escape and resistance to immunotherapy. In this review, we discuss the findings regarding the collaborative biological events among CTCs, immune cells, and microbiome associated to immune escape and metastatic progression.

[...]due to the appearance of new metastatic lesions in the liver and multiple cardioembolic ischemic stroke, the patient was moved to palliative care unit. The explanation could be that we obtained the sample 6 days after starting treatment with amphotericin B and that bone marrow aspiration studies have a sensitivity of only 60% in the diagnosis of visceral leishmaniasis. According to Filippis et al. and Roy et al., PD-1 blocking and anti-PD1 drugs seem to improve immune recognition and macrophage destruction of Leishmania parasite in vitro.

The automation strategies currently used in HVAC systems do not control the system temperature variables (supplied air, chilled, and condensation water temperatures) in an optimized way. Normally, these temperatures are fixed in design conditions, or vary according to the weather conditions. However, studies demonstrate that adequate control of these three temperatures can provide significant reductions in the energy consumption of the air conditioner system. Therefore, this work analyzes the benefits of individualized and integrated automation of these three variable temperatures in different tropical and subtropical weather conditions through computer simulation for a typical commercial building. The results of integrated automation show savings in consumption between 5.03% and 19.68% compared to a fixed control, and between 3.22% and 8.21% compared to a weather-based control alone, showing that the integrated strategies are better than both models adopted as market benchmarks.

Background Although the benefit of first-line epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) over chemotherapy has been demonstrated in several clinical trials, data from clinical practice is lacking and the optimal EGFR TKI to be used remains unclear. This study aims to assess the real-life diagnostic and clinical management and outcome of patients with advanced non-small-cell lung cancer (NSCLC) carrying EGFR mutations in Spain. Methods All consecutive patients recently diagnosed with advanced or metastatic NSCLC from April 2010 to December 2011 in 18 Spanish hospitals and carrying EGFR mutations were retrospectively evaluated. Results Between March and November 2013, a total of 187 patients were enrolled (98.3% Caucasian, 61.9% female, 54.9% never-smokers, 89.0% adenocarcinoma). Mutation testing was mainly performed on biopsy tumour tissue specimens (69.0%) using a qPCR-based test (90%) (47.0% Therascreen EGFR PCR Kit). Common sensitising mutations were detected in 79.8% of patients: 57.1% had exon 19 deletions and 22.6% exon 21 L858R point mutations. The vast majority of patients received first-line therapy ( n  = 168; 92.8%). EGFR TKIs were the most commonly used first-line treatment (81.5%), while chemotherapy was more frequently administered as a second- and third-line option (51.9% and 56.0%, respectively). Of 141 patients who experienced disease progression, 79 (56.0%) received second-line treatment. After disease progression on first-line TKIs ( n  = 112), 33.9% received chemotherapy, 8.9% chemotherapy and a TKI, and 9.8% continued TKI therapy. Most patients received first-line gefitinib (83.0%), while erlotinib was more frequently used in the second-line setting (83.0%). Progression-free survival (PFS) and overall survival (OS) in patients harbouring common mutations were 11.1 months and 20.1 months respectively (exon 19 deletions: 12.4 and 21.4 months; L858R: 8.3 and 14.5 months), and 3.9 months and 11.1 months respectively for those with rare mutations. Conclusion EGFR TKIs (gefitinib and erlotinib) are used as the preferred first-line treatment while chemotherapy is more frequently administered as a second- and third-line option in routine clinical practice in Spain. In addition, efficacy data obtained in the real-life setting seem to concur with data from EGFR TKI phase III pivotal studies in NSCLC.

Targeted therapy in metastatic melanoma often achieves a major tumour regression response and significant long-term survival via the release of antigens that reinduce immunocompetence. The biomarkers thus activated may guide the prediction of response, but this association and its mechanism have yet to be established. Blood samples were collected from nineteen consecutive patients with metastatic melanoma before, during, and after treatment with targeted therapy. Differential gene expression analysis was performed, which identified the genes involved in the treatment, both in the first evaluation of response and during progression. Although clinical characteristics of the patients were poorer than those obtained in pivotal studies, radiological responses were similar to those reported previously (objective response rate: 73.7%). In the first tumour assessment, the expression of some genes increased (CXCL-10, SERPING1, PDL1, and PDL2), while that of others decreased (ARG1, IL18R1, IL18RAP, IL1R1, ILR2, FLT3, SLC11A1, CD163, and S100A12). The analysis of gene expression in blood shows that some are activated and others inhibited by targeted therapy. This response pattern may provide biomarkers of the immune reinduction response, which could be used to study potential combination treatments. Nevertheless, further studies are needed to validate these results.

Understanding the determinants of vaccine hesitancy is paramount to reinstate confidence in immunizations. The objective of this investigation was to explore the characteristics of the vaccination decision-making process that may result in the refusal of childhood immunization in Peru, during February-June 2020. A descriptive, cross-sectional study involving telephone interviews was executed in Peru. The Parents Attitudes about Childhood Vaccines (PACV) survey was used. A demographic analysis was done, followed by an unadjusted exploratory subgroup analysis. Out of 552 subjects, 9.8% were considered vaccine hesitant, 70.3% had purposively delayed vaccination, 88.4% thought fewer vaccines were better and 52.2% were concerned about vaccine safety. The level of hesitancy was inversely proportional to the level of education and the number of children at home. Mothers and subjects aged ≤29 years showed a greater level of vaccine hesitancy. This population displays a vaccine-hesitant conduct. Vaccine safety and the number of vaccines to administer are important determining factors. This behavior could be influenced by variables such as level of education, number of children at home, parental relationship, and age. These results help understand local vaccination behaviors. More studies are encouraged to confirm and validate these findings.

Adagrasib is a KRASG12C inhibitor that demonstrated promising activity against KRASG12C-mutated advanced non-small-cell lung cancer (NSCLC) in a phase 2 trial. Here we aimed to compare the efficacy and safety of adagrasib versus docetaxel in patients with KRASG12C-mutated advanced NSCLC previously treated with chemotherapy and immunotherapy. KRYSTAL-12 is a randomised, multicentre, open-label, phase 3 trial conducted at 230 centres in 22 countries. Patients with Kirsten rat sarcoma viral oncogene homologue (KRAS)G12C-mutated locally advanced or metastatic NSCLC, who had previously received both platinum-based chemotherapy and anti-programmed cell death protein 1 or anti-programmed death ligand 1 therapy, were randomly allocated in a 2:1 ratio to receive 600 mg adagrasib (twice a day orally) or 75 mg/m2 docetaxel (every 3 weeks intravenously) using a centralised interactive web response system. Randomisation was stratified by region (non-Asia–Pacific vs Asia–Pacific) and previous treatment (sequential vs concurrent chemotherapy or immunotherapy). Treatment continued until disease progression, unacceptable toxicity, investigator or patient decision, or death. The primary endpoint was progression-free survival assessed by blinded independent central review in all randomised patients (intention-to-treat [ITT] population). Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov (NCT04685135), and is active but no longer recruiting. Between Feb 23, 2021, and Nov 16, 2023, 453 patients were randomly allocated to receive adagrasib (301 [66%]) or docetaxel (152 [34%]). In each group, 298 (99%) patients received adagrasib and 140 (92%) received docetaxel. In the ITT population (median follow-up 7·2 months [95% CI 5·8–8·7]), median progression-free survival was 5·5 months (95% CI 4·5–6·7) with adagrasib and 3·8 months (95% CI 2·7–4·7) with docetaxel (hazard ratio 0·58 [95% CI 0·45–0·76]; p<0·0001). Grade 3 and above treatment-related adverse events occurred in 140 (47%) of 298 patients treated with adagrasib and 64 (46%) of 140 with docetaxel. There were four (1%) treatment-related deaths in the adagrasib group and one (1%) treatment-related death in the docetaxel group. Adagrasib demonstrated a statistically significant improvement in progression-free survival over docetaxel in patients with previously treated KRASG12C-mutated NSCLC, without new safety signals. Mirati Therapeutics, a Bristol Myers Squibb company.

La falta de mediciones de oleaje es una realidad presente a la hora de realizar diseños de ingeniería marítima en Chile. Eventos como las marejadas del 3 julio 2013 y 8 agosto 2015 que dejaron cuantiosos daños estructurales, evidenciaron la falta de una red continua y de largo plazo de monitoreo de oleaje a la hora de estimar la frecuencia de ocurrencia de estos eventos. Esto implica que, en la actualidad, se debe confiar en bases de datos de oleaje de modelos de re-análisis globales, cuya calidad es desconocida para este propósito. En esta contribución se caracteriza la incertidumbre en la estimación de la frecuencia de ocurrencia de eventos extremos de oleaje. Para esto se analizan valores extremos de distintas bases de datos de oleaje disponibles. La comparación entre los valores de retorno encontrados es significativa, alcanzándose diferencias del orden de cientos de años en la estimación del período de retorno de un determinado evento. La calidad de la información de estas bases de datos para valores extremos se evaluó comparando el 10% de los valores más altos de la estadística de la altura significativa espectral con mediciones satelitales en ocho zonas a lo largo de Chile. La incertidumbre en la altura significativa espectral de período de retorno de 50 años tiende a aumentar de norte a sur, con diferencias entre bases de datos de 2,3 a 6,7 m. Los estadígrafos utilizados en la comparación con mediciones satelitales, muestran en general, mejores ajustes en el norte que en el sur a excepción de [R.sup.2]. Las correlaciones encontradas son muy bajas, con valores de [R.sup.2] cercanos a 0 para puntos en la zona norte y donde la mejor correlación la alcanza la base de datos IFREMER frente al Golfo Coronados con un [R.sup.2] = 0,66. Los sesgos son en general negativos, indicando subestimaciones cercanas a 1 m para las alturas significativas mayores.