Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma

PURPOSE: To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC) and to evaluate in vitro their mechanism of action in sunitinib resistance. METHODS: We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs) in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41). The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101). In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance. RESULTS: TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074). High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance. CONCLUSIONS: We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies

Effectiveness of a smartphone application for improving healthy lifestyles, a randomized clinical trial (EVIDENT II) : study protocol

Background: New technologies could facilitate changes in lifestyle and improve public health. However, no large randomized, controlled studies providing scientific evidence of the benefits of their use have been made. The aims of this study are to develop and validate a smartphone application, and to evaluate the effect of adding this tool to a standardized intervention designed to improve adherence to the Mediterranean diet and to physical activity. An evaluation is also made of the effect of modifying habits upon vascular structure and function, and therefore on arterial aging. Methods/Design: A randomized, double-blind, multicenter, parallel group clinical trial will be carried out. A total of 1215 subjects under 70 years of age from the EVIDENT trial will be included. Counseling common to both groups (control and intervention) will be provided on adaptation to the Mediterranean diet and on physical activity. The intervention group moreover will receive training on the use of a smartphone application designed to promote a healthy diet and increased physical activity, and will use the application for three months. The main study endpoints will be the changes in physical activity, assessed by accelerometer and the 7-day Physical Activity Recall (PAR) interview, and adaptation to the Mediterranean diet, as evaluated by an adherence questionnaire and a food frequency questionnaire (FFQ). Evaluation also will be made of vascular structure and function based on central arterial pressure, the radial augmentation index, pulse velocity, the cardio-ankle vascular index, and carotid intima-media thickness. Discussion: Confirmation that the new technologies are useful for promoting healthier lifestyles and that their effects are beneficial in terms of arterial aging will have important clinical implications, and may contribute to generalize their application in favor of improved population health. Trial registration: Clinical Trials.gov Identifier: NCT0201601

De novo erythroleukemia chromosome features include multiple rearrangements, with special involvement of chromosomes 11 and 19

Erythroid leukemia (ERL or AML-M6) is an uncommon subtype of acute myeloid leukemia, the clinical, morphological, and genetic behavior of which needs further characterization. We analyzed a homogeneous group of 23 de novo AML-M6 patients whose bone marrow cells showed complex karyotypes. We also analyzed eight leukemia cell lines with erythroid phenotype, performing detailed molecular cytogenetic analyses, including spectral karyotyping (SKY) in all samples. The main features are: (1) A majority of patients (56%) had hypodiploidy. Loss of genetic material was the most common genetic change, especially monosomies of chromosome 7 or 18, and deletions of chromosome arm 5q. Taken together, 87% of the cases displayed aberrations involving chromosome 5 or 8. (2) We describe a novel, cryptic, and recurrent translocation, t(11;19)(p11.2;q13.1). Another translocation, t(12;21)(p11.2;q11.2), was found to be recurrent in a patient with ERL and in the K562 cell line. (3) MLL gene rearrangements were detected in 20% of cases (three translocations and three amplifications) and, overall, we defined 52 rearrangements (excluding deletions) with a mean of 2.3 translocations per patient. (4) Of the structural aberrations, 21% involved chromosomes 11 and 19. Most of the rearrangements were unbalanced; only 13 reciprocal translocations were observed. The general picture of chromosomal aberrations in cell lines did not reflect what occurred in patient samples. However, both primary samples and cell lines shared three common breakpoints at 19q13.1, 20q11.2, and 21q11.2. This is the first molecular cytogenetic description of the karyotype abnormalities present in patients with ERL. It should assist in the identification of genes involved in erythroleukemogenesis

A Predictive Model and Risk Factors for Case Fatality of COVID-19

This study aimed to create an individualized analysis model of the risk of intensive care unit (ICU) admission or death for coronavirus disease 2019 (COVID-19) patients as a tool for the rapid clinical management of hospitalized patients in order to achieve a resilience of medical resources. This is an observational, analytical, retrospective cohort study with longitudinal follow-up. Data were collected from the medical records of 3489 patients diagnosed with COVID-19 using RT-qPCR in the period of highest community transmission recorded in Europe to date: February-June 2020. The study was carried out in in two health areas of hospital care in the Madrid region: the central area of the Madrid capital (Hospitales de Madrid del Grupo HM Hospitales (CH-HM), n = 1931) and the metropolitan area of Madrid (Hospital Universitario Príncipe de Asturias (MH-HUPA) n = 1558). By using a regression model, we observed how the different patient variables had unequal importance. Among all the analyzed variables, basal oxygen saturation was found to have the highest relative importance with a value of 20.3%, followed by age (17.7%), lymphocyte/leukocyte ratio (14.4%), CRP value (12.5%), comorbidities (12.5%), and leukocyte count (8.9%). Three levels of risk of ICU/death were established: low-risk level (20%). At the high-risk level, 13% needed ICU admission, 29% died, and 37% had an ICU-death outcome. This predictive model allowed us to individualize the risk for worse outcome for hospitalized patients affected by COVID-19

Leigh syndrome associated with TRMU gene mutations

tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) deficiency causes an early onset potentially reversible acute liver failure, so far reported in less than 30 patients. We describe two new unrelated patients with an acute liver failure and a neuroimaging compatible with Leigh syndrome (LS) due to TRMU deficiency, a combination not previously reported. Our report enlarges the phenotypical spectrum of TRMU disease

Role of Innate and Adaptive Cytokines in the Survival of COVID-19 Patients

SARS-CoV-2 is a new coronavirus characterized by a high infection and transmission capacity. A significant number of patients develop inadequate immune responses that produce massive releases of cytokines that compromise their survival. Soluble factors are clinically and pathologically relevant in COVID-19 survival but remain only partially characterized. The objective of this work was to simultaneously study 62 circulating soluble factors, including innate and adaptive cytokines and their soluble receptors, chemokines and growth and wound-healing/repair factors, in severe COVID-19 patients who survived compared to those with fatal outcomes. Serum samples were obtained from 286 COVID-19 patients and 40 healthy controls. The 62 circulating soluble factors were quantified using a Luminex Milliplex assay. Results. The patients who survived had decreased levels of the following 30 soluble factors of the 62 studied compared to those with fatal outcomes, therefore, these decreases were observed for cytokines and receptors predominantly produced by the innate immune system-IL-1 alpha, IL-1 alpha, IL-18, IL-15, IL-12p40, IL-6, IL-27, IL-1Ra, IL-1RI, IL-1RII, TNF alpha, TGF alpha, IL-10, sRAGE, sTNF-RI and sTNF-RII-for the chemokines IL-8, IP-10, MCP-1, MCP-3, MIG and fractalkine; for the growth factors M-CSF and the soluble receptor sIL2Ra; for the cytokines involved in the adaptive immune system IFN gamma, IL-17 and sIL-4R; and for the wound-repair factor FGF2. On the other hand, the patients who survived had elevated levels of the soluble factors TNF beta, sCD40L, MDC, RANTES, G-CSF, GM-CSF, EGF, PDGFAA and PDGFABBB compared to those who died. Conclusions. Increases in the circulating levels of the sCD40L cytokine; MDC and RANTES chemokines; the G-CSF and GM-CSF growth factors, EGF, PDGFAA and PDGFABBB; and tissue-repair factors are strongly associated with survival. By contrast, large increases in IL-15, IL-6, IL-18, IL-27 and IL-10; the sIL-1RI, sIL1RII and sTNF-RII receptors; the MCP3, IL-8, MIG and IP-10 chemokines; the M-CSF and sIL-2Ra growth factors; and the wound-healing factor FGF2 favor fatal outcomes of the disease

De-escalation: Testicular cancer

OBJETIVOS: Establecer la prioridad de los distintos procedimientos diagnósticos, terapéuticos y de seguimiento sobre el cáncer de testículo para adaptarse adecuadamente a la situación asistencial de cada centro. Valorar precauciones y adaptaciones durante la situación actual de desescalada en el curso de la pandemia COVID-19. Valoración del paciente con cáncer de testículo en presencia de pandemia infectiva.MATERIAL Y MÉTODOS: Revisión de la literatura relevante publicada hasta la fecha, elaboración de un borrador corregido por técnica de grupo nominal modificada, hasta obtener un documento de consenso entre los autores. RESULTADOS: En ausencia de evidencia científica relevante la mayor parte de las publicaciones, y la conclusiónde los autores, abogan por priorizar los procedimientos diagnósticos y terapéuticos de los pacientes. Una vez priorizados será menos complejo adaptar los recursos limitados a las necesidades más perentorias de los pacientes. En el cáncer de testículo los procedimientos iniciales que incluyen ecografía escrotal, orquiectomía, estudio de extensión, y tratamiento complementario si necesario, son de máxima necesidad. Se propone disminuir el uso de fármacos con potencial toxicidad respiratoria, y aumentar la utilización de los estimulantes de colonias hematopoyéticas, asi como promover seguimiento activo en estadio clínico I sin factores de riesgo. En caso de infección activa subrayamos que la mayoría de los pacientes son potencialmente curables. CONCLUSIONES: En el proceso de desescalada los pacientes con cáncer de testículo deben ser atendidos de forma preferente, especialmente durante evaluación y tratamiento iniciales. Las revisiones de pacientes con remisiones estables pueden retrasarse razonablemente sin excesivo riesgo de progresion en estadios bajos.OBJECTIVES: To provide a priority algorithm for determinate diagnostic, therapeutic and follow-up procedures regarding at testicular concer, adjusted by institutional requirements. Testicular cancer patient assessment during COVID-19 Pandemia. MATERIAL AND METHODS: Review of relevant manuscript published up to date, draft creation corrected though modified nominal group until final corrected manuscript. RESULTS: A lack of scientific evidence exists through a large amount of manuscripts. The authors support prioritizing diagnostic and therapeutic procedures. Once priorities have been established, that will facilitate providing each patients the limited resources. Initial diagnostic procedures for testicular cancer such as scrotal US, orchiectomy, staging CT and adjuvant treatment (if required) ore priority. Reducing the usage of chemotherapy with respiratory toxicity and increasing the usage of growth factors during chemotherapy treatment are the main stakeholders of treatment. Besides, providing active surveillance on non-risk factor clinical stage I is also a priority. In case of positive COVID-19, it is important to highlight that the vast majority of patients are tentatively cured. CONCLUSIONS: During de-escalation phases, patients diagnosed with testicular cancer should receive priority care during initial assessment. The follow-ups of patients with low -risk and without recurrence for a long time, might be delayed

Docetaxel in prostate cancer: a familiar face as the new standard in a hormone-sensitive setting

The increasing knowledge of prostate cancer is leading to many questions about its natural history and to reconsider conventional therapeutic strategies. Androgen ablation therapy has been the standard therapy in the advanced setting. Although docetaxel has demonstrated increased survival in patients with metastatic prostate cancer who had progressed to hormone treatments, due to its potential toxicity the role of chemotherapy has been relegated to patients who were symptomatic or who had high tumor burden. Several studies have assessed whether docetaxel could have a role in hormone-sensitive disease or even in earlier stages with no distant metastases. In the CHAARTED and STAMPEDE studies, docetaxel provides an unprecedented increase in overall survival (OS). This review summarizes the evidence behind the paradigm shift to strengthening docetaxel as a new standard of treatment that prolongs survival in earlier stages of prostate cancer

Optimizing the recognition and feature extraction of wind turbines through hybrid semantic segmentation architectures

Updating the mapping of wind turbines farms-found in constant expansion-is important to predict energy production or to minimize the risk of these infrastructures during storms. This geoinformation is not usually provided by public mapping agencies, and the alternative sources are usually consortiums or individuals interested in mapping and study. However, they do not offer metadata or genealogy, and their quality is unknown. This article presents a methodology oriented to optimize the recognition and extraction of features (wind turbines) using hybrid architectures of semantic segmentation. The aim is to characterize the quality of these datasets and help to improve and update them automatically at a large-scale. To this end, we intend to evaluate the capacity of hybrid semantic segmentation networks trained to extract features representing wind turbines from high-resolution images and to characterize the positional accuracy and completeness of a dataset whose genealogy and quality are unknown. We built a training dataset composed of 5140 tiles of aerial images and their cartography to train six different neural network architectures. The networks were evaluated on five test areas (covering 520 km2 of the Spanish territory) to identify the best segmentation architecture (in our case, LinkNet as base architecture and EfficientNet-b3 as the backbone). This hybrid segmentation model allowed us to characterize the completeness-both by commission and by omission-of the available georeferenced wind turbine dataset, as well as its geometric quality