A Braf kinase-inactive mutant induces lung adenocarcinoma.

The initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown, a fact that complicates the development of selective targeted therapies. Yet these tumours harbour a number of alterations without obvious oncogenic function including BRAF-inactivating mutations. Inactivating BRAF mutants in lung predominate over the activating V600E mutant that is frequently observed in other tumour types. Here we demonstrate that the expression of an endogenous Braf(D631A) kinase-inactive isoform in mice (corresponding to the human BRAF(D594A) mutation) triggers lung adenocarcinoma in vivo, indicating that BRAF-inactivating mutations are initiating events in lung oncogenesis. Moreover, inactivating BRAF mutations have also been identified in a subset of KRAS-driven human lung tumours. Co-expression of Kras(G12V) and Braf(D631A) in mouse lung cells markedly enhances tumour initiation, a phenomenon mediated by Craf kinase activity, and effectively accelerates tumour progression when activated in advanced lung adenocarcinomas. We also report a key role for the wild-type Braf kinase in sustaining Kras(G12V)/Braf(D631A)-driven tumours. Ablation of the wild-type Braf allele prevents the development of lung adenocarcinoma by inducing a further increase in MAPK signalling that results in oncogenic toxicity; this effect can be abolished by pharmacological inhibition of Mek to restore tumour growth. However, the loss of wild-type Braf also induces transdifferentiation of club cells, which leads to the rapid development of lethal intrabronchiolar lesions. These observations indicate that the signal intensity of the MAPK pathway is a critical determinant not only in tumour development, but also in dictating the nature of the cancer-initiating cell and ultimately the resulting tumour phenotype.

Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas.

KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.

Polluting macrophytes Colombian lake Fúquene used as substrate by edible fungus Pleurotus ostreatus.

Invasive aquatic plants from Lake Fúquene (Cundinamarca, Colombia), water hyacinth (Eichhornia crassipes C. Mart.) and Brazilian elodea (Egeria densa Planch.) have been removed mechanically from the lake and can be used for edible mushrooms production. The growth of the oyster mushroom (Pleurotus ostreatus) on these aquatic macrophytes was investigated in order to evaluate the possible use of fruiting bodies and spent biomass in food production for human and animal nutrition, respectively. Treatments included: water hyacinth, Brazilian elodea, sawdust, rice hulls and their combinations, inoculated with P. ostreatus at 3%. Water hyacinth mixed with sawdust stimulated significantly fruiting bodies production (P = 3.3 × 10(-7)) with 71% biological efficacy, followed by water hyacinth with rice husk (55%) and elodea with rice husk (48%), all of these have protein contents between 26 and 47%. Loss of lignin (0.9-21.6%), cellulose (3.7-58.3%) and hemicellulose (1.9-53.8%) and increment in vitro digestibility (16.7-139.3%) and reducing sugars (73.4-838.4%) were observed in most treatments. Treatments spent biomass presented Relative Forage Values (RFV) from 46.1 to 232.4%. The results demonstrated the fungus degrading ability and its potential use in aquatic macrophytes conversion biomass into digestible ruminant feed as added value to the fruiting bodies production for human nutrition.

Predictive usefulness of qSOFA, NEWS and GYM scores in the elderly patient: EDEN-5 study.

OBJECTIVE: To analyze the prognostic accuracy of the scores NEWS, qSOFA, GYM used in hospital emergency department (ED) in the assessment of elderly patients who consult for an infectious disease. METHODS: Data from the EDEN (Emergency Department and Elderly Need) cohort were used. This retrospective cohort included all patients aged ≥65 years seen in 52 Spanish EDs during two weeks (from 1-4-2019 to 7-4-2019 and 30/3/2020 to 5/4/2020) with an infectious disease diagnosis in the emergency department. Demographic variables, demographic variables, comorbidities, Charlson and Barthel index and needed scores parameters were recorded. The predictive capacity for 30-day mortality of each scale was estimated by calculating the area under the receiver operating characteristic (ROC) curve, and sensitivity and specificity were calculated for different cut-off points. The primary outcome variable was 30-day mortality. RESULTS: 6054 patients were analyzed. Median age was 80 years (IQR 73-87) and 45.3% women. 993 (16,4%) patients died. NEWS score had better AUC than qSOFA (0.765, 95CI: 0.725-0.806, versus 0.700, 95%CI: 0.653-0.746; P < .001) and GYM (0.716, 95%CI: 0.675-0.758; P = .024), and there was no difference between qSOFA and GYM (P = .345). The highest sensitivity scores for 30-day mortality were GYM ≥ 1 point (85.4%) while the qSOFA score ≥2 points showed high specificity. In the case of the NEWS scale, the cut-off point ≥4 showed high sensitivity, while the cut-off point NEWS ≥ 8 showed high specificity. CONCLUSION: NEWS score showed the highest predictive capacity for 30-day mortality. GYM score ≥1 showed a great sensitivity, while qSOFA ≥2 scores provide the highest specificity but lower sensitivity.

Prognostic implications of serum microRNA-21 in colorectal cancer.

BACKGROUND AND OBJECTIVES: MicroRNAs (miRNAs) are small, noncoding RNAs that are involved in carcinogenesis through postranscriptional gene regulatory activity. Few studies have focused on the detection of miR-21 in serum rather than in tissue. The current study aimed to measure serum miR-21 expression levels and to evaluate their association with the outcome of colorectal cancer (CRC). METHODS: Blood samples were collected from 102 CRC patients undergoing surgery with curative intent. The expression levels of miR-21 were measured using a quantitative reverse transcription polymerase chain reaction (qRT-PCR). The results were analysed to assess the relationship between serum miR-21 levels and patient survival. RESULTS: A univariate analysis revealed that lower expression levels of serum miR-21 were associated with higher local recurrence (P = 0.025) and mortality (P = 0.029). A logistic regression analysis demonstrated that the relative overexpression of miR-21 (expression > 1) was associated with a 51% reduction in the risk of recurrence. A Cox regression analysis identified miR-21 expression as an independent predictor of survival (P = 0.048); a relative increase in miR-21 expression (>1) was associated with a 50% reduction in the risk of mortality. CONCLUSION: The expression level of serum miR-21 correlates with the recurrence and mortality of CRC patients. Our results suggest that circulating serum miR-21 is a promising prognostic tumour marker, and they highlight the potential clinical utility of miR-21 expression as a prognostic marker for CRC prognosis.

Coronavirus disease 2019 and lung cancer: where are we?

Oncology patients are more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to hospital contact and an immunological system that can be compromised by antineoplastic therapy and supportive treatments. Certain similarities have been described in the physiopathology of coronavirus disease 2019 (COVID-19) and lung cancer (LC) that may explain the higher probability of these patients of developing a more serious disease with more frequent hospitalizations and even death, especially with the addition of smoking, cardiovascular and respiratory comorbidities, old age and corticosteroids use. Pre-existing lesions and cancer therapies change the normal architecture of the lungs, so diagnostic scales such as COVID-19 Reporting and Data System (CO-RADS) are of vital importance for a correct diagnosis and patient homogenization, with a high inter-observer correlation. Moreover, anticancer treatments have required an adaptation to reduce the number of visits to the hospital [hypofractionated radiotherapy (RT), larger intervals between chemotherapy cycles, delay in follow-up tests, among others]. In a way, this has also caused a delay in the diagnosis of new cancers. On the other hand, vaccination has had a positive impact on the mortality of these patients, who maintain a similar seroprevalence to the rest of the population, with a similar impact in mortality.

Efectividad de Férulas de Descarga Oclusivas como Tratamiento para la Disfunción Temporomandibular. Revisión Sistemática

El objetivo de este estudio de revisión sistemática consistió en la búsqueda de hallazgos clínicos en estudios de calidad sobre la efectividad de la terapia con férulas de descarga oclusales. Esta investigación bibliográfica se realizó en PubMed, Embase, SciELO, Science Direct, Scopus, Google Scholar y en el Registro Central de Ensayos clínicos Cochrane; delimitando la búsqueda desde el 1 de enero de 2011 al 1 de junio de 2022. Se incluyeron un total de 21 artículos, todos relacionados con la disfunción de la articulación temporomandibular y la eficacia de las férulas de descarga oclusales como tratamiento. Las férulas de descarga oclusales reducen eficazmente los síntomas dolorosos en pacientes con trastornos temporomandibulares, tanto en patologías musculares como articulares, aunque con mayor eficacia en casos de disfunción muscular, ya que se han observado desplazamientos recurrentes de disco en patologías articulares.

The objective of this systematic review study was to search for clinical findings in quality studies on the effectiveness of occlusal splint therapy. This literature search was conducted in PubMed, Embase, SciELO, Science Direct, Scopus, Google Scholar, and the Cochrane Central Register of Clinical Trials; delimiting the search from January 1, 2011 to June 1, 2022. A total of 21 articles were included, all related to temporomandibular joint dysfunction and the efficacy of occlusal splints as a treatment. Occlusal splints effectively reduce painful symptoms in patients with temporomandibular disorders, both in muscular and joint pathologies, although more effectively in cases of muscular dysfunction, since recurrent disc displacements have been observed in joint pathologies.

Modeling lung cancer evolution and preclinical response by orthotopic mouse allografts.

Cancer evolution is a process that is still poorly understood because of the lack of versatile in vivo longitudinal studies. By generating murine non-small cell lung cancer (NSCLC) orthoallobanks and paired primary cell lines, we provide a detailed description of an in vivo, time-dependent cancer malignization process. We identify the acquisition of metastatic dissemination potential, the selection of co-driver mutations, and the appearance of naturally occurring intratumor heterogeneity, thus recapitulating the stochastic nature of human cancer development. This approach combines the robustness of genetically engineered cancer models with the flexibility of allograft methodology. We have applied this tool for the preclinical evaluation of therapeutic approaches. This system can be implemented to improve the design of future treatments for patients with NSCLC.