Eukaryotic Initiation Factor 5A2 localizes to actively translating ribosomes to promote cancer cell protrusions and invasive capacity.

BACKGROUND: Eukaryotic Initiation Factor 5A (eIF-5A), an essential translation factor, is post-translationally activated by the polyamine spermidine. Two human genes encode eIF-5A, being eIF5-A1 constitutively expressed whereas eIF5-A2 is frequently found overexpressed in human tumours. The contribution of both isoforms with regard to cellular proliferation and invasion in non-small cell lung cancer remains to be characterized. METHODS: We have evaluated the use of eIF-5A2 gene as prognosis marker in lung adenocarcinoma (LUAD) patients and validated in immunocompromised mice. We have used cell migration and cell proliferation assays in LUAD lines after silencing each eIF-5A isoform to monitor their contribution to both phenotypes. Cytoskeleton alterations were analysed in the same cells by rhodamine-phalloidin staining and fluorescence microscopy. Polysome profiles were used to monitor the effect of eIF-5A2 overexpression on translation. Western blotting was used to study the levels of eIF-5A2 client proteins involved in migration upon TGFB1 stimulation. Finally, we have co-localized eIF-5A2 with puromycin to visualize the subcellular pattern of actively translating ribosomes. RESULTS: We describe the differential functions of both eIF-5A isoforms, to show that eIF5-A2 properties on cell proliferation and migration are coincident with its features as a poor prognosis marker. Silencing of eIF-5A2 leads to more dramatic consequences of cellular proliferation and migration compared to eIF-5A1. Overexpression of eIF-5A2 leads to enhanced global translation. We also show that TGFß signalling enhances the expression and activity of eIF-5A2 which promotes the translation of polyproline rich proteins involved in cytoskeleton and motility features as it is the case of Fibronectin, SNAI1, Ezrin and FHOD1. With the use of puromycin labelling we have co-localized active ribosomes with eIF-5A2 not only in cytosol but also in areas of cellular protrusion. We have shown the bulk invasive capacity of cells overexpressing eIF-5A2 in mice. CONCLUSIONS: We propose the existence of a coordinated temporal and positional interaction between TFGB and eIF-5A2 pathways to promote cell migration in NSCLC. We suggest that the co-localization of actively translating ribosomes with hypusinated eIF-5A2 facilitates the translation of key proteins not only in the cytosol but also in areas of cellular protrusion. Video Abstract.

Role of heme oxygenase in the regulation of the renal hemodynamics in a model of sex-dependent programmed hypertension by maternal diabetes.

Intrauterine programming of cardiovascular and renal function occurs in diabetes because of the adverse maternal environment. Heme oxygenase 1 (HO-1) and -2 (HO-2) exert vasodilatory and antioxidant actions, particularly in conditions of elevated HO-1 expression or deficient nitric oxide levels. We evaluated whether the activity of the heme-HO system is differentially regulated by oxidative stress in the female offspring of diabetic mothers, contributing to the improved cardiovascular function in comparison with males. Diabetes was induced in pregnant rats by a single dose of streptozotocin (STZ, 50 mg/kg ip) in late gestation. Three-month-old male offspring from diabetic mothers (MODs) exhibited higher blood pressure (BP), higher renal vascular resistance (RVR), worse endothelium-dependent response to acetylcholine (ACH), and an increased constrictor response to phenylephrine (PHE) compared with those in age-matched female offspring of diabetic mothers (FODs), which were abolished by chronic tempol (1 mM) treatment. In anesthetized animals, stannous mesoporphyrin (SnMP; 40 µmol/kg iv) administration, to inhibit HO activity, increased RVR in FODs and reduced glomerular filtration rate (GFR) in MODs, without altering these parameters in control animals. When compared with MODs, FODs showed lower nitrotirosyne levels and higher HO-1 protein expression in renal homogenates. Indeed, chronic treatment with tempol in MODs prevented elevations in nitrotyrosine levels and the acute renal hemodynamics response to SnMP. Then, maternal diabetes results in sex-specific hypertension and renal alterations associated with oxidative stress mainly in adult male offspring, which are reduced in the female offspring by elevation in HO-1 expression and lower oxidative stress levels.

Pose Estimation for Visible Light Systems Using a Quadrature Angular Diversity Aperture Receiver.

The quadrature angular diversity aperture (QADA) receiver, consisting of a quadrant photodiode (QPD) and an aperture placed above the QPD, has been investigated for pose estimation for visible light systems. Current work on pose estimation for the QADA receiver uses classical camera sensor algorithms well known in computer vision. To this end, however, the light spot center first has to be obtained based on the RSS. However, this is less straightforward than for camera sensors, as in contrast to such sensors where the relationships are linear, the RSS output from the QADA is a non-linear function of the light spot position. When applying closed form solutions or iterative methods for cameras on a QADA, the non-linearity will degrade their performance. Furthermore, since in practice the aperture is not always perfectly aligned with the QPD, a procedure to calibrate the receiver is needed. Current work on calibration requires additional sophisticated equipment to measure the pose during calibration, which increases the difficulty of implementation. In this paper, we target the above problems for pose estimation and calibration of the QADA receiver. To this end, we first study the effect of the strategy of differencing and normalization on the probability density function (PDF), a commonly applied strategy for the QPD's robustness against RSS variation, and it is shown that the applied strategy results in a complex PDF, which makes an effective and efficient estimation hard to achieve. Therefore, we derive an approximated PDF in a simple closed-form, based on which the calibration and the pose estimation algorithms using the least squares principle are proposed. The proposed calibration does not require any information about the pose of the receiver and is robust to variation of the received power and imperfect knowledge of the radiation pattern of the LED, making it easy to implement. We also derive the corresponding Cramér-Rao lower bound on the misalignment to benchmark the performance of the misalignment and to serve as an indicator to determine the required signal-to-noise ratio (SNR) or number of LEDs to obtain a desired accuracy. The calibration and pose estimation are evaluated by means of a Monte Carlo simulation. Computer simulations show that this theoretical bound is close to the RMSE of the proposed estimator and that the proposed pose estimator outperforms the PnP algorithm.

Electromyographic and patient-reported outcomes of a computer-guided occlusal adjustment performed on patients suffering from chronic myofascial pain.

OBJECTIVES: Muscular hyperactivity is a potential source of symptoms in patients with temporal-mandibular disorders. An adequate occlusal adjustment may relieve such symptoms. This study aims to measure the effect of shortening the protrusive disclusion time (DT) and balancing the center of occlusal forces (COF) on the EMG recordings and assess the pain reported by chronic patients one month after the computer-guided occlusal adjustment. STUDY DESIGN: The sample studied comprised 34 patients suffering from chronic facial pain in which the EMG activity of both masseters was recorded by electromyography. By selective grinding we alleviated all the occlusal interferences during the mandibular protrusion from the habitual closure position in order to establish an immediate posterior disclusion and an equilibration of the COF. RESULTS: At follow-up 76.5% of the patients reported no facial pain. Moreover, the EMG activity and protrusive DT were significantly reduced, and occlusal and muscular function were significantly more symmetric than at baseline. CONCLUSIONS: According to this EMG study, this computer-guided occlusal adjustment is able to reduce the activity of the masseters and the self-reported muscular pain of patients one-month after treatment.

Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. METHODS: We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (> 18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m(2) on day 1 plus docetaxel (75 mg/m(2) on day 1) or gemcitabine (1250 mg/m(2) on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m(2) or AUC 5 with gemcitabine 1000 mg/m(2)) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥ 1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. FINDINGS: Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p < 0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. INTERPRETATION: Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. FUNDING: Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.

Screening for epidermal growth factor receptor mutations in lung cancer.

BACKGROUND: Activating mutations in the epidermal growth factor receptor gene (EGFR) confer hypersensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced non-small-cell lung cancer. We evaluated the feasibility of large-scale screening for EGFR mutations in such patients and analyzed the association between the mutations and the outcome of erlotinib treatment. METHODS: From April 2005 through November 2008, lung cancers from 2105 patients in 129 institutions in Spain were screened for EGFR mutations. The analysis was performed in a central laboratory. Patients with tumors carrying EGFR mutations were eligible for erlotinib treatment. RESULTS: EGFR mutations were found in 350 of 2105 patients (16.6%). Mutations were more frequent in women (69.7%), in patients who had never smoked (66.6%), and in those with adenocarcinomas (80.9%) (P<0.001 for all comparisons). The mutations were deletions in exon 19 (62.2%) and L858R (37.8%). Median progression-free survival and overall survival for 217 patients who received erlotinib were 14 months and 27 months, respectively. The adjusted hazard ratios for the duration of progression-free survival were 2.94 for men (P<0.001); 1.92 for the presence of the L858R mutation, as compared with a deletion in exon 19 (P=0.02); and 1.68 for the presence of the L858R mutation in paired serum DNA, as compared with the absence of the mutation (P=0.02). The most common adverse events were mild rashes and diarrhea; grade 3 cutaneous toxic effects were recorded in 16 patients (7.4%) and grade 3 diarrhea in 8 patients (3.7%). CONCLUSIONS: Large-scale screening of patients with lung cancer for EGFR mutations is feasible and can have a role in decisions about treatment.

The effects of physical activity on dietary habits in young adults from madrid.

BACKGROUND: The main objective of the study was to analyze the relation between the physical activity levels and diet quality of a group of young adults from Madrid. METHODS: The nutritional and activity records of a group of 222 young adults (113 females and 109 males), with ages ranging from 18 to 30 years, were evaluated using dietary and activity questionnaires, and anthropometric measurements. From the data collected, the food, energy, macro and micronutrients intake, activity coefficient, body mass index, and body fat percentage were calculated. RESULTS: The study revealed that 67.1 % of the individuals evaluated (82.3 % of the females and 51.3 % of the males) were classified as sedentary. The sedentary individuals had a higher percentage of body fat compared to active individuals. Generally, active individuals consumed more cereals and less fat. The nutritional intake of the participants did not follow the recommended daily intake, however the nutritional intake of the active individuals was closer to the recommended, with higher micronutrient intakes. CONCLUSION: These results suggest that active individuals follow healthier diets and keep a more adequate body weight, which provides protection against several chronic diseases.

New roles for AP-1/JUNB in cell cycle control and tumorigenic cell invasion via regulation of cyclin E1 and TGF-ß2.

BACKGROUND: JUNB transcription factor contributes to the formation of the ubiquitous transcriptional complex AP-1 involved in the control of many physiological and disease-associated functions. The roles of JUNB in the control of cell division and tumorigenic processes are acknowledged but still unclear. RESULTS: Here, we report the results of combined transcriptomic, genomic, and functional studies showing that JUNB promotes cell cycle progression via induction of cyclin E1 and repression of transforming growth factor (TGF)-ß2 genes. We also show that high levels of JUNB switch the response of TGF-ß2 stimulation from an antiproliferative to a pro-invasive one, induce endogenous TGF-ß2 production by promoting TGF-ß2 mRNA translation, and enhance tumor growth and metastasis in mice. Moreover, tumor genomic data indicate that JUNB amplification associates with poor prognosis in breast and ovarian cancer patients. CONCLUSIONS: Our results reveal novel functions for JUNB in cell proliferation and tumor aggressiveness through regulation of cyclin E1 and TGF-ß2 expression, which might be exploited for cancer prognosis and therapy.

[New patient care techniques: nutritional coaching]. / Nuevas técnicas de atención al paciente: el coaching nutricional.

INTRODUCTION: To achieve behavioral changes, as well as to prevent the appearance of non-communicable diseases, nutritional education has traditionally been used. However, the prevalence of some chronic diseases is still increasing. This has led to the development of new patient care techniques such as nutritional coaching, in which the patient plays an active role during the change process. The available scientific evidence indicates that nutritional coaching, as well as health coaching, is an effective tool to achieve lasting changes in diet and lifestyle.

INTRODUCCIÓN: Para conseguir cambios de comportamiento, así como para prevenir la aparición de enfermedades no transmisibles, tradicionalmente se ha empleado la educación nutricional. Sin embargo, la prevalencia de algunas enfermedades crónicas sigue aumentado. Esto ha hecho que se hayan desarrollado nuevas técnicas de atención al paciente como el coaching,, así como el coaching de salud, en el que el paciente juega un papel activo durante el proceso del cambio. La evidencia científica disponible señala que el coaching nutricional es una herramienta efectiva para conseguir cambios duraderos en la dieta y el estilo de vida.

[Weight status, body composition, and diet quality of Spanish schoolchildren according to their level of adherence to the 24-hour movement guidelines]. / Situación ponderal, composición corporal y calidad de la dieta de los escolares españoles en función del nivel de adherencia a las guías de movimiento de 24 horas.

INTRODUCTION: Introduction: moderate to vigorous physical activity, limiting sedentary behaviors, and getting adequate rest are lifestyle factors that help prevent overweight and obesity. However, there are few studies that relate all of these factors to weight status, body composition, and diet quality in school children. Objective: to assess the differences in anthropometric status and diet quality in a group of Spanish schoolchildren, according to their level of adherence to the 24-hour movement guidelines. Methods: a total of 367 schoolchildren aged 7-11 years were studied. Anthropometric, dietary, and movement patterns were collected. Subsequently, they were divided into three groups based on their adherence to the extant guidelines: low adherence (BA), medium adherence (AM) and high adherence (AA). Results: only 15 % of the schoolchildren met the guidelines. The percentage of overweight was higher in the BA group than in the AM and AA groups. The BA group also had a lower fibre intake; a lower contribution to the recommendations for vitamins B6, B12 and C, selenium and magnesium; and a higher intake of saturated fatty acids. The schoolchildren who did not meet screen time recommendations had a higher odds ratio for overweight/obesity (OR = 1.92 (1.10-3.36); p = 0.022). Conclusion: schoolchildren who adhere to 2 or more movement guideline recommendations had less overweight and a diet of better nutritional quality. Non-compliance with the screen time recommendation leads to a higher risk of overweight or obesity.

INTRODUCCIÓN: Introducción: la actividad física moderada o vigorosa, la limitación de los comportamientos sedentarios y el descanso adecuado son factores del estilo de vida que ayudan a prevenir el sobrepeso y la obesidad. Sin embargo, existen pocos trabajos que relacionen el conjunto de estos factores con la situación ponderal, la composición corporal y la calidad de la dieta en escolares. Objetivo: conocer las diferencias en cuanto a situación antropométrica y calidad de la dieta de un grupo de escolares españoles en función del nivel de adherencia a las guías de movimiento de 24 horas. Métodos: se han estudiado 367 escolares de 7-11 años de edad. Se recogieron datos antropométricos, dietéticos y de comportamientos de movimiento. Posteriormente se dividieron en tres grupos sobre la base de su adherencia a las guías: baja adherencia (BA), adherencia media (AM) y alta adherencia (AA). Resultados: solo un 15 % de los escolares cumplía con las guías. El porcentaje de sobrepeso era mayor en el grupo BA que en el AM y el AA. El grupo BA también presentaba una menor ingesta de fibra; una menor contribución a las recomendaciones de vitaminas B6, B12 y C, selenio y magnesio; y una mayor ingesta de ácidos grasos saturados. Los escolares que incumplían la recomendación referente al tiempo de pantalla tenían mayor riesgo de desarrollar sobrepeso u obesidad (OR = 1,92 (1,10-3,36); p = 0,022). Conclusión: los escolares que se adhieren a 2 o más recomendaciones de las guías de movimiento presentan menos sobrepeso y una mejor calidad nutricional de la dieta. El incumplimiento de la recomendación de tiempo de pantalla supone un mayor riesgo de sobrepeso u obesidad.

Efficacy of nintedanib plus docetaxel in patients with refractory advanced epidermal growth factor receptor mutant lung adenocarcinoma.

BACKGROUND: Anti-angiogenic agents are reported to exert clinical activity in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We evaluated the outcomes of the combination of docetaxel plus nintedanib in refractory NSCLC patients harboring EGFR mutations. METHODS: We retrospectively analyzed 19 patients with advanced EGFR-mutant NSCLC who had progressed to EGFR tyrosine kinase inhibitors (TKI) and platinum-based chemotherapy receiving docetaxel and nintedanib at 14 Spanish institutions from January 2013 to December 2019. Kaplan-Meier and log-rank tests were used to evaluate progression-free survival (PFS) and overall survival (OS). RESULTS: Median age was 58.9 years (range 42.8-81), 73.7% were female. All patients were Caucasian, and 73.7% were never or light smokers. The baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 94.7% of patients. All patients had adenocarcinoma. Brain and liver metastases were present in 47.4% and 31.6% of patients, respectively. The most common EGFR mutations were exon 19 deletion (52.6%) and exon 21 L858R mutation (36.8%); 47.4% patients presented the EGFR T790M. 94.8% of the patients had received 2-3 previous treatment lines. Docetaxel was administered at 75 mg/m2/3 weeks to 16 patients, at 60 mg/m2 to 2 patients and at 45 mg/m2 to one patient. Nintedanib was given until disease progression or unacceptable toxicity at 200 mg twice daily except in 2 patients who received 150 mg twice daily and one patient who received 100 mg/12 h. With a median follow-up of 11.4 months (1-38), the median PFS was 6.1 months [95% confidence interval (CI), 4.9-7.3] and the median OS 10.1 months (95% CI 5.9-14.3). The objective response rate (ORR) was 44.4% (23.7-66.8%) and the disease control rate (DCR) 72.2% (49.4-88.5%). Efficacy tended to be greater in patients with the acquired T790M who had received osimertinib, with a median PFS of 6.3 (95% CI 2.1-10.5) versus (vs.) 4.8 (95% CI 3.5-6.1) and a median OS of 12.3 months (95% CI 8.6-16.0) vs. 6.7 months (95% CI 3.9-9.4), although this tendency was not statistically significant (p = 0.468 and p = 0.159, respectively). Sixteen patients (84.2%) had a total of 34 adverse events (AEs), with a median of two (0-6) AEs per patient. The most frequent AEs were asthenia (20.6%) and diarrhea (20.6%). One treatment-related death due to portal thrombosis was reported. CONCLUSIONS: Our data indicate that the combination of docetaxel and nintedanib can be considered to be an effective treatment for EGFR TKI-resistant EGFR-mutant NSCLC.

Correction: Pardo-Sánchez et al. Increased Tumor Growth Rate and Mesenchymal Properties of NSCLC-Patient-Derived Xenograft Models during Serial Transplantation. Cancers 2021, 13, 2980.

The authors would like to make a correction to their published paper [...].

Increased Tumor Growth Rate and Mesenchymal Properties of NSCLC-Patient-Derived Xenograft Models during Serial Transplantation.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. The high mortality is very often a consequence of its late diagnosis when the cancer is already locally advanced or has disseminated. Advances in the study of NSCLC tumors have been achieved by using in vivo models, such as patient-derived xenografts. Apart from drug screening, this approach may also be useful for study of the biology of the tumors. In the present study, surgically resected primary lung cancer samples (n = 33) were implanted in immunodeficient mice, and nine were engrafted successfully, including seven adenocarcinomas, one squamous-cell carcinoma, and one large-cell carcinoma. ADC tumors bearing the KRAS-G12C mutation were the most frequently engrafted in our PDX collection. Protein expression of vimentin, ezrin, and Ki67 were evaluated in NSCLC primary tumors and during serial transplantation by immunohistochemistry, using H-score. Our data indicated a more suitable environment for solid adenocarcinoma, compared to other lung tumor subtypes, to grow and preserve its architecture in mice, and a correlation between higher vimentin and ezrin expression in solid adenocarcinomas. A correlation between high vimentin expression and lung adenocarcinoma tumors bearing KRAS-G12C mutation was also observed. In addition, tumor evolution towards more proliferative and mesenchymal phenotypes was already observed in early PDX tumor passages. These PDX models provide a valuable platform for biomarker discovery and drug screening against tumor growth and EMT for lung cancer translational research.

Phase II clinical trial with metronomic oral vinorelbine and tri-weekly cisplatin as induction therapy, subsequently concomitant with radiotherapy (RT) in patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC). Analysis of survival and value of ctDNA for patient selection.

BACKGROUND: Little progress has been achieved in non-small cell lung cancer (NSCLC) patients with unresectable stage III disease and new drug schemes are warranted. MATERIAL AND METHODS: In this open-label, single-arm, phase II trial 65 treatment-naïve stage III NSCLC deemed surgically unresectable by a multidisciplinary team were treated with 2 cycles of induction cisplatin at 80 mg/m2 every 21 days plus metronomic oral vinorelbine at 50 mg/day every Monday, Wednesday and Friday. During the concomitant treatment with thoracic radiotherapy cisplatin was administered in the same manner but oral vinorelbine was reduced to 30 mg/day. The objective was to administer a total radiotherapy dose of 66 Gy in 33 daily fractions of 2 Gy. The primary endpoint was progression-free survival (PFS). Correlation between circulating tumor DNA (ctDNA) levels and survival was also evaluated. RESULTS: Fifty-five (78.5 %) patients completed treatment. Overall response rate, by RECIST criteria, was 66.2 %. Four (6.2 %) patients had complete response, 39 (60.0 %) partial response and 12 (18.5 %) stable disease. Seven patients (10.8 %) had progressive disease during the induction period. Median follow-up was 29.1 months (m), median PFS was 11.5 m (95 %CI: 9.6-15.4). PFS at 12 m in the intention-to-treat (ITT) population was 47.8 % (95 %CI: 35.1-59.4 %) and median OS was 35.6 m (95 %CI: 24.4-46.8). Grade ≥3 treatment-related adverse events occurred in 14 (21.5 %) patients during induction and in 13 (24.5 %) patients during concomitant treatment with esophagitis occurring in 3% and pneumonitis in 1.5 % of the patients. Patients with undetectable ctDNA after 3 m follow-up had median PFS and OS of 18.1 m (95 %CI: 8.8-NR) and not reached (NR) (95 %CI: 11.3-NR), respectively, compared with 8.0 m (95 %CI: 2.7-NR) and 24.7 m (95 %CI: 5.7-NR) for patients who remained ctDNA positive at that time point. CONCLUSIONS: Metronomic oral vinorelbine and cisplatin obtains similar efficacy results with significantly lower toxicity than the same chemotherapy at standard doses. ctDNA can identify populations with particularly good prognosis.

Adrenal schwannoma in a female patient; A rare benign neoplasm: Case report and literature review.

INTRODUCTION: Schwannomas are rare, slow-growing, usually benign tumors that originate from myelin-producing Schwann cells. Adrenal schwannomas are an exceptionally rare subset of these tumors, with few cases reported in the literature. PRESENTATION OF CASE: We present the case of a 44-year old female patient being evaluated for chronic abdominal pain at the outpatient clinic. Clinical and laboratory workup was unremarkable. An abdominal CT scan was performed, revealing a left suprarenal solid mass (5 × 6 cm). Surgical resection of the adrenal gland was performed, given the patient's symptoms, the size of the tumor, and its malignant potential. The patient completed the postoperative period satisfactorily, and her symptoms improved. Histopathological findings were compatible with a benign adrenal schwannoma. DISCUSSION: Schwannomas generally appear in the head, neck and extremities, with the vestibulocochlear nerve being the most frequently involved site. Retroperitoneal schwannomas account for 1-5% of retroperitoneal masses and comprise only 1-3% of all schwannomas. Their incidence increases with age, from 4% in the general population, reaching 7% in patients over 70 years of age. CONCLUSION: Adrenal incidentalomas represent a diagnostic challenge. Because of the malignant potential of large (> 4 cm) adrenal masses and the lack of characteristic findings using conventional imaging techniques and laboratory diagnostic tools, surgical excision with histopathology and immunohistochemistry analysis are required for definitive diagnosis and optimal management.

Renal dysplasia/hypoplasia, Williams Syndrome phenotype and non-Hodgkin lymphoma in the same patient: only a coincidence?

Congenital renal anomalies, Williams Syndrome and non-Hodgkin lymphoma all occur separately at low incidence, so their simultaneous presence in the same patient is exceptional. We present a young patient manifesting all three conditions. This child is a boy with a Williams Syndrome phenotype who was diagnosed with severe chronic kidney disease secondary to bilateral renal dysplasia/hypoplasia. Due to his small size, he received treatment with growth hormone. He progressed to end stage kidney disease and, after 8 months, a renal transplant was performed. A number of suspicious abdominal adenopathies were removed during the surgery and, thereafter, immunosupressive treatment with prednisone, azathioprine and cyclosporine was initiated. Examination of the biopsy tissue confirmed the presence of a T-cell lymphoblastic lymphoma. Appropriate chemotherapy was given, and the immunosupressive regimen was eventually reduced to prednisone alone. Now, 8 years since the initial diagnosis of T-cell lymphoblastic lymphoma and 6 years after the completion of the chemotherapy, the patient is still in complete remission with a functional donor kidney. We discuss some possible explanations of this association. Chemotherapy has not appeared to have affected the viability of the grafted kidney and, in fact, it may even have induced immunotolerance.

[Nutritional value of dairy products and recommended daily consumption]. / Valor nutricional de los lácteos y consumo diario aconsejado.

INTRODUCTION: Objective: messages that are given recently have encouraged to reduce the consumption of dairy products, by noting them as dispensable or even harmful in relation to certain pathologies. The objective of this present work is to review the nutritional value of this group of foods and their recommended consumption. Methods: bibliographic search related to the topic. Results: dairy products provide proteins of high biological value, vitamins and minerals, especially calcium and vitamins B2 and B12, as well as essential fatty acids, and some antioxidants, among other nutrients. Although its fat is mostly saturated (65%), it does not seem to adversely affect cardiovascular risk and may even have a slight protective effect. More than 75% of individuals have calcium intakes lower than recommended, and since more than 50% of the calcium in the diet comes from dairy products, increasing their consumption may be recommended. Moderate milk intake during pregnancy is positively associated with birth weight and length of the offspring and bone mineral content during childhood. In adults, dairy consumption it is associated with a lower risk of metabolic syndrome, coronary heart disease and myocardial infarction, colorectal and gallbladder cancer, and type 2 diabetes. Moreover in older people it is associated with a lower risk of sarcopenia and vertebral fractures. Conclusions: the population ignores what is the nutritional value of dairy products and their advisable consumption (2-4 servings / day). The latest studies support the need to have an adequate consumption in all stages of life due to its relationship with the prevention and control of chronic diseases. Dairy consumption is less than 2 servings / day in 37.1% of children and 42.3% of adults, so it would be desirable to improve this situation.

INTRODUCCIÓN: Objetivos: mensajes recientes han animado a disminuir el consumo de lácteos al señalarlos como prescindibles o incluso perjudiciales en relación a ciertas patologías. El objetivo del presente trabajo consiste en revisar el valor nutricional de este grupo de alimentos y su consumo aconsejado. Métodos: búsqueda bibliográfica relacionada con el tema. Resultados: los lácteos aportan proteínas de alto valor biológico, vitaminas y minerales, especialmente calcio y vitaminas B2 y B12, así como ácidos grasos esenciales y algunos antioxidantes, entre otros nutrientes. Aunque su grasa es mayoritariamente saturada (65%), parece no afectar adversamente al riesgo cardiovascular y puede tener incluso un ligero efecto protector. Más de un 75% de los individuos tiene ingestas de calcio inferiores a las recomendadas, y dado que más del 50% del calcio de la dieta proviene de lácteos, aumentar su consumo puede ser recomendable. La ingesta moderada de leche durante el embarazo se asocia positivamente con el peso al nacer del descendiente y con su longitud y contenido mineral óseo durante la infancia. En adultos el consumo de lácteos se asocia con menor riesgo de síndrome metabólico, enfermedad coronaria e infarto de miocardio, cáncer colorrectal y de vesícula y diabetes tipo 2; en personas mayores, se asocia a un menor riesgo de fragilidad, sarcopenia y fracturas vertebrales. Conclusiones: la población desconoce cuál es el valor nutricional de los lácteos y su consumo aconsejable (2-4 raciones/día). Los últimos estudios avalan la necesidad de tener un consumo adecuado en todas las etapas de la vida por su relación con la prevención y el control de enfermedades crónicas. El consumo de lácteos es menor de 2 raciones/día en el 37,1% de los niños y en el 42,3% de los adultos, por lo que conviene mejorar esta situación.

Lung tumorspheres reveal cancer stem cell-like properties and a score with prognostic impact in resected non-small-cell lung cancer.

The high resistance against current therapies found in non-small-cell lung cancer (NSCLC) has been associated to cancer stem-like cells (CSCs), a population for which the identification of targets and biomarkers is still under development. In this study, primary cultures from early-stage NSCLC patients were established, using sphere-forming assays for CSC enrichment and adherent conditions for the control counterparts. Patient-derived tumorspheres showed self-renewal and unlimited exponential growth potentials, resistance against chemotherapeutic agents, invasion and differentiation capacities in vitro, and superior tumorigenic potential in vivo. Using quantitative PCR, gene expression profiles were analyzed and NANOG, NOTCH3, CD44, CDKN1A, SNAI1, and ITGA6 were selected to distinguish tumorspheres from adherent cells. Immunoblot and immunofluorescence analyses confirmed that proteins encoded by these genes were consistently increased in tumorspheres from adenocarcinoma patients and showed differential localization and expression patterns. The prognostic role of genes significantly overexpressed in tumorspheres was evaluated in a NSCLC cohort (N = 661) from The Cancer Genome Atlas. Based on a Cox regression analysis, CDKN1A, SNAI1, and ITGA6 were found to be associated with prognosis and used to calculate a gene expression score, named CSC score. Kaplan-Meier survival analysis showed that patients with high CSC score have shorter overall survival (OS) in the entire cohort [37.7 vs. 60.4 months (mo), p = 0.001] and the adenocarcinoma subcohort [36.6 vs. 53.5 mo, p = 0.003], but not in the squamous cell carcinoma one. Multivariate analysis indicated that this gene expression score is an independent biomarker of prognosis for OS in both the entire cohort [hazard ratio (HR): 1.498; 95% confidence interval (CI), 1.167-1.922; p = 0.001] and the adenocarcinoma subcohort [HR: 1.869; 95% CI, 1.275-2.738; p = 0.001]. This score was also analyzed in an independent cohort of 114 adenocarcinoma patients, confirming its prognostic value [42.90 vs. not reached (NR) mo, p = 0.020]. In conclusion, our findings provide relevant prognostic information for lung adenocarcinoma patients and the basis for developing novel therapies. Further studies are required to identify suitable markers and targets for lung squamous cell carcinoma patients.

[Sociodemographic and lifestyle factors involved in excess weight]. / Factores sociodemográficos y de estilo de vida implicados en el exceso de peso.

OBJECTIVES: given the growing increase in overweight and obesity, it is important to pay attention to all sociodemographic and lifestyle influences that contribute to unbalance the energy balance, favoring this trend. METHODS: bibliographic searching in relation to the subject. RESULTS: as factors associated with the obesity condition, it is observed that sedentary lifestyle, scarce physical activity, passive leisure and a high number of hours in front of screens (TV, computer...) and reduction in the time spent sleeping. Moreover, low level of income and low educational level, favor excess weight, there being an additional association between these sociodemographic factors with non-compliance with the Dietary Guidelines and the gap of the diet from to what is marked as advisable. Particularly, spent a lot of time in front of a screen and a short duration of sleep are associated with more frequent consumption of foods with high energy density and few micronutrients and low consumption of fruits and vegetables. Specifically, in men and adjusting for age, it is observed that an insufficient intake of cereals (< 4 servings / day) and fruits and vegetables (< 5 servings / day) is associated with greater risk of overweight and of central adiposity, being remarkable the worst adherence to recommended dietary guidelines in individuals with excess weight and central adiposity. CONCLUSIONS: strategies to prevent and reduce excess weight should consider these influences, which are associated and potentiated, in order to achieve more efficiency in the weight improvement of the population.

OBJETIVOS: ante el aumento creciente del sobrepeso y de la obesidad es importante prestar atención a todas las influencias sociodemográficasy de estilo de vida que contribuyen a desequilibrar el balance energético y que favorecen esta tendencia. MÉTODOS: búsqueda bibliográfica relacionada con el tema. RESULTADOS: como factores asociados al padecimiento de obesidad, se constata el creciente sedentarismo, la escasa actividad física, el ocio pasivo, el elevado número de horas delante de pantallas (televisión, ordenador…) y la reducción del tiempo dedicado a dormir. Por otra parte, el bajo nivel de ingresos y el bajo nivel educativo favorecen el exceso de peso, y existe una asociación adicional entre estos factores sociodemográficos y el incumplimiento de las guías de alimentación con el alejamiento de la dieta respecto a lo marcado como aconsejable. En concreto, un elevado tiempo ante una pantalla y una corta duración del sueño se asocian con una mayor frecuencia del consumo de alimentos con alta densidad energética y pobres en micronutrientes y con bajo consumo de frutas y vegetales. En este sentido, en varones y ajustando por edad, se observa que un consumo insuficiente de cereales (< 4 raciones/día) y de frutas y verduras (< 5 raciones/día) se asocia con mayor riesgo de sobrepeso y de adiposidad central. Destaca la peor adherencia a las pautas dietéticas aconsejadas en individuos con exceso de peso y adiposidad central. CONCLUSIONES: las estrategias para prevenir y reducir el exceso de peso deben tener en cuenta estas influencias, que se asocian y potencian, para lograr más eficacia en la mejora ponderal de la población.

[Nutrition and fertility]. / Nutrición y fertilidad.

INTRODUCTION: in recent decades, there has been an increase in the prevalence of infertility in the population. Numerous studies confirm that the nutritional status plays a key role in fertility. OBJECTIVE: analyze the nutritional factors that may influence the fertility in men and women. MATERIAL AND METHODS: a review was performed on the nutritional factors that may influence male and female fertility. RESULTS: there are several factors associated with infertility such as advanced age, the presence of structural alterations in the reproductive system and diseases, environmental pollution and lifestyle. In relation to the diet, it is emphasized that the high intake of saturated fats, trans fatty acids, proteins of animal origin, could have a detrimental effect on fertility, whilst the intake of complex carbohydrates, fibre, monounsaturated fats and omega-3 fatty acids could have a benefit effect. Also, it is essential provide an adequate intake of folic acid, B12, vitamin A, D, C y E, calcium, iron, zinc, selenium and iodine to prevent impairments in fertility. CONCLUSION: the prevention and treatment of fertility impairment in women and men should consider the nutritional approach given its importance in the reproduction.

INTRODUCCIÓN: en las últimas décadas se ha observado un incremento en la prevalencia de infertilidad en la población. Numerosos estudios constatan que la situación nutricional juega un papel clave en la fertilidad. OBJETIVO: analizar los factores nutricionales que pueden influir en la fertilidad en la mujer y en el hombre. MATERIAL Y MÉTODOS: se ha realizado una revisión sobre los factores nutricionales que tienen mayor influencia en la fertilidad masculina y en la femenina. RESULTADOS: existen diversos factores asociados con la infertilidad, tales como la edad avanzada, la presencia de alteraciones estructurales en el aparato reproductor y enfermedades como la obesidad, la contaminación ambiental y el estilo de vida. En relación con la alimentación, se destaca que la ingesta en exceso de grasas saturadas, ácidos grasos trans y proteínas de origen animal podría tener un efecto perjudicial en la fertilidad, mientras que la ingesta de hidratos de carbono complejos, fibra, grasas monoinsaturadas y ácidos grasos omega-3 podría tener un efecto beneficioso. Asimismo, es indispensable tener un aporte adecuado de ácido fólico, B12, vitaminas A, D, C y E, calcio, hierro, zinc, selenio y yodo para evitar problemas en la fertilidad. CONCLUSIÓN: la prevención y el tratamiento de las alteraciones de la fertilidad en la mujer y en el hombre deben contemplar el abordaje nutricional, dada su importancia en la reproducción.