Differential contribution for ERK1 and ERK2 kinases in BRAFV600E-triggered phenotypes in adult mouse models.

The BRAF gene is mutated in a plethora of human cancers. The majority of such molecular lesions result in the expression of a constitutively active BRAF variant (BRAFV600E) which continuously bolsters cell proliferation. Although we recently addressed the early effects triggered by BRAFV600E-activation, the specific contribution of ERK1 and ERK2 in BRAFV600E-driven responses in vivo has never been explored. Here we describe the first murine model suitable for genetically dissecting the ERK1/ERK2 impact in multiple phenotypes induced by ubiquitous BRAFV600E-expression. We unveil that ERK1 is dispensable for BRAFV600E-dependent lifespan shortening and for BRAFV600E-driven tumor growth. We show that BRAFV600E-expression provokes an ERK1-independent lymphocyte depletion which does not rely on p21CIP1-induced cell cycle arrest and is unresponsive to ERK-chemical inhibition. Moreover, we also reveal that ERK1 is dispensable for BRAFV600E-triggered cytotoxicity in lungs and that ERK-chemical inhibition abrogates some of these detrimental effects, such as DNA damage, in Club cells but not in pulmonary lymphocytes. Our data suggest that ERK1/ERK2 contribution to BRAFV600E-driven phenotypes is dynamic and varies dependently on cell type, the biological function, and the level of ERK-pathway activation. Our findings also provide useful insights into the comprehension of BRAFV600E-driven malignancies pathophysiology as well as the consequences in vivo of novel ERK pathway-targeted anti-cancer therapies.

Factors associated with high and low mental well-being in Spanish university students.

BACKGROUND: Previous studies conducted in various nationally representative samples of the general population show that positive mental health is related to social prosperity. However, specific studies in university populations are scarce. In this study, we set out to explore factors associated with mental well-being (MWB) in a representative sample of first-year university students in Spain. METHODS: MWB was assessed with the short version of the Warwick-Edinburgh Mental Well-Being Scale. Multinomial logistic regressions were performed to explore the association between different blocks of factors, including relational, adversity, stress, lifestyle, spiritual, health, and self-perceived health variables with high and low MWB, controlling for sociodemographic and university-related variables. RESULTS: Data from 2082 students (18.6 ± 1.2 years; 56.6 % females) were analysed. Being male, being born in a foreign country, "high" self-perceived support, and "high" self-perceived mental health increased the odds of high MWB. Growing up in the suburbs, stressful experiences, and anxiety disorders reduced the odds of high MWB. Mood and anxiety disorders increased the odds of low MWB. "Middle" self-perceived support, sleeping ≥8 h per day, and "high" self-perceived mental health reduced the odds of low MWB. LIMITATIONS: The cross-sectional design precludes establishing causal relationships. Data were collected in the 2014-15 academic year using self-reported online surveys. CONCLUSION: The factors associated with high and low MWB do not always mirror each other, so specific plans are needed to successfully address each of the two poles. Interventions and policies targeting these factors for health promotion and disease prevention would improve the MWB of university students.

Mindfulness-based cognitive therapy neurobiology in treatment-resistant obsessive-compulsive disorder: A domain-related resting-state networks approach.

Mindfulness-based cognitive therapy (MBCT) stands out as a promising augmentation psychological therapy for patients with obsessive-compulsive disorder (OCD). To identify potential predictive and response biomarkers, this study examines the relationship between clinical domains and resting-state network connectivity in OCD patients undergoing a 3-month MBCT programme. Twelve OCD patients underwent two resting-state functional magnetic resonance imaging sessions at baseline and after the MBCT programme. We assessed four clinical domains: positive affect, negative affect, anxiety sensitivity, and rumination. Independent component analysis characterised resting-state networks (RSNs), and multiple regression analyses evaluated brain-clinical associations. At baseline, distinct network connectivity patterns were found for each clinical domain: parietal-subcortical, lateral prefrontal, medial prefrontal, and frontal-occipital. Predictive and response biomarkers revealed significant brain-clinical associations within two main RSNs: the ventral default mode network (vDMN) and the frontostriatal network (FSN). Key brain nodes -the precuneus and the frontopolar cortex- were identified within these networks. MBCT may modulate vDMN and FSN connectivity in OCD patients, possibly reducing symptoms across clinical domains. Each clinical domain had a unique baseline brain connectivity pattern, suggesting potential symptom-based biomarkers. Using these RSNs as predictors could enable personalised treatments and the identification of patients who would benefit most from MBCT.

Protocol for the generation and purification of high-molecular-weight covalent RNA-DNA hybrids with T4 RNA ligase.

RNA-DNA covalent hybrids (RDHs) are widely employed in biology. Although RDHs can be manufactured, the synthesis of molecules longer than 120 nucleotides is challenging. Here, we present a protocol for the generation and purification of high-grade purified high-molecular-weight 5'-RNA-DNA-3' hybrids. We describe steps for preparing oligos and buffers, ligation reaction, and high-performance liquid chromatography-based RDH purification. This protocol is executable in standard molecular biology laboratories.

Impact of Stress on Brain Morphology: Insights into Structural Biomarkers of Stress-related Disorders.

Exposure to acute and chronic stress has a broad range of structural effects on the brain. The brain areas commonly targeted in the stress response models include the hippocampus, the amygdala, and the prefrontal cortex. Studies in patients suffering from the so-called stress-related disorders -embracing post-traumatic stress, major depressive and anxiety disorders- have fairly replicated animal models of stress response -particularly the neuroendocrine and the inflammatory models- by finding alterations in different brain areas, even in the early neurodevelopment. Therefore, this narrative review aims to provide an overview of structural neuroimaging findings and to discuss how these studies have contributed to our knowledge of variability in response to stress and the ulterior development of stress-related disorders. There are a gross number of studies available but neuroimaging research of stress-related disorders as a single category is still in its infancy. Although the available studies point at particular brain circuitries involved in stress and emotion regulation, the pathophysiology of these abnormalities -involving genetics, epigenetics and molecular pathways-, their relation to intraindividual stress responses -including personality characteristics, self-perception of stress conditions…-, and their potential involvement as biomarkers in diagnosis, treatment prescription and prognosis are discussed.

The social and health consequences of the war for Ukrainian children and adolescents: a rapid systematic review.

OBJECTIVES: Despite the growing interest on the Russian-Ukrainian war and its repercussion on the children's health, there is no previous systematic review compiling the current evidence on this topic. This study conducted a rapid systematic review to investigate the current findings concerning the impact of the Ukraine war on the social and health aspects of the Ukrainian pediatric population. METHODS: A rapid systematic review was conducted. PubMed, Scopus, CINAHL, PsycINFO, Web of Science, and Virtual Health Library (BVS Spain) were searched between February and April 2023. In addition, high-impact journals and institutions focused on pediatric health and human rights were also consulted. All relevant original articles, letters, editorials, and policy papers assessing the health and social repercussions of the war on Ukrainian children were included. RESULTS: From 134 publications matching the search criteria, 23 were included. These publications were categorized into three distinct domains: 'Public health challenges for the physical and mental health of children and adolescents', 'Lack of Healthcare resources and initiatives to mitigate suffering', and 'Policies, Government, and Children's rights'. Our findings revealed that the war is seriously impacting the life and the health of Ukrainian children, resulting in worse physical and mental health outcomes and perpetrating a deprived situation. To overcome such problems, several initiatives have been proposed by European and non-European countries, relying mostly on receiving refugees, providing mental health support, complementing lack of resources, and establishing policies to improve health care. CONCLUSION: It could help health professionals, policy makers, and governments to plan preventive, promotive, and therapeutic strategies for Ukrainian children.

MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis.

MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER+) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility and functional assays from human and syngeneic mouse BCa models to show that MAF directly interacts with oestrogen receptor alpha (ERα), thereby promoting a unique chromatin landscape that favours metastatic spread. We identify metastasis-promoting genes that are de novo licensed following oestrogen exposure in a MAF-dependent manner. The histone demethylase KDM1A is key to the epigenomic remodelling that facilitates the expression of the pro-metastatic MAF/oestrogen-driven gene expression program, and loss of KDM1A activity prevents this metastasis. We have thus determined that the molecular basis underlying MAF/oestrogen-mediated metastasis requires genetic, epigenetic and hormone signals from the systemic environment, which influence the ability of BCa cells to metastasize.

Restoring a balanced pool of host-derived and microbiota-derived ligands of the aryl hydrocarbon receptor is beneficial after stroke.

Background: Stroke is a major cause of morbidity and mortality, and its incidence increases with age. While acute therapies for stroke are currently limited to intravenous thrombolytics and endovascular thrombectomy, recent studies have implicated an important role for the gut microbiome in post-stroke neuroinflammation. After stroke, several immuno-regulatory pathways, including the aryl hydrocarbon receptor (AHR) pathway, become activated. AHR is a master regulatory pathway that mediates neuroinflammation. Among various cell types, microglia (MG), as the resident immune cells of the brain, play a vital role in regulating post-stroke neuroinflammation and antigen presentation. Activation of AHR is dependent on a dynamic balance between host-derived and microbiota-derived ligands. While previous studies have shown that activation of MG AHR by host-derived ligands, such as kynurenine, is detrimental after stroke, the effects of post-stroke changes in microbiota-derived ligands of AHR, such as indoles, is unknown. Our study builds on the concept that differential activation of MG AHR by host-derived versus microbiome-derived metabolites affects outcomes after ischemic stroke. We examined the link between stroke-induced dysbiosis and loss of essential microbiota-derived AHR ligands. We hypothesize that restoring the balance between host-derived (kynurenine) and microbiota-derived (indoles) ligands of AHR is beneficial after stroke, offering a new potential avenue for therapeutic intervention in post-stroke neuroinflammation. Method: We performed immunohistochemical analysis of brain samples from stroke patients to assess MG AHR expression after stroke. We used metabolomics analysis of plasma samples from stroke and non-stroke control patients with matched comorbidities to determine the levels of indole-based AHR ligands after stroke. We performed transient middle cerebral artery occlusion (MCAO) in aged (18 months) wild-type (WT) and germ-free (GF) mice to investigate the effects of post-stroke treatment with microbiota-derived indoles on outcome. To generate our results, we employed a range of methodologies, including flow cytometry, metabolomics, and 16S microbiome sequencing. Results: We found that MG AHR expression is increased in human brain after stroke and after ex vivo oxygen-glucose deprivation and reperfusion (OGD/R). Microbiota-derived ligands of AHR are decreased in the human plasma at 24 hours after ischemic stroke. Kynurenine and indoles exhibited differential effects on aged WT MG survival after ex vivoOGD/R. We found that specific indole-based ligands of AHR (indole-3-propionic acid and indole-3-aldehyde) were absent in GF mice, thus their production depends on the presence of a functional gut microbiota. Additionally, a time-dependent decrease in the concentration of these indole-based AHR ligands occurred in the brain within the first 24 hours after stroke in aged WT mice. Post-stroke treatment of GF mice with a cocktail of microbiota-derived indole-based ligands of AHR regulated MG-mediated neuroinflammation and molecules involved in antigen presentation (increased CD80, MHC-II, and CD11b). Post-stroke treatment of aged WT mice with microbiota-derived indole-based ligands of AHR reduced both infarct volume and neurological deficits at 24 hours. Conclusion: Our novel findings provide compelling evidence that the restoration of a well-balanced pool of host-derived kynurenine-based and microbiota-derived indole-based ligands of AHR holds considerable therapeutic potential for the treatment of ischemic stroke.

If you feel you can't, you won't: the role of subjective and objective cognitive competence on psychosocial functioning in depression.

BACKGROUND: The purpose of this exploratory study is to examine the role of sociodemographic, clinical, and cognitive - both objective and subjective - factors in overall and in specific domains of psychosocial functioning, in patients with depression at different clinical states of the disease (remitted and non-remitted). METHODS: A sample of 325 patients with major depressive disorder, 117 in remission and 208 in non-remission, were assessed with a semi-structured interview collecting sociodemographic, clinical, cognitive (with neuropsychological tests and the Perceived Deficit Questionnaire), and functional (Functioning Assessment Short Test) characteristics. Backward regression models were conducted to determine associations of global and specific areas of functioning with independent factors, for both clinical states. RESULTS: Residual depressive symptomatology and self-appraisal of executive competence were significantly associated with psychosocial functioning in remitted patients, in overall and some subdomains of functioning, particularly cognitive and interpersonal areas. While depressive symptoms, executive deficits and self-appraisal of executive function were significantly related to functional outcomes in non-remitted patients, both in overall functioning and in most of subdomains. DISCUSSION: This study evidences the strong association of one's appraisal of executive competence with psychosocial functioning, together with depressive symptoms, both in remitted and non-remitted patients with depression. Therefore, to achieve full recovery, clinical management of patients should tackle not only the relief of core depressive symptoms, but also the cognitive ones, both those that are objectified with neuropsychological tests and those that are reported by the patients themselves.

Telomerase RNA-based aptamers restore defective myelopoiesis in congenital neutropenic syndromes.

Telomerase RNA (TERC) has a noncanonical function in myelopoiesis binding to a consensus DNA binding sequence and attracting RNA polymerase II (RNA Pol II), thus facilitating myeloid gene expression. The CR4/CR5 domain of TERC is known to play this role, since a mutation of this domain found in dyskeratosis congenita (DC) patients decreases its affinity for RNA Pol II, impairing its myelopoietic activity as a result. In this study, we report that two aptamers, short single-stranded oligonucleotides, based on the CR4/CR5 domain were able to increase myelopoiesis without affecting erythropoiesis in zebrafish. Mechanistically, the aptamers functioned as full terc; that is, they increased the expression of master myeloid genes, independently of endogenous terc, by interacting with RNA Pol II and with the terc-binding sequences of the regulatory regions of such genes, enforcing their transcription. Importantly, aptamers harboring the CR4/CR5 mutation that was found in DC patients failed to perform all these functions. The therapeutic potential of the aptamers for treating neutropenia was demonstrated in several preclinical models. The findings of this study have identified two potential therapeutic agents for DC and other neutropenic patients.

Outcomes and factors associated with mortality in patients with atrial fibrillation and heart failure: FARAONIC study.

BACKGROUND: Heart failure (HF) and atrial fibrillation (AF) are common and coexistent conditions. HYPOTHESIS: To investigate the adverse events and mortality risk factors in patients with AF and HF treated with rivaroxaban in Spain. METHODS: Multicenter, prospective and observational study with a follow-up of 2 years, that included adults, with a diagnosis of nonvalvular AF and chronic HF, anticoagulated with rivaroxaban at least 4 months before being enrolled. RESULTS: A total of 672 patients from 71 Spanish centers were recruited, of whom 658 (97.9%) were included in the safety analysis and 552 (82.1%) in the per protocol analysis. At baseline, the mean age was 73.7 ± 10.9 years, 65.9% were male, 51.3% had HF with preserved ejection fraction and 58.7% were on New York Heart Association functional class II. CHA2 DS2 -VASc was 4.1 ± 1.5. During the follow-up, 11.6% of patients died and around one-quarter of patients were hospitalized or visited the emergency department, being HF worsening/progression the main cause (51.1%), with a 2.9% of thromboembolic events and 2.0% of acute coronary syndromes. Major bleeding occurred in 3.1% of patients, with 0.5% experiencing intracranial bleeding but no fatalities. Compliance with HF treatment was associated with a lower risk of death (hazard ratio: 0.092; 95% confidence interval: 0.03-0.31). CONCLUSIONS: Among patients with HF and AF anticoagulated with rivaroxaban, incidences of thromboembolic or hemorrhagic complications were low. The most important factor for improving survival was compliance with HF drugs, what strengths the need for early treatment with HF disease-modifying therapy and anticoagulation.

Telomerase Upregulation Induces Progression of Mouse BrafV600E-Driven Thyroid Cancers and Triggers Nontelomeric Effects.

Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the paradigm of a cross-cancer alteration in a noncoding region. TERT promoter mutations (TPM) are biomarkers of poor prognosis in cancer, including thyroid tumors. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, thus reactivating a bona fide oncoprotein. To study TERT deregulation and its downstream consequences, we generated a Tert mutant promoter mouse model via CRISPR/Cas9 engineering of the murine equivalent locus (Tert-123C>T) and crossed it with thyroid-specific BrafV600E-mutant mice. We also employed an alternative model of Tert overexpression (K5-Tert). Whereas all BrafV600E animals developed well-differentiated papillary thyroid tumors, 29% and 36% of BrafV600E+Tert-123C>T and BrafV600E+K5-Tert mice progressed to poorly differentiated cancers at week 20, respectively. Tert-upregulated tumors showed increased mitosis and necrosis in areas of solid growth, and older animals displayed anaplastic-like features, that is, spindle cells and macrophage infiltration. Murine TPM increased Tert transcription in vitro and in vivo, but temporal and intratumoral heterogeneity was observed. RNA-sequencing of thyroid tumor cells showed that processes other than the canonical Tert-mediated telomere maintenance role operate in these specimens. Pathway analysis showed that MAPK and PI3K/AKT signaling, as well as processes not previously associated with this tumor etiology, involving cytokine, and chemokine signaling, were overactivated. These models constitute useful preclinical tools to understand the cell-autonomous and microenvironment-related consequences of Tert-mediated progression in advanced thyroid cancers and other aggressive tumors carrying TPMs. IMPLICATIONS: Telomerase-driven cancer progression activates pathways that can be dissected and perhaps therapeutically exploited.

Experience sampling methods for the personalised prediction of mental health problems in Spanish university students: protocol for a survey-based observational study within the PROMES-U project.

INTRODUCTION: There is a high prevalence of mental health problems among university students. Better prediction and treatment access for this population is needed. In recent years, short-term dynamic factors, which can be assessed using experience sampling methods (ESM), have presented promising results for predicting mental health problems. METHODS AND ANALYSIS: Undergraduate students from five public universities in Spain are recruited to participate in two web-based surveys (at baseline and at 12-month follow-up). A subgroup of baseline participants is recruited through quota sampling to participate in a 15-day ESM study. The baseline survey collects information regarding distal risk factors, while the ESM study collects short-term dynamic factors such as affect, company or environment. Risk factors will be identified at an individual and population level using logistic regressions and population attributable risk proportions, respectively. Machine learning techniques will be used to develop predictive models for mental health problems. Dynamic structural equation modelling and multilevel mixed-effects models will be considered to develop a series of explanatory models for the occurrence of mental health problems. ETHICS AND DISSEMINATION: The project complies with national and international regulations, including the Declaration of Helsinki and the Code of Ethics, and has been approved by the IRB Parc de Salut Mar (2020/9198/I) and corresponding IRBs of all participating universities. All respondents are given information regarding access mental health services within their university and region. Individuals with positive responses on suicide items receive a specific alert with indications for consulting with a health professional. Participants are asked to provide informed consent separately for the web-based surveys and for the ESM study. Dissemination of results will include peer-reviewed scientific articles and participation in scientific congresses, reports with recommendations for universities' mental health policy makers, as well as a well-balanced communication strategy to the general public. STUDY REGISTRATION: osf.io/p7csq.

Hopelessness in Patients with Early-Stage Relapsing-Remitting Multiple Sclerosis.

Background: Hopelessness is a risk factor for depression and suicide. There is little information on this phenomenon among patients with relapsing-remitting multiple sclerosis (RRMS), one of the most common causes of disability and loss of autonomy in young adults. The aim of this study was to assess state hopelessness and its associated factors in early-stage RRMS. Methods: A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS, a disease duration ≤ 3 years, and an Expanded Disability Status Scale (EDSS) score of 0-5.5 were included. The State-Trait Hopelessness Scale (STHS) was used to measure patients´ hopelessness. A battery of patient-reported and clinician-rated measurements was used to assess clinical status. A multivariate logistic regression analysis was conducted to determine the association between patients' characteristics and state hopelessness. Results: A total of 189 patients were included. Mean age (standard deviation-SD) was 36.1 (9.4) years and 71.4% were female. Median disease duration (interquartile range-IQR) was 1.4 (0.7, 2.1) years. Symptom severity and disability were low with a median EDSS (IQR) score of 1.0 (0, 2.0). A proportion of 65.6% (n=124) of patients reported moderate-to-severe hopelessness. Hopelessness was associated with older age (p=0.035), depressive symptoms (p=<0.001), a threatening illness perception (p=0.001), and psychological and cognitive barriers to workplace performance (p=0.029) in the multivariate analysis after adjustment for confounders. Conclusion: Hopelessness was a common phenomenon in early-stage RRMS, even in a population with low physical disability. Identifying factors associated with hopelessness may be critical for implementing preventive strategies helping patients to adapt to the new situation and cope with the disease in the long term.

Short telomeres in alveolar type II cells associate with lung fibrosis in post COVID-19 patients with cancer.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic. The severity of COVID-19 increases with each decade of life, a phenomenon that suggest that organismal aging contributes to the fatality of the disease. In this regard, we and others have previously shown that COVID-19 severity correlates with shorter telomeres, a molecular determinant of aging, in patient's leukocytes. Lung injury is a predominant feature of acute SARS-CoV-2 infection that can further progress to lung fibrosis in post-COVID-19 patients. Short or dysfunctional telomeres in Alveolar type II (ATII) cells are sufficient to induce pulmonary fibrosis in mouse and humans. Here, we analyze telomere length and the histopathology of lung biopsies from a cohort of alive post-COVID-19 patients and a cohort of age-matched controls with lung cancer. We found loss of ATII cellularity and shorter telomeres in ATII cells concomitant with a marked increase in fibrotic lung parenchyma remodeling in post- COVID-19 patients compared to controls. These findings reveal a link between presence of short telomeres in ATII cells and long-term lung fibrosis sequel in Post-COVID-19 patients.

An eHealth ecosystem for stepped and early psychosocial care in advanced lung cancer: Rationale and protocol for a randomized control trial.

Background: Receiving a diagnosis of lung cancer is an emotional event, not least because it is usually diagnosed at advanced stages with limited life expectancy. Although evidence-based educational, emotional, and social interventions exist, they reach few patients and usually when it is too late. Objective: This project will be carried out in a comprehensive center for cancer care and health research, aiming to study the efficacy, costs, and utility of an eHealth ecosystem to meet the psychosocial needs of patients with advanced lung cancer. Method: We will enroll 76 patients with advanced lung cancer into an eHealth ecosystem of stepped and personalized psychosocial care for 9 months. These patients will be compared with another 76 receiving usual care in a non-inferiority randomized controlled trial. The following main outcomes will be measured every 3 months: emotional distress, spirituality, demoralization, quality of life, and medication adherence. Secondary outcomes will include symptomatology, health education, cost-utility analyses, usability and satisfaction with the platform, and time to detect emotional needs and provide care. Baseline differences between groups will be measured with the Student t-test or chi-square test, as appropriate. We will then compare the main outcomes between groups over time using multilevel linear models, report effect sizes (Hedges' g), and assess non-inferiority. The cost-utility of both interventions will be considered in terms of quality adjusted life years and quality of life given the costs of providing each treatment. Discussion: This randomized controlled trial should provide new evidence on the efficacy and cost-utility of an eHealth ecosystem to deliver personalized and timely psychosocial care to patients with advanced lung cancer. Trial registration: ClinicalTrials.gov ID "NCT05497973".

Calcifilaxis en una paciente en hemodiálisis: complicación grave con elevada mortalidad / Calciphylaxis in a hemodialysis patient: a serious complication with high mortality

Descripción del caso: Paciente con enfermedad renal crónica terminal en tratamiento de hemodiálisis desde hace 1 año. Acude a sesión de hemodiálisis refiriendo lesiones cutáneas muy dolorosas con aspecto necrótico de 2 semanas de evolu-ción en extremidades inferiores distales sugestivas de calcifi-laxis. Dados los antecedentes clínicos de fibrilación auricular paroxística, anticoagulada con acenocumarol y los factores de riesgo que presenta, se inician medidas inmediatas dado el mal pronóstico de dicha enfermedad. Descripción/evaluación del plan de cuidados: Se suspende tratamiento con acenocumarol iniciando anticoagulación con heparina de bajo peso molecular, también se suspenden los suplementos de vitamina D. Se inicia administración de bifos-fonatos como inhibidores del calcio, de tiosulfato de sodio como vasodilatador y quelante del fósforo. Se instaura pauta de analgesia siendo uno de los objetivos más importantes del plan de cuidados, el control del dolor, con la administración de opiáceos, antiinflamatorios no esteroideos o mórficos. Aunque fue de difícil manejo, el papel de enfermería ha sido fundamental para procurar el máximo confort. También fue muy importante la vigilancia y el cuidado de las lesiones para prevenir infecciones y controlar la enfermedad observándose una adversa y rápida evolución a pesar de las terapias coad-yuvantes, puesto que cuando se diagnosticó ya presentaba lesiones necróticas. Conclusiones: La calcifilaxis es una complicación poco fre-cuente pero grave que suele observarse en pacientes con enfermedad renal crónica, sobre todo en hemodiálisis. Eltratamiento es multidisciplinar y es importante identificar precozmente a estos pacientes. Desgraciadamente, como en nuestro caso, los resultados no son siempre favorables.(AU)

Case description: Patient with end-stage renal disease undergoing hemodialysis treatment for 1 year. The patient presents to the hemodialysis session with extremely painful necrotic-looking skin lesions on the distal lower extremities, suggestive of calciphylaxis, which have been present for 2 weeks. Given the patient’s medical history of paroxysmal atrial fibrillation and anticoagulation with acenocoumarol, along with the risk factors present, immediate measures are initiated due to the poor prognosis of this condition. Description/evaluation of the care plan: Acenocoumarol treatment is discontinued, and anticoagulation with low molecular weight heparin is initiated. Vitamin D supplements are also discontinued. Bisphosphonates are started as calcium inhibitors, sodium thiosulfate is administered as a vasodilator, and phosphate binder. An analgesic regimen is established, with pain control being one of the most important goals of he care plan. This includes the administration of opioids, nonsteroidal anti-inflammatory drugs, or morphine. Although challenging, the nursing role has been crucial in providing maximum comfort. Close monitoring and wound care are also important to prevent infections and control the disease, although an adverse and rapid progression was observed despite the adjunctive therapies, as necrotic lesions were already present at the time of diagnosis. Conclusions: Calciphylaxis is a rare but serious complication often observed in patients with chronic kidney disease, especially in those undergoing hemodialysis. Treatment is multidisciplinary, and early identification of these patients is important. Unfortunately, as in our case, the outcomes are not always favorable.(AU)

Telomerase deficiency and dysfunctional telomeres in the lung tumor microenvironment impair tumor progression in NSCLC mouse models and patient-derived xenografts.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer death. Tumor progression depends on interactions of cancer cells with the tumor microenvironment. Here, we find increased copy number and mRNA expression of the catalytic subunit of telomerase, TERT, in tumors from NSCLC patients, contributing to a lower survival. Moreover, TERT expression in NSCLC patients from the TCGA cohort is mainly associated to the reduced infiltration of CD8+ T lymphocytes, as well as to increased infiltration of myeloid-derived suppressor cells (MDSCs). We also show that TERT deficiency and dysfunctional telomeres induced by 6-thio-dG treatment in mice reduced lung tumor implantation and vascularization, increased DNA damage response, cell cycle arrest and apoptosis, as well as reduced proliferation, inflammation, lung tumor immunosupression and invasion upon induction of a Lewis lung carcinoma (LLC). Furthermore, 6-thio-dG-treated human NSCLC xenografts exhibited increased telomere damage, cell cycle arrest and apoptosis, as well as reduced proliferation, resulting in a reduced tumor growth. Our results show that targeting telomeres might be an effective therapeutic strategy in NSCLC.

Telomerase reactivation induces progression of mouse Braf V600E -driven thyroid cancers without telomere lengthening.

Mutations in the promoter of the telomerase reverse transcriptase ( TERT ) gene are the paradigm of a cross-cancer alteration in a non-coding region. TERT promoter mutations (TPMs) are biomarkers of poor prognosis in several tumors, including thyroid cancers. TPMs enhance TERT transcription, which is otherwise silenced in adult tissues, thus reactivating a bona fide oncoprotein. To study TERT deregulation and its downstream consequences, we generated a Tert mutant promoter mouse model via CRISPR/Cas9 engineering of the murine equivalent locus (Tert -123C>T ) and crossed it with thyroid-specific Braf V600E -mutant mice. We also employed an alternative model of Tert overexpression (K5-Tert). Whereas all Braf V600E animals developed well-differentiated papillary thyroid tumors, 29% and 36% of Braf V600E +Tert -123C>T and Braf V600E +K5-Tert mice progressed to poorly differentiated thyroid cancers at week 20, respectively. Braf+Tert tumors showed increased mitosis and necrosis in areas of solid growth, and older animals from these cohorts displayed anaplastic-like features, i.e., spindle cells and macrophage infiltration. Murine Tert promoter mutation increased Tert transcription in vitro and in vivo , but temporal and intra-tumoral heterogeneity was observed. RNA-sequencing of thyroid tumor cells showed that processes other than the canonical Tert-mediated telomere maintenance role operate in these specimens. Pathway analysis showed that MAPK and PI3K/AKT signaling, as well as processes not previously associated with this tumor etiology, involving cytokine and chemokine signaling, were overactivated. Braf+Tert animals remained responsive to MAPK pathway inhibitors. These models constitute useful pre-clinical tools to understand the cell-autonomous and microenvironment-related consequences of Tert-mediated progression in advanced thyroid cancers and other aggressive tumors carrying TPMs.

Lurasidone for the treatment of schizophrenia in adult and paediatric populations.

Schizophrenia is a common debilitating disorder characterized by significant impairments in how reality is perceived, combined with behavioural changes. In this review, we describe the lurasidone development programme for adult and paediatric patients. Both the pharmacokinetic and pharmacodynamic characteristics of lurasidone are revisited. In addition, pivotal clinical studies conducted on both adults and children are summarized. Several clinical cases, which demonstrate the role of lurasidone in real-world practice, are also presented. Current clinical guidelines recommend lurasidone as the first-line treatment in the acute and long-term management of schizophrenia in both adult and paediatric populations.