Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity.

An important epigenetic component of tyrosine kinase signaling is the phosphorylation of histones, and epigenetic readers, writers, and erasers. Phosphorylation of protein arginine methyltransferases (PRMTs), have been shown to enhance and impair their enzymatic activity. In this study, we show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates tyrosine residues (Y149 and Y334) in coactivator-associated arginine methyltransferase 1 (CARM1), an important target in hematologic malignancies, increasing its methyltransferase activity and altering its target specificity. While non-phosphorylatable CARM1 methylates some established substrates (e.g. BAF155 and PABP1), only phospho-CARM1 methylates the RUNX1 transcription factor, on R223 and R319. Furthermore, cells expressing non-phosphorylatable CARM1 have impaired cell-cycle progression and increased apoptosis, compared to cells expressing phosphorylatable, wild-type CARM1, with reduced expression of genes associated with G2/M cell cycle progression and anti-apoptosis. The presence of the JAK2-V617F mutant kinase renders acute myeloid leukemia (AML) cells less sensitive to CARM1 inhibition, and we show that the dual targeting of JAK2 and CARM1 is more effective than monotherapy in AML cells expressing phospho-CARM1. Thus, the phosphorylation of CARM1 by hyperactivated JAK2 regulates its methyltransferase activity, helps select its substrates, and is required for the maximal proliferation of malignant myeloid cells.

MicroRNA-204 Regulates Angiogenesis and Vasculogenic Mimicry in CD44+/CD24- Breast Cancer Stem-like Cells.

Tumors have high requirements in terms of nutrients and oxygen. Angiogenesis is the classical mechanism for vessel formation. Tumoral vascularization has the function of nourishing the cancer cells to support tumor growth. Vasculogenic mimicry, a novel intratumoral microcirculation system, alludes to the ability of cancer cells to organize in three-dimensional (3D) channel-like architectures. It also supplies the tumors with nutrients and oxygen. Both mechanisms operate in a coordinated way; however, their functions in breast cancer stem-like cells and their regulation by microRNAs remain elusive. In the present study, we investigated the functional role of microRNA-204 (miR-204) on angiogenesis and vasculogenic mimicry in breast cancer stem-like cells. Using flow cytometry assays, we found that 86.1% of MDA-MB-231 and 92% of Hs-578t breast cancer cells showed the CD44+/CD24- immunophenotype representative of cancer stem-like cells (CSCs). The MDA-MB-231 subpopulation of CSCs exhibited the ability to form mammospheres, as expected. Interestingly, we found that the restoration of miR-204 expression in CSCs significantly inhibited the number and size of the mammospheres. Moreover, we found that MDA-MB-231 and Hs-578t CSCs efficiently undergo angiogenesis and hypoxia-induced vasculogenic mimicry in vitro. The transfection of precursor miR-204 in both CSCs was able to impair the angiogenesis in the HUVEC cell model, which was observed as a diminution in the number of polygons and sprouting cells. Remarkably, miR-204 mimics also resulted in the inhibition of vasculogenic mimicry formation in MDA-MB-231 and Hs-578t CSCs, with a significant reduction in the number of channel-like structures and branch points. Mechanistically, the effects of miR-204 were associated with a diminution of pro-angiogenic VEGFA and ß-catenin protein levels. In conclusion, our findings indicated that miR-204 abrogates the angiogenesis and vasculogenic mimicry development in breast cancer stem-like cells, suggesting that it could be a potential tool for breast cancer intervention based on microRNA replacement therapies.

The Promotion of Mental Health and Prevention of First-Episode Psychosis: A Pilot and Feasibility Non-Randomised Clinical Trial.

BACKGROUND: Mental-health-related stigma prevents active help seeking and therefore early therapeutic approaches and the recovery of functionality. National and international agencies recommend the implementation of prevention and mental health promotion programs that support the elimination of stigma in the classroom, since most mental health problems usually start in the adolescent stage. In view of the evidence that teachers present stigmatizing attitudes towards mental health, it has been considered as convenient to carry out an anti-stigma program with the main objective of evaluating the impact of an intervention based on the education and promotion of mental health, aimed at teachers and counsellors of a secondary school. The specific objectives were to get to know which were the most stigmatising attitudes that prevailed in the sample before and after the intervention; to evaluate the knowledge of the teaching staff and counsellors on psychosis before the intervention; to analyse correlations between clinically relevant variables; and assess whether this programme was beneficial and feasible for alphabetising counsellors/teachers of educational centres on stigma and FEP. METHODS: This was a non-randomised clinical trial in which a nursing intervention was performed. TOOLS: a psychosis test (pre), Stigma Attribution Questionnaire (AQ-27) (pre-post), and satisfaction survey (post) were used. The inferential analysis included the Wilcoxon and the Pearson Correlation Test. RESULTS: In the sample (n = 22), the predominant stigmatising attitude was "Help". The p-values obtained in the Wilcoxon Test were statistically significant, except for "Responsibility" and "Pity". The following constructs of interest were faced: "Fear"-"Age" and "Professional experience"; and "Help"-"Psychosis test". CONCLUSIONS: Despite the scores obtained in "Responsibility" and "Pity", the intervention was useful for reducing stigma in the sample. Implications for the profession: There are adolescents who have suffered stigma from their teachers, and consequently have minimized their symptoms and not asked for help. For this reason, we implemented a nursing intervention based on the education and promotion of mental health, with the aim of expanding knowledge and reducing stigma. In fact, this intervention, which we carried out on high school teachers, managed to reduce the majority of stigmatizing attitudes measured on the stigma attribution scale.

All I missed in the therapeutic relationship: The lived experience narrative of a mental health nurse receiving mental healthcare.

WHAT IS KNOWN ON THE SUBJECT?: The therapeutic relationship is crucial for mental health practice, especially to practice that is recovery-orientated. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: This lived experience suggests that mental health professionals can be a long way from knowing the service users' feelings and their precise needs. The narrative reveals how mental health professionals maintain stereotypes and prejudices against people with mental health conditions and how these are reflected in their practice through lack of respect and users' dignity. WHAT ARE THE IMPLICATIONS FOR MENTAL HEALTH NURSING?: This lived experience narrative highlights the need to humanize care. ABSTRACT: INTRODUCTION: The therapeutic relationship is not always functional in clinical practice due to various factors, such as lack of time, lack of job motivation, exhaustion and rejection towards the person cared for. AIM: The aim of this study is to illustrate to professionals the needs of the persons they care for and how they see the world. METHOD: The aim was achieved through the development of a lived experience narrative. RESULTS: This lived experience narrative describes the experience of a mental health nurse since her first psychotic symptoms and her perceptions of the therapeutic relationship with mental health staff in her trajectory from the first psychiatric appointment until her last contact with the community mental health services. DISCUSSION: This narrative suggests that mental health professionals are sometimes far from discovering what service users are feeling and their precise needs. This highlights the need to humanize mental healthcare.

Non-tunneled catheter tip depth position in urgent hemodialysis: a randomized controlled trial.

BACKGROUND: The average accepted depth for non-tunneled catheters (NTC) insertion does not guarantee its correct position, so controversy exists. The aim of this study was to assess the effect of two NTC placement depths on the number of NTC complication episodes. METHODS: We designed a triple blind, parallel group, randomized controlled trial in a single Hemodialysis Center in Mexico (Registry: ACTRN12619000774123). We included patients in urgent need of hemodialysis via internal right jugular vein NTC. The length of the NTC tip placement depth was randomized to second intercostal space (2ICS) or fourth intercostal space (4ICS), using physical landmarks. The primary outcome was to compare the composite number of NTC dysfunction, repositioning, and relocation episodes for 48 hours post-procedure. RESULTS: One hundred and sixty-five patients were included, 86 and 79 patients to NTC placement in the 2ICS and 4ICS, respectively. All patients underwent intention-to-treat analysis. The incidence of the composite outcome was lower in the 2ICS group compared to the 4ICS group, 4 (4.6%) and 50 (63%) combined episodes, respectively (P<0.001). Compared to the 4ICS group, the 2ICS group presented a relative risk of 0.06 (CI: 0.02-0.21, P<0.001) and number needed to treat (NNT) of 2.1. No adverse events occurred, derived from the NTC placement. CONCLUSIONS: NTC tip placement in the 2ICS compared to 4ICS decreases the incidence of the combined number of dysfunctions, repositioning and relocation episodes, with a NNT of 2 for its prevention.

Using nuclear magnetic resonance urine metabolomics to develop a prediction model of early stages of renal disease in subjects with type 2 diabetes.

Type 2 diabetes mellitus (DM2) is a multimorbidity, long-term condition, and one of the worldwide leading causes of chronic kidney disease (CKD) -a silent disease, usually detected when non-reversible renal damage have already occurred. New strategies and more effective laboratory methods are needed for more opportune diagnosis of DM2-CKD. This study comprises clinical parameters and nuclear magnetic resonance (NMR)-based urine metabolomics data from 60 individuals (20-65 years old, 67.7% females), sorted in 5 experimental groups (healthy subjects; diabetic patients without any clinical sign of CKD; and patients with mild, moderate, and severe DM2-CKD), according to KDIGO. DM2-CKD produces a continuous variation of the urine metabolome, characterized by an increase/decrement of a group of metabolites that can be used to monitor CKD progression (trigonelline, hippurate, phenylalanine, glycolate, dimethylamine, alanine, 2-hydroxybutyrate, lactate, and citrate). NMR profiles were used to obtain a statistical model, based on partial least squares analysis (PLS-DA) to discriminate among groups. The PLS-DA model yielded good validation parameters (sensitivity, specificity, and area under the curve (AUC) of the receiver operating characteristic curve (ROC) plot: 0.692, 0.778 and 0.912, respectively) and, thus, it can differentiate between subjects with DM2-CKD in early stages, from subjects with a mild or severe condition. This metabolic signature exhibits a molecular variation associated to DM2-CKD, and data suggests it can be used to predict risk of DM2-CKD in patients without clinical signs of renal disease, offering a new alternative to current diagnosis methods.

The utility of the Barthel index as an outcome predictor in older patients with acute infection attending the emergency department.

BACKGROUND: Functional decline and frailty are common in older adults and influence the risk of adverse outcomes. We aimed to assess the value of a Barthel index at the Emergency Department (ED-BI) score in predicting 30-day mortality and ED reconsultation among older patients with acute infection. METHODS: We performed a prospective multicentre cohort study of older patients (≥75 years) diagnosed with acute infection in 69 Spanish EDs. Demographic, comorbidities, functional status, clinical and analytical data were collected. Unadjusted and adjusted logistic regression models were used to assess the association between ED-BI score, mortality and ED reconsultation. RESULTS: In total 1596 patients with a mean age of 84.7 years were included in the study and 51.7% female. The most frequent focus of infection was respiratory in 918 patients (57.5%). Patients with an ED-BI< 60 points were significantly older, predominantly female, more likely institutionalized and more urinary infections. When comparing patients with an ED-BI score ≥ 60 points with those< 60 points no differences were found in ED reconsultation but in the latter group mortality at 30-days was higher (p < 0.001). CONCLUSION: An ED-BI score< 60 points appears to be a strong predictor of mortality at the 30-day follow up in older patients with acute infection. DATA AVAILABILITY: The data used to support the findings of this study are included within the article.

Involving Persons With Lived Experience to Improve Vocational Students' Stigmatizing Attitudes Toward Mental Disorders: A Quasi-Experimental Study.

BACKGROUND: Mental health problems are estimated to affect one in six individuals in the European Union. Fifty percent of mental disorders start in adolescence, around the age of 14. The stigma associated with having a mental health problem is one of the main barriers to seeking help for psychiatric and psychological disorders among adolescents and young adults. Interventions to reduce social stigma could contribute to increased help-seeking behavior in this population. AIMS: To assess the effectiveness of a direct contact intervention in the classroom by persons with lived experience to reduce vocational students' stigmatizing attitudes. METHOD: One person with lived experience and one first-degree relative implemented a classroom intervention lasting 90 min. Its effectiveness was measured using a quasi-experimental study with a pretest-posttest design and within-subject control. RESULTS: A total of 128 students from three different Vocational and Technical Schools from Spain participated in the study. After the intervention, statistically significant differences were observed in the scores of 11 of the 13 dimensions measured with the Spanish Mental Illness Stigma Attribution Questionnaire (AQ-27-E) and the Community Attitudes toward Mental Illness (CAMI) questionnaires. No differences associated with gender or familiarity with the mental disorder were observed. CONCLUSION: Vocational students' negative attitudes and emotions can be improved through a direct contact intervention in the classroom involving people who have experienced a mental disorder themselves. The age range for optimal results with this type of intervention appears to be 18 to 20 years.

Predictors of revisits within 1 year by patients after acute COVID-19: the HUBCOVID365 cohort study. / Predictores de revisita en pacientes con infección aguda COVID-19 con seguimiento al año: estudio de cohorte HUBCOVID365.

OBJECTIVES: To analyze the frequencies of 3 types of hospital revisits by patients after treatment for COVID-19 in the emergency department. MATERIAL AND METHODS: Retrospective observational study of consecutive patients who came to the emergency department in March and April 2020 and were discharged alive with a diagnosis of COVID-19. Baseline and acute episode data were collected and the patients were followed for 1 year. We analyzed variables associated with revisits for any reason, revisits related to COVID-19, and early COVID-19-related revisits (within 30 days). RESULTS: A total of 1352 patients with a mean age of 62.1 years (52.9% male) were studied. A total of 553 revisits were made by 342 patients (25.3%) for any reason; 132 (9.8%) revisited in relation to COVID-19 at least once. Of those, 103 (7.6%) revisited within 30 days (early) and 29 (2.2%) came later. COVID-19-related revisits were associated with thrombotic events (odds ratio [OR], 7.58; 95% CI, 1.75-32.81) and pulmonary fibrosis (OR, 4.95; 95% CI, 1.27-19.24); early revisits were inversely associated with follow-up management by a contracted health care support service (OR, 0.18; 95% CI, 0.03-0.92). Hospital admission during the initial visit was significantly associated with fewer revisits for any reason or related to COVID-19 at any time. CONCLUSION: Fewer than half the total number of emergency department revisits after initial care for COVID-19 were related to the novel coronavirus infection. Revisits occurred more often in the first 30 days after discharge. Later COVID-19-related revisits were uncommon, but given the large number of patients with this infection, such visits can be expected.

OBJETIVO: Analizar diferentes categorías de revisita (RV) al año en pacientes con infección COVID-19 que consultan en un servicio de urgencias hospitalario (SUH). METODO: Estudio observacional, retrospectivo, que incluyó pacientes consecutivos que consultaron al SUH en los meses de marzo y abril de 2020 con diagnóstico de COVID-19 y fueron dados de alta vivos del hospital. Se recogieron variables basales y del episodio agudo y se realizó un seguimiento al año. Se hicieron tres comparaciones identificando variables asociadas a la RV total, RV relacionada con COVID-19 (RCovid) y RCovid precoz (# 30 días). RESULTADOS: Se analizaron 1.352 pacientes con edad media de 62,1 años y 52,9% varones. En el seguimiento al año hubo 553 RV en 342 (25,3%) pacientes, 132 (9,8%) con al menos una RCovid, 103 (7,6%) precoz y 29 (2,2%) tardía. La RCovid se relacionó con la presencia de fenómenos trombóticos [OR 7,58 (IC 95%: 1,75-32,81)] y la fibrosis pulmonar [OR 4,95 (IC 95%: 1,27-19,24)]; y la RCovid precoz se relacionó inversamente con alta a dispositivo de soporte sanitario [OR 0,18 (IC 95%: 0,03-0,92)]. El ingreso hospitalario en el evento índice disminuyó la RV total y RCovid y las hospitalizaciones derivadas de esta RV de manera significativa a largo plazo. CONCLUSIONES: Menos de la mitad de la RV total tras una infección COVID-19 está relacionada con la infección, y es más frecuente en los primeros 30 días. La RCovid tardía no es frecuente, pero dado el elevado número de pacientes que han sido infectados por COVID-19 se debe tener en cuenta.

Stigma towards Mental Disorders among Nursing Students and Professionals: A Bibliometric Analysis.

Stigma is one of the main barriers to prevention, treatment and recovery from mental illness. However, bibliometric studies in this area are still scarce. Therefore, our aim was to quantify and analyze the scientific literature on the stigma of nursing students and professionals towards mental disorders. To this purpose, bibliometric indicators of scientific production, impact and collaboration were used. Among our results, it stands out that only 14.3% of the total number of studies analyzed measure the efficacy of the interventions carried out to reduce stigma. Furthermore, with exceptions such as Happell B and Byrne L, collaborations between authors and institutions are limited. "Service user involvement" appeared as a prominent keyword in 2018, coinciding with the increase in publications on the effectiveness of interventions. Interventions based on the involvement of people with psychiatric diagnoses in the design of nursing curricula seem to become a promising line of research. More studies measuring the efficacy of such interventions are needed. Knowledge of the lines of research that are being developed and of the researchers and institutions involved can contribute to creating synergy between the different researchers and to continue adding projects to the existing ones, thus contributing to the generation of more robust results that show the most indicated interventions to reduce the still present stigma and improve care for people with psychiatric diagnoses.

p300 suppresses the transition of myelodysplastic syndromes to acute myeloid leukemia.

Myelodysplastic syndromes (MDS) are hematopoietic stem and progenitor cell (HSPC) malignancies characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Epigenetic regulators are recurrently mutated in MDS, directly implicating epigenetic dysregulation in MDS pathogenesis. Here, we identified a tumor suppressor role of the acetyltransferase p300 in clinically relevant MDS models driven by mutations in the epigenetic regulators TET2, ASXL1, and SRSF2. The loss of p300 enhanced the proliferation and self-renewal capacity of Tet2-deficient HSPCs, resulting in an increased HSPC pool and leukemogenicity in primary and transplantation mouse models. Mechanistically, the loss of p300 in Tet2-deficient HSPCs altered enhancer accessibility and the expression of genes associated with differentiation, proliferation, and leukemia development. Particularly, p300 loss led to an increased expression of Myb, and the depletion of Myb attenuated the proliferation of HSPCs and improved the survival of leukemia-bearing mice. Additionally, we show that chemical inhibition of p300 acetyltransferase activity phenocopied Ep300 deletion in Tet2-deficient HSPCs, whereas activation of p300 activity with a small molecule impaired the self-renewal and leukemogenicity of Tet2-deficient cells. This suggests a potential therapeutic application of p300 activators in the treatment of MDS with TET2 inactivating mutations.

Sudden cardiac death in persons aged 50 years or younger: diagnostic yield of a regional molecular autopsy program using massive sequencing.

INTRODUCTION AND OBJECTIVES: Sudden cardiac death (SCD) in young people often has a genetic cause. Consequently, the results of "molecular autopsy" may have important implications for their relatives. Our objective was to evaluate the diagnostic yield of a molecular autopsy program using next-generation sequencing. METHODS: We performed a prospective study of a cohort of consecutive patients who died from nonviolent SCD, aged ≤ 50 years, and who underwent molecular autopsy using large panels of next-generation sequencing, with subsequent clinical and genetic family screening. We analyzed demographic, clinical, toxicological, and genetic data. RESULTS: We studied 123 consecutive cases of SCD in persons aged ≤ 50 years. The incidence of SCD was 5.8 cases/100 000 individuals/y, mean age was 36.15±12.7 years, and 95 were men (77%). The cause was cardiac in 53%, unexplained SCD in 24%, toxic in 10.6%, and infant SCD in 4%. Among cardiac causes, ischemic heart disease accounted for 38% of deaths, arrhythmogenic cardiomyopathy for 7%, hypertrophic cardiomyopathy for 5%, and idiopathic left ventricular hypertrophy for 11%. Genetic analysis was performed in 62 cases (50.4%). Genetic variants were found in 42 cases (67.7%), with a mean of 3.4±4 genetic variants/patient, and the variant found was considered to be pathogenic or probably pathogenic in 30.6%. In unexplained SCD, 70% showed some genetic variant. Family screening diagnosed 21 carriers or affected individuals, 5 of whom were at risk, indicating an implantable cardiac defibrillator. CONCLUSIONS: Protocol-based and exhaustive study of SCD from cardiac causes in persons aged ≤ 50 years is feasible and necessary. In a high percentage of cases, the cause is genetic, indicating the existence of relatives at risk who could benefit from early diagnosis and treatment to avoid complications.

A qualitative emancipatory inquiry into relationships between people with mental disorders and health professionals.

WHAT IS KNOWN ON THE SUBJECT?: A therapeutic alliance with people with mental disorders could help increase the efficacy of treatment. The paradigm shift from a paternalistic model to one that respects the person's autonomy has led to professionals accepting the active role of people with mental disorders making decisions that affect their treatment. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: People with mental disorders perceive paternalistic and stigmatizing attitudes from health professionals, and they do not feel involved in decisions about their health, which can render effective therapeutic alliances difficult. The findings reveal that although people in Mediterranean countries are used to paternalistic treatment from health professionals due to cultural factors, people with mental disorders are increasingly critical of how they are treated and demand greater autonomy and respect in the decision to undergo drug therapy. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: In their interactions with people with mental disorders, health professionals should include efforts aimed at improving shared decision-making capabilities and avoiding paternalistic or stigmatizing attitudes. ABSTRACT: Introduction A therapeutic alliance with people is essential for the efficacy of treatments. However, the traditional paternalistic values of the Mediterranean society may be incompatible with patient autonomy. Aim To explore the therapeutic relationship from the perspective of people diagnosed with mental disorders with health professionals, including nurses. Methods This emancipatory research was performed through focus groups, with people with mental disorders who had a variety of diagnoses and experiences of acute and community-based mental health services and other healthcare services. Data were analysed using the content analysis method. Results Four main themes emerged: stereotypes and prejudice; quality of interactions and treatment; emotional and behavioural impacts; and demands. Discussion According to the participants' descriptions, health professionals are not exempt from prejudice against persons with psychiatric diagnoses. They reported experiencing abuse of power, malpractice, and overmedication. Thus, in the Mediterranean culture, professional attitudes may represent a barrier for an appropriate therapeutic alliance, and people with mental disorders do not feel involved in making decisions about their health. Implications for practice Knowing how people with mental disorders perceive their interactions with health professionals and the effects is necessary to move the care model towards more symmetric relationships that facilitate a therapeutic alliance.

Metabolomics of the diabetic nephropathy: behind the fingerprint of development and progression indicators. / Metabolómica de la nefropatía diabética: tras la huella de indicadores de desarrollo y progresión.

Current diagnostic methods are not very sensitive to detect the initial stages diabetic nephropathy of type 2. In this work, a review of metabolomic approximation studies for the identification of biomarkers of this disease with potential to differentiate between early stages, evaluate and direct treatment and help slow kidney damage. Using public (Pubmed and Google Scholar) and private (Scopus and Web of Knowledge) databases, a systematic search of the information published related to metabolomics of diabetic nephropathy in different biospecimens (urine, serum, plasma and blood) was made. Later, the MetaboAnalyst 4.0 software was used to identify the metabolic pathways associated with these metabolites. Groups of potential metabolites were identified for monitoring diabetic nephropathy with the available literature data. In the urine, oxide-3-hydroxyisovalerate, TMAO, aconite and citrate and hydroxypropionate derivatives are highlighted; meanwhile, in the serum: citrate, creatinine, arginine and its derivatives; and in the plasma: amino acids such as histidine, methionine and arginine has a potential contribution. Using MetaboAnalyst 4.0 the metabolic pathways related to these metabolites were related. The search for biomarkers to measure the progression of diabetic nephropathy, together with analytical strategies for their detection and quantification, are the starting point for designing new methods of clinical chemistry analysis. The association between the metabolic pathway dysfunction could be useful for the overall assessment of the treatment and clinical follow-up of this disease.

Anti-inflammatory and antioxidant activity of essential amino acid α-ketoacid analogues against renal ischemia-reperfusion damage in Wistar rats. / Actividad antiinflamatoria y antioxidante de los α-cetoanálogos de aminoácidos esenciales en un modelo de daño por isquemia-reperfusión en ratas Wistar

INTRODUCTION: Essential amino acid α-keto acid analogs are used in the treatment of chronic kidney disease to delay the symptoms of uremia. However, it is unknown whether essential amino acid α-keto acid analogs affect the oxidative stress and the inflammation in acute renal injury such as those produced by ischemia-reperfusion. OBJECTIVE: To evaluate the effect of essential amino acid α-keto acid analogs on renal ischemia-reperfusion injury in Wistar rats. MATERIALS AND METHODS: Rats were divided into 11 groups (n=6/group): Two groups received physiological saline with or without ischemia-reperfusion injury (45 min/24 h), six groups received essential amino acid α-keto acid analogs (400, 800, or 1,200 mg/kg/24 h/7d) with or without ischemia-reperfusion injury (essential amino acid α-keto acid analogs + ischemia-reperfusion), and two groups received allopurinol (50 mg/kg/24 h/7d) with or without ischemia-reperfusion injury. Biochemical markers included creatinine and blood urea nitrogen (BUN), proinflammatory cytokines (IL-1ß, IL-6, and TNF-α), renal damage markers (cystatin C, KIM-1, and NGAL), and markers of oxidative stress such as malondialdehyde (MDA) and total antioxidant activity. RESULTS: The essential amino acid α-keto acid analog- and allopurinol-treated groups had lower levels of creatinine, BUN, renal damage markers, proinflammatory cytokines, and MDA than their corresponding ischemia-reperfusion groups. These changes were related to the essential amino acid α-keto acid analogs dosage. Total antioxidant activity was lower in essential amino acid α-keto acid analog- and allopurinol-treated groups than in the corresponding ischemia-reperfusion groups. CONCLUSIONS: This is a new report on the nephroprotective effects of essential amino acid α-keto acid analogs against ischemia-reperfusion injury. Essential amino acid α-keto acid analogs decreased the levels of biochemical markers, kidney injury markers, proinflammatory cytokines, and MDA while minimizing total antioxidant consumption.

Introducción. Los α-cetoanálogos de aminoácidos esenciales se utilizan en el tratamiento de la enfermedad renal crónica para retrasar los síntomas de la uremia. Sin embargo, se desconoce si los α-cetoanálogos de aminoácidos esenciales afectan el estrés oxidativo y la inflamación en la lesión renal aguda tal como en la producida por la isquemia-reperfusión. Objetivo. Evaluar el efecto de las α-cetoanálogos de aminoácidos esenciales sobre la lesión renal por isquemia-reperfusión en ratas Wistar. Materiales y métodos. Se emplearon 11 grupos de ratas (n=6): dos grupos recibieron solución salina fisiológica con lesión isquemia-reperfusión o sin ella (45 min/24 h), seis grupos recibieron α-cetoanálogos de aminoácidos esenciales (400, 800 o 1.200 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella (α-cetoanálogos de aminoácidos esenciales + isquemia-reperfusión), y dos grupos recibieron (50 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella. Los marcadores bioquímicos incluyeron creatinina y nitrógeno ureico en sangre (BUN), citocinas proinflamatorias (IL-1ß, IL-6 y TNF-α), marcadores de daño renal (cistatina C, KIM-1 y NGAL) y marcadores del estrés oxidativo como el malondialdehído (MDA) y la actividad antioxidante total. Resultados. Los grupos tratados con α-cetoanálogos de aminoácidos esenciales y alopurinol tuvieron niveles inferiores de creatinina, BUN, marcadores de daño renal, citocinas proinflamatorias, actividad antioxidante total y MDA que los grupos isquemia-reperfusión correspondientes. Estos cambios se asociaron con la dosis. La actividad antioxidante total fue menor en los grupos tratados con α-cetoanálogos de aminoácidos esenciales que en los grupos isquemia-reperfusión correspondientes. Conclusiones. Este es un nuevo informe de los efectos nefroprotectores de las α-cetoanálogos de aminoácidos esenciales contra la lesión isquemia-reperfusión. Los α-cetoanálogos de aminoácidos esenciales disminuyeron los niveles de los marcadores bioquímicos, de los de lesión renal, de las citocinas proinflamatorias y el MDA, a la vez que minimizaron el consumo total de antioxidantes.

Anti-inflammatory and antioxidant activity of essential amino acid α-ketoacid analogues against renal ischemia­reperfusion damage in Wistar rats / Actividad antiinflamatoria y antioxidante de los α-cetoanálogos de aminoácidos esenciales en un modelo de daño por isquemia-reperfusión en ratas Wistar

Introduction: Essential amino acid α-keto acid analogs are used in the treatment of chronic kidney disease to delay the symptoms of uremia. However, it is unknown whether essential amino acid α-keto acid analogs affect the oxidative stress and the inflammation in acute renal injury such as those produced by ischemia-reperfusion. Objective: To evaluate the effect of essential amino acid α-keto acid analogs on renal ischemia-reperfusion injury in Wistar rats. Materials and methods: Rats were divided into 11 groups (n=6/group): Two groups received physiological saline with or without ischemia-reperfusion injury (45 min/24 h), six groups received essential amino acid α-keto acid analogs (400, 800, or 1,200 mg/kg/24 h/7d) with or without ischemia-reperfusion injury (essential amino acid α-keto acid analogs + ischemia-reperfusion), and two groups received allopurinol (50 mg/kg/24 h/7d) with or without ischemia-reperfusion injury. Biochemical markers included creatinine and blood urea nitrogen (BUN), proinflammatory cytokines (IL-1ß, IL-6, and TNF-α), renal damage markers (cystatin C, KIM-1, and NGAL), and markers of oxidative stress such as malondialdehyde (MDA) and total antioxidant activity. Results: The essential amino acid α-keto acid analog- and allopurinol-treated groups had lower levels of creatinine, BUN, renal damage markers, proinflammatory cytokines, and MDA than their corresponding ischemia-reperfusion groups. These changes were related to the essential amino acid α-keto acid analogs dosage. Total antioxidant activity was lower in essential amino acid α-keto acid analog- and allopurinol-treated groups than in the corresponding ischemia-reperfusion groups. Conclusions: This is a new report on the nephroprotective effects of essential amino acid α-keto acid analogs against ischemia-reperfusion injury. Essential amino acid α-keto acid analogs decreased the levels of biochemical markers, kidney injury markers, proinflammatory cytokines, and MDA while minimizing total antioxidant consumption.

Introducción. Los α-cetoanálogos de aminoácidos esenciales se utilizan en el tratamiento de la enfermedad renal crónica para retrasar los síntomas de la uremia. Sin embargo, se desconoce si los α-cetoanálogos de aminoácidos esenciales afectan el estrés oxidativo y la inflamación en la lesión renal aguda tal como en la producida por la isquemia-reperfusión. Objetivo. Evaluar el efecto de las α-cetoanálogos de aminoácidos esenciales sobre la lesión renal por isquemia-reperfusión en ratas Wistar. Materiales y métodos. Se emplearon 11 grupos de ratas (n=6): dos grupos recibieron solución salina fisiológica con lesión isquemia-reperfusión o sin ella (45 min/24 h), seis grupos recibieron α-cetoanálogos de aminoácidos esenciales (400, 800 o 1.200 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella (α-cetoanálogos de aminoácidos esenciales + isquemia-reperfusión), y dos grupos recibieron (50 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella. Los marcadores bioquímicos incluyeron creatinina y nitrógeno ureico en sangre (BUN), citocinas proinflamatorias (IL-1ß, IL-6 y TNF-α), marcadores de daño renal (cistatina C, KIM-1 y NGAL) y marcadores del estrés oxidativo como el malondialdehído (MDA) y la actividad antioxidante total. Resultados. Los grupos tratados con α-cetoanálogos de aminoácidos esenciales y alopurinol tuvieron niveles inferiores de creatinina, BUN, marcadores de daño renal, citocinas proinflamatorias, actividad antioxidante total y MDA que los grupos isquemia-reperfusión correspondientes. Estos cambios se asociaron con la dosis. La actividad antioxidante total fue menor en los grupos tratados con α-cetoanálogos de aminoácidos esenciales que en los grupos isquemia-reperfusión correspondientes. Conclusiones. Este es un nuevo informe de los efectos nefroprotectores de las α-cetoanálogos de aminoácidos esenciales contra la lesión isquemia-reperfusión. Los α-cetoanálogos de aminoácidos esenciales disminuyeron los niveles de los marcadores bioquímicos, de los de lesión renal, de las citocinas proinflamatorias y el MDA, a la vez que minimizaron el consumo total de antioxidantes.

PRMT5-mediated histone arginine methylation antagonizes transcriptional repression by polycomb complex PRC2.

Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues in histones H3 and H4, marks that are generally associated with transcriptional repression. However, we found that PRMT5 inhibition or depletion led to more genes being downregulated than upregulated, indicating that PRMT5 can also act as a transcriptional activator. Indeed, the global level of histone H3K27me3 increases in PRMT5 deficient cells. Although PRMT5 does not directly affect PRC2 enzymatic activity, methylation of histone H3 by PRMT5 abrogates its subsequent methylation by PRC2. Treating AML cells with an EZH2 inhibitor partially restored the expression of approximately 50% of the genes that are initially downregulated by PRMT5 inhibition, suggesting that the increased H3K27me3 could directly or indirectly contribute to the transcription repression of these genes. Indeed, ChIP-sequencing analysis confirmed an increase in the H3K27me3 level at the promoter region of a quarter of these genes in PRMT5-inhibited cells. Interestingly, the anti-proliferative effect of PRMT5 inhibition was also partially rescued by treatment with an EZH2 inhibitor in several leukemia cell lines. Thus, PRMT5-mediated crosstalk between histone marks contributes to its functional effects.

Operational Definition of Serious Mental Illness: Heterogeneity in a Review of the Research on Quality-of-Life Interventions.

BACKGROUND: An operational definition of serious mental illness (SMI) with well-defined inclusion criteria allows the identification of the most vulnerable individuals and secures resources to meet their needs and develop social programs for their treatment, rehabilitation, and recovery. In addition, the contents of a clinical construct such as SMI have an impact on both the development and the clinical application of the research results. However, currently, different ways of operationalizing the definition of SMI coexist. AIMS: The aim of this review was to explore whether unanimity exists in the operationalization of SMI definitions in quality-of-life interventions research. METHODS: A review of the literature based on searches of the MEDLINE and PsycINFO databases was conducted. Intervention studies were selected in which quality of life was the outcome variable and adults with SMI were the subject population. RESULTS: A wide range of definition of SMI is used in the scientific literature. CONCLUSIONS: There is a lack of unanimity in the variables considered necessary to identify SMI. The scientific literature uses different approaches to operationalize SMI, and these approaches vary considerably among studies. Caution is required when interpreting quality-of-life research that includes individuals labeled with SMI. It is necessary to reach a consensus on the criteria for applying the SMI label to ensure its content validity.

TAF1 plays a critical role in AML1-ETO driven leukemogenesis.

AML1-ETO (AE) is a fusion transcription factor, generated by the t(8;21) translocation, that functions as a leukemia promoting oncogene. Here, we demonstrate that TATA-Box Binding Protein Associated Factor 1 (TAF1) associates with K43 acetylated AE and this association plays a pivotal role in the proliferation of AE-expressing acute myeloid leukemia (AML) cells. ChIP-sequencing indicates significant overlap of the TAF1 and AE binding sites. Knockdown of TAF1 alters the association of AE with chromatin, affecting of the expression of genes that are activated or repressed by AE. Furthermore, TAF1 is required for leukemic cell self-renewal and its reduction promotes the differentiation and apoptosis of AE+ AML cells, thereby impairing AE driven leukemogenesis. Together, our findings reveal a role of TAF1 in leukemogenesis and identify TAF1 as a potential therapeutic target for AE-expressing leukemia.

Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015-2019).

Sustained proliferative capacity and gene dysregulation are hallmarks of cancer. In mammalian cells, cyclin-dependent kinases (CDKs) control critical cell cycle checkpoints and key transcriptional events in response to extracellular and intracellular signals leading to proliferation. Significant clinical activity for the treatment of hormone receptor positive metastatic breast cancer has been demonstrated by palbociclib, ribociclib and abemaciclib, dual CDK4/6 inhibitors recently FDA-approved. SY-1365, a CDK7 inhibitor has shown initial encouraging data in phase I for solid tumors treatment. These results have rejuvenated the CDKs research field. This review provides an overview of relevant advances on CDK inhibitor research since 2015 to 2019, with special emphasis on transcriptional CDK inhibitors, new emerging strategies such as target protein degradation and compounds under clinical evaluation.