Radiology of fibrosis. Part I: Thoracic organs.

Sustained injury from factors such as hypoxia, infection, or physical damage may provoke improper tissue repair and the anomalous deposition of connective tissue that causes fibrosis. This phenomenon may take place in any organ, ultimately leading to their dysfunction and eventual failure. Tissue fibrosis has also been found to be central in both the process of carcinogenesis and cancer progression. Thus, its prompt diagnosis and regular monitoring is necessary for implementing effective disease-modifying interventions aiming to reduce mortality and improve overall quality of life. While significant research has been conducted on these subjects, a comprehensive understanding of how their relationship manifests through modern imaging techniques remains to be established. This work intends to provide a comprehensive overview of imaging technologies relevant to the detection of fibrosis affecting thoracic organs as well as to explore potential future advancements in this field.

Radiology of fibrosis part II: abdominal organs.

Fibrosis is the aberrant process of connective tissue deposition from abnormal tissue repair in response to sustained tissue injury caused by hypoxia, infection, or physical damage. It can affect almost all organs in the body causing dysfunction and ultimate organ failure. Tissue fibrosis also plays a vital role in carcinogenesis and cancer progression. The early and accurate diagnosis of organ fibrosis along with adequate surveillance are helpful to implement early disease-modifying interventions, important to reduce mortality and improve quality of life. While extensive research has already been carried out on the topic, a thorough understanding of how this relationship reveals itself using modern imaging techniques has yet to be established. This work outlines the ways in which fibrosis shows up in abdominal organs and has listed the most relevant imaging technologies employed for its detection. New imaging technologies and developments are discussed along with their promising applications in the early detection of organ fibrosis.

Radiology of fibrosis part III: genitourinary system.

Fibrosis is a pathological process involving the abnormal deposition of connective tissue, resulting from improper tissue repair in response to sustained injury caused by hypoxia, infection, or physical damage. It can impact any organ, leading to their dysfunction and eventual failure. Additionally, tissue fibrosis plays an important role in carcinogenesis and the progression of cancer.Early and accurate diagnosis of organ fibrosis, coupled with regular surveillance, is essential for timely disease-modifying interventions, ultimately reducing mortality and enhancing quality of life. While extensive research has already been carried out on the topics of aberrant wound healing and fibrogenesis, we lack a thorough understanding of how their relationship reveals itself through modern imaging techniques.This paper focuses on fibrosis of the genito-urinary system, detailing relevant imaging technologies used for its detection and exploring future directions.

Severity and mortality of acute respiratory failure in pediatrics: A prospective multicenter cohort in Bogotá, Colombia.

Background and Aims: Acute respiratory failure (ARF) is the most frequent cause of cardiorespiratory arrest and subsequent death in children worldwide. There have been limited studies regarding ARF in high altitude settings. The aim of this study was to calculate mortality and describe associated factors for severity and mortality in children with ARF. Methods: The study was conducted within a prospective multicentric cohort that evaluated the natural history of pediatric ARF. For this analysis three primary outcomes were studied: mortality, invasive mechanical ventilation, and pediatric intensive care unit (PICU) length of stay. Eligible patients were children older than 1 month and younger than 18 years of age with respiratory difficulty at the time of admission. Patients who developed ARF were followed at the time of ARF, 48 h later, at the time of discharge, and at 30 and 60 days after discharge. It was conducted in the pediatric emergency, in-hospital, and critical-care services in three hospitals in Bogotá, Colombia, from April 2020 to June 2021. Results: Out of a total of 685 eligible patients, 296 developed ARF for a calculated incidence of ARF of 43.2%. Of the ARF group, 90 patients (30.4%) needed orotracheal intubation, for a mean of 9.57 days of ventilation (interquartile range = 3.00-11.5). Incidence of mortality was 6.1% (n = 18). The associated factors for mortality in ARF were a history of a neurologic comorbidity and a higher fraction of inspired oxygen at ARF diagnosis. For PICU length of stay, the associated factors were age between 2 and 5 years of age, exposure to smokers, and respiratory comorbidity. Finally, for mechanical ventilation, the risk factors were obesity and being unstable at admission. Conclusions: ARF is a common cause of morbidity and mortality in children. Understanding the factors associated with greater mortality and severity of ARF might allow earlier recognition and initiation of prompt treatment strategies.

A Thorough Literature Review of the Potential Benefits and Drawbacks of Long-Term Aspirin Use for the Primary Prevention of Cardiovascular Disease.

This article examines the role of aspirin in the primary prevention of cardiovascular disease. It highlights findings from major studies such as ASPREE (ASPirin in Reducing Events in the Elderly), ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events), and ASPREE-XT (ASPirin in Reducing Events in the Elderly - eXTension) , among others. The review focuses on aspirin's role in primary prevention for specific populations including older adults, diabetics, hypertension patients, rheumatoid arthritis patients, kidney transplant recipients, and those with specific lipoprotein(a) genotypes, among other groups. We review these studies, noting aspirin's role in reducing events such as myocardial infarctions and its potential for increasing bleeding risks. The review also considers the implications for patients with kidney disease, referencing the Chronic Renal Insufficiency Cohort (CRIC) study and the International Polycap Study-3 (TIPS-3) trial. Additionally, it addresses the shifting paradigms in guidelines from the US Preventive Services Task Force and other entities, underscoring the importance of individualized aspirin use by balancing benefits against bleeding risks. The article further explores the concept of platelet reactivity, discusses strategies for improving adherence to aspirin therapy, and identifies existing research gaps, such as the phenomenon of aspirin resistance. It concludes by suggesting potential areas for future investigation to enhance understanding and application of aspirin in cardiovascular disease prevention.

Detección de violencia machista entre las mujeres atendidas por tentativa autolítica en un servicio de urgencias / Detection of interpersonal partner violence among women treated for attempted suicide in an emergency department

Introducción: Existe evidencia sobre una asociación directa entre la Violencia Machista/Violencia de Género (VdG) y el suicidio, e incluso se señala que la VdG es el principal factor precipitante para que una mujer realice una tentativa suicida. Además, se ha demostrado que las mujeres con enfermedades mentales crónicas sufren especialmente más violencia que la población en general. Sin embargo, existen relativamente pocos datos sobre la capacidad de detección de VdG de los servicios de urgencias. En Catalunya, el Programa Código Riesgo de Suicidio (CRS) atendió a 12.596 persones con episodios de conducta suicida y ha demostrado su eficacia en nuestro hospital. Objetivo principal: Cuantificar el grado de detección de la VdG de nuestros registros sanitarios en mujeres visitadas en el servicio urgencias de nuestro hospital por ideación y/o tentativa suicida y que han sido incluidas en el Programa CRS. Hipótesis principal: La detección actual de VdG en las mujeres es <10%. Metodología: Estudio descriptivo retrospectivo basado en registros electrónicos sanitarios. Se identificaron todas las mujeres que habían estado en seguimiento telefónico en los últimos 12 meses por haber acudido al servicio de urgencias de nuestro Hospital por ideación y/o intento suicida. El período de análisis incluyó del 1 de enero al 31 de diciembre de 2020. Se realizó una revisión completa de todos los informes de alta de estas mujeres visitadas en urgencias y de los registros clínicos de todos los profesionales (médicos, psiquiatrías, enfermeras...) disponibles en la historia clínica informatizada. Se realizó un análisis descriptivo simple de los datos. Resultados: Durante el período de estudio, se detectaron cuatro casos de violencia machista/VdG (1,92%) y dos casos de violencia familiar entre las 208 mujeres que se visitaron por ideación y/o intento autolítico...(AU)

Introduction: There is evidence of a direct association between interpersonal partner/sexist/gender violence (IPV) and suicide, and it is even pointed out that IPV is the main precipitating factor for a woman to make a suicide attempt. In addition, it has been shown that women with chronic mental illness suffer especially more violence than the general population. However, there is relatively little data on the IPV detection capacity of emergency departments. In Catalonia, the Suicide Risk Code Program (CRS) treated 12,596 people with episodes of suicidal behaviour and has demonstrated its effectiveness in our hospital. Main objective: To quantify the degree of detection of IPV in our health records in women visited in the emergency department of our hospital for suicidal ideation and/or attempt and who have been included in the CRS Program.Main hypothesis: Current detection of IPV in women is <10%. Methodology: Retrospective descriptive study based on electronic health records. All the women who had been in telephone follow-up in the last 12 months for having gone to the emergency department of our hospital for suicidal ideation and/or attempt were identified. The analysis period included from January 1 to December 31, 2020. A complete review of all the discharge reports of the women visited in the emergency room and of all the clinical records of all the professionals (doctors, psychiatrists, nurses...) available in the computerized medical record was carried out. A simple descriptive analysis of the data was performed. Results: During the study period, four cases of IPV (1.92%) and two cases of family violence were detected among the 208 women who were visited for suicidal ideation and/or attempt. All the women who were detected with IPV were recommended to visit the Women’s Care Center, but it is unknown if they were actually referred to other professionals or if they actually attended...(AU)

Breast stiffness, a risk factor for cancer and the role of radiology for diagnosis.

Over the last five decades, breast density has been associated with increased risk of developing breast cancer. Mammographically dense breasts are considered those belonging to the heterogeneously dense breasts, and extremely dense breasts subgroups according to the American College of Radiology's Breast Imaging Reporting and Data System (BI-RADS). There is a statistically significant correlation between the increased mammographic density and the presence of more glandular tissue alone. However, the strength of this correlation is weak. Although the mechanisms driving breast density-related tumor initiation and progression are still unknown, there is evidence suggesting that certain molecular pathways participating in epithelial-stromal interactions may play a pivotal role in the deposition of fibrillar collagen, increased matrix stiffness, and cell migration that favor breast density and carcinogenesis. This article describes these molecular mechanisms as potential "landscapers" for breast density-related cancer. We also introduce the term "Breast Compactness" to reflect collagen density of breast tissue on chest CT scan and the use of breast stiffness measurements as imaging biomarkers for breast cancer screening and risk stratification.

Analogies between the periphery of cancer and the leading edge of pulmonary fibrosis.

The periphery of malignant tumors and the leading edge of fibrotic tissue have analogous metabolic pathways. Both use glycolysis as the primary source of energy to produce biomass with consequential acidification of the microenvironment. A low PH has been shown to increase the ability of cancer cells to invade the surrounding tissue in both in vitro and in vivo studies. The pH-dependent activation of TGF-B leading to myofibroblast activation is an important step in the initiation and progression of fibrosis. Markers of accelerated cell proliferation have also been reported in the periphery of malignant tumors and the leading edge of fibrosis. Understanding the shared molecular and metabolic characteristics of these conditions may explain the increased prevalence of cancer among patients with fibrosis.

Codon adaptation by synonymous mutations impacts the functional properties of the estrogen receptor-alpha protein in breast cancer cells.

Oestrogen receptor-alpha (ERα) positivity is intimately associated with the development of hormone-dependent breast cancers. A major challenge in the treatment of these cancers is to understand and overcome the mechanisms of endocrine resistance. Recently, two distinct translation programmes using specific transfer RNA (tRNA) repertoires and codon usage frequencies were evidenced during cell proliferation and differentiation. Considering the phenotype switch of cancer cells to more proliferating and less-differentiated states, we can speculate that the changes in the tRNA pool and codon usage that likely occur make the ERα coding sequence no longer adapted, impacting translational rate, co-translational folding and the resulting functional properties of the protein. To verify this hypothesis, we generated an ERα synonymous coding sequence whose codon usage was optimized to the frequencies observed in genes expressed specifically in proliferating cells and then investigated the functional properties of the encoded receptor. We demonstrate that such a codon adaptation restores ERα activities to levels observed in differentiated cells, including: (a) an enhanced contribution exerted by transactivation function 1 (AF1) in ERα transcriptional activity; (b) enhanced interactions with nuclear receptor corepressor 1 and 2 [NCoR1 and NCoR2 (also known as SMRT) respectively], promoting repressive capability; and (c) reduced interactions with SRC proto-oncogene, non-receptor tyrosine kinase (Src) and phosphoinositide 3-kinase (PI3K) p85 kinases, inhibiting MAPK and AKT signalling pathway.

Desenlaces adversos perioperatorios en ancianos con fractura de cadera, antes y después de la implementación de un protocolo de ortogeriatría / Adverse perioperative outcomes in elderly patients with hip fracture before and after the implementation of an orthogeriatric protocol

Introducción: la fractura de cadera en adultos mayores constituye un problema de salud importante, ya que está asociada a mayor morbilidad y mortalidad. Por esta razón, se han creado protocolos de ortogeriatría para su abordaje, los cuales reportan resultados favorables.Objetivo: evaluar los desenlaces adversos perioperatorios en adultos mayores con fractura de cadera antes y después de la implementación de un protocolo de evaluación geriátrica integral (EGI).Metodología: estudio de casos y controles realizado en 136 pacientes (casos: 43; controles: 93) >65 años con fractura de cadera que fueron atendidos en un hospital de referencia entre 2020 y 2021 (casos), y 2015 y 2017 (controles). Se determinaron diferencias entre grupos mediante un análisis bivariado usando las pruebas de chi cuadrado o exacta de Fisher en variables categóricas, y las pruebas t de student o de Wilcoxon de los rangos con signo en variables continuas según la distribución de los datos.Resultados: los desenlaces adversos perioperatorios ocurrieron en el 62,7% de los casos y el 84,0% de los controles (p=0,007; OR:0,32; IC95%:0,13-0,73). La mediana de duración de la estancia hospitalaria fue 10 y 17 días en los casos y controles, respectivamente (RIQ: 8-14; RIQ 11-26), mientras que el tiempo entre el ingreso a urgencias y la cirugía fue 7 días (RIQ:5-11) y 11 días (RIQ:8-17), respectivamente (p=0.002). Conclusiones: la implementación de la EGI redujo los desenlaces adversos por fractura de cadera, principal-mente la duración de la estancia hospitalaria y el tiempo entre el ingreso y la cirugía, donde se observaron diferencias estadísticamente significativas entre ambos grupos

Introduction: Hip fracture in elderly patients is a major health concern, as it is associated with increased morbidity and mortality. For this reason, orthogeriatric protocols have been created to approach it, reporting favorable outcomes.Objective: To evaluate adverse perioperative outcomes in elderly patients with hip fractures before and after the implementation of a comprehensive geriatric assessment (CGA) protocol.Methodology: Case-control study performed on 136 patients (cases: 43; controls: 93) >65 years old with a hip fracture, who were treated at a referral hospital between 2020 and 2021 (cases) and 2015 and 2017 (controls). Differences between groups were determined through bivariate analysis using Fisher's chi-square or exact tests on categorical variables, and Student's t-test or Wilcoxon signed-rank test on continuous variables depending on the distribution of the data.Results: Adverse perioperative outcomes occurred in 62.7% of cases and 84.0% of controls (p=0.007; OR:0.32; 95%CI:0.13-0.73). The median length of hospital stay was 10 and 17 days in cases and controls, respectively (IQR: 8-14; IQR 11-26), while the time between ED admission and surgery was 7 days (IQR:5-11) and 11 days (IQR:8-17), respectively (p=0.002).Conclusions: The implementation of the CGA protocol reduced adverse outcomes associated with hip fracture, mainly the length of hospital stay and the time between admission and surgery, in which statistically significant differences were observed between both groups

Lobar Gross Endobronchial Disease Predicts for Overall Survival and Grade 5 Pulmonary Toxicity in Medically Inoperable Early Stage Non-Small Cell Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy.

PURPOSE: Stereotactic body radiation therapy (SBRT) is considered standard of care for medically inoperable early stage non-small cell lung cancer (ES-NSCLC). Central tumor location is a known risk factor for severe SBRT related toxicity. Bronchoscopy allows for visualization of the central airways prior to treatment. Five fraction SBRT approaches have been advocated to mitigate treatment induced toxicity. In this report, we examine the mature clinical outcomes of a diverse cohort of ES-NSCLC patients with both peripheral and central tumors treated with a conservative 5 fraction SBRT approach and evaluate the role of lobar gross endobronchial disease (LGED) in predicting overall survival and treatment-related death. METHODS: Medically inoperable biopsy-proven, lymph node-negative ES-NSCLC patients were treated with SBRT. Bronchoscopy was completed prior to treatment in all centrally located cases. The Kaplan-Meier method was used to estimate overall survival (OS), local control (LC), regional control (RC), distant metastasis free survival (DMFS) and disease-free survival (DFS). Overall survival was stratified based on clinical stage, histology, tumor location and LGED. Toxicities were scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. RESULTS: From December 2010 to December 2015, 50 consecutive patients were treated uniformly with a 50 Gy in 5 fraction SBRT approach (tumor BED10 ≥ 100 Gy) and followed for a minimum of 5 years or until death. At a median follow up of 42 months for all patients, 3-year OS was 50%. Three-year OS did not statistically differ between stage I and stage II disease (51% vs. 47%; p=0.86), adenocarcinoma and squamous cell carcinoma (50% vs. 45%; p=0.68), or peripheral and central tumors (56% vs. 45%; p=0.46). Five central tumors were found to have LGED, and 3-year OS for this cohort was quite poor at 20%. Cox regression analysis identified LGED as a predictor of OS while controlling for age, stage and location (OR:4.536, p-value=0.038). Despite the relatively low dose delivered, treatment likely contributed to the death of 4 patients with central tumors. Lobar gross endobronchial disease was an independent predictor for grade 5 pulmonary toxicity (n=4, p=0.007). Specifically, 3 of the 5 patients with LGED developed fatal radiation-induced bronchial stricture. Three-year LC, RC, DMFS and DFS results for the group were similar to contemporary studies at 90%, 90%, 82% and 65%. CONCLUSIONS: Central location of ES-NSCLC is a well-established predictor for severe SBRT-related toxicity. Here we identify LGED as a significant predictor of poor overall survival and grade 5 pulmonary toxicity. The relatively high rates of severe treatment-related toxicity seen in patients with central ES-NSCLC may be due in part to LGED. Underlying LGED may cause irreparable damage to the lobar airway, unmitigated by SBRT treatment thus increasing the risk of severe treatment-related toxicity. These findings should be verified in larger data sets. Future prospective central ES-NSCLC clinical trials should require staging bronchoscopy to identify LGED and further assess its clinical significance.

Minority Women.

Perceptions of illness, pain, and death are not static. They vary among populations according to their cultural and biological characteristics. Older black and Hispanic/Latinx women are unique in their approach to health care with respect to mentation, mobility, medication adherence, and what matters to them. It is the complexity of these components, which affect the ability of these women to age gracefully.

On the Track of the Missing tRNA Genes: A Source of Non-Canonical Functions?

Cellular tRNAs appear today as a diverse population of informative macromolecules with conserved general elements ensuring essential common functions and different and distinctive features securing specific interactions and activities. Their differential expression and the variety of post-transcriptional modifications they are subject to, lead to the existence of complex repertoires of tRNA populations adjusted to defined cellular states. Despite the tRNA-coding genes redundancy in prokaryote and eukaryote genomes, it is surprising to note the absence of genes coding specific translational-active isoacceptors throughout the phylogeny. Through the analysis of different releases of tRNA databases, this review aims to provide a general summary about those "missing tRNA genes." This absence refers to both tRNAs that are not encoded in the genome, as well as others that show critical sequence variations that would prevent their activity as canonical translation adaptor molecules. Notably, while a group of genes are universally missing, others are absent in particular kingdoms. Functional information available allows to hypothesize that the exclusion of isodecoding molecules would be linked to: 1) reduce ambiguities of signals that define the specificity of the interactions in which the tRNAs are involved; 2) ensure the adaptation of the translational apparatus to the cellular state; 3) divert particular tRNA variants from ribosomal protein synthesis to other cellular functions. This leads to consider the "missing tRNA genes" as a source of putative non-canonical tRNA functions and to broaden the concept of adapter molecules in ribosomal-dependent protein synthesis.

Expression, purification and initial characterization of human serum albumin domain I and its cysteine 34.

Human serum albumin presents in its primary structure only one free cysteine (Cys34) which constitutes the most abundant thiol of plasma. An antioxidant role can be attributed to this thiol, which is located in domain I of the protein. Herein we expressed domain I as a secretion protein using the yeast Pichia pastoris. In the initial step of ammonium sulfate precipitation, a brown pigment co-precipitated with domain I. Three chromatographic methods were evaluated, aiming to purify domain I from the pigment and other contaminants. Purification was achieved by cation exchange chromatography. The protein behaved as a non-covalent dimer. The primary sequence of domain I and the possibility of reducing Cys34 to the thiol state while avoiding the reduction of internal disulfides were confirmed by mass spectrometry. The reactivity of the thiol towards the disulfide 5,5´-dithiobis(2-nitrobenzoate) was studied and compared to that of full-length albumin. A ~24-fold increase in the rate constant was observed for domain I with respect to the entire protein. These results open the door to further characterization of the Cys34 thiol and its oxidized derivatives.

Pseudohypertriglyceridemia: A Novel Case with Important Clinical Implications.

Pseudohypertriglyceridemia is an overestimation of serum triglyceride levels that may incorrectly lead to a diagnosis of hypertriglyceridemia. Glycerol kinase deficiency is a condition in which glycerol cannot be phosphorylated to glycerol-3-phosphate, resulting in elevated levels of serum glycerol. Laboratory assays that measure triglycerides indirectly may be affected by elevated glyerol levels and incorrectly report serum tryglyceride levels. We present a case of a novel missense mutation in the GK gene leading to isolated glycerol kinase deficiency and pseudohypertriglyceridemia in a male infant of a mother with gestational diabetes. This paper reviews glycerol kinase deficiency, describes the challenges in diagnosing pseudohypertriglyceridemia, and provides suggestions on improving diagnostic accuracy. Additionally, a potential maternal-fetal interaction between gestational diabetes and glycerol kinase deficiency is discussed.

Fine-tuning the metabolic rewiring and adaptation of translational machinery during an epithelial-mesenchymal transition in breast cancer cells.

BACKGROUND: During breast cancer progression, the epithelial to mesenchymal transition has been associated with metastasis and endocrine therapy resistance; however, the underlying mechanisms remain elusive. To gain insight into this process, we studied the transition undergone by MCF7-derived cells, which is driven by the constitutive nuclear expression of a MKL1 variant devoid of the actin-binding domain (MKL1 ΔN200). We characterized the adaptive changes that occur during the MKL1-induced cellular model and focused on regulation of translation machinery and metabolic adaptation. METHODS: We performed a genome-wide analysis at the transcriptional and translational level using ribosome profiling complemented with RNA-Seq and analyzed the expression of components of the translation machinery and enzymes involved in energy metabolism. NGS data were correlated with metabolomic measurements and quantification of specific mRNAs extracted from polysomes and western blots. RESULTS: Our results reveal the expression profiles of a luminal to basal-like state in accordance with an epithelial to mesenchymal transition. During the transition, the synthesis of ribosomal proteins and that of many translational factors was upregulated. This overexpression of the translational machinery appears to be regulated at the translational level. Our results indicate an increase of ribosome biogenesis and translation activity. We detected an extensive metabolic rewiring occurring in an already "Warburg-like" context, in which enzyme isoform switches and metabolic shunts indicate a crucial role of HIF-1α along with other master regulatory factors. Furthermore, we detected a decrease in the expression of enzymes involved in ribonucleotide synthesis from the pentose phosphate pathway. During this transition, cells increase in size, downregulate genes associated with proliferation, and strongly upregulate expression of cytoskeletal and extracellular matrix genes. CONCLUSIONS: Our study reveals multiple regulatory events associated with metabolic and translational machinery adaptation during an epithelial mesenchymal-like transition process. During this major cellular transition, cells achieve a new homeostatic state ensuring their survival. This work shows that ribosome profiling complemented with RNA-Seq is a powerful approach to unveil in-depth global adaptive cellular responses and the interconnection among regulatory circuits, which will be helpful for identification of new therapeutic targets.

Nuclear accumulation of MKL1 in luminal breast cancer cells impairs genomic activity of ERα and is associated with endocrine resistance.

Estrogen receptor (ERα) is central in driving the development of hormone-dependent breast cancers. A major challenge in treating these cancers is to understand and overcome endocrine resistance. The Megakaryoblastic Leukemia 1 (MKL1, MRTFA) protein is a master regulator of actin dynamic and cellular motile functions, whose nuclear translocation favors epithelial-mesenchymal transition. We previously demonstrated that nuclear accumulation of MKL1 in estrogen-responsive breast cancer cell lines promotes hormonal escape. In the present study, we confirm through tissue microarray analysis that nuclear immunostaining of MKL1 is associated with endocrine resistance in a cohort of breast cancers and we decipher the underlining mechanisms using cell line models. We show through gene expression microarray analysis that the nuclear accumulation of MKL1 induces dedifferentiation leading to a mixed luminal/basal phenotype and suppresses estrogen-mediated control of gene expression. Chromatin immunoprecipitation of DNA coupled to high-throughput sequencing (ChIP-Seq) shows a profound reprogramming in ERα cistrome associated with a massive loss of ERα binding sites (ERBSs) generally associated with lower ERα-binding levels. Novel ERBSs appear to be associated with EGF and RAS signaling pathways. Collectively, these results highlight a major role of MKL1 in the loss of ERα transcriptional activity observed in certain cases of endocrine resistances, thereby contributing to breast tumor cells malignancy.

Integrative proteomic and glycoproteomic profiling of Mycobacterium tuberculosis culture filtrate.

Despite being the subject of intensive research, tuberculosis, caused by Mycobacterium tuberculosis, remains at present the leading cause of death from an infectious agent. Secreted and cell wall proteins interact with the host and play important roles in pathogenicity. These proteins are explored as candidate diagnostic markers, potential drug targets or vaccine antigens, and more recently special attention is being given to the role of their post-translational modifications. With the purpose of contributing to the proteomic and glycoproteomic characterization of this important pathogen, we performed a shotgun analysis of culture filtrate proteins of M. tuberculosis based on a liquid nano-HPLC tandem mass spectrometry and a label-free spectral counting normalization approach for protein quantification. We identified 1314 M. tuberculosis proteins in culture filtrate and found that the most abundant proteins belong to the extracellular region or cell wall compartment, and that the functional categories with higher protein abundance factor were virulence, detoxification and adaptation, and cell wall and cell processes. We could identify a group of proteins consistently detected in previous studies, most of which were highly abundant proteins. In culture filtrate, 140 proteins were predicted to contain one of the three types of bacterial N-terminal signal peptides. Besides, various proteins belonging to the ESX secretion systems, and to the PE and PPE families, secreted by the type VII secretion system using nonclassical secretion signals, were also identified. O-glycosylation was identified in 46 proteins, many of them lipoproteins and cell wall associated proteins. Finally, we provide proteomic evidence for 33 novel O-glycosylated proteins, aiding to the glycoproteomic characterization of relevant antigenic membrane and exported proteins. These findings are expected to collaborate with the research on pathogen derived biomarkers, virulence factors and vaccine candidates, and to provide clues to the understanding of the pathogenesis and survival strategies adopted by M. tuberculosis.

Alternative Mechanisms of p53 Action During the Unfolded Protein Response.

The tumor suppressor protein p53 orchestrates cellular responses to a vast number of stresses, with DNA damage and oncogenic activation being some of the best described. The capacity of p53 to control cellular events such as cell cycle progression, DNA repair, and apoptosis, to mention some, has been mostly linked to its role as a transcription factor. However, how p53 integrates different signaling cascades to promote a particular pathway remains an open question. One way to broaden its capacity to respond to different stimuli is by the expression of isoforms that can modulate the activities of the full-length protein. One of these isoforms is p47 (p53/47, Δ40p53, p53ΔN40), an alternative translation initiation variant whose expression is specifically induced by the PERK kinase during the Unfolded Protein Response (UPR) following Endoplasmic Reticulum stress. Despite the increasing knowledge on the p53 pathway, its activity when the translation machinery is globally suppressed during the UPR remains poorly understood. Here, we focus on the expression of p47 and we propose that the alternative initiation of p53 mRNA translation offers a unique condition-dependent mechanism to differentiate p53 activity to control cell homeostasis during the UPR. We also discuss how the manipulation of these processes may influence cancer cell physiology in light of therapeutic approaches.