Evaluation of Anomalies and Neurodevelopment in Children Exposed to ZIKV during Pregnancy.

Zika virus (ZIKV) infection in pregnancy is associated with birth and developmental alterations in infants. In this study, clinical records of 47 infants whose mothers had Zika during pregnancy or clinical manifestations compatible with Zika were reviewed. A description of the infants' anomalies was established, and a neurodevelopmental assessment was performed on 18 infants, using the Evaluation of Infant Development (EDI for its initialism in Spanish) and DDST-II (Denver Developmental Screening Test II) tests. From his sample, 74.5% of the infants evaluated had major anomalies and 51.9% had minor anomalies. The incidence of major anomalies, related to trimester of pregnancy, was 84.2% for the first trimester, 77.8% for the second trimester, and 37.5% in the third trimester. A similar trend was observed in the frequency of infants without anomalies and was less evident in the incidence of minor anomalies (p = 0.016). Through neurodevelopmental assessments, EDI identified 27.8% of infants as having normal development, while 55.5% of affected infants had developmental delay, and 16.7% were at risk for developmental delay. The DDSST-II showed that 77.7% infants had delay in the gross motor and language area, 88.8% in the fine-adaptative motor area, and 72.2% in the personal-social area. In this work, children of mothers with ZIKV infection during pregnancy may have major or minor anomalies regardless of the trimester of pregnancy in which the infection occurred. The neurodevelopmental assessment shows that ZIKV can cause a developmental delay in infants with the fine-adaptative motor area being the most affected.

Influence of type 2 diabetes mellitus on mortality in women with breast cancer: A matched case-control study.

AIMS: The study assessed the association between the presence of type2 diabetes mellitus (T2DM) and mortality in women with breast cancer (BC). METHODS: A matched pair case-control study was conducted at the State Cancer Center, which is located in Xalapa, Veracruz, Mexico. It was matched by age (±3 years) within a cohort of 1442 patients with BC. Descriptive statistics were performed. Analysis through paired odds ratio (OR and multivariate analyses were used to calculate the association between BC mortality and the variables studied. RESULTS: 166 cases and 166 controls with confirmed diagnosis of BC were studied, with a mean age of 52.9 ± 11.9 years. The T2DM was associated with an increased mortality of women with BC (OR = 1.75 95 %CI 1.06-2.89). Similarly, metastasis (OR = 14.17 95 %CI 6.19-32.342), advanced clinical stage (OR = 3.04 95 %CI 1.45 - 6.38), and the molecular subtypes Her2 (OR = 2.0 95 %CI 1.02-3.92), and triple negative (OR = 3.54 95 %CI 1.72-7.32). There was no difference in mean glucose between cases and controls (208.9 ± 132 vs 194.4 ± 90.4 mg/dL, respectively). CONCLUSION: T2DM was found to be a relevant risk factor for BC mortality in this Mexican population. Thus, it is important to consider the presence and evolution of DM in the prevention programs, diagnostic algorithms and treatments established for BC.

Age Under 30 Years As a Predictor of Poor Survival in a Cohort of Mexican Women With Breast Cancer.

INTRODUCTION: Young women under 30 years with breast cancer (BC) are an emerging challenge. The purpose is to identify prognostic factors for survival in young women under 30 years of age with BC. MATERIAL AND METHODS: A retrospective cohort study was conducted among women younger than or equal to 40 years with BC and who were treated at the State Cancer Center during the period 2012-2017. Overall survival was assessed using the Kaplan-Meier method and the log-rank test. Univariate and multivariate analysis assessed survival predictors using Cox proportional hazards regression model. RESULTS: 282 young women were included. The >30-year-old subgroup showed a significant association with excess weight (P = .002) compared to the <30-year-old group. The <30-year-old subgroup showed a poor overall survival (56.7%), as well as highly significant values in advanced clinical stages, metastatic nodules, metastasis, and neoadjuvant therapy (P < .001). In Model 3 of the multivariate analysis, age <30 years (HR = 3.0; 95% CI 1.1 to 8.6), triple negative subtype (HR = 2.6; 95% CI 1.1 to 6.0), tumor size >5 cm HR = 2.3; 95% CI 1.03 to 5.1), and advanced clinical stages (HR = 6.6 95% CI 1.3 to 35.5) persisted as predictors. CONCLUSIONS: Being very young (<30 years) is a predictor for limited survival compared to the age of 30-40 years, as well as the tumor covariates for a worse prognosis: triple negative subtype, advanced stages, positive lymph nodes, and distant metastases in liver.

Eukaryotic initiation factor 4A (eIF4A) during viral infections.

The helicase eIF4A is part of the cellular eIF4F translation initiation complex. The main functions of eIF4A are to remove secondary complex structures within the 5'-untranslated region and to displace proteins attached to mRNA. As intracellular parasites, viruses regulate the processes involved in protein synthesis, and different mechanisms related to controlling translation factors, such as eIF4A, have been found. The inhibitors of this factor are currently known; these substances could be used in the near future as part of antiviral pharmacological therapies in instances of replication cycles in which eIF4A is required. In this review, the particularities of how some viruses make use of this initiation factor to synthesize their proteins are discussed.

Knowledge, Attitudes, and Practices about Zika among a University Community Located in an Endemic Zone in Mexico.

To assess the knowledge, attitudes, and practices about the Zika virus in both students and workers at the University of Veracruz, an online survey was conducted. The participants were divided into two groups: one according to sex, the other according to whether they were workers or students. Their answers were classified into knowledge, attitudes, and practices and they were rated as low, medium, and high. The results showed that knowledge about Zika prevailing among the university population is considered as medium in 79.4% of the study population. Most respondents know that the mosquito spreads the Zika virus (98.8%) and the clinical characteristics, while sexual transmission by the virus is little known (36.85%). Both the univariate analysis (OR (CI5) 0.227 (0.070⁻0.735), p = 0.013] and multivariate analysis (OR (CI95) 0.234 (0.071⁻778), p = 0.018] showed that belonging to the health sciences area is related to having a greater knowledge about Zika. Despite the existing knowledge, a low level of prevention practices prevails in the whole community (55%). A medium level of knowledge about Zika prevailed, while proper implementation of preventive measures for Zika is low, despite the fact that the state of Veracruz-the place where the University is located-is an endemic area.

4EBP1 Is Dephosphorylated by Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) requires protein biosynthesis machinery to generate progeny. There is evidence that RSV might alter some translation components since stress granules are formed in their host cells. Consistent with these observations, we found that RSV induces dephosphorylation of 4EBP1 (eIF4E-binding protein), an important cellular translation factor. Our results show no correlation between the 4EBP1 dephosphorylation time and the decrease in the global rate of protein synthesis. Interestingly, treatment with rapamycin stimulates virus generation. The results suggest that RSV is a virus that still contains unknown mechanisms involved in the translation of their mRNAs through the alteration or modification of some translation factors, such as 4EBP1, possibly to favor its replicative cycle.

Matrix metalloproteinases and their tissue inhibitors in gastric cancer as molecular markers.

Gastric cancer is a complex disease that involves a range of biological individuals and tumors with histopathological features. The pathogenesis of this disease is multi-factorial and includes the interaction of genetic predisposition with environmental factors. Gastric cancer is normally diagnosed in advanced stages where there are few alternatives to offer and the prognosis is difficult to establish. Metastasis is the leading cause of cancer deaths. Identification of key genes and signaling pathways involved in metastasis and recurrence could predict these events and thereby identify therapeutic targets. In this context, the extracellular matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) represent a potential prognostic tool, because both genetic families regulate growth, angiogenesis, invasion, immune response, epithelial mesenchymal transition and cellular survival. Proteolytic parameters based on MMP/TIMP expression could be useful in the identification of patients with a high probability of developing distant metastases or peritoneal dissemination for each degree of histological malignancy. It is also probable that these parameters can allow improvement in the extent of surgery and dictate the most suitable therapy. We reviewed papers focused on human gastric epithelial cancer as a model and focus on the potential use of MMPs and TIMPs as molecular markers; also we include literature regarding gastric cancer risk factors, classification systems and MMP/TIMP regulation.

Helicobacter pylori and gastritis: the role of extracellular matrix metalloproteases, their inhibitors, and the disintegrins and metalloproteases--a systematic literature review.

Helicobacter pylori (H. pylori) is the etiologic agent of gastritis; it has been estimated that 50 % of the world's population could be infected by this bacteria. Gastritis may progress to chronic atrophic gastritis, a condition associated with the development of gastric cancer (GC). Several matrix metalloproteases (MMP) and tissue inhibitors of MMPs (TIMP) as well as disintegrins and metalloproteases (ADAM) have been reported as being involved in gastritis. Among other processes, these protein families participate in remodeling the extracellular matrix, cell signaling, immune response, angiogenesis, inflammation and epithelial mesenchymal transition. This systematic review analyzes the scientific evidence surrounding the relationship between members of the MMP, TIMP and ADAM families and infection by H. pylori in gastritis, considering both in vitro and in vivo studies. Given the potential clinical value of certain members of the MMP, TIMP and ADAM families as molecular markers in gastritis and the association of gastritis with GC, the need for further study is highlighted.

[Matrix metalloproteases as molecular markers in gastric cancer]. / Metaloproteasas de la matriz extracelular como marcadores moleculares en cáncer gástrico.

Gastric cancer is the second leading cause of cancer-associated mortality in the world. Prognosis in patients with gastric cancer is difficult to establish because it is commonly diagnosed when gastric wall invasion and metastasis have occurred. Currently, some members of the extracellular matrix metalloproteinases have been identified, whose expression in gastric tumor tissue is significantly elevated compared to healthy gastric tissue. Matrix metalloproteinases are 24 zinc-dependent endopeptidases that catalyze the proteolysis of the extracellular matrix. This degradation allows the cancer cells invade the surrounding stroma and trigger metastasis. Upregulation of certain matrix metalloproteinases in gastric cancer has been associated with a poor prognosis and elevated invasive capacity. This review compiles evidence about the genetic expression of matrix metalloproteinases in gastric cancer and their role in tumour invasion and metastasis, emphasizing their potential as molecular markers of prognosis.

The regulation of matrix metalloproteinases and their inhibitors.

The matrix metalloproteinases (MMP) are a family of 23 enzymes in man. These enzymes were originally described as cleaving extracellular matrix (ECM) substrates with a predominant role in ECM homeostasis, but it is now clear that they have much wider functionality. Control over MMP and/or tissue inhibitor of metalloproteinases (TIMP) activity in vivo occurs at different levels and involves factors such as regulation of gene expression, activation of zymogens and inhibition of active enzymes by specific inhibitors. Whilst these enzymes and inhibitors have clear roles in physiological tissue turnover and homeostasis, if control of their expression or activity is lost, they contribute to a number of pathologies including e.g. cancer, arthritis and cardiovascular disease. The expression of many MMPs and TIMPs is regulated at the level of transcription by a variety of growth factors, cytokines and chemokines, though post-transcriptional pathways may contribute to this regulation in specific cases. The contribution of epigenetic modifications has also been uncovered in recent years. The promoter regions of many of these genes have been, at least partly, characterised including the role of identified single nucleotide polymorphisms. This article aims to review current knowledge across these gene families and use a bioinformatic approach to fill the gaps where no functional data are available.

Activation of p38 and JNK MAPK pathways abrogates requirement for new protein synthesis for phorbol ester mediated induction of select MMP and TIMP genes.

The human matrix metalloproteinase (MMP) gene family includes 24 genes whose regulated expression, together with that of four tissue inhibitors of metalloproteinases (TIMPs), is essential in tissue remodelling and cell signalling. Quantitative real-time-PCR (qPCR) analysis was used to evaluate the shared and unique patterns of control of these two gene families in human MRC-5 and WI-38 fibroblasts in response to the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate (PMA). The requirement for ongoing translation was analysed using three protein synthesis inhibitors, anisomycin, cycloheximide and emetine. PMA induced MMP1, 3, 8, 9, 10, 12, 13, 14 and TIMP1 and TIMP3 RNAs after 4-8 h, and induction of all except MMP9 and TIMP3 was blocked by all protein synthesis inhibitors. However, even though all inhibitors effectively blocked translation, PMA-induction of MMP9 and TIMP3 was blocked by emetine but was insensitive to cycloheximide and anisomycin. Anisomycin alone induced MMP9 and TIMP3, along with MMP25 and MMP19. The extracellular signal-regulated kinases (ERKs)-1/2 were strongly activated by PMA, while anisomycin activated the c-Jun N-terminal kinase (JNK) and p38 pathways, and cycloheximide activated p38, but emetine had no effect on the stress-activated mitogen-activated protein kinase (MAPK) pathways. The involvement of the p38 and JNK pathways in the selective effects of anisomycin and cycloheximide on MMP/TIMP expression was supported by use of pharmacological inhibitors. These data confirm that most inducible MMPs and TIMP1 behave as "late" activated, protein synthesis-dependent genes in fibroblasts. However, the requirement of protein synthesis for PMA-induction of MMPs and TIMPs is not universal, since it is abrogated for MMP9 and TIMP3 by stimulation of the stress-activated MAPK pathways. The definition of clusters of co-regulated genes among the two gene families will aid in bioinformatic dissection of control mechanisms.

Tissue inhibitor of metalloproteinase-3 is up-regulated by transforming growth factor-beta1 in vitro and expressed in fibroblastic foci in vivo in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by fibroblast expansion and extracellular matrix accumulation. However, the mechanisms involved in matrix remodeling have not been elucidated. In this study, the authors aimed to evaluate the expression of the tissue inhibitors of matrix metalloproteinases (TIMPs) in human fibroblasts and whole tissues from IPF and normal lungs. They also determined the role of mitogen-activated protein kinase (MAPK) in TIMP3 expression. TIMP1, TIMP2, and TIMP3 were highly expressed in lung fibroblasts. Transforming growth factor (TGF)-beta1, a profibrotic mediator, induced strong up-regulation of TIMP3 at the mRNA and protein levels. The authors examined whether the MAPK pathway was involved in TGF-beta1-induced TIMP3 expression. TGF-beta1 induced the phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2. Biochemical blockade of p38 by SB203580, but not of the ERK MAPK pathway, inhibited the effect of this factor. The effect was also blocked by the tyrosine kinase inhibitor genistein and by antagonizing TGF-beta1 receptor type I (activin-linked kinase [ALK5]). In IPF tissues TIMP3 gene expression was significantly increased and the protein was localized to fibroblastic foci and extracellular matrix. Our findings suggest that TGF-beta1-induced TIMP3 may be an important mediator in lung fibrogenesis.

Membrane type-matrix metalloproteinases in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by fibroblast expansion and extracellular matrix accumulation. Some secreted matrix metalloproteinases (MMPs) as MMP2 are highly upregulated in IPF lungs. Membrane-type (MT)-MMPs participate in the activation of pro-MMP2. However, they have not been examined in IPF. METHODS: Type I transmembrane MT-MMPs, MT1, MT2, MT3, and MT5-MMP were analyzed by real-time PCR and immunohistochemistry in IPF and normal lungs. MMP-2 was also immunolocalized and evaluated by gelatin zymography in BAL fluids. Additionally, the MT-MMPs were examined by real time PCR in lung fibroblasts stimulated with TGF-beta1 and IFN-gamma. RESULTS: MT1-MMP, was the most highly expressed followed by MT2- and MT5-MMP, and by a moderate expression of MT3-MMP. Regarding their localization, MT1- and MT2-MMPs were found in alveolar epithelial cells, MT3-MMP in fibroblasts from fibroblastic foci and alveolar epithelial cells and MT5-MMP in basal bronchiolar epithelial cells and in areas of squamous metaplasia. MMP2 was localized in alveolar and basal bronchiolar epithelial cells and fibroblasts, and increased active enzyme was observed in BAL fluids. In lung fibroblasts, TGF-beta1 induced a strong upregulation of MT3-MMP, both at the gene and protein level. This effect was blocked by genistein, a protein tyrosin kinase inhibitor and partially repressed by SB203580 a p38 MAP kinase inhibitor. IFN-gamma had no effect. CONCLUSIONS: MT-MMPs are expressed in IPF, in the same cell types as MMP2. Mostly by different types of epithelial cells a pivotal component in the aberrant remodeling of the lung microenvironment. Interestingly MT3-MMP that was found in fibroblastic foci was upregulated in vitro by TGF-beta1 a potent profibrotic mediator.

Differential effects of histone deacetylase inhibitors on phorbol ester- and TGF-beta1 induced murine tissue inhibitor of metalloproteinases-1 gene expression.

Expression of the tissue inhibitor of metalloproteinases-1 (Timp-1) gene can be induced by either phorbol myristate acetate (PMA) or transforming growth factor beta1 (TGF-beta1), although the signalling pathways involved are not clearly defined. Canonically, histone deacetylase inhibitors (HDACi) such as trichostatin A (TSA) or sodium butyrate (NaB) increase total cellular histone acetylation and activate expression of susceptible genes. Remarkably, PMA and TGF-beta1 stimulation of Timp-1 show a differential response to TSA or NaB. TSA or NaB potentiate PMA-induced Timp-1 expression but repress TGF-beta1-induced Timp-1 expression. The repression of TGF-beta1-induced Timp-1 by TSA was maximal at 5 ng.mL(-1), while for the superinduction of PMA-induced Timp-1 expression, the maximal dose is > 500 ng x mL(-1) TSA. A further HDACi, valproic acid, did not block TGF-beta1-induced Timp-1 expression, demonstrating that different HDACs impact on the induction of Timp-1. For either PMA or TGF-beta1 to induce Timp-1 expression, new protein synthesis is required, and the induction of AP-1 factors closely precedes that of Timp-1. The effects of the HDACi can be reiterated in transient transfection using Timp-1 promoter constructs. Mutation or deletion of the AP-1 motif (-59/-53) in the Timp-1 promoter diminishes PMA-induction of reporter constructs, however, the further addition of TSA still superinduces the reporter. In c-Jun-/- cells, PMA still stimulates Timp-1 expression, but TSA superinduction is lost. Transfection of a series of Timp-1 promoter constructs identified three regions through which TSA superinduces PMA-induced Timp-1 and we have demonstrated specific protein binding to two of these regions which contain either an avian erythroblastosis virus E26 (v-ets) oncogene homologue (Ets) or Sp1 binding motif.

Expression analysis of the entire MMP and TIMP gene families during mouse tissue development.

Matrix metalloproteinases (MMPs) and adamalysins (ADAMs) cleave many extracellular proteins, including matrix, growth factors, and receptors. We profiled the RNA levels of every MMP, several ADAMs, and inhibitors of metalloproteinases (TIMPs and RECK) in numerous mouse tissues during development and in the uterus during pregnancy. Observations include: most secreted MMPs are expressed at low to undetectable levels in tissues, whereas membrane-bound MMPs, ADAMs and inhibitors are abundant; almost every proteinase and inhibitor is present in the uterus or placenta at some time during gestation; the mouse collagenases mColA and mColB are found exclusively in the uterus and testis; and each tissue has its unique signature of proteinase and inhibitor expression.