The Role of Matrix Metalloproteinase-9 (MMP-9) as a Prognostic Factor in Epithelial and Lymphatic Neoplasia.

Matrix metalloproteinase 9 is a zinc-dependent extracellular matrix remodeling endopeptidase directly involved in the local invasion mechanisms and in metastasis. The current review aims to evaluate the expression of MMP-9 and its prognostic value in the most common epithelial and lymphatic neoplasia of the pelvic-abdominal region. We included 19 studies published between January 1st, 1995 and July 31st 2015, involving a total of 1523 patients. The analysis indicate that MMP-9 is valid marker of poor survival in epithelial and lymphatic neoplasia.

Glutamate release in the ventromedial hypothalamus of the female rat during copulation: modulation by estradiol.

Binding of glutamate or its ionotropic receptor agonists in the ventromedial hypothalamus (VMH) of female rats inhibits both appetitive and consummatory aspects of sexual behavior. Because vaginocervical stimulation activates glutamate neurons in the VMH, and administration of estradiol benzoate (EB) and progesterone (P) delays this effect, the present study examined the effects of hormonal priming on glutamate release within the VMH of female rats paired with sexually vigorous males. Ovariectomized, sexually experienced rats were implanted with guide cannula aimed at the ventrolateral VMH, through which microdialysis probes were inserted prior to testing. Females were assigned randomly to one of three hormone treatment conditions: EB+P, EB alone, or the oil vehicle. Testing was conducted over 5h, including a 120-min period of habituation to the testing chamber, a 60-min period of baseline sample collection, and a 120-min period during which a sexually vigorous male was introduced into the testing chamber. Dialysates were collected every 20min during the test and were analyzed for glutamate using HPLC. Females primed with oil had large and significant increases in glutamate release from baseline once the male was introduced to the chamber. Treatment with EB alone decreased glutamate release in response to male cues. Although treatment with EB+P did not differ significantly from EB alone, the degree of reduced glutamate release was less than with EB alone. These results indicate that priming with EB reduces glutamate transmission in the VMH in response to male cues. Taken together with our previous findings, estradiol blunts the activation of glutamate neurons in the VMH thus allowing female rats to copulate.

Telesonography: virtual 3D image processing of remotely acquired abdominal, vascular, and fetal sonograms.

PURPOSE: To design and test a new telesonography technique using remote volume acquisition by untrained operators in locations without access to trained sonographers, postprocessing, and interpretation done at expert centers. MATERIALS AND METHODS: The technique was tested with 84 sonograms of organs acquired in pregnant women (n = 8) and patients with various abdominal pathologic conditions (n = 11) located in French Guyana (France), Ceuta (Spain), and Murighiol (Romania). An operator inexperienced in sonography (US) placed the transducer over the predetermined acoustic window for each organ, then swept it from a -45° to a +45° position to scan the targeted organ. The acquired volume dataset was sent to an expert center via the Internet and reconstructed using a proprietary software, which allowed a trained sonographer to navigate through the appropriately reconstructed sonograms. RESULTS: After three-dimensional processing at the expert center, the organs scanned in the obstetrical cases were adequately visualized by the expert in seven of eight (88%) examinations of the fetal head, femur, and umbilical cord and eight of eight (100%) examinations of the fetal abdomen and placenta, whereas in the general abdominal cases, the liver, gallbladder, portal vein, and right kidney were correctly visualized in 10 of 11 (91%) examinations. CONCLUSIONS: Telesonography allowed untrained operators to scan and transfer the US volume datasets over the Internet to an expert center where an expert sonographer could navigate through the reconstructed US volume and visualize sonograms of diagnostic quality.

Global activation of oncogenic pathways underlies therapy resistance in diffuse midline glioma.

Diffuse midline gliomas (DMGs) are aggressive pediatric brain tumors with dismal prognosis due to therapy-resistant tumor growth and invasion. We performed the first integrated histologic/genomic/proteomic analysis of 21 foci from three pontine DMG cases with supratentorial dissemination. Histone H3.3-K27M was the driver mutation, usually at high variant allele fraction due to recurrent chromosome 1q copy number gain, in combination with germline variants in ATM, FANCM and MYCN genes. Both previously reported and novel recurrent copy number variations and somatic pathogenic mutations in chromatin remodeling, DNA damage response and PI3K/MAPK growth pathways were variably detected, either in multiple or isolated foci. Proteomic analysis showed global upregulation of histone H3, lack of H3-K27 trimethylation, and further impairment of polycomb repressive complex 2 by ASXL1 downregulation. Activation of oncogenic pathways resulted from combined upregulation of N-MYC, SOX2, p65/p50 NF-κB and STAT3 transcription factors, EGFR, FGFR2, PDGFRα/ß receptor tyrosine kinases, and downregulation of PHLPP1/2, PTEN and p16/INK4A tumor suppressors. Upregulation of SMAD4, PAI-1, CD44, and c-SRC in multiple foci most likely contributed to invasiveness. This integrated comprehensive analysis revealed a complex spatiotemporal evolution in diffuse intrisic pontine glioma, recommending pontine and cerebellar biopsies for accurate populational genetic characterization, and delineated common signaling pathways and potential therapeutic targets. It also revealed an unsuspected activation of a multitude of oncogenic pathways, including cancer cell reprogramming, explaining the resistance of DMG to current therapies.

Cortical stabilization of beta-catenin contributes to NHERF1/EBP50 tumor suppressor function.

Anchorage-independent growth is a hallmark of tumor growth and results from enhanced proliferation and altered cell-cell and cell-matrix interactions. By using gene-deficient mouse embryonic fibroblasts (MEFs), we showed for the first time that NHERF1/EBP50 (Na/H exchanger regulator factor 1/ezrin-radixin-moesin binding phosphoprotein 50), an adapter protein with membrane localization under physiological conditions, inhibits cell motility and is required to suppress anchorage-independent growth. Both NHERF1 PDZ domains are necessary for the tumor suppressor effect. NHERF1 associates directly through the PDZ2 domain with beta-catenin and is required for beta-catenin localization at the cell-cell junctions in MEFs. Mechanistically, the absence of NHERF1 selectively decreased the interaction of beta-catenin with E-cadherin, but not with N-cadherin. The ensuing disorganization of E-cadherin-mediated adherens junctions as well as the observed moderate increase in beta-catenin transcriptional activity contributed most likely to the anchorage-independent growth of NHERF1-deficient MEFs. In vivo, NHERF1 is specifically localized at the apical brush-border membrane in intestinal epithelial cells and is required to maintain a fraction of the cortical beta-catenin at this level. Thus, NHERF1 emerges as a cofactor essential for the integrity of epithelial tissues by maintaining the proper localization and complex assembly of beta-catenin.

Autophagy-inducing agents augment the antitumor effect of telerase-selve oncolytic adenovirus OBP-405 on glioblastoma cells.

Oncolytic adenoviruses are a promising tool in cancer therapy. In this study, we characterized the role of autophagy in oncolytic adenovirus-induced therapeutic effects. OBP-405, an oncolytic adenovirus regulated by the human telomerase reverse transcriptase promoter (hTERT-Ad, OBP-301) with a tropism modification (RGD) exhibited a strong antitumor effect on glioblastoma cells. When autophagy was inhibited pharmacologically, the cytotoxicity of OBP-405 was attenuated. In addition, autophagy-deficient Atg5(-/-) mouse embryonic fibroblasts (MEFs) were less sensitive than wild-type MEFs to OBP-405. These findings indicate that OBP-405-induced autophagy is a cell killing effect. Moreover, autophagy-inducing therapies (temozolomide and rapamycin) synergistically sensitized tumor cells to OBP-405 by stimulating the autophagic pathway without altering OBP-405 replication. Mice harboring intracranial tumors treated with OBP-405 and temozolomide survived significantly longer than those treated with temozolomide alone, and mice treated with OBP-405 and the rapamycin analog RAD001 survived significantly longer than those treated with RAD001 alone. The observation that autophagy inducers increase OBP-405 antitumor activity suggests a novel strategy for treating patients with glioblastoma.

Sjögren's syndrome associated with chronic hepatitis C - the benefit of the antiviral treatment.

Chronic hepatitis C virus infection (CHCV) has high prevalence of immunological abnormalities. Extrahepatic manifestations (EHM) have been reported in association with CHCV infection, whose heterogeneity makes difficult any correlation between the two disorders. Among extrahepatic symptoms of C virus hepatitis, sicca syndrome is also registered. Sjögren's or sicca syndrome (SS) is a chronic, slowly progressive disease, with inflammatory-immune mediation characterized by lymphocytic infiltration of the lachrymal and salivary glands. A distinct primary form and a secondary one, occurring when presented in the context of an autoimmune or hepatic disease have been described. We present a case of SS in a patient with CHCV, commenting a possible link between primary SS and the CHCV, as well as the similarities and the distinctions among these conditions. Our conclusion is that CHCV can induce SS with some clinical particularities like presence of pericapillary and not pericanalicular lymphocytic infiltrate without destroying the salivary glands, in the absence of SS-A/SS-B antibodies. The favorable evolution of SS under IFN therapy is an argument for an authentic relation. Further studies are necessary to determine if CHCV is an etiological agent of SS or of it can induce a pseudo-sicca syndrome, characterized by a simple glandular inflammation consisting mainly in a simple lymphocytic adenitis.

Associations between lifestyle factors and smoking status during pregnancy in a group of Romanian women.

BACKGROUND: There is an estimated birth rate of 9.27 births/1,000 population in Romania each year, with approximately 8.4% born with low birth weight (LBW). Our purpose was to evaluate the relationships between maternal smoking and LBW and preterm birth in Mureș County, Romania. METHODS: We conducted a cross-sectional survey of 1,278 mothers who had given birth in Mureș County obstetrical wards in 2015, based on a lifestyle questionnaire of 109 items and personal and laboratory data from hospitals records. RESULTS: The variables associated with smoking during pregnancy taken into account were: Rroma ethnicity, education <8 grades, income lower than 140 dollars (minimum wages in our country), and lack of facilities in their households. In a multivariable model, smoking during pregnancy was correlated with a low level of education (p = .02), coffee and alcohol use (p = .0001), and lack of interest in potential environmental and behavioral risks during pregnancy (including smoking and diet). The newborn baby's weight was associated with smoker status of the mother (OR 1.71, 95%CI 1.09-2.66, p = .01), by the lack of ownership of a household (OR 3.52, 95%CI 2.27-5.47, p = .0001), and by the pregnant woman not receiving proper information regarding a healthy behavior and diet during pregnancy (OR 1.91, 95%CI 1.33-2.74, p = .0005). CONCLUSION: Our study aimed to emphasize the high rates of maternal smoking during pregnancy and its importance in LBW outcomes in Romanian pregnant women. Moreover, the study highlights disparities in smoking status observed in ethnic minorities and those living in poverty.

Biological effects of c-Mer receptor tyrosine kinase in hematopoietic cells depend on the Grb2 binding site in the receptor and activation of NF-kappaB.

The c-Mer receptor tyrosine kinase (RTK) is most closely related to chicken c-Eyk and belongs to the Axl RTK subfamily. Although not detected in normal lymphocytes, c-Mer is expressed in B- and T-cell leukemia cell lines, suggesting an association with lymphoid malignancies. To gain an understanding of the role of this receptor in lymphoid cells, we expressed in murine interleukin-3 (IL-3)-dependent Ba/F3 pro-B-lymphocyte cells a constitutively active receptor, CDMer, formed from the CD8 extracellular domain and the c-Mer intracellular domain. Cells transfected with a plasmid encoding the CDMer receptor became IL-3 independent. When tyrosine (Y)-to-phenylalanine (F) mutations were introduced into c-Mer, only the Y867 change significantly reduced the IL-3-independent cell proliferation. The Y867 residue in the CDMer receptor mediated the binding of Grb2, which recruited the p85 phosphatidylinositol 3-kinase (PI 3-kinase). Despite the difference in promotion of proliferation, both the CDMer and mutant F867 receptors activated Erk in transfected cells. On the other hand, we found that both transcriptional activation of NF-kappaB and activation of PI 3-kinase were significantly suppressed with the F867 mutant receptor, suggesting that the activation of antiapoptotic pathways is the major mechanism for the observed phenotypic difference. Consistent with this notion, apoptosis induced by IL-3 withdrawal was strongly prevented by CDMer but not by the F867 mutant receptor.

Variation in uterus position prior to brachytherapy of the cervix: A case report.

Rationale: brachytherapy is administered in the treatment of patients with locally advanced cervical cancer following chemoradiotherapy. Lack of local anatomy evaluation prior to this procedure might lead to the selection of an inappropriate brachytherapy applicator, increasing the risk of side effects (e.g. uterus perforation, painful procedure ...). Objective: To assess the movement of the uterus and cervix prior to brachytherapy in patients with gynecological cancer, in order to select the proper type of brachytherapy applicator. Also we wanted to promote the replacement of the plain X-ray brachytherapy with the image-guided procedure. Methods and results: We presented the case of a 41-year-old female diagnosed with a biopsy that was proven cervical cancer stage IIIB. At diagnosis, the imaging studies identified an anteverted uterus. The patient underwent preoperative chemoradiotherapy. Prior to brachytherapy, the patient underwent a pelvic magnetic resonance imaging (MRI), which identified a displacement of the uterus in the retroverted position. Discussion: A great variety of brachytherapy applicators is available nowadays. Major changes in uterus position and lack of evaluation prior to brachytherapy might lead to a higher rate of incidents during this procedure. Also, by using orthogonal simulation and bidimensional (2D) treatment planning, brachytherapy would undoubtedly fail to treat the remaining tumoral tissue. This is the reason why we proposed the implementation of a prior imaging of the uterus and computed tomography (CT)/ MRI-based simulation in the brachytherapy procedure. Abbreviations: MRI = magnetic resonance imaging, CT = computed tomography, CTV = clinical target volume, DVH = dose-volume histogram, EBRT = external beam radiotherapy, GTV = gross tumor volume, Gy = Gray (unit), ICRU = International Commission of Radiation Units, IGRT = image guided radiotherapy, IM = internal margin, IMRT = image modulated radiotherapy, ITV = internal target volume, MRI = magnetic resonance imaging, OAR = organs at risk, PTV = planning target volume, QUANTEC = Quantitative Analyses of Normal Tissue Effects in the Clinic.

Assessing the Degree of Severity of Acute Pancreatitis by Using Multiparameter Scores.

AIM: To establish a clinical severity diagnosis and a therapeutical strategy in acute pancreatitis (A.P.) by using multiparameter bioclinical and morphological scores. MATERIAL AND METHOD: 71 patients, diagnosed with A.P., between 2012-2016, admitted to the surgical clinics of the Military Emergency Hospital "Dr. Stefan Odobleja" and the Clinical County Emergency Hospital of Craiova, were investigated, following the severity diagnosis, both at admission and in evolution, with the aim of obtaining an optimal therapeutic approach. The Ranson, Imre, Marshall, Balthazar and EPIC scores were used. RESULTS: By analyzing specially the values of the computer tomography severity index of the study group patients, 14.29% of patients were classified as light severity AP with favorable prognosis, 37.14% of patients moderate severity AP, and 48.57% severe AP. The examination of the CT, one of the most important diagnosis tests for AP, established that 34.29% of patients suffered from AP in Balthazar grade B and 22.85% Balthazar grade C, the severity forms we encountered most in our study. The correlation between HCT (hematocrit) value and Ranson score presents a Pearson correlation coefficient r of-0.339, which indicates the existence of a statistically significant inversely proportional relation. CONCLUSION: Corroboration of the bioclinical and imagistic data, summed as multiparameter scores, allowed us to classify AP into different severity forms: moderate severity AP (14.29%), moderate-severe AP (37.14%) and severe AP (48.57%), which will then facilitate choosing the right therapeutic approach.

Utilizing Multiparameter Scores and Procalcitonin as Prognosis Markers for the Degree of Severity of Acute Pancreatitis.

AIM: Corroborating the Ranson, Marshall, computer tomography severity index (EPIC score) multiparameter tests with the biological marker procalcitonin in order to establish the degree of severity of acute pancreatitis for therapeutic management and rate of complications. MATERIAL AND METHOD: 20 patients were surveyed, diagnosed with acute pancreatitis in the surgery clinic of the Military Emergency Hospital Dr. Ștefan Odobleja, between 2016-2017, with the aim of determining the clinical, etiological and severity diagnosis by corroborating the multiparameter scores with the plasma level of procalcitonin. RESULTS: Following the use of multiparameter scores to identify the degree of severity of acute pancreatitis, we established that the best prediction is achieved by the Ranson score and the computer tomography severity index (EPIC score), with an accuracy of 90% . As for the values of the correlation coefficient, this was highly significant when correlating Ranson score and procalcitonin (r = 0.918). Other correlations were also highly significant, with values of r = 0.797 when correlating EPIC score and procalcitonin, and r = 0.736 when correlating Marshall score with procalcitonin. CONCLUSION: Our study achieved an early identification of the severe form of acute pancreatitis, by using the multiparameter tests and the biologic marker procalcitonin, allowing for the appropriate therapy to be implemented and thus decreasing the complication rate of this pathological entity. Levels of serum procalcitonin exceeded the normal limit of 2 ng/ml for 37.5% of the intermediate - severe form patients, and for 100% of the severe form patients. The levels of procalcitonin were highly correlated with the Ranson score, with a slightly lower correlation for the Marshall and EPIC scores.

Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor.

PTEN is a tumor suppressor frequently inactivated in brain, prostate, and uterine cancer. It acts as a phosphoinositide phosphatase and consists of an amino-terminal phosphatase domain tightly linked to a COOH-terminal C2 domain involved in lipid membrane-binding. We investigated the functions of the C2 domain and their relevance for tumor growth. To discriminate between PTEN C2 domain ability to recruit or to position the active site to the membrane, we artificially membrane-targeted PTEN by a myristoylation signal. This modification increased wild-type PTEN growth inhibition but did not rescue a C2 mutant defective in lipid-binding, suggesting a model in which PTEN C2 domain positions the active site productively with respect to the membrane-bound phosphoinositide substrate. When tumor-derived mutations in the loops that connect the C2 beta-strands were analyzed, we found that these generally destabilized the protein but had variable effects on the phosphatase activity and tumor growth. The magnitude of these effects was dependent on the presence of the COOH-terminal PEST sequences and on the cell type where the mutant proteins were expressed, suggesting the existence of fluctuating structural defects of the mutant protein. One of the C2 loop mutants induced a total loss of PTEN tumor-suppressor function, most likely by affecting both the membrane binding and the protein stability. These data support a double role for PTEN C2 domain in protein stability and in productive orientation of the catalytic site.

Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics.

Dysregulated signal transduction from receptor tyrosine kinases to phosphatidylinositol 3-kinase (PI3K), AKT (protein kinase B), and its effector FKBP-rapamycin-associated protein (FRAP) occurs via autocrine stimulation or inactivation of the tumor suppressor PTEN in many cancers. Here we demonstrate that in human prostate cancer cells, basal-, growth factor-, and mitogen-induced expression of hypoxia-inducible factor 1 (HIF-1) alpha, the regulated subunit of the transcription factor HIF-1, is blocked by LY294002 and rapamycin, inhibitors of PI3K and FRAP, respectively. HIF-1-dependent gene transcription is blocked by dominant-negative AKT or PI3K and by wild-type PTEN, whereas transcription is stimulated by constitutively active AKT or dominant-negative PTEN. LY294002 and rapamycin also inhibit growth factor- and mitogen-induced secretion of vascular endothelial growth factor, the product of a known HIF-1 target gene, thus linking the PI3K/PTEN/AKT/FRAP pathway, HIF-1, and tumor angiogenesis. These data indicate that pharmacological agents that target PI3K, AKT, or FRAP in tumor cells inhibit HIF-1alpha expression and that such inhibition may contribute to therapeutic efficacy.

First report of OXA-72 producing Acinetobacter baumannii in Romania.

This is the first report of an OXA-72-producing Acinetobacter baumannii strain in Romania, isolated from chronic leg ulcer samples. Identification of the strain was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Presence of carbapenem resistance genes was investigated by PCR and sequencing. Our data support the spread of the bla OXA-72 gene in Eastern Europe.

Investigation of the hydration process in 3CaO.SiO(2)-plasticizer-water systems by X-ray diffraction.

The development of the hydration-hydrolysis processes in the 3CaO. SiO(2)-H(2)O system is studied by X-ray diffraction in presence of varying contents of a new plasticizer, belonging to the lignosulphonates class. The influence of the additives upon these processes with increasing time is observed and it is shown to depend on the nature and content of the additives and the reaction time. This influence of the additives on the kinetics of the hydration-hydrolysis processes, retardation or acceleration, is due to the strong adsorption of these admixtures on the surface of the anhydrous or partially hydrated particles of the system. The influence of the additives also appears during the development of the formed hydrocompounds according to structure and composition. As a result of these complex actions provided in the forming system (3CaO. SiO(2)-H(2)O), the mechanical strength is favorized mainly by certain proportions of plasticizer admixtures (0.1% LSC and 2% ADCOM).

Evaluation of radical products from beta-alanine/sugar mixtures by use of GC-MS with the galvinoxyl radical.

We have quantified the radical production of Maillard systems with beta-alanine and different sugars by a method that uses the free radical scavenger capacity of galvinoxyl (2,6-di-tert-butyl-alpha-(3, 5-di-tert-butyl-4-oxo-2,5-cyclohexadiene-1-ylidene)-p-tolyloxy) and a GC-MS separation and quantification. We have compared the results with the spectrophotometrical conclusions and highlight the importance of the radical production in the Maillard systems. The method is precise (CV < 5%), accurate (>97%), sensitive (limit of detection 10 ng/mL galvinoxyl), and may be used for the detection and quantification of radical activity in the chemical and biological systems.

Fetal vascular response to maternal deep-vein thrombosis and subsequent heparin therapy.

The fetal umbilical and cerebral Doppler changes were recorded in a 27-year-old primigravida referred at 38 weeks for the treatment of an iliofemoral vein thrombosis. On admission and in comparison to a previous Doppler assessment systematically performed during growth scan at 37 weeks, the umbilical resistance index (URI) demonstrated an increase of 19%, the cerebral resistance index (CRI) a reduction of 15% and the cerebral-umbilical (C/U) ratio a decrease of 29% reaching the lowest value of 1.05. Under intravenous heparin therapy, Doppler normalisation was observed within 1 week and the mother delivered a healthy, non-hypoxemic baby by caesarean section at 39 weeks and 2 days. This observation suggests that deep-vein thrombosis (DVT) may, in some cases, be responsible for transient fetal hypoxia. Moreover, treatment with intravenous heparin had a direct beneficial effect on the fetus as it improved placental hemodynamics and fetal oxygenation.

[Cerebral HITS: diagnosis, clinical relevance, outlook]. / Hits cérébraux: diagnostic, pertinence clinique, perspectives.

After 6 years of experience, Spencer and colleagues described the detection of embolus signals as height intensity transient signals (HITS) within Doppler flow spectrum from intracranial vessels. These signals (gaseous or materials) are recorded in many situations such as cardiac prosthetic valves, atrial fibrillation, carotid stenosis, carotid surgery or angioplasty. The clinical value is not well known: neurological impairment associated with brain lesions is described in case of cardiac prosthetic valves. The observation of HITS in carotid stenosis is associated with an increased risk of stroke. The detection of HITS offers a new orientation in studying stroke but some technical and/or clinical difficulties have to be solved.

The Black Sea Tele-Diab System: development-implementation-clinical evaluation.

This paper describes the application of the GEHR (Good European Health Record) architecture to develop a system to enable the storage and exchange of EHCRs (Electronic Health Care Record) of patients with diabetes, in the Black Sea area. The objectives of the Black Sea Tele Diab System (BSTD) were to develop and evaluate the use of a fully-computerised healthcare record system in a clinical setting, to promote the use of electronic data exchange of healthcare information and to provide a framework for the epidemiological study and monitoring of diabetes care.