Modeling tumor growth inhibition and toxicity outcome after administration of anticancer agents in xenograft mice: A Dynamic Energy Budget (DEB) approach.

Host features, such as cell proliferation rates, caloric intake, metabolism and energetic conditions, significantly influence tumor growth; at the same time, tumor growth may have a dramatic impact on the host conditions. For example, in clinics, at certain stages of the tumor growth, cachexia (body weight reduction) may become so relevant to be considered as responsible for around 20% of cancer deaths. Unfortunately, anticancer therapies may also contribute to the development of cachexia due to reduced food intake (anorexia), commonly observed during the treatment periods. For this reason, cachexia is considered one of the major toxicity findings to be evaluated also in preclinical studies. However, although various pharmacokinetic-pharmacodynamic (PK-PD) tumor growth inhibition (TGI) models are currently available, the mathematical modeling of cachexia onset and TGI after an anticancer administration in preclinical experiments is still an open issue. To cope with this, a new PK-PD model, based on a set of tumor-host interaction rules taken from Dynamic Energy Budget (DEB) theory and a set of drug tumor inhibition equations taken from the well-known Simeoni TGI model, was developed. The model is able to describe the body weight reduction, splitting the cachexia directly induced by tumor and that caused by the drug treatment under study. It was tested in typical preclinical studies, essentially designed for efficacy evaluation and routinely performed as a part of the industrial drug development plans. For the first time, both the dynamics of tumor and host growth could be predicted in xenograft mice untreated or treated with different anticancer agents and following different schedules. The model code is freely available for downloading at http://repository.ddmore.eu (model number DDMODEL00000274).

Long-term wireless pH monitoring of the distal esophagus: prolonging the test beyond 48 hours is unnecessary and may be misleading.

Wireless pH monitoring of the esophagus has been widely used to detect GERD for more than a decade. It is generally well tolerated and accepted by patients, but it is still unclear whether prolonging a recording beyond the usual 48 hours can improve the test's diagnostic value. The aim of this study is to examine the diagnostic yield of 96-hour pH monitoring vis-à-vis 24- and 48-hour tests, and to ascertain whether any gain in diagnostic terms was of genuine clinical utility. Patients with suspected GERD underwent 4-day PPI-off wireless pH monitoring of the distal esophagus. The capsule was inserted under endoscopic control, 6 cm above the squamocolumnar junction. Average acid exposure time was calculated after 24, 48, and 96 hours of recording. Ninety-nine patients completed the 96 hour test, and formed the study sample. The wireless test method was used in 42 patients (42.4%) unable to tolerate the traditional pH-monitoring catheter, and in 57 (57.6%) with a previous negative pH study despite symptoms suggestive of GERD. On complete analysis, 47 patients (47.5%) had a pathological test result: 19 patients within the first 24 hours (19.2%, 24 hour group); another 16 after 48 hours (+16.2%, 48 hour group), and a further 12 (+12.1%, 96 hour group) only after 96 hours of monitoring. All 47 patients with an abnormal acid exposure were offered and accepted surgery (10 patients) or medical therapy (37 patients). Clinical follow-up was obtained in all patients with a positive Bravo test result after a median 67 months (IQR: 38-98) using a validated symptom questionnaire. A good outcome after fundoplication or medical therapy was achieved in 73.7% of patients in the 24 hour group, in 62.5% of those in the 48 hour group, and in only 25% of those in the 96 hour group, P = 0.02. Long-term wireless pH monitoring enables an increase in the diagnostic yield over traditional 24- and 48-hour pH studies, but prolonging the test may constitute an unwanted bias and prompt the recruitment of more complex patients, in whom the outcome of surgical or medical therapy may prove less than satisfactory. These findings should be taken into account when establishing the guidelines for assessing GERD with such long-term pH monitoring methods.

Cisplatin plus paclitaxel and maintenance of bevacizumab on tumour progression, dissemination, and survival of ovarian carcinoma xenograft models.

BACKGROUND: Bevacizumab is being incorporated as first-line therapy with standard-of-care chemotherapy on epithelial ovarian carcinoma (EOC). We investigated bevacizumab combined with chemotherapy on tumour progression and mouse survival in EOC xenograft models. METHODS: Bevacizumab was administered concomitantly with cisplatin plus paclitaxel (DDP+PTX), continued after induction (maintenance) or started after chemotherapy. The effect on tumour progression was monitored by bioluminescence imaging (BLI) (1A9-luc xenograft). Tumour dissemination into the peritoneal organs and ascites formation (HOC22 xenograft) was evaluated by histological analysis at the end of treatment (interim) and at euthanasia (survival). The effects on overall survival (OS) were investigated in both EOC models. RESULTS: Bevacizumab with PTX+DDP delayed tumour progression in mice bearing EOC xenografts. OS was significantly extended, with complete responses, by bevacizumab continued after stopping chemotherapy in the HOC22 xenograft. Bevacizumab alone inhibited ascites formation, with only limited effect on tumour burden, but combined with PTX+DDP reduced ascites and metastases. Bevacizumab started after induction with PTX+DDP and maintained was equally effective on tumour progression and survival on 1A9-luc xenograft. CONCLUSION: Bevacizumab combined with chemotherapy not only affected tumour progression, but when administered as maintenance regimen significantly prolonged survival, reducing ascites, and tumour dissemination. We believe our findings are consistent with the clinical results and shed light on the potential effects of this kind of treatment on tumour progression.

Impact on grafted kidney function of rocuronium-sugammadex vs cisatracurium-neostigmine strategy for neuromuscular block management. An Italian single-center, 2014-2017 retrospective cohort case-control study.

BACKGROUND: The impact of sugammadex in patients with end-stage renal disease undergoing kidney transplantation is still far from being defined. The aim of the study is to compare sugammadex to neostigmine for reversal of rocuronium- and cisatracurium-induced neuromuscular block (NMB), respectively, in patients undergoing kidney transplantation. METHODS: A single-center, 2014-2017 retrospective cohort case-control study was performed. A total of 350 patients undergoing kidney transplantation, equally divided between a sugammadex group (175 patients) and a neostigmine group (175 patients), were considered. Postoperative kidney function, evaluated by monitoring of serum creatinine and urea and estimated glomerular filtration rate (eGFR), was the endpoint. Other endpoints were anesthetic and surgical times, post-anesthesia care unit length of stay, postoperative intensive care unit admission, and recurrent NMB or complications. RESULTS: No significant differences in patient or, with the exception of drugs involved in NMB management, anesthetic, and surgical characteristics, were observed between the two groups. Serum creatinine (median [interquartile range]: 596.0 [478.0-749.0] vs 639.0 [527.7-870.0] µmol/L, p = 0.0128) and serum urea (14.9 [10.8-21.6] vs 17.1 [13.1-22.0] mmol/L, p = 0.0486) were lower, while eGFR (8.0 [6.0-11.0] vs 8.0 [6.0-10.0], p = 0.0473) was higher in the sugammadex group than in the neostigmine group after surgery. The sugammadex group showed significantly lower incidence of postoperative severe hypoxemia (0.6% vs 6.3%, p = 0.006), shorter PACU stay (70 [60-90] min vs 90 [60-105] min, p < 0.001), and reduced ICU admissions (0.6% vs 8.0%, p = 0.001). CONCLUSIONS: Compared to cisatracurium-neostigmine, the rocuronium-sugammadex strategy for reversal of NMB showed a better recovery profile in patients undergoing kidney transplantation.

Inhibition of tyrosine kinase receptors by SU6668 promotes abnormal stromal development at the periphery of carcinomas.

Dynamic contrast-enhanced (albumin-Gd-DTPA) magnetic resonance imaging, performed during 2 weeks of daily administration of an inhibitor of tyrosine kinase receptors (SU6668) in an HT-29 colon carcinoma model, revealed the onset of a hyper-enhancing rim, not observed in untreated tumours. To account for tissue heterogeneity in the quantitative analysis, we segmented tumours into three subunits automatically identified by cluster analysis of the enhancement curves using a k-means algorithm. Transendothelial permeability (Kps) and fractional plasma volume (fPV) were calculated in each subunit. An avascular and necrotic region, an intermediate zone and a well-vascularised periphery were reliably identified. During untreated tumour growth, the identified sub-regions did not substantially change their enhancement pattern. Treatment with SU6668 induced major changes at tumour periphery where a significant increase of Kps and fPV was observed with respect to control tumours. Histology revealed a sub-capsular layer composed of hyper-dense viable tumour cells in the periphery of untreated tumours. The rim of viable neoplastic cells was reduced in treated tumours, and replaced by loose connective tissue characterised by numerous vessels, which explains the observed hyper-enhancement. The present data show a peripheral abnormal development of cancer-associated stroma, indicative of an adaptive response to anti-angiogenic treatment.

Psychometric properties of the Brazilian version of the Difficulties in Emotion Regulation Scale (DERS).

INTRODUCTION: Emotion regulation can be defined as the process by which individuals manage their emotional experience. It has been demonstrated that deficits in this ability are associated with various psychiatric disorders. In this direction, the Difficulties in Emotion Regulation Scale (DERS) was developed to measure difficulties in emotion regulation. OBJECTIVE: To examine the psychometric properties of the Brazilian Portuguese version of the DERS. METHOD: A total of 377 individuals from the general population, selected by convenience, completed a sociodemographic form, the adapted Brazilian Portuguese DERS and the Depression Anxiety Stress Scale (DASS-21). Factor structure, reliability, and concurrent validity of the adapted version of the instrument were investigated. RESULTS: The confirmatory factor analysis replicated the six-factor structure originally proposed for the instrument and confirmed the acceptability of a hierarchical model where all DERS subscales loaded on a general emotion dysregulation factor. Internal consistency indicators had adequate values for the general factor and subscales. The positive association between DERS and DASS-21 scores supports the instrument's concurrent validity. CONCLUSION: These results suggest that the Brazilian version of the DERS is reliable both as a general measure of difficulties in emotion regulation and as a measure of the constituents of this construct. Future research should investigate the psychometric properties of the scale in clinical and nonclinical populations, with equal gender proportions and diverse backgrounds, and preferably employing longitudinal designs.

Predicting the active doses in humans from animal studies: a novel approach in oncology.

The success rate of clinical drug development is significantly lower in oncology than in other therapeutic areas. Predicting the activity of new compounds in humans from preclinical data could substantially reduce the number of failures. A novel approach for predicting the expected active doses in humans from the first animal studies is presented here. The method relies upon a PK/PD model of tumour growth inhibition in xenografts, which provides parameters describing the potency of the tested compounds. Anticancer drugs, currently used in the clinic, were evaluated in xenograft models and their potency parameters were estimated. A good correlation was obtained between these parameters and the exposures sustained at the therapeutically relevant dosing regimens. Based on the corresponding regression equation and the potency parameters estimated in the first preclinical studies, the therapeutically active concentrations of new compounds can be estimated. An early knowledge of level of exposure or doses to be reached in humans will improve the risk evaluation and decision making processes in anticancer drug development.

[Pre-adolescents and sport: results of a health survey in some secondary schools of Brianza]. / I preadolescenti e lo sport: risultati di un'indagine in alcune scuole medie dell'area brianzola.

This study is aimed at assessing time dedicated to, motivation and involvement in physical activity on behalf of pre-adolescents. 802 students (49.3% boys and 50.7% girls; mean age: 12.6) attending 43 classes of 11 Brianza's post-elementary schools. A questionnaire was prepared and administered to the involved sample. Classes took part in this study through randomized selection and data were analyzed using program Epi Info 6. Most of the respondents (60.1%) stay involved in sport because "it makes me feel good" and 32.4% because sport is "enjoyable and entertaining". Pre-adolescents chose the sport in which they become engaged on the basis of personal inclination (40%), in order to share experiences and their free time with friends (15.4%); 13.7% declare to prefer sport to be practiced in team. (13.7%). The most practiced sport are: football (51.3% boys, 4.5% girls), volley (3.9%-36.4%), dance (0.8%-25.2%) e swimming (9.4%-14%). 80.8% in the sample practice physical activity in settings outside schools and, among these, 51.7% dedicate three or more hours weekly to extra-school activities. There are significant differences (p < 0.05) between males' and females' engagement in physical activity (mean value: 4.1 hours; males: 4.6 h, females: 3.5 h). Among pre-teens, 18% declare to be physically inactive at all; 15.7% do not take part in sport activities because afraid to be bullied or shamed by peers. Research show that males are significantly more involved in physical activity than females.

HIV-1 proviral DNA polymerase chain reaction detection in chorionic villi after exclusion of maternal contamination by variable number of tandem repeats analysis.

OBJECTIVE: The study of the placental HIV infection in cases of seropositive pregnant women after exclusion of maternal contamination of chorionic villi samples by variable number of tandem repeats (VNTR) analysis. METHODS: We studied 30 HIV-positive women: 17 terminated their pregnancy (11 in the first trimester and six in the second) and 13 delivered at term (one was a twin gestation). We selected chorionic villi and ruled out maternal contamination by VNTR analysis. DNA from chorionic villi and cord and maternal blood were tested for HIV by PCR. All infants underwent a paediatric follow-up. RESULTS: All maternal blood samples tested positive for HIV-1 by polymerase chain reaction. No maternal contamination was revealed and HIV was found in six out of 11 first trimester placentas, in all second trimester samples, and in 10 out of 14 at term. Cord blood tested positive in all second trimester cases and in seven out of 14 liveborns. In no case was HIV found in cord blood without infection of the corresponding placenta; conversely, three placentas tested positive but cord blood was negative. Two infants were HIV-positive, 11 were uninfected (one case was lost to follow-up). CONCLUSION: Our study indicates that HIV-1 can infect the placenta from first trimester onwards. HIV was found in two-thirds of our cord blood samples but it is possible that some viral DNA in cord blood may have come from infected placental cells. Additional studies are needed to assess the source of HIV in cord blood and the possible contribution of placental or maternal cells infected with HIV to vertical transmission of the virus.

Enhanced HIV infectivity and changes in GP120 conformation associated with viral incorporation of human leucocyte antigen class I molecules.

BACKGROUND: Assembly of human immunodeficiency virus type 1 (HIV-1) occurs at the level of the plasma membrane of the host cell. During this process HIV incorporates significant quantities of cell surface-derived molecules into its lipid bilayer including human leucocyte antigen (HLA) class I and II, intercellular adhesion molecule-1 and lymphocyte function antigen-1. Several studies indicate that virion-bound host-cell-derived molecules are functional and affect the biological properties of HIV-1. Virion-associated HLA class II and intercellular adhesion molecule-1 enhance the infectivity of T-cell line-adapted (TCLA) viruses. No role for virion-associated HLA class I molecules has yet been identified. OBJECTIVE: To investigate the role of HLA class I molecules in HIV replication and infectivity. METHODS: HLA class I negative human cells lines transfected with the HLA Cw4 gene were infected with different TCLA viruses as well as primary X4 isolates. The infectivity of HLA Cw4 positive and negative viruses was determined on indicator cell lines and on phytohaemagglutinin-activated peripheral blood mononuclear cells. An entry polymerase chain reaction assay was used to determine differences in entry-competence of Cw4 positive and negative viruses. The expression of selected gp120 epitopes on native Env molecules derived from Cw4 positive and negative viruses was determined by a monoclonal antibody-based enzyme-linked immunosorbent assay. Immunoprecipitation experiments were performed to investigate the presence of gp120/HLA Cw4 complexes. Neutralization assays determined the differences in susceptibility to neutralization between HLA Cw4 negative and positive viruses. RESULTS AND CONCLUSIONS: The infectivity of primary HIV-1 X4 isolates and of TCLA viruses is increased upon viral incorporation of HLA Cw4 molecules. This effect is associated with changes in viral envelope proteins conformation including an enhanced expression of the V3 loop of gp120, and of epitopes that are exposed upon CD4 binding. The gp120 conformational changes are consistent with the formation of a multimolecular complex between HLA class I and gp120/160. HLA Cw4 incorporation is also associated to a lower susceptibility to antibody neutralization. These findings have important implications for understanding the immune response to cryptic and conformational epitopes of the viral envelope.

Purine and 1-deazapurine ribonucleosides and deoxyribonucleosides: synthesis and biological activity.

A series of 6-(hydroxylamino)purine and -1-deazapurine nucleosides were synthesized and tested for their antitumor and adenosine deaminase inhibitory activity. All the examined molecules displayed an in vitro activity comparable to that of the reference compounds 6-(hydroxylamino)-9-beta-D-ribofuranosylpurine (HAPR) and ara-A, their ID50 ranging from 0.9 microM to approximately 100 microM. The 6-hydroxylamino derivatives of 1-deazapurine 9, 12, and 17 and also the blocked compound 13 are inhibitors of ADA whereas the purine derivatives 4 and 6 and the nitro compounds 11 and 16 are resistant to the enzyme. 7-(Hydroxylamino)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3H-imi dazo[4,5- b]pyridine, the less cytotoxic but the most active ADA inhibitor in the series (Ki = 2.7 x 10(-7)), greatly potentiates the antitumor activity of ara-A in vitro.

Role of CD4 and CCR5 levels in the susceptibility of primary macrophages to infection by CCR5-dependent HIV type 1 isolates.

Macrophages are a preferred target for sexually transmitted human immunodeficiency virus type 1 (HIV-1) isolates that use CCR5 as a coreceptor in combination with CD4. To assess whether the susceptibility of MDMs to infection by an R5 isolate was influenced by CD4 and/or CCR5 expression, levels of membrane CD4 or CCR5 transcripts at the time of infection and ID50 values 15 days postinfection were measured in cultures of primary macrophages infected with HIV-1(10005). To analyze the data, subjects were divided so as to maximize differences in the levels of CD4 or CCR5 expression between groups. Indeed, the difference in CD4 expression between the CD4high (MFI, 16.7 +/- 2.2) and CD4low (MFI, 6.7 +/- 0.7) groups attained high significance (p < 0.005). Of note, susceptibility to infection of MDMs isolated from CD4high donors was strikingly enhanced as compared with CD4low subjects, as shown by a fourfold increase in ID50 titers at day 15 postinfection (p < 0.002). In contrast, no significant difference in ID50 was apparent when the subjects were grouped according to the levels of CCR5 transcripts, even though CCR5 expression in the two groups differed significantly (p = 0.01). These results suggest that, regardless of variations among individuals, the intensity of CD4 expression in macrophages is such that CCR5 levels are above the threshold required for efficient HIV-1 infection. Consistent with this hypothesis, macrophages from three additional donors selected for high CD4 expression and low CCR5 transcripts were found to be highly susceptible to HIV-1 infection.

In vivo activity of novel sulphonic derivatives of distamycin A.

Solid tumor growth can be modulated through inhibition of vascularization elicited by angiogenic factors. With the objective to complex these factors, new derivatives of distamycin A were synthesized and evaluated in vitro [1] and in vivo for their ability, after i.v. administration, to inhibit bFGF-induced vascularization and the growth of M5076 murine reticulosarcoma implanted i.m. The tested compounds were able to block angiogenesis with inhibition values ranging between 70-100%. Moreover, they were found to be capable of inducing tumor inhibition with values ranging between 40% and 95% at non-toxic doses.

Antitumor activity of FCE 26644 a new growth-factor complexing molecule.

FCE 26644, or 7,7'-(carbonyl-bis[imino-N-methyl-4, 2 pyrrole carbonyl-imino(N-methyl-4,2-pyrrole)carbonyl-imino])-bis-(1,3- naphthalene)disulfonic acid, belongs to the newly synthesized class of sulfonated derivatives of distamycin A. FCE 26644 is a noncytotoxic molecule capable of inhibiting the binding of basic fibreblast growth factor (bFGF), platelet-derived growth factor (PDGF beta) and interleukin 1 (IL-7) to their receptors and to block bFGF-induced vascularization in vivo as well as neovascularization in the chorioallantoic membrane. FCE 26644 and suramin, a compound possessing the same terminal half-life (t1/2) in mice and, presumably, the same mode of action, inhibit the growth of solid murine tumors, M5076 reticulosarcoma, and MXT and S180 fibrosarcoma and are inactive against B16F10 melanoma. The activity of FCE 26644 was constantly observed at nontoxic doses, at variance with suramin. FCE 26644 was also found to maintain activity against M5076 resistant to cyclophosphamide and to be equally active against UV 2237 and UV 2237/ADR fibrosarcoma.

Polymer-bound camptothecin: initial biodistribution and antitumour activity studies.

Camptothecin (CPT) is a potent, antitumour drug acting mainly through inhibition of topoisomerase I during the S-phase of the cell cycle. Despite its impressive antitumour activity, clinical development was halted for unpredictable toxic events. Two soluble N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers were synthesised to contain CPT (5 wt.% and 10 wt.%). CPT was covalently linked at its alpha-hydroxyl group to the polymers through a Gly-Phe-Leu-Gly- spacer. In-vitro, CPT-conjugates were fairly resistant to hydrolysis in plasma as in buffer at neutral pH (0.2-0. 4% free CPT/h), while elastase and cysteine-proteases were able to release the active drug. Plasma levels in mice after intravenous administration of CPT-conjugates confirmed the modest hydrolysis in plasma. Plasma levels were approximately 5-fold lower than those observed at the highest tolerated dose of CPT administered in classical vehicles. Biodistribution in HT29 human colon carcinoma bearing mice was carried out after i.v. injection of [3H]CPT-conjugate and free [3H]CPT. Radioactivity uptake in tumour was evident only after [3H]CPT-conjugate treatment. Repeated intravenous administration of CPT-conjugates to HT29-bearing mice gave more than 90% tumour inhibition, some complete tumour regressions and no toxic deaths. The improved pharmacological profile on HT29 human colon carcinoma xenografts of the first poly(HPMA)-CPT conjugates might be ascribed to their prolonged intra-tumour retention and sustained release of the active drug.

3-Methylcholanthrene induces differential inhibition of humoral and cell mediated immune responses in mice of different ages.

C57B1/6 mice aged 2-3 and 13-14 months were treated i.p. with 3-methylcholanthrene. A single dose of 25 mg/kg reduced primary antibody production to the T-dependent antigen sheep red blood cells by 20% in mice aged 2-3 months and by 90% in 13-14-month-old animals. The same treatment did not reduce antibody production to the T-independent antigen pneumococcal polysaccharide type III in young mice, but reduced this response by 50% in 13-14-month-old animals. Blastogenesis to concanavalin A, phytohemagglutinin and alloantigens, that is mediated by T lymphocytes, was consistently reduced in young animals but only marginally affected, when at all, in 13-14-month-old mice. Blastogenesis to lipopolysaccharide, mediated by B lymphocytes, was reduced in mice of both ages, though in older mice it was affected later than in younger animals. Addition of 3-methylcholanthrene in vitro increased T lymphocyte responses equally in mice of both ages and did not modify B lymphocyte proliferation. Results presented here show that older mice are not necessarily more susceptible to all types of immunosuppression induced by a xenobiotic like 3-methylcholanthrene and that the sensitivity of the different facets of the immune response can change with aging.

Hyperkeratosis-associated coryneform infection in severe combined immunodeficient mice.

Hyperkeratosis-associated coryneform (HAC) is a coryneform bacterium, with a biochemical profile similar to Corynebacterium bovis, that causes hyperkeratotic dermatitis in athymic nude mice. In the present study 28 severe combined immunodeficient (SCID) mice coming from six different animal facilities were submitted for bacteriological and pathological examination. HAC was isolated from 10 SCID mice belonging to two of these facilities. Two of the HAC-infected mice showed macroscopical lesions consisting in large alopecic areas, with small white flakes, involving the dorsum, flanks, neck and cheeks. Histologically, the skin of these animals was characterized by diffuse acanthosis and hyperkeratosis. In the other eight HAC-infected SCID mice no macroscopical lesions were observed but focal areas of minimal to mild acanthosis were histologically detected in five cases. These results suggest that HAC can infect SCID mice inducing skin lesions similar, although generally less severe, to those observed in nude mice with hyperkeratotic dermatitis. Our results pointed out that SCID mice may play an important role in the epidemiology of hyperkeratotic dermatitis of athymic nude mice.

Psychometric properties of the Brazilian version of the Difficulties in Emotion Regulation Scale (DERS) / Propriedades psicométricas da versão Brasileira da Difficulties in Emotion Regulation Scale (DERS)

Abstract Introduction: Emotion regulation can be defined as the process by which individuals manage their emotional experience. It has been demonstrated that deficits in this ability are associated with various psychiatric disorders. In this direction, the Difficulties in Emotion Regulation Scale (DERS) was developed to measure difficulties in emotion regulation. Objective: To examine the psychometric properties of the Brazilian Portuguese version of the DERS. Method: A total of 377 individuals from the general population, selected by convenience, completed a sociodemographic form, the adapted Brazilian Portuguese DERS and the Depression Anxiety Stress Scale (DASS-21). Factor structure, reliability, and concurrent validity of the adapted version of the instrument were investigated. Results: The confirmatory factor analysis replicated the six-factor structure originally proposed for the instrument and confirmed the acceptability of a hierarchical model where all DERS subscales loaded on a general emotion dysregulation factor. Internal consistency indicators had adequate values for the general factor and subscales. The positive association between DERS and DASS-21 scores supports the instrument's concurrent validity. Conclusion: These results suggest that the Brazilian version of the DERS is reliable both as a general measure of difficulties in emotion regulation and as a measure of the constituents of this construct. Future research should investigate the psychometric properties of the scale in clinical and nonclinical populations, with equal gender proportions and diverse backgrounds, and preferably employing longitudinal designs.

Resumo Introdução: Regulação emocional pode ser definida como o processo pelo qual os indivíduos regulam sua experiência emocional. Tem sido demonstrado que déficits na regulação emocional podem estar associados a vários transtornos psiquiátricos. Nesta linha, a Difficulties in Emotion Regulation Scale (DERS) é um instrumento que foi desenvolvido para acessar dificuldades na regulação emocional. Objetivo: Examinar as propriedades psicométricas de uma versão da DERS adaptada ao português brasileiro. Método: Um total de 377 indivíduos da população geral foram selecionados por conveniência para completar um questionário sociodemográfico, a versão adaptada ao português brasileiro da DERS e a Depression Anxiety Stress Scale (DASS-21). Foram investigadas a estrutura fatorial, confiabilidade e validade concorrente da versão adaptada da DERS. Resultados: A análise fatorial confirmatória replicou a estrutura de seis fatores originalmente proposta para o instrumento e confirmou a aceitabilidade de um modelo hierárquico em que todas as subescalas são carregadas em um fator de desregulação emocional geral. Os indicadores de consistência interna apresentaram valores adequados para o fator geral e subescalas. A associação positiva entre os escores obtidos na DERS e na DASS-21 dá suporte à validade concorrente do instrumento. Conclusão: Esses resultados sugerem que a versão brasileira da DERS é confiável como medida geral de dificuldades na regulação emocional e como medida dos constituintes desta construção. Pesquisas futuras devem investigar as propriedades psicométricas da escala em populações clínicas e não clínicas, com igual proporção de gênero e diversas origens e, de preferência, empregando desenhos longitudinais.

Vírus zika - Epidemiologia e diagnóstico laboratorial / Zika virus - Epidemiology and laboratory diagnosis

O vírus Zika (ZIKV) pode ser considerado um patógeno emergente disseminado para a Oceania e a América causando surtos sazonais. No Brasil a infecção começou a ser registrada em 2015 no Nordeste do país, embora a doença seja autolimitada e manifeste sintomas brandos, ocorreram relatos de complicações neurológicas associadas ao ZIKV em recém-nascidos e em adultos. Essa revisão descreve as características epidemiológicas da infecção pelo ZIKV no Brasil e no Rio Grande do Sul, e efetua análise dos métodos utilizados no diagnóstico laboratorial da infecção. As fontes de pesquisa foram artigos científicos em português e em inglês que referiam casos de infecção por ZIKV, no período de 2007 a 2017, citados nos repositórios digitais PubMed, PubMed Central (PMC) e SciELO, foram utilizados os descritores: Zika, diagnóstico, sorologia e epidemiologia. Apesar do decréscimo nos casos notificados no ano de 2017, o ZIKV continua em circulação. O diagnóstico laboratorial utiliza técnicas em métodos moleculares e sorológicas. A reação da transcriptase reversa (RT-PCR) é a metodologia com maior especificidade comparada à de enzimaimunoensaio e à de neutralização por redução de placas. (AU)

Zika virus can be considered a widespread emerging pathogen for Oceania and America causing seasonal outbreaks. Zika's disease began registered in 2015 in Brazil northeast, although the disease is self limited and manifest mild symptoms, there have been reports of neurological complications associated with ZIKV in neonates and adults. This review describes the epidemiological characteristics of ZIKV infection in Brazil and Rio Grande do Sul, and reports the methods used in laboratory diagnosis. The sources of research were scientific articles in Portuguese and English that reported cases of ZIKV infection and with a focus on laboratory diagnosis cited in the digital repositories PubMed, PubMed Central (PMC) and SciELO, from 2007 to 2017, the descriptors : Zika, diagnosis, serology and epidemiology. Despite the decrease in cases described in 2017, ZIKV keeps circulating. The definitive diagnosis is based on molecular and serological methods. Molecular diagnosis by reverse transcription polymerase chain reaction (RT-PCR) is the more specific method than the serological methods by enzyme immunoassay and platelet neutralization test. (AU)

Anti-tumour efficacy on glioma models of PHA-848125, a multi-kinase inhibitor able to cross the blood-brain barrier.

BACKGROUND AND PURPOSE: Malignant gliomas, the most common primary brain tumours, are highly invasive and neurologically destructive neoplasms with a very bad prognosis due to the difficulty in removing the mass completely by surgery and the limited activity of current therapeutic agents. PHA-848125 is a multi-kinase inhibitor with broad anti-tumour activity in pre-clinical studies and good tolerability in phase 1 studies, which could affect two main pathways involved in glioma pathogenesis, the G1-S phase progression control pathway through the inhibition of cyclin-dependent kinases and the signalling pathways mediated by tyrosine kinase growth factor receptors, such as tropomyosin receptors. For this reason, we tested PHA-848125 in glioma models. EXPERIMENTAL APPROACH: PHA-848125 was tested on a panel of glioma cell lines in vitro to evaluate inhibition of proliferation and mechanism of action. In vivo efficacy was evaluated on two glioma models both as single agent and in combination with standard therapy. KEY RESULTS: When tested on a subset of representative glioma cell lines, PHA-848125 blocked cell proliferation, DNA synthesis and inhibited both cell cycle and signal transduction markers. Relevantly, PHA-848125 was also able to induce cell death through autophagy in all cell lines. Good anti-tumour efficacy was observed by oral route in different glioma models both with s.c. and intracranial implantation. Indeed, we demonstrate that the drug is able to cross the blood-brain barrier. Moreover, the combination of PHA-848125 with temozolomide resulted in a synergistic effect, and a clear therapeutic gain was also observed with a triple treatment adding PHA-848125 to radiotherapy and temozolomide. CONCLUSIONS AND IMPLICATIONS: All the pre-clinical data obtained so far suggest that PHA-848125 may become a useful agent in chemotherapy regimens for glioma patients and support its evaluation in phase 2 trials for this indication.