Clinical Impact of CDK4/6 Inhibitors in De Novo or PR- or Very Elderly Post-Menopausal ER+/HER2- Advanced Breast Cancers.

The CDK4/6 inhibitors significantly increase progression-free survival (PFS) in ER+/HER2- advanced breast cancer patients. In clinical trials, overall survival (OS) improvement has been demonstrated for ribociclib and abemaciclib but not for palbociclib. We undertook a real-world evaluation of PFS and OS in 227 post-menopausal patients who received first-line CDK4/6 inhibitors. There is no significant difference in median PFS (27.5 months vs. 25.7 months, p = 0.3) or median OS (49.5 months vs. 50.2 months, p = 0.67) in patients who received either palbociclib or ribociclib, respectively. De novo disease is significantly associated with prolonged median PFS and median OS compared with recurrence disease (47.1 months vs. 20.3 months (p = 0.0002) and 77.4 months vs. 37.3 months (p = 0.0003), respectively). PR- tumours have significantly reduced median PFS and OS compared with PR+ disease (19.2 months vs. 38 months (p = 0.003) and 34.3 months vs. 62.6 months (p = 0.02), respectively). In the very elderly (>80 years), median PFS and OS are significantly shorter compared with patients who are 65 years or below (14.5 months vs. 30.2 months (p = 0.01), and 77.4 months vs. 29.6 months (p = 0.009), respectively) in the palbociclib group. Our data suggest that the benefit in the very elderly is limited, and PR+/de novo disease obtains the maximum survival benefit.

Validation of the single-platform ISHAGE protocol for enumeration of CD34+ hematopoietic stem cells in umbilical cord blood in a Brazilian center.

BACKGROUND: This study aims to validate the single-platform method for enumeration of CD34+ cells, by comparing the performance of two different commercial kits, as well as to evaluate the efficiency of the AccuriTM C6 cytometer in providing direct counts of absolute cell numbers. METHOD: We evaluated 20 samples from umbilical cord blood (UCB), comparing the two different methodologies for enumeration of CD34+ cells: single and dual-platform. For the assessment of the single-platform, Procount and SCE kits were used, both of which use fluorescent beads as a counting reference to obtain absolute CD34+ cells numbers. Moreover, after the acquisition of samples in flow cytometer AccuriTM C6, following the protocol established for each kit, the number of CD34+ cells was recalculated, considering the cell count provided by the AccuriTM C6. MAIN RESULTS: In our analysis, the results showed a strong correlation between the number of CD34+ cells/µL (r2=0.77) when comparing the SCE kit and the current dual-platform method. On the other hand, the comparison between Procount kit and dual-platform results showed a moderate correlation for the number of CD34+/µL cells (r2=0.64). CONCLUSION: Our results showed that the AccuriTM C6 flow cytometer can be used safely, applying both the dual and single platform analysis strategy. Considering the ISHAGE protocol-based single-platform approach, as the most appropriate methodology for CD34+ cells enumeration, our results demonstrated that the SCE kit has great potential for national standardization of UCB samples analysis methodology.

Effects of orthodontic treatment with aligners and fixed appliances on speech.

OBJECTIVES: To evaluate effects of orthodontic treatment with aligners and conventional fixed appliances on production of speech. MATERIALS AND METHODS: This was a parallel, randomized clinical trial. Patients with Angle Class I malocclusion, moderate crowding, and no speech impairment were randomly allocated to two groups: patients with orthodontic aligners (OAs; n = 20; mean age = 23.60 ± 5.65 years) and those with conventional fixed appliances (n = 20; mean age = 20.56 ± 4.51 years) and treated at the University of North Parana's clinic in Londrina, Brazil. Evaluation of speech production was performed semiobjectively by a speech therapist (myofunctional orofacial examination) and subjectively (self-assessment) at five time points: baseline, immediately after insertion of appliances, and subsequently at 3, 30, and 180 days after insertion. For intergroup comparison, independent t, χ2, Fisher exact, and Mann-Whitney tests were used; for intragroup comparison, the Friedman test was applied (α = 5%). RESULTS: In the semiobjective evaluation, patients with OAs exhibited a change in production of speech production, compared with patients with fixed appliances, immediately and 3 days after insertion of appliances (P < .001). Thirty days after insertion, the groups were similar (P = .487), an outcome that was unchanged at 180 days. However, in the self-assessments, patients in both groups reported significant speech difficulties immediately and 3 days after insertion of appliances, but such impairment was no longer perceived at 30 days or 180 days. CONCLUSIONS: Although the speech therapist identified changes in speech production at the start of treatment in the OA group only, patient self-assessments demonstrated that orthodontic treatment, regardless of the type of appliance used, interfered with their perception of speech.

Distribution of species enterovirus B in patients with central nervous system infections in São Paulo State, Brazil.

Enteroviruses (EV) are most common cause of central nervous system (CNS) infection, mainly aseptic meningitis. In Brazil, data available concerning the distribution of EV types are scarce. The aim of this study was to describe of types EV in patients with infection of the CNS in São Paulo State. This retrospective study was conducted in clinical samples collected from patients with infections of the CNS from 2004 to 2014. We investigated the presence of EV by virus isolation in cell culture. The samples that showed cytopathic effect in the cell culture were submitted by indirect immunofluorescence assay, reverse transcription polymerase chain reaction and VP1 partial sequencing to identification of EV isolated. A total of 176 EV isolated in cell culture was detected and typed in 14.5% (n = 176/1215) of clinical samples analyzed; corresponding to 71.0% of AM, and 19.3% of encephalitis and meningoencephalitis. Echoviruses (E) were isolated most frequently, with 155 strains (88.1%), Coxsackievirus B (CV-B), with 20 cases (11.4%), CV-A, with 01 case (0.6%). E-6 was the most commonly identified followed in decreasing order by E-30; E-18; CV-B5; E-4; E-11; CV-B2 and E-9; E-7; CV-A9, CV-B1, CV-B3, CV-B4, E-13, E-14, and E-21. EV detected were classified as belonging to the species enterovirus B. EV were detected in all the period of the year with the highest rate in the spring and summer months. Data obtained in this study contribute to the knowledge about EV circulation implicated in CNS infections over a 11-year period in São Paulo State, Brazil.

miRNA expression profiling of hereditary breast tumors from BRCA1- and BRCA2-germline mutation carriers in Brazil.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene expression regulation and have been described as key regulators of carcinogenesis. Aberrant miRNA expression has been frequently reported in sporadic breast cancers, but few studies have focused on profiling hereditary breast cancers. In this study, we aimed to identify specific miRNA signatures in hereditary breast tumors and to compare with sporadic breast cancer and normal breast tissues. METHODS: Global miRNA expression profiling using NanoString technology was performed on 43 hereditary breast tumors (15 BRCA1, 14 BRCA2, and 14 BRCAX), 23 sporadic breast tumors and 8 normal breast tissues. These normal breast tissues derived from BRCA1- and BRCA2- mutation carriers (n = 5) and non-mutation carriers (n = 3). Subsequently, we performed receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic performance of differentially expressed miRNAs. Putative target genes of each miRNAs considered as potential biomarkers were identified using miRDIP platform and used for pathway enrichment analysis. RESULTS: miRNA expression analyses identified several profiles that were specific to hereditary breast cancers. A total of 25 miRNAs were found to be differentially expressed (fold change: > 2.0 and p < 0.05) and considered as potential biomarkers (area under the curve > 0.75) in hereditary breast tumors compared to normal breast tissues, with an expressive upregulation among BRCAX cases. Furthermore, bioinformatic analysis revealed that these miRNAs shared target genes involved in ErbB, FoxO, and PI3K-Akt signaling pathways. CONCLUSIONS: Our results showed that miRNA expression profiling can differentiate hereditary from sporadic breast tumors and normal breast tissues. These miRNAs were remarkably deregulated in BRCAX hereditary breast cancers. Therefore, miRNA signatures can be used as potential novel diagnostic biomarkers for the prediction of BRCA1/2- germline mutations and may be useful for future clinical management.

Clinicopathological significance of ataxia telangiectasia-mutated (ATM) kinase and ataxia telangiectasia-mutated and Rad3-related (ATR) kinase in MYC overexpressed breast cancers.

PURPOSE: MYC transcription factor has critical roles in cell growth, proliferation, metabolism, differentiation, transformation and angiogenesis. MYC overexpression is seen in about 15% of breast cancers and linked to aggressive phenotypes. MYC overexpression also induces oxidative stress and replication stress in cells. ATM signalling and ATR-mediated signalling are critical for MYC-induced DNA damage response. Whether ATM and ATR expressions influence clinical outcomes in MYC overexpressed breast cancers is unknown. METHODS: We investigated ATM, ATR and MYC at the transcriptional level [Molecular Taxonomy of Breast Cancer International Consortium cohort (n = 1950)] and at the protein level in the Nottingham series comprising 1650 breast tumours. We correlated ATM, ATR and MYC expressions to clinicopathological features and survival outcomes. RESULTS: In MYC over expressed tumours, high ATR or low ATM levels were associated with aggressive breast cancer features such as higher tumour grade, de-differentiation, pleomorphism, high mitotic index, high-risk Nottingham Prognostic Index, triple negative and basal-like breast cancers (all adjusted p values < 0.05). Tumours with low ATM or high ATR levels in conjunction with MYC overexpression also have worse overall breast cancer-specific survival (BCSS) (p value < 0.05). CONCLUSIONS: We conclude that ATR/ATM-directed stratification and personalisation of therapy may be feasible in MYC overexpressed breast cancer.

Clinical Impact of Tumor DNA Repair Expression and T-cell Infiltration in Breast Cancers.

Impaired DNA repair drives mutagenicity, which increases neoantigen load and immunogenicity. We investigated the expression of proteins involved in the DNA damage response (ATM, Chk2), double-strand break repair (BRCA1, BLM, WRN, RECQL4, RECQL5, TOPO2A, DNA-PKcs, Ku70/Ku80), nucleotide excision repair (ERCC1), base excision repair (XRCC1, pol ß, FEN1, PARP1), and immune responses (CD8, PD-1, PD-L1, FOXP3) in 1,269 breast cancers and validated our findings in an independent estrogen receptor-negative (ER-) cohort (n = 279). Patients with tumors that expressed low XRCC1, low ATM, and low BRCA1 were not only associated with high numbers of CD8+ tumor-infiltrating lymphocytes, but were also linked to higher grades, high proliferation indexes, presence of dedifferentiated cells, ER- cells, and poor survival (all P ≤ 0.01). PD-1+ or PD-L1+ breast cancers with low XRCC1 were also linked to an aggressive phenotype that was high grade, had high proliferation indexes, contained dedifferentiated cells and ER- (all with P values ≤ 0.01), and poor survival (P = 0.00021 and P = 0.00022, for PD-1+ and PD-L1+ cancers, respectively) including in an independent ER- validation cohort (P = 0.007 and P = 0.047, respectively). We conclude that the interplay between DNA repair, CD8, PD-L1, and PD-1 can promote aggressive tumor phenotypes. XRCC1-directed personalization of immune checkpoint inhibitor therapy may be feasible and warrants further investigation in breast cancer. Cancer Immunol Res; 5(4); 292-9. ©2017 AACR.

Outbreak of G2P[4] rotavirus gastroenteritis in a retirement community, Brazil, 2015: An important public health risk?

The present study described a group A rotavirus (RVA) outbreak in an age-care facility in Brazil, using epidemiologic and molecular diagnostic methods. A descriptive clinical, epidemiological and environmental investigation was conducted. Stool samples were collected and screened for RVA, Norovirus (NoV), Enteric Adenovirus 40/41 (AdV 40/41) and Astrovirus (AstV) using ELISA, RT-PCR, qRT-PCR, electron microscopy and sequencing methods. Outbreak occurred during 26th-29th October, 2015; 28 individuals affected (22 residents; 6 staff). The attack rate was 25.9% and 8.5% among residents (median-age: 85.5 years) and staff (median-age: 28 years), respectively. Female staff was identified as the index case. RVA G2P[4] genotype was detected in 87.5% (7/8). Genetic analysis demonstrated that the outbreak involved one single strain, suggesting a common-source infection. RVA should be considered during outbreaks investigations in residential facilities, and raise the question if the current licensed RVA vaccines for children could also be helpful for the elderly.

Detection of the emerging rotavirus G12P[8] genotype at high frequency in brazil in 2014: Successive replacement of predominant strains after vaccine introduction.

The continuum characterization of rotavirus (RVA) genotypes is essential to understand how vaccine introduction could impact virus epidemiology. In the present study, an unexpected rapid changing pattern of RVA genotypes distribution in Brazilian population during three followed seasons is described. From January/2012 to December/2014, a total of 3441 fecal specimens were collected from collaborating centers across Southern, Southeastern and Midwest of Brazil. All specimens were screened for RVA using ELISA, and genotyped by RT-PCR. Differences in proportions were tested using Chi-Squares. A p-value of less than 0.05 was considered statistically significant. RVA was detected in 19.7% (677/3441). Among RVA positive cases (n=677), a total of 652 (96.3%) samples were successfully amplified by RT-PCR. G3P[8] remained prevalent in 2012 (37.6%, 69/185) and 2013 (40.1%, 74/186) (χ(2)=0.107, p=0.743), but declined markedly in 2014 (3.5%, 10/281) (χ(2)=71.770, p=0.000). G12P[8] was second highest strain in 2012 (22.7%, 42/185), decrease rapidly in 2013 (2.7%, 5/186) (χ(2)=26.224, p=0.000) and re-emerged as the predominant genotype in 2014 (86.6%, 243/281) (χ(2)=118.299, p=0.000). From July/2014, G12P[8] was the single genotype detected in all regions studied. The sudden emergence, spread and predominance of G12P[8] strain in Brazil, raised the hypothesis of a possible G12 outbreak being in progress. Nationally, the long term decline in gastroenteritis hospitalization observed in the country after RVA vaccine introduction was confirmed. Nevertheless, the sharp increase in diarrhea hospitalization prevalence from 2013 to 2014 observed in Southern and Southeastern regions is consistent with what appears to be an outbreak of G12P[8]. Continued surveillance is needed to verify the effectiveness of the RotarixTM vaccine in Brazil together with potential emergence of unusual genotypes.

Cytogenomic Evaluation of Subjects with Syndromic and Nonsyndromic Conotruncal Heart Defects.

Despite considerable advances in the detection of genomic abnormalities in congenital heart disease (CHD), the etiology of CHD remains largely unknown. CHD is the most common birth defect and is a major cause of infant morbidity and mortality, and conotruncal defects constitute 20% of all CHD cases. We used array comparative genomic hybridization (array-CGH) to retrospectively study 60 subjects with conotruncal defects and identify genomic imbalances. The DNA copy number variations (CNVs) detected were matched with data from genomic databases, and their clinical significance was evaluated. We found that 38.3% (23/60) of CHD cases possessed genomic imbalances. In 8.3% (5/60) of these cases, the imbalances were causal or potentially causal CNVs; in 8.3% (5/60), unclassified CNVs were identified; and in 21.6% (13/60), common variants were detected. Although the interpretation of the results must be refined and there is not yet a consensus regarding the types of CHD cases in which array-CGH should be used as a first-line test, the identification of these CNVs can assist in the evaluation and management of CHD. The results of such studies emphasize the growing importance of the use of genome-wide assays in subjects with CHD to increase the number of genomic data sets associated with this condition.

Evaluation of antioxidant and antiangiogenic properties of caesalpinia echinata extracts.

Natural products contain important combinations of ingredients, which may to some extent help to modulate the effects produced by oxidation substrates in biological systems. It is known that substances capable of modulating the action of these oxidants on tissue may be important allies in the control of neovascularization in pathological processes. The aim of this study was to evaluate the antioxidant and antiangiogenic properties of an ethanol extract of Caesalpinia echinata. The evaluation of antioxidant properties was tested using two methods (DPPH inhibition and sequestration of nitric oxide). The antiangiogenic properties were evaluated using the inflammatory angiogenesis model in the corneas of rats. The extract of C. echinata demonstrated a high capacity to inhibit free radicals, with IC50 equal to 42.404 µg/mL for the DPPH test and 234.2 µg/mL for nitric oxide. Moreover, it showed itself capable of inhibiting the inflammatory angiogenic response by 77.49%. These data suggest that biochemical components belonging to the extract of C. echinata interfere in mechanisms that control the angiogenic process, mediated by substrates belonging to the arachidonic acid cascade, although the data described above also suggest that the NO buffer may contribute to some extent to the reduction in the angiogenic response.

Intersectorality and bonding in tuberculosis control in Family Health.

This is a qualitative study which aims to analyze the performance of the Family Health teams in the control of tuberculosis according to the relationship between bonding and the development of intersectoral actions in the metropolitan region of João Pessoa, Paraíba, Brazil. To construct the empirical material focus group techniques were used. Seven focus groups were conducted, involving 37 professionals of the Family Health teams. For analysis, the discourse analysis technique was used. It was concluded that the lack of intersectoral action weakens the bond between tuberculosis patients, their families and the Family Health team. It is noteworthy that intersectoral measures are fundamental in the development of integral care for tuberculosis patients in the context of Primary Health Care.

[Tuberculosis treatment drop out and relations of bonding to the family health team]. / Abandono do tratamento de tuberculose e relações de vínculo com a equipe de saúde da família.

This study aimed to analyze the relation between the singularities of the sick subject with the history of dropping out of the tuberculosis treatment and the care given by the family health team in light of the bonding concept. The empirical material was built through recorded interviews, in the period from July to September of 2008, using the Thematic Oral History methodology. Interviews were taken with nine users whose drop out was the criteria for closing the treatment to tuberculosis in two municipalities of the metropolitan region of João Pessoa, Paraíba, Brazil. The analysis was performed according to the discourse analysis technique. The study identified that a therapeutic relation, sharing commitments and the user's valuation, strengthens the bonding and produces the care management democratization. On the other hand, a vertical relation, with fragile bonding, is opposed to the purpose of an intersubjective practice in the perspective of the care co-management.

[Performance and parasitologic infestation of male dairy cattle supplemented with proteic salt containing or not homeopathic medicines]. / Desempenho e infestação por parasitos em machos leiteiros suplementados com sal proteinado com ou sem os medicamentos homeopáticos.

The objective of this study was to evaluate the performance and parasitologic infection of male dairy cattle submitted to supplemental proteic salt with and without the use of homeopathic medicines. Were used crossbred Gir x Holstein castrated males calves, with 10 months of age and live weight of 150.75 kg, distributed in a completely randomized design with eight replicates per treatment, totaling 16 animals. The calves of each treatment remained in a pasture of Brachiaria brizantha cv. Marandu, managed in continuous grazing system for 8 months. The treatments employed were: supplementation with 300 g/animal/day of protein (40% of crude protein (CP) and 25% CP in the dry and rainy season, respectively) added or not with 5 g/animal/day of the homeopathic medicines FATOR PRO® and C & MC®. The addition of homeopathic medicines in the protein supplement did not affect (P > 0.05) the development of body male crossbred to pasture. The counting of the larvae and adults of ticks in scrapings were lower (P < 0.05) in animals that did not receive homeopathic medicines in the protein supplement. The females tick in the body anterior third (simplifying counting), nymphs in scrapings and the number of eggs per gram of helminths were not affected (P > 0.05) by the treatments. It was concluded that the use of homeopathic medicines did not affect the development of male crossbred Gir x Holstein dairy cattle neither their parasitic infection.