An Observational Cohort Study on Delayed-Onset Infections after Mandibular Third-Molar Extractions.

OBJECTIVES: The purpose of the present study was to investigate the occurrence and clinical features of delayed-onset infections after mandibular third-molar extractions. METHOD AND MATERIALS: An observational cohort study was conducted on 179 patients undergoing mandibular third-molar extraction between January 2013 and December 2015, for a total of 217 extractions. Data were recorded at the time of extraction (T0), on suture removal seven days later (T1), and 30 days after the extraction, when patients were contacted and asked about their healing process (T2). The statistical analysis was performed with nonparametric tests. A p value lower than 0.05 was considered statistically significant. RESULTS: Eight delayed-onset infections were recorded, amounting to 3.7% of all extractions. The median time elapsing from the extraction to the delayed-onset infection was 35 days (IQR 28-40; min 24-max 49). Younger age and longer surgical procedures seemed to be more often associated with this complication. CONCLUSION: Delayed-onset infections after third-molar extractions are relatively rare postoperative complications characterized by a swelling, usually with a purulent discharge. Patients should be informed of this possibility, which might develop even several weeks after the extraction

Reprodução na juventude: perfis sociodemográficos, comportamentais e reprodutivos na PNDS 2006

OBJETIVO: Analizar características sociodemográficas y de conductas sexual y reproductiva de mujeres jóvenes. MÉTODOS: Estudio poblacional transversal con representatividad nacional sobre el comportamiento sexual, anticonceptivo y reproductivo de 2.991 mujeres de 15 a 20 años en la Investigación Nacional de Demografía y Salud del Niño y de la Mujer (PNDS) 2006. Las jóvenes se clasificaron en tres grupos: iniciaron la vida sexual y se embarazaron antes de los 20 años (grupo A); iniciaron la vida sexual y no se embarazaron antes de los 20 (grupo B) y no iniciaron la vida sexual (grupo C). Mujeres de hasta 25 años se consideraron para el estudio de las tasas de embarazo y de sus consecuencias en la vida. Los análisis estadísticos consideraron los pesos y la planificación del muestreo complejo. La asociación entre dos variables categóricas fue evaluada por la prueba Chi-cuadrado. Para las conductuales, se utilizó el modelo linear global. RESULTADOS: Mujeres del grupo A eran principalmente negras, más pobres y con menor escolaridad. Tuvieron la primera relación sexual más precozmente, comportamiento anticonceptivo más desprotegido y menor conocimiento de la fisiología de la reproducción con relación al grupo B; las jóvenes del grupo C se caracterizaron por frecuentar más la escuela, y la preservación de la virginidad para el matrimonio fue relatada por 1/3 del grupo. En las mujeres con hasta 25 años, el embarazo antes de los 20 fue percibido con más consecuencias positivas que negativas en la vida amorosa, conyugal, social y autoestima. CONCLUSIONES: Hay asociación significativa entre embarazo antes de los 20 años con mayor pobreza y menor escolaridad. En ausencia de mejores condiciones de vida y de oportunidades, el embarazo, aunque no sea previsto, se establece como "proyecto de vida" en comparación con su inexistencia.OBJECTIVE: Analyze the sociodemographic characteristics and the sexual and reproductive behavior of young women. METHODS: A cross-sectional nationally representative study was performed about sexual, contraceptive and reproductive behavior with 2,991 women age 15 to 20 years in the National Survey on Demography and Health of Women and Children, 2006. The women were classified into three groups: sexual initiation and pregnancy before the age of 20 (group A); sexual initiation but no pregnancy before the age of 20 (group B) and no sexual initiation (group C). Women until age 25 years were included in the study about reasons for becoming pregnant and the implications for their lives. Statistical analysis considered survey weights and the complex sample design. The association between two categorical variables was assessed by chi-square test. The behavior variables were assessed using a global linear model. RESULTS: Women in group A were mainly black, poorer and with lower education level. These women had an early sexual initiation, less safe contraceptive behavior and less knowledge of reproduction physiology in comparison with group B; young women in group C were characterized by greater attendance at school and 1/3 of this group claimed to maintain their virginity until marriage. For women up to the age of 25, pregnancy before 20 years was perceived as having more positive than negative impacts upon their love life, spousal relationships, social lives and self-esteem. CONCLUSIONS: There is a significant association between pregnancy before the age of 20 and higher poverty and lower educational level. In the absence of better living conditions and opportunities, pregnancy, although unplanned, becomes "a plan for life", and is not seen as a lack of life planning.OBJETIVO: Analisar características sociodemográficas e do comportamento sexual e reprodutivo de mulheres jovens. MÉTODOS: Estudo populacional transversal com representatividade nacional sobre o comportamento sexual, contraceptivo e reprodutivo de 2.991 mulheres de 15 a 20 anos na Pesquisa Nacional de Demografia e Saúde da Criança e da Mulher 2006. As jovens foram classificadas em três grupos: iniciaram a vida sexual e engravidaram antes dos 20 anos (grupo A); iniciaram a vida sexual e não engravidaram antes dos 20 (grupo B) e não iniciaram a vida sexual (grupo C). Mulheres de até 25 anos foram consideradas para o estudo das razões da gravidez e de suas implicações na vida. As análises estatísticas consideraram os pesos e o planejamento amostral complexo. A associação entre duas variáveis categóricas foi avaliada pelo teste tipo qui-quadrado. Quanto às comportamentais, utilizou-se modelo linear global. RESULTADOS: Mulheres do grupo A eram principalmente negras, mais pobres e com menor escolaridade. Tiveram a primeira relação sexual mais precocemente, comportamento contraceptivo mais desprotegido e menor conhecimento da fisiologia da reprodução em relação ao grupo B; as jovens do grupo C caracterizaram-se por maior frequência à escola e a preservação da virgindade para o casamento foi alegada por um 1/3 desse grupo. Para as mulheres com até 25 anos, a gravidez antes dos 20 foi percebida como tendo implicações mais positivas que negativas na vida amorosa, conjugal, social e autoestima. CONCLUSÕES: Há associação significativa entre gravidez antes dos 20 anos com maior pobreza e menor escolaridade. Na ausência de melhores condições de vida e de oportunidades, a gravidez, embora não prevista, configura-se como "projeto de vida" e não sua mera ausência

Osmotic tolerance and freezability of isolated caprine early-staged follicles

Isolated caprine early-staged follicles were submitted to osmotic tolerance tests in the presence of sucrose, ethylene glycol (EG), or NaCl solutions and were exposed to and cryopreserved (by slow or rapid cooling) in MEM alone or MEM supplemented with sucrose, EG (1.0 or 4.0 M), or both. When follicles were exposed to 1.5 M NaCl, only 2% of the follicles were viable, whereas 87% of the follicles were viable after exposure to 4.0 M EG. Regarding exposure time, the highest percentage of viable follicles was obtained when follicles were exposed for 10 min to 1.0 M EG + 0.5 M sucrose; exposure for 60 s to 4.0 M EG + 0.5 M sucrose also maintained high percentage viability in follicles. Slow cooling in the presence of 1.0 M EG + 0.5 M sucrose (75%) or rapid cooling in the presence of 4.0 M EG + 0.5 M sucrose (71%) resulted in a significantly higher proportion of viable follicles than all other treatments (P < 0.05). A 24-h culture of frozen-thawed follicles was used to assess survival; only slow-frozen follicles showed viability rates similar to control follicles (64% vs. 69% respectively; P > 0.05). Interestingly, the percentage of viable rapid-cooled follicles (59%) was similar to that obtained after in vitro culture of conventional slow-cooled follicles but was significantly lower than that in controls. Thus, in addition to determining improved procedures for the exposure of follicles to EG and sucrose before and after freezing of caprine early-staged follicles, we report the development of rapid- and slow-cooling protocols

A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer.

Background Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss.Patients and methods mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated.Results Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples.Conclusions The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway.Clinical trial number NCT02525068

Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing

Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.

By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein-protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC50s) in the sub-micromolar and low micromolar range

Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with <i>BRCA1/2</i>- and Non-<i>BRCA1/2</i>-Mutant Cancers.

Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)-deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K-AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K-AKT pathway alterations. SIGNIFICANCE: In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic-pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K-AKT pathway alterations.This article is highlighted in the In This Issue feature, p. 1426