Cyclin D1/CDK4 activity is upregulated in up to 50% of breast cancers and CDK4-mediated phosphorylation negatively regulates the TGFβ superfamily member Smad3. We sought to determine if CDK4 inhibition and doxorubicin chemotherapy could impact Smad3-mediated cell/colony growth and apoptosis in breast cancer cells. Parental and cyclin D1-overexpressing MCF7 cells were treated with CDK4 inhibitor, doxorubicin, or combination therapy and cell proliferation, apoptosis, colony formation, and expression of apoptotic proteins were evaluated using an MTS assay, TUNEL staining, 3D Matrigel assay, and apoptosis array/immunoblotting. Study cells were also transduced with WT Smad3 or a Smad3 construct resistant to CDK4 phosphorylation (5M) and colony formation and expression of apoptotic proteins were assessed. Treatment with CDK4 inhibitor/doxorubicin combination therapy, or transduction with 5M Smad3, resulted in a similar decrease in colony formation. Treating cyclin D overexpressing breast cancer cells with combination therapy also resulted in the greatest increase in apoptosis, resulted in decreased expression of anti-apoptotic proteins survivin and XIAP, and impacted subcellular localization of pro-apoptotic Smac/DIABLO. Additionally, transduction of 5M Smad3 and doxorubicin treatment resulted in the greatest change in apoptotic protein expression. Collectively, this work showed the impact of CDK4 inhibitor-mediated, Smad3-regulated tumor suppression, which was augmented in doxorubicin-treated cyclin D-overexpressing study cells.

Objective. There is a growing interest in the use of carbon and its allotropes for microelectrodes in neural probes because of their inertness, long-term electrical and electrochemical stability, and versatility. Building on this interest, we introduce a new electrode material system consisting of an ultra-thin monoatomic layer of graphene (Gr) mechanically supported by a relatively thicker layer of glassy carbon (GC). Approach. Due to its high electrical conductivity and high double-layer capacitance, Gr has impressive electrical and electrochemical properties, two key properties that are useful for neural recording and stimulation applications. However, because of its two-dimensional nature, Gr exhibits a lack of stiffness in the transverse direction and hence almost non-existent flexural and out-of-plane rigidity that will severely limit its wider use. On the other hand, GC is one of carbon’s important allotropes and consists of three-dimensional microstructures of Gr fragments with a natural molecular similarity to Gr. Further, GC has exceptional chemical inertness, good electrical properties, high electrochemical stability, purely capacitive charge injection, and fast surface electrokinetics coupled with lithography patternability. This makes GC an ideal candidate for addressing Gr’s lack of out-of-plane rigidity through providing a matching sturdier and robust mechanical backing. Combining the strengths of these two allotropes of carbon, we introduce a new neural probe that consists of ∼1 nm thick layer of patterned Gr microelectrodes supported by another layer of 3–5 μm thick patterned GC. Main results. We present the fabrication technology for the new Gr on GC (graphene on glassy carbon) microelectrodes and the accompanying pattern transfer technology on flexible substrate and report on the bond between these two allotropes of carbon through FTIR, surface morphology through SEM, topography through atomic force microscopy, and microstructure imaging through scanning transmission electron microscopy. A long-term (18 weeks) in vivo study of the use of these Gr on GC microelectrodes assessed the quality of the electrocorticography-based neural signal recording and stimulation through electrophysiological measurements. The probes were demonstrated to be functionally and structurally stable over the 18 week period with minimal glial response—the longest reported so far for Gr-based microelectrodes. Significance. The Gr on GC microelectrodes presented here offers a compelling case for expanding the potentials of Gr-based technology in the broad areas of neural probes.

RESUMO A pancreatite aguda é uma doença que tem como substrato um processo inflamatório da glândula pancreática, decorrente da ação de enzimas inadequadamente ativadas. Considerando a importância do tema, esse estudo visa revisar o disponível na literatura acerca dessa patologia. A metodologia aplicada nesse trabalho foi a pesquisa bibliográfica. Foram selecionados 10 artigos. O tratamento inicial da pancreatite aguda é clínico, devendo ser realizado em unidades de terapia intensiva, na dependência de sua gravidade. As medidas iniciais são jejum oral, hidratação parenteral, nutrição parenteral e analgesia sistêmica. Ainda hoje discute-se o valor da utilização rotineira de sonda nasogástrica, bloqueadores da secreção gástrica, bloqueadores da secreção pancreática, análogos da somatostatina e antibióticos.

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572 Background: For premenopausal patients with ER+ breast cancer, a 5-year course of tamoxifen results in a 47% reduction in annual recurrence risk and a 26% reduction in annual mortality. Despite these benefits, adherence rates for tamoxifen are low, particularly among younger women. We hypothesize that fertility concerns are causally related to the poor tamoxifen adherence rates observed among young breast cancer survivors. Methods: With IRB approval, a retrospective analysis of 535 women with breast cancer between 2000-2012 was undertaken. Patients were younger than age 46, premenopausal and had ER+ breast cancer. 138 patients did not complete a 5-year course. Patient and provider factors that influenced tamoxifen initiation and adherence were reviewed: (1) evidence of referral to a fertility specialist; (2) documentation of discussion about tamoxifen-related fertility concerns; (3) agreement to take tamoxifen; (4) duration of tamoxifen use. Phone interviews conducted with 27 patients focused on lack of initiation or early discontinuation. The Log-rank (Mantel-Cox) test was used to compare Kaplan-Meier curves and generate hazard ratios. Results: Of the 138 patients who did not complete 5 years of therapy, 38 (27.5%) failed to initiate or discontinued tamoxifen secondary to fertility concerns. Only 114 (21.3%) charts documented referral to a fertility specialist. Patients who expressed a desire to maintain fertility or to have children in the future (115 patients, 21.5%) were more likely to discontinue tamoxifen treatment (HR=2.7, p=0.001). Other critical factors included being unmarried (HR=1.9, p=0.011) and lack of college education (HR=2.5, p=0.0008). Major themes from phone interviews: (1) patients felt they were not adequately informed about fertility preservation and had to pursue information independently; (2) patients did not initiate/resume tamoxifen postpartum because of inadequate physician guidance. Conclusions: Concerns about fertility have a significant negative impact on the initiation and adherence to tamoxifen for young breast cancer patients. Efforts to improve tamoxifen adherence among young cancer patients should include prioritization of fertility preservation as part of the treatment plan.