Phase I study of CC-90010, a reversible, oral BET inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin's lymphoma.

BACKGROUND: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of genes involved in oncogenesis. CC-90010 is a novel, oral, reversible, small-molecule BET inhibitor. PATIENTS AND METHODS: CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I dose-escalation and expansion study of CC-90010 in patients with advanced or unresectable solid tumors and relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL). We report results from the dose escalation phase, which explored 11 dose levels and four dosing schedules, two weekly (2 days on/5 days off; 3 days on/4 days off), one biweekly (3 days on/11 days off), and one monthly (4 days on/24 days off). The primary objectives were to determine the safety, maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) and schedule. Secondary objectives were to evaluate signals of early antitumor activity, pharmacokinetics, and pharmacodynamics. RESULTS: This study enrolled 69 patients, 67 with solid tumors and two with diffuse large B-cell lymphoma (DLBCL). The median age was 57 years (range, 21-80) and the median number of prior regimens was four (range, 1-9). Treatment-related adverse events (TRAEs) were mostly mild and manageable; grade 3/4 TRAEs reported in more than two patients were thrombocytopenia (13%), anemia, and fatigue (4% each). Six patients had dose-limiting toxicities. MTDs were 15 mg (2 days on/5 days off), 30 mg (3 days on/11 days off), and 45 mg (4 days on/24 days off). The RP2D and schedule selected for expansion was 45 mg (4 days on/24 days off). As of 8 October 2019, one patient with grade 2 astrocytoma achieved a complete response, one patient with endometrial carcinoma had a partial response, and six patients had prolonged stable disease ≥11 months. CONCLUSIONS: CC-90010 is well tolerated, with single-agent activity in patients with heavily pretreated, advanced solid tumors.

Delaying mitotic exit downregulates FLIP expression and strongly sensitizes tumor cells to TRAIL.

Many of the current antitumor therapeutic strategies are based on the perturbation of the cell cycle, especially during mitosis. Antimitotic drugs trigger mitotic checkpoint activation, mitotic arrest and eventually cell death. However, mitotic slippage represents a major mechanism of resistance to these treatments. In an attempt to circumvent the process of slippage, targeting mitotic exit has been proposed as a better strategy to kill tumor cells. In this study, we show that treatments that induce mitotic checkpoint activation and mitotic arrest downregulate FLICE-like inhibitory protein (FLIP) levels and sensitize several tumor cell lines to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis. Interestingly, we also demonstrate that in absence of mitotic checkpoint activation, mitotic arrest induced either by Cdc20 knockdown or overexpression of nondegradable cyclin B is sufficient to induce both FLIP downregulation and sensitivity to TRAIL. In summary, our data suggest that a combination of antimitotic drugs targeting cyclin B degradation and TRAIL might prevent mitotic slippage and allow tumor cells to reach the threshold for apoptosis induction, thereby facilitating tumor suppression.

Mitotic arrest and JNK-induced proteasomal degradation of FLIP and Mcl-1 are key events in the sensitization of breast tumor cells to TRAIL by antimicrotubule agents.

Breast tumor cells are often resistant to tumor necrosis factor-related apoptosis-inducing ligand (tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)/APO-2 L). Here, we describe the sensitization by microtubule-interfering agents (MIAs) to TRAIL-induced apoptosis in breast tumor cells through a mitotic arrest and c-Jun N-terminal kinase (JNK)-dependent mechanism. MIA treatment resulted in BubR1-dependent mitotic arrest leading to the sustained activation of JNK and the proteasome-mediated downregulation of cellular FLICE-inhibitory protein (cFLIP) and myeloid cell leukemia-1 (Mcl-1) expression. The JNK inhibitor SP600125 abrogated MIA-induced mitotic arrest and downregulation of cFLIP and Mcl-1 and reduced the apoptosis caused by the combination of MIAs and TRAIL. Silencing of cFLIP and Mcl-1 expression by RNA interference resulted in a marked sensitization to TRAIL-induced apoptosis. Furthermore, in FLIP-overexpressing cells, MIA-induced sensitization to TRAIL-activated apoptosis was markedly reduced. In summary, our results show that mitotic arrest imposed by MIAs activates JNK and facilitates TRAIL-induced activation of an apoptotic pathway in breast tumor cells by promoting the proteasome-mediated degradation of cFLIP and Mcl-1.

Secreción salival, streptococcus mutans y caries dental en adultos jóvenes. Reporte preliminar / Salivary secretion, streptococcus mutans and dental caries in young adults. A preliminary report

A 96 alumnos del módulo salud bucal de la carrera de estomatología de la Universidad Autónoma Metropolitana Unidad Xochimilco (UAMX) se les registraron los niveles salivales de streptococcus mutans, el promedio de secreción salival y la experiencia anterior de caries dental a través del índice CPO-D. El índice de caries determinado para este grupo fue de 8.7 +/- 5.4, siendo el número de dientes obturados el componente más importante de éste. Del total del grupo estudiado, el 34.4 por ciento tuvo 10 a la sexta de streptococcus mutans, al 53.1 por ciento se les resgistró entre 10 a la quinta - 10 a la sexta y el 12.5 por ciento tuvo < 10 a la sexta por ml. de saliva. El 65.6 por ciento de los alumnos tuvo un promedio de secreción salival de +0.05 ml/min. El análisis de correlación demostró que el recuento de streptococcus mutans cuando se relacionó con la experiencia anterior de caries fue una relación débil (r=0.315). probablemente porque el mayor componente del índice fue el de dientes obturados. No se encontraron asociaciones significativas entre los factores salivales estudiados y el proceso carioso

[Enamel resistance to acid dissolution and its correlation with dental caries]. / Resistencia del esmalte a la disolución ácida y su correlación con la caries dental.

Enamel resistance to acid dissolution is a factor which has an influence upon dental caries susceptibility. The objectives of this study were to determine enamel resistance to acid dissolution by applying the RM technique, and to correlate data obtained to the prevalence of dental caries. Two hundred and seventy one children between seven and nine years of age were chosen by non probabilistic sampling in two city districts, (six public schools in Mexico City). These children's central permanent incisives had already erupted. The DMF-T and dmf-t indexes were recorded, and the RM enamel resistance test was performed on them. A total of 56.4% of the subjects in the sample had very resistant enamel and 27.3%, less resistant enamel. A proportion of 57.9% was free of dental caries on the permanent dentition and 10% in the temporary dentition. The average obtained for the DMF-T index was 0.93 +/- 1.34 and that for dmf-t was 4.7 +/- 3.1. Data suggest that enamel resistance distribution is not homogeneous and this increases proportionally in relation to the eruption third (p < 0.05.) Spearman's correlation coefficient was found to be negative and statistically significant at p < 0.05. The RM technique showed the presence of individuals with different enamel resistance to acid dissolution.

Análisis de las tendencias en la prevalencia de caries dental en dos delegaciones de la ciudad de México / Trends analysis in dental caries prevalence in two delegations from Mexico city

Se examinaron 266 niños, de 7, 8 y 9 años de edad provenientes de las escuelas públicas federales de las delegaciones Tláhuac y Miguel Hidalgo. Dichas delegaciones se detectaron en 1980 como dos de las tres zonas en el distrito federal con menor prevalencia de caries. El promedio de los índice de caries en la delegación Tláhuac, son para la dentición temporal 4.64 +- 3.0 (CEO-D) y para la permanente 1.08 +- (CPO-D). En la delegación Miguel Hidalgo se determinó un índice CEO-D de 4.58 +- 3.1 y un CPO-D de 0.69 +- 1.1. El 9.4 por ciento de los niños se encontró libre de caries (6 por ciento Tláhuac y 3.4 por ciento Miguel Hidalgo). Al comparar los resultados con el estudio realizado por la Secretaría de Salud en 1980 se demostró que no hay cambios importantes en los niveles de caries para la dentición temporal, pero sí en la experiencia de caries para la dentición permanente, lo cual sugiere que las medidas preventivas utilizadas en este sector de la población, han tenido impacto en los últimos 12 años

[Occlusion distribution in a 7- to 14-year old student population]. / Distribución de la oclusión en una población escolar entre 7 y 14 años.

The epidemiological characterization of the occlusion was made on basis of the classical Angle Classification through a statistical selection from a total of 4363 females and males children; which ages ranged between 7 to 14 years old. These were students registered in public federal schools located in the south of the metropolitan area. The results of the study were determined as follows: Class I, 84.7%; Class II, 10.9%, Class III 4.3%.