Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC.

Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response. Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines. The Chou-Talalay method was used for the quantitative determination of drug interaction. We examined tumor growth inhibition in one EGFR-mutant NSCLC xenograft model (n = 4 mice per group). STAT3 and YAP1 expression was evaluated in tumors from 119 EGFR-mutant NSCLC patients (64 in an initial cohort and 55 in a validation cohort) by quantitative polymerase chain reaction. Kaplan-Meier and Cox regression analyses were used to assess the correlation between survival and gene expression. All statistical tests were two-sided. Results: We discovered that lung cancer cells survive initial EGFR inhibitor treatment through activation of not only STAT3 but also Src-YAP1 signaling. Cotargeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines with a combination index of 0.59 (95% confidence interval [CI] = 0.54 to 0.63) for the PC-9 and 0.59 (95% CI = 0.54 to 0.63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio [HR] = 3.02, 95% CI = 1.54 to 5.93, P = .001, and HR = 2.57, 95% CI = 1.30 to 5.09, P = .007, respectively) in an initial cohort of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKIs. Similar results were observed in a validation cohort. Conclusions: Our study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhance clinical outcomes.

Design, synthesis and biological evaluation of pyrido[2,3-d]pyrimidin-7-(8H)-ones as HCV inhibitors.

The design and selection of a combinatorial library of pyrido[2,3-d]pyrimidin-7(8H)-ones (4) has allowed the synthesis of 121 compounds, using known and new synthetic methodologies, and the evaluation of the inhibitory activity against hepatitis C virus (HCV) genotype 1b replicon. Among these compounds, 21{4,10} and 24{2,10} presented very high activities [EC50 = 0.027 µM (CC50 = 5.3 µM) and EC50 = 0.034 µM (CC50 = 13.5 µM), respectively] and high selectivity indexes, 196 and 397. These values are similar to the EC50 reported for sofosbuvir (2) (0.048 µM) using a similar methodological approach and the same virus subtype. 21{4,10} and 24{2,10} are obtained through shorter synthetic itineraries than sofosbuvir and 24{2,10} is achiral contrary to sofosbuvir which presents 4 stereogenic centers. In silico studies suggest that 21{4,10} and 24{2,10} inhibits NS5B polymerase through allosteric site binding.

Incidencia y factores asociados para recurrencia bioquímica en pacientes sometidos a prostatectomía radical por cáncer de próstata localizado, Hospital Nacional Edgardo Rebagliati Martins, 2000-2004 / Incidence and associated factors for biochemical recurrence in patients undergoing radical prostatectomy for localized prostate cancer, National Hospital Edgardo Rebagliati Martins, 2000-2004

OBJETIVO: Este estudio estuvo dirigido a determinar cuál fue la incidencia de recurrencia bioquímica entre los pacientes sometidos a prostatectomía radical por cáncer de próstata localizado en el Hospital Nacional Edgardo Rebagliati Martins durante el periodo enero 2000-diciembre 2004 y cuáles fueron sus factores asociados. MATERIALES Y METODOS: Estudio descriptivo tipo retrospectivo, correlacional. RESULTADOS: Se estudiaron 144 pacientes. La incidencia de PSA>0.4: se presenta en un 36.1 por ciento. El PSA>0.4 y el estadio T2b final, da un p=0.00001 OR: 0.08 (0.03-0.20). PSA>0.4 y los márgenes positivos, da un p=0.00002 OR 0.23 (0.12-0.35). PSA>0.4 y Gleason de la biopsia, da un p=0.0002 OR 0.15 (0.05-0.45). PSA>0.4 y Gleason del espécimen da un p=0.0001 OR 0.05 (0.01-0.38). PSA>0.4 y PSA prequirúrgico >10, da un p=0.00002 OR 0.08 (0.02-0.27). CONCLUSION: Se encontró estadísticamente significativa con un valor de p<0.05, PSA preoperatorio >10, el estadio clínico T2c, márgenes positivos y el score de Gleason 4+3 o mayor en la pieza quirúrgica son predictores independientes de recurrencia bioquímica en pacientes con cáncer de próstata.

OBJECTIVE: This study was aimed to determine what was the incidence of biochemical recurrence in patients undergoing radical prostatectomy for localized prostate cancer in the Edgardo Rebagliati Martins National Hospital during the period January 2000-December 2004 and what were the factors associated. MATERIALS AND METHODS: A retrospective descriptive study, correlational. RESULTS: 144 patients were studied. The incidence of PSA>04: comes in a 36.1 per cent. The PSA>0.4 and T2b stage end, gives p=0.00001 OR: 0.08 (0.03 to 0.20). PSA>0.4 and positive margins, gives p=0.00002 OR 0.23 (0.12 to 0.35). PSA>0.4 and Gleason biopsy gives a p=0.0002 OR 0.15 (0.05-0.45). PSA>0.4 and specimen Gleason gives a p=0.0001 OR 0.05 (0.01 to 0.38). PSA>0.4 and preoperative PSA>10, gives p=0.00002 OR 0.08 (0.02 to 0.27). CONCLUSION: We found statistically significant with a p-value<0.05, preoperative PSA>10, clinical stage T2c, positive margins and Gleason score 4+3 or greater in the surgical specimen are independent predictors of biochemical recurrence in patients with cancer prostate.

Dual fluorescence in 9-amino-2,7,12,17-tetraphenylporphycene.

The absorption spectrum of the asymmetric 9-amino-2,7,12,17-tetraphenylporphycene shows new, strongly red-shifted bands compared to the symmetric parental 2,7,12,17-tetraphenylporphycene and to the also asymmetric 9-acetoxy-2,7,12,17-tetraphenylporphycene. Dual emission is also observed with relative contributions that depend strongly on the excitation wavelength and temperature. The gap between the two fluorescence bands is 84 nm. Tautomerization in both the ground and excited states is shown to account for these observations, the 9-amino group being particularly able to selectively lower the energy of the first excited singlet state of just one of the trans tautomers. Introduction of amino groups in porphycenes may be a convenient way to gain a deeper insight into the tautomerization mechanisms in this macrocyclic core.