We have isolated a novel gene, DIR1, from L132 cells that is transiently repressed after exposure to low radiation doses and has a potential role in induced radioresistance. Molecular and cellular characterization of this gene reveals that it is unique but has similarities to a family of heat-shock-related proteins known as immunophilins. These have been implicated in various cellular functions including general stress responses and control of the cell cycle. Antisense strategies have demonstrated that the DIR1 gene also appears to have some involvement in the control of the cell cycle. Furthermore, there appears be a potential role for this gene product in the phenomenon of induced radioresistance through a mechanism that increases the rate of DNA repair in cells exposed to X rays and subsequently increases the cells' resistance to radiation. This is the first description of an immunophilin-like gene that has a possible role in adaptive/inducible responses to X rays in mammalian cells.

Background TNT previously reported that patients(pts) with advanced triple negative breast cancer(TNBC) and germline BRCA1/2(gBRCA+) mutations are more likely to respond to carboplatin(C) than to docetaxel(D), and have longer progression-free survival with C. Here, we report results from a pre-planned biological analysis to test whether BRCA silencing or methylation status confer sensitivity to platinum. Methods Pts eligible for TNT had ER-, PgR-, HER2- BC or were known gBRCA+(any ER/PgR/HER2). Pts were randomized to C(AUC 6 q3wk) or D(100mg/m2 q3wk) for 6-8 cycles or until disease progression if sooner, with crossover possible on progression. Blood and archival tissue samples were requested for BRCA1/2 genotyping, central analysis of TN and DNA repair deficiency biomarkers. Primary endpoint was intention-to-treat objective response rate(ORR) up to cycle 6. BRCA1 mRNA level was estimated from whole-genome total RNA sequencing(RNA-Seq). BRCA1 methylation analysis was quantified by bisulfite sequencing. A methylation score for the sample was computed as percentage of methylated reads relative to total number of reads that were either methylated or not methylated for CpG sites. A sample with a score >10% was considered methylated(BRCA1meth)? a BRCA1 mRNA level "silenced" subgroup(BRCA1 silencing) was defined as value of log2(mRNA)<8.4, based on bimodal distribution. Results 212 and 191 pts' samples were assessed for BRCA1 methylation and mRNA levels. 33 pts (15.6%) were found to be BRCA1meth. Pts with BRCA1meth had a better response to D (42%, 95%CI: 20, 64) than C (21%, 95%CI: -0.1, 43)? absolute difference (C-D) -21% (95%CI: -52, 10)? p=0.28), but not statistically significant. There was no evidence of a difference when gBRCA+ tumours were excluded. 31 pts (16%) had BRCA1 silencing. Concordant with BRCA1meth, pts with BRCA1 silencing had a better response to D (65%, 95%CI: 42, 87) than C (29%, 95%CI: 4.9, 52)? absolute difference (C-D) -36% (95%CI: -69, -3.3)? p=0.07), with an odds ratio 0.22 (95%CI: 0.035, 1.2) in favor of D, interaction with treatment not significant (p=0.066). 19 pts with BRCA1meth and BRCA1 silencing had a better response to D (60%, 95%CI: 30, 90) than C (22%, 95%CI: -5.0, 49)? absolute difference (C-D) -38% (95%CI: -79, 2.9) in favor of D (p=0.17), and the interaction was not significant (p=0.15). Further exploratory analyses examining any relationship between a response to C and new cutpoints for BRCA1meth or BRCA1 mRNA level did not suggest any evidence of a signal. Conclusion Our data did not support a priori hypotheses that BRCA1 methylation or silencing would be associated with a greater response to C than D, which is consistent with other reports in ovarian cancer. As BRCA1 methylation will not always lead to significant silencing or be the only cause of low BRCA1 gene expression, exploratory analysis is investigating the interaction of BRCA silenced group with D sensitivity. RNA-seq is ongoing and results from the final database will be presented. Citation Format: Tutt A, Cheang MCU, Kilburn L, Tovey H, Gillett C, Pinder S, Lanchbury J, Abraham J, Barrett S, Barrett-Lee P, Chan S, Gazinska P, Grigoriadis A, Kernaghan S, Hoadley K, Gutin A, Harper-Wynne C, Hatton M, Owen J, Parker P, Roylance R, Shaw A, Smith I, Thompson R, Timms K, Wardley A, Wilson G, Harries M, Ellis P, Ashworth A, Perou C, Bliss J, Rahman N, Brown R, On Behalf of the TNT Trial Management Group and Investigators. BRCA1 methylation status, silencing and treatment effect in the TNT trial: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S6-01.

In 1994 a moving car and its driver, on a highway in southern Madrid (Getafe), were struck by a falling rock. Eighty-one additional fragments (total weight : 55.926 kg) were later recovered, which all pointed towards a meteorite fall. A study of the composition of this object revealed an ultrarefractory material displaying a most unusual chemical make-up which differs from any known meteorite class, and for some elements and minerals approaches the composition of CAÍ (Ca-Al-rich inclusions in chondrites). A study of some cosmic-ray-produced stable and radioactive nuclides indicates: a) space and terrestrial exposure ages which do not exceed 1,000 and 520,000 years, respectively; b) the presence of a small 22 Ne excess (1,100 °C fraction), which suggests either a nucleogenic contribution from the 19 F(a,n) 2 Ne reaction or a trapped Ne signature distinct from atmospheric Ne, and c) the existence of minor variations in the 3 Ar/ 36 Ar ratios also indicating a nucleogenic component or fractionation effects. 14 C data are consistent with "modern" carbón originated in the period 1955-1958 and not earlier or more recently. The possibility that the Getafe rock could have a man-made origin (i.e. ceramic and refractory tiles, industrial slag) is also considered. Keywords:Getafe rock. FalL Composition. Cosmic ray records. Meteorite. Slag. Madrid. Spain. La roca de Getafe: Caída, composición y registro de rayos cósmicos de un material inusual ultrarrefractario de escoriaResumen En 1994, una roca impactó, en trayectoria descendente, contra un coche que circulaba por la zona sur de Madrid (Getafe), dañando al conductor en el proceso de caída. Posteriormente, se recuperaron otros ochenta y un fragmentos adicionales, con un peso total de 55.926 kg, apuntando todo ello a que se trataba de una típica caída meteorítica. El estudio mineralógico y geoquímico de la roca de Getafe revela que se trata de un material ultrarrefractario, que muestra una composición muy inusual que difiere de los meteoritos conocidos y que, para algunos elementos y minerales, se aproxima a la composición de las CAÍ (inclusiones ricas en Ca-Al en condritas). El estudio de algunos núclidos estables y radiactivos producidos por los rayos cósmicos indica: a) edades de exposición en el espacio y terrestres que no sobrepasan los 1.000 y 520.000 años, respectivamente; b) la presencia de un pequeño exceso de 22

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Background: The proliferation antigen Ki67 has been shown to be a reliable predictive marker of treatment efficacy in the neoadjuvant treatment of breast cancer but its prognostic significance remains uncertain. This study assesses Ki67 before and after neoadjuvant chemotherapy (NAC) in relation to long-term outcome. Methods: 117 patients with primary breast cancer due to undergo NAC were studied (median age 48 years, range 25-78; T2-4, N0-3, M0) and information gathered from a prospectively maintained database. Immunohistochemically derived Ki67 expression was obtained from pretreatment core biopsy and surgical specimens. Their relationship to DFS and OS was analyzed along with known prognostic variables (age, ER/PR/HER2 status, clinical and pathologic T and N stage, grade), NAC regimen, response and adjuvant treatment. Survival curves were estimated using the Kaplan-Meier method and a log-rank test used to determine significance using a two-tailed p-value of 0.05. A multivariate Cox proportional hazards regression model performed in a stepwise fashion was used to determine the prognostic value of each signifcant variable. Results: 84 patients with matched biopsy and surgical samples were assessable for pre and post NAC Ki67 levels. The majority (90%) received anthracycline based NAC (median number of cycles 6, range 2-6). On univariate analysis, the only significant pretreatment predictive factor for shorter DFS was higher clinical nodal stage (cN) (P<0.001). Posttreatment variables that predicted for worse DFS were: Ki67 at surgery (HR 1.52, p=0.048), pathologic nodal stage (pN) (p=0.001) and grade (p=0.013). On multivariate analysis, pN was the most powerful predictor for DFS (chi-squared test 19.8, 3 df, P<0.001). Univariate analysis of pretherapy factors for OS revealed that Ki67 at biopsy (HR 2.06, p=0.039), cN (HR 4.44, P<0.001) and PR positivity (HR 0.41, p=0.012) were significant. Significant posttreatment variables for OS were Ki67 at surgery (HR 2.01, p=0.006), pN (p=0.001), and grade (p=0.009). PR status and pN remained important predictors of OS on multivariate analyses. Conclusions: The expression of Ki67 is a widely accepted marker of cellular proliferation in breast cancer. Ki67 levels after NAC were a better predictor for long-term outcome than pretherapy Ki67, although nodal status appears to be the most powerful determinant overall. High Ki67 levels post NAC may identify patients with poorer outcomes who are candidates for further systemic therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD07-04.