Cancers with dysfunctional mutations in BRCA1 or BRCA2, most commonly associated with some breast cancers, are deficient in the DNA damage repair pathway called homologous recombination (HR), which makes them exquisitely vulnerable to poly(ADP-ribose) polymerase (PARP) inhibitors, such as olaparib. This functional state and therapeutic sensitivity is referred to as “BRCAness”. Pharmaceutical induction of BRCAness could expand the use of PARP inhibitors to other tumor types. For example, BRCA mutations are present in only a small proportion of prostate cancer (PCa) patients. We found that castration-resistant PCa (CRPC) cells increased expression of a set of HR-associated genes, including BRCA1, RAD54L and RMI2. Androgen-targeted therapy is typically not effective in CRPC patients. However, the androgen receptor (AR) inhibitor enzalutamide suppressed the expression of those HR genes, thus creating HR deficiency and BRCAness in CRPC cells. In a manner dependent on these gene expression effects, a “lead-in” treatment strategy, in which enzalutamide was followed by the combination of enzalutamide and olaparib, promoted DNA damage-induced cell death and inhibited clonal proliferation of PCa cells in culture and suppressed the growth of PCa xenografts in mice. Thus, our study suggests that anti-androgen and PARP inhibitor combination therapy may be effective for patients with CRPC, and that pharmaceutically-induced BRCAness may expand the clinical use of PARP inhibitors.
Poly(acrylonitrile) (PAN) solutions in N,N-dimethylformamide were electrospun into webs consisting of 350 nm ultra-fine fibers. The webs were oxidatively stabilized and followed by heat treatment in the range of 700-1000 • C. Characterization of the microstructure of PAN-based carbon nanofibers was performed by x-ray diffraction, field-emission scanning electron microscopy, electrical conductivity and Raman spectroscopy. The L c.002/ and L a.10/ values were calculated to be 1.85-2.15 and 2.23-3.36 nm, respectively. The L c.002/ and L a.10/ values increased by about 86% and 66%, respectively, when the heat treatment temperature (HTT) was increased from 700 to 1000 • C. The electrical conductivity of carbonized PAN nanofiber webs increased with increasing carbonization temperature, being 6.8 × 10 −3 and 1.96 S cm −1 at 700 and 1000 • C, respectively. The D and G bands from Raman scattering were fitted into a Gaussian-Lorentzian hybridized function, and the crystallite sizes in the nanofibers were evaluated from the R-values determined from the ratios of the intensity of the G band to that of the D band. The domain size of the graphitic layers was in the range 1.6-3.2 nm with higher values at higher HTT.
Purpose: We investigated MYCN-regulated molecular pathways in castration-resistant prostate cancer (CRPC) classified by morphologic criteria as adenocarcinoma or neuroendocrine to extend the molecular phenotype, establish driver pathways, and identify novel approaches to combination therapy for neuroendocrine prostate cancer (NEPC).Experimental Design and Results: Using comparative bioinformatics analyses of CRPC-Adeno and CRPC-Neuro RNA sequence data from public data sets and a panel of 28 PDX models, we identified a MYCN-PARP-DNA damage response (DDR) pathway that is enriched in CRPC with neuroendocrine differentiation (NED) and CRPC-Neuro. ChIP-PCR assay revealed that N-MYC transcriptionally activates PARP1, PARP2, BRCA1, RMI2, and TOPBP1 through binding to the promoters of these genes. MYCN or PARP1 gene knockdown significantly reduced the expression of MYCN-PARP-DDR pathway genes and NED markers, and inhibition with MYCNsi and/or PARPsi, BRCA1si, or RMI2si significantly suppressed malignant activities, including cell viability, colony formation, and cell migration, in C4-2b4 and NCI-H660 cells. Targeting this pathway with AURKA inhibitor PHA739358 and PARP inhibitor olaparib generated therapeutic effects similar to those of gene knockdown in vitro and significantly suppressed tumor growth in both C4-2b4 and MDACC PDX144-13C subcutaneous models in vivo.Conclusions: Our results identify a novel MYCN-PARP-DDR pathway that is driven by N-MYC in a subset of CRPCAdeno and in NEPC. Targeting this pathway using in vitro and in vivo CRPC-Adeno and CRPC-Neuro models demonstrated a novel therapeutic strategy for NEPC. Further investigation of N-MYC-regulated DDR gene targets and the biological and clinical significance of MYCN-PARP-DDR signaling will more fully elucidate the importance of the MYCN-PARP-DDR signaling pathway in the development and maintenance of NEPC.
Membrane separations are considered to be sustainable technologies because of their relatively low energy consumption. However, the fabrication of membranes is yet to turn green. Thin film composite (TFC) membranes...
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