The spread of cancer throughout the body is driven by circulating tumour cells (CTCs)1. These cells detach from the primary tumour and move from the blood stream to a new site of subsequent tumour growth. They also carry information about the primary tumour and have the potential to be valuable biomarkers for disease diagnosis and progression, and for the molecular characterization of certain biological properties of the tumour. However, the limited sensitivity and specificity of current methods to measure and study these cells in patient blood samples prevent the realization of their full clinical potential. The use of microfluidic devices is a promising method for isolating CTCs2, 3; however, the devices are reliant on three-dimensional structures, which limit further characterization and expansion of cells on the chip. Here we demonstrate an effective approach to isolate CTCs from blood samples of pancreatic, breast and lung cancer patients, by using functionalised graphene oxide nanosheets on a patterned gold surface. CTCs were captured with high sensitivity at low concentration of target cells (73% ± 32.4 at 3–5 cells/mL blood).

The BRCA1 gene on chromosome 17q21 is responsible for an autosomal dominant syndrome of increased susceptibility to breast and ovarian cancer but no somatic mutations in tumours have yet been described. To study the potential role of BRCA1 in sporadic carcinogenesis, we analysed the genomic DNA of tumour and normal fractions of 47 ovarian cancers for mutations in BRCA1 using the single-strand conformation polymorphism technique. We now describe somatic mutations in the DNA of four tumours which also had loss of heterozygosity (LOH) at a BRCA1 intragenic marker. Our data support a tumour suppressor mechanism for BRCA1; somatic mutations and LOH may result in inactivation of BRCA1 in at least a small number of ovarian cancers.

PurposeEnzalutamide resistance could result from raised androgens and be overcome by combination with abiraterone acetate. PLATO (ClinicalTrials.gov identifier: NCT01995513) interrogated this hypothesis using a randomized, double-blind, placebo-controlled design.Patients and MethodsIn period one, men with chemotherapy-naïve metastatic castration-resistant prostate cancer received open-label enzalutamide 160 mg daily. Men with no prostate-specific antigen (PSA) increase at weeks 13 and 21 were treated until PSA progression (≥ 25% increase and ≥ 2 ng/mL above nadir), then randomly assigned at a one-to-one ratio in period two to abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily with either enzalutamide or placebo (combination or control group, respectively) until disease progression as defined by the primary end point: progression-free survival (radiographic or unequivocal clinical progression or death during study). Secondary end points included time to PSA progression and PSA response in period two.ResultsOf 509 patients enrolled in period one, 251 were randomly assigned in period two. Median progression-free survival was 5.7 months in the combination group and 5.6 months in the control group (hazard ratio, 0.83; 95% CI, 0.61 to 1.12; P = .22). There was no difference in the secondary end points. Grade 3 hypertension (10% v 2%) and increased ALT (6% v 2%) or AST (2% v 0%) were more frequent in the combination than the control group.ConclusionCombining enzalutamide with abiraterone acetate and prednisone is not indicated after PSA progression during treatment with enzalutamide alone; hypertension and elevated liver enzymes are more frequent with combination therapy.

Bio-/synthetic hybrid materials have recently received considerable attention owing to their potential biomedical applications. [1] The most reliable way of identifying any biological target is through its genetic code. [2] However, the current commercial DNA microarray requires costly and time-consuming PCR to multiply the number of analyte DNA molecules and label the analyte DNA with a fluorescent dye because of the low detection limit. In this context, devising self-signal-amplifying DNA microarrays can realize low-cost, fast, and reliable detection of nucleic acids. Herein, we report signal-amplifying DNA chips fabricated by on-chip DNA synthesis on a thin film of a newly developed conjugated polymer ( Figure 1 and the chemical structure in Figure 2 a).Conjugated polymer-based biosensors are an attractive approach to improve the detection limit because an environmental change at a single site can affect the properties of the collective system, producing large signal amplification. [3] Therefore, if one devises a strategy combining the signalamplification scheme of conjugated polymers and efficient on-chip DNA synthesis, signal-amplifying DNA microarrays can be conveniently prepared. On-chip oligonucleotide synthesis [2d, 4] has the unique advantage of being performed in a parallel fashion, is flexible in sequence design, easy to manufacture, and has a high sequence fidelity compared with other recently developed methods, such as the pin microdotting method, [2c] the ink-jet microdropping method, [5] and the electrostatic addressing method. [6] Almost all the on-chip DNA synthesis technologies, however, require harsh conditions such as long exposure to UV light and/or to strong acids. Under these harsh conditions, conventional conjugated polymers will be photobleached or chemically degraded.We have developed a novel conjugated polymer with a strong fluorescence emission and unique stability under the above-mentioned harsh conditions. Figure 2 a shows the chemical structure of the poly(oxadiazole-co-phenylene-cofluorene) P1 with oxadiazole units and amine side chains. All monomer units of P1 were designed to have their own contribution to the final property of P1 and synthesized through multiple synthetic steps (see the Supporting Information). Oxadiazole is an electron-poor heterocyclic molecule that has been used in polymer design in which the improvement of electron transport and/or stability of the polymer is required. [7] We designed an oxadiazole-containing monomer (M3) and incorporated this unit into the conjugated polymer backbone by using a Pd-based Suzuki coupling method. [8] The oxadiazole-containing monomer unit M3 of P1 has an intense blue fluorescence emission at 413 nm in a chloroform solution and is stable when exposed to strong UV irradiation and a strong acidic environment. The amine groups on the phenylene unit (M1) of P1 serve as functional groups for immobilization of P1 on a glass substrate as well as linkers for direct on-chip synthesis of oligonucleotides on the resulting thin-layer f...

Transforming growth factor-beta (TGF-beta) inhibits pancreatic acinar cell growth. In many cell types, TGF-beta mediates its growth inhibitory effects by activation of Smad proteins. Recently, it has been reported that Smad proteins may interact with the mitogen-activated protein (MAP) kinase signaling pathways. In this study, we report on the interactions between the TGF-beta and MAP kinase signaling pathways in isolated rat pancreatic acinar cells. TGF-beta activated the MAP kinases extracellular signal-related kinases (ERKs) and p38 in pancreatic acinar cells, but had no effect on c-jun NH2-terminal kinase activity. Activation of MAP kinase by TGF-beta was maximal 4 h after treatment. The ability of TGF-beta to activate ERKs was concentration dependent and dependent on protein synthesis. TGF-beta's stimulation of ERK activation was blocked by PD-98059, an inhibitor of MAP kinase kinase 1, and by adenoviral transfer of dominant negative RasN17. Furthermore, adenoviral-mediated expression of dominant negative Smad4 blocked the ability of TGF-beta to activate acinar cell MAP kinase, demonstrating that this activation is downstream of Smads. The biological relevance of ERK activation by TGF-beta was indicated by demonstrating that inhibition of ERK signaling by PD-98059 blocked the ability of TGF-beta to activate the transcription factor activator protein-1. These studies provide new insight into the signaling mechanisms by which TGF-beta mediates biological actions in pancreatic acinar cells.