Comprehensive Serum Profiling for the Discovery of Epithelial Ovarian Cancer Biomarkers

FDA-cleared ovarian cancer biomarkers are limited to CA-125 and HE4 for monitoring and recurrence and OVA1, a multivariate panel consisting of CA-125 and four additional biomarkers, for referring patients to a specialist. Due to relatively poor performance of these tests, more accurate and broadly applicable biomarkers are needed. We evaluated the dysregulation of 259 candidate cancer markers in serum samples from 499 patients. Sera were collected prospectively at 11 monitored sites under a single well-defined protocol. All stages of ovarian cancer and common benign gynecological conditions were represented. To ensure consistency and comparability of biomarker comparisons, all measurements were performed on a single platform, at a single site, using a panel of rigorously calibrated, qualified, high-throughput, multiplexed immunoassays and all analyses were conducted using the same software. Each marker was evaluated independently for its ability to differentiate ovarian cancer from benign conditions. A total of 175 markers were dysregulated in the cancer samples. HE4 (AUC = 0.933) and CA-125 (AUC = 0.907) were the most informative biomarkers, followed by IL-2 receptor α, α1-antitrypsin, C-reactive protein, YKL-40, cellular fibronectin, CA-72-4 and prostasin (AUC>0.800). To improve the discrimination between cancer and benign conditions, a simple multivariate combination of markers was explored using logistic regression. When combined into a single panel, the nine most informative individual biomarkers yielded an AUC value of 0.950, significantly higher than obtained when combining the markers in the OVA1 panel (AUC 0.912). Additionally, at a threshold sensitivity of 90%, the combination of the top 9 markers gave 88.9% specificity compared to 63.4% specificity for the OVA1 markers. Although a blinded validation study has not yet been performed, these results indicate that alternative biomarker combinations might lead to significant improvements in the detection of ovarian cancer

Genome-Wide Fitness and Expression Profiling Implicate Mga2 in Adaptation to Hydrogen Peroxide

Caloric restriction extends lifespan, an effect once thought to involve attenuation of reactive oxygen species (ROS) generated by aerobic metabolism. However, recent evidence suggests that caloric restriction may in fact raise ROS levels, which in turn provides protection from acute doses of oxidant through a process called adaptation. To shed light on the molecular mechanisms of adaptation, we designed a series of genome-wide deletion fitness and mRNA expression screens to identify genes involved in adaptation to hydrogen peroxide. Combined with known transcriptional interactions, the integrated data implicate Yap1 and Skn7 as central transcription factors of both the adaptive and acute oxidative responses. They also identify the transcription factors Mga2 and Rox1 as active exclusively in the adaptive response and show that Mga2 is essential for adaptation. These findings are striking because Mga2 and Rox1 have been thought to control the response to hypoxic, not oxidative, conditions. Expression profiling of mga2Δ and rox1Δ knockouts shows that these factors most strongly regulate targets in ergosterol, fatty-acid, and zinc metabolic pathways. Direct quantitation of ergosterol reveals that its basal concentration indeed depends on Mga2, but that Mga2 is not required for the decrease in ergosterol observed during adaptation

A comprehensive overview of radioguided surgery using gamma detection probe technology

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology

Visible-light sensitisation of near-infrared luminescence from Yb(III), Nd(III) and Er(III) complexes of 3,6-bis(2-pyridyl)tetrazine

Reaction of the potentially bis-bidentate bridging ligand 3,6-bis(2-pyridyl)tetrazine (BPTZ) with various lanthanide complexes [Ln(tta)3(H2O)2] [Htta = thenoyl(trifluoro) acetone; Ln = La, Nd, Gd, Er, Yb] in aqueous ethanol afforded the mononuclear complexes [Ln(tta)3(BPTZ)] (Ln = La, Nd) or the dinuclear complexes [{Ln(tta)3}2(μ-BPTZ)] (Ln = Gd, Er, Yb) in which one or two, respectively, lanthanide tris-diketonate {Ln(tta)3} units are bound to the N,N-bidentate compartments of BPTZ. Crystal structures of the dinuclear complexes [{Yb(tta)3}2(μ-BPTZ)] ·CH2Cl2 and [{Gd(tta)3} 2(μ-BPTZ)]·2CH2Cl2 show that the metal centres have an approximately square-antiprismatic eight-coordinate geometry; there are close contacts above and below the plane of the BPTZ bridging ligand between peripheral trifluoromethyl groups from a tta ligand associated with each metal centre. It is not apparent why the larger lanthanides La and Nd only give a mononuclear complex whereas the smaller lanthanides Gd, Er and Yb give the dinuclear complex in each case. UV/Vis spectroscopic titrations of a solution of BPTZ in CH2Cl2 with increasing amounts of [Ln(tta)3(H2O)2] (Ln = La and Yb) show very similar behaviour, with stepwise binding constants K1 and K2 for association of the two {Ln(tta)3} units of ca. 106 M-1 and 105 M-1; allowing for the expected statistical factor of 4 there is an additional reduction in the value of K2 compared to K1 which may be associated with a steric interaction between the two {Ln(tta)3} units when the dinuclear complex forms. Steady-state and time-resolved luminescence studies on the complexes with Yb, Nd and Er, both in the solid state and CH 2Cl2 solution, show that near-IR luminescence on the microsecond timescale can be sensitised by irradiation either at 337 nm into the tta-based transition, or at 520 nm into the low-energy BPTZ-centred transition. © The Royal Society of Chemistry 2003

Sensitised near-infrared emission from lanthanides using a covalently-attached Pt(II) fragment as an antenna group.

In a series of heterodinuclear complexes in which a Pt(PPh3)2(catecholate) chromophore is covalently linked to a lanthanide tris(diketonate) unit, sensitised near-IR emission from Yb(III), Nd(III) and Er(III) occurs on excitation of the Pt(II) chromophore at 520 nm