Glucose-6-phosphate-dehydrogenase deficiency as a risk factor in proliferative disorder development

Glucose-6-phosphate dehydrogenase (G6PD) is an important site of metabolic control in the pentose phosphate pathway (PPP) which provides reducing power (NADPH) and pentose phosphates. The former is mainly involved in the detoxification of chemical reactive species; the latter in the regulation of cell proliferation. G6PD deficiency is the most common enzymopathy in the human population, characterized by decreased G6PD activity, mainly in red blood cells, but actually also in nucleated cells. This decreased activity is not due to enzyme synthesis impairment, but rather to reduced enzyme stability, which leads to a shortening of its half-life. Therefore, a major problem is to understand the underlying mechanisms linking G6PD deficiency to oxidative stress and cell proliferation. In order to address this issue, in the present study we utilized, as an experimental model, fibroblasts isolated from pterygium, an ocular proliferative lesion, from G6PD normal and deficient (PFs+ and PFs-, respectively) patients. Our choice was determined by the fact that pterygium is believed to be caused by chronic oxidative stress induced by UV exposure, and that pterygium fibroblasts resemble a tumorigenic phenotype. As controls we utilized fibroblasts isolated from conjunctiva from G6PD normal and deficient patients (NCFs+ and NCFs-, respectively) who had undergone cataract surgery. 
Growth rate analysis revealed that PFs grow faster than NCFs, but while NCFs- grow more slowly than NCFs+, PFs- and PFs+ grow at the same rate. This was associated with significantly lower G6PD activity in NCFs+ compared to NCFs-, while no significant differences in the G6PD activity of PFs+ and PFs- were noted. This result was supported by the finding that in PFs-, G6PD mRNA levels were significantly higher than in PFs+. Another interesting finding of this study was increased green autofluorescence in both NCFs- and PFs- compared to corresponding positive cells, indicative of pronounced oxidative stress in deficient cells. Finally, abnormal accumulation of neutral lipids, mainly cholesterol esters was observed both in PFs- and PFs+ compared to NCFs- and NCFs+. Though further studies are necessary for better understanding the exact mechanism which links G6PD to oxidative stress and cell proliferation, our data allow to speculate on the role of G6PD on tumorigenesis, and to consider G6PD-deficient subjects at major risk to develop common and dreaded proliferative disorders, such as atherosclerosis and cancer. 
&#xa

CT-based tumour response criteria compared after combined treatment for liver metastases of colorectal cancer

open6noPurpose: The aim of this analysis is to compare different tumour response criteria (TRC) after chemotherapy combined with bevacizumab in liver metastases from colorectal cancer (mCRC) to ascertain the best early prognostic indicator of response. Methods and Materials: 103 target liver metastases from 65 mCRC patients treated with chemoterapy plus bevacizumab were examined at the Istituto Oncologico Veneto IOV-IRCSS (March 2008-January 2013). All patients had baseline CT and at least one follow-up scan. Tumour response was retrospectively analyzed by two radiologists using RECIST1.1, modified Choi, and Chun morphologic criteria. Tumour response, classified as good (complete or partial response) or poor (stable or progressive disease), was compared with progression-free survival (PFS) at first follow-up (t1) and time of best response. Interobserver agreement and concordance between TRC were measured. Results: At t1, 32.31% showed a good response according to RECIST1.1 (median PFS 11.1), 84.62% according to Choi (median PFS 10.8). These percentages rose to 49.23% (median PFS 12.1) and 87.69% (median PFS 10.8), respectively, at the time of best response. According to Chun, 67.69% showed a good response at the time of best response (median PFS 10.8). The Choi criteria detected a higher proportion of good responders at t1, showing a better correlation with PFS; all methods correlated with PFS at the time of best response. Conclusion: The Choi criteria proved more consistent in the early detection of response in mCRC treated with chemotherapy plus bevacizumab, underscoring the importance of using these criteria in the early assessment of response to combined treatment.openopenVarotto, A.; Di Grazia, L.; Aliberti, C.; Bergamo, F.; Nardin, M.; Pomerri, F.Varotto, A.; Di Grazia, L.; Aliberti, C.; Bergamo, F.; Nardin, M.; Pomerri, Fabi

Characterization of dust activity on Mars from MY27 to MY32 by PFS-MEX observations

We present spatial and temporal distributions of dust on Mars from Ls = 331 in MY26 until Ls = 80 in MY33 retrieved from the measurements taken by the Planetary Fourier Spectrometer (PFS) aboard Mars Express. In agreement with previous observations, large dust opacity is observed mostly in the southern hemisphere spring/summer and particularly over regions of higher terrain and large topographic variation. We present a comparison with dust opacities obtained from Thermal Emission Spectrometer (TES) - Mars Global Surveyor (MGS) measurements. We found good consistency between observations of two instruments during overlapping interval (Ls = 331 in MY26 until Ls = 77 in MY27). We found a different behavior of the dust opacity with latitude in the various Martian years (inter-annual variations). A global dust storm occurred in MY28. We observe a different spatial distribution, a later occurrence and dissipation of the dust maximum activity in MY28 than in other Martian years. A possible precursor signal to the global dust storm in MY 28 is observed at Ls = 200 - 235 especially over west Hellas. Heavy dust loads alter atmospheric temperatures. Due to the absorption of solar radiation and emission of infrared radiation to space by dust vertically non-uniformly distributed, a strong heating of high atmospheric levels (40 - 50 km) and cooling below around 30 km are observed.Comment: in press in Icarus. 47 pages, 15 figure

Optical Design of the SuMIRe PFS Spectrograph

The SuMIRe Prime Focus Spectrograph (PFS), developed for the 8-m class SUBARU telescope, will consist of four identical spectrographs, each receiving 600 fibers from a 2394 fiber robotic positioner at the telescope prime focus. Each spectrograph includes three spectral channels to cover the wavelength range 0.38-1.26 um with a resolving power ranging between 2000 and 4000. A medium resolution mode is also implemented to reach a resolving power of 5000 at 0.8 um. Each spectrograph is made of 4 optical units: the entrance unit which produces three corrected collimated beams and three camera units (one per spectral channel). The beam is split by using two large dichroics; and in each arm, the light is dispersed by large VPH gratings. The proposed optical design was optimized to achieve the requested image quality while simplifying the manufacturing of the whole optical system. The camera design consists in an innovative Schmidt camera observing a large field-of-view (10 degrees) with a very fast beam. To achieve such a performance, the classical spherical mirror is replaced by a catadioptric mirror (i.e meniscus lens with a reflective surface on the rear side of the glass, like a Mangin mirror). This article focuses on the optical architecture of the PFS spectrograph and the perfornance achieved. We will first described the global optical design of the spectrograph. Then, we will focus on the Mangin-Schmidt camera design. The analysis of the optical performance and the results obtained are presented in the last section.Comment: 8 pages - submitted at SPIE Astronomical Telescopes - Instrumentation 2014 - Montrea

Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up.

PurposeIn the initial PALOMA-2 (NCT01740427) analysis with median follow-up of 23 months, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) [hazard ratio (HR) 0.58; P < 0.001]. Herein, we report results overall and by subgroups with extended follow-up.MethodsIn this double-blind, phase 3 study, post-menopausal women with ER+/HER2- ABC who had not received prior systemic therapy for their advanced disease were randomized 2:1 to palbociclib-letrozole or placebo-letrozole. Endpoints include investigator-assessed PFS (primary), safety, and patient-reported outcomes (PROs).ResultsAfter a median follow-up of approximately 38 months, median PFS was 27.6 months for palbociclib-letrozole (n = 444) and 14.5 months for placebo-letrozole (n = 222) (HR 0.563; 1-sided P < 0.0001). All subgroups benefited from palbociclib treatment. The improvement of PFS with palbociclib-letrozole was maintained in the next 2 subsequent lines of therapy and delayed the use of chemotherapy (40.4 vs. 29.9 months for palbociclib-letrozole vs. placebo-letrozole). Safety data were consistent with the known profile. Patients' quality of life was maintained.ConclusionsWith approximately 15 months of additional follow-up, palbociclib plus letrozole continued to demonstrate improved PFS compared with placebo plus letrozole in the overall population and across all patient subgroups, while the safety profile remained favorable and quality of life was maintained. These data confirm that palbociclib-letrozole should be considered the standard of care for first-line therapy in patients with ER+/HER2- ABC, including those with low disease burden or long disease-free interval. Sponsored by Pfizer; ClinicalTrials.gov: NCT01740427

Use of the metastatic breast cancer progression (MBC-P) questionnaire to assess the value of progression-free survival for women with metastatic breast cancer.

While overall survival (OS) has historically been the primary endpoint for clinical trials in oncology, progression-free survival (PFS) has gained acceptance as a valuable surrogate endpoint. However, there are no known published reports about the value of PFS from the patient's perspective. We developed a questionnaire that included items regarding quality of life (QoL) and the importance of different treatment outcomes and presented hypothetical scenarios for which respondents were asked to indicate their preferences concerning treatments as they relate to PFS. 282 women with metastatic breast cancer (MBC), ranging in age from 21 to 80 years completed an online version of this questionnaire. The majority of women (66 %) had been diagnosed with MBC within the previous 3 years and 56 % had been told their MBC had progressed. When asked to rank five treatment characteristics from most important to least important, respondents ranked "extending PFS" as the second most important treatment outcome after OS. When presented with a hypothetical scenario of two women receiving different treatments, respondents preferred the treatment that resulted in longer PFS (16 vs. 12 months), even when OS and side effects were assumed to be equal. Specifically, when asked to consider which woman within the hypothetical scenario had better QoL, physical functioning, and emotional well-being, respondents more often chose the woman who experienced longer PFS (QoL: 40 vs. 6 %; physical functioning: 32 vs. 8 %; emotional well-being: 58 vs. 6 %) compared to the woman within the hypothetical scenario who had a shorter time of progression. Respondents rated their own QoL highest after being told their MBC was responding to treatment (mean score 76.6) versus after the initial diagnosis of breast cancer and MBC (68.5 and 60.3). These findings suggest that extending PFS is an important treatment outcome and, from a patient perspective, improves overall QoL, physical functioning, and emotional well-being

Scalable Bayesian model averaging through local information propagation

We show that a probabilistic version of the classical forward-stepwise variable inclusion procedure can serve as a general data-augmentation scheme for model space distributions in (generalized) linear models. This latent variable representation takes the form of a Markov process, thereby allowing information propagation algorithms to be applied for sampling from model space posteriors. In particular, we propose a sequential Monte Carlo method for achieving effective unbiased Bayesian model averaging in high-dimensional problems, utilizing proposal distributions constructed using local information propagation. We illustrate our method---called LIPS for local information propagation based sampling---through real and simulated examples with dimensionality ranging from 15 to 1,000, and compare its performance in estimating posterior inclusion probabilities and in out-of-sample prediction to those of several other methods---namely, MCMC, BAS, iBMA, and LASSO. In addition, we show that the latent variable representation can also serve as a modeling tool for specifying model space priors that account for knowledge regarding model complexity and conditional inclusion relationships

Imaging ultra thin layers with helium ion microscopy: Utilizing the channeling contrast mechanism

Background: Helium ion microscopy is a new high-performance alternative to classical scanning electron microscopy. It provides superior resolution and high surface sensitivity by using secondary electrons.\ud \ud Results: We report on a new contrast mechanism that extends the high surface sensitivity that is usually achieved in secondary electron images, to backscattered helium images. We demonstrate how thin organic and inorganic layers as well as self-assembled monolayers can be visualized on heavier element substrates by changes in the backscatter yield. Thin layers of light elements on heavy substrates should have a negligible direct influence on backscatter yields. However, using simple geometric calculations of the opaque crystal fraction, the contrast that is observed in the images can be interpreted in terms of changes in the channeling probability.\ud \ud Conclusion: The suppression of ion channeling into crystalline matter by adsorbed thin films provides a new contrast mechanism for HIM. This dechanneling contrast is particularly well suited for the visualization of ultrathin layers of light elements on heavier substrates. Our results also highlight the importance of proper vacuum conditions for channeling-based experimental methods\u

Weekly versus three weeks chemotherapy for advanced ovarian cancer. A meta-analysis

Aim: Three weeks paclitaxel and carboplatin has been considered the standard of care for primary treatment of ovarian cancer (OC). Whether weekly therapy will further improve the clinical outcomes or not is still unclear. We conducted a meta-analysis to compare the two regimens. Method: Articles were selected with a systematic approach, using PubMed databases. Trials concerning comparison between carboplatin plus weekly paclitaxel (dose-dense regimen) and carboplatin plus paclitaxel every 3 weeks were considered. Outcomes included overall survival (OS), progression free survival (PFS) and severe acute toxicity. Results: Dose-dense regimen was associated with significant improvement of PFS compared with standard schedule, with HR of 0.73 (95% CI 0.61-0.88, p = 0.001). There was no difference in OS between treatment regimens (HR 0.95, 95% CI 0.77-1.16, p=0.06), as well as in term of severe acute toxicity. Conclusion: Dose-dense regimen is superior to standard schedule in terms of PFS. Further studies are necessary to firmly confirm this evidence in advanced OC treatment