PDT in the Thoracic Cavity: Spectroscopic Methods and Fluence Modeling for Treatment Planning

PDT for the thoracic cavity provides a promising cancer treatment modality, but improvements in treatment planning, particularly in PDT dosimetry, can be made to improve uniformity of light delivery. When a cavity of arbitrary geometry is illuminated, the fluence increases due to multiple-scattered photons, referred to as the Integrating Sphere Effect (ISE). Current pleural PDT treatment protocol at the University of Pennsylvania monitors light fluence (hereafter simply fluence, measured in W/cm2) via seven isotropic detectors sutured at different locations in thoracic cavity of a patient. This protocol monitors light at discrete locations, but does not provide a measurement of fluence for the thoracic cavity as a whole. Current calculation of light fluence includes direct light only and thus does not account for the unique optical properties of each tissue type present, which in turn affects the accuracy of the calculated light distribution in the surrounding tissue and, in turn, the overall cell death and treatment efficacy. Treatment planning for pleural PDT can be improved, in part, by considering the contribution of scattered light, which is affected by the two factors of geometry and in vivo optical properties. We expanded the work by Willem Star in regards to the ISE in a spherical cavity. A series of Monte Carlo (MC) simulations were run for semi-infinite planar, spherical, and ellipsoidal geometries for a range of optical properties. The results of these simulations are compared to theory and numerical solutions for fluence in the cavity and at the cavity-medium boundary. The development via MC simulations offers a general method of calculating the required light fluence specialized to each patient, based on the treatment surface area. The scattered fluence calculation is dependent on in vivo optical properties (μa and μs\u27) of the tissues treated. Diffuse reflectance and fluorescence spectroscopy methods are used to determine the optical properties and oxygenation (reflectance measurements) and drug concentration (fluorescence measurements) of different tissues in vivo, before and after treatment, in patients enrolled the Phase I HPPH study ongoing at the University of Pennsylvania. This work aims to provide the building blocks essential to pleural PDT treatment planning by more accurately calculating the required fluence using a model that accounts for the effects of treatment geometry and optical properties measured in vivo

Human clade 2.3.4.4 A/H5N6 influenza virus lacks mammalian adaptation markers and does not transmit via the airborne route between ferrets

Since their emergence in 1997, A/H5N1 influenza viruses of the A/goose/ Guangdong/1/96 lineage have diversified in multiple genetic and antigenic clades upon continued circulation in poultry in several countries in Eurasia and Africa. Since 2009, reassortant viruses carrying clade 2.3.4.4 hemagglutinin (HA) and internal and neuraminidase (NA) genes of influenza A viruses of different avian origin have been detected, yielding various HA-NA combinations, such as A/H5N1, A/H5N2, A/H5N3, A/H5N5, A/H5N6, and A/H5N8. Previous studies reported on the low pathogenicity and lack of airborne transmission of A/H5N2 and A/H5N8 viruses in the ferret model. However, although A/H5N6 viruses are the only clade 2.3.4.4 viruses that crossed the species barrier and infected humans, the risk they pose for human health remains poorly characterized. Here, the characterization of A/H5N6 A/Guangzhou/39715/2014 virus in vitro and in ferrets is described. This A/H5N6 virus possessed high polymerase activity, mediated by the E627K substitution in the PB2 protein, which corresponds to only one biological trait out of the three that were previously shown to confer airborne transmissibility to A/H5N1 viruses between ferrets. This might explain its lack of airborne transmission between ferrets. After intranasal inoculation, A/H5N6 virus replicated to high titers in the respiratory tracts of ferrets and was excreted for at least 6 days. Moreover, A/H5N6 virus caused severe pneumonia in ferrets upon intratracheal inoculation. Thus, A/H5N6 virus causes a more severe disease in ferrets than previously investigated clade 2.3.4.4 viruses, but our results demonstrate that the risk from airborne spread is currently low

OGHReS: star formation in the outer galaxy (ℓ = 250○-280○)

We have used data from the Outer Galaxy High-Resolution Survey (OGHReS) to refine the velocities, distances, and physical properties of a large sample of 3 584 clumps detected in far infrared/submillimetre emission in the Hi-GAL survey located in the ℓ = 250◦ −280◦ region of the Galactic plane. Using 12CO and 13CO spectra, we have determined reliable velocities to 3 412 clumps (95 per cent of the sample). In comparison to the velocities from the Hi-GAL catalogue, we find good agreement for 80 per cent of the sample (within 5 km s−1 ). Using the higher resolution and sensitivity of OGHReS has allowed us to correct the velocity for 632 clumps and provide velocities for 687 clumps for which no velocity had been previously allocated. The velocities are used with a rotation curve to refine the distances to the clumps and to calculate the clumps’ properties using a distance-dependent gas-to-dust ratio. We have determined reliable physical parameters for 3 200 outer Galaxy dense clumps (∼90 per cent of the Hi-GAL sources in the region). We find a trend of decreasing luminosityto-mass ratio with increasing Galactocentric distance, suggesting the star formation efficiency is lower in the outer Galaxy or that it is resulting in more lower mass stars than in the inner Galaxy. We also find a similar surface density for protostellar clumps located in the inner and outer Galaxy, revealing that the surface density requirements for star formation are the same across the Galactic disc

Status of an Investigation of the 3-He Wave Function by Quasi-Free Scattering

This research was sponsored by the National Science Fooundation Grant NSF PHY-931478

Chronic Stress, Sense of Belonging, and Depression Among Survivors of Traumatic Brain Injury

To test whether chronic stress, interpersonal relatedness, and cognitive burden could explain depression after traumatic brain injury (TBI). Design : A nonprobability sample of 75 mild-to-moderately injured TBI survivors and their significant others, were recruited from five TBI day-rehabilitation programs. All participants were within 2 years of the date of injury and were living in the community. Methods : During face-to-face interviews, demographic information, and estimates of brain injury severity were obtained and participants completed a cognitive battery of tests of directed attention and short-term memory, responses to the Perceived Stress Scale, Interpersonal Relatedness Inventory, Sense of Belonging Instrument, Neurobehavioral Functioning Inventory, and Center for Epidemiological Studies Depression Scale;. Findings : Chronic stress was significantly and positively related to post-TBI depression. Depression and postinjury sense of belonging were negatively related. Social support and results from the cognitive battery did not explain depression. Conclusions : Postinjury chronic stress and sense of belonging were strong predictors of post-injury depression and are variables amenable to interventions by nurses in community health, neurological centers, or rehabilitation clinics. Future studies are needed to examine how these variables change over time during the recovery process.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72593/1/j.1547-5069.2002.00221.x.pd

PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1

Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.Peer reviewe

Genetic predisposition to ductal carcinoma in situ of the breast

Background: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci. Methods: To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip. Results: Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10-8. Conclusion: In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist

Voting on sustainable transport: communication and governance challenges in Greater Manchester's ‘congestion charge’ referendum

In December 2008, the Greater Manchester electorate voted to reject a £3 billion package of transport measures that would have included investment in the conurbation's bus, tram and rail networks and walking and cycling infrastructure, together with, and partially funded by, the introduction of a congestion charge. The proposals followed a successful bid to the UK Government Transport Innovation Fund (TIF). High levels of car use present challenges to cities, and the TIF bid can be seen as an attempt to address these by promoting and facilitating a modal shift. The paper reflects on the debates surrounding the proposals, which led to a referendum. In particular, it explores the challenges of communicating complex, controversial plans in a fragmented and contested political arena

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.UK funding includes Cancer Research UK and NIH.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-016-0718-