Wavelength Shifting Phoswich Detectors for Superior Depth-of-Interaction Resolution

In order to simultaneously achieve both high spatial resolution and high sensitivity in small Positron Emission Tomography (PET) systems, scintillation detectors must be long in the radial direction as well as able to provide depth-of-interaction (DOI) information. DOI information is typically provided by constructing detectors from two or more layers of scintillators that are identifiable due to their different decay times. This approach has worked well in tomographs such as the High Resolution Research Tomograph (HRRT, CTI PET Systems, Inc.) in which the emission and excitation bands of the scintillator layers do not overlap each other. However, many potentially important pairs of scintillator crystals exist in which the emission of one crystal is, in fact, absorbed and re-emitted by the second crystal, thus impacting the pulse shape discrimination process used to identify the scintillator layers. These potentially useful pairs of scintillators are unlikely to be implemented in phoswich detectors without a comprehensive understanding of the complex emission that results when the light of one crystal is absorbed by the second crystal and then reemitted. Our objective is to develop a fundamental understanding of the optical phenomena that occur in phoswich detectors and to exploit these phenomena to achieve improved spatial resolution in small high sensitivity PET scanners

Geography of Spring Landbird Migration Through Riparian Habitats in Southwestern North America

Migration stopover resources, particularly riparian habitats, are critically important to landbirds migrating across the arid southwestern region of North America. To explore the effects of species biogeography and habitat affinity on spring migration patterns, we synthesized existing bird abundance and capture data collected in riparian habitats of the borderlands region of the U.S. and Mexico. We determined the importance of geographic factors (longitude and latitude) in explaining variation in abundances and capture rates of 32 long-distance and three short-distance migrant species. Abundances and capture rates of 13 and 11 species, respectively, increased with increasing longitude, and four species\u27 abundance and capture rates decreased with increasing longitude. Riparian associates, but not nonriparian species, were more abundant in western sites. Their abundance patterns were only weakly influenced by species biogeography. In contrast, biogeography did influence abundance patterns of nonriparian birds, suggesting that they choose the shortest, most direct route between wintering and breeding areas. We hypothesize that riparian obligate birds may, to some degree, adjust their migration routes to maximize time spent in high-quality riparian zones, but they are able to find suitable habitat opportunistically when crossing more hostile landscapes. In contrast, nonriparian birds adhere more closely to a hierarchical model in which the migratory route is determined by biogeographic constraints. Conservation of riparian habitats is necessary to meet future habitat stopover requirements of many western Neotropical migrant birds. We advocate a coordinated research effort to further elucidate patterns of distribution and habitat use so that conservation activities can be focused effectively

Needs, trends, and advances in scintillators for radiographic imaging and tomography

Scintillators are important materials for radiographic imaging and tomography (RadIT), when ionizing radiations are used to reveal internal structures of materials. Since its invention by R\"ontgen, RadIT now come in many modalities such as absorption-based X-ray radiography, phase contrast X-ray imaging, coherent X-ray diffractive imaging, high-energy X- and $\gamma-$ray radiography at above 1 MeV, X-ray computed tomography (CT), proton imaging and tomography (IT), neutron IT, positron emission tomography (PET), high-energy electron radiography, muon tomography, etc. Spatial, temporal resolution, sensitivity, and radiation hardness, among others, are common metrics for RadIT performance, which are enabled by, in addition to scintillators, advances in high-luminosity accelerators and high-power lasers, photodetectors especially CMOS pixelated sensor arrays, and lately data science. Medical imaging, nondestructive testing, nuclear safety and safeguards are traditional RadIT applications. Examples of growing or emerging applications include space, additive manufacturing, machine vision, and virtual reality or `metaverse'. Scintillator metrics such as light yield and decay time are correlated to RadIT metrics. More than 160 kinds of scintillators and applications are presented during the SCINT22 conference. New trends include inorganic and organic scintillator heterostructures, liquid phase synthesis of perovskites and $\mu$m-thick films, use of multiphysics models and data science to guide scintillator development, structural innovations such as photonic crystals, nanoscintillators enhanced by the Purcell effect, novel scintillator fibers, and multilayer configurations. Opportunities exist through optimization of RadIT with reduced radiation dose, data-driven measurements, photon/particle counting and tracking methods supplementing time-integrated measurements, and multimodal RadIT.Comment: 45 pages, 43 Figures, SCINT22 conference overvie

Identification of Piwil2-Like (PL2L) Proteins that Promote Tumorigenesis

PIWIL2, a member of PIWI/AGO gene family, is expressed in the germline stem cells (GSCs) of testis for gametogenesis but not in adult somatic and stem cells. It has been implicated to play an important role in tumor development. We have previously reported that precancerous stem cells (pCSCs) constitutively express Piwil2 transcripts to promote their proliferation. Here we show that these transcripts de facto represent Piwil2-like (PL2L) proteins. We have identified several PL2L proteins including PL2L80, PL2L60, PL2L50 and PL2L40, using combined methods of Gene-Exon-Mapping Reverse Transcription Polymerase Chain Reaction (GEM RT-PCR), bioinformatics and a group of novel monoclonal antibodies. Among them, PL2L60 rather than Piwil2 and other PL2L proteins is predominantly expressed in various types of human and mouse tumor cells. It promotes tumor cell survival and proliferation in vitro through up-regulation of Stat3 and Bcl2 gene expressions, the cell cycle entry from G0/1 into S-phase, and the nuclear expression of NF-κB, which contribute to the tumorigenicity of tumor cells in vivo. Consistently, PL2L proteins rather than Piwil2 are predominantly expressed in the cytoplasm or cytoplasm and nucleus of euchromatin-enriched tumor cells in human primary and metastatic cancers, such as breast and cervical cancers. Moreover, nuclear PL2L proteins are always co-expressed with nuclear NF-κB. These results reveal that PL2L60 can coordinate with NF-κB to promote tumorigenesis and might mediate a common pathway for tumor development without tissue restriction. The identification of PL2L proteins provides a novel insight into the mechanisms of cancer development as well as a novel bridge linking cancer diagnostics and anticancer drug development

The HOG Pathway Dictates the Short-Term Translational Response after Hyperosmotic Shock

In the global osmoshock translational response in yeast, some gene products were translationally mobilized without transcriptional up-regulation. Conversely, other transcriptionally up-regulated mRNAs were translationally inhibited. Analogous changes occurred on the protein level. These translational responses were strongly dependent on Hog1 and Rck2

Synergistic antitumour effects of rapamycin and oncolytic reovirus.

There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent, Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anticancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an antireovirus-neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin. However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death Annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic antitumour efficacy of reovirus and rapamycin combination

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Resolvins suppress tumor growth and enhance cancer therapy

National Cancer Institute grants RO1 01CA170549-02 (to D. Panigrahy and C.N. Serhan), ROCA148633-01A4 (to D. Panigrahy), and GM095467 (to C.N. Serhan); the Stop and Shop Pediatric Brain Tumor Fund (to M.W. Kieran); the CJ Buckley Pediatric Brain Tumor Fund (to M.W. Kieran); Alex Lemonade Stand (to M.W. Kieran); Molly’s Magic Wand for Pediatric Brain Tumors (to M.W. Kieran); the Markoff Foundation Art-In-Giving Foundation (to M.W. Kieran); the Kamen Foundation (to M.W. Kieran); Jared Branfman Sunflowers for Life (to M.W.K.); and The Wellcome Trust program 086867/Z/08 (to M. Perretti)

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival