Sugardale Marketing Research - Group 5

Sugardale research findings for group

Prospective, multisite, international comparison of \u3csup\u3e18\u3c/sup\u3eF-fluoromethylcholine PET/CT, multiparametric MRI, and \u3csup\u3e68\u3c/sup\u3eGa-HBED-CC PSMA-11 PET/CT in men with high-risk features and biochemical failure after radical prostatectomy: Clinical performance and patient outcomes

A significant proportion of men with rising prostate-specific antigen (PSA) levels after radical prostatectomy (RP) fail prostate fossa (PF) salvage radiation treatment (SRT). This study was done to assess the ability of F-fluoromethylcholine ( F-FCH) PET/CT (hereafter referred to as F-FCH), Ga-HBED-CC PSMA-11 PET/CT (hereafter referred to as PSMA), and pelvic multiparametric MRI (hereafter referred to as pelvic MRI) to identify men who will best benefit from SRT. Methods: Prospective, multisite imaging studies were carried out in men who had rising PSA levels after RP, high-risk features, and negative/equivocal conventional imaging results and who were being considered for SRT. F-FCH (91/91), pelvic MRI (88/91), and PSMA (31/91) (Australia) were all performed within 2 wk. Imaging was interpreted by experienced local/central interpreters who were masked with regard to other imaging results, with consensus being reached for discordant interpretations. Expected management was documented before and after imaging, and data about all treatments and PSA levels were collected for 3 y. The treatment response to SRT was defined as a reduction in PSA levels of .50% without androgen deprivation therapy. Results: The median Gleason score, PSA level at imaging, and PSA doubling time were 8, 0.42 (interquartile range, 0.29–0.93) ng/mL, and 5.0 (interquartile range, 3.3–7.6) months. Recurrent prostate cancer was detected in 28% (25/88) by pelvic MRI, 32% (29/91) by F-FCH, and 42% (13/31) by PSMA. This recurrence was found within the PF in 21.5% (19/88), 13% (12/91), and 19% (6/31) and at sites outside the PF (extra-PF) in 8% (7/88), 19% (17/91), and 32% (10/31) by MRI, F-FCH, and PSMA, respectively (P, 0.004). A total of 94% (16/17) of extra-PF sites on F-FCH were within the pelvic MRI field. Intra-pelvic extra-PF disease was detected in 90% (9/10) by PSMA and in 31% (5/16) by MRI. F-FCH changed management in 46% (42/91), and MRI changed management in 24% (21/88). PSMA provided additional management changes over F-FCH in 23% (7/31). The treatment response to SRT was higher in men with negative results or disease confined to the PF than in men with extra-PF disease ( F-FCH 73% [32/44] versus 33% [3/9] [P, 0.02], pelvic MRI 70% [32/46] versus 50% [2/4] [P was not significant], and PSMA 88% [7/ 8] versus 14% [1/7] [P, 0.005]). Men with negative imaging results (MRI, F-FCH, or PSMA) had high (78%) SRT response rates. Conclusion: F-FCH and PSMA had high detection rates for extra-PF disease in men with negative/equivocal conventional imaging results and rising PSA levels after RP. These findings affected management and treatment responses, suggesting an important role for PET in triaging men being considered for curative SRT. 18 18 18 68 18 18 18 18 18 18 18 18 1

Immunohistochemical analysis of changes in signaling pathway activation downstream of growth factor receptors in pancreatic duct cell carcinogenesis

<p>Abstract</p> <p>Background</p> <p>The pathogenesis of pancreatic ductal adenocarcinoma (PDAC) involves multi-stage development of molecular aberrations affecting signaling pathways that regulate cancer growth and progression. This study was performed to gain a better understanding of the abnormal signaling that occurs in PDAC compared with normal duct epithelia.</p> <p>Methods</p> <p>We performed immunohistochemistry on a tissue microarray of 26 PDAC, 13 normal appearing adjacent pancreatic ductal epithelia, and 12 normal non-PDAC ducts. We compared the levels of 18 signaling proteins including growth factor receptors, tumor suppressors and 13 of their putative downstream phosphorylated (p-) signal transducers in PDAC to those in normal ductal epithelia.</p> <p>Results</p> <p>The overall profiles of signaling protein expression levels, activation states and sub-cellular distribution in PDAC cells were distinguishable from non-neoplastic ductal epithelia. The ERK pathway activation was correlated with high levels of ^S2448p-mTOR (100%, p = 0.05), ^T389p-S6K (100%, p = 0.02 and ^S235/236p-S6 (86%, p = 0.005). Additionally, ^T389p-S6K correlated with ^S727p-STAT3 (86%, p = 0.005). Advanced tumors with lymph node metastasis were characterized by high levels of ^S276p-NFκB (100%, p = 0.05) and ^S9p-GSK3β (100%, p = 0.05). High levels of PKBβ/AKT2, EGFR, as well as nuclear ^T202/Y204p-ERK and ^T180/Y182p-p38 were observed in normal ducts adjacent to PDAC compared with non-cancerous pancreas.</p> <p>Conclusion</p> <p>Multiple signaling proteins are activated in pancreatic duct cell carcinogenesis including those associated with the ERK, PKB/AKT, mTOR and STAT3 pathways. The ERK pathway activation appears also increased in duct epithelia adjacent to carcinoma, suggesting tumor micro-environmental effects.</p

Mutation of a Single Residue Renders Human Tetherin Resistant to HIV-1 Vpu-Mediated Depletion

The recently identified restriction factor tetherin/BST-2/CD317 is an interferon-inducible trans-membrane protein that restricts HIV-1 particle release in the absence of the HIV-1 countermeasure viral protein U (Vpu). It is known that Tantalus monkey CV1 cells can be rendered non-permissive to HIV-1 release upon stimulation with type 1 interferon, despite the presence of Vpu, suggesting species-specific sensitivity of tetherin proteins to viral countermeasures such as Vpu. Here we demonstrate that Tantalus monkey tetherin restricts HIV-1 by nearly two orders of magnitude, but in contrast to human tetherin the Tantalus protein is insensitive to HIV-1 Vpu. We have investigated tetherin's sensitivity to Vpu using positive selection analyses, seeking evidence for evolutionary conflict between tetherin and viral countermeasures. We provide evidence that tetherin has undergone positive selection during primate evolution. Mutation of a single amino acid (showing evidence of positive selection) in the trans-membrane cap of human tetherin to that in Tantalus monkey (T45I) substantially impacts on sensitivity to HIV-1 Vpu, but not on antiviral activity. Finally, we provide evidence that cellular steady state levels of tetherin are substantially reduced by Vpu, and that the T45I mutation abrogates this effect. This study provides evidence that tetherin is important in protecting mammals against viral infection, and that the HIV-1 Vpu–mediated countermeasure is specifically adapted to act against human tetherin. It also emphasizes the power of selection analyses to illuminate the molecular details of host–virus interactions. This work suggests that tetherin binding agents might protect it from viral encoded countermeasures and thus make powerful antivirals

HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency.

Lentiviruses such as HIV-1 traverse nuclear pore complexes (NPC) and infect terminally differentiated non-dividing cells, but how they do this is unclear. The cytoplasmic NPC protein Nup358/RanBP2 was identified as an HIV-1 co-factor in previous studies. Here we report that HIV-1 capsid (CA) binds directly to the cyclophilin domain of Nup358/RanBP2. Fusion of the Nup358/RanBP2 cyclophilin (Cyp) domain to the tripartite motif of TRIM5 created a novel inhibitor of HIV-1 replication, consistent with an interaction in vivo. In contrast to CypA binding to HIV-1 CA, Nup358 binding is insensitive to inhibition with cyclosporine, allowing contributions from CypA and Nup358 to be distinguished. Inhibition of CypA reduced dependence on Nup358 and the nuclear basket protein Nup153, suggesting that CypA regulates the choice of the nuclear import machinery that is engaged by the virus. HIV-1 cyclophilin-binding mutants CA G89V and P90A favored integration in genomic regions with a higher density of transcription units and associated features than wild type virus. Integration preference of wild type virus in the presence of cyclosporine was similarly altered to regions of higher transcription density. In contrast, HIV-1 CA alterations in another patch on the capsid surface that render the virus less sensitive to Nup358 or TRN-SR2 depletion (CA N74D, N57A) resulted in integration in genomic regions sparse in transcription units. Both groups of CA mutants are impaired in replication in HeLa cells and human monocyte derived macrophages. Our findings link HIV-1 engagement of cyclophilins with both integration targeting and replication efficiency and provide insight into the conservation of viral cyclophilin recruitment

Promoting information literacy through media literacy

Mass media messages have overwhelmed modern culture. Many of these messages are not created with the best interest of the recipient in mind (Potter, 2008). The Mass media does not operate as a public service. It's big business. Good daily decision making has become increasingly dependent on the ability to be "information literate" - to effectively evaluate the accuracy, currency, and completeness of media messages. But these critical information literacy skills are surprisingly lacking today (Asher & Duke, 2012). One recent study suggests that information literacy skills can be effectively developed through training in media literacy (Van De Vord, 2010). This thesis has replicated this study in an effort to validate the correlation between information literacy and media literacy. Aside from the Van De Vord study, the communications theory of Media Ecology, as proposed by McLuhan, and developed by Postman is foundational to this work. Also referenced are McCombs and Shaw's agenda setting and Noelle-Neumann's spiral of silence theories. Additionally, the work of Potter in media literacy; of McChesney in media economics; and of Duke & Asher in information literacy are also foundational. Quantitative research for this thesis was conducted using an internet-based survey. The gathered empirical data was used in a statistical correlation analysis between information literacy and media literacy. The test results validated that the two variables were weakly correlated in a positive direction with evidence of statistically significant probability. The weakness of the correlation and the limitations inherent in the testing methods suggest that additional study is needed - perhaps utilizing alternate testing methods. Further comparison between the differing methods that are traditionally used in teaching the two different literacies is also suggested

A comparison of a new multinomial stopping rule with stopping rules of fleming and gehan in single arm phase II cancer clinical trials

Abstract Background Response rate (RR) alone may be insensitive to drug activity in phase II trials. Early progressive disease (EPD) could improve sensitivity as well as increase stage I stopping rates. This study compares the previously developed dual endpoint stopping rule (DESR), which incorporates both RR and EPD into a two-stage, phase II trial, with rules using only RR. Methods Stopping rules according to the DESR were compared with studies conducted under the Fleming (16 trials) or Gehan (23 trials) designs. The RR hypothesis for the DESR was consistent with the comparison studies (ralt = 0.2, rnul = 0.05). Two parameter sets were used for EPD rates of interest and disinterest respectively (epdalt, epdnul): (0.4, 0.6) and (0.3, 0.5). Results Compared with Fleming, the DESR was more likely to allow stage two of accrual and to reject the null hypothesis (Hnul) after stage two, with rejection being more common with EPD parameters (0.4, 0.6) than (0.3, 0.5). Compared with Gehan, both DESR parameter sets accepted Hnul in 15 trials after stage I compared with 8 trials by Gehan, with consistent conclusions in all 23 trials after stage II. Conclusions The DESR may reject Hnul when EPD rates alone are low, and thereby may improve phase II trial sensitivity to active, cytostatic drugs having limited response rates. Conversely, the DESR may invoke early stopping when response rates are low and EPD rates are high, thus shortening trials when drug activity is unlikely. EPD parameters should be chosen specific to each trial.</p