Material mapping of QCT-derived scapular models : a comparison with micro-CT loaded specimens using digital volume correlation

Subject- and site-specific modeling techniques greatly improve finite element models (FEMs) derived from clinical-resolution CT data. A variety of density-modulus relationships are used in scapula FEMs, but the sensitivity to selection of relationships has yet to be experimentally evaluated. The objectives of this study were to compare quantitative-CT (QCT) derived FEMs mapped with different density-modulus relationships and material mapping strategies to experimentally loaded cadaveric scapular specimens. Six specimens were loaded within a micro-CT (33.5 μm isotropic voxels) using a custom-hexapod loading device. Digital volume correlation (DVC) was used to estimate full-field displacements by registering images in pre- and post-loaded states. Experimental loads were measured using a 6-DOF load cell. QCT-FEMs replicated the experimental setup using DVC-driven boundary conditions (BCs) and were mapped with one of fifteen density-modulus relationships using elemental or nodal material mapping strategies. Models were compared based on predicted QCT-FEM nodal reaction forces compared to experimental load cell measurements and linear regression of the full-field nodal displacements compared to the DVC full-field displacements. Comparing full-field displacements, linear regression showed slopes ranging from 0.86 to 1.06, r-squared values of 0.82–1.00, and max errors of 0.039 mm for all three Cartesian directions. Nearly identical linear regression results occurred for both elemental and nodal material mapping strategies. Comparing QCT-FEM to experimental reaction forces, errors ranged from − 46 to 965% for all specimens, with specimen-specific errors as low as 3%. This study utilized volumetric imaging combined with mechanical loading to derive full-field experimental measurements to evaluate various density-modulus relationships required for QCT-FEMs applied to whole-bone scapular loading. The results suggest that elemental and nodal material mapping strategies are both able to simultaneously replicate experimental full-field displacements and reactions forces dependent on the density-modulus relationship used

The Challenge of Generating Causal Hypotheses Using Network Models

Statistical network models based on Pairwise Markov Random Fields (PMRFs) are popular tools for analyzing multivariate psychological data, in large part due to their perceived role in generating insights into causal relationships: a practice known as causal discovery in the causal modeling literature. However, since network models are not presented as causal discovery tools, the role they play in generating causal insights is poorly understood among empirical researchers. In this paper, we provide a treatment of how PMRFs such as the Gaussian Graphical Model (GGM) work as causal discovery tools, using Directed Acyclic Graphs (DAGs) and Structural Equation Models (SEMs) as causal models. We describe the key assumptions needed for causal discovery and show the equivalence class of causal models that networks identify from data. We clarify four common misconceptions found in the empirical literature relating to networks as causal skeletons; chains of relationships; collider bias; and cyclic causal models

Development and biocompatibility characterization of a biomems sensor for monitoring the progression of fracture healing

[No abstract available

Disrupting the Ethical Imperatives of “Junior” Critical Qualitative Scholars in the Era of Conservative Modernization

In this article, we wrestle with the core issue of how early career researchers translate central tenets and core concepts of critical theory and critical methodology into their research practice. By way of creative representation, we draw from bell hooks and Cornel West’s (1991) written rendition of their verbal dialogue in Breaking Bread: Insurgent Black Intellectual Life. Their hope was to offer the book in a dialogic format in such a way that mirrored the synergy in their verbal discussions as friends and intellectual colleagues. In a similar vein, we hope to share with readers the synergy and depth of the narratives that have transpired during our ongoing discussions on the important topic of critical praxis as part of a collaborative research group called the Disruptive Dialogue Project (Gildersleeve, Kuntz, Pasque & Carducci, 2010; Kuntz, Pasque, Carducci, & Gildersleeve, 2009).Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer

Published online: 6 September 2023BACKGROUND: Resistance to androgen receptor signalling inhibitors (ARSIs) represents a major clinical challenge in prostate cancer. We previously demonstrated that the ARSI enzalutamide inhibits only a subset of all AR-regulated genes, and hypothesise that the unaffected gene networks represent potential targets for therapeutic intervention. This study identified the hyaluronan-mediated motility receptor (HMMR) as a survival factor in prostate cancer and investigated its potential as a co-target for overcoming resistance to ARSIs. METHODS: RNA-seq, RT-qPCR and Western Blot were used to evaluate the regulation of HMMR by AR and ARSIs. HMMR inhibition was achieved via siRNA knockdown or pharmacological inhibition using 4-methylumbelliferone (4-MU) in prostate cancer cell lines, a mouse xenograft model and patient-derived explants (PDEs). RESULTS: HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs. CONCLUSION: Co-targeting HMMR and AR represents an effective strategy for improving response to ARSIs.Josephine A. Hinneh, Joanna L. Gillis, Chui Yan Mah, Swati Irani, Raj K. Shrestha, Natalie K. Ryan, Enomoto Atsushi, Zeyad D. Nassar, David J. Lynn, Luke A. Selth, Masashi Kato, Margaret M. Centenera and Lisa M. Butle

Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV

A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1 sigma. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is estimated to be 1.8 sigma. More data are required to ascertain the origin of this excess.Comment: Submitted to Physics Letters

Measurement of isolated photon production in pp and PbPb collisions at sqrt(sNN) = 2.76 TeV

Isolated photon production is measured in proton-proton and lead-lead collisions at nucleon-nucleon centre-of-mass energies of 2.76 TeV in the pseudorapidity range |eta|<1.44 and transverse energies ET between 20 and 80 GeV with the CMS detector at the LHC. The measured ET spectra are found to be in good agreement with next-to-leading-order perturbative QCD predictions. The ratio of PbPb to pp isolated photon ET-differential yields, scaled by the number of incoherent nucleon-nucleon collisions, is consistent with unity for all PbPb reaction centralities.Comment: Submitted to Physics Letters

A patient-derived explant (PDE) model of hormone-dependent cancer

Breast and prostate cancer research to date has largely been predicated on the use of cell lines in vitro or in vivo. These limitations have led to the development of more clinically relevant models, such as organoids or murine xenografts that utilize patient-derived material; however, issues related to low take rate, long duration of establishment, and the associated costs constrain use of these models. This study demonstrates that ex vivo culture of freshly resected breast and prostate tumor specimens obtained from surgery, termed patient-derived explants (PDEs), provides a high-throughput and cost-effective model that retains the native tissue architecture, microenvironment, cell viability, and key oncogenic drivers. The PDE model provides a unique approach for direct evaluation of drug responses on an individual patient's tumor, which is amenable to analysis using contemporary genomic technologies. The ability to rapidly evaluate drug efficacy in patient-derived material has high potential to facilitate implementation of personalized medicine approaches.Margaret M. Centenera, Theresa E. Hickey, Shalini Jindal, Natalie K. Ryan, Preethi Ravindranathan, Hisham Mohammed, Jessica L. Robinson, Matthew J. Schiewer, Shihong Ma, Payal Kapur, Peter D. Sutherland, Clive E. Hoffmann, Claus G. Roehrborn, Leonard G. Gomella, Jason S. Carroll, Stephen N. Birrell, Karen E. Knudsen, Ganesh V. Raj, Lisa M. Butler, Wayne D. Tille

Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone

The latency associated with bone metastasis emergence in castrate-resistant prostate cancer is attributed to dormancy, a state in which cancer cells persist prior to overt lesion formation. Using single-cell transcriptomics and ex vivo profiling, we have uncovered the critical role of tumor-intrinsic immune signaling in the retention of cancer cell dormancy. We demonstrate that loss of tumor-intrinsic type I IFN occurs in proliferating prostate cancer cells in bone. This loss suppresses tumor immunogenicity and therapeutic response and promotes bone cell activation to drive cancer progression. Restoration of tumor-intrinsic IFN signaling by HDAC inhibition increased tumor cell visibility, promoted long-term antitumor immunity, and blocked cancer growth in bone. Key findings were validated in patients, including loss of tumor-intrinsic IFN signaling and immunogenicity in bone metastases compared to primary tumors. Data herein provide a rationale as to why current immunotherapeutics fail in bone-metastatic prostate cancer, and provide a new therapeutic strategy to overcome the inefficacy of immune-based therapies in solid cancers.Katie L Owen, Linden J Gearing, Damien J Zanker, Natasha K Brockwell, Weng Hua Khoo, Daniel L Roden, Marek Cmero, Stefano Mangiola, Matthew K Hong, Alex J Spurling, Michelle McDonald, Chia-Ling Chan, Anupama Pasam, Ruth J Lyons, Hendrika M Duivenvoorden, Andrew Ryan, Lisa M Butler, John M Mariadason, Tri Giang Phan, Vanessa M Hayes, Shahneen Sandhu, Alexander Swarbrick, Niall M Corcoran, Paul J Hertzog, Peter I Croucher, Chris Hovens, Belinda S Parke

Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered