A Two-Year Longitudinal Study of Bone Mineral Density in Collegiate Distance Runners

Research has shown that weight-bearing physical activity such as running results in osteogenesis; distance runners, however, may experience deficiencies at specific sites. The purpose of this investigation was to examine changes in bone mineral density (BMD) of male and female collegiate cross-country runners over two years. Methods: BMD of 29 collegiate distance runners (16 men and 13 women) were measured five times over 24 months using dual-energy x- ray absorptiometry (DXA) at the anterior-posterior (AP) and lateral (LAT) spine, femoral neck (FN), total hip (TH), whole body (WB), and ultra-distal (UD) forearm. A repeated measures multivariate analysis of covariance, with bone free lean mass (BFLM) as covariate, was used to compare mean BMD values. Results: Adjusted for BFLM, there were no significant differences (p\u3e0.05) in BMD at any site between sexes. There were no significant differences at the AP or LAT spine, or FN across visits for either sex. There was a significant increase in BMD (p=0.044) at the UD forearm over two years in males. However, 56% of the men (n=9) had a z-score \u3c-1 at the UD forearm. Seven of 11 women had z-scores \u3c-1.0 at the LAT spine and four of 13 had z-scores \u3c-1.0 at the AP spine. Conclusion: There were no significant changes in BMD at any site over the two-year time frame, except the men had a significant increase in BMD at the non-dominant forearm. The spine appears to be an area of concern for the women in this study when examining z-score results

A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma

Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells, We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.Patrik Johansson, Cecilia Krona and Soumi Kundu share first authorship</p

Decitabine immunosensitizes human gliomas to NY-ESO-1 specific T lymphocyte targeting through the Fas/Fas Ligand pathway

<p>Abstract</p> <p>Background</p> <p>The lack of effective treatments for gliomas makes them a significant health problem and highlights the need for the development of novel and innovative treatment approaches. Immunotherapy is an appealing strategy because of the potential ability for immune cells to traffic to and destroy infiltrating tumor cells. However, the absence of well-characterized, highly immunogenic tumor-rejection antigens (TRA) in gliomas has limited the implementation of targeted immune-based therapies.</p> <p>Methods</p> <p>We hypothesized that treatment with the demethylating agent, decitabine, would upregulate the expression of TRA on tumor cells, thereby facilitating enhanced surveillance by TRA-specific T cells.</p> <p>Results and Discussion</p> <p>Treatment of human glioma cells with decitabine increased the expression of NY-ESO-1 and other well characterized cancer testes antigens. The upregulation of NY-ESO-1 made these tumors susceptible to NY-ESO-1-specific T-cell recognition and lysis. Interestingly, decitabine treatment of T98 glioma cells also sensitized them to Fas-dependent apoptosis with an agonistic antibody, while a Fas blocking antibody could largely prevent the enhanced functional recognition by NY-ESO-1 specific T cells. Thus, decitabine treatment transformed a non-immunogenic glioma cell into an immunogenic target that was efficiently recognized by NY-ESO-1--specific T cells.</p> <p>Conclusions</p> <p>Such data supports the hypothesis that agents which alter epigenetic cellular processes may "immunosensitize" tumor cells to tumor-specific T cell-mediated lysis.</p

NYESO-1/LAGE-1s and PRAME Are Targets for Antigen Specific T Cells in Chondrosarcoma following Treatment with 5-Aza-2-Deoxycitabine

Chondrosarcoma has no proven systemic option in the metastatic setting. The development of a non-cross-resistant strategy, such as cellular immunotherapy using antigen-specific T cells would be highly desirable. NY-ESO-1 and PRAME are members of the Cancer Testis Antigen (CTA) family that have been identified as promising targets for T cell therapy. LAGE-1 is a cancer testis antigen 90% homologous to NY-ESO-1, sharing the 157-165 A*0201 NY-ESO-1 epitope with its transcript variant, LAGE-1s. A number of CTA's have been induced using 5-Aza-2-Deoxycitabine (5-Aza-dC) in other cancers. We sought to evaluate the feasibility of targeting chondrosarcoma tumors using NY-ESO-1/LAGE-1s and PRAME specific T cells using 5-Aza-dC to induce antigen expression.We used 11 flash frozen tumors from the University of Washington tumor bank to test for the expression of NY-ESO-1, PRAME, LAGE-1s and LAGE-1L in chondrosarcoma tumors. Using four chondrosarcoma cell lines we tested the expression of these CTA's with and without 5-Aza-dC treatments. Finally, using NY-ESO-1/LAGE-1s and PRAME specific effectors that we generated from sarcoma patients, we evaluated the ability of these T cells to lyse A*0201 expressing chondrosarcoma cell lines in vitro both with and without 5-Aza-dC treatment.A minority (36%) of chondrosarcoma tumors expressed either NY-ESO-1 or LAGE-1s at >10% of our reference value and none expressed PRAME at that level. However, in all four of the chondrosarcoma cell lines tested, NY-ESO-1 and PRAME expression could be induced following treatment with 5-Aza-dC including in cell lines where expression was absent or barely detectable. Furthermore, NY-ESO-1/LAGE-1s and PRAME specific CD8+ effector T cells were able to specifically recognize and lyse A*0201 expressing chondrosarcoma cell lines following 5-Aza-dC treatment.These data suggest that adoptive immunotherapy in combination with 5-Aza-dC may be a potential strategy to treat unresectable or metastatic chondrosarcoma patients where no proven systemic therapies exist

A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma

Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells, We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM

Simulation of the fluid dynamics of a bubbling fluidized bed. Experimental validation of the two-fluid model and evaluation of a parallel multiblock solver

A mesh refinement study and validation of two-fluid model closures were carried out for a bubbling fluidized bed application. The mesh refinement study indicates that a higher degree of mesh refinement is required for atmospheric than for pressurized fluidization. Statistical bubble parameters (bubble frequency, mean bubble rise velocity, mean pierced bubble length and mean bubble volume fraction) were evaluated. The simulated statistical bubble quantities are computed from voidage signals derived from the transient multidimensional solution of two-fluid models. The algorithm for computing these quantities is taken directly from the evaluation program treating the measurement signals. To remedy the long simulation times required to obtain acceptable statistical values, a parallel version of the two-fluid model solver was developed, based on a domain decomposition method for distributed memory computers. A number of problems related to the parallelization are investigated. These are optimal treatment of velocity components on multi-block boundaries, frequency of data exchange at multi-block boundaries, local errors at multi-block boundaries and simulation time requirements

The Relationship Between Muscular Strength, Jump Power, and Bone Health in Collegiate Distance Runners

International Journal of Exercise Science 16(4): 563-575, 2023. Participation in sports, especially those involving impact loading, enhance bone mineral content (BMC) and density (BMD). Additionally, participation in impact loading sports may strengthen relationships between strength or power and bone variables. The purpose of this investigation was to examine relationships between measures of muscular performance and bone variables in Division I endurance athletes (29 males, 31 females, 19.6 ± 1.4 years). Dual-energy x-ray absorptiometry (DXA) scans were analyzed at the anterior-posterior (AP) and lateral (LAT) spine, femoral neck (FN), total hip (TH), whole body (WB), and ultra-distal forearm (UD) for BMC and BMD measures. WB scans provided information for bone-free lean mass (BFLM). Performance measures included absolute, and relative (to body weight), grip strength (GS) and absolute lower body power (LBP) derived from a vertical jump. Pearson correlation coefficients were determined between bone variables and muscular performance measures. Hierarchical multiple regression was used to quantify the variance explained in bone variables. Male runners showed strong relationships between absolute and relative GS and numerous bone variables. Female runner had significant relationships between absolute jump power and numerous bone variables. Sex, GS, and LBP explained 41-76% of BMC at the various bone sites and 12-30% of BMD. Results indicate that in collegiate men, greater strength is related to higher BMC and BMD, however this was not the case for women. In female collegiate distance runners, higher jump power was related to greater BMC and BMD