Re: Nancy Garden Annie On My Mind Epub Download
Edelira Longinotti
This issue of The Journal of the American Osteopathic Association (JAOA) features abstracts from the posters that were presented at the 62nd Annual American Osteopathic Association (AOA) Research Dissemination Track.
Statement of Significance: Cardiovascular disease is the leading cause of morbidity and mortality in long-term cancer survivors. Chemotherapy with doxorubicin and other anthracyclines is the most common cause of cardiac toxicity in treated cancer patients. These agents are used to manage both hematologic and solid-tumor malignancies. Cardiac manifestations often develop months to years after initial exposure, causing cardiomyopathy and heart failure. Osteopathic medicine approaches disease in a holistic manner attempting to prevent major complications earlier in the disease course. Preventing or reducing chemotherapy-induced cardiotoxicity would greatly improve the outlook for these patients and their overall wellbeing.
Data Analysis: We used transthoracic echocardiography to measure cardiac function in Wild Type and Smad3 deficient mice. We then conducted a cardiac vessel analysis using immunohistochemistry. Parameters measured were vascular area, capillary and arteriolar density, and cardiac fibrosis. We also measured the weights of hearts to look for changes between wild type and Smad3 deficient mice.
Results: Using transthoracic echocardiography, we detected depressed cardiac function in doxorubicin treated WT mice but not in Smad3-deficient mice. Specifically, ejection fraction and radial strain were increased in doxorubicin treated Smad3 deficient mice compared with WT mice while the cardiac function was decreased in WT mice but unchanged in Smad3 deficient mice. Cardiac vessel analysis indicated a trend of increasing vascular area in doxorubicin-treated mice vs saline-treated mice. There were no differences in capillary and arteriolar density, heart weight, and cardiac fibrosis area between saline- and doxorubicin-treated hearts.
Conclusion: Doxorubicin-induced contractile and vascular defects were attenuated in Smad3-deficient mice, highlighting the importance of the TGFβ pathway in the development of cardiomyopathy. The inhibition of TGFβ/Smad3 pathway is a feasible approach to alleviate doxorubicin-induced cardiotoxicity in treated cancer patients. Preventing chemotherapy-induced cardiotoxicity would vastly improve the outlook for patients treated with anthracyclines. This research fits into the osteopathic approach to patient care by focusing on a disease pathway at a point before symptoms arise when it is too late for prevention.
Statement of Significance: CST1 is highly expressed in certain senescent cells and cancer cells but remains poorly understood. Among the cystatins, CSTA, CST5, and CST3 have been shown to inhibit EMT. However, it is not known if CST1 plays any role in EMT progression. Considering the potential benefit in targeting EMT to help halt metastasis and reduce chemoresistance, it is of great interest to further our understanding of the intricacy of EMT signaling networks. Results obtained from this study are expected to help shed light into the biological role of CST1 in EMT and future cancer therapeutic development. This project highlights the interconnectivity of systems by focusing on the biomolecules involved in growth and circulatory transport of tumor cells.
Methods: Human breast carcinoma MDA-MB-231 cells were stably transduced with control vector, CST1 or CST6 cDNA by retroviral gene transfer. After transduction and selection, the cell lines were treated with 60 nM Taxol or DMSO for 7 hours prior to collection of cell pellets for analysis. Levels of EMT signaling molecules were analyzed by Western blotting using specific antibodies and HRP-conjugated secondary antibodies. Chemiluminescent signals on the blots were imaged using a ChemiDocTM XRS+ Molecular Imager fitted with Image LabTM Software.
Data Analysis: Relative intensities of chemiluminescent signals were compared between treated and untreated cell lines and responses of CST1-transduced cells compared with that of vector controls. Image analysis was done using NIH's ImageJ and Microsoft Excel.
Results: CST1-transduced cells exhibited reduced expression levels of mesenchymal markers Snail and ZEB1. Moreover, low dose Taxol treatment of MDA-MB-231 cells led to increased expression of vimentin, Snail, and ZEB1, reduced phosphorylation of AKT1, and little to no change in β-catenin and phosphorylated GSK-3β. Interestingly, while cells transduced with CST1 exhibited increased expression of vimentin upon Taxol treatment in a manner comparable to the treated vector control, little to no change in Snail or ZEB1 was detected in CST1 transduced cells upon Taxol treatment.
Conclusion: Our data suggest that CST1 may inhibit the EMT process by downregulating expression of transcription factors Snail and ZEB1 in MDA-MB-231 triple-negative breast cancer cells. Furthermore, the result suggests that low dose Taxol may activate EMT signaling. This mechanism, however, is blocked by the transduction of CST1. Breast cancer is the most common type of cancer affecting women. While chemotherapy continues to be the gold standard, prognosis remains poor. Treatment regimens commonly include Taxol, but nearly one-third of Taxol-resistant breast cancers are triple-negative. The role of cysteine protease inhibitors is a topic of focus in the development of novel chemotherapeutic agents, although their role in breast cancer remains under-investigated. In this study, we observed the inhibitory function of CST1 on low-dose Taxol-induced increase in EMT in a triple-negative breast cancer cell line. Future studies should aim to elucidate the mechanism by which CST1 expression inhibits EMT and potential role of this novel avenue in cancer therapy.
Acknowledgment/Funding Source: This study is sponsored by the Department of Basic Sciences at Touro University California-College of Osteopathic Medicine and the College of Pharmacy.
Statement of Significance: Hip osteoarthritis (OA) causes patients to experience pain, stiffness and swelling leading to reduced function and disability. Patients with hip OA walk with characteristic compensatory gait strategies. Notably, they tend to either decrease pelvic obliquity on the affected side leading to a Trendelenburg gait or increase pelvic obliquity leading to pelvic elevation. Patients also either increase or decrease step width. Despite documentation of these patterns, the relationship between factors underlying these compensatory mechanisms are not fully understood. It's unknown how either are related to whole-body stability and balance in the frontal plane, nor why certain participants would adopt one or the other strategy.
Methods: This study was approved by the NYIT Institutional Review Board. Human participants without any gait abnormalities were recruited to participate in the study, and were instructed to adopt gaits that mimic those seen in hip OA patients. This was done in order to get a more detailed look at the relationships between these select biomechanical factors while avoiding the sagittal plane gait abnormalities and asymmetric gait patterns that hip OA patients typically experience. 3-dimensional (3-D) kinematic data was collected as participants walked on AMTI force plate treadmill. Kinematic data was recorded using a 12-camera Vicon system at 150 frames per second and using the plug-in gait full body marker set. All data was collected with the participants walking on the treadmill at 1.0 m/s. Participants were first instructed to walk with normal, narrow and wide step widths. Narrow and wide step widths for each participant was calculated based on their normal step width. The target for wide step width was 2x that of normal step width and the target for narrow step width was a step width of zero. Following this, participants were instructed to walk with a 3 types of pelvis motions normal, pelvic drop and pelvic elevation. These pelvic motions were selected to mimic the gait of patients with hip OA. For each pelvic motion, trials for each of the prescribed step width conditions were also recorded.
Data Analysis: All 3-D marker kinematic data was filtered using a Woltring filter. Marker positions and joint angles were calculated using Vicon Nexus. Step widths were calculated using custom written script using MATLAB.
Conclusion: Initial results suggest a relationship exists between induced pelvic motion and step width. A direct relationship was found between pelvic obliquity and step width when controlling for pelvic motion. When the pelvis dropped, the step width decreased and when the pelvis was elevated, the step width increased. When the step width was controlled for, the range of motion of pelvic obliquity was reduced for both the narrow and wide step widths when compared with a normal step width. However, wide steps also caused pelvic obliquity to change directionality, leading to slight elevation on the swing side towards the end of stance. Preliminary results suggest that step width likely has implications in support and stability during gait. Hip OA patients who have issues with gait stability may ultimately select to walk with wide-based gaits as it may provide additional stability. Patients without stability issues may actually seek to minimize abductor muscle force, which is done with narrower steps leading to a Trendelenberg gait.
DDX11, a DNA helicase, functions in DNA repair pathways and maintaining stabilization of the genome. Mutation of DDX11 is up-regulated in a diverse set of tumors such as advanced melanoma, colorectal cancer, and cervical cancer. Rational treatment is based on understanding the interrelationship of structure and function. Here we are aim to gain understand DDX11 knockdown effects cancer cells and possible treatment alternative to cancer.
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