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Investigating an early source of IFN-gamma production post large vessel occlusion in mice
No full textIn the United States, strokes are one of the leading causes of death- with ischemic strokes being the most common. The etiology by which ischemic strokes occur may be due to large vessel occlusion. Typically, this process occurs by which a thrombus or embolus occludes a major vessel within the brain leading to reduced blood flow (ischemia) precipitating damage to brain tissue. Large vessel occlusion is a critical event, in which a rapid response is required to ensure the survival of brain tissue. It is understood that IFN-gamma is involved in the production of various inflammatory mediators, however, in the context of the stroke, it is not known where the IFN-gamma production is sourced from early in the stroke cascade. This study investigates the production of IFN-gamma in the context of a large vessel occlusion in mice. In vitro and in vivo studies were utilized to (1) compare the production of IFN-gamma amongst large vessel pre-occlusion, large vessel post-occlusion, and a distal vascular site (2) examine the direct relationship between oxygen-glucose deprivation applied to mixed cortical cultures and naïve lymphocytes (3) investigate the source of IFN-gamma production. Collected data was analyzed by utilizing flow cytometry. Findings revealed that in comparison to the pre-occlusion, the post-occlusion sample of blood contained increased levels of IFN-gamma. Mixed cortical cultures were examined under ischemic-like conditions and demonstrated increased IFN-gamma production from naïve cells. Evidence also suggested that the most likely source of IFN-gamma production stems from macrophages. IFN-gamma could potentially be an important modulator in the exacerbation of brain parenchymal damage, especially in the context of post-large vessel occlusion.MIG Pilot Gran
Trigger Point Injections as a Potential First Line Therapy for Persistent Myofascial Pain Syndrome
No full textBackground
Myofascial pain syndrome (MPS), characterized by pain from myofascial trigger points in skeletal muscles, often responds to conservative treatments. However, in this case, the patient's persistent symptoms resisted conservative methods but found relief only with trigger point injections. Using trigger point injections as the primary treatment method for MPS is unique. While trigger point injections are documented, their role as a first-line treatment for MPS is underexplored. This case reinforces the potential of trigger point injections for patients unresponsive to conventional treatments and underscores the importance of personalized management for myofascial pain. Teaching points in this case highlight the significance of clinical expertise in the diagnosis and the role of advanced diagnostic tools like ultrasonography, emphasizing meticulous diagnosis in cases where traditional treatments fall short.
Case Summary
A 58 year old male ex-Army Ranger presented with persistent bilateral posterior leg pain and tightness after failed conservative treatments such as massages, stretching, and NSAIDs for more than a year. A preliminary differential diagnosis included chronic exertional compartment syndrome, vascular claudication, as well as myofascial trigger points. Ultrasound-guided trigger point injections were administered, significantly reducing pain, increasing function, and improving their range of motion. This success highlights the efficacy of trigger point injections in treating MPS that resists conservative methods.
Conclusion
Literature on MPS primarily focuses on non-invasive treatments and explores trigger point injections as an adjuvant to other treatments. However, this case is different because it features a patient with chronic lower extremity MPS unresponsive to conventional therapies. The case challenges the traditional view that non-invasive methods suffice for MPS and highlights trigger point injections as a potential first-line treatment. For similar unresponsive MPS cases, future management should consider the early use of trigger point injections, particularly with ultrasound guidance for safety and precision. This case stresses the importance of individualized care, encouraging healthcare practitioners to explore alternative treatments when conventional ones fall short
Store-Operated Calcium Entry and Podocyte Injury in Diabetic Nephropathy
Get PDFDiabetic nephropathy (DN) is the leading cause of chronic kidney disease. Proteinuria/albuminuria is not only the early clinical manifestation of DN, but also exacerbates kidney injury in DN and is associated with the mortality and cardiovascular event of DN. Podocytes are one of the major components of glomerular filtration barrier, and podocyte injury is the primary cause of proteinuria. Hyperglycemia is the major initiator of podocyte injury in DN. However, the underlying molecular mechanisms remain poorly understood. Store-operated calcium entry (SOCE) is a multifunctional calcium signaling in both excitable cells and non-excitable cells. Recent studies imply the pivotal roles of calcium signaling pathway in maintaining podocyte integrity, metabolism, and survival. However, the role of SOCE in podocytes in the setting of diabetes is not known. The present study aimed to determine the role of SOCE in podocytes in diabetic settings and the underlying molecular mechanisms. Our first specific aim was to determine that enhanced SOCE contributes to high glucose (HG)-induced podocyte injury. We first identified that the Orai1-mediated SOCE was enhanced in HG-treated podocytes. We further discovered that pharmacological and genetic inhibition of SOCE prevented nephrin protein loss and cytoskeleton disorganization in HG-treated human podocytes, suggesting a detrimental effect of exaggerated SOCE in podocytes. The second specific aim was to determine that the calpain signaling mediated HG/SOCE-induced podocyte injury. In immortalized human podocytes, HG treatment enhanced calpain activity, which was blunted by an SOCE inhibitor (BTP2). Furthermore, a calpain-1 and calpain-2 inhibitor (calpeptin) significantly attenuated podocyte nephrin protein loss induced by HG treatment. Theses results suggest that the calpain signaling pathway participates in HG/SOCE-induced podocyte injury. The last specific aim was to identify that SOCE contributed to podocyte injury in DN by impairing mitochondrial function. Using cultured immortalized human podocytes, we found that the SOCE inhibitor (BTP2) suppressed HG-induced depolarization of the mitochondria membrane potential, reduced ATP production, and impaired mitochondria respiration function. In addition, angiotensin II (Ang II), a known SOCE activator and a podocyte injury inducer in DN, also induced mitochondrial dysfunction in podocytes. Consistent with the results from HG treatment, inhibition of SOCE by BTP2 significantly attenuated the Ang II-induced podocyte mitochondria damage, suggesting the mitochondrial mechanism underlying the SOCE-induced podocyte injury. In conclusion, our present study suggests that enhanced SOCE is a new detrimental mechanism contributing to HG-induced podocyte injury by upregulating the calpain signaling pathway and impairing mitochondrial function. Therefore, suppressing SOCE and its downstream pathways would potentially slow down the development of DN
Survivin as a Prognostic Marker in Breast Cancer
No full textPurpose: Breast cancer is the second leading cause of cancer-related death for women in the United States and continues to pose a threat to millions of women globally. Incidence rates of breast cancer continue to rise across ethnic/ racial groups and survival rates continue to increase with the development of screening protocols and targeted therapeutics. However, despite the advances in disease diagnosis and management a racial disparity continues to be evident. Even with advanced therapeutics and the development of various prognostic markers, Black women continue to have higher rates of breast cancer mortality when compared to other racial groups. Mortality is also correlated with the status of metastasis, as advanced disease points to poor outcomes and survival rates. The evident racial disparity and advanced staging reflect the need for new and more efficient prognostic markers to be developed to better manage and treat breast cancer. Existing prognostic factors include immunohistochemical markers such as estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor-2. One potential immunohistochemical marker is the Inhibitor of Apoptosis Protein (IAP), survivin, with elevated levels of expression found in various cancer types, including breast cancer. Previous research has linked elevated levels of survivin expression with increased resistance to therapeutics like chemotherapy and radiation. However, there remains some question of the true clinical significance of survivin as a prognostic factor. The objective of this literature review is to provide an overview of research on the use of survivin expression as a clinically useful prognostic marker in breast cancer. Methods: Relevant research articles were collected mainly through the PubMed database. Studies investigating survivin expression alone or with other prognostic markers of breast cancer using immunohistochemistry or PCR analysis of breast tumor tissue were selected. Results: Review of this literature showed that the majority of studies found a significant correlation between levels of survivin expression and poor prognosis. Fourteen studies from the total seventeen analyzed identified various established prognostic markers to be correlated with survivin expression. Increased levels of survivin were associated with poor prognosis through findings of higher grade, greater lymph node metastasis, increased proliferation, and other indicators. Conclusion: These findings suggest that survivin has the potential to be used clinically in combination with other biomarkers to bolster diagnostics. In addition, the results indicate that survivin may be used as a marker in disease management as well as a unique focus of targeted therapy
MECHANISM OF ACTION AND DRUG DELIVERY OF HYBRID NITRIC OXIDE DONATING AND ANTIOXIDANT SMALL MOLECULES IN EXPERIMENTAL MODEL OF OCULAR HYPERTENSION
No full textPrimary open angle glaucoma (POAG) belongs to a group of optic neuropathies characterized by the damage to the optic nerve head, and the slow progressive deterioration of retinal ganglion cells (RGCs). POAG is predominantly asymptomatic in its early phases, and the leading cause of irreversible blindness globally. The underlying mechanisms of POAG include but not limited to; elevated intraocular pressure (IOP), excitotoxicity, and oxidative stress. Additionally, reduced trabecular meshwork (TM) cellularity, viability and decreases in antioxidant enzymes have been reported to be implicated in the pathogenesis of POAG. Currently, IOP reduction remains the mainstay for slowing down the progression of RGC degeneration and TM cell death. However, IOP lowering alone does not eliminate the progressive neurodegeneration events. Therefore, the development of novel therapeutic strategies that can reduce IOP and simultaneously provide neuroprotective benefits is essential for the effective management of POAG. To this end, we designed and synthesized novel hybrid nitric oxide donor and antioxidant small molecules (SA-2, SA-9, and SA-10) with the goal of lowering IOP and providing neuroprotection in experimental models of glaucoma. In the present study, we evaluated the in-vitro efficacy of SA-analogs in protecting TM cells from oxidative stress induced cell death. Additionally, we aimed at understanding the mechanism of action of SA-2 and assessed its in-vivo IOP lowering efficacy and toxicity profile in PLGA encapsulated nanoparticles after topical administration. Considering that less than 5% of a topically applied drug reaches intraocular tissues due to limited ocular absorption, rapid precorneal drug elimination, and the corneal epithelial barrier, our overarching goal was to provide a sustained and prolonged IOP lowering effect to reduce the frequency of dosing and potential adverse effects to ocular tissues. We demonstrated the utility of SA-2, SA-9, and SA-10 as novel strategies to promote survival of TM cells by scavenging reactive oxygen species. We found that SA-2 and the second-generation sulfur containing hybrid NO donor-antioxidants: SA-9 and its active metabolite SA-10 scavenged broad-spectrum ROS while maintaining NO bioavailability. We observed significant improvement in antioxidant enzymes following treatment with SA-2. Notably, catalase, glutathione peroxidase and total antioxidant enzyme levels were increased with SA-2 treatment along with increased TM mitochondrial respiration. Our studies showed that the SA-2 encapsulated in PLGA polymer was readily bioavailable to both the anterior segment and posterior regions of the eye. This observation reflected in the sustained IOP reduction of SA-2 lasting for 6 days with no overt toxicity and functional decline in C57BL6/J mice eyes. In summary, this dissertation project provides an alternate therapeutic strategy in the management of POAG. Our modified formulation of SA-2NPs is a promising candidate for a sustainably reducing IOP while providing neuroprotection to the RGCs and TM
Tracheobronchopathia Osteochondroplastica Presenting as Acute Shortness of Breath
No full textAn outpatient case of tracheobronchopathia osteochondroplastica is reported in a 58-year-old male presenting from the Dallas-Fort Worth area. Tracheobronchopathia osteochondroplastica (TO) is an exceedingly rare, non-neoplastic tracheobronchial condition characterized by multitudinous sessile, cartilaginous nodules, most prominent along the anterolateral walls and projecting into the lumen of the trachea and bronchi (Silveira et al 2017). Here we highlight the case of a middle-aged male presenting to the outpatient clinic with acute shortness of breath and cough. Chest CT without contrast was promptly ordered, displaying anterior and lateral endotracheal submucosal nodularity. Subsequent bronchoscopy confirmed the diagnosis of TO. Diagnosis and management of this condition is limited by clinicians' lack of familiarity with this pathology. Unfortunately, because of its rarity and potentially broad array of presenting symptoms, diagnosis may often be delayed resulting in increased stress for the expectant patient. The time between first symptoms and ultimate diagnosis is about 4 years in most cases; however, can be greater than 25 years according to some reports (Jabbardarjani et al 2008). Radiographically, tracheobronchopathia osteochondroplastica can look similar to other conditions in the trachea such as relapsing polychondritis, granulomatous processes such as granulomatosis with polyangiitis, and sarcoidosis. Amyloidosis, inflammatory bowel disease, and certain infectious processes should be considered as well. As such, the purpose of this case report is to increase clinical awareness of this rare condition to potentially expedite its management and diagnosis
Encouraging Maternal and Birthing people through Resources, Access, Coordination and Education (EMBRACE)
No full textPurpose: According to Commonwealth Fund, 2023 Scorecard on State Health Performance, Texas ranks 51 of 51 in Access & Affordability, 49 of 51 in Reproductive & Women’s Health, 48 of 51 in Prevention & Treatment and 38 in Racial & Ethnic Health Equity. In this report, 29% of birthing individuals did not receive prenatal care in the first trimester and one-third of women, 18-44 years old, did not a consistent source of health care. Not only does Texas not have a system of care in place, it has decided not to expand Medicaid through the Affordable Care Act (ACA). This further makes pregnant and postpartum people, especially the uninsured, most vulnerable to tragic maternal and birth outcomes. There’s significant racial disparities between Black and hispanic women vs. non-hispanic white women as they are two to three times more likely to die from pregnancy related complications. Postpartum period must be addressed as well because one in three pregnancy related deaths happen one week after birth to one year. We propose the Encouraging Maternal and Birthday people through Resources, Access, Coordination and Education (EMBRACE) program to address these health disparities through an integrated care model. This model will integrate doulas, highly trained individuals who provide community based maternal support services during pregnancy, labor, delivery, and after delivery to improve pregnant & postpartum health outcomes.
Methods: We will work with community stakeholders invested in maternal health that have authority to make change. Then discover potential challenges and needs for the development and implementation of EMBRACE after reviewing our current resources. Furthermore, we will learn about diverse perspectives, inclusion voices, and expertise in development and implementation of community programs serving disadvantaged communities (Healthy Start, etc). The Healthy Equity principles will then be embedded into every aspect of the project model guided by the CMS Framework for Health Equity.
Results: Once the grant is approved, we can communicate with hospital and clinic administration to smoothly incorporate COMSS into their system.
Conclusion: In recent years, the infant mortality rate has improved. However, the maternal mortality rate is still rising, especially in minority populations such as black and hispanic. Studies have shown significant improvement in maternal mortality rate when doulas and community health workers are involved. We have created a model that incorporates them into the public system in areas where these populations are the most affected
Photophysical Characterization and In Vitro Evaluation of alpha-Mangostin-Loaded HDL Mimetic Nano-Complex in LN-229 Glioblastoma Spheroid Model
Get PDFCytotoxic activity has been reported for the xanthone alpha-mangostin (AMN) against Glioblastoma multiforme (GBM), an aggressive malignant brain cancer with a poor prognosis. Recognizing that AMN's high degree of hydrophobicity is likely to limit its systemic administration, we formulated AMN using reconstituted high-density lipoprotein (rHDL) nanoparticles. The photophysical characteristics of the formulation, including fluorescence lifetime and steady-state anisotropy, indicated that AMN was successfully incorporated into the rHDL nanoparticles. To our knowledge, this is the first report on the fluorescent characteristics of AMN with an HDL-based drug carrier. Cytotoxicity studies in a 2D culture and 3D spheroid model of LN-229 GBM cells and normal human astrocytes showed an enhanced therapeutic index with the rHDL-AMN formulation compared to the unincorporated AMN and Temozolomide, a standard GBM chemotherapy agent. Furthermore, treatment with the rHDL-AMN facilitated a dose-dependent upregulation of autophagy and reactive oxygen species generation to a greater extent in LN-229 cells compared to astrocytes, indicating the reduced off-target toxicity of this novel formulation. These studies indicate the potential therapeutic benefits to GBM patients via selective targeting using the rHDL-AMN formulation.This work was possible due to support from The Peggy Dickerman Brain Cancer Research Fund (#300253), The Virginia Kincaid Foundation (#300001), and Wheels for Wellness, Fort Worth (#300187). This work is also partially supported (A.S.D.) by a grant (#RP210046) from the Cancer Prevention and Research Institute of Texas (CPRIT) and (A.K.) by a T32 Training Grant in the Neurobiology of Aging and Alzheimer's Disease from the National Institutes of Health/National Institute on Aging (#AG020494)
Prenatal Providers’ Perceptions of Texas Policy Change and Reproductive Healthcare
No full textBackground: Stringent healthcare policies and laws can exacerbate pre-existing disparities in access to healthcare. In Texas, there has been a rise in state-level mandates that restrict access to reproductive healthcare, criminally penalize healthcare providers, or limit the scope of practice among prenatal providers. These developments have created a unique environment for clinicians in Texas. Thus, this study aimed to investigate the impact of policy shifts within Texas on the provision of prenatal care by Texas prenatal providers to their pregnant patients.
Methods: Texas prenatal providers(n=17;OB/GYNs,/CNMs,/ARNPs/PAs) were recruited from a range of practice settings such as outpatient hospitals, community clinics, and private practices. One-hour in-depth interviews guided by the Consolidated Framework for Implementation Research (CFIR)were conducted with participants. As part of the Outer Setting domain of CFIR, clinicians were asked how recent policy changes in Texas impacted the care of their patients. Interviews were audio-recorded, transcribed, and thematically coded using MAXQDA.
Findings: In this analysis, two policy themes surfaced: prenatal COVID vaccines and access to abortion care. Clinicians noticed resistance among their prenatal patients in receiving the COVID vaccine, influenced by Texas’ COVID response and recommendations. They underscored how Texas laws hindered patient access to abortion care, especially within the six-week time frame. Clinicians detailed how these policies heightened the need for documentation and oversight regarding miscarriage and abortion care, including obtaining ethical approval from leadership before delivering care.
Implications: The results suggest that prenatal providers perceived the implementation of new policies in Texas as introducing several challenges in their provision of reproductive healthcare. Subsequent research should explore how providers adjust their practices in response to these policy changes when caring for patients.Early Stage Investigator Gran
LN-229 glioblastoma multiforme cell line expresses CD155 (PVR), a target for Natural Killer Cell-mediated immunotherapy
No full textPurpose: Glioblastoma multiforme (GBM) is the most common form of primary brain cancer in adults. Currently, it has a dismal five-year survival rate of less than 7%. Current commonplace treatment options include surgery, chemotherapy, and radiation. In recent years, there has been a major attempt at bringing the immunotherapy revolution into the treatment pillars for GBM. Immunotherapies depend upon targeting molecular antigens that are unique to cancer cells. Our lab is currently working to identify novel antigens on GBM as future candidates for Natural Killer (NK) cell-mediated immunotherapy. In several cancers, the surface antigen known as CD155 (PVR) has been shown to be overexpressed and is important as part of a mechanism for cancer cells to evade NK cell and T cell-mediated immune responses. Typically, CD155 is not highly expressed on healthy cells, making it an attractive immunotherapy target. We set out here to investigate the expression of CD155 on LN-229 cells. Methods: We examined the expression of CD155 on the LN-229 GBM cell line using flow cytometry utilizing PE-labeled antibodies specific for CD155. Our hypothesis: LN-229 cells would show increased detection of fluorescence signal (from anti-CD155 antibodies) when compared to the fluorescence detection of negative control groups (no staining group and PE-isotype control group). Results: CD155 detected on LN-229 cells via the detection of increased fluorescence signal (versus negative controls). Conclusions: Based on our results, we concluded that CD155 is overexpressed on the LN-229 cell line and is a sufficient candidate for studying NK cell-mediated immunotherapy in in vitro contexts using LN-229 cells. Currently, we are evaluating blocking inhibitory signals to NK cells mediated through the CD155-TIGIT interaction to target GBM for NK cytotoxicity in LN-229 cells.CPRIT OSCR Fellowshi