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Bilateral Ortohogonality Generative Acquisitions Method for Transmit Field Inhomogeneity Correction in Magnetic Resonance Imaging
Get PDFUltra-high field (>7T) magnetic resonance imaging (MRI) systems result in higher intrinsic signal to noise ratio compared to the lower field systems and have been previously utilized for acquisition of high-resolution images and reducing scan time. However, transmit field inhomogeneity of ultra-high field systems, present an obstacle for widespread clinical utilization. In literature, radiofrequency pulse design and multi-acquisition methods with and without parallel transmission systems have been demonstrated for addressing the transmit field inhomogeneity. While substantial improvements have been demonstrated with these methods, they can be limited to certain contrasts, require a library of pulses for specific radiofrequency coils and regions of interest and contain residual field inhomogeneity effects.
Herein, the Bilateral Orthogonality Generative Acquisitions method has been developed as a multi-acquisition transmit field inhomogeneity correction method using parallel transmission system that does not require calibration scans or data libraries. Through the applications demonstrated in this work, it has been shown that this method eliminates the transmit field effects without any residual inhomogeneity in the final images and can be utilized for variety of image contrasts. Performance comparisons of the novel method with the previously introduced methods are presented where applicable.
Initially, the Bilateral Orthogonality Generative Acquisitions method was utilized for obtaining homogeneous whole brain T2* weighted MRI contrast using dual-echo gradient echo images, where phase information between echoes is preserved. Moreover, accuracy of the phase information is validated by quantitative susceptibility mapping in brain and Dixon imaging in liver and kidney. The multi-contrast turbo spin echo application of the method is also demonstrated for T1, T2 and proton density weighted MRI contrasts. Lastly, implementations of the developed method in quantitative multi-parametric imaging are investigated using the phase cycled balanced steady state free precession sequence and chemical exchange saturation transfer imaging.
In conclusion, it has been shown that Bilateral Orthogonality Generative Acquisitions method is a versatile transmit field inhomogeneity correction method that results in homogeneous images at high and ultra-high field strength. As shown in this work, this novel method can be utilized for any region of interest, parallel transmission system, and radiofrequency coil or field strength for many contrasts
Small Molecules Target Identification Using Medicinal Chemistry and Forward Genetics
Get PDFSmall molecule drugs have had a profound impact on medicine, and by extension, human health and our understanding of basic biology. Understanding the genetic drivers of disease has led to the description of dozens of potentially tractable protein targets, especially in oncology, and helped facilitate 'target-based' screens to identify therapeutic small molecules. Alternatively, small molecule libraries can be applied to find phenotypes of interest, such as anti-cancer activity, but this creates the challenge of identifying the small molecule's cellular target. Knowledge of a small molecule's target allows for therapeutic development and application in an appropriate clinical setting. To date, there are few robust methods to facilitate the target identification process and this has limited the latter approach. Herein, I discuss the application of two methods to identify the cellular target and mechanism-of-action for several anti-cancer small molecules. The first method utilized medicinal chemistry and biochemistry to identify the target of a tetracyclic dicarboximide (MM0299) with anti-glioblastoma activity. I discovered that MM0299 binds to and inhibits lanosterol synthase (LSS), an enzyme involved in cholesterol biosynthesis. I further demonstrated that MM0299's mode-of-action in glioblastoma is distinct, with MM0299-mediated inhibition of LSS causing diversion of cholesterol biosynthesis and production of the toxic cholesterol metabolite, 24(S),25-epoxycholesterol. An alternative, yet complementary, approach that I utilized for small molecule target identification is forward genetics-based identification of compound-resistant alleles. Relying on random mutagenesis endowed by its intrinsic mismatch repair deficiency, our lab has used the colorectal cancer cell line, HCT116, as a forward genetics tool. Despite its utility, there are inherent challenges to identifying compound-resistant alleles using HCT116 and I have developed an inducible forward genetics platform to circumvent these challenges. I have used this system to identify the targets of several small-molecule anti-cancer toxins including orphan compounds from high throughput screens, and natural products
Simulation Research Forum Scholarship Outcomes Over Seven Years
Get PDFThe 63rd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 28, 2025; 3-6 p.m.; D1.700 Lecture Hall)BACKGROUND: In 2018 our medical center established a campus-wide simulation center and established scholarship as a priority, including hosting an annual simulation research forum. The purpose of this study was to evaluate the outcomes of this forum over seven years.
METHODS: Using the CDC's Program Evaluation Framework, we performed a structured analysis of content presented at the research forum from 2018 to 2024. A qualitative analysis was performed to code each abstract according to simulation modality, targeted competencies, study design, learner numbers and types, and outcomes measured using Kirkpatrick's model. A literature search was performed to determine the extent to which abstracts resulted in peer-reviewed manuscript publications. Data were analyzed using Kruskal-Wallis with post-hoc Dunn's tests (p ≤ 0.05 significant).
RESULTS: Over seven years, a total of 272 abstracts were presented (106 oral, 166 posters), including 95 involving institutions outside UT Southwestern. Presentations represented a variety of modalities (29% task, 15% high fidelity, 8% standardized patients, 48% other), competencies (46% patient care, 15% interpersonal and communication, 25% practice-based learning and improvement, 14% other), and study designs (36% cohort, 23% curriculum design, 17% technology, 11% validity). Abstracts encompassed a substantial number of learners (total 20,624), primarily graduate medical education (29%) and undergraduate medical education (23%). A significant increase in number of learners occurred from 2020 to 2021 (375%, p=0.04). 114 (42%) abstracts were associated with a Kirkpatrick Level 0, whereas 158 (58%) had higher levels. 76 (28%) abstracts resulted in peer-reviewed manuscript publications.
CONCLUSIONS: These data demonstrate that our annual research forum has supported a large volume of scholarly activity. This novel program evaluation may inform future efforts for our institution and others.Southwestern Medical Foundatio
Fetal Inflammatory Response and Its Severity Is Associated with Meconium Aspiration Syndrome
Get PDFThe 63rd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 28, 2025; 3-6 p.m.; D1.700 Lecture Hall)BACKGROUND: Fetal hypoxia-ischemia is a key trigger for Meconium aspiration syndrome (MAS) in term infants. However, many neonates develop MAS without evidence of hypoxia-ischemia, suggesting the presence of covert but important risk factors. Our objective was to evaluate the association of MAS with the evidence and severity of fetal inflammatory response (FIR) on placental histopathologic analysis and perinatal clinical markers of inflammation.
METHODS/STUDY DESIGN: This is a single center retrospective observational study of term infants (≥37 weeks GA) born through meconium-stained amniotic fluid (MSAF) at Parkland Hospital between 2010-2018. Infant demographics, maternal factors during pregnancy, and clinical information during hospitalization were recorded. Placental pathology data was retrieved from the electronic medical records. Placental pathologic evidence and severity of maternal inflammatory response (MIR) and fetal inflammatory response (FIR) was defined using the Amsterdam Placental Workshop Group Consensus Statement. MAS was defined as respiratory distress in an infant born to a mother with MSAF, admitted to NICU for requiring respiratory support for at least 48 hours, with radiographic findings consistent with MAS.
RESULTS: Of 2196 term singleton neonates with MSAF born Parkland Hospital Dallas,118 (5.4%) developed MAS. Of these infants, 1696 (80%) had placental histopathologic analysis done. Univariate analysis showed that MAS development was associated with clinical variables including post-term delivery, non-reassuring fetal heart pattern, cesarean delivery, thick meconium, low 1-and 5-min APGAR scores and severe fetal acidosis. MAS was also associated with evidence of MIR and fetal inflammatory response, and the severity of FIR (P<0.001). After controlling for APGAR scores, evidence of fetal hypoxia-asphyxia, gestational age, severe fetal acidosis on multivariate regression analysis, infants with FIR still had 2.5 times higher odds of developing MAS (P<0.01, OR 2.50, 95% CI 1.41, 4.82), while the association with MIR was lost (P=0.32, OR 1.34, 95% CI 0.75, 2.40). Moreover, infants with moderate to severe FIR had 5 times higher odds of developing MAS (P<0.01, OR 5.43, 95% CI 2.83, 10.40), thus indicating that severity and magnitude of FIR is associated with higher odds of developing MAS.
CONCLUSION: Our data from a large cohort of neonates suggests that fetal inflammatory response and its severity and progression is one of the key independent variables of MAS development, together with fetal hypoxia-ischemia.Southwestern Medical Foundatio
GLUT3 Mediates Drug Resistance in Melanoma
Get PDFThe 63rd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 28, 2025; 3-6 p.m.; D1.700 Lecture Hall)BACKGROUND: Melanoma is the fifth most common cancer in the USA with its two most common oncogenic driver mutations being BRAF (40-45%) or NRAS (15-25%). When immune checkpoint blockade fails, targeted therapies include BRAF-inhibitors (BRAFi) and MEK-inhibitor (MEKi) can be useful. However, over 50% of melanomas will acquire resistance within one year. Previously, we discovered that GLUT3 interacts with RAS and could promote PAK activation through its intracytoplasmic loop domain (Yu et al., 2023). PAK activation has been shown to promote BRAFi and BRAFi/MEKi resistance (Lu et al., 2017). As RAS is an established PAK activator, we hypothesized that GLUT3 could promote melanoma BRAFi/MEKi resistance by activating an alternative RAS-PAK pathway.
METHODS: Drug resistance was induced in UACC62 (BRAFV600E), and Mel-Juso (NRASQ61L) through BRAFi or MEKi treatment for two months. UACC62 cells were treated with (1) BRAFi only (vemurafenib 0.5 μM), or (2) BRAFi/MEKi combination therapy (dabrafenib 100 nM and trametinib 10 nM). Mel-Juso cells were treated with MEKi only (trametinib 10 nM) or BRAFi/MEKi (dabrafenib 100 nM and trametinib 10 nM). Cells were harvested and analyzed for expression of pPAK, pERK, pSTAT3, pSMAD3, GLUT3, and GLUT1 via Western Blots, which was compared to their parental cell lines.
RESULTS: pPAK expression was increased in all drug resistant cell lines, confirming the findings of Lu et al. (2017). In BRAFV600E cells, GLUT3 and pERK expression were increased in BRAFi resistance. However, for BRAFi/MEKi resistance, GLUT3 and pERK expression decreased while GLUT1 expression increased. In NRASQ61L cells, GLUT3 expression was also increased in MEKi-resistance. For BRAFi/MEKi resistance, GLUT3 expression was decreased. pERK expression decreased in all drug resistant NRASQ61L cells.
CONCLUSIONS: GLUT3 may promote BRAFi resistance in BRAFV600E melanomas by activating the alternate RAS-PAK pathway. GLUT3 also may mediate MEKi resistance in NRASQ61L melanomas, but via a pERK-independent pathway. However, BRAFi/MEKi dual resistant melanomas may use GLUT3-independent mechanisms to promote PAK activation and drug resistance.Southwestern Medical Foundatio
Community based approaches to disease prevention
Get PDFDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern’s Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.UT Southwestern--Internal Medicin
The Cost
Get PDFThe author submitted this entry in the Open Verse Poetry category (Amateur division) for the 2025 On My Own Time™ (OMOT) Art Show.This poem was inspired by many years of scientific research with animals, a responsibility with which many (myself included) have great difficulty. It was also inspired by the last newspaper column written by the war correspondent Ernie Pyle, who was killed in Germany near the end of the Second World War in April 1945. Found in his pocket when his body was recovered, bits and pieces of the poem are paraphrased from it. An excerpt reads as follows: "Last summer I wrote that I hoped the end of the war could be a gigantic relief, but not an elation. In the joyousness of high spirits it is so easy for us to forget the dead. Those who are gone would not wish themselves to be a millstone of gloom around our necks. But there are so many of the living who have had burned into their brains forever the unnatural sight of cold dead men scattered over the hillsides and in the ditches along the high rows of hedge throughout the world. Dead men by mass production-in one country after another-month after month and year after year. Dead men in winter and dead men in summer. Dead men in such familiar promiscuity that they become monotonous. Dead men in such monstrous infinity that you come almost to hate them. Those are the things that you at home need not even try to understand. To you at home they are columns of figures, or he is a near one who went way and just didn't come back. You didn't see him lying so grotesque and pasty beside the gravel road in France. We saw him, saw him by the multiple thousands. That's the difference."
Understanding the Role of Loner in Myoblast Fusion
No full textThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.Cell-cell fusion is a fundamental process in the development and physiology of multicellular organisms. During myogenesis, mononucleated myoblasts fuse together to form multinucleated muscle fibers. The fruit fly Drosophila offers a genetically tractable model organism to myoblast fusion. The Drosophila embryonic musculature results from the fusion between two types of cells - muscle founder cells and fusion competent myoblasts (FCMs). Previous studies have revealed an asymmetric "fusogenic synapse", wherein the FCM generates an F-actin-enriched podosome-like structure (PLS) to invade the founder cell to promote cell membrane fusion. Previous work from our lab identified a Sec7 and PH domain-containing guanine nucleotide exchange factor (GEF), Loner, that activates the Arf GTPases in myoblast fusion. However, its precise mechanism of action during myoblast fusion remains poorly understood. Genetic rescue experiments showed that while Loner in required in both founder cells and FCMs, it plays a major role in the FCMs. Consistent with this, Loner is enriched at the fusogenic synapse in the FCMs but not the founder cells. This is likely due to the interaction between Loner and the FCM-specific cell adhesion molecule, Sns, the latter of which recruits Loner into phase-separated condensates. We show that the cytoplasmic domain of Sns involved in recruiting Loner is required for Sns function in myoblast fusion. Interestingly, the N-terminal domain of Loner is involved in phase separation with Sns, but it is dispensable for Loner's function when the C-terminal half of Loner containing Sec7 and PH domains is overexpressed, suggesting that the function of phase separation is to increase the local concentration of Loner at the fusogenic synapse. We found that the F-actin structures at the fusogenic synapses in loner mutant embryos appear diffused and unstable, thus failing to induce cell fusion. Co-immunoprecipitation assays revealed biochemical interactions between Loner (and an Arf GTPase) and the actin nucleation-promoting factors (NPFs) for branched actin polymerization, WASP and Scar. We propose that Loner is enriched at the fusogenic synapse to recruit NPFs and activate Arf, which in turn enhances the activities of the NPFs to promote myoblast fusion
White Coat
Get PDFThe author submitted this entry in the 10-Word Story category (Amateur division) for the 2025 On My Own Time™ (OMOT) Art Show.This work received a First Place Award in the "10-Word Story" category in the 2025 OMOT show.A career in medicine can be profound and meaningful. But the path there -- the years of intense training and school -- can take a heavy toll on the body and mind. Every physician I know can recall a colleague who struggled with mental health challenges during medical school. Too many of us have lost friends and would-be colleagues to these struggles. When they pass, they also leave things behind -- people like loving parents, who mourn in their own ways; and artifacts like white coats, which are awarded in anticipation of the future that in case never comes
The historical relationship of medicine and public health: friends? enemies? frenemies? (The Daniel W. Foster, M.D., Visiting Lectureship in Medical Ethics)
No full textThe Daniel W. Foster, M.D. Visiting Lectureship in Medical Ethics (in Conjunction with Ethics Grand Rounds). Tuesday, December 9, 2025; noon to 1 p.m. (Central Time); via Zoom. "The Historical Relationship of Medicine and Public Health: Friends? Enemies? Frenemies?". Allan M. Brandt, Ph.D., The Amalie Moses Kass Professor of the History of Medicine in the Department of Global Health and Social Medicine at Harvard Medical School and Professor of the History of Science at Harvard University.This lecture will trace the history of the relationship between medicine and public health over the course of the last century. The talk will center attention on tensions and ambivalence between approaches to health that centered on the diagnosis and treatment of individual patients by physicians and other health care providers versus approaches to prevention through changes in the environment and other social determinants of disease. The lecture will suggest that this bifurcation misrepresents essential aspects of both medicine and public health. As a result, I will propose new strategies to integrate medicine and public health moving forward.UT Southwestern--Program in Ethic