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Current insights in the etiology, treatment and outcomes of early-onset colorectal cancer
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
Muscle talks: myositis, mimics and metabolism
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
Changing the culture of culturing: diagnostic stewardship for healthcare-associated infections
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
Leap, and the NET will appear: a story about antiphospholipid syndrome and COVID-19
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
Butterflies on Paper
Get PDFThe author submitted this entry in the 10-Word Story category (Amateur division) for the 2023 On My Own Time (OMOT) Art Show.When you have many ideas, they flutter through your mind until finally one lands on paper via your pen
Signal Transduction Pathways That Impact Polar Flagellar Biogenesis
No full textBacterial flagella are rotating nanomachines required for motility. Flagellar gene expression and protein secretion are coordinated for efficient flagellar biogenesis. Polar flagellates, unlike peritrichous bacteria, commonly order flagellar rod and hook gene transcription as a separate step after production of the MS ring, rotor, and flagellar type III secretion system (fT3SS) core proteins. This thesis describes two different ways MS ring-rotor-fT3SS assembly regulates flagellar gene expression. MS ring-rotor-fT3SS assembly stimulates expression of the next stage of flagellar genes establishing a unique polar flagellar transcriptional program. Conserved regulatory mechanisms in diverse polar flagellates to create this polar flagellar transcriptional program centered on MS ring-rotor-fT3SS assembly have not been thoroughly examined. Using in silico and genetic analyses and our previous findings in Campylobacter jejuni as a foundation, we observed that a large subset of Gram-negative bacteria with the FlhF/FlhG regulatory system for polar flagellation also possess flagellum-associated two-component signal transduction systems (TCS). I present data supporting a general theme in polar flagellates where MS ring, rotor, and fT3SS proteins contribute to a regulatory checkpoint during polar flagellar biogenesis. I demonstrated that Vibrio cholerae and Pseudomonas aeruginosa require the formation of this regulatory checkpoint for the TCS to directly activate subsequent rod and hook gene transcription, which are hallmarks of the polar flagellar transcriptional program. By reprogramming transcription in V. cholerae to more closely follow the peritrichous flagellar transcriptional program, I discovered a link between the polar flagellar transcription program and the activity of FlhF and FlhG flagellar biogenesis regulators in which the transcriptional program allows polar flagellates to continue to produce flagella for motility when FlhF or FlhG activity may be altered. I discovered a second mechanism by which the MS ring-rotor-fT3SS regulates polar flagellar gene expression as V. cholerae MS ring-rotor-fT3SS mutants increased expression of flrB, the sensor kinase of flagellar FlrBC TCS in V. cholerae. This suggested that MS ring-rotor-fT3SS formation may act as a feedback inhibition mechanism to repress the activity of the master flagellar regulator, FlrA. I examined if this effect was on flrA transcription or FlrA activity and found that early flagellar formation appears to impact V. cholerae FlrA activity. I hypothesized that early flagellar formation may repress FlrA activity through c-di-GMP in a FlhG-independent or dependent manner. I then examined the effect of DGC and PDE mutants that either 1) increased c-di-GMP levels in a FlhA mutant or 2) were known to affect V. cholerae motility to identify DGC or PDE that may link early flagellar formation to FlrA activity. I found evidence for two different early flagellar formation feedback inhibition mechanisms: a possibly c-di-GMP-independent mechanism through FlhA, and a c-di-GMP-related mechanism through FlhG, CdgE, and RocS. Although more characterization is needed, our data suggests a complex previously undescribed feedback inhibition mechanism that links completion of the MS ring-rotor-fT3SS complex to both repress FlrA activity and stimulate flagella-associated TCS
Flexibility of Functional Neuronal Assemblies Supports Human Memory
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.BACKGROUND: Assemblies, groups of neurons that fire together on short timescales, could provide the fundamental building block of cognition but have eluded observation in human recordings.
OBJECTIVE: Leveraging a large single unit dataset obtained from human epilepsy patients, we observe neuronal assemblies and relate their composition and dynamics to human memory for the first time.
METHODS: We enrolled human epilepsy patients implanted with electrodes capable of recording both large-scale brain oscillations as well as the spiking activity of single neurons. Using established methods, we identified groups of neurons that consistently fire within 25 ms of each other across recording. We extracted several features of these assemblies, such as the order of neuron firing within the identified groups, the relationship of assembly activity to underlying gamma oscillations (40 Hz), and the dynamics of neuron membership in assemblies across recording.
RESULTS: We find that assemblies are comprised of sequences of neurons phase-locked to underlying gamma oscillations, and that both the consistency of these sequences and their reactivation rate correlates with successful memory. Further, we find that the relative contribution of each neuron to the assembly drifts across recording. The magnitude of drift predicts memory performance and varies along the hippocampal longitudinal axis.
CONCLUSION: Our data provide human validation to the hypothesized relevance of transiently co-active neurons to memory. This work has important implications for the continuing efforts to develop brain computer interface devices that rescue cognitive deficits and for elucidating the fundamental mechanisms by which the brain constructs thought
Ethics and VCA transplants: same issues or new challenges?
Get PDFTuesday, September 12, 2023; noon to 1 p.m. (Central Time); Room NB2.100A or via Zoom. "Ethics and VCA Transplants—Same Issues or New Challenges?" Jeffrey P. Kahn, Ph.D., M.P.H., The Andreas C. Dracopoulos Director of the Johns Hopkins Berman Institute of Bioethics and the Robert Henry Levi and Ryda Hecht Levi Professor of Bioethics and Public Policy at Johns Hopkins University.Vascular composite allografts (VCAs) are transplants of hands, face, penis, or uterus from deceased and sometimes (in the case of uterus) living donors. The ethics of solid organ donation and transplant have been discussed for decades, with policies and practices long established and ethics approaches widely discussed. VCAs have many characteristics that make them similar to solid organ transplants, but they also raise novel issues including risk-benefit balance for non-lifesaving therapies, decisions about deceased donation, evaluation of recipients, alternative therapies, and others. This talk will assess the similar and novel ethical issues and propose a framework for assessing the ethics of VCAs.UT Southwestern--Program in Ethic
Improving Adherence to Opioid Prescribing CDC Guidelines for Chronic Pain
Get PDFBACKGROUND: The Centers for Disease Control and Prevention have released treatment guidelines for chronic pain care as concerns about opioid overuse and abuse increase. Additionally, The Texas Medical Board has outlined their policy for the use of medication for non-malignant chronic pain purposes in Rule 170.3 of the Texas Administrative Code. Some of the requirements include a signed pain management agreement, regular review of the Prescription Monitoring Program, a urine drug screen, and documentation of completion of requirements in patient's medical records.
OBJECTIVE: Establish baseline adherence to TMB policy for opioid prescribing and implement electronic medical record tools to facilitate completion of requirements
METHODS: A preliminary chart review of patients on the opioid registry, an intervention in early phase of implementation meant to easily identify patients receiving opioids for chronic pain, was conducted to determine baseline adherence to Rule 170.3 amongst physicians. Several CDC guidelines which corresponded with TMB requirements were chosen. Post-intervention data was collected from the chronic opioid registry regarding the percentage of patients who had annual review of Prescription Monitoring Database, a urine drug screen, a pain management agreement, and documentation of completion of requirements in patient's medical records.
RESULTS: Of the 206 patients studied through chart review pre-intervention, only 6% had all three TMB mandated elements in their charts. After implementing the EMR tools meant to facilitate completion of TMB laws and CDC guidelines, the percentage of patients with a urine drug screen and review of PDMP increased while the percentage of patients with a pain management agreement in their chart decreased.
CONCLUSION: Poor compliance in the UTSW system necessitates tools that will streamline the process for completing and documenting the requirements. The implementation of the EHR tools and the opioid registry best practice alerts, as they were rolled out by the Opioid Task Force, helped facilitate completion of requirements
A Cytokine Receptor Masked IL-2 Prodrug Selectively Activates Tumor-Infiltrating Lymphocytes for Potent Antitumor Therapy
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.Cancers are very difficult to treat, and many cancer patients fail to respond to numerous standard of care therapies. Many of these tumors have been observed to lack functional CD8 T cells, which have been observed to be correlated with improved patient prognosis. One of the main strategies to combat the lack of functional tumor infiltrating immune cells is to treat patients with immune stimulating cytokines such as interleukin-2 (IL-2). As a potent lymphocyte activator, IL-2 is an FDA approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, limitations of both recombinant IL-2 and these next generation IL-2 variants are addressed through the engineering of a novel IL-2 prodrug (ProIL2). Numerous designs of ProIL2 were designed, engineered, and tested until a final optimal construct was synthesized. The activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein is masked with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Furthermore, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Lastly, ProIL2 can also synergize with radiation therapy to more effectively control both primary and metastatic cancer. Further protein engineering strategies are being implemented to overcome potential limitations of ProIL2. Taken together, this approach presents an effective tumor targeting therapy with reduced toxicity