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Structural Functional Investigation of HAP40
No full textSTRUCTURAL FUNCTIONAL INVESTIGATION OF HAP40
Amanda Marie Solbach
Dissertation Advisor: Sheng Zhang, Ph.D.
Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the Huntingtin (HTT) gene, resulting in a mutant huntingtin (mHTT) protein with an elongated polyglutamine tract. While the genetic basis of HD is well established, the mechanisms underlying mHTT toxicity and its impact on cellular function remain incompletely understood. Recent discoveries implicate Huntingtin-associated protein 40 (HAP40) as a critical regulator of HTT stability and intracellular function. However, the physiological and pathological significance of this interaction has not been fully explored.
This dissertation investigates the structure-function relationship of HAP40, with a focus on its evolutionarily conserved BΦ (Basic-Hydrophobic) motif, which I hypothesize to be a key regulatory domain. Using a combination of mammalian cell culture and Drosophila models, I systematically dissected HAP40’s role in HTT stabilization, endosomal trafficking, and neurodegeneration. Structural modeling revealed remarkable conservation of the HTT-HAP40 complex across species, and functional studies demonstrated that deletion of the BΦ motif does not impair HAP40’s ability to stabilize HTT. However, the BΦ motif is essential for the proper endosomal localization of HTT and the regulation of late endosomal morphology. Loss of BΦ selectively impaired Rab7+ endosome growth and disrupted HTT targeting to endosomal membranes.
Furthermore, in a Drosophila model of HD, co-expression of mutant HTT with HAP40-ΔBΦ exacerbated neurodegeneration relative to full-length HAP40, indicating that the BΦ domain plays a protective role in modulating HTT toxicity. These findings suggest that while HAP40’s BΦ motif is dispensable for HTT binding, it is essential for key aspects of HTT’s subcellular function, particularly in the endolysosomal pathway. Taken together, this work advances our understanding of the HTT-HAP40 interaction and highlights the BΦ motif as a structurally conserved domain with functional significance in neuronal homeostasis and HD pathogenesis
Accidental Left Ventricular Placement of a Leadless Micra Pacemaker Through a Patent Foramen Ovale
No full textThe Micra device is a leadless pacemaker implanted in the right ventricle via a femoral vein transcatheter approach. There are several indications for and advantages to using a leadless pacemaker, and the device\u27s role in the field of cardiology will probably continue to increase. This article presents the case of a rare complication probably due to inadvertent placement of the device in the left ventricle across an undiagnosed patent foramen ovale
Platypnea-Orthodeoxia and Patent Foramen Ovale in a Patient in the Setting of COVID-19
No full textPlatypnea-orthodeoxia syndrome is a rare condition characterized by positional dyspnea and hypoxemia, with symptoms presenting in the upright position and improving when recumbent. Hypoxemia in platypnea-orthodeoxia syndrome is defined as a drop in Pa
Cholesterol Metabolism Regulated by CAMKK2-Creb Signaling Promotes Castration-Resistant Prostate Cancer
No full textCastration-resistant prostate cancer (CRPC) remains an incurable disease in need of improved treatments. CAMKK2 is an emerging therapeutic target whose oncogenic effects in prostate cancer have, to date, been largely attributed to its activation of AMP-activated protein kinase (AMPK). Here, we demonstrate that CAMKK2 promotes prostate cancer growth through an alternative downstream pathway involving CAMKI and CREB. Unbiased transcriptomics identify CREB-mediated transcription as a CAMKK2-regulated process, findings that we validate using diverse molecular, genetic, and pharmacological approaches in vitro and in vivo. CAMKK2 promotes CREB phosphorylation/activation through CAMKIα independently of AMPK, CAMKIV, or other CAMKI isoforms. Functionally, the CREB family members CREB1 and ATF1 exhibit close redundancy, necessitating co-targeting for optimal anti-tumor efficacy. An inhibitor of CREB1/ATF1 blocks CRPC with minimal side effects. Mechanistically, CAMKK2 and CREB increase CRPC growth through augmenting cholesterol metabolism. Together, these findings identify an oncogenic pathway that could be exploited for the treatment of CRPC
A Method for Sensitivity Analysis of Automatic Contouring Algorithms Across Different Contrast Weightings Using Synthetic Magnetic Resonance Imaging
No full textBackground and purpose: A majority of institution-specific automatic magnetic resonance imaging (MRI)-based contouring algorithms utilize one contrast-weighting (i.e., T2-weighted), however their performance within this contrast-weighting (i.e., across different repetition time, TR, and echo time, TE) is under-investigated and poorly understood. The purpose of this study was to develop a method to evaluate the robustness of automatic contouring algorithms to varying MRI contrast-weightings.
Materials and methods: One healthy volunteer and one patient were scanned using the multi-delay multi-echo (MDME) scan on a 3T MRI. The parotid and submandibular glands in these subjects were contoured using an automatic contouring algorithm trained on T2-weighted MRIs. Ground truth consensus contours were created by two radiation oncology residents and one pre-resident physician. A total of 216 different TR and TE combinations were simulated across T1-, T2-, and PD-weighted contrast ranges using SyMRI. Comparisons between automatic contouring algorithm contours and the ground truth were determined using the Dice similarity coefficient (DSC) and 95th percentile Hausdorff distance (HD95) with interobserver variability used as a threshold for clinical acceptance.
Results: Differences in the automatic contouring model\u27s performance were seen across the contrast-weighted regions. The range of discrepancy in DSC and HD95 exceeded 0.2 and 3.66 mm, respectively. In the T2-weighted contrast region, 100 %, 40 %, 24 %, and 57 % for the DSC in the left parotid, right parotid, left submandibular, and right submandibular gland, respectively, exceeded interobserver variability.
Conclusions: This study demonstrates the variable performance of MRI-based automatic contouring algorithms across varying TR and TE combinations even within the same contrast-weighting region (i.e., T2-weighted)
Immunization Week: Faculty, Staff, and Student Publications
Full text linkWorld Immunization Week, celebrated in the last week of April, highlights the collective action needed and to promote the use of vaccines to protect people of all ages against disease. This year, it takes place from April 24-30, 2025. The goal of World Immunization Week is for more individuals and communities are protected from vaccine-preventable diseases.
To explore some of this research, check out a selection of publications from the past three years in Digital Commons@TMC
CINAHL Has a New Look
Full text linkThe new CINAHL Platform is now available!
The CINAHL database is now on a new platform! The next time you log in, you’ll see a redesigned interface that improves navigation and search features.
Need help searching? Reach out to a librarian at askus.library.tmc.edu, we\u27re happy to assist
Implementation of a Discharge Process for Pediatric Patients Hospitalized with Asthma Exacerbations to Improve Post-Discharge Follow-up
No full textPurpose
This quality improvement project aimed to improve pediatric pulmonary outpatient follow-up after hospital discharge for pediatric patients hospitalized with asthma exacerbations through the implementation of a standardized discharge process designed to improve communication, education, and care coordination.
Background
The project was completed in acute care and intermediate care units within a women\u27s and children’s hospital in San Antonio, Texas.
Methodology
Following the IHI Improvement Model, serial PDSA cycles were completed over a 10-week period. An interprofessional team developed a standardized process map and interventions, including a discharge checklist, communication board, patient/family education, medications in hand at discharge, community asthma and pediatric pulmonology referrals. Hospital staff/residents were educated prior to implementation. Twenty patients met the inclusion criteria. Limitations included project implementation delays, rotating resident services, and inconsistencies in documentation.
Results
Outpatient pediatric pulmonary referrals were placed for 71% of patients, and 55% were seen for follow-up after discharge. The discharge checklist was used for 67% of patients. Staff post-survey results show 71% felt the discharge checklist was beneficial to their workflow.
Implications
A standardized discharge process may enhance care coordination, strengthen communication, and improve follow-up adherence for pediatric patients with asthma. The importance of discharge planning is highlighted by these results. The unexpected limitations highlight opportunities to improve implementation strategies to fully integrate this process across disciplines. These results may also inform strategies to reduce healthcare resource utilization within the healthcare system
Differential Efficacy of Bevacizumab and Erlotinib in Preclinical Models of Renal Medullary Carcinoma and Fumarate Hydratase-Deficient Renal Cell Carcinoma
No full textRenal medullary carcinoma (RMC) and fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) are rare and highly aggressive cancers. Although the combination of vascular endothelial growth factor (VEGF) inhibition by bevacizumab and epidermal growth factor receptor (EGFR) inhibition by erlotinib is clinically used for both diseases, the differential effect of each component has not been investigated. Transcriptomic profiling revealed that RMC and FH-deficient tumor tissues demonstrate increased EGFR but not VEGF expression compared with adjacent normal kidney. Subsequent in vitro studies revealed that RMC and FH-deficient cell lines are sensitive to erlotinib treatment, whereas clear cell RCC cell lines are resistant. We developed patient-derived xenograft (PDX) models of tumors exposed to first-line therapies to represent treatment-experienced RMC and FH-deficient RCC models. These models were then used to determine tumor growth response to angiogenesis inhibition by bevacizumab alone or in combination with erlotinib. The FH-deficient RCC PDX model responded to either bevacizumab or erlotinib alone or in combination while the RMC PDX responded only to erlotinib consistent with clinical and preclinical data suggesting that RMC is refractory to angiogenesis inhibition. Statistically higher expression of EGFR was observed in the RMC PDX model compared to the FH-deficient model; while higher phosphorylated tyrosine-416 SRC expression was observed in FH-deficient PDX model compared to the RMC model. Our preclinical data suggest that EGFR signaling differentially modulates tumor growth in RMC and FH-deficient RCC and that angiogenesis inhibition is a valid target in FH-deficient RCC but not RMC
Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in Women With Hormone-Sensitive Breast Cancer: An Updated Joint Position Statement of the IOF, CABS, ECTS, IEG, ESCEO, IMS, and SIOG
No full textBackground: Women with hormone-responsive breast cancer who receive adjuvant endocrine treatment with aromatase inhibitors (AI) are known to be at higher fracture risk due to a marked increase in bone resorption. In 2017, several interdisciplinary cancer and bone societies involved in the management of women with AI-associated bone loss (AIBL) published a joint position statement comprising evidence-based recommendations and a practical management algorithm for the assessment of fracture risk and optimal treatment of this patient population.
Patients and methods: In order to provide updated recommendations that reflect recent advances in the assessment and management of AIBL since publication of the 2017 joint position statement, a systematic literature review was undertaken to identify relevant studies for analysis, including systematic reviews and meta-analyses. Individual trials identified were assessed for their level of evidence based on design, size, follow-up, and evaluation of safety, as well as the impact of bone directed treatments on breast cancer outcomes.
Results: New evidence was combined with the existing recommendations to provide an updated joint position statement regarding fracture risk assessment and implementation of bone-directed therapy.
Conclusion: Current published literature, including recent clinical trial reports, systematic reviews and meta-analyses, continue to affirm the high risk of fractures in women with breast cancer who are receiving adjuvant AI treatment, a risk which has been observed to increase with the commonly used approach of extended duration AI therapy (\u3e5 years). Risk factors for fracture and risk assessment in this patient population as well as the most suitable treatment modalities have been updated. Finally, the influence of bone protective treatments on breast cancer outcomes such as incidence of bone metastasis and breast cancer related overall survival have been included