DigitalCommons@The Texas Medical Center
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Integrating Digital Archives and Scholarship: Raising Awareness of Library Historical Collections
No full textThe Texas Medical Center (TMC) is home to the largest concentration of medical professionals and experts anywhere in the world. Collectively, the Texas Medical Center is the largest employer in Houston and the 8th largest business district in the United States. The TMC includes 50 medicine-related institutions, including 21 hospitals and two specialty institutions, two medical schools, six nursing schools, and schools of dentistry, public health, and pharmacy. The TMC Library plays a vital role for the institutions inhabiting the 2.10 square mile campus that is the TMC. The Texas Medical Center Library has been around since 1915, way before Texas Medical Center existed, and the library has been utilizing Digital Commons for over 20 years. DigitalCommons@TMC is not only a platform for students to submit electronic dissertations, institution members to host health science related journals, but also has a wide variety of digitized archival materials. Since 2022, The TMC Library started using Digital Commons Exhibits, adding 15k items to its 18yr institution repository to include more library archival materials. Traffic of archival collections jumped from 4k, 36k to 107k downloads in 2024, bringing greater impact to not only archives, but the entire library community. Our Head of Archivist & Special Collections Librarian at McGovern Historical Center has commented that to track their statistical usage, a separate space was needed to track Digital Common was needed, which shows how much folks worldwide access materials via Digital Commons. Other beneficial impacts have been identified since additional archival materials have been integrated within our institutional repository. Other than more people who have been accessing McGovern Historical Center using their services and materials, The Texas Medical Center Library has noticed changes since more download traffic has been noticed on our institutional repository. In general, more foot traffic, in terms of students using our library services, study rooms, as well as our research materials have also increased. To date, The Texas Medical Center has been utilizing Digital Commons since 2005, starting at 2 articles in 2005, and The Texas Medical Center Library reached its 2 million download milestone in January 2024. We are looking forward to reaching our next milestone when we get to 2.5 million soon
Lessons in Longevity From Blood Stem Cells Under Protein Stress
No full textBlood stem cells are among the body\u27s longest-living cells despite being highly vulnerable to proteotoxic damage, which accelerates their aging. To maintain protein homeostasis (proteostasis), hematopoietic stem cells (HSCs) employ mechanisms such as reduced translation rates, high chaperone activity, autophagy, and selective protein degradation. These strategies mitigate protein misfolding, maintain quiescence, and preserve regenerative potential. Disruptions in proteostasis can lead to the elimination of impaired HSCs through differentiation or apoptosis, ensuring the integrity of the stem cell pool. Due to the systemic impact of the blood on aging and its experimental and clinical accessibility, investigating HSC proteostasis provides insights into longevity and potential therapeutic strategies. This review examines emerging mechanistic links between proteostasis and HSC fate, concluding with unresolved questions and challenges of the current research
Integrative Spatial Omics Reveals Distinct Tumor-Promoting Multicellular Niches and Immunosuppressive Mechanisms in Black American and White American Patients With TNBC
No full textRacial disparities in the clinical outcomes of triple-negative breast cancer (TNBC) have been well-documented, but the underlying biological mechanisms remain poorly understood. To investigate these disparities, we employed a multi-omic approach integrating imaging mass cytometry and spatial transcriptomics to characterize the tumor microenvironment (TME) in self-identified Black American (BA) and White American (WA) TNBC patients. Our analysis revealed that the TME in BA patients is marked by a network of endothelial cells, macrophages, and mesenchymal-like cells, which correlates with reduced patient survival. In contrast, the WA TNBC microenvironment is enriched in T-cells and neutrophils, indicative of T-cell exhaustion and suppressed immune responses. Ligand-receptor and pathway analyses further demonstrated that BA TNBC tumors exhibit a relatively immune-cold profile, while WA TNBC tumors display features of an inflamed TME, suggesting the evolution of a unique immunosuppressive mechanism. These findings provide insight into racially distinct tumor-promoting and immunosuppressive microenvironments, which may contribute to the observed differences in clinical outcomes among BA and WA TNBC patients
The Infected Diabetic Foot: Risk Factors for Re-Infection After Treatment for Diabetic Foot Osteomyelitis
No full textOur objective was to evaluate risk factors for re-infection in patients after treatment for diabetic foot osteomyelitis (OM). We used pooled patient level data from two RTCs that evaluated patients with diabetic foot infections. We evaluated 171 patients with OM. OM was confirmed with bone culture or histopathology. Data from the 12-month follow-up were used to determine clinical outcomes. Re-infection occurred in 47 (27.5%) patients. Risk factors for re-infection were Toe Brachial Index \u3c 0.40 (25.7% vs. 9.8%, p = 0.02), skin perfusion pressure \u3c 40 mmHg (6.3% vs. 5.9%, p = 0.04), wound healing (55.3% vs. 75.0%, p = 0.01), time to heal (156.0, 69.5-365 vs. 91.5, 38.8-365, p = 0.001), and history of MI (14.9% vs. 3.2%, p = 0.005). During 12-month follow-up, patients with re-infections were 198.8 times more likely to require a foot related hospitalisation (81.8% vs. 0.0%, p = 0.001), 10.4 times more likely have an all-cause hospitalisation (70.2% vs. 18.5%, p = 0.001) and 9.4 times more likely to need an amputation (36.2% vs. 5.6%, p = 0.001). Patients with re-infection had a significantly longer median length of hospitalisation (20.0, 13.5-34.5 vs. 14.0, 10.0-22.0, p = 0.003) and median length of antibiotic duration (55.0, 35.0-87.0 vs. 46.0, 22.8-68.0, p = 0.03). Patients with re-infection are less likely to heal and have more foot-related hospitalizations and amputations
A Qualitative Exploration of Child, Caregiver, and Clinician Perspectives on Mental Health in Children With Osteogenesis Imperfecta
No full textOsteogenesis imperfecta (OI) is a heritable connective disorder with clinical manifestations including bone fragility and short stature. Previous research identified psychosocial themes related to mental health among children with OI and their caregivers, such as independence, social isolation, depression, and anxiety. Several studies have also examined clinicians of individuals with OI for their perspectives on mental health among their patients. However, no known studies have compared psychosocial themes among all three participant groups concurrently. This qualitative study examined mood and anxiety, along with risk and protective factors, from perspectives of youths, parents, and clinicians. Semi-structured interviews were conducted, which were coded independently by two researchers. Codes were analyzed for extraction of themes. Relevant themes include depressed and anxious mood experienced in individuals with OI, as well as risk factors and protective factors for these symptoms. Participants reported functional limitations and social isolation as key risk factors for symptoms of anxious or depressed mood. In contrast, they discussed positive attitudes, social support, multidisciplinary medical groups, and mental health access as key protective factors. Implications for clinical care and future research are discussed. Convergence and divergence of themes across study samples are discussed in detail
Methadone for Critically Ill Patients Under Mechanical Ventilation in the Intensive Care Unit: A Systematic Review
No full textPurpose: Pain may pose significant challenges in the intensive care unit, especially in mechanically ventilated patients. Methadone has recently emerged as an alternative option for eliciting acute analgesia. In this systematic review, we evaluated the use of methadone in mechanically ventilated patients in the intensive care unit.
Source: We searched MEDLINE, EMBASE, Wiley\u27s Cochrane Library, CINAHL, PubMed (non-MEDLINE), Scopus, and LILACS databases from inception to January 24th, 2025. Eligible studies included randomized controlled trials and observational studies that compared the use of methadone to the standard of care or to other analgosedation strategies in mechanically ventilated patients in the intensive care unit. The primary outcome was the duration of mechanical ventilation. The secondary outcomes included opioid-associated adverse effects and scores regarding pain, agitation, and delirium.
Principal: findings: The search strategy yielded 3,523 studies. A total of 773 patients were included across the 12 studies (including 7 abstracts and 5 manuscripts). Patient populations included patients with trauma, those with burns, those at high risk for fentanyl abstinence syndrome, those with opioid use disorder, those with opioid withdrawal symptoms, and those who had received fentanyl for 72 hours prior to weaning. Overall, compared with the group that did not receive methadone, the methadone group was associated with more ventilator-free days, shorter weaning times, and a greater probability of successful weaning on day 5. Most of the studies exhibited high risks of bias; moreover, the overall quality of the evidence was low.
Conclusion: Few studies have evaluated the use of methadone in mechanically ventilated patients. Based on the low-quality evidence, methadone may be associated with improved patient-centered outcomes. Further research is warranted with respect to this topic
Mapping snoRNA-Target RNA Interactions in an RNA-Binding Protein-Dependent Manner With Chimeric eCLIP
No full textBackground: Small nucleolar RNAs (snoRNAs) are non-coding RNAs that function in ribosome and spliceosome biogenesis, primarily by guiding modifying enzymes to specific sites on ribosomal RNA (rRNA) and spliceosomal RNA (snRNA). However, many orphan snoRNAs remain uncharacterized, with unidentified or unvalidated targets, and studies on additional snoRNA-associated proteins are limited.
Results: We adapted an enhanced chimeric eCLIP approach to comprehensively profile snoRNA-target RNA interactions using both core and accessory snoRNA-binding proteins as baits. Using core snoRNA-binding proteins, we confirmed most annotated snoRNA-rRNA and snoRNA-snRNA interactions in mouse and human cell lines and called novel, high-confidence interactions for orphan snoRNAs. While some of these interactions result in chemical modification, others may have modification-independent functions. We showed that snoRNA ribonucleoprotein complexes containing certain accessory proteins, like WDR43 and NOLC1, enriched for specific subsets of snoRNA-target RNA interactions with distinct roles in ribosome and spliceosome biogenesis. Notably, we discovered that SNORD89 guides 2\u27-O-methylation at two neighboring sites in U2 snRNA that fine-tune splice site recognition.
Conclusions: Chimeric eCLIP of snoRNA-associating proteins enables a comprehensive framework for studying snoRNA-target interactions in an RNA-binding protein-dependent manner, revealing novel interactions and regulatory roles in RNA biogenesis
Transcriptional Remodeling Shapes Therapeutic Vulnerability to Necroptosis in Acute Lymphoblastic Leukemia
No full textInsufficient eradication of cancer cells and survival of drug tolerant clones are major relapse driving forces. Underlying molecular mechanisms comprise activated prosurvival and antiapoptotic signaling, leading to insufficient apoptosis and drug resistance. The identification of programmed cell death pathways alternative to apoptosis opens up possibilities to antagonize apoptosis escape routes. We have earlier shown that acute lymphoblastic leukemia (ALL) harbors a distinct propensity to undergo cell death by receptor-interacting protein kinase 1 (RIPK1)-dependent necroptosis, activated by small-molecule second mitochondria-derived activators of caspase (SMAC) mimetics. Despite demonstrated safety and tolerability of SMAC mimetics in clinical trials, their efficacy as single agent seems still limited, highlighting the need for combinatorial treatments. Here, we investigate so far unexplored regulatory mechanisms of necroptosis and identify targets for interference to augment the necroptotic antileukemia response. Ex vivo drug response profiling in a model of the bone marrow microenvironment reveals powerful synergy of necroptosis induction with histone deacetylase (HDAC) inhibition. Subsequent transcriptome analysis and functional in vivo CRISPR screening identify gene regulatory circuitries through the master transcription regulators specificity protein 1 (SP1), p300, and HDAC2 to drive necroptosis. Although deletion of SP1 or p300 confers resistance to necroptosis, loss of HDAC2 sensitizes cells to RIPK1-dependent cell death by SMAC mimetics. Consequently, our data inform strong in vivo antileukemic activity of combinatorial necroptosis induction and HDAC inhibition in patient-derived human leukemia models. Thus, transcriptional dependency of necroptosis activation is a key regulatory mechanism that identifies novel targets for interference, pointing out a strategy to exploit alternative nonapoptotic cell death pathways to eradicate resistant disease
TRAF2 and RIPK1 Redundantly Mediate Classical NFκB Signaling by TNFR1 and CD95-Type Death Receptors
No full textThis study suggests a modified model of TNFR1-induced complex I-mediated NFκB signaling. Evaluation of a panel of five tumor cell lines (HCT116-PIK3CAmut, SK-MEL-23, HeLa-RIPK3, HT29, D10) with TRAF2 knockout revealed in two cell lines (HT29, HeLa-RIPK3) a sensitizing effect for death receptor-induced necroptosis and in one cell line (D10) a mild sensitization for TNFR1-induced apoptosis. TRAF2 deficiency inhibited death receptor-induced classical NFκB-mediated production of IL-8 only in a subset of cell lines and only partly. TRAF5, furthermore, failed to improve DR-induced NFκB signaling in HCT116-PIK3CAmut and HCT116-PIK3CAmut-TRAF2KO cells. These findings argue for a non-obligatory role of TRAF2 in death receptor-induced classical NFκB signaling. Similar as in TRAF2-deficient cells, TNF- and CD95L-induced NFκB signaling was found to be only poorly affected in RIPK1KO cells and in cells treated with the RIPK1-specific PROTAC LD4172. Intriguingly, however, death receptor-induced NFκB signaling was completely inhibited in HCT116-PIK3CAmut cells double deficient for TRAF2 and RIPK1 and in TRAF2-deficient cells treated with LD4172. Moreover, with exception of recruitment of TRADD, acting upstream to TRAF2 and parallel to RIPK1, TNFR1 signaling complex formation was abrogated in TRAF2-RIPK1 DKO cells. Based on our findings, two distinguishable types of TNFR1-interacting complexes promote TNF-induced NFκB signaling: First, a TRADD-TRAF2/cIAP utilizing complex Ia which becomes evident in RIPK1-deficient cells. Second, a non-modified RIPK1 utilizing complex Ib which acts in TRADD- or TRAF2-deficient cells. Complex Ia and Ib may furthermore interact and cooperate to ubiquitinate RIPK1 resulting in a modified complex Ia/b preventing complex Ia and Ib to convert to the established TNFR1-induced cytotoxic complexes IIa and IIb
Diagnostic and Prognostic Value of Cystatin C in Acute Coronary Syndrome: An Up-to-Date Meta-Analysis
No full textBackground: The role of Cystatin C (CysC) in the diagnosis and prognosis of cardiovascular disease, particularly acute coronary syndrome (ACS), is increasingly significant. The goal of this meta-analysis was to assess the diagnostic and prognostic value of CysC in patients with ACS, as well as its association with major adverse cardiovascular events (MACE), defined as mortality, myocardial infarction, heart failure, and stroke.
Methods: The present study is a systematic review and meta-analysis. Using PubMed, Web of Science, Cochrane Library, and Embase, a literature review of cohort and case control studies reporting MACE and using the terms ACS and Cystatin C was conducted, excluding studies published after August 1, 2024. the meta-analysis using a random effects model.
Results: CysC concentrations were significantly higher in patients with ACS compared to controls [mean difference (MD) = 0.36, p \u3c 0.001], and in acute myocardial infarction (AMI) vs. unstable angina (MD = 0.18, p \u3c 0.001). No significant differences were observed between ST elevation myocardial infarction (STEMI) and Non-ST elevation myocardial infarction (NSTEMI). Patients with MACE had higher CysC levels than those without (MD = 0.25, p \u3c 0.001). Hospital survivors had lower CysC levels compared to those who died (MD = -0.25, p \u3c 0.001). Higher CysC concentrations were associated with increased risks of MACE, cardiac death, overall mortality, myocardial reinfarction, and stroke, both during hospitalization and beyond.
Conclusions: CysC is a promising biomarker for both diagnosis and prognosis in patients with ACS, especially in the context of predicting MACE, mortality and heart failure risk. The use of CysC may improve risk stratification and support therapeutic decision-making in clinical practice