DigitalCommons@The Texas Medical Center
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RNase1-Driven Alk-Activation Is an Oncogenic Driver and Therapeutic Target in Non-small Cell Lung Cancer
No full textTargeted therapy has achieved significant success in the treatment of non-small cell lung cancer (NSCLC), particularly in patients harboring common oncogenic driver mutations such as EGFR, KRAS, and ALK rearrangement. However, ~35-50% of NSCLC patients without tyrosine kinase mutation or rearrangement (non-mutated) cannot benefit from these targeted treatments, highlighting the urgent need for novel therapeutic strategies for this patient population. In this study, we report a non-canonical role of human secretory ribonuclease 1 (RNase1), which binds to and activates wild-type ALK in lung cancer cells, thereby triggering its downstream signaling pathway. RNase1-driven ALK-activation (RDAA) cells exhibit enhanced cell proliferation, migration, and colony formation. Additionally, RDAA facilitates tumor formation in fibroblast models, further underscoring its oncogenic potential in vivo. Importantly, RDAA lung cancer cells exhibit marked sensitivity to FDA-approved ALK inhibitors. Tumor growth suppression and survival were substantially improved in both RDAA-positive NSCLC cell line-derived and patient-derived xenograft tumor models treated with ALK inhibitors. Monoclonal antibodies against RNase1 and phosphorylated-ALK were used to analyze two different human NSCLC tissue cohorts by immunohistochemical staining identified 10.4% (5/48) and 8.5% (100/1173) patients who were RDAA positive, respectively. Notably, among the nine RDAA-positive NSCLC patients who accepted ALK inhibitor treatment, five achieved objective response including two who experienced complete response (CR). Together, the current study identifies RDAA as an oncogenic driver and proposes an effective targeted therapy strategy for non-mutated NSCLC patients
Ligand-Activated Egfr/Mapk Signaling but Not PI3K, Are Key Resistance Mechanisms to Egfr-Therapy in Colorectal Cancer
No full textUnderstanding mechanisms of resistance to active therapies is crucial for developing more effective treatments. Here, we investigate resistance to anti-EGFR and anti-VEGF plus chemotherapy treatment in colorectal cancer (CRC) patients from the IMblaze370 trial (NCT02788279). While anti-VEGF does not select for secondary mutations, anti-EGFR leads to simultaneous mutations in EGFR and MAPK, but not PI3K pathway genes. Notably, we observe frequent acquired mutations in the EGFR extracellular but not intracellular domain and that patients with higher baseline expression of EGFR-ligands are prone to acquire resistant mutations. This data reveals a ligand-activated EGFR/MAPK-signaling dependency in CRC. We also observe enrichment for 8q gains in anti-EGFR treated patients, potentially linked to MYC amplification, a finding further supported by baseline expression analysis. This work adds to the evidence supporting broader evaluation of EGFR and pan-KRAS inhibitor combinations in CRC patients. It also underscores the utility of EGFR ligands as anti-EGFR efficacy biomarkers and provides a rationale for developing ligand blockers to complement and/or improve conventional anti-EGFR therapies in CRC
Caspase 3-Specific Cleavage of Ubiquitin-Specific Peptidase 48 Enhances Drug-Induced Apoptosis in AML
No full textDysfunction or dysregulation of deubiquitination is closely related to the initiation and development of multiple cancers. Targeted regulation of deubiquitination has been recognized as an important strategy in tumor therapy. However, the mechanism by which drugs regulate deubiquitinase is not clear. Here, we identified ubiquitin-specific peptidase 48 (USP48), a member of the ubiquitin-specific protease family highly expressed in various tumors, as a specific substrate for the activated caspase-3. During drug induced apoptosis of AML cells, activated caspase-3 cleaves USP48 through recognizing the conservative motif DEQD located at 611-614 sites of human USP48. Subsequent analysis showed that the cleavage USP48 N-terminal fragment which contains catalytic active domain is easily degraded by ubiquitination. Meanwhile knockdown experiment showed that inhibiting the expression of USP48 could also promotes apoptosis and enhance the efficacy of chemotherapy drugs. Altogether, these results suggest that targeting USP48 may represent a novel therapeutic strategy in AML
Superior Vena Cava Stenting Complicated by Perforation and Cardiac Tamponade
No full textSuperior vena cava (SVC) syndrome is a clinical condition characterized by impaired venous return from the upper body due to intrinsic or extrinsic obstruction of the SVC. Endovascular stenting has become an effective intervention for symptomatic relief. However, the procedure carries a rare risk of life-threatening complications, including SVC perforation and cardiac tamponade. This study describes a 60-year-old male with SVC syndrome secondary to squamous cell carcinoma of the lung who developed SVC perforation and cardiac tamponade during endovascular stenting. Despite initial hemodynamic compromise and cardiac arrest, prompt intervention with pericardiocentesis, aggressive resuscitation, and deployment of a covered stent resulted in a successful outcome within 4 minutes. This report highlights the critical role of anesthetic management in SVC syndrome cases, emphasizing the importance of airway precautions, hemodynamic stability, and access to inferior venous return for large-volume resuscitation. This case underscores the need for vigilance in recognizing and managing SVC stenting complications. Furthermore, it advocates for a multidisciplinary approach involving anesthesiology, interventional radiology, and cardiothoracic surgery to optimize outcomes
Patient Outcomes Following Parasagittal Interlaminar Epidural Steroid Injections for Bilateral Lumbar Radicular Symptoms: Correlation of Contrast Spread With Symptom Relief
No full textIntroduction Bilateral lumbar radicular symptoms are commonly treated with interlaminar epidural steroid injections (ILESIs). The parasagittal approach often results in unilateral contrast spread, which may influence the degree of bilateral symptom relief. This study evaluates whether unilateral contrast spread correlates with symptom improvement in both ipsilateral and contralateral symptoms. Methods A retrospective review of six patients with bilateral lumbar radiculopathy secondary to lumbar degenerative disc disease, spondylosis, or disc herniation was conducted. All patients underwent ILESIs using a parasagittal approach. The injectate consisted of bupivacaine, preservative-free normal saline, and triamcinolone. Contrast spread was assessed fluoroscopically, and symptom relief was evaluated at a two-week follow-up using patient-reported outcome measures. Results Ipsilateral symptom relief ranged from 75% to 100% (mean: 89.2%), while contralateral relief ranged from 0% to 90% (mean: 35.8%). Notably, two patients experienced substantial bilateral relief (80-90%) despite unilateral contrast spread. These findings suggest that while ipsilateral relief is typically achieved, contralateral relief is variable. Conclusion The side of contrast spread strongly correlates with ipsilateral symptom improvement at short-term follow-up, while bilateral symptom relief is less predictable. Understanding the relationship between unilateral contrast spread and bilateral symptom relief is critical in optimizing injection techniques for patients with lumbar radiculopathy. Future research should focus on larger cohorts, randomized controlled trials, and direct comparisons between the parasagittal approach and midline or bilateral transforaminal techniques to optimize bilateral symptom relief strategies
Its Own Architect: Flipping Cardiolipin Synthase
No full textCurrent dogma assumes that lipid asymmetry in biological membranes is actively maintained and dispensable for cell viability. The inner (cytoplasmic) membrane (IM) of Escherichia coli is asymmetric. However, the molecular mechanism that maintains this uneven distribution is unknown. We engineered a conditionally lethal phosphatidylethanolamine (PE)-deficient mutant in which the presence of cardiolipin (CL) on the periplasmic leaflet of the IM is essential for viability, revealing a mechanism that provides CL on the desired leaflet of the IM. CL synthase (ClsA) flips its catalytic cytoplasmic domain upon depletion of PE to supply nonbilayer-prone CL in the periplasmic leaflet of the IM for cell viability. In the presence of a physiological amount of PE, osmotic down-shock induces a topological inversion of ClsA, establishing the biological relevance of membrane protein reorientations in wild-type cells. These findings support a flippase-less mechanism for maintaining membrane lipid asymmetry in biogenic membranes by self-organization of a lipid-synthesizing enzyme
Implementation Mapping to Guide Adoption of a Semi-Structured Intraoperative Anesthesia Handoff Tool
No full textThere frequently exists a gap between known best practices and real-world methods. Closing this gap involves thoughtful implementation, typically involving multiple implementation strategies. Implementation mapping is a technique that links the innovation being implemented with potential barriers to implementation and connects these barriers to the strategies that form the implementation plan. This study demonstrates the application of implementation mapping to guide the adoption of the Epic Health Systems Intraoperative Anesthesia Handoff Report. The objective is to create a comprehensive implementation plan tailored to the anticipated challenges of the local environment. There are five steps in implementation mapping: (1) performing a needs assessment, (2) creating a matrix of change, (3) identifying the mechanisms of change and strategies for change, (4) creating implementation materials, and (5) measuring implementation outcomes. Through the creation of this map, a multi-pronged implementation strategy was created and executed. This implementation plan resulted in high acceptability, appropriateness, and feasibility scores among frontline anesthesia clinicians adopting the intraoperative anesthesia tool. The logical connections between the barriers and the implementation strategies further facilitated changes to the implementation plan as new challenges arose during the implementation process. This study addresses a critical gap in clinical practice by providing a structured approach to implementing best practices in anesthesiology. Implementation mapping can potentially be a valuable technique for guiding quality improvement projects involving implementing new clinical practices in anesthesiology
Single-Cell Analysis Identifies Ifi27l2a as a Gene Regulator of Microglial Inflammation in the Context of Aging and Stroke in Mice
No full textInflammation is a significant driver of ischemic stroke pathology in the brain. To identify potential regulators of inflammation, we performed single-cell RNA sequencing (scRNA-seq) of young and aged mouse brains following stroke and found that interferon alpha-inducible protein 27 like 2 A (Ifi27l2a) was significantly up-regulated, particularly in microglia of aged brain. Ifi27l2a is induced by interferons for viral host defense and has been linked with pro-inflammatory cellular mechanisms. However, its potential role in neurodegeneration is unknown. Using a combination of cell culture, experimental stroke models in mice, and human autopsy brain samples, we demonstrated that induction of Ifi27l2a occurs in microglia in response to aging, ischemic stroke, and pro-inflammatory molecules. We further showed that induction of Ifi27l2a in microglia was sufficient to stimulate mitochondrial ROS production and promote a pro-inflammatory phenotype. Lastly, using an ischemic stroke model, we demonstrated that hemizygous deletion of Ifi27l2a (Ifi27l2
Instagram Versus Reality: Who Are Actually Plastic Surgeons?
No full textBackground: Instagram has become one of the most powerful marketing tools available to plastic surgeons because patients have increasingly turned to online resources to find physicians. Within, we review the online presence of self-ascribed plastic surgeons in the United States to identify potential misinformation and dishonest advertising.
Methods: The Inflact database was queried for the search terms: plastic surgeon/surgery, plastic and reconstructive surgeon/surgery, aesthetic surgeon/surgery, and cosmetic surgeon/surgery. US physician account information, history of medical training, American Board of Plastic Surgery (ABPS) certification status, and posts were reviewed.
Results: In total, 1399 physicians practicing within the United States were identified. Most attended medical school in the United States (93%), a minority received integrated plastic surgery training in the United States (14%), and the majority attended general surgery residency in the United States (57%) followed by independent plastic surgery residency in the United States (50%). Altogether, 1141 individuals were explicitly listed as plastic surgeons on Instagram, nearly a quarter of these (325 individuals, 28%) were not certified by the ABPS, and nearly a fifth (251 individuals, 22%) received no training in plastic surgery.
Conclusions: Nearly one-third of plastic surgeons on Instagram are not certified through the ABPS. This is detrimental to the reputation of plastic surgery and has the potential to create broader consequences and may lead to patients mistakenly receiving care from unqualified physicians. It is paramount that plastic surgeons create a united front against such endeavors through advocacy efforts within the American Society of Plastic Surgeons
Development and Pilot Testing of an Addiction Clinic-Based Pre-Exposure Prophylaxis Uptake and Adherence Intervention for Women with Substance Use Disorders: Protocol for a Pilot Randomized Trial
No full textBackground: Black and Hispanic women in the United States continue to bear disproportionate incidence of HIV related to sexual transmission and injection drug use. Specifically, women with substance use disorders (SUDs) are more likely to engage in vaginal or anal condomless sex associated with HIV transmission. Pre-exposure prophylaxis (PrEP) is a highly effective HIV prevention tool but is not widely used by racial or ethnic minority women. Effective interventions for engaging women with SUDs in HIV prevention interventions that are culturally appropriate and, therefore, more appealing to racial or ethnic minority women with SUDs are critically needed.
Objective: This 3-phased study, including a pilot randomized controlled trial (RCT), will assess the initial efficacy, feasibility, and acceptability of an addiction clinic-based behavioral and PrEP services intervention to increase the uptake and adherence to PrEP among racial or ethnic minority women.
Methods: A 3-phased mixed methods research design will involve formative qualitative methods using thematic analysis to design the intervention (phase 1), theatre testing to adapt and refine the intervention (phase 2), and RCT methods to pilot test the intervention for efficacy, feasibility, and acceptability (phase 3). The pilot RCT will enroll and randomize 60 women to either the standard SUD treatment program or SUD treatment integrated with PrEP services. The addiction clinic-based behavioral intervention will include 4 motivational counseling sessions guided by the Information-Motivation-Behavioral Skills Model to increase the uptake of PrEP. A mobile health app will be used to engage participants with the intention of motivating PrEP initiation and supporting adherence to PrEP. Following phase 3, generalized linear modeling will be used to model effects of the proportion of participants who fill their prescription and take at least 1 dose as a function of the intervention group.
Results: Findings from individual qualitative interviews informed the development of the addiction clinic-based behavioral intervention. Study recruitment for the randomized pilot (phase 3) launched in May 2024. Additional statistical analyses will be performed upon completion of the study.
Conclusions: This addiction clinic-based behavioral intervention aims to increase PrEP uptake and adherence among racial or ethnic minority women who engage in sexual and substance use behaviors associated with increased susceptibility to HIV transmission. The addiction clinic-based behavioral intervention has the potential to reduce HIV-related disparities among Black and Hispanic women with SUDs. Findings from this study will provide a foundation for future HIV prevention interventions for racial or ethnic minority women with SUDs.
Trial registration: ClinicalTrials.gov NCT06158607; https://clinicaltrials.gov/study/NCT06158607?term=NCT06158607&rank=1.
International registered report identifier (irrid): DERR1-10.2196/64961