Poor Clinical Outcome In Patients Research Articles

Plasminogen activator inhibitor-1 promotes immune evasion in tumors by facilitating the expression of programmed cell death-ligand 1.

Increased levels of plasminogen activator inhibitor-1 (PAI-1) in tumors have been found to correlate with poor clinical outcomes in patients with cancer. Although abundant data support the involvement of PAI-1 in cancer progression, whether PAI-1 contributes to tumor immune surveillance remains unclear. The purposes of this study are to determine whether PAI-1 regulates the expression of immune checkpoint molecules to suppresses the immune response to cancer and demonstrate the potential of PAI-1 inhibition for cancer therapy. The effects of PAI-1 on the expression of the immune checkpoint molecule programmed cell death ligand 1 (PD-L1) were investigated in several human and murine tumor cell lines. In addition, we generated tumor-bearing mice and evaluated the effects of a PAI-1 inhibitor on tumor progression or on the tumor infiltration of cells involved in tumor immunity either alone or in combination with immune checkpoint inhibitors. PAI-1 induces PD-L1 expression through the JAK/STAT signaling pathway in several types of tumor cells and surrounding cells. Blockade of PAI-1 impedes PD-L1 induction in tumor cells, significantly reducing the abundance of immunosuppressive cells at the tumor site and increasing cytotoxic T-cell infiltration, ultimately leading to tumor regression. The anti-tumor effect elicited by the PAI-1 inhibitor is abolished in immunodeficient mice, suggesting that PAI-1 blockade induces tumor regression by stimulating the immune system. Moreover, combining a PAI-1 inhibitor with an immune checkpoint inhibitor significantly increases tumor regression. PAI-1 protects tumors from immune surveillance by increasing PD-L1 expression; hence, therapeutic PAI-1 blockade may prove valuable in treating malignant tumors.

Hepatocellular carcinoma and musculoskeletal system: A narrative literature review.

Musculoskeletal alterations in hepatocellular carcinoma (HCC) are less common than liver-related complications. However, they can significantly impact the quality of life and overall prognosis of patients with HCC. The main obstacle in the clinical assessment of HCC-induced musculoskeletal alterations is related to effective and timely diagnosis because these complications are often asymptomatic and unapparent during routine clinical evaluations. This narrative literature review aimed to provide a comprehensive overview of the contemporary literature related to the changes in the musculoskeletal system in patients with HCC, focusing on its clinical implications and underlying etiopathogenetic mechanisms. Osteolytic bone metastases are the most common skeletal alterations associated with HCC, which could be associated with an increased risk of low-trauma bone fracture. Moreover, previous studies reported that osteopenia, sarcopenia, and myosteatosis are associated with poor clinical outcomes in patients with HCC. Even though low bone mineral density and sarcopenia are consistently reported as reliable predictors of pretransplantation and post-transplantation mortality in HCC patients, these complications are frequently overlooked in the clinical management of patients with HCC. Taken together, contemporary literature suggests that a multidisciplinary approach is essential for early recognition and clinical management of HCC-associated musculoskeletal alterations to improve patient prognosis. Further research into the mechanisms and treatment options for musculoskeletal complications is warranted to enhance our understanding and clinical management of this aspect of HCC.

Association of clinical outcome and imaging endpoints in extensive ischemic stroke—comparing measures of cerebral edema

Abstract Objectives Ischemic edema is associated with worse clinical outcomes, especially in large infarcts. Computed tomography (CT)–based densitometry allows direct quantification of absolute edema volume (EV), which challenges indirect biomarkers like midline shift (MLS). We compared EV and MLS as imaging biomarkers of ischemic edema and predictors of malignant infarction (MI) and very poor clinical outcome (VPCO) in early follow-up CT of patients with large infarcts. Materials and methods Patients with anterior circulation stroke, large vessel occlusion, and Alberta Stroke Program Early CT Score (ASPECTS) ≤ 5 were included. VPCO was defined as modified Rankin scale (mRS) ≥ 5 at discharge. MLS and EV were quantified at admission and in follow-up CT 24 h after admission. Correlation was analyzed between MLS, EV, and total infarct volume (TIV). Multivariable logistic regression and receiver operating characteristics curve analyses were performed to compare MLS and EV as predictors of MI and VPCO. Results Seventy patients (median TIV 110 mL) were analyzed. EV showed strong correlation to TIV (r = 0.91, p < 0.001) and good diagnostic accuracy to classify MI (EV AUC 0.74 [95%CI 0.61–0.88] vs. MLS AUC 0.82 [95%CI 0.71–0.94]; p = 0.48) and VPCO (EV AUC 0.72 [95%CI 0.60–0.84] vs. MLS AUC 0.69 [95%CI 0.57–0.81]; p = 0.5) with no significant difference compared to MLS, which did not correlate with TIV < 110 mL (r = 0.17, p = 0.33). Conclusion EV might serve as an imaging biomarker of ischemic edema in future studies, as it is applicable to infarcts of all volumes and predicts MI and VPCO in patients with large infarcts with the same accuracy as MLS. Clinical relevance statement Utilization of edema volume instead of midline shift as an edema parameter would allow differentiation of patients with large and small infarcts based on the extent of edema, with possible advantages in the prediction of treatment effects, complications, and outcome. Key Points • CT densitometry–based absolute edema volume challenges midline shift as current gold standard measure of ischemic edema. • Edema volume predicts malignant infarction and poor clinical outcome in patients with large infarcts with similar accuracy compared to MLS irrespective of the lesion extent. • Edema volume might serve as a reliable quantitative imaging biomarker of ischemic edema in acute stroke triage independent of lesion size.

Progressive sarcopenia and myosteatosis predict prognosis of advanced HCC patients treated with immune checkpoint inhibitors.

Immunotherapy stands as a pivotal modality in the therapeutic landscape for the treatment of advanced hepatocellular carcinoma, yet responses vary among patients. This study delves into the potential impact of sarcopenia, myosteatosis and adiposity indicators, as well as their changes during immunotherapy, on treatment response and prognosis in patients with advanced hepatocellular carcinoma treated with immune checkpoint inhibitors. In this retrospective analysis, 116 patients with advanced hepatocellular carcinoma receiving immune checkpoint inhibitors were recruited. Skeletal muscle, intramuscular, subcutaneous, and visceral adipose tissue were assessed by computed tomography at the level of the third lumbar vertebrae before and after 3 months of treatment. Sarcopenia and myosteatosis were evaluated by skeletal muscle index and mean muscle density using predefined threshold values. Patients were stratified based on specific baseline values or median values, along with alterations observed during the treatment course. Overall survival (OS) and progression-free survival (PFS) were compared using the log-rank test and a multifactorial Cox proportional risk model. A total of 116 patients were recruited and divided into two cohorts, 81 patients for the training set and 35 patients for the validating set. In the overall cohort, progressive sarcopenia (P=0.021) and progressive myosteatosis (P=0.001) were associated with objective response rates, whereas progressive myosteatosis (P<0.001) was associated with disease control rates. In the training set, baseline sarcopenia, myosteatosis, and subcutaneous and visceral adipose tissue were not significantly associated with PFS and OS. In multivariate analysis adjusting for sex, age, and other factors, progressive sarcopenia(P=0.002) and myosteatosis (P=0.018) remained independent predictors of PFS. Progressive sarcopenia (P=0.005), performance status (P=0.006) and visceral adipose tissue index (P=0.001) were all independent predictors of OS. The predictive models developed in the training set also had good feasibility in the validating set. Progressive sarcopenia and myosteatosis are predictors of poor clinical outcomes in patients with advanced hepatocellular carcinoma receiving immune checkpoint inhibitors, and high baseline visceral adiposity is associated with a poorer survival.

Identification of Siglec-1-negative alveolar macrophages with proinflammatory phenotypes in chronic obstructive pulmonary disease.

Alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD) orchestrate persistent inflammation in the airway. However, subpopulations of AMs participating in chronic inflammation have been poorly characterized. We previously reported that Siglec-1 expression on AMs, which is important for bacteria engulfment, was decreased in COPD. Here, we show that Siglec-1-negative AMs isolated from COPD lung tissues exhibit a proinflammatory phenotype and are associated with poor clinical outcomes in patients with COPD. Using flow cytometry, we segregated three subsets of AMs based on the expression of Siglec-1 and their side scattergram (SSC) and forward scattergram (FSC) properties: Siglec-1+SSChiFSChi, Siglec-1-SSChiFSChi, and Siglec-1-SSCloFSClo subsets. The Siglec-1-SSCloFSClo subset number was increased in COPD. RNA sequencing revealed upregulation of multiple proinflammatory signaling pathways and emphysema-associated matrix metalloproteases in the Siglec-1-SSCloFSClo subset. Gene set enrichment analysis indicated that the Siglec-1-SSCloFSClo subset adopted intermediate phenotypes between monocytes and mature alveolar macrophages. Functionally, these cells produced TNF-α, IL-6, and IL-8 at baseline, and these cytokines were significantly increased in response to viral RNA. The increase in Siglec-1-negative AMs in induced sputum is associated with future exacerbation risk and lung function decline in patients with COPD. Collectively, the novel Siglec-1-SSCloFSClo subset of AMs displays proinflammatory properties, and their emergence in COPD airways may be associated with poor clinical outcomes.NEW & NOTEWORTHY Alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD) orchestrate persistent inflammation in the airway. We find that Siglec-1-negative alveolar macrophages have a wide range of proinflammatory landscapes and a protease-expressing phenotype. Moreover, this subset is associated with the pathogenesis of COPD and responds to viral stimuli.

Abstract 192: Orchestrating CDC42 turnover to regulate membrane protrusion and tumor metastasis

Abstract F-actin cytoskeleton remodeling is essential for cell migration, organ development, and immune responses. CDC42, a factor orchestrating F-actin remodeling for membrane dynamics, switches between its inactive GDP- and active GTP-bound forms. However, the biological and clinical significance of the mechanisms regulating CDC42 protein turnover remains unclear. Here we show that KLHL23-mediated CDC42·GTP polyubiquitylation for degradation and RhoGDI-mediated CDC42·GDP sequestration away from the plasma membrane co-inactivate CDC42 in a spatiotemporal context, influencing membrane dynamics and homeostasis during migration. Via a functional genomic screen, we identified KLHL23 as a suppressor of tumor invasion. Decreased KLHL23 level was associated with tumor metastasis and poor clinical outcomes in patients with liver and pancreas cancers. KLHL23 functions as the E3 ligase responsible for CDC42 polyubiquitylation and degradation. KLHL23 shares with RhoGDI the switch II region of CDC42 for binding, enhancing selective targeting of CDC42·GTP and CDC42·GDP, respectively. KLHL23 depletion in cells leads to F-actin and membrane over-protrusion, as well as epithelial-mesenchymal transition and tumor metastasis. Fluorescence resonance energy transfer assays reveal that the KLHL23—CDC42·GTP interaction plays a primary role in quenching CDC42 activity during membrane protrusion-retraction, while the RhoGDI—CDC42·GDP interaction occurs lately. Our results demonstrate the spatiotemporal interplay between RhoGDI and KLHL23 in regulating CDC42 turnover for membrane dynamics. As KLHL23/RhoGDI—CDC42 axis dysregulation causes tumor metastasis, our findings open avenues for exploring novel therapeutics. Citation Format: Sen-Yung Hsieh. Orchestrating CDC42 turnover to regulate membrane protrusion and tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 192.

Abstract 2628: Generation of multi-antigen specific T cells for ovarian cancer using Prussian Blue nanoparticles and photothermal therapy

Abstract The immunosuppressive nature of ovarian cancer (OC) allows these tumors to evade the immune system, contributing to late-stage diagnoses and poor clinical outcomes for patients. However, a higher number of tumor-infiltrating lymphocytes is associated with improved clinical outcomes in OC. One type of lymphocyte, the T cell, can traffic to the tumor and kill tumor cells. We have shown that treating tumor cells with Prussian Blue nanoparticles and photothermal therapy (PBNP-PTT) results in immunogenic cell death, a form of cell death that is visible to the immune system, including T cells. PBNP-PTT-treated tumor cells were then used to expand tumor-specific T cells from partially genetically matched healthy donors against breast and brain cancer cell lines. These expanded T cells were better able to recognize and kill the target tumor cell lines than bulk unexpanded T cells from the same donors. Hence, we hypothesized that using PBNP-PTT-treated OC cells would allow us to expand a polyclonal tumor-specific T cell product that is cytolytic against OC cells in vitro and in vivo.We first evaluated whether multi-antigen OC-specific T cells could be expanded from partially genetically matched healthy donors and confirmed that PBNP-PTT elicited immunogenic cell death in the HLA-A*02:01 human OC cell lines Hey and TykNu. Using our established in vitro T cell expansion protocol, we then successfully expanded T cells from multiple HLA-A*02:01 healthy donors (n=3) against these cell lines. Functional analyses—including interferon-gamma ELISPOT, multi-color flow cytometry, and cytotoxicity assays—demonstrated that the expanded T cells had enhanced anti-tumor responses against OC cell lines compared to bulk unexpanded T cells derived from the same donors. Current work is expanding this approach to a syngeneic murine setting in C57BL/6J mice. Moreover, we will evaluate HLA-matched T cells and tumor cells from patients with OC ex vivo. Collectively, these efforts serve as a novel approach towards a curative immunotherapy for OC. Citation Format: Erin E. Grundy, Abigail Lee, Samantha Chin, Melissa Hadley, Danielle Schmidt, Loretta Wang, Olivia Cox, Khadra Omar, Catherine M. Bollard, Rohan Fernandes, Katherine B. Chiappinelli. Generation of multi-antigen specific T cells for ovarian cancer using Prussian Blue nanoparticles and photothermal therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2628.

Abstract 6574: UCHL1 is a molecular indicator and a therapeutic target for neuroendocrine carcinomas

Abstract Neuroendocrine carcinomas, such as neuroendocrine prostate cancer (NEPC), small cell lung cancer (SCLC), and neuroblastoma, share common histological features, including expression of neuroendocrine markers, rapid relapse after treatment, and poor prognosis. Due to the poor clinical outcome of patients with neuroendocrine carcinomas, there is a critical need to identify new drivers, therapeutic targets, and effective therapeutic strategies for these malignancies. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a protease that has a dual function in regulating protein stability. We demonstrated that UCHL1 is significantly elevated in tissues from patients with NEPC, SCLC, and neuroblastoma. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of key transcriptional factors, E2F1 and c-MYC. Conversely, UCHL1 binds p53 and promotes p53 degradation. Importantly, treatment with UCHL1 inhibitors significantly reduces tumor growth and metastasis of neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, halts tumor growth in pre-clinical settings. Our study reveals new mechanisms of UCHL1 function in neuroendocrine carcinomas tumorigenesis and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosis and monitoring treatment responses in neuroendocrine carcinomas. Citation Format: Shiqin Liu, Timothy Chai, Fernando Marques, Qingqing Yin, En-Chi Hsu, Michelle Shen, Angus Toland, Abel Bermudez, Alifiani B. Hartono, Christopher F. Massey, Chung S. Lee, Liwei Zheng, Maya Baron, Caden J. Denning, Merve Aslan, Holly Nguyen, Rosalie Nolley, Amina Zoubeidi, Millie Das, Christian Kunder, Brooke Howitt, H Tom Soh, Irving L. Weissman, Michael A. Liss, Arnold I. Chin, James D. Brooks, Eva Corey, Sharon Pitteri, Jiaoti Huang, Tanya Ivanova Stoyanova. UCHL1 is a molecular indicator and a therapeutic target for neuroendocrine carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6574.

High Pretreatment DHEA Is Associated with Inferior Immunotherapy Response in Metastatic Non-Small Cell Lung Cancer.

Background: Sex difference in the immune response may influence patients' response to immune checkpoint inhibitors (ICIs). We conducted a prospective observation study to determine the correlation between pretreatment sex hormone levels and response to ICIs in metastatic non-small cell lung cancer (NSCLC). Method: Pretreatment plasma samples from 61 patients with newly diagnosed NSCLC prior to ICI therapy were collected. Six sex hormone levels [pyrazole triol, 17 β-estradiol, 5-androstenediol, 3β-androstenediol, dehydroepiandrosterone (DHEA), and S-equol] were measured using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Overall survival (OS) and progression-free survival (PFS) were compared between the high- and low-level groups in the whole cohort. Result: Among the six sex hormones measured, DHEA levels were significantly higher among patients without clinical benefits in the discovery cohort; the remaining sex hormones did not differ significantly. In the whole cohort, median PFS was 22 months for patients with low DHEA levels vs. 3.8 months for those with high DHEA [hazard ratio, 14.23 (95% CI, 4.7-43); p < 0.001]. A significant association was also observed for OS [hazard ratio, 8.2 (95% CI, 2.89-23.35); p < 0.0001]. Conclusions: High pretreatment plasma DHEA levels were associated with poor clinical outcomes for patients with metastatic NSCLC treated with ICIs.

78 Targeting tumor-promoting myeloid cell functions in head & neck cancer

Myeloid cells are a major component of immune cells infiltrating tumors, interacting with each other, with tumor cells and other stromal cells, and demonstrating a prominent plasticity. Tumor-associated myeloid cells, such as neutrophils (or so-called MDSCs: suppressory neutrophils) contribute to cancer progression via multiple mechanisms. Neutrophils are the most abundant myeloid blood cells, which have been shown to exert heterogeneous phenotypic and functional states: reaching from anti- to protumoral. On the one hand these cells can suppress anti-tumor immune responses, support tumor angiogenesis or metastatic dissemination. On the other hand, neutrophils actively kill tumor cells, or activate T-cell dependent immune responses.There is still little information on tumor-infiltrating neutrophils and their clinical relevance. Nevertheless, neutrophils were demonstrated to be associated with poor clinical outcome in patients with different kinds of cancer, including renal cancer, non-small-cell lung carcinoma, melanoma and head and neck cancer. Enrichment of neutrophils was also associated with metastases in various tumor entities. The recruitment of neutrophils within the tumor microenvironment is strictly regulated by chemokines, such as CXCL2 or CXCL8/IL-8.Neutrophil activity strongly depends on the stimulus present in the microenvironment. Since these cells are highly plastic and can easily alter their functionality, they are an ideal target for designing anti-tumor therapies. However, most of therapeutic strategies to target neutrophils in tumor-bearing hosts are dealing with the blocking of their migration into the tumor site. The efficiency of such approaches is, however, limited, as it does not address heterogeneity of these cells, and thus depletes as well antitumoral cells, leading to cancer progression and infectious complications.Given a critical role of neutrophils in tumor progression, we tested several alternative strategies to neutralize pro-tumoral activity of these cells, including reprogramming and inhibition of their immunosuppressive functions. Our recent data using own designed CCL2 peptide MyeloMIB show promising therapeutic results in head and neck cancer preclinical models. Application of this peptide leads not only to the specific inhibition of neutrophil migration into tumor tissue, but also reprograms these cells into anti-tumoral state. These results suggest a dual-edged role of neutrophils as essential regulators of anti-cancer immune responses and argue for approaches fostering anti-cancer activity of these cells, not only their migration, during cancer immunotherapy.

Predicting long-term outcomes for acute ischemic stroke using multi-model MRI radiomics and clinical variables.

The objective of this study was to create and validate a novel prediction model that incorporated both multi-modal radiomics features and multi-clinical features, with the aim of accurately identifying acute ischemic stroke (AIS) patients who faced a higher risk of poor outcomes. A cohort of 461 patients diagnosed with AIS from four centers was divided into a training cohort and a validation cohort. Radiomics features were extracted and selected from diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) images to create a radiomic signature. Prediction models were developed using multi-clinical and selected radiomics features from DWI and ADC. A total of 49 radiomics features were selected from DWI and ADC images by the least absolute shrinkage and selection operator (LASSO). Additionally, 20 variables were collected as multi-clinical features. In terms of predicting poor outcomes in validation set, the area under the curve (AUC) was 0.727 for the DWI radiomics model, 0.821 for the ADC radiomics model, 0.825 for the DWI + ADC radiomics model, and 0.808 for the multi-clinical model. Furthermore, a prediction model was built using all selected features, the AUC for predicting poor outcomes increased to 0.86. Radiomics features extracted from DWI and ADC images can serve as valuable biomarkers for predicting poor clinical outcomes in patients with AIS. Furthermore, when these radiomics features were combined with multi-clinical features, the predictive performance was enhanced. The prediction model has the potential to provide guidance for tailoring rehabilitation therapies based on individual patient risks for poor outcomes.

ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway.

Ubiquitin-specific protease 7 inhibitors (USP7i) are considered a novel class of anticancer drugs. Cancer cells occasionally become insensitive to anticancer drugs, known as chemoresistance, by acquiring multidrug resistance, resulting in poor clinical outcomes in patients with cancer. However, the chemoresistance of cancer cells to USP7i (P22077 and P5091) and mechanisms to overcome it have not yet been investigated. In the present study, we generated human cancer cells with acquired resistance to USP7i-induced cell death. Gene expression profiling showed that heat stress response (HSR)- and unfolded protein response (UPR)-related genes were largely upregulated in USP7i-resistant cancer cells. Biochemical studies showed that USP7i induced the phosphorylation and activation of heat shock transcription factor 1 (HSF1), mediated by the endoplasmic reticulum (ER) stress protein kinase R-like ER kinase (PERK) signaling pathway. Inhibition of HSF1 and PERK significantly sensitized cancer cells to USP7i-induced cytotoxicity. Our study demonstrated that the ER stress-PERK axis is responsible for chemoresistance to USP7i, and inhibiting PERK is a potential strategy for improving the anticancer efficacy of USP7i.

Factors Associated with Poor Clinical Outcomes in Patients with Post- Cataract Surgery Endophthalmitis: A systematic review

Introduction &amp; Objectives : Postoperative Endophthalmitis has remained one of the rare yet most devastating complications of cataract surgery. The previous study mentioned that 15-30% of POE patients have an unfavorable outcome on visual acuity of less than 20/200 and may even result in the loss of the eye. Thus, this study aims to review and summarize prognostic factors that can affect the final outcome of postoperative endophthalmitis from cataract surgery.&#x0D; Methods : We systematically searched with PRISMA 2020 across 5 databases (PubMed, Scopus, SAGE, Embase, and Cochrane) with the search term “(prognosis OR prognostic factor) AND postoperative endophthalmitis) AND (cataract surgery)”, as well as reference screening for any additional relevant studies. The risk of bias from included studies will be assessed using Newcastle-Ottawa Quality Assessment Scale.&#x0D; Results : Out of 314 studies, we decided to only include 13 studies that match our inclusion and exclusion criteria. All of the studies are cohort studies with a total of 753 patients affecting 753 eyes and most of them are coming from Asian countries. Both diagnosis and intervention given are based on Endophthalmitis Vitrectomy Study (EVS) result.&#x0D; Conclusion : Prognostic factors for post-cataract surgery endophthalmitis are corneal involvement, microbiological investigation result, intervention timing, treatment modality, comorbidities, and other complications

Abstract TP106: Intravenous Thrombolysis Door-to-Needle Times of English and Non-English Speaking Patients

Introduction: Language barriers between acute ischemic stroke patients and clinicians can create challenges in use of intravenous thrombolysis (IVT) as successful administration hinges on quick information gathering, shared decision making and consent with the patient and family. Our objectives were to compare IVT door-to-needle (DTN) times and consent between English and non-English speaking patients. Methods: We conducted a single institution retrospective chart analysis from 2018-2023 via manual data extraction of the electronic medical record to determine any disparities in quality metrics between English and non-English speakers treated with IVT. Standard time-based metrics were pulled from the AHA Get with the Guidelines registry. We included adult patients treated onsite, excluding telestroke encounters. We used standard descriptive statistics and a 2-paired t-test to compare treatment times. Results: We included 215 English speakers and 19 non-English speakers in our analysis. Consent was obtained in 92% (197/215) of English speakers and 90% (17/19) of non-English speakers, the remaining implied consent or consent was undocumented. Mean DTN times were 48.8 min and 48.2 min for English and non-English speakers, respectively, and differences were not statistically significant. Discussion: Previous studies have reported lower IVT use, longer DTN times and poorer clinical outcomes in patients who required an interpreter. However, others reported no difference in DTN times in non-English patients, attributing availability of translating services and diversity of healthcare providers. In our population, DTN times remained equally fast, but we remain unsure if our non-English speakers are appropriately consented, understanding their acute care. Future directions include improving consent documentation, and conducting qualitative interviews of English and non-English speakers who receive IVT. Our ultimate goal is to ensure quality of care for this vulnerable population.

Prognostic implication of Vasoactive Inotropic Score in adult patients with cardiogenic shock on veno-arterial extracorporeal membrane oxygenation.

Vasopressors and inotropes are crucial in managing cardiogenic shock (CS) as they enhance microcirculation in patients. Numerous studies have demonstrated the adverse outcomes associated with excessive use of vasoactive drugs and the vasoactive drug scoring system has emerged as a valuable prognostic tool, particularly in pediatric patients. This study aimed to examine the prognostic significance of the Vasoactive Inotropic Score (VIS) in adult patients with CS receiving veno-arterial extracorporeal membrane oxygenation (VA-ECMO) treatment. This retrospective multi-center study involved 2,453 adult patients who underwent VA-ECMO in China between 2015 and 2021. Among them, 1,742 adult patients with CS following VA-ECMO were finally included. The maximum VIS (VISmax) was determined by considering the highest doses of vasoactive and inotropic drugs administered within the first 6 hours before ECMO initiation. Based on the VISmax, patients were classified into two groups: 0-20 and >20. The primary outcome of this study was in-hospital mortality. A total of 1,146 patients were included in the high VISmax group, while 596 patients were assigned to the low VISmax group. Overall, 882 (50.6%) patients experienced in-hospital mortality, with significantly higher rates observed among those with higher VISmax scores (41.4% for VIS ≤20 versus 68.3% for VIS >20; P<0.001). Similar trends were observed for 30-day mortality (40.7% for VIS ≤20 versus 64.9% for VIS >20; P<0.001). Multivariable regression analysis demonstrated that a VIS score exceeding 20 independently predicted in-hospital mortality [odds ratio (OR) 2.64; 95% confidence interval (CI): 2.10-3.33; P<0.001]. The receiver operating characteristic (ROC) analysis revealed that VIS had an area under the curve (AUC) of 0.65 (95% CI: 0.63-0.68; P<0.001) as a predictor of in-hospital mortality, with an optimal cutoff value of 20.1. Moreover, the VIS exhibited good predictive ability for in-hospital mortality in patients with acute myocarditis (AUC 0.70; 95% CI: 0.63-0.78; P<0.001). Firstly, higher maximum level of VIS within the first 6 hours before ECMO initiation independently predicted poorer clinical outcomes in patients supported with ECMO for CS. Secondly, VIS exceeding 20 was significantly associated with increased risks of in-hospital mortality and 30-day mortality. Thirdly, when categorized by the cause of CS, a high VIS exhibited good predictive ability in patients with acute myocardial infarction, heart failure, and acute myocarditis.

Relevance of HOTAIR rs920778 and rs12826786 Genetic Variants in Bladder Cancer Risk and Survival.

The long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR) is associated with oncogenic features in bladder cancer and is predictive of poor clinical outcomes in patients diagnosed with this disease. In this study, we evaluated the impact of the HOTAIR single nucleotide polymorphisms rs920778 and rs12826786 on bladder cancer risk and survival. This case-control study included 106 bladder cancer patients and 199 cancer-free controls. Polymorphisms were evaluated through PCR-restriction fragment length polymorphism. The odds ratio and 95% confidence intervals were tested using univariable and multivariable logistic regressions. The effects on patient survival were evaluated using the log-rank test and Cox regression models. Our data showed that the HOTAIR rs920778 and rs12826786 genetic variants are not associated with the risk of developing bladder cancer. Nevertheless, survival analyses suggested that the HOTAIR rs920778 TT genotype and rs12826786 CC genotype are associated with increased survival in male bladder cancer patients and in patients, both male and female, who have primary tumors with a pathological stage of pT2. Together, these results suggest that, despite not being associated with bladder cancer risk, HOTAIR rs920778 and rs12826786 polymorphisms might represent new prognostic factors in this type of cancer. This is particularly important as these polymorphisms might be easily evaluated in bladder cancer patients in a minimally invasive manner to better predict their clinical outcomes.

Alteration of functionality and differentiation directed by changing gene expression patterns in myeloid-derived suppressor cells (MDSCs) in tumor microenvironment and bone marrow through early to terminal phase of tumor progression.

Myeloid-derived suppressor cells are heterogenous immature myeloid lineage cells that can differentiate into neutrophils, monocytes, and dendritic cells as well. These cells have been characterized to have potent immunosuppressive capacity in neoplasia and a neoplastic chronic inflammatory microenvironment. Increased accumulation of myeloid-derived suppressor cells was reported with poor clinical outcomes in patients. They support neoplastic progression by abrogating antitumor immunity through inhibition of lymphocyte functions and directly by facilitating tumor development. Yet the shifting genetic signatures of this myeloid lineage cell toward immunosuppressive functionality in progressive tumor development remain elusive. We have attempted to identify the gene expression profile using lineage-specific markers of these unique myeloid lineage cells in a tumor microenvironment and bone marrow using a liquid transplantable mice tumor model to trace the changing influence of the tumor microenvironment on myeloid-derived suppressor cells. We analyzed the phenotype, functional shift, suppressive activity, differentiation status, and microarray-based gene expression profile of CD11b+Gr1+ lineage-specific cells isolated from the tumor microenvironment and bone marrow of 4 stages of tumor-bearing mice and compared them with control counterparts. Our analysis of differentially expressed genes of myeloid-derived suppressor cells isolated from bone marrow and the tumor microenvironment reveals unique gene expression patterns in the bone marrow and tumor microenvironment-derived myeloid-derived suppressor cells. It also suggests T-cell suppressive activity of myeloid-derived suppressor cells progressively increases toward the mid-to-late phase of the tumor and a significant differentiation bias of tumor site myeloid-derived suppressor cells toward macrophages, even in the presence of differentiating agents, indicating potential molecular characteristics of myeloid-derived suppressor cells in different stages of the tumor that can emerge as an intervention target.

OTX1 regulates tumorigenesis and metastasis in glioma

The most prevalent kind of primary brain tumors, gliomas, have a dismal prognosis. Recent advances in the tumor-promoting ability of OTX1 have drawn increasing attention. The overexpression of OTX1 has been reported to be associated with tumor-promoting effects in several malignancies, but its expression in gliomas is unknown. The oncogene OTX1 is increased in gliomas and is linked to a poor prognosis, as we show here. The degree of OTX1 positive expression is doubtlessly concomitant with the grade of glioma. We observed that OTX1 was up-regulated in gliomas, influenced the epithelial-mesenchymal transition (EMT), encouraged glioma cell growth and proliferation, and was linked to a poor clinical outcome for patients. At present, the prognosis of glioma is still not optimistic, and further research is needed to find a new target for treatment. According to our research, OTX1 is anticipated to emerge as a novel biological target for determining glioma prognosis and treatment.

Defining Endogenous Mitochondrial Transfer in Muscle After Rotator Cuff Injury

Background: Rotator cuff muscle degeneration leads to poor clinical outcomes for patients with rotator cuff tears. Fibroadipogenic progenitors (FAPs) are resident muscle stem cells with the ability to differentiate into fibroblasts as well as white and beige adipose tissue. Induction of the beige adipose phenotype in FAPs has been shown to improve muscle quality after rotator cuff tears, but the mechanisms of how FAPs exert their beneficial effects have not been fully elucidated. Purpose: To study the horizontal transfer of mitochondria from FAPs to myogenic cells and examine the effects of β-agonism on this novel process. Study Design: Controlled laboratory study. Methods: In mice that had undergone a massive rotator cuff tear, single-cell RNA sequencing was performed on isolated FAPs for genes associated with mitochondrial biogenesis and transfer. Murine FAPs were isolated by fluorescence-activated cell sorting and treated with a β-agonist versus control. FAPs were stained with mitochondrial dyes and cocultured with recipient C2C12 myoblasts, and the rate of transfer was measured after 24 hours by flow cytometry. PdgfraCreERT/MitoTag mice were generated to study the effects of a rotator cuff injury on mitochondrial transfer. PdgfraCreERT/tdTomato mice were likewise generated to perform lineage tracing of PDGFRA+ cells in this injury model. Both populations of transgenic mice underwent tendon transection and denervation surgery, and MitoTag-labeled mitochondria from Pdgfra+ FAPs were visualized by fluorescent microscopy, spinning disk confocal microscopy, and 2-photon microscopy; overall mitochondrial quantity was compared between mice treated with β-agonists and dimethyl sulfoxide. Results: Single-cell RNA sequencing in mice that underwent rotator cuff tear demonstrated an association between transcriptional markers of adipogenic differentiation and genes associated with mitochondrial biogenesis. In vitro cocultures of murine FAPs with C2C12 cells revealed that treatment of cells with a β-agonist increased mitochondrial transfer compared to control conditions (17.8% ± 9.9% to 99.6% ± 0.13% P < .0001). Rotator cuff injury in PdgfraCreERT/MitoTag mice resulted in a robust increase in MitoTag signal in adjacent myofibers compared with uninjured mice. No accumulation of tdTomato signal from PDGFRA+ cells was seen in injured fibers at 6 weeks after injury, suggesting that FAPs do not fuse with injured muscle fibers but rather contribute their mitochondria. Conclusion: The authors have described a novel process of endogenous mitochondrial transfer that can occur within the injured rotator cuff between FAPs and myogenic cells. This process may be leveraged therapeutically with β-agonist treatment and represents an exciting target for improving translational therapies available for rotator cuff muscle degeneration. Clinical Relevance: Promoting endogenous mitochondrial transfer may represent a novel translational strategy to address muscle degeneration after rotator cuff tears.

Low LDL-C/HDL-C Ratio is Associated with Poor Clinical Outcome After Intracerebral Hemorrhage: A Retrospective Analysis of Multicenter, Prospective Cohort Data in China.

The association between low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio and the clinical outcomes of acute intracranial hemorrhage (ICH) remains unclear. In this study, we attempt to investigate whether low LDL-C/HDL-C ratio is associated with poor clinical outcomes in patients with ICH. The database was collected from a multicenter, prospective, observational cohort study, conducted in 13 hospitals in Beijing from January 2014 to September 2016. A total of 1,964 patients with ICH were initially screened in our database. Next, we selected patients with admission serum lipid information for retrospective analysis. Patients were categorized into four groups based on LDL-C/HDL-C ratio quartiles. The main outcomes were 30-day and 90-day poor functional outcome, which is defined as modified Rankin Scale score of 3 to 6, and 90-day all-cause death. Logistic regression was used to assess the association between LDL-C/HDL-C ratio and 30-day or 90-day poor functional outcome. Kaplan-Meier survival analysis and Cox regression were used to assess the association between LDL-C/HDL-C ratio and 90-day all-cause death. Restricted cubic splines were used to explore the nonlinear association between LDL-C/HDL-C ratio and the outcome of patients with ICH. A total of 491 patients with spontaneous ICH were finally enrolled in our study. The mean age was 57.6years old, and 72.1% (357/491) were men. After adjustment for confounders, patients in the lowest LDL-C/HDL-C quartile (< 1.74) had a significantly higher risk of 30-day and 90-day poor functional outcome compared with those in the highest quartile (> 3.16; 30-day: adjusted odds ratio 3.61, 95% confidence interval 1.68-7.72; 90-day: adjusted odds ratio 2.82, 95% confidence interval 1.33-5.95). Restricted cubic splines depicted a nonlinear association between LDL-C/HDL-C ratio and 90-day poor functional outcomes, indicating LDL-C/HDL-C ratio of 3.1-3.5 was correlated with better 90-day functional outcome. However, no significant correlation was found between low LDL-C/HDL-C ratio and 90-day all-cause death. Lower LDL-C/HDL-C ratio (< 1.74) is independently associated with an increased risk of poor functional outcome in patients with ICH. In the population of patients whom we studied, there is a nonlinear association between LDL-C/HDL-C ratio and 90-day poor functional outcome, and patients with an LDL-C/HDL-C ratio of 3.1 to 3.5 tend to have the lowest risk of 90-day poor functional outcome.