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The Role of IL-17 and Th17 Cells in Keloid Pathogenesis
No full textKeloids are characterized histologically by excessive fibroblast proliferation and connective tissue deposition, and clinically by scar tissue extending beyond the original site of skin injury. These scars can cause pruritus, pain, physical disfigurement, anxiety, and depression. As a result, keloid patients often have a diminished quality of life with a disproportionate burden on ethnic minorities. Despite advances in understanding keloid pathology, there is no effective Food and Drug Administration (FDA)-approved pharmacotherapy. Recent studies have highlighted the possible pathologic role of T helper (Th)17 cells and interleukin (IL)-17 in keloid formation, as well as their implication in other inflammatory disorders. This systematic review characterizes the role of Th17 cells and IL-17 in keloid pathogenesis, highlighting this pathway as a potential therapeutic target. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive search on PubMed, Embase, MEDLINE, and Web of Science databases on June 5, 2024. The search included terms related to Th17 cells, IL-17, and keloids. Thirteen studies met the inclusion criteria, comprising basic science and bioinformatic studies focusing on Th17 cells and IL-17. Key findings include increased Th17 cell infiltration and IL-17 expression in keloids, IL-17\u27s role in amplifying the inflammatory and fibrotic response via the promotion of IL-6 expression, and IL-17\u27s involvement in upregulating fibrotic markers via SDF-1 and HIF-1α pathways. IL-17 also activates the transforming growth factor beta (TGF-β)/Smad pathway in keloid fibroblasts. Th17 cells and IL-17 significantly contribute to the inflammatory and fibrotic processes in keloid pathogenesis. Therefore, targeting the IL-17 pathway offers a potential new therapeutic target to improve keloid patients\u27 outcomes. Future research could further elucidate the role of Th17 cells and IL-17 in keloid pathogenesis and assess the safety and efficacy of targeting this pathway in human studies
Treatment of Acute Myocardial Infarction and Cardiogenic Shock: Outcomes of the RECOVER III Postapproval Study by Society of Cardiovascular Angiography and Interventions Shock Stage
No full textBACKGROUND: The Society for Cardiovascular Angiography and Interventions proposed a staging system (A-E) to predict prognosis in cardiogenic shock. Herein, we report clinical outcomes of the RECOVER III study for the first time, according to Society for Cardiovascular Angiography and Interventions shock classification. METHODS AND RESULTS: The RECOVER III study is an observational, prospective, multicenter, single-arm, postapproval study of patients with acute myocardial infarction with cardiogenic shock undergoing percutaneous coronary intervention with Impella support. Patients enrolled in the RECOVER III study were assigned a baseline Society for Cardiovascular Angiography and Interventions shock stage. Staging was then repeated within 24 hours after initiation of Impella. Kaplan-Meier survival curve analyses were conducted to assess survival across Society for Cardiovascular Angiography and Interventions shock stages at both time points. At baseline assessment, 16.5%, 11.4%, and 72.2% were classified as stage C, D, and E, respectively. At ≤24-hour assessment, 26.4%, 33.2%, and 40.0% were classified as stage C, D, and E, respectively. Thirty-day survival among patients with stage C, D, and E shock at baseline was 59.7%, 56.5%, and 42.9%, respectively (=0.003). Survival among patients with stage C, D, and E shock at ≤24 hours was 65.7%, 52.1%, and 29.5%, respectively (\u3c0.001). After multivariable analysis of impact of shock stage classifications at baseline and ≤24 hours, only stage E classification at ≤24 hours was a significant predictor of mortality (odds ratio, 4.8; \u3c0.001). CONCLUSIONS: In a real-world cohort of patients with acute myocardial infarction with cardiogenic shock undergoing percutaneous coronary intervention with Impella support, only stage E classification at ≤24 hours was significantly predictive of mortality, suggesting that response to therapy may be more important than clinical severity of shock at presentation
Exploring the Dynamics of Adult Axin2 Cell Lineage Integration Into Dentate Gyrus Granule Neurons
No full textThe Wnt pathway plays critical roles in neurogenesis. The expression of Axin2 is induced by Wnt/β-catenin signaling, making this gene a reliable indicator of canonical Wnt activity. We employed pulse-chase genetic lineage tracing with the Axin2-CreERT2 allele to follow the fate of Axin2+ lineage in the adult hippocampal formation. We found Axin2 expressed in astrocytes, neurons and endothelial cells, as well as in the choroid plexus epithelia. Simultaneously with the induction of Axin2 fate mapping by tamoxifen, we marked the dividing cells with 5-ethynyl-2\u27-deoxyuridine (EdU). Tamoxifen induction led to a significant increase in labeled dentate gyrus granule cells three months later. However, none of these neurons showed any EdU signal. Conversely, six months after the pulse-chase labeling with tamoxifen/EdU, we identified granule neurons that were positive for both EdU and tdTomato lineage tracer in each animal. Our data indicates that Axin2 is expressed at multiple stages of adult granule neuron differentiation. Furthermore, these findings suggest that the integration process of adult-born neurons from specific cell lineages may require more time than previously thought
Impact of Body Mass Index on Cardiopulmonary Outcomes of COVID-19 Hospitalizations Complicated by Severe Sepsis
No full textBACKGROUND: Body Mass Index (BMI) has a significant impact on Coronavirus disease (COVID-19) patient outcomes; however, major adverse cardiac and cerebrovascular outcomes in patients with severe sepsis have been poorly understood. Our study aims to explore and provide insight into its association.
METHODS: This is an observational study looking at the impact of BMI on COVID-19-severe sepsis hospitalizations. The primary outcomes are adjusted odds of all-cause in-hospital mortality, respiratory failure, and major adverse cardiac and cerebrovascular events (MACCE), which include acute myocardial infarction, cardiac arrest, and acute ischemic stroke. The secondary outcome was healthcare resource utilization. Coexisting comorbidities and patient features were adjusted with multivariable regression analyses.
RESULTS: Of 51,740 patients with severe COVID-19-sepsis admissions, 11.4% were overweight, 24.8% had Class I obesity (BMI 30-34.9), 19.8% had Class II obesity (BMI 35-39.9), and 43.9% had the categorization of Class III obesity (BMI \u3e40) cohorts with age\u3e18 years. The odds of MACCE in patients with class II obesity and class III obesity (OR 1.09 and 1.54; 95CI 0.93-1.29 and 1.33-1.79) were significantly higher than in overweight (p \u3c 0.001). Class I, Class II, and Class III patients with obesity revealed lower odds of respiratory failure compared to overweight (OR 0.89, 0.82, and 0.82; 95CI 0.75-1.05, 0.69-0.97, and 0.70-0.97), but failed to achieve statistical significance (p = 0.079). On multivariable regression analysis, all-cause in-hospital mortality revealed significantly higher odds in patients with Class III obesity, Class II, and Class I (OR 1.56, 1.17, and 1.06; 95CI 1.34-1.81, 0.99-1.38, and 0.91-1.24) vs. overweight patients (p \u3c 0.001).
CONCLUSIONS: Patients with Class II and Class III obesity had significantly higher odds of MACCE and in-hospital mortality in COVID-19-severe sepsis admissions
Tolerability and Safety Outcomes of First-Line Oral Second-Generation Antipsychotics in Patients With Schizophrenia
No full textINTRODUCTION: Antipsychotics are the foundation of pharmacologic treatment for schizophrenia. There are many oral antipsychotics available and given that these medications are generally considered comparably efficacious when titrated to an adequate dose, their varied tolerability, and safety profiles become critically important for medication selection. AREAS COVERED: This paper reviews tolerability and safety considerations for first-line second-generation oral antipsychotics currently approved for the treatment of schizophrenia in the USA. Excluded from consideration are clozapine and non-oral formulations. EXPERT OPINION: Among antipsychotics, there are many differences in adverse reactions observed in clinical trials, such as variable likelihood to cause sedation vs insomnia, weight gain and abnormalities in glucose/lipid metabolism, hyperprolactinemia, potential for impact on the QT interval, and motoric adverse effects. Additional safety data that can help with medication selection include safety in pregnancy and lactation, and potential for drug-drug interactions. Ultimately, working with patients to personalize treatment by focusing on safety and individual tolerability considerations for various adverse effects can help in building a therapeutic alliance and improving patients\u27 outcomes
Good Publication Practice (Gpp) Guidelines for Company-Sponsored Biomedical Research From the Point of View of the Diverse Authors Involved in Its Publication
No full textGenetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology
No full textType 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care
The Weight of Frailty in Neurosurgery Patients: Analyzing the Combined Effect of Frailty and Body Mass Index on 30-Day Postoperative Mortality
No full textOBJECTIVE: There is a rising prevalence of overweight and obese persons in the US, and there is a paucity of information about the relationship between frailty and body mass index. Therefore, we examined discrimination thresholds and independent relationships of the risk analysis index (RAI), modified frailty index-5 (mFI-5), and increasing patient age in predicting 30-day postoperative mortality.
METHODS: This retrospective American College of Surgeons National Surgical Quality Improvement Program analysis compared all overweight or obese adult patients who underwent neurosurgery procedures between 2012 and 2020. We compared discrimination using receiver operating characteristic curve analysis for RAI, mFI-5, and increasing patient age. Furthermore, multivariable analyses, as well as subgroup analyses by procedure type i.e., spine, skull base, and other (vascular and functional) were performed, and reported as odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS: We included 315,725/412,909 (76.5%) neurosurgery patients, with a median age of 59 years (interquartile range: 48-68), predominately White 76.7% and male 54.3%. Receiver operating characteristic analysis for 30-day postoperative mortality demonstrated a higher discriminatory threshold for RAI (C-statistic: 0.790, 95%CI: 0.782-0.800) compared to mFI-5 (C-statistic: 0.692, 95%CI: 0.620-0.638) and increasing patient age (C-statistic: 0.659, 95%CI: 0.650-0.668). Multivariable analyses showed a dose-dependent association and a larger magnitude of effect by RAI: frail patients OR: 11.82 (95%CI: 10.57-13.24), and very frail patients OR: 31.19 (95%CI: 24.87-39.12). A similar trend was observed in all subgroup analyses i.e., spine, skull base, and other (vascular and functional) procedures (P ≤ 0.001).
CONCLUSIONS: Increasing frailty was associated with a higher rate of 30-day postoperative mortality, with a dose-dependent effect. Furthermore, the RAI had a higher threshold for discrimination and larger effect sizes than mFI-5 and increasing patient age. These findings support RAI\u27s use in preoperative assessments, as it has the potential to improve postoperative outcomes through targeted interventions
COL26A1 is a Biomarker for Aggressive Papillary Thyroid Cancer - Diagnostic, Prognostic, and Therapeutic Implications
No full textPapillary thyroid cancer (PTC) is the most common cancer in young women and has been increasing in incidence over the last several decades. While PTC is often indolent and treatable, recurrence years to decades later occurs in ~30% of patients (now only in their 40s/50s), decreasing survival ~60%. Therefore, the identification of prognostic biomarkers and actionable therapeutic targets for this high-risk PTC is a critically important, unmet need. RNA-Sequencing identified collagen 26A1 (COL26A1) as significantly upregulated in patient samples with extrathyroidal extension (ETE), lymph node metastasis (LNM), and multifocal tumors, indicating high-risk for recurrence. The Cancer Genome Atlas (TCGA) data demonstrated increased COL26A1 expression decreases survival probability by 25% and correlated with MACIS score, thyroid differentiation score (TDS), ERK score, tumor stage, and ETE, further denoting high-risk PTC. Additionally, COL26A1 correlated with known metastatic signature genes for PTC, genes involved in stiff tumor texture, and with that, the strong positive correlation with cancer-associated fibroblast infiltration, all of which suggest a poor prognosis.
To establish a manipulable in vitro cell model, PTC cell lines were investigated for COL26A1 expression. COL26A1 expression was significantly higher in PTC cell lines K1 and TPC1 compared to normal thyroid epithelial cells, NThy-ori-3-1. CRISPR inhibition using two independent short guides successfully repressed COL26A1 expression at both the RNA and protein level in both K1 and TPC1. RNA-Sequencing of knock-down compared to control cells demonstrated significantly differentially expressed biological processes including apoptosis, cell adhesion, cell migration, and cell proliferation, specifically with modulations to MAPK, Wnt, and PI3K signaling. Exploration of the effects of COL26A1 knock-down demonstrated that metastatic phenotypes were significantly decreased, including invasion, migration, motility, gelatin degradation, cell-cell and -matrix adhesion, anchorage-dependent and -independent clonogenicity, and proliferation compared to controls. This coincided with the effect of collagens on epithelial-mesenchymal transition (EMT) including reduced anoikis resistance, altered matrix metalloprotease secretion, and decreased mesenchymal markers with increases in epithelial markers and restoration of TDS. The partial induction of EMT is a characteristic of an intermediate population of cells that are more effective at undergoing metastasis through survival signals with collective migration. Notably, E-cadherin expression, while an epithelial marker, was reduced in the knock-down cells. Functionally, the ability of cells to maintain their cell-cell contact and promote their metastatic phenotype was assessed through hanging-droplet 3D spheroid formation. 3D spheroids were smaller in size and number, which further demonstrated a reduction in their Matrigel growth and 3D collagen dissemination. This confirmed COL26A1 promotes the invasive and metastatic abilities of PTC in vitro. COL26A1 secretion in conditioned media from K1 and TPC1 was seen at higher levels compared to NThy. COL26A1 repression decreased levels of secretion in the knock-down cells to that of NThy. Treatment of NThy and knock-down cells with control cell conditioned media was performed to assess the effect of COL26A1 expression and the secreteome changes on metastatic phenotypes. Treatment of knock-down cells with control media restored the migration ability of the cells and treatment of NThy increased both migration and anoikis resistance. This in vitro validation of secreted COL26A1 in conditioned media prompted the identification of protease cleavage sites that could uncover pathologically relevant fragments serving as non-invasive biomarkers.
Qiagen Ingenuity Pathway Analysis (IPA) elucidated a link with androgen receptor (AR), coinciding with the known effects of sex hormones on collagen expression and organization, and the sex disparity in PTC. In TCGA-THCA, COL26A1 expression significantly negatively correlated with AR expression and furthermore, COL26A1 expression strongly positively correlated with genes repressed by AR activation. Physiological levels of androgen decrease COL26A1 RNA and protein expression in K1 cells expressing functional AR. This coincided with the demonstrated protective effects of AR on PTC through induction of senescence. Bioinformatic analysis also identified oncogenic lncRNA NEAT1 as a potential positive regulator of COL26A1 expression through complementary binding to miRNA targets. Thus, COL26A1 may serve as a novel therapeutic target and prognostic biomarker, identifying patients with a Stage I or II tumor at diagnosis whose tumor has a propensity to become Stage III or IV, and hence requiring more aggressive therapeutic approaches and follow-up