Hydroxy-Safflower Yellow A Mitigates Vascular Remodeling in Rat Pulmonary Arterial Hypertension.

Purpose: The underlying causes of pulmonary arterial hypertension (PAH) often remain obscure. Addressing PAH with effective treatments presents a formidable challenge. Studies have shown that Hydroxysafflor yellow A (HSYA) has a potential role in PAH, While the mechanism underlies its protective role is still unclear. The study was conducted to investigate the potential mechanisms of the protective effects of HSYA. Methods: Using databases such as PharmMapper and GeneCards, we identified active components of HSYA and associated PAH targets, pinpointed intersecting genes, and constructed a protein-protein interaction (PPI) network. Core targets were singled out using Cytoscape for the development of a model illustrating drug-component-target-disease interactions. Intersection targets underwent analysis for Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Selected components were then modeled for target interaction using Autodock and Pymol. In vivo validation in a monocrotaline-induced PAH (MCT-PAH) animal model was utilized to substantiate the predictions made by network pharmacology. Results: We associated HSYA with 113 targets, and PAH with 1737 targets, identifying 34 mutual targets for treatment by HSYA. HSYA predominantly affects 9 core targets. Molecular docking unveiled hydrogen bond interactions between HSYA and several PAH-related proteins such as ANXA5, EGFR, SRC, PPARG, PGR, and ESR1. Conclusion: Utilizing network pharmacology and molecular docking approaches, we investigated potential targets and relevant human disease pathways implicating HSYA in PAH therapy, such as the chemical carcinogenesis receptor activation pathway and the cancer pathway. Our findings were corroborated by the efficacious use of HSYA in an MCT-induced rat PAH model, confirming its therapeutic potential.

Resident operative time as an independent predictor of early post-operative cataract surgery outcomes and supervising attending surgeon impact: a retrospective case series.

BACKGROUND: The authors sought to determine if resident operative time in cataract extraction and intraocular lens insertion (CE/IOL) affects early visual outcomes and post-operative recovery. They further sought to investigate if attending surgeons can reduce resident operative time. METHODS: This retrospective, chart-review, case series at single Veterans Affairs Hospital (VA Tennessee Valley Healthcare System) studied resident cataract surgeries between March 1, 2018 and March 31, 2020. Following power analysis, 420 eyes of 400 patients from all resident cataract surgeries were included. Eyes with attending as primary surgeon, laser-assisted cataract surgery, or concurrent secondary procedures were excluded. Linear mixed effect models were used to study the association between operative time and visual outcomes while adjusting for covariates including cumulative dissipated energy, preoperative factors, and intraoperative complications. RESULTS: Longer operative time was statistically associated with worse post-operative-day 1 (POD1) pinhole visual acuity (PH-VA) adjusting for cumulative dissipated energy and other operative factors (p = 0.049). Although resident physicians were the primary surgeons, the operative times were different between the ten supervising attending surgeons in the study (p < 0.001). CONCLUSION: The results suggest that increased resident operative time is a significant, independent risk factor for decreased POD1 PH-VA. Increased resident operative time is not associated with worsened long term visual outcomes. Attending surgeons may be able to reduce resident operative time, which is associated with improved early visual outcomes.

A Pilot Nonrandomized Controlled Trial Examining the Use of Artificial Tears on the Radioactivity of Tears After Radioactive Iodine Treatment for Thyroid Cancer.

Background: Nasolacrimal duct obstruction (NLDO) is an adverse effect of high dose radioactive iodine (RAI) therapy for thyroid carcinoma. There are currently no established preventive measures. This study assesses whether preservative free artificial tears (PFATs) can decrease the 131I sodium iodide (131I) activity in the tears of patients following RAI therapy for thyroid carcinoma, and potentially serve as a preventive measure for RAI-associated NLDO. Methods: This non-randomized prospective pilot clinical trial recruited contact-lens wearing patients undergoing RAI therapy for thyroid cancer to self-administer PFATs into the right eye for four days starting on the day of RAI ingestion. Left eyes were the controls. While wearing contacts, patients self-administered PFATs per the following-Day 1: every 15 minutes for 2 hours, then every 30 minutes until bedtime, day 2: every hour for at least 12 hours, day 3: four times a day, and day 4: two times a day. Contact lenses were changed daily, and all lenses were collected one week later. Levels of 131I activity were measured by a well counter, decay-corrected, and converted to units of becquerel. Statistical analyses were performed to compare the 131I activities of the experimental and control eyes. Results: Sixteen eyes of eight patients treated with an average of 145.7 mCi (range 108-159) of 131I for papillary thyroid cancer were included. On day 1, artificial tears decreased the geometric mean 131I activity by 26% in the experimental eyes (p = 0.008). Artificial tears also decreased the geometric mean area under the curve over four days by 23% (p = 0.002). Conclusions: 131I is present in the tears following RAI therapy for thyroid carcinoma. Frequent PFATs starting on the day of RAI ingestion may decrease the level of 131I in the tears. This finding could have implications for lowering the risk of NLDO. Future multi-center clinical trials are needed to determine whether the use of artificial tears after RAI therapy may decrease the risk of NLDO. Clinical Trial Registration: NCT04327999.

Applicant Perceptions of In-Person versus Virtual Interview Format for Surgical Retina Fellowship.

Purpose This article compares applicants' perceptions of and experiences with virtual and in-person interviews for surgical retina fellowship. Methods A survey was distributed via email to all applicants of three vitreoretinal surgery fellowship programs for the 2021 to 2022 and 2022 to 2023 application cycles. Main Outcome Measures Participants were surveyed regarding cost; burden of scheduling; number of applications and interviews completed; ability to gain a true feel of the program, location, and preceptor; and number of work and surgical days missed. Results Of 151 applicants contacted, 36 completed the survey (23.8% response rate). Of the respondents, 25.0% attended only virtual interviews, 19.4% attended mostly virtual interviews, 30.6% attended mostly in-person interviews, and 25.0% attended half virtual and half in-person interviews. Average expenditure was significantly lower for applicants with mostly and completely virtual interviews compared with applicants with mostly in-person and half virtual, half in-person ( p < 0.001). Applicants with mostly virtual interviews reported a lower ability to gain a true perception of the program and the program location ( p = 0.003 and p < 0.001, respectively). There was no difference in burden of scheduling, number of interviews completed, or number of work and surgical days missed. When applicants were asked what type of interview format they would prefer if they could repeat the cycle, those who interviewed mostly in-person largely chose in-person as their preference (72.7%), while participants who interviewed mostly or completely virtually were evenly split between in-person, virtual, and hybrid ( p = 0.136). Conclusion As fellowship programs and institutions decide whether they will return to in-person interviews or maintain a virtual interview format in the long term, they must weigh the lower cost of virtual interviews with the improved ability to gain a more accurate perception of the program and location allowed by in-person interviews, as well as potentially greater satisfaction with the in-person format.

Trends in Imaging Utilization Among United States Medicare Beneficiaries and the Impact of the COVID-19 Pandemic.

This study characterizes trends in ophthalmic imaging volume and utilization in the United States among and assesses the potential impact of the COVID-19 pandemic using data from the Centers for Medicare and Medicaid Services. Utilization of macular optical coherence tomography (OCT), optic nerve OCT, and fundus photography steadily increased from 2013 to 2020 and was not impacted by the COVID-19 pandemic. At the same time, there was minimal adoption of anterior segment OCT and a decline in the utilization of dye-based angiography. Utilization patterns may be impacted by the advent of new technologies, role of the clinician, and alignment with treatment paradigms. [Ophthalmic Surg Lasers Imaging Retina 2023;54:661-665.].

Diagnostic performance of RASSF1A and SHOX2 methylation combined with EGFR mutations for differentiation between small pulmonary nodules.

BACKGROUND AND AIM: Aberrant methylation of Ras association domain family 1, isoform A (RASSF1A), and short-stature homeobox gene 2 (SHOX2) promoters has been validated as a pair of valuable biomarkers for diagnosing early lung adenocarcinomas (LUADs). Epidermal growth factor receptor (EGFR) is the key driver mutation in lung carcinogenesis. This study aimed to investigate the aberrant promoter methylation of RASSF1A and SHOX2, and the genetic mutation of EGFR in 258 specimens of early LUADs. METHODS: We retrospectively selected 258 paraffin-embedded samples of pulmonary nodules measuring 2 cm or less in diameter and evaluated the diagnostic performance of individual biomarker assays and multiple panels between noninvasive (group 1) and invasive lesions (groups 2A and 2B). Then, we investigated the interaction between genetic and epigenetic alterations. RESULTS: The degree of RASSF1A and SHOX2 promoter methylation and EGFR mutation was significantly higher in invasive lesions than in noninvasive lesions. The three biomarkers distinguished between noninvasive and invasive lesions with reliable sensitivity and specificity: 60.9% sensitivity [95% confidence interval (CI) 52.41-68.78] and 80.0% specificity (95% CI 72.14-86.07). The novel panel biomarkers could further discriminate among three invasive pathological subtypes (area under the curve value > 0.6). The distribution of RASSF1A methylation and EGFR mutation was considerably exclusive in early LUAD (P = 0.002). CONCLUSION: DNA methylation of RASSF1A and SHOX2 is a pair of promising biomarkers, which may be used in combination with other driver alterations, such as EGFR mutation, to support the differential diagnosis of LUADs, especially for stage I.

Metabolomics profiling of AKT/c-Met-induced hepatocellular carcinogenesis and the inhibitory effect of Cucurbitacin B in mice.

Hepatocellular carcinoma (HCC), the most common kind of liver cancer, accounts for the majority of liver cancer diagnoses and fatalities. Clinical aggressiveness, resistance to traditional therapy, and a high mortality rate are all features of this disease. Our previous studies have shown that co-activation of AKT and c-Met induces HCC development, which is the malignant biological feature of human HCC. Cucurbitacin B (CuB), a naturally occurring tetracyclic triterpenoid compound with potential antitumor activity. However, the metabolic mechanism of AKT/c-Met-induced Hepatocellular Carcinogenesis and CuB in HCC remains unclear. In this study, we established an HCC mouse model by hydrodynamically transfecting active AKT and c-Met proto-oncogenes. Based on the results of hematoxylin-eosin (H&E), oil red O (ORO) staining, and immunohistochemistry (IHC), HCC progression was divided into two stages: the early stage of HCC (3 weeks after AKT/c-Met injection) and the formative stage of HCC (6 weeks after AKT/c-Met injection), and the therapeutic effect of CuB was evaluated. Through UPLC-Q-TOF-MS/MS metabolomics, a total of 26 distinct metabolites were found in the early stage of HCC for serum samples, while in the formative stage of HCC, 36 distinct metabolites were found in serum samples, and 13 different metabolites were detected in liver samples. 33 metabolites in serum samples and 11 in live samples were affected by CuB administration. Additionally, metabolic pathways and western blotting analysis revealed that CuB influences lipid metabolism, amino acid metabolism, and glucose metabolism by altering the AKT/mTORC1 signaling pathway, hence decreasing tumor progression. This study provides a metabolic basis for the early diagnosis, therapy, and prognosis of HCC and the clinical application of CuB in HCC.

Regulatory Mechanism of circEIF4G2 Targeting miR-26a in Acute Myocardial Infarction.

Background: Acute myocardial infarction (AMI) involves a series of complex cellular and molecular events, including circular RNAs (circRNAs), microRNAs (miRNAs) and other noncoding RNAs. Objective: In this study, the regulation mechanism of circEIF4G2 acting on miR-26a on HUVECs (Human Umbilical Vein Endothelial Cells) proliferation, cell cycle and angiogenesis ability was mainly explored in the vascular endothelial growth factor induced (VEGF-induced) angiogenesis model. Methods: VEGF induced HUVECs angiogenesis model was constructed, and the expression of circEIF4G2 and miR-26a in VEGF model was detected by qRT-PCR. When circEIF4G2 and miR-26a were knocked down or overexpressed in HUVECs, qRT-PCR was used to detect the expression of circEIF4G2 and miR-26a, CCK-8 was used to detect cell proliferation, flow cytometry was used to detect the cell cycle transition of HUVECs, and cell formation experiment was used to detect the ability of angiogenesis. MiRanda database and Targetscan predicted the binding site of circEIF4G2 and miR-26a, lucifase reporting assay and RNA pull down assay verified the interaction between circEIF4G2 and miR-26a. Results: After HUVECs were treated with VEGF, circEIF4G2 was significantly upregulated. After circEIF4G2 was knocked down, the proliferation and angiogenesis of HUVECs cells were decreased, and the process of cell cycle G0/G1 phase was blocked. The overexpression of miR-26a reduced the proliferation and angiogenesis of HUVECs cells and blocked the cell cycle progression of G0/G1 phase. Double lucifase reporter gene assay verified that circEIF4G2 could directly interact with miR-26a through the binding site, and RNA Pull down assay further verified the interaction between circEIF4G2 and miR-26a. When circEIF4G2 and miR-26a were knocked down simultaneously in HUVECs, it was found that knocking down miR-26a could reverse the inhibition of circEIF4G2 on cell proliferation, cycle and angiogenesis. Conclusion: In the VEGF model, circEIF4G2 was highly expressed and miR-26a was low expressed. MiR-26a regulates HUVECs proliferation, cycle and angiogenesis by targeting circEIF4G2.

Association of intraoperative hypotension with acute kidney injury after liver resection surgery: an observational cohort study.

BACKGROUND: Acute kidney injury (AKI) is a major complication following liver resection. The aim of this study was to determine the risk factors for AKI after hepatic resection and whether intraoperative hypotension (IOH) was related to AKI. METHODS: Adult patients (≥ 18 years) undergoing liver resection between November 2017 and November 2019 at our hospital were retrospectively reviewed. AKI was defined as ≥50% increase in serum creatinine from baseline value within 48 h after surgery. IOH was defined as the lowest absolute mean arterial pressure (MAP) < 65 mmHg for more than 10 cumulative minutes during the surgery. Patients were divided into AKI group and non-AKI group, and were stratified by age ≥ 65 years. RESULTS: 796 patients who met our inclusion and exclusion criteria were analyzed. After multivariable regression analysis, the IOH (OR, 2.565; P = 0.009) and age ≥ 65 years (OR, 2.463; P = 0.008) were risk factors for AKI. The IOH (OR, 3.547; P = 0.012) and received red blood cell (OR, 3.032; P = 0.036) were risk factors of AKI in age ≥ 65 years patients. CONCLUSIONS: The IOH and age ≥ 65 years were risk factors for postoperative AKI, and IOH was associated with AKI in age ≥ 65 years patients following liver resection.

miR-141 regulation of EIF4E expression affects docetaxel chemoresistance of non-small cell lung cancer.

The present study investigated the role of miR-141 regulation of eukaryotic initiation factor-4E (EIF4E) expression in docetaxel chemoresistance of human non-small cell lung cancer (NSCLC). The expression of miR-141 in docetaxel chemoresistant patients with NSCLCs was markedly higher than those of non-docetaxel chemoresistant patients with NSCLCs. The expression of EIF4E in docetaxel chemoresistant patients with NSCLCs was markedly lower than those of non-docetaxel chemoresistant patients with NSCLCs. Downregulation of miR-141 suppressed cell proliferation, induced cell death and increased caspase-3 activity in H1299 or H2009/docetaxel cells. Downregulation of miR-141 also increased the protein expression of EIF4E, VEGF, c-Myc and Bax in H1299 or H2009/docetaxel cells. Conversely, up-regulation of miR-141 promoted cell proliferation, inhibited cell death and caspase-3 activity in H1299 or H2009/docetaxel cell. Upregulation of miR-141 suppressed EIF4E, VEGF, c-Myc protein expression and inhibited Bax in H1299 or H2009/docetaxel cells. Thus, the present study is the first to show the induction of miR-141/EIF4E expression in an acquired model of docetaxel chemoresistant patients with NSCLCs. This serves as a mechanism of acquired docetaxel chemoresistant patients with NSCLCs, possibly through direct interactions with VEGF, c-Myc, and Bax, therefore presenting a potential therapeutic target for the treatment of docetaxel chemoresistant patients with NSCLCs.

Survivin expression and serum levels in pancreatic cancer.

BACKGROUND: Survivin, an inhibitor of apoptosis, is overexpressed in pancreatic ductal adenocarcinoma (PDAC). Its expression is known to be associated with poor clinical outcome. However, to our knowledge, there has been no study to characterize its usefulness as a serum marker for human pancreatic cancer. Furthermore, the relation between survivin expression and the serum level of survivin has not been widely studied in PDAC. We performed this study to investigate the expression and serum level of survivin in PDAC and its clinical significance as a prognostic factor. METHODS: We performed immunohistochemical staining for survivin in formalin-fixed, paraffin-embedded blocks from 80 PDAC tissues. The serum level of survivin from the patients (n = 80) and age-matched healthy volunteers (n = 80) were analyzed by enzyme-linked immunosorbent assays (ELISAs) prior to surgical resection. Levels of expression were correlated with clinicopathological parameters. RESULTS: Serum survivin concentrations were significantly elevated in patients with PDAC when compared with healthy sera (P < 0.001). High serum survivin levels were significantly associated with perineural invasion, venous invasion, lymph node status (N stage), cell differentiation, and recurrence but not with the tumor size, age, gender of the patients, or tumor location. The median overall survival time of the group with normal serum survivin levels was longer than that of the group with elevated serum survivin. The independent factors associated with overall survival were advanced pancreatic cancer and elevated serum survivin level. Of the 80 cases of PDAC, 65 (81.25 %) were positive for survivin expression. There were significant associations between survivin expression and perineural invasion, venous invasion, and lymph node status. A significant difference in overall survival was associated with survivin expression. CONCLUSIONS: Patients with elevated serum survivin level and high survivin expression at diagnosis demonstrated a poor outcome. Detection of serum survivin or tissue survivin expression may predict the prognosis of patients with PDAC.