EGFR, HER2, and MET gene amplification and protein expression profiles in biliary tract cancer and their prognostic significance.

BACKGROUND: There are limited conventional chemotherapy options for biliary tract cancers (BTCs), a heterogenous group of lethal, rare malignancies. The receptor tyrosine kinase (RTK) is closely associated with the progression of human malignancies through the regulation of cell cycle. Overexpression or amplification of RTKs has been investigated as a potential biomarker and therapeutic target in BTC; herein, we investigate the value of such interventions. MATERIALS AND METHODS: Overexpression of RTK proteins was examined by immunohistochemistry in 193 BTC samples, of which 137 were gallbladder carcinoma, 29 were perihilar cholangiocarcinoma, and 27 were intrahepatic cholangiocarcinoma. Silver in situ hybridization of MET and HER2 was performed to assess gene amplification. RESULTS: In the entire cancer group, gallbladder, perihilar, and intrahepatic, MET amplification rates were 15.7%, 19.0%, 3.4%, and 14.8%, respectively, and of HER2 amplification rates were 22.4%, 27.2%, 17.2%, and 3.7%, respectively. MET and HER2 protein expressions were significantly correlated with their gene amplification status. RTKs were significantly associated with adverse clinicopathologic features such as advanced pT category and lymph node metastasis. Overall survival was significantly shorter in MET-amplified (P = .024) and EGFR-overexpressed cases (P = .045). Recurrence-free survival was significantly correlated with HER2-amplified (P = .038) and EGFR-overexpressed cases (P = .046) in all patient groups. Overall and recurrence-free survival were significantly shorter in patients who were double positive for HER2 and EGFR. CONCLUSION: Our data suggested that MET, HER2, and EGFR might be potential therapeutic targets and that their co-expression is a strong prognostic factor for BTCs.

Vasorelaxant and Blood Pressure-Lowering Effects of Cnidium monnieri Fruit Ethanol Extract in Sprague Dawley and Spontaneously Hypertensive Rats.

Cnidium monnieri (L.) Cusson, a member of the Apiaceae family, is rich in coumarins, such as imperatorin and osthole. Cnidium monnieri fruit (CM) has a broad range of therapeutic potential that can be used in anti-bacterial, anti-cancer, and sexual dysfunction treatments. However, its efficacy in lowering blood pressure through vasodilation remains unknown. This study aimed to assess the potential therapeutic effect of CM 50% ethanol extract (CME) on hypertension and the mechanism of its vasorelaxant effect. CME (1-30 µg/mL) showed a concentration-dependent vasorelaxation on constricted aortic rings in Sprague Dawley rats induced by phenylephrine via an endothelium-independent mechanism. The vasorelaxant effect of CME was inhibited by blockers of voltage-dependent and Ca2+-activated K+ channels. Additionally, CME inhibited the vascular contraction induced by angiotensin II and CaCl2. The main active compounds of CM, i.e., imperatorin (3-300 µM) and osthole (1-100 µM), showed a concentration-dependent vasorelaxation effect, with half-maximal effective concentration values of 9.14 ± 0.06 and 5.98 ± 0.06 µM, respectively. Orally administered CME significantly reduced the blood pressure of spontaneously hypertensive rats. Our research shows that CME is a promising treatment option for hypertension. However, further studies are required to fully elucidate its therapeutic potential.

Vasorelaxant and Hypotensive Effects of Galla chinensis in Rats.

Previous studies have revealed the medicinal and therapeutic effects of Galla chinensis. However, no studies have focused on the antihypertensive effects of G. chinensis. Therefore, we aimed to determine the vasorelaxant and hypotensive effects of G. chinensis 50% ethanolic extract (GCE). To evaluate the vascular relaxing effect of GCE, experiments were conducted using aortic segments dissected from Sprague Dawley rats. GCE showed a vasorelaxant effect via the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway, inhibiting Ca2+ channels, and activating K+ channels. The hypotensive effects of GCE were evaluated in spontaneously hypertensive rats (SHRs). The SHRs were randomly divided into a control group and orally administered GCE group (100 or 300 mg/kg). The systolic and diastolic blood pressure decreased significantly by -19.47 ± 4.58% and -31.14 ± 7.66% in the GCE 100 mg/kg group, and -21.64 ± 2.40% and -31.91 ± 5.75% in the GCE 300 mg/kg group at 4 h after administration. Considering its vasorelaxant and hypotensive effects, our results indicate that GCE may be a valuable solution for the control of hypertension. However, further studies on the long-term administration and toxicity of GCE are required.

Effect of Torilis japonica Fruit Extract for Endothelium-Independent Vasorelaxation and Blood Pressure Lowering in Rats.

Torilis japonica (TJ) fruit, is a herb that is traditionally used for erectile dysfunction (ED). Given the shared mechanisms of ED and hypertension through vascular smooth muscle, we hypothesized that TJ would be effective in vasodilation and blood pressure reduction. This study confirmed the authenticity of TJ samples via DNA barcoding and quantified the main active compound, torilin, using HPLC. TJ was extracted with distilled water (TJW) and 50% ethanol (TJE), yielding torilin contents of 0.35 ± 0.01% and 2.84 ± 0.02%, respectively. Ex vivo tests on thoracic aortic rings from Sprague-Dawley rats showed that TJE (3-300 µg/mL) induced endothelium-independent, concentration-dependent vasodilation, unlike TJW. Torilin caused concentration-dependent relaxation with an EC50 of 210 ± 1.07 µM. TJE's effects were blocked by a voltage-dependent K+ channel blocker and alleviated contractions induced by CaCl2 and angiotensin II. TJE inhibited vascular contraction induced by phenylephrine or KCl via extracellular CaCl2 and enhanced inhibition with nifedipine, indicating involvement of voltage-dependent and receptor-operated Ca2+ channels. Oral administration of TJE (1000 mg/kg) significantly reduced blood pressure in spontaneously hypertensive rats. These findings suggest TJ extract's potential for hypertension treatment through vasorelaxant mechanisms, though further research is needed to confirm its efficacy and safety.

Development of nursing handoff competency scale: a methodological study.

BACKGROUND: Nursing handoff competency is the ability of the nurse performing the handoff to select and interpret the necessary information for patient care and to convey it efficiently to the nurse accepting the handoff. Nursing handoff is an important nursing task that ensures nursing care continuity, quality and patient safety. This study aimed to develop a scale to measure nursing handoff competency and verify its validity and reliability. METHODS: This study adopted a methodological design. A research process included three phases: (1) scale development (literature review and interviews); (2) scale validation (validity and reliability); (3) standard setting. Data were collected from 496 clinical nurses currently working in hospital wards, intensive care units, and emergency rooms, and who independently perform a handoff in South Korea. RESULTS: The final scale comprises a self-reported 4-points Ilert scale with 25 items based on four factors: knowledge on handoff methods, identification of patient information, judgment and transfer of nursing situation, and "formation of supportive relationships. Construct validity, criterion-related validity, and discrimination validities were verified and the fitness of the scale revealed good results in confirmatory factor analysis. The Cronbach's α of the whole tool was.912 and the cut-off score for satisfied/unsatisfied was.72. CONCLUSIONS: The developed scale can evaluate the nurse's handoff competencies and determine whether training is necessary. The measurement results of the scale can be used to select training subjects and compose the contents of the education program.

Effects of governmental support on clinical nurse educators in South Korea: A repeated cross-sectional study.

AIM: To assess the effectiveness of the Clinical Nurse Educator Support Project and offer valuable insights for supporting nursing education. BACKGROUND: Allocating clinical nursing educators is crucial for supporting novice nurses' transition into the clinical setting and improving their performance. INTRODUCTION: In 2019, the Ministry of Health and Welfare in South Korea implemented the Clinical Nurse Educator Support Project, which involves governmental financial support for the employment of clinical nurse educators. METHODS: This study employed a repeated cross-sectional design to assess the project outcomes. Following the framework of the Kirkpatrick Evaluation Model, secondary data from annual self-program evaluation reports were analyzed to assess program satisfaction, clinical adaptation, and turnover rates of novice nurses. The "Strengthening the Reporting of Observational Studies in Epidemiology checklist" guided the reporting of the study. RESULTS: The project played a pivotal role in enhancing the quality of nursing education. Novice nurses' program satisfaction and clinical adaptation consistently remained high or exhibited an increase. The project led to a decrease in turnover rate among novice nurses, while the coronavirus 2019 pandemic resulted in increased turnover rates due to limited clinical practice opportunities for nursing students. CONCLUSION: Government support for clinical nurse educators has positively impacted the institutionalization of nursing education. The pressing need is to prioritize not only the enhancement of nursing education quality and the improvement of nurses' working conditions but also the development of healthcare policies and programs to effectively respond to unforeseen challenges and crises. IMPLICATIONS FOR NURSING POLICY: Government and healthcare institutions must collaborate to strengthen clinical education, crucial for novice nurses' clinical adaptation. Prioritizing the improvement of nursing education quality and nurses' working conditions is essential. Continuous research and evaluation of the Clinical Nurse Educator Support Project is imperative to assess its impact and make necessary adjustments.

Sakuranetin as a Potential Regulator of Blood Pressure in Spontaneously Hypertensive Rats by Promoting Vasorelaxation through Calcium Channel Blockade.

Natural compounds, known for diverse pharmacological properties, have attracted attention as potential sources for hypertension treatment. Previous studies have revealed the hypotensive effect and vascular relaxation of prunetin, a natural compound derived from Prunus yedoensis. However, the potential blood pressure-lowering and vasorelaxant effects of sakuranetin, another representative compound found in plants belonging to the genus Prunus, have remained unexplored. We aimed to fill this gap by investigating the hypotensive and vasorelaxant effects of sakuranetin in rats. Results indicated that sakuranetin, particularly in the sakuranetin 20 mg/kg group, led to significant reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) by -14.53 ± 5.64% and -19.83 ± 6.56% at 4 h after administration. In the sakuranetin 50 mg/kg group, the SBP and DBP decreased by -13.27 ± 6.86% and -16.62 ± 10.01% at 2 h and by -21.61 ± 4.49% and -30.45 ± 5.21% at 4 h after administration. In addition, we identified the vasorelaxant effects of sakuranetin, attributing its mechanisms to the inhibition of calcium influx and the modulation of angiotensin II. Considering its hypotensive and vasorelaxant effects, sakuranetin could potentially serve as an antihypertensive agent. However, further research is required to evaluate the safety and long-term efficacy.

Blood-Pressure-Lowering and Endothelium-Dependent Vasorelaxant Effects of Nutgall Tree in Rats.

Hypertension is the crucial modifiable risk factor for cardiovascular diseases, and efforts to identify functional foods that are effective for hypertension control are increasing. The nutgall tree (NT, Rhus chinensis Mill.) is used in traditional medicine and food because of its medicinal value. However, the role of NT in hypertension has not been investigated. Therefore, the hypotensive effect of NT leaf ethanol extract (NTE) was investigated in spontaneously hypertensive rats (SHRs). SHRs were allocated to three groups (control, 300, or 1000 mg/kg NTE), and blood pressure was measured before and after oral administration. Systolic and diastolic blood pressure significantly decreased in the NTE 1000 mg/kg group and was the lowest at 2 h after administration (-26.4 ± 10.3, -33.5 ± 9.8%, respectively). Daily NTE administration for five days also resulted in a similar effect. Further, the vasorelaxant effects and related mechanisms were investigated in the aortas of Sprague Dawley rats. NTE showed the dose-dependent blood-vessel-relaxing effect, and its mechanism involves the NO-sGC-cGMP pathway, activation of K+ channels, and reduction in the vasoconstrictive action of angiotensin II. Therefore, our study provides basic data indicating the potential use of NTE as a functional food for high blood pressure.

Tumoural Pellino-1 expression and Pellino-1-expressive cytotoxic T-cells are associated with poor prognosis in diffuse large B-cell lymphoma.

Pellino-1 plays a role in regulating inflammation and immune responses, and its effects on tumours are complex, with different outcomes reported in various studies. Additionally, the role of Pellino-1 in diffuse large B-cell lymphoma (DLBCL) has not been thoroughly investigated. We aimed to examine the expression of Pellino-1 in tumour cells and tumour-infiltrating lymphocytes (TILs) separately and identify the clinicopathological significance of Pellino-1 expression in DLBCL. We evaluated Pellino-1 expression in 104 patients with DLBCL. The density of specific cell types was quantitatively analysed using digital image analysis after a multiplex immunofluorescence staining with Pellino-1, CD20, CD8, FOXP3, and PD-1. Pellino-1 expression was mostly observed in CD20+ tumour cells and CD8+ TILs. The high CD8+/Pellino-1+ group was significantly associated with the non-GCB subtype and higher numbers of Foxp3+ T-cells. Patients with high CD20+/Pellino-1+ and high CD8+/Pellino-1+ cell densities had significantly shorter event-free survival (EFS) rates. The multivariate Cox-regression analysis showed that CD20+/Pellino-1+ cell density and CD8+/Pellino-1+ cell density were independent poor prognostic factors for EFS. Furthermore, patients with low densities of both CD20+/Pellino-1+ and CD8+/Pellino-1+ cells demonstrated a prognosis superior to that of patients with high Pellino-1+ cell densities, either alone or in combination. Additionally, the multivariate analysis demonstrated that the combination of CD20+/Pellino-1+ and CD8+/Pellino-1+ cell densities was an independent prognostic factor for EFS and overall survival. Pellino-1 expression was observed in both tumour cells and TILs, particularly in cytotoxic T-cells, and was correlated with poor outcomes in DLBCL. Thus, Pellino-1 might have an oncogenic effect on DLBCL and might be a potential target for improving cytotoxic T-cell activity.

Genomic and single-cell characterization of patient-derived tumor organoid models of head and neck squamous cell carcinoma.

Head and Neck Squamous Cell Carcinoma (HNSCC) remains a significant health burden due to tumor heterogeneity and treatment resistance, emphasizing the need for improved biological understanding and tailored therapies. This study enrolled 31 HNSCC patients for the establishment of patient-derived tumor organoids (PDOs), which faithfully maintained genomic features and histopathological traits of primary tumors. Long-term culture preserved key characteristics, affirming PDOs as robust representative models. PDOs demonstrated predictive capability for cisplatin treatment responses, correlating ex vivo drug sensitivity with patient outcomes. Bulk and single-cell RNA sequencing unveiled molecular subtypes and intratumor heterogeneity (ITH) in PDOs, paralleling patient tumors. Notably, a hybrid epithelial-mesenchymal transition (hEMT)-like ITH program is associated with cisplatin resistance and poor patient survival. Functional analyses identified amphiregulin (AREG) as a potential regulator of the hybrid epithelial/mesenchymal state. Moreover, AREG contributes to cisplatin resistance via EGFR pathway activation, corroborated by clinical samples. In summary, HNSCC PDOs serve as reliable and versatile models, offer predictive insights into ITH programs and treatment responses, and uncover potential therapeutic targets for personalized medicine.

Prunus yedoensis Bark Downregulates the Expression of Cell Adhesion Molecules in Human Endothelial Cell Lines and Relaxes Blood Vessels in Rat Aortic Rings.

The incidence of cardiovascular diseases, such as high blood pressure, is increasing worldwide, owing to population aging and irregular lifestyle habits. Previous studies have reported the vasorelaxant effects of Prunus yedoensis bark methanol extract. However, various solvent extracts of P. yedoensis bark and their vascular relaxation mechanisms have not been sufficiently studied. We prepared extracts of P. yedoensis bark using various solvents (water, 30% ethanol, and 70% ethanol). P. yedoensis bark 30% ethanol extract (PYB-30E) decreased the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin in human umbilical vein endothelial cells (HUVECs) activated with 200 ng/mL TNF-α. Additionally, PYB-30E showed vasodilatory effects on isolated rat aortic rings. This was confirmed to be the result of the activation of the NO/cGMP pathway, regulation of non-selective calcium-activated K+ channels, and calcium channel blockade. Additionally, PYB-30E significantly reduced systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR). Taken together, our results indicated that PYB-30E is a candidate functional material with preventive and therapeutic effects against hypertension.

A phase 2 study of spartalizumab (PDR001) among patients with recurrent or metastatic esophageal squamous cell carcinoma (KCSG HN18-17, K-MASTER project 12).

Spartalizumab (PDR001) is a humanized IgG4 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We conducted a single-arm, phase 2 trial to investigate the efficacy and safety of spartalizumab in patients with refractory esophageal squamous cell carcinoma (ESCC). Patients with histologically confirmed ESCC who experienced disease progression after platinum-based chemotherapy received 300 mg of intravenous spartalizumab every three weeks until disease progression or occurrence of unacceptable toxicity. The primary endpoint was centrally assessed objective response according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events were closely monitored throughout the study. From March 2020 through April 2021, 44 patients with ESCC were enrolled. Of the 44 patients, the objective response rate was 20.5% (95% confidence interval: 8.5-32.4). With a median follow-up of 10.9 months, median progression-free survival and overall survival were 3.2 months and 11.2 months, respectively. In addition, the median duration of response was 24.7 months. The most common grade 3 or 4 adverse event was grade 3 dysphagia (eight [18%] patients). Biomarker analyses explored programmed cell death ligand 1 and CD20 as potential predictive markers for PD-1 blockade. Spartalizumab showed promising activity with a manageable safety profile, indicating its potential as a new treatment option for patients with refractory ESCC. Trial registration: The trial was registered at ClinicalTrials.gov under the identifier NCT03785496.

Durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: a phase II trial.

We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic and/or recurrent soft tissue sarcoma (STS). In this single-arm phase 2 trial (NCT03798106), treatment consisted of pazopanib 800 mg orally once a day and durvalumab 1500 mg once every 3 weeks. Primary outcome was overall response rate (ORR) and secondary outcomes included progression-free survival (PFS), overall survival, disease control rate, immune-related response criteria, and safety. The ORR was 30.4% and the trial met the pre-specified endpoint. The median PFS was 7.7 months (95% confidence interval: 5.7-10.4). The common treatment-related adverse events of grades 3-4 included neutropenia (9 [19.1%]), elevated aspartate aminotransferase (7 [14.9%]), alanine aminotransferase (5 [10.6%]), and thrombocytopenia (4 [8.5%]). In a prespecified transcriptomic analysis, the B lineage signature was a significant key determinant of overall response (P = 0.014). In situ analysis also showed that tumours with high CD20+ B cell infiltration and vessel density had a longer PFS (P = 6.5 × 10-4) than those with low B cell infiltration and vessel density, as well as better response (50% vs 12%, P = 0.019). CD20+ B cell infiltration was identified as the only independent predictor of PFS via multivariate analysis. Durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile.

Histopathologic image-based deep learning classifier for predicting platinum-based treatment responses in high-grade serous ovarian cancer.

Platinum-based chemotherapy is the cornerstone treatment for female high-grade serous ovarian carcinoma (HGSOC), but choosing an appropriate treatment for patients hinges on their responsiveness to it. Currently, no available biomarkers can promptly predict responses to platinum-based treatment. Therefore, we developed the Pathologic Risk Classifier for HGSOC (PathoRiCH), a histopathologic image-based classifier. PathoRiCH was trained on an in-house cohort (n = 394) and validated on two independent external cohorts (n = 284 and n = 136). The PathoRiCH-predicted favorable and poor response groups show significantly different platinum-free intervals in all three cohorts. Combining PathoRiCH with molecular biomarkers provides an even more powerful tool for the risk stratification of patients. The decisions of PathoRiCH are explained through visualization and a transcriptomic analysis, which bolster the reliability of our model's decisions. PathoRiCH exhibits better predictive performance than current molecular biomarkers. PathoRiCH will provide a solid foundation for developing an innovative tool to transform the current diagnostic pipeline for HGSOC.

Hypotensive and Endothelium-Dependent Vasorelaxant Effects of Grayblue Spicebush Ethanol Extract in Rats.

Hypertension is one of the most common chronic diseases, and its prevalence is increasing worldwide. Lindera glauca (Siebold & Zucc.) Blume, known as grayblue spicebush (GS), has been used as food and for medicinal purposes; however, studies about its hypotensive or vasorelaxant effects are lacking. Therefore, the hypotensive effect of an ethanolic extract of the GS branch (GSE) was investigated in 15-week-old spontaneously hypertensive rats (SHRs) using the tail cuff method. The GSE administration group (1000 mg/kg SHR body weight) showed a decrease in their systolic and diastolic blood pressure measured 4 h after its administration. In addition, we investigated its vasorelaxant effect using the thoracic aorta dissected from Sprague-Dawley rats. The GSE (0.5, 1, 2, 5, 10, and 20 µg/mL) showed an endothelium-dependent vasorelaxant effect, and its mechanisms were found to be relevant to the inward rectifier, voltage-dependent, and non-selective K+ channels. Moreover, the GSE (20 µg/mL) showed an inhibitory effect on aortic rings constricted with angiotensin II. Considering its hypotensive and vasorelaxant effects, GSE has potential as a functional food to help treat and prevent high blood pressure. However, further studies on the identification of the active components of GSE and safety evaluations of its use are needed.

Creeping fat exhibits distinct Inflammation-specific adipogenic preadipocytes in Crohn's disease.

Creeping fat (CrF) is an extraintestinal manifestation observed in patients with Crohn's disease (CD). It is characterized by the accumulation of mesenteric adipose tissue (MAT) that wraps around the intestinal wall. Although the role of CrF in CD is still debated, multiple studies have highlighted a correlation between CrF and inflammation, as well as fibrostenosais of the intestine, which contributes to the worsening of CD symptoms. However, the mechanism underlying the potential role of CrF in the development of Crohn's fibrosis remains an enigma. This study aimed to analyze CrF comprehensively using single-cell RNA sequencing analysis. The data was compared with transcriptomic data from adipose tissue in other disease conditions, such as ulcerative colitis, lymphedema, and obesity. Our analysis classified two lineages of preadipocyte (PAC) clusters responsible for adipogenesis and fibrosis in CrF. Committed PACs in CrF showed increased cytokine expression in response to bacterial stimuli, potentially worsening inflammation in patients with CD. We also observed an increase in fibrotic activity in PAC clusters in CrF. Co-analyzing the data from patients with lymphedema, we found that pro-fibrotic PACs featured upregulated pentraxin-3 expression, suggesting a potential target for the treatment of fibrosis in CrF. Furthermore, PACs in CrF exhibited a distinct increase in cell-to-cell communication via cytokines related to inflammation and fibrosis, such as CCL, LIGHT, PDGF, MIF, and SEMA3. Interestingly, these interactions also increased in PACs of the lymphedema, whereas the increased MIF signal of PACs was found to be a distinct characteristic of CrF. In immune cell clusters in CrF, we observed high immune activity of pro-inflammatory macrophages, antigen-presenting macrophages, B cells, and IgG+ plasma cells. Finally, we have demonstrated elevated IgG+ plasma cell infiltration and increased pentraxin-3 protein levels in the fibrotic regions of CrF in CD patients when compared to MAT from both UC patients and healthy individuals. These findings provide new insights into the transcriptomic features related to the inflammation of cells in CrF and suggest potential targets for attenuating fibrosis in CD.