bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pancreatic cancer derived 3D organoids as a clinical tool to evaluate the treatment response
Authors: Shukla Hem D , Dukic Tijana , Roy Sanjit , Bhandary Binny , Gerry Andrew , Poirier Yannick , Lamichhane Narottam , Molitoris Jason , Carrier France , Banerjee Aditi , Regine William F. , Polf Jerimy C. 
Published: January 2023

Background and purposePancreatic cancer (PC) is the fourth leading cause of cancer death in both men and women. The standard of care for patients with locally advanced PC of chemotherapy, stereotactic radiotherapy (RT), or chemo-radiation-therapy has shown highly variable and limited success rates. However, three-dimensional (3D) Pancreatic tumor organoids (PTOs) have shown promise to study tumor response to drugs, and emerging treatments under in vitro conditions. We investigated the potential for using 3D organoids to evaluate the precise radiation and drug dose responses of in vivo PC tumors.MethodsPTOs were created from mouse pancreatic tumor tissues, and their microenvironment was compared to that of in vivo tumors using immunohistochemical and immunofluorescence staining. The organoids and in vivo PC tumors were treated with fractionated X-ray RT, 3-bromopyruvate (3BP) anti-tumor drug, and combination of 3BP + fractionated RT.ResultsPancreatic tumor organoids (PTOs) exhibited a similar fibrotic microenvironment and molecular response (as seen by apoptosis biomarker expression) as in vivo tumors. Untreated tumor organoids and in vivo tumor both exhibited proliferative growth of 6 folds the original size after 10 days, whereas no growth was seen for organoids and in vivo tumors treated with 8 (Gray) Gy of fractionated RT. Tumor organoids showed reduced growth rates of 3.2x and 1.8x when treated with 4 and 6 Gy fractionated RT, respectively. Interestingly, combination of 100 µM of 3BP + 4 Gy of RT showed pronounced growth inhibition as compared to 3-BP alone or 4 Gy of radiation alone. Further, positive identification of SOX2, SOX10 and TGFβ indicated presence of cancer stem cells in tumor organoids which might have some role in resistance to therapies in pancreatic cancer.ConclusionsPTOs produced a similar microenvironment and exhibited similar growth characteristics as in vivo tumors following treatment, indicating their potential for predicting in vivo tumor sensitivity and response to RT and combined chemo-RT treatments.
Adherence and treatment patterns of disease-specific drugs among patients with pulmonary arterial hypertension: A nationwide, new-user cohort study
Authors: Tsai Cheng-Yu , Shen Chuan-Wei , Lai Hsuan-Lin , Chen Chung-Yu 
Published: January 2023

Background: Pulmonary arterial hypertension (PAH) is an incurable pulmonary disease that might result in right heart failure and death. Treatment guidelines recommend upfront or sequential combination therapy for patients with PAH. Recently, several PAH-targeted medications have been approved in Taiwan. This study aimed to investigate treatment patterns and medication adherence in real-world settings.Method: This was a new-user design study on patients treated with PAH-specific medication between 1 January 2014, and 31 December 2019. Data were extracted from the National Health Insurance Research Database. Medication adherence was evaluated by the proportion of days covered (PDC). Adherence was defined as PDC ≥ .8. Statistical analyses were performed to compare the study outcomes. Logistic regression analysis was performed to identify the association between baseline characteristics and adherence. P &lt; .05 indicated statistical significance.Results: A total of 1,900 patients with PAH were identified, and 75.3% of them were females. The mean (standard deviation (SD)) age was 57.2 (17.5) years. Only 23 (1.2%) patients began the initial combination therapy. A total of 148 (7.8%) patients switched their initial treatment to another treatment, and 159 (8.4%) patients had sequential combination therapy. The most common combination therapy was endothelin receptor antagonist (ERA) plus phosphodiesterase-5 inhibitor (PDE5i), mostly macitentan plus sildenafil, for initial or sequential combination. The mean (SD) PDC was .71 (.33), and 1,117 (58.8%) patients were adherent. A significant difference in mean PDC was observed between initial ERA users and PDE5i users (p &lt; .0001). No factor was significantly associated with medication adherence.Conclusion: Patients with PAH mostly initiated sildenafil as monotherapy, and macitentan was added as a sequential combination therapy. The initial ERA and combination groups showed higher medication adherence. Further investigations are needed to identify other factors associated with adherence.
Factors associated with the uptake of biosimilars for breast cancer treatment from the perspectives of physicians and patients-Evidence from China
Authors: Wu Qiyou , Lian Zhiwei , Wang Xin , Cheng Hanchao , Sun Jing , Yu Hui , Zhang Gong , Wu Fan , Liu Jian , Chen Chuanben 
Published: January 2023

Objective: To investigate the factors associated with the treatment of breast cancer with biosimilars from the perspectives of physicians and patients, and to generate evidence for promoting the uptake of biosimilars.Methods: This study targeted trastuzumab and its indicated human epidermal growth factor receptor 2 (HER2) positive breast cancer and included female HER2 positive breast cancer patients under treatment of trastuzumab at a provincial oncology medical center in southern China from 1 January 2021, to 31 December 2021. The study extracted patients’ demographic, socioeconomic and clinical information and the basic information of their attending physicians from the hospital information system. We performed a bivariate multiple logistic regression analysis of predictive factors of the use of trastuzumab biosimilar.Results: A total of 446 patients (aged ranging between 26 and 74, 51.4 ± 9.06) were included in the analysis, and 19.1% chose biosimilar trastuzumab. Older patients, patients enrolled in the urban and rural resident health insurance program compared with those enrolled in the urban employee health insurance program, patients who initiated treatment after January 2021 when biosimilar entered clinical use compared with those who initiated treatment before, patients with female attending physicians, younger attending physicians and with chief attending physicians compared with deputy chief attending physicians were more likely to adopt biosimilar trastuzumab for treatment (p &lt; 05). Controlling the other factors unchanged, when the patient’s attending physician was deputy chief physician, increasing 1 year age of the patient was associated with an increased probability of adopting biosimilar by .8% (dy/dx = .008, 95%CI: .002–.01, p = .01). When the patient was aged between 26 and 60, the probability of adopting biosimilar for the patient whose attending physician was a chief physician was higher than for those whose attending physician was a deputy chief physician, and the gap was the largest when the patient was at the age of 45 (dy/dx = .20, 95%CI: .13–.27, p &lt; .01).Conclusion: The uptake rate of biosimilars is still low at its initial development stage in China. Educational policies and physicians making recommendations to the indicated patients at the initiation stage of treatment are helpful to avoid reduced willingness to switch to biosimilars due to non-clinical reasons. Patients with lower ability-to-pay will have better accessibility to biologic regimens through the uptake of biosimilars. Official guidelines and professional training are critical to enhancing physicians’ willingness and confidence in adopting biosimilars.
Fast cycling of intermittent hypoxia in a physiomimetic 3D environment: A novel tool for the study of the parenchymal effects of sleep apnea
Authors: Jurado Alicia , Ulldemolins Anna , Lluís Helena , Gasull Xavier , Gavara Núria , Sunyer Raimon , Otero Jorge , Gozal David , Almendros Isaac , Farré Ramon 
Published: January 2023

Background: Patients with obstructive sleep apnea (OSA) experience recurrent hypoxemic events with a frequency sometimes exceeding 60 events/h. These episodic events induce downstream transient hypoxia in the parenchymal tissue of all organs, thereby eliciting the pathological consequences of OSA. Whereas experimental models currently apply intermittent hypoxia to cells conventionally cultured in 2D plates, there is no well-characterized setting that will subject cells to well-controlled intermittent hypoxia in a 3D environment and enable the study of the effects of OSA on the cells of interest while preserving the underlying tissue environment.Aim: To design and characterize an experimental approach that exposes cells to high-frequency intermittent hypoxia mimicking OSA in 3D (hydrogels or tissue slices).Methods: Hydrogels made from lung extracellular matrix (L-ECM) or brain tissue slices (300–800-μm thickness) were placed on a well whose bottom consisted of a permeable silicone membrane. The chamber beneath the membrane was subjected to a square wave of hypoxic/normoxic air. The oxygen concentration at different depths within the hydrogel/tissue slice was measured with an oxygen microsensor.Results: 3D-seeded cells could be subjected to well-controlled and realistic intermittent hypoxia patterns mimicking 60 apneas/h when cultured in L-ECM hydrogels ≈500 μm-thick or ex-vivo in brain slices 300–500 μm-thick.Conclusion: This novel approach will facilitate the investigation of the effects of intermittent hypoxia simulating OSA in 3D-residing cells within the parenchyma of different tissues/organs.
Gel formulated with Bryophyllum pinnatum leaf extract promotes skin wound healing in vivo by increasing VEGF expression: A novel potential active ingredient for pharmaceuticals
Authors: Araújo Edilane Rodrigues Dantas , Xavier-Santos Jacinthia Beatriz , da Silva Valéria Costa , de Lima Juliana Bessa Figueiredo , Schlamb Jade , Fernandes-Pedrosa Matheus de Freitas , da Silva Júnior Arnóbio Antônio , de Araújo Júnior Raimundo Fernandes , Rathinasabapathy Thirumurugan , Moncada Marvin , Esposito Debora , Guerra Gerlane Coelho Bernardo , Zucolotto Silvana Maria 
Published: January 2023

Bryophyllumpinnatum(Crassulaceae) is used in traditional medicine for treating skin wounds. In our previous study, a topical gel containingB. pinnatumaqueous leaf extract showed a preclinical anti-inflammatory effect inin vivoacute edema models. In continuation, the present study aims to evaluate the phytochemical content and the stability of a formulation in gel containingB. pinnatumaqueous leaf extract and its healing properties and mechanism of action through an experimental model of induction of skin wounds in rats andin vitroassays. The animals were treated topically for 7 or 14 days with a formulation in gel containing extract at 5% or a placebo or Fibrinase®in cream. In addition, to establish some quality control parameters, the total phenolic content (TPC), total flavonoid content (TFC), and a study focusing on the phytochemical and biological stability of a gel for 30 days at two different conditions (room temperature and 40°C/75% RH) were performed. Gel formulation containing extract showed a TPC and TFC of 2.77 ± 0.06 mg of gallic acid/g and 1.58 ± 0.03 mg of quercetin/g, respectively. Regarding the stability study, the formulation in gel showed no significant change in the following parameters: pH, water activity, chromatographic profile, and the content of the major compound identified in the extract. The gel formulation containing extract stimulated skin wound healing while reducing the wound area, as well as decreasing the inflammatory infiltrate, reducing the levels of IL-1β and TNF-α, and stimulating angiogenesis with increased expression of VEGF, an effect similar to Fibrinase. In conclusion, the gel formulation containing extract exhibited relevant skin wound healing properties and, therefore, has the potential to be applied as a novel active ingredient for developing wound healing pharmaceuticals.
Comprehensive in vitro and in silico assessments of metabolic capabilities of 24 genomic variants of CYP2C19 using two different substrates
Authors: Seo Myung-Eui , Min Byung-Joo , Heo Nayoon , Lee Kye Hwa , Kim Ju Han 
Published: January 2023

Introduction: Most hepatically cleared drugs are metabolized by cytochromes P450 (CYPs), and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide curated clinical references for CYPs to apply individual genome data for optimized drug therapy. However, incorporating novel pharmacogenetic variants into guidelines takes considerable time.Methods: We comprehensively assessed the drug metabolizing capabilities of CYP2C19 variants discovered through population sequencing of two substrates, S-mephenytoin and omeprazole.Results: Based on established functional assays, 75% (18/24) of the variants not yet described in Pharmacogene Variation (PharmVar) had significantly altered drug metabolizing capabilities. Of them, seven variants with inappreciable protein expression were evaluated as protein damaging by all three in silico prediction algorithms, Sorting intolerant from tolerant (SIFT), Polymorphism Phenotyping v2 (PolyPhen-2), and Combined annotation dependent depletion (CADD). The five variants with decreased metabolic capability (&lt;50%) of wild type for either substrates were evaluated as protein damaging by all three in silico prediction algorithms, except CADD exact score of NM_000769.4:c.593T&gt;C that was 19.68 (&lt;20.0). In the crystal structure of the five polymorphic proteins, each altered residue of all those proteins was observed to affect the key structures of drug binding specificity. We also identified polymorphic proteins indicating different tendencies of metabolic capability between the two substrates (5/24).Discussion: Therefore, we propose a methodology that combines in silico prediction algorithms and functional assays on polymorphic CYPs with multiple substrates to evaluate the changes in the metabolism of all possible genomic variants in CYP genes. The approach would reinforce existing guidelines and provide information for prescribing appropriate medicines for individual patients.
Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux
Authors: Zhang Cheng , Wu Xuewen , Shi Pengmin , Ma Hongyu , Fang Fei , Feng Qianlang , Zhao Shuang , Zhang Ruipu , Huang Jinyuan , Xu Xinting , Xiao Weilie , Cao Guang , Ji Xu 
Published: January 2023

Introduction: Atherosclerosis is the main cause of many cardiovascular diseases and contributes to morbidity and mortality worldwide. The formation of macrophage-derived foam cells plays a critical role in the early stage of atherosclerosis pathogenesis. Diterpenoids found in the flowers of Callicarpa rubella Lindl., a traditional Chinese medicine, have been reported to have anti-inflammatory activity. However, little is known about the effects of these diterpenoids on macrophage foam cell formation.Methods: A macrophage-derived foam cell formation model was established by treating RAW264.7 cells with oxidized low-density lipoprotein (ox-LDL) for 24 h. Oil red O staining were used to detect the intracellular lipids. The cholesterol efflux capacity was assayed by labeling cells with 22-NBD-cholesterol. Western blots and real-time PCRs were performed to quantify protein and mRNA expressions.Results: Two diterpenoid molecules, 14α-hydroxyisopimaric acid (C069002) and isopimaric acid (C069004), extracted from the flowers of Callicarpa rubella Lindl., significantly attenuated ox-LDL-induced foam cell formation in RAW264.7 macrophages. Further investigation showed that these two diterpenoids could promote cholesterol efflux from RAW264.7 macrophages to apolipoprotein A-I or high-density lipoproteins, which was associated with upregulated expression of ATP-binding cassette A1/G1 (ABCA1/G1), liver X receptor-α (LXRα), and peroxisome proliferator-activated receptor-γ (PPARγ). Unexpectedly, the diterpenoids C069002 and C069004 failed to enhance the mRNA transcription of the ABCG1 gene in macrophage-derived foam cells induced by ox-LDL. To evaluate the effects of diterpenoids on macrophage foam cell formation and determine the underlying mechanism, two drugs (lovastatin and rosiglitazone) were used as positive controls. Although both drugs could reduce macrophage foam cell formation and promote cholesterol efflux, they each had distinctive abilities to modulate the expression of cholesterol efflux-related genes. In contrast to lovastatin, rosiglitazone showed a similar influence on the expression of cholesterol efflux-related genes (including ABCA1, LXRα, and PPARγ) as the diterpenoids regardless of the presence or absence of ox-LDL, implying a similar mechanism by which they may exert atheroprotective effects.Conclusion: Our research indicates that diterpenoids effectively inhibit ox-LDL-induced macrophage foam cell formation by promoting cholesterol efflux from macrophages via the PPARγ-LXRα-ABCA1 pathway. Further investigation of diterpenoids as potential drugs for the treatment of atherosclerosis is warranted.
Extensive diet-induced atherosclerosis in scavenger receptor class B type 1-deficient mice is associated with substantial leukocytosis and elevated vascular cell adhesion molecule-1 expression in coronary artery endothelium
Authors: Fuller Mark T. , Dadoo Omid , Xiong Ting , Chivukula Pardh , MacDonald Melissa E. , Lee Samuel K. , Austin Richard C. , Igdoura Suleiman A. , Trigatti Bernardo L. 
Published: January 2023

High levels of low density lipoprotein (LDL) cholesterol and low levels of high density lipoprotein (HDL) cholesterol are risk factors for cardiovascular disease. Mice that lack genes involved in the clearance of LDL from the bloodstream, such as the LDL receptor and apolipoprotein E, are widely used models of experimental atherosclerosis. Conversely, mice that lack the HDL receptor, scavenger receptor class B type I, and therefore have disrupted HDL functionality, also develop diet-inducible atherosclerosis but are a seldom-used disease model. In this study, we compared atherosclerosis and associated phenotypes in scavenger receptor class B type I knockout mice with those of wild type, LDL receptor knockout, and apolipoprotein E knockout mice after 20 weeks of being fed an atherogenic diet containing sodium cholate. We found that while scavenger receptor class B type I knockout mice had substantially lower plasma cholesterol than LDL receptor and apolipoprotein E knockout mice, they developed atherosclerotic plaques with similar sizes and compositions in their aortic sinuses, and more extensive atherosclerosis in their descending aortas and coronary arteries. This was associated with elevated tumor necrosis factor alpha levels in scavenger receptor class B type I knockout mice compared to wild type and LDL receptor knockout mice, and lymphocytosis, monocytosis, and elevated vascular cell adhesion molecule expression in coronary artery endothelial cells compared to the other mice examined. We conclude that extensive atherosclerosis in arteries that are not generally susceptible to atherosclerosis in scavenger receptor class B type I knockout mice is driven by factors in addition to hypercholesterolemia, including inflammation, dysregulation of the immune system and increased sensitivity of endothelial cells in arteries that are normally resistant to atherosclerosis. Scavenger receptor class B type I knockout mice fed a cholate containing atherogenic diet may prove to be a useful model to study mechanisms of atherosclerosis and evaluate treatments that rely on intact LDL clearance pathways.
Maternal pre-eclampsia serum increases neurite growth and mitochondrial function through a potential IL-6-dependent mechanism in differentiated SH-SY5Y cells
Authors: Barron Aaron , Manna Samprikta , McElwain Colm J. , Musumeci Andrea , McCarthy Fergus P. , O’Keeffe Gerard W. , McCarthy Cathal M. 
Published: January 2023

Introduction: Pre-eclampsia (PE) is a common and serious hypertensive disorder of pregnancy, which affects 3%–5% of first-time pregnancies and is a leading cause of maternal and neonatal morbidity and mortality. Prenatal exposure to PE is associated with an increased risk of neurodevelopmental disorders in affected offspring, although the cellular and molecular basis of this increased risk is largely unknown.Methods: Here, we examined the effects of exposure to maternal serum from women with PE or a healthy uncomplicated pregnancy on the survival, neurite growth and mitochondrial function of neuronally differentiated human SH-SY5Y neuroblastoma cells, which are commonly used to study neurite growth. Neurite growth and mitochondrial function are two strongly linked neurodevelopmental parameters in which alterations have been implicated in neurodevelopmental disorders. Following this, we investigated the pleiotropic cytokine interleukin-6 (IL-6) levels as a potential mechanism.Results: Cells exposed to 3% (v/v) PE serum for 72 h exhibited increased neurite growth (p &lt; 0.05), which was validated in the human neural progenitor cell line, ReNcell® VM (p &lt; 0.01), and mitochondrial respiration (elevated oxygen consumption rate (p &lt; 0.05), basal mitochondrial respiration, proton leak, ATP synthesis, and non-mitochondrial respiration) compared to control serum-treated cells. ELISA analysis showed elevations in maternal IL-6 in PE sera (p &lt; 0.05) and placental explants (p &lt; 0.05). In support of this, SH-SY5Y cells exposed to 3% (v/v) PE serum for 24 h had increased phospho-STAT3 levels, which is a key intracellular mediator of IL-6 signalling (p &lt; 0.05). Furthermore, treatment with anti-IL-6 neutralizing antibody blocked the effects of PE serum on neurite growth (p &lt; 0.05), and exposure to IL-6 promoted neurite growth in SH-SY5Y cells (p &lt; 0.01).Discussion: Collectively these data show elevated serum levels of maternal IL-6 in PE, which increases neurite growth and mitochondrial function in SH-SY5Y cells. This rationalizes the further study of IL-6 as a potential mediator between PE exposure and neurodevelopmental outcome in the offspring.
A vascular smooth muscle-specific integrin-α8 Cre mouse for lymphatic contraction studies that allows male-female comparisons and avoids visceral myopathy
Authors: Davis Michael J. , Kim Hae Jin , Li Min , Zawieja Scott D. 
Published: January 2023

Introduction: The widely-used, tamoxifen-inducible, smooth muscle (SM)-specific Cre, Myh11-CreERT2, suffers from two disadvantages: 1) it is carried on the Y-chromosome and thus only effective for gene deletion in male mice, and 2) it recombines in both vascular and non-vascular SM, potentially leading to unwanted or confounding gastrointestinal phenotypes. Here, we tested the effectiveness of a new, SM-specific Cre, based on the integrin α8 promoter (Itga8-CreERT2), that has been recently developed and characterized, to assess the effects of Cav1.2 deletion on mouse lymphatic SM function.Methods:Cav1.2 (the L-type voltage-gated calcium channel) is essential for lymphatic pacemaking and contraction and its deletion using either Myh11-CreERT2 or Itga8-CreERT2 abolished spontaneous lymphatic contractions. Mouse lymphatic contractile function was assessed using two ex vivo methods.Results:Myh11-CreERT2; Cav1.2f/f mice died of gastrointestinal obstruction within 20 days of the first tamoxifen injection, preceded by several days of progressively poor health, with symptoms including weight loss, poor grooming, hunched posture, and reduced overall activity. In contrast, Itga8-CreERT2; Cav1.2f/f mice survived for &gt;80 days after induction and were in normal health until the time of sacrifice for experimental studies. Cav1.2 deletion was equally effective in male and female mice.Discussion: Our results demonstrate that Itga8-CreERT2 can be used to effectively delete genes in lymphatic smooth muscle while avoiding potentially lethal visceral myopathy and allowing comparative studies of lymphatic contractile function in both male and female mice.