bluuebunny/crossref_metadata_2025_split huggingface dataset:
Canine diabetes mellitus demonstrates multiple markers of chronic inflammation including Th40 cell increases and elevated systemic-immune inflammation index, consistent with autoimmune dysregulation
Authors: Vaitaitis Gisela , Webb Tracy , Webb Craig , Sharkey Christina , Sharkey Steve , Waid Dan , Wagner David H. 
Published: January 2024

IntroductionCanine diabetes mellitus (CDM) is a relatively common endocrine disease in dogs. Many CDM clinical features resemble human type 1 diabetes mellitus (T1DM), but lack of autoimmune biomarkers makes calling the disease autoimmune controversial. Autoimmune biomarkers linking CDM and T1DM would create an alternative model for drug development impacting both human and canine disease. MethodsWe examined peripheral blood of diagnosed CDM dog patients comparing it to healthy control (HC) dogs. Dogs were recruited to a study at the Colorado State University Veterinary Teaching Hospital and blood samples collected for blood chemistry panels, complete blood counts (CBC), and immunologic analysis. Markers of disease progression such as glycated albumin (fructosamine, the canine equivalent of human HbA1c) and c-peptide were addressed. ResultsSignificant differences in adaptive immune lymphocytes, innate immune macrophages/monocytes and neutrophils and differences in platelets were detected between CDM and HC based on CBC. Significant differences in serum glucose, cholesterol and the liver function enzyme alkaline phosphatase were also detected. A systemic immune inflammation index (SII) and chronic inflammation index (CII) as measures of dynamic changes in adaptive and innate cells between inflammatory and non-inflammatory conditions were created with highly significant differences between CDM and HC. Th40 cells (CD4+CD40+ T cells) that are demonstrably pathogenic in mouse T1DM and able to differentiate diabetic from non-diabetic subjects in human T1DM were significantly expanded in peripheral blood mononuclear cells.ConclusionsBased on each clinical finding, CDM can be categorized as an autoimmune condition. The association of significantly elevated Th40 cells in CDM when compared to HC or to osteoarthritis, a chronic but non-autoimmune disease, suggests peripheral blood Th40 cell numbers as a biomarker that reflects CDM chronic inflammation. The differences in SII and CII further underscore those findings.
Immune evasion by proteolytic shedding of natural killer group 2, member D ligands in Helicobacter pylori infection
Authors: Anthofer Margit , Windisch Markus , Haller Rosa , Ehmann Sandra , Wrighton Sebastian , Miller Michael , Schernthanner Lorenz , Kufferath Iris , Schauer Silvia , Jelušić Barbara , Kienesberger Sabine , Zechner Ellen L. , Posselt Gernot , Vales-Gomez Mar , Reyburn Hugh T. , Gorkiewicz Gregor 
Published: January 2024

BackgroundHelicobacter pylori (H. pylori) uses various strategies that attenuate mucosal immunity to ensure its persistence in the stomach. We recently found evidence that H. pylori might modulate the natural killer group 2, member 2 (NKG2D) system. The NKG2D receptor and its ligands are a major activation system of natural killer and cytotoxic T cells, which are important for mucosal immunity and tumor immunosurveillance. The NKG2D system allows recognition and elimination of infected and transformed cells, however viruses and cancers often subvert its activation. Here we aimed to identify a potential evasion of the NKG2D system in H. pylori infection.MethodsWe analyzed expression of NKG2D system genes in gastric tissues of H. pylori gastritis and gastric cancer patients, and performed cell-culture based infection experiments using H. pylori isogenic mutants and epithelial and NK cell lines.ResultsIn biopsies of H. pylori gastritis patients, NKG2D receptor expression was reduced while NKG2D ligands accumulated in the lamina propria, suggesting NKG2D evasion. In vitro, H. pylori induced the transcription and proteolytic shedding of NKG2D ligands in stomach epithelial cells, and these effects were associated with specific H. pylori virulence factors. The H. pylori-driven release of soluble NKG2D ligands reduced the immunogenic visibility of infected cells and attenuated the cytotoxic activity of effector immune cells, specifically the anti-tumor activity of NK cells.ConclusionH. pylori manipulates the NKG2D system. This so far unrecognized strategy of immune evasion by H. pylori could potentially facilitate chronic bacterial persistence and might also promote stomach cancer development by allowing transformed cells to escape immune recognition and grow unimpeded to overt malignancy.
Berotralstat in hereditary angioedema due to C1 inhibitor deficiency: first real-world evidence from a Canadian center
Authors: Srinivasan Cindy , Ritchie Bruce , Adatia Adil 
Published: January 2024

BackgroundHereditary angioedema due to C1 inhibitor deficiency is a rare genetic condition that causes recurrent swelling with consequent functional impairment and decreased quality of life. Long-term prophylaxis (LTP) to prevent angioedema episodes is a key component of disease management. Berotralstat, an oral, once-daily plasma kallikrein inhibitor, was approved for LTP by Health Canada in 2022.MethodsWe conducted a retrospective, real-world study investigating the effectiveness and adverse effects of berotralstat. Data on angioedema frequency, disease control, and adverse events were tabulated. Patient satisfaction with treatment was scored on a 5-point Likert scale, with 1 representing very unsatisfied and 5 representing very satisfied with therapy.ResultsFrom June, 2022 and May, 2023, 8 patients with HAE type 1 or type 2 received berotralstat. Effectiveness data were available for 7 patients who continued the drug for at least 3 months, 4 of whom switched to berotralstat from plasma-derived C1 inhibitor LTP. In these 7 patients, the average number of attacks per month decreased from 3.3 to 1.6 (p&lt;0.05), representing a ~52% reduction in attack frequency. Median angioedema control test score numerically improved from 8 to 13 (p=0.0781). Of the 8 patients who received berotralstat, 3 reported no adverse effects and 5 experienced gastrointestinal side effects, which were mild and transient in 3 and led to discontinuation in 1. Average treatment satisfaction was between satisfied and very satisfied at 4.3.ConclusionBerotralstat is an effective agent for long-term prophylaxis in HAE. Most patients experienced no adverse effects or mild, transient gastrointestinal symptoms.
Real-world impact of the introduction of chemo-immunotherapy in extended small cell lung cancer: a multicentric analysis
Authors: Bonanno Laura , Calvetti Lorenzo , Dal Maso Alessandro , Pavan Alberto , Bao Loc Carlo , De Nuzzo Mattia , Frega Stefano , Sartori Giulia , Ferro Alessandra , Pasello Giulia , Morandi Paolo , Aprile Giuseppe , Guarneri Valentina 
Published: January 2024

BackgroundRecent clinical trials demonstrated longer survival in extended small cell lung cancer (SCLC) patients treated with immunotherapy in addition to chemotherapy. However, the magnitude of benefit is modest and the impact in real-world setting has to be fully established.MethodsWe collected clinical data and radiological imaging of patients affected by extended or relapsing SCLC and consecutively treated according to clinical practice between 2016 and 2023. As primary end-point, we compared pre-defined outcome indicators before and after the introduction of chemo-immunotherapy (May 2020): 6-month and 12-month progression free survival (PFS) rate, 12-month and 18-month overall survival (OS). Among those who were treated after May 2020, patients who did not receive immunotherapy according to treating physician’s choice were included in the analysis to minimize clinical selection bias.ResultsThe analysis included 214 patients: 132 (61.7%) were treated in an Academic cancer center and 82 (38.3%) in two community hospitals; 104 were treated before May 2020. Median PFS of the overall study population was 4.8 months (95% confidence interval [95% CI]: 4.4-5.4), median OS was 7.1 months (95% CI: 6.3-7.7). Estimated PFS and OS were significantly longer in patients treated after May 2020 with hazard ratio (HR) for PFS and OS of 0.61 (95% CI: 0.46-0.81, p &lt; 0.001) and 0.70 (95% CI: 0.52-0.93, p = 0.015), respectively. 6-month PFS rate increased from 27% to 40% (p = 0.04) while 12-months PFS raised from 1% to 11% (p = 0.003). 12-month and 18-month OS rate increased from 15% to 28% (p = 0.03) and from 2.1% to 12% (p = 0.009), respectively. After May 2020 the median number of hospitalization days per patient decreased significantly and the incidence of severe AEs was similar. Among patients treated with chemo-immunotherapy, the onset of immune-related AEs was associated with improved PFS and OS (HR 0.55, 95% CI: 0.35-0.89, p = 0.012 and HR 0.47, 95%CI 0.28-0.77, p = 0.002, respectively).ConclusionsThe real-world analysis shows a meaningful improvement of outcome indicators after the introduction of chemo-immunotherapy, with reduction of the duration of hospitalization, thus supporting the use of chemo-immunotherapy and the need for further biomarker research.
Real-life study to assess effectiveness and safety of eculizumab in patients with neuromyelitis optica spectrum disorders in France: protocol for ECUP4, an observational study
Authors: Marignier Romain , Laplaud David , Zéphir Hélène , Papeix Caroline , Leray Emmanuelle , Amri Ekbel , Piotaix Mickaël , de Sèze Jérôme 
Published: January 2024

BackgroundEculizumab, a humanized monoclonal antibody targeting the C5 complement protein, has been approved for the treatment of neuromyelitis optica spectrum disorders (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive (Ab+). The aim of this study is to evaluate the long-term effectiveness and safety of eculizumab in French adults with NMOSD and to describe patients' characteristics, disability, and quality of life using data collected in a real-world setting.MethodsThis is the protocol for ECUP4, an ongoing prospective, observational, non-comparative, multicenter study conducted in 32 reference centers in France. Eligible patients must also be enrolled in NOMADMUS, a nested cohort of the French national multiple sclerosis registry (OFSEP). The primary endpoint is the annualized relapse rate. Secondary endpoints include the long-term safety of eculizumab, as well as patients' characteristics, treatment outcomes, disability, pain, visual acuity, and quality of life. Visits and treatments follow routine clinical practice. The case report forms (CRF) comprise data recorded in the context of the NOMADMUS cohort, collected during routine visits. The inclusion period is planned for 3 years, with no limitation on the number of patients enrolled. The maximum follow-up duration will be 5.5 years.ConclusionThe efficacy and safety of eculizumab in patients with AQP4+ NMOSD have been demonstrated in randomized clinical trials that showed a significant reduction in the risk of relapse, with a safety profile consistent with other indications. This study will provide clinical and patient-reported evidence of the benefits of eculizumab, using data from a real-world setting in France.Trial registration numberThis study is registered at the French public repertory Health data Hub, N° F20211228123801. All information can be accessed at: https://www.health-data-hub.fr/.
Effect of epiretinal electrical stimulation on the glial cells in a rabbit retinal eyecup model
Authors: Henze Dean , Majdi Joseph A. , Cohen Ethan D. 
Published: January 2024

IntroductionWe examined how pulse train electrical stimulation of the inner surface of the rabbit retina effected the resident glial cells. We used a rabbit retinal eyecup preparation model, transparent stimulus electrodes, and optical coherence tomography (OCT). The endfeet of Müller glia processes line the inner limiting membrane (ILM).MethodsTo examine how epiretinal electrode stimulation affected the Müller glia, we labeled them post stimulation using antibodies against soluble glutamine synthetase (GS). After 5 min 50 Hz pulse train stimulation 30 μm from the surface, the retina was fixed, immunostained for Müller glia, and examined using confocal microscopic reconstruction. Stimulus pulse charge densities between 133–749 μC/cm2/ph were examined.ResultsHigh charge density stimulation (442–749 μC/cm2/ph) caused significant losses in the GS immunofluorescence of the Müller glia endfeet under the electrode. This loss of immunofluorescence was correlated with stimuli causing ILM detachment when measured using OCT. Müller cells show potassium conductances at rest that are blocked by barium ions. Using 30 msec 20 μA stimulus current pulses across the eyecup, the change in transretinal resistance was examined by adding barium to the Ringer. Barium caused little change in the transretinal resistance, suggesting under low charge density stimulus pulse conditions, the Müller cell radial conductance pathway for these stimulus currents was small. To examine how epiretinal electrode stimulation affected the microglia, we used lectin staining 0–4 h post stimulation. After stimulation at high charge densities 749 μC/cm2/ph, the microglia under the electrode appeared rounded, while the local microglia outside the electrode responded to the stimulated retina by process orientation inwards in a ring by 30 min post stimulation.DiscussionOur study of glial cells in a rabbit eyecup model using transparent electrode imaging suggests that epiretinal electrical stimulation at high pulse charge densities, can injure the Müller and microglia cells lining the inner retinal surface in addition to ganglion cells.
Case report: Pemigatinib-induced retinopathy: a serial examination of subretinal fluid secondary to an FGFR inhibitor
Authors: Barmas-Alamdari Daniel , Jiao George , Lieberman Ronni 
Published: January 2024

BackgroundModern chemotherapeutic agents continue to evolve as modern monoclonal antibody treatments are designed to directly target proteins, enzymes, and focal loci. A particular class of these medications, fibroblast growth factor (FGFR) inhibitors, specifically pemigatinib (Pemazyre®; Incyte), has been approved by the US Food and Drug Administration since April 2020 for the treatment of advanced or metastatic cholangiocarcinoma. As it is a relatively new medication, its side-effect profile is manifesting in active clinical practice. The presence of FGFR receptors in the retinal pigment epithelium makes the retina susceptible to potential adverse effects secondary to pemigatinib use.Case presentationA 69-year-old African-American male with a tumor mutation burden 3 (TMB-3) metastatic adenocarcinoma of the liver from primary cholangiocarcinoma, who was undergoing chemotherapy with pemigatinib, was found to have asymptomatic bilateral subretinal fluid accumulation. Serial monitoring with optical coherence tomography (OCT) demonstrated complete resolution of the subretinal fluid while off-cycle and asymptomatic re-accumulation of subretinal fluid while on-cycle, with no significant changes in visual acuity.ConclusionsSubretinal fluid accumulation secondary to pemigatinib may develop during the active treatment cycles without causing any significant visual symptoms for the patient. Serial monitoring demonstrates fluctuations of subretinal fluid during the patient’s on- and off-cycles. This case strengthens the current guidelines for continuing pemigatinib in asymptomatic patients found to have subretinal fluid. Further studies are warranted to identify patients who may be at higher risk for developing subretinal fluid.
Outpatient depression current care expenditure changes in Liaoning Province from 2015 to 2020: a study based on the “system of health accounts 2011”
Authors: Ma Yuedan , Shi Xiaoxia , Sznajder Kristin K. , Zhao Yue , Wan Quan , Chai Peipei , Yang Xiaoshi 
Published: January 2024

Introduction: Depression is the leading cause of disability worldwide and has become a health issue of global concern. Based on the “System of Health Accounts 2011” (SHA 2011) for patients with depression, this paper studies the changes in the current curative expenditure (CCE) of outpatient depression in Liaoning Province, China, and provides policy recommendations.Method: A stratified multistage random sample of 56,994 patients with depression included from 1,227 healthcare facilities in Liaoning Province were included. The significance of differences in variables within groups was analyzed by univariate analysis (including descriptive statistics analysis, Mann-Whitney U test and Kruskal–Wallis H test), and factors influencing depression outpatient CCE were analyzed by multiple linear regression analysis and constructing structural equation models (SEM).Results: The CCE of outpatient depression was ranging from CNY 75.57 million to CNY 100.53 million in 2015–2020, with the highest of CNY 100.53 million in 2018, CNY 103.28 million in 2019. Medical expenditures are mainly concentrated in general hospitals and provincial healthcare institutions, accounting for about 90% of all provincial scope expenditures. The multiple regression results show that provincial healthcare institutions, purchase of drug, select medical treatment for depression, general hospitals and urban employees’ health insurance are the main influencing factors for depression outpatient CCE. The results of SEM show that insurance status negative impact outpatient expenditure.Conclusion: Health insurance is an important factor in equitable access to healthcare resources for patients, and medication expenditure is the influential factor affecting the high expenditure of outpatient clinics. It is of great importance to reduce the medical burden of patients by increasing the coverage of medical insurance, increasing the proportion of bills that are eligible for reimbursement, and improving the system by guaranteeing the supply of psychotropic medication.
Compound Danshen dripping pills prevent early diabetic retinopathy: roles of vascular protection and neuroprotection
Authors: Xu Xiaoyu , Wang Mengchen , Zhang Shuxia , Wang Jing , Li Xinxin , Ma Xiaohui , Luo Yun , Sun Xiaobo 
Published: January 2024

Introduction: Diabetic retinopathy (DR) represents a major cause of adult blindness, and early discovery has led to significant increase in the number of patients with DR. The drugs currently used for treatment, such as ranibizumab, mainly focus on the middle and late periods of DR, and thus do not meet the clinical need. Here, the potential mechanisms by which compound Danshen Dripping Pills (CDDP) might protect against early DR were investigated.Methods: Db/db mice were used to establish a DR model. The initial weights and HbA1c levels of the mice were monitored, and retinal pathology was assessed by hematoxylin-eosin (HE) staining. The vascular permeability of the retina and thickness of each retinal layer were measured, and electroretinogram were performed together with fundus fluorescein angiography and optical coherence tomography. The levels of inflammatory factors were examined in retinal tissue, as well as those of intercellular adhesion molecule 1 (ICAM-1), IL-6, and monocyte chemoattractant protein 1 (MCP-1) in the serum using ELISA. Immunohistochemistry was used to evaluate levels of vascular endothelial growth factor (VEGF), B-cell lymphoma 2 (Bcl-2), and Bclassociated X protein (Bax). Retinal cell injury and apoptosis were examined by TdT-mediated dUTP Nick End Labeling (TUNEL) assays.Results: The data showed that CDDP significantly improved cellular disarrangement. Imaging data indicated that CDDP could reduce vascular permeability and the amplitude of oscillatory potentials (OPs), and restore the thickness of the ganglion cell layer. Moreover, CDDP reduced the expression levels of inflammatory factors in both the retina and serum.Conclusion: These findings strongly suggest that CDDP prevents early DR through vascular and neuroprotection.
Dual inhibition of MEK and PI3Kβ/δ–a potential therapeutic strategy in PTEN-wild-type docetaxel-resistant metastatic prostate cancer
Authors: Ruiz de Porras Vicenç , Bernat-Peguera Adrià , Alcon Clara , Laguia Fernando , Fernández-Saorin Maria , Jiménez Natalia , Senan-Salinas Ana , Solé-Blanch Carme , Feu Andrea , Marín-Aguilera Mercedes , Pardo Juan Carlos , Ochoa-de-Olza Maria , Montero Joan , Mellado Begoña , Font Albert 
Published: January 2024

Background: Docetaxel remains the standard treatment for metastatic castration-resistant prostate cancer (mCRPC). However, resistance frequently emerges as a result of hyperactivation of the PI3K/AKT and the MEK/ERK pathways. Therefore, the inhibition of these pathways presents a potential therapeutic approach. In this study, we evaluated the efficacy of simultaneous inhibition of the PI3K/AKT and MEK/ERK pathways in docetaxel-resistant mCRPC, both in vitro and in vivo.Methods: Docetaxel-sensitive and docetaxel-resistant mCRPC cells were treated with selumetinib (MEK1/2 inhibitor), AZD8186 (PI3Kβ/δ inhibitor) and capivasertib (pan-AKT inhibitor) alone and in combination. Efficacy and toxicity of selumetinib+AZD8186 were tested in docetaxel-resistant xenograft mice. CRISPR-Cas9 generated a PTEN-knockdown docetaxel-resistant cell model. Changes in phosphorylation of AKT, ERK and downstream targets were analyzed by Western blot. Antiapoptotic adaptations after treatments were detected by dynamic BH3 profiling.Results: PI3K/AKT and MEK/ERK pathways were hyperactivated in PTEN-wild-type (wt) docetaxel-resistant cells. Selumetinib+AZD8186 decreased cell proliferation and increased apoptosis in PTEN-wt docetaxel-resistant cells. This observation was further confirmed in vivo, where docetaxel-resistant xenograft mice treated with selumetinib+AZD8186 exhibited reduced tumor growth without additional toxicity.Conclusion: Our findings on the activity of selumetinib+AZD8186 in PTEN-wt cells and in docetaxel-resistant xenograft mice provide an excellent rationale for a novel therapeutic strategy for PTEN-wt mCRPC patients resistant to docetaxel, in whom, unlike PTEN-loss patients, a clinical benefit of treatment with single-agent PI3K and AKT inhibitors has not been demonstrated. A phase I-II trial of this promising combination is warranted.