bluuebunny/crossref_metadata_2025_split huggingface dataset:
TGF-β is elevated in hyperuricemic individuals and mediates urate-induced hyperinflammatory phenotype in human mononuclear cells
Authors: Klück Viola , Cabău Georgiana , Mies Linda , Bukkems Femke , van Emst Liesbeth , Bakker René , van Caam Arjan ,   HINT consortium, Pop Ioan V. , Popp Radu A. , Rednic Simona , Pamfil Cristina , Farcaş Marius , Marginean Dragoş H. , Gaal Orsolya I. , Badii Medeea O. , Hotea Ioana , Peca Loredana , Mirea Andreea-Manuela , Nica Valentin , Colcear Doina , Pop Mariana S. , Rus Ancuta , Crişan Tania O. , Joosten Leo A. B. 
Published: February 2023

AbstractBackgroundSoluble urate leads to a pro-inflammatory phenotype in human monocytes characterized by increased production of IL-1β and downregulation of IL-1 receptor antagonist, the mechanism of which remains to be fully elucidated. Previous transcriptomic data identified differential expression of genes in the transforming growth factor (TGF)-β pathway in monocytes exposed to urate in vitro. In this study, we explore the role of TGF-β in urate-induced hyperinflammation in peripheral blood mononuclear cells (PBMCs).MethodsTGF-β mRNA in unstimulated PBMCs and protein levels in plasma were measured in individuals with normouricemia, hyperuricemia and gout. For in vitro validation, PBMCs of healthy volunteers were isolated and treated with a dose ranging concentration of urate for assessment of mRNA and pSMAD2. Urate and TGF-β priming experiments were performed with three inhibitors of TGF-β signalling: SB-505124, 5Z-7-oxozeaenol and a blocking antibody against TGF-β receptor II.ResultsTGF-β mRNA levels were elevated in gout patients compared to healthy controls. TGF-β-LAP levels in serum were significantly higher in individuals with hyperuricemia compared to controls. In both cases, TGF-β correlated positively to serum urate levels. In vitro, urate exposure of PBMCs did not directly induce TGF-β but did enhance SMAD2 phosphorylation. The urate-induced pro-inflammatory phenotype of monocytes was partly reversed by blocking TGF-β.ConclusionsTGF-β is elevated in individuals with hyperuricemia and correlated to serum urate concentrations. In addition, the urate-induced pro-inflammatory phenotype in human monocytes is mediated by TGF-β signalling. Future studies are warranted to explore the intracellular pathways involved and to assess the clinical significance of urate-TGF-β relation.
Phospholipase C delta 1 inhibits WNT/β‐catenin and EGFR-FAK-ERK signaling and is disrupted by promoter CpG methylation in renal cell carcinoma
Authors: Xie Jianlian , Zhou Jun , Xia Jiliang , Zeng Ying , Huang Guo , Zeng Weihong , Fan Tingyu , Li Lili , Zeng Xi , Tao Qian 
Published: February 2023

Abstract
Background
PLCD1, located at 3p22, encodes an enzyme that mediates cellular metabolism and homeostasis, intracellular signal transduction and movement. PLCD1 plays a pivotal role in tumor suppression of several types of cancers; however, its expression and underlying molecular mechanisms in renal cell carcinoma (RCC) pathogenesis remain elusive.

Methods
RT-PCR and Western blot were used to detect PLCD1 expression in RCC cell lines and normal tissues. Bisulfite treatment, MSP and BGS were utilized to explore the CpG methylation status of PLCD1 promoter. Online databases were analyzed for the association between PLCD1 expression/methylation and patient survival. In vitro experiments including CCK8, colony formation, wound-healing, transwell migration and invasion, immunofluorescence and flow cytometry assays were performed to evaluate tumor cell behavior. Luciferase assay and Western blot were used to examine effect of PLCD1 on WNT/β‐catenin and EGFR‐FAK-ERK signaling.

Results
We found that PLCD1 was widely expressed in multiple adult normal tissues including kidney, but frequently downregulated or silenced in RCC due to its promoter CpG methylation. Restoration of PLCD1 expression inhibited the viability, migration and induced G2/M cell cycle arrest and apoptosis in RCC cells. PLCD1 restoration led to the inhibition of signaling activation of WNT/β-catenin and EGFR-FAK-ERK pathways, and the EMT program of RCC cells.

Conclusions
Our results demonstrate that PLCD1 is a potent tumor suppressor frequently inactivated by promoter methylation in RCC and exerts its tumor suppressive functions via suppressing WNT/β‐catenin and EGFR‐FAK-ERK signaling. These findings establish PLCD1 as a promising prognostic biomarker and treatment target for RCC.
Masitinib for mild-to-moderate Alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trial
Authors: Dubois Bruno , López-Arrieta Jesús , Lipschitz Stanley , Doskas Triantafyllos , Spiru Luiza , Moroz Svitlana , Venger Olena , Vermersch Patrick , Moussy Alain , Mansfield Colin D. , Hermine Olivier , Tsolaki Magda ,   for the AB09004 Study Group Investigators
Published: February 2023

AbstractBackgroundMasitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB09004 evaluated masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate dementia due to probable Alzheimer’s disease (AD).MethodsStudy AB09004 was a randomized, double-blind, two parallel-group (four-arm), placebo-controlled trial. Patients aged ≥50 years, with clinical diagnosis of mild-to-moderate probable AD and a Mini-Mental State Examination (MMSE) score of 12–25 were randomized (1:1) to receive masitinib 4.5 mg/kg/day (administered orally as two intakes) or placebo. A second, independent parallel group (distinct for statistical analysis and control arm), randomized patients (2:1) to masitinib at an initial dose of 4.5 mg/kg/day for 12 weeks that was then titrated to 6.0 mg/kg/day, or equivalent placebo. Multiple primary outcomes (each tested at a significance level of 2.5%) were least-squares mean change from baseline to week 24 in the Alzheimer’s Disease Assessment Scale - cognitive subscale (ADAS-cog), or the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL). Safety for each masitinib dose level was compared against a pooled placebo population.ResultsMasitinib (4.5 mg/kg/day) (n=182) showed significant benefit over placebo (n=176) according to the primary endpoint of ADAS-cog, −1.46 (95% CI [−2.46, −0.45]) (representing an overall improvement in cognition) versus 0.69 (95% CI [−0.36, 1.75]) (representing increased cognitive deterioration), respectively, with a significant between-group difference of −2.15 (97.5% CI [−3.48, −0.81]);p<0.001. For the ADCS-ADL primary endpoint, the between-group difference was 1.82 (97.5% CI [−0.15, 3.79]);p=0.038 (i.e., 1.01 (95% CI [−0.48, 2.50]) (representing an overall functional improvement) versus −0.81 (95% CI [−2.36, 0.74]) (representing increased functional deterioration), respectively). Safety was consistent with masitinib’s known profile (maculo-papular rash, neutropenia, hypoalbuminemia). Efficacy results from the independent parallel group of titrated masitinib 6.0 mg/kg/day versus placebo (n=186 and 91 patients, respectively) were inconclusive and no new safety signal was observed.ConclusionsMasitinib (4.5 mg/kg/day) may benefit people with mild-to-moderate AD. A confirmatory study has been initiated to substantiate these data.Trial registrationEudraCT: 2010-021218-50.ClinicalTrials.gov: NCT01872598
Drug-induced interstitial lung disease due to over-the-counter cold medicine taken daily for 25 years: a case report
Authors: Matsumoto Masataka , Ito Isao , Kadowaki Seizo 
Published: February 2023

Abstract
Introduction
We report a rare case of drug-induced interstitial lung disease due to over-the-counter cold medicine taken daily for 25 years to clear the patient’s head.

Case presentation
A 77-year-old Japanese man presented to our hospital with a worsening cough that started 5 years ago. Chest radiographs and computed tomography images showed bilateral opacities, and transbronchial lung biopsy specimens showed an organizing pneumonia pattern. He reported taking the same over-the-counter cold medicine daily for the past 25 years to clear his head. We suspected that the cold medicine caused the lung opacities and asked him to stop taking them. His cough, general fatigue, and chest infiltrate gradually diminished. However, 6 months later, he resumed the same treatment because of a cold. The following month, he presented with severe worsening cough and chest radiographical findings. We diagnosed drug-induced interstitial lung disease. He improved by stopping the cold medicine again and taking prednisolone.

Conclusions
Over-the-counter cold medicines are easily accessible at the drugstore. In cases of diffuse lung disease, we should consider drug-induced interstitial lung disease due to over-the-counter cold medicine, which patients have been taking not only for weeks or months but also years.
Metastatic gastric adenocarcinoma with appendiceal phlegmon: a case report
Authors: Mohammadi Farshid , Razzaghi Mehta , Mousivand Sajad , Amjadinia Ehsan 
Published: February 2023

Abstract
Background
Gastric carcinoma is one of the most frequent malignancies worldwide. Gastric cancer metastasis to the appendix is uncommon in incidence, and has been rarely described in acute-appendicitis-related literature reviews. In this presented case, we have reported a rare case of appendiceal phlegmon, due to a diagnosis of metastatic gastric adenocarcinoma with uncommon symptoms.

Case presentation
A 79-year-old Caucasian male presented to the emergency department with history of weakness, anorexia, lethargy, and mood changes for 2 months. Abdominopelvic computed tomography showed an abscess in right iliac muscle. After percutaneous drainage of the abscess and 6 weeks antibiotic therapy, an appendectomy was done for the patient. Histopathologic findings revealed the involvement of the appendiceal wall by adenocarcinoma, most probably with gastrointestinal origin. Gastric cancer was confirmed later by upper endoscopy and pathologic report.

Conclusions
Although the presence of tumor in appendectomy specimens is rare, and metastasis to appendix is even rarer, it should be considered as a cause of appendicitis, especially in elderly patients.
Impact of lower co-payments on risk-reducing salpingo-oophorectomy and BRCA testing in Japan
Authors: Konnai Katsuyuki , Fujiwara Hiroyuki , Kitagawa Masakazu , Wakabayashi Reina , Yumori Asuna , Notomi Tsuguto , Onose Ryo , Kato Hisamori , Narimatsu Hiroto 
Published: February 2023

Abstract
Background
In April 2020, insurance coverage for risk-reducing salpingo-oophorectomy (RRSO) for breast cancer patients with hereditary breast and ovarian cancer (HBOC) syndrome and BRCA testing were started in Japan. We investigated the impact of insurance coverage on the number of RRSO and BRCA tests performed.

Methods
The subjects were 370 breast cancer patients and 23 of their relatives who received genetic counseling at our institution between April 2014 and December 2021. Finally, 349 patients and 15 relatives were analyzed. We retrospectively compared the number of BRCA tests, RRSO, insurance status, and co-payment of medical expenses before and after insurance coverage based on medical records.

Results
In the 6-year pre-coverage period, 226 patients (mean: 37/year) received genetic counseling and 106 (17/year) received BRCA testing. In the 21-month post-coverage period, 161 patients (92/year) received genetic counseling and 127 (72/year) received BRCA testing. The rate of testing/counseling significantly increased in the post-coverage period (46.9% vs. 78.8%; p < .001). The number of patients who were diagnosed with HBOC were 24 (4/year) and 18 (10/year) and RRSO was performed for 7 (1/year) and 11 (6/year) patients in the pre- and post-coverage periods, respectively. The rate of RRSO/HBOC was significantly increased in the post-coverage period (29.1% vs. 61.1%; p = 0.039). RRSO patients' co-payment rates decreased from 64% to 25% pre- and post-coverage.

Conclusions
Our findings suggest that decreased co-payments were the primary reason for these increases. Insurance coverage is an important factor when promoting preventive medical services such as RRSO.
Associations between sex differences, eating disorder behaviors, physical and mental health, and self-harm among Chinese adolescents
Authors: Wang Yuanyuan , Ma Zhihao , Lu Su , Duan Zhizhou , Wilson Amanda , Jia Yinwei , Yang Yong , Chen Runsen 
Published: February 2023

Abstract
Background and aim
Eating Disorders (ED) result in impaired well-being, but there exist an insufficient number of studies that have focused on the influence of sex and sexual orientation disparities within ED behaviors. Thus, we aimed to investigate ED behaviors among male and female adolescents with different sexual orientations in a school sample to understand prevalence and correlates of different ED behaviors.

Method
Data was analysed from 11,440 Chinese school adolescents with a mean age of 14.74 years (SD = 1.46). Reported data was gathered on sociodemographic information including sexual orientation, ED behaviors, health factors (reported health, cognitive function), mental health factors (depression, anxiety, suicidal ideation, non-suicidal self-injurious behavior), and social functioning (school bully victimization, and school bully perpetration). Logistic regression models were used to estimate the associations with ED behaviors, using the heterosexual orientation as the reference group as they are the majority.

Results
Compared to female adolescents, male adolescents reported lower anxiety symptoms (t = − 12.39, p < 0.001, Cohen’s d = − 0.233), were more likely to be the perpetrator of school bullying (χ2 = 190.61, p < 0.001, φ = 0.129), and reported a lower likelihood of taking dietary restriction (χ2 = 290.08, p < 0.001, φ = 0.160). Overall, the prevalence of dietary restriction presented sex disparities. Adolescents who reported no sexual attraction were less likely to engage in ED behaviors. Using heterosexual orientation as the reference group, the group who reported no sexual attraction was associated with lower risk in dietary restriction and purging in both male and female adolescents. Using the heterosexual orientation as the reference group, female sexual minority groups were at high risk of ED behaviors, with bisexual orientation and gay/lesbian orientation having a higher likelihood of engaging in objective binge eating.

Conclusions
The results revealed significant sex and sexual orientation differences of ED behaviors. The study suggests that adolescents is a period of sexuality development and could be critical for understanding adolescents’ eating behaviors. It is important to guide adolescents to healthy eating during their development and considerations should be made by clinicians when creating interventions for ED behaviors among the different sex and sexual orientation groups.
Early progression of a pancreatic metastasis of synovial sarcoma after pancreatectomy
Authors: Okazaki Mitsuyoshi , Katano Kaoru , Sugita Hiroaki , Tokoro Tomokazu , Gabata Ryousuke , Takada Satoshi , Nakanuma Shinichi , Makino Isamu , Yagi Shintaro 
Published: February 2023

Abstract
Background
Synovial sarcoma is a malignant tumor that constitutes up to 10% of all soft-tissue sarcomas. The most frequent metastatic sites of synovial sarcoma are the lungs, lymph nodes, and bone, whereas pancreatic metastasis is extremely rare. Here, we report a case of pancreatic metastasis of synovial sarcoma.

Case presentation
Nine years before presentation, a 31-year-old woman underwent extensive resection of the primary tumor after chemotherapy for left upper extremity synovial sarcoma. Six months before presentation, interscapulothoracic amputation was performed for an enlarged mass in the left upper extremity; the patient was treated with pazopanib. Three months before presentation, chest computed tomography showed multiple lung metastases; during subsequent follow-up, abdominal computed tomography revealed a pancreatic metastasis of synovial sarcoma. The doubling time of the pancreatic tumor was 14 days, and it grew rapidly. Furthermore, treatment-resistant pancreatitis symptoms were detected; thus, we performed distal pancreatectomy and administered one course of a 70% dose of trabectedin. However, the patient died of rapid progression of lung metastasis and respiratory failure within 2 months after surgery.

Conclusions
Pancreatectomy may be carefully performed in cases of isolated pancreatic metastasis. However, the presence of other distant extrapancreatic metastases (e.g., uncontrolled lung metastases) may rule out pancreatectomy treatment.
A window of opportunity trial evaluating intratumoral injection of Copaxone® in patients with percutaneously accessible tumors
Authors: Baranda Joaquina C. , Mohyuddin Ghulam Rehman , Bur Andrés M. , Shnayder Yelizaveta , Sweeney Kyle R. , Kakarala Kiran , Prouty Megan , Pathak Harsh , Puri Rajni , Mitra Amrita , Madan Rashna , Forrest M. Laird , Huang Aric , Weir Scott , Godwin Andrew K. , Alhakamy Nabil A. , Griffin J. Daniel , Berkland Cory J. 
Published: February 2023

Abstract
Background
This window of opportunity trial evaluated the safety of intratumoral Copaxone® and profiled immune markers in biopsies before and after treatment.

Methods
Patients with percutaneously accessible malignancies scheduled for surgical resection with curative intent were eligible to participate. Adverse events from one, two, or three injections of Copaxone® were monitored leading up to surgical resection. Using RNA sequencing and spatial protein profiling of immune-related targets, changes in mRNA and protein expression patterns, respectively were assessed in tumor biopsy samples pre- and post-treatment.

Results
Adverse events at the injection site were mild and consistent with historic subcutaneous administration of Copaxone®. Increased intratumoral immune activity was evident in most patients, including the upregulation of genes associated with immune stimulation and targets of checkpoint inhibitor therapy.

Conclusions
Intratumoral injection of Copaxone® was well tolerated, and immune profile changes in the tumor microenvironment warrant its further evaluation as human intratumoral immunotherapy.

Trial registration
clinicaltrials.gov, NCT03982212 First posted June 11th,
2019
Is post-transplant day + 14 immature reticulocyte fraction (IRF) a reliable surrogate marker for predicting early platelet engraftment in pediatric hematopoietic stem cell transplant?
Authors: Ghias Zainab , Zaidi Uzma , Borhany Munira , Samad Shafaq Abdul , Durrani Noureen , Fatima Mushkbar , Zafar Sidra , Jamal Aisha , Shamsi Tahir 
Published: February 2023

Abstract
Background
Prophylactic platelet transfusion is given to patients when the platelet count is less than ten thousand to prevent clinically significant bleeding till platelet engraftment is documented. Despite a very low platelet count, if platelet engraftment is confidently predicted, then platelet transfusion can be avoided in an otherwise stable patient.

Objective
To determine the role of post-transplant day + 14 immature reticulocyte fraction (IRF) and immature platelet fraction (IPF) as surrogate markers for early prediction of platelet engraftment in pediatric hematopoietic stem cell transplant patients.

Material and methods
This prospective study was done at the National Institute of Blood Diseases and Bone Marrow Transplantation between January 2017 and December 2020. A total of 56 and 31 patients were enrolled in the deviation and validation cohorts respectively. IPF and IRF were tested on a Sysmex XN-1000 hematology analyzer on days + 14 and + 21 of the bone marrow transplant. Platelet count on day + 14 and the day of engraftment was documented. Spearman correlation analysis and receiver operating characteristic curve (ROC) calculation were done using the statistical package STATA version 12, to determine IRF and IPF cut-off values to predict a median platelet engraftment day.

Results
The derivation and validation cohorts were statistically comparable. The area under the receiver operating characteristic curve (ROC) for IPF and IRF was 0.53 (95% CI: 0.37 – 0.68, p = 0.750) and 0.74 (95% CI: 0.61 – 0.89, p = 0.001) respectively. A weak inverse correlation (rs0.36, p = 0.007) between IRF and platelet engraftment day was found. The ROC demonstrated that the cut-off value for Day + 14 IRF of 13% has a sensitivity and specificity of 92.9% and 37% respectively. This finding was confirmed in the validation group with sensitivity and specificity of 88.2% and 45.2% respectively.

Conclusion
This study found that Day + 14 IRF but not IPF value can reliably predict platelet engraftment by day + 17 post-transplant.
The Association and Joint Effect of Adipocyte Fatty Acid Binding Protein and Obesity Phenotype With Cardiovascular Events
Authors: Hu Tingting , Shen Yun , Cao Weijie , Xu Yiting , Wang Yufei , Bao Yuqian , Ma Xiaojing 
Published: February 2023

AbstractContextThere is little evidence regarding the joint effect of serum adipocyte fatty acid binding protein (A-FABP) levels and obesity phenotype on the risk of cardiovascular events.ObjectiveTo explore the association between serum A-FABP levels and obesity phenotype defined by fat percentage (fat%) and visceral fat area (VFA), and their joint impact on incident cardiovascular events.MethodsA total of 1345 residents (579 men and 766 women) without previous cardiovascular diseases at baseline, with body composition and serum A-FABP data available, were included. A bioelectrical impedance analyzer and magnetic resonance imaging were used to assess fat% and VFA, respectively.ResultsDuring a mean follow-up of 7.6 years, 136 cases of cardiovascular events (13.9 per 1000 person-years) occurred. Per 1-unit increase in loge-transformed A-FABP levels was associated with an increase in cardiovascular events risk (hazard ratio [HR] 1.87, 95% CI 1.33-2.63). The highest tertiles of fat% and VFA levels were related to higher risks of cardiovascular events (fat%: HR 2.38, 95% CI 1.49-3.81; VFA: HR 1.79, 95% CI 1.09-2.93). The association between A-FABP levels and cardiovascular events was more pronounced in participants with low fat%, regardless of VFA levels. The joint effect of high A-FABP levels and obesity resulted in a greater risk of cardiovascular events.ConclusionSerum A-FABP levels were significantly associated with the risk of cardiovascular events, and this pattern of association was more prominent among the population with low fat%, which was independent of VFA.
Information Value Analysis for Real-Time Silo Fill-Level Monitoring
Authors: Greif Toni , Stein Nikolai , Flath Christoph M. 
Published: February 2023

Supply chains in the construction industry are less efficient than in other industries (e.g., retail or automotive). The reason for the less optimized supply chains is often the lack of accurate, up-to-date information. For a leading supplier of building materials and construction systems, we perform a value of information analysis to guide future investments in costly sensors for silo fill-level monitoring. Silo inventory is vendor-managed as construction sites withdraw material from silos as they need it. Ensuring continuous availability of material requires proactive replenishment across products and customers. We establish the optimal purchase level of (partial) information for different hardware costs and service levels. Based on the current ensured service level regime, the minimum total costs are achieved with approximately 50% sensor-equipped silos for medium and high annual sensor costs. The findings on the appropriate use of information technology to improve decision making with partial information are generally relevant for suppliers looking to stand out with service guarantees and short delivery times. History: This paper was refereed.