bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-18 receptor-α signalling pathway contributes to autoantibody-induced arthritis via neutrophil recruitment and mast cell activation
Authors: Kaieda Shinjiro , Kinoshita Takashi , Chiba Asako , Miyake Sachiko , Hoshino Tomoaki 
Published: June 2023

ABSTRACT

Objectives
The interleukin (IL)-18 signalling pathway is involved in animal models of collagen-induced arthritis, but the role of this pathway in autoantibody-induced arthritis is poorly understood. An autoantibody-induced arthritis model, K/BxN serum transfer arthritis, reflects the effector phase of arthritis and is important in innate immunity including neutrophils and mast cells. This study aimed to investigate the role of the IL-18 signalling pathway in autoantibody-induced arthritis using IL-18 receptor (IL-18R) α-deficient mice.

Methods
K/BxN serum transfer arthritis was induced in IL-18Rα−/− and wild-type B6 (controls) mice. The severity of arthritis was graded, and histological and immunohistochemical examinations were performed on paraffin-embedded ankle sections. Total Ribonucleic acid (RNA) isolated from mouse ankle joints was analysed by real-time reverse transcriptase–polymerase chain reaction.

Results
IL-18 Rα−/− mice had significantly lower arthritis clinical scores, neutrophil infiltration, and numbers of activated, degranulated mast cells in the arthritic synovium than in controls. IL-1β, which is indispensable for the progression of arthritis, was significantly downregulated in inflamed ankle tissue in IL-18 Rα−/− mice.

Conclusions
IL-18/IL-18Rα signalling contributes to the development of autoantibody-induced arthritis by enhancing synovial tissue expression of IL-1β and inducing neutrophil recruitment and mast cell activation. Therefore, inhibition of the IL-18Rα signalling pathway might be a new therapeutic strategy for rheumatoid arthritis.
Safety and effectiveness of sarilumab in Japanese patients with rheumatoid arthritis refractory to previous treatments: An interim analysis of a post-marketing surveillance
Authors: Kameda Hideto , Tasaka Sadatomo , Takahashi Toshiya , Suzuki Katsuhisa , Soeda Naoki , Tanaka Yoshiya 
Published: June 2023

ABSTRACT

Objectives
An interim analysis of post-marketing surveillance data to assess the safety and effectiveness of sarilumab in Japanese patients with rheumatoid arthritis refractory to previous treatment.

Methods
The interim analysis included patients who initiated sarilumab therapy between June 2018 and January 2021. The primary objective of this surveillance was safety.

Results
In total, 1036 patients were enrolled and registered by 12 January 2021 (interim cut-off date). Of these, 678 were included in the safety analysis [75.4% female; mean age (± standard deviation) 65.8 ± 13.0 years]. Adverse drug reactions, defined as adverse events classified as possibly or probably related to sarilumab, were reported in 170 patients (incidence: 25.1%), with white blood cell count decreased (4.4%) and neutrophil count decreased (1.6%) most frequently reported. Serious haematologic disorders (3.4%) and serious infections (including tuberculosis) (2.5%) were the most frequently reported priority surveillance items. No malignant tumour was reported. An absolute neutrophil count (ANC) below the minimum standard value did not increase the incidence of serious infections.

Conclusions
Sarilumab was well tolerated, and no new safety signals were noted in this analysis. There was no difference in the frequency of serious infections between patients with an ANC below or above normal.
DDMut: predicting effects of mutations on protein stability using deep learning
Authors: Zhou Yunzhuo , Pan Qisheng , Pires Douglas E V , Rodrigues Carlos H M , Ascher David B 
Published: June 2023

Abstract
Understanding the effects of mutations on protein stability is crucial for variant interpretation and prioritisation, protein engineering, and biotechnology. Despite significant efforts, community assessments of predictive tools have highlighted ongoing limitations, including computational time, low predictive power, and biased predictions towards destabilising mutations. To fill this gap, we developed DDMut, a fast and accurate siamese network to predict changes in Gibbs Free Energy upon single and multiple point mutations, leveraging both forward and hypothetical reverse mutations to account for model anti-symmetry. Deep learning models were built by integrating graph-based representations of the localised 3D environment, with convolutional layers and transformer encoders. This combination better captured the distance patterns between atoms by extracting both short-range and long-range interactions. DDMut achieved Pearson's correlations of up to 0.70 (RMSE: 1.37 kcal/mol) on single point mutations, and 0.70 (RMSE: 1.84 kcal/mol) on double/triple mutants, outperforming most available methods across non-redundant blind test sets. Importantly, DDMut was highly scalable and demonstrated anti-symmetric performance on both destabilising and stabilising mutations. We believe DDMut will be a useful platform to better understand the functional consequences of mutations, and guide rational protein engineering. DDMut is freely available as a web server and API at https://biosig.lab.uq.edu.au/ddmut.
Sordarin bound eEF2 unlocks spontaneous forward and reverse translocation on CrPV IRES
Authors: Ou Zheren , Petrov Alexey 
Published: June 2023

Abstract
The Intergenic Region Internal Ribosome Entry Sites (IGR IRESs) of Discistroviridae promote protein synthesis without initiation factors, with IRES translocation by elongation factor 2 (eEF2) being the first factor-catalysed reaction. Here, we developed a system that allows for the observation of intersubunit conformation of eukaryotic ribosomes at the single-molecule level by labeling rRNA. We used it to follow translation initiation and subsequent translocation of the cricket paralysis virus IRES (CrPV IRES). We observed that pre-translocation 80S–IRES ribosomes spontaneously exchanged between non-rotated and semi-rotated conformations, but predominantly occupied a semi-rotated conformation. In the presence of eEF2, ribosomes underwent forward and reverse translocation. Both reactions were eEF2 concentration dependent, indicating that eEF2 promoted both forward and reverse translocation. The antifungal, sordarin, stabilizes eEF2 on the ribosome after GTP hydrolysis in an extended conformation. 80S–CrPV IRES–eEF2-sordarin complexes underwent multiple rounds of forward and reverse translocations per eEF2 binding event. In the presence of sordarin, neither GTP hydrolysis nor a phosphate release were required for IRES translocation. Together, these results suggest that in the presence of sordarin, eEF2 promotes the mid and late stages of CrPV IRES translocation by unlocking ribosomal movements, with mid and late stages of translocation being thermally driven.
DNA mismatch repair in cancer immunotherapy
Authors: Guan Junhong , Li Guo-Min 
Published: June 2023

Abstract
Tumors defective in DNA mismatch repair (dMMR) exhibit microsatellite instability (MSI). Currently, patients with dMMR tumors are benefitted from anti-PD-1/PDL1-based immune checkpoint inhibitor (ICI) therapy. Over the past several years, great progress has been made in understanding the mechanisms by which dMMR tumors respond to ICI, including the identification of mutator phenotype-generated neoantigens, cytosolic DNA-mediated activation of the cGAS-STING pathway, type-I interferon signaling and high tumor-infiltration of lymphocytes in dMMR tumors. Although ICI therapy shows great clinical benefits, ∼50% of dMMR tumors are eventually not responsive. Here we review the discovery, development and molecular basis of dMMR-mediated immunotherapy, as well as tumor resistant problems and potential therapeutic interventions to overcome the resistance.
Short-chain fatty acids and insulin sensitivity: a systematic review and meta-analysis
Authors: Pham Nhan H T , Joglekar Mugdha V , Wong Wilson K M , Nassif Najah T , Simpson Ann M , Hardikar Anandwardhan A 
Published: June 2023

Abstract

Context
There is substantial evidence that reduced short-chain fatty acids (SCFAs) in the gut are associated with obesity and type 2 diabetes, although findings from clinical interventions that can increase SCFAs are inconsistent.

Objective
This systematic review and meta-analysis aimed to assess the effect of SCFA interventions on fasting glucose, fasting insulin, and homeostatic model assessment of insulin resistance (HOMA-IR).

Data Sources
Relevant articles published up to July 28, 2022, were extracted from PubMed and Embase using the MeSH (Medical Subject Headings) terms of the defined keywords [(short-chain fatty acids) AND (obesity OR diabetes OR insulin sensitivity)] and their synonyms. Data analyses were performed independently by two researchers who used the Cochrane meta-analysis checklist and the PRISMA guidelines.

Data Extraction
Clinical studies and trials that measured SCFAs and reported glucose homeostasis parameters were included in the analysis. Standardized mean differences (SMDs) with 95%CIs were calculated using a random-effects model in the data extraction tool Review Manager version 5.4 (RevMan 5.4). The risk-of-bias assessment was performed following the Cochrane checklist for randomized and crossover studies.

Data Analysis
In total, 6040 nonduplicate studies were identified, 23 of which met the defined criteria, reported fasting insulin, fasting glucose, or HOMA-IR values, and reported change in SCFA concentrations post intervention. Meta-analyses of these studies indicated that fasting insulin concentrations were significantly reduced (overall effect: SMD = −0.15; 95%CI = −0.29 to −0.01, P = 0.04) in treatment groups, relative to placebo groups, at the end of the intervention. Studies with a confirmed increase in SCFAs at the end of intervention also had a significant effect on lowering fasting insulin (P = 0.008). Elevated levels of SCFAs, compared with baseline levels, were associated with beneficial effects on HOMA-IR (P &lt; 0.00001). There was no significant change in fasting glucose concentrations.

Conclusion
Increased postintervention levels of SCFAs are associated with lower fasting insulin concentrations, offering a beneficial effect on insulin sensitivity.

Systematic Review Registration
PROSPERO registration number CRD42021257248.
Comparing 7-Day Versus 6–8-Day Penicillin Treatment Intervals Among Pregnant People With Syphilis of Late or Unknown Duration: No Difference Found in Incidence of Congenital Syphilis
Authors: Johnson Kelly A , Burghardt Nicole O , Snyder Robert E , Plotzker Rosalyn E , Imp Brandon M , Murphy Ryan , Jacobson Kathleen , Tang Eric C 
Published: June 2023

Abstract

Background
Guidelines recommend that pregnant patients with syphilis of late/unknown duration be treated with benzathine penicillin G, dosed as 3 weekly intramuscular injections (BPGx3) given ideally at strict 7-day intervals. Given limited pharmacokinetic data, it is unknown whether more flexible BPG treatment intervals might be effective in preventing congenital syphilis (CS).

Methods
We used California surveillance data to identify birthing parent/infant dyads wherein the pregnant parent had syphilis of late/unknown duration between January 1, 2016 – June 30, 2019. We divided the dyads into 3 groups based on prenatal treatment: (1) BPGx3 at strict 7-day intervals, (2) BPGx3 at 6-8 day intervals, and (3) no/inadequate treatment. We then compared CS incidence among infants in each group.

Results
We analyzed 1,092 parent/infant dyads: 607 (55.6%) in the 7-day treatment group, 70 (6.4%) in the 6–8 day treatment group, and 415 (38.0%) in the no/inadequate treatment group. The incidence proportion of infants meeting CS criteria in each group was, respectively, 5.6%, 5.7%, and 36.9%. Compared with BPGx3 at 7-day intervals, the odds of CS were 1.0 [95% CI 0.4–3.0] in the 6–8 day group and 9.8 [95% CI 6.6–14.7] in the no/inadequate treatment group.

Conclusions
Prenatal BPGx3 at 6–8 days was no more likely to lead to CS in infants than 7-days. These findings hint that 6-8-day intervals might be adequate to prevent CS among pregnant people with syphilis of late/unknown duration. Consequently, it is possible that CS evaluation beyond an RPR at delivery may be unnecessary in asymptomatic infants whose parents received BPGx3 at 6–8 days.
Propensity-Score Matched Analysis of the Effectiveness of Baricitinib in Patients With Coronavirus Disease 2019 (COVID-19) Using Nationwide Real-World Data: An Observational Matched Cohort Study From the Japan COVID-19 Task Force
Authors: Tanaka Hiromu , Chubachi Shotaro , Namkoong Ho , Sato Yasunori , Asakura Takanori , Lee Ho , Azekawa Shuhei , Otake Shiro , Nakagawara Kensuke , Fukushima Takahiro , Watase Mayuko , Sakurai Kaori , Kusumoto Tatsuya , Kondo Yasushi , Masaki Katsunori , Kamata Hirofumi , Ishii Makoto , Kaneko Yuko , Hasegawa Naoki , Ueda Soichiro , Sasaki Mamoru , Izumo Takehiro , Inomata Minoru , Miyazawa Naoki , Kimura Yasuhiro , Suzuki Yusuke , Harada Norihiro , Ichikawa Masako , Takata Tohru , Ishikura Hiroyasu , Yoshiyama Takashi , Kokuto Hiroyuki , Murakami Koji , Sano Hirohito , Ueda Tetsuya , Kuwahara Naota , Fujiwara Akiko , Ogura Takashi , Inoue Takashi , Asami Takahiro , Mutoh Yoshikazu , Nakachi Ichiro , Baba Rie , Nishi Koichi , Tani Mayuko , Kagyo Junko , Hashiguchi Mizuha , Oguma Tsuyoshi , Asano Koichiro , Nishikawa Masanori , Watanabe Hiroki , Okada Yukinori , Koike Ryuji , Kitagawa Yuko , Kimura Akinori , Imoto Seiya , Miyano Satoru , Ogawa Seishi , Kanai Takanori , Fukunaga Koichi 
Published: June 2023

Abstract

Background
To determine the effectiveness of baricitinib in patients with coronavirus disease 2019 (COVID-19), investigate whether baricitinib prevents the need for invasive mechanical ventilation and identify patient subgroups that would benefit from baricitinib.

Methods
This observational matched-cohort study was conducted by the Japan COVID-19 Task Force, a nationwide multicenter consortium. Patients with COVID-19 aged ≥18 years were identified from 70 hospitals in Japan. Among patients with confirmed COVID-19 from February 2020 to September 2021, those receiving baricitinib were propensity-score matched with controls.

Results
Among 3309 patients, 144 propensity score-matched pairs were identified. Thirteen (9.0%) patients in the baricitinib group and 27 (18.8%) in the control group required invasive mechanical ventilation during the disease course (odds ratio, 0.43). Although the baricitinib group had more severe disease, there were no significant differences in the intensive care unit admission rates (odds ratio, 1.16) and mortality rates (odds ratio, 0.74) between groups. In subgroup analyses, baricitinib was associated with a significant reduction in the need for invasive mechanical ventilation in patients requiring oxygen support (odds ratio, 0.28), with rapid shadow spread on chest radiography (odds ratio, 0.11), or treated with remdesivir (odds ratio, 0.27), systemic corticosteroids (odds ratio, 0.31), or anticoagulants (odds ratio, 0.17).

Conclusions
Baricitinib is effective at preventing the need for invasive mechanical ventilation in patients with COVID-19.
Less Irradiation to Lymphocyte-Related Organs Reduced the Risk of G4 Lymphopenia in Esophageal Cancer: Re-Analysis of Prospective Trials
Authors: Tseng Ihsuan , Li Fangfang , Ai Dashan , Chen Yun , Xu Yang , Yu Lu , Hao Shengnan , Zhu Hongcheng , Deng Jiaying , Liu Qi , Pan Fan , Su Fengtao , Zhao Kuaile 
Published: June 2023

Abstract

Background
This study aimed to explore the relationship between irradiation of lymphocyte-related organs at risk (LOARs) and lymphopenia during definitive concurrent chemoradiotherapy (dCCRT) for esophageal squamous cell carcinoma (ESCC).

Materials and Methods
Cases of ESCC patients who received dCCRT from 2 prospective clinical trials were identified. To find its correlation with survival outcomes, grades of absolute lymphocyte counts (ALCs) nadir during radiotherapy were recorded following COX analysis. Associations of lymphocytes at nadir and dosimetric parameters including relative volumes of spleen and bone marrow receiving 0.5, 1, 2, 3, 5, 10, 20, 30, and 50Gy (V0.5, V1, V2, V3, V5, V10, V20, V30, and V50), and effective dose to circulating immune cells (EDIC) were examined by logistic risk regression analysis. The cutoffs of dosimetric parameters were determined by the receiver operating characteristic curve (ROC).

Results
A total of 556 patients were included. The incidences of grades 0, 1, 2, 3, and 4 (G4) lymphopenia during dCCRT were 0.2%, 0.5%, 9.7%, 59.7%, and 29.8%, respectively. Their median overall survival (OS) and progression-free survival (PFS) time were 50.2 and 24.3 months, respectively; the incidence of local recurrence and distant metastasis were 36.6% and 31.8%, respectively. Patients once suffering from G4 nadir during radiotherapy had unfavorable OS (HR, 1.28; P = .044) and a higher incidence of distant metastasis (HR, 1.52; P = .013). Furthermore, patients with EDIC ≤8.3Gy plus spleen V0.5 ≤11.1% and bone marrow V10 ≤33.2% were strongly associated with lower risk of G4 nadir (OR, 0.41; P = .004), better OS (HR, 0.71; P = .011) and lower risk of distant metastasis (HR, 0.56; P = .002).

Conclusions
Smaller relative volumes of spleen V0.5 and bone marrow V10 plus lower EDIC were jointly prone to reduce the incidence of G4 nadir during definitive concurrent chemoradiotherapy. This modified therapeutic strategy could be a significant prognostic factor for survival outcomes in ESCC.
The Value of Pharmaceutical Industry-Sponsored Patient Registries in Oncology Clinical Research
Authors: Flick E Dawn , Terebelo Howard R , Fish Susan , Kitali Amani , Mahajan Vrinda , Nifenecker Melissa , Sullivan Kristen , Thaler Paul , Ussery Sarah , Grinblatt David L 
Published: June 2023

Abstract
In May 2019, the US Food and Drug Administration (FDA) released the Framework for FDA’s Real-World Evidence (RWE) Program, a draft guidance to evaluate the potential use of real-world data in facilitating regulatory decisions. As a result, pharmaceutical companies and medical communities see patient registries, which are large, prospective, noninterventional cohort studies, as becoming increasingly important in providing evidence of treatment effectiveness and safety in clinical practice. Patient registries are designed to collect longitudinal clinical data on a broad population to address critical medical questions over time. With their large sample sizes and broad inclusion criteria, patient registries are often used to generate RWE in the general and underrepresented patient populations that are less likely to be studied in controlled clinical trials. Here, we describe the value of industry-sponsored patient registries in oncology/hematology settings to healthcare stakeholders, in drug development, and in fostering scientific collaboration.
Impact of Volumetric Dosimetry on the Projected Cost of Radiation-Related Late Effects Screening After Childhood Cancer: A Real-World Cohort Analysis
Authors: Cohen-Cutler Sally , Kaplan Cameron , Olch Arthur , Wong Kenneth , Malvar Jemily , Constine Louis S , Freyer David R 
Published: June 2023

Abstract

Background
Screening guidelines for childhood cancer survivors treated with radiation currently rely on broad anatomic irradiated regions (IR) to determine risk for late effects. However, contemporary radiotherapy techniques use volumetric dosimetry (VD) to define organ-specific exposure, which supports more specific screening recommendations that could be less costly.

Patients and Methods
This was a cross-sectional study of 132 patients treated with irradiation at Children’s Hospital Los Angeles from 2000 to 2016. For 5 key organs (cochlea, breast, heart, lung, and colon), radiation exposure was determined retrospectively using both IR and VD methods. Under each method, Children’s Oncology Group Long-Term Follow-Up Guidelines were used to identify organs flagged for screening and recommended screening tests. Projected screening costs incurred under each method were computed through age 65 using insurance claims data.

Results
Median age at the end of treatment was 10.6 years (range, 1.4-20.4). Brain tumor was the most common diagnosis (45%) and head/brain the most common irradiated region (61%). For all 5 organs, use of VD rather than IR resulted in fewer recommended screening tests. This led to average cumulative estimated savings of $3769 (P = .099), with significant savings in patients with CNS tumors (P = .012). Among patients with savings, average savings were $9620 per patient (P = .016) and significantly more likely for females than males (P = .027).

Conclusion
Use of VD to enhance precision of guideline-based screening for radiation-related late effects permits fewer recommended screening tests and generates cost-savings.
Exocrine Pancreatic Insufficiency Induced by Immune Checkpoint Inhibitors
Authors: Satish Deepika , Lin I-Hsin , Flory James , Gerdes Hans , Postow Michael A , Faleck David M 
Published: June 2023

Abstract

Background
Scant data describe exocrine pancreatic insufficiency (EPI) secondary to immune checkpoint inhibitor (ICI) use. The goal of this study is to describe the incidence, risk factors, and clinical characteristics of patients with ICI-related EPI.

Patients and Methods
A single center, retrospective case-control study was performed of all ICI-treated patients at Memorial Sloan Kettering Cancer Center between January 2011 and July 2020. ICI-related EPI patients had steatorrhea with or without abdominal discomfort or weight loss, started pancrelipase after initiation of ICI, and demonstrated symptomatic improvement with pancrelipase. Controls were matched 2:1 by age, race, sex, cancer type, and year of ICI start.

Results
Of 12 905 ICI-treated patients, 23 patients developed ICI-related EPI and were matched to 46 controls. The incidence rate of EPI was 1.18 cases per 1000 person-years and the median onset of EPI was 390 days after the first dose of ICI. All 23 (100%) EPI cases had steatorrhea that improved with pancrelipase, 12 (52.2%) had weight loss, and 9 (39.1%) had abdominal discomfort; none had changes of chronic pancreatitis on imaging. Nine (39%) EPI patients had episodes of clinical acute pancreatitis preceding the onset of EPI, compared to 1 (2%) control (OR 18.0 (2.5-789.0), P &lt; .001). Finally, the EPI group exhibited higher proportions of new or worsening hyperglycemia after ICI exposure compared with the control group (9 (39.1%) vs. 3 (6.5%), P &lt; .01).

Conclusion
ICI-related EPI is a rare but clinically significant event that should be considered in patients with late onset diarrhea after ICI treatment and often is associated with development of hyperglycemia and diabetes.
Gene-based drug therapy in children
Authors: Rassekh S Rod , Rieder Michael , ‘t Jong Geert 
Published: June 2023

Abstract
The past two decades have seen enormous advancements in medical knowledge around the role of genetic factors of variability, both in human disease and drug response. This knowledge is increasingly being translated into guidelines that inform drug dosing, monitoring for efficacy and safety, and determining the suitability of specific agents to treat patients. Health Canada and the U.S. Food and Drug Administration have recommended using genetic information to guide dosing for more than 20 drugs. There are no current, comprehensive paediatric guidelines to assist health care professionals in the use of genetics to inform medication dosing, safety, and efficacy in children, and such guidance is urgently needed. This statement helps to guide clinician understanding of the role of pharmacogenetics and how to use this information when prescribing medications in paediatrics.