bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune checkpoint inhibitors associated granulomatous small vessel vasculitis accompanied with tubulointerstitial nephritis: a case report
Authors: Tominaga Kenta , Takeuchi Kazuhiro , Takakuma Shoichiro , Sakamoto Emi , Hatanaka Saeko , Kajimoto Yusuke , Toda Etsuko , Terasaki Yasuhiro , Kunugi Shinobu , Terasaki Mika , Shimizu Akira 
Published: March 2023

Abstract
Background
Immune checkpoint inhibitors (ICIs) have provided significant benefits in cancer treatment, but they could develop immune-related adverse events (irAE). ICI-associated renal adverse effects are rare and tubulointerstitial nephritis (TIN) is the most common in the renal irAE. However, only a few case reports of renal vasculitis associated with ICI have been reported. In addition, the characteristics of infiltrating inflammatory cells of ICI-associated TIN and renal vasculitis have been uncertain.

Case presentation
A 65-year-old man received immune checkpoint inhibitors (ICIs), anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and anti-PD-1 (programmed cell death 1) antibodies for aggravated metastatic malignant melanoma. About 1 week after the second administration of nivolumab and ipilimumab, acute kidney injury developed. A renal biopsy was performed that showed TIN and non-necrotizing granulomatous vasculitis in interlobular arteries. Massive CD3+ T cells and CD163+ macrophages infiltrated both tubulointerstitium and interlobular arteries. Many infiltrating cells tested positive for Ki-67 and PD-1 ligand (PD-L1), but negative for PD-1. In CD3+ T cells, CD8+ T cells were predominantly infiltrated, and these cells were positive for Granzyme B (GrB) and cytotoxic granule TIA-1, but negative for CD25, indicating antigen-independent activated CD8+ T cells. Infiltration of CD4+ T cells was noted without obvious CD4+ CD25+ regulatory T (Treg) cells. His renal dysfunction recovered within 2 months of treatment with prednisolone in addition to discontinuation of nivolumab and ipilimumab.

Conclusions
We herein reported a case of ICI-related TIN and renal granulomatous vasculitis with infiltration of massive antigen-independent activated CD8+ T cells and CD163+ macrophages, and none or few CD4+ CD25+ Treg cells. These infiltrating cells might be a characteristic of the development of renal irAE.
Controlling Nutritional Status (CONUT) score is a prognostic marker in III-IV NSCLC patients receiving first-line chemotherapy
Authors: Zhang Yi , Kong Fei-Fei , Zhu Zheng-Qiu , Shan Hai-Xia 
Published: March 2023

Abstract
Background
To investigate the prognostic impact of the controlling nutritional status (CONUT) score in non-small-cell lung cancer (NSCLC) patients receiving first-line chemotherapy.

Methods
We retrospectively reviewed 278 consecutive patients undergoing chemotherapy for stage III-IV NSCLC between May 2012 and July 2020. CONUT score was calculated by incorporating serum albumin, total cholesterol, and total lymphocyte count. The patients were divided into two groups: CONUT ≥ 3 and CONUT < 3, according to receiver operating characteristic (ROC) analysis. The associations of CONUT with clinicopathological factors and survival were evaluated.

Results
A high CONUT score was significantly associated with older age(P = 0.003), worse ECOG-PS(P = 0.018), advanced clinical stage(P = 0.006), higher systematic inflammation index (SII) (P < 0.001)and lower prognostic nutritional index (PNI) (P < 0.001).The high CONUT group had a significantly shorter progression-free survival(PFS) and overall survival(OS) than the low CONUT group. In the univariate analysis, higher SII, higher CONUT, advanced clinical stage and lower PNI were associated with worse PFS (Pall < 0.05). Worse ECOG-PS, higher SII, higher CONUT, advanced clinical stage and lower PNI were associated with worse OS (Pall < 0.05). In multivariate analysis, CONUT(HR, 2.487; 95%CI 1.818 ~ 3.403; P < 0.001) was independently associated with PFS, while PNI(HR, 0.676; 95%CI 0.494 ~ 0.927; P = 0.015) and CONUT(HR, 2.186; 95%CI 1.591 ~ 3.002; P < 0.001)were independently associated with OS. In ROC analysis, CONUT had a higher area under the ROC curve (AUC) for the prediction of 24-month PFS and OS than the SII or PNI. When the time-dependent AUC curve was used to predict PFS and OS, CONUT tended to maintain its predictive accuracy for long-term prognosis at a significantly higher level for an extended period after chemotherapy when compared with the other markers tested. The CONUT score showed better accuracy of predicting OS (C-index: 0.711) and PFS(C-index: 0.753).

Conclusion
CONUT score is an independent prognostic indicator of poor outcomes for patients with stage III-IV NSCLC and is superior to the SII and PNI in terms of prognostic ability.
IgG4-related ophthalmic disease masquerading as ciliary body tumors and scleritis in both eyes: a case report
Authors: Ma Jiayue , Xie Manyun , Long Kejun , Deng Mi , Zhou Liang , Luo Jing 
Published: March 2023

Abstract
Background
To report a rare case of IgG4-related ophthalmic disease (IgG4-ROD) manifesting as intraocular masses and scleritis in both eyes in a 61-year-old male and to investigate the changes in multimodal imaging features of the lesion sites and helper T-cell type 1 (Th 1)/Th 2/Th 17 cytokine levels in the aqueous humor.

Case presentation
A patient with IgG4-ROD seemingly manifested with an intraocular tumor in the left eye and sequentially, with an inflammatory mass in the ciliary body and scleritis in the right eye. The patient complained of vision loss of 6 months duration in the left eye at his first visit. With a preliminary diagnosis of an intraocular tumor, enucleation of the left eyeball and histopathological examination were performed. Approximately 3 months later, the patient started to experience headache, eye pain, and declining vision in the right eye. Ophthalmic imaging revealed a ciliary mass and scleritis. Th 1/Th 2/Th 17 cytokine levels and multimodal imaging findings were analyzed before and after corticosteroid treatment. Histopathological examination and immunohistochemistry (IHC) of the enucleated left eye demonstrated lymphoplasmacytic infiltration with an IgG4+/IgG+ cell ratio of approximately 40%, pointing to the diagnosis of probable IgG4-ROD. Long-term treatment with corticosteroids led to significant improvement in the signs and symptoms of the left eye. Th 1/Th 2/Th 17 cytokine profile monitoring of the aqueous humor and multimodal imaging of the right eye showed gradual regression of the mass and attenuation of ocular inflammation during treatment.

Conclusions
Patients with an atypical presentation of IgG4-ROD, such as intraocular masses and scleritis, are likely to experience a significant delay in diagnosis. This case demonstrates the significance of IgG4-ROD in the differential diagnosis of intraocular tumors and ocular inflammation. IgG4-RD is a newly diagnosed disease with multi-organ involvement and little is known about its pathogenesis, particularly in the eye. The present case will open new challenges in the clinico-pathological diagnosis and research of this disease. Combined investigations of multimodal imaging and cytokine level detection of intraocular fluid provide a new and effective way to monitor disease progression.
Weight-dependent and weight-independent effects of dulaglutide on blood pressure in patients with type 2 diabetes
Authors: Ferdinand Keith C. , Dunn Julia , Nicolay Claudia , Sam Flora , Blue Emily K. , Wang Hui 
Published: March 2023

Abstract
Background
Patients with type 2 diabetes (T2D) treated with glucagon-like peptide-1 receptor agonists may experience reductions in weight and blood pressure. The primary objective of the current study was to determine the weight-dependent and weight-independent effects of ~ 6 months treatment with dulaglutide 1.5 mg treatment in participants with T2D.

Methods
Mediation analysis was conducted for five randomized, placebo-controlled trials of dulaglutide 1.5 mg to estimate the weight-dependent (i.e., mediated by weight) and weight-independent effects from dulaglutide vs. placebo on change from baseline for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure. A random-effects meta-analysis combined these results. To investigate a dose response between dulaglutide 4.5 mg and placebo, mediation analysis was first conducted in AWARD-11 to estimate the weight-dependent and weight-independent effects of dulaglutide 4.5 mg vs. 1.5 mg, followed by an indirect comparison with the mediation result for dulaglutide 1.5 mg vs. placebo.

Results
Baseline characteristics were largely similar across the trials. In the mediation meta-analysis of placebo-controlled trials, the total treatment effect of dulaglutide 1.5 mg after placebo-adjustment on SBP was − 2.6 mmHg (95% CI − 3.8, − 1.5; p < 0.001) and was attributed to both a weight-dependent effect (− 0.9 mmHg; 95% CI: − 1.4, − 0.5; p < 0.001) and a weight-independent effect (− 1.5 mmHg; 95% CI: − 2.6, − 0.3; p = 0.01), accounting for 36% and 64% of the total effect, respectively. For pulse pressure, the total treatment effect of dulaglutide (− 2.5 mmHg; 95% CI: − 3.5, − 1.5; p < 0.001) was 14% weight-dependent and 86% weight-independent. For DBP there was limited impact of dulaglutide treatment, with only a small weight-mediated effect. Dulaglutide 4.5 mg demonstrated an effect on reduction in SBP and pulse pressure beyond that of dulaglutide 1.5 mg which was primarily weight mediated.

Conclusions
Dulaglutide 1.5 mg reduced SBP and pulse pressure in people with T2D across the placebo-controlled trials in the AWARD program. While up to one third of the effect of dulaglutide 1.5 mg on SBP and pulse pressure was due to weight reduction, the majority was independent of weight. A greater understanding of the pleotropic effects of GLP-1 RA that contribute to reduction in blood pressure could support developing future approaches for treating hypertension.
Trial registrations (clinicaltrials.gov) NCT01064687, NCT00734474, NCT01769378, NCT02597049, NCT01149421, NCT03495102
The vascular function effects of adding exenatide or meal insulin to basal insulin therapy in early type 2 diabetes
Authors: Retnakaran Ravi , Pu Jiajie , Ye Chang , Emery Alexandra , Kramer Caroline K. , Zinman Bernard 
Published: March 2023

Abstract
Objective
Basal insulin glargine has a neutral effect on cardiovascular risk in type 2 diabetes (T2DM). In practice, basal insulin is often paired with a glucagon-like peptide-1 receptor agonist (GLP1-RA) or meal insulin; however, the cardiovascular implications of these combinations have not been fully elucidated. In this context, we sought to evaluate the vascular function effects of adding the GLP1-RA exenatide or meal insulin lispro to basal glargine therapy in early T2DM.

Methods
In this 20-week trial, adults with T2DM of < 7-years duration were randomized to 8-weeks treatment with (i) insulin glargine (Glar), (ii) glargine + thrice-daily lispro (Glar/Lispro), or (iii) glargine + twice-daily exenatide (Glar/Exenatide), followed by 12-weeks washout. At baseline, 8-weeks, and washout, fasting endothelial function was assessed with reactive hyperemia index (RHI) measurement by peripheral arterial tonometry.

Results
At baseline, there were no differences in blood pressure (BP), heart rate (HR) or RHI between participants randomized to Glar (n = 24), Glar/Lispro (n = 24), and Glar/Exenatide (n = 25). At 8-weeks, Glar/Exenatide decreased systolic BP (mean − 8.1 mmHg [95%CI − 13.9 to − 2.4], p = 0.008) and diastolic BP (mean − 5.1 mmHg [− 9.0 to − 1.3], p = 0.012) compared to baseline, with no significant changes in HR or RHI. Notably, baseline-adjusted RHI (mean ± SE) did not differ between the groups at 8-weeks (Glar 2.07 ± 0.10; Glar/Lispro 2.00 ± 0.10; Glar/Exenatide 1.81 ± 0.10; p = 0.19), nor did baseline-adjusted BP or HR. There were no differences between the groups in baseline-adjusted RHI, BP or HR after 12-weeks washout.

Conclusion
Adding either exenatide or lispro to basal insulin therapy does not appear to affect fasting endothelial function in early T2DM.
Trial Registration: ClinicalTrials.Gov NCT02194595.
RNA N6-methyladenosine modification in female reproductive biology and pathophysiology
Authors: Huang Erqing , Chen Lijuan 
Published: March 2023

AbstractGene expression and posttranscriptional regulation can be strongly influenced by epigenetic modifications. N6-methyladenosine, the most extensive RNA modification, has been revealed to participate in many human diseases. Recently, the role of RNA epigenetic modifications in the pathophysiological mechanism of female reproductive diseases has been intensively studied. RNA m6A modification is involved in oogenesis, embryonic growth, and foetal development, as well as preeclampsia, miscarriage, endometriosis and adenomyosis, polycystic ovary syndrome, premature ovarian failure, and common gynaecological tumours such as cervical cancer, endometrial cancer, and ovarian cancer. In this review, we provide a summary of the research results of m6A on the female reproductive biology and pathophysiology in recent years and aim to discuss future research directions and clinical applications of m6A-related targets. Hopefully, this review will add to our understanding of the cellular mechanisms, diagnostic biomarkers, and underlying therapeutic strategies of female reproductive system diseases.
Sex-specific innate immunity and ageing in long-lived fresh water turtles (Kinosternon flavescens: Kinosternidae)
Authors: Bronikowski Anne M. , Hedrick Ashley R. , Kutz Greta A. , Holden Kaitlyn G. , Reinke Beth , Iverson John B. 
Published: March 2023

Abstract
Background
The progressive deregulation of the immune system with age, termed immunosenescence, has been well studied in mammalian systems, but studies of immune function in long-lived, wild, non-mammalian populations are scarce. In this study we leverage a 38-year mark-recapture study to quantify the relationships among age, sex, survival, reproductive output and the innate immune system in a long-lived reptile, yellow mud turtles (Kinosternon flavescens; Testudines; Kinosternidae).

Methods
We estimated rates of survival and age-specific mortality by sex based on mark-recapture data for 1530 adult females and 860 adult males over 38 years of captures. We analyzed bactericidal competence (BC), and two immune responses to foreign red blood cells - natural antibody-mediated haemagglutination (NAbs), and complement-mediated haemolysis ability (Lys) - in 200 adults (102 females; 98 males) that ranged from 7 to 58 years of age captured in May 2018 during their emergence from brumation, and for which reproductive output and long-term mark-recapture data were available.

Results
We found that females are smaller and live longer than males in this population, but the rate of accelerating mortality across adulthood is the same for both sexes. In contrast, males exhibited higher innate immunity than females for all three immune variables we measured. All immune responses also varied inversely with age, indicating immunosenescence. For females that reproduced in the preceding reproductive season, egg mass (and therefore total clutch mass) increased with age,. In addition to immunosenescence of bactericidal competence, females that produced smaller clutches also had lower bactericidal competence.

Conclusions
Contrary to the general vertebrate pattern of lower immune responses in males than females (possibly reflecting the suppressive effects of androgens), we found higher levels of all three immune variables in males. In addition, contrary to previous work that found no evidence of immunosenescence in painted turtles or red-eared slider turtles, we found a decrease in bactericidal competence, lysis ability, and natural antibodies with age in yellow mud turtles.
A mobilization poster stimulates early in-hospital rehabilitation after cardiac surgery: a prospective sequential-group study
Authors: Halfwerk Frank R. , Wielens Nicole , Hulskotte Stephanie , Brusse-Keizer Marjolein , Grandjean Jan G. 
Published: March 2023

Abstract
Background
Patients infrequently mobilize at the surgical ward after cardiac surgery. Inactivity results in prolonged hospital stay, readmissions and increased cardiovascular mortality. Next, the course of in-hospital mobilization activities for patients is unclear. The aim was to evaluate early mobilization after heart surgery with a mobilization poster on the Activity Classification Guide for Inpatient Activities score from the American College for Sports Medicine (ACSM). Second, to develop a Thorax Centrum Twente (TCT) score to assess distinctive activities performed.

Methods
A poster was developed for the Moving is Improving! study to stimulate hospital mobilization after heart surgery. In this sequential-group study at a cardiothoracic surgery ward, 32 patients were included in the usual care group and 209 patients in the poster mobilization group. Change of ACSM and TCT scores over time were both defined as primary endpoints. Secondary endpoints included length of stay and survival. A subgroup analysis for coronary artery bypass grafting (CABG) was performed.

Results
ACSM score increased during hospital stay (p < 0.001). No significant increase of ACSM score was observed with a mobilization poster (p = 0.27), nor in the CABG subgroup (p = 0.15). The poster increased mobility to chair, toilet, corridor (all p < 0.01) and cycle ergometer (p = 0.02) as measured by the activity-specific TCT scores, without differences in length of stay or survival.

Conclusions
ACSM score measured day-to-day functional changes, without significant differences between the poster mobilization and usual care group. Actual activities measured with the TCT score did improve. The mobilization poster is now new standard care, and effects in other centers and other departments should be assessed.

Trial registration

This study does not fall under the ICMJE trial definition and was not registered.
Extensive sequence duplication in Arabidopsis revealed by pseudo-heterozygosity
Authors: Jaegle Benjamin , Pisupati Rahul , Soto-Jiménez Luz Mayela , Burns Robin , Rabanal Fernando A. , Nordborg Magnus 
Published: March 2023

Abstract
Background
It is apparent that genomes harbor much structural variation that is largely undetected for technical reasons. Such variation can cause artifacts when short-read sequencing data are mapped to a reference genome. Spurious SNPs may result from mapping of reads to unrecognized duplicated regions. Calling SNP using the raw reads of the 1001 Arabidopsis Genomes Project we identified 3.3 million (44%) heterozygous SNPs. Given that Arabidopsis thaliana (A. thaliana) is highly selfing, and that extensively heterozygous individuals have been removed, we hypothesize that these SNPs reflected cryptic copy number variation.

Results
The heterozygosity we observe consists of particular SNPs being heterozygous across individuals in a manner that strongly suggests it reflects shared segregating duplications rather than random tracts of residual heterozygosity due to occasional outcrossing. Focusing on such pseudo-heterozygosity in annotated genes, we use genome-wide association to map the position of the duplicates. We identify 2500 putatively duplicated genes and validate them using de novo genome assemblies from six lines. Specific examples included an annotated gene and nearby transposon that transpose together. We also demonstrate that cryptic structural variation produces highly inaccurate estimates of DNA methylation polymorphism.

Conclusions
Our study confirms that most heterozygous SNP calls in A. thaliana are artifacts and suggest that great caution is needed when analyzing SNP data from short-read sequencing. The finding that 10% of annotated genes exhibit copy-number variation, and the realization that neither gene- nor transposon-annotation necessarily tells us what is actually mobile in the genome suggests that future analyses based on independently assembled genomes will be very informative.
A novel rhein-huprine hybrid ameliorates disease-modifying properties in preclinical mice model of Alzheimer’s disease exacerbated with high fat diet
Authors: Espinosa-Jiménez Triana , Cano Amanda , Sánchez-López Elena , Olloquequi Jordi , Folch Jaume , Bulló Mònica , Verdaguer Ester , Auladell Carme , Pont Caterina , Muñoz-Torrero Diego , Parcerisas Antoni , Camins Antoni , Ettcheto Miren 
Published: March 2023

Abstract
Background
Alzheimer’s disease (AD) is characterized by a polyetiological origin. Despite the global burden of AD and the advances made in AD drug research and development, the cure of the disease remains elusive, since any developed drug has demonstrated effectiveness to cure AD. Strikingly, an increasing number of studies indicate a linkage between AD and type 2 diabetes mellitus (T2DM), as both diseases share some common pathophysiological features. In fact, β-secretase (BACE1) and acetylcholinesterase (AChE), two enzymes involved in both conditions, have been considered promising targets for both pathologies. In this regard, due to the multifactorial origin of these diseases, current research efforts are focusing on the development of multi-target drugs as a very promising option to derive effective treatments for both conditions.
In the present study, we evaluated the effect of rhein-huprine hybrid (RHE-HUP), a synthesized BACE1 and AChE inhibitor, both considered key factors not only in AD but also in metabolic pathologies. Thus, the aim of this study is to evaluate the effects of this compound in APP/PS1 female mice, a well-established familial AD mouse model, challenged by high-fat diet (HFD) consumption to concomitantly simulate a T2DM-like condition.

Results
Intraperitoneal treatment with RHE-HUP in APP/PS1 mice for 4 weeks reduced the main hallmarks of AD, including Tau hyperphosphorylation, Aβ42 peptide levels and plaque formation. Moreover, we found a decreased inflammatory response together with an increase in different synaptic proteins, such as drebrin 1 (DBN1) or synaptophysin, and in neurotrophic factors, especially in BDNF levels, correlated with a recovery in the number of dendritic spines, which resulted in memory improvement. Notably, the improvement observed in this model can be attributed directly to a protein regulation at central level, since no peripheral modification of those alterations induced by HFD consumption was observed.

Conclusions
Our results suggest that RHE-HUP could be a new candidate for the treatment of AD, even for individuals with high risk due to peripheral metabolic disturbances, given its multi-target profile which allows for the improvement of some of the most important hallmarks of the disease.