bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective inhibition of integrin αvβ6 leads to rapid induction of urinary bladder tumors in cynomolgus macaques
Authors: Guffroy Magali , Trela Bruce , Kambara Takahito , Stawski Lukasz , Chen Huidong , Luus Lia , Montesinos Monica S , Olson Lauren , He Yupeng , Maisonave Kevin , Carr Tracy , Lu Min , Ray Adrian S , Hazelwood Lisa A 
Published: December 2022

AbstractAdministration of a novel and selective small molecule integrin αvβ6 inhibitor, MORF-627, to young cynomolgus monkeys for 28 days resulted in the rapid induction of epithelial proliferative changes in the urinary bladder of 2 animals, in the absence of test agent genotoxicity. Microscopic findings included suburothelial infiltration by irregular nests and/or trabeculae of epithelial cells, variable cytologic atypia, and high mitotic rate, without invasion into the tunica muscularis. Morphologic features and patterns of tumor growth were consistent with a diagnosis of early-stage invasive urothelial carcinoma. Ki67 immunohistochemistry demonstrated diffusely increased epithelial proliferation in the urinary bladder of several monkeys, including those with tumors, and αvβ6 was expressed in some epithelial tissues, including urinary bladder, in monkeys and humans. Spontaneous urothelial carcinomas are extremely unusual in young healthy monkeys, suggesting a direct link of the finding to the test agent. Inhibition of integrin αvβ6 is intended to locally and selectively block transforming growth factor beta (TGF-β) signaling, which is implicated in epithelial proliferative disorders. Subsequent in vitro studies using a panel of integrin αvβ6 inhibitors in human bladder epithelial cells replicated the increased urothelial proliferation observed in monkeys and was reversed through exogenous application of TGF-β. Moreover, analysis of in vivo models of liver and lung fibrosis revealed evidence of epithelial hyperplasia and cell cycle dysregulation in mice treated with integrin αvβ6 or TGF-β receptor I inhibitors. The cumulative evidence suggests a direct link between integrin αvβ6 inhibition and decreased TGF-β signaling in the local bladder environment, with implications for epithelial proliferation and carcinogenesis.
Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells
Authors: Li Yuxi , Li Xilin , Cournoyer Patrick , Choudhuri Supratim , Yu Xiaozhong , Guo Lei , Chen Si 
Published: December 2022

AbstractCannabidiol (CBD), one of the major cannabinoids in the plant Cannabis sativa L., is the active ingredient in a drug approved for the treatment of seizures associated with certain childhood-onset epileptic disorders. CBD has been shown to induce male reproductive toxicity in multiple animal models. We previously reported that CBD inhibits cellular proliferation in the mouse Sertoli cell line TM4 and in primary human Sertoli cells. In this study, using a transcriptomic approach with mRNA-sequencing analysis, we identified molecular mechanisms underlying CBD-induced cytotoxicity in primary human Sertoli cells. Analysis of differentially expressed genes demonstrated that DNA replication, cell cycle, and DNA repair were the most significantly affected pathways. We confirmed the concentration-dependent changes in the expression of key genes in these pathways using real-time PCR. mRNA sequencing showed upregulation of a group of genes tightly associated with the senescence-associated secretory phenotype (SASP) and with the activation of the p53 signaling pathway, a key upstream event in cellular senescence. Prolonged treatment of 10 μM CBD-induced cellular senescence, as evidenced by the stable cessation of proliferation and the activation of senescence-associated β-galactosidase (SA-β-gal), 2 hallmarks of senescence. Additionally, using real-time PCR and Western blotting assays, we observed that CBD treatment increased the expression of p16, an important marker of cellular senescence. Taken together, our results show that CBD exposure disturbs various interrelated signaling pathways and induces cellular senescence in primary human Sertoli cells.
EU energy governance—moving targets and flexible ambitions between opacity and opportunism?
Authors: Hancher Leigh 
Published: December 2022

Abstract
This article examines the robustness of the architecture of European energy and climate governance and the instruments developed to execute climate governance based on EU-wide targets and the ambition of ‘net-zero’ by 2050. Its primary focus is on the quality of the European energy and climate governance process.The Commission’s primary task is to monitor closely national efforts to achieve the EU’s binding targets for example on energy efficiency, greenhouse gas (GHG) emission reduction and renewables production, to report regularly on progress or lack thereof. Although a considerable literature on climate governance has now evolved its focus is primarily on the tools available to the Commission to realize the Union’s climate and energy governance strategy in the absence of legally binding national targets. Many important and central questions about this governance process remain largely unanswered and unresolved. Legally binding union-wide climate targets are embraced by the new EU Climate Law of 2021, and various measures to promote renewable energy, energy efficiency and emission reduction are expressed to be ‘legally binding’ on the European institutions. But what does this mean in practice – especially in the current ‘energy emergency’ situation? Are there any effective legal constraints if the Commission’s actions or its failure to act is likely to imperil the timely realization of these ‘binding’ European wide targets. The first part of this article analyses the climate and energy governance and assesses the Commission’s role and responsibilities. Two additional and inter-related instruments of European ‘net zero governance’ are dealt with in the second and third parts. These are the reliance on delegated acts (part two) and the use of state aid control (part three). The scope of the Commission’s discretion when drawing up delegated rules has become an essential element of the ‘net zero’ governance process. An assessment of the application of the Treaty state aid rules to national schemes to support fossil fuels provides useful legal as well as policy insights. It serves as an important testing ground for policy coherence and continuity in pursuing the Union’s climate goals. This assessment contributes to a practical appraisal of the quality of governance from the perspective of this article – in terms of the scope of discretion open to the Commission to continue to approve such subsidies even in the light of the Climate Law’s binding targets.
Artificially sweetened beverages and urinary incontinence—a secondary analysis of the Women's Health Initiative Observational Study
Authors: Ringel Nancy E. , Hovey Kathleen M. , Andrews Chris A. , Mossavar-Rahmani Yasmin , Shadyab Aladdin H. , Snetselaar Linda G. , Howard Barbara V. , Iglesia Cheryl B. 
Published: December 2022

Abstract

Objective
The aim of this study was to determine if higher artificially sweetened beverage intake is associated with higher prevalence of urinary incontinence symptoms.

Methods
We conducted a secondary analysis of data from the Women's Health Initiative Observational Study. Our analytic cohort included 80,388 women. Participants who answered questions about beverage consumption and urinary incontinence symptoms at a 3-year follow-up visit were included. Demographic characteristics were compared between three groups of beverage consumers: never to less than one serving per week, one to six servings per week, and greater than or equal to one serving per day. Multivariable logistic regression models were constructed to estimate odds and type of urinary incontinence and adjust for potential confounders.

Results
Most participants (64%) were rare consumers of artificially sweetened beverages, with 13% (n = 10,494) consuming greater than or equal to 1 serving per day. The unadjusted odds of reporting urinary incontinence were 10% to 12% higher in women consuming one to six servings per week (odds ratio [OR], 1.10; 95% CI, 1.06-1.14) or greater than or equal to one serving per day (OR, 1.12; 95% CI, 1.07-1.18) versus never to less than one serving per week. In multivariable analyses, women consuming greater than or equal to one serving per day (ref: never to <1 serving/wk) had 10% higher odds of reporting mixed urinary incontinence (OR, 1.10; 95% CI, 1.02-1.19). There were no significant differences for stress or urgency urinary incontinence symptoms between groups.

Conclusions
When compared to never to less than one serving per week, women consuming greater than or equal to one serving per day of artificially sweetened beverages had 10% greater odds of reporting mixed urinary incontinence after adjustments. Amount of artificially sweetened beverage consumption was not associated with stress or urgency urinary incontinence symptoms.
Smoking Cessation Interventions for Patients With Chronic Obstructive Pulmonary Disease
Authors: Coleman Sulamunn R. M. , Menson Katherine E. , Kaminsky David A. , Gaalema Diann E. 
Published: December 2022

Purpose:
Reducing disease burden in patients with chronic obstructive pulmonary disease (COPD) focuses, in part, on helping patients become more functional through programs such as pulmonary rehabilitation (PR). Smoking cessation may be a prerequisite or component of PR, and determining which smoking interventions (eg, behavioral, pharmacotherapy, combination) are most effective can help guide efforts to extend them to patients with COPD. The purpose of this narrative review was to summarize evidence from studies testing smoking cessation interventions in patients with COPD and discuss how these interventions may be integrated into PR programs.

Review Methods:
Searches were conducted in the PubMed and Web of Science databases. Search terms included “(smoking cessation) AND (RCT OR clinical trial OR intervention) AND (pulmonary OR chronic bronchitis OR emphysema OR COPD).” Published original studies were included if they used a prospective, experimental design, tested a smoking cessation intervention, reported smoking cessation rate, and included patients with COPD or a subgroup analysis focused on smokers with COPD.

Summary:
Twenty-seven distinct studies were included in the review. Most studies tested multitreatment smoking cessation interventions involving some form of counseling in combination with pharmacotherapy and/or health education. Overall, smoking cessation interventions may help promote higher rates of smoking abstinence in patients with COPD, particularly multifaceted interventions that include intensive counseling (eg, individual, group, and telephone support), smoking cessation medication or nicotine replacement therapy, and health education.
One institutions’ experience with a true standard 15 mCi dose of I-131 for the treatment of Graves’ disease
Authors: Muhleman Mitchel A. , Fahim Ali , Benefield Thad , Oldan Jorge D. , Khandani Amir H. 
Published: December 2022

Introduction
Currently, there is a lack of consensus on the fixed dosage of RAI to be administered for this purpose between the main guideline frameworks set forth by the American Thyroid Association (ATA), Society of Nuclear Medicine and Molecular Imaging (SNMMI), European Association of Nuclear Medicine (EANM) and the European Thyroid Association (ETA). In this retrospective study, we will investigate the effectiveness of using a standard dose of 15 mCi ±10% of RAI in the treatment of Graves’.

Methods
A retrospective chart review was conducted for the period between 1 May 2014 and 2 September 2020, to identify patients diagnosed with hyperthyroidism due to Graves’ disease. The patients were grouped based on outcome and assessed for the efficacy of the dosage of 15 mCi ±10% of RAI in a successful treatment.

Results
Sixty-seven patients were identified that met the inclusion criteria between 1 May 2014 and 2 September 2020. Of the 67 RAI ablations; 60 patients became hypothyroid [60/67, (89.55%)], 2 euthyroid [2/67, (2.99%)] and 5 remained hyperthyroid [5/67, (7.46%)].

Conclusions
For the treatment of Graves’ disease, the use of a standard low dose of 15 mCi ±10% has a high success rate without additional measurements or calculations beyond a standard planar image and 24-h uptake %. The adoption of a standard low dose of 15 mCi of I-131 across institutional guidelines would streamline dosage questions and eliminate the need to determine the weight of the thyroid for calculations in all RAI treatments for hyperthyroidism caused by Graves’ disease.
Influence of the methodological aspects of the dichotomization of total metabolic tumor volume measured through baseline fluorine-18 fluorodeoxyglucose PET on survival prediction in lymphoma
Authors: Lue Kun-Han , Chen Yu-Hung , Wu Yi-Feng , Liu Shu-Hsin 
Published: December 2022

Objective
The total metabolic tumor volume (TMTV) measured from fluorine-18 fluorodeoxyglucose (18F-FDG) PET can be useful for determining the prognosis of patients with lymphoma. Stratifying patients into high- and low-TMTV risk groups requires a cutoff point, which is determined through the dichotomization method. This study investigated whether different TMTV dichotomization methods influenced survival prediction in patients with lymphoma.

Methods
We retrospectively enrolled 129 patients with lymphoma who had undergone baseline 18F-FDG PET. TMTV was calculated using a fixed standardized uptake value threshold of 4.0. A total of six methods were employed to determine the optimal TMTV cutoff point using receiver-operating characteristic curve analyses, X-Tile bioinformatics software, and the Cutoff Finder web application. The prognostic performance of each method in survival prediction was examined.

Results
The median (interquartile range) TMTV was 123 cm3 (21–335 cm3). The optimal TMTV cutoff values for predicting progression-free survival (PFS) and overall survival (OS) were in the range of 144–748 cm3. The cutoff points were used to dichotomize patients into two groups with distinct prognoses. All TMTV dichotomizations were significantly predictive of PFS and OS. The survival curves showed significant differences between the high- and low-TMTV groups. The C-indices of the survival models did not significantly differ in any of the dichotomizations.

Conclusion
The prognostic significance of TMTV was maintained regardless of the methodological aspects of dichotomization. However, the optimal TMTV cutoff point varied according to the chosen dichotomization method. Care should be taken when establishing an optimal TMTV cutoff point for clinical use.
Associations Between Dysfunctional Thoughts, Leisure Activities, and IL-6 in Caregivers of Family Members With Dementia
Authors: Vara-García Carlos , Romero-Moreno Rosa , Barrera-Caballero Samara , Pedroso-Chaparro María del Sequeros , Jiménez-Gonzalo Lucía , Olazarán Javier , Mausbach Brent , von Känel Roland , Losada-Baltar Andrés 
Published: December 2022

ABSTRACT

Objective
Dementia caregiving is associated with negative physical health consequences, including inflammation processes. The objective of this study was to analyze the associations between dysfunctional thoughts, frequency of leisure activities, and interleukin 6 (IL-6) in a sample of dementia family caregivers.

Methods
One hundred forty dementia caregivers participated in this cross-sectional study. The relationships among caregivers’ dysfunctional thoughts, leisure activities, and IL-6 were adjusted for demographic characteristics, stressors, and physical and mental health indicators in a linear regression analysis.

Results
Higher levels of dysfunctional thoughts (t = −2.02, p = .045) were significantly associated with lower frequency of leisure activities. In turn, lower frequency of leisure activities was significantly associated with higher levels of IL-6 (t = −2.03, p = .045). Dysfunctional thoughts were no longer significantly associated with IL-6 levels when both dysfunctional thoughts and leisure activities were included in the same model (t = 1.78, p = .076). A significant indirect effect was found for the association between higher levels of dysfunctional thoughts and higher levels of IL-6 (standardized indirect effect = 0.036, bootstrap standard error = 0.026, 95% confidence interval = 0.0001–0.1000) through its association with fewer leisure activities.

Conclusions
Our findings suggest that the direct effect of caregivers’ dysfunctional thoughts on IL-6 may be mediated by the impact on caregivers’ frequency of leisure activities. Results suggest that training caregivers in reducing dysfunctional thoughts to thereby increase leisure activities may be useful in reducing inflammation.
Isolating the Effect of COVID-19-Related Disruptions on HIV Diagnoses in the United States in 2020
Authors: Viguerie Alex , Song Ruiguang , Johnson Anna Satcher , Lyles Cynthia M. , Hernandez Angela , Farnham Paul G. 
Published: December 2022

Background:
Diagnoses of HIV in the United States decreased by 17% in 2020 due to COVID-related disruptions. The extent to which this decrease is attributable to changes in HIV testing versus HIV transmission is unclear. We seek to better understand this issue by analyzing the discrepancy in expected versus observed HIV diagnoses in 2020 among persons who acquired HIV between 2010 and 2019 because changes in diagnosis patterns in this cohort cannot be attributed to changes in transmission.

Methods:
We developed 3 methods based on the CD4-depletion model to estimate excess missed diagnoses in 2020 among persons with HIV (PWH) infected from 2010 to 2019. We stratified the results by transmission group, sex assigned at birth, race/ethnicity, and region to examine differences by group and confirm the reliability of our estimates. We performed similar analyses projecting diagnoses in 2019 among PWH infected from 2010 to 2018 to evaluate the accuracy of our methods against surveillance data.

Results:
There were approximately 3100–3300 (approximately 18%) fewer diagnoses than expected in 2020 among PWH infected from 2010 to 2019. Females (at birth), heterosexuals, persons who inject drugs, and Hispanic/Latino PWH missed diagnoses at higher levels than the overall population. Validation and stratification analyses confirmed the accuracy and reliability of our estimates.

Conclusions:
The substantial drop in number of previously infected PWH diagnosed in 2020 suggests that changes in testing played a substantial role in the observed decrease. Levels of missed diagnoses differed substantially across population subgroups. Increasing testing efforts and innovative strategies to reach undiagnosed PWH are needed to offset this diagnosis gap. These analyses may be used to inform future estimates of HIV transmission during the COVID-19 pandemic.
Sacrospinous Fixation and Vaginal Uterosacral Suspension—Evaluation in Uterine Preservation Surgery
Authors: Woodburn Katherine L. , Yuan Angela S. , Torosis Michele , Roberts Kasey , Ferrando Cecile A. , Gutman Robert E. 
Published: December 2022

Importance
Vaginal hysteropexy can be performed via the uterosacral or the sacrospinous ligament(s), but little data exist comparing these routes.

Objective
The aim of the study was to compare prolapse recurrence, retreatment, and symptoms along with the incidence of adverse events between patients undergoing vaginal uterosacral hysteropexy and sacrospinous hysteropexy.

Study Design
This was a multicenter retrospective cohort study of patients who underwent vaginal uterosacral or sacrospinous hysteropexy (SSHP) between 2015 and 2019. Anatomic failure was the primary outcome, defined as prolapse beyond the hymen. Composite failure was defined as anatomic failure, bulge symptoms, and/or retreatment for prolapse.

Results
At 4 geographically diverse referral centers, 147 patients underwent SSHP and 114 underwent uterosacral hysteropexy. The 1-year follow-up rate was 32% (83/261) with no difference between groups. There were 10 (3.8%) anatomic failures: 3 (2%) sacrospinous and 7 (6.1%) uterosacral (P = 0.109). There was no difference in bulge symptoms (9.9%), composite failure (13%), or median prolapse stage (2).
The overall incidence of complications was low (7%; 95% confidence interval, 4.12%–10.43%) with a higher rate of ureteral kinking in the uterosacral group (7% vs 1.4%, P = 0.023). With a median follow-up of 17 months, 4.6% underwent subsequent hysterectomy and 6.5% had treatment for uterine/cervical pathology.

Conclusions
One year after hysteropexy, 1 in 3 patients were available for follow-up, and there were no differences in prolapse recurrence between patients who underwent uterosacral hysteropexy versus SSHP. The incidence of adverse events was low, and less than 5% of patients underwent subsequent hysterectomy for prolapse.
Biochemical network motifs can transduce and process oscillatory information
Authors: Reja Jamil , Fallon Tess K. , Leader Andrew M. , Azeloglu Evren U. 
Published: December 2022

AbstractBiological networks that are formed through amalgamation of signaling pathways include recurrent configurations called network motifs. These statistically over-represented subgraphs are often formed through interconnected enzyme-substrate relationships that are known to result in highly dynamic downstream behavior, including oscillatory output. Such signals are abundant in biology: heartbeats, circadian rhythms, and cell cycles all exhibit characteristic frequencies. Though there has been great emphasis on how oscillations can be generated through network dynamics, little is known about oscillatory information processing or transduction capacity of network motifs. We employ ordinary differential equations-based dynamical modeling to understand how different network topologies impact oscillatory signal propagation through a multi-enzyme network. We model enzyme-substrate interactions of 20 commonly observed motifs using Michaelis-Menten kinetics. We then perform deterministic Monte Carlo simulations using a range of biologically relevant enzymatic parameters and input frequencies. From these simulations, we quantify signal propagation characteristics using cluster analysis, categorize different motif responses based on output characteristics, and identify potential mechanisms for oscillatory signal processing using parameter sensitivity analysis. We see that the input-output responses depend on network topology and enzyme kinetic parameters. Enzymatic motifs show median oscillatory suppression of 30-135 decibels, with three-node coherent feedforward loops showing the lowest propensity for oscillatory signal suppression. Motifs that contained negative feedback or four-node coherent feedforward loops had the biggest potential to act as AC-to-DC converters, translating oscillatory input signals into transient impulses or sustained continuous outputs, respectively. We conclude that enzyme networks can process and decode information within oscillatory inputs in a frequency- and network-dependent manner.