bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients with Advanced Gastrointestinal Stromal Tumor
Authors: George Suzanne , Heinrich Michael C. , Somaiah Neeta , Oppelt Peter , McLeod Robert , Nishioka Satoshi , Kundu Madan G. , Qian Xiaozhong , Kumar Prasanna , Laadem Abderrahmane , Lau Yvonne , Tran Brittany P. , Fallon Maura , Dosunmu Ololade , Shi Julia , Naito Yoichi 
Published: June 2023

Abstract

Purpose:
To evaluate DS-6157a, an antibody–drug conjugate targeting G protein–coupled receptor 20 (GPR20), in gastrointestinal stromal tumors (GIST).

Patients and Methods:
In this phase I multicenter, open-label, multiple-dose study, patients with previously treated advanced GIST received intravenous DS-6157a on Day 1 of 21-day cycles, with a starting dose of 1.6 mg/kg. The primary objective evaluated the safety and tolerability of DS-6157a, while determining dose-limiting toxicity (DLT) and the MTD. Secondary objectives included plasma pharmacokinetics parameters, plasma antidrug antibodies (ADA), and efficacy.

Results:
A total of 34 patients enrolled. DS-6157a was well tolerated, with DLTs in 4 patients (11.8%) at doses of 6.4 mg/kg, 9.6 mg/kg, and 12.8 mg/kg; the MTD was determined to be 6.4 mg/kg. Treatment-emergent adverse events (TEAE) grade ≥3 occurred in 17 patients (50.0%), including decreased platelet count (23.5%), anemia (20.6%), decreased neutrophil count (14.7%), and decreased white blood cell count (11.8%). Four patients (11.8%) experienced serious adverse events related to DS-6157a. Six patients died with 5 due to disease progression and 1 due to DS-6157a-related TEAE. Tumor shrinkage was observed in 7 patients (20.6%), and 1 patient (2.9%) achieved a partial response. Plasma concentrations and exposure of intact DS-6157a, DXd, and total anti-GPR20 antibody all demonstrated a dose-dependent profile. No treatment-emergent ADAs were observed.

Conclusions:
Targeting GPR20 with DS-6157a was tolerated in patients with advanced GIST with tumor shrinkage demonstrated in KIT/PDGFRA wild-type GIST. However, the study did not proceed further due to lower efficacy outcomes than anticipated.
Nrf2 Drives Hepatocellular Carcinoma Progression through Acetyl-CoA–Mediated Metabolic and Epigenetic Regulatory Networks
Authors: Xi Caixia , Pang Junfeng , Barrett Amanda , Horuzsko Anatolij , Ande Satyanarayana , Mivechi Nahid F. , Zhu Xingguo 
Published: June 2023

Abstract

Correlations between the oxidative stress response and metabolic reprogramming have been observed during malignant tumor formation; however, the detailed mechanism remains elusive. The transcription factor Nrf2, a master regulator of the oxidative stress response, mediates metabolic reprogramming in multiple cancers. In a mouse model of hepatocellular carcinoma (HCC), through metabolic profiling, genome-wide gene expression, and chromatin structure analyses, we present new evidence showing that in addition to altering antioxidative stress response signaling, Nrf2 ablation impairs multiple metabolic pathways to reduce the generation of acetyl-CoA and suppress histone acetylation in tumors, but not in tumor-adjacent normal tissue. Nrf2 ablation and dysregulated histone acetylation impair transcription complex assembly on downstream target antioxidant and metabolic regulatory genes for expression regulation. Mechanistic studies indicate that the regulatory function of Nrf2 is low glucose dependent, the effect of which is demolished under energy refeeding. Together, our results implicate an unexpected effect of Nrf2 on acetyl-CoA generation, in addition to its classic antioxidative stress response regulatory activity, integrates metabolic and epigenetic programs to drive HCC progression.

Implications:
This study highlights that Nrf2 integrates metabolic and epigenetic regulatory networks to dictate tumor progression and that Nrf2 targeting is therapeutically exploitable in HCC treatment.
A Novel Type of Monocytic Leukemia Stem Cell Revealed by the Clinical Use of Venetoclax-Based Therapy
Authors: Pei Shanshan , Shelton Ian T. , Gillen Austin E. , Stevens Brett M. , Gasparetto Maura , Wang Yanan , Liu Lina , Liu Jun , Brunetti Tonya M. , Engel Krysta , Staggs Sarah , Showers William , Sheth Anagha Inguva , Amaya Maria L. , Minhajuddin Mohammad , Winters Amanda , Patel Sweta B. , Tolison Hunter , Krug Anna E. , Young Tracy N. , Schowinsky Jeffrey , McMahon Christine M. , Smith Clayton A. , Pollyea Daniel A. , Jordan Craig T. 
Published: June 2023

Abstract

The BCL2 inhibitor venetoclax has recently emerged as an important component of acute myeloid leukemia (AML) therapy. Notably, use of this agent has revealed a previously unrecognized form of pathogenesis characterized by monocytic disease progression. We demonstrate that this form of disease arises from a fundamentally different type of leukemia stem cell (LSC), which we designate as monocytic LSC (m-LSC), that is developmentally and clinically distinct from the more well-described primitive LSC (p-LSC). The m-LSC is distinguished by a unique immunophenotype (CD34−, CD4+, CD11b−, CD14−, CD36−), unique transcriptional state, reliance on purine metabolism, and selective sensitivity to cladribine. Critically, in some instances, m-LSC and p-LSC subtypes can co-reside in the same patient with AML and simultaneously contribute to overall tumor biology. Thus, our findings demonstrate that LSC heterogeneity has direct clinical significance and highlight the need to distinguish and target m-LSCs as a means to improve clinical outcomes with venetoclax-based regimens.

Significance:
These studies identify and characterize a new type of human acute myeloid LSC that is responsible for monocytic disease progression in patients with AML treated with venetoclax-based regimens. Our studies describe the phenotype, molecular properties, and drug sensitivities of this unique LSC subclass.
This article is featured in Selected Articles from This Issue, p. 1949
Putting wetland science to practice: a review
Authors: Adhya Tiasa , Dey Partha 
Published: June 2023

Book review:
Causal factors for Wetland Management and Restoration: A Concise Guide
Author: Paul A. Keddy
eBook ISBN 978-3-031-21788-3
Published: 11 March 2023
Pages: XIII, 158 pp.
Publisher: Springer Cham.
Mediators of Improvement in TAVR Outcomes Over Time: Insights From the STS-ACC TVT Registry
Authors: Arnold Suzanne V. , Manandhar Pratik , Vemulapalli Sreekanth , Vekstein Andrew M. , Kosinski Andrzej S. , Carroll John D. , Thourani Vinod H. , Mack Michael J. , Cohen David J. 
Published: June 2023

BACKGROUND:
Over the past decade, there has been substantial improvement in outcomes after transcatheter aortic valve replacement. Many patient and procedural factors have also changed over that time, making it challenging to untangle the drivers of those improvements.

METHODS:
Among patients who underwent transcatheter aortic valve replacement from 2012 to 2018 within the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry, we examined the relative contribution of changes in patient factors, device modifications, improving experience/skill, and advances in periprocedural care to the observed improvement in outcomes after transcatheter aortic valve replacement. Mediator clusters included demographics, noncardiovascular comorbidities, cardiovascular comorbidities, device-related factors, and nondevice-related procedural factors. Using logistic regression, we serially adjusted for the mediator clusters to examine the contribution of each to the observed improvement in outcomes over time.

RESULTS:

Among 161 196 patients treated with transcatheter aortic valve replacement at 596 sites, outcomes improved steadily from 2012 to 2018, including 30-day mortality (6.7% to 2.4%), 30-day composite adverse events (25.3% to 10.5%), and 1-year mortality (19.9% to 10.1%; all
P
<0.001). In sequential models, the unadjusted odds ratio for 30-day mortality was 0.82 per year (95% CI, 0.80–0.84), which was progressively attenuated with addition of each covariate cluster. Most of the improvement was explained by device factors and nondevice procedural factors. Results were similar for 30-day composite adverse events, although the observed temporal improvement was not fully explained by measured factors, suggesting improved technical skill as an additional mediator. In contrast to 30-day outcomes, each cluster of patient and procedural factors contributed similarly to the temporal improvement in 1-year mortality, indicating a greater impact of patient factors on longer-term outcomes.

CONCLUSIONS:
While US patients undergoing transcatheter aortic valve replacement have become younger, healthier, and lower risk over time, the most important factors contributing to improvements in short-term outcomes relate to advances in device technology and procedural factors, whereas changing patient characteristics had a greater impact on improvement in 1-year outcomes.
How Social Connection and Engagement Relate to Functional Limitations and Depressive Symptoms Outcomes After Stroke
Authors: Elayoubi Joanne , Haley William E. , Nelson Monica E. , Hueluer Gizem 
Published: June 2023

BACKGROUND:
Stroke commonly leads to disability and depression. Social connection and engagement can be protective against functional decline and depression in the general population. We investigated the effects of social connection and engagement on trajectories of function and depressive symptoms in stroke.

METHODS:
This is a longitudinal study, which included 898 participants with incident stroke from the HRS study (Health and Retirement Study) between 1998 and 2012. Multilevel modeling was used to examine associations of social connection and engagement with changes in functional limitations in instrumental activities of daily living (IADLs) and depressive symptoms over time. Models controlled for age, gender, education, and race/ethnicity. Moderation analyses examined whether high social connection and engagement reduced depressive symptoms for survivors with high IADL impairment.

RESULTS:
Social connection and engagement were generally associated with fewer IADL limitations and depressive symptoms at the time of stroke and after stroke. For example, participants who felt lonely and did not provide help to others before stroke had more IADL limitations. Prestroke volunteering was associated with less increase in IADL limitations with stroke and increase in having friends and providing help to others compared with one’s prestroke status were associated with fewer IADL limitations after stroke. For depressive symptoms, participants who felt lonely and did not have a friend or partner before stroke had more depressive symptoms, and participants who had children residing nearby before stroke showed less increase in depressive symptoms. Moderation effects were not found for social connection and engagement on high IADL impairment and depressive symptoms.

CONCLUSIONS:
Findings suggest that social connection and engagement may reduce the negative physical and psychological outcomes of stroke, both at baseline and after stroke. Efforts to enhance social engagement and diminish loneliness may both enhance population well-being and enhance resilience and recovery from stroke and other illnesses.
Modeling the Effect of Psycho-Socio-Economic Consequences of COVID-19 on Life Satisfaction: The Role of Deviation from a Balanced Time Perspective
Authors: Fedáková Denisa , Adamkovič Matúš , Loziak Alexander , Kačmár Pavol 
Published: June 2023

Abstract
This paper aims to study the role of deviation from a balanced time perspective in the broader context of COVID-19-related variables. We examined a structural model that depicted how the difficulty with adhering to COVID-19 restrictions and their psycho-socio-economic consequences were related to life satisfaction in a sample of 1,423 participants. The results suggest that the difficulty with adhering to the anti-pandemic measures was associated with increased loneliness, decreased contentment with the authorities’ management of the pandemic situation and a worsened personal economic situation. These factors were related to higher levels of COVID-19-related stress and anxiety and lower levels of life satisfaction. Importantly, deviation from the balanced time perspective was one of the strongest predictors of overall life satisfaction within the model.
Preparation and properties of double percolated co-continuous PC/PET/MWCNT/GNP engineering polymer blend nanocomposites
Authors: Zallaghi Maryam , Azizi Hamed 
Published: June 2023

This study reports on the preparation and characterization of nanocomposites based on polycarbonate (PC)/poly ethylene terephthalate (PET) blend containing low amounts of hybrid of multiwalled carbon nanotube (MWCNTs) and graphene nanoplates (GNPs) by melt mixing. To use double percolation mechanism, at first a co-continuous polymer blend was prepared and the influence of nanofiller content on morphology, electrical conductivity, rheological and mechanical properties of co-continuous PC/PET blend was investigated. Blend containing 60 wt. % PET showed co-continuous morphology as observed by scanning electron microscopy and it was found that co-continuity remained unchanged by the addition of nanofillers. The direct current (DC) electrical conductivity results showed a low electrical percolation threshold around 0.5 phr. The results obtained from differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) showed an increase in thermal stability and crystallinity of nanocomposites. By increasing nanofiller amount, the storage modulus, loss modulus, and complex viscosity of samples increased as an indication of the strong network formation between nanofillers and polymer chains. The rheological percolation threshold was also found in the range of 2.5–3.5 phr of nanofillers. The tensile measurements results showed that the addition PC to PET increases the tensile strength of PET.
Timing of Transport of Patients with COVID-19
Authors: Hayes Jane M. , Richards Jeremy B. , Frakes Michael A. , Cocchi Michael N. , Cohen Ari , Cohen Jason E. , Dargin James , Friedman Franklin D. , Wilcox Susan R. 
Published: June 2023

Rationale The objective of this study was to evaluate the risk of mortality or ECMO cannulation for patients with confirmed or suspected COVID-19 transferred from sending hospitals to receiving tertiary care centers as a function of the duration of time at the sending hospital. Objective To determine outcomes of critically ill patients with COVID-19 who were transferred to tertiary or quarternary care medical centers. Materials and Methods Retrospective cohort study of critical care transports of patients to one of seven consortium tertiary care centers from March 1, 2020, through September 4, 2020. Age 14 years and older with confirmed or suspected COVID-19 transported from a sending hospital to a receiving tertiary care center by the critical care transport organization. Results Patients transported with confirmed or suspected COVID-19 to tertiary care centers had a mortality rate of 38.0%. Neither the number of days admitted, nor the number of days intubated at the sending hospital correlated with mortality (correlation coefficient 0.051 and −0.007, respectively). Similarly, neither the number of days admitted, nor number of days intubated at the sending hospital correlated with ECMO cannulation (correlation coefficient 0.008 and −0.036, respectively). Conclusion It may be reasonable to transfer a critically ill COVID-19 patient to a tertiary care center even if they have been admitted at the sending hospital for several days.
Examination of compressive and flexural behaviors of acrylonitrile-butadiene-styrene filled with hemp fiber particles
Authors: Ozenc Osman , Dundar Mehmet Akif , Sahin Davut Erdem 
Published: June 2023

Effects of the addition of hemp fiber particles on the compressive and flexural behaviors of an industrially important amorphous thermoplastic, Acrylonitrile-Butadiene-Styrene (ABS), were investigated for the first time in this study. Particles with a size of 67–500 μm were first extracted from 10% NaOH alkaline-treated hemp fibers, and then incorporated into ABS at three various weight ratios (1wt%, 5wt% and 10wt%). Compression and three-point bending tests results revealed that both the compressive and flexural modulus of ABS increase with increasing particle content, but its compressive post-yield and flexural strengths decrease as enhancing particle content. The test results also showed that increasing particle content results in a significant improvement in the compressive modulus of ABS, but a slight enhancement in its flexural modulus. The notch-impact test results revealed that the impact strength of ABS is adversely affected by the incorporation of hemp fiber particles. The FT-IR (Fourier Transform Infrared Spectroscopy) analysis results indicated that mechanical bonding is formed between matrix and natural particles rather than chemical bonding. The SEM (Scanning Electron Microscopy) results put forth that the observed decrease in both the compressive post-yield and flexural strength is mainly due to the lack of strong mechanical bonding between ABS and particles. The three-point bending test data of the materials were satisfactorily reproduced using the linear Drucker-Prager material model in Abaqus engineering software.
Early Origins of Frailty: Do Later-Life Social Relationships Alter Trajectories of Decline?
Authors: Williams-Farrelly Monica M. , Ferraro Kenneth F. 
Published: June 2023

Objectives: Social relationships are widely regarded as salubrious, but do they mediate the influence of childhood experiences on frailty in later life? Drawing from cumulative inequality theory, we assess the influence of childhood experiences and adult relationships on frailty trajectories. Methods: We analyzed data from the Health and Retirement Study to examine the influence of six domains of childhood experiences and social relationships on frailty trajectories over 8 years. Mediation analyses were completed with structural equation models. Results: Risky adolescent behavior, chronic disease, and impairments during childhood are associated directly with higher risk of initial frailty, but not over time. More social roles and higher social support mediate the relationship between childhood experiences and frailty, and the effect of more social roles continues over time. Discussion: This study provides compelling evidence that supportive social relationships mediate the risk and severity of frailty in later life associated with noxious childhood experiences.
Participatory management effects on nurses’ organizational support and moral distress
Authors: Hasanzadeh Moghadam Mahdieh , Heshmati Nabavi Fatemeh , Heydarian Miri Hamid , Saleh Moghadam Amir Reza , Mirhosseini Seyedmohammad 
Published: June 2023

Research question/aim/objectives Providing care for hospitalized children causes moral distress to nurses. Employee participation in discovering and solving the everyday problems of the workplace is one of the ways to hear the voices of nurses. This study aimed to evaluate the effect of participatory management programs on perceived organizational support and moral distress in pediatric nurses. Research design A quasi-experimental study. Participants and research context The present study was conducted on 114 pediatric nurses in Iran. Data were collected using the Perceived Organizational Support Scale and the Moral Distress Scale of nurses. The intervention included implementing a participatory management program in three treatment departments that were randomly selected and it lasted 4 months. Participatory management was at the level of problem-solving with a focus on investigating, solving, and correcting issues and problems of work shifts and departments concerning the physical environment, equipment of the department, improvement of work processes, and team cooperation. In the control group, ordinary organizational approaches to problem-solving were used. Ethical considerations This study was approved by the Ethics Committee of Mashhad School of Nursing and Midwifery. Informed consent was obtained from the study participants. Findings/results Based on the results, both groups were homogenous before the intervention in terms of moral distress and perceived organizational support. The results showed that the moral distress mean scores in the intervention group decreased from 1.45 (0.52) to 1.03 (0.37) after the intervention. Also, the score of the perceived organizational support was 2.12 (1.2) increased after the intervention to 2.68 (1.10) in the intervention group. Conclusions It was found that the participation of nurses in the problem-solving process to solve daily workplace issues can be effective in increasing their perceived organizational support and reducing their moral distress.
Latency Antibiotics in Preterm Prelabor Rupture of Membranes: A Comparison of Azithromycin Regimens
Authors: Day Kimberly N. , Vircks Julie A. , Henricks Christine E. , Reaves Kaci M. , Holmes Ashley K. , Florio Karen L. 
Published: June 2023

Background: Treatment with antibiotics at the time of preterm prelabor rupture of membranes (PPROM) has been shown to prolong pregnancy. Due to the recurrent shortage of erythromycin, azithromycin has been substituted in the traditional regimen; however, there are little data on optimal dosing. Objective: The objective of this study was to determine whether there is a difference in latency from onset of PPROM to delivery in patients who received a single dose of azithromycin compared with a 5-day course. Methods: This was a single-center, multisite, retrospective, IRB approved analysis of patients admitted with a diagnosis of PPROM. Patients were included if rupture occurred between 22 0/7 and 33 6/7 weeks of gestation and received either a single dose or a 5-day course of azithromycin along with a beta lactam. Results: A total of 376 patients were reviewed with 296 patients included in the final analysis. There was no statistical difference in the primary outcome of latency days in patients who received the 5-day versus the single-dose course (4 vs 5 days, P = 0.641). There was a significantly higher rate of histologic chorioamnionitis in the single-dose course of azithromycin (46.4% vs 62.6%, P = 0.006). Conclusions and Relevance: There was no difference in latency for patients who received a 5-day course of azithromycin versus a single dose for the treatment of PPROM. A higher rate of histologic chorioamnionitis was observed in those who received the single-day course. Prospective follow-up studies are needed to confirm these findings.