bluuebunny/crossref_metadata_2025_split huggingface dataset:
Screening of predicted synergistic multi-target therapies in glioblastoma identifies new treatment strategies
Authors: Houweling Megan , Giczewska Anna , Abdul Kulsoom , Nieuwenhuis Ninke , Küçükosmanoglu Asli , Pastuszak Krzysztof , Buijsman Rogier C , Wesseling Pieter , Wedekind Laurine , Noske David , Supernat Anna , Bailey David , Watts Colin , Wurdinger Thomas , Westerman Bart A 
Published: June 2023

Abstract

Background
IDH-wildtype glioblastoma (GBM) is a highly malignant primary brain tumor with a median survival of 15 months after standard of care, which highlights the need for improved therapy. Personalized combination therapy has shown to be successful in many other tumor types and could be beneficial for GBM patients.

Methods
We performed the largest drug combination screen to date in GBM, using a high-throughput effort where we selected 90 drug combinations for their activity onto 25 patient-derived GBM cultures. 43 drug combinations were selected for interaction analysis based on their monotherapy efficacy and were tested in a short-term (3 days) as well as long-term (18 days) assay. Synergy was assessed using dose-equivalence and multiplicative survival metrics.

Results
We observed a consistent synergistic interaction for 15 out of 43 drug combinations on patient-derived GBM cultures. From these combinations, 11 out of 15 drug combinations showed a longitudinal synergistic effect on GBM cultures. The highest synergies were observed in the drug combinations Lapatinib with Thapsigargin and Lapatinib with Obatoclax Mesylate, both targeting epidermal growth factor receptor and affecting the apoptosis pathway. To further elaborate on the apoptosis cascade, we investigated other, more clinically relevant, apoptosis inducers and observed a strong synergistic effect while combining Venetoclax (BCL targeting) and AZD5991 (MCL1 targeting).

Conclusions
Overall, we have identified via a high-throughput drug screening several new treatment strategies for GBM. Moreover, an exceptionally strong synergistic interaction was discovered between kinase targeting and apoptosis induction which is suitable for further clinical evaluation as multi-targeted combination therapy.
A Phase I Trial of Bevacizumab and Temsirolimus in Combination With Valproic Acid in Advanced Solid Tumors
Authors: Nelson Blessie Elizabeth , Tsimberidou Apostolia M , Fu Xueyao , Fu Siqing , Subbiah Vivek , Sood Anil K , Rodon Jordi , Karp Daniel D , Blumenschein George , Kopetz Scott , Pant Shubham , Piha-Paul Sarina A 
Published: June 2023

Abstract

Background
Preclinical models suggest synergy between anti-angiogenesis therapy, mammalian target of rapamycin (mTOR), and histone deacetylase inhibitors to promote anticancer activity.

Methods
This phase I study enrolled 47 patients between April 2012 and 2018 and determined safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) when combining bevacizumab, temsirolimus, and valproic acid in patients with advanced cancer.

Results
Median age of enrolled patients was 56 years. Patients were heavily pretreated with a median of 4 lines of prior therapy. Forty-five patients (95.7%) experienced one or more treatment-related adverse events (TRAEs). Grade 3 TRAEs were lymphopenia (14.9%), thrombocytopenia (8.5%), and mucositis (6.4%). Grade 4 TRAEs included lymphopenia (2.1%) and CNS cerebrovascular ischemia (2.1%). Six patients developed DLTs across 10 dose levels with grade 3 infection, rash, mucositis, bowel perforation, elevated lipase, and grade 4 cerebrovascular ischemia. The MTD was dose level 9 (bevacizumab 5 mg/kg days 1 and 15 intravenously (IV) plus temsirolimus 25 mg days 1, 8, 15, and 22 IV and valproic acid 5 mg/kg on days 1-7 and 15-21 per orally (PO)). Objective response rate (ORR) was 7.9% with confirmed partial response (PRs) in 3 patients (one each in parotid gland, ovarian, and vaginal cancers). Stable disease (SD) ≥+6 months was seen in 5 patients (13.1%). Clinical benefit state (CBR: PR + SD ≥+6 months) was 21%.

Conclusion
Combination therapy with bevacizumab, temsirolimus, and valproic acid was feasible, but there were numerous toxicities, which will require careful management for future clinical development (ClinicalTrials.gov Identifier: NCT01552434).
Prolonged Survival of NUT Midline Carcinoma and Current Approaches to Treatment
Authors: Kaplan Henry G , Subramaniam Somasundaram , Vallières Eric , Barnett Todd 
Published: June 2023

Abstract
NUT midline carcinoma is a rare malignancy most commonly seen in adolescents and young adults. The disease presents most often in the lung or head and neck area but can be seen occasionally elsewhere. The diagnosis can be difficult and requires a high degree of suspicion with demonstration of the classic fusion rearrangement mutation of the NUTM1 gene with one of a variety of partners by immunohistochemistry, fluorescent in situ hybridization, or genomic analysis. Survival is usually only a number of months with few long-term survivors. Here we report one of the longest-known survivors of this disease treated with surgery and radiation without additional therapy. Systemic treatment approaches including the use of chemotherapy and BET and histone deacetylase inhibitors have yielded modest results. Further studies of these, as well as p300 and CDK9 inhibitors and combinations of BET inhibitors with chemotherapy or CDK 4/6 inhibitors, are being evaluated. Recent reports suggest there may be a role for immune checkpoint inhibitors, even in the absence of high tumor mutation burden or PD-L1 positivity. RNA sequencing of this patient’s tumor demonstrated overexpression of multiple potentially targetable genes. Given the altered transcription that results from the causative mutation multi-omic evaluation of these tumors may uncover druggable targets for treatment.
Short duration of parenteral antibiotics in infants with urinary tract infections
Authors: Menon Nikita , Mutinta Deasy Anne , Woo Kellan , Tarabishi Jalal , Chan Eugene Yu-hin , Kang Kristopher , Carwana Matthew , Nama Nassr 
Published: June 2023

Abstract

Objectives
Current guidelines by the Canadian Paediatric Society on treating urinary tract infections (UTIs) exclude infants ≤ 60 days old. There is considerable practice variability in this age group, especially around the optimal duration of parenteral antibiotics. The study aimed to assess local practice patterns, and the safety of a short course (≤3 days) of parenteral antibiotics in young infants.

Methods
In this retrospective cohort study, 95 infants (≤60 days) with confirmed UTIs were identified at British Columbia Children’s Hospital. Patients receiving short (≤3 days) and long (&gt;3 days) duration of parenteral antibiotics were compared. Outcomes of interest included urinary tract infection recurrence within 30 days, hospital length of stay (LOS), representation, and readmission.

Results
Twenty infants (21%) received a short course of parenteral antibiotics. These infants were older (median 47 days versus 28 days) and non-bacteremic. Urinary tract infection recurrence was identified in 8 patients (8%), of which 7 were treated with a long duration (P = 1.0). Patients treated with a short duration had a significantly shorter LOS, with a mean difference of 4.21 days [95% CI: 3.37 to 5.05] (P &lt; 0.001). All five (5%) bacteremic patients were treated exclusively with parenteral antibiotics.

Conclusions
In a Canadian setting, a short course of parenteral antibiotics is safe in young, non-bacteremic infants with UTIs. Despite substantial evidence, local practice patterns suggest a tendency towards prescription of long courses, providing an opportunity for quality improvement.
Scarlet macaw (Ara macao) breeding at the Mimbres archaeological site of Old Town (early AD 1100s) in Southwestern New Mexico
Authors: Conrad Cyler , Wurth Kimberly , Tenner Travis , Naes Benjamin , LeBlanc Steven A , Creel Darrell , Williams Katharine , Beacham E Bradley 
Published: June 2023

Abstract
Examination of avian eggshell at the Old Town archaeological site in Southwestern New Mexico, United States of America, indicates that scarlet macaw (Ara macao) breeding occurred during the Classic Mimbres period (early AD 1100s). Current archaeological and archaeogenomic evidence from throughout the American Southwest/Mexican Northwest (SW/NW) suggests that Indigenous people bred scarlet macaws at an unknown location(s) between AD 900 and 1200 and likely again at the northwestern Mexico site of Paquimé post-AD 1275. However, there is a lack of direct evidence for breeding, or the location(s) of scarlet macaw breeding itself, within this area. This research, for the first time, provides evidence of scarlet macaw breeding using scanning electron microscopy of eggshells from Old Town.
Positive parenting moderates associations between childhood stress and corticolimbic structure
Authors: Kahhalé Isabella , Barry Kelly R , Hanson Jamie L 
Published: June 2023

Abstract
Childhood stress has a deleterious impact on youth behavior and brain development. Resilience factors such as positive parenting (e.g. expressions of warmth and support) may buffer youth against the negative impacts of stress. We sought to determine whether positive parenting buffers against the negative impact of childhood stress on youth behavior and brain structure and to investigate differences between youth-reported parenting and caregiver-reported parenting. Cross-sectional behavioral and neuroimaging data were analyzed from 482 youth (39% female and 61% male, ages 10–17) who participated in an ongoing research initiative, the Healthy Brain Network (HBN). Regression models found that youth-reported positive parenting buffered against the association between childhood stress and youth behavioral problems (β = −0.10, P = 0.04) such that increased childhood stress was associated with increased youth behavior problems only for youth who did not experience high levels of positive parenting. We also found that youth-reported positive parenting buffered against the association between childhood stress and decreased hippocampal volumes (β = 0.07, P = 0.02) such that youth who experienced high levels of childhood stress and who reported increased levels of positive parenting did not exhibit smaller hippocampal volumes. Our work identifies positive parenting as a resilience factor buffering youth against the deleterious impact of stressful childhood experiences on problem behaviors and brain development. These findings underscore the importance of centering youth perspectives of stress and parenting practices to better understand neurobiology, mechanisms of resilience, and psychological well-being.
A subcellular biochemical model for T6SS dynamics reveals winning competitive strategies
Authors: Lin Yuexia Luna , Smith Stephanie N , Kanso Eva , Septer Alecia N , Rycroft Chris H 
Published: June 2023

Abstract
The type VI secretion system (T6SS) is a broadly distributed interbacterial weapon that can be used to eliminate competing bacterial populations. Although unarmed target populations are typically used to study T6SS function in vitro, bacteria most likely encounter other T6SS-armed competitors in nature. However, the connection between subcellular details of the T6SS and the outcomes of such mutually lethal battles is not well understood. Here, we incorporate biological data derived from natural competitors of Vibrio fischeri light organ symbionts to build a biochemical model for T6SS at the single-cell level, which we then integrate into an agent-based model (ABM). Using the ABM, we isolate and experiment with strain-specific physiological differences between competitors in ways not possible with biological samples to identify winning strategies for T6SS-armed populations. Through in vitro experiments, we discover that strain-specific differences exist in T6SS activation speed. ABM simulations corroborate that faster activation is dominant in determining survival during competition. Once competitors are fully activated, the energy required for T6SS creates a tipping point where increased weapon building and firing becomes too costly to be advantageous. Through ABM simulations, we identify the threshold where this transition occurs in the T6SS parameter space. We also find that competitive outcomes depend on the geometry of the battlefield: unarmed target cells survive at the edges of a range expansion where unlimited territory can be claimed. Alternatively, competitions within a confined space, much like the light organ crypts where natural V. fischeri compete, result in the rapid elimination of the unarmed population.
Disagreement Does Not Always Mean Division: Evidence from Five Decades of American Public Opinion
Authors: Perrett Stuart 
Published: June 2023

Abstract
Are those things on which Americans most disagree the same things that divide liberals and conservatives or Democrats and Republicans? How has this changed over time? To answer these questions, I use 350 subjective items from five decades of the General Social Survey. Estimating disagreement with ordinal dispersion and using a novel measure of sorting by party and ideological identification, I find an increasing positive association between the two phenomena. In the 1970s, the likelihood that opinion on contentious items divided partisans was low. Since then, this probability has increased. Disagreement has been more consistently associated with higher levels of ideological sorting, though this relationship has also strengthened since the 1980s. I then ask which items and substantive domains have propelled the politicization of disagreement. I decompose the estimated coefficients between disagreement and sorting by item to quantify their contribution in each decade. I find that opinions from two domains play a large role throughout the period: public spending, and sexuality and abortion. Nevertheless, there is a great deal of heterogeneity within domains and over time. Though disagreement between Americans has increasingly sorted, a relatively small number of items drive this relationship in any one decade. Even among voters, a good proportion of disagreement remains unrelated to ideological or partisan divisions.
Increased CD8+ tissue resident memory T cells, regulatory T cells and activated natural killer cells in systemic sclerosis lungs
Authors: Padilla Cristina M , Valenzi Eleanor , Tabib Tracy , Nazari Banafsheh , Sembrat John , Rojas Mauricio , Fuschiotti Patrizia , Lafyatis Robert 
Published: June 2023

Abstract

Objective
Multiple observations indicate a role for lymphocytes in driving autoimmunity in SSc. While T and NK cells have been studied in SSc whole blood and bronchoalveolar lavage fluid, their role remains unclear, partly because no studies have analysed these cell types in SSc-interstitial lung disease (ILD) lung tissue. This research aimed to identify and analyse the lymphoid subpopulations in SSc-ILD lung explants.

Methods
Lymphoid populations from 13 SSc-ILD and 6 healthy control (HC) lung explants were analysed using Seurat following single-cell RNA sequencing. Lymphoid clusters were identified by their differential gene expression. Absolute cell numbers and cell proportions in each cluster were compared between cohorts. Additional analyses were performed using pathway analysis, pseudotime and cell ligand-receptor interactions.

Results
Activated CD16+ NK cells, CD8+ tissue resident memory T cells and Treg cells were proportionately higher in SSc-ILD compared with HC lungs. Activated CD16+ NK cells in SSc-ILD showed upregulated granzyme B, IFN-γ and CD226. Amphiregulin, highly upregulated by NK cells, was predicted to interact with epidermal growth factor receptor on several bronchial epithelial cell populations. Shifts in CD8+ T cell populations indicated a transition from resting to effector to tissue resident phenotypes in SSc-ILD.

Conclusions
SSc-ILD lungs show activated lymphoid populations. Activated cytotoxic NK cells suggest they may kill alveolar epithelial cells, while their expression of amphiregulin suggests they may also induce bronchial epithelial cell hyperplasia. CD8+ T cells in SSc-ILD appear to transition from resting to the tissue resident memory phenotype.
A k-mer-Based Approach for Phylogenetic Classification of Taxa in Environmental Genomic Data
Authors: Van Etten Julia , Stephens Timothy G , Bhattacharya Debashish 
Published: June 2023

Abstract
In the age of genome sequencing, whole-genome data is readily and frequently generated, leading to a wealth of new information that can be used to advance various fields of research. New approaches, such as alignment-free phylogenetic methods that utilize k-mer-based distance scoring, are becoming increasingly popular given their ability to rapidly generate phylogenetic information from whole-genome data. However, these methods have not yet been tested using environmental data, which often tends to be highly fragmented and incomplete. Here, we compare the results of one alignment-free approach (which utilizes the D2 statistic) to traditional multi-gene maximum likelihood trees in 3 algal groups that have high-quality genome data available. In addition, we simulate lower-quality, fragmented genome data using these algae to test method robustness to genome quality and completeness. Finally, we apply the alignment-free approach to environmental metagenome assembled genome data of unclassified Saccharibacteria and Trebouxiophyte algae, and single-cell amplified data from uncultured marine stramenopiles to demonstrate its utility with real datasets. We find that in all instances, the alignment-free method produces phylogenies that are comparable, and often more informative, than those created using the traditional multi-gene approach. The k-mer-based method performs well even when there are significant missing data that include marker genes traditionally used for tree reconstruction. Our results demonstrate the value of alignment-free approaches for classifying novel, often cryptic or rare, species, that may not be culturable or are difficult to access using single-cell methods, but fill important gaps in the tree of life.
Decreased GPX3 mRNA level in peripheral blood mononuclear cells is associated with HBV-related hepatocellular carcinoma
Authors: Han Li-Yan , Sun Wei-Juan , Zhao Ze-Hua , Gao Shuai , Wang Kai 
Published: June 2023

ABSTRACT

Background
Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is one of the most common malignancies with increasing mortality. In this study, we aim to determine the alteration and diagnostic value of GXP3 expression for HBV-related HCC.

Methods
We recruited 243 subjects, including 132 HBV-related HCC patients, 78 chronic hepatitis B (CHB) patients and 33 healthy controls (HCs). The mRNA level of GPX3 in peripheral blood mononuclear cells (PBMCs) was assessed by quantitative real-time PCR. The GPX3 plasma level was detected by ELISA.

Results
The GPX3 mRNA level was significantly decreased in HBV-related HCC patients compared with in CHB patients and HCs (p&lt;0.05). The plasma GPX3 level was significantly lower in patients with HBV-related HCC than in CHB patients and HCs (p&lt;0.05). In the HCC subgroup, the GPX3 mRNA level was significantly lower in patients with positive HBeAg, ascites, advanced stage and poor differentiation compared with in the other groups (p&lt;0.05). The receiver operating characteristic curve was constructed to estimate the diagnostic value of the GPX3 mRNA level for HBV-related HCC. The GPX3 mRNA level showed a significantly better diagnostic ability compared with alpha fetoprotein (AFP) (area under the curve 0.769 vs 0.658, p&lt;0.001).

Conclusions
A decreased GPX3 mRNA level might be a potential non-invasive biomarker for HBV-related HCC. It showed better diagnostic ability than AFP.
A review of traffic behaviour and intelligent driving at roundabouts based on a microscopic perspective
Authors: Jiang Haobin , Shen Qingyuan , Li Aoxue , Yin Chenhui 
Published: June 2023

AbstractThe contradiction between increasing traffic and the relatively poor roundabout infrastructure is getting stronger. The control and optimization of the macroscopic traffic flow needs to be improved to resolve congestion and safety problems at roundabouts and the connected road network. In order to better understand the gaps and trends in this field, we have systematically reviewed the main research and developments in traffic phenomena, driving behaviour, autonomous vehicles (AVs), intelligent connected vehicles and real vehicle trajectory data sets at roundabouts. The study is based on 388 papers about roundabouts, selected through a comprehensive literature search. The review demonstrates that based on a microscopic perspective, sensing, prediction, decision-making, planning and control aspects of AVs and intelligent connected vehicles can be designed and optimized to fundamentally and significantly improve traffic capacity and driving safety at roundabouts. However, the generation mechanism of traffic conflicts among traffic participants at roundabouts is complex, which is a tremendous challenge for the systematic design of AVs. Therefore, based on naturalistic driving data and machine learning theory, it is an important research direction to build driver models by learning and imitating human driver decision-making and driving behaviours.
LRRC8A anion channels modulate vascular reactivity via association with myosin phosphatase rho interacting protein
Authors: Choi Hyehun , Miller Michael R. , Nguyen Hong‐Ngan , Rohrbough Jeffrey C. , Koch Stephen R. , Boatwright Naoko , Yarboro Michael T. , Sah Rajan , McDonald W. Hayes , Reese J. Jeffrey , Stark Ryan J. , Lamb Fred S. 
Published: June 2023

AbstractLeucine‐rich repeat containing 8A (LRRC8A) volume regulated anion channels (VRACs) are activated by inflammatory and pro‐contractile stimuli including tumor necrosis factor alpha (TNFα), angiotensin II and stretch. LRRC8A associates with NADPH oxidase 1 (Nox1) and supports extracellular superoxide production. We tested the hypothesis that VRACs modulate TNFα signaling and vasomotor function in mice lacking LRRC8A exclusively in vascular smooth muscle cells (VSMCs, Sm22α‐Cre, Knockout). Knockout (KO) mesenteric vessels contracted normally but relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) was enhanced compared to wild type (WT). Forty‐eight hours of ex vivo exposure to TNFα (10 ng/mL) enhanced contraction to norepinephrine (NE) and markedly impaired dilation to ACh and SNP in WT but not KO vessels. VRAC blockade (carbenoxolone, CBX, 100 μM, 20 min) enhanced dilation of control rings and restored impaired dilation following TNFα exposure. Myogenic tone was absent in KO rings. LRRC8A immunoprecipitation followed by mass spectroscopy identified 33 proteins that interacted with LRRC8A. Among them, the myosin phosphatase rho‐interacting protein (MPRIP) links RhoA, MYPT1 and actin. LRRC8A‐MPRIP co‐localization was confirmed by confocal imaging of tagged proteins, Proximity Ligation Assays, and IP/western blots. siLRRC8A or CBX treatment decreased RhoA activity in VSMCs, and MYPT1 phosphorylation was reduced in KO mesenteries suggesting that reduced ROCK activity contributes to enhanced relaxation. MPRIP was a target of redox modification, becoming oxidized (sulfenylated) after TNFα exposure. Interaction of LRRC8A with MPRIP may allow redox regulation of the cytoskeleton by linking Nox1 activation to impaired vasodilation. This identifies VRACs as potential targets for treatment or prevention of vascular disease.