bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stochastic nonlinear model for nanoparticles and viruses escape from endosomes
Authors: Sholokhov Vladimir , Makoveeva Eugenya V. , Fedotov Sergei , Alexandrov Dmitri V. 
Published: July 2024

AbstractA stochastic nonlinear model for Rab5 and Rab7 proteins describing the transformation of early endosomes into late endosomes was formulated. This model consists of two stochastic nonlinear differential equations for Rab5 and Rab7 protein levels on the endosome surface. The primary goal of this paper is to understand the impact of multiplicative noise on the nonlinear dynamics of Rab5 and Rab7. The main idea is to introduce the stochastic variable T, which defines the random time when the conversion from Rab5 to Rab7 occurs. It follows from the dynamics of pH level that T can also be considered as the escape time of pH-sensitive nanoparticles and viruses from endosomes. The probability density function for T was obtained numerically. It was shown that the average conversion time T is shifted to the right when compared to the deterministic one, potentially influencing the pH distribution function and, consequently, the average escape time of viruses and nanoparticles.
Radiological Evaluation of the Accuracy of Demirjian, Nolla, and Willems Methods for Dental Age Estimation in 3–17‐Year‐Old Iranian Children
Authors: Pliska Benjamin , Nahvi Azam , Pakdaman Nikta , Dadgar Sepideh , Aryana Mehdi , Sobouti Farhad 
Published: July 2024

Background: The stage of tooth formation is one of the most reliable indicators for predicting a patient’s developmental age by radiographs. This study compared the accuracy of three distinct dental age estimation methods (Demirjian, Nolla, and Willems) in children aged 3–17 in the northern Iranian population.Methods: This cross‐sectional study examined panoramic radiographs of 434 children aged 3–17 from Mazandaran Province, Iran, who had teeth 31–37 present on the left mandible. This study employed the Demirjian, Nolla, and Willems methods to estimate the dental age of the sample and compare it with the chronological age. The data were analyzed using SPSS v16. A paired t‐test was used to compare chronological and dental ages. The Pearson correlation was used to correlate the chronological and dental ages. The errors of different methods were compared using the Wilcoxon test. P values < 0.05 were considered significant for all tests except Wilcoxon. For Wilcoxon, a P value < 0.017 was considered significant.Results: The three methods presented differing mean estimated ages. The Demirjian method delivered the highest mean, and all three methods differed significantly when compared in pairs. The results showed that the Demirjian method overestimated chronological age by 0.25 years (P < 0.001) in girls and 0.09 years (P = 0.28) in boys. The Willems method underestimated chronological age by 0.05 years (P = 0.47) in girls and 0.12 years (P = 0.13) in boys. The Nolla method underestimated chronological age by 0.41 years (P < 0.001) in girls and 0.40 years (P < 0.001) in boys. The accuracy of each method varied with the patient’s age.Conclusion: According to the findings, the Willems method outperformed the Demirjian method, and the Demirjian method exceeded the Nolla method for estimating dental age in Iranian children aged 3–17. Overall, the Demirjian method overestimated the age of the study population, whereas the other two underestimated it.
Integrative Multiomics Analyses Identify Molecular Subtypes of Head and Neck Squamous Cell Carcinoma with Distinct Therapeutic Vulnerabilities
Authors: Diao Pengfei , Dai Yibin , Wang An , Bu Xiaoxuan , Wang Ziyu , Li Jin , Wu Yaping , Jiang Hongbing , Wang Yanling , Cheng Jie 
Published: July 2024

Abstract
Substantial heterogeneity in molecular features, patient prognoses, and therapeutic responses in head and neck squamous cell carcinomas (HNSCC) highlights the urgent need to develop molecular classifications that reliably and accurately reflect tumor behavior and inform personalized therapy. Here, we leveraged the similarity network fusion bioinformatics approach to jointly analyze multiomics datasets spanning copy number variations, somatic mutations, DNA methylation, and transcriptomic profiling and derived a prognostic classification system for HNSCC. The integrative model consistently identified three subgroups (IMC1-3) with specific genomic features, biological characteristics, and clinical outcomes across multiple independent cohorts. The IMC1 subgroup included proliferative, immune-activated tumors and exhibited a more favorable prognosis. The IMC2 subtype harbored activated EGFR signaling and an inflamed tumor microenvironment with cancer-associated fibroblast/vascular infiltrations. Alternatively, the IMC3 group featured highly aberrant metabolic activities and impaired immune infiltration and recruiting. Pharmacogenomics analyses from in silico predictions and from patient-derived xenograft model data unveiled subtype-specific therapeutic vulnerabilities including sensitivity to cisplatin and immunotherapy in IMC1 and EGFR inhibitors (EGFRi) in IMC2, which was experimentally validated in patient-derived organoid models. Two signatures for prognosis and EGFRi sensitivity were developed via machine learning. Together, this integrative multiomics clustering for HNSCC improves current understanding of tumor heterogeneity and facilitates patient stratification and therapeutic development tailored to molecular vulnerabilities.
Significance: Head and neck squamous cell carcinoma classification using integrative multiomics analyses reveals subtypes with distinct genetics, biological features, clinicopathological traits, and therapeutic vulnerabilities, providing insights into tumor heterogeneity and personalized treatment strategies.
Augmenting CAR T-cell Functions with LIGHT
Authors: Cai Winson , Tanaka Kento , Mi Xiaoli , Rajasekhar Vinagolu K. , Khan Jonathan F. , Yoo Sarah , de Stanchina Elisa , Rahman Jahan , Mathew Serena , Abrahimi Parwiz , Souness Sydney , Purdon Terence J. , McDowell James R. , Meyerberg Jeremy , Fujino Takeshi , Healey John H. , Abdel-Wahab Omar , Scheinberg David A. , Brentjens Renier J. , Daniyan Anthony F. 
Published: July 2024

Abstract
Chimeric antigen receptor (CAR) T-cell therapy has resulted in remarkable clinical success in the treatment of B-cell malignancies. However, its clinical efficacy in solid tumors is limited, primarily by target antigen heterogeneity. To overcome antigen heterogeneity, we developed CAR T cells that overexpress LIGHT, a ligand of both lymphotoxin-β receptor on cancer cells and herpes virus entry mediator on immune cells. LIGHT-expressing CAR T cells displayed both antigen-directed cytotoxicity mediated by the CAR and antigen-independent killing mediated through the interaction of LIGHT with lymphotoxin-β receptor on cancer cells. Moreover, CAR T cells expressing LIGHT had immunostimulatory properties that improved the cells’ proliferation and cytolytic profile. These data indicate that LIGHT-expressing CAR T cells may provide a way to eliminate antigen-negative tumor cells to prevent antigen-negative disease relapse.
Contributions of Germline and Somatic Mosaic Genetics to Thoracic Aortic Aneurysms in Nonsyndromic Individuals
Authors: Chen Ming Hui , Deng Ellen S. , Yamada Jessica M. , Choudhury Sangita , Scotellaro Julia , Kelley Lily , Isselbacher Eric , Lindsay Mark E. , Walsh Christopher A. , Doan Ryan N. 
Published: July 2024

Background
Thoracic aortic aneurysm (TAA) is associated with significant morbidity and mortality. Although individuals with family histories of TAA often undergo clinical molecular genetic testing, adults with nonsyndromic TAA are not typically evaluated for genetic causes. We sought to understand the genetic contribution of both germline and somatic mosaic variants in a cohort of adult individuals with nonsyndromic TAA at a single center.

Methods and Results

One hundred eighty‐one consecutive patients <60 years who presented with nonsyndromic TAA at the Massachusetts General Hospital underwent deep (>500×) targeted sequencing across 114 candidate genes associated with TAA and its related functional pathways. Samples from 354 age‐ and sex‐matched individuals without TAA were also sequenced, with a 2:1 matching. We found significant enrichments for germline (odds ratio [OR], 2.44,
P
=4.6×10
−6
[95% CI, 1.67–3.58]) and also somatic mosaic variants (OR, 4.71,
P
=0.026 [95% CI, 1.20–18.43]) between individuals with and without TAA. Likely genetic causes were present in 24% with nonsyndromic TAA, of which 21% arose from germline variants and 3% from somatic mosaic alleles. The 3 most frequently mutated genes in our cohort were
FLNA
(encoding Filamin A),
NOTCH3
(encoding Notch receptor 3), and
FBN1
(encoding Fibrillin‐1). There was increased frequency of both missense and loss of function variants in TAA individuals.

Conclusions
Likely contributory dominant acting genetic variants were found in almost one quarter of nonsyndromic adults with TAA. Our findings suggest a more extensive genetic architecture to TAA than expected and that genetic testing may improve the care and clinical management of adults with nonsyndromic TAA.
Outcomes in Cardiac Transthyretin Amyloidosis and Association With New York Heart Association Class: Real‐World Data
Authors: Müller Maximilian Leo , Latinova Ekaterina , Brand Anna , Mattig Isabel , Spethmann Sebastian , Messroghli Daniel , Hahn Katrin , Landmesser Ulf , Heidecker Bettina 
Published: July 2024

Background
Results from ATTR‐ACT (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy) indicate that tafamidis prolongs survival and reduces cardiovascular hospitalizations in cardiac transthyretin amyloidosis (ATTR‐CA). However, real‐world data supporting these findings are scarce. Thus, we sought to characterize the clinical outcome of patients with ATTR‐CA treated with tafamidis in a real‐world setting and assess the prognostic role of the New York Heart Association (NYHA) classification.

Methods and Results
We conducted a retrospective observational study, enrolling a consecutive sample of patients with ATTR‐CA (wild‐type or variant) treated with tafamidis. Clinical outcome was tracked through follow‐up visits or phone calls. Primary outcomes were death and major adverse cardiac events (MACE), a composite end point of death and hospitalizations for acute cardiac decompensation, myocardial infarction, severe arrythmias, or stroke. Kaplan‐Meier analysis estimated overall and MACE‐free survival including NYHA subgroups (NYHA I/II versus NYHA III).

One hundred sixty‐seven patients with ATTR‐CA (94.6% wild‐type) were enrolled and followed for a median of 539 [323–869] days. Median overall survival was not reached. Estimated 1‐year, 2‐year, and 5‐year overall survival among the whole cohort was 93.5%, 85.9%, and 70.2%, respectively. Overall survival was higher in the NYHA I/II subgroup (
P
=0.002). Median MACE‐free survival time was 1082 (95% CI, 962–1202) days. MACE‐free survival was higher in the NYHA I/II subgroup (
P
<0.001). With respective hazard ratios of 5.85 (95% CI, 1.48–23.18;
P
=0.012) and 3.95 (95% CI, 1.99–7.84;
P
<0.001), NYHA III was an independent predictor of death and MACE.

Conclusions
Treatment of ATTR‐CA with tafamidis led to substantial improvements of clinical outcome. NYHA classification at treatment initiation is a reliable tool to provide patients with individualized prognostic information.
Subpolar North Atlantic Mean State Affects the Response of the Atlantic Meridional Overturning Circulation to the North Atlantic Oscillation in CMIP6 Models
Authors: Reintges Annika , Robson Jon I. , Sutton Rowan , Yeager Stephen G. 
Published: July 2024

Abstract
The Atlantic meridional overturning circulation (AMOC) plays an important role in climate, transporting heat and salt to the subpolar North Atlantic. The AMOC’s variability is sensitive to atmospheric forcing, especially the North Atlantic Oscillation (NAO). Because AMOC observations are short, climate models are a valuable tool to study the AMOC’s variability. Yet, there are known issues with climate models, like uncertainties and systematic biases. To investigate this, preindustrial control experiments from models participating in the phase 6 of Coupled Model Intercomparison Project (CMIP6) are evaluated. There is a large, but correlated, spread in the models’ subpolar gyre mean surface temperature and salinity. By splitting models into groups of either a warm–salty or cold–fresh subpolar gyre, it is shown that warm–salty models have a lower sea ice cover in the Labrador Sea and, hence, enable a larger heat loss during a positive NAO. Stratification in the Labrador Sea is also weaker in warm–salty models, such that the larger NAO-related heat loss can also affect greater depths. As a result, subsurface density anomalies are much stronger in the warm–salty models than in those that tend to be cold and fresh. As these anomalies propagate southward along the western boundary, they establish a zonal density gradient anomaly that promotes a stronger delayed AMOC response to the NAO in the warm–salty models. These findings demonstrate how model mean state errors are linked across variables and affect variability, emphasizing the need for improvement of the subpolar North Atlantic mean states in models.
Momelotinib for the treatment of myelofibrosis
Authors: Bose Prithviraj 
Published: July 2024

Abstract
In September 2023, the US Food and Drug Administration approved momelotinib for the treatment of myelofibrosis (MF) with anemia, marking the fourth US regulatory approval of a Janus kinase inhibitor for MF. A positive opinion from the European Medicines Agency followed in November 2023. Momelotinib’s ability to address splenomegaly, symptoms, and anemia, including in patients with thrombocytopenia (with platelet counts of ≥25 × 109/L), the ease of switching from ruxolitinib, and good tolerability uniquely position it to substantially impact the MF treatment landscape.
WTAP/IGF2BP3-mediated GBE1 expression accelerates the proliferation and enhances stemness in pancreatic cancer cells via upregulating c-Myc
Authors: Jin Weiwei , Yao Yanru , Fu Yuhan , Lei Xiangxiang , Fu Wen , Lu Qiliang , Tong Xiangmin , Xu Qiuran , Su Wei , Hu Xiaoge 
Published: July 2024

Abstract
Background
Pancreatic cancer (PC) is one of the most malignant cancers with highly aggressiveness and poor prognosis. N6-methyladenosine (m6A) have been indicated to be involved in PC development. Glucan Branching Enzyme 1 (GBE1) is mainly involved in cell glycogen metabolism. However, the function of GBE1 and Whether GBE1 occurs m6A modification in PC progression remains to be illustrated.

Methods
The clinical prognosis of GBE1 was analyzed through online platform. The expression of GBE1 was obtained from online platform and then verified in normal and PC cell lines. Lentivirus was used to generated GBE1 stable-overexpression or knockdown PC cells. Cell Counting Kit (CCK-8), colony formation assay, sphere formation assay and flow cytometry assay were conducted to analyze cell proliferation and stemness ability in vitro. Subcutaneous and orthotopic mouse models were used to verify the function of GBE1 in vivo. RNA immunoprecipitation (RIP) assay, RNA stability experiment and western blots were conducted to explore the molecular regulation of GBE1 in PC.

Results
GBE1 was significantly upregulated in PC and associated with poor prognosis of PC patients. Functionally, GBE1 overexpression facilitated PC cell proliferation and stemness-like properties, while knockdown of GBE1 attenuated the malignancy of PC cells. Importantly, we found the m6A modification of GBE1 RNA, and WTAP and IGF2BP3 was revealed as the m6A regulators to increase GBE1 mRNA stability and expression. Furthermore, c-Myc was discovered as a downstream gene of GBE1 and functional rescue experiments showed that overexpression of c-Myc could rescue GBE1 knockdown-induced PC cell growth inhibition.

Conclusions
Our study uncovered the oncogenic role of GBE1/c-Myc axis in PC progression and revealed WTAP/IGF2BP3-mediated m6A modification of GBE1, which highlight the potential application of GBE1 in the targeted therapy of PC.
Violence in the emergency department: a quantitative survey study of healthcare providers in India
Authors: Ahluwalia Tania , Singh Sukhpreet , Gandhi Navvin , Toy Serkan , Douglass Katherine , Blanchard Janice , Davey Kevin 
Published: July 2024

Abstract
Background
Workplace violence (WPV) in Emergency Departments (EDs) is an increasingly recognized challenge healthcare providers face in low-resource settings. While studies have highlighted the increased prevalence of WPV in healthcare, most of the existing research has been conducted in developed countries with established laws and repercussions for violence against healthcare providers. More data on WPV against ED providers practicing in low-resource settings is necessary to understand these providers’ unique challenges.

Objective
This study aims to gain insight into the incidence and characteristics of WPV among ED healthcare providers in India.

Methods
This study was conducted at two EDs in geographically distinct regions of India. A survey was designed to assess violence in EDs among healthcare providers. Surveys were distributed to ED workplace providers, completed by hand, and returned anonymously. Data was entered and stored in the RedCAP database to facilitate analysis.

Results
Two hundred surveys were completed by physicians, nurses, and paramedics in Indian EDs. Most reported events involved verbal abuse (68%), followed by physical abuse (26%), outside confrontation (17%), and stalking (5%). By far, the most common perpetrators of violence against healthcare workers were bystanders including patient family members or other accompanying individuals. Notably, reporting was limited, with most cases conveyed to ED or hospital administration.

Conclusion
These results underscore the prevalence of WPV among Indian ED healthcare providers. High rates of verbal abuse followed by physical abuse are of concern. Most perpetrators of WPV against healthcare providers in this study were patient family members or bystanders rather than the patients themselves. It is imperative to prioritize implementing prevention strategies to create safer work environments for healthcare workers.
Development of pre-implantation genetic testing protocol for monogenic disorders (PGT-M) of Hb H disease
Authors: Somboonchai Pannarai , Charoenkwan Pimlak , Piyamongkol Sirivipa , Lattiwongsakorn Worashorn , Pantasri Tawiwan , Piyamongkol Wirawit 
Published: July 2024

AbstractHb H disease is the most severe form of α-thalassemia compatible with post-natal life. Compound heterozygous α0-thalassemia− SEA deletion/α+-thalassemia− 3.7kb deletion is the commonest cause of Hb H disease in Thailand. Preimplantation genetics testing for monogenic disorders (PGT-M) is an alternative for couples at risk of the disorder to begin a pregnancy with a healthy baby. This study aims to develop a novel PCR protocol for PGT-M of Hb H disease− SEA/−3.7kb using multiplex fluorescent PCR. A novel set of primers for α+-thalassemia− 3.7kb deletion was developed and tested. The PCR protocol for α0-thalassemia− SEA deletion was combined for Hb H disease− SEA/−3.7kb genotyping. The PCR protocols were applied to genomic DNA extracted from subjects with different thalassemia genotypes and on whole genome amplification (WGA) products from clinical PGT-M cycles of the families at risk of Hb Bart’s. The results were compared and discussed. The results showed three PCR products from α+-thalassemia− 3.7kb primer set, and three from α0thalassemiaSEA primer set. The results were consistent with the known thalassemia genotypes. The novel -α3.7 primers protocol was also tested on 37 WGA products from clinical PGT-M cycles giving accurate genotyping results and a satisfying amplification efficiency with the ADO rates of 2.7%, 0%, and 0% for HBA2, HBA1, and internal control fragments, respectively. This novel PCR protocol can precisely distinguish Hb H disease− SEA/−3.7kb from other genotypes. Additionally, this is the first PCR protocol for Hb H disease− SEA/−3.7kb which is optimal for PGT-M.
Screening for frailty and its association with activities of daily living, cognitive impairment, and falls among community-dwelling older adults in China
Authors: Ji Dakang , Guo Haijian , Qiu Shanhu , Dong Lirong , Shen Ya , Shen Zhengkai , Xu Jinshui 
Published: July 2024

Abstract
Objectives
Frailty is a prevalent geriatric condition that significantly impacts the health of older adults. This study aimed to examine the prevalence of frailty among older Chinese adults aged ≥ 65 years and to assess its association with adverse geriatric outcomes.

Method
This study included 20,724 older adults aged ≥ 65 years in Jiangsu Province, China, utilizing a random, stratified, multistage cluster sampling approach. Frailty was assessed using the 5-item FRAIL scale. Geriatric outcomes, such as independence in activities of daily living (ADL), cognitive impairment, and frequent fall events (occurring four or more times in the preceding year), were evaluated. Logistic regression models were employed to evaluate the association between frailty and geriatric outcomes, with results presented as odds ratios (ORs) and 95% confidence intervals (CIs).

Results
The mean age of the participants was 73.4 ± 6.4 years. The standardized prevalence of prefrailty and frailty was 35.2% and 10.3%, respectively. Individuals identified as prefrail or frail tended to live in rural areas, have lower educational levels, be widowed, have lower incomes, and engage in less physical activity. Prefrailty and frailty were associated with an increased risk of limitations in BADL (OR: 9.62, 95% CI: 7.43–12.46; and OR: 29.25, 95% CI: 22.42–38.17, respectively) and IADL (OR: 2.54, 95% CI 2.35–2.74; and OR: 5.19, 95% CI 4.66–5.78, respectively), positive cognitive impairment screening (OR: 1.23, 95% CI: 1.16–1.31; and OR: 1.72, 95% CI: 1.56–1.91, respectively), and frequent falls (occurring four or more times in the preceding year) (OR: 3.38, 95% CI: 2.50–4.56; and OR: 8.37, 95% CI: 6.01–11.65). The association between frailty and both limitations in BADL and falls was notably more pronounced among the younger age groups (p for interaction < 0.001).

Conclusions
According to the 5-item FRAIL scale, frailty was associated with limitations in BADLs and IADLs, positive cognitive impairment screening, and recent falls among older adults living in the community. Screening for frailty in younger age groups has the potential to prevent declines in physical function and falls.
The use of technology by seniors with neurocognitive disorders in long-term care: a scoping review
Authors: Hardy Marie-Soleil , Fanaki Chaimaa , Savoie Camille 
Published: July 2024

Abstract
Background
To map the current state of knowledge about the use of technology with seniors with neurocognitive disorders in long-term care to foster interactions, wellness, and stimulation.

Methods
Cumulative Index to Nursing and Allied Health Literature (CINAHL Plus); MEDLINE; PsycINFO; Embase and Web of Science were searched in eligible literature, with no limit of time, to describe the current use of technology by seniors with neurocognitive disorders in long-term care. All types of literature were considered except for theses, editorial, social media. This scoping review was built around the recommendations of Peters et al. (2020 version). Three researchers collaborated on the selection of articles and independently reviewed the papers, based on the eligibility criteria and review questions.

Results
The search yielded 3,605 studies, of which 39 were included. Most technology type reported was robotics. Included studies reports different positive effects on the use of such technology such as increase of engagement and positive.

Conclusion
The study highlights different types and potential benefits of technology for long-term care residents with neurocognitive disorders, emphasizing the crucial need for additional research to refine interventions and their use.