bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast Cancer Mutations HER2V777L and PIK3CAH1047R Activate the p21–CDK4/6–Cyclin D1 Axis to Drive Tumorigenesis and Drug Resistance
Authors: Cheng Xiaoqing , Sun Yirui , Highkin Maureen , Vemalapally Nagalaxmi , Jin Xiaohua , Zhou Brandon , Prior Julie L. , Tipton Ashley R. , Li Shunqiang , Iliuk Anton , Achilefu Samuel , Hagemann Ian S. , Edwards John R. , Bose Ron 
Published: June 2023

Abstract

In metastatic breast cancer, HER2-activating mutations frequently co-occur with mutations in PIK3CA, TP53, or CDH1. Of these co-occurring mutations, HER2 and PIK3CA are the most commonly comutated gene pair, with approximately 40% of HER2-mutated breast cancers also having activating mutations in PIK3CA. To study the effects of co-occurring HER2 and PIK3CA mutations, we generated genetically engineered mice with the HER2V777L; PIK3CAH1047R transgenes (HP mice) and studied the resulting breast cancers both in vivo as well as ex vivo using cancer organoids. HP breast cancers showed accelerated tumor formation in vivo and increased invasion and migration in in vitro assays. HP breast cancer cells were resistant to the pan-HER tyrosine kinase inhibitor, neratinib, but were effectively treated with neratinib plus the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan. Proteomic and RNA-seq analysis of HP breast cancers identified increased gene expression of cyclin D1 and p21WAF1/Cip1 and changes in cell-cycle markers. Combining neratinib with CDK4/6 inhibitors was another effective strategy for treating HP breast cancers, with neratinib plus palbociclib showing a statistically significant reduction in development of mouse HP tumors as compared to either drug alone. The efficacy of both the neratinib plus trastuzumab deruxtecan and neratinib plus palbociclib combinations was validated using a human breast cancer patient-derived xenograft with very similar HER2 and PIK3CA mutations to the HP mice. Further, these two drug combinations effectively treated spontaneous lung metastasis in syngeneic mice transplanted with HP breast cancer organoids. This study provides valuable preclinical data to support the ongoing phase 1 clinical trials of these drug combinations in breast cancer.

Significance:
In HER2-mutated breast cancer, PIK3CA mutation activates p21–CDK4/6–cyclin D1 signaling to drive resistance to HER2-targeted therapies, which can be overcome using CDK4/6 inhibitors.
Identification of evolutionary mechanisms of myelomatous effusion by single-cell RNA sequencing
Authors: Sun Zhengxu , Ji Jiamei , Li Yating , Cui Yunqi , Fan Lei , Li Jianyong , Qu Xiaoyan 
Published: June 2023

Abstract
Myelomatous effusion (ME) is a rare manifestation of extramedullary multiple myeloma (MM) with limited therapeutic options and poor outcomes. The molecular mechanisms underlying ME are incompletely understood. We profiled transcriptomes of bone marrow, peripheral blood (PB), and pleural effusion/ascites from 3 patients with ME using single-cell RNA sequencing analysis. We found that ME contained a higher percentage of cytotoxic T cells, whereas PB contained a higher proportion of naive T cells. Malignant cells varied within and between sites and patients in their expression of signatures. We identified a gene module highly expressed in intramedullary and extramedullary plasma cell clusters and defined cell clusters expressing this gene set as extramedullary-initiating cells (EMICs). This gene set was associated with increased cellular proliferation, involved in p53 signaling, and related to poor prognosis in MM. The transcriptional regulators E2F1, YY1, and SMAD1 were activated in EMICs. Leukocyte immunoglobulin–like receptor subfamily B4 (LILRB4) was upregulated in extramedullary EMICs. We confirmed that LILRB4 promoted MM cell migration in vitro. This study provided insight into the evolutionary mechanisms of ME and defined EMICs and LILRB4 associated with extramedullary development.
Pegaspargase-modified risk-oriented program for adult acute lymphoblastic leukemia: results of the GIMEMA LAL1913 trial
Authors: Bassan Renato , Chiaretti Sabina , Della Starza Irene , Spinelli Orietta , Santoro Alessandra , Paoloni Francesca , Messina Monica , Elia Loredana , De Propris Maria Stefania , Scattolin Anna Maria , Audisio Ernesta , Marbello Laura , Borlenghi Erika , Zappasodi Patrizia , Mauro Elisa , Martinelli Giovanni , Mattei Daniele , Fracchiolla Nicola , Bocchia Monica , De Fabritiis Paolo , Bonifacio Massimiliano , Candoni Anna , Cassibba Vincenzo , Di Bartolomeo Paolo , Latte Giancarlo , Trappolini Silvia , Guarini Anna , Vitale Antonella , Fazi Paola , Piciocchi Alfonso , Rambaldi Alessandro , Foà Robin 
Published: June 2023

Abstract
Pediatric-inspired chemotherapy is the standard of care for younger adults with Philadelphia chromosome–negative acute lymphoblastic leukemia/lymphoma (Ph– ALL/LL). In LAL1913 trial, the Gruppo Italiano Malattie EMatologiche dell’Adulto added pegaspargase 2000 IU/m2 to courses 1, 2, 5, and 6 of an 8-block protocol for patients aged from 18 to 65 years, with dose reductions in patients aged &gt;55 years. Responders were risk stratified for allogeneic hematopoietic cell transplantation (HCT) or maintenance per clinical characteristics and minimal residual disease (MRD). Of 203 study patients (median age, 39.8 years), 91% achieved a complete remission. The 3-year overall survival, event-free, and disease-free survival (DFS) rates were 66.7%, 57.7%, and 63.3%, respectively, fulfilling the primary study end point of a 2-year DFS &gt;55%. Although based on the intention-to-treat, the DFS being 74% and 50% in the chemotherapy (n = 94) and HCT (n = 91) assignment cohorts, respectively, a time-dependent analysis proved the value of HCT in patients who were eligible (DFS HCT 70% vs no HCT 26%; P &lt;.0001). In multivariate analysis, age and MRD were independent factors predicting DFS rates of 86% (age ≤ 40 and MRD-negative), 64%-65% (MRD-positive or age &gt; 40) and 25% (age &gt; 40 and MRD-positive); P &lt; .0001. Grade ≥2 pegaspargase toxicity was mainly observed at course 1, contributing to induction death in 2 patients but was rare thereafter. This program improved outcomes of patients with Ph– ALL/LL aged up to 65 years in a multicenter national setting. This trial was registered at www.clinicaltrials.gov as #NCT02067143.
Is book reading always best? Children learn and transfer complex scientific explanations from books or animations
Authors: Ronfard Samuel , Brown Sarah A. , Pitt Emma , Kelemen Deborah 
Published: June 2023

Abstract
Background
Storybooks are an effective tool for teaching complex scientific mechanisms to young children when presented in child-friendly, joint-attentional contexts like read-aloud sessions. However, static storybooks are limited in their ability to convey change across time and, relative to animated storybooks, are harder to disseminate to a wide audience. This study examined second graders’ abilities to learn the deeply counterintuitive concepts of adaptation and speciation from multi-day interventions centered around two storybooks about natural selection that were either read-aloud (static) or watched on a screen (animated). The storybook sequence was progressive and first explained—in counter-essentialist and non-teleological terms—how the relative distribution of a terrestrial mammal’s trait changed over time due to behavioral shifts in their primary food resource (adaptation, book 1). It then explained how–after a sub-population of this species became geographically isolated–they evolved into an entirely different aquatic species over many generations via selection on multiple foraging-relevant traits (speciation, book 2). The animated and static versions of the storybooks used the same text and illustrations, but while the animations lacked joint-attentional context, they more dynamically depicted successive reproductive generations. Storybook and animation presentations were interspersed with five parallel talk-aloud assessment interviews over three days.

Results
Findings revealed substantial learning from the read-aloud static storybook sequence. They also revealed substantial learning from the animation condition with patterns suggesting that the dynamic representations of change over time particularly scaffolded acquisition of the deeply counterintuitive idea that a species can evolve into an entirely different category of species by natural selection.

Conclusions
The results provide much-needed optimism in a context of increasing demands for scalable solutions to promote effective learning: animated storybooks are just as good (and may even be better) than static storybooks.
Correlation between KRAS and NRAS mutational status and clinicopathological features in 414 cases of metastatic colorectal cancer in Morocco: the largest North African case series
Authors: Mahdi Youssef , Khmou Mouna , Souadka Amine , Agouri Hajar El , Ech-charif Soumaya , Mounjid Chaimaa , Khannoussi Basma El 
Published: June 2023

Abstract
Background
Advances in molecular biology have improved understanding of the molecular features of carcinogenesis and progression of colorectal cancer. It is clear that the efficacy of anti-EGFR depends upon the RAS mutational status, since any mutation in RAS is associated with resistance to anti-EGFR therapy. The aim of this study is to report the largest North African description of KRAS and NRAS status in metastatic colorectal cancer and to describe the association of these mutations with clinicopathological characteristics.

Methods
This is a prospective study of all consecutive unselected metastatic colorectal cancer samples, collected from the Laboratory of Pathology at the National Institute of Oncology of Rabat, Morocco, from January 1st 2020 to December 31st 2021. The molecular analysis was performed on the Idylla™ platform (fully automated real-time polymerase chain reaction-based assay) for KRAS and NRAS mutations in exons 2, 3 and 4. These mutations were correlated to gender, primary tumor site, histological type and degree of differentiation of tumor using adequate statistical methods.

Results
Four hundred fourteen colorectal tumors were screened for KRAS and NRAS mutations. These mutations occurred in 51.7% of tumors for KRAS (mainly in exon 12) and in 3% of tumors for NRAS. There was a significant correlation between NRAS mutation and age of colorectal patients in this study. The low rate of invalid RAS tests (1.7% for KRAS and 3.1% for NRAS) was certainly obtained due to the strict respect of pre-analytical factors such as cold ischemia time and formalin fixation.

Conclusion
We report the largest North African analysis of NRAS and KRAS status in colorectal metastatic patients. This study showed the ability in low middle income countries to perform a high rate of valid tests and the unusual trend towards older patients for NRAS mutations.
Assessment of Anti-SARS-CoV-2 antibody levels among university students vaccinated with different COVID-19 primary and booster doses — fall 2021, Wisconsin
Authors: DeJonge Peter M. , Lambrou Anastasia S. , Segaloff Hannah E. , Bateman Allen , Sterkel Alana , Griggs Carol , Baggott Jake , Kelly Patrick , Thornburg Natalie , Epperson Monica , Desamu-Thorpe Rodel , Abedi Glen , Hsu Christopher H. , Nakayama Jasmine Y. , Ruffin Jasmine , Turner-Harper Darlene , Matanock Almea , Almendares Olivia , Whaley Melissa , Chakrabarti Ayan , DeGruy Kyle , Daly Michele , Westergaard Ryan , Tate Jacqueline E. , Kirking Hannah L. 
Published: June 2023

AbstractBackgroundUniversity students commonly received COVID-19 vaccinations before returning to U.S. campuses in the Fall of 2021. Given likely immunologic variation among students based on differences in type of primary series and/or booster dose vaccine received, we conducted serologic investigations in September and December 2021 on a large university campus in Wisconsin to assess anti-SARS-CoV-2 antibody levels.MethodsWe collected blood samples, demographic information, and COVID-19 illness and vaccination history from a convenience sample of students. Sera were analyzed for both anti-spike (anti-S) and anti-nucleocapsid (anti-N) antibody levels using World Health Organization standardized binding antibody units per milliliter (BAU/mL). Levels were compared across categorical primary COVID-19 vaccine series received and binary COVID-19 mRNA booster status. The association between anti-S levels and time since most recent vaccination dose was estimated by mixed-effects linear regression.ResultsIn total, 356 students participated, of whom 219 (61.5%) had received a primary vaccine series of Pfizer-BioNTech or Moderna mRNA vaccines and 85 (23.9%) had received vaccines from Sinovac or Sinopharm. Median anti-S levels were significantly higher for mRNA primary vaccine series recipients (2.90 and 2.86 log [BAU/mL], respectively), compared with those who received Sinopharm or Sinovac vaccines (1.63 and 1.95 log [BAU/mL], respectively). Sinopharm and Sinovac vaccine recipients were associated with a significantly faster anti-S decline over time, compared with mRNA vaccine recipients (P<.001). By December, 48/172 (27.9%) participants reported receiving an mRNA COVID-19 vaccine booster, which reduced the anti-S antibody discrepancies between primary series vaccine types.ConclusionsOur work supports the benefit of heterologous boosting against COVID-19. COVID-19 mRNA vaccine booster doses were associated with increases in anti-SARS-CoV-2 antibody levels; following an mRNA booster dose, students with both mRNA and non-mRNA primary series receipt were associated with comparable levels of anti-S IgG.
Benefit finding in men affected by prostate cancer prior to and following radical prostatectomy – a cross-sectional study with a stratified sample
Authors: Jahnen Matthias , Bayer Patrick , Meissner Valentin H. , Schiele Stefan , Schulwitz Helga , Gschwend Jürgen E. , Herkommer Kathleen , Dinkel Andreas 
Published: June 2023

Abstract
Background
Benefit finding (BF) - the occurrence of positive life-changes in the aftermath of traumatic live events - has been repeatedly reported in prostate cancer (PCa) survivors, but it remains unclear in which way BF might vary over time. The current study aimed to investigate the extent of BF and associated factors in different phases of the survivorship continuum.

Methods
In this cross-sectional study, men affected by PCa who were either already treated with radical prostatectomy or going to be treated with radical prostatectomy at a large German PCa center were included. These men were stratified into four groups (prior to surgery, up to 12 months after surgery, 2–5 years and ≥ 6–10 years after surgery). BF was assessed using the German version of the 17-item Benefit Finding Scale (BFS). The items are rated on a five-point Likert scale ranging from 1 to 5. A total mean score ≥ 3 was considered as moderate-to-high BF. Associations with clinical and psychological factors were assessed in men presenting before and in those who participated after surgery. Multiple linear regression was applied to identify intendent determinants of BF.

Results
2,298 men affected by PCa (mean age at survey: 69.5,SD = 8.2; median follow-up: 3 years (25th -75th percentile 0.5-7)) were included. 49.6% of men reported moderate-to-high BF. The mean BF score was 2.91 (SD = 0.92). BF reported by men before surgery did not differ significantly from BF reported by men in the years after surgery (p = 0.56). Higher BF prior to and following radical prostatectomy was associated with higher perceived severity of the disease (pre-surgery: ß = 0.188, p = 0.008; post-surgery: ß = 0.161, p = < 0.0001) and higher cancer-related distress (pre-surgery: ß ? 0.155, p = 0.03; post-surgery: ß = 0.089, p < 0.0001). Post radical prostatectomy BF was also associated with biochemical recurrence during follow-up (ß = 0.089, p = 0.001), and higher quality of life (ß = 0.124, p < 0.001).

Conclusions
Many men affected by PCa perceive BF already soon after diagnosis. The subjective perception of threat or severity associated with the diagnosis of PCa is an essential factor for higher levels of BF, probably more important than objective indicators of the severity of the disease. The early onset of BF and the high degree of similarity of BF reported across the different phases of survivorship suggests that BF is, to a large extent, a dispositional personal characteristic and a cognitive strategy of positively coping with cancer.
Human cornea thermo-viscoelastic behavior modelling using standard linear solid model
Authors: Ahmed Hassan M. , Salem Nancy M. , Al-Atabany Walid 
Published: June 2023

Abstract
Background
Corneal biomechanics is of great interest to researchers recently. Clinical findings relate them to corneal diseases and to outcomes of refractive surgery. To have a solid understanding of corneal diseases’ progression, it is important to understand corneal biomechanics. Also, they are essential for better explaining outcomes of refractive surgeries and their undesired consequences. There is a difficulty for studying corneal biomechanics in-vivo and multiple limitations arise for ex-vivo studies. Hence mathematical modelling is considered as a proper solution to overcome such obstacles. Mathematical modelling of cornea in-vivo allows studying corneal viscoelasticity with taking into consideration all boundary conditions existing in real in-vivo situation.

Methods
Three mathematical models are used to simulate corneal viscoelasticity and thermal behavior in two different loading situations: constant and transient loading. Two models of the three are used for viscoelasticity simulation which are Kelvin-Voigt and standard linear solid models. Also, temperature rise due to the ultrasound pressure push is calculated using bioheat transfer model for both the axial direction and as a 2D spatial map using the third model (standard linear solid model).

Results
Viscoelasticity simulation results show that standard linear solid model is efficient for describing the viscoelastic behavior of human cornea in both loading conditions. Results show also that the deformation amplitude obtained from standard linear solid model is more reasonable for corneal soft-tissue deformation with respect to corresponding clinical findings than that obtained from Kelvin-Voigt model. Thermal behavior results estimated corneal temperature rise to be roughly 0.2 °C, which conforms with FDA regulations for soft tissue safety.

Conclusion
Standard Linear Solid (SLS) model is better describing the human corneal behavior in response to constant and transient load more efficiently. Temperature rise (TR) for the corneal tissue of about 0.2 °C is conforming with FDA regulations and even less than the FDA regulations for soft tissue safety.
Increased METTL3 expression and m6A RNA methylation may contribute to the development of dry eye in primary Sjögren’s syndrome
Authors: Ma Jun , Wang Xiaotang , Yang Xue , Wang Xi , Tan Tongshan , Fang Hongping , Zhong Yu , Zhang Qi 
Published: June 2023

Abstract
Background
Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disorder defined by xerostomia and keratoconjunctivitis sicca, and its etiology remains unknown. N6-methyladenosine (m6A) is the predominant posttranscriptional modification in eukaryotic mRNAs and is dynamically regulated by m6A regulators. Dysregulation of m6A modification is closely associated with several autoimmune disorders, but the role of m6A modification in pSS remains unknown. This study investigated the potential role of m6A and m6A-related regulators in pSS patients with dry eye.

Methods
This cross-sectional study included forty-eight pSS patients with dry eye and forty healthy controls (HCs). Peripheral blood mononuclear cells (PBMCs) were isolated, and the level of m6A in total RNA was measured. The expression of m6A regulators was determined utilizing real-time PCR and western blotting. The serological indicators detected included autoantibodies, immunoglobulins (Igs), complement factors (Cs), and inflammatory indicators. Dry eye symptoms and signs were measured, including the ocular surface disease index, Schirmer’s test (ST), corneal fluorescein staining score (CFS), and tear break-up time. Spearman’s correlation coefficient was employed to assess the associations of m6A and m6A-related regulator expression with clinical characteristics.

Results
The expression level of m6A was markedly increased in the PBMCs of pSS patients with dry eye compared to HCs (P value<0.001). The relative mRNA and protein expression levels of the m6A regulators methyltransferase-like 3 (METTL3) and YT521-B homology domains 1 were markedly elevated in pSS patients with dry eye (both P value<0.01). The m6A RNA level was found to be positively related to METTL3 expression in pSS patients (r = 0.793, P value<0.001). Both the m6A RNA level and METTL3 mRNA expression correlated with the anti-SSB antibody, IgG, ST, and CFS (all P values < 0.05). The m6A RNA level was associated with C4 (r = -0.432, P value = 0.002), while METTL3 mRNA expression was associated with C3 (r = -0.313, P value = 0.030).

Conclusions
Our work revealed that the upregulation of m6A and METTL3 was associated with the performance of serological indicators and dry eye signs in pSS patients with dry eye. METTL3 may contribute to the pathogenesis of dry eye related to pSS.
Infusing wellness opportunities into integrated youth services
Authors: Glowacki Krista , Affolder Jennifer , Macnab Brooke , Ewert Alayna , Tee Karen , Wenger Matt , Chan Godwin , Mathias Steve , Barbic Skye 
Published: June 2023

Abstract
Background
Appropriate health services and health promotion strategies for young people with mental health and substance use (MHSU) concerns are critical for recovery. Foundry, an integrated youth services (IYS) initiative for young people ages 12-24 in British Columbia (BC), Canada, has recently added leisure and recreational activities (referred to as the Wellness Program) into its services. The objectives of this study were to: (1) describe how the Wellness Program was implemented over a two-year period into IYS (2) provide an overview of what the Wellness Program is, who accessed the program since inception and initial evaluation results.

Methods
This study was part of the developmental evaluation of Foundry. A phased approach was used to implement the program at nine centres. Data was accessed from Foundry’s centralized platform ‘Toolbox’ and included activity type, number of unique youth and visits, additional services sought, information about how youth found out about the centre, and demographics. Qualitative data was also accessed from focus groups (n=2) conducted with young people (n=9).

Results
Over the two-year period, 355 unique youth accessed the Wellness Program, with 1319 unique visits. Almost half (40%) of youth identified the Wellness Program as the first point of access to Foundry. A total of 384 different programs were offered targeting five wellness domains (physical, mental/emotional, social, spiritual, and cognitive/intellectual). The majority of youth identified as young girls/women (58.2%), 22.6% as gender diverse, and 19.2% as young men/boys. The mean age was 19 years, and most participants were between the ages of 19-24 years (43.6%). From the thematic analysis of focus groups, we found young people enjoyed the social aspect of the program with peers and facilitators, and identified program improvements that are being considered as the program grows.

Conclusions
This study provides insight into the development and implementation of leisure-based activities (known as the Wellness Program) into IYS and can be used as a guide by international IYS initiatives. The initial reach of programs over two years is promising, and these programs are acting as a potential gateway for young people to access other health services.