bluuebunny/crossref_metadata_2025 huggingface dataset:
Somewhere, Somehow: Young Children Imagine Possibilities and Ask About Them
Authors: Harris Paul L.
Published: December 2024

Studies of young children's communication with adults and of their engagement in make-believe play have typically been conducted in parallel, with little dialogue between the two research programs. This review seeks to underline close connections between children's communication with adults and the emergence of the imagination, especially among 2- and 3-year-olds. Young children's ability to imagine currently uncertain possibilities shapes the information-seeking questions that they put to other people. Their ability to imagine as-yet unrealized but desirable possibilities shapes the requests that they make of other people. In each case, children appraise the responses that they receive. In the absence of answers that resolve their information-seeking questions, they repeat their questions. In the absence of compliance with their requests, they repeat their requests. By implication, from an early age, children seek information and help from other people with as-yet unknown or unrealized possibilities in mind.
Creating Inclusive Environments: Enabling Children to Reject Prejudice and Discrimination
Authors: Rutland Adam , Cameron Lindsey , Killen Melanie
Published: December 2024

Developmental psychology researchers who investigate the multifaceted nature of prejudice, shown within everyday peer interactions, emphasize the importance of creating inclusive environments for children where equity and justice are promoted. This article uses the Social Reasoning Developmental (SRD) model to explore how children and adolescents reason about social inclusion and exclusion, drawing on moral, social group, and psychological considerations. The role of bystanders in challenging social exclusion is highlighted, with a focus on promoting proactive bystander intervention to create inclusive environments. This review identifies age, group identity, group norms, intergroup contact, empathy, and theory of mind as key influences on children's and adolescents’ bystander reactions. It emphasizes that interventions promoting inclusive peer and school norms, confidence in intergroup contact, empathy, and social perspective-taking can foster inclusive environments and empower bystander action that challenges intergroup social exclusion.
Heartwheels! STEM Mobile Outreach program
Authors: Monreal Gretel , Koenig Steven C.
Published: December 2024

Heartwheels! STEM Mobile Outreach is an innovative, portable, scaled-down version of the authors’ research laboratory that they take out into the schools and communities to engage and connect with people young and old in the cardiovascular sciences, improve health literacy and awareness of heart-healthy living, and spark curiosity in the science, technology, engineering, and mathematics (STEM) fields through fun, hands-on, experiential educational activities.
Enhanced quantification of α-cell suppression by hyperglycemia using a high-sensitivity glucagon assay
Authors: Dyer Roy B. , Laurenti Marcello C. , Christie Hannah E. , Mohan Sneha , Egan Aoife M. , Dalla Man Chiara , Vella Adrian
Published: December 2024

We describe a method that lowers the limit of quantification of a glucagon immunoassay thereby enhancing the ability to differentiate between normal and abnormal α-cell responsiveness to glucagon.
Alterations of the Intestinal Mucosal Barrier and Gut Fungal Microbiome in Asymptomatic HIV‐Infected Patients
Authors: Li Wenjie , Qing Yong , Yu Qiuyue , Zhang Hulian , Rang Zhen , Li Shuangli , Cui Fan
Published: December 2024

Damage to the intestinal mucosal barrier and dysbiosis of the gut microbiota are critical factors in HIV progression, reciprocally influencing each other. Besides bacteria, the fungal microbiota, a significant component of the gut, plays a pivotal role in this dysregulation. This study aims to investigate changes in the gut mucosal barrier and mycobiota during the initial stages of HIV infection, focusing on the involvement of intestinal fungi and their secretions in mucosal damage. Peripheral blood, intestinal mucosa, and fecal samples were collected from 13 asymptomatic HIV‐infected individuals at the non‐AIDS stage and 13 healthy controls. Assessments included colonoscopy, immune function analysis, and measurement of mucosal damage markers (LPS, I‐FABP, and D‐LA) and inflammatory cytokines (IL‐6 and IL‐18). Additionally, Claudin‐1 levels in mucosal samples and fungal profiles in fecal samples were evaluated. The study found that colonic abnormalities were significantly more prevalent in the HIV group compared to healthy controls (p < 0.001) and Claudin‐1 levels were notably lower in the HIV group (p <  0.001). Candida albicans (p = 0.0084), its secretion SAP1 (p = 0.023), and the levels of IL‐18 (p = 0.0016) and IL‐6 (p < 0.001) were all significantly higher in the HIV group. CD4+ T‐cell counts were positively correlated with Claudin‐1 expression (p = 0.034, r = 0.417). Candida albicans showed negative correlations with several virulence factors, while other fungi exhibited varied correlations. Additionally, Claudin‐1 levels were significantly negatively correlated with Candida albicans (p = 0.013, r = −0.668), SAP1 (p = 0.027, r = −0.609), IL‐18 (p < 0.001, r = −0.922), and IL‐6 (p < 0.001, r = −0.920). Overall, these findings suggest that asymptomatic HIV‐infected individuals have already exhibited intestinal mucosal damage in the early stage and highlight the critical role of Candida albicans and its secretions in early‐stage intestinal mucosal barrier damage.
Numerical Simulation of Plasma Plume Sheath and Secondary Electron Emission Based on DSMC‐PIC Parallel Algorithm
Authors: Yang Fuxiang , Li Jie , Liu Wei , Chen Houling
Published: December 2024

The temporal and spatial evolution of plasma plume is accompanied by sheath, secondary electron emission (SEE), and other phenomena that have a crucial impact on the working characteristics and performance improvement of plasma devices. In this paper, a direct simulation Monte Carlo (DSMC) and particle‐in‐cell (PIC) hybrid parallel algorithm is employed for numerical simulation, which is a fully kinetic PIC method. Energy‐based outlet and wall boundary conditions of charge conservation are investigated. This paper discusses the influence of different models on the flow field. First, four SEE energy spectrum models—the Mozorov model, the Furman model, the vertical model, and the three temperature model—are discussed. Then, four kinds of insulation wall materials—boron nitride, silicon carbide, alumina, and graphite—as simulated by the modified Mozorov coefficient model are investigated. Through the simulation of axisymmetric cases, the influence of SEE energy spectrum; secondary electron emission coefficient (SEC); electric field action; and other factors on the spatiotemporal evolution of H2, H, X, , H+, and e in the flow field is demonstrated. This paper analyzes the structural characteristics of cloud images with different models through number densities in detail. The SEE energy spectrum has an important influence on the distribution of the field potential and the number density of charged particles, but it is not as important as the SEC.
Plant Biodiversity, Wetland Indicators, and Ecosystem Analysis of Human‐Made Wetlands in Central Ethiopia
Authors: Moges Admasu , Dibaba Abyot
Published: December 2024

Despite vital in conserving biodiversity, most natural wetlands were degraded and declined in numbers due to anthropogenic factors, thereby human‐made wetlands have been established in Ethiopia. Thus, this study aimed to analyze plant diversity, wetland indicators, characteristic species, and ecosystem conditions of Ethiopian highland human‐made wetlands. A systematic sampling design was employed for laying 20 quadrats (2 m2 each) in each wetland at a 50‐m interval, where plant specimen sampling and cover estimation were made. A survey identified 74 plant species. These species belong to 26 families and 57 genera. Notably, 92% of the identified plants were herbs. Asteraceae and Poaceae were the most dominant families. The richness of Washa and Borale sites was 51 and 64, respectively, showed a significance difference at p < 0.05. The Shannon diversity and evenness of Washa and Borale sites were 2.32 and 0.93, and 2.53 and 0.96, respectively, also displayed significant differences at p < 0.05. Yet, 71% plant species similarity was observed between the two wetlands. In each wetland, > 52% and < 30% species were upland and wetland indicators with many annual species, respectively, indicating the ecosystem disturbance of the two wetlands and their being invaded by upland species. The ecological condition of Washa and Borale were also directly rated as mid‐and high‐impaired sites, respectively. Briefly, despite both Washa and Borale wetlands rich in plant diversity, they differed significantly in average richness, diversity, and evenness, besides in the richness of their upland and annual species, due to likely variations in their ecological and hydrological modifications. Hence, urgent in situ and ex situ community‐based participatory restoring strategies are required.
Adolescents’ Sexual Reproductive Health Service Utilization and Associated Factors Among Bahir Dar City High School Students, Amhara Region, Ethiopia: A Cross‐Sectional Study
Authors: Elefachew Addis , Alemu Yibeltal , Chanie Belaynesh , Getachew Eyob , Bogale Solomon Ketema , Bogale Eyob Ketema
Published: December 2024

Introduction: All across the world, youths struggle with a variety of health issues. Adolescents everywhere are entering puberty earlier and engaging in more premarital sex. There was limited evidence about the current adolescent sexual reproductive health (RH) service utilization status and its associated factors in the study area, especially after the occurrence of COVID‐19 and the war between the Ethiopian federal government and Tigray regional forces.

Objective: The study is aimed at assessing the magnitude of sexual RH service utilization and associated factors among Bahir Dar City high school students, Amhara region, Ethiopia, in 2022.

Methods: An institution‐based cross‐sectional study design was conducted among Bahir Dar City high school students from December 18, 2022, to January 12, 2022. A multistage sampling technique was applied to select study participants. A total of 629 respondents participated in the study. The data were collected using a pretested, structured, self‐administered questionnaire. The data were entered into EpiData Version 3.1 and then exported to SPSS Version 25 for analysis. Bivariable and multivariable logistic regression was used for analysis.

Results: The magnitude of adolescent sexual RH service utilization was found to be 30.4%. School RH club participation (AOR = 5.93, CI: 3.29–10.71), having ever had sexual exposure (AOR = 6.03, CI: 3.31–10.98), history of sexual RH problems (AOR = 3.26, CI: 1.41–7.51), being perceived as at risk of sexual RH problems (AOR = 6, CI: 3.26–11.04), hearing information about adolescent sexual RH (AOR = 5.19, CI: 3–8.97), and knowing the place to use RH service (AOR = 2.37, CI: 1.47–3.82) were associated with utilization of adolescent sexual RH service.

Conclusions: The magnitude of adolescent sexual RH service utilization was found to be 30.4%. School RH club participation, having ever had sexual exposure, a history of sexual RH problems, being perceived as at risk of sexual RH problems, hearing information about sexual RH, and knowing the place where to get RH services were associated with the utilization of sexual RH services.
Properties, Bounds, and Estimation of Rényi Entropy in Consecutive k‐out‐of‐n:G Systems
Authors: Shrahili Mansour
Published: December 2024

This study investigates the Renyi entropy properties of consecutive k‐out‐of‐n : G systems. Initially, a formula for the Renyi entropy of the lifetime of a consecutive k‐out‐of‐n:G system is derived, offering a thorough insight into its Renyi entropy characteristics. A comparative analysis is performed between two consecutive k‐out‐of‐n:G systems with varying component lifetimes. Moreover, some useful bounds for the Renyi entropy of the lifetime of these systems are established, augmenting the comprehension of Renyi entropy variability within such systems. To aid practical implementation, nonparametric estimators for the novel Renyi entropy measure are devised. The efficiency of the estimators is showcased through the utilization of simulated datasets and then numerical demonstrations are conducted using real‐world datasets.
Development and Psychometric Evaluation of a Questionnaire to Assess Attitudes Towards Invisible Gender‐Based Violence (Q‐AIGV)
Authors: Fernández-Férez Alba , Fernández-Vargas Anabel , Dobarrio-Sanz Iria , Ochoa-Pineda Amada Cesibel , Abarca-Duran Ximena , Martínez-Abarca Ana Lucía , Fernández-Sola Cayetano , Hernández-Padilla José Manuel
Published: December 2024

Objective: To develop and psychometrically evaluate a questionnaire to assess attitudes towards invisible gender‐based violence (Q‐AIGV).

Background: Invisible gender‐based violence is defined as discriminatory attitudes and beliefs towards women that are culturally accepted and normalised in society.

Methodology: This is a cross‐sectional descriptive observational study. The development of the initial version of the questionnaire, a pilot study (N = 63) and a final validation study (N = 1264) were carried out. Reliability, validity, stability and readability were tested.

Results: Exploratory factor analysis revealed that the Q‐AIGV is composed of 15 items distributed in three factors. Known‐groups analysis detected significant differences in two groups with different characteristics (age and relationship duration). Criterion validity indicated the existence of a moderate and significant correlation (r = 0.469; p < 0.001) between the mean score of the Q‐AIGV and the ‘Scale of Attitudes towards Gender‐based Violence’. The Q‐AIGV’s content validity index (CVI‐t = 0.96) and internal consistency (α = 0.906) were excellent.

Conclusion: The Q‐AIGV showed very good results for reliability, validity, stability and readability. This suggests that the Q‐AIGV could be a good tool for assessing attitudes towards invisible gender‐based violence.
Gain-of-Function Chromatin Remodeling Activity of Oncogenic FOXL2-C134W Reprograms Glucocorticoid Receptor Occupancy to Drive Granulosa Cell Tumors
Authors: Welte Thomas , Vuttaradhi Veena K. , Khlebus Eleonora Y. , Brodsky Allison , Flores Legarreta Alejandra , Celestino Joseph , Powell Reid T. , Stephan Clifford C. , Nguyen Nghi , Li Jian , Takamatsu Shiro , Calzoncinth Katherine , Sood Anil K. , Gershenson David M. , Futreal P. Andrew , Lawson Barrett , Hillman Robert Tyler.
Published: December 2024

Adult type ovarian granulosa cell tumors (AGCTs) are rare malignancies with the near universal c.C402G (p.Cys134Trp) somatic mutation in FOXL2, a Forkhead box-family transcription factor important for ovarian function. Relapsed AGCT is incurable, but the mechanism of the unique FOXL2 mutation could confer therapeutic vulnerabilities. To identify FOXL2-C134W-dependent pharmacologic synergies, we created and characterized endogenous FOXL2 isogenic AGCT cells and an AGCT tumoroid biobank. A drug screen identified that glucocorticoids promote FOXL2-C134W-dependent AGCT growth. Epigenetic investigation revealed that the Cys134Trp mutation exposes latent DNA sequence-specific chromatin remodeling activity in FOXL2. FOXL2-C134W-dependent chromatin remodeling activity redirected glucocorticoid receptor chromatin occupancy to drive hyaluronan synthase 2 gene expression and increase extracellular hyaluronan secretion. Treatment of AGCT models with hyaluronidase reduced viability, and dexamethasone rescued this effect. Combinatorial drug-drug interaction experiments demonstrated that dexamethasone antagonizes the potency of paclitaxel, a chemotherapy agent frequently used in the treatment of AGCT. Thus, gain-of-function pioneering activity contributes to the oncogenic mechanism of FOXL2-C134W and creates a potentially targetable synergy with glucocorticoid signaling.
Abstract A002: Computational identification for missense mutations of bladder cancer candidate genes using TCGA datasets
Authors: He Kai , Wang Lucas , Bai Yongsheng
Published: December 2024

Bladder cancer is the fourth most common cancer in men. According to the American Cancer Society, there were roughly over 80,000 cases in the United States in 2023, and nine out of ten people with this cancer are over the age of 55. The Cancer Genome Atlas (TCGA) project has made it possible for researchers to study mutations and other types of genetic signatures for multiple cancers including Bladder Urothelial Carcinoma (BLCA). A missense mutation is where a single nucleotide change in the DNA sequence results in the substitution of one amino acid for another in the protein. This could lead to a protein with an altered function. The impact of a missense mutation could be benign or harmful. In our previous study, 54 significant clusters for 15 cancer types were identified in The Cancer Genome Atlas (TCGA) network. In this study, we further investigated genes in two significant clusters reported for BLCA. We initially aim to identify genes that have missense mutations that have functional impact. To achieve this goal, we plugged the two clusters of genes (199) into the cBioPortal website and identified eight genes that had missense mutations or met three criteria (Firstly, numbers of mutations in sample must be greater than or equal to 5; secondly, functional impact must meet the following both: SIFT impact is deleterious and Polyphen-2 impact is possibly damaging or probably damaging): AKT3, PARP1, PRKN, APC, GNA11, KMT2A, NEGR1, and FYN. Further analysis showed what specific amino acid had been substituted at what specific position on the sequence. For example, for gene AKT3, at position 286, amino acid K had been substituted into amino acid N. Similarly, for gene PARP1, at position 913, amino acid G had been substituted into amino acid A. We then identified every amino acid missense substitution for all eight genes. By examining the mutation pattern, we hope to identify key genes as biomarkers so that therapeutic efficacy can be optimized.

Citation Format: Kai He, Lucas Wang, Yongsheng Bai. Computational identification for missense mutations of bladder cancer candidate genes using TCGA datasets. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A002
Abstract A015: Design and deciphering of precision peptide inhibitors for cancer stemness using generative deep learning and molecular dynamics simulations
Authors: Selvaraj Gurudeeban , Kaliamurthi Satyavani , Peslherbe Gilles H.
Published: December 2024

The use of artificial intelligence (AI) and machine learning (ML) for exploring vast amino acid sequence spaces has recently gained traction in the discovery of antibiotics and the design of biomaterials with a wide array of algorithms. However, despite some advancements, designing peptide inhibitors to specifically modulate protein-protein interactions remains a significant challenge. In this contribution, we explore the use of a Long Short-Term Memory (LSTM) network - a type of recurrent neural network - to model peptide sequences, given its ability to process sequential data and capture long-term dependencies, critical for peptide design. Our research focuses on developing precision peptides that target the interaction between the Notch intracellular domain (NICD) and CBF1/RBPJ transcription factors, key regulators of the Notch signaling pathway implicated in breast and pancreatic cancer stemness. We inferred hydrophobic, hydrophilic, van der Waals, and salt bridge interactions from experimentally determined three-dimensional protein complex structures, which were used for feature engineering via one-hot encoding. Peptides, each 20 amino acids in length, were generated using temperature scaling in the LSTM model. These peptides were then structurally optimized and subjected to molecular dynamics (MD) simulations, followed by molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) analysis to assess their interactions and binding affinities with the Notch receptor. The MD simulations provide valuable molecular-level insights into the peptide-Notch interactions, helping to evaluate their binding strength. Further biological testing is underway to validate the efficacy of these lead peptide inhibitors and elucidate their molecular mechanisms in targeting cancer stem cells associated with breast cancer.

Citation Format: Gurudeeban Selvaraj, Satyavani Kaliamurthi, Gilles H. Peslherbe. Design and deciphering of precision peptide inhibitors for cancer stemness using generative deep learning and molecular dynamics simulations. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A015
Abstract A016: Targeting calpain-1 and calpain-2 for prevention of breast cancer metastasis: In vivo insights and drug discovery approaches
Authors: Shapovalov Ivan , Poudel Pitambar , Panday Shailesh K. , Harper Danielle , Min Jung Yeon , Gao Yan , Nouri Kazem , Alexov Emil , Greer Peter A.
Published: December 2024

Calpain-1 and calpain-2 are heterodimeric calcium-dependent cysteine proteases composed of the catalytic subunits CAPN1 or CAPN2, respectively, and the common regulatory subunit CAPNS1. They are associated with cancer progression, metastasis, and treatment resistance in breast cancer. Here, we present novel insights into the therapeutic potential of calpain inhibition by combining genetic disruption and preclinical mouse tumor models and biosensor-based detection of calpain heterodimerization with ongoing efforts to discover small-molecule and peptide inhibitors. CRISPR-Cas9-mediated knockout of CAPN1, CAPN2, or CAPNS1 in MDA-MB-231 human triple-negative breast cancer (TNBC) cells revealed that disruption of both calpains, through CAPNS1 knockout, significantly reduced cell migration and inhibited spontaneous metastasis in a mouse orthotopic engraftment model by over 80%. Individual knockouts of CAPN1 or CAPN2 also reduced metastasis but to a lesser extent, highlighting the necessity of dual inhibition for optimal therapeutic effect. In parallel, we have been actively seeking small molecules and peptide inhibitors to target calpain through two approaches: inhibiting the PEF-PEF interaction that mediates heterodimerization using small molecules; and targeting the active site using a calpastatin (CAST)-based peptide. To identify small molecules capable of disrupting the PEF-PEF interaction, we conducted in silico screens of over 3.6 million compounds from several libraries. These compounds were evaluated based on their calculated binding affinity and potential to sterically hinder the conformational changes required for calpain activity. The CAST-based peptide inhibitor was designed based on the active site binding B-domain and tested on a purified calpain-2. These efforts lay the groundwork for novel therapeutic approaches targeting calpain-1 and calpain-2, which have emerged as promising targets for preventing metastasis in TNBC. We will present our progress in identifying and validating these small molecules and peptides for further development.

Citation Format: Ivan Shapovalov, Pitambar Poudel, Shailesh K. Panday, Danielle Harper, Jung Yeon Min, Yan Gao, Kazem Nouri, Emil Alexov, Peter A. Greer. Targeting calpain-1 and calpain-2 for prevention of breast cancer metastasis: In vivo insights and drug discovery approaches. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A016
Abstract A018: Somatic mutations in the PIK3CA gene and its prognostic implications among Ethiopian Breast cancer patients
Authors: Desalegn Woldesonbet Zelalem
Published: December 2024

Purpose: The phosphatidylinositol-4, 5-bisphosphate 3-kinase (PIK3CA), catalytic subunit alpha (c) is frequently mutated in breast cancer (BC). Although the biological impact of PIK3CA mutations in BC has been studied in various parts of the world, limited data is available from sub-Saharan Africa. In this study, the frequency and the prognostic role of PIK3CA mutations were investigated among BC patients from Ethiopia. Objective: The aim of the study was to determine the frequency of PIK3CA mutations and its prognostic role in patients with breast cancer in Ethiopia. Methods: Formalin-fixed paraffin-embedded blocks and fresh frozen BC tissue samples were collected from patients newly diagnosed with BC. Histopathological evaluation was carried out using immunohistochemistry (IHC). PIK3CA mutation profiling was carried out using TaqMan® Mutation detection assay. The association between PIK3CA mutation status and clinical and histopathological features was evaluated. A survival regression (Cox’s model) was employed to assess the effect of PIK3CA mutation and other variables on survival. Results: The prevalence of the PIK3CA mutations was 20.4%. Mutation of the PIK3CA gene was mainly observed among younger (24%), early pT stage (19.4%), and G1/G2 tumors (22.3%). The proportion of mutation was 24.4%, 27.3% and 20% in ER+, PR+ and HER2- tumors, respectively. A marked difference was observed in the PIK3CA mutation frequency across the four major tumor subgroups. However, most of the mutated tumors were found among HR+/HER2− (24.1%) followed by HR+/HER2+ tumors (27.8%). In his study, only TNBC was negatively associated with the proportion of mutation in the PIK3CA gene (p-value= 0.02) in comparison to HR+/HER2- tumors. In multivariate Cox’s regression analysis, the advanced pT stage and HR−/HER2- IHC group independently predicted worse overall survival. However, PIK3CA mutation status was not associated with survival. Conclusions: The PIK3CA mutation was relatively high in HR+ tumors. Mutation rates of PIK3CA in Ethiopian BC tumors are similar to those reported for other populations. This finding highlighted that molecular aberrations including mutations in a specific could give insight on prognosis and clinical outcome.

Citation Format: Zelalem Desalegn Woldesonbet. Somatic mutations in the PIK3CA gene and its prognostic implications among Ethiopian Breast cancer patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A018.
Abstract IA011: Strategies to close the translational gap for nanoscale drug delivery systems
Authors: Straehla Joelle P.
Published: December 2024

Nanoscale drug delivery systems have enormous potential to leverage innovative chemistry and encapsulate a wide range of cargo. However, compared to the large number and diverse scope of nanoscale systems described in preclinical manuscripts, there are relatively few approved drug products representing a narrow range of chemistries. There are many reasons for this translational gap, ranging from manufacturing and regulatory challenges to clinical relevance and safety. This presentation outlines key strategies to address the multifaceted challenges that hinder the clinical adoption of nanoscale drug delivery systems. One of the first barriers is the difficulty of scaling up the production of nanoscale systems while maintaining quality and consistency. An illustrative case study will be shared of an approved nanotherapeutic becoming unavailable due to manufacturing concerns, and the resultant change in clinical practice. For a new investigational agent, the work required to optimize a promising nanoformulation is time-consuming and may not result in immediate, publishable findings, creating tension between essential translational work and projects more likely to yield high-profile publications and contribute to academic promotion. In the industry setting, successfully navigating this hurdle is likely to require significant capital, again without a guarantee of success. Without a stable and robust formulation that can be scaled for good manufacturing practice, the benefits of an innovative formulation cannot be fully realized. Another key principle underlying successful translation is identifying a clear clinical indication, which will guide clinical trial design and improve the likelihood of regulatory approval. Recent data suggest that national research funding trends heavily influence the focus of nanotechnology studies, resulting in a misalignment between clinical needs and the investigational agents being developed. In the future, a funding re-alignment may open additional opportunities for basket trials in patient populations lacking a standard of care, or in diseases where the current treatment options are highly toxic. Expanding the clinical indications for nanotherapeutics will likely require academic-industry partnerships to bring together a robust drug product and a strong clinical rationale. The regulatory process for nanoscale therapeutics is evolving, making early communication between investigators and regulators crucial for successfully transitioning nanoscale drug delivery systems from the lab to clinical use for cancer patients.

Citation Format: Joelle P. Straehla. Strategies to close the translational gap for nanoscale drug delivery systems [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA011.
Abstract IA013: Discovery of the dual A2A/A2B receptor antagonist MK-1088 for the treatment of solid tumors
Authors: DeMong Duane E. , Ranganath Sheila , Cumming Jared , Larsen Matthew , Zhang Yonglian , Plummer Christopher , Ali Amjad , Palmieri Anthony , Barry Evan , Daublain Pierre , Gupta Pranav , Chatterjee Manash , Presland Jeremy , Schneider Sebastian , Ciaccio Paul , Tatosian Daniel , Sather Aaron , Turnbull Ben , Silverman Steven , Chobanian Harry , Krishnamurthy Harini , Wnek Richard , Crowley Stephen , Miller Alita , Ayers Mark , Hinton Marlene , Chrencik Jill , Rottey Sylvie , O'Neil Jennifer
Published: December 2024

In the tumor microenvironment (TME), adenosine levels have been shown to be elevated relative to normal tissues. This increase in adenosine levels renders an immunosuppressive effect via direct effects on T cells via agonism of the A2A receptor and indirect effects via agonism of both A2A and A2B receptors on myeloid cells. With these observations as a backdrop, we sought to develop a dual A2A/A2B receptor antagonist with properties that would enable maintenance of high levels of target engagement of the A2A and A2B receptors even at trough concentration. Drawing on our organization’s significant prior experience developing A2A receptor antagonists for the potential treatment of Parkinson’s disease, we developed MK-1088, a highly potent A2A/A2B dual receptor antagonist that was purposefully designed to possess excellent selectivity over the related A1 and A3 receptors. This presentation will detail the discovery and development strategy that was employed to identify molecules that met the profile exemplified by this molecule. A single ascending dose study of MK-1088 in healthy human volunteers demonstrated our ability to achieve, at trough concentration, >99% target engagement (TE) at the A2A receptor and >90% TE at the A2B receptor. Details of the pharmacokinetics, safety, and tolerability from this study will be highlighted.

Citation Format: Duane E. DeMong, Sheila Ranganath, Jared Cumming, Matthew Larsen, Yonglian Zhang, Christopher Plummer, Amjad Ali, Anthony Palmieri, Evan Barry, Pierre Daublain, Pranav Gupta, Manash Chatterjee, Jeremy Presland, Sebastian Schneider, Paul Ciaccio, Daniel Tatosian, Aaron Sather, Ben Turnbull, Steven Silverman, Harry Chobanian, Harini Krishnamurthy, Richard Wnek, Stephen Crowley, Alita Miller, Mark Ayers, Marlene Hinton, Jill Chrencik, Sylvie Rottey, Jennifer O'Neil. Discovery of the dual A2A/A2B receptor antagonist MK-1088 for the treatment of solid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA013.
Abstract IA020: Discovery of brain-penetrant inhibitors for the treatment of BRAF mutant tumors
Authors: Kahn Dean
Published: December 2024

Many tumors are driven by oncogenic kinases. While a majority of the most prevalent oncogenic kinases currently have existing targeted therapies available, most of the molecules were not designed to be CNS penetrant and are therefore unable to control CNS metastatic tumors. By employing principles for the design of CNS penetrant molecules, we discovered two brain-penetrant BRAF inhibitors, which both progressed into clinical trials. The first candidate, ARRY-461, was designed to inhibit class I mutant BRAF V600E tumors. The second candidate, ARRY-440, was designed to inhibit class I, II, III, and indel mutant BRAF tumors. Additionally, ARRY-440 was designed to overcome both the paradoxical activation of BRAF as well as inhibit mBRAF:wtCRAF heterodimers, two features that most 1st generation BRAF V600E inhibitors lack. Finally, we were pleased to see that ARRY-440 led to clinical responses in a variety of different BRAF V600E tumors, including in some tumors that harbored both a BRAF V600E mutation and an oncogenic NRAS mutation.

Citation Format: Dean Kahn. Discovery of brain-penetrant inhibitors for the treatment of BRAF mutant tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA020.
Abstract PR003: Structure-guided design and optimization of small molecule CD73 inhibitors with excellent drug-like properties: discovery of quemliclustat
Authors: Jeffrey Jenna
Published: December 2024

In the tumor microenvironment, high concentrations of extracellular adenosine promote tumor proliferation through various immunosuppressive mechanisms. High expression of CD73—an ecto-nucleotidase that produces adenosine from adenosine monophosphate—has been associated with poorer prognosis in several tumor types. Herein, we describe the drug discovery efforts that resulted in the discovery of quemliclustat, a highly potent and selective inhibitor of CD73. As a small molecule with excellent drug-like properties, quemliclustat offers several advantages over CD73 antibodies in development, such as greater inhibition of CD73 enzymatic activity (both soluble and membrane-bound), deeper tumor penetration, and the potential for both IV and oral formulations. Quemliclustat was the first small molecule CD73 inhibitor to enter clinical development and is currently being evaluated in various Phase 1/2 studies in advanced solid tumors, including lung and pancreatic cancers. Recent data in metastatic pancreatic cancer are supportive of further study in this disease setting.

Citation Format: Jenna Jeffrey Structure-guided design and optimization of small molecule CD73 inhibitors with excellent drug-like properties: discovery of quemliclustat. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr PR003
Time to Loss of Disease Control Following Guselkumab Withdrawal in Relation to Initial Speed of Response: A Post-Hoc Analysis of the VOYAGE 2 Trial
Authors: Kirby Brian , Chiricozzi Andrea , Gorecki Patricia , Buyze Jozefien , Parker Raphaelle , Wegner Sven , Puig Lluis
Published: December 2024

Background:
Psoriasis is a chronic inflammatory skin disorder typically requiring lifelong treatment. As such, patients may occasionally need treatment breaks. Understanding factors predicting maintenance of disease control during treatment breaks could improve long-term disease management. This post-hoc analysis of data from the Phase 3 VOYAGE 2 clinical trial evaluates how initial speed of response to guselkumab treatment affects time to loss of disease control following treatment withdrawal and identifies baseline characteristics corresponding with maintenance of disease control.

Methods:
Patients with moderate-to-severe plaque psoriasis assigned to treatment withdrawal following achievement of a Psoriasis Area and Severity Index (PASI)90 response after two or four guselkumab doses. Loss of disease control was defined as time to PASI ≥3 and was assessed using Kaplan–Meier analysis. The relationship between baseline characteristics and maintenance of response was evaluated using a Cox proportional hazards model.

Results:
Of patients who were randomized to placebo and switched to guselkumab at Week 16, 149/248 (60%) achieved PASI90 after two guselkumab doses (Week 28). Of patients who were randomized to guselkumab, 377/496 (76%) achieved PASI90 after four guselkumab doses (Week 28), of whom 182 were then re-randomized to withdrawal. Of these, 131 had achieved PASI90 after two guselkumab doses (Week 12) and 51 had achieved PASI90 after four guselkumab doses (Week 28). Maintenance of disease control following guselkumab withdrawal was longer in patients who achieved PASI90 after two versus four guselkumab doses. Lower body mass index, biologic naïve status, and shorter disease duration at baseline corresponded with a longer time to PASI ≥3 following withdrawal.

Conclusion:
Faster initial response to guselkumab resulted in longer maintenance of disease control after treatment withdrawal. These findings may be used to inform personalized dosing strategies with guselkumab, which may increase patient compliance to treatment and improve long-term treatment outcomes.
Obituary. Tipu Zahed Aziz, 1956-2024
Authors: Pereira Erlick AC , Green Alexander L. , Nandi Dipankar
Published: December 2024

The extraordinary life of Tipu Aziz is described through anecdotes told to his former residents and fellows. A giant of functional neurosurgery, his primate experiments first demonstrated the subthalamic nucleus and pedunculopontine nucleus as targets for surgery for Parkinson's disease and he pioneered deep brain stimulation for pain including of the anterior cingulate cortex. Despite various career cul-de-sacs he climbed the ziggurat to the pinnacles of British neurosurgery and neuroscience. A pinball wizard of functional neurosurgery, he was mentored by a bygone Madmen era of gentlemen: chain-smoking, heavy-drinking workaholics whose nonchalant bravado, ‘can-do’ attitude, love of mischief, merriment and well-placed profanity he exemplified. Sometimes sharing a cigarette with a patient before surgery, we will not see his like again.
Pagamentos por serviços ambientais: teoria e prática: a experiência do estado de São Paulo
Authors:   Universidade de São Paulo. Instituto de Estudos Avançados, Ruggiero Patricia G. C. , Chaves Rafael B. ,   Universidade Federal do Rio Grande do Norte, Sousa Fernando Henrique de ,   Universidade de São Paulo. Escola Superior de Agricultura Luiz de Queiroz, Sparovek Gerd ,   Universidade de São Paulo. Escola Superior de Agricultura Luiz de Queiroz, Leite Sandra A. ,   Universidade Estadual de Campinas. Faculdade de Educação, Hahn Claudette M. , Bruno Oswaldo José , Silva Dylan Rocha ,   Governo do Estado de São Paulo. Departamento de Fomento à Proteção da Biodiversidade, Tiberio Carolina Kors , Karvelis Victoria , von Glehn Helena de Queiroz Carrascosa
Published: December 2024

Esta Nota Técnico-Científica 4 integra a Série Biota Síntese e aborda as questões relacionadas aos Pagamentos por Serviços Ambientais (PSA), que se expandiram rapidamente pelo globo, em especial pelos países em desenvolvimento nas últimas décadas. Os PSA são posicionados na chamada agenda positiva em contraste com as usuais estratégias tensas de comando-e-controle. Aqui descrevemos o mecanismo, refletimos sobre o seu funcionamento e apontamos, com base na literatura científica e nas experiências implementadas no estado de São Paulo até o momento, o que parecem ser os elementos centrais que regem o funcionamento do PSA. A intenção é que esse material faça sentido para gestores e tomadores de decisão na área ambiental permitindo a eles avaliar se PSA é uma solução adequada para os problemas que precisam ser resolvidos e contribuindo para um desenho eficaz da intervenção. Esta publicação é direcionada ao corpo técnico de órgãos públicos, empresas e entidades de meio ambiente e do meio rural.
Unveiling new fungal discoveries in Yunnan Province, China
Authors: JAYASIRI SUBASHINI CHATHUMINI , TIBPROMMA SAOWALUCK , XU RUIFANG , BHAT DARBHE JAYARAMA , ELGORBAN ABDALLAH M. , KARUNARATHNA SAMANTHA C. , RAMPELOTTO PABULO H. , HAN MEIYAN , XU JIANCHU
Published: December 2024

Fungal taxa can be found almost anywhere and China is recognized as one of the most diverse regions globally. Within Asia, China leads major fungal hotspot studies, with Yunnan Province noted for its high plant and fungal diversity compared to other regions in the country. The Kunming Institute of Botany (KIB), Chinese Academy of Sciences (CAS), is a leading research institute with a botanical garden focused on the taxonomy and phylogeny of plants, fungi, lichen, and related projects. This study introduces new and known taxa from KIB collections based on comprehensive morphological and molecular analyses. Detailed morphological descriptions, illustrations and multigene phylogenetic analyses were used to identify four taxa within the class Dothideomycetes (Pleosporales). This includes a new genus (Paracrassiperidium), a new species (P. fusiforme), and two previously known species (Chaetopyrena penicillata and Pseudokeissleriella bambusicola). The new genus is characterized by dome-shaped, semi-immersed to immersed ascomata with a thick-walled peridium, a hamathecium composed of branched pseudoparaphyses, cylindrical to cylindric-clavate pedicellate asci with a well-developed ocular chamber, and fusiform, hyaline to light brown, septate ascospores.
A novel species and a new geographical record of Nigropunctata from Bambusa vulgaris in northern Thailand
Authors: TUN ZAW LIN , GOMDOLA DEECKSHA , BHUNJUN CHITRABHANU S. , MAHARACHCHIKUMBURA SAJEEWA S.N. , ALOTIBI FATIMAH , HYDE KEVIN D.
Published: December 2024

Nigropunctata species are characterized by brown to dark brown, cylindrical, aseptate and guttulate ascospores, with a germ slit occasionally present. The ascospores are sometimes surrounded by a mucilaginous sheath. To date, no asexual morph of Nigropunctata species has been documented. Species in this genus are saprobes isolated from dead bamboo branches. Nigropunctata was initially introduced as an incertae sedis genus in Xylariales, but has recently been accommodated in Pallidoperidiaceae. Since Nigropunctata species share similar morphological characters and are cryptic, species identification based solely on morphology is insufficient. Therefore, we used a biphasic approach, incorporating morphology and multi-gene phylogenetic analyses of ITS, LSU, β-tub, rpb2 and tef-1α sequences to establish a new species, Nigropunctata chiangraiensis, and a new geographical record for N. khalidii. Our isolates match the morphological species concept of Nigropunctata in having dark brown and aseptate ascospores. However, the sheath of N. chiangraiensis is not constricted at the center, as seen in most Nigropunctata species.
Ophioglossum hongii (Ophioglossaceae), a new species from Xizang, China
Authors: LI MIN-YU , YANG FU-SHENG , YAN YUE-HONG , CHEN LI-JUN , HUANG ZHI-CONG , SHU JIANG-PING , QIN XIN-SHENG
Published: December 2024

Ophioglossum hongii (Ophioglossaceae) is described as a new species from the plateau area of Xizang, China. It was recorded as the species O. nudicaule previously, but obviously differs in its shorter sporophores and the conspicuous persistent petiole bases at the top of rhizome. O. hongii is similar to O. polyphyllum in morphology, but it can be distinguished from the latter by plant size, trophophyll shape, fertile stalk and exospore ornamentation. O. hongii is the sister to the clade (O. polyphyllum, O. engelmannii) according to molecular phylogenetic analysis of seven plastid fragments (atpB, matK, psbA-trnH, rbcL, rps4, rps4-trnS, and trnL-F). Detailed taxonomic description, distribution, ecology, conservation status and chloroplast genome resources are provided.
Factors That Limit Evaluation of Velopharyngeal Closure During Nasopharyngoscopy
Authors: Snodgrass Taylor D. , Sitzman Thomas J. , Chee-Williams Jessica L. , Temkit Hamy , Perry Jamie L.
Published: December 2024

Objective

To assess the quality of nasopharyngoscopy video recordings used for velopharyngeal insufficiency (VPI) surgical planning and identify factors that limit evaluation of velopharyngeal closure.

Design

Prospective observational study.

Setting

Metropolitan-based hospitals with craniofacial clinics in the United States and Canada.

Participants

One-hundred and forty-two (142) patients with VPI across 10 hospitals.

Assessment(s)

Nasopharyngoscopy video recordings used for VPI surgical planning .

Main Outcome Measure(s)

Ratability of nasopharyngoscopy video recordings, with “ratable” defined as the video (1) visualized the velum, lateral pharyngeal wall, and posterior pharyngeal walls at some point during speech production and (2) contained an oral speech sample at the phrase level or above.

Results

One-hundred and forty-two (142) nasopharyngoscopy video recordings were obtained from patients undergoing VPI evaluation, of which 59.9% (n=85) were ratable. A multilevel logistic regression model was used to identify factors that influenced the quality of nasopharyngoscopy video recordings. Factors associated with unratable nasopharyngoscopy videos were age ( P=.030), sex ( P=.005*), type of scope camera used ( P=.039), presence of compensatory misarticulations ( P=.008), and a limited speech sample ( P=.040).

Conclusions

A substantial proportion of nasopharyngoscopy video recordings obtained during VPI evaluation are not sufficient for rating velopharyngeal closure. Lack of ratability could impact the surgery selected to treat VPI. Younger patients, those with limited speech samples, or patients with extensive compensatory articulations may be more successful in completing other VPI imaging techniques, such as videofluoroscopy or magnetic resonance imaging.