bluuebunny/crossref_metadata_2025_split huggingface dataset:
KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma
Authors: Budczies Jan , Romanovsky Eva , Kirchner Martina , Neumann Olaf , Blasi Miriam , Schnorbach Johannes , Shah Rajiv , Bozorgmehr Farastuk , Savai Rajkumar , Stiewe Thorsten , Peters Solange , Schirmacher Peter , Thomas Michael , Kazdal Daniel , Christopoulos Petros , Stenzinger Albrecht 
Published: June 2024

Abstract
Background
Predictive biomarkers in use for immunotherapy in advanced non-small cell lung cancer are of limited sensitivity and specificity. We analysed the potential of activating KRAS and pathogenic TP53 mutations to provide additional predictive information.

Methods
The study cohort included 713 consecutive immunotherapy patients with advanced lung adenocarcinomas, negative for actionable genetic alterations. Additionally, two previously published immunotherapy and two surgical patient cohorts were analyzed. Therapy benefit was stratified by KRAS and TP53 mutations. Molecular characteristics underlying KRASmut/TP53mut tumours were revealed by the analysis of TCGA data.

Results
An interaction between KRAS and TP53 mutations was observed in univariate and multivariate analyses of overall survival (Hazard ratio [HR] = 0.56, p = 0.0044 and HR = 0.53, p = 0.0021) resulting in a stronger benefit for KRASmut/TP53mut tumours (HR = 0.71, CI 0.55–0.92). This observation was confirmed in immunotherapy cohorts but not observed in surgical cohorts. Tumour mutational burden, proliferation, and PD-L1 mRNA were significantly higher in TP53-mutated tumours, regardless of KRAS status. Genome-wide expression analysis revealed 64 genes, including CX3CL1 (fractalkine), as specific transcriptomic characteristic of KRASmut/TP53mut tumours.

Conclusions
KRAS/TP53 co-mutation predicts ICI benefit in univariate and multivariate survival analyses and is associated with unique molecular tumour features. Mutation testing of the two genes can be easily implemented using small NGS panels.
Strand-resolved mutagenicity of DNA damage and repair
Authors: Anderson Craig J. , Talmane Lana , Luft Juliet , Connelly John , Nicholson Michael D. , Verburg Jan C. , Pich Oriol , Campbell Susan , Giaisi Marco , Wei Pei-Chi , Sundaram Vasavi , Connor Frances , Ginno Paul A. , Sasaki Takayo , Gilbert David M. ,   Liver Cancer Evolution Consortium, Aitken Stuart , Arnedo-Pac Claudia , Daunesse Maëlle , Drews Ruben M. , Ewing Ailith , Feig Christine , Flicek Paul , Kaiser Vera B. , Kentepozidou Elissavet , López-Arribillaga Erika , Lukk Margus , Rayner Tim F. , Sentís Inés , López-Bigas Núria , Semple Colin A. , Odom Duncan T. , Aitken Sarah J. , Taylor Martin S. 
Published: June 2024

AbstractDNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small alkylation adducts of DNA, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky UV-induced adducts5. The accumulation of multiple distinct mutations at the site of persistent lesions provides the means to quantify the relative efficiency of repair processes genome wide and at single-base resolution. At multiple scales, we show DNA damage-induced mutations are largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can actively drive oncogenic mutagenesis by corrupting the fidelity of nucleotide excision repair. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance and repair of DNA damage, thereby shaping cancer genome evolution.
Endoplasmic reticulum–plasma membrane contact gradients direct cell migration
Authors: Gong Bo , Johnston Jake D. , Thiemicke Alexander , de Marco Alex , Meyer Tobias 
Published: June 2024

AbstractDirected cell migration is driven by the front–back polarization of intracellular signalling1–3. Receptor tyrosine kinases and other inputs activate local signals that trigger membrane protrusions at the front2,4–6. Equally important is a long-range inhibitory mechanism that suppresses signalling at the back to prevent the formation of multiple fronts7–9. However, the identity of this mechanism is unknown. Here we report that endoplasmic reticulum–plasma membrane (ER–PM) contact sites are polarized in single and collectively migrating cells. The increased density of these ER–PM contacts at the back provides the ER-resident PTP1B phosphatase more access to PM substrates, which confines receptor signalling to the front and directs cell migration. Polarization of the ER–PM contacts is due to microtubule-regulated polarization of the ER, with more RTN4-rich curved ER at the front and more CLIMP63-rich flattened ER at the back. The resulting ER curvature gradient leads to small and unstable ER–PM contacts only at the front. These contacts flow backwards and grow to large and stable contacts at the back to form the front–back ER–PM contact gradient. Together, our study suggests that the structural polarity mediated by ER–PM contact gradients polarizes cell signalling, directs cell migration and prolongs cell migration.
Interactions between immune cell types facilitate the evolution of immune traits
Authors: Dubovik Tania , Lukačišin Martin , Starosvetsky Elina , LeRoy Benjamin , Normand Rachelly , Admon Yasmin , Alpert Ayelet , Ofran Yishai , G’Sell Max , Shen-Orr Shai S. 
Published: June 2024

AbstractAn essential prerequisite for evolution by natural selection is variation among individuals in traits that affect fitness1. The ability of a system to produce selectable variation, known as evolvability2, thus markedly affects the rate of evolution. Although the immune system is among the fastest-evolving components in mammals3, the sources of variation in immune traits remain largely unknown4,5. Here we show that an important determinant of the immune system’s evolvability is its organization into interacting modules represented by different immune cell types. By profiling immune cell variation in bone marrow of 54 genetically diverse mouse strains from the Collaborative Cross6, we found that variation in immune cell frequencies is polygenic and that many associated genes are involved in homeostatic balance through cell-intrinsic functions of proliferation, migration and cell death. However, we also found genes associated with the frequency of a particular cell type that are expressed in a different cell type, exerting their effect in what we term cyto-trans. The vertebrate evolutionary record shows that genes associated in cyto-trans have faced weaker negative selection, thus increasing the robustness and hence evolvability2,7,8 of the immune system. This phenomenon is similarly observable in human blood. Our findings suggest that interactions between different components of the immune system provide a phenotypic space in which mutations can produce variation with little detriment, underscoring the role of modularity in the evolution of complex systems9.
PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial
Authors: Dorff Tanya B. , Blanchard M. Suzette , Adkins Lauren N. , Luebbert Laura , Leggett Neena , Shishido Stephanie N. , Macias Alan , Del Real Marissa M. , Dhapola Gaurav , Egelston Colt , Murad John P. , Rosa Reginaldo , Paul Jinny , Chaudhry Ammar , Martirosyan Hripsime , Gerdts Ethan , Wagner Jamie R. , Stiller Tracey , Tilakawardane Dileshni , Pal Sumanta , Martinez Catalina , Reiter Robert E. , Budde Lihua E. , D’Apuzzo Massimo , Kuhn Peter , Pachter Lior , Forman Stephen J. , Priceman Saul J. 
Published: June 2024

AbstractDespite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CAR T cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805.
Chromosome-level genome assembly and annotation of a potential model organism Gossypium arboreum ZB-1
Authors: Sun Rongnan , Wu Yuqing , Zhang Xinyu , Lv Minghua , Yu Dongliang , Sun Yuqiang 
Published: June 2024

AbstractRecent advancements in plant regeneration and synthetic polyploid creation have been documented in Gossypium arboreum ZB-1. These developments make ZB-1 a potential model within the Gossypium genus for investigating gene function and polyploidy. This work generated the sequence and annotation of the ZB-1 genome. The contig-level genome was constructed using the PacBio high-fidelity reads, encompassing 81 contigs with an N50 length of 112.12 Mb. The Hi-C data assisted the construction of the chromosome-level genome, which consists of 13 pseudo-chromosomes and 39 un-anchored contigs, with a total length of about 1.67 Gb. Repetitive sequences accounted for about 69.7% of the genome in length. Based on ab initio and evidence-based prediction, we have identified 48,021 protein-coding genes in the ZB-1 genome. Comparative genomics analysis revealed conserved gene content and arrangement between ZB-1 and G. arboreum SXY1. The single nucleotide polymorphism occurrence rate between ZB-1 and SXY1 was about 0.54 per 1,000 nucleotides. This study enriched the genomic resources for further exploration into cotton regeneration and polyploidy mechanisms.
Point-of-care AI-enhanced novice echocardiography for screening heart failure (PANES-HF)
Authors: Huang Weiting , Koh Tracy , Tromp Jasper , Chandramouli Chanchal , Ewe See Hooi , Ng Choon Ta , Lee Audry Shan Yin , Teo Louis Loon Yee , Hummel Yoran , Huang Feiqiong , Lam Carolyn Su Ping 
Published: June 2024

AbstractThe increasing prevalence of heart failure (HF) in ageing populations drives demand for echocardiography (echo). There is a worldwide shortage of trained sonographers and long waiting times for expert echo. We hypothesised that artificial intelligence (AI)-enhanced point-of-care echo can enable HF screening by novices. The primary endpoint was the accuracy of AI-enhanced novice pathway in detecting reduced LV ejection fraction (LVEF) < 50%. Symptomatic patients with suspected HF (N = 100, mean age 61 ± 15 years, 56% men) were prospectively recruited. Novices with no prior echo experience underwent 2-weeks’ training to acquire echo images with AI guidance using the EchoNous Kosmos handheld echo, with AI-automated reporting by Us2.ai (AI-enhanced novice pathway). All patients also had standard echo by trained sonographers interpreted by cardiologists (reference standard). LVEF < 50% by reference standard was present in 27 patients. AI-enhanced novice pathway yielded interpretable results in 96 patients and took a mean of 12 min 51 s per study. The area under the curve (AUC) of the AI novice pathway was 0.880 (95% CI 0.802, 0.958). The sensitivity, specificity, positive predictive and negative predictive values of the AI-enhanced novice pathway in detecting LVEF < 50% were 84.6%, 91.4%, 78.5% and 94.1% respectively. The median absolute deviation of the AI-novice pathway LVEF from the reference standard LVEF was 6.03%. AI-enhanced novice pathway holds potential to task shift echo beyond tertiary centres and improve the HF diagnostic workflow.
Bio-oil modified binder derived from cotton stalks as an eco-friendly alternative binder for flexible pavements
Authors: Ullah Sahib , Zaidi Syed Bilal Ahmed , Khan Diyar , Fareed Ayyaz , Mohd Hasan Mohd Rosli , Milad Abdalrhman , Ali Basit 
Published: June 2024

AbstractScientists and engineers encounter considerable environmental and economic obstacles stemming from the depletion of crude oil or petroleum fossil fuel reservoirs. To mitigate this challenge, alternative solutions like bio-oil-modified binder derived from biomass have been innovated. This research aims to examine the feasibility of using bio-oil-modified binder obtained from cotton stalk waste as a modifier. Various mechanical and physical tests, including penetration, softening point, ductility, and dynamic shear rheometer tests, were conducted on asphalt binder incorporating 5% and 10% bio-oil-modified binder. Wheel tracker, four-point beam fatigue, and dynamic modulus tests were used to evaluate asphalt mixture performance, including rutting, fatigue, and dynamic stiffness. A rolling bottle test (RBT) and asphalt binder bond strength (BBS) were used to assess moisture susceptibility. A bio-oil-modified binder enhanced ductility and penetration characteristics while reducing the softening point. With the addition of a bio-oil-modified binder, stiffness was reduced in parameters such as complex shear modulus and phase angle. In fact, for both specimens containing 5% and 10% bio-oil-modified binder, statistically significant differences were observed among the measured samples. As a result of this reduced stiffness, the modified asphalt binder is more suitable for low-temperature applications. Additionally, 5.8% increased at 10% and 3.1% at 5% CS. Bio-oil-modified binder, compared to virgin mixtures, supports equal rut resistance. However, the RBT and BBS tests revealed that the addition of bio-oil-modified binder increased the susceptibility of conventional asphalt binder to moisture. The findings suggest that bio-oil-modified binder can enhance asphalt binder properties in low-temperature regions, but further research is needed to improve moisture resistance.
Effect of binder and activator composition on the characteristics of alkali-activated slag-based concrete
Authors: Heshmat Mohamed , Amer Ismail , Elgabbas Fareed , Khalaf Mohamed A. 
Published: June 2024

AbstractAlkali Activated Slag Concrete (AASC) has been a sustained research activity over the past two decades. Its promising characteristics and being environmentally friendly compared to Ordinary Portland Cement made AASC of exceptional interest. However, there is still no firm mix design, for the AASC, that can provide desirable fresh and hardened properties based on the composition of the binder and activator. This research specifically aims to investigate the affecting parameters on the slump and compressive strength of alkali-activated slag/lime-based concrete and provide a better understanding of the potential reasons for these characteristics. The experimental program consisted of two stages; the first stage studied the effect of different binder and activator compositions, and the second stage studied the water-to-binder ratio and binder content effects on the slump and compressive strength of alkali-activated slag/lime-based concrete. The binder and activator compositions were defined through two main parameters, the hybrid factor (HF = CaO/Si2O + Al2O3) and the solution modulus (Ms = SiO2/Na2O). The compressive strength, initial slump, and slump loss were measured to evaluate the different mixes and specify the optimum range of compositions. Based on the studied parameters, the effective range to achieve desirable slump and concrete compressive strength is from HF 0.6 up to 0.8 at Ms 1.5, this would achieve a compressive strength of more than 30 MPa and a slump of 100 mm after 90 min.
An improved Differential evolution with Sailfish optimizer (DESFO) for handling feature selection problem
Authors: Azzam Safaa. M. , Emam O. E. , Abolaban Ahmed Sabry 
Published: June 2024

AbstractAs a preprocessing for machine learning and data mining, Feature Selection plays an important role. Feature selection aims to streamline high-dimensional data by eliminating irrelevant and redundant features, which reduces the potential curse of dimensionality of a given large dataset. When working with datasets containing many features, algorithms that aim to identify the most valuable features to improve dataset accuracy may encounter difficulties because of local optima. Many studies have been conducted to solve this problem. One of the solutions is to use meta-heuristic techniques. This paper presents a combination of the Differential evolution and the sailfish optimizer algorithms (DESFO) to tackle the feature selection problem. To assess the effectiveness of the proposed algorithm, a comparison between Differential Evolution, sailfish optimizer, and nine other modern algorithms, including different optimization algorithms, is presented. The evaluation used Random forest and key nearest neighbors as quality measures. The experimental results show that the proposed algorithm is a superior algorithm compared to others. It significantly impacts high classification accuracy, achieving 85.7% with the Random Forest classifier and 100% with the Key Nearest Neighbors classifier across 14 multi-scale benchmarks. According to fitness values, it gained 71% with the Random forest and 85.7% with the Key Nearest Neighbors classifiers.
Antagonistic potential and biological control mechanisms of Pseudomonas strains against banded leaf and sheath blight disease of maize
Authors: Sahgal Manvika , Saini Neha , Jaggi Vandana , Brindhaa N. T. , Kabdwal Manisha , Singh Rajesh Pratap , Prakash Anil 
Published: June 2024

AbstractRhizoctonia solani, the causal agent of banded leaf and sheath blight (BL&SB), poses a significant threat to maize and various crops globally. The increasing concerns surrounding the environmental and health impacts of chemical fungicides have encouraged intensified concern in the development of biological control agents (BCAs) as eco-friendly alternatives. In this study, we explored the potential of 22 rhizobacteria strains (AS1–AS22) isolates, recovered from the grasslands of the Pithoragarh region in the Central Himalayas, as effective BCAs against BL&SB disease. Among these strains, two Pseudomonas isolates, AS19 and AS21, exhibited pronounced inhibition of fungal mycelium growth in vitro, with respective inhibition rates of 57.04% and 54.15% in cell cultures and 66.56% and 65.60% in cell-free culture filtrates. Additionally, both strains demonstrated effective suppression of sclerotium growth. The strains AS19 and AS21 were identified as Pseudomonas sp. by 16S rDNA phylogeny and deposited under accession numbers NAIMCC-B-02303 and NAIMCC-B-02304, respectively. Further investigations revealed the mechanisms of action of AS19 and AS21, demonstrating their ability to induce systemic resistance (ISR) and exhibit broad-spectrum antifungal activity against Alternaria triticina, Bipolaris sorokiniana, Rhizoctonia maydis, and Fusarium oxysporum f. sp. lentis. Pot trials demonstrated significant reductions in BL&SB disease incidence (DI) following foliar applications of AS19 and AS21, with reductions ranging from 25 to 38.33% compared to control treatments. Scanning electron microscopy revealed substantial degradation of fungal mycelium by the strains, accompanied by the production of hydrolytic enzymes. These findings suggest the potential of Pseudomonas strains AS19 and AS21 as promising BCAs against BL&SB and other fungal pathogens. However, further field trials are warranted to validate their efficacy under natural conditions and elucidate the specific bacterial metabolites responsible for inducing systemic resistance. This study contributes to the advancement of sustainable disease management strategies and emphasizes the potential of Pseudomonas strains AS19 and AS21 in combating BL&SB and other fungal diseases affecting agricultural crops.
Constraint optimization of an integrated production model utilizing history matching and production forecast uncertainty through the ensemble Kalman filter
Authors: Fadaei Mehdi , Ameri Mohammad Javad , Rafiei Yousef 
Published: June 2024

AbstractThe calibration of reservoir models using production data can enhance the reliability of predictions. However, history matching often leads to only a few matched models, and the original geological interpretation is not always preserved. Therefore, there is a need for stochastic methodologies for history matching. The Ensemble Kalman Filter (EnKF) is a well-known Monte Carlo method that updates reservoir models in real time. When new production data becomes available, the ensemble of models is updated accordingly. The initial ensemble is created using the prior model, and the posterior probability function is sampled through a series of updates. In this study, EnKF was employed to evaluate the uncertainty of production forecasts for a specific development plan and to match historical data to a real field reservoir model. This study represents the first attempt to combine EnKF with an integrated model that includes a genuine oil reservoir, actual production wells, a surface choke, a surface pipeline, a separator, and a PID pressure controller. The research optimized a real integrated production system, considering the constraint that there should be no slug flow at the inlet of the separator. The objective function was to maximize the net present value (NPV). Geological data was used to model uncertainty using Sequential Gaussian Simulation. Porosity scenarios were generated, and conditioning the porosity to well data yielded improved results. Ensembles were employed to balance accuracy and efficiency, demonstrating a reduction in porosity uncertainty due to production data. This study revealed that utilizing a PID pressure controller for the production separator can enhance oil production by 59% over 20 years, resulting in the generation of 2.97 million barrels of surplus oil in the field and significant economic gains.