bluuebunny/crossref_metadata_2025_split huggingface dataset:
Information guided adaptation of complex biological systems
Authors: Herndon R. Craig 
Published: June 2023

Introduction: Functional information transmission through a complex biological system is introduced as a method for biological response (bioresponse) adaptation using qualified biological marker (biomarker) data.Methods: This information guided adaptation methodology traverses the series of complex connections, defined by disparate bioresponse and biomarkers data sets, by placing both data sets on the common platiorm defined by information. The absolute uncertainty associated with these data sets can be defined in terms of decimal digits of information. This relationship between the data’s absolute uncertainty and its information entropy is used to decompose information entropy into functional and relative uncertainty components, where the functional component quantifies the function or meaning of a data set in units of information.Results: Application of functional information to adapt patient medical treatments using the information values for the bioresponse model and the biomarker model are outlined in detail and presented tabularly.Discussion: Functional information provides a mathematical connection between a bioresponse model and a biomarker model by quantifying both data sets in the units of information and thereby providing the means to implement precision therapeutic plans by quantitatively adapting patient treatments using their biomarker measurements.
Pixel-wise statistical analysis of myocardial injury in STEMI patients with delayed enhancement MRI
Authors: Duchateau Nicolas , Viallon Magalie , Petrusca Lorena , Clarysse Patrick , Mewton Nathan , Belle Loic , Croisille Pierre 
Published: June 2023

ObjectivesMyocardial injury assessment from delayed enhancement magnetic resonance images is routinely limited to global descriptors such as size and transmurality. Statistical tools from computational anatomy can drastically improve this characterization, and refine the assessment of therapeutic procedures aiming at infarct size reduction. Based on these techniques, we propose a new characterization of myocardial injury up to the pixel resolution. We demonstrate it on the imaging data from the Minimalist Immediate Mechanical Intervention randomized clinical trial (MIMI: NCT01360242), which aimed at comparing immediate and delayed stenting in acute ST-Elevation Myocardial Infarction (STEMI) patients.MethodsWe analyzed 123 patients from the MIMI trial (62 ± 12 years, 98 male, 65 immediate 58 delayed stenting). Early and late enhancement images were transported onto a common geometry using techniques inspired by statistical atlases, allowing pixel-wise comparisons across population subgroups. A practical visualization of lesion patterns against specific clinical and therapeutic characteristics was also proposed using state-of-the-art dimensionality reduction.ResultsInfarct patterns were roughly comparable between the two treatments across the whole myocardium. Subtle but significant local differences were observed for the LCX and RCA territories with higher transmurality for delayed stenting at lateral and inferior/inferoseptal locations, respectively (15% and 23% of myocardial locations with a p-value &lt;0.05, mainly in these regions). In contrast, global measurements were comparable for all territories (no statistically significant differences for all-except-one measurements before standardization / for all after standardization), although immediate stenting resulted in more subjects without reperfusion injury.ConclusionOur approach substantially empowers the analysis of lesion patterns with standardized comparisons up to the pixel resolution, and may reveal subtle differences not accessible with global observations. On the MIMI trial data as illustrative case, it confirmed its general conclusions regarding the lack of benefit of delayed stenting, but revealed subgroups differences thanks to the standardized and finer analysis scale.
Molecular characterization and re-interpretation of HNF1A variants identified in Indian MODY subjects towards precision medicine
Authors: Kavitha Babu , Ranganathan Sampathkumar , Gopi Sundaramoorthy , Vetrivel Umashankar , Hemavathy Nagarajan , Mohan Viswanathan , Radha Venkatesan 
Published: June 2023

BackgroundHNF1A is an essential component of the transcription factor network that controls pancreatic β-cell differentiation, maintenance, and glucose stimulated insulin secretion (GSIS). A continuum of protein malfunction is caused by variations in the HNF1A gene, from severe loss-of-function (LOF) variants that cause the highly penetrant Maturity Onset Diabetes of the Young (MODY) to milder LOF variants that are far less penetrant but impart a population-wide risk of type 2 diabetes that is up to five times higher. Before classifying and reporting the discovered variations as relevant in clinical diagnosis, a critical review is required. Functional investigations offer substantial support for classifying a variant as pathogenic, or otherwise as advised by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) ACMG/AMP criteria for variant interpretation.ObjectiveTo determine the molecular basis for the variations in the HNF1A gene found in patients with monogenic diabetes in India.MethodsWe performed functional protein analyses such as transactivation, protein expression, DNA binding, nuclear localization, and glucose stimulated insulin secretion (GSIS) assay, along with structural prediction analysis for 14 HNF1A variants found in 20 patients with monogenic diabetes.ResultsOf the 14 variants, 4 (28.6%) were interpreted as pathogenic, 6 (42.8%) as likely pathogenic, 3 (21.4%) as variants of uncertain significance, and 1 (7.14%) as benign. Patients harboring the pathogenic/likely pathogenic variants were able to successfully switch from insulin to sulfonylureas (SU) making these variants clinically actionable.ConclusionOur findings are the first to show the need of using additive scores during molecular characterization for accurate pathogenicity evaluations of HNF1A variants in precision medicine.
Case report: Application of targeted NGS for the detection of non-canonical driver variants in MPN
Authors: Zhang Jin , Shen Kefeng , Xiao Min , Huang Jinjin , Wang Jin , Wang Yaqin , Hong Zhenya 
Published: June 2023

Background: JAK2, CALR, and MPL gene mutations are recognized as driver mutations of myeloproliferative neoplasms (MPNs). MPNs without these mutations are called triple-negative (TN) MPNs. Recently, novel mutation loci were continuously discovered using next-generation sequencing (NGS), along with continued discussion and modification of the traditional TN MPN.Case presentation: Novel pathogenic mutations were discovered by targeted NGS in 4 patients who were diagnosed as JAK2 unmutated polycythaemia vera (PV) or TN MPN. Cases 1, 2, and 3 were of patients with PV, essential thrombocythemia (ET), and primary myelofibrosis (PMF); NGS detected JAK2 p.H538_K539delinsQL (uncommon), CALR p.E380Rfs*51 (novel), and MPL p.W515_Q516del (novel) mutations. Case 4 involved a patient with PMF; JAK2, CALR, or MPL mutations were not detected by qPCR or NGS, but a novel mutation SH2B3 p.S337Ffs*3, which is associated with the JAK/STAT signal transduction pathway, was found by NGS.Conclusion: NGS, a more multidimensional and comprehensive gene mutation detection, is required for patients suspected of having MPN to detect non-canonical driver variants and avoid the misdiagnosis of TN MPN. SH2B3 p.S337Ffs*3 can drive MPN occurrence, and SH2B3 mutation may also be a driver mutation of MPN.
Constructing a novel signature and predicting the immune landscape of colon cancer using N6-methylandenosine-related lncRNAs
Authors: Wang Yongfeng , Zhang Dongzhi , Li Yuxi , Wu Yue , Ma Haizhong , Jiang Xianglai , Fu Liangyin , Zhang Guangming , Wang Haolan , Liu Xingguang , Cai Hui 
Published: June 2023

Background: Colon cancer (CC) is a prevalent malignant tumor that affects people all around the world. In this study, N6-methylandenosine-related long non-coding RNAs (m6A-related lncRNAs) in 473 colon cancers and 41 adjacent tissues of CC patients from The Cancer Genome Atlas (TCGA) were investigated.Method: The Pearson correlation analysis was conducted to examine the m6A-related lncRNAs, and the univariate Cox regression analysis was performed to screen 38 prognostic m6A-related lncRNAs. The least absolute shrinkage and selection operator (LASSO) regression analysis were carried out on 38 prognostic lncRNAs to develop a 14 m6A-related lncRNAs prognostic signature (m6A-LPS) in CC. The availability of the m6A-LPS was evaluated using the Kaplan–Meier and Receiver Operating Characteristic (ROC) curves.Results: Three m6A modification patterns with significantly different N stages, survival time, and immune landscapes were identified. It has been discovered that the m6A-LPS, which is based on 14 m6A-related lncRNAs (TNFRSF10A-AS1, AC245041.1, AL513550.1, UTAT33, SNHG26, AC092944.1, ITGB1-DT, AL138921.1, AC099850.3, NCBP2-AS1, AL137782.1, AC073896.3, AP006621.2, AC147651.1), may represent a new, promising biomarker with great potential. It was re-evaluated in terms of survival rate, clinical features, tumor infiltration immune cells, biomarkers related to Immune Checkpoint Inhibitors (ICIs), and chemotherapeutic drug efficacy. The m6A-LPS has been revealed to be a novel potential and promising predictor for evaluating the prognosis of CC patients.Conclusion: This study revealed that the risk signature is a promising predictive indicator that may provide more accurate clinical applications in CC therapeutics and enable effective therapy strategies for clinicians.
Important functional role of the protein osteopontin in the progression of malignant pleural mesothelioma
Authors: Digifico Elisabeth , Erreni Marco , Mannarino Laura , Marchini Sergio , Ummarino Aldo , Anfray Clément , Bertola Luca , Recordati Camilla , Pistillo Daniela , Roncalli Massimo , Bossi Paola , Zucali Paolo Andrea , D’Incalci Maurizio , Belgiovine Cristina , Allavena Paola 
Published: June 2023

BackgroundMalignant Pleural Mesothelioma (MPM) is an aggressive cancer of the mesothelial lining associated with exposure to airborne non-degradable asbestos fibers. Its poor response to currently available treatments prompted us to explore the biological mechanisms involved in its progression. MPM is characterized by chronic non-resolving inflammation; in this study we investigated which inflammatory mediators are mostly expressed in biological tumor samples from MPM patients, with a focus on inflammatory cytokines, chemokines and matrix components.MethodsExpression and quantification of Osteopontin (OPN) was detected in tumor and plasma samples of MPM patients by mRNA, immunohistochemistry and ELISA. The functional role of OPN was investigated in mouse MPM cell lines in vivo using an orthotopic syngeneic mouse model.ResultsIn patients with MPM, the protein OPN was significantly more expressed in tumors than in normal pleural tissues and predominantly produced by mesothelioma cells; plasma levels were elevated in patients and associated with poor prognosis. However, modulation of OPN levels was not significantly different in a series of 18 MPM patients receiving immunotherapy with durvalumab alone or with pembrolizumab in combination with chemotherapy, some of whom achieved a partial clinical response. Two established murine mesothelioma cell lines: AB1 and AB22 of sarcomatoid and epithelioid histology, respectively, spontaneously produced high levels of OPN. Silencing of the OPN gene (Spp1) dramatically inhibited tumor growth in vivo in an orthotopic model, indicating that OPN has an important promoting role in the proliferation of MPM cells. Treatment of mice with anti-CD44 mAb, blocking a major OPN receptor, significantly reduced tumor growth in vivo.ConclusionThese results demonstrate that OPN is an endogenous growth factor for mesothelial cells and inhibition of its signaling may be helpful to restrain tumor progression in vivo. These findings have translational potential to improve the therapeutic response of human MPM.
Goat milk extracellular vesicles: immuno-modulation effects on porcine monocyte-derived macrophages in vitro
Authors: Franzoni Giulia , Mecocci Samanta , De Ciucis Chiara Grazia , Mura Lorena , Dell’Anno Filippo , Zinellu Susanna , Fruscione Floriana , De Paolis Livia , Carta Tania , Anfossi Antonio G. , Dei Guidici Silvia , Chiaradia Elisabetta , Pascucci Luisa , Oggiano Annalisa , Cappelli Katia , Razzuoli Elisabetta 
Published: June 2023

IntroductionExtracellular vesicles (EVs) are nanometric-membrane-bound sub-cellular structures, which can be recovered from milk. Milk EVs have drawn increasing interest due to their potential biomedical applications, therefore it is important to investigate their impact on key immune cells, such as macrophages.MethodsIn this work, the immunomodulatory effects of goat milk EVs on untreated (moMФ) and classically activated (moM1) porcine monocyte-derived macrophages were investigated using flow cytometry, ELISA, and gene expression assays.ResultsThese particles were efficiently internalized by macrophages and high doses (60 mg protein weight) triggered the upregulation of MHC I and MHC II DR on moMФ, but not on moM1. In moMФ, exposure to low doses (0.6 mg) of mEVs enhanced the gene expression of IL10, EBI3, and IFNB, whereas high doses up-regulated several pro-inflammatory cytokines. These nanosized structures slightly modulated cytokine gene expression on moM1. Accordingly, the cytokine (protein) contents in culture supernatants of moMФ were mildly affected by exposure to low doses of mEVs, whereas high doses promoted the increased release of TNF, IL-8, IL-1a, IL-1b, IL-1Ra, IL-6, IL-10, and IL-12. The cytokines content in moM1 supernatants was not critically affected.DiscussionOverall, our data support a clinical application of these molecules: they polarized macrophages toward an M1-like phenotype, but this activation seemed to be controlled, to prevent potentially pathological over-reaction to stressors.
Modeling the effects of large-scale interior headland restoration on tidal hydrodynamics and salinity transport in an open coast, marine-dominant estuary
Authors: Passeri Davina L. , Jenkins Robert L. , Poisson Autumn , Bilskie Matthew V. , Bacopoulos Peter 
Published: June 2023

The effects of large-scale interior headland restoration on tidal hydrodynamics and salinity transport in an open coast, marine dominant estuary (Grand Bay, Alabama, U.S.A) are investigated using a two-dimensional model, the Discontinuous-Galerkin Shallow Water Equations Model (DG-SWEM). Three restoration alternatives are simulated for present-day conditions, as well as under 0.5 m of sea level rise (SLR). Model results show that the restoration alternatives have no impact on tidal range within the estuary but change maximum tidal velocities by ±5 cm/s in the present-day scenarios and by ±7 cm/s in the scenarios with 0.5 m of SLR. Differences in average salinity concentrations for simulated tropical and frontal seasons show increases and decreases on the order of 2 pss in the embayments surrounding the restoration alternatives; differences were larger (on the order of ±4 pss) for the scenarios with 0.5 m of SLR. There were minimal changes in average salinity outside of the estuary and no changes offshore. The size and position of the alternatives played a role in the salinity response as a result of changing the estuarine shoreline geometry and affecting the fetch within the bay. SLR was more impactful in increasing exposure to low salinity values (i.e., less than 5 pss) than the presence of the restoration alternatives. Overall, the modeled results indicate that these large-scale restoration actions have limited and localized impacts on the hydrodynamics and salinity patterns in this open coast estuary. The results also demonstrate the nonlinear response of salinity to SLR, with increases and decreases in the maximum, mean and minimum daily salinity concentrations from present-day conditions. This nonlinear response was a result of changes in the directions of the residual currents, which affected salinity transport.
Excessively increased thalamocortical connectivity and poor initial antiseizure medication response in epilepsy patients
Authors: Zhong Jiyuan , Tan Ge , Wang Haijiao , Chen Yangmei 
Published: June 2023

ObjectivesThe network mechanism underlying the initial response to antiseizure medication in epilepsy has not been revealed yet. Given the central role of the thalamus in the brain network, we conducted a case-control study to investigate the association between thalamic connectivity and medication response.MethodsWe recruited 39 patients with newly diagnosed and medication-naïve epilepsy of genetic or unknown etiology, including 26 with a good response (GR group) and 13 with a poor response (PR group), and 26 matched healthy participants (control group). We measured the gray matter density (GMD) and the amplitude of low-frequency fluctuation (ALFF) of bilateral thalami. We then set each thalamus as the seed region of interest (ROI) to calculate voxel-wise functional connectivity (FC) and assessed ROI-wise effective connectivity (EC) between the thalamus and targeted regions.ResultsWe found no significant difference between groups in the GMD or ALFF of bilateral thalami. However, we observed that the FC values of several circuits connecting the left thalamus and the cortical areas, including the bilateral Rolandic operculum, the left insula, the left postcentral gyrus, the left supramarginal gyrus, and the left superior temporal gyrus, differed among groups (False Discovery Rate correction, P &lt; 0.05), with a higher value in the PR group than in the GR group and/or the control group (Bonferroni correction, P &lt; 0.05). Similarly, both the outflow and the inflow EC in each thalamocortical circuit were higher in the PR group than in the GR group and the control group, although these differences did not remain statistically significant after applying the Bonferroni correction (P &lt; 0.05). The FC showed a positive correlation with the corresponding outflow and inflow ECs for each circuit.ConclusionOur finding suggested that patients with stronger thalamocortical connectivity, potentially driven by both thalamic outflowing and inflowing information, may be more likely to respond poorly to initial antiseizure medication.
Rac and Cdc42 inhibitors reduce macrophage function in breast cancer preclinical models
Authors: Torres-Sanchez Anamaris , Rivera-Robles Michael , Castillo-Pichardo Linette , Martínez-Ferrer Magaly , Dorta-Estremera Stephanie M. , Dharmawardhane Suranganie 
Published: June 2023

BackgroundMetastatic disease lacks effective treatments and remains the primary cause of mortality from epithelial cancers, especially breast cancer. The metastatic cascade involves cancer cell migration and invasion and modulation of the tumor microenvironment (TME). A viable anti-metastasis strategy is to simultaneously target the migration of cancer cells and the tumor-infiltrating immunosuppressive inflammatory cells such as activated macrophages, neutrophils, and myeloid-derived suppressor cells (MDSC). The Rho GTPases Rac and Cdc42 are ideal molecular targets that regulate both cancer cell and immune cell migration, as well as their crosstalk signaling at the TME. Therefore, we tested the hypothesis that Rac and Cdc42 inhibitors target immunosuppressive immune cells, in addition to cancer cells. Our published data demonstrate that the Vav/Rac inhibitor EHop-016 and the Rac/Cdc42 guanine nucleotide association inhibitor MBQ-167 reduce mammary tumor growth and prevent breast cancer metastasis from pre-clinical mouse models without toxic effects.MethodsThe potential of Rac/Cdc42 inhibitors EHop-016 and MBQ-167 to target macrophages was tested in human and mouse macrophage cell lines via activity assays, MTT assays, wound healing, ELISA assays, and phagocytosis assays. Immunofluorescence, immunohistochemistry, and flow cytometry were used to identify myeloid cell subsets from tumors and spleens of mice following EHop-016 or MBQ-167 treatment.ResultsEHop-016 and MBQ-167 inhibited Rac and Cdc42 activation, actin cytoskeletal extensions, migration, and phagocytosis without affecting macrophage cell viability. Rac/Cdc42 inhibitors also reduced tumor- infiltrating macrophages and neutrophils in tumors of mice treated with EHop-016, and macrophages and MDSCs from spleens and tumors of mice with breast cancer, including activated macrophages and monocytes, following MBQ-167 treatment. Mice with breast tumors treated with EHop-016 significantly decreased the proinflammatory cytokine Interleukin-6 (IL-6) from plasma and the TME. This was confirmed from splenocytes treated with lipopolysaccharide (LPS) where EHop-016 or MBQ-167 reduced IL-6 secretion in response to LPS.ConclusionRac/Cdc42 inhibition induces an antitumor environment via inhibition of both metastatic cancer cells and immunosuppressive myeloid cells in the TME.
The complexity of DNA damage by radiation follows a Gamma distribution: insights from the Microdosimetric Gamma Model
Authors: Bertolet Alejandro , Chamseddine Ibrahim , Paganetti Harald , Schuemann Jan 
Published: June 2023

IntroductionDNA damage is the main predictor of response to radiation therapy for cancer. Its Q8 quantification and characterization are paramount for treatment optimization, particularly in advanced modalities such as proton and alpha-targeted therapy.MethodsWe present a novel approach called the Microdosimetric Gamma Model (MGM) to address this important issue. The MGM uses the theory of microdosimetry, specifically the mean energy imparted to small sites, as a predictor of DNA damage properties. MGM provides the number of DNA damage sites and their complexity, which were determined using Monte Carlo simulations with the TOPAS-nBio toolkit for monoenergetic protons and alpha particles. Complexity was used together with a illustrative and simplistic repair model to depict the differences between high and low LET radiations.ResultsDNA damage complexity distributions were were found to follow a Gamma distribution for all monoenergetic particles studied. The MGM functions allowed to predict number of DNA damage sites and their complexity for particles not simulated with microdosimetric measurements (yF) in the range of those studied.DiscussionCompared to current methods, MGM allows for the characterization of DNA damage induced by beams composed of multi-energy components distributed over any time configuration and spatial distribution. The output can be plugged into ad hoc repair models that can predict cell killing, protein recruitment at repair sites, chromosome aberrations, and other biological effects, as opposed to current models solely focusing on cell survival. These features are particularly important in targeted alpha-therapy, for which biological effects remain largely uncertain. The MGM provides a flexible framework to study the energy, time, and spatial aspects of ionizing radiation and offers an excellent tool for studying and optimizing the biological effects of these radiotherapy modalities.