bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel “SMARTer” Clinical Trial Design Improves Odds of Approval and Can Reduce Study Size By 80%: Modeling Use of a ctDNA “Optimizing Diagnostic” for Early Therapy Switching in Immuno-Oncology Trials
Authors: Taub Floyd Elliot , Gao Dexiang 
Published: February 2023

AbstractNovel pivotal trial designs, that more clearly demonstrate increased benefit over Standard of Care (SOC), especially in oncology and immuno-oncology (IO), are presented. The benefit of therapy is maximized and sample size is dramatically reduced. The novel methodology includes the introduction of a biochemical “Optimizing Diagnostic”, for example a cfDNA test that can detect poor response, when performed early after therapy is begun; this is used to change the therapy of the tested person early in the trial (typically to SOC), before clinical progression. Patients remain in “the new drug first” group, which is compared to SOC. An “Optimizing Diagnostic” is analogous to a “Companion Diagnostic”; both potentially allow approval of drugs that would otherwise fail. A companion diagnostic predicts benefit prior to therapy, the optimizing diagnostic (more accurately) predicts likelihood of benefit after initial therapy. Those patients deemed less likely to respond remain in the novel drug first arm, but are switched to SOC. A Sequential Multiple Assignment Randomized Trial” (SMART) design is proposed to evaluate if switching to SOC or SOC plus continuing the novel therapy is most beneficial. These designs will allow approval of therapy paths including novel agents when the novel agent could not be approved without this design. A good optimizing test may reduce the number of patients needed by 80%, dramatically reducing cost and time; more patients benefit and accrual is easier.Key PointsA new clinical trial design focused on testing a path that begins with a novel regimen (IO is featured) is presented.The path includes an “optimizing diagnostic” that determines, early during treatment, if a patient should remain on the new regimen.Companion diagnostics define the path at a pre-treatment stage, optimizing diagnostics define the path early during treatment. Changes in therapy, typically to the SOC, is made based on the post-test probability of success.The novel path is significantly more likely to lead to approval than the novel regimen alone.Use of the novel method can reduce the size of a trial by 80%, and allow approval of the path, when approval of the novel regimen, based on a head-to-head trial vs SOC, would not be possible.
Application of comprehensive evaluation framework to Coronavirus Disease 19 studies: A systematic review of translational aspects of artificial intelligence in health care
Authors: Casey Aaron , Ansari Saba , Nakisa Bahareh , Kelly Blair , Brown Pieta , Cooper Paul , Muhammad Imran , Livingstone Steven , Reddy Sandeep , Makinen Ville-Petteri 
Published: February 2023

AbstractBackgroundDespite immense progress in artificial intelligence (AI) models, there has been limited deployment in healthcare environments. The gap between potential and actual AI applications is likely due to the lack of translatability between controlled research environments (where these models are developed) and clinical environments for which the AI tools are ultimately intended.ObjectiveWe have previously developed the Translational Evaluation of Healthcare AI (TEHAI) framework to assess the translational value of AI models and to support successful transition to healthcare environments. In this study, we apply the TEHAI to COVID-19 literature in order to assess how well translational topics are covered.MethodsA systematic literature search for COVID-AI studies published between December 2019-2020 resulted in 3,830 records. A subset of 102 papers that passed inclusion criteria were sampled for full review. Nine reviewers assessed the papers for translational value and collected descriptive data (each study was assessed by two reviewers). Evaluation scores and extracted data were compared by a third reviewer for resolution of discrepancies. The review process was conducted on the Covidence software platform.ResultsWe observed a significant trend for studies to attain high scores for technical capability but low scores for the areas essential for clinical translatability. Specific questions regarding external model validation, safety, non-maleficence and service adoption received failed scores in most studies.ConclusionsUsing TEHAI, we identified notable gaps in how well translational topics of AI models are covered in the COVID-19 clinical sphere. These gaps in areas crucial for clinical translatability could, and should, be considered already at the model development stage to increase translatability into real COVID-19 healthcare environments.
Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients
Authors: Severson Tesa M. , Zhu Yanyun , Prekovic Stefan , Schuurman Karianne , Nguyen Holly M. , Brown Lisha G. , Hakkola Sini , Kim Yongsoo , Kneppers Jeroen , Linder Simon , Stelloo Suzan , Lieftink Cor , van der Heijden Michiel , Nykter Matti , van der Noort Vincent , Sanders Joyce , Morris Ben , Jenster Guido , van Leenders Geert JLH , Pomerantz Mark , Freedman Matthew L. , Beijersbergen Roderick L. , Urbanucci Alfonso , Wessels Lodewyk , Corey Eva , Zwart Wilbert , Bergman Andries M. 
Published: February 2023

AbstractAndrogen Receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase II clinical trial, we epigenetically profiled enhancer/promoter activities with H3K27ac chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identified a distinct subset of H3K27ac-differentially marked regions that associated with treatment responsiveness. These data were successfully validated in mCRPC patient-derived xenograft models (PDX).In silicoanalyses revealed HDAC3 as a critical factor that can drive resistance to hormonal interventions, which we validatedin vitro. Using cell lines and mCRPC PDX tumorsin vitro, we identified drug-drug synergy between enzalutamide and the pan-HDAC inhibitor vorinostat, providing therapeutic proof-of-concept. These findings demonstrate rationale for new therapeutic strategies using a combination of AR and HDAC inhibitors to improve patient outcome in advanced stages of mCRPC.
A luminal intermediate cell state maintains long-term prostate homeostasis and contributes to tumorigenesis
Authors: Luo Fu , Tshering Lara F. , Tutuska Karis , Szenk Mariola , Rubel Diana , Rail James G. , Russ Savanah , Liu Jingxuan , Nemajerova Alice , Balázsi Gábor , Talos Flaminia 
Published: February 2023

SummaryCellular heterogeneity poses tremendous challenges for developing cell-targeted therapies and biomarkers of clinically significant prostate cancer. The origins of this heterogeneity within normal adult and aging tissue remain unknown, leaving cellular states and transcriptional programs that allow expansions of malignant clones unidentified. To define cell states that contribute to early cancer development, we performed clonal analyses and single cell transcriptomics of normal prostate from genetically-engineered mouse models. We uncovered a luminal transcriptional state with a unique “basal-like” Wnt/p63 signaling (luminal intermediate, LumI) which contributes to the maintenance of long-term prostate homeostasis. Moreover, LumI cells greatly expand during early stages of tumorigenesis in several mouse models of prostate cancer. Genetic ablation of p63in vivoin luminal cells reduced the formation of aggressive clones in mouse prostate tumor models. Finally, the LumI cells and Wnt signaling appear to significantly increase in human aging prostate and prostate cancer samples, highlighting the importance of this hybrid cell state for human pathologies with potential translational impact.
Mitochondrial Calcium Uptake Declines during Aging and is Directly Activated by Oleuropein to Boost Energy Metabolism and Skeletal Muscle Performance
Authors: Gherardi Gaia , Weiser Anna , Bermont Flavien , Migliavacca Eugenia , Brinon Benjamin , Jacot Guillaume E. , Hermant Aurélie , Sturlese Mattia , Nogara Leonardo , Barron Denis , Moro Stefano , Blaauw Bert , Rizzuto Rosario , Feige Jerome N. , Mammucari Cristina , Marchi Umberto De 
Published: February 2023

SUMMARYMitochondrial calcium (mtCa2+) uptake via the Mitochondrial Calcium Uniporter (MCU) couples the regulation of calcium homeostasis to energy production. mtCa2+uptake is rate-limiting for mitochondrial activation during muscle contraction, but how MCU is affected during physiopathology and whether it can be stimulated therapeutically remains largely uncharacterized. By profiling human and preclinical aging of skeletal muscle, we discovered a conserved down-regulation of MCUR1 during aging that decreases mtCa2+uptake and drives sarcopenia. Through a screen of 5000 bioactive nutrients, we identify the natural polyphenol Oleuropein as a specific MCU activator that stimulates mitochondrial respiration via binding to MICU1. Oleuropein activates mtCa2+uptake and oxidative energy metabolism to enhance endurance and limit fatigue in vivo both in young and aged. These effects of Oleuropein are mediated by an MCU-dependent mechanism in skeletal muscle as they are lost upon muscle-specific MCU KO. Our work demonstrates that impaired mtCa2+uptake causes mitochondrial dysfunction during aging and establishes Oleuropein as a novel nutrient that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.
Epigenetic modifications mediate cultivar-specific root development and metabolic adaptation to nitrogen availability in wheat
Authors: Zhang Hao , Cui Fa , Zhao Long , Zhang Xiaoyu , Chen Jinchao , Zhang Jing , Li Yongpeng , Niu Yanxiao , Wang Lei , Gao Caixia , Fu Xiangdong , Tong Yiping , Ling Hong-Qing , Li Junming , Xiao Jun 
Published: February 2023

AbstractThe breeding of crops with improved nitrogen use efficiency (NUE) is crucial for sustainable agriculture. However, the role of epigenetic modification in the regulation of cultivar-specific responses to low nitrogen (LN) constraint is not well understood. Here, we analyzed the chromatin landscapes in roots, leaves, and seeds in two wheat cultivars (KN9204 and J411) that differ radically in NUE under normal and nitrogen-limited conditions. Transcriptional regulatory chromatin regions exhibited a clear cultivar-specificity between KN9204 and J411. Cultivar-specific regulation of nitrogen metabolism genes (NMGs) is linked to variation in histone modification levels, rather than differences in DNA sequence. Cultivar-specific histone modification regions were found to contribute to the genetic regulation of NUE-related traits, such as QTL locus of maximum root length of qMRL-7B. Furthermore, LN-induced H3K27ac and H3K27me3 dynamics enhanced root growth more in KN9204, while strengthened the nitrogen uptake system more in J411. Evidence from histone deacetylase inhibitor treatment and transgenic plants with loss-of-function of the H3K27me3 methyltransferase further showed that changes in epigenetic modifications can alter the strategy for root development and nitrogen uptake in response to LN constraint. Taken together, the results of our study highlight the importance of epigenetic regulation in mediating cultivar-specific root development and metabolic adaptation to LN in wheat.
Auto-STEED: A data mining tool for automated extraction of experimental parameters and risk of bias items fromin vivopublications
Authors: Zurrer Wolfgang Emanuel , Cannon Amelia Elaine , Ewing Ewoud , Rosso Marianna , Reich Daniel S. , Ineichen Benjamin V. 
Published: February 2023

AbstractBackgroundSystematic reviews, i.e., research summaries that address focused questions in a structured and reproducible manner, are a cornerstone of evidence-based medicine and research. However, certain systematic review steps such as data extraction are labour-intensive which hampers their applicability, not least with the rapidly expanding body of biomedical literature.ObjectiveTo bridge this gap, we aimed at developing a data mining tool in the R programming environment to automate data extraction from neurosciencein vivopublications. The function was trained on a literature corpus (n=45 publications) of animal motor neuron disease studies and tested in two validation corpora (motor neuron diseases, n=31 publications; multiple sclerosis, n=244 publications).ResultsOur data mining tool Auto-STEED (Automated and STructured Extraction of Experimental Data) was able to extract key experimental parameters such as animal models and species as well as risk of bias items such as randomization or blinding fromin vivostudies. Sensitivity and specificity were over 85 and 80%, respectively, for most items in both validation corpora. Accuracy and F-scores were above 90% and 0.9 for most items in the validation corpora. Time savings were above 99%.ConclusionsOur developed text mining tool Auto-STEED is able to extract key experimental parameters and risk of bias items from the neurosciencein vivoliterature. With this, the tool can be deployed to probe a field in a research improvement context or to replace one human reader during data extraction resulting in substantial time-savings and contribute towards automation of systematic reviews. The function is available on Github.
Activity-dependent induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation
Authors: Sardar Debosmita , Cheng Yi-Ting , Woo Junsung , Choi Dong-Joo , Lee Zhung-Fu , Kwon Wookbong , Chen Hsiao-Chi , Lozzi Brittney , Cervantes Alexis , Rajendran Kavitha , Huang Teng-Wei , Jain Antrix , Arenkiel Benjamin , Maze Ian , Deneen Benjamin 
Published: February 2023

AbstractNeuronal activity drives global alterations in gene expression within neurons, yet how it directs transcriptional and epigenomic changes in neighboring astrocytes in functioning circuits is unknown. Here we show that neuronal activity induces widespread transcriptional upregulation and downregulation in astrocytes, highlighted by the identification of a neuromodulator transporter Slc22a3 as an activity-inducible astrocyte gene regulating sensory processing in the olfactory bulb. Loss of astrocytic Slc22a3 reduces serotonin levels in astrocytes, leading to alterations in histone serotonylation. Inhibition of histone serotonylation in astrocytes reduces expression of GABA biosynthetic genes and GABA release, culminating in olfactory deficits. Our study reveals that neuronal activity orchestrates transcriptional and epigenomic responses in astrocytes, while illustrating new mechanisms for how astrocytes process neuromodulatory input to gate neurotransmitter release for sensory processing.
Human APOBEC3B promotes tumor heterogeneityin vivoincluding signature mutations and metastases
Authors: Durfee Cameron , Temiz Nuri Alpay , Levin-Klein Rena , Argyris Prokopios P. , Alsøe Lene , Carracedo Sergio , de la Vega Alicia Alonso , Proehl Joshua , Holzhauer Anna M. , Seeman Zachary J. , Lin Yu-Hsiu T. , Vogel Rachel I. , Sotillo Rocio , Nilsen Hilde , Harris Reuben S. 
Published: February 2023

SUMMARYThe antiviral DNA cytosine deaminase APOBEC3B has been implicated as a source of mutation in many different cancers. Despite over 10 years of work, a causal relationship has yet to be established between APOBEC3B and any stage of carcinogenesis. Here we report a murine model that expresses tumor-like levels of human APOBEC3B after Cre-mediated recombination. Animals appear to develop normally with full-body expression of APOBEC3B. However, adult males manifest infertility and older animals of both sexes show accelerated rates of tumorigenesis (mostly lymphomas or hepatocellular carcinomas). Interestingly, primary tumors also show overt heterogeneity, and a subset spreads to secondary sites. Both primary and metastatic tumors exhibit increased frequencies of C-to-T mutations in TC dinucleotide motifs consistent with the established biochemical activity of APOBEC3B. Elevated levels of structural variation and insertion-deletion mutations also accumulate in these tumors. Together, these studies provide the first cause-and-effect demonstration that human APOBEC3B is an oncoprotein capable of causing a wide range of genetic changes and driving tumor formationin vivo.
Reduced steroid activation of elephant shark GR and MR after inserting four amino acids from the DNA-binding domain of lamprey corticoid receptor-1
Authors: Katsu Yoshinao , Zhang Jiawen , Baker Michael E. 
Published: February 2023

AbstractAtlantic sea lamprey contains two corticoid receptors (CRs), CR1 and CR2, that have identical amino acid sequences, except for a four amino acid insert (Thr-Arg-Gln-Gly) in the CR1 DNA-binding domain (DBD). Steroids are stronger transcriptional activators of CR2 than of CR1 suggesting that the insert reduces the transcriptional response of lamprey CR1 to steroids. The DBD in elephant shark mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), which are descended from a CR, lack these four amino acids, suggesting that a CR2 is their common ancestor. To determine if, similar to lamprey CR1, the presence of this insert in elephant shark MR and GR decreases transcriptional activation by corticosteroids, we inserted these four CR1-specific residues into the DBD of elephant shark MR and GR. Compared to steroid activation of wild-type elephant shark MR and GR, cortisol, corticosterone, aldosterone, 11-deoxycorticosterone and 11-deoxycortisol had lower transcriptional activation of these mutant MR and GR receptors, indicating that the absence of this four-residue segment in the DBD in wild-type elephant shark MR and GR increases transcriptional activation by corticosteroids.
Exploring the phytobeneficial and biocontrol capacities of endophytic bacteria isolated from hybrid vanilla pods
Authors: Lalanne-Tisné Guillaume , Barral Bastien , Taibi Ahmed , Coulibaly Zana Kpatolo , Burguet Pierre , Rasoarahona Felah , Quinton Loic , Meile Jean-Christophe , Boubakri Hasna , Kodja Hippolyte 
Published: February 2023

AbstractFew studies have been conducted on endophytic bacteria of vanilla. In this study, 58 bacterial strains were isolated from two hybrid vanilla plants from Madagascar,Manitra ampotonyandTsy taitra. They were genetically characterised and divided into four distinct phylotypes. A selection of twelve strains corresponding to the identified genetic diversity were testedin vitrofor four phytobeneficial capacities: phosphate solubilisation, free nitrogen fixation, phytohormone and siderophore production. They were also evaluatedin vitrofor their ability to biocontrol the growth of the vanilla pathogenic fungi,Fusarium oxysporum f. sp. radicis vanillaeandCholletotrichum orchidophilum. Bacteria belonging to three different phyla were found to be highly competent in each of the phytobeneficial capacities tested. Bacteria belonging to the phylum related toBacillus siamensisshowed the best capacity to inhibit fungal growth making them good candidates for controlling fungal diseases of vanilla. This competence was highlighted with spectral imaging showing the production of lipopeptides by the bacterial strains confronted with the pathogenic fungi of vanilla.
International Multi-Specialty Expert Physician Preoperative Identification of Extranodal Extension in Oropharyngeal Cancer Patients using Computed Tomography: Prospective Blinded Human Inter-Observer Performance Evaluation
Authors:   Multidisciplinary Oropharyngeal Cancer Extra-Nodal Extension (OPC ENE) Assessment Working Group
Published: February 2023

ABSTRACTImportanceExtranodal extension (pENE) is a critical prognostic factor in oropharyngeal cancer (OPC) that drives therapeutic disposition. Determination of pENE from radiological imaging has been associated with high inter-observer variability. However, the impact of clinician specialty on human observer performance of imaging-detected extranodal extension (iENE) remains poorly understood.ObjectiveTo characterize the impact of clinician specialty on the accuracy of pre-operative iENE in human papillomavirus-positive (HPV+) OPC using computed tomography (CT) images.Design, Setting, and ParticipantsThis prospective observational human performance study analyzed pre-therapy CT images from 24 HPV+ OPC patients, with duplication of 6 scans (n=30) of which 21 were pathologically confirmed pENE. Thirty-four expert observers, including 11 radiologists, 12 surgeons, and 11 radiation oncologists, independently assessed these scans for iENE and reported human-detected radiologic criteria and observer confidence.Main Outcomes and MeasuresThe primary outcomes included accuracy, sensitivity, specificity, area under the receiver operating characteristic curve (AUC), and Brier score for each physician, compared to ground-truth pENE. The significance of radiographic signs for prediction of pENE were determined through logistic regression analysis. Fleiss’ kappa measured interobserver agreement, and Hanley-MacNeil AUC discrimination testing.ResultsMedian accuracy across all specialties was 0.57 (95%CI 0.39 to 0.73), with no specialty showing discriminate performance greater than random estimation (median AUC 0.64, 95%CI 0.44 to 0.83). Significant differences between radiologists and surgeons in Brier scores (0.33 vs. 0.26, p < 0.01), radiation oncologists and surgeons in sensitivity (0.48 vs. 0.69, p > 0.1), and radiation oncologists and radiologists/surgeons in specificity (0.89 vs. 0.56, p > 0.1). Indistinct capsular contour and nodal necrosis were significant predictors of correct pENE status among all specialties. Interobserver agreement was weak for all the radiographic criteria, regardless of specialty (κ<0.6).Conclusions and RelevanceMultiobserver testing shows physician discrimination of HPV+OPC pENE on pre-operative CT remains non-different than blind guessing, with high inter-rater variability and low diagnostic accuracy, regardless of clinician specialty. While minor differences in diagnostic performance among specialties are noted, they do not significantly affect the overall poor agreement and discrimination rates observed. The findings underscore the need for further research into automated detection systems or enhanced imaging techniques to improve the accuracy and reliability of iENE assessments in clinical practice.Abstract FigureVisual Abstract
Microsnoop: A Generalized Tool for Unbiased Representation of Diverse Microscopy Images
Authors: Xun Dejin , Wang Rui , Zhang Xingcai , Wang Yi 
Published: February 2023

AbstractMicroscopy image profiling is becoming increasingly important in biological research. Microsnoop is a new deep learning-based representation tool that has been trained on large-scale microscopy images using masked self-supervised learning, eliminating the need for manual annotation. Microsnoop can unbiasedly profile a wide range of complex and heterogeneous images, including single-cell, fully imaged, and batch-experiment data. Its performance was evaluated on seven high-quality datasets, containing over 358,000 images and 1,270,000 single cells with varying resolutions and channels from cellular organelles to tissues. The results show that Microsnoop outperforms previous generalist and even custom algorithms, demonstrating its robustness and state-of-the-art performance in all biological applications. Furthermore, Microsnoop can contribute to multi-modal studies and is highly inclusive of GPU and CPU capabilities. It can be easily and freely deployed on local or cloud computing platforms.