bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibody-Drug Conjugates in Breast Cancer: Spotlight on HER2
Authors: Abelman Rachel Occhiogrosso , Medford Arielle , Spring Laura , Bardia Aditya 
Published: November 2022

Abstract
Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies linked to a cytotoxic payload, enabling targeted delivery of more potent chemotherapy. In the past decade, there has been rapid development of ADCs aimed at different types of breast cancer. The success of the monoclonal antibody trastuzumab has led to the evolution of several ADCs targeting HER2-positive breast cancer. Trastuzumab-emtansine, the first approved ADC targeting HER2-positive breast cancer, has become standard of care for patients with high-risk early-stage HER2-positive breast cancer who have residual disease after neoadjuvant chemotherapy. More recently, the observation of the bystander effect, in which ADCs target both antigen-positive cells and adjacent antigen-negative cells, has led to the reclassification of “HER2-low” breast cancer and the development of trastuzumab-deruxtecan to target this population. This article reviews the history of HER2-directed ADCs in breast cancer as well as ongoing ADCs in development.
Antibody-Drug Conjugates in Myeloid Leukemias
Authors: Senapati Jayastu , Daver Naval G. , Pemmaraju Naveen 
Published: November 2022

Abstract
Targeted therapy in oncology brings with it the promise to maximize cancer cell cytotoxicity with minimal off-target effects. Antibody-drug conjugates (ADCs), an important group of such targeted agents, consist of a monoclonal antibody conjugated to a potent cytotoxic drug. In the field of leukemia, ADCs form an important component of therapeutic arsenal through the use of gemtuzumab ozogamicin in acute myeloid leukemia and inotuzumab ozogamicin (InO) in B-cell acute lymphoblastic leukemia, 2 approved agents. A recombinant fusion protein, tagraxofusp, which function similar to ADC, has gained approval for therapy in blastic plasmacytic dendritic cell neoplasm. The use of such agents as monotherapy or as part of a combination therapy has led to improved response rates and outcomes in certain specific disease subtypes and has led to further studies to identify novel cellular targets and improved delivery of cytotoxic agents using ADC. In this review, we will discuss about ADCs in myeloid leukemia and understand their development and current use in the field.
SPECKLE TRACKING QUANTIFICATION PARASTERNAL INTERCOSTAL MUSCLE LONGITUDINAL STRAIN TO PREDICT WEANING OUTCOMES: A MULTICENTRIC OBSERVATIONAL STUDY
Authors: Xu Qiancheng , Yang Xiao , Qian Yan , Hu Chang , Lu Weihua , Cai Shuhan , Li Jianguo , Hu Bo 
Published: November 2022

ABSTRACT

Background: The purpose of this study was to determine the feasibility, reliability, and reproducibility of parasternal intercostal muscle longitudinal strain (LSim) quantification by speckle tracking and the value of maximal LSim to predict weaning outcomes. Methods: This study was divided into three phases. Phases 1 and 2 comprehended prospective observational programs to evaluate the feasibility, reliability, and repeatability of speckle tracking to assess LSim in healthy subjects and mechanically ventilated patients. Phase 3 was a multicenter retrospective study to evaluate the value of maximal LSim, intercostal muscle thickening fraction (TFim), diaphragmatic thickening fraction, diaphragmatic excursion, and rapid shallow breathing index to predict weaning outcomes. Results: A total of 25 healthy subjects and 20 mechanically ventilated patients were enrolled in phases 1 and 2, respectively. Maximal LSim was easily accessible, and the intraoperator reliability and interoperator reliability were excellent in eupnea, deep breathing, and mechanical ventilation. The intraclass correlation coefficient ranged from 0.85 to 0.96. Moreover, 83 patients were included in phase 3. The areas under the receiver operating characteristic curve of maximal LSim, TFim, diaphragmatic thickening fraction, diaphragmatic excursion, and rapid shallow breathing index were 0.91, 0.79, 0.71, 0.70, and 0.78 for the prediction of successful weaning, respectively. The best cutoff values of LSim and TFim were >−6% (sensitivity, 100%; specificity, 64.71%) and <7.6% (sensitivity, 100%; specificity, 50.98%), respectively. Conclusions: The quantification of LSim by speckle tracking was easily achievable in healthy subjects and mechanically ventilated patients and presented a higher predictive value for weaning success compared with conventional weaning parameters. Trial registration no. ChiCTR2100049817
Surgical Cost Awareness Program Study: Impact of a Novel, Real-Time, Cost Awareness Intervention on Operating Room Expenses in Thoracoscopic Lobectomy
Authors: Dayan Gabriel , Soder Stephan A , Dahan Zachary , Langleben Ian , Pollock Clare , Mignault Alexandre , Ferraro Pasquale , Nasir Basil , Potter Brian , Liberman Moishe 
Published: November 2022

BACKGROUND:
For surgical patients, operating room expenses are significant drivers of overall hospitalization costs. Surgical teams often lack awareness of the costs associated with disposable surgical supplies, which may lead to unnecessary expenditures. The aim of this study is to evaluate whether a Surgical Cost Awareness Program would reduce operating room costs.

STUDY DESIGN:
A prototype software displays the types and costs of disposable instruments used in real-time during surgery and generates insight-driven operative cost reports, which are automatically sent to the surgeons. A prospective pre–post controlled trial of thoracoscopic lobectomy procedures performed by 7 surgeons at a single academic center was conducted. Control and intervention groups consisted of consecutive cases from February 2nd through June 23, 2021, and from June 28th through December 22, 2021, respectively. The primary outcome was mean per case surgical disposables cost.

RESULTS:
Three hundred twenty-two lobectomies were evaluated throughout the study period (control: n = 164; intervention: n = 158). Baseline characteristics were comparable between groups. Mean disposables cost per case was $3,320.73 ± $814.83 in the control group compared with $2,567.64 ± $594.59 in the intervention group, representing a mean cost reduction of $753.08 (95% CI, $622.29 to $883.87; p < 0.001). All surgeons experienced a reduction in disposable costs after the intervention. Intraoperative and postoperative outcomes did not differ between the cohorts.

CONCLUSIONS:
Providing real-time educational feedback to surgical teams significantly reduced costs associated with disposable surgical equipment without compromising perioperative outcomes for lobectomy. Integrating the novel AssistIQ software across other procedural settings may generate further data insights with the potential for significant cost savings on a larger scale.
Loss ofGFAPcauses optico-retinal dysplasia and vision impairment
Authors: Sarusie Menachem Viktor Khamo , Rönnbäck Cecilia , Jespersgaard Cathrine , Baungaard Sif , Ali Yeasmeen , Kessel Line , Christensen Søren Tvorup , Nielsen Karen Brøndum- , Møllgård Kjeld , Rosenberg Thomas , Larsen Lars Allan , Grønskov Karen 
Published: November 2022

ABSTRACTDiagnosis of genetic diseases has taken tremendous steps forward since the human genome project and technical advancements such as next generation sequencing. However, in the past years it has become evident that the classical “one gene – one phenotype” model is insufficient to encompass the intricacies of human genetics. Examples are emerging that variants in a gene can cause quite diverging phenotypes depending on the specific location in the gene or on the specific type of variant. In the era of precision medicine this is important knowledge, both when interpreting genomic data, but also when designing treatment strategies.Gain-of-function variants inGFAPleads to protein aggregation and is the cause of the severe neurodegenerative disorder Alexander Disease (AxD), while loss of GFAP function has been considered benign. Here, we report a loss-of-function variant inGFAPas the cause of optico-retinal dysplasia and vision impairment in a six-generation family.Whole genome sequencing analysis of family members with gliosis of the optic nerve head and visual impairment revealed a frameshift variant inGFAP(c.928dup, p.(Met310Asnfs*113)) segregating with disease. Analysis of human embryonic tissues revealed strong expression of GFAP in retinal neural progenitors. A zebrafish model verified that c.928dup does not result in extensive GFAP protein aggregation and zebrafishgfaploss-of-function mutants showed vision impairment and retinal dysplasia, characterized by a significant loss of Müller glia cells and photoreceptor cells.Our findings show how different mutational mechanisms can cause diverging phenotypes and reveal a novel function of GFAP in human eye development.
KATPChannel Prodrugs Reduce Inflammatory and Neuropathic Hypersensitivity, Morphine Induced Hypersensitivity, and Precipitated Withdrawal in Mice
Authors: Doucette Alexis , Johnson Kayla , Hulke Shelby , Mujteba Sunna , Miller Elena , Dosa Peter I. , Klein Amanda H. 
Published: November 2022

AbstractPrevious studies show ATP-sensitive potassium (KATP) channel openers can reduce hypersensitivity associated with chronic pain models in rodents, and reduce morphine tolerance. Many agonists of KATPchannels are not soluble in physiologically relevant vehicles, requiring adaptation for clinical use. This study compared the antinociception activity of novel KATPchannel targeting prodrugs, CKLP1, CKLP2, and CF3-CKLP. These prodrugs are activated by endogenous alkaline phosphatase enzymes present in the peripheral and central nervous systems. Analgesic capabilities of intrathecally injected prodrugs were tested in rodent models of spinal nerve ligation (SNL) and Complete Freund’s Adjuvant (CFA) as models for neuropathic and inflammatory pain, respectively. CKLP1 and CKLP2 significantly increased mechanical paw withdrawal thresholds 1-2 hours after intrathecal administration in the SNL model, but all three prodrugs were able to attenuate hypersensitivity up to 7 days after CFA treatment. The reduction of opioid tolerance and opioid-induced hypersensitivity in mice treated chronically with morphine was significantly reduced in CKLP1 and CKLP2 treated animals. Prodrug cleavage was confirmed in mouse spinal cords using liquid chromatography. These studies may aid in the further development of KATPchannel prodrugs for use in treatments of chronic pain, opioid tolerance, and withdrawal.
FASSO: An AlphaFold based method to assign functional annotations by combining sequence and structure orthology
Authors: Andorf Carson M , Sen Shatabdi , Hayford Rita K , Portwood John L , Cannon Ethalinda K , Harper Lisa C , Gardiner Jack M , Sen Taner Z , Woodhouse Margaret R 
Published: November 2022

AbstractMethods to predict orthology play an important role in bioinformatics for phylogenetic analysis by identifying orthologs within or across any level of biological classification. Sequence-based reciprocal best hit approaches are commonly used in functional annotation since orthologous genes are expected to share functions. The process is limited as it relies solely on sequence data and does not consider structural information and its role in function. Previously, determining protein structure was highly time-consuming, inaccurate, and limited to the size of the protein, all of which resulted in a structural biology bottleneck. With the release of AlphaFold, there are now over 200 million predicted protein structures, including full proteomes for dozens of key organisms. The reciprocal best structural hit approach uses protein structure alignments to identify structural orthologs. We propose combining both sequence- and structure-based reciprocal best hit approaches to obtain a more accurate and complete set of orthologs across diverse species, called Functional Annotations using Sequence and Structure Orthology (FASSO). Using FASSO, we annotated orthologs between five plant species (maize, sorghum, rice, soybean, Arabidopsis) and three distance outgroups (human, budding yeast, and fission yeast). We inferred over 270,000 functional annotations across the eight proteomes including annotations for over 5,600 uncharacterized proteins. FASSO provides confidence labels on ortholog predictions and flags potential misannotations in existing proteomes. We further demonstrate the utility of the approach by exploring the annotation of the maize proteome.
Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma
Authors: Dolgalev Igor , Zhou Hua , Shenker-Tauris Nina , Le Hortense , Sakellaropoulos Theodore , Coudray Nicolas , Zhu Kelsey , Vasudevaraja Varshini , Yeaton Anna , Goparaju Chandra V. , Li Yonghua , Sulaiman Imran , Tsay Jun-Chieh J. , Meyn Peter , Mohamed Hussein , Sydney Iris , Ramaswami Sitharam , Narula Navneet , Kulicke Ruth , Davis Fred P. , Stransky Nicolas , Smolen Gromoslaw A. , Cheng Wei-Yi , Cai James , Punekar Salman , Velcheti Vamsidhar , Poirier J.T. , Neel Ben , Wong Kwok-Kin , Chiriboga Luis , Heguy Adriana , Papagiannakopoulos Thales , Snuderl Matija , Segal Leopoldo N. , Moreira Andre L. , Pass Harvey I. , Tsirigos Aristotelis 
Published: November 2022

AbstractEarly-stage lung adenocarcinoma is typically treated by surgical resection of the tumor. While in the majority of cases surgery can lead to cure, approximately 30% of patients progress. Despite intense efforts to map the genetic landscape of early-stage lung tumors, there has been limited success in discovering accurate biomarkers that can predict clinical outcomes. Meanwhile, the role of the tumor-adjacent tissue in cancer progression has been largely ignored. To test whether tumor-adjacent tissue can be informative of progression-free survival and to probe the underlying molecular pathways involved, we designed a multi-omic study in both tumor and matched tumor-adjacent histologically normal lung tissue from the same patient. Our study includes 143 treatment naive stage I cases with long-term patient follow-up and is, to our knowledge, the largest such study with the longest follow-up. We performed a comprehensive histologic characterization of all tumors, mapped the mutational landscape and probed the transcriptome of both tumor and adjacent normal tissue. We evaluated the predictive power of each data modality and showed that the transcriptome of tumor-adjacent histologically normal lung tissue is the only reliable predictor of clinical outcome. Unbiased discovery of co-expressed gene modules revealed that inflammatory pathways are upregulated in the tumor-adjacent tissue of patients at high risk for disease progression. Furthermore, single-cell transcriptome analysis in the tumor-adjacent lung demonstrated that progression-associated inflammatory signatures were broadly expressed by both immune and non-immune cells including mesothelial cells, alveolar type 2 cells and fibroblasts, CD1 dendritic cells and MAST cells. Collectively, our studies suggest that molecular profiling of tumor-adjacent tissue can identify patients that are at high risk for disease progression.
Genetic pathways regulating the longitudinal acquisition of cocaine self-administration in inbred and recombinant inbred mice
Authors: Khan Arshad H. , Bagley Jared R. , LaPierre Nathan , Gonzalez-Figueroa Carlos , Spencer Tadeo C. , Choudhury Mudra , Xiao Xinshu , Eskin Eleazar , Jentsch James D. , Smith Desmond J. 
Published: November 2022

AbstractTo identify genetic pathways for addiction, we analyzed intravenous self-administration of cocaine or saline in a panel of 84 inbred and recombinant inbred mouse strains over 10 days. We integrated the behavior data with RNA-Seq data from the medial frontal cortex and nucleus accumbens from 41 strains. The self-administration of cocaine and saline showed distinct genetic bases. We maximized power to map loci for cocaine intake by using a linear mixed model to account for this longitudinal phenotype while correcting for population structure. A total of 15 unique significant loci were identified in the genome-wide association study (GWAS). A transcriptome-wide association study (TWAS) highlighted theTrpv2ion channel as a key locus for cocaine self-administration from the GWAS. In addition, 17 genes supplementary to the GWAS were identified includingArhgef26, Slc18b1andSlco5a1. We found numerous instances where alternate splice site selection or RNA editing altered transcript abundance. Our work emphasizes the importance ofTrpv2, a known cannabinoid receptor, for the response to cocaine as well as identifying further relevant loci.
Nucleation of Biomolecular Condensates from Finite-Sized Simulations
Authors: Li Lunna , Paloni Matteo , Finney Aaron R. , Barducci Alessandro , Salvalaglio Matteo 
Published: November 2022

AbstractThe nucleation of protein condensates is a concentration-driven process of assembly. When modelled in the canonical ensemble, condensation is affected by finite-size effects. Here, we present a general and efficient route to obtain ensemble properties of protein condensates in the macroscopic limit from finite-sized nucleation simulations. The approach is based on a theoretical description of droplet nucleation in the canonical ensemble and enables estimating thermodynamic and kinetic parameters, such as the macroscopic equilibrium density of the dilute protein phase, the condensates surface tension and nucleation free energy barriers. We apply the method to coarse-grained simulations of NDDX4 and FUS-LC, two phase-separating disordered proteins with different physicochemical characteristics. Our results show that NDDX4 condensate droplets, characterised by lower surface tension, higher solubility, and faster monomer exchange dynamics than FUS-LC, form with negligible nucleation barriers. In contrast, FUS-LC condensates form via an activated process over a wide range of concentrations.Abstract FigureGraphical Table of Contents.
A simple approach for image-based modelling of the heart that enables robust simulation of highly heterogeneous electrical excitation
Authors: Colman Michael A , Benson Alan P 
Published: November 2022

AbstractRemodelling of cardiac tissue structure, including intercellular electrical coupling, is a major determinant of the complex and heterogeneous excitation patterns associated with cardiac arrhythmias. Evaluation of the precise mechanisms by which local tissue structure determines global arrhythmic excitation patterns is a major challenge that may be critically important for the development of effective treatment strategies. Computational modelling is a key tool in the study of cardiac arrhythmias, yet the established approaches for organ-scale modelling are unsuitable to capture the impact of local conduction heterogeneities; a novel approach is required to provide this multi-scale mechanistic insight.We present a fundamentally simple yet powerful approach to simulate electrical excitation in highly heterogeneous whole-heart models that exploits the underlying discreteness of the myocardium. Preliminary simulations demonstrate that this approach can capture lower conduction velocities and reproduce wave breakdown and the development of re-entry in conditions where the established approaches cannot.
VarSCAT: A computational tool for sequence context annotations of genomic variants
Authors: Wang Ning , Khan Sofia , Elo Laura L. 
Published: November 2022

AbstractThe sequence contexts of genomic variants play important roles in understanding biological significances of variants and potential sequencing related variant calling issues. However, methods for assessing the diverse sequence contexts of genomic variants such as tandem repeats and unambiguous annotations have been limited. Herein, we describe the Variant Sequence Context Annotation Tool (VarSCAT) for annotating the sequence contexts of genomic variants, including breakpoint ambiguities, flanking sequences, variant nomenclatures, adjacent variants, and tandem repeats with user customizable options. Our analysis demonstrate that VarSCAT is more versatile and customizable than current methods or strategies for annotating variants in short tandem repeat (STR) regions. Variant sequence context annotations of high-confidence human variant sets with VarSCAT revealed that more than 75% of all human individual germline and clinically relevant insertions and deletions (indels) have breakpoint ambiguities. Moreover, we illustrate that more than 80% of human individual germline small variants in STR regions are indels and that the sizes of these indels correlated with STR motif sizes. VarSCAT is available athttps://github.com/elolab/VarSCAT.Author SummaryThe sequence contexts have significant impacts on the biological and technical aspects of genomic variants. The sequence contexts, such as tandem repeats or nearby indels, may increase the mutation rate of a region compared to other genome regions. Besides, variants in specific sequence contexts like STRs may also have distinguished biological consequences, which can lead to certain human diseases and thus they may be used as biomarkers for disease diagnosis and treatments. Moreover, potential ambiguous variant representations such as equivalent or redundant indels are also related with their sequence contexts, which may complicate variant harmonization from different sources. Our previous study demonstrated that more than half of false positive indel calls detected through next generation sequencing data are related with STRs. Thus, the sequence contexts of genomic variants are important and cannot be ignored. However, the current methods or strategies for assessing the sequence contexts of genomic variants are limited and not feasible to use. Here, we developed a computational tool VarSCAT for sequence contexts annotation of genomic variants. Our tool provides diverse sequence contexts annotations providing users information to further explore the variants of their interests. By applying VarSCAT to high confidence human variant sets, we demonstrate the influence of sequence context of genomic variants and emphasize the importance of sequence context assessment.
Extinction drives a discontinuous temporal pattern of species-area relationships in a microbial microcosm system
Authors: Deng Wei , Li Na , Zhang Chao-Zhi , An Rui , Yang Xiao-Yan , Xiao Wen 
Published: November 2022

AbstractThe species area relationship (SAR) can be a general law in ecology only if its formation mechanisms are clarified. Essentially, the SAR addresses the relationship between regional area and biodiversity, which is shaped by processes of speciation, extinction and dispersal. Since those three processes has temporal dynamics, we propose the hypothesis that the occurrence of SAR should also have temporal dynamics. Here, we designed independent closed microcosm systems, in which dispersal/speciation can be excluded/neglected, to reveal the role of extinction in shaping the temporal dynamics pattern of SAR. We find that extinction can shape SAR in this system independently. Due to the temporal dynamics of the extinction, SAR was temporally discontinuous. We also observe that small-scale extinctions modified community structure to promote ecosystem stability and shaped SAR, while mass extinction pushed the microcosm system into the next successional stage and dismissed SAR. Our result suggested that SAR could serve as an indicator of ecosystem stability; moreover, temporal discontinuity can be the explaination for many controversies in SAR studies.