bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunomodulating Therapies in Acute Myocarditis and Recurrent/Acute Pericarditis
Authors: Ammirati Enrico , Bizzi Emanuele , Veronese Giacomo , Groh Matthieu , Van de Heyning Caroline M. , Lehtonen Jukka , Pineton de Chambrun Marc , Cereda Alberto , Picchi Chiara , Trotta Lucia , Moslehi Javid J. , Brucato Antonio
Published: March 2022

The field of inflammatory disease of the heart or “cardio-immunology” is rapidly evolving due to the wider use of non-invasive diagnostic tools able to detect and monitor myocardial inflammation. In acute myocarditis, recent data on the use of immunomodulating therapies have been reported both in the setting of systemic autoimmune disorders and in the setting of isolated forms, especially in patients with specific histology (e.g., eosinophilic myocarditis) or with an arrhythmicburden. A role for immunosuppressive therapies has been also shown in severe cases of coronavirus disease 2019 (COVID-19), a condition that can be associated with cardiac injury and acute myocarditis. Furthermore, ongoing clinical trials are assessing the role of high dosage methylprednisolone in the context of acute myocarditis complicated by heart failure or fulminant presentation or the role of anakinra to treat patients with acute myocarditis excluding patients with hemodynamically unstable conditions. In addition, the explosion of immune-mediated therapies in oncology has introduced new pathophysiological entities, such as immune-checkpoint inhibitor-associated myocarditis and new basic research models to understand the interaction between the cardiac and immune systems. Here we provide a broad overview of evolving areas in cardio-immunology. We summarize the use of new imaging tools in combination with endomyocardial biopsy and laboratory parameters such as high sensitivity troponin to monitor the response to immunomodulating therapies based on recent evidence and clinical experience. Concerning pericarditis, the normal composition of pericardial fluid has been recently elucidated, allowing to assess the actual presence of inflammation; indeed, normal pericardial fluid is rich in nucleated cells, protein, albumin, LDH, at levels consistent with inflammatory exudates in other biological fluids. Importantly, recent findings showed how innate immunity plays a pivotal role in the pathogenesis of recurrent pericarditis with raised C-reactive protein, with inflammasome and IL-1 overproduction as drivers for systemic inflammatory response. In the era of tailored medicine, anti-IL-1 agents such as anakinra and rilonacept have been demonstrated highly effective in patients with recurrent pericarditis associated with an inflammatory phenotype.
DOK2 Has Prognostic and Immunologic Significance in Adults With Acute Myeloid Leukemia: A Novel Immune-Related Therapeutic Target
Authors: Xu Jiaxuan , Dong Xiaoqing , Wang Ruoyi , Chen Bing
Published: March 2022

Background

The role of downstream tyrosine kinase 2 (DOK2), a major member of the DOK family, remains poorly defined in acute myeloid leukemia (AML). Herein, we investigated the expression levels, clinical outcomes, and biological functions of DOK2 in patients with AML.

Methods

Datasets were obtained from the Cancer Genome Atlas (TCGA) database for transcriptomic and clinical information. Nomogram construction and assessment were conducted using Cox regression analysis, receiver operating characteristic (ROC) curves, and calibration plots. Public databases, including the Gene Expression Omnibus, Cancer Cell Line Encyclopedia, LinkedOmics, GeneMANIA, TISIDB, and Gene Set Cancer Analysis, were employed for relevant bioinformatic studies. Moreover, we utilized the CIBERSORT algorithm to evaluate the level of infiltration of immune cells into the bone marrow microenvironment.

Results

We observed that DOK2 transcription levels were markedly upregulated in AML samples (P < 0.001), and its high expression was associated with inferior overall survival (OS) (HR = 2.17, P < 0.001) and disease-free survival (DFS) (HR = 2.50, P < 0.001). ROC curve analysis also showed the reliable diagnostic efficiency of DOK2 in AML. For treatment regimens, patients with high DOK2 expression could significantly prolong OS by receiving hematopoietic stem cell transplantation (HSCT) (P < 0.001), whereas those with low DOK2 expression were more likely to improve DFS by chemotherapy alone rather than HSCT. Nomograms constructed for predicting OS and DFS exhibited satisfactory discrimination and accuracy. Functional enrichment analysis identified that DOK2 was involved in important pathways associated with immune-related activities. Furthermore, CIBERSORT scores reflected negative correlations of DOK2 with activated mast cells and resting CD4+ memory T cells, which indicated its adverse immunomodulatory potential.

Conclusion

We suggest that elevated DOK2 expression could be an unfavorable prognostic indicator of survival in patients with AML. Our findings provide new insights into the role of DOK2 in AML, with promising clinical implications.
Rectal Colonization and Nosocomial Transmission of Carbapenem-Resistant Acinetobacter baumannii in an Intensive Care Unit, Southwest Nigeria
Authors: Odih Erkison Ewomazino , Irek Emmanuel Oladayo , Obadare Temitope O. , Oaikhena Anderson O. , Afolayan Ayorinde O. , Underwood Anthony , Adenekan Anthony T. , Ogunleye Veronica O. , Argimon Silvia , Dalsgaard Anders , Aanensen David M. , Okeke Iruka N. , Aboderin A. Oladipo
Published: March 2022

Background

Acinetobacter baumannii are of major human health importance because they cause life-threatening nosocomial infections and often are highly resistant to antimicrobials. Specific multidrug-resistant A. baumannii lineages are implicated in hospital outbreaks globally. We retrospectively investigated a suspected outbreak of carbapenem-resistant A. baumannii (CRAB) colonizing patients in an intensive care unit (ICU) of a tertiary hospital in Southwest Nigeria where genomic surveillance of Acinetobacter has hitherto not been conducted.

Methods

A prospective observational study was conducted among all patients admitted to the ICU between August 2017 and June 2018. Acinetobacter species were isolated from rectal swabs and verified phenotypically with the Biomerieux Vitek 2 system. Whole genome sequencing (WGS) was performed on the Illumina platform to characterize isolates from a suspected outbreak during the study period. Phylogenetic analysis, multilocus sequence typing, and antimicrobial resistance gene prediction were carried out in silico.

Results

Acinetobacter isolates belonging to the A. baumannii complex were recovered from 20 (18.5%) ICU patients. Single nucleotide polymorphism (SNP) analysis and epidemiological information revealed a putative outbreak clone comprising seven CRAB strains belonging to the globally disseminated international clone (IC) 2. These isolates had ≤2 SNP differences, identical antimicrobial resistance and virulence genes, and were all ST1114/1841.

Conclusion

We report a carbapenem-resistant IC2 A. baumannii clone causing an outbreak in an ICU in Nigeria. The study findings underscore the need to strengthen the capacity to detect A. baumannii in human clinical samples in Nigeria and assess which interventions can effectively mitigate CRAB transmission in Nigerian hospital settings.
Indian Polyvalent Antivenom Accelerates Recovery From Venom-Induced Consumption Coagulopathy (VICC) in Sri Lankan Russell’s Viper (Daboia russelii) Envenoming
Authors: Silva Anjana , Scorgie Fiona E. , Lincz Lisa F. , Maduwage Kalana , Siribaddana Sisira , Isbister Geoffrey K.
Published: March 2022

Background

Venom-induced consumption coagulopathy (VICC) is an important clinical consequence of Russell’s viper (Daboia russelii) envenoming. There is limited evidence for antivenom effectiveness in resolving VICC. We aimed to compare the recovery of VICC in patients who received and did not receive antivenom following Russell’s viper envenoming.

Patients and Methods

This was a non-randomized observational study comparing patients with VICC from Russell’s viper envenoming given antivenom for systemic envenoming and those not given antivenom. Antivenom administration was decided by the treating physicians. We included 44 patients with confirmed Russell’s viper bites with one or more International Normalized Ratio (INR) value ≥ 1.5 (VICC). We compared five patients who did not receive antivenom with 39 patients who did receive antivenom. The primary outcome was the proportion of patients with an INR < 1.5 by 48 h post-bite.

Results

The antivenom group had higher peak serum venom concentrations [median (IQR) = 272 (96–1,076) ng/mL versus 21 (8–58) ng/mL] and more severe VICC compared to the no antivenom group. Twenty seven of 39 patients (69%) in the antivenom group had an INR < 1.5 at 48 h post-bite compared to none of the five patients (0%) in the no antivenom group (absolute difference: 69%; 95%CI: 13 to 83%; p = 0.006; Fisher’s exact test). The fibrinogen recovered in 32 of 39 patients (82%) in the antivenom group compared to one of five patients (20%) in the no antivenom group (absolute difference 62%; 95% CI: 28 to 95%; p = 0.001; Fisher’s exact test). Both INR and fibrinogen were significantly improved between 24 and 48 h post-bite in the antivenom group compared to the no antivenom group.

Conclusion

Antivenom accelerated the recovery of VICC in patients with Russell’s viper envenoming, compared to no recovery in a smaller group of patients with milder VICC not receiving antivenom. This supports the efficacy of antivenom in patients with VICC.
Performance of Chimeric Trypanosoma cruzi Antigens in Serological Screening for Chagas Disease in Blood Banks
Authors: Santos Emily Ferreira dos , Silva Ângelo Antônio Oliveira , Freitas Natália Erdens Maron , Leony Leonardo Maia , Daltro Ramona Tavares , Santos Carlos Antônio de Souza Teles , Almeida Maria da Conceição Chagas de , Araújo Fernando Luiz Vieira de , Celedon Paola Alejandra Fiorani , Krieger Marco Aurélio , Zanchin Nilson Ivo Tonin , Reis Mitermayer Galvão dos , Santos Fred Luciano Neves
Published: March 2022

Chagas disease (CD) is among the top 10 causes of inability to blood donation. Blood donation centers screen for anti-Trypanosoma cruzi antibodies using highly sensitive immunoenzymatic (ELISA) or chemiluminescent methods, which can lead to false positive results. Since positive samples cannot be used, to avoid the loss of valuable blood donations, it is necessary to improve specificity without reducing the sensitivity of the tests used for blood screening. For this purpose, our group has developed four chimeric proteins (IBMP-8.1, IBMP-8.2, IBMP-8.3, and IBMP-8.4) that have been evaluated in phase I and II studies with high performance and low cross-reactivity rates. The study included a panel of 5,014 serum samples collected from volunteer blood donors at the Hematology and Hemotherapy Foundation of the State of Bahia (Brazil). They were subjected to the detection of anti-T. cruzi antibodies, using all four IBMP antigens individually and latent class analysis (LCA) as a reference test, since there is no gold standard test for this purpose. Considering the sample size analyzed, LCA classified 4,993 (99.6%) samples as T. cruzi-negative and 21 (0.42%) as T. cruzi-positive. Sensitivity values ranged from 85.71% for IBMP-8.1 and 90.48% for IBMP-8.2–95.24% for IBMP-8.3 and 100% for IBMP-8.4, while specificity ranged from 99.98% for IBMP-8.3 and IBMP-8.4–100% for IBMP-8.1 and IBMP-8.2. Accuracy values ranged from 99.4 to 99.98%. The pretest probability for the molecules was 0.42, whereas the positive posttest probability ranged from 95.24 to 99.95% and the negative posttest probability ranged from 0.00001 to 0.0006% for all antigens. The higher odds ratio diagnosis was found for IBMP-8.4, which has been shown to be a safe single antigen for serological screening of CD in blood samples. The use of chimeric IBMP antigens is an alternative to reduce the number of bags discarded due to false-positive results. These molecules have high diagnostic performance and were shown to be suitable for use in screening CD in blood banks, isolated (IBMP-8.4) or in combination; and their use in blood banks could significantly reduce unnecessary disposal of blood bags or the risk of T. cruzi transmission.
Characterization of Vegetative Incompatibility in Morchella importuna and Location of the Related-Genes by Bulk Segregant Analysis
Authors: Chai Hongmei , Liu Ping , Ma Yuanhao , Chen Weimin , Tao Nan , Zhao Yongchang
Published: March 2022

Vegetative incompatibility (VI) is a widespread phenomenon developed in Morchella importuna, a species of ascomycete fungus that is cultivated on a rapidly expanding scale in China. Understanding the genetic bases of this nonself-recognition phenomenon is beneficial for resolving some problems that are associated with the production of this highly prized edible fungus, such as crossbreeding, strain classification, and pathogen transmission. VI is genetically controlled by het genes, organized in two different systems, namely allelic and nonallelic. These het genes have been well characterized in Podospora anserina and Neurospora crassa. In this work, putative het-homologs were identified in the genome of M. importuna, but their low allelic polymorphism in different vegetative compatibility groups (VCGs) suggested that VI in this fungus might not be regulated by these het genes. The progeny derived from vegetative compatible parents became a VCG, while the single-ascospore strains from vegetative incompatible parents were divided into four VCGs, and the interaction between the inter-group strains led to the formation of two types of barrages, viz., thin dark line and raised aggregate of hyphae. The Bulk Segregant Analysis confirmed that the genes mimpvic32 and mimpvic33 were linked to VI reactions in M. importuna; nevertheless, the formation of barrages also occurred between the pairs carrying the same allele of these two genes. In sum, the VI control system in M. importuna was complicated, and there were more other allelic or non-allelic VI-related genes.
Microbe-Mediated Thermotolerance in Plants and Pertinent Mechanisms- A Meta-Analysis and Review
Authors: Dastogeer Khondoker M. G. , Zahan Mst. I. , Rhaman Mohammad S. , Sarker Mohammad S. A. , Chakraborty Anindita
Published: March 2022

Microbial symbionts can mediate plant stress responses by enhancing thermal tolerance, but less attention has been paid to measuring these effects across plant-microbe studies. We performed a meta-analysis of published studies as well as discussed with relevant literature to determine how the symbionts influence plant responses under non-stressed versus thermal-stressed conditions. As compared to non-inoculated plants, inoculated plants had significantly higher biomass and photosynthesis under heat stress conditions. A significantly decreased accumulation of malondialdehyde (MDA) and hydrogen peroxide (H2O2) indicated a lower oxidation level in the colonized plants, which was also correlated with the higher activity of catalase, peroxidase, glutathione reductase enzymes due to microbial colonization under heat stress. However, the activity of superoxide dismutase, ascorbate oxidase, ascorbate peroxidase, and proline were variable. Our meta-analysis revealed that microbial colonization influenced plant growth and physiology, but their effects were more noticeable when their host plants were exposed to high-temperature stress than when they grew under ambient temperature conditions. We discussed the mechanisms of microbial conferred plant thermotolerance, including at the molecular level based on the available literature. Further, we highlighted and proposed future directions toward exploring the effects of symbionts on the heat tolerances of plants for their implications in sustainable agricultural production.
Selectivity and Sociality: Aggression and Affiliation Shape Vole Social Relationships
Authors: Lee Nicole S. , Beery Annaliese K.
Published: March 2022

The formation of selective social relationships is not a requirement of group living; sociality can be supported by motivation for social interaction in the absence of preferences for specific individuals, and by tolerance in place of social motivation. For species that form selective social relationships, these can be maintained by preference for familiar partners, as well as by avoidance of or aggression toward individuals outside of the social bond. In this review, we explore the roles that aggression, motivation, and tolerance play in the maintenance of selective affiliation. We focus on prairie voles (Microtus ochrogaster) and meadow voles (Microtus pennsylvanicus) as rodent species that both exhibit the unusual tendency to form selective social relationships, but differ with regard to mating system. These species provide an opportunity to investigate the mechanisms that underlie social relationships, and to compare mechanisms supporting pair bonds with mates and same-sex peer relationships. We then relate this to the role of aggression in group composition in a comparative context.
MicroCT Can Characterize Clots Retrieved With Mechanical Thrombectomy From Acute Ischemic Stroke Patients–A Preliminary Report
Authors: Dumitriu LaGrange Daniela , Braunersreuther Vincent , Wanke Isabel , Berberat Jatta , Luthman Siri , Fitzgerald Seán , Doyle Karen M. , Brina Olivier , Reymond Philippe , Platon Alexandra , Muster Michel , Machi Paolo , Poletti Pierre-Alexandre , Vargas Maria Isabel , Lövblad Karl-Olof
Published: March 2022

Background

Characterization of the clot occluding the arteries in acute ischemic stroke received ample attention, in terms of elucidating the relationship between the clot composition, its etiology and its amenability for pharmacological treatment and mechanical thrombectomy approaches. Traditional analytical techniques such as conventional 2D histopathology or electron microscopy sample only small parts of the clot. Visualization and analysis in 3D are necessary to depict and comprehend the overall organization of the clot. The aim of this study is to investigate the potential of microCT for characterizing the clot composition, structure, and organization.

Methods

In a pilot study, we analyzed with microCT clots retrieved from 14 patients with acute ischemic stroke. The following parameters were analyzed: overall clot density, clot segmentation with various density thresholds, clot volume.

Results

Our findings show that human clots are heterogeneous in terms of CT intra-clot density distribution. After fixation in formalin, the clots display a shift toward negative values. On average, we found the mean HU values of red clots retrieved from patients to be −153 HU, with SD = 23.8 HU, for the intermediate clots retrieved from patients −193 HU, SD = 23.7 HU, and for the white clots retrieved from patients −229 HU, SD = 64.8 HU.

Conclusion

Our study shows that volumetric and density analysis of the clot opens new perspectives for clot characterization and for a better understanding of thrombus structure and composition.
Foreign Language Learning in Older Adults: Anatomical and Cognitive Markers of Vocabulary Learning Success
Authors: Fong Manson Cheuk-Man , Ma Matthew King-Hang , Chui Jeremy Yin To , Law Tammy Sheung Ting , Hui Nga-Yan , Au Alma , Wang William Shiyuan
Published: March 2022

In recent years, foreign language learning (FLL) has been proposed as a possible cognitive intervention for older adults. However, the brain network and cognitive functions underlying FLL has remained largely unconfirmed in older adults. In particular, older and younger adults have markedly different cognitive profile—while older adults tend to exhibit decline in most cognitive domains, their semantic memory usually remains intact. As such, older adults may engage the semantic functions to a larger extent than the other cognitive functions traditionally considered the most important (e.g., working memory capacity and phonological awareness). Using anatomical measurements and a cognitive test battery, the present study examined this hypothesis in twenty cognitively normal older adults (58–69 years old), who participated in a two-month Italian learning programme. Results showed that the immediate learning success and long-term retention of Italian vocabularies were most consistently predicted by the anatomical measures of the left pars orbitalis and left caudal middle frontal cortex, which are implicated in semantic and episodic memory functions. Convergent evidence was also found based on the pattern of cognitive associations. Our results are consistent with a prominent role of semantic and episodic memory functions in vocabulary learning in older learners.
Open Frontiers in Neural Cell Type Investigations; Lessons From Caenorhabditis elegans and Beyond, Toward a Multimodal Integration
Authors: Rapti Georgia
Published: March 2022

Nervous system cells, the building blocks of circuits, have been studied with ever-progressing resolution, yet neural circuits appear still resistant to schemes of reductionist classification. Due to their sheer numbers, complexity and diversity, their systematic study requires concrete classifications that can serve reduced dimensionality, reproducibility, and information integration. Conventional hierarchical schemes transformed through the history of neuroscience by prioritizing criteria of morphology, (electro)physiological activity, molecular content, and circuit function, influenced by prevailing methodologies of the time. Since the molecular biology revolution and the recent advents in transcriptomics, molecular profiling gains ground toward the classification of neurons and glial cell types. Yet, transcriptomics entails technical challenges and more importantly uncovers unforeseen spatiotemporal heterogeneity, in complex and simpler nervous systems. Cells change states dynamically in space and time, in response to stimuli or throughout their developmental trajectory. Mapping cell type and state heterogeneity uncovers uncharted terrains in neurons and especially in glial cell biology, that remains understudied in many aspects. Examining neurons and glial cells from the perspectives of molecular neuroscience, physiology, development and evolution highlights the advantage of multifaceted classification schemes. Among the amalgam of models contributing to neuroscience research, Caenorhabditis elegans combines nervous system anatomy, lineage, connectivity and molecular content, all mapped at single-cell resolution, and can provide valuable insights for the workflow and challenges of the multimodal integration of cell type features. This review reflects on concepts and practices of neuron and glial cells classification and how research, in C. elegans and beyond, guides nervous system experimentation through integrated multidimensional schemes. It highlights underlying principles, emerging themes, and open frontiers in the study of nervous system development, regulatory logic and evolution. It proposes unified platforms to allow integrated annotation of large-scale datasets, gene-function studies, published or unpublished findings and community feedback. Neuroscience is moving fast toward interdisciplinary, high-throughput approaches for combined mapping of the morphology, physiology, connectivity, molecular function, and the integration of information in multifaceted schemes. A closer look in mapped neural circuits and understudied terrains offers insights for the best implementation of these approaches.
Alteration in Functional Magnetic Resonance Imaging Signal Complexity Across Multiple Time Scales in Patients With Migraine Without Aura
Authors: Wang Xiao , Zhang Yutong , Qi Wenchuan , Xu Tao , Wang Ziwen , Liao Huaqiang , Wang Yanan , Liu Jie , Yu Yang , He Zhenxi , Gao Shan , Li Dehua , Zhang Guilin , Zhao Ling
Published: March 2022

Background

Migraine is a primary neurological disorder associated with complex brain activity. Recently, mounting evidence has suggested that migraine is underpinned by aberrant dynamic brain activity characterized by linear and non-linear changes across a variety of time scales. However, the abnormal dynamic brain activity at different time scales is still unknown in patients with migraine without aura (MWoA). This study aimed to assess the altered patterns of brain activity dynamics over different time scales and the potential pathophysiological mechanisms of alterations in patients with MWoA.

Methods

Multiscale entropy in 50 patients and 20 healthy controls (HCs) was calculated to investigate the patterns and altered brain complexity (BC) across five different time scales. Spearman rank correlation analysis between BC in regions showing significant intergroup differences and clinical scores (i.e., frequency of migraine attacks, duration, headache impact test) was conducted in patients with MWoA.

Results

The spatial distribution of BC varied across different time scales. At time scale1, BC was higher in the posterior default mode network (DMN) across participants. Compared with HCs, patients with MWoA had higher BC in the DMN and sensorimotor network. At time scale2, BC was mainly higher in the anterior DMN across participants. Patients with MWoA had higher BC in the sensorimotor network. At time scale3, BC was mainly higher in the frontoparietal network across participants. Patients with MWoA had increased BC in the parietal gyrus. At time scale4, BC is mainly higher in the sensorimotor network. Patients with MWoA had higher BC in the postcentral gyrus. At time scale5, BC was mainly higher in the DMN. Patients with MWoA had lower BC in the posterior DMN. In particular, BC values in the precuneus and paracentral lobule significantly correlated with clinical symptoms.

Conclusion

Migraine is associated with alterations in dynamic brain activity in the sensorimotor network and DMN over multiple time scales. Time-varying BC within these regions could be linked to instability in pain transmission and modulation. Our findings provide new evidence for the hypothesis of abnormal dynamic brain activity in migraine.
Bio-Mimicking, Electrical Excitability Phenomena Associated With Synthetic Macromolecular Systems: A Brief Review With Connections to the Cytoskeleton and Membraneless Organelles
Authors: Wnek Gary E. , Costa Alberto C. S. , Kozawa Susan K.
Published: March 2022

Electrical excitability of cells, tissues and organs is a fundamental phenomenon in biology and physiology. Signatures of excitability include transient currents resulting from a constant or varying voltage gradient across compartments. Interestingly, such signatures can be observed with non-biologically-derived, macromolecular systems. Initial key literature, dating to roughly the late 1960’s into the early 1990’s, is reviewed here. We suggest that excitability in response to electrical stimulation is a material phenomenon that is exploited by living organisms, but that is not exclusive to living systems. Furthermore, given the ubiquity of biological hydrogels, we also speculate that excitability in protocells of primordial organisms might have shared some of the same molecular mechanisms seen in non-biological macromolecular systems, and that vestigial traces of such mechanisms may still play important roles in modern organisms’ biological hydrogels. Finally, we also speculate that bio-mimicking excitability of synthetic macromolecular systems might have practical biomedical applications.
The Feasibility of Combining ADC Value With Texture Analysis of T2WI, DWI and CE-T1WI to Preoperatively Predict the Expression Levels of Ki-67 and p53 of Endometrial Carcinoma
Authors: Jiang Xueyan , Jia Haodong , Zhang Zhongyuan , Wei Chao , Wang Chuanbin , Dong Jiangning
Published: March 2022

Purpose

To evaluate the feasibility of apparent diffusion coefficient (ADC) value combined with texture analysis (TA) in preoperatively predicting the expression levels of Ki-67 and p53 in endometrial carcinoma (EC) patients.

Methods

Clinical, pathological and MRI findings of 110 EC patients were analyzed retrospectively. The expression levels of Ki-67 and p53 in EC tissues were detected by immunohistochemistry. ADC value was calculated, and three-dimensional (3D) texture features were measured on T2-weighted images (T2WI), diffusion-weighted images (DWI), and contrast-enhanced T1-weighted images (CE-T1WI). The univariate and multivariate logistic regression and cross-validations were used for the selection of texture features. The receiver operating characteristic (ROC) curve was performed to estimate the diagnostic efficiency of prediction model by the area under the curve (AUC) in the training and validation cohorts.

Results

Significant differences of the ADC values were found in predicting Ki-67 and p53 (P=0.039, P=0.007). The AUC of the ADC value in predicting the expression levels of Ki-67 and p53 were 0.698, 0.853 and 0.626, 0.702 in the training and validation cohorts. The AUC of the TA model based on T2WI, DWI, CE-T1WI, and ADC value combined with T2WI + DWI + CE-T1WI in the training and validation cohorts for predicting the expression of Ki-67 were 0.741, 0.765, 0.733, 0.922 and 0.688, 0.691, 0.651, 0.938, respectively, and for predicting the expression of p53 were 0.763, 0.805, 0.781, 0.901 and 0.796, 0.713, 0.657, 0.922, respectively.

Conclusion

ADC values combined with TA are beneficial for predicting the expression levels of Ki-67 and p53 in EC patients before surgery, and they provide higher auxiliary diagnostic values for clinical application.
A Novel Multimodal Radiomics Model for Predicting Prognosis of Resected Hepatocellular Carcinoma
Authors: He Ying , Hu Bin , Zhu Chengzhan , Xu Wenjian , Ge Yaqiong , Hao Xiwei , Dong Bingzi , Chen Xin , Dong Qian , Zhou Xianjun
Published: March 2022

Objective

To explore a new model to predict the prognosis of liver cancer based on MRI and CT imaging data.

Methods

A retrospective study of 103 patients with histologically proven hepatocellular carcinoma (HCC) was conducted. Patients were randomly divided into training (n = 73) and validation (n = 30) groups. A total of 1,217 radiomics features were extracted from regions of interest on CT and MR images of each patient. Univariate Cox regression, Spearman’s correlation analysis, Pearson’s correlation analysis, and least absolute shrinkage and selection operator Cox analysis were used for feature selection in the training set, multivariate Cox proportional risk models were established to predict disease-free survival (DFS) and overall survival (OS), and the models were validated using validation cohort data. Multimodal radiomics scores, integrating CT and MRI data, were applied, together with clinical risk factors, to construct nomograms for individualized survival assessment, and calibration curves were used to evaluate model consistency. Harrell’s concordance index (C-index) values were calculated to evaluate the prediction performance of the models.

Results

The radiomics score established using CT and MR data was an independent predictor of prognosis (DFS and OS) in patients with HCC (p < 0.05). Prediction models illustrated by nomograms for predicting prognosis in liver cancer were established. Integrated CT and MRI and clinical multimodal data had the best predictive performance in the training and validation cohorts for both DFS [(C-index (95% CI): 0.858 (0.811–0.905) and 0.704 (0.563–0.845), respectively)] and OS [C-index (95% CI): 0.893 (0.846–0.940) and 0.738 (0.575–0.901), respectively]. The calibration curve showed that the multimodal radiomics model provides greater clinical benefits.

Conclusion

Multimodal (MRI/CT) radiomics models can serve as effective visual tools for predicting prognosis in patients with liver cancer. This approach has great potential to improve treatment decisions when applied for preoperative prediction in patients with HCC.
Interest of the Addition of Taxanes to Standard Treatment in First-Line Advanced HER2 Positive Gastroesophageal Adenocarcinoma in Selective Patients
Authors: Orillard Emeline , Henriques Julie , Vernerey Dewi , Almotlak Hamadi , Calcagno Fabien , Fein Francine , Fratté Serge , Jary Marine , Klajer Elodie , Vienot Angelique , Borg Christophe , Kim Stefano
Published: March 2022

Background

Studies have reported a beneficial role of the addition of trastuzumab to platin-5-FU based chemotherapy in first-line advanced HER2 positive gastroesophageal adenocarcinoma (GEA). However, the effect of taxanes combined with platin-5FU + trastuzumab (PFT) is understudied.

Methods

We performed a retrospective cohort study to evaluate the interest of taxanes among HER2-positive advanced GEA patients treated with PFT. We enrolled HER2-positive advanced GEA patients who underwent treatment between January 2009 to March 2021 in seven hospitals centers in France, treated with PFT alone (S group) or with taxanes + PFT regimen (T group). The primary outcome was progression-free survival (PFS). Also, overall survival (OS), response rate, conversion surgery rate, and safety were evaluated.

Results

Overall, 65 patients received PFT-based therapy, 24 patients in the T group, and 41 patients in the S group. To avoid the selection bias, only those patients presenting an ECOG-PS of 0-1 and synchronous metastasis (21 patients in the T group and 19 patients in the S group) were included for analysis. The median PFS was 9.3 months (95%CI 7.0 to 17.2) in the T group and 5.9 months (95%CI 3.7 to 9.6) in the S group (log-rank p=0.038). Treatment by taxanes was significantly associated with a better PFS in univariate (HR 0.49; 95%CI 0.25 to 0.98, p=0.042) and multivariate Cox regression analysis (HR 0.44; 95%CI 0.21 to 0.94, p=0.033), and IPTW method (HR 0.56; 95% CI 0.34 to 0.91, p=0.019). OS was prolonged (19.0 months (95%CI 7.8 to 45.2) vs 13.0 months (95%CI 5.5 to 14.8), log-rank p=0.033) in favor of the T group. Treatment by taxanes was significantly associated with a better OS in univariate Cox regression analysis (HR 0.49; 95%CI 0.21 to 0.96, p=0.038) and IPTW method (HR 0.49; 95% CI 0.29 to 0.84, p=0.009). The response rate was higher in the T group, with conversion surgery in five patients. No treatment-related death was observed in both groups.

Conclusions

Given the improvement in PFS and OS, the addition of taxanes to standard chemotherapy could be considered as a promising treatment for selected HER2-positive advanced GEA patients, with PS 0-1 and synchronous metastasis (NCT04920747).
Dalpiciclib Combined With Pyrotinib and Letrozole in Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (LORDSHIPS): A Phase Ib Study
Authors: Zhang Jian , Meng Yanchun , Wang Biyun , Wang Leiping , Cao Jun , Tao Zhonghua , Li Ting , Yao Wenqing , Hu Xichun
Published: March 2022

Purpose

The LORDSHIPS study aimed to explore the safety and efficacy of a novel fully oral triplet combination of dalpiciclib (a potent cyclin-dependent kinase 4/6 inhibitor), pyrotinib (a HER2 tyrosine kinase inhibitor) and endocrine therapy letrozole in patients with HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) in the front-line setting.

Patients and Methods

Postmenopausal women with HER2-positive, HR-positive MBC were recruited in the dose-finding phase Ib trial. A standard 3 + 3 design was used to determine safety, tolerability, and recommended phase II dose (RP2D) for the combination.

Results

A total of 15 patients were enrolled to three dose combination cohorts (letrozole/pyrotinib/dalpiciclib, level/I: 2.5/400/125 mg, n=5; level/L1: 2.5/400/100 mg, n=6; level/L2: 2.5/320/125 mg, n=4). Three patients experienced dose-limiting toxicities (level/I, n=2; level/L1, n=1) and level/L2 was identified as RP2D. The most frequent grade 3-4 adverse events were neutropenia (46.7%), leukopenia (40.0%), oral mucositis (26.7%) and diarrhea (20.0%). The confirmed objective response rate (ORR) was 66.7% (95% CI: 38.4% to 88.2%). The confirmed ORR of study treatment as first line (1L) and second line (2L) HER2-targeted therapy was 85.7% (6/7) and 50.0% (4/8), respectively. Median progression-free survival (PFS) was 11.3 months (95% CI: 5.3 months to not reached). PFS in 1L setting was not reached yet, while PFS in 2L setting was 10.9 months (95% CI: 1.8 to 13.7 months).

Conclusions

The fully oral combination of dalpiciclib, pyrotinib and letrozole is a promising chemotherapy-sparing treatment option for HER2-positive, HR-positive MBC patients. The planned dose-expansion phase II study is ongoing.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT03772353.
BK002 Induces miR-192-5p-Mediated Apoptosis in Castration-Resistant Prostate Cancer Cells via Modulation of PI3K/CHOP
Authors: Park Moon Nyeo , Park Hyunmin , Rahman Md. Ataur , Kim Jeong Woo , Park Se Sun , Cho Yongmin , Choi Jinwon , Son So-Ri , Jang Dae Sik , Shim Bum-Sang , Kim Sung-Hoon , Ko Seong-Gyu , Cheon Chunhoo , Kim Bonglee
Published: March 2022

BK002 consists of Achyranthes japonica Nakai (AJN) and Melandrium firmum Rohrbach (MFR) that have been used as herbal medicines in China and Korea. AJN and MFR have been reported to have anti-inflammatory, anti-oxidative, and anti-cancer activities, although the synergistic targeting multiple anti-cancer mechanism in castration-resistant prostate cancer (CRPC) has not been well reported. However, the drug resistance and transition to the androgen-independent state of prostate cancer contributing to CRPC is not well studied. Here, we reported that BK002 exerted cytotoxicity and apoptosis in CRPC PC3 cell lines and prostate cancer DU145 cell lines examined by cytotoxicity, western blot, a LIVE/DEAD cell imaging assay, reactive oxygen species (ROS) detection, quantitative real-time polymerase chain reaction (RT-PCR), and transfection assays. The results from our investigation found that BK002 showed more cellular cytotoxicity than AJN and MFR alone, suggesting that BK002 exhibited potential cytotoxic properties. Consistently, BK002 increased DNA damage, and activated p-γH2A.X and depletion of survivin-activated ubiquitination of pro-PARP, caspase9, and caspase3. Notably, live cell imaging using confocal microscopy found that BK002 effectively increased DNA-binding red fluorescent intensity in PC3 and DU145 cells. Also, BK002 increased the anti-proliferative effect with activation of the C/EBP homologous protein (CHOP) and significantly attenuated PI3K/AKT expression. Notably, BK002-treated cells increased ROS generation and co-treatment of N-Acetyl-L-cysteine (NAC), an ROS inhibitor, significantly preventing ROS production and cellular cytotoxicity, suggesting that ROS production is essential for initiating apoptosis in PC3 and DU145 cells. In addition, we found that BK002 significantly enhanced miR-192-5p expression, and co-treatment with BK002 and miR-192-5p inhibitor significantly reduced miR-192-5p expression and cellular viability in PC3 and DU145 cells, indicating modulation of miR-192-5p mediated apoptosis. Finally, we found that BK002-mediated CHOP upregulation and PI3K downregulation were significantly reduced and restrained by miR-192-5p inhibitor respectively, suggesting that the anti-cancer effect of BK002 is associated with the miR-192-5p/PI3K/CHOP pathway. Therefore, our study reveals that a combination of AJN and MFR might be more effective than single treatment against apoptotic activities of both CRPC cells and prostate cancer cells.
Comparison of Treatment Efficacy and Survival Outcomes Between Asian and Western Patients With Unresectable Gastric or Gastro-Esophageal Adenocarcinoma: A Systematic Review and Meta-Analysis
Authors: Zhang Zhening , Liu Zining , Chen Zeyang
Published: March 2022

Background

Gastric cancer and gastro-esophageal adenocarcinoma are geographically heterogeneous diseases. Previous studies suggested that Asian and Western patients with late-stage gastric or gastro-esophageal adenocarcinoma possess distinct survival outcomes. However, the interregional differences of multiple systemic therapies in unresectable diseases have not been comprehensively described.

Materials and Methods

We searched PubMed-MEDLINE, Embase, Web of Science and Cochrane Library from inception to 31 October 2021 and reviewed major conference abstracts for controlled trials of systemic therapies in unresectable gastric or gastro-esophageal adenocarcinoma that reported hazard ratios stratified by geographical region. The primary measurements were overall survival and progression-free survival. The pooled hazard ratios and 95% confidence intervals for overall survival and progression-free survival in Asian and Western populations were calculated using a random effect model. A linear regression model was adopted to compare the overall survival and progression-free survival between Asian and Western patients.

Results

A total of 9033 patients from 20 studies were included for analysis. Immunotherapy was associated with an improvement in the overall survival for both Asian (hazard ratio, 0.80; 95% confidence interval, 0.65–0.98) and Western (hazard ratio, 0.90; 95% confidence interval, 0.81–1.00) patients, with no significant difference between the two groups (P = 0.32). Trends of survival benefit with anti-HER2 therapy and anti-angiogenic therapy versus control were observed in both Asian and Western patients, although statistical significance was not denoted. Subgroup analyses yielded a statistically superior overall survival of Asian versus Western patients in trials that investigated first-line immunotherapy (P = 0.04). Due to the linear regression analyses with scatter plot graphs, Asian patients showed a higher overall survival, but not progression-free survival, than Western patients irrespective of treatment type.

Conclusion

Asian and Western patients with unresectable gastric or gastro-esophageal adenocarcinoma show similar responses to systemic therapies with limited interregional differences. Exceptionally, first-line immunotherapy could elicit superior survival among Asian populations. In addition, Asian patients with gastric or gastro-esophageal adenocarcinoma display a superior OS compared with Western counterparts.
Suppressive Effect of Autocrine FGF21 on Autophagy-Deficient Hepatic Tumorigenesis
Authors: Kim Jinyoung , Lee Soyeon , Lee Myung-Shik
Published: March 2022

Mice with hepatocyte-specific deletion ofautophagy-related 7(Atg7ΔHepmice) develop hepatoma, suggesting that autophagy deficiency could be a factor in the initiation of tumorigenesis. We have shown that FGF21 is induced as a ‘mitokine’ whenAtg7is disrupted in insulin target tissues such as the liver, which could affect systemic metabolism through endocrine activity. Since FGF21 or other endocrine FGF such as FGF19 can affect tumor growth, we hypothesized that FGF21 produced byAtg7-knockout (KO) hepatocytes may affect the behavior ofAtg7-KO hepatoma in an autocrine manner. We, thus, crossedAtg7ΔHepmice with systemicFgf21-KO (Fgf21−/−) mice to generateAtg7ΔHepFgf21−/−mice. The number and size of hepatoma ofAtg7ΔHepmice were significantly increased by additionalFgf21KO. The proliferation ofAtg7-KO hepatocyte was significantly increased byFgf21KO. pYAP1/YAP1 representing YAP1 degradation was significantly decreased in the liver ofAtg7ΔHepFgf21−/−mice compared toAtg7ΔHepFgf21+/+mice. Consistently, expression of YAP1/TAZ downstream genes was significantly increased in the liver ofAtg7ΔHepFgf21−/−mice compared toAtg7ΔHepFgf21+/+mice, which could explain the increased size of hepatoma inAtg7ΔHepFgf21−/−mice. Accumulation of ROS and ROS-mediated DNA damage were increased in the liver ofAtg7ΔHepFgf21+/+mice, which was further aggravated by additionalFgf21KO probably due to the absence of positive effect of FGF21 on mitochondrial function, explaining the increased number of hepatoma inAtg7ΔHepFgf21−/−mice compared toAtg7ΔHepFgf21+/+mice. These results show that FGF21 produced by autophagy-deficient hepatocytes could have autocrine or paracrine effects on the number and proliferation of autophagy-deficient hepatoma, suggesting that hormones or factors released from autophagy-deficient tumors can influence the behavior or prognosis of the tumor in addition to the effects on host metabolism.
Circular RNA circLMO1 Suppresses Cervical Cancer Growth and Metastasis by Triggering miR-4291/ACSL4-Mediated Ferroptosis
Authors: Ou Rongying , Lu Shun , Wang Luhui , Wang Yebo , Lv Mingfen , Li Tian , Xu Yunsheng , Lu Jieqiang , Ge Ren-shan
Published: March 2022

Background

A number of studies have demonstrated that circular RNA (circRNA) plays a critical role in tumorigenesis and tumor progression. However, the biological effects of most circRNAs on cervical cancer remain unclear. Hsa_circ_0021087 (thereafter named circLMO1) is a circRNA generated from the circularization of exon 2 and exon 3 of LIM Domain Only 1 (LMO1) and first identified as a tumor suppressor in gastric cancer. We aimed to identify the role of circLMO1 in cervical cancer progression.

Methods

CircLMO1 was verified through qPCR and Sanger sequencing. The biological role of circLMO1 in regulating cervical cancer growth and metastasis was investigated both in vitro and in the nude mouse xenograft tumor model. The dual luciferase reporter assay and rescue experiment were conducted to evaluate the interactions among circLMO1, microRNA (miR)-4291, and acyl-CoA synthetase long chain family member 4 (ACSL4). The role of circLMO1 in regulating ferroptosis was assessed by analyzing lipid reactive oxygen species (ROS), and malonyl dialdehyde (MDA), and glutathione (GSH) content.

Results

The level of circLMO1 was down-regulated in cervical cancer tissues and was associated with the International Federation of Gynecology and Obstetrics (FIGO) staging. Functionally, circLMO1 overexpression inhibited cervical cancer growth and metastasis both in vitro and in vivo, whereas circLMO1 depletion promoted cervical cancer cell proliferation and invasion. Mechanistically, circLMO1 acted as a competing endogenous RNA (ceRNA) by sponging miR-4192 to repress target gene ACSL4. CircLMO1 promoted cervical cancer cell ferroptosis through up-regulating ACSL4 expression. Overexpression of miR-4291 or knockdown of ACSL4 reversed the effect of circLMO1 on facilitating ferroptosis and repressing cervical cancer cell proliferation and invasion.

Conclusion

CircLMO1 acted as a tumor suppressor of cervical cancer by regulating miR-4291/ACSL4-mediated ferroptosis, and could be a promising biomarker for the clinical management of cervical cancer.
Bidirectional Effect of IFN-γ on Th17 Responses in Experimental Autoimmune Uveitis
Authors: Shao Hui , Kaplan Henry J. , Sun Deming
Published: March 2022

Pro- and ant-inflammatory effects of IFN-γ have been repeatedly found in various immune responses, including cancer and autoimmune diseases. In a previous study we showed that the timing of treatment determines the effect of adenosine-based immunotherapy. In this study we examined the role of IFN-γ in pathogenic Th17 responses in experimental autoimmune uveitis (EAU). We observed that IFN-γ has a bidirectional effect on Th17 responses, when tested bothin vitroandin vivo. Anti-IFN-γ antibody inhibits Th17 responses when applied in the initial phase of the immune response; however, it enhances the Th17 response if administered in a later phase of EAU. In the current study we showed that IFN-γ is an important immunomodulatory molecule in γδ T cell activation, as well as in Th17 responses. These results should advance our understanding of the regulation of Th17 responses in autoimmunity.