bluuebunny/crossref_metadata_2025 huggingface dataset:
Agreement Between Predicted and Actual Measured Ablation Depth After FS-LASIK Using Different Rotating Scheimpflug Cameras and OCT
Authors: Chen Hao , Wang Ziqian , Li Kunke , Wang Yiran , Li Xin , Du Lan , Lin Meimin , Savini Giacomo , Wang Qinmei , Yu Ayong , Chen Sisi
Published: May 2022

Purpose

To compare the predicted ablation depth (AD) with the postoperatively measured corneal ablation depth (postop-AD) at central, paracentral, and midperipheral locations using two rotating Scheimpflug analyzers and a Fourier-domain optical coherence tomographer in eyes that underwent femtosecond laser-assisted LASIK (FS-LASIK).

Methods

The values of corneal thickness were measured preoperatively and postoperatively at one and three months. The difference between preoperative and postoperative was defined as postop-AD. Measurements were performed at the corneal vertex and mid-peripheral area. The mid-peripheral corneal thickness was measured at the superior, inferior, nasal, and temporal locations at a distance of 1.0 or 2.5 mm from the corneal vertex. The predicted AD was calculated by ORK-CAM software (Schwind eye tech-solutions GmbH, Kleinostheim, Germany), and the difference between the predicted AD and postop-AD was defined as Δ-AD. Paired t-test analysis was employed to evaluate the differences, agreement was assessed by the Bland-Altman method.

Results

Forty-two eyes of 42 patients were investigated. At one month, the predicted AD in the central and paracentral areas was underestimated by the Pentacam HR (Oculus, Wetzlar, Germany), Sirius (Costruzione Strumenti Oftalmici, Florence, Italy) and RTVue OCT (Optovue Inc., Freemont, CA, United States), whereas Δ-AD was negative as established by all devices and predominantly statistically significant. The Δ-AD values approximated zero at three months. The mean difference of Δ-AD at three months at the corneal vertex was 0.67 ± 9.39 mm, −7.92 ± 9.05 mm and −1.36 ± 8.31 mm, respectively. The mid-peripheral measurements had positive values at one month and even more highly positive at three months (with statistically significant differences in most of the cases). The agreement between the predicted and postop-AD was moderate with all devices, but slightly better with RTVue.

Conclusion

The predicted AD seems to be underestimated in the central and paracentral corneal area and overestimated in the mid-periphery.

Translational Relevance

The study could help to partly explain and prevent the refractive errors after FS-LASIK.
SIRT2 Promotes HBV Transcription and Replication by Targeting Transcription Factor p53 to Increase the Activities of HBV Enhancers and Promoters
Authors: Wu Dai-Qing , Ding Qiu-Ying , Tao Na-Na , Tan Ming , Zhang Yuan , Li Fan , Zhou Yu-Jiao , Dong Mei-Ling , Cheng Sheng-Tao , Ren Fang , Chen Juan , Ren Ji-Hua
Published: May 2022

Chronic hepatitis B (CHB) virus infection is one of the leading causes of cirrhosis and liver cancer. Although the major drugs against CHB including nucleos(t)ide analogs and PEG-interferon can effectively control human hepatitis B virus (HBV) infection, complete cure of HBV infection is quite rare. Targeting host factors involved in the viral life cycle contributes to developing innovative therapeutic strategies to improve HBV clearance. In this study, we found that the mRNA and protein levels of SIRT2, a class III histone deacetylase, were significantly upregulated in CHB patients, and that SIRT2 protein level was positively correlated with HBV viral load, HBsAg/HBeAg levels, HBcrAg, and ALT/AST levels. Functional analysis confirmed that ectopic SIRT2 overexpression markedly increased total HBV RNAs, 3.5-kb RNA and HBV core DNA in HBV-infected HepG2-Na+/taurocholate cotransporting polypeptide cells and primary human hepatocytes. In contrast, SIRT2 silencing inhibited HBV transcription and replication. In addition, we found a positive correlation between SIRT2 expression and HBV RNAs synthesis as well as HBV covalently closed circular DNA transcriptional activity. A mechanistic study suggested that SIRT2 enhances the activities of HBV enhancer I/HBx promoter (EnI/Xp) and enhancer II/HBc promoter (EnII/Cp) by targeting the transcription factor p53. The levels of HBV EnI/Xp and EnII/Cp-bound p53 were modulated by SIRT2. Both the mutation of p53 binding sites in EnI/Xp and EnII/Cp as well as overexpression of p53 abolished the effect of SIRT2 on HBV transcription and replication. In conclusion, our study reveals that, in terms of host factors, a SIRT2-targeted program might be a more effective therapeutic strategy for HBV infection.
Metagenomic Analysis Reveals Changes in Bacterial Communities and Antibiotic Resistance Genes in an Eye Specialty Hospital and a General Hospital Before and After Wastewater Treatment
Authors: Ma Xueli , Dong Xu , Cai Jiabei , Fu Chunyan , Yang Jing , Liu Yuan , Zhang Yan , Wan Tian , Lin Shudan , Lou Yongliang , Zheng Meiqin
Published: May 2022

The spread of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in hospital wastewater poses a great threat to public health, and wastewater treatment plants (WWTPs) play an important role in reducing the levels of ARB and ARGs. In this study, high-throughput metagenomic sequencing was used to analyze the bacterial community composition and ARGs in two hospitals exposed to different antibiotic use conditions (an eye specialty hospital and a general hospital) before and after wastewater treatment. The results showed that there were various potential pathogenic bacteria in the hospital wastewater, and the abundance and diversity of the influent ARGs in the general hospital were higher than those in the eye hospital. The influent of the eye hospital was mainly composed of Thauera and Pseudomonas, and sul1 (sulfonamide) was the most abundant ARG. The influent of the general hospital contained mainly Aeromonas and Acinetobacter, and tet39 (tetracycline) was the most abundant ARG. Furthermore, co-occurrence network analysis showed that the main bacteria carrying ARGs in hospital wastewater varied with hospital type; the same bacteria in wastewater from different hospitals could carry different ARGs, and the same ARG could also be carried by different bacteria. The changes in the bacterial community and ARG abundance in the effluent from the two hospitals showed that the activated sludge treatment and the direct chlorination disinfection can effectively remove some bacteria and ARGs in wastewater but have limitations. The species diversity increased significantly after the activated sludge treatment, while the direct chlorination disinfection did not increase the diversity. The activated sludge treatment has a better effect on the elimination of ARGs than the direct chlorination disinfection. In summary, we investigated the differences in bacterial communities and ARGs in wastewater from two hospitals exposed to different antibiotic usage conditions, evaluated the effects of different wastewater treatment methods on the bacterial communities and ARGs in hospital wastewater, and recommended appropriate methods for certain clinical environments.
Microbial Community Analysis and Food Safety Practice Survey-Based Hazard Identification and Risk Assessment for Controlled Environment Hydroponic/Aquaponic Farming Systems
Authors: Dong Mengyi , Feng Hao
Published: May 2022

Hydroponic and aquaponic farming is becoming increasingly popular as a solution to address global food security. Plants in hydroponic systems are grown hydroponically under controlled environments and are considered to have fewer food safety concerns than traditional field farming. However, hydroponics and aquaponics might have very different sources of microbial food safety risks that remain under-examined. In this study, we investigated the microbiomes, microbial hazards, and potential bacterial transmission routes inside two commercial hydroponic and aquaponic farming systems using 16S-ITS-23S rRNA sequencing and a hydroponic food safety practice survey. The hydroponic farming system microbiome was analyzed from the fresh produce, nutrient solution, tools, and farmworkers. Proteobacteria, Actinobacteria, Cyanobacteria, Bacteroidetes, and Firmicutes were the main components of hydroponic/aquaponic farming systems, with Pseudomonas being the most abundant genus in fresh produce samples. We further identified the presence of multiple spoilage bacteria and potential human, plant, and fish pathogens at the subspecies level. Spoilage Pseudomonas spp. and spoilage Clostridium spp. were abundant in the hydroponic microgreen farm and aquaponic lettuce farm, respectively. Moreover, we demonstrated the mapping of Escherichia coli 16s-ITS-23s rRNA sequence reads (∼2,500 bp) to small or large subunit rRNA databases and whole-genome databases to confirm pathogenicity and showed the potential of using 16s-ITS-23s rRNA sequencing for pathogen identification. With the SourceTracker and overlapping amplicon sequence variants, we predicted the bidirectional transmission route between plants and the surrounding environment and constructed the bacteria transmission map, which can be implemented in future food safety risk control plans.
Genome-Wide Mutant Screening in Yeast Reveals that the Cell Wall is a First Shield to Discriminate Light From Heavy Lanthanides
Authors: Grosjean Nicolas , Le Jean Marie , Chalot Michel , Mora-Montes Héctor M. , Armengaud Jean , Gross Elisabeth M. , Blaudez Damien
Published: May 2022

The rapidly expanding utilization of lanthanides (Ln) for the development of new technologies, green energies, and agriculture has raised concerns regarding their impacts on the environment and human health. The absence of characterization of the underlying cellular and molecular mechanisms regarding their toxicity is a caveat in the apprehension of their environmental impacts. We performed genomic phenotyping and molecular physiology analyses of Saccharomyces cerevisiae mutants exposed to La and Yb to uncover genes and pathways affecting Ln resistance and toxicity. Ln responses strongly differed from well-known transition metal and from common responses mediated by oxidative compounds. Shared response pathways to La and Yb exposure were associated to lipid metabolism, ion homeostasis, vesicular trafficking, and endocytosis, which represents a putative way of entry for Ln. Cell wall organization and related signaling pathways allowed for the discrimination of light and heavy Ln. Mutants in cell wall integrity-related proteins (e.g., Kre1p, Kre6p) or in the activation of secretory pathway and cell wall proteins (e.g., Kex2p, Kex1p) were resistant to Yb but sensitive to La. Exposure of WT yeast to the serine protease inhibitor tosyl phenylalanyl chloromethyl ketone mimicked the phenotype of kex2∆ under Ln, strengthening these results. Our data also suggest that the relative proportions of chitin and phosphomannan could modulate the proportion of functional groups (phosphates and carboxylates) to which La and Yb could differentially bind. Moreover, we showed that kex2∆, kex1∆, kre1∆, and kre6∆ strains were all sensitive to light Ln (La to Eu), while being increasingly resistant to heavier Ln. Finally, shotgun proteomic analyses identified modulated proteins in kex2∆ exposed to Ln, among which several plasmalemma ion transporters that were less abundant and that could play a role in Yb uptake. By combining these different approaches, we unraveled that cell wall components not only act in Ln adsorption but are also active signal effectors allowing cells to differentiate light and heavy Ln. This work paves the way for future investigations to the better understanding of Ln toxicity in higher eukaryotes.
Stirred Yogurt as a Delivery Matrix for Freeze-Dried Microcapsules of Synbiotic EVOO Nanoemulsion and Nanocomposite
Authors: El-Sayed Hoda S. , Youssef Khamis , Hashim Ayat F.
Published: May 2022

Nowadays, dairy products are considered a good matrix to deliver many functional substances either vital oils or probiotic cells. Two models of microcapsules were produced from co-encapsulation of extra virgin olive oil (EVOO) nanoemulsion or nanocomposite and synbiotic bacteria (maltodextrin with Lactobacillus acidophilus and Bifidobacterium bifidum) using the freeze-drying technique. These models of microcapsules were added to stirred yogurt, and then its storage effect on microbiology, chemically, and sensory properties were evaluated for 21 days. The average droplet size and zeta potential distribution of EVOO nanoemulsion and nanocomposite were investigated. Also, oxidative stability, microencapsulation efficiency, release profile, and antioxidant activity were studied. The results showed that the average particle size of EVOO nanoemulsion and nanocomposite ranged between 416 and 475 nm, while zeta potential was −39.6 and −33.6 mV, respectively. The induction period of EVOO extracted from nanoemulsion and nanocomposite microcapsules models was 11.30 and 8 h. The microencapsulation efficiency of probiotic and EVOO was determined at 88.84 and 65.61% for the nanoemulsion microcapsules model, while the nanocomposite microcapsules model showed 98.49 and 72%. The two models of microcapsules have boosted the viability of probiotic bacteria inside stirred yogurt than free cells. Also, the presence of microcapsules did not affect the viability of stirred yogurt starter cultures, and high values for the total solid and protein were detected. Therefore, the results recommended that stirred yogurt is a good delivery carrier for highly antioxidant and healthy microcapsules of synbiotic EVOO nanoemulsion and nanocomposite.
The Role of the Thioredoxin Detoxification System in Cancer Progression and Resistance
Authors: Jovanović Mirna , Podolski-Renić Ana , Krasavin Mikhail , Pešić Milica
Published: May 2022

The intracellular redox homeostasis is a dynamic balancing system between the levels of free radical species and antioxidant enzymes and small molecules at the core of cellular defense mechanisms. The thioredoxin (Trx) system is an important detoxification system regulating the redox milieu. This system is one of the key regulators of cells’ proliferative potential as well, through the reduction of key proteins. Increased oxidative stress characterizes highly proliferative, metabolically hyperactive cancer cells, which are forced to mobilize antioxidant enzymes to balance the increase in free radical concentration and prevent irreversible damage and cell death. Components of the Trx system are involved in high-rate proliferation and activation of pro-survival mechanisms in cancer cells, particularly those facing increased oxidative stress. This review addresses the importance of the targetable redox-regulating Trx system in tumor progression, as well as in detoxification and protection of cancer cells from oxidative stress and drug-induced cytotoxicity. It also discusses the cancer cells’ counteracting mechanisms to the Trx system inhibition and presents several inhibitors of the Trx system as prospective candidates for cytostatics’ adjuvants. This manuscript further emphasizes the importance of developing novel multitarget therapies encompassing the Trx system inhibition to overcome cancer treatment limitations.
Brain Functional Alterations in Prepubertal Boys With Autism Spectrum Disorders
Authors: Yue Xipeng , Zhang Ge , Li Xiaochen , Shen Yu , Wei Wei , Bai Yan , Luo Yu , Wei Huanhuan , Li Ziqiang , Zhang Xianchang , Wang Meiyun
Published: May 2022

Objectives

Abnormal brain function in ASD patients changes dynamically across developmental stages. However, no one has studied the brain function of prepubertal children with ASD. Prepuberty is an important stage for children’s socialization. This study aimed to investigate alterations in local spontaneous brain activity in prepubertal boys with ASD.

Materials and Methods

Measures of the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) acquired from resting-state functional magnetic resonance imaging (RS-fMRI) database, including 34 boys with ASD and 49 typically developing (TD) boys aged 7 to 10 years, were used to detect regional brain activity. Pearson correlation analyses were conducted on the relationship between abnormal ALFF and ReHo values and Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R) scores.

Results

In the ASD group, we found decreased ALFF in the left inferior parietal lobule (IPL) and decreased ReHo in the left lingual gyrus (LG), left superior temporal gyrus (STG), left middle occipital gyrus (MOG), and right cuneus (p < 0.05, FDR correction). There were negative correlations between ReHo values in the left LG and left STG and the ADOS social affect score and a negative correlation between ReHo values in the left STG and the calibrated severity total ADOS score.

Conclusion

Brain regions with functional abnormalities, including the left IPL, left LG, left STG, left MOG, and right cuneus may be crucial in the neuropathology of prepubertal boys with ASD. Furthermore, ReHo abnormalities in the left LG and left STG were correlated with sociality. These results will supplement the study of neural mechanisms in ASD at different developmental stages, and be helpful in exploring the neural mechanisms of prepubertal boys with ASD.
Chronic Consumption of Cranberries (Vaccinium macrocarpon) for 12 Weeks Improves Episodic Memory and Regional Brain Perfusion in Healthy Older Adults: A Randomised, Placebo-Controlled, Parallel-Groups Feasibility Study
Authors: Flanagan Emma , Cameron Donnie , Sobhan Rashed , Wong Chloe , Pontifex Matthew G. , Tosi Nicole , Mena Pedro , Del Rio Daniele , Sami Saber , Narbad Arjan , Müller Michael , Hornberger Michael , Vauzour David
Published: May 2022

Background

Ageing is highly associated with cognitive decline and modifiable risk factors such as diet are believed to protect against this process. Specific dietary components and in particular, (poly)phenol-rich fruits such as berries have been increasingly recognised for their protection against age-related neurodegeneration. However, the impact of cranberries on cognitive function and neural functioning in older adults remains unclear.

Design

A 12-week parallel randomised placebo-controlled trial of freeze-dried cranberry powder was conducted in 60 older adults aged between 50 and 80 years. Cognitive assessment, including memory and executive function, neuroimaging and blood sample collection were conducted before and after the intervention to assess the impact of daily cranberry consumption on cognition, brain function and biomarkers of neuronal signalling.

Results

Cranberry supplementation for 12 weeks was associated with improvements in visual episodic memory in aged participants when compared to placebo. Mechanisms of action may include increased regional perfusion in the right entorhinal cortex, the accumbens area and the caudate in the cranberry group. Significant decrease in low-density lipoprotein (LDL) cholesterol during the course of the intervention was also observed. No significant differences were, however, detected for BDNF levels between groups.

Conclusions

The results of this study indicate that daily cranberry supplementation (equivalent to 1 small cup of cranberries) over a 12-week period improves episodic memory performance and neural functioning, providing a basis for future investigations to determine efficacy in the context of neurological disease. This trial was registered at clinicaltrials.gov as NCT03679533 and at ISRCTN as ISRCTN76069316.
Integrated Analysis Reveals the Targets and Mechanisms in Immunosuppressive Effect of Mesalazine on Ulcerative Colitis
Authors: Li Rong , Huang Xue , Yang Lu , Liang Xiao , Huang Wenjun , Lai Keng Po , Zhou Liming
Published: May 2022

Background

Ulcerative colitis (UC) is an inflammatory bowel disease that causes inflammation and ulcers in the digestive tract. Approximately 3 million US adults suffer from this disease. Mesalazine, an anti-inflammatory agent, is commonly used for the treatment of UC. However, some studies have demonstrated side effects of mesalazine, such as acute pancreatitis and hypereosinophilia. Therefore, a better understanding of the anti-inflammatory mechanism of mesalazine in UC could help improve the effectiveness of the drug and reduce its side effects. In this study, we used a dextran sodium sulfate-induced UC mouse model, and applied network pharmacology and omics bioinformatics approaches to uncover the potential pharmaceutical targets and the anti-inflammatory mechanism of mesalazine.

Results

Network pharmacology analysis identified the core targets of mesalazine, biological processes, and cell signaling related to immunity and inflammatory responses mediated by mesalazine. Molecular docking analysis then indicated possible binding motifs on the core targets (including TNF-α, PTGS2, IL-1β, and EGFR). Metabolomics and 16S metagenomic analyses highlighted the correlation between gut microbiota and metabolite changes caused by mesalazine in the UC model.

Conclusions

Collectively, the omics and bioinformatics approaches and the experimental data unveiled the detailed molecular mechanisms of mesalazine in UC treatment, functional regulation of the gut immune system, and reduction of intestinal inflammation. More importantly, the identified core targets could be targeted for the treatment of UC.
Nutritional Status and Other Clinical Variables Are Associated to the Resting Energy Expenditure in Patients With Chronic Kidney Disease: A Validity Study
Authors: Ramos-Acevedo Samuel , Rodríguez-Gómez Luis , López-Cisneros Sonia , González-Ortiz Ailema , Espinosa-Cuevas Ángeles
Published: May 2022

Background

Estimating energy requirements (ER) is crucial for nutritional attention to chronic kidney disease (CKD) patients. Current guidelines recommend measuring ER with indirect calorimetry (IC) when possible. Due to clinical settings, the use of simple formulas is preferred. Few studies have modeled equations for estimating ER for CKD. Nevertheless, variables of interest such as nutritional status and strength have not been explored in these models. This study aimed to develop and validate a model for estimating REE in patients with CKD stages 3–5, who were not receiving renal replacement therapy (RTT), using clinical variables and comparing it with indirect calorimetry as the gold standard.

Methods

In this study 80 patients with CKD participated. Indirect calorimetry (IC) was performed in all patients. The calorimeter analyzed metabolic measurements every minute for 15 min after autocalibration with barometric pressure, temperature, and humidity. Bioelectrical Impedance Analysis (BIA) was performed. Fat-free mass (FFM) was registered among other bioelectrical components. Handgrip strength (HGS) was evaluated and an average of 3 repetitions was recorded. Nutritional status was assessed with the subjective global assessment (SGA). Patients categorized as B or C were then considered as having malnutrition.

Results

We analyzed 71 patients and 3 models were generated. Model 1a included FFM; Model 2a included weight; Model 3c included handgrip strength (HGS). All other variables were stepwise, computer-selected with a p < 0.01 significance level; Malnutrition was consistently associated with ER among other clinical variables in all models (p < 0.05). The model that included BIA-FFM had R2adjusted = 0.46, while the model that included weight (Kg) had an adjusted R2adjusted = 0.44. The models had moderate concordance, LC = 0.60–0.65 with the gold standard, whereas other energy expenditure estimation equations had LC = 0.36 and 0.55 with indirect calorimetry. Using these previously validated equations as a reference, our models had concordance values ranging from 0.66 to 0.80 with them.

Conclusion

Models incorporating nutritional status and other clinical variables such as weight, FFM, comorbidities, gender, and age have a moderate agreement with REE. The agreement between our models and others previously validated for the CKD patient is good; however, the agreement between the latter and IC measurements is moderate. The KDOQI lowest recommendation (25 Kcals/kg body weight) considering the 22% difference with respect to the IC for total energy expenditure rather than for REE.
Prediction Breast Molecular Typing of Invasive Ductal Carcinoma Based on Dynamic Contrast Enhancement Magnetic Resonance Imaging Radiomics Characteristics: A Feasibility Study
Authors: Xu Aqiao , Chu Xiufeng , Zhang Shengjian , Zheng Jing , Shi Dabao , Lv Shasha , Li Feng , Weng Xiaobo
Published: May 2022

Objective

To investigate the feasibility of radiomics in predicting molecular subtype of breast invasive ductal carcinoma (IDC) based on dynamic contrast enhancement magnetic resonance imaging (DCE-MRI).

Methods

A total of 303 cases with pathologically confirmed IDC from January 2018 to March 2021 were enrolled in this study, including 223 cases from Fudan University Shanghai Cancer Center (training/test set) and 80 cases from Shaoxing Central Hospital (validation set). All the cases were classified as HR+/Luminal, HER2-enriched, and TNBC according to immunohistochemistry. DCE-MRI original images were treated by semi-automated segmentation to initially extract original and wavelet-transformed radiomic features. The extended logistic regression with least absolute shrinkage and selection operator (LASSO) penalty was applied to identify the optimal radiomic features, which were then used to establish predictive models combined with significant clinical risk factors. Receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis were adopted to evaluate the effectiveness and clinical benefit of the models established.

Results

Of the 223 cases from Fudan University Shanghai Cancer Center, HR+/Luminal cancers were diagnosed in 116 cases (52.02%), HER2-enriched in 71 cases (31.84%), and TNBC in 36 cases (16.14%). Based on the training set, 788 radiomic features were extracted in total and 8 optimal features were further identified, including 2 first-order features, 1 gray-level run length matrix (GLRLM), 4 gray-level co-occurrence matrices (GLCM), and 1 3D shape feature. Three multi-class classification models were constructed by extended logistic regression: clinical model (age, menopause, tumor location, Ki-67, histological grade, and lymph node metastasis), radiomic model, and combined model. The macro-average areas under the ROC curve (macro-AUC) for the three models were 0.71, 0.81, and 0.84 in the training set, 0.73, 0.81, and 0.84 in the test set, and 0.76, 0.82, and 0.83 in the validation set, respectively.

Conclusion

The DCE-MRI-based radiomic features are significant biomarkers for distinguishing molecular subtypes of breast cancer noninvasively. Notably, the classification performance could be improved with the fusion analysis of multi-modal features.
A Radiomics Model Based on Gd-EOB-DTPA-Enhanced MRI for the Prediction of Microvascular Invasion in Solitary Hepatocellular Carcinoma ≤ 5 cm
Authors: Qu Chengming , Wang Qiang , Li Changfeng , Xie Qiao , Cai Ping , Yan Xiaochu , Sparrelid Ernesto , Zhang Leida , Ma Kuansheng , Brismar Torkel B.
Published: May 2022

Aim

The aim of this study is to establish and validate a radiomics-based model using preoperative Gd-EOB-DTPA-enhanced MRI to predict microvascular invasion (MVI) in patients with hepatocellular carcinoma ≤ 5 cm.

Methods

Clinicopathologic and MRI data of 178 patients with solitary hepatocellular carcinoma (HCC) (≤5 cm) were retrospectively collected from a single medical center between May 2017 and November 2020. Patients were randomly assigned into training and test subsets by a ratio of 7:3. Imaging features were extracted from the segmented tumor volume of interest with 1-cm expansion on arterial phase (AP) and hepatobiliary phase (HBP) images. Different models based on the significant clinical risk factors and/or selected imaging features were established and the predictive performance of the models was evaluated.

Results

Three radiomics models, the AP_model, the HBP_model, and the AP+HBP_model, were constructed for MVI prediction. Among them, the AP+HBP_model outperformed the other two. When it was combined with a clinical model, consisting of tumor size and alpha-fetoprotein (AFP), the combined model (AP+HBP+Clin_model) showed an area under the curve of 0.90 and 0.70 in the training and test subsets, respectively. Its sensitivity and specificity were 0.91 and 0.76 in the training subset and 0.60 and 0.79 in the test subset, respectively. The calibration curve illustrated that the combined model possessed a good agreement between the predicted and the actual probabilities.

Conclusions

The radiomics-based model combining imaging features from the arterial and hepatobiliary phases of Gd-EOB-DTPA-enhanced MRI and clinical risk factors provides an effective and reliable tool for the preoperative prediction of MVI in patients with HCC ≤ 5 cm.
Real-World Therapy Management and Outcomes of First-Line Axitinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma in the United States
Authors: Zakharia Yousef , Thomaidou Despina , Li Benjamin , Siu Gordon , Levin Rebecca , Vlahiotis Anna , Rao Dharanija , Zanotti Giovanni
Published: May 2022

Background

Combination axitinib plus pembrolizumab is a standard of care in the first-line treatment of patients with advanced clear cell renal cell carcinoma (RCC). This analysis describes the clinical characteristics, treatment management and outcomes of patients receiving first-line (1L) axitinib plus pembrolizumab in a real-world US setting.

Methods

Electronic health record (EHR)-derived data from the Flatiron Health Database, which includes ~280 cancer clinics across 800 sites in the US, were used. Patients had confirmed Stage IV or metastatic RCC and initiated 1L axitinib plus pembrolizumab on or after 1/1/2018 to 3/31/2021. Outcomes were best overall response rate; real-world progression-free survival (rwPFS) and overall survival (OS) at landmark time periods (3, 6, 9, and 12 months). Therapy management (TM) included dose hold, dose change and discontinuation. Data are reported as medians (IQR) unless otherwise noted.

Results

355 patients received 1L axitinib plus pembrolizumab, with median follow-up of 9.7 (0.1–24.3) months. IMDC Risk Score was favorable, intermediate, and poor in 27 (7.6%), 126 (35.5%), and 76 (21.4%) patients, respectively (23.4% intermediate/poor, 12.1% unknown). 270 patients (76.1%) received only 1L axitinib plus pembrolizumab and 85 patients (24.3%) received ≥1 subsequent line of treatment; cabozantinib was the most frequent subsequent line of treatment (47.9%). rwPFS at 3 months and 1 year was 77.2% and 39.3%, respectively. OS ranged from 90.8% at 3 months to 73.5% at 1 year. Best overall response rate was 47.9%. Toxicity was the most common reason for first TM events of dose hold, change and discontinuation at, 58.6%, 58.5%, and 45.8%, respectively. Over 80% of patients with TM were able to continue with 1L axitinib plus pembrolizumab.

Conclusions

In a real-world setting, axitinib plus pembrolizumab was effective as a 1L treatment for patients with advanced RCC. Dose holds, changes and discontinuation were driven by treatment-related toxicity. Dose holds may represent an effective TM strategy to toxicity.
Targeting the Tumor Microenvironment: A Close Up of Tumor-Associated Macrophages and Neutrophils
Authors: Russo Massimo , Nastasi Claudia
Published: May 2022

The importance of the tumor microenvironment (TME) in dynamically regulating cancer progression and influencing the therapeutic outcome is widely accepted and appreciated. Several therapeutic strategies to modify or modulate the TME, like angiogenesis or immune checkpoint inhibitors, showed clinical efficacy and received approval from regulatory authorities. Within recent decades, new promising strategies targeting myeloid cells have been implemented in preclinical cancer models. The predominance of specific cell phenotypes in the TME has been attributed to pro- or anti-tumoral. Hence, their modulation can, in turn, alter the responses to standard-of-care treatments, making them more or less effective. Here, we summarize and discuss the current knowledge and the correlated challenges about the tumor-associated macrophages and neutrophils targeting strategies, current treatments, and future developments.
A Systematic Framework for Identifying Prognostic Genes in the Tumor Microenvironment of Colon Cancer
Authors: Liu Jinyang , Lan Yu , Tian Geng , Yang Jialiang
Published: May 2022

As one of the most common cancers of the digestive system, colon cancer is a predominant cause of cancer-related deaths worldwide. To investigate prognostic genes in the tumor microenvironment of colon cancer, we collected 461 colon adenocarcinoma (COAD) and 172 rectal adenocarcinoma (READ) samples from The Cancer Genome Atlas (TCGA) database, and calculated the stromal and immune scores of each sample. We demonstrated that stromal and immune scores were significantly associated with colon cancer stages. By analyzing differentially expressed genes (DEGs) between two stromal and immune score groups, we identified 952 common DEGs. The significantly enriched Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms for these DEGs were associated with T-cell activation, immune receptor activity, and cytokine–cytokine receptor interaction. Through univariate Cox regression analysis, we identified 22 prognostic genes. Furthermore, nine key prognostic genes, namely, HOXC8, SRPX, CCL22, CD72, IGLON5, SERPING1, PCOLCE2, FABP4, and ARL4C, were identified using the LASSO Cox regression analysis. The risk score of each sample was calculated using the gene expression of the nine genes. Patients with high-risk scores had a poorer prognosis than those with low-risk scores. The prognostic model established with the nine-gene signature was able to effectively predict the outcome of colon cancer patients. Our findings may help in the clinical decisions and improve the prognosis for colon cancer.
Management of Children With Food-Induced Anaphylaxis: A Cross-Sectional Survey of Parental Knowledge, Attitude, and Practices
Authors: Polloni Laura , Baldi Ileana , Amadi Margherita , Tonazzo Valentina , Bonaguro Roberta , Lazzarotto Francesca , Toniolo Alice , Gregori Dario , Muraro Antonella
Published: May 2022

Background

Anaphylaxis is a life-threatening event, but it is frequently undertreated in pediatric patients with food allergies. Previous studies showed that auto-injectable adrenaline (AAI) is underused by patients and parents. This is especially troubling since fatal anaphylaxis has been associated with delayed adrenaline administration.

Objectives

This study aimed to investigate parental practice and knowledge in anaphylaxis management, and perceived barriers and facilitators in using AAI.

Results

A retrospective survey was completed by 75 parents (41 mothers, 34 fathers) of children with food allergy and AAI prescription attending the Food Allergy Referral Center of Veneto, Italy. Results showed poor parental preparedness and reluctance to use AAI despite a high/moderate self-rated knowledge (median total score of 23–min. 3, max. 30). Most parents (77%) declared they were carrying AAI but only 20% used it in case of a severe reaction. Most reported Fear/Fear of making mistakes (46 parents) and Concern about possible side effects as barriers (35), while Poor knowledge of the correct AAI use (1) and Lack of knowledge/ incorrect assessment of symptoms (2) were reported less frequently. Theoretical-practical courses for parents on AAI use (65), Psycho-education/Psychological support (3) for better dealing with the emotional aspects of anaphylaxis and Written instructions (1) have been suggested as main facilitators.

Conclusion

Understanding parents' experience and perspective on managing anaphylaxis is crucial to implement effective educational programs. A multidisciplinary approach should be considered.
Ethical Considerations in Ever-Expanding Utilization of ECLS: A Research Agenda
Authors: Clark Jonna D. , Baden Harris P. , Berkman Emily R. , Bourget Erica , Brogan Thomas V. , Di Gennaro Jane L. , Doorenbos Ardith Z. , McMullan D. Michael , Roberts Joan S. , Turnbull Jessica M. , Wilfond Benjamin S. , Lewis-Newby Mithya ,   Seattle Ethics in ECLS (SEE) Consortium
Published: May 2022

Technological advancements and rapid expansion in the clinical use of extracorporeal life support (ECLS) across all age ranges in the last decade, including during the COVID-19 pandemic, has led to important ethical considerations. As a costly and resource intensive therapy, ECLS is used emergently under high stakes circumstances where there is often prognostic uncertainty and risk for serious complications. To develop a research agenda to further characterize and address these ethical dilemmas, a working group of specialists in ECLS, critical care, cardiothoracic surgery, palliative care, and bioethics convened at a single pediatric academic institution over the course of 18 months. Using an iterative consensus process, research questions were selected based on: (1) frequency, (2) uniqueness to ECLS, (3) urgency, (4) feasibility to study, and (5) potential to improve patient care. Questions were categorized into broad domains of societal decision-making, bedside decision-making, patient and family communication, medical team dynamics, and research design and implementation. A deeper exploration of these ethical dilemmas through formalized research and deliberation may improve equitable access and quality of ECLS-related medical care.
Structural and Functional Characterization of a Novel Scorpion Toxin that Inhibits NaV1.8 via Interactions With the DI Voltage Sensor and DII Pore Module
Authors: George Kiran , Lopez-Mateos Diego , Abd El-Aziz Tarek Mohamed , Xiao Yucheng , Kline Jake , Bao Hong , Raza Syed , Stockand James D. , Cummins Theodore R. , Fornelli Luca , Rowe Matthew P. , Yarov-Yarovoy Vladimir , Rowe Ashlee H.
Published: May 2022

Voltage-gated sodium channel NaV1.8 regulates transmission of pain signals to the brain. While NaV1.8 has the potential to serve as a drug target, the molecular mechanisms that shape NaV1.8 gating are not completely understood, particularly mechanisms that couple activation to inactivation. Interactions between toxin producing animals and their predators provide a novel approach for investigating NaV structure-function relationships. Arizona bark scorpions produce Na+ channel toxins that initiate pain signaling. However, in predatory grasshopper mice, toxins inhibit NaV1.8 currents and block pain signals. A screen of synthetic peptide toxins predicted from bark scorpion venom showed that peptide NaTx36 inhibited Na+ current recorded from a recombinant grasshopper mouse NaV1.8 channel (OtNaV1.8). Toxin NaTx36 hyperpolarized OtNaV1.8 activation, steady-state fast inactivation, and slow inactivation. Mutagenesis revealed that the first gating charge in the domain I (DI) S4 voltage sensor and an acidic amino acid (E) in the DII SS2 – S6 pore loop are critical for the inhibitory effects of NaTx36. Computational modeling showed that a DI S1 – S2 asparagine (N) stabilizes the NaTx36 – OtNaV1.8 complex while residues in the DI S3 – S4 linker and S4 voltage sensor form electrostatic interactions that allow a toxin glutamine (Q) to contact the first S4 gating charge. Surprisingly, the models predicted that NaTx36 contacts amino acids in the DII S5 – SS1 pore loop instead of the SS2 – S6 loop; the DII SS2 – S6 loop motif (QVSE) alters the conformation of the DII S5 – SS1 pore loop, enhancing allosteric interactions between toxin and the DII S5 – SS1 pore loop. Few toxins have been identified that modify NaV1.8 gating. Moreover, few toxins have been described that modify sodium channel gating via the DI S4 voltage sensor. Thus, NaTx36 and OtNaV1.8 provide tools for investigating the structure-activity relationship between channel activation and inactivation gating, and the connection to alternative pain phenotypes.
Treatment of Refractory/High-Risk Pregnancies With Antiphospholipid Syndrome: A Systematic Review of the Literature
Authors: Hoxha Ariela , Tormene Daniela , Campello Elena , Simioni Paolo
Published: May 2022

Different treatment protocols have been employed to manage heparin/low-dose aspirin refractory or high-risk pregnancies in antiphospholipid antibody syndrome (APS) pregnancies. A systematic review of the literature on additional treatments used in refractory and/or high-risk APS pregnancies was conducted. Records from February 2006 to October 2021 were retrieved from PubMed, Web of Science, Cochrane, and the www.clinicaltrials.gov platform. Twenty-one studies met our eligibility criteria. Live birth rate is this study’s primary endpoint, while pregnancy complications and adverse events are secondary endpoints. A total of 434 pregnancies, 162 (37.3%) refractory and 272 (62.7%) high-risk/refractory pregnancies, were included. Both IVIG <2 gr/kg/monthly/HCQ/LDS and PEX/IA ± LDS led to 100% viable infants in refractory APS. Furthermore, HCQ 200–400 mg showed a higher live birth rate than HCQ + LDS (88.6% vs. 82.7%). Following treatment protocol with HCQ 200–400 mg and IVIG <2 gr/kg/monthly/HCQ/LDS, pregnancy complications rates of 16.7 and 83.3% were registered, respectively. Pravastatin 20 mg, IA weekly + IVIG 2 gr/monthly, and PEX weekly + IVIg 2 gr/kg/monthly showed higher live birth rates in high-risk APS pregnancies of 100, 100 and 92%, respectively, whereas the lower severe pregnancy complications were reported in pregnancies treated with PEX weekly + IVIg 2 gr/kg/monthly (11.1%). One (0.6%) case of dermatitis during treatment with HCQ was observed. The results of this study showed that HCQ 200–400 mg and PEX weekly + IVIG 2 gr/kg/monthly achieved a higher live birth rate in refractory APS and high-risk/refractory APS, respectively. The results presented provide clinicians with up-to-date knowledge in the management of APS pregnancies according to risk stratification.
A Candidate Drug Screen Strategy: The Discovery of Oroxylin A in Scutellariae Radix Against Sepsis via the Correlation Analysis Between Plant Metabolomics and Pharmacodynamics
Authors: Han Lingyu , Yuan Yue , Chen Xinyi , Huang Jian , Wang Guan , Zhou Chao , Dong Jianjian , Zhang Na , Zhang Yuxin , Yin Hang , Jiang Yunyao
Published: May 2022

Sepsis is an acute systemic infectious disease with high mortality, which urgently needs more effective treatment. Scutellariae radix (SR), a commonly used traditional Chinese medicine (TCM) for clearing heat and detoxification, contains rich natural products possessing anti-inflammatory activity. In previous studies, it was found that the anti-inflammatory activities of SR extracts from different ecological conditions varied wildly. Based on this, in the present study, a screening strategy of antisepsis active components from SR based on correlation analysis between plant metabolomics and pharmacodynamics was established, and the mechanism was explored. First of all, a mass spectrum database of SR (above 240 components) was established to lay the foundation for the identification of plant metabolomics by liquid chromatography tandem mass spectrometry (LC–MS/MS). Through the correlation analysis between plant metabolomics and anti-inflammatory activity of SR from different ecology regions, 10 potential components with high correlation coefficients were preliminarily screened out. After the evaluation of anti-inflammatory activity and toxicity at the cellular level, the pharmacodynamic evaluation in vivo found that oroxylin A had the potentiality of antisepsis both in LPS- and CLP-induced endotoxemia mice. Network pharmacology and Western blot (WB) results indicated that oroxylin A significantly inhibited the toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway, which was further confirmed by secreted embryonic alkaline phosphatase (SEAP) assay. Moreover, the molecular docking analysis indicated that oroxylin A might competitively inhibit LPS binding to myeloid differentiation 2 (MD-2) to block the activation of TLR4. The study provided a feasible research strategy for the screening and discovery of antisepsis candidate drugs from TCM.
Innate Immunity at the Core of Sex Differences in Osteoarthritic Pain?
Authors: Valdrighi Natália , Vago Juliana P. , Blom Arjen B. , Loo Fons A.J. van de , Blaney Davidson Esmeralda N.
Published: May 2022

Osteoarthritis (OA) is a progressive whole-joint disease; no disease-modifying drugs are currently available to stop or slow its process. Symptoms alleviation is the only treatment option. OA is the major cause of chronic pain in adults, with pain being the main symptom driving patients to seek medical help. OA pathophysiology is closely associated with the innate immune system, which is also closely linked to pain mediators leading to joint pain. Pain research has shown sex differences in the biology of pain, including sexually dimorphic responses from key cell types in the innate immune system. Not only is OA more prevalent in women than in men, but women patients also show worse OA outcomes, partially due to experiencing more pain symptoms despite having similar levels of structural damage. The cause of sex differences in OA and OA pain is poorly understood. This review provides an overview of the involvement of innate immunity in OA pain in joints and in the dorsal root ganglion. We summarize the emerging evidence of sex differences regarding innate immunity in OA pain. Our main goal with this review was to provide a scientific foundation for future research leading to alternative pain relief therapies targeting innate immunity that consider sex differences. This will ultimately lead to a more effective treatment of pain in both women and men.
Pharmacist-Urologist Collaborative Management Improves Clinical Outcomes in Patients With Castration-Resistant Prostate Cancer Receiving Enzalutamide
Authors: Hirabatake Masaki , Ikesue Hiroaki , Iwama Yuna , Irie Kei , Yoshino Shintaro , Yamasaki Toshinari , Hashida Tohru , Kawakita Mutsushi , Muroi Nobuyuki
Published: May 2022

Background: Enzalutamide is useful for the treatment of castration-resistant prostate cancer (CRPC). Despite its usefulness, adverse events (AEs) sometimes force patients to discontinue treatment. To maximize patient care, we developed an ambulatory care pharmacy practice that allows collaboration between a pharmacist and urologist to manage patients with CRPC receiving enzalutamide. In this study, we investigated the efficacy of this collaborative management.

Methods: A retrospective chart review of 103 patients with CRPC receiving enzalutamide in our hospital between May 2014 and December 2020 was performed. Our collaborative management was implemented in October 2016. Before being examined by urologists, patients visited the oncology pharmacy consultation room for a face-to-face consultation, wherein the oncology pharmacists assessed factors such as adherence to enzalutamide, any AEs and their grades, and provided their suggestions to the urologists. The time to enzalutamide discontinuation and prostate-specific antigen progression were compared between patients who started enzalutamide before (n = 41) and after (n = 62) the implementation of the collaborative management. A multivariate Cox regression analysis was performed to analyze the factors associated with enzalutamide discontinuation.

Results: After implementing collaborative management, the pharmacists had 881 patient consultations. Among the 476 suggestions from pharmacists, 345 were accepted by urologists. The most frequent suggestion was supportive care in enzalutamide treatment (224 suggestions). Multivariate analysis showed that collaborative management [hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.31–0.89, p = 0.017] and higher prostate-specific antigen (PSA; HR 2.41, 95% CI 1.36–4.28, p = 0.003) were significantly associated with enzalutamide discontinuation. The median time to discontinuation (18.9 vs. 7.6 months, p = 0.012), time to discontinuation due to AEs (not reached in both groups, p = 0.001), and time to PSA progression (13.3 vs. 5.8 months, p = 0.002) were all significantly longer in the after group.

Conclusions: We implemented a pharmacist-urologist collaborative management program for outpatients with CRPC receiving enzalutamide. The results revealed that collaborative management was useful for prolonging the time to enzalutamide discontinuation.