bluuebunny/crossref_metadata_2025 huggingface dataset:
Automatic segmentation of white matter hyperintensities in routine clinical brain MRI by 2D VB-Net: A large-scale study
Authors: Zhu Wenhao , Huang Hao , Zhou Yaqi , Shi Feng , Shen Hong , Chen Ran , Hua Rui , Wang Wei , Xu Shabei , Luo Xiang
Published: July 2022

White matter hyperintensities (WMH) are imaging manifestations frequently observed in various neurological disorders, yet the clinical application of WMH quantification is limited. In this study, we designed a series of dedicated WMH labeling protocols and proposed a convolutional neural network named 2D VB-Net for the segmentation of WMH and other coexisting intracranial lesions based on a large dataset of 1,045 subjects across various demographics and multiple scanners using 2D thick-slice protocols that are more commonly applied in clinical practice. Using our labeling pipeline, the Dice consistency of the WMH regions manually depicted by two observers was 0.878, which formed a solid basis for the development and evaluation of the automatic segmentation system. The proposed algorithm outperformed other state-of-the-art methods (uResNet, 3D V-Net and Visual Geometry Group network) in the segmentation of WMH and other coexisting intracranial lesions and was well validated on datasets with thick-slice magnetic resonance (MR) images and the 2017 medical image computing and computer assisted intervention WMH Segmentation Challenge dataset (with thin-slice MR images), all showing excellent effectiveness. Furthermore, our method can subclassify WMH to display the WMH distributions and is very lightweight. Additionally, in terms of correlation to visual rating scores, our algorithm showed excellent consistency with the manual delineations and was overall better than those from other competing methods. In conclusion, we developed an automatic WMH quantification framework for multiple application scenarios, exhibiting a promising future in clinical practice.
Identification of diagnostic signatures associated with immune infiltration in Alzheimer’s disease by integrating bioinformatic analysis and machine-learning strategies
Authors: Tian Yu , Lu Yaoheng , Cao Yuze , Dang Chun , Wang Na , Tian Kuo , Luo Qiqi , Guo Erliang , Luo Shanshun , Wang Lihua , Li Qian
Published: July 2022

Objective

As a chronic neurodegenerative disorder, Alzheimer’s disease (AD) is the most common form of progressive dementia. The purpose of this study was to identify diagnostic signatures of AD and the effect of immune cell infiltration in this pathology.

Methods

The expression profiles of GSE109887, GSE122063, GSE28146, and GSE1297 were downloaded from the Gene Expression Omnibus (GEO) database to obtain differentially expressed genes (DEGs) between AD and control brain samples. Functional enrichment analysis was performed to reveal AD-associated biological functions and key pathways. Besides, we applied the Least Absolute Shrinkage Selection Operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) analysis to screen potential diagnostic feature genes in AD, which were further tested in AD brains of the validation cohort (GSE5281). The discriminatory ability was then assessed by the area under the receiver operating characteristic curves (AUC). Finally, the CIBERSORT algorithm and immune cell infiltration analysis were employed to assess the inflammatory state of AD.

Results

A total of 49 DEGs were identified. The functional enrichment analysis revealed that leukocyte transendothelial migration, cytokine receptor interaction, and JAK-STAT signaling pathway were enriched in the AD group. MAF basic leucine zipper transcription factor F (MAFF), ADCYAP1, and ZFP36L1 were identified as the diagnostic biomarkers of AD with high discriminatory ability (AUC = 0.850) and validated in AD brains (AUC = 0.935). As indicated from the immune cell infiltration analysis, naive B cells, plasma cells, activated/resting NK cells, M0 macrophages, M1 macrophages, resting CD4+ T memory cells, resting mast cells, memory B cells, and resting/activated dendritic cells may participate in the development of AD. Additionally, all diagnostic signatures presented different degrees of correlation with different infiltrating immune cells.

Conclusion

MAFF, ADCYAP1, and ZFP36L1 may become new candidate biomarkers of AD, which were closely related to the pathogenesis of AD. Moreover, the immune cells mentioned above may play crucial roles in disease occurrence and progression.
Constructing prediction models for excessive daytime sleepiness by nomogram and machine learning: A large Chinese multicenter cohort study
Authors: Deng Penghui , Xu Kun , Zhou Xiaoxia , Xiang Yaqin , Xu Qian , Sun Qiying , Li Yan , Yu Haiqing , Wu Xinyin , Yan Xinxiang , Guo Jifeng , Tang Beisha , Liu Zhenhua
Published: July 2022

Objective

Although risk factors for excessive daytime sleepiness (EDS) have been reported, there are still few cohort-based predictive models for EDS in Parkinson’s disease (PD). This 1-year longitudinal study aimed to develop a predictive model of EDS in patients with PD using a nomogram and machine learning (ML).

Materials and methods

A total of 995 patients with PD without EDS were included, and clinical data during the baseline period were recorded, which included basic information as well as motor and non-motor symptoms. One year later, the presence of EDS in this population was re-evaluated. First, the baseline characteristics of patients with PD with or without EDS were analyzed. Furthermore, a Cox proportional risk regression model and XGBoost ML were used to construct a prediction model of EDS in PD.

Results

At the 1-year follow-up, EDS occurred in 260 of 995 patients with PD (26.13%). Baseline features analysis showed that EDS correlated significantly with age, age of onset (AOO), hypertension, freezing of gait (FOG). In the Cox proportional risk regression model, we included high body mass index (BMI), late AOO, low motor score on the 39-item Parkinson’s Disease Questionnaire (PDQ-39), low orientation score on the Mini-Mental State Examination (MMSE), and absence of FOG. Kaplan–Meier survival curves showed that the survival prognosis of patients with PD in the high-risk group was significantly worse than that in the low-risk group. XGBoost demonstrated that BMI, AOO, PDQ-39 motor score, MMSE orientation score, and FOG contributed to the model to different degrees, in decreasing order of importance, and the overall accuracy of the model was 71.86% after testing.

Conclusion

In this study, we showed that risk factors for EDS in patients with PD include high BMI, late AOO, a low motor score of PDQ-39, low orientation score of MMSE, and lack of FOG, and their importance decreased in turn. Our model can predict EDS in PD with relative effectivity and accuracy.
The past, present, and future of research on neuroinflammation-induced mild cognitive impairment: A bibliometric analysis
Authors: Cai Ming , Zhang Yuanqi , Chen Si , Wu Zhan , Zhu Lei
Published: July 2022

Background

Mild cognitive impairment (MCI) is a precursor to dementia, and neuroinflammation in the brain is thought to be one of the main pathogenic mechanisms of MCI. However, the underlying neurobiological mechanisms have not been fully explored. The purpose of this study was to establish a visual model map of the articles in the field of neuroinflammation-induced MCI over the past 11 years to reveal the research hotspots and predict the future development trends in this field, which will help to promote the research and development for MCI.

Methods

The “neuroinflammation” and “mild cognitive impairment” were used as search terms, and literature about neuroinflammation-induced MCI published between 2011 and 2021 was collected from the Web of Science. CiteSpace and VOSviewer were used to create visual model maps, and assess collaboration among different authors, countries, and institutions. Finally, the current research hotspots and future research directions were analyzed by using high-frequency keywords analysis and co-cited reference burst analysis.

Results

A total of 226 articles were retrieved. The number of publications in neuroinflammation-induced MCI shows an upward trend. Since 2018, the number of papers published in this field has increased significantly, with an average of more than 100 published each year. The United States had the highest literature production and the number of cited journals in this research area, and the National Institute on Aging was the most productive research institution. Brooks D.J. and Heneka M.T. had the highest number of publications and had the highest frequency of co-citations. The co-cited references revealed the evolution of the research themes, and the current studies are mainly focused on the effects of various metabolites on the control of microglial activation. “Cerebrospinal fluid,” “mouse model,” “tau,” “microglial activation,” “astrocytes,” and “TREM2” were the current high-frequency and emerging keywords.

Conclusion

Research on neuroinflammation-induced MCI is burgeoning, and the close collaboration with different nations and institutions need to be further strengthened. Current research hotspots are focused on the effects of various metabolites on microglia activation. Future studies should focus on how to regulate the phenotypes of microglia and astrocyte to reduce neuroinflammation and treat MCI.
Time-Restricted Ketogenic Diet in Huntington's Disease: A Case Study
Authors: Phillips Matthew C. L. , McManus Eileen J. , Brinkhuis Martijn , Romero-Ferrando Beatriz
Published: July 2022

Huntington's disease (HD) is a progressive, fatal neurodegenerative disorder with limited treatment options. Substantial evidence implicates mitochondria dysfunction in brain and skeletal muscle in the pathogenesis of HD. Metabolic strategies, such as fasting and ketogenic diets, theoretically enhance brain and muscle metabolism and mitochondria function, which may improve the clinical symptoms of HD. We report the case of a 41-year-old man with progressive, deteriorating HD who pursued a time-restricted ketogenic diet (TRKD) for 48 weeks. Improvements were measured in his motor symptoms (52% improvement from baseline), activities of daily living (28% improvement), composite Unified HD Rating Scale (cUHDRS) score (20% improvement), HD-related behavior problems (apathy, disorientation, anger, and irritability improved by 50–100%), and mood-related quality of life (25% improvement). Cognition did not improve. Weight remained stable and there were no significant adverse effects. This case study is unique in that a patient with progressive, deteriorating HD was managed with a TRKD, with subsequent improvements in his motor symptoms, activities of daily living, cUHDRS score, most major HD-related behavior problems, and quality of life. Our patient remains dedicated to his TRKD, which continues to provide benefit for him and his family.
The effect of hyperbaric oxygen therapy on cognition, performance, proteomics, and telomere length—The difference between zero and one: A case report
Authors: Maroon Joseph C.
Published: July 2022

Introduction

Hyperbaric oxygen (HBO2) therapy has recently been suggested for the treatment of different brain injuries as well as for physical and cognitive enhancement. The author recently carried out a self-experiment to obtain objective information on the effects of HBO2 therapy on neurocognition, cardiopulmonary function, neuroimaging and its effect on novel biomarkers such as telomere length and proteomics. In the following case report, the author will present and discuss the results and the differences between zero and one.

Methods

This is a personal case report on a single subject, myself, who underwent a protocol of 60 daily HBO2 therapy sessions within 3 months. Pre- and post-therapy objective evaluation measured included computerized cognitive assessment, brain imaging, cardiopulmonary exercise test, physical assessments and blood tests including telomere length and proteomics.

Results

Neurocognitive results showed a 3.1–3.8% improvements in global cognitive function as well as all other cognitive function domains. In the perfusion MRI, there was a relative increase ranging from 43.3 to 52.3% in cerebral perfusion in various areas subserving memory, coordination, and visual motor cortex function. Similar improvements in cerebral perfusion were seen in the SPECT scans, which ranged from 8.79 to 16.12% increased perfusion in the temporal pole and entorhinal cortex subserving memory, as well as in the subcallosal area and lingual gyrus. MRI-DTI showed prominent increases in fractional anisotropy in several white matter areas including 9% in the body of the corpus callosum, 16.85% in for the fornix and 22.06% in the tapetum. In the physical domains, there were improvements in both anaerobic threshold, exercise endurance, muscle strength, gait speed and grip strength in the 7–15% range. The telomeres length was doubled and clusters of inflammatory proteins dropped around the 40th session and remained low at the 60th session.

Conclusion

The difference between zero and one in this single case study of HBO2 therapy confirmed improvement in objective biomarkers which measured cognition, memory, brain processing speed, athletic performance and neuroimaging modalities measuring cerebral perfusion, blood flow and tractography. Additional studies with larger sample size and randomized clinical trials using similar biomarkers are needed to confirm the results and to delineate the longevity of these improvements.
Combining electro- and magnetoencephalography data using directional archetypal analysis
Authors: Olsen Anders S. , Høegh Rasmus M. T. , Hinrich Jesper L. , Madsen Kristoffer H. , Mørup Morten
Published: July 2022

Metastable microstates in electro- and magnetoencephalographic (EEG and MEG) measurements are usually determined using modified k-means accounting for polarity invariant states. However, hard state assignment approaches assume that the brain traverses microstates in a discrete rather than continuous fashion. We present multimodal, multisubject directional archetypal analysis as a scale and polarity invariant extension to archetypal analysis using a loss function based on the Watson distribution. With this method, EEG/MEG microstates are modeled using subject- and modality-specific archetypes that are representative, distinct topographic maps between which the brain continuously traverses. Archetypes are specified as convex combinations of unit norm input data based on a shared generator matrix, thus assuming that the timing of neural responses to stimuli is consistent across subjects and modalities. The input data is reconstructed as convex combinations of archetypes using a subject- and modality-specific continuous archetypal mixing matrix. We showcase the model on synthetic data and an openly available face perception event-related potential data set with concurrently recorded EEG and MEG. In synthetic and unimodal experiments, we compare our model to conventional Euclidean multisubject archetypal analysis. We also contrast our model to a directional clustering model with discrete state assignments to highlight the advantages of modeling state trajectories rather than hard assignments. We find that our approach successfully models scale and polarity invariant data, such as microstates, accounting for intersubject and intermodal variability. The model is readily extendable to other modalities ensuring component correspondence while elucidating spatiotemporal signal variability.
Nutrient Profiling of Japanese Dishes: The Development of a Novel Ajinomoto Group Nutrient Profiling System
Authors: Furuta Chie , Jinzu Hiroko , Cao Lili , Drewnowski Adam , Okabe Yuki
Published: July 2022

Government agencies and private companies have supported the development of nutrient profiling (NP) systems to facilitate the selection of nutrient-dense foods by consumers, promote nutritious food development, and limit excessive advertising of products with low nutritional value. While most NP models were developed to assess individual foods, the Ajinomoto Group Nutrient Profiling System (ANPS) was developed to assess the overall nutritional value of cooked dishes that are culturally specific to Japan. Based on the national dietary recommendations and nutritional surveys, target values were created for 13 dish categories, while considering the combinations of meal units. For the ANPS, the four evaluating elements were protein and vegetables, which should be encouraged, and sodium and saturated fatty acids, which should be limited. The ANPS algorithm for dishes was the sum of the scores of individual elements, with a maximum of 10 points per serving. The sum of scores was then multiplied by 2.5 to convert to the 100-point scale. Convergent validity was tested using the nutrient-rich food index (NRF) score of 6.3. In total, 1,089 popular Japanese dishes were evaluated using the ANPS, and the median score of ANPS was 70.0 points (interquartile range, 55–78.8), and the average score was 67.7 (standard deviation, 16.5) points. Since salt intake is a major health risk in Japan, this tool was designed to evaluate sodium content with high sensitivity, and low-salt dishes significantly improved sodium and ANPS scores compared with regular dishes. The Pearson’s correlation coefficient between the total score of NRF 6.3 and ANPS in 1,089 dishes was r = 0.452 (p < 0.0001). This newly developed ANPS could be used to evaluate culture-specific cooked dishes per serving size. It can determine the nutritional values of dishes, with a high sensitivity to sodium content, a major Japanese nutritional issue. Further research is needed to determine the accuracy and usefulness of the ANPS as a system that would lead to changes in eating behavior nationwide.
Therapeutic targets and functions of curcumol against COVID-19 and colon adenocarcinoma
Authors: Li Jun , Peng Peng , Lai Keng Po
Published: July 2022

Since 2019, the coronavirus disease (COVID-19) has caused 6,319,395 deaths worldwide. Although the COVID-19 vaccine is currently available, the latest variant of the virus, Omicron, spreads more easily than earlier strains, and its mortality rate is still high in patients with chronic diseases, especially cancer patients. So, identifying a novel compound for COVID-19 treatment could help reduce the lethal rate of the viral infection in patients with cancer. This study applied network pharmacology and systematic bioinformatics analysis to determine the possible use of curcumol for treating colon adenocarcinoma (COAD) in patients infected with COVID-19. Our results showed that COVID-19 and COAD in patients shared a cluster of genes commonly deregulated by curcumol. The clinical pathological analyses demonstrated that the expression of gamma-aminobutyric acid receptor subunit delta (GABRD) was associated with the patients' hazard ratio. More importantly, the high expression of GABRD was associated with poor survival rates and the late stages of COAD in patients. The network pharmacology result identified seven-core targets, including solute carrier family 6 member 3, gamma-aminobutyric acid receptor subunit pi, butyrylcholinesterase, cytochrome P450 3A4, 17-beta-hydroxysteroid dehydrogenase type 2, progesterone receptor, and GABRD of curcumol for treating patients with COVID-19 and COAD. The bioinformatic analysis further highlighted their importance in the biological processes and molecular functions in gland development, inflammation, retinol, and steroid metabolism. The findings of this study suggest that curcumol could be an alternative compound for treating patients with COVID-19 and COAD.
p53 as a biomarker and potential target in gastrointestinal stromal tumors
Authors: Wu Chiao-En , Chen Chiao-Ping , Huang Wen-Kuan , Pan Yi-Ru , Aptullahoglu Erhan , Yeh Chun-Nan , Lunec John
Published: July 2022

KIT and PDGFRA play a major role in the oncogenic process in gastrointestinal stroma tumors (GIST) and small molecules have been employed with great success to target the KIT and PDGFRA pathways in this cancer. However, approximately 10% of patients with GIST are resistant to current targeted drug therapy. There is a need to explore other potential targets. Although p53 alterations frequently occur in most cancers, studies regarding p53 in GIST have been limited. The CDKN2A/MDM2/p53 axis regulates cell cycle progression and DNA damage responses, which in turn control tumor growth. This axis is the major event required for transformation from low- to high-risk GIST. Generally, p53 mutation is infrequent in GIST, but p53 overexpression has been reported to be associated with high-risk GIST and unfavorable prognosis, implying that p53 should play a critical role in GIST. Also, Wee1 regulates the cell cycle and the antitumor activity of Wee1 inhibition was reported to be p53 mutant dependent. In addition, Wee1 was reported to have potential activity in GIST through the regulation of KIT protein and this mechanism may be dependent on p53 status. In this article, we review previous reports regarding the role of p53 in GIST and propose targeting the p53 pathway as a novel additional treatment strategy for GIST.
Early changes in peripheral blood cytokine levels after the treatment of metastatic hepatic carcinoma with CalliSpheres microspheres drug-eluting beads transcatheter arterial chemoembolization
Authors: Liu Ying , Liu Song , Zhao Guang Sheng , Li Xiang , Gao Fei , Ren Zhi Zhong , Bian Jie , Wu Jian Lin , Zhang Yue Wei
Published: July 2022

Objective

To observe the early changes in peripheral blood cytokine levels after treatment of metastatic hepatic carcinoma (MHC) with CalliSpheres microspheres drug-eluting beads (DEB) transcatheter arterial chemoembolization (CSM-TACE).

Methods

Twenty-eight patients with refractory MHC who underwent CSM-TACE were selected prospectively, and 5mL of peripheral blood was collected before CSM-TACE and on the 2nd and 5th day after CSM-TACE. Flow cytometry was used to detect immunological indicators. The early changes in levels of peripheral blood cell inflammatory factors Th1 (interleukin 2 (IL-2), tumor necrosis factor-α (TNF-a), interferon (IFN-r)), Th2 (IL-4, IL-6, IL-10), and Th17 (IL-17A) were observed after CSM-TACE, as well as the ratio of CD4+/CD8+.

Results

All the 28 patients underwent CSM-TACE successfully. CT at 4 days after CSM-TACE showed clear outline low-density changes in liver tumors, and honeycomb necrosis was observed in the tumors in some cases. After CSM-TACE, the IL-6 and IL-10 levels were increased and then decreased again. After CSM-TACE, IL-2 showed a trend of transient increase and then decreased again, and the TNF-a level decreased temporarily, and then decreased. After CSM-TACE, the IFN-r level showed a continuous and slowly increasing trend. The IL-17 level showed a continuous downward trend, and the CD4+/CD8+ ratio showed a gradual and continuous upward trend, and there was a negative correlation between them.

Conclusions

There are complex dynamic changes in TH1/Th2 in the early stage of CSM-TACE, and the acute inflammatory response and the enhancement of the body’s immune anti-tumor response coexist.
Case report: A case of heterogeneity of the antitumor response to immune checkpoint inhibitors in a patient with relapsed hepatocellular carcinoma
Authors: Bao Yingying , Wen Liang , Chen Wen , Zhao Jianhui , Yang Yixiao , Wei Tao , Zhang Jian , Liang Tingbo
Published: July 2022

The existence of tumor heterogeneity is widely recognized; however, heterogeneity of the antitumor response in multiple tumor nodules in the same patient has not been reported. Sintilimab, a monoclonal antiprogrammed cell death receptor-1 (PD-1) antibody, was used to treat patients with unresectable hepatocellular carcinoma (HCC). In the present study, we report a case of therapeutic heterogeneity in relapsed HCC with lung metastases. A 57-year-old female patient was diagnosed with HCC and underwent radical hepatectomy. One and a half years later, imaging scans found multiple metastatic tumors in the lung, which were accompanied by an increased α-fetoprotein (AFP) level. The patient then started to receive sintilimab. In the first 6 months after sintilimab treatment, all the metastatic nodules regressed gradually and ultimately disappeared, except for one nodule, which remained stable in the following 3 months. Finally, the patient underwent pulmonary lobectomy to remove the remaining nodule. Thereafter, follow-up visits showed the AFP level decreased to normal and imaging scans showed no signs of recurrence, confirming that the patient exhibited a clinically complete response. Pathological assessments showed that in the primary tumor site, the tumor comprised moderately differentiated HCC with a few infiltrated cytotoxic T cells and negative PD-L1 expression. While in the metastatic site, the nodule was composed of poorly differentiated HCC with cytotoxic T-cell infiltration with few cells inside the tumor and expressed PD-L1 in some areas of the tumor. There were dynamic alterations of PD-L1 expression and cytotoxic T-cell infiltration in the primary and relapsed HCC lesions after anti-PD-1 treatment. This case presented the heterogeneities of both the tumor microenvironment and the following antitumor response among the metastatic nodules in the same patient and revealed the importance of comprehensive therapy in cancer treatment.
Umbilical cord blood: A promising source for allogeneic CAR-T cells
Authors: Liu Dian-Dian , Hong Wei-Cong , Qiu Kun-Yin , Li Xin-Yu , Liu Yong , Zhu Li-Wen , Lai Wei-Xin , Chen Han- , Yang Hua-Qing , Xu Lu-Hong , Fang Jian-Pei
Published: July 2022

Chimeric antigen receptor T (CAR-T) cell therapy is an effective treatment for relapsed and refractory acute lymphoblastic leukemia (R/R ALL). However, autologous CAR-T cells derived from patients with B-ALL often show poor amplification ability, exhaustion, and anergy. To overcome these limitations, allogeneic CAR-T cells may be used as effective substitutes; however, which source would be the best substitute is unclear. In this study, we compared the immunophenotype and antitumor efficacy of anti-CD19 CAR-T cells derived from healthy donor cord blood (CB), healthy donor peripheral blood (PB), and PB of B-ALL patients [PB (patient)] in vitro and NOD-Prkdcem26cd52Il2rgem26Cd22/Nju (NCG)-immunodeficient mice, respectively. The results revealed that CAR-T cells derived from healthy donor CB and PB showed a higher proportion of naive T cells and longer tumor suppression in tumor-bearing mice than those of PB (patient). PB (patient) CAR-T cells had a higher proportion of regulatory T cells (Treg cells) and released high levels of interluekin-10 (IL-10), which also suggest a poor prognosis. Thus, CAR-T cells derived from healthy donors have better antitumor efficacy than CAR-T cells derived from PB (patient), and CB may be a good source of allogeneic CAR-T cells.
Whole-genome/exome analysis of circulating tumor DNA and comparison to tumor genomics from patients with heavily pre-treated ovarian cancer: subset analysis of the PERMED-01 trial
Authors: Sabatier Renaud , Garnier Séverine , Guille Arnaud , Carbuccia Nadine , Pakradouni Jihane , Adelaide José , Provansal Magali , Cappiello Maria , Rousseau Frédérique , Chaffanet Max , Birnbaum Daniel , Mamessier Emilie , Gonçalves Anthony , Bertucci François
Published: July 2022

Introduction

The poor prognosis of ovarian carcinoma (OvC) is due to the advanced stage at diagnosis, a high risk of relapse after first-line therapies, and the lack of efficient treatments in the recurrence setting. Circulating tumor DNA (ctDNA) analysis is a promising tool to assess treatment-resistant OvC and may avoid iterative tissue biopsies. We aimed to evaluate the genomic profile of recurrent heavily pre-treated OvC.

Methods

We performed tumor panel-based sequencing as well as low-coverage whole-genome sequencing (LC-WGS) of tumor and plasma collected in patients with ovarian cancer included in the PERMED-01 trial. Whole-exome sequencing (WES) data of plasma samples were also analyzed and compared to mutation and copy number alteration (CNA) tumor profiles. The prognostic value [progression-free survival (PFS)] of these alterations was assessed in an exploratory analysis.

Results

Tumor and plasma genomic analyses were done for 24 patients with heavily pretreated OvC [67% high-grade serous carcinoma (HGSC)]. Tumor mutation burden was low (median 2.04 mutations/Mb) and the most frequent mutated gene was TP53 (94% of HGSC). Tumor CNAs were frequent with a median of 50% of genome altered fraction. Plasma LC-WGS and WES detected ctDNA in 21/24 cases (88%) with a median tumor fraction of 12.7%. We observed a low correlation between plasma and tumor CNA profiles. However, this correlation was significant in cases with the highest circulating tumor fraction. Plasma genome altered fraction and plasma mutation burden (p = 0.011 and p = 0.041, respectively, log-rank tests) were associated with PFS.

Conclusions

Combination of LC-WGS and WES can detect ctDNA in most pre-treated OvCs. Some ctDNA characteristics, such as genome altered fraction and plasma mutation burden, showed prognostic value. ctDNA assessment with LC-WGS may be a promising and non-expansive tool to evaluate disease evolution in this disease with high genomic instability.

Clinical Trial Registration

https://clinicaltrials.gov/ct2/show/NCT02342158, identifier NCT02342158.
Safety of Tumor Treating Fields (TTFields) therapy in pediatric patients with malignant brain tumors: Post-marketing surveillance data
Authors: Goldman Stewart , Margol Ashley , Hwang Eugene I. , Tanaka Kazuhiro , Suchorska Bogdana , Crawford John R. , Kesari Santosh
Published: July 2022

There is an unmet need to develop effective and tolerable treatments for pediatric patients with malignant central nervous system tumors. This is especially essential for pediatric patients with aggressive brain tumors such as high-grade gliomas, which have a typical survival rate of under 2 years. Tumor Treating Fields (TTFields) are locoregional, noninvasive electric fields that produce an antimitotic effect on cancerous cells when applied to the skin via arrays. TTFields therapy (200 kHz) is currently approved in adult patients with newly diagnosed glioblastoma (GBM), with temozolomide, and recurrent GBM as monotherapy. Positive preclinical and clinical data have encouraged off-label use of TTFields therapy in pediatric patients with brain tumors, and this study aims to explore the safety of TTFields therapy in pediatric patients (0–18 years of age) based on data from an unsolicited post-marketing surveillance safety database. The real-world data reported here demonstrate that TTFields therapy has a favorable safety profile for pediatric patients with brain tumors, with no new safety signals observed. Findings from this study warrant further research into the efficacy of TTFields therapy, as well as its potential impact on the quality of life in pediatric patients.
Serum levels of IL-6 and CRP can predict the efficacy of mFOLFIRINOX in patients with advanced pancreatic cancer
Authors: Shen Feifei , Liu Chuan , Zhang Weiguo , He Sijia , Wang Fan , Wang Jingjue , Li Qi , Zhou Fei
Published: July 2022

Objectives

There is an urgent need for biomarkers that predict the survival outcome of patients diagnosed with metastatic pancreatic cancer, undergoing systemic chemotherapy. This study aimed to identify biomarkers associated with the survival of mPC patients treated with modified FOLFIRINOX (mFOLFIRINOX) as first-line chemotherapy.

Methods

This was a retrospective study of 30 patients with mPC who received mFOLFIRINOX between October 2018 and March 2021. Data on carcinoembryonic antigen (CEA), cancer antigen (CA)199, interleukin (IL)-6, C-reactive protein (CRP), neutrophils, platelets, lymphocytes, and albumin were collected and dichotomized using the upper or lower limit, as appropriate. These markers were examined for their association with progression-free survival (PFS). A receiver operating characteristic (ROC) curve analysis was used to explore a suitable model to predict mFOLFIRINOX effectiveness.

Results

IL-6 and CRP levels were associated with poor progression (P = 0.004 and P = <0.001, respectively) of mPC. The high IL-6 level was an independent poor prognostic factor for PFS (HR=4.66, 95%CI: 1.32-16.37, P=0.016) in the multivariable analysis. Patients with high IL-6 levels had a shorter PFS than those with low IL-6 levels (median PFS: 257 vs. 150 days, P=0.020). An increase in IL-6 and CRP levels during chemotherapy positively correlated with disease progression (P = <0.001 for both). The model combining IL-6 with CRP levels helped predict the outcomes of mPC patients treated with mFOLFIRINOX (AUC: 0.811, 95%CI: 0.639-0.983, P=0.003).

Conclusions

The serum levels of IL-6 and CRP might be considered as valuable biomarkers in predicting the outcomes of patients with mPC who received the mFOLFIRINOX regimen.
Association of preoperative albumin–bilirubin with surgical textbook outcomes following laparoscopic hepatectomy for hepatocellular carcinoma
Authors: Xu Fei-Qi , Ye Tai-Wei , Wang Dong-Dong , Xie Ya-Ming , Zhang Kang-Jun , Cheng Jian , Xiao Zun-Qiang , Liu Si-Yu , Jiang Kai , Yao Wei-Feng , Shen Guo-Liang , Liu Jun-Wei , Zhang Cheng-Wu , Huang Dong-Sheng , Liang Lei
Published: July 2022

Background and aims

Recently, the effectiveness of “textbook outcomes (TO)” in the evaluation of surgical quality has been recognized by more and more scholars. This study tended to examine the association between preoperative albumin–bilirubin (ALBI) grades and the incidence of achieving or not achieving TO (non-TO) in patients with hepatocellular carcinoma (HCC) undergoing laparoscopic hepatectomy.

Methods

The patients were stratified into two groups: ALBI grade 1 (ALBI ≤ -2.60) and ALBI grade 2/3 (ALBI > -2.60). The characteristics of patients and the incidence of non-TO were compared. Multivariate analyses were performed to determine whether ALBI grade was independently associated with TO.

Results

In total, 378 patients were enrolled, including 194 patients (51.3%) in the ALBI grade 1 group and 184 patients (48.7%) in the ALBI grade 2/3 group. In the whole cohort, 198 patients (52.4%) did not achieve TO, and the incidence of non-TO in the ALBI grade 2/3 group was obviously higher than that in the ALBI grade 1 group (n = 112, 60.9% vs. n = 86, 44.3%, P = 0.001). The multivariate analyses showed that ALBI grade 2/3 was an independent risk factor for non-TO (OR: 1.95, 95%CI: 1.30–2.94, P = 0.023).

Conclusions

More than half (52.4%) of the patients with hepatocellular carcinoma did not achieve TO after laparoscopic hepatectomy, and preoperative ALBI grade 2/3 was significantly associated with non-TO. Improving the liver function reserve of patients before operation, thereby reducing the ALBI grade, may increase the probability for patients to reach TO and enable patients to benefit more from surgery.
Adjusting CA19-9 values with clinical stage and bilirubin to better predict survival of resectable pancreatic cancer patients: 5-year-follow-up of a single center
Authors: Wu Zuowei , Zhao Pengcheng , Wang Zihe , Huang Xing , Wu Chao , Li Mao , Wang Li , Tian Bole
Published: July 2022

Background

Pancreatic cancer mortality is growing every year, and radical resection is the most essential therapy strategy. It is critical to evaluate the long-term prognosis of individuals receiving radical surgery. CA19-9 is a biomarker for patient recurrence and survival, however obstructive jaundice has a significant impact on this index. Researchers have attempted to modify the index using various modification methods, but the results have been unsatisfactory. In this study, we adjusted CA19-9 values based on clinical stage and bilirubin and found that it provided better prediction than CA19-9 alone in assessing patients.

Methods

We analyzed over 5 years follow-up records of patients who underwent radical pancreatic cancer surgery between August 2009 and May 2017 in a single center. We investigated the association of risk factors with overall survival (OS) as well as disease-free survival (DFS) after surgery. Threshold values for high-risk features associated with poor prognosis in resectable pancreatic cancer were determined. The hazard ratios of the indicators were eventually examined under the stratification of patients’ clinical stages.

Results

A total of 202 patients were involved in the study. The optimum cut-off values for CA19-9 and CA19-9/TB for predicting overall survival were 219.4 (p = 0.0075) and 18.8 (p = 0.0353), respectively. CA19-9>219.4 increased the risk of patient mortality by 1.70 times (95% CI 1.217-2.377, p = 0.002), and tumor poor differentiation raised the risk by 1.66 times (95% CI 1.083-2.553, P = 0.02). Based on clinical stage stratification, we found discrepancies in the predictive efficacy of CA19-9 and CA19-9/TB. CA19-9 was a better predictor in clinical stage 1 (HR = 2.056[CI 95%1.169-3.616], P = 0.012), whereas CA19-9/TB indications were better in stages 2 (HR = 1.650[CI 95%1.023-2.662], P = 0.040) and 3 (HR = 3.989[CI95%1.145-13.896], P = 0.030).

Conclusions

CA19-9, CEA, and tumor differentiation are predictors for patients with resectable PDAC. CA19-9 values can be adjusted based on clinical stage and bilirubin levels to better predict overall survival in patients with resectable PDAC. CA19-9>219.4 predicted poor survival in individuals in clinical stage 1, whereas CA19-9/TB>18.8 predicted poor survival for individuals in stages 2 and 3.
Identification of critical genes associated with radiotherapy resistance in cervical cancer by bioinformatics
Authors: Zhang Zhenhua , Xiang Kechao , Tan Longjing , Du Xiuju , He Huailin , Li Dan , Li Li , Wen Qinglian
Published: July 2022

Background

Cervical cancer (CC) is one of the common malignant tumors in women, Currently, 30% of patients with intermediate to advanced squamous cervical cancer are still uncontrolled or recurrent after standard radical simultaneous radiotherapy; therefore, the search for critical genes affecting the sensitivity of radiotherapy may lead to new strategies for treatment.

Methods

Firstly, differentially expressed genes (DEGs) between radiotherapy-sensitivity and radiotherapy-resistance were identified by GEO2R from the gene expression omnibus (GEO) website, and prognosis-related genes for cervical cancer were obtained from the HPA database. Subsequently, the DAVID database analyzed gene ontology (GO). Meanwhile, the protein-protein interaction network was constructed by STRING; By online analysis of DEGs, prognostic genes, and CCDB data that are associated with cervical cancer formation through the OncoLnc database, we aim to search for the key DEGs associated with CC, Finally, the key gene(s) was further validated by immunohistochemistry.

Result

298 differentially expressed genes, 712 genes associated with prognosis, and 509 genes related to cervical cancer formation were found. The results of gene function analysis showed that DEGs were mainly significant in functional pathways such as variable shear and energy metabolism. By further verification, two genes, ASPH and NKAPP1 were identified through validation as genes that affect both sensitivities to radiotherapy and survival finally. Then, immunohistochemical results showed that the ASPH gene was highly expressed in the radiotherapy-resistant group and had lower Overall survival (OS) and Progression-free survival (PFS).

Conclusion

This study aims to better understand the characteristics of cervical cancer radiation therapy resistance-related genes through bioinformatics and provide further research ideas for finding new mechanisms and potential therapeutic targets related to cervical cancer radiation therapy.
Do not forget asthma comorbidities in pediatric severe asthma!
Authors: Ronco Lucia , Folino Anna , Goia Manuela , Crida Benedetta , Esposito Irene , Bignamini Elisabetta
Published: July 2022

Asthma is the most common chronic respiratory disease in childhood. The long-term goals in managing asthma aim to control symptoms and prevent exacerbations, as well as to reduce side effects of therapy and mortality disease-related. Most of patients have mild to moderate asthma and respond well to standard therapies. However, a minor proportion of children with asthma has severe disease that remains uncontrolled despite optimal adherence to prescribed therapy and treatment of contributory factors, including trigger exposures and comorbidities, which can mimic or worsen asthma and contribute to exacerbations and poor quality of life. Evaluation of comorbidities is fundamental to optimize the management of the disease in a subgroup of patients with poor responder asthma. The overall aim of this article is to describe characteristics of main pediatric severe asthma comorbidities reported in literature, giving clinicians tools to recognize and manage properly these conditions.
A Moss 2-Oxoglutarate/Fe(II)-Dependent Dioxygenases (2-ODD) Gene of Flavonoids Biosynthesis Positively Regulates Plants Abiotic Stress Tolerance
Authors: Wang Huijuan , Liu Shenghao , Fan Fenghua , Yu Qian , Zhang Pengying
Published: July 2022

Flavonoids, the largest group of polyphenolic secondary metabolites present in all land plants, play essential roles in many biological processes and defense against abiotic stresses. In the flavonoid biosynthesis pathway, flavones synthase I (FNSI), flavanone 3-hydroxylase (F3H), flavonol synthase (FLS), and anthocyanidin synthase (ANS) all belong to 2-oxoglutarate/Fe(II)-dependent dioxygenases (2-ODDs) family, which catalyzes the critical oxidative reactions to form different flavonoid subgroups. Here, a novel 2-ODD gene was cloned from Antarctic moss Pohlia nutans (Pn2-ODD1) and its functions were investigated both in two model plants, Physcomitrella patens and Arabidopsis thaliana. Heterologous expression of Pn2-ODD1 increased the accumulation of anthocyanins and flavonol in Arabidopsis. Meanwhile, the transgenic P. patens and Arabidopsis with expressing Pn2-ODD1 exhibited enhanced tolerance to salinity and drought stresses, with larger gametophyte sizes, better seed germination, and longer root growth. Heterologous expression of Pn2-ODD1 in Arabidopsis also conferred the tolerance to UV-B radiation and oxidative stress by increasing antioxidant capacity. Therefore, we showed that Pn2-ODD1 participated in the accumulation of anthocyanins and flavonol in transgenic plants, and regulated the tolerance to abiotic stresses in plants, contributing to the adaptation of P. nutans to the polar environment.
Insights into the control of taxane metabolism: Molecular, cellular, and metabolic changes induced by elicitation in Taxus baccata cell suspensions
Authors: Perez-Matas Edgar , Hanano Abdulsamie , Moyano Elisabeth , Bonfill Mercedes , Cusido Rosa M. , Palazon Javier
Published: July 2022

More knowledge is needed about the molecular/cellular control of paclitaxel (PTX) production in Taxus spp. cell cultures. In this study, the yield of this anticancer agent in Taxus baccata cell suspensions was improved 11-fold after elicitation with coronatine (COR) compared to the untreated cells, and 18-fold when co-supplemented with methyl-β-cyclodextrins (β-CDs). In the dual treatment, the release of taxanes from the producer cells was greatly enhanced, with 81.6% of the total taxane content being found in the medium at the end of the experiment. The experimental conditions that caused the highest PTX production also induced its maximum excretion, and increased the expression of taxane biosynthetic genes, especially the flux-limiting BAPT and DBTNBT. The application of COR, which activates PTX biosynthesis, together with β - CDs, which form inclusion complexes with PTX and related taxanes, is evidently an efficient strategy for enhancing PTX production and release to the culture medium. Due to the recently described role of lipid droplets (LDs) in the trafficking and accumulation of hydrophobic taxanes in Taxus spp. cell cultures, the structure, number and taxane storage capacity of these organelles was also studied. In elicited cultures, the number of LDs increased and they mainly accumulated taxanes with a side chain, especially PTX. Thus, PTX constituted up to 50-70% of the total taxanes found in LDs throughout the experiment in the COR + β - CD-treated cultures. These results confirm that LDs can store taxanes and distribute them inside and outside cells.
Intrinsically disordered protein, DNA binding with one finger transcription factor (OsDOF27) implicates thermotolerance in yeast and rice
Authors: Gandass Nishu , Kajal  , Salvi Prafull
Published: July 2022

Intrinsically disorder regions or proteins (IDRs or IDPs) constitute a large subset of the eukaryotic proteome, which challenges the protein structure–function paradigm. These IDPs lack a stable tertiary structure, yet they play a crucial role in the diverse biological process of plants. This study represents the intrinsically disordered nature of a plant-specific DNA binding with one finger transcription factor (DOF-TF). Here, we have investigated the role of OsDOF27 and characterized it as an intrinsically disordered protein. Furthermore, the molecular role of OsDOF27 in thermal stress tolerance has been elucidated. The qRT-PCR analysis revealed that OsDOF27 was significantly upregulated under different abiotic stress treatments in rice, particularly under heat stress. The stress-responsive transcript induction of OsDOF27 was further correlated with enriched abiotic stress-related cis-regulatory elements present in its promoter region. The in vivo functional analysis of the potential role of OsDOF27 in thermotolerance was further studied in yeast and in planta. Ectopic expression of OsDOF27 in yeast implicates thermotolerance response. Furthermore, the rice transgenic lines with overexpressing OsDOF27 revealed a positive role in mitigating heat stress tolerance. Collectively, our results evidently show the intrinsically disorderedness in OsDOF27 and its role in thermal stress response in rice.
Unleashing the mechanism among salesforce control system, salesforce ambidexterity, and emotional exhaustion to enhance the competitive advantage of organizations
Authors: Ahmad Bilal , Liu Da , Irfan Muhammad , Álvarez-García José
Published: July 2022

The service-sales interaction should be aligned within and outside the organization, but many companies are not harvesting the benefits of this technique. In line with the conservation of resources (COR) theory, the current research investigates the impact of the salesforce control system on salesforce ambidexterity (service and sales interface), which eventually leads to emotional exhaustion service-related performance outcomes. We assess the proposed model using cross-sectional data of 321 Pakistani salespeople from B2B organizations and employ structural equation modeling for data analysis purposes. First, the study results show that behavior-based control has an inverse influence on salesforce ambidexterity. On the other hand, outcome-based control is positively associated with salesforce ambidexterity. In addition, salesforce ambidexterity is positively linked with emotional exhaustion. However, emotional exhaustion has a negative impact on both service innovation implementation and service recovery performance. Finally, the results demonstrate the significant and positive moderating influence of self-efficacy and customer demandingness between exogenous and endogenous constructs. The study is particularly important to B2B sales organizations struggling with the difficulties of salesforce ambidexterity and how they control their sales representatives.