bluuebunny/crossref_metadata_2025 huggingface dataset:
The Activation and Regulation of β2 Integrins in Phagocytes and Phagocytosis
Authors: Sun Hao , Zhi Kangkang , Hu Liang , Fan Zhichao
Published: March 2021

Phagocytes, which include neutrophils, monocytes, macrophages, and dendritic cells, protect the body by removing foreign particles, bacteria, and dead or dying cells. Phagocytic integrins are greatly involved in the recognition of and adhesion to specific antigens on cells and pathogens during phagocytosis as well as the recruitment of immune cells. β2 integrins, including αLβ2, αMβ2, αXβ2, and αDβ2, are the major integrins presented on the phagocyte surface. The activation of β2 integrins is essential to the recruitment and phagocytic function of these phagocytes and is critical for the regulation of inflammation and immune defense. However, aberrant activation of β2 integrins aggravates auto-immune diseases, such as psoriasis, arthritis, and multiple sclerosis, and facilitates tumor metastasis, making them double-edged swords as candidates for therapeutic intervention. Therefore, precise regulation of phagocyte activities by targeting β2 integrins should promote their host defense functions with minimal side effects on other cells. Here, we reviewed advances in the regulatory mechanisms underlying β2 integrin inside-out signaling, as well as the roles of β2 integrin activation in phagocyte functions.
Gender Differences in Hemocyte Immune Parameters of Hong Kong Oyster Crassostrea hongkongensis During Immune Stress
Authors: Lu Jie , Shi Yanyan , Yao Tuo , Bai Changming , Jiang Jingzhe , Ye Lingtong
Published: March 2021

Gender differences in individual immune responses to external stimuli have been elucidated in many invertebrates. However, it is unclear if gender differences do exist in the Hong Kong oyster Crassostrea hongkongensis, one of the most valuable marine species cultivated along the coast of South China. To clarify this, we stimulated post-spawning adult C. hongkongensis with Vibrio harveyi and lipopolysaccharide (LPS). Gender-based differences in some essential functional parameters of hemocytes were studied via flow cytometry. Obvious gender-, subpopulation-, and immune-specific alterations were found in the hemocyte immune parameters of C. hongkongensis. Three hemocyte subpopulations were identified: granulocytes, semi-granulocytes, and agranulocytes. Granulocytes, the chief phagocytes and major producers of esterase, reactive oxygen species, and nitric oxide, were the main immunocompetent hemocytes. Immune parameter alterations were notable in the accumulation of granulocyte esterase activities, lysosomal masses, nitric oxide levels, and granulocyte numbers in male oysters. These results suggest that post-spawning-phase male oysters possess a more powerful immune response than females. Gender and subpopulation differences in bivalve immune parameters should be considered in the future analysis of immune parameters when studying the impact of pathogenic or environmental factors.
Residual Viremia Is Linked to a Specific Immune Activation Profile in HIV-1-Infected Adults Under Efficient Antiretroviral Therapy
Authors: Younas Mehwish , Psomas Christina , Reynes Christelle , Cezar Renaud , Kundura Lucy , Portalès Pierre , Merle Corinne , Atoui Nadine , Fernandez Céline , Le Moing Vincent , Barbuat Claudine , Sotto Albert , Sabatier Robert , Winter Audrey , Fabbro Pascale , Vincent Thierry , Reynes Jacques , Corbeau Pierre
Published: March 2021

Chronic immune activation persists in persons living with HIV-1 even though they are aviremic under antiretroviral therapy, and fuels comorbidities. In previous studies, we have revealed that virologic responders present distinct profiles of immune activation, and that one of these profiles is related to microbial translocation. In the present work, we tested in 140 HIV-1-infected adults under efficient treatment for a mean duration of eight years whether low-level viremia might be another cause of immune activation. We observed that the frequency of viremia between 1 and 20 HIV-1 RNA copies/mL (39.5 ± 24.7% versus 21.1 ± 22.5%, p = 0.033) and transient viremia above 20 HIV-1 RNA copies/mL (15.1 ± 16.9% versus 3.3 ± 7.2%, p = 0.005) over the 2 last years was higher in patients with one profile of immune activation, Profile E, than in the other patients. Profile E, which is different from the profile related to microbial translocation with frequent CD38+ CD8+ T cells, is characterized by a high level of CD4+ T cell (cell surface expression of CD38), monocyte (plasma concentration of soluble CD14), and endothelium (plasma concentration of soluble Endothelial Protein C Receptor) activation, whereas the other profiles presented low CD4:CD8 ratio, elevated proportions of central memory CD8+ T cells or HLA-DR+ CD4+ T cells, respectively. Our data reinforce the hypothesis that various etiological factors shape the form of the immune activation in virologic responders, resulting in specific profiles. Given the type of immune activation of Profile E, a potential causal link between low-level viremia and atherosclerosis should be investigated.
End-to-End AI-Based Point-of-Care Diagnosis System for Classifying Respiratory Illnesses and Early Detection of COVID-19: A Theoretical Framework
Authors: Belkacem Abdelkader Nasreddine , Ouhbi Sofia , Lakas Abderrahmane , Benkhelifa Elhadj , Chen Chao
Published: March 2021

Respiratory symptoms can be caused by different underlying conditions, and are often caused by viral infections, such as Influenza-like illnesses or other emerging viruses like the Coronavirus. These respiratory viruses, often, have common symptoms: coughing, high temperature, congested nose, and difficulty breathing. However, early diagnosis of the type of the virus, can be crucial, especially in cases, such as the COVID-19 pandemic. Among the factors that contributed to the spread of the COVID-19 pandemic were the late diagnosis or misinterpretation of COVID-19 symptoms as regular flu-like symptoms. Research has shown that one of the possible differentiators of the underlying causes of different respiratory diseases could be the cough sound, which comes in different types and forms. A reliable lab-free tool for early and accurate diagnosis, which can differentiate between different respiratory diseases is therefore very much needed, particularly during the current pandemic. This concept paper discusses a medical hypothesis of an end-to-end portable system that can record data from patients with symptoms, including coughs (voluntary or involuntary) and translate them into health data for diagnosis, and with the aid of machine learning, classify them into different respiratory illnesses, including COVID-19. With the ongoing efforts to stop the spread of the COVID-19 disease everywhere today, and against similar diseases in the future, our proposed low cost and user-friendly theoretical solution could play an important part in the early diagnosis.
Prediction of Mortality in Surgical Intensive Care Unit Patients Using Machine Learning Algorithms
Authors: Yun Kyongsik , Oh Jihoon , Hong Tae Ho , Kim Eun Young
Published: March 2021

Objective: Predicting prognosis of in-hospital patients is critical. However, it is challenging to accurately predict the life and death of certain patients at certain period. To determine whether machine learning algorithms could predict in-hospital death of critically ill patients with considerable accuracy and identify factors contributing to the prediction power.

Materials and Methods: Using medical data of 1,384 patients admitted to the Surgical Intensive Care Unit (SICU) of our institution, we investigated whether machine learning algorithms could predict in-hospital death using demographic, laboratory, and other disease-related variables, and compared predictions using three different algorithmic methods. The outcome measurement was the incidence of unexpected postoperative mortality which was defined as mortality without pre-existing not-for-resuscitation order that occurred within 30 days of the surgery or within the same hospital stay as the surgery.

Results: Machine learning algorithms trained with 43 variables successfully classified dead and live patients with very high accuracy. Most notably, the decision tree showed the higher classification results (Area Under the Receiver Operating Curve, AUC = 0.96) than the neural network classifier (AUC = 0.80). Further analysis provided the insight that serum albumin concentration, total prenatal nutritional intake, and peak dose of dopamine drug played an important role in predicting the mortality of SICU patients.

Conclusion: Our results suggest that machine learning algorithms, especially the decision tree method, can provide information on structured and explainable decision flow and accurately predict hospital mortality in SICU hospitalized patients.
Endometriosis-Related Pleural Effusion: A Case Report and a PRISMA-Compliant Systematic Review
Authors: Wang Ping , Meng Zhilan , Li Yakun , Xu Zuojun
Published: March 2021

Background: Endometriosis-related pleural effusion (PE) is a relatively rare but treatable cause of bloody PE. The clinical characteristics and outcome of patients with endometriosis-related PE remain unknown.

Objectives: We present a case of endometriosis-related PE diagnosed on pleural fluid cytology. A systematic review of all endometriosis-related PE cases in literature was conducted to elucidate the clinical characteristics, explore the diagnostic yield of pathological examinations, and to summarize the outcomes of therapeutic approaches in this disease.

Methods: A case of endometriosis-related PE diagnosed in study hospital was reported. PubMed, Web of Science, and EMBASE were searched for publications pertaining to cases of endometriosis-related PE using predefined search terms. This case and those identified from PubMed, Web of Science, and EMBASE were analyzed.

Results: A total of 67 patients were included. Catamential symptoms were presented in 30 (44.8%) patients. Dyspnea was presented in 50 patients (74.6%), followed by right chest/shoulder pain in 34 (50.7%) and cough in 18 (26.9%). 82.8% of the patients had concomitant pelvic endometriosis and 76.7% was infertile or nulliparous. The diagnostic yield of pleural fluid cytological examination, percutaneous pleural biopsy, and surgical biopsy was 9.0, 45.5, and 78.7%, respectively. The patients who received surgery-based therapy had a significantly longer time to relapse than those who received progestational agents or GnRH analogs alone (P = 0.025) or hysterectomy and bilateral salpingoophorectomy (HBSO) (P = 0.040).

Conclusions: High clinical awareness of pleural endometriosis is essential in all female with hemorrhagic PE, especially in young females who have infertility and/or pelvic endometriosis. Plerual fluid cytology might be a simple minimally invasive and cost-effective modality in the diagnosis of endometriosis-related PE. Treatment is challenging due to high recurrence and the optimal management of endometriosis-related PE needs further evaluation. The combined approach by surgery and hormonal therapy may achieve the best relapse-free survival.
Mutant Allele Frequency-Based Intra-Tumoral Genetic Heterogeneity Related to the Tumor Shrinkage Mode After Neoadjuvant Chemotherapy in Breast Cancer Patients
Authors: Zheng Chun-hui , Liu Zhao-yun , Yuan Chen-xi , Dong Xiao-yun , Li Hai-mei , Wang Jin-jin , Zhang Zhao-peng , Liu Hong-Ying , Ding Xiao-yan , Wu Wendy , Wang Rui-ru , Wang Yong-sheng
Published: March 2021

The shrinkage mode of tumor extent after neoadjuvant chemotherapy (NAC) is an important index to evaluate the odds of breast-conserving surgery. However, there is no sufficient measurement to predict the shrinkage mode after NAC. In this study, we analyzed 24 patients' formalin-fixed, paraffin-embedded samples before and after treatment and analyzed 456 cancer-related genes panel by using target next-generation sequencing. Meanwhile, the pathological shrinkage mode was reconstructed in three dimensions after surgery, and the genetic heterogeneity level was estimated by mutant-allele tumor heterogeneity (MATH). We measured the genetic intra-tumor heterogeneity and explored its correlation with the shrinkage mode after NAC. A total of 17 matched pair samples of primary tumor tissue and residual tumor tissue were successfully accessed. It was found that the most common mutated genes were TP53 and PIK3CA in both samples before and after NAC, and no recurrent mutations were significantly associated with the shrinkage mode. Besides, the MATH value of formalin-fixed, paraffin-embedded samples before and after NAC was analyzed by the area under the curve of the receiver operating characteristic, and it is feasible to classify patients into concentric shrinkage mode and non-concentric shrinkage mode in NAC based on the MATH threshold of 58. Our findings indicate that the MATH value was associated with the shrinkage mode of breast cancer in a non-linear model. Patients with the MATH value below the threshold of 58 before and after NAC displayed a concentric shrinkage mode. The area under the curve was 0.89, with a sensitivity of 0.69 and specificity of 1. Our study might provide a promising application of intra-tumor heterogeneity that is measured by MATH to make a choice of surgery.
Enhanced Reactive Blue 4 Biodegradation Performance of Newly Isolated white rot fungus Antrodia P5 by the Synergistic Effect of Herbal Extraction Residue
Authors: Yuan Tianjie , Zhang Shuyi , Chen Yifei , Zhang Ran , Chen Letian , Ruan Xiaoshu , Zhang Sen , Zhang Fang
Published: March 2021

In this study, a white rot fungus Antrodia was newly isolated and named P5. Then its dye biodegradation ability was investigated. Our results showed that P5 could effectively degrade 1,000 mg/L Reactive Blue 4 (RB4) in 24 h with 95% decolorization under shaking conditions. It could tolerate a high dye concentration of 2,500 mg/L as well as 10% salt concentration and a wide range of pH values (4–9). Herbal extraction residues (HER) were screened as additional medium elements for P5 biodegradation. Following the addition of Fructus Gardeniae (FG) extraction residue, the biodegradation performance of P5 was significantly enhanced, achieving 92% decolorization in 12 h. Transcriptome analysis showed that the expression of multiple peroxidase genes was simultaneously increased: Lignin Peroxidase, Manganese Peroxidase, Laccase, and Dye Decolorization Peroxidase. The maximum increase in Lignin Peroxidase reached 10.22-fold in the presence of FG. The results of UV scanning and LC-HRMS showed that with the synergistic effect of FG, P5 could remarkably accelerate the biodegradation process of RB4 intermediates. Moreover, the fungal treatment with FG also promoted the abatement of RB4 toxicity. In sum, white rot fungus and herbal extraction residue were combined and used in the treatment of anthraquinone dye. This could be applied in practical contexts to realize an efficient and eco-friendly strategy for industrial dye wastewater treatment.
Lytic Bacteriophage EFA1 Modulates HCT116 Colon Cancer Cell Growth and Upregulates ROS Production in an Enterococcus faecalis Co-culture System
Authors: Kabwe Mwila , Meehan-Andrews Terri , Ku Heng , Petrovski Steve , Batinovic Steven , Chan Hiu Tat , Tucci Joseph
Published: March 2021

Enterococcus faecalisis an opportunistic pathogen in the gut microbiota that’s associated with a range of difficult to treat nosocomial infections. It is also known to be associated with some colorectal cancers. Its resistance to a range of antibiotics and capacity to form biofilms increase its virulence. Unlike antibiotics, bacteriophages are capable of disrupting biofilms which are key in the pathogenesis of diseases such as UTIs and some cancers. In this study, bacteriophage EFA1, lytic againstE. faecalis, was isolated and its genome fully sequenced and analyzedin silico. Electron microscopy images revealed EFA1 to be aSiphovirus. The bacteriophage was functionally assessed and shown to disruptE. faecalisbiofilms as well as modulate the growth stimulatory effects ofE. faecalisin a HCT116 colon cancer cell co-culture system, possibly via the effects of ROS. The potential exists for further testing of bacteriophage EFA1 in these systems as well asin vivomodels.
The Role of Human Centromeric RNA in Chromosome Stability
Authors: Leclerc Simon , Kitagawa Katsumi
Published: March 2021

Chromosome instability is a hallmark of cancer and is caused by inaccurate segregation of chromosomes. One cellular structure used to avoid this fate is the kinetochore, which binds to the centromere on the chromosome. Human centromeres are poorly understood, since sequencing and analyzing repeated alpha-satellite DNA regions, which can span a few megabases at the centromere, are particularly difficult. However, recent analyses revealed that these regions are actively transcribed and that transcription levels are tightly regulated, unveiling a possible role of RNA at the centromere. In this short review, we focus on the recent discovery of the function of human centromeric RNA in the regulation and structure of the centromere, and discuss the consequences of dysregulation of centromeric RNA in cancer.
Analysis of Gait Motion Changes by Intervention Using Robot Suit Hybrid Assistive Limb (HAL) in Myelopathy Patients After Decompression Surgery for Ossification of Posterior Longitudinal Ligament
Authors: Ezaki Seioh , Kadone Hideki , Kubota Shigeki , Abe Tetsuya , Shimizu Yukiyo , Tan Chun Kwang , Miura Kousei , Hada Yasushi , Sankai Yoshiyuki , Koda Masao , Suzuki Kenji , Yamazaki Masashi
Published: March 2021

Ossification of the posterior longitudinal ligament (OPLL) is a hyperostonic condition in which the posterior longitudinal ligament becomes thick and loses its flexibility, resulting in ectopic ossification and severe neurologic deficit (Matsunaga and Sakou, 2012). It commonly presents with myelopathy and radiculopathy and with myelopathy progression motor disorders and balance disorders can appear. Even after appropriate surgical decompression, some motor impairments often remain. The Hybrid Assistive Limb (HAL) is a wearable powered suit designed to assist and support the user's voluntary control of hip and knee joint motion by detecting bioelectric signals from the skin surface and force/pressure sensors in the shoes during movement. In the current study, the HAL intervention was applied to 15 patients diagnosed with OPLL who presented with myelopathy after decompression surgery (6 acute and 9 chronic stage). Following the HAL intervention, there were significant improvements in gait speed, cadence, stride length, in both acute and chronic groups. Joint angle analysis of the lower limbs showed that range of motion (ROM) of hip and knee joints in acute group, and also ROM of hip joint and toe-lift during swing in chronic group increased significantly. ROM of knee joint became closer to healthy gait in both groups. Electromyography analysis showed that hamstrings activity in the late swing phase increased significantly for acute patients. Immidiate effect from HAL session was also observed. EMG of vastus medialis were decreased except chronic 7th session and EMG of gastrocnemius were decreased except acute 7th session, which suggests the patients were learning to walk with lesser knee-hypertension during the sessions. After all, double knee action appeared in both acute and chronic groups after the HAL intervention, rather than knee hyper-extension which is a common gait impairment in OPLL. We consider that these improvements lead to a smoother and healthier gait motion.
Microglia in Health and Disease: The Strength to Be Diverse and Reactive
Authors: Uriarte Huarte Oihane , Richart Lorraine , Mittelbronn Michel , Michelucci Alessandro
Published: March 2021

Microglia are the resident immune effector cells of the central nervous system (CNS) rapidly reacting to any perturbation in order to maintain CNS homeostasis. Although their outstanding reactive properties have been elucidated over the last decades, their heterogeneity in healthy tissue, such as across brain regions, as well as their diversity in the development and progression of brain diseases, are currently opening new avenues to understand the cellular and functional states of microglia subsets in a context-dependent manner. Here, we review the main breakthrough studies that helped in elucidating microglia heterogeneity in the healthy and diseased brain and might pave the way to critical functional screenings of the inferred cellular diversity. We suggest that unraveling the cellular and molecular mechanisms underlying specific functionalities of microglial subpopulations, which may ultimately support or harm the neuronal network in neurodegenerative diseases, or may acquire pro- or anti-tumorigenic phenotypes in brain tumors, will possibly uncover new therapeutic avenues for to date non-curable neurological disorders.
Machine Learning-Enabled 30-Day Readmission Model for Stroke Patients
Authors: Darabi Negar , Hosseinichimeh Niyousha , Noto Anthony , Zand Ramin , Abedi Vida
Published: March 2021

Background and Purpose: Hospital readmissions impose a substantial burden on the healthcare system. Reducing readmissions after stroke could lead to improved quality of care especially since stroke is associated with a high rate of readmission. The goal of this study is to enhance our understanding of the predictors of 30-day readmission after ischemic stroke and develop models to identify high-risk individuals for targeted interventions.

Methods: We used patient-level data from electronic health records (EHR), five machine learning algorithms (random forest, gradient boosting machine, extreme gradient boosting–XGBoost, support vector machine, and logistic regression-LR), data-driven feature selection strategy, and adaptive sampling to develop 15 models of 30-day readmission after ischemic stroke. We further identified important clinical variables.

Results: We included 3,184 patients with ischemic stroke (mean age: 71 ± 13.90 years, men: 51.06%). Among the 61 clinical variables included in the model, the National Institutes of Health Stroke Scale score above 24, insert indwelling urinary catheter, hypercoagulable state, and percutaneous gastrostomy had the highest importance score. The Model's AUC (area under the curve) for predicting 30-day readmission was 0.74 (95%CI: 0.64–0.78) with PPV of 0.43 when the XGBoost algorithm was used with ROSE-sampling. The balance between specificity and sensitivity improved through the sampling strategy. The best sensitivity was achieved with LR when optimized with feature selection and ROSE-sampling (AUC: 0.64, sensitivity: 0.53, specificity: 0.69).

Conclusions: Machine learning-based models can be designed to predict 30-day readmission after stroke using structured data from EHR. Among the algorithms analyzed, XGBoost with ROSE-sampling had the best performance in terms of AUC while LR with ROSE-sampling and feature selection had the best sensitivity. Clinical variables highly associated with 30-day readmission could be targeted for personalized interventions. Depending on healthcare systems' resources and criteria, models with optimized performance metrics can be implemented to improve outcomes.
Case Report and Literature Analysis: Guillain-Barré Syndrome With Delayed Unilateral Facial Palsy
Authors: Huang Xuanyu , Lan Ziwei , Zhan Yajing , Hu Zhiping
Published: March 2021

Guillain-Barré syndrome (GBS) is an acute inflammatory polyradiculoneuropathy in which most patients have cranial nerve involvement, with facial nerve involvement being the most common. However, delayed facial palsy (DFP) with asymmetric facial palsy is a rare manifestation of GBS, and the mechanism is unclear. We report a case of GBS combined with delayed unilateral facial palsy and review previously reported cases of GBS combined with DFP. A total of 28 cases of GBS with DFP, including the case in this report, were included in this study. The occurrence of DFP may be related to early subclinical demyelination of the facial nerve, the blood-nerve barrier of the facial nerve, facial movement, and descending reversible paralysis. The occurrence of unilateral facial palsy may be related to Campylobacter jejuni, specific anti-ganglioside antibodies, and the site of central nervous system anatomical involvement. There is no evidence that immunotherapy is related to the shortening of DFP course and improving patients' prognosis.
Global Variability in Deep Brain Stimulation Practices for Parkinson’s Disease
Authors: Mahajan Abhimanyu , Butala Ankur , Okun Michael S. , Mari Zoltan , Mills Kelly A.
Published: March 2021

Introduction

Deep brain stimulation (DBS) has become a standard treatment option for select patients with Parkinson’s disease (PD). The selection process and surgical procedures employed have, to date, not been standardized.

Methods

A comprehensive 58-question web-based survey was developed with a focus on DBS referral practices and peri-operative management. The survey was distributed to the Parkinson’s Foundation Centers of Excellence, members of the International Parkinson’s Disease and Movement Disorders Society, and the Parkinson Study Group (Functional Neurosurgery Working Group) between December 2015 and May 2016.

Results

There were 207 individual respondents (20% response rate) drawn from 59 countries and 6 continents, of whom 64% received formal training in DBS. Thirteen percent of centers reported that DBS could proceed despite a confidence level of < 50% for PD diagnosis. A case-based approach to DBS candidacy was applied in 51.3% of centers without a cut-off for levodopa-responsiveness. Surprisingly, 33% of centers regularly used imaging for diagnostic confirmation of idiopathic PD. Thirty-one percent of centers reported that neuropsychological evaluation did not affect DBS target selection. Approximately half of the respondents reported determination of DBS candidacy based on a multidisciplinary committee evaluation and 1/3rd reported that a committee was used for target selection. Eight percent of respondents felt that psychosocial factors should not impact DBS candidacy nor site selection. Involvement of allied health professionals in the preoperative process was sparse. There was high variability in preoperative education about DBS outcome expectations. Approximately half of the respondents did not utilize a “default brain target,” though STN was used more commonly than GPi. Specific DBS procedure techniques applied, as well as follow-up timelines, were highly variable.

Conclusion

Results revealed high variability on the best approaches for DBS candidate selection, brain target selection, procedure type, and postoperative practices. Cognitive and mood assessments were underutilized. There was low reliance on multidisciplinary teams or psychosocial factors to impact the decision-making process. There were small but significant differences in practice across global regions, especially regarding multidisciplinary teams. The wide variability of responses across multiple facets of DBS care highlights the need for prospective studies to inform evidence-based guidelines.
Impact of the Olig Family on Neurodevelopmental Disorders
Authors: Szu Jenny , Wojcinski Alexandre , Jiang Peng , Kesari Santosh
Published: March 2021

TheOliggenes encode members of the basic helix-loop-helix (bHLH) family of transcription factors. Olig1, Olig2, and Olig3 are expressed in both the developing and mature central nervous system (CNS) and strictly regulate cellular specification and differentiation. Extensive studies have established functional roles ofOlig1andOlig2in directing neuronal and glial formation during different stages in development. Recently, Olig2 overexpression was implicated in neurodevelopmental disorders down syndrome (DS) and autism spectrum disorder (ASD) but its influence on cognitive and intellectual defects remains unknown. In this review, we summarize the biological functions of the Olig family and how it uniquely promotes cellular diversity in the CNS. This is followed up with a discussion on how abnormal Olig2 expression impacts brain development and function in DS and ASD. Collectively, the studies described here emphasize vital features of the Olig members and their distinctive potential roles in neurodevelopmental disease states.
Cooking at Home and Adherence to the Mediterranean Diet During the COVID-19 Confinement: The Experience From the Croatian COVIDiet Study
Authors: Pfeifer Danijela , Rešetar Josip , Gajdoš Kljusurić Jasenka , Panjkota Krbavčić Ines , Vranešić Bender Darija , Rodríguez-Pérez Celia , Ruíz-López María Dolores , Šatalić Zvonimir
Published: March 2021

Introduction: The primary aims of this study were to evaluate the changes in dietary behavior among the Croatian adult population during the COVID-19 outbreak and to explore the impact of confinement on cooking habits.

Methods: The study was based on results from COVIDiet_Int cross-sectional study—a part of COVIDiet project (NCT04449731). A self-administered online questionnaire was used to assess the frequency of food consumption, eating habits, and sociodemographic information. A total number of 4,281 participants (80.5% females and 19.4% males) completed the questionnaire.

Results: The Mediterranean Diet Adherence Screener (MEDAS) score before the confinement was 5.02 ± 1.97, while during the confinement, the MEDAS score increased to 5.85 ± 2.04. Participants who had higher adherence to the Mediterranean diet (MedDiet) during the confinement were mostly females (88.8%), aged between 20 and 50 years, with the highest level of education (66.3%) and normal BMI (70.6%). The majority of participants maintained their dietary behavior as it was before COVID-19 confinement, while 36.9% decreased their physical activity. Participants with higher MEDAS score were more eager to increase their physical activity. Additionally, higher median values of MEDAS score were noted for participants with body mass index values below 24.9 kg/m2 (6.0 vs. 5.0 for participants with BMI above 25 kg/m2). Participants in all residence places increased their cooking frequency during the confinement (53.8%), which was associated with an increase in vegetables, legumes, as well as fish and seafood consumption.

Conclusions: According to our findings, Croatian adults exhibited medium adherence to the MedDiet during the COVID-19 confinement. The results suggest that cooking frequency could be positively associated with overall dietary quality, which is of utmost importance in these demanding times.
Development and Validation of a Simple-to-Use Nomogram for Predicting the Upgrade of Atypical Ductal Hyperplasia on Core Needle Biopsy in Ultrasound-Detected Breast Lesions
Authors: Huang Yun-Xia , Chen Ya-Ling , Li Shi-Ping , Shen Ju-Ping , Zuo Ke , Zhou Shi-Chong , Chang Cai
Published: March 2021

Background

The rate of carcinoma upgrade for atypical ductal hyperplasia (ADH) diagnosed on core needle biopsy (CNB) is variable on open excision. The purpose of the present study was to develop and validate a simple-to-use nomogram for predicting the upgrade of ADH diagnosed with ultrasound (US)-guided core needle biopsy in patients with US-detected breast lesions.

Methods

Two retrospective sets, the training set (n = 401) and the validation set (n = 186), from Fudan University Shanghai Cancer Center between January 2014 and December 2019 were retrospectively analyzed. Clinicopathological and US features were selected using univariate and multivariable logistic regression, and the significant features were incorporated to build a nomogram model. Model discrimination and calibration were assessed in the training set and validation set.

Results

Of the 587 ADH biopsies, 67.7% (training set: 267/401, 66.6%; validation set: 128/186, 68.8%) were upgraded to cancers. In the multivariable analysis, the risk factors were age [odds ratio (OR) 2.739, 95% confidence interval (CI): 1.525–5.672], mass palpation (OR 3.008, 95% CI: 1.624–5.672), calcifications on US (OR 4.752, 95% CI: 2.569–9.276), ADH extent (OR 3.150, 95% CI: 1.951–5.155), and suspected malignancy (OR 4.162, CI: 2.289–7.980). The model showed good discrimination, with an area under curve (AUC) of 0.783 (95% CI: 0.736–0.831), and good calibration (p = 0.543). The application of the nomogram in the validation set still had good discrimination (AUC = 0.753, 95% CI: 0.666–0.841) and calibration (p = 0.565). Instead of surgical excision of all ADHs, if those categorized with the model to be at low risk for upgrade were surveillanced and the remainder were excised, then 63.7% (37/58) of surgeries of benign lesions could have been avoided and 78.1% (100/128) malignant lesions could be treated in time.

Conclusions

This study developed a simple-to-use nomogram by incorporating clinicopathological and US features with the overarching goal of predicting the probability of upgrade in women with ADH. The nomogram could be expected to decrease unnecessary surgery by nearly two-third and to identify most of the malignant lesions, helping guide clinical decision making with regard to surveillance versus surgical excision of ADH lesions.
The CSRNP Gene Family Serves as a Prognostic Biomarker in Clear Cell Renal Cell Carcinoma
Authors: Zhang Huaru , Qiu Xiaofu , Yang Guosheng
Published: March 2021

The cysteine-serine-rich nuclear protein (CSRNP) family has prognostic value for various cancers. However, the association between this proteins and prognosis of clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to determine the prognostic value of theCSRNPfamily for patients with ccRCC. Therefore, the gene expression profiling interactive analysis database was used to analyze the mRNA expression ofCSRNPfamily members (CSRNPs) in relation with survival. Combined and independent prognostic values of CSRNPs were evaluated using SurvExpress and multivariate Cox regression analyses, respectively. Potential signaling pathways impacted byCSRNPswere evaluated using Metascape. Associations between theCSRNPfamily and immunocyte infiltration were determined from single-sample gene set enrichment analysis. Both cBioPortal and MethSurv were used to explore whether genomic and epidemic alterations might influence prognosis. We found that when bothCSRNP1andCSRNP3had a low expression, patients with ccRCC had a worse overall survival (OS). Therefore, a prognostic signature was constructed as follows: risk score = −0.224 × expmRNA ofCSRNP1+ 0.820 × expmRNA ofCSRNP2− 1.428 × expmRNA ofCSRNP3. We found that OS was worse in patients from the high- than from the low-risk groups (AUC = 0.69). Moreover, this signature was an independent predictor after adjusting for clinical features. Functional enrichment analysis positively associated CSRNPs with the acute inflammatory response and humoral immune response pathways. This was validated by correlating eachCSRNPwith 28 types of immunocytes in tumor and normal tissues. A higher expression ofCSRNP1andCSRNP3was associated with a better prognosis in both the high- and low-mutant burden groups. Cg19538674, cg07772537, and cg07811002 ofCSRNP1,CSRNP2, andCSRNP3, respectively, were the predominant DNA methylation sites affecting OS. TheCSRNPgene family signature may serve as a prognostic biomarker for predicting OS in patients with ccRCC. The association betweenCSRNPsand immune infiltration might offer future clinical treatment options.
Decitabine With or Without Micro-Transplantation for the Treatment of Intermediate or High-Risk Myelodysplastic Syndrome: A Chinese Single-Center Retrospective Study of 22 Patients
Authors: Li MinMing , Li Chao , Geng SuXia , Chen XiaoMei , Wu Ping , Deng ChengXin , Chen XiaoFang , Lu ZeSheng , Weng JianYu , Du Xin
Published: March 2021

The treatment outcomes of intermediate or high-risk myelodysplastic syndrome (MDS) remain unsatisfactory. This study was designed to evaluate the safety and efficacy of human leukocyte antigen (HLA)-mismatched hematopoietic stem cell micro-transplantation (MST) in patients with MDS. A total of 22 patients with MDS, ranging between the ages of 39 and 74, were enrolled in this study. Eleven patients were given decitabine (DAC), a DNA methyltransferase inhibitor, combined with HLA-mismatched MST (MST-DAC group), and the remaining patients were given decitabine only (DAC group). The median overall survival (OS) of the MST-DAC group was higher than that of the DAC group (24 vs. 14.3 months; HR 0.32; 95% CI: 0.11–0.96; p = 0.04), although it is a study with small samples. The overall response rate (ORR), marrow complete remission (mCR), plus hematological improvement (HI) rates of the MST-DAC group were higher than that of the DAC group (81.8 vs. 54.5%, p = 0.36; 63.6 vs. 27.3%, p = 0.09, respectively); however, there were no statistical differences between the two groups, which may be attributed to the limited number of cases evaluated in this study. No graft-vs.-host disease was observed in the MST-DAC group. Patients in the MST-DAC group demonstrated a slightly lower incidence of hematological and non-hematological adverse events (AEs). DAC combined with HLA-mismatched MST may provide a novel, effective, and safe treatment for use in intermediate or high-risk MDS pathologies.
Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model
Authors: Qiao Tianyun , Xiong Yanlu , Feng Yangbo , Guo Wenwen , Zhou Yongsheng , Zhao Jinbo , Jiang Tao , Shi Changhong , Han Yong
Published: March 2021

Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infiltration and activity of immune cells and turn tumors into hot tumors. Therefore, we constructed a humanized mouse model to evaluate the efficacy of using classical LDH inhibitor oxamate and pembrolizumab alone or in combination in non-small cell lung cancer (NSCLC). We found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth; moreover, combination therapy showed better results. Immunofluorescence analysis showed that oxamate treatment increased the infiltration of activated CD8+ T cells in the tumor, which might have enhanced the therapeutic effects of pembrolizumab. Treatment of the humanized mice with anti-CD8 abrogated the therapeutic effects of oxamate, indicating CD8+ T cells as the main force mediating the effect of oxamate. In conclusion, Our preclinical findings position that oxamate not only inhibits tumor growth at a high safe dose but also enhances the efficacy of pembrolizumab in Hu-PBMC-CDX mice. Our study also provides a preclinical model for exploring the efficacy of other immune-based combination therapies for NSCLC.
Discovering and Characterizing of Survivin Dominant Negative Mutants With Stronger Pro-apoptotic Activity on Cancer Cells and CSCs
Authors: Guo Wei , Ma Xingyuan , Fu Yunhui , Liu Chang , Liu Qiuli , Hu Fabiao , Miao Hui , Zhang Tong , Liu Yuping , Han Myong Hun , You Fang , Yang Yi , Zheng Wenyun
Published: March 2021

Survivin as a member of the inhibitor of apoptosis proteins (IAPs) family is undetectable in normal cells, but highly expressed in cancer cells and cancer stem cells (CSCs) which makes it an attractive target in cancer therapy. Survivin dominant negative mutants have been reported as competitive inhibitors of endogenous survivin protein in cancer cells. However, there is a lack of systematic comparative studies on which mutants have stronger effect on promoting apoptosis in cancer cells, which will hinder the development of novel anti-cancer drugs. Here, based on the previous study of survivin and its analysis of the relationship between structure and function, we designed and constructed a series of different amino acid mutants from survivin (TmSm34, TmSm48, TmSm84, TmSm34/48, TmSm34/84, and TmSm34/48/84) fused cell-permeable peptide TATm at the N-terminus, and a dominant negative mutant TmSm34/84 with stronger pro-apoptotic activity was selected and evaluated systematically in vitro. The double-site mutant of survivin (TmSm34/84) showed more robust pro-apoptotic activity against A549 cells than others, and could reverse the resistance of A549 CSCs to adriamycin (ADM) (reversal index up to 7.01) by decreasing the expression levels of survivin, P-gp, and Bcl-2 while increasing cleaved caspase-3 in CSCs. This study indicated the selected survivin dominant negative mutant TmSm34/84 is promising to be an excellent candidate for recombinant anti-cancer protein by promoting apoptosis of cancer cells and their stem cells and sensitizing chemotherapeutic drugs.
Genomics-Guided Drawing of Molecular and Pathophysiological Components of Malignant Regulatory Signatures Reveals a Pivotal Role in Human Diseases of Stem Cell-Associated Retroviral Sequences and Functionally-Active hESC Enhancers
Authors: Glinsky Gennadi V.
Published: March 2021

Repetitive DNA sequences (repeats) colonized two-third of human genome and a majority of repeats comprised of transposable genetic elements (TE). Evolutionary distinct categories of TE represent nucleic acid sequences that are repeatedly copied from and pasted into chromosomes at multiple genomic locations and acquired a multitude of regulatory functions. Here, genomics-guided maps of stemness regulatory signatures were drawn to dissect the contribution of TE to clinical manifestations of malignant phenotypes of human cancers. From patients’ and physicians’ perspectives, the clinical definition of a tumor’s malignant phenotype could be restricted to the early diagnosis of sub-types of malignancies with the increased risk of existing therapy failure and high likelihood of death from cancer. It is the viewpoint from which the understanding of stemness and malignant regulatory signatures is considered in this contribution. Genomics-guided analyses of experimental and clinical observations revealed the pivotal role of human stem cell-associated retroviral sequences (SCARS) in the origin and pathophysiology of clinically-lethal malignancies. SCARS were defined as the evolutionary- and biologically-related family of genomic regulatory sequences, the principal physiological function of which is to create and maintain the stemness phenotype during human preimplantation embryogenesis. For cell differentiation to occur, SCARS expression must be silenced and SCARS activity remains repressed in most terminally-differentiated human cells which are destined to perform specialized functions in the human body. Epigenetic reprogramming, de-repression, and sustained activity of SCARS results in various differentiation-defective phenotypes. One of the most prominent tissue- and organ-specific clinical manifestations of sustained SCARS activities is diagnosed as a pathological condition defined by a consensus of morphological, molecular, and genetic examinations as the malignant growth. Here, contemporary evidence are acquired, analyzed, and reported defining both novel diagnostic tools and druggable molecular targets readily amenable for diagnosis and efficient therapeutic management of clinically-lethal malignancies. These diagnostic and therapeutic approaches are based on monitoring of high-fidelity molecular signals of continuing SCARS activities in conjunction with genomic regulatory networks of thousands’ functionally-active embryonic enhancers affecting down-stream phenotype-altering genetic loci. Collectively, reported herein observations support a model of SCARS-activation triggered singular source code facilitating the intracellular propagation and intercellular (systemic) dissemination of disease states in the human body.
Autophagy in Human T-Cell Leukemia Virus Type 1 (HTLV-1) Induced Leukemia
Authors: Ducasa Nicolás , Grasso Daniel , Benencio Paula , Papademetrio Daniela L. , Biglione Mirna , Kashanchi Fatah , Berini Carolina , Garcia Maria Noé
Published: March 2021

Viruses play an important role in the development of certain human cancers. They are estimated to contribute 16% to all human cancers. Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus to be discovered and is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive T-cell malignancy with poor prognosis. HTLV-1 viral proteins interact with mechanisms and proteins present in host cells for their own benefit, evading the immune system and promoting the establishment of disease. Several viruses manipulate the autophagy pathway to achieve their infective goals, and HTLV-1 is not the exception. HTLV-1 Tax viral protein engages NF-κB and autophagy pathways prone favoring viral replication and T cell transformation. In this review we focus on describing the relationship of HTLV-1 with the autophagy machinery and its implication in the development of ATLL.
Case Report: Grade 2 Metastatic Pancreatic Neuroendocrine Tumor With Progression of One Metastasis After Pregnancy to Grade 3 Large-Cell Neuroendocrine Carcinoma: One Case Cured by Resection With Genomic Characterization of the Two Components
Authors: Raoul Jean-Luc , Heymann Marie-Françoise , Dumont Frédéric , Morel Alain , Senellart Hélène , Bertucci François
Published: March 2021

Temporal and spatial tumor heterogeneity can be observed in pancreatic neuroendocrine tumor. We report the case of a young woman with long term stabilization of a G2 metastatic pancreatic NET that, after pregnancy, suddenly progressed into one single liver metastasis corresponding to a transformation into G3 large-cell neuroendocrine cancer. The patient underwent liver resection (the progressive and one dormant metastasis). With a 45 months follow-up the patient is without evolutive disease. Exome sequencing of the two metastases revealed completely different genomic signatures and gene alterations: the dormant metastasis was MSS without any gene alteration; the poorly differentiated tumor was MSI, with gain of many mutations including MEN1, BCL2, MLH1 and TP53 corresponding to a mutational signature 11. Could temozolomide play a role in this transformation?
Apolipoprotein B Is Associated With the Microenvironment of Cholangiocarcinoma
Authors: Xu Xiaofeng , Chen Diyu , Feng Xiaode , Hu Jiating , Ge Jiangzhen , Yan Chaobiao , Zhang Deguo , Ling Zhenan , Chen Jianzhong , Wu Jian
Published: March 2021

Background

Cholangiocarcinoma (CCA) is a kind of devastating malignancy, which is correlated with the extremely high mortality. Due to the occult pathogenesis of CCA, most patients are diagnosed in the advanced stage. However, the efficacy of chemotherapy and immunotherapy is limited for these patients. The cause for this phenomenon is unclear, the recent researches indicate that it could be related to predisposing genetic factors and tumor microenvironment (TME) changes. The TME is created by the tumor and dominated by tumor-induced interactions. And the tumor prognosis could be influenced by the extent of infiltrating immune cells and stromal cells in TME.

Materials and methods

The abundance ratio of immune cells for each sample was obtained via the CIBERSORT algorithm, and we used ESTIMATE score system to calculate the immune and stromal scores in CCA. The CCA cases in TCGA database were categorized into high and low score groups according to their immune/stromal scores. And then, we identified the differential expressed genes (DEGs) in two groups. Functional enrichment analysis and protein‐protein interaction networks were carried out for DEGs. Interestingly, we found out that apolipoprotein B (APOB) is the most down-regulated among these genes. Then we performed the immunohistochemistry staining of APOB in a CCA tumor microarray which contained 100 CCA cases, APOB was down-regulated in CCA samples. Thus, we evaluated the APOB function in the TME of CCA through TIMER.

Results and Conclusion

The results demonstrate that the infiltration degree of immune cells in CCA could be influenced by the expression of APOB, and the APOB expression could be mediated by DNA methylation. Our study not only indicates APOB is a potential target for CCA immunotherapy but also provides new ideas for researchers to explore the immunotherapy of various tumors.