bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid Detection of Multi-Resistance Strains Carrying mcr-1 Gene Using Recombinase-Aided Amplification Directly on Clinical Samples
Authors: Fan Zheng , Feng Yanling , Xu Wenjian , Feng Junxia , Yan Chao , Fu Tongtong , Zhao Hanqing , Cui Jinghua , Gan Lin , Liu Shiyu , Du Shuheng , Zhang Rui , Xu Ziying , Li Nannan , Xue Guanhua , Yuan Jing
Published: March 2022

With the increasingly severe problem of bacterial resistance, colistin, as the last line of defense, has attracted attention again. Mobile colistin resistance (mcr-1) gene is involved in the horizontal transmission of colistin resistance in Gram-negative bacteria (GNB), which is a serious threat to human health. Therefore, rapid detection of mcr-1 gene presence in clinical samples is crucial. In this study, a Recombinase-aided amplification(RAA) method for mcr-1 was successfully constructed, with sensitivity of 20 copies/reaction. In addition, amplification signal could only be detected in the strain containing mcr-1 gene among 14 different bacterial species. The method was then used to test a total of 672 clinical samples from a pediatric hospital in Beijing. Five strains harbored mcr-1 genes were isolated from mcr-1-positive clinical samples and identified as Escherichia coli. Multi-locus sequence typing (MLST) analysis showed that the five E. coli belonged to different ST types. Notably, the mcr-1 gene from the isolates could be transferred conjugately to the recipient strain E. coli J53, with highest transfer efficiency up to 57–58%, suggesting that the mcr-1 gene was located on the plasmid. These findings showed that the RAA assay has potential to be a rapid and sensitive mcr-1 gene screening test for clinical samples, and mcr-1 could be transmitted vertically and horizontally between and within bacterial species in a plasmid-mediated manner.
Identification of the Key Pathways and Genes in Hypoxia Pulmonary Arterial Hypertension Following Intrauterine Growth Retardation
Authors: Zhu Weifen , Zhang Ziming , Gui Weiwei , Shen Zheng , Chen Yixin , Yin Xueyao , Liang Li , Li Lin
Published: March 2022

High-throughput sequencing and weighted gene co-expression network analysis (WGCNA) were used to identify susceptibility modules and genes in liver tissue for the hypoxic pulmonary arterial hypertension (PAH) animal model following intrauterine growth retardation (IUGR). A total of 5,000 genes were clustered into eight co-expression modules via WGCNA. Module blue was mostly significantly correlated with the IUGR–hypoxia group. Gene Ontology analysis showed that genes in the module blue were mainly enriched in the fatty acid metabolic process, lipid modification, and fatty acid catabolic process. The Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that the genes in module blue were mainly associated with fatty acid metabolism, PPAR signaling pathway, and biosynthesis of unsaturated fatty acids. In addition, the maximal clique centrality method was used to identify the hub genes in the subnetworks, and the obtained results were verified using real-time quantitative PCR. Finally, we identified that four genes including Cyp2f4, Lipc, Acadl, and Hacl1 were significantly associated with IUGR-hypoxia. Our study identified a module and several key genes that acted as essential components in the etiology of the long-term metabolic consequences in hypoxia PAH following IUGR.
Multi-Granularity Analysis of Brain Networks Assembled With Intra-Frequency and Cross-Frequency Phase Coupling for Human EEG After Stroke
Authors: Ren Bin , Yang Kun , Zhu Li , Hu Lang , Qiu Tao , Kong Wanzeng , Zhang Jianhai
Published: March 2022

Evaluating the impact of stroke on the human brain based on electroencephalogram (EEG) remains a challenging problem. Previous studies are mainly analyzed within frequency bands. This article proposes a multi-granularity analysis framework, which uses multiple brain networks assembled with intra-frequency and cross-frequency phase-phase coupling to evaluate the stroke impact in temporal and spatial granularity. Through our experiments on the EEG data of 11 patients with left ischemic stroke and 11 healthy controls during the mental rotation task, we find that the brain information interaction is highly affected after stroke, especially in delta-related cross-frequency bands, such as delta-alpha, delta-low beta, and delta-high beta. Besides, the average phase synchronization index (PSI) of the right hemisphere between patients with stroke and controls has a significant difference, especially in delta-alpha (p = 0.0186 in the left-hand mental rotation task, p = 0.0166 in the right-hand mental rotation task), which shows that the non-lesion hemisphere of patients with stroke is also affected while it cannot be observed in intra-frequency bands. The graph theory analysis of the entire task stage reveals that the brain network of patients with stroke has a longer feature path length and smaller clustering coefficient. Besides, in the graph theory analysis of three sub-stags, the more stable significant difference between the two groups is emerging in the mental rotation sub-stage (500–800 ms). These findings demonstrate that the coupling between different frequency bands brings a new perspective to understanding the brain's cognitive process after stroke.
Transitional and Long-Term Rehabilitation Care System After Stroke in Korea
Authors: Leigh Ja-Ho , Kim Won-Seok , Sohn Dong-Gyun , Chang Won Kee , Paik Nam-Jong
Published: March 2022

Stroke is one of the leading causes of mortality and disability in Korea. Patients who experience stroke require adequate management throughout the acute to subacute and chronic stages. Many patients with long-term functional issues require rehabilitative management even in the chronic stage. A comprehensive rehabilitation and care model for patients who experience stroke is necessary to effectively manage their needs during rehabilitation and allocate medical resources throughout the stages, thus ensuring reduced unmet needs and improved post-stroke quality of life. In Korea, the government and medical specialists are working on re-organizing the rehabilitation care model, including standardized triage and discharge planning after acute stroke treatment, and establishing systematic transitional and long-term rehabilitation care plans. This review briefly introduces the general rehabilitation triage after acute stroke and describes the current transitional and continuous care systems available for these patients in Korea. We also present the issues faced in transitional and long-term care plans of the current system and the efforts invested in resolving them and promoting long-term care in stroke cases.
Cerebral Small Vessel Disease in Elderly Patients With Vestibular Neuritis
Authors: Oussoren Fieke K. , Poulsen Louise N. F. , Kardux Joost J. , Schermer Tjard R. , Bruintjes Tjasse D. , van Leeuwen Roeland B.
Published: March 2022

Background

Acute audiovestibular loss is a neurotologic emergency of which the etiology is frequently unknown. In vestibular neuritis a viral genesis is expected, although there is insufficient evidence to support viruses as the only possible etiological factor. In sudden deafness, a vascular etiology has been proposed in elderly patients, since cardiovascular risk factors are more frequently present and a higher risk of developing a stroke was seen compared to the general population. So far, very little research has been carried out on vascular involvement in elderly patients with vestibular neuritis. Cardiovascular risk factors have a positive correlation with cerebral small vessel disease, visible as white matter hyperintensities, brain infarctions, microbleeds and lacunes on MRI. The presence of these characteristics indicate a higher risk of developing a stroke.

Aim

We investigated whether elderly patients with vestibular neuritis have a higher prevalence of vascular lesions on MRI compared to a control cohort.

Materials and Methods

Patients of 50-years and older, diagnosed with vestibular neuritis in a multidisciplinary tertiary referral hospital, were retrospectively reviewed and compared to a control cohort. The primary outcome was the difference in cerebral small vessel disease on MRI imaging, which was assessed by the number of white matter hyperintensities using the ordinal Fazekas scale. Secondary outcomes were the presence of brain infarctions on MRI and the difference in cardiovascular risk factors.

Results

Patients with vestibular neuritis (N = 101) had a 1.60 higher odds of receiving a higher Fazekas score than the control cohort (N = 203) (p = 0.048), there was no difference in presence of brain infarctions (p = 1.0). Hyperlipidemia and atrial fibrillation were more common in patients experiencing vestibular neuritis.

Conclusion

We found a positive correlation of white matter hyperintensities and VN which supports the hypothesis of vascular involvement in the pathophysiology of vestibular neuritis in elderly patients. Further prospective research is necessary to confirm this correlation.
Diagnostic Utility of Superb Microvascular Imaging and Power Doppler Ultrasonography for Visualizing Enriched Microvascular Flow in Patients With Carpal Tunnel Syndrome
Authors: Endo Takeshi , Matsui Yuichiro , Kawamura Daisuke , Urita Atsushi , Momma Daisuke , Ota Mitsutoshi , Shibayama Hiroki , Iwai Takahito , Nishida Mutsumi , Iwasaki Norimasa
Published: March 2022

Recent studies suggest that blood flow changes in the median nerve may help confirm a diagnosis of carpal tunnel syndrome (CTS). Herein, we examined the utility of superb microvascular imaging (SMI), a new ultrasonographic (US) technique for visualizing microvascular flow, for detecting blood flow differences between CTS patients and healthy controls. We performed a retrospective analysis of 28 hands with suspected CTS. Patients received both nerve conduction and US examinations. Ten healthy volunteers were enrolled as the control group. The nerve compression ratio and the blood flow signal area were quantified using color Doppler US (CDUS), power Doppler US (PDUS), and SMI. Correlation analyses between the blood flow signal area, the compound muscle action potential of the thenar muscle, and the nerve compression ratio were performed. As a result, the mean nerve compression ratio was found to be significantly higher in the CTS group. There were no differences in the blood flow signal area between the groups using CDUS, while PDUS and SMI showed higher blood flow signals in the CTS group. The blood flow signal area measured by SMI had stronger correlations with the compound muscle action potential amplitude and the nerve compression ratio than those for PDUS. The diagnostic utility of SMI was equivalent to PDUS, but superior to conventional CDUS. Nevertheless, the blood flow signal by SMI was more strongly correlated with the electrophysiological severity and compression ratio than for PDUS. Use of SMI in future studies may help clarify the underlying mechanisms of blood flow changes in CTS.
Dural Immune Cells, CGRP, and Migraine
Authors: Balcziak Louis K. , Russo Andrew F.
Published: March 2022

Migraine is the most common neurological disorder in the world, affecting 12% of the population. Migraine involves the central nervous system, trigeminal nerves and meninges. Recent advances have shown that targeting calcitonin gene-related peptide (CGRP) through either antibodies or small molecule receptor antagonists is effective at reducing episodic and chronic migraine episodes, but these therapeutics are not effective in all patients. This suggests that migraine does not have a singular molecular cause but is likely due to dysregulated physiology of multiple mechanisms. An often-overlooked part of migraine is the potential involvement of the immune system. Clinical studies have shown that migraine patients may have dysregulation in their immune system, with abnormal plasma cytokine levels either during the attack or at baseline. In addition, those who are immunocompromised appear to be at a higher risk of migraine-like disorders. A recent study showed that migraine caused changes to transcription of immune genes in the blood, even following treatment with sumatriptan. The dura mater is densely packed with macrophages, mast and dendritic cells, and they have been found to associate with meningeal blood vessels and trigeminal afferent endings. Recent work in mice shows activation and morphological changes of these cells in rodents following the migraine trigger cortical spreading depression. Importantly, each of these immune cell types can respond directly to CGRP. Since immune cells make up a large portion of the dura, have functional responses to CGRP, and interact with trigeminal afferents, CGRP actions on the dural immune system are likely to play key roles in migraine.
AUTS2 Syndrome: Molecular Mechanisms and Model Systems
Authors: Biel Alecia , Castanza Anthony S. , Rutherford Ryan , Fair Summer R. , Chifamba Lincoln , Wester Jason C. , Hester Mark E. , Hevner Robert F.
Published: March 2022

AUTS2 syndrome is a genetic disorder that causes intellectual disability, microcephaly, and other phenotypes. Syndrome severity is worse when mutations involve 3’ regions (exons 9-19) of the AUTS2 gene. Human AUTS2 protein has two major isoforms, full-length (1259 aa) and C-terminal (711 aa), the latter produced from an alternative transcription start site in exon 9. Structurally, AUTS2 contains the putative “AUTS2 domain” (∼200 aa) conserved among AUTS2 and its ohnologs, fibrosin, and fibrosin-like-1. Also, AUTS2 contains extensive low-complexity sequences and intrinsically disordered regions, features typical of RNA-binding proteins. During development, AUTS2 is expressed by specific progenitor cell and neuron types, including pyramidal neurons and Purkinje cells. AUTS2 localizes mainly in cell nuclei, where it regulates transcription and RNA metabolism. Some studies have detected AUTS2 in neurites, where it may regulate cytoskeletal dynamics. Neurodevelopmental functions of AUTS2 have been studied in diverse model systems. In zebrafish, auts2a morphants displayed microcephaly. In mice, excision of different Auts2 exons (7, 8, or 15) caused distinct phenotypes, variously including neonatal breathing abnormalities, cerebellar hypoplasia, dentate gyrus hypoplasia, EEG abnormalities, and behavioral changes. In mouse embryonic stem cells, AUTS2 could promote or delay neuronal differentiation. Cerebral organoids, derived from an AUTS2 syndrome patient containing a pathogenic missense variant in exon 9, exhibited neocortical growth defects. Emerging technologies for analysis of human cerebral organoids will be increasingly useful for understanding mechanisms underlying AUTS2 syndrome. Questions for future research include whether AUTS2 binds RNA directly, how AUTS2 regulates neurogenesis, and how AUTS2 modulates neural circuit formation.
Greenhouse Gas Emissions Associated With the Mexican Diet: Identifying Social Groups With the Largest Carbon Footprint
Authors: López-Olmedo Nancy , Stern Dalia , Bakhtsiyarava Maryia , Pérez-Ferrer Carolina , Langellier Brent
Published: March 2022

Background

Most studies of the climate footprint of diets have been conducted in countries in the global north, but the majority of the world population lives in global south countries. We estimated total dietary greenhouse gas emissions (GHGE) in Mexico, examined the contribution of major food and beverage groups, and assessed variation across social groups.

Methods

We linked individual-level dietary data from the Mexican National Health and Nutrition Survey 2018 to the SHARP Indicators Database, containing GHGE estimates for 182 primary food and beverages.

Results

Mean dietary GHGE was 3.9 kg of carbon dioxide equivalent per person per day. Dietary GHGE is highest among those in young adulthood and middle age versus adolescents and older adults, and among males, those with higher educational attainment, higher socioeconomic status, that do not speak an indigenous language, and that live in urban areas.

Conclusion

The Mexican diet has a much lower carbon footprint than diets in other Latin American countries for which such estimates are available. In contrast to patterns observed in Argentina and Brazil, dietary GHGE was lowest in those in lower socioeconomic and educational strata and in rural areas. A better understanding of the differences in diet sustainability between and within countries will be needed for developing global and local strategies that meet the environmental sustainability goals.
Comparing SARC-CalF With SARC-F for Screening Sarcopenia in Adults With Type 2 Diabetes Mellitus
Authors: Xu Zeru , Zhang Ping , Chen Yifei , Jiang Jiahong , Zhou Zijun , Zhu Hong
Published: March 2022

Background

The prevalence of sarcopenia is high in older people with type 2 diabetes mellitus (T2DM) and is now considered a critical problem in the healthcare sector. However, the preferred screening tool for identifying sarcopenia remains unknown. Thus, the aim of this study was to ensure that the diagnostic values of the SARC-F (strength, assisting with walking, rising from a chair, climbing stairs, and falling) and SARC-CalF (SARC and calf circumference) scales were compared with five reference diagnostic criteria for sarcopenia.

Methods

This was a cross-sectional study. Patients diagnosed with diabetes were treated at the First Affiliated Hospital of Wenzhou Medical University. Appendicular skeletal muscle mass, muscle strength, and physical performance were assessed using dual-energy X-ray absorptiometry, handgrip strength, and gait speed assessment. Five diagnostic criteria for sarcopenia (Asian Working Group for Sarcopenia, International Working Group on Sarcopenia, Foundation for the National Institutes of Health, Sarcopenia Project, Society on Sarcopenia Cachexia and Wasting Disorders, and European Working Group on Sarcopenia in Older People criteria) were utilized. Sensitivity and specificity analyses were performed on the SARC-CalF and SARC-F scales. The diagnostic precision of both instruments was determined using the receiver-operating characteristic (ROC) curves and area under the ROC curves (AUC).

Results

This study included 689 subjects (459 men and 230 women) with a mean age of 58.1 ± 13.2 years. In accordance with the five reference diagnostic parameters, the prevalence of sarcopenia was between 4.5 and 19.2%. In addition, the range of sensitivity of SARC-F and SARC-CalF ranged from 61.4 to 67.4 and 82.6 to 91.8%, respectively. Concurrently, the specificity ranged from 63.1 to 67.3 and 51.5 to 61.2%, respectively. Overall, AUC values for SARC-CalF were higher than those for SARC-F, regardless of the diagnostic standard, sex, or age.

Conclusion

The results of this study suggest that SARC-CalF significantly enhances the sensitivity and overall diagnosis of SARC-F. SARC-CalF appears to be an optimal screening tool for sarcopenia in adults with T2DM.
Adherence to the Mediterranean Diet in Pregnancy and Its Benefits on Maternal-Fetal Health: A Systematic Review of the Literature
Authors: Zaragoza-Martí Ana , Ruiz-Ródenas Nuria , Herranz-Chofre Irene , Sánchez-SanSegundo Miriam , Serrano Delgado Verónica de la Cruz , Hurtado-Sánchez Jose Antonio
Published: March 2022

Introduction

Pregnancy is a transcendent period for the mother and the fetus, characterized by an increase on energy requirements. Mediterranean diet (MD) is considered a healthy eating pattern that can provide the nutritional requirements of pregnancy and protect from the development of obstetric pathologies.

Objective

To know the relationship between adherence to the MD and its maternal-fetal benefits.

Methodology

A systematic review was conducted by identifying articles in the PubMed and Cochrane databases. The publication date of the studies was between 2010 and 2020, and the inclusion criteria established were that the articles were written in English and Spanish and were accessible in full text. Studies concerning assisted reproduction, gene modulation, conference abstracts, systematic reviews, and pilot studies were excluded.

Results

Finally, a total of 14 studies were included in the review. The association between the MD and the reduction of some pathologies of pregnancy, such as gestational diabetes, overweight or obesity, sleep quality, complications of childbirth, urinary tract infections (UTIs), and alterations in fetal growth was demonstrated, as well as perinatal problems, including birth weight, prematurity, gastroschisis, and other childhood problems.

Conclusion

The MD is an optimal diet to consume during pregnancy.
The Effect of Coronavirus Disease-19 Pandemic Lockdown and the Overlapping Ramadan Fasting Period on Glucose Control in Insulin-Treated Patients With Diabetes: A Flash Glucose Monitoring Study
Authors: Helal Radwa , Ashraf Tanveer , Majeed Maria , Lessan Nader
Published: March 2022

Background

A strict lockdown was enforced during coronavirus disease (COVID-19) pandemic in many countries including the UAE. Lockdown period overlapped with Ramadan which is accompanied by its own drastic changes in lifestyle that include meal timings.

Aims

We report the impact of COVID-19 lockdown (between 22/3/2020 and 24/6/2020) on glucose control pre- and postlockdown and during Ramadan, in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) on insulin therapy.

Methods

A number of twenty-four patients (19 men, 6 women) who were monitoring their glucose levels using flash glucose monitoring (FGM) and remotely connected to the diabetes clinic in Imperial College London Diabetes Centre (ICLDC), Abu Dhabi, UAE were included. Using the international consensus on the use of continuous glucose monitoring guidelines, analyses of data were performed on glucose management indicator (GMI), time in range (TIR), time in hyperglycemia, time in hypoglycemia, low blood glucose index (LBGI) and high blood glucose index (HBGI). Variables were calculated for each period: 30 days before lockdown 14/2/2020–14/3/2020, 30 days into lockdown and pre-Ramadan 20/3/2020–18/4/2020, and 30 days into lockdown and Ramadan 24/4/2020–23/5/2020, using cgmanalysis package in R-studio software.

Results

Mean average glucose (MAG) remained steady before and during lockdown, and no significant differences were observed in TIR, time in hypoglycemia, and LBGI between prelockdown and lockdown periods. However, there was a statistically significant difference in GMI and percentage of time in hyperglycemia (>10.0 mmol/L) between Ramadan and pre-Ramadan during the lockdown period in p = 0.007, 0.006, and 0.004, respectively. Percentage of TIR (3.9–10.0 mmol/L) was significantly lower in Ramadan as compared to pre-Ramadan (50.3% vs. 56.1%; p = 0.026). Mean absolute glucose (MAG) (182.0 mmol/L vs. 166.6 mmol/L, p = 0.007) and HBGI (10.2 (6.8, 14.8) vs. 11.9 (7.9, 17.8), p = 0.037) were significantly higher in Ramadan compared to pre-Ramadan period. There was no statistically significant difference in percentage of time in hypoglycemia (<3.9 mmol/L) and LBGI between Ramadan and pre-Ramadan periods.

Conclusion

The lockdown period had no significant effects in the markers of glycemic control in the population studied. However, Ramadan fasting period embedded within this time was associated with several changes that include increase in GMI, HBGI, and glycemic variability similar to what has been reported in other Ramadan studies.
Effects of Dietary Intervention on Inflammatory Markers in Metabolic Syndrome: A Systematic Review and Meta-Analysis
Authors: Wang Mengjun , Liu Junliang , Zhang Zhao , Zhang Haixiong , Wang Ning , Chen Xi , Han Xuemei , Lu Qian , Chi Shanshan
Published: March 2022

Background

Dietary interventions may modulate inflammatory indicators, but the correlations between dietary intervention and inflammatory markers in metabolic syndrome (MetS) settings remain opaque.

Objective

To evaluate the effects of dietary intervention on interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) in patients with MetS by systematic review and meta-analysis.

Methods

Databases, including PubMed, Embase, Cochrane Library, Scopus, and Google scholar, were searched from June 2011 to June 2021 for relevant available articles. Standardized mean difference (SMD) was generated as effect size by meta-analysis for continuous variants, including IL-1β, IL-6, TNF-α, and CRP levels. Then, according to study characteristics by dietary patterns of the intervention, subgroup analyses were performed.

Results

Finally, 13 studies comprising a total of 1,101 participants were included for the meta-analysis. IL-6 levels in dietary patients were significantly lower than controls (SMD = −0.30, 95% CI = −0.55, 0.04, p = 0.02, I2 = 64%). However, IL-1β, TNF-α, and CRP levels did not change significantly compared with the control group. Sensitivity analyses further yielded similar results.

Conclusions

Dietary intervention may help decrease IL-6 rather than IL-1β, TNF-α, or CRP levels in patients with MetS.
Digestive Characteristics of Hericium erinaceus Polysaccharides and Their Positive Effects on Fecal Microbiota of Male and Female Volunteers During in vitro Fermentation
Authors: Tian Baoming , Geng Yan , Xu Tianrui , Zou Xianguo , Mao Rongliang , Pi Xionge , Wu Weicheng , Huang Liangshui , Yang Kai , Zeng Xiaoxiong , Sun Peilong
Published: March 2022

Hericium erinaceus polysaccharides (HEPs) have attracted widespread attention in regulating gut microbiota (GM). To investigate digestibility and fermentation of HEPs and their effects on GM composition, three polysaccharide fractions, namely, HEP-30, HEP-50, and HEP-70, were fractionally precipitated with 30%, 50%, and 70% ethanol concentrations (v/v) from hot water-soluble extracts of Hericium erinaceus, respectively. Three kinds of prepared HEPs were structurally characterized and simulated gastrointestinal digestion, and their effects on human fecal microbiota fermentations of male and female and short-chain fatty acid (SCFA) production in vitro were clarified. Under digestive conditions simulating saliva, stomach, and small intestine, HEPs were not significantly influenced and safely reached the distal intestine. After 24 h of in vitro fermentation, the content of SCFAs was significantly enhanced (p < 0.05), and the retention rates of total and reducing sugars and pH value were significantly decreased (p < 0.05). Thus, HEPs could be utilized by GM, especially HEP-50, and enhanced the relative abundance of SCFA-producing bacteria, e.g., Bifidobacterium, Faecalibacterium, Blautia, Butyricicoccus, and Lactobacillus. Furthermore, HEPs reduced the relative abundances of opportunistic pathogenic bacteria, e.g., Escherichia-Shigella, Klebsiella, and Enterobacter. This study suggests that gradual ethanol precipitation is available for the preparation of polysaccharides from Hericium erinaceus, and the extracted polysaccharide could be developed as functional foods with great development value.
Boron Neutron Capture Therapy: Current Status and Challenges
Authors: Wang Song , Zhang Zhengchao , Miao Lele , Li Yumin
Published: March 2022

Boron neutron capture therapy (BNCT) is a re-emerging therapy with the ability to selectively kill tumor cells. After the boron delivery agents enter the tumor tissue and enrich the tumor cells, the thermal neutrons trigger the fission of the boron atoms, leading to the release of boron atoms and then leading to the release of the α particles (4He) and recoil lithium particles (7Li), along with the production of large amounts of energy in the narrow region. With the advantages of targeted therapy and low toxicity, BNCT has become a unique method in the field of radiotherapy. Since the beginning of the last century, BNCT has been emerging worldwide and gradually developed into a technology for the treatment of glioblastoma multiforme, head and neck cancer, malignant melanoma, and other cancers. At present, how to develop and innovate more efficient boron delivery agents and establish a more accurate boron-dose measurement system have become the problem faced by the development of BNCT. We discuss the use of boron delivery agents over the past several decades and the corresponding clinical trials and preclinical outcomes. Furthermore, the discussion brings recommendations on the future of boron delivery agents and this therapy.
Harnessing the Anti-Tumor Mediators in Mast Cells as a New Strategy for Adoptive Cell Transfer for Cancer
Authors: Fereydouni Mohammad , Motaghed Mona , Ahani Elnaz , Kafri Tal , Dellinger Kristen , Metcalfe Dean D. , Kepley Christopher L.
Published: March 2022

The emergence of cancer immunotherapies utilizing adoptive cell transfer (ACT) continues to be one of the most promising strategies for cancer treatment. Mast cells (MCs) which occur throughout vascularized tissues, are most commonly associated with Type I hypersensitivity, bind immunoglobin E (IgE) with high affinity, produce anti-cancer mediators such as tumor necrosis factor alpha (TNF-α) and granulocyte macrophage colony-stimulating factor (GM-CSF), and generally populate the tumor microenvironments. Yet, the role of MCs in cancer pathologies remains controversial with evidence for both anti-tumor and pro-tumor effects. Here, we review the studies examining the role of MCs in multiple forms of cancer, provide an alternative, MC-based hypothesis underlying the mechanism of therapeutic tumor IgE efficacy in clinical trials, and propose a novel strategy for using tumor-targeted, IgE-sensitized MCs as a platform for developing new cellular cancer immunotherapies. This autologous MC cancer immunotherapy could have several advantages over current cell-based cancer immunotherapies and provide new mechanistic strategies for cancer therapeutics alone or in combination with current approaches.
Effectiveness of TKI Inhibitors Combined With PD-1 in Patients With Postoperative Early Recurrence of HCC: A Real-World Study
Authors: Li Zixiong , Han Ning , Ren Xueying , Zhang Yuanjing , Chu Xiaoyuan
Published: March 2022

Objective

To observe the efficacy of TKI inhibitor combined with PD-1 treatment in patients with early recurrence after radical resection of HCC, and to analyze the factors that affect the efficacy.

Methods

The baseline demographic and clinical data of 58 patients with early recurrence after radical resection of HCC (including surgical resection and liver transplantation) were collected. Recurrence and metastasis were classified into early (< or =2 years) and late phase (>2 years). After systemic drug treatment (sorafenib, lenvatinib, PD-1), the efficacy was evaluated based on the RECIST 1.1 standard. COX regression model was used to analyze the factors affecting PFS and OS in HCC patients. Survival curves were drawn by Kaplan-Meier method.

Results

The study finally included 58 patients who underwent radical resection of HCC, of which 39 were in the TKIs group and 19 were in the TKIs + ICIs combined treatment group. There was no statistical difference in the baseline data of the two groups in HB, PLT, Child-Pugh score and other indicators. Efficacy evaluation results showed that in the 39 TKIs group, 7 patients were PD and 9 patients were PR; while in the 19 TKIs combined with PD-1 group, 2 patients were PD and 6 patients were PR. The median PFS of the TKIs group was 6.2 months, while the median PFS of the TKIs combined PD-1 group was 14.0 months (HR= 0.469, P=0.031). The median OS of the TKIs group was 18.0 months, while the median OS of the TKIs combined with PD-1 group was 35.8 months, an extension of 17.8 months (HR= 0.444, P=0.053).

Conclusion

In the first-line treatment of patients with early recurrence after radical resection of HCC, patients treated with TKIs combined with PD-1 therapy has a survival advantage over those treated with TKIs alone. Ascites, HBV DNA positivity, and high levels of AFP often indicate poor efficacy of systemic drug therapy, suggesting that such patients should be closely monitored after surgery and that comprehensive systemic treatment should be administrated in time to improve the prognosis.
Development and Validation of a Novel Radiomics-Based Nomogram With Machine Learning to Preoperatively Predict Histologic Grade in Pancreatic Neuroendocrine Tumors
Authors: Wang Xing , Qiu Jia-Jun , Tan Chun-Lu , Chen Yong-Hua , Tan Qing-Quan , Ren Shu-Jie , Yang Fan , Yao Wen-Qing , Cao Dan , Ke Neng-Wen , Liu Xu-Bao
Published: March 2022

Backgroud

Tumor grade is the determinant of the biological aggressiveness of pancreatic neuroendocrine tumors (PNETs) and the best current tool to help establish individualized therapeutic strategies. A noninvasive way to accurately predict the histology grade of PNETs preoperatively is urgently needed and extremely limited.

Methods

The models training and the construction of the radiomic signature were carried out separately in three-phase (plain, arterial, and venous) CT. Mann–Whitney U test and least absolute shrinkage and selection operator (LASSO) were applied for feature preselection and radiomic signature construction. SVM-linear models were trained by incorporating the radiomic signature with clinical characteristics. An optimal model was then chosen to build a nomogram.

Results

A total of 139 PNETs (including 83 in the training set and 56 in the independent validation set) were included in the present study. We build a model based on an eight-feature radiomic signature (group 1) to stratify PNET patients into grades 1 and 2/3 groups with an AUC of 0.911 (95% confidence intervals (CI), 0.908–0.914) and 0.837 (95% CI, 0.827–0.847) in the training and validation cohorts, respectively. The nomogram combining the radiomic signature of plain-phase CT with T stage and dilated main pancreatic duct (MPD)/bile duct (BD) (group 2) showed the best performance (training set: AUC = 0.919, 95% CI = 0.916–0.922; validation set: AUC = 0.875, 95% CI = 0.867–0.883).

Conclusions

Our developed nomogram that integrates radiomic signature with clinical characteristics could be useful in predicting grades 1 and 2/3 PNETs preoperatively with powerful capability.
Agonists Specific for κ-Opioid Receptor Induces Apoptosis of HCC Cells Through Enhanced Endoplasmic Reticulum Stress
Authors: Tan Mengyuan , Wang Hanyu , Gao Cheng , Jiang Zhen , Yin Ying , Xing Ruyi , Hu Ling , Xu Jiegou , Zhang Min , Xie Yanhu
Published: March 2022

Cancer pain is an important factor affecting life quality of patients especially in the advanced stage and relieving pain is one of fundamental strategies for cancer treatment. Opioids such as morphine are the most widely used in clinics. However, they have been reported to be associated with the occurrence and development of several types of cancer. Thus, search for an opioid that has analgesic effect and can retard cancer progress simultaneously is critical for cancer management. In this study, we first examined the expression of μ and κ (MOR and KOR) in cell lines and tumor tissues of hepatocellular carcinoma (HCC), a malignant tumor with high mortality, and then compared the effects of opioid receptors-specific agonists on malignant phenotypes of HCC cells in vitro and tumor growth in an HCC xenograft mouse model. KOR and MOR were found to be highly expressed in HCC cell lines and HCC tissues. The KOR-specific agonist U50488h, oxycodone (agonist for both KOR and MOR) and the MOR-specific agonist morphine inhibited HCC cell proliferation, while only U50488h and oxycodone suppressed colony formation and migration of HCC cells. U50488h and oxycodone, but not morphine, induced HCC apoptosis. Further detection of PERK, GRP78 and CHOP revealed that PERK signaling was upregulated by treatment with U50488h, while treatment with the PERK inhibitor GSK2656157 partially reversed the promotion of apoptosis and inhibition of cell proliferation by U50488h, indicating that endoplasmic reticulum stress is associated with its suppressing effect on HCC malignant phenotypes. Similar to the in vitro results, HCC growth was significantly reduced by administration of U50488h and oxycodone, but not by morphine, in the HCC xenograft mouse model. PERK and caspase-3 in the HCC tissues were up-regulated by U50488h treatment as detected by immunohistochemistry and western blotting. Taken together, our results revealed that activation of KOR by U50488h inhibited malignant phenotypes of HCC both in vitro and in vivo, while activation of MOR by morphine did not have such effect. Because of their dual roles in the relief of pain and in the suppression of malignant phenotypes, opioids such as U50488h that act on KOR should be considered as the first choice for HCC management.
In Vitro Characterization of 177Lu-DOTA-M5A Anti-Carcinoembryonic Antigen Humanized Antibody and HSP90 Inhibition for Potentiated Radioimmunotherapy of Colorectal Cancer
Authors: Mohajershojai Tabassom , Jha Preeti , Boström Anna , Frejd Fredrik Y. , Yazaki Paul J. , Nestor Marika
Published: March 2022

Carcinoembryonic antigen (CEA) is an antigen that is highly expressed in colorectal cancers and widely used as a tumor marker. 131I and 90Y-radiolabeled anti-CEA monoclonal antibodies (mAbs) have previously been assessed for radioimmunotherapy in early clinical trials with promising results. Moreover, the heat shock protein 90 inhibitor onalespib has previously demonstrated radiotherapy potentiation effects in vivo. In the present study, a 177Lu-radiolabeled anti-CEA hT84.66-M5A mAb (M5A) conjugate was developed and the potential therapeutic effects of 177Lu-DOTA-M5A and/or onalespib were investigated. The 177Lu radiolabeling of M5A was first optimized and characterized. Binding specificity and affinity of the conjugate were then evaluated in a panel of gastrointestinal cancer cell lines. The effects on spheroid growth and cell viability, as well as molecular effects from treatments, were then assessed in several three-dimensional (3D) multicellular colorectal cancer spheroid models. Stable and reproducible radiolabeling was obtained, with labeling yields above 92%, and stability was retained at least 48 h post-radiolabeling. Antigen-specific binding of the radiolabeled conjugate was demonstrated on all CEA-positive cell lines. Dose-dependent therapeutic effects of both 177Lu-DOTA-M5A and onalespib were demonstrated in the spheroid models. Moreover, effects were potentiated in several dose combinations, where spheroid sizes and viabilities were significantly decreased compared to the corresponding monotherapies. For example, the combination treatment with 350 nM onalespib and 20 kBq 177Lu-DOTA-M5A resulted in 2.5 and 2.3 times smaller spheroids at the experimental endpoint than the corresponding monotreatments in the SNU1544 spheroid model. Synergistic effects were demonstrated in several of the more effective combinations. Molecular assessments validated the therapy results and displayed increased apoptosis in several combination treatments. In conclusion, the combination therapy of anti-CEA 177Lu-DOTA-M5A and onalespib showed enhanced therapeutic effects over the individual monotherapies for the potential treatment of colorectal cancer. Further in vitro and in vivo studies are warranted to confirm the current study findings.
Comprehensive Analysis of 5-Methylcytosine (m5C) Regulators and the Immune Microenvironment in Pancreatic Adenocarcinoma to Aid Immunotherapy
Authors: Wang Ronglin , Guo Yongdong , Ma Peixiang , Song Yang , Min Jie , Zhao Ting , Hua Lei , Zhang Chao , Yang Cheng , Shi Jingjie , Zhu Liaoliao , Gan Dongxue , Li Shanshan , Li Junqiang , Su Haichuan
Published: March 2022

Background

Pancreatic adenocarcinoma (PAAD) is one of the most malignant cancers and has a poor prognosis. As a critical RNA modification, 5-methylcytosine (m5C) has been reported to regulate tumor progression, including PAAD progression. However, a comprehensive analysis of m5C regulators in PAAD is lacking.

Methods

In the present study, PAAD datasets were obtained from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and ArrayExpress databases. The expression pattern of m5C regulators were analyzed and patients were divided into different m5C clusters according to consensus clustering based on m5C regulators. Additionally, m5C differentially expressed genes (DEGs) were determined using Limma package. Based on m5C DEGs, patients were divided into m5C gene clusters. Moreover, m5C gene signatures were derived from m5C DEGs and a quantitative indicator, the m5C score, was developed from the m5C gene signatures.

Results

Our study showed that m5C regulators were differentially expressed in patients with PAAD. The m5C clusters and gene clusters based on m5C regulators and m5C DEGs were related to immune cell infiltration, immune-related genes and patient survival status, indicating that m5C modification play a central role in regulating PAAD development partly by modulating immune microenvironment. Additionally, a quantitative indicator, the m5C score, was also developed and was related to a series of immune-related indicators. Moreover, the m5C score precisely predicted the immunotherapy response and prognosis of patients with PAAD.

Conclusion

In summary, we confirmed that m5C regulators regulate PAAD development by modulating the immune microenvironment. In addition, a quantitative indicator, the m5C score, was developed to predict immunotherapy response and prognosis and assisted in identifying PAAD patients suitable for tailored immunotherapy strategies.
Outcomes of Newly Diagnosed Acute Myeloid Leukemia Patients Treated With Hypomethylating Agents With or Without Venetoclax: A Propensity Score-Adjusted Cohort Study
Authors: Mustafa Ali Moaath K. , Corley Elizabeth M. , Alharthy Hanan , Kline Kathryn A. F. , Law Jennie Y. , Lee Seung Tae , Niyongere Sandrine , Duong Vu H. , Emadi Ashkan , Baer Maria R.
Published: March 2022

There is a deficiency of real-world data on the impact of combining venetoclax (VEN) with hypomethylating agents (HMAs) in newly diagnosed acute myeloid leukemia (AML) patients. We conducted a single-center, propensity-adjusted retrospective cohort study to compare composite complete remission (CCR) rates, median overall survival (m-OS) and median event-free survival (m-EFS). A total of 170 adult AML patients were treated with first-line azacitidine (AZA) or decitabine (DEC) +/- VEN. Median age was 71 years and 99 (58%) were male. Median follow-up in HMA and HMA-VEN groups was 79 and 21 months. Treatments included AZA alone (n=35, 21%), DEC alone (n=84, 49%), AZA-VEN (n=24, 14%) and DEC-VEN (n=27, 16%). VEN improved CCR rates to HMAs overall (52% vs. 27%, P<0.05) and to AZA (54% vs. 10%, P<0.05), but not to DEC (43% vs. 32%, P=0.35); it did not improve OS, and only improved EFS for AZA (10.5 vs. 3.8 months, P<0.05). CCR rates were lower with AZA than with DEC (13% vs. 33%, P<0.05), but OS and EFS were not different statistically. CCR rates did not differ for AZA-VEN vs. DEC-VEN (CCR: 58% vs. 52%, P=0.66), but OS and EFS were longer for AZA-VEN (m-OS: 12.3 vs. 2.2 months, P<0.05; m-EFS: 9.2 vs. 2.1 months, P<0.05). Our analysis showed that combining VEN with AZA in newly diagnosed AML patients improved outcomes, but combining VEN with DEC did not. AZA-VEN was associated with improved outcomes compared to DEC-VEN. Further studies are needed to test the benefit of combining VEN with DEC.
Harnessing the Utility of Ex Vivo Patient Prostate Tissue Slice Cultures
Authors: Perez Lillian M. , Nonn Larisa
Published: March 2022

Patient-derived prostate tissue explant cultures are powerful research tools that offer the potential for personalized medicine. These cultures preserve the local microenvironment of the surrounding stroma but are not without limitations and challenges. There are several methods and processing techniques to culture tissue ex vivo, that include explant tissue chunks and precision-cut tissue slices. Precision-cut tissue slices provide a consistent distribution of nutrients and gases to the explant. Herein we summarize the prostate tissue slice method, its limitations and discuss the utility of this model, to investigate prostate biology and therapeutic treatment responses.
Nutritional Management of Moderate- and Late-Preterm Infants Commenced on Intravenous Fluids Pending Mother's Own Milk: Cohort Analysis From the DIAMOND Trial
Authors: Alexander Tanith , Meyer Michael , Harding Jane E. , Alsweiler Jane M. , Jiang Yannan , Wall Clare , Muelbert Mariana , Bloomfield Frank H. ,   The DIAMOND Study Group
Published: March 2022

Background

Exclusive breastmilk is the desired enteral nutrition for babies born moderate- and late-preterm between 32+0 and 36+6 weeks' gestation; however, this goal is often difficult to achieve.

Methods

A prospective cohort of babies 32+0 −35+6 weeks' gestation enrolled in the DIAMOND trial were randomized to a condition specifying that babies should receive mother's own milk (MOM) as the only enteral feed. Factors associated with the successful transition to MOM, defined as MOM being the sole enteral feeding at the time of the first cessation of intravenous (IV) fluids, were investigated by logistic regression. Time to commencement of a milk other than MOM was analyzed by Kaplan–Meier survival curves.

Results

A total of 151 eligible babies (60% boys) were included, 93 (63%) of whom successfully transitioned from IV fluids onto MOM only. Alternative sources of milk, mostly formula, were used to transition from IV fluids onto enteral feeds more often in multiples and Māori, and was commenced earlier in Māori than other ethnicities (p = 0.007) and in late-preterm compared with moderate-preterm babies (p=0.01). Receiving exclusively breastmilk at discharge was more likely for babies who successfully transitioned from IV fluids onto MOM only [OR (95% confidence intervals) 4.9 (2.3–10.6)] and who received only MOM in the first week after birth [4.8 (2.2–10.4)], both p < 0.0001. Receiving breastmilk exclusively at discharge was less likely for Māori than Caucasian babies [0.2 (0.1–0.6), p < 0.0006]. There was no difference in the use of alternative sources of milk in babies who received parenteral nutrition or dextrose or between small-for-gestational-age and appropriate-for-gestational-age babies.

Conclusions

Despite an intention to provide only MOM, significant numbers of moderate- and late-preterm babies received formula to transition from IV fluids, and this differed by ethnicity. The drivers underlying these decisions require further investigation. These data highlight an urgent need for quality initiatives to support and encourage mothers of moderate- and late-preterm babies in their lactation.
Efficacy of a Transitional Support Program Among Adolescent Patients With Childhood-Onset Chronic Diseases: A Randomized Controlled Trial
Authors: Morisaki-Nakamura Mayumi , Suzuki Seigo , Kobayashi Asuka , Kita Sachiko , Sato Iori , Iwasaki Miwa , Hirata Yoichiro , Sato Atsushi , Oka Akira , Kamibeppu Kiyoko
Published: March 2022

It is recommended that patients with childhood-onset chronic diseases (CCD) be transferred from pediatric to adult healthcare systems when they reach adulthood. Transitional support helps adolescents with CCD transition smoothly. Transition readiness is one of the key concepts to assess the efficacy of transitional support programs. This study aims to investigate the effect of a transitional support program on transition readiness, self-esteem, and independent consciousness among Japanese adolescents with various CCD using a randomized controlled trial. Adolescents with CCD aged 12–18 years participated in a randomized controlled trial evaluating the efficacy of a transitional support program. The patients in the intervention group visited transitional support outpatient clinics twice. They answered questionnaires regarding their disease and future perspectives to healthcare professionals and independently made a short summary of their disease. All the participants answered the questionnaires four times. Eighty patients participated in this study. Among those in the intervention group, transition readiness within one, three, and 6 months after interventions, and self-esteem within 1 month after interventions were higher than that of the control group. The scores on the “dependence on parents” subscale at 6 months after interventions were lower for the intervention group as compared to the control group. This program is expected to help patients transition smoothly from pediatric to adult healthcare systems.