bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune Trait Shifts in Association With Tobacco Smoking: A Study in Healthy Women
Authors: Piaggeschi Giulia , Rolla Simona , Rossi Niccolò , Brusa Davide , Naccarati Alessio , Couvreur Simon , Spector Tim D. , Roederer Mario , Mangino Massimo , Cordero Francesca , Falchi Mario , Visconti Alessia
Published: March 2021

Tobacco smoking is known to impact circulating levels of major immune cells populations, but its effect on specific immune cell subsets remains poorly understood. Here, using high-resolution data from 223 healthy women (25 current and 198 never smokers), we investigated the association between smoking status and 35,651 immune traits capturing immune cell subset frequencies. Our results confirmed that active tobacco smoking is associated with increased frequencies of circulating CD8+ T cells expressing the CD25 activation marker. Moreover, we identified novel associations between smoking status and relative abundances of CD8+ CD25+ memory T cells, CD8+ memory T cells expressing the CCR4 chemokine receptor, and CD4+CD8+ (double-positive) CD25+ T cells. We also observed, in current smokers, a decrease in the relative frequencies of CD4+ T cells expressing the CD38 activation marker and an increase in class-switched memory B cell isotypes IgA, IgG, and IgE. Finally, using data from 135 former female smokers, we showed that the relative frequencies of immune traits associated with active smoking are usually completely restored after smoking cessation, with the exception of subsets of CD8+ and CD8+ memory T cells, which persist partially altered. Our results are consistent with previous findings and provide further evidence on how tobacco smoking shapes leukocyte cell subsets proportion toward chronic inflammation.
Triggering Receptor Expressed on Myeloid Cells-1 Agonist Regulates Intestinal Inflammation via Cd177+ Neutrophils
Authors: Seo Dong Hyuk , Che Xiumei , Kim Soochan , Kim Da Hye , Ma Hyun Woo , Kim Jae Hyeon , Kim Tae Il , Kim Won Ho , Kim Seung Won , Cheon Jae Hee
Published: March 2021

Triggering receptor expressed on myeloid cell-1 (TREM-1) signaling is expressed on neutrophils and monocytes that is necessary for the successful antimicrobial response and resolution of inflammation in the gut. In this study, we determined the effect of an anti-TREM-1 agonistic antibody (α-TREM-1) on colitis and identify its underlying mechanism of action. Administration of α-TREM-1 alleviated colitis in mice and resolved dysbiosis, which required TLR4/Myd88 signaling. α-TREM-1 increased the production of neutrophil extracellular traps and interleukin-22 by CD177+ neutrophils, which led to pathogen clearance and protection of the intestinal barrier. TREM-1 activation using an α-TREM-1 antibody protects against colitis by rebalancing the microbiota and protecting the epithelium against the immune response as well as modulates the function of neutrophils and macrophages. These results highlight the importance of the TREM-1 pathway in intestinal homeostasis and suggest that α-TREM-1 treatment may be an effective therapeutic strategy for inflammatory bowel disease.
NiCo Nanorod Array Supported on Copper Foam as a High-Performance Catalyst for Hydrogen Production From Ammonia Borane
Authors: Li Liling , Guo Binshan , Li Hang , Zhang Xibin , Feng Yufa , Liao Jinyun
Published: March 2021

Searching for inexpensive, durable, and active catalysts for the dehydrogenation of ammonia borane (AB) is an important subject in the field of hydrogen energy. In this study, we have fabricated NiCo nanorod arrays anchored on copper foam (CF) by a simple hydrothermal process. The catalytic performance of those array catalysts in AB hydrolysis was studied. It was found that NiCo-1/CF showed the highest catalytic activity with a hydrogen generation rate (HGR) of 1.03 Lhydrogen g−1 min−1, which was much higher than that for the unsupported NiCo-1 catalyst. It has been demonstrated that strong base can significantly enhance hydrogen production. After six catalytic cycles, the morphology, crystal structure, and catalytic activity were maintained, indicating that the NiCo-1/CF sample showed good reusability and high durability. Considering their low cost and high performance, the NiCo nanorod arrays anchored on CF can be a strong candidate catalyst for hydrogen generation for mobile hydrogen-oxygen fuel cells.
Prevalence and Genetic Diversity of Listeria monocytogenes Isolated From Retail Pork in Wuhan, China
Authors: Wang Yiqian , Ji Qiang , Li Shaowen , Liu Mei
Published: March 2021

Listeria monocytogenes is a ubiquitous bacteria and causative agent of zoonotic listeriosis with high mortality. The consumption of contaminated animal-derived foods has been linked with both epidemic and sporadic listeriosis. In this work, a total of 64 L. monocytogenes isolates from 259 pork samples sold in 11 supermarket chains were identified and characterized by comparative whole-genome analysis. All isolates were delineated into eight clonal complexes (CCs), namely CC2, CC8, CC9, CC11, CC155, CC121, CC204, and CC619, spanning two lineages (I and II) and carrying 3–5 antibiotic-resistant genes (fosX, lnu, mprF, tetM, and dhfR). It is noted that Listeria pathogenicity island (LIPI)-1, LIPI-3, and LIPI-4 were distributed in all ST619 isolates from two supermarket chains that were closely related with clinical isolates (<40 SNP). Some of the isolates from different supermarket chains with 0 SNP difference indicated a common pork supply source. Notably, 57.81% of the strains carried types IB, IIA, or IIIB CRISPR-Cas system, CC121 isolates carried both types IB and IIA CRISPR-Cas systems, Cas proteins of CC155 isolates located between two CRISPR loci, each CC has unique organization of Cas proteins as well as CRISPR loci. CRISPR-Cas system-based subtyping improved discrimination of pork-derived L. monocytogenes isolates. Comparisons at the genome level contributed to understand the genetic diversities and variations among the isolates and provided insights into the genetic makeup and relatedness of these pathogens.
The sTREM2 Concentrations in the Blood: A Marker of Neurodegeneration?
Authors: Ferri Evelyn , Rossi Paolo Dionigi , Geraci Annalisa , Ciccone Simona , Cesari Matteo , Arosio Beatrice
Published: March 2021

Microglia performs a variety of functions during brain development designed to maintain brain homeostasis. Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in microglial cells modulating phagocytosis, cytokine production, cell proliferation, and cell survival. Interestingly, the levels of soluble TREM2 (the secreted ectodomain of TREM2, sTREM2) were higher in cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients than subjects without cognitive decline. It is noteworthy that, while CSF sTREM2 levels have been extensively studied, few studies have investigated sTREM2 in blood producing conflicting results. We aimed to investigate the levels of sTREM2 in CSF and blood from a cohort of well-characterized AD comparing the results to those obtained in patients suffering from idiopathic normal pressure hydrocephalus (iNPH), a potentially reversible cognitive impairment. Our findings underlined a significantly lower plasma sTREM2 concentration in AD patients compared to iNPH subjects [39.1 ng/mL (standard deviation (SD), 15.0) and 47.2 ng/mL (SD, 19.5), respectively; p = 0.01], whereas no difference was revealed between the two groups in the CSF sTREM2 levels. The adjusted regression analyses evidenced in AD patients an association between plasma and CSF sTREM2 levels [B = 0.411; 95% confidence interval (CI), 0.137–0.685, p = 0.004], as well as β-amyloid concentrations (B = 0.035; 95% CI, 0.007–0.063, p = 0.01) and an association between CSF sTREM2 and phospho-Tau concentrations (B = 0.248; 95% CI, 0.053–0.443; p = 0.01). No significant relation was found in iNPH patients. In conclusion, these differences in sTREM2 profiles between AD and iNPH reinforce the notion that this receptor has a role in neurodegeneration.
Persistent Dark Cones in Oligocone Trichromacy Revealed by Multimodal Adaptive Optics Ophthalmoscopy
Authors: Li Joanne , Liu Tao , Flynn Oliver J. , Turriff Amy , Liu Zhuolin , Ullah Ehsan , Liu Jianfei , Dubra Alfredo , Johnson Mary A. , Brooks Brian P. , Hufnagel Robert B. , Hammer Daniel X. , Huryn Laryssa A. , Jeffrey Brett G. , Tam Johnny
Published: March 2021

Dark cone photoreceptors, defined as those with diminished or absent reflectivity when observed with adaptive optics (AO) ophthalmoscopy, are increasingly reported in retinal disorders. However, their structural and functional impact remain unclear. Here, we report a 3-year longitudinal study on a patient with oligocone trichromacy (OT) who presented with persistent, widespread dark cones within and near the macula. Diminished electroretinogram (ERG) cone but normal ERG rod responses together with normal color vision confirmed the OT diagnosis. In addition, the patient had normal to near normal visual acuity and retinal sensitivity. Occasional dark gaps in the photoreceptor layer were observed on optical coherence tomography, in agreement with reflectance AO scanning light ophthalmoscopy, which revealed that over 50% of the cones in the fovea were dark, increasing to 74% at 10° eccentricity. In addition, the cone density was 78% lower than normal histologic value at the fovea, and 20–40% lower at eccentricities of 5–15°. Interestingly, color vision testing was near normal at locations where cones were predominantly dark. These findings illustrate how a retina with predominant dark cones that persist over at least 3 years can support near normal central retinal function. Furthermore, this study adds to the growing evidence that cones can continue to survive under non-ideal conditions.
High-Frequency Stimulation of Ventral CA1 Neurons Reduces Amygdala Activity and Inhibits Fear
Authors: Graham Jalina , D’Ambra Alexa F. , Jung Se Jung , Teratani-Ota Yusuke , Vishwakarma Nina , Venkatesh Rasika , Parigi Abhijna , Antzoulatos Evan G. , Fioravante Diasynou , Wiltgen Brian J.
Published: March 2021

The hippocampus can be divided into distinct segments that make unique contributions to learning and memory. The dorsal segment supports cognitive processes like spatial learning and navigation while the ventral hippocampus regulates emotional behaviors related to fear, anxiety and reward. In the current study, we determined how pyramidal cells in ventral CA1 respond to spatial cues and aversive stimulation during a context fear conditioning task. We also examined the effects of high and low frequency stimulation of these neurons on defensive behavior. Similar to previous work in the dorsal hippocampus, we found that cells in ventral CA1 expressed high-levels of c-Fos in response to a novel spatial environment. Surprisingly, however, the number of activated neurons did not increase when the environment was paired with footshock. This was true even in the subpopulation of ventral CA1 pyramidal cells that send direct projections to the amygdala. When these cells were stimulated at high-frequencies (20 Hz) we observed feedforward inhibition of basal amygdala neurons and impaired expression of context fear. In contrast, low-frequency stimulation (4 Hz) did not inhibit principal cells in the basal amygdala and produced an increase in fear generalization. Similar results have been reported in dorsal CA1. Therefore, despite clear differences between the dorsal and ventral hippocampus, CA1 neurons in each segment appear to make similar contributions to context fear conditioning.
The Effect of Transcranial Random Noise Stimulation on Cognitive Training Outcome in Healthy Aging
Authors: Brambilla Michela , Dinkelbach Lars , Bigler Annelien , Williams Joseph , Zokaei Nahid , Cohen Kadosh Roi , Brem Anna-Katharine
Published: March 2021

Background and Objective: Aging is associated with a decline in attentional and executive abilities, which are linked to physiological, structural, and functional brain changes. A variety of novel non-invasive brain stimulation methods have been probed in terms of their neuroenhancement efficacy in the last decade; one that holds significant promise is transcranial random noise stimulation (tRNS) that delivers an alternate current at random amplitude and frequency. The aim of this study was to investigate whether repeated sessions of tRNS applied as an add-on to cognitive training (CT) may induce long-term near and far transfer cognitive improvements.

Methods: In this sham-controlled, randomized, double-blinded study forty-two older adults (age range 60–86 years) were randomly assigned to one of three intervention groups that received 20 min of 0.705 mA tRNS (N = 14), 1 mA tRNS (N = 14), or sham tRNS (N = 19) combined with 30 min of CT of executive functions (cognitive flexibility, inhibitory control, working memory). tRNS was applied bilaterally over the dorsolateral prefrontal cortices for five sessions. The primary outcome (non-verbal logical reasoning) and other cognitive functions (attention, memory, executive functions) were assessed before and after the intervention and at a 1-month follow-up.

Results: Non-verbal logical reasoning, inhibitory control and reaction time improved significantly over time, but stimulation did not differentially affect this improvement. These changes occurred during CT, while no further improvement was observed during follow-up. Performance change in logical reasoning was significantly correlated with age in the group receiving 1 mA tRNS, indicating that older participants profited more from tRNS than younger participants. Performance change in non-verbal working memory was significantly correlated with age in the group receiving sham tRNS, indicating that in contrast to active tRNS, older participants in the sham group declined more than younger participants.

Interpretation: CT induced cognitive improvements in all treatment groups, but tRNS did not modulate most of these cognitive improvements. However, the effect of tRNS depended on age in some cognitive functions. We discuss possible explanations leading to this result that can help to improve the design of future neuroenhancement studies in older populations.
Intermittent Light Exposures in Humans: A Case for Dual Entrainment in the Treatment of Alzheimer's Disease
Authors: Figueiro Mariana G. , Leggett Sagan
Published: March 2021

Circadian sleep disorders are common among American adults and can become especially acute among older adults, especially those living with Alzheimer's disease (AD) and mild cognitive impairment (MCI), leading to the exacerbation of symptoms and contributing to the development and advancement of the diseases. This review explores the connections between circadian sleep disorders, cognition, and neurodegenerative disease, offering insights on rapidly developing therapeutic interventions employing intermittent light stimuli for improving sleep and cognition in persons with AD and MCI. Light therapy has the potential to affect sleep and cognition via at least two pathways: (1) a regular and robust light-dark pattern reaching the retina that promotes circadian phase shifting, which can promote entrainment and (2) 40 Hz flickering light that promotes gamma-wave entrainment. While this is a new area of research, preliminary evidence shows the potential of dual circadian and gamma-wave entrainment as an important therapy not only for those with AD, but for others with cognitive impairment.
A Novel Pathogenic HSPG2 Mutation in Schwartz–Jampel Syndrome
Authors: Lin Po-Yu , Hung Jia-Horung , Hsu Chao-Kai , Chang Yao-Tsung , Sun Yuan-Ting
Published: March 2021

Schwartz–Jampel syndrome is a rare autosomal recessive disease caused by mutation in the heparan sulfate proteoglycan 2 (HSPG2) gene. Its cardinal symptoms are skeletal dysplasia and neuromuscular hyperactivity. Herein, we identified a new pathogenic mutation site (NM_005529.6:c.1125C>G; p.Cys375Trp) of HSPG2 leading to Schwartz–Jampel syndrome by whole-exome sequencing. This mutation carried by the asymptomatic parents was previously registered in a single-nucleotide polymorphism database of the National Institutes of Health as a coding sequence variant rs543805444. The pathogenic nature of this missense mutation was demonstrated by in silico pathogenicity assessment, clinical presentations, and cellular function of primary fibroblast derived from patients. Various in silico software applications predicted the mutation to be pathogenic [Sorting Intolerant From Tolerant (SIFT), 0; Polyphen-2, 1; CADD (Combined Annotation Dependent Depletion), 23.7; MutationTaster, 1; DANN (deleterious annotation of genetic variants using neural networks); 0.9]. Needle electromyography revealed extensive complex repetitive discharges and multiple polyphasic motor unit action potentials in axial and limb muscles at rest. Short exercise test for myotonia showed Fournier pattern I. At cellular levels, mutant primary fibroblasts had reduced levels of secreted perlecan and impaired migration ability but normal capability of proliferation. Patients with this mutation showed more neuromuscular instability and relatively mild skeletal abnormality comparing with previously reported cases.
Quantitative Assessment of the Impact of Geometric Distortions and Their Correction on fMRI Data Analyses
Authors: Abreu Rodolfo , Duarte João Valente
Published: March 2021

Functional magnetic resonance imaging (fMRI) data is typically collected with gradient-echo echo-planar imaging (GE-EPI) sequences, which are particularly prone to the susceptibility artifact as a result of B0 field inhomogeneity. The component derived from in-plane spin dephasing induces pixel intensity variations and, more critically, geometric distortions. Despite the physical mechanisms underlying the susceptibility artifact being well established, a systematic investigation on the impact of the associated geometric distortions, and the direct comparison of different approaches to tackle them, on fMRI data analyses is missing. Here, we compared two different distortion correction approaches, by acquiring additional: (1) EPI data with reversed phase encoding direction (TOPUP), and (2) standard (and undistorted) GE data at two different echo times (GRE). We first characterized the geometric distortions and the correction approaches based on the estimated ΔB0 field offset and voxel shift maps, and then conducted three types of analyses on the distorted and corrected fMRI data: (1) registration into structural data, (2) identification of resting-state networks (RSNs), and (3) mapping of task-related brain regions of interest. GRE estimated the largest voxel shifts and more positively impacted the quality of the analyses, in terms of the (significantly lower) cost function of the registration, the (higher) spatial overlap between the RSNs and appropriate templates, and the (significantly higher) sensitivity of the task-related mapping based on the Z-score values of the associated activation maps, although also evident when considering TOPUP. fMRI data should thus be corrected for geometric distortions, with the choice of the approach having a modest, albeit positive, impact on the fMRI analyses.
Magnetic Resonance Imaging-Based Robotic Radiosurgery of Arteriovenous Malformations
Authors: Greve Tobias , Ehret Felix , Hofmann Theresa , Thorsteinsdottir Jun , Dorn Franziska , Švigelj Viktor , Resman-Gašperšič Anita , Tonn Joerg-Christian , Schichor Christian , Muacevic Alexander
Published: March 2021

Objective

CyberKnife offers CT- and MRI-based treatment planning without the need for stereotactically acquired DSA. The literature on CyberKnife treatment of cerebral AVMs is sparse. Here, a large series focusing on cerebral AVMs treated by the frameless CyberKnife stereotactic radiosurgery (SRS) system was analyzed.

Methods

In this retrospective study, patients with cerebral AVMs treated by CyberKnife SRS between 2005 and 2019 were included. Planning was MRI- and CT-based. Conventional DSA was not coregistered to the MRI and CT scans used for treatment planning and was only used as an adjunct. Obliteration dynamics and clinical outcome were analyzed.

Results

215 patients were included. 53.0% received SRS as first treatment; the rest underwent previous surgery, embolization, SRS, or a combination. Most AVMs were classified as Spetzler-Martin grade I to III (54.9%). Hemorrhage before treatment occurred in 46.0%. Patients suffered from headache (28.8%), and seizures (14.0%) in the majority of cases. The median SRS dose was 18 Gy and the median target volume was 2.4 cm³. New neurological deficits occurred in 5.1% after SRS, with all but one patient recovering. The yearly post-SRS hemorrhage incidence was 1.3%. In 152 patients who were followed-up for at least three years, 47.4% showed complete AVM obliteration within this period. Cox regression analysis revealed Spetzler-Martin grade (P = 0.006) to be the only independent predictor of complete obliteration.

Conclusions

Although data on radiotherapy of AVMs is available, this is one of the largest series, focusing exclusively on CyberKnife treatment. Safety and efficacy compared favorably to frame-based systems. Non-invasive treatment planning, with a frameless SRS robotic system might provide higher patient comfort, a less invasive treatment option, and lower radiation exposure.
Cost-Effectiveness Analysis of Hepatic Arterial Infusion of FOLFOX Combined Sorafenib for Advanced Hepatocellular Carcinoma With Portal Vein Invasion
Authors: Li Meiyue , Lin Shen , Wilson Leslie , Huang Pinfang , Wang Hang , Lai Shubin , Dong Liangliang , Xu Xiongwei , Weng Xiuhua
Published: March 2021

Background

Hepatic arterial infusion (HAI) of oxaliplatin, leucovorin, and fluorouracil (FOLFOX) plus sorafenib has a more desirable effect versus sorafenib for hepatocellular carcinoma (HCC) patients with portal vein invasion. However, considering the high cost of hepatic arterial infusion of chemotherapy (HAIC), this study evaluated the cost-effectiveness of HAIC plus sorafenib (SoraHAIC) versus standard care for HCC patients from the Chinese health system perspective.

Methods

A Markov multi-state model was constructed to simulate the disease course and source consumption of SoraHAIC. Costs of primary therapeutic drugs were calculated based on the national bid price, and hepatic artery catheterization fee was collected from the Fujian Provincial Price Bureau. Clinical data, other costs, and utility values were extracted from references. Primary outcomes included life-years (LYs), quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER). The robustness of model was verified by uncertainty sensitivity analyses.

Results

SoraHAIC gained 1.18 QALYs (1.68 LYs) at a cost of $65,254, while the effectiveness and cost of sorafenib were 0.52 QALYs (0.79 LYs) and $14,280, respectively. The ICER of SoraHAIC vs sorafenib was $77,132/QALY ($57,153/LY). Parameter that most influenced the ICER was utility of PFS state. The probabilistic sensitivity analysis (PSA) showed that SoraHAIC was not cost-effective in the WTP threshold of 3*Gross Domestic Product (GDP) per capita of China ($30,492/QALY). But about 38.8% of the simulations were favorable to SoraHAIC at the WTP threshold of 3*GDP per capita of Beijing ($72,000/QALY). When 3*GDP per capita of Fujian ($47,285/QALY) and Gansu Province ($14,595/QALY) were used as WTP threshold, the acceptability of SoraHAIC was 0.3% and 0%, respectively.

Conclusions

The study results indicated that SoraHAIC was not cost-effective in medium-, and low-income regions of China. In developed areas of China (Beijing), there was a 38.8% probability that the SoraHAIC regimen would be cost-effective.
A 15-Gene Signature and Prognostic Nomogram for Predicting Overall Survival in Non-Distant Metastatic Oral Tongue Squamous Cell Carcinoma
Authors: Liu Muyuan , Tong Litian , Liang Bin , Song Xuhong , Xie Lingzhu , Peng Hanwei , Huang Dongyang
Published: March 2021

Background

Oral tongue squamous cell carcinoma (OTSCC) is a devastating tumor with poor prognosis. There is an urgent need for reliable biomarkers to help predict prognosis and guide treatment for OTSCC. In the current study, we aimed to develop a robust multi-gene signature and prognostic nomogram to predict the prognosis of patients with non-distant metastatic OTSCC.

Methods

OTSCC-related differentially-expressed genes were screened from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression based on 1,000 bootstrap replicates, LASSO regression and stepwise multivariate Cox regression were utilized to develop a novel multi-mRNA signature for predicting overall survival in OTSCC. The concordance index, area under receiver operating characteristic (ROC AUC) and calibration curve were employed to assess the prediction capacity of the novel multi-gene model. In addition, a prognostic nomogram was constructed to facilitate the clinical use of the fitted model. The Kaplan-Meier with log-rank test was employed to assess differences in overall survival.

Results

We successfully established a novel 15-mRNA prognostic model for predicting overall survival of non-distant metastatic OTSCC, involving ADTRP, ITGA3, RFC4, CCDC96, CYP2J2, NELL2, SPHK1, SPAG16, HBEGF, S100A9, EGFL6, ADGRG6, PDE4D, ABCA4, and CTTN. The prediction ability of this 15-gene signature was independent of other clinicopathological factors, with an HR of 11.5 (95% CI: 4.70–28.3). Moreover, internal validation by bootstrap analysis yielded a C-index of 0.849, with a 3-year AUC of 0.907 and 5-year AUC of 0.944, which implied excellent prediction accuracy of the fitted model. In addition, external validation by using the GEO dataset (GSE41116) yielded a C-index of 0.804, with a 3-year AUC of 0.868 and 5-year AUC of 0.855, which also indicated good prediction ability of the 15-gene model. Finally, a prognostic nomogram integrating risk group, grade, T stage and N stage was established.

Conclusion

Our results demonstrate our 15-gene signature was independently associated with overall survival in non-distant metastatic OTSCC. Moreover, the prognostic nomogram integrating the 15-gene signature and clinicopathological factors has potential to be developed as a prognostic tool.
Comparative Effectiveness and Safety of High-Intensity Focused Ultrasound for Uterine Fibroids: A Systematic Review and Meta-Analysis
Authors: Wang Yi , Geng Jinsong , Bao Haini , Dong Jiancheng , Shi Jianwei , Xi Qinghua
Published: March 2021

Background: Uterine fibroids are common benign tumors among premenopausal women. High- intensity focused ultrasound (HIFU) is an emerging non-invasive intervention which uses the high-intensity ultrasound waves from ultrasound probes to focus on the targeted fibroids. However, the efficacy of HIFU in comparison with that of other common treatment types in clinical procedure remains unclear.

Objective: To investigate the comparative effectiveness and safety of HIFU with other techniques which have been widely used in clinical settings.

Methods: We searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, Cumulative Index to Nursing & Allied Health Literature, Web of Science, ProQuest Nursing & Allied Health Database, and three Chinese academic databases, including randomized controlled trials (RCTs), non-RCTs, and cohort studies. The primary outcome was the rate of re-intervention, and the GRADE approach was used to interpret the findings.

Results: About 18 studies met the inclusion criteria. HIFU was associated with an increased risk of re-intervention rate in comparison with myomectomy (MYO) [pooled odds ratio (OR): 4.05, 95% confidence interval (CI): 1.82–8.9]. The results favored HIFU in comparison with hysterectomy (HYS) on the change of follicle-stimulating hormone [pooled mean difference (MD): −7.95, 95% CI: −8.92–6.98), luteinizing hormone (MD: −4.38, 95% CI: −5.17−3.59), and estradiol (pooled MD: 43.82, 95% CI: 36.92–50.72)]. HIFU had a shorter duration of hospital stay in comparison with MYO (pooled MD: −4.70, 95% CI: −7.46−1.94, p < 0.01). It had a lower incidence of fever (pooled OR: 0.15, 95% CI: 0.06–0.39, p < 0.01) and a lower incidence of major adverse events (pooled OR: 0.04, 95% CI: 0.00–0.30, p < 0.01) in comparison with HYS.

Conclusions: High-intensity focused ultrasound may help maintain feminity and shorten the duration of hospital stay. High-quality clinical studies with a large sample size, a long-term follow-up, and the newest HIFU treatment protocol for evaluating the re-intervention rate are suggested to be carried out. Clinical decision should be based on the specific situation of the patients and individual values.
Near-Infrared Fluorescence Imaging of Breast Cancer and Axillary Lymph Nodes After Intravenous Injection of Free Indocyanine Green
Authors: Bourgeois Pierre , Veys Isabelle , Noterman Danielle , De Neubourg Filip , Chintinne Marie , Vankerckhove Sophie , Nogaret Jean-Marie
Published: March 2021

Background

Near-infrared fluorescence imaging (NIRFI) of breast cancer (BC) after the intravenous (IV) injection of free indocyanine green (fICG) has been reported to be feasible. However, some questions remained unclarified.

Objective

To evaluate the distribution of fICG in BC and the axillary lymph nodes (LNs) of women undergoing surgery with complete axillary LN dissection (CALND) and/or selective lymphadenectomy (SLN) of sentinel LNs (NCT no. 01993576 and NCT no. 02027818).

Methods

An intravenous injection of fICG (0.25 mg/kg) was administered to one series of 20 women undergoing treatment with mastectomy, the day before surgery in 5 (group 1) and immediately before surgery in 15 (group 2: tumor localization, 25; and pN+ CALND, 4) as well as to another series of 20 women undergoing treatment with tumorectomy (group 3). A dedicated NIR camera was used for ex vivo fluorescence imaging of the 45 BC lesions and the LNs.

Results

In group 1, two of the four BC lesions and one large pN+ LN exhibited fluorescence. In contrast, 24 of the 25 tumors in group 2 and all of the tumors in group 3 were fluorescent. The sentinel LNs were all fluorescent, as well as some of the LNs in all CALND specimens. Metastatic cells were found in the fluorescent LNs of the pN+ cases. Fluorescent BC lesions could be identified ex vivo on the surface of the lumpectomy specimen in 14 of 19 cases.

Conclusions

When fICG is injected intravenously just before surgery, BC can be detected using NIRFI with high sensitivity, with metastatic axillary LNs also showing fluorescence. Such a technical approach seems promising in the management of BC and merits further investigation.
Whole-Tumor Histogram and Texture Imaging Features on Magnetic Resonance Imaging Combined With Epstein-Barr Virus Status to Predict Disease Progression in Patients With Nasopharyngeal Carcinoma
Authors: Li Qiao , Wang TingTing , Huang Yan , Li Qin , Liu PeiYao , Grimm Robert , Fu CaiXia , Zhang YunYan , Gu Yajia
Published: March 2021

Purpose: We aimed to investigate whether Epstein–Barr virus (EBV) could produce differences on MRI by examining the histogram and texture imaging features. We also sought to determine the predictive value of pretreatment MRI texture analyses incorporating with EBV status for disease progression (PD) in patients with primary nasopharyngeal carcinoma (NPC).

Materials and Methods: Eighty-one patients with primary T2-T4 NPC and known EBV status who underwent contrast-enhanced MRI were included in this retrospective study. Whole-tumor-based histogram and texture features were extracted from pretreatment T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and contrast-enhanced (CE)-T1WI images. Mann–Whitney U-tests were performed to identify the differences in histogram and texture parameters between EBV DNA-positive and EBV DNA-negative NPC images. The effects of clinical variables as well as histogram and texture features were estimated by using univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curve analysis was used to predict the EBV status and PD. Finally, an integrated model with the best performance was built.

Results: Of the 81 patients included, 54 had EBV DNA-positive NPC, and 27 had EBV DNA-negative NPC. Patients who were tested EBV DNA-positive had higher overall stage (P = 0.016), more lymphatic metastases (p < 0.0001), and easier distant metastases (P = 0.026) than the patients who were tested EBV DNA-negative. Tumor volume, T1WISkewness and T2WIKurtosis showed significant differences between the two groups. The combination of the three features achieved an AUC of 0.783 [95% confidence interval (CI) 0.678–0.888] with a sensitivity and specificity of 70.4 and 74.1%, respectively, in differentiating EBV DNA-positive tumors from EBV DNA-negative tumors. The combination of overall stage and tumor volume of T2WIKurtosis and EBV status was the most effective model for predicting PD in patients with primary NPC. The overall accuracy was 84.6%, with a sensitivity and specificity of 93.8 and 66.2%, respectively (AUC, 0.800; 95% CI 0.700–0.900).

Conclusion: This study demonstrates that MRI-based radiological features and EBV status can be used as an aid tool for the evaluation of PD, in order to develop tailored treatment targeting specific characteristics of individual patients.
In Vivo Efficacy and Toxicity of Curcumin Nanoparticles in Breast Cancer Treatment: A Systematic Review
Authors: Ombredane Alicia S. , Silva Vitória R. P. , Andrade Laise R. , Pinheiro Willie O. , Simonelly Mayara , Oliveira Jaqueline V. , Pinheiro Andréia C. , Gonçalves Gabriel F. , Felice Gisela J. , Garcia Mônica P. , Campos Patrícia M. , Luz Glécia V. S. , Joanitti Graziella A.
Published: March 2021

Breast cancer is one of the most prevalent types of malignant tumors in the world, resulting in a high incidence of death. The development of new molecules and technologies aiming to apply more effective and safer therapy strategies has been intensively explored to overcome this situation. The association of nanoparticles with known antitumor compounds (including plant-derived molecules such as curcumin) has been considered an effective approach to enhance tumor growth suppression and reduce adverse effects. Therefore, the objective of this systematic review was to summarize published data regarding evaluations about efficacy and toxicity of curcumin nanoparticles (Cur-NPs) in in vivo models of breast cancer. The search was carried out in the databases: CINAHL, Cochrane, LILACS, Embase, FSTA, MEDLINE, ProQuest, BSV regional portal, PubMed, ScienceDirect, Scopus, and Web of Science. Studies that evaluated tumor growth in in vivo models of breast cancer and showed outcomes related to Cur-NP treatment (without association with other antitumor molecules) were included. Of the 528 initially gathered studies, 26 met the inclusion criteria. These studies showed that a wide variety of NP platforms have been used to deliver curcumin (e.g., micelles, polymeric, lipid-based, metallic). Attachment of poly(ethylene glycol) chains (PEG) and active targeting moieties were also evaluated. Cur-NPs significantly reduced tumor volume/weight, inhibited cancer cell proliferation, and increased tumor apoptosis and necrosis. Decreases in cancer stem cell population and angiogenesis were also reported. All the studies that evaluated toxicity considered Cur-NP treatment to be safe regarding hematological/biochemical markers, damage to major organs, and/or weight loss. These effects were observed in different in vivo models of breast cancer (e.g., estrogen receptor-positive, triple-negative, chemically induced) showing better outcomes when compared to treatments with free curcumin or negative controls. This systematic review supports the proposal that Cur-NP is an effective and safe therapeutic approach in in vivo models of breast cancer, reinforcing the currently available evidence that it should be further analyzed in clinical trials for breast cancer treatments.
Developing a lncRNA Signature to Predict the Radiotherapy Response of Lower-Grade Gliomas Using Co-expression and ceRNA Network Analysis
Authors: Li Zhongyang , Cai Shang , Li Huijun , Gu Jincheng , Tian Ye , Cao Jianping , Yu Dong , Tang Zaixiang
Published: March 2021

Background

Lower-grade glioma (LGG) is a type of central nervous system tumor that includes WHO grade II and grade III gliomas. Despite developments in medical science and technology and the availability of several treatment options, the management of LGG warrants further research. Surgical treatment for LGG treatment poses a challenge owing to its often inaccessible locations in the brain. Although radiation therapy (RT) is the most important approach in this condition and offers more advantages compared to surgery and chemotherapy, it is associated with certain limitations. Responses can vary from individual to individual based on genetic differences. The relationship between non-coding RNA and the response to radiation therapy, especially at the molecular level, is still undefined.

Methods

In this study, using The Cancer Genome Atlas dataset and bioinformatics, the gene co-expression network that is involved in the response to radiation therapy in lower-grade gliomas was determined, and the ceRNA network of radiotherapy response was constructed based on three databases of RNA interaction. Next, survival analysis was performed for hub genes in the co-expression network, and the high-efficiency biomarkers that could predict the prognosis of patients with LGG undergoing radiotherapy was identified.

Results

We found that some modules in the co-expression network were related to the radiotherapy responses in patients with LGG. Based on the genes in those modules and the three databases, we constructed a ceRNA network for the regulation of radiotherapy responses in LGG. We identified the hub genes and found that the long non-coding RNA, DRAIC, is a potential molecular biomarker to predict the prognosis of radiotherapy in LGG.
NEDD4 Induces K48-Linked Degradative Ubiquitination of Hepatitis B Virus X Protein and Inhibits HBV-Associated HCC Progression
Authors: Wan Tao , Lei Zhao , Tu Biao , Wang Tianyin , Wang Jiale , Huang Feizhou
Published: March 2021

Neural precursor cell expressed developmentally downregulated gene 4 (NEDD4) plays two opposite roles in carcinogenesis. It has been reported that NEDD4 inhibits hepatocellular carcinoma (HCC) progression; however, little is known about its potential function and molecular mechanism in HCC in the context of hepatitis B virus (HBV) infection. In this study, we analyzed NEDD4 expression in 199 HCC specimens with or without HBV infection and observed that NEDD4 expression was unrelated to HBV exposure in HCC tumor tissue but that high NEDD4 expression conferred better overall survival (OS) and progression-free survival (PFS) than low NEDD4 expression in patients with HBV-associated HCC. Upregulation of NEDD4 inhibited proliferation, migration and invasion in HBV-related HCC cell lines. We demonstrated that NEDD4 interacts with HBV X protein (HBx) and that HBx upregulation could reverse the suppression of proliferation and mobility induced by NEDD4 overexpression. Furthermore, we confirmed that NEDD4 induced the degradation of HBx in a ubiquitin/proteasome-dependent manner via K48-linked ubiquitination. Our findings suggest that NEDD4 exerts a tumor-suppressive effect in HBV-associated HCC by acting as an E3 ubiquitin ligase for HBx degradation and provide new insights into the function of NEDD4.
Overexpression of NPTX2 Promotes Malignant Phenotype of Epithelial Ovarian Carcinoma via IL6-JAK2/STAT3 Signaling Pathway Under Hypoxia
Authors: Han Xiaotian , Lu Yechen , Li Xiaoqi , Xia Lingfang , Wen Hao , Feng Zheng , Ju Xingzhu , Chen Xiaojun , Wu Xiaohua
Published: March 2021

Background

Epithelial ovarian cancer (EOC) is the main subtype of ovarian cancer and shows an aggressive phenotype and poor prognosis. Neuronal pentraxin II (NPTX2) is a member of the neuronal pentraxin family and plays a contradictory role in different tumors. However, there has been no report about the possible role and effect of NPTX2 in EOC.

Methods

Bioinformatics analysis, qPCR, western blotting and immunohistochemistry were used to detect the expression of NPTX2 in EOC. Lentivirus-based transfection for NPTX2 overexpression or knockdown was performed on the EOC cell lines A2780, HEY, SKOV3 and OVCAR-3. The effect of NPTX2 on the malignant phenotype of EOC was examined through methods of MTS assay, Edu assay, transwell assay, western blotting analysis, qPCR analysis, luciferase reporter assay and xenograft experiment.

Results

EOC tissues showed higher NPTX2 expression than the normal tissues with poor prognosis. NPTX2 overexpression can promote the proliferation, invasion, migration and tumorigenesis of EOC via IL6-JAK2/STAT3 signaling pathway. Moreover, hypoxia-inducible factor-1(HIF-1) can promote the transcription and expression of NPTX2 under the hypoxic environment. NPTX2 knockdown abolished the hypoxia-induced malignant phenotypes in ECO.

Conclusions

The above results suggest that NPTX2 may play a novel role in ovarian cancer’s malignant phenotype and act as a promising treatment target for EOC molecular therapy.
Inter-Observer Variation in Delineating the Pharyngeal Constrictor Muscle as Organ at Risk in Radiotherapy for Head and Neck Cancer
Authors: Petkar Imran , McQuaid Dualta , Dunlop Alex , Tyler Justine , Hall Emma , Nutting Chris
Published: March 2021

Background and Purpose

To evaluate the inter-observer variation (IOV) in pharyngeal constrictor muscle (PCM) contouring, and resultant impact on dosimetry and estimated toxicity, as part of the pre-trial radiotherapy trial quality assurance (RTQA) within DARS, a multicenter phase III randomized controlled trial investigating the functional benefits of dysphagia-optimized intensity-modulated radiotherapy (Do-IMRT) in pharyngeal cancers.

Methods and Materials

Outlining accuracy of 15 clinicians’ superior and middle PCM (SMPCM) and inferior PCM (IPCM) were retrospectively assessed against gold standards (GS) using volume, location, and conformity indices (CIs) on a pre-trial benchmark case of oropharyngeal cancer. The influence of delineation variability on dose delivered to the constrictor muscles with Do-IMRT and resultant normal tissue complication probability (NTCP) for physician-scored radiation-associated dysphagia at 6 months was evaluated.

Results

For GS, SMPCM, and IPCM volumes were 13.51 and 1.67 cm3; corresponding clinician mean volumes were 12.18 cm3 (SD 3.0) and 2.40 cm3 (SD 0.9) respectively. High IOV in SMPCM and IPCM delineation was observed by the low DICE similarity coefficient value, along with high geographical miss index and discordance index values. Delineation variability did not significantly affect the mean dose delivered to the constrictors, relative to the GS plan. Mean clinician NTCP was 24.6% (SD 0.6), compared to the GS-NTCP of 24.7%.

Conclusions

Results from this benchmark case demonstrate that inaccurate PCM delineation existed, even with protocol guidelines. This did not impact on delivered dose to this structure with Do-IMRT, or on estimated swallowing toxicity, in this single benchmark case.
Development of Dosimetric Verification System for Patient-Specific Quality Assurance of High-Dose-Rate Brachytherapy
Authors: Kang Sang-Won , Chung Jin-Beom , Kim Kyeong-Hyeon , Choi Chang Heon , Kang Seonghee , Shin Dong-Seok , Cho Woong , Eom Kuen-Yong , Park Hae-Jin , Kim Jin-Young , Song Changhoon , Kim In Ah , Kim Jae-Sung , Suh Tae Suk , Park Justin C.
Published: March 2021

Purpose: The aim of this study was to develop a dosimetric verification system (DVS) using a solid phantom for patient-specific quality assurance (QA) of high-dose-rate brachytherapy (HDR-BT).

Methods: The proposed DVS consists of three parts: dose measurement, dose calculation, and analysis. All the dose measurements were performed using EBT3 film and a solid phantom. The solid phantom made of acrylonitrile butadiene styrene (ABS, density = 1.04 g/cm3) was used to measure the dose distribution. To improve the accuracy of dose calculation by using the solid phantom, a conversion factor [CF(r)] according to the radial distance between the water and the solid phantom material was determined by Monte Carlo simulations. In addition, an independent dose calculation program (IDCP) was developed by applying the obtained CF(r). To validate the DVS, dosimetric verification was performed using gamma analysis with 3% dose difference and 3 mm distance-to-agreement criterion for three simulated cases: single dwell position, elliptical dose distribution, and concave elliptical dose distribution. In addition, the possibility of applying the DVS in the high-dose range (up to 15 Gy) was evaluated.

Results: The CF(r) between the ABS and water phantom was 0.88 at 0.5 cm. The factor gradually increased with increasing radial distance and converged to 1.08 at 6.0 cm. The point doses 1 cm below the source were 400 cGy in the treatment planning system (TPS), 373.73 cGy in IDCP, and 370.48 cGy in film measurement. The gamma passing rates of dose distributions obtained from TPS and IDCP compared with the dose distribution measured by the film for the simulated cases were 99.41 and 100% for the single dwell position, 96.80 and 100% for the elliptical dose distribution, 88.91 and 99.70% for the concave elliptical dose distribution, respectively. For the high-dose range, the gamma passing rates in the dose distributions between the DVS and measurements were above 98% and higher than those between TPS and measurements.

Conclusion: The proposed DVS is applicable for dosimetric verification of HDR-BT, as confirmed through simulated cases for various doses.
Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the Epicenter
Authors: Kordella Chryssoula , Lamprianidou Eleftheria , Kotsianidis Ioannis
Published: March 2021

Abnormal DNA methylation patterns are thought to drive the pathobiology of high-risk myelodysplastic syndromes (HR-MDS) and acute myeloid leukemia (AML). Sixteen years after their initial approval, the hypomethylating agents (HMAs), 5-azacytidine (AZA) and 5-aza-2′-deoxycytidine, remain the mainstay of treatment for HR-MDS and AML. However, a connection of the hypomethylating or additional effects of HMAs with clinical responses remains yet to be shown, and the mode of action of HMAs remains obscure. Given the relatively short-lived responses and the inevitable development of resistance in HMAs, a thorough understanding of the antineoplastic mechanisms employed by HMAs holds critical importance. Recent data in cancer cell lines demonstrate that reactivation of endogenous retroelements (EREs) and induction of a cell-intrinsic antiviral response triggered by RNA neotranscripts may underlie the antitumor activity of HMAs. However, data on primary CD34+ cells derived from patients with HR-MDS failed to confirm a link between HMA-mediated ERE modulation and clinical response. Though difficult to reconcile the apparent discrepancy, it is possible that HMAs mediate their effects in more advanced levels of differentiation where cells become responsive to interferon, whereas, inter-individual variations in the process of RNA editing and, in particular, in the ADAR1/OAS/RNase L pathway may also confound the associations of clinical response with the induction of viral mimicry. Further ex vivo studies along with clinical correlations in well-annotated patient cohorts are warranted to decipher the role of ERE derepression in the antineoplastic mechanisms of HMAs.