bluuebunny/crossref_metadata_2025 huggingface dataset:
Global Functional Connectivity Analysis Indicating Dysconnectivity of the Hate Circuit in Major Depressive Disorder
Authors: Pan Pan , Wang Lu , Wu Chujun , Jin Kun , Cao Song , Qiu Yan , Teng Ziwei , Li Sujuan , Shao Tiannan , Huang Jing , Wu Haishan , Xiang Hui , Chen Jindong , Liu Feng , Tang Hui , Guo Wenbin
Published: February 2022

Background

Abnormalities of functional connectivity (FC) in certain brain regions are closely related to the pathophysiology of major depressive disorder (MDD). Findings are inconsistent with different presuppositions in regions of interest. Our research focused on voxel-wise brain-wide FC changes in patients with MDD in an unbiased manner.

Method

We examined resting-state functional MRI in 23 patients with MDD and 26 healthy controls. Imaging data were analyzed by using global-brain FC (GFC) and used to explore the correlation of abnormal GFC values with clinical variables.

Results

Increased GFC values in the left medial superior frontal gyrus (SFGmed) and decreased GFC values in the right supplementary motor area (SMA) were observed in the patients with MDD compared with the controls. The decreased GFC values in the right SMA had a positive correlation with vitamin D and Hamilton Anxiety Scale (HAM-A) scores.

Conclusion

Abnormal GFC in the hate circuit, particularly increased GFC in the left SFGmed and decreased GFC in the right SMA, appears to be a new sight for comprehending the pathological alterations in MDD.
Role of Specialized Pro-resolving Mediators in Reducing Neuroinflammation in Neurodegenerative Disorders
Authors: Ponce Jana , Ulu Arzu , Hanson Corrine , Cameron-Smith Erin , Bertoni John , Wuebker Jenna , Fisher Alfred , Siu Ka-Chun , Marmelat Vivien , Adamec Jiri , Bhatti Danish
Published: February 2022

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are neurodegenerative disorders that affect millions of individuals worldwide. As incidence of these conditions increases with age, there will undoubtedly be an increased prevalence of cases in the near future. Neuroinflammation is a hallmark in the development and progression of neurodegenerative diseases and prevention or resolution of chronic neuroinflammation may represent a novel approach to treatment. The present review highlights the potential of the anti-inflammatory and pro-resolving effects of polyunsaturated fatty acid (PUFA)-derived mediators (Specialized Pro-resolving Mediators—SPM) in neurodegenerative disorders. PUFA-derived SPM are biosynthesized in response to chemicals produced from acute inflammatory responses. Preclinical studies from both AD and PD models suggest a dysregulation of SPM and their receptors in neurological disorders. Decreased SPM may be due to inadequate substrate, an imbalance between SPM and pro-inflammatory mediators or a disruption in SPM synthesis. SPMs hold great promise for neuroprotection in AD by altering expression of pro-inflammatory genes, modulating macrophage function, serving as a biomarker for AD status, and promoting resolution of neuroinflammation. In PD, data suggest SPM are able to cross the blood-brain barrier, inhibit microglial activation and decrease induced markers of inflammation, possibly as a result of their ability to downregulate NFκB signaling pathways. Several in vivo and in vitro studies suggest a benefit from administration of SPMs in both neurodegenerative disorders. However, extrapolation of these outcomes to humans is difficult as no models are able to replicate all features of AD or PD. Minimal data evaluating these PUFA-derived metabolites in humans with neurodegenerative disorders are available and a gap in knowledge exists regarding behavior of SPM and their receptors in patients with these conditions. There is also large gap in our knowledge regarding which lipid mediator would be most effective in which model of AD or PD and how dietary intake or supplementation can impact SPM levels. Future direction should include focused, translational efforts to investigate SPM as an add-on (in addition to standard treatment) or as standalone agents in patients with neurodegenerative disorders.
Postsynaptic Potential Energy as Determinant of Synaptic Plasticity
Authors: Chen Huanwen , Xie Lijuan , Wang Yijun , Zhang Hang
Published: February 2022

Metabolic energy can be used as a unifying principle to control neuronal activity. However, whether and how metabolic energy alone can determine the outcome of synaptic plasticity remains unclear. This study proposes a computational model of synaptic plasticity that is completely determined by energy. A simple quantitative relationship between synaptic plasticity and postsynaptic potential energy is established. Synaptic weight is directly proportional to the difference between the baseline potential energy and the suprathreshold potential energy and is constrained by the maximum energy supply. Results show that the energy constraint improves the performance of synaptic plasticity and avoids setting the hard boundary of synaptic weights. With the same set of model parameters, our model can reproduce several classical experiments in homo- and heterosynaptic plasticity. The proposed model can explain the interaction mechanism of Hebbian and homeostatic plasticity at the cellular level. Homeostatic synaptic plasticity at different time scales coexists. Homeostatic plasticity operating on a long time scale is caused by heterosynaptic plasticity and, on the same time scale as Hebbian synaptic plasticity, is caused by the constraint of energy supply.
A Meta-Analysis of Rupture Risk for Intracranial Aneurysms 10 mm or Less in Size Selected for Conservative Management Without Repair
Authors: Chandra Ronil V. , Maingard Julian , Slater Lee-Anne , Cheung Nicholas K. , Lai Leon T. , Gall Seana L. , Thrift Amanda G. , Phan Thanh G.
Published: February 2022

Background

Small unruptured intracranial aneurysms (UIAs) are considered to have low risk of rupture. The proportion of UIAs measuring 10 mm or less in size that rupture when selected for conservative management without repair is not well known. The aim of this study is to determine the proportion of UIAs that rupture by size threshold from ≤10 to ≤3 mm when selected for management without repair and to determine the level of precision and sources of heterogeneity in the rupture risk estimate.

Methods

This study was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42019121522). The Ovid MEDLINE, EMBASE, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials were searched (inception to August 2020). Studies with longitudinal follow-up of patients with UIAs ( ≤10 mm to ≤3 mm) without endovascular or neurosurgical repair were eligible. We included studies, which provided details of aneurysm size and in which UIA rupture was reported as an outcome. The primary outcome of the pooled proportion of UIA rupture during follow-up was synthesized with random-effects meta-analysis; heterogeneity was explored using meta-regression.

Results

A total of 31 studies that included 13,800 UIAs ≤10 mm in size were eligible for data synthesis. The pooled proportion of ≤10 mm UIAs that ruptured when managed without repair was 1.1% (95% CI 0.8–1.5; I2 = 52.9%) over 3.7 years. Findings were consistent in sensitivity analyses at all the size stratified thresholds including ≤5 and ≤3 mm; rupture occurred in 1.0% (95% CI 0.8–1.3; I2 = 0%) of 7,280 ≤5 mm UIAs and 0.8% (95% CI 0.4–1.5; I2 = 0%) of 1,228 ≤3 mm UIAs managed without repair. In higher quality studies with lower risk of bias, rupture occurred in 1.8% (95% CI 1.5–2.0; I2 = 0%) over 3.9 years. In meta-regression, aneurysm size, shape, anatomical location, and exposure to prior subarachnoid hemorrhage were not identified as sources of heterogeneity.

Conclusion

For every 1,000 UIAs that are 10 mm or less in size and selected for conservative management without repair, between 8 and 15 UIAs are estimated to rupture over 3.7 years. When stratified by size, these pooled rupture risk estimates are consistent and clinically applicable for ≤5 mm UIAs selected for management without repair.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/, identifier: CRD42019121522.
Serum Creatine, Not Neurofilament Light, Is Elevated in CHCHD10-Linked Spinal Muscular Atrophy
Authors: Järvilehto Julius , Harjuhaahto Sandra , Palu Edouard , Auranen Mari , Kvist Jouni , Zetterberg Henrik , Koskivuori Johanna , Lehtonen Marko , Saukkonen Anna Maija , Jokela Manu , Ylikallio Emil , Tyynismaa Henna
Published: February 2022

Objective

To characterize serum biomarkers in mitochondrial CHCHD10-linked spinal muscular atrophy Jokela (SMAJ) type for disease monitoring and for the understanding of pathogenic mechanisms.

Methods

We collected serum samples from a cohort of 49 patients with SMAJ, all carriers of the heterozygous c.197G>T p.G66V variant in CHCHD10. As controls, we used age- and sex-matched serum samples obtained from Helsinki Biobank. Creatine kinase and creatinine were measured by standard methods. Neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) were measured with single molecule array (Simoa), fibroblast growth factor 21 (FGF-21), and growth differentiation factor 15 (GDF-15) with an enzyme-linked immunosorbent assay. For non-targeted plasma metabolite profiling, samples were analyzed with liquid chromatography high-resolution mass spectrometry. Disease severity was evaluated retrospectively by calculating a symptom-based score.

Results

Axon degeneration marker, NfL, was unexpectedly not altered in the serum of patients with SMAJ, whereas astrocytic activation marker, GFAP, was slightly decreased. Creatine kinase was elevated in most patients, particularly men. We identified six metabolites that were significantly altered in serum of patients with SMAJ in comparison to controls: increased creatine and pyruvate, and decreased creatinine, taurine, N-acetyl-carnosine, and succinate. Creatine correlated with disease severity. Altered pyruvate and succinate indicated a metabolic response to mitochondrial dysfunction; however, lactate or mitochondrial myopathy markers FGF-21 or GDF-15 was not changed.

Conclusions

Biomarkers of muscle mass and damage are altered in SMAJ serum, indicating a role for skeletal muscle in disease pathogenesis in addition to neurogenic damage. Despite the minimal mitochondrial pathology in skeletal muscle, signs of a metabolic shift can be detected.
Infections in the Developing Brain: The Role of the Neuro-Immune Axis
Authors: Kim John , Erice Clara , Rohlwink Ursula K. , Tucker Elizabeth W.
Published: February 2022

Central nervous system (CNS) infections occur more commonly in young children than in adults and pose unique challenges in the developing brain. This review builds on the distinct vulnerabilities in children's peripheral immune system (outlined in part 1 of this review series) and focuses on how the developing brain responds once a CNS infection occurs. Although the protective blood-brain barrier (BBB) matures early, pathogens enter the CNS and initiate a localized innate immune response with release of cytokines and chemokines to recruit peripheral immune cells that contribute to the inflammatory cascade. This immune response is initiated by the resident brain cells, microglia and astrocytes, which are not only integral to fighting the infection but also have important roles during normal brain development. Additionally, cytokines and other immune mediators such as matrix metalloproteinases from neurons, glia, and endothelial cells not only play a role in BBB permeability and peripheral cell recruitment, but also in brain maturation. Consequently, these immune modulators and the activation of microglia and astrocytes during infection adversely impact normal neurodevelopment. Perturbations to normal brain development manifest as neurodevelopmental and neurocognitive impairments common among children who survive CNS infections and are often permanent. In part 2 of the review series, we broadly summarize the unique challenges CNS infections create in a developing brain and explore the interaction of regulators of neurodevelopment and CNS immune response as part of the neuro-immune axis.
Characterization of a Novel Monoclonal Antibody for Serine-129 Phosphorylated α-Synuclein: A Potential Application for Clinical and Basic Research
Authors: Liu Weijin , Zhang Qidi , Xing Hao , Gao Ge , Liu Jia , Huang Yue , Yang Hui
Published: February 2022

The Lewy bodies (LBs) are the pathological hallmark of Parkinson's disease (PD). More than 90% of α-synuclein (α-syn) within LBs is phosphorylated at the serine-129 residue [pSer129 α-syn (p-α-syn)]. Although various studies have revealed that this abnormally elevated p-α-syn acts as a pathological biomarker and is involved in the pathogenic process of PD, the exact pathophysiological mechanisms of p-α-syn are still not fully understood. Therefore, the development of specific and reliable tools for p-α-syn detection is important. In this study, we generated a novel p-α-syn mouse monoclonal antibody (C140S) using hybridoma technology. To further identify the characteristics of C140S, we performed several in vitro assays using recombinant proteins, along with ex vivo assays utilizing the brains of Thy1-SNCA transgenic (Tg) mice, the preformed fibril (PFF)-treated neurons, and the brain sections of patients with PD. Our C140S specifically recognized human and mouse p-α-syn proteins both in vitro and ex vivo, and similar to commercial p-α-syn antibodies, the C140S detected higher levels of p-α-syn in the midbrain of the Tg mice. Using immunogold electron microscopy, these p-α-syn particles were partly deposited in the cytoplasm and colocalized with the outer mitochondrial membrane. In addition, the C140S recognized p-α-syn pathologies in the PFF-treated neurons and the amygdala of patients with PD. Overall, the C140S antibody was a specific and potential research tool in the detection and mechanistic studies of pathogenic p-α-syn in PD and related synucleinopathies.
Secure Attachment Representation in Adolescence Buffers Heart-Rate Reactivity in Response to Attachment-Related Stressors
Authors: Gander Manuela , Karabatsiakis Alexander , Nuderscher Katharina , Bernheim Dorothee , Doyen-Waldecker Cornelia , Buchheim Anna
Published: February 2022

To date, we know very little about the effects of the differences in attachment classifications on the physiological correlates of stress regulation in adolescent age groups. The present study examined for the first time heart rate (HR) and heart rate variability (HRV) during an attachment interview in adolescents. HR and HRV data were collected during a baseline assessment as well as during the administration of the Adult Attachment Projective Picture System (AAP) in a community-based sample of 56 adolescents (26 females and 30 males, mean age = 16.05 years [SD = 1.10]). We additionally used the Adult Attachment Interview (AAI) in 50% of our sample to test the convergent validity. Adolescents with a secure attachment representation showed a higher HRV from baseline to the AAP interview compared to those with an insecure-dismissing (Ds) and the unresolved group. A comparison between the two insecure attachment groups showed no significant difference related to HR and HRV. Cohen’s Kappa (κ = 0.81) revealed an almost perfect agreement between the AAP and the AAI for the four-group classification. Our results indicate that adolescents with a secure attachment representation are more capable of dealing with attachment-related distress which is represented in higher HRV during an attachment interview.
Middle Ear Surgeries for Chronic Otitis Media Improve Cognitive Functions and Quality of Life of Age-Related Hearing Loss Patients
Authors: Gao Juanjuan , Chen Junyan , Xu Jia , Liang Sichao , Yi Haijin
Published: February 2022

Age-related hearing loss (ARHL) may limit communication, which is closely associated with cognitive decline of the elderly and negatively affects their quality of life. In ARHL patients who suffer chronic otitis media (COM), hearing impairment may worsen and negatively affect the cognition and quality of life. It is currently unknown whether restoration of the conductive hearing in the mixed hearing loss through middle ear surgeries can improve both the cognitive function and quality of life of the ARHL patients. Therefore, in the present study, the ARHL patients were followed up for 6 months after middle ear surgeries for COM, and both the cognitive functions and quality of life of the patients were assessed using Montreal Cognitive Assessment and Glasgow Benefit Inventory. It was found that both the cognitive functions and quality of life were improved 6 months after middle ear surgeries. In conclusion, hearing recovery after middle ear surgeries could improve cognitive functions and quality of life of ARHL patients with COM, and surgical intervention is, hence, recommended for COM.
Integrative Functional, Molecular, and Transcriptomic Analyses of Altered Intrinsic Timescale Gradient in Depression
Authors: Han Shaoqiang , Zheng Ruiping , Li Shuying , Zhou Bingqian , Jiang Yu , Wang Caihong , Wei Yarui , Pang Jianyue , Li Hengfen , Zhang Yong , Chen Yuan , Cheng Jingliang
Published: February 2022

The pathophysiology and pharmacology of depression are hypothesized to be related to the imbalance of excitation–inhibition that gives rise to hierarchical dynamics (or intrinsic timescale gradient), further supporting a hierarchy of cortical functions. On this assumption, intrinsic timescale gradient is theoretically altered in depression. However, it remains unknown. We investigated altered intrinsic timescale gradient recently developed to measure hierarchical brain dynamics gradient and its underlying molecular architecture and brain-wide gene expression in depression. We first presented replicable intrinsic timescale gradient in two independent Chinese Han datasets and then investigated altered intrinsic timescale gradient and its possible underlying molecular and transcriptional bases in patients with depression. As a result, patients with depression showed stage-specifically shorter timescales compared with healthy controls according to illness duration. The shorter timescales were spatially correlated with monoamine receptor/transporter densities, suggesting the underlying molecular basis of timescale aberrance and providing clues to treatment. In addition, we identified that timescale aberrance-related genes ontologically enriched for synapse-related and neurotransmitter (receptor) terms, elaborating the underlying transcriptional basis of timescale aberrance. These findings revealed atypical timescale gradient in depression and built a link between neuroimaging, transcriptome, and neurotransmitter information, facilitating an integrative understanding of depression.
Sustainable Food Systems in Fruits and Vegetables Food Supply Chains
Authors: Cassani Lucía , Gomez-Zavaglia Andrea
Published: February 2022

Fruits and vegetables wastes (e.g., peel fractions, pulps, pomace, and seeds) represent ~16% of total food waste and contribute ~6% to global greenhouse gas emissions. The diversity of the fruit-horticultural production in several developing countries and the excess of certain fruits or vegetables in the months of greatest production offer unique opportunities for adding value to these wastes (co-products). Within the scope of the Circular Economy, valorization of such wastes for the production of innovative bio-ingredients can open great market opportunities if efficiently exploited. In this context, this review deals with the current situation of wastes arising from fruits and vegetables (availability, characterization) as sources of valuable ingredients (fiber, polyphenols, pigments) suitable to be incorporated into food, pharmaceutical and cosmeceutical products. In addition, an integral and systematic approach including the sustainable technologies generally used at both lab and industrial scale for efficient extraction of bioactive compounds from fruits and vegetables wastes are addressed. Overall, this review provides a general updated overview regarding the situation of fruits and vegetables chain supplies in the post-pandemic era, offering an integrative perspective that goes beyond the recovery of fiber and phytochemicals from the previous mentioned wastes and focuses on whole processes and in their social and economic impacts.
Patient-Wise Methodology to Assess Glycemic Health Status: Applications to Quantify the Efficacy and Physiological Targets of Polyphenols on Glycemic Control
Authors: Olivera-Nappa Álvaro , Contreras Sebastian , Tevy María Florencia , Medina-Ortiz David , Leschot Andrés , Vigil Pilar , Conca Carlos
Published: February 2022

A growing body of evidence indicates that dietary polyphenols could be used as an early intervention to treat glucose-insulin (G-I) dysregulation. However, studies report heterogeneous information, and the targets of the intervention remain largely elusive. In this work, we provide a general methodology to quantify the effects of any given polyphenol-rich food or formulae over glycemic regulation in a patient-wise manner using an Oral Glucose Tolerance Test (OGTT). We use a mathematical model to represent individual OGTT curves as the coordinated action of subsystems, each one described by a parameter with physiological interpretation. Using the parameter values calculated for a cohort of 1198 individuals, we propose a statistical model to calculate the risk of dysglycemia and the coordination among subsystems for each subject, thus providing a continuous and individual health assessment. This method allows identifying individuals at high risk of dysglycemia—which would have been missed with traditional binary diagnostic methods—enabling early nutritional intervention with a polyphenol-supplemented diet where it is most effective and desirable. Besides, the proposed methodology assesses the effectiveness of interventions over time when applied to the OGTT curves of a treated individual. We illustrate the use of this method in a case study to assess the dose-dependent effects of Delphinol® on reducing dysglycemia risk and improving the coordination between subsystems. Finally, this strategy enables, on the one hand, the use of low-cost, non-invasive methods in population-scale nutritional studies. On the other hand, it will help practitioners assess the effectiveness of an intervention based on individual vulnerabilities and adapt the treatment to manage dysglycemia and avoid its progression into disease.
Analysis of BRCA Germline Mutations in Chinese Prostate Cancer Patients
Authors: Chen Wei , Xia Wei , Xue Song , Huang Hang , Lin Qi , Liu Yi , Liu Tongtong , Zhang Yiqun , Zhang Panwang , Wang Jianfei , Yang Yining , Dong Baijun , Yu Zhixian
Published: February 2022

Recent studies have indicated that prostate cancer (PCa) with BRCA2 mutations is more aggressive. However, these reports mostly focused on Caucasus populations, and large-scale studies on BRCA mutations in Chinese PCa populations remain limited. Herein, we screened, from multiple centers in China, a total of 172 patients with PCa carrying BRCA1/2 germline mutations. The variant distribution and type, associated somatic variant, and frequency of the BRCA germline variants in these patients were analyzed retrospectively. We found that Chinese patients with PCa carrying BRCA1/2 germline mutations were diagnosed at an earlier age, i.e., 67 years (range, 34–89 years), and most had metastatic castration-resistant PCa (mCRPC) (54.65%, 94/172). The top three BRCA variants were frameshift, missense, and splicing variants. The overall pathogenic rates of the BRCA1 and BRCA2 variants were 17.46% (11/63) and 56.55% (82/145), respectively. Among the somatic mutations associated with BRCA2 germline mutations, the highest frequency was for FOXA1 (circulating tumor DNA [ctDNA] sequencing, 7.4%; tissue samples, 52%) and NCOR2 mutations (ctDNA sequencing, 7.4%; tissue samples, 24%); TP53 was the dominant somatic mutation associated with BRCA1 germline mutations (ctDNA sequencing, 25%; tissue samples, 17%). Ultimately, in Chinese patients, PCa with BRCA1/2 germline mutations tends to be more aggressive. Compared with BRCA1, BRCA2 has a higher frequency of germline pathogenic mutations. FOXA1, NCOR2, and TP53 somatic mutations associated with higher BRCA1/2 germline pathogenic mutations. Our description of BRCA germline mutations in the Chinese PCa patients provides more reference data for the precise diagnosis and treatment of Chinese PCa patients.
Prognostic Value of Body Mass Index Stratified by Alcohol Drinking Status in Patients With Esophageal Squamous Cell Carcinoma
Authors: Chen Shao-bin , Liu Di-tian , Chen Yu-ping
Published: February 2022

Background

The goal of this study was to investigate the prognostic value of body mass index (BMI) in patients with esophageal squamous cell carcinoma (ESCC) when stratified by alcohol drinking status.

Methods

A total of 620 patients with ESCC who underwent esophagectomy were analyzed. A receiver operating characteristic curve was constructed to set the appropriate cutoff point for BMI. Alcohol drinking was divided into ever and never. Kaplan-Meier and multivariate Cox regression analyses were conducted to investigate the association between clinicopathological factors and survival.

Results

The cutoff point was 18.75 kg/m2 for BMI. Two hundred and twenty-nine patients were ever drinkers, while the other 391 patients were never drinkers. The ever drinker group was found to have more males, longer tumor lengths, advanced pT category disease, advanced pN category disease, and lower tumor locations. However, no significant difference in BMI was found between ever drinkers and never drinkers. For ever drinkers, low BMI was significantly correlated with worse overall survival (hazard ratio = 1.690; P=0.035) and cancer-specific survival (hazard ratio = 1.763; P=0.024) than high BMI after adjusting for other factors. However, BMI was not a prognostic factor in univariate and multivariate analyses for never drinkers.

Conclusions

BMI is a prognostic factor only in ever drinkers with ESCC but not in never drinkers. Further studies are needed to elucidate the mechanism underlying the effect of the interaction between BMI and alcohol consumption on the prognosis of patients with ESCC.
Biological Effects of Monoenergetic Carbon Ions and Their Associated Secondary Particles
Authors: Buglewicz Dylan J. , Walsh Kade D. , Hirakawa Hirokazu , Kitamura Hisashi , Fujimori Akira , Kato Takamitsu A.
Published: February 2022

DNA double-strand breaks (DSBs) are the main factor behind carbon-ion radiation therapy (CIRT)-induced cell death. Nuclear interactions along the beam path between the primary carbon ions and targets result in nuclear fragmentation of carbon ions and recoiled particles. These secondary particles travel further distances past the Bragg peak to the tail region, leading to unwanted biological effects that may result in cytotoxicity in critical organs and secondary induced tumors following CIRT. Here, we confirmed that the density of the DSB distributions increases as the cell survival decreases at the Bragg peak and demonstrated that by visualizing DSBs, the various LET fragmentation ions and recoiled particles produced differences in their biological effects in the post-Bragg peak tail regions. This suggests that the density of the DSBs within the high-LET track structures, rather than only their presence, is important for inducing cell death. These results are essential for CIRT treatment planning to limit the amount of healthy cell damage and reducing both the late effect and the secondary tumor-associated risk.
Establishment of a Novel Mouse Hepatocellular Carcinoma Model for Dynamic Monitoring of Tumor Development by Bioluminescence Imaging
Authors: Cao Xiangyi , Zhang Yulong , Zhou Qianqian , Sun Sujing , He Minwei , Wang Xiaohui , Ma Ping , Yang Xiaoang , Lv Liping , Zhan Linsheng
Published: February 2022

In this study, a novel mouse model of hepatocellular carcinoma (HCC) was established by simultaneously knocking out Pten and p53 suppressor genes and overexpressing c-Met and △90-β-catenin proto-oncogenes in the livers of mice via hydrodynamic injection (HDI). The mutations were introduced using the CRISPR/Cas9 and Sleeping Beauty transposon systems. In this way, a primary liver cancer model was established within six weeks. In addition, macrophages expressing arginase-1(Arg1) promoter coupled with firefly luciferase were engineered for bioluminescence imaging (BLI) of the tumor microenvironment. This novel, rapidly-generated model of primary hepatocellular carcinoma can be monitored noninvasively, which can facilitate not only applications of the model, but also the development of new drugs and treatment strategies of HCC.
Early Alpha-Fetoprotein Response Is Associated With Survival in Patients With HBV-Related Hepatocellular Carcinoma Receiving Lenvatinib
Authors: Liu Bo , Shang Xiao , Shi Jin-Yu , Cui Guo-Zhen , Li Xi , Wang Nan-Ya
Published: February 2022

Background/Purpose

Lenvatinib is a first-line treatment for unresectable hepatocellular carcinoma (uHCC). We assessed the value of early alpha-fetoprotein (AFP) response for predicting clinical outcomes with lenvatinib treatment in patients with HBV-related uHCC and elevated AFP levels.

Methods

This retrospective analysis included patients with HBV-related uHCC and baseline AFP levels ≥20 ng/ml who received lenvatinib for >1 month between November 2018 and May 2021. Early AFP response was defined as a >20% decrease in AFP serum level from baseline after 4 weeks of lenvatinib treatment. Radiological response (Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival, and overall survival were assessed in AFP responders and non-responders.

Results

Of the 46 patients analyzed, 30 (65.2%) were early AFP responders and 16 (34.8%) were non-responders. Compared to the non-responders, early AFP responders had a significantly higher objective response rate (34.5% vs 6.3%, p=0.0349), disease control rate (82.8% vs 50.0%; p=0.0203) and longer median progression-free survival (13.0 vs 7.0 months; HR, 0.464; 95% CI, 0.222-0.967; p=0.028). A subsequent multivariate analysis confirmed that early AFP response (HR, 0.387; 95% CI, 0.183-0.992; p=0.0154), Eastern Cooperative Oncology Group Performance Status of 0 (HR, 0.890; 95% CI, 0.811-0.976; p=0.0132) and Albumin-Bilirubin grade 1 (HR, 0.457; 95% CI, 0.269-0.963; p=0.0327) were independent prognostic factors for longer progression-free survival.

Conclusion

AFP is an important prognostic factor and a predictive biomarker for survival benefit with lenvatinib treatment in patients with HBV-related uHCC.
Reveal the Heterogeneity in the Tumor Microenvironment of Pancreatic Cancer and Analyze the Differences in Prognosis and Immunotherapy Responses of Distinct Immune Subtypes
Authors: Wang Xiaoqin , Li Lifang , Yang Yang , Fan Linlin , Ma Ying , Mao Feifei
Published: February 2022

Purpose

The current clinical classification of pancreatic ductal adenocarcinoma (PDAC) cannot well predict the patient’s possible response to the treatment plan, nor can it predict the patient’s prognosis. We use the gene expression patterns of PDAC patients to reveal the heterogeneity of the tumor microenvironment of pancreatic cancer and analyze the differences in the prognosis and immunotherapy response of different immune subtypes.

Methods

Firstly, use ICGC’s PACA-AU PDAC expression profile data, combined with the ssGSEA algorithm, to analyze the immune enrichment of the patient’s tumor microenvironment. Subsequently, the spectral clustering algorithm was used to extract different classifications, the PDAC cohort was divided into four subtypes, and the correlation between immune subtypes and clinical characteristics and survival prognosis was established. The patient’s risk index is obtained through the prognostic prediction model, and the correlation between the risk index and immune cells is prompted.

Results

We can divide the PDAC cohort into four subtypes: immune cell and stromal cell enrichment (Immune-enrich-Stroma), non-immune enrichment but stromal cell enrichment (Non-immune-Stroma), immune-enriched Collective but non-matrix enrichment (Immune-enrich-non-Stroma) and non-immune enrichment and non-stromal cell enrichment (Non-immune-non-Stroma). The five-year survival rate of immune-enrich-Stroma and non-immune-Stroma of PACA-CA is quite different. TCGA-PAAD’s immune-enrich-Stroma and immune-enrich-non-Stroma groups have a large difference in productivity in one year. The results of the correlation analysis between the risk index and immune cells show that the patient’s disease risk is significantly related to epithelial cells, megakaryocyte-erythroid progenitor (MEP), and Th2 cells.

Conclusion

The tumor gene expression characteristics of pancreatic cancer patients are related to immune response, leading to morphologically recognizable PDAC subtypes with prognostic/predictive significance.
Analysis of Subset Chimerism for MRD-Detection and Pre-Emptive Treatment in AML
Authors: Georgi Julia-Annabell , Stasik Sebastian , Bornhäuser Martin , Platzbecker Uwe , Thiede Christian
Published: February 2022

Allogeneic hematopoietic stem cell transplantation (alloHCT) represents the only potentially curative treatment in high-risk AML patients, but up to 40% of patients suffer from relapse after alloHCT. Treatment of overt relapse poses a major therapeutic challenge and long-term disease control is achieved only in a minority of patients. In order to avoid post-allograft relapse, maintenance as well as pre-emptive therapy strategies based on MRD-detection have been used. A prerequisite for the implementation of pre-emptive therapy is the accurate identification of patients at risk for imminent relapse. Detection of measurable residual disease (MRD) represents an effective tool for early relapse prediction in the post-transplant setting. However, using established MRD methods such as multicolor flow cytometry or quantitative PCR, sensitive MRD monitoring is only applicable in about half of the patients with AML and advanced MDS undergoing alloHCT. Donor chimerism analysis, in particular when performed on enriched leukemic stem and progenitor cells, e.g. CD34+ cells, is a sensitive method and has emerged as an alternative option in the post alloHCT setting. In this review, we will focus on the current strategies for lineage specific chimerism analysis, results of pre-emptive treatment using this technology as well as future developments in this field.
Sources of Stress, Family Functioning, and Needs of Families With a Chronic Critically Ill Child: A Qualitative Study
Authors: Grandjean Chantal , Ullmann Pascale , Marston Mark , Maitre Marie-Christine , Perez Marie-Hélène , Ramelet Anne-Sylvie ,   The OCToPuS Consortium
Published: February 2022

PICU hospitalization is particularly stressful for families. When it is prolonged and the prognostic is uncertain, it can significantly and negatively affect the whole family. To date, little is known on how families with a chronic critically ill (CCI) child are affected. This national study explored the specific PICU-related sources of stress, family functioning and needs of families of CCI patients during a PICU hospitalization. This descriptive qualitative study was conducted in the eight pediatric intensive care units in Switzerland. Thirty-one families with a child meeting the CCI criteria participated in semi-structured interviews. Interviews, including mothers only (n = 12), fathers only (n = 8), or mother and father dyads (n = 11), were conducted in German, French, or English by two trained researchers/clinical nurses specialists. Interviews were recorded, transcribed verbatim, and analyzed using deductive and inductive content analyses. Five overarching themes emerged: (1) high emotional intensity, (2) PICU-related sources of stress, (3) evolving family needs, (4) multi-faceted family functioning, and (5) implemented coping strategies. Our study highlighted the importance of caring for families with CCI children. Parents reported high negative emotional responses that affect their family functioning. Families experience was highly dependent on how HCPs were able to meet the parental needs, provide emotional support, reinforce parental empowerment, and allow high quality of care coordination.
Incidence, Clinical Characteristics, and Genotype Distribution of Rotavirus in a Neonatal Intensive Care Unit 5 Years After Introducing Rotavirus Vaccine
Authors: Yoon Hye Sun , Lim Jiseun , Sohn Yong-Hak , Kim Seung Yeon
Published: February 2022

Background

Rotavirus (RV) is a common cause of viral gastroenteritis in children worldwide. We aimed to investigate the incidence, symptoms, and genotype of RV infection in a neonatal intensive care unit (NICU) in South Korea 5 years after the introduction of RV vaccination to evaluate its effect on newborn infants.

Methods

A total of 431 fecal specimens were collected from patients admitted to NICU between April 20, 2012 and September 10, 2013. Enzyme-linked immunoassays were used to detect RV antigen. Nested multiplex polymerase chain reaction was used for genotyping.

Results

The overall incidence of RV infection was 43.9% and was significantly higher in preterm infants, infants born in the study hospital, low birth weight infants, and cesarean births (P < 0.05). Symptoms of diarrhea, poor feeding, abdominal distension, and apnea were significantly higher in infants with RV infection than those without infection. RV infection gradually increased depending on infant care at home, postpartum clinic, or hospital (26.0, 45.1, and 60.2%, respectively; P = 0.000). The dominant RV genotype in the NICU was G4P[6] at 95.4%.

Conclusion

Current RV vaccines did not affect the incidence of RV infection in newborn and preterm infants in the NICU. Most RV-positive patients in the NICU had symptoms, and the incidence of RV infection was relatively higher in hospitals and postpartum clinics with group life than home. The dominant RV genotype was G4P[6] across study groups.
The Mitochondrial Deubiquitinase USP30 Regulates AKT/mTOR Signaling
Authors: Zhang Ruohan , Ozgen Serra , Luo Hongke , Krigman Judith , Zhao Yutong , Xin Gang , Sun Nuo
Published: February 2022

Mitophagy is an intracellular mechanism to maintain mitochondrial health by removing dysfunctional mitochondria. The E3 ligase Parkin ubiquitinates the membrane proteins on targeted mitochondria to initiate mitophagy, whereas USP30 antagonizes Parkin-dependent mitophagy by removing ubiquitin from Parkin substrates. The AKT/mTOR signaling is a master regulator of cell proliferation, differentiation, apoptosis, and autophagy. Although mounting evidence suggests that perturbations in the AKT/mTOR signaling pathway may contribute to mitophagy regulation, the specific mechanisms between Parkin/USP30 and AKT/mTOR signaling have not been elucidated. In this study, we employ a set of genetic reagents to investigate the role of Parkin and USP30 in regulating the AKT/mTOR signaling during mitophagy. We demonstrated that, in the setting of mitochondrial stress, the AKT/mTOR signaling is regulated, at least in part, by the activity of Parkin and USP30. Parkin inhibits AKT/mTOR signaling following an in vitro mitochondrial stress, thereby promoting apoptosis. However, USP30 overexpression antagonizes the activity of Parkin to sustain AKT/mTOR activity and inhibit apoptosis. These findings provide new insights into Parkin and USP30’s role in apoptosis and suggest that inhibiting USP30 might provide a specific strategy to synergize with AKT/mTOR inhibitors in cancer treatment.
A Dynamic Mass Redistribution Assay for the Human Sweet Taste Receptor Uncovers G-Protein Dependent Biased Ligands
Authors: Servant Nicole B. , Williams Mark E. , Brust Paul F. , Tang Huixian , Wong Melissa S. , Chen Qing , Lebl-Rinnova Marketa , Adamski-Werner Sara L. , Tachdjian Catherine , Servant Guy
Published: February 2022

The sweet taste receptor is rather unique, recognizing a diverse repertoire of natural or synthetic ligands, with a surprisingly large structural diversity, and with potencies stretching over more than six orders of magnitude. Yet, it is not clear if different cell-based assays can faithfully report the relative potencies and efficacies of these molecules. Indeed, up to now, sweet taste receptor agonists have been almost exclusively characterized using cell-based assays developed with overexpressed and promiscuous G proteins. This non-physiological coupling has allowed the quantification of receptor activity via phospholipase C activation and calcium mobilization measurements in heterologous cells on a FLIPR system, for example. Here, we developed a novel assay for the human sweet taste receptor where endogenous G proteins and signaling pathways are recruited by the activated receptor. The effects of several sweet taste receptor agonists and other types of modulators were recorded by measuring changes in dynamic mass redistribution (DMR) using an Epic® reader. Potency and efficacy values obtained in the DMR assay were compared to those results obtained with the classical FLIPR assay. Results demonstrate that for some ligands, the two assay systems provide similar information. However, a clear bias for the FLIPR assay was observed for one third of the agonists evaluated, suggesting that the use of non-physiological coupling may influence the potency and efficacy of sweet taste receptor ligands. Replacing the promiscuous G protein with a chimeric G protein containing the C-terminal tail 25 residues of the physiologically relevant G protein subunit Gαgustducin reduced or abrogated bias.
Physics of Organelle Membrane Bridging via Cytosolic Tethers is Distinct From Cell Adhesion
Authors: Kamal Mohammad Arif , Janeš Josip Augustin , Li Long , Thibaudau Franck , Smith Ana-Sunčana , Sengupta Kheya
Published: February 2022

Tremendous progress has been made recently in imaging the contacts between intra-cellular organelles, which are thought to be mediated by soluble tethers. However, they are still difficult to study in cellulo, and reconstituting them in vitro is a standing challenge. Here we take a mimetic approach to study Giant unilamellar vesicles (GUVs) and supported lipid bilayers (SLBs) interacting via single- (or double-) stranded DNA sequences of two different lengths. Like intra-cellular tethers which may reside in the cytosol when unbound, the DNA-tethers are soluble, but can insert into the membrane with the help of cholesterol moieties found at their extremities. Tether-exchange between the bulk “cytosol” and the GUV/SLB membrane leads to a novel statistical ensemble in which the entire system equilibrates together, rather than individual GUVs behaving as separate closed systems. As a consequence, adhesion between the GUV and the SLB is driven by collective entropic effects amplified by tether shape changes associated with membrane bridging. A direct experimental consequence is an unusual dependence on tether-concentration, which becomes an important control parameter at low concentrations, while tether length/flexibility are less important. The establishment of this fundamentally different interaction between two membranes suggests that in physiological conditions, the regulation of contact formation inside cells may be very different from the case of the much studied ligand-receptor mediated cell adhesion.
Ultrasound Contrast Imaging: Fundamentals and Emerging Technology
Authors: Yusefi Hossein , Helfield Brandon
Published: February 2022

The development of microbubble contrast agents has broadened the scope of medical ultrasound imaging. Along with dedicated imaging techniques, these agents provide enhanced echoes from the blood pool and have enabled diagnostic ultrasound to assess and quantify microvascular blood flow. Contrast-enhanced ultrasound is currently used worldwide with clinical indications in cardiology and radiology, and it continues to evolve and develop through innovative technological advancements. In this review article, we present an overview of the basic microbubble physics and bubble-specific imaging techniques that enable this modality, and follow this with a discussion on new and emerging applications.
Effect of Nonequilibrium Transient Electronic Structures on Lattice Stability in Metals: Density Functional Theory Calculations
Authors: Zhang Qi , Yu Xiaoxiang , Zeng Qiyu , Zhang Hengyu , Zhang Shen , Gao Cheng , Kang Dongdong , Wu Jianhua , Dai Jiayu
Published: February 2022

The electronic structures of metals undergo transient nonequilibrium states during the photoexcitation process caused by isochoric heating of X-ray free-electron laser, and their lattice stability is, thus, significantly affected. By going beyond frozen core approximation, we manually introduced nonequilibrium electron distribution function in finite-temperature density functional theory with the framework of Kohn–Sham–Mermin to investigate such transient states, and their effect on lattice stability in metals is demonstrated by phonon dispersion calculated using the finite displacement method. We found that the perfect lattice of a metal collapses due to the exotic electronic structure of nonequilibrium transient state created by isochoric heating of X-ray free-electron laser. Further increase of the number of holes created in the sample (i.e., an increase of laser fluence) still results in lattice instability for aluminum, while for copper, it results in phonon hardening. The potential energy surface is calculated for the extreme case of both Al and Cu with exactly one hole created in its inner shell for each one of the atoms. A double-well structure is clearly observed for Al, while the potential energy surface becomes steeper for Cu.
A Low-Profile Broadband Metasurface Antenna With Polarization Conversion Based on Characteristic Mode Analysis
Authors: Dong Jian , Wu Rigeng , Pan Yaxi
Published: February 2022

In this paper, a low-profile, broadband metasurface antenna for polarization conversion is proposed based on characteristic mode analysis (CMA). A new type of metasurface unit with a partially chamfered symmetrical triangular structure is designed. The inherent physical characteristics of the antenna are analyzed based on CMA, and the expected characteristic modes are selected for excitation at a suitable position. Slot-coupled feeding via microstrip line realizes the performance of wide impedance bandwidth and axial ratio bandwidth (ARBW). The measured -10 dB impedance bandwidth of 36.3% (4.38–6.32 GHz) and the 3 dB ARBW of 20.1% (5.41–6.62 GHz) are achieved. The left-hand circular polarization (LHCP) is realized, and the measured highest gain in the working frequency band is 6.05 dBic. The overall size of the designed and fabricated metasurface antenna is 0.58 λ0 × 0.58 λ0 × 0.07 λ0at 5 GHz. The proposed metasurface antenna can be well used in C-band satellite communications due to its low profile, broadband, and circular polarization.