bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracellular Vesicles From Hyperammonemic Rats Induce Neuroinflammation in Cerebellum of Normal Rats: Role of Increased TNFα Content
Authors: Izquierdo-Altarejos Paula , Martínez-García Mar , Felipo Vicente
Published: July 2022

Hyperammonemia plays a main role in the neurological impairment in cirrhotic patients with hepatic encephalopathy. Rats with chronic hyperammonemia reproduce the motor incoordination of patients with minimal hepatic encephalopathy, which is due to enhanced GABAergic neurotransmission in cerebellum as a consequence of neuroinflammation. Extracellular vesicles (EVs) could play a key role in the transmission of peripheral alterations to the brain to induce neuroinflammation and neurological impairment in hyperammonemia and hepatic encephalopathy. EVs from plasma of hyperammonemic rats (HA-EVs) injected to normal rats induce neuroinflammation and motor incoordination, but the underlying mechanisms remain unclear. The aim of this work was to advance in the understanding of these mechanisms. To do this we used an ex vivo system. Cerebellar slices from normal rats were treated ex vivo with HA-EVs. The aims were: 1) assess if HA-EVs induce microglia and astrocytes activation and neuroinflammation in cerebellar slices of normal rats, 2) assess if this is associated with activation of the TNFR1-NF-kB-glutaminase-GAT3 pathway, 3) assess if the TNFR1-CCL2-BDNF-TrkB pathway is activated by HA-EVs and 4) assess if the increased TNFα levels in HA-EVs are responsible for the above effects and if they are prevented by blocking the action of TNFα. Our results show that ex vivo treatment of cerebellar slices from control rats with extracellular vesicles from hyperammonemic rats induce glial activation, neuroinflammation and enhance GABAergic neurotransmission, reproducing the effects induced by hyperammonemia in vivo. Moreover, we identify in detail key underlying mechanisms. HA-EVs induce the activation of both the TNFR1-CCL2-BDNF-TrkB-KCC2 pathway and the TNFR1-NF-kB-glutaminase-GAT3 pathway. Activation of these pathways enhances GABAergic neurotransmission in cerebellum, which is responsible for the induction of motor incoordination by HA-EVs. The data also show that the increased levels of TNFα in HA-EVs are responsible for the above effects and that the activation of both pathways is prevented by blocking the action of TNFα. This opens new therapeutic options to improve motor incoordination in hyperammonemia and also in cirrhotic patients with hepatic encephalopathy and likely in other pathologies in which altered cargo of extracellular vesicles contribute to the propagation of the pathology.
Type I Interferons Promote Germinal Centers Through B Cell Intrinsic Signaling and Dendritic Cell Dependent Th1 and Tfh Cell Lineages
Authors: Dahlgren Madelene W. , Plumb Adam W. , Niss Kristoffer , Lahl Katharina , Brunak Søren , Johansson-Lindbom Bengt
Published: July 2022

Type I interferons (IFNs) are essential for antiviral immunity, appear to represent a key component of mRNA vaccine-adjuvanticity, and correlate with severity of systemic autoimmune disease. Relevant to all, type I IFNs can enhance germinal center (GC) B cell responses but underlying signaling pathways are incompletely understood. Here, we demonstrate that a succinct type I IFN response promotes GC formation and associated IgG subclass distribution primarily through signaling in cDCs and B cells. Type I IFN signaling in cDCs, distinct from cDC1, stimulates development of separable Tfh and Th1 cell subsets. However, Th cell-derived IFN-γ induces T-bet expression and IgG2c isotype switching in B cells prior to this bifurcation and has no evident effects once GCs andbona fideTfh cells developed. This pathway acts in synergy with early B cell-intrinsic type I IFN signaling, which reinforces T-bet expression in B cells and leads to a selective amplification of the IgG2c+GC B cell response. Despite the strong Th1 polarizing effect of type I IFNs, the Tfh cell subset develops into IL-4 producing cells that control the overall magnitude of the GCs and promote generation of IgG1+GC B cells. Thus, type I IFNs act on B cells and cDCs to drive GC formation and to coordinate IgG subclass distribution through divergent Th1 and Tfh cell-dependent pathways.
Nitrogen Enrichment Reduces the Diversity of Bacteria and Alters Their Nutrient Strategies in Intertidal Zones
Authors: Xu Yuan-Feng , Dong Xu-Meng , Luo Cheng , Ma Shuo-Nan , Xu Ji-Lin , Cui Yong-De
Published: July 2022

Intertidal ecosystems are affected by severe nitrogen (N) pollution as a result of anthropogenic activities, and it is unclear how this may affect intertidal microbial communities, which play critical roles in regulating biogeochemical cycles. To address this gap, we conducted a two-month mesocosm experiment using six targeted concentrations of total N. The findings indicated that N entering seawaters has direct negative effects on the bacterial diversity. Dose dependence was found for the effects of N on bacterial diversity in sediment: low N addition increased the bacterial diversity, but a reduction in bacterial diversity occurred when N exceeded a certain value (≥ 3 mg L−1). Additionally, N enrichment caused clear shifts in bacterial community composition with increases in the relative abundance of Balneola (organic-degrading), Phalacroma mitra (carbohydrate-fermenting), and Bacteroides (phosphorus (P)-solubilizing), and decreases in Leptolyngbya_PPC_6406 (N2-fixing). The increased abundance in P-solubilizing and organic-degrading bacteria and decrease in N-fixing bacteria, combined with the upregulated activity of alkaline phosphatase and downregulation of urease activity, implied that the bacterial assemblage tended to be more effective in P and carbon acquisition but reduced N acquisition. Further path analysis suggested that N had direct effects on bacteria and contributed 50%–100% to the variations in bacterial diversity, whereas environmental changes such as dissolved oxygen and pH played minor roles. Overall, bacteria occurring in sediment were likely more stress-resistant to high N exposure than those occurring in seawater, possibly due to the high buffering capacity of sediment and growth tolerances of bacteria in the sediment. These findings point to the vulnerability of microbes in water systems to increasing global N loading, and that N reduction is needed to combat the loss of microbial diversity.
Revealing Selection in Breeding and Genetic Characteristics of Economically Important Traits of New Species of Apostichopus Japonicas Based on Genome Resequencing and GWAS Analysis
Authors: Guo Chao , Li Yuanxin , Xie Jiahui , Han Lingshu , Wang Youquan , Zhang Xianglei , Wu YangLei , Song Jian , Chang Yaqing , Ding Jun
Published: July 2022

Apostichopus japonicas is an economically important species with high nutritional value. However, our knowledge of its genetic diversity and the genetic changes that occurred during its domestication or trait selection is quite limited. In this study, the whole genomes of 254 A. japonicas samples were resequenced. Analyses of the population genetic structure revealed that the genetic diversity of A. japonicas in the north of China is generally high, there was no difference in the population structure among the six cultured populations, and they were divided into two subpopulations together with AY-1 (new species). The results also showed that the genetic diversity of the AY-1 population was relatively low, the degree of linkage of alleles was high, and this population had been subjected to more positive selection. Based on Tajima’s D, FST analysis, and ROD analysis, the selected intervals and genes of the AY-1 population were identified, with some of the candidate intervals being related to an economically important trait and breeding target, namely, the number of parapodia. Gene Ontology analysis of the candidate genes revealed that the two subpopulations differed in their immune function, protein synthesis, decomposition, and transport, among others. Using GWAS, we identified 39 candidate genes for four economically important traits of A. japonicas, and we verified that those genes contained non-synonymous SNPs. Through this verification, BSL78_00022 and BSL78_00023 were found to be key genes for the number of parapodia in A. japonicas. Of these two genes, BSL78_00022 encodes a protein related to cell differentiation and proliferation, so it was assumed that three non-synonymous substitutions (Ser-Phe, Glu-Asp, and Ala-Val) in this gene are related to the changes in the number of parapodia. Meanwhile, the pleiotropic gene BSL78_04631, which is related to body weight and body wall weight, and promotes protein synthesis and cell growth, has a non-synonymous substitution (IlE-Val), which is assumed to be the reason for the difference in body weight and body wall weight of A. japonicas. These results provide a new perspective for explaining the genetic structure characteristics of A. japonicas and analyzing the selection and economically important traits in the breeding of new species.
How Efficient Are Monte Carlo Calculations Together With the Q-System to Determine Radioactive Transport Limits? Case Study on Medical Radionuclides
Authors: Maietta Maddalena , Haddad Ferid , Avila Sebastien
Published: July 2022

The development of the so-called theranostics approach, in which imaging information are used to define a personalized therapeutic strategy, is driving the increasing use of radionuclides in nuclear medicine. They are artificially produced either in nuclear reactors, charged particle accelerators, or using radionuclide generators. Each method leads to radioisotopes with different characteristics and then clinical utility. In the first two cases they are extracted from stable or radioactive target bombarded with a particle beam. After extraction/purification of the target, the radionuclides, either implanted on solid or in liquid form, needs to be transported to a centralized production site, a radiopharmacy or an hospital. The transport of needed radioactive material must obey strict rules. For a radionuclide, a limit in activity that it is possible to transport has been established for each type of allowed packages. For type A package these limits are called A1 (for special form sources, i.e., certified perfectly sealed and encapsulated sources) and A2 (for non-special form sources). However, these limits can be easily reached if the activity to transport is high or if the radionuclide of interest is a “non–conventional” one. Indeed, for many radionuclides, there are no available/tabulated A1 and A2 and, in these cases, a very conservative set of values is imposed. This is in particular the case for some of the non-conventional radionuclide of interest in medicine (as for example Tb-149 or Tb-161). The non-tabulated values, and in general the A1/A2 limit, can be evaluated following the so-called Q-system and using Monte Carlo calculations. In the present work, we have used the MCNPX Monte Carlo code to evaluate dose rate values in different exposure scenarios. This has allowed us to determine A1/A2 coefficients for several non-conventional radionuclides of interest for medical applications. The developed technique can be extended easily to other radionuclides and can be adapted in case of changes in regulatory rules.
Pancreatic neuroendocrine carcinoma with unique morphological features mimicking intraductal papillary mucinous carcinoma: A case report
Authors: Tanaka Hidekazu , Minaga Kosuke , Otsuka Yasuo , Masuta Yasuhiro , Kamata Ken , Yamao Kentaro , Takenaka Mamoru , Hyodo Tomoko , Kimura Masatomo , Watanabe Tomohiro , Kudo Masatoshi
Published: July 2022

Background

Pancreatic neuroendocrine carcinoma (PanNEC) is a rare disease entity with rapid progression and poor prognosis. Here, we report a PanNEC case with unique morphological features mimicking intraductal papillary mucinous carcinoma.

Case presentation

A 69-year-old Japanese man was referred to our hospital for further evaluation of weight loss and deterioration of diabetes mellitus. Contrast-enhanced computed tomography showed a solid and cystic mass with hypo-enhancement at the tail of the pancreas. The main pancreatic duct (MPD) was diffusely dilated without obstruction, accompanied by marked parenchymal atrophy. Multiple peritoneal and omental nodules were observed, suggesting tumor dissemination. Endoscopic retrograde cholangiopancreatography revealed that the mass correlated with the dilated MPD. During pancreatography, a large amount of mucus was extruded from the pancreatic orifice of the ampulla. Based on these imaging findings, intraductal papillary mucinous carcinoma was suspected. Per-oral pancreatoscopy (POPS)-guided tumor biopsies were conducted for the lesion's solid components. Histopathological examination of the biopsied material confirmed small-cell-type PanNEC with a Ki-67 labeling index of 90%. Due to his condition's rapid decline, the patient was given the best supportive care and died 28 days after diagnosis.

Conclusion

Although rare, PanNEC, which correlates with the MPD and is accompanied by marked dilation of the MPD, does exist as one phenotype. In such cases, POPS-guided biopsy could be a useful diagnostic modality.
Mycobiota and C-Type Lectin Receptors in Cancers: Know thy Neighbors
Authors: Zhang Lilong , Chai Dongqi , Chen Chen , Li Chunlei , Qiu Zhendong , Kuang Tianrui , Parveena Mungur , Dong Keshuai , Yu Jia , Deng Wenhong , Wang Weixing
Published: July 2022

Numerous studies have demonstrated the importance of gut bacteria in the development of malignancy, while relatively little research has been done on gut mycobiota. As a part of the gut microbiome, the percentage of gut mycobiota is negligible compared to gut bacteria. However, the effect of gut fungi on human health and disease is significant. This review systematically summarizes the research progress on mycobiota, especially gut fungi, in patients with head and neck cancer (HNC), esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), pancreatic cancer, melanoma, breast cancer, and lung carcinoma-induced cachexia. Moreover, we also describe, for the first time in detail, the role of the fungal recognition receptors, C-type lectin receptors (CLRs) (Dectin-1, Dectin-2, Dectin-3, and Mincle) and their downstream effector caspase recruitment domain-containing protein 9 (CARD9), in tumors to provide a reference for further research on intestinal fungi in the diagnosis and treatment of malignant tumors.
Casein Kinase 2 Signaling in White Matter Stroke
Authors: Nguyen Hung , Zhu Wenbin , Baltan Selva
Published: July 2022

The growth of the aging population, together with improved stroke care, has resulted in an increase in stroke survivors and a rise in recurrent events. Axonal injury and white matter (WM) dysfunction are responsible for much of the disability observed after stroke. The mechanisms of WM injury are distinct compared to gray matter and change with age. Therefore, an ideal stroke therapeutic must restore neuronal and axonal function when applied before or after a stroke, and it must also protect across age groups. Casein kinase 2 (CK2), is expressed in the brain, including WM, and is regulated during the development and numerous disease conditions such as cancer and ischemia. CK2 activation in WM mediates ischemic injury by activating the Cdk5 and AKT/GSK3β signaling pathways. Consequently, CK2 inhibition using the small molecule inhibitor CX-4945 (Silmitasertib) correlates with preservation of oligodendrocytes, conservation of axon structure, and axonal mitochondria, leading to improved functional recovery. Remarkably, CK2 inhibition promotes WM function when applied after ischemic injury by specifically regulating the AKT/GSK3β pathways. The blockade of the active conformation of AKT confers post-ischemic protection to young and old WM by preserving mitochondria, implying AKT as a common therapeutic target across age groups. Using a NanoString nCounter miRNA expression profiling, comparative analyses of ischemic WM with or without CX-4945 treatment reveal that miRNAs are expressed at high levels in WM after ischemia, and CX-4945 differentially regulates some of these miRNAs. Therefore, we propose that miRNA regulation may be one of the protective actions of CX-4945 against WM ischemic injury. Silmitasertib is FDA approved and currently in use for cancer and Covid patients; therefore, it is plausible to repurpose CK2 inhibitors for stroke patients.
Sarcopenia: Body Composition and Gait Analysis
Authors: Fan Yuxuan , Zhang Bo , Huang Guohao , Zhang Guoying , Ding Zhiyuan , Li Zhiyu , Sinclair Jonathan , Fan Yifang
Published: July 2022

Background

Age-induced sarcopenia negatively affects walking stability and increases the risk of falls, which is the leading cause of accidental death in the elderly.

Objective

This study aimed to analyze and contrast body composition and gait characteristics in those with sarcopenia in relation to healthy controls to shed some light on the prevention of falls in elderly patients with sarcopenia.

Materials and Methods

In this study, 68 community dwellers were scanned by the Hologic QDR-4500A Dual-energy X-ray absorptiometry (DXA). The appendicular lean mass index (ALMI) results were used to distinguish the normal participants from those with sarcopenia: 24 in the sarcopenia group, and 44 into the normal group. The participants were asked to undergo gait analysis on a plantar pressure measurement system. Statistical analysis was conducted to contrast both groups' gait and butterfly parameters from their gait test, and then a gait forward dynamics method was performed to quantify the analysis for both groups.

Results

The ALMI of the female was not related to their age (r = 0.06) while that of the male was weakly related (r = 0.17). Body mass index (BMI) from both groups was normal, although with a statistically greater BMI from the normal group compared with sarcopenia (p < 0.001). Greater values and significant differences were found in step length and stride length from the normal elderly group (p < 0.01), and so was the length of the gait line and single support line (p < 0.05). Gait forward dynamics analysis results showed no motor neural or musculoskeletal disorders in their gait performance from the sarcopenia group.

Conclusion

For the elderly, age did not largely affect the ALMI, BMI, or T-score, but BMI and ALMI were strongly correlated. In this study, significant differences were found in certain gait parameters between the elderly with sarcopenia and the normal elderly, which were related to absolute muscle strength, suggesting that sarcopenia was a disease mainly caused by decreased muscle mass. In addition, when abnormities were identified in step length, stride length, length of gait line, or length of single support line, it is proposed to take a DXA scan to confirm whether the elderly suffer from sarcopenia.
Associations Between Posterior Communicating Artery Aneurysms and Morphological Characteristics of Surrounding Arteries
Authors: Hao Weili , Hao Hong , Ren Chun-Feng , Wang Xiangling , Gao Bulang
Published: July 2022

Objectives

To explore the associations between posterior communicating artery (PComA) aneurysms and morphological characteristics of arteries upstream of and around the PComA bifurcation site.

Methods

In this study, fifty-seven patients with PComA aneurysms and sixty-two control subjects without aneurysms were enrolled. The centerlines of the internal carotid artery (ICA) and important branches were generated for the measurement and analysis of morphological parameters, such as carotid siphon types, diameters of two fitting circles, and the angle formed by them (D1, D2, and ϕ), length (L) and tortuosity (TL) of ICA segment between an ophthalmic artery and PComA bifurcations, bifurcation angle (θ), tortuosity (TICA and TPComA), and flow direction changes (θICA and θPComA) around the PComA bifurcation site.

Results

No significant difference (p > 0.05) was found in the siphon types (p = 0.467) or L (p = 0.114). Significant differences (p < 0.05) were detected in D1 (p = 0.036), TL (p < 0.001), D2 (p = 0.004), ϕ (p = 0.008), θ (p = 0.001), TICA (p < 0.001), TPComA (p = 0.012), θICA (p < 0.001), and θPComA (p < 0.001) between the two groups. TICA had the largest area under the curve (AUC) (0.843) in the receiver operating characteristic (ROC) analysis in diagnosing the probability of PComA aneurysms presence and was identified as the only potent morphological parameter (OR = 11.909) associated with PComA aneurysms presence.

Conclusions

The high tortuosity of the ICA segment around the PComA bifurcation is associated with PComA aneurysm presence.
Case Report: Trigeminocardiac Reflex in Endovascular Recanalization of Intracranial Internal Carotid Artery Occlusion
Authors: Ren Hecheng , Wang Yubo , Luo Bin , Ma Lin , Ma Yuxiang , Yin Long , Huang Ying
Published: July 2022

Background

The trigeminocardiac reflex (TCR) is a unique brainstem reflex that manifests as sudden negative hemodynamic changes. Although rare, TCR may develop during interventional neuroradiology procedures. Intracranial internal carotid artery occlusion (ICAO) is a cause or risk factor of ischemic stroke. Endovascular recanalization is an effective treatment for intracranial ICAO. The occurrence of TCR during the endovascular treatment of intracranial ICAO has not been reported previously.

Methods

We identified and reviewed four intracranial ICAO cases who suffered a sudden negative hemodynamic change during endovascular therapy at our hospital between March 2019 and December 2020.

Results

There were five sudden heart rate and/or blood pressure drops in the four cases; all occurred just after contrast agents were injected. Some angioarchitectural characteristics were common among the four cases. First, the intracranial internal carotid artery distal to the ophthalmic artery was occluded, leaving the ophthalmic artery as the only outflow tract. Second, there were obstructive factors proximal to the end of the guiding catheter, including a vasospasm or dilated balloon. This type of angioarchitecture with a limited outflow tract creates a “blind alley.” The five negative hemodynamic events all recovered: two spontaneously and three after drug administration. Postoperatively, two of the four patients developed ocular symptoms.

Conclusions

Intracranial ICAOs may produce a distinctive angioarchitecture, such as a blind alley, that predisposes patients to TCR. Surgeons should pay special attention to the possibility of TCR during the endovascular recanalization of intracranial ICAO. Low-pressure contrast injections should be attempted, and anticholinergics should be ready for use.
A Review on Headaches Due to COVID-19 Infection
Authors: Togha Mansoureh , Hashemi Seyedeh Melika , Yamani Nooshin , Martami Fahimeh , Salami Zhale
Published: July 2022

Since December 2019, the time when the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was spotted, numerous review studies have been published on COVID-19 and its neuro invasion. A growing number of studies have reported headaches as a common neurological manifestation of COVID-19. Although several hypotheses have been proposed regarding the association between headache and the coronavirus, no solid evidence has been presented for the mechanism and features of headache in COVID-19. Headache also is a common complaint with the omicron variant of the virus. COVID-19 vaccination also is a cause of new-onset headaches or aggravation of the previous headache in migraine or tension headache sufferers. In this review study, the types of headaches reported in previous studies and their possible pathogenic mechanisms are outlined. To accomplish this objective, various types of headaches are classified and their patterns are discussed according to ICHD-3 diagnostic criteria, including, headaches attributed to systemic viral infection, viral meningitis or encephalitis, non-infectious inflammatory intracranial disease, hypoxia and/or hypercapnia, cranial or cervical vascular disorder, increased cerebrospinal fluid (CSF) pressure, refractive error, external-compression headache, and cough headache. Then, their pathogeneses are categorized into three main categories, direct trigeminal involvement, vascular invasion, and inflammatory mediators. Furthermore, persistent headache after recovery and the predictors of intensity is further investigated. Post-vaccination headache is also discussed in this review.
Iron and Alzheimer’s Disease: From Pathology to Imaging
Authors: Tran Dean , DiGiacomo Phillip , Born Donald E. , Georgiadis Marios , Zeineh Michael
Published: July 2022

Alzheimer’s disease (AD) is a debilitating brain disorder that afflicts millions worldwide with no effective treatment. Currently, AD progression has primarily been characterized by abnormal accumulations of β-amyloid within plaques and phosphorylated tau within neurofibrillary tangles, giving rise to neurodegeneration due to synaptic and neuronal loss. While β-amyloid and tau deposition are required for clinical diagnosis of AD, presence of such abnormalities does not tell the complete story, and the actual mechanisms behind neurodegeneration in AD progression are still not well understood. Support for abnormal iron accumulation playing a role in AD pathogenesis includes its presence in the early stages of the disease, its interactions with β-amyloid and tau, and the important role it plays in AD related inflammation. In this review, we present the existing evidence of pathological iron accumulation in the human AD brain, as well as discuss the imaging tools and peripheral measures available to characterize iron accumulation and dysregulation in AD, which may help in developing iron-based biomarkers or therapeutic targets for the disease.
Correlation Between Serum High-Sensitivity C-Reactive Protein, Tumor Necrosis Factor-Alpha, Serum Interleukin-6 and White Matter Integrity Before and After the Treatment of Drug-Naïve Patients With Major Depressive Disorder
Authors: Chen Liping , Zeng Xiangling , Zhou Sijia , Gu Zhiwen , Pan Jiyang
Published: July 2022

Background

Previous studies have noticed that systemic inflammation may alter the integrity of white matter. However, how the levels of serum cytokine affect the integrity of white matter in major depressive disorder (MDD) patients are unclear. Our study aimed to investigate the association between the inflammatory cytokine levels and white matter microstructure in drug-naïve patients with MDD pre- and post-treatment.

Method

In total, 29 MDD patients and 25 healthy controls (HC) were included in this study. Diffusion tensor imaging (DTI) was conducted in all subjects at baseline, and the MDD patients were reassessed after venlafaxine treatment, using a tract-based spatial statistics (TBSS) analysis. Morning serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and high-sensitivity C-reactive protein (hs-CRP) concentrations in MDD patients were also measured pre- and post-treatment.

Results

Significantly reduced fractional anisotropy (FA) values were found in the bilateral superior fronto-occipital fasciculus (SFO), posterior limb of the internal capsule (IC-PL), and fornix compared with the HC, and FA values in these regions in MDD patients have risen to normal levels except the bilateral SFO after treatment. The FA value of the left IC-PL was inversely correlated with the peripheral hs-CRP levels in both pre- and post-treatment MDD patients.

Conclusion

Our results suggested that the white matter integrity in the left IC-PL was significantly inversely correlated with the peripheral hs-CRP levels in both pre- and post-treatment MDD patients.
Multi-Data Integration Towards a Global Understanding of the Neurological Impact of Human Brain Severe Acute Respiratory Syndrome Coronavirus 2 Infection
Authors: Mesmoudi Salma , Lapina Colline , Rodic Mathieu , Peschanski Denis
Published: July 2022

As the COVID-19 pandemic continues to unfold, numerous neurological symptoms emerge. The literature reports more and more manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) related to headache, dizziness, impaired consciousness, cognitive impairment, and motor disorders. Moreover, the infection of SARS-CoV-2 may have a durable neurological impact. ACE2/TMPRSS2 is the main entry point into cells for some strains of coronaviruses (CoVs), including SARS-CoV-2, which uses it to target the central nervous system (CNS). The aim of this study was to characterize the scope of the potential complex impact of a SARS-CoV-2 infection in the brain. It concerns different scales: the topographic, cognitive, sensorimotor, and genetic one. We investigated which cognitive and sensorimotor functions are associated with the brain regions where ACE2/TMPRSS2 is overexpressed, hypothesising that they might be particularly affected by the infection. Furthermore, overexpressed genes in these regions are likely to be impacted by COVID-19. This general understanding is crucial to establish the potential neurological manifestations of the infection. Data on mRNA expression levels of genes were provided by the Allen Institute for Brain Science (AIBS), and the localisation of brain functions by the LinkRbrain platform. The latter was also used to analyze the spatial overlap between ACE2/TMPRSS2 overexpression, and either function-specific brain activations or regional overexpression of other genes. The characterisation of these overexpressed genes was based on the GeneCards platform and the gene GSE164332 from the Gene Expression Omnibus database. We analysed the cognitive and sensorimotor functions whose role might be impaired, of which 88 have been categorised into seven groups: memory and recollection, motor function, pain, lucidity, emotion, sensory, and reward. Furthermore, we categorised the genes showing a significant increase in concentration of their mRNAs in the same regions where ACE2/TMPRSS2 mRNA levels are the highest. Eleven groups emerged from a bibliographical research: neurodegenerative disease, immunity, inflammation, olfactory receptor, cancer/apoptosis, executive function, senses, ischemia, motor function, myelination, and dependence. The results of this exploration could be in relation to the neurological symptoms of COVID-19. Furthermore, some genes from peripheral blood are already considered as biomarker of COVID-19. This method could generate new hypotheses to explore the neurological manifestations of COVID-19.
The Impact of Theta-Burst Stimulation on Cortical GABA and Glutamate in Treatment-Resistant Depression: A Surface-Based MRSI Analysis Approach
Authors: Spurny-Dworak Benjamin , Godbersen Godber Mathis , Reed Murray Bruce , Unterholzner Jakob , Vanicek Thomas , Baldinger-Melich Pia , Hahn Andreas , Kranz Georg S. , Bogner Wolfgang , Lanzenberger Rupert , Kasper Siegfried
Published: July 2022

Background: Theta burst stimulation (TBS) belongs to one of the biological antidepressant treatment options. When applied bilaterally, excitatory intermittent TBS (iTBS) is commonly targeted to the left and inhibitory continuous TBS (cTBS) to the right dorsolateral prefrontal cortex. TBS was shown to influence neurotransmitter systems, while iTBS is thought to interfere with glutamatergic circuits and cTBS to mediate GABAergic neurotransmission.

Objectives: We aimed to expand insights into the therapeutic effects of TBS on the GABAergic and glutamatergic system utilizing 3D-multivoxel magnetic resonance spectroscopy imaging (MRSI) in combination with a novel surface-based MRSI analysis approach to investigate changes of cortical neurotransmitter levels in patients with treatment-resistant depression (TRD).

Methods: Twelve TRD patients (five females, mean age ± SD = 35 ± 11 years) completed paired MRSI measurements, using a GABA-edited 3D-multivoxel MEGA-LASER sequence, before and after 3 weeks of bilateral TBS treatment. Changes in cortical distributions of GABA+/tNAA (GABA+macromolecules relative to total N-acetylaspartate) and Glx/tNAA (Glx = mixed signal of glutamate and glutamine), were investigated in a surface-based region-of-interest (ROI) analysis approach.

Results: ANCOVAs revealed a significant increase in Glx/tNAA ratios in the left caudal middle frontal area (pcorr. = 0.046, F = 13.292), an area targeted by iTBS treatment. Whereas, contralateral treatment with cTBS evoked no alterations in glutamate or GABA concentrations.

Conclusion: This study demonstrates surface-based adaptions in the stimulation area to the glutamate metabolism after excitatory iTBS but not after cTBS, using a novel surface-based analysis of 3D-MRSI data. The reported impact of facilitatory iTBS on glutamatergic neurotransmission provides further insight into the neurobiological effects of TBS in TRD.
Correlations Between Iron Status and Body Composition in Patients With Type 2 Diabetes Mellitus
Authors: Zimiao Chen , Dongdong Luo , Shuoping Chen , Peng Zhou , Fan Zheng , Rujun Chen , Xiaohua Gong
Published: July 2022

Background

Our study aimed to investigate the association between iron metabolism and body composition in patients with type 2 diabetes mellitus (T2DM).

Methods

A total of 824 patients with T2DM were enrolled. Measurements of body composition were obtained by dual-energy X-ray absorptiometry. Patients were stratified into three groups according to their sex-specific ferritin levels. Basic information, laboratory results, and body composition were collected.

Results

Serum iron and transferrin saturation (TSAT) were increased significantly with increased serum ferritin (all p < 0.05). Total iron-binding capacity (TIBC) was decreased significantly with increased serum ferritin (p < 0.05). Visceral fat mass (VF), android fat/total body fat mass, android-to-gynoid fat ratio (A/G ratio), and high-sensitivity C-reactive protein were all increased significantly with increased serum ferritin (all p < 0.05). Patients with a high A/G ratio (A/G ratio ≧ 1) had significantly higher serum iron, ferritin, and TSAT, but significantly lower TIBC. In the model adjusted for age and gender, higher ferritin levels were associated with a higher VF (all p < 0.05). Serum iron was positively correlated with the occurrence of a high A/G ratio (A/G ratio ≧ 1) after the adjustment of confounding factors [an odds ratio (OR = 1.09, 95% CI, 1.02–1.19, p = 0.02)]. With receiver operating curve analysis, the cutoff value of serum iron for a high A/G ratio was 18.56, and the area under the curve was 0.771 (sensitivity 88.9%and specificity 63.9%, p = 0.01).

Conclusion

Higher serum iron and ferritin concentrations were positively associated with a higher VF. Higher serum iron concentrations were positively correlated with a high A/G ratio. This study indicates the potential relationship between iron overload and the body composition in patients with T2DM.
Pectin Stabilized Fish Gelatin Emulsions: Physical Stability, Rheological, and Interaction Properties
Authors: Huang Sheng , Wang Hui , Wang Shu , Sha Xiaomei , Chen Ning , Hu Yueming , Tu Zongcai
Published: July 2022

Pectin, a kind of natural polysaccharide, shows the attractive potential as a natural stabilizer for protein emulsion. The aim of this study is to investigate the effect of pectin on the physical stability, rheology, interface, and interaction properties of the fish gelatin (FG) emulsion, as pectin was utilized to improve the stability of FG, fish oil emulsion. During the study, when pH < 6, the FG-pectin emulsion displayed better storage stability and salinity tolerance. Analyzing the result, pectin could avoid phase separation at the freeze-thaw process and prevent the liquid-gel transition of FG emulsions during storage. On the other hand, when pH ≥ 6, the emulsion displayed high viscosity due to the complex flocculation and stratified during long-term storage. Electrostatic interactions, hydrophobic interactions, and hydrogen bonding of the FG-pectin complexes in the emulsion were all reduced. Overall, pectin improved the stability of FG emulsions through electrostatic repulsion, hydrophobic interactions, and steric hindrance.
Optimal Selection of Imaging Examination for Lymph Node Detection of Breast Cancer With Different Molecular Subtypes
Authors: Zheng Mingjie , Huang Yue , Peng Jinghui , Xia Yiqin , Cui Yangyang , Han Xu , Wang Shui , Xie Hui
Published: July 2022

Objective

Axillary lymph node management is an important part of breast cancer surgery and the accuracy of preoperative imaging evaluation can provide adequate information to guide operation. Different molecular subtypes of breast cancer have distinct imaging characteristics. This article was aimed to evaluate the predictive ability of imaging methods in accessing the status of axillary lymph node in different molecular subtypes.

Methods

A total of 2,340 patients diagnosed with primary invasive breast cancer after breast surgery from 2013 to 2018 in Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University were included in the study. We collected lymph node assessment results from mammography, ultrasounds, and MRIs, performed receiver operating characteristic (ROC) analysis, and calculated the sensitivity and specificity of each test. The C-statistic among different imaging models were compared in different molecular subtypes to access the predictive abilities of these imaging models in evaluating the lymph node metastasis.

Results

In Her-2 + patients, the C-statistic of ultrasound was better than that of MRI (0.6883 vs. 0.5935, p=0.0003). The combination of ultrasound and MRI did not raise the predictability compared to ultrasound alone (p=0.492). In ER/PR+HER2- patients, the C-statistic of ultrasound was similar with that of MRI (0.7489 vs. 0.7650, p=0.5619). Ultrasound+MRI raised the prediction accuracy compared to ultrasound alone (p=0.0001). In ER/PR-HER2- patients, the C-statistics of ultrasound was similar with MRI (0.7432 vs. 0.7194, p=0.5579). Combining ultrasound and MRI showed no improvement in the prediction accuracy compared to ultrasound alone (p=0.0532).

Conclusion

From a clinical perspective, for Her-2+ patients, ultrasound was the most recommended examination to assess the status of axillary lymph node metastasis. For ER/PR+HER2- patients, we suggested that the lymph node should be evaluated by ultrasound plus MRI. For ER/PR-Her2- patients, ultrasound or MRI were both optional examinations in lymph node assessment. Furthermore, more new technologies should be explored, especially for Her2+ patients, to further raise the prediction accuracy of lymph node assessment.
The Safety and Efficacy of Nanosecond Pulsed Electric Field in Patients With Hepatocellular Carcinoma: A Prospective Phase 1 Clinical Study Protocol
Authors: Xu Min , Xu Danxia , Dong Gang , Ren Zhigang , Zhang Wu , Aji Tuerganaili , Zhao Qiyu , Chen Xinhua , Jiang Tian’an
Published: July 2022

Background

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy. Irreversible electroporation (IRE) is an ablative modality that uses high-voltage electrical pulses to permeabilize the cell membrane leading to cell necrosis. Unlike traditional thermal ablation, IRE is hardly affected by the “heat-sink” effect and can prevent damage of the adjacent vital structures. Nanosecond pulsed electric field (nsPEF) is a new IRE technique using ultra-short pulses (nanosecond duration), can not only penetrate the cell membranes, but also act on the organelles. Sufficient preclinical researches have shown that nsPEF can eliminate HCC without damaging vital organs, and elicit potent anti-tumor immune response.

Objective

This is the first clinical study to evaluate feasibility, efficacy, and safety of nsPEF for the treatment of HCC, where thermal ablation is unsuitable due to proximity to critical structures.

Methods and analysis

We will conduct an open-labeled, single-arm, prospective, multicenter, and objective performance criteria trial. One hundred and ninety-two patients with HCC, in which the tumor is located immediately (<0.5 cm) adjacent to the portal vein, hepatic veins, bile duct, gastrointestinal tract, or diaphragm, will be enrolled among 4 academic medical centers. The primary outcomes are the rate of complete ablation at 1 month and adverse events. Secondary outcomes include technical success, technique efficacy, nsPEF procedural characteristics, local tumor progression, and local progression-free survival.

Ethics and dissemination

The trial will be conducted according to the ethical principles of the Declaration of Helsinki and has been approved by the ethics committee of all participating centers. The results of this study will be published in peer-reviewed scientific journals and presented at relevant academic conferences.

Conclusions

This study is the Phase 1 clinical trial to evaluate the efficacy and safety of nsPEF in patients with HCC at high-risk locations where thermal ablation is contra-indicated. The results may expand the options and offer an alternative therapy for HCC.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT04309747.
Necroptosis-Related Genes Signatures Identified Molecular Subtypes and Underlying Mechanisms in Hepatocellular Carcinoma
Authors: Wei Jianguo , Hou Shuqian , Li Minhua , Yao Xiaofei , Wang Li , Zheng Zhen , Mo Haiqian , Chen Yu , Yuan Xiaolu
Published: July 2022

Background

Although emerging evidence supports the relationship between necroptosis (NEC) related genes and hepatocellular carcinoma (HCC), the contribution of these necroptosis-related genes to the development, prognosis, and immunotherapy of HCC is unclear.

Methods

The expression of genes and relevant clinical information were downloaded from TCGA-LIHC, LIRI-JP, GSE14520/NCI, GSE36376, GSE76427, GSE20140, GSE27150, and IMvigor210 datasets. Next, we used an unsupervised clustering method to assign the samples into phenotype clusters base on 15 necroptosis-related genes. Subsequently, we constructed a NEC score based on NEC phenotype-related prognostic genes to quantify the necroptosis related subtypes of individual patients.

Results

We divided the samples into the high and low NEC score groups, and the high NEC score showed a poor prognosis. Simultaneously, NEC score is an effective and stable model and had a good performance in predicting the prognosis of HCC patients. A high NEC score was characterized by activation of the stroma and increased levels of immune infiltration. A high NEC score was also related to low expression of immune checkpoint molecules (PD-1/PD-L1). Importantly, the established NEC score would contribute to predicting the response to anti-PD-1/L1 immunotherapy.

Conclusions

Our study provide a comprehensive analysis of necroptosis-related genes in HCC. Stratification based on the NEC score may enable HCC patients to benefit more from immunotherapy and help identify new cancer treatment strategies.
The Evolution of BRAF Activation in Non-Small-Cell Lung Cancer
Authors: Zhang Longyao , Zheng Linpeng , Yang Qiao , Sun Jianguo
Published: July 2022

Non-small-cell lung cancer (NSCLC) is the most common subtype of lung cancer, of which approximate 4% had BRAF activation, with an option for targeted therapy. BRAF activation comprises of V600 and non-V600 mutations, fusion, rearrangement, in-frame deletions, insertions, and co-mutations. In addition, BRAF primary activation and secondary activation presents with different biological phenotypes, medical senses and subsequent treatments. BRAF primary activation plays a critical role in proliferation and metastasis as a driver gene of NSCLC, while secondary activation mediates acquired resistance to other targeted therapy, especially for epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI). Treatment options for different activation of BRAF are diverse. Targeted therapy, especially two-drug combination therapy, is an important option. Besides, immune checkpoint inhibitors (ICIs) would be another option since BRAF activation would be a positive biomarker of tumor response of ICIs therapy. To date, no high level evidences support targeted therapy or immunotherapy as prioritized recommendation. After targeted therapy, the evolution of BRAF includes the activation of the upstream, downstream and bypass pathways of BRAF. In this review, therapeutic modalities and post-therapeutic evolutionary pathways of BRAF are discussed, and future research directions are also provided.
Case Report: An Unusual Case of Pulmonary Metastatic Adenocarcinoma From Low-Grade Appendiceal Mucinous Neoplasms
Authors: Zhao Xin-Yu , Li Chun-Qiang , Zhang Shi-Yao , Liu Gang
Published: July 2022

Background

Low-grade appendiceal mucinous neoplasms (LAMNs) are indolent tumors with low-grade cytology. Although peritoneal dissemination is common due to tumor rupture and mucinous deposits on the visceral peritoneal surface, distant involvement, such as lung, is rarely seen due to lack of invasiveness.

Case Presentation

A 70-year-old woman presented to the hospital due to continuously elevated carcinoembryonic antigen (CEA) levels for 10 months without any symptoms. PET/CT revealed two lesions located in the left lung and appendix. The postoperative pathology results revealed pulmonary mucinous adenocarcinoma and LAMN. Then we performed next-generation sequencing (NGS) to clarify the relationship between the two tumors. The sequencing result showed that both tumors harbored the common tumor mutations, KRAS (p.G12D), GNAS (p.R201H), and BRAF (p.R735Q), which indicated that the pulmonary tumor was a metastasis of LAMN.

Conclusion

This case is unusual in that the primary LAMN and the pulmonary metastasis are present at the time of diagnosis. This study reported the first pulmonary metastasis from LAMN verified by NGS.