bluuebunny/crossref_metadata_2025 huggingface dataset:
MRI appearance of chronic subdural hematoma
Authors: Hasan Dimah , Nikoubashman Omid , Pjontek Rastislav , Stockero Andrea , Hamou Hussam Aldin , Wiesmann Martin
Published: August 2022

Objective

We aimed to describe the magnetic resonance imaging (MRI) characteristics of chronic subdural hematoma (cSDH) and to ascribe MRI patterns.

Methods

A total of 20 patients having 27 subdural hematomas underwent contrast-enhanced (CE) MRI of the brain at our institution between April 2019 and May 2021. The images were independently evaluated by two experienced neuroradiologists with regard to imaging characteristics on T1w, T2w, T2*-GRE, FLAIR, diffusion-weighted magnetic resonance imaging (DWI), and CE images.

Results

The signal characteristics of cSDH on T1- and T2-weighted images were rather heterogeneous. The majority of hematomas (74%) had internal septations. Surprisingly, contrast enhancement along the outer membrane adjacent to the cranium was noticed in all hematomas. There was also contrast enhancement along the inner membrane adjacent to the brain in more than one-third of the hematomas (37%). In approximately two-thirds of the cSDH (62%), there was a mass-like enhancement of the hematoma. Most hematomas (89%) were partially hypointense on T2*-GRE and/or susceptibility-weighted imaging (SWI). Restricted diffusion was detected in approximately one-third of the hematomas (33%).

Conclusion

Consistent contrast enhancement along the outer membrane, triangular-shaped contrast enhancement at the borders of the cSDH, and infrequent enhancement of the inner membrane may help to distinguish cSDH from other entities such as empyema and tumors. Mass-like enhancement may refer to non-solid hematomas and could be an indicator for hematoma growth and a possible surrogate for successful endovascular embolization. Restricted diffusion in a subdural mass is not specific for empyema but may also be found in cSDH.
Metabolic connectivity of resting-state networks in alpha synucleinopathies, from prodromal to dementia phase
Authors: Boccalini Cecilia , Bortolin Elisa , Carli Giulia , Pilotto Andrea , Galbiati Andrea , Padovani Alessandro , Ferini-Strambi Luigi , Perani Daniela
Published: August 2022

Previous evidence suggests that the derangement of large-scale brain networks reflects structural, molecular, and functional mechanisms underlying neurodegenerative diseases. Although the alterations of multiple large-scale brain networks in Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are reported, a comprehensive study on connectivity reconfiguration starting from the preclinical phase is still lacking. We aimed to investigate shared and disease-specific changes in the large-scale networks across the Lewy Bodies (LB) disorders spectrum using a brain metabolic connectivity approach. We included 30 patients with isolated REM sleep behavior disorder (iRBD), 28 with stable PD, 30 with DLB, and 30 healthy controls for comparison. We applied seed-based interregional correlation analyses (IRCA) to evaluate the metabolic connectivity in the large-scale resting-state networks, as assessed by [18F]FDG-PET, in each clinical group compared to controls. We assessed metabolic connectivity changes by applying the IRCA and specific connectivity metrics, such as the weighted and unweighted Dice similarity coefficients (DC), for the topographical similarities. All the investigated large-scale brain resting-state networks showed metabolic connectivity alterations, supporting the widespread involvement of brain connectivity within the alpha-synuclein spectrum. Connectivity alterations were already evident in iRBD, severely affecting the posterior default mode, attentive and limbic networks. Strong similarities emerged in iRBD and DLB that showed comparable connectivity alterations in most large-scale networks, particularly in the posterior default mode and attentive networks. Contrarily, PD showed the main connectivity alterations limited to motor and somatosensory networks. The present findings reveal that metabolic connectivity alterations in the large-scale networks are already present in the early iRBD phase, resembling the DLB metabolic connectivity changes. This suggests and confirms iRBD as a risk condition for progression to the severe LB disease phenotype. Of note, the neurobiology of stable PD supports its more benign phenotype.
Contribution of blood-brain barrier-related blood-borne factors for Alzheimer’s disease vs. vascular dementia diagnosis: A pilot study
Authors: Gong Min , Jia Jianping
Published: August 2022

Background

Alzheimer’s disease (AD) and vascular dementia (VaD) are the two most common types of neurodegenerative dementia among the elderly with similar symptoms of cognitive decline and overlapping neuropsychological profiles. Biological markers to distinguish patients with VaD from AD would be very useful. We aimed to investigate the expression of blood-brain barrier (BBB)-related blood-borne factors of soluble low-density lipoprotein receptor-related protein 1 (sLRP1), cyclophilin A (CyPA), and matrix metalloproteinase 9 (MMP9) and its correlation with cognitive function between patients with AD and VaD.

Materials and methods

Plasma levels of sLRP1, CyPA, and MMP9 were analyzed in 26 patients with AD, 27 patients with VaD, and 27 normal controls (NCs). Spearman’s rank correlation analysis was used to explore the relationships among biomarker levels, cognitive function, and imaging references. Receiver operating characteristic (ROC) curve analysis was used to discriminate the diagnosis of AD and VaD.

Results

Among these BBB-related factors, plasma CyPA levels in the VaD group were significantly higher than that in the AD group (p < 0.05). Plasma sLRP1 levels presented an increasing trend in VaD while maintaining slightly low levels in patients with AD (p > 0.05). Plasma MMP9 in different diagnostic groups displayed the following trend: VaD group > AD group > NC group, but the difference was not statistically significant (p > 0.05). Furthermore, plasma sLRP1 levels were positively related to MoCA scores, and plasma CyPA levels were significantly correlated with MTA scores (p < 0.05) in the AD group. Plasma MMP9 levels were negatively correlated with MoCA scores (p < 0.05) in the VaD groups. No significant correlation was detected between the other factors and different cognitive scores (p > 0.05). ROC analysis showed a good preference of plasma CyPA [AUC = 0.725, 95% CI (0.586–0.865); p = 0.0064] in diagnosis.

Conclusion

The plasma CyPA level is a reference index when distinguishing between an AD and subcortical ischemic vascular dementia (SIVD) diagnosis. Blood-derived factors associated with the BBB may provide new insights into the differential diagnosis of neurodegenerative dementia and warrant further investigation.
The role of sex and ovarian hormones in hippocampal damage and cognitive deficits induced by chronic exposure to hypobaric hypoxia
Authors: Zhu Dongyong , Zhang Mengdi , He Bo , Wan Yixuan , Wang Lei , Gao Fabao
Published: August 2022

Purpose

This study aims to investigate the role of sex and ovarian hormones in hippocampal damage and cognitive deficits and behavioral dysfunction in rats induced by chronic exposure to hypobaric hypoxia.

Methods

Six-week-old male and female SD rats were housed for 3 months either in a real altitude (4,250 m) environment as the model of chronic hypobaric-hypoxia (CHH) or in a plain as controls. The animal behavioral and hippocampal neurons at subcellular, molecular, and ultrastructural levels were characterized after CHH exposure.

Results

After 3 months of CHH exposure, (1) male CHH rats’ serum testosterone level was lower than male controls’ whereas female CHH rats’ serum estradiol level was higher than female controls’; (2) Morris water maze test finds that male rats showed more learning and spatial memory deficits than female rats; (3) male rats showed more severe hippocampal damage, hippocampal inflammation, oxidative stress and decreased hippocampal integrity (neurogenesis and dendritic spine density) than female rats; (4) Western blot analysis shows that, compared with the male control group, in male CHH group’s hippocampus, expression of nNOS, HO-1, and Bax protein increased whereas that of Bcl-2 protein decreased; (5) Expression of PON2 protein in male rats (CHH and controls) was lower than female rats (CHH and controls). In addition, CHH exposure decreased the expression of PON2 protein in both male and female rats; (6) qPCR analysis reveals that CHH exposure reduced the gene expression of N-methyl-D-aspartate receptor NR2A and NR2B subunits in male rats’ hippocampus. In addition, compared with the sham CHH group, the expression level of PON2 protein decreased in the OVX-CHH group’s hippocampus whereas oxidative stress, neuroinflammation, and degeneration of hippocampal neurons increased in the OVX-CHH group’s hippocampus.

Conclusion

After CHH exposure, male rats were significantly more likely than female rats to develop hippocampal damage, hippocampal neuroinflammation, and cognitive decline and deficits, suggesting that sex and ovarian hormones were significantly involved in regulating the rats’ susceptibility to CHH exposure-induced hippocampal damage.
Verification of a neuromorphic computing network simulator using experimental traffic data
Authors: Kleijnen Robert , Robens Markus , Schiek Michael , van Waasen Stefan
Published: August 2022

Simulations are a powerful tool to explore the design space of hardware systems, offering the flexibility to analyze different designs by simply changing parameters within the simulator setup. A precondition for the effectiveness of this methodology is that the simulation results accurately represent the real system. In a previous study, we introduced a simulator specifically designed to estimate the network load and latency to be observed on the connections in neuromorphic computing (NC) systems. The simulator was shown to be especially valuable in the case of large scale heterogeneous neural networks (NNs). In this work, we compare the network load measured on a SpiNNaker board running a NN in different configurations reported in the literature to the results obtained with our simulator running the same configurations. The simulated network loads show minor differences from the values reported in the ascribed publication but fall within the margin of error, considering the generation of the test case NN based on statistics that introduced variations. Having shown that the network simulator provides representative results for this type of —biological plausible—heterogeneous NNs, it also paves the way to further use of the simulator for more complex network analyses.
Synapse-specific roles for microglia in development: New horizons in the prefrontal cortex
Authors: Blagburn-Blanco Sara V. , Chappell Megan S. , De Biase Lindsay M. , DeNardo Laura A.
Published: August 2022

Dysfunction of both microglia and circuitry in the medial prefrontal cortex (mPFC) have been implicated in numerous neuropsychiatric disorders, but how microglia affect mPFC development in health and disease is not well understood. mPFC circuits undergo a prolonged maturation after birth that is driven by molecular programs and activity-dependent processes. Though this extended development is crucial to acquire mature cognitive abilities, it likely renders mPFC circuitry more susceptible to disruption by genetic and environmental insults that increase the risk of developing mental health disorders. Recent work suggests that microglia directly influence mPFC circuit maturation, though the biological factors underlying this observation remain unclear. In this review, we discuss these recent findings along with new studies on the cellular mechanisms by which microglia shape sensory circuits during postnatal development. We focus on the molecular pathways through which glial cells and immune signals regulate synaptogenesis and activity-dependent synaptic refinement. We further highlight how disruptions in these pathways are implicated in the pathogenesis of neurodevelopmental and psychiatric disorders associated with mPFC dysfunction, including schizophrenia and autism spectrum disorder (ASD). Using these disorders as a framework, we discuss microglial mechanisms that could link environmental risk factors including infections and stress with ongoing genetic programs to aberrantly shape mPFC circuitry.
Dynamic Hippocampal CA2 Responses to Contextual Spatial Novelty
Authors: Bhasin Guncha , Nair Indrajith R.
Published: August 2022

Hippocampal place cells are functional units of spatial navigation and are present in all subregions: CA1, CA2, CA3, and CA4. Recent studies on CA2 have indicated its role in social and contextual memories, but its contribution to spatial novelty detection and encoding remains largely unknown. The current study aims to uncover how CA2 processes spatial novelty and to distinguish its functional role towards the same from CA1. Accordingly, a novel 3-day paradigm was designed where animals were introduced to a completely new environment on the first day, and on subsequent days, novel segments were inserted into the existing spatial environment while the other segments remained the same, allowing us to compare novel and familiar parts of the same closed-loop track on multiple days. We found that spatial novelty leads to dynamic and complex hippocampal place cell firings at both individual neuron and population levels. Place cells in both CA1 and CA2 had strong responses to novel segments, leading to higher average firing rates and increased pairwise cross correlations across all days. However, CA2 place cells that fired for novel areas had lower spatial information scores than CA1 place cells active in the same areas. At the ensemble level, CA1 only responded to spatial novelty on day 1, when the environment was completely novel, whereas CA2 responded to it on all days, each time novelty was introduced. Therefore, CA2 was more sensitive and responsive to novel spatial features even when introduced in a familiar environment, unlike CA1.
The effect of dietary patterns on mild cognitive impairment and dementia incidence among community-dwelling older adults
Authors: Malek Rivan Nurul Fatin , Shahar Suzana , Fakhruddin Nik Nur Izzati Nik Mohd , You Yee Xing , Che Din Normah , Rajikan Roslee
Published: August 2022

Multiple studies have shown that dietary patterns have beneficial health effects on cognitive function. However, information on this relationship is presently limited, particularly among older adults. Thus, this study aimed to determine the effects of dietary patterns on mild cognitive impairment (MCI) and dementia incidence among Malaysian community-dwelling older adults. In this prospective cohort study, a total of 280 participants aged 60 years and above were included in the 5-year follow-up analysis. Participants’ sociodemographic, medical history, anthropometry, blood pressure, body composition, biochemical indices, cognitive assessments, psychosocial functions, functional status, and dietary intake were obtained. MCI was classified based on Petersen criteria, whereas dementia status was assessed using clinical dementia rating (CDR). Univariate analysis was performed for all variables, followed by multinomial regression analysis to identify the ability of dietary patterns in predicting the incidence of MCI and dementia. After controlling for confounding factors, the findings indicated that “local snacks-fish and seafood-high salt foods” dietary pattern was associated with an increased risk of MCI incidence, where the T3 [adjusted OR = 3.943 (95% CI: 1.212–12.832), p = 0.032] had the highest OR compared to T2 [adjusted OR = 3.252 (95% CI: 1.108–9.546), p = 0.023]. Meanwhile, a negative association across the tertiles of tropical fruits-oats dietary pattern and dementia incidence was observed [T2: adjusted OR = 0.152 (95% CI: 0.026–0.871), p = 0.034; T3: Adjusted OR = 0.101 (95% CI: 0.011–0.967), p = 0.047]. In conclusion, specific dietary patterns, particularly “local snacks-fish and seafoods-high salt foods,” were shown to increase the risk of MCI, while increasing intakes of “tropical fruits-oats” dietary patterns would protect against the dementia incidence among Malaysian older adults.
The prebiotic and anti-fatigue effects of hyaluronan
Authors: Huang Guoxin , Su Lu , Zhang Ni , Han Ruixuan , Leong Wai Kit , Li Xiaoang , Ren Xuecong , Hsiao W. L. Wendy
Published: August 2022

Hyaluronan (HA) is a mucopolysaccharide that naturally exists in all living organisms as the main component of the extracellular matrix. Over the last 30 years, HA has been used as the main ingredient in cosmetic products, eye drops, and medicinal products. It is also taken orally as a health supplement. However, the physiological effect of the ingested HA is not clear. In the current study, the interaction between HA and gut microbiota, and the potential prebiotic effects were investigated. HA was used to treat the C57BL/6 mice for 15 consecutive days, then fecal genomic DNA was extracted from fecal samples for 16S rRNA amplicon sequencing. The results showed that HA could significantly change the composition of gut microbiota (GM), e.g., increased the relative abundance of beneficial bacteria, including short-chain fatty acids (SCFAs)-producing bacteria and xylan/cellulose-degrading bacteria, whereas decreased the relative abundance of potential pathogens including sulfate-reducing bacteria (SRB), inflammation and cancer-related bacteria. The rotarod test was used to evaluate the anti-fatigue effects of HA in C57BL/6 mice. The results showed that HA could lengthen the mice's retention time on the accelerating rotarod. HA increased the concentration of glycogen and superoxide dismutase (SOD) in mice's muscle and liver, whereas decreased the serum concentration of malondialdehyde (MDA). Moreover, the metabolic products of Desulfovibrio vulgaris (MPDV), the model SRB bacteria, showed cytotoxic effects on H9c2 cardiomyocytes in a dosage-dependent manner. MPDV also caused mitochondrial damage by inducing mitochondrial fragmentation, depolarization, and powerless ATP production. Taken together, we show that HA possesses significant prebiotic and anti-fatigue effects in C57BL/6 mice.
Case Report: Efficacy of ensartinib treatment in pulmonary inflammatory myofibroblastic tumor with a rare GCC2-ALK fusion
Authors: He Wenguang , Ji Xiao , Song Congcong , Song Shanshan , Liu Lixia
Published: August 2022

Background

Inflammatory myofibroblastic tumors (IMTs) are rare with distal metastasis. Approximately 50% of patients have anaplastic lymphoma kinase (ALK) fusion. Patients with non-small cell lung cancer with ALK fusion are usually highly sensitive to ALK tyrosine kinase inhibitors (TKIs), but the application of TKI in IMT needs further exploration.

Case presentation

A 66-year-old man was diagnosed with IMT with bone metastasis, cT4N0M1c, IVB stage. Immunohistochemistry results showed that he was ALK positive, and next-generation sequencing revealed GCC2-ALK fusion in the IMT. The patient was administered first-line ensartinib 225-mg QD, which targeted GCC2-ALK fusion, and denosumab 120-mg Q4w anti-bone metastasis therapy. The patient developed a grade III rash, and the ensartinib dose was reduced to 125 mg QD; consequently, he achieved a partial response (PR), and the side effects significantly reduced. Computed tomography results showed that the patient maintained PR after 7 months of follow-up, and he was still in a state of progression-free survival without obvious side effects after 11 months of follow-up.

Conclusion

To our knowledge, this is the first case of the GCC2-ALK fusion type in IMT and the first report showing that the use of ensartinib as a TKI in IMT has clinical benefits.
Prediction of BRAF mutation status in glioblastoma multiforme by preoperative ring enhancement appearances on MRI
Authors: Cai Xiaomin , Chen Zheng , Chang Bowen , Tu Ming , Li Shiting , Wang Xuhui , Chen Ming
Published: August 2022

Background

Ring enhancement on magnetic resonance imaging (MRI) is an important characteristic of GBM. Though patients suffering from glioblastoma multiforme (GBM) with BRAF mutation (MUT BRAF) in V600E benefit from BRAF-targeted inhibitors, the relationship between ring enhancement and MUT BRAF remains elusive. The purpose of this study was to investigate the relationship between BRAF mutation status and the appearance of ring enhancement so as to guide preoperative targeted therapy for MUT BRAF GBM.

Methods

Patient’s population, clinical data and characteristic ring enhancement appearances on MRI were compared between GBM with MUT BRAF and GBM with WT BRAF. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the differential diagnostic significance. A nomogram was developed to predict the mutation status of BRAF. Moreover, all the variables were re-analyzed between epithelioid GBM (E-GBM) with or without MUT BRAF.

Results

Compared to GBM with WT BRAF, GBM with MUT BRAF had specific ring enhancement appearances with multiple rings, multiple located lobes, regular shape of ring, uniform thickness of ring and smaller diameter of ring. Area under the curve (AUC) of all the variables’ combination was 0.929. The nomogram was developed and validated. The re-analyzed results between E-GBM with or without MUT BRAF were similar to these above. AUC of the combination of quantity of ring, quantity of located lobe and shape of ring was 0.962.

Conclusion

The characteristic ring enhancement appearances of GBM may play an important role in predicting BRAF mutation status preoperatively, especially in E-GBM. Further study with larger cases may provide more evidences to guide the pretreatment of targeted medicine for GBM patients with MUT BRAF in future.
Chemotherapy reinforces anti-tumor immune response and enhances clinical efficacy of immune checkpoint inhibitors
Authors: Zhang Lin , Zhou Chao , Zhang Songou , Chen Xiaozhen , Liu Jian , Xu Fangming , Liang Wenqing
Published: August 2022

New evidence suggests that the clinical success of chemotherapy is not merely due to tumor cell toxicity but also arises from the restoration of immunosurveillance, which has been immensely neglected in previous preclinical and clinical researches. There is an urgent need for novel insights into molecular mechanisms and regimens that uplift the efficacy of immunotherapy since only a minority of cancer patients are responsive to immune checkpoint inhibitors (ICIs). Recent findings on combination therapy of chemotherapy and ICIs have shown promising results. This strategy increases tumor recognition and elimination by the host immune system while reducing immunosuppression by the tumor microenvironment. Currently, several preclinical studies are investigating molecular mechanisms that give rise to the immunomodulation by chemotherapeutic agents and exploit them in combination therapy with ICIs in order to achieve a synergistic clinical activity. In this review, we summarize studies that exhibit the capacity of conventional chemotherapeutics to elicit anti-tumor immune responses, thereby facilitating anti-tumor activities of the ICIs. In conclusion, combining chemotherapeutics with ICIs appears to be a promising approach for improving cancer treatment outcomes.
Swin transformer-based GAN for multi-modal medical image translation
Authors: Yan Shouang , Wang Chengyan , Chen Weibo , Lyu Jun
Published: August 2022

Medical image-to-image translation is considered a new direction with many potential applications in the medical field. The medical image-to-image translation is dominated by two models, including supervised Pix2Pix and unsupervised cyclic-consistency generative adversarial network (GAN). However, existing methods still have two shortcomings: 1) the Pix2Pix requires paired and pixel-aligned images, which are difficult to acquire. Nevertheless, the optimum output of the cycle-consistency model may not be unique. 2) They are still deficient in capturing the global features and modeling long-distance interactions, which are critical for regions with complex anatomical structures. We propose a Swin Transformer-based GAN for Multi-Modal Medical Image Translation, named MMTrans. Specifically, MMTrans consists of a generator, a registration network, and a discriminator. The Swin Transformer-based generator enables to generate images with the same content as source modality images and similar style information of target modality images. The encoder part of the registration network, based on Swin Transformer, is utilized to predict deformable vector fields. The convolution-based discriminator determines whether the target modality images are similar to the generator or from the real images. Extensive experiments conducted using the public dataset and clinical datasets showed that our network outperformed other advanced medical image translation methods in both aligned and unpaired datasets and has great potential to be applied in clinical applications.
Expression profiles of m6A RNA methylation regulators, PD-L1 and immune infiltrates in gastric cancer
Authors: Xu Zhiyuan , Chen Qiuli , Shu Lilu , Zhang Chunye , Liu Wenjun , Wang Peter
Published: August 2022

Gastric cancer is the fourth most frequent cancer and has a high death rate. Immunotherapy represented by PD-1 has brought hope for the treatment of advanced gastric cancer. Methylation of the m6A genes is linked to the onset and progression of numerous cancers, but there are few studies on gastric cancer. The main purpose of this study aims to analyze the relationship between m6A RNA methylation regulators, PD-L1, prognosis and tumor immune microenvironment (TIME) in gastric cancer. The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases were used to acquire transcriptomic data and clinical information from gastric cancer patients. The changes in m6A regulator expression levels in gastric cancer tissues and normal tissues were studied. Consensus clustering analysis was used to separate gastric cancer samples into two categories. We employed Least Absolute Shrinkage, Selection Operator (LASSO) Cox regression analysis, Gene Set Enrichment Analysis (GSEA), and cBioPortal to analyze the m6A regulators, PD-L1 and TIME in gastric cancer. In gastric cancer tissues, the majority of m6A regulatory factors are considerably overexpressed. Two gastric cancer subgroups (Cluster1/2) based on consensus clustering of 21 m6A regulators. PD-L1 and PD-1 expression levels were significantly higher in gastric cancer tissues, and they were significantly linked with METTL3, WTAP, HNRNPD, ZC3H7B, METTL14, FTO, PCIF1, HNRNPC, YTHDF1 and YTDHF2. Cluster1 showed a large increase in resting memory CD4+ T cells, regulatory T cells, naïve B cells, active NK cells, and resting Mast cells. Cluster1 and Cluster2 were shown to be involved in numerous critical signaling pathways, including base excision repair, cell cycle, nucleotide excision repair, RNA degradation, and spliceosome pathways. Gastric cancer RiskScores based on prognostic factors have been found as independent prognostic indicators. The amount of tumor-infiltrating immune cells is dynamically affected by changes in the copy number of m6A methylation regulators associated with TIME.
Upregulated integrin α11 in the stroma of cutaneous squamous cell carcinoma promotes skin carcinogenesis
Authors: Martínez-Nieto Guillermo A. , Teppo Hanna-Riikka , Petrelius Noora , Izzi Valerio , Devarajan Raman , Petäistö Tiina , Liu Hengshuo , Kim Kris S. , Karppinen Sanna-Maria , Ruotsalainen Heli , Koivunen Jarkko , Mäki Joni M. , Walker Gilbert C. , Pihlajaniemi Taina , Gullberg Donald , Heljasvaara Ritva
Published: August 2022

Integrin α11β1 is a collagen-binding integrin that is needed to induce and maintain the myofibroblast phenotype in fibrotic tissues and during wound healing. The expression of the α11 is upregulated in cancer-associated fibroblasts (CAFs) in various human neoplasms. We investigated α11 expression in human cutaneous squamous cell carcinoma (cSCC) and in benign and premalignant human skin lesions and monitored its effects on cSCC development by subjecting α11-knockout (Itga11−/−) mice to the DMBA/TPA skin carcinogenesis protocol. α11-deficient mice showed significantly decreased tumor cell proliferation, leading to delayed tumor development and reduced tumor burden. Integrin α11 expression was significantly upregulated in the desmoplastic tumor stroma of human and mouse cSCCs, and the highest α11 expression was detected in high-grade tumors. Our results point to a reduced ability of α11-deficient stromal cells to differentiate into matrix-producing and tumor-promoting CAFs and suggest that this is one causative mechanism underlying the observed decreased tumor growth. An unexpected finding in our study was that, despite reduced CAF activation, the α11-deficient skin tumors were characterized by the presence of thick and regularly aligned collagen bundles. This finding was attributed to a higher expression of TGFβ1 and collagen crosslinking lysyl oxidases in the Itga11-/- tumor stroma. In summary, our data suggest that α11β1 operates in a complex interactive tumor environment to regulate ECM synthesis and collagen organization and thus foster cSCC growth. Further studies with advanced experimental models are still needed to define the exact roles and molecular mechanisms of stromal α11β1 in skin tumorigenesis.
Connections Between Febrile Infection-Related Epilepsy Syndrome and Autoimmune Encephalitis. A Case Report of a Child With New Anti-neuronal Antibodies
Authors: Basso Martina , Gastaldi Matteo , Leonardi Valeria , Izzo Giana , Olivotto Sara , Ferrario Stefania , Veggiotti Pierangelo , Franciotta Diego , Bova Stefania M.
Published: August 2022

Acute encephalitis and febrile infection-related epilepsy syndrome (FIRES) are debilitating neurological disorders. It is increasingly accepted that FIRES should be considered an autoinflammation-mediated epileptic encephalopathy, but the debate about its etiopathogenesis is still very much open. Despite showing a considerable overlap with encephalitis, it continues to be regarded as a distinct entity. We describe the case of a previously healthy 5-year-old child who, following a fever, developed acute encephalopathy, status epilepticus, neurological, neuropsychological, and psychiatric manifestations, and claustrum involvement on MRI. At symptom onset, his clinical and instrumental data met the diagnostic criteria for both FIRES and acute encephalitis. He received benzodiazepines, levetiracetam, phenytoin, phenobarbital, thiopental, and first-line immunotherapy for acute inflammatory encephalopathy (intravenous methylprednisolone and immunoglobulins), without substantial improvement. Following the detection of anti-neuronal antibodies through immunohistochemistry performed on rat brain slices, he received therapeutic plasma exchange (TPE). His neurological and behavioral conditions improved drastically and his antibody titer fell sharply from the first to the last course of PE. Claustrum abnormalities on MRI disappeared. The patient’s long-term outcome is favorable. At 13 months after discharge, he experienced a focal seizure and carbamazepine was started, achieving seizure control. At 10 years of age, he is still on carbamazepine, with well-controlled seizures, focal EEG abnormalities, and an otherwise normal neurological and cognitive profile and normal MRI. This case strengthens the view that FIRES might constitute the initial clinical presentation of a CNS inflammatory disease that could have, among multiple distinct etiologies, an autoimmune cause. Immunological and specific second- or third-level investigations including immunohistochemistry should be included in the diagnostic work up of patients with FIRES-like phenotypes. PE could be effective in this subset of patients, protecting them from long-term neurological sequelae.
Risk factors for severe COVID-19 in people with cystic fibrosis: A systematic review
Authors: Terlizzi Vito , Motisi Marco Antonio , Pellegrino Roberta , Padoan Rita , Chiappini Elena
Published: August 2022

Background

People with cystic fibrosis (CF) are considered a clinically fragile population with an intrinsic higher risk of developing severe COVID-19, though a certain variability in terms of outcomes and hospitalization has been noticed.

Aim

To highlight the main risk factors for severe COVID-19 in patients with CF.

Methods

A systematic review of the current literature was conducted through PubMed and EMBASE databases. English-written articles reporting clinical data on CF subjects with SARS-CoV2 infection were included and analyzed. Selected reports were evaluated for adherence to STROBE recommendations.

Results

After the selection phase, 9 observational studies were included, 5 of which reported data from CF Registry Global Harmonization Group. The hospitalization rate ranged from 18.2 to 58.1%. The main risk factors for severe outcome were as follows: FEV1 < 70%p, CF-related diabetes, age > 40 years, pancreatic insufficiency, underweight, previous transplant, azithromycin use. Use of dornase alfa was associated with decreased risk for severe disease, while there was insufficient evidence to establish the role of inhaled steroids or CFTR modulators. No solid data regarding specific SARS-CoV-2 therapies in patients with CF emerged.

Conclusion

Most people with CF experience a mild course of SARS-CoV-2 infection, nevertheless subgroups with higher risk of severe outcome emerged. Maintenance therapies for CF overall did not show a clear preventive effect against severe outcomes, although dornase alfa seems to give some protection. Due to the current lack of data on specific COVID-19 therapies and immunization in patients with CF, further studies are needed to establish their impact in this population.
Distribution of HLA-B Alleles and Haplotypes in Qatari: Recommendation for Establishing Pharmacogenomic Markers Screening for Drug Hypersensitivity
Authors: Dashti Mohammed , Al-Matrouk Abdullah , Channanath Arshad , Hebbar Prashantha , Al-Mulla Fahd , Thanaraj Thangavel Alphonse
Published: August 2022

Human leukocyte antigen (HLA) proteins are present at the cellular surface of antigen-presenting cells and play a crucial role in the adaptive immune response. Class I genes, specifically certain HLA-B alleles, are associated with adverse drug reactions (ADRs) and are used as pharmacogenetic markers. Although ADRs are a common causes of hospitalization and mortality, the data on the prevalence of HLA-B pharmacogenetics markers in Arab countries are scarce. In this study, we investigated the frequencies of major HLA-B pharmacogenomics markers in the Qatari population. Next-generation sequencing data from 1,098 Qatari individuals were employed for HLA-B typing using HLA-HD version 1.4.0 and IPD-IMGT/HLA database. In addition, HLA-B pharmacogenetics markers were obtained from the HLA Adverse Drug Reaction Database. In total, 469 major HLA-B pharmacogenetic markers were identified, with HLA-B*51:01 being the most frequent pharmacogenetic marker (26.67%) in the Qatari population. Moreover, HLA-B*51:01 is associated with phenytoin- and clindamycin-induced ADRs. The second most frequent pharmacogenetic marker was the HLA-B*58:01 allele (6.56%), which is associated with allopurinol-induced ADRs. The third most frequent pharmacogenetic marker was the HLA-B*44:03 allele, which is associated with phenytoin-induced ADRs. The establishment of a pharmacogenetics screening program in Qatar for cost effective interventions aimed at preventing drug-induced hypersensitivity can be aided by the highly prevalent HLA-B pharmacogenetic markers detected here.
Therapeutic potential of nanotechnology-based approaches in osteoarthritis
Authors: Xiao Likang , Cui Jiarui , Sun Zhuang , Liu Yunke , Zheng Jia , Dong Yonghui
Published: August 2022

Osteoarthritis (OA) is a multifactorial disease that affects the entire joint, often resulting in severe pain, disability, psychological distress, and a lower quality of life. Patient self-management is emphasized in OA clinical recommendations. Currently, the clinical treatment of OA mainly focuses on pain relief and the improvement of joint function, with few options for regenerating degenerative cartilage or slowing the progression of OA. Therefore, we first reviewed the current treatment of OA, and then summarized the research advances of nanotechnology in OA treatment, including nano drug delivery systems for small molecule drugs, nucleic acids and proteins, nano-scaffolds for cartilage regeneration, and nanoparticle lubricants. Finally, we discussed the opportunities and potential challenges of nanotechnology in OA treatment.
Traditional Chinese Medicine in Treating Primary Podocytosis: From Fundamental Science to Clinical Research
Authors: Lin Lirong , Tian En , Ren Jiangwen , Wu Zhifeng , Deng Junhui , Yang Jurong
Published: August 2022

Podocytes form a key component of the glomerular filtration barrier. Damage to podocytes is referred to as “podocyte disease.” There are many causes of podocyte injury, including primary injury, secondary injury, and gene mutations. Primary podocytosis mostly manifests as nephrotic syndrome. At present, first-line treatment is based on glucocorticoid administration combined with immunosuppressive therapy, but some patients still progress to end-stage renal disease. In Asia, especially in China, traditional Chinese medicine (TCM) still plays an important role in the treatment of kidney diseases. This study summarizes the potential mechanism of TCM and its active components in protecting podocytes, such as repairing podocyte injury, inhibiting podocyte proliferation, reducing podocyte apoptosis and excretion, maintaining podocyte skeleton structure, and upregulating podocyte-related protein expression. At the same time, the clinical efficacy of TCM in the treatment of primary podocytosis (including idiopathic membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis) is summarized to support the development of new treatment strategies for primary podocytosis.
Ameliorative effect and mechanism of Si-Ni-San on chronic stress-induced diarrhea-irritable bowel syndrome in rats
Authors: Chen Hui-Yu , Liu Jian , Weng Ding-Zhou , Yan Li , Pan Chun-Shui , Sun Kai , Guo Xiao , Wang Di , Anwaier Gulinigaer , Jiao Ying-Qian , Li Zhi-Xin , Han Jing-Yan
Published: August 2022

Background: Chronic stress-induced diarrhea is a common clinical condition, characterized by an abnormal bowel movement and loose stools, which lacks effective treatment in the clinic. Si-Ni-San (SNS) is a compound traditional Chinese medicine extensively used in China for stress-related diarrhea. However, the mechanism is unclear.

Methods: Male Wistar rats (200 ± 20 g) were placed in a restraint cylinder and fixed horizontally for 3 h once daily for 21 consecutive days to establish a chronic restraint stress (CRS) rat model. SNS (0.6944 g/kg or 1.3888 g/kg) was given by gavage 1 h before the restraint once daily for 21 consecutive days. We examined the fecal score, dopamine β hydroxylase (DβH), and c-fos expression in locus coeruleus, norepinephrine (NE) content in ileum and plasma, expression of α1 adrenergic receptors, MLCK, MLC, and p-MLC in the colon and mesenteric arteries, contraction of isolated mesenteric arteries, The expression of subunit δ of ATP synthase (ATP5D) in intestinal tissues, ATP, ADP, and AMP content in the ileum and colon, occludin expression between ileum epithelial cells, the number of enterochromaffin cells (ECs) and mast cells (MCs) in the ileum, and 5-hydroxytryptamine (5-HT) content in the ileum and plasma.

Results: After SNS treatment, the fecal score was improved. The increased expression of DβH and c-fos in locus coeruleus was inhibited. SNS suppressed the increased NE content in the ileum and plasma, down-regulated α1 adrenergic receptors in mesenteric arteries and MLCK, MLC, p-MLC in the colon and mesenteric arteries, and inhibited the contraction of mesenteric arteries. SNS also increased the ATP content in the ileum and colon, inhibited low expression of ATP5D in intestinal tissues, inhibited the decrease of ATP/ADP in the ileum and ATP/AMP in the colon, and up-regulated the occludin expression between ileum epithelial cells. In addition, SNS inhibited the increase of ECs and MCs in the ileum and the increase of 5-HT content in the ileum and plasma.

Conclusion: This study demonstrated that SNS could improve CRS-induced abnormal feces in rats. This effect was related to the inhibition of CRS-induced increased expression of DβH and c-fos in the locus coeruleus, NE content in the ileum and plasma, and the contraction of isolated mesenteric arteries; inhibition of energy metabolism abnormality and decreased occludin expression; inhibition of increased ECs and MCs in the ileum, and 5-HT content in the ileum and plasma.
Identification of circular RNAs in cardiac hypertrophy and cardiac fibrosis
Authors: Chen Yan , Zhou Junteng , Wei Zisong , Cheng Yue , Tian Geer , Quan Yue , Kong Qihang , Wu Wenchao , Liu Xiaojing
Published: August 2022

Cardiac hypertrophy initially serves as an adaptive response to physiological and pathological stimuli. Sustained hypertrophy progress to pathological cardiac hypertrophy, cardiac fibrosis and ultimately lead to heart failure, one of the leading medical causes of mortality worldwide. Intervention of pathological cardiac hypertrophy can effectively reduce the occurrence of heart failure. Abundant factors, such as adrenergic, angiotensin, and endothelin (ET-1) receptors, have been shown to participate in the regulation of pathological cardiac hypertrophy. Recently, an increasing number of studies have indicated that circRNA and circRNA-miRNA–mRNA network regulation is indispensable for the posttranscriptional regulation of mRNA in cardiac hypertrophy. In our study, the morphological, cardiac function and pathological changes during cardiac hypertrophy were investigated. RNA sequencing identified 93 circRNAs that were differentially expressed in the TAC_2w group, and 55 circRNAs in the TAC_4w group compared with the sham group. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses identified several significant pathways, including hypertrophic cardiomyopathy, extracellular matrix (ECM)-receptor interaction and focal adhesion. Coexpression analyses were performed for differentially expressed circRNAs and differentially expressed mRNAs. Based on gene set enrichment analysis (GSEA), 8 circRNAs (mmu-Nfkb1_0001, mmu-Smad4_0007, mmu-Hecw2_0009, mmu-Itgbl1_0002, mmu-Lrrc2_0005, mmu-Cpeb3_0007, mmu-Ryr2_0040, and mmu-Rtn4_0001) involved in cardiac hypertrophy and cardiac fibrosis were identified. We validated some key circRNAs by qPCR. The crucial coexpression of circRNA–mRNA and its interaction with miRNA showed the possible mechanism of circRNAs in the process of cardiac dysfunction. Our results may provide promising targets for the treatment of pathological cardiac hypertrophy and fibrosis.
Adapalene inhibits the growth of triple-negative breast cancer cells by S-phase arrest and potentiates the antitumor efficacy of GDC-0941
Authors: Mehraj Umar , Wani Nissar Ahmad , Hamid Abid , Alkhanani Mustfa , Almilaibary Abdullah , Mir Manzoor Ahmad
Published: August 2022

Although advances in diagnostics and therapeutics have prolonged the survival of triple-negative breast cancer (TNBC) patients, metastasis, therapeutic resistance, and lack of targeted therapies remain the foremost hurdle in the effective management of TNBC. Thus, evaluation of new therapeutic agents and their efficacy in combination therapy is urgently needed. The third-generation retinoid adapalene (ADA) has potent antitumor activity, and using ADA in combination with existing therapeutic regimens may improve the effectiveness and minimize the toxicities and drug resistance. The current study aimed to assess the anticancer efficacy of adapalene as a combination regimen with the PI3K inhibitor (GDC-0941) in TNBC in vitro models. The Chou–Talalay’s method evaluated the pharmacodynamic interactions (synergism, antagonism, or additivity) of binary drug combinations. Flow cytometry, Western blotting, and in silico studies were used to analyze the mechanism of GDC–ADA synergistic interactions in TNBC cells. The combination of GDC and ADA demonstrated a synergistic effect in inhibiting proliferation, migration, and colony formation of tumor cells. Accumulation of reactive oxygen species upon co-treatment with GDC and ADA promoted apoptosis and enhanced sensitivity to GDC in TNBC cells. The findings indicate that ADA is a promising therapeutic agent in treating advanced BC tumors and enhance sensitivity to GDC in inhibiting tumor growth in TNBC models while reducing therapeutic resistance.
Muscle strength, aerobic capacity, and exercise tolerance are impaired in left ventricular assist devices recipients: A pilot study
Authors: Gobbo Stefano , Favro Francesco , Bullo Valentina , Cugusi Lucia , Blasio Andrea Di , Bortoletto Alessandro , Bocalini Danilo Sales , Gasperetti Andrea , Ermolao Andrea , Bergamin Marco
Published: August 2022

Background: Left ventricular assist devices (LVAD) are increasingly being used as a therapy for advanced heart failure, both as a bridge to heart transplant and, given the rapid advances in the LVAD’s functionality and safety, and constant lack in availability of donor organs, as long-term destination therapy. With the diffusion of such therapy, it is crucial to assess patients’ muscle strength, aerobic capacity and exercise tolerance, to improve their functional capacity.

Methods: 38 LVAD recipients (33 men and five women) were included. Exercise testing including a maximal cardiopulmonary exercise test (CPET), handgrip, isometric and isokinetic strength testing of knee and ankle flexion/extension, and Romberg balance test in three conditions (eyes open, eyes closed, double task). Given the small and heterogeneous final sample size, a mostly descriptive statistical approach was chosen.

Results: 12 participants were classified as “Obese” (BMI>29.9). The most common comorbidities were type II diabetes and chronic kidney disease. Only 12 participants were able to successfully complete all the assessments. CPET and isokinetic strength trials were the least tolerated tests, and the handgrip test the best tolerated. Mean VO2 peak was 12.38 ± 3.43 ml/kg/min, with 15 participants below 50% of predicted VO2 max, of which 6 below 30% VO2max. Mean handgrip strength was 30.05 ± 10.61 Kg; 25 participants were below the 25° percentile of their population’s normative reference values for handgrip strength, 10 of which were below the 5° percentile. Issues with the management of the external pack of the LVAD and its influence on the test limited the validity of the balance tests data, therefore, no solid conclusions could be drawn from them. VO2 peak did not correlate with handgrip strength or with any of the lower limb strength measures.

Conclusion: LVAD recipients show greatly reduced functional capacity and tolerance to exercise and exercise testing, with low overall strength levels. As strength variables appear to be independent from VO2 peak, different lower limbs strength tests should be explored to find a tolerable alternative in this population, which is subjected to muscle wasting due to old age, reduced tissue perfusion, side effects from the pharmacological therapies, and prolonged periods of bedrest.