bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypermethylation of Smad7 in CD4+ T cells is associated with the disease activity of rheumatoid arthritis
Authors: Hu Yiping , Xu Bihua , He Juan , Shan Hongying , Zhou Gengmin , Wang Deli , Bai Lu , Shang Hongxi , Nie Liping , Pan Fan , Lan Hui Yao , Wang Qingwen
Published: February 2023

Background

Smad7 is protective in a mouse model of rheumatoid arthritis. Here we investigated whether Smad7-expressing CD4+ T cells and the methylation of Smad7 gene in CD4+ T cells contribute to the disease activity of RA in patients.

Methods

Peripheral CD4+ T cells were collected from 35 healthy controls and 57 RA patients. Smad7 expression by CD4+ T cells were determined and correlated with the clinical parameters of RA including RA score and serum levels of IL-6, CRP, ESR, DAS28-CRP, DAS28-ESR, Swollen joints and Tender joints. Bisulfite sequencing (BSP-seq) was used to determine the DNA methylation in Smad7 promoter (-1000 to +2000) region in CD4+ T cells. In addition, a DNA methylation inhibitor, 5-Azacytidine (5-AzaC), was added to CD4+ T cells to examine the possible role of Smad7 methylation in CD4+ T cell differentiation and functional activity.

Results

Compared to the heath controls, Smad7 expression was significantly decreased in CD4+ T cells from RA patients and inversely correlated with the RA activity score and serum levels of IL-6 and CRP. Importantly, loss of Smad7 in CD4+ T cell was associated with the alteration of Th17/Treg balance by increasing Th17 over the Treg population. BSP-seq detected that DNA hypermethylation occurred in the Smad7 promoter region of CD4+ T cells obtained from RA patients. Mechanistically, we found that the DNA hypermethylation in the Smad7 promoter of CD4+ T cells was associated with decreased Smad7 expression in RA patients. This was associated with overreactive DNA methyltransferase (DMNT1) and downregulation of the methyl-CpG binding domain proteins (MBD4). Inhibition of DNA methylation by treating CD4+ T cells from RA patients with 5-AzaC significantly increased Smad7 mRNA expression along with the increased MBD4 but reduced DNMT1 expression, which was associated with the rebalance in the Th17/Treg response.

Conclusion

DNA hypermethylation at the Smad7 promoter regions may cause a loss of Smad7 in CD4+ T cells of RA patients, which may contribute to the RA activity by disrupting the Th17/Treg balance.
Designing neoantigen cancer vaccines, trials, and outcomes
Authors: Biswas Nupur , Chakrabarti Shweta , Padul Vijay , Jones Lawrence D. , Ashili Shashaanka
Published: February 2023

Neoantigen vaccines are based on epitopes of antigenic parts of mutant proteins expressed in cancer cells. These highly immunogenic antigens may trigger the immune system to combat cancer cells. Improvements in sequencing technology and computational tools have resulted in several clinical trials of neoantigen vaccines on cancer patients. In this review, we have looked into the design of the vaccines which are undergoing several clinical trials. We have discussed the criteria, processes, and challenges associated with the design of neoantigens. We searched different databases to track the ongoing clinical trials and their reported outcomes. We observed, in several trials, the vaccines boost the immune system to combat the cancer cells while maintaining a reasonable margin of safety. Detection of neoantigens has led to the development of several databases. Adjuvants also play a catalytic role in improving the efficacy of the vaccine. Through this review, we can conclude that the efficacy of vaccines can make it a potential treatment across different types of cancers.
The co-inhibitory receptor TIGIT regulates NK cell function and is upregulated in human intrahepatic CD56bright NK cells
Authors: Ziegler Annerose E. , Fittje Pia , Müller Luisa M. , Ahrenstorf Annika E. , Hagemann Kerri , Hagen Sven H. , Hess Leonard U. , Niehrs Annika , Poch Tobias , Ravichandran Gevitha , Löbl Sebastian M. , Padoan Benedetta , Brias Sébastien , Hennesen Jana , Richard Myrtille , Richert Laura , Peine Sven , Oldhafer Karl J. , Fischer Lutz , Schramm Christoph , Martrus Glòria , Bunders Madeleine J. , Altfeld Marcus , Lunemann Sebastian
Published: February 2023

The crosstalk between NK cells and their surrounding environment is enabled through activating and inhibitory receptors, which tightly control NK cell activity. The co-inhibitory receptor TIGIT decreases NK cell cytotoxicity and is involved in NK cell exhaustion, but has also been associated with liver regeneration, highlighting that the contribution of human intrahepatic CD56bright NK cells in regulating tissue homeostasis remains incompletely understood. A targeted single-cell mRNA analysis revealed distinct transcriptional differences between matched human peripheral blood and intrahepatic CD56bright NK cells. Multiparameter flow cytometry identified a cluster of intrahepatic NK cells with overlapping high expression of CD56, CD69, CXCR6, TIGIT and CD96. Intrahepatic CD56bright NK cells also expressed significantly higher protein surface levels of TIGIT, and significantly lower levels of DNAM-1 compared to matched peripheral blood CD56bright NK cells. TIGIT+ CD56bright NK cells showed diminished degranulation and TNF-α production following stimulation. Co-incubation of peripheral blood CD56bright NK cells with human hepatoma cells or primary human hepatocyte organoids resulted in migration of NK cells into hepatocyte organoids and upregulation of TIGIT and downregulation of DNAM-1 expression, in line with the phenotype of intrahepatic CD56bright NK cells. Intrahepatic CD56bright NK cells represent a transcriptionally, phenotypically, and functionally distinct population of NK cells that expresses higher levels of TIGIT and lower levels of DNAM-1 than matched peripheral blood CD56bright NK cells. Increased expression of inhibitory receptors by NK cells within the liver environment can contribute to tissue homeostasis and reduction of liver inflammation.
DKK3’s protective role in prostate cancer is partly due to the modulation of immune-related pathways
Authors: Shareef Zainab Al , Hachim Mahmood Y. , Talaat Iman M. , Bhamidimarri Poorna Manasa , Ershaid Mai Nidal Asad , Ilce Burcu Yener , Venkatachalam Thenmozhi , Eltayeb Abdulla , Hamoudi Rifat , Hachim Ibrahim Y.
Published: February 2023

While it is considered one of the most common cancers and the leading cause of death in men worldwide, prognostic stratification and treatment modalities are still limited for patients with prostate cancer (PCa). Recently, the introduction of genomic profiling and the use of new techniques like next-generation sequencing (NGS) in many cancers provide novel tools for the discovery of new molecular targets that might improve our understanding of the genomic aberrations in PCa and the discovery of novel prognostic and therapeutic targets. In this study, we investigated the possible mechanisms through which Dickkopf-3 (DKK3) produces its possible protective role in PCa using NGS in both the DKK3 overexpression PCa cell line (PC3) model and our patient cohort consisting of nine PCa and five benign prostatic hyperplasia. Interestingly, our results have shown that DKK3 transfection-modulated genes are involved in the regulation of cell motility, senescence-associated secretory phenotype (SASP), and cytokine signaling in the immune system, as well as in the regulation of adaptive immune response. Further analysis of our NGS using our in vitro model revealed the presence of 36 differentially expressed genes (DEGs) between DKK3 transfected cells and PC3 empty vector. In addition, both CP and ACE2 genes were differentially expressed not only between the transfected and empty groups but also between the transfected and Mock cells. The top common DEGs between the DKK3 overexpression cell line and our patient cohort are the following: IL32, IRAK1, RIOK1, HIST1H2BB, SNORA31, AKR1B1, ACE2, and CP. The upregulated genes including IL32, HIST1H2BB, and SNORA31 showed tumor suppressor functions in various cancers including PCa. On the other hand, both IRAK1 and RIOK1 were downregulated and involved in tumor initiation, tumor progression, poor outcome, and radiotherapy resistance. Together, our results highlighted the possible role of the DKK3-related genes in protecting against PCa initiation and progression.
End-member characteristics of sediment grain size in modern Yellow River delta sediments and its environmental significance
Authors: Meng Liwei , Wang Longsheng , Zhao Jiawen , Zhan Chao , Liu Xianbin , Cui Buli , Zeng Lin , Wang Qing
Published: February 2023

Introduction

The sediments of the Yellow River delta record the environmental changes in the Yellow River basin on a long time scale and are sensitive to the river diversion and sedimentary environment evolution.

Methods

In this study, cores YDC and YDG in the delta near the estuary of the Yellow River since 1976 were taken as the research object, and the parameterized end-member analysis model was used to analyze the grain-size data of the cores.

Results

The results show that: The main sediments were silty and sand (58% and 77.9%). The grain-size parameters showed opposite changes with wide grain-size ranges and mixed sizes obviously. End member 1 (EM1) and end member 2 (EM2) were composed of clay and fine silt with fine particle sizes of 0.04 mm and 9.8 mm, respectively, and were deposited under weak hydrodynamic conditions during long-distance transport along the Yellow River. End member 3 (EM3) and end member 4 (EM4) were coarse silt with mode particle sizes of 40.14 mm and 66.89 mm, respectively. These were deposited by waves and tidal currents under strong dynamic conditions.

Discussion

According to the channel changes and the sedimentary facies data of the modern Yellow River delta, before the Yellow River was diverted in 1996, the cores YDC and YDG were both in the estuary-front bar sedimentary environment. In 1996, the Yellow River was diverted to the Qing 8 course. Subsequently, the core YDC changed to the delta-plain sedimentary facies, and the core YDG changed to the delta-front facies. The sediment sources of the two cores changed from the Yellow River sediments to coastal sediment erosion and resuspension. The sedimentary environment changed from siltation to erosion. The results of this study are of great practical significance for estuary management and coastal engineering construction in the modern Yellow River delta and can provide a scientific basis for ecological protection and high-quality development of the Yellow River basin.
Can circulating oxidative stress-related biomarkers be used as an early prognostic marker for COVID-19?
Authors: Uysal Pelin , Yüksel Arzu , Durmus Sinem , Cuhadaroglu Çaglar , Gelisgen Remise , Uzun Hafize
Published: February 2023

Background

Oxidative stress plays an important role in the pathogenesis of many diseases. This study aimed to investigate the relationship between nuclear factor kappa B (NF-κB) and oxidative stress and the severity of the disease in new COVID-19 patients, and, to compare the levels of NF-κB, oxidized LDL (oxLDL), and lectin-like oxidized-LDL receptor-1 (LOX-1) with oxygen saturation, which is an indicator of the severity parameters of the disease in COVID-19 patients.

Methods

In this prospective study, 100 COVID-19 patients and 100 healthy subjects were selected.

Results

LOX-1, NF-κB, and oxLDL were found to be higher in COVID-19 patients compared to the healthy subjects (p < 0.001 for all). According to the results of correlation analysis, it was found that there was no significant relationship between oxygen saturation and LOX-1, NF-κB and oxLDL parameters. There was significant relationship between oxLDL with LOX-1 and NF-κB in patients with COVID-19 disease. ROC analysis results of the highest discrimination power were oxLDL (AUC: 0.955, CI: 0.904–1.000; sensitivity: 77%, and specificity: 100%, for cutoff: 127.944 ng/l) indicating COVID-19.

Conclusion

Oxidative stress plays an essential role in COVID-19. NF-κB, oxLDL, and LOX-1 seem to represent good markers in COVID-19. Our study also showed that oxLDL has the highest power in distinguishing patients with COVID-19 from the healthy subjects.
SWI/SNF complex, promising target in melanoma therapy: Snapshot view
Authors: Mollapour Sisakht Mahsa , Amirkhani Mohammad Amir , Nilforoushzadeh Mohammad Ali
Published: February 2023

Therapeutic strategies based on epigenetic regulators are rapidly increasing in light of recent advances in discovering the role of epigenetic factors in response and sensitivity to therapy. Although loss-of-function mutations in genes encoding the SWItch/Sucrose NonFermentable (SWI/SNF) subunits play an important role in the occurrence of ~34% of melanomas, the potential of using inhibitors and synthetic lethality interactions between key subunits of the complex that play an important role in melanoma progression must be considered. Here, we discuss the importance of the clinical application of SWI/SNF subunits as a promising potential therapeutic in melanoma.
Propanol and 1, 3-propanediol enhance fatty acid accumulation synergistically in Schizochytrium ATCC 20888
Authors: Wang Tiantian , Wang Fangzhong , Zeng Lei , Guo Pengfei , Wu Yawei , Chen Lei , Zhang Weiwen
Published: February 2023

The effects of propanol and 1, 3-propanediol on fatty acid and biomass accumulation in Schizochytrium ATCC 20888 were explored. Propanol increased the contents of saturated fatty acids and total fatty acids by 55.4 and15.3%, while 1, 3-propanediol elevated the polyunsaturated fatty acids, total fatty acids and biomass contents by 30.7, 17.0, and 6.89%. Although both of them quench ROS to increase fatty acids biosynthesis, the mechanisms are different. The effect of propanol did not reflect on metabolic level while 1, 3-propanediol elevated osmoregulators contents and activated triacylglycerol biosynthetic pathway. The triacylglycerol content and the ratio of polyunsaturated fatty acids to saturated fatty acids were significantly increased by 2.53-fold, which explained the higher PUFA accumulation in Schizochytrium after adding 1, 3- propanediol. At last, the combination of propanol and 1, 3-propanediol further elevated total fatty acids by approximately 1.2-fold without compromising cell growth. These findings are valuable for scale-up production of designed Schizochytrium oil for various application purposes.
In vitro digestion of ESC-resistant Escherichia coli from poultry meat and evaluation of human health risk
Authors: Buberg May Linn , Wasteson Yngvild , Lindstedt Bjørn Arne , Witsø Ingun Lund
Published: February 2023

Introduction

The spread of antimicrobial resistance (AMR) has become a threat against human and animal health. Third and fourth generation cephalosporins have been defined as critically important antimicrobials by The World Health Organization. Exposure to Extended spectrum cephalosporin-resistant E. coli may result in consumers becoming carriers if these bacteria colonize the human gut or their resistance genes spread to other bacteria in the gut microbiota. In the case that these resistant bacteria at later occasions cause disease, their resistance characteristics may lead to failure of treatment and increased mortality. We hypothesized that ESC-resistant E. coli from poultry can survive digestion and thereby cause infections and/or spread their respective resistance traits within the gastro-intestinal tract.

Methods

In this study, a selection of 31 ESC-resistant E. coli isolates from retail chicken meat was exposed to a static in vitro digestion model (INFOGEST). Their survival, alteration of colonizing characteristics in addition to conjugational abilities were investigated before and after digestion. Whole genome data from all isolates were screened through a custom-made virulence database of over 1100 genes for virulence- and colonizing factors.

Results and discussion

All isolates were able to survive digestion. Most of the isolates (24/31) were able to transfer their blaCMY2-containing plasmid to E. coli DH5-á, with a general decline in conjugation frequency of digested isolates compared to non-digested. Overall, the isolates showed a higher degree of cell adhesion than cell invasion, with a slight increase after digestion compared non-digested, except for three isolates that displayed a major increase of invasion. These isolates also harbored genes facilitating invasion. In the virulence-associated gene analysis two isolates were categorized as UPEC, and one isolate was considered a hybrid pathogen. Altogether the pathogenic potential of these isolates is highly dependent on the individual isolate and its characteristics. Poultry meat may represent a reservoir and be a vehicle for dissemination of potential human pathogens and resistance determinants, and the ESC-resistance may complicate treatment in the case of an infection.
Retrospective analysis of Plasmodium vivax genomes from a pre-elimination China inland population in the 2010s
Authors: Liu Ying , Zhang Tao , Chen Shen-Bo , Cui Yan-Bing , Wang Shu-Qi , Zhang Hong-Wei , Shen Hai-Mo , Chen Jun-Hu
Published: February 2023

Introduction

In malaria-free countries, imported cases are challenging because interconnections with neighboring countries with higher transmission rates increase the risk of parasite reintroduction. Establishing a genetic database for rapidly identifying malaria importation or reintroduction is crucial in addressing these challenges. This study aimed to examine genomic epidemiology during the pre-elimination stage by retrospectively reporting whole-genome sequence variation of 10 Plasmodium vivax isolates from inland China.

Methods

The samples were collected during the last few inland outbreaks from 2011 to 2012 when China implemented a malaria control plan. After next-generation sequencing, we completed a genetic analysis of the population, explored the geographic specificity of the samples, and examined clustering of selection pressures. We also scanned genes for signals of positive selection.

Results

China’s inland populations were highly structured compared to the surrounding area, with a single potential ancestor. Additionally, we identified genes under selection and evaluated the selection pressure on drug-resistance genes. In the inland population, positive selection was detected in some critical gene families, including sera, msp3, and vir. Meanwhile, we identified selection signatures in drug resistance, such as ugt, krs1, and crt, and noticed that the ratio of wild-type dhps and dhfr-ts increased after China banned sulfadoxine-pyrimethamine (SP) for decades.

Discussion

Our data provides an opportunity to investigate the molecular epidemiology of pre-elimination inland malaria populations, which exhibited lower selection pressure on invasion and immune evasion genes than neighbouring areas, but increased drug resistance in low transmission settings. Our results revealed that the inland population was severely fragmented with low relatedness among infections, despite a higher incidence of multiclonal infections, suggesting that superinfection or co-transmission events are rare in low-endemic circumstances. We identified selective signatures of resistance and found that the proportion of susceptible isolates fluctuated in response to the prohibition of specific drugs. This finding is consistent with the alterations in medication strategies during the malaria elimination campaign in inland China. Such findings could provide a genetic basis for future population studies, assessing changes in other pre-elimination countries.
In-silico drug design for the novel Karachi-NF001 strain of brain-eating amoeba: Naegleria fowleri
Authors: Saleem Tayyab , Jamal Syed Babar , Alzahrani Badr , Basheer Amina , Wajid Abbasi Sumra , Ali Mahwish , Rehman Ashfaq Ur , Faheem Muhammad
Published: February 2023

Naegleria fowleri (N. fowleri) is a free-living thermophilic amoeba of fresh water and soil. The amoeba primarily feeds on bacteria but can be transmitted to humans upon contact with freshwater sources. Furthermore, this brain-eating amoeba enters the human body through the nose and travels to the brain to cause primary amebic meningoencephalitis (PAM). N. fowleri has been reported globally since its discovery in 1961. Recently a new strain of N. fowleri named Karachi-NF001 was found in a patient who had traveled from Riyadh, Saudi Arabia to Karachi in 2019. There were 15 unique genes identified in the genome of the Karachi-NF001 strain compared to all the previously reported strains of N. fowleri worldwide. Six of these genes encode well-known proteins. In this study, we performed in-silico analysis on 5 of these 6 proteins, namely, Rab family small GTPase, NADH dehydrogenase subunit 11, two Glutamine-rich protein 2 proteins (locus tags: 12086 and 12110), and Tigger transposable element-derived protein 1. We conducted homology modeling of these 5 proteins followed by their active site identification. These proteins were subjected to molecular docking against 105 anti-bacterial ligand compounds as potential drugs. Subsequently, the 10 best-docked compounds were determined for each protein and ranked according to the number of interactions and their binding energies. The highest binding energy was recorded for the two Glutamine-rich protein 2 proteins with different locus tags, and results have shown that the protein-inhibitor complex was stable throughout the simulation run. Moreover, future in-vitro studies could validate the findings of our in-silico analysis and identify potential therapeutic drugs against N. fowleri infections.
Identification of AKR1B10 as a key gene in primary biliary cholangitis by integrated bioinformatics analysis and experimental validation
Authors: Wang Huiwen , Zhang Jian , Liu Jinqing , Jiang Yongfang , Fu Lei , Peng Shifang
Published: February 2023

Background: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease that eventually progresses to cirrhosis and hepatocellular carcinoma (HCC) in the absence of proper treatment. However, Gene expression and molecular mechanisms involved in the pathogenesis of PBC have not been completely elucidated.

Methods: Microarray expression profiling dataset GSE61260 was downloaded from the Gene Expression Omnibus (GEO) database. Data were normalized to screen differentially expressed genes (DEGs) using the limma package in R. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed. A protein–protein interaction (PPI) network was constructed to identify hub genes and an integrative regulatory network of transcriptional factor–DEG–microRNA was established. Gene Set Enrichment Analysis (GSEA) was used to analyze differences in biological states for groups with different expressions of aldo-keto reductase family 1 member B10 (AKR1B10). Immunohistochemistry (IHC) analysis was performed to validate the expression of hepatic AKR1B10 in patients with PBC. The association of hepatic AKR1B10 levels with clinical parameters was evaluated using one-way analysis of variance (ANOVA) and Pearson’s correlation analysis.

Results: This study identified 22 upregulated and 12 downregulated DEGs between patients with PBC and healthy controls. GO and KEGG analysis revealed that DEGs were mainly enriched in immune reactions. AKR1B10 was identified as a key gene and was further analyzed by screening out hub genes from the PPI network. GSEA analysis indicated that high expression of AKR1B10 might promote PBC to develop into HCC. Immunohistochemistry results verified the increased expression of hepatic AKR1B10 in patients with PBC and demonstrated its positive correlation with the severity of PBC.

Conclusion: AKR1B10 was identified as a hub gene in PBC by integrated bioinformatics analysis and clinical validation. The increase of AKR1B10 expression in patients with PBC was associated with disease severity and might promote the progression of PBC to HCC.
Genetic and clinical analysis of TP73 gene in amyotrophic lateral sclerosis patients from Chinese mainland
Authors: Tang Xuxiong , Yuan Yanchun , Liu Zhen , Bu Yue , Tang Linxin , Zhao Qianqian , Jiao Bin , Guo Jifeng , Shen Lu , Jiang Hong , Tang Beisha , Wang Junling
Published: February 2023

Introduction

TP73 was recently identified as a novel causative gene for amyotrophic lateral sclerosis (ALS). We aimed to determine the contribution of variations in TP73 in the Chinese ALS population and to further explore the genotype-phenotype correlations.

Methods

We screened rare, putative pathogenic TP73 mutations in a large Chinese ALS cohort and performed association analysis of both rare and common TP73 variations between cases and controls.

Results

Of the 985 ALS patients studied, six rare, heterozygous putative pathogenic variants in TP73 were identified among six unrelated sALS patients. Exon 14 of TP73 might be a mutant hotspot in our cohort. Patients with ALS with only rare, putative pathogenic TP73 mutations exhibited a characteristic clinical profile. Patients harboring multiple mutations in TP73 and other ALS-related genes displayed a significantly earlier onset of ALS. Association analysis revealed that rare TP73 variants in the untranslated regions (UTRs) were enriched among ALS patients; meanwhile, two common variants in the exon-intron boundary were discovered to be associated with ALS.

Discussion

We demonstrate that TP73 variations also have contributed to ALS in the Asian population and broaden the genotypic and phenotypic spectrum of TP73 variants in the ALS-frontotemporal dementia (FTD) spectrum. Furthermore, our findings first suggest that TP73 is not only a causative gene, but also exerts a disease-modifying effect. These results may contribute to a better understanding of the molecular mechanism of ALS.
Research on steel rail surface defects detection based on improved YOLOv4 network
Authors: Mi Zengzhen , Chen Ren , Zhao Shanshan
Published: February 2023

Introduction

The surface images of steel rails are extremely difficult to detect and recognize due to the presence of interference such as light changes and texture background clutter during the acquisition process.

Methods

To improve the accuracy of railway defects detection, a deep learning algorithm is proposed to detect the rail defects. Aiming at the problems of inconspicuous rail defects edges, small size and background texture interference, the rail region extraction, improved Retinex image enhancement, background modeling difference, and threshold segmentation are performed sequentially to obtain the segmentation map of defects. For the classification of defects, Res2Net and CBAM attention mechanism are introduced to improve the receptive field and small target position weights. The bottom-up path enhancement structure is removed from the PANet structure to reduce the parameter redundancy and enhance the feature extraction of small targets.

Results

The results show the average accuracy of rail defects detection reaches 92.68%, the recall rate reaches 92.33%, and the average detection time reaches an average of 0.068 s per image, which can meet the real-time of rail defects detection.

Discussion

Comparing the improved method with the mainstream target detection algorithms such as Faster RCNN, SSD, YOLOv3 and other algorithms, the improved YOLOv4 has excellent comprehensive performance for rail defects detection, the improved YOLOv4 model obviously better than several others in Pr, Rc, and F1 value, and can be well-applied to rail defect detection projects.
Optimal CT perfusion thresholds for core and penumbra in acute posterior circulation infarction
Authors: Edwards Leon Stephen , Cappelen-Smith Cecilia , Cordato Dennis , Bivard Andrew , Churilov Leonid , Lin Longting , Chen Chushuang , Garcia-Esperon Carlos , Butcher Kenneth , Kleinig Tim , Choi Phillip M. C. , Cheng Xin , Dong Qiang , Aviv Richard I. , Parsons Mark William
Published: February 2023

Background

At least 20% of strokes involve the posterior circulation (PC). Compared to the anterior circulation, posterior circulation infarction (POCI) are frequently misdiagnosed. CT perfusion (CTP) has advanced stroke care by improving diagnostic accuracy and expanding eligibility for acute therapies. Clinical decisions are predicated upon precise estimates of the ischaemic penumbra and infarct core. Current thresholds for defining core and penumbra are based upon studies of anterior circulation stroke. We aimed to define the optimal CTP thresholds for core and penumbra in POCI.

Methods

Data were analyzed from 331-patients diagnosed with acute POCI enrolled in the International-stroke-perfusion-registry (INSPIRE). Thirty-nine patients with baseline multimodal-CT with occlusion of a large PC-artery and follow up diffusion weighted MRI at 24–48 h were included. Patients were divided into two-groups based on artery-recanalization on follow-up imaging. Patients with no or complete recanalisation were used for penumbral and infarct-core analysis, respectively. A Receiver operating curve (ROC) analysis was used for voxel-based analysis. Optimality was defined as the CTP parameter and threshold which maximized the area-under-the-curve. Linear regression was used for volume based analysis determining the CTP threshold which resulted in the smallest mean volume difference between the acute perfusion lesion and follow up MRI. Subanalysis of PC-regions was performed.

Results

Mean transit time (MTT) and delay time (DT) were the best CTP parameters to characterize ischaemic penumbra (AUC = 0.73). Optimal thresholds for penumbra were a DT >1 s and MTT>145%. Delay time (DT) best estimated the infarct core (AUC = 0.74). The optimal core threshold was a DT >1.5 s. The voxel-based analyses indicated CTP was most accurate in the calcarine (Penumbra-AUC = 0.75, Core-AUC = 0.79) and cerebellar regions (Penumbra-AUC = 0.65, Core-AUC = 0.79). For the volume-based analyses, MTT >160% demonstrated best correlation and smallest mean-volume difference between the penumbral estimate and follow-up MRI (R2 = 0.71). MTT >170% resulted in the smallest mean-volume difference between the core estimate and follow-up MRI, but with poor correlation (R2 = 0.11).

Conclusion

CTP has promising diagnostic utility in POCI. Accuracy of CTP varies by brain region. Optimal thresholds to define penumbra were DT >1 s and MTT >145%. The optimal threshold for core was a DT >1.5 s. However, CTP core volume estimates should be interpreted with caution.
Novel variant c.92T > G (p.Val31Gly) in the PFN1 gene (ALS18) responsible for a specific phenotype in a large Bulgarian amyotrophic lateral sclerosis pedigree
Authors: Angelov Teodor , Chamova Teodora , Atemin Slavena , Todorov Tihomir , Ormandzhiev Slavko , Tourtourikov Ivan , Todorova Albena , Devos David , Tournev Ivailo
Published: February 2023

Objectives

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive deterioration of motor function, disability, and death. Variants in the PFN1 gene, encoding the Profilin-1 protein, are related to ALS18.

Methods

We present a pedigree consisting of 3 generations and 4 affected individuals, 3 of which carry a novel heterozygous variant: c.92T > G (p.Val31Gly) in the PFN1 gene. This variant was discovered through means of whole exome sequencing (WES) and targeted analysis of ALS-related genes.

Results

The mean age of onset in our pedigree was 59.75 (±10.11 SD) years with a significant difference between the first two generations (females) and the third (male) of 22.33 (±3.4 SD) years. For this ALS form, we observed a longer disease progression of 4 (±1.87 SD) years (three of four affected are still alive). Clinical manifestations displayed predominant impairment of the lower motor neuron (LMN) in one limb, with gradual involvement of other limbs. A novel heterozygous missense variant c.92T > G, p. Val31Gly (NM_005022.4) in exon 1 in the PFN1 gene was discovered through means of whole exome sequencing (WES). Segregation analysis in the family showed that the detected variant was inherited from the affected mother, and the affected aunt also turned out to be a variant carrier.

Conclusions

ALS18 is a very rare form of the disease. We report here a relatively large pedigree with a novel variant, leading to late onset (after 50 years), initial involvement of the lower limbs and relatively slow progression.
Antiplatelet therapy adjustment improved the radiomic characteristics of acute silent cerebral infarction after stent-assisted coiling in patients with high on-treatment platelet reactivity: A prospective study
Authors: Li Wenqiang , Wang Anxin , Ma Chao , Wang Yanmin , Zhao Yapeng , Zhang Yisen , Wang Kun , Zhang Ying , Wang Yang , Yang Xinjian , Liu Jian , Liu Xianzhi
Published: February 2023

Background

We aimed to investigate the effects of high on-treatment platelet reactivity (HPR) and antiplatelet therapy adjustment on high-risk radiomic features in patients with antiplatelet therapy adjustment on acute silent cerebral infarction (ASCI) who had unruptured intracranial aneurysms (UIA) after stent placement.

Methods

This single-institution study prospectively included 230 UIA patients who had ACSI after stent placement in our hospital between January 2015 and July 2020. All patients underwent magnetic resonance imaging with diffusion-weighted imaging (MRI-DWI) after stent placement and 1,485 radiomic features were extracted from each patient. The least absolute shrinkage and selection operator regression methods were used for selection of high-risk radiomic features associated with clinical symptoms. In addition, 199 patients with ASCI were classified into three groups: controls without HPR (n = 113), HPR patients with standard antiplatelet therapy (n = 63) and HPR patients with antiplatelet therapy adjustment (n = 23). We compared high-risk radiomic features between three groups.

Results

Of the patients who had acute infarction after MRI-DWI, 31 (13.5%) exhibited clinical symptoms. Eight risk radiomic features associated with clinical symptoms were selected, and the radiomics signature exhibited good performance. In ASCI patients, compared with controls, the radiomic characteristics of ischemic lesion in HPR patients were consistent with the following high-risk radiomic features associated with clinical symptoms: higher gray-level values, greater variance in intensity values, and greater homogeneity. However, the adjustment of antiplatelet therapy in HPR patients modified the high-risk radiomic features, which showed lower gray-level values, less variance in intensity values, and more heterogeneous texture. The radiomic shape feature of elongation showed no notable difference between three groups.

Conclusion

Adjustment of antiplatelet therapy might reduce the high-risk radiomic features of UIA patients with HPR after stent placement.
Non-overlapping sets of neurons encode behavioral response determinants across different tasks in the posterior medial prefrontal cortex
Authors: Awan Muhammad Ali Haider , Mushiake Hajime , Matsuzaka Yoshiya
Published: February 2023

Higher mammals are able to simultaneously learn and perform a wide array of complex behaviors, which raises questions about how the neural representations of multiple tasks coexist within the same neural network. Do neurons play invariant roles across different tasks? Alternatively, do the same neurons play different roles in different tasks? To address these questions, we examined neuronal activity in the posterior medial prefrontal cortex of primates while they were performing two versions of arm-reaching tasks that required the selection of multiple behavioral tactics (i.e., the internal protocol of action selection), a critical requirement for the activation of this area. During the performance of these tasks, neurons in the pmPFC exhibited selective activity for the tactics, visuospatial information, action, or their combination. Surprisingly, in 82% of the tactics-selective neurons, the selective activity appeared in a particular task but not in both. Such task-specific neuronal representation appeared in 72% of the action-selective neurons. In addition, 95% of the neurons representing visuospatial information showed such activity exclusively in one task but not in both. Our findings indicate that the same neurons can play different roles across different tasks even though the tasks require common information, supporting the latter hypothesis.
Liver transplantation in gastroenteropancreatic neuroendocrine tumors
Authors: Fernandes Eduardo de Souza M. , Kyt Camila V. Garcia , de Mello Felipe Pedreira Tavares , Pimentel Leandro Savattone , Andrade Ronaldo de Oliveira , Girão Camila , César Camilla , Siqueira Munique , Monachesi Maria Eduarda , Brito Anderson , Tavares de Sousa Claudia Cristina , Andraus Wellington , Torres Orlando Jorge M.
Published: February 2023

Neuroendocrine tumors are part of a heterogeneous group of tumors located in organs such as the gastrointestinal tract (GIT), lungs, thymus, thyroid, and adrenal glands. The most prevalent sites are the small intestine, cecal appendix, and pancreas. More than 50% of these tumors are associated with metastases at the time of diagnosis. Neuroendocrine tumors are classified according to the degree of cell differentiation and the histopathological proliferation index of the lesion. Neuroendocrine tumors can be well differentiated or poorly differentiated. G3 tumors are characterized by Ki-67 expression greater than 20% and can be either well differentiated (G3 NET) or poorly differentiated (G3 NEC). Neuroendocrine carcinoma (NEC G3) is subdivided into small-cell and large-cell types. When neuroendocrine tumors present clinical and compressive symptoms, carcinoid syndrome is evident. Carcinoid syndrome occurs when the tumor produces neuroendocrine mediators that cannot be metabolized by the liver due to either the size of the tumor or their secretion by the liver itself. Several therapeutic strategies have been described for the treatment of metastatic neuroendocrine tumors, including curative or palliative surgical approaches, peptide receptor radionuclide therapy, percutaneous therapy, systemic chemotherapy, and radiotherapy. Liver surgery is the only approach that can offer a cure for metastatic patients. Liver metastases must be completely resected, and in this context, orthotopic liver transplantation has gained prominence for yielding very promising outcomes in selected cases. The aim of this study is to review the literature on OLT as a form of treatment with curative intent for patients with gastroenteropancreatic neuroendocrine tumors with liver metastasis.
Marked paper: Type 2 diabetes mellitus indicates increased postoperative complications and poor prognosis in colorectal cancer patients receiving curative surgery
Authors: Liu Daoli , Zhang Xubing , Zhou Hong , Zhu Zhiqiang , He Yiren , Wan Xiao , Zhang Bo , Liu Shaojun , Liu Liu
Published: February 2023

Purpose

This study aimed to evaluate the impact of type 2 diabetes mellitus (T2DM) on the short-term outcomes and long-term survival of patients with colorectal cancer (CRC) who underwent curative resection.

Methods

This study retrospectively included 136 patients (T2DM group) with resectable CRC and T2DM from Jan 2013 to Dec 2017. Propensity score-matched control group consisting of 136 patients (non-T2DM group) were selected from 1143 CRC patients without T2DM. The short-term outcomes and prognosis were compared between the T2DM and non-T2DM group.

Results

A total of 272 patients (136 patients for each group) were included in this study. Patients in T2DM group had higher body mass index (BMI), higher proportion of hypertension and cerebrovascular diseases (P<0.05). T2DM group had more overall complications (P=0.001), more major complications (P=0.003) and higher risk of reoperation (P=0.007) when compared with non-T2DM patients. T2DM patients had longer hospitalization time than non-T2DM (20.7 ± 10.2 vs. 17.5 ± 6.2, P=0.002). As for the prognosis, T2DM patients had worse 5-year overall survival (OS) (P=0.024) and 5-year disease-free survival (DFS) (P=0.019) in all stage. Moreover, T2DM and TNM stage were the independent predictors of OS and DFS for CRC patients.

Conclusions

T2DM increases overall complications and major complications, and prolongs the hospitalization time after CRC surgery. In addition, T2DM indicates the poor prognosis of CRC patients. A prospective study with large sample size is required to confirm our findings.
Clinical features and gene variation analysis of COQ8B nephropathy: Report of seven cases
Authors: Liang Rui , Chen Xuelan , Zhang Ying , Law Chak-Fun , Yu Sijie , Jiao Jia , Yang Qin , Wu Daoqi , Zhang Gaofu , Chen Han , Wang Mo , Yang Haiping , Wang Anshuo
Published: February 2023

Objective

COQ8B nephropathy is a relatively rare autosomal recessive kidney disease characterized by proteinuria and a progressive deterioration of renal function, eventually leading to end-stage renal disease (ESRD). The objective is to study the characteristics and correlation between the genotype and the clinical phenotype of COQ8B nephropathy.

Methods

This is a retrospective study focusing on the clinical characteristics of seven COQ8B nephropathy patients diagnosed by gene sequencing. Basic clinical information, clinical manifestations, examinations, imaging, genomes, pathology, treatments, and prognosis of the patients were reviewed.

Results

Of the seven patients, two were male children and five were female children. The median age at the disease onset was 5 years and 3 months. The initial main clinical manifestations were proteinuria and renal insufficiency. Four patients had severe proteinuria, four had focal segmental glomerulosclerosis (FSGS) diagnosed by a renal biopsy, and two had nephrocalcinosis after an ultrasound was performed on them. There were no other clinical manifestations such as neuropathy, muscle atrophy, and so on in all of them. Their gene mutations were all exon variants, which were classified as heterozygous or homozygous variants by performing family verification analysis. Compound heterozygous variants were predominant in all, and all gene variants were inherited from their parents. One novel mutation, c.1465c>t, was found in this study. This gene mutation resulted from changes in the amino acid sequence, thus leading to an abnormal protein structure. Two patients with early diagnosis of COQ8B nephropathy presented with no renal insufficiency and were treated with oral coenzyme Q10 (CoQ10), and they maintained normal renal function. For the remaining five who were treated with CoQ10 following renal insufficiency, the deterioration of renal function could not be reversed, and they progressed to ESRD within a short time (median time: 7 months). A follow-up of these patients showed normal renal function with a CoQ10 supplement.

Conclusion

For unexplained proteinuria, renal insufficiency, or steroid-resistant nephrotic syndrome, gene sequencing should be considered, in addition to renal biopsy, as early as possible. Timely diagnosis of COQ8B nephropathy and early supplementation of sufficient CoQ10 can help control the progression of the disease and significantly improve the prognosis.
Mechanism of action of non-coding RNAs and traditional Chinese medicine in myocardial fibrosis: Focus on the TGF-β/Smad signaling pathway
Authors: Li Chunjun , Meng Xiangxiang , Wang Lina , Dai Xia
Published: February 2023

Cardiac fibrosis is a serious public health problem worldwide that is closely linked to progression of many cardiovascular diseases (CVDs) and adversely affects both the disease process and clinical prognosis. Numerous studies have shown that the TGF-β/Smad signaling pathway plays a key role in the progression of cardiac fibrosis. Therefore, targeted inhibition of the TGF-β/Smad signaling pathway may be a therapeutic measure for cardiac fibrosis. Currently, as the investigation on non-coding RNAs (ncRNAs) move forward, a variety of ncRNAs targeting TGF-β and its downstream Smad proteins have attracted high attention. Besides, Traditional Chinese Medicine (TCM) has been widely used in treating the cardiac fibrosis. As more and more molecular mechanisms of natural products, herbal formulas, and proprietary Chinese medicines are revealed, TCM has been proven to act on cardiac fibrosis by modulating multiple targets and signaling pathways, especially the TGF-β/Smad. Therefore, this work summarizes the roles of TGF-β/Smad classical and non-classical signaling pathways in the cardiac fibrosis, and discusses the recent research advances in ncRNAs targeting the TGF-β/Smad signaling pathway and TCM against cardiac fibrosis. It is hoped, in this way, to give new insights into the prevention and treatment of cardiac fibrosis.
Parthenium hysterophorus alleviates wilt stress in tomato plants caused by Ralstonia solanacearum through direct antibacterial effect and indirect upregulation of host resistance
Authors: Najeeb Saba , Li Yan
Published: February 2023

Heavy damage to tomato crops due to wilt stress caused by the pathogenic bacterium Ralstonia solanacearum and the insufficient availability of management strategies with desired control levels urged the researchers to investigate more reliable control methods to manage this issue in tomato and other horticultural crops. In this study, Parthenium hysterophorus, a locally and freely available herbaceous plant, was successfully used to manage bacterial wilt of tomatoes. The significant growth reduction ability of P. hysterophorus leaf extract was recorded in an agar well diffusion test and its ability to severally damage the bacterial cells was confirmed in SEM analysis. In both greenhouse and field trials, soil amended with P. hysterophorus leaf powder at 25 g/kg soil was found to effectively suppress the pathogen population in soil and significantly reduce the wilt severity on tomato plants, resulting in increased growth and yield of tomato plants. P. hysterophorus leaf powder at concentrations greater than 25 g/kg soil caused phytotoxicity in tomato plants. The results showed that P. hysterophorus powder applied through the mixing of soil for a longer period of time before transplanting tomato plants was more effective than mulching application and a shorter period of transplantation. Finally, the indirect effect of P. hysterophorus powder in managing bacterial wilt stress was evaluated using expression analysis of two resistance-related genes, PR2 and TPX. The upregulation of these two resistance-related genes was recorded by the soil application of P. hysterophorus powder. The findings of this study revealed the direct and indirect action mechanisms of P. hysterophorus powder applied to the soil for the management of bacterial wilting stress in tomato plants and provided the basis for including this technique as a safe and effective management strategy in an integrated disease management package.