bluuebunny/crossref_metadata_2025 huggingface dataset:
Permafrost Active Layer Microbes From Ny Ålesund, Svalbard (79°N) Show Autotrophic and Heterotrophic Metabolisms With Diverse Carbon-Degrading Enzymes
Authors: Sipes Katie , Paul Raegan , Fine Aubrey , Li Peibo , Liang Renxing , Boike Julia , Onstott Tullis C. , Vishnivetskaya Tatiana A. , Schaeffer Sean , Lloyd Karen G.
Published: February 2022

The active layer of permafrost in Ny Ålesund, Svalbard (79°N) around the Bayelva River in the Leirhaugen glacier moraine is measured as a small net carbon sink at the brink of becoming a carbon source. In many permafrost-dominating ecosystems, microbes in the active layers have been shown to drive organic matter degradation and greenhouse gas production, creating positive feedback on climate change. However, the microbial metabolisms linking the environmental geochemical processes and the populations that perform them have not been fully characterized. In this paper, we present geochemical, enzymatic, and isotopic data paired with 10 Pseudomonas sp. cultures and metagenomic libraries of two active layer soil cores (BPF1 and BPF2) from Ny Ålesund, Svalbard, (79°N). Relative to BPF1, BPF2 had statistically higher C/N ratios (15 ± 1 for BPF1 vs. 29 ± 10 for BPF2; n = 30, p < 10–5), statistically lower organic carbon (2% ± 0.6% for BPF1 vs. 1.6% ± 0.4% for BPF2, p < 0.02), statistically lower nitrogen (0.1% ± 0.03% for BPF1 vs. 0.07% ± 0.02% for BPF2, p < 10–6). The d13C values for inorganic carbon did not correlate with those of organic carbon in BPF2, suggesting lower heterotrophic respiration. An increase in the δ13C of inorganic carbon with depth either reflects an autotrophic signal or mixing between a heterotrophic source at the surface and a lithotrophic source at depth. Potential enzyme activity of xylosidase and N-acetyl-β-D-glucosaminidase increases twofold at 15°C, relative to 25°C, indicating cold adaptation in the cultures and bulk soil. Potential enzyme activity of leucine aminopeptidase across soils and cultures was two orders of magnitude higher than other tested enzymes, implying that organisms use leucine as a nitrogen and carbon source in this nutrient-limited environment. Besides demonstrating large variability in carbon compositions of permafrost active layer soils only ∼84 m apart, results suggest that the Svalbard active layer microbes are often limited by organic carbon or nitrogen availability and have adaptations to the current environment, and metabolic flexibility to adapt to the warming climate.
Insights Into the Coinfections of Human Immunodeficiency Virus-Hepatitis B Virus, Human Immunodeficiency Virus-Hepatitis C Virus, and Hepatitis B Virus-Hepatitis C Virus: Prevalence, Risk Factors, Pathogenesis, Diagnosis, and Treatment
Authors: Shahriar Sagarika , Araf Yusha , Ahmad Rasel , Kattel Pravakar , Sah Ganga Sagar , Rahaman Tanjim Ishraq , Sadiea Rahila Zannat , Sultana Shahnaj , Islam Md. Sayeedul , Zheng Chunfu , Hossain Md. Golzar
Published: February 2022

Human immunodeficiency virus, hepatitis B virus, and hepatitis C virus are three blood-borne viruses that can cause major global health issues by increasing severe morbidity. There is a high risk of coinfection with these viruses in individuals because of their same transmission routes through blood using shared needles, syringes, other injection equipment, sexual transmission, or even vertical transmission. Coinfection can cause various liver-related illnesses, non-hepatic organ dysfunction, followed by death compared to any of these single infections. The treatment of coinfected patients is complicated due to the side effects of antiviral medication, resulting in drug resistance, hepatotoxicity, and a lack of required responses. On the other hand, coinfected individuals must be treated with multiple drugs simultaneously, such as for HIV either along with HBV or HCV and HBV and HCV. Therefore, diagnosing, treating, and controlling dual infections with HIV, HBV, or HCV is complicated and needs further investigation. This review focuses on the current prevalence, risk factors, and pathogenesis of dual infections with HIV, HBV, and HCV. We also briefly overviewed the diagnosis and treatment of coinfections of these three blood-borne viruses.
Armillaria mellea Symbiosis Drives Metabolomic and Transcriptomic Changes in Polyporus umbellatus Sclerotia
Authors: Xing Yong-Mei , Li Bing , Liu Liu , Li Yang , Yin Shu-Xue , Yin Shu-Chao , Chen Juan , Guo Shun-Xing
Published: February 2022

Sclerotia, the medicinal part of Polyporus umbellatus, play important roles in diuresis and renal protection, with steroids and polysaccharides as the main active ingredients. The sclerotia grow and develop only after symbiosis with Armillaria sp. In this study, a systematic metabolomics based on non-targeted UPLC-MS method was carried out between the infected part of the separated cavity wall of the sclerotia (QR) and the uninfected part (the control group, CK) to find and identify differential metabolites. The biosynthetic pathway of characteristic steroids in sclerotia of P. umbellatus was deduced and the content of ergosterol, polyporusterone A and B in the QR and CK groups were detected with the High Performance Liquid Chromatography (HPLC). Furthermore, the expression patterns of putative genes associated with steroid biosynthesis pathway were also performed with quantitative real-time PCR. The results showed that a total of 258 metabolites originated from fungi with the fragmentation score more than 45 and high resolution mass were identified, based on UPLC-MS metabolomic analysis, and there were 118 differentially expressed metabolites (DEMs) between both groups. The metabolic pathways indicated that steroids, fatty acid and carbohydrate were active and enriched during P. umbellatus sclerotia infected by A. mellea. The content of ergosterol, polyporusterone A and B in the QR group increased by 32.2, 75.0, and 20.0%, in comparison to that of the control group. The qRT-PCR analysis showed that series of enzymes including C-8 sterol isomerase (ERG2), sterol C-24 methyltransferase (ERG6) and sterol 22-desaturase (ERG5), which played important roles in the final steps of ergosterol biosynthesis, all presented up-regulated patterns in the QR group in P. umbellatus. The comprehensive metabolomic and transcriptomic information will contribute to further study concerning the mechanisms of P. umbellatus sclerotial formation infected by A. mellea in the future.
Characteristics of the Gut Microbiome and Its Relationship With Peripheral CD4+ T Cell Subpopulations and Cytokines in Rheumatoid Arthritis
Authors: Wang Qi , Zhang Sheng-Xiao , Chang Min-Jing , Qiao Jun , Wang Cai-Hong , Li Xiao-Feng , Yu Qi , He Pei-Feng
Published: February 2022

This study investigated the association between intestinal microbiota abundance and diversity and cluster of differentiation (CD)4+ T cell subpopulations, cytokine levels, and disease activity in rheumatoid arthritis RA. A total of 108 rheumatoid arthritis (RA) patients and 99 healthy control (HC) subjects were recruited. PICRUSt2 was used for functional metagenomic predictions. Absolute counts of peripheral CD4+ T cell subpopulations and cytokine levels were detected by flow cytometry and with a cytokine bead array, respectively. Correlations were analyzed with the Spearman rank correlation test. The results showed that the diversity of intestinal microbiota was decreased in RA patients compared to HCs. At the phylum level, the abundance of Firmicutes, Fusobacteriota, and Bacteroidota was decreased while that of Actinobacteria and Proteobacteria was increased and at the genus level, the abundance of Faecalibacterium, Blautia, and Escherichia-Shigella was increased while that of Bacteroides and Coprococcus was decreased in RA patients compared to HC subjects. The linear discriminant analysis effect size indicated that Bifidobacterium was the most significant genus in RA. The most highly enriched Kyoto Encyclopedia of Genes and Genomes pathway in RA patients was amino acid metabolism. The relative abundance of Megamonas, Monoglobus, and Prevotella was positively correlated with CD4+ T cell counts and cytokine levels; and the relative numbers of regulatory T cells (Tregs) and T helper (Th17)/Treg ratio were negatively correlated with disease activity in RA. These results suggest that dysbiosis of certain bacterial lineages and alterations in gut microbiota metabolism lead to changes in the host immune profile that contribute to RA pathogenesis.
Metagenomics Versus Metatranscriptomics of the Murine Gut Microbiome for Assessing Microbial Metabolism During Inflammation
Authors: Jovel Juan , Nimaga Aissata , Jordan Tracy , O’Keefe Sandra , Patterson Jordan , Thiesen Aducio , Hotte Naomi , Bording-Jorgensen Michael , Subedi Sudip , Hamilton Jessica , Carpenter Eric J. , Lauga Béatrice , Elahi Shokrollah , Madsen Karen L. , Wong Gane Ka-Shu , Mason Andrew L.
Published: February 2022

Shotgun metagenomics studies have improved our understanding of microbial population dynamics and have revealed significant contributions of microbes to gut homeostasis. They also allow in silico inference of the metagenome. While they link the microbiome with metabolic abnormalities associated with disease phenotypes, they do not capture microbial gene expression patterns that occur in response to the multitude of stimuli that constantly ambush the gut environment. Metatranscriptomics closes that gap, but its implementation is more expensive and tedious. We assessed the metabolic perturbations associated with gut inflammation using shotgun metagenomics and metatranscriptomics. Shotgun metagenomics detected changes in abundance of bacterial taxa known to be SCFA producers, which favors gut homeostasis. Bacteria in the phylum Firmicutes were found at decreased abundance, while those in phyla Bacteroidetes and Proteobacteria were found at increased abundance. Surprisingly, inferring the coding capacity of the microbiome from shotgun metagenomics data did not result in any statistically significant difference, suggesting functional redundancy in the microbiome or poor resolution of shotgun metagenomics data to profile bacterial pathways, especially when sequencing is not very deep. Obviously, the ability of metatranscriptomics libraries to detect transcripts expressed at basal (or simply low) levels is also dependent on sequencing depth. Nevertheless, metatranscriptomics informed about contrasting roles of bacteria during inflammation. Functions involved in nutrient transport, immune suppression and regulation of tissue damage were dramatically upregulated, perhaps contributed by homeostasis-promoting bacteria. Functions ostensibly increasing bacteria pathogenesis were also found upregulated, perhaps as a consequence of increased abundance of Proteobacteria. Bacterial protein synthesis appeared downregulated. In summary, shotgun metagenomics was useful to profile bacterial population composition and taxa relative abundance, but did not inform about differential gene content associated with inflammation. Metatranscriptomics was more robust for capturing bacterial metabolism in real time. Although both approaches are complementary, it is often not possible to apply them in parallel. We hope our data will help researchers to decide which approach is more appropriate for the study of different aspects of the microbiome.
Comprehensive Analysis of the Prognostic and Immunological Role of PAFAH1B in Pan-Cancer
Authors: Yuan Yixiao , Jiang Xiulin , Tang Lin , Wang Juan , Duan Lincan
Published: February 2022

Platelet-activating factor acetylhydrolase 1B3 (PAFAH1B3) plays a critical role in cancer initiation, metastasis, and progression; however, it remains unknown how PAFAH1B3 impacts cancer diagnosis and prognosis or regulates the immune response to different types of cancer. In this study, PAFAH1B3 was elevated in human pan-cancer, and this correlated with greater pathology and poor prognosis, in particular for non-small cell lung cancer (NSCLC) and liver hepatocellular carcinoma (LIHC). In addition, PAFAH1B3 expression was positively associated with tumor mutational burden (TMB), microsatellite instability (MSI), immune cell infiltration, immune-modulatory related gene expression, and diverse cancer drug sensitivity in human cancer. Increased PAFAH1B3 expression correlated with poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) of NSCLC and LIHC, and has potential as an independent risk factor for overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) during LIHC. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis confirmed that PAFAH1B3 is primarily involved in immune regulation. More importantly, results demonstrated that PAFAH1B3 was upregulated in liver cancer cells lines and that knockdown of this gene significantly inhibited cell proliferation, migration, and invasion in liver hepatocellular carcinoma (LIHC). In summary, this study elucidates the clinical significance and biological function of PAFAH1B3 during liver hepatocellular carcinoma (LIHC) and may serve as a potential biomarker for the diagnosis and prognosis of various cancer types.
Aquaglyceroporin Modulators as Emergent Pharmacological Molecules for Human Diseases
Authors: Pimpão Catarina , Wragg Darren , da Silva Inês V. , Casini Angela , Soveral Graça
Published: February 2022

Aquaglyceroporins, a sub-class of aquaporins that facilitate the diffusion of water, glycerol and other small uncharged solutes across cell membranes, have been recognized for their important role in human physiology and their involvement in multiple disorders, mostly related to disturbed energy homeostasis. Aquaglyceroporins dysfunction in a variety of pathological conditions highlighted their targeting as novel therapeutic strategies, boosting the search for potent and selective modulators with pharmacological properties. The identification of selective inhibitors with potential clinical applications has been challenging, relying on accurate assays to measure membrane glycerol permeability and validate effective functional blockers. Additionally, biologicals such as hormones and natural compounds have been revealed as alternative strategies to modulate aquaglyceroporins via their gene and protein expression. This review summarizes the current knowledge of aquaglyceroporins’ involvement in several pathologies and the experimental approaches used to evaluate glycerol permeability and aquaglyceroporin modulation. In addition, we provide an update on aquaglyceroporins modulators reported to impact disease, unveiling aquaglyceroporin pharmacological targeting as a promising approach for innovative therapeutics.
Genetic Algorithms for Optimized Diagnosis of Alzheimer’s Disease and Frontotemporal Dementia Using Fluorodeoxyglucose Positron Emission Tomography Imaging
Authors: Díaz-Álvarez Josefa , Matias-Guiu Jordi A. , Cabrera-Martín María Nieves , Pytel Vanesa , Segovia-Ríos Ignacio , García-Gutiérrez Fernando , Hernández-Lorenzo Laura , Matias-Guiu Jorge , Carreras José Luis , Ayala José L. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: February 2022

Genetic algorithms have a proven capability to explore a large space of solutions, and deal with very large numbers of input features. We hypothesized that the application of these algorithms to 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) may help in diagnosis of Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD) by selecting the most meaningful features and automating diagnosis. We aimed to develop algorithms for the three main issues in the diagnosis: discrimination between patients with AD or FTD and healthy controls (HC), differential diagnosis between behavioral FTD (bvFTD) and AD, and differential diagnosis between primary progressive aphasia (PPA) variants. Genetic algorithms, customized with K-Nearest Neighbor and BayesNet Naives as the fitness function, were developed and compared with Principal Component Analysis (PCA). K-fold cross validation within the same sample and external validation with ADNI-3 samples were performed. External validation was performed for the algorithms distinguishing AD and HC. Our study supports the use of FDG-PET imaging, which allowed a very high accuracy rate for the diagnosis of AD, FTD, and related disorders. Genetic algorithms identified the most meaningful features with the minimum set of features, which may be relevant for automated assessment of brain FDG-PET images. Overall, our study contributes to the development of an automated, and optimized diagnosis of neurodegenerative disorders using brain metabolism.
Erythrocytic α-Synuclein Species for Parkinson’s Disease Diagnosis and the Correlations With Clinical Characteristics
Authors: Yu Zhenwei , Liu Genliang , Li Yang , Arkin Ehsan , Zheng Yuanchu , Feng Tao
Published: February 2022

Background

Erythrocytes contain most of the peripheral α-synuclein (α-syn), which is the key pathological molecular of α-synucleinopathies including Parkinson’s disease (PD). Our objectives were to assess the efficiency of erythrocytic total and oligomeric α-syn levels as PD diagnostic biomarkers, and to identify the correlations between erythrocytic α-syn levels and physiological/psychiatrical assessment scales.

Methods

Home-brewed electrochemiluminescence assays were applied to assess the concentrations of erythrocytic total and oligomeric α-syn levels in a cohort including 124 patients with PD and 79 healthy controls (HCs). The correlations between erythrocytic α-syn levels and clinical measurements were assessed using Spearman’s rank test.

Results

Both the erythrocytic total and oligomeric α-syn levels were significantly higher in PD patients than HCs. The biomarkers adjusted for age and sex discriminated PDs from HCs well with 80% sensitivity, 89% specificity and 79% sensitivity, 83% specificity, respectively. Combining erythrocytic total and oligomeric α-syn levels by using binary logistic regression analysis with the controlling of age and sex generated a factor discriminates PDs from HCs with 88% sensitivity and 85% specificity. The erythrocytic total but not oligomeric α-syn levels adjusted for age and sex significantly correlated with anxiety scales and the MDS-UPDRS III scales in PD patients, respectively.

Conclusion

We showed the usefulness of erythrocytic total and oligomeric α-syn levels as biomarkers for PD. Our results also suggest the capability of erythrocytic α-syn as a potential pathological factor and therapeutic target for psychiatric symptoms in PD patients.
GWLS: A Novel Model for Predicting Cognitive Function Scores in Patients With End-Stage Renal Disease
Authors: Zhang Yutao , Xi Zhengtao , Zheng Jiahui , Shi Haifeng , Jiao Zhuqing
Published: February 2022

The scores of the cognitive function of patients with end-stage renal disease (ESRD) are highly subjective, which tend to affect the results of clinical diagnosis. To overcome this issue, we proposed a novel model to explore the relationship between functional magnetic resonance imaging (fMRI) data and clinical scores, thereby predicting cognitive function scores of patients with ESRD. The model incorporated three parts, namely, graph theoretic algorithm (GTA), whale optimization algorithm (WOA), and least squares support vector regression machine (LSSVRM). It was called GTA-WOA-LSSVRM or GWLS for short. GTA was adopted to calculate the area under the curve (AUC) of topological parameters, which were extracted as the features from the functional networks of the brain. Then, the statistical method and Pearson correlation analysis were used to select the features. Finally, the LSSVRM was built according to the selected features to predict the cognitive function scores of patients with ESRD. Besides, WOA was introduced to optimize the parameters in the LSSVRM kernel function to improve the prediction accuracy. The results validated that the prediction accuracy obtained by GTA-WOA-LSSVRM was higher than several comparable models, such as GTA-SVRM, GTA-LSSVRM, and GTA-WOA-SVRM. In particular, the root mean square error (RMSE), mean absolute error (MAE), and mean absolute percentage error (MAPE) between the predicted scores and the actual scores of patients with ESRD were 0.92, 0.88, and 4.14%, respectively. The proposed method can more accurately predict the cognitive function scores of ESRD patients and thus helps to understand the pathophysiological mechanism of cognitive dysfunction associated with ESRD.
Daily Remote Ischemic Conditioning Can Improve Cerebral Perfusion and Slow Arterial Progression of Adult Moyamoya Disease—A Randomized Controlled Study
Authors: Xu Jiali , Zhang Qian , Rajah Gary B. , Zhao Wenbo , Wu Fang , Ding Yuchuan , Zhang Bowei , Guo Wenting , Yang Qi , Xing Xiurong , Li Sijie , Ji Xunming
Published: February 2022

Background and Purpose

Moyamoya disease (MMD) is a complicated cerebrovascular disease with recurrent ischemic or hemorrhagic events. This study aimed to prove the safety and efficacy of remote ischemic conditioning (RIC) on MMD.

Methods

In total, 34 patients with MMD participated in this pilot, prospective randomized controlled study for 1 year. 18 patients were allocated into the RIC group, and 16 patients accepted routine medical treatment only. RIC-related adverse events were recorded. The primary outcome was the improvement ratio of mean cerebral blood flow (mCBF) in middle cerebral artery territory measured by multidelay pseudocontinuous arterial spin labeling, and the secondary outcomes were the cumulative incidence of major adverse cerebrovascular events (MACEs), the prevalence of stenotic-occlusive progression, and periventricular anastomosis at 1-year follow-up.

Results

In total, 30 of the 34 patients with MMD completed the final follow-up (17 in the RIC group and 13 in the control group). No adverse events of RIC were observed. The mCBF improvement ratio of the RIC group was distinctively higher compared with the control group (mCBF−whole-brain: 0.16 ± 0.15 vs. −0.03 ± 0.13, p = 0.001). Stenotic-occlusive progression occurred in 11.8% hemispheres in the RIC group and 38.5% in the control group (p = 0.021). The incidence of MACE was 5.9% in the RIC group and 30.8% in the control group (hazard ratio with RIC, 0.174; 95% CI, 0.019–1.557; p = 0.118). No statistical difference was documented in the periventricular anastomosis between the two groups after treatment.

Conclusions

Remote ischemic conditioning has the potential to be a safe and effective adjunctive therapy for patients with MMD largely due to improving cerebral blood flow and slowing the arterial progression of the stenotic-occlusive lesions. These findings warrant future studies in larger trials.
Tissue-Resident Macrophages in the Stria Vascularis
Authors: Ito Taku , Kurata Natsuko , Fukunaga Yoko
Published: February 2022

Tissue-resident macrophages play an important role in clearance, development, and regulation of metabolism. They also function as sentinel immune cells, initiating inflammatory responses, clearing inflammatory debris, and maintaining homeostatic tissue environment. In the cochlea, the roles of tissue-resident macrophages include maintaining steady-state tissues, immunological defense, and repairing pathological conditions associated with noise, ototoxic drugs, aging, and various pathogens. Perivascular macrophages (PVMs) are a unique subset of tissue-resident macrophages that are closely associated with blood vessels and have unique expression markers in certain tissues. PVMs are found in the inner ear, brain, skin, liver, and retina. The origin of PVMs in the inner ear is unclear, but they are already present during embryonic development. PVMs are members of the blood labyrinth barrier and regulate blood vessel permeability in the stria vascularis, which lies on the lateral wall of the cochlear duct and is crucial for endocochlear potential formation. The cytoplasm of strial PVMs can contain pigment granules that increase in number with age. Strial PVMs are activated by the loss of Slc26a4 in the cochleae, and they subsequently phagocytose aggregated pigment granules and possibly degenerated intermediate cells. This review summarizes the current knowledge of characteristic features and proposed roles of PVMs in the stria vascularis. We also address macrophage activation and involvement of pigment granules with the loss of Slc26a4 in the cochleae.
Disruption of KCC2 in Parvalbumin-Positive Interneurons Is Associated With a Decreased Seizure Threshold and a Progressive Loss of Parvalbumin-Positive Interneurons
Authors: Herrmann Tanja , Gerth Melanie , Dittmann Ralf , Pensold Daniel , Ungelenk Martin , Liebmann Lutz , Hübner Christian A.
Published: February 2022

GABAA receptors are ligand-gated ion channels, which are predominantly permeable for chloride. The neuronal K-Cl cotransporter KCC2 lowers the intraneuronal chloride concentration and thus plays an important role for GABA signaling. KCC2 loss-of-function is associated with seizures and epilepsy. Here, we show that KCC2 is expressed in the majority of parvalbumin-positive interneurons (PV-INs) of the mouse brain. PV-INs receive excitatory input from principle cells and in turn control principle cell activity by perisomatic inhibition and inhibitory input from other interneurons. Upon Cre-mediated disruption of KCC2 in mice, the polarity of the GABA response of PV-INs changed from hyperpolarization to depolarization for the majority of PV-INs. Reduced excitatory postsynaptic potential-spike (E-S) coupling and increased spontaneous inhibitory postsynaptic current (sIPSC) frequencies further suggest that PV-INs are disinhibited upon disruption of KCC2. In vivo, PV-IN-specific KCC2 knockout mice display a reduced seizure threshold and develop spontaneous sometimes fatal seizures. We further found a time dependent loss of PV-INs, which was preceded by an up-regulation of pro-apoptotic genes upon disruption of KCC2.
MicroRNA miR-155 Activity in Mouse Choline Acetyltransferase-Positive Neurons Is Critical for the Rate of Early and Late Paraplegia After Transient Aortic Cross-Clamping
Authors: Kelani Hesham , Nuovo Gerard , Bratasz Anna , Rajan Jayanth , Efanov Alexander A. , Michaille Jean-Jacques , Awad Hamdy , Tili Esmerina
Published: February 2022

Aortic aneurism open repair surgery can cause spinal cord (SC) injury with 5–15% of patients developing paraparesis or paraplegia. Using a mouse model of transient aortic cross-clamping (ACC), we have previously found that the expression of proinflammatory microRNA miR-155 increases in motoneurons (MNs) and endothelial cells (ECs) of ischemic SCs, and that global miR-155 deletion decreases the percentage of paraplegia by 37.4% at 48-h post-ACC. Here, we investigated the cell-specific contribution of miR-155 in choline acetyltransferase-positive (ChAT+) neurons (that include all MNs of the SC) and ECs to SC injury after ACC. Mice lacking miR-155 in ChAT+ neurons (MN-miR-155-KO mice) developed 24.6% less paraplegia than control mice at 48-h post-ACC. In contrast, mice lacking miR-155 in ECs (ECs-miR-155-KO mice) experienced the same percentage of paraplegia as control mice, despite presenting smaller central cord edema. Unexpectedly, mice overexpressing miR-155 in ChAT+ neurons were less likely than control mice to develop early paraplegia during the first day post-ACC, however they reached the same percentage of paraplegia at 48-h. In addition, all mice overexpressing miR-155 in ECs (ECs-miR-155-KI mice) were paraplegic at 48-h post-ACC. Altogether, our results suggest that miR-155 activity in ChAT+ neurons protects the SC against ischemic injury during the first day post-ACC before becoming deleterious during the second day, which indicates that early and late paraplegias arise from different molecular malfunctions. These results point to the need to develop specific protective therapeutics aimed at inhibiting both the early and late deleterious events after open repair surgery of aortic aneurisms.
Prevention of Oxaliplatin-Induced Peripheral Neuropathy: A Systematic Review and Meta-Analysis
Authors: Peng Siyu , Ying Ariel Fangting , Chan Nicholas Jian Hao , Sundar Raghav , Soon Yu Yang , Bandla Aishwarya
Published: February 2022

Background

Oxaliplatin-induced peripheral neuropathy (OIPN) has significant clinical impact on the quality of life for cancer patients and is a dose limiting toxicity. Trials studying preventive measures have been inconclusive. A systematic review and meta-analysis were conducted to evaluate the existing pharmacological and non-pharmacological interventions to prevent chronic OIPN.

Methods

Literature databases PubMed-MEDLINE, Embase and Scopus, were searched from 1 Jan 2005 to 08 Aug 2020 and major conferences’ abstracts were reviewed for randomized controlled trials that examined the efficacy of any preventive measure for OIPN. The primary outcome measure was the incidence of chronic OIPN with a preventive intervention as compared to placebo or no intervention. The pooled risk ratio and its 95% confidence interval were calculated using a random effects model. A network meta-analysis was conducted to derive indirect evidence of any preventive effect of an intervention against placebo when original trials compared one intervention against another.

Results

Forty-four trials were analyzed describing 29 chemoprotective interventions, including combinations, and 1 non-pharmacological intervention. Ratings were assessed via a combination of outcomes with quality assessment using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Of the 30 interventions examined, there were six interventions supporting potential efficacy, 11 interventions with insufficient evidence and 13 interventions not recommended.

Conclusion

Currently, there is insufficient certainty to support any intervention as effective in preventing OIPN. Of note is that most of these studies have focused on pharmacological interventions; non-pharmacological interventions are underexplored. Further research on ways to limit OIPN is needed.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=225095, Prospero Registration Number: CRD42021225095.
Development and Validation of a Prognostic Nomogram for Predicting Cancer-Specific Survival in Patients With Lymph Node Positive Bladder Cancer: A Study Based on SEER Database
Authors: Zhan Xiangpeng , Jiang Ming , Deng Wen , Liu Xiaoqiang , Chen Luyao , Fu Bin
Published: February 2022

Purpose

To construct a prognostic model to predict the cancer-specific survival (CSS) for bladder cancer patients with lymph node-positive.

Patients and Methods

We enrolled 2,050 patients diagnosed with lymph node-positive bladder cancer from the Surveillance Epidemiology and End Results (SEER) database (2004–2015). All patients were randomly split into development cohort (n = 1,438) and validation cohort (n = 612) at a ratio of 7:3. The univariate and multivariate Cox regression analysis were performed to identify prognostic factors. A nomogram predicting CSS was established based on the results of multivariate Cox analysis. Its performance was evaluated by calibration curves, the receiver operating characteristic (ROC) curves, and the concordance index (C-index). Internal verification was performed in the validation cohort. The Kaplan–Meier method with the log-rank test was applied in the different risk groups.

Results

The nomogram incorporated summary stage, tumor size, chemotherapy, regional nodes examined and positive lymph nodes. The C-index of the nomogram in the development cohort was 0.716 (0.707–0.725), while the value of the C-index was 0.691 (0.689–0.693) in the validation cohort. The AUC of the nomogram was 0.803 for 3-year and 0.854 for 5-year in the development cohort, while was 0.773 for 3-year and 0.809 for 5-year in the validation cohort. Calibration plots for 3-year and 5-year CSS showed good concordance. Significant differences were observed between high, medium, and low risk groups (P <0.001).

Conclusions

We have established a prognostic nomogram providing an accurate individualized probability of cancer-specific survival in bladder cancer patients with lymph node-positive. The nomogram could contribute to patient counseling, follow-up scheduling, and selection of treatment.
18F-DCFPyL PET/CT in Newly Diagnosed Prostate Cancer: Diagnostic Value of Intraprostatic PSMA Uptake in Risk Classification of Prostate Cancer
Authors: Zhou Shuoming , Liu Tiantian , Zhu Ziqiang , Zhang Lin , Qian Subo , Fu Hongliang , Cao Qifeng , Kang Jian
Published: February 2022

Purpose

18F-DCFPyL prostate-specific membrane antigen (PSMA) PET/CT is commonly applied to locate lesions of prostate cancer (PCa), but its diagnostic function of quantitative parameters is ignored. Our study evaluates the parameters of intraprostatic PSMA uptake in patients newly diagnosed with PCa and explores their predictive value in risk classification, which is similar to D’Amico criteria.

Materials and Methods

We quantified the maximal standardized uptake value (SUVmax), mean SUV (SUVmean), total lesion (TL)-PSMA, prostate/muscle (P/M) ratio of the primary tumor, and PSMA-derived tumor volume (PSMA-TV) from 62 patients with histologically proven PCa. Patients newly diagnosed with PCa were allocated into risk groups (at low, intermediate, and high risk, respectively) in accordance with D’Amico criteria. Afterwards, the five parameters mentioned above among three different risk groups were compared, and their predictive values in the risk classification of PCa were explored.

Results

Significantly decreased levels of SUVmax, SUVmean, TL-PSMA, and P/M ratio were observed in the risk groups of low or intermediate or both, compared with the high-risk group. However, only the P/M ratio significantly elevated in patients with intermediate risk [mean ± SD (median): 46.58 ± 9.74 (45.27), P = 0.042] or high risk [98.95 ± 38.83 (97.52), P < 0.001], compared with low-risk patients [12.33 ± 5.93 (9.81)]. When P/M ratio was used to distinguish between low-risk and intermediate-risk patients, its c-statistics was 0.660. On the other hand, when distinguishing between intermediate-risk and high-risk groups, the c-statistics of P/M ratio was 0.667. Finally, when P/M ratio was used to distinguish between low-risk and high-risk patients, the c-statistics was 0.969. P/M ratio had a positive correlation with prostate-specific antigen in all enrolled PCa patients.

Conclusion

The quantitative parameters of 18F-DCFPyL PET/CT, including SUVmax, SUVmean, and P/M ratio, might assist in distinguishing low-risk or intermediate-risk groups from the high-risk group. Of these parameters, P/M ratio appears to be the better promising parameter for risk classification of prostate cancer than SUVmax.
Quantitative Parameters of Diffusion Spectrum Imaging: HER2 Status Prediction in Patients With Breast Cancer
Authors: Mao Chunping , Jiang Wei , Huang Jiayi , Wang Mengzhu , Yan Xu , Yang Zehong , Wang Dongye , Zhang Xiang , Shen Jun
Published: February 2022

Objective

To explore the value of quantitative parameters derived from diffusion spectrum imaging (DSI) in preoperatively predicting human epidermal growth factor receptor 2 (HER2) status in patients with breast cancer.

Methods

In this prospective study, 114 and 56 female patients with invasive ductal carcinoma were consecutively included in a derivation cohort and an independent validation cohort, respectively. Each patient was categorized into HER2-positive or HER2-negative groups based on the pathologic result. All patients underwent DSI and conventional MRI including dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI). The tumor size, type of the time-signal intensity curve (TIC) from DCE-MRI, apparent diffusion coefficient (ADC) from DWI, and quantitative parameters derived from DSI, including diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), mean apparent propagator (MAP), and neurite orientation dispersion and density imaging (NODDI) of primary tumors, were measured and compared between the HER2-positive and HER2-negative groups in the derivation cohort. Univariable and multivariable logistic regression analyses were used to determine the potential independent predictors of HER2 status. The discriminative ability of quantitative parameters was assessed by receiver operating characteristic (ROC) curve analyses and validated in the independent cohort.

Results

In the derivation cohort, the tumor size, TIC type, and ADC values did not differ between the HER2-positive and HER2-negative groups (p = 0.126–0.961). DSI quantitative parameters including axial kurtosis of DKI (DKI_AK), non-Gaussianity (MAP_NG), axial non-Gaussianity (MAP_NGAx), radial non-Gaussianity (MAP_NGRad), return-to-origin probability (MAP_RTOP), return-to-axis probability of MAP (MAP_RTAP), and intracellular volume fraction of NODDI (NODDI_ICVF) were lower in the HER2-positive group than in the HER2-negative group (p ≤ 0.001–0.035). DSI quantitative parameters including radial diffusivity (DTI_RD), mean diffusivity of DTI (DTI_MD), mean squared diffusion (MAP_MSD), and q-space inverse variance of MAP (MAP_QIV) were higher in the HER2-positive group than in the HER2-negative group (p = 0.016–0.049). The ROC analysis showed that the area under the curve (AUC) of ADC was 0.632 and 0.568, respectively, in the derivation and validation cohorts. The AUC values of DSI quantitative parameters ranged from 0.628 to 0.700 and from 0.673 to 0.721, respectively, in the derivation and validation cohorts. Logistic regression analysis showed that only NODDI_ICVF was an independent predictor of HER2 status (p = 0.001), with an AUC of 0.700 and 0.721, respectively, in the derivation and validation cohorts.

Conclusions

DSI could be helpful for preoperative prediction of HER2, but DSI alone may not be sufficient in predicting HER2 status preoperatively in patients with breast cancer.
Ailanthone Inhibits Proliferation, Migration and Invasion of Osteosarcoma Cells by Downregulating the Serine Biosynthetic Pathway
Authors: Zhang Yawen , Gong Runze , Liu Yong , Sun Xipeng , Liang Jinrong , Zhou Yan , Wang Yaling , Yu Wenxi , Wang Yonggang , Tang Lina , He Aina , Shen Zan , Yao Yang , Hu Haiyan , Liu Xin , Zhang Jianjun
Published: February 2022

Osteosarcoma (OS) is the most common primary bone sarcoma, chemoresistance becomes an obstacle to its treatment. Metabolic reprogramming is a hallmark of malignancy, targeting the metabolic pathways might provide a reasonable therapeutic strategy for OS. Here we demonstrated that Ailanthone (AIL), a major component of the Chinese medicine Ailanthus altissima, significantly suppressed OS cell growth in vitro and in vivo. Furthermore, AIL dose-dependently inhibited cell migration and invasion, induced cell cycle arrest and apoptosis in OS cells. Combined transcriptomics, proteomics and metabolomics analyses revealed that AIL induced widespread changes in metabolic programs in OS cells, while the serine biosynthetic pathway (SSP) was the most significantly altered pathway. qRT-PCR and Western blot assay confirmed that the transcript and protein levels of the SSP genes (PHGDH, PSAT1 and PSPH) were downregulated dose-dependently by AIL. In addition, we found out that many downstream pathways of the SSP including the one-carbon pool by folate, purine metabolism, pyrimidine metabolism, DNA replication and sphingolipid metabolism were downregulated after AIL treatment. In the revere test, PHGDH overexpression but not exogenous serine supplementation clearly attenuated the effects of AIL on OS cells. Taken together, AIL exerts antitumor effects on OS through mediating metabolic reprogramming, at least in part, by suppressing the SSP. Our findings suggest that AIL could emerge as a potential therapeutic strategy in OS.
Fabrication of pH/Redox Dual-Responsive Mixed Polyprodrug Micelles for Improving Cancer Chemotherapy
Authors: Luo Ji , Zhang Shuguang , Zhu Peiyao , Liu Wenke , Du Jiang
Published: February 2022

In this work, we prepared pH/redox dual-responsive mixed polyprodrug micelles (MPPMs), which were co-assembled from two polyprodrugs, namely, poly(ethylene glycol) methyl ether-b-poly (β-amino esters) conjugated with doxorubicin (DOX) via redox-sensitive disulfide bonds (mPEG-b-PAE-ss-DOX) and poly(ethylene glycol) methyl ether-b-poly (β-amino esters) conjugated with DOX via pH-sensitive cis-aconityl bonds (mPEG-b-PAE-cis-DOX) for effective anticancer drug delivery with enhanced therapeutic efficacy. The particle size of MPPMs was about 125 nm with low polydispersity index, indicating the reasonable size and uniform dispersion. The particle size, zeta-potential, and critical micelle concentration (CMC) of MPPMs at different mass ratios of the two kinds of polyprodrugs were dependent on pH value and glutathione (GSH) level, suggesting the pH and redox responsiveness. The drug release profiles in vitro of MPPMs at different conditions were further studied, showing the pH—and redox-triggered drug release mechanism. Confocal microscopy study demonstrated that MPPMs can effectively deliver doxorubicin molecules into MDA-MB-231 cells. Cytotoxicity assay in vitro proved that MPPMs possessed high toxic effect against tumor cells including A549 and MDA-MB-231. The results of in vivo experiments demonstrated that MPPMs were able to effectively inhibit the tumor growth with reduced side effect, leading to enhanced survival rate of tumor-bearing mice. Taken together, these findings revealed that this pH/redox dual-responsive MPPMs could be a potential nanomedicine for cancer chemotherapy. Furthermore, it could be a straightforward way to fabricate the multifunctional system basing on single stimuli-responsive polyprodrugs.
A Cannabinoid 2-Selective Agonist Inhibits Allogeneic Skin Graft Rejection In Vivo
Authors: Jayarajan Senthil , Meissler Joseph J. , Adler Martin W. , Eisenstein Toby K.
Published: February 2022

Previous work from our laboratory showed that a CB2 selective agonist, O-1966, blocked the proliferative response of C57BL/6 mouse spleen cells exposed to spleen cells of C3HeB/FeJ mice in vitro in the mixed lymphocyte reaction (MLR). The MLR is widely accepted as an in vitro correlate of in vivo grant rejection. Mechanisms of the immunosuppression induced by the cannabinoid were explored, and it was shown that O-1966 in this in vitro assay induced CD25+Foxp3+ Treg cells and IL-10, as well as down-regulated mRNA for CD40 and the nuclear form of the transcription factors NF-κB and NFAT in T-cells. The current studies tested the efficacy of O-1966 in prolonging skin grafts in vivo. Full thickness flank skin patches (1-cm2) from C3HeB/FeJ mice were grafted by suturing onto the back of C57BL/6 mice. O-1966 or vehicle was injected intraperitoneally into treated or control groups of animals beginning 1 h pre-op, and then every other day until 14 days post-op. Graft survival was scored based on necrosis and rejection. Treatment with 5 mg/kg of O-1966 prolonged mean graft survival time from 9 to 11 days. Spleens harvested from O-1966 treated mice were significantly smaller than those of vehicle control animals based on weight. Flow cytometry analysis of CD4+ spleen cells showed that O-1966 treated animals had almost a 3-fold increase in CD25+Foxp3+ Treg cells compared to controls. When dissociated spleen cells were placed in culture ex vivo and stimulated with C3HeB/FeJ cells in an MLR, the cells from the O-1966 treated mice were significantly suppressed in their proliferative response to the allogeneic cells. These results support CB2 selective agonists as a new class of compounds to prolong graft survival in transplant patients.
Protective Effect of Isoorientin on Oleic Acid-Induced Oxidative Damage and Steatosis in Rat Liver Cells
Authors: Luo Tongwang , Jiang Sheng , Zhou Bin , Song Quanjiang , Du Jing , Liu Ping , Wang Xiaodu , Song Houhui , Shao Chunyan
Published: February 2022

The harm of nonalcoholic fatty liver disease to human health is increasing, which calls for urgent prevention and treatment of the disease. Isoorientin is an effective ingredient of Chinese herbal medicine with anti-inflammatory and antioxidant effects. However, the effect of isoorientin in nonalcoholic fatty liver disease is still unclear. In this study, combined in vivo and in vitro experiments, through pathological observation, flow cytometry, immunofluorescence and western blot analysis to explore the role of isoorientin in steatosis and reveal its molecular mechanism. The results demonstrated that oleic acid treatment significantly increased the content of ROS and lipid droplets in rat hepatocytes, and promoted the expression of γH2AX, HO-1, PPARγ, SREBP-1c, FAS. The ROS content in the cells of co-treated with isoorientin and oleic acid was significantly reduced compared to the oleic acid group, and the expression of γH2AX, HO-1, PPARγ, SREBP-1c, FAS, and the nuclear translocation of NF-κB p65 were also significantly inhibited. Our data showed that oleic acid induce oxidative damage and steatosis in hepatocytes both in vitro and in vivo, and activate the PPARγ/NF-κB p65 signal pathway. Moreover, isoorientin can significantly reduce oleic acid -induced oxidative damage and steatosis by regulating the PPARγ/NF-kB p65 signal pathway.
Water in Deep Eutectic Solvents: New Insights From Inelastic Neutron Scattering Spectroscopy
Authors: Nolasco Mariela M. , Pedro Sónia N. , Vilela Carla , Vaz Pedro D. , Ribeiro-Claro Paulo , Rudić Svemir , Parker Stewart F. , Freire Carmen S.R. , Freire Mara G. , Silvestre Armando J. D.
Published: February 2022

The effect of water on the physicochemical properties of deep eutectic solvents (DES) is a trending research topic. In this work, inelastic neutron scattering (INS) spectroscopy, was used to probe intermolecular interactions in the water-deep eutectic solvent mixtures for the cases of choline chloride (the hydrogen bond acceptor) and three different hydrogen bond donors, with different degrees of acidity: urea, glycerol and lactic acid. It was found that quenching samples in liquid nitrogen is a procedure that may retain the liquid phase morphology of DES at the low temperatures required by INS spectroscopy. The three studied systems share the preference of water molecules to bind to chloride anion, as predicted by numerous molecular dynamics simulations. Despite this similarity, the three systems present several distinct INS features upon water addition that are related to their unique properties and structure at the molecular level. In the choline chloride:urea system, water molecules promote a strengthening of hydrogen bonds with the NH and OH donors, while for the choline chloride:lactic acid system INS probed the existence of solvated DES clusters instead of specifically interfering water molecules. This study takes advantage from the unique capabilities of INS and paves the way for future studies in these systems.