bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomarkers in the diagnostic algorithm of myalgic encephalomyelitis/chronic fatigue syndrome
Authors: Gravelsina Sabine , Vilmane Anda , Svirskis Simons , Rasa-Dzelzkaleja Santa , Nora-Krukle Zaiga , Vecvagare Katrine , Krumina Angelika , Leineman Iana , Shoenfeld Yehuda , Murovska Modra
Published: October 2022

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease that is mainly diagnosed based on its clinical symptoms. Biomarkers that could facilitate the diagnosis of ME/CFS are not yet available; therefore, reliable and clinically useful disease indicators are of high importance. The aim of this work was to analyze the association between ME/CFS clinical course severity, presence of HHV-6A/B infection markers, and plasma levels of autoantibodies against adrenergic and muscarinic acetylcholine receptors. A total of 134 patients with ME/CFS and 33 healthy controls were analyzed for the presence of HHV-6A/B using PCRs, and antibodies against beta2-adrenergic receptors (β2AdR) and muscarinic acetylcholine receptors (M3 AChR and M4 AChR) using ELISAs. HHV-6A/B U3 genomic sequence in whole-blood DNA was detected in 19/31 patients with severe ME/CFS, in 18/73 moderate ME/CFS cases, and in 7/30 mild ME/CFS cases. Severity-related differences were found among those with a virus load of more than 1,000 copies/106 PBMCs. Although no disease severity-related differences in anti-β2AdR levels were observed in ME/CFS patients, the median concentration of these antibodies in plasma samples of ME/CFS patients was 1.4 ng/ml, while in healthy controls, it was 0.81 ng/ml, with a statistically significant increased level in those with ME/CFS (p = 0.0103). A significant difference of antibodies against M4 AChR median concentration was found between ME/CFS patients (8.15 ng/ml) and healthy controls (6.45 ng/ml) (p = 0.0250). The levels of anti-M4 plotted against disease severity did not show any difference; however, increased viral load correlates with the increase in anti-M4 level. ME/CFS patients with high HHV-6 load have a more severe course of the disease, thus confirming that the severity of the disease depends on the viral load—the course of the disease is more severe with a higher viral load. An increase in anti-M4 AchR and anti-β2AdR levels is detected in all ME/CFS patient groups in comparison to the control group not depending on ME/CFS clinical course severity. However, the increase in HHV-6 load correlates with the increase in anti-M4 level, and the increase in anti-M4 level, in turn, is associated with the increase in anti-β2AdR level. Elevated levels of antibodies against β2AdR and M4 receptors in ME/CFS patients support their usage as clinical biomarkers in the diagnostic algorithm of ME/CFS.
HTLV-1 persistence and leukemogenesis: A game of hide-and-seek with the host immune system
Authors: Tan Benjy J. Y. , Sugata Kenji , Ono Masahiro , Satou Yorifumi
Published: October 2022

Human T-cell leukemia virus type 1 (HTLV-1), a retrovirus which mainly infects CD4+T cells and causes adult T-cell leukemia/lymphoma (ATL), is primarily transmittedviadirect cell-to-cell transmission. This feature generates a wide variety of infected clones in hosts, which are maintainedviaclonal proliferation, resulting in the persistence and survival of the virus. The maintenance of the pool of infected cells is achieved by sculpting the immunophenotype of infected cells and modulating host immune responses to avoid immune surveillance. Here, we review the processes undertaken by HTLV-1 to modulate and subvert host immune responses which contributes to viral persistence and development of ATL.
Transcriptome analysis of malate-induced Schizochytrium sp. FJU-512 reveals a novel pathway for biosynthesis of docosahexaenoic acid with enhanced expression of genes responsible for acetyl-CoA and NADPH accumulation
Authors: Zhang Mingliang , Gao YangLe , Yu Cui , Wang Jun , Weng Kexin , Li Qin , He Yongjin , Guo Zheng , Zhang Huaidong , Huang Jianzhong , Li Li
Published: October 2022

Schizochytrium is one of the few oleaginous microalgae that produce docosahexaenoic acid (DHA)-rich lipids. In this study, global changes in gene expression levels of Schizochytrium sp. FJU-512 cultured with malate in a 15 l-bioreactor was analyzed using comparative transcriptomics. The changes were found mainly in the genes involved in oxidative phosphorylation, β-oxidation, and pentose phosphate pathways. Consequently, the global changes in genes associated with the pathways could lead to an increase in the influx throughputs of pyruvate, branched-chain amino acids, fatty acids, and vitamin B6. Our transcriptome analysis indicated pyruvate dehydrogenase E2 component and acetolactate synthase I/II/III large subunit as major contributors to acetyl-CoA biosynthesis, whereas glucose-6-phosphate dehydrogenase was indicated as the major contributor to the biosynthesis of NADPH. An increase in DHA titer of up to 22% was achieved with the addition of malate to the fed-batch culture of Schizochytrium sp. FJU-512. This study provides an alternate method to enhance DHA production in Schizochytrium sp. FJU-512 through malate induced upregulation of genes responsible for acetyl-CoA and NADPH biosynthesis.
A designed antimicrobial peptide with potential ability against methicillin resistant Staphylococcus aureus
Authors: Yuan Bingqian , Lu Xiaoyu , Yang Min , He Qiyi , Cha Zhuocen , Fang Yaqun , Yang Yan , Xu Lei , Yan Jingting , Lai Ren , Wang Aili , Yu Xiaodong , Duan Zilei
Published: October 2022

Staphylococcus aureus (S. aureus) is a Gram-positive pathogenic bacterium, which persistently colonizes the anterior nares of approximately 20–30% of the healthy adult population, and up to 60% is intermittently colonized. With the misuse and overuse of antibiotics, large-scale drug-resistant bacteria, including methicillin-resistant S. aureus (MRSA), have been appeared. MRSA is among the most prevalent pathogens causing community-associated infections. Once out of control, the number of deaths caused by antimicrobial resistance may exceed 10 million annually by 2050. Antimicrobial peptides (AMPs) are regarded as the best solution, for they are not easy to develop drug resistance. Based on our previous research, here we designed a new antimicrobial peptide named GW18, which showed excellent antimicrobial activity against S. aureus, even MRSA, with the hemolysis less than 5%, no cytotoxicity, and no acute toxicity. Notably, administration of GW18 significantly decreased S. aureus infection in mouse model. These findings identify GW18 as the ideal candidate against S. aureus infection.
Prenatal exposure to inflammation increases anxiety-like behaviors in F1 and F2 generations: possible links to decreased FABP7 in hippocampus
Authors: Chen Jing , Zhang Zhe-Zhe , Luo Bao-Ling , Yang Qi-Gang , Ni Ming-Zhu , Wu Qi-Tao , Li Yun , Li Xue-Wei , Chen Gui-Hai
Published: October 2022

Anxiety disorder has a high prevalence, and the risk of anxiety increases with age. Prenatal inflammation during key developmental timepoints can result in long-term changes in anxiety phenotype, even over a lifetime and across generations. However, whether maternal inflammation exposure during late gestation has intergenerational transmission effects on age-related anxiety-like behaviors and the possible underlying mechanisms are largely unknown. Fatty acid binding protein 7 (FABP7) is critical in hippocampal neurogenesis and is closely related to neuropsychiatric diseases, including anxiety disorder. The current study investigated the effects of maternal (F0 generation) lipopolysaccharide administration (50 μg/kg, i.p.) during late gestation on anxiety-like behaviors and FABP7 expression in F1 and F2 offspring, as well as the potential sex-specificity of intergenerational effects. Anxiety-like behaviors were evaluated using open field (OF), elevated plus maze, and black–white alley (BWA) tests at 3 and 13 months of age. The protein and messenger RNA levels of FABP7 in the hippocampus were measured using Western blot and real-time quantitative polymerase chain reaction (PCR), respectively. Overall, gestational LPS exposure in the F0 generation increased anxiety levels and decreased FABP7 expression levels in the F1 generation, which carried over to the F2 generation, and the intergenerational effects were mainly transferred via the maternal lineage. Moreover, hippocampal FABP7 expression was significantly correlated with performance in the battery of anxiety tests. The present study suggested that prenatal inflammation could increase age-related anxiety-like behaviors both in F1 and F2 offspring, and these effects possibly link to the FABP7 expression.
Long-term efficacy of enucleation combined with primary orbital implantation in children with retinoblastoma histopathological invasion of optic nerve
Authors: Wang Nan , Liu Rui , Li Jing , Wang Jinjin , Xu Liangyuan , Guo Qihan , Zhang Xuan , Ma Jianmin
Published: October 2022

Objective

This study aimed to observe the long-term effect of enucleation combined with primary orbital implantation in children with histopathologic optic nerve invasive retinoblastoma (RB).

Methods

We retrospectively analyzed the clinical data and outcomes of children with RB optic nerve invasion confirmed by histopathology who underwent enucleation combined with primary orbital implantation between March 2010 and April 2014 in Beijing Tongren Hospital. The follow-up time ranged from 81 to 129 months, with a mean follow-up of 96 ± 14 months.

Results

A total of 59 children were included in this study. There were 32 males and 27 females; 52 children were affected in one eye and seven children in both eyes. The time from onset of symptoms to visit was between 3 days and 16 months, with a mean of 2.2 ± 2.8 months. The age at the of surgery was between 2 and 65 months, with an average of 24 ± 13 months. Patients were classified based on the degree of optic nerve invasion into four grades: grade 1 (invasion of prelaminar) in 28 cases, grade 2 (invasion of laminar) in 14 cases, grade 3 (invasion of retrolaminar but not reaching the optic nerve transection) in 16 cases, and grade 4 (invasion of the optic nerve transection) in 1 case. Post-operatively, all children were treated with 0–9 cycles of intravenous chemotherapy based on histopathology results from the removed eye. Of the 59 children, 13 had postoperative complications, and one died from recurrence. The survival rate was 98% (58/59). There was one case of orbital implant exposure, one of orbital cellulitis, six of enophthalmos and superior sulcus deformity, two of blepharoptosis, one of granuloma complicated with blepharoptosis, and one with a subconjunctival cyst.

Conclusion

For children with RB histopathologic invasion of the optic nerve, enucleation combined with primary orbital implantation reveals future potential treatment options when combined with a full course of intravenous chemotherapy.
Design and implementation of a Stroke Rehabilitation Registry for the systematic assessment of processes and outcomes and the development of data-driven prediction models: The STRATEGY study protocol
Authors: Chiavilli Marco , Campagnini Silvia , Baretta Teresa , Castagnoli Chiara , Paperini Anita , Politi Angela Maria , Pellicciari Leonardo , Baccini Marco , Basagni Benedetta , Marignani Sara , Bardi Donata , Sodero Alessandro , Lombardi Gemma , Guolo Erika , Navarro Jorge Solano , Galeri Silvia , Montesano Angelo , Falco Lucia , Rovaris Marco Giuseppe , Carrozza Maria Chiara , Macchi Claudio , Mannini Andrea , Cecchi Francesca
Published: October 2022

Background

Stroke represents the second preventable cause of death after cardiovascular disease and the third global cause of disability. In countries where national registries of the clinical quality of stroke care have been established, the publication and sharing of the collected data have led to an improvement in the quality of care and survival of patients. However, information on rehabilitation processes and outcomes is often lacking, and predictors of functional outcomes remain poorly explored. This paper describes a multicenter study protocol to implement a Stroke rehabilitation Registry, mainly based on a multidimensional assessment proposed by the Italian Society of Physical and Rehabilitation Medicine (PMIC2020), in a pilot Italian cohort of stroke survivors undergoing post-acute inpatient rehabilitation, to provide a systematic assessment of processes and outcomes and develop data-driven prediction models of functional outcomes.

Methods

All patients with a diagnosis of ischemic or haemorrhagic stroke confirmed by clinical assessment, admitted to intensive rehabilitation units within 30 days from the acute event, aged 18+, and providing informed consent will be enrolled. Measures will be taken at admission (T0), at discharge (T1), and at follow-up, 3 months (T2) and 6 months (T3) after the stroke. Assessment variables include anamnestic data, clinical and nursing complexity information and measures of body structures and function, activity and participation (PMIC2020), rehabilitation interventions, adverse events and discharge data. The modified Barthel Index will be our primary outcome. In addition to classical biostatistical analysis, learning algorithms will be cross-validated to achieve data-driven prognosis prediction models.

Conclusions

This study will test the feasibility of a stroke rehabilitation registry in the Italian health context and provide a systematic assessment of processes and outcomes for quality assessment and benchmarking. By the development of data-driven prediction models in stroke rehabilitation, this study will pave the way for the development of decision support tools for patient-oriented therapy planning and rehabilitation outcomes maximization.

Clinical tial registration

The registration on ClinicalTrials.gov is ongoing and under review. The identification number will be provided when the review process will be completed.
Abnormal synergies and associated reactions post-hemiparetic stroke reflect muscle activation patterns of brainstem motor pathways
Authors: McPherson Laura M. , Dewald Julius P. A.
Published: October 2022

Individuals with moderate-to-severe post-stroke hemiparesis cannot control proximal and distal joints of the arm independently because they are constrained to stereotypical movement patterns called flexion and extension synergies. Accumulating evidence indicates that these synergies emerge because of upregulation of diffusely projecting brainstem motor pathways following stroke-induced damage to corticofugal pathways. During our recent work on differences in synergy expression among proximal and distal joints, we serendipitously observed some notable characteristics of synergy-driven muscle activation. It seemed that: paretic wrist/finger muscles were activated maximally during contractions of muscles at a different joint; differences in the magnitude of synergy expression occurred when elicited via contraction of proximal vs. distal muscles; and associated reactions in the paretic limb occurred during maximal efforts with the non-paretic limb, the strength of which seemed to vary depending on which muscles in the non-paretic limb were contracting. Here we formally investigated these observations and interpreted them within the context of the neural mechanisms thought to underlie stereotypical movement patterns. If upregulation of brainstem motor pathways occurs following stroke-induced corticofugal tract damage, then we would expect a pattern of muscle dependency in the observed behaviors consistent with such neural reorganization. Twelve participants with moderate-to-severe hemiparetic stroke and six without stroke performed maximal isometric torque generation in eight directions: shoulder abduction/adduction and elbow, wrist, and finger flexion/extension. Isometric joint torques and surface EMG were recorded from shoulder, elbow, wrist, and finger joints and muscles. For some participants, joint torque and muscle activation generated during maximal voluntary contractions were lower than during maximal synergy-induced contractions (i.e., contractions about a different joint), particularly for wrist and fingers. Synergy-driven contractions were strongest when elicited via proximal joints and weakest when elicited via distal joints. Associated reactions in the wrist/finger flexors were stronger than those of other paretic muscles and were the only ones whose response depended on whether the non-paretic contraction was at a proximal or distal joint. Results provide indirect evidence linking the influence of brainstem motor pathways to abnormal motor behaviors post-stroke, and they demonstrate the need to examine whole-limb behavior when studying or seeking to rehabilitate the paretic upper limb.
Altered regional homogeneity and functional connectivity of brain activity in young HIV-infected patients with asymptomatic neurocognitive impairment
Authors: Han Shuai , Aili Xire , Ma Juming , Liu Jiaojiao , Wang Wei , Yang Xue , Wang Xi , Sun Lijun , Li Hongjun
Published: October 2022

Objective

Asymptomatic neurocognitive impairment (ANI) is a predominant form of cognitive impairment in young HIV-infected patients. However, the neurophysiological mechanisms underlying this disorder have not been clarified. We aimed to evaluate the altered patterns of functional brain activity in young HIV-infected patients with ANI by quantifying regional homogeneity (ReHo) and region of interest (ROI)-based functional connectivity (FC).

Methods

The experiment involved 44 young HIV-infected patients with ANI and 47 well-matched healthy controls (HCs) undergoing resting-state functional magnetic resonance imaging (rs-fMRI) and neurocognitive tests. Reho alterations were first explored between the ANI group and HC groups. Subsequently, regions showing differences in ReHo were defined as ROIs for FC analysis. Finally, the correlation of ReHo and FC with cognitive function and clinical variables was assessed.

Results

Compared with HCs, ANI patients had a significant ReHo decrease in the right lingual gyrus (LING. R), right superior occipital gyrus (SOG. R), left superior occipital gyrus (SOG. L), left middle occipital gyrus (MOG. L), right middle frontal gyrus (MFG. R), cerebellar vermis, ReHo enhancement in the left middle frontal gyrus (MFG. L), and left insula (INS L). The ANI patients showed increased FC between the LING. R and MOG. L compared to HC. For ANI patients, verbal and language scores were negatively correlated with increased mean ReHo values in the MFG.L. Increased mean ReHo values in the INS. L was positively correlated with disease duration—the mean ReHo values in the LING. R was positively correlated with the abstraction and executive function scores. Increased FC between the LING. R and MOG. L was positively correlated with verbal and language performance.

Conclusion

The results suggest that the visual network might be the most vulnerable area of brain function in young HIV-infected patients with ANI. The middle frontal gyrus, cerebellar vermis, and insula also play an important role in asymptomatic neurocognitive impairment. The regional homogeneity and functional connectivity of these regions have compound alterations, which may be related to the course of the disease and neurocognitive function. These neuroimaging findings will help us understand the characteristics of brain network modifications in young HIV-infected patients with ANI.
Incorporating neck circumference or neck-to-height ratio into the GOAL questionnaire to better detect and describe obstructive sleep apnea with application to clinical decisions
Authors: Zhao Ying , Yan Xiangru , Liang Chunguang , Wang Liying , Zhang Hui , Yu Haitao
Published: October 2022

Objective

Although neck circumference (NC) and neck-to-height ratio (NHR) have been recognized as effective predictors of the clinical diagnosis of adult obstructive sleep apnea (OSA), they have not been included in the widely used GOAL questionnaire. Not coincidentally, the NHR has not been adequately considered in the development and validation of the STOP-Bang questionnaire, No-Apnea score and the NoSAS score. The motivation for the study was (1) to combine the GOAL questionnaire with the NC and NHR, respectively, to evaluate its predictive performance and (2) to compare it with the STOP-Bang questionnaire, the No-Apnea score, the NOSAS score, and the GOAL questionnaire.

Materials and methods

This retrospectively allocated cross-sectional study was conducted from November 2017 to March 2022 in adults who underwent nocturnal polysomnography (PSG) or home sleep apnea testing (HSAT). In this paper, the GOAL questionnaire was combined with the NC and NHR, respectively, using logistic regression. The performance of the six screening tools was assessed by discriminatory ability [area under the curve (AUC) obtained from receiver operating characteristic (ROC) curves] and a 2 × 2 league table [including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR−)] and compared under AHI ≥5/h, AHI ≥15/h, and AHI ≥30/h conditions.

Results

A total of 288 patients were enrolled in the study. For all severity OSA levels, the sensitivity of GOAL+NC ranged from 70.12 to 70.80%, and specificity ranged from 86.49 to 76.16%. The sensitivity of GOAL+NHR ranged from 73.31 to 81.75%, while specificity ranged from 83.78 to 70.86%. As for area under the curve (AUC) value under ROC curve, when AHI ≥5/h, compared with GOAL (0.806), No-Apnea (0.823), NoSAS (0.817), and GOAL+NC (0.815), GOAL+NHR (0.831) obtained the highest AUC value, but lower than STOP-Bang (0.837).

Conclusion

The predictive power of incorporating NC or NHR into the GOAL questionnaire was significantly better than that of the GOAL itself. Furthermore, GOAL+NHR was superior to GOAL+NC in predicting OSA severity and better than the No-Apnea score and the NoSAS score.
Effect of flavonoids on skeletal muscle mass, strength and physical performance in middle-aged and older adults with or without Sarcopenia: A meta-analysis of randomized controlled trials
Authors: Li Yuzhuo , Liu Yun , Tan Rongshao , Liu Yan
Published: October 2022

The role of flavonoids in regulating the synthesis and function of skeletal muscles is increasingly recognized. However, randomized controlled trials have yielded inconsistent results on the influence of flavonoids on human muscular parameters. Therefore, we performed a meta-analysis to evaluate the possible effects of flavonoids on sarcopenia-related parameters in middle-aged and elderly people. Eligible literature and randomized controlled trials reports have been extensively searched from PubMed, Cochrane Library, Web of Science, and EMBASE databases until April 2022. A total of 20 articles involving 796 participants were available for the meta-analysis. There were significant benefits for participants in appendicular muscle mass gain (SMD = 0.29; 95% CI: 0.07, 0.52; P = 0.01) and 6-min walk distance (SMD = 0.37; 95% CI: 0.01, 0.73; P = 0.05). A subgroup analysis indicated that flavonoid significantly improves appendicular muscle mass (SMD = 0.50; 95% CI: 0.21, 0.80; P < 0.01) and Timed-Up and Go test (SMD = −0.47; 95% CI: −0.85, −0.09; P = 0.02) in Sarcopenia population. Our results provide insight into the effects of flavonoids on skeletal muscle mass and gait speed for those without exercise. However, there was no significant improvement in the subjects' muscle strength.

Systematic review registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=334383, identifier: CRD42022334383.
Mendelian randomization in blood metabolites identifies triglycerides and fatty acids saturation level as associated traits linked to pancreatitis risk
Authors: Mi Jiarui , Liu Zhengye , Jiang Lingjuan , Li Meizi , Wu Xia , Zhao Nan , Wan Ziqi , Bai Xiaoyin , Feng Yunlu
Published: October 2022

Background

There is very limited evidence on the causal effects of blood metabolites on pancreatitis risks. To reveal the causal associations between plasma metabolites and pancreatitis risks, we performed two-sample Mendelian randomization (MR) and Bayesian model averaging (MR-BMA) analyses in European ancestry.

Methods

The summary-level statistics from two genome-wide association studies with 249 and 123 metabolic traits derived from two separate cohorts involving ~115,000 (UK Biobank) and ~25,000 individuals from European ancestry were used for the analyses. The summary statistics of four pancreatitis datasets from FinnGen R5 and two pancreatitis datasets from UK Biobank were exploited as the outcome. We first performed univariable MR analysis with different metabolic GWAS data on multiple pancreatitis datasets to demonstrate the association pattern among different metabolites categories. Next, we exploited the MR-BMA method to pinpoint the dominating factors on the increased risk of pancreatitis.

Results

In the primary analysis with 249 traits, we found that plasma triglycerides were positively associated with pancreatitis risk. Intriguingly, a large number of traits associated with saturation or unsaturation of fatty acids also demonstrated causal associations. The replication study analyzing 123 metabolic traits suggested that bisallylic groups levels and omega-3 fatty acids were inversely correlated with pancreatitis risk. MR-BMA analyses indicated that the ratio of triglycerides to total lipid in various HDL particles played leading roles in pancreatitis susceptibility. In addition, the degree of unsaturation, the ratio of polyunsaturated fatty acids to monounsaturated fatty acids and the level of monounsaturated fatty acids showed causal associations with either decreased or increased pancreatitis susceptibility.

Conclusions

Our MR study provided an atlas of causal associations of genetically predicted blood metabolites on pancreatitis, and offered genetic insights showing intervention in triglycerides and the supplementation of unsaturated fatty acids are potential strategies in the primary prevention of pancreatitis.
MBTPS1 regulates proliferation of colorectal cancer primarily through its action on sterol regulatory element-binding proteins
Authors: Hartal-Benishay Liat H. , Saadi Esraa , Toubiana Shir , Shaked Lior , Lalzar Maya , Abu Hatoum Ossama , Tal Sharon , Selig Sara , Barki-Harrington Liza
Published: October 2022

Among the main metabolic pathways implicated in cancer cell proliferation are those of cholesterol and fatty acid synthesis, both of which are tightly regulated by sterol regulatory element-binding proteins (SREBPs). SREBPs are activated through specific cleavage by membrane-bound transcription factor protease 1 (MBTPS1), a serine protease that cleaves additional substrates (ATF6, BDNF, CREBs and somatostatin), some of which are also implicated in cell proliferation. The goal of this study was to determine whether MBTPS1 may serve as a master regulator in proliferation of colorectal cancer (CRC). Tumors from CRC patients showed variable levels of MBTPS1 mRNA, which were in positive correlation with the levels of SREBPs and ATF6, and in reverse correlation with BDNF levels. Chemical inhibition of MBTPS1 activity in two CRC-derived cell lines resulted in a marked decrease in the levels of SREBPs, but not of its other substrates and a marked decrease in cell proliferation, which suggested that MBTPS1 activity is critical for proliferation of these cells. In accordance, CRISPR/Cas9 targeted knockout (KO) of the MBTPS1 gene resulted in the survival of only a single clone that presented a phenotype of severely attenuated proliferation and marked downregulation of several energy metabolism pathways. We further showed that survival of the MBTPS1 KO clone was dependent upon significant upregulation of the type-1 interferon pathway, the inhibition of which halted proliferation entirely. Finally, rescue of the MBTPS1 KO cells, resulted in partial restoration of MBTPS1 levels, which was in accordance with partial recovery in proliferation and in SREBP levels. These finding suggest that MBTPS1 plays a critical role in regulating colon cancer proliferation primarily through SREBP-associated lipid metabolism, and as such may serve as a possible therapeutic target in CRC.
Identification of a dysregulated CircRNA-associated gene signature for predicting prognosis, immune landscape, and drug candidates in bladder cancer
Authors: Shen Chong , Li Zhi , Zhang Yinglang , Zhang Zhe , Wu Zhouliang , Da La , Yang Shaobo , Wang Zejin , Zhang Yu , Qie Yunkai , Zhao Gangjian , Lin Yuda , Huang Shiwang , Zhou Mingli , Hu Hailong
Published: October 2022

Increasing evidences have demonstrated that circular RNA (circRNAs) plays a an essential regulatory role in initiation, progression and immunotherapy resistance of various cancers. However, circRNAs have rarely been studied in bladder cancer (BCa). The purpose of this research is to explore new circRNAs and their potential mechanisms in BCa. A novel ceRNA-regulated network, including 87 differentially expressed circRNAs (DE-circRNAs), 126 DE-miRNAs, and 217 DE-mRNAs was constructed to better understanding the biological processes using Cytoscape 3.7.1 based on our previously high-throughput circRNA sequencing and five GEO datasets. Subsequently, five randomly selected circRNAs (upregulated circ_0001681; downregulated circ_0000643, circ_0001798, circ_0006117 and circ_0067900) in 20 pairs of BCa and paracancerous tissues were confirmed using qRT-PCR. Functional analysis results determined that 772 GO functions and 32 KEGG pathways were enriched in the ceRNA network. Ten genes (PFKFB4, EDNRA, GSN, GAS1, PAPPA, DTL, TGFBI, PRSS8, RGS1 and TCF4) were selected for signature construction among the ceRNA network. The Human Protein Atlas (HPA) expression of these genes were consistent with the above sequencing data. Notably, the model was validated in multiple external datasets (GSE13507, GSE31684, GSE48075, IMvigor210 and GSE32894). The immune-infiltration was evaluated by 7 published algorithms (i.e., TIMER, CIBERSORT, CIBERSORT-ABS, QUANTISEQ, MCPCOUNTER, XCELL and EPIC). Next, Correlations between riskscore or risk groups and clinicopathological data, overall survival, recognized immunoregulatory cells or common chemotherapeutic agents of BCa patients were performed using wilcox rank test, chi-square test, cox regression and spearman’s correlation analysis; and, these results are significant. According to R package “GSVA” and “clusterProfiler”, the most significantly enriched HALLMARK and KEGG pathway was separately the ‘Epithelial Mesenchymal Transition’ and ‘Ecm Receptor Interaction’ in the high- vs. low-risk group. Additionally, the functional experiments in vitro also revealed that the overexpression of has_circ_0067900 significantly impaired the proliferation, migration, and invasion capacities of BCa cells. Collectively, the results of the current study provide a novel landscape of circRNA-associated ceRNA-regulated network in BCa. The ceRNA-associated gene model which was constructed presented a high predictive performance for the prognosis, immunotherapeutic responsiveness, and chemotherapeutic sensitivity of BCa. And, has_circ_0067900 was originally proposed as tumor suppressor for patients with BCa.
An external validation of the nocera nomogram: Predicting non-organ confined stage of ≥pT3 in cT1 clear cell renal cell carcinoma
Authors: Wenzel Mike , Hoeh Benedikt , Rührup Jessica , Gambetta Hanna , Nocera Luigi , Würnschimmel Christoph , Tian Zhe , Karakiewicz Pierre I. , Briganti Alberto , Chun Felix K.H. , Roos Frederik C. , Becker Andreas , Krimphove Marieke J.
Published: October 2022

Background

Only one previously published study by Nocera et al. addressed the risk of upstaging to ≥pT3 in cT1 clear cell renal cell carcinoma (ccRCC) by using characteristics of the R.E.N.A.L and PADUA score (age, tumor size, rim location, exophytic rate, polar involvement) developing an accurate nomogram. However, this nomogram has never been externally validated yet.

Material and methods

The study cohort consisted of 288 patients with cT1a-b ccRCC, diagnosed between 2008-2021 at the University Hospital Frankfurt, Germany. Analyses addressed clinical, tumor and radiographic characteristics. The external validation of the nomogram relied on accuracy calculations derived from the area under the curve of the receiver operator characteristic analysis.

Results

Overall, 11.8% (n=34) patients harbored ≥pT3 ccRCC. Median radiographic tumor size (3.6 vs. 5.3cm), R.E.N.A.L. (8 vs. 9 points) and PADUA score (9 vs. 11 points), as well as proportions of renal sinus involvement (82.4% vs. 51.6%), renal hilus involvement (44.1 vs. 13.0%), and medial rim location significantly differed between the pT1-2 and ≥pT3 group (all p ≤ 0.01). In subgroup analyses of small renal mass ccRCC patients (<4cm, cT1a), only 3.8% (n=6) patients had ≥pT3 pathology. Upstaged patients were significantly older and more frequently had endophytic tumor than pT1-2 counterparts (p<0.05). The external validation of the Nocera nomogram showed a good accuracy of 76.6%. Using the suggested cut-off of 21%, 26.5% of patients exhibited ≥pT3 ccRCC. Conversely, within patients below cut-off, 5.9% patients exhibited ≥pT3 ccRCC.

Conclusion

We reported the first external validation of the nomogram addressing the risk of ≥pT3 in cT1 ccRCC patients, demonstrating a good accuracy, with a low false-negative rate. Therefore, the nomogram can accurately be used for patients’ counselling and treatment decision making.
Minimal length multi-segment clothoid return paths for vehicles with turn rate constraints
Authors: Tuttle Theodore , Wilhelm Jay P.
Published: October 2022

Continuous curvature recovery paths are needed to accurately return a fixed wing autonomous vehicle with turn rate constraints back to a missions path in the correct direction after collision avoidance. Clothoid paths where curvature is linearly dependent to arc length can be used to make multi-segment splines with continuous curvature, but require optimization to ensure that the path is of minimal length while meeting curvature and sharpness limits. The present work considers the problem of returning a fixed wing aircraft back to its original path facing the correct direction after a leaving it during collision avoidance by presenting a method of optimizing a three segment clothoid spline to be of minimal length while meeting fixed wing turn rate constraints and targeting a path function. The impact of this work is enabling accurate path recovery after collision avoidance with minimal length paths that minimize the time spent off a missions planned route, giving better control over time of arrival for the planned route and more time to complete mission objectives.
Fetal aortic coarctation: A combination of third-trimester echocardiographic parameters to improve the prediction of postnatal outcome
Authors: Tuo Giulia , Paladini Dario , Marasini Lucia , Buratti Silvia , De Tonetti Gabriele , Calevo Maria G. , Marasini Maurizio
Published: October 2022

Objectives

This study aims to determine a combination of third-trimester echocardiographic parameters for improving the prenatal prediction of coarctation of the aorta (CoA) after birth.

Methods

We included all cases of suspected CoA during fetal echocardiography performed in the second and/or third trimester of pregnancy at Gaslini Children's Hospital between January 2010 and December 2020. The last prenatal ultrasound evaluation was reviewed considering most of the echocardiographic criteria were already published for prenatal CoA diagnosis. Associated minor cardiac anomalies, such as a ventricular septal defect, persistent left superior vena cava (PLSCV), and redundant foramen ovale (FO) membrane, as well as postnatal outcomes, were reported. Initial perinatal management was defined based on the risk stratification of CoA during prenatal echocardiography. Neonates were divided into two groups depending on the presence or absence of CoA after birth.

Results

A total of 91 fetuses with CoA suspicion were selected, of which 27 (30%) were confirmed with CoA after birth and underwent surgical repair. All cardiac parameters except redundant FO membrane and PLSCV showed a significant correlation with CoA. Statistical analysis confirmed that cardiovascular disproportion with right predominance carries an increased risk for occurrence of CoA, especially if already evident during the ultrasound evaluation in the second trimester. Aortic valve (AV) z-score and distal transverse aortic arch (TAA) z-score resulted as the best predictors of CoA after birth. The best cutoff point for CoA discrimination with ROC analysis was an AV z-score of −1.25 and a distal TAA z-score of −0.37. A total of 46% of those without CoA were diagnosed with a cardiac defect, which was not diagnosed in utero, pulmonary hypertension, or a genetic syndrome.

Conclusion

The current criteria for diagnosing CoAin uteroallow accurate diagnosis of most severe cases but the rate of false positives remains relatively high for milder cases. A combination of anatomic and functional echocardiographic parameters might be used in stratifying the risk of CoA. We proposed the AV and the TAA diameter z-scores as the best predictors of CoA after birth. In addition, neonates without CoA deserve proper monitoring at birth because prenatal evidence of a significant cardiovascular discrepancy between the right and left cardiac structures has an inherent risk for additional morbidity postnatally.
A comprehensive analysis of the prognostic value and immune infiltration of low expression DBT in clear cell renal cell carcinoma
Authors: Xie Wenjie , Xi Ping , Liu Yifu , Zhang Zhicheng , Sun Ting
Published: October 2022

Background: Although DBT is strongly associated with human tumorigenesis and progression through a variety of pathways, the role of DBT in clear cell renal cell carcinoma (ccRCC) has not been well established.

Materials and methods: The Cancer Genome Atlas (TCGA)-Kidney renal clear cell carcinoma (KIRC) databset provides RNA sequencing data and clinicopathological information on ccRCC. The Gene Expression Omnibus (GEO) database was used to validate the DBT expression levels, and qPCR was used to examine the DBT expression in renal cancer cell lines and ccRCC tissue samples from our centre. In parallel, DBT protein expression was explored in the Human Protein Atlas (HPA) database, and western blotting and immunohistochemistry of renal cancer cell lines and ccRCC tissues validated the results. Additionally, the diagnostic and prognostic value of DBT was comprehensively evaluated by receiver operating characteristic (ROC) curves, univariate and multivariate Cox regression analyses, and Kaplan‒Meier survival analysis. The protein‒protein interaction (PPI) network based on the STRING website, Gene Ontology (GO) analysis, Kyoto Gene and Genome Encyclopedia (KEGG) analysis and gene set enrichment analysis (GSEA) further provided a landscape of the molecular mechanisms of DBT in ccRCC. Finally, the TIMER 2.0, GEPIA and TISIDB websites were used to understand the relationship between DBT and immune characteristics.

Results: The mRNA expression and protein expression of DBT were significantly downregulated in ccRCC tissues relative to normal tissues, which was associated with poor clinical outcomes. DBT has an encouraging discriminatory power for ccRCC and is an independent prognostic factor for ccRCC patients. Mechanistically, DBT is mainly involved in the regulation of immune-related signalling pathways in ccRCC; it is associated with a variety of immune infiltrating cells and immune checkpoints.

Conclusion: DBT is a tumour suppressor gene in ccRCC and could be used as a new biomarker for diagnostic and prognostic purposes, and it is associated with immune infiltration in ccRCC.
Stem cell‐derived extracellular vesicles reduce the expression of molecules involved in cardiac hypertrophy—In a model of human-induced pluripotent stem cell-derived cardiomyocytes
Authors: Constantin Alina , Comarița Ioana Karla , Alexandru Nicoleta , Filippi Alexandru , Bojin Florina , Gherghiceanu Mihaela , Vîlcu Alexandra , Nemecz Miruna , Niculescu Loredan Stefan , Păunescu Virgil , Georgescu Adriana
Published: October 2022

Cardiac pathological hypertrophy is the major risk factor that usually progresses to heart failure. We hypothesized that extracellular vesicles (EVs), known to act as important mediators in regulating physiological and pathological functions, could have the potential to reduce the cardiac hypertrophy and the ensuing cardiovascular diseases. Herein, the effects of mesenchymal stem cell-derived extracellular vesicles (EV-MSCs) on cardiac hypertrophy were investigated. EVs were isolated from the secretome of human adipose tissue-derived stem cells (EV-ADSCs) or bone marrow-derived stem cells (EV-BMMSCs). Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were stimulated with AngII and TGF-β1, in absence or presence of EVs. The results showed that exposure of hiPSC-CMs to AngII and TGF-β1 generated in vitro model of hypertrophic cardiomyocytes characterized by increases in surface area, reactive oxygen species production, protein expression of cardiac-specific biomarkers atrial natriuretic factor, migration inhibitory factor, cTnI, COL1A1, Cx43, α-SMA and signalling molecules SMAD2 and NF-kBp50. The presence of EV-ADSCs or EV-BMMSCs in the hiPSC-CM culture along with hypertrophic stimuli reduced the protein expressions of hypertrophic specific markers (ANF, MIF, cTnI, COL1A1) and the gene expressions of IL-6 molecule involved in inflammatory process associated with cardiac hypertrophy and transcription factors SMAD2, SMAD3, cJUN, cFOS with role in cardiomyocyte hypertrophic response induced by AngII and TGF-β1. The EV-ADSCs were more effective in reducing the protein expressions of hypertrophic and inflammatory markers, while EV-BMMSCs in reducing the gene expressions of transcription factors. Notably, neither EV-ADSCs nor EV-BMMSCs induced significant changes in cardiac biomarkers Cx43, α-SMA and fibronectin. These different effects of stem cell-derived EVs could be attributed to their miRNA content: some miRNAs (miR-126-3p, miR-222-3p, miR-30e-5p, miR-181b-5p, miR-124-3p, miR-155-5p, miR-210-3p hsa-miR-221-3p) were expressed in both types of EVs and others only in EV-ADSCs (miR-181a-5p, miR-185-5p, miR-21-5p) or in EV-BMMSCs (miR-143-3p, miR-146a-5p, miR-93-5p), some of these attenuating the cardiac hypertrophy while others enhance it. In conclusion, in hiPSC-CMs the stem cell-derived EVs through their cargo reduced the expression of hypertrophic specific markers and molecules involved in inflammatory process associated with cardiac hypertrophy. The data suggest the EV potential to act as therapeutic mediators to reduce cardiac hypertrophy and possibly the subsequent cardiovascular events.
Mechanisms of isoniazid and rifampicin-induced liver injury and the effects of natural medicinal ingredients: A review
Authors: Zhuang Xiuping , Li Li , Liu Tianyi , Zhang Rui , Yang Peimin , Wang Xin , Dai Long
Published: October 2022

Isoniazid (INH) and rifampicin (RFP) are the first-line medications for tuberculosis treatment, and liver injury is the major adverse effect. Natural medicinal ingredients provide distinct benefits in alleviating patients’ symptoms, lowering the liver injury risk, delaying disease progression, and strengthening the body’s ability to heal. This paper summarises the recent research on the mechanisms of INH and RFP-induced liver injury and the effects of natural medicinal ingredients. It is believed that INH-induced liver injury may be attributed to oxidative stress, mitochondrial dysfunction, drug metabolic enzymes, protoporphyrin IX accumulation, endoplasmic reticulum stress, bile transport imbalance, and immune response. RFP-induced liver injury is mainly related to cholestasis, endoplasmic reticulum stress, and liver lipid accumulation. However, the combined effect of INH and RFP on liver injury risk is still uncertain. RFP can increase INH-induced hepatotoxicity by regulating the expression of drug-metabolizing enzymes and transporters. In contrast, INH can antagonize RFP-induced liver injury by reducing the total bilirubin level in the blood. Sagittaria sagittifolia polysaccharide, quercetin, gallic acid, and other natural medicinal ingredients play protective roles on INH and RFP-induced liver injury by enhancing the body’s antioxidant capacity, regulating metabolism, inhibiting cell apoptosis, and reducing the inflammatory response. There are still many gaps in the literature on INH and RFP-induced liver injury mechanisms and the effects of natural medicinal ingredients. Thus, further research should be carried out from the perspectives of liver injury phenotype, injury markers, in vitro and in vivo liver injury model construction, and liver-gut axis. This paper comprehensively reviewed the literature on mechanisms involved in INH and RFP-induced liver injury and the status of developing new drugs against INH and RFP-induced liver injury. In addition, this review also highlighted the uses and advantages of natural medicinal ingredients in treating drug-induced liver injury.
Cancer cells can be killed mechanically or with combinations of cytoskeletal inhibitors
Authors: Tijore Ajay , Yang Bo , Sheetz Michael
Published: October 2022

For over two centuries, clinicians have hypothesized that cancer developed preferentially at the sites of repeated damage, indicating that cancer is basically “continued healing.” Tumor cells can develop over time into other more malignant types in different environments. Interestingly, indefinite growth correlates with the depletion of a modular, early rigidity sensor, whereas restoring these sensors in tumor cells blocks tumor growth on soft surfaces and metastases. Importantly, normal and tumor cells from many different tissues exhibit transformed growth without the early rigidity sensor. When sensors are restored in tumor cells by replenishing depleted mechanosensory proteins that are often cytoskeletal, cells revert to normal rigidity-dependent growth. Surprisingly, transformed growth cells are sensitive to mechanical stretching or ultrasound which will cause apoptosis of transformed growth cells (Mechanoptosis). Mechanoptosis is driven by calcium entry through mechanosensitive Piezo1 channels that activate a calcium-induced calpain response commonly found in tumor cells. Since tumor cells from many different tissues are in a transformed growth state that is, characterized by increased growth, an altered cytoskeleton and mechanoptosis, it is possible to inhibit growth of many different tumors by mechanical activity and potentially by cytoskeletal inhibitors.
Biofunctionalization of cardiovascular stents to induce endothelialization: Implications for in- stent thrombosis in diabetes
Authors: Marei Isra , Ahmetaj-Shala Blerina , Triggle Chris R.
Published: October 2022

Stent thrombosis remains one of the main causes that lead to vascular stent failure in patients undergoing percutaneous coronary intervention (PCI). Type 2 diabetes mellitus is accompanied by endothelial dysfunction and platelet hyperactivity and is associated with suboptimal outcomes following PCI, and an increase in the incidence of late stent thrombosis. Evidence suggests that late stent thrombosis is caused by the delayed and impaired endothelialization of the lumen of the stent. The endothelium has a key role in modulating inflammation and thrombosis and maintaining homeostasis, thus restoring a functional endothelial cell layer is an important target for the prevention of stent thrombosis. Modifications using specific molecules to induce endothelial cell adhesion, proliferation and function can improve stents endothelialization and prevent thrombosis. Blood endothelial progenitor cells (EPCs) represent a potential cell source for the in situ-endothelialization of vascular conduits and stents. We aim in this review to summarize the main biofunctionalization strategies to induce the in-situ endothelialization of coronary artery stents using circulating endothelial stem cells.