Miracle-dz/UniFAR-FTUs huggingface dataset:
Correlation between Early Tumor Marker Response and Imaging Response in Patients with Advanced Hepatocellular Carcinoma Treated with Lenvatinib

Aim: This study investigated early tumor marker response and treatment response in patients with advanced hepatocellular carcinoma (HCC) treated with lenvatinib. Methods: Twenty patients with advanced HCC who received lenvatinib were enrolled in this retrospective study. α-Fetoprotein (AFP) and des-γ-carboxyprothrombin (DCP) levels were measured before treatment as well as 2 and 4 weeks after treatment. The objective response rate was evaluated by mRECIST at 6 weeks. Results: The response rate was 30% (complete response/partial response/stable disease/progressive disease: n = 0/6/6/8 cases) by mRECIST. At 4 weeks, the AFP levels of 12 patients (80%) were lower than at baseline. The AFP levels of 9 patients (60%) continued decreasing from 2 weeks to 4 weeks (sustained-reduction group). In this group, the response rate was 67%. The median AFP change rate was –39% at 4 weeks. In imaging responders, the AFP change rate significantly decreased (p = 0.02). The DCP change rate had no significant correlation with imaging response. The AFP-sustained-reduction group had significantly higher adherence to lenvatinib than the non-sustained-reduction group (p = 0.02). Conclusion: With lenvatinib therapy for HCC, the AFP levels of most patients had declined at 2 weeks, and at 4 weeks the AFP-sustained-reduction group demonstrated a higher objective response.
Contribution of Genetic Polymorphisms of Inflammation Response Genes on Sporadic Colorectal Cancer Predisposition Risk in Malaysian Patients – A Case Control Study

AIM: To investigate the frequencies and association of polymorphic genotypes of IL-8 -251 T>A, TNF-α -308 G>A, ICAM-1 K469E, ICAM-1 R241G, IL-6 -174 G>C, and PPAR-γ 34 C>G in modulating susceptibility risk in Malaysian colorectal cancer (CRC) patients. Methods: In this case-control study, peripheral blood samples of 560 study subjects (280 CRC patients and 280 controls) were collected, DNA extracted and genotyped using PCR-RFLP and Allele Specific PCR. The association between polymorphic genotype and CRC susceptibility risk was determined using Logistic Regression analysis deriving Odds ratio (OR) and 95% CI. Results: On comparing the frequencies of genotypes of all single nucleotide polymorphisms ( SNPs ) in patients and controls, the homozygous variant genotypes IL-8 -251 AA and TNF-α -308 AA and variant A alleles were significantly higher in CRC patients. Investigation on the association of the variant alleles and genotypes singly, with susceptibility risk showed the homozygous variant A alleles and genotypes IL-8 -251 AA and TNF-α -308 AA to be at higher risk for CRC predisposition. Analysis based on age, gender and smoking habits showed that the polymorphisms IL8 -251 T>A and TNF – α 308 G>A contribute to a significantly higher risk among male and female who are more than 50 years and for smokers in this population. Conclusion: We observed an association between variant allele and genotypes of IL-8-251 T>A and TNF-α-308 G>A polymorphisms and CRC susceptibility risk in Malaysian patients. These two SNPs in inflammatory response genes which undoubtedly contribute to individual risks to CRC susceptibility may be considered as potential genetic predisposition factors for CRC in Malaysian population.
High BMI is associated with low ALS risk

Identifying mechanisms of neurodegenerative disease causation seemed to be beyond the pale of traditional epidemiologic tools. Elucidating a plausible mechanism for initiation of amyotrophic lateral sclerosis (ALS) appeared particularly elusive.1 The principal barrier to discerning ALS pathogenesis was the need to conceptualize ALS correctly2: an active process, initiated in cortical motor neurons, that dismantles the human motor neuronal supernetwork systematically.1
Exo-miRNAs as a New Tool for Liquid Biopsy in Lung Cancer

Lung cancer is the predominant cause of cancer-related deaths. The high mortality rates are mainly due to the lack of diagnosis before the cancer is at a late stage. Liquid biopsy is a promising technique that could allow early diagnosis of lung cancer and better treatment selection for patients. Cell-free microRNAs have been detected in biological fluids, such as serum and plasma, and are considered interesting biomarkers for lung cancer screening and detection. Exosomes are nanovesicles of 30–150 nm and can be released by different cell types within the tumor microenvironment. Their exosomal composition reflects that of their parental cells and could be potentially useful as a biomarker for lung cancer diagnosis. This review summarizes the state-of-the-art of circulating microRNAs (miRNAs) in lung cancer, focusing on their potential use in clinical practice. Moreover, we describe the importance of exosomal miRNA cargo in lung cancer detection and their potential role during lung carcinogenesis. Finally, we discuss our experience with the analysis of circulating exosomal miRNAs in the bioMILD screening trial.
Tissue stem cells: the new actors in the aneuploidy field

ABSTRACT The development of multicellular organisms and the maintenance of its tissues relies on mitosis. However, this process represents a major challenge for genomic stability as each time a cell division occurs there are multiple steps where errors can lead to an abnormal chromosomal content in daughter cells – aneuploidy. Aneuploidy was first postulated to act as a tumour promoting agent over one century ago. Since then, we have learned to appreciate the complexity involving the cellular responses to aneuploidy and to value the importance of models where aneuploidy is induced in vivo and in a cell-type specific manner. Recent data suggests that stem cells evolved a distinct response to aneuploidy, being able to survive and proliferate as aneuploid. Since stem cells are the main cells responsible for tissue renewal, it is of the utmost importance to place the spotlight on stem cells within the aneuploidy field. Here, we briefly review some of the biological mechanisms implicated in aneuploidy, the relationship between aneuploidy and tissue pathologies, and summarize the most recent findings in Drosophila on how tissue stem cells respond to aneuploidy. Once we understand how stem cell behavior is impacted by aneuploidy, we might be able to better describe the complicated link between aneuploidy and tumourigenesis.
Isotomidae of Japan and Asiatic part of Russia. II. The genus Tetracanthella of the Far East

Abstract The paper considers new and little-known species of the genus Tetracanthella distributed in the Far East of Russia and in Japan. Sensillar chaetotaxy and labial palp, two less known morphological characters for the genus, are discussed. Two new species T.annulatasp. nov. and T.tardokisp. nov. are described; T.manschurica Kutyreva, 1980 and T czernovae Kutyreva, 1980 are redescribed. For the latter species a lectotype and paralectotypes are designated. Remarks are provided for T.sylvatica Yosii, 1939. A second undescribed species is recorded for Japan. New records for T.orientalis Martynova, 1977 and T.sibirica Deharveng, 1987 are listed.
What Frequency of Technical Activity Is Needed to Improve Results? New Approach to Analysis of Match Status in Professional Soccer

The aim of the research detailed here has been to assess the frequency with which football players engage in technical activity of various different types, in relation to seven phases of a game associated with changes in match status. To this end, 2016–2017 domestic-season matches in Germany’s Bundesliga were analyzed, the relevant data being retrieved using an Opta Sportsdata Company system. Technical activity taken into consideration included shots, passes, ball possession, dribbles, and tackles. It was found that there was a large impact of frequency of shots on target (H = 466.999(6); p = 0.001) in relation to the different match-status phases. Furthermore, moderate effect sizes were then obtained for frequency of shots (H = 187.073(6); p = 0.001), frequency of passes (H = 133.547(6); p = 0.001), and percentage of ball possession (H = 123.401(6); p = 0.001). The implication would be that a team trying to change the match score of a game experienced at a given moment in a more favorable direction will need to raise the frequency and accuracy of passes, the percentage of ball possession, and the percentage of tackles ending in success. The maintenance of a winning match status requires a high frequency of occurrence of shots and shots on target as well as greater frequency and effectiveness of dribbling. The main finding from our work is that consideration of the consequences of a game presented in relation to seven potential phases to match status can point to a novel approach to analysis.
Serious infection risk in rheumatoid arthritis compared with non-inflammatory rheumatic and musculoskeletal diseases: a US national cohort study

Objectives To identify serious infection (SI) risk by aetiology and site in patients with rheumatoid arthritis (RA) compared with those with non-inflammatory rheumatic and musculoskeletal diseases (NIRMD). Methods Patients participating in FORWARD from 2001 to 2016 were assessed for SIs; defined by infections requiring hospitalisation, intravenous antibiotics or followed by death. SIs were categorised by aetiology and site. SI risk was assessed through Cox proportional hazards models. Best models were selected using machine learning Least Absolute Shrinkage and Selection Operator (LASSO) methodology. Results Among 20 361 patients with RA and 6176 patients with NIRMD, 1600 and 276 first SIs were identified, respectively. Incidence of SIs was higher in RA compared with NIRMD (IRR = 1.5; 95% CI 1.2 to 1.5). The risk persisted after adjusting using the LASSO model (HR 1.7; 95% CI 1.5 to 1.8), but attenuated when additionally adjusted for glucocorticoid use (HR 1.3; 95% CI 1.2 to 1.5). SI risk was significantly higher in RA versus NIRMD for bacterial infections as well as for respiratory, skin, bone, joint, bloodstream infections and sepsis irrespective of glucocorticoid use. Compared with NIRMD, SI risk was significantly increased in patients with RA who were in moderate and high disease activity but was similar to those in low disease activity/remission (p trend < 0.001). Conclusions The risk of all SIs, particularly bacterial, respiratory, bloodstream, sepsis, skin, bone and joint infections are significantly increased in patients with RA compared with patients with NIRMD. This infection risk appears to be greatest in those with higher RA disease activity.
The antipsychotic medication, risperidone, causes global immunosuppression in healthy mice

Atypical antipsychotic medications such as risperidone are widely prescribed for diverse psychiatric indications including schizophrenia, bipolar disorder and depression. These medications have complex pharmacology and are associated with significant endocrine and metabolic side effects. This class of medications also carries FDA black box warnings due to increased risk of death in elderly patients. Clinical reports indicate that patients treated with these medications are more susceptible to infections; however, the underlying mechanisms/pharmacology are unclear. We have previously reported that risperidone and it’s active metabolite distributes to the bone marrow in clinically relevant concentrations in preclinical species, leading us to hypothesize that the hematopoietic system may be impacted by these medications. To test this hypothesis, using proteomic and cytokine array technology, we evaluated the expression of genes involved in inflammatory and immune function following short term (5 days) and longer term (4 weeks) treatment in healthy animals. We report that low-dose risperidone treatment results in global immunosuppression in mice, observed following 5 days of dosing and exacerbated with longer term drug treatment (4 weeks). These data are consistent with increased susceptibility to infection in patients administered these medications and have profound implications for the increasing off-label prescribing to vulnerable patient populations including children and the elderly.
Phosphoethanolamine N-methyltransferase 1 contributes to maintenance of root apical meristem by affecting ROS and auxin regulated cell differentiation in Arabidopsis.

The continuous growth of roots requires the balance between cell division and differentiation. Reactive oxygen species (ROS) and auxin are important regulators of root development by affecting cell division and differentiation. The mechanism controlling the coordinating of cell division and differentiation is not well understood. Using a forward genetic screen, we isolated a mutant, dpr2, defective in root apical meristem (RAM) maintenance. The DPR2 gene encodes phosphoethanolamine N-methyltransferase 1 (PEAMT1) that catalyzes phosphocholine biosynthesis in Arabidopsis. We characterized the primary root phenotypes of dpr2 using various marker lines, histochemical and pharmacological analysis to probe early root development. Loss-of-function of DPR2/PEAMT1 resulted in RAM consumption by affecting root stem cell niche, division zone, elongation and differentiation zone (EDZ). PIN-FORMED (PIN) protein abundance, PIN2 polar distribution and general endocytosis were impaired in the root tip of dpr2. Excess hydrogen peroxide and auxin accumulate in the EDZ of dpr2, leading to RAM consumption by accelerating cell differentiation. Suppression of ROS over-accumulation or inhibition of auxin signaling partially prevent RAM differentiation in dpr2 after choline starvation. Taken together, we conclude that the EDZ of the root tip is most sensitive to choline shortage, leading to RAM consumption through a ROS-auxin regulation module. This article is protected by copyright. All rights reserved.
Arterial wall shear rate response to reactive hyperaemia is markedly different between young and older humans

The vasodilatory response to reactive hyperaemia is impaired with advancing age, but it is unclear whether this is because of an altered wall shear rate (WSR) stimulus or an altered flow‐mediated dilatation (FMD) response. Using new technology that allows detailed WSR measurement, we assessed the WSR–FMD response in healthy older people. Our data show that older people have a markedly altered and diminished WSR response to reactive hyperaemia compared to young people, but reduced WSR alone does not fully explain reduced FMD. In young people, WSR appears to be coupled to FMD but, by age ∼65 years, the arterial vasodilatory response has begun to uncouple from the WSR stimulus. These findings point to the importance and utility of comprehensively characterizing the WSR–FMD response when using reactive hyperaemia to assess vascular function, as well as giving new insight into the age‐related alteration in vascular function.
Identification of a Multiplex Biomarker Panel for Hypertrophic Cardiomyopathy Using Quantitative Proteomics and Machine Learning*

Exploratory myocardial and plasma proteomics screens in patients with hypertrophic cardiomyopathy identified new biomarkers that were developed into a multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay for validation across a larger cohort of patients with this disease. Using quantitative proteomics and supervised machine learning, this six-biomarker panel shows a relationship with myocardial substrate changes in patients with hypertrophic cardiomyopathy and with their estimated sudden cardiac death risk. Graphical Abstract Highlights Quantitative proteomics and machine learning to study plasma biomarkers in HCM. Six peptides are increased in plasma of LVH+ HCM compared to controls. Peptide biomarkers correlate with imaging markers of phenotype severity. Peptide biomarkers correlate with the estimated sudden cardiac death risk. Hypertrophic cardiomyopathy (HCM) is defined by pathological left ventricular hypertrophy (LVH). It is the commonest inherited cardiac condition and a significant number of high risk cases still go undetected until a sudden cardiac death (SCD) event. Plasma biomarkers do not currently feature in the assessment of HCM disease progression, which is tracked by serial imaging, or in SCD risk stratification, which is based on imaging parameters and patient/family history. There is a need for new HCM plasma biomarkers to refine disease monitoring and improve patient risk stratification. To identify new plasma biomarkers for patients with HCM, we performed exploratory myocardial and plasma proteomics screens and subsequently developed a multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay to validate the 26 peptide biomarkers that were identified. The association of discovered biomarkers with clinical phenotypes was prospectively tested in plasma from 110 HCM patients with LVH (LVH+ HCM), 97 controls, and 16 HCM sarcomere gene mutation carriers before the development of LVH (subclinical HCM). Six peptides (aldolase fructose-bisphosphate A, complement C3, glutathione S-transferase omega 1, Ras suppressor protein 1, talin 1, and thrombospondin 1) were increased significantly in the plasma of LVH+ HCM compared with controls and correlated with imaging markers of phenotype severity: LV wall thickness, mass, and percentage myocardial scar on cardiovascular magnetic resonance imaging. Using supervised machine learning (ML), this six-biomarker panel differentiated between LVH+ HCM and controls, with an area under the curve of ≥ 0.87. Five of these peptides were also significantly increased in subclinical HCM compared with controls. In LVH+ HCM, the six-marker panel correlated with the presence of nonsustained ventricular tachycardia and the estimated five-year risk of sudden cardiac death. Using quantitative proteomic approaches, we have discovered six potentially useful circulating plasma biomarkers related to myocardial substrate changes in HCM, which correlate with the estimated sudden cardiac death risk.
Transcriptomic Analysis Reveals the High-Oleic Acid Feedback Regulating the Homologous Gene Expression of Stearoyl-ACP Desaturase 2 (SAD2) in Peanuts

Peanuts with high oleic acid content are usually considered to be beneficial for human health and edible oil storage. In breeding practice, peanut lines with high monounsaturated fatty acids are selected using fatty acid desaturase 2 (FAD2), which is responsible for the conversion of oleic acid (C18:1) to linoleic acid (C18:2). Here, comparative transcriptomics were used to analyze the global gene expression profile of high- and normal-oleic peanut cultivars at six time points during seed development. First, the mutant type of FAD2 was determined in the high-oleic peanut (H176). The result suggested that early translation termination occurred simultaneously in the coding sequence of FAD2-A and FAD2-B, and the cultivar H176 is capable of utilizing a potential germplasm resource for future high-oleic peanut breeding. Furthermore, transcriptomic analysis identified 74 differentially expressed genes (DEGs) involved in lipid metabolism in high-oleic peanut seed, of which five DEGs encoded the fatty acid desaturase. Aradu.XM2MR belonged to the homologous gene of stearoyl-ACP (acyl carrier protein) desaturase 2 (SAD2) that converted the C18:0 into C18:1. Further subcellular localization studies indicated that FAD2 was located at the endoplasmic reticulum (ER), and Aradu.XM2MR was targeted to the plastid in Arabidopsis protoplast cells. To examine the dynamic mechanism of this finding, we focused on the peroxidase (POD)-mediated fatty acid (FA) degradation pathway. The fad2 mutant significantly increased the POD activity and H2O2 concentration at the early stage of seed development, implying that redox signaling likely acted as a messenger to connect the signaling transduction between the high-oleic content and Aradu.XM2MR transcription level. Taken together, transcriptome analysis revealed the feedback mechanism of SAD2 (Aradu.XM2MR) associated with FAD2 mutation during the seed developmental stage, which could provide a potential peanut breeding strategy based on identified candidate genes to improve the content of oleic acid.
Acellular dermal matrix and coronally advanced flap or tunnel technique in the treatment of multiple adjacent gingival recessions. A 12-year follow-up from a randomized clinical trial.

AIM To evaluate the long-term outcomes of Acellular Dermal Matrix (ADM) with Coronally Advanced Flap (CAF) or Tunnel technique (TUN) in the treatment of multiple adjacent gingival recessions (MAGRs). MATERIAL AND METHODS Nineteen of the original 24 patients contributing to a total number of 33 sites for CAF and 34 for TUN were available for the 12 years follow-up examination. Recession depth, mean root coverage (mRC), keratinized tissue width (KTW), gingival thickness (GT) were evaluated and compared with baseline values and 6-months results. Regression analysis was performed to identify factors related to the stability of the gingival margin. RESULTS A highly significant drop in mRC was observed for both groups from the 6 months timepoint to the 12 years recall (p<0.001). While there were no statistically significant differences between the two groups in terms of Clinical Attachment Level (CAL), KTW, GT changes and Root Coverage Esthetic Score at each timepoint (p>0.05). KTW ≥ 2 mm and GT ≥ 1.2 mm at 6-months were two predictors for stability of the gingival margin (p= 0.03 and p=0.01, respectively). CONCLUSIONS A significant relapse of the gingival margin of MAGRs treated with CAF or TUN + ADM was observed after 12 years. This article is protected by copyright. All rights reserved.
Exposure to the Harmful Algal Bloom (HAB) Toxin Microcystin-LR (MC-LR) Prolongs and Increases Severity of Dextran Sulfate Sodium (DSS)-Induced Colitis

Inflammatory Bowel Disease (IBD) represents a collection of gastrointestinal disorders resulting from genetic and environmental factors. Microcystin-leucine arginine (MC-LR) is a toxin produced by cyanobacteria during algal blooms and demonstrates bioaccumulation in the intestinal tract following ingestion. Little is known about the impact of MC-LR ingestion in individuals with IBD. In this study, we sought to investigate MC-LR’s effects in a dextran sulfate sodium (DSS)-induced colitis model. Mice were separated into four groups: (a) water only (control), (b) DSS followed by water (DSS), (c) water followed by MC-LR (MC-LR), and (d) DSS followed by MC-LR (DSS + MC-LR). DSS resulted in weight loss, splenomegaly, and severe colitis marked by transmural acute inflammation, ulceration, shortened colon length, and bloody stools. DSS + MC-LR mice experienced prolonged weight loss and bloody stools, increased ulceration of colonic mucosa, and shorter colon length as compared with DSS mice. DSS + MC-LR also resulted in greater increases in pro-inflammatory transcripts within colonic tissue (TNF-α, IL-1β, CD40, MCP-1) and the pro-fibrotic marker, PAI-1, as compared to DSS-only ingestion. These findings demonstrate that MC-LR exposure not only prolongs, but also worsens the severity of pre-existing colitis, strengthening evidence of MC-LR as an under-recognized environmental toxin in vulnerable populations, such as those with IBD.