Reduced muscle mass is an important part of Global Leadership Initiative on Malnutrition criteria in nutritional diagnosis of hepatocellular carcinoma.

BACKGROUND: The Global Leadership Initiative on Malnutrition criteria (GLIM) was established to build a global consensus on the diagnostic criteria for malnutrition. The study aimed to assess the prevalence of the malnutrition diagnosed by GLIM criteria for patients with hepatocellular carcinoma (HCC), and to determine the role of the reduced muscle mass defined by CT scans in the GLIM criteria. METHODS: This cohort research was conducted on adult cirrhotic patients with HCC. The risk of malnutrition was screened by Nutritional Risk Screening 2002 (NRS-2002), and malnutrition was diagnosed by GLIM criteria. The third lumbar vertebrae (L3-SMI) were used to represent the muscle mass in GLIM criteria. The variables associated with overall mortality were assessed by multivariate Cox regression analyses. RESULTS: The incidence of malnutrition diagnosed by GLIM criteria was 49.7% (179/360) in patients with HCC. If reduced muscle mass was not included in GLIM criteria, the prevalence of malnutrition was 31.7% (114/360). GLIM-defined malnutrition (HR = 1.979, 95%CI 1.019-3.841, P = 0.044) was independently associated with overall mortality in patients with HCC. However, the GLIM-defined malnutrition (without muscle mass) was not associated with overall mortality (HR = 0.863, 95%CI 0.399-1.867, P = 0.709). CONCLUSIONS: Skeletal muscle mass is an integral component of the GLIM criteria for patients with HCC. The malnutrition is common in patients with HCC, and malnourishment is associated with higher overall mortality. GLIM criteria are recommended to assess the nutritional status of hospitalized patients with HCC, which is recommended and can be used as the basis for nutritional interventions.

Case report: POEMS syndrome with portal hypertension.

This patient was an elderly patient with abdominal distension and shortness of breath. According to relevant examinations, his condition was initially considered to be related to cirrhosis, but pathological biopsy confirmed the diagnosis of noncirrhotic portal hypertension of unknown etiology. The portal vein pressure was significantly reduced after transjugular intrahepatic portosystemic shunt (TIPS). Nevertheless, the relief of the hydrothorax and ascites was not significant, and the numbness in both lower limbs gradually worsened. POEMS syndrome was ultimately diagnosed following a comprehensive examination. After two courses of bortezomib combined with dexamethasone, the patient died due to a systemic infection. The clinical symptoms of the patient were atypical, as was the presence of portal hypertension, which hindered the diagnosis of POEMS. Due to the patient's advanced age, the diagnosis was delayed, and the prognosis was poor. This case reminds clinicians that POEMS patients can also have portal hypertension as the main manifestation.

Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy.

PURPOSE: Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy. METHODS: We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8+ T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism. RESULTS: Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays. CONCLUSION: Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future.

LONP1 ameliorates liver injury and improves gluconeogenesis dysfunction in acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe liver disease with complex pathogenesis. Clinical hypoglycemia is common in patients with ACLF and often predicts a worse prognosis. Accumulating evidence suggests that glucose metabolic disturbance, especially gluconeogenesis dysfunction, plays a critical role in the disease progression of ACLF. Lon protease-1 (LONP1) is a novel mediator of energy and glucose metabolism. However, whether gluconeogenesis is a potential mechanism through which LONP1 modulates ACLF remains unknown. METHODS: In this study, we collected liver tissues from ACLF patients, established an ACLF mouse model with carbon tetrachloride (CCl 4 ), lipopolysaccharide (LPS), and D-galactose (D-gal), and constructed an in vitro hypoxia and hyperammonemia-triggered hepatocyte injury model. LONP1 overexpression and knockdown adenovirus were used to assess the protective effect of LONP1 on liver injury and gluconeogenesis regulation. Liver histopathology, biochemical index, mitochondrial morphology, cell viability and apoptosis, and the expression and activity of key gluconeogenic enzymes were detected to explore the underlying protective mechanisms of LONP1 in ACLF. RESULTS: We found that LONP1 and the expressions of gluconeogenic enzymes were downregulated in clinical ACLF liver tissues. Furthermore, LONP1 overexpression remarkably attenuated liver injury, which was characterized by improved liver histopathological lesions and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ACLF mice. Moreover, mitochondrial morphology was improved upon overexpression of LONP1. Meanwhile, the expression and activity of the key gluconeogenic enzymes were restored by LONP1 overexpression. Similarly, the hepatoprotective effect was also observed in the hepatocyte injury model, as evidenced by improved cell viability, reduced cell apoptosis, and improved gluconeogenesis level and activity, while LONP1 knockdown worsened liver injury and gluconeogenesis disorders. CONCLUSION: We demonstrated that gluconeogenesis dysfunction exists in ACLF, and LONP1 could ameliorate liver injury and improve gluconeogenic dysfunction, which would provide a promising therapeutic target for patients with ACLF.

Peptide ARHGEF9 Inhibits Glioma Progression via PI3K/AKT/mTOR Pathway.

Background: The most prevalent malignant tumor in a human brain nervous system is called glioma. Peptide is a compound formed by the peptide bond of α-amino acids, and the development of polypeptide drugs has been widely used in many fields. We plan to investigate the underlying peptides with clinical value in glioma. Method: Based on public databases, we targeted the common genes between glioma differentially expressed genes (DEGs) and peptide genes related to glioma prognosis. Then, these common genes were analyzed by LASSO-Cox analysis, prognostic risk model, and nomogram to identify key prognostic peptide genes and the target gene in this study. Next, the mechanism of target gene in glioma was explored by bioinformatics analysis and functional experiments. Results: We obtained a total of 26 overlapping genes for the following study. After that, 6 independent prognostic factors (REPIN1, PSD3, RDX, CDK4, FANCI, and ARHGEF9) were obtained and applied to construct the prognostic nomogram, and ARHGEF9 was the target gene in the study. Next, peptide ARHGEF9 was found to inhibit glioma cell development. Through Spearman's correlation analysis, ARHGEF9 had a close relation with PI3K/AKT/mTOR pathway. In functional experiments, peptide ARHGEF9 could suppress the protein expressions of p-PIK3K, p-AKT and p-mTOR, while IGF-1 could reverse this effect. Conclusion: This study identifies 6 new prognostic biomarkers for glioma patients. Among them, peptide ARHGEF9 gene is an inhibitory gene functioning by targeting PI3K/AKT/mTOR pathway.

Pharmacokinetic Analysis of Rosmarinic Acid and its Analog in Rat Plasma Using Liquid Chromatography-Tandem Mass Spectrometry.

The anticancer effects of rosmarinic acid (RA) are a hotspot of current research. In order to enhance its pharmacological activity, N-substituted RA was prepared, and it has been shown to exhibit notable antitumor effects. In order to elucidate the underlying mechanisms of action, pharmacokinetic analysis is necessary. In the present study, liquid chromatography-tandem mass spectrometric method, was used to determine the concentrations of RA and its analog, (E)-3-(3,4-dihydroxyphenyl)-2-(3-(3,4-dihydroxyphenyl)acrylamido)propanoic acid (A2) in plasma from rats. The analyses were divided into a C18 column (1.9 µm, 2.1 mm × 100 mm) with a security guard C18 column (5 µm, 2.1 mm × 10 mm) and a triple-quadrupole mass spectrometry with an electrospray ionization ion-source generates ions. The sample pretreatment is relevant to the one-step protein precipitation with isopropanol:ethyl acetate (v/v, 1:1) This method presented a linear association within ranges at the concentration of 5-2000 ng/mL for A2 and RA. Relative standard deviations in daily courses were <15% and the relative errors registered within 15%. The methods used in the present study make the unambiguous quantification and identification of RA and A2 possible in vivo. The present study is the first to focus on determining A2 and RA in rat plasma following oral administration. The results may provide a meaningful basis for the evaluation of the application of RA and its analog in clinical practice and also provide a reference method for the pharmacokinetic analysis of RA analogs.

Total bile acid to platelet ratio: A noninvasive index for predicting liver fibrosis in primary biliary cholangitis.

The aim of the study was to develop a new early noninvasive diagnostic model for primary biliary cholangitis (PBC).A total of 118 PBC patients who had undergone a liver biopsy were enrolled in the study, and were randomized into a model group (78 patients) and a validation group (40 patients). The patients' histological stages were based on the classifications of the Scheuer's stage. All common parameters and liver pathological results were analyzed. And total bile acid to platelet ratio, aspartate aminotransferase to platelet ratio index, fibrosis index based on 4 factors and red cell distribution width to platelet ratio were calculated.There were 106 (89.8%) women and 12 men in this study, and the number of patients in Scheuer stage I, II, III, and IV hepatic fibrosis was 52 (44.1%), 36 (30.5%), 26 (22.0%), and 4 (3.4%), respectively. The areas under the receiver operating characteristic curves of the total bile acid to platelet ratio (TPR), the aspartate aminotransferase to platelet ratio index, the fibrosis index based on 4 factors , and the red cell distribution width to platelet ratio for predicting advanced liver fibrosis were 0.771, 0.715, 0.618, and 0.517 respectively. The areas under the receiver operating characteristic curves of the TPR was higher than other non-invasive serological models.As a simple, inexpensive and easily accessible non-invasive liver fibrosis diagnostic model, the TPR may be a new noninvasive marker for predicting histologic severity of PBC.

Estimating the ploidy of Gracilariopsis lemaneiformis at both the cellular and genomic level1.

The determination of the ploidy level of an organism is a prerequisite for studies of evolution, cellular function, and genomic construction. Identification of the ploidy of the economically important red alga Gracilariopsis lemaneiformis has been hindered by its small genome and large number of chromosomes. Therefore, in the current study, PloidyNGS, a tool that calculates the number of reads supporting different alleles at each position along the genome sequence, and fluorescence in situ hybridization coupled with tyramide signal amplification (TSA-FISH) were used to clarify the ploidy of G. lemaneiformis. In addition, flow cytometry (FCM) was used to estimate the ploidy of different somatic cells. The PloidyNGS results showed that most of the alleles in the gametophyte were monomorphic, whereas the TSA-FISH results showed that one hybridization signal was observed in gametophytic nuclei and two in tetrasporophytic nuclei when the nuclei were hybridized by single copy gene probes. These results confirmed that G. lemaneiformis is a haploid in the gametophytic generation and diploid in the sporophytic generation. Moreover, the FCM result suggested that G. lemaneiformis was not an endopolyploid. Based on previous studies, we hypothesize that the nuclear number is important for the cellular differentiation and function of this species. We also suggest that G. lemaneiformis evolved from a paleopolyploid, the genome of which has been diploidized, and that traces of genomic doubling are no longer apparent. Thus, this study provides important evidence for further studies on the evolution and genomes of red algae.

3' Uridylation Confers miRNAs with Non-canonical Target Repertoires.

Many microRNAs (miRNAs) exist alongside abundant miRNA isoforms (isomiRs), most of which arise from post-maturation sequence modifications such as 3' uridylation. However, the ways in which these sequence modifications affect miRNA function remain poorly understood. Here, using human miR-27a in cell lines as a model, we discovered that a nonfunctional target site unable to base-pair extensively with the miRNA seed sequence can regain function when an upstream adenosine is able to base-pair with a post-transcriptionally added uridine in the miR-27a tail. This tail-U-mediated repression (TUMR) is abolished in cells lacking the uridylation enzymes TUT4 and TUT7, indicating that uridylation alters miRNA function by modulating target recognition. We identified a set of non-canonical targets in human cells that are specifically regulated by uridylated miR-27a. We provide evidence that TUMR expands the targets of other endogenous miRNAs. Our study reveals a function of uridylated isomiRs in regulating non-canonical miRNA targets.

Structural Differences between Pri-miRNA Paralogs Promote Alternative Drosha Cleavage and Expand Target Repertoires.

MicroRNA (miRNA) processing begins with Drosha cleavage, the fidelity of which is critical for downstream processing and mature miRNA target specificity. To understand how pri-miRNA sequence and structure influence Drosha cleavage, we studied the maturation of three pri-miR-9 paralogs, which encode the same mature miRNA but differ in the surrounding scaffold. We show that pri-miR-9-1 has a unique Drosha cleavage profile due to its distorted and flexible stem structure. Cleavage of pri-miR-9-1, but not pri-miR-9-2 or pri-miR-9-3, generates an alternative miR-9 with a shifted seed sequence that expands the scope of its target RNAs. Analyses of low-grade glioma patient samples indicate that the alternative-miR-9 has a potential role in tumor progression. Furthermore, we provide evidence that distortion of pri-miRNA stems induced by asymmetric internal loops correlates with Drosha cleavage at non-canonical sites. Our studies reveal that pri-miRNA paralogs can have distinct functions via differential Drosha processing.

QuagmiR: a cloud-based application for isomiR big data analytics.

SUMMARY: MicroRNAs (miRNAs) function as master regulators of gene expression. Recent studies demonstrate that miRNA isoforms (isomiRs) play a unique role in cancer development. Here, we present QuagmiR, the first cloud-based tool to analyze isomiRs from next generation sequencing data. Using a novel and flexible searching algorithm designed for the detection and annotation of heterogeneous isomiRs, it permits extensive customization of the query process and reference databases to meet the user 's diverse research needs. AVAILABILITY AND IMPLEMENTATION: QuagmiR is written in Python and can be obtained freely from GitHub (https://github.com/Gu-Lab-RBL-NCI/QuagmiR). QuagmiR can be run from the command line on local machines, as well as on high-performance servers. A web-accessible version of the tool has also been made available for use by academic researchers through the National Cancer Institute-funded Seven Bridges Cancer Genomics Cloud (https://cancergenomicscloud.org). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A new avenue for obtaining insight into the functional characteristics of long noncoding RNAs associated with estrogen receptor signaling.

Estrogen receptor signalling plays important regulatory roles in multiple mammalian physiological processes. Dysregulation of estrogen receptor (ER) expression and/or its associated signalling pathway is strongly associated with the development, progression, transition, and endocrine-resistance of breast cancer. Non-coding transcripts are essential regulators of almost every level of gene regulation. However, few long non-coding transcripts (lncRNAs) associated with the estrogen receptor signalling pathway have been well-described. We used array-based methods to identify 33 estrogen receptor agitation-related (ERAR) lncRNAs. A coding-non-coding gene co-expression network analysis suggested that 15 ERAR lncRNAs were associated with mitosis, DNA damage, and DNA repair. Kaplan-Meier analysis indicated that five ERAR lncRNAs selected using the Random Forest-Recursive Feature Elimination algorithm were significantly correlated with endocrine resistance-free survival and distant metastasis-free survival as well as disease free survival. Our results suggest that ERAR lncRNAs may serve as novel biomarkers for guiding breast cancer treatment and prognosis. Furthermore, our findings reveal a new avenue by which estrogen receptor signalling can be further explored.