Distinct characteristics of the gut virome in patients with osteoarthritis and gouty arthritis.

BACKGROUND/PURPOSE(S): The gut microbiota and its metabolites play crucial roles in pathogenesis of arthritis, highlighting gut microbiota as a promising avenue for modulating autoimmunity. However, the characterization of the gut virome in arthritis patients, including osteoarthritis (OA) and gouty arthritis (GA), requires further investigation. METHODS: We employed virus-like particle (VLP)-based metagenomic sequencing to analyze gut viral community in 20 OA patients, 26 GA patients, and 31 healthy controls, encompassing a total of 77 fecal samples. RESULTS: Our analysis generated 6819 vOTUs, with a considerable proportion of viral genomes differing from existing catalogs. The gut virome in OA and GA patients differed significantly from healthy controls, showing variations in diversity and viral family abundances. We identified 157 OA-associated and 94 GA-associated vOTUs, achieving high accuracy in patient-control discrimination with random forest models. OA-associated viruses were predicted to infect pro-inflammatory bacteria or bacteria associated with immunoglobulin A production, while GA-associated viruses were linked to Bacteroidaceae or Lachnospiraceae phages. Furthermore, several viral functional orthologs displayed significant differences in frequency between OA-enriched and GA-enriched vOTUs, suggesting potential functional roles of these viruses. Additionally, we trained classification models based on gut viral signatures to effectively discriminate OA or GA patients from healthy controls, yielding AUC values up to 0.97, indicating the clinical utility of the gut virome in diagnosing OA or GA. CONCLUSION: Our study highlights distinctive alterations in viral diversity and taxonomy within gut virome of OA and GA patients, offering insights into arthritis etiology and potential treatment and prevention strategies.

Transcranial sonography with clinical and demographic characteristics to predict cognitive impairment in PD: a longitudinal study.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease and is clinically characterized by a series of motor symptoms (MS) and nonmotor symptoms (NMS). NMS often appear before MS, while cognitive impairment mostly occurs within a few years after the diagnosis of PD. Therefore, we aimed to predict the risk factors for cognitive impairment (CI) in PD patients based on transcranial sonography, clinical symptoms, and demographic characteristics. METHODS: Based on the occurrence time of CI, a total of 172 PD patients were divided into non-CI (N-CI, n = 48), CI at the first treatment (F-CI, n = 58), and CI at the last treatment (L-CI, n = 66) groups. Clinical data (including MS and NMS) and ultrasonic data of all patients at the first treatment and the last treatment were collected retrospectively. Independent samples t tests were used to compare continuous data, and chi-square tests were used to compare categorical data. The risk factors for CI and Parkinson's disease dementia were identified by logistic regression analysis, and an ROC curve was established to explore the diagnostic efficacy. RESULTS: 1) The age of onset, first treatment and smoking history of CI patients were significantly different from those of N-CI patients. When age of first treatment ≥61 years was considered the boundary value to diagnose CI, the sensitivity and specificity were 77.40 and 66.70%, respectively. 2) The severity of depression was significantly different between F-CI and N-CI patients at the first treatment, while the cumulative and new or aggravated memory deficit was significantly different between the L-CI and N-CI patients at the last treatment. 3) There was a significant difference in TCS grading between the first and last treatment in L-CI patients. 4) Depression, sexual dysfunction, and olfactory dysfunction in NMS were independent risk factors for CI during the last treatment. 5) The sensitivity and specificity of predicting CI in PD patients were 81.80 and 64.60%, respectively. CONCLUSIONS: PD patients with CI were older, and most of them had a history of smoking. Furthermore, there was good diagnostic efficiency for predicting CI in PD via TCS combined with clinical characteristics (especially NMS).

Preoperative prediction of extrathyroidal extension: radiomics signature based on multimodal ultrasound to papillary thyroid carcinoma.

BACKGROUND: There is a recognized need for additional approaches to improve the accuracy of extrathyroidal extension (ETE) diagnosis in papillary thyroid carcinoma (PTC) before surgery. Up to now, multimodal ultrasound has been widely applied in disease diagnosis. We investigated the value of radiomic features extracted from multimodal ultrasound in the preoperative prediction of ETE. METHODS: We retrospectively pathologically confirmed PTC lesions in 235 patients from January 2019 to April 2022 in our hospital, including 45 ETE lesions and 205 non-ETE lesions. MaZda software was employed to obtain radiomics parameters in multimodal sonography. The most valuable radiomics features were selected by the Fisher coefficient, mutual information, probability of classification error and average correlation coefficient methods (F + MI + PA) in combination with the least absolute shrinkage and selection operator (LASSO) method. Finally, the multimodal model was developed by incorporating the clinical records and radiomics features through fivefold cross-validation with a linear support vector machine algorithm. The predictive performance was evaluated by sensitivity, specificity, accuracy, F1 scores and the area under the receiver operating characteristic curve (AUC) in the training and test sets. RESULTS: A total of 5972 radiomics features were extracted from multimodal sonography, and the 13 most valuable radiomics features were selected from the training set using the F + MI + PA method combined with LASSO regression. The multimodal prediction model yielded AUCs of 0.911 (95% CI 0.866-0.957) and 0.716 (95% CI 0.522-0.910) in the cross-validation and test sets, respectively. The multimodal model and radiomics model showed good discrimination between ETE and non-ETE lesions. CONCLUSION: Radiomics features based on multimodal ultrasonography could play a promising role in detecting ETE before surgery.

Ochrobactrum chromiisoli sp. nov., Isolated from Chromium-Contaminated Soil.

A Gram-stain-negative, non-spore-forming, flagellated, motile, aerobic, rod-shaped bacteria strain, designated YY2XT, was isolated from chromium-contaminated soil. Phylogenetic analysis based on 16S rRNA gene, recA gene, and whole genome indicated that the strain represented a new member of the genus Ochrobactrum, family Brucellaceae, class Alphaproteobacteria. The phylogenetic trees based on 16 s rRNA gene, revealed that Falsochrobactrum ovis DSM26720T (96.7%), Ochrobactrum gallinifaecis DSM15295T (96.2%), and Pseudochrobactrum asaccharolyticum DSM25619T (96.2%) are the most closely related phylogenetic neighbors of strain YY2XT. The draft genome of YY2XT was approximately 4,650,646 bp in size with a G + C content of 53.0 mol%. Average nucleotide identity and digital DNA-DNA hybridization values among strain YY2XT and the selected Brucellaceae species were 71.4-83.1% and 13.5-42.7%, which are below the recommended cut-off values for species delineation. Growth of strain YY2XT occurred within pH 5-10 (optimum, pH 7-8), 4 â„ƒ-42 °C (optimum, 30 °C), and NaCl concentrations of 0.0-6.0% (optimum, 1.0%). Major quinone system was ubiquinone 10, the major fatty acids were C16:0, C18:1ω7c, and C16:1ω7c and the major polyamines were spermidine and putrescine. Major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylmonomethylethanolamine, phosphatidylethanolamine, and four undefined lipids. On the basis of the phenotypic, genotypic and chemotaxonomic traits, strain YY2XT was considered to represent a novel species of the genus Ochrobactrum, for which the name Ochrobactrum chromiisoli sp. nov. is proposed. The type strain is YY2XT (= CCTCC AB 2023035T = JCM 36000T).

Circular RNA circ_0002137 regulated the progression of osteosarcoma through regulating miR-433-3p/ IGF1R axis.

Current clinical treatment targeting osteosarcoma (OS) are limited for OS patients with pulmonary metastasis or relapse, which led to high mortality (70%-85%) for advanced osteosarcoma patients. Although ongoing efforts have been made to illustrate the mechanisms of tumorigenesis and progression in OS; however, it was far for us to learn a comprehensive molecular mechanism implies in OS development. In our study, we implicated a circRNA hsa_circ_0002137, which was higher expressed in osteosarcoma tumours compared with paracancerous tissue. The dysregulated expression pattern was also found in osteosarcoma cell lines. The role of circ_0002137 was explored via down- or up-regulated experiments. It was proved that down-regulation of circ_0002137 suppressed the progress of OS, including cell invasion, cell cycle and cell apoptosis. Furthermore, the correlation between circ_0002137 and miR-433-3p was predicted using bioinformatic tools and verified utilizing RNA pull-down assay and luciferase reporter assay. Interestingly, we found that the inhibitory effect of circ_0002137 on OS was dependent of insulin-like growth factor-1 receptor (IGF1R). In conclusion, it was demonstrated that circ_0002137 could restrain the progression of OS through regulating miR-433-3p/IGF1R axis, providing a comprehensive landscape of circ_0002137 in the generation and development of OS.

Physiological integration between Bermudagrass ramets improves overall salt resistance under heterogeneous salt stress.

Connected ramets of colonal plants often suffer from different environmental conditions such as light, nutrient, and stress. Colonal Bermudagrass (Cynodon dactylon [L.] Pers.) can form interconnected ramets and this connection facilitates the tolerance to abiotic stress, which is a kind of physiological integration. However, how bermudagrass responds to heterogeneously distributed salt stress needs to be further elucidated. Here, we demonstrated that severance of stolons aggravated the damage of salt-stressed ramets, displaying higher relative electrolytic leakage (EL), lower content of chlorophyll, higher accumulation of Na+ , and serious oxidative damages. This finding implied the positive effects of the physiological integration of bermudagrass on salt tolerance. The unstressed ramets connected with the stressed one were mildly injured, implying the supporting and sacrifice function of the unstressed ramets. Physiological integration did not mediate the translocation of Na+ among ramets, but induced a higher expression of salt overly sensitive (SOS) genes in the stressed ramets, consequently reducing the accumulation of Na+ in leaves and roots. In addition, physiological integration upregulated the genes expression and enzymes activity of catalase (CAT) and peroxidase (POD) in both stressed and unstressed ramets. This granted a stronger antioxidant ability of the whole clonal plants under salt stress. Enhanced Na+ transfer and increased reactive oxygen species (ROS) scavenging are mechanisms that likely contribute to the physiological integration leading to the salt tolerance of bermudagrass.

Evaluation of Biomarkers from Routine Laboratory Indicators for Establishing Molecular Age Score with Considering Survival Probability.

BACKGROUND: The goal was to establish a system for assessing molecular age (MA) based on common biomarkers of aging, disease, and end-of-life processes for assessing the development of chronic diseases at the molecular level. METHODS: Routine clinical laboratory indexes, including biochemical lab tests and complete blood count, were used as common biomarkers in end-of-life patients, who underwent treatment at the intensive care unit (ICU) of a hospital and died within one month. Biomarkers that were significantly different both between the patients and the controls and between the young and elderly groups could be used for the establishment of a MA index at the molecular level. RESULTS: Only albumin (ALB) was suitable as an index of MA. MA score could be obtained by using survival probability as dependent variable and using age and Alb as independent variable. MA score was 0.02Alb - 0.01age + 0.45. MA score was presented as the value of survival probability. MA score was < 0.5 in 94.3% of the ICU patients with chronic disease. For normal individuals an MA score < 0.5 was found in 5.1%. The percentage of patients an MA score < 0.50 was considerably higher in cancer, COPD, and cardiocerebrovascular diseases groups than in the elderly group, although the chronological age of elderly group was similar with the diseases groups. CONCLUSIONS: When considering death, the MA score is suitable for assessing the prechronic disease and health status at the molecular level and could provide a simple and effective tool for the early diagnosis and management of chronic conditions.

S100 calcium-binding protein A9 from tumor-associated macrophage enhances cancer stem cell-like properties of hepatocellular carcinoma.

Tumor-associated macrophages (TAMs) are crucial components of the tumor microenvironment. They play vital roles in hepatocellular carcinoma (HCC) progression. However, the interactions between TAMs and HCC cells have not been fully characterized. In this study, TAMs were induced using human monocytic cell line THP-1 cells in vitro to investigate their functions in HCC progression. S100 calcium-binding protein A9 (S100A9), an inflammatory microenvironment-related secreted protein, was identified to be significantly upregulated in TAMs. S100A9 expression in tumor tissues was associated with poor survival of HCC patients. It could enhance the stem cell-like properties of HepG2 and MHCC-97H cells by activating nuclear factor-kappa B signaling pathway through advanced glycosylation end product-specific receptor in a Ca2+ -dependent manner. Furthermore, we found that, after treatment with S100A9, HepG2 and MHCC-97H cells recruited more macrophages via chemokine (CC motif) ligand 2, which suggests a positive feedback between TAMs and HCC cells. Taken together, our findings reveal that TAMs could upregulate secreted protein S100A9 and enhance the stem cell-like properties of HCC cells and provide a potential therapeutic target for combating HCC.

[Effective components of Shengxian Decoction and its mechanism of action in treating chronic heart failure based on UHPLC-Q-TOF-MS integrated with network pharmacology].

This study aimed to elucidate the effective components of Shengxian Decoction and its mechanism of action in treating chronic heart failure. Firstly, UHPLC-Q-TOF-MS was established to identify the main chemical constituents in the rat serum after intragastric administration with Shengxian Decoction. Secondly, the absorbed components in serum were then used for the network pharmacology analysis to infer the mechanism and effective components. Targets for constituents in serum were predicted at TCMSP and Swiss-TargetPrediction database. An association network map was drawn by network visualization software Cytoscape 3.6.1. Finally, GO enrichment analysis and KEGG pathway enrichment analysis were carried out for the core target genes. By UHPLC-Q-TOF-MS, 18 prototype compounds were definitely identified, including five compounds from Astragali Radix, four compounds from Anemarrhenae Rhizoma, four compounds from Bupleuri Radix, four compounds from Cimicifugae Rhizoma, and one compound from Platycodonis Radix. Those components of Shengxian Decoction were closely associated with 13 key protein targets, including inflammatory factors, like IL6, IL1 B, TNF, PTGS2, IL10; redox enzymes CAT, HMOX1, and MPO; cardiovascular targets, like VEGFA, NOS3, and NOS2; and transmememial proteins CAV1 and INS. Network pharmacology analysis showed that the 18 compounds could be responsible for the treatment of chronic heart failure by regulating HIF-1 signaling pathways, PI3 K-Akt signaling pathways, cGMP-PKG signaling pathways, cAMP signaling pathways and TNF signaling pathways. This study provided a scientific basis for mechanism and effective ingredients of Shengxian Decoction.

Green Tea Consumption and Esophageal Cancer Risk: A Meta-analysis.

Background: The protective role of green tea against cancer is still unknown.Objectives: To investigate the association between green tea consumption and esophageal cancer risk through meta-analysis.Methods: We searched MEDLINE, EMBASE, Web of Science and Cochrane Library for studies on the relationship between green tea and esophageal cancer risk. We assessed heterogeneity (I2) and publication bias (Begg's and Egger's tests). Pooled relative risks (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random effects models.Results: A total of 20 studies were included. The RRs for all studies was 0.65 (95% CI: 0.57-0.73), with I2 = 75.3% and P = 0. In the subgroup analysis, the following variables showed marked heterogeneity: Asian (RR: 0.64; 95% CI: 0.56-0.73) and non-Asian countries (RR: 0.74; 95% CI: 0.45-1.03), female (RR: 0.55; 95% CI: 0.39-0.71) and male + female (RR: 0.64; 95% CI: 0.54-0.75), case-control study (RR: 0.62; 95% CI: 0.52-0.71), impact factor >3 (RR: 0.65; 95% CI: 0.56-0.75), impact factor <3 (RR: 0.64; 95% CI: 0.48-0.80), Newcastle-Ottawa Scale >7 (RR: 0.82; 95% CI: 0.66-0.97) and Newcastle-Ottawa Scale ≤7 (RR: 0.59; 95% CI: 0.49-0.68).Conclusion: Green tea consumption could be a protective factor for esophageal cancer.

A grading system from health to death using routine experimental indicators based on the pre-chronic disease status theory.

BACKGROUND: To establish a system for assessing pre-chronic disease status (PCDS) whereby changes in biomolecule levels occur before the appearance of physical damage to body organs. We based our study on the common biomarkers of aging, disease and end-of-life processes. METHODS: The red blood cell count as well as levels of albumin, creatinine and aspartate aminotransferase were used as indicators for measurement. The basic premise for determining PCDS was that the measured value was outside the reference range for a healthy individual. A binary outcome was determined according to reference range given by the laboratory undertaking the measurements. The Biological Age Index (BAI) was used to ascertain PCDS. RESULTS: The four indictors that we chose were sensitive for end-of-life and aging. The BAI score for each age group increased significantly with increasing age. The BAI score of patients with cardiac disease, cerebrovascular disease, cancer or chronic obstructive pulmonary disease were mostly higher than those in healthy age-matched people. CONCLUSION: A system for assessing PCDS centered on biomolecular detection and independent of the pathologic diagnosis could be effective.

[Application of traditional Chinese medicine(TCM) traceability system based on TCM quality characteristics and HACCP system].

It is crucial to establish a complete set of traditional Chinese medicine(TCM) quality traceability management process system, in order to stabilize the pricing order of TCM market and reconstruct the transmission path of TCM quality signals. In this study, we reviewed the mature experience of food and drug supervision at home and abroad, analyzed the quality characteristics of TCM, and put forward that the quality control of TCM products can learn from the hazard analysis and critical control point(HACCP) system in food safety quality control. This study points out that the HACCP system provides not only technical guidance for the traceability management of TCM, but also ideas for improving the quality of TCM products and the safety risk control of TCM. The application of the HACCP system in TCM quality control can help establish an international dialogue platform for TCM and help realize the modernization and internationalization of TCM industry.

Patient satisfaction of radiofrequency ablation for symptomatic benign solid thyroid nodules: our experience for 2-year follow up.

BACKGROUND: The patient satisfaction of symptoms improvement and disease factors that may affect long-term treatment efficacy of radiofrequency ablation (RFA) for non-functioning solid benign thyroid nodules (TNs) over a 2-year follow up study was investigated. METHODS: This retrospective study evaluated 194 non-functioning solid benign TNs of 103 patients. The TNs were categorized as small (≤5 ml), medium (5.1 to 13 ml), intermediate (13.1 to 30 ml) and large (over 30 ml) according to the initial volume of TNs before ablation. Clinical evaluation and contrast-enhanced ultrasound (CEUS) were carried out before ablation and the follow up at 1, 3, 6 months and every 6 months after ablation. All patients were asked to assess the cosmetic score (1-4 scores) and symptom score (0-10 scores) before ablation and every follow up after ablation. RESULTS: All patients underwent RFA without any major complications. The mean treatment sessions were 1.5 ± 0.6. 98 nodules required a single session (98/194, 50.5%), 87 required two sessions (87/194, 44.9%), 9 required three sessions (9/194, 4.6%). The average follow up months were 16.3 ± 5.6 (range, 6-24 months) and no nodule regrew in our study. After RFA treatment, the TNs volume significantly decreased (P < 0.001). The small group of nodules shrunk larger compared to the medium, intermediate and large groups (P < 0.001). Cosmetic signs and pressure symptoms were significantly improved, particularly in the intermediate and large groups (P < 0.05). CONCLUSIONS: RFA is effective for treating non-functioning solid benign TNs and controlling clinical symptoms with a low complication rate during 2 years follow up. The reduction rate was related to the initial volume of nodules. Patients were satisfied with cosmetic signs and pressure symptoms improvement, particularly in the intermediate and large groups. However, multiple RFA treatments should be used in larger nodules to achieve the desired clinical outcomes.

Establishment of an analysis model based on measurement of hepatitis B viral infection serum markers.

BACKGROUND: Using serum markers of hepatitis B virus (HBV) infection, we aimed to develop a quantitative model that explains the complicated immune response to this infection. METHODS: Serum samples from HBV-infected patients were randomly selected and divided into groups based on HBV-DNA positivity or negativity. Quantitative markers of HBV were measured. Formulae for Antibody index (IAb) [(anti-HBs * 1/anti-HBe + anti-HBs * 1/anti-HBc + 1/anti-HBc * 1/anti-HBe)0.5] and Antigen index (IAg) [(HBsAg * HBeAg)0.5] were introduced. RESULTS: IAg values were statistically higher (p < 0.05) in the HBV-DNA-positive group than in the -negative group, but no statistically significant difference in IAb values was observed. When IAb values were > 50, IAg values were mostly < 250; when IAg values were > 250, IAb values were mostly < 50. CONCLUSION: IAb and IAg values can efficiently reflect the status of immune response to HBV and may be suitable for assessment of the infection process and the possible outcome of infection.

[Correlation between Ultrasound-guided Fine-needle Aspiration Combined with BRAF V600EDetection and Invasive Pathological Features of Papillary Thyroid Cancer].

To analyze the potential associations of ultrasound-guided fine-needle aspiration(FNA),BRAF V600E gene mutation detection,and the combination of these two techniques with the clinicopathological features of papillary thyroid cancer(PTC). Methods Patients with PTC confirmed by surgery from April 2016 to July 2017 were included in this study.The relationship between clinicopathological features and BRAF V600E mutation,FNA results,and the combination of them were explored. Results The sensitivity of FNA was 86.3%(227/263)and the mutation rate of BRAF V600E was 85.9%(226/263)in 263 patients with PTC.The mutation rate of papillary thyroid microcarcinoma(PTMC)was 91.1%(153/168)and that of non-PTMC was 76.8%(73/95).A total of 225 patients underwent lymph node dissection.The lymph node metastasis rate was 35.6%(80/225),and it was 23.8%(34/143)in PTMC,56.1%(46/82)in non-PTMC;in addition,9.9%(26/263)of PTC patients had extracapsular invasion.BRAF V600E mutation rate was higher in patients with the following features:aged over 45 years(P=0.043);the tumor was FNA diagnosed as malignant or suspected malignant(P=0.011);the tumor had a maximum diameter of ≤1 cm(P=0.001);and the primary tumor was in stage T1(P=0.039);however,there was no significant difference in BRAF V600E mutation rate among patients with different sex,capsule invasion,or lymph node metastasis.The diagnostic sensitivity of FNA was not statistically different under different clinical and pathological characteristics.The clinicopathologic features of FNA and BRAF V600E double-positive patients were not significantly different from those of other patients. Conclusion FNA-confirmed malignancy,BRAF V600E gene mutation,and their double-positive results are not correlated with the invasive pathological features of PTC,and thus their roles in guiding an extended operation(or not)are limited.

LINC00968 functions as an oncogene in osteosarcoma by activating the PI3K/AKT/mTOR signaling.

Osteosarcoma is recognized as a malignant tumor in the skeletal system. Long non-coding RNAs (lncRNAs) have been exhibited to play crucial roles in osteosarcoma development. Our current study focused on the biological effects and mechanism of LINC00968 in osteosarcoma pathogenesis. We observed that LINC00968 was dramatically elevated in osteosarcoma cells including U2OS, MG63, Saos-2, SW1353, and 143-B cells compared to human osteoblast cell line hFOB. Silence of LINC00968 inhibited osteosarcoma cell growth and proliferation in vitro. Reversely, overexpression of LINC00968 promoted osteosarcoma cell survival and cell colony formation ability in Saos-2 and 143-B cells. In addition, LINC00968 was able to induce osteosarcoma cell migration and invasion through up-regulating MMP-2 and MMP-9 protein levels. The phosphoinosmde-3-kinase/Protein Kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway has been reported to participate in several cancer types. Here, in our study, we found that PI3K/AKT/mTOR pathway was involved in osteosarcoma progression. Knockdown of LINC00968 inactivated PI3K/AKT/mTOR signaling pathway in vitro. Subsequently, in vivo tumor xenografts were established using 143-B cells to investigate whether LINC00968 can induce osteosarcoma development in vivo. Consistently, it was indicated that inhibition of LINC00968 significantly inhibited osteosarcoma progression in vivo. Taken these together, in our research, LINC00968 could be provided as a novel prognostic biomarker and therapeutic target in osteosarcoma diagnosis and treatment.

RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis.

BACKGROUND/AIMS: Effective drug treatment for intrahepatic cholangiocarcinoma (ICC) is currently lacking. Therefore, there is an urgent need for new targets and new drugs that can prolong patient survival. Recently targeting the ubiquitin proteasome pathway has become an attractive anti-cancer strategy. In this study, we aimed to evaluate the therapeutic effect of and identify the potential mechanisms involved in targeting the proteasome subunit ADRM1 for ICC. METHODS: The expression of ADRM1 and its prognostic value in ICC was analyzed using GEO and TCGA datasets, tumor tissues, and tumor tissue arrays. The effects of RA190 on the proliferation and survival of both established ICC cell lines and primary ICC cells were examined in vitro. Annexin V/propidium iodide staining, western blotting and immunohistochemical staining were performed. The in vivo anti-tumor effect of RA190 on ICC was validated in subcutaneous xenograft and patient-derived xenograft (PDX) models. RESULTS: ADRM1 levels were significantly higher in ICC tissues than in normal bile duct tissues. ICC patients with high ADRM1 levels had worse overall survival (hazard ratio [HR] = 2.383, 95% confidence interval [CI] =1.357 to 4.188) and recurrence-free survival (HR = 1.710, 95% CI =1.045 to 2.796). ADRM1 knockdown significantly inhibited ICC growth in vitro and in vivo. The specific inhibitor RA190 targeting ADRM1 suppressed proliferation and reduced cell vitality of ICC cell lines and primary ICC cells significantly in vitro. Furthermore, RA190 significantly inhibited the proteasome by inactivating ADRM1, and the consequent accumulation of ADRM1 substrates decreased the activating levels of NF-κB to aggravate cell apoptosis. The therapeutic benefits of RA190 treatment were further demonstrated in both subcutaneous implantation and PDX models. CONCLUSIONS: Our findings indicate that up-regulated ADRM1 was involved in ICC progression and suggest the potential clinical application of ADRM1 inhibitors (e.g., RA190 and KDT-11) for ICC treatment.

Molecular mechanism of seed dormancy release induced by fluridone compared with cod stratification in Notopterygium incisum.

BACKGROUND: Notopterygium incisum is an important Chinese medicinal plant. Its mature seeds have underdeveloped embryos and are physiological dormant. We found the seeds with full developed embryos can germinate after treated by fluridone (FL), an inhibitor of abscisic acid (ABA). In order to understand the molecular mechanisms underlying seed dormancy release by FL, we compared the transcriptomic changes in dormancy release induced by two different methods, FL and cold stratification (CS) in N. incisum. We further analyzed the gene expression patterns involved in seed germination and dormancy using quantitative reverse-transcription PCR. RESULTS: RNA-sequence analysis revealed more dramatic changes in the transcriptomes of FL than those in CS, particularly for genes involved in the biosynthesis and regulation of gibberellins (GAs) and ABA. The down-regulation of ABA biosynthesis genes and the dramatic up-regulation of NiCYP707As, an ABA catabolic gene, contributed to the reduced ABA levels in FL. The increased GA3 levels in CS-treated seeds were due to the up-regulation of NiGA3OX. Both NiABI5 (a positive ABA regulator) and NiGAI (a negative regulator of GA) were down-regulated in FL and CS. The upregulation of strigolactones (SLs; the metabolites with the same precursor as ABA) biosynthesis and regulatory genes in both FL- and CS-treated seeds indicates that SLs contribute positively to seed dormancy release in N. incisum. CONCLUSIONS: Our results indicated that FL- and CS-seed dormancy release possibly depends on two totally different mechanisms: alleviation of the effects of ABA and potentiation of the effects of GA, respectively. However, NiABI5 and NiGAI probably function as common factors integrating the effects of ABA and GA on seed dormancy release.

Effects of Parathyroidectomy on Plasma iPTH and (1-84) PTH Levels in Patients with Stage 5 Chronic Kidney Disease.

Currently, the second-generation intact parathyroid hormone (iPTH) assay is commonly used for measuring PTH levels. The iPTH assay detects both full-length (1-84)PTH and (7-84)PTH fragments, which have antagonistic effects on (1-84)PTH in bones and kidneys. The third-generation PTH assay is specific for (1-84)PTH. This study examined the features of different PTH fragments in stage 5 chronic kidney disease (CKD) and the effects of parathyroidectomy (PTX) on the above markers in severe secondary hyperparathyroidism (SHPT) patients. The cross-sectional study included 262 stage 5 CKD patients and 90 controls. A prospective follow-up study was then conducted in 34 PTX patients. Second- and third-generation assays were used to measure plasma iPTH and (1-84)PTH levels, respectively. Circulating (7-84)PTH levels were calculated by subtracting the (1-84)PTH value from the iPTH value. Different plasma PTH fragments were higher, and (1-84)PTH/iPTH was lower in CKD patients than in controls. Plasma (1-84)PTH and (7-84)PTH concentrations increased as iPTH levels increased, and (7-84)PTH increased more evidently. Plasma iPTH, (1-84)PTH and (7-84)PTH levels were 1530.5 (885.0-2111.5) pg/ml, 683.1 (431.4-1018.0) pg/ml, and 739.3 (452.6-1261.0) pg/ml, respectively, in PTX patients. Plasma iPTH, (1-84)PTH and (7-84)PTH concentrations decreased considerably, and the (1-84)PTH/iPTH ratio increased after PTX (median follow-up interval: 10.9 months). Stage 5 CKD patients had higher plasma levels of different PTH fragments, and lower (1-84)PTH/iPTH ratio. PTX could significantly reverse these abnormalities in severe SHPT patients. The iPTH assay overestimated the function of the parathyroid glands; thus, the third-generation PTH assay is likely better for the management of CKD patients.

Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies, outcomes, and IgM rebound.

Ibrutinib is the first approved therapy for symptomatic patients with Waldenström macroglobulinemia (WM). The reasons for discontinuing ibrutinib and subsequent outcomes have not been previously evaluated in WM patients. We therefore conducted a retrospective review of 189 WM patients seen at our institution who received treatment with ibrutinib, of whom 51 (27%) have discontinued therapy. Reasons for discontinuation include: disease progression (n = 27; 14%), toxicity (n = 15; 8%), nonresponse (n = 5; 3%), and other unrelated reasons (n = 4; 2%). The cumulative incidence of ibrutinib discontinuation at 12, 24, 36, and 48 months from treatment initiation was 22%, 26%, 35%, and 43%, respectively. A baseline platelet count ≤100 K/µL and presence of tumor CXCR4 mutations were independently associated with 4-fold increased odds of ibrutinib discontinuation. An IgM rebound (≥25% increase in serum IgM) was observed in 37 patients (73%) following ibrutinib discontinuation and occurred within 4 weeks for nearly half of patients. The response rate to salvage therapy was 71%; responses were higher in patients without an IgM rebound and when salvage therapy was initiated within 2 weeks of stopping ibrutinib. Patients who discontinued ibrutinib due to disease progression versus nonprogression events had significantly shorter overall survival (21 versus 32 months; P = .046). Response to salvage therapy was associated with an 82% reduction in the risk of death following ibrutinib discontinuation. WM patients who discontinue ibrutinib require close monitoring, and continuation of ibrutinib until the next therapy should be considered to maintain disease control.