New aporphine alkaloids with antitumor activities from the roots of Thalictrum omeiense.

Two new aporphine alkaloids, 6aR-2'-(3-oxobutenyl)-thaliadin (1) and N-methylthalisopynine (2), along with ten known analogs (3-12), were isolated from the roots of Thalictrum omeiense W. T. Wang et S. H. Wang. Their structures were determined by extensive spectroscopic and X-ray crystallographic analyses. Compounds 1-7 and 9-12 were tested for their antiproliferative effects in vitro against two human cancer cell lines (A549 and MCF-7). Among them, compounds 1, 3, and 7 exhibited moderate inhibitory activity against the tested cell lines with IC50 values ranging from 23.73 to 34.97 µM.

CT Radiomics for the Prediction of Synchronous Distant Metastasis in Clear Cell Renal Cell Carcinoma.

PURPOSE: The aim of this study was to construct and verify a computed tomography (CT) radiomics model for preoperative prediction of synchronous distant metastasis (SDM) in clear cell renal cell carcinoma (ccRCC) patients. METHODS: Overall, 172 patients with ccRCC were enrolled in the present research. Contrast-enhanced CT images were manually sketched, and 2994 quantitative radiomic features were extracted. The radiomic features were then normalized and subjected to hypothesis testing. Least absolute shrinkage and selection operator (LASSO) was applied to dimension reduction, feature selection, and model construction. The performance of the predictive model was validated through analysis of the receiver operating characteristic curve. Multivariate and subgroup analyses were performed to verify the radiomic score as an independent predictor of SDM. RESULTS: The patients randomized into a training (n = 104) and a validation (n = 68) cohort in a 6:4 ratio. Through dimension reduction using LASSO regression, 9 radiomic features were used for the construction of the SDM prediction model. The model yielded moderate performance in both the training (area under the curve, 0.89; 95% confidence interval, 0.81-0.97) and the validation cohort (area under the curve, 0.83; 95% confidence interval, 0.69-0.95). Multivariate analysis showed that the CT radiomic signature was an independent risk factor for clinical parameters of ccRCC. Subgroup analysis revealed a significant connection between the SDM and radiomic signature, except for the lower pole of the kidney subgroup. CONCLUSIONS: The CT-based radiomics model could be used as a noninvasive, personalized approach for SDM prediction in patients with ccRCC.

Factors associated with insomnia in older adult outpatients vary by gender: a cross-sectional study.

BACKGROUND: Insomnia is a common sleep disturbance in older adults and is associated with many poor health outcomes. This study aimed to explore factors associated with insomnia in older adult outpatient clinics, and to further analyze the influence of gender on factors associated with insomnia. METHODS: This cross-sectional study was conducted in the outpatient clinics of a tertiary hospital in Southern Taiwan from July to September 2018. A total of 400 consecutive subjects aged 60 years or older were recruited. Insomnia was defined as a score of ≥6 points on the Athens Insomnia Scale (AIS). Socio-demographics, health behaviors and clinical data were collected by face-to-face interview. Multivariable logistic regression was adopted for statistical analysis of the entire sample and stratified by gender. RESULTS: Participants' mean age was 74.74 ± 8.54 years, and the majority (93%) had more than one chronic disease. The prevalence of insomnia accounted for 30% (120/400) of all subjects, with males 22.9% (46/201) and females 37.2% (74/199). Gender, appetite, exercise, depressive symptoms, and sleep-related conditions such as short sleep duration, sleeping pills usage, medium-high risk of obstructive sleep apnea (OSA) and restless leg syndrome (RLS) were factors associated with insomnia in older adults. Exercise, sleeping pills usage, and RLS were independently associated with insomnia only in men, while appetite and medium-high risk of OSA were associated with insomnia in women only. In addition, after further adjusting for covariates, prevalence of the insomnia-related symptoms such as sleep induction, total sleep duration, sleep quality and sleepiness during the day was significantly higher in females than in males. CONCLUSIONS: Insomnia symptoms are highly prevalent among older adults, predominantly females. Significant differences are found between genders in factors associated with insomnia and insomnia-related symptoms. Understanding gender differences may help clinicians to modify associated factors when managing older adults with insomnia.

Clinical aggressiveness of myxofibrosarcomas associates with down-regulation of p12CDK2AP1: prognostic implication of a putative tumor suppressor that induces cell cycle arrest and apoptosis via mitochondrial pathway.

BACKGROUND: Attenuated endogenous protein levels of cyclin-dependent kinase 2 associated protein 1 (p12(CDK2AP1)) and its active homodimer p25(CDK2AP1) were found in myxofibrosarcoma-derived cell lines. Clinical and biological significances of this putative tumor suppressor in myxofibrosarcoma were studied. METHODS: Plasmids carrying the CDK2AP1 gene and small hairpin RNA interference (shRNAi) targeting CDK2AP1 were transfected into NMFH-1 and/or OH931 cells to evaluate the effects on the CDK2, active caspase 3 (CASP3), cleaved-CASP8 and -CASP9 levels, cell cycle regulation, and/or apoptotic responses. Immunostaining of p12(CDK2AP1) was interpretable in 102 primary myxofibrosarcomas and correlated with clinicopathological variables, CDK2, Ki-67 and active CASP3 protein levels, and disease-specific survival. RESULTS: Exogenous expression of p12(CDK2AP1) in NMFH-1 and OH931 cells significantly induced G0/G1 cell cycle arrest and down-regulated CDK2 protein level. In NMFH-1 cells, these aspects were reversed by shRNAi targeting CDK2AP1 gene. Increased active CASP3 and cleaved-CASP9, but not -CASP8, were detected after CDK2AP1 overexpression, suggesting the cellular apoptosis were induced through the mitochondrial pathway. Immunostains of p12(CDK2AP1) were aberrantly decreased in 56.9 % of cases; positively and negatively correlated with protein levels of CDK2 (p = 0.023), Ki-67 (p = 0.001) and active CASP3 (p < 0.001), respectively. Following by high histological grades, p12(CDK2AP1) down-regulation was predictive of worse disease-specific survival in univariate (p = 0.003) and multivariate (p = 0.004) analyses. CONCLUSIONS: Through down-regulation of CDK2, high p12(CDK2AP1) level induced cell cycle arrest and the mitochondrial-dependent apoptotic pathway. Low p12(CDK2AP1) level represents a poor prognostic factor in patients with myxofibrosarcoma.

Tumor necrosis factor-α inhibitor for successful treatment of toxic epidermal necrolysis with severe infection: a case series.

Toxic epidermal necrolysis (TEN) is a rare severe cutaneous adverse reaction that involves more than 30% of the body surface area. TEN can be accompanied by a series of systemic symptoms and has a high risk of death. Tumor necrosis factor (TNF)-α inhibitors such as adalimumab and etanercept have been shown to be safe and effective for the treatment of TEN in some cases. However, clinical data on the use of TNF-α inhibitors to treat TEN with severe systemic infection are scarce. In the present study, three adult patients who developed TEN with serious active infection were successfully treated with etanercept. One of the three patients had active open pulmonary tuberculosis, and the other two had septicemia and/or fungal sepsis. All patients' skin lesions significantly improved after several days, and none of the patients developed emerging or re-emerging infectious diseases, adverse reactions, or a similar rash during follow-up. TNF-α inhibitors may be an effective treatment choice for TEN with severe systemic infection. However, further studies with large samples are still required for validation because clinical experience is limited.

Acupuncture, an effective treatment for post-stroke neurologic dysfunction.

Stroke episodes represent a significant subset of cerebrovascular diseases globally, often resulting in diverse neurological impairments such as hemiparesis, spasticity, dysphagia, sensory dysfunction, cognitive impairment, depression, aphasia, and other sequelae. These dysfunctions markedly diminish patients' quality of life and impose substantial burdens on their families and society. Consequently, the restoration of neurological function post-stroke remains a primary objective of clinical treatment. Acupuncture, a traditional Chinese medicine technique, is endorsed by the World Health Organization (WHO) for stroke treatment due to its distinct advantages in managing cerebrovascular diseases, including ischemic stroke. Numerous clinical studies have substantiated the efficacy of acupuncture in ameliorating neurological dysfunctions following stroke. This review systematically examines the improvements in post-stroke neurological dysfunction attributable to acupuncture treatment and elucidates potential mechanisms of action proposed in recent years. Additionally, this article aims to present novel therapeutic concepts and strategies for the clinical management of post-stroke neurological dysfunction.

Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of Ser7²7 on STAT3 in prostate cancer cells.

Cyclin-dependent kinase 5 (Cdk5) is known to regulate prostate cancer metastasis. Our previous results indicated that Cdk5 activates androgen receptor (AR) and supports prostate cancer growth. We also found that STAT3 is a target of Cdk5 in promoting thyroid cancer cell growth, whereas STAT3 may play a role as a regulator to AR activation under cytokine control. In this study, we investigated the regulation of Cdk5 and its activator p35 on STAT3/AR signaling in prostate cancer cells. Our results show that Cdk5 biochemically interacts with STAT3 and that this interaction depends on Cdk5 activation in prostate cancer cells. The phosphorylation of STAT3 at Ser7²7 (p-Ser7²7-STAT3) is regulated by Cdk5 in cells and xenograft tumors. The mutant of STAT3 S727A reduces its interaction with Cdk5. We further show that the nuclear distribution of p-Ser7²7-STAT3 and the expression of STAT3-regulated genes (junB, c-fos, c-myc, and survivin) are regulated by Cdk5 activation. STAT3 mutant does not further decrease cell proliferation upon Cdk5 inhibition, which implies that the role of STAT3 regulated by Cdk5 correlates to cell proliferation control. Interestingly, Cdk5 may regulate the interaction between STAT3 and AR through phosphorylation of Ser7²7-STAT3 and therefore upregulate AR protein stability and transactivation. Correspondingly, clinical evidence shows that the level of p-Ser7²7-STAT3 is significantly correlated with Gleason score and the levels of upstream regulators (Cdk5 and p35) as well as downstream protein (AR). In conclusion, this study demonstrates that Cdk5 regulates STAT3 activation through Ser7²7 phosphorylation and further promotes AR activation by protein-protein interaction in prostate cancer cells.

Predicting the Risk of Nail Involvement in Psoriasis Patients: Development and Assessment of a Predictive Nomogram.

BACKGROUND: Nail involvement has a tremendous impact on psoriasis patients. Early detection and prompt intervention of psoriatic nail damage are necessary. METHODS: A total of 4290 patients confirmed to have psoriasis between June 2020 and September 2021 were recruited from the Follow-up Study of Psoriasis database. Among them, 3920 patients were selected and divided into the nail involvement group (n = 929) and the non-nail involvement group (n = 2991) by inclusion and exclusion criteria. Univariate and multivariable logistic regression analyses were performed to identify the predictors of nail involvement for the nomogram. Calibration plots, the receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to evaluate the discriminative and calibrating ability and clinical utility of the nomogram. RESULTS: Sex, age at onset, duration, smoking, drug allergy history, comorbidity, sub-type of psoriasis, scalp involvement, palmoplantar involvement, genital involvement, and PASI score were selected to establish the nomogram for nail involvement. AUROC (0.745; 95% CI: 0.725-0.765) indicated the satisfactory discriminative ability of the nomogram. The calibration curve showed favorable consistency, and the DCA showed the good clinical utility of the nomogram. CONCLUSION: A predictive nomogram with good clinical utility was developed to assist clinicians in evaluating the risk of nail involvement in psoriasis patients.

miR167d-ARFs Module Regulates Flower Opening and Stigma Size in Rice.

Flower opening and stigma exertion are two critical traits for cross-pollination during seed production of hybrid rice (Oryza sativa L.). In this study, we demonstrate that the miR167d-ARFs module regulates stigma size and flower opening that is associated with the elongation of stamen filaments and the cell arrangement of lodicules. The overexpression of miR167d (OX167d) resulted in failed elongation of stamen filaments, increased stigma size, and morphological alteration of lodicule, resulting in cleistogamy. Blocking miR167d by target mimicry also led to a morphological alteration of the individual floral organs, including a reduction in stigma size and alteration of lodicule cell morphology, but did not show the cleistogamous phenotype. In addition, the four target genes of miR167d, namely ARF6, ARF12, ARF17, and ARF25, have overlapping functions in flower opening and stigma size. The loss-of-function of a single ARF gene did not influence the flower opening and stigma size, but arf12 single mutant showed a reduced plant height and aborted apical spikelets. However, mutation in ARF12 together with mutation in either ARF6, ARF17, or ARF25 led to the same defective phenotypes that were observed in OX167d, including the failed elongation of stamen filaments, increased stigma size, and morphological alteration of lodicule. These findings indicate that the appropriate expression of miR167d is crucial and the miR167d-ARFs module plays important roles in the regulation of flower opening and stigma size in rice.

Relationship of interleukin-8 gene polymorphisms with hepatocellular carcinoma susceptibility and pathological development.

BACKGROUND AND OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide, and the second leading cause of death from cancer in Taiwan. Interleukin-8 (IL-8) is an angiogenic chemokine with important roles in the development and progression of many human malignancies including HCC. This study investigates the effects of single-nucleotide polymorphisms (SNPs) in the IL-8 gene on the susceptibility and clinicopathological characteristics of HCC. METHODS: One hundred thirty-one HCC patients and 340 control subjects were analyzed for four IL-8 SNPs (-251 T/A, +781 C/T, +1633 C/T, and +2767 A/T) using PCR-RFLP genotyping analysis. RESULTS: After adjusting for other confounders, results show that individuals with the IL-8 +781 T/T polymorphic genotype had a significantly lower risk of developing HCC than those with the wild-type (C/C) genotype (AOR = 0.346; 95% CI: 0.132-0.909). Multiple regression analysis showed that the presence of T/A or A/A at IL-8 -251 may indicate higher potential risk of hepatitis B infection (AOR = 2.847; 95% CI: 1.083-8.656). Additionally, these four IL-8 SNPs did not associate with liver-related clinicopathological markers in serum. CONCLUSIONS: Genetic polymorphism at IL-8 +781 is an important factor in determining susceptibility to HCC in the Taiwanese population.

Engineering an Indium Selenide van der Waals Interface for Multilevel Charge Storage.

As the continuous miniaturization of floating-gate transistors approaches a physical limit, new innovations in device architectures, working principles, and device materials are in high demand. This study demonstrated a nonvolatile memory structure with multilevel data storage that features a van der Waals gate architecture made up of a partially oxidized surface layer/indium selenide (InSe) van der Waals interface. The key functionality of this proof-of-concept device is provided through the generation of charge-trapping sites via an indirect oxygen plasma treatment on the InSe surface layer. In contrast to floating-gate nonvolatile memory, these sites have the ability to retain charge without the help of a gate dielectric. Together with the layered structure, the surface layer with charge-trapping sites facilitates continual electrostatic doping in the underlying InSe layers. The van der Waals gating effect is further supported by trapped charge-induced core-level energy shifts and relative work function variations obtained from operando scanning X-ray photoelectron spectroscopy and Kelvin probe microscopy, respectively. On modulating the amount of electric field-induced trapped electrons by the electrostatic gate potential, eight distinct storage states remained over 3000 s. Moreover, the device exhibits a high current switching ratio of 106 within 11 cycles. The demonstrated characteristics suggest that the engineering of an InSe interface has potential applications for nonvolatile memory.

Constructing a superhydrophobic surface on polydimethylsiloxane via spin coating and vapor-liquid sol-gel process.

In this study, a superhydrophobic surface on polydimethylsiloxane (PDMS) substrate was constructed via the proposed vapor-liquid sol-gel process in conjunction with spin coating of dodecyltrichlorosilane (DTS). Unlike the conventional sol-gel process where the reaction takes place in the liquid phase, layers of silica (SiO(2)) particles were formed through the reaction between the reactant spin-coated on the PDMS surface and vapor of the acid solution. This led to the SiO(2) particles inlaid on the PDMS surface. Followed by subsequent spin coating of DTS solution, the wrinkle-like structure was formed, and the static contact angle of the water droplet on the surface could reach 162 degrees with 2 degrees sliding angle and less than 5 degrees contact angle hysteresis. The effect of layers of SiO(2) particles, concentrations of DTS solution and surface topography on superhydrophobicity of the surface is discussed.

Preoperative Ultrasound Radiomics Signatures for Noninvasive Evaluation of Biological Characteristics of Intrahepatic Cholangiocarcinoma.

RATIONALE AND OBJECTIVES: The purpose of this study was to establish and validate radiomics signatures based on ultrasound (US) medicine images to assess the biological behaviors of intrahepatic cholangiocarcinoma (ICC) in a noninvasive manner. MATERIALS AND METHODS: This study consisted of 128 ICC patients. We focused on evaluating six pathological features: microvascular invasion, perineural invasion, differentiation, Ki-67, vascular endothelial growth factor, and cytokeratin 7. Region of interest (ROI) of ICC was identified by manually plotting the tumor contour on the grayscale US image. We extracted radiomics features from medical US imaging. Then, dimensionality reduction methods and classifiers were used to develop radiomic signatures for evaluating six pathological features in ICC. Finally, independent validation datasets were used to assess the radiomic signatures performance. RESULTS: We extracted 1076 quantitative characteristic parameters on the US medicine images. Based on extracted radiomics features, the best performing radiomic signatures for evaluating microvascular invasion features were produced by hypothetical test + support vector machine (SVM), perineural invasion subgroup were least absolute shrinkage and selection operator + principal component analysis + support vector machine, differentiation subgroup were hypothetical test + decision tree, Ki-67 subgroup were hypothetical test + logistic regression, vascular endothelial growth factor subgroup were hypothetical test + Gradient Boosting Decision Tree (GBDT), and cytokeratin 7 subgroup were hypothetical test + bagging, respectively. CONCLUSION: Through the high-throughput radiomics analysis based on US medicine images, we proposed radiomics signatures that have moderate efficiency in predicting the biological behaviors of ICC noninvasively.

Radiomic profiles in diffuse glioma reveal distinct subtypes with prognostic value.

PURPOSE: To evaluate a radiomic approach for the stratification of diffuse gliomas with distinct prognosis and provide additional resolution of their clinicopathological and molecular characteristics. METHODS: For this retrospective study, a total of 704 radiomic features were extracted from the multi-channel MRI data of 166 diffuse gliomas. Survival-associated radiomic features were identified and submitted to distinguish glioma subtypes using consensus clustering. Multi-layered molecular data were used to observe the different clinical and molecular characteristics between radiomic subtypes. The relative profiles of an array of immune cell infiltrations were measured gene set variation analysis approach to explore differences in tumor immune microenvironment. RESULTS: A total of 6 categories, including 318 radiomic features were significantly correlated with the overall survival of glioma patients. Two subgroups with distinct prognosis were separated by consensus clustering of radiomic features that significantly associated with survival. Histological stage and molecular factors, including IDH status and MGMT promoter methylation status were significant differences between the two subtypes. Furthermore, gene functional enrichment analysis and immune infiltration pattern analysis also hinted that the inferior prognosis subtype may more response to immunotherapy. CONCLUSION: A radiomic model derived from multi-parameter MRI of the gliomas was successful in the risk stratification of diffuse glioma patients. These data suggested that radiomics provided an alternative approach for survival estimation and may improve clinical decision-making.

Reduced expression of microRNA-139-5p in hepatocellular carcinoma results in a poor outcome: An exploration the roles of microRNA-139-5p in tumorigenesis, advancement and prognosis at the molecular biological level using an integrated meta-analysis and bioinformatic investigation.

Hepatocellular carcinoma (HCC) is generally considered one of the most common gastrointestinal malignant tumors, characterized by high invasiveness and metastatic rate, as well as insidious onset. A relationship between carcinogenicity and aberrant microRNA-139-5p (miR-139-5p) expression has been identified in multiple tumors while the specific molecular mechanisms of miR-139-5p in HCC have not yet been thoroughly elucidated. A meta-analysis of available data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus, ArrayExpress and Oncomine databases, as well as the published literature, was comprehensively conducted with the aim of examining the impact of miR-139-5p expression on HCC. Additionally, predicted downstream target genes were confirmed using a series of bioinformatics tools. Moreover, a correlative biological analysis was performed to ascertain the precise function of miR-139-5p in HCC. The results revealed that the expression of miR-139-5p was noticeably lower in HCC compared with non-tumor liver tissues according to the pooled standard mean difference, which was -0.84 [95% confidence interval (CI): -1.36 to -0.32; P<0.001]. Furthermore, associations were detected between miR-139-5p expression and certain clinicopathological characteristics of TCGA samples, including tumor grade, pathological stage and T stage. Moreover, the pooled hazard ratio (HR) for overall survival (HR=1.37; 95% CI: 1.07-1.76; P=0.001) indicated that decreased miR-139-5p expression was a risk factor for adverse outcomes. Additionally, 382 intersecting genes regulated by miR-139-5p were obtained and assembled in signaling pathways, including 'transcription factor activity, sequence-specific DNA binding', 'pathways in cancer' and 'Ras signaling pathway'. Notably, four targeted genes that were focused in 'pathways in cancer' were identified as hub genes and immunohistochemical staining of the proteins encoded by these four hub genes in liver tissues, explored using the Human Protein Atlas database, confirmed their expression patterns in HCC and normal liver tissues Findings of the present study suggest that reduced miR-139-5p expression is capable of accelerating tumor progression and is associated with a poor clinical outcome by modulating the expression of downstream target genes involved in tumor-associated signaling pathways.

Irradiance-dependent UVB Photocarcinogenesis.

Ultraviolet B (UVB) radiation from the sun may lead to photocarcinogenesis of the skin. Sunscreens were used to protect the skin by reducing UVB irradiance, but sunscreen use did not reduce sunburn episodes. It was shown that UVB-induced erythema depends on surface exposure but not irradiance of UVB. We previously showed that irradiance plays a critical role in UVB-induced cell differentiation. This study investigated the impact of irradiance on UVB-induced photocarcinogenesis. For hairless mice receiving equivalent exposure of UVB radiation, the low irradiance (LI) UVB treated mice showed more rapid tumor development, larger tumor burden, and more keratinocytes harboring mutant p53 in the epidermis as compared to their high irradiance (HI) UVB treated counterpart. Mechanistically, using cell models, we demonstrated that LI UVB radiation allowed more keratinocytes harboring DNA damages to enter cell cycle via ERK-related signaling as compared to its HI UVB counterpart. These results indicated that at equivalent exposure, UVB radiation at LI has higher photocarcinogenic potential as compared to its HI counterpart. Since erythema is the observed sunburn at moderate doses and use of sunscreen was not found to associate with reduced sunburn episodes, the biological significance of sunburn with or without sunscreen use warrants further investigation.

Cdk5 Directly Targets Nuclear p21CIP1 and Promotes Cancer Cell Growth.

The significance of Cdk5 in cell-cycle control and cancer biology has gained increased attention. Here we report the inverse correlation between the protein levels of Cdk5 and p21CIP1 from cell-based and clinical analysis. Mechanistically, we identify that Cdk5 overexpression triggers the proteasome-dependent degradation of p21CIP1 through a S130 phosphorylation in a Cdk2-independent manner. Besides, the evidence from cell-based and clinical analysis shows that Cdk5 primarily regulates nuclear p21CIP1 protein degradation. S130A-p21CIP1 mutant enables to block either its protein degradation or the increase of cancer cell growth caused by Cdk5. Notably, Cdk5-triggered p21CIP1 targeting primarily appears in S-phase, while Cdk5 overexpression increases the activation of Cdk2 and its interaction with DNA polymerase δ. The in vivo results show that Cdk2 might play an important role in the downstream signaling to Cdk5. In summary, these findings suggest that Cdk5 in a high expression status promotes cancer growth by directly and rapidly releasing p21CIP1-dependent cell-cycle inhibition and subsequent Cdk2 activation, which illustrates an oncogenic role of Cdk5 potentially applied for future diagnosis and therapy. Cancer Res; 76(23); 6888-900. ©2016 AACR.

Epidemiology, management, and economic evaluation of screening of gallstone disease among type 2 diabetics: A systematic review.

The knowledge of gallstone disease (GSD) is crucial to manage this condition when organizing screening and preventive strategies and identifying the appropriated clinical therapies. Although cholecystectomy still be the gold standard treatment for patients with symptomatic GSD, expectant management could be viewed as a valid therapeutic method for this disorder. If early treatment of GSD decreases the morbidity or avoids further cholecystectomy, it may save clinical care costs in later disease periods sufficiently to offset the screening and early treatment costs. In addition, whether routine screening for GSD is worthwhile depends on whether patients are willing to pay the ultrasonography screening cost that would reduce the risk of cholecystectomy. In this review we discuss the epidemiology, management, and economic evaluation of screening of GSD among type 2 diabetics.

Upregulation of cyclin-dependent kinase inhibitors CDKN1B and CDKN1C in hepatocellular carcinoma-derived cells via goniothalamin-mediated protein stabilization and epigenetic modifications.

Cell cycle deregulation is common in human hepatocellular carcinoma (HCC). To ensure proper cell cycle controlling, cyclin/cyclin-dependent kinases (CDK) complexes are tightly regulated by CDK inhibitors (CKIs) in normal cells. However, insufficient cyclin-dependent kinase inhibitor 1B (CDKN1B, also known as p27Kip1) and CDKN1C (p57Kip2) proteins are characteristics of high-risk HCC. In two HCC-derived cell lines with distinct genetic backgrounds, we identified a small natural compound, goniothalamin (GTN), serving as an inducer of CKIs. In TP53-mutated (Y220C) and retinoblastoma 1 (RB1)-positive Huh-7 cells, GTN stabilized CDKN1B protein levels by targeting the degradation of its specific E3 ubiquitin ligase (S-phase kinase-associated protein 2). Alternatively, in TP53- and RB1-negative Hep-3B cells, GTN increased CDKN1C transcription and its subsequent translation by acting as a histone deacetylase inhibitor. In both cell lines, GTN induced G0/G1 cell cycle arrest, delayed S phase entry of cells and inhibited anchorage-independent cell growth which might be attributed to the upregulation of CKIs and downregulation of several positive cell cycle regulators, including CDC28 protein kinase regulator subunit 1B, cyclin E1 and D1, cyclin-dependent kinase 2 (CDK2), CDK4, CDK6, E2F transcription factor 1 and/or transcription factor Dp-1. Therefore, GTN might represent a novel class of anticancer drug that induces CKIs through post-translational and epigenetic modifications.