Diagnostic Model for Proliferative HCC Using LI-RADS: Assessing Therapeutic Outcomes in Hepatectomy and TKI-ICI Combination.

BACKGROUND: Proliferative hepatocellular carcinoma (HCC), aggressive with poor prognosis, and lacks reliable MRI diagnosis. PURPOSE: To develop a diagnostic model for proliferative HCC using liver imaging reporting and data system (LI-RADS) and assess its prognostic value. STUDY TYPE: Retrospective. POPULATION: 241 HCC patients underwent hepatectomy (90 proliferative HCCs: 151 nonproliferative HCCs), divided into the training (N = 167) and validation (N = 74) sets. 57 HCC patients received combination therapy with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). FIELD STRENGTH/SEQUENCE: 3.0 T, T1- and T2-weighted, diffusion-weighted, in- and out-phase, T1 high resolution isotropic volume excitation and dynamic gadoxetic acid-enhanced imaging. ASSESSMENT: LI-RADS v2018 and other MRI features (intratumoral artery, substantial hypoenhancing component, hepatobiliary phase peritumoral hypointensity, and irregular tumor margin) were assessed. A diagnostic model for proliferative HCC was established, stratifying patients into high- and low-risk groups. Follow-up occurred every 3-6 months, and recurrence-free survival (RFS), progression-free survival (PFS) and overall survival (OS) in different groups were compared. STATISTICAL TESTS: Fisher's test or chi-square test, t-test or Mann-Whitney test, logistic regression, Harrell's concordance index (C-index), Kaplan-Meier curves, and Cox proportional hazards. Significance level: P < 0.05. RESULTS: The diagnostic model, incorporating corona enhancement, rim arterial phase hyperenhancement, infiltrative appearance, intratumoral artery, and substantial hypoenhancing component, achieved a C-index of 0.823 (training set) and 0.804 (validation set). Median follow-up was 32.5 months (interquartile range [IQR], 25.1 months) for postsurgery patients, and 16.8 months (IQR: 13.2 months) for combination-treated patients. 99 patients experienced recurrence, and 30 demonstrated tumor nonresponse. Differences were significant in RFS and OS rates between high-risk and low-risk groups post-surgery (40.3% vs. 65.8%, 62.3% vs. 90.1%, at 5 years). In combination-treated patients, PFS rates differed significantly (80.6% vs. 7.7% at 2 years). DATA CONCLUSION: The MR-based model could pre-treatment identify proliferative HCC and assist in prognosis evaluation. TECHNICAL EFFICACY: Stage 2.

ROCK1 inhibition improves wound healing in diabetes via RIPK4/AMPK pathway.

Refractory wounds are a severe complication of diabetes mellitus that often leads to amputation because of the lack of effective treatments and therapeutic targets. The pathogenesis of refractory wounds is complex, involving many types of cells. Rho-associated protein kinase-1 (ROCK1) phosphorylates a series of substrates that trigger downstream signaling pathways, affecting multiple cellular processes, including cell migration, communication, and proliferation. The present study investigated the role of ROCK1 in diabetic wound healing and molecular mechanisms. Our results showed that ROCK1 expression significantly increased in wound granulation tissues in diabetic patients, streptozotocin (STZ)-induced diabetic mice, and db/db diabetic mice. Wound healing and blood perfusion were dose-dependently improved by the ROCK1 inhibitor fasudil in diabetic mice. In endothelial cells, fasudil and ROCK1 siRNA significantly elevated the phosphorylation of adenosine monophosphate-activated protein kinase at Thr172 (pThr172-AMPKα), the activity of endothelial nitric oxide synthase (eNOS), and suppressed the levels of mitochondrial reactive oxygen species (mtROS) and nitrotyrosine formation. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that ROCK1 inhibited pThr172-AMPKα by binding to receptor-interacting serine/threonine kinase 4 (RIPK4). These results suggest that fasudil accelerated wound repair and improved angiogenesis at least partially through the ROCK1/RIPK4/AMPK pathway. Fasudil may be a potential treatment for refractory wounds in diabetic patients.

Risks and protection: a qualitative study on the factors for internet addiction among elderly residents in Southwest China communities.

BACKGROUND: In the global trend of actively promoting the participation of older adults in the digital age, the relevant negative issues featuring potential Internet Addiction (IA) among them has risen to be a new challenge facing the global public health. However, there is a severe lack of related research. This study aimed to gain a comprehensive understanding of the phenomenon and process of IA among the elderly. The purpose of this paper is to introduce factors that may influence IA in the demographic. METHODS: This study employed qualitative descriptive research methods to investigate older adults' perceptions and experiences of IA. Semi-structured in-depth personal interviews were conducted between March and June 2023 with 36 senior citizens from urban communities in Chongqing, Southwest China. Data were analyzed via inductive content analysis methods. RESULTS: Through data analysis, 2 main categories concerning IA in older adults were identified: risk factors and protective factors. The risk factor categories include 5 individual factors (e.g., Internet as the major avenue for pursuing personal hobbies and interests, etc.), 3 family factors (e.g., household WIFI increasing the risk of prolonged Internet use indoors, etc.), 2 peer factors (e.g., peer recommendation and guidance as catalysts for intensified Internet engagement, etc.), 2 socio-environmental factors (e.g., the widespread daily Internet use spurs offline intolerance, etc.), and 3 Internet platform factors (e.g., the plenitude of online content triggers endless viewing/browsing behaviors, etc.). The category of protective factors encompasses 2 individual factors (e.g., a higher level of perceived risk regarding internet health hazards, etc.) and 2 family factors (e.g., more family commitment, etc.). CONCLUSIONS: Older adults' Internet addictive behaviors are shaped by multiple and complex internal and external factors. A higher level of online health risk perception is a key protective factor to effectively avoid the occurrence and deterioration of IA among the aged, a distinct finding from this study. It is believed that the "individual-family-peer-community" synergy strategy is expected to become an essential direction for IA intervention for older adults, in order to promote healthy Internet use among older adults.

Preoperative Gadoxetic Acid-Enhanced MRI Features for Evaluation of Vessels Encapsulating Tumor Clusters and Microvascular Invasion in Hepatocellular Carcinoma: Creating Nomograms for Risk Assessment.

BACKGROUND: Vessels encapsulating tumor cluster (VETC) and microvascular invasion (MVI) have a synergistic effect on prognosis assessment and treatment selection of hepatocellular carcinoma (HCC). Preoperative noninvasive evaluation of VETC and MVI is important. PURPOSE: To explore the diagnosis value of preoperative gadoxetic acid (GA)-enhanced magnetic resonance imaging (MRI) features for MVI, VETC, and recurrence-free survival (RFS) in HCC. STUDY TYPE: Retrospective. POPULATION: 240 post-surgery patients with 274 pathologically confirmed HCC (allocated to training and validation cohorts with a 7:3 ratio) and available tumor marker data from August 2014 to December 2021. FIELD STRENGTH/SEQUENCE: 3-T, T1-, T2-, diffusion-weighted imaging, in/out-phase imaging, and dynamic contrast-enhanced imaging. ASSESSMENT: Three radiologists subjectively reviewed preoperative MRI, evaluated clinical and conventional imaging features associated with MVI+, VETC+, and MVI+/VETC+ HCC. Regression-based nomograms were developed for HCC in the training cohort. Based on the nomograms, the RFS prognostic stratification system was further. Follow-up occurred every 3-6 months. STATISTICAL TESTS: Chi-squared test or Fisher's exact test, Mann-Whitney U-test or t-test, least absolute shrinkage and selection operator-penalized, multivariable logistic regression analyses, receiver operating characteristic analysis, Harrell's concordance index (C-index), Kaplan-Meier plots. Significance level: P < 0.05. RESULTS: In the training group, 44 patients with MVI+ and 74 patients with VETC+ were histologically confirmed. Three nomograms showed good performance in the training (C-indices: MVI+ vs. VETC+ vs. MVI+/VETC+, 0.892 vs. 0.848 vs. 0.910) and validation (C-indices: MVI+ vs. VETC+ vs. MVI+/VETC+, 0.839 vs. 0.810 vs. 0.855) cohorts. The median follow-up duration for the training cohort was 43.6 (95% CI, 35.0-52.2) months and 25.8 (95% CI, 16.1-35.6) months for the validation cohort. Patients with either pathologically confirmed or nomogram-estimated MVI, VETC, and MVI+/VETC+ suffered higher risk of recurrence. DATA CONCLUSION: GA-enhanced MRI and clinical variables might assist in preoperative estimation of MVI, VETC, and MVI+/VETC+ in HCC. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is still incurable and characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. METHODS: Cell proliferation, drug resistance, and chromosomal instability (CIN) induced by CHEK1 were confirmed by Giemsa staining, exon sequencing, immunofluorescence and xenograft model in vivo. Bone lesion was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining. The existence of circCHEK1_246aa was evaluated by qPCR, Sanger sequencing and Mass Spectrometer. RESULTS: We demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. Increased CHEK1 expression induced MM cellular proliferation and evoked drug-resistance in vitro and in vivo. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced CIN. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by upregulating NFATc1 expression. Intriguingly, we discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation. CONCLUSIONS: Our findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and BM niche.

First Report of Blackleg DiseaseCaused by Epicoccum sorghinumon on Lavender (Lavandula stoechas) in China.

Lavender (Lavandula angustifolia Mill) is an ornamental plant and worldwidely grown for its aromatic and pharmacological qualities. In June 2020, the symptoms of blackleg disease on lavender plants were observed, with more than 50% incidence in Chaohu city (117°38'19.12″N, 31°47'18.94″W) of Anhui Province, China. The disease symptoms progressed from stem wilt and necrosis to prolonged necrosis and bending of leaves, and all infected lavender plants died eventually. Ten necrotic stem lesions werecollectedfrom ten independent plants for the isolation of pathogen. All samples were washed in 70% ethanol for 1 minute, rinsed twice in sterile distilled water and placed on water agar (WA) plates containing 30 mg/liter of kanamycin. All 16 fungal isolates were transferred onto potato dextrose agar (PDA) and incubated at 26°C for 5 days, and all fungal colonies were isolated consistently, which produced redish-gray mycelium at 26°C with a 12-h photoperiod on PDA media. They developed black pycnidia with abundant hyaline, unicellular, oval shaped conidia (4.5 to 5.9 × 2.1 to 2.5 µm) after 14 days. DNA was extracted (10-day-old culture) using the Fungal DNA Mini Kit (Omega Bio-tek, China), according to the manufacturer's protocol. The internal transcribed spacer (ITS), beta-tubulin (ß-tub) and translation elongation factor 1-alpha (tef1-α) genes of three isolates were amplified using the primers: ITS1/ITS4 (White et al. 1990), Bt2a/Bt2b (Glass et al. 1995) and EF1-728F/EF1-986R (Carbone et al. 1999), respectively. The ITS(MT883331), ß-tub(MT896891) andtef1-α (MT874165) genes were sequenced and analyzed through BLASTn. The ITS sequence showed 99.81% with Epicoccum sorghinum (GenBank Accession No. MK020690.1). The ß-tub and tef1-α showed 100% homology with Epicoccum sorghinum (GenBank AccessionMN554062.1 and MN512426.1), respectively. To complete Koch's postulates, pathogenicity tests were performed by spraying the fungal spore suspension (1×105 CFU/ml) prepared from 14-day-old cultures onto needling wounded stems of 1-year-old potted healthy L. angustifolia plants. The healthy plants were sprayed with sterilized water onto needling wounded stems served as negative control. Wilting and stem necrosis were observed 5 days afterinoculation and incubation in a growth chamber at 26°C, with a 12-h photoperiod. All fungal infected plants died after 10 days, while, the control plants remained healthy. The fungus was re-isolated from the lesions of the inoculated plants and verified. Based on morphological characteristics, sequence analysis and pathogenicity test, the pathogen was identified as E. sorghinum. The pathogen has been observed previously on many plants such as tea (Bao et al. 2019) and taro (Liu et al. 2018), in China. To our knowledge, this is the first report of E. sorghinum causing blackleg disease of lavender in China and worldwide.

Biological Activity of Pyraclostrobin Against Coniella granati Causing Pomegranate Crown Rot.

Pomegranate crown rot caused by Coniella granati is one of the most severe diseases of pomegranate. No fungicides have been registered for controlling this disease in China. Pyraclostrobin, belonging to strobilurin fungicides, has a broad spectrum of activity against many phytopathogens. In this study, based on the mycelial growth and conidial germination inhibition methods, we investigated the biological activity of pyraclostrobin against C. granati in the presence of 50 µg/ml of salicylhydroxamic acid using 80 isolates collected from different orchards in China from 2012 to 2018. The EC50 (50% effective concentration) values ranged from 0.040 to 0.613 µg/ml for mycelial growth and 0.013 to 0.110 µg/ml for conidium germination. Treated with pyraclostrobin, the hyphae morphology changed and conidial production of C. granati decreased significantly. The result of transmission electron microscope showed that treatment of pyraclostrobin could make the cell wall thinner and lead to ruptured cell membrane and formation of intracellular organelle autophagosomes. The pyraclostrobin showed good protective and curative activities against C. granati on detached pomegranate fruits. In field trials, pyraclostrobin showed excellent control efficacy against this disease, in which the treatment of 25% pyraclostrobin EC 1,000× provided 92.25 and 92.58% control efficacy in 2019 and 2020, respectively, significantly higher than that of other treatments. Therefore, pyraclostrobin could be a candidate fungicide for the control of pomegranate crown rot.

Activity of A Novel Succinate Dehydrogenase Inhibitor Fungicide Pydiflumetofen Against Fusarium fujikuroi causing Rice Bakanae Disease.

New fungicides are tools to manage fungal diseases and overcome emerging resistance in fungal pathogens. In this study, a total of 121 Fusarium fujikuroi isolates were collected from various geographical regions of China and their sensitivity to a novel succinate dehydrogenase inhibitor (SDHI) fungicide 'pydiflumetofen' was evaluated. The 50% effective concentration (EC50) value of pydiflumetofen for mycelial growth suppression ranged from 0.0101 to 0.1012 µg/ml and for conidial germination inhibition ranged from 0.0051 to 0.1082 µg/ml. Pydiflumetofen-treated hyphae showed contortion and increased branching, cell membrane permeability, and glycerol content significantly. The result of electron microscope transmission indicated that pydiflumetofen damaged the mycelial cell wall and the cell membrane, and almost broke up the cells, which increased the intracellular plasma leakage. There was no cross-resistance between pydiflumetofen and the widely used fungicides such as carbendazim, prochloraz, and phenamacril. Pydiflumetofen was found safe to seeds and rice seedlings of four rice cultivars, used up to 400 µg/ml. Seed treatment significantly decreased the rate of diseased plants in the greenhouse as well as in field trials in 2017 and 2018. Pydiflumetofen showed superb results against the rice bakanae disease (RBD), when used at 10 or 20 g a.i./100 kg of treated seeds, providing over 90% control efficacy (the maximum control efficacy was up to 97%), which was significantly higher than that of 25% phenamacril (SC) at 10 g or carbendazim at 100 g. Pydiflumetofen is highly effective against F. fujikuroi growth and sporulation as well as RBD in the field.

Activation of BDNF-AS/ADAR/p53 Positive Feedback Loop Inhibits Glioblastoma Cell Proliferation.

Despite progress in conventional treatment for glioblastoma (GBM), the prognosis remains poor due to high tumor recurrence. Therefore, identification of new molecular mechanisms is a pressing need for betterment of GBM patient outcomes. qRT-PCR was used to determine BDNF-AS expression in GBM cells. CCK-8, EdU incorporation, and caspase-3 activity assays were employed to analyze biological functions of BDNF-AS. RIP and RNA pull-down were conducted to detect the interactions among BDNF-AS, ADAR, and p53. Actinomycin D was utilized to examine the stability of p53 mRNA. ChIP and luciferase reporter assays were performed to detect transcriptional activation of BDNF-AS by p53. We found that BDNF-AS was significantly downregulated in GBM cell lines, and its overexpression inhibited GBM cell growth, and promoted apoptosis. Importantly, we illustrated that BDNF-AS coupled with ADAR protein to potentiate stability of p53 mRNA and thus upregulate p53. Interestingly, we further identified p53 as a transcription factor of BDNF-AS, activating transcription of BNDF-AS. This study firstly demonstrated that BDNF-AS acted as a tumor suppressor in GBM and the positive feedback circuit of BDNF-AS/ADAR/p53 served an important mechanism to control GBM proliferation. Targeting this auto-regulatory loop may provide a potential therapeutic strategy for GBM patients.

Development and Evaluation of a New Spectral Disease Index to Detect Wheat Fusarium Head Blight Using Hyperspectral Imaging.

Fusarium head blight (FHB) is a major disease threatening worldwide wheat production. FHB is a short cycle disease and is highly destructive under conducive environments. To provide technical support for the rapid detection of the FHB disease, we proposed to develop a new Fusarium disease index (FDI) based on the spectral data of 374-1050 nm. This study was conducted through the analysis of reflectance spectral data of healthy and diseased wheat ears at the flowering and filling stages by hyperspectral imaging technology and the random forest method. The characteristic wavelengths selected were 570 nm and 678 nm for the late flowering stage, 565 nm and 661 nm for the early filling stage, 560 nm and 663 nm for the combined stage (combining both flowering and filling stages) by random forest. FDI at each stage was derived from the wavebands of each corresponding stage. Compared with other 16 existing spectral indices, FDI demonstrated a stronger ability to determine the severity of the FHB disease. Its determination coefficients (R2) values exceeded 0.90 and the RMSEs were less than 0.08 in the models for each stage. Furthermore, the model for the combined stage performed better when used at single growth stage, but its effect was weaker than that of the models for the two individual growth stages. Therefore, using FDI can provide a new tool to detect the FHB disease at different growth stages in wheat.

Correction to: Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma.

As a result of an author oversight in the original article [1], the legend of Figure 5A and C is inaccurate and one panel in Figure 5C (FOXM1N H929 cells shown in the top row, left) is wrong.

Rapid Detection of Alternaria Species Involved in Pear Black Spot Using Loop-Mediated Isothermal Amplification.

Alternaria species are the most important fungal pathogens that attack various crops as well as fruit trees such as pear and cause black spot disease. Here, a loop-mediated isothermal amplification (LAMP) assay is developed for the detection of Alternaria species. A. alternata cytochrome b (cyt-b) gene was used to design two pairs of primers and amplified a 229-bp segment of Aacyt-b gene. The results showed that LAMP assay is faster and simpler than polymerase chain reaction (PCR). LAMP assay is highly sensitive method for the detection of about 1 pg of genomic DNA of A. alternata by using optimized concentration of MgCl2 (4 mM) in final LAMP reaction. In contrast, the limit of detection was 1 ng of target DNA via conventional PCR. Among the genomic DNA of 46 fungal species, only the tubes containing DNA of Alternaria spp. except A. porri, A. solani, and A. infectoria changed color from orange to yellowish green with SYBR Green I including the main pathogens of pear black spot. The yellowish green color was indicative of DNA amplification. Moreover, LAMP assay was used for testing infected tissues among 22 healthy and diseased pear tissues; the orange color changed to yellowish green for infected tissues only. Altogether, we conclude that cyt-b gene can be used for the detection of Alternaria spp. via LAMP assay, which is involved in pear black spot disease.

Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma.

BACKGROUND: Following up on previous work demonstrating the involvement of the transcription factor forkhead box M1 (FOXM1) in the biology and outcome of a high-risk subset of newly diagnosed multiple myeloma (nMM), this study evaluated whether FOXM1 gene expression may be further upregulated upon tumor recurrence in patients with relapsed multiple myeloma (rMM). Also assessed was the hypothesis that increased levels of FOXM1 diminish the sensitivity of myeloma cells to commonly used myeloma drugs, such as the proteasome inhibitor bortezomib (Bz) and the DNA intercalator doxorubicin (Dox). METHODS: FOXM1 message was evaluated in 88 paired myeloma samples from patients with nMM and rMM, using gene expression microarrays as measurement tool. Sources of differential gene expression were identified and outlier analyses were performed using statistical methods. Two independent human myeloma cell lines (HMCLs) containing normal levels of FOXM1 (FOXM1N) or elevated levels of lentivirus-encoded FOXM1 (FOXM1Hi) were employed to determine FOXM1-dependent changes in cell proliferation, survival, efflux-pump activity, and drug sensitivity. Levels of retinoblastoma (Rb) protein were determined with the assistance of Western blotting. RESULTS: Upregulation of FOXM1 occurred in 61 of 88 (69%) patients with rMM, including 4 patients that exhibited > 20-fold elevated expression peaks. Increased FOXM1 levels in FOXM1Hi myeloma cells caused partial resistance to Bz (1.9-5.6 fold) and Dox (1.5-2.9 fold) in vitro, using FOXM1N myeloma as control. Reduced sensitivity of FOXM1Hi cells to Bz was confirmed in vivo using myeloma-in-mouse xenografts. FOXM1-dependent regulation of total and phosphorylated Rb agreed with a working model of myeloma suggesting that FOXM1 governs both chromosomal instability (CIN) and E2F-dependent proliferation, using a mechanism that involves interaction with NIMA related kinase 2 (NEK2) and cyclin dependent kinase 6 (CDK6), respectively. CONCLUSIONS: These findings enhanced our understanding of the emerging FOXM1 genetic network in myeloma and provided preclinical support for the therapeutic targeting of the FOXM1-NEK2 and CDK4/6-Rb-E2F pathways using small-drug CDK and NEK2 inhibitors. Clinical research is warranted to assess whether this approach may overcome drug resistance in FOXM1Hi myeloma and, thereby, improve the outcome of patients in which the transcription factor is expressed at high levels.

Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats.

Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In the present study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of prorenin in organ injury was examined. Four groups of rats (cyp1a1 prorenin transgenic male and female rats and non-transgenic littermates) were assigned to receive a diet containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. Plasma prorenin concentration was increased and mean arterial pressure (MAP) increased from 80 ± 18 to 138 ± 17 (mmHg), whereas renal prorenin/renin protein expression was unchanged, in transgenic rats fed with I3C diet. The intact prorenin, not renin, in plasma and urine samples was further observed by Western blot analysis. Importantly, transgenic rats with high levels of prorenin developed albuminuria, glomerular and tubulointerstitial fibrosis associated with increased expression of transforming growth factor ß (TGFß) 1 (TGFß1), plasminogen activator inhibitor-1 (PAI-1), collagen, and fibronectin (FN). These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weight to body weight (HW/BW). Cardiac collagen in interstitial and perivascular regions was prominent, accompanied by the increase in mRNA contents of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), ß-myosin heavy chain (ß-MHC), TGFß1, PAI-1, and collagen in the heart tissue. Furthermore, renal protein levels of p-NF-κB-p65 and monocyte chemoattractant protein-1 (MCP-1), NAPDH oxidases, malondialdehyde (MDA) and 8-isoprostane (8-IP), p-ERK, p-ß-catenin, and p-Akt were dramatically increased in prorenin overexpressing rats. These results indicate that prorenin, without being converted into renin, causes hypertension, renal and cardiac fibrosis via the induction of inflammation, oxidative stress and the ERK, ß-catenin, and Akt-mediated signals.

[Effect of extensively hydrolyzed formula on growth and development of infants with very/extremely low birth weight].

OBJECTIVE: To study the effect of extensively hydrolyzed formula on the growth and development in very low birth weight (VLBW) and extremely low birth weight (ELBW) infants. METHODS: A total of 375 VLBW or ELBW infants were enrolled and divided into an observation group (187 infants) and a control group (188 infants) using a random number table. The infants in the observation group were given extensively hydrolyzed formula, and when the amount of extensively hydrolyzed formula reached 10 mL/time, it was changed to the standard formula for preterm infants. The infants in the control group were given standard formula for preterm infants. Both groups were fed for 4 consecutive weeks and were compared in terms of incidence rate of feeding intolerance, time to establish full enteral feeding, time to complete meconium excretion, number of spontaneous bowel movements, growth and development, motilin level at 4 and 10 days after feeding, and incidence rate of infection. RESULTS: Compared with the control group, the observation group had a lower rate of feeding intolerance (P<0.05), a shorter duration to full enteral feeding and time to complete meconium excretion (P<0.05), a higher mean number of daily spontaneous bowel movements (P<0.05), higher body weight (1 793±317 g vs 1 621±138 g; P<0.05), head circumference (30.5±1.1 cm vs 30.0±1.6 cm; P<0.05), and body length (43.9±1.2 cm vs 42.1±2.0 cm; P<0.05), a higher motilin level at 4 and 10 days after feeding (P<0.05), and a significantly lower infection rate (P<0.05). CONCLUSIONS: Extensively hydrolyzed formula can increase motilin level, improve gastrointestinal feeding tolerance, promote early growth and development, and reduce the incidence of infection in VLBW and ELBW infants.

An additive effect of anti-PAI-1 antibody to ACE inhibitor on slowing the progression of diabetic kidney disease.

While angiotensin II blockade slows the progression of diabetic nephropathy, current data suggest that it alone cannot stop the disease process. New therapies or drug combinations will be required to further slow or halt disease progression. Inhibition of plasminogen activator inhibitor type 1 (PAI-1) aimed at enhancing ECM degradation has shown therapeutic potential in diabetic nephropathy. Here, using a mouse model of type diabetes, the maximally therapeutic dose of the PAI-1-neutralizing mouse monoclonal antibody (MEDI-579) was determined and compared with the maximally effective dose of enalapril. We then examined whether addition of MEDI-579 to enalapril would enhance the efficacy in slowing the progression of diabetic nephropathy. Untreated uninephrectomized diabetic db/db mice developed progressive albuminuria and glomerulosclerosis associated with increased expression of transforming growth factor (TGF)-ß1, PAI-1, type IV collagen, and fibronectin from weeks 18 to 22, which were reduced by MEDI-579 at 3 mg/kg body wt, similar to enalapril given alone from weeks 12 to 22 Adding MEDI-579 to enalapril from weeks 18 to 22 resulted in further reduction in albuminuria and markers of renal fibrosis. Renal plasmin generation was dramatically reduced by 57% in diabetic mice, a decrease that was partially reversed by MEDI-579 or enalapril given alone but was further restored by these two treatments given in combination. Our results suggest that MEDI-579 is effective in slowing the progression of diabetic nephropathy in db/db mice and that the effect is additive to ACEI. While enalapril is renal protective, the add-on PAI-1 antibody may offer additional renoprotection in progressive diabetic nephropathy via enhancing ECM turnover.

miR-383 inhibits hepatocellular carcinoma cell proliferation via targeting APRIL.

Mounting evidence has shown that microRNAs (miRNAs), a class of small non-coding RNAs, are frequently deregulated in human malignancies and have pivotal roles in diverse biological processes including cancer cell proliferation. Herein, we investigated the expression pattern of miR-383 in 64 hepatocellular carcinoma (HCC) tissues and 4 HCC cell lines and found that miR-383 was downregulated in HCC tissues and cell lines. Moreover, miR-383 expression in HCC was significantly correlated with tumor size and tumor-node-metastasis (TNM) stage. Kaplan-Meier analysis showed that decreased miR-383 expression was associated with poor overall survival of HCC patients. In addition, Cox regression analysis indicated that miR-383 was an independent prognostic factor for HCC patients. Then, functional studies demonstrated that ectopic miR-383 expression could significantly suppress the in vitro proliferation of HCC cells, as well as induce cell cycle arrest and cell apoptosis. Luciferase reporter assay further identified that a proliferation-inducing ligand (APRIL), a member in the tumor necrosis factor (TNF) superfamily, was a novel target gene for miR-383. Subsequent investigation revealed that miR-383 expression was inversely correlated with APRIL messenger RNA (mRNA) expression in HCC tissues. Besides, recombinant human APRIL (rhAPRIL) could rescue HCC cell proliferation inhibited by miR-383. Taken together, our present study provided the first evidence that miR-383 was decreased in HCC and associated with tumor progression and prognosis of HCC patients. Furthermore, our findings confirmed that miR-383 might inhibit HCC cell proliferation partially via downregulating APRIL expression. Thus, this study might provide a promising strategy by targeting with the miR-383-APRIL axis in the treatment of HCC.

Discovery of potent and orally bioavailable inhibitors of Human Uric Acid Transporter 1 (hURAT1) and binding mode prediction using homology model.

This Letter describes the discovery of a series of potent inhibitors of Human Uric Acid Transporter 1 (hURAT1). Lead generation and optimization via 3D pharmacophore analysis resulted in compound 41. With an IC50 of 33.7nM, 41 also demonstrated good oral bioavailability in rat (74.8%) and displayed a consistent PK profile across all species tested (rat, dog and monkey).

Genotypes and Phenotypic Characterization of Field Fusarium asiaticum Isolates Resistant to Carbendazim in Anhui Province of China.

Fusarium asiaticum is a causal agent of Fusarium head blight (FHB) of wheat in the southern part of China. Carbendazim has been extensively used for controlling FHB for more than 30 years, leading to the widespread carbendazim-resistant isolates in all major wheat-producing provinces in China, especially in Anhui Province. F. asiaticum isolates were collected throughout Anhui Province between 2010 and 2012 to monitor their sensitivity to carbendazim. In total, 74 of 899 single-spore isolates F. asiaticum were found to be resistant to carbendazim. Resistant isolates were collected from all of the sampled sites except Hefei of Anhui Province. The overall frequency of carbendazim resistance was shown to be 8.2%. Of the 74 isolates, 1, 68, and 5 had low resistance (LR), moderate resistance (MR) ,and high resistance (HR), respectively, to carbendazim. Five types of point mutations (F167Y, E198L, E198K, F200Y, and E198Q) in the ß2-tubulin gene conferring resistance to carbendazim were detected in the field-resistant isolates with frequencies of 89.2, 2.7, 4.1, 2.7, and 1.4%, respectively. The point mutations at codon 167, 198, or 200 of the ß2-tubulin gene were correlated with different levels of carbendazim resistance. Some of the sensitive and resistant isolates appeared to possess different biological characteristics; however, these might not be due to resistance. Because carbendazim resistance was generally widespread throughout Anhui Province, the sensitivity of F. asiaticum populations to carbendazim should be constantly monitored for the development of carbendazim resistance in natural populations.