Storage and redistribution of anthropogenic CO2 in the western North Pacific: The role of subtropical mode water transportation.

Oceanic uptake and storage of anthropogenic CO2 (CANT) are regulated by ocean circulation and ventilation. To decipher the storage and redistribution of CANT in the western North Pacific, where a major CANT sink develops, we investigated the water column carbonate system, dissolved inorganic radiocarbon and ancillary parameters in May and August 2018, spanning the Kuroshio Extension (KE, 35-39 °N), Kuroshio Recirculation (KR, 27-35 °N) and subtropical (21-27 °N) zones. Water column CANT inventories were estimated to be 40.5 ± 1.1 mol m-2 in the KR zone and 37.2 ± 0.9 mol m-2 in the subtropical zone. In comparison with historical data obtained in 2005, relatively high rates of increase of the CANT inventory of 1.05 ± 0.20 and 1.03 ± 0.12 mol m-2 yr-1 in the recent decade were obtained in the KR and subtropical zones, respectively. Our water-mass-based analyses suggest that formation and transport of subtropical mode water dominate the deep penetration, storage, and redistribution of CANT in those two regions. In the KE zone, however, both the water column CANT inventory and the decadal CANT accumulation rate were small and uncertain owing to the dynamic hydrology, where the naturally uplifting isopycnal surfaces make CANT penetration relatively shallow. The findings of this study improve the understanding of the spatiotemporal variations of CANT distribution, storage, and transport in the western North Pacific.

Identification of rare variants in PTCH2 associated with non-syndromic orofacial clefts.

Orofacial clefts (OFCs) represent the most prevalent congenital craniofacial anomalies, significantly impacting patients' appearance, oral function, and psychological well-being. Among these, non-syndromic OFCs (NSOFCs) are the most predominant type, with the etiology attributed to a combination of genetic and environmental factors. Rare variants of key genes involved in craniofacial development-related signaling pathway are crucial in the occurrence of NSOFCs, and our recent studies have identified PTCH1, a receptor-coding gene in the Hedgehog signaling pathway, as a causative gene for NSOFCs. However, the role of PTCH2, the paralog of PTCH1, in pathogenesis of NSOFCs remains unclear. Here, we perform whole-exome sequencing to explore the genetic basis of 144 sporadic NSOFC patients. We identify five heterozygous variants of PTCH2 in four patients: p.L104P, p.A131G, p.R557H, p.I927S, and p.V978D, with the latter two co-occurring in a single patient. These variants, all proven to be rare through multiple genomic databases, with p.I927S and p.V978D being novel variants and previously unreported. Sequence alignment suggests that these affected amino acids are evolutionarily conserved across vertebrates. Utilizing predictive structural modeling tools such as AlphaFold and SWISS-MODEL, we propose that these variants may disrupt the protein's structure and function. In summary, our findings suggest that PTCH2 may be a novel candidate gene predicted to be associated with NSOFCs, thereby broadening the spectrum of causative genes implicated in the craniofacial anomalies.

Glutathione S-transferase activity facilitates rice tolerance to the barnyard grass root exudate DIMBOA.

BACKGROUND: In paddy fields, the noxious weed barnyard grass secretes 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (DIMBOA) to interfere with rice growth. Rice is unable to synthesize DIMBOA. Rice cultivars with high or low levels of allelopathy may respond differently to DIMBOA. RESULTS: In this study, we found that low concentrations of DIMBOA (≤ 0.06 mM) promoted seedling growth in allelopathic rice PI312777, while DIMBOA (≤ 0.08 mM) had no significant influence on the nonallelopathic rice Lemont. DIMBOA treatment caused changes in the expression of a large number of glutathione S-transferase (GST) proteins, which resulting in enrichment of the glutathione metabolic pathway. This pathway facilitates plant detoxification of heterologous substances. The basal levels of GST activity in Lemont were significantly higher than those in PI312777, while GST activity in PI312777 was slightly induced by increasing DIMBOA concentrations. Overexpression of GST genes (Os09g0367700 and Os01g0949800) in these two cultivars enhanced rice resistance to DIMBOA. CONCLUSIONS: Taken together, our results indicated that different rice accessions with different levels of allelopathy have variable tolerance to DIMBOA. Lemont had higher GST activity, which helped it tolerate DIMBOA, while PI312777 had lower GST activity that was more inducible. The enhancement of GST expression facilitates rice tolerance to DIMBOA toxins from barnyard grass root exudates.

A new method for estimating Sharpe ratio function via local maximum likelihood.

The Sharpe ratio function is a commonly used risk/return measure in financial econometrics. To estimate this function, most existing methods take a two-step procedure that first estimates the mean and volatility functions separately and then applies the plug-in method. In this paper, we propose a direct method via local maximum likelihood to simultaneously estimate the Sharpe ratio function and the negative log-volatility function as well as their derivatives. We establish the joint limiting distribution of the proposed estimators, and moreover extend the proposed method to estimate the multivariate Sharpe ratio function. We also evaluate the numerical performance of the proposed estimators through simulation studies, and compare them with existing methods. Finally, we apply the proposed method to the three-month US Treasury bill data and that captures a well-known covariate-dependent effect on the Sharpe ratio.

Concentrations and controls of dissolved inorganic carbon in Arctic summer sea ice and adjacent surface seawaters.

The carbonate chemistry of sea ice plays a critical role in global ocean carbon cycles, particularly in polar regions which are subject to significant climate change-induced sea ice variation. However, less is known about the interaction of carbonate system between sea ice and its adjacent seawaters due to sparse sampling and disparities in reported results. Here we provide an insight into this issue by collecting and measuring dissolved inorganic carbon (DIC) and associated environmental parameters in Arctic sea ice during a cruise in the summer of 2014. Our observations show that DIC in Arctic summer sea ice has a mean concentration of 463.3 ± 213.0 µmol/kg and appears to be controlled mainly by the fraction of brine water in the ice. The low Chl a and nutrients content in sea ice indicate minor contribution of biological uptake to sea-ice DIC in the western Arctic Ocean. The DIC concentration in surface water (<100 m depth) decreased from a mean of 2108.3 ± 45.4 µmol/kg in 1994 to a mean of 2052.4 ± 98.6 µmol/kg in 2014, due to the enhanced sea ice melting that dilutes the DIC concentrations of surrounding seawaters.

Involvement of IGF1 in endoplasmic reticulum stress contributes to cataract formation through regulating Nrf2/NF-κB signaling.

Endoplasmic reticulum (ER) stress is reportedly involved in the development of ophthalmic diseases. This study aimed to investigate the role and potential mechanism of insulin-like growth factor 1 (IGF1) in ER stress. A mouse cataract model was constructed by subcutaneous injection of sodium selenite, and sh-IGF1 was used to evaluate the effect of silencing IGF1 on cataract progression. Slit-lamp and histological examination of the lens were performed to examine lens damage. The regulatory effects of IGF1 on inflammatory responses, oxidative stress, and ER stress were evaluated using ELISA, reverse transcription-quantitative PCR (RT-qPCR), and immunoblotting analysis. Tunicamycin was used to induce ER stress in the lens of epithelial cells. The NF-E2 related factor-2 (Nrf2) inhibitor ML385 and nuclear factor-κB (NF-κB) agonist diprovocim were used to confirm whether IGF1 regulates inflammation and ER stress through Nrf2/NF-κB signaling. Silencing IGF1 alleviated lens damage and reduced lens turbidity in the cataract mice. Silencing IGF1 inhibited inflammatory response, oxidative stress and ER stress response. Meanwhile, IGF1 was highly expressed in sodium selenite-treated lens epithelial cells. The ER stress agonist tunicamycin suppressed cell viability as well as induced ER stress, oxidative stress and inflammation. Silencing IGF1 increased cell viability, EdU-positive rate and migration. Also, silencing of IGF1 reduced inflammation and ER stress via regulating Nrf2/NF-κB pathway. This study reveals silencing IGF1 attenuated cataract through regulating Nrf2/NF-κB signaling, which shares novel insights into the underlying mechanism of cataract and provides potential therapeutic target for cataract.

Phase 1 dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of FCN-159 in adults with neurofibromatosis type 1-related unresectable plexiform neurofibromas.

BACKGROUND: Surgery is a common treatment strategy for patients with neurofibromatosis type 1 (NF1)-related plexiform neurofibroma (PN) and has limited efficacy. FCN-159 is a novel anti-tumorigenic drug via selective inhibition of MEK1/2. This study assesses the safety and efficacy of FCN-159 in patients with NF1-related PN. METHODS: This is a multicenter, open-label, single-arm, phase I dose-escalation study. Patients with NF1-related PN that was non-resectable or unsuitable for surgery were enrolled; they received FCN-159 monotherapy daily in 28-day cycles. RESULTS: Nineteen adults were enrolled in the study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. Among patients included in dose-limiting toxicity (DLT) analysis, DLTs (grade 3 folliculitis) were reported in 1 of 8 patients (16.7%) receiving 8 mg and 3 of 3 (100%) patients receiving 12 mg. The maximum tolerated dose was determined to be 8 mg. FCN-159-related treatment-emergent adverse events (TEAEs) were observed in 19 patients (100%); most of which were grade 1 or 2. Nine (47.4%) patients reported grade 3 study-drug-related TEAEs across all dose levels, including four experiencing paronychia and five experiencing folliculitis. Of the 16 patients analyzed, all (100%) had reduced tumor size and six (37.5%) achieved partial responses; the largest reduction in tumor size was 84.2%. The pharmacokinetic profile was approximately linear between 4 and 12 mg, and the half-life supported once daily dosing. CONCLUSIONS: FCN-159 was well tolerated up to 8 mg daily with manageable adverse events and showed promising anti-tumorigenic activity in patients with NF1-related PN, warranting further investigation in this indication. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04954001. Registered 08 July 2021.

The complete change in bile acids and steroids in systematic metabolomics applied to the intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific hepatobiliary disease, leading to an abnormal increase in total bile acid in the blood of pregnant women. To systematically explore the similarities and differences in metabolites and metabolic pathways among three types of biological samples from ICP women, a study of 18 ICP and 6 healthy (as a normal control) pregnant women was performed to investigate their clinical information and biochemical features. Based on validated LC-MS/MS methods 1-5 for hydrophilic and hydrophobic metabolites (molecular weight <2000 Dalton), an untargeted-metabolomic strategy was applied to 24 pregnant women to determine the metabolites from 22 serum, 15 placental and 22 urine samples. Then 1137 metabolites from serum, 876 metabolites from placental tissue and 311 metabolites from urine with a coefficient of variation <30% in the pooled quality control samples were found. Furthermore, orthogonal partial least squares-discriminate analysis (OPLS-DA), correlation analysis, chemical enrichment analysis and metabolic pathway analysis were carried out by a bioinformatics process. On the OPLS-DA model analysis, the metabolites in urine were better than those in serum or placental tissue to reflect the metabolic changes of ICP disease. Some metabolites were significantly changed in serum (n = 71), placental tissue (n = 46) and urine (n = 36), such as bile acids, triacylglycerols, lysoPCs, and steroids. Primary bile acid biosynthesis was the main metabolic pathway in ICP disease, and taurine and hypotaurine metabolism and sphingolipid metabolism were also found. More specifically, bile acids increased and steroids decreased in the serum, placental and urine samples. For complex metabolic diseases such as ICP disease, untargeted-metabolomic analysis of multiple biological samples could provide a systematic understanding of the changes in metabolic types and pathways.

Climate change drives rapid decadal acidification in the Arctic Ocean from 1994 to 2020.

The Arctic Ocean has experienced rapid warming and sea ice loss in recent decades, becoming the first open-ocean basin to experience widespread aragonite undersaturation [saturation state of aragonite (Ωarag) < 1]. However, its trend toward long-term ocean acidification and the underlying mechanisms remain undocumented. Here, we report rapid acidification there, with rates three to four times higher than in other ocean basins, and attribute it to changing sea ice coverage on a decadal time scale. Sea ice melt exposes seawater to the atmosphere and promotes rapid uptake of atmospheric carbon dioxide, lowering its alkalinity and buffer capacity and thus leading to sharp declines in pH and Ωarag. We predict a further decrease in pH, particularly at higher latitudes where sea ice retreat is active, whereas Arctic warming may counteract decreases in Ωarag in the future.

Panax quinquefolius Polysaccharides Ameliorate Antibiotic-Associated Diarrhoea Induced by Lincomycin Hydrochloride in Rats via the MAPK Signaling Pathways.

American ginseng (Panax quinquefolius L.) is an herbal medicine with polysaccharides as its important active ingredient. The purpose of this research was to identify the effects of the polysaccharides of P. quinquefolius (WQP) on rats with antibiotic-associated diarrhoea (AAD) induced by lincomycin hydrochloride. WQP was primarily composed of galacturonic acid, glucose, galactose, and arabinose. The yield, total sugar content, uronic acid content, and protein content were 6.71%, 85.2%, 31.9%, and 2.1%, respectively. WQP reduced the infiltration of inflammatory cells into the ileum and colon, reduced the IL-1ß, IL-6, IL-17A, and TNF-α levels, increased the levels of IL-4 and IL-10 in colon tissues, improved the production of acetate and propionate, regulated the gut microbiota diversity and composition, improved the relative richness of Lactobacillus and Bacteroides, and reduced the relative richness of Blautia and Coprococcus. The results indicated that WQP can enhance the recovery of the intestinal structure in rats, reduce inflammatory cytokine levels, improve short-chain fatty acid (SCFA) levels, promote recovery of the gut microbiota and intestinal mucosal barrier, and alleviate antibiotic-related side effects such as diarrhoea and microbiota dysbiosis caused by lincomycin hydrochloride. We found that WQP can protect the intestinal barrier by increasing Occludin and Claudin-1 expression. In addition, WQP inhibited the MAPK inflammatory signaling pathway to improve the inflammatory status. This study provides a foundation for the treatment of natural polysaccharides to reduce antibiotic-related side effects.

Are Older Adults More Optimistic? Evidence From China, Israel, and the United States.

OBJECTIVES: Optimistic bias refers to the phenomenon that individuals believe bad things are less likely to happen to themselves than to others. However, whether optimistic bias could vary across age and culture is unknown. The present study aims to investigate (a) whether individuals exhibit optimistic bias in the context of coronavirus disease 2019 (COVID-19) pandemic, and (b) whether age and culture would moderate such bias. METHOD: 1,051 participants recruited from China, Israel, and the United States took the online survey. Risk perceptions consist of 3 questions: estimating the infected probability of different social distance groups (i.e., self, close others, and nonclose others), the days that it would take for the number of new infections to decrease to zero and the trend of infections in regions of different geographical distances (i.e., local place, other places inside participants' country, and other countries). Participants in China and the United States also reported their personal communal values measured by Schwartz's Value Survey. RESULTS: Results from Hierarchical Linear Modeling generally confirmed that (a) all participants exhibited optimistic bias to some extent, and (b) with age, Chinese participants had a higher level of optimistic bias than the Israeli and U.S. participants. Compared to their younger counterparts, older Chinese are more likely to believe that local communities are at lower risk of COVID-19 than other countries. DISCUSSION: These findings support the hypothesis that age differences in risk perceptions might be influenced by cultural context. Further analysis indicated that such cultural and age variations in optimistic bias were likely to be driven by age-related increase in internalized cultural values.

[Research and development strategies of new Chinese medicines based on new regulations].

In recent years, only a small number of new Chinese medicines have been approved for marketing, which has embodied the bottleneck in the development of the Chinese medicine industry. To tackle this problem, the National Medical Products Administration has issued a series of regulations and technical requirements. In the context of new regulations, this study deeply explored the research and development strategies of new Chinese medicines under the guidance of the new classification of drug registration, and discussed the key technical issues in the research and development.

Use of non-contact infrared thermometers in rehabilitation patients: a randomized controlled study.

OBJECTIVE: In this randomized controlled study, we aimed to determine whether non-contact infrared thermometers (NCITs) are more time-efficient and create less patient distress than mercury axillary thermometers (MATs) and infrared tympanic thermometers (ITTs). METHODS: Forty-five rehabilitation inpatients were randomly assigned to one of three groups (NCIT, MAT, and ITT). Time required to measure body temperature with an NCIT, MAT, and ITT was recorded. We examined associations between time required to take patients' temperature and measuring device used. Patient distress experienced during temperature measurement using the three thermometers was recorded. RESULTS: A significantly longer average time was required to measure temperatures using the MAT (mean 43.17, standard deviation [SD] 8.39) than the ITT (mean 13.74, SD 1.63) and NCIT (mean 12.13, SD 1.18). The thermometer used influenced the time required to measure body temperature (t = 33.99). There were significant differences among groups (NCIT vs. ITT, NCIT vs. MAT, and ITT vs. MAT) regarding patient distress among the different thermometers. Most distress arose owing to needing help from others, sleep disruption, and boredom. CONCLUSION: The NCIT has clinically relevant advantages over the ITT and MAT in measuring body temperature among rehabilitation patients, including saving nurses' time and avoiding unnecessary patient distress.Clinical trial registration number (http://www.chictr.org.cn): ChiCTR1800019756.

Treatment Effect of a Vascular-Disrupting Agent Dynamically Monitored by DWI: An Animal Experimental Study.

Objective: To investigate the treatment effect of a vascular-disrupting agent, M410, using diffusion-weighted imaging in a rabbit model of hepatic VX2 tumor. Methods: 28 New Zealand white rabbit models with VX2 liver tumors were established and were randomly divided into M410 (intravenous injection of M410 at a dose of 25 mg/kg every three days) and control (intravenous injection of saline every three days) groups. Conventional and diffusion-weighted imaging (DWI) were acquired on a 3.0 T MR unit at baseline, 4 h, d 1, d 4, d 7, and d 14 posttreatment. B-value with 700 (s/mm2) was chosen during DWI examinations. Tumor volume and apparent diffusion coefficient (ADC) values of the entire tumor and solid component of the tumor at every time point were measured. Two randomly chosen rabbits from each group were sacrificed for H&E staining and CD34 immunohistochemical assessments at each time point. An independent sample t-test was used to assess differences in tumor sizes and ADC values of the entire tumor and solid component of tumors between two groups, with P < 0.05 considered statistically significant. Result: There was no significant difference in tumor volume between the two groups at baseline, 4 h, and d 1. With time, the tumors in the control group grew significantly faster than those in the M410 group, and the average ADC values of the M410 group were lower than those of the control group at d 1 and higher than those of the control group at d 4; as such, there were statistical differences between the two groups at these two time points but not at the other four time points. The following pathological results reflected the underlying morphological changes and vascular alterations. Conclusions: M410 performed well in inhibiting the growth of the hepatic VX2 tumor which could be noninvasively monitored by DWI metrics.

Combined polymorphisms in genes encoding the inflammasome components NLRP3 and CARD8 confer risk of ischemic stroke in men.

INTRODUCTION: Previous studies have reported the involvement of nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the inflammatory activation and pathophysiology of Ischemic Stroke (IS). Variations in genes encoding the constituent proteins of NLRP3 inflammasome can alter the risk of IS. OBJECTIVE: We investigated the role of the NLRP3 inflammasome in the pathogenesis of IS by establishing associations between combined polymorphisms of caspase recruitment domain-containing protein 8 (CARD8) rs2043211 and NLRP3 rs10754558 and the susceptibility to IS in a Chinese population. METHODS: Single nucleotide polymorphisms (SNPs) in CARD8 rs2043211 and NLRP3 rs10754558 were analyzed using TaqMan SNP genotyping assays in patients with IS (n=234) and healthy controls (n=115). Logistic regression analysis was carried out to evaluate potential interactions between CARD8 and NLRP3. RESULTS: Compared with healthy controls, there were no significant differences in the minor allele frequency (MAF) and the genotype frequency of NLRP3 rs10754558 or CARD8 rs2043211 in patients with IS(P>0.05). After stratification by gender, there was an increased risk for IS in men carrying heterozygous CARD8 rs2043211 when a co-dominant genetic model was applied (P=0.021, OR=3.83[1.22-12.03]). Logistic regression analysis indicated that men carrying both CARD8 rs2043211 AT and NLRP3 rs10754558 CG had a significantly higher risk of IS (P=0.046, OR=7.116[1.033-49.044]). CONCLUSIONS: Nucleotide variations in the genes encoding NLRP3 inflammasome proteins may be important to IS, and men carrying CARD8 rs2043211 and NLRP3 rs10754558, both heterozygous, confer a higher risk of IS.

Topical Delivery of Four Neuroprotective Ingredients by Ethosome-Gel: Synergistic Combination for Treatment of Oxaliplatin-Induced Peripheral Neuropathy.

BACKGROUND: Peripheral neuropathy is a common and painful side effect that occurs in patients with cancer induced by Oxaliplatin (OXL). The neurotoxicity correlates with the damage of dorsal root ganglion (DRG) neurons and Schwann cells (SCs). Hydroxysafflor yellow A (HSYA), icariin, epimedin B and 3, 4-dihydroxybenzoic acid (DA) are the main neuroprotective ingredients identified in Wen-Luo-Tong (WLT), a traditional Chinese medicinal topical compound. The purpose of this study was to prepare and evaluate the efficacy of an ethosomes gel formulation loaded with a combination of HSYA, icariin, epimedin B and DA. However, the low LogP value, poor solubility and macromolecule are several challenges for topical delivery of these drugs. METHODS: Ethosomes were prepared by the single-step injection technique. Particle size, entrapment efficiency and in vitro drug deposition studies were determined to select the optimum ethosomes. The optimized ethosomes were further incorporated into carbopol to obtain a gel. The rheological properties, morphology, in vitro drug release, in vitro gel application and skin distribution of the ethosomes gels were studied. A rat model of oxaliplatin-induced neuropathy was established to assess the therapeutic efficacy of the ethosomes gel. RESULTS: Seventy percent (v/v) ethanol, cinnamaldehyde and Phospholipon 90G were employed to develop ethosomes a carrier system. This system had a high entrapment efficiency, carried large amounts of HSYA, epimedin B, DA and icarrin, and penetrated deep into the epidermis and dermis. The optimized ethosomes had the maximum deposition of icariin, HSYA, epimedin B and relative higher amount of DA in epidermis (2.00±0.13 µg/cm2, 5.72±0.75 µg/cm2, 1.97±0.27 µg/cm2 and 9.25±1.21 µg/cm2, respectively). 0.5% carbopol 980 was selected to develop the ethosomes gel with desirable viscoelasticity and spreadability, which was suitable for topical application. The mechanical allodynia and hyperalgesia induced by OXL in rats were significantly reduced after the new ethosomes gel was applied to rats compared to model group. CONCLUSION: Based on our findings, the ethosomes gel delivery system provided a new formulation for the topical delivery of HSYA, icariin, epimedin B and DA to counteract OXL-induced peripheral neuropathy.

Development and in-vitro evaluation of co-loaded berberine chloride and evodiamine ethosomes for treatment of melanoma.

Berberine chloride (BBR) and evodiamine (EVO) are two main active ingredients of "ZuoJinWan", a classical Chinese herbal medicine, and these compounds are known to have a synergistic inhibitory effect on various cancer cell lines. Several recent studies have reported anti-melanoma effects for both BBR and EVO. However, topical delivery of the two compounds has been challenging, due to their poor aqueous solubility and their low skin penetration. In the current study, we have combined BBR and EVO into an ethosomes delivery system with the future aim to design a novel topical anti-melanoma formulation. The ethosomes formulations were characterized using particle size, entrapment efficiency and an in vitro skin drug deposition study. The ethosome formulation displaying maximum drug deposition in the epidermis was selected for further study. This formulation contained ethosomes with mean size of 171 nm and 90% or above entrapment efficiency for both BBR and EVO. Cell viability tests proved the optimized ethosomes increased the inhibitory effect on B16 melanoma cells. These results corroborate that ethosomes containing a combination of BBR and EVO are a promising delivery system for potential use in melanoma therapy.

P16 Methylation Leads to Paclitaxel Resistance of Advanced Non-Small Cell Lung Cancer.

Paclitaxel-based chemotherapy is widely used as the first-line treatment for non-small cell lung cancer (NSCLC). However, only 20%-40% of patients have shown sensitivity to paclitaxel. This study aimed to investigate whether P16 methylation could be used to predict paclitaxel chemosensitivity of NSCLC. Advanced NSCLC (N=45) were obtained from patients who were enrolled in a phase-III randomized paclitaxel-based clinical trial. Genomic DNA samples were extracted from the biopsies prior to chemotherapy. P16 methylation was detected using MethyLight. The association between P16 methylation and the sensitivity of paclitaxel in cell lines was determined by in vitro assay using a P16-specific DNA demethylase (P16-TET) and methyltransferase (P16-Dnmt). The total response rate of the low-dose paclitaxel-based chemo-radiotherapy was significantly lower in P16 methylation-positive NSCLCs than that in the P16 methylation-negative NSCLCs (2/15 vs. 16/30: adjusted OR=0.085; 95%CI, 0.012-0.579). Results revealed that P16 demethylation significantly decreased paclitaxel resistance of lung cancer H1299 cells (IC50 values decreased from 2.15 to 1.13 µg/ml, P<0.001). In contrast, P16-specific methylation by P16-Dnmt significantly increased paclitaxel resistance of lung cancer HCC827 cells and gastric cancer BGC823 cells (IC50 values increased from 18.2 to 24.0 ng/ml and 0.18 to 0.81 µg/ml, respectively; P=0.049 and <0.001, respectively). The present results suggest that P16 methylation may lead to paclitaxel resistance and be a predictor of paclitaxel chemosensitivity of NSCLC.

Association of glycated hemoglobin with the risk of advanced fibrosis in non-alcoholic fatty liver disease patients without diabetes.

BACKGROUND: Association of diabetes with non-alcoholic steatohepatitis has been well documented. However, it remains unclear whether there is an association between levels of glycated hemoglobin (HbA1c) with severity of non-alcoholic fatty liver disease (NAFLD). This study was aimed to explore the relationship between levels of HbA1c and the risk of advanced fibrosis in patients with NAFLD. METHODS: A cross-sectional study was performed on 4826 apparently healthy Chinese, who underwent a health check between January 2015 and December 2016. NAFLD was defined as hepatic steatosis on ultrasonography in the absence of excessive alcohol use or other identifiable causes. The risk of advanced fibrosis was assessed by NAFLD fibrosis Score. RESULTS: Among 4826 individuals studied, 1630 were diagnosed with NAFLD. In a multivariable-adjusted model, high HbA1c levels were associated independently with increased prevalence of NAFLD. The adjusted odds ratio [95% confidence interval (95% CI)] for NAFLD, when compared with the highest HbA1c quartile and the lowest HbA1c quartile, was 2.72 (2.07-3.58; P for trend < 0.001). A strong association was also observed between HbA1c level and the risk of fibrosis in patients with NAFLD in multivariable analyses, with the extreme-quartile odds ratio of 2.69 (95% CI: 1.60-4.53; P for trend < 0.001). This association remained significant even in subjects without diabetes. CONCLUSIONS: We concluded that high HbA1c level was associated strongly and independently with increased risk of advanced fibrosis in NAFLD patients without diabetes.

Interpretation the Hepatotoxicity Based on Pharmacokinetics Investigated Through Oral Administrated Different Extraction Parts of Polygonum multiflorum on Rats.

The liver injury induced by Polygonum multiflorum (PM) used for clinical treatment has recently received widespread attention. This study aimed to determine the hepatotoxicity of PM through pharmacokinetics studies. The extract of PM was separated to isolate the anthraquinone fraction, the tannin and polysaccharide fraction, the hydroxystilbene fraction, and the combined anthraquinone fraction. A rapid LC-MS/MS method was developed and validated to simultaneously analyze 2,3,5,4'-tetrahydroxystilbene-2-O-ß-glucoside (TSG), emodin-8-O-ß-D-glucopyranoside (EDG), and emodin in rat plasma, and was applied to the pharmacokinetics (PK) studies. The hepatotoxicity of different extracted parts of PM was evaluated through the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBil), direct bilirubin (DBil), and indirect bilirubin (IBil) in rat serum. The results showed that liver injury occurred in all the treated groups and that the hepatotoxicity performance of the total extract was different from other groups. The pharmacokinetic studies showed that the Cmax, Tmax, AUC, t1/2, and MRT of the major compounds of different extracted parts were significantly different in rat plasma at same dosage. Emodin-O-hex-sulfate, tetrahydroxystilbene-O-(galloyl)-hex, emodin (original and generated through EDG deglycosylation), and other free anthraquinones might be responsible for the hepatotoxicity of PM in vivo. PM extracts produced inhibitory effects on drug metabolic enzymes, include CYP3A4, CYP2C19, CYP2E1, UGT1A1, etc. And these effects may be related to its hepatotoxicity and pharmacokinetic behavior different. This information on hepatotoxicity and the pharmacokinetic comparison may be useful to understand the toxicological effects of PM.