Multi-organ Mapping of Cancer Risk.

Cancers are distributed unevenly across the body, but the importance of cell intrinsic factors such as stem cell function in determining organ cancer risk is unknown. Therefore, we used Cre-recombination of conditional lineage tracing, oncogene, and tumor suppressor alleles to define populations of stem and non-stem cells in mouse organs and test their life-long susceptibility to tumorigenesis. We show that tumor incidence is determined by the life-long generative capacity of mutated cells. This relationship held true in the presence of multiple genotypes and regardless of developmental stage, strongly supporting the notion that stem cells dictate organ cancer risk. Using the liver as a model system, we further show that damage-induced activation of stem cell function markedly increases cancer risk. Therefore, we propose that a combination of stem cell mutagenesis and extrinsic factors that enhance the proliferation of these cell populations, creates a "perfect storm" that ultimately determines organ cancer risk. VIDEO ABSTRACT.

Critical Role for the DNA Sensor AIM2 in Stem Cell Proliferation and Cancer.

Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune sensor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in Aim2-deficient mice; however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with healthy wild-type mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.

A pharmacovigilance study of association between proton-pump inhibitors and rhabdomyolysis event based on FAERS database.

BACKGROUND AND AIM: The association between proton-pump inhibitors (PPIs) and rhabdomyolysis were unclear. The aim of this study was to explore and systematically analyze the potential link between five PPIs and the rhabdomyolysis events using the FDA Adverse Event Reporting System (FAERS) database. METHODS: Suspected rhabdomyolysis events associated with PPIs were identified by data mining with the reporting odds ratio (ROR), proportional reporting ratio (PRR), the information component (IC), and Empirical Bayes Geometric Mean (EBGM). Demographic information, drug administration, and outcomes of PPI-induced rhabdomyolysis events were also analyzed. RESULTS: There were 3311 reports associated with PPI-induced rhabdomyolysis that were identified. After removing duplicates, 1899 cases were determined to contain complete patient demographic data. The average age was 65 ± 18 year and 57% were male. Omeprazole and pantoprazole had the same largest percentage of reports. Lansoprazole had the highest ROR index of 12.67, followed by esomeprazole (11.18), omeprazole (10.27), rabeprazole (10.06), and pantoprazole (9.24). PRR, IC, and EBGM showed similar patterns. This suggested that lansoprazole exhibited the strongest correlation with rhabdomyolysis. In rhabdomyolysis events, PPIs were mainly "concomitant" (>60%), and only a few cases were "primary suspects" (<15%). Rabeprazole showed the lowest death rate while lansoprazole showed the highest. CONCLUSIONS: The study suggested that significant rhabdomyolysis signals were associated with PPIs. Further research should be performed in drug safety evaluation for a more comprehensive association.

Hg2+-enhanced oxidase-like activity of platinum nanoparticles immobilized on porphyrin-based porous organic polymer for the colorimetric detection and removal of Hg2.

Porphyrin-based porous organic polymer (POP) with uniformly immobilized platinum nanoparticles (Pt NPs) were designed and synthesized, and it was demonstrated that such nanocomposites (Pt/POP) have oxidase-like activity. Surprisingly, Hg2+ significantly enhanced the oxidase-like activity of Pt/POP. The enhancement was attributed to the capture of Hg2+ by the thioether group in Pt/POP and the subsequent redox reaction of Hg2+ with Pt NPs, accelerating the electron transfer. In the presence of Hg2+, Pt/POP catalyzed the colorless 3,3',5,5'-tetramethylbenzidine (TMB) to turn blue rapidly and changed its absorbance at 652 nm. Based on this, a fast-response colorimetric sensor was constructed for the sensitive detection of Hg2+ with a linear range of 0.2-50 µM and a detection limit of 36.5 nM. Importantly, Pt/POP can be used as an adsorbent for the efficient removal of Hg2+ with a removal efficiency as high as 99.4%. This work provides a valuable strategy for colorimetric detection and efficient removal of Hg2+.

Identifying Sex-Specific Serum Patterns of Alzheimer's Mice through Deep TMT Profiling and a Concentration-Dependent Concatenation Strategy.

Alzheimer's disease (AD) is the most prevalent form of dementia, disproportionately affecting women in disease prevalence and progression. Comprehensive analysis of the serum proteome in a common AD mouse model offers potential in identifying possible AD pathology- and gender-associated biomarkers. Here, we introduce a multiplexed, nondepleted mouse serum proteome profiling via tandem mass-tag (TMTpro) labeling. The labeled sample was separated into 475 fractions using basic reversed-phase liquid chromatography (RPLC), which were categorized into low-, medium-, and high-concentration fractions for concatenation. This concentration-dependent concatenation strategy resulted in 128 fractions for acidic RPLC-tandem mass spectrometry (MS/MS) analysis, collecting ∼5 million MS/MS scans and identifying 3972 unique proteins (3413 genes) that cover a dynamic range spanning at least 6 orders of magnitude. The differential expression analysis between wild type and the commonly used AD model (5xFAD) mice exhibited minimal significant protein alterations. However, we detected 60 statistically significant (FDR < 0.05), sex-specific proteins, including complement components, serpins, carboxylesterases, major urinary proteins, cysteine-rich secretory protein 1, pregnancy-associated murine protein 1, prolactin, amyloid P component, epidermal growth factor receptor, fibrinogen-like protein 1, and hepcidin. The results suggest that our platform possesses the sensitivity and reproducibility required to detect sex-specific differentially expressed proteins in mouse serum samples.

A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the most common pediatric liver cancer. Its predominant occurrence in very young children led us to investigate whether the neonatal liver provides a protumorigenic niche to HB development. APPROACH AND RESULTS: HB development was compared between orthotopic transplantation models established in postnatal day 5 (P5) and 60 (P60) mice (P5Tx and P60Tx models). Single-cell RNA-sequencing (sc-RNAseq) was performed using tumor and liver tissues from both models and the top candidate cell types and genes identified are investigated for their roles in HB cell growth, migration, and survival. CONCLUSIONS: We found that various HB cell lines including HepG2 cells were consistently and considerably more tumorigenic and metastatic in the P5Tx model than in the P60Tx models. Sc-RNAseq of the P5Tx and P60Tx HepG2 models revealed that the P5Tx tumor was more hypoxic and had a larger number of activated hepatic stellate cells (aHSCs) in the tumor-surrounding liver that express significantly higher levels of Cxcl1 than those from the P60Tx model. We found these differences were developmentally present in normal P5 and P60 liver. We showed that the Cxcl1/Cxcr2 axis mediated HB cell migration and was critical to HB cell survival under hypoxia. Treating HepG2 P60Tx model with recombinant CXCL1 protein induced intrahepatic and pulmonary metastasis and CXCR2 knockout (KO) in HepG2 cells abolished their metastatic potential in the P5Tx model. Lastly, we showed that in tumors from patients with metastatic HB, there was a similar larger population of aHSCs in the tumor-surrounding liver than in localized tumors, and tumor hypoxia was uniquely associated with prognosis of patients with HB among pediatric cancers. We demonstrated that the neonatal liver provides a prometastatic niche to HB development through the Cxcl1/Cxcr2 axis.

Trousseau's syndrome in a non-small cell lung cancer patient aggravated by pembrolizumab.

INTRODUCTION: We present a case of Trousseau's syndrome in a non-small cell lung cancer patient recurrently aggravated by pembrolizumab. The adverse events related to immune checkpoint inhibitors (ICIs) on thrombogenesis remain unclear. CASE REPORT: A 48-year-old woman was diagnosed with right lung adenocarcinoma (cT1bN3M1a, IVA) and with programmed cell death-1 positive. Brain magnetic resonance imaging (MRI) showed multiple asymptomatic bilateral cerebral infarctions as Trousseau's syndrome. After the patient was administered pembrolizumab, bilateral cerebral infarctions were aggravated. MANAGEMENT AND OUTCOME: Although the patient was given prophylactic anticoagulant therapy respectively before two doses of pembrolizumab, Trousseau's syndrome still aggravated recurrently. DISCUSSION: Trousseau's syndrome is rarely reported following the administration of ICIs. It is possible that pembrolizumab may trigger disorders of the coagulation-fibrinolysis system in cancer patients.

Hollow porphyrin-based porous organic polymer with dual enzyme-like activities for ultra-fast colorimetric detection of Cr (VI) in wastewater.

A hollow porphyrin-based porous organic polymer (H-Fe-POP) was prepared for rapid and sensitive colorimetric determination of Cr(VI), which exhibited excellent dual enzyme-like activities, including oxidase-like and peroxidase-like activities. Due to the specific binding of 8-hydroxyquinoline (8-HQ) to Cr(VI), 3,3',5,5'-tetramethylbenzidine (TMB) was liberated, and TMB was oxidized to blue ox-TMB catalyzed by H-Fe-POP. Based on the excellent oxidase-like activity of H-Fe-POP, an ultra-fast colorimetric platform for the detection of Cr(VI) was constructed, allowing the quantification of Cr(VI) in the range 2-130 µM within 30 s with a detection limit of 0.23 µM. Importantly, the sensor can accurately determine Cr(VI) in industrial wastewater, indicating its high potential for environmental monitoring.

Evaluating linezolid dose regimens against methicillin-resistant Staphylococcus aureus based on renal function in populations with different body weight.

WHAT IS KNOWN AND OBJECTIVE: Linezolid is an alternative first-line agent for MRSA pneumonia. This study assessed whether dose adjustments of linezolid against methicillin-resistant Staphylococcus aureus (MRSA) infections were needed based on renal function in populations with different body weight. METHODS: Monte Carlo simulations were conducted to evaluate renal function in relation to the probability of target attainment (PTA) in three population groups with different body weight. Area under the concentration time curve (AUC)/ minimum inhibitory concentration (MIC) ratio and percentage of time above the MIC (%T > MIC) were regarded as pharmacokinetic/pharmacodynamic targets. The PTA and cumulative fractions of response (CFR) were calculated to assess the efficacy. Regarding safety, trough plasma concentration (Cmin ) > 8 mg/L was used as target for toxicity. RESULTS AND DISCUSSION: Using AUC/MIC >100 as the target pharmacodynamic (PD) index, the CFR of linezolid at the standard dose (600 mg every 12 h [q12h]) were 57.01%, 93.22%, and 99.93% in patients with normal renal function, patients with renal dysfunction and low body weight patients with renal dysfunction, respectively. Using 100%T > MIC as the target PD index, all the CFR of three population groups were more than 90% at the standard dose. The percentages of Cmin > 8 mg/L at the standard dose of linezolid were 24.16%, 53.24%, and 90.10% in three population groups on day 7. WHAT IS NEW AND CONCLUSION: The risk of thrombocytopenia of linezolid was extremely higher in low body weight patients with renal impairment when receiving standard linezolid dose compared with patients with normal renal function. 450 mg q12h and 300 mg q12h might be effective and safe against MRSA infection in patients with renal dysfunction and low body weight patients with renal dysfunction, respectively.

In ovo feeding of vitamin C regulates splenic development through purine nucleotide metabolism and induction of apoptosis in broiler chickens.

Nutrition in early life has a long-term influence on later health. In order to the explore effects of in ovo feeding (IOF) of vitamin C on splenic development, splenic metabolism and apoptosis were detected in embryo, adult chickens and in vitro. A total of 360 fertile eggs were selected and randomly assigned to control (CON) and vitamin C (VC) groups which were injected with saline and vitamin C on embryonic day 11, respectively. Functional enrichment of differentially expressed genes by transcriptome on embryonic day 19 suggested that purine nucleotide metabolism might be a potential pathway for the IOF of vitamin C to regulate spleen development. Additionally, the IOF of vitamin C significantly increased splenic vitamin C content on post-hatch day 21. Meanwhile, the splenic expression of adenosine deaminase, serine/threonine kinase 1 and proliferating cell nuclear antigen was down-regulated, whereas the expression of cysteinyl aspartate specific proteinase 9 was up-regulated in the VC group. On post-hatch day 42, the IOF of vitamin C significantly down-regulated the splenic expression of B-cell lymphoma 2 and increased the mRNA level of cysteinyl aspartate specific proteinase 9. The IOF of vitamin C could regulate the expression of genes related to adenylate metabolism and increased the apoptosis rate in vitro, which is consistent with the result in vivo. In conclusion, the IOF of vitamin C regulated splenic development and maturation by affecting purine nucleotide metabolism pathway and promoting apoptosis.

Early bone formation in mini-lateral window sinus floor elevation with simultaneous implant placement: An in vivo experimental study.

OBJECTIVE: To investigate the early bone formation in beagles with mini-lateral window sinus floor elevation and simultaneous implant placement. MATERIAL AND METHODS: Six beagles were selected for the split-mouth design procedures. In each animal, one maxillary recess received a 5 mm-diameter mini-round lateral osteotomy (test group), and the contralateral maxillary recess received a large rectangular osteotomy (10 mm long and 8 mm wide), (control group). Simultaneous implant installation was executed on bilateral maxillary recesses. Tetracycline and calcein dyes were administered on the 14th, 13th days and the 4th, 3rd days prior to sacrifice, respectively. After 8 weeks of healing, the beagles were euthanized for fluorescent labeling and histomorphometric analyses. RESULTS: In both groups, new bone formation initiated from the circumferential native bone of the maxillary recesses and extended toward the central sub-recess cavities. The maxillary recesses with the mini-window procedures exhibited superior mineral apposition rate, bone formation rate, and the percentage of new bone area to those of the group exposed to large osteotomy procedure (p < .05). While there was no significant difference in the value of bone-to-implant contact, the mini-window group displayed a tendency for an increase in this aspect (p > .05). Bone formation rate and new bone amount were not statistically correlated with bone-to-implant contact (p > .05). CONCLUSION: The hypothesis that mini-lateral window sinus floor elevation with simultaneous implant placement would improve early new bone formation in augmented sinus compared with large lateral window procedure is accepted.

Drug-drug interaction comparison between tacrolimus and phenobarbital in different formulations for paediatrics and adults.

To compare drug-drug interaction (DDI) between tacrolimus and different formulations of phenobarbital in paediatrics and adults.Physiologically based pharmacokinetics (PBPK) models were used to evaluate DDI between phenobarbital (oral (p.o.) and intravenous (i.v.) formulations) and tacrolimus in paediatrics and adults. All dosing regimens were maintained for 7 days.Compared to i.v. phenobarbital, p.o. phenobarbital could decrease pharmacokinetic (PK) parameters of tacrolimus much more in both paediatrics and adults. On day 7, the results showed that the ratio of Cmax for tacrolimus in the presence and absence of phenobarbital were 0.13 (p.o.) and 0.48 (i.v.), respectively, in paediatrics, while 0.54 (p.o.) and 0.73 (i.v.) in adults, respectively. The ratios of the area under the concentration-time curve (AUC) were 0.06 (p.o.) and 0.18 (i.v.) in paediatrics, while 0.46 (p.o.) and 0.53 (i.v.) in adults, respectively. PK parameters of tacrolimus decreased more significantly in paediatrics compared to adults.In paediatric, phenobarbital had a greater impact on PK of tacrolimus than that in adults. P.o. phenobarbital reduced PK parameters of tacrolimus even more than i.v. administration. In clinical practice, the concentration monitoring and dosage adjustment of tacrolimus should be emphasised when co-administrated with phenobarbital, especially in paediatric or in p.o. formulation.Key pointsThe results indicated that p.o. and i.v. phenobarbital both had a significant DDI with tacrolimus in paediatrics and adults.Phenobarbital had a greater impact on the PK of tacrolimus over time in paediatrics.P.o. administration of phenobarbital can reduce the PK parameters of tacrolimus more.

Linezolid-induced thrombocytopenia in a child with a liver transplant: A case report.

OBJECTIVE: Linezolid-induced thrombocytopenia is rarely reported in liver transplant patients, especially in children. CASE SUMMARY: We report a case of a 7-month-old liver-transplanted child who suffered from thrombocytopenia induced by linezolid. We simulated the pharmacokinetics of linezolid in a healthy adult using the physiologically based pharmacokinetic (PBPK) model and found that the liver is the most abundant organ for the distribution of linezolid. PRACTICE IMPLICATIONS: Linezolid has a high distribution in the liver. As a result, an increased awareness about the risk of linezolid-induced thrombocytopenia should be strengthened in patients with liver injury. Effects of ethnicity: The differences between Chinese patients and patients of other ethnicities may lead to the diverse effects of linezolid in different patients. The influence of body weight (BW) difference in pharmacokinetics (PK) of linezolid between Asian (Chinese and Japanese) and Caucasians was demonstrated in several population PK studies [1, 2, 3]. The average BW of Asians is lower than that of the Caucasian population, the clearance and apparent volume of distribution are lower than in the European population, and Cmax is higher than in the Western population. Therefore, the adverse effects of linezolid at the same dose may increase in Chinese patients.

Research Progress of Radiolabeled Asn-Gly-Arg (NGR) Peptides for Imaging and Therapy.

Asn-Gly-Arg (NGR) motifs have vasculature-homing properties via interactions with the aminopeptidase N (CD13) expressed on tumor neovasculature. Numerous NGR peptides with different molecular scaffolds have been exploited for targeted delivery of different compounds for imaging and therapy. When conjugated with NGR, complexes recognize the CD13 receptor expressed on the tumor vasculature, which improves the specificity to tumor and avoids systematic toxic reactions. Both preclinical and clinical studies performed with these products suggest that NGR-mediated vascular targeting is an effective strategy for delivering bioactive amounts of cytokines to tumor endothelial cells. For molecular imaging, radiolabeled peptides have been the most successful approach and have been translated into clinic. This review describes current data on radiolabeled tumor vasculature-homing NGR peptides for imaging and therapy.

Assessment of micafungin loading dosage regimens against Candida spp. in ICU patients by Monte Carlo simulations.

OBJECTIVE: To assess the efficacy of loading dose on micafungin by simulating different dosage regimens. METHODS: A published study of micafungin in ICU patients was employed to simulate nine different dosage regimens which were sorted out three groups in terms of three maintenance doses. Using pharmacokinetic parameters and pharmacodynamic data, 5000-subject Monte Carlo simulations were conducted to simulate concentration-time profiles of micafungin, calculate probabilities of target attainment (PTAs), and cumulative fractions of response (CFRs) in terms of AUC/MIC targets. PTAs were calculated using AUC/MIC cut-offs: 285 (Candida parapsilosis), 3000 (all Candida spp.), and 5000 (non-parapsilosis Candida spp.). PTA or CFR > 90% was considered optimal for a dosage regimen. RESULTS: The concentration-time profiles of micafungin-simulated dosage regimens were obtained. PTA values were over 90% while applying the loading dose in each group of regimens: for Candida albicans and Candida glabrata (AUC/MIC = 5000), all regimens with loading dose provided PTAs of ≥ 90% for MIC ≤ 0.008 mg/L. The PTAs (AUC/MIC = 3000) were over 90% for MIC ≤ 0.008 mg/L in any regimen. However, for MIC inferior to 0.016 mg/L, only loading dosage regimens provided PTAs exceeding 90%. For C. parapsilosis (AUC/MIC = 285), the maximum MIC of achieving a PTA ≥ 90% was 0.25 mg/L both in the regimens of B (150 mg maintenance dose) and C (200 mg maintenance dose) with loading dose. In addition, CFR of any regimen with loading dose was ≥ 90% against C. albicans and C. glabrata. None of the dosage regimens achieved an expected CFR against C. parapsilosis. CONCLUSIONS: The dosage regimen of micafungin which had a loading dose of 1.5 times was more suitable for ICU patients infected by Candida spp.

Association between probiotic supplementation and asthma incidence in infants: a meta-analysis of randomized controlled trials.

Objective: The increased social and economic burdens for asthma in infants make the prevention of asthma a major public health goal. Probiotics may reduce the risk of asthma in infants. However, randomized controlled trials (RCTs) have shown mixed efficacy outcomes. We performed a meta-analysis of RCTs to investigate whether probiotics are associated with a lower asthma incidence in infants. Methods: The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to August 2018. RCTs comparing the effects of probiotic supplements with a placebo for asthma or wheeze incidence in infants were included. A meta-analysis was performed to calculate risk ratio (RR) and 95% confidence interval (CI) using the Mantel-Haenszel statistical method. Results: A total of 19 randomized trials involving 5157 children fulfilled the inclusion criteria. There was no significant association of probiotics with risk of asthma (RR, 0.94 [95% CI, 0.82-1.09]) or wheeze (RR, 0.97 [95% CI, 0.88-1.06]) compared with placebo. Subgroup analysis by asthma risk showed that probiotics significantly reduced wheeze incidence among infants with atopy disease (RR, 0.61 [95% CI, 0.42-0.90]), but no significant associations were found in the other subgroup analyses by participants receiving the intervention, timing of intervention, prevention regimen, probiotic organism, duration of intervention, and duration of follow-up. Conclusions: The use of probiotic supplementation compared with placebo was not associated with a lower risk of asthma in infants. These findings do not support recommendation to use probiotics in the prevention of asthma in infants.

Impact of body composition on pharmacokinetics of tacrolimus in liver transplantation recipients.

1. There are still no studies examining the relationship between body composition and tacrolimus pharmacokinetics in liver transplantation recipients. We aimed to investigate the influence of body composition on tacrolimus pharmacokinetics in liver transplantation recipients.2. Body composition was measured in 80 patients who underwent liver transplantation at Tianjin First Central Hospital, China, between 2015 and 2018. Blood concentrations of tacrolimus were collected from therapeutic drug monitoring data. Pharmacokinetic model fitting and Bayesian estimation were performed using nonlinear mixed-effects modeling (NONMEM) and SPSS was used to examine the effect of body composition on tacrolimus pharmacokinetics.3. The apparent volume of distribution (V/F) and clearance (CL/F) of tacrolimus were 179 L and 15.4 L/h, respectively. In liver transplantation recipients with percentage body fat (PBF) ≥ 30%, the apparent V/F of tacrolimus is lower than that in liver transplantation recipients with PBF < 30% at 1 week after liver transplantation.4. The new finding is important due to the severe adverse effects of tacrolimus. In clinical practice, an effective dosage adjustment of tacrolimus may need to be considered in patients with PBF ≥ 30% at 1 week after liver transplantation.

Transcriptome analysis reveals delaying of the ripening and cell-wall degradation of kiwifruit by hydrogen sulfide.

BACKGROUND: Hydrogen sulfide (H2 S) is a known signaling molecule in plants, which has the ability to delay fruit ripening. Our previous studies have shown that H2 S treatment could delay the maturation of kiwifruits by inhibiting ethylene production, improving protective enzyme activities, and decreasing the accumulation of reactive oxygen species to protect the cell membrane during storage. The mechanism related to the way in which H2 S affected kiwifruit maturation was still unclear. We performed transcriptome sequencing to explore the influences of H2 S on the softening of kiwifruit. RESULTS: The firmness and the soluble solids content (SSC) of the kiwifruit were significantly better maintained with H2 S treatment compared to the control during the storage period (P < 0.05). Transmission electron microscopy (TEM) showed that degradation of the cell wall was inhibited after H2 S treatment. Based on transcriptome data analysis and quantitative real-time polymerase chain reaction (qRT-PCR), expression levels of endo-1,4-ß-glucanase (ß-glu), ß-galactosidase (ß-gal) and pectinesterase (PME) decreased whereas pectinesterase inhibitor (PMEI) significantly increased in response to H2 S. The members of the signal transduction pathway involved in ethylene were also identified. Hydrogen sulfide inhibited the expression of ethylene receptor 2 (ETR2), ERF003, ERF5, and ERF016, and increased the expression of ethylene-responsive transcription factor 4 (ERF4) and ERF113. CONCLUSION: Hydrogen sulfide could delay the ripening and senescence of kiwifruit by regulating the cell-wall degrading enzyme genes and affecting ethylene signal transduction pathway genes. Our results revealed the effect of H2 S treatment on the softening of kiwifruit at the transcription level, laying a foundation for further research. © 2020 Society of Chemical Industry.

Acquisition of Cholangiocarcinoma Traits during Advanced Hepatocellular Carcinoma Development in Mice.

Past studies have identified hepatic tumors with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) characteristics that have a more aggressive behavior and a poorer prognosis than classic HCC. Whether this pathologic heterogeneity is due to a cell of origin of bipotent liver progenitors or the plasticity of cellular constituents comprising these tumors remains debated. In this study, we investigated the potential acquisition of CC-like traits during advanced development of HCC in mice. Primary and rare high-grade HCC developed in a genetic mouse model. A mouse model of highly efficient HCC invasion and metastasis by orthotopic transplantation of liver cancer organoids propagated from primary tumors in the genetic model was further developed. Invasive/metastatic tumors developed in both models closely recapitulated advanced human HCC and displayed a striking acquisition of CC-related pathologic and molecular features, which was absent in the primary HCC tumors. Our study directly demonstrates the pathologic evolution of HCC during advanced tumor development, providing the first evidence that tumors with mixed HCC and CC features, or at least a subset of these tumors, represent a more advanced developmental stage of HCC. Finally, liver cancer organoid-generated high-grade tumors exhibited significantly increased extracellular vesicle secretion, suggesting that identifying tumor-specific extracellular vesicle proteins in plasma may be a promising tool for liver cancer detection.

C/EBPα-dependent preneoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer.

Recent publications show that classic hepatoblastoma (HBL) is the result of failure of hepatic stem cells to differentiate into hepatocytes, while hepatocellular carcinoma (HCC) is caused by the dedifferentiation of hepatocytes into cancer stem cells. However, the mechanisms of aggressive HBL and the mechanisms that cause dedifferentiation of hepatocytes into cancer stem cells are unknown. We found that, similar to HCC but opposite to classic HBL, aggressive HBL is the result of dedifferentiation of hepatocytes into cancer stem cells. In both cases of liver cancer, the dephosphorylation of tumor suppressor protein CCAAT/enhancer binding protein α (C/EBPα) at Ser193 (Ser190 in human protein) or mutation of Ser193 to Ala results in a modified protein with oncogenic activities. We have investigated liver cancer in a mouse model C/EBPα-S193A, in a large cohort of human HBL samples, and in Pten/p53 double knockout mice and found that these cancers are characterized by elevation of C/EBPα that is dephosphorylated at Ser190/193. We found that dephosphorylated C/EBPα creates preneoplastic foci with cancer stem cells that give rise to HCC and aggressive HBL. C/EBPα-dependent dedifferentiation of hepatocytes into cancer stem cells includes increased proliferation of hepatocytes, followed by generation of multinucleated hepatocytes and subsequent appearance of hepatocytes with delta-like 1 homolog-positive intranuclear inclusions. We further isolated C/EBPα-dependent multinucleated hepatocytes and found that they possess characteristics of tumor-initiating cells, including elevation of stem cell markers. C/EBPα-dependent cancer stem cells are observed in patients with aggressive HBL and in patients with a predisposition for liver cancer. CONCLUSION: The earliest steps of adult HCC and aggressive pediatric liver cancer have identical features that include conversion of the tumor suppressor C/EBPα into an oncogenic isoform, which further creates preneoplastic foci where hepatocytes dedifferentiate into cancer cells, giving rise to liver cancer. (Hepatology 2018;67:1857-1871).