Deterministic positioning and alignment of a single-molecule exciton in plasmonic nanodimer for strong coupling.

Experimental realization of strong coupling between a single exciton and plasmons remains challenging as it requires deterministic positioning of the single exciton and alignment of its dipole moment with the plasmonic fields. This study aims to combine the host-guest chemistry approach with the cucurbit[7]uril-mediated active self-assembly to precisely integrate a single methylene blue molecule in an Au nanodimer at the deterministic position (gap center of the nanodimer) with the maximum electric field (EFmax) and perfectly align its transition dipole moment with the EFmax, yielding a large spectral Rabi splitting of 116 meV for a single-molecule exciton-matching the analytical model and numerical simulations. Statistical analysis of vibrational spectroscopy and dark-field scattering spectra confirm the realization of the single exciton strong coupling at room temperature. Our work may suggest an approach for achieving the strong coupling between a deterministic single exciton and plasmons, contributing to the development of room-temperature single-qubit quantum devices.

Cell-free DNA testing for early hepatocellular carcinoma surveillance.

BACKGROUND: Liver cirrhosis (LC) is the highest risk factor for hepatocellular carcinoma (HCC) development worldwide. The efficacy of the guideline-recommended surveillance methods for patients with LC remains unpromising. METHODS: A total of 4367 LCs not previously known to have HCC and 510 HCCs from 16 hospitals across 11 provinces of China were recruited in this multi-center, large-scale, cross-sectional study. Participants were divided into Stage Ⅰ cohort (510 HCCs and 2074 LCs) and Stage Ⅱ cohort (2293 LCs) according to their enrollment time and underwent Tri-phasic CT/enhanced MRI, US, AFP, and cell-free DNA (cfDNA). A screening model called PreCar Score was established based on five features of cfDNA using Stage Ⅰ cohort. Surveillance performance of PreCar Score alone or in combination with US/AFP was evaluated in Stage Ⅱ cohort. FINDINGS: PreCar Score showed a significantly higher sensitivity for the detection of early/very early HCC (Barcelona stage A/0) in contrast to US (sensitivity of 51.32% [95% CI: 39.66%-62.84%] at 95.53% [95% CI: 94.62%-96.38%] specificity for PreCar Score; sensitivity of 23.68% [95% CI: 14.99%-35.07%] at 99.37% [95% CI: 98.91%-99.64%] specificity for US) (P < 0.01, Fisher's exact test). PreCar Score plus US further achieved a higher sensitivity of 60.53% at 95.08% specificity for early/very early HCC screening. INTERPRETATION: Our study developed and validated a cfDNA-based screening tool (PreCar Score) for HCC in cohorts at high risk. The combination of PreCar Score and US can serve as a promising and practical strategy for routine HCC care. FUNDING: A full list of funding bodies that contributed to this study can be found in Acknowledgments section.

The development of a cSMART-based integrated model for hepatocellular carcinoma diagnosis.

BACKGROUND: Hepatocellular carcinoma (HCC) generally arises from a background of liver cirrhosis (LC). Patients with cirrhosis and suspected HCC are recommended to undergo serum biomarker tests and imaging diagnostic evaluation. However, the performance of routine diagnostic methods in detecting early HCC remains unpromising. METHODS: Here, we conducted a large-scale, multicenter study of 1675 participants including 490 healthy controls, 577 LC patients, and 608 HCC patients from nine clinical centers across nine provinces of China, profiled gene mutation signatures of cell-free DNA (cfDNA) using Circulating Single-Molecule Amplification and Resequencing Technology (cSMART) through detecting 931 mutation sites across 21 genes. RESULTS: An integrated diagnostic model called "Combined method" was developed by combining three mutation sites and three serum biomarkers. Combined method outperformed AFP in the diagnosis of HCC, especially early HCC, with sensitivities of 81.25% for all stages and 66.67% for early HCC, respectively. Importantly, the integrated model exhibited high accuracy in differentiating AFP-negative, AFP-L3-negative, and PIVKA-II-negative HCCs from LCs.

Magnetic Resonance Imaging Features and Misdiagnosis of Spinal Epidural Cavernous Hemangioma.

OBJECTIVE: Spinal epidural cavernous hemangiomas (SECHs) are rare, and merely a few have previously been described in case reports. The present study aims to explore the magnetic resonance imaging (MRI) features of SECHs and analyze the causes of their preoperative misdiagnosis. METHODS: The present retrospective study included 11 patients (three male and eight female patients, mean age ± standard deviation: 47.55±17.39 years old) with histopathologically confirmed SECH between January 2015 and April 2021. The MRI features of SECH were analyzed by two radiologists. RESULTS: The cervical, thoracic and thoracolumbar segments were involved in 2, 7 and 2 patients, respectively. All lesions grew along the long axis of the spine. The tumors were shuttle-shaped in six patients, oval in two patients, pseudopodia-shaped in one patient, clamp-shaped in one patient, and growing outward along the intervertebral foramen in one patient. Nine SECHs had relatively uniform isointense or hypointense T1-weighted imaging (T1WI) and hyperintense T2-weighted imaging (T2WI) signals. On the T2WI, filamentary low-signal shadows (i.e., the hairline or grid sign) with significant contrast enhancement and asymptotic strengthening were observed. Two SECHs had mixed high and low signals on T1WI and T2WI, with significant heterogeneous enhancement, hemorrhage, and hemosiderin deposition. The SECH was misdiagnosed as meningioma, neurofibromatosis and schwannoma in 1, 1 and 4 patients, respectively, while this was not diagnosed in one patient. The preoperative diagnosis was correct in merely approximately 36% of patients. Among the four patients with a correct preoperative diagnosis, hemosiderin deposition was found in three patients and small tortuous vascular shadows were found in one patient. CONCLUSION: SECH presents as a long spindle-shaped mass, and the "'pen cap sign" is common at the lesion edges. SECH also exhibits a hairline or grid sign on T2WI. Furthermore, some lesions present with hemorrhage and hemosiderin deposition. Therefore, the hairline, grid sign and hemosiderin deposition are valuable diagnostic features of SECH.

The effect of adjuvant transarterial chemoembolization for hepatocellular carcinoma after liver resection based on risk stratification.

BACKGROUND: There is currently no standard adjuvant treatment proven to prevent hepatocellular carcinoma (HCC) recurrence. Recent studies suggest that postoperative adjuvant transarterial chemoembolization (PA-TACE) is beneficial for patients at high risk of tumor recurrence. However, it is difficult to select the patients. The present study aimed to develop an easy-to-use score to identify these patients. METHODS: A total of 4530 patients undergoing liver resection were recruited. Independent risk factors were identified by Cox regression model in the training cohort and the Primary liver cancer big data transarterial chemoembolization (PDTE) scoring system was established. RESULTS: The scoring system was composed of ten risk factors including alpha-fetoprotein (AFP), albumin-bilirubin (ALBI) grade, operative bleeding loss, resection margin, tumor capsular, satellite nodules, tumor size and number, and microvascular and macrovascular invasion. Using 5 points as risk stratification, the patients with PA-TACE had higher recurrence-free survival (RFS) compared with non-TACE in > 5 points group (P < 0.001), whereas PA-TACE patients had lower RFS compared with non-TACE in ≤ 5 points group (P = 0.013). In the training and validation cohorts, the C-indexes of PDTE scoring system were 0.714 [standard errors (SE) = 0.010] and 0.716 (SE = 0.018), respectively. CONCLUSIONS: The model is a simple tool to identify PA-TACE for HCC patients after liver resection with a favorable performance. Patients with > 5 points may benefit from PA-TACE.

Cavity spectral-hole-burning to boost coherence in plasmon-emitter strong coupling systems.

Significant decoherence of the plasmon-emitter (i.e., plexcitonic) strong coupling systems hinders the progress towards their applications in quantum technology due to the unavoidable lossy nature of the plasmons. Inspired by the concept of spectral-hole-burning (SHB) for frequency-selective bleaching of the emitter ensemble, we propose 'cavity SHB' by introducing cavity modes with moderate quality factors to the plexcitonic system to boost its coherence. We show that the detuning of the introduced cavity mode with respect to the original plexcitonic system, which defines the location of the cavity SHB, is the most critical parameter. Simultaneously introducing two cavity modes of opposite detunings, the excited-state population of the emitter can be enhanced by 4.5 orders of magnitude within 300 fs, and the attenuation of the emitter's population can be slowed down by about 56 times. This theoretical proposal provides a new approach of cavity engineering to enhance the plasmon-emitter strong coupling systems' coherence, which is important for realistic hybrid-cavity design for applications in quantum technology.

Fano effect induced giant and robust enhancement of photon correlations in cavity QED systems.

The Fano effect arising from the interference between two dissipation channels of the radiation continuum enables tuning of the photon statistics. Understanding the role of the Fano effect and exploiting it to achieve strong photon correlations are of both fundamental and applied significance. We present an analytical description of Fano-enhanced photon correlations based on cavity quantum electrodynamics to show that the Fano effect in atom-cavity systems can improve the degree of antibunching by over four orders of magnitude. The enhancement factors and the optimal conditions are explicitly given, and found to relate to the Fano parameter q. Remarkably, the Fano enhancement manifests robustness against the decoherence processes and can survive in the weak coupling regime. We expect our work to provide insight to tuning the photon statistics through the Fano effect, which offers a new, to the best of our knowledge, route to enhance the photon correlations, as well as the possibility of generating nonclassical light in a wider diversity of systems without the need of a strong light-matter interaction.

The Landscape of Cell-Free HBV Integrations and Mutations in Cirrhosis and Hepatocellular Carcinoma Patients.

PURPOSE: Intratumoral hepatitis B virus (HBV) integrations and mutations are related to hepatocellular carcinoma (HCC) progression. Circulating cell-free DNA (cfDNA) has shown itself as a powerful noninvasive biomarker for cancer. However, the HBV integration and mutation landscape on cfDNA remains unclear. EXPERIMENTAL DESIGN: A cSMART (Circulating Single-Molecule Amplification and Resequencing Technology)-based method (SIM) was developed to simultaneously investigate HBV integration and mutation landscapes on cfDNA with HBV-specific primers covering the whole HBV genome. Patients with HCC (n = 481) and liver cirrhosis (LC; n = 517) were recruited in the study. RESULTS: A total of 6,861 integration breakpoints including TERT and KMT2B were discovered in HCC cfDNA, more than in LC. The concentration of circulating tumor DNA (ctDNA) was positively correlated with the detection rate of these integration hotspots and total HBV integration events in cfDNA. To track the origin of HBV integrations in cfDNA, whole-genome sequencing (WGS) was performed on their paired tumor tissues. The paired comparison of WGS data from tumor tissues and SIM data from cfDNA confirmed most recurrent integration events in cfDNA originated from tumor tissue. The mutational landscape across the whole HBV genome was first generated for both HBV genotype C and B. A region from nt1100 to nt1500 containing multiple HCC risk mutation sites (OR > 1) was identified as a potential HCC-related mutational hot zone. CONCLUSIONS: Our study provides an in-depth delineation of HBV integration/mutation landscapes at cfDNA level and did a comparative analysis with their paired tissues. These findings shed light on the possibilities of noninvasive detection of virus insertion/mutation.

Harvesting triplet excitons for near-infrared electroluminescence via thermally activated delayed fluorescence channel.

Near-infrared (NIR) emission is useful for numerous practical applications, such as communication, biomedical sensors, night vision, etc., which encourages researchers to develop materials and devices for the realization of efficient NIR organic light-emitting devices. Recently, the emerging organic thermally activated delayed fluorescence (TADF) emitters have attracted wide attention because of the full utilization of electron-generated excitons, which is crucial for achieving high device efficiency. Up to now, the TADF emitters have shown their potential in the deep red/NIR region. Considering the color purity and efficiency, however, the development of NIR TADF emitters still lags behind RGB TADF emitters, indicating that there is still much room to improve their performance. In this regard, this perspective mainly summarizes the past progress of molecular design on constructing TADF NIR emitters. We hope this perspective could provide a new vista in developing NIR materials and enlighten breakthroughs in both fundamental research and applications.

"Smoking paradox" is not true in patients with ischemic stroke: a systematic review and meta-analysis.

BACKGROUND: Ischemic stroke (IS) is a common cause of death from vascular diseases. Studies have found that smoking increases the risk of ischemic stroke, but the association of smoking with the outcome of IS remains unclear. This meta-analysis aims to investigate the effect of smoking on the prognosis of IS. METHODS: We searched four electronic databases including PubMed, EMBASE, Cochrane library and Web of science for papers, published before January 2019. In this meta-analysis, Review Manager 5.3 software was used to calculate for the pooled estimate effect, as well as the inverse-variance method for pooled mean difference (MD) and odds ratio (OR) of incidence in two groups of population. RESULTS: A total of 14,789 citations were identified during the literature search, 21 studies were included in the meta-analyses after screening. The full-adjusted OR of poor prognostic outcome in smoking and nonsmoking patients with stroke was pooled as 0.96 (95% CI 0.77-1.21), suggested that smoking or not has no impact on prognosis of IS. The pooled MD of onset age between smoking and nonsmoking IS patients was - 10.05 (- 12.91, - 7.19), indicated that smoking causes first onset of IS to occur 10 years earlier. CONCLUSIONS: This meta-analysis showed that smoking was not a protective factor for poor prognosis of IS. Smoking patients with IS are 10 years younger than nonsmoking patients at time of the first onset of stroke.

The Correlation Between the Types of Initial Bacterial Infection and Clinical Prognosis in Patients With Septic AKI.

BACKGROUND: Acute kidney injury (AKI) is a common complication of sepsis and is an independent risk factor for mortality. It is unclear whether different bacteria play different roles in the occurrence and development of sepsis-associated AKI (S-AKI). We observed the clinical characteristics and outcomes of patients that have types of bacterial infection, and different infections sites before the occurrence of AKI, respectively. METHODS: Data of patients who were diagnosed with sepsis and later developed AKI from 2008 to 2019 were retrieved from the MIMIC-IV 1.0 database. Patients were first divided into the two groups according to the bacterial culture results obtained prior to AKI occurrence: bacterial cultured positive (N = 1,785) and bacterial cultured negative (N = 8,777). Patients with bacteria culture positive were divided into culture bacteria Gram-positive (CGP, N = 1248) and Gram-negative (CGN, N = 537) groups. RESULTS: Overall, 1,785 patients were included in the present analysis. The patients in CGN group were older (70 vs. 66, p < 0.001), had lower body mass index (BMI) (27.0 vs. 28.4, p < 0.001), higher acute physiology III (APS III) score (63.0 vs. 58, p = 0.001), shorter time from positive microbial culture to diagnosis of AKI (2.94 vs. 3.16 days, p = 0.013) and longer intensive care unit (ICU) stay time (5.94 vs. 4.77 days, p < 0.001) compared with those in the CGP group (n = 1,248). In the culture gram-negative bacteria in patients with positive blood cultures (CGNb) group, the rate of vasopressors using (73.1 vs. 56.4%, P = 0.007), the Sequential Organ Failure Assessment (SOFA) score (10 vs. 9, p = 0.005), and the level of lactate (3.7 vs. 2.5, p = 0.001) were higher than those in the culture gram-positive bacteria in patients with positive blood cultures (CGPb) group. The time from positive microbial culture to the diagnosis of AKI was shorter (2.23 vs. 3 days, p = 0.001) in the CGNb group. However, there was no significant difference in the continuous renal replacement treatment (CRRT) application or short-term mortality rates between CGN and CGP groups. CONCLUSION: The Gram types of bacteria cultured prior to S-AKI occurrence was not related to AKI stage, CRRT application, and short-term mortality. Compared with the Gram-positive bacterial infections, Gram-negative bacterial infections take a shorter time to develop into AKI, and had a higher disease severity score.

Targeted sequencing reveals the mutational landscape responsible for sorafenib therapy in advanced hepatocellular carcinoma.

Rationale: The existence of primary and acquired drug resistance is the main obstacle for the effect of multi-kinase inhibitor sorafenib and regorafenib in advanced hepatocellular carcinoma (HCC). However, plenty of patients did not significantly benefit from sorafenib treatment and little is known about the mechanism of drug resistance. Methods: Laser capture microdissection was used to acquire matched normal liver and tumor tissues on formalin-fixed paraffin-embedded specimens collected before sorafenib therapy from the first surgery of 119 HCC patients. Ultra-deep sequencing (~1000×) targeting whole exons of 440 genes in microdissected specimens and siRNA screen in 7 cell lines were performed to find mutations associated with differential responses to sorafenib. Patient-derived xenograft models were employed to determine the role of TP53 in response to sorafenib. Lentiviruses harboring wild-type and c.G52C-mutant OCT4 were applied to explore the function of OCT4 in resistance to sorafenib. ChIP-PCR assay for analysis of OCT4 transcriptional activity was performed to explore the affinity with the KITLG promoter. Statistical analyses were used to associate levels of p53 and OCT4 with tumor features and patient outcomes. Results: Total 1,050 somatic mutations and 26 significant driver genes were identified. SiRNA screening in 7 HCC cell lines was further performed to identify mutations associated with differential responses to sorafenib. A recurrent nonsynonymous mutation c.G52C in OCT4 (OCT4mut) was strongly associated with good response to sorafenib, whereas the stop-gain mutation in TP53 showed the opposite outcome both in vitro and in vivo. OCT4wt-induced stem cell factor (encoded by KITLG gene, SCF) expression and cross-activation of c-KIT/FLT3-BRAF signals were identified indispensably for sorafenib resistance, which could be reversed by the combination of c-KIT tyrosine kinase inhibitors or neutralizing antibody against SCF. Mechanistically, an OCT4 binding site in upstream of KITLG promoter was identified with a higher affinity to wildtype of OCT4 rather than G52C-mutant form, which is indispensable for OCT4-induced expression of KITLG and sorafenib resistance. Conclusion: Our study reported a novel somatic mutation in OCT4 (c.G52C) responsible for the sorafenib effect, and also shed new light on the treatment of HCC through the combination of specific tyrosine kinase inhibitors according to individual genetic patterns.

Plasma circular RNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma: A large-scale, multicenter study.

To explore whether plasma circular RNAs (circRNAs) can diagnose hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), microarray and qPCR were used to identify plasma circRNAs that were increased in HBV-related HCC patients compared to controls (including healthy controls, chronic hepatitis B and HBV-related liver cirrhosis). A logistic regression model was constructed using a training set (n = 313) and then validated using another two independent sets (n = 306 and 526, respectively). Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. We identified a plasma circRNA panel (CircPanel) containing three circRNAs (hsa_circ_0000976, hsa_circ_0007750 and hsa_circ_0139897) that could detect HCC. CircPanel showed a higher accuracy than AFP (alpha-fetoprotein) to distinguish individuals with HCC from controls in all three sets (AUC, 0.863 [95% confidence interval, CI: 0.819-0.907] vs. 0.790 [0.738-0.842], p = 0.036 in training set; 0.843 [0.796-0.890] vs. 0.747 [0.691-0.804], p = 0.011 in validation set 1 and 0.864 [0.830-0.898] vs. 0.769 [0.728-0.810], p < 0.001 in validation set 2). CircPanel also performed well in detecting Small-HCC (solitary, ≤3 cm), AFP-negative HCC and AFP-negative Small-HCC.

Circular RNAs negatively regulate cancer stem cells by physically binding FMRP against CCAR1 complex in hepatocellular carcinoma.

Circular RNA (circRNA) possesses great pre-clinical diagnostic and therapeutic potentials in multiple cancers. It has been reported playing roles in multiple malignant behaviors including proliferation, migration, metastasis and chemoresistance. However, the underlying correlation between circRNAs and cancer stem cells (CSCs) has not been reported yet. Methods: circZKSCAN1 level was detected in HCC tissue microarrays to clarify its prognostic values. Gain and loss function experiments were applied to investigate the role of circZKSCAN1 in HCC stemness. Bioinformatic analysis was used to predict the possible downstream RNA binding protein and further RNA immunoprecipitation sequencing was carried out to identify the RBP-regulated genes. Results: The absence of circZKSCAN1 endowed several malignant properties including cancer stemness and tightly correlated with worse overall and recurrence-free survival rate in HCC. Bioinformatics analysis and RNA immunoprecipitation-sequencing (RIP-seq) results revealed that circZKSCAN1 exerted its inhibitive role by competitively binding FMRP, therefore, block the binding between FMRP and ß-catenin-binding protein-cell cycle and apoptosis regulator 1 (CCAR1) mRNA, and subsequently restrain the transcriptional activity of Wnt signaling. In addition, RNA-splicing protein Quaking 5 was found downregulated in HCC tissues and responsible for the reduction of circZKSCAN1. Conclusion: Collectively, this study revealed the mechanisms underlying the regulatory role of circZKSCAN1 in HCC CSCs and identified the newly discovered Qki5-circZKSCAN1-FMRP-CCAR1-Wnt signaling axis as a potentially important therapeutic target for HCC treatment.

Development and validation of a prognostic score predicting recurrence in resected combined hepatocellular cholangiocarcinoma.

Purpose: To develop and validate a decision aid to help make individualized estimates of tumor recurrence for patients with resected combined hepatocellular cholangiocarcinoma (CHC). Patients and methods: Risk factors of recurrence were identified in the derivation cohort of 208 patients who underwent liver resection between 1995 and 2014 at Zhongshan Hospital to develop a prediction score. The model was subsequently validated in an external cohort of 101 CHC patients using the C concordance statistic and net reclassification index (NRI). Results: On multivariate analysis, five independent predictors associated with tumor recurrence were identified, including sex, γ-glutamyl transferase, macrovascular invasion, hilar lymphoid metastasis and adjuvant transcatheter arterial chemoembolization. The prediction score was constructed using these 5 variables, with scores ranging from 0 to 5. A patient with a score of 0 had a predicted 1- and 5-year recurrence risk of 11.1% and 22.2%, respectively. In the validation cohort, the NRIs of prediction score vs American Joint Committee on Cancer 7th TNM staging system at 1-year and 5-year were 0.185 (95% CI, 0.090-0.279, P<0.001) and 0.425 (95% CI, 0.044-0.806, P=0.03), respectively. Conclusion: Our developed and validated prediction score might be a simple and reliable method in postoperative CHC patients and help clinicians identify candidates who may benefit from future adjuvant therapies.

A novel HBx genotype serves as a preoperative predictor and fails to activate the JAK1/STATs pathway in hepatocellular carcinoma.

BACKGROUND & AIMS: Genetic variability in the hepatitis B virus X gene (HBx) is frequently observed and is associated with hepatocellular carcinoma (HCC) progression. However, a genotype classification based on the full-length HBx sequence and the impact of genotypes on hepatitis B virus (HBV)-related HCC prognosis remain unclear. We therefore aimed to perform this genotype classification and assess its clinical impact. METHODS: We classified the genotypes of the full-length HBx gene through sequencing and a cluster analysis of HBx DNA from a cohort of patients with HBV-related HCC, which served as the primary cohort (n = 284). Two independent HBV-related HCC cohorts, a validation cohort (n = 171) and a serum cohort (n = 168), were used to verify the results. Protein microarray assay analysis was performed to explore the underlying mechanism. RESULTS: In the primary cohort, the HBx DNA was classified into 3 genotypes: HBx-EHBH1, HBx-EHBH2, and HBx-EHBH3. HBx-EHBH2 (HBx-E2) indicated better recurrence-free survival and overall survival for patients with HCC. HBx-E2 was significantly correlated with the absence of liver cirrhosis, a small tumor size, a solitary tumor, complete encapsulation and Barcelona Clinic Liver Cancer (BCLC) stage A-0 tumors. Additionally, HBx-E2 served as a significant prognostic factor for patients with BCLC stage B HCC after hepatectomy. Mechanistically, HBx-E2 is unable to promote proliferation in HCC cells and normal hepatocytes. It also fails to activate the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3)/STAT5 pathway. CONCLUSION: Our study identifies a novel HBx genotype that is unable to promote the proliferation of HCC cells and suggests a potential marker to preoperatively predict the prognosis of patients with BCLC stage B, HBV-associated, HCC. LAY SUMMARY: We classified a novel genotype of the full-length hepatitis B virus X gene (HBx), HBx-E2. This genotype was identified in tumor and nontumor tissues from patients with hepatitis B virus-related hepatocellular carcinoma. HBx-E2 could preoperatively predict the prognosis of patients with intermediate stage hepatocellular carcinoma, after resection.

Somatostatin Octapeptide Inhibits Cell Invasion and Metastasis in Hepatocellular Carcinoma Through PEBP1.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a major threat to human health. The condition carries a high risk of death; 45% of new cases occur in China. Surgical resection is the first choice for treatment of HCC, but 30.9% of patients experience recurrence within 6 months after the operation. To improve patient survival, we must determine how to reduce the probability of recurrence and metastasis and elucidate the underlying mechanism of disease. We therefore studied the effect of somatostatin octapeptide (octreotide) on the invasion and metastasis of HCC. METHODS: The migration and invasion cytological tests were used to detect the effect of octreotide on liver cancer cells (SK-Hep-1 and HepG2). PEBP1 RNAi was used to knockdown expression. Invasion and metastasis were measured with transwell migration and wound-healing assays. Western blotting was used to detect changes in levels of PEBP1 and invasion pathway proteins after octreotide treatment. The effect of octreotide was studied in vivo by establishing a pulmonary metastasis model using SK-Hep-1 cells in nude mice. In-vivo bioluminescence imaging and hematoxylin and eosin staining of lung tissue were used to verify the results. RESULTS: Increasing concentrations of octreotide were progressively more effective in halting the invasion and metastasis of liver cancer cells. Octreotide may upregulate PEBP1, TIMP-2, and E-cadherin while downregulating MMP-2 and Twist to inhibit cell invasion and metastasis. And downregulation of PEBP1 would also change the expression of MMP-2, TIMP-2 and Twist. The in-vivo experiments showed no cancer cell metastasis in 4 of the 6 mice in the octreotide-treatment group, while all of the mice in the control group displayed pulmonary metastasis of human HCC cells. And the survival period of the mice in the octreotide-treatment group was significantly prolonged. CONCLUSIONS: Octreotide may weaken invasion and metastasis through the upregulation of PEBP1. Octreotide may reduce the risk of recurrence and metastasis after surgery for liver cancer.

Partial Inhibition of HO-1 Attenuates HMP-Induced Hepatic Regeneration against Liver Injury in Rats.

We found better liver graft regeneration with hypothermic machine perfusion (HMP) compared with static cold storage (SCS) for the first time in our pilot study, but the underlying mechanisms are unknown. Upregulated heme oxygenase- (HO-) 1 expression has been reported to play a pivotal role in promoting hepatocyte proliferation. Here, we evaluated the novel role of HO-1 in liver graft protection by HMP. Rats with a heterozygous knockout of HO-1 (HO-1+/-) were generated and subjected to 3 h of SCS or HMP pre-half-size liver transplantation (HSLT) in vivo or 6 h of SCS or HMP in vitro; control rats were subjected to the same conditions (HO-1+/+). We found that HSLT induced significant elevation of the HO-1 protein level in the regenerated liver and that HO-1 haplodeficiency resulted in decreased proliferation post-HSLT. Compared with SCS, HMP induced significant elevation of the HO-1 protein level along with better liver recovery, both of which were reduced by HO-1 haplodeficiency. HO-1 haplodeficiency-induced decreased proliferation was responsible for the attenuated regenerative ability of HMP. Mechanistically, HO-1 haploinsufficiency resulted in suppression of hepatocyte growth factor (HGF)/Akt activity. Our results suggest that inhibition of HO-1 mitigates HMP-induced liver recovery effects related to proliferation, in part, by downregulating the HGF-Akt axis.

Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial.

OBJECTIVE: There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need. DESIGN AND RESULTS: A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI -12.59 to -2.50; p=0.0018), respectively. CONCLUSIONS: This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group. TRIAL REGISTRATION: NCT01770431; Post-results.