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Abstract Of the estimated 50 million new cases of hepatitis B virus (HBV) infection diagnosed annually, 5–10% of adults and up to 90% of infants will become chronically infected, 75% of these in Asia where hepatitis B is the leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). In Indonesia, 4.6% of the population was positive for HBsAg in 1994 and of these, 21% were positive for HBeAg and 73% for anti-HBe; 44% and 45% of Indonesian patients with cirrhosis and HCC, respectively, were HBsAg positive. In the Philippines, there appear to be two types of age-specific HBsAg prevalence, suggesting different modes of transmission. In Thailand, 8–10% of males and 6–8% of females are HBsAg positive, with HBsAg also found in 30% of patients with cirrhosis and 50–75% of those with HCC. In Taiwan, 75–80% of patients with chronic liver disease are HBsAg positive, and HBsAg is found in 34% and 72% of patients with cirrhosis and HCC, respectively. In China, 73% of patients with chronic hepatitis and 78% and 71% of those with cirrhosis and HCC, respectively, are HBsAg positive. In Singapore, the prevalence of HBsAg has dropped since the introduction of HBV vaccination and the HBsAg seroprevalence of unvaccinated individuals over 5 years of age is 4.5%. In Malaysia, 5.24% of healthy volunteers, with a mean age of 34 years, were positive for HBsAg in 1997. In the highly endemic countries in Asia, the majority of infections are contracted postnatally or perinatally. Three phases of chronic HBV infection are recognized: phase 1 patients are HBeAg positive with high levels of virus in the serum and minimal hepatic inflammation; phase 2 patients have intermittent or continuous hepatitis of varying degrees of severity; phase 3 is the inactive phase during which viral concentrations are low and there is minimal inflammatory activity in the liver. In general, patients who clear HBeAg have a better prognosis than patients who remain HBeAg-positive for prolonged periods of time. The outcome after anti-HBe seroconversion depends on the degree of pre-existing liver damage and any subsequent HBV reactivation. Without pre-existing cirrhosis, there may be only slight fibrosis or mild chronic hepatitis, but with pre-existing cirrhosis, further complications may ensue. HBsAg-negative chronic hepatitis B is a phase of chronic HBV infection during which a mutation arises resulting in the inability of the virus to produce HBeAg. Such patients tend to have more severe liver disease and run a more rapidly progressive course. The annual probability of developing cirrhosis varies from 0.1 to 1.0% depending on the duration of HBV replication, the severity of disease and the presence of concomitant infections or drugs. The annual incidence of hepatic decompensation in HBV-related cirrhosis varies from 2 to 10% and in these patients the 5-year survival rate drops dramatically to 14–35%. The annual risk of developing HCC in patients with cirrhosis varies between 1 and 6%; the overall reported annual detection rate of HCC in surveillance studies, which included individuals with chronic hepatitis B and cirrhosis, is 0.8–4.1%. Chronic hepatitis B is not a static disease and the natural history of the disease is affected by both viral and host factors. The prognosis is poor with decompensated cirrhosis and effective treatment options are limited. Prevention of HBV infection thorough vaccination is still, therefore, the best strategy for decreasing the incidence of hepatitis B-associated cirrhosis and HCC. [ABSTRACT FROM AUTHOR]

Background: Cancer stem cell model suggested that tumor progression is driven by the overpopulation of cancer stem cells and eradicating or inhibiting the symmetric division of cancer stem cells would become the most important therapeutic strategy. However, clinical evidence for this hypothesis is still scarce. To evaluate the overpopulation hypothesis of cancer stem cells the association of percentage of CD133+ tumor cells with clinicopathological parameters in colon cancer was investigated since CD133 is a putative cancer stem cell marker shared by multiple solid tumors.Patients and Methods: Tumor tissues matched with adjacent normal tissues were collected from 104 stage IIIB colon cancer patients who were subject to radical resection between January, 1999 to July, 2003 in this center. The CD133 expression was examined with immunohistochemical staining. The correlation of the percentage of CD133+ cell with clinicopathological parameters and patients' 5-year survival was analyzed.Results: The CD133+ cells were infrequent and heterogeneous distribution in the cancer tissue. Staining of CD133 was localized not only on the glandular-luminal surface of cancer cells but also on the invasive budding and the poorly differentiated tumors with ductal structures. Both univariate and multivariate survival analysis revealed that the percentage of CD133+ cancer cells and the invasive depth of tumor were independently prognostic. The patients with a lower percentage of CD133+ cancer cells (less than 5%) were strongly associated with a higher 5-year survival rate than those with a higher percentage of CD133+ cancer cells (greater than or equal to 55%). Additionally, no correlation was obtained between the percentage of CD133+ cancer cells and the other clinicopathological parameters including gender, age, site of primary mass, pathologic types, grades, and invasive depth.Conclusion: The fact that a higher percentage CD133+ cells were strongly associated with a poorer prognosis in patients with locally advanced colon cancer implicated that CD133+ cancer cells contribute to the tumor progression, and the overpopulation hypothesis of cancer stem cell seems reasonable. [ABSTRACT FROM AUTHOR]

Background: RBC deformability after trauma and hemorrhagic shock (T/HS) leads to the microcirculatory dysfunction and clinical manifestations of organ failure. However, the cellular mechanism of this phenomenon remains unknown. Spectrins are important for the shape and physical properties of erythrocytes, such as deformability and resistance to mechanical stress. Previous studies have shown that erythrocyte alpha-spectrin is ubiquitinated. Studies of sickled cells and aged erythrocytes, 2 conditions known to have decreased RBC deformability, have shown decreased alpha-spectrin ubiquitination, which may contribute to the inability of these cells to change shape. It was hypothesized that decreased alpha-spectrin ubiquitination could participate in the mechanism(s) whereby T/HS erythrocytes become less deformable.Methods: The level of alpha-spectrin ubiquitination in erythrocytes isolated from T/HS rats was determined and compared with erythrocytes from control sham-shocked (T/SS) animals. After T/SS (n = 4) or T/HS (n = 7), alpha- and beta-spectrin subunits were isolated using a low ionic-strength buffer at 37 degrees C for 30 minutes. The relative amount of ubiquitinated alpha-spectrin was evaluated by Western blotting using a monoclonal antibody to ubiquitin.Results: The relative level of alpha-spectrin ubiquitination (normalized to total alpha-spectrin in the same preparation) was found to be significantly decreased after T/HS (.319 +/- .03) compared with T/SS control erythrocytes (.485 +/- .06, P < .05). To evaluate the content and relative amounts of the other membrane proteins, the profiles of T/HS and T/SS erythrocytes were compared by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. This did not reveal any significant quantitative differences between T/SS and T/HS spectrin or other membrane proteins.Conclusions: The finding of decreased alpha-spectrin ubiquitination after T/HS suggests that this mechanism could contribute to increased rigidity of the erythrocyte membrane. [ABSTRACT FROM AUTHOR]

The development of facile and convenient atom-economical methods for the preparation of organosulfur compounds from CS 2 is a challenging endeavor. Herein, a one-pot, environmentally friendly method to access S -aryl/alkyl dithiocarbamates has been demonstrated by a three-component coupling involving aryl/alkyl thiols, CS 2 and amines in the presence of a common base K 2 CO 3 . The transformation process can proceed in an H 2 O-DMAc (3 : 1) mixed solvent without requiring any catalysts or extensive prefunctionalization of reactants. The protocol is operationally simple and affords dithiocarbamates with various moieties (including aryl, aliphatic, heteroaryl and alkenyl) in good yields.

To achieve efficient resource utilization of fly ash and multi-source organic waste, a composting experiment was carried out to investigate the effects of fly ash on co-aerobic composting using kitchens, chicken manure, and sawdust (15:5:2). The effects of different application doses (5 % and 10 %, calculated in total wet weight of organic solid waste) of fly ash on physical and chemical properties, nutrient elements, and bacterial community structure during co-composting were evaluated. The results showed that the addition dose of 5 % and 10 % fly ash significantly increased the highest temperature (56.6 ℃ and 56.9 ℃) and extended the thermophilic period to nine days. Compared with that in the control, the total nutrient content of compost products in the treatments of 5 % FA and 10 % FA was increased by 4.09 % and 13.55 %, respectively. The bacterial community structure changed greatly throughout the composting, and the bacterial diversity of all treatments increased obviously. In the initial stage of composting, Proteobacteria was the dominant phylum of bacteria, with a relative abundance ranging from 35.26 % to 39.40 %. In the thermophilic period, Firmicutes dominated; its relative abundance peaked at 52.46 % in the 5 % FA treatment and 67.72 % in the 10 % FA treatment. Bacillus and Thermobifida were the predominant groups in the thermophilic period of composting. The relative abundance of Bacillus and Thermobifida in the 5 % FA and 10 % FA treatments were 33.41 % and 62.89 %( Bacillus ) and 33.06 % and 12.23 %( Thermobifida ), respectively. The results of the redundancy analysis (RDA) revealed that different physicochemical indicators had varying degrees of influence on bacteria, with organic matter, pH, available phosphorus, and available potassium being the main environmental factors influencing bacterial community structure. In summary, the addition of fly ash promoted the harmlessness and maturation of co- aerobic composting of urban multi-source organic waste, while optimizing microbial community structure and improving the quality and efficiency of composting.

The combination of small-interfering RNA (siRNA)-mediated gene silencing and chemotherapeutic agents for lung cancer treatment has attracted widespread attention in terms of a greater therapeutic effect, minimization of systemic toxicity, and inhibition of multiple drug resistance (MDR). In this work, three amphiphiles, CBN1 - CBN3 , were first designed and synthesized as a camptothecin (CPT) conjugate and gene condensation agents by the combination of CPT prodrugs and di(triazole-[12]aneN 3 ) through the ROS-responsive phenylborate ester and different lengths of alkyl chains (with 6, 9, 12 carbon chains for CBN1 - CBN3 , respectively). CBN1 - CBN3 were able to be self-assembled into liposomes with an average diameter in the range of 320-240 nm, showing the ability to effectively condense siRNA. Among them, CBN2 , with a nine-carbon alkyl chain, displayed the best anticancer efficiency in A549 cells. In order to give nanomedicines a stealth property and PEGylation/dePEGylation transition, a GSH-responsive PEGylated TPE derivative containing a disulfide linkage ( TSP ) was further designed and prepared. A combination of CBN2 /siRNA complexes and DOPE with TSP resulted in GSH/ROS dual-responsive lipid-polymer hybrid nanoparticles ( CBN2-DP /siRNA NPs). In present GSH and H 2 O 2 , CBN2-DP /siRNA NPs were decomposed, resulting in the controlled release of CPT drug and siRNA. In vitro , CBN2-DP /siPHB1 NPs showed the best anticancer activity for suppression of about 75% of A549 cell proliferation in a serum medium. The stability of CBN2-DP /siRNA NPs was significantly prolonged in blood circulation, and they showed effective accumulation in the A549 tumor site through an enhanced permeability and retention (EPR) effect. In vivo , CBN2-DP /siPHB1 NPs demonstrated enhanced synergistic cancer therapy efficacy and tumor inhibition as high as 71.2%. This work provided a strategy for preparing lipid-polymer hybrid NPs with GSH/ROS dual-responsive properties and an intriguing method for lung cancer therapy.

Purpose: There is currently no consensus on the optimal drilling direction of the fibular bone tunnel for anterior talofibular ligament (ATFL) reconstruction, and few studies have investigated the potential injury to the peroneus longus and brevis tendons and the possibility of fibular fractures during the drilling process. The aim of this study was to assess the potential risk of drilling the tunnel from different directions and determine the most appropriate tunnel direction. The hypothesis was that drilling the tunnel in the 45-degree direction would be the safest and most suitable for the fibular tunnel., Methods: Forty-eight fibular tunnels were drilled on fresh ankle specimens using a K-wire guide and a 5.0 mm hollow drill. Three tunnel orientations were created, parallel to the sagittal plane of the long axis of the fibula and angled 30°, 45°, and 60° to the coronal plane. The length of the fibular tunnel and the distances from the outlet of the K-wire to the peroneus longus and brevis tendons were measured. The occurrence of a fibula fracture was also observed., Results: The lengths of the bone tunnels in the three groups were 32.9 ± 6.1 mm (30°), 27.2 ± 4.4 mm (45°) and 23.6 ± 4.0 mm (60°). The length of the tunnel drilled at 30° was the longest when compared with that of the tunnels drilled at 45° and 60° (all p values < 0.05). The distances from the outlet of the K-wire to the peroneus longus tendon were 3.0 ± 3.8 mm (30°), 3.8 ± 3.2 mm (45°) and 5.3 ± 1.8 mm (60°), and the distances to the peroneus brevis tendon were 4.2 ± 4.0 mm (30°), 6.1 ± 3.8 mm (45°), 7.9 ± 3.5 mm (60°). In terms of protecting the peroneus longus and brevis tendons, drilling in the 60° direction was better than drilling in the 30° and 45° directions (all p values < 0.05). The risk of injury to the peroneal longus and brevis tendons was 62.5% (30°), 31.3% (45°), and 0% (60°). Although no fibular fractures were observed in any of the three directions, drilling the bone tunnel in the 60° direction disrupted the lateral cortex of the fibula., Conclusion: This study shows that drilling the tunnel in the 45° direction is less likely to cause injury to the peroneus longus and brevis tendons, while ensuring that the tunnel has a sufficient length and avoiding fracturing the distal fibula. Drilling a fibular bone tunnel in a 45° direction is safer and recommended for ATFL reconstruction., (© 2023. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Aryl sulfides are common and ubiquitous motifs in natural products and pharmaceuticals. Presented herein is the first example of the synthesis of diaryl sulfide derivatives via dehydroaromatization under simple basic conditions. Dehydroaromatization reactions between indolines or cyclohexanones with aryl thiols are performed in an environmentally benign manner by the use of air (molecular oxygen) as the oxidant, with producing water as the only byproduct. The methodology provides a simple and practical route to diaryl sulfides with wide functional groups in good to excellent yields. Preliminary mechanistic studies suggest that a radical process is involved in the transformation.

Enzyme-responsive drug delivery systems have drawn much attention in the field of cancer theranostics due to their high sensitivity and substrate specificity under mild conditions. In this study, an amphiphilic polymer T1 is reported, which contains a tetraphenylethene unit and a poly(ethylene glycol) chain linked by an esterase-responsive phenolic ester bond. In aqueous solution, T1 formed stable micelles via self-assembly, which showed an aggregation-induced emission enhancement of 32-fold at 532 nm and a critical micelle concentration of 0.53 μM as well as esterase-responsive activity. The hydrophobic drug doxorubicin (DOX) was efficiently encapsulated into the micelles with a drug loading of 21%. In the presence of the esterase, the selective decomposition of drug-loaded T1 micelles was observed, and DOX was subsequently released with a half-life of 5 h. In vitro antitumor studies showed that T1@DOX micelles exhibited good therapeutic effects on HeLa cells, while normal cells remained mostly intact. In vivo anticancer experiments revealed that T1@DOX micelles indeed suppressed tumor growth and had reduced side effects compared to DOX·HCl. The present work showed the potential clinical application of esterase-responsive drug delivery in cancer therapy.

Background: Chylous ascites (CA) presents a challenge as a relatively common postoperative complication in gastric cancer (GC). Primary conservative therapy involved total parenteral nutrition, continuous low-pressure drainage, somatostatin, and a low-fat diet. Drainage tube (DT) clamping has been presented as a potential alternative conservative treatment for GC patients with CA., Aim: To propose novel conservative treatment strategies for CA following GC surgery., Methods: The data of patients with CA after GC surgery performed at the Fudan University Shanghai Cancer Center between 2006 and 2021 were evaluated retrospectively., Results: 53 patients underwent surgery for GC and exhibited postoperative CA during the study period. Postoperative hospitalization and time of DT removal showed a significant positive association ( R 2 = 0.979, P < 0.001). We further observed that delayed DT removal significantly extended the total and postoperative hospitalization, antibiotic usage duration, and hospitalization cost (postoperative hospitalization: 25.8 d vs 15.5 d, P < 0.001; total hospitalization: 33.2 d vs 24.7 d, P < 0.01; antibiotic usage duration: 10.8 d vs 6.2 d, P < 0.01; hospitalization cost: ¥9.2 × 10 4 vs ¥6.5 × 10 4 , P < 0.01). Multivariate analysis demonstrated that postoperative infection and antibiotic usage were independent factors for delayed DT removal. Furthermore, DT removal times were shorter in seven patients who underwent DT clamping (clamped DT vs normal group, 11.8 d vs 13.6 d, P = 0.047; clamped DT vs delayed group, 13.6 d vs 27.4 d, P < 0.001). In addition, our results indicated that removal of the DT may be possible after three consecutive days of drainage volumes less than 300 mL in GC patients with CA., Conclusion: Infection and antibiotic usage were vital independent factors that influenced delayed DT removal in patients with CA. Appropriate standards for DT removal can significantly reduce the duration of hospitalization. Furthermore, DT clamping might be a recommended option for conservative treatment of postoperative CA., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Stimuli-responsive drug delivery systems (DDSs) based on amphiphilic polymers have attracted much attention. In this study, we reported an innovative H 2 O 2 -responsive amphiphilic polymer (TBP), bearing a H 2 O 2 -sensitive phenylboronic ester, AIE fluorophore tetraphenylethene (TPE) hydrophobic, and polyethylene glycol hydrophilic (PEG) moieties. TBP could self-assemble into micelles with an encapsulation efficiency as high as 74.9% for doxorubicin (DOX) in aqueous solution. In the presence of H 2 O 2 , TBP micelles was decomposed by oxidation, hydrolysis and rearrangement, leading to almost 80% DOX release from TBP@DOX micelles. TBP and the corresponding degradation products were biocompatible, while TBP@DOX micelles only displayed obvious toxicity toward cancer cells. Drug delivery process was clearly monitored by confocal laser scanning microscopic (CLSM) and flow cytometry (FCM) analysis. Moreover, in vivo anticancer study showed that TBP@DOX micelles were accumulated in tumor region of nude mice and effectively inhibited tumor growth. The results suggested that the reported H 2 O 2 -responsive amphiphilic polymer displayed great potential in drug delivery and tumor therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A four-component reaction strategy for access to acyclic nitrile-substituted all-carbon quaternary centers is disclosed. In the presence of a DABCO-based ionic liquid catalyst, the reactions proceed smoothly with a wide range of substrates efficiently to deliver nitrile-substituted all-carbon quaternary centers under mild reaction conditions. This protocol is further demonstrated as an efficient method for the construction of contiguous all-carbon quaternary centers. All the reactions are easily operated in a green manner, producing water as the only byproduct. Some of the products show excellent activity against specific fungi.

Background: Extended-duration work shifts (EDWSs) might affect the health of physician residents, causing autonomic alteration. Skin sympathetic nerve activity (SKNA) recorded by noninvasive neuro-electrocardiography (neuECG) is used to estimate cardiac sympathetic tone. In this study, we aim to evaluate the impact of EDWSs on nocturnal SKNA assessed in resident doctors., Methods: Twenty-four residents working EDWSs and 12 PhD students not working nightshift schedules were prospectively recruited. The neuECG was performed between 12 am and 6 am for 5 consecutive nights. SKNA was filtered from neuECG recorded signals. The questionnaires regarding work stress and sleep quality, blood pressure, and salivary alpha-amylase and cortisol levels were administered., Results: The hours of weekly working and sleep opportunities were similar between residents and students, while residents reported more work stress and worse sleep quality. In residents, SKNA at 6 am (SKNA 6am ) was significantly higher than SKNA 2am during the precall night, revealing a dipping pattern. However, the SKNA dipping disappeared during the on-call night and prominently flattened during the first postcall night, the full recovery of which was delayed until the second postcall nights. The morning blood pressure and salivary alpha-amylase and cortisol levels were similar between the precall and postcall days. In contrast, SKNA in students exhibited a constant dipping profile for all recorded nights., Conclusions: In healthy young adults, SKNA presents a dip night. The SKNA dip is impaired by working a nightshift, with a delayed recovery. The neuECG might serve as a useful tool to detect subclinical autonomic disturbances in shiftworkers., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) present unique molecular signatures, but the tumorigenesis of EBVaGCs and the role EBV plays during this process remain poorly understood., Methods: We applied whole-exome sequencing, EBV genome sequencing, and whole-genome bisulfite sequencing to multiple samples (n = 123) derived from the same patients (n = 25), which covered saliva samples and different histological stages from morphologically normal epithelial tissues to dysplasia and EBVaGCs. We compared the genomic landscape between EBVaGCs and their precursor lesions and traced the clonal evolution for each patient. We also analyzed genome sequences of EBV from samples of different histological types. Finally, the key molecular events promoting the tumor evolution were demonstrated by MTT, IC50, and colony formation assay in vitro experiments and in vivo xenograft experiments., Results: Our analysis revealed increasing mutational burden and EBV load from normal tissues and low-grade dysplasia (LD) to high-grade dysplasia (HD) and EBVaGCs, and oncogenic amplifications occurred late in EBVaGCs. Interestingly, within each patient, EBVaGCs and HDs were monoclonal and harbored single-strain-originated EBV, but saliva or normal tissues/LDs had different EBV strains from that in EBVaGCs. Compared with precursor lesions, tumor cells showed incremental methylation in promotor regions, whereas EBV presented consistent hypermethylation. Dominant alterations targeting the PI3K-Akt and Wnt pathways were found in EBV-infected cells. The combinational inhibition of these two pathways in EBV-positive tumor cells confirmed their synergistic function., Conclusions: We portrayed the (epi) genomic evolution process of EBVaGCs, revealed the extensive genomic diversity of EBV between tumors and normal tissue sites, and demonstrated the synergistic activation of the PI3K and Wnt pathways in EBVaGCs, offering a new potential treatment strategy for this disease., (© 2021. The Author(s).)

A highly efficient strategy for the direct thiolation of phenols under transition metal-free and solvent-free conditions has been developed. These reactions are operationally simple with employing air (molecular oxygen) as an ideal oxidant and can selectively provide mono- and dithiolation products in good to excellent yields under basic conditions. The reaction tolerates a broad range of aryl thiols and arenes and is especially applicable for large-scale synthesis.

Introduction: Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) versus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) in IMbrave150. Efficacy and safety data from the Chinese subpopulation are reported., Methods: IMbrave150, a global, randomized, open-label, phase 3 study in patients with systemic treatment-naive unresectable HCC, included an extension phase that enrolled additional patients from mainland China. Patients were randomized (2:1) to receive intravenous atezolizumab 1,200 mg plus bevacizumab 15 mg/kg once every 3 weeks or sorafenib 400 mg twice a day until unacceptable toxicity or loss of clinical benefit. Co-primary endpoints were OS and independent review facility-assessed PFS per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population., Results: Of 194 Chinese patients enrolled from April 16, 2018, to April 8, 2019 (137 in the global study and 57 in the China extension phase), 133 received atezolizumab plus bevacizumab and 61 received sorafenib. At the data cutoff (August 29, 2019), the stratified hazard ratio for OS was 0.44 (95% CI, 0.25-0.76) and for PFS was 0.60 (95% CI, 0.40-0.90). The respective median OS and PFS with atezolizumab plus bevacizumab were not reached (NR; 95% CI, 13.5 months to NR) and 5.7 months (95% CI, 4.2-8.3) versus 11.4 months (95% CI, 6.7 to NR) and 3.2 months (95% CI, 2.6-4.8) with sorafenib. Grade 3-4 adverse events (AEs) occurred in 78 of 132 (59.1%) atezolizumab plus bevacizumab-treated and 27 of 58 (46.6%) sorafenib-treated patients. The most common grade 3-4 AE with atezolizumab plus bevacizumab was hypertension, occurring in 15.2% of patients; however, other high-grade AEs were infrequent., Conclusion: Clinically meaningful improvements in OS and PFS observed with atezolizumab plus bevacizumab versus sorafenib suggest that atezolizumab plus bevacizumab may become a practice-changing treatment for Chinese patients with unresectable HCC., Competing Interests: T.Y. has received honoraria from Bristol Myers Squibb and MSD Oncology and served in a consulting or advisory role for Bristol Myers Squibb. L.L. is an employee of Roche. S.H. is an employee of Genentech. D.-Z.X. is an employee of Roche. S.M. is an employee of, and owns stock in, F. Hoffmann-La Roche. Y.W. is an employee of Roche. H.S. is an employee of Roche. A.-L.C. has received honoraria from AstraZeneca, Bayer Yakuhin, Eisai, Genentech/Roche, and Lilly, and has served in a consulting or advisory role for AstraZeneca; Bayer Schering Pharma; BeiGene; Bristol Myers Squibb; CSR Pharma Group; Eisai; Genentech/Roche; IQVIA; MSD; Novartis; and Ono Pharmaceutical. Others claimed no conflicts of interest. A.-L.C. is an associate editor of the journal Liver Cancer., (Copyright © 2021 by S. Karger AG, Basel.)

Background: Understanding patients' experience of cancer treatment is important. We aimed to evaluate patient-reported outcomes (PROs) with atezolizumab plus bevacizumab versus sorafenib in patients with advanced hepatocellular carcinoma in the IMbrave150 trial, which has already shown significant overall survival and progression-free survival benefits with this combination therapy., Methods: We did an open-label, randomised, phase 3 trial in 111 hospitals and cancer centres across 17 countries or regions. We included patients aged 18 years or older with systemic, treatment-naive, histologically, cytologically, or clinically confirmed unresectable hepatocellular carcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with disease that was not amenable to curative surgical or locoregional therapies, or progressive disease after surgical or locoregional therapies. Participants were randomly assigned (2:1; using permuted block randomisation [blocks of six], stratified by geographical region; macrovascular invasion, extrahepatic spread, or both; baseline alpha-fetoprotein concentration; and ECOG performance status) to receive 1200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously once every 3 weeks or 400 mg sorafenib orally twice a day, until loss of clinical benefit or unacceptable toxicity. The independent review facility for tumour assessment was masked to the treatment allocation. Previously reported coprimary endpoints were overall survival and independently assessed progression-free survival per Response Evaluation Criteria in Solid Tumors 1.1. Prespecified secondary and exploratory analyses descriptively evaluated treatment effects on patient-reported quality of life, functioning, and disease symptoms per the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (QLQ-C30) and quality-of-life questionnaire for hepatocellular carcinoma (QLQ-HCC18). Time to confirmed deterioration of PROs was analysed in the intention-to-treat population; all other analyses were done in the PRO-evaluable population (patients who had a baseline PRO assessment and at least one assessment after baseline). The trial is ongoing; enrolment is closed. This trial is registered with ClinicalTrials.gov, NCT03434379., Findings: Between March 15, 2018, and Jan 30, 2019, 725 patients were screened and 501 patients were enrolled and randomly assigned to atezolizumab plus bevacizumab (n=336) or sorafenib (n=165). 309 patients in the atezolizumab plus bevacizumab group and 145 patients in the sorafenib group were included in the PRO-evaluable population. At data cutoff (Aug 29, 2019) the median follow-up was 8·6 months (IQR 6·2-10·8). EORTC QLQ-C30 completion rates were 90% or greater for 23 of 24 treatment cycles in both groups (range 88-100% in the atezolizumab plus bevacizumab group and 80-100% in the sorafenib group). EORTC QLQ-HCC18 completion rates were 90% or greater for 20 of 24 cycles in the atezolizumab plus bevacizumab group (range 88-100%) and 21 of 24 cycles in the sorafenib group (range 89-100%). Compared with sorafenib, atezolizumab plus bevacizumab reduced the risk of deterioration on all EORTC QLQ-C30 generic cancer symptom scales that were prespecified for analysis (appetite loss [hazard ratio (HR) 0·57, 95% CI 0·40-0·81], diarrhoea [0·23, 0·16-0·34], fatigue [0·61, 0·46-0·81], pain [0·46, 0·34-0·62]), and two of three EORTC QLQ-HCC18 disease-specific symptom scales that were prespecified for analysis (fatigue [0·60, 0·45-0·80] and pain [0·65, 0·46-0·92], but not jaundice [0·76, 0·55-1·07]). At day 1 of treatment cycle five (after which attrition in the sorafenib group was more than 50%), the mean EORTC QLQ-C30 score changes from baseline in the atezolizumab plus bevacizumab versus sorafenib groups were: -3·29 (SD 17·56) versus -5·83 (20·63) for quality of life, -4·02 (19·42) versus -9·76 (21·33) for role functioning, and -3·77 (12·82) versus -7·60 (15·54) for physical functioning., Interpretation: Prespecified analyses of PRO data showed clinically meaningful benefits in terms of patient-reported quality of life, functioning, and disease symptoms with atezolizumab plus bevacizumab compared with sorafenib, strengthening the combination therapy's positive benefit-risk profile versus that of sorafenib in patients with unresectable hepatocellular carcinoma., Funding: F Hoffmann-La Roche and Genentech., Competing Interests: Declaration of interests PRG has had a consulting or advisory role and received honoraria from AdaptImmune, AstraZeneca, Bayer, Bristol Myers Squibb, MSD, Eisai, Lilly, Ipsen, Roche, and Sirtex; has been on a speakers' bureau for AstraZeneca, Bayer, Bristol Myers Squibb, MSD, Eisai, Lilly, Ipsen, Roche, and Sirtex; has received research funding from Bayer and Roche; has provided expert testimony for Lilly; and has received travel or accommodation expenses from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Lilly, Ipsen, and F Hoffmann-La Roche. RSF has had a consulting or advisory role and received consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Exelixis, F Hoffmann-La Roche and Genentech, Lilly, Merck, Novartis, and Pfizer; has received institutional research funding from Bayer, Bristol Myers Squibb, Eisai, Lilly, Merck, Novartis, Pfizer, and F Hoffmann-La Roche and Genentech, and has provided expert testimony for Novartis. MI has received institutional grant support from Bayer, Eisai, Eli Lilly Japan, Chugai Pharmaceutical, AstraZeneca, MSD, Novartis, Bristol Myers Squibb, and Merck Serono; honoraria from Bayer, Eisai, Eli Lilly Japan, Chugai Pharmaceutical, and Sumitomo Dainippon Pharma; and has had a consulting or advisory role for Bayer, Eisai, Eli Lilly Japan, Chugai Pharmaceutical, and Takeda. AXZ has had a consulting or advisory role with F Hoffmann La-Roche, Meck Lilly, Bayer, Sanofi, Eisai, and Exelixis. MK has received honoraria from Lilly, Bayer, Eisai, Merck Sharp & Dohme, Bristol-Myers Squibb, and EA Pharma; had a consulting or advisory role for Eisai, Ono, MSD, Bristol Myers Squibb, and F Hoffmann-La Roche; and received research funding from Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, EA Pharma, AbbVie, and Eisai. VB has received advisory or consultancy fees and travel and accommodation expenses from F Hoffmann-La Roche, MSD, Eisai, and Bristol-Myers Squibb; advisory or consultancy fees from Ipsen; and travel and accommodation expenses from Bayer. PM is on advisory boards for Bayer, Eisai, Exelixis, Ipsen, Lilly, Roche, AstraZeneca, Bristol Myers Squibb, MSD, Merck, and Onxeo. AK has received research support from F Hoffmann-La Roche, Bristol Myers Squibb, Exelixis, Bayer, AdaptImmune, Immatics, Merck, and Eisai. DL has had a consulting or advisory role and received honoraria from Lexicon, Ipsen, Bayer, Eisai, Exelixis, F Hoffmann-La Roche and Genentech, Taiho, Advanced Accelerator Applications, and QED; has been on a speaker's bureau for Lexicon, Ipsen, Eisai, Exelixis, Advanced Accelerator Applications, Coherus, and Sun Pharma; and has received institutional research funding from Brooklyn Immunotherapeutics. SM is a full-time employee of, and owns stock in, F Hoffmann-La Roche. WV is a full-time employee of Genentech. D-ZX is a full-time employee of F Hoffmann-La Roche. SH is a full-time employee of Genentech. BD is a full-time employee of Genentech. JL is a full-time employee of Shanghai Roche Pharmaceuticals. CH is a full-time employee of Shanghai Roche Pharmaceuticals. HYL has received advisory or consulting fees from Bayer, Eisai, Bristol-Myers Squibb, Ono, AstraZeneca, and F Hoffmann-La Roche. A-LC has received honoraria from AstraZeneca, Bristol Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix, IPSEN Innovation, Bayer Healthcare, MSD, F Hoffmann-La Roche and Genentech, BeiGene, CSR Pharma Group, and IQVIA; advisory or consulting fees from AstraZeneca, Bristol Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix, IPSEN Innovation, Bayer Healthcare, MSD, Roche and Genentech, BeiGene, CSR Pharma Group, F Hoffmann-La Roche, and IQVIA; speaker bureau fees from Bayer Yakuhin, Novartis, Eisai, Oxal, and Amgen Taiwan; and travel and accommodation expenses from Bayer Yakuhin, F Hoffmann-La Roche and Genentech, and IQVIA. MD has received honoraria and advisory or consultancy fees from F Hoffmann-La Roche, Merck Serono, Bayer, Ipsen, Servier, Amgen, MSD, and Pierre Fabre; research funding from F Hoffmann-La Roche, Merck Serono, and Bayer; and travel and accommodation expenses from F Hoffmann-La Roche, MSD, and Servier. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Phase 1b GO30140 and phase 3 IMbrave150 studies evaluated first-line atezolizumab + bevacizumab for unresectable hepatocellular carcinoma (HCC). Here, we evaluated pharmacokinetics (PK) and safety by hepatic impairment status and geographic region., Methods: Patients received atezolizumab 1,200 mg + bevacizumab 15 mg/kg IV every 3 weeks. Drug concentrations were evaluated by descriptive statistics and population PK. PK and adverse event frequencies were evaluated by hepatic impairment status and region., Results: 323 IMbrave150 patients and 162 GO30140 patients were PK evaluable. Compared with IMbrave150 patients who had normal hepatic function per the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria ( n = 123), patients with mild impairment ( n = 171) had a geometric mean ratio (GMR) of 0.92 for cycle 1 atezolizumab area under the concentration-time curve (AUC); patients with moderate impairment ( n = 27) had a GMR of 0.88. Patients in Asia ([ n = 162] vs. outside [ n = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [ n = 61]), patients with mild impairment ( n = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment ( n = 9) had a GMR of 0.94. Patients in Asia ( n = 111) versus outside Asia ( n = 51) had a GMR of 0.94 for cycle 1 peak bevacizumab concentration. PK results were generally comparable when evaluated based on additional hepatic functional definitions (Child-Pugh or albumin/bilirubin criteria) or study enrollment in Japan. No associations between atezolizumab PK and HCC etiology were seen. Adverse event frequencies were similar across evaluated groups., Conclusions: IMbrave150 and GO30140 patients with unresectable HCC had varying baseline hepatic impairment and high enrollment from Asia. PK data demonstrated considerable exposure overlap across groups. Treatment was tolerable across groups. No need for dose adjustment based on mild or moderate hepatic impairment or region is recommended based on this analysis., Competing Interests: C.S.S., P.C., D.C., S.V., and B.W. are employees of Genentech, Inc., and Roche stockholders. H.S. and D.X. are employees of F. Hoffmann-La Roche Ltd. and Roche stockholders. R.B. is an employee of Roche France and is a Roche stockholder. D.C. of Combs Consulting Services was contracted by Genentech Inc during the course of the study., (Copyright © 2021 by S. Karger AG, Basel.)

Background: Pseudomyxoma peritonei (PMP) is a clinical malignant syndrome mainly originating from the appendix, with an incidence of 2-4 per million people. As a rare disease, an early and accurate diagnosis of PMP is difficult. It was not until the 1980s that the systematic study of this disease was started., Main Body: As a result of clinical and basic research progress over the last 4 decades, a comprehensive strategy based on cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) has been established and proved to be an effective treatment for PMP. Currently, CRS + HIPEC was recommended as the standard treatment for PMP worldwide. There are several consensuses on PMP management, playing an important role in the standardization of CRS + HIPEC. However, controversies exist among consensuses published worldwide. A systematic evaluation of PMP consensuses helps not only to standardize PMP treatment but also to identify existing controversies and point to possible solutions in the future. The controversy underlying the consensus and vice versa promotes the continuous refinement and updating of consensuses and continue to improve PMP management through a gradual and continuous process. In this traditional narrative review, we systemically evaluated the consensuses published by major national and international academic organizations, aiming to get a timely update on the treatment strategies of CRS + HIPEC on PMP., Conclusion: Currently, consensuses have been reached on the following aspects: pathological classification, terminology, preoperative evaluation, eligibility for surgical treatment, maximal tumor debulking, CRS technical details, and severe adverse event classification system. However, controversies still exist regarding the HIPEC regimen, systemic chemotherapy, and early postoperative intraperitoneal chemotherapy.

Background: Premature ventricular complexes (PVCs) exhibit circadian fluctuation. We determine if PVCs of different origin exhibit specific circadian patterns., Methods: We analyzed Holter recordings from patients with monomorphic PVCs who underwent catheter ablation. PVC circadian patterns were classified as fast-heart rate- (HR-) dependent (F-PVC), slow-HR-dependent (S-PVC), or HR-independent (I-PVC). PVC origins were determined intraprocedurally., Results: In a retrospective cohort of 407 patients, F-PVC and S-PVC typically exhibited diurnal and nocturnal predominance, respectively. Despite decreased circadian fluctuation, I-PVC generally had heavier nocturnal than diurnal burden. PVCs of left anterior fascicle origin were predominantly S-PVC, while those of posterior hemibranch origin were mostly F-PVC. PVCs originating from the aortic sinus of Valsalva (ASV) were predominantly I-PVC, while most PVCs arising from the left ventricular outflow tract (LVOT) were F-PVC. Using a diurnal/nocturnal PVC burden ratio of 0.92 as the cutoff value to distinguish LVOT from ASV origin achieved 97% sensitivity and, as further verification, an accuracy of 89% (16/18) in a prospective cohort of patients with PVCs originating from either ASV or LVOT. In contrast, PVCs originating from right ventricles, such as right ventricular outflow tract, did not show distinct circadian patterns., Conclusions: The circadian patterns exhibit origin specificity for PVCs arising from left ventricles. An analysis of Holter monitoring provides useful information on PVC localization in ablation procedure planning., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2020 Mu Chen et al.)

We describe an unprecedented dual C-H functionalization of indolin-2-one via an oxidative C(sp 3 )-H/N-H/X-H (X = N, C, S) cross-coupling protocol, which is catalyzed by a simple iron salt under mild and ligand-free conditions and employs air (molecular oxygen) as the terminal oxidant. This method is readily applicable for the construction of tetrasubstituted carbon centers from methylenes and provides a wide variety of spiro N-heterocyclic oxindoles.

Background: The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma., Methods: In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1)., Results: The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent., Conclusions: In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT03434379.)., (Copyright © 2020 Massachusetts Medical Society.)

Presented herein is the first direct alkylation and hydroxylation reaction between two different C(sp 3 )-H bonds, indolin-2-ones and alkyl-substituted N-heteroarenes, through an oxidative cross-coupling reaction. The reaction is catalyzed by a simple iron salt under mild ligand-free and base-free conditions. The reaction is environmentally benign, employs air (molecular oxygen) as the terminal oxidant and oxygen source for the synthesis of O-containing compounds, and produces only water as the byproduct., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Compressive sensing (CS) has been used in LiDAR systems utilizing one single-photon-counting avalanche diode. We demonstrate an unexpected grayscale inversed image of an object at an unchosen depth, which appears in the reconstruction of the infrared single-pixel LiDAR system due to the pile-up effect. A correction algorithm and the sparse measurement are proposed and experimentally verified to effectively reduce the photon pile-up influence, so that the negative images can be completely removed. The correction methods in this research can improve the accuracy and the flexibility of the single-pixel LiDAR systems employing detectors with a low maximum light count.

The mechanisms of J wave syndrome (JWS) are incompletely understood. Here, we showed that the concomitant activation of small-conductance calcium-activated potassium (SK) current (IKAS) and inhibition of sodium current by cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) recapitulate the phenotypes of JWS in Langendorff-perfused rabbit hearts. CyPPA induced significant J wave elevation and frequent spontaneous ventricular fibrillation (SVF), as well as sinus bradycardia, atrioventricular block, and intraventricular conduction delay. IKAS activation by CyPPA resulted in heterogeneous shortening of action potential (AP) duration (APD) and repolarization alternans. CyPPA inhibited cardiac sodium current (INa) and decelerated AP upstroke and intracellular calcium transient. SVFs were typically triggered by short-coupled premature ventricular contractions, initiated with phase 2 reentry and originated more frequently from the right than the left ventricles. Subsequent IKAS blockade by apamin reduced J wave elevation and eliminated SVF. β-Adrenergic stimulation was antiarrhythmic in CyPPA-induced electrical storm. Like CyPPA, hypothermia (32.0°C) also induced J wave elevation and SVF. It facilitated negative calcium-voltage coupling and phase 2 repolarization alternans with spatial and electromechanical discordance, which were ameliorated by apamin. These findings suggest that IKAS activation contributes to the development of JWS in rabbit ventricles.

Key Points: It is unknown if a sex difference exists in cardiac apamin-sensitive small conductance Ca 2+ -activated K + (SK) current (I KAS ). There is no sex difference in I KAS in the basal condition. However, there is larger I KAS in female rabbit ventricles than in male during isoproterenol infusion. I KAS activation by isoproterenol leads to action potential triangulation in females, indicating its abundant activation at early phases of repolarization. I KAS activation in females induces negative Ca 2+ -voltage coupling and promotes electromechanically discordant phase 2 repolarization alternans. I KAS is important in the mechanisms of ventricular fibrillation in females during sympathetic stimulation., Abstract: Sex has a large influence on cardiac electrophysiological properties. Whether sex differences exist in apamin-sensitive small conductance Ca 2+ -activated K + (SK) current (I KAS ) remains unknown. We performed optical mapping, transmembrane potential, patch clamp, western blot and immunostaining in 62 normal rabbit ventricles, including 32 females and 30 males. I KAS blockade by apamin only minimally prolonged action potential (AP) duration (APD) in the basal condition for both sexes, but significantly prolonged APD in the presence of isoproterenol in females. Apamin prolonged APD at the level of 25% repolarization (APD 25 ) more prominently than APD at the level of 80% repolarization (APD 80 ), consequently reversing isoproterenol-induced AP triangulation in females. In comparison, apamin prolonged APD to a significantly lesser extent in males and failed to restore the AP plateau during isoproterenol infusion. I KAS in males did not respond to the L-type calcium current agonist BayK8644, but was amplified by the casein kinase 2 (CK2) inhibitor 4,5,6,7-tetrabromobenzotriazole. In addition, whole-cell outward I KAS densities in ventricular cardiomyocytes were significantly larger in females than in males. SK channel subtype 2 (SK2) protein expression was higher and the CK2/SK2 ratio was lower in females than in males. I KAS activation in females induced negative intracellular Ca 2+ -voltage coupling, promoted electromechanically discordant phase 2 repolarization alternans and facilitated ventricular fibrillation (VF). Apamin eliminated the negative Ca 2+ -voltage coupling, attenuated alternans and reduced VF inducibility, phase singularities and dominant frequencies in females, but not in males. We conclude that β-adrenergic stimulation activates ventricular I KAS in females to a much greater extent than in males. I KAS activation plays an important role in ventricular arrhythmogenesis in females during sympathetic stimulation., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Based on the Prussian blue spectrophotometric method, one high-throughput screening strategy for screening lignin-degrading microorganisms was built on 24-well plate at room temperature. One high activity of alkali lignin-degrading strain Rhodococcus pyridinivorans CCZU-B16 was isolated from soil. After the optimization of biodegradation, 30.2% of alkali lignin (4 g/L) was degraded under the nitrogen-limited condition (30/1 of C/N ratio; g/g) at 30 °C for 72 h. It was found that syringyl (S) units and guaiacyl (G) in lignin decreased after biodegradation. Moreover, the accumulated lipid in cells had a fatty acid profile rich in C16 and C18 with four major constituent fatty acids including palmitic acid (C16:0; 22.4%), palmitoleic acid (C16:1; 21.1%), stearic acid (C18:0; 16.2%), and oleic acid (C18:1; 23.1%). In conclusion, Rhodococcus pyridinivorans CCZU-B16 showed high potential application in future.

An HBsAg-HBIG therapeutic vaccine (Yeast-derived Immune Complexes, YIC) for chronic hepatitis B (CHB) patients has undergone a series of clinical trials. The HBeAg sero-conversion rate of YIC varied from 21.9% to 14% depending on the immunization protocols from 6 to 12 injections. To analyze the immunological mechanisms exerted by 6 injections of YIC, 44 CHB patients were separately immunized with YIC, alum as adjuvant control or normal saline as blank control, with add on of antiviral drug Adefovir in all groups. Kinetic increase in Th1 and Th2 cells CD4 + T cell sub-populations with association in decrease in Treg cells and increase of Tc1 and Tc17 cells in CD8 + T cells were observed in YIC immunized group. No such changes were found in the other groups. By multifunctional analysis of cytokine profiles, significant increase of IL-2 levels was observed, both in CD4 + and CD8 + T cells in the YIC immunized group, accompanied by increase in IFN-gamma and decrease of inhibitory factors (IL-10, TGF-β and Foxp3) in CD4 + T cells. In the alum immunized group, slight increase of IL-10, TGF-β and Foxp3 in CD4 + T cells was found after the second injection, but decreased after more injections, suggesting that alum induced early inflammatory responses to a certain extent. Similar patterns of responses of IL-17A and TNF-α in CD8 + T cells were shown between YIC and the saline group. Results indicate that add on of Adefovir, did not affect host specific immune responses.

We have previously shown that Sema4D expressed on the platelet plasma membrane can be cleaved by the metalloprotease ADAM17, producing a 120-kDa exodomain fragment that retains biological activity and remnant fragments of 24-28 kDa that remain associated with the platelet membrane. This process is modulated by calmodulin. Here we investigated the potential role of protein kinase A (PKA) in these events. Using a pharmacological approach, we now show that inhibition of PKA by H89 is sufficient to induce Sema4D exodomain shedding, while activation of PKA inhibits agonist-initiated shedding. Studies on the regulatory mechanism show that the shedding induced by PKA inhibition is mediated by ADAM17, but, unlike agonist-induced shedding, does not involve the dissociation of calmodulin from the Sema4D cytoplasmic domain. In attempt to identify the cleavage sites for shedding, we found that ADAM17 mediates variable cleavages in the juxtamembrane region. Therefore, our data reveal a potential regulatory mechanism for the shedding of Sema4D in platelets.

Background: Long non-coding RNAs (lncRNAs) have emerged as critical regulators of tumor progression. However, the role and molecular mechanism of lncRNA XIST in gastric cancer is still unknown., Methods: Real-time PCR analysis was performed to measure the expression levels of lncRNA XIST in gastric cancer tissues and cell lines, the correlation between lncRNA XIST expression and clinicopathological characteristics and prognosis was analyzed in gastric cancer patients. The biological function of lncRNA XIST on gastric cancer cells were determined both in vitro and in vivo. The regulating relationship between lncRNA XIST and miR-101 was investigated in gastric cancer cells., Results: lncRNA XIST was significantly up-regulated in gastric cancer tissues and cell lines. Overexpression of lncRNA XIST was markedly associated with larger tumor size, lymph node invasion, distant metastasis and TNM stage in gastric cancer patients. Functionally, knockdown of lncRNA XIST exerted tumor-suppressive effects by inhibiting cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. Furthermore, an inverse relationship between lncRNA XIST and miR-101 was found. Polycomb group protein enhancer of zeste homolog 2 (EZH2), a direct target of miR-101, could mediated the biological effects that lncRNA XIST exerted., Conclusions: lncRNA XIST is up-regulated and is associated with aggressive tumor phenotypes and patient survival in gastric cancer, and the newly identified lncRNA XIST/miR-101/EZH2 axis could be a potential biomarkers or therapeutic targets for gastric cancer patients.

Aim: To examine the association between interferon (IFN) therapy and loss of hepatitis B surface antigen (HBsAg) in inactive HBsAg carriers., Methods: This was a retrospective cohort study in inactive HBsAg carriers, who were treatment-naive, with a serum HBsAg level < 100 IU/mL and an undetectable hepatitis B virus (HBV) DNA level (< 100 IU/mL). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBsAg, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group., Results: Thirteen (65.0%) of 20 treated patients achieved HBsAg loss, 12 of whom achieved HBsAg seroconversion. Mean HBsAg level in treated patients decreased to 6.69 ± 13.04 IU/mL after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/mL. Serum HBV DNA level remained undetectable (< 100 IU/mL) in all treated patients during the study. HBsAg level of the control group decreased from 25.72 ± 25.58 IU/mL at baseline to 17.11 ± 21.62 IU/mL at week 96 (P = 0.108). In the control group, no patient experienced HBsAg loss/seroconversion, and two (5.0%) developed HBV reactivation., Conclusion: IFN treatment results in HBsAg loss and seroconversion in a considerable proportion of inactive HBsAg carriers with low HBsAg concentrations.

Objective: To investigate the efficacy and related factors of pegylated-interferon alpha-2a (PEG-IFN-2a) treatment in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) who achieved partial viral response with nucleoside analogue (NA) therapy., Methods: Patients with HBeAg-positive CHB and partial viral response to NA treatment were administered a PEG-IFN-2a therapy regimen of 180 g subcutaneous injection once weekly for a personlized duration of time. The existing NA therapy was continued in combination with the new PEG-IFN-2a treatment for 12 weeks. Measurements of serum HBV DNA load, hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), HBeAg and hepatitis B e antibody (anti-HBe) were taken at baseline (prior to addition of the PEG-IFN-2a therapy) and every 3 months afterwards.For determining response to treatment, primary efficacy was defined as undetectable HBsAg and seroconversion, and secondary efficacy was defined as HBsAg less than 10 IU/mL and HBeAg seroconversion.Statistical analysis was carried out using SPSS statistical software., Results: A total of 81 consecutive patients with an average of 12.0 months (range: 6.0-24.0 months) of NA therapy were included in the study and received an average of 19.6 months (range: 15.5-33.3 months) of PEG-IFN-2a treatment. At the end of PEG-IFN-2a therapy, 7 (8.6%) of the patients achieved undetectable HBsAg and seroconversion, and 14 (17.3%) showed HBsAg less than 10IU/mL. In addition, 40.7% achieved undetectable HBeAg and seroconversion, a rate that was slightly higher than that (38.3%) seen in treatment-naive patients who received PEG-IFN-2a. Statistical analyses suggest that baseline level of HBsAg at less than 1500 IU/mL may predict end of PEG-IFN-2a treatment response for HBsAg less than 10 IU/mL, as evidenced by the area under the curve measure of 0.747, sensitivity measure of 87.3%, specificity measure of 33.3%, positive predictive value of 82.1% and negative predictive value of 42.8%., Conclusion: Patients with HBeAg-positive CHB and partial viral response to NA therapy can achieve undetectable HBsAg and HBeAg seroconversion after switching to PEG-IFN-2a treatment. Baseline HBsAg level may be predictive of response to this therapeutic strategy.

The canonical statistics describes the statistical properties of an open system by assuming its coupling with the heat bath is infinitesimal in comparison with the total energy in thermodynamic limit. In this paper, we generally derive a noncanonical density matrix for the open system with a finite coupling to the heat bath, which deforms the energy shell to effectively modify the conventional canonical way. The obtained noncanonical distribution reflects the back action of system on the bath and thus depicts the statistical correlations between two subsystems by the mutual information as a result of energy conservation.

The authors have previously shown that recombinant factor XIII (rFXIII) eliminates early manifestations of multiple-organ injury caused by experimental superior mesenteric artery occlusion or trauma-hemorrhagic shock. The aim of the present study was to test the hypothesis that rFXIII provides similar protective effect in experimental burn injury. Rats were randomly divided into five groups (eight animals per group): group 1: burn + placebo treatment; group 2: burn + rFXIII pretreatment; group 3: burn + rFXIII treatment; group 4: sham burn + placebo treatment, and group 5: sham burn + rFXIII treatment. Burn (40% of TBSA) was achieved by immersing the back and abdomen of a rat into 97°C water for 10 and 5 seconds, respectively. Infusion of rFXIII (1 mg/kg) or placebo was performed immediately after burn/sham burn in treatment groups or 24 hours before burn and repeated immediately after it in pretreatment group. Endpoint parameters measured 3 hours after burn/sham burn included muscle blood flow and PO2, lung permeability, gut histology, lung and gut myeloperoxidase activity, neutrophil respiratory burst, and FXIII activity. Both treatment and pretreatment with rFXIII partially preserved microvascular blood flow in the muscle. Muscle PO2 in pretreated rats did not differ from that in shams. Pretreatment but not treatment with rFXIII preserved lung permeability. rFXIII did not have any protective effect on other endpoint parameters. In contrast to superior mesenteric artery occlusion and trauma-hemorrhagic shock experimental models, rFXIII at the doses tested has a limited effect on preventing early manifestations of multiple-organ injury after experimental burn.

The homing ability of hematopoietic stem cells (HSCs) was a critical step for transplantation and subsequent hematopoiesis. Although the HSC transplantation was widely used for many diseases, the mechanism by which HSC homing was regulated remained poorly understood. F-box protein S-phase kinase associated protein2 (Skp2), a component of the Skp2-SCF E3 ligase complex, was regarded as a cell cycle regulator by controlling the level of p21 and p27 through ubiquitination. We recently reported an important role of Skp2 in maintaining HSC pool size, quiescent stage and self-renewal ability. In this current study, we showed that Skp2 was a novel and critical regulator for maintaining the homing of HSCs as well as their residence in the endosteal niche. Microarray analysis together with biochemical validations revealed that Skp2 deficiency profoundly reduced the expression of β-catenin and its target genes. Knockdown of β-catenin mimicked the decline of HSC homing upon Skp2 deficiency, suggesting that Skp2 may regulate β-catenin and its target gene expression to orchestrate HSC homing. Our study not only identified Skp2 as a new regulator for maintaining β-catenin expression and HSC homing, but also suggested that Skp2 may serve as a predictive marker for monitoring the transplantation efficiency., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Indications of implantable cardioverter-defibrillator (ICD) for patients with an old myocardial infarction (OMI) and left ventricular dysfunction (LVD) were expanded in Western countries after the results of MADIT II. However, the prognosis of OMI patients with LVD and the merits of prophylactic implantation of ICD, based on evidence in Japan, have not yet been clarified. This subanalysis of the Japanese Coronary Artery Disease (JCAD) Study focused on MADIT II-compatible patients to clarify the prognosis of OMI patients with LVD in Japan., Methods and Results: Consecutive 6,868 OMI patients were prospectively followed up for 3 years or until clinical events occurred. 291 patients had left ventricular ejection fraction (LVEF) ≤30%. Clinical events, congestive heart failure, cardiopulmonary arrest on arrival and vascular events were significantly more frequent in patients with LVEF ≤30% than in those with better LVEF. In the LVEF ≤30% group, cardiopulmonary arrest on arrival comprised 33% of all-cause deaths, and the survival curves at 2 years of the LVEF ≤30% group were almost compatible with those of the MADIT II ICD group., Conclusions: In this subanalysis, LVD was less frequent than in Western countries. The annual death rate in JCAD was better than for the MADIT II ICD group. The prophylactic use of ICD seemed to be less effective than in Western countries but still expected to be useful for OMI patients with LVD in Japan.