Previous mass screening studies have shown that IgA antibodies against Epstein–Barr Virus (EBV) can facilitate early detection of nasopharyngeal carcinoma (NPC), but the impact of EBV-antibody ...screening for NPC-specific mortality remains unknown.
A prospective, cluster randomized, controlled trial for NPC screening (PRO-NPC-001) was conducted in 3 selected towns of Zhongshan City and 13 selected towns of Sihui City in southern China beginning in 2008. Serum samples of the screening group were tested for two previously selected anti-EBV antibodies. Subjects with serological medium risk were subsequently retested annually for 3 years, and those with serological high risk were referred to otorhinolaryngologists for diagnostic check-up. An interim analysis was carried out to evaluate the primary end points of the NPC-specific mortality and the early diagnostic rate, and the secondary end point of the NPC incidence, through linkage with the database of Zhongshan City.
Among 70 296 total subjects, 29 413 screened participants (41.8% of the total subjects) in the screening group and 50 636 in the control group, 153 (43.3 per 100 000 person-year), 62 (55.3 per 100 000 person-year) and 99 (33.1 per 100 000 person-year) NPC cases were identified. The early diagnostic rates of NPC were significantly higher in the participants (79.0%, P < 0.0001) and the screening group (45.9%, P < 0.0001) compared with the control group (20.6%). Although no differences were found between NPC-specific mortality of the screening group and the control group relative risk (RR)= 0.82, 95% confidence interval (CI) 0.37–1.79, lower NPC-specific mortality was noticed among participants from the screening group versus the control group (RR = 0.22, 95% CI 0.09–0.49).
IgA antibodies against EBV can identify high-risk population and was effective in screening for early asymptomatic NPC. Although the mortality reduction was not significant in the primary end point, we noted encouraging evidence of a mortality reduction in screening participants in this interim analysis.
NCT00941538.
Summary
Background
Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. It remains incompletely understood in the real world how anti‐viral therapy affects ...survival after HCC diagnosis.
Methods
This was an international multicentre cohort study of 2518 HBV‐related HCC cases diagnosed between 2000 and 2015. Cox proportional hazards models were utilised to estimate hazard ratios (HR) with 95% (CI) for anti‐viral therapy and cirrhosis on patients' risk of death.
Results
Approximately, 48% of patients received anti‐viral therapy at any time, but only 17% were on therapy at HCC diagnosis (38% at US centres, 11% at Asian centres). Anti‐viral therapy would have been indicated for >60% of the patients not on anti‐viral therapy based on American criteria. Patients with cirrhosis had lower 5‐year survival (34% vs 46%; P < 0.001) while patients receiving anti‐viral therapy had increased 5‐year survival compared to untreated patients (42% vs 25% with cirrhosis and 58% vs 36% without cirrhosis; P < 0.001 for both). Similar findings were seen for other patient subgroups by cancer stages and cancer treatment types. Anti‐viral therapy was associated with a decrease in risk of death, whether started before or after HCC diagnosis (adjusted HR 0.62 and 0.79, respectively; P < 0.001).
Conclusions
Anti‐viral therapy improved overall survival in patients with HBV‐related HCC across cancer stages and treatment types but was underutilised at both US and Asia centres. Expanded use of anti‐viral therapy in HBV‐related HCC and better linkage‐to‐care for HBV patients are needed.
Immunity acquired from infection or vaccination protects humans from symptomatic hepatitis E. However, whether the risk of hepatitis E virus (HEV) infection is reduced by the immunity remains ...unknown. To understand this issue, a cohort with 12 409 participants randomized to receive the hepatitis E vaccine Hecolin® or placebo were serologically followed up for 2 years after vaccination. About half (47%) of participants were initially seropositive. A total of 139 infection episodes, evidenced by four-fold or greater rise of anti-HEV level or positive seroconversion, occurred in participants who received three doses of treatment. Risk of infection was highest among the baseline seronegative placebo group participants (2.04%). Pre-existing immunity and vaccine-induced immunity lower the risk significantly, to 0.52% and 0.30%, respectively. In conclusion, both vaccine-induced and naturally acquired immunity can effectively protect against HEV infection.
In quantum field theory, Lorentz invariance leads to three types of fermion-Dirac, Weyl and Majorana. Although the existence of Weyl and Majorana fermions as elementary particles in high-energy ...physics is debated, all three types of fermion have been proposed to exist as low-energy, long-wavelength quasiparticle excitations in condensed-matter systems. The existence of Dirac and Weyl fermions in condensed-matter systems has been confirmed experimentally, and that of Majorana fermions is supported by various experiments. However, in condensed-matter systems, fermions in crystals are constrained by the symmetries of the 230 crystal space groups rather than by Lorentz invariance, giving rise to the possibility of finding other types of fermionic excitation that have no counterparts in high-energy physics. Here we use angle-resolved photoemission spectroscopy to demonstrate the existence of a triply degenerate point in the electronic structure of crystalline molybdenum phosphide. Quasiparticle excitations near a triply degenerate point are three-component fermions, beyond the conventional Dirac-Weyl-Majorana classification, which attributes Dirac and Weyl fermions to four- and two-fold degenerate points, respectively. We also observe pairs of Weyl points in the bulk electronic structure of the crystal that coexist with the three-component fermions. This material thus represents a platform for studying the interplay between different types of fermions. Our experimental discovery opens up a way of exploring the new physics of unconventional fermions in condensed-matter systems.
Abstract Extravillus trophoblast (EVT) invasion plays a critical role in placental development. Integrins bind to extracellular matrix (ECM) proteins to mediate EVT cell adhesion, migration, and ...invasion. Changes in O -glycans on β1-integrin have been found to regulate cancer cell behavior. We hypothesize that O -glycosyltransferases can regulate EVT invasion through modulating the glycosylation and function of β1-integrin. Here, we found that the GALNT1 and GALNT2 mRNA were highly expressed in HTR8/SVneo and first trimester EVT cells. Immunohistochemstry and immunofluorescence staining showed that GALNT2 was expressed in subpopulations of EVT cells in deciduas, but not in syncytiotrophoblasts and cytotrophoblasts of placental villi. The percentage of GALNT2-positive EVT cells increased with gestational ages. Overexpression of GALNT2 in HTR8/SVneo cells significantly enhanced cell-collagen IV adhesion, but suppressed cell migration and invasion. Notably, we found that GALNT2 increased the expression of Tn antigen (GalNAc-Ser/Thr) on β1-integrin as revealed by Vicia Villosa agglutinin (VVA) binding. Furthermore, GALNT2 suppressed the phosphorylation of focal adhesion kinase (FAK), a crucial downstream signaling molecule of β1-integrin. Our findings suggest that GALNT2 is a critical initiating enzyme of O -glycosylation for regulating EVT invasion.
Caveolin-1 (Cav1) is an integral membrane, scaffolding protein found in plasma membrane invaginations (caveolae). Cav1 regulates multiple cancer-associated processes. In breast cancer, a tumor ...suppressive role for Cav1 has been suggested; however, Cav1 is frequently overexpressed in aggressive breast cancer subtypes, suggesting an oncogenic function in advanced-stage disease. To further delineate Cav1 function in breast cancer progression, we evaluated its expression levels among a panel of cell lines representing a spectrum of breast cancer phenotypes. In basal-like (the most aggressive BC subtype) breast cancer cells, Cav1 was consistently upregulated, and positively correlated with increased cell proliferation, anchorage-independent growth, and migration and invasion. To identify mechanisms of Cav1 gene regulation, we compared DNA methylation levels within promoter 'CpG islands' (CGIs) with 'CGI shores', recently described regions that flank CGIs with less CG-density. Integration of genome-wide DNA methylation profiles ('methylomes') with Cav1 expression in 30 breast cancer cell lines showed that differential methylation of CGI shores, but not CGIs, significantly regulated Cav1 expression. In breast cancer cell lines having low Cav1 expression (despite promoter CGI hypomethylation), we found that treatment with a DNA methyltransferase inhibitor induced Cav1 expression via CGI shore demethylation. In addition, further methylome assessments revealed that breast cancer aggressiveness associated with Cav1 CGI shore methylation levels, with shore hypermethylation in minimally aggressive, luminal breast cancer cells and shore hypomethylation in highly aggressive, basal-like cells. Cav1 CGI shore methylation was also observed in human breast tumors, and overall survival rates of breast cancer patients lacking estrogen receptor α (ERα) negatively correlated with Cav1 expression. Based on this first study of Cav1 (a potential oncogene) CGI shore methylation, we suggest this phenomenon may represent a new prognostic marker for ERα-negative, basal-like breast cancer.
Resveratrol, a phytochemical found in various plants and Chinese herbs, is associated with multiple tumor-suppressing activities, has been tested in clinical trials. However, the molecular mechanisms ...involved in resveratrol-mediated tumor suppressing activities are not yet completely defined. Here, we showed that treatment with resveratrol inhibited cell mobility through induction of the mesenchymal-epithelial transition (MET) in lung cancer cells. We also found that downregulation of FOXC2 (forkhead box C2) is critical for resveratrol-mediated suppression of tumor metastasis in an in vitro and in vivo models. We also identified a signal cascade, namely, resveratrol-∣miRNA-520h-∣PP2A/C-∣Akt → NF-κB → FOXC2, in which resveratrol inhibited the expression of FOXC2 through regulation of miRNA-520h-mediated signal cascade. This study identified a new miRNA-520h-related signal cascade involved in resveratrol-mediated tumor suppression activity and provide the clinical significances of miR-520h, PP2A/C and FOXC2 in lung cancer patients. Our results indicated a functional link between resveratrol-mediated miRNA-520h regulation and tumor suppressing ability, and provide a new insight into the role of resveratrol-induced molecular and epigenetic regulations in tumor suppression.
There are still no effective therapies for hyposalivation caused by irradiation. In our previous study, bone marrow stem cells can be transdifferentiated into acinar-like cells in vitro. Therefore, ...we hypothesized that transplantation with bone marrow stem cells or acinar-like cells may help functional regeneration of salivary glands. Bone marrow stem cells were labeled with nanoparticles and directly co-cultured with acinar cells to obtain labeled acinar-like cells. In total, 140 severely combined immune-deficiency mice were divided into 4 groups for cell therapy experiments: (1) normal mice, (2) mice receiving irradiation around their head-and-neck areas; (3) mice receiving irradiation and intra-gland transplantation with labeled stem cells; and (4) mice receiving irradiation and intra-gland transplantation with labeled acinar-like cells. Our results showed that salivary glands damaged due to irradiation can be rescued by cell therapy with either bone marrow stem cells or acinar-like cells for recovery of saliva production, body weight, and gland weight. Transdifferentiation of bone marrow stem cells into acinar-like cells in vivo was also noted. This study demonstrated that cell therapy with bone marrow stem cells or acinar-like cells can help functional regeneration of salivary glands, and that acinar-like cells showed better therapeutic potentials than those of bone marrow stem cells.
Weyl semimetals are a class of materials that can be regarded as three-dimensional analogs of graphene upon breaking time-reversal or inversion symmetry. Electrons in a Weyl semimetal behave as Weyl ...fermions, which have many exotic properties, such as chiral anomaly and magnetic monopoles in the crystal momentum space. The surface state of a Weyl semimetal displays pairs of entangled Fermi arcs at two opposite surfaces. However, the existence of Weyl semimetals has not yet been proved experimentally. Here, we report the experimental realization of a Weyl semimetal in TaAs by observing Fermi arcs formed by its surface states using angle-resolved photoemission spectroscopy. Our first-principles calculations, which match remarkably well with the experimental results, further confirm that TaAs is a Weyl semimetal.
The clinical analgesic efficacy of buprenorphine Raffa, R. B.; Haidery, M.; Huang, H.-M. ...
Journal of clinical pharmacy and therapeutics,
December 2014, Letnik:
39, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Summary
What is known and objective
Based on in vitro assays and select animal models, buprenorphine is commonly called a ‘partial agonist’. An implication is that it should produce less analgesic ...effect in humans than so‐called ‘full agonists’ such as morphine or fentanyl. However, buprenorphine has a multimechanistic pharmacology, and thus partial agonism at a specific receptor is not particularly relevant to its overall analgesic action. We review published clinical trials that directly compared the magnitude of buprenorphine's analgesic effect to analgesics commonly considered full agonists.
Comment
Due to different signal transduction pathways, a drug can be a full agonist on one endpoint and a partial agonist on another. Therefore, we limited the present review to buprenorphine's analgesic effect.
What is new and conclusion
Twenty‐four controlled clinical trials were identified, plus a case report and dose–response curve. Based on complete or comparable pain relief, in buprenorphine had full clinical analgesic efficacy in 25 of the 26 studies.
Buprenorphine is commonly called a ‘partial‐agonist’. However, it has a multimechanistic pharmacology, and thus partial agonism at a specific receptor is not particularly relevant to its overall analgesic action. In this review of published clinical trials that directly compared the magnitude of buprenorphine's analgesic effect to analgesics commonly considered full‐agonists buprenorphine had full clinical analgesic efficacy in 25 of the 26 studies.
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