Expansion of anti-AFP Th1 and Tc1 responses in hepatocellular carcinoma occur in different stages of disease

Copyright @ 2010 Cancer Research UK. This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.Background: α-Fetoprotein (AFP) is a tumour-associated antigen in hepatocellular carcinoma (HCC) and is a target for immunotherapy. However, there is little information on the pattern of CD4 (Th1) and CD8 (Tc1) T-cell response to AFP in patients with HCC and their association with the clinical characteristics of patients. Methods: We therefore analysed CD4 and CD8 T-cell responses to a panel of AFP-derived peptides in a total of 31 HCC patients and 14 controls, using an intracellular cytokine assay for IFN-γ. Results: Anti-AFP Tc1 responses were detected in 28.5% of controls, as well as in 25% of HCC patients with Okuda I (early tumour stage) and in 31.6% of HCC patients with stage II or III (late tumour stages). An anti-AFP Th1 response was detected only in HCC patients (58.3% with Okuda stage I tumours and 15.8% with Okuda stage II or III tumours). Anti-AFP Th1 response was mainly detected in HCC patients who had normal or mildly elevated serum AFP concentrations (P=0.00188), whereas there was no significant difference between serum AFP concentrations in these patients and the presence of an anti-AFP Tc1 response. A Th1 response was detected in 44% of HCC patients with a Child–Pugh A score (early stage of cirrhosis), whereas this was detected in only 15% with a B or C score (late-stage cirrhosis). In contrast, a Tc1 response was detected in 17% of HCC patients with a Child–Pugh A score and in 46% with a B or C score. Conclusion: These results suggest that anti-AFP Th1 responses are more likely to be present in patients who are in an early stage of disease (for both tumour stage and liver cirrhosis), whereas anti-AFP Tc1 responses are more likely to be present in patients with late-stage liver cirrhosis. Therefore, these data provide valuable information for the design of vaccination strategies against HCC.Association for International Cancer Research and Polkemmet Fund, London Clinic

Dynamic Fracture Instability Of Tough Bulk Metallic Glass

We report the observations of a clear fractographic evolution from vein pattern, dimple structure, and then to periodic corrugation structure, followed by microbranching pattern, along the crack propagation direction in the dynamic fracture of a tough Zr41.2Ti13.8Cu12.5Ni10Be22.5 (Vit.1) bulk metallic glass (BMGs) under high-velocity plate impact. A model based on fracture surface energy dissipation and void growth is proposed to characterize this fracture pattern transition. We find that once the dynamic crack propagation velocity reaches a critical fraction of Rayleigh wave speed, the crack instability occurs; hence, crack microbranching goes ahead. Furthermore, the correlation between the critical velocity of amorphous materials and their intrinsic strength such as Young's modulus is uncovered. The results may shed new insight into dynamic fracture instability for BMGs. (C) 2008 American Institute of Physics

Are published standards for haematological indices in pregnancy applicable across populations: an evaluation in healthy pregnant Jamaican women

<p>Abstract</p> <p>Background</p> <p>The haematological profile of the pregnant woman has an impact on the outcome of the pregnancy. Published guidelines indicate acceptable levels for haematological indices in pregnancy but they are population specific. Indicators of haemoglobin concentration are the most commonly utilized of the indices. These published international norms are used across populations, however, there is no evidence confirming their applicability to a population such as the Jamaican pregnant woman. This study was therefore undertaken with the intent of documenting the haematological profile of pregnant primigravid Jamaican women and comparing these to the established norms to determine whether the norms apply or whether there was a need to establish local norms.</p> <p>Methods</p> <p>This was a longitudinal study done on a cohort of 157 healthy primigravid women ages 15 to 25 and without anaemia, and who were recruited from the antenatal clinic of the University Hospital of the West Indies, Kingston, Jamaica. The haemoglobin concentration, packed cell volume, mean cell volume, mean cell haemoglobin, mean cell haemoglobin concentration, white blood cell count, red blood cell count and platelet count were measured on samples of blood obtained from each consenting participant during each of the three trimesters. The results were analysed using SPSS for windows (Version 11) and the data expressed as means ± S.D. Means were compared using the student's paired <it>t-test</it>. Comparison was then made with the international norms as recommended by the United States Center for Disease Control (1989). Ethical approval for this study was obtained from the University Hospital of the West Indies/University of the West Indies Ethics Committee.</p> <p>Results</p> <p>The results showed changes by trimester in all measured variables. For most of the indices the changes achieved levels of significance across trimesters. These changes were however in keeping with the expected physiological response in pregnancy and the values were similar to the published international norms.</p> <p>Conclusion</p> <p>The findings suggest that the international norms for haematological indices in pregnancy are applicable across populations and to the pregnant Jamaican primigravid woman. This finding may be reassuring to others with a similar population and stage of development as Jamaica.</p

Increasing the sensitivity of terahertz split ring resonator metamaterials for dielectric sensing by localized substrate etching

We demonstrate a significant enhancement in the sensitivity of split ring resonator terahertz metamaterial dielectric sensors by the introduction of etched trenches into their inductive-capacitive gap area, both through finite element simulations and in experiments performed using terahertz time-domain spectroscopy. The enhanced sensitivity is demonstrated by observation of an increased frequency shift in response to overlaid dielectric material of thicknesses up to 18 μm deposited on to the sensor surface. We show that sensitivity to the dielectric is enhanced by a factor of up to ~2.7 times by the incorporation of locally etched trenches with a depth of ~3.4 μm, for example, and discuss the effect of the etching on the electrical properties of the sensors. Our experimental findings are in good agreement with simulations of the sensors obtained using finite element methods

A behavioral comparison of male and female adults with high functioning autism spectrum conditions

Autism spectrum conditions (ASC) affect more males than females in the general population. However, within ASC it is unclear if there are phenotypic sex differences. Testing for similarities and differences between the sexes is important not only for clinical assessment but also has implications for theories of typical sex differences and of autism. Using cognitive and behavioral measures, we investigated similarities and differences between the sexes in age- and IQ-matched adults with ASC (high-functioning autism or Asperger syndrome). Of the 83 (45 males and 38 females) participants, 62 (33 males and 29 females) met Autism Diagnostic Interview-Revised (ADI-R) cut-off criteria for autism in childhood and were included in all subsequent analyses. The severity of childhood core autism symptoms did not differ between the sexes. Males and females also did not differ in self-reported empathy, systemizing, anxiety, depression, and obsessive-compulsive traits/symptoms or mentalizing performance. However, adult females with ASC showed more lifetime sensory symptoms (p = 0.036), fewer current socio-communication difficulties (p = 0.001), and more self-reported autistic traits (p = 0.012) than males. In addition, females with ASC who also had developmental language delay had lower current performance IQ than those without developmental language delay (p<0.001), a pattern not seen in males. The absence of typical sex differences in empathizing-systemizing profiles within the autism spectrum confirms a prediction from the extreme male brain theory. Behavioral sex differences within ASC may also reflect different developmental mechanisms between males and females with ASC. We discuss the importance of the superficially better socio-communication ability in adult females with ASC in terms of why females with ASC may more often go under-recognized, and receive their diagnosis later, than males

Children's vomiting following posterior fossa surgery: A retrospective study

<p>Abstract</p> <p>Background</p> <p>Nausea and vomiting is a problem for children after neurosurgery and those requiring posterior fossa procedures appear to have a high incidence. This clinical observation has not been quantified nor have risk factors unique to this group of children been elucidated.</p> <p>Methods</p> <p>A six year retrospective chart audit at two Canadian children's hospitals was conducted. The incidence of nausea and vomiting was extracted. Hierarchical multivariable logistic regression was used to quantify risk and protective factors at 120 hours after surgery and early vs. late vomiting.</p> <p>Results</p> <p>The incidence of vomiting over a ten day postoperative period was 76.7%. Documented vomiting ranged from single events to greater than 20 over the same period. In the final multivariable model: adolescents (age 12 to <17) were less likely to vomit by 120 hours after surgery than other age groups; those who received desflurane, when compared to all other volatile anesthetics, were more likely to vomit, yet the use of ondansetron with desflurane decre kelihood. Children who had intraoperative ondansetron were more likely to vomit in the final multivariable model (perhaps because of its use, in the clinical judgment of the anesthesiologist, for children considered at risk). Children who started vomiting in the first 24 hours were more likely to be school age (groups 4 to <7 and 7 to <12) and receive desflurane. Nausea was not well documented and was therefore not analyzed.</p> <p>Conclusion</p> <p>The incidence of vomiting in children after posterior fossa surgery is sufficient to consider all children requiring these procedures to be at high risk for POV. Nausea requires better assessment and documentation.</p

Alpha-santalol, a chemopreventive agent against skin cancer, causes G2/M cell cycle arrest in both p53-mutated human epidermoid carcinoma A431 cells and p53 wild-type human melanoma UACC-62 cells

<p>Abstract</p> <p>Background</p> <p>α-Santalol, an active component of sandalwood oil, has shown chemopreventive effects on skin cancer in different murine models. However, effects of α-santalol on cell cycle have not been studied. Thus, the objective of this study was to investigate effects of α-santalol on cell cycle progression in both p53 mutated human epidermoid carcinoma A431 cells and p53 wild-type human melanoma UACC-62 cells to elucidate the mechanism(s) of action.</p> <p>Methods</p> <p>MTT assay was used to determine cell viability in A431 cells and UACC-62; fluorescence-activated cell sorting (FACS) analysis of propidium iodide staining was used for determining cell cycle distribution in A431 cells and UACC-62 cells; immunoblotting was used for determining the expression of various proteins and protein complexes involved in the cell cycle progression; siRNA were used to knockdown of p21 or p53 in A431 and UACC-62 cells and immunofluorescence microscopy was used to investigate microtubules in UACC-62 cells.</p> <p>Results</p> <p>α-Santalol at 50-100 μM decreased cell viability from 24 h treatment and α-santalol at 50 μM-75 μM induced G₂/M phase cell cycle arrest from 6 h treatment in both A431 and UACC-62 cells. α-Santalol altered expressions of cell cycle proteins such as cyclin A, cyclin B1, Cdc2, Cdc25c, p-Cdc25c and Cdk2. All of these proteins are critical for G₂/M transition. α-Santalol treatment up-regulated the expression of p21 and suppressed expressions of mutated p53 in A431 cells; whereas, α-santalol treatment increased expressions of wild-type p53 in UACC-62 cells. Knockdown of p21 in A431 cells, knockdown of p21 and p53 in UACC-62 cells did not affect cell cycle arrest caused by α-santalol. Furthermore, α-santalol caused depolymerization of microtubules similar to vinblastine in UACC-62 cells.</p> <p>Conclusions</p> <p>This study for the first time identifies effects of α-santalol in G₂/M phase arrest and describes detailed mechanisms of G₂/M phase arrest by this agent, which might be contributing to its overall cancer preventive efficacy in various mouse skin cancer models.</p

Role of the supine lateral radiograph of the spine in vertebroplasty for osteoporotic vertebral compression fracture: a prospective study

<p>Abstract</p> <p>Background</p> <p>Severely collapsed vertebral compression fracture (VCF) is usually considered as a contraindication for vertebroplasty because of critically decreased vertebral height (less than one-third the original height). However, osteoporotic VCF can possess dynamic mobility with intravertebral cleft (IVC), which can be demonstrated on supine lateral radiographs (SuLR) and standing lateral radiographs (StLR). The purposes of this study were to: (1) evaluate the efficacy of SuLR to detect IVCs and assess the intravertebral mobility in VCFs, and (2) evaluate the short-term results of vertebroplasty in severely collapsed VCFs with IVCs.</p> <p>Methods</p> <p>We enrolled 37 patients with 40 symptomatic osteoporotic VCFs for vertebroplasty; 11 had severely collapsed VCFs with concurrent IVCs detected on the SuLR, the others had not-severely collapsed VCFs. A preoperative StLR, SuLR, magnetic resonance imaging (MRI), and postoperative StLR were taken from all patients. Radiographs were digitized to calculate vertebral body morphometrics including vertebral height ratio and Cobb's kyphotic angle. The intensity of the patient's pain was assessed by the visual analogue scale (VAS) on the day before operation and 1 day, 1 month, and 4 months after operation. The patient's VAS scores and image measurement results were assessed with the paired <it>t</it>-test and Pearson correlation tests; Mann-Whitney U test was used for VAS subgroup comparison. Significance was defined as <it>p </it>< 0.05.</p> <p>Results</p> <p>IVCs in patients with not-severely collapsed VCFs were detected in 21 vertebrae (72.4%) by MRI, in 15 vertebrae (51.7%) by preoperative SuLR, and in 7 vertebrae (24.1%) by preoperative StLR. Using the MRI as a gold standard to detect IVCs, SuLR exhibit a sensitivity of 0.71 as compared to StLR that yield a sensitivity of 0.33. In patients with VCFs with IVCs detected on SuLR, the average of the postoperative restoration in vertebral height ratio was significantly higher than that in those without IVCs (17.1% vs. 6.4%). There was no statistical difference in the VAS score between severely collapsed VCFs with IVCs detected on SuLR and not-severely collapsed VCFs at any follow-up time point.</p> <p>Conclusions</p> <p>The SuLR efficiently detects an IVC in VCF, which indicates a better vertebral height correction after vertebroplasty compared to VCF without IVC. Before performing a costly MRI, SuLR can identify more IVCs than StLR in patients with severely collapsed VCFs, whom may become the candidates for vertebroplasty.</p

Structure–activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells

The cytotoxicity of three alkaloids from the roots of Aconitum yesoense var. macroyesoense as well as 36 semi-synthetic C20-diterpenoid atisine-type alkaloid derivatives against A549 human lung carcinoma cells was examined. Ten acylated alkaloid derivatives, pseudokobusine 11-veratroate (9), 11-anisoate (12), 6,11-dianisoate (14), 11-p-nitrobenzoate (18), 11,15-di-p-nitrobenzoate (22), 11-cinnamate (25) and 11-m-trifluoromethylbenzoate (27), and kobusine 11-p-trifluoromethylbenzoate (35), 11-m-trifluoromethylbenzoate (36) and 11,15-di-p-nitrobenzoate (39), exhibited cytotoxic activity, and 11,15-dianisoylpseudokobusine (16) was found to be the most potent cytotoxic agent. Their IC50 values against A549 cells ranged from 1.72 to 5.44 μM. In the occurrence of cytotoxic effects of atisine-type alkaloids, replacement by an acyl group at both C-11 and C-15 resulted in the enhancement of activity of the parent alkaloids compared to that from having hydroxy groups at this position, and the presence of a hydroxy group at the C-6 position was required for the cytotoxic effects. These acylated alkaloid derivatives inhibit cell growth through G1 arrest

Cellular Reactive Oxygen Species Inhibit MPYS Induction of IFNβ

Many inflammatory diseases, as well as infections, are accompanied by elevation in cellular levels of Reactive Oxygen Species (ROS). Here we report that MPYS, a.k.a. STING, which was recently shown to mediate activation of IFNβ expression during infection, is a ROS sensor. ROS induce intermolecular disulfide bonds formation in MPYS homodimer and inhibit MPYS IFNβ stimulatory activity. Cys-64, -148, -292, -309 and the potential C88xxC91 redox motif in MPYS are indispensable for IFNβ stimulation and IRF3 activation. Thus, our results identify a novel mechanism for ROS regulation of IFNβ stimulation