Boron neutron capture therapy induces apoptosis of glioma cells through Bcl-2/Bax

<p>Abstract</p> <p>Background</p> <p>Boron neutron capture therapy (BNCT) is an alternative treatment modality for patients with glioma. The aim of this study was to determine whether induction of apoptosis contributes to the main therapeutic efficacy of BNCT and to compare the relative biological effect (RBE) of BNCT, γ-ray and reactor neutron irradiation.</p> <p>Methods</p> <p>The neutron beam was obtained from the Xi'an Pulsed Reactor (XAPR) and γ-rays were obtained from [⁶⁰Co] γ source of the Fourth Military Medical University (FMMU) in China. Human glioma cells (the U87, U251, and SHG44 cell lines) were irradiated by neutron beams at the XAPR or [⁶⁰Co] γ-rays at the FMMU with different protocols: Group A included control nonirradiated cells; Group B included cells treated with 4 Gy of [⁶⁰Co] γ-rays; Group C included cells treated with 8 Gy of [⁶⁰Co] γ-rays; Group D included cells treated with 4 Gy BPA (p-borono-phenylalanine)-BNCT; Group E included cells treated with 8 Gy BPA-BNCT; Group F included cells irradiated in the reactor for the same treatment period as used for Group D; Group G included cells irradiated in the reactor for the same treatment period as used for Group E; Group H included cells irradiated with 4 Gy in the reactor; and Group I included cells irradiated with 8 Gy in the reactor. Cell survival was determined using the 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium (MTT) cytotoxicity assay. The morphology of cells was detected by Hoechst33342 staining and transmission electron microscope (TEM). The apoptosis rate was detected by flow cytometer (FCM). The level of Bcl-2 and Bax protein was measured by western blot analysis.</p> <p>Results</p> <p>Proliferation of U87, U251, and SHG44 cells was much more strongly inhibited by BPA-BNCT than by irradiation with [⁶⁰Co] γ-rays (<it>P </it>< 0.01). Nuclear condensation was determined using both a fluorescence technique and electron microscopy in all cell lines treated with BPA-BNCT. Furthermore, the cellular apoptotic rates in Group D and Group E treated with BPA-BNCT were significantly higher than those in Group B and Group C irradiated by [⁶⁰Co] γ-rays (<it>P </it>< 0.01). The clonogenicity of glioma cells was reduced by BPA-BNCT compared with cells treated in the reactor (Group F, G, H, I), and with the control cells (<it>P </it>< 0.01). Upon BPA-BNCT treatment, the Bax level increased in glioma cells, whereas Bcl-2 expression decreased.</p> <p>Conclusions</p> <p>Compared with ��-ray and reactor neutron irradiation, a higher RBE can be achieved upon treatment of glioma cells with BNCT. Glioma cell apoptosis induced by BNCT may be related to activation of Bax and downregulation of Bcl-2.</p

Nodular melanoma presenting with rapid progression and widespread metastases: a case report

<p>Abstract</p> <p>Introduction</p> <p>Melanoma is responsible for 1% to 2% of all cancer deaths around the world. Nodular melanoma often carries a poor prognosis because of no prodromal radial growth phase, early distant metastasis and significant tumor volume.</p> <p>Case presentation</p> <p>We present a case of progressive melanoma. A 51-year-old man was admitted to our hospital with dyspnea and skin lesions. These were multiple, dark colored, firm, and nodular and varied in size. He was diagnosed with melanoma. Temozolomide was administered, but he died of respiratory failure within a week after diagnosis.</p> <p>Conclusion</p> <p>Nodular melanoma tends to spread rapidly and eventually metastasize to vital organs. It may be fatal within months of recognition.</p

Curves on Heisenberg invariant quartic surfaces in projective 3-space

This paper is about the family of smooth quartic surfaces $X \subset \mathbb{P}^3$ that are invariant under the Heisenberg group $H_{2,2}$. For a very general such surface $X$, we show that the Picard number of $X$ is 16 and determine its Picard group. It turns out that the general Heisenberg invariant quartic contains 320 smooth conics and that in the very general case, this collection of conics generates the Picard group.Comment: Updated references, corrected typo

Financial Legislation: The Promise and Record of the Financial Modernization Act of 1999

On November 12, 1999, President Clinton signed the most significant piece of financial services regulation to be enacted since the Great Depression, at least up to that time. When the Financial Service Modernization Act of 1999, better known as the Gramm-Leach-Bliley Act (GLBA), was signed, the financial services industry faced strong pressures for deregulation of the rigid structure imposed during the Great Depression. During the 2007-08 financial crises and ensuing debate regarding financial services regulation, the GLBA became a target as members of the financial sector, academia and government considered possible triggers that may have precipitated the crisis

Antikaon production in nucleon-nucleon reactions near threshold

The antikaon production cross section from nucleon-nucleon reactions near threshold is studied in a meson exchange model. We include both pion and kaon exchange, but neglect the interference between the amplitudes. In case of pion exchange the antikaon production cross section can be expressed in terms of the antikaon production cross section from a pion-nucleon interaction, which we take from the experimental data if available. Otherwise, a $K^*$-resonance exchange model is introduced to relate the different reaction cross sections. In case of kaon exchange the antikaon production cross section is related to the elastic $KN$ and $\bar KN$ cross sections, which are again taken from experimental measurements. We find that the one-meson exchange model gives a satisfactory fit to the available data for the $NN\to NNK\bar K$ cross section at high energies. We compare our predictions for the cross section near threshold with an earlier empirical parameterization and that from phase space models.Comment: 16 pages, LaTeX, 5 postscript figures included, submitted to Z. Phys.

A pilot randomised controlled trial of personalised care for depressed patients with symptomatic coronary heart disease in South London general practices: the UPBEAT-UK RCT protocol and recruitment.

ABSTRACT: Background: Community studies reveal people with coronary heart disease (CHD) are twice as likely to be depressed as the general population and that this co-morbidity negatively affects the course and outcome of both conditions. There is evidence for the efficacy of collaborative care and case management for depression treatment, and whilst NICE guidelines recommend these approaches only where depression has not responded to psychological, pharmacological, or combined treatments, these care approaches may be particularly relevant to the needs of people with CHD and depression in the earlier stages of stepped care in primary care settings. Methods: This pilot randomised controlled trial will evaluate whether a simple intervention involving a personalised care plan, elements of case management and regular telephone review is a feasible and acceptable intervention that leads to better mental and physical health outcomes for these patients. The comparator group will be usual general practitioner (GP) care. 81 participants have been recruited from CHD registers of 15 South London general practices. Eligible participants have probable major depression identified by a score of ≥8 on the Hospital Anxiety and Depression Scale depression subscale (HADS-D) together with symptomatic CHD identified using the Modified Rose Angina Questionnaire. Consenting participants are randomly allocated to usual care or the personalised care intervention which involves a comprehensive assessment of each participant’s physical and mental health needs which are documented in a care plan, followed by regular telephone reviews by the case manager over a 6-month period. At each review, the intervention participant’s mood, function and identified problems are reviewed and the case manager uses evidence based behaviour change techniques to facilitate achievement of goals specified by the patient with the aim of increasing the patient’s self efficacy to solve their problems. Depressive symptoms measured by HADS score will be collected at baseline and 1, 6- and 12 months post randomisation. Other outcomes include CHD symptoms, quality of life, wellbeing and health service utilisation. Discussion: This practical and patient-focused intervention is potentially an effective and accessible approach to the health and social care needs of people with depression and CHD in primary care. Trial registration: ISRCTN21615909

Pontocerebellar hypoplasia type 2: a neuropathological update

Pontocerebellar hypoplasia type 2 (PCH-2; MIM 277470), an autosomal recessive neurodegeneration with fetal onset, was studied in six autopsies with ages at death ranging between 1 and 22 years. Three patients were distantly related. A case of olivopontocerebellar hypoplasia (OPCH; MIM 225753) was studied for comparison. Typical findings are: short cerebellar folia with poor branching (“hypoplasia”), relative sparing of the vermis, sharply demarcated areas of full thickness loss of cerebellar cortex probably resulting from regression at an early stage of development, segmental loss of dentate nuclei with preserved islands and reactive changes, segmental loss in the inferior olivary nucleus with reactive changes, loss of ventral pontine nuclei with near absence of transverse pontine fibers and sparing of spinal anterior horn cells. Variable findings are: cystic cerebellar degeneration, found in two, with vascular changes limited to the cerebellum in one. Comparison to olivopontocerebellar hypoplasia (OPCH) strongly suggests a continuum of pathology between this disorder and PCH-2. Immunohistochemical evaluation of the endoplasmic reticulum stress response is negative. We conclude that the neuropathological findings in PCH-2 are sufficiently specific to enable an unequivocal diagnosis based on neuropathology

Hepatitis C virus cell-cell transmission and resistance to direct-acting antiviral agents

Hepatitis C virus (HCV) is transmitted between hepatocytes via classical cell entry but also uses direct cell-cell transfer to infect neighboring hepatocytes. Viral cell-cell transmission has been shown to play an important role in viral persistence allowing evasion from neutralizing antibodies. In contrast, the role of HCV cell-cell transmission for antiviral resistance is unknown. Aiming to address this question we investigated the phenotype of HCV strains exhibiting resistance to direct-acting antivirals (DAAs) in state-of-the-art model systems for cell-cell transmission and spread. Using HCV genotype 2 as a model virus, we show that cell-cell transmission is the main route of viral spread of DAA-resistant HCV. Cell-cell transmission of DAA-resistant viruses results in viral persistence and thus hampers viral eradication. We also show that blocking cell-cell transmission using host-targeting entry inhibitors (HTEIs) was highly effective in inhibiting viral dissemination of resistant genotype 2 viruses. Combining HTEIs with DAAs prevented antiviral resistance and led to rapid elimination of the virus in cell culture model. In conclusion, our work provides evidence that cell-cell transmission plays an important role in dissemination and maintenance of resistant variants in cell culture models. Blocking virus cell-cell transmission prevents emergence of drug resistance in persistent viral infection including resistance to HCV DAAs

The mitochondrial genome sequence of the ciliate Paramecium caudatum reveals a shift in nucleotide composition and codon usage within the genus Paramecium

<p>Abstract</p> <p>Background</p> <p>Despite the fact that the organization of the ciliate mitochondrial genome is exceptional, only few ciliate mitochondrial genomes have been sequenced until today. All ciliate mitochondrial genomes are linear. They are 40 kb to 47 kb long and contain some 50 tightly packed genes without introns. Earlier studies documented that the mitochondrial guanine + cytosine contents are very different between <it>Paramecium tetraurelia </it>and all studied <it>Tetrahymena </it>species. This raises the question of whether the high mitochondrial G+C content observed in <it>P. tetraurelia </it>is a characteristic property of <it>Paramecium </it>mtDNA, or whether it is an exception of the ciliate mitochondrial genomes known so far. To test this question, we determined the mitochondrial genome sequence of <it>Paramecium caudatum </it>and compared the gene content and sequence properties to the closely related <it>P. tetraurelia</it>.</p> <p>Results</p> <p>The guanine + cytosine content of the <it>P. caudatum </it>mitochondrial genome was significantly lower than that of <it>P. tetraurelia </it>(22.4% vs. 41.2%). This difference in the mitochondrial nucleotide composition was accompanied by significantly different codon usage patterns in both species, i.e. within <it>P. caudatum </it>clearly A/T ending codons dominated, whereas for <it>P. tetraurelia </it>the synonymous codons were more balanced with a higher number of G/C ending codons. Further analyses indicated that the nucleotide composition of most members of the genus <it>Paramecium </it>resembles that of <it>P. caudatum </it>and that the shift observed in <it>P. tetraurelia </it>is restricted to the <it>P. aurelia </it>species complex.</p> <p>Conclusions</p> <p>Surprisingly, the codon usage bias in the <it>P. caudatum </it>mitochondrial genome, exemplified by the effective number of codons, is more similar to the distantly related <it>T. pyriformis </it>and other single-celled eukaryotes such as <it>Chlamydomonas</it>, than to the closely related <it>P. tetraurelia</it>. These differences in base composition and codon usage bias were, however, not reflected in the amino acid composition. Most probably, the observed picture is best explained by a hitherto unknown (neutral or adaptive) mechanism that increased the guanine + cytosine content in <it>P. tetraurelia </it>mtDNA on the one hand, and strong purifying selection on the ancestral amino acid composition on the other hand. These contradicting forces are counterbalanced by a considerably altered codon usage pattern.</p