Bloom Syndrome is a rare recessive disease which includes a susceptibility to various cancers. It is caused by homozygous mutations of the BLM gene. To investigate whether heterozygous carriers of a ...BLM mutation are predisposed to breast cancer, we sequenced BLM in 617 patients from Polish families with a strong family history of breast cancer. We detected a founder mutation (c.1642C>T, p.Gln548Ter) in 3 of the 617 breast cancer patients (0.49%) who were sequenced. Then, we genotyped 14,804 unselected breast cancer cases and 4698 cancer-free women for the founder mutation. It was identified in 82 of 14,804 (0.55%) unselected cases and in 26 of 4698 (0.55%) controls (OR = 1.0; 95%CI 0.6–1.6). Clinical characteristics of breast cancers in the BLM mutation carriers and non-carriers were similar. Loss of the wild-type BLM allele was not detected in cancers from the BLM mutation carriers. No cancer type was more common in the relatives of mutation carriers compared to relatives of non-carriers. The BLM founder mutation p.Gln548Ter, which in a homozygous state is a cause of Bloom syndrome, does not appear to predispose to breast cancer in a heterozygous state. The finding casts doubt on the designation of BLM as an autosomal dominant breast cancer susceptibility gene.
To determine whether three of
single nucleotide polymorphisms, c.142C > G, c.355G > T and c.1294C > G are associated with a lung cancer risk.
A total of 112 lung cancer patients and 100 controls were ...genotyped using the RFLP-PCR.
In the c.142C > G polymorphisms, G allele was more frequent in lung cancer patients than in controls (p < 0.001), while in the c.1294C > G polymorphisms, C allele was more frequent in lung cancer patients, than in controls (p = 0.012). In the c.355G > T polymorphism, the distribution of alleles in both analyzed groups was similar. The GTC haplotype turned out to be correlated with the increased lung cancer risk, compared with the most common CGG haplotype (OR: 2.38; p = 0.001).
gene polymorphisms appear to influence lung cancer susceptibility.
Background
XRCC2
participates in homologous recombination and in DNA repair.
XRCC2
has been reported to be a breast cancer susceptibility gene and is now included in several breast cancer ...susceptibility gene panels.
Methods
We sequenced
XRCC2
in 617 Polish women with familial breast cancer and found a founder mutation. We then genotyped 12,617 women with breast cancer and 4599 controls for the
XRCC2
founder mutation.
Results
We identified a recurrent truncating mutation of
XRCC2
(c.96delT, p.Phe32fs) in 3 of 617 patients with familial breast cancer who were sequenced. The c.96delT mutation was then detected in 29 of 12,617 unselected breast cancer cases (0.23%) compared to 11 of 4599 cancer-free women (0.24%) (OR = 0.96; 95% CI 0.48–1.93). The mutation frequency in 1988 women with familial breast cancer was 0.2% (OR = 0.84, 95% CI 0.27–2.65). Breast cancers in
XRCC2
mutation carriers and non-carriers were similar with respect to age of diagnosis and clinical characteristics. Loss of the wild-type
XRCC2
allele was observed only in one of the eight breast cancers from patients who carried the
XRCC2
mutation. No cancer type was more common in first- or second-degree relatives of
XRCC2
mutation carriers than in relatives of the non-carriers.
Conclusion
XRCC2
c.96delT is a protein-truncating founder variant in Poland. There is no evidence that this mutation predisposes to breast cancer (and other cancers). It is premature to consider
XRCC2
as a breast cancer-predisposing gene.
Astron.Astrophys.423:821,2004 Luminet et al. (2003) suggested that WMAP data are better matched by a
Poincar\'e dodecahedral FLRW model of global geometry, rather than by an
infinite flat model. The ...analysis by Cornish et al. (2003) for angular radii
25-90 degrees failed to support this. Here, a matched circles analysis
specifically designed to detect dodecahedral patterns of matched circles is
performed over angular radii in the range 1-40 degrees on the one-year WMAP ILC
map, using a correlation statistic and an rms difference statistic. Extreme
value distributions of these statistics are calculated for left-handed and
right-handed 36 degree `screw motions' (Clifford translations) when matching
circles and for a zero (unphysical) rotation. The most correlated circles
appear for circle radii of 11\pm1 degrees, for the left-handed screw motion,
but not for the right-handed one, nor for the zero rotation. The favoured six
dodecahedral face centres in galactic coordinates are (l,b)= (252, +65), (51,
+51), (144,+38), (207,+10), (271,+3), (332,+25) and their opposites. The six
pairs of circles_independently_ each favour a circle angular radius of 11\pm1
degrees. Whether or not these six circle pairs centred on dodecahedral faces
match via a 36 degree rotation only due to unexpected statistical properties of
the WMAP ILC map, or whether they match due to global geometry, it is clear
that the WMAP ILC map has some unusual statistical properties which mimic a
potentially interesting cosmological signal. The software for reading the WMAP
data and for carrying out this analysis are released under the GNU General
Public License.
Luminet et al. (2003) suggested that WMAP data are better matched by a Poincaré dodecahedral FLRW model of global geometry, rather than by an infinite flat model. The analysis by Cornish et al. ...(2003) for angular radii 25-90 degrees failed to support this. Here, a matched circles analysis specifically designed to detect dodecahedral patterns of matched circles is performed over angular radii in the range 1-40 degrees on the one-year WMAP ILC map, using a correlation statistic and an rms difference statistic. Extreme value distributions of these statistics are calculated for left-handed and right-handed 36 degree `screw motions' (Clifford translations) when matching circles and for a zero (unphysical) rotation. The most correlated circles appear for circle radii of 11\pm1 degrees, for the left-handed screw motion, but not for the right-handed one, nor for the zero rotation. The favoured six dodecahedral face centres in galactic coordinates are (l,b)= (252, +65), (51, +51), (144,+38), (207,+10), (271,+3), (332,+25) and their opposites. The six pairs of circles_independently_ each favour a circle angular radius of 11\pm1 degrees. Whether or not these six circle pairs centred on dodecahedral faces match via a 36 degree rotation only due to unexpected statistical properties of the WMAP ILC map, or whether they match due to global geometry, it is clear that the WMAP ILC map has some unusual statistical properties which mimic a potentially interesting cosmological signal. The software for reading the WMAP data and for carrying out this analysis are released under the GNU General Public License.
Phenylbutyrate (PBA) is an aromatic short-chain fatty acid which is a chemical derivative of butyric acid naturally produced by colonic bacteria fermentation. At the intestinal level butyrate exerts ...a multitude of activities including amelioration of mucosal inflammation, regulation of transepithelial fluid transport, improvement in oxidative status and colon cancer prevention. Moreover, increasing number of studies report the beneficial role of butyric acid in prevention or inhibition of other types of malignancies, leading to cancer cell growth arrest and apoptosis. Similarly, phenylbutyrate displays potentially favorable effects on many pathologies including cancer, genetic metabolic syndromes, neuropathies, diabetes, hemoglobinopathies, and urea cycle disorders. The mechanisms by which PBA exerts these effects are different. Some of them are connected with the regulation of gene expression, playing the role of a histone deacetylase inhibitor, while others contribute to the ability of rescuing conformational abnormalities of proteins, serving as chemical chaperone, and some are dedicated to its metabolic characteristic enabling excretion of toxic ammonia, thus acting as ammonia scavenger. Phenylbutyrate may exert variable effects depending on the cell type, thus the term "butyrate paradox" has been proposed. These data indicate a broad spectrum of beneficial effects evoked by PBA with a high potential in therapy. In this review, we focus on cellular and systemic effects of PBA treatment with special attention to the three main branches of its molecular activity: ammonia scavenging, chaperoning and histone deacetylase inhibiting, and describe its particular role in various human diseases.
A growing body of evidence indicates that dietary polyphenols show protective effects against various cancers. However, little is known yet about their activity in brain tumors. Here we investigated ...the interaction of dietary flavonoid quercetin (QCT) with the human glioblastoma A172 and LBC3 cell lines. We demonstrated that QCT evoked cytotoxic effect in both tested cell lines. Microscopic observations, Annexin V-FITC/PI staining, and elevated expression and activity of caspase 3/7 showed that QCT caused predominantly apoptotic death of A172 cells. Further analyses confirmed enhanced ROS generation, deregulated expression of SOD1 and SOD2, depletion of ATP levels, and an overexpression of CHOP, suggesting the activation of oxidative stress and ER stress upon QCT exposure. Finally, elevated expression and activity of caspase 9, indicative of a mitochondrial pathway of apoptosis, was detected. Conversely, in LBC3 cells the pro-apoptotic effect was observed only after 24 h incubation with QCT, and a shift towards necrotic cell death was observed after 48 h of treatment. Altogether, our data indicate that exposure to QCT evoked cell death via activation of intrinsic pathway of apoptosis in A172 cells. These findings suggest that QCT is worth further investigation as a potential pharmacological agent in therapy of brain tumors.
Recently, the focus of oncological research has been on the optimization of therapeutic strategies targeted at malignant diseases. Nanomedicine utilizing silicon dioxide nanoparticles (SiNPs) is one ...such strategy and is rapidly developing as a promising tool for cancer diagnosis, imaging, and treatment. Nevertheless, little is known about the mechanisms of action of SiNPs in brain tumors.
Here, we explored the effects of 5-15 nm SiNPs in the human glioblastoma cell line LN229. In this respect, MTT assays, microscopic observations, flow cytometry analyses, and luminescent assays were performed. Moreover, RT-qPCR and Western blot analyses were done to determine gene and protein expressions.
We demonstrated that SiNPs triggered evident cytotoxicity, with microscopic observations of the nuclei, annexin V-fluorescein isothiocyanate/propidium iodide staining, and elevated caspase 3/7 activity, suggesting that SiNPs predominantly induced apoptotic death in LN229 cells. We further showed the occurrence of oxidative stress induced by enhanced reactive oxygen-species generation. This effect was followed by deregulated expression of genes encoding the antioxidant enzymes SOD1, SOD2, and CAT, and impaired mitochondria function. SiNP- induced mitochondrial dysfunction was characterized by membrane-potential collapse, ATP depletion, elevated expression of
,
, and
with simultaneous downregulation of
, and activation of caspase 9. Moreover, RT-qPCR and Western blot analyses demonstrated increased levels of the endoplasmic reticulum stress markers GRP78, GRP94, and DDIT3, as well as strongly increased expressions of the
and
genes, suggesting activation of endoplasmic reticulum stress and a proinflammatory response.
Altogether, our data indicate that in LN229 cells, SiNPs evoke cell death via activation of the intrinsic apoptosis pathway and suggest that other aspects of cellular function may also be affected. As such, SiNPs represent a potentially promising agent for facilitating further progress in brain cancer therapy. However, further exploration of SiNP long-term toxicity and molecular effects is necessary prior to their widespread application.
Proteasomes play an important role in the physiology of cancer cells, and inhibition of their activity may be used as a promising therapeutic strategy against glioblastoma (GBM). Although certain ...proteasome inhibitors (PIs) have been approved for the treatment of other malignancies, they have limited effectiveness against GBM due to low brain bioavailability. Marizomib (MZB) is an irreversible, second-generation proteasome inhibitor, which unlike other PIs can penetrate through the blood–brain barrier, making it a promising therapeutic tool in brain malignancies. The antitumor activity of MZB was investigated in LN229 and U118 cells. The MTT test and the ATP-based assay were performed to evaluate cytotoxicity. Flow cytometry analysis was used to determine the apoptotic death of GBM cells. Luminescent assays were used to assess levels of reactive oxygen species (ROS) and the activity of caspase 3/7. RT-qPCR and Western blot analyses were used to determine gene and protein expressions. Marizomib decreased the viability and caused apoptotic death of GBM cells. The proapoptotic effect was accompanied by activation of caspase 3 and overexpression of cl-PARP, Noxa, Cyt C, and DR5. Moreover, treatment with MZB triggered endoplasmic reticulum (ER) stress, as shown by increased expressions of GRP78, IRE1α, p-EIF2α, p-SAPK/JNK, CHOP, ATF6α, and ATF4. On the contrary, overproduction of ROS or increased expressions of ERO1α, LC3 II, Beclin 1, and ATG5 were not detected, suggesting that neither oxidative stress nor autophagy were involved in the process of MZB-induced cell death. Thus, marizomib represents a potentially promising compound for facilitating further progress in brain cancer therapy.
Despite intensive investigations, nanoparticle-induced cellular damage is an important problem that has not been fully elucidated yet. Here, we report that silica nanoparticles (SiNPs) demonstrated ...anticancer influence on glioblastoma cells by the induction of apoptosis or necrosis. These effects are highly cell type-specific, as well as dependent on the size and dose of applied nanoparticles. Exposure of LN-18 and LBC3 cells to different sizes of SiNPs-7 nm, 5-15 nm, or 10-20 nm-at dosages, ranging from 12.5 to 1000 µg/mL, for 24 and 48 h reduced the viability of these cells. Treatment of LN-18 and LBC3 cells with 7 nm or 10-20 nm SiNPs at doses ≥50 µg/mL caused a strong induction of apoptosis, which is connected with an increase of intracellular reactive oxygen species (ROS) production. The 5-15 nm SiNPs exhibited distinct behavior comparing to silica nanoparticles of other studied sizes. In contrast to LBC3, in LN-18 cells exposed to 5-15 nm SiNPs we did not observe any effect on apoptosis. These nanoparticles exerted only strong necrosis, which was connected with a reduction in ROS generation. This suggests that SiNPs can trigger different cellular/molecular effects, depending on the exposure conditions, the size and dose of nanoparticles, and cell type of glioblastoma.
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