HLA gene polymorphism is a modifier of age-related breast cancer penetrance in carriers of BRCA1 pathogenic alleles.

Purpose: Female carriers of germline BRCA1 mutations almost invariably develop breast cancer (BC); however, the age at onset is a subject of variation. We hypothesized that the age-related penetrance of BRCA1 mutations may depend on inherited variability in the host immune system.

Methods: Next-generation sequencing was utilized for genotyping of HLA class I/II genes (HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQB1, and HLA-DRB1/3/4/5) in patients with BRCA1-associated BC with early (< / = 38 years, n = 215) and late (> / = 58 years, n = 108) age at onset.

Unexpected "Lazarus response" to single-agent bevacizumab in heavily pretreated patients with HER2-positive breast cancer.

Early clinical trials aimed to halt cancer progression by inhibiting the growth of new blood vessels in tumors through single-agent targeted therapy with bevacizumab. These trials largely proved unsuccessful. However, bevacizumab turned out to be efficient when administered in combination with other anticancer drugs.

Expression of Cytoskeletal Proteins (GFAP, Vimentin), Proapoptotic Protein (Caspase-3) and Protective Protein (S100) in the Epileptic Focus in Adults and Children with Drug-Resistant Temporal Lobe Epilepsy Associated with Focal Cortical Dysplasia.

The European Commission of the International League Against Epilepsy (ILAE) has identified glial mechanisms of seizures and epileptogenesis as top research priorities. The aim of our study was to conduct a comparative analysis of the expression levels of cytoskeletal proteins (glial fibrillar acidic protein (GFAP) and vimentin), protective protein S100, and proapoptotic caspase-3 protein in patients with drug-resistant epilepsy (DRE) associated with focal cortical dysplasia (FCD). We aimed to investigate how the expression levels of these proteins depend on age (both in children and adults), gender, and disease duration, using immunohistochemistry.

Changes in the concentration of EGFR-mutated plasma DNA in the first hours of targeted therapy allow the prediction of tumor response in patients with EGFR-driven lung cancer.

Purpose: This study aimed to analyze changes in the plasma concentration of EGFR-mutated circulating tumor DNA (ctDNA) occurring immediately after the start of therapy with EGFR tyrosine kinase inhibitors (TKIs).

Methods: Serial plasma samples were collected from 30 patients with EGFR-driven non-small cell lung cancer before intake of the first tablet and at 0.5, 1, 2, 3, 6, 12, 24, 36 and 48 h after the start of the therapy.

Content of circulating tumor DNA depends on the tumor type and the dynamics of tumor size, but is not influenced significantly by physical exercise, time of the day or recent meal.

Purpose: This study aimed to investigate factors, which influence the content of circulating tumor DNA (ctDNA).

Methods: 398 serial plasma samples were collected within 1-7 consecutive days from patients with EGFR-mutated lung cancer (n = 13), RAS/RAF-mutated colorectal cancer (n = 54) and BRAF-mutated melanoma (n = 17), who presented with measurable tumor disease. The amount of ctDNA was determined by ddPCR.

Mitigating effect of paxilline against injury produced by Cd in rat pheochromocytoma PC12 and ascites hepatoma AS-30D cells.

On two rat cell lines, pheochromocytoma PC12 and ascites hepatoma AS-30D, and on rat liver mitochondria we studied action of paxilline (lipophilic mycotoxin from fungus Penicillium paxilli which is blocker of large-conductance potassium channels) against harmful effects of Cd(II) - one of the most dangerous toxic metals and environmental pollutants. We investigated an influence of paxilline on cell viability and mitochondrial function in the presence and in the absence of Cd. As found, paxilline protected partially from the Cd-induced cytotoxicity, namely taken in concentration of 1 μM it decreased the Cd-induced cell necrosis in average by 10-14 or 13-23% for AS-30D and PC12 cells, respectively.

The first crenarchaeon capable of growth by anaerobic carbon monoxide oxidation coupled with H production.

The ability to grow by anaerobic CO oxidation with production of H from water is known for some thermophilic bacteria, most of which belong to Firmicutes, as well as for a few hyperthermophilic Euryarchaeota isolated from deep-sea hydrothermal habitats. A hyperthermophilic, neutrophilic, anaerobic filamentous archaeon strain 1505=VKM B-3180=KCTC 15798 was isolated from a terrestrial hot spring in Kamchatka (Russia) in the presence of 30% CO in the gas phase. Strain 1505 could grow lithotrophically using carbon monoxide as the energy source with the production of hydrogen according to the equation CO+HO→CO+H; mixotrophically on CO plus glucose; and organotrophically on peptone, yeast extract, glucose, sucrose, or Avicel.

Genomic Insights Into Energy Metabolism of Coupling Hydrogenogenic CO Oxidation With the Reduction of Fe(III) Minerals.

The genus forms a deeply branching family in the class and is currently represented by three physiologically diverse species of thermophilic prokaryotes. The type strain of the type species, 41, is an obligate chemolithoautotroph growing exclusively by hydrogenogenic CO oxidation. Another strain, isolated from a hot spring at Uzon caldera, Kamchatka in the course of this work, is capable of coupling carboxydotrophy and dissimilatory reduction of Fe(III) from oxic and phyllosilicate minerals.

First-Line Cetuximab Monotherapy in KRAS/NRAS/BRAF Mutation-Negative Colorectal Cancer Patients.

Background: Colorectal carcinomas (CRCs) are sensitive to treatment by anti-epidermal growth factor receptor (EGFR) antibodies only if they do not carry activating mutations in down-stream EGFR targets (KRAS/NRAS/BRAF). Most clinical trials for chemo-naive CRC patients involved combination of targeted agents and chemotherapy, while single-agent cetuximab or panitumumab studies included either heavily pretreated patients or subjects who were not selected on the basis of molecular tests. We hypothesized that anti-EGFR therapy would have significant efficacy in chemo-naive patients with KRAS/NRAS/BRAF mutation-negative CRC.

Isolation and Characterization of the First Xylanolytic Hyperthermophilic Euryarchaeon Thermococcus sp. Strain 2319x1 and Its Unusual Multidomain Glycosidase.

Enzymes from (hyper)thermophiles "Thermozymes" offer a great potential for biotechnological applications. Thermophilic adaptation does not only provide stability toward high temperature but is also often accompanied by a higher resistance to other harsh physicochemical conditions, which are also frequently employed in industrial processes, such as the presence of, e.g.

Characterization of a family B DNA polymerase from Thermococcus barophilus Ch5 and its application for long and accurate PCR.

The family B DNA polymerase gene from the euryarchaeon Thermococcus barophilus Ch5 (Tba5) contains an open reading frame of 6198 base pairs that encodes 2065 amino acid residues. The gene is split by three inteins that must be spliced out to form the mature DNA polymerase. A Tba5 DNA polymerase gene without inteins (genetically intein-spliced) was expressed under the control of the pET-28b(+)T7lac promoter in E.

Complete Genome Sequence of the Hyperthermophilic and Piezophilic Archaeon Thermococcus barophilus Ch5, Capable of Growth at the Expense of Hydrogenogenesis from Carbon Monoxide and Formate.

We report here the complete sequence and fully manually curated annotation of the genome of strain Ch5, a new member of the piezophilic hyperthermophilic species Thermococcus barophilus.

GM1 and GD1a gangliosides modulate toxic and inflammatory effects of E. coli lipopolysaccharide by preventing TLR4 translocation into lipid rafts.

Exogenous gangliosides are known to inhibit the effects of Escherichia coli lipopolysaccharide (LPS) in different cells exhibiting anti-inflammatory and immunosuppressive activities. The mechanisms underlying ganglioside action are not fully understood. Because LPS recognition and receptor complex formation occur in lipid rafts, and gangliosides play a key role in their maintenance, we hypothesize that protective effects of exogenous gangliosides would depend on inhibition of LPS signaling via prevention of TLR4 translocation into lipid rafts.

GM1 ganglioside activates ERK1/2 and Akt downstream of Trk tyrosine kinase and protects PC12 cells against hydrogen peroxide toxicity.

Ganglioside GM1 at micro- and nanomolar concentrations was shown to increase the viability of pheochromocytoma PC12 cells exposed to hydrogen peroxide and diminish the accumulation of reactive oxygen species and oxidative inactivation of Na(+),K(+)-ATPase, the effects of micromolar GM1 being more pronounced than those of nanomolar GM1. These effects of GM1 were abolished by Trk receptor tyrosine kinase inhibitor and diminished by MEK1/2, phosphoinositide 3-kinase and protein kinase C inhibitors. Hydrogen peroxide activates Trk tyrosine kinase; Akt and ERK1/2 are activated downstream of this protein kinase.

Thermosipho activus sp. nov., a thermophilic, anaerobic, hydrolytic bacterium isolated from a deep-sea sample.

A novel obligately anaerobic, extremely thermophilic, organotrophic bacterium, strain Rift-s3(T), was isolated from a deep-sea sample containing Riftia pachyptila sheath from Guaymas Basin, Gulf of California. Cells of the novel isolate were rods, 0.3-0.

α-Tocopherol at nanomolar concentration protects PC12 cells from hydrogen peroxide-induced death and modulates protein kinase activities.

The aim of this work was to compare protective and anti-apoptotic effects of α-tocopherol at nanomolar and micromolar concentrations against 0.2 mM H(2)O(2)-induced toxicity in the PC12 neuronal cell line and to reveal protein kinases that contribute to α-tocopherol protective action. The protection by 100 nM α-tocopherol against H(2)O(2)-induced PC12 cell death was pronounced if the time of pre-incubation with α-tocopherol was 3-18 h.

Mitochondrial electron transport chain in heavy metal-induced neurotoxicity: effects of cadmium, mercury, and copper.

To clarify the role of mitochondrial electron transport chain (mtETC) in heavy-metal-induced neurotoxicity, we studied action of Cd(2+), Hg(2+), and Cu(2+) on cell viability, intracellular reactive oxygen species formation, respiratory function, and mitochondrial membrane potential of rat cell line PC12. As found, the metals produced, although in a different way, dose- and time-dependent changes of all these parameters. Importantly, Cd(2+) beginning from 10 [mu]M and already at short incubation time (3 h) significantly inhibited the FCCP-uncoupled cell respiration; besides, practically the complete inhibition of the respiration was reached after 3 h incubation with 50 [mu]M Hg(2+) or 500 [mu]M Cd(2+), whereas even after 48 h exposure with 500 [mu]M Cu(2+), only a 50% inhibition of the respiration occurred.

Evidence for horizontal gene transfer of anaerobic carbon monoxide dehydrogenases.

Carbon monoxide (CO) is commonly known as a toxic gas, yet both cultivation studies and emerging genome sequences of bacteria and archaea establish that CO is a widely utilized microbial growth substrate. In this study, we determined the prevalence of anaerobic carbon monoxide dehydrogenases ([Ni,Fe]-CODHs) in currently available genomic sequence databases. Currently, 185 out of 2887, or 6% of sequenced bacterial and archaeal genomes possess at least one gene encoding [Ni,Fe]-CODH, the key enzyme for anaerobic CO utilization.

Complete genome sequence of the hyperthermophilic archaeon Thermococcus sp. strain AM4, capable of organotrophic growth and growth at the expense of hydrogenogenic or sulfidogenic oxidation of carbon monoxide.

Analysis of the complete genome of Thermococcus sp. strain AM4, which was the first lithotrophic Thermococcales isolate described and the first archaeal isolate to exhibit a capacity for hydrogenogenic carboxydotrophy, reveals a proximity with Thermococcus gammatolerans, corresponding to close but distinct species that differ significantly in their lithotrophic capacities.

Anaerobic transformation of carbon monoxide by microbial communities of Kamchatka hot springs.

Carbon monoxide (CO) is one of the common gaseous compounds found in hot volcanic environments. It is known to serve as the growth substrate for a number of thermophilic prokaryotes, both aerobic and anaerobic. The goal of this work was to study the process of anaerobic transformation of CO by microbial communities inhabiting natural thermal environments: hot springs of Uzon Caldera, Kamchatka.

Carboxydothermus islandicus sp. nov., a thermophilic, hydrogenogenic, carboxydotrophic bacterium isolated from a hot spring.

An anaerobic, thermophilic bacterium, strain SET IS-9(T), was isolated from an Icelandic hot spring. Cells of strain SET IS-9(T) are short, slightly curved, motile rods. The strain grows chemolithotrophically on CO, producing equimolar quantities of H(2) and CO(2).

Formate-driven growth coupled with H(2) production.

Although a common reaction in anaerobic environments, the conversion of formate and water to bicarbonate and H(2) (with a change in Gibbs free energy of ΔG° = +1.3 kJ mol(-1)) has not been considered energetic enough to support growth of microorganisms. Recently, experimental evidence for growth on formate was reported for syntrophic communities of Moorella sp.

Protective and antioxidative effects of GM1 ganglioside in PC12 cells exposed to hydrogen peroxide are mediated by Trk tyrosine kinase.

GM1 ganglioside was found to increase the survival of PC12 cells exposed to H(2)O(2), its action was blocked by Trk tyrosine kinase inhibitor K-252a. Thus, the inhibition of H(2)O(2) cytotoxic action by GM1 constituted 52.8 +/- 4.

Diversity and ecophysiological features of thermophilic carboxydotrophic anaerobes.

Both natural and anthropogenic hot environments contain appreciable levels of carbon monoxide (CO). Anaerobic microbial communities play an important role in CO conversion in such environments. CO is involved in a number of redox reactions.

Carboxydothermus siderophilus sp. nov., a thermophilic, hydrogenogenic, carboxydotrophic, dissimilatory Fe(III)-reducing bacterium from a Kamchatka hot spring.

A novel anaerobic, thermophilic, Fe(III)-reducing, CO-utilizing bacterium, strain 1315(T), was isolated from a hot spring of Geyser Valley on the Kamchatka Peninsula. Cells of the new isolate were Gram-positive, short rods. Growth was observed at 52-70 degrees C, with an optimum at 65 degrees C, and at pH 5.