Variants in estrogen-biosynthesis genes CYP17 and CYP19 and breast cancer risk: a family-based genetic association study

BACKGROUND: Case-control studies have reported inconsistent results concerning breast cancer risk and polymorphisms in genes that control endogenous estrogen biosynthesis. We report findings from the first family-based association study examining associations between female breast cancer risk and polymorphisms in two key estrogen-biosynthesis genes CYP17 (T→C promoter polymorphism) and CYP19 (TTTA repeat polymorphism). METHODS: We conducted the study among 278 nuclear families containing one or more daughters with breast cancer, with a total of 1123 family members (702 with available constitutional DNA and questionnaire data and 421 without them). These nuclear families were selected from breast cancer families participating in the Metropolitan New York Registry, one of the six centers of the National Cancer Institute's Breast Cancer Family Registry. We used likelihood-based statistical methods to examine allelic associations. RESULTS: We found the CYP19 allele with 11 TTTA repeats to be associated with breast cancer risk in these families. We also found that maternal (but not paternal) carrier status of CYP19 alleles with 11 repeats tended to be associated with breast cancer risk in daughters (independently of the daughters' own genotype), suggesting a possible in utero effect of CYP19. We found no association of a woman's breast cancer risk either with her own or with her mother's CYP17 genotype. CONCLUSION: This family-based study indicates that a woman's personal and maternal carrier status of CYP19 11 TTTA repeat allele might be related to increased breast cancer risk. However, because this is the first study to report an association between CYP19 11 TTTA repeat allele and breast cancer, and because multiple comparisons have been made, the associations should be interpreted with caution and need confirmation in future family-based studies

The effects of an additive on the release of potassium in biomass combustion

This study focuses on the effects of an aluminosilicate additive on the fate of potassium during biomass combustion. Such additives have shown some success in mitigating slagging and fouling problems in boilers and furnaces, and the mobility of potassium in combustion systems is one of the key factors dictating ash behaviour. To investigate this, a flame emission spectroscopy technique was used to evaluate the differences in the gas-phase potassium release profiles during the combustion of 5 mm diameter pellets of different biomass suspended in a methane-air flame. The biomass pellets were evaluated with various mixes of an aluminosilicate based additive (5, 15 and 25 wt%). Potassium emission detection, coupled with high speed video of the combustion process, indicated that potassium evolves over the three stages of volatile combustion (a sharp peak in the emission profile), char combustion (a broader peak) and “ash cooking” (a very broad peak over an extended period, long after the end of combustion). In the absence of additive, the three biomass studied (softwood, wheat straw, olive residue) behaved quite differently in terms of potassium release profiles. When the results are normalized for the amount of potassium in the fuel, it is clear that a large fraction of potassium enters the gas phase during the volatile and char combustion of the softwood. Olive residue, releases a lower fraction of potassium during the volatile and char combustion stages, indicating that more potassium is fixed in the ash. In contrast, wheat straw shows a release of potassium during combustion, and then, after a period of “ash cooking”, a substantial gradual release with continued exposure to hot combustion gases. The difference in the emission profiles can be interpreted in terms of the K:Cl ratios and the K:(Si+Al) ratios: high chlorine and/or low (Si+Al) facilitates the release of KCl or KOH to the gas phase, while high (Si+Al) helps to fix K in the solid phase. The addition of the aluminosilicate additive shows a clear reduction in the potassium released from all the biomass pellets, particularly during the char-oxidation and “ash cooking” stages, and the level of additive required is related to the amount of K in the biomass. The potassium emission experiments were complemented by laboratory-scale preparation of ash at different temperatures, and detection of residual potassium in the ash using Atomic Absorption Spectroscopy (AAS). These results validated the findings and quantified the higher fractions of potassium retained within the ash when additives are used. For the wood ash 70-100% of K is retained in the ash in the presence of additive; for the wheat straw, this figure is 60-80% and for the olive pellets it is 70-100%

Gas phase potassium release from a single particle of biomass during high temperature combustion

A notable characteristic of solid biomass fuels as compared to coal is their significantly higher potassium content. Potassium influences ash deposition and corrosion mechanisms in furnaces and boilers, the effects of which may differ depending on phase transformations of potassium species in the gas phase and condensed phase. An understanding of how potassium is released from biomass fuels during the combustion process is therefore useful for plant designers and operators assessing means of avoiding or mitigating these potential problems. An experimental method is used to measure release patterns from single particles of biomass fuels using flame emission spectroscopy and a single-particle combustion rig. The experimental arrangement also allowed simultaneous thermal imaging of the combusting particle in order to determine the surface temperature. A model of the single particle combustion is presented. Using experimental data on devolatilisation and burnout times for different sized particles and the measured surface temperature profiles, the thermal and kinetic sub-models are verified. A model for potassium release is described and this is integrated to the single particle combustion model to allow prediction of the temporal patterns of release of gas-phase potassium. The modelled release patterns were compared with those observed. Good agreement between modelled and measured potassium release patterns was attained confirming that the proposed mechanisms affecting potassium release are valid

HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes

Histone deacetylases (HDACs) regulate the acetylation of histones in the control of gene expression. Many non-histone proteins are also targeted for acetylation, including TGF-ß signalling pathway components such as Smad2, Smad3 and Smad7. Our studies in mouse C3H10T1/2 fibroblasts suggested that a number of TGF-ß-induced genes that regulate matrix turnover are selectively regulated by HDACs. Blockade of HDAC activity with trichostatin A (TSA) abrogated the induction of a disintegrin and metalloproteinase 12 (Adam12) and tissue inhibitor of metalloproteinases-1 (Timp-1) genes by TGF-ß, whereas plasminogen activator inhibitor-1 (Pai-1) expression was unaffected. Analysis of the activation of cell signalling pathways demonstrated that TGF-ß induced robust ERK and PI3K activation with delayed kinetics compared to the phosphorylation of Smads. The TGF-ß induction of Adam12 and Timp-1 was dependent on such non-Smad signalling pathways and, importantly, HDAC inhibitors completely blocked their activation without affecting Smad signalling. Analysis of TGF-ß-induced Adam12 and Timp-1 expression and ERK/PI3K signalling in the presence of semi-selective HDAC inhibitors valproic acid, MS-275 and apicidin implicated a role for class I HDACs. Furthermore, depletion of HDAC3 by RNA interference significantly down-regulated TGF-ß-induced Adam12 and Timp-1 expression without modulating Pai-1 expression. Correlating with the effect of HDAC inhibitors, depletion of HDAC3 also blocked the activation of ERK and PI3K by TGF-ß. Collectively, these data confirm that HDACs, and in particular HDAC3, are required for activation of the ERK and PI3K signalling pathways by TGF-ß and for the subsequent gene induction dependent on these signalling pathways

Prediction of Occupational Fluorosis in Aluminum Production Workers in View of Comorbidities

Introduction: Modern research on occupational medicine has shown that general diseases contribute the most to health deterioration in workers of hazardous industries and significantly affect the timing of the onset of occupational diseases. Objective: To assess the impact of comorbid disorders on the probability of occupational fluoride toxicity in aluminum production workers. Materials and methods: The paper describes existing international scales used to assess comorbid disorders and emphasizes the relevance of publications on the comorbidity of workers of hazardous and harmful industries. The comorbidity index was calculated for each of 201 aluminum production workers. Comorbidity index calculations, health indicators, and parameters of working conditions were entered in the electronic database. The article presents a method for determining the probability of occupational disease development using a logistic regression. Results: A prognostic model was built using a logistic regression and comorbidity indices to determine the influence of human body systems on the probability of developing occupational fluoride poisoning (fluorosis). Conclusion: Using the logistic regression, we have determined combinations of comorbidity indices having a strongest effect on the probability of fluoride poisoning for prediction and implementation of appropriate preventive measures. To reduce the likelihood of occupational diseases, it is necessary to treat comorbid disorders in workers of harmful industries. © 2023, Federal Center for Hygiene and Epidemiology. All rights reserved

Short-term results of cardiac rehabilitation of coronary artery bypass graft patients using cardio-pulmonary exercise stress test

The paper presents an evaluation of short-term results of medical rehabilitation of patients treated by surgical myocardial revascularization. The rehabilitation programme has been carried out in a specialized rehabilitation facility. In addition to medication, the programme includes exercise therapy and physiotherapy. In response to rehabilitation treatment, the patients have exhibited higher exercise performance, improved respiratory function, myocardial electrical stability and lower functional class of angina. As a result of the treatment, the existing postinfarction cardiosclerosis has not affected the improved results oftreadmill-stresstest.В работе представлена оценка непосредственных результатов восстановительного лечения пациентов, перенесших хирургическую реваскуляризацию сердца. Реабилитационная программа осуществлялась в специализированном реабилитационном отделении и включала не только медикаментозную терапию, но и процедуры лечебной физкультуры и физиотерапевтические воздействия. У пациентов удалось увеличить физическую работоспособность, электрическую стабильность миокарда, достичь снижение класса стенокардии, улучшить показатели функции внешнего дыхания. Наличие постинфарктного кардиосклероза не влияло на улучшение результатов теста с дозированной физической нагрузкой в результате лечения

Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation

<p>Abstract</p> <p>Background</p> <p>The anti-epileptic drug valproic acid (VPA) has attracted attention as an anti-cancer agent.</p> <p>Methods</p> <p>The present study investigated effects of VPA exposure on histone deacetylase (HDAC) inhibition, cell growth, cell speed, and the degree of Erk1/2 phosphorylation in 10 cell lines (BT4C, BT4Cn, U87MG, N2a, PC12-E2, CSML0, CSML100, HeLa, L929, Swiss 3T3).</p> <p>Results</p> <p>VPA induced significant histone deacetylase (HDAC) inhibition in most of the cell lines, but the degree of inhibition was highly cell type-specific. Moreover, cell growth, motility and the degree of Erk1/2 phosphorylation were inhibited, activated, or unaffected by VPA in a cell type-specific manner. Importantly, no relationship was found between the effects of VPA on HDAC inhibition and changes in the degree of Erk1/2 phosphorylation, cell growth, or motility. In contrast, VPA-induced modulation of the MAPK pathway downstream of Ras but upstream of MEK (i.e., at the level of Raf) was important for changes in cell speed.</p> <p>Conclusions</p> <p>These results suggest that VPA can modulate the degree of Erk1/2 phosphorylation in a manner unrelated to HDAC inhibition and emphasize that changes in the degree of Erk1/2 phosphorylation are also important for the anti-cancer properties of VPA.</p

Effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line

<p>Abstract</p> <p>Background</p> <p>Management of peritoneal dissemination is the most critical problem in gastric cancer. This study was performed to investigate the inhibitory effects of valproic acid (VPA) on a highly peritoneal-seeding cell line of human scirrhous gastric cancer, OCUM-2MD3, and to explore the mechanism and the potential of VPA.</p> <p>Methods</p> <p>The effects of VPA on the growth of OCUM-2MD3 cells were assessed by MTT assay. In addition, paclitaxel (PTX) was combined with VPA to evaluate their synergistic effects. HDAC1 and HDAC2 expression were evaluated by western blotting in OCUM-2MD3 cells and other gastric cancer cell lines (TMK-1, MKN-28). The acetylation status of histone H3 and α-tubulin after exposure to VPA were analyzed by western blotting. The activities of cell cycle regulatory proteins and apoptosis-modulating proteins were also examined by western blotting. The effects of VPA <it>in vivo </it>were evaluated in a xenograft model, and apoptotic activity was assessed by TUNEL assay.</p> <p>Results</p> <p>OCUM-2MD3 cells showed high levels of HDAC1 and HDAC2 expression compared with TMK-1 and MKN-28. The concentration of VPA required for significant inhibition of cell viability (<it>P </it>< 0.05) was 5 mM at 24 h and 0.5 mM at 48 h and 72 h. The inhibition of VPA with PTX showed dose-dependent and combinatorial effects. VPA increased acetyl-histone H3, acetyl-α-tubulin, and p21WAF1 levels accompanied by upregulation of p27, caspase 3, and caspase 9, and downregulation of bcl-2, cyclin D1, and survivin. In the xenograft model experiment, the mean tumor volume of the VPA-treated group was significantly reduced by 36.4%, compared with that of the control group at 4 weeks after treatment (<it>P </it>< 0.01). The apoptotic index was significantly higher in the VPA-treated group (42.3% ± 3.5%) than in the control group (7.7% ± 2.5%) (<it>P </it>< 0.001).</p> <p>Conclusions</p> <p>VPA induced dynamic modulation of histone H3 and α-tubulin acetylation in relation with the anticancer effect and the enhancement of PTX in the OCUM-2MD3 cell line. Therefore, VPA in combination with PTX is expected to be a promising therapy for peritoneal dissemination of scirrhous gastric cancer.</p