Inhibition of histone demethylase,LSD2 (KDM1B), attenuates DNA methylation and increases sensitivity to DNMT inhibitor-induced apoptosis in breast cancer cells

Increasing evidence suggests that dysfunction of histone lysine demethylase is associated with abnormal chromatin remodeling and gene silencing, contributing to breast tumorigenesis. In silico analysis shows that the newly identified histone demethylase lysine-specific demethylase 2 is highly expressed in breast cancer, especially in invasive tumors. However, it is currently unknown how LSD2 regulates chromatin remodeling and gene expression regulation in breast cancer. Using short hairpin RNA, we stably knocked down LSD2 (LSD2-KD) in MDA-MB-231 breast cancer cells. LSD2-KD led to accumulation of H3K4me1/2 without changing methylation levels of other key histone lysine residues, suggesting that LSD2 acts as a bona fide H3K4 demethylase in breast cancer cells. LSD2-KD resulted in decreased colony formation and attenuated global DNA methylation in MDA-MB-231 cells. Additionally, treatment with the DNMT inhibitor, 5-aza-deoxycytidine (DAC), synergistically increased mRNA expression of aberrantly silenced genes important in breast cancer development, including PR, RARβ, ERα, SFRP1, SFRP2, and E-cadherin in LSD2-KD cells. Furthermore, LSD2-KD cells are more susceptible to cell death than scramble controls, and combined treatment with tranylcypromine, an LSD2 inhibitor, and DAC resulted in synergistic growth inhibition of breast cancer cells. DNMT inhibition by DAC in LSD2-KD cells led to internucleosomal DNA fragmentation, enhanced PARP cleavage and increased sub-G1 apoptotic cell population. These results demonstrate an important role for LSD2 in regulation of DNA methylation and gene silencing in breast cancer, and suggest that inhibition of LSD2 in combination with DNA methyltransferase inhibition represents a novel approach for epigenetic therapy of breast cancer.     

The course of depression and anxiety in patients undergoing disc surgery: a longitudinal observational study

ObjectiveThis study examines longitudinal depression and anxiety rates in disc surgery patients in comparison to the general population, the change and associated determinants of depression and anxiety over time.MethodsThe longitudinal observational study refers to 305 consecutive disc surgery patients (age range: 18–55 years). Depression and anxiety was assessed with the Hospital Anxiety and Depression Scale. Random effects regression models for unbalanced panel data were used.ResultsDepression and anxiety decreases significantly during nine months after surgery. Depression rates vary between 23.6% (T0), 9.6% (T1) and 13.1% (T2). Only at T0 the depression rate differs significantly from the general population. Anxiety rates range between 23.7% (T0), 10.9% (T1) and 11.1% (T2). Compared to the general population anxiety rates are significantly higher at all three assessment points. Risk factors for anxiety or depression at the time of the surgery are psychiatric comorbidity before surgery, higher age, female gender, lower educational level, lower physical health status and higher pain intensity. Regarding depression and anxiety in the course of time significant time interactions were found for the existence of other chronic diseases, higher pain intensity and vocational dissatisfaction.ConclusionsCompared to the general population patients undergoing herniated disc surgery are often affected by depression and anxiety during hospital treatment and also in the course of time. Multimodal diagnostics regarding psychological well-being, pain and physical health status may help to identify this risk group. The assistance by mental health professionals during hospital and rehabilitation treatment may reduce poor postoperative outcome.     

Influence of intrahepatic vessels on volume and shape of percutaneous thermal ablation zones: in vivo evaluation in a porcine model

OBJECTIVES: Aim of the study was to evaluate the precise influence of different intrahepatic vessels, vessel sizes, and distances from the applicator on volume and shape of hepatic laser ablation zones in an in vivo porcine model. MATERIALS AND METHODS: The study was approved by the institutional animal care and use committee. Eighteen computed tomography-guided Nd:YAG laser ablations were performed in the livers of 10 pigs at varying distances from hepatic veins and portal fields. After hepatectomy the livers were cut into 2-mm slices perpendicular to the laser applicator axes. For each ablation zone the maximum achievable (ideal) volume, the segmented (real) volume, the maximum radius, and the radius at the position of adjacent hepatic vessels were determined. The shapes of the ablation zones were evaluated qualitatively. Comparative statistics using the unpaired t test and a multiple linear regression analysis were performed. RESULTS: Ideal and real ablation zone volumes differed by 27.3% (8.6 +/- 1.5 mL vs. 6.4 +/- 1.1 mL; P < 0.0001). Thirty-eight of 60 (63%) hepatic veins versus 28 of 31 (90%) portal veins within the central slices of the 18 ablation zones led to a reduction of the ablation zone's radius, depending on the distance between the vessel and the applicator and the vessel type. Portal fields revealed stronger effects than hepatic veins. The vessel diameter showed no independent effect (P > 0.05). When influencing, all hepatic veins showed a focal indentation whereas portal fields always showed broad flattening of the ablation zone. CONCLUSIONS: Portal fields lead to more heat sink than hepatic veins. The effects decreased with the distance between vessel and applicator tip, but less so for portal fields. The 2 vessel types induced considerably different shape alterations of the ablation zones. These results were not dependent on vessel size. This should be considered in the planning of thermal tumor ablations.     

How do visual,spectroscopic and biomechanical changes of cartilage correlate in osteoarthritic knee joints?

Background

Characteristic changes in cartilage of human knee joints with different degrees of osteoarthritis (OA) have been investigated by visual, biophotonical and biomechanical examination. Knowledge about the cartilage composition and changes during the development of OA is important for diagnostic decisions and understanding the pathogenesis of OA.

Methods

Thirty two patients with severe knee OA received endoprosthetic replacement. During surgical intervention cartilage specimen were harvested from defined surface areas of the joints. The degree of cartilage defects was classified visually (ICRS Grade: International Cartilage Repair Society), biophotonically (NIRS: near infrared spectroscopy) and biomechanically (Young’s Modulus). To characterise links between the investigated parameters the Spearman’s rank correlation coefficient was used.

Findings

Significant negative correlations were found between visual macroscopic degree of degeneration (ICRS Grade) and biophotonic characteristics (NIRS) (ρ = −0.467) or cartilage stiffness (Young’s Modulus) (ρ = −0.501). Between NIRS and Young’s Modulus significant positive correlation of ρ = 0.535 was detected.

Interpretation

Visual, biophotonic and biomechanical properties of cartilage reveal strong correlations in all degrees of cartilage defects in patients with severe OA. According to these results, we indicate that an objective, non-invasive and non-destructive measurement of cartilage properties during open and arthroscopic knee surgery is possible by NIRS and provide a novel tool to evaluate disease intervention and treatment.     

The role of single nucleotide polymorphisms in breast cancer metastasis

Our understanding of many aspects of cancer biology has been advanced through the use of modern genetics. These studies have already shown that germ line polymorphisms play a significant role in disease initiation and response to therapy. However, what is less well studied is the role of germ line polymorphisms in cancer progression. Studies in rodents indicate that differential susceptibility to cancer metastasis can be heritable; thus, the search for the genes that control cancer metastasis is underway. Although some provocative studies suggest potential candidates for metastasis regulating genes, the conclusive identification of a specific inherited genetic variant that alters metastatic potential awaits further studies.     

A Miniprep DNA Verifiable Method from Denatured Samples for DNA Barcoding and Sequencing Applications

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Exploration on DNA-based investigations is frequently obscured by being constrained to work in suboptimal...     

Coordination of Noble Metals in Poly(vinyl mercaptoethanol) Particles Prepared by Precipitation/Emulsion Polymerization

S-Vinyl monomers react readily in radical polymerizations resulting in polymers with interesting features such as enhanced refractive indices, increased thermal stability, or the ability to coordinate various metals. Among them, vinyl mercaptoethanol (VME) can be produced in industrial scale, but the poor solubility of the resulting homopolymer limits its application. In this contribution, polymerizations of the monomer are investigated in water forming a heterogeneous system. The good solubility of the monomer in water imparts the system with mixed characteristics between a precipitation and an emulsion polymerization. Evaluating various surfactants, only polyvinyl alcohol (PVA) is found to create stable dispersions, although micrometer-sized particles are formed with a broad size distribution. Nevertheless, the particles are able to coordinate silver or gold ions. Attempts to reduce the noble metal ions by commercial reducing agents fail. However, exposure to sunlight unexpectedly results in a controlled reduction of the metal ions and the formation of composite particles. Silver ion-containing dispersions demonstrate strong antibacterial properties, while the effect is diminished in the corresponding composite. Overall, the precipitation/emulsion polymerization of VME represents a promising pathway to stable sulfur-rich polymer dispersions with the ability to coordinate metal ions or form reactive metal composites.     

Compression of cognitive morbidity by higher education in individuals aged 75+ living in Germany

Background

Previous studies have shown that higher education may reduce dementia risk and promote a better cognitive functioning in older age.

Objective

The study investigated to what extent higher education leads to compression of cognitive morbidity, and thus a shorter lifetime affected by cognitive impairment and dementia, in individuals aged 75 years and older living in Germany.

Methods

Our sample included n = 742 individuals of the population‐based Leipzig Longitudinal Study of the Aged (LEILA75+; 1998‐2013), who were free of dementia at baseline. The impact of higher education on compression of cognitive morbidity was studied by analyzing the association between education and (1) cognitive functioning over the study period and age at dementia onset, (2) age at death, and (3) the cumulative lifetime cognitive morbidity.

Results

Individuals with more years of education had a higher cumulative cognitive functioning over the lifetime period 75 to 100 years (weighted for survival probability), but not a later age of dementia onset nor a later age at death.

Conclusion

Our results suggest, in individuals aged 75 years and older, higher education only compresses cognitive morbidity prior to dementia onset. Findings may be specific to countries where education is not a necessary requirement for access to good quality health care services.