Epigenetically-targeted therapies for the treatment of hematological malignancies

Epigenetic modifications, which are heritable changes in gene expression not involving DNA sequence alterations, are important early events in the multi -step process of tumorigenesis. Among them, DNA methylation and histone acetylation are the most extensively studied. Although they are, by definition, somatically heritable, epigenetic modifications of DNA and histones are also reversible. This characteristic difference from genetic alterations makes them interesting targets for therapeutic intervention. The huge amount of knowledge gathered in the field of epigenetics the last decade, was followed by the development of novel therapies: old drugs finding new identity and new targets and an increasing list of novel compounds for the treatment of malignant diseases. Hematological malignancies offer a broad spectrum of diseases where epigenetic therapies are shown to be active, providing encouraging results. Some of the more recent reports on this field of therapeutic interventions are reviewed below.     

FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation

The recently described DNA replication-based mechanisms of fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR) were previously shown to catalyze complex exonic, genic and genomic rearrangements. By analyzing a large number of isochromosomes of the long arm of chromosome X (i(Xq)), using whole-genome tiling path array comparative genomic hybridization (aCGH), ultra-high resolution targeted aCGH and sequencing, we provide evidence that the FoSTeS and MMBIR mechanisms can generate large-scale gross chromosomal rearrangements leading to the deletion and duplication of entire chromosome arms, thus suggesting an important role for DNA replication-based mechanisms in both the development of genomic disorders and cancer. Furthermore, we elucidate the mechanisms of dicentric i(Xq) (idic(Xq)) formation and show that most idic(Xq) chromosomes result from non-allelic homologous recombination between palindromic low copy repeats and highly homologous palindromic LINE elements. We also show that non-recurrent-breakpoint idic(Xq) chromosomes have microhomology-associated breakpoint junctions and are likely catalyzed by microhomology-mediated replication-dependent recombination mechanisms such as FoSTeS and MMBIR. Finally, we stress the role of the proximal Xp region as a chromosomal rearrangement hotspot.     

Computerized Provider Order Entry—What are health professionals concerned about? A qualitative study in an Australian hospital

Purpose

To identify the main concerns of a broad range of hospital staff about the implementation of a new Computerized Provider Order Entry (CPOE) system for medication management.

Methods

The study was conducted in a large Australian teaching hospital using semi-structured interviews (n = 20) and focus groups (six focus groups involving a total of 30 participants) from a broad section of health professionals including doctors, nurses, managers, pharmacists and senior health executives. Systematic concurrent analysis of the data was undertaken by a team of researchers.

Results

We identified 20 recurrent themes related to nine areas of shared concern including work practices, software/hardware, relationships/communication, education and training, inexperienced staff and de-skilling. A higher level of analysis identified four interrelated constructs that highlight what people are concerned about: (1) Will it help? (2) Will it work? (3) Will we cope? (4) Will it impair existing interaction?

Limitations

The research provides a snapshot overview of perceptions from a range of hospital personnel in the lead up to CPOE implementation. Generalizability is limited by the size of the sample and the contextual circumstances of the hospital being studied.

Discussion

This work contributes valuable evidence about an often-neglected dimension in the evaluation of computer systems in hospitals, namely the pre-implementation concerns of staff. These pre-conceptions can have a significant effect on how technology is implemented and utilised. Acknowledging and addressing people's concerns can contribute to the establishment of durable channels of negotiation and communication. Further research informed by the findings of this study will help advance this process.     

Optimizing Outcomes in the Jehovah’s Witness Following Trauma: Special Management Concerns for a Unique Population

Abstract Background:   The objective of this study was to describe the management of the Jehovah’s Witness (JW) in an intensely active level I trauma center and review the modern therapeutic options available for the trauma care of these patients. Study design:   A retrospective review of injured JWs admitted to a busy trauma center over a 13-year period was conducted. Results:   Over the study period, 143 JWs were identified. Among these, 15.4% (22/143) overall and 32.3% (10/31) requiring surgical intensive care unit (SICU) admission accepted transfusion. Overall, 56.6% of JWs (81/143) required operation and 21.7% (31/143) were admitted to the SICU with a complication rate of 4.2% (6/143) and a mortality of 1.4% (2/143). One patient of the 31 patients that were admitted to the SICU received 10 ml of blood with subsequent discontinuation of the transfusion and was excluded from analysis. Of the 30 JWs admitted to the SICU, 20 (66.7%) did not receive transfusion and demonstrated mean admission and nadir hemoglobin (Hb) levels of 12.7 (±2.5) and 9.1 (±3.0) mg/dl, respectively. Ten patients accepted transfusion. This group had longer mean SICU stays (23.3 vs. 5.5 days) but similar mortality (10%, 1/10 vs. 5%, 1/20) compared to non-transfused counterparts. Only one complication (1/20, 5%) was observed in the JWs who were not transfused, compared to a 40% (4/10) complication rate in those accepting transfusion. Conclusion:   Although our experience was limited, we found no significant difference in the mortality or morbidity between JW patients who received or abstained from transfusion following major trauma. We should keep in mind that the population was small, in order to extract safe conclusions regarding whether we should transfuse or not transfuse trauma patients. We can, however, see interesting insights on the value of trauma resuscitation.     

Severity of cardiovascular disease in postmenopausal women: associations with common estrogen receptor alpha polymorphic variants

OBJECTIVE: Impaired estrogen action is a risk factor for coronary artery disease (CAD). Associations of CAD with estrogen receptor alpha (ER alpha) polymorphisms, which may influence sensitivity to estrogen, have been reported for men; the data concerning women are not conclusive. We investigated the association of common ER alpha polymorphisms with the severity of CAD and with metabolic and reproductive factors in postmenopausal women undergoing coronary angiography. METHODS: ER alpha polymorphisms at positions c.454-397 T>C (PvuII) and c.454-351 A>G (XbaI) were studied in 157 women (age 45-88 years). The severity of CAD was assessed by the number of arteries with >50% stenosis in the angiography. RESULTS: There was a significant association between the TT, TC, and CC genotypes (PvuII) and the severity of CAD (P=0.008); similar results were obtained for the XbaI polymorphism (P=0.021). These associations were independent of other risk factors for CAD. Women homozygous for the C allele had significantly higher triglyceride and insulin levels; they belonged more frequently to the group with a low number of births (n相似文献   

Is chromosome radiosensitivity and apoptotic response to irradiation correlated with cancer susceptibility?

PURPOSE: Individuals who have been treated for breast cancer have been reported to have increased lymphocyte chromosomal sensitivity to ionizing radiation and a significantly lower apoptotic response to irradiation compared to controls. We set out to test these findings using a substantial number of cases sampled before treatment (which could alter the parameters measured), compared to age-matched controls with normal mammograms. MATERIAL AND METHODS: We used the G2 chromosome breakage, and apoptotic response assays of peripheral blood lymphocytes to ionizing radiation to compare 211 unselected newly diagnosed and untreated breast cancer patients, with 170 age, sex and ethnically matched controls. RESULTS: We found no significant differences between breast cancer patients and their matched controls in the G2 assay or apoptotic response. However, there was some evidence that both cases and controls with a strong family history of breast cancer had higher radiosensitivity than those without. CONCLUSIONS: This is the largest and best controlled study of its kind, but it has not replicated previous reports of differences between chromosome breakage or apoptotic response in breast cancer cases vs. controls. However there was a suggestion of increased radiosensitivity in patients with a strong family history, which may indicate a heritable cancer susceptibility trait, warranting further study.     

Effects of phosphodiesterase-5 inhibitors on sperm parameters and fertilizing capacity

The aim of this review study is to elucidate the effects that phosphodiesterase 5 （PDE5） inhibitors exert on spermatozoa motility, capacitation process and on their ability to fertilize the oocyte. Second messenger systems such as the cAMP/adenylate cyclase （AC） system and the cGMP/guanylate cyclase （GC） system appear to regulate sperm functions. Increased levels of intracytosolic cAMP result in an enhancement of sperm motility and viability. The stimulation of GC by low doses of nitric oxide （NO） leads to an improvement or maintenance of sperm motility, whereas higher concentrations have an adverse effect on sperm parameters. Several in vivo and in vitro studies have been carried out in order to examine whether PDE5 inhibitors affect positively or negatively sperm parameters and sperm fertilizing capacity. The results of these studies are controversial. Some of these studies demonstrate no significant effects of PDE5 inhibitors on the motility, viability, and morphology of spermatozoa collected from men that have been treated with PDE5 inhibitors. On the other hand, several studies demonstrate a positive effect of PDE5 inhibitors on sperm motility both in vivo and in vitro. In vitro studies of sildenafil citrate demonstrate a stimulatory effect on sperm motility with an increase in intracellular cAMP suggesting an inhibitory action of sildenafil citrate on a PDE isoform other than the PDE5. On the other hand, tadalafil＇s actions appear to be associated with the inhibitory effect of this compound on PDE11. In vivo studies in men treated with vardenafil in a daily basis demonstrated a significantly larger total number of spermatozoa per ejaculate, quantitative sperm motility, and qualitative sperm motility; it has been suggested that vardenafil administration enhances the secretory function of the prostate and subsequently increases the qualitative and quantitative motility of spermatozoa. The effect that PDE5 inhibitors exert on sperm parameters may lead to the improvement of the outcome of assi     

Multiple sclerosis, cannabinoids, and cognition

There is increasing interest in the therapeutic potential of cannabis-based medicinal extracts in multiple sclerosis. Cognitive deficits that have been attributed to long-term heavy recreational use of cannabis are not necessarily extended to controlled pharmaceutical use of cannabis-based medicinal extracts. Available data indicate that after relatively short-term administration of cannabis-based medicinal extracts no significant cognitive decline occurs. Due to the absence of large scale long-term systematic clinical trials of cannabis-based medicinal extracts in multiple sclerosis therapeutics, however, many issues remain unresolved, including the possible adverse effects of cannabis-based medicinal extracts on cognition. This article critically reviews the current literature and considers the potential for cognitive adverse effects of long-term cannabinoid use in multiple sclerosis therapeutics.