Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Intrinsic Thermal Sensing Controls Proteolysis of Yersinia Virulence Regulator RovA

Pathogens, which alternate between environmental reservoirs and a mammalian host, frequently use thermal sensing devices to adjust virulence gene expression. Here, we identify the Yersinia virulence regulator RovA as a protein thermometer. Thermal shifts encountered upon host entry lead to a reversible conformational change of the autoactivator, which reduces its DNA-binding functions and renders it more susceptible for proteolysis. Cooperative binding of RovA to its target promoters is significantly reduced at 37°C, indicating that temperature control of rovA transcription is primarily based on the autoregulatory loop. Thermally induced reduction of DNA-binding is accompanied by an enhanced degradation of RovA, primarily by the Lon protease. This process is also subject to growth phase control. Studies with modified/chimeric RovA proteins indicate that amino acid residues in the vicinity of the central DNA-binding domain are important for proteolytic susceptibility. Our results establish RovA as an intrinsic temperature-sensing protein in which thermally induced conformational changes interfere with DNA-binding capacity, and secondarily render RovA susceptible to proteolytic degradation

Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy

Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The most common mechanisms of epigenetic regulation are the methylation of CpG islands within the DNA and the modification of amino acids in the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its progression may not occur only due to genetic mutations but also because of changes in the patterns of epigenetic modifications. In contrast to genetic mutations, which are almost impossible to reverse, epigenetic changes are potentially reversible. This implies that they are amenable to pharmacological interventions. Therefore, a lot of work in recent years has focussed on the development of small molecule enzyme inhibitors like DNA-methyltransferase inhibitors or inhibitors of histone-modifying enzymes. These may reverse misregulated epigenetic states and be implemented in the treatment of cancer or other diseases, e.g., neurological disorders. Today, several epigenetic drugs are already approved by the FDA and the EMEA for cancer treatment and around ten histone deacetylase (HDAC) inhibitors are in clinical development. This review will give an update on recent clinical trials of the HDAC inhibitors used systemically that were reported in 2009 and 2010 and will present an overview of different biomarkers to monitor the biological effects

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Association of peripartum management and high maternal blood loss at cesarean delivery for placenta accreta spectrum (PAS): A multinational database study

INTRODUCTION: Placenta accreta spectrum (PAS) carries a high burden of adverse maternal outcomes, especially significant blood loss, which can be life-threatening. Different management strategies have been proposed but the association of clinical risk factors and surgical management options during cesarean delivery with high blood loss is not clear. MATERIAL AND METHODS: In this international multicenter study, 338 women with PAS undergoing cesarean delivery were included. Fourteen European and one non-European center (USA) provided cases treated retrospectively between 2008 and 2014 and prospectively from 2014 to 2019. Peripartum blood loss was estimated visually and/or by weighing and measuring of volume. Participants were grouped based on blood loss above or below the 75th percentile (>3500 ml) and the 90th percentile (>5500 ml). RESULTS: Placenta percreta was found in 58% of cases. Median blood loss was 2000 ml (range: 150-20 000 ml). Unplanned hysterectomy was associated with an increased risk of blood loss >3500 ml when compared with planned hysterectomy (adjusted OR [aOR] 3.7 [1.5-9.4], p = 0.01). Focal resection was associated with blood loss comparable to that of planned hysterectomy (crude OR 0.7 [0.2-2.1], p = 0.49). Blood loss >3500 ml was less common in patients undergoing successful conservative management (placenta left in situ, aOR 0.1 [0.0-0.6], p = 0.02) but was more common in patients who required delayed hysterectomy (aOR 6.5 [1.7-24.4], p = 0.001). Arterial occlusion methods (uterine or iliac artery ligation, embolization or intravascular balloons), application of uterotonic medication or tranexamic acid showed no significant effect on blood loss >3500 ml. Patients delivered by surgeons without experience in PAS were more likely to experience blood loss >3500 ml (aOR 3.0 [1.4-6.4], p = 0.01). CONCLUSIONS: In pregnant women with PAS, the likelihood of blood loss >3500 ml was reduced in planned vs unplanned cesarean delivery, and when the surgery was performed by a specialist experienced in the management of PAS. This reinforces the necessity of delivery by an expert team. Conservative management was also associated with less blood loss, but only if successful. Therefore, careful patient selection is of great importance. Our study showed no consistent benefit of other adjunct measures such as arterial occlusion techniques, uterotonics or tranexamic acid