Aim of the studyTo evaluate the frequency of MRE11/RAD50/NBS1 (MRN)-complex loss of protein expression in endometrial cancers (EC) and to determine whether loss of MRE11 renders the cancer cells sensitive to Poly(ADP-ribose) polymerase (PARP)-inhibitory treatment.MethodsMRN expression was examined in 521 samples of endometrial carcinomas and in 10 cancer cell lines. A putative mutation hotspot in the form of an intronic poly(T) allele in MRE11 was sequenced in selected cases (n = 26). Sensitivity to the PARP-inhibitor, BMN673 was tested in colony formation assays before and after MRE11 silencing using siRNA. Homologous recombination (HR) DNA repair was evaluated by RAD51-foci formation assay upon irradiation and drug treatment.ResultsLoss of MRE11 protein was found in 30.7% of EC tumours and significantly associated with loss of RAD50, NBS1 and mismatch repair protein expression. One endometrial cell line showed a markedly reduced MRE11 expression due to a homozygous poly(T) mutation of MRE11, thereby exhibiting an increased sensitivity to BMN673. MRE11 depletion sensitizes MRE11 expressing EC cell lines to the treatment with BMN673. The increased sensitivity to PARP-inhibition correlates with reduced RAD51 foci formation upon ionizing radiation in MRE11-depleted cells.ConclusionLoss of the MRE11 protein predicts sensitivity to PARP-inhibitor sensitivity in vitro, defining it as an additional synthetic lethal gene with PARP. The high incidence of MRE11 loss in ECs can be potentially exploited for PARP-inhibitor therapy. Furthermore, MRE11 protein expression using immunohistochemistry could be investigated as a predictive biomarker for PARP-inhibitor treatment.

Kisspeptins, the peptide products of the KiSS-1 gene, bind to the G protein coupled receptor 54 (GPR54). Since 2003, research has revealed the important role of kisspeptins in initiating puberty, timing puberty and regulating fertility in adulthood. Specific mutations in GPR54 gene cause either delayed/absent puberty or precocious puberty. The KiSS-1/GPR54 system stimulates the gonadotrophin releasing hormone (GnRH) neurons and is involved in the feedback regulation of the HPG axis by gonadal steroids. Different hypothalamic nuclei are involved in negative (arcuate nucleus; ARC) and positive (anteroventral periventricular nucleus; AVPV) feedback in mice. Continuous administration of kisspeptins down-regulates the HPG axis. During pregnancy, kisspeptins are secreted from the placenta in large amounts and are responsible for the physiological invasion of primary human trophoblast. Kisspeptins have been administered to normal male and female individuals as well as to women with hypothalamic secondary amenorrhoea. In all cases, gonadotrophin secretion was potently stimulated. Kisspeptin antagonists have been synthesized to successfully suppress GnRH and gonadotrophin release. These agonists and antagonists appear as valuable new tools for manipulating the HPG axis and are promising drugs for future treatment. The scope of this review highlights the role of kisspeptins in regulating gonadotrophin secretion and explores their possible therapeutic use.

Histone deacetylase (HDAC) inhibitors such as vorinostat (suberoylanilide hydroxamic acid), valproic acid, romidepsin , and LBH589 comprise a relatively new class of potent anticancer agents. This study provides evidence for the potential of vorinostat to cause acquisition of multidrug resistance protein-independent resistance in HCT116 colon tumor cells. This acquired resistance is moderate (two-fold to three-fold), is nonreversible, and correlates with the loss of responses typically seen with HDAC inhibitors, that is the loss of acetylation of the histones H2A, H2B, H3, and H4, the loss of the G2/M checkpoint activation, and the loss of caspase 3-dependent and caspase 7-dependent apoptosis. This acquired resistance also associates with cross-resistance to the hydroxamate-class (LBH589 and JNJ26481585) and to the aliphatic acid-class (valproic acid) HDAC inhibitors but not to the benzamideclass (MGCD0103) and the cyclic peptide-class (romidepsin) HDAC inhibitors. The acquired HDAC inhibitor resistance described hereis not a result of altered HDAC and histone acetyltransferase activities and differs from that previously reported for romidepsin. The present study provides evidence for the potential of vorinostat to cause acquisition of MDRindependent resistance in HCT116 colon tumor cells. This acquired resistance is moderate (2 to 3-fold), is non-reversible, and correlates with the loss of responses typically seen with HDAC inhibitors, i.e. the loss of acetylation of the histones H2A, H2B, H3, and H4, the loss of the G2/M checkpoint activation, and the loss of caspase 3-and caspase 7-dependent apoptosis. This acquired resistance also associates with cross-resistance to the hydroxamate-class (LBH589 and JNJ26481585) and to the aliphatic acid-class (VPA) HDAC inhibitors but not to the benzamideclass (MGCD0103) and the cyclic peptide-class (romidepsin) HDAC inhibitors. The herein described acquired HDAC inhibitor resistance is not due to altered HDAC and HAT activities and differs from that previously reported for romidepsin.

Circular isthmic-cervical suture is a quick, safe, simple and effective technique for controlling peripartum haemorrhage during caesarean section for placenta praevia accreta.

CM performed by an experienced obstetrician can be safe in selected patients who are without additional preexisting risk factors. Risk factors that are associated with increased blood loss in women with uterine leiomyomatas include a larger size of the leiomyoma (≥5 cm) and a maternal age of ≥40 years.