Aetiology, prophylaxis and management of preeclampsia

Although preeclampsia affects approximately 3%–8% of pregnancies worldwide and is a major contributor to maternal and neonatal mortality and morbidity, the aetiology of preeclampsia is still not fully understood. This review presents the current knowledge on the aetiology of preeclampsia, with a special emphasis on risk factors and their role, and describes recommendations for the prevention and treatment of preeclampsia

Clinical Outcomes after Uncomplicated Cataract Surgery with Implantation of the Tecnis Toric Intraocular Lens

Purpose. To evaluate the clinical outcomes after uncomplicated cataract surgery with implantation of an aspheric toric intraocular lens (IOL) during a 6-month follow-up. Methods. Prospective study including 27 consecutive eyes of 18 patients (mean age: 66.1±11.4 years) with a visually significant cataract and corneal astigmatism ≥ 0.75 D and undergoing uncomplicated cataract surgery with implantation of the Tecnis ZCT toric IOL (Abbott Medical Optics). Visual, refractive, and keratometric outcomes as well as IOL rotation were evaluated during a 6-month follow-up. At the end of the follow-up, patient satisfaction and perception of optical/visual disturbances were also evaluated using a subjective questionnaire. Results. At 6 months after surgery, mean LogMAR uncorrected (UDVA) and corrected distance visual acuity (CDVA) were 0.19±0.12 and 0.14±0.10, respectively. Postoperative UDVA of 20/40 or better was achieved in 92.6% of eyes. Mean refractive cylinder decreased significantly from −3.73±1.96 to −1.42±0.88 D (p<0.001), while keratometric cylinder did not change significantly (p=0.44). Mean absolute IOL rotation was 1.1±2.4°, with values of more than 5° in only 2 eyes (6.9%). Mean patient satisfaction score was 9.70±0.46, using a scale from 0 (not at all satisfied) to 10 (very satisfied). No postoperative optical/visual disturbances were reported. Conclusion. Cataract surgery with implantation of the Tecnis toric IOL is an effective method of refractive correction in eyes with corneal astigmatism due to the good IOL positional stability, providing high levels of patient’s satisfaction

CBP/p300 Bromodomain Inhibitor–I–CBP112 Declines Transcription of the Key ABC Transporters and Sensitizes Cancer Cells to Chemotherapy Drugs

The high expression of some ATP-binding cassette (ABC) transporters is linked to multidrug resistance in cancer cells. We aimed to determine if I-CBP112, which is a CBP/p300 bromodomain inhibitor, altered the vulnerability of the MDA-MB-231 cell line to chemotherapy drugs, which are used in neoadjuvant therapy in patients with triple negative breast cancer (TNBC). MDA-MB-231 cells represent TNBC, which is negative for the expression of estrogen and progesterone receptors and HER2 protein. An I-CBP112-induced decrease in the expression of all the studied ABCs in the breast, but also in the lung (A549), and hepatic (HepG2) cancer cell lines was associated with increased accumulation of doxorubicin, daunorubicin, and methotrexate inside the cells as well as with considerable cell sensitization to a wide range of chemotherapeutics. Gene promoters repressed by I-CBP112 in MDA-MB-231 cells, such as ABCC1 and ABCC10, were characterized by enhanced nucleosome acetylation and, simultaneously, by considerably lower trimethylation in the transcription-promoting form of H3K4me3. The CBP/p300 bromodomain inhibitor induced the recruitment of LSD1 to the gene promoters. The inhibition of this demethylase in the presence of I-CBP112 prevented the repression of ABCC1 and ABCC10 and, to a considerable extent, cancer cells’ sensitization to drugs. In conclusion, the CBP/p300 bromodomain inhibitor I-CBP112 can be considered as a potent anti-multidrug-resistance agent, capable of repressing key ABC transporters responsible for drug efflux in various cancer types.This research was funded by National Centre for Research and Development, grant number LIDER/22/0122/L-10/18/NCBR/2019

PARP Traps Rescue the Pro-Inflammatory Response of Human Macrophages in the In Vitro Model of LPS-Induced Tolerance

Secondary infections cause sepsis that lead to patient disability or death. Contact of macrophages with bacterial components (such as lipopolysaccharide—LPS) activates the intracellular signaling pathway downstream of Toll-like receptors (TLR), which initiate an immune proinflammatory response. However, the expression of nuclear factor-kappa B (NF-κB)-dependent proinflammatory cytokines significantly decreases after single high or multiple LPS stimulations. Knowing that poly(ADP-ribose) polymerase-1 (PARP1) serves as a cofactor of NF-κB, we aimed to verify a hypothesis of the possible contribution of PARP1 to the development of LPS-induced tolerance in human macrophages. Using TNF-α mRNA expression as a readout, we demonstrate that PARP1 interaction with the TNF-α promoter, controls macrophage immunoparalysis. We confirm that PARP1 is extruded from the gene promoter, whereas cell pretreatment with Olaparib maintains macrophage responsiveness to another LPS treatment. Furthermore, cell pretreatment with proteasome inhibitor MG132 completely abrogates the effect of Olaparib, suggesting that PARP1 acts with NF-κB in the same regulatory pathway, which controls pro-inflammatory cytokine transcription. Mechanistically, PARP1 trapping allows for the re-rebinding of p65 to the TNF-α promoter in LPS-stimulated cells. In conclusion, PARP traps prevent PARP1 extrusion from the TNF-α promoter upon macrophage stimulation, thereby maintaining chromatin responsiveness of TLR activation, allowing for the re-binding of p65 and TNF-α transcription

Activation of <i>ABCC</i> Genes by Cisplatin Depends on the CoREST Occurrence at Their Promoters in A549 and MDA-MB-231 Cell Lines

Although cisplatin-based therapies are common among anticancer approaches, they are often associated with the development of cancer drug resistance. This phenomenon is, among others, caused by the overexpression of ATP-binding cassette, membrane-anchored transporters (ABC proteins), which utilize ATP to remove, e.g., chemotherapeutics from intracellular compartments. To test the possible molecular basis of increased expression of ABCC subfamily members in a cisplatin therapy mimicking model, we generated two cisplatin-resistant cell lines derived from non-small cell lung cancer cells (A549) and triple-negative breast cancer cells (MDA-MB-231). Analysis of data for A549 cells deposited in UCSC Genome Browser provided evidence on the negative interdependence between the occurrence of the CoREST complex at the gene promoters and the overexpression of ABCC genes in cisplatin-resistant lung cancer cells. Pharmacological inhibition of CoREST enzymatic subunits—LSD1 and HDACs—restored gene responsiveness to cisplatin. Overexpression of CoREST-free ABCC10 in cisplatin-resistant phenotypes was caused by the activity of EP300 that was enriched at the ABCC10 promoter in drug-treated cells. Cisplatin-induced and EP300-dependent transcriptional activation of ABCC10 was only possible in the presence of p53. In summary, the CoREST complex prevents the overexpression of some multidrug resistance proteins from the ABCC subfamily in cancer cells exposed to cisplatin. p53-mediated activation of some ABCC genes by EP300 occurs once their promoters are devoid of the CoREST complex