Epigenetic polypharmacology: from combination therapy to multitargeted drugs

The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed

Healthcare professionals’ views on patient-centered care in hospitals

Background: Patient-centered care (PCC) is a main determinant of care quality. Research has shown that PCC is a multi-dimensional concept, and organizations that provide PCC well report better patient and organizational outcomes. However, little is known about the relative importance of PCC dimensions. The aim of this study was therefore to investigate the relative importance of the eight dimensions of PCC according to hospital-based healthcare professionals, and examine whether their viewpoints are determined by context. Methods: Thirty-four healthcare professionals (16 from the geriatrics department, 15 from a surgical intensive care unit, 3 quality employees) working at a large teaching hospital in New York City were interviewed using Q methodology. Participants were asked to rank 35 statements representing eight dimensions of PCC extracted from the literature: patient preferences, physical comfort, coordination of care, emotional support, acce

The Impact of Error-Management Climate, Error Type and Error Originator on Auditors’ Reporting Errors Discovered on Audit Work Papers

We examine factors affecting the auditor’s willingness to report their own or their peers’ self-discovered errors in working papers subsequent to detailed working paper review. Prior research has shown that errors in working papers are detected in the review process; however, such detection rates only rarely exceed 50% of the seeded errors. Hence, measures that encourage auditors to be alert to their own (or their peers’) potential errors any time they revisit the audit working papers may be valuable in detecting such residual errors and potentially correcting them before damage occurs to the audit firm or its client. We hypothesize that three factors affect the auditor’s willingness to report post detailed review discovered errors: the local office error-management climate (open versus blame), the type of error (mechanical versus conceptual) and who committed the error (the individual who committed the error (self) or a peer). Local office error-management climate is said to be open and supportive where errors and mistakes are accepted as part of everyday life as long as they are learned from and not repeated. In alternative, a blame error-management climate focuses on a “get it right the first time” culture where mistakes are not tolerated and blame gets attached to those admitting to or found committing such errors. We find that error-management climate has a significant overall effect on auditor willingness to report errors, as does who committed the error originally. We find both predicted and unpredicted significant interactions among the three factors that qualify these observed significant main effects. We discuss implications for audit practice and further research

An Integrated Paleomagnetic, Multimethod- Paleointensity, and Radiometric Study on Cretaceous and Paleogene Lavas From the Lesser Caucasus: Geomagnetic and Tectonic Implications

Sixteen rhyolitic and dacitic Cretaceous and Paleocene-Eocene lavas from the Lesser Caucasus have been subjected to paleomagnetic and multimethod paleointensity experiments to analyze the variations of the Earth's magnetic field. Paleointensity experiments were performed with two methods. Thellier-type experiments with the IZZI method on 65 specimens (nine flows) yielded 15 successful determinations and experiments with the multispecimen method on 14 samples (seven flows) yielded two successful determinations. The joint analysis of the results obtained with both methods produced a mean FuK = (19.9 ± 3.7) µT for upper Cretaceous and FPg = (20.7 ± 3.3) µT for Paleogene sites. Low virtual axial dipole moments for the Cretaceous (3.4 × 1022 Am2) and Paleogene (3.5 × 1022 Am2) samples support the idea of a lower average dipole moment during periods of stable polarity of the Earth magnetic field. Mean flow paleomagnetic directions did not match expected upper Cretaceous to Paleogene directions calculated from the European Apparent Polar Wander Path. While inclination results roughly agreed with expected values, a group of sites showed nearly North-South paleodeclinations (D = 1.1° ± 14.2°), and another group displayed eastward deviated paleodeclinations (D = 72.9° ± 26.6°). These results suggest the occurrence of nearly vertical-axis rotations, probably as a result of continental collision since Oligocene. In addition to paleomagnetic and palaeointensity analyses, new K-Ar absolute age determinations have been performed on three of the studied sites, yielding Late Cretaceous ages (78.7 ± 1.7, 79.7 ± 1.6, and 83.4 ± 1.8 Ma (2σ)).Project PID2019-105796GB-100/AEI/10.13039/501100011033 (Agencia Estatal de Investigación, Spain). M. Calvo-Rathert acknowledges funding from the Fulbright Commission and the Spanish Ministry of Science, Innovation, and Universities for a research stay at Hawaii University at Manoa. A. Goguitchaichvili acknowledges financial support from UNAM-PAPIIT no. IN101920. N. García-Redondo acknowledges financial support from Junta de Castilla y León and the European Research Development Fund (ERDF). EHB acknowledges financial support for laboratory maintenance and measurements to SOEST-HIGP and National Science Foundation grants. These is SOEST 11143 and HIGP 2420 contribution

A proteomic approach for the identification of novel lysine methyltransferase substrates

<p>Abstract</p> <p>Background</p> <p>Signaling via protein lysine methylation has been proposed to play a central role in the regulation of many physiologic and pathologic programs. In contrast to other post-translational modifications such as phosphorylation, proteome-wide approaches to investigate lysine methylation networks do not exist.</p> <p>Results</p> <p>In the current study, we used the ProtoArray^®platform, containing over 9,500 human proteins, and developed and optimized a system for proteome-wide identification of novel methylation events catalyzed by the protein lysine methyltransferase (PKMT) SETD6. This enzyme had previously been shown to methylate the transcription factor RelA, but it was not known whether SETD6 had other substrates. By using two independent detection approaches, we identified novel candidate substrates for SETD6, and verified that all targets tested <it>in vitro </it>and in cells were genuine substrates.</p> <p>Conclusions</p> <p>We describe a novel proteome-wide methodology for the identification of new PKMT substrates. This technological advance may lead to a better understanding of the enzymatic activity and substrate specificity of the large number (more than 50) PKMTs present in the human proteome, most of which are uncharacterized.</p

Paleointensity Results From Pliocene Lavas of the Lesser Caucasus Obtained Using the Multispecimen Parallel Differential pTRM Method: A Comparison With Thellier- Thellier and IZZI Data

We report paleointensity results obtained with the multispecimen method (MSP) over the Pliocene sequence of Apnia (Georgia) which records a polarity reversal. Paleointensity determinations with the multispecimen technique were performed on 12 flows with the original (MSP-DB) and the domain-state corrected (MSP-DSC) protocol. Eight MSP-DSC determinations passed the proposed quality criteria. To obtain highly reliable data through the agreement between intensity values from different methods, MSP results were combined with paleointensities from a previous study with Thellier-type methods and especially strict selection criteria (RCRIT) on same flows (Sánchez-Moreno et al., 2020). Application of this multimethod procedure resulted in three new paleointensities including both MSP and Thellier-type results and an additional one obtained with two different Thellier-type methods, yielding one paleointensity of 36.9 µT in the normal-polarity, and three paleointensities between 19.2 and 24.1 µT in the reverse-polarity section. Additionally, Thellier-type data have been reinterpreted in this study with more flexible criteria (TTP) and the results combined with the MSP data. As a result, four flows yield paleointensities including MSP and Thellier-type determinations and seven include paleointensities obtained with two different Thellier-type methods. Results range from 37.2 and 44.3 μT in the normal-polarity and from 12.5 to 24.6 μT in the reverse-polarity section. Comparison of results from the four flows yielding multimethod determinations applying RCRIT criteria with those from the same flows under TTP criteria yields no significant difference in paleointensity values and their experimental uncertainty. Thus, application of a multimethod approach supports the possibility of using TTP criteria.Project PID2019-105796/10.13039/501100011033 (Agencia Estatal de Investigación, Spain), project BU066U16 (Junta de Castilla y León, Spain) and pre-doctoral grant BES-2013-064060 (MINECO, Spain). MCR acknowledges funding from the Fulbright Commission and the Spanish Ministry of Science, Innovation and Universities for a research stay at Hawaii University at Manoa. AG is grateful to the financial support given by DGAPA-PAPIIT IN101717. At Montpellier laboratory, the FUReMAG rapid furnace construction was supported by the French National Agency for Research (ANR-12-BS06-0015)