The Promise and Reality of Public Engagement in the Governance of Human Genome Editing Research.

This paper analyses the activities of five organizations shaping the debate over the global governance of genome editing in order to assess current approaches to public engagement (PE). We compare the recommendations of each group with its own practices. All recommend broad engagement with the general public, but their practices vary from expert-driven models dominated by scientists, experts, and civil society groups to citizen deliberation-driven models that feature bidirectional consultation with local citizens, as well as hybrid models that combine elements of both approaches. Only one group practices PE that seeks community perspectives to advance equity. In most cases, PE does little more than record already well-known views held by the most vocal groups, and thus is unlikely to produce more just or equitable processes or policy outcomes. Our exploration of the strengths, weaknesses, and possibilities of current forms of PE suggests a need to rethink both "public" and "engagement."

Launching of the Anaemia Research Peruvian Cohort (ARPEC): a multicentre birth cohort project to explore the iron adaptive homeostasis, infant growth and development in three Peruvian regions.

BACKGROUND: Preventing infantile anaemia and ensuring optimal growth and development during early childhood, particularly in resource-constrained settings, represent an ongoing public health challenge. Current responses are aligned to treatment-based solutions, instead of determining the roles of its inter-related causes. This project aims to assess and understand the complex interplay of eco-bio-social-political factors that determine infantile anaemia to inform policy, research design and prevention practices. METHODS: This is a longitudinal birth cohort study including four components: (1) biological, will assess known blood markers of iron homeostasis and anaemia and stool microbiota to identify and genetically analyse the participants' flora; (2) ecological, will assess and map pollutants in air, water and soil and evaluate features of nutrition and perceived food security; (3) social, which will use different qualitative research methodologies to explore key stakeholders and informants' perceptions related to nutritional, environmental and anaemia topics, participant observations and a participatory approach and (4) a political analysis, to identify and assess the impact of policies, guidelines and programmes at all levels for infantile anaemia in the three regions. Finally, we will also explore the role of social determinants and demographic variables longitudinally for all study participants. This project aims to contribute to the evidence of the inter-related causal factors of infantile anaemia, addressing the complexity of influencing factors from diverse methodological angles. We will assess infantile anaemia in three regions of Peru, including newborns and their mothers as participants, from childbirth until their first year of age. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Institutional Research Ethics Committee of the Instituto Nacional de Salud del Niño (Lima, Peru), CIEI-043-2019. An additional opinion has been granted by the Ethical Committee of Queen Mary University of London (London, UK). Dissemination across stakeholders is taking part as a continues part of the research process.

Sex-dependent mechanisms involved in renal tolerance to ischemia-reperfusion: Role of inflammation and histone H3 citrullination.

Ischemia-reperfusion (I/R) injury, an inevitable result of kidney transplantation, triggers early inflammatory events that affect graft viability. Evidence from human transplantation and preclinical models of I/R suggests that a female hormonal environment positively influences the ability to recover from ischemic injury. However, the mechanisms behind these effects remain mostly unexplored. Here, we studied the influence of sex on pro-inflammatory mediators involved in the pathophysiology of acute I/R injury in male, female, and female ovariectomized (OVX) Wistar rats that underwent unilateral renal ischemia for 45 min, followed by 24 h of reperfusion. We found improved renal function, reduced cytokine expression, and decreased infiltration of myeloperoxidase-positive cells in females after I/R, when compared to their male and female OVX counterparts. Remarkably, citrullination of histone H3 was exacerbated in serum and renal tubules of females after I/R. In contrast, we observed lower levels of citrullinated histone H3 in male and female OVX rats in response to I/R, mostly in neutrophil extracellular traps. Our results demonstrate that female sex promotes renal I/R tolerance by attenuating pro-inflammatory mediators involved in I/R-induced damage.

Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.

Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies.

Anesthetic preconditioning increases sirtuin 2 gene expression in a renal ischemia reperfusion injury model.

BACKGROUND: Renal transplant surgical proceedings are known to elicit periods of hypoxia and consequent blood flow reestablishment triggering ischemia-reperfusion (I-R) injury. Kidney damage induced by I-R injury associates with a higher risk of graft dysfunction and rejection. Anesthetic preconditioning exerts a beneficial effect on I-R injury by reducing oxidative stress, inflammation and apoptosis. However, the degree of renoprotection stimulated by commonly used anesthetics, as well as their mechanisms of action, are largely unknown. Sirtuins are class III histone deacetylases that reduce cellular stress, promote genome stability and regulate senescence. So far, the relationship between sirtuins and anesthetic preconditioning in the context of renal I-R has not been studied. The main objective of the present work was to determine the renal expression of sirtuins after I-R damage in rats under different anesthetic preconditioning treatments. METHODS: Unilateral ischemia was performed via occlusion of the left renal hilum for 45 min and followed by 24 hours of reperfusion. Anesthetic preconditioning schemes (morphine 0.5 mg/kg, fentanyl 10 µg/kg, propofol 7.5 mg/kg, or dexmedetomidine 25 µg/kg) were administered 1 hour before ischemia. Creatinine levels were determined in serum, and expression of kidney injury molecule 1 and sirtuin 1, 2, 3 and 7 in kidney tissue was quantified by RT-PCR. RESULTS: Anesthetic preconditioning with morphine, fentanyl, propofol and dexmedetomidine reduced kidney injury markers after I-R and modulated sirtuin gene expression. Opioids or dexmedetomidine administration before ischemia increased sirtuin 2 expression and correlated with improved renal function. CONCLUSIONS: Anesthetic preconditioning is a promising strategy to prevent I-R injury associated with transplantation. Our results suggest that sirtuin 2 is involved in the protective mechanisms of some commonly used anesthetics against I-R damage.

Opioids Preconditioning Upon Renal Function and Ischemia-Reperfusion Injury: A Narrative Review.

Kidneys have an important role in regulating water volume, blood pressure, secretion of hormones and acid-base and electrolyte balance. Kidney dysfunction derived from acute injury can, under certain conditions, progress to chronic kidney disease. In the late stages of kidney disease, treatment is limited to replacement therapy: Dialysis and transplantation. After renal transplant, grafts suffer from activation of immune cells and generation of oxidant molecules. Anesthetic preconditioning has emerged as a promising strategy to ameliorate ischemia reperfusion injury. This review compiles some significant aspects of renal physiology and discusses current understanding of the effects of anesthetic preconditioning upon renal function and ischemia reperfusion injury, focusing on opioids and its properties ameliorating renal injury. According to the available evidence, opioid preconditioning appears to reduce inflammation and reactive oxygen species generation after ischemia reperfusion. Therefore, opioid preconditioning represents a promising strategy to reduce renal ischemia reperfusion injury and, its application on current clinical practice could be beneficial in events such as acute renal injury and kidney transplantation.

ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia.

The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors.

Quiste hidatídico hepático manejo laparoscópico: reporte de caso / Hepatic hydatid cyst, laparoscopic management. Case report

Se reporta el caso de un paciente de sexo masculino de 32 años de edad, con antecedente de cirugía torácica por Quiste Hidatídico Pulmonar a los 9 años de edad; que ingresa al Servicio de Cirugía General y Digestiva del Hospital II Lima Norte Callao Luis Negreiros Vega, con tiempo de enfermedad de 1 año aproximadamente, refiriendo dolor abdominal tipo opresivo de leve a moderada intensidad a predominio de hemiabdomen superior, principalmente hipocondrio derecho y sensación de masa en dicha zona. Concomitantemente refiere el antecedente de cirugía previa en región torácica y con antecedente epidemiológico positivo. Luego de la evaluación clínica por el equipo de cirugía de consultorio externo y de la observación e informe de la Tomografía Espiral Multicorte en la que se observa lesión bien definida de aspecto multiquístico en segmento IV y V, que muestra realce periférico luego de administración de contraste; asociado a Western Blot positivo, se decide programación quirúrgica. Se realizó cirugía laparoscópica que consistió en destechamiento del quiste, aspiración y lavado del interior con hipersodio (ClNa 20%) y colocación de drenaje mixto. El paciente presento en el postoperatorio fistula biliar que se resolvió en 5 semanas; con inicio de tolerancia oral el primer día postoperatorio y controles de perfil hepático dentro de rangos normales al alta de cirugía que se realizó al 4 día post operatorio...

We report a case of male patient of 32 years old; with a history of thoracic surgery for hydatid cyst at 9 years of age; admission was at the general surgery Service of the Hospital II Lima Norte Callao Luis Negreiros Vega, with a history of illness of 1 year, referring abdominal pain oppressive predominance of the upper abdomen, especially on right upper quadrant. Refers concomitantly history of previous surgery in thoracic region and positive epidemiological history. After clinical evaluation by the staff of surgery, outpatient clinic and the observation and reporting of CT in which well-defined lesions in segment IV and V multicystic appearance and lesser sac showing peripheral enhancement it is observed after administration contrast; associated with positive Western Blot, surgical treatment is decided. Laparoscopic Surgery was performed consisting of cyst aspiration drainage and washing the interior with hipersodio (20% ClNa) and placement of laminar drain was done. Presented a postoperative biliary fistula that was resolved in five weeks, beginning of oral tolerance on the first postoperative day and liver function controls within normal ranges discharge was performed four days after surgery...

Biaryl analogues of teriflunomide as potent DHODH inhibitors.

The structure-activity relationships of a novel series of biaryl dihydroorotate dehydrogenase (DHODH) inhibitors related to teriflunomide are disclosed. These biaryl derivatives were the result of structure-based design and proved to be potent DHODH inhibitors which in addition showed good antiproliferative activities on peripheral blood mononuclear cells and good efficacies in vivo in the rat adjuvant-induced-arthritis model.

Emerging opportunities and concerns for drug discovery at serotonin 5-HT2B receptors.

5-HT(2B) receptors have been reported to play an important role at cardiac, intestinal and central levels, as well as in bone marrow formation and growth. In the last decade, 5-HT(2B) receptors have also gained much attention as new targets in therapeutics, but also as off-targets because their activation along with the inhibition of serotonin transporters plays a significant role in the pathogenesis of 5-HT induced valvulopathy. Taking this into account, the present review focuses on the new therapeutic applications of 5-HT(2B) receptor ligands as well as on the potential concerns.

Retinoblastoma (Rb) tumor-suppressor pathway alterations in meningeal hemangiopericytomas: High E2F transcription factor 1 expression and loss of Rb expression: study by double immunofluorescence staining and laser-scanning confocal microscopy.

BACKGROUND: The authors analyzed the retinoblastoma (Rb) tumor-suppressor pathway in meningeal hemangiopericytomas (MHPCs). METHODS: : Immunohistochemical detection of the Rb pathway proteins (Rb; E2F transcription factor 1 [E2F1]; cyclins D1, D3, and E; cyclin-dependent kinase 4 [CDK4]; and the CDK4 inhibitor p16/INKa) was followed by double immunofluorescence (DIF) staining and laser-scanning confocal microscopy (LSCM) in 11 MHPC specimens and from 4 specimens of recurrent disease from 1, 2, and 4 recurrences (total, 18 specimens). RESULTS: : All specimens displayed Rb pathway alterations, including low or negative Rb protein expression (17 specimens), high Rb protein expression (1 specimen), and loss of p16/INK4a expression (17 specimens). High levels of positive cell-cycle regulators were observed for E2F1 (10 specimens), cyclin E (7 specimens), CDK4 (5 specimens), cyclin D3 (1 specimen), and cyclin D1 (1 specimen). DIF and LSCM revealed no or very weak Rb and E2F1 colocalization, indicating that Rb does not act as a growth suppressor. High levels of human mouse double-minute 2 (HDM2) expression were observed in a previous study of these tumors, and they displayed colocalization with E2F1 and Rb in the current study, which supports the argument that HDM2 activates E2F1 and inactivates Rb. CONCLUSIONS: : The current findings demonstrated that loss of Rb and p16/INKa expression and high E2F1 expression indicate impairment of the Rb suppressor pathway. HDM2 colocalization with E2F1 and Rb also indicates that Rb suppressor pathway inactivation and transactivation of DNA synthesis genes may play pathogenic roles in MHPCs. High expression levels of cyclin E, cyclin D1, cyclin D3, and CDK4 were associated with Rb suppressor pathway neutralization.

2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 1. Structure-activity relationships and optimization of heterocyclic substituents.

Previously we have described a novel series of potent and selective A 2A receptor antagonists (e.g., 1) with excellent aqueous solubility. While these compounds are efficacious A 2A antagonists in vivo, the presence of an unsubstituted furyl moiety was a cause of some concern. In order to avoid the potential metabolic liabilities that could arise from an unsubstituted furyl moiety, an optimization effort was undertaken with the aim of replacing the unsubstituted furan with a more metabolically stable group while maintaining potency and selectivity. Herein, we describe the synthesis and SAR of a range of novel heterocyclic systems and the successful identification of a replacement for the unsubstituted furan moiety with a methylfuran or thiazole moiety while maintaining potency and selectivity.

2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 2. Reduction of hERG activity, observed species selectivity, and structure-activity relationships.

Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.

Synthesis of N-pyrimidinyl-2-phenoxyacetamides as adenosine A2A receptor antagonists.

A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease.

2,6-Diaryl-4-phenacylaminopyrimidines as potent and selective adenosine A(2A) antagonists with reduced hERG liability.

In this report, the design and synthesis of a series of pyrimidine based adenosine A(2A) antagonists are described. The strategy and outcome of expanding SAR exploration to attenuate hERG and improve selectivity over A(1) are discussed. Compound 33 exhibited excellent potency, selectivity over A(1), and reduced hERG liability.

Identification of novel, water-soluble, 2-amino-N-pyrimidin-4-yl acetamides as A2A receptor antagonists with in vivo efficacy.

Potent adenosine hA2A receptor antagonists are often accompanied by poor aqueous solubility, which presents issues for drug development. Herein we describe the early exploration of the structure-activity relationships of a lead pyrimidin-4-yl acetamide series to provide potent and selective 2-amino-N-pyrimidin-4-yl acetamides as hA2A receptor antagonists with excellent aqueous solubility. In addition, this series of compounds has demonstrated good bioavailability and in vivo efficacy in a rodent model of Parkinson's disease, despite having reduced potency for the rat A2A receptor versus the human A2A receptor.

Structure of human CD1b with bound ligands at 2.3 A, a maze for alkyl chains.

The human genome encodes five nonpolymorphic major histocompatibility complex class I-like glycoproteins, CD1a to CD1e, that present lipid antigens for specific recognition by T lymphocytes. Using single alkyl chain detergents, we developed a protocol to generate recombinant human CD1b-lipid complexes. We present here the crystal structures of CD1b in complex with either phosphatidylinositol or ganglioside GM2 at 2.3 A and 2.8 A resolutions, respectively. The antigen-binding groove houses four interlinked hydrophobic channels that are occupied by the alkyl chains of the glycolipid plus two detergent molecules. A distinct exit beneath the alpha 2 helix further contributes to the plasticity of the binding groove. These structures reveal the mechanism by which two alkyl chain lipids bind to CD1b, and how CD1b can adapt to ligands of different alkyl chain length. They also suggest how very long alkyl chains, such as those of mycolic acid, could be fully contained within the binding groove. These results extend the spectrum of potential CD1b ligands by revealing that, in addition to two alkyl chain lipids, mono-alkyl and triple-alkyl chain lipids can be accommodated in the binding groove.