Combining the platinum(ii) drug candidate kiteplatin with 1,10-phenanthroline analogues

Platinum complexes of the type [Pt(PL)(AL)]2+ where PL is a derivative of 1,10-phenanthroline and AL is cis-1,4-diaminocyclohexane (1,4-dach), have been synthesised and characterised by ultraviolet spectroscopy, elemental microanalysis, nuclear magnetic resonance and X-ray crystallography. The calf-thymus DNA binding affinity of these complexes was determined by isothermal titration calorimetry, revealing higher DNA affinity than their 1S,2S-diaminocyclohexane analogues. In vitro cytotoxicity was assessed in eleven human cell lines, revealing unexpectedly low activity for the 1,4-dach complexes

Absence of 2009 Pandemic H1N1 Influenza A Virus in Fresh Pork

The emergence of the pandemic 2009 H1N1 influenza A virus in humans and subsequent discovery that it was of swine influenza virus lineages raised concern over the safety of pork. Pigs experimentally infected with pandemic 2009 H1N1 influenza A virus developed respiratory disease; however, there was no evidence for systemic disease to suggest that pork from pigs infected with H1N1 influenza would contain infectious virus. These findings support the WHO recommendation that pork harvested from pandemic influenza A H1N1 infected swine is safe to consume when following standard meat hygiene practices

Pediatric Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations

This 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (CoSTR) for pediatric life support is based on the most extensive evidence evaluation ever performed by the Pediatric Life Support Task Force. Three types of evidence evaluation were used in this review: systematic reviews, scoping reviews, and evidence updates. Per agreement with the evidence evaluation recommendations of the International Liaison Committee on Resuscitation, only systematic reviews could result in a new or revised treatment recommendation. Systematic reviews performed for this 2020 CoSTR for pediatric life support included the topics of sequencing of airway-breaths-compressions versus compressions-airway-breaths in the delivery of pediatric basic life support, the initial timing and dose intervals for epinephrine administration during resuscitation, and the targets for oxygen and carbon dioxide levels in pediatric patients after return of spontaneous circulation. The most controversial topics included the initial timing and dose intervals of epinephrine administration (new treatment recommendations were made) and the administration of fluid for infants and children with septic shock (this latter topic was evaluated by evidence update). All evidence reviews identified the paucity of pediatric data and the need for more research involving resuscitation of infants and children

Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability

XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective Xpg mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. These unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

A Scalable System for Production of Functional Pancreatic Progenitors from Human Embryonic Stem Cells

Development of a human embryonic stem cell (hESC)-based therapy for type 1 diabetes will require the translation of proof-of-principle concepts into a scalable, controlled, and regulated cell manufacturing process. We have previously demonstrated that hESC can be directed to differentiate into pancreatic progenitors that mature into functional glucose-responsive, insulin-secreting cells in vivo. In this study we describe hESC expansion and banking methods and a suspension-based differentiation system, which together underpin an integrated scalable manufacturing process for producing pancreatic progenitors. This system has been optimized for the CyT49 cell line. Accordingly, qualified large-scale single-cell master and working cGMP cell banks of CyT49 have been generated to provide a virtually unlimited starting resource for manufacturing. Upon thaw from these banks, we expanded CyT49 for two weeks in an adherent culture format that achieves 50–100 fold expansion per week. Undifferentiated CyT49 were then aggregated into clusters in dynamic rotational suspension culture, followed by differentiation en masse for two weeks with a four-stage protocol. Numerous scaled differentiation runs generated reproducible and defined population compositions highly enriched for pancreatic cell lineages, as shown by examining mRNA expression at each stage of differentiation and flow cytometry of the final population. Islet-like tissue containing glucose-responsive, insulin-secreting cells was generated upon implantation into mice. By four- to five-months post-engraftment, mature neo-pancreatic tissue was sufficient to protect against streptozotocin (STZ)-induced hyperglycemia. In summary, we have developed a tractable manufacturing process for the generation of functional pancreatic progenitors from hESC on a scale amenable to clinical entry

A community-based lifestyle and weight loss intervention promoting a Mediterranean-style diet pattern evaluated in the stroke belt of North Carolina: the Heart Healthy Lenoir Project

Abstract Background Because residents of the southeastern United States experience disproportionally high rates of cardiovascular disease (CVD), it is important to develop effective lifestyle interventions for this population. Methods The primary objective was to develop and evaluate a dietary, physical activity (PA) and weight loss intervention for residents of the southeastern US. The intervention, given in eastern North Carolina, was evaluated in a 2 year prospective cohort study with an embedded randomized controlled trial (RCT) of a weight loss maintenance intervention. The intervention included: Phase I (months 1–6), individually-tailored intervention promoting a Mediterranean-style dietary pattern and increased walking; Phase II (months 7–12), option of a 16-week weight loss intervention for those with BMI ≥ 25 kg/m2 offered in 2 formats (16 weekly group sessions or 5 group sessions and 10 phone calls) or a lifestyle maintenance intervention; and Phase III (months 13–24), weight loss maintenance RCT for those losing ≥ 8 lb with all other participants receiving a lifestyle maintenance intervention. Change in diet and PA behaviors, CVD risk factors, and weight were assessed at 6, 12, and 24 month follow-up. Results Baseline characteristics (N = 339) were: 260 (77 %) females, 219 (65 %) African Americans, mean age 56 years, and mean body mass index 36 kg/m2. In Phase I, among 251 (74 %) that returned for 6 month follow-up, there were substantial improvements in diet score (4.3 units [95 % CI 3.7 to 5.0]), walking (64 min/week [19 to 109]), and systolic blood pressure (−6.4 mmHg [−8.7 to −4.1]) that were generally maintained through 24 month follow-up. In Phase II, 138 (57 group only, 81 group/phone) chose the weight loss intervention and at 12 months, weight change was: −3.1 kg (−4.9 to −1.3) for group (N = 50) and −2.1 kg (−3.2 to −1.0) for group/phone combination (N = 75). In Phase III, 27 participants took part in the RCT. At 24 months, weight loss was −2.1 kg (−4.3 to 0.0) for group (N = 51) and −1.1 kg (−2.7 to 0.4) for combination (N = 72). Outcomes for African American and whites were similar. Conclusions The intervention yielded substantial improvement in diet, PA, and blood pressure, but weight loss was modest. Trial registration clinicaltrials.gov Identifier: NCT0143348

CXCL12-Mediated Guidance of Migrating Embryonic Stem Cell-Derived Neural Progenitors Transplanted into the Hippocampus

Stem cell therapies for neurodegenerative disorders require accurate delivery of the transplanted cells to the sites of damage. Numerous studies have established that fluid injections to the hippocampus can induce lesions in the dentate gyrus (DG) that lead to cell death within the upper blade. Using a mouse model of temporal lobe epilepsy, we previously observed that embryonic stem cell-derived neural progenitors (ESNPs) survive and differentiate within the granule cell layer after stereotaxic delivery to the DG, replacing the endogenous cells of the upper blade. To investigate the mechanisms for ESNP migration and repair in the DG, we examined the role of the chemokine CXCL12 in mice subjected to kainic acid-induced seizures. We now show that ESNPs transplanted into the DG show extensive migration through the upper blade, along the septotemporal axis of the hippocampus. Seizures upregulate CXCL12 and infusion of the CXCR4 antagonist AMD3100 by osmotic minipump attenuated ESNP migration. We also demonstrate that seizures promote the differentiation of transplanted ESNPs toward neuronal rather than astrocyte fates. These findings suggest that ESNPs transplanted into the adult rodent hippocampus migrate in response to cytokine-mediated signals