Probing the mechanism for hydrogel-based stasis induction in human pluripotent stem cells : is the chemical functionality of the hydrogel important?

It is well-known that pluripotent human embryonic stem cells (hPSC) can differentiate into any cell type. Recently, we reported that hPSC colonies enter stasis when immersed in an extremely soft hydrogel comprising hydroxyl-functional block copolymer worms (I. Canton, N. J. Warren, A. Chahal, K. Amps, A. Wood, R. Weightman, E. Wang, H. Moore and S. P. Armes, ACS Centr. Sci., 2016, 2, 65–74). The gel modulus and chemical structure of this synthetic hydrogel are similar to that of natural mucins, which are implicated in the mechanism of diapause for mammalian embryos. Does stasis induction occur merely because of the very soft nature of such hydrogels or does chemical functionality also play a role? Herein, we address this key question by designing a new hydrogel of comparable softness in which the PGMA stabilizer chains are replaced with non-hydroxylated poly(ethylene glycol) [PEG]. Immunolabeling studies confirm that hPSC colonies immersed in such PEG-based hydrogels do not enter stasis but instead proliferate (and differentiate if no adhesion substrate is present). However, pluripotency is retained if an appropriate adhesion substrate is provided. Thus, the chemical functionality of the hydrogel clearly plays a decisive role in the stasis induction mechanism

Small‐angle X‐ray scattering studies of block copolymer nano‐objects: Formation of ordered phases in concentrated solution during polymerization‐induced self‐assembly

We report that polymerization‐induced self‐assembly (PISA) can be used to prepare lyotropic phases comprising diblock copolymer nano‐objects in non‐polar media. RAFT dispersion polymerization of benzyl methacrylate (BzMA) at 90 °C using a trithiocarbonate‐capped hydrogenated polybutadiene (PhBD) steric stabilizer block in n‐dodecane produces either spheres or worms that exhibit long‐range order at 40% w/w solids. NMR studies enable calculation of instantaneous copolymer compositions for each phase during the BzMA polymerization. As the PBzMA chains grow longer when targeting PhBD 80 ‐PBzMA 40 , time‐resolved small‐angle X‐ray scattering reveals intermediate body‐centred cubic (BCC) and hexagonally close‐packed (HCP) sphere phases prior to formation of a final hexagonal cylinder phase (HEX). The HEX phase is lost on serial dilution and the aligned cylinders eventually form disordered flexible worms. The HEX phase undergoes an order‐disorder transition on heating to 150 °C and a pure HCP phase forms on cooling to 20 °C

Final analysis from RESONATE: Up to six years of follow‐up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma

Ibrutinib, a once‐daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single‐agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high‐risk features. Here we report the final analysis from RESONATE with median follow‐up on study of 65.3 months (range, 0.3‐71.6) in the ibrutinib arm. Median progression‐free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113‐0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high‐risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080‐0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418‐0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all‐grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long‐term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high‐risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707)

Review article: the future of microbiome-based therapeutics

Published online 24 May 2022Background: From consumption of fermented foods and probiotics to emerging applications of faecal microbiota transplantation, the health benefit of manipulating the human microbiota has been exploited for millennia. Despite this history, recent technological advances are unlocking the capacity for targeted microbial manipulation as a novel therapeutic.Aim: This review summarises the current developments in microbiome- based medicines and provides insight into the next steps required for therapeutic development.Methods: Here we review current and emerging approaches and assess the capabilities and weaknesses of these technologies to provide safe and effective clinical inter-ventions. Key literature was identified through Pubmed searches with the following key words, ‘microbiome’, ‘microbiome biomarkers’, ‘probiotics’, ‘prebiotics’, ‘synbiotics’, ‘faecal microbiota transplant’, ‘live biotherapeutics’, ‘microbiome mimetics’ and ‘postbiotics’.Results: Improved understanding of the human microbiome and recent technological advances provide an opportunity to develop a new generation of therapies. These therapies will range from dietary interventions, prebiotic supplementations, single probiotic bacterial strains, human donor-derived faecal microbiota transplants, ra-tionally selected combinations of bacterial strains as live biotherapeutics, and the beneficial products or effects produced by bacterial strains, termed microbiome mimetics.Conclusions: Although methods to identify and refine these therapeutics are continually advancing, the rapid emergence of these new approaches necessitates accepted technological and ethical frameworks for measurement, testing, laboratory practices and clinical translation.Emily L. Gulliver, Remy B. Young, Michelle Chonwerawong, Gemma L. D'Adamo, Tamblyn Thomason, James T. Widdop, Emily L. Rutten, Vanessa Rossetto Marcelino, Robert V. Bryant, Samuel P. Costello, Claire L. O'Brien, Georgina L. Hold, Edward M. Giles, Samuel C. Forste

Stuart Warren (24 Dec 1938–22 Mar 2020)

Celebrating the life of Stuart Warren

Heavy Quarks and Heavy Quarkonia as Tests of Thermalization

We present here a brief summary of new results on heavy quarks and heavy quarkonia from the PHENIX experiment as presented at the "Quark Gluon Plasma Thermalization" Workshop in Vienna, Austria in August 2005, directly following the International Quark Matter Conference in Hungary.Comment: 8 pages, 5 figures, Quark Gluon Plasma Thermalization Workshop (Vienna August 2005) Proceeding

Single Electrons from Heavy Flavor Decays in p+p Collisions at sqrt(s) = 200 GeV

The invariant differential cross section for inclusive electron production in p+p collisions at sqrt(s) = 200 GeV has been measured by the PHENIX experiment at the Relativistic Heavy Ion Collider over the transverse momentum range $0.4 <= p_T <= 5.0 GeV/c at midrapidity (eta <= 0.35). The contribution to the inclusive electron spectrum from semileptonic decays of hadrons carrying heavy flavor, i.e. charm quarks or, at high p_T, bottom quarks, is determined via three independent methods. The resulting electron spectrum from heavy flavor decays is compared to recent leading and next-to-leading order perturbative QCD calculations. The total cross section of charm quark-antiquark pair production is determined as sigma_(c c^bar) = 0.92 +/- 0.15 (stat.) +- 0.54 (sys.) mb.Comment: 329 authors, 6 pages text, 3 figures. Submitted to Phys. Rev. Lett. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Nuclear Modification of Electron Spectra and Implications for Heavy Quark Energy Loss in Au+Au Collisions at sqrt(s_NN)=200 GeV

The PHENIX experiment has measured mid-rapidity transverse momentum spectra (0.4 < p_T < 5.0 GeV/c) of electrons as a function of centrality in Au+Au collisions at sqrt(s_NN)=200 GeV. Contributions from photon conversions and from light hadron decays, mainly Dalitz decays of pi^0 and eta mesons, were removed. The resulting non-photonic electron spectra are primarily due to the semi-leptonic decays of hadrons carrying heavy quarks. Nuclear modification factors were determined by comparison to non-photonic electrons in p+p collisions. A significant suppression of electrons at high p_T is observed in central Au+Au collisions, indicating substantial energy loss of heavy quarks.Comment: 330 authors, 6 pages text, 3 figures. Submitted to Phys. Rev. Lett. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Dilepton mass spectra in p+p collisions at sqrt(s)= 200 GeV and the contribution from open charm

The PHENIX experiement has measured the electron-positron pair mass spectrum from 0 to 8 GeV/c^2 in p+p collisions at sqrt(s)=200 GeV. The contributions from light meson decays to e^+e^- pairs have been determined based on measurements of hadron production cross sections by PHENIX. They account for nearly all e^+e^- pairs in the mass region below 1 GeV/c^2. The e^+e^- pair yield remaining after subtracting these contributions is dominated by semileptonic decays of charmed hadrons correlated through flavor conservation. Using the spectral shape predicted by PYTHIA, we estimate the charm production cross section to be 544 +/- 39(stat) +/- 142(syst) +/- 200(model) \mu b, which is consistent with QCD calculations and measurements of single leptons by PHENIX.Comment: 375 authors from 57 institutions, 18 pages, 4 figures, 2 tables. Submitted to Physics Letters B. v2 fixes technical errors in matching authors to institutions. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm