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A first-in-human phase I clinical trial investigating the safety and efficacy of repeat dosing MSCTRAIL cell therapy in addition to chemotherapy and immunotherapy in patients with advanced lung cancer
No full textIntroduction
Despite recent progress, advanced non-small cell lung cancer (NSCLC) has poor survival
outcomes, necessitating the development of novel therapies. TNF-related apoptosis-inducing
ligand (TRAIL) selectively induces cancer cell death and can be delivered to tumours by
mesenchymal stromal cells (MSCs) due to the cells’ migratory properties. This first-inhuman phase I trial assessed safety and dose of umbilical cord-derived MSCs expressing
TRAIL (UC-MSCTRAIL) alongside standard NSCLC therapy.
Methods
Participants performance status 0-1 with treatment-naïve, inoperable stage IIIB/IV NSCLC
received UC-MSCTRAIL infusions with each cycle of chemotherapy and immunotherapy, up
to 3 cycles. A dose de-escalation design was used. Exploratory in vitro and in vivo studies
further characterised UC-MSCTRAIL properties.
Results
Six participants enrolled; four received 4×10⁸ cells/infusion (median 5.4x106 cells/kg), and
two received 2×10⁸ cells/infusion (median 2.4x106 cells/kg). Early termination occurred due
to asymptomatic pulmonary emboli (N=5), which included two patients that were
anticoagulated as a protocol amendment with prophylactic low molecular weight heparin
(enoxaparin 40mg) and rivaroxaban 20mg, respectively. Exploratory analyses found no clear
pro-coagulant or immunogenic mechanisms, though participants receiving UC-MSCTRAIL
had elevated inflammatory markers.
Conclusion
This first-in-human study was terminated due to a high incidence of pulmonary emboli.
Though exact mechanism remains unclear, UC-MSCTRAIL may have contributed to a proinflammatory environment in participants already at elevated risk of thrombosis due to their
malignancy. Future MSC-based therapies should incorporate close monitoring for
asymptomatic thrombosis and follow a dose escalation design for safety
Clearing out at Clare College, Cambridge, England: a late nineteenth-century material culture
No full textAn assemblage deposited at Clare College, Cambridge, England, in 1879–1885 represents the largest archaeologically recovered assemblage from a nineteenth-century Cambridge college. It contains a wide range of material deriving from the corporate collegiate household, including ceramics, glassware, clay tobacco pipes and other materials. This material comprises a mixture of corporate and individual material, which can be interpreted in light of the predominantly young adult male college population, while also shedding light on marginalized groups, particularly women and servants. It also indicates distinctions between collegiate and domestic material culture in Cambridge
Re-visiting cognitive reserve: The importance of multiple brain measures.
Get PDFThe term 'cognitive reserve' broadly refers to better-than-expected cognitive abilities in old age, presumed to reflect environmental/lifestyle factors earlier in life. This commentary addresses the question of what determines 'better than expected' cognition; specifically, whether cognitive reserve can be 'explained away' by considering multiple brain measurements. Using simulations, I show that, once one allows for multiple brain properties related to cognition, differential maintenance of those properties can reproduce the clinical picture associated with cognitive reserve. Using real data, I then show that white-matter microstructure and functional connectivity explain significant additional variance in fluid intelligence beyond grey-matter volume (at least cross-sectionally), supporting the importance of measuring multiple brain properties. Using multimodal, longitudinal data to identify changes in those brain properties that are especially important for changes in cognition will help decide which interventions are most likely to be effective at maintaining cognition in old age
HIV drug resistance during antiretroviral therapy scale-up in Uganda, 2012-19: a population-based, longitudinal study.
Get PDFBACKGROUND: With scale-up of antiretroviral therapy (ART) in sub-Saharan Africa, increasing pretreatment HIV drug resistance has been reported; however, the broader effect of ART expansion on population-level resistance patterns remains insufficiently quantified. We aimed to estimate the longitudinal prevalence of drug resistance and resistance-conferring mutations. METHODS: This study used data collected as part of the Rakai Community Cohort Study (RCCS), an open population-based census and cohort study conducted in southern Uganda. At each survey round, residents aged 15-49 years are invited to participate and receive a structured questionnaire that obtains sociodemographic, behavioural, and health information, including self-reported past and current ART use. Voluntary HIV testing is conducted using a rapid test algorithm and a venous blood sample. People with HIV provide samples for viral load quantification and deep sequencing. We analysed RCCS survey, HIV viral load, and deep sequencing (which was used to predict resistance) data from five survey rounds. The key outcomes were the population prevalence of viraemic people with HIV with non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), protease inhibitor, or multiclass resistance among all participants (regardless of HIV serostatus) in the 2015 and 2017 surveys. Prevalence of class-specific resistance and resistance-conferring substitutions were estimated using robust log-Poisson regression. FINDINGS: Between Aug 10, 2011, and Nov 4, 2020, there were 43 361 participants in the RCCS and 7923 (18·27%) people with HIV. Over five survey rounds, 93 622 participant visits occurred, among which 17 460 (18·65%) were from people with HIV. Over the analysis period, the median age of study participants remained similar (28 years [22-35] in 2012 and 29 years [21-38] in 2019). Sufficient data were available to reliably genotype 4072 (90·03%) of 4523 participant visits from 3407 people with HIV for at least one drug. Overall population prevalence of resistance contributed by viraemic pretreatment people with HIV decreased between 2012 and 2017 from 0·56% (95% CI 0·42-0·75) to 0·25% (0·18-0·33) for NNRTI and from 0·24% (0·15-0·37) to 0·05% (0·02-0·10) for NRTI (prevalence ratio 0·44 [0·29-0·68] for NNRTI and 0·21 [0·09-0·47] for NRTI). Between 2012 and 2017, NNRTI resistance among viraemic pretreatment people with HIV increased from 4·86% (3·69-6·42) to 9·61% (7·27-12·7; prevalence ratio 1·98 [1·34-2·91]). The prevalence of NNRTI and NRTI resistance was substantially higher among viraemic treatment-experienced people with HIV (51·49% [46·24-57·34] for NNRTI and 36·46% [30·06-44·22] for NRTI in 2017) than among pretreatment people with HIV. NNRTI and NRTI resistance was predominantly attributable to rtK103N and rtM184V. inT97A was observed at a similar prevalence among viraemic treatment-experienced (9·96% [6·41-15·48]) and viraemic pretreatment (10·56% [8·01-13·93]) people with HIV; no major dolutegravir resistance mutations were observed. INTERPRETATION: Despite rising NNRTI resistance among pretreatment people with HIV, overall population prevalence of pretreatment HIV drug-resistant viraemia decreased due to increasing ART uptake and viral suppression. This finding underscores the crucial role of achieving and maintaining high ART coverage in reducing transmission of drug-resistant HIV. The high prevalence of mutations conferring resistance to components of first-line ART regimens among viraemic people with HIV is potentially concerning. FUNDING: National Institutes of Health, Johns Hopkins University Center for AIDS Research, Bill & Melinda Gates Foundation, and the US Centers for Disease Control and Prevention
The People’s Politics: Jean Béraud at the Salle Graffard
Get PDFAbstract
Jean Béraud’s À la Salle Graffard was widely considered to be a highlight of the 1884 Paris Salon, singled out by critics for its witty take on leftist demagoguery. Béraud’s spectacle of a rowdy assembly was praised for its true-to-life vision, skewering those types of contemporary socialism familiar to a bourgeois audience from the mainstream press. This essay investigates the kind of political tourism that Béraud’s scene performs, including as it was critiqued by radical commentators such as Jules Vallès. It reconstructs the particularity of the meeting’s setting, and the new, troubling form of political deliberation such meetings represented in the wake of the Republic’s 1881 law on the freedom of assembly. More than a simple document of proletarian politics, Béraud’s barely-studied painting offers, I argue, a self-ironising vision of the people’s politics, which playfully reconfigures the ur-scene of Republican popular sovereignty: the Tennis Court Oath of 1789.</jats:p
Anti-Corrosion Interfacial Design for Aqueous Zn Metal Batteries with Enhanced Calendar Life.
Get PDFAqueous Zn metal batteries are promising for grid-scale energy storage, owing to intrinsic safety, environmental friendliness, and low cost. However, their practical deployment is hindered by their poor and overlooked calendar life. Here, we quantitatively demonstrate that the Zn corrosion rate during calendar aging is jointly governed by the hydrogen evolution barrier and Zn deposition homogeneity. Therefore, we propose a universal anti-corrosion interfacial design that simultaneously elevates the hydrogen evolution energy barrier and promotes uniform Zn deposition through early stage dispersed nucleation. This anti-corrosion interface effectively suppresses the Zn corrosion rate by 68.9% compared with the untreated interface, leading to a Zn powder pouch cell with 80.6% capacity retention at high reversible capacity of 245.4 mAh g-1 over 200 cycles, achieved under a rigorous calendar aging process. This study establishes quantified correlations between interfacial properties and Zn corrosion, offering fundamental guidance for future interfacial designs to boost the calendar life and commercial-level applications of aqueous Zn batteries
Digital Minilateralism: How governments cooperate on digital governance
Get PDFNew research from the Digital State Project argues for the critical function of small, agile, digitally enabled and focused networks of leaders to foster strong international cooperation on digital governance issues. This type of cooperative working, described as ‘digital minilateralism’, has a role to play in shaping how individual governments learn, adopt and govern the use of new and emerging technologies, and how they create common or aligned policies. It is also important as cross-border digital infrastructure and services become increasingly common.
The policy paper, co-authored by Dr. Tanya Filer, who leads the Digital State project, and Dr. Antonio Weiss, affiliated researcher, draws on the example of the Digital Nations, a network of 10 ‘leading digital’ countries, to advance understanding of how digital leaders and policymakers can best develop and use minilateral networks, and of the particular affordances that this approach offers.
Key findings:
Already beginning to prove effective, digital minilateralism has a role to play in shaping how individual governments learn, adopt and govern the use of new and emerging technologies, and how they create common or aligned policy.
National governments should recognise and reinforce the strategic value of digital minilaterals without stamping out, through over-bureaucratisation, the qualities of trust, open conversation, and ad-hocness in which their value lies.
As digital minilateral networks grow and mature, they will need to find mechanisms through which to retain (or adapt) their core principles while scaling across more boundaries.
To demonstrate their value to the global community, digital multilaterals must feed into formal multilateral conversations and arrangements
Publish, Perish, or Build Community? Towards Alternative Ethical Publication and Dissemination Practices
No full textOptimal Hybrid Energy System Sizing for Green Hydrogen Production: Scenario-Based Techno-Economic Approach
Get PDFThis study presents a comprehensive techno-economic assessment to optimize a hybrid renewable energy system for green hydrogen production in Jordan. Using the Hybrid Optimization Model for Electric Renewables (HOMERs) and System Advisor Model (SAM) software, this study evaluates multiple cost projections for 2030 technology costs. Key parameters such as capital cost, efficiency, and lifetime are varied extensively. Highlighted results show a wide range in the Levelized Cost of Hydrogen (LCOH), reaching 1.59 to 3.49 USD/kg, and the Levelized Cost of Energy (LCOE) from 0.0072 to 0.0301 USD/kWh. Furthermore, Net Present Value (NPV) spans from USD 424 to 927 million, depending on the scenario and sensitivity case. Technically, the system’s optimized capacities vary significantly. PV ranges from 203 to 457 MW, wind capacities range from 0 to 220 MW, and electrolyzers range from 192 to 346 MW, demonstrating the flexibility required to meet different cost and performance assumptions. The study’s broad relevance extends to developing countries with grid constraints, where off-grid green hydrogen production is feasible. Its framework can be adapted globally, offering valuable insights
Reanalysis of Immunopeptidomics Datasets Provides Mechanistic Insight into TAPBPR-Mediated Peptide Editing on HLA-A, -B and -C Molecules.
Get PDFBACKGROUND: Major histocompatibility class I (MHC-I, human leukocyte antigen [HLA] class I in humans) molecules present small fragments of the proteome on the cell surface for immunosurveillance, which is pivotal to control infected and malignant cells. Immunogenic peptides are generated and selected in the MHC-I antigen processing and presentation pathway. In this pathway, two homologous molecules, tapasin and TAPBPR, optimise the MHC-I peptide repertoire that is ultimately presented at the plasma membrane. Peptide exchange on HLA class I by human TAPBPR involves the flexible loop region K22-D35, with the leucine at position 30 (L30) involved in mediating peptide dissociation. However, our understanding of the exact molecular mechanisms governing TAPBPR-mediated peptide exchange on HLA class I allotypes remains incomplete. METHODS: Here, in-depth re-analyses of published immunopeptidomics datasets was used to further examine TAPBPR peptide editing activity and mechanism of action on HLA class I. The role of the TAPBPR editing loop in opening the HLA class I peptide binding groove was assessed using molecular dynamics simulations and a peptide exchange assay. RESULTS: We show that TAPBPR shapes the peptide repertoire on HLA-A, -B and -C allotypes. The TAPBPR editing loop was not essential to allow HLA class I to adopt an open state but did allow for the HLA-A*68:02 peptide binding groove to stay open for a sustained period. L30 in the TAPBPR editing loop was typically sufficient to mediate peptide repertoire restriction on the three HLA class I allotypes expressed by HeLa cells. TAPBPR was also able to load peptides onto HLA class I in a loop-dependent manner. CONCLUSIONS: These results suggest that the TAPBPR editing loop is involved both in peptide filtering and loading