Inhibition of monocarboxylate transporter 1 has been proposed as a therapeutic approach to perturb lactate shuttling in tumor cells that lack monocarboxylate transporter 4. We examined the ...monocarboxylate transporter 1 inhibitor AZD3965, currently in phase I clinical studies, as a potential therapy for diffuse large B-cell lymphoma and Burkitt lymphoma. Whilst extensive monocarboxylate transporter 1 protein was found in 120 diffuse large B-cell lymphoma and 10 Burkitt lymphoma patients' tumors, monocarboxylate transporter 4 protein expression was undetectable in 73% of the diffuse large B-cell lymphoma samples and undetectable or negligible in each Burkitt lymphoma sample. AZD3965 treatment led to a rapid accumulation of intracellular lactate in a panel of lymphoma cell lines with low monocarboxylate transporter 4 protein expression and potently inhibited their proliferation. Metabolic changes induced by AZD3965 in lymphoma cells were consistent with a feedback inhibition of glycolysis. A profound cytostatic response was also observed
: daily oral AZD3965 treatment for 24 days inhibited CA46 Burkitt lymphoma growth by 99%. Continuous exposure of CA46 cells to AZD3965 for 7 weeks
resulted in a greater dependency upon oxidative phosphorylation. Combining AZD3965 with an inhibitor of mitochondrial complex I (central to oxidative phosphorylation) induced significant lymphoma cell death
and reduced CA46 disease burden
These data support clinical examination of AZD3965 in Burkitt lymphoma and diffuse large B-cell lymphoma patients with low tumor monocarboxylate transporter 4 expression and highlight the potential of combination strategies to optimally target the metabolic phenotype of tumors.
IntroductionPaediatric heart transplant patients are disproportionately affected by Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disease (PTLD) compared with other childhood ...solid organ recipients. The drivers for this disparity remain poorly understood. A potential risk factor within this cohort is the routine surgical removal of the thymus—a gland critical for the normal development of T-lymphocyte-mediated antiviral immunity—in early life, which does not occur in other solid organ transplant recipients. Our study aims to describe the key immunological differences associated with early thymectomy, its impact on the temporal immune response to EBV infection and subsequent risk of PTLD.Methods and analysisProspective and sequential immune monitoring will be performed for 34 heart transplant recipients and 6 renal transplant patients (aged 0–18 years), stratified into early (<1 year), late (>1 year) and non-thymectomy groups. Peripheral blood samples and clinical data will be taken before transplant and at 3, 6, 12 and 24 months post-transplant. Single cell analysis of circulating immune cells and enumeration of EBV-specific T-lymphocytes will be performed using high-dimensional spectral flow cytometry with peptide-Major Histocompatibilty Complex (pMHC) I/II tetramer assay, respectively. The functional status of EBV-specific T-lymphocytes, along with EBV antibodies and viral load will be monitored at each of the predefined study time points.Ethics and disseminationEthical approval for this study has been obtained from the North of Scotland Research Ethics Committee. The results will be disseminated through publications in peer-reviewed journals, presentations at scientific conferences and patient-centred forums, including social media.Trial registration numberISRCTN10096625.
Genetic dissection of complex, polygenic trait variation is a key goal of medical and evolutionary genetics. Attempts to identify genetic variants underlying complex traits have been plagued by low ...mapping resolution in traditional linkage studies, and an inability to identify variants that cumulatively explain the bulk of standing genetic variation in genome-wide association studies (GWAS). Thus, much of the heritability remains unexplained for most complex traits. Here we describe a novel, freely available resource for the Drosophila community consisting of two sets of recombinant inbred lines (RILs), each derived from an advanced generation cross between a different set of eight highly inbred, completely resequenced founders. The Drosophila Synthetic Population Resource (DSPR) has been designed to combine the high mapping resolution offered by multiple generations of recombination, with the high statistical power afforded by a linkage-based design. Here, we detail the properties of the mapping panel of >1600 genotyped RILs, and provide an empirical demonstration of the utility of the approach by genetically dissecting alcohol dehydrogenase (ADH) enzyme activity. We confirm that a large fraction of the variation in this classic quantitative trait is due to allelic variation at the Adh locus, and additionally identify several previously unknown modest-effect trans-acting QTL (quantitative trait loci). Using a unique property of multiparental linkage mapping designs, for each QTL we highlight a relatively small set of candidate causative variants for follow-up work. The DSPR represents an important step toward the ultimate goal of a complete understanding of the genetics of complex traits in the Drosophila model system.
Mechanically tunable hydrogels are attractive platforms for 3D cell culture, as hydrogel stiffness plays an important role in cell behavior. Traditionally, hydrogel stiffness has been controlled ...through altering either the polymer concentration or the stoichiometry between crosslinker reactive groups. Here, an alternative strategy based upon tuning the hydrophilicity of an elastin‐like protein (ELP) is presented. ELPs undergo a phase transition that leads to protein aggregation at increasing temperatures. It is hypothesized that increasing this transition temperature through bioconjugation with azide‐containing molecules of increasing hydrophilicity will allow direct control of the resulting gel stiffness by making the crosslinking groups more accessible. These azide‐modified ELPs are crosslinked into hydrogels with bicyclononyne‐modified hyaluronic acid (HA‐BCN) using bioorthogonal, click chemistry, resulting in hydrogels with tunable storage moduli (100–1000 Pa). Human mesenchymal stromal cells (hMSCs), human umbilical vein endothelial cells (HUVECs), and human neural progenitor cells (hNPCs) are all observed to alter their cell morphology when encapsulated within hydrogels of varying stiffness. Taken together, the use of protein hydrophilicity as a lever to tune hydrogel mechanical properties is demonstrated. These hydrogels have tunable moduli over a stiffness range relevant to soft tissues, support the viability of encapsulated cells, and modify cell spreading as a consequence of gel stiffness.
Matrix stiffness is a critical cue that affects cell phenotype and hence is an important variable in biomaterials design. A novel strategy to control the stiffness of protein‐engineered biomaterials by tuning protein hydrophilicity is demonstrated. This strategy allows synthesis of gels with storage moduli ranging from 100–1000 Pa, resulting in variable cell spreading for a variety of cell types.
The Biomedical Advanced Research and Development Authority, part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services, recognizes that ...the evaluation of medical countermeasures under the Animal Rule requires well-characterized and reproducible animal models that are likely to be predictive of clinical benefit. Marburg virus (MARV), one of two members of the genus Marburgvirus, is characterized by a hemorrhagic fever and a high case fatality rate for which there are no licensed vaccines or therapeutics available. This natural history study consisted of twelve cynomolgus macaques challenged with 1000 PFU of MARV Angola and observed for body weight, temperature, viremia, hematology, clinical chemistry, and coagulation at multiple time points. All animals succumbed to disease within 8 days and exhibited signs consistent with those observed in human cases, including viremia, fever, systemic inflammation, coagulopathy, and lymphocytolysis, among others. Additionally, this study determined the time from exposure to onset of disease manifestations and the time course, frequency, and magnitude of the manifestations. This study will be instrumental in the design and development of medical countermeasures to Marburg virus disease.
The rates of survival with functional recovery for out of hospital cardiac arrest remain unacceptably low. Extracorporeal cardiopulmonary resuscitation (ECPR) quickly resolves the low-flow state of ...conventional cardiopulmonary resuscitation (CCPR) providing valuable perfusion to end organs. Observational studies have shown an association with the use of ECPR and improved survivability. Two recent randomized controlled studies have demonstrated improved survival with functional neurologic recovery when compared to CCPR. Substantial resources and coordination amongst different specialties and departments are crucial for the successful implementation of ECPR. Standardized protocols, simulation based training, and constant communication are invaluable to the sustainability of a program. Currently there is no standardized protocol for the post-cannulation management of these ECPR patients and, ideally, upcoming studies should aim to evaluate these protocols.
Climate change is anticipated to influence all parts of agricultural production systems. However, the potential impacts on crop storage have rarely been assessed, even though storage is an important ...component of a grower’s marketing strategy and is essential for the continuous supply of a commodity for processors, exporters, and consumers. The Michigan chip-processing potato industry provides an example of the importance of crop storage. Michigan is the largest producer of chip-processing potatoes in the USA, and potatoes are stored on farms from September to June. We use an ensemble of climate projections developed for three future time slices (early, mid, and late century) from 16 climate models forced by three greenhouse gas concentration pathways to assess future changes in potato storage conditions. Our findings indicate an increased future demand for ventilation and/or refrigeration immediately after harvest and again in spring and early summer, even for the early-century time slice. Furthermore, the period of reliably cold storage temperatures during winter is anticipated, when averaged across all models, to shorten by 11–17 days in Michigan’s primary production area and 14–20 days in the more southern secondary area by mid-century, and by 15–29 days and 31–35 days, respectively, for the northern and southern production areas by late century. The level of uncertainty, as indicated by the ensemble range, is large, although the sign of the projected changes in storage parameters is consistent. This case study provides an example of the potentially large effects of climate change on the storage conditions for agricultural commodities.
Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is increasingly used to manage severe respiratory failure. Unfortunately, refractory hypoxemia often complicates VV-ECMO support. Both ...circuit- and patient-related etiologies can drive this, and a structured approach is necessary to diagnose and treat the condition. We present the case of a patient on VV-ECMO for acute respiratory distress syndrome who suffered from several distinct etiologies of refractory hypoxemia over a short timeframe. Frequent recalculation of cardiac output and oxygen delivery enabled early diagnosis and treatment of these conditions. We highlight the need for a structured and oft-repeated approach to this complex problem.
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