Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets ...of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies. Barriers to effective CAR-T cell therapy include severe life-threatening toxicities, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration. In addition, the host and tumor microenvironment interactions with CAR-T cells critically alter CAR-T cell function. Furthermore, a complex workforce is required to develop and implement these treatments. In order to overcome these significant challenges, innovative strategies and approaches to engineer more powerful CAR-T cells with improved anti-tumor activity and decreased toxicity are necessary. In this review, we discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CAR-T cell therapy in both hematological malignancy and solid tumors.
This review gives a worldwide overview on Power-to-Gas projects producing hydrogen or renewable substitute natural gas focusing projects in central Europe. It deepens and completes the content of ...previous reviews by including hitherto unreviewed projects and by combining project names with details such as plant location. It is based on data from 153 completed, recent and planned projects since 1988 which were evaluated with regards to plant allocation, installed power development, plant size, shares and amounts of hydrogen or substitute natural gas producing examinations and product utilization phases. Cost development for electrolysis and carbon dioxide methanation was analyzed and a projection until 2030 is given with an outlook to 2050.
The results show substantial cost reductions for electrolysis as well as for methanation during the recent years and a further price decline to less than 500 euro per kilowatt electric power input for both technologies until 2050 is estimated if cost projection follows the current trend. Most of the projects examined are located in Germany, Denmark, the United States of America and Canada. Following an exponential global trend to increase installed power, today's Power-to-Gas applications are operated at about 39 megawatt. Hydrogen and substitute natural gas were investigated on equal terms concerning the number of projects.
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•Electrolysis and methanation costs are estimated to fall by up to 75% under 500 €/kWel until 2050.•Most projects are located in Germany, Denmark, the United States and Canada.•95 Power-to-Gas projects with a combined load of 38.6 MWel are active in early 2019.•Exponential global increase in installed PtG-capacity is expected between 1993 and 2050.•The years 2012–2015 mark a breakthrough in average plant size and installed capacity.
Chimeric antigen receptor (CAR)-T cell therapy is an emerging staple in the treatment of certain hematological malignancies. While CAR-T cells have produced robust responses in certain hematological ...malignancies, toxicities associated with the therapy have limited their use. Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) is a potentially life-threatening neurotoxicity that commonly occurs with CAR-T cell therapy. Here we will discuss ICANS, its treatment, possible mechanisms, and potential solutions to this critical limitation of CAR-T cell therapy. As the field of CAR-T cell therapy evolves, improved treatments and methods to circumvent or overcome ICANS are necessary to improve morbidity, mortality, and decrease the cost of CAR-T cell therapy. This serious, life-threatening side effect needs to be studied to better understand its mechanisms and develop treatments and alternative strategies.
Traumatic spinal cord injury (SCI) is a devastating condition that is often associated with significant loss of function and/or permanent disability. The pathophysiology of SCI is complex and occurs ...in two phases. First, the mechanical damage from the trauma causes immediate acute cell dysfunction and cell death. Then, secondary mechanisms of injury further propagate the cell dysfunction and cell death over the course of days, weeks, or even months. Among the secondary injury mechanisms, inflammation has been shown to be a key determinant of the secondary injury severity and significantly worsens cell death and functional outcomes. Thus, in addition to surgical management of SCI, selectively targeting the immune response following SCI could substantially decrease the progression of secondary injury and improve patient outcomes. In order to develop such therapies, a detailed molecular understanding of the timing of the immune response following SCI is necessary. Recently, several studies have mapped the cytokine/chemokine and cell proliferation patterns following SCI. In this review, we examine the immune response underlying the pathophysiology of SCI and assess both current and future therapies including pharmaceutical therapies, stem cell therapy, and the exciting potential of extracellular vesicle therapy.
The feasibility of implementing power-to-gas systems, to absorb surplus solar power from electricity distribution networks and carbon dioxide from biomass anaerobic digestion (AD) plant, in order to ...produce synthetic methane was investigated for a region of Southern Germany that has a high solar power penetration. The analysis was based on time series electricity data for 2012 from which future load profiles were computed in accordance with the expected installed capacities of solar power across the period 2015–2025. The electrolyser capacity required to absorb 20% of excess solar energy occurring within the region's low voltage network in 2025 was estimated to be 370 MWe. First order considerations of the region's gas grid, electricity network and existing AD sites suggest that such a deployment could be achieved by installing sub-MW (and some multi-MW) power-to-gas plant at several hundred AD sites.
•Electrolyser operation for absorbing excess solar power in low voltage networks.•Co-location of power-to-gas systems and anaerobic digesters for producing synthetic methane from excess solar power.•Decarbonisation of low pressure gas distribution networks.•Power-to-gas implementation strategy for Bavaria.
Monolayer graphene exhibits exceptional electronic and mechanical properties, making it a very promising material for nanoelectromechanical devices. Here, we conclusively demonstrate the ...piezoresistive effect in graphene in a nanoelectromechanical membrane configuration that provides direct electrical readout of pressure to strain transduction. This makes it highly relevant for an important class of nanoelectromechanical system (NEMS) transducers. This demonstration is consistent with our simulations and previously reported gauge factors and simulation values. The membrane in our experiment acts as a strain gauge independent of crystallographic orientation and allows for aggressive size scalability. When compared with conventional pressure sensors, the sensors have orders of magnitude higher sensitivity per unit area.
Kelps can be included in integrated multitrophic aquaculture (IMTA) where their growth and quality might benefit from the nutrient load released by other species like finfish and mussels transforming ...effluents from the cultured animals into valuable products. We studied how different nutrient concentrations affect growth, photosynthesis, chemical composition and pigment content of the kelp
Saccharina latissima
. We exposed kelps to natural seawater, water enriched to levels of ammonium and nitrate simulating finfish cage waste (IMTA1) and a combination of such enrichment with natural effluents coming from mussels (IMTA2). The algal biomass was higher and produced elevated total organic content when exposed to both IMTA1 and IMTA2. The photosynthetic responses in terms of relative electron transfer rate (rETR
max
), PSII saturation irradiance (
E
k
) and total nitrogen content were also positively affected by both IMTA1 and IMTA2. We found a significant enhancement in pigment content only when algae were exposed to the strongest enrichment of our study (IMTA2). Finally, we found a positive relationship between rETR
max
and growth, and the content of chlorophyll
a
and fucoxanthin. Our results show significant physiological responses of
S. latissima
to nutrient enrichment mimicking IMTA settings, as well as the benefit of added nutrients through a boost in photosynthetic activity that leads to higher kelp biomass and pigment production. This study suggests that modest nitrogen enrichment such as the one in our IMTA2 setup is enough to generate not only higher kelp biomass, but also an increased biomass quality with potentially higher market value.
As with many immunopathologically driven diseases, the malignant T cells of cutaneous T-cell lymphomas (CTCLs), such as Sézary syndrome, display aberrant cytokine secretion patterns that contribute ...to pathology and disease progression. Targeting this disordered release of cytokines is complicated by the changing cytokine milieu that drives the phenotypic changes of CTCLs. Here, we characterize a novel signaling pathway that can be targeted to inhibit the secretion of cytokines by modulating either CXCR4 or CXCR4-mediated signaling. We demonstrate that upon ligation of the T-cell antigen receptor (TCR), the TCR associates with and transactivates CXCR4 via phosphorylation of S339-CXCR4 in order to activate a PREX1-Rac1–signaling pathway that stabilizes interleukin-2 (IL-2), IL-4, and IL-10 messenger RNA (mRNA) transcripts. Pharmacologic inhibition of either TCR-CXCR4 complex formation or PREX1-Rac1 signaling in primary human T cells decreased mRNA stability and inhibited secretion of IL-2, IL-4, and IL-10. Applying this knowledge to Sézary syndrome, we demonstrate that targeting various aspects of this signaling pathway blocks both TCR-dependent and TCR-independent cytokine secretion from a Sézary syndrome–derived cell line and patient isolates. Together, these results identify multiple aspects of a novel TCR-CXCR4–signaling pathway that could be targeted to inhibit the aberrant cytokine secretion that drives the immunopathogenesis of Sézary syndrome and other immunopathological diseases.
•T-cell activation induces TCR transactivation of CXCR4 to stabilize cytokine mRNA transcripts via a PREX1-Rac1–signaling pathway.•Inhibition of the TCR-CXCR4–signaling pathway impairs TCR-dependent and TCR-independent cytokine secretion by CTCL cells.
Immunotherapies can lead to an immune compromised state that can allow for opportunistic pathogens such as Rhodococcus to flourish. The vast majority of Rhodococcus infections occur in ...immunocompromised hosts. Here we describe disseminated Rhodococcus equi infection in a patient with diffuse large B-cell lymphoma treated with immunotherapy. Infection with Rhodococcus can be diagnosed with the aid of cytomorphology and histochemical findings and the organism confirmed by sequencing. In conclusion, Rhodococcus should be considered in the differential of granulomatous inflammation in immunocompromised individuals treated with immunotherapies.
Chimeric antigen receptor T (CAR-T) cell therapy is a new pillar in cancer therapeutics; however, its application is limited by the associated toxicities. These include cytokine release syndrome ...(CRS) and neurotoxicity. Although the IL-6R antagonist tocilizumab is approved for treatment of CRS, there is no approved treatment of neurotoxicity associated with CD19-targeted CAR-T (CART19) cell therapy. Recent data suggest that monocytes and macrophages contribute to the development of CRS and neurotoxicity after CAR-T cell therapy. Therefore, we investigated neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential strategy to manage CART19 cell–associated toxicities. In this study, we show that GM-CSF neutralization with lenzilumab does not inhibit CART19 cell function in vitro or in vivo. Moreover, CART19 cell proliferation was enhanced and durable control of leukemic disease was maintained better in patient-derived xenografts after GM-CSF neutralization with lenzilumab. In a patient acute lymphoblastic leukemia xenograft model of CRS and neuroinflammation (NI), GM-CSF neutralization resulted in a reduction of myeloid and T cell infiltration in the central nervous system and a significant reduction in NI and prevention of CRS. Finally, we generated GM-CSF–deficient CART19 cells through CRISPR/Cas9 disruption of GM-CSF during CAR-T cell manufacturing. These GM-CSFk/o CAR-T cells maintained normal functions and had enhanced antitumor activity in vivo, as well as improved overall survival, compared with CART19 cells. Together, these studies illuminate a novel approach to abrogate NI and CRS through GM-CSF neutralization, which may potentially enhance CAR-T cell function. Phase 2 studies with lenzilumab in combination with CART19 cell therapy are planned.
•GM-CSF neutralization with lenzilumab during CART19 therapy prevents CRS and neuroinflammation and is a viable therapeutic solution.•GM-CSF neutralization and GM-CSF knockout in CAR-T cells enhance their antitumor functions.
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