Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia.

Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance

The calcium looping cycle for CO2 capture from power generation, cement manufacture and hydrogen production

Calcium looping is a CO2 capture scheme using solid CaO-based sorbents to remove CO2 from flue gases, e.g., from a power plant, producing a concentrated stream of CO2 (∼95%) suitable for storage. The scheme exploits the reversible gas-solid reaction between CO2 and CaO(s) to form CaCO3(s). Calcium looping has a number of advantages compared to closer-to-market capture schemes, including: the use of circulating fluidised bed reactors-a mature technology at large scale; sorbent derived from cheap, abundant and environmentally benign limestone and dolomite precursors; and the relatively small efficiency penalty that it imposes on the power/industrial process (i.e., estimated at 6-8 percentage points, compared to 9.5-12.5 from amine-based post-combustion capture). A further advantage is the synergy with cement manufacture, which potentially allows for decarbonisation of both cement manufacture and power production. In addition, a number of advanced applications offer the potential for significant cost reductions in the production of hydrogen from fossil fuels coupled with CO2 capture. The range of applications of calcium looping are discussed here, including the progress made towards demonstrating this technology as a viable post-combustion capture technology using small-pilot scale rigs, and the early progress towards a 2MW scale demonstrator. © 2010 The Institution of Chemical Engineers

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Emerging CO2 capture systems

In 2005, the IPCC SRCCS recognized the large potential for developing and scaling up a wide range of emerging CO2 capture technologies that promised to deliver lower energy penalties and cost. These included new energy conversion technologies such as chemical looping and novel capture systems based on the use of solid sorbents or membrane-based separation systems. In the last 10 years, a substantial body of scientific and technical literature on these topics has been produced from a large number of R&D projects worldwide, trying to demonstrate these concepts at increasing pilot scales, test and model the performance of key components at bench scale, investigate and develop improved functional materials, optimize the full process schemes with a view to a wide range of industrial applications, and to carry out more rigorous cost studies etc. This paper presents a general and critical review of the state of the art of these emerging CO2 capture technologies paying special attention to specific process routes that have undergone a substantial increase in technical readiness level toward the large scales required by any CO2 capture system

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Precision Therapy for Mesothelioma: Feasibility and New Opportunities

Malignant pleural mesotheliomas (MPMs) are characterised by their wide variation in natural history, ranging from minimally to highly aggressive, associated with both interpatient and intra-tumour genomic heterogeneity. Recent insights into the nature of this genetic variation, the identification of drivers, and the emergence of novel strategies capable of targeting vulnerabilities that result from the inactivation of key tumour suppressors suggest that new approaches to molecularly strategy therapy for mesothelioma may be feasible

Analysis of Gene Expression in 3D Spheroids Highlights a Survival Role for ASS1 in Mesothelioma

To investigate the underlying causes of chemoresistance in malignant pleural mesothelioma, we have studied mesothelioma cell lines as 3D spheroids, which acquire increased chemoresistance compared to 2D monolayers. We asked whether the gene expression of 3D spheroids would reveal mechanisms of resistance. To address this, we measured gene expression of three mesothelioma cell lines, M28, REN and VAMT, grown as 2D monolayers and 3D spheroids. A total of 209 genes were differentially expressed in common by the three cell lines in 3D (138 upregulated and 71 downregulated), although a clear resistance pathway was not apparent. We then compared the list of 3D genes with two publicly available datasets of gene expression of 56 pleural mesotheliomas compared to normal tissues. Interestingly, only three genes were increased in both 3D spheroids and human tumors: argininosuccinate synthase 1 (ASS1), annexin A4 (ANXA4) and major vault protein (MVP); of these, ASS1 was the only consistently upregulated of the three genes by qRT-PCR. To measure ASS1 protein expression, we stained 2 sets of tissue microarrays (TMA): one with 88 pleural mesothelioma samples and the other with additional 88 pleural mesotheliomas paired with matched normal tissues. Of the 176 tumors represented on the two TMAs, ASS1 was expressed in 87 (50%; staining greater than 1 up to 3+). For the paired samples, ASS1 expression in mesothelioma was significantly greater than in the normal tissues. Reduction of ASS1 expression by siRNA significantly sensitized mesothelioma spheroids to the pro-apoptotic effects of bortezomib and of cisplatin plus pemetrexed. Although mesothelioma is considered by many to be an ASS1-deficient tumor, our results show that ASS1 is elevated at the mRNA and protein levels in mesothelioma 3D spheroids and in human pleural mesotheliomas. We also have uncovered a survival role for ASS1, which may be amenable to targeting to undermine mesothelioma multicellular resistance