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•Ion foam fractionation was used to remove trace concentrations of hazardous Cr(VI).•Cr(VI) at interface decreased foamability but improved drainage, enhancing separation.•The ...mechanism of Cr(VI) adsorption was studied using FTIR and surface excess analysis.•The effect of operating parameters was investigated to obtain 92.5% removal.•99% removal was achieved by a multistage unit with residue having 0.02 mg/L of Cr(VI).
Ion foam fractionation is a green and cost-effective technology where separation of molecules exploits the difference in surface affinity. In this work, a batch ion foam fractionation system was designed and optimized for the separation of trace hexavalent chromium (Cr(VI)) from aqueous solutions. The effect of surfactant head groups (collectors) on the adsorption dynamics was analyzed. Cetyl trimethyl ammonium bromide (CTAB), a cationic surfactant showed high efficiency for the removal of Cr(VI) from aqueous solutions. An experimental investigation of the effect of different operational parameters on the separation characteristics is presented. The recovery of Cr(VI) increased with the increase in CTAB/Cr(VI) molar ratio and reached a maximum of 92.5% at optimum operating conditions. However, with CTAB concentrations close to the critical micelle concentration (CMC) wet foams were produced resulting in high liquid hold-up and poor enrichment ratio. The presence of Cr(VI) at the gas-liquid interface significantly improved the drainage characteristics of the foam decreasing the liquid hold-up. Further, a three-stage ion foam fractionation unit was developed with Cr(VI) removal efficiency of more than 99%. The concentration of Cr(VI) in the residue after the three-stage operation was less than 0.02 mg/L which is below the USEPA recommended standards for drinking water.
Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens ...with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NFκB pathway, as a negative regulator of MHC-I but not PD-L1. The
-knockout gene expression signature is associated with better survival in ICB-naïve patients with cancer and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified Second Mitochondria-derived Activator of Caspase (SMAC) mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T cell-dependent killing, and adds to ICB efficacy. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy. SIGNIFICANCE: MHC-I loss or downregulation in cancer cells is a major mechanism of resistance to T cell-based immunotherapies. Our study reveals that birinapant may be used for patients with low baseline MHC-I to enhance ICB response. This represents promising immunotherapy opportunities given the biosafety profile of birinapant from multiple clinical trials.
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Eight isolates of cellulose-degrading bacteria (CDB) were isolated from four different invertebrates (termite, snail, caterpillar, and bookworm) by enriching the basal culture medium with filter ...paper as substrate for cellulose degradation. To indicate the cellulase activity of the organisms, diameter of clear zone around the colony and hydrolytic value on cellulose Congo Red agar media were measured. CDB 8 and CDB 10 exhibited the maximum zone of clearance around the colony with diameter of 45 and 50 mm and with the hydrolytic value of 9 and 9.8, respectively. The enzyme assays for two enzymes, filter paper cellulase (FPC), and cellulase (endoglucanase), were examined by methods recommended by the International Union of Pure and Applied Chemistry (IUPAC). The extracellular cellulase activities ranged from 0.012 to 0.196 IU/mL for FPC and 0.162 to 0.400 IU/mL for endoglucanase assay. All the cultures were also further tested for their capacity to degrade filter paper by gravimetric method. The maximum filter paper degradation percentage was estimated to be 65.7 for CDB 8. Selected bacterial isolates CDB 2, 7, 8, and 10 were co-cultured with Saccharomyces cerevisiae for simultaneous saccharification and fermentation. Ethanol production was positively tested after five days of incubation with acidified potassium dichromate.
Nutrient restriction reprograms cellular signaling and metabolic network to shape cancer phenotype. Lactate dehydrogenase A (LDHA) has a key role in aerobic glycolysis (the Warburg effect) through ...regeneration of the electron acceptor NAD+ and is widely regarded as a desirable target for cancer therapeutics. However, the mechanisms of cellular response and adaptation to LDHA inhibition remain largely unknown. Here, we show that LDHA activity supports serine and aspartate biosynthesis. Surprisingly, however, LDHA inhibition fails to impact human melanoma cell proliferation, survival, or tumor growth. Reduced intracellular serine and aspartate following LDHA inhibition engage GCN2‐ATF4 signaling to initiate an expansive pro‐survival response. This includes the upregulation of glutamine transporter SLC1A5 and glutamine uptake, with concomitant build‐up of essential amino acids, and mTORC1 activation, to ameliorate the effects of LDHA inhibition. Tumors with low LDHA expression and melanoma patients acquiring resistance to MAPK signaling inhibitors, which target the Warburg effect, exhibit altered metabolic gene expression reminiscent of the ATF4‐mediated survival signaling. ATF4‐controlled survival mechanisms conferring synthetic vulnerability to the approaches targeting the Warburg effect offer efficacious therapeutic strategies.
Synopsis
Lactate Dehydrogenase A (LDHA) has a key role in tumor metabolism, but how malignant cells adapt to LDHA inhibition remains unclear. Here, LDHA blockade is shown to remodel amino acid biosynthesis by engaging ATF4‐dependent metabolic reprograming, suggesting new therapeutic strategies based on synthetic vulnerabilities.
LDHA is dispensable for human melanoma cell proliferation and survival under normoxic conditions.
LDHA inhibition suppresses serine and aspartate biosynthesis to activate GCN2‐ATF4‐mediated transcription.
ATF4 induces SLC1A5 to increase uptake of glutamine and essential amino acid, thereby enhancing mTORC1 activity.
Co‐targeting LDHA and mTORC1 shows a synergistic effect in suppressing melanoma cell proliferation and tumor growth.
An ATF4‐dependent increase in the uptake of glutamine and essential amino acids allows melanoma cells to overcome pharmacological LDHA blockade by stimulating mTORC1 activity.
In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer's mutational profile when analyzing a single tumor biopsy. In this ...study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.
Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor ...expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with increased expression of inflammasome components, recruitment and activation of dendritic cells and reduced expression of antimicrobial peptides in intestinal epithelial cells. Reduced UPR expression is also seen in murine and human melanoma tumor specimens that responded to immune checkpoint therapy. Co-housing of Rnf5
and WT mice abolishes the anti-tumor immunity and tumor inhibition phenotype, whereas transfer of 11 bacterial strains, including B. rodentium, enriched in Rnf5
mice, establishes anti-tumor immunity and restricts melanoma growth in germ-free WT mice. Altered UPR signaling, exemplified in Rnf5
mice, coincides with altered gut microbiota composition and anti-tumor immunity to control melanoma growth.
Despite the success of targeted therapies including immunotherapies in cancer treatments, tumor resistance to targeted therapies remains a fundamental challenge. Tumors can evolve resistance to a ...therapy that targets one gene by acquiring compensatory alterations in another gene, such compensatory interaction between two genes is referred to as synthetic rescue (SR) interactions. To identify SRs, here we describe an algorithm, INCISOR, that leverages tumor transcriptomics and clinical information from 10,000 patients as well as data from experimental screens. INCISOR can identify SRs that are common across several cancer-types in genome-wide fashion by sifting through half a billion possible gene-gene combinations and provide a framework to design therapies to tackle resistance.
γδ T cells are potent anticancer effectors with the potential to target tumours broadly, independent of patient-specific neoantigens or human leukocyte antigen background
. γδ T cells can sense ...conserved cell stress signals prevalent in transformed cells
, although the mechanisms behind the targeting of stressed target cells remain poorly characterized. Vγ9Vδ2 T cells-the most abundant subset of human γδ T cells
-recognize a protein complex containing butyrophilin 2A1 (BTN2A1) and BTN3A1 (refs.
), a widely expressed cell surface protein that is activated by phosphoantigens abundantly produced by tumour cells. Here we combined genome-wide CRISPR screens in target cancer cells to identify pathways that regulate γδ T cell killing and BTN3A cell surface expression. The screens showed previously unappreciated multilayered regulation of BTN3A abundance on the cell surface and triggering of γδ T cells through transcription, post-translational modifications and membrane trafficking. In addition, diverse genetic perturbations and inhibitors disrupting metabolic pathways in the cancer cells, particularly ATP-producing processes, were found to alter BTN3A levels. This induction of both BTN3A and BTN2A1 during metabolic crises is dependent on AMP-activated protein kinase (AMPK). Finally, small-molecule activation of AMPK in a cell line model and in patient-derived tumour organoids led to increased expression of the BTN2A1-BTN3A complex and increased Vγ9Vδ2 T cell receptor-mediated killing. This AMPK-dependent mechanism of metabolic stress-induced ligand upregulation deepens our understanding of γδ T cell stress surveillance and suggests new avenues available to enhance γδ T cell anticancer activity.
The phenotypic effect of perturbing a gene’s activity depends on the activity level of other genes, reflecting the notion that phenotypes are emergent properties of a network of functionally ...interacting genes. In the context of cancer, contemporary investigations have primarily focused on just one type of functional relationship between two genes—synthetic lethality (SL). Here, we define the more general concept of “survival-associated pairwise gene expression states” (SPAGEs) as gene pairs whose joint expression levels are associated with survival. We describe a data-driven approach called SPAGE-finder that when applied to The Cancer Genome Atlas (TCGA) data identified 71,946 SPAGEs spanning 12 distinct types, only a minority of which are SLs. The detected SPAGEs explain cancer driver genes’ tissue specificity and differences in patients’ response to drugs and stratify breast cancer tumors into refined subtypes. These results expand the scope of cancer SPAGEs and lay a conceptual basis for future studies of SPAGEs and their translational applications.
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•Data-driven approach identifies survival-associated pairwise gene expression states•Identify 72,000 pairwise gene relationships spanning 12 distinct types in TCGA•Identified gene pairs explain tissue specificity of driver genes and drug response•Expression of identified gene pairs help refine breast tumor stratification
Previous investigations of gene interactions focused on synthetic lethality (SL). Magen et al. generalize this notion to identify gene pairs whose joint expression states associate with patient survival. Application to TCGA identifies 12 distinct types of relationships that extend beyond SLs and provide rich complementary molecular characterization of tumors.
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