Biosorption of heavy metals using dried algal biomass has been extensively described but rarely implemented. We contend this is because available algal biomass is a valuable product with a ready ...market. Therefore, we considered an alternative and practical approach to algal bioremediation in which algae were cultured directly in the waste water stream. We cultured three species of algae with and without nutrient addition in water that was contaminated with heavy metals from an Ash Dam associated with coal-fired power generation and tested metal uptake and bioremediation potential. All species achieved high concentrations of heavy metals (to 8% dry mass). Two key elements, V and As, reached concentrations in the biomass of 1543 mg.kg(-1) DW and 137 mg.kg(-1) DW. Growth rates were reduced by more than half in neat Ash Dam water than when nutrients were supplied in excess. Growth rate and bioconcentration were positively correlated for most elements, but some elements (e.g. Cd, Zn) were concentrated more when growth rates were lower, indicating the potential to tailor bioremediation depending on the pollutant. The cosmopolitan nature of the macroalgae studied, and their ability to grow and concentrate a suite of heavy metals from industrial wastes, highlights a clear benefit in the practical application of waste water bioremediation.
Drug resistance continues to be a major barrier to the delivery of curative therapies in cancer. Historically, drug resistance has been associated with over‐expression of drug transporters, changes ...in drug kinetics or amplification of drug targets. However, the emergence of resistance in patients treated with new‐targeted therapies has provided new insight into the complexities underlying cancer drug resistance. Recent data now implicate intratumoural heterogeneity as a major driver of drug resistance. Single cell sequencing studies that identified multiple genetically distinct variants within human tumours clearly demonstrate the heterogeneous nature of human tumours. The major contributors to intratumoural heterogeneity are (i) genetic variation, (ii) stochastic processes, (iii) the microenvironment and (iv) cell and tissue plasticity. Each of these factors impacts on drug sensitivity. To deliver curative therapies to patients, modification of current therapeutic strategies to include methods that estimate intratumoural heterogeneity and plasticity will be essential.
Osteosarcoma (OS) is the most common primary bone tumour in the paediatric age group. Treatment-refractory pulmonary metastasis continues to be the major complication of OS, reducing the 5-year ...survival rate for these patients to 10–20%. The mechanisms underlying the metastatic process in OS are still unclear, but undoubtedly, a greater understanding of the factors and interactions involved in its regulation will open new and much needed opportunities for therapeutic intervention. Recent published data have identified a new role for bone-specific macrophages (osteoclasts) and tumour-associated macrophages (TAMs), in OS metastasis. In this review we discuss the contribution of TAMs and osteoclasts in the establishment and maintenance of secondary metastatic lesions, and their novel role in the prevention of metastatic disease in a primary bone cancer such as osteosarcoma.
A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to ...reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.
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•A strategy for improving the ADCC potential of therapeutic antibodies is presented•Temporary inhibition of endocytosis increases tumor cell antigen presentation•Prochlorperazine could be repurposed to enhance the efficacy of anti-tumor mAbs•Potential to reduce heterogeneity in tumor cell responses to many IgG1 antibodies
Endocytosis inhibitors, such as prochlorperazine, can be used to move tumor cell antigens that are the targets of therapeutic monoclonal antibodies but hiding inside the cell to the cell surface for improved therapeutic antibody binding and tumor cell destruction by NK cells.
Human papillomavirus (HPV) E7 oncogene plays the most important role in cervical cancer. However, whether E7 oncoprotein is continuously expressed, associated with AKT(Ser473)/p-Src(Tyr527) signaling ...to trigger cervical carcinogenesis remains unclear. Here, we explored first if HPV16 E7 oncoprotein could be detected in clinical biopsies and is sustainedly expressed, and then investigated how this oncoprotein interacted with AKT(Ser473)/p-Src(Tyr527) signaling in cancer progression. We used ZHPV16E7384 affibody to detect E7 expression in HPV16-positive cervical cancer biopsies and animal tumors by immunohistochemistry (IHC). Results showed that ZHPV16E7384 affibody had intense and specific staining for E7 oncoprotein in the detected specimen. The E7 oncoprotein was continuously expressed to correspond with the development of precancerous lesions to invasive cervical cancer. IHC staining also revealed that AKT, p-AKT(Ser473), Src and p-Src(Tyr527) proteins were expressed in both patient biopsies and animal tumors, with the highest levels of p-AKT(Ser473)/p-Src(Tyr527) present in invasive cancer. Furthermore, siRNA experiments revealed that HPV16 E7 knockdown significantly impaired expression of p-AKT(Ser473)/p-Src(Tyr527) in both HPV16 E7-positive cancer cells and transformed cells. In addition, transient expression of HPV16 E7 protein promoted significantly expression of p-AKT(Ser473)/p-Src(Tyr527) in primary human keratinocytes. Finally, co-immunoprecipitation analysis proved that HPV 16 E7 protein interacted reciprocally with p-AKT(Ser473)/p-Src(Tyr527). In conclusion, we demonstrate that HPV16 E7 oncoprotein is continuously expressed to promote expression of p-AKT(Ser473)/p-Src(Tyr527) leading to drive the initiation and progression of cervical cancer. Our data provide a novel insight that HPV16 E7 activates p-AKT(Ser473)/p-Src(Tyr527) to establish a mechanistic link between the oncogene and the AKT/Src signaling to trigger cervical carcinogenesis.
The goal of this study is to use comprehensive molecular profiling to characterize clinical response to anti-TNF therapy in a real-world setting and identify reproducible markers differentiating good ...responders and non-responders in rheumatoid arthritis (RA).
Whole-blood mRNA, plasma proteins, and glycopeptides were measured in two cohorts of biologic-naïve RA patients (n = 40 and n = 36) from the Corrona CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory coNditions) registry at baseline and after 3 months of anti-TNF treatment. Response to treatment was categorized by EULAR criteria. A cell type-specific data analysis was conducted to evaluate the involvement of the most common immune cell sub-populations. Findings concordant between the two cohorts were further assessed for reproducibility using selected NCBI-GEO datasets and clinical laboratory measurements available in the CERTAIN database.
A treatment-related signature suggesting a reduction in neutrophils, independent of the status of response, was indicated by a high level of correlation (ρ = 0.62; p < 0.01) between the two cohorts. A baseline, response signature of increased innate cell types in responders compared to increased adaptive cell types in non-responders was identified in both cohorts. This result was further assessed by applying the cell type-specific analysis to five other publicly available RA datasets. Evaluation of the neutrophil-to-lymphocyte ratio at baseline in the remaining patients (n = 1962) from the CERTAIN database confirmed the observation (odds ratio of good/moderate response = 1.20 95% CI = 1.03-1.41, p = 0.02).
Differences in innate/adaptive immune cell type composition at baseline may be a major contributor to response to anti-TNF treatment within the first 3 months of therapy.
Targeted antibody therapies improve outcomes for chronic lymphocytic leukemia (CLL) patients. However, resistance often develops. We have previously shown that resistance to therapeutic antibodies, ...by monocyte derived macrophages (referred to as nurse like cells, NLCs), from CLL patients is characterized by suppression of antibody dependent phagocytosis (ADP). The mechanism(s) contributing to the muted ADP responses remain unresolved. In this regard, an innate immune checkpoint was recently described that uses the CD47:SIRPα axis to suppress phagocytic responses by macrophages. In this study we examine whether the SIRPα axis regulates ADP responses to the anti-CD20 antibody, obinutuzumab, by NLCs. Using siRNA depletion strategies we show that SIRPα is a suppressor of ADP responses. Moreover, we show that this innate immune checkpoint contributes to the resistance phenotype in NLCs derived from CLL patients. Finally, we show that SIRPα suppression is mediated
the phosphatase, Shp1, which in turn suppresses SYK-dependent activation of ADP. Thus, we identify a druggable pathway that could be exploited to enhance sensitivity to existing therapeutic antibodies used in CLL. This is the first study to show that activation of the CD47:SIRPα innate immune checkpoint contributes to ADP resistance in NLCs from CLL patients.
Patient mortality rates have remained stubbornly high (40%) for the past 35 years in head and neck squamous cell carcinoma (HNSCC) due to inherent or acquired drug resistance. Thus, a critical issue ...in advanced SCC is to identify and target the mechanisms that contribute to therapy resistance. We report that the transcriptional inhibitor, E2F7, is mislocalized to the cytoplasm in >80% of human HNSCCs, whereas the transcriptional activator, E2F1, retains localization to the nucleus in SCC. This results in an imbalance in the control of E2F-dependent targets such as
, which is derepressed and drives resistance to anthracyclines in HNSCC. Specifically, we show that (i) E2F7 is subject to exportin 1 (XPO1)-dependent nuclear export, (ii) E2F7 is selectively mislocalized in most of SCC and multiple other tumor types, (iii) mislocalization of E2F7 in HNSCC causes derepression of Sphk1 and drives anthracycline resistance, and (iv) anthracycline resistance can be reversed with a clinically available inhibitor of XPO1, selinexor, in xenotransplant models of HNSCC. Thus, we have identified a strategy to repurpose anthracyclines for use in SCC. More generally, we provide a strategy to restore the balance of E2F1 (activator) and E2F7 (inhibitor) activity in cancer.
Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent cancers diagnosed worldwide and is associated with a 5-year survival rate of 55%. EZH2, a component of the polycomb ...repressor complex 2, trimethylates H3K27 (H3K27me3), which has been shown to drive squamous differentiation in normal keratinocytes. This study determined whether inhibition of EZH2-mediated epigenetic silencing could induce differentiation or provide therapeutic benefit in HNSCC.
We determined the effects of inhibiting EZH2, by either RNA interference or pharmacologically, on HNSCC growth, viability, and differentiation in vitro. Xenografts of HNSCC cell lines were used to assess efficacy of 3-deazaneplanocin A (DZNep), an inhibitor of H3K27 trimethylation, in vivo.
EZH2 was highly expressed in HNSCC cell lines in vitro and tissue microarray analysis revealed high expression in (n = 59) in situ relative to normal oral epithelium (n = 12). Inhibition of EZH2 with siRNA could induce expression of differentiation genes in differentiation-refractory squamous cell carcinoma cell lines. Differentiation-refractory HNSCC cell lines displayed persistent H3K27me3 on the promoters of differentiation genes. DZNep caused cancer-cell-specific apoptosis in addition to a profound reduction in colony-forming efficiency and induction of some squamous differentiation genes. Furthermore, in vivo, DZNep attenuated tumor growth in two different xenograft models, caused intratumor inhibition of EZH2, and induction of differentiation genes in situ.
Collectively, these data suggest that aberrant differentiation in HNSCC may be attributed to epigenetic dysregulation and suggest that inhibition of PRC2-mediated gene repression may represent a potential therapeutic target.
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