Effects of the Three Gorges Dam on spatiotemporal distribution of silicon in the tributary: evidence from the Xiangxi River

Abstract

In order to get insight into the impact of Three Gorges Dam construction on silicon distribution pattern due to the altered hydraulic and environmental conditions, the Xiangxi River was chosen as the delegate of the tributaries in the Three Gorges Reservoir; dissolved silica (DSi), biogenic silica (BSi), and lithogenic silica (LSi) were investigated monthly from November 2015 to October 2016 and the hydrodynamic conditions and environmental parameters were addressed synchronously. DSi, BSi, and LSi ranged from 56.07 to 106.07 μmol/L, 0 to 5.64 μmol/L, and 0.49 to 11.47 μmol/L, with the average concentration of 81.84 ± 14.65 μmol/L, 1.11 ± 0.69 μmol/L, and 2.68 ± 1.97 μmol/L, respectively. DSi was significantly lower in the wet season than the dry season (P < 0.05), but BSi and LSi showed a converse trend. DSi was the dominant component in the total silicon (> 90%) and it has a higher concentration in the midstream than other sites. While BSi and LSi exhibited a decrease trend from the upstream to the downstream. Statistical analysis showed that DSi and LSi was primarily controlled by discharge. BSi concentration was affected by algal growth since it was positively correlated with Chla. The backwater area retained 3.67% total silicon. It was concluded that the spatiotemporal heterogeneity of silicon distribution related to hydrodynamics was determined by the regulation of dam; permanent backwater area was the main deposition area for silicon.

https://ift.tt/2QCZoni

A Targeted Bivalent Androgen Receptor Binding Compound for Prostate Cancer Therapy

Abstract

The androgen-directed treatment of prostate cancer (PCa) is fraught with the recurrent profile of failed treatment due to drug resistance and must be addressed if we are to provide an effective therapeutic option. The most singular difficulty in the treatment of PCa is the failure to respond to classical androgen withdrawal or androgen blockade therapy, which often develops as the malignancy incurs genetic alterations and gain-of-function somatic mutations in the androgen receptor (AR). Physical cellular damaging therapeutic agents, such as radiation or activatable heat-generating transducers would circumvent classical "anti-functional" biological resistance, but to become ultimately effective would require directed application modalities. To this end, we have developed a novel AR-directed therapeutic agent by creating bivalent androgen hormone-AF-2 compounds that bind with high affinity to AR within cells. Here, we used molecular modeling and synthetic chemistry to create a number of compounds by conjugating 5α-dihydrotestosterone (DHT) to various AF-2 motif sequence peptides, through the use of a glycine and other spacer linkers. Our data indicates these compounds will bind to the AR in vitro and that altering the AF-2 peptide composition of the compound does indeed improve affinity for the AR. We also show that many of these bivalent compounds can readily pass through the plasma membrane and effectively compete against androgens alone.

https://ift.tt/2LpPI9J

Synthesis of novel waste batteries-sawdust-based adsorbent via a two-stage activation method for Pb 2+ removal

Abstract

The novel waste alkaline battery-sawdust-based adsorbents (WABAs) are prepared by a two-stage activation method with the negative electrode materials as activator and different doping ratio of the positive electrode materials and pine sawdust as raw materials. The characteristics of the WABAs are analyzed by SEM, XRD, FT-IR, and specific surface determination (S_BET). The Pb²⁺ adsorption properties of the WABAs are studied by changing the pH of solution, contact time, initial concentration, and temperature. It turns out that when the doping mass ratio is 1:4, the optimum performance of the WABAs is obtained, and comparing with the samples prepared by pure biomass, the iodine adsorption value, total acid groups, and cation exchange capacity (CEC) separately increased by 13, 106, and 22%, respectively. Kinetic studies show that the pseudo-second-order model is more suitable for describing the Pb²⁺ adsorption process and the Langmuir isotherm provides better fitting to the equilibrium data. The thermodynamic parameters indicate the adsorption process would be spontaneous and endothermic. Besides, the prepared WABAs could be reused for 5 cycles with high removal efficiency. This study provides an alternative route for waste alkaline battery treatment.

Graphical abstract

The schematic diagram of synthesis of waste batteries-sawdust-based adsorbent via a two-stage activation method for Pb²⁺ removal

https://ift.tt/2CksC1m

Identification and characterization of an alternative cancer-derived PD-L1 splice variant

Abstract

Therapeutic blockade of the PD-1/PD-L1 axis is recognized as an effective treatment for numerous cancer types. However, only a subset of patients respond to this treatment, warranting a greater understanding of the biological mechanisms driving immune evasion via PD-1/PD-L1 signaling and other T-cell suppressive pathways. We previously identified a head and neck squamous cell carcinoma with human papillomavirus integration in the PD-L1 locus upstream of the transmembrane domain-encoding region, suggesting expression of a truncated form of PD-L1 (Parfenov et al., Proc Natl Acad Sci USA 111(43):15544–15549, 2014). In this study, we extended this observation by performing a computational analysis of 33 other cancer types as well as human cancer cell lines, and identified additional PD-L1 isoforms with an exon 4 enrichment expressed in 20 cancers and human cancer cell lines. We demonstrate that cancer cell lines with high expression levels of exon 4-enriched PD-L1 generate a secreted form of PD-L1. Further biochemical studies of exon 4-enriched PD-L1 demonstrated that this form is secreted and maintains the capacity to bind PD-1 as well as to serve as a negative regulator on T cell function, as measured by inhibition of IL-2 and IFNg secretion. Overall, we have demonstrated that truncated forms of PD-L1 exist in numerous cancer types, and have validated that truncated PD-L1 can be secreted and negatively regulate T cell function.

https://ift.tt/2S8pHy6

A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression

Abstract

Targeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgkin lymphoma. PD-L1 is a co-inhibitory molecule whose expression on the surface of tumor cells is associated with worse prognosis in many tumors. Here we describe a splice variant (secPD-L1) that does not splice into the transmembrane domain, but instead produces a secreted form of PD-L1 that has a unique 18 amino acid tail containing a cysteine that allows it to homodimerize and more effectively inhibit lymphocyte function than monomeric soluble PD-L1. We show that recombinant secPD-L1 can dimerize and inhibit T-cell proliferation and IFN-gamma production in vitro. The secPD-L1 variant is expressed by malignant cells in vitro that also express high levels of full-length PD-L1. Transcriptomic analysis of gene expression across The Cancer Genome Atlas found the strongest association of secPD-L1 with full-length PD-L1, but also with subsets of immunologic genes, such as in myeloid-derived suppressor cells. Moreover, the splice variant is also expressed in normal tissues and within normal peripheral blood cells it is preferentially expressed in activated myeloid cells. This is the first report of a form of secreted PD-L1 that homodimerizes and is functionally active. SecPD-L1 may function as a paracrine negative immune regulator within the tumor, since secPD-L1 does not require a cell-to-cell interaction to mediate its inhibitory effect.

https://ift.tt/2A2Iu74

The Italian Network for Tumor Bio-Immunotherapy (NIBIT) Foundation: ongoing and prospective activities in immuno-oncology

Abstract

The ongoing revolution in cancer immunotherapy stems from the knowledge that distinct immune-checkpoints regulate the physiological crosstalk between and among immune cells by delivering inhibitory or activating signals. These notions, and the availability of mAb directed to diverse immune-checkpoint molecules, have led to a significant clinical improvement in cancer treatment. In this scenario, further achievements are undoubtedly to be expected from the contribution of novel, proof-of-principle clinical trials designed to explore the therapeutic efficacy of new immunotherapy-based combinations and treatment sequences. Along these lines, the clinical translation of pre-clinical evidence generated by non-profit research entities is likely to provide a significant contribution to gaining new insights that will further boost the field of cancer immunotherapy. To pursue this goal, and to provide comprehensive educational programs in immune-oncology (I-O), several national and global networks have been revitalized or newly established in recent years. This rapidly evolving scenario led the Board of Directors of the Italian Network of Tumor Bio-Immunotherapy (NIBIT) to establish the NIBIT Foundation. This Focused Research Review summarizes the main ongoing and prospective I-O activities of the NIBIT Foundation.

https://ift.tt/2SUUOx8

Addressing current challenges and future directions in immuno-oncology: expert perspectives from the 2017 NIBIT Foundation Think Tank, Siena, Italy

Abstract

A collaborative think tank involving panellists from immuno-oncology networks, clinical/translational investigators and the pharmaceutical industry was held in Siena, Italy, in October 2017 to discuss the evolving immune-oncology landscape, identify selected key challenges, and provide a perspective on the next steps required in the translation of current research and knowledge to clinical reality. While there is a trend of combining new agents (e.g., co-stimulator agonists) with a PD-1/PD-L1 treatment backbone, use of alternative combination therapy approaches should also be considered. While the rapid evolution in systems biology provides a deeper understanding of tumor and tumor microenvironment heterogeneity, there remains the need to identify and define genuinely predictive biomarkers to guide treatment and patient selection. Cross-specialty and cross-sector collaboration, along with a broader collective data-sharing approach are key to optimizing immuno-oncology therapy in clinical practice. Continued support of younger research-clinicians is essential for future success in clinical, translational and basic science investigations.

https://ift.tt/2CjW5Zl