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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2014)

The formation of a substantial foam layer has severe impacts on the overall digestion process that is responsible for the major portion of waste stabilization. An understanding of dynamics of foam produced by three primary causes - dispersed gas bubbles, surface-active materials, and hydrophobic compounds - provides insight into the prevention of the foam layer and into the control of the foam stability. To better understand the mechanisms in three-phase foam dynamics, we developed a systematic methodology to characterize foam drainage behavior using electrical conductance measurements.

With no sludge conditions, all tested sodium dodecyl sulfate (SDS) foams exhibit a node-dominated drainage regime with high mobility at bubble surfaces. Drainage regime under similar foaming conditions was consistent with existing drainage studies using other measurement techniques in the literature.

The drainage of sodium dodecylbenzenesulfonate (SDBS) surfactant solution, a commercial form of linear alkylbenzene sulfonate (LAS) that is most frequently found in anaerobic sludge, was studied in detail by several approaches. Two complementary methods of macroscopic drainage investigations (forced and free drainage) were conducted to gain confidence in its validity. The experimental data can be fitted using a power law with an exponent of 1/3 for forced drainage and of 1.0 for free drainage. These data indicate the following drainage behavior: mobile bubble surfaces, causing plug-like flow within Plateau borders, thus dissipation mainly occurs inside the nodes.

With the drainage studies for a variety of aqueous surfactant solutions, experimental and theoretical studies to include wastewater sludge are important for understanding the stability of three-phase foams, and therefore foaming in anaerobic digesters. The drainage behavior of sludge-containing foams was characterized by our developed method. The presence of anaerobic sludge at total solid (TS) concentrations of approximately 2.5-2.8% induced a transition from the node-dominated regime to a Plateau-border (PB)-dominated regime. This apparent transition was verified in both forced and free drainage experiments. These drainage studies supported a more detailed estimation of foam stability in relation to its structure.

In summary, our developed method using the electrical conductance measurements was applied to understand the key aspects of foam stability required for prediction and control of foaming in anaerobic digesters. A systematic methodology for assessing foam dynamics was proposed and discussed in two- and three-phase foams.

    Cover page: A Systematic Analysis of Foam Drainage and Stability: Measurements, Mechanisms, and Implications for Anaerobic Digester Foaming
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2015)
    Expansion of myeloid cells associated with solid tumor development is a key contributor to neoplastic progression. Despite their clinical relevance, the mechanisms controlling myeloid cell production and activity in cancer remains poorly understood. Using a multistage mouse model of breast cancer, we show that production of atypical T cell-suppressive neutrophils occurs during early tumor progression, at the onset of malignant conversion, and that these cells preferentially accumulate in peripheral tissues but not in the primary tumor. Production of these cells results from activation of a myeloid differentiation program in bone marrow (BM) by a novel mechanism in which tumor-derived granulocyte-colony stimulating factor (G-CSF) directs expansion and differentiation of hematopoietic stem cells to skew hematopoiesis toward the myeloid lineage. Chronic skewing of myeloid production occurred in parallel to a decrease in erythropoiesis in BM in mice with progressive disease. Significantly, we reveal that prolonged G-CSF stimulation is both necessary and sufficient for the distinguishing characteristics of tumor-induced immunosuppressive neutrophils. These results demonstrate that prolonged G-CSF may be responsible for both the development and activity of immunosuppressive neutrophils in cancer.
      Cover page: Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2019)
      Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.
        Cover page: Clonal Deletion of Tumor-Specific T Cells by Interferon-γ Confers Therapeutic Resistance to Combination Immune Checkpoint Blockade.
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2019)
        While immune checkpoint blockade leads to potent antitumor efficacy, it also leads to immune-related adverse events in cancer patients. These toxicities stem from systemic immune activation resulting in inflammation of multiple organs, including the gastrointestinal tract, lung, and endocrine organs. We developed a dual variable domain immunoglobulin of anti-CTLA4 antibody (anti-CTLA4 DVD, where CTLA4 is defined as cytotoxic T lymphocyte-associated antigen-4) possessing an outer tumor-specific antigen-binding site engineered to shield the inner anti-CTLA4-binding domain. Upon reaching the tumor, the outer domain was cleaved by membrane type-serine protease 1 (MT-SP1) present in the tumor microenvironment, leading to enhanced localization of CTLA4 blockade. Anti-CTLA4 DVD markedly reduced multiorgan immune toxicity by preserving tissue-resident Tregs in Rag 1-/- mice that received naive donor CD4+ T cells from WT C57BL/6j mice. Moreover, anti-CTLA4 DVD induced potent antitumor effects by decreasing tumor-infiltrating Tregs and increasing the infiltration of antigen-specific CD8+ T lymphocytes in TRAMP-C2-bearing C57BL/6j mice. Treg depletion was mediated through the antibody-dependent cellular cytotoxicity (ADCC) mechanism, as anti-CTLA4 without the FcγR-binding portion (anti-CTLA4 DANA) spared Tregs, preventing treatment-induced toxicities. In summary, our results demonstrate an approach to anti-CTLA4 blockade that depletes tumor-infiltrating, but not tissue-resident, Tregs, preserving antitumor effects while minimizing toxicity. Thus, our tumor-conditional anti-CTLA4 DVD provides an avenue for uncoupling antitumor efficacy from immunotherapy-induced toxicities.
          Cover page: Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity.
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