Your Sewing Machine - Its Care and Adjustment

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Guadecitabine, in combination with Cyclophosphamide, promotes anti- cancer immunity in BALB/c mice bearing 4T1 mouse mammary carcinoma

Background: The extremely high mortality rate of patients diagnosed with triple negative breast cancer makes it one of the deadliest forms of cancer. Due to the heterogenous nature of tumors, complete clearance is not achieved and clonal selection occurs resulting in tumor cells evading the immune system. I aim to design a therapeutic intervention that is able to elicit an effective immune response against the tumor and instill immunological memory to eradicate primary and metastatic lesions. I hypothesize that the combination of Guad and Cyp will synergize and promote anticancer immunity via increased expression of neo-tumor antigens and depletion of MDSCs and T-regs. Methods: Guadecitabine (Guad), is a second-generation DNA methyltransferase inhibitor (DMNTi) that has been reported to increase antigenicity and deplete myeloid-derived suppressor cells (MDSC’s). Cyclophosphamide (Cyp) is a chemotherapy that has been shown to deplete regulatory T-cells (T-regs). Both MDSD’s and T-regs suppress antitumor immunity. BALB/c mice were challenged with 4T1 tumor cells subcutaneously in the mammary fat pad region. 4T1-bearing mice were administered low-dose Guad and Cyp for ten consecutive days. Tumor growth curves, tumor-infiltrating lymphocytes (TILs) were measured and MDSC’s and T- regs levels were assessed by flow cytometry. Results: Results from this experiment showed significant synergy between Guad and Cyp with both drugs reducing the tumor size over monotherapy. Conclusions: Further analysis of the data along with future experiments will elucidate if this synergy is driven by the depletion of MDSC’s and T-regs alone or the increase in tumor antigenicity inducing increased numbers of TILs.https://scholarscompass.vcu.edu/gradposters/1078/thumbnail.jp

Interaction between Injection Points during Hydraulic Fracturing

We present a model of the hydraulic fracturing of heterogeneous poroelastic media. The formalism is an effective continuum model that captures the coupled dynamics of the fluid pressure and the fractured rock matrix and models both the tensile and shear failure of the rock. As an application of the formalism, we study the geomechanical stress interaction between two injection points during hydraulic fracturing (hydrofracking) and how this interaction influences the fracturing process. For injection points that are separated by less than a critical correlation length, we find that the fracturing process around each point is strongly correlated with the position of the neighboring point. The magnitude of the correlation length depends on the degree of heterogeneity of the rock and is on the order of 30-45 m for rocks with low permeabilities. In the strongly correlated regime, we predict a novel effective fracture-force that attracts the fractures toward the neighboring injection point.Comment: Submitte

Multitasking associative networks

We introduce a bipartite, diluted and frustrated, network as a sparse restricted Boltzman machine and we show its thermodynamical equivalence to an associative working memory able to retrieve multiple patterns in parallel without falling into spurious states typical of classical neural networks. We focus on systems processing in parallel a finite (up to logarithmic growth in the volume) amount of patterns, mirroring the low-level storage of standard Amit-Gutfreund-Sompolinsky theory. Results obtained trough statistical mechanics, signal-to-noise technique and Monte Carlo simulations are overall in perfect agreement and carry interesting biological insights. Indeed, these associative networks pave new perspectives in the understanding of multitasking features expressed by complex systems, e.g. neural and immune networks.Comment: to appear on Phys.Rev.Let

Phenotype, functions and fate of adoptively transferred tumor draining lymphocytes activated ex vivo in mice with an aggressive weakly immunogenic mammary carcinoma

<p>Abstract</p> <p>Background</p> <p>Regression of established tumors can be induced by adoptive immunotherapy with tumor draining lymph node lymphocytes activated with bryostatin and ionomycin. We hypothesized that tumor regression is mediated by a subset of the transferred T lymphocytes, which selectively infiltrate the tumor draining lymph nodes and proliferate <it>in vivo</it>.</p> <p>Results</p> <p>Adoptive transfer of B/I activated tumor draining lymphocytes induces regression of advanced 4T1 tumors, and depletion of CD8, but not CD4 T cells, abrogated tumor regression in mice. The predominant mediators of tumor regression are CD8+ and derived from CD62L^-T cells. Transferred lymphocytes reached their peak concentration (10.5%) in the spleen 3 days after adoptive transfer and then rapidly declined. Adoptively transferred cells preferentially migrated to and/or proliferated in the tumor draining lymph nodes, peaking at day 5 (10.3%) and remained up to day 28. CFSE-stained cells were seen in tumors, also peaking at day 5 (2.1%). Bryostatin and ionomycin-activated cells proliferated vigorously <it>in vivo</it>, with 10 generations evident in the tumor draining lymph nodes on day 3. CFSE-stained cells found in the tumor draining lymph nodes on day 3 were 30% CD8⁺, 72% CD4⁺, 95% CD44⁺, and 39% CD69⁺. Pre-treatment of recipient mice with cyclophosphamide dramatically increased the number of interferon-gamma producing cells.</p> <p>Conclusions</p> <p>Adoptively transferred CD8+ CD62L^lowT cells are the principal mediators of tumor regression, and host T cells are not required. These cells infiltrate 4T1 tumors, track preferentially to tumor draining lymph nodes, have an activated phenotype, and proliferate <it>in vivo</it>. Cyclophosphamide pre-treatment augments the anti-tumor effect by increasing the proliferation of interferon-gamma producing cells in the adoptive host.</p

Cyclical population dynamics of automatic versus controlled processing : an evolutionary pendulum

Psychologists, neuroscientists, and economists often conceptualize decisions as arising from processes that lie along a continuum from automatic (i.e., “hardwired” or over-learned, but relatively inflexible) to controlled (less efficient and effortful, but more flexible). Control is central to human cognition, and plays a key role in our ability to modify the world to suit our needs. Given its advantages, reliance on controlled processing may seem predestined to increase within the population over time. Here, we examine whether this is so by introducing an evolutionary game theoretic model of agents that vary in their use of automatic versus controlled processes, and in which cognitive processing modifies the environment in which the agents interact. We find that, under a wide range of parameters and model assumptions, cycles emerge in which the prevalence of each type of processing in the population oscillates between two extremes. Rather than inexorably increasing, the emergence of control often creates conditions that lead to its own demise by allowing automaticity to also flourish, thereby undermining the progress made by the initial emergence of controlled processing. We speculate that this observation may have relevance for understanding similar cycles across human history, and may lend insight into some of the circumstances and challenges currently faced by our species