Chemoattractant receptors BLT1 and CXCR3 regulate anti-tumor immunity by facilitating CD8+ T cell migration to tumors.

Presence of increased numbers of CD8+ T cells in the tumors correspond to better overall survival in the patients. Variety of immuno-therapies have shown considerable efficacy in the clinic, however, a multitude of patients remain unresponsive. Most of these immunotherapies rely on effector T cell responses in the tumor. A major obstacle in the success of these immunotherapies is poor recruitment of CD8+ T cells into tumors despite intact effector responses in the periphery. Therefore understanding the mechanisms that regulate CTL infiltration into tumors becomes essential. Previous studies in our laboratory suggested an important role for BLT1 in immune surveillance against tumors by regulating CTL migration in a syngeneic cervical cancer tumor model. In this thesis, we investigated the roles of leukotriene B4 (LTB4) receptor - BLT1; and CXCR3, the receptor for CXCL9, CXCL10 and CXCL11 in anti-tumor immunity using a syngeneic B16 melanoma tumor model. BLT1-/- mice and CXCR3-/- mice on a C57BL/6 background were used to examine the function of these receptors in tumor progression. Significant acceleration in tumor growth and reduced survival was observed in both BLT1-/- and CXCR3-/- mice as compared to the WT mice. Analysis of tumor infiltrating leukocytes revealed significant reduction of CD8+ T cells in the tumors of BLT1-/- and CXCR3-/- mice as compared to WT tumors; their frequencies being similar in the periphery (spleen and TdLN). Significant reduction of Granzyme-B and IFNγ transcripts were observed in tumors of knockout mice compared to WT mice. Adoptive transfer of tumor experienced WT but not BLT1-/- or CXCR3-/- CD8+ T cells reduced tumor growth significantly in Rag2-/- mice, which correlated with reduced infiltration of knockout CD8+ T cells into tumors. Co-transfer of WT CD8+ T cells with either of the knockout CD8+ T cells in tumor bearing Rag2-/- mice showed that WT CD8+ T cells did not facilitate additional knockout CD8+ T cell infiltration to tumors. BLT1/CXCR3 double deficient mice displayed similar tumor kinetics as single knockout mice and showed lack of synergism. The requirement for BLT1 and CXCR3 in inducing checkpoint blockade mediated anti-tumor response was tested. While anti-PD-1 based vaccine significantly attenuated tumor growth in WT mice, the vaccine completely lost its efficacy in BLT1-/-, CXCR3-/- or BLT1-/-CXCR3-/- mice that correlated with failure of knockout CD8+ T cell infiltration into tumors. These results demonstrate a critical role for BLT1 and CXCR3 in CTL migration to tumors and thus can be targeted to enhance effective anti-tumor responses

Essential Role of Lyn in Fibrosis.

Fibrotic disorders involve replacement of normal parenchyma with myofibroblasts, which deposit connective tissue, leading to obliteration of the function of the underlying organ. The treatment options are inadequate and reflect the fact that signaling targets in myofibroblasts are unknown. Here we identify the hyperactive Lyn signaling in myofibroblasts of patients with chronic pancreatitis-induced fibrosis. Lyn activation coexpress with markers of activated myofibroblasts, and is increased ~11-fold in chronic pancreatitis compared to normal tissue. Inhibition of Lyn with siRNA or INNO-406 leads to the substantial decrease of migration and proliferation of human chronic pancreatitis myofibroblasts in vitro, while leaving migration and proliferation of normal myofibroblasts only slightly affected. Furthermore, inhibition of Lyn prevents synthesis of procollagen and collagen in myofibroblasts in a mouse model of chronic pancreatitis-induced fibrosis. We conclude that Lyn, as a positive regulator of myofibroblast migration, proliferation, and collagen production, is a key target for preventing fibrosis

Using mass spectrometry imaging to map fluxes quantitatively in the tumor ecosystem

Tumors are comprised of a multitude of cell types spanning different microenvironments. Mass spectrometry imaging (MSI) has the potential to identify metabolic patterns within the tumor ecosystem and surrounding tissues, but conventional workflows have not yet fully integrated the breadth of experimental techniques in metabolomics. Here, we combine MSI, stable isotope labeling, and a spatial variant of Isotopologue Spectral Analysis to map distributions of metabolite abundances, nutrient contributions, and metabolic turnover fluxes across the brains of mice harboring GL261 glioma, a widely used model for glioblastoma. When integrated with MSI, the combination of ion mobility, desorption electrospray ionization, and matrix assisted laser desorption ionization reveals alterations in multiple anabolic pathways. De novo fatty acid synthesis flux is increased by approximately 3-fold in glioma relative to surrounding healthy tissue. Fatty acid elongation flux is elevated even higher at 8-fold relative to surrounding healthy tissue and highlights the importance of elongase activity in glioma

Ookami: An A64FX Computing Resource

We present a look at Ookami, a project providing community access to a testbed supercomputer with the ARM-based A64FX processors developed by a collaboration between RIKEN and Fujitsu and deployed in the Japanese supercomputer Fugaku. We provide an overview of the project and details of the hardware, and describe the user base and education/training program. We present highlights from previous performance studies of two astrophysical simulation codes and present a strong scaling study of a full 3D supernova simulation as an example of the the machine’s capability

High-Throughput Experimentation, Theoretical Modeling, and Human Intuition: Lessons Learned in Metal–Organic-Framework-Supported Catalyst Design

We have screened an array of 23 metals deposited onto the metal-organic framework (MOF) NU-1000 for propyne dimerization to hexadienes. By a first-of-its-kind study utilizing data-driven algorithms and high-throughput experimentation (HTE) in MOF catalysis, yields on Cu-deposited NU-1000 were improved from 0.4 to 24.4%. Characterization of the best-performing catalysts reveal conversion to hexadiene to be due to the formation of large Cu nanoparticles, which is further supported by reaction mechanisms calculated with density functional theory (DFT). Our results demonstrate both the strengths and weaknesses of the HTE approach. As a strength, HTE excels at being able to find interesting and novel catalytic activity; any a priori theoretical approach would be hard-pressed to find success, as high-performing catalysts required highly specific operating conditions difficult to model theoretically, and initial simple single-atom models of the active site did not prove representative of the nanoparticle catalysts responsible for conversion to hexadiene. As a weakness, our results show how the HTE approach must be designed and monitored carefully to find success; in our initial campaign, only minor catalytic performances (up to 4.2% yield) were achieved, which were only improved following a complete overhaul of our HTE approach and questioning our initial assumptions

A phase II study of laser interstitial thermal therapy combined with doxorubicin in patients with recurrent glioblastoma

BACKGROUND: The blood-brain barrier (BBB) is a major limiting factor for drug delivery in brain tumors. Laser interstitial thermal therapy (LITT) disrupts the peritumoral BBB. In this study, we examine survival in patients with recurrent glioblastoma (GBM) treated with LITT followed by low-dose doxorubicin, a potent anti-neoplastic drug with poor BBB permeability. METHODS: Forty-one patients with recurrent GBM were enrolled; thirty patients were evaluable. Participants underwent LITT followed by 6 weekly doxorubicin treatments starting within one week (Early Arm) or at 6-8 weeks (Late Arm) after LITT. The overall survival (OS), local progression-free survival (PFS), and any PFS were compared to historical controls treated with bevacizumab salvage therapy ( RESULTS: The Late Arm and all patients (Early Arm + Late Arm) demonstrated significant improvement in OS compared to historical controls treated with bevacizumab ( CONCLUSIONS: Low-dose doxorubicin given after LITT is well tolerated and correlated with higher OS compared to historical controls treated with bevacizumab or LITT with standard salvage chemotherapy. A larger study is needed to further characterize survival and progression patterns

A Model for Interprofessional Health Disparities Education: Student-Led Curriculum on Chronic Hepatitis B Infection

Although health disparities are commonly addressed in preclinical didactic curricula, direct patient care activities with affected communities are more limited. To address this problem, health professional students designed a preclinical service-learning curriculum on hepatitis B viral (HBV) infection, a major health disparity affecting the Asian/Pacific Islander (API) population, integrating lectures, skills training, and direct patient care at student-run clinics. An urban health professions campus. Medical and other health professional students at University of California, San Francisco, organized a preclinical didactic and experiential elective, and established two monthly clinics offering HBV screening, vaccination, and education to the community. Between 2004 and 2009, 477 students enrolled in the student-led HBV curriculum. Since the clinics’ inception in 2007, 804 patients have been screened for chronic HBV; 87% were API immigrants, 63% had limited English proficiency, and 46% were uninsured. Serologically, 10% were found to be chronic HBV carriers, 44% were susceptible to HBV, and 46% were immune. Our student-led didactic and experiential elective can serve as an interprofessional curricular model for learning about specific health disparities while providing important services to the local community