Preclinical modeling and gene expression analyses have yielded distinct observations for the role of immune checkpoint, IDO1, in glioblastoma (GBM). Accordingly, our recent work differs with Garg et ...al. (2017) with respect to IDO1 among preclinical and bioinformatic GBM datasets. Here, we discuss the methodological differences that affected study interpretation, and potentially, future clinical decision-making for IDO1-targeting approaches against GBM.
Immunogenic tumors grow progressively even when heavily infiltrated by CD8(+) T cells. We investigated how to rescue CD8(+) T cell function in long-established immunogenic melanomas that contained a ...high percentage of endogenous PD-1(+) tumor-specific CD8(+) T cells that were dysfunctional. Treatment with αPD-L1 and αCTLA-4 blocking antibodies did not prevent tumors from progressing rapidly. We then tested exogenous tumor-specific antigen delivery into tumors using Salmonella Typhimurium A1-R to increase antigen levels and generate a proinflammatory tumor microenvironment. Antigen-producing A1-R rescued the endogenous tumor-specific CD8(+) T cell response: proliferation was induced in the lymphoid organs and effector function was recovered in the tumor. Treatment with antigen-producing A1-R led to improved mouse survival and resulted in 32% rejection of long-established immunogenic melanomas. Following treatment with antigen-producing A1-R, the majority of tumor-specific CD8(+) T cells still expressed a high level of PD-1 in the tumor. Combining antigen-producing A1-R with αPD-L1 blocking antibody enhanced the expansion of tumor-specific CD8(+) T cells and resulted in 80% tumor rejection. Collectively, these data demonstrate a powerful new therapeutic approach to rescue dysfunctional endogenous tumor-specific CD8(+) T cells and eradicate advanced immunogenic tumors.
Dynamic contrast-enhanced MRI (DCE-MRI) has become a standard component of multiparametric protocols for MRI examination of the prostate, and its use is incorporated into current guidelines for ...prostate MRI examination. Analysis of DCE-MRI data for the prostate is usually based on the distribution of gadolinium-based agents, such as gadodiamide, into two well-mixed compartments, and it assumes that gadodiamide does not enter into the glandular lumen. However, this assumption has not been directly tested. The purpose of this study was to use x-ray fluorescence microscopy (XFM) imaging in situ to measure the concentration of gadodiamide in the epithelia and lumens of the prostate of healthy mice after IV injection of the contrast agent.
Six C57Bl6 male mice (age, 28 weeks) were sacrificed 10 minutes after IV injection of gadodiamide (0.13 mmol/kg), and three mice were sacrificed after saline injection. Prostate tissue samples obtained from each mouse were harvested and frozen; 7-μm-thick slices were sectioned for XFM imaging, and adjacent 5-μm-thick slices were sectioned for H and E staining. Elemental concentrations were determined from XFM images.
A mean (± SD) baseline concentration of gadolinium of 0.01 ± 0.01 mM was determined from XFM measurements of prostatic tissue samples when no gadodiamide was administered, and it was used to determine the measurement error. When gadodiamide was added, the mean concentrations of gadolinium in the epithelia and lumens in 32 prostatic glands from six mice were 1.00 ± 0.13 and 0.36 ± 0.09 mM, respectively.
Our data suggest that IV administration of gadodiamide results in uptake of contrast agent by the glandular lumens of the mouse prostate. We were able to quantitatively determine gadodiamide distributions in mouse prostatic epithelia and lumens.
We tested how to eradicate long-established immunogenic tumors that were resistant to the monoclonal antibody-mediated blockade of PD-L1 (PD-1 ligand 1) and cytotoxic T lymphocyte-associated protein ...4 (CTLA4). Bacterial vaccination with a tumor-specific peptide exhibiting a high affinity for its respective MHC molecule consistently eradicated tumors when combined with a PD-L1 blocking antibody. This approach can be translated to the clinic by combining cancer cell whole-exome sequencing with algorithms to identify mutant peptides with high peptide-MHC binding affinity.
The effective treatment of adult and pediatric malignant glioma is a significant clinical challenge. In adults, glioblastoma (GBM) accounts for the majority of malignant glioma diagnoses with a ...median survival of 14.6 mo. In children, malignant glioma accounts for 20% of primary CNS tumors with a median survival of less than 1 y. Here, we discuss vaccine treatment for children diagnosed with malignant glioma, through targeting EphA2, IL-13Rα2 and/or histone H3 K27M, while in adults, treatments with RINTEGA, Prophage Series G-100 and dendritic cells are explored. We conclude by proposing new strategies that are built on current vaccine technologies and improved upon with novel combinatorial approaches.
The provocative lumbar facet joint Binder, David S.; Nampiaparampil, Devi E.
Current reviews in musculoskeletal medicine,
03/2009, Letnik:
2, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Low back pain is the most common pain symptom experienced by American adults and is the second most common reason for primary care physician visits. There are many structures in the lumbar spine that ...can serve as pain generators and often the etiology of low back pain is multifactorial. However, the facet joint has been increasingly recognized as an important cause of low back pain. Facet joint pain can be diagnosed with local anesthetic blocks of the medial branches or of the facet joints themselves. Subsequent radiofrequency lesioning of the medial branches can provide more long-term pain relief. Despite some of the pitfalls associated with facet joint blocks, they have been shown to be valid, safe, and reliable as a diagnostic tool. Medial branch denervation has shown some promise for the sustained control of lumbar facet joint-mediated pain, but at this time, there is insufficient evidence that it is a wholly efficacious treatment option. Developing a universal algorithm for evaluating facet joint-mediated pain and standard procedural techniques may facilitate the performance of larger outcome studies. This review article provides an overview of the anatomy, pathophysiology, diagnosis, and treatment of facet joint-mediated pain.
Abstract
Background
Radioresistance represents a major problem in the treatment of head and neck cancer (HNC) patients. To improve response, understanding tumor microenvironmental factors that ...contribute to radiation resistance is important. Regulatory T cells (Tregs) are enriched in numerous cancers and can dampen the response to radiation by creating an immune-inhibitory microenvironment. The purpose of this study was to investigate mechanisms of Treg modulation by radiation in HNC.
Methods
We utilized an orthotopic mouse model of HNC. Anti-CD25 was used for Treg depletion. Image-guided radiation was delivered to a dose of 10 Gy. Flow cytometry was used to analyze abundance and function of intratumoral immune cells. Enzyme-linked immunosorbent assay was performed to assess secreted factors. For immune-modulating therapies, anti–PD-L1, anti-CTLA-4, and STAT3 antisense oligonucleotide (ASO) were used. All statistical tests were two-sided.
Results
Treatment with anti-CD25 and radiation led to tumor eradication (57.1%, n = 4 of 7 mice), enhanced T-cell cytotoxicity compared with RT alone (CD4 effector T cells Teff: RT group mean = 5.37 0.58 vs RT + αCD25 group mean =10.71 0.67, P = .005; CD8 Teff: RT group mean = 9.98 0.81 vs RT + αCD25 group mean =16.88 2.49, P = .01) and induced tumor antigen-specific memory response (100.0%, n = 4 mice). In contrast, radiation alone or when combined with anti-CTLA4 did not lead to durable tumor control (0.0%, n = 7 mice). STAT3 inhibition in combination with radiation, but not as a single agent, improved tumor growth delay, decreased Tregs, myeloid-derived suppressor cells, and M2 macrophages and enhanced effector T cells and M1 macrophages. Experiments in nude mice inhibited the benefit of STAT3 ASO and radiation.
Conclusion
We propose that STAT3 inhibition is a viable and potent therapeutic target against Tregs. Our data support the design of clinical trials integrating STAT3 ASO in the standard of care for cancer patients receiving radiation.
Karl Popper developed a theory of deductive logic in the late 1940s. In his approach, logic is a metalinguistic theory of deducibility relations that are based on certain purely structural rules. ...Logical constants are then characterized in terms of deducibility relations. Characterizations of this kind are also called inferential definitions by Popper. In this paper, we expound his theory and elaborate some of his ideas and results that in some cases were only sketched by him. Our focus is on Popper's notion of duality, his theory of modalities, and his treatment of different kinds of negation. This allows us to show how his works on logic anticipate some later developments and discussions in philosophical logic, pertaining to trivializing (
-like) connectives, the duality of logical constants, dual-intuitionistic logic, the (non-)conservativeness of language extensions, the existence of a bi-intuitionistic logic, the non-logicality of minimal negation, and to the problem of logicality in general.
The expression problem describes how most types can easily be extended with new ways to produce the type or new ways to consume the type, but not both. When abstract syntax trees are defined as an ...algebraic data type, for example, they can easily be extended with new consumers, such as print or eval, but adding a new constructor requires the modification of all existing pattern matches. The expression problem is one way to elucidate the difference between functional or data-oriented programs (easily extendable by new consumers) and object-oriented programs (easily extendable by new producers). This difference between programs which are extensible by new producers or new consumers also exists for dependently typed programming, but with one core difference: Dependently-typed programming almost exclusively follows the functional programming model and not the object-oriented model, which leaves an interesting space in the programming language landscape unexplored. In this paper, we explore the field of dependently-typed object-oriented programming by deriving it from first principles using the principle of duality. That is, we do not extend an existing object-oriented formalism with dependent types in an ad-hoc fashion, but instead start from a familiar data-oriented language and derive its dual fragment by the systematic use of defunctionalization and refunctionalization. Our central contribution is a dependently typed calculus which contains two dual language fragments. We provide type- and semantics-preserving transformations between these two language fragments: defunctionalization and refunctionalization. We have implemented this language and these transformations and use this implementation to explain the various ways in which constructions in dependently typed programming can be explained as special instances of the general phenomenon of duality.
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