The potential role of exercise in neuro-oncology

Patients with brain and other central nervous system cancers experience debilitating physical, cognitive, and emotional effects, which significantly compromise quality of life. Few efficacious pharmacological strategies or supportive care interventions exist to ameliorate these sequelae and patients report high levels of unmet needs in these areas. There is strong theoretical rationale to suggest exercise may be an effective intervention to aid in the management of neuro-oncological disorders. Clinical research has established the efficacy of appropriate exercise in counteracting physical impairments such as fatigue and functional decline, cognitive impairment, as well as psychological effects including depression and anxiety. While there is promise for exercise to enhance physical and psychosocial wellbeing of patients diagnosed with neurologic malignancies, these patients have unique needs and research is urgently required to explore optimal exercise prescription specific to these patients to maximize safety and efficacy. This perspective article is a discussion of potential rehabilitative effects of targeted exercise programs for patients with brain and other central nervous system cancers and highlights future research directions

Reprogramming the anti-tumor immune response via CRISPR genetic and epigenetic editing

Precise clustered regularly interspaced short palindromic repeats (CRISPR)-mediated genetic and epigenetic manipulation of the immune response has become a promising immunotherapeutic approach towards combating tumorigenesis and tumor progression. CRISPR-based immunologic reprograming in cancer therapy comprises the locus-specific enhancement of host immunity, the improvement of tumor immunogenicity and the suppression of tumor immunoevasion. To date, the ex vivo re-engineering of immune cells directed to inhibit the expression of immune checkpoints or to express synthetic immune receptors (chimeric antigen receptor therapy) has shown success in some settings, such as in the treatment of melanoma, lymphoma, liver and lung cancer. However, advancements in nuclease-deactivated CRISPR-associated nuclease-9 (dCas9)-mediated transcriptional activation or repression and Cas13-directed gene suppression presents novel avenues for the development of tumor immunotherapies. In this review, the basis for development, mechanism of action and outcomes from recently published Cas9-based clinical trial (genetic editing) and dCas9/Cas13-based pre-clinical (epigenetic editing) data are discussed. Lastly, we review cancer immunotherapy-specific considerations and barriers surrounding use of these approaches in the clinic

Characteristics of TCR repertoire associated with successful immune checkpoint therapy responses

Immunotherapies have revolutionized cancer treatment. In particular, immune checkpoint therapy (ICT) leads to durable responses in some patients with some cancers. However, the majority of treated patients do not respond. Understanding immune mechanisms that underlie responsiveness to ICT will help identify predictive biomarkers of response and develop treatments to convert non-responding patients to responding ones. ICT primarily acts at the level of adaptive immunity. The specificity of adaptive immune cells, such as T and B cells, is determined by antigen-specific receptors. T cell repertoires can be comprehensively profiled by high-throughput sequencing at the bulk and single-cell level. T cell receptor (TCR) sequencing allows for sensitive tracking of dynamic changes in antigen-specific T cells at the clonal level, giving unprecedented insight into the mechanisms by which ICT alters T cell responses. Here, we review how the repertoire influences response to ICT and conversely how ICT affects repertoire diversity. We will also explore how changes to the repertoire in different anatomical locations can better correlate and perhaps predict treatment outcome. We discuss the advantages and limitations of current metrics used to characterize and represent TCR repertoire diversity. Discovery of predictive biomarkers could lie in novel analysis approaches, such as network analysis of amino acids similarities between TCR sequences. Single-cell sequencing is a breakthrough technology that can link phenotype with specificity, identifying T cell clones that are crucial for successful ICT. The field of immuno-sequencing is rapidly developing and cross-disciplinary efforts are required to maximize the analysis, application, and validation of sequencing data. Unravelling the dynamic behavior of the TCR repertoire during ICT will be highly valuable for tracking and understanding anti-tumor immunity, biomarker discovery, and ultimately for the development of novel strategies to improve patient outcomes

Percolation in three-dimensional random field Ising magnets

The structure of the three-dimensional random field Ising magnet is studied by ground state calculations. We investigate the percolation of the minority spin orientation in the paramagnetic phase above the bulk phase transition, located at [Delta/J]_c ~= 2.27, where Delta is the standard deviation of the Gaussian random fields (J=1). With an external field H there is a disorder strength dependent critical field +/- H_c(Delta) for the down (or up) spin spanning. The percolation transition is in the standard percolation universality class. H_c ~ (Delta - Delta_p)^{delta}, where Delta_p = 2.43 +/- 0.01 and delta = 1.31 +/- 0.03, implying a critical line for Delta_c < Delta <= Delta_p. When, with zero external field, Delta is decreased from a large value there is a transition from the simultaneous up and down spin spanning, with probability Pi_{uparrow downarrow} = 1.00 to Pi_{uparrow downarrow} = 0. This is located at Delta = 2.32 +/- 0.01, i.e., above Delta_c. The spanning cluster has the fractal dimension of standard percolation D_f = 2.53 at H = H_c(Delta). We provide evidence that this is asymptotically true even at H=0 for Delta_c < Delta <= Delta_p beyond a crossover scale that diverges as Delta_c is approached from above. Percolation implies extra finite size effects in the ground states of the 3D RFIM.Comment: replaced with version to appear in Physical Review

Tumor infiltrating effector memory Antigen-Specific CD8+ T Cells predict response to immune checkpoint therapy

Immune checkpoint therapy (ICT) results in durable responses in individuals with some cancers, but not all patients respond to treatment. ICT improves CD8+ cytotoxic T lymphocyte (CTL) function, but changes in tumor antigen-specific CTLs post-ICT that correlate with successful responses have not been well characterized. Here, we studied murine tumor models with dichotomous responses to ICT. We tracked tumor antigen-specific CTL frequencies and phenotype before and after ICT in responding and non-responding animals. Tumor antigen-specific CTLs increased within tumor and draining lymph nodes after ICT, and exhibited an effector memory-like phenotype, expressing IL-7R (CD127), KLRG1, T-bet, and granzyme B. Responding tumors exhibited higher infiltration of effector memory tumor antigen-specific CTLs, but lower frequencies of regulatory T cells compared to non-responders. Tumor antigen-specific CTLs persisted in responding animals and formed memory responses against tumor antigens. Our results suggest that increased effector memory tumor antigen-specific CTLs, in the presence of reduced immunosuppression within tumors is part of a successful ICT response. Temporal and nuanced analysis of T cell subsets provides a potential new source of immune based biomarkers for response to ICT

Revisiting the scaling of the specific heat of the three-dimensional random-field Ising model

We revisit the scaling behavior of the specific heat of the three-dimensional random-field Ising model with a Gaussian distribution of the disorder. Exact ground states of the model are obtained using graph-theoretical algorithms for different strengths = 268 3 spins. By numerically differentiating the bond energy with respect to h, a specific-heat-like quantity is obtained whose maximum is found to converge to a constant in the thermodynamic limit. Compared to a previous study following the same approach, we have studied here much larger system sizes with an increased statistical accuracy. We discuss the relevance of our results under the prism of a modified Rushbrooke inequality for the case of a saturating specific heat. Finally, as a byproduct of our analysis, we provide high-accuracy estimates of the critical field hc = 2.279(7) and the critical exponent of the correlation exponent ν = 1.37(1), in excellent agreement to the most recent computations in the literature

Negative Energy and Angular Momentum Modes of Thin Accretion Disks

This work derives the linearized equations of motion, the Lagrangian density, the Hamiltonian density, and the canonical angular momentum density for general perturbations [$\propto \exp(im\phi)$ with $m=0,\pm 1,..$] of a geometrically thin self-gravitating, homentropic fluid disk including the pressure. The theory is applied to ``eccentric,'' $m=\pm 1$ perturbations of a geometrically thin Keplerian disk. We find $m=1$ modes at low frequencies relative to the Keplerian frequency. Further, it shown that these modes can have negative energy and negative angular momentum. The radial propagation of these low frequency $m=1$ modes can transport angular momentum away from the inner region of a disk and thus increase the rate of mass accretion. Depending on the radial boundary conditions there can be discrete low-frequency, negative-energy, $m=1$ modes.Comment: 24 pages, 8 figure

Critical aspects of the random-field Ising model

We investigate the critical behavior of the three-dimensional random-field Ising model (RFIM) with a Gaussian field distribution at zero temperature. By implementing a computational approach that maps the ground-state of the RFIM to the maximum-flow optimization problem of a network, we simulate large ensembles of disorder realizations of the model for a broad range of values of the disorder strength h and system sizes  = L3, with L ≤ 156. Our averaging procedure outcomes previous studies of the model, increasing the sampling of ground states by a factor of 103. Using well-established finite-size scaling schemes, the fourth-order’s Binder cumulant, and the sample-to-sample fluctuations of various thermodynamic quantities, we provide high-accuracy estimates for the critical field hc, as well as the critical exponents ν, β/ν, and γ̅/ν of the correlation length, order parameter, and disconnected susceptibility, respectively. Moreover, using properly defined noise to signal ratios, we depict the variation of the self-averaging property of the model, by crossing the phase boundary into the ordered phase. Finally, we discuss the controversial issue of the specific heat based on a scaling analysis of the bond energy, providing evidence that its critical exponent α ≈ 0−

Black Hole Spin via Continuum Fitting and the Role of Spin in Powering Transient Jets

The spins of ten stellar black holes have been measured using the continuum-fitting method. These black holes are located in two distinct classes of X-ray binary systems, one that is persistently X-ray bright and another that is transient. Both the persistent and transient black holes remain for long periods in a state where their spectra are dominated by a thermal accretion disk component. The spin of a black hole of known mass and distance can be measured by fitting this thermal continuum spectrum to the thin-disk model of Novikov and Thorne; the key fit parameter is the radius of the inner edge of the black hole's accretion disk. Strong observational and theoretical evidence links the inner-disk radius to the radius of the innermost stable circular orbit, which is trivially related to the dimensionless spin parameter a_* of the black hole (|a_*| < 1). The ten spins that have so far been measured by this continuum-fitting method range widely from a_* \approx 0 to a_* > 0.95. The robustness of the method is demonstrated by the dozens or hundreds of independent and consistent measurements of spin that have been obtained for several black holes, and through careful consideration of many sources of systematic error. Among the results discussed is a dichotomy between the transient and persistent black holes; the latter have higher spins and larger masses. Also discussed is recently discovered evidence in the transient sources for a correlation between the power of ballistic jets and black hole spin.Comment: 30 pages. Accepted for publication in Space Science Reviews. Also to appear in hard cover in the Space Sciences Series of ISSI "The Physics of Accretion onto Black Holes" (Springer Publisher). Changes to Sections 5.2, 6.1 and 7.4. Section 7.4 responds to Russell et al. 2013 (MNRAS, 431, 405) who find no evidence for a correlation between the power of ballistic jets and black hole spi