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OBJECTIVE A prospective clinical trial was performed to evaluate the efficacy and tolerance of high-flow nasal cannula (HFNC) in dogs with hypoxemia. ANIMALS 20 client-owned dogs failing conventional oxygen therapy (COT). PROCEDURES Patients admitted to the ICU for treatment of hypoxemic respiratory failure were enrolled in the study. PaO2, SPO2, respiratory rate (RR), and acute patient physiologic and laboratory evaluation scores were obtained at the time of COT failure and after initiation of HFNC. Complications and patient tolerance while receiving HFNC were also recorded. RESULTS Compared to COT, the median PaO2 and SO2 were significantly higher when dogs were receiving HFNC (60.8 vs 135.6 mm Hg and 90.7% vs 99.25%, respectively). Dogs receiving HFNC had a significant reduction in median RR as compared to dogs undergoing COT (52 vs 36 breaths per minute). After the initiation of HFNC, all dogs showed clinical improvement as measured by PaO2, SO2, and RR. Of 20 dogs, 6 ultimately failed HFNC and mechanical ventilation was recommended. Nine dogs undergoing HFNC survived to discharge, and acute patient physiologic and laboratory evaluation scores had a significant positive severity correlation with death. Complications included pneumothorax in 1 dog. CLINICAL RELEVANCE COT has limited flow rates due to airway irritation caused by room temperature, nonhumidified oxygen. HFNC uses vapor humidification and heated oxygen, allowing for higher flow rates. In people, HFNC is used as escalation of oxygen therapy when COT fails. Dogs treated with HFNC had significant improvements in PaO2, SO2, and RR as compared to COT. HFNC is well tolerated and effective in treating hypoxemia in dogs.

Suppl. Fig. 3. Flow cytometry analysis of T-cell surface marker expression

Supplementary Legends and Methods

Purpose:Mesenchymal stem cells (MSCs) show an inherent brain tumor tropism that can be exploited for targeted delivery of therapeutic genes to invasive glioma. We assessed whether a motile MSC-based local immunomodulation is able to overcome the immunosuppressive glioblastoma microenvironment and to induce an antitumor immune response.Experimental Design:We genetically modified MSCs to coexpress high levels of IL12 and IL7 (MSCIL7/12, Apceth-301). Therapeutic efficacy was assessed in two immunocompetent orthotopic C57BL/6 glioma models using GL261 and CT2A. Immunomodulatory effects were assessed by multicolor flow cytometry to profile immune activation and exhaustion of tumor-infiltrating immune cells. Diversity of the tumor-specific immune response as analyzed using T-cell receptor sequencing.Results:Intratumoral administration of MSCIL7/12 induced significant tumor growth inhibition and remission of established intracranial tumors, as demonstrated by MR imaging. Notably, up to 50% of treated mice survived long-term. Rechallenging of survivors confirmed long-lasting tumor immunity. Local treatment with MSCIL7/12 was well tolerated and led to a significant inversion of the CD4+/CD8+ T-cell ratio with an intricate, predominantly CD8+ effector T-cell–mediated antitumor response. T-cell receptor sequencing demonstrated an increased diversity of TILs in MSCIL7/12-treated mice, indicating a broader tumor-specific immune response with subsequent oligoclonal specification during generation of long-term immunity.Conclusions:Local MSC-based immunomodulation is able to efficiently alter the immunosuppressive microenvironment in glioblastoma. The long-lasting therapeutic effects warrant a rapid clinical translation of this concept and have led to planning of a phase I/II study of apceth-301 in recurrent glioblastoma.

Glioblastoma are highly invasive and associated with limited therapeutic options and a grim prognosis. Using stem cells to extend current therapeutic strategies by targeted drug delivery to infiltrated tumors cells is highly attractive. This study analyzes the tumor homing and therapeutic abilities of clinical grade human mesenchymal stem cells (MSCs) in an orthotopic glioblastoma mouse model. Our time course analysis demonstrated that MSCs display a rapid targeted migration to intracerebral U87 glioma xenografts growing in the contralateral hemisphere within the first 48h hours after application as assessed by histology and 7T magnetic resonance imaging. MSCs accumulated predominantly peritumorally but also infiltrated the main tumor mass and targeted distant tumor satellites while no MSCs were found in other regions of the brain. Intratumoral application of MSCs expressing herpes simplex virus thymidine kinase followed by systemic prodrug application of ganciclovir led to a significant tumor growth inhibition of 86% versus the control groups (p

The principle of convergence stability for geometric flows is the combination of the continuous dependence of the flow on initial conditions, with the stability of fixed points. It implies that if the flow from an initial state $g_0$ exists for all time and converges to a stable fixed point, then the flows of solutions that start near $g_0$ also converge to fixed points. We show this in the case of the Ricci flow, carefully proving the continuous dependence on initial conditions. Symmetry assumptions on initial geometries are often made to simplify geometric flow equations. As an application of our results, we extend known convergence results to open sets of these initial data, which contain geometries with no symmetries., 18 pages

Purpose: Mesenchymal stem cells (MSCs) show an inherent brain tumor tropism that can be exploited for targeted delivery of therapeutic genes to invasive glioma. We assessed whether a motile MSC-based local immunomodulation is able to overcome the immunosuppressive glioblastoma microenvironment and to induce an antitumor immune response. Experimental Design: We genetically modified MSCs to coexpress high levels of IL12 and IL7 (MSCIL7/12, Apceth-301). Therapeutic efficacy was assessed in two immunocompetent orthotopic C57BL/6 glioma models using GL261 and CT2A. Immunomodulatory effects were assessed by multicolor flow cytometry to profile immune activation and exhaustion of tumor-infiltrating immune cells. Diversity of the tumor-specific immune response as analyzed using T-cell receptor sequencing. Results: Intratumoral administration of MSCIL7/12 induced significant tumor growth inhibition and remission of established intracranial tumors, as demonstrated by MR imaging. Notably, up to 50% of treated mice survived long-term. Rechallenging of survivors confirmed long-lasting tumor immunity. Local treatment with MSCIL7/12 was well tolerated and led to a significant inversion of the CD4+/CD8+ T-cell ratio with an intricate, predominantly CD8+ effector T-cell–mediated antitumor response. T-cell receptor sequencing demonstrated an increased diversity of TILs in MSCIL7/12-treated mice, indicating a broader tumor-specific immune response with subsequent oligoclonal specification during generation of long-term immunity. Conclusions: Local MSC-based immunomodulation is able to efficiently alter the immunosuppressive microenvironment in glioblastoma. The long-lasting therapeutic effects warrant a rapid clinical translation of this concept and have led to planning of a phase I/II study of apceth-301 in recurrent glioblastoma.

Let (M, g) be a closed Riemannian manifold. The RG-2 flow is defined by $$\begin{aligned} \frac{\partial }{\partial t} \, g(t) \, =\, -2 \mathrm {Ric}(t) \, -\, \frac{\alpha }{2} \mathrm {Rm}^2(t), \end{aligned}$$ where $$ g = \mathrm {Riemannian \ metric}, \mathrm {Ric} = \mathrm {Ricci \ curvature, } \ \mathrm {Rm}^2_{ij}:=\mathrm {R}_{irmk}\mathrm {R}_j^{rmk},$$ and $$\alpha \ge 0$$ is a parameter. This is the geometric flow associated with the second-order approximation to the perturbative renormalization group flow for the nonlinear sigma model. It is invariant under diffeomorphisms, but not under scaling of the metric, the latter of which gives rise to several delicate problems from the point of view of geometric analysis. To address the lack of scaling we introduce a geometrically defined coupling constant $$\alpha _g$$ that leads to an equivalent, scale-invariant flow. We further find a modified Perelman entropy for the flow, and prove local existence of the resulting variational system. The crucial idea is to modify the flow by two diffeomorphisms, the first being the usual DeTurck diffeomorphism and the second being strictly related to the geometrical characterization of the coupling constant $$\alpha _g$$ . We minimize the entropy functional so introduced to characterize a natural extension $$\Lambda [g]$$ of the Perelman’s $$\lambda (g)$$ –functional, and show that $$\Lambda [g]$$ is monotonic under the RG-2 flow. Although the modified Perelman entropy is monotonic, the RG-2 flow is not a gradient flow with respect this functional. We discuss this issue in detail, showing how to deform the functional in order to give rise to a gradient flow for a DeTurck modified RG-2 flow.

We prove local existence for the second order Renormalization Group flow initial value problem on closed Riemannian manifolds (M, g) in general dimensions, for initial metrics whose sectional curvatures KP satisfy the condition 1 + αKP > 0, at all points p ∈ M and planes P ⊂ TpM . This extends results previously proven for two and three dimensions. The second order approximation of the Renormalization Group flow for the nonlinear sigma model of quantum field theory, which we label the RG-2 flow, is specified by the PDE system (1) ∂ ∂t g = −2 Rc− 2 Rm . Here g is a Riemannian metric, Rc is its Ricci curvature, Rmij = g ggRiklmRjpqn, and α is a positive parameter. We note that for our purposes here, α can assume any real value. For α = 0, this system (1) reduces to the Ricci flow. One can see that the sign of the right hand side, which is roughly 1+α×Curvature, should have an impact on the behavior of the flow, and this has been confirmed in various settings: in particular, the size of the term influences the parabolicity of the flow. Oliynyk has shown in [10] that on a two-dimensional manifold, if the Gaussian curvature K satisfies the condition 1 + αK > 0, then the flow is (weakly) parabolic; while if 1 + αK 0 is satisfied for all sectional curvatures KP . In this note we extend this curvature criterion for short-time existence for RG-2 flow to all dimensions, as first announced in [7]. Our main result is the following: Theorem 1. Let (M, g0) be a closed n-dimensional Riemannian manifold. If 1 + αKP > 0 for all sectional curvatures KP (g0), at all points p ∈M and planes P ⊂ TpM , then there exists a unique solution g(t) of the initial value problem ∂ ∂tg = −2 Rc− α 2 Rm , g(0) = g0, on some time interval [0, T ). Remark 2. In [10], Oliynyk finds open subspaces of the space of smooth metrics that are invariant under the two-dimensional RG-2 flow, and for which the flow remains parabolic (resp. backward parabolic). We are currently investigating this for general dimensions. Proof. To prove the theorem, we calculate the principal symbol of the DeTurck-modified version of RG-2 flow, which is generated by the PDE system (compare with (1) above) (2) ∂ ∂t gij = −2Rij + LWu,ggij − α 2 Rmij . Here Wu,g = −giju−1 jk gg(∇puql− 1 2∇lupq) is the standard vector field usually chosen to modify the Ricci flow into the related (parabolic) DeTurck version of Ricci flow, with u a fixed metric. Letting φt be the one-parameter family of diffeomorphisms generated by the vector field −Wu,g, then φt g is a solution of the RG-2 flow (see also [8]). As in the analogous Ricci flow case, if one can show (for a class of choices of the initial metric) that the PDE system (2) is parabolic, then short-time existence holds for the RG-2 flow (1) as well as for the DeTurck-modified flow (2). Date: January 7, 2014. KG is partially supported by the NSF under grant DGE-1144155. CG is partially supported by the Simons Foundation Collaboration Grant for Mathematicians 283083. JI is partially supported by the NSF under grant PHY-1306441 at the University of Oregon. He also wishes to thank the Mathematical Sciences Research Institute in Berkeley, California, for support under grant 0932078 000. Some of this work was carried out while JI was in residence at MSRI during the fall of 2013. 1 2 KARSTEN GIMRE, CHRISTINE GUENTHER, AND JAMES ISENBERG To calculate the symbol of the system (2), we first linearize the flow. For the first two terms of the right hand side of (2), this linearization effectively produces the Laplacian (see [4], or Theorem 2.1 in [5]). For the remaining term, Rm, it is useful to recall the formula for the variation of the Riemann curvature tensor with respect to the metric (see pg. 74 in [2]): [DRmg(h)] l ijk = [ ∂ ∂e Rm(g + eh) ∣∣∣∣ e=0 ]l

Mesenchymal stem cells (MSCs) show an inherent brain tumor cell tropism that can be exploited for targeted delivery of therapeutic genes to invasive glioma. We assessed whether a motile MSC-based local immunomodulation is able to overcome the immunosuppressive glioblastoma microenvironment and to induce an antitumor immune response. Apceth-301 is a cell-based immunotherapy consisting of MSCs which are genetically modified to co-express high levels of IL-12 and IL-7. In vitro characterization demonstrated increased T-cell activation, as measured by increased secretion of IFNg and TNFa, and promoted NK cell mediated killing of GBM cell lines in co-culture assays. Therapeutic efficacy was assessed in two immunocompetent orthotopic C57BL/6 glioma models using GL261 and CT2A. Intratumoral administration of MSCIL7/12 induced a significant tumor growth inhibition and displayed tumor necrosis MR imaging. Notably, up to 50% of treated mice survived long-term. Re-challenging of survivors confirmed long-lasting tumor immunity. Immunomodulatory effects were assessed by immunehistology and multicolor flow-cytometry to comprehensively profile immune activation of tumor-infiltrating lymphocytes (TIL). Local treatment with MSC-IL12/7 was well tolerated and led to a significant inversion of CD4+/CD8+ T-cell ratio with an intricate predominantly CD8+ T-cell mediated anti-tumor response. T-cell receptor sequencing demonstrated increased diversity of TILs in MSCIL7/12-treated mice, indicating a broader tumor-specific immune response with subsequent oligoclonal specification during generation of long-term immunity. Local MSC-based immunomodulation is able to efficiently alter the immunosuppressive microenvironment in glioblastoma. The long lasting therapeutic effects warrant a rapid clinical translation of this concept and have led to planning of a phase I/II study.

e14648 Background: TREAT-ME-1, a Phase 1/2 open-label, first-in-human, first-in-class trial, evaluated the safety, tolerability and efficacy of treatment with genetically modified autologous mesenchymal stromal cells (MSC),MSC_ apceth_101, in combination with ganciclovir in patients with advanced gastrointestinal adenocarcinoma. Methods: All patients (6 in Phase 1; 7 in Phase 2) received three treatment cycles of MSC_apceth_101 on Day 0, 7, and 14 followed by ganciclovir administration according to the manufacturer’s instructions for 48─72 hours after MSC_apceth_101 injection. Three patients were treated with a total dose of 1.5 x 106cells/kg MSC_apceth_101 (DL1). Ten patients were treated with a total dose of 3.0 x 106cells/kg MSC_apceth_101 (DL2). Immunological and inflammatory markers were assessed.Time to progression, overall survival was evaluated by RECISTwithin 56 days after administration of MSC_apceth_101 administration. Results: A total of 54 AEs occurred in 9/13 patients, thereof 18 AEs in three patients of DL1 and 36 AEs in six patients of DL2. Six AEs were CTC-AE grade 3, all other AEs were lower CTC-AE grades.Five SAEs emerged in two patients of DL1 and six SAEs in four patients of DL2. Eight patients achieved stable disease (change in target lesions of -2 to +28%). For all patients, the median time to progression was 1.9 months (95% CI: 1.3, 3.6 months). Median overall survival could not be estimated as 8/10 patients were still alive at the end of the study (one year) and therefore censored. Post-study observation of patients showed a median overall survival of 15.6 months (ranging from 2.2─27.0 months). Treatment with MSC_apceth_101 and ganciclovir did not induce a consistent increase or decrease in levels of any of the tumor markers analyzed. No clear trends in the immunological markers assessed were observed. Conclusions: MSC_apceth_101 in combination with ganciclovir was safe and tolerable in patients with advanced gastrointestinal adenocarcinoma, with preliminary signs of efficacy in terms of clinical stabilization of disease. Clinical trial information: NCT02008539.

The Ricci flow has been of fundamental importance in mathematics, most famously through its use as a tool for proving the Poincare conjecture and Thurston’s geometrization conjecture. It has a parallel life in physics, arising as the first-order approximation of the renormalization group flow for the nonlinear sigma model of quantum field theory. There recently has been interest in the second-order approximation of this flow, called the RG-2 flow, which mathematically appears as a natural nonlinear deformation of the Ricci flow. A curvature flow arising from quantum field theory seems to us to capture the spirit of Yvonne Choquet-Bruhat’s extensive work in mathematical physics, and so in this commemorative article we give a geometric introduction to the RG-2 flow. A number of new results are presented as part of this narrative: short-time existence and uniqueness results in all dimensions if the sectional curvatures K ij satisfy certain inequalities; the calculation of fixed points for n = 3 dimensions; a reformulation of constant curvature solutions in terms of the Lambert W function; a classification of the solutions that evolve only by homothety; an analogue for RG flow of the 2-dimensional Ricci flow solution known to mathematicians as the cigar soliton, and discussed in the physics literature as Witten’s black hole. We conclude with a list of open problems whose resolutions would substantially increase our understanding of the RG-2 flow both physically and mathematically.

We study the dependence of chronoamperometric data on the kinetic parameters for a bimolecular reaction, characterizing the behavior of an electrochemical mechanism that pertains to lithium/sulfur dioxide batteries. The reaction entails first the reduction of a reactant O to a product R by an instantaneous charge transfer, followed by a homogeneous chemical reaction between O and R to produce an electrochemically inert product P. We model this by a semilinear reaction-diffusion system with discontinuous initial conditions and mixed Dirichlet and Neumann boundary conditions, and develop a procedure to extract from a single potential step experiment the forward and reverse rate constants for the reaction. To do so we define a function \({\mathcal{J}(t):=j(t)\sqrt{t}}\) , where j(t) is the current density from the chronoamperometric output, and use maximum principle and scaling arguments to exploit the location of the minimum of \({\mathcal{J}(t)}\) versus t.

We prove the stability of the torus, and with suitable rescaling, hyperbolic space under the (two-loop) renormalization group flow for the nonlinear sigma model. To prove stability we use similar techniques to \cite{GIK02}, where the stability of the torus under Ricci flow was first established. The main technical tool is maximal regularity theory., May differ slightly from the published version

In this article we prove the existence of a fundamental solution for the linear parabolic operator L(u) = (Δ − ∂/∂t − h)u, on a compact n-dimensional manifold M with a time-parameterized family of smooth Riemannian metrics g(t). Δ is the time-dependent Laplacian based on g(t), and h(x, t) is smooth. Uniqueness, positivity, the adjoint property, and the semigroup property hold. We further derive a Harnack inequality for positive solutions of L(u) = 0 on (M, g(t) on a time interval depending on curvature bounds and the dimension of M, and in the special case of Ricci flow, use it to find lower bounds on the fundamental solution of the heat operator in terms of geometric data and an explicit Euclidean type heat kernel.

Streptococcus pneumoniae (S. pneumoniae) may cause severe and lethal infections months and years following stem cell transplantation (SCT). In a prospective survey over a 3.5-year period, we assessed the incidence, risk factors and outcome for invasive pneumococcal infection (IPI) following SCT. Fifty-one episodes of IPI were reported: 43 episodes after bone marrow transplantation (BMT) and 8 after peripheral blood stem cell transplantation (PBSCT); 35 after allogeneic SCT and 16 after autologous SCT. Seven IPI episodes, all bacteraemias, were defined as early, occurring 1-35 d (median 3 d) post transplantation. Forty-four episodes were defined as late (> or = 100 d post SCT), occurring 4 months to 10 years (median 17 months) post transplantation. The incidences of early and late IPI were 2.03/1000 and 8.63/1000 transplantations respectively (P = 0.001). A higher incidence of late IPI was observed after BMT than after PBSCT (10.99 versus 3.23/1000; P < 0.01) and after allogeneic versus autologous SCT (12.20 versus 4.60/1000; P < 0.01). There was a higher estimated incidence of IPI in allogeneic patients with than in those without graft-versus-host disease (GVHD) (18.85 versus 8.25/1000; P = 0.015). The mortality rate was 20%, including 2/7 of early and 8/44 of late IPI. S. pneumoniae is a rare but important complication during the aplastic phase after SCT. In conclusion, S. pneumoniae is a significant cause of morbidity late post-transplantation, especially in allogeneic patients, and particularly those with GVHD. The high IPI mortality rate, both early and late post-transplantation, requires preventive approaches, mainly effective immunization.

To describe the effects of high flow oxygen therapy (HFOT) in canine patients failing traditional oxygen therapy (TOT).Retrospective study.Private referral practice.Six client-owned dogs with primary pulmonary hypoxemia.None.High flow oxygen was delivered by high flow nasal prongs to dogs assessed clinically to be failing TOTs. HFOT was able to significantly improve PaO2 compared to TOT in severely hypoxemic dogs (median, 133.75 mm Hg; range, 109.2-304.8) versus median 61.85 mm Hg (range, 52.3-71.8; xsP = 0.0412). Flow rates were significantly higher with HFOT compared to TOT (median, 688 mL/kg/min; range, 523-1,667 mL/kg/min) versus median 122 mL/kg/min (range, 80-208; P = 0.0412). Complications included patient discomfort requiring light sedation in 1/6 dogs and persistence of a pneumothorax in 1 dog. Hypoxemia resolved in 4/6 dogs.These data suggest HFOT is a viable clinical intervention for dogs with moderate-to-severe hypoxemia assessed to be failing TOT. Further studies are needed to determine if HFOT can be used as an alternative to mechanical ventilation in resource limited settings and to characterize the complications associated with this therapy.

We study the behavior of the second order Renormalization Group flow on locally homogeneous metrics on closed three-manifolds. In the cases $\mathbb R^3$ and $\text{SO}(3)\times \R$, the flow is qualitatively the same as the Ricci flow. In the cases $\text{H}(3)$ and $\text{H}(2)\times \R$, if the curvature is small, then the flow expands as in the Ricci flow case, while if the curvature is large, then the flow contracts and forms a singularity in finite time. The main focus of the paper is the flow on the $\text{SU}(2)$, $\text{Nil}$, $\text{Sol}$, and $\text{SL}(2,\R)$ 3-geometries, with two of the three principal directions set equal. The configuration spaces for these geometries are two dimensional, and we can consequently apply phase plane techniques to the study. For the $\text{SU}(2)$ case, the flow is everywhere qualitatively the same as Ricci flow. For the $\text{Nil}$, $\text{Sol}$, and $\text{SL}(2,\R)$ cases, we show that the configuration space is partitioned into two regions which are delineated by a solution curve of the flow that depends on the coupling parameter: in one of the regions, the flow develops cigar or pancake singularities characteristic of the Ricci flow, while in the other both directions shrink. In the $\text{Nil}$ case we obtain a characterization of the full 3-dimensional flow.