Amplitudes and 4D Gauss-Bonnet theory Bonifacio, James; Hinterbichler, Kurt; Johnson, Laura A.
Physical review. D,
07/2020, Letnik:
102, Številka:
2
Journal Article
Recenzirano
Odprti dostop
It has recently been argued that there may be a nontrivial four-dimensional limit of the higher-dimensional Gauss-Bonnet and Lovelock interactions and that this might provide a loophole allowing for ...new four-dimensional gravitational theories, possibly without a standard Lagrangian. We investigate this claim by studying tree-level graviton scattering amplitudes, allowing us to draw conclusions independently of the Lagrangian. By taking four-dimensional limits of higher-dimensional scattering amplitudes of the Gauss-Bonnet theory, we find four-dimensional amplitudes that are different from general relativity; however, these amplitudes are not new since they all come from certain scalar-tensor theories. The nontrivial limit that does not lead to infinite strong coupling around flat space leads to (∂ϕ)4 theory. We argue that there cannot be any six-derivative purely gravitational four-point amplitudes in any dimension other than those coming from Lovelock theory by directly constructing the on-shell amplitudes. In particular, there can be no new such amplitudes in four dimensions beyond those of general relativity. We also present some new results on the spin-averaged cross section for graviton-graviton scattering in general relativity and Gauss-Bonnet theory in arbitrary dimensions.
Chimeric antigen receptor （CAR） gene-engineered T cell therapy holds the potential to make a meaningful differ- ence in the lives of patients with terminal cancers. For decades, cancer therapy was ...based on biophysical parameters, with surgical resection to debulk, followed by radiation and chemotherapy to target the rapidly growing tumor cells, while mostly sparing quiescent normal tissues. One breakthrough occurred with allogeneic bone-marrow transplant for patients with leukemia, which provided a sometimes curative therapy. The field of adoptive cell therapy for sol- id tumors was established with the discovery that tumor-infiltrating lymphocytes could be expanded and used to treat and even cure patients with metastatic melanoma. Tumor-specific T-cell receptors （TCRs） were identified and engineered into patient peripheral blood lymphocytes, which were also found to treat tumors. However, these were limited by patient HLA-restriction. Close behind came generation of CAR, combining the exquisite recognition of an antibody with the effector function of a T cell. The advent of CD19-targeted CARs for treating patients with multiple forms of advanced B-cell malignancies met with great success, with up to 95% response rates. Applying CAR treat- ment to solid tumors, however, has just begun, but already certain factors have been made clear： the tumor target is of utmost importance for clinicians to do no harm; and solid tumors respond differently to CAR therapy compared with hematologic ones. Here we review the state of clinical gene-engineered T cell immunotherapy, its successes, chal- lenges, and future.
A
bstract
We propose and study a BCJ double-copy of massive particles, showing that it is equivalent to a KLT formula with a kernel given by the inverse of a matrix of massive bi-adjoint scalar ...amplitudes. For models with a uniform non-zero mass spectrum we demonstrate that the resulting double-copy factors on physical poles and that up to at least 5-particle scattering, color-kinematics duality satisfying numerators always exist. For the scattering of 5 or more particles, the procedure generically introduces spurious singularities that must be cancelled by imposing additional constraints. When massive particles are present, color-kinematics duality
is not enough
to guarantee a physical double-copy. As an example, we apply the formalism to massive Yang-Mills and show that up to 4-particle scattering the double-copy construction generates physical amplitudes of a model of dRGT massive gravity coupled to a dilaton and a two-form with dilaton parity violating couplings. We show that the spurious singularities in the 5-particle double-copy do not cancel in this example, and the construction fails to generate physically sensible amplitudes. We conjecture sufficient constraints on the mass spectrum, which in addition to massive BCJ relations, guarantee the absence of spurious singularities.
A
bstract
We consider various decoupling limits of ghost-free massive gravity on (A)dS. The first is a decoupling limit on AdS space where the mass goes to zero while the AdS radius is held fixed. ...This results in an interacting massive Proca vector theory with a Λ
2
∼ (
M
Pl
m
)
1/2
strong coupling scale which is ghost-free by construction and yet can not be put in the form of the generalized Proca theories considered so far. We comment on the existence of a potential duality between this Proca theory and a CFT on the boundary. The second decoupling limit we consider is a new limit on dS, obtained by sending the mass towards the finite partially massless value. We do this by introducing the scalar Stückelberg field which restores the partially massless symmetry. For generic values of the parameters, only a finite number of operators enter the partially massless decoupling limit and take the form of dS Galileons. If the interactions are chosen to be precisely those of the ‘candidate’ non-linear partially massless theory, the resulting strong coupling scale has a higher value and the resulting decoupling limit includes an infinite number of interactions which we give in closed form. These interactions preserve both the linear partially massless symmetry and the dS version of the Galileon shift symmetry.
The most common mutation in human melanoma, BRAF(V600E), activates the serine/threonine kinase BRAF and causes excessive activity in the mitogen-activated protein kinase pathway. BRAF(V600E) ...mutations are also present in benign melanocytic naevi, highlighting the importance of additional genetic alterations in the genesis of malignant tumours. Such changes include recurrent copy number variations that result in the amplification of oncogenes. For certain amplifications, the large number of genes in the interval has precluded an understanding of the cooperating oncogenic events. Here we have used a zebrafish melanoma model to test genes in a recurrently amplified region of chromosome 1 for the ability to cooperate with BRAF(V600E) and accelerate melanoma. SETDB1, an enzyme that methylates histone H3 on lysine 9 (H3K9), was found to accelerate melanoma formation significantly in zebrafish. Chromatin immunoprecipitation coupled with massively parallel DNA sequencing and gene expression analyses uncovered genes, including HOX genes, that are transcriptionally dysregulated in response to increased levels of SETDB1. Our studies establish SETDB1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid ...tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.
•Cancer cells of many tissues express an abnormal glycoform of MUC1, Tn-MUC1•Normal human tissue does not express detectable Tn-MUC1 on the cellular surface•CAR T cells are engineered to target Tn-MUC1 lyse tumor cells in vitro and in vivo•Abnormal glycoform epitopes are valid clinical targets for CAR T cells
Posey and colleagues developed a CAR T cell therapy to break immune tolerance to solid tumors by targeting an aberrantly glycosylated, cancer-specific glycoprotein in multiple cancer histotypes and demonstrated efficacy and safety in tumors as diverse as leukemia and pancreatic cancer.
BACKGROUNDMirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve ...obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by 18F-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).
Pseudolinear spin-2 interactions Bonifacio, James; Hinterbichler, Kurt; Johnson, Laura A.
Physical review. D,
01/2019, Letnik:
99, Številka:
2
Journal Article
Recenzirano
Odprti dostop
We show how the pseudolinear interactions for spin-2 particles can be straightforwardly extended to include multiple massive and massless fields without introducing ghosts. When massive spin-2 fields ...are included, these give simple analogues of bigravity and multigravity theories with mass terms that break linear gauge symmetries. The interactions containing only massless particles cannot be written in terms of linearized curvature tensors and are gauge invariant only up to a total derivative. These correspond to known theories that exist in more than four dimensions and evade the no-go results on interacting massless spin-2 particles.
TCF-1 is a key transcription factor in progenitor exhausted CD8 T cells (Tex). Moreover, this Tex cell subset mediates responses to PD-1 checkpoint pathway blockade. However, the role of the ...transcription factor TCF-1 in early fate decisions and initial generation of Tex cells is unclear. Single-cell RNA sequencing (scRNA-seq) and lineage tracing identified a TCF-1+Ly108+PD-1+ CD8 T cell population that seeds development of mature Tex cells early during chronic infection. TCF-1 mediated the bifurcation between divergent fates, repressing development of terminal KLRG1Hi effectors while fostering KLRG1Lo Tex precursor cells, and PD-1 stabilized this TCF-1+ Tex precursor cell pool. TCF-1 mediated a T-bet-to-Eomes transcription factor transition in Tex precursors by promoting Eomes expression and drove c-Myb expression that controlled Bcl-2 and survival. These data define a role for TCF-1 in early-fate-bifurcation-driving Tex precursor cells and also identify PD-1 as a protector of this early TCF-1 subset.
Display omitted
•scRNA-seq defines an effector versus exhausted Tex cell-fate decision•TCF-1 plays a central role in initially establishing Tex precursor cells•PD-1 supports the TCF-1+ Tex precursor cells at early phase of chronic infection•Eomes and c-Myb play key roles in Tex cell persistence downstream of TCF-1
The initiation of the T cell exhaustion program remains poorly understood. In this study, Chen et al. define an effector (Teff) versus exhausted (Tex) CD8 T cell binary-fate decision during chronic infection and find that TCF-1 supports the Tex precursor development by antagonizing Teff-like cell differentiation through multiple transcription factors.
Opioids administered to treat postsurgical pain are a major contributor to the opioid crisis, leading to chronic use in a considerable proportion of patients. Initiatives promoting opioid-free or ...opioid-sparing modalities of perioperative pain management have led to reduced opioid administration in the operating room, but this reduction could have unforeseen detrimental effects in terms of postoperative pain outcomes, as the relationship between intraoperative opioid usage and later opioid requirements is not well understood.
To characterize the association between intraoperative opioid usage and postoperative pain and opioid requirements.
This retrospective cohort study evaluated electronic health record data from a quaternary care academic medical center (Massachusetts General Hospital) for adult patients who underwent noncardiac surgery with general anesthesia from April 2016 to March 2020. Patients who underwent cesarean surgery, received regional anesthesia, received opioids other than fentanyl or hydromorphone, were admitted to the intensive care unit, or who died intraoperatively were excluded. Statistical models were fitted on the propensity weighted data set to characterize the effect of intraoperative opioid exposures on primary and secondary outcomes. Data were analyzed from December 2021 to October 2022.
Intraoperative fentanyl and intraoperative hydromorphone average effect site concentration estimated using pharmacokinetic/pharmacodynamic models.
The primary study outcomes were the maximal pain score during the postanesthesia care unit (PACU) stay and the cumulative opioid dose, quantified in morphine milligram equivalents (MME), administered during the PACU stay. Medium- and long-term outcomes associated with pain and opioid dependence were also evaluated.
The study cohort included a total of 61 249 individuals undergoing surgery (mean SD age, 55.44 17.08 years; 32 778 53.5% female). Increased intraoperative fentanyl and intraoperative hydromorphone were both associated with reduced maximum pain scores in the PACU. Both exposures were also associated with a reduced probability and reduced total dosage of opioid administration in the PACU. In particular, increased fentanyl administration was associated with lower frequency of uncontrolled pain; a decrease in new chronic pain diagnoses reported at 3 months; fewer opioid prescriptions at 30, 90, and 180 days; and decreased new persistent opioid use, without significant increases in adverse effects.
Contrary to prevailing trends, reduced opioid administration during surgery may have the unintended outcome of increasing postoperative pain and opioid consumption. Conversely, improvements in long-term outcomes might be achieved by optimizing opioid administration during surgery.
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