2,143 research outputs found
Immune profiling of pediatric solid tumors
Pediatric cancers, particularly high-risk solid tumors, urgently need effective and specific therapies. Their outlook has not appreciably improved in decades. Immunotherapies such as immune checkpoint inhibitors offer much promise, but most are only approved for use in adults. Though several hundred clinical trials have tested immune-based approaches in childhood cancers, few have been guided by biomarkers or clinical-grade assays developed to predict patient response and, ultimately, to help select those most likely to benefit. There is extensive evidence in adults to show that immune profiling has substantial predictive value, but few studies focus on childhood tumors, because of the relatively small disease population and restricted use of immune-based therapies. For instance, only one published study has retrospectively examined the immune profiles of pediatric brain tumors after immunotherapy. Furthermore, application and integration of advanced multiplex techniques has been extremely limited. Here, we review the current status of immune profiling of pediatric solid tumors, with emphasis on tumor types that represent enormous unmet clinical need, primarily in the context of immune checkpoint inhibitor therapy. Translating optimized and informative immune profiling into standard practice and access to personalized combination therapy will be critical if childhood cancers are to be treated effectively and affordably
Enhancing the potential of immunotherapy in paediatric sarcomas: Breaking the immunosuppressive barrier with receptor tyrosine kinase inhibitors
Despite aggressive surgery, chemotherapy, and radiotherapy, survival of children and adolescents and young adults (AYAs) with sarcoma has not improved significantly in the past four decades. Immune checkpoint inhibitors (ICIs) are an exciting type of immunotherapy that offer new opportunities for the treatment of paediatric and AYA sarcomas. However, to date, most children do not derive a benefit from this type of treatment as a monotherapy. The immunosuppressive tumour microenvironment is a major barrier limiting their efficacy. Combinations of ICIs, such as anti-PD-1 therapy, with targeted molecular therapies that have immunomodulatory properties may be the key to breaking through immunosuppressive barriers and improving patient outcomes. Preclinical studies have indicated that several receptor tyrosine kinase inhibitors (RTKi) can alter the tumour microenvironment and boost the efficacy of anti-PD-1 therapy. A number of these combinations have entered phase-1/2 clinical trials, mostly in adults, and in most instances have shown efficacy with manageable side-effects. In this review, we discuss the status of ICI therapy in paediatric and AYA sarcomas and the rationale for co-treatment with RTKis. We highlight new opportunities for the integration of ICI therapy with RTK inhibitors, to improve outcomes for children with sarcoma
Size constancy in bat biosonar?
Perception and encoding of object size is an important feature of sensory systems. In the visual system object size is encoded by the visual angle (visual aperture) on the retina, but the aperture depends on the distance of the object. As object distance is not unambiguously encoded in the visual system, higher computational mechanisms are needed. This phenomenon is termed "size constancy". It is assumed to reflect an automatic re-scaling of visual aperture with perceived object distance. Recently, it was found that in echolocating bats, the 'sonar aperture', i.e., the range of angles from which sound is reflected from an object back to the bat, is unambiguously perceived and neurally encoded. Moreover, it is well known that object distance is accurately perceived and explicitly encoded in bat sonar. Here, we addressed size constancy in bat biosonar, recruiting virtual-object techniques. Bats of the species Phyllostomus discolor learned to discriminate two simple virtual objects that only differed in sonar aperture. Upon successful discrimination, test trials were randomly interspersed using virtual objects that differed in both aperture and distance. It was tested whether the bats spontaneously assigned absolute width information to these objects by combining distance and aperture. The results showed that while the isolated perceptual cues encoding object width, aperture, and distance were all perceptually well resolved by the bats, the animals did not assign absolute width information to the test objects. This lack of sonar size constancy may result from the bats relying on different modalities to extract size information at different distances. Alternatively, it is conceivable that familiarity with a behaviorally relevant, conspicuous object is required for sonar size constancy, as it has been argued for visual size constancy. Based on the current data, it appears that size constancy is not necessarily an essential feature of sonar perception in bats
Chimeric antigen receptor t cell therapy and the immunosuppressive tumor microenvironment in pediatric sarcoma
Sarcomas are a diverse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or meta-static disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of adoptive cell therapy that potentially offers new hope for these children. In early trials, promising outcomes have been achieved in some pediatric patients with sarcoma. However, many children do not derive ben-efit despite significant expression of the targeted tumor antigen. The success of CAR T cell therapy in sarcomas and other solid tumors is limited by the immunosuppressive tumor microenvironment (TME). In this review, we provide an update of the CAR T cell therapies that are currently being tested in pediatric sarcoma clinical trials, including those targeting tumors that express HER2, NY‐ ESO, GD2, EGFR, GPC3, B7‐H3, and MAGE‐A4. We also outline promising new CAR T cells that are in pre‐clinical development. Finally, we discuss strategies that are being used to overcome tu-mor‐mediated immunosuppression in solid tumors; these strategies have the potential to improve clinical outcomes of CAR T cell therapy for children with sarcoma
A new CP violating observable for the LHC
We study a new type of CP violating observable that arises in three body
decays that are dominated by an intermediate resonance. If two interfering
diagrams exist with different orderings of final state particles, the required
CP-even phase arises due to the different virtualities of the resonance in each
of the two diagrams. This method can be an important tool for accessing new CP
phases at the LHC and future colliders.Comment: 22 pages, v2: discussion of charged particle decays and a few
references added v3: typos corrected, matches published versio
Identification of a novel type of spacer element required for imprinting in fission yeast
Asymmetrical segregation of differentiated sister chromatids is thought to be important for cellular differentiation in higher
eukaryotes. Similarly, in fission yeast, cellular differentiation involves the asymmetrical segregation of a chromosomal
imprint. This imprint has been shown to consist of two ribonucleotides that are incorporated into the DNA during laggingstrand
synthesis in response to a replication pause, but the underlying mechanism remains unknown. Here we present key
novel discoveries important for unravelling this process. Our data show that cis-acting sequences within the mat1 cassette
mediate pausing of replication forks at the proximity of the imprinting site, and the results suggest that this pause dictates
specific priming at the position of imprinting in a sequence-independent manner. Also, we identify a novel type of cis-acting
spacer region important for the imprinting process that affects where subsequent primers are put down after the
replication fork is released from the pause. Thus, our data suggest that the imprint is formed by ligation of a not-fullyprocessed
Okazaki fragment to the subsequent fragment. The presented work addresses how differentiated sister
chromatids are established during DNA replication through the involvement of replication barriers
Electroweak Symmetry Breaking in the DSSM
We study the theoretical and phenomenological consequences of modifying the
Kahler potential of the MSSM two Higgs doublet sector. Such modifications
naturally arise when the Higgs sector mixes with a quasi-hidden conformal
sector, as in some F-theory GUT models. In the Delta-deformed Supersymmetric
Standard Model (DSSM), the Higgs fields are operators with non-trivial scaling
dimension 1 < Delta < 2. The Kahler metric is singular at the origin of field
space due to the presence of quasi-hidden sector states which get their mass
from the Higgs vevs. The presence of these extra states leads to the fact that
even as Delta approaches 1, the DSSM does not reduce to the MSSM. In
particular, the Higgs can naturally be heavier than the W- and Z-bosons.
Perturbative gauge coupling unification, a large top quark Yukawa, and
consistency with precision electroweak can all be maintained for Delta close to
unity. Moreover, such values of Delta can naturally be obtained in
string-motivated constructions. The quasi-hidden sector generically contains
states charged under SU(5)_GUT as well as gauge singlets, leading to a rich,
albeit model-dependent, collider phenomenology.Comment: v3: 40 pages, 3 figures, references added, typos correcte
The flavor puzzle in multi-Higgs models
We reconsider the flavor problem in the models with two Higgs doublets. By
studying two generation toy models, we look for flavor basis independent
constraints on Yukawa couplings that will give us the mass hierarchy while
keeping all Yukawa couplings of the same order. We then generalize our findings
to the full three generation Standard Model. We find that we need two
constraints on the Yukawa couplings to generate the observed mass hierarchy,
and a slight tuning of Yukawa couplings of order 10%, much less than the
Standard Model. We briefly study how these constraints can be realized, and
show how flavor changing currents are under control for mixing in
the near-decoupling limit.Comment: 26 pages, typos are corrected, references are added, the final
versio
Light MSSM Higgs boson mass to three-loop accuracy
The light CP even Higgs boson mass, Mh, is calculated to three-loop accuracy
within the Minimal Supersymmetric Standard Model (MSSM). The result is
expressed in terms of DRbar parameters and implemented in the computer program
H3m. The calculation is based on the proper approximations and their
combination in various regions of the parameter space. The three-loop effects
to Mh are typically of the order of a few hundred MeV and opposite in sign to
the two-loop corrections. The remaining theory uncertainty due to higher order
perturbative corrections is estimated to be less than 1 GeV.Comment: 39 pages, 13 figures. v2: minor changes, typos fixe
Beautiful Mirrors at the LHC
We explore the "Beautiful Mirrors" model, which aims to explain the measured
value of , discrepant at the level. This scenario
introduces vector-like quarks which mix with the bottom, subtly affecting its
coupling to the . The spectrum of the new particles consists of two
bottom-like quarks and a charge -4/3 quark, all of which have electroweak
interactions with the third generation. We explore the phenomenology and
discovery reach for these new particles at the LHC, exploring single mirror
quark production modes whose rates are proportional to the same mixing
parameters which resolve the anomaly. We find that for mirror quark
masses is required to
reasonably establish the scenario and extract the relevant mixing parameters.Comment: version to be published in JHE
- …