Medulloblastoma is the most common pediatric malignant brain tumor. Advances in molecular profiling have uncovered significant heterogeneity among medulloblastomas and led to the identification of ...four distinct subgroups (wingless WNT, sonic hedgehog SHH, group 3, and group 4) that represent distinct disease entities in both underlying biology and clinical characteristics. The rapidly expanding repertoire of tools to study developmental and cancer biology is providing a wealth of knowledge about these embryonal tumors and is continuously refining the understanding of this complex cancer. In this review, the history of discovery in medulloblastoma is discussed, setting a foundation to outline the current state of understanding of the molecular underpinnings of this disease, with a focus on genomic events that define the aforementioned subgroups and evolving areas of focus, such as the cell of origin of medulloblastoma and medulloblastoma subtypes. With these recent discoveries in mind, the current state of medulloblastoma treatment and clinical trials is reviewed, including a novel risk stratification system that accounts for the molecular biomarkers of patients with a high risk for refractory disease. Lastly, critical areas of focus for future basic science and clinical research on this disease are discussed, such as the complexities of medulloblastoma metastases and recurrence as well as the priorities and strategies to implement in future clinical trials.
Medulloblastoma: From Myth to Molecular Ramaswamy, Vijay; Taylor, Michael D
Journal of clinical oncology,
2017-Jul-20, 2017-07-20, 20170720, Letnik:
35, Številka:
21
Journal Article
Recenzirano
Current therapies for medulloblastoma were introduced primarily in the 1980s and consist of predominantly cytotoxic, nontargeted approaches. Mortality from medulloblastoma remains significant. In ...addition, many survivors suffer from severe treatment-related effects of radiation and cytotoxic chemotherapy. Further intensification of nonspecific therapy is unlikely to offer additional benefits, because survival rates have reached a plateau. Recent publications in medulloblastoma have revolved largely around the recognition that medulloblastoma per se does not exist, but rather, that there are a group of histologically similar but clinically and molecularly distinct entities that have been grouped under that rubric. Distinguishing the four molecular subgroups of medulloblastoma-wingless (WNT), sonic hedgehog (SHH), group 3, and group 4-in the daily treatment of patients, as well in the setting of clinical trials, is an important challenge in the near term for the pediatric neuro-oncology community. The preponderance of morbidity in treating patients with medulloblastoma is secondary to the treatment or prophylaxis of leptomeningeal metastases, and the cause of most deaths is leptomeningeal metastases. Recurrence of medulloblastoma is a nearly universally fatal event, with no significant salvage rate. The extent of spatial and temporal intratumoral heterogeneity as medulloblastoma metastasizes to leptomeninges and as it evolves in the face of radiation and cytotoxic chemotherapy is just beginning to be understood as a major barrier to therapeutic success. Pediatric neuro-oncology clinicians and scientists must now determine how best to incorporate rapid changes in our biologic understanding of medulloblastoma into the next generation of upfront clinical trials, with the goal of both improving survival for the highest-risk patients and improving quality of life for survivors.
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.
Human glioblastomas harbour a subpopulation of glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between glioblastoma cells remains ...poorly understood. Here we study the clonal evolution of barcoded glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of glioblastoma clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in glioblastoma stem cells. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, which in turn generates non-proliferative cells. We also identify rare 'outlier' clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant glioblastoma stem cells. Finally, we show that functionally distinct glioblastoma stem cells can be separately targeted using epigenetic compounds, suggesting new avenues for glioblastoma-targeted therapy.
The octanuclear Co(
ii
) cubic coordination cage system
H
(or
H
W
if it bears external water-solubilising substituents) has two types of binding site for guests. These are (i) the partially-enclosed ...central cavity where neutral hydrophobic organic species can bind, and (ii) the six 'portals' in the centres of each of the faces of the cubic cage where anions bind
via
formation of a network of CH X hydrogen bonds between the anion and CH units on the positively-charged cage surface, as demonstrated by a set of crystal structures. The near-orthogonality of these guest binding modes provides the basis for an unusual dual-probe fluorescence displacement assay in which either a cavity-bound fluorophore (4-methyl-7-amino-coumarin,
MAC
;
λ
em
= 440 nm), or a surface-bound anionic fluorophore (fluorescein,
FLU
;
λ
em
= 515 nm), is displaced and has its emission 'switched on' according to whether the analyte under investigation is cavity-binding, surface binding, or a combination of both. A completely orthogonal system is demonstrated based using a
H
w
/
MAC
/
FLU
combination: addition of the anionic analyte ascorbate displaced solely
FLU
from the cage surface, increasing the 515 nm (green) emission component, whereas addition of a neutral hydrophobic guest such as cyclooctanone displaced solely
MAC
from the cage central cavity, increasing the 440 nm (blue) emission component. Addition of chloride results in some release of both components, and an intermediate colour change, as chloride is a rare example of a guest that shows both surface-binding and cavity-binding behaviour. Thus we have a colourimetric response based on differing contributions from blue and green emission components in which the specific colour change signals the binding mode of the analyte. Addition of a fixed red emission component from the complex Ru(bipy)
3
2+
(
Ru
) provides a baseline colour shift of the overall colour of the luminescence closer to neutral, meaning that different types of guest binding result in different colour changes which are easily distinguishable by eye.
Orthogonal binding of neutral or anionic fluorophores to the cavity or surface, respectively, of a coordination cage host allows a dual-probe displacement assay which gives a different fluorescence colorimetric response according to where analyte species bind.
The Kemp elimination (reaction of benzisoxazole with base to give 2-cyanophenolate) is catalyzed in the cavity of a cubic M8L12 coordination cage because of a combination of (i) benzisoxazole ...binding in the cage cavity driven by the hydrophobic effect, and (ii) accumulation of hydroxide ions around the 16+ cage surface driven by ion-pairing. Here we show how reaction of the cavity-bound guest is modified by the presence of other anions which can also accumulate around the cage surface and displace hydroxide, inhibiting catalysis of the cage-based reaction. Addition of chloride or fluoride inhibits the reaction with hydroxide to the extent that a new autocatalytic pathway becomes apparent, resulting in a sigmoidal reaction profile. In this pathway the product 2-cyanophenolate itself accumulates around the cationic cage surface, acting as the base for the next reaction cycle. The affinity of different anions for the cage surface is therefore 2-cyanophenolate (generating autocatalysis) > chloride > fluoride (which both inhibit the reaction with hydroxide but cannot deprotonate the benzisoxazole guest) > hydroxide (default reaction pathway). The presence of this autocatalytic pathway demonstrates that a reaction of a cavity-bound guest can be induced with different anions around the cage surface in a controllable way; this was confirmed by adding different phenolates to the reaction, which accelerate the Kemp elimination to different extents depending on their basicity. This represents a significant step toward the goal of using the cage as a catalyst for bimolecular reactions between a cavity-bound guest and anions accumulated around the surface.
Tryptophan (Trp) plays a variety of critical functional roles in protein biochemistry; however, owing to its low natural frequency and poor nucleophilicity, the design of effective methods for both ...single protein bioconjugation at Trp as well as for in situ chemoproteomic profiling remains a challenge. Here, we report a method for covalent Trp modification that is suitable for both scenarios by invoking photo-induced electron transfer (PET) as a means of driving efficient reactivity. We have engineered biaryl N-carbamoyl pyridinium salts that possess a donor–acceptor relationship that enables optical triggering with visible light whilst simultaneously attenuating the probe’s photo-oxidation potential in order to prevent photodegradation. This probe was assayed against a small bank of eight peptides and proteins, where it was found that micromolar concentrations of the probe and short irradiation times (10–60 min) with violet light enabled efficient reactivity toward surface exposed Trp residues. The carbamate transferring group can be used to transfer useful functional groups to proteins including affinity tags and click handles. DFT calculations and other mechanistic analyses reveal correlations between excited state lifetimes, relative fluorescence quantum yields, and chemical reactivity. Biotinylated and azide-functionalized pyridinium salts were used for Trp profiling in HEK293T lysates and in situ in HEK293T cells using 440 nm LED irradiation. Peptide-level enrichment from live cell labeling experiments identified 290 Trp modifications, with 82% selectivity for Trp modification over other π-amino acids, demonstrating the ability of this method to identify and quantify reactive Trp residues from live cells.
Commentary: Maybe it is better to be a lefty Taylor, Michael D.
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
12/2021, Letnik:
162, Številka:
6
Journal Article
Cancers are caused by genomic alterations known as drivers. Hundreds of drivers in coding genes are known but, to date, only a handful of noncoding drivers have been discovered-despite intensive ...searching
. Attention has recently shifted to the role of altered RNA splicing in cancer; driver mutations that lead to transcriptome-wide aberrant splicing have been identified in multiple types of cancer, although these mutations have only been found in protein-coding splicing factors such as splicing factor 3b subunit 1 (SF3B1)
. By contrast, cancer-related alterations in the noncoding component of the spliceosome-a series of small nuclear RNAs (snRNAs)-have barely been studied, owing to the combined challenges of characterizing noncoding cancer drivers and the repetitive nature of snRNA genes
. Here we report a highly recurrent A>C somatic mutation at the third base of U1 snRNA in several types of tumour. The primary function of U1 snRNA is to recognize the 5' splice site via base-pairing. This mutation changes the preferential A-U base-pairing between U1 snRNA and the 5' splice site to C-G base-pairing, and thus creates novel splice junctions and alters the splicing pattern of multiple genes-including known drivers of cancer. Clinically, the A>C mutation is associated with heavy alcohol use in patients with hepatocellular carcinoma, and with the aggressive subtype of chronic lymphocytic leukaemia with unmutated immunoglobulin heavy-chain variable regions. The mutation in U1 snRNA also independently confers an adverse prognosis to patients with chronic lymphocytic leukaemia. Our study demonstrates a noncoding driver in spliceosomal RNAs, reveals a mechanism of aberrant splicing in cancer and may represent a new target for treatment. Our findings also suggest that driver discovery should be extended to a wider range of genomic regions.
Silicone composites featuring inclusions of liquid metal particles are soft and stretchable materials with useful electric, dielectric, mechanical, and thermal properties. Until recently, these ...materials have primarily been cast as films. This work examines the possibility of using uncured liquid metal-elastomer (LME) composites as inks for direct writing. The liquid metal inclusions act as rheological modifiers for the silicone, forming a gel-structure that can be extruded from a nozzle and hold its shape after printing. Additionally, by tuning the particle size, larger particles in the printed structures can settle to form metal-rich regions at the bottom of the structures, encased by metal-depleted (insulating) regions. Using mechanical force, the liquid metal-rich interior can be rendered conductive by sintering without affecting the insulating exterior. Thus, it is possible to print this soft and stretchable material while creating conductors with self-insulating shells.
Silicone composites featuring inclusions of liquid metal particles are soft and stretchable materials with useful electric, dielectric, mechanical, and thermal properties.
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