Lu-177 has been developed for the treatment of patients with peptide receptor radionuclide therapy (PRRT). A second generation pure no-carrier-added Lu-177 has a high specific activity and has waste ...disposal advantages over the first generation carrier-added Lu-177. PRRT has recently been developed for the treatment of neuroendocrine tumors (NETs). The majority of pancreatic and gastroenteric NETs (GEP-NETs) express the somatostatin receptors (SSTRs) 2 and 5. These receptors can be specifically targeted with a somatostatin peptide analogue (DOTATOC/DOTATATE) which can be chelated to a positron emission tomography (PET) emitting radioisotope such as Ga-68 for imaging or to a β-emitting radioisotope Lu-177 for therapy. A key advantage of this approach is that the receptor expression can be demonstrated by PET imaging before the patient is treated. Clinical studies in G1 and G2 GEP-NETS have demonstrated that PRRT is extremely effective in terms of progression free survival (PFS), symptom control and quality of life, with a well-established safety profile. A beneficial effect on outcome survival awaits to be confirmed. The first commercially available product Lu-177-DOTATATE was approved following the NETTER-1 trial in G1 and G2 GE-NETS. Lu-177-DOTATATE 7,4 GBq every 8 weeks for 4 cycles, together with octreotide LAR 30 mg monthly, demonstrated a median PFS of 28,4 months compared to 8,5 months for octreotide LAR 60 mg monthly. A second pivotal study COMPETE is currently in progress, comparing no carrier-added (n.c.a.) Lu-177-DOTATOC to the m-TOR inhibitor Everolimus in both GE-NETs and PNETs. Two studies, NETTER-2 and COMPOSE are currently underway in patients with high grade G2 and G3 NETs. Novel SSTR antagonists are being developed as next generation targeting molecules for SSTR2-expressing tumors. Antagonists have a higher tumor binding to receptors than agonists, opening up the potential indications for SSTR2 targeting to tumors which have a relatively lower expression of SSTR2 compared to NET such as small cell lung cancer, hepatocellular carcinoma and breast cancer. In addition to Lu-177, radioisotopes with different radiation properties such as Tb-161 and the α-emitter Ac-225 are being developed which have the potential to improve treatment efficacy across the range of G1 to G3 NETs.
Intestinal dysbiosis is thought to be an important cause of disease progression and the gastrointestinal symptoms experienced in patients with inflammatory bowel disease (IBD). Inflammation appears ...to be a major contributor in perpetuating a dysregulated gut microbiota. Although current drug therapies can significantly induce and maintain disease remission, there is no cure for these diseases. Nevertheless, ongoing human studies investigating dietary fibre interventions may potentially prove to exert beneficial outcomes for IBD. Postulated mechanisms include direct interactions with the gut mucosa through immunomodulation, or indirectly through the microbiome. Component species of the microbiome may degrade dietary-fibre polysaccharides and ferment the products to form short-chain fatty acids such as butyrate. Prebiotic dietary fibres may also act more directly by altering the composition of the microbiome. Longer term benefits in reducing the risk of more aggressive disease or colorectal cancer may require other dietary fibre sources such as wheat bran or psyllium. By critically examining clinical trials that have used dietary fibre supplements or dietary patterns containing specific types or amounts of dietary fibres, it may be possible to assess whether varying the intake of specific dietary fibres may offer an efficient treatment for IBD patients.
Machine Learning is a powerful tool to reveal and exploit correlations in a multi-dimensional parameter space. Making predictions from such correlations is a highly non-trivial task, in particular ...when the details of the underlying dynamics of a theoretical model are not fully understood. Using adversarial networks, we include a priori known sources of systematic and theoretical uncertainties during the training. This paves the way to a more reliable event classification on an event-by-event basis, as well as novel approaches to perform parameter fits of particle physics data. We demonstrate the benefits of the method explicitly in an example considering effective field theory extensions of Higgs boson production in association with jets.
: RIP1 kinase is a serine/threonine-protein kinase that has recently emerged as a central regulator of TNF-α dependent programmed necrosis (necroptosis), an inflammatory form of cell death, with ...important roles in inflammation and neurodegeneration. Small molecule RIP1 kinase inhibitors may provide new opportunities for treating a variety of autoimmune, inflammatory, and neurodegenerative diseases, among others, and thus have attracted widespread drug development efforts and a corresponding large amount of patent activity in recent years.
: This review focuses on the patent literature covering small molecule inhibitors of RIP1 kinase from 2016-present.
: Inhibition of programmed necrosis (necroptosis) by RIP1 kinase inhibitors is a new field that has attracted widespread recent interest as a possible therapeutic means to treat a number of diseases in the inflammatory, neurodegenerative, and oncology areas. The interest in the therapeutic potential of RIP1kinase is evidenced by more than 40 small molecule patent applications published since 2016. To date, only a few RIP1 kinase inhibitors have entered the clinic. An understanding of the optimal clinical setting, in terms of dosing and disease indications for RIP1 inhibition, will require further clinical readouts as the current inhibitors progress and additional molecules enter into full development.
New jet observables are defined which characterize both fractal and scale-dependent contributions to the distribution of hadrons in a jet. These infrared safe observables, named Extended Fractal ...Observables (EFOs), have been applied to quark–gluon discrimination to demonstrate their potential utility. The EFOs are found to be individually discriminating and only weakly correlated to variables used in existing discriminators. Consequently, their inclusion improves discriminator performance, as here demonstrated with particle level simulation from the parton shower.
The xyloglucans of monocotyledons are known to vary in the abundance of fucosylated side chains, with most commelinid monocotyledons having xyloglucans with lower proportions than non-commelinid ...monocotyledons. In many commelinid species, and some non-commelinid species that have lower proportions of fucosylated side chains, these side chains have been shown to be cell-type specific. To determine whether it is just the fucosylated side chains that are cell-type specific, or whether xyloglucan is cell-type specific in these species, we used the monoclonal antibody LM15 in conjunction with immmunofluorescence microscopy. We examined the distribution of cell-wall labelling among cell types in these species. The primary walls of all cell types were shown to contain xyloglucans in all species that had cell-type specific distributions of fucosylated side chains. This indicates that it is the fucosylated side chains of xyloglucans that is cell-type specific. Although the functional significance of xyloglucan fucosylation remains unknown, such cell-type specificity supports hypotheses that the fucosylated side chains may indeed have a functional role within the cell wall.
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•Cell walls of monocotyledons without fucogalactoxyloglucans do contain xyloglucans.•The primary cell walls of all cell types examined contain xyloglucans.•Fucosylation of monocotyledon xyloglucans must be regulated by cell type.
Herpes simplex virus (HSV)-1 and HSV-2 are significant human pathogens causing recurrent disease. During infection, HSV modulates cell death pathways using the large subunit (R1) of ribonucleotide ...reductase (RR) to suppress apoptosis by binding to and blocking caspase-8. Here, we demonstrate that HSV-1 and HSV-2 R1 proteins (ICP6 and ICP10, respectively) also prevent necroptosis in human cells by inhibiting the interaction between receptor-interacting protein kinase 1 (RIP1) and RIP3, a key step in tumor necrosis factor (TNF)-induced necroptosis. We show that suppression of this cell death pathway requires an N-terminal RIP homotypic interaction motif (RHIM) within R1, acting in concert with the caspase-8-binding domain, which unleashes necroptosis independent of RHIM function. Thus, necroptosis is a human host defense pathway against two important viral pathogens that naturally subvert multiple death pathways via a single evolutionarily conserved gene product.
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•HSV-1 and HSV-2 R1 homologs block death receptor-induced necroptosis in human cells•HSV R1 homologs disrupt RIP1-RIP3 RHIM-dependent necrosome formation•Suppression of RIP3-mediated necroptosis requires both RHIM and caspase-8-binding domains•Caspase-8 inhibition blocks apoptosis but opens a necroptotic trap door
Herpes simplex virus (HSV) modulates cell death to promote infection. Guo et al. show that the HSV early protein, R1, inhibits necroptosis in human cells as a RHIM signaling competitor to disrupt RIP1-RIP3 interactions. A separate C-terminal R1 function known to inhibit caspase-8 sensitizes infected cells to necroptosis.
A
bstract
In this paper, we present a method of embedding physics data manifolds with metric structure into lower dimensional spaces with simpler metrics, such as Euclidean and Hyperbolic spaces. We ...then demonstrate that it can be a powerful step in the data analysis pipeline for many applications. Using progressively more realistic simulated collisions at the Large Hadron Collider, we show that this embedding approach learns the underlying latent structure. With the notion of volume in Euclidean spaces, we provide for the first time a viable solution to quantifying the true search capability of model agnostic search algorithms in collider physics (i.e. anomaly detection). Finally, we discuss how the ideas presented in this paper can be employed to solve many practical challenges that require the extraction of physically meaningful representations from information in complex high dimensional datasets.
A variant of the autophagy gene
is associated with Crohn's disease, an inflammatory bowel disease (IBD), and poor survival in allogeneic hematopoietic stem cell transplant recipients. We demonstrate ...that ATG16L1 in the intestinal epithelium is essential for preventing loss of Paneth cells and exaggerated cell death in animal models of virally triggered IBD and allogeneic hematopoietic stem cell transplantation. Intestinal organoids lacking ATG16L1 reproduced this loss in Paneth cells and displayed TNFα-mediated necroptosis, a form of programmed necrosis. This cytoprotective function of ATG16L1 was associated with the role of autophagy in promoting mitochondrial homeostasis. Finally, therapeutic blockade of necroptosis through TNFα or RIPK1 inhibition ameliorated disease in the virally triggered IBD model. These findings indicate that, in contrast to tumor cells in which autophagy promotes caspase-independent cell death, ATG16L1 maintains the intestinal barrier by inhibiting necroptosis in the epithelium.
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