Dendritic cells (DCs) are key regulators of the immune system that shape T cell responses. Regulation of T cell induction by DCs may occur via the intracellular enzyme indoleamine 2,3‐dioxygenase 1 ...(IDO), which catalyzes conversion of the essential amino acid tryptophan into kynurenine. Here, we examined the role of IDO in human peripheral blood plasmacytoid DCs (pDCs), and type 1 and type 2 conventional DCs (cDC1s and cDC2s). Our data demonstrate that under homeostatic conditions, IDO is selectively expressed by cDC1s. IFN‐γ or TLR ligation further increases IDO expression in cDC1s and induces modest expression of the enzyme in cDC2s, but not pDCs. IDO expressed by conventional DCs is functionally active as measured by kynurenine production. Furthermore, IDO activity in TLR‐stimulated cDC1s and cDC2s inhibits T cell proliferation in settings were DC‐T cell cell‐cell contact does not play a role. Selective inhibition of IDO1 with epacadostat, an inhibitor currently tested in clinical trials, rescued T cell proliferation without affecting DC maturation status or their ability to cross‐present soluble antigen. Our findings provide new insights into the functional specialization of human blood DC subsets and suggest a possible synergistic enhancement of therapeutic efficacy by combining DC‐based cancer vaccines with IDO inhibition.
Among human blood dendritic cell subsets, cDC1s uniquely express biologically active IDO at steady‐state, whereas cDC2s express IDO upon IFN‐γ‐ or TLR agonist‐mediated signaling. The enzyme converts tryptophan into kynurenine, thereby limiting T cell proliferation. Selective inhibition of IDO by epacadostat impedes IDO‐mediated immunosuppressive effects in conventional DCs.
Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas and similar projects have provided a ...comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal Analysis Consortium (GLASS) aims to systemically catalog the longitudinal changes in gliomas. The GLASS initiative will provide essential insights into the evolution of glioma toward a lethal phenotype, with the potential to reveal targetable vulnerabilities and, ultimately, improved outcomes for a patient population in need.
Transplantation of microencapsulated cells has been proposed as a cure for many types of endocrine disorders. Alginate-based microcapsules have been used in many of the feasibility studied addressing ...cure of the endocrine disorders, and different cancer types. Despite years of intensive research it is still not completely understood which factors have to be controlled and documented for achieving adequate mechanical stability. Here we studied the strength and elasticity of microcapsules of different composition with and without cell load. We compared strength (force) versus elasticity (time) required to compress individual microcapsule to 60% deformation. It is demonstrated that the alginate viscosity, the size of the beads, the alginate type, the gelling time, the storage solution and the cell load are dominant factors in determining the final strength of alginate-based microcapsules while the type of gelling ion, the polyamino acid incubation time, the type of polyamino acid and the culturing time determines the elasticity of the alginate-based microcapsules.
Our data underpin the essence of documenting the above mentioned factors in studies on encapsulated cells as mechanical stability is an essential factor in the success and failure of encapsulated grafts.
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•Mechanical stability of alginate capsules dominates the success encapsulated cells.•Mechanical stability is dependent on the force and time required for compression.•Force determines the strength, and time determines the elasticity of microcapsules.
Dendritic cells (DCs) are central players of immune responses; they become activated upon infection or inflammation and migrate to lymph nodes, where they can initiate an antigen-specific immune ...response by activating naive T cells. Two major types of naturally occurring DCs circulate in peripheral blood, namely, myeloid and plasmacytoid DCs (pDCs). Myeloid DCs (mDCs) can be subdivided based on the expression of either CD1c or CD141. These human DC subsets differ in surface marker expression, Toll-like receptor (TLR) repertoire, and transcriptional profile, suggesting functional differences between them. Here, we directly compared the capacity of human blood mDCs and pDCs to activate and polarize CD4+ T cells. CD141+ mDCs show an overall more mature phenotype over CD1c+ mDC and pDCs; they produce less IL-10 and more IL-12 than CD1c+ mDCs. Despite these differences, all subsets can induce the production of IFN-γ in naive CD4+ T cells. CD1c+ and CD141+ mDCs especially induce a strong T helper 1 profile. Importantly, naive CD4+ T cells are not polarized towards regulatory T cells by any subset. These findings further establish all three human blood DCs—despite their differences—as promising candidates for immunostimulatory effectors in cancer immunotherapy.
PREMISE OF THE STUDY:
Pentaclethra and Dimorphandra (Leguminosae) have long been considered a possible enigmatic link between caesalpinioids and mimosoids because they both have an imbricate calyx ...and heteromorphic androecium, floral features that are rare among mimosoids but common among caesalpinioids. This study compared the developing flowers of Dimorphandra mollis and Pentaclethra macroloba to determine whether the shared floral conditions also have the same ontogenetic origin.
METHODS:
Buds of different sizes and flowers were processed for surface (scanning electron microscopy) and histological (light microscopy) examination.
KEY RESULTS:
The floral meristem initiates five sepal primordia in a modified helical order in both species. The median sagittal sepal is adaxial. The overlap of the sepals during elongation culminates with the formation of the imbricate calyx. Heteromorphic androecia arise in the intermediate stages of development. In P. macroloba, the fertile pollen‐bearing stamens are antesepalous, robust and short, and the anthers carry a robust apical gland; the staminodes are long and white with a vestigial apical gland. In contrast, in D. mollis the fertile pollen‐bearing stamens are antepetalous without glands and as long as the staminodes. The staminodes are thinner with an expanded apical region.
CONCLUSIONS:
The imbricate calyx and the heteromorphic androecium in the studied species originated via distinct pathways, favoring the hypothesis of homoplasy of these conditions. The pathways observed in P. macroloba are more similar to those observed in caesalpinioids than to those observed in mimosoids, indicating that although the floral development differs between the species studied, it supports the basal placement of Pentaclethra among mimosoids.
Bioassay-guided investigation of the EtOAc-soluble extract of a culture of the marine-derived fungus Peroneutypa sp. M16 led to the isolation of seven new polyketide- and terpenoid-derived ...metabolites (1, 2, 4–8), along with known polyketides (3, 9–13). Structures of compounds 1, 2, and 4–8 were established by analysis of spectroscopic data. Absolute configurations of compounds 1, 2, 4, 6, 7, and 8 were determined by the comparison of experimental ECD spectra with calculated CD data. Compound 5 exhibited moderate antiplasmodial activity against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum.
A
bstract
The ratio
R
= Γ(
K
S
→ πeν
)
/
Γ(
K
S
→ π
+
π
−
) has been measured with a sample of 300 million
K
S
mesons produced in
ϕ → K
L
K
S
decays recorded by the KLOE experiment at the DAΦNE
e
+
e
...−
collider.
K
S
→ πeν
events are selected by a boosted decision tree built with kinematic variables and time-of-flight measurements. Data control samples of
K
L
→ πeν
decays are used to evaluate signal selection efficiencies. With 49647
±
316 signal events we measure
R
= (1
.
0421
±
0
.
0066
stat
±
0
.
0075
syst
)
×
10
−
3
. The combination with our previous measurement gives
R
= (1
.
0338
±
0
.
0054
stat
±
0
.
0064
syst
)
×
10
−
3
. From this value we derive the branching fraction
B
(
K
S
→ πeν
) = (7
.
153
±
0
.
037
stat
±
0
.
044
syst
)
×
10
−
4
and
f
+
(0)
|V
us
|
= 0
.
2170
±
0
.
009.
Current guidelines recommend transarterial chemoembolization (TACE) as the standard treatment of Barcelona-Clinic Liver Cancer (BCLC)-B patients. However, the long-term survival outcomes of patients ...managed with this technique do not appear fully satisfactory; in addition, intermediate-stage hepatocellular carcinoma (HCC) includes a heterogeneous population of patients with varying tumour burdens, liver function and disease aetiology. Therefore, not all patients with intermediate-stage HCC may derive similar benefit from TACE, and some patients may benefit from other treatment options, which are currently approved or being explored. These include different TACE modalities, such as selective TACE or drug-eluting beads TACE and radioembolization. The introduction of sorafenib in the therapeutic armamentarium for HCC has provided a new therapeutic option for the treatment of BCLC-B patients who are unsuitable to TACE or in whom TACE resulted in unacceptable toxicity. In addition, clinical trials aimed at investigating the potential role of this molecule in the treatment of patients with intermediate-stage HCC within combination therapeutic regimens are ongoing. This narrative review will present and discuss the most recent evidence on the locoregional or medical treatment with sorafenib in patients with intermediate-stage HCC.
Neutral kaon pairs produced in ϕ decays in anti-symmetric entangled state can be exploited to search for violation of CPT symmetry and Lorentz invariance. We present an analysis of the CP-violating ...process ϕ→KSKL→π+π−π+π− based on 1.7 fb−1 of data collected by the KLOE experiment at the Frascati ϕ-factory DAΦNE. The data are used to perform a measurement of the CPT-violating parameters Δaμ for neutral kaons in the context of the Standard Model Extension framework. The parameters measured in the reference frame of the fixed stars are:Δa0=(−6.0±7.7stat±3.1syst)×10−18 GeV,ΔaX=(0.9±1.5stat±0.6syst)×10−18 GeV,ΔaY=(−2.0±1.5stat±0.5syst)×10−18 GeV,ΔaZ=(3.1±1.7stat±0.5syst)×10−18 GeV. These are presently the most precise measurements in the quark sector of the Standard Model Extension.
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