Histone deacetylase (HDAC) inhibitors (HDIs) are promising anticancer therapies and have been clinically used for the treatment of hematological malignancy. However, their efficacy in solid tumors is ...marginal and drug resistance hampers their further clinical utility. To develop novel strategies for the HDI-based anticancer therapeutics in non-small cell lung cancer (NSCLC), in the present study, we investigated the mechanisms underlying resistance to HDI treatment in NSCLC cells. We show the STAT3-mediated IGF2/IGF-1R signaling cascade as a key modulator for both acquired and primary HDI resistance. The treatment with HDI upregulated IGF2 transcription in NSCLC cells carrying intrinsic or acquired drug resistance via direct binding of STAT3 in IGF2 P3 and P4 promoters. Acetylated STAT3 emerged upon HDAC inhibition was protected from the proteasome-mediated degradation of STAT3 and functioned as a direct transcription factor for IGF2 expression. Genomic or pharmacological strategies targeting STAT3 diminished the HDI-induced IGF2 mRNA expression and overcame the resistance to HDI treatment in HDI-resistant NSCLC- or patient-derived tumor xenograft models. These findings provide new insights into the role of acetylated STAT3-mediated activation of IGF2 transcription in HDI resistance, suggesting IGF2 or STAT3 as novel targets to overcome HDI resistance in NSCLC.
The enamel knot (EK), located at the center of cap stage tooth germs, is a transitory cluster of nondividing epithelial cells. The EK acts as a signaling center that provides positional information ...for tooth morphogenesis and regulates the growth of tooth cusps. To identify species-specific cuspal patterns, this study analyzed the cellular mechanisms in the EK that were related to bone morphogenetic protein (Bmp), which plays a crucial role in cell proliferation and apoptosis. To understand the cellular mechanisms in the EK, the differences between 2 species showing different cuspal patterning, mouse (pointy bunodont cusp) and gerbil (flat lophodont cusp), were analyzed with quantitative reverse transcriptase polymerase chain reaction and immunofluorescent staining. Based on these, we performed protein-soaked bead implantation on tooth germs of the 2 different EK regions and compared the cellular behavior in the EKs of the 2 species. Many genes related with cell cycle, cell apoptosis, and cell proliferation were involved in BMP signaling in the EK during tooth development. A comparison of the cell proliferation and apoptosis associated with Bmp revealed distinctive patterns of the cellular mechanisms. Our findings indicate that the cellular mechanisms, such as cell proliferation and apoptosis, in the EK are related to Bmp4 and play an important role in tooth morphogenesis.
The excellent cryogenic tensile properties of the CrMnFeCoNi alloy are generally caused by deformation twinning, which is difficult to achieve at room temperature because of insufficient stress for ...twinning. Here, we induced twinning at room temperature to improve the cryogenic tensile properties of the CrMnFeCoNi alloy. Considering grain size effects on the critical stress for twinning, twins were readily formed in the coarse microstructure by cold rolling without grain refinement by hot rolling. These twins were retained by partial recrystallization and played an important role in improving strength, allowing yield strengths approaching 1 GPa. The persistent elongation up to 46% as well as the tensile strength of 1.3 GPa are attributed to additional twinning in both recrystallized and non-recrystallization regions. Our results demonstrate that non-recrystallized grains, which are generally avoided in conventional alloys because of their deleterious effect on ductility, can be useful in achieving high-strength high-entropy alloys.
Purpose
This multi-center, randomized, phase III study was conducted to demonstrate the non-inferiority of DA-3031 compared with daily filgrastim in patients during the first cycle of chemotherapy ...for breast cancer in terms of the duration of severe neutropenia (DSN).
Methods
Seventy-four patients with breast cancer who were receiving combination chemotherapy with docetaxel, doxorubicin, and cyclophosphamide (TAC) were enrolled. All participants were randomized to receive either daily subcutaneous injections of filgrastim 100 μg/m
2
/day for up to 10 days or a single subcutaneous injection of DA-3031 at fixed doses of 6 mg on day 2 of each chemotherapy cycle.
Results
The mean duration of grade 4 (G4) neutropenia in cycle 1 was 2.08 ± 0.85 days for the filgrastim group and 2.28 ± 1.14 days for the DA-3031 group. The difference between groups was 0.2 ± 1.10 days (95 % confidence interval (CI) = −0.26, 0.66), which supported non-inferiority. No statistically significant differences were observed in nadir absolute neutrophil count (ANC) (154.34/mm
3
and 161.75/mm
3
for the filgrastim and DA-3031 groups, respectively;
P
= 0.8414) or in time to ANC recovery (10.03 ± 0.75 and 9.83 ± 1.56 days in the filgrastim and DA-3031 groups, respectively;
P
= 0.0611) during cycle 1. Serious AEs occurred in six (15.8 %) patients receiving filgrastim and in ten (27.8 %) patients receiving DA-3031; however, none was determined to be related to the study drug.
Conclusions
DA-3031 and daily filgrastim are similar in regard to DSN and safety in breast cancer patients receiving TAC chemotherapy.
We report the discovery of a giant planet in the OGLE-2017-BLG-1522 microlensing event. The planetary perturbations were clearly identified by high-cadence survey experiments despite the relatively ...short event timescale of tE ∼ 7.5 days. The Einstein radius is unusually small, θE = 0.065 mas, implying that the lens system either has very low mass or lies much closer to the microlensed source than the Sun, or both. A Bayesian analysis yields component masses and source-lens distance , implying that this is a brown-dwarf/Jupiter system that probably lies in the Galactic bulge, a location that is also consistent with the relatively low lens-source relative proper motion = 3.2 0.5 mas yr−1. The projected companion-host separation is , indicating that the planet is placed beyond the snow line of the host, i.e., asl ∼ 0.12 au. Planet formation scenarios combined with the small companion-host mass ratio q ∼ 0.016 and separation suggest that the companion could be the first discovery of a giant planet that formed in a protoplanetary disk around a brown-dwarf host.
Summary
Background
Transient receptor potential vanilloid subfamily, member 1 (TRPV1) may play an important role in pruritus and inflammation induction in atopic dermatitis (AD). The treatment effect ...of TRPV1 antagonist via topical application in patients with AD remains unknown.
Objectives
To assess the clinical efficacy and safety of PAC‐14028, a TRPV1 antagonist, via topical application in patients with AD.
Methods
In this 8‐week, phase IIb, randomized, double‐blind, multicentre, vehicle‐controlled study, patients with mild‐to‐moderate AD were randomized to receive PAC‐14028 cream 0·1%, 0·3%, 1·0% or vehicle cream twice daily. The primary efficacy end point was the Investigator's Global Assessment (IGA) success rate defined as the percentage of patients with an IGA score of 0 or 1 at week 8. The secondary efficacy end points included the severity Scoring of Atopic Dermatitis (SCORAD) index and Eczema Area and Severity Index (EASI) 75/90.
Results
A total of 194 patients were enrolled. IGA success rates at week 8 were 14·58% for vehicle cream, 42·55% for PAC‐14028 cream 0·1% (P = 0·0025 vs. vehicle), 38·30% for PAC‐14028 cream 0·3% (P = 0·0087 vs. vehicle) and 57·45% for PAC‐14028 cream 1·0% (P < 0·001 vs. vehicle). In particular, statistically significant differences were found between the vehicle and treatment groups in the IGA success rates with two‐grade improvement. The SCORAD index, EASI 75/90, sleep disturbance score and pruritus visual analogue scale showed a trend towards improvement. No significant safety issues were reported.
Conclusions
PAC‐14028 cream may be an effective and safe treatment modality for the treatment of patients with mild‐to‐moderate AD.
What is already known about this topic?
Atopic dermatitis (AD) is one of the most common inflammatory skin diseases characterized by pruritic erythematous skin lesions and barrier dysfunction.
Transient receptor potential vanilloid subfamily, member 1 (TRPV1) antagonists suppress the release of pruritic and proinflammatory mediators.
The preclinical results demonstrate the feasibility of TRPV1 as a potential therapeutic target for the treatment of AD.
What does this study add?
TRPV1 regulates inflammation and pruritus in patients with AD.
PAC‐14028 cream, a novel TRPV1 antagonist, was superior to vehicle in improving clinical symptoms and signs with a favourable safety profile in adults with mild‐to‐moderate AD.
TRPV1 antagonism may play a role as a promising nonsteroidal topical treatment target for AD with a new mechanism of action.
Linked Editorial: Song and Armstrong. Br J Dermatol 2019; 180:971–972.
Plain language summary available online
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Current microlensing surveys are sensitive to free-floating planets down to Earth-mass objects. All published microlensing events attributed to unbound planets were identified based on their short ...timescale (below two days), but lacked an angular Einstein radius measurement (and hence lacked a significant constraint on the lens mass). Here, we present the discovery of a Neptune-mass free-floating planet candidate in the ultrashort (tE = 0.320 0.003 days) microlensing event OGLE-2016-BLG-1540. The event exhibited strong finite-source effects, which allowed us to measure its angular Einstein radius of θE = 9.2 0.5 as. There remains, however, a degeneracy between the lens mass and distance. The combination of the source proper motion and source-lens relative proper motion measurements favors a Neptune-mass lens located in the Galactic disk. However, we cannot rule out that the lens is a Saturn-mass object belonging to the bulge population. We exclude stellar companions up to ∼15 au.
Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a ...possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1
; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca
/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1
; CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.
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