Abstract
In this work, 1272 superflares on 311 stars are collected from 22,539 solar-type stars from the second-year observation of the Transiting Exoplanet Survey Satellite (TESS), which almost ...covered the northern hemisphere of the sky. Three superflare stars contain hot Jupiter candidates or ultrashort-period planet candidates. We obtain
γ
= −1.76 ± 0.11 of the correlation between flare frequency and flare energy (
) for all superflares and get
β
= 0.42 ± 0.01 of the correlation between superflare duration and energy (
T
duration
∝
E
β
), which supports that a similar mechanism is shared by stellar superflares and solar flares. Stellar photometric variability (
R
var
) is estimated for all solar-type stars, and the relation of
is included. An indicator of chromospheric activity (
S
-index) is obtained by using data from the Large Sky Area Multi-Object Fiber Spectroscopic Telescope (LAMOST) for 7454 solar-type stars. Distributions of these two properties indicate that the Sun is generally less active than superflare stars. We find that saturation-like feature of
R
var
∼ 0.1 may be the reason for superflare energy saturating around 10
36
erg. Object TIC 93277807 was captured by the TESS first-year mission and generated the most energetic superflare. This superflare is valuable and unique in that it can be treated as an extreme event, which may be generated by different mechanisms than other superflares.
Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) ...metastasis and chemoresistance have not been fully characterized.
CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1.
CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/β-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients.
CAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC.
High tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to ...investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1.
We reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360 mg d1, Q3W) with oxaliplatin 130 mg/m2 qd, d1, capecitabine 1000 mg/m2 b.i.d., d1–d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy.
In cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group 14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24–0.96), P = 0.038, while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs.
Toripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent.
ClinicalTrials.gov NCT02915432.
Programmed cell death (PCD), referring to apoptosis, autophagy and programmed necrosis, is proposed to be death of a cell in any pathological format, when mediated by an intracellular program. These ...three forms of PCD may jointly decide the fate of cells of malignant neoplasms; apoptosis and programmed necrosis invariably contribute to cell death, whereas autophagy can play either pro‐survival or pro‐death roles. Recent bulk of accumulating evidence has contributed to a wealth of knowledge facilitating better understanding of cancer initiation and progression with the three distinctive types of cell death. To be able to decipher PCD signalling pathways may aid development of new targeted anti‐cancer therapeutic strategies. Thus in this review, we present a brief outline of apoptosis, autophagy and programmed necrosis pathways and apoptosis‐related microRNA regulation, in cancer. Taken together, understanding PCD and the complex interplay between apoptosis, autophagy and programmed necrosis may ultimately allow scientists and clinicians to harness the three types of PCD for discovery of further novel drug targets, in the future cancer treatment.
Summary
Background
Women with polycystic ovary syndrome (PCOS) are almost three times more likely to be obese than those without PCOS. However, we have no specific interventions to induce weight loss ...so far and rely on drugs used to treat other symptoms of the syndrome or obesity in the general population.
Objective
The objective of this study is to compare the effectiveness of metformin, inositol, liraglutide and orlistat to induce weight loss in women with PCOS and overweight/obesity.
Methods
A search was conducted using the MEDLINE, EMBASE, PubMed and CENTRAL databases. Individually randomized, parallel group trials that evaluated the effects of these pharmacological treatments among adults or adolescents with PCOS and overweight/obesity, compared with a placebo or metformin group, were considered eligible. Registration number: PROSPERO CRD 42017076625.
Results
Twenty‐three trials reporting on 941 women were included in the network meta‐analysis. The amount of weight lost differed significantly among the drugs (in descending order): liraglutide, orlistat and metformin. Liraglutide alone, liraglutide/metformin and metformin alone significantly reduced waist circumference, but no change was found with orlistat. Data for waist‐to‐hip ratio were only available for metformin, which had no significant effect.
Conclusion
Liraglutide appears superior to the other drugs in reducing weight and waist circumference.
The rotation curve (RC) of the Milky Way out to ~100 kpc has been constructed using ~16,000 primary red clump giants (PRCGs) in the outer disc selected from the LAMOST Spectroscopic Survey of the ...Galactic Anti-centre (LSS-GAC) and the Sloan Digital Sky Survey (SDSS)-III/APOGEE survey, combined with ~5700 halo K giants (HKGs) selected from the SDSS/SEGUE survey. To derive the RC, the PRCG sample of the warm disc population and the HKG sample of halo stellar population are, respectively, analysed using a kinematical model allowing for the asymmetric drift corrections and re-analysed using the spherical Jeans equation along with measurements of the anisotropic parameter beta currently available. The typical uncertainties of RC derived from the PRCG and HKG samples are, respectively, 5-7 km s super( -1) and several tens km s super( -1). We determine a circular velocity at the solar position, ... and an azimuthal peculiar speed of the Sun, ..., both in good agreement with the previous determinations. The newly constructed RC has a generally flat value of 240 km s super( -1) within a Galactocentric distance rof 25 kpc and then decreases steadily to 150 km s super( -1) at r ~ 100 kpc. On top of this overall trend, the RC exhibits two prominent localized dips, one at r ~ 11 kpc and another at r ~ 19 kpc. From the newly constructed RC, combined with other constraints, we have built a parametrized mass model for the Galaxy, yielding a virial mass of the Milky Way's dark matter halo of ... and a local dark matter density, ... (ProQuest: ... denotes formulae/symbols omitted.)
The possibility that a fraction of dark matter is comprised of massive compact halo objects (MACHOs) remains unclear, especially in the 20–100 M⊙ window. MACHOs could make up binaries, whose mergers ...may be detected by LIGO as gravitational wave events. On the other hand, the cosmological origin of fast radio burst (FRBs) has been confirmed. We investigate the possibility of detecting FRBs gravitational lensed by MACHO binaries to constrain their properties. Since lensing events could generate more than one image, lensing by binaries could cause multiple-peak FRBs. The angular separation between these images is roughly 10−3 mas, which is too small to be resolved. The typical time interval between different images is roughly 1 millisecond (ms). The flux ratio between different images is from approximately 10 to 103. With the expected detection rate of 104 FRBs per year by the upcoming experiments, we could expect five multi-peak FRBs observed per year with a time interval larger than 1 ms and flux ratio less than 103 if the fraction of dark matter in MACHOs is f ~ 0.01. A null search of multiple-peak FRBs for time intervals larger than 1 ms and flux ratio less than 103 with 104 FRBs would constrain the fraction f of dark matter in MACHOs to f < 0.001.
ABSTRACT We propose a new model-independent method to test the cosmic curvature by comparing the proper distance and transverse comoving distance. Using the measurements of the Hubble parameter H(z) ...and the angular diameter distance dA, the cosmic curvature parameter is constrained to be −0.09 0.19, which is consistent with a flat universe. We also use a Monte Carlo simulation to test the validity and efficiency, and find that our method can give a reliable and efficient constraint on cosmic curvature. Compared with other model-independent methods testing the cosmic curvature, our method can avoid some drawbacks and give a better constraint.
Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates phosphatidylinositol 3-kinase signaling and is a tumor suppressor in some types of cancers. However, we have found that it ...is frequently upregulated in human colon cancer cells. Here we show that silencing of INPP4B blocks activation of Akt and serum- and glucocorticoid-regulated kinase 3 (SGK3), inhibits colon cancer cell proliferation and retards colon cancer xenograft growth. Conversely, overexpression of INPP4B increases proliferation and triggers anchorage-independent growth of normal colon epithelial cells. Moreover, we demonstrate that the effect of INPP4B on Akt and SGK3 is associated with inactivation of phosphate and tensin homolog through its protein phosphatase activity and that the increase in INPP4B is due to Ets-1-mediated transcriptional upregulation in colon cancer cells. Collectively, these results suggest that INPP4B may function as an oncogenic driver in colon cancer, with potential implications for targeting INPP4B as a novel approach to treat this disease.
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