We present Atacama Large Millimeter Array observations at an angular resolution of 0 1-0 2 of the disk surrounding the young Herbig Ae star MWC 758. The data consist of images of the dust continuum ...emission recorded at 0.88 millimeter, as well as images of the 13CO and C18O J = 3-2 emission lines. The dust continuum emission is characterized by a large cavity of roughly 40 au in radius which might contain a mildly inner warped disk. The outer disk features two bright emission clumps at radii of ∼47 and 82 au that present azimuthal extensions and form a double-ring structure. The comparison with radiative transfer models indicates that these two maxima of emission correspond to local increases in the dust surface density of about a factor 2.5 and 6.5 for the south and north clumps, respectively. The optically thick 13CO peak emission, which traces the temperature, and the dust continuum emission, which probes the disk midplane, additionally reveal two spirals previously detected in near-IR at the disk surface. The spirals seen in the dust continuum emission present, however, a slight shift of a few au toward larger radii and one of the spirals crosses the south dust clump. Finally, we present different scenarios to explain the complex structure of the disk.
We report the results of ALMA observations of a protoplanetary disk surrounding the Herbig Ae star AB Aurigae. We obtained high-resolution (0 1; 14 au) images in 12CO J = 2 − 1 emission and in the ...dust continuum at the wavelength of 1.3 mm. The continuum emission is detected at the center and at the ring with a radius (r) of ∼120 au. The CO emission is dominated by two prominent spirals within the dust ring. These spirals are trailing and appear to be about 4 times brighter than their surrounding medium. Their kinematics is consistent with Keplerian rotation at an inclination of 23°. The apparent two-arm-spiral pattern is best explained by tidal disturbances created by an unseen companion located at r of 60-80 au, with dust confined in the pressure bumps created outside this companion orbit. An additional companion at r of 30 au, coinciding with the peak CO brightness and a large pitch angle of the spiral, would help to explain the overall emptiness of the cavity. Alternative mechanisms to excite the spirals are discussed. The origin of the large pitch angle detected here remains puzzling.
Sorafenib (SOR) resistance remains a major obstacle in the effective treatment of hepatocellular carcinoma (HCC). A number of long noncoding RNAs (lncRNAs) are responsible for this chemoresistance. ...This study aimed to reveal the essential function of a recently defined lncRNA, lncRNA‐POIR, in the epithelial–mesenchymal transition (EMT) and SOR sensitivity of HCC cells. SOR‐induced cytotoxicity was analyzed via cell counting kit‐8 and ethynyl‐2'‐deoxyuridine incorporation assays, whereas immunoblotting and confocal immunofluorescence were used to determine the expression levels of EMT markers. Furthermore, loss‐ or gain‐of‐function approaches were used to demonstrate the role of lncRNA‐POIR/miR‐182‐5p on EMT and SOR sensitivity in HCC. The direct interaction between lncRNA‐POIR and miR‐182‐5p was verified using a luciferase reporter assay. We found that knockdown of lncRNA‐POIR sensitized HCC cells to SOR and simultaneously reversed EMT. As expected, miR‐182‐5p was confirmed as the downstream target of lncRNA‐POIR. Moreover, miR‐182‐5p overexpression clearly reversed EMT and promoted SOR‐induced cytotoxicity in representative HCC cells, whereas miR‐182‐5p downregulation played a contrasting role; miR‐182‐5p knockdown abolished the modulatory effects of lncRNA‐POIR siRNA on EMT and SOR sensitivity. Together, these pieces of data suggest that lncRNA‐POIR promotes EMT progression and suppresses SOR sensitivity simultaneously by sponging miR‐182‐5p. Thus, we proposed a compelling rationale for the use of lncRNA‐POIR as a promising predictor of SOR response and as a potential therapeutic target for HCC treatment in the future.
In this study, we verified the biological functions of lncRNA‐POIR as an aberrantly expressed lncRNA in hepatocellular carcinoma (HCC) cells. lncRNA‐POIR modulated EMT and sorafenib sensitivity of HCC cells via functioning as a competing endogenous RNA (ceRNA) of miR‐182‐5p. Our findings provide a compelling rationale for the use of lncRNA‐POIR as a predictor of SOR response and a promising therapeutic target for future HCC treatment.
Background
In pancreatic cancer, methods to predict early recurrence (ER) and identify patients at increased risk of relapse are urgently required.
Purpose
To develop a radiomic nomogram based on MR ...radiomics to stratify patients preoperatively and potentially improve clinical practice.
Study Type
Retrospective.
Population
We enrolled 303 patients from two medical centers. Patients with a disease‐free survival ≤12 months were assigned as the ER group (n = 130). Patients from the first medical center were divided into a training cohort (n = 123) and an internal validation cohort (n = 54). Patients from the second medical center were used as the external independent validation cohort (n = 126).
Field Strength/Sequence
3.0T axial T1‐weighted (T1‐w), T2‐weighted (T2‐w), contrast‐enhanced T1‐weighted (CET1‐w).
Assessment
ER was confirmed via imaging studies as MRI or CT. Risk factors, including clinical stage, CA19‐9, and radiomic‐related features of ER were assessed. In addition, to determine the intra‐ and interobserver reproducibility of radiomic features extraction, the intra‐ and interclass correlation coefficients (ICC) were calculated.
Statistical Tests
The area under the receiver‐operator characteristic (ROC) curve (AUC) was used to evaluate the predictive accuracy of the radiomic signature in both the training and test groups. The results of decision curve analysis (DCA) indicated that the radiomic nomogram achieved the most net benefit.
Results
The AUC values of ER evaluation for the radiomics signature were 0.80 (training cohort), 0.81 (internal validation cohort), and 0.78 (external validation cohort). Multivariate logistic analysis identified the radiomic signature, CA19‐9 level, and clinical stage as independent parameters of ER. A radiomic nomogram was then developed incorporating the CA19‐9 level and clinical stage. The AUC values for ER risk evaluation using the radiomic nomogram were 0.87 (training cohort), 0.88 (internal validation cohort), and 0.85 (external validation cohort).
Data Conclusion
The radiomic nomogram can effectively evaluate ER risks in patients with resectable pancreatic cancer preoperatively, which could potentially improve treatment strategies and facilitate personalized therapy in pancreatic cancer.
Level of Evidence: 4
Technical Efficacy: Stage 4
J. Magn. Reson. Imaging 2020;52:231–245.
Tumor-associated macrophages (TAM) have multifaceted roles in tumor development but they have been associated particularly closely with tumor angiogenesis. However, although the accumulation of TAM ...(M2 phenotype) promotes tumor angiogenesis, the mechanism through which monocytes differentiate to generate TAM is unclear. Here, we report that the mTOR pathway is a critical element in the regulation of monocyte differentiation to TAM. In human peripheral monocytes stimulated by lipopolysaccharide, mTOR was inhibited by rapamycin or activated by RNA interference-mediated knockdown of the mTOR repressor tuberous sclerosis complex 2 (TSC2). Rapamycin caused the monocytes to differentiate into M1 macrophages releasing more interleukin (IL)-12 and less IL-10, whereas TSC2 knockdown caused the monocytes to differentiate into M2 macrophages releasing less IL-12 and more IL-10. In parallel fashion, angiogenic properties were promoted or reduced in human umbilical vein endothelial cells cocultured with TSC2-deficient monocytes or rapamycin-treated monocytes, respectively. Furthermore, tumor angiogenesis and growth in murine xenografts were promoted or reduced by infusion of hosts with TSC2-deficient or TSC2-overexpressing monocytes, respectively. Finally, in vivo depletion of macrophages was sufficient to block the antiangiogenic effects of rapamycin on tumors. Our results define the TSC2-mTOR pathway as a key determinant in the differentiation of monocytes into M2 phenotype TAM that promote angiogenesis.
Background
Limited evidence supports the omission of routine bone marrow (BM) examination (biopsy and aspiration) in patients with nasal‐type extranodal NK/T‐cell lymphoma (ENKTCL). This study was ...aimed at assessing whether BM examination provides valuable information for positron emission tomography/computed tomography (PET/CT)–based staging in this patient population.
Patients and Methods
Patients newly diagnosed with ENKTCL who underwent initial staging with both PET/CT and BM examination between 2013 and 2020 were retrospectively identified in two Chinese institutions. Overall, 742 patients were included; the BM examination was positive in 67 patients.
Results
Compared with BM biopsy alone, the combination of BM biopsy and aspiration assessment did not afford any additional diagnostic value. No patient with a positive BM biopsy was found to have early‐stage disease by PET/CT. BM biopsy or PET/CT led to upstaging from stage III to IV as a result of BM involvement in 21 patients. In 135 patients with distant organ involvement, BM involvement was associated with worse overall survival (OS) and progression‐free survival (PFS) compared with the corresponding durations in patients without BM involvement (2‐year OS: 35.9% vs. 60.4%, p < .001; PFS: 26% vs. 40.7%, p = .003). No difference in survival was noted between groups judged positive based on PET/CT and BM biopsy.
Conclusion
Compared with aspiration, BM biopsy led to the detection of more BM lesions. Baseline PET/CT can be safely used to exclude BM involvement in early‐stage disease. Overall, routine BM examination affords diagnostic or prognostic value over PET/CT in patients with advanced‐stage nasal‐type ENKTCL.
Baseline positron emission tomography/computed tomography (PET/CT) can be safely used to exclude bone marrow (BM) involvement in patients with early‐stage nasal‐type extranodal NK/T‐cell lymphoma (ENKTCL). Compared with PET/CT alone, routine BM examination can afford better diagnostic and prognostic value in advanced‐stage nasal‐type ENKTCL.
Abstract
Asymmetrical features in disks provide indirect evidence of embedded objects, such as planets. Observed with the Atacama Large Millimeter/submillimeter Array (ALMA), the circumstellar disk ...in MWC 758 traced with thermal dust continuum emission at wavelengths of 0.9 mm with an angular resolution up to 01 (15 au) exhibits an asymmetrical dust ring with additional features. In order to analyze the structures azimuthally and radially, we split the dust ring into small segments in azimuth. For each segment, we fit two-Gaussian functions to the radial intensity profile. The obtained best-fit parameters as a function of azimuth are analyzed. Three spiral-like arm structures are identified. When fitting the 0.9 mm features with the spiral density wave theory using the WKB approximation, two sets of disk aspect ratios are found: one solution gives relatively low values (∼0.03) while the other solution is at the upper bound of the free parameter (∼0.2). The planet locations suggested by the upper-bound result are similar to the ones determined by Benisty et al. for the NIR polarized intensity image. Comparing the reported spiral-like structures with the higher angular resolution (004) ALMA image in Dong et al., we identify different structures in the west of the disk due to differences in the adopted analysis methods and the respective resolutions of the images.
The nervous and endocrine systems coordinate with each other to closely influence physiological and behavioural responses in animals. Here we show that WAKE (encoded by wide awake, also known as ...wake) modulates membrane levels of GABA
receptor Resistance to Dieldrin (Rdl), in insulin-producing cells of adult male Drosophila melanogaster. This results in changes to secretion of insulin-like peptides which is associated with changes in juvenile hormone biosynthesis in the corpus allatum, which in turn leads to a decrease in 20-hydroxyecdysone levels. A reduction in ecdysone signalling changes neural architecture and lowers the perception of the male-specific sex pheromone 11-cis-vaccenyl acetate by odorant receptor 67d olfactory neurons. These finding explain why WAKE-deficient in Drosophila elicits significant male-male courtship behaviour.
FOLFIRINOX chemotherapy has shown remarkable responses in patients with metastatic pancreatic cancer (MPC), and has significantly improved prognosis. However, FOLFIRINOX is currently not frequently ...applied in China because of its high incidence of adverse events, and there is no recognized optimization for this therapy in Chinese population. Modification of FOLFIRINOX may be better for its acceptance in China. In this study, we evaluated the efficacy and safety of modified-FOLFIRINOX in patients with MPC. A total of 62 MPC patients were treated with modified-FOLFIRINOX (no Fluorouracil bolus, 85% Oxaliplatin and 75% Irinotecan) between April 2014 and April 2017 in our institute. 40 of them were evaluated, with a response rate of 32.5% (13/40). The frequent grade 3/4 adverse events are neutropenia (29%) and alanine aminotransferase elevation (14.5%). No treatment-related death was observed. The median overall survival and median progression-free survival are 10.3 months and 7.0 months, respectively. In conclusion, modified-FOLFIRINOX had significantly improved tolerance with similar efficacy to FOLFIRINOX. These findings may provide evidence for the use of FOLFIRINOX in Chinese patients with MPC.
•This is the first prospective study to evaluate FOLFIRINOX in patients with metastatic pancreatic cancer from China.•The median overall survival and progression free survival time are extended to 10.3 m and 7.0 m respectively in 62 metastatic pancreatic cancer patients with modified-FOLFIRINOX regimens.•Our dose modification results in attenuated toxicity with an objective response rate of 32.5% and our plan is worthy to recommend to clinical use in China population.
Rad23 was identified as a DNA repair protein, although a role in protein degradation has been described. The protein degradation function of Rad23 contributes to cell cycle progression, stress ...response, endoplasmic reticulum proteolysis, and DNA repair. Rad23 binds the proteasome through a UbL (ubiquitin-like) domain and contains UBA (ubiquitin-associated) motifs that bind multiubiquitin chains. These domains allow Rad23 to function as a substrate shuttle-factor. This property is shared by structurally similar proteins (Dsk2 and Ddi1) and is conserved among the human and mouse counterparts of Rad23. Despite much effort, the regulation of Rad23 interactions with ubiquitinated substrates and the proteasome is unknown. We report here that Rad23 is extensively phosphorylated in vivo and in vitro. Serine residues in UbL are phosphorylated and influence Rad23 interaction with proteasomes. Replacement of these serine residues with acidic residues, to mimic phosphorylation, reduced proteasome binding. We reported that when UbL is overexpressed, it can compete with Rad23 for proteasome interaction and can inhibit substrate turnover. This effect is not observed with UbL containing acidic substitutions, consistent with results that phosphorylation inhibits interaction with the proteasome. Loss of both Rad23 and Rpn10 caused pleiotropic defects that were suppressed by overexpressing either Rad23 or Rpn10. Rad23 bearing a UbL domain with acidic substitutions failed to suppress rad23Δ rpn10Δ, confirming the importance of regulated Rad23/proteasome binding. Strikingly, threonine 75 in human HR23B also regulates interaction with the proteasome, suggesting that phosphorylation is a conserved mechanism for controlling Rad23/proteasome interaction.
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•Rad23 is a shuttle-factor that delivers proteolytic substrates to the proteasome.•Rad23 is phosphorylated in vivo.•Ser residues in the UbL domain, which binds the proteasome, are phosphorylated.•The phosphorylation of UbL in Rad23 prevents interaction with the proteasome.•Phosphorylation provides a mechanism to regulate Rad23/proteasome interaction.
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