Abstract
New observations are presented of four evolved objects that display long, multiyear variations in their light curves. These are interpreted as good evidence of their binary nature, with the ...modulation caused by the barycenter motion of the evolved star resulting in a periodic obscuration by a circumbinary disk. Although protoplanetary nebulae (PPNe) commonly possess bipolar nebulae, which are thought to be shaped by a binary companion, there are very few PPNe in which a binary companion has been found. Three of the objects in this study appear to be PPNe, IRAS 07253−2001, 08005−2356, and 17542−0603, with long periods of 5.2, 6.9, and 8.2 yr, respectively. The binary nature of IRAS 08005−2356 has recently been confirmed by a radial velocity study. Two samples, one of PPNe and the other of post-AGB star candidates, are investigated for further evidence on how common is a long-period light-curve variation. Both samples suggest such light-curve variations are not common. The fourth object, IRAS 20056+1834 (QY Sge), is an obscured RV Tau variable of the RVb subclass, with a long period of 3.9 yr and pulsation periods of 102.9 and 51.5 days. The period of this object is seen to vary by 2%. Evidence is presented for a recent mass ejection in IRAS 17542−0603.
Hepatocellular carcinoma (HCC) is the second leading cancer death because of its high metastasis and drug resistance. Regorafenib was newly approved by FDA for HCC treatment, but its resistance is ...not understood. The unique isomerase Pin1 is critical for HCC development, but its role in metastasis and drug resistance is unknown. Here we generated Regorafenib-resistant HCC cells and found that they exhibited enhanced tumor invasion and metastasis in vitro and in vivo, and elevated Pin1 levels. Furthermore, Pin1 was highly overexpressed and closely related to the EMT in human HCC tissues. Depletion or overexpression of Pin1 correspondingly inhibited or promoted HCC cell migration and invasion, with altered expression of EMT-related molecules, E-cadherin and Snail. Significantly, Pin1 interacted with Gli1, a regulator of the EMT, and silencing Gli1 partly blocked Pin1-induced EMT in HCC cells. Moreover, genetic or chemical Pin1 inhibition reversed Regorafenib resistance of HCC with reducing EMT, migration, invasion and metastasis in vitro and in vivo. These results reveal a novel molecular mechanism underlying Regorafenib resistance in HCC, and also provide first evidence that Pin1 inhibitors offer an attractive strategy for treating Regorafenib-resistant HCC.
•Regorafenib-resistant HCC cells have strong invasion and metastasis ability in vitro and in vivo.•Pin1 is abnormally overexpressed in Regorafenib-resistant HCC cells.•Pin1 regulates the epithelial-mesenchymal transition via the Gli1/Snail/E-cadherin pathway.•Pin1 inhibition reversed Regorafenib resistance by reducing metastasis and reversing EMT.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths worldwide largely due to lack of effective targeted drugs to simultaneously block multiple cancer-driving pathways. The ...identification of all-trans retinoic acid (ATRA) as a potent Pin1 inhibitor provides a promising candidate for HCC targeted therapy because Pin1 is overexpressed in most HCC and activates numerous cancer-driving pathways. However, the efficacy of ATRA against solid tumors is limited due to its short half-life of 45min in humans. A slow-releasing ATRA formulation inhibits solid tumors such as HCC, but can be used only in animals. Here, we developed a one-step, cost-effective route to produce a novel biocompatible, biodegradable, and non-toxic controlled release formulation of ATRA for effective HCC therapy. We used supercritical carbon dioxide process to encapsulate ATRA in largely uniform poly L-lactic acid (PLLA) microparticles, with the efficiency of 91.4% and yield of 68.3%, and ~4-fold higher Cmax and AUC over the slow-releasing ATRA formulation. ATRA-PLLA microparticles had good biocompatibility, and significantly enhanced the inhibitory potency of ATRA on HCC cell growth, improving IC50 by over 3-fold. ATRA-PLLA microparticles exerted its efficacy likely through degrading Pin1 and inhibiting multiple Pin1-regulated cancer pathways and cell cycle progression. Indeed, Pin1 knock-down abolished ATRA inhibitory effects on HCC cells and ATRA-PLLA did not inhibit normal liver cells, as expected because ATRA selectively inhibits active Pin1 in cancer cells. Moreover ATRA-PLLA microparticles significantly enhanced the efficacy of ATRA against HCC tumor growth in mice through reducing Pin1, with a better potency than the slow-releasing ATRA formulation, consistent with its improved pharmacokinetic profiles. This study illustrates an effective platform to produce controlled release formulation of anti-cancer drugs, and ATRA-PLLA microparticles might be a promising targeted drug for HCC therapy as PLLA is biocompatible, biodegradable and nontoxic to humans.
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The human prolyl isomerase PIN1, best known for its association with carcinogenesis, has recently been indicated in the disease of pancreatic ductal adenocarcinoma (PDAC). However, the functions of ...PIN1 and the feasibility of targeting PIN1 in PDAC remain elusive. For this purpose, we examined the expression of PIN1 in cancer, related paracarcinoma and metastatic cancer tissues by immunohistochemistry and analyzed the associations with the pathogenesis of PDAC in 173 patients. The functional roles of PIN1 in PDAC were explored in vitro and in vivo using both genetic and chemical PIN1 inhibition. We showed that PIN1 was upregulated in pancreatic cancer and metastatic tissues. High PIN1 expression is significantly association with poor clinicopathological features and shorter overall survival and disease‐free survival. Further stratified analysis showed that PIN1 phenotypes refined prognostication in PDAC. Inhibition of PIN1 expression with RNA interference or with all trans retinoic acid decreased not only the growth but also the migration and invasion of PDAC cells through regulating the key molecules of multiple cancer‐driving pathways, simultaneously resulting in cell cycle arrest and mesenchymal‐epithelial transition in vitro. Furthermore, genetic and chemical PIN1 ablation showed dramatic inhibition of the tumorigenesis and metastatic spread and then reduced the tumor burden in vivo. We provided further evidence for the use of PIN1 as a promising therapeutic target in PDAC. Genetic and chemical PIN1 ablation exerted potent antitumor effects through blocking multiple cancer‐driving pathways in PDAC. More potent and specific PIN1 targeted inhibitors could be exploited to treat this aggressive cancer.
PIN1 was highly expressed in pancreatic cancer and metastatic tissues. PIN1 high expression is significantly associated with lymph node metastasis. PIN1 ablation dramatically decreased migration and invasion in vitro and inhibited the tumorigenesis and metastatic spread of PDAC cells in vivo through regulating the key molecules of multiple cancer‐driving pathways.
The origin of elemental chromium for the archaeological weapons from the pits of Qin terracotta warriors in China has been highly controversial. Although previous studies have highlighted that the ...chromium on the surface of weapon originated from the contamination of surrounding lacquer, the exact origin of chromium in the lacquer remains unclear. In this work, the measurement by inductively coupled plasma-mass spectrometer (ICP-MS) firstly confirmed that the elemental chromium was indeed contained in the archaeological Qin original lacquer. Nevertheless, the amount of elemental chromium in the Qin lacquer was as low as 0.0759 μg/mg, disclosing that it was impossible to artificially add extra refined chromium-containing substance to the lacquer in the preparation of the terracotta warriors. The soil from the archaeological site of Qin lacquer was found to have a chromium amount of 0.0660 μg/mg by ICP-MS. After the hygrothermal and soil-buried aging cycles for the lab-prepared lacquer, the surface and depth elemental analyses by time of flight-secondary ion mass spectrometer (TOF–SIMS) showed a gradient distribution of elemental chromium from the surface to interior of aged lacquer, indicating the migration and enrichment behavior of elemental chromium from the burial soil towards the lacquer. To explore the migration mechanism of elemental chromium, fluorescence imaging technique was employed in combination with Fourier transform infrared spectrometry (FT-IR) and X-ray photoelectron spectroscopy (XPS) characterizations. The results revealed that catechol-containing fragments were formed during hygrothermal and soil-buried aging of lacquer and consequently coordinated with chromium ions, inducing the migration of elemental chromium towards the lacquer.
Regorafenib is approved for patients with unresectable hepatocellular carcinoma (HCC) following sorafenib. However, the effect of regorafenib on HCC metastasis and its mechanism are poorly ...understood. Here, our data showed that regorafenib significantly restrained the migration, invasion and vasculogenic mimicry (VM) of HCC cells, and downregulated the expression of epithelial‐to‐mesenchymal transition (EMT)/VM‐related molecules. Using RNA‐seq and cellular thermal shift assays, we found that inhibitor of differentiation 1 (ID1) was a key target of regorafenib. In HCC tissues, the protein expression of ID1 was positively correlated with EMT and VM formation (CD34−/PAS+). Functionally, ID1 knockdown inhibited HCC cell migration, invasion, metastasis, and VM formation in vitro and in vivo, with upregulation of E‐cadherin and downregulation of Snail and VE‐cadherin. Moreover, Snail overexpression promoted the migration, invasion, and VM formation of ID1 knockdown cells. Snail knockdown reduced the migration, invasion, and VM formation of ID1 overexpression cells. Finally, regorafenib suppressed VM formation and decreased the expression of ID1, VE‐cadherin and Snail in HCC PDX model. In conclusion, we manifested that regorafenib distinctly inhibited EMT in HCC cells via targeting ID1, leading to the suppression of cell migration, invasion and VM formation. These findings suggest that regorafenib may be developed as a suitable therapeutic agent for HCC metastasis.
Hepatocellular carcinoma (HCC) is one of the most prevalent and malignant cancers with high inter- and intra-tumor heterogeneity. A central common signaling mechanism in cancer is proline-directed ...phosphorylation, which is further regulated by the unique proline isomerase Pin1. Pin1 is prevalently overexpressed in human cancers including ~70% of HCC, and promotes tumorigenesis by activating multiple cancer-driving pathways. However, it was challenging to evaluate the significance of targeting Pin1 in cancer treatment until the recent identification of all-trans retinoic acid (ATRA) as a Pin1 inhibitor. Here we systematically investigate functions of Pin1 and its inhibitor ATRA in the development and treatment of HCC. Pin1 knockdown potently inhibited HCC cell proliferation and tumor growth in mice. ATRA-induced Pin1 degradation inhibited the growth of HCC cells, although at a higher IC50 as compared with breast cancer cells, likely due to more active ATRA metabolism in liver cells. Indeed, inhibition of ATRA metabolism enhanced the sensitivity of HCC cells to ATRA. Moreover, slow-releasing ATRA potently and dose-dependently inhibited HCC growth in mice. Finally, chemical or genetic Pin1 ablation blocked multiple cancer-driving pathways simultaneously in HCC cells. Thus, targeting Pin1 offers a promising therapeutic approach to simultaneously stop multiple cancer-driving pathways in HCC.
The shaping of the nebula is currently one of the outstanding unsolved problems in planetary nebula (PN) research. Several mechanisms have been proposed, most of which require a binary companion. ...However, direct evidence for a binary companion is lacking in most PNs. We have addressed this problem by obtaining precise radial velocities of seven bright proto-planetary nebulae (PPNs), objects in transition from the asymptotic giant branch to the PN phases of stellar evolution. These have F-G spectral types and have the advantage over PNs of having more and sharper spectral lines, leading to better precision. Our observations were made in two observing intervals, 1991-1995 and 2007-2010, and we have included in our analysis some additional published and unpublished data. Only one of the PPNs, IRAS 22272+5435, shows a long-term variation that might tentatively be attributed to a binary companion, with P > 22 yr, and from this, limiting binary parameters are calculated. Selection effects are also discussed. These results set significant restrictions on the range of possible physical and orbital properties of any binary companions: they have periods greater than 25 yr or masses of brown dwarfs or super-Jupiters. While not ruling out the binary hypothesis, it seems fair to say that these results do not support it.
Hepatocellular carcinoma (HCC) is the sixth most common cancer, but is the second leading cause of cancer deaths, partially due to its heterogeneity and drug resistance. Sorafenib is the only medical ...treatment with a proven efficacy against advanced HCC, but its overall clinical efficacy is still modest. Therefore, a major challenge is how to improve its therapeutic efficacy. The unique prolyl isomerase Pin1 regulates numerous cancer-driving pathways. Notably, Pin1 is overexpressed in about 70% HBV-positive HCC patients and contributes to HCC tumorigenesis. However, the role of Pin1 in the efficacy of sorafenib against HCC is unknown. Here we found that sorafenib down-regulated Pin1 mRNA and protein expression, likely through inhibition of Pin1 transcription by the Rb/E2F pathway. Importantly, Pin1 knockdown potently enhanced the ability of sorafenib to induce cell death in HCC, which was further supported by the findings that Pin1 knockdown led to stabilization of Fbxw7 and destabilization of Mcl-1. Furthermore, all-trans retinoic acid (ATRA), a known anticancer drug that inhibits and ultimately induces degradation of active Pin1 in cancer cells, also potently sensitized HCC cells to sorafenib-induced cell death at least in part through a caspase-dependent manner. Moreover, ATRA also synergistically enhanced the ability of sorafenib to reduce Pin1 and inhibit tumor growth of HCC in mouse xenograft models. Collectively, these results not only demonstrate that Pin1 down-regulation is a key event underlying the anti-tumor effects of sorafenib, but also uncover that Pin1 inhibitors offer a novel approach to enhance the therapeutic efficacy of sorafenib against HCC.
We have carried out long-term (14 years) V and R photometric monitoring of 12 carbon-rich proto-planetary nebulae. The light and color curves display variability in all of them. The light curves are ...complex and suggest multiple periods, changing periods, and/or changing amplitudes, which are attributed to pulsation. A dominant period has been determined for each and found to be in the range of approx150 days for the coolest (G8) to 35-40 days for the warmest (F3). A clear, linear inverse relationship has been found in the sample between the pulsation period and the effective temperature and also an inverse relationship between the amplitude of light variation and the effective temperature. These are consistent with the expectation for a pulsating post-asymptotic giant branch (post-AGB) star evolving toward higher temperature at constant luminosity. The published spectral energy distributions and mid-infrared images show these objects to have cool (200 K), detached dust shells and published models imply that intensive mass loss ended 400-2000 years ago. The detection of periods as long as 150 days in these requires a revision in the published post-AGB evolution models that couple the pulsation period to the mass loss rate and that assume that intensive mass loss ended when the pulsation period had decreased to 100 days. This revision will have the effect of extending the timescale for the early phases of post-AGB evolution. It appears that real time evolution in the pulsation periods of individual objects may be detectable on the timescale of two or three decades.
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