Pressure and temperature dependentab-initioquasi-harmonic thermoelastic properties of tungsten.

We present theab-initiotemperature and pressure dependent thermoelastic properties of body-centered cubic tungsten. The temperature dependent quasi-harmonic elastic constants (ECs) are computed at several reference volumes including both the phonon and the electronic excitations contribution to the free energy and interpolated at different temperatures and pressures. Good agreement with the experimental ECs on a single crystal at ambient pressure is found. The pressure and temperature dependence of the shear sound velocity measured on polycrystalline tungsten by Qiet alis also in agreement with theory. Some discrepancies are found instead for the compressional velocity at high temperature and this is attributed to the temperature derivative of the bulk modulus, higher in theory than in experiment. These conclusions are reached both by PBE and by PBEsol functionals. The two give elastic properties with a similar pressure and temperature dependence although the latter is closer to experiment at 0 K.

Incidence trends and survival analysis of appendiceal tumors in the United States: Primarily changes in appendiceal neuroendocrine tumors.

BACKGROUND: Appendiceal tumors are considered to be a relatively rare tumor of the gastrointestinal tract and the prognosis is unclear. This study comprehensively investigated trends in the epidemiology and survival of appendiceal tumors in the United States over the past approximately 20 years. METHODS: Patients with pathologically confirmed appendiceal tumors from 2000 to 2017 were selected from the Surveillance, Epidemiology and End Results (SEER) database. Age-adjusted incidence rates were calculated by SEER*Stat 8.4.0. The Kaplan-Meier method was used to analyze survival and prognostic factors were investigated by a multivariate Cox proportional risk model. RESULTS: Ultimately, 13,546 patients with appendiceal tumors between 2000 and 2017 were included. The annual incidence of colonic adenocarcinoma and mucinous adenocarcinoma remained relatively stable. Interestingly, the annual incidence of appendiceal neuroendocrine tumors (aNETs) increased significantly, from 0.03 to 0.90 per 100,000 person-years, with the most dramatic increase in the number of patients with localized disease. Patients with aNETs showed a significant improvement in survival between 2009-2017, compared to the period 2000-2008. Moreover, this improvement in survival over time was seen at all stages (localized, regional, distant) of aNETs. However, this improved survival over time was not seen in colonic and mucinous adenocarcinoma. CONCLUSIONS: The incidence of appendiceal neoplasms has increased significantly over the past nearly two decades, which is mainly due to the increased incidence and significant migration to earlier stages in aNETs. We must note that despite the increased incidence of aNETs, survival rates have improved at different disease stages.

Hypoxia promotes immune escape of pancreatic cancer cells by lncRNA NNT-AS1/METTL3-HuR-mediated ITGB1 m6A modification.

Pancreatic cancer (PC) cell immune escape is a crucial element in PC malignant development. Some previous studies have reported that LncRNA NNT-AS1 played a carcinogenic role in various tumors. However, the effect of lncRNA NNT-AS1 in PC cell immune escape remains unclear. To evaluate PC cell immune escape, PC cells were co-cultured with CD8+ T cells under a hypoxic condition. PC cell proliferation and migration were evaluated using the colony formation assay and transwell assay. CD8+ T cell proliferation and aoptosis were measured using the carboxy fluorescein diacetate succinimidyl ester (CFSE) assay and flow cytometry. The secretion of antitumor cytokines was assessed using enzyme-linked immunosorbent assay (ELISA). The molecular interactions were analyzed using chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), or dual-luciferase reporter gene assays. A tumor xenograft model was established to evaluate the effects of lncRNA NNT-AS1 on PC in vivo. It was found that lncRNA NNT-AS1 was highly expressed in PC, and its silencing inhibited hypoxia-induced PC cell growth and immune escape in vivo and in vitro. Mechanically, HIF-1α transcriptionally activated NNT-AS1 expression and NNT-AS1 increased ITGB1 stability and expression in a METTL3-HuR dependent manner. ITGB1 overexpression reversed the inhibitory effects of NNT-AS1 knockdown on hypoxia-induced PC cell immune escape. In conclusion, Hypoxia promoted PC cell immune escape through lncRNA NNT-AS1/METTL3-HuR-mediated m6A modification to increase ITGB1 expression, which provided a theoretical foundation and a potential therapeutic target for PC.

Selenium Nanodots (SENDs) as Antioxidants and Antioxidant-Prodrugs to Rescue Islet ß Cells in Type 2 Diabetes Mellitus by Restoring Mitophagy and Alleviating Endoplasmic Reticulum Stress.

Preventing islet ß-cells death is crucial for treating type 2 diabetes mellitus (T2DM). Currently, clinical drugs are being developed to improve the quality of T2DM care and self-care, but drugs focused on reducing islets ß-cell death are lacking. Given that ß-cell death in T2DM is dominated ultimately by excessive reactive oxygen species (ROS), eliminating excessive ROS in ß-cells is a highly promising therapeutic strategy. Nevertheless, no antioxidants have been approved for T2DM therapy because most of them cannot meet the long-term and stable elimination of ROS in ß-cells without eliciting toxic side-effects. Here, it is proposed to restore the endogenous antioxidant capacity of ß-cells to efficiently prevent ß-cell death using selenium nanodots (SENDs), a prodrug of the antioxidant enzyme glutathione peroxidase 1 (GPX1). SENDs not only scavenge ROS effectively, but also "send" selenium precisely to ß-cells with ROS response to greatly enhance the antioxidant capacity of ß-cells by increasing GPX1 expression. Therefore, SENDs greatly rescue ß-cells by restoring mitophagy and alleviating endoplasmic reticulum stress (ERS), and demonstrate much stronger efficacy than the first-line drug metformin for T2DM treatment. Overall, this strategy highlights the great clinical application prospects of SENDs, offering a paradigm for an antioxidant enzyme prodrug for T2DM treatment.

Cytoskeletal and Cytoskeleton-Associated Proteins: Key Regulators of Cancer Stem Cell Properties.

Cancer stem cells (CSCs) are a subpopulation of cancer cells possessing stemness characteristics that are closely associated with tumor proliferation, recurrence and resistance to therapy. Recent studies have shown that different cytoskeletal components and remodeling processes have a profound impact on the behavior of CSCs. In this review, we outline the different cytoskeletal components regulating the properties of CSCs and discuss current and ongoing therapeutic strategies targeting the cytoskeleton. Given the many challenges currently faced in targeted cancer therapy, a deeper comprehension of the molecular events involved in the interaction of the cytoskeleton and CSCs will help us identify more effective therapeutic strategies to eliminate CSCs and ultimately improve patient survival.

Novel end-to-side one-layer continuous pancreaticojejunostomy vs. end-to-end invaginated pancreaticojejunostomy in pancreatoduodenectomy: A single-center retrospective study.

Background and Objective: Postoperative pancreatic fistula (POPF) is the most common critical complication after pancreatoduodenectomy (PD) and is the primary reason for increased mortality and morbidity after PD. We aim to investigate the clinical significance of a novel approach, i.e., end-to-side one-layer continuous pancreaticojejunostomy, for patients with PD. Methods: The clinical data of 65 patients who underwent pancreatoduodenectomy at the Xiangya Hospital, Central South University, from September 2020 to December 2021 were retrospectively analyzed. Results: Forty patients underwent end-to-end invaginated pancreaticojejunostomy, and 25 underwent the novel end-to-side one-layer continuous pancreaticojejunostomy. No significant differences were observed in pancreatic fistula, intraperitoneal infection, intraperitoneal bleeding, reoperation, postoperative hospital stay, or perioperative death between the two groups. However, the novel end-to-side one-layer continuous pancreaticojejunostomy group had significantly shorter operation duration (32.6 ± 5.1 min vs. 8.3 ± 2.2 min, p < 0.001). The incidence of pancreatic fistula in the novel pancreaticojejunostomy group was 12%, including two cases of grade A POPF and only one case of grade B POPF. No cases of grade C POPF occurred. No deaths were observed during the perioperative period. Conclusions: The novel anastomosis method leads to a shorter operation duration than the traditional anastomosis method and does not increase postoperative complications. In conclusion, it is a simplified and feasible method for pancreatic anastomosis.

PREX2 promotes the proliferation, invasion and migration of pancreatic cancer cells by modulating the PI3K signaling pathway.

[This retracts the article DOI: 10.3892/ol.2016.4688.].

LncRNA MALAT-1 promotes growth and metastasis of epithelial ovarian cancer via sponging microrna-22.

LncRNAs and miRNAs are emerging players in epithelial ovarian cancer (EOC). LncRNA MALAT-1 and miR-22 play vital roles in the onset and development of multiple cancers. Both of them are abnormally expressed in ovarian cancer, but the molecular basis for their involvement in EOC is unclear. In this study, we found MALAT-1 was up-regulated but miR-22 was down-regulated in EOC tissues and cell lines when compared to normal ovarian epithelial cell line IOSE80. Both of MALAT-1shRNA and miR-22 mimics inhibited ovarian cell proliferation, migration, and invasion, while simultaneously overexpressing MALAT-1 and miR-22 largely canceled out this inhibitory effect. Consistently, MALAT-1 silencing and miR-22 overexpression restrained tumor growth and metastasis to lungs in nude mice, which could be largely counteracted by co-overexpressing MALAT-1 and miR-22. Mechanistically, MALAT-1 targeted and sponged miR-22, counteracting its inhibitory effect on c-myc and c-myc-mediated epithelial-mesenchymal transition. Our findings for the first time demonstrated that MALAT-1 supports EOC progression through sponging miR-22, providing a novel insight into the role of MALAT-1 in ovarian cancer.

Modern quantum chemistry with [Open]Molcas.

MOLCAS/OpenMolcas is an ab initio electronic structure program providing a large set of computational methods from Hartree-Fock and density functional theory to various implementations of multiconfigurational theory. This article provides a comprehensive overview of the main features of the code, specifically reviewing the use of the code in previously reported chemical applications as well as more recent applications including the calculation of magnetic properties from optimized density matrix renormalization group wave functions.

Single Crystal Investigations Unravel the Magnetic Anisotropy of the "Square-In Square" Cr4Dy4 SMM Coordination Cluster.

In the search for new single molecule magnets (SMM), i.e., molecular systems that can retain their magnetization without the need to apply an external magnetic field, a successful strategy is to associate 3d and 4f ions to form molecular coordination clusters. In order to efficiently design such systems, it is necessary to chemically project both the magnetic building blocks and the resultant interaction before the synthesis. Lanthanide ions can provide the required easy axis magnetic anisotropy that hampers magnetization reversal. In the rare examples of 3d/4f SMMs containing CrIII ions, the latter turn out to act as quasi-isotropic anchors which can also interact via 3d-4f coupling to neighbouring Ln centres. This has been demonstrated in cases where the intramolecular exchange interactions mediated by CrIII ions effectively reduce the efficiency of tunnelling without applied magnetic field. However, describing such high nuclearity systems remains challenging, from both experimental and theoretical perspectives, because the overall behaviour of the molecular cluster is heavily affected by the orientation of the individual anisotropy axes. These are in general non-collinear to each other. In this article, we combine single crystal SQUID and torque magnetometry studies of the octanuclear [Cr4Dy4(µ3-OH)4(µ-N3)4(mdea)4(piv)8]·3CH2Cl2 single molecule magnet (piv=pivalate and mdea=N-methyldiethanol amine). These experiments allowed us to probe the magnetic anisotropy of this complex which displays slow magnetization dynamics due to the peculiar arrangement of the easy-axis anisotropy on the Dy sites. New ab initio calculations considering the entire cluster are in agreement with our experimental results.

Mahanimbine Exerts Anticancer Effects on Human Pancreatic Cancer Cells by Triggering Cell Cycle Arrest, Apoptosis, and Modulation of AKT/Mammalian Target of Rapamycin (mTOR) and Signal Transducer and Activator of Transcription 3 (STAT3) Signalling Pathways.

BACKGROUND Pancreatic cancer causes tremendous mortality across the globe mainly due to late diagnosis and unavailability of efficient chemotheruptic agents. In the current study the anticancer potential of a plant derived alkaloid, Mahanimbine, was examined against a panel of pancreatic cancer cells. MATERIAL AND METHODS The cell proliferation was determined by MTT assay. Annexin V/PI and DAPI staining were performed to detect apoptosis. Cell cycle distribution was investigated by flow cytometery. Cell migration was detected by wound healing assay and protein expression was checked by western blotting. RESULTS The results revealed that Mahanimbine could inhibit the proliferation of the all the pancreatic cancer cells with lower cytoxicity against the normal cells. The IC50 ranged from 3.5 to 64 µM against the pancreatic cancer cell lines. The lowest IC50 of 3.5 µM was observed tor the Capan-2 and SW119 pancreatic cancer cell lines. The anticancer activity of Mahanimbine against the Capan-2 and SW119 cells was found to be due to G0/G1 cell cycle arrest and induction of apoptosis. Mahanimbine prompted apoptosis was also associated with decline in Bcl-2 and enhancement of the Bax expression. Further, it was observed that Mahanimbine could inhibit the AKT/mTOR and STAT3 signalling pathways in the Capan-2 and SW119 pancreatic cancer cells. The effects of the Mahanimbine were also examined on the migration of the Capan-2 and SW119 pancreatic cancer cells. It was found that Mahanimbine could inhibit the motility and migration of both the pancreatic cancer cell lines. CONCLUSIONS We found that Mahanimbine inhibits the proliferation of pancreatic cancer cells and as such Mahanimbine may prove beneficial in the management of pancreatic cancer.

Suppressive role of microRNA-29 in hepatocellular carcinoma via targeting IGF2BP1.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, ranking as the second leading cause of male cancer death worldwide. MicroRNA-29 (miR-29) has been demonstrated to act as a tumor suppressor in HCC. However, the regulatory mechanism of miR-29 underlying HCC growth and metastasis still remains obscure. In the present study, we showed that the expression of miR-29 was significantly reduced in HCC tissues and cell lines, and low miR-29 expression was associated with disease progression and shorter survival time of HCC patients. In vitro experiments showed that restoration of miR-29 expression caused a significant reduction in HCC cell proliferation, migration and invasion. Insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) was identified as a novel target gene of miR-29. The expression of IGF2BP1 was significantly increased in HCC tissues and cell lines. Moreover, IGF2BP1 was negatively regulated by miR-29 at the post-transcriptional levels in HCC cells. Furthermore, overexpression of IGF2BP1 attenuated the suppressive effects of miR-29 on the proliferation, migration, and invasion of HCC cells. According to these above findings, our study suggests that miR-29 may play a suppressive role in HCC growth and metastasis through directly targeting IGF2BP1. Therefore, miR-29 may be used as a potential candidate for the treatment of HCC.

MiR-142 modulates human pancreatic cancer proliferation and invasion by targeting hypoxia-inducible factor 1 (HIF-1α) in the tumor microenvironments.

MicroRNAs regulate most protein-coding genes, including genes important in cancer and other diseases. In this study, we demonstrated that the expression of miR-142 could be significantly suppressed in pancreatic cancer specimens and cell lines compared to their adjacent tissues and normal pancreatic cells. Growth and invasion of PANC-1 and SW1990 cells were attenuated by overexpression of miR-142 in vitro With the help of bioinformatics analysis, hypoxia-inducible factor 1 (HIF-1α) was identified to be a direct target of miR-142, and a luciferase reporter experiment confirmed this discovery. Overexpression of miR-142 decreases protein expression of HIF-1α. In the hypoxic microenvironment, HIF-1α was up-regulated while miR-142 was down-regulated. The invaded cells significantly increased in the hypoxic microenvironment compared to the normoxic microenvironment. The hypoxia treatment induced cells' proliferation, and invasion could be inhibited by miR-142 overexpression or HIF-1α inhibition. Moreover, expression of epithelial-mesenchymal transition (EMT) markers, Vimentin, VEGF-C and E-cad, was altered under hypoxia conditions and regulated by miR-142/HIF-1α. Above all, these findings provided insights on the functional mechanism of miR-142, suggesting that the miR-142/HIF-1α axis may interfere with the proliferative and invasive properties of pancreatic cancer cells, and indicated that miR-142 could be a potential therapeutic target for pancreatic cancer.

The lncRNA XIST interacts with miR-140/miR-124/iASPP axis to promote pancreatic carcinoma growth.

Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is involved in the development and progression of many tumors. In this study, XIST was specifically upregulated in pancreatic carcinoma tissues and cell lines; a higher XIST expression was correlated to poorer clinicopathologic features. After XIST knockdown, the proliferation of PC cell lines was suppressed and cell cycle stagnated in G1 phase; XIST knockdown also reduced the protein levels of inhibitor of apoptosis-stimulating protein of p53 (iASPP) and Cyclin-dependent kinase 1 (CDK1), increased the protein level of P21, a potent CDK inhibitor. In PC cell lines, XIST and miR-140/miR-124, two tumor-associated miRNAs, could inversely regulate each other, respectively; miR-140/miR-124 could bind to XIST and the 3'UTR of PPP1R13L, respectively. XIST and miR-140/miR-124 exerted opposite effects on iASPP, CDK1, P21 and P27 proteins; whereas the effects of LV-sh-XIST on the indicated protein levels could be partially reversed by miR-140 and/or miR-124 inhibitor. In PC tissues, miR-140 and miR-124 expression was down-regulated, iASPP and CDK1 mRNA expression was up-regulated. XIST positively correlated with iASPP and CDK1, inversely correlated with miR-140 and miR-124, respectively. Taken together, our data indicated that XIST might be an oncogenic lncRNA that promoted proliferation of PC cell line through inhibiting miR-140/miR-124 expression and promoting cell cycle-related factor expression, and could be regarded as a therapeutic target in human pancreatic carcinoma.

PREX2 promotes the proliferation, invasion and migration of pancreatic cancer cells by modulating the PI3K signaling pathway.

Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger factor 2 (PREX2) is a novel regulator of the small guanosine triphosphatase Rac, and has been observed to be implicated in human cancer by inhibiting the activity of phosphatase and tensin homolog (PTEN), thus upregulating the activity of the phosphoinositide 3-kinase (PI3K) signaling pathway. However, the exact role of PREX2 in pancreatic cancer has not been reported to date. In the present study, the expression levels of PREX2 were observed to be frequently increased in pancreatic cancer specimens compared with those in their matched adjacent normal tissues. In addition, PREX2 expression was also frequently upregulated in several pancreatic cancer cell lines, including AsPC-1, BxPC-3, PANC-1 and CFAPC-1, compared with that in the normal pancreatic epithelial cell line HPC-Y5. Overexpression of PREX2 significantly promoted the proliferation, invasion and migration of pancreatic cancer PANC-1 cells, while small interfering RNA-induced knockdown of PREX2 expression significantly inhibited the proliferation, invasion and migration of these cells. Investigation of the molecular mechanism revealed that the overexpression of PREX2 upregulated the phosphorylation levels of PTEN, indicating that the activity of PTEN was reduced, which further increased the phosphorylation levels of AKT, which indicated that the activity of the PI3K signaling pathway was upregulated. By contrast, knockdown of PREX2 upregulated the activity of PTEN and inhibited the activity of the PI3K signaling pathway. In conclusion, the present study demonstrated that PREX2 regulates the proliferation, invasion and migration of pancreatic cancer cells, probably at least via modulation of the activity of PTEN and the PI3K signaling pathway.

The Circular RNA Cdr1as Act as an Oncogene in Hepatocellular Carcinoma through Targeting miR-7 Expression.

CircRNAs are a class of endogenous RNA that regulates gene expression at the post-transcriptional or transcriptionallevel through interacting with other molecules or microRNAs. Increasing studies have demonstrated that circRNAs play a crucial role in biology processes. CircRNAs are proved as potentialbiomarkers in many diseases including cancers. However, the role of Cdr1as in Hepatocellular carcinoma (HCC) remains to be elucidated. We demonstrated that Cdr1as expression was upregulated in HCC tissues compared with the adjacent non-tumor tissues. In addtion, miR-7 expression was downregulated in HCC tissues compared with the adjacent non-tumor tissues. Moreover, the expression level of miR-7 was inversely correlated with that in HCC tissues. Knockdown of Cdr1as suppressed the HCC cell proliferation and invasion. Overexpression of miR-7 inhibited the HCC cell proliferation and invasion. Overexpression of miR-7 could suppress the direct target gene CCNE1 and PIK3CD expression. Knockdown of Cdr1as suppressed the expression of miR-7 and also inhibited the CCNE1 and PIK3CD expression. Furthermore, knockdown of Cdr1as suppressed the HCC cell proliferation and invasion through targeting miR-7. These data suggested that Cdr1as acted as an oncogene partly through targeting miR-7 in HCC.

MicroRNA-140 regulates cell growth and invasion in pancreatic duct adenocarcinoma by targeting iASPP.

MicroRNAs are ∼22 nucleotide RNAs processed from RNA hairpin structures that play important roles in regulating protein expression level via binding to mRNA, either suppressing its translation or speeding up its degradation. In humans, they regulate most protein-coding genes, including genes important in cancer and other diseases. In this study, the expression of microRNA-140 (miR-140) was demonstrated to be significantly suppressed in pancreatic duct adenocarcinoma specimens and cell lines, compared with their adjacent normal tissues. With the help of bioinformatics analysis, inhibitor of apoptosis-stimulating protein of p53 (iASPP) was identified to be a direct target of miR-140, and luciferase reporter experiment confirmed this discovery. Overexpression of miR-140 decreases the protein expressions of iASPP, ΔNp63, MMP2, and MMP9. Growth and invasion of PANC-1 cells were attenuated by overexpression of miR-140 in vitro. The suppressive effect of miR-140 on PANC-1 cell line could be partly balanced out by manual overexpression of iASPP. Above all, these findings provided insights into the functional mechanism of miR-140, suggested that the miR-140/iASPP axis may interfere with the proliferative and invasive property of pancreatic duct adenocarcinoma cells, and indicated that miR-140 could be a potential therapeutic target for pancreatic duct adenocarcinoma.

miR-454 functions as an oncogene by inhibiting CHD5 in hepatocellular carcinoma.

Previous studies showed that miR-454 acted as an oncogene or tumor suppressor in cancer. However, its function in HCC remains unknown. In this study, we found that miR-454 expression was upregulated in HCC cell lines and tissues. Knockdown of miR-454 inhibited HCC cell proliferation and invasion and epithelial mesenchymal transition (EMT), whereas overexpression of miR-454 promoted HCC cell proliferation and invasion and EMT. Furthermore, we identified the CHD5 as a direct target of miR-454. CHD5 was downregulated in HCC tissues and cell lines and the expression level of CHD5 was inversely correlated with the expression of miR-454 in HCC tissues. In addition, knockdown of miR-454 inhibited the growth of HepG2-engrafted tumors in vivo. Taken together, these results indicated that miR-454 functioned as an oncogene in HCC.

Epigenetic therapy for solid tumors: from bench science to clinical trials.

The cancer epigenome is characterized by global DNA methylation and chromatin changes, such as the hypermethylation of specific CpG island promoters. Epigenetic agents like DNA methyltransferase or histone deacetylase inhibitors induce phenotype changes by reactivation of epigenetically silenced tumor suppressor genes. Despite initial promise in hematologic malignancies, epigenetic agents have not shown significant efficacy as monotherapy against solid tumors. Recent trials showed that epigenetic agents exert favorable modifier effects when combined with chemotherapy, hormonal therapy, or other epigenetic agents. Due to the novel nature of their mechanism, it is important to reconsider the optimal patient selection, drug regimen, study design, and outcome measures when pursuing future trials in order to discover the full potential of this new therapeutic modality.