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Lightweight magnesium alloys are attractive as structural materials for improving energy efficiency in applications such as weight reduction of transportation vehicles. One major obstacle for widespread applications is the limited ductility of magnesium, which has been attributed to 〈c + a〉 dislocations failing to accommodate plastic strain. We demonstrate, using in situ transmission electron microscope mechanical testing, that 〈c + a〉 dislocations of various characters can accommodate considerable plasticity through gliding on pyramidal planes. We found that submicrometer-size magnesium samples exhibit high plasticity that is far greater than for their bulk counterparts. Small crystal size usually brings high stress, which in turn activates more 〈c + a〉 dislocations in magnesium to accommodate plasticity, leading to both high strength and good plasticity.

Growth factors and nutrients enhance protein synthesis and suppress overall protein degradation by activating the protein kinase mammalian target of rapamycin (mTOR). Conversely, nutrient or serum deprivation inhibits mTOR and stimulates protein breakdown by inducing autophagy, which provides the starved cells with amino acids for protein synthesis and energy production. However, it is unclear whether proteolysis by the ubiquitin proteasome system (UPS), which catalyzes most protein degradation in mammalian cells, also increases when mTOR activity decreases. Here we show that inhibiting mTOR with rapamycin or Torin1 rapidly increases the degradation of long-lived cell proteins, but not short-lived ones, by stimulating proteolysis by proteasomes, in addition to autophagy. This enhanced proteasomal degradation required protein ubiquitination, and within 30 min afterm TOR inhibition, the cellular content of K48-linked ubiquitinated proteins increased without any change in proteasome content or activity. This rapid increase in UPS-mediated proteolysis continued for many hours and resulted primarily from inhibition of mTORC1 (not mTORC2), but did not require new protein synthesis or key mTOR targets: S6Ks, 4E-BPs, or Ulks. These findings do not support the recent report that mTORC1 inhibition reduces proteolysis by suppressing proteasome expression [Zhang Y, et al. (2014) Nature 513(7518):440–443]. Several growth-related proteins were identified that were ubiquitinated and degraded more rapidly after mTOR inhibition, including HMG-CoA synthase, whose enhanced degradation probably limits cholesterol biosynthesis upon insulin deficiency. Thus, mTOR inhibition coordinately activates the UPS and autophagy, which provide essential amino acids and, together with the enhanced ubiquitination of anabolic proteins, help slow growth.

Black phosphorus (BP) as a novel class of two-dimension (2D) materials has recently attracted enormous attention as a result of its unique physical and chemical features. The remarkably strong light-matter interaction and tunable direct band-gap at a wide range make it an ideal candidate especially in the mid-infrared wavelength region as the saturable absorber (SA). In this paper, the simple and effective liquid phase exfoliation (LPE) method was used to fabricate BP. By introducing the same BP SA into two specifically designed rare earth ions doped fluoride fiber lasers at mid-infrared wavebands, Q-switching with the pulse energy of 4.93 μJ and mode-locking with the pulse duration of 8.6 ps were obtained, respectively. The operation wavelength of ~2970 nm for generated pulse is the reported longest wavelength for BP SA based fiber lasers.

Background Cardiac tumors in children are rare and usually have no obvious clinical symptoms. However, a small number of children may experience serious conditions such as arrhythmia, heart obstruction, and even death. When severe arrhythmia cannot be controlled by conservative treatment, surgical intervention is needed. Case presentation A 20-day-old male neonate, born full-term via cesarean section, was admitted to the emergency department with complaints of jaundice for 16 days and a rapid heart rate detected for one day. The heart rate was recorded at 280 beats per minute. An electrocardiogram (ECG) initially suggested supraventricular tachycardia, later progressing to ventricular tachycardia. A bedside echocardiogram indicated an intracardiac mass. Conservative treatment failed to restore normal heart rhythm, then the patient underwent emergency surgery with tumor resection under general anesthesia and cardiopulmonary bypass. Post-surgery, ventilator-assisted breathing was administered, along with inotropic support, diuretics, anti-infective therapy, and fluid management. the heart rate and rhythm returned to normal. Postoperative pathology revealed the presence of a cardiac rhabdomyoma, and follow-up was arranged post-discharge. Conclusion Cardiac tumors in children are relatively rare, mostly benign, and have a good prognosis. But for some emergency situations or heart tumors that cause adverse effects, timely and effective intervention is needed to avoid adverse consequences.

Sorafenib, an orally available kinase inhibitor, is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), and it exerts potent inhibitory activity against epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR) by inhibiting mitogen-activated protein kinase (MAPK) signaling in HCC. However, after long-term exposure to sorafenib, HCC cells exhibit EMT and resistance to sorafenib. The activation of AKT by sorafenib is thought to be responsible for the development of these characteristics. The present study aims to examine the underlying mechanism and seek potential strategies to reverse this resistance and the progression to EMT. Sorafenib-resistant cells showed increased metastatic and invasive ability, with a higher expression of P-glycoprotein (P-gp), compared with the parental cells. This phenomenon was at least partially due to EMT and the appearance of MDR in sorafenib-resistant HCC cells. Moreover, MDR was a downstream molecular event of EMT. Silencing Snail with siRNA blocked EMT and partially reversed the MDR, thereby markedly abolishing invasion and metastasis in sorafenib-resistant HCC cells, but silencing of MDR1 had no effect on the EMT phenotype. Additionally, HCC parental cells that were stably transfected with pCDNA3.1-Snail exhibited EMT and MDR. Two sorafenib-resistant HCC cell lines, established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to MK-2206, a novel allosteric AKT inhibitor. Thus, the combination of sorafenib and MK-2206 led to significant reversion of the EMT phenotype and P-gp-mediated MDR by downregulating phosphorylated AKT. These findings underscore the significance of EMT, MDR and enhanced PI3K/AKT signaling in sorafenib-resistant HCC cells.

In shotgun proteomics experiments, modified peptides account for a large part of the unassigned spectra and can be identified using ultra-tolerant database searches. Fewer than half of all tandem mass spectrometry (MS/MS) spectra acquired in shotgun proteomics experiments are typically matched to a peptide with high confidence. Here we determine the identity of unassigned peptides using an ultra-tolerant Sequest database search that allows peptide matching even with modifications of unknown masses up to ± 500 Da. In a proteome-wide data set on HEK293 cells (9,513 proteins and 396,736 peptides), this approach matched an additional 184,000 modified peptides, which were linked to biological and chemical modifications representing 523 distinct mass bins, including phosphorylation, glycosylation and methylation. We localized all unknown modification masses to specific regions within a peptide. Known modifications were assigned to the correct amino acids with frequencies >90%. We conclude that at least one-third of unassigned spectra arise from peptides with substoichiometric modifications.

Hepatocellular carcinoma (HCC)—the most common form of liver cancer—is an aggressive malignancy with few effective treatment options 1 . Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit 2 . Here, using a kinome-centred CRISPR–Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer. The combination of the EGFR inhibitor gefitinib and lenvatinib displays potent anti-proliferative effects in vitro in liver cancer cell lines that express EGFR and in vivo in xenografted liver cancer cell lines, immunocompetent mouse models and patient-derived HCC tumours in mice. Mechanistically, inhibition of fibroblast growth factor receptor (FGFR)  by lenvatinib treatment leads to feedback activation of the EGFR–PAK2–ERK5 signalling axis, which is blocked by EGFR inhibition. Treatment of 12 patients with advanced HCC who were unresponsive to lenvatinib treatment with the combination of lenvatinib plus gefitinib (trial identifier NCT04642547) resulted in meaningful clinical responses. The combination therapy identified here may represent a promising strategy for the approximately 50% of patients with advanced HCC who have high levels of EGFR. EGFR inhibition and lenvatinib treatment of liver cancer cells in vitro and in in vivo mouse models has potent anti-proliferative effects, and lenvatinib plus gefitinib treatment of 12 patients with advanced liver cancer resulted in meaningful clinical responses.

Background Microwave ablation (MWA) is an effective minimally invasive technique for lung tumours. We aim to evaluate its role for pulmonary oligorecurrence after radical surgery of non-small-cell lung cancer (NSCLC). Methods From June 2012 to Jan 2020, a total of 103 patients with pulmonary oligorecurrence after previous radical surgical resection of NSCLC were retrospectively analysed. The primary endpoint was postoperative progression-free survival (PFS). Secondary endpoints were postoperative overall survival (OS), patterns of failure, complications and predictive factors associated with prognosis. Results Of the 103 patients identified, 135 pulmonary oligorecurrences developed at a median interval of 34.8 months. In total, 143 sessions of MWA were performed to ablate all the nodules. The median PFS and OS were 15.1 months and 40.6 months, respectively. After MWA, 15 (14.6%) patients had local recurrence as the first event, while intrathoracic oligorecurrence and distant metastases were observed in 45 (43.7%) and 20 (19.4%) patients, respectively. In the multivariate analysis, local recurrence and intrathoracic oligorecurrence were not significant predictors for OS ( P  = 0.23 and 0.26, respectively). However, distant metastasis was predictive of OS (HR = 5.37, 95% CI, 1.04–27.84, P  = 0.04). Conclusion MWA should be considered to be an effective and safe treatment option for selected patients with pulmonary oligorecurrence after NSCLC radical surgical resection.

Background Acquired resistance to sorafenib greatly limits its therapeutic efficiency in the treatment of hepatocellular carcinoma (HCC). Increasing evidence indicates that long noncoding RNAs (lncRNAs) play important roles in the resistance to anti-cancer drugs. The present study aims to explore the involvement of lncRNA SNHG1 (small nucleolar RNA host gene 1) in sorafenib resistance and how SNHG1 is associated with overexpressed microRNA-21 (miR-21) and the activated Akt pathway, which have been demonstrated to mediate this resistance in HCC cells. Methods Sorafenib-resistant HCC (SR-HCC) cells were generated and their sorafenib-resistant properties were confirmed by cell viability and apoptosis assays. Potential lncRNAs were screened by using multiple bioinformatics analyses and databases. The expression of genes and proteins was detected by qRT-PCR, Western blot and in situ hybridization. Gene silencing was achieved by specific siRNA or lncRNA Smart Silencer. The effects of anti-SNHG1 were evaluated in vitro and in experimental animals by using quantitative measures of cell proliferation, apoptosis and autophagy. The binding sites of miR-21 and SNHG1 were predicted by using the RNAhybrid algorithm and their interaction was verified by luciferase assays. Results The Akt pathway was highly activated by overexpressed miR-21 in SR-HCC cells compared with parental HCC cells. Among ten screened candidates, SNHG1 showed the largest folds of alteration between SR-HCC and parental cells and between vehicle- and sorafenib-treated cells. Overexpressed SNHG1 contributes to sorafenib resistance by activating the Akt pathway via regulating SLC3A2. Depletion of SNHG1 enhanced the efficacy of sorafenib to induce apoptosis and autophagy of SR-HCC cells by inhibiting the activation of Akt pathway. Sorafenib induced translocation of miR-21 to the nucleus, where it promoted the expression of SNHG1, resulting in upregulation of SLC3A2, leading to the activation of Akt pathway. In contrast, SNHG1 was shown to have little effect on the expression of miR-21, which downregulated the expression of PTEN, leading to the activation of the Akt pathway independently of SNHG1. Conclusions The present study has demonstrated that lncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and its nuclear expression is promoted by miR-21, whose nuclear translocation is induced by sorafenib. These results indicate that SNHG1 may represent a potentially valuable target for overcoming sorafenib resistance for HCC.

Background Hepatocellular carcinoma (HCC) is the major histological type of liver cancer with high morbidity and mortality worldwide. Long noncoding RNAs (lncRNA) has been proved to be associated with various cancer types, while its regulation in HCC is largely unknown. Methods To figure out the specific role of lncRNA EPB41L4A-AS2 in HCC. Fluorescence in situ hybridization (FISH) was first used to determine the cellular sublocalization of EPB41L4A-AS2 to determine its primary mode of action. QRT-PCR, Western blot and hematoxylin-eosin staining were then used to measure the expression of genes in cells and tissues. Cell proliferation and invasion assays were performed to determine the effects of EPB41L4A-AS2, miR-301a-5p and FOXL1 on the malignant phenotype of tumor cells. With luciferase reporter assay, the direct interaction between target genes were further confirmed for research on molecular mechanism. Finally, the mice hepatocarcinoma model was also established to disclose the tumor suppressor effects of EPB41L4A-AS2 in vivo. Results Here, we have identified a novel lncRNA EPB41L4A-AS2, which is significantly downregulated both in HCC cells and tissues, and plays a negative regulatory role in HCC proliferation and invasion. Mechanistically, cytoplasmic lncRNA EPB41L4A-AS2 functions as an efficient miR-301a-5p sponge, thereby release the expression inhibition of forkhead box L1 (FOXL1). Indeed, lncRNA EPB41L4A-AS2 inhibits proliferation and migration by upregulating FOXL1 expression and FOXL1 was confirmed as a direct target of miR-301a-5p. MiR-301a-5p shows an inverse correlation with EPB41L4A-AS2 expression and was verified as a direct target of EPB41L4A-AS2 as well. Correspondingly, FOXL1 and miR-301a-5p show opposite biological effects in cell proliferation and migration. Moreover, miR-301a-5p overexpression rescued the EPB41L4A-AS2 upregulation induced depression in proliferation, migration and invasion of HCC cells, as well as promotion effect on FOXL1 expression. Also, in vivo experiments proved that EPB41L4A-AS2 suppress tumor growth and extrahepatic metastasis (lung) via the miR-301a-5p-FOXL1 axis. Conclusions Taken together, this research revealed a concrete mechanism of lncRNA EPB41L4A-AS2 in HCC, which may serve as a potential biomarkers and novel therapeutic targets for further clinical application.