The BioPlex Network: A Systematic Exploration of the Human Interactome.

Protein interactions form a network whose structure drives cellular function and whose organization informs biological inquiry. Using high-throughput affinity-purification mass spectrometry, we identify interacting partners for 2,594 human proteins in HEK293T cells. The resulting network (BioPlex) contains 23,744 interactions among 7,668 proteins with 86% previously undocumented. BioPlex accurately depicts known complexes, attaining 80%-100% coverage for most CORUM complexes. The network readily subdivides into communities that correspond to complexes or clusters of functionally related proteins. More generally, network architecture reflects cellular localization, biological process, and molecular function, enabling functional characterization of thousands of proteins. Network structure also reveals associations among thousands of protein domains, suggesting a basis for examining structurally related proteins. Finally, BioPlex, in combination with other approaches, can be used to reveal interactions of biological or clinical significance. For example, mutations in the membrane protein VAPB implicated in familial amyotrophic lateral sclerosis perturb a defined community of interactors.

Acetylation-dependent regulation of Skp2 function.

Aberrant Skp2 signaling has been implicated as a driving event in tumorigenesis. Although the underlying molecular mechanisms remain elusive, cytoplasmic Skp2 correlates with more aggressive forms of breast and prostate cancers. Here, we report that Skp2 is acetylated by p300 at K68 and K71, which is a process that can be antagonized by the SIRT3 deacetylase. Inactivation of SIRT3 leads to elevated Skp2 acetylation, which leads to increased Skp2 stability through impairment of the Cdh1-mediated proteolysis pathway. As a result, Skp2 oncogenic function is increased, whereby cells expressing an acetylation-mimetic mutant display enhanced cellular proliferation and tumorigenesis in vivo. Moreover, acetylation of Skp2 in the nuclear localization signal (NLS) promotes its cytoplasmic retention, and cytoplasmic Skp2 enhances cellular migration through ubiquitination and destruction of E-cadherin. Thus, our study identifies an acetylation-dependent regulatory mechanism governing Skp2 oncogenic function and provides insight into how cytoplasmic Skp2 controls cellular migration.

EGFR activation limits the response of liver cancer to lenvatinib.

Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options1. 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 benefit2. 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.

Metabolic regulation of protein N-alpha-acetylation by Bcl-xL promotes cell survival.

Previous experiments suggest a connection between the N-alpha-acetylation of proteins and sensitivity of cells to apoptotic signals. Here, we describe a biochemical assay to detect the acetylation status of proteins and demonstrate that protein N-alpha-acetylation is regulated by the availability of acetyl-CoA. Because the antiapoptotic protein Bcl-xL is known to influence mitochondrial metabolism, we reasoned that Bcl-xL may provide a link between protein N-alpha-acetylation and apoptosis. Indeed, Bcl-xL overexpression leads to a reduction in levels of acetyl-CoA and N-alpha-acetylated proteins in the cell. This effect is independent of Bax and Bak, the known binding partners of Bcl-xL. Increasing cellular levels of acetyl-CoA by addition of acetate or citrate restores protein N-alpha-acetylation in Bcl-xL-expressing cells and confers sensitivity to apoptotic stimuli. We propose that acetyl-CoA serves as a signaling molecule that couples apoptotic sensitivity to metabolism by regulating protein N-alpha-acetylation.

A protein complex network of Drosophila melanogaster.

Determining the composition of protein complexes is an essential step toward understanding the cell as an integrated system. Using coaffinity purification coupled to mass spectrometry analysis, we examined protein associations involving nearly 5,000 individual, FLAG-HA epitope-tagged Drosophila proteins. Stringent analysis of these data, based on a statistical framework designed to define individual protein-protein interactions, led to the generation of a Drosophila protein interaction map (DPiM) encompassing 556 protein complexes. The high quality of the DPiM and its usefulness as a paradigm for metazoan proteomes are apparent from the recovery of many known complexes, significant enrichment for shared functional attributes, and validation in human cells. The DPiM defines potential novel members for several important protein complexes and assigns functional links to 586 protein-coding genes lacking previous experimental annotation. The DPiM represents, to our knowledge, the largest metazoan protein complex map and provides a valuable resource for analysis of protein complex evolution.

SARS-CoV-2 Antibody Response Is Associated with Age and Body Mass Index in Convalescent Outpatients.

COVID-19 has had an unprecedented global impact on human health. Understanding the Ab memory responses to infection is one tool needed to effectively control the pandemic. Among 173 outpatients who had virologically confirmed SARS-CoV-2 infection, we evaluated serum Ab concentrations, microneutralization activity, and enumerated SARS-CoV-2-specific B cells in convalescent human blood specimens. Serum Ab concentrations were variable, allowing for stratification of the cohort into high and low responders. Neither participant sex, the timing of blood sampling following the onset of illness, nor the number of SARS-CoV-2 spike protein-specific B cells correlated with serum Ab concentration. Serum Ab concentration was positively associated with microneutralization activity and participant age, with participants under the age of 30 showing the lowest Ab level. These data suggest that young adult outpatients did not generate as robust Ab memory, compared with older adults. Body mass index was also positively correlated with serum Ab levels. Multivariate analyses showed that participant age and body mass index were independently associated with Ab levels. These findings have direct implications for public health policy and current vaccine efforts. Knowledge gained regarding Ab memory following infection will inform the need for vaccination in those previously infected and allow for a better approximation of population-wide protective immunity.

Integration of ATAC-Seq and RNA-Seq reveals FOSL2 drives human liver progenitor-like cell aging by regulating inflammatory factors.

BACKGROUND: Human primary hepatocytes (PHCs) are considered to be the best cell source for cell-based therapies for the treatment of end-stage liver disease and acute liver failure. To obtain sufficient and high-quality functional human hepatocytes, we have established a strategy to dedifferentiate human PHCs into expandable hepatocyte-derived liver progenitor-like cells (HepLPCs) through in vitro chemical reprogramming. However, the reduced proliferative capacity of HepLPCs after long-term culture still limits their utility. Therefore, in this study, we attempted to explore the potential mechanism related to the proliferative ability of HepLPCs in vitro culture. RESULTS: In this study, analysis of assay for transposase accessible chromatin using sequencing (ATAC-seq) and RNA sequencing (RNA-seq) were performed for PHCs, proliferative HepLPCs (pro-HepLPCs) and late-passage HepLPCs (lp-HepLPCs). Genome-wide transcriptional and chromatin accessibility changes during the conversion and long-term culture of HepLPCs were studied. We found that lp-HepLPCs exhibited an aged phenotype characterized by the activation of inflammatory factors. Epigenetic changes were found to be consistent with our gene expression findings, with promoter and distal regions of many inflammatory-related genes showing increased accessibility in the lp-HepLPCs. FOSL2, a member of the AP-1 family, was found to be highly enriched in the distal regions with increased accessibility in lp-HepLPCs. Its depletion attenuated the expression of aging- and senescence-associated secretory phenotype (SASP)-related genes and resulted in a partial improvement of the aging phenotype in lp-HepLPCs. CONCLUSIONS: FOSL2 may drive the aging of HepLPCs by regulating inflammatory factors and its depletion may attenuate this phenotypic shift. This study provides a novel and promising approach for the long-term in vitro culture of HepLPCs.

Glutaminase 1 blockade alleviates nonalcoholic steatohepatitis via promoting proline metabolism.

Nonalcoholic steatohepatitis (NASH) is emerging as a major cause of end-stage liver disease, but nowadays no pharmacological therapies are approved and there is an urgent need to develop new therapeutic targets. Glutaminase 1 (GLS1) knockdown had been put forward to alleviate NASH, but its mechanism is still unclear. Herein, to explore the exact relationship between glutamine metabolism and NASH development, we establish a NASH mice model and identified JHU-083, a proven GLS1 inhibitor, could efficiently alleviate NASH. Remarkably, JHU-083 could decrease lipid contents in the liver by enhancing fatty acid oxidation capacity considerably and transcriptomic analysis revealed JHU-083 administration could influence proline metabolism. Then we found the efficacy of JHU-083 on lipid metabolism relied on proline and when proline metabolism was blocked, GLS1 inhibitors no longer worked. Our data suggest that inhibiting glutamine hydrolysis could promote fatty acid oxidation by regulating proline metabolism, which is closely associated with NASH development and could be considered a new possible therapeutic target for NASH therapy.

Safety and efficacy of microwave versus radiofrequency ablation for large hepatic hemangioma: a multicenter retrospective study with propensity score matching.

OBJECTIVES: To compare the safety and efficacy of microwave ablation (MWA) and radiofrequency ablation (RFA) for such hemangiomas (5-9.9 cm in diameter). METHODS: This multicenter retrospective cohort study investigated the differences in technical success, ablation time, complete ablation, complications, hospital stay, and clinical response between MWA and RFA. A total of 452 patients with hepatic hemangiomas were screened. Propensity score matching was performed. Univariable and multivariate regression analyses were used. RESULTS: Among the 452 patients, 394 met the eligibility criteria and completed the follow-up. After the propensity score matching analysis, 72 pairs of patients were created. No technical failures were found. The RFA group had a longer ablation time (48.63 ± 18.11 min versus [vs.] 37.18 ± 15.86 min, p < 0.001), higher morbidity of hemoglobinuria (77.78% vs. 50.00%, p < 0.001), and longer hospital stay (5.01 ± 1.56 days vs. 4.34 ± 1.42 days, p < 0.05) than the MWA group. The treatment methods (p = 0.032, OR = 0.105, 95% CI = 0.013-0.821), size of the hemangioma (p = 0.021, OR = 5.243, 95% CI = 1.285-21.391), and time of ablation (p = 0.031, OR = 1.145, 95% CI = 1.013-1.294) were significant independent risk factors associated with hemoglobinuria. No recurrence or delayed complications were observed. There were no differences in complete ablation, clinical response, and health-related quality of life between the groups. CONCLUSIONS: MWA and RFA appear to be effective treatments for large hepatic hemangiomas. However, MWA had a shorter ablation time than RFA, and MWA was associated with fewer hemolysis-related complications and shorter hospital stays. KEY POINTS: • MWA and RFA appear to be effective treatments for large hepatic hemangiomas. • MWA had a shorter ablation time than RFA. • MWA was associated with fewer hemolysis-related complications and shorter hospital stays.

Optimization of pleural multisite anesthetic technique during CT-guide microwave ablation of peripheral lung malignancy for improving treatment tolerance.

OBJECTIVE: To assess the effect and safety of subpleural multisite anesthesia based on the area of thermal radiation during CT-guided lung malignancy microwave ablation (MWA) on the incidence of moderate or severe pain and the analgesic drug usage. MATERIALS AND METHODS: Consecutive patients with lung malignancies were retrospectively evaluated between January 2016 and December 2019. Patients undergoing CT-guided lung malignancy MWA were either given in the method of (a) standard subpleural puncture point anesthesia between January 2016 and June 2018 and (b) subpleural multisite anesthesia based on the area of thermal radiation between July 2018 and December 2019. The relationship between local anesthesia mode and moderate or severe pain, and pain medications usage was assessed by using multivariable logistic regression models. RESULTS: A total of 243 consecutive patients were included in the study. Moderate or severe pain occurred in 84 of 124 (67.7%) patients with subpleural puncture point anesthesia and in 20 of 119 (16.8%) patients with subpleural anesthesia in the area of thermal radiation (p=.001). The intravenous pain medication was required in 56 of 124 (45.2%) patients with subpleural puncture point anesthesia and in 9 of 119 (7.6%) patients with subpleural multisite anesthesia based on the area of thermal radiation (p=.001). Local anesthesia methods (p = 0.001), pleura-to-lesion distance (p=.02) and tumor size (p=.015) were independent risk factors for developing moderate or severe pain. There were no differences in adverse events and local tumor progression rate. CONCLUSIONS: Subpleural multisite anesthesia based on the area of thermal radiation for peripheral lung malignancy MWA can result in lower intraprocedural pain compared with the subpleural puncture point anesthesia. Thus, a subpleural multisite anesthesia technique may be most helpful when performing MWA of peripheral malignancy in patients who are not sedated with general or intravenous anesthesia.

Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase.

The three EglN prolyl hydroxylases (EglN1, EglN2, and EglN3) regulate the stability of the HIF transcription factor. We recently showed that loss of EglN2, however, also leads to down-regulation of Cyclin D1 and decreased cell proliferation in a HIF-independent manner. Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a. FOXO transcription factors can repress Cyclin D1 transcription. Failure to hydroxylate FOXO3a promotes its accumulation in cells, which in turn suppresses Cyclin D1 expression. These findings provide new insights into post-transcriptional control of FOXO3a and provide a new avenue for pharmacologically altering Cyclin D1 activity.

Multicentre study of microwave ablation for pulmonary oligorecurrence after radical resection of non-small-cell lung cancer.

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.

Technical safety and efficacy of a blunt-tip microwave ablation electrode for CT-guided ablation of pulmonary ground-glass opacity nodules.

OBJECTIVES: To evaluate the safety and technical efficacy of a customized blunt-tip microwave ablation (MWA) electrode for CT-guided ablation of pulmonary ground-glass opacity nodules (GGOs). MATERIALS AND METHODS: This was a retrospective before-after study. All consented patients with GGOs who underwent MWA treatment using conventional sharp-tip electrodes (group A) between January 2018 and December 2018 or new blunt-tip electrodes (group B) between January 2019 and December 2019 in our institution were included. The individual features of each patient and lesion, as well as technical and clinical information, were collected and analyzed. RESULTS: Sixteen (7 males, 9 females; mean age, 64.9 ± 12.3 years) and twenty-six (11 males, 15 females; mean age, 66.5 ± 10.7 years) patients were enrolled in groups A and B, respectively. The technique was successfully performed in all patients and a follow-up CT scan at 24 h after MWA showed that the technical efficacy rate was 100% in both groups. Twelve (75.0%) grade I complications were noted in group A, whereas 11 (42.3%) were noted in group B (p = 0.039, chi-square test). No bleeding occurred within the lesions in group B. CONCLUSIONS: The blunt-tip MWA electrode is a safe and technically effective tool for ablating GGO lesions. KEY POINTS: • A new blunt-tip MWA electrode was used for CT-guided ablation of GGO lesions. • The blunt-tip MWA electrode could improve the safety of GGO ablation. • The technical efficacy of ablation was maintained by using the blunt-tip MWA electrode.

Microwave ablation for peribiliary hepatocellular carcinoma: propensity score analyses of long-term outcomes.

OBJECTIVE: To compare the long-term outcomes of MWA as the first-line treatment for HCC in peribiliary versus non-peribiliary locations using propensity score matching analysis. METHODS: The study participants were recruited between April 2012 and October 2016. In total, 236 patients with HCC <5 cm who underwent ultrasonography-guided percutaneous MWA as the first-line treatment were enrolled. The patients were grouped into two according to tumor location: peribiliary (n = 74) and non-peribiliary (n = 162). The progression-free survival (PFS) and overall survival (OS) rates were compared before and after propensity score matching. Subgroup analyses were conducted for the peribiliary group according to the biliary grading. RESULTS: Propensity score matching yielded 63 matched pairs of patients. In the two matched groups, cumulative PFS rates were 29.0% and 14.0% in the peribiliary group, and 51.0% and 31.0% in the non-peribiliary group at 3 and 5 years, respectively. Corresponding OS rates were 51.0% and 49.0% in the peribiliary group, and 77.0% and 70.0% in the non-peribiliary group at 3 and 5 years, respectively. In addition, there were significant differences in major complication rates between the two groups (25.7% vs 8.0%; p < .001). In contrast to peribiliary HCCs adjacent to the second-degree branches of intrahepatic bile duct (67.1 ± 5.2 months), subgroup analysis indicated that the mean OS was significantly lower in peribiliary HCCs adjacent to the first-degree branches (51.2 ± 7.5 months) (p = .015). CONCLUSION: The application of MWA for peribiliary HCC leads to a higher rate of complications and worse long-term tumor control than for non-peribiliary HCC.KEY POINTSThe application of MWA for peribiliary HCC leads to a higher rate of complications than for non-peribiliary HCC.The application of MWA for peribiliary HCC leads to worse long-term tumor control than for non-peribiliary HCC. Abbreviations: Hepatocellular carcinoma (HCC); microwave ablation (MWA); α-fetoprotein (α-FP); local tumor progression (LTP); intrahepatic distal recurrence (IDR); progression-free survival (PFS); overall survival (OS).

Study of microRNA Expression Profile in Different Regions of Ram Epididymis.

The regional expression of epididymal genes provides a guarantee for sperm maturation. As a class of endogenous non-coding small RNAs, microRNAs (miRNAs) play an important role in spermatogenesis, maturation and fertilization. Currently, the regulatory role of miRNA in the epididymis is poorly understood. Here, transcriptome sequencing was used to analyse miRNA expression profiles in three regions of the epididymis of rams, including caput, corpus and cauda. The results showed that there were 13 known miRNAs between the caput and corpus controls, 29 between the caput and cauda and 22 differences between the corpus and cauda. Based on the analysis of miRNA target genes by GO and KEGG, a negative regulation network of miRNA-mRNA was constructed in which let-7, miR-541-5p, miR-133b and miR-150 may play an important regulatory role in the maturation regulation of ram epididymal sperm. This research provides a reference for studying the regulation mechanism of sperm maturation in male epididymis and improving semen quality and male reproductive performance.

Long-term results of percutaneous microwave ablation for colorectal liver metastases.

BACKGROUND: Radiofrequency ablation (RFA) has been used for therapy of colorectal liver metastases (CRLMs) several years, with considerable data confirming its safety and efficacy. However, there are few studies focusing on the long-term results of percrtaneous microwave ablation (PMWA) for CRLMs. The aim of this study was to evaluate the long-term survival and prognostic factors in patients with CRLMs undergoing PMWA. METHODS: We retrospectively analyzed treatment and survival parameters of 210 patients with CRLMs who had received PMWA in a single center from January 2010 to December 2017. Prognostic factors for survival were evaluated by means of univariate and multivariate analyses. RESULTS: The median follow-up time after PMWA was 48 months. The median overall survival (OS) time were 40.0 months (95% CI, 31.4 to 48.5 months), with 1-, 2, 3-, 4, and 5-year cumulative survival rates of 98.6%, 73.3%, 53.3%, 42.2%, and 32.9%, respectively. Tumor number (P = 0.004; HR: 1.838; CI: 1.213- 2.784), main tumor size (P = 0.017; HR: 1.631; CI: 1.093- 2.436), and serum CEA level (P = 0.032; HR: 1.559; CI: 1.039-2.340) were found as independent predictors of OS. The median OS time for patients with resectable lesions was 60.91 months (95% CI, 51.36 to 70.47 months), with 5-year cumulative survival rates of 53.5%. CONCLUSION: PMWA is a safe and effective treatment for CRLMs, with a favorable long-term outcome. Multiple lesions, main tumor diameter>3 cm, and serum CEA >30 ng/ml have a significant negative effect on OS.

Integrating high-throughput microRNA and mRNA expression data to identify risk mRNA signature for pancreatic cancer prognosis.

Pancreatic cancer is a malignancy of the digestive system characterized by poor prognosis. A number of prognostic messenger RNA (mRNA) signatures have been identified by using the high-throughput expression profiles. MicroRNAs (miRNA) play a critical role in regulating multiple cellular functions. However, no such integrated analysis of miRNAs and mRNAs for studying the prognostic mechanisms of pancreatic cancer has been reported. In this study, we first identified prognostic mRNAs and miRNAs based on The Cancer Genome Atlas datasets, and then performed an enrichment analysis to explore the underlying biological mechanisms involved in pancreatic cancer prognosis at the mRNA level. Furthermore, we performed an integrated analysis of mRNAs and miRNAs to identify prognostic subpathways, which were closely associated with pancreatic cancer genes and tumor hallmarks and involved in hypoxia, oxidative phosphyorylation and xenobiotic metabolisms. Meanwhile, we performed a random walk algorithm based on global network, prognostic mRNAs and miRNAs, and identified top risk mRNAs as the prognostic signature. Finally, an independent testing set was used to confirm the predictive power of the top mRNA signature, and most of these genes involved were known oncogenes. In conclusion, we performed a series of integrated analyses by comprehensively exploring pancreatic cancer prognosis and systematically optimized the prognostic signature for clinical use.

Identification of a robust functional subpathway signature for pancreatic ductal adenocarcinoma by comprehensive and integrated analyses.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy and its mortality continues to rise globally. Because of its high heterogeneity and complex molecular landscapes, published gene signatures have demonstrated low specificity and robustness. Functional signatures containing a group of genes involved in similar biological functions may display a more robust performance. METHODS: The present study was designed to excavate potential functional signatures for PDAC by analyzing maximal number of datasets extracted from available databases with a recently developed method of FAIME (Functional Analysis of Individual Microarray Expression) in a comprehensive and integrated way. RESULTS: Eleven PDAC datasets were extracted from GEO, ICGC and TCGA databases. By systemically analyzing these datasets, we identified a robust functional signature of subpathway (path:00982_1), which belongs to the drug metabolism-cytochrome P450 pathway. The signature has displayed a more powerful and robust capacity in predicting prognosis, drug response and chemotherapeutic efficacy for PDAC, particularly for the classical subtype, in comparison with published gene signatures and clinically used TNM staging system. This signature was verified by meta-analyses and validated in available cell line and clinical datasets with chemotherapeutic efficacy. CONCLUSION: The present study has identified a novel functional PDAC signature, which has the potential to improve the current systems for predicting the prognosis and monitoring drug response, and to serve a linkage to therapeutic options for combating PDAC. However, the involvement of path:00982_1 subpathway in the metabolism of anti-PDAC chemotherapeutic drugs, particularly its biological interpretation, requires a further investigation. Video Abstract.

Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus.

Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and metabolism. Akt hyperactivation contributes to many pathophysiological conditions, including human cancers, and is closely associated with poor prognosis and chemo- or radiotherapeutic resistance. Phosphorylation of Akt at S473 (ref. 5) and T308 (ref. 6) activates Akt. However, it remains unclear whether further mechanisms account for full Akt activation, and whether Akt hyperactivation is linked to misregulated cell cycle progression, another cancer hallmark. Here we report that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. Mechanistically, phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation. Furthermore, deletion of the cyclin A2 allele in the mouse olfactory bulb leads to reduced S477/T479 phosphorylation and elevated cellular apoptosis. Notably, cyclin A2-deletion-induced cellular apoptosis in mouse embryonic stem cells is partly rescued by S477D/T479E-Akt1, supporting a physiological role for cyclin A2 in governing Akt activation. Together, the results of our study show Akt S477/T479 phosphorylation to be an essential layer of the Akt activation mechanism to regulate its physiological functions, thereby providing a new mechanistic link between aberrant cell cycle progression and Akt hyperactivation in cancer.

Microwave ablation versus transcatheter arterial embolization for large hepatic hemangiomas: clinical outcomes.

PURPOSE: To evaluate the safety and effect of microwave ablation (MWA) compared with transcatheter arterial embolization (TAE) for the treatment of large hepatic hemangiomas. MATERIALS AND METHODS: A total of 135 patients with symptomatic or/and enlarging hepatic hemangiomas (5-10 cm) from two centers underwent either MWA (n = 82) or TAE (n = 53) as first-line treatment. We compared the two groups in terms of radiologic response, clinical response, operative time, postoperative analgesic requirements, hospital stay and complications. RESULTS: MWA had a significantly higher rate of complete radiologic response (89.0% vs. 37.7%, p<.001) and complete clinical response (88.6% vs. 69.2%, p=.046), fewer minor complications (43.9% vs. 66.0%, p=.019), shorter time of using analgesics (p<.001) and shorter hospital stays (p=.003) than did TAE. The operative time and major complications were comparable between the two groups. CONCLUSION: Both MWA and TAE are safe and effective in treating patients with large hepatic hemangiomas. MWA had a higher rate of complete response than did TAE, and it was associated with fewer minor complications, faster recovery and shorter hospital stay.