Effects of Ado-Trastuzumab Emtansine and Fam-Trastuzumab Deruxtecan on Metastatic Breast Cancer Harboring HER2 Amplification and the L755S Mutation.

Somatic mutations in human epidermal growth factor receptor 2 (HER2) are present in approximately 3% of breast cancers. Some HER2 mutations are activating, and they represent a mechanism of resistance to conventional anti-HER2 therapies such as trastuzumab and lapatinib. Consistently, in patients with HER2-amplified breast cancer, these mutations are predominantly observed in metastatic tumors obtained after exposure to anti-HER2 systemic therapies, possibly after clonal selection. Therefore, it is rare to find coexistent HER2 mutation and amplification in the early clinical course, and thus, the clinical relevance of HER2 mutation to the sensitivity to HER2-targeted drugs, particularly antibody-drug conjugates (ADCs) such as ado-trastuzumab emtansine (T-DM1) and the recently approved fam-trastuzumab deruxtecan (T-DXd), remains unclear. In this article, we describe a patient with de novo metastatic breast cancer who exhibited both HER2 amplification and the L755S mutation in the untreated primary breast tumor obtained at the initial diagnosis, and the lesion responded to T-DM1 and T-DXd after exhibiting clinical resistance to other HER2-targeted drugs. Our current case findings suggested that anti-HER2 ADCs should be prioritized over conventional trastuzumab- or lapatinib-based therapies for patients with HER2-amplified and comutated tumors. KEY POINTS: Although HER2 mutations were implicated in resistance to anti-HER2 monoclonal antibodies or HER2 tyrosine kinase inhibitors in preclinical studies, their clinical impact on sensitivity to anti-HER2 drugs is unclear owing to the rarity of concomitant HER2 mutation and HER2 amplification. A case of de novo metastatic breast cancer harboring both HER2 amplification and the L755S mutation in an untreated breast primary tumor displayed clinical resistance to standard trastuzumab- or lapatinib-based therapies but good responses to ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (T-DXd). Anti-HER2 antibody-drug conjugates such as T-DM1 and T-DXd may be prioritized over conventional trastuzumab- or lapatinib-containing therapies for patients with HER2-amplified and comutated tumors.

Ephrin-B2 controls PDGFRß internalization and signaling.

B-class ephrins, ligands for EphB receptor tyrosine kinases, are critical regulators of growth and patterning processes in many organs and species. In the endothelium of the developing vasculature, ephrin-B2 controls endothelial sprouting and proliferation, which has been linked to vascular endothelial growth factor (VEGF) receptor endocytosis and signaling. Ephrin-B2 also has essential roles in supporting mural cells (namely, pericytes and vascular smooth muscle cells [VSMCs]), but the underlying mechanism is not understood. Here, we show that ephrin-B2 controls platelet-derived growth factor receptor ß (PDGFRß) distribution in the VSMC plasma membrane, endocytosis, and signaling in a fashion that is highly distinct from its role in the endothelium. Absence of ephrin-B2 in cultured VSMCs led to the redistribution of PDGFRß from caveolin-positive to clathrin-associated membrane fractions, enhanced PDGF-B-induced PDGFRß internalization, and augmented downstream mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK) activation but impaired Tiam1-Rac1 signaling and proliferation. Accordingly, mutant mice lacking ephrin-B2 expression in vascular smooth muscle developed vessel wall defects and aortic aneurysms, which were associated with impaired Tiam1 expression and excessive activation of MAP kinase and JNK. Our results establish that ephrin-B2 is an important regulator of PDGFRß endocytosis and thereby acts as a molecular switch controlling the downstream signaling activity of this receptor in mural cells.

Management of regional bone bank during declaration of a state of emergency concerning the COVID-19 in Japan.

Bone banks are necessary for providing biological allografts for a series of orthopedic procedures. As nations cope with new realities driven by the 2019 coronavirus disease (COVID-19) pandemic, health-care providers, institutions, and patients share a particular concern about the effect of COVID-19 on organ donation and transplantation. Here, we describe the management of the Kitasato University Bone Bank during the state of emergency declared in response to COVID-19. Living donors received pre-operative screening by PCR, and allograft bone from COVID-19-negative donors was cryopreserved as transplantable tissues. The weekly rate of infection gradually increased from February 2-9 to April 5-11 in the dead donor-derived allograft bone-harvesting region covered by the Bank. It is becoming clear that the virus can be transmitted by asymptomatic patients, and that this route may have facilitated the spread of COVID-19. Therefore, the Bank stopped dead donor donation to consider the safety of medical staff. Three recipients received bone allografts following pre-operative COVID-19 screening by PCR. All patients were asymptomatic after bone allograft. Our experience may provide helpful information for the management of tissue banks.

In Vivo Pharmacokinetic Analysis Utilizing Non-Targeted and Targeted Mass Spectrometry and In Vitro Assay against Transient Receptor Potential Channels of Maobushisaishinto and Its Constituent Asiasari Radix.

The Japanese traditional medicine maobushisaishinto (MBST) has been prescribed for treating upper respiratory tract infections, such as a common cold. However, its mode of action is poorly understood, especially concerning the MBST constituent Asiasari Radix (AR). In this study, we focused on AR, with an objective of clarifying its bioavailable active ingredients and role within MBST by performing pharmacokinetic and pharmacological studies. Firstly, we performed qualitative non-targeted analysis utilizing high-resolution mass spectrometry to explore the bioavailable ingredients of AR as well as quantitative targeted analysis to reveal plasma concentrations following oral administration of MBST in rats. Secondly, we performed in vitro pharmacological study of bioavailable AR ingredients in addition to other ingredients of MBST to confirm any agonistic activities against transient receptor potential (TRP) channels. As a result, methyl kakuol and other compounds derived from AR were detected in the rat plasma and showed agonistic activity against TRPA1. This study suggests that methyl kakuol as well as other compounds have the potential to be an active ingredient in AR and thus presumably would contribute in part to the effects exerted by MBST.

Suppression of CCL2 angiocrine function by adrenomedullin promotes tumor growth.

Within the tumor microenvironment, tumor cells and endothelial cells regulate each other. While tumor cells induce angiogenic responses in endothelial cells, endothelial cells release angiocrine factors, which act on tumor cells and other stromal cells. We report that tumor cell-derived adrenomedullin has a pro-angiogenic as well as a direct tumor-promoting effect, and that endothelium-derived CC chemokine ligand 2 (CCL2) suppresses adrenomedullin-induced tumor cell proliferation. Loss of the endothelial adrenomedullin receptor CALCRL or of the G-protein Gs reduced endothelial proliferation. Surprisingly, tumor cell proliferation was also reduced after endothelial deletion of CALCRL or Gs. We identified CCL2 as a critical angiocrine factor whose formation is inhibited by adrenomedullin. Furthermore, CCL2 inhibited adrenomedullin formation in tumor cells through its receptor CCR2. Consistently, loss of endothelial CCL2 or tumor cell CCR2 normalized the reduced tumor growth seen in mice lacking endothelial CALCRL or Gs. Our findings show tumor-promoting roles of adrenomedullin and identify CCL2 as an angiocrine factor controlling adrenomedullin formation by tumor cells.

Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer.

Cancer-associated fibroblasts (CAFs) are important components in the tumor microenvironment, and we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC). In this study, we established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells. RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we identified that the expression of periostin (POSTN), which is known to be overexpressed in various solid tumors and promote cancer progression, was significantly higher in CAFs than in NFs. POSTN increased cell proliferation via NSCLC cells' ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for osimertinib treatment. Collectively, our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN could be a potential therapeutic strategy for NSCLC. KEY MESSAGES: • POSTN is significantly upregulated in CAFs compared to normal fibroblasts in NCSLC. • POSTN increases cell proliferation via activation of the NSCLC cells' ERK pathway. • POSTN induces EMT in NSCLC cells and improves the migration ability. • POSTN knockdown improves the sensitivity for osimertinib in EGFR-mutant NSCLC cells.

Functional dissection of LIS1 and NDEL1 towards understanding the molecular mechanisms of cytoplasmic dynein regulation.

LIS1 and NDEL1 are known to be essential for the activity of cytoplasmic dynein in living cells. We previously reported that LIS1 and NDEL1 directly regulated the motility of cytoplasmic dynein in an in vitro motility assay. LIS1 suppressed dynein motility and inhibited the translocation of microtubules (MTs), while NDEL1 dissociated dynein from MTs and restored dynein motility following suppression by LIS1. However, the molecular mechanisms and detailed interactions of dynein, LIS1, and NDEL1 remain unknown. In this study, we dissected the regulatory effects of LIS1 and NDEL1 on dynein motility using full-length or truncated recombinant fragments of LIS1 or NDEL1. The C-terminal fragment of NDEL1 dissociated dynein from MTs, whereas its N-terminal fragment restored dynein motility following suppression by LIS1, demonstrating that the two functions of NDEL1 localize to different parts of the NDEL1 molecule, and that restoration from LIS1 suppression is caused by the binding of NDEL1 to LIS1, rather than to dynein. The truncated monomeric form of LIS1 had little effect on dynein motility, but an artificial dimer of truncated LIS1 suppressed dynein motility, which was restored by the N-terminal fragment of NDEL1. This suggests that LIS1 dimerization is essential for its regulatory function. These results shed light on the molecular interactions between dynein, LIS1, and NDEL1, and the mechanisms of cytoplasmic dynein regulation.

Drug-interaction between paclitaxel and goshajinkigan extract and its constituents.

Paclitaxel, a standard chemotherapeutic agent for several types of cancer, including ovarian, breast, and non-small-cell lung cancer, causes peripheral neuropathy as an adverse effect in 60-70% of the patients. The utility of combination therapy with paclitaxel and goshajinkigan, a traditional Japanese Kampo medicine, in managing paclitaxel-induced neuropathy during chemotherapy has been explored. Paclitaxel is predominantly metabolized in the liver by cytochrome P450 (CYP) 2C8 to produce 6α-hydroxypaclitaxel and by CYP3A4 to produce 3'-p-hydroxypaclitaxel. In this study, we evaluated the inhibitory or inducing effects of goshajinkigan extract (GJG) and its representative and bioavailable constituents, geniposidic acid, plantagoguanidinic acid, paeoniflorin, catalpol, loganin, and neoline, on the metabolism of paclitaxel via CYP2C8 and CYP3A4 using pooled human liver microsomes and cultured human cryopreserved hepatocytes to provide the drug information about the pharmacokinetic interaction of this combination therapy. GJG significantly inhibited the production of 3'-p-hydroxypaclitaxel and 6α-hydroxypaclitaxel in vitro in a concentration-dependent manner. The half maximal inhibitory concentration (IC50) values of GJG were 4.5 and 7.8 mg/ml, respectively, for 3'-p-hydroxypaclitaxel and 6α-hydroxypaclitaxel productions. Neoline inhibited the production of 3'-p-hydroxypaclitaxel at 50 µM, but not at lower concentrations. Apart from neoline, other GJG constituents (at concentrations up to 50 or 10 µM of all test substances) did not exhibit inhibitory or inducing effects. Since GJG showed the inhibitory effect on the metabolism of paclitaxel at much higher concentrations than those used clinically, it can be concluded that GJG product does not exhibit any pharmacokinetic interaction with paclitaxel in clinical practice.

Desorption of micropollutant from superfine and normal powdered activated carbon in submerged-membrane system due to influent concentration change in the presence of natural organic matter: Experiments and two-component branched-pore kinetic model.

Submerged-membrane hybrid systems (SMHSs) that combine membrane filtration with powdered activated carbon (PAC) take advantage of PAC's ability to adsorb and remove contaminants dissolved in water. However, the risk of contaminant desorption due to temporal changes in the influent concentration of the contaminant has not been thoroughly explored. In this study, we used a SMHS with conventionally-sized PAC or superfine PAC (SPAC) to remove 2-methylisoborneol (MIB), a representative micropollutant, from water containing natural organic matter (NOM), with the goal of elucidating adsorption-desorption phenomena in the SMHS. We found that 20-40% of the MIB that adsorbed on PAC and SPAC while the influent was contaminated with MIB (6 h, contamination period) desorbed to the liquid phase within 6 h from the time that the MIB-containing influent was replaced by MIB-free influent (no-contamination period). The percentage of desorption during the no-contamination period increased with increasing MIB breakthrough concentration during the contamination period. These findings indicate that the PAC/SPAC in the SMHS should be replaced while the breakthrough concentration is low, not only to keep a high removal rate but also to decrease the desorption risk. SPAC is fast in removal by adsorption, but it is also fast in release by desorption. SPAC (median diameter: 0.94 µm) showed almost the same adsorption-desorption kinetics as PAC (12.1 µm) of a double dose. A two-component branched-pore diffusion model combined with an IAST (ideal adsorbed solution theory)-Freundlich isotherm was used to describe and analyze the adsorption-desorption of MIB. The diffusivity of MIB molecules in the pores of the activated carbon particles decreased markedly in a short period of time. This decrease, which was attributed to fouling of the activated carbon in the SMHS by coagulant-treated water containing NOM, not only reduced the rate of MIB removal during the contamination period but also hindered the rate of MIB desorption during the no-contamination period and thus prevented the effluent MIB concentration from becoming high. On the other hand, coagulation did not change the concentration of NOM that competes with MIB for adsorption sites.

Maoto, a traditional Japanese medicine, controls acute systemic inflammation induced by polyI:C administration through noradrenergic function.

Maoto, a traditional Japanese medicine (Kampo), is widely used to treat upper respiratory tract infections, including influenza virus infection. Although maoto is known to inhibit pro-inflammatory responses in a rodent model of acute inflammation, its underlying mechanism remains to be determined. In this study, we investigated the involvement of immune responses and noradrenergic function in the inhibitory action of maoto. In a mouse model of polyI:C-induced acute inflammation, maoto was administered orally in conjunction with intraperitoneal injection of PolyI:C (6 mg/kg), and blood was collected after 2 h for measurement of plasma cytokines by ELISA. Maoto significantly decreased PolyI:C-induced TNF-α levels and increased IL-10 production. Neither pretreatment with IL-10 neutralizing antibodies nor T-cell deficiency using nude mice modified the inhibitory effect of maoto, indicating that the anti-inflammatory effects of maoto are independent of IL-10 and T cells. Furthermore, the inhibitory effects of maoto on PolyI:C-induced TNF-α production were not observed in ex vivo splenocytes, suggesting that maoto does not act directly on inflammatory cells. Lastly, pretreatment with a ß-adrenergic receptor antagonist partially cancelled the anti-inflammatory effects of maoto. Collectively, these results suggest that maoto mediates its anti-inflammatory effects via ß-adrenergic receptors in vivo.

Whole-body MRI: detecting bone metastases from prostate cancer.

Whole-body magnetic resonance imaging (WB-MRI) is currently used worldwide for detecting bone metastases from prostate cancer. The 5-year survival rate for prostate cancer is > 95%. However, an increase in survival time may increase the incidence of bone metastasis. Therefore, detecting bone metastases is of great clinical interest. Bone metastases are commonly located in the spine, pelvis, shoulder, and distal femur. Bone metastases from prostate cancer are well-known representatives of osteoblastic metastases. However, other types of bone metastases, such as mixed or inter-trabecular type, have also been detected using MRI. MRI does not involve radiation exposure and has good sensitivity and specificity for detecting bone metastases. WB-MRI has undergone gradual developments since the last century, and in 2004, Takahara et al., developed diffusion-weighted Imaging (DWI) with background body signal suppression (DWIBS). Since then, WB-MRI, including DWI, has continued to play an important role in detecting bone metastases and monitoring therapeutic effects. An imaging protocol that allows complete examination within approximately 30 min has been established. This review focuses on WB-MRI standardization and the automatic calculation of tumor total diffusion volume (tDV) and mean apparent diffusion coefficient (ADC) value. In the future, artificial intelligence (AI) will enable shorter imaging times and easier automatic segmentation.

Systematic review: generating evidence-based guidelines on the concurrent use of dietary antioxidants and chemotherapy or radiotherapy.

The risk-benefit ratio for concurrent use of dietary antioxidants with chemotherapy or radiation therapy is a controversial topic. In this review, the medical literature on concurrent antioxidant use with chemotherapy or radiotherapy was assessed and further steps for generating evidence-based guidelines are suggested. The clinical cancer research community should cooperate and focus new studies on the use of a specific combination of antioxidant and chemotherapy or radiotherapy, and determine optimal doses for a specific cancer setting. Mechanistic studies on the interaction between antioxidants and conventional cancer therapy could lead to novel biomarkers for assessing dose adequacy.

Effects of pre, post, and simultaneous loading of natural organic matter on 2-methylisoborneol adsorption on superfine powdered activated carbon: Reversibility and external pore-blocking.

Three different natural organic matter (NOM)-loading methods were compared for the adsorptive removal of 2-methylisoborneol (MIB) by superfine powdered activated carbon (SPAC) and conventionally-sized powdered activated carbon (PAC). The three NOM-loading methods were: NOM adsorption followed by MIB (MIB adsorption on NOM-preloaded carbon), MIB adsorption followed by NOM (MIB adsorption on NOM post-loaded carbon), and simultaneous NOM and MIB loading (MIB adsorption on NOM-simultaneously loaded carbon). MIB removals were similar for the smaller-sized carbon (SPAC) at higher AC dosages and at lower initial NOM concentrations. The similar MIB removals indicate direct site competition between MIB and NOM with MIB adsorption reversibility (complete desorption of MIB by NOM). At lower AC doses, especially for PACs, and at higher initial NOM concentrations, the adsorption of MIBs depended on the sequence of MIB or NOM adsorption. MIB removal was lowest for the NOM-preloaded carbon, followed by NOM-simultaneously loaded carbon. The highest MIB removal was achieved by post-loading of NOM, indicating that the adsorption is irreversible. MIB adsorption on SPAC was more reversible than on PAC, although the pore size distributions of the two carbons were similar. The high degree of adsorption irreversibility for PAC compared with SPAC indicated that pore blocking occurs due to NOM loading at the PAC particle surface. Images of the external adsorption were obtained using isotope mapping and 15N-labeled effluent organic matter.

The effect of the reconstruction algorithm for the pulmonary nodule detection under the metal artifact caused by a pacemaker.

The aim was to compare the effects of metal artifacts from a pacemaker on pulmonary nodule detection among computed tomography (CT) images reconstructed using filtered back projection (FBP), single-energy metal artifact reduction (SEMAR), and forward-projected model-based iterative reconstruction solution (FIRST).Nine simulated nodules were placed inside a chest phantom with a pacemaker. CT images reconstructed using FBP, SEMAR, and FIRST were acquired at low and standard dose, and were evaluated by 2 independent radiologists.FIRST demonstrated the most significantly improved metal artifact and nodule detection on low dose CT (P < .0032), except at 10 mA and 5-mm thickness. At standard-dose CT, SEMAR showed the most significant metal artifact reduction (P < .00001). In terms of nodule detection, no significant differences were observed between FIRST and SEMAR (P = .161).With a pacemaker present, FIRST showed the best nodule detection ability at low-dose CT and SEMAR is comparable to FIRST at standard dose CT.

Disturbed flow-induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis.

Atherosclerosis develops preferentially in areas of the arterial system, in which blood flow is disturbed. Exposure of endothelial cells to disturbed flow has been shown to induce inflammatory signaling, including NF-κB activation, which leads to the expression of leukocyte adhesion molecules and chemokines. Here, we show that disturbed flow promotes the release of adrenomedullin from endothelial cells, which in turn activates its Gs-coupled receptor calcitonin receptor-like receptor (CALCRL). This induces antiinflammatory signaling through cAMP and PKA, and it results in reduced endothelial inflammation in vitro and in vivo. Suppression of endothelial expression of Gαs, the α subunit of the G-protein Gs; CALCRL; or adrenomedullin leads to increased disturbed flow-induced inflammatory signaling in vitro and in vivo. Furthermore, mice with induced endothelial-specific deficiency of Gαs, CALCRL, or adrenomedullin show increased atherosclerotic lesions. Our data identify an antiinflammatory signaling pathway in endothelial cells stimulated by disturbed flow and suggest activation of the endothelial adrenomedullin/CALCRL/Gs system as a promising approach to inhibit progression of atherosclerosis.

Ultra high-resolution computed tomography with 1024-matrix: Comparison with 512-matrix for the evaluation of pulmonary nodules.

PURPOSE: To determine whether a 1024-matrix provides superior image quality for the evaluation of pulmonary nodules. MATERIALS AND METHODS: Prospective evaluation conducted between December 2017 and April 2018, during which CT images showing lung nodules of more than 6 mm and less than 30 mmm were reconstructed with 2 different protocols: 0.5-mm thickness, 512 × 512 matrix, 34.5-cm field of view (FOV) (0.5-512 protocol); and 2-mm thickness, 1024 × 1024 matrix, 34.5-cm FOV (2-1024 protocol). Lung nodule characteristics such as margin, lobulation, pleural indentation, spiculation as well as peripheral vessels and bronchioles visibility and overall image quality were evaluated by three chest radiologists, using a 5-point scale. Image noise was evaluated by measuring the standard deviation in the region of interest for each image. RESULTS: A total of 89 nodules were evaluated. The 2-1024 protocol performed significantly better for the subjective evaluation of pulmonary nodules (p = 0.006 ∼ p < 0.0001). However, image noise was significantly higher both subjectively and objectively (p = 0.036, p < 0.0001). CONCLUSION: The use of a 2-1024 protocol does not increase the amount of images and allows better assessment of pulmonary nodules, despite noise increase.

Shear stress-induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure.

Hypertension is a primary risk factor for cardiovascular diseases including myocardial infarction and stroke. Major determinants of blood pressure are vasodilatory factors such as nitric oxide (NO) released from the endothelium under the influence of fluid shear stress exerted by the flowing blood. Several endothelial signaling processes mediating fluid shear stress-induced formation and release of vasodilatory factors have been described. It is, however, still poorly understood how fluid shear stress induces these endothelial responses. Here we show that the endothelial mechanosensitive cation channel PIEZO1 mediated fluid shear stress-induced release of adrenomedullin, which in turn activated its Gs-coupled receptor. The subsequent increase in cAMP levels promoted the phosphorylation of endothelial NO synthase (eNOS) at serine 633 through protein kinase A (PKA), leading to the activation of the enzyme. This Gs/PKA-mediated pathway synergized with the AKT-mediated pathways leading to eNOS phosphorylation at serine 1177. Mice with endothelium-specific deficiency of adrenomedullin, the adrenomedullin receptor, or Gαs showed reduced flow-induced eNOS activation and vasodilation and developed hypertension. Our data identify fluid shear stress-induced PIEZO1 activation as a central regulator of endothelial adrenomedullin release and establish the adrenomedullin receptor and subsequent Gs-mediated formation of cAMP as a critical endothelial mechanosignaling pathway regulating basal endothelial NO formation, vascular tone, and blood pressure.

aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability.

Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer. The polarity protein atypical protein kinase C lambda/iota (aPKCλ) is associated with cell proliferation through unknown mechanisms. In endothelial cells, suppression of aPKCλ impairs proliferation despite hyperactivated mitogenic signaling. Here we show that aPKCλ phosphorylates the DNA binding domain of forkhead box O1 (FoxO1) transcription factor, a gatekeeper of endothelial growth. Although mitogenic signaling excludes FoxO1 from the nucleus, consequently increasing c-Myc abundance and proliferation, aPKCλ controls c-Myc expression via FoxO1/miR-34c signaling without affecting its localization. We find this pathway is strongly activated in the malignant vascular sarcoma, angiosarcoma, and aPKC inhibition reduces c-Myc expression and proliferation of angiosarcoma cells. Moreover, FoxO1 phosphorylation at Ser218 and aPKC expression correlates with poor patient prognosis. Our findings may provide a potential therapeutic strategy for treatment of malignant cancers, like angiosarcoma.