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Background: Pegylated arginine deiminase (ADI-PEG 20) is a metabolism-based strategy that depletes arginine, resulting in tumoral stress and cytotoxicity. Preclinically, ADI-PEG 20 modulates T-cell activity and enhances the therapeutic efficacy of programmed death-1 (PD-1) inhibition. Methods: A phase 1b study, including a dose-escalation cohort and an expansion cohort, was undertaken to explore the effects of ADI-PEG 20 in combination with pembrolizumab, an anti-PD-1 antibody, for safety, pharmacodynamics, and response. CD3 levels and programmed death-ligand 1 (PD-L1) expression were assessed in paired biopsies collected prior to and after ADI-PEG 20 treatment but before pembrolizumab. Results: Twenty-five patients, nine in the dose-escalation cohort and sixteen in the expansion cohort, were recruited. Treatment was feasible with adverse events consistent with those known for each agent, except for Grade 3/4 neutropenia which was higher than expected, occurring in 10/25 (40%) patients. Mean arginine levels were suppressed for 1-3 weeks, but increased gradually. CD3+ T cells increased in 10/12 (83.3%) subjects following ADI-PEG 20 treatment, including in three partial responders (p = .02). PD-L1 expression was low and increased in 3/10 (30%) of subjects. Partial responses occurred in 6/25 (24%) heavily pretreated patients, in both argininosuccinate synthetase 1 proficient and deficient subjects. Conclusions: The immunometabolic combination was safe with the caveat that the incidence of neutropenia might be increased compared with either agent alone. ADI-PEG 20 treatment increased T cell infiltration in the low PD-L1 tumor microenvironment. The recommended phase 2 doses are 36 mg/m² weekly for ADI-PEG 20 and 200 mg every 3 weeks for pembrolizumab. [ABSTRACT FROM AUTHOR]

Background: Dysregulated epidermal growth factor receptor (EGFR)-phosphoinositide-3-kinase (PI3K)-AKT signaling is considered pivotal for oral cancer, and the pathway is a potential candidate for therapeutic targeting. Results: A total of 108 archival samples which were from surgically resected oral cancer were examined. Immunohistochemical staining showed the protein expression of membranous wild-type EGFR and cytoplasmic phosphorylated AKT was detected in 63.9% and 86.9% of the specimens, respectively. In 49.1% of the samples, no phosphatase and tensin homolog (PTEN) expression was detected. With regard to the EGFR variant III (EGFRvIII), 75.0% of the samples showed positive expression for moderate to severe staining, 31.5% of which had high expression levels. Real-time polymerase chain reaction assays for gene copy number assessment of PIK3CA revealed that 24.8% of the samples had alterations, and of EGFR showed that 49.0% had amplification. Direct sequencing of PIK3CA gene showed 2.3% of the samples had a hotspot point mutation. Statistical assessment showed the expression of the EGFRvIII correlated with the T classification and TNM stage. The Kaplan-Meier analyses for patient survival showed that the individual status of phosphorylated AKT and EGFRvIII led to significant differences in survival outcome. The multivariate analysis indicated that phosphorylated AKT, EGFRvIII expression and disease stage were patient survival determinants. Conclusions: Aberrations in the EGFR-PI3K-AKT pathway were frequently found in oral cancers. EGFRvIII and phosphorylated AKT were predictors for the patient survival and clinical outcome. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor (HIF) accumulates when tumors grow under hypoxic conditions. The genesis of tumors, however, usually involves normoxic conditions. In this study, we were interested in examining the potential role of aryl hydrocarbon receptor nuclear translocator (ARNT)/HIF-1β in tumor growth under normoxic conditions, specifically when cells are treated with epidermal growth factor (EGF), which is known to affect the gene expression of tumor growth-related protein COX-2 (cyclooxygenase-2). The results showed that EGF receptor inhibitor, AG 1478, abolished EGF-induced nuclear accumulation of ARNT as well as the expression of COX-2. ARNT small interfering RNA inhibited the promoter activity, mRNA level, and protein expression of COX-2 in cells treated with EGF. In contrast, CoCl2-induced HIF-1α exhibited no effect on COX-2 expression. EGF also stimulated the formation of the ARNT·c-Jun complex as well as the complex binding to the COX-2 promoter. ARNT small interfering RNAs blocked EGF-activated cell migration. Moreover, COX-2 and ARNT were cohorts present distinctively in clinical specimens of human cervical squamous cell carcinoma and were almost nondetectable in adjacent normal or noncancerous cervical tissues. Our results revealed that ARNT plays an important role in EGF-regulated COX-2 gene expression and may thus be related to either a cause or a consequence of tumorigenesis in cervical cancer. [ABSTRACT FROM AUTHOR]

The adaptive T cell response is accompanied by continuous rewiring of the T cell's electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report in mice that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency in mice causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) activation is a major cause of metastasis in such cancers as head and neck squamous cell carcinoma (HNSCC); however, whether the metabolic enzyme, pyruvate dehydrogenase kinase 1 (PDK1), mediates EGF-enhanced HNSCC metastasis remains unclear. Of interest, we found that EGF induced PDK1 expression in HNSCC. Tumor cell transformation induced by EGF was repressed by PDK1 knockdown, and the down-regulation of PDK1 expression or inhibition of its activity significantly blocked EGF-enhanced cell migration and invasion. In addition, depletion of PDK1 impeded EGF-enhanced binding of HNSCC cells to endothelial cells as well as the metastatic seeding of tumor cells in lungs. PDK1 depletion inhibited EGF-induced matrix metalloproteinase-1 (MMP-1), MMP-2, MMP-3, MMP-9, and fibronectin expression and Rac1/cdc42 activation. Furthermore, PDK1 overexpression induced MMP-1, MMP-2, MMP-3, MMP-9, and fibronectin expression and Rac1/cdc42 activation. Of interest, depletion of fibronectin inhibited PDK1-enhanced MMP-1-3 and MMP-9 expression as well as Rac1/cdc42 activation and tumor invasion. These results demonstrate that EGF-induced PDK1 expression enhances HNSCC metastasis via activation of the fibronectin signaling pathway. Inhibition of PDK1 may be a potential strategy for the treatment of EGFR-mediated HNSCC metastasis. [ABSTRACT FROM AUTHOR]

Background: Glioma stem-like cells (GSCs) are proposed to be responsible for high resistance in glioblastoma multiforme (GBM) treatment. In order to find new strategies aimed at reducing GSC stemness and improving GBM patient survival, we investigated the effects and mechanism of a histone deacetylases (HDACs) inhibitor, suberoylanilide hydroxamic acid (SAHA), since HDAC activity has been linked to cancer stem-like cell (CSC) abundance and properties. Methods: Human GBM cell lines were plated in serum-free suspension cultures allowed for sphere forming and CSC enrichment. Subsequently, upon SAHA treatment, the stemness markers, cell proliferation, and viability of GSCs as well as cellular apoptosis and senescence were examined in order to clarify whether inhibition of GSCs occurs. Results: We demonstrated that SAHA attenuated cell proliferation and diminished the expression stemness-related markers (CD133 and Bmi1) in GSCs. Furthermore, at high concentrations (more than 5 μM), SAHA triggered apoptosis of GSCs accompanied by increases in both activation of caspase 8- and caspase 9-mediated pathways. Interestingly, we found that a lower dose of SAHA (1 μM and 2.5 μM) inhibited GSCs via cell cycle arrest and induced premature senescence through p53 up-regulation and p38 activation. Conclusion: SAHA induces apoptosis and functions as a potent modulator of senescence via the p38-p53 pathway in GSCs. Our results provide a perspective on targeting GSCs via SAHA treatment, and suggest that SAHA could be used as a potent agent to overcome drug resistance in GBM patients. [ABSTRACT FROM AUTHOR]

Background: Combined radiotherapy and chemotherapy is considered the standard of care for locally advanced nasopharyngeal carcinoma (LA-NPC) in Epstein-Barr virus infection endemic area. This study compared the long-term outcomes between LA-NPC patients treated with neoadjuvant chemotherapy followed by radiotherapy (NACT) and those treated with concurrent chemoradiotherapy (CCRT). Methods: From 2003 to 2007, a total of 128 histopathologically proven LA-NPC patients receiving either NACT or CCRT were consecutively enrolled at the National Cheng Kung University Hospital in Taiwan. NACT consisted of 3-week cycles of mitomycin, epirubicin, and cisplatin on day 1 and fluorouracil and leucovorin on day 8 (MEPFL) or weekly alternated cisplatin on day 1 and fluorouracil and leucovorin on day 8 (P-FL). CCRT comprised 3-week cycles of cisplatin (Cis 100) or 4-week cycles of cisplatin and fluorouracil (PF4). The first failure site, disease free survival (DFS), overall survival (OS), and other prognostic factors were analyzed. Results: Thirty-eight patients (30%) received NACT. Median follow-up duration was 53 months. More patients with advanced nodal disease (N2-N3) (86.8% vs 67.8%, p =0.029) and advanced clinical stage (stage IVA-IVB) enrolled in the NACT group (55.2% vs 26.7%, p =0.002). For NACT, both MEPFL and P-FL had similar 5-year DFS and OS (52.9% vs 50%, p =0.860 and 73.5% vs 62.5%, p =0.342, respectively). For CCRT, both PF4 and Cis 100 had similar 5-year DFS and OS (62.8% vs 69.6%, p =0.49 and 72.9% vs 73.9%, p =0.72, respectively). Compared to CCRT, NACT had similar 5-year DFS and OS (51.5% vs 65.1%, p =0.28 and 71.7% vs 74.3%, p =0.91, respectively). Among patients who were recurrence-free in the first 2 years after treatment, those treated with NACT experienced poorer locoregional control compared to those treated with CCRT (Hazard ratio =2.57, 95% confidence interval: 1.02 to 6.47, p =0.046). Conclusions: For LA-NPC, both CCRT and NACT were similarly efficacious treatment strategies in terms of long-term disease control and survival probability. Close locoregional follow-up is recommended for patients receiving NACT, because these patients are more prone to develop locoregional failure than patients receiving CCRT. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC), a major cause of cancer-related death in Southeast Asia, is frequently associated with hepatitis B virus (HBV) infection. HBV X protein (HBx), encoded by a viral non-structural gene, is a multifunctional regulator in HBV-associated tumor development. We investigated novel signaling pathways underlying HBx-induced liver tumorigenesis and found that the signaling pathway involving IκB kinase β (IKKβ), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1), was upregulated when HBx was overexpressed in hepatoma cells. HBx-induced S6K1 activation was reversed by IKKβ inhibitor Bay 11-7082 or silencing IKKβ expression using siRNA. HBx upregulated cell proliferation and vascular endothelial growth factor (VEGF) production, and these HBx-upregulated phenotypes were abolished by treatment with IKKβ inhibitor Bay 11-7082 or mTOR inhibitor rapamycin. The association of HBx-modulated IKKβ/mTOR/S6K1 signaling with liver tumorigenesis was verified in a HBx transgenic mouse model in which pIKKβ, pS6K1, and VEGF expression was found to be higher in cancerous than noncancerous liver tissues. Furthermore, we also found that pIKKβ levels were strongly correlated with pTSC1 and pS6K1 levels in HBV-associated hepatoma tissue specimens taken from 95 patients, and that higher pIKKβ, pTSC1, and pS6K1 levels were correlated with a poor prognosis in these patients. Taken together, our findings demonstrate that HBx deregulates TSC1/ mTOR signaling through IKKβ, which is crucially linked to HBV-associated HCC development. [ABSTRACT FROM AUTHOR]

yl hydrocarbon receptor nuclear translocator (ARNT) binds to other basic helix-loop-helix Per/ARNT/Sim (bHLH-PAS) proteins to form functional transcriptional complexes in order to regulate specific biological pathways. Here, we report a novel mechanism that upon EGF treatment, ARNT associated with non-bHLH-PAS transcription factors, c-Jun/Sp1, and regulated gene expression, through forming a c-Jun/ARNT/Sp1 complex and binding to the Sp1 site of the gene promoter. EGF-induced promoter activity and the mRNA level of 12(S)- lipoxygenase as well as the association between c-Jun and Sp1 were reduced by ARNT knockdown. Notably, dominant negative c-Jun mutant, TAM-67, blocked ARNT-mediated 12(S)- lipoxygenase expression, demonstrating that c-Jun was responsible for the transcriptional activation. Moreover, ARNT knockdown also inhibited other EGF-induced c-Jun/Sp1 mediated gene expression, such as p21. Our results reveal a novel mechanism by which ARNT acts as a modulator to bridge the c-Jun/Sp1 interaction and plays a role in EGF-mediated gene expression under normoxic conditions. [ABSTRACT FROM AUTHOR]

Aim To better understand the spectrum of primary lymphomas in the upper aerodigestive tract, a common site of extranodal lymphoma. Materials and methods Lymphoma cases diagnosed at an institution in southern Taiwan from 1992 to 2007 were retrospectively studied with pathology and history review, immunohistochemistry, in situ hybridisation for Epstein-Barr virus (EBER-ISH), and statistical analysis. Results 70 patients were identified. The male to female ratio was 2:1, and the median age was 61.5 years (range 8-87); 73% of cases occurred in Waldeyer's ring or the oral cavity. Phenotypically, there were 45 (64%) B cell and 25 (36%) T cell or extranodal natural killer (NK)/T cell lymphoma (ENKL) including 42 (60%) diffuse large B cell lymphomas (DLBCLs), 22 (31%) ENKLs, three unspecified peripheral T cell lymphomas, two follicular lymphomas and one Burkitt lymphoma. EBER-ISH was positive in three (7%) of 42 DLBCLs and all 22 ENKLs. Most patients received chemotherapy with or without radiotherapy. The 5-year overall survival for all patients was 56.3% with B and T or NK/T cell lymphomas at 66.0% and 40.6%, respectively. Univariate analysis revealed that sinonasal presentation, T or NK/T cell phenotype, raised lactate dehydrogenase (LDH) activity, and Ann Arbor stage III/IV diseases were associated with prognostically significant higher hazard ratio (HR) of lymphoma-related death. However, only raised LDH remained significant on multivariate analysis. For DLBCLs, only raised LDH was prognostically significant on either univariate or multivariate analysis. Conclusions Only a limited number of lymphoma entities occurred primarily in this anatomical region. The 5-year overall survival rate was comparable to other reports, and raised LDH at diagnosis was the only significant prognostic factor identified. A relatively high incidence of EBV positivity was identified in DLBCLs in this anatomical region, and further studies are warranted to elucidate the clinicopathological significance of these tumours. [ABSTRACT FROM AUTHOR]