Responses of cancer cells with wild-type or tyrosine kinase domain-mutated epidermal growth factor receptor (EGFR) to EGFR-targeted therapy are linked to downregulation of hypoxia-inducible factor-1α

<p>Abstract</p> <p>Background</p> <p>Searching for novel molecular markers that dependably predict or indicate responses of human cancer cells to epidermal growth factor receptor (EGFR)-targeted therapy is strongly warranted. The purpose of the current study was to evaluate hypoxia-inducible factor-1α (HIF-1α) as a novel response marker compared with previously explored markers following treatment with an EGFR-blocking monoclonal antibody (cetuximab) and a small-molecule EGFR tyrosine kinase inhibitor (gefitinib) in a group of cancer cell lines containing wild-type or tyrosine kinase domain-mutated EGFR.</p> <p>Results</p> <p>We found that, compared with previously studied response markers, including EGFR <it>per se </it>and three EGFR downstream signal molecules (ERK, Akt, and STAT3), which showed variable post-treatment changes in levels of phosphorylation and no consistent link of the changes to therapeutic responses, HIF-1α showed a selective decrease in protein levels only in responsive cell lines. To demonstrate a critical role of HIF-1α downregulation by EGFR-targeted treatment, we introduced a constitutively expressed HIF-1α mutant (HIF-1α/ΔODD) that is resistant to cetuximab-induced downregulation in a cetuximab-responsive cell line (A431); we found that the HIF-1α/ΔODD-transfected cells remained sensitive to cetuximab-induced inhibition of Akt and ERK phosphorylation but were remarkably less responsive to cetuximab-induced growth inhibition compared with corresponding control cells.</p> <p>Conclusion</p> <p>Our data indicates that downregulation of HIF-1α is associated with positive therapeutic responses of cancer cells to EGFR-targeted therapy and suggest further investigation using HIF-1α as an indicator of tumor response to EGFR-targeted therapy in preclinical studies and in the clinical setting.</p

Genome-wide linkage analysis of blood pressure under locus heterogeneity

We describe a method for mapping quantitative trait loci that allows for locus heterogeneity. A genome-wide linkage analysis of blood pressure was performed using sib-pair data from the Framingham Heart Study. Evidence of linkage was found on four markers (GATA89G08, GATA23D06, GATA14E09, and 049xd2) at a significance level of 0.01. Two of them (GATA14E09 and 049xd2) seem to overlap with linkage signals reported previously, while the other two are not linked to any known signals

Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A.

INTRODUCTION: Valoctocogene roxaparvovec is an investigational AAV5-based factor VIII (FVIII) gene therapy that has demonstrated sustained clinical benefit in people with severe haemophilia A. AIM: To report safety, tolerability, efficacy, and quality of life (QOL) among participants who received valoctocogene roxaparvovec in a phase 1/2 clinical study (NCT02576795). METHODS: Men ≥18 years of age with severe haemophilia A (FVIII ≤1 IU/dl) without history of FVIII inhibitors or anti-AAV5 antibodies received a single infusion of valoctocogene roxaparvovec and were followed for 5 years (6 × 1013 vg/kg dose, n = 7) and 4 years (4 × 1013 vg/kg dose, n = 6). RESULTS: Over the past 2 years, few adverse events and no FVIII inhibitors were reported. Per chromogenic substrate (CSA) assay at years 5 and 4, four of seven and three of six participants in the 6 × 1013 and 4 × 1013 vg/kg cohorts, respectively, maintained median FVIII levels >5 IU/dl, corresponding to mild haemophilia. By regression analysis, rate of change in FVIII activity was -0.14 (95% confidence interval [CI]: -.32 to .03) IU/dl/wk in the 6 × 1013 vg/kg cohort in year 5 and -.06 (95% CI: -.14 to .01) IU/dl/wk in the 4 × 1013 vg/kg cohort in year 4. No participants resumed FVIII prophylaxis, and eight of 13 participants reported zero bleeds in the past 2 years. Improved QOL from baseline persisted in the 6 × 1013 vg/kg cohort; all six Haemo-QOL-A domain scores increased. For the 4 × 1013 vg/kg cohort, high baseline Haemo-QOL-A scores persisted. CONCLUSION: These results demonstrate transgene expression and haemostatic response for up to 5 years in individuals with haemophilia A

1, 9-Pyrazoloanthrones Downregulate HIF-1α and Sensitize Cancer Cells to Cetuximab-Mediated Anti-EGFR Therapy

Cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR), is currently approved for the treatment of several types of solid tumors. We previously showed that cetuximab can inhibit hypoxia-inducible factor-1 alpha (HIF-1α) protein synthesis by inhibiting the activation of EGFR downstream signaling pathways including Erk, Akt, and mTOR. 1, 9-pyrazoloanthrone (1, 9 PA) is an anthrapyrazolone compound best known as SP600125 that specifically inhibits c-jun N-terminal kinase (JNK). Here, we report 1, 9 PA can downregulate HIF-1α independently of its inhibition of JNK. This downregulatory effect was abolished when the oxygen-dependent domain (ODD) of HIF-1α (HIF-1α-ΔODD, the domain responsible for HIF-1α degradation) was experimentally deleted or when the activity of HIF-1α prolyl hydroxylase (PHD) or the 26S proteasomal complex was inhibited, indicating that the 1, 9 PA downregulates HIF-1α by promoting PHD-dependent HIF-1α degradation. We found that the combination of 1, 9 PA and cetuximab worked synergistically to induce apoptosis in cancer cells in which cetuximab or 1, 9 PA alone had no or only weak apoptotic activity. This synergistic effect was substantially decreased in cancer cells transfected with HIF-1α-ΔODD, indicating that downregulation of HIF-1α was the mechanism of this synergistic effect. More importantly, 1, 9 PA can downregulate HIF-1α in cancer cells that are insensitive to cetuximab-induced inhibition of HIF-1α expression due to overexpression of oncogenic Ras (RasG12V). Our findings suggest that 1, 9 PA is a lead compound of a novel class of drugs that may be used to enhance the response of cancer cells to cetuximab through a complementary effect on the downregulation of HIF-1α

Differential responses to doxorubicin-induced phosphorylation and activation of Akt in human breast cancer cells

INTRODUCTION: We have shown previously that overexpression of constitutively active Akt or activation of Akt caused by constitutively active Ras or human epidermal growth factor receptor-2 (HER2) confers on breast cancer cells resistance to chemotherapy or radiotherapy. As an expanded study we here report differential responses in terms of phosphorylation and activation of Akt as a result of treatment with doxorubicin in a panel of breast cancer cell lines. METHODS: The levels of Akt phosphorylation and activity were measured by Western blot analysis with an anti-Ser473-phosphorylated Akt antibody and by in vitro Akt kinase assay using glycogen synthase kinase-3 as a substrate. RESULTS: Within 24 hours after exposure to doxorubicin, MCF7, MDA468 and T47D cells showed a drug-dose-dependent increase in the levels of phosphorylated Akt; in contrast, SKBR3 and MDA231 cells showed a decrease in the levels of phosphorylated Akt, and minimal or no changes were detected in MDA361, MDA157 and BT474 cells. The doxorubicin-induced Akt phosphorylation was correlated with increased kinase activity and was dependent on phosphoinositide 3-kinase (PI3-K). An increased baseline level of Akt was also found in MCF7 cells treated with ionizing radiation. The cellular responses to doxorubicin-induced Akt phosphorylation were potentiated after the expression of Akt upstream activators including HER2, HER3 and focal adhesion kinase. CONCLUSION: Taken together with our recent published results showing that constitutive Akt mediates resistance to chemotherapy or radiotherapy, our present data suggest that the doxorubicin-induced phosphorylation and activation of Akt might reflect a cellular defensive mechanism of cancer cells to overcome doxorubicin-induced cytotoxic effects, which further supports the current efforts of targeting PI3-K/Akt for enhancing the therapeutic responses of breast cancer cells to chemotherapy and radiotherapy

Vibration analysis of undersea pipelines with arbitrary bedding conditions

Offshore pipelines have been used extensively to transport hydrocarbons across seabeds. They serve as a critical link between storage units and offshore fields. The consequences of pipeline failure would be severe both economically and environmentally. Offshore oil and gas pipelines are being subjected to deeper water depths, more extreme environmental conditions, and harsher operating requirements than ever before. Given these conditions, free spanning pipelines are becoming more common and are often unavoidable during pipeline installation. Free spans occur as a result of irregular seafloor topography at installation or during pipeline operation as a result of vibration and scour. The pipeline with tree span or regional and local scour will suffer fatigue damage due to oscillatory loads induced by vortex shedding. In this paper, a general solution of the vibration of a pipeline system with arbitrary type of discontinuity at arbitrary number of locations is presented. The pipeline on the seabed is simplified as a simply supported beam on elastic foundation. Two parameters are used to describe the scour or free span in the pipeline that are the central location of the scour or span and the width of the scour or span. Due to the generic nature of the solution and the problem, the present method can be utilized in structural health monitoring of the underwater pipeline system

Enhancement Mechanism of Pt/Pd-Based Catalysts for Oxygen Reduction Reaction

The oxygen reduction reaction (ORR) is one of the key catalytic reactions for hydrogen fuel cells, biofuel cells and metal–air cells. However, due to the complex four-electron catalytic process, the kinetics of the oxygen reduction reaction are sluggish. Platinum group metal (PGM) catalysts represented by platinum and palladium are considered to be the most active ORR catalysts. However, the price and reserves of Pt/Pd are major concerns and issues for their commercial application. Improving the catalytic performance of PGM catalysts can effectively reduce their loading and material cost in a catalytic system, and they will be more economical and practical. In this review, we introduce the kinetics and mechanisms of Pt/Pd-based catalysts for the ORR, summarize the main factors affecting the catalytic performance of PGMs, and discuss the recent progress of Pt/Pd-based catalysts. In addition, the remaining challenges and future prospects in the design and improvement of Pt/Pd-based catalysts of the ORR are also discussed

Dynamic field monitoring data analysis of an ancient wooden building in seismic and operational environments

The engineering background of this article is an ancient wooden building with extremely high historic and cultural values in Tibet. A full understanding of the dynamic behaviour of this historic building under in-service environments is the basis to assess the condition of the structure, especially its responses to earthquake, environmental and operational loading. A dynamic monitoring system has been installed in the building for over one year and the large amounts of high quality data have been obtained. The paper aims at studying the dynamic behaviour of the wooden building in seismic and operational conditions using the field monitoring data. Specifically the effects of earthquake and crowd loading on the structure's dynamic response are investigated. The monitoring data are decomposed into principal components using the Singular Spectrum Analysis (SSA) technique. The relationship between the average acceleration amplitude and frequencies of the principle components and operational conditions has been discussed. One main contribution is to understand the health condition of complex ancient building based on large databases collected on the field

Recent Progress of Energy-Storage-Device-Integrated Sensing Systems

With the rapid prosperity of the Internet of things, intelligent human–machine interaction and health monitoring are becoming the focus of attention. Wireless sensing systems, especially self-powered sensing systems that can work continuously and sustainably for a long time without an external power supply have been successfully explored and developed. Yet, the system integrated by energy-harvester needs to be exposed to a specific energy source to drive the work, which provides limited application scenarios, low stability, and poor continuity. Integrating the energy storage unit and sensing unit into a single system may provide efficient ways to solve these above problems, promoting potential applications in portable and wearable electronics. In this review, we focus on recent advances in energy-storage-device-integrated sensing systems for wearable electronics, including tactile sensors, temperature sensors, chemical and biological sensors, and multifunctional sensing systems, because of their universal utilization in the next generation of smart personal electronics. Finally, the future perspectives of energy-storage-device-integrated sensing systems are discussed

Recent Progress of Energy-Storage-Device-Integrated Sensing Systems

With the rapid prosperity of the Internet of things, intelligent human&ndash;machine interaction and health monitoring are becoming the focus of attention. Wireless sensing systems, especially self-powered sensing systems that can work continuously and sustainably for a long time without an external power supply have been successfully explored and developed. Yet, the system integrated by energy-harvester needs to be exposed to a specific energy source to drive the work, which provides limited application scenarios, low stability, and poor continuity. Integrating the energy storage unit and sensing unit into a single system may provide efficient ways to solve these above problems, promoting potential applications in portable and wearable electronics. In this review, we focus on recent advances in energy-storage-device-integrated sensing systems for wearable electronics, including tactile sensors, temperature sensors, chemical and biological sensors, and multifunctional sensing systems, because of their universal utilization in the next generation of smart personal electronics. Finally, the future perspectives of energy-storage-device-integrated sensing systems are discussed