Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic

Reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease (Ref-1/APE1) is a critical node in tumor cells, both as a redox regulator of transcription factor activation and as part of the DNA damage response. As a redox signaling protein, Ref-1/APE1 enhances the transcriptional activity of STAT3, HIF-1α, nuclear factor kappa B, and other transcription factors to promote growth, migration, and survival in tumor cells as well as inflammation and angiogenesis in the tumor microenvironment. Ref-1/APE1 is activated in a variety of cancers, including prostate, colon, pancreatic, ovarian, lung and leukemias, leading to increased aggressiveness. Transcription factors downstream of Ref-1/APE1 are key contributors to many cancers, and Ref-1/APE1 redox signaling inhibition slows growth and progression in a number of tumor types. Ref-1/APE1 inhibition is also highly effective when paired with other drugs, including standard-of-care therapies and therapies targeting pathways affected by Ref-1/APE1 redox signaling. Additionally, Ref-1/APE1 plays a role in a variety of other indications, such as retinopathy, inflammation, and neuropathy. In this review, we discuss the functional consequences of activation of the Ref-1/APE1 node in cancer and other diseases, as well as potential therapies targeting Ref-1/APE1 and related pathways in relevant diseases. APX3330, a novel oral anticancer agent and the first drug to target Ref-1/APE1 for cancer is entering clinical trials and will be explored in various cancers and other diseases bringing bench discoveries to the clinic

A German lawyer in the far east: Investing and doing business in China

Shortly after the end of the Cultural Revolution, some four decades ago, there were no passenger cars in China when Volkswagen AG started its negotiations inthis country. The country was poor and underdeveloped. Today, the GDP of China reached USD 17.6 billion compared to the US’ 17.4 billion USD. Car production in China is now more than 18 million cars per year, more than in the USA. Today, China is still a socialist country and its economic system is called ‘socialist market economy’ but there are about 50 million private companies, 400 million people are belonging to the middle class and there are about 800 super rich having more than 100 million USD on average. In this ‘sino-marxist’ country, there are even 130 multi billionaires in USD. No wonder that under these circumstances, joint ventures and wholly foreign-owned enterprises, especially also in the automotive industry, are welcome. Volkswagen started its negotiations with its Chinese partner, STAC (Shanghai Tractor and Automobile Investment Corporation), BoC (Bank of China) and CNAIC (China National Automotive Industry Corporation) in 1979. These negotiations ended in 1984 by setting up the ‘Shanghai-Volkswagen’ joint venture which started the production of the Santana in 1985. Some years later, in 1988, Volkswagen started the negotiations with FAW (First Automobile Work) in Changchun. These negotiations lasted much shorter and the second VW joint venture, ‘FAWVW’, started with the production of Jetta and Audi 100, 100, 000 cars per year in 1991.In 2004, the ‘Volkswagen Group China’ (VGC), a wholly VW-owned holding company was set up in Beijing in order to coordinate the VWparticipations, the sales and marketing of its joint ventures, the purchasing, personnel and governmental relations as well as finance. Today, VGC has, including its 16 subsidiaries, 95,000 employees, has built 30 million cars at 30 Chinese production sites and sold them by 5,000 dealers (with 330,000 employees). In 2016, VGC has built about 4 million cars

Environmental benefits of large‐scale second‐generation bioethanol production in the EU: an integrated supply chain network optimization and life cycle assessment approach

The use of agricultural residues for the generation of bioethanol has the potential to substitute fuels such as petrol or first‐generation bioethanol and thereby generate environmental benefits. Scientific research in this field typically confines the environmental dimension to global warming, disregarding other environmental impact and damage categories. By multi‐criteria mixed‐integer linear programming, this work examines environmental benefits and economic viability of optimal second‐generation bioethanol production network configurations to substitute petrol and/or first‐generation bioethanol in the EU. The results comprise environmentally optimal decisions for 18 impact and 3 damage categories, as well as economically optimal solutions for different excise and carbon tax scenarios. The impact categories global warming potential, particulate matter, and land use are affected the most. Optimal network decisions for different environmental objectives can be clustered into three groups of mutual congruencies, but opportunity costs between the different groups can be very high, indicating conflicting decisions. The decision to substitute petrol or first‐generation ethanol has the greatest influence. The results of the multi‐dimensional analysis suggest that the damage categories human health and ecosystem quality are suitable to unveil tradeoffs between conflicting environmental impacts, for example, global warming and land use. Taking human health and ecosystem quality as environmental decision criteria, second‐generation bioethanol should be used to concurrently substitute first‐generation bioethanol and petrol (100% and 18% of today's demand in the EU, respectively). However, economic optimization shows that with current taxation, bioethanol is hardly competitive with petrol, and that excise tax abatement or carbon taxes are needed to achieve these volumes. This article met the requirements for a gold‐gold JIE data openness badge described at http://jie.click/badges.Horizon 2020 Framework Programme http://dx.doi.org/10.13039/10001066

Role of artificial intelligence in diagnosing Barrett’s esophagus-related neoplasia

Barrett’s esophagus is associated with an increased risk of adenocarcinoma. Thorough screening during endoscopic surveillance is crucial to improve patient prognosis. Detecting and characterizing dysplastic or neoplastic Barrett’s esophagus during routine endoscopy are challenging, even for expert endoscopists. Artificial intelligence-based clinical decision support systems have been developed to provide additional assistance to physicians performing diagnostic and therapeutic gastrointestinal endoscopy. In this article, we review the current role of artificial intelligence in the management of Barrett’s esophagus and elaborate on potential artificial intelligence in the future

Endoscopic hemostasis state of the art - nonvariceal bleeding

New endoscopic techniques for hemostasis in nonvariceal bleeding were introduced and known methods further improved. Hemospray and Endoclot are two new compounds for topical treatment of bleeding. Initial studies in this area have shown a good hemostatic effect, especially in active large scale oozing bleeding, e.g., tumor bleedings. For further evaluation larger prospective studies comparing the substanced with other methods of endoscopic hemostasis are needed. For localized active arterial bleeding primary injection therapy in the area of ​​bleeding as well as in the four adjacent quadrants offers a good method to reduce bleeding activity. The injection is technically easy to learn and practicable. After bleeding activity is reduced the bleeding source can be localized more clearly for clip application. Today many different through-the-scope (TTS) clips are available. The ability to close and reopen a clip can aid towards good positioning at the bleeding site. Even more important is the rotatability of a clip before application. Often multiple TTS clips are required for secure closure of a bleeding vessel. One model has the ability to use three clips in series without changing the applicator. Severe arterial bleeding from vessels larger than 2 mm is often unmanageable with these conventional methods. Here is the over-the-scope-clip system another newly available method. It is similar to the ligation of esophageal varices and involves aspiration of tissue into a transparent cap before closure of the clip. Thus a greater vascular occlusion pressure can be achieved and larger vessels can be treated endoscopically. Patients with severe arterial bleeding from the upper gastrointestinal tract have a very high rate of recurrence after initial endoscopic treatment. These patients should always be managed in an interdisciplinary team of interventional radiologist and surgeons

Fostering proactive behaviour: The role of work‐related reflection, psychological empowerment, and participative safety for innovative behaviour and job crafting

This contribution aimed at investigating how work-related reflection as cognitive efforts towards developing an understanding of work tasks, the surrounding work context, and one's professional competencies adds to the role of psychological empowerment and participative safety in predicting innovative behaviour and job crafting as two forms of proactivity. Quantitative data from 295 employees of micro, small, and medium-sized organizations in the information sector were collected with a cross-sectional questionnaire. For hypotheses testing, structural equation modelling was employed. The results of the study showed that work-related reflection and psychological empowerment were substantially related to innovative behaviour and job crafting while participative safety only played a minor role. These findings imply that jobs need to contain empowering and sufficiently complex work tasks that require reflection and provide occasions for reflective interactions to enable employees to create efficient routines and adapt to changes at work. Furthermore, experiences of empowerment need to be rooted in social interactions at work. Likewise, the value of reflection will only unfold if employees and supervisors regularly engage in reflectio

Impedance planimetry-guided peroral endoscopic myotomy of the fundoplication valve

We present a novel approach involving impedance planimetry with the endoscopic functional lumen imaging probe (EndoFLIP) to guide peroral endoscopic myotomy of the fundoplication valve (FP-POEM)