Bioengineering and biomechanical approaches for pancreatic cancer

Pancreatic cancer is the fourth-leading cause of cancer related mortality and is predicted to be the second leading cause of cancer death by 2030. A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is dense fibrotic stroma surrounding the tumor, composed of extracellular matrix (ECM) and cells such as myofibroblasts. The properties of this stroma and functional contribution to carcinogenesis and disease progression has been the subject of intense focus in the past decade; yet, the role of mechanobiology in modulating the phenotype of immune cells in the tumor microenvironment remains to be elucidated. Although a lack of understanding PDAC etiology and progression limits effective treatments that can be deployed by clinicians, current methods of diagnosing PDAC likely are insufficient even if such treatments exist, especially if there is a narrow early window for drug efficacy. Recently, however, extracellular vesicles have emerged as powerful circulating blood biomarkers, thus paving the way for a new era of non-invasive cancer diagnostics. However, currently the process of extracellular vesicle isolation and detection is not only highly inefficient, but also technically challenging. This thesis describes bioengineering tools and biomechanical investigations of pancreatic cancer. In Chapter 2, the biomechanical phenotype of macrophages is studied in context of a stromal modulation agent, the chemotherapeutic drug tamoxifen. Tamoxifen was found to regulate macrophage focal adhesion dynamics, cytoskeletal activity, migratory behavior, and expression of TLR4. In Chapter 3, a novel microfluidic device was modeled and built to determine cell adhesion strength with potential applications to investigate regulation of focal adhesion structure by candidate drugs. Chapter 4 describes the development of methods and devices for isolation and detection of extracellular vesicles using acoustophoresis and a graphene field effect transistor, respectively. Such tools and perspectives could serve to detect PDAC earlier as well as identify and test new therapies.Open Acces

Extending political participation in China: new opportunities for citizens in the policy process

Authoritarian political systems are portrayed as offering few opportunities for citizens to participate in politics – particularly in the policy process. This paper’s contribution is to set out new mechanisms that enable Authoritarian political systems are portrayed as offering few opportunities for citizens to participate in politics – particularly in the policy process. This paper’s contribution is to set out new mechanisms that enable Chinese citizens to evaluate government performance, contribute to decision-making, shape policy agendas and feed back on implementation. Based on fieldwork in the city of Hangzhou, we argue that the local party-state orchestrates citizen participation in the policy process, but members of the public nevertheless do have influence. Political participation is widening in China, but it is still controlled. It is not yet clearly part of a process of democratization, but it does establish the principle of citizen rights to oversee the government

Cytosolic calcium and protein kinase C reduce complement-mediated glomerular epithelial injury

Cytosolic calcium and protein kinase C reduce complement-mediated glomerular epithelial injury. In rat membranous nephropathy, proteinuria is due to formation of the C5b-9 membrane attack complex of complement (C), and is associated with morphological evidence of glomerular epithelial cell (GEC) injury. Analogous morphological changes are induced by C5b-9 in cultured GEC. In addition, in cultured GEC C5b-9 induces Ca2+ influx, as well as Ca2+ mobilization and increased 1,2-diacylglycerol due to the activation of phospholipase C. In this study we investigated how this GEC activation pattern might influence C-mecliated GEC injury. We demonstrate that the C5b-9-induced increase in cytosolic Ca2+ concentration ([Ca2+]i) did not impair ATP generation by mitochondria, suggesting that it does not contribute to cytotoxicity. Moreover, this increase in [Ca2+]i protected GEC from C-mediated cytolysis. However, a large increase in [Ca2+]i (produced by the Ca2+ ionophore A23187) impaired ATP generation and aggravated C-mediated cytotoxicity, suggesting that intact mitochondrial activity is necessary for GEC to withstand C attack. Activation of protein kinase C (PKC) by phorbol myristate acetate (PMA) also decreased C-mediated cytolysis. Conversely, C lysis was enhanced in GEC that had been pretreated for 18 hours with a high dose of PMA to deplete PKC, and following PKC inhibition with H-7. Therefore, PKC activation, possibly resulting from C5b-9-induced increase in 1,2-diacylglycerol, triggered mechanisms that protected GEC from C-mediated injury. Thus, as a consequence of C5b-9-induced phospholipase activation, the amount of C-induced GEC injury is diminished

China’s Artificial Intelligence Innovation:A Top-Down National Command Approach?

China’s open embracing of the age of artificial intelligence (AI) has attracted considerable academic and media attention. Many argue that China has taken advantage of its national approach to contest for AI supremacy and geopolitical dominance. The relevant analyses assume China’s AI plans as being Beijing’s coherent top‐down geopolitically driven national strategy, reflecting Chinese leaders’ global ambitions. This article argues that these views are mistaken. It argues that China’s AI plans are primarily driven by contestation and the struggle for resources among domestic stakeholders who are economically motivated and have little awareness of the bigger geopolitical picture. Instead of a top‐down command approach, China’s national AI plan is an upgrade of existing local AI initiatives to the national level, reflecting a bottom‐up development. This article suggests that the existing analyses vastly exaggerate: (1) Beijing’s capacity to coordinate domestic capital and actors towards a unified, specific strategic objective; and (2) the extent of China’s AI advancement and its geopolitical threat, triggering unnecessary anxiety among China’s near competitors

Why do authoritarian regimes provide public goods? Policy communities, external shocks and ideas in China’s rural social policy making

Recent research on authoritarian regimes argues that they provide public goods in order to prevent rebellion. This essay shows that the ‘threat of rebellion’ alone cannot explain Chinese party-state policies to extend public goods to rural residents in the first decade of the twenty-first century. Drawing on theories of policy making, it argues that China’s one-party regime extended public goods to the rural population under the influence of ideas and policy options generated by policy communities of officials, researchers, international organisations and other actors. The party-state centre adopted and implemented these ideas and policy options when they provided solutions to external shocks and supported economic development goals. Explanations of policies and their outcomes in authoritarian political systems need to include not only ‘dictators’ but also other actors, and the ideas they generate

Tamoxifen mechanically reprograms the tumor microenvironment via HIF‐1A and reduces cancer cell survival

The tumor microenvironment is fundamental to cancer progression, and the influence of its mechanical properties is increasingly being appreciated. Tamoxifen has been used for many years to treat estrogen‐positive breast cancer. Here we report that tamoxifen regulates the level and activity of collagen cross‐linking and degradative enzymes, and hence the organization of the extracellular matrix, via a mechanism involving both the G protein‐coupled estrogen receptor (GPER) and hypoxia‐inducible factor‐1 alpha (HIF‐1A). We show that tamoxifen reduces HIF‐1A levels by suppressing myosin‐dependent contractility and matrix stiffness mechanosensing. Tamoxifen also downregulates hypoxia‐regulated genes and increases vascularization in PDAC tissues. Our findings implicate the GPER/HIF‐1A axis as a master regulator of peri‐tumoral stromal remodeling and the fibrovascular tumor microenvironment and offer a paradigm shift for tamoxifen from a well‐established drug in breast cancer hormonal therapy to an alternative candidate for stromal targeting strategies in PDAC and possibly other cancers.See also: E Cortes et al (January 2019) andM Pein & T Oskarsson (January 2019)EMBO Reports (2019) 20: e46557Peer reviewe

Weapons of the Powerful: Authoritarian Elite Competition and Politicized Anticorruption in China

What motivates authoritarian regimes to crack down on corruption? We argue that just as partisan competition in democracies tends to politicize corruption, authoritarian leaders may exploit anticorruption campaigns to target rival supporters during internal power struggles for consolidating their power base. We apply this theoretical framework to provincial leadership turnover in China and test it using an anticorruption data set. We find that intraelite power competition, captured by the informal power configuration of government incumbents and their predecessors, can increase investigations of corrupt senior officials by up to 20%. The intensity of anticorruption propaganda exhibits a similar pattern. The findings indicate that informal politics can propel strong anticorruption drives in countries without democratically-accountable institutions, although the drives tend to be selective, arbitrary, and factionally biased.postprin

Molecular imaging of cell death in vivo by a novel small molecule probe

Apoptosis has a role in many medical disorders, therefore assessment of apoptosis in vivo can be highly useful for diagnosis, follow-up and evaluation of treatment efficacy. ApoSense is a novel technology, comprising low molecular-weight probes, specifically designed for imaging of cell death in vivo. In the current study we present targeting and imaging of cell death both in vitro and in vivo, utilizing NST-732, a member of the ApoSense family, comprising a fluorophore and a fluorine atom, for both fluorescent and future positron emission tomography (PET) studies using an 18F label, respectively. In vitro, NST-732 manifested selective and rapid accumulation within various cell types undergoing apoptosis. Its uptake was blocked by caspase inhibition, and occurred from the early stages of the apoptotic process, in parallel to binding of Annexin-V, caspase activation and alterations in mitochondrial membrane potential. In vivo, NST-732 manifested selective uptake into cells undergoing cell-death in several clinically-relevant models in rodents: (i) Cell-death induced in lymphoma by irradiation; (ii) Renal ischemia/reperfusion; (iii) Cerebral stroke. Uptake of NST-732 was well-correlated with histopathological assessment of cell-death. NST-732 therefore represents a novel class of small-molecule detectors of apoptosis, with potential useful applications in imaging of the cell death process both in vitro and in vivo

Microvesicles Derived from Mesenchymal Stem Cells Enhance Survival in a Lethal Model of Acute Kidney Injury

Several studies demonstrated that treatment with mesenchymal stem cells (MSCs) reduces cisplatin mortality in mice. Microvesicles (MVs) released from MSCs were previously shown to favor renal repair in non lethal toxic and ischemic acute renal injury (AKI). In the present study we investigated the effects of MSC-derived MVs in SCID mice survival in lethal cisplatin-induced AKI. Moreover, we evaluated in vitro the effect of MVs on cisplatin-induced apoptosis of human renal tubular epithelial cells and the molecular mechanisms involved. Two different regimens of MV injection were used. The single administration of MVs ameliorated renal function and morphology, and improved survival but did not prevent chronic tubular injury and persistent increase in BUN and creatinine. Multiple injections of MVs further decreased mortality and at day 21 surviving mice showed normal histology and renal function. The mechanism of protection was mainly ascribed to an anti-apoptotic effect of MVs. In vitro studies demonstrated that MVs up-regulated in cisplatin-treated human tubular epithelial cells anti-apoptotic genes, such as Bcl-xL, Bcl2 and BIRC8 and down-regulated genes that have a central role in the execution-phase of cell apoptosis such as Casp1, Casp8 and LTA. In conclusion, MVs released from MSCs were found to exert a pro-survival effect on renal cells in vitro and in vivo, suggesting that MVs may contribute to renal protection conferred by MSCs

Lost in Translation? Accountability and Governance of Clinical Stem Cell Research in China

Despite China’s regulatory initiatives to promote its research accountability, it still needs to prove itself as a trusted player in life science research. In addition, in contrast to its huge investment, China is losing the race in delivering quality application of stem cells. The trial implementation of the 2015 ministerial regulations seemed to offer hope in ending this dual ‘lost-in-translation’. Yet skepticism remains. By examining China’s regulatory trajectory in the last 15 years, this paper illustrates that it is a post-hoc pragmatic policy rationale and a soft centralisation regulatory approach that have hampered China’s governance. To improve China’s governance of accountability, policy-makers need to get beyond an ‘act-in-response’ regulatory ethos and engage with diverse stakeholders