Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy.

The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK:

NAD+ depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition.

Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.

PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance.

Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.

Factors influencing migration of short-finned eels (Anguilla australis) over 3 years from a wetland system, Lake Condah, south-east Australia, downstream to the sea.

Anguillid eel populations are under threat globally. A particularly vulnerable life-cycle stage is the migration of mature adult eels downstream from freshwater habitats through estuaries into the sea to spawn. This study investigated the factors associated with downstream migration of the short-finned eel Anguilla australis (Richardson 1841) from a coastal wetland (Lake Condah) in south-east Australia, using acoustic telemetry. Migration was associated with time of the year, higher water level and river flows, decreasing water temperature, and darker moon phases. Larger individuals and those in better condition were more likely to migrate from the wetland. Downstream migration peaked in spring, in contrast to the typical autumn migration period for other temperate anguillids. Variable responses, in comparison to other studies, highlight how migration cues may not be universal. In south-east Australia, short-finned eels may have evolved to migrate in multiple phases by first migrating to the estuary during typical seasonal spring flow pulses (e.g., to avoid being stranded in upland reaches during dry summer periods) and then migrating into the ocean in autumn. More research is needed to unravel these processes and causes, especially considering that the relationship between migration and hydrology may be complex and confounded (e.g., by human-induced disruptions to migratory pathways).

Construction of a radiogenomic association map of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) persists as a malignancy with high morbidity and mortality that can benefit from new means to characterize and detect these tumors, such as radiogenomics. In order to address this gap in the literature, constructed a transcriptomic-CT radiogenomic (RG) map for PDAC. METHODS: In this Institutional Review Board approved study, a cohort of subjects (n = 50) with gene expression profile data paired with histopathologically confirmed resectable or borderline resectable PDAC were identified. Studies with pre-operative contrast-enhanced CT images were independently assessed for a set of 88 predefined imaging features. Microarray gene expression profiling was then carried out on the histopathologically confirmed pancreatic adenocarcinomas and gene networks were constructed using Weighted Gene Correlation Network Analysis (WCGNA) (n = 37). Data were analyzed with bioinformatics analyses, multivariate regression-based methods, and Kaplan-Meier survival analyses. RESULTS: Survival analyses identified multiple features of interest that were significantly associated with overall survival, including Tumor Height (P = 0.014), Tumor Contour (P = 0.033), Tumor-stroma Interface (P = 0.014), and the Tumor Enhancement Ratio (P = 0.047). Gene networks for these imaging features were then constructed using WCGNA and further annotated according to the Gene Ontology (GO) annotation framework for a biologically coherent interpretation of the imaging trait-associated gene networks, ultimately resulting in a PDAC RG CT-transcriptome map composed of 3 stage-independent imaging traits enriched in metabolic processes, telomerase activity, and podosome assembly (P < 0.05). CONCLUSIONS: A CT-transcriptomic RG map for PDAC composed of semantic and quantitative traits with associated biology processes predictive of overall survival, was constructed, that serves as a reference for further mechanistic studies for non-invasive phenotyping of pancreatic tumors.

Overexpression of laminin-5 gamma-2 promotes tumorigenesis of pancreatic ductal adenocarcinoma through EGFR/ERK1/2/AKT/mTOR cascade.

Pancreatic ductal adenocarcinoma (PDAC) is correlated with poor outcomes because of limited therapeutic options. Laminin-5 gamma-2 (LAMC2) plays a critical role in key biological processes. However, the detailed molecular mechanism and potential roles of LAMC2 in PDAC stay unexplored. The present study examines the essential role and molecular mechanisms of LAMC2 in the tumorigenesis of PDAC. Here, we identified that LAMC2 is significantly upregulated in microarray cohorts and TCGA RNA sequencing data of PDAC patients compared to non-cancerous/normal tissues. Patients with higher transcript levels of LAMC2 were correlated with clinical stages; dismal overall, as well as, disease-free survival. Additionally, we confirmed significant upregulation of LAMC2 in a panel of PDAC cell lines and PDAC tumor specimens in contrast to normal pancreatic tissues and cells. Inhibition of LAMC2 significantly decreased cell growth, clonogenic ability, migration and invasion of PDAC cells, and tumor growth in the PDAC xenograft model. Mechanistically, silencing of LAMC2 suppressed expression of ZEB1, SNAIL, N-cadherin (CDH2), vimentin (VIM), and induced E-cadherin (CDH1) expression leading to a reversal of mesenchymal to an epithelial phenotype. Interestingly, co-immunoprecipitation experiments demonstrated LAMC2 interaction with epidermal growth factor receptor (EGFR). Further, stable knockdown of LAMC2 inhibited phosphorylation of EGFR, ERK1/2, AKT, mTOR, and P70S6 kinase signaling cascade in PDAC cells. Altogether, our findings suggest that silencing of LAMC2 inhibited PDAC tumorigenesis and metastasis through repression of epithelial-mesenchymal transition and modulation of EGFR/ERK1/2/AKT/mTOR axis and could be a potential diagnostic, prognostic, and therapeutic target for PDAC.

Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation.

Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a "ductal-like" state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo "ductal retrogression" to form IPMN-PDA. We further identify critical antagonistic roles for Brahma-related gene 1 (Brg1), a catalytic subunit of the SWI/SNF complexes, during IPMN-PDA development. In mature duct cells, Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We further show that JQ1, a drug that is currently being tested in clinical trials for hematological malignancies, impairs PDA tumorigenesis by both mimicking some and inhibiting other Brg1-mediated functions. In summary, our study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA.

Society for Vascular Surgery appropriate use criteria for management of intermittent claudication.

The Society for Vascular Surgery appropriate use criteria (AUC) for the management of intermittent claudication were created using the RAND appropriateness method, a validated and standardized method that combines the best available evidence from medical literature with expert opinion, using a modified Delphi process. These criteria serve as a framework on which individualized patient and clinician shared decision-making can grow. These criteria are not absolute. AUC should not be interpreted as a requirement to administer treatments rated as appropriate (benefit outweighs risk). Nor should AUC be interpreted as a prohibition of treatments rated as inappropriate (risk outweighs benefit). Clinical situations will occur in which moderating factors, not included in these AUC, will shift the appropriateness level of a treatment for an individual patient. Proper implementation of AUC requires a description of those moderating patient factors. For scenarios with an indeterminate rating, clinician judgement combined with the best available evidence should determine the treatment strategy. These scenarios require mechanisms to track the treatment decisions and outcomes. AUC should be revisited periodically to ensure that they remain relevant. The panelists rated 2280 unique scenarios for the treatment of intermittent claudication (IC) in the aortoiliac, common femoral, and femoropopliteal segments in the round 2 rating. Of these, only nine (0.4%) showed a disagreement using the interpercentile range adjusted for symmetry formula, indicating an exceptionally high degree of consensus among the panelists. Post hoc, the term "inappropriate" was replaced with the phrase "risk outweighs benefit." The term "appropriate" was also replaced with "benefit outweighs risk." The key principles for the management of IC reflected within these AUC are as follows. First, exercise therapy is the preferred initial management strategy for all patients with IC. Second, for patients who have not completed exercise therapy, invasive therapy might provide net a benefit for selected patients with IC who are nonsmokers, are taking optimal medical therapy, are considered to have a low physiologic and technical risk, and who are experiencing severe lifestyle limitations and/or a short walking distance. Third, considering the long-term durability of the currently available technology, invasive interventions for femoropopliteal disease should be reserved for patients with severe lifestyle limitations and a short walking distance. Fourth, in the common femoral segment, open common femoral endarterectomy will provide greater net benefit than endovascular intervention for the treatment of IC. Finally, in the infrapopliteal segment, invasive intervention for the treatment of IC is of unclear benefit and could be harmful.

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity.

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor survival and resistance to conventional therapies. PI3K signaling is implicated in both disease initiation and progression, and specific inhibitors of selected PI3K p110 isoforms for managing solid tumors are emerging. We demonstrate that increased activation of PI3K signals cooperates with oncogenic Kras to promote aggressive PDAC in vivo. The p110γ isoform is overexpressed in tumor tissue and promotes carcinogenesis via canonical AKT signaling. Its selective blockade sensitizes tumor cells to gemcitabine in vitro, and genetic ablation of p110γ protects against Kras-induced tumorigenesis. Diet/obesity was identified as a crucial means of p110 subunit up-regulation, and in the setting of a high-fat diet, p110γ ablation failed to protect against tumor development, showing increased activation of pAKT and hepatic damage. These observations suggest that a careful and judicious approach should be considered when targeting p110γ for therapy, particularly in obese patients.

Searching for laws of economics: causality, conservation, and ideology.

This review is intended for scientists who may be curious about "laws" of economics. Here, I search for laws governing value, including the value of money (inflation). I begin by searching out early scientists, e.g., Aristotle, Copernicus, and Galileo, who contributed to theories of value, or who, like Isaac Newton and J. Willard Gibbs, inspired students of political economy and thereby profoundly influenced the evolution of economic thinking. From a period ranging from Aristotle to John Stuart Mill in the mid-nineteenth century, I extract two candidates for "laws" of economics, one the well-known "law of supply and demand" (LSD) and the other, less well-known, "Fisher's equation of exchange" (FEE). LSD, in one form or another, has been central to the development of economic thought, but it has proven impossible to express LSD in any compact, deterministic form with causal implications. I propose, however, that, as suggested by Irving Fisher early in the twentieth century and 100 years later by Nobelist Thomas Schelling, FEE is analogous to the first law of thermodynamics (FLT). I argue that both FEE and FLT can be viewed as "accounting identities," pertaining to energies in the case of FLT and money in the case of FEE. Both, however, suffer from a similar limitation: neither provides any information concerning causal relations among the relevant variables. I reflect upon the impact of the absence of firm, fact-based, economic laws with causal implications on modern economic policy, allowing it to be dominated by ideologies damaging to American society.

Poorly differentiated histologic grade correlates with worse survival in SMAD4 negative pancreatic adenocarcinoma patients.

BACKGROUND AND OBJECTIVES: This study investigated the influence of the transcription factor SMAD4 on overall patient survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC). METHODS: The SMAD4 status of 125 surgically resected PDAC specimens at a large academic center from 2014 to 2017 was routinely determined prospectively and correlated with clinicopathologic characteristics and overall survival. RESULTS: SMAD4 loss was identified in 62% of patients and was not associated with overall survival (OS). On multivariate Cox proportional hazards survival analysis, histologic grade was the best predictor of survival in the SMAD4(-) population (adjusted hazard ratio = 4.8, p < .0001). In the SMAD4(+) population, histologic grade was not associated with survival on multivariate analysis. In the SMAD4(-) population, median OS for well/moderately differentiated patients and poorly differentiated patients was 39.6 and 8.6 months, respectively. CONCLUSION: In this large cohort of resected PDAC, routine SMAD4 assessment identified a subpopulation of patients with SMAD4(-) and histologically poorly differentiated tumors that had significantly poor prognosis with median OS of 8.6 months. Characterization of the role of SMAD4 within the context of poorly differentiated tumors may help settle the controversy regarding SMAD4 in PDAC and lead to identification of personalized therapeutic strategies for subgroups of PDAC.

Intestinal mucormycosis initially identified by next-generation sequencing of cell-free DNA.

Mucormycosis is a rare fungal infection that typically affects severely immunocompromised individuals, often resulting in significant morbidity and mortality. Although early and aggressive intervention is necessary to prevent poor outcomes, diagnosis of this infection remains difficult. We report the first case, to our knowledge, of invasive gastrointestinal mucormycosis initially identified by next-generation sequencing of cfDNA from the blood, and discuss the various benefits and challenges which come with new molecular diagnostic techniques.

The urbanisation-environment conflict: Insights from material stock and productivity of transport infrastructure in Hanoi, Vietnam.

Developing regions experience rapid population growth and urbanisation, which require large quantities of materials for civil infrastructure. The production of construction materials, especially for urban transport systems, however, contributes to local and global environmental change. Political agendas may overlook the environmental implications of urban expansion, as economic growth tends to be prioritised. While elevating the standard of living is imperative, decision-making without careful environmental assessments can undermine the overall welfare of society. In this study, we evaluate the material demand and in-use stock productivity for the large-scale development plan for transport infrastructure in the city of Hanoi, Vietnam, from 2010 to 2030, combining geospatial and socioeconomic data with statistics on roads and railways. The results show that the total material stock could rise threefold from 66 Tg in 2010 to 269 Tg in 2030, which roughly translates to an addition of 30 Empire State Buildings per year by mass. The materials we account are required for construction exceed the availability of local sand and will need to be gathered farther away. Furthermore, the material stock productivity of the transport infrastructure appears to have been declining overall since 2010, and this trend may continue to 2030. These findings demonstrate the importance of informing urban planning with a comprehensive assessment of construction materials demand, supply capacity, and environmental impacts. Policy priorities for improving the in-use stock productivity are also recommended towards achieving a more efficient utilisation of natural resources.

Review: The effectiveness of Theraplay for children under 12 - a systematic literature review.

BACKGROUND: Theraplay is a relationship-focused model of treatment based on attachment theory involving both adult and child. The study aims to review the quality of Theraplay research and Theraplay's effectiveness for children aged 12 years and under with a range of presenting difficulties, to inform future practice and identify areas for further research. METHODS: A systematic literature search was conducted using PsycINFO, CINAHL, MEDLINE and Web of Science. Quantitative studies using Theraplay only as a treatment for children aged 12 years and under with any presenting difficulty were identified. Additional manual searching was conducted, including eligible studies' reference lists. Critical appraisal tools were used to provide a narrative synthesis of Theraplay's effectiveness and research quality. RESULTS: Only six eligible articles were identified, meaning there was a lack of rigorous evidence eligible to offer conclusions into Theraplay's effectiveness. The review highlighted the small evidence base, mixed quality research methodology and high levels of heterogeneity in how Theraplay is practiced and evaluated. Of the eligible studies, Theraplay was found promising in its effectiveness when used with internalising and externalising difficulties, dual diagnoses and developmental disabilities. CONCLUSIONS: Theraplay is regularly practiced across the world; however, the evidence base of rigorous research to inform Theraplay's effectiveness and mechanisms of change is lacking. Firm conclusions could not be offered, although Theraplay was shown to be promising intervention for some presentations. Further research into Theraplay's effectiveness and key mechanisms of change are recommended to enhance the quality and depth of Theraplay literature.

Identification of the Active Catalyst for Nickel-Catalyzed Stereospecific Kumada Coupling Reactions of Ethers.

A series of nickel complexes in varying oxidation states were evaluated as precatalysts for the stereospecific cross-coupling of benzylic ethers. These results demonstrate rapid redox reactions of precatalysts, such that the oxidative state of the precatalyst does not dictate the oxidation state of the active catalyst in solution. These data provide the first experimental evidence for a Ni0 -NiII catalytic cycle for a stereospecific alkyl-alkyl cross-coupling reaction, including spectroscopic analysis of the catalyst resting state.

Interpretation of peripheral arterial and venous Doppler waveforms: A consensus statement from the Society for Vascular Medicine and Society for Vascular Ultrasound.

This expert consensus statement on the interpretation of peripheral arterial and venous spectral Doppler waveforms was jointly commissioned by the Society for Vascular Medicine (SVM) and the Society for Vascular Ultrasound (SVU). The consensus statement proposes a standardized nomenclature for arterial and venous spectral Doppler waveforms using a framework of key major descriptors and additional modifier terms. These key major descriptors and additional modifier terms are presented alongside representative Doppler waveforms, and nomenclature tables provide context by listing previous alternate terms to be replaced by the new major descriptors and modifiers. Finally, the document reviews Doppler waveform alterations with physiologic changes and disease states, provides optimization techniques for waveform acquisition and display, and provides practical guidance for incorporating the proposed nomenclature into the final interpretation report.

A spatial framework to explore needs and opportunities for interoperable urban flood management.

Managing current and future urban flood risks must consider the connection (i.e. interoperability) between existing (and new) infrastructure systems to manage stormwater (pluvial flooding). Yet, due to a lack of systematic approaches to identify interoperable flood management interventions, opportunities are missed to combine investments of existing infrastructure (e.g. drainage, roads, land use and buildings) with blue-green infrastructure (e.g. sustainable urban drainage systems, green roofs, green spaces). In this study, a spatial analysis framework is presented combining hydrodynamic modelling with spatial information on infrastructure systems to provide strategic direction for systems-level urban flood management (UFM). The framework is built upon three categories of data: (i) flood hazard areas (i.e. characterize the spatial flood problem); (ii) flood source areas (i.e. areas contributing the most to surface flooding); (iii) the interoperable potential of different systems (i.e. which infrastructure systems can contribute to water management functions). Applied to the urban catchment of Newcastle-Upon-Tyne (UK), the study illustrates the novelty of combining spatial data sources in a systematic way, and highlights the spatial (dis)connectivity in terms of flood source areas (where most of the flood management intervention is required) and the benefit areas (where most of the reduction in flooding occurs). The framework provides a strategic tool for managing stormwater pathways from an interoperable perspective that can help city-scale infrastructure development that considers UFM across multiple systems. This article is part of the theme issue 'Urban flood resilience'.

Habitat use, movement and activity of two large-bodied native riverine fishes in a regulated lowland weir pool.

The construction of dams and weirs, and associated changes to hydrological and hydraulic (e.g., water level and velocity) characteristics of rivers is a key environmental threat for fish. These multiple stressors potentially can affect fish in a variety of ways, including by causing changes in their movement, habitat use and activity. Understanding how and why these changes occur can inform management efforts to ameliorate these threats. In this context, we used acoustic telemetry to examine habitat use, longitudinal movement and activity of two lowland river fishes, Murray cod Maccullochella peelii and golden perch Macquaria ambigua, in a weir pool environment in south-eastern Australia. We compared our results to published studies on riverine populations to determine if their behaviours are similar (or not). We show that M. peelii and M. ambigua in a weir pool exhibited some similar behaviours to conspecific riverine populations, such as strong site fidelity and use of woody habitat for M. ambigua. However, some behaviours, such as large-scale (tens-hundreds of kilometres) movements documented for riverine populations, were rarely observed. These differences potentially reflect flow regulation (e.g., stable water levels, loss of hydraulic cues) in the weir pool. The two species also exhibited contrasting responses to dissolved oxygen conditions in the weir pool, which may reflect differences in their life history. Overall, this study shows that although some aspects of these two native fishes' life history can continue despite flow regulation, other aspects may change in weir pools, potentially impacting on long-term population persistence.

Lysine methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming.

OBJECTIVE: Despite advances in the identification of epigenetic alterations in pancreatic cancer, their biological roles in the pathobiology of this dismal neoplasm remain elusive. Here, we aimed to characterise the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumourigenesis. DESIGN: DNA methylation sequencing and gene expression microarrays were employed to investigate CpG methylation and expression patterns of KMTs and KDMs in pancreatic cancer tissues versus normal tissues. Gene expression was assessed in five cohorts of patients by reverse transcription quantitative-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using an XF24-3 Analyzer, while quantitative evaluation of lipids was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumour growth in vivo. RESULTS: We define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer. KMT2D is transcriptionally repressed in human pancreatic tumours through DNA methylation. Clinically, lower levels of this methyltransferase associate with poor prognosis and significant weight alterations. RNAi-based genetic inactivation of KMT2D promotes tumour growth and results in loss of H3K4me3 mark. In addition, KMT2D inhibition increases aerobic glycolysis and alters the lipidomic profiles of pancreatic cancer cells. Further analysis of this phenomenon identified the glucose transporter SLC2A3 as a mediator of KMT2D-induced changes in cellular, metabolic and proliferative rates. CONCLUSION: Together our findings define a new tumour suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer.

Mitochondrial Dysfunction, Through Impaired Autophagy, Leads to Endoplasmic Reticulum Stress, Deregulated Lipid Metabolism, and Pancreatitis in Animal Models.

BACKGROUND & AIMS: Little is known about the signaling pathways that initiate and promote acute pancreatitis (AP). The pathogenesis of AP has been associated with abnormal increases in cytosolic Ca2+, mitochondrial dysfunction, impaired autophagy, and endoplasmic reticulum (ER) stress. We analyzed the mechanisms of these dysfunctions and their relationships, and how these contribute to development of AP in mice and rats. METHODS: Pancreatitis was induced in C57BL/6J mice (control) and mice deficient in peptidylprolyl isomerase D (cyclophilin D, encoded by Ppid) by administration of L-arginine (also in rats), caerulein, bile acid, or an AP-inducing diet. Parameters of pancreatitis, mitochondrial function, autophagy, ER stress, and lipid metabolism were measured in pancreatic tissue, acinar cells, and isolated mitochondria. Some mice with AP were given trehalose to enhance autophagic efficiency. Human pancreatitis tissues were analyzed by immunofluorescence. RESULTS: Mitochondrial dysfunction in pancreas of mice with AP was induced by either mitochondrial Ca2+ overload or through a Ca2+ overload-independent pathway that involved reduced activity of ATP synthase (80% inhibition in pancreatic mitochondria isolated from rats or mice given L-arginine). Both pathways were mediated by cyclophilin D and led to mitochondrial depolarization and fragmentation. Mitochondrial dysfunction caused pancreatic ER stress, impaired autophagy, and deregulation of lipid metabolism. These pathologic responses were abrogated in cyclophilin D-knockout mice. Administration of trehalose largely prevented trypsinogen activation, necrosis, and other parameters of pancreatic injury in mice with L-arginine AP. Tissues from patients with pancreatitis had markers of mitochondrial damage and impaired autophagy, compared with normal pancreas. CONCLUSIONS: In different animal models, we find a central role for mitochondrial dysfunction, and for impaired autophagy as its principal downstream effector, in development of AP. In particular, the pathway involving enhanced interaction of cyclophilin D with ATP synthase mediates L-arginine-induced pancreatitis, a model of severe AP the pathogenesis of which has remained unknown. Strategies to restore mitochondrial and/or autophagic function might be developed for treatment of AP.