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ObjectiveHere, we evaluate the contribution of AT-rich interaction domain-containing protein 1A (ARID1A), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models.DesignMice with a targeted deletion of Arid1a in the pancreas by itself and in the context of two common genetic alterations in PDAC, Kras and p53, were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes.Results Arid1a deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant Kras cooperates with homozygous deletion of Arid1a, leading to intraductal papillary mucinous neoplasm (IPMN). Arid1a loss in the context of mutant Kras and p53 leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from Arid1a-mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on Arid1a loss for dysregulation.ConclusionsARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN. Arid1a-deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.

Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA – including Kras, Tp53, Arid1a and Smad4 – as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations. Among commonly mutated genes in CCA, we found that Smad4 functions uniquely to restrict reactive cholangiocyte expansion to liver injury through restraint of the proliferative response. Inactivation of Smad4 accelerates carcinogenesis, provoking pre-neoplastic biliary lesions and CCA development in an injury setting. Expression analyses of Smad4-perturbed reactive cholangiocytes and CCA lines demonstrated shared enriched pathways, including cell-cycle regulation, MYC signaling and oxidative phosphorylation, suggesting that Smad4 may act via these mechanisms to regulate cholangiocyte proliferation and progression to CCA. Overall, we showed that TGFβ/SMAD4 signaling serves as a critical barrier restraining cholangiocyte expansion and malignant transformation in states of biliary injury.

This book is about the life of a navy, from its conception in the nineteenth century to its seventy-fifth birthday in 1985.

Neoliberalism and Commodity Production in Mexico details the impact of neoliberal practice on the production and exchange of basic resources in working-class communities in Mexico. Using anthropological investigations and a market-driven approach, contributors explain how uneven policies have undermined constitutional protections and working-class interests since the Mexican Revolution of 1910. Detailed ethnographic fieldwork shows how foreign investment, privatization, deregulation, and elimination of welfare benefits have devastated national industries and natural resources and threatened agriculture, driving the campesinos and working class deeper into poverty. Focusing on specific commodity chains and the changes to production and marketing under neoliberalism, the contributors highlight the detrimental impacts of policies by telling the stories of those most affected by these changes. They detail the complex interplay of local and global forces, from the politically mediated systems of demand found at the local level to the increasingly powerful municipal and state governments and the global trade and banking institutions. Sharing a common theoretical perspective and method throughout the chapters, Neoliberalism and Commodity Production in Mexico is a multi-sited ethnography that makes a significant contribution to studies of neoliberal ideology in practice.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common hepatic malignancy, and a number of recent studies have identified an increasing trend in incidence and mortality. As an aggressive disease characterized by early metastasis, surgical resection is not an option for most patients, and chemotherapy has limited benefit. Thus, the prognosis is extremely poor, warranting the development of novel models to improve detection and treatment strategies for this lethal cancer. In this regard, significant technological advancements have provided key tools to model and study iCCA. Furthermore, these technologies are addressing the need for models that can readily be adapted to address different genetic contexts, an important consideration for genetically diverse cancers such as iCCA. In this review, we outline these various available tools, discussing specifically how they have been employed to study iCCA while highlighting important therapeutic implications. Finally, we discuss novel strategies utilizing patient-derived tumor tissue which have promising translational applications. Keywords: cholangiocarcinoma, biliary cancer, models, cell of origin, Cre-Lox, sleeping beauty

Chronic injury and inflammation are among the most established determinants of cancer risk, and the myriad of factors that contribute to this association is an active area of investigation. A key aspect of injury is the consequent regenerative and proliferative response. Understanding the mechanisms which restrain these proliferative processes and how these controls can be bypassed may shed light on the processes that drive early cancer development. Focusing on the mouse liver as a model tissue, we sought to determine how common oncogenic mutations impact the ductular reaction, the liver’s response to injury and one of the earliest events in cholangiocarcinoma development. Here we identify, among the most commonly mutated genes in cholangiocarcinoma, a uniquely critical role for the tumor suppressor Smad4 in restraining proliferation of ductular reactive cells, the biliary/epithelial compartment of the ductular reaction. Experiments testing the tumor suppressive role of Smad4 in mouse liver revealed a complex role as a suppressor of hepatocellular carcinoma, cholangiocarcinoma, and biliary cyst development. Focusing on Smad4’s role in the ductular reaction, we identify an IGF activation signature in Smad4-perturbed ductular reactive cells and in SMAD4-mutant cancers that is potentially mediated by SMAD4-regulated transcription of IGF binding proteins, key inhibitors of IGF signaling. This study therefore importantly links a key tumor suppressive pathway to regulation of the injury response, thereby shedding light on the earliest events in cancer development. In a related project, we sought to understand the cellular origins of cholangiocarcinoma. Hepatocytes and biliary epithelial cells may both be potential cells of origin for cholangiocarcinoma, although the contexts in which this has been demonstrated are limited. For example, although hepatocytes can be cells of origin in the setting of active Notch signaling, a key driver of biliary differentiation, Notch pathway mutations are not common events in human cases; therefore, it remains unknown if common genetic lesions identified in human cholangiocarcinoma are sufficient to promote hepatocyte-derived cholangiocarcinoma. To shed light on these matters, we demonstrate that targeting Kras and Tp53 mutations, two of the most common mutations in human cholangiocarcinoma, to the SOX9+ biliary compartment promotes cholangiocarcinoma development. Similarly, targeting these mutations to the hepatocyte compartment can lead to cholangiocarcinoma development in the setting of injury. We further establish that Tp53 in particular has a critical function in restricting reprogramming of hepatocytes to biliary epithelial cells, a role that likely enables hepatocyte-derived iCCA when it is mutated. Finally, mirroring what has been observed in other biliary tract-derived models, we observed active Notch and Wnt signaling in our hepatocyte-derived model, suggesting hepatocyte-derived cholangiocarcinoma may have similar programming regarding these important targetable pathways. Understanding distinguishing biological features of hepatocyte-derived and biliary tract-derived cholangiocarcinoma may prove to have clinically relevant prognostic and therapeutic value.

This study examined the impact on length of stay and discharge placement when a family therapy program was introduced in an adolescent state psychiatric hospital. Data was gathered from hospital records for the entire inpatient population during an 18 month period prior to the family therapy program and during an 18 month period after the family therapy program was in effect. Variables gathered for each patient were: age, sex, race, urban/suburban background, diagnosis, length of stay, discharge placement, and participation in the family therapy program. The study was based on a total of 478 patients who were evenly divided between the two time periods. The age range was from 14 to 18 years. Sex was evenly divided. Race distribution was white: 56%, Black: 29%, and hispanic: 13%. Discharge diagnoses were divided into three categories: Affective, 41%; conduct, 34%; psychotic, 25%. The hypothesis was that those patients who were involved in the systems oriented family therapy program would have a greater likelihood of returning to their families upon discharge and would be discharged more quickly than patients who did not participate. The rationale for this hypothesis lay in the clinical observation that families who were involved in the treatment of their children were more likely to seek their return to the family following discharge. A static-group comparison showed no significant difference between the two populations in either length of stay or ratio of discharge to family versus out-of-family placements. Patients diagnosed as \"affective\" had lengths of stay significantly shorter than other diagnostic categories. Those patients who were selected for the family therapy program had lengths of stay significantly longer than those who were not selected. Within racial categories, both white and black patients had significantly increased lengths of stay in the family therapy program. Hispanic patients, however, had no significant increase in length of stay. A multiple regression analysis showed that black patients were selected for the family therapy program significantly less than either white or hispanic patients.

Improve your skills in visual diagnosis Speed and accuracy of diagnosis is the key to saving lives in emergency and critical care medicine. Careful visual inspection of the patient, the data (radiography, electrocardiogram), and related clues can often help providers choose the right diagnosis and ultimately the best treatment – but this knowledge comes with experience. This book provides 110 randomly presented visual diagnosis cases for self-testing, imitating real-life situations found in the emergency department setting. Written by distinguished emergency and critical care physicians, and thoroughly revised and updated throughout, this second edition includes 25% new cases and is an ideal aid for trainees preparing for Board examinations as well as an invaluable 'refresher' for qualified emergency and critical care providers. This title is also available as a mobile App from MedHand Mobile Libraries. Buy it now from Google Play or the MedHand Store.

The resistance topic is timely given current events. The emergence of mysterious new diseases, such as SARS, and the looming threat of bioterrorist attacks remind us of how vulnerable we can be to infectious agents. With advances in medical technologies, we have tamed many former microbial foes, yet with few new antimicrobial agents and vaccines in the pipeline, and rapidly increasing drug resistance among infectious microbes, we teeter on the brink of loosing the upperhand in our ongoing struggle against these foes, old and new. The Resistance Phenomenon in Microbes and Infectious Disease Vectors examines our understanding of the relationships among microbes, disease vectors, and human hosts, and explores possible new strategies for meeting the challenge of resistance.