Genetic mouse models as in vivo tools for cholangiocarcinoma research

Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is effectively supported by genetic mouse models, which serve as sophisticated tools to systematically investigate CCA pathobiology and treatment response. These in vivo models feature many of the genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis (encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease) and provide an ideal experimental setting to study the interplay between tumor cells and the surrounding stroma. This review is intended to serve as a compendium of CCA mouse models, including traditional transgenic models but also genetically flexible approaches based on either the direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a resource for CCA researchers to aid in the selection of the most appropriate in vivo model system

Bezüge auf Familie als Moment der Vergeschlechtlichung pädagogischer Professionalität: Diskursanalytische Perspektiven auf Äußerungen in Gruppendiskussionen mit Kita-Teams

Die Autor*innen konzipieren professionelles Handeln wie Geschlecht als diskursive Konstruktion von Herausforderungen, praktischen Handlungsproblemen und legitimen Strategien des Umgangs im beruflichen Feld. Im Beitrag stellen sie die Frage, wie pädagogische Fachkräfte in Kindertageseinrichtungen das Verhältnis von Professionalität und Geschlecht im Austausch über das eigene berufliche Handeln herstellen und ordnen. Die Autor_innen analysieren hierzu beispielhaft zwei Auszüge aus im Rahmen eines Forschungsprojekts durchgeführten Gruppendiskussionen, in denen die Themenfeldern Kooperation mit Kolleg_innen, Disziplinierung sowie Bedarf an Männern in Kitas von den Fachkräften bearbeitet werden. Das Autor_innenteam rekonstruiert diskursanalytisch, wie die Diskussionsteilnehmer_innen das professionelle Handeln vergeschlechtlichen, indem dieses auf eine binäre, komplementäre und heteronormative Familien(geschlechter)ordnung bezogen wird. Das historische Konzept der ‚geistigen Mütterlichkeit‘ scheint dabei abgelöst von jenem einer ‚Väterlichkeit‘, das vor allem über einen Rekurs auf Erfahrung in Anschlag gebracht wird. (DIPF/Orig.

Bezüge auf Familie als Moment der Vergeschlechtlichung pädagogischer Professionalität. Diskursanalytische Perspektiven auf Äußerungen in Gruppendiskussionen mit Kita-Teams

Die Autor*innen konzipieren professionelles Handeln wie Geschlecht als diskursive Konstruktion von Herausforderungen, praktischen Handlungsproblemen und legitimen Strategien des Umgangs im beruflichen Feld. Im Beitrag stellen sie die Frage, wie pädagogische Fachkräfte in Kindertageseinrichtungen das Verhältnis von Professionalität und Geschlecht im Austausch über das eigene berufliche Handeln herstellen und ordnen. Die Autor_innen analysieren hierzu beispielhaft zwei Auszüge aus im Rahmen eines Forschungsprojekts durchgeführten Gruppendiskussionen, in denen die Themenfeldern Kooperation mit Kolleg_innen, Disziplinierung sowie Bedarf an Männern in Kitas von den Fachkräften bearbeitet werden. Das Autor_innenteam rekonstruiert diskursanalytisch, wie die Diskussionsteilnehmer_innen das professionelle Handeln vergeschlechtlichen, indem dieses auf eine binäre, komplementäre und heteronormative Familien(geschlechter)ordnung bezogen wird. Das historische Konzept der ‚geistigen Mütterlichkeit‘ scheint dabei abgelöst von jenem einer ‚Väterlichkeit‘, das vor allem über einen Rekurs auf Erfahrung in Anschlag gebracht wird. (DIPF/Orig.

Criteria for preclinical models of cholangiocarcinoma:scientific and medical relevance

Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA

Genetic Mouse Models as In Vivo Tools for Cholangiocarcinoma Research

Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is effectively supported by genetic mouse models, which serve as sophisticated tools to systematically investigate CCA pathobiology and treatment response. These in vivo models feature many of the genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis (encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease) and provide an ideal experimental setting to study the interplay between tumor cells and the surrounding stroma. This review is intended to serve as a compendium of CCA mouse models, including traditional transgenic models but also genetically flexible approaches based on either the direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a resource for CCA researchers to aid in the selection of the most appropriate in vivo model system

Molecular diagnostics and therapies for gastrointestinal tumors: a real-world experience

Purpose!#!Several targeted agents demonstrated efficacy in early clinical trials for gastrointestinal (GI) cancers, but in many cases, phase-III trials and/or approval by the European Medicines Agency (EMA) are lacking. The primary focus of this study was to assess the regulatory processes associated with use and reimbursement of off-label treatment in precision oncology and to evaluate the benefit of targeted therapy in a real-world population in Germany.!##!Methods!#!Our cohort comprises 137 patients with GI cancers and is biased towards cancer entities with a high frequency of known targetable alterations, such as cholangiocarcinoma. Genetic testing was used to identify molecular targets, and therapy response was evaluated based on CT scans.!##!Results!#!A molecular target for precision oncology was identified in 53 patients and 43 requests for cost coverage were submitted to health insurance companies. 60% of the requests received approval after initial application and another 7% after appeal. Half of the rejected requests were denied despite ESCAT IA level evidence. The median time between initiation of molecular testing and start of therapy was 75 days. 35 patients received matched targeted therapies (n = 28) or, in the case of MSI, immunotherapy (IO) (n = 7). We observed a trend in favor of molecular therapy when compared to the immediate prior treatment.!##!Conclusion!#!Relevant treatment options were identified by molecular testing in a significant subset of patients. When targeted therapies that lack EMA approval are considered, treatment initiation may be delayed by the duration of the molecular analysis and the regulatory processes

Genetic mouse models as in vivo tools for cholangiocarcinoma research

Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is effectively supported by genetic mouse models, which serve as sophisticated tools to systematically investigate CCA pathobiology and treatment response. These in vivo models feature many of the genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis (encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease) and provide an ideal experimental setting to study the interplay between tumor cells and the surrounding stroma. This review is intended to serve as a compendium of CCA mouse models, including traditional transgenic models but also genetically flexible approaches based on either the direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a resource for CCA researchers to aid in the selection of the most appropriate in vivo model system

Potent Antitumor Activity of Liposomal Irinotecan in an Organoid- and CRISPR-Cas9-Based Murine Model of Gallbladder Cancer

Gallbladder cancer is associated with a dismal prognosis, and accurate in vivo models will be elemental to improve our understanding of this deadly disease and develop better treatment options. We have generated a transplantation-based murine model for gallbladder cancer that histologically mimics the human disease, including the development of distant metastasis. Murine gallbladder–derived organoids are genetically modified by either retroviral transduction or transfection with CRISPR/Cas9 encoding plasmids, thereby allowing the rapid generation of complex cancer genotypes. We characterize the model in the presence of two of the most frequent oncogenic drivers—Kras and ERBB2—and provide evidence that the tumor histology is highly dependent on the driver oncogene. Further, we demonstrate the utility of the model for the preclinical assessment of novel therapeutic approaches by showing that liposomal Irinotecan (Nal-IRI) is retained in tumor cells and significantly prolongs the survival of gallbladder cancer–bearing mice compared to conventional irinotecan