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Article ; Online: Chemotherapy Assessment in Advanced Multicellular 3D Models of Pancreatic Cancer: Unravelling the Importance of Spatiotemporal Mimicry of the Tumor Microenvironment.

Gupta, Priyanka / Bermejo-Rodriguez, Camino / Kocher, Hemant / Pérez-Mancera, Pedro A / Velliou, Eirini G

Advanced biology

2024 , Page(s) e2300580

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a challenge for global health with very low survival rate and high therapeutic resistance. Hence, advanced preclinical models for treatment screening are of paramount importance. Herein, chemotherapeutic ( ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is a challenge for global health with very low survival rate and high therapeutic resistance. Hence, advanced preclinical models for treatment screening are of paramount importance. Herein, chemotherapeutic (gemcitabine) assessment on novel (polyurethane) scaffold-based spatially advanced 3D multicellular PDAC models is carried out. Through comprehensive image-based analysis at the protein level, and expression analysis at the mRNA level, the importance of stromal cells is confirmed, primarily activated stellate cells in the chemoresistance of PDAC cells within the models. Furthermore, it is demonstrated that, in addition to the presence of activated stellate cells, the spatial architecture of the scaffolds, i.e., segregation/compartmentalization of the cancer and stromal zones, affect the cellular evolution and is necessary for the development of chemoresistance. These results highlight that, further to multicellularity, mapping the tumor structure/architecture and zonal complexity in 3D cancer models is important for better mimicry of the in vivo therapeutic response.
Language	English
Publishing date	2024-02-07
Publishing country	Germany
Document type	Journal Article
ISSN	2701-0198
ISSN (online)	2701-0198
DOI	10.1002/adbi.202300580
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The molecular landscape of pancreatic ductal adenocarcinoma.

Sivapalan, L / Kocher, H M / Ross-Adams, H / Chelala, C

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.

2022 Volume 22, Issue 7, Page(s) 925–936

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related mortality within the next decade, with limited effective treatment options and a dismal long-term prognosis for patients. Surgical resection of ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related mortality within the next decade, with limited effective treatment options and a dismal long-term prognosis for patients. Surgical resection of early, localised disease provides the only chance for potentially curative treatment; however, most patients with PDAC present with advanced disease and are not suitable for surgery. Genomic analyses of PDAC tumour lesions have identified a small number of recurrent alterations that are detected across most tumours, and beyond that a large number that either occur at a low (<5%) prevalence or are patient-specific in nature. This molecular heterogeneity has presented a significant challenge for the characterisation of tumour subtypes and effective molecular biomarkers, which have not yet manifested clinical benefits for diagnosis, treatment or prognosis in PDAC. These challenges are compounded by the overall lack of tumour biopsies for sequencing, the invasive nature of tissue sampling and the confounding effects of low tumour cellularity in many PDAC biopsy specimens, which have limited the applications of molecular profiling in unresectable patients and for longitudinal tumour monitoring. Further investigation into alternative sources of tumour analytes that can be sampled using minimally invasive methods and used to complement molecular analyses from tissue sequencing are required.
MeSH term(s)	Humans ; Carcinoma, Pancreatic Ductal/diagnosis ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/pathology ; Pancreatic Neoplasms/diagnosis ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Prognosis ; Genomics ; Biomarkers, Tumor/genetics ; Pancreatic Neoplasms
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2022-07-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2056680-3
ISSN	1424-3911 ; 1424-3903
ISSN (online)	1424-3911
ISSN	1424-3903
DOI	10.1016/j.pan.2022.07.010
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Article ; Online: Systematic review of the incidence, presentation and management of gastroduodenal artery pseudoaneurysm after pancreatic resection.

Brodie, B / Kocher, H M

BJS open

2019 Volume 3, Issue 6, Page(s) 735–742

Abstract: Background: Gastroduodenal artery (GDA) pseudoaneurysm is a serious complication following pancreatic resection, associated with high morbidity and mortality rates. This review aimed to report the incidence of GDA pseudoaneurysm after pancreatic surgery, ...

Abstract	Background: Gastroduodenal artery (GDA) pseudoaneurysm is a serious complication following pancreatic resection, associated with high morbidity and mortality rates. This review aimed to report the incidence of GDA pseudoaneurysm after pancreatic surgery, and describe clinical presentation and management. Methods: MEDLINE and Embase were searched systematically for clinical studies evaluating postoperative GDA pseudoaneurysm. Incidence was calculated by dividing total number of GDA pseudoaneurysms by the total number of pancreatic operations. Additional qualitative data related to GDA pseudoaneurysm presentation and management following pancreatic resection were extracted and reviewed from individual reports. Results: Nine studies were selected for systematic review involving 4227 pancreatic operations with 55 GDA pseudoaneurysms, with a reported incidence of 1·3 (range 0·2-8·3) per cent. Additional data were extracted from 39 individual examples of GDA pseudoaneurysm from 14 studies. The median time for haemorrhage after surgery was at 15 (range 4-210) days. A preceding complication in the postoperative period was documented in four of 21 patients (67 per cent), and sentinel bleeding was observed in 14 of 20 patients (70 per cent). Postoperative complications after pseudoaneurysm management occurred in two-thirds of the patients (14 of 21). The overall survival rate was 85 per cent (33 of 39). Conclusion: GDA pseudoaneurysm is a rare yet serious cause of haemorrhage after pancreatic surgery, with high mortality. The majority of the patients had a preceding complication. Sentinel bleeding was an important clinical indicator.
MeSH term(s)	Aneurysm, False/diagnosis ; Aneurysm, False/epidemiology ; Aneurysm, False/etiology ; Aneurysm, False/therapy ; Angiography ; Embolization, Therapeutic/statistics & numerical data ; Endovascular Procedures/statistics & numerical data ; Hepatic Artery/diagnostic imaging ; Hepatic Artery/surgery ; Humans ; Incidence ; Pancreatectomy/adverse effects ; Postoperative Hemorrhage/diagnosis ; Postoperative Hemorrhage/epidemiology ; Postoperative Hemorrhage/etiology ; Postoperative Hemorrhage/therapy ; Survival Rate ; Time Factors
Language	English
Publishing date	2019-09-30
Publishing country	England
Document type	Journal Article ; Systematic Review
ISSN	2474-9842
ISSN (online)	2474-9842
DOI	10.1002/bjs5.50210
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Article: Pancreatic Cancer Organotypic Models.

Coetzee, Abigail / Grose, Richard / Kocher, Hemant

Current topics in microbiology and immunology

2019 Volume 430, Page(s) 183–198

Abstract: Pancreatic cancer has a dismal prognosis for patients due to late diagnosis and ineffective treatment options. There is a desperate need for more accurate disease models to enable improved therapies and diagnostic tests to reach the clinic. Pancreatic ... ...

Abstract	Pancreatic cancer has a dismal prognosis for patients due to late diagnosis and ineffective treatment options. There is a desperate need for more accurate disease models to enable improved therapies and diagnostic tests to reach the clinic. Pancreatic tumours have a high content of desmoplastic stroma, which forms a stiff, hypoxic tumour mass and contributes significantly to tumour development and metastatic spread. Therefore, 2D cell culture is not sufficient for understanding the complex biology of this disease. 3D in vitro models offer a more representative method of culturing cells for research in the laboratory. There are many different 3D models that can be used in research, organoids formed from patient or murine tumours are grown embedded in collagen or matrigel matrices, giving the potential for screening treatment options and personalised therapy in the future. Also, organotypic models using pancreatic cancer cell lines and stromal cells can be easily manipulated to study different aspects of pancreatic cancer and new therapeutic options in the laboratory. There are new emerging pancreatic cancer 3D models being developed, including microchip technology or synthetic scaffolds instead collagen and matrigel. All of these 3D culturing methods give an advantage over traditional 2D cell culture and could lead to improved understanding of this disease, translating to a better prognosis for patients in the clinic.
MeSH term(s)	Animals ; Cell Culture Techniques ; Humans ; Mice ; Pancreatic Neoplasms ; Stromal Cells
Language	English
Publishing date	2019-02-16
Publishing country	Germany
Document type	Journal Article
ISSN	0070-217X
ISSN	0070-217X
DOI	10.1007/82_2019_155
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Article ; Online: Molecular profiling of ctDNA in pancreatic cancer: Opportunities and challenges for clinical application.

Sivapalan, L / Kocher, H M / Ross-Adams, H / Chelala, C

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.

2020 Volume 21, Issue 2, Page(s) 363–378

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related mortality within the next decade, with limited effective treatment options and a dismal long-term prognosis for patients. Genomic profiling has not yet manifested clinical benefits for diagnosis, treatment or prognosis in PDAC, due to the lack of available tissues for sequencing and the confounding effects of low tumour cellularity in many biopsy specimens. Increasing focus is now turning to the use of minimally invasive liquid biopsies to enhance the characterisation of actionable PDAC tumour genomes. Circulating tumour DNA (ctDNA) is the most comprehensively studied liquid biopsy analyte in blood and can provide insight into the molecular profile and biological characteristics of individual PDAC tumours, in real-time and in advance of traditional imaging modalities. This can pave the way for identification of new therapeutic targets, novel risk variants and markers of tumour response, to supplement diagnostic screening and provide enhanced scrutiny in treatment stratification. In the roadmap towards the application of precision medicine for clinical management in PDAC, ctDNA analyses may serve a leading role in streamlining candidate biomarkers for clinical integration. In this review, we highlight recent developments in the use of ctDNA-based liquid biopsies for PDAC and provide new insights into the technical, analytical and biological challenges that must be overcome for this potential to be realised.
MeSH term(s)	Biomarkers, Tumor/blood ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/metabolism ; Circulating Tumor DNA/metabolism ; Humans ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/metabolism ; Transcriptome
Chemical Substances	Biomarkers, Tumor ; Circulating Tumor DNA
Language	English
Publishing date	2020-12-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2056680-3
ISSN	1424-3911 ; 1424-3903
ISSN (online)	1424-3911
ISSN	1424-3903
DOI	10.1016/j.pan.2020.12.017
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Book ; Thesis: Untersuchungen zum Abbau des Herbizids 2-Chlor-3-(4-chlorphenyl)propionsäuremethylester im Boden und durch Bodenmikroorganismen

Köcher, Helmut

1973

Language	German
Size	78 S.
Publishing country	Germany
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Hohenheim, Univ., Diss. 1974
HBZ-ID	HT013853598
Database	Catalogue ZB MED Nutrition, Environment, Agriculture

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DissT 502	order for loan	Geschlossenes Magazin (U2)

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Article: A Novel Scaffold-Based Hybrid Multicellular Model for Pancreatic Ductal Adenocarcinoma-Toward a Better Mimicry of the

Gupta, Priyanka / Pérez-Mancera, Pedro A / Kocher, Hemant / Nisbet, Andrew / Schettino, Giuseppe / Velliou, Eirini G

Frontiers in bioengineering and biotechnology

2020 Volume 8, Page(s) 290

Abstract: With a very low survival rate, pancreatic ductal adenocarcinoma (PDAC) is a deadly disease. This has been primarily attributed to (i) its late diagnosis and (ii) its high resistance to current treatment methods. The latter specifically requires the ... ...

Abstract	With a very low survival rate, pancreatic ductal adenocarcinoma (PDAC) is a deadly disease. This has been primarily attributed to (i) its late diagnosis and (ii) its high resistance to current treatment methods. The latter specifically requires the development of robust, realistic
Language	English
Publishing date	2020-04-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2719493-0
ISSN	2296-4185
ISSN	2296-4185
DOI	10.3389/fbioe.2020.00290
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Article: Translocation and Metabolic Conversion of C-Labeled Assimilates in Detached and Attached Leaves of Phaseolus vulgaris L. in Different Phases of Leaf Expansion.

Köcher, H / Leonard, O A

Plant physiology

2006 Volume 47, Issue 2, Page(s) 212–216

Abstract: Leaf excision greatly affected the actual levels of (14)C-assimilates in laminas and petioles of primary bean leaves (Phaseolus vulgaris L.) following a transport period. However, it did not affect the percentage of starch in the insoluble residue; ... ...

Abstract	Leaf excision greatly affected the actual levels of (14)C-assimilates in laminas and petioles of primary bean leaves (Phaseolus vulgaris L.) following a transport period. However, it did not affect the percentage of starch in the insoluble residue; starch decreased from 20% of the insoluble residue after exposure to (14)CO(2) to 3% after 5 hr in both attached and detached leaves. The transition from import to export of attached and detached leaves was at the same stage, i.e., when the cotyledons were 63 to 85% depleted. The composition of the (14)C-assimilates in importing leaves was different from that in exporting leaves. In the former, only 5% of the soluble label was free sugar, while 74% was free sugar in the latter. The failure of importing leaves to export was not due to the labeled substances being nontransferable. Extracts from importing leaves applied to exporting leaves were exported; these extracts were high in amino acids and organic acids but low in free sugar. However, exporting leaves exposed to (14)CO(2) appeared to export sugars more readily than amino acids. Cotyledon excision did not delay transition of leaves from import to export. Actually, excision seemed to enhance slightly the transition of the primary leaves from import to export.
Language	English
Publishing date	2006-04-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	208914-2
ISSN	1532-2548 ; 0032-0889
ISSN (online)	1532-2548
ISSN	0032-0889
DOI	10.1104/pp.47.2.212
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Article ; Online: Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers Part 1: GI carcinomas.

Neuzillet, Cindy / Rousseau, Benoît / Kocher, Hemant / Bourget, Philippe / Tournigand, Christophe

Pharmacology & therapeutics

2017 Volume 174, Page(s) 145–172

Abstract: Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the molecular biology of cancer cell has led to the therapeutic revolution of targeted therapies, i.e. ... ...

Abstract	Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the molecular biology of cancer cell has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents being more specific to cancer cells were expected to be less toxic than cytotoxic agents. Targeted agents have provided clinical benefit in many GI cancer types. For example, antiangiogenics and anti-EGFR therapies have significantly improved survival of patients affected by metastatic colorectal cancer and have deeply changed the therapeutic strategy in this disease. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms (e.g., RAS mutation for anti-EGFR therapies), or to an activity restricted to some tumour settings (e.g., lack of activity in other cancer types, or on the microscopic residual disease in adjuvant setting). Many studies are negative in overall population but positive in some specific patient subgroups (e.g., trastuzumab in HER2-positive gastric cancer), illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this first part, we will focus on adenocarcinomas and squamous cell carcinomas, for which targeted therapies are mostly used in combination with chemotherapy.
Language	English
Publishing date	2017-06
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	194735-7
ISSN	1879-016X ; 0163-7258
ISSN (online)	1879-016X
ISSN	0163-7258
DOI	10.1016/j.pharmthera.2017.02.028
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Article ; Online: Fibronectin acts as a molecular switch to determine SPARC function in pancreatic cancer.

Munasinghe, Amanda / Malik, Khalisha / Mohamedi, Fatemia / Moaraf, Stan / Kocher, Hemant / Jones, Lucy / Hill, Natasha J

Cancer letters

2020 Volume 477, Page(s) 88–96

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all solid tumours and more effective therapy is urgently needed. The stroma is thought to play a critical role in tumour development and metastasis, and high stromal expression of the ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all solid tumours and more effective therapy is urgently needed. The stroma is thought to play a critical role in tumour development and metastasis, and high stromal expression of the matricellular protein SPARC has been robustly associated with poor patient prognosis. However, the precise role of SPARC has been highly controversial, with multiple studies demonstrating tumour-suppressor properties of this protein in vitro. This conflicting data has been a barrier to the development of new therapeutic approaches targeting SPARC, despite current interest in stromal-therapy. We show conclusively that SPARC acts directly on cancer cells to promote pancreatic cancer cell proliferation. This contradicts previous in vitro studies, but is consistent with the observed clinical association between SPARC expression and poor patient prognosis. However, depletion of fibronectin switches the activity of SPARC from promoting cancer cell proliferation to growth inhibition and induction of apoptosis. Thus, targeting the interaction between SPARC and fibronectin could be used to turn the highly expressed tumour protein SPARC against the tumour to induce tumour cytotoxicity, and is a novel target for PDAC therapy.
MeSH term(s)	Carcinoma, Pancreatic Ductal/metabolism ; Carcinoma, Pancreatic Ductal/pathology ; Caspases/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Fibronectins/metabolism ; Humans ; Osteonectin/genetics ; Osteonectin/metabolism ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Pancreatic Stellate Cells/metabolism ; Pancreatic Stellate Cells/pathology ; Protein Interaction Maps ; Stromal Cells/metabolism
Chemical Substances	FN1 protein, human ; Fibronectins ; Osteonectin ; SPARC protein, human ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2020-02-27
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2020.02.031
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