Imperial College London

DrJonathanKrell

Faculty of MedicineDepartment of Surgery & Cancer

Clinical SL in Medical Oncology (Gynaecological Oncology)
 
 
 
//

Contact

 

j.krell

 
 
//

Location

 

Institute of Reproductive and Developmental BiologyHammersmith Campus

//

Summary

 

Publications

Publication Type
Year
to

132 results found

Khan M, Naresh K, Krell J, Diamond E, Borysiewicz Cet al., 2019, A challenging case of indeterminate cell histiocytosis with only partial response treatment., 16th International Workshop on Langerhans Cells (LC), Publisher: WILEY, Pages: 18-19, ISSN: 0014-2980

Conference paper

Hall M, Savvatis K, Nixon K, Kyrgiou M, Hariharan K, Padwick M, Owens O, Cunnea P, Campbell J, Farthing A, Stumpfle R, Vazquez I, Watson N, Krell J, Gabra H, Rustin G, Fotopoulou Cet al., 2019, Maximal-effort cytoreductive surgery for ovarian cancer patients with a high tumor burden: variations in practice and impact on outcome, Annals of Surgical Oncology, Vol: 26, Pages: 2943-2951, ISSN: 1068-9265

BackgroundThis study aimed to compare the outcomes of two distinct patient populations treated within two neighboring UK cancer centers (A and B) for advanced epithelial ovarian cancer (EOC).MethodsA retrospective analysis of all new stages 3 and 4 EOC patients treated between January 2013 and December 2014 was performed. The Mayo Clinic surgical complexity score (SCS) was applied. Cox regression analysis identified the impact of treatment methods on survival.ResultsThe study identified 249 patients (127 at center A and 122 in centre B) without significant differences in International Federation of Gynecology and Obstetrics (FIGO) stage (FIGO 4, 29.7% at centers A and B), Eastern Cooperative Oncology Group (ECOG) performance status (ECOG < 2, 89.9% at centers A and B), or histology (serous type in 84.1% at centers A and B). The patients at center A were more likely to undergo surgery (87% vs 59.8%; p < 0.001). The types of chemotherapy and the patients receiving palliative treatment alone were equivalent between the two centers (3.6%). The median SCS was significantly higher at center A (9 vs 2; p < 0.001) with greater tumor burden (9 vs 6 abdominal fields involved; p < 0.001), longer median operation times (285 vs 155 min; p < 0.001), and longer hospital stays (9 vs 6 days; p < 0.001), but surgical morbidity and mortality were equivalent. The independent predictors of reduced overall survival (OS) were non-serous histology (hazard ratio [HR], 1.6; 95% confidence interval [CI] 1.04–2.61), ECOG higher than 2 (HR, 1.9; 95% CI 1.15–3.13), and palliation alone (HR, 3.43; 95% CI 1.51–7.81). Cytoreduction, of any timing, had an independent protective impact on OS compared with chemotherapy alone (HR, 0.31 for interval surgery and 0.39 for primary surgery), even after adjustment for other prognostic factors.ConclusionsIncorporating surgery into the initia

Journal article

Ottaviani S, Stebbing J, Frampton AE, Zagorac S, Krell J, de Giorgio A, Trabulo SM, Nguyen VTM, Magnani L, Feng H, Giovannetti E, Funel N, Gress TM, Jiao LR, Lombardo Y, Lemoine NR, Heeschen C, Castellano Let al., 2019, Author Correction: TGF-beta induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression, Nature Communications, Vol: 10, ISSN: 2041-1723

Journal article

Liu DSK, Prado MM, Giovannetti E, Jiao LR, Krell J, Frampton AEet al., Can circulating tumor and exosomal nucleic acids act as biomarkers for pancreatic ductal adenocarcinoma?, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, ISSN: 1473-7159

Journal article

Cristofanilli M, Pierga J-Y, Reuben J, Rademaker A, Davis AA, Peeters DJ, Fehm T, Nole F, Gisbert-Criado R, Mavroudis D, Grisanti S, Giuliano M, Garcia-Saenz JA, Stebbing J, Caldas C, Gazzaniga P, Manso L, Zamarchi R, de lascoiti AF, de Mattos-Arruda L, Ignatiadis M, Cabel L, van Laere SJ, Meier-Stiegen F, Sandri M-T, Vidal-Martinez J, Politaki E, Consoli F, Generali D, Cappelletti MR, Diaz-Rubio E, Krell J, Dawson S-J, Raimondi C, Rutten A, Janni W, Munzone E, Caranana V, Agelaki S, Almici C, Dirix L, Solomayer E-F, Zorzino L, Darrigues L, Reis-Filho JS, Gerratana L, Michiels S, Bidard F-C, Pantel Ket al., 2019, The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper, CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, Vol: 134, Pages: 39-45, ISSN: 1040-8428

Journal article

Gourley C, Dalton HJ, Banerjee SN, Buscema J, Lockley M, Krell J, Monk BJet al., 2018, PRO-105, a phase II open-label study of NUC-1031 in patients with platinum-resistant ovarian cancer., Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X

Conference paper

Ottaviani S, Stebbing J, Frampton AE, Zagorac S, Krell J, de Giorgio A, Trabulo SM, Nguyen VTM, Magnani L, Feng H, Giovannetti E, Funel N, Gress TM, Jiao LR, Lombardo Y, Lemoine NR, Heeschen C, Castellano Let al., 2018, TGF-beta induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression, Nature Communications, Vol: 9, ISSN: 2041-1723

TGF-β/Activin induces epithelial-to-mesenchymal transition and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-β transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-β also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-β-mediated response indicating that these miRNAs are important TGF-β effectors. We integrate AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell–cell junctions’ pathways. Together, we uncover that TGF-β induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b play opposing roles in controlling PDAC tumourigenesis.

Journal article

Frampton AE, Mato Prado M, Lopez Jimenez ME, Fajardo Puerta AB, Jawad ZR, Lawton P, Giovannetti E, Habib N, Castellano L, Stebbing J, Krell J, Jiao Let al., 2018, Glypican-1 is enriched in circulating-exosomes in pancreatic cancer and correlates with tumor burden, Oncotarget, Vol: 9, Pages: 19006-19013, ISSN: 1949-2553

Background: Glypican-1 (GPC1) is expressed in pancreatic ductal adenocarcinoma (PDAC) cells and adjacent stroma fibroblasts. Recently, GPC1 circulating exosomes (crExos) have been shown to be able to detect early stages of PDAC. This study investigated the usefulness of crExos GPC1 as a biomarker for PDAC.Methods: Plasma was obtained from patients with benign pancreatic disease (n = 16) and PDAC (n = 27) prior to pancreatectomy, and crExos were isolated by ultra-centrifugation. Protein was extracted from surgical specimens (adjacent normal pancreas, n = 13; and PDAC, n = 17). GPC1 levels were measured using enzyme-linked immunosorbent assay (ELISA). Results: There was no significant difference in GPC1 levels between normal pancreas and PDAC tissues. This was also true when comparing matched pairs. However, GPC1 levels were enriched in PDAC crExos (n = 11), compared to the source tumors (n = 11; 97 ± 54 vs. 20.9 ± 12.3 pg/mL; P < 0.001). In addition, PDACs with high GPC1 expression tended to have crExos with high GPC1 levels. Despite these findings, we were unable to distinguish PDAC from benign pancreatic disease using crExos GPC1 levels. Interestingly, we found that in matched pre and post-operative plasma samples there was a significant drop in crExos GPC1 levels after surgical resection for PDAC (n = 11 vs. 11; 97 ± 54 vs. 77.8 ± 32.4 pg/mL; P = 0.0428). Furthermore, we found that patients with high crExos GPC1 levels have significantly larger PDACs (>4 cm; P = 0.012). Conclusions: High GPC1 crExos may be able to determine PDAC tumor size and disease burden. However, further efforts are needed to elucidate its role as a diagnostic and/or prognostic biomarker using larger cohorts of PDAC patients.

Journal article

Carter P, Alifrangis CC, Cereser B, Chandrasinghe P, Del Bel Belluz L, Moderau N, Poyia F, Schwartzberg LS, Tabassum N, Wen J, Krell J, Stebbing Jet al., 2018, Molecular profiling of advanced breast cancer tumors is beneficial in assisting clinical treatment plans, Oncotarget, Vol: 9, Pages: 17589-17596, ISSN: 1949-2553

We used data obtained by Caris Life Sciences, to evaluate the benefits of tailoring treatments for a breast carcinoma cohort by using tumor molecular profiles to inform decisions. Data for 92 breast cancer patients from the commercial Caris Molecular Intelligence database was retrospectively divided into two groups, so that the first always followed treatment recommendations, whereas in the second group all patients received at least one drug after profiling that was predicted to lack benefit. The biomarker and drug associations were based on tests including fluorescent in situ hybridization and DNA sequencing, although immunohistochemistry was the main test used.Patients whose drugs matched those recommended according to their tumor profile had an average overall survival of 667 days, compared to 510 days for patients that did not (P=0.0316). In the matched treatment group, 26% of patients were deceased by the last time of monitoring, whereas this was 41% in the unmatched group (P=0.1257). We therefore confirm the ability of tumor molecular profiling to improve survival of breast cancer patients. Immunohistochemistry biomarkers for the androgen, estrogen and progesterone receptors were found to be prognostic for survival.

Journal article

Carter P, Alifrangis C, Cereser B, Chandrasinghe P, Del Bel Belluz L, Herzog T, Levitan J, Moderau N, Schwartzberg L, Tabassum N, Wen J, Krell J, Stebbing Jet al., 2018, Correction: Does molecular profiling of tumors using the Caris molecular intelligence platform improve outcomes for cancer patients?, Oncotarget, Vol: 9, Pages: 15166-15166, ISSN: 1949-2553

Corrections for article DOI: 10.18632/oncotarget.24258

Journal article

Carter P, Alifrangis C, Cereser B, Chandrasinghe P, Del Bel Belluz L, Fotopoulou C, Frilling A, Herzog T, Moderau N, Tabassum N, Krell J, Stebbing Jet al., 2018, Correction: Assessing tumor molecular profiling to guide treatments for patients with advanced female genital tract malignancy, Oncotarget, Vol: 9, Pages: 15164-15164, ISSN: 1949-2553

Correction to article DOI: https://dx.doi.org/10.18632/oncotarget.23675

Journal article

Carter P, Alifrangis C, Chandrasinghe P, Cereser B, Del Bel Belluz L, Leo CA, Moderau N, Tabassum N, Warusavitarne J, Krell J, Stebbing Jet al., 2018, Correction: The benefit of tumor molecular profiling on predicting treatments for colorectal adenocarcinomas, Oncotarget, Vol: 9, Pages: 15165-15165, ISSN: 1949-2553

Corrections for article DOI: https://dx.doi.org/10.18632/oncotarget.24257.].

Journal article

Alifrangis C, Carter P, Cereser B, Chandrasinghe P, Belluz LDB, Lim E, Moderau N, Poyia F, Tabassum N, Zhang H, Krell J, Stebbing Jet al., 2018, Investigating the benefits of molecular profiling of advanced non-small cell lung cancer tumors to guide treatments., Oncotarget, Vol: 9, Pages: 12805-12811, ISSN: 1949-2553

In this study we utilized data on patient responses to guided treatments, and we evaluated their benefit for a non-small cell lung cancer cohort. The recommended therapies used were predicted using tumor molecular profiles that involved a range of biomarkers but primarily used immunohistochemistry markers. A dataset describing 91 lung non-small cell lung cancer patients was retrospectively split into two. The first group's drugs were consistent with a treatment plan whereby all drugs received agreed with their tumor's molecular profile. The second group each received one or more drug that was expected to lack benefit. We found that there was no significant difference in overall survival or mortality between the two groups. Patients whose treatments were predicted to be of benefit survived for an average of 402 days, compared to 382 days for those that did not (P = 0.7934). In the matched treatment group, 48% of patients were deceased by the time monitoring had finished compared to 53% in the unmatched group (P = 0.6094). The immunohistochemistry biomarker for the ERCC1 receptor was found to be a marker that could be used to predict future survival; ERCC1 loss was found to be predictive of poor survival.

Journal article

Carter P, Alifrangis CC, Cereser B, Chandrasinghe P, Del Bel Belluz L, herzog T, levitan J, Moderau N, Schwartzberg L, Tabassum N, Wen J, Krell J, Stebbing Jet al., 2018, Does molecular profiling of tumors using the Caris molecular intelligence platform improve outcomes for cancer patients?, Oncotarget, Vol: 9, Pages: 9456-9467, ISSN: 1949-2553

We evaluated the effect of tailoring treatments based on predictions informed by tumor molecular profiles across a range of cancers, using data from Caris Life Sciences. These included breast carcinoma, colorectal adenocarcinoma, female genital tract malignancy, lung non-small cell lung cancer, neuroendocrine tumors, ovarian surface epithelial carcinomas, and urinary tract cancers.Molecular profiles using mostly immunohistochemistry (IHC) and DNA sequencing for tumors from 841 patients had been previously used to recommend treatments; some physicians followed the suggestions completely while some did not. This information was assessed to find out if the outcome was better for the patients where their received drugs matched recommendations.The IHC biomarker for the progesterone receptor and for the androgen receptor were found to be most prognostic for survival overall. The IHC biomarkers for P-glycoprotein (PGP), tyrosine-protein kinase Met (cMET) and the DNA excision repair protein ERCC1 were also shown to be significant predictors of outcome. Patients whose treatments matched those predicted to be of benefit survived for an average of 512 days, compared to 468 days for those that did not (P = 0.0684). In the matched treatment group, 34% of patients were deceased at the completion of monitoring, whereas this was 47% in the unmatched group (P = 0.0001).

Journal article

Carter P, Alifrangis CC, Chandrasinghe P, Cereser B, Del Bel Belluz L, Leo CA, Moderau N, Tabassum N, Warusavitarne J, Krell J, Stebbing Jet al., 2018, The benefit of tumor molecular profiling on predicting treatments for colorectal adenocarcinomas, Oncotarget, Vol: 9, Pages: 11371-11376, ISSN: 1949-2553

We evaluated the benefit of tailoring treatments for a colorectal adenocarcinoma cancer cohort according to tumor molecular profiles, by analyzing data collected on patient responses to treatments that were guided by a tumor profiling technology from Caris Life Sciences. DNA sequencing and immunohistochemistry were the main tests that predictions were based upon, but also fragment analysis, and in situ hybridization. The status of the IHC biomarker for the thymidylate synthase receptor was a good indicator for future survival. Data collected for the clinical treatments of 95 colorectal adenocarcinoma patients was retrospectively divided into two groups: the first group was given drugs that always matched recommended treatments as suggested by the tumor molecular profiling service; the second group received at least one drug after profiling that was predicted to lack benefit. In the matched treatment group, 19% of patients were deceased at the end of monitoring compared to 49% in the unmatched group, indicating a benefit in mortality by tumor molecular profiling colorectal adenocarcinoma patients.

Journal article

Carter P, Alifrangis C, Cereser B, Chandrasinghe P, Del Bel Belluz L, Fotopoulou C, Frilling A, Herzog T, Moderau N, Tabassum N, Krell J, Stebbing Jet al., 2017, Assessing tumor molecular profiling to guide treatments for patients with advanced female genital tract malignancy, Oncotarget, Vol: 9, Pages: 6007-6014, ISSN: 1949-2553

Tumor molecular profiling has enabled selection of targeted therapies in a host of solid tumors. Here we used a retrospective clinical cohort, to evaluate the benefit of tailoring treatments for female genital tract malignancy, using tumor molecular profiles. Clinical outcome data for 112 patients was retrospectively separated into two groups. These either followed a matched treatment plan that incorporated at least one drug recommended according to their tumor profile and none that were expected to have no benefit (64 patients), or was unmatched with suggested treatments and received at least one drug that was anticipated to lack benefit for that tumor (48 patients).In the group of patients whose drugs matched those recommended by molecular profiling of their tumor, their overall survival was 593 days on average, compared to 449 days for patients that did not; removing drugs predicted to have no benefit from treatment regimens received after profiling increased survival by 144 days on average (P = 0.0265). In the matched treatment group, 30% of patients had died by the last time of monitoring, whereas this was 40% in the unmatched group (P = 0.2778). The IHC biomarker for the progesterone receptor was demonstrated to be prognostic for survival.

Journal article

Frampton AE, Funel N, Giovannetti E, Ahmad R, Castellano L, Knoesel T, Jiao LR, Stebbing J, Krell Jet al., 2017, y Dicing and slicing pancreatic cancer, 20th Annual Scientific Meeting of the Association-of-Upper-Gastrointestinal-Surgeons-of-Great-Britain-and-Ireland (AUGIS), Publisher: WILEY, Pages: 13-13, ISSN: 0007-1323

Conference paper

Nasser S, Kyrgiou M, Krell J, Haidopoulos D, Bristow R, Fotopoulou Cet al., 2017, A Review of Thoracic and Mediastinal Cytoreductive Techniques in Advanced Ovarian Cancer: Extending the Boundaries, Annals of Surgical Oncology, Vol: 24, Pages: 3700-3705, ISSN: 1068-9265

The aim of this study was to review the surgical and clinical outcomes of intrathoracic and mediastinal surgical cytoreduction in stage IV epithelial ovarian cancer (EOC). Relevant articles were identified from MEDLINE and EMBASE. Only analyses or reports that described actual intrathoracic cytoreduction via pleurectomy and/or resection of cardiophrenic/mediastinal lymph nodes were included. Imaging articles that merely described thoracic tumor patterns were excluded. A total of nine studies were identified, the oldest originating in 2007. Procedures described were transdiaphragmatic resection of cardiophrenic lymph nodes and pleural disease (n = 5) and video-assisted thoracoscopic and mediastinal tumorectomies including pleurectomy (n = 4). The number of operated patients ranged between 1 and 30 with complete cytoreduction rates ranging between 68 and 100%. No surgical deaths directly related to the thoracic cytoreduction were reported and only one patient (1/30) experienced a postoperative complication in terms of a pneumothorax. None of the studies presented a direct comparison of survival to patients with thoracic disease who did not undergo thoracic cytoreduction, and therefore the survival benefit of thoracic cytoreduction could not be quantified. In conclusion, thoracic cytoreduction in advanced EOC seems feasible and with acceptable morbidity while offering a better understanding of the extent of disease and hence allowing the tailoring of intraabdominal resections. Nevertheless, its direct impact on patients’ survival by a potential overruling of a more adverse tumor biology remains to be established in larger-scale prospective and ideally randomized trials.

Journal article

Meijer LL, Frampton AE, Garajova I, Caparello C, Le Large TYS, Funel N, Vasile E, Stebbing J, Krell J, Kazemier G, Giovannetti Eet al., 2017, Circulating microRNAs as dynamic biomarkers of response to treatment with FOLFIRINOX combination therapy in advanced pancreatic ductal adenocarcinoma, LANCET, Vol: 389, Pages: 68-68, ISSN: 0140-6736

Journal article

Castellano L, Dabrowska A, Pellegrino L, Ottaviani S, Cathcart P, Frampton A, Krell J, Stebbing Jet al., 2017, Sustained expression of miR-26a promotes chromosomal instability and tumorigenesis through regulation of CHFR, Nucleic Acids Research, Vol: 45, Pages: 4401-4412, ISSN: 1362-4962

MicroRNA 26a (miR-26a) reduces cell viability in several cancers, indicating that miR-26a could be used as a therapeutic option in patients. We demonstrate that miR-26a not only inhibits G1-S cell cycle transition and promotes apoptosis, as previously described, but also regulates multiple cell cycle checkpoints. We show that sustained miR-26a over-expression in both breast cancer (BC) cell lines and mouse embryonic fibroblasts (MEFs) induces oversized cells containing either a single-large nucleus or two nuclei, indicating defects in mitosis and cytokinesis. Additionally, we demonstrate that miR-26a induces aneuploidy and centrosome defects and enhances tumorigenesis. Mechanistically, it acts by targeting G1-S transition genes as well as genes involved in mitosis and cytokinesis such as CHFR, LARP1 and YWHAE. Importantly, we show that only the re-expression of CHFR in miR-26a over-expressing cells partially rescues normal mitosis and impairs the tumorigenesis exerted by miR-26a, indicating that CHFR represents an important miR-26a target in the regulation of such phenotypes. We propose that miR-26a delivery might not be a viable therapeutic strategy due to the potential deleterious oncogenic activity of this miRNA.

Journal article

Alifrangis C, Thornton A, Fotopoulou C, Krell J, Gabra Het al., 2016, Response to sunitinib (Sutent) in chemotherapy refractory clear cell ovarian cancer, Gynecologic Oncology Reports, Vol: 18, Pages: 42-44, ISSN: 2352-5789

Journal article

Prado MM, Frampton AE, Giovannetti E, Stebbing J, Castellano L, Krell Jet al., 2016, Investigating miRNA-mRNA regulatory networks using crosslinking immunoprecipitation methods for biomarker and target discovery in cancer, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 16, Pages: 1155-1162, ISSN: 1473-7159

Journal article

Le Large TYS, Prado MM, Krell J, Bijlsma MF, Meijer LL, Kazemier G, Frampton AE, Giovannetti Eet al., 2016, Bioinformatic analysis reveals pancreatic cancer molecular subtypes specific to the tumor and the microenvironment, Expert Review of Molecular Diagnostics, Vol: 16, Pages: 733-736, ISSN: 1473-7159

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by a dense desmoplastic reaction surrounding malignant epithelial cells. Interaction between the epithelial and stromal compartments is suggested to enhance its aggressive nature. Indeed, therapies targeting the stroma, as well as the tumor cells, may improve survival outcomes for patients. The evaluated study by Moffitt et al. used bioinformatic techniques to separate gene expression patterns of normal tissues from PDAC and stroma in a large cohort of samples. The researchers identified two different subtypes of PDAC (‘classical’ and ‘basal-like’) and surrounding stroma (‘normal’ and ‘activated’). The basal-like subtype was associated with worse prognosis and a trend towards better response to adjuvant therapy. Hopefully, the molecular stratification of PDAC will potentially allow more personalized treatment strategies and guide clinical decision making.

Journal article

Frampton AE, Krell J, Mato Prado M, Gall T, Abbassi-Ghadi N, Del Vecchio Blanco G, Funel N, Giovannetti E, Castellano L, Basyouny M, Habib N, Kaltsidis H, Vlavianos P, Stebbing J, Jiao Let al., 2016, Prospective validation of microRNA signatures for detecting pancreatic malignant transformation in endoscopic-ultrasound guided fine-needle aspiration biopsies, Oncotarget, Vol: 7, ISSN: 1949-2553

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Novel biomarkers are required to aid treatment decisions and improve patient outcomes. MicroRNAs (miRNAs) are potentially ideal diagnostic biomarkers, as they are stable molecules, and tumour and tissue specific. Results: Logistic regression analysis revealed an endoscopic-ultrasound fine-needle aspiration (EUS-FNA) 2-miRNA classifier (miR-21 + miR-155) capable of distinguishing benign from malignant pancreatic lesions with a sensitivity of 81.5% and a specificity of 85.7% (AUC 0.930). Validation FNA cohorts confirmed both miRNAs were overexpressed in malignant disease, while circulating miRNAs performed poorly.Methods: Fifty-five patients with a suspicious pancreatic lesion on cross-sectional imaging were evaluated by EUS-FNA. At echo-endoscopy, the first part of the FNA was sent for cytological assessment and the second part was used for total RNA extraction. Candidate miRNAs were selected after careful review of the literature and expression was quantified by qRT-PCR. Validation was performed on an independent cohort of EUS-FNAs, as well as formalin-fixed paraffin embedded (FFPE) and plasma samples.Conclusions: We provide further evidence for using miRNAs as diagnostic biomarkers for pancreatic malignancy. We demonstrate the feasibility of using fresh EUS-FNAs to establish miRNA-based signatures unique to pancreatic malignant transformation and the potential to enhance risk stratification and selection for surgery.

Journal article

Bidard F-C, Peeters D, Fehm T, Nole F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali D, Garcia-Saenz JA, Stebbing J, Caldas C, Gazzaniga P, Manso L, Zamarchi R, Fernandez de Lascoiti A, de Mattos-Arruda L, Ignatiadis M, van Laere SJ, Meier-Stiegen F, Sandri M-T, Vidal-Martinez J, Politaki E, Consoli F, Bottini A, Diaz-Rubio E, Krell J, Dawson S-J, Raimondi C, Rutten A, Janni W, Munzone E, Caranana V, Agelaki S, Almici C, Dirix L, Solomayer E, Zorzino L, Reis-Filho JS, Squifflet P, Pantel K, Belie N, Sleijfers S, Pierga J-Y, Michiels Set al., 2016, Circulating tumor cells count-based nomograms to predict survival of metastatic breast cancer patients: Results from the European pooled analysis, 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Bidard F-C, Peeters D, Fehm T, Nole F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali D, Garcia-Saenz JA, Stebbing J, Caldas C, Gazzaniga P, Manso L, Zamarchi R, de Lascoiti AF, de Mattos-Arruda L, Ignatiadis M, van Laere SJ, Meier-Stiegen F, Sandri M-T, Vidal-Martinez J, Politaki E, Consoli F, Bottini A, Diaz-Rubio E, Krell J, Dawson S-J, Raimondi C, Rutten A, Janni W, Munzone E, Caranana V, Agelaki S, Almici C, Dirix L, Solomayer E, Zorzino L, Reis-Filho JS, Squifflet P, Pantel K, Beije N, Sleijfers S, Pierga J-Y, Michiels Set al., 2016, Circulating tumor cells count-based nomograms to predict survival of metastatic breast cancer patients: Results from the European pooled analysis, 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Bidard F-C, Peeters D, Fehm T, Nole F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali D, Garcia-Saenz JA, Stebbing J, Caldas C, Gazzaniga P, Manso L, Zamarchi R, de Lascoiti AF, de Mattos-Arruda L, Ignatiadis M, van Laere SJ, Meier-Stiegen F, Sandri M-T, Vidal-Martinez J, Politaki E, Consoli F, Bottini A, Diaz-Rubio E, Krell J, Dawson S-J, Raimondi C, Rutten A, Janni W, Munzone E, Caranana V, Agelaki S, Almici C, Dirix L, Solomayer E, Zorzino L, Reis-Filho JS, Squifflet P, Pantel K, Beije N, Sleijfers S, Pierga J-Y, Michiels Set al., 2016, Circulating tumor cells count-based nomograms to predict survival of metastatic breast cancer patients: Results from the European pooled analysis, 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Pardo OE, Munro CE, Castellano L, Hu Y, Mauri F, Krell J, Lara R, Pinho FG, Pellegrino L, Pshezhetskiy D, Wang Y, Waxman J, Seckl MJ, Stebbing Jet al., 2016, miR-515-5p controls cancer cell migration through MARK4 regulation, EMBO Reports, Vol: 17, Pages: 570-584, ISSN: 1469-221X

Here we show that miR-515-5p inhibits cancer cell migration and metastasis. RNA-seqanalyses of both estrogen receptor-positive and negative breast cancer cells overexpressingmiR-515-5p reveals down-regulation of NRAS, FZD4, CDC42BPA, PIK3C2Band MARK4 mRNAs. We demonstrate that miR-515-5p inhibits MARK4 directly 3’UTRinteraction and that MARK4 knockdown mimics the effect of miR-515-5p on breast andlung cancer cell migration. MARK4 over-expression rescues the inhibitory effects of miR-515-5p, suggesting miR-515-5p mediates this process through MARK4 down-regulation.Furthermore, miR-515-5p expression is reduced in metastases compared to primarytumours derived from both in vivo xenografts and samples from patients with breastcancer. Conversely, miR-515-5p overexpression prevents tumour cell dissemination ina mouse metastatic model. Moreover, high miR-515-5p and low MARK4 expressioncorrelate with increased breast and lung cancer patients’ survival, respectively. Takentogether, these data demonstrate the importance of miR-515-5p/MARK4 regulation incell migration and metastasis across two common cancers.

Journal article

Mato Prado M, Frampton AE, Stebbing J, Krell Jet al., 2016, Single-cell sequencing in cancer research., Expert Review of Molecular Diagnostics, Vol: 16, Pages: 1-5, ISSN: 1473-7159

Genome-wide single-cell sequencing investigations have the potential to classify individual cells within a tumor mass. In recent years, various single-cell DNA and RNA quantification techniques have facilitated significant advances in our ability to classify subpopulations of cells within a heterogeneous population. These approaches provide the possibility of unraveling the complex variability in genetic, epigenetic and transcriptional interactions that occur within identical cells in a tumor. This should enhance our knowledge of the underlying biological phenotypes and could have a huge impact in designing more precise anticancer treatments in order to improve outcomes and avoid tumor resistance. In addition, single-cell sequencing analysis has the potential to allow the development of better diagnostic and prognostic biomarkers, and thus aid the delivery of more personalized targeted cancer therapy. Nevertheless, further research is still required to overcome technical, biological and computational problems before clinical application.

Journal article

Krell J, Stebbing J, Carissimi C, Dabrowska AF, de Giorgio A, Frampton AE, Harding V, Fulci V, Macino G, Colombo T, Castellano Let al., 2015, TP53 regulates miRNA association with AGO2 to remodel the miRNA-mRNA interaction network., Genome Research, ISSN: 1549-5469

DNA damage activates TP53-regulated surveillance mechanisms that are crucial in suppressing tumorigenesis. TP53 orchestrates these responses directly by transcriptionally modulating genes, including microRNAs (miRNAs), and by regulating miRNA biogenesis through interacting with the DROSHA complex. However, whether the association between miRNAs and AGO2 is regulated following DNA damage is not yet known. Here we show that, following DNA damage, TP53 interacts with AGO2 to induce or reduce AGO2's association of a subset of miRNAs, including multiple let-7 family members. Furthermore, we show that specific mutations in TP53 decrease rather than increase the association of let-7 family miRNAs, reducing their activity without preventing TP53 from interacting with AGO2. This is consistent with the oncogenic properties of these mutants. Using AGO2 RIP-seq and PAR-CLIP-seq we show that the DNA-damage-induced increase in binding of let-7 family members to the RISC complex is functional. We unambiguously determine the global miRNA-mRNA interaction networks involved in the DNA damage response, validating them through the identification of miRNA-target chimeras formed by endogenous ligation reactions. We find that the target complementary region of the let-7 seed tends to have highly fixed positions and more variable ones. Additionally, we observe that miRNAs whose cellular abundance or differential association with AGO2 is regulated by TP53 are involved in an intricate network of regulatory feedback and feedforward circuits. TP53-mediated regulation of AGO2-miRNA interaction represents a new mechanism of miRNA regulation in carcinogenesis.

Journal article

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00691517&limit=30&person=true