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Article ; Online: MHC Class II is Induced by IFNγ and Follows Three Distinct Patterns of Expression in Colorectal Cancer Organoids.

Pickles, Oliver J / Wanigasooriya, Kasun / Ptasinska, Anetta / Patel, Akshay J / Robbins, Helen L / Bryer, Claire / Whalley, Celina M / Tee, Louise / Lal, Neeraj / Pinna, Claudia M A / Elzefzafy, Nahla / Taniere, Philippe / Beggs, Andrew D / Middleton, Gary M

Cancer research communications

2023 Volume 3, Issue 8, Page(s) 1501–1513

Abstract: Tumor-specific MHC class II (tsMHC-II) expression impacts tumor microenvironmental immunity. tsMHC-II positive cancer cells may act as surrogate antigen-presenting cells and targets for CD4: Significance: Cancer cell expression of MHC class II ... ...

Abstract	Tumor-specific MHC class II (tsMHC-II) expression impacts tumor microenvironmental immunity. tsMHC-II positive cancer cells may act as surrogate antigen-presenting cells and targets for CD4 Significance: Cancer cell expression of MHC class II significantly impacts tumor microenvironmental immunity. Previous studies investigating mechanisms of repression of IFNγ-inducible class II expression using cell lines demonstrate epigenetic silencing of IFN pathway genes as a frequent immune evasion strategy. Unlike cell lines, patient-derived organoids maintain epigenetic fidelity to tissue of origin. In the first such study, we analyze patterns, dynamics, and epigenetic control of IFNγ-induced class II expression in a series of colorectal cancer organoids.
MeSH term(s)	Humans ; Genes, MHC Class II ; Interferon-gamma/pharmacology ; Methylation ; Cell Line ; Colorectal Neoplasms/genetics
Chemical Substances	Interferon-gamma (82115-62-6)
Language	English
Publishing date	2023-08-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.CRC-23-0091
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Paradox breaker BRAF inhibitors have comparable potency and MAPK pathway reactivation to encorafenib in BRAF mutant colorectal cancer.

Pickles, Oliver J / Drozd, Aneta / Tee, Louise / Beggs, Andrew D / Middleton, Gary W

Oncotarget

2020 Volume 11, Issue 34, Page(s) 3188–3197

Abstract: The BEACON CRC trial demonstrated a survival advantage over chemotherapy for a combination of targeted agents comprising the potent BRAF inhibitor encorafenib together with cetuximab and binimetinib. Resistance to BRAF inhibition in CRC arises in part ... ...

Abstract	The BEACON CRC trial demonstrated a survival advantage over chemotherapy for a combination of targeted agents comprising the potent BRAF inhibitor encorafenib together with cetuximab and binimetinib. Resistance to BRAF inhibition in CRC arises in part through the generation and activation of RAF dimers resulting in MEK-ERK pathway reactivation. Paradox breaker BRAF inhibitors, such as PLX8394, are designed to inhibit RAF dimer formation. We analyzed whether paradox breakers reduce pathway reactivation and so have enhanced potency compared with encorafenib in BRAF mutant CRC. The potency of encorafenib and PLX8394 was greater than vemurafenib and the degree of pathway reactivation somewhat less. However, dose response curves for encorafenib and PLX8394 were similar and there was no significant differences in degree of pathway reactivation. To our knowledge these data represent the first comparative data of encorafenib and paradox breaker inhibitors in BRAF mutant CRC. Whilst these results support further investigation of PLX8394, all three agents tested reactivated the pathway in melanoma cells, a disease in which monotherapy is effective. Strategies focused on restricting RAF dimerization fail to address the impact that specific context of BRAF mutation in CRC has on targeted therapy outcomes.
Language	English
Publishing date	2020-08-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.27681
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Article: Patient Derived Organoids Confirm That PI3K/AKT Signalling Is an Escape Pathway for Radioresistance and a Target for Therapy in Rectal Cancer.

Wanigasooriya, Kasun / Barros-Silva, Joao D / Tee, Louise / El-Asrag, Mohammed E / Stodolna, Agata / Pickles, Oliver J / Stockton, Joanne / Bryer, Claire / Hoare, Rachel / Whalley, Celina M / Tyler, Robert / Sillo, Toritseju / Yau, Christopher / Ismail, Tariq / Beggs, Andrew D

Frontiers in oncology

2022 Volume 12, Page(s) 920444

Abstract: Objectives: Partial or total resistance to preoperative chemoradiotherapy occurs in more than half of locally advanced rectal cancer patients. Several novel or repurposed drugs have been trialled to improve cancer cell sensitivity to radiotherapy, with ... ...

Abstract	Objectives: Partial or total resistance to preoperative chemoradiotherapy occurs in more than half of locally advanced rectal cancer patients. Several novel or repurposed drugs have been trialled to improve cancer cell sensitivity to radiotherapy, with limited success. We aimed to understand the mechanisms of resistance to chemoradiotherapy in rectal cancer using patient derived organoid models. Design: To understand the mechanisms underlying this resistance, we compared the pre-treatment transcriptomes of patient-derived organoids (PDO) with measured radiotherapy sensitivity to identify biological pathways involved in radiation resistance coupled with single cell sequencing, genome wide CRISPR-Cas9 and targeted drug screens. Results: RNA sequencing enrichment analysis revealed upregulation of PI3K/AKT/mTOR and epithelial mesenchymal transition pathway genes in radioresistant PDOs. Single-cell sequencing of pre & post-irradiation PDOs showed mTORC1 and PI3K/AKT upregulation, which was confirmed by a genome-wide CRSIPR-Cas9 knockout screen using irradiated colorectal cancer (CRC) cell lines. We then tested the efficiency of dual PI3K/mTOR inhibitors in improving cancer cell sensitivity to radiotherapy. After irradiation, significant AKT phosphorylation was detected ( Conclusions: The PI3K/AKT/mTOR pathway upregulation contributes to radioresistance and its targeted pharmacological inhibition leads to significant radiosensitisation in CRC organoids, making it a potential target for clinical trials.
Language	English
Publishing date	2022-07-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.920444
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Article ; Online: Immune checkpoint blockade: releasing the breaks or a protective barrier to COVID-19 severe acute respiratory syndrome?

Pickles, Oliver J / Lee, Lennard Y W / Starkey, Thomas / Freeman-Mills, Luke / Olsson-Brown, Anna / Cheng, Vinton / Hughes, Daniel J / Lee, Alvin / Purshouse, Karin / Middleton, Gary

British journal of cancer

2020 Volume 123, Issue 5, Page(s) 691–693

Abstract: The rapid emergence of COVID-19 has sent shockwaves through healthcare systems globally, with cancer patients at increased risk. The interplay of the virus and host immune system has been implicated in the development of ARDS. Immunotherapy agents have ... ...

Abstract	The rapid emergence of COVID-19 has sent shockwaves through healthcare systems globally, with cancer patients at increased risk. The interplay of the virus and host immune system has been implicated in the development of ARDS. Immunotherapy agents have the potential to adversely potentiate this phenomenon, requiring careful real-world observation.
MeSH term(s)	B7-H1 Antigen/antagonists & inhibitors ; Betacoronavirus/immunology ; COVID-19 ; CTLA-4 Antigen/antagonists & inhibitors ; Clinical Decision-Making ; Coronavirus Infections/epidemiology ; Coronavirus Infections/immunology ; Coronavirus Infections/virology ; Humans ; Immunosuppression Therapy/adverse effects ; Immunosuppression Therapy/methods ; Immunosuppressive Agents/adverse effects ; Immunosuppressive Agents/pharmacology ; Immunosuppressive Agents/therapeutic use ; Incidence ; Interleukin-6/antagonists & inhibitors ; Interleukin-6/blood ; Neoplasms/therapy ; Oncologists/psychology ; Pandemics ; Pneumonia, Viral/epidemiology ; Pneumonia, Viral/immunology ; Pneumonia, Viral/virology ; Respiratory Distress Syndrome/immunology ; SARS-CoV-2 ; Treatment Outcome
Chemical Substances	B7-H1 Antigen ; CD274 protein, human ; CTLA-4 Antigen ; CTLA4 protein, human ; IL6 protein, human ; Immunosuppressive Agents ; Interleukin-6
Keywords	covid19
Language	English
Publishing date	2020-06-16
Publishing country	England
Document type	Journal Article
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-020-0930-7
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Article ; Online: Immune checkpoint blockade

Pickles, Oliver J. / Lee, Lennard Y. W. / Starkey, Thomas / Freeman-Mills, Luke / Olsson-Brown, Anna / Cheng, Vinton / Hughes, Daniel J. / Lee, Alvin / Purshouse, Karin / Middleton, Gary

British Journal of Cancer

releasing the breaks or a protective barrier to COVID-19 severe acute respiratory syndrome?

2020 Volume 123, Issue 5, Page(s) 691–693

Keywords	Cancer Research ; Oncology ; covid19
Language	English
Publisher	Springer Science and Business Media LLC
Publishing country	us
Document type	Article ; Online
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-020-0930-7
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Article: Immune checkpoint blockade: releasing the breaks or a protective barrier to COVID-19 severe acute respiratory syndrome?

Pickles, Oliver J / Lee, Lennard Y W / Starkey, Thomas / Freeman-Mills, Luke / Olsson-Brown, Anna / Cheng, Vinton / Hughes, Daniel J / Lee, Alvin / Purshouse, Karin / Middleton, Gary

Br J Cancer

Abstract	The rapid emergence of COVID-19 has sent shockwaves through healthcare systems globally, with cancer patients at increased risk. The interplay of the virus and host immune system has been implicated in the development of ARDS. Immunotherapy agents have the potential to adversely potentiate this phenomenon, requiring careful real-world observation.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #601809
Database	COVID19

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Article ; Online: Satisfaction with cognitive remediation therapy: its effects on implementation and outcomes using the cognitive remediation satisfaction scale.

Schizophrenia (Heidelberg, Germany)

2023 Volume 9, Issue 1, Page(s) 67

Abstract: Cognitive Remediation (CR) improves cognition and functioning but is implemented in a variety of ways (independent, group and one-to-one). There is no information on whether service users find these implementation methods acceptable or if their ... ...

Abstract	Cognitive Remediation (CR) improves cognition and functioning but is implemented in a variety of ways (independent, group and one-to-one). There is no information on whether service users find these implementation methods acceptable or if their satisfaction influences CR outcomes. We used mixed participatory methods, including focus groups, to co-develop a CR satisfaction scale. This was refined using three psychometric criteria (Cronbach's alpha, item discrimination, test-retest agreement) to select items. Factor analysis explored potential substructures. The refined measure was used in structural equation joint modelling to evaluate whether satisfaction with CR is affected by implementation method and treatment engagement or influences recovery outcome, using data from a randomised controlled trial. Four themes (therapy hours, therapist, treatment effects, computer use) generated a 31-item Cognitive Remediation Satisfaction scale (CRS) that reduced to 18 Likert items, 2 binary and 2 open-ended questions following psychometric assessment. CRS had good internal consistency (Alpha = 0.814), test-retest reliability (r= 0.763), and concurrent validity using the Working Alliance Inventory (r = 0.56). A 2-factor solution divided items into therapy engagement and therapy effects. Satisfaction was not related to implementation method but was significantly associated with CR engagement. Therapy hours were significantly associated with recovery, but there was no direct effect of satisfaction on outcome. Although satisfaction is important to therapy engagement, it has no direct effect on outcome. CR therapy hours directly affect outcome irrespective of which implementation model is used, so measuring satisfaction early might help to identify those who are likely to disengage. The study has mixed methods design.
Language	English
Publishing date	2023-09-30
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	3133210-9
ISSN	2754-6993 ; 2754-6993
ISSN (online)	2754-6993
ISSN	2754-6993
DOI	10.1038/s41537-023-00390-9
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Article ; Online: KRAS Mutation and Consensus Molecular Subtypes 2 and 3 Are Independently Associated with Reduced Immune Infiltration and Reactivity in Colorectal Cancer.

Lal, Neeraj / White, Brian S / Goussous, Ghaleb / Pickles, Oliver / Mason, Mike J / Beggs, Andrew D / Taniere, Philippe / Willcox, Benjamin E / Guinney, Justin / Middleton, Gary W

Clinical cancer research : an official journal of the American Association for Cancer Research

2017 Volume 24, Issue 1, Page(s) 224–233

Abstract: Purpose: ...

Abstract	Purpose:
MeSH term(s)	Biomarkers, Tumor ; Chemokine CXCL10/metabolism ; Colorectal Neoplasms/diagnosis ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/immunology ; Colorectal Neoplasms/metabolism ; Humans ; Immunohistochemistry ; Immunomodulation ; Interferon-gamma/metabolism ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Mutation ; Proto-Oncogene Proteins p21(ras)/genetics ; STAT1 Transcription Factor/metabolism
Chemical Substances	Biomarkers, Tumor ; CXCL10 protein, human ; Chemokine CXCL10 ; KRAS protein, human ; STAT1 Transcription Factor ; STAT1 protein, human ; Interferon-gamma (82115-62-6) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2017-10-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-17-1090
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Article ; Online: Psychological, social and financial impacts of COVID-19 on culturally and linguistically diverse communities in Sydney, Australia.

Muscat, Danielle Marie / Ayre, Julie / Mac, Olivia / Batcup, Carys / Cvejic, Erin / Pickles, Kristen / Dolan, Hankiz / Bonner, Carissa / Mouwad, Dana / Zachariah, Dipti / Turalic, Una / Santalucia, Yvonne / Chen, Tingting / Vasic, Gordana / McCaffery, Kirsten J

BMJ open

2022 Volume 12, Issue 5, Page(s) e058323

Abstract: Objective: To explore the psychological, social and financial outcomes of COVID-19-and the sociodemographic predictors of those outcomes-among culturally and linguistically diverse communities in Sydney, Australia.: Design: Cross-sectional survey ... ...

Abstract	Objective: To explore the psychological, social and financial outcomes of COVID-19-and the sociodemographic predictors of those outcomes-among culturally and linguistically diverse communities in Sydney, Australia. Design: Cross-sectional survey informed by the Framework for Culturally Competent Health Research conducted between March and July 2021. Setting: Participants who primarily speak a language other than English at home were recruited from Greater Western Sydney, New South Wales. Participants: 708 community members (mean age: 45.4 years (range 18-91)). 88% (n=622) were born outside of Australia, 31% (n=220) did not speak English well or at all, and 41% (n=290) had inadequate health literacy. Outcome measures: Thirteen items regarding COVID-19-related psychological, social and financial outcomes were adapted from validated scales, previous surveys or co-designed in partnership with Multicultural Health and interpreter service staff. Logistic regression models (using poststratification weighted frequencies) were used to identify sociodemographic predictors of outcomes. Surveys were available in English or translated (11 languages). Results: In this analysis, conducted prior to the 2021 COVID-19 outbreak in Sydney, 25% of the sample reported feeling nervous or stressed most/all of the time and 22% felt lonely or alone most/all of the time. A quarter of participants reported negative impacts on their spousal relationships as a result of COVID-19 and most parents reported that their children were less active (64%), had more screen time (63%) and were finding school harder (45%). Mean financial burden was 2.9/5 (95% CI 2.8 to 2.9). Regression analyses consistently showed more negative outcomes for those with comorbidities and differences across language groups. Conclusion: Culturally and linguistically diverse communities experience significant psychological, social and financial impacts of COVID-19. A whole-of-government approach is needed to support rapid co-design of culturally safe support packages in response to COVID-19 and other national health emergencies, tailored appropriately to specific language groups and accounting for pre-existing health disparities.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Australia/epidemiology ; COVID-19/epidemiology ; Child ; Cross-Sectional Studies ; Health Literacy ; Humans ; Language ; Middle Aged ; Young Adult
Language	English
Publishing date	2022-05-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2021-058323
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Effects of tea consumption on renal function in a metropolitan Chinese population: the Guangzhou biobank cohort study.

van Hasselt, Tim J / Pickles, Oliver / Midgley-Hunt, Alex / Jiang, Chao Quiang / Zhang, Wei Sen / Cheng, Kar Keung / Thomas, Graham Neil / Lam, Tai Hing

Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation

2014 Volume 24, Issue 1, Page(s) 26–31

Abstract: Objective: Green tea consumption has been associated with many prophylactic health benefits. This study examined for the first time associations between tea consumption and renal function in a Chinese population.: Design and methods: Cross-sectional ... ...

Abstract	Objective: Green tea consumption has been associated with many prophylactic health benefits. This study examined for the first time associations between tea consumption and renal function in a Chinese population. Design and methods: Cross-sectional baseline data including demographics, and lifestyle and weekly consumption of green, black, and oolong tea were analyzed from 12,428 ambulatory subjects aged 50 to 85 years (67.3% female) that were randomly selected from the membership list of a community social and welfare association in Guangzhou, China. Intervention: Associations between tea consumption and renal function were assessed using regression analyses to adjust for potential confounding factors. Main outcome measure: Renal function was assessed using the estimated glomerular filtration rate (eGFR) and in a subcohort of 1,910 participants using a spot urinary albumin-to-creatinine ratio. Results: Six thousand eight hundred and seventy-two participants drank at least 1 type of tea. Oolong tea consumption was negatively associated with eGFR (β-coefficient -0.019, P = .025), but in a gender-stratified analysis this was not the case. In men, black tea was positively associated with eGFR (β-coefficient 0.037, P = .013), but not in women (β-coefficient -0.002, P = .856). Otherwise, no statistically significant consistent associations between the measures of renal function and consumption of green tea, black tea, or oolong tea individually or total tea consumption were identified. Conclusion: Overall there was no clear evidence to suggest any consistent association between renal function and tea consumption in this large population-based study of older Chinese individuals.
MeSH term(s)	Aged ; Aged, 80 and over ; Albuminuria/metabolism ; Asian Continental Ancestry Group ; China ; Cohort Studies ; Creatinine/urine ; Cross-Sectional Studies ; Female ; Glomerular Filtration Rate ; Humans ; Kidney/physiology ; Life Style ; Male ; Middle Aged ; Regression Analysis ; Risk Factors ; Tea
Chemical Substances	Tea ; Creatinine (AYI8EX34EU)
Language	English
Publishing date	2014-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1080003-7
ISSN	1532-8503 ; 1051-2276
ISSN (online)	1532-8503
ISSN	1051-2276
DOI	10.1053/j.jrn.2013.08.006
Database	MEDical Literature Analysis and Retrieval System OnLINE

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