ORCID Profile
0000-0002-3283-307X
Current Organisations
Memorial Sloan Kettering Cancer Center
,
Johannes Kepler Universität Linz
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Publisher: Springer Science and Business Media LLC
Date: 07-11-2022
DOI: 10.1186/S12961-022-00901-7
Abstract: In 2019, WHO prioritized updating recommendations relating to three labour induction topics: labour induction at or beyond term, mechanical methods for labour induction, and outpatient labour induction. As part of this process, we aimed to review the evidence addressing factors beyond clinical effectiveness (values, human rights and sociocultural acceptability, health equity, and economic and feasibility considerations) to inform WHO Guideline Development Group decision-making using the WHO-INTEGRATE evidence-to-decision framework, and to reflect on how methods for identifying, synthesizing and integrating this evidence could be improved. We adapted the framework to consider the key criteria and sub-criteria relevant to our intervention. We searched for qualitative and other evidence across a variety of sources and mapped the eligible evidence to country income setting and perspective. Eligibility assessment and quality appraisal of qualitative evidence syntheses was undertaken using a two-step process informed by the ENTREQ statement. We adopted an iterative approach to interpret the evidence and provided both summary and detailed findings to the decision-makers. We also undertook a review to reflect on opportunities to improve the process of applying the framework and identifying the evidence. Using the WHO-INTEGRATE framework allowed us to explore health rights and equity in a systematic and transparent way. We identified a lack of qualitative and other evidence from low- and middle-income settings and in populations that are most impacted by structural inequities or traditionally excluded from research. Our process review highlighted opportunities for future improvement, including adopting more systematic evidence mapping methods and working with social science researchers to strengthen theoretical understanding, methods and interpretation of the evidence. Using the WHO-INTEGRATE evidence-to-decision framework to inform decision-making in a global guideline for induction of labour, we identified both challenges and opportunities relating to the lack of evidence in populations and settings of need and interest the theoretical approach informing the development and application of WHO-INTEGRATE and interpretation of the evidence. We hope these insights will be useful for primary researchers as well as the evidence synthesis and health decision-making communities, and ultimately contribute to a reduction in health inequities.
Publisher: Elsevier BV
Date: 2019
Publisher: MDPI AG
Date: 09-06-2022
Abstract: Chemotherapy is a mainstay of colorectal cancer treatment, and often involves a combination drug regime. CpG island methylator phenotype (CIMP)-positive tumors are potentially more responsive to the topoisomerase-inhibitor irinotecan. The mechanistic basis of the increased sensitivity of CIMP cancers to irinotecan is poorly understood. Mutated in Colorectal Cancer (MCC) is emerging as a multifunctional tumor suppressor gene in colorectal and liver cancers, and has been implicated in drug responsiveness. Here, we found that CIMP tumors undergo MCC loss almost exclusively via promoter hypermethylation rather than copy number variation or mutations. A subset of cancers display hypomethylation which is also associated with low MCC expression, particularly in rectal cancer, where CIMP is rare. MCC knockdown or deletion was found to sensitize cells to SN38 (the active metabolite of irinotecan) or the PARP-inhibitor Olaparib. A synergistic effect on cell death was evident when these drugs were used concurrently. The improved SN38/irinotecan efficacy was accompanied by the down-regulation of DNA repair genes. Thus, differential methylation of MCC is potentially a valuable biomarker to identify colorectal cancers suitable for irinotecan therapy, possibly in combination with PARP inhibitors.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2017
DOI: 10.1038/ONC.2017.362
Abstract: E-cadherin and β-catenin are key proteins that are essential in the formation of the epithelial cell layer in the colon but their regulatory pathways that are disrupted in cancer metastasis are not completely understood. Mutated in colorectal cancer (MCC) is a tumour suppressor gene that is silenced by promoter methylation in colorectal cancer and particularly in patients with increased lymph node metastasis. Here, we show that MCC methylation is found in 45% of colon and 24% of rectal cancers and is associated with proximal colon, poorly differentiated, circumferential and mucinous tumours as well as increasing T stage and larger tumour size. Knockdown of MCC in HCT116 colon cancer cells caused a reduction in E-cadherin protein level, which is a hallmark of epithelial-mesenchymal transition in cancer, and consequently diminished the E-cadherin/β-catenin complex. MCC knockdown disrupted cell-cell adhesive strength and integrity in the dispase and transepithelial electrical resistance assays, enhanced hepatocyte growth factor-induced cell scatter and increased tumour cell invasiveness in an organotypic assay. The Src/Abl inhibitor dasatinib, a candidate anti-invasive drug, abrogated the invasive properties induced by MCC deficiency. Mechanistically, we establish that MCC interacts with the E-cadherin/β-catenin complex. These data provide a significant advance in the current understanding of cell-cell adhesion in colon cancer cells.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2021
DOI: 10.1038/S41586-021-03995-1
Abstract: Derailed cytokine and immune cell networks account for the organ damage and the clinical severity of COVID-19 (refs.
Location: Australia
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Fahad Benthani.