Implications For Personalized Medicine Research Articles

An Exploration of Organoid Technology: Present Advancements, Applications, and Obstacles.

Organoids are in vitro models that exhibit a three-dimensional structure and effectively replicate the structural and physiological features of human organs. The capacity to research complex biological processes and disorders in a controlled setting is laid out by these miniature organ-like structures. This work examines the potential applications of organoid technology, as well as the challenges and future directions associated with its implementation. It aims to emphasize the pivotal role of organoids in disease modeling, drug discovery, developmental biology, precision medicine, and fundamental research. The manuscript was put together by conducting a comprehensive literature review, which involved an in-depth evaluation of globally renowned scientific research databases. The field of organoids has generated significant attention due to its potential applications in tissue development and disease modelling, as well as its implications for personalised medicine, drug screening, and cell-based therapies. The utilisation of organoids has proven to be effective in the examination of various conditions, encompassing genetic disorders, cancer, neurodevelopmental disorders, and infectious diseases. The exploration of the wider uses of organoids is still in its early phases. Research shall be conducted to integrate 3D organoid systems as alternatives for current models, potentially improving both fundamental and clinical studies in the future.

Ethical and legal considerations influencing human involvement in the implementation of artificial intelligence in a clinical pathway: A multi-stakeholder perspective.

Ethical and legal factors will have an important bearing on when and whether automation is appropriate in healthcare. There is a developing literature on the ethics of artificial intelligence (AI) in health, including specific legal or regulatory questions such as whether there is a right to an explanation of AI decision-making. However, there has been limited consideration of the specific ethical and legal factors that influence when, and in what form, human involvement may be required in the implementation of AI in a clinical pathway, and the views of the wide range of stakeholders involved. To address this question, we chose the exemplar of the pathway for the early detection of Barrett's Oesophagus (BE) and oesophageal adenocarcinoma, where Gehrung and colleagues have developed a "semi-automated", deep-learning system to analyse samples from the CytospongeTM TFF3 test (a minimally invasive alternative to endoscopy), where AI promises to mitigate increasing demands for pathologists' time and input. We gathered a multidisciplinary group of stakeholders, including developers, patients, healthcare professionals and regulators, to obtain their perspectives on the ethical and legal issues that may arise using this exemplar. The findings are grouped under six general themes: risk and potential harms; impacts on human experts; equity and bias; transparency and oversight; patient information and choice; accountability, moral responsibility and liability for error. Within these themes, a range of subtle and context-specific elements emerged, highlighting the importance of pre-implementation, interdisciplinary discussions and appreciation of pathway specific considerations. To evaluate these findings, we draw on the well-established principles of biomedical ethics identified by Beauchamp and Childress as a lens through which to view these results and their implications for personalised medicine. Our findings are not only relevant to this context but have implications for AI in digital pathology and healthcare more broadly.

EMQN best practice guidelines for genetic testing in dystrophinopathies

Dystrophinopathies are X-linked diseases, including Duchenne muscular dystrophy and Becker muscular dystrophy, due to DMD gene variants. In recent years, the application of new genetic technologies and the availability of new personalised drugs have influenced diagnostic genetic testing for dystrophinopathies. Therefore, these European best practice guidelines for genetic testing in dystrophinopathies have been produced to update previous guidelines published in 2010.These guidelines summarise current recommended technologies and methodologies for analysis of the DMD gene, including testing for deletions and duplications of one or more exons, small variant detection and RNA analysis. Genetic testing strategies for diagnosis, carrier testing and prenatal diagnosis (including non-invasive prenatal diagnosis) are then outlined. Guidelines for sequence variant annotation and interpretation are provided, followed by recommendations for reporting results of all categories of testing. Finally, atypical findings (such as non-contiguous deletions and dual DMD variants), implications for personalised medicine and clinical trials and incidental findings (identification of DMD gene variants in patients where a clinical diagnosis of dystrophinopathy has not been considered or suspected) are discussed.

PO-523 Sensitivity of colorectal cancer (CRC) CRIS subtypes to SMAC mimetic birinapant with standard of care chemotherapeutics: implications for personalised medicine

IntroductionColorectal cancer (CRC) is a worldwide cause of death and requires better treatment options. The stratification of CRC cell-lines into tumour representative molecular subtypes may improve drug screening in-vitro to identify improved chemotherapeutics. The CRIS classifier identifies five ‘CRC intrinsic subtypes’ within the cancer cell transcriptome: A, B, C, D and E. This classifier improves cell line subtype mapping by considering only tumour cell transcripts. The inhibitor of apoptosis (IAP) proteins are promising targets in personalised medicine as CRC tumours dysregulate IAPs to avoid apoptosis. This study explored the efficacy of Birinapant - a potent SMAC mimetic and antagonist of IAPs, along with synergistic agents to promote optimal cell death in vitro using a model of CRC intrinsic subtypes.Material and methodsThe CRIS classifier analysis was performed on 150 CRC cell transcriptomes to select 10 cell lines: CRIS A (DLD-1, LS174T), CRIS B (LoVo, HT29), CRIS C (Gp5D, LIM1215), CRIS D (HCT116, RKO) and CRIS E (HCT116 p53-/-, LS513). The cells were treated with 1 µM Birinapant alone, and/or the cytotoxic pair Oxaliplatin and 5-Fluorouracil (2 µM, 10 µM), and/or TNF-alpha. Post-treatment cellular sensitivity was measured at 24, 48 and 72 hours by assessing Annexin V/Propidium Iodide positivity using high content microscopy.Results and discussionsThe cell death data from the entire panel showed that Birinapant cannot induce apoptosis when administered alone. However, Birinapant elicits synergistic effects in combination with Oxaliplatin/5-Flourouracil, or the pro-inflammatory cytokine TNF-alpha. The greatest degree of sensitivity was observed in the HCT116 and RKO CRIS D cell lines and least in the DLD1 and HT29 CRIS A subtypes. Of note, the p53-deficient HCT116 CRIS E model was less sensitive to the combined effects of Birinapant and chemotherapy, suggesting an important role for p53 in mediating this synergy.ConclusionFuture work will expand the analysis to more CRIS D cell lines and investigate the molecular mechanisms behind the p53-dependence of the chemotherapy/IAP antagonist interactions. These results have clinical relevance as in parallel studies, we have shown that patients with CRIS D subtype tumours have a suboptimal response to standard-of-care chemotherapy.1Reference1. WL Allen et al., JCO Precision Oncology, 2018 (in press)

A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine

BackgroundPrimary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels.MethodsIn this multi-institutional study, we first examined the histological features displayed by each collected tumour (n = 74) and analysed their etiological relationship with human papillomavirus (HPV) infection. The intratumoural immune cell subsets (CD4, CD8, Foxp3), the expression of immune checkpoints (PD-1, PD-L1), the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined. Finally, the prognostic significance of each clinicopathological variable was assessed.ResultsPhenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities. Importantly, anal gland/transitional-type cancers, which poorly respond to standard treatments, displayed less mutations in downstream effectors of the EGFR signalling pathway (i.e., KRAS and NRAS) and demonstrated a significantly higher expression of the immune inhibitory ligand-receptor pair PD-1/PD-L1 compared to their counterparts arising from the colorectal mucosa.ConclusionsTaken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits.

Exploring genetic and epigenetic variation of the cannabinoid receptor-1 gene; implications for personalised medicine

Exploring genetic and epigenetic variation of the cannabinoid receptor-1 gene; implications for personalised medicine

High-depth sequencing of paired primary and metastatic tumours: Implications for personalised medicine

BackgroundNext-generation sequencing of large panel of genes had been associated with clinical benefit in a significant proportion of patients with advanced cancer. However, the molecular profile of the primary tumour from the initial surgical specimen might significantly differ from the molecular profile in a tumour sample obtained from a biopsy of a metastatic site. Patients and methodsWe compare the genetic profile of primary tumours and paired metastases by using a large panel of cancer genes. Training and validation set including a total of 152 primary and metastatic tumour pairs were sequenced (up to 429 genes) focussing on variants described in the Catalogue of Somatic Mutations in Cancer (COSMIC). ResultsTraining and validation set including a total of 152 primary and metastatic tumour pairs were sequenced focussing on variants described in COSMIC. Agreement rate between the couples of primary and metastasis on COSMIC variants was 65% (24/37) and 43% (49/115) in the training and validation cohort, respectively. That rose to 74% (20/27) and 58% (42/73) when focussing on targetable mutations. In five cases, the discordance was related to appearance of secondary resistance mutation, giving a targetable refined agreement rate of 67% (67/100). ConclusionUp to 40% of paired primary tumour/metastases have discordant molecular profile. Liquid biopsies may overcome, in the near future, the limits of tumour tissue genotyping.

The genetic heterogeneity of hepatocellular carcinoma and the implications for personalised medicine

Liver cancer is one from the most lethal cancers, ranking second only to lung cancer in terms of its global mortality (1).