Predictive Testing Research Articles

Biomarkers for Early Disease Detection: Advancements in Predictive Medicine and Diagnostic Testing

Biomarkers have emerged as invaluable tools in predictive medicine and diagnostic testing, revolutionizing our approach to early disease detection. This paper examines recent advancements in biomarker research and their implications for identifying diseases at their earliest stages. Through genomic, proteomic, metabolic, and microbiome-based biomarkers, coupled with the power of liquid biopsies and artificial intelligence, clinicians can now detect diseases with unprecedented accuracy and timeliness. We explore the role of genomic biomarkers, such as BRCA1/BRCA2 mutations, proteomic markers like PSA for prostate cancer, and metabolic indicators such as blood glucose levels for diabetes. Liquid biopsies offer non-invasive methods for detecting early-stage cancers and monitoring treatment response. Microbiome-based biomarkers illuminate the intricate relationship between microbial communities and disease states.

Testing the Adaptive Market Hypothesis and Time-Varying Efficiency in the Indian Equity Market

The study examines the adaptive market hypothesis (AMH) as an evolutionary principle of the alternative efficient market hypothesis in the Indian stock market (Sensex and Nifty50) on the daily return from April 2014 to May 2020. Based on AMH, investors behave, learn, and adapt to market conditions. This distinction of dynamic market conditions is divided into bull and bear market classifications. We apply three variations of the variance ratio test and the returns have been whitened using the Autoregressive model with generalized autoregressive conditional heteroskedasticity (AR-GARCH) approach to examine the nonlinear predictability test. Further, we evaluate a fixed-length subsample window framework to detect the time-varying predictability and examine whether market conditions affect stock return predictability and market condition. The study confirms inefficient market behaviour during crises, fear, panic, macroeconomic events and each market adapts differently to certain market conditions. Furthermore, the return series exhibits significant periods of efficiency and inefficiency consistent with the adaptive market hypothesis. The evidence of our findings sheds light on efficient market behaviour in dynamic market conditions and market environments for researchers, investors in investment strategies and policy intervention in risk containment measures and control market manipulation.

Interaction networks within disease-associated GαS variants characterized by an integrative biophysical approach

Activation of G proteins through nucleotide exchange initiates intracellular signaling cascades essential for life processes. Under normal conditions, nucleotide exchange is regulated by the formation of G protein–G protein-coupled receptor (GPCR) complexes. Single point mutations in the Gα subunit of G proteins bypass this interaction, leading to loss-of-function or constitutive gain-of-function, which is closely linked with the onset of multiple diseases. Despite the recognized significance of Gα mutations in disease pathology, structural information for most variants is lacking, potentially due to inherent protein dynamics that pose challenges for crystallography. To address this, we leveraged an integrative spectroscopic and computational approach to structurally characterize seven of the most frequently observed clinically-relevant mutations in the stimulatory Gα subunit, GαS. A previously proposed allosteric model of Gα activation linked structural changes in the nucleotide binding pocket with functionally important changes in interactions between switch regions. We investigated this allosteric connection in GαS by integrating data from variable temperature CD spectroscopy, which measured changes in global protein structure and stability, and molecular dynamics (MD) simulations, which observed changes in interaction networks between GαS switch regions. Further, saturation-transfer difference NMR (STD–NMR) spectroscopy was applied to observe changes in nucleotide interactions with residues within the nucleotide binding site. These data have enabled testing of predictions regarding how mutations in GαS result in loss or gain of function and evaluation of proposed structural mechanisms. The integration of experimental and computational data allowed us to propose a more nuanced classification of mechanisms underlying GαS gain-of-function and loss-of-function mutations.

Lynch syndrome

Patients with Lynch syndrome, one of the most common hereditary tumor predisposition syndromes, harbor an increased risk for abroad spectrum of especially gastrointestinal and gynecological tumors. Causative for the syndrome are variants in DNA mismatch repair genes, which are passed on to the offspring at a50% chance (autosomal dominant inheritance). The tumor tissue of these patients usually shows microsatellite instability, which is of increasing relevance regarding prognosis and therapeutic decisions. The detection of acausative genetic variant in apatient enables predictive testing of family members to provide relief to noncarriers and provide carriers with intensified risk-adapted surveillance. In addition, chemoprevention with aspirin (acetylsalicylic acid) has been proven useful for chemoprevention in studies. Therefore, the diagnosis of Lynch syndrome is important for patients and their relatives.

Multi-specimen comprehensive genomic profiling for diagnostic disambiguation in advanced and metastatic solid tumors.

e15166 Background: Predictive biomarker testing for therapy selection is the primary intended use of tissue-based comprehensive genomic profiling (CGP) in advanced and metastatic cancer patients. This study aimed to characterize oncologists’ use of multi-specimen CGP to elucidate diagnostic uncertainty in the course of usual care for advanced and metastatic cancer patients. Methods: To assess the nature and extent to which CGP is potentially used for diagnostic disambiguation, we retrospectively identified patients tested at a reference laboratory with CGP at least twice (Illumina TruSight Oncology 500 assay), and the first two serial CGP tests for each patient were selected for study inclusion. We then explored patient demographics, rare ( < 20 cases per 100k individuals) vs common diagnoses, tested tissue characteristics, time between CGP orders, and differences in genomic variant profiles between test pairs to characterize potential diagnostic use cases. Results: In all, 337/15,717 (2.1%) of patients underwent multi-CGP (June 2021-December 2023). All CGP test pairs were performed using different tissue specimens from 2 separate surgical cases (80.7%) or 2 different blocks for the same surgical case (19.3%). Compared to single-CGP, patients with multi-CGP were younger on average (65 vs 68 years), more often female (54.6% vs 50.6%), and had a greater proportion of lung (45.7% v 39.8%), breast (10.7% vs 6.7%), and unknown primary (7.1% vs 5.2%) tumors. CGP test pairs were grouped for comparison by test order diagnoses submitted by oncologists as: (Group 1) 2 different primary tumors (16%); (Group 2) same primary tumor, different histologic subtypes (19%), or; (Group 3) same primary tumor, same histologic subtype (65%). In Group 1, multi-CGP was performed more frequently for patients with a rare diagnosis for at least 1 test compared to Groups 2 and 3 (81.5% vs 43.8% or 19.6%, p < 0.001), especially for cancers of unknown primary origin (31.5% vs 7.8% and 0.9%, p < 0.001). In Groups 1 and 2, testing for both a primary and a metastatic site was twice as common compared to Group 3 (43% and 41% vs 22%, p = 0.017). In Group 3, 80% of patients were represented by common tumor types, and were most often tested > 30 days apart (64.4%). The mean percent overlap in detected genomic variants was lowest for patients in Groups 1 and 2 where patients had 2 different primary diagnoses or 2 different histologies, and highest in Group 3, where patients had the same primary diagnosis and histology for both tests, (41.5%, 54.5%, 60%, p = 0.008). Conclusions: In practice, most multi-CGP testing is ordered serially for a subset of advanced cancer patients with common tumor types. Use of simultaneous multi-CGP for diagnostic decision-making appears to be limited to a fraction of patients representing more rare tumors with distinct diagnostic conundrums, warranting further exploration of clinical utility.

Genetic counselling for at-risk family members with hereditary transthyretin amyloidosis: data from a single-centre study

Background Hereditary transthyretin-related amyloidosis is an autosomal dominant disorder. Recently, disease-modifying therapies (DMTs) have been developed. For at-risk individuals, genetic analysis aids in the early administration of medical care; however, few studies have evaluated the current status of genetic counselling and management of presymptomatic carriers of amyloidogenic variants. Methods We retrospectively evaluated the medical records of 202 consecutive participants. Results A total of 103 clients who received genetic counselling for predictive testing were at-risk, and 83 underwent predictive testing. Genetic testing results were positive in 33 patients, 11 of whom had confirmed amyloid deposition and were administered DMTs. For presymptomatic V30M (p.V50M) carriers, 32.0 ± 2.4 years (median ± standard error) was the age when amyloid deposition was first identified (95% confidence interval 27.4–36.6). Serum transthyretin (TTR) levels decreased serially with an estimated slope of −1.2 mg/dL/year. Conclusions Our study suggests the clinical utility of management using a combination of predictive testing and monitoring methods. Psychosocial support should be considered with collaboration between geneticists/genetic counsellors and psychologists. For a more optimised protocol for monitoring and designing future interventional trials in presymptomatic carriers, prospective cohort studies are necessary to clarify the natural history, particularly in the early stages of the disease.

Incidental Germline Findings During Comprehensive Genomic Profiling of Pancreatic and Colorectal Cancer: Single-center, Molecular Tumor Board Experience.

Abstract Multidisciplinary molecular tumor boards (MTB) are already well established in many comprehensive cancer centers and play an important role in the individual treatment planning for cancer patients. Comprehensive genomic profiling of tumor tissue based on next-generation sequencing is currently performed for diagnostic and mainly predictive testing. If somatic genomic variants are identified, which are suspected to be pathogenic germline variants (PGVs), MTB propose genetic counseling and germline DNA testing. Commonly used comprehensive genomic profiling approaches of tumor tissue do not include a matched germline DNA control. Therefore, the detection of PGVs could be only predicted based on the content of tumor cells (CTC) in selected tumor area (%) and variant allele frequency score (%). For conclusion, the role of a medical geneticist is essential in these cases. The overall prevalence of PGVs in patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) is approximately 10%. In this single-center study, we present 37 patients with PDAC and 48 patients with CRC who were presented at MTB and tested using the large combined DNA/RNA sequencing panel. Content of tumor cells and variant allele frequency scores were evaluated in all tested patients. In case of suspicion of PGV and no previous genetic testing based on the standard guidelines, genetic counseling was recommended regardless of age, sex, and family history. In the PDAC subgroup, five patients were recommended by MTB for genetic counseling based on suspicious genetic findings. Based on a medical geneticist’s decision, germline DNA sequencing was performed in four of these cases, and all of them tested positive for PGV in the following genes: ATM, ATM, BRCA1, and BRCA2. In the CRC subgroup, no PGV was confirmed in the two patients genetically tested based on the MTB recommendations. Furthermore, we present data from our center’s registry of patients with PDAC and CRC who underwent genetic counseling and germline DNA testing based on the standard screening criteria. Our data confirm that comprehensive genomic profiling of tumor tissue can identify patients with hereditary forms of PDAC, who could remain unidentified by standard screening for hereditary forms of cancer.

Regional differences in predictive biomarker testing rates for patients with metastatic NSCLC in the Netherlands

BackgroundPredictive biomarker testing has a key role in the treatment decision-making for patients with non-small cell lung cancer (NSCLC) and is mandated by (inter)national guidelines. The aim of this study was to establish guideline-adherent biomarker testing rates in the Netherlands in 2019 and to examine associations of demographical, clinical, and environmental factors with guideline-adherent testing. MethodsThis study involved the integration of clinical data of the Netherlands Cancer Registry with pathology reports of the Dutch Nationwide Pathology Databank. Data extracted from these reports included sample type, diagnosis, and molecular testing status of predictive biomarkers. The study population comprised all patients diagnosed with metastatic non-squamous NSCLC in the Netherlands in 2019. ResultsIn the cohort of 3877 patients with metastatic non-squamous NSCLC under investigation, overall molecular testing rates for non-fusion predictive biomarkers (EGFR, KRAS, BRAF, ERBB2, MET) ranged from 73.9 to 89.0 %, while molecular testing for fusion-drivers (ALK, ROS1, RET, NTRK) ranged from 12.6 % to 63.9 %. Guideline-adherent testing of EGFR, KRAS, and ALK was performed in 85.2 % of patients, with regional rates spanning from 76.0 % to 90.8 %. Demographical and clinical factors associated with guideline-adherent biomarker testing included lower age (OR = 1.05 per one year decrease; p < 0.001), female sex (OR = 1.36; p = 0.002), diagnosis of adenocarcinoma (OR = 2.48; p < 0.001), availability of histological tumor material (OR = 2.46; p < 0.001), and clinical stage of metastatic disease (p = 0.002). Other factors associated with guideline-adherent biomarker testing included diagnosis at academic center (OR = 1.87; p = 0.002) and patient’s region of residence (p < 0∙001). ConclusionOptimization of the chain-of-care of predictive biomarker testing in patients with NSCLC in the Netherlands is needed to provide adequate care for these patients.

Genomics and insurance in the United Kingdom: increasing complexity and emerging challenges.

This article identifies issues relating to the use of genetics and genomics in risk-rated insurance that may challenge existing regulatory models in the UK and elsewhere. We discuss three core issues: (1) As genomic testing advances, and results are increasingly relevant to guide healthcare across an individual's lifetime, the distinction between diagnostic and predictive testing that the current UK insurance code relies on becomes increasingly blurred. (2) The emerging category of pharmacogenetic tests that are predictive only in the context of a specific prescribing moment. (3) The increasing availability and affordability of polygenic scores that are neither clearly diagnostic nor highly predictive, but which nonetheless might have incremental value for risk-rated insurance underwriting beyond conventional factors. We suggest a deliberative approach is required to establish when and how genetic information can be used in risk-rated insurance.

Predictive genetic testing for Huntington's disease: Exploring participant experiences of uncertainty and ambivalence between clinic appointments.

Ambivalence and uncertainty are key themes throughout the psychology of healthcare literature. This is especially so for individuals at risk of Huntington's disease (HD) deliberating the decision to undergo genetic testing because there is currently no treatment that modifies disease progression. A better understanding of the experience of making a decision about genetic prediction will help practitioners support and guide individuals through this process. Our aim was to capture participants' experiences of uncertainty and ambivalence in between their genetic counseling appointments. We explored these issues through the experiences of nine participants who were referred for predictive HD testing at four regional genetics services in England and Wales. Data consisted of recordings of clinic consultations, diaries, and an in-depth interview conducted at the end of the testing process. Data were analyzed thematically. Four themes were identified representing four possible futures, each future dependent on the decision to undergo testing and the result of that test. Our results showed that participants, as well as attending more to a future that represents their current situation of not having undergone predictive testing, also attended more to a distant future where a positive predictive result is received and symptoms have started. Participants attended less to the two futures that were more immediate once testing was undertaken (a future where a positive result is received and symptoms have not started and a future where a negative result is received). The use of diaries gave us a unique insight into these participants' experiences of ambivalence and uncertainty, psychological distress, and the emotional burden experienced. These findings help inform discussions within the clinic appointment as well as encourage researchers to consider diary use as a method of exploring what happens for individuals outside of clinical encounters.

Quality-Assured Analysis of PIK3CA Mutations in Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer Tissue

In precision oncology, reliable testing of predictive molecular biomarkers is the prerequisite for optimal patient treatment. Interlaboratory comparisons are a crucial tool to verify diagnostic performance and reproducibility of one's approach. Here, we describe the design and results of the first recurrent, internationally performed PIK3CA Breast Cancer Tissue external quality assessment (EQA), which was organized by German Quality in Pathology (QuIP) GmbH and started in 2021. After the internal pretesting phase performed by the (lead) panel institutes, in both 2021 and 2022, each EQA test set comprised n=10 tissue samples of hormone receptor-positive, human epidermal growth factor receptor 2-negative invasive breast cancer (IBC) that had to be analyzed and reported by the participants. In 2021, the results were evaluated separately for German-speaking countries (part 1) and international laboratories (part 2). In 2022, the EQA was performed across the European Union. The EQA success rates were 84.6% (n=11/13), 88.6% (n=39/44), and 87.9% (n=29/33) for EQA 2021 part 1, EQA 2021 part 2, and EQA 2022, respectively. The most commonly used methodologies were next-generation sequencing and mutation-/allele-specific qualitative polymerase-chain-reaction-based assays. In summary, this recurrent PIK3CA EQA proved to be a suitable approach for quality assessment in predictive molecular biomarker testing, to obtain an international overview of methods used for PIK3CA mutation analysis and to identify the strengths and weaknesses of individual methods.

Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2 Expression Rates in Invasive Breast Carcinoma: A Study of 21 Institutions.

Laboratories performing predictive marker testing for breast carcinoma are encouraged to compare patient results to published benchmarks. To collect expression rates for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) in invasive breast carcinoma from multiple laboratories. Participants submitted data from up to 50 primary cases during the study period. Participants reported ER, PgR, and HER2 results in addition to demographic and histologic information. Participants also provided annual institution-level expression rates. A total of 21 institutions submitted data for 687 cases. Aggregate positivity rates for ER and PgR were 85.6% and 75.1%, respectively. Receptor positivity rates were higher in well-differentiated (grade 1) tumors (ER, 97.4%; PgR, 88.0%) compared with moderately differentiated (grade 2) tumors (ER, 92.4%; PgR, 84.0%) and poorly differentiated (grade 3) tumors (ER, 61.8%; PgR, 48.0%). Expression rates were higher in postmenopausal women (ER, 87.2%) than premenopausal women (ER, 79.6%) and higher in lobular carcinomas (ER, 98.7%; PgR, 85.3%) than ductal carcinomas (ER, 84.1%; PgR, 74.5%). The aggregate HER2 positivity (score 3+) rate was 9.0%. The aggregate HER2 equivocal (score 2+) rate was 14.5%. Of 81 equivocal (score 2+) cases, 70 (86.4%) were nonamplified. The data from this study provide multi-institutional benchmark data to assist laboratories performing periodic comparisons as part of a quality management program. Overall expression rates were generally similar to those of other published reports, with the exception of the ER-negative and HER2-positive rates, both of which were somewhat lower.

Experiences of predictive genetic testing in inherited motor neuron disease: Findings from a qualitative interview study

Experiences of predictive genetic testing in inherited motor neuron disease: Findings from a qualitative interview study

Pain and gain of predictive genetic testing: Particular case of fragile X syndrome

IntroductionThe purpose of predictive genetic tests is to identify carriers or the onset of a disease in pre-symptomatic individuals. Prediction is linked to a negative psychological impact (anxiety, depression, etc.), depending on the perception of risk, the severity of the disease, and the availability and effectiveness of treatments.ObjectivesHere, we report on genetic counselling during predictive genetic testing offered to an Arab family affected by fragile X condition (FXS) caused by the unstable expansion of a CGG repeat (CGGR) in the FMR1 gene.MethodsA 10-year-old boy who harbored a mental retardation was referred to our genetic counselling for genetic testing as he was suspected to be affected by FXS. Screening of FMR1 gene mutations was conducted for the index case and his mother. A predictive genetic testing for the family members (brothers, sisters and others) was offered, focusing on knowledge of genetics and medical risks of FXS.ResultsFMR1 molecular analysis showed a full mutation (300 to 2000 CGGR) for the boy and a large premutation (100 CGGR) for the mother. During genetic counselling, the family was informed about the significance of the genetic results. In FXS initiated by an expansion of over 200 CGGR. While mental retarded males usually harbor the full mutation, the mother carry a premutation (70 to 200 CGGR). The deficiency of FMR protein (FMRP) in the neurons of affected males leads to brain developmental abnormalities. Some pre-mutated children may show signs of the autism spectrum disorder and females may develop FMR1-related premature ovarian insufficiency. An increased risk of a late onset fragile X tremor ataxia syndrome is identified in pre-mutated men (55 to 200 CGGR) and less in women.ConclusionsThe reduction or loss of FMRP leads to multisystem damage. Neuropsychiatric disorders such as mental retardation, speech and language delay, autism spectrum disorder, sensory hyperexcitation, social anxiety, abnormal eye contact, shyness and aggressive behaviour are common in individuals with the mutation. Affected women are often under-diagnosed because mental retardation is not constant, but minor disorders including a borderline IQ with learning difficulties and emotional disturbances have been reported. Conditions associated with fragile X premutation, a term proposed by the European Fragile X Network (FXPAC), seem to be characterized by many physical and psychological health symptoms. Anxiety, depression, sleep disorders and mood disorders are more common in permutated individuals. However, new reports suggested that FXS patients could be at unusually low risk of cancers, because FMRP is over-expressed in multiple cancer tissues.Disclosure of InterestNone Declared

Multinational experience with next-generation sequencing: opportunity to identify transthyretin cardiac amyloidosis and Fabry disease.

Sarcomeric hypertrophic cardiomyopathy (HCM) must be differentiated from phenotypically similar conditions because clinical management and prognosis may greatly differ. Patients with unexplained left ventricular hypertrophy require an early, confirmed genetic diagnosis through diagnostic or predictive genetic testing. We tested the feasibility and practicality of the application of a 17-gene next-generation sequencing (NGS) panel to detect the most common genetic causes of HCM and HCM phenocopies, including treatable phenocopies, and report detection rates. Identification of transthyretin cardiac amyloidosis (ATTR-CA) and Fabry disease (FD) is essential because of the availability of disease-specific therapy. Early initiation of these treatments may lead to better clinical outcomes. In this international, multicenter, cross-sectional pilot study, peripheral dried blood spot samples from patients of cardiology clinics with an unexplained increased left ventricular wall thickness (LVWT) of ≥13 mm in one or more left ventricular myocardial segments (measured by imaging methods) were analyzed at a central laboratory. NGS included the detection of known splice regions and flanking regions of 17 genes using the Illumina NextSeq 500 and NovaSeq 6000 sequencing systems. Samples for NGS screening were collected between May 2019 and October 2020 at cardiology clinics in Colombia, Brazil, Mexico, Turkey, Israel, and Saudi Arabia. Out of 535 samples, 128 (23.9%) samples tested positive for pathogenic/likely pathogenic genetic variants associated with HCM or HCM phenocopies with double pathogenic/likely pathogenic variants detected in four samples. Among the 132 (24.7%) detected variants, 115 (21.5%) variants were associated with HCM and 17 (3.2%) variants with HCM phenocopies. Variants in MYH7 (n=60, 11.2%) and MYBPC3 (n=41, 7.7%) were the most common HCM variants. The HCM phenocopy variants included variants in the TTR (n=7, 1.3%) and GLA (n=2, 0.4%) genes. The mean (standard deviation) ages of patients with HCM or HCM phenocopy variants, including TTR and GLA variants, were 42.8 (17.9), 54.6 (17.0), and 69.0 (1.4) years, respectively. The overall diagnostic yield of 24.7% indicates that the screening strategy effectively identified the most common forms of HCM and HCM phenocopies among geographically dispersed patients. The results underscore the importance of including ATTR-CA (TTR variants) and FD (GLA variants), which are treatable disorders, in the differential diagnosis of patients with increased LVWT of unknown etiology.

Pleural effusion supernatant: a reliable resource for cell-free DNA in molecular testing of lung cancer

DNA extracted from malignant pleural effusion (PE) sediments is the traditional source of tumor DNA for predictive biomarker molecular testing (MT). Few recent studies have proposed the utility of cell-free DNA (cfDNA) extracted from effusion cytology centrifuged supernatants (CCS) in MT. The aim of this study was to assess the feasibility and utility of molecular testing on cfDNA extracted from PE CCS in lung cancer patients. The study was of prospective design. All PE CCS were collected and stored. Subsequently, in patients confirmed as primary lung adenocarcinoma (LUAD) and where patient matched effusion sediment/tissue biopsy/plasma was being tested for EGFR mutations, cfDNA extraction and EGFR MT by real-time polymerase chain reaction (qPCR) were performed. Custom panel targeted next-generation sequencing (NGS) (Ion Torrent; Thermo Fisher, Carlsbad, CA) was also performed wherever feasible. Out of 299 PE CCS collected, 20 CCS samples were included in the study. Concordant EGFR mutations were detected in pleural effusion CCS of 10 of 11 (91%) EGFR mutant cases as per qPCR performed on the matched sediment DNA (n = 8), lung biopsy (n = 2), and plasma (n = 1) samples. In 1 positive sample, CCS detected additional EGFR T790M mutation. Among 10 CCS samples also tested by NGS, additional EGFR mutations missed by qPCR were picked up in 2 (2 of 10). Success of mutation detection in CCS cfDNA did not correlate with cfDNA quantity or tumor fraction in sediment. cfDNA from effusion CCS is a reliable and independent source of tumor DNA highly amenable for MT and complement results from other tumor DNA sources for comprehensive mutation profiling in LUAD patients.

Genetic Variations Related to Angiotensin II Production and Risk for Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most prevalent human neoplasm, with constantly increasing annual incidence. Despite its slow growth, BCC is locally invasive and, if left untreated, can cause severe complications, including metastasis and death. The renin-angiotensin system (RAS) plays a key role in electrolyte balance, atrial pressure, tissue development, homeostasis, and inflammation, but also in cancer development. After binding to its type 1 receptor (AT1R), angiotensin II (ANGII), the system's principal hormonal effector, regulates cancer pathways spanning from the formation of the initial cancer cell to the construction and nutrition of the tumor microenvironment, angiogenesis, proliferation, and metastasis. Although the role of RAS in the development of skin pathologies has not been widely researched, RAS-targeting antihypertensive medications have been shown to have a chemoprotective effect against BCC. Based on those findings, our group conducted a series of genetic association studies to investigate the association between common functional variations in key genes related to ANGII production (AGT, ACE, ACE2, AT1R, AT2R, and CMA1) and the risk of BCC occurrence. This review provides a summary of the current understanding of the ANGII involvement in BCC development. The reliable and easily assessed pool of genetic biomarkers may be used for predictive testing and prevention purposes in high-risk individuals.

Predictive Pharmacogenetic Testing in Psychiatry: Pros and Cons

Pharmacogenetic testing (PGx) is an important diagnostic tool for achieving an optimal balance between the effectiveness and safety of psychotropic drugs, especially those requiring long-term use. The most prescribed medications in psychiatric practice are antipsychotics (APs). Despite the long period of use of APs, their safety profile remains insufficiently high. Due to the high incidence of adverse drug reactions (ADRs), from the central nervous system (CNS) and other organs and tissues of the human body. Therapeutic drug monitoring can help predict and diagnose AP-induced ADRs only if the patient is receiving APs. PGx helps to individually select an AP, its dose and clarify the risk of ADRs before prescribing an AP, or at the start of therapy. This explains the importance of PGx in psychiatrist practice. However, to date, most practicing psychiatrists rarely use predictive PGx or do not use this method. PGx is more often prescribed in the case of a long history of un-successful AP-therapy, or in the case of the development of serious ADRs, the risk of which could be significantly reduced if predictive PGx was used. This case report of PGx in a 56-year-old woman with severe bipolar disorder demonstrates that the trajectory of ADRs and socialization could be significantly improved if this method was prescribed before the initiation of APs, rather than in the event of the development of serious ADRs.

The adaptive markets hypothesis: Insights into small stock market efficiency

ABSTRACT In this paper, we explore whether the adaptive markets hypothesis (AMH) describes the efficiency of the Finnish stock market better than the efficient markets hypothesis (EMH) does. Building on this, we also test how small market size and market liberalization impact the efficiency of the Finnish stock market and examine the relationship between market volatility and return in this market. We conduct this study by applying the subsample analysis and the rolling window analysis to the daily returns of the OMXH25 index and by measuring the efficiency through three linear and two nonlinear predictability tests. The results of our study strongly support the AMH. They also suggest that small market size alone does not make a market less efficient; opening a market to foreign investors improves its efficiency after a delay; and the correlation between market volatility and return varies over time in the Finnish stock market, being usually negative. These findings mostly contradict the traditional investment paradigm.

Abstract 4247: Miniaturizing patient-derived organoid screening assays for predictive drug testing

Abstract Colorectal cancer (CRC) ranks as the third leading cause of both cancer incidence and cancer-related mortality. A significant portion of CRC patients diagnosed with de novo metastatic disease face limited benefits from conventional treatment options, often accompanied by substantial side effects. This underscores the pressing need for more effective preclinical models to predict patient responses in clinical settings. Patient-derived organoids (PDOs or HUB Organoids®) represent a pivotal breakthrough in preclinical modeling. These organoids are directly derived from patient tissue, faithfully mirroring the patient's disease. While HUB Organoid Technology is currently applicable for preclinical drug screening, it is essential to expedite the transition from patient diagnosis to the delivery of PDO-based results to directly benefit patients. In a collaborative effort with Yamaha Motor, we have optimized the Yamaha CELL HANDLERTM for the automated transfer of organoids, offering enhanced precision and efficiency in handling a significantly reduced number of organoids per screening plate, compared to conventional methods. Moreover, we have developed an image-based readout system that enables precise quantification of organoid numbers, ensuring high assay quality. Utilizing this developed automated platform, we conducted a proof-of-concept investigation into PDO responses to chemotherapy in comparison to corresponding patient responses. The correlation between PDO and patient responses demonstrated a strong connection, highlighting the potential of the developed automated platform for predictive drug testing. In summary, this work signifies the development of an automated workflow that synergizes patient-representative HUB Organoids® with cutting-edge robotics from Yamaha Motor. The described workflow reduces the number of organoids needed per screening well, streamlining patient response prediction, potentially leading to faster diagnoses, and ultimately optimizing patient outcomes. Citation Format: Yasmine Abouleila, Roel Verkerk, Mayke Doorn, Timo Voskuilen, Gakuro Harada, Masahiko Watanabe, Lidwien Smabers, Hideaki Kyan, Takahiko Kumagai, Yuichi Hikichi, Rene Overmeer, Jeanine Roodhart, Kiyotaka Matsuno, Carla Verissimo, Sylvia Boj. Miniaturizing patient-derived organoid screening assays for predictive drug testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4247.