Considerations into pharmacogenomics of COVID-19 pharmacotherapy: Hope, hype and reality.

COVID-19 medicines, such as molnupiravir are beginning to emerge for public health and clinical practice. On the other hand, drugs display marked variability in their efficacy and safety. Hence, COVID-19 medicines, as with all drugs, will be subject to the age-old maxim "one size prescription does not fit all". In this context, pharmacogenomics is the study of genome-by-drug interactions and offers insights on mechanisms of patient-to-patient and between-population variations in drug efficacy and safety. Pharmacogenomics information is crucial to tailoring the patients' prescriptions to achieve COVID-19 preventive and therapeutic interventions that take into account the host biology, patients' genome, and variable environmental exposures that collectively influence drug efficacy and safety. This expert review critically evaluates and summarizes the pharmacogenomics and personalized medicine aspects of the emerging COVID-19 drugs, and other selected drug interventions deployed to date. Here, we aim to sort out the hope, hype, and reality and suggest that there are veritable prospects to advance COVID-19 medicines for public health benefits, provided that pharmacogenomics is considered and implemented adequately. Pharmacogenomics is an integral part of rational and evidence-based medical practice. Scientists, health care professionals, pharmacists, pharmacovigilance practitioners, and importantly, patients stand to benefit by expanding the current pandemic response toolbox by the science of pharmacogenomics, and its applications in COVID-19 medicines and clinical trials.

The Long View on COVID-19 Theranostics and Oral Antivirals: Living with Endemic Disease and Lessons from Molnupiravir.

The long view on living with COVID-19 as an endemic disease calls for expanding the planetary health intervention toolbox. We will need a battery of vaccines, small molecule oral antiviral drugs, and biomarkers to forecast antiviral drug efficacy and safety. In this context, theranostics refers to fusion of therapeutics and diagnostics. We examine here emerging pathways to theranostics innovation for COVID-19 oral antiviral drugs, with molnupiravir as a case study. With new virus variants (1) variations in the molnupiravir efficacy target, viral RNA-dependent RNA polymerase, (2) variability in pharmacokinetics and exposure to molnupiravir active moiety in fluids on virus entry points to the host (e.g., saliva, tears, and nasal secretions), (3) variability in transformation from prodrug molnupiravir to its active form, and (4) variability in putative adverse effects on human/host cells, all warrant attention for prospects and challenges vis à vis theranostics innovation for COVID-19 oral antivirals. The emerging lessons from molnupiravar are of interest to future design of COVID-19 theranostic research with other oral antiviral medications. Regulatory agencies, the pharmaceutical industry, research funders, governments, and ministries of health around the world have important stewardship roles to advance the subpopulation level analyses of clinical trial data on oral antiviral drugs for COVID-19. This would remedy the current lag in clinically relevant multiomics theranostics for oral antivirals in the battle against COVID-19.

Thanatechnology and the Living Dead: New Concepts in Digital Transformation and Human-Computer Interaction.

In a digital society, shall we be the authors of our own experience, not only during our lifetime but also after we die? We ask this question because dying and bereavement have become even harder, and much less private, in the digital age. New big data-driven digital industries and technologies are on the rise, with promises of interactive 3D avatars and storage of digital memories of the deceased, so they can continue to exist online as the "living dead" in a digital afterlife. Famous rock and roll icons like Roy Orbison, Frank Zappa, Ronnie James Dio, and Amy Winehouse have famously been turned into holograms that can once again give "live" performances on the touring circuit, often pulling in large audiences. Death studies, dying, and grief have become virtual in the 21st century. We live in truly unprecedented times for human-computer interactions. Thanatology is the scientific study of death, dying, loss, and grief. In contrast to the biological study of biological aging (cellular senescence) and programmed cell death (apoptosis), thanatology employs multiple professional lenses, medical, psychological, physical, spiritual, ethical, descriptive, and normative. In 1997, Carla Sofka introduced the term thanatechnology as "technological mechanisms such as interactive videodiscs and computer programs that are used to access information or aid in learning about thanatology topics." Onward to 2021, the advent of social media, the Internet of Things, and sensors that digitize and archive nearly every human movement and experience are taking thanatechnology, and by extension, digital transformation, to new heights. For example, what happens to digital remains of persons once they cease to exist physically? This article offers a critical study and snapshot of this nascent field, and the "un-disciplinary" sociotechnical issues digital thanatechnologies raise in relation to big data. We also discuss how best to critically govern this new frontier in systems science and the digital society. We suggest that new policy narratives such as (1) the right to nonparticipation in relation to information and communication technologies and (2) the planetary public goods deserve further attention to democratize thanatechnology and big data. To the extent that systems science often depends on data from online platforms, for example, in times of pandemics and ecological crises, "critical thanatechnology studies," introduced in this article, is a timely and essential field of scholarship with broad importance for systems science and planetary health.

Biomonitoring of Heavy Metal(oid)s in the Residents of Abandoned Mining District in Northern Cyprus.

Several heavy metal(oid)s are known mutagens and/or carcinogens. Exposure to these elements can lead to the development of malignancies. Gemikonagi, which is in the western part of Cyprus, was the hometown of mining operations. It is believed that the mining site is a significant heavy metal(oid) source for the environment and residents. In this biomonitoring study, a total of 60 blood samples from Gemikonagi region (n = 30) and from a control region located 40 km northeast from the mining site, Tepebasi (n = 30), and 5 soil samples from each region were collected to conduct heavy metal analysis using ICP-MS. To conduct genotoxicity analysis, alkaline comet assay and in vivo micronucleus assays were used. t test for independent samples and Mann-Whitney U tests were applied. Copper and iron were found to be enriched in Gemikonagi, while arsenic was found to be enriched in Tepebasi. Genotoxicity analyses demonstrated a statistically significant increase in parameters of micronuclei frequency (p value = 0.0001) and Comet Assay statistics upon exposure to some elements, such as arsenic (p value = 0.04) and copper (p value = 0.012). The results indicate that a general enrichment in heavy elements is not endemic to Gemikonagi, but a problem that might be generalized to the entirety of Cyprus. Graphical abstract.

Challenge-comet assay, a functional and genomic biomarker for precision risk assessment and disease prevention among exposed workers.

Advancements in genomic technologies have ushered application of innovative changes into biomedical sciences and clinical medicine. Consequently, these changes have created enormous opportunities to implement precision population/occupational disease prevention and target-specific disease intervention (or personalized medicine). To capture the opportunities, however, it is necessary is to develop novel, especially genomic-based, biomarkers which can provide precise and individualized health risk assessment. In this review, development of the Challenge-comet assay is used as an example to demonstrate how assays need to be validated for its sensitivity, specificity, and functional and quantitative features, and how assays can be used to provide individualized health risk assessment for precision prevention and intervention. Other examples of genomic-based novel biomarkers will also be discussed. Furthermore, no biomarkers can be used alone therefore their integrated usage with other biomarkers and with personal data bases will be discussed.

It Is Time to Revitalize the Antibiotic Pipeline: Systems Ecology Can Help.

Antimicrobials have been known for millennia, but innovative antibiotics are currently in short supply. New antimicrobial discoveries are being threatened by planetary scale loss of biodiversity that has important impacts on species and ecosystems. This expert review underscores that microorganisms in nature and their diversity are essential cornerstones to revitalize the antibiotic innovation and discovery pipeline. The recent rise of systems ecology and planetary health offers new and actionable potentials in this regard. Without a systems scale focus and appreciation of systems ecology, the global threats to human and planetary health from inappropriate use of antibiotics and antimicrobial resistance will continue to escalate with serious consequences to all life on the planet. With acutely pressing research and development needs to revitalize antibiotic treatment and novel diagnostic tools for personalized medicine, national health systems ought to work across knowledge silos not only within but also across the ministries, for example, health, agriculture, environment, economy, trade, and social services ministries that collectively impact on systems ecology and by extension on health innovations including the antibiotic discovery pipeline. Such systems vision can also help to revitalize antibiotic discovery pipeline as most antibiotics have natural origins or have designs inspired or based on molecules in the environment and microorganisms that produce antibiotics. Above all, our audience and responsibility include every person who has an interest in his or her own health, in the health of his or her fellow human beings and all life on the planet, and in the health of future generations.

Digging Deeper into Precision/Personalized Medicine: Cracking the Sugar Code, the Third Alphabet of Life, and Sociomateriality of the Cell.

Precision/personalized medicine is a hot topic in health care. Often presented with the motto "the right drug, for the right patient, at the right dose, and the right time," precision medicine is a theory for rational therapeutics as well as practice to individualize health interventions (e.g., drugs, food, vaccines, medical devices, and exercise programs) using biomarkers. Yet, an alien visitor to planet Earth reading the contemporary textbooks on diagnostics might think precision medicine requires only two biomolecules omnipresent in the literature: nucleic acids (e.g., DNA) and proteins, known as the first and second alphabet of biology, respectively. However, the precision/personalized medicine community has tended to underappreciate the third alphabet of life, the "sugar code" (i.e., the information stored in glycans, glycoproteins, and glycolipids). This article brings together experts in precision/personalized medicine science, pharmacoglycomics, emerging technology governance, cultural studies, contemporary art, and responsible innovation to critically comment on the sociomateriality of the three alphabets of life together. First, the current transformation of targeted therapies with personalized glycomedicine and glycan biomarkers is examined. Next, we discuss the reasons as to why unraveling of the sugar code might have lagged behind the DNA and protein codes. While social scientists have historically noted the importance of constructivism (e.g., how people interpret technology and build their values, hopes, and expectations into emerging technologies), life scientists relied on the material properties of technologies in explaining why some innovations emerge rapidly and are more popular than others. The concept of sociomateriality integrates these two explanations by highlighting the inherent entanglement of the social and the material contributions to knowledge and what is presented to us as reality from everyday laboratory life. Hence, we present a hypothesis based on a sociomaterial conceptual lens: because materiality and synthesis of glycans are not directly driven by a template, and thus more complex and open ended than sequencing of a finite length genome, social construction of expectations from unraveling of the sugar code versus the DNA code might have evolved differently, as being future-uncertain versus future-proof, respectively, thus potentially explaining the "sugar lag" in precision/personalized medicine diagnostics over the past decades. We conclude by introducing systems scientists, physicians, and biotechnology industry to the concept, practice, and value of responsible innovation, while glycomedicine and other emerging biomarker technologies (e.g., metagenomics and pharmacomicrobiomics) transition to applications in health care, ecology, pharmaceutical/diagnostic industries, agriculture, food, and bioengineering, among others.

Drug-associated cardiovascular risks: A retrospective evaluation of withdrawn drugs.

A considerable number of drugs were withdrawn from the world market in the last decades due to safety reasons. A retrospective review of withdrawals is important in determining the adequacy of regulations regarding the safety and efficacy of drugs. The scope of the present study was to focus on cardiovascular adverse reactions of 61 withdrawn medicinal products, as well as 40 additional drugs withdrawn due to non-cardiovascular toxicity, while being cardiovascular agents themselves. A detailed web-based data search was held to draw a list of withdrawn pharmaceutical products from the pharmaceutical market by regulatory authorities between 1950 and 2017 due to safety reasons. A total of 464 medicinal products were withdrawn from the pharmaceutical markets between 1950 and 2017 due to safety reasons. Hepatotoxicity was the most commonly reported adverse drug reaction (ADR) that led to withdrawal, followed by immune-related reactions, neurotoxicity, and cardiovascular toxicity. The underlying mechanisms leading to cardiovascular toxicity should be investigated in depth to avoid the use of risky drugs for long periods, especially in consideration of the fact that some cardiovascular drugs persisted in the market for many decades. Furthermore, improved reporting of suspected adverse reactions and stricter regulations will lead to quicker detection of ADRs, thus emphasizing the importance of this public health problem and highlighting the need for improved "early warning systems" to manage the risks of high-risk drugs.

Panvigilance: Integrating Biomarkers in Clinical Trials for Systems Pharmacovigilance.

Drug safety and pharmacovigilance are rapidly changing with biomarkers and new technologies such as artificial intelligence. However, we need new ideas and application contexts for integration of biomarkers and emerging technologies in modern pharmacovigilance. A new concept, panvigilance, has been recently introduced for proactive "stress testing" of new drug candidates in panels of patients or healthy volunteers identified by biomarkers, and who are situated in population edges in terms of pharmacokinetic (PK) and/or molecular target interindividual variability. Panvigilance aims to provide upper and lower bound estimates for drug performance under conditions that mimic population edges. Subsequently, it becomes easier to extrapolate pharmacovigilance signals with regard to individuals who reside in between the population edges. In this expert review, we explain that the prefix "pan," meaning everything or all, refers to the three-pronged panvigilance goals to (1) decipher the full population scale variability in medicinal product PKs and molecular target variability, (2) empower forecasting of pharmacovigilance signals within and across populations through knowledge of biomarker variations worldwide, and (3) integration of pharmacovigilance signals across government ministries, civil society organizations, and other stakeholders through, for example, institutional innovation such as centers for panvigilance. We note that panvigilance and pharmacovigilance are complementary, and underscore the added value of panvigilance for global clinical trials. Panvigilance offers a new opportunity for meaningful biomarker application in clinical trials beyond traditional contexts such as personalized medicine. In sum, panvigilance is a systems approach to pharmacovigilance and poised to innovate risk governance in medicinal product development and clinical trials.

Role of DNA repair genes XRCC3 and XRCC1 in predisposition to type 2 diabetes mellitus and diabetic nephropathy / Papel de los genes de reparación del ADN XRCC3 y XRCC1 en la predisposición a la diabetes mellitus de tipo 2 y a la nefropatía diabética

Introduction: Increasing number of experimental and clinical studies suggest a strong relationship between hyperglycemia, oxidative stress, DNA damage and diabetic nephropathy (DN). Also, epidemiologic studies remark an enhanced risk of cancer with type 2 diabetes. This research aims to assess whether the X-ray cross complementing group 3 (XRCC3) gene T241M polymorphism (rs861539) and X-ray cross complementing group 1 (XRCC1) gene A399G polymorphism (rs25487) are related with predisposition to type 2 diabetes mellitus (T2DM) and to diabetic nephropathy in Turkish population. Materials and methods: Polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was performed to identify the distribution of genotypes and frequency of alleles of T241M polymorphism of the XRCC3 gene (XRCC3 T241M) and A399G polymorphism of the XRCC1 gene (XRCC1 A399G). The study population included 238 subjects residing in Istanbul, Turkey; 116 with T2DM, 50 with DN and 72 with normal glucose metabolism. Results and conclusion: Polymorphic Gln allele of XRCC1 gene was significantly related with T2DM and DN (OR 3.09, 95% CI 1.14-8.40 and OR 3.29 95% CI 1.23-8.80, respectively) however, there was no statistical association of XRCC3 T241M with T2DM or DN. The results of this study suggest that XRCC1 399Gln polymorphism is related with an increased susceptibility to T2DM and DN in the studied Turkish population

Introducción: Un número creciente de estudios experimentales y clínicos sugiere una sólida relación entre hiperglucemia, estrés oxidativo, daño en el ADN y nefropatía diabética (ND). Además, los estudios epidemiológicos advierten mayor riesgo de cáncer con diabetes de tipo 2. Esta investigación tiene como objetivo evaluar si el polimorfismo del gen T241M del grupo 3 (XRCC3) complementario cruzado de rayos X (rs861539) y el polimorfismo del gen A399G del grupo 1 (XRCC1) complementario cruzado de rayos X (rs25487) están relacionados con la predisposición a la diabetes mellitus de tipo 2 (DM2) y a la nefropatía diabética en la población turca. Materiales y métodos: Se realizó un polimorfismo de longitud de fragmento de restricción basado en la reacción en cadena de la polimerasa (PCR-RFLP) para identificar la distribución de genotipos y la frecuencia de los alelos del polimorfismo T241M del gen XRCC3 (XRCC3 T241M) y el polimorfismo A399G del gen XRCC1(XRCC1 A399G). La población de estudio incluyó a 238 individuos que residían en Estambul, Turquía; 116 de ellos con DM2, 50 con ND y 72 con metabolismo de la glucosa normal. Resultados y conclusión: El alelo Gln polimórfico del gen XRCC1 se relacionó de manera importante con DM2 y ND (OR: 3,09; IC95%: 1,14-8,40 y OR: 3,29; IC95%:1,23-8,80, respectivamente). Sin embargo, no hubo asociación estadística de XRCC3 T241M con DM2 o ND. Los resultados de este estudio sugieren que el polimorfismo XRCC1 399Gln está relacionado con un aumento de la susceptibilidad a la DM2 y a la ND en la población turca estudiada

Role of DNA repair genes XRCC3 and XRCC1 in predisposition to type 2 diabetes mellitus and diabetic nephropathy.

INTRODUCTION: Increasing number of experimental and clinical studies suggest a strong relationship between hyperglycemia, oxidative stress, DNA damage and diabetic nephropathy (DN). Also, epidemiologic studies remark an enhanced risk of cancer with type 2 diabetes. This research aims to assess whether the X-ray cross complementing group 3 (XRCC3) gene T241M polymorphism (rs861539) and X-ray cross complementing group 1 (XRCC1) gene A399G polymorphism (rs25487) are related with predisposition to type 2 diabetes mellitus (T2DM) and to diabetic nephropathy in Turkish population. MATERIALS AND METHODS: Polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was performed to identify the distribution of genotypes and frequency of alleles of T241M polymorphism of the XRCC3 gene (XRCC3 T241M) and A399G polymorphism of the XRCC1 gene (XRCC1 A399G). The study population included 238 subjects residing in Istanbul, Turkey; 116 with T2DM, 50 with DN and 72 with normal glucose metabolism. RESULTS AND CONCLUSION: Polymorphic Gln allele of XRCC1 gene was significantly related with T2DM and DN (OR 3.09, 95% CI 1.14-8.40 and OR 3.29 95% CI 1.23-8.80, respectively) however, there was no statistical association of XRCC3 T241M with T2DM or DN. The results of this study suggest that XRCC1 399Gln polymorphism is related with an increased susceptibility to T2DM and DN in the studied Turkish population.

How Does Infection with Human Papillomavirus 16 and 18 Impact on DNA Damage and Repair in Cervical Cells and Peripheral Blood?

Human papillomavirus (HPV) infection is one of the most common sexually transmitted diseases worldwide and a prime cause of cervical cancer. The HPV DNA is detected in approximately 80-90% of all cervical cancers, with HPV 16 and 18 being the high risk conferring human carcinogens. DNA damage and diminished DNA repair mechanisms are potential biological surrogates of HPV infection that warrant further research in different tissues and populations. Notably, we do not know the extent to which the high risk HPV 16 and 18 differentially affect cervical cells versus other systems such as peripheral blood lymphocytes (PBLs). We evaluated DNA damage and repair in women who tested positive for HPV 16 or HPV 18 and healthy control women without HPV 16 or HPV 18 infection. We found that the DNA damage as measured by the Comet assay was markedly greater in cervical cells of women with HPV 16 (mean: 8.1 as% DNA in tail, 95% CI: 7.6-8.7) or HPV 18 infection (mean: 9.6, 95% CI: 8.9-10.2) than controls (mean: 6.7, 95% CI: 6.2-7.4) (p < 0.05). By contrast, in PBLs, we did not find a significant difference in DNA damage between women with HPV 16 or 18 infection versus controls, as measured by the Comet assay or the Conventional Chromosomal Aberration analysis (p > 0.05). We observed, however, the DNA repair capacity, as measured by the X-ray induced challenge (XRC) assay, was significantly impaired in PBLs from women with HPV 16 or 18 infection compared to controls (p < 0.05). This is the first comparative study, to the best of our knowledge, suggesting that the cervical swab cells might be better suited than peripheral lymphocytes as biosamples for detection of HPV 16 or 18 biological effects on DNA damage. In addition, these findings suggest that the Comet assay performed only in PBLs may potentially lead to false negative diagnosis of DNA damage. Taken together, these observations contribute to development of future diagnostic innovation and precision sampling strategies for robust detection of the biological effects of HPV 16 or 18 in women. We conclude by a brief discussion of implications for HPV clinical diagnostics and precision medicine innovation.

Investigation of genotoxicity risk and DNA repair capacity in breast cancer patients using anastrozole.

OBJECTIVE: Breast cancer is the most common cancer in women worldwide and the incidence increases in postmenopausal women. Anastrozole is a non-steroidal (type II), third-generation aromatase inhibitor (AI) that is used in the treatment of postmenopausal estrogen-related breast cancer. Several studies have been conducted to assess the efficacy, safety, and superiority of AIs to tamoxifen; however, a literature search did not reveal a study that investigated the genotoxic potential of AIs. The aim of this study was to investigate the possible DNA damage risk profile and individual DNA repair capacity of patients using anastrozole with the modified alkaline comet assay in order to contribute to public health and health economics. METHODS: Women diagnosed with breast cancer after menopause comprised the study group. Six patients who had taken anastrozole for at least 6 months were retrospectively enrolled, and 12 patients who had not yet received treatment were prospectively enrolled as a control group. Peripheral blood lymphocytes were used to measure oxidized DNA damage using formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (endo III) in a modified comet assay. Individual DNA repair capacity was evaluated with the comet assay after a hydrogen peroxide (H2O2) challenge to examine the difference in DNA damage susceptibility. RESULTS: Analysis of DNA damage, oxidative base damage, susceptibility to DNA damage, and repair capacity revealed no significant difference between the control group and the patients taking anastrozole (p>0.05). Susceptibility to H2O2 damage was observed to increase with age (p<0.05). CONCLUSION: According to the results obtained in this study, anastrozole did not contribute to oxidative DNA damage. An H2O2 challenge with the comet assay is useful to evaluate circumstances of increased vulnerability to damage, such as aging and cancer.

Evaluation of the wound healing potential of Aloe vera-based extract of Nerium oleander.

OBJECTIVE: Nerium oleander (Apocynaceae) and Aloe vera (Liliaceae) are among the widely used herbal remedies for treating skin diseases and possess numerous activities such as antibacterial, antiviral, antifungal, and antioxidant. The aim of this study was to investigate the possible wound healing effect of Aloev era-based extract of the N. oleander leaf (NAE-8®) based on its antioxidant, anti-inflammatory, and DNA repair capacity along with histological changes and to compare them with the traditional silver sulfadiazine treatment (SSD). METHODS: Twenty-four Wistar albino rats were randomly grouped as follows: i) control, ii) burn alone (burn), iii) burn with topical NAE-8® (burn+NAE-8®) treatment, and iv) burn with topical 1% silver sulfadiazine (burn+SSD) treatment. All groups received their related topical application twice a day for 14 consecutive days. Upon completion of the experimental protocol, trunk blood and skin tissues were collected for measuring malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO), tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), %DNA in the tail (%DNAT) levels along with histological examinations. RESULTS: Thermal injury-induced alterations in MDA, GSH, MPO, TNF-α, IL-1ß, and %DNAT levels were significantly reversed by NAE-8® treatment. These ameliorative effects were also supported by histological findings. CONCLUSION: Findings of the present study suggest that NAE-8® is a promising remedy for treating skin burn injury.

Personalized medicine beyond genomics: alternative futures in big data-proteomics, environtome and the social proteome.

No field in science and medicine today remains untouched by Big Data, and psychiatry is no exception. Proteomics is a Big Data technology and a next generation biomarker, supporting novel system diagnostics and therapeutics in psychiatry. Proteomics technology is, in fact, much older than genomics and dates to the 1970s, well before the launch of the international Human Genome Project. While the genome has long been framed as the master or "elite" executive molecule in cell biology, the proteome by contrast is humble. Yet the proteome is critical for life-it ensures the daily functioning of cells and whole organisms. In short, proteins are the blue-collar workers of biology, the down-to-earth molecules that we cannot live without. Since 2010, proteomics has found renewed meaning and international attention with the launch of the Human Proteome Project and the growing interest in Big Data technologies such as proteomics. This article presents an interdisciplinary technology foresight analysis and conceptualizes the terms "environtome" and "social proteome". We define "environtome" as the entire complement of elements external to the human host, from microbiome, ambient temperature and weather conditions to government innovation policies, stock market dynamics, human values, political power and social norms that collectively shape the human host spatially and temporally. The "social proteome" is the subset of the environtome that influences the transition of proteomics technology to innovative applications in society. The social proteome encompasses, for example, new reimbursement schemes and business innovation models for proteomics diagnostics that depart from the "once-a-life-time" genotypic tests and the anticipated hype attendant to context and time sensitive proteomics tests. Building on the "nesting principle" for governance of complex systems as discussed by Elinor Ostrom, we propose here a 3-tiered organizational architecture for Big Data science such as proteomics. The proposed nested governance structure is comprised of (a) scientists, (b) ethicists, and (c) scholars in the nascent field of "ethics-of-ethics", and aims to cultivate a robust social proteome for personalized medicine. Ostrom often noted that such nested governance designs offer assurance that political power embedded in innovation processes is distributed evenly and is not concentrated disproportionately in a single overbearing stakeholder or person. We agree with this assessment and conclude by underscoring the synergistic value of social and biological proteomes to realize the full potentials of proteomics science for personalized medicine in psychiatry in the present era of Big Data.

Harnessing Knowledge on Very Important Pharmacogenes CYP2C9 and CYP2C19 Variation for Precision Medicine in Resource-Limited Global Conflict Zones.

Pharmacogenomics harnesses the utility of a patient's genome (n = 1) in decisions on which therapeutic drugs and in what amounts should be administered. Often, patients with shared ancestry present with comparable genetic profiles that predict drug response. However, populations are not static, thus, often, population mobility through migration, especially enmasse as is seen for refugees, changes the pharmacogenetic profiles of resultant populations and therefore observed responses to commonly used therapeutic drugs. For example, in the aftermath of the Syrian civil war since 2011, millions have fled their homes to neighboring countries in the Middle East. The growing permanence of refugees and mass migrations is a call to shift our focus in the life sciences community from old models of pharmaceutical innovation. These seismic social changes demand faster decisions for "population-to-population bridging," whereby novel drugs developed in or for particular regions/countries can meet with rational regulatory decisions/approval in world regions impacted by migrant/refugee populations whose profiles are dynamic, such as in the Eastern Mediterranean region at present. Thus, it is important to characterize and report on the prevalence of pharmacogenes that affect commonly used medications and predict if population changes may call for attention to particular differences that may impact health of patients. Thus, we report here on four single-nucleotide polymorphism (SNP) variations in CYP2C9 and CYP2C19 genes among Mersin-Turkish healthy volunteers in the Mersin Province in the Eastern Mediterranean region that is currently hosting a vast number of migrant populations from Syria. Both CYP2C9 and CYP2C19 are very important pharmacogene molecular targets. We compare and report here on the observed SNP genetic variation in our sample with data on 12 world populations from dbSNP and discuss the feasibility of forecasting the pharmacokinetics of drugs utilized by migrant communities in Mersin and the Eastern Mediterranean region. This study can serve as a catalyst to invest in research in Syrian populations currently living in the Eastern Mediterranean. The findings have salience for rapid and rational regulatory decision-making for worldwide precision medicine and, specifically, "pharmacogenovigilance-guided bridging of pharmacokinetics" across world populations in the current era of planetary scale migration.

The role of oxidative DNA damage and GSTM1, GSTT1, and hOGG1 gene polymorphisms in coronary artery disease risk.

OBJECTIVE: Atherosclerotic coronary artery disease (CAD) appears to be a multifactorial process caused by the interaction of environmental risk factors with multiple predisposing genes. Therefore, in this study we aimed to determine the role of oxidative DNA damage and some variations in glutathione S-transferase (GSTM1 and GSTT1) and DNA repair (hOGG1) genes in CAD risk. METHODS: A case-control study was conducted on 59 individuals who had undergone coronary angiographic evaluation. Of these, 29 were patients diagnosed with CAD (mean age =61.5±10.3) and 30 were controls examined for reasons other than suspected CAD and who had angiographically documented normal coronary arteries (mean age =60.4±11.6). Basal DNA damage as well as pyrimidine and purine base damage were evaluated in peripheral blood lymphocytes using the modified comet assay. Polymerase chain reaction-restriction length polymorphism (PCR-RFLP)-based assay was used for genotyping. RESULTS: Basal DNA damage levels in patients [9.16 (3.26)] were significantly higher than those in controls [7.59 (3.23); p=0.017], and basal DNA and pyrimidine base damage levels were significantly correlated with disease severity based on Gensini scoring (r=0.352, p=0.006; r=0.318, p=0.014, respectively). However, no significant differences were observed in terms of oxidized DNA bases between patients and controls. The frequencies of studied genotypes (GSTM1, GSTT1, and hOGG1) were similar between groups. CONCLUSION: The results of this study pointed out the role of DNA damage in CAD and its severity. However, GSTM1, GSTT1, and hOGG1 gene polymorphisms seemed to have no effect on individual susceptibility for disease progression.

An Appeal to the Global Health Community for a Tripartite Innovation: An "Essential Diagnostics List," "Health in All Policies," and "See-Through 21(st) Century Science and Ethics".

Diagnostics spanning a wide range of new biotechnologies, including proteomics, metabolomics, and nanotechnology, are emerging as companion tests to innovative medicines. In this Opinion, we present the rationale for promulgating an "Essential Diagnostics List." Additionally, we explain the ways in which adopting a vision for "Health in All Policies" could link essential diagnostics with robust and timely societal outcomes such as sustainable development, human rights, gender parity, and alleviation of poverty. We do so in three ways. First, we propose the need for a new, "see through" taxonomy for knowledge-based innovation as we transition from the material industries (e.g., textiles, plastic, cement, glass) dominant in the 20(th) century to the anticipated knowledge industry of the 21st century. If knowledge is the currency of the present century, then it is sensible to adopt an approach that thoroughly examines scientific knowledge, starting with the production aims, methods, quality, distribution, access, and the ends it purports to serve. Second, we explain that this knowledge trajectory focus on innovation is crucial and applicable across all sectors, including public, private, or public-private partnerships, as it underscores the fact that scientific knowledge is a co-product of technology, human values, and social systems. By making the value systems embedded in scientific design and knowledge co-production transparent, we all stand to benefit from sustainable and transparent science. Third, we appeal to the global health community to consider the necessary qualities of good governance for 21st century organizations that will embark on developing essential diagnostics. These have importance not only for science and knowledge-based innovation, but also for the ways in which we can build open, healthy, and peaceful civil societies today and for future generations.