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Anosmia is common in COVID-19 patients, lasting for weeks or months following recovery. The biological mechanism underlying olfactory deficiency in COVID-19 does not involve direct damage to nasal olfactory neurons, which do not express the proteins required for SARS-CoV-2 infection. A recent study suggested that anosmia results from downregulation of olfactory receptors. We hypothesized that anosmia in COVID-19 may also reflect SARS-CoV-2 infection-driven elevated expression of regulator of G protein signaling 2 (RGS2), a key regulator of odorant receptors, thereby silencing their signaling. To test our hypothesis, we analyzed gene expression of nasopharyngeal swabs from SARS-CoV-2 positive patients and non-infected controls (two published RNA-sequencing datasets, 580 individuals). Our analysis found upregulated RGS2 expression in SARS-CoV-2 positive patients (FC = 14.5, Padj = 1.69 × 10−5 and FC = 2.4; Padj = 0.001, per dataset). Additionally, RGS2 expression was strongly correlated with PTGS2, IL1B, CXCL8, NAMPT and other inflammation markers with substantial upregulation in early infection. These observations suggest that upregulated expression of RGS2 may underlie anosmia in COVID-19 patients. As a regulator of numerous G-protein coupled receptors, RGS2 may drive further neurological symptoms of COVID-19. Studies are required for clarifying the cellular mechanisms by which SARS-CoV-2 infection drives the upregulation of RGS2 and other genes implicated in inflammation. Insights on these pathway(s) may assist in understanding anosmia and additional neurological symptoms reported in COVID-19 patients.

Bipolar disorder (BD) is a neuropsychiatric mood disorder manifested by recurrent episodes of mania and depression. More than half of BD patients are non-responsive to lithium, the first-line treatment drug, complicating BD clinical management. Given its unknown etiology, it is pertinent to understand the genetic signatures that lead to variability in lithium treatment. We discovered a set of differentially expressed genes from the LCLs of 10 controls and 19 BD patients belonging mainly to the immunoglobulin gene family that can be used as potential biomarkers to diagnose and treat BD. Importantly, we trained a machine learning algorithm on our datasets that predicted the lithium response of BD subtypes with no errors, even when used on a different cohort of 24 BD patients acquired by a different laboratory. This proves the scalability of our methodology for predicting lithium response in BD and for a prompt and suitable decision on therapeutic interventions.

Alpha 1 antitrypsin (A1AT) is the major human blood serine protease inhibitor. Transmembrane serine protease 2 (TMPRSS2), which is crucial for SARS-CoV-2 cell entry, is inhibited by A1AT. Therefore, we hypothesized that individuals with diminished levels of A1AT may be more prone to SARS-CoV-2 infection and severe COVID-19 disease. Our aim in this study was to evaluate the level of A1AT in hospitalized COVID-19 patients in comparison to hospitalized patients with non-COVID-19 pneumonia.We conducted an observational prospective study between October 2020 and April 2021 in Rabin Medical Centre in Israel. A1AT levels were measured from the routine serum samples of hospitalized patients with COVID-19 and non-COVID-19 pneumonia (control group). The primary outcome was A1AT level, secondary outcomes were clinical outcomes and predictors of morality.Overall, 145 patients were included in the study, 98 in the COVID-19 group and 47 in the control group. The median A1AT level was 222 mg/dL (interquartile range (IQR) 188-269) and 258 mg/dL (IQR 210-281) in the COVID-19 and control groups, respectively (Patients admitted due to severe COVID-19 had lower A1AT levels in comparison to patients admitted due to non-COVID pneumonia. This observation may suggest an association between mildly diminished A1AT and higher risk of SARS-CoV-2 infection with severe COVID-19 disease.

Mutations in over 100 genes are implicated in autism spectrum disorder (ASD). DNA SNPs, CNVs, and epigenomic modifications also contribute to ASD. Transcriptomics analysis of blood samples may offer clues for pathways dysregulated in ASD. To expand and validate published findings of RNA-sequencing (RNA-seq) studies, we performed RNA-seq of whole blood samples from an Israeli discovery cohort of eight children with ASD compared with nine age- and sex-matched neurotypical children. This revealed 10 genes with differential expression. Using quantitative real-time PCR, we compared RNAs from whole blood samples of 73 Israeli and American children with ASD and 26 matched neurotypical children for the 10 dysregulated genes detected by RNA-seq. This revealed higher expression levels of the pro-inflammatory transcripts

With increased life expectancies in developed countries, cancer rates are becoming more common among the elderly. Cancer is typically driven by a combination of germline and somatic mutations accumulating during an individual's lifetime. Yet, many centenarians reach exceptionally old age without experiencing cancer. It was suggested that centenarians have more robust DNA repair and mitochondrial function, allowing improved maintenance of DNA stability. In this study, we applied real-time quantitative PCR to examine the expression of ATM in lymphoblastoid cell lines (LCLs) from 15 healthy female centenarians and 24 younger female donors aged 21-88 years. We observed higher ATM mRNA expression of in LCLs from female centenarians compared with both women aged 21-48 years (FD = 2.0, p = .0016) and women aged 56-88 years (FD = 1.8, p = .0094. Positive correlation was found between ATM mRNA expression and donors age (p = .0028). Levels of hsa-miR-181a-5p, which targets ATM, were lower in LCLs from centenarians compared with younger women. Our findings suggest a role for ATM in protection from age-related diseases, possibly reflecting more effective DNA repair, thereby reducing somatic mutation accumulation during aging. Further studies are required for analyzing additional DNA repair pathways in biosamples from centenarians and younger age men and women.

Activity-dependent neuroprotective protein (ADNP) is essential for brain formation and function. As such, de novo mutations in ADNP lead to the autistic ADNP syndrome and somatic ADNP mutations may drive Alzheimer's disease (AD) tauopathy. Sirtuin 1 (SIRT1) is positively associated with aging, the major risk for AD. Here, we revealed two key interaction sites for ADNP and SIRT1. One, at the microtubule end-binding protein (EB1 and EB3) Tau level, with EB1/EB3 serving as amplifiers for microtubule dynamics, synapse formation, axonal transport, and protection against tauopathy. Two, on the DNA/chromatin site, with yin yang 1, histone deacetylase 2, and ADNP, sharing a DNA binding motif and regulating SIRT1, ADNP, and EB1 (MAPRE1). This interaction was linked to sex- and age-dependent altered histone modification, associated with ADNP/SIRT1/WD repeat-containing protein 5, which mediates the assembly of histone modification complexes. Single-cell RNA and protein expression analyses as well as gene expression correlations placed SIRT1-ADNP and either MAPRE1 (EB1), MAPRE3 (EB3), or both in the same mouse and human cell; however, while MAPRE1 seemed to be similarly regulated to ADNP and SIRT1, MAPRE3 seemed to deviate. Finally, we demonstrated an extremely tight correlation for the gene transcripts described above, including related gene products. This correlation was specifically abolished in affected postmortem AD and Parkinson's disease brain select areas compared to matched controls, while being maintained in blood samples. Thus, we identified an ADNP-SIRT1 complex that may serve as a new target for the understanding of brain degeneration.

Mutations in over 100 genes are implicated in autism spectrum disorder (ASD). DNA mutations and epigenomic modifications also contribute to ASD. Transcriptomics analysis of blood samples may offer clues for pathways dysregulated in ASD. To expand and validate published findings of RNA-sequencing (RNA-seq) studies, we performed RNA-seq of whole blood samples from a discovery cohort of eight children with ASD compared with nine age- and sex-matched neurotypical children. This revealed 10 genes with differential expression. Using real-time PCR, we compared whole blood samples from 35 children with ASD and 21 matched neurotypical children for the 10 dysregulated genes detected by RNA-seq. This revealed higher expression levels of the proinflammatory transcripts BATF2 and FCGR1A, and lower expression levels of the anti-inflammatory transcripts ISG15 and MT2A in the ASD compared to the control group. BATF2 and FCGR1A were recently reported as upregulated in blood samples of Japanese adults with ASD. Coupled with that publication, our findings support involvement of these genes in ASD phenotypes, independent of age and ethnicity. Upregulation of BATF2 and FCGR1A and downregulation of ISG15 and MT2A were reported to reduce cancer risk. Implications of the dysregulated genes for pro-inflammatory phenotypes, immunity, and cancer risk in ASD are discussed.

Several comorbidities including diabetes, immune deficiency, and chronic respiratory disorders increase the risk of severe Covid-19 and fatalities among SARS-CoV-2 infected individuals. Severe Covid-19 risk among diabetes patients may reflect reduced immune response to viral infections. SARS-CoV-2 initially infects respiratory tract epithelial cells by binding to the host cell membrane ACE2, followed by proteolytic priming for cell entry by the host cell membrane serine protease TMPRSS2. Additionally, the protease FURIN facilitates cell exit of mature SARS-CoV-2 virions. Alpha-1 antitrypsin (AAT), the major plasma serine protease inhibitor, encoded by SERPINA1, is known to promote immune response to viral infections. AAT inhibits neutrophil elastase, a key inflammatory serine protease implicated in alveolar cell damage during respiratory infections, and AAT deficiency is associated with susceptibility to lung infections. AAT is implicated in Covid-19 as it inhibits TMPRSS2, a protease essential for SARS-CoV-2 cell entry. Here we show that treatment of A549 human lung epithelial cells for 7 days with 25 mM d-galactose, an inducer of diabetic-like and oxidative stress cellular phenotypes, leads to increased mRNA levels of ACE2, TMPRSS2, and FURIN, along with reduced SERPINA1 mRNA. Together, the dysregulated transcription of these genes following d-galactose treatment suggests that chronic diabetic-like conditions may facilitate SARS-CoV-2 infection of lung epithelial cells. Our findings may in part explain the higher severe Covid-19 risk in diabetes, and highlight the need to develop special treatment protocols for diabetic patients.

αvβ3 integrin, a plasma membrane protein, is amply expressed on an array of tumors. We identified nuclear αvβ3 pool in ovarian cancer cells and were interested to explore this phenomenon in two rare and aggressive types of leukemia, T-cell acute lymphoblastic leukemia (T-ALL) and Mast cell leukemia (MCL) using Jurkat and HMC-1 cell lines, respectively. Moreover, we collected primary cells from patients with chronic lymphocytic leukemia (CLL, n = 11), the most common chronic adult leukemia and used human lymphoblastoid cell lines (LCL) generated from normal B cells. Nuclear αvβ3 integrin was assessed by Western blots, confocal microscopy, and the ImageStream technology which combines flow-cytometry with microscopy. We further examined post translational modifications (phosphorylation/glycosylation), nuclear trafficking regulation using inhibitors for MAPK (U0126) and PI3K (LY294002), as well as nuclear interactions by performing Co-immunoprecipitation (Co-IP). αvβ3 integrin was identified in all cell models within the nucleus and is N-glycosylated. In primary CLL cells the β3 integrin monomer is tyrosine Y759 phosphorylated, suggesting an active receptor conformation. MAPK and PI3K inhibition in Jurkat and CLL cells led to αvβ3 enhancement in the nucleus and a reduction in the membrane. The nuclear αvβ3 integrin interacts with ERK, Histone H3 and Lamin B1 in Jurkat, Histone H3 in CLL cells, but not in control LCL cells. To conclude, this observational study provides the identification of nuclear αvβ3 in hematological malignancies and lays the basis for novel cancer-relevant actions, which may be independent from the membrane functions.

Bipolar disorder (BD) is a complex neuropsychiatric disorder characterized by recurrent mania and depression episodes and requiring lifelong treatment with mood stabilizing drugs. Several lines of evidence, including with BD patient iPSC-derived neurons, suggest that neuronal hyperexcitability may underlie the key clinical symptoms of BD. Indeed, higher mRNA levels of SCN11A, coding for the voltage-gated sodium channel NaV 1.9 implicated in nociception, were detected in iPSC-derived neurons from BD patients, and were normalized by in vitro lithium. Here we studied SCN11A expression in peripheral blood mononuclear cells (PBMCs) from well-phenotyped female BD patients and controls and evaluated their association with several clinical sub-phenotypes. We observed higher mRNA levels of SCN11A in PBMCs from female BD patients with no records of alcohol dependence (p = .0050), no records of psychosis (p = .0097), or no records of suicide attempts (p = .0409). A trend was observed for higher SCN11A expression (FD = 1.91; p = .052) in BD PBMCs compared with controls. Datamining of published postmortem gene expression datasets indicated higher SCN11A expression in dorsolateral prefrontal cortex and orbitofrontal cortex tissues from BD patients compared with controls. Higher phenotype-associated expression levels in PBMC from BD patients were also observed for ID2 (alcohol dependence, suicide attempts) and HDGFRP3 (seasonal BD pattern). Our findings suggest that higher PBMC SCN11A expression levels may be associated with certain behavioral BD sub-phenotypes, including lack of alcohol dependence and psychosis, among BD patients. The NaV 1.9 voltage-gated sodium channel thus deserves consideration as a tentative phenotype modifier in BD.

The peptide hormone oxytocin is an established regulator of social function in mammals, and dysregulated oxytocin signaling is implicated in autism spectrum disorder (ASD). Several clinical trials examining the effects of intranasal oxytocin for improving social and behavioral function in ASD have had mixed or inclusive outcomes. The heterogeneity in clinical trials outcomes may reflect large inter-individual expression variations of the oxytocin and/or vasopressin receptor genes OXTR and AVPR1A, respectively. To explore this hypothesis we examined the expression of both genes in peripheral blood mononuclear cells (PBMC) from ASD children, their non-ASD siblings, and age-matched neurotypical children aged 3 to 16 years of age as well as datamined published ASD datasets. Both genes were found to have large inter-individual variations. Higher OXTR and AVPR1A expression was associated with lower Aberrant Behavior Checklist (ABC) scores. OXTR expression was associated with less severe behavior and higher adaptive behavior on additional standardized measures. Combining the sum expression levels OXTR, AVPR1A, and IGF1 yielded the strongest correlation with ABC scores. We propose that future clinical trials in ASD children with oxytocin, oxytocin mimetics and additional tentative therapeutics should assess the prognostic value of their PBMC mRNA expression of OXTR, AVPR1A, and IGF1.

MicroRNAs (miRNAs) are short, noncoding RNAs functioning as regulators of the transcription of protein-coding genes in eukaryotes. During the last two decades, studies on miRNAs indicate that they have potential as diagnostic and prognostic biomarkers for a wide range of cancers. Research interest in miRNAs has moved to embrace further medical disciplines, including neuropsychiatric disorders, comparing miRNA expression and mRNA targets between patient and control blood samples and postmortem brain tissues, as well as in animal models of neuropsychiatric disorders. This manuscript reviews recent findings on miRNAs implicated in the pathology of mood disorders, schizophrenia, and autism, as well as their diagnostic potential, and their potential as tentative targets for future therapeutics. The plausible contribution of X chromosome miRNAs to the larger prevalence of major depression among women is also evaluated. .Los microARN (miARNs) son ARN cortos y no codificantes que funcionan como reguladores de la transcripción de genes que codifican proteínas en los eucariotes. Durante las últimas dos décadas, los estudios sobre miARNs señalan que tienen un potencial como biomarcadores diagnósticos y pronósticos para una amplia gama de cánceres. El interés de la investigación en los miARNs se ha extendido a otras disciplinas médicas, como los trastornos neuropsiquiátricos, donde se compara la expresión de los miARNs y los blancos de ARNm entre las muestras de sangre de pacientes y controles y los tejidos cerebrales postmortem, como también en modelos animales de trastornos neuropsiquiátricos. Este artículo revisa los hallazgos más recientes sobre los miARNs implicados en los trastornos del ánimo, la esquizofrenia y el autismo, así como su potencial en el diagnóstico y como blancos experimentales para futuras terapias. También se evalúa la eventual contribución de los miARNs del cromosoma X a la mayor prevalencia de depresión mayor entre las mujeres.Les micro-ARN (miARN) sont de courts ARN non codants, fonctionnant comme des régulateurs de la transcription des gènes codant la protéine dans les cellules eucaryotes. D’après des études menées au cours des dix dernières années, les micro-ARN ont un potentiel en tant que biomarqueurs diagnostiques et pronostiques dans une large gamme de cancers. Les centres d’intérêt de la recherche sur les miARN se sont élargis à d’autres disciplines médicales, dont l’étude des maladies neuropsychiatriques, en comparant l’expression des miARN et des ARNm cibles dans des échantillons de sang de patients avec des échantillons de contrôle, dans des tissus cérébraux post-mortem, ainsi que dans des modèles animaux de maladies neuropsychiatriques. Cet article passe en revue les découvertes les plus récentes sur les miARN impliqués dans les pathologies des troubles de l’humeur, la schizophrénie et l’autisme ainsi que leur potentiel diagnostique et thérapeutique en tant que cibles expérimentales pour de futures thérapies. Il y sera également étudié la possible implication des miARN du chromosome X dans la prévalence plus grande de la dépression majeure chez les femmes.

Aim: The need for pharmacogenomic education is becoming more and more urgent. Our aim was to evaluate the progress in pharmacogenomics education since then, and to put forward further recommendations. Methods: A survey was sent to 248 schools of medicine, pharmacy, nursing and health professions around the world. Results: The majority of the study programs (87%) include pharmacogenomics education, which is generally taught as part of the pharmacology curriculum. On average, educators and teachers have selected appropriate and highly relevant pharmacogenomics biomarkers to include in their teaching programs. Conclusions: Based on the results, we can conclude that the state of pharmacogenomics education at the surveyed universities has improved substantially since 2005. ispartof: PHARMACOGENOMICS vol:20 issue:9 pages:643-657 ispartof: location:England status: published

Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line antidepressant drug treatment for major depressive disorder (MDD). Treatment-resistant depression (TRD), defined as failure to achieve remission despite adequate treatment, affects ~30% of persons with MDD. The current recommended treatment for TRD is electroconvulsive therapy (ECT), while ketamine is an experimentally suggested treatment. This study aimed to elucidate the transcriptional differences in peripheral blood mononuclear cells (PBMC) between individuals with TRD and a control group without a psychiatric illness; and between patients with TRD, treated with either standard antidepressant drugs alone, or in combination with ECT or ketamine. Additionally, PBMC transcriptomics were compared between treatment responders, following completion of their treatment protocols. Total RNA was extracted from PBMC of the TRD group at two time points, and RNA and miRNA expression were profiled. Multiple mRNAs and miRNAs were found to be modified, with two protein coding genes, FKBP5 and ITGA2B, which are up- and downregulated, respectively; and several miRNAs have shown changes following successful ECT treatment. Further analysis demonstrated the direct functional regulation of ITGA2B by miR-24-3p. Our findings suggest that PBMC expression levels of FKBP5, ITGA2B, and miR-24-3p should be further explored as tentative ECT response biomarkers.

Intranasal treatment with oxytocin showed beneficial effects in post-traumatic stress disorder and autism spectrum disorders; however, it was not investigated as much in depression. Keeping in mind the favorable effects of oxytocin on animal models of anxiety and depression, we postulated that synergy between prescribed first choice drugs, selective serotonin reuptake inhibitors (SSRIs) and oxytocin could improve the treatment outcome compared with SSRI monotherapy. Our previous in vitro genome-wide transcriptomic study on human lymphoblastoid cell lines exposed to paroxetine resulted in increase of integrin β3 (ITGB3) gene expression, and further, ITGB3/CHL1 expression ratio was hypothesized to influence the sensitivity to SSRIs. The aim of this report was to explore molecular mechanisms behind the antidepressant-like oxytocin effect, alone and in synergy with citalopram, on behavioral and molecular level in corticosterone treated rats, a paradigm used to model anxiety and depression in animals. Oxytocin treatment (1) ameliorated corticosterone-induced reduction of neurogenesis and number of parvalbumin-positive interneurons in the hippocampal CA1 region, (2) enhanced anxiolytic- and antidepressant-like effects of citalopram in the open field test, and (3) the SSRI/oxytocin synergy persisted in reversing the reduction of the Itgb3 gene expression and increased Itgb3/Chl1 ratio in the prefrontal cortices. These results support the existence of synergy between citalopram and oxytocin in reversing the molecular and behavioral changes induced by corticosterone treatment and point to possible molecular mechanisms behind antidepressant-like effect of oxytocin.

Activity-dependent neuroprotective protein (ADNP) is essential for brain formation and function. As such, de novo mutations in ADNP lead to the autistic ADNP syndrome and somatic ADNP mutations may drive Alzheimer's disease (AD) tauopathy. Sirtuin 1 (SIRT1) is positively associated with aging, the major risk for AD. Here, we revealed two key interaction sites for ADNP and SIRT1. One, at the microtubule end-binding protein (EB1 and EB3) Tau level, with EB1/EB3 serving as amplifiers for microtubule dynamics, synapse formation, axonal transport, and protection against tauopathy. Two, on the DNA/chromatin site, with yin yang 1, histone deacetylase 2, and ADNP, sharing a DNA binding motif and regulating SIRT1, ADNP, and EB1 (MAPRE1). This interaction was linked to sex- and age-dependent altered histone modification, associated with ADNP/SIRT1/WD repeat-containing protein 5, which mediates the assembly of histone modification complexes. Single-cell RNA and protein expression analyses as well as gene expression correlations placed SIRT1-ADNP and either MAPRE1 (EB1), MAPRE3 (EB3), or both in the same mouse and human cell; however, while MAPRE1 seemed to be similarly regulated to ADNP and SIRT1, MAPRE3 seemed to deviate. Finally, we demonstrated an extremely tight correlation for the gene transcripts described above, including related gene products. This correlation was specifically abolished in affected postmortem AD and Parkinson's disease brain select areas compared to matched controls, while being maintained in blood samples. Thus, we identified an ADNP-SIRT1 complex that may serve as a new target for the understanding of brain degeneration.

Infection rates, severity, and fatalities due to COVID‐19, the pandemic mediated by SARS‐CoV‐2, vary greatly between countries. With few exceptions, these are lower in East and Southeast Asian and Sub‐Saharan African countries compared with other regions. Epidemiological differences may reflect differences in border closures, lockdowns, and social distancing measures taken by each county, and by cultural differences, such as common use of face masks in East and Southeast Asian countries. The plasma serine protease inhibitor alpha‐1 antitrypsin was suggested to protect from COVID‐19 by inhibiting TMPRSS2, a cell surface serine protease essential for the SARS‐CoV‐2 cell entry. Here, we present evidence that population differences in alpha‐1 antitrypsin deficiency allele frequencies may partially explain national differences in the COVID‐19 epidemiology. Our study compared reported national estimates for the major alpha‐1 antitrypsin deficiency alleles PiZ and PiS (SERPINA1 rs28929474 and rs17580, respectively) with the Johns Hopkins University Coronavirus Resource Center dataset. We found a significant positive correlation (R = .54, P = 1.98e−6) between the combined frequencies of the alpha‐1 antitrypsin PiZ and PiS deficiency alleles in 67 countries and their reported COVID‐19 mortality rates. Our observations suggest that alpha‐1 antitrypsin deficiency alleles may contribute to national differences in COVID‐19 infection, severity, and mortality rates. Population‐wide screening for carriers of alpha‐1 antitrypsin deficiency alleles should be considered for prioritizing individuals for stricter social distancing measures and for receiving a SARS‐CoV‐2 vaccine once it becomes available.

Uncertainties remain concerning the pathophysiology, epidemiology, and potential therapeutics for COVID‐19. Among unsettled controversies is whether tobacco smoking increases or protects from severe COVID‐19. Several epidemiological studies reported reduced COVID‐19 hospitalizations among smokers, while other studies reported the opposite trend. Some authors assumed that smokers have elevated airway expression of ACE2, the cell recognition site of the SARS‐Cov‐2 spike protein, but this suggestion remains unverified. We therefore performed data mining of two independent NCBI GEO genome‐wide RNA expression files (GSE7894 and GSE994) and report that in both data sets, current smokers and never smokers have, on average, closely similar bronchial epithelial cell mRNA levels of ACE2, as well as TMPRSS2, coding for a serine protease priming SARS‐Cov‐2 for cell entry, and ADAM17, coding for a protease implicated in ACE2 membrane shedding. In contrast, the expression levels of TMPRSS4, coding for a protease that primes SARS‐CoV‐2 for cell entry similarly to TMPRSS2, were elevated in bronchial epithelial cells from current smokers compared with never smokers, suggesting that higher bronchial TMPRSS4 levels in smokers might put them at higher SARS‐Cov‐2 infection risk. The effects of smoking on COVID‐19 severity need clarification with larger studies. Additionally, the postulated protective effects of nicotine and nitric oxide, which may presumably reduce the risk of a “cytokine storm” in infected individuals, deserve assessment by controlled clinical trials.

Since its outbreak in late 2019, the SARS‐Cov‐2 pandemic already infected over 3.7 million people and claimed more than 250,000 lives globally. At least 1 year may take for an approved vaccine to be in place, and meanwhile millions more could be infected, some with fatal outcome. Over thousand clinical trials with COVID‐19 patients are already listed in ClinicalTrials.com, some of them for assessing the utility of therapeutics approved for other conditions. However, clinical trials take many months, and are typically done with small cohorts. A much faster and by far more efficient method for rapidly identifying approved therapeutics that can be repurposed for treating COVID‐19 patients is data mining their past and current electronic health and prescription records for identifying drugs that may protect infected individuals from severe COVID‐19 symptoms. Examples are discussed for applying health and prescription records for assessing the potential repurposing (repositioning) of angiotensin receptor blockers, estradiol, or antiandrogens for reducing COVID‐19 morbidity and fatalities. Data mining of prescription records of COVID‐19 patients will not cancel the need for conducting controlled clinical trials, but could substantially assist in trial design, drug choice, inclusion and exclusion criteria, and prioritization. This approach requires a strong commitment of health provides for open collaboration with the biomedical research community, as health provides are typically the sole owners of retrospective drug prescription records.

Lithium is the first-line treatment for bipolar affective disorder (BPAD) but two-thirds of patients respond only partially or not at all. The reasons for this high variability in lithium response are not well understood. Transcriptome-wide profiling, which tests the interface between genes and the environment, represents a viable means of exploring the molecular mechanisms underlying lithium response variability. Thus, in the present study we performed co-expression network analyses of whole-blood-derived RNA-seq data from n = 50 lithium-treated BPAD patients. Lithium response was assessed using the well-validated ALDA scale, which we used to define both a continuous and a dichotomous measure. We identified a nominally significant correlation between a co-expression module comprising 46 genes and lithium response represented as a continuous (i.e., scale ranging 0–10) phenotype (cor = −0.299, p = 0.035). Forty-three of these 46 genes had reduced mRNA expression levels in better lithium responders relative to poorer responders, and the central regulators of this module were all mitochondrially-encoded (MT-ND1, MT-ATP6, MT-CYB). Accordingly, enrichment analyses indicated that genes involved in mitochondrial functioning were heavily over-represented in this module, specifically highlighting the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS) as affected processes. Disrupted ETC and OXPHOS activity have previously been implicated in the pathophysiology of BPAD. Our data adds to previous evidence suggesting that a normalisation of these processes could be central to lithium’s mode of action, and could underlie a favourable therapeutic response.

Laron syndrome (LS), or primary growth hormone (GH) insensitivity, is the best-characterized entity among the congenital insulin-like growth factor 1 (IGF1) deficiencies. Life-long exposure to minute endogenous IGF1 levels is linked to low stature as well as a number of endocrine and metabolic abnormalities. While elevated IGF1 is correlated with increased cancer incidence, epidemiological studies revealed that patients with LS do not develop tumors. The mechanisms associated with cancer protection in LS are yet to be discovered. Recent genomic analyses identified a series of metabolic genes that are overrepresented in patients with LS. Given the augmented expression of these genes in a low IGF1 milieu, we hypothesized that they may constitute targets for IGF1 action. Thioredoxin-interacting protein (TXNIP) plays a critical role in cellular redox control by thioredoxin. TXNIP serves as a glucose and oxidative stress sensor, being commonly silenced by genetic or epigenetic events in cancer cells. Consistent with its enhanced expression in LS, we provide evidence that TXNIP gene expression is negatively regulated by IGF1. These results were corroborated in animal studies. In addition, we show that oxidative and glucose stresses led to marked increases in TXNIP expression. Supplementation of IGF1 attenuated TXNIP levels, suggesting that IGF1 exerts its antiapoptotic effect via inhibition of TXNIP Augmented TXNIP expression in LS may account for cancer protection in this condition. Finally, TXNIP levels could be potentially useful in the clinic as a predictive or diagnostic biomarker for IGF1R-targeted therapies.

Microhaplotypes have become a new type of forensic marker with a great ability to identify and deconvolute mixtures because massively parallel sequencing (MPS) allows the alleles (haplotypes) of the multi-SNP loci to be determined directly for an individual. As originally defined, a microhaplotype locus is a short segment of DNA with two or more SNPs defining three or more haplotypes. The length is short enough, less than about 300 bp, that the read length of current MPS technology can produce a phase-known sequence of each chromosome of an individual. As part of the discovery phase of our studies, data on 130 microhaplotype loci with estimates of haplotype frequency data on 83 populations have been published. To provide a better picture of global allele frequency variation, we have now tested 13 more populations for 65 of the microhaplotype loci from among those with higher levels of inter-population gene frequency variation, including 8 loci not previously published. These loci provide clear distinctions among 6 biogeographic regions and provide some information distinguishing up to 10 clusters of populations. Electronic supplementary material The online version of this article (10.1007/s00414-017-1748-6) contains supplementary material, which is available to authorized users.

Objectives: Lithium remains the oldest and most effective treatment for mood stabilisation in bipolar disorder (BD), even though at least half of patients are only partially responsive or d...

Clinical pharmacology & therapeutics : CPT 106(2), 313-316 (2019). doi:10.1002/cpt.1471 special issue: "Pharmacogenetics Pharmacogenomics", Published by Wiley-Blackwell, Hoboken, NJ

The growth hormone (GH)–insulin-like growth factor-1 (IGF1) pathway emerged in recent years as a critical player in cancer biology. Enhanced expression or activation of specific components of the GH–IGF1 axis, including the IGF1 receptor (IGF1R), is consistently associated with a transformed phenotype. Recent epidemiological studies have shown that patients with Laron syndrome (LS), the best-characterized entity among the congenital IGF1 deficiencies, seem to be protected from cancer development. To identify IGF1-dependent genes and signaling pathways associated with cancer protection in LS, we conducted a genome-wide analysis using immortalized lymphoblastoid cells derived from LS patients and healthy controls of the same gender, age range, and ethnic origin. Our analyses identified a collection of genes that are either over- or under-represented in LS-derived lymphoblastoids. Gene differential expression occurs in several gene families, including cell cycle, metabolic control, cytokine–cytokine receptor interaction, Jak-STAT signaling, and PI3K-AKT signaling. Major differences between LS and healthy controls were also noticed in pathways associated with cell cycle distribution, apoptosis, and autophagy. Our results highlight the key role of the GH–IGF1 axis in the initiation and progression of cancer. Furthermore, data are consistent with the concept that homozygous congenital IGF1 deficiency may confer protection against future tumor development.

Over the last two decades, and in particular since the completion of the Human Genome Project, medicine has been slowly but persistently moving towards personalized medicine – medical treatments tailored for the individual patient based on genetic and genomic information derived from patients' biological samples (blood samples and biopsied tissues). A major aim of this approach is to prescribe the right drug at the right dosage and right time for each patient. Another key aim of precision medicine is allowing earlier disease diagnosis, so that patients are treated with preventive therapeutics before the disease has caused irreparable damage. However, personalized medicine research is often hampered by high costs and lack of high-quality biological samples. Human lymphoblastoid cell lines (LCLs) are an affordable research tool that can be of high value for disease and drug response biomarker discovery in the context of personalized medicine exploration and can be obtained from many human biobanks.

The derived human alcohol dehydrogenase (ADH)1B*48His allele of the ADH1B Arg48His polymorphism (rs1229984) has been identified as one component of an East Asian specific core haplotype that underwent recent positive selection. Our study has been extended to Southwest Asia and additional markers in East Asia. Fst values (Sewall Wright’s fixation index) and long-range haplotype analyses identify a strong signature of selection not only in East Asian but also in Southwest Asian populations. However, except for the ADH2B*48His allele, different core haplotypes occur in Southwest Asia compared to East Asia and the extended haplotypes also differ. Thus, the ADH1B*48His allele, as part of a core haplotype of 10 kb, has undergone recent rapid increases in frequency independently in the two regions after divergence of the respective populations. Emergence of agriculture may be the common factor underlying the evident selection.

Barbara Prainsack1† & David Gurwitz2 †Author for correspondence 1King’s College London, Centre for Biomedicine & Society (CBAS), Strand, London, WC2R 2LS, UK Tel.: +44 (0)20 7848 1585; E-mail: barbara.prainsack@ kcl.ac.uk 2National Laboratory for the Genetics of Israeli Populations, Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel Tel.: +972 3640 7611; Fax: +972 3640 7611; E-mail: gurwitz@post.tau.ac.il ‘...the increasing prevalence of large public databases and the uncertainty surrounding their potential future uses drives public fears and raises questions regarding their legitimacy in the era of the internet.’

Dr David Gurwitz has been a Director of The National Laboratory for the Genetics of Israeli Populations at the Sackler Faculty of Medicine, Tel-Aviv University, since its establishment in 1995. His research and teaching interests are focused on pharmacogenomics and its implications for personalized medicine, mainly in the context of neurology and psychiatry.

The Human Genome Project, the most celebrated human consortium effort in biomedicine and one of the greatest scientific achievements of modern time, has yet to deliver the anticipated improvements in healthcare [1] . The blueprint of a human being, the complete 3.2 billion nucleotides of the human DNA sequence, has been available since April 2002. Up to the present day, however, we still understand very little about the biology of common complex disorders, such as diabetes, hypertension, osteoarthritis, osteoporosis, Alzheimer’s disease, schizophrenia, and depression, despite the fact that the genetic determination of each of these conditions is reliably established.

The first and crucial step in sensory processing, the transduction of stimuli, such as odor, light and sound, into a cellular response, are all regulated by genetic pathways. The past years have provided a significant increase in our understanding of some of these pathways, due in large part to the genes found to be associated with inherited hearing loss (HL).

This study aimed to critically appraise the current level of economic evidence available for thiopurine S-methyltransferase (TPMT) testing of thiopurine drugs, such as azathioprine. Six economic evaluations of testing were identified, which all recommended that TPMT testing is a cost-effective use of healthcare resources. Critical appraisal, using published guidelines, showed potential limitations in model structures, approaches to data analysis and input parameters, which were mainly based on expert opinion. Where data did exist these were from retrospective studies. To conduct economic evaluations with more robust findings, decision analysts need good quality data for the following key parameters: current prevalence of profound neutropenia among patients prescribed thiopurine drugs; mean length of related hospitalization and clinical outcome; impact of introducing the test on clinical pathways in terms of resource use; and clinical effectiveness data in terms of number of cases of neutropenia averted and subsequent impact on mortality and health-related quality of life. An iterative approach may be used to stimulate the production of a sufficient evidence base for innovative technologies, such as pharmacogenetic testing. Such an iterative approach involves starting with simple models using available existing clinical and resource use data, as in the case of TPMT testing. The use of formal value of information methods may guide the decision whether prospective studies are required to address uncertainties in the key parameters driving the model results. The results from well-designed prospective studies can then be used to populate more complex economic models.

Alzheimer’s Disease (AD) is the most common cause of dementia in the elderly. Centenarians – reaching the age of >100 years while maintaining good cognitive skills – seemingly have unique biological features allowing healthy aging and protection from dementia. Here, we studied the expression of SIRT1 along with miR-132 and miR-212, two microRNAs known to regulate SIRT1, in lymphoblastoid cell lines (LCLs) from 45 healthy donors aged 21 to 105 years and 24 AD patients, and in postmortem olfactory bulb and hippocampus tissues from 14 AD patients and 20 age-matched non-demented individuals. We observed 4.0-fold (P = 0.001) lower expression of SIRT1, and correspondingly higher expression of miR-132 (1.7-fold; P = 0.014) and miR-212 (2.1-fold; P = 0.036), in LCLs from AD patients compared with age-matched healthy controls. Additionally, SIRT1 expression was 2.2-fold (P = 0.001) higher in centenarian LCLs compared with LCLs from individuals aged 56–82 years; while centenarian LCLs miR-132 and miR-212 indicated 7.6-fold and 4.1-fold lower expression, respectively. Correlations of SIRT1, miR-132 and miR-212 expression with cognitive scores were observed for AD patient-derived LCLs and postmortem AD olfactory bulb and hippocampus tissues, suggesting that higher SIRT1 expression, possibly mediated by lower miR-132 and miR-212, may protect aged individuals from dementia and is reflected in their peripheral tissues.

Aim: The identification of antidepressant drugs (ADs) response biomarkers in depression is of high clinical importance. We explored CHL1 and ITGB3 expression as tentative response biomarkers. Materials & methods: In vitro sensitivity to ADs, as well as gene expression and genetic variants of the candidate genes CHL1, ITGB3 and SLC6A4 were measured in lymphoblastoid cell lines (LCLs) of 58 depressed patients. Results: An association between the clinical remission of depression and the basal expression of CHL1 and ITGB3 was discovered. Individuals whose LCLs expressed higher levels of CHL1 or ITGB3 showed a significantly better remission upon AD treatment. In addition individuals with the CHL1 rs1516338 TT genotype showed a significantly better remission after 5 weeks AD treatment than those carrying a CC genotype. No association between the in vitro sensitivity of LCLs toward AD and the clinical remission could be detected. Conclusion: CHL1 expression in patient-derived LCLs correlated with the clinical outcome. Thus, it could be a valid biomarker to predict the success of an antidepressant therapy. Original submitted 8 December 2014; Revision submitted 2 March 2015