Abstract Biomarkers which predict response to atypical antipsychotic drugs (AAPDs) increases their benefit/risk ratio. We sought to identify common variants in genes which predict response to ...lurasidone, an AAPD, by associating genome-wide association study (GWAS) data and changes (Δ) in Positive And Negative Syndrome Scale (PANSS) scores from two 6-week randomized, placebo-controlled trials of lurasidone in schizophrenia (SCZ) patients. We also included SCZ risk SNPs identified by the Psychiatric Genomics Consortium using a polygenic risk analysis. The top genomic loci, with uncorrected p < 10 − 4 , include: 1) synaptic adhesion ( PTPRD , LRRC4C , NRXN1 , ILIRAPL1 , SLITRK1 ) and scaffolding ( MAGI1 , MAGI2, NBEA ) genes, both essential for synaptic function; 2) other synaptic plasticity-related genes ( NRG1/3 and KALRN) ; 3) the neuron-specific RNA splicing regulator, RBFOX 1; and 4) ion channel genes, e.g. KCNA10 , KCNAB1 , KCNK9 and CACNA2D3 ). Some genes predicted response for patients with both European and African Ancestries. We replicated some SNPs reported to predict response to other atypical APDs in other GWAS. Although none of the biomarkers reached genome-wide significance, many of the genes and associated pathways have previously been linked to SCZ. Two polygenic modeling approaches, GCTA-GREML and PLINK-Polygenic Risk Score, demonstrated that some risk genes related to neurodevelopment, synaptic biology, immune response, and histones, also contributed to prediction of response. The top hits predicting response to lurasidone did not predict improvement with placebo. This is the first evidence from clinical trials that SCZ risk SNPs are related to clinical response to an AAPD. These results need to be replicated in an independent sample.
Abstract Background Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25–50% of patients expected to achieve a ...pathologic response. Validated biomarkers predictive of response are currently lacking. Objective To discover and validate biomarkers predictive of response to NAC for MIBC. Design, setting, and participants Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments–certified laboratory. Outcome measurements and statistical analysis The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. Results and limitations Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery ( p = 0.024) and validation ( p = 0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM , RB1 , and FANCC predicted pathologic response ( p < 0.001; 87% sensitivity, 100% specificity) and better overall survival ( p = 0.007). This test remained predictive for pathologic response in the validation set ( p = 0.033), with a trend towards better overall survival ( p = 0.055). These results require further validation in additional sample sets. Conclusions Genomic alterations in the DNA repair-associated genes ATM , RB1 , and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. Patient summary Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.
To describe trends in suicides with opioid poisoning noted as a contributing cause of death.
Using National Vital Statistics data (1999-2014), we calculated age-adjusted rates of suicide with opioid ...poisoning (International Classification of Diseases, Tenth Revision codes T40.0-T40.4) per 100 000 population per year and annual percentage change (APC) in rates. We used Joinpoint regression to examine trends in suicide rates and proportion of suicides involving opioids.
The annual age-adjusted death rate from suicide with opioid poisoning as a contributing cause of death increased from 0.3 per 100 000 in 1999 to 0.7 per 100 000 in 2009 (APC = 8.1%; P < .001), and remained at 0.6 to 0.7 per 100 000 through 2014. The percentage of all suicides with opioid poisoning listed as a contributing cause of death increased from 2.2% in 1999 to 4.4% in 2010 (P < .001). Rates were similar for men and women, higher among Whites than non-Whites, higher in the West, and highest for individuals aged 45 to 64 years.
Opioid involvement in suicides has doubled since 1999. These analyses underscore the need for health care providers to assess suicidal risk in patients receiving opioids.
The use of chronic opioid therapy (COT) for chronic non-cancer pain (CNCP) has increased dramatically in the past two decades. There has also been a marked increase in the abuse of prescribed opioids ...and in accidental opioid overdose. Misuse of prescribed opioids may link these trends, but has thus far only been studied in small clinical samples. We therefore sought to validate an administrative indicator of opioid misuse among large samples of recipients of COT and determine the demographic, clinical, and pharmacological risks associated with possible and probable opioid misuse. A total of 21,685 enrollees in commercial insurance plans and 10,159 in Arkansas Medicaid who had at least 90 days of continuous opioid use 2000-2005 were studied for one year. Criteria were developed for possible and probable opioid misuse using administrative claims data concerning excess days supplied of short-acting and long-acting opioids, opioid prescribers and opioid pharmacies. We estimated possible misuse at 24% of COT recipients in the commercially insured sample and 20% in the Medicaid sample and probable misuse at 6% in commercially insured and at 3% in Medicaid. Among non-modifiable factors, younger age, back pain, multiple pain complaints and substance abuse disorders identify patients at high risk for misuse. Among modifiable factors, treatment with high daily dose opioids (especially >120 mg MED per day) and short-acting Schedule II opioids appears to increase the risk of misuse. The consistency of the findings across diverse patient populations and the varying levels of misuse suggest that these results will generalize broadly, but await confirmation in other studies.
This review considers pharmacogenetics of the so called 'second-generation' antipsychotics. Findings for polymorphisms replicating in more than one study are emphasized and compared and contrasted ...with larger-scale candidate gene studies and genome-wide association study analyses. Variants in three types of genes are discussed: pharmacokinetic genes associated with drug metabolism and disposition, pharmacodynamic genes encoding drug targets, and pharmacotypic genes impacting disease presentation and subtype. Among pharmacokinetic markers, CYP2D6 metabolizer phenotype has clear clinical significance, as it impacts dosing considerations for aripiprazole, iloperidone and risperidone, and variants of the ABCB1 gene hold promise as biomarkers for dosing for olanzapine and clozapine. Among pharmacodynamic variants, the TaqIA1 allele of the DRD2 gene, the DRD3 (Ser9Gly) polymorphism, and the HTR2C -759C/T polymorphism have emerged as potential biomarkers for response and/or side effects. However, large-scale candidate gene studies and genome-wide association studies indicate that pharmacotypic genes may ultimately prove to be the richest source of biomarkers for response and side effect profiles for second-generation antipsychotics.
Opioids are widely prescribed for non-cancer pain conditions (NCPC), but there have been no large observational studies in actual clinical practice assessing patterns of opioid use over extended ...periods of time. The TROUP (Trends and Risks of Opioid Use for Pain) study reports on trends in opioid therapy for NCPC in two disparate populations, one national and commercially insured population (HealthCore plan data) and one state-based and publicly-insured (Arkansas Medicaid) population over a six year period (2000-2005). We track enrollees with the four most common NCPC conditions: arthritis/joint pain, back pain, neck pain, headaches, as well as HIV/AIDS. Rates of NCPC diagnosis and opioid use increased linearly during this period in both groups, with the Medicaid group starting at higher rates and the HealthCore group increasing more rapidly. The proportion of enrollees receiving NCPC diagnoses increased (HealthCore 33%, Medicaid 9%), as did the proportion of enrollees with NCPC diagnoses who received opioids (HealthCore 58%, Medicaid 29%). Cumulative yearly opioid dose (in mg. morphine equivalents) received by NCPC patients treated with opioids increased (HealthCore 38%, Medicaid 37%) due to increases in number of days supplied rather than dose per day supplied. Use of short-acting Drug Enforcement Administration Schedule II opioids increased most rapidly, both in proportion of NCPC patients treated (HealthCore 54%, Medicaid 38%) and in cumulative yearly dose (HealthCore 95%, Medicaid 191%). These trends have occurred without any significant change in the underlying population prevalence of NCPC or new evidence of the efficacy of long-term opioid therapy and thus likely represent a broad-based shift in opioid treatment philosophy.
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy for which new therapeutic approaches are required. One such potential therapeutic strategy is to target the ubiquitin-like ...modifier-activating enzyme 1 (UBA1), the initiating enzyme in the ubiquitylation cascade in which proteins are tagged with ubiquitin moieties to regulate their degradation or function. Here, we evaluated TAK-243, a first-in-class UBA1 inhibitor, in preclinical models of AML. In AML cell lines and primary AML samples, TAK-243 induced cell death and inhibited clonogenic growth. In contrast, normal hematopoietic progenitor cells were more resistant. TAK-243 preferentially bound to UBA1 over the related E1 enzymes UBA2, UBA3, and UBA6 in intact AML cells. Inhibition of UBA1 with TAK-243 decreased levels of ubiquitylated proteins, increased markers of proteotoxic stress and DNA damage stress. In vivo, TAK-243 reduced leukemic burden and targeted leukemic stem cells without evidence of toxicity. Finally, we selected populations of AML cells resistant to TAK-243 and identified missense mutations in the adenylation domain of UBA1. Thus, our data demonstrate that TAK-243 targets AML cells and stem cells and support a clinical trial of TAK-243 in this patient population. Moreover, we provide insight into potential mechanisms of acquired resistance to UBA1 inhibitors.
Background In Australian remote communities, First Nations children with otitis media (OM)-related hearing loss are disproportionately at risk of developmental delay and poor school performance, ...compared to those with normal hearing. Our objective was to compare OM-related hearing loss in children randomised to one of 2 pneumococcal conjugate vaccine (PCV) formulations. Methods and findings In 2 sequential parallel, open-label, randomised controlled trials (the PREVIX trials), eligible infants were first allocated 1:1:1 at age 28 to 38 days to standard or mixed PCV schedules, then at age 12 months to PCV13 (13-valent pneumococcal conjugate vaccine, +P) or PHiD-CV10 (10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine, +S) (1:1). Here, we report prevalence and level of hearing loss outcomes in the +P and +S groups at 6-monthly scheduled assessments from age 12 to 36 months. From March 2013 to September 2018, 261 infants were enrolled and 461 hearing assessments were performed. Prevalence of hearing loss was 78% (25/32) in the +P group and 71% (20/28) in the +S group at baseline, declining to 52% (28/54) in the +P groups and 56% (33/59) in the +S group at age 36 months. At primary endpoint age 18 months, prevalence of moderate (disabling) hearing loss was 21% (9/42) in the +P group and 41% (20/49) in the +S group (difference −19%; (95% confidence interval (CI) −38, −1, p = 0.07) and prevalence of no hearing loss was 36% (15/42) in the +P group and 16% (8/49) in the +S group (difference 19%; (95% CI 2, 37, p = 0.05). At subsequent time points, prevalence of moderate hearing loss remained lower in the +P group: differences −3%; (95% CI −23, 18, p = 1.00 at age 24 months), −12%; (95% CI −30, 6, p = 0.29 at age 30 months), and −9%; (95% CI −23, 5, p = 0.25 at age 36 months). A major limitation was the small sample size, hence low power to reach statistical significance, thereby reducing confidence in the effect size. Conclusions In this study, we observed a high prevalence and persistence of moderate (disabling) hearing loss throughout early childhood. We found a lower prevalence of moderate hearing loss and correspondingly higher prevalence of no hearing loss in the +P group, which may have substantial benefits for high-risk children, their families, and society, but warrant further investigation. Trial registration ClinicalTrials.gov NCT01735084 and NCT01174849
Abstract Schizophrenia (SZ) is a neuropsychiatric disorder that affects about 1% of the adult population. Numerous genes have been implicated in SZ susceptibility. MicroRNAs (miRNA) are small RNA ...molecules that regulate the translation of mRNAs via interactions with their 3′ untranslated regions. Identification of known miRNA targets on all human genes indicated that miRNA-346 targets SZ susceptibility genes listed in the SchizophreniaGene database twice as frequently as expected relative to other genes in the genome. The gene encoding this miRNA, miR-346 , is located in intron 2 of the glutamate receptor ionotropic delta 1 ( GRID1 ) gene, which has been previously implicated in SZ susceptibility. We used quantitative real-time PCR to determine the expression levels of miR-346 and GRID1 using brain RNA samples from the Stanley Array Collection, Stanley Medical Research Institute. Expression of both miR-346 and GRID1 is lower in SZ patients than that in normal controls ( P = 0.017 and 0.086, respectively). However, the expression of miR-346 and GRID1 is less correlated in SZ patients than in bipolar patients or in normal controls. This study implicates the importance of a miRNA in SZ.
Use of prescription opioids for chronic pain is increasing, as is abuse of these medications, though the nature of the link between these trends is unclear. These increases may be most marked in ...patients with mental health (MH) and substance use disorders (SUDs). We analyzed trends between 2000 and 2005 in opioid prescribing among individuals with noncancer pain conditions (NCPC), with and without MH and SUDs.
Secondary data analysis of longitudinal administrative data from 2 dissimilar populations: a national, commercially insured population and Arkansas Medicaid enrollees. We examined these opioid outcomes: (1) rates of any prescription opioid use in the past year, (2) rates of chronic use of prescription opioids (greater than 90 d in the past year), (3) mean days supply of opioids, (4) mean daily opioid dose in morphine equivalents, and (5) percentage of total opioid dose that was Schedule II opioids.
In 2000, among individuals with NCPC, chronic opioid use was more common among those with a MH or SUD than among those without in commercially insured (8% vs. 3%, P<0.001) and Arkansas Medicaid (20% vs. 13%, P<0.001) populations. Between 2000 and 2005, in commercially insured, rates of chronic opioid use increased by 34.9% among individuals with an MH or SUD and 27.8% among individuals without these disorders. In Arkansas Medicaid chronic, opioid use increased by 55.4% among individuals with an MH or SUD and 39.8% among those without.
Chronic use of prescription opioids for NCPC is much higher and growing faster in patients with MH and SUDs than in those without these diagnoses. Clinicians should monitor the use of prescription opioids in these vulnerable groups to determine whether opioids are substituting for or interfering with appropriate MH and substance abuse treatment.
PDF
