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Summary Background Interleukin-23 inhibitors are effective and safe for treating moderate-to-severe plaque psoriasis. Objectives To evaluate the efficacy and safety of mirikizumab in adult patients with moderate-to-severe plaque psoriasis through 52 weeks in a phase III randomized controlled trial. Methods OASIS-1 (NCT03482011) was a double-blind, placebo-controlled, randomized withdrawal, phase III trial. Patients (n = 530, randomized 4 : 1) received subcutaneous mirikizumab 250 mg or placebo every 4 weeks (Q4W) through week 16. Coprimary endpoints were superiority of mirikizumab vs. placebo on static Physician’s Global Assessment (sPGA; score of 0 or 1 with ≥ 2-point improvement) and ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90, responders) at week 16. Mirikizumab responders were rerandomized (1 : 1 : 1) to mirikizumab 250 mg every 8 weeks (Q8W), mirikizumab 125 mg Q8W, or placebo Q8W through week 52. Secondary endpoints were evaluated at weeks 16 and 52. Safety was monitored in all patients. Results All primary and key secondary endpoints were met. At week 16, sPGA(0,1) responses were significantly greater with mirikizumab (293 of 423, 69·3%) than placebo (seven of 107, 6·5%) (P < 0·001). PASI 90 response was also greater with mirikizumab (272 of 423, 64·3%) than placebo (seven of 107, 6·5%) (P < 0·001). Significantly more patients in the mirikizumab arms achieved PASI 75 and PASI 100 (mirikizumab 349, 82·5% and 137, 32·4%; placebo 10, 9·3% and 1, 0·9%, respectively; all P < 0·001). At week 52, PASI 90, PASI 100 and sPGA(0,1) responses were mirikizumab 250Q4W/placeboQ8W (N = 91; 19%, 10%, 18%), mirikizumab 250Q4W/125Q8W (N = 90; 86%, 59%, 86%) and mirikizumab 250Q4W/250Q8W (N = 91; 86%, 60%, 82%; all P < 0·001), respectively. Rates of serious adverse events were similar across treatments (induction: mirikizumab 1·2% vs. placebo 1·9%; maintenance: mirikizumab 250Q4W/125Q8W 1%, mirikizumab 250Q4W/250Q8W 3% vs. placebo 3%). No deaths occurred. Conclusions Mirikizumab was superior to placebo at week 16 and maintained efficacy through week 52, with no new safety signals. What is already known about this topic? Interleukin (IL)-23 is a key cytokine in the pathogenesis of psoriasis. Drugs targeting the p19 subunit of IL-23 have recently been approved for the treatment of adult patients with moderate-to-severe plaque psoriasis.Patients with moderate-to-severe plaque psoriasis achieved significantly greater improvements in skin measures and patient-reported quality-of-life measures after 16 weeks when treated every 8 weeks with mirikizumab compared with placebo in a phase II clinical trial. What does this study add? Compared with placebo, mirikizumab demonstrated high levels of efficacy at week 16 in a large phase III trial; safety profiles were similar between the mirikizumab and placebo arms.After week 16, patients maintained on doses of mirikizumab 250 mg every 8 weeks (Q8W) or 125 mg Q8W showed similar efficacy and favourable safety profiles over 52 weeks, whereas patients switched to placebo gradually lost efficacy over time.

Background Clinical diagnosis of Alzheimer disease (AD) is challenging, with a 70.9%–87.3% sensitivity and 44.3%–70.8% specificity, compared with autopsy diagnosis. Florbetapir F18 positron emission tomography (FBP-PET) estimates beta-amyloid plaque density antemortem. Methods Of 2052 patients (≥55 years old) clinically diagnosed with mild or moderate AD dementia from 2 solanezumab clinical trials, 390 opted to participate in a FBP-PET study addendum. We analyzed baseline prerandomization characteristics. Results A total of 22.4% had negative FBP-PET scans, whereas 72.5% of mild and 86.9% of moderate AD patients had positive results. No baseline clinical variable reliably differentiated negative from positive FBP-PET scan groups. Conclusions These data confirm the challenges of correctly diagnosing AD without using biomarkers. FBP-PET can aid AD dementia differential diagnosis by detecting amyloid pathology antemortem, even when the diagnosis of AD is made by expert clinicians.

Background The objective of this study was to examine patient characteristics and health care resource utilization (HCRU) in the 36 months prior to a confirmatory diagnosis of Alzheimer’s disease (AD) compared to a matched cohort without dementia during the same time interval. Methods Patients newly diagnosed with AD (with ≥2 claims) were identified between January 1, 2013 to September 31, 2015, and the date of the second claim for AD was defined as the index date. Patients were enrolled for at least 36 months prior to index date. The AD cohort was matched to a cohort with no AD or dementia codes (1:3) on age, gender, race/ethnicity, and enrollment duration prior to the index date. Descriptive analyses were used to summarize patient characteristics, HCRU, and healthcare costs prior to the confirmatory AD diagnosis. The classification and regression tree analysis and logistic regression were used to identify factors associated with the AD diagnosis. Results The AD cohort (N = 16,494) had significantly higher comorbidity indices and greater odds of comorbid mental and behavioral diagnoses, including mild cognitive impairment, mood and anxiety disorders, behavioral disturbances, and cerebrovascular disease, heart disease, urinary tract infections, and pneumonia than the matched non-AD or dementia cohort (N = 49,482). During the six-month period before the confirmatory AD diagnosis, AD medication use and diagnosis of mild cognitive impairment, Parkinson’s disease, or mood disorder were the strongest predictors of a subsequent confirmatory diagnosis of AD. Greater HCRU and healthcare costs were observed for the AD cohort primarily during the six-month period before the confirmatory AD diagnosis. Conclusion The results of this study demonstrated a higher comorbidity burden and higher costs for patients prior to a diagnosis of AD in comparison to the matched cohort. Several comorbidities were associated with a subsequent diagnosis of AD. Electronic supplementary material The online version of this article (10.1186/s12877-018-0920-2) contains supplementary material, which is available to authorized users.

Background We evaluated the relationship between florbetapir-F18 positron emission tomography (FBP PET) and cerebrospinal fluid (CSF) biomarkers. Methods Alzheimer's Disease Neuroimaging Initiative-Grand Opportunity and Alzheimer's Disease Neuroimaging Initiative 2 (GO/2) healthy control (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia subjects with clinical measures and CSF collected ±90 days of FBP PET data were analyzed using correlation and logistic regression. Results In HC and MCI subjects, FBP PET anterior and posterior cingulate and composite standard uptake value ratios correlated with CSF amyloid beta (Aβ 1–42 ) and tau/Aβ 1–42 ratios. Using logistic regression, Aβ 1–42 , total tau (t-tau), phosphorylated tau 181P (p-tau), and FBP PET composite each differentiated HC versus AD. Aβ 1–42 and t-tau distinguished MCI versus AD, without additional contribution by FBP PET. Total tau and p-tau added discriminative power to FBP PET when classifying HC versus AD. Conclusion Based on cross-sectional diagnostic groups, both amyloid and tau measures distinguish healthy from demented subjects. Longitudinal analyses are needed.

Clinical diagnosis of Alzheimer's disease (AD) is challenging, with 20% or more of patients misdiagnosed, even by expert clinicians. The authors conducted a retrospective, cross-sectional analysis comparing baseline neuropsychiatric and other clinical characteristics in 199 expert-diagnosed mild and moderate AD dementia patients participating in industry-sponsored clinical trials of an investigational therapy, where 18% lacked florbetapir positron emission tomography (PET) evidence of AD neuropathology. Significant differences were found only for cognition and ApoE ε4 status, but the large degree of score overlap would preclude using these measures to predict AD misdiagnosis. This study highlights the value of amyloid PET when evaluating patients with seemingly typical AD.

To assess the effects of olanzapine long-acting injection (olanzapine-LAI) on levels of functioning in acutely ill patients with schizophrenia.During this 8-week randomized, double-blind, placebo-controlled trial, 404 inpatients were randomized to four treatment arms (olanzapine-LAI 210 mg/2 weeks = 106; olanzapine-LAI 300 mg/2 weeks = 100; olanzapine-LAI 405 mg/4 weeks = 100; placebo = 98). Also, data from the three active dosing arms were combined and compared to placebo data.NCT00088478.The treatment group comparison of mean change from baseline to endpoint in the total score and four subdomains of the Heinrichs-Carpenter Quality of Life Scale (QLS) and in the 2 summary scores and 8 subscale scores of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) were assessed using an ANOVA model.All three olanzapine-LAI treatment groups and the combined olanzapine-LAI group were superior to placebo on the QLS total score (all p-values 0.01) and the Intrapsychic Foundations subdomain (all p-values 0.02). Olanzapine-LAI 210 mg/2 weeks (p 0.001), 300 mg/2 weeks (p = 0.006), and the combined olanzapine-LAI group (p = 0.003) were superior to placebo on the Interpersonal Relations subdomain. The 300 mg/2 weeks group (p = 0.027) and the combined olanzapine-LAI group (p = 0.014) were also superior to placebo on the Instrumental Role subdomain. For the SF-36, the 300 mg/2 weeks and 405 mg/4 weeks olanzapine-LAI groups and the combined olanzapine-LAI group were superior to placebo on the Mental component score (all p-values 0.05). Each olanzapine-LAI group and the combined group were superior on the Mental Health scale (all p-values 0.05). Significant negative correlations between PANSS scores and measures of functioning indicate that as symptoms decreased, functioning increased.These results suggest that olanzapine-LAI may improve level of functioning in acutely ill patients with schizophrenia within 8 weeks of initiating treatment.

To determine the effects of long-term atomoxetine treatment on sexual development in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) as compared with placebo and with a national US survey in non-Hispanic white children and adolescents.This double-blind, placebo-controlled, relapse prevention, multicenter trial was conducted in pediatric patients (6-15 years) with DSM-IV diagnosed ADHD and lasting for ∼ 18 months. All patients received 10 weeks of open-label atomoxetine treatment (0.5-1.8 mg/kg/day). Patients responding in the last 2 weeks of treatment were randomized to double-blind treatment with either placebo or atomoxetine for up to 9 months, after which atomoxetine patients were re-randomized to either continued atomoxetine treatment or to placebo for up to another 6 months. Patients randomized to placebo at first randomization remained on placebo. The Tanner stage was assessed by the investigator at baseline and at approximately 6, 12, and 18 months, and the rate of sexual development (change in the Tanner stage) was compared between treatment groups.No statistically significant differences were observed between treatment groups either in sexual development (mean time, in days, to the first Tanner stage change: atomoxetine, 464.3 ± 23.0; placebo, 433.1 ± 14.4; p = 0.33) or in the duration of treatment exposure (atomoxetine, 315.3 days; placebo, 315.1 days; p = 0.90). Similar proportions of patients had at least one Tanner stage increase (atomoxetine: 27.1%; placebo: 31.9%; p = 0.39). Proportions of patients in each baseline Tanner stage group moving to higher stages were not statistically significantly different (p = 0.88, p = 0.18, p0.99, p = 0.68 for baseline Tanner stages 1-4, respectively). The puberty onset age was similar across treatment groups and consistent with US normative data.Long-term atomoxetine treatment was not associated with any appreciable impact on or delay in sexual maturation in children with ADHD compared with US normative data.Study limitations include the relatively short duration of exposure to atomoxetine treatment, and the fact that half of the patients had been previously treated with stimulants. In addition, the Tanner stage data were collected as a secondary measure.

ObjectiveAdding another antipsychotic to a treatment regimen was previously used in evaluating the medication's efficacy. Supplementation of depot antipsychotics with oral antipsychotics is particularly meaningful because depot formulations are typically chosen for patients struggling with adherence to oral antipsychotics. This post-hoc analysis assessed supplementation of olanzapine long-acting injection (olanzapine-LAI) with oral olanzapine.Subjects and methodsWe used 12 months of data from an open-label, single-arm extension study of patients with schizophrenia or schizoaffective disorder (N = 931) treated with olanzapine-LAI. The prevalence, duration, time to first supplementation, and best predictors of oral supplementation were assessed.ResultsOral supplementation occurred in 21% of patients for a median of 31 days with mean modal dose of 10.8 mg/day. Mean time to first supplementation was shorter for patients who were at least moderately ill at baseline compared to less ill patients (47 vs. 97 days, p < 0.001). Best predictors of oral supplementation included a more severe illness profile at baseline, lower olanzapine-LAI dose prior to oral supplementation, supervised living arrangements, and being African-American.ConclusionSupplementation of olanzapine-LAI appears to be infrequent, of relatively short duration, and reserved for more severely ill patients who may require a targeted rescue medication due to signs of impending relapse.

Objective To assess the long-term safety and tolerability of atomoxetine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder treated for ≥3 years. Method Data from 13 double-blind, placebo-controlled trials and 3 open-label extension studies were pooled. Outcome measures were patient-reported treatment-emergent adverse events (AEs); discontinuations due to AEs, serious AEs, and changes in body weight, height, vital signs, electrocardiogram, and hepatic function tests. Results In total, 714 patients were treated with atomoxetine for ≥3 years (mean follow-up 4.8 years [SD 1.1 years]), including a subset of 508 treated for ≥4 years (mean follow-up 5.3 years [SD 0.8 years]). Most subjects were younger than 12 years at entry (73.8%), male (78.4%), and white (88.9%). The mean final daily dose of atomoxetine was 1.35 mg/kg (SD 0.37 mg/kg). No new or unexpected AEs were observed compared with acute-phase treatment. Less than 6% of patients exhibited aggressive/hostile behaviors, and less than 1.6% reported suicidal ideation/behavior. No clinically significant effects were seen on growth rate, vital signs, or electrocardiographic parameters, and ≤2% of patients showed potentially clinically significant hepatic changes. Conclusion Atomoxetine was safe and well tolerated for children and adolescents with ≥3 and/or ≥4 years of treatment.

Aims: To assess how hippocampal volume (HV) from volumetric magnetic resonance imaging (vMRI) is related to the amyloid status at different stages of Alzheimer's disease (AD) and its relevance to patient care. Methods: We evaluated the ability of HV to predict the florbetapir positron emission tomography (PET) amyloid positive/negative status by group in healthy controls (HC, n = 170) and early/late mild cognitive impairment (EMCI, n = 252; LMCI, n = 136), and AD dementia (n = 75) subjects from the Alzheimer's Disease Neuroimaging Initiative Grand Opportunity (ADNI-GO) and ADNI2. Logistic regression analyses, including elastic net classification modeling with 10-fold cross-validation, were used with age and education as covariates. Results: HV predicted amyloid status only in LMCI using either logistic regression [area under the curve (AUC) = 0.71, p < 0.001] or elastic net classification modeling [positive predictive value (PPV) = 72.7%]. In EMCI, age (AUC = 0.70, p < 0.0001) and age and/or education (PPV = 63.1%), but not HV, predicted amyloid status. Conclusion: Using clinical neuroimaging, HV predicted amyloid status only in LMCI, suggesting that HV is not a biomarker surrogate for amyloid PET in clinical applications across the full diagnostic spectrum.

Up to 60% of children with attention-deficit/hyperactivity disorder (ADHD) suffer from comorbid affective or behavioral impairments, the most common condition being oppositional defiant disorder (ODD), which occurs in 40–60% of children with ADHD. This post hoc meta-analysis was performed to determine the effect of the presence of comorbid ODD symptoms on clinical outcomes among pediatric and adolescent subjects being treated for ADHD. Acute-phase data were analyzed from three randomized, double-blind, placebo-controlled studies in outpatients aged 6–16 and meeting the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for ADHD. Subjects received placebo or atomoxetine (max 1.8 mg/kg/day, daily) for 6–8 weeks. Patients were diagnosed with comorbid ODD on structured diagnostic interview (Schedule for Affective Disorders and Schizophrenia for School-aged Children—Present and Lifetime Versions). Of the 512 subjects studied, 158 were diagnosed with comorbid ODD. Relative to placebo, atomoxetine treatment significantly reduced ADHD symptoms in both ODD-comorbid and noncomorbid subjects irrespective of the comorbidity with ODD. ADHD subjects also showed significant improvements from baseline on most of the psychosocial measures of the child health questionnaire irrespective of the comorbidity with ODD. Reduction in ODD symptoms was highly related to the magnitude of ADHD response. Atomoxetine treatment significantly reduced ADHD symptoms in both ODD-comorbid and noncomorbid subjects to similar extents, indicating that the presence of comorbid symptoms of oppositionality does not affect clinical outcomes of treatment of ADHD with atomoxetine.

P2P-R is a nuclear protein that can bind both p53 and Rb1. Its functions include roles in the control of RNA metabolism, apoptosis, and p53-dependent transcription. The expression of P2P-R also is repressed in G1 arrested terminally differentiated cells. The current studies therefore evaluated if P2P-R undergoes cell cycle-associated changes in its abundance and/or localization. Western blots show that relative to G0 quiescent cells, P2P-R protein levels are higher in populations of G2/M cells prepared by the physiological parasynchronization technique of serum deprivation followed by serum stimulation. More striking is the > 10-fold enrichment of P2P-R protein in specimens of highly purified mitotic cells prepared by the mitotic shake-select technique, or by synchrony with the mitotic spindle disruption agents nocodazole or vinblastine. These changes in P2P-R protein occur without a concomitant change in P2P-R mRNA expression suggesting that P2P-R immunoreactivity increases during mitosis. Confocal microscopy next established the localization of P2P-R to nucleoli in interphase cells and at the periphery of chromosomes in mitotic cells that lack nucleoli. The high levels of P2P-R localized to the periphery of chromosomes in mitotic cells suggest that P2P-R shares characteristics with other nucleolar proteins that associate with the periphery of chromosomes during mitosis. These include: nucleolin, B23, Ki67, and fibrillarin.

Binding of type I interferons (IFNs) to their receptors induces rapid tyrosine phosphorylation of multiple proteins, including the alpha and beta subunits of the receptor, the polypeptides that form the transcriptional activator ISGF3 alpha (Stat113, Stat84, and Stat91), and the p135tyk2 and Jak-1 tyrosine kinases. In this report, we demonstrate that the alpha subunit of the type I IFN receptor (IFN-R) corresponds to the product of a previously cloned receptor subunit cDNA and, further, that the p135tyk2 tyrosine kinase directly binds and tyrosine phosphorylates this receptor subunit. Glutathione S-transferase (GST) fusion proteins encoding the different regions of the cytoplasmic domain of the alpha subunit can bind the p135tyk2 contained in human cell lysates. The association between the alpha subunit and Tyk2 was demonstrated by immunoblotting with anti-Tyk2 and antiphosphotyrosine antibodies and by using an in vitro kinase assay. Analogous experiments were then performed with recombinant baculoviruses encoding constitutively active Jak family tyrosine kinases. In this case, p135tyk2, but not Jak-1 or Jak-2 protein, binds to the GST-IFN-R proteins, suggesting that the interaction between these two proteins is both direct and specific. We also demonstrate that Tyk2, from extracts of either IFN alpha-treated human cells or insect cells infected with the recombinant baculoviruses, can catalyze in vitro phosphorylation of GST-IFN-R protein in a specific manner. Deletion mutants of the GST-IFN-R protein were used to localize both the binding and tyrosine phosphorylation site(s) to a 46-amino-acid juxtamembrane region of the alpha subunit, which shows sequence homology to functionally similar regions of other cytokine receptor proteins. These data support the hypothesis that the Tyk2 protein functions as part of a receptor complex to initiate intracellular signaling in response to type I IFNs.

Background To treat acute schizophrenia, a long-acting injectable antipsychotic needs a rapid onset of action and therapeutic profile similar to that of oral agents. The present post-hoc analyses compared results from a randomized, double-blind, placebo-controlled trial of olanzapine long-acting injection (LAI) for acute schizophrenia with those observed in similarly designed trials of oral olanzapine. Methods Six-week results from the olanzapine LAI study (N = 404) were compared with those of 3 oral studies (study 1: olanzapine vs. haloperidol vs. placebo [N = 335]; study 2: olanzapine vs. haloperidol vs. low-dose olanzapine [N = 431]; study 3: olanzapine vs. placebo vs. low-dose olanzapine [N = 152]). All patients had baseline Brief Psychiatric Rating Scale (BPRS) scores ≥24 (0–6 scale). Six-week effect sizes were calculated. Efficacy onset, pharmacokinetics, discontinuations, weight gain, and extrapyramidal symptoms were also assessed. Results At 6 weeks, mean BPRS scores decreased by 14 to 15 points for olanzapine LAI (405 mg/4 weeks, 210 or 300 mg/2 weeks), by 8 to 16 for oral olanzapine (10 ± 2.5 or 15 ± 2.5 mg/day), and by 12 to 13 for haloperidol (15 ± 5 mg/day). For those same dose groups, effect sizes vs. placebo for the BPRS were 0.7 to 0.8 for olanzapine LAI, 0.5 to 0.7 for oral olanzapine, and 0.6 for haloperidol. The first statistically significant separation from placebo on the BPRS occurred at 3 days for the olanzapine LAI groups and at 1 week for oral olanzapine and haloperidol (15 ± 5 mg/day) in oral study 1 although as late as week 6 for the 10-mg/day olanzapine dose in oral study 3. Olanzapine concentrations were similar across studies. Weight gain ≥7% of baseline occurred in up to 35% of olanzapine LAI and oral patients versus up to 12% of haloperidol and placebo patients. Extrapyramidal symptoms were lowest in the olanzapine LAI groups and significantly greater in the haloperidol groups. No post-injection delirium/sedation syndrome events occurred in the olanzapine LAI study. Conclusions Patients treated acutely with olanzapine LAI showed a similar pattern of improvement to that seen historically with oral olanzapine. With the exception of injection-related adverse events, the efficacy and tolerability profile of olanzapine LAI is similar to oral olanzapine. Trial registration ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00088478; ClinicalStudyResults.org ID; URL: http://www.clinicalstudyresults.org/: 917, 978, 982, and 5984.

Objective: Early non-response to oral antipsychotics was previously shown to be a robust predictor of subsequent non-response to continued treatment with the same oral antipsychotic medication in the treatment of schizophrenia. This study assessed whether early response or early non-response to treatment can serve as a clinical marker in the treatment of schizophrenia with an atypical antipsychotic in long-acting injection formulation (depot). Methods: This post-hoc analysis used data (n=233) from an 8-week randomized, double-blind, placebocontrolled study of olanzapine long-acting injection (olanzapine LAI) in the treatment of inpatients with schizophrenia. Early response to olanzapine LAI was defined as a ≥30% improvement on the PANSS total score (items scored 0-6) from baseline to 4 weeks of treatment. Subsequent response was defined as a ≥40% improvement on the PANSS total score from baseline to endpoint. Predictive accuracy was assessed by calculating sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall predictive accuracy. Early responders and early nonresponders to olanzapine LAI were also compared on change in clinical and functional outcome measures. Results: Early response/non-response to olanzapine LAI, assessed following 4 weeks of treatment, predicted subsequent response/nonresponse with a high level of overall accuracy (79%), sensitivity (85%), specificity (72%), PPV (78%), and NPV (80%). Compared to early nonresponders, early responders had significantly longer time to all-cause treatment discontinuation, greater symptom improvement at all time points (per PANSS total and subscale scores), and greater improvement in quality of life and level of social functioning (all at p≤.01). Conclusions: In this study of inpatients with schizophrenia, early response to olanzapine LAI was found to be a robust predictor of subsequent response to the medication. Early responders experienced significantly better clinical and functional outcomes compared to early nonresponders and had longer treatment duration. Current findings are consistent with previous research on oral antipsychotics and will require replication in future studies.

SV40 large T oncoprotein-transformed murine mesenchymal 3T3 T stem cells (CSV3 cells) can be induced to growth arrest and then differentiate into adipocytes. When differentiation occurs, SV40 T oncoprotein expression is repressed (Estervig et al., J Virol 63:2713, 1989). To determine if repression of T oncoprotein expression can also be induced pharmacologically, the effect of a variety of agents that have been reported to effect differentiation in various cell types but not in 3T3 T or CSV3 cells was tested. This rationale suggests that if any of these agents repress T oncoprotein expression in CSV3 cells, then the results would establish that repression of T oncoprotein expression can be mediated by mechanisms independent of overt differentiation. The results show that dimethylsulfoxide (DMSO) is the only agent tested that represses T oncoprotein expression in CSV3 cells. Repression occurs in a dosage-dependent manner within 24–96 hours after exposure to DMSO. The effect of DMSO on T oncoprotein expression is mediated by posttranslational mechanisms that decrease the stability of the T oncoprotein. DMSO-induced repression of T oncoprotein expression is also associated with reversion of the transformed phenotype in CSV3 cells as demonstrated by the loss of responsiveness to a specific transformation-associated mitogen. These data support the conclusion that the pharmacological repression of T oncoprotein expression represents a form of cancer suppressor activity that can be mediated by a distinct molecular mechanism. © 1992 Wiley-Liss, Inc.

The interaction between receptors and kinases of the Janus kinase (Jak) family is critical for signaling by growth factors, cytokines, and IFNs. Therefore, the characterization of the domains involved in these interactions is pivotal not only in understanding kinase activation but also in the development of drugs that mimic or inhibit signaling. In this report, we have characterized the domains of Jak1 required to associate with distinct cytokine receptor subunits: IFN-αRβL, IFN-γRα, IL-10Rα, IL-2Rβ, and IL-4Rα. We demonstrate that two regions of Jak1 are necessary for the interaction with cytokine receptors. First, a common N-terminal region that includes Jak homology (JH) domain 7 and the first 19 aa of JH6, and, second, a C-terminal region (JH6–3) that was different for distinct receptors. The contribution of the two different regions of Jak1 to cytokine receptor binding was also variable. Deletion of JH7–6 impaired the association of IL-2Rβ and IL-4Rα chains with Jak1 but did not have a major impact on the binding of Jak1 to IFN-αRβL or IL-10Rα. Interestingly, regardless of the effect on receptor binding, removal of JH7–6 completely abrogated kinase activation, indicating that this domain is required for ligand-driven kinase activation and, thus, for proper signaling through cytokine receptors.

Coexpression of the alpha and betaL subunits of the human interferon alpha (IFNalpha) receptor is required for the induction of an antiviral state by human IFNalpha. To explore the role of the different domains of the betaL subunit in IFNalpha signaling, we coexpressed wild-type alpha subunit and truncated forms of the betaL chain in L-929 cells. Our results demonstrated that the first 82 amino acids (AAs) (AAs 265-346) of the cytoplasmic domain of the betaL chain are sufficient to activate the Jak-Stat pathway and trigger an antiviral state after IFNalpha2 binding to the receptor. This region of the betaL chain, required for Jak1 binding and activation, contains the Box 1 motif that is important for the interaction of some cytokine receptors with Jak kinases. However, using glutathione S-transferase fusion proteins containing amino- and carboxyl-terminal deletions of the betaL cytoplasmic domain, we demonstrate that the main Jak1-binding region (corresponding to AAs 300-346 on the beta subunit) is distinct from the Box 1 domain (AAs 287-295).

Terminal differentiation is associated with repression in the expression of the proliferation potential proteins (P2P) subset of heterogeneous nuclear ribonucleoprotein (hnRNP) proteins. We report here the cloning and characterization of a 5173-bp P2P-related (P2P-R) cDNA that contains a 4214-bp open reading frame. Probes to this cDNA detect a single 8-kb mRNA in multiple murine tissues and in proliferating 3T3T cells, but not in terminally differentiated 3T3T adipocytes. Evidence that this cDNA can encode peptides with domains for hnRNP association was established by showing that such peptides are recognized by two monoclonal antibodies known to detect core hnRNP proteins, and by showing that the C130 monoclonal antibody, produced against a cDNA-derived fusion protein, also selectively detects native P2P hnRNP proteins. In addition, P2P-R cDNA-derived fusion proteins bind single-stranded nucleic acids, and a P2P-R cDNA-derived antisense oligonucleotide selectively represses P2P expression. Because terminal differentiation is associated with modulation in Rb1 function, we assayed if products of this cDNA might interact with Rb1. Evidence that the P2P-R cDNA encodes a protein domain that binds Rb1 was established using a glutathione S -transferase fusion protein to selectively precipitate Rb1 from cellular extracts. Data also show that this binding is reduced by competition with the adenovirus E1a protein, indicating that binding occurs through the “pocket” domain of Rb1. These results establish that the P2P-R cDNA encodes protein domains involved in both hnRNP association and Rb1 binding and complement recent reports that localize Rb1 to sites of RNA processing in the nucleus.

In this study we compared Pittsburgh compound-B (PIB) positron emission tomography (PET) amyloid imaging, fluorodeoxyglucose PET for metabolism, and magnetic resonance imaging (MRI) for structure to predict conversion from amnestic mild cognitive impairment (MCI) to Alzheimer's dementia using data from the Alzheimer's Disease Neuroimaging Initiative cohort. Numeric neuroimaging variables generated by the Alzheimer's Disease Neuroimaging Initiative-funded laboratories for each neuroimaging modality along with apolipoprotein-E genotype (n = 29) were analyzed. Performance of these biomarkers for predicting conversion from MCI to Alzheimer's dementia at 2 years was evaluated in 50 late amnestic MCI subjects, 20 of whom converted. Multivariate modeling found that among individual modalities, MRI had the highest predictive accuracy (67%) which increased by 9% to 76% when combined with PIB-PET, producing the highest accuracy among any biomarker combination. Individually, PIB-PET generated the best sensitivity, and fluorodeoxyglucose PET had the lowest. Among individual brain regions, the temporal cortex was found to be most predictive for MRI and PIB-PET.

The Jak kinases and Stat transcription factors play a major role in signaling of various cytokines including IFNα. In this report we show a ligand-independent interaction between Tyk-2 and Jak-1 kinases. We also demonstrate that the Tyk-2 kinase forms a homodimer that has the ability to undergo intermolecular tyrosine phosphorylation. The formation of the Tyk-2 homodimer is independent of both tyrosine phosphorylation and the presence of the tyrosine kinase domain.

The ability to "sex" unknown dried bloodstains is frequently of evidentiary value in forensic casework. Chelex-extracted DNA from 115 specimens (105 dried blood standards and 10 casework samples) was amplified for specific ZFX and ZFY regions of the X and Y chromosomes and subsequent restriction enzyme digestion. The polymerase chain reaction (PCR) yielded a 209 base pair (bp) product containing a polymorphic position with a Y chromosome portion including an additional Hae III restriction site while the X chromosome portion contains only one. The digested PCR product was separated by polyacrylamide gel electrophoresis (PAGE) and detected by silver staining. Female samples exhibit bands of 172 bp and 37 bp only while male samples (XY) exhibit 2 additional bands appearing as an 88/84 bp doublet. Initially the 105 known bloodstains were typed according to the procedure discussed here and correct gender determination was achieved for all samples therefore establishing the reliability of this method. The 10 casework samples yielded the expected results as well. This assay demonstrates potential in both presumptive and confirmatory capacities.

Background In patients with schizophrenia, early non-response to oral antipsychotic therapy robustly predicts subsequent non-response to continued treatment with the same medication. This study assessed whether early response predicted later response when using a long-acting injection (LAI) antipsychotic. Methods Data were taken from an 8-week, randomized, double-blind, placebo-controlled study of olanzapine LAI in acutely ill patients with schizophrenia (n = 233). Early response was defined as ≥30% improvement from baseline to Week 4 in Positive and Negative Syndrome Scale (PANSS0-6) Total score. Subsequent response was defined as ≥40% baseline-to-endpoint improvement in PANSS0-6 Total score. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and predictive accuracy were calculated. Clinical and functional outcomes were compared between Early Responders and Early Non-responders. Results Early response/non-response to olanzapine LAI predicted later response/non-response with high sensitivity (85%), specificity (72%), PPV (78%), NPV (80%), and overall accuracy (79%). Compared to Early Non-responders, Early Responders had significantly greater improvement in PANSS0-6 Total scores at all time points and greater baseline-to-endpoint improvement in PANSS subscale scores, Quality of Life Scale scores, and Short Form-36 Health Survey scores (all p ≤ .01). Among Early Non-responders, 20% demonstrated response by Week 8. Patients who lacked early improvement (at Week 4) in Negative Symptoms and Disorganized Thoughts were more likely to continue being non-responders at Week 8. Conclusions Among acutely ill patients with schizophrenia, early response predicted subsequent response to olanzapine LAI. Early Responders experienced significantly better clinical and functional outcomes than Early Non-responders. Findings are consistent with previous research on oral antipsychotics. Clinical Trials Registry F1D-MC-HGJZ: Comparison of Intramuscular Olanzapine Depot With Placebo in the Treatment of Patients With Schizophrenia http://clinicaltrials.gov/ct2/show/NCT00088478?term=olanzapine+depot&rank=3 Registry identifier - NCT00088478