Quantifying the treatment goals of people recently diagnosed with schizophrenia using best-worst scaling.

OBJECTIVE: This study seeks to quantify the treatment goals of people recently diagnosed with schizophrenia and explore their impact on treatment plan. METHODS: People aged 18-35 years with a confirmed diagnosis of schizophrenia within the past 5 years were surveyed in the UK, Germany, and Italy. Treatment goals were assessed via a validated best-worst scaling instrument, where participants evaluated subsets of 13 possible treatment goals identified using a balanced incomplete block design. Participants identified the most and least important goals within each task. Data were also collected on current treatment and preference for daily oral versus long-acting injectable (LAI) treatment. Hierarchical Bayes was used to identify preference weights for the goals, and latent class analysis was used to identify segments of people with similar goals. The segments were compared with the current treatment and preference for oral versus LAI treatment. RESULTS: Across 100 participants, the average age was 26 years, 75% were male and 50% were diagnosed within 2 years ago. Overall, preferences were most favorable for reduced disease symptoms, think clearly, reduced hospitalizations, reduced anxiety, and take care of self. A total of 61% preferred oral medication and 39% LAI. Two groups were identified with different treatment goals; 50% of participants emphasized clinical goals, including reduced disease symptoms (preference weight =19.7%), reduced hospitalizations (15.5%), and reduced anxiety (10.5%). The other 50% emphasized functional goals, including improved relationships with family/friends (11.4%), increased interest in work (10.6%), experiencing a fuller range of emotions (8.4%), and ability to socialize (7.5%). Those emphasizing functional goals were more likely to be on LAI (44% versus 26%; p=0.059) and preferred LAI (46% versus 32%; p=0.151). CONCLUSIONS: People with recent-onset schizophrenia may focus more on clinical goals or functional goals, a discussion of which may help facilitate patient engagement.

Development of a stated-preference instrument to prioritize treatment goals in recent onset schizophrenia.

OBJECTIVE: This study sought to evaluate a new stated-preference instrument to prioritize multiple treatment goals among people with recent onset schizophrenia. METHODS: A draft survey instrument was developed to assess preferences for 13 key treatment goals that were identified based on the literature. The survey incorporates best-worst scaling (BWS), which shows repeated subsets comprising 4 of the 13 goals, and respondents identify which is most important and which is least important to them. Pre-test interviews were conducted in the UK, Italy, and Germany among people aged 18 to 35 diagnosed with schizophrenia within the past 5 years. Specifically, participants completed the instrument online in their native language, followed by a telephone interview to provide feedback on the clarity, relevance, and comprehensiveness of the survey. The interview data were analyzed to assess interpretation and content validity of the survey. RESULTS: Fifteen participants (five per country) provided feedback (mean age = 31; 60% male). Feedback was comparable across countries and confirmed that the key treatment goals assessed were relevant and meaningful. Probing by interviewers ascertained that respondents interpreted the questions appropriately and identified the treatment goals that were most and least important to them. Based on the characterization of the goals, a conceptual model was developed illustrating hypothesized associations among them. CONCLUSION: The results confirm that the BWS methodology and key treatment goals in this new instrument are appropriate for use in recent onset schizophrenia. These results will help guide measurement of patient-relevant endpoints in future studies.

Estrogen withdrawal, increased breast cancer risk and the KRAS-variant.

The KRAS-variant is a biologically functional, microRNA binding site variant, which predicts increased cancer risk especially for women. Because external exposures, such as chemotherapy, differentially impact the effect of this mutation, we evaluated the association of estrogen exposures, breast cancer (BC) risk and tumor biology in women with the KRAS-variant. Women with BC (n = 1712), the subset with the KRAS-variant (n = 286) and KRAS-variant unaffected controls (n = 80) were evaluated, and hormonal exposures, KRAS-variant status, and pathology were compared. The impact of estrogen withdrawal on transformation of isogenic normal breast cell lines with or without the KRAS-variant was studied. Finally, the association and presentation characteristics of the KRAS-variant and multiple primary breast cancer (MPBC) were evaluated. KRAS-variant BC patients were more likely to have ovarian removal pre-BC diagnosis than non-variant BC patients (p = 0.033). In addition, KRAS-variant BC patients also appeared to have a lower estrogen state than KRAS-variant unaffected controls, with a lower BMI (P < 0.001). Finally, hormone replacement therapy (HRT) discontinuation in KRAS-variant patients was associated with a diagnosis of triple negative BC (P < 0.001). Biologically confirming our clinical findings, acute estrogen withdrawal led to oncogenic transformation in KRAS-variant positive isogenic cell lines. Finally, KRAS-variant BC patients had greater than an 11-fold increased risk of presenting with MPBC compared to non-variant patients (45.39% vs 6.78%, OR 11.44 [3.42-37.87], P < 0.001). Thus, estrogen withdrawal and a low estrogen state appear to increase BC risk and to predict aggressive tumor biology in women with the KRAS-variant, who are also significantly more likely to present with multiple primary breast cancer.

5' isomiR variation is of functional and evolutionary importance.

We have sequenced miRNA libraries from human embryonic, neural and foetal mesenchymal stem cells. We report that the majority of miRNA genes encode mature isomers that vary in size by one or more bases at the 3' and/or 5' end of the miRNA. Northern blotting for individual miRNAs showed that the proportions of isomiRs expressed by a single miRNA gene often differ between cell and tissue types. IsomiRs were readily co-immunoprecipitated with Argonaute proteins in vivo and were active in luciferase assays, indicating that they are functional. Bioinformatics analysis predicts substantial differences in targeting between miRNAs with minor 5' differences and in support of this we report that a 5' isomiR-9-1 gained the ability to inhibit the expression of DNMT3B and NCAM2 but lost the ability to inhibit CDH1 in vitro. This result was confirmed by the use of isomiR-specific sponges. Our analysis of the miRGator database indicates that a small percentage of human miRNA genes express isomiRs as the dominant transcript in certain cell types and analysis of miRBase shows that 5' isomiRs have replaced canonical miRNAs many times during evolution. This strongly indicates that isomiRs are of functional importance and have contributed to the evolution of miRNA genes.

A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis.

Endometriosis is found in 5-15% of women of reproductive age and is more frequent in relatives of women with the disease. Activation of KRAS results in de novo endometriosis in mice, however, activating KRAS mutations have not been identified in women. We screened 150 women with endometriosis for a polymorphism in a let-7 microRNA (miRNA) binding site in the 3'-UTR of KRAS and detected a KRAS variant allele in 31% of women with endometriosis as opposed to 5% of a large diverse control population. KRAS mRNA and protein expression were increased in cultured endometrial stromal cells of women with the KRAS variant. Increased KRAS protein was due to altered miRNA binding as demonstrated in reporter assays. Endometrial stromal cells from women with the KRAS variant showed increased proliferation and invasion. In a murine model, endometrial xenografts containing the KRAS variant demonstrated increased proliferation and decreased progesterone receptor levels. These findings suggest that an inherited polymorphism of a let-7 miRNA binding site in KRAS leads to abnormal endometrial growth and endometriosis. The LCS6 polymorphism is the first described genetic marker of endometriosis risk.

MicroRNA signatures differentiate melanoma subtypes.

Melanoma is an aggressive cancer that is highly resistance to therapies once metastasized. We studied microRNA (miRNA) expression in clinical melanoma subtypes and evaluated different miRNA signatures in the background of gain of function somatic and inherited mutations associated with melanoma. Total RNA from 42 patient derived primary melanoma cell lines and three independent normal primary melanocyte cell cultures was evaluated by miRNA array. MiRNA expression was then analyzed comparing subtypes and additional clinicopathologic criteria including somatic mutations. The prevalence and association of an inherited variant in a miRNA binding site in the 3'UTR of the KRAS oncogene, referred to as the KRAS-variant, was also evaluated. We show that seven miRNAs, miR-142-3p, miR-486, miR-214, miR-218, miR-362, miR-650 and miR-31, were significantly correlated with acral as compared to non-acral melanomas (p < 0.04). In addition, we discovered that the KRAS-variant was enriched in non-acral melanoma (25%), and that miR-137 under expression was significantly associated with melanomas with the KRAS-variant. Our findings indicate that miRNAs are differentially expressed in melanoma subtypes and that their misregulation can be impacted by inherited gene variants, supporting the hypothesis that miRNA misregulation reflects biological differences in melanoma.

Cryptic splice sites and split genes.

We describe a new program called cryptic splice finder (CSF) that can reliably identify cryptic splice sites (css), so providing a useful tool to help investigate splicing mutations in genetic disease. We report that many css are not entirely dormant and are often already active at low levels in normal genes prior to their enhancement in genetic disease. We also report a fascinating correlation between the positions of css and introns, whereby css within the exons of one species frequently match the exact position of introns in equivalent genes from another species. These results strongly indicate that many introns were inserted into css during evolution and they also imply that the splicing information that lies outside some introns can be independently recognized by the splicing machinery and was in place prior to intron insertion. This indicates that non-intronic splicing information had a key role in shaping the split structure of eukaryote genes.

Cancer microRNAs: from subtype profiling to predictors of response to therapy.

MicroRNAs (miRNAs) are key regulators of gene expression that regulate important oncogenes and tumor suppressors. Many miRNAs can also act as oncogenes or tumor suppressors, and thus the altered expression of miRNAs is a hallmark of many cancer types. Dysregulated miRNAs provide a potentially powerful new tool that could be used to enable the characterization of tumor environments and identify novel and important oncogenic pathways. More recently, there has been growing interest in the field of miRNAs as biomarkers of cancer risk, diagnosis and response to therapy. Understanding the associations between miRNA expression and cancer phenotypes, and the potential of miRNA profiling in clinical applications, promises to be highly rewarding in the field of cancer research.

Alpha7 nicotinic acetylcholine receptor expression in Alzheimer's disease: receptor densities in brain regions of the APP(SWE) mouse model and in human peripheral blood lymphocytes.

The brains of people with Alzheimer's disease (AD) display several characteristic pathological features, including deposits (plaques) of beta-amyloid 1-42 (Abeta1-42), intraneuronal accumulations (tangles) of hyperphosphorylated tau, degeneration of the basal forebrain cholinergic pathway, and gliosis. Abeta1-42 plaques develop in specific brain regions, including hippocampus and cortex, as well as in the vasculature. Abeta1-42 might promote neurodegeneration through the induction of free radicals and disruption of Ca2+ homeostasis, giving rise to the symptoms of AD. Abeta1-42 interacts with the alpha7 subtype of the nicotinic acetylcholine receptor (alpha7 nAChR), which is widely expressed throughout the central and peripheral nervous systems, as well as in several nonneuronal loci, such as epithelial cells, lymphoid tissues, and peripheral blood lymphocytes. Western blot and autoradiographic analyses indicate that the alpha7 nAChR subunit protein is up-regulated in human brain samples from Alzheimer patients, as well as in animal models of AD (Dineley et al., 2001; Bednar et al., 2002), and might be involved in nicotine-mediated reduction of Abeta1-42 deposition (Hellstrom et al., 2004), although the nature of this relationship remains ill-defined. We have undertaken a semiquantitative histological evaluation of alpha7 nAChR expression in a mouse model of AD pathology, as well as a comparison of alpha7 nAChR levels in lymphocytes from AD patients and control subjects.