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Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a metaanalysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P= 2.1 x 10(-12) and LGR6, P = 1.4 x 10(-8)), 2p24.1 (P = 4.6 x 10(-8)) and 16q12.2 (FTO, P = 4.0 x 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P> 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

Abstract Background Although oral opioid agonist therapies (OATs), buprenorphine and methadone, are effective first-line treatments, OAT remains largely underutilized due to low retention rates and wide variation across programs. This rapid review therefore sought to summarize the retention rates reported by randomized controlled trials (RCTs) and controlled observational study designs that compared methadone to buprenorphine (or buprenorphine-naloxone). Methods We searched four electronic databases (EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, CINAHL, up to April 2018) for RCTs and controlled observational studies that compared oral fixed-dose methadone to buprenorphine versus methadone (or buprenorphine-naloxone). Data were extracted separately for two different definitions of retention in treatment: (1) length of time retained in the study and (2) presence on the final day of a study. Separate random effects meta-analyses were performed for RCTs and controlled observational studies. Data from controlled observational studies where retention was measured as the length of time retained in the study were not amenable to meta-analysis. Results Among 7603 studies reviewed, 10 RCTs and 3 observational studies met inclusion criteria (n = 5065) and compared fixed-dose oral buprenorphine with methadone. Across studies, the average retention rate was highly variable (RCTs: buprenorphine 20.0–82.5% and methadone 30.7–83.8%; observational studies: buprenorphine 20.2–78.3% and methadone 48.3–74.8%). For time period retained in the study, we observed no significant difference in treatment retention for buprenorphine versus methadone in RCTs (standardized mean difference [SMD] = − 0.07; 95% CI − 0.35–0.21, p = 0.63; quality of evidence: low). For presence on the final study day, we observed no significant difference between buprenorphine and methadone treatment retention in RCTs (risk ratio [RR] = 0.89; 95% CI 0.73–1.08, p = 0.24; quality of evidence: low) and controlled observational studies (RR = 0.75; 95% CI 0.36–1.58, p = 0.45). Conclusion Meta-analysis of existing RCTs suggests retention in oral fixed-dose opioid agonist therapy with methadone appears to be generally equal to buprenorphine (or buprenorphine-naloxone), with wide variation across studies. Similarly, a meta-analysis of three controlled observational studies indicated no difference in treatment retention although there was significant heterogeneity among the included studies. The length of follow-up did not appear to affect the retention rate. Systematic review registration PROSPERO CRD42018104452.

Funding: Royal Society - UF150663, RGF\EA\180141; Wellcome Trust - 217065/Z/19/Z; H2020 European Research Council - 694189; NWO - 451-15-017; National Health and Medical Research Council - 1173896; Canadian Institute for Health Research - MOP-133440. Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6–19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06–1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions. Publisher PDF Peer reviewed

SummaryWe have investigated the role of individual members of the Raf/Mek/Erk cascade in the onset of K-Ras oncogene-driven non-small cell lung carcinoma (NSCLC). Ablation of Erk1 or Erk2 in K-Ras oncogene-expressing lung cells had no significant effect due to compensatory activities. Yet, elimination of both Erk kinases completely blocked tumor development. Similar results were obtained with Mek kinases. Ablation of B-Raf had no significant effect on tumor development. However, c-Raf expression was absolutely essential for the onset of NSCLC. Interestingly, concomitant elimination of c-Raf and B-Raf in adult mice had no deleterious consequences for normal homeostasis. These results indicate that c-Raf plays a unique role in mediating K-Ras signaling and makes it a suitable target for therapeutic intervention.

The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to N-ɛ-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates. Targeted modifications to CP2 based on crystallographic and mass spectrometry analyses results in variants with greater proteolytic robustness. Peptide dosing in cells manifests KDM4A target stabilization. Although further development is required to optimize cellular activity, the results reveal the feasibility of highly selective non-metal chelating, substrate-competitive inhibitors of the JmjC KDMs. JmjC histone demethylases (KDMs) are cancer targets due to their links to cell proliferation, but selective inhibition remains a challenge. Here the authors identify potent inhibitors of KDM4A-C—via in vitro selection from a vast library of cyclic peptides—that show selectivity over other KDMs.

Due to scientific and technological advancements, investigations in modern medicine are producing more measurement data than ever before. Since a large amount of information exists, and it is also being produced at ever-increasing rates, no single person can digest all current knowledge of diseases. Data collected from large patient cohorts may contain valuable knowledge of diseases, which could be useful to clinicians when making diagnoses or choosing treatments. Making use of the large volumes of data in clinical decision-making requires ancillary help from information technologies, but such systems have not yet become widely available. This thesis addresses the challenge by proposing a computer-based decision support method that is suited to clinical use. This thesis presents the Disease State Index (DSI), a supervised machine learning method intended for the analysis of patient data. The DSI comprehensively compares patient data with previously diagnosed cases with or without a disease. Based on this comparison, the method provides an estimate of the state of disease progression in the patient. Interpreting the DSI is made possible by its visual counterpart, the Disease State Fingerprint (DSF), which allows domain experts to gain a comprehensive view of patient data and the state of the disease at a quick glance. In the design and development of these methods, both performance and applicability in clinical use were taken into account equally. Alzheimer's disease (AD) is a slowly progressing neurodegenerative disease and one of the largest social and economic burdens in the world today, and it will continue to be so in the future. Studies with large patient cohorts have significantly improved our knowledge of AD during the last decade. This information should be made extensively available at memory clinics to maximize the benefits for diagnostics and treatment of the disease. The DSI and DSF methods proposed in this thesis were studied in the early diagnosis of AD and as a measure of disease progression in six original publications. The methods themselves and their implementation within a clinical decision support system, the PredictAD tool, were quantitatively evaluated with regard to their performance and potential benefits in clinical use. The results show that the methods and clinical decision support tool based on these methods can be used to follow disease progression objectively and provide earlier diagnoses of AD. These, in turn, could improve treatment efficacy due to earlier interventions and make drug trials more efficient by allowing better patient selection.

A desirable but as yet unachieved property of a human immunodeficiency virus type 1 (HIV-1) vaccine candidate is the ability to induce broadly neutralizing antibodies (bNAbs). One approach to the problem is to create trimeric mimics of the native envelope glycoprotein (Env) spike that expose as many bNAb epitopes as possible, while occluding those for non-neutralizing antibodies (non-NAbs). Here, we describe the design and properties of soluble, cleaved SOSIP.664 gp140 trimers based on the subtype A transmitted/founder strain, BG505. These trimers are highly stable, more so even than the corresponding gp120 monomer, as judged by differential scanning calorimetry. They are also homogenous and closely resemble native virus spikes when visualized by negative stain electron microscopy (EM). We used several techniques, including ELISA and surface plasmon resonance (SPR), to determine the relationship between the ability of monoclonal antibodies (MAbs) to bind the soluble trimers and neutralize the corresponding virus. In general, the concordance was excellent, in that virtually all bNAbs against multiple neutralizing epitopes on HIV-1 Env were highly reactive with the BG505 SOSIP.664 gp140 trimers, including quaternary epitopes (CH01, PG9, PG16 and PGT145). Conversely, non-NAbs to the CD4-binding site, CD4-induced epitopes or gp41ECTO did not react with the trimers, even when their epitopes were present on simpler forms of Env (e.g. gp120 monomers or dissociated gp41 subunits). Three non-neutralizing MAbs to V3 epitopes did, however, react strongly with the trimers but only by ELISA, and not at all by SPR and to only a limited extent by EM. These new soluble trimers are useful for structural studies and are being assessed for their performance as immunogens. Author Summary A protective HIV-1 vaccine is badly needed, but no candidate has yet provided an adequate level of protection against infection. Most existing vaccines provide immune protection by inducing neutralizing antibodies, also a goal of many HIV-1 immunogen design projects. The trimeric envelope protein complex on the HIV-1 surface is the only relevant target for neutralizing antibodies, and is the basis for most strategies aimed at their induction. However, making a soluble, recombinant envelope protein complex that adequately mimics the structure present on the virus has been challenging. Here, we describe a newly designed and engineered Env protein that has the appropriate properties. This protein, termed BG505 SOSIP.664 gp140, binds most of the known neutralizing antibodies but generally does not bind antibodies that lack neutralization activity. Its appearance in negative stain electron micrographs also resembles native envelope complexes.