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HOX genes are highly expressed in many acute myeloid leukemia (AML) samples, but the patterns of expression and associated regulatory mechanisms are not clearly understood. We analyzed RNA sequencing data from 179 primary AML samples and normal hematopoietic cells to understand the range of expression patterns in normal versus leukemic cells. HOX expression in AML was restricted to specific genes in the HOXA or HOXB loci, and was highly correlated with recurrent cytogenetic abnormalities. However, the majority of samples expressed a canonical set of HOXA and HOXB genes that was nearly identical to the expression signature of normal hematopoietic stem/progenitor cells. Transcriptional profiles at the HOX loci were similar between normal cells and AML samples, and involved bidirectional transcription at the center of each gene cluster. Epigenetic analysis of a subset of AML samples also identified common regions of chromatin accessibility in AML samples and normal CD34 + cells that displayed differences in methylation depending on HOX expression patterns. These data provide an integrated epigenetic view of the HOX gene loci in primary AML samples, and suggest that HOX expression in most AML samples represents a normal stem cell program that is controlled by epigenetic mechanisms at specific regulatory elements.

Acute promyelocytic leukemia (APL) is initiated by the PML-RARA ( PR ) fusion oncogene and has a characteristic expression profile that includes high levels of the Notch ligand Jagged-1 ( JAG1 ). In this study, we used a series of bioinformatic, in vitro , and in vivo assays to assess the role of Notch signaling in human APL samples, and in a PML-RARA knock-in mouse model of APL (Ctsg-PML-RARA) . We identified a Notch expression signature in both human primary APL cells and in Kit+Lin−Sca1+ cells from pre-leukemic Ctsg-PML-RARA mice. Both genetic and pharmacologic inhibition of Notch signaling abrogated the enhanced self-renewal seen in hematopoietic stem/progenitor cells from pre-leukemic Ctsg-PML-RARA mice, but had no influence on cells from age-matched wild-type mice. In addition, six of nine murine APL tumors tested displayed diminished growth in vitro when Notch signaling was inhibited pharmacologically. Finally, we found that genetic inhibition of Notch signaling with a dominant-negative Mastermind-like protein reduced APL growth in vivo in a subset of tumors. These findings expand the role of Notch signaling in hematopoietic diseases, and further define the mechanistic events important for PML-RARA -mediated leukemogenesis.

Rheumatoid arthritis (RA) is a systemic, chronic, immune-mediated inflammatory condition. Treatments options encompass conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biologic disease-modifying antirheumatic drugs (bDMARDs) like tumor necrosis factor (TNF) inhibitors (TNFis) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) including Janus Kinase inhibitors (JAKinibs). Orally administered JAKinibs have demonstrated comparable or, in specific cases, superior efficacy compared to bDMARDs in inflammatory conditions. However, the escalating clinical utilization has been accompanied by the emergence of serious adverse effects, including major adverse cardiac events (MACE), malignancies and venous thrombotic episodes (VTE), leading to regulatory restrictions imposed by health authorities in both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

BackgroundRheumatoid arthritis (RA) and other rheumatic conditions can lead to work disability, and temporary or permanent exit from the labour market. The indirect costs related to work disability, are higher than direct treatment costs, and pose an economic burden on patients and society. Workability in RA is influenced by many factors, including symptoms, such as pain, swelling and stiffness, muscle strength, or physical or mental exhaustion, which are components of the frailty syndrome.ObjectivesThis study aimed to determine the association of workability with disease activity, pain, functional disability and frailty in patients with seropositive rheumatoid arthritis.MethodsWe conducted a monocentric cross-sectional study at a rheumatologic outpatient clinic and day hospital including 100 seropositive RA patients (according to 2010 EULAR classification) in the working age (<65 years). Workability was assessed with the self-administered Work Ability Index questionnaire. For disease activity, we used the Clinical Disease Activity Index (CDAI), a Visual analogue scale for pain assessment, for functional disability the self-administered Health Assessment Questionnaire Disability Index (HAQ-DI) and for the degree of frailty the SHARE Frailty Instrument (SHARE-FI). After testing for normal distribution, bivariate correlations between workability and associated variables were calculated using Spearman's correlation coefficients.ResultsOf 100 patients for 58 the workability index could be assessed. The remaining 42 were either unemployed, on disability pension, or employed but currently not working. These 58 patients, 37 women and 21 men, had an average age of 64.8 years (min-max=22–59, SD=9.3) and an average disease duration of 93.9 months (min-max=3–360, SD=86.7). 8 patients reported excellent workability, 27 good workability, 16 moderate workability and 7 poor workability. The workability was weakly correlated with age (r s= -0.37, p<0.004), and moderately correlated with pain intensity (r s=0.42, p<0.001), disease activity (r s=0.40, p<0.002), functional disability (r s=0.64, p<0.000) and frailty (r s=0.623, p<0.000).ConclusionsA considerable portion of employed RA patients reported poor or moderate workability, which is significantly associated with disease activity but also with the other parameters assessed. An adequate therapy may therefore not only improve well-being and state of health in RA patients but also provide socioeconomically advantage by maintaining patients' workability.Disclosure of InterestNone declared

Company observational post-marketing studies (COPS) claim to provide essential data about drug risks and effectiveness in special populations not admitted to pre-approval clinical trials. Since COPS are often mainly regarded as a marketing activity, this study-based analysis tries to evaluate the scientific contributions of COPS. Thirty-five COPS were identified by hand-searching through medical journals, writing to pharmaceutical manufacturers and using MEDLINE. Fourteen COPS evaluated cardiovascular drugs, 9 evaluated NSAIDs and 12 evaluated various other indications. Thirty-five COPS listed effectiveness, 31 listed safety and 8 listed patient compliance as principal objectives. Not a single COPS included a control group. Seventeen of 21 evaluable COPS mentioned extensive exclusion criteria similar to those in clinical trials. Median observation time was 8 weeks, too short for chronic diseases and for adverse drug reactions with longer latency periods. One new adverse event was regarded. Global assessments of the outcomes by physicians dominated and were not based on objective clinical findings. None of the studies specified any details concerning the standardisation of observations or quality-control procedures. The current COPS scheme does not contribute significantly to our knowledge of drug safety and the effects in special populations. Despite serious criticism over the past 20 years, the poor quality of COPS compared with dramatic improvements of pre-approval trials - implies a need for detailed guidelines for non-experimental phase IV research, similar to the Good Clinical Practice-Guideline of the European Community.

We demonstrate a 4-channel O-band transmitter comprising a Silicon Photonics RM array co-packaged with a SiGe BiCMOS integrated driver chip. 4×40 Gb/s data modulation with an average ER of 3.39 dB is reported, with the transmitter module exhibiting a high energy efficiency of 2.52 pJ/bit.