Federated electronic health records research technology to support clinical trial protocol optimization: Evidence from EHR4CR and the InSite platform.

OBJECTIVE: To determine if inclusion/exclusion (I/E) criteria of clinical trial protocols can be represented as structured queries and executed using a secure federated research platform (InSite) on hospital electronic health records (EHR) systems, to estimate the number of potentially eligible patients. METHODS: Twenty-three clinical trial protocols completed during 2011-2017 across diverse disease areas were analyzed to construct queries that were executed with InSite using EHR records from 24 European hospitals containing records of >14 million patients. The number of patients matching I/E criteria of each protocol was estimated. RESULTS: All protocols could be formalized to some extent into a medical coding system (e.g. ICD-10CM, ATC, LOINC, SNOMED) and mapped to local hospital coding systems. The median number of I/E criteria of protocols tested was 29 (range: 14-47). A median of 55% (range 38-89%) of I/E criteria in each protocol could be transformed into a computable format. The median number of eligible patients identified was 26 per hospital site (range: 1-134). CONCLUSION: Clinical trial I/E eligibility criteria can be structured computationally and executed as queries on EHR systems to estimate the patient recruitment pool at each site. The results further suggest that an increase in structured coded information in EHRs would increase the number of I/E criteria that could be evaluated. Additional work is needed on broader deployment of federated platforms such as InSite.

Mepazine Inhibits RANK-Induced Osteoclastogenesis Independent of Its MALT1 Inhibitory Function.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular cysteine protease (paracaspase) that plays an integral role in innate and adaptive immunity. The phenothiazine mepazine has been shown to inhibit the proteolytic activity of MALT1 and is frequently used to study its biological role. MALT1 has recently been suggested as a therapeutic target in rheumatoid arthritis. Here, we analyzed the effect of mepazine on the receptor activator of nuclear factor κ-B (RANK)-induced osteoclastogenesis. The treatment of mouse bone marrow precursor cells with mepazine strongly inhibited the RANK ligand (RANKL)-induced formation of osteoclasts, as well as the expression of several osteoclast markers, such as TRAP, cathepsin K, and calcitonin. However, RANKL induced osteoclastogenesis equally well in bone marrow cells derived from wild-type and Malt1 knock-out mice. Furthermore, the protective effect of mepazine was not affected by MALT1 deficiency. Additionally, the absence of MALT1 did not affect RANK-induced nuclear factor κB (NF-κB) and activator protein 1 (AP-1) activation. Overall, these studies demonstrate that MALT1 is not essential for RANK-induced osteoclastogenesis, and implicate a MALT1-independent mechanism of action of mepazine that should be taken into account in future studies using this compound.

A20 inhibits LUBAC-mediated NF-κB activation by binding linear polyubiquitin chains via its zinc finger 7.

Linear polyubiquitination of proteins has recently been implicated in NF-κB signalling and is mediated by the linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP and Sharpin. However, the mechanisms that regulate linear ubiquitination are still unknown. Here, we show that A20 is rapidly recruited to NEMO and LUBAC upon TNF stimulation and that A20 inhibits LUBAC-induced NF-κB activation via its C-terminal zinc-finger 7 (ZF7) domain. Expression of a polypeptide corresponding to only ZF7 was sufficient to inhibit TNF-induced NF-κB activation. Both A20 and ZF7 can form a complex with NEMO and LUBAC, and are able to prevent the TNF-induced binding of NEMO to LUBAC. Finally, we show that ZF7 preferentially binds linear polyubiquitin chains in vitro, indicating A20-ZF7 as a novel linear ubiquitin-binding domain (LUBID). We thus propose a model in which A20 inhibits TNF- and LUBAC-induced NF-κB signalling by binding to linear polyubiquitin chains via its seventh zinc finger, which prevents the TNF-induced interaction between LUBAC and NEMO.

Adenomyosis in Pregnancy-Should It Be Managed in High-Risk Obstetric Units?

BACKGROUND: Uterine adenomyosis is an increasingly frequent disorder. Our study aimed to demonstrate the presence of obstetric complications in the population affected by this condition to demonstrate the need for follow-up in high-risk obstetric units. MATERIAL AND METHODS: The data for the study were obtained from TriNetX, LLC, between 2010 and 2020. The outcomes analyzed were intrauterine growth restriction (IUGR), preterm delivery, cesarean delivery, hypertension, abruption placentae, and spontaneous abortion. Seven thousand six hundred and eight patients were included in the cohort of pregnant patients with adenomyosis, and 566,153 women in the cohort of pregnant patients without any history of endometriosis. RESULTS: Upon calculating the total risk of presenting any of these problems during pregnancy, we obtained an OR = 1.521, implying that a pregnancy with adenomyosis was 52.1% more likely to present some complication. We found: IUGR OR = 1.257 (95% CI: 1.064-1.485) (p = 0.007); preterm delivery OR = 1.422 (95% CI: 1.264-1.600) (p = 0.0001); cesarean delivery OR = 1.099 (95% CI: 1.002-1.205) (p = 0.046); hypertensive disorders OR = 1.177 (95% CI: 1.076-1.288) (p = 0.0001); abruption placentae OR = 1.197 (95% CI: 1.008-1.422) (p = 0.040), and spontaneous abortion OR = 1.529 (95% CI: 1.360-1.718) (p = 0.0001). CONCLUSION: We conclude that the review carried out and the data we obtained on increased risk provide sufficient evidence to recommend that patients with adenomyosis should be managed in obstetric high-risk units.

Building an i2b2-Based Population Repository for COVID-19 Research.

Reuse of Electronic Health Records (EHRs) for specific diseases such as COVID-19 requires data to be recorded and persisted according to international standards. Since the beginning of the COVID-19 pandemic, Hospital Universitario 12 de Octubre (H12O) evolved its EHRs: it identified, modeled and standardized the concepts related to this new disease in an agile, flexible and staged way. Thus, data from more than 200,000 COVID-19 cases were extracted, transformed, and loaded into an i2b2 repository. This effort allowed H12O to share data with worldwide networks such as the TriNetX platform and the 4CE Consortium.

PI3K/mTOR mediate mitogen-dependent HDAC1 phosphorylation in breast cancer: a novel regulation of estrogen receptor expression.

Histone deacetylase 1 (HDAC1) is an important epigenetic controller involved in transcriptional regulation through modification of chromatin structure. Genetic and epigenetic changes and deregulation of signal transduction pathways have been implicated in the development of breast cancer. Downregulation of estrogen receptor α (ERα) expression is one of the mechanisms behind the acquisition of endocrine resistance. Sustained and increased hormone and growth factor receptor signaling in breast cancer cells contribute to resistance to endocrine therapy. Both HDACs and the PI3K/mTOR signaling pathway are becoming promising targets in breast cancer, reversing also acquired hormone resistance. Here we show how mitogens, activating the PI3K/mTOR pathway, trigger the phosphorylation of HDAC1 in breast cancer cells, which is completely dependent on the activity of the p70 S6 kinase (S6K1). Our findings show that S6K1, overexpressed in many breast cancers, controls HDAC1-dependent transcriptional regulation of ERα levels upon mitogenic stimuli, controlling HDAC1 recruitment to the ERα promoter. Furthermore, cell treatment with both mTOR and HDACs inhibitors shows an additive effect in inhibiting breast cancer proliferation. This confirms the novel cross-talk between the HDAC1 and PI3K pathways with clinical implications towards the treatment of this malignant disease.