Synergistic drug combinations from electronic health records and gene expression.

ObjectiveUsing electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding.MethodWe applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis.ResultsFrom EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence.ConclusionsThis is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing

A novel synonymous KMT2B variant in a patient with dystonia causes aberrant splicing

BACKGROUND: Heterozygous KMT2B variants are a common cause of dystonia. A novel synonymous KMT2B variant, c.5073C>T (p.Gly1691=) was identified in an individual with childhood-onset progressive dystonia. METHODS: The splicing impact of c.5073C>T was assessed using an in vitro exon-trapping assay. The genomic region of KMT2B exons 23-26 was cloned into the pSpliceExpress plasmid between exon 2 and 3 of the rat Ins2 gene. The c.5073C>T variant was then introduced through site-directed mutagenesis. The KMT2B wild-type and c.5073C>T plasmids were transfected separately into HeLa cells and RNA was extracted 48 hours after transfection. The RNA was reverse transcribed to produce cDNA, which was PCR amplified using primers annealing to the flanking rat Ins2 sequences. RESULTS: Sanger sequencing of the PCR products revealed that c.5073C>T caused a novel splice donor site and therefore a 5-bp deletion of KMT2B exon 23 in mature mRNA, leading to a coding frameshift and premature stop codon (p.Lys1692AsnfsTer7). CONCLUSION: To our knowledge, this is the first report of a KMT2B synonymous variant associated with dystonia. Reassessment of synonymous variants may increase diagnostic yield for inherited disorders including monogenic dystonia. This is of clinical importance, given the generally favourable response to deep brain stimulation for KMT2B-related dystonia

Epidural Corticosteroids, Lumbar Spinal Drainage, and Selective Hemodynamic Control for the Prevention of Spinal Cord Ischemia in Thoracoabdominal Endovascular Aortic Repair: A New Clinical Protocol

In patients undergoing thoracoabdominal aorta repair, spinal cord ischemia (SCI) remains one of the most common and important complications resulting in transient paraparesis through to permanent flaccid paraplegia. In this manuscript, after a brief introduction to spinal cord ischemia complication and its prevention in thoracoabdominal endovascular aortic repair (TEVAR), we propose a new clinical protocol potentially able to prevent such complication. The proposed protocol suggests the use of high dosages of corticosteroids by epidural route, along with drainage of cerebrospinal fluid and controlled vascular hypertension, to reduce the incidence of SCI in TEVAR. Moreover, we paid particular attention to the control of the hemodynamic parameters to obtain adequate peripheral tissue perfusion (oxygen delivery), including in the spinal cord. We applied this new protocol in 50 consecutive patients treated with TEVAR for thoracoabdominal aortic aneurysms (TAAs); 47 patients completed the procedure: 27 patients Crawford type I and 20 Crawford type II. Three patients died during surgery because of untreatable aneurysm rupture. The results show that in all patients there were no cases of SCI, after 5 days from TEVAR. To the best of our knowledge, there are no clinical studies on the use of epidural corticosteroids in patients undergoing treatment of aortic syndrome (both in "open surgery" and endovascular aortic repair). This initial study on 50 consecutive patients has shown that the clinical protocol used could be of great interest to prevent one of the worse complications of TEVAR. Its limitations are the low number of patients studied till now, and the non-randomized protocol adopted. Further studies would be necessary. Our experience and the results obtained with this new perioperative protocol with epidural corticosteroid and accurate hemodynamic control have been encouraging and it seems a valid proposal to be explored in future by well-structured prospective, randomized protocols

Primary right atrium angiosarcoma mimicking pericarditis

<p>Abstract</p> <p>Background</p> <p>Primary cardiac neoplasms occur rarely and most of them are benign. Malignant tumors including angiosarcoma are extremely rare and have a non specific clinical presentation and a poor prognosis.</p> <p>Case presentation</p> <p>We present a case of a young male who was transferred to our hospital because of shock and multiple organ failure after a complicated pericardial biopsy. During the previous seven months he presented with recurrent episodes of pericardial effusions and tamponade. Chest computed tomography revealed a mass in the right atrium, infiltrating the myocardium and pericardium. During emergency surgery that followed, the patient died because of uncontrolled hemorrhage. Autopsy revealed the mass of the right atrium, which was identified on histological examination as primary cardiac angiosarcoma.</p> <p>Conclusion</p> <p>This case highlights the difficulties both in early diagnosis and in the management of patients with cardiac angiosarcoma.</p

Psychiatric disorders, myoclonus dystonia and SGCE:An international study

OBJECTIVE: Myoclonus-dystonia (M-D) is a hyperkinetic movement disorder, typically alcohol-responsive upper body myoclonus and dystonia. The majority of autosomal dominant familial cases are caused by epsilon-sarcoglycan gene (SGCE) mutations. Previous publications have observed increased rates of psychiatric disorders amongst SGCE mutation-positive populations. We analyzed the psychiatric data from four international centers, forming the largest cohort to date, to further determine the extent and type of psychiatric disorders in M-D.METHODS: Psychiatric data from SGCE mutation-positive M-D cohorts, collected by movement disorder specialists in the Netherlands, United Kingdom, United States, and Germany, were analyzed. These data were collected using standardized, systematic questionnaires allowing classification of symptoms according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria. Based on motor findings and SGCE mutation analysis, participants were classified into one of three groups: manifesting carriers, nonmanifesting carriers and noncarriers.RESULTS: Data from 307 participants were evaluated (140 males, 167 females, mean age at examination: 42.5 years). Two-thirds of motor affected mutation carriers (n = 132) had ≥1 psychiatric diagnosis, specific, and social phobias being most common followed by alcohol dependence and obsessive-compulsive disorder (OCD). Compared to familial controls, affected mutation carriers had significantly elevated overall rates of psychiatric disorders (P &lt; 0.001). The most significant differences were observed with alcohol dependence (P &lt; 0.001), OCD (P &lt; 0.001), social and specific phobias (P &lt; 0.001).INTERPRETATION: M-D due to SGCE mutations is associated with specific psychiatric disorders, most commonly OCD, anxiety-related disorders, and alcohol dependence. These suggest either a potential pleiotropic function for SGCE within the central nervous system or a secondary effect of the motor disorder.</p

Kat-ARC accelerated 4D flow CMR: clinical validation for transvalvular flow and peak velocity assessment

Background: To validate the k-adaptive-t autocalibrating reconstruction for Cartesian sampling (kat-ARC), an exclusive sparse reconstruction technique for four-dimensional (4D) flow cardiac magnetic resonance (CMR) using conservation of mass principle applied to transvalvular flow.   Methods: This observational retrospective study (2020/21-075) was approved by the local ethics committee at the University of East Anglia. Consent was waived. Thirty-five patients who had a clinical CMR scan were included. CMR protocol included cine and 4D flow using Kat-ARC acceleration factor 6. No respiratory navigation was applied. For validation, the agreement between mitral net flow (MNF) and the aortic net flow (ANF) was investigated. Additionally, we checked the agreement between peak aortic valve velocity derived by 4D flow and that derived by continuous-wave Doppler echocardiography in 20 patients.   Results: The median age of our patient population was 63 years (interquartile range [IQR] 54–73), and 18/35 (51%) were male. Seventeen (49%) patients had mitral regurgitation, and seven (20%) patients had aortic regurgitation. Mean acquisition time was 8 ± 4 min. MNF and ANF were comparable: 60 mL (51−78) versus 63 mL (57−77), p = 0.310). There was an association between MNF and ANF (rho = 0.58, p < 0.001). Peak aortic valve velocity by Doppler and 4D flow were comparable (1.40 m/s, [1.30−1.75] versus 1.46 m/s [1.25−2.11], p = 0.602) and also correlated with each other (rho = 0.77, p < 0.001).   Conclusions: Kat-ARC accelerated 4D flow CMR quantified transvalvular flow in accordance with the conservation of mass principle and is primed for clinical translation

Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis.

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations

Rare germline copy number variants (CNVs) and breast cancer risk.

Funder: CIHRGermline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies

Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Results Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 x 10(-2)), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.Peer reviewe