Immune-Mediated Drug Induced Liver Injury: A Multidisciplinary Approach

This thesis presents an approach to expose relationships between immune mediated drug induced liver injury (IMDILI) and the three-dimensional structural features of toxic drug molecules and their metabolites. The series of analyses test the hypothesis that drugs which produce similar patterns of toxicity interact with targets within common toxicological pathways and that activation of the underlying mechanisms depends on structural similarity among toxic molecules. Spontaneous adverse drug reaction (ADR) reports were used to identify cases of IMDILI. Network map tools were used to compare the known and predicted protein interactions with each of the probe drugs to explore the interactions that are common between the drugs. The IMDILI probe set was then used to develop a pharmacophore model which became the starting point for identifying potential toxicity targets for IMDILI. Pharmacophore screening results demonstrated similarities between the probe IMDILI set of drugs and Toll-Like Receptor 7 (TLR7) agonists, suggesting TLR7 as a potential toxicity target. This thesis highlights the potential for multidisciplinary approaches in the study of complex diseases. Such approaches are particularly helpful for rare diseases where little knowledge is available, and may provide key insights into mechanisms of toxicity that cannot be gleaned from a single disciplinary study

Immune-Mediated Drug Induced Liver Injury: A Multidisciplinary Approach

This thesis presents an approach to expose relationships between immune mediated drug induced liver injury (IMDILI) and the three-dimensional structural features of toxic drug molecules and their metabolites. The series of analyses test the hypothesis that drugs which produce similar patterns of toxicity interact with targets within common toxicological pathways and that activation of the underlying mechanisms depends on structural similarity among toxic molecules. Spontaneous adverse drug reaction (ADR) reports were used to identify cases of IMDILI. Network map tools were used to compare the known and predicted protein interactions with each of the probe drugs to explore the interactions that are common between the drugs. The IMDILI probe set was then used to develop a pharmacophore model which became the starting point for identifying potential toxicity targets for IMDILI. Pharmacophore screening results demonstrated similarities between the probe IMDILI set of drugs and Toll-Like Receptor 7 (TLR7) agonists, suggesting TLR7 as a potential toxicity target. This thesis highlights the potential for multidisciplinary approaches in the study of complex diseases. Such approaches are particularly helpful for rare diseases where little knowledge is available, and may provide key insights into mechanisms of toxicity that cannot be gleaned from a single disciplinary study

901-11 Late Clinical and Echocardiographic Follow-up After Left Ventricular Endoaneurysmorrhaphy

Infarct expansion and aneurysm (LVA) formation has a poor prognosis. Traditional techniques of LVA resection may be associated with suboptimal results, and do not fully restore LV geometry. LV endoaneurysmorrhaphy(LVEA) is a newer operative technique which utilizes an endocardial patch to exclude the aneurysm and normalize LV geometry. Late clinical and echocardiographic features of these patients (pts) is unknown. We prospectively followed 51 consecutive pts who had undergone LVEA. Average duration of follow-up (F/U) was 4.6 years (range 2-10 years). All pts had clinical evaluation and review of medical records.ResultsThere were 2 (4%) peri-operative deaths, 2 (4%) in-hospital deaths, and 13 (24%) late deaths. Clinical improvement was noted in all 34 survivors:NYHAClassPre-opF/UCCSPre-opF/Un(%)n(%)n(%)n(%)I5(15)21(62)I12(35)29(85)II9(26)8(24)II3(9)5(15)III13(38)4(12)III5(15)0IV7(21)1(3)IV14(41)030 surviving pts had F/U 2D echocardiograms (2DE). Near normal LV geometry was restored in all pts, and no patch aneurysms were noted at late F/U. 24/30 2DEs were adequate for quantitative analysis. The average LVEF post-op was 40.2% using the modified biplane analysis.ConclusionsLV endoaneurysmorrhaphy was associated with a 72% overall survival after average 4.6 year F/U. All survivors had improvement in clinical status and normalization of LV geometry

Development of a Core Outcome Set for Studies on Cardiac Disease in Pregnancy (COSCarP): A study protocol

Background: Clinical studies looking at interventions to optimize pregnancy and long-term outcomes for women with cardiac disease and their babies are inconsistent in their reporting of clinical outcomes, making it difficult to compare results across studies and draw meaningful conclusions. The development of a core outcome set (COS) - a standardized, minimum set of outcomes that must be collected and reported in all studies - is a practical solution to this problem. Methods/design: We will follow a five-step process in developing a COS for studies on pregnant women with cardiac disease. First, a systematic literature review will identify all reported outcomes (including patient-reported outcomes) and definitions. Second, semi-structured interviews with stakeholders involved in the care of pregnant women with cardiac disease will determine their perspective and add new outcomes that they consider important. Third, an international electronic Delphi survey will narrow outcomes obtained through the first two steps, in an attempt to arrive at a consensus. Fourth, a face-to-face consensus meeting will deliberate to finalize the COS. Finally, measurement tools and definitions for included outcomes will be determined through a series of literature reviews and Delphi surveys. Discussion: This protocol provides an overview of the steps involved in the development of a COS that must be reported in studies involving pregnant women with cardiac disease, in an attempt to harmonize outcome reporting and ensure the validity of study results that will not only inform clinical practice and future research but also encourage the development of COS in other areas of medicine. COMET core outcome set registration: http://www.comet initiative.org/studies/details/83

The Role of Exosomal miR-181c-3p Within the Ovarian Tumor Microenvironment

https://openworks.mdanderson.org/sumexp22/1034/thumbnail.jp

Mitral regurgitation in hypertrophic obstructive cardiomyopathy: relationship to obstruction and relief with myectomy

AbstractOBJECTIVESThis study examined: 1) the impact of myectomy on postoperative mitral regurgitation (MR) and 2) the association between the severity of MR and the left ventricular outflow tract (LVOT) gradient.BACKGROUNDFor patients with hypertrophic obstructive cardiomyopathy (HOCM) and MR, controversy exists as to whether myectomy alone is sufficient in eliminating MR. Furthermore, the relationship between the degree of MR and the LVOT peak gradient has not been well defined.METHODSWe performed pre- and postoperative transthoracic as well as intraoperative transesophageal studies in 104 consecutive patients with HOCM undergoing septal myectomy. Left ventricular outflow tract gradient and the nature of MR were assessed.RESULTSIn the 93 patients without independent mitral valve disease, a relationship was observed between MR severity and the LVOT gradient. Left ventricular outflow tract gradient (mean ± standard deviation) for trivial, mild, moderate and severe MR were: 23.2 ± 19.1, 43.8 ± 25.4, 70.1 ± 21.0 and 104 ± 21.0 mm Hg (p < 0.001). Early postoperative, MR was absent or trivial in 80%, mild in 19% and moderate in 1%. None of these patients required additional mitral valve surgery. For patients with independent mitral valve disease (n = 11), five required mitral valve surgery as well as myectomy. The remainder had significant reductions in the degree of MR with myectomy alone.CONCLUSIONSFor patients with HOCM and MR not due to independent mitral valve disease, myectomy significantly reduced the degree of MR, without requirement for additional mitral valve surgery. In these patients the severity of MR was directly related to the magnitude of the LVOT gradient

Long-term cardiovascular outcomes after pregnancy in women with heart disease

BACKGROUND: Women with heart disease are at risk for pregnancy complications, but their long-term cardiovascular outcomes after pregnancy are not known. METHODS AND RESULTS: We examined long-term cardiovascular outcomes after pregnancy in 1014 consecutive women with heart disease and a matched group of 2028 women without heart disease. The primary outcome was a composite of mortality, heart failure, atrial fibrillation, stroke, myocardial infarction, or arrhythmia. Secondary outcomes included cardiac procedures and new hypertension or diabetes mellitus. We compared the rates of these outcomes between women with and without heart disease and adjusted for maternal and pregnancy characteristics. We also determined if pregnancy risk prediction tools (CARPREG [Canadian Cardiac Disease in Pregnancy] and World Health Organization) could stratify long-term risks. At 20-year follow-up, a primary outcome occurred in 33.1% of women with heart disease, compared with 2.1% of women without heart disease. Thirty-one percent of women with heart disease required a cardiac procedure. The primary outcome (adjusted hazard ratio, 19.6; 95% CI, 13.8–29.0; P\u3c0.0001) and new hypertension or diabetes mellitus (adjusted hazard ratio, 1.6; 95% CI, 1.4–2.0; P\u3c0.0001) were more frequent in women with heart disease compared with those without. Pregnancy risk prediction tools further stratified the late cardiovascular risks in women with heart disease, a primary outcome occurring in up to 54% of women in the highest pregnancy risk category. CONCLUSIONS: Following pregnancy, women with heart disease are at high risk for adverse long-term cardiovascular outcomes. Current pregnancy risk prediction tools can identify women at highest risk for long-term cardiovascular events

Spatially Resolved Transcriptomics Identified Distinct Tumor-Stroma Crosstalk Networks Associated With Chemoresistance in Ovarian Cancer

https://openworks.mdanderson.org/sumexp21/1135/thumbnail.jp