Publications by authors named "Melissa Thomas"

112 Publications

Food Insecurity and its Impact on Body Weight, Type 2 Diabetes, Cardiovascular Disease, and Mental Health.

Curr Cardiovasc Risk Rep 2021 5;15(9):15. Epub 2021 Jul 5.

Department of Primary Care, Ohio University Heritage College of Osteopathic Medicine, Athens, Ohio 45701 USA.

Purpose Of Review: Food insecurity (FI) is a serious public health issue affecting 2 billion people worldwide. FI is associated with increased risk for multiple chronic diseases, including obesity, type 2 diabetes, cardiovascular disease, and mental health. We selected these four chronic diseases given their global prevalence and comorbid associations with each other. We evaluated the most recent literature published over the past 5 years and offer strategies for the screening of FI.

Recent Findings: Recent systematic reviews and meta-analyses report an association between FI and obesity in adult women as well as adult men and women living in low- and middle-income countries. Gender differences also were observed between FI and type 2 diabetes, such that adult women showed an increased risk for type 2 diabetes. This association was influenced by social determinants of health. Very low food security (i.e., high FI) was associated with increased risk for cardiovascular disease and a higher risk for cardiovascular disease mortality. Finally, several studies showed an association between FI and adverse mental health outcomes, including increased risk for stress, depression, anxiety, sleep disorders, and suicidal ideation.

Summary: FI and its negative association with body weight, type 2 diabetes, cardiovascular disease, and mental health provide a compelling rationale for identification of FI in clinical settings. Brief, well-validated screening measures are available in multiple languages. Despite the need for FI screening, many guidelines do not address its implementation. For this reason, more research and targeted interventions are needed to increase FI screening rates and close the loop in the coordination of resources.
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http://dx.doi.org/10.1007/s12170-021-00679-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255162PMC
July 2021

Reconstruction of the Fas-Based Death-Inducing Signaling Complex (DISC) Using a Protein-Protein Docking Meta-Approach.

J Chem Inf Model 2021 Jul 1;61(7):3543-3558. Epub 2021 Jul 1.

Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Göteborg, Sweden.

The death-inducing signaling complex (DISC) is a fundamental multiprotein complex, which triggers the extrinsic apoptosis pathway through stimulation by death ligands. DISC consists of different death domain (DD) and death effector domain (DED) containing proteins such as the death receptor Fas (CD95) in complex with FADD, procaspase-8, and cFLIP. Despite many experimental and theoretical studies in this area, there is no global agreement neither on the DISC architecture nor on the mechanism of action of the involved species. In the current work, we have tried to reconstruct the DISC structure by identifying key protein interactions using a new protein-protein docking meta-approach. We combined the benefits of five of the most employed protein-protein docking engines, HADDOCK, ClusPro, HDOCK, GRAMM-X, and ZDOCK, in order to improve the accuracy of the predicted docking complexes. Free energy of binding and hot spot interacting residues were calculated and determined for each protein-protein interaction using molecular mechanics generalized Born surface area and alanine scanning techniques, respectively. In addition, a series of protein-fragment complementation assays were conducted to validate the protein-protein docking procedure. The results show that the DISC formation initiates by dimerization of adjacent Fas trimers followed by recruitment of FADD through homotypic DD interactions with the oligomerized death receptor. Furthermore, the outcomes indicate that cFLIP cannot bind directly to FADD; instead, cFLIP recruitment to the DISC is a hierarchical and cooperative process where FADD initially recruits procaspase-8, which in turn recruits and heterodimerizes with cFLIP. Finally, a possible structure of the entire DISC is proposed based on the docking results.
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http://dx.doi.org/10.1021/acs.jcim.1c00301DOI Listing
July 2021

Light chain subunit of a poorly soluble human IgG2λ crystallizes in physiological pH environment both in cellulo and in vitro.

Biochim Biophys Acta Mol Cell Res 2021 Aug 10;1868(9):119078. Epub 2021 Jun 10.

Department of Therapeutic Discovery, Amgen Inc., Thousand Oaks, CA 91320, USA.

Prominent inclusion bodies can develop in the endoplasmic reticulum (ER) when overexpressed antibodies possess intrinsically high condensation propensities. These observations suggest that antibodies deemed to show notable solubility problems may reveal such characteristics preemptively in the form of ER-associated inclusion bodies during antibody overexpression. To define the relationships between solubility problems and inclusion body phenotypes, we investigated the biosynthesis of a model human IgG2λ that shows severe opalescence in an acidic formulation buffer yet retains high solubility at physiological pH. Consistent with the pH-dependent solubility characteristics, the model antibody did not induce notable inclusion body in the physiological pH environment of the ER lumen. However, when individual subunit chains of the antibody were expressed separately, the light chain (LC) spontaneously induced notable crystal-like inclusion bodies in the ER. The LC crystallization event was readily reproducible in vitro by simply concentrating the purified LC protein at physiological pH. Two independent structural determinants for the LC crystallization were identified through rational mutagenesis approach by monitoring the effect of amino acid substitutions on intracellular LC crystallogenesis. The effect of mutations on crystallization was also recapitulated in vitro using purified LC proteins. Importantly, when introduced directly into the model antibody, a mutation that prevents the LC crystallization remediated the antibody's solubility problem without compromising the secretory output or antigen binding. These results illustrate that the ER can serve as a "physiological test tube" that not only reports secretory cargo's high condensation propensity at physiological pH, but also provides an orthogonal method that guides antibody engineering strategy.
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http://dx.doi.org/10.1016/j.bbamcr.2021.119078DOI Listing
August 2021

Insulin-like growth factor-1, growth hormone and disease outcomes in acromegaly: A population study.

Clin Endocrinol (Oxf) 2021 Jul 4;95(1):143-152. Epub 2021 Apr 4.

Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, UK.

Context: A lack of consensus remains about the relative importance of insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in predicting adverse outcomes in patients with acromegaly.

Objective: To describe the differing association between IGF-1 and GH and major disease outcomes in acromegaly.

Design: Retrospective cohort study.

Patients: United Kingdom National Health Service patients with acromegaly who had an IGF-1 and/or a GH measurement recorded following diagnosis, prior to December 2019.

Measurements: A composite endpoint including all-cause mortality (ACM), type 2 diabetes (DM), major adverse cardiovascular events (MACE) or cancer was the primary outcome. These outcomes were also analysed individually. Follow-up period was capped at 5 years.

Results: A maximum of 417 cases and 332 cases were eligible for the IGF-1 and GH analyses, respectively, comprising 1041.5 and 938.9 years of follow-up. There was a direct association between increased IGF-1 concentration and adjusted event risk for the composite endpoint (hazard ratio [HR] = 1.2; 95% confidence interval [CI] = 1.02-1.5); in GH, the HR was 1.1 (1.0-1.2). For the individual endpoints in relation to IGF-1 level, the HRs were ACM (1.2; 0.93-1.5), MACE (1.2; 0.64-2.1), DM (1.53; 1.09-2.2) and cancer (1.3; 0.95-1.7). For GH, the HRs were ACM (1.1; 0.97-1.2), MACE (0.99; 0.73-1.3), DM (1.1; 0.99-1.2) and cancer (0.90; 0.66-1.2).

Conclusions: In this contemporary data set with extended follow-up, IGF-1 and GH concentrations showed an association with major adverse outcomes from acromegaly.
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http://dx.doi.org/10.1111/cen.14468DOI Listing
July 2021

Deep learning dose prediction for IMRT of esophageal cancer: The effect of data quality and quantity on model performance.

Phys Med 2021 Mar 10;83:52-63. Epub 2021 Mar 10.

UCLouvain - Institut de Recherche Expérimentale et Clinique - Molecular Imaging Radiotherapy and Oncology (MIRO), Brussels, Belgium; KU Leuven - Department of Oncology - Laboratory of Experimental Radiotherapy, Leuven, Belgium.

Purpose: To investigate the effect of data quality and quantity on the performance of deep learning (DL) models, for dose prediction of intensity-modulated radiotherapy (IMRT) of esophageal cancer.

Material And Methods: Two databases were used: a variable database (VarDB) with 56 clinical cases extracted retrospectively, including user-dependent variability in delineation and planning, different machines and beam configurations; and a homogenized database (HomDB), created to reduce this variability by re-contouring and re-planning all patients with a fixed class-solution protocol. Experiment 1 analysed the user-dependent variability, using 26 patients planned with the same machine and beam setup (E26-VarDB versus E26-HomDB). Experiment 2 increased the training set by groups of 10 patients (E16, E26, E36, E46, and E56) for both databases. Model evaluation metrics were the mean absolute error (MAE) for selected dose-volume metrics and the global MAE for all body voxels.

Results: For Experiment 1, E26-HomDB reduced the MAE for the considered dose-volume metrics compared to E26-VarDB (e.g. reduction of 0.2 Gy for D95-PTV, 1.2 Gy for Dmean-heart or 3.3% for V5-lungs). For Experiment 2, increasing the database size slightly improved performance for HomDB models (e.g. decrease in global MAE of 0.13 Gy for E56-HomDB versus E26-HomDB), but increased the error for the VarDB models (e.g. increase in global MAE of 0.20 Gy for E56-VarDB versus E26-VarDB).

Conclusion: A small database may suffice to obtain good DL prediction performance, provided that homogenous training data is used. Data variability reduces the performance of DL models, which is further pronounced when increasing the training set.
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http://dx.doi.org/10.1016/j.ejmp.2021.02.026DOI Listing
March 2021

Balancing quality and utilization: Emergency physician level correlation between 72 h returns, admission, and CT utilization rates.

Am J Emerg Med 2021 Feb 4. Epub 2021 Feb 4.

Department of Emergency Medicine, Yale University School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1016/j.ajem.2021.01.078DOI Listing
February 2021

A study to investigate the influence of cardiac motion on the robustness of pencil beam scanning proton plans in oesophageal cancer.

Phys Imaging Radiat Oncol 2020 Oct 13;16:50-53. Epub 2020 Oct 13.

KU Leuven - University of Leuven, Department of Oncology - Laboratory Experimental Radiotherapy, Leuven, Belgium.

While proton therapy offers an excellent dose conformity and sparing of organs at risk, this can be compromised by uncertainties, e.g. organ motion. This study aimed to investigate the influence of cardiac motion on the contoured oesophagus using electrocardiogram-triggered imaging and to assess the impact of this motion on the robustness of proton therapy plans in oesophageal cancer patients. Limited cardiac-induced motion of the oesophagus was observed with a negligible impact on the robustness of proton therapy plans. Therefore, our data suggest that cardiac motion may be safely ignored in the robust optimisation strategy for proton planning in oesophageal cancer.
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http://dx.doi.org/10.1016/j.phro.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807867PMC
October 2020

Kidney Outcomes and Hypertension in Survivors of Wilms Tumor: A Prospective Cohort Study.

J Pediatr 2021 03 5;230:215-220.e1. Epub 2020 Dec 5.

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, PA. Electronic address:

Objective: To assess the prevalence of therapy-related kidney outcomes in survivors of Wilms tumor (WT).

Study Design: This prospective cohort study included survivors of WT who were ≥5 years old and ≥1 year from completing therapy, excluding those with preexisting hypertension, prior dialysis, or kidney transplant. Participants completed 24-hour ambulatory blood pressure monitoring (ABPM). Abnormal blood pressure (BP) was defined as ≥90th percentile. Masked hypertension was defined as having normal office BP and abnormal ABPM findings. Urine was analyzed for kidney injury molecule-1, interleukin-18, epidermal growth factor, albumin, and creatinine. The estimated glomerular filtration rate (eGFR) was calculated using the bedside chronic kidney disease in children equation. Recent kidney ultrasound examinations and echocardiograms were reviewed for contralateral kidney size and left ventricular hypertrophy, respectively. Clinical follow-up data were collected for approximately 2 years after study enrollment.

Results: Thirty-two participants (median age, 13.6 years [IQR, 10.5-16.3 years]; 75% stage 3 or higher WT) were evaluated at a median of 8.7 years (IQR, 6.5-10.8 years) after therapy; 29 participants underwent unilateral radical nephrectomy, 2 bilateral partial nephrectomy, and 1 radical and contralateral partial nephrectomy. In this cohort, 72% received kidney radiotherapy and 75% received doxorubicin. Recent median eGFR was 95.6 mL/min/1.73 m (IQR, 84.6-114.0; 11 [34%] had an eGFR of <90 mL/min/1.73 m). Abnormal ABPM results were found in 22 of 29 participants (76%), masked hypertension in 10 of 29 (34%), and microalbuminuria in 2 of 32 (6%). Of the 32 participants, 22 (69%) had abnormal epidermal growth factor; few had abnormal kidney injury molecule-1 or interleukin-18. Seven participants with previous unilateral nephrectomy lacked compensatory contralateral kidney hypertrophy. None had left ventricular hypertrophy.

Conclusions: In survivors of WT, adverse kidney outcomes were common and should be closely monitored.
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http://dx.doi.org/10.1016/j.jpeds.2020.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914174PMC
March 2021

Proposal for the delineation of neoadjuvant target volumes in oesophageal cancer.

Radiother Oncol 2021 03 5;156:102-112. Epub 2020 Dec 5.

KU Leuven - University of Leuven, Department of Oncology - Laboratory of Experimental Radiotherapy, Belgium; University Hospitals Leuven, Department of Radiation Oncology, Belgium.

Purpose: To define instructions for delineation of target volumes in the neoadjuvant setting in oesophageal cancer.

Materials And Methods: Radiation oncologists of five European centres participated in the following consensus process: [1] revision of published (MEDLINE) and national/institutional delineation guidelines; [2] first delineation round of five cases (patient 1-5) according to national/institutional guidelines; [3] consensus meeting to discuss the results of step 1 and 2, followed by a target volume delineation proposal; [4] circulation of proposed instructions for target volume delineation and atlas for feedback; [5] second delineation round of five new cases (patient 6-10) to peer review and validate (two additional centres) the agreed delineation guidelines and atlas; [6] final consensus on the delineation guidelines depicted in an atlas. Target volumes of the delineation rounds were compared between centres by Dice similarity coefficient (DSC) and maximum/mean undirected Hausdorff distances (H/H).

Results: In the first delineation round, the consistency between centres was moderate (CTVtotal: DSC = 0.59-0.88; H = 0.2-0.4 cm). Delineations in the second round were much more consistent. Lowest variability was obtained between centres participating in the consensus meeting (CTVtotal: DSC: p < 0.050 between rounds for patients 6/7/8/10; H: p < 0.050 for patients 7/8/10), compared to validation centres (CTVtotal: DSC: p < 0.050 between validation and consensus meeting centres for patients 6/7/8; H: p < 0.050 for patients 7/10). A proposal for delineation of target volumes and an atlas were generated.

Conclusion: We proposed instructions for target volume delineation and an atlas for the neoadjuvant radiation treatment in oesophageal cancer. These will enable a more uniform delineation of patients in clinical practice and clinical trials.
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http://dx.doi.org/10.1016/j.radonc.2020.11.032DOI Listing
March 2021

Obesity Risk Among West Point Graduates Later in Life.

J Strength Cond Res 2020 Dec 3. Epub 2020 Dec 3.

Yale University, School of Medicine, New Haven, Connecticut.

Szivak, TK, Thomas, MM, Pietrzak, RH, Nguyen, DR, Ryan, DM, and Mazure, CM. Obesity Risk Among West Point Graduates Later in Life. J Strength Cond Res XX(X): 000-000, 2020-The purpose of this investigation was to evaluate sex differences in health and fitness outcomes among United States Military Academy (USMA) graduates (class years 1980-2011). Subjects (n = 701 men, 641 women, age: 45.7 ± 9.3 years) were surveyed as a part of a larger investigation on risk and resiliency factors among USMA graduates. Physical activity was assessed using the International Physical Activity Questionnaire (IPAQ) short form and calculation of weekly metabolic equivalents (METs). Overweight and obesity status were assessed by body mass index (BMI). Significance for the study was set at p ≤ 0.05. Obesity rates for men (30.1%) were significantly higher than for women (16.6%). Men reported significantly higher (p = 0.01) vigorous METs·wk (1,214.6 ± 1,171.6) than women (1,046.8 ± 1,133.2) despite significantly higher (p = 0.00) BMI values (28.75 ± 4.53 kg·m) than women (25.90 ± 5.48 kg·m). Women were 89% more likely to have ever been on a diet and reported higher (15.2%) Army Body Composition Program enrollment rates than men (6.3%). Obesity rates among men reflect trends seen in the broader military, Veteran, and U.S. adult populations, whereas obesity rates among women were lower. Men may be at a greater risk for obesity later in life despite higher self-reported physical activity; however, lean body mass and self-report bias should be considered. Because lifetime obesity may be influenced by factors other than physical activity, health initiatives should use a comprehensive approach early in the career of military officers.
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http://dx.doi.org/10.1519/JSC.0000000000003824DOI Listing
December 2020

The use of tumour markers in oesophageal cancer to quantify setup errors and baseline shifts during treatment.

Clin Transl Radiat Oncol 2021 Jan 5;26:8-14. Epub 2020 Nov 5.

KU Leuven - University of Leuven, Department of Oncology - Laboratory of Experimental Radiotherapy, Leuven, Belgium.

Purpose: To prospectively evaluate the feasibility of solid gold marker placement in oesophageal cancer patients and to quantify inter-fractional and intra-fractional (baseline shift) marker motion during radiation treatment. Radiotherapy target margins and matching strategies were investigated.

Materials/methods: Thirty-four markers were implanted by echo-endoscopy in 10 patients. Patients received a planning 4D CT, daily pre-treatment cone-beam CT (CBCT) and a post-treatment CBCT for at least five fractions. For fractions with both pre- and post-treatment CBCT, marker displacement between planning CT and pre-treatment CBCT (inter-fractional) and between pre-treatment and post-treatment CBCT (intra-fractional; only for fractions without rotational treatment couch correction) were calculated in left-right (LR), cranio-caudal (CC) and anterior-posterior (AP) direction after bony-anatomy and soft-tissue matching. Systematic/random setup errors were estimated; treatment margins were calculated.

Results: No serious adverse events occurred. Twenty-three (67.6%) markers were visible during radiotherapy (n = 3 middle oesophagus, n = 16 distal oesophagus, n = 4 proximal stomach). Margins for inter-fractional displacement after bony-anatomy match depended on the localisation of the primary tumour and were 11.2 mm (LR), 16.4 mm (CC) and 8.2 mm (AP) for distal markers. Soft-tissue matching reduced the CC margin for these markers (16.4 mm to 10.5 mm). The mean intra-fractional shift of 12 distal markers was 0.4 mm (LR), 2.3 mm (CC) and 0.7 mm (AP). Inclusion of this shift resulted in treatment margins for distal markers of 12.8 mm (LR), 17.3 mm (CC) and 10.4 mm (AP) after bony-anatomy matching and 12.4 mm (LR), 11.4 mm (CC) and 9.7 mm (AP) after soft-tissue matching.

Conclusion: This study demonstrated that the implantation of gold markers was safe, albeit less stable compared to other marker types. Inter-fractional motion was largest cranio-caudally for markers in the distal oesophagus, which was reduced after soft-tissue compared to bony-anatomy matching. The impact of intra-fractional baseline shifts on margin calculation was rather small.
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http://dx.doi.org/10.1016/j.ctro.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677672PMC
January 2021

Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes.

J Clin Endocrinol Metab 2021 Jan;106(2):388-396

Eli Lilly and Company, Indianapolis, IN, USA.

Context: Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide.

Objective: Explore mechanisms of glucose control by tirzepatide.

Design: Post hoc analyses of fasting biomarkers and multiple linear regression analysis.

Setting: Forty-seven sites in 4 countries.

Patients Or Other Participants: Three hundred and sixteen subjects with type 2 diabetes.

Interventions: Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo.

Main Outcome Measures: Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks.

Results: Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively.

Conclusions: Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.
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http://dx.doi.org/10.1210/clinem/dgaa863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823251PMC
January 2021

AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer.

Clin Cancer Res 2021 Mar 17;27(5):1526-1537. Epub 2020 Nov 17.

Oncology Research, Amgen Research, Thousand Oaks, California.

Purpose: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, a half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)-a target that is selectively expressed in SCLC tumors, but with minimal normal tissue expression.

Experimental Design: AMG 757 efficacy was evaluated in SCLC cell lines and in orthotopic and patient-derived xenograft (PDX) mouse SCLC models. Following AMG 757 administration, changes in tumor volume, pharmacodynamic changes in tumor-infiltrating T cells (TILs), and the spatial relationship between the appearance of TILs and tumor histology were examined. Tolerability was assessed in nonhuman primates (NHPs).

Results: AMG 757 showed potent and specific killing of even those SCLC cell lines with very low DLL3 expression (<1,000 molecules per cell). AMG 757 effectively engaged systemically administered human T cells, induced T-cell activation, and redirected T cells to lyse tumor cells to promote significant tumor regression and complete responses in PDX models of SCLC and in orthotopic models of established primary lung SCLC and metastatic liver lesions. AMG 757 was well tolerated with no AMG 757-related adverse findings up to the highest tested dose (4.5 mg/kg weekly) in NHP. AMG 757 exhibits an extended half-life in NHP, which is projected to enable intermittent administration in patients.

Conclusions: AMG 757 has a compelling safety and efficacy profile in preclinical studies making it a viable option for targeting DLL3-expressing SCLC tumors in the clinical setting.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2845DOI Listing
March 2021

Student Journal Club to Improve Cultural Humility with LGBTQ Patients.

J Prim Care Community Health 2020 Jan-Dec;11:2150132720963686

Ohio University Heritage College of Osteopathic Medicine, Dublin, OH, USA.

Health degree programs provide opportunities to reduce disparities in care for LGBTQ patients by exposing students to LGBTQ communities and current health issues. However, LGBTQ content is mostly absent from medical school curricula. This mixed method assessment study, conducted during the 2018 to 2019 academic year, examined the feasibility of implementing a medical student journal club focused specifically on LGBTQ health issues as a complementary training tool to support efforts to create an inclusive educational environment. Compared to the pre-test, mean response scores increased for most of the parameters including familiarity with LGBTQ healthcare issues, confidence in the ability to identify harmful medical provider practices, and reading and assessing scientific literature. Qualitative data showed increased confidence, comfort and knowledge about LGBTQ health barriers. This study offers a framework for using a journal club to provide an effective platform for enhancing students' LGBTQ cultural humility and research literacy.
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http://dx.doi.org/10.1177/2150132720963686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557682PMC
June 2021

Role of sex and high-fat diet in metabolic and hypothalamic disturbances in the 3xTg-AD mouse model of Alzheimer's disease.

J Neuroinflammation 2020 Sep 29;17(1):285. Epub 2020 Sep 29.

Department of Neuroscience & Experimental Therapeutics, Albany Medical College, 47 New Scotland Avenue, MC-136, Albany, NY, 12208, USA.

Background: Hypothalamic dysfunction occurs early in the clinical course of Alzheimer's disease (AD), likely contributing to disturbances in feeding behavior and metabolic function that are often observed years prior to the onset of cognitive symptoms. Late-life weight loss and low BMI are associated with increased risk of dementia and faster progression of disease. However, high-fat diet and metabolic disease (e.g., obesity, type 2 diabetes), particularly in mid-life, are associated with increased risk of AD, as well as exacerbated AD pathology and behavioral deficits in animal models. In the current study, we explored possible relationships between hypothalamic function, diet/metabolic status, and AD. Considering the sex bias in AD, with women representing two-thirds of AD patients, we sought to determine whether these relationships vary by sex.

Methods: WT and 3xTg-AD male and female mice were fed a control (10% fat) or high-fat (HF 60% fat) diet from ~ 3-7 months of age, then tested for metabolic and hypothalamic disturbances.

Results: On control diet, male 3xTg-AD mice displayed decreased body weight, reduced fat mass, hypoleptinemia, and mild systemic inflammation, as well as increased expression of gliosis- and inflammation-related genes in the hypothalamus (Iba1, GFAP, TNF-α, IL-1β). In contrast, female 3xTg-AD mice on control diet displayed metabolic disturbances opposite that of 3xTg-AD males (increased body and fat mass, impaired glucose tolerance). HF diet resulted in expected metabolic alterations across groups (increased body and fat mass; glucose intolerance; increased plasma insulin and leptin, decreased ghrelin; nonalcoholic fatty liver disease-related pathology). HF diet resulted in the greatest weight gain, adiposity, and glucose intolerance in 3xTg-AD females, which were associated with markedly increased hypothalamic expression of GFAP and IL-1β, as well as GFAP labeling in several hypothalamic nuclei that regulate energy balance. In contrast, HF diet increased diabetes markers and systemic inflammation preferentially in AD males but did not exacerbate hypothalamic inflammation in this group.

Conclusions: These findings provide further evidence for the roles of hypothalamic and metabolic dysfunction in AD, which in the 3xTg-AD mouse model appears to be dependent on both sex and diet.
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http://dx.doi.org/10.1186/s12974-020-01956-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526387PMC
September 2020

Man With Elbow Swelling Following Trauma.

Ann Emerg Med 2020 09;76(3):e45-e46

Department of Emergency Medicine, University of Kansas Health System, Kansas City, KS.

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http://dx.doi.org/10.1016/j.annemergmed.2020.03.018DOI Listing
September 2020

Intraoral human herpes viruses detectable by PCR in majority of patients.

Oral Dis 2021 Mar 27;27(2):378-387. Epub 2020 Jul 27.

Department of Dermatology, Royal Melbourne Hospital, Melbourne, Vic., Australia.

Objectives: To identify factors which influence the intraoral prevalence of human herpes viruses (HHVs) using mucosal swabs, saliva samples and qPCR analysis.

Methodology: In this cross-sectional observational study, matched saliva and oral swabs were collected from a total of 115 subjects: 70 immunocompetent subjects with no mucosal abnormalities, 22 with mucosal abnormalities and 23 therapeutically immunocompromised individuals. Extracted DNA was analysed by multiplex qPCR for detection and quantification of HHVs 1-6.

Results: At least one human herpes virus was detected in 77.1% of immunocompetent individuals with no mucosal abnormalities, with EBV the most commonly detected at 61.4%. HHV-6 was detected in 17.1%, HSV-1 in 4.3% and CMV in 1.1%. Detection was higher in saliva than in oral swabs. There was no detection of HSV-2 or VZV. Neither presence of oral mucosal abnormality nor therapeutic immunocompromise was related to increased detection of human herpes virus.

Conclusion: Commensal detection rates of EBV are high, and caution in clinical correlation of positive detection is warranted. Commensal CMV rates are low, and detection is likely to be clinically relevant. This study presents a comprehensive commensal detection rate of HHVs 1-6 by qPCR in saliva and swabs.
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http://dx.doi.org/10.1111/odi.13523DOI Listing
March 2021

In-transit fumigation of shipping containers with ethyl formate + nitrogen on road and continued journey on sea.

J Environ Sci Health B 2020 1;55(9):820-826. Epub 2020 Jul 1.

Harry Butler Institute, Murdoch University, Murdoch, Western Australia, Australia.

Fumigation is required as an appropriate biosecurity measure to exterminate insect pests in shipping containers. The aim of this study was to determine if ethyl formate (EF) + nitrogen could be safely applied as an in-transit fumigant for containers transported on land and then by sea. In-transit fumigation trials were conducted in four 20 ft shipping containers during a four-day journey in December 2019 in Western Australia. Ethyl formate (90 g m) was released with nitrogen into the containers. Ethyl formate concentrations inside the containers and the surrounding environment on the barge were monitored at timed intervals throughout the overnight voyage. This study added new data on in-transit fumigation with ethyl formate + nitrogen via road and has successfully demonstrated safety of in-transit fumigation with ethyl formate + nitrogen via the marine sector. There was no detectable risk to the public, crew members on the barge or workers throughout the journey. In addition, all tested containers were ready to be opened and unloaded with 5-10 minutes aeration or without aeration upon arrival.
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http://dx.doi.org/10.1080/03601234.2020.1786328DOI Listing
September 2020

Discovery of LY3325656: A GPR142 agonist suitable for clinical testing in human.

Bioorg Med Chem Lett 2020 03 27;30(5):126857. Epub 2019 Dec 27.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States. Electronic address:

The discovery and optimization of a novel series of GPR142 agonists are described. These led to the identification of compound 21 (LY3325656), which demonstrated anti-diabetic benefits in pre-clinical studies and ADME/PK properties suitable for human dosing. Compound 21 is the first GPR142 agonist molecule advancing to phase 1 clinic trials for the treatment of Type 2 diabetes.
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http://dx.doi.org/10.1016/j.bmcl.2019.126857DOI Listing
March 2020

Biosecurity risks posed by a large sea-going passenger vessel: challenges of terrestrial arthropod species detection and eradication.

Sci Rep 2019 12 18;9(1):19339. Epub 2019 Dec 18.

Harry Butler Institute, Murdoch University, Murdoch, WA, 6150, Australia.

Large sea-going passenger vessels can pose a high biosecurity risk. The risk posed by marine species is well documented, but rarely the risk posed by terrestrial arthropods. We conducted the longest running, most extensive monitoring program of terrestrial arthropods undertaken on board a passenger vessel. Surveillance was conducted over a 19-month period on a large passenger (cruise) vessel that originated in the Baltic Sea (Estonia). The vessel was used as an accommodation facility to house workers at Barrow Island (Australia) for 15 months, during which 73,061 terrestrial arthropods (222 species - four non-indigenous (NIS) to Australia) were collected and identified on board. Detection of Tribolium destructor Uytt., a high-risk NIS to Australia, triggered an eradication effort on the vessel. This effort totalled more than 13,700 human hours and included strict biosecurity protocols to ensure that this and other non-indigenous species (NIS) were not spread from the vessel to Barrow Island or mainland Australia. Our data demonstrate that despite the difficulties of biosecurity on large vessels, stringent protocols can stop NIS spreading from vessels, even where vessel-wide eradication is not possible. We highlight the difficulties associated with detecting and eradicating NIS on large vessels and provide the first detailed list of species that inhabit a vessel of this kind.
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http://dx.doi.org/10.1038/s41598-019-55554-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920439PMC
December 2019

Development and validation of a targeted gene sequencing panel for application to disparate cancers.

Sci Rep 2019 11 19;9(1):17052. Epub 2019 Nov 19.

Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour's molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy.
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http://dx.doi.org/10.1038/s41598-019-52000-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864073PMC
November 2019

NTCP model for postoperative complications and one-year mortality after trimodality treatment in oesophageal cancer.

Radiother Oncol 2019 12 17;141:33-40. Epub 2019 Oct 17.

KU Leuven - University of Leuven, Department of Oncology - Laboratory Experimental Radiotherapy, Leuven, Belgium; UZ Leuven - University Hospitals Leuven, Department of Radiation Oncology, Leuven, Belgium. Electronic address:

Purpose/objectives: To develop normal tissue complication probability (NTCP) models for postoperative pulmonary and cardiac complications and one-year mortality after preoperative chemoradiotherapy and surgery in oesophageal cancer patients.

Methods: 691 patients from two institutions (2002-2017) were included; 134 treated with protons. Multivariable logistic regression analyses on 601 patients studied the predictive value of clinical/treatment-related (gender, age, body mass index (BMI), smoking, cardiac comorbidity, chronic obstructive pulmonary disease, histology, cT/N) and dosimetric variables (absolute/relative lung/heart volumes receiving or spared from xGy, mean doses, planning target volume) for the presence of pulmonary complications, cardiac complications and one-year mortality. Model validation was performed using a nonrandom split-sample of 90 patients. Model performance was assessed by AUC and calibration plots.

Results: Respectively 144/601 (24.0%) and 165/601 (27.5%) patients developed a pulmonary or cardiac complication. For pulmonary complications, an NTCP model with optimism-corrected AUC of 0.75 (95%CI = 0.73-0.76) was obtained. The model contained mean lung dose (OR = 1.15, 95%CI = 1.09-1.22, p < 0.001), increasing age (OR = 1.03, 95%CI = 1.01-1.06, p = 0.002), BMI (OR = 1.04, 95%CI = 0.99-1.08, p = 0.084) and squamous cell carcinoma (OR = 3.22, 95%CI = 1.97-5.24, p < 0.001) as predictors. In validation, AUC of 0.79 was obtained (calibration slope 1.26). For cardiac complications, only age (OR = 1.06, 95%CI = 1.04-1.09, p < 0.001) with optimism-corrected AUC of 0.67 (95%CI = 0.65-0.68) was selected. For one-year mortality, an NTCP model with optimism-corrected AUC of 0.63 (95%CI = 0.58-0.66) was obtained. Lung absolute V (OR = 1.0016, 95%CI = 1.0007-1.0026, p = 0.001), cN (OR = 2.45, 95%CI = 1.18-5.09, p = 0.017), cT4 (OR = 2.51, 95%CI = 1.10-5.74, p = 0.029) and cardiac comorbidity (OR = 2.91, 95%CI = 1.46-5.77, p = 0.002) were selected as predictors. At validation, AUC of 0.57 was obtained (calibration slope 0.75).

Conclusion: We were able to build and validate NTCP models for the presence of a postoperative pulmonary complication and for one-year mortality after trimodality treatment in oesophageal cancer.
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http://dx.doi.org/10.1016/j.radonc.2019.09.015DOI Listing
December 2019

Cardiovascular risk scoring and magnetic resonance imaging detected subclinical cerebrovascular disease.

Eur Heart J Cardiovasc Imaging 2020 06;21(6):692-700

Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.

Aims: Cardiovascular risk factors are used for risk stratification in primary prevention. We sought to determine if simple cardiac risk scores are associated with magnetic resonance imaging (MRI)-detected subclinical cerebrovascular disease including carotid wall volume (CWV), carotid intraplaque haemorrhage (IPH), and silent brain infarction (SBI).

Methods And Results: A total of 7594 adults with no history of cardiovascular disease (CVD) underwent risk factor assessment and a non-contrast enhanced MRI of the carotid arteries and brain using a standardized protocol in a population-based cohort recruited between 2014 and 2018. The non-lab-based INTERHEART risk score (IHRS) was calculated in all participants; the Framingham Risk Score was calculated in a subset who provided blood samples (n = 3889). The association between these risk scores and MRI measures of CWV, carotid IPH, and SBI was determined. The mean age of the cohort was 58 (8.9) years, 55% were women. Each 5-point increase (∼1 SD) in the IHRS was associated with a 9 mm3 increase in CWV, adjusted for sex (P < 0.0001), a 23% increase in IPH [95% confidence interval (CI) 9-38%], and a 32% (95% CI 20-45%) increase in SBI. These associations were consistent for lacunar and non-lacunar brain infarction. The Framingham Risk Score was also significantly associated with CWV, IPH, and SBI. CWV was additive and independent to the risk scores in its association with IPH and SBI.

Conclusion: Simple cardiovascular risk scores are significantly associated with the presence of MRI-detected subclinical cerebrovascular disease, including CWV, IPH, and SBI in an adult population without known clinical CVD.
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http://dx.doi.org/10.1093/ehjci/jez226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237958PMC
June 2020

Radiation dose and pathological response in oesophageal cancer patients treated with neoadjuvant chemoradiotherapy followed by surgery: a multi-institutional analysis.

Acta Oncol 2019 Oct 21;58(10):1358-1365. Epub 2019 Aug 21.

Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven - University of Leuven , Leuven , Belgium.

To explore whether a higher neoadjuvant radiation dose increases the probability of a pathological complete response (pCR) or pathological major response (pMR) response in oesophageal cancer patients. Between 2000 and 2017, 1048 patients from four institutions were stratified according to prescribed neoadjuvant radiation doses of 36.0 Gy (13.3%), 40.0 Gy (7.4%), 41.4 Gy (20.1%), 45.0 Gy (25.5%) or 50.4 Gy (33.7%) in 1.8-2.0 Gy fractions. Endpoints were pCR (tumour regression grade (TRG) 1) and pMR (TRG 1 + 2). Multivariable binary (TRG 1 + 2 vs. TRG > 2) and ordinal (TRG 1 vs. TRG 2 vs. TRG > 2) logistic regression analyses were performed, with subgroup analyses according to histology (squamous cell carcinoma (SCC) vs. adenocarcinoma (AC)). Variables entered in the regression model along with neoadjuvant radiation dose were clinical tumour stage (cT), histology, chemotherapy regimen, induction chemotherapy and time from neoadjuvant chemoradiation to surgery. A pCR was observed in 312 patients (29.8%); in 22.7% patients with AC and in 49.6% patients with SCC. No radiation dose-response relation was observed for pCR (OR = 1.01, 95% CI: 0.98-1.05 for AC and OR = 1.03, 95% CI: 0.96-1.10 for SCC). A pMR was observed in 597 patients (57.0%); in 53.4% patients with AC and in 67.2% patients with SCC. A higher radiation dose increased the probability of achieving pMR (OR = 1.04, 95% CI: 1.02-1.05). Factors reducing this probability were advanced cT stage (reference = cT1-2; cT3: OR = 0.54, 95% CI: 0.37-0.80; cT4: OR = 0.45, 95% CI: 0.24-0.84), AC histology (reference = SCC; OR = 0.62, 95% CI: 0.44-0.88), the use of non-platinum based chemotherapy in SCC patients (OR = 0.30, 95% CI: 0.10-0.91) and platinum based chemotherapy without induction chemotherapy in patients with AC (OR = 0.56, 95% CI: 0.42-0.76). The radiation dose-response relation was confirmed in a subgroup analysis of histologic subtypes (OR = 1.02, 95% CI: 1.01-1.04 for AC and OR = 1.05, 95% CI: 1.02-1.08 for SCC). Neoadjuvant radiation dose impacts pathological response in terms of pMR in oesophageal cancer patients. No radiation dose-response effect was observed for pCR. Further prospective trials are needed to investigate the dose-response relation in terms of pCR.
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http://dx.doi.org/10.1080/0284186X.2019.1646432DOI Listing
October 2019

Commercial trials evaluating the novel use of ethyl formate for in-transit fumigation of shipping containers.

J Environ Sci Health B 2019 22;54(8):717-727. Epub 2019 Jun 22.

Harry Butler Institute, Murdoch University , Murdoch , WA , Australia.

The use of shipping containers for cargo transportation has the potential to transport insect pests from infested to non-infested areas. Therefore, fumigation is required as an appropriate biosecurity measure to exterminate these pests. In-transit fumigation trials were conducted in two 20 ft shipping containers during a two-day journey in both September and December 2017. Ethyl formate (90 g m) was purged with nitrogen (EF + N) into the containers. Ethyl formate concentration inside containers and the surrounding environment were monitored at timed intervals throughout the journey. Fumigation achieved sufficient concentration × time () products in the containers during the journey, which can exterminate all stages of most common insect pests. The products in-transit were greater than those in a shipping container being fumigated in a stationary position at a dose rate of 90 g m³ for 24 hours exposure. Levels of EF in the environment between 1-15 m downwind from the containers and driver's cabin were less than 0.5 ppm at each of the timed intervals, 200 times below 100 ppm of EF Threshold Limit Value (TLV). Our study indicates that in-transit EF + N technology has the potential to deliver cost savings in the fumigation process through reduction of the Labor cost, elimination of the time a container and cargo must remain stationary in a fumigation yard and a significant decrease in total supply chain time (between container packing and receival).
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http://dx.doi.org/10.1080/03601234.2019.1631101DOI Listing
November 2019

Analysis of patients scheduled for neoadjuvant therapy followed by surgery for esophageal cancer, who never made it to esophagectomy.

World J Surg Oncol 2019 May 27;17(1):89. Epub 2019 May 27.

Department of Thoracic Surgery, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.

Background: Neoadjuvant treatment followed by esophagectomy is standard practice in locally advanced esophageal cancer. However, not all patients who started neoadjuvant treatment will undergo esophageal resection. The purpose of our study was to investigate the group of patients, scheduled for neoadjuvant treatment followed by esophagectomy, who never made it to esophageal resection.

Methods: We retrospectively analyzed patients treated between 2002 and 2015 for locally advanced esophageal cancer, who did not undergo esophagectomy after neoadjuvant treatment. Subanalysis was performed according to time period (2002-2010 versus 2011-2015) and histology (adenocarcinoma versus squamous cell carcinoma).

Results: In 114 of 679 patients (16.8%), surgery was not performed after neoadjuvant treatment. Reasons for cancelation were disease progression (50 patients, 43.9%), poor general condition (26 patients, 22.8%), irresectability (14 patients, 12.3%), patients' own decision (15 patients, 13.2%), and death during neoadjuvant treatment (9 patients, 7.9%). In the second time period, there were less irresectable tumors (17.7% versus 5.8%; p = 0.044). Median overall survival was not different over time (9.2 versus 12.5 months; p = 0.937). Irresectability (p = 0.032), patients' refusal (p = 0.012), and poor general condition (p = 0.002) were more frequent as reasons for cancelation in squamous cell carcinoma patients. Median overall survival was, respectively, 12.5 and 9.9 months for adenocarcinoma and squamous cell carcinoma patients (p = 0.441). The majority of patients refusing surgery had a clinical complete response (73.3%). They had a median overall survival of 33.2 months.

Conclusions: One in six patients starting neoadjuvant treatment for locally advanced esophageal cancer never made it to esophagectomy, more than half of them for oncological reasons, but also 1.3% because of death during treatment. Over time, irresectability as reason decreased. As a result, the relative weight of medical inoperability increased, indicating the importance of upfront testing of medical operability. Cancelation of surgery was significantly more common in patients with a squamous cell carcinoma, and this histology seems to represent a more complex oncological and functional entity. Refusal of esophagectomy based on clinical complete response showed a significant survival benefit compared to those who did not undergo esophagectomy because of other reasons.
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http://dx.doi.org/10.1186/s12957-019-1630-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537364PMC
May 2019

Analysis of Morbidity and Outcomes Associated With Use of Subdural Grids vs Stereoelectroencephalography in Patients With Intractable Epilepsy.

JAMA Neurol 2019 06;76(6):672-681

Department of Neurology, McGovern Medical School, University of Texas Health, Houston.

Importance: A major change has occurred in the evaluation of epilepsy with the availability of robotic stereoelectroencephalography (SEEG) for seizure localization. However, the comparative morbidity and outcomes of this minimally invasive procedure relative to traditional subdural electrode (SDE) implantation are unknown.

Objective: To perform a comparative analysis of the relative efficacy, procedural morbidity, and epilepsy outcomes consequent to SEEG and SDE in similar patient populations and performed by a single surgeon at 1 center.

Design, Setting And Participants: Overall, 239 patients with medically intractable epilepsy underwent 260 consecutive intracranial electroencephalographic procedures to localize their epilepsy. Procedures were performed from November 1, 2004, through June 30, 2017, and data were analyzed in June 2017 and August 2018.

Interventions: Implantation of SDE using standard techniques vs SEEG using a stereotactic robot, followed by resection or laser ablation of the seizure focus.

Main Outcomes And Measures: Length of surgical procedure, surgical complications, opiate use, and seizure outcomes using the Engel Epilepsy Surgery Outcome Scale.

Results: Of the 260 cases included in the study (54.6% female; mean [SD] age at evaluation, 30.3 [13.1] years), the SEEG (n = 121) and SDE (n = 139) groups were similar in age (mean [SD], 30.1 [12.2] vs 30.6 [13.8] years), sex (47.1% vs 43.9% male), numbers of failed anticonvulsants (mean [SD], 5.7 [2.5] vs 5.6 [2.5]), and duration of epilepsy (mean [SD], 16.4 [12.0] vs17.2 [12.1] years). A much greater proportion of SDE vs SEEG cases were lesional (99 [71.2%] vs 53 [43.8%]; P < .001). Seven symptomatic hemorrhagic sequelae (1 with permanent neurological deficit) and 3 infections occurred in the SDE cohort with no clinically relevant complications in the SEEG cohort, a marked difference in complication rates (P = .003). A greater proportion of SDE cases resulted in resection or ablation compared with SEEG cases (127 [91.4%] vs 90 [74.4%]; P < .001). Favorable epilepsy outcomes (Engel class I [free of disabling seizures] or II [rare disabling seizures]) were observed in 57 of 75 SEEG cases (76.0%) and 59 of 108 SDE cases (54.6%; P = .003) amongst patients undergoing resection or ablation, at 1 year. An analysis of only nonlesional cases revealed good outcomes in 27 of 39 cases (69.2%) vs 9 of 26 cases (34.6%) at 12 months in SEEG and SDE cohorts, respectively (P = .006). When considering all patients undergoing evaluation, not just those undergoing definitive procedures, favorable outcomes (Engel class I or II) for SEEG compared with SDE were similar (57 of 121 [47.1%] vs 59 of 139 [42.4%] at 1 year; P = .45).

Conclusions And Relevance: This direct comparison of large matched cohorts undergoing SEEG and SDE implantation reveals distinctly better procedural morbidity favoring SEEG. These modalities intrinsically evaluate somewhat different populations, with SEEG being more versatile and applicable to a range of scenarios, including nonlesional and bilateral cases, than SDE. The significantly favorable adverse effect profile of SEEG should factor into decision making when patients with pharmacoresistant epilepsy are considered for intracranial evaluations.
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http://dx.doi.org/10.1001/jamaneurol.2019.0098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563575PMC
June 2019

Disrupting the CD95-PLCγ1 interaction prevents Th17-driven inflammation.

Nat Chem Biol 2018 12 14;14(12):1079-1089. Epub 2018 Nov 14.

CLCC Eugène Marquis, Equipe Ligue Contre Le Cancer, Rennes, France.

CD95L is a transmembrane ligand (m-CD95L) that is cleaved by metalloproteases to release a soluble ligand (s-CD95L). Unlike m-CD95L, interaction between s-CD95L and CD95 fails to recruit caspase-8 and FADD to trigger apoptosis and instead induces a Ca response via docking of PLCγ1 to the calcium-inducing domain (CID) within CD95. This signaling pathway induces accumulation of inflammatory Th17 cells in damaged organs of lupus patients, thereby aggravating disease pathology. A large-scale screen revealed that the HIV protease inhibitor ritonavir is a potent disruptor of the CD95-PLCγ1 interaction. A structure-activity relationship approach highlighted that ritonavir is a peptidomimetic that shares structural characteristics with CID with respect to docking to PLCγ1. Thus, we synthesized CID peptidomimetics abrogating both the CD95-driven Ca response and transmigration of Th17 cells. Injection of ritonavir and the CID peptidomimetic into lupus mice alleviated clinical symptoms, opening a new avenue for the generation of drugs for lupus patients.
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http://dx.doi.org/10.1038/s41589-018-0162-9DOI Listing
December 2018

Biogenesis, Stabilization, and Transport of microRNAs in Kidney Health and Disease.

Noncoding RNA 2018 Nov 3;4(4). Epub 2018 Nov 3.

Wales Kidney Research Unit, Division of Infection and Immunity, School of Medicine, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF14 4XN, UK.

The kidneys play key roles in the maintenance of homeostasis, including fluid balance, blood filtration, erythropoiesis and hormone production. Disease-driven perturbation of renal function therefore has profound pathological effects, and chronic kidney disease is a leading cause of morbidity and mortality worldwide. Successive annual increases in global chronic kidney disease patient numbers in part reflect upward trends for predisposing factors, including diabetes, obesity, hypertension, cardiovascular disease and population age. Each kidney typically possesses more than one million functional units called nephrons, and each nephron is divided into several discrete domains with distinct cellular and functional characteristics. A number of recent analyses have suggested that signaling between these nephron regions may be mediated by microRNAs. For this to be the case, several conditions must be fulfilled: (i) microRNAs must be released by upstream cells into the ultrafiltrate; (ii) these microRNAs must be packaged protectively to reach downstream cells intact; (iii) these packaged microRNAs must be taken up by downstream recipient cells without functional inhibition. This review will examine the evidence for each of these hypotheses and discuss the possibility that this signaling process might mediate pathological effects.
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http://dx.doi.org/10.3390/ncrna4040030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315559PMC
November 2018
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