Research Spotlight

McMillin, M., S. DeMorrow, S. Glaser, J. Venter, K. Kyritsi, T. Zhou, S. Grant, T. Giang, J. F. Greene, Jr., N. Wu, B. Jefferson, F. Meng and G. Alpini (2017). “Melatonin inhibits hypothalamic gonandotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats.” Am J Physiol Gastrointest Liver Physiol: 2017 Jul [Epub ahead of print].

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Melatonin is a hormone produced by the pineal gland with increased circulating levels shown to inhibit biliary hyperplasia and fibrosis during cholestasis. Melatonin also has the capability to suppress the release of hypothalamic gonadotropin releasing hormone (GnRH), a hormone that promotes cholangiocyte proliferation when serum levels are elevated. However, the interplay and contribution of neural melatonin and GnRH to cholangiocyte proliferation and fibrosis in bile duct-ligated (BDL) rats has not been investigated. In order to test this, cranial levels of melatonin were increased by implanting osmotic minipumps that performed an intracerebroventricular (ICV) infusion of melatonin or saline for 7 days starting at the time of BDL. Hypothalamic GnRH mRNA and cholangiocyte secretion of GnRH and melatonin was assessed. Cholangiocyte proliferation and fibrosis was measured. Primary human hepatic stellate cells (HSCs) were treated with cholangiocyte supernatants, GnRH, or the GnRH receptor 1 (GnRHR1) antagonist, cetrorelix acetate and cell proliferation and fibrosis gene expression were assessed. Melatonin infusion reduced hypothalamic GnRH mRNA expression and led to decreased GnRH and increased melatonin secretion from cholangiocytes. Infusion of melatonin was found to reduce hepatic injury, cholangiocyte proliferation and fibrosis during BDL-induced liver injury. HSCs supplemented with BDL cholangiocyte supernatant had increased proliferation and this increase was reversed when HSCs were supplemented with supernatants from melatonin-infused rats. GnRH stimulated fibrosis gene expression in HSCs and this was reversed by cetrorelix acetate co-treatment. Increasing bioavailability of melatonin in the brain may improve outcomes during cholestatic liver disease.

McNeill, N., A. Nasca, A. Reyes, B. Lemoine, B. Cantarel, A. Vanderver, R. Schiffmann and D. Ghezzi (2017). “Functionally pathogenic ears2 variants in vitro may not manifest a phenotype in vivo.” Neurol Genet 3(4): e162.

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OBJECTIVE: To investigate the genetic etiology of a patient diagnosed with leukoencephalopathy, brain calcifications, and cysts (LCC). METHODS: Whole-exome sequencing was performed on a patient with LCC and his unaffected family members. The variants were subject to in silico and in vitro functional testing to determine pathogenicity. RESULTS: Whole-exome sequencing uncovered compound heterozygous mutations in EARS2, c.328G>A (p.G110S), and c.1045G>A (p.E349K). This gene has previously been implicated in the autosomal recessive leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The p.G110S mutation has been found in multiple patients with LTBL. In silico analysis supported pathogenicity in the second variant. In vitro functional testing showed a significant mitochondrial dysfunction demonstrated by an approximately 11% decrease in the oxygen consumption rate and approximately 43% decrease in the maximum respiratory rate in the patient’s skin fibroblasts compared with the control. EARS2 protein levels were reduced to 30% of normal controls in the patient’s fibroblasts. These deficiencies were corrected by the expression of the wild-type EARS2 protein. However, a further unrelated genetic investigation of our patient revealed the presence of biallelic variants in a small nucleolar RNA (SNORD118) responsible for LCC. CONCLUSIONS: Here, we report seemingly pathogenic EARS2 mutations in a single patient with LCC with no biochemical or neuroimaging presentations of LTBL. This patient illustrates that variants with demonstrated impact on protein function should not necessarily be considered clinically relevant.

Lima, B., O. Dur, J. Chuang, T. Chamogeorgakis, D. J. Farrar, K. S. Sundareswaran, J. Felius, S. M. Joseph, S. A. Hall and G. V. Gonzalez-Stawinski (2017). “Novel cardiac coordinate modeling system for three-dimensional quantification of inflow cannula malposition of heartmate ii lvads.” Asaio j: 1-16.

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Optimal function of left ventricular assist devices (LVADs) depends on proper alignment of the inflow cannula (IC). Quantitative guidelines for IC angulation are lacking because of variation in cardiac geometry and difficulty in analyzing three-dimensional (3D) cannula orientation relative to the left ventricle (LV). Based on contrast-enhanced computed tomography images from five normal and five clinically malpositioned IC cases in patients with HeartMate II LVADs, we developed a method for 3D quantification of IC malpositioning. Using Mimics image software (Materialise, Leuven, Belgium), the native heart, major arteries, and LVAD were segmented to create patient-specific 3D models, allowing LV cavity volume and long-axis length to be measured directly. The deviation of the IC was quantified in a cylindrical coordinate system at the IC insertion point relative to the mitral valve and septum, and IC occlusion was assessed by the distance between cannula inlet and the proximal endocardium. Compared with normal cases, patients with malpositioned pumps had shorter LV length (p = 0.03) and reduced pump pocket depth (p = 0.009). Malpositioned pumps may experience greater obstruction by the nearby myocardium. This quantitative 3D modeling tool may help identify different modes of pump malalignment and migration and may facilitate preoperative planning and minimally invasive approaches via virtual LVAD implantation.

Krop, I., N. Ismaila, F. Andre, R. C. Bast, W. Barlow, D. E. Collyar, M. E. Hammond, N. M. Kuderer, M. C. Liu, R. G. Mennel, C. Van Poznak, A. C. Wolff and V. Stearns (2017). “Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American society of clinical oncology clinical practice guideline focused update.” J Clin Oncol: 2017 Jul [Epub ahead of print].

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Purpose This focused update addresses the use of MammaPrint (Agendia, Irvine, CA) to guide decisions on the use of adjuvant systemic therapy. Methods ASCO uses a signals approach to facilitate guideline updates. For this focused update, the publication of the phase III randomized MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) study to evaluate the MammaPrint assay in 6,693 women with early-stage breast cancer provided a signal. An expert panel reviewed the results of the MINDACT study along with other published literature on the MammaPrint assay to assess for evidence of clinical utility. Recommendations If a patient has hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-negative breast cancer, the MammaPrint assay may be used in those with high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy due to its ability to identify a good-prognosis population with potentially limited chemotherapy benefit. Women in the low clinical risk category did not benefit from chemotherapy regardless of genomic MammaPrint risk group. Therefore, the MammaPrint assay does not have clinical utility in such patients. If a patient has hormone receptor-positive, HER2-negative, node-positive breast cancer, the MammaPrint assay may be used in patients with one to three positive nodes and a high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy. However, such patients should be informed that a benefit from chemotherapy cannot be excluded, particularly in patients with greater than one involved lymph node. The clinician should not use the MammaPrint assay to guide decisions on adjuvant systemic therapy in patients with hormone receptor-positive, HER2-negative, node-positive breast cancer at low clinical risk, nor any patient with HER2-positive or triple-negative breast cancer, because of the lack of definitive data in these populations.

Hayek, A. J., H. D. White, S. Ghamande, C. Spradley and A. C. Arroliga (2017). “Is therapeutic hypothermia for acute respiratory distress syndrome the future?” J Intensive Care Med 32(7): 460-464.

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INTRODUCTION: Severe acute respiratory distress syndrome (ARDS) has a high mortality, and there is limited knowledge about management of severe ARDS refractory to standard therapy. Early evidence suggests that therapeutic hypothermia (TH) could be a viable treatment for acute respiratory failure. We present 2 cases where TH was successfully used to manage refractory ARDS on extracorporeal membrane oxygenation (ECMO) and a review of the literature around TH and acute respiratory failure. RESULTS: We present 2 cases of ARDS secondary to H1N1 influenza and human metapneumovirus. Both patients were treated with the current evidence-based therapy for ARDS. Venovenous ECMO was used in both patients for refractory hypoxemia. Therapeutic hypothermia was applied for 24 hours with improved oxygenation. We did a review of the literature summarizing 38 patients in 10 publications where TH was successfully utilized in the treatment of acute respiratory failure. CONCLUSION: Therapeutic hypothermia may be a viable salvage therapy for ARDS refractory to the current evidence-based therapy but needs further evaluation.