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"Fishbein, Michael"
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In vivo imaging of mitochondrial membrane potential in non-small-cell lung cancer
Mitochondria are essential regulators of cellular energy and metabolism, and have a crucial role in sustaining the growth and survival of cancer cells. A central function of mitochondria is the synthesis of ATP by oxidative phosphorylation, known as mitochondrial bioenergetics. Mitochondria maintain oxidative phosphorylation by creating a membrane potential gradient that is generated by the electron transport chain to drive the synthesis of ATP
1
. Mitochondria are essential for tumour initiation and maintaining tumour cell growth in cell culture and xenografts
2
,
3
. However, our understanding of oxidative mitochondrial metabolism in cancer is limited because most studies have been performed in vitro in cell culture models. This highlights a need for in vivo studies to better understand how oxidative metabolism supports tumour growth. Here we measure mitochondrial membrane potential in non-small-cell lung cancer in vivo using a voltage-sensitive, positron emission tomography (PET) radiotracer known as 4-[
18
F]fluorobenzyl-triphenylphosphonium (
18
F-BnTP)
4
. By using PET imaging of
18
F-BnTP, we profile mitochondrial membrane potential in autochthonous mouse models of lung cancer, and find distinct functional mitochondrial heterogeneity within subtypes of lung tumours. The use of
18
F-BnTP PET imaging enabled us to functionally profile mitochondrial membrane potential in live tumours.
A positron emission tomography imaging tracer is developed to image mitochondrial function in vivo, and application of this tracer to a mouse model of lung cancer identifies distinct functional mitochondrial heterogeneity between tumour cells.
Journal Article
Sympathetic innervation of the supraclavicular brown adipose tissue: A detailed anatomical study
The supraclavicular fossa is the dominant location for human brown adipose tissue (BAT). Activation of BAT promotes non-shivering thermogenesis by utilization of glucose and free fatty acids and has been the focus of pharmacological and non-pharmacological approaches for modulation in order to improve body weight and glucose homeostasis. Sympathetic neural control of supraclavicular BAT has received much attention, but its innervation has not been extensively investigated in humans.
Dissection of the cervical region in human cadavers was performed to find the distribution of sympathetic nerve branches to supraclavicular fat pad. Furthermore, proximal segments of the 4th cervical nerve were evaluated histologically to assess its sympathetic components.
Nerve branches terminating in supraclavicular fat pad were identified in all dissections, including those from the 3rd and 4th cervical nerves and from the cervical sympathetic plexus. Histology of the proximal segments of the 4th cervical nerves confirmed tyrosine hydroxylase positive thin nerve fibers in all fascicles with either a scattered or clustered distribution pattern. The scattered pattern was more predominant than the clustered pattern (80% vs. 20%) across cadavers. These sympathetic nerve fibers occupied only 2.48% of the nerve cross sectional area on average.
Human sympathetic nerves use multiple pathways to innervate the supraclavicular fat pad. The present finding serves as a framework for future clinical approaches to activate human BAT in the supraclavicular region.
Journal Article
Cardiac Dysfunction in the BACHD Mouse Model of Huntington’s Disease
While Huntington's disease (HD) is classified as a neurological disorder, HD patients exhibit a high incidence of cardiovascular events leading to heart failure and death. In this study, we sought to better understand the cardiovascular phenotype of HD using the BACHD mouse model. The age-related decline in cardiovascular function was assessed by echocardiograms, electrocardiograms, histological and microarray analysis. We found that structural and functional differences between WT and BACHD hearts start at 3 months of age and continue throughout life. The aged BACHD mice develop cardiac fibrosis and ultimately apoptosis. The BACHD mice exhibited adaptive physiological changes to chronic isoproterenol treatment; however, the medication exacerbated fibrotic lesions in the heart. Gene expression analysis indicated a strong tilt toward apoptosis in the young mutant heart as well as changes in genes involved in cellular metabolism and proliferation. With age, the number of genes with altered expression increased with the large changes occurring in the cardiovascular disease, cellular metabolism, and cellular transport clusters. The BACHD model of HD exhibits a number of changes in cardiovascular function that start early in the disease progress and may provide an explanation for the higher cardiovascular risk in HD.
Journal Article
Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis
Dysregulation of Fractalkine (CX3CL1) and its receptor CX3CR1 has been linked to the pathobiology of chronic inflammatory conditions. We explored CX3CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial.
We collected lung tissue at the time of lung transplantation at UCLA from SSc-ILD patients (n = 12) and healthy donors (n = 12); and serum samples from the prospective Oslo University Hospital SSc cohort (n = 292) and healthy donors (n = 100). CX3CL1 was measured by ELISA. Cellular sources of CX3CL1/CX3CR1 in lung tissues were determined by immunohistochemistry and immunofluorescence. ILD progression and new onset PH endpoints were analysed.
CX3CL1 concentrations were increased in SSc in lung tissue as well as in sera. In the UCLA cohort, CX3CL1 was highly correlated with DLCO. In the SSc-ILD lungs, CX3CL1 was identified in reactive type II pneumocytes and airway epithelial cells. CX3CR1 stained infiltrating interstitial mononuclear cells, especially plasma cells. In the Oslo cohort, CX3CL1 correlated with anti-Topoisomerase-I-antibody and lung fibrosis. CX3CL1 was associated with ILD progression in multivariable regression analysis but not PH.
CX3CL1 is associated with progressive SSc-ILD but not SSc-PH. The CX3CR1/CX3CL1-biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD.
Journal Article
The prognostic importance of CXCR3 chemokine during organizing pneumonia on the risk of chronic lung allograft dysfunction after lung transplantation
Since the pathogenesis of chronic lung allograft dysfunction (CLAD) remains poorly defined with no known effective therapies, the identification and study of key events which increase CLAD risk is a critical step towards improving outcomes. We hypothesized that bronchoalveolar lavage fluid (BALF) CXCR3 ligand concentrations would be augmented during organizing pneumonia (OP) and that episodes of OP with marked chemokine elevations would be associated with significantly higher CLAD risk.
All transbronchial biopsies (TBBX) from patients who received lung transplantation between 2000 to 2010 were reviewed. BALF concentrations of the CXCR3 ligands (CXCL9, CXCL10 and CXCL11) were compared between episodes of OP and \"healthy\" biopsies using linear mixed-effects models. The association between CXCR3 ligand concentrations during OP and CLAD risk was evaluated using proportional hazards models with time-dependent covariates.
There were 1894 bronchoscopies with TBBX evaluated from 441 lung transplant recipients with 169 (9%) episodes of OP and 907 (49%) non-OP histopathologic injuries. 62 (37%) episodes of OP were observed during routine surveillance bronchoscopy. Eight hundred thirty-eight (44%) TBBXs had no histopathology and were classified as \"healthy\" biopsies. There were marked elevations in BALF CXCR3 ligand concentrations during OP compared with \"healthy\" biopsies. In multivariable models adjusted for other injury patterns, OP did not significantly increase the risk of CLAD when BAL CXCR3 chemokine concentrations were not taken into account. However, OP with elevated CXCR3 ligands markedly increased CLAD risk in a dose-response manner. An episode of OP with CXCR3 concentrations greater than the 25th, 50th and 75th percentiles had HRs for CLAD of 1.5 (95% CI 1.0-2.3), 1.9 (95% CI 1.2-2.8) and 2.2 (95% CI 1.4-3.4), respectively.
This study identifies OP, a relatively uncommon histopathologic finding after lung transplantation, as a major risk factor for CLAD development when considered in the context of increased allograft expression of interferon-γ inducible ELR- CXC chemokines. We further demonstrate for the first time, the prognostic importance of BALF CXCR3 ligand concentrations during OP on subsequent CLAD risk.
Journal Article
Arteriosclerosis: Rethinking the Current Classification
Context.—Arteriosclerosis is the vascular disease that is the leading cause of mortality in industrialized countries. Currently, there are 3 lesions within the broader category of arteriosclerosis: atherosclerosis, Mönckeberg medial calcific sclerosis, and arteriolosclerosis.
Objective.—In this review, we discuss the history of the terminology and current classification of arteriosclerosis and problems with the current classification. We also discuss recently described new arterial lesions that are not in the current classification.
Data Sources.—In spite of the prevalence and importance of arteriosclerotic vascular disease, and the widespread use of the current terminology, there are major problems with the current classification: (1) the current classification has an inconsistent naming convention, (2) the classification fails to use terms that accurately describe the lesions, and (3) important arterial lesions are absent from the classification. In addition, although the terms arteriosclerosis and atherosclerosis describe different lesions, these terms are often used interchangeably.
Conclusion.—Consideration should be given for a new more inclusive and accurate classification of “arteriosclerotic” lesions that more accurately reflects the pathology of these important vascular lesions.
Journal Article
Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms
Cardiac dysfunction is a prominent cause of mortality in myotonic dystrophy I (DM1), a disease where expanded CUG repeats bind and disable the muscleblind-like family of splice regulators. Deletion of muscleblind-like 1 (
Mbnl1
ΔE2/ΔE2
) in 129 sv mice results in QRS, QTc widening, bundle block and STc narrowing at 2–4 months of age. With time, cardiac function deteriorates further and at 6 months, decreased R wave amplitudes, sinus node dysfunction, cardiac hypertrophy, interstitial fibrosis, multi-focal myocardial fiber death and calcification manifest. Sudden death, where no end point illness is overt, is observed at a median age of 6.5 and 4.8 months in ~67% and ~86% of male and female
Mbnl1
ΔE2/ΔE2
mice, respectively. Mbnl1 depletion results in the persistence of embryonic splice isoforms in a network of cardiac RNAs, some of which have been previously implicated in DM1, regulating sodium and calcium currents,
Scn5a
,
Junctin
,
Junctate
,
Atp2a1
,
Atp11a
,
Cacna1s
,
Ryr2
, intra and inter cellular transport,
Clta
,
Stx2
,
Tjp1
, cell survival,
Capn3
,
Sirt2
,
Csda
, sarcomere and cytoskeleton organization and function,
Trim55
,
Mapt
,
Pdlim3
,
Pdlim5
,
Sorbs1
,
Sorbs2
,
Fhod1
,
Spag9
and structural components of the sarcomere,
Myom1
,
Tnnt2
,
Zasp
. Thus this study supports a key role for Mbnl1 loss in the initiation of DM1 cardiac disease.
Journal Article