Glycolytic metabolism of pathogenic T cells enables early detection of GVHD by 13C-MRI.

Graft-versus-host disease (GVHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (AHSCT). Definitive diagnosis of GVHD is invasive, and biopsies of involved tissues pose a high risk of bleeding and infection. T cells are central to GVHD pathogenesis, and our previous studies in a chronic GVHD mouse model showed that alloreactive CD4+ T cells traffic to the target organs ahead of overt symptoms. Because increased glycolysis is an early feature of T-cell activation, we hypothesized that in vivo metabolic imaging of glycolysis would allow noninvasive detection of liver GVHD as activated CD4+ T cells traffic into the organ. Indeed, hyperpolarized 13C-pyruvate magnetic resonance imaging detected high rates of conversion of pyruvate to lactate in the liver ahead of animals becoming symptomatic, but not during subsequent overt chronic GVHD. Concomitantly, CD4+ T effector memory cells, the predominant pathogenic CD4+ T-cell subset, were confirmed to be highly glycolytic by transcriptomic, protein, metabolite, and ex vivo metabolic activity analyses. Preliminary data from single-cell sequencing of circulating T cells in patients undergoing AHSCT also suggested that increased glycolysis may be a feature of incipient acute GVHD. Metabolic imaging is being increasingly used in the clinic and may be useful in the post-AHSCT setting for noninvasive early detection of GVHD.

Toxic erythema of chemotherapy affecting the ears of an infant: A case report.

A 15-month-old boy presented with new onset symmetric erythema of the conchal bowls bilaterally in the setting of treatment with cytarabine. Findings were consistent with a diagnosis of toxic erythema of chemotherapy, an adverse effect of chemotherapy. In this report, we detail this uncommon manifestation in a young child along with a brief literature review of the background, pathophysiology, and treatment strategies of toxic erythema of chemotherapy to increase awareness of this presentation in pediatric populations.

Current Perspectives Among U.S. Dermatologists on Chemoprevention of Nonmelanoma Skin Cancer: A Survey-Based Study.

Introduction: Nonmelanoma skin cancer (NMSC) is the most common malignancy in the US Primary prevention of NMSC with physical photoprotective measures are often not sufficient to impact skin cancer incidence in high-risk individuals. Chemoprevention is the use of agents to prevent, suppress, and reverse carcinogenic progression. Many agents have been investigated, but preclinical and clinical studies are often inconsistent.

Methods: A cross-sectional study was designed to assess current practices, perceptions, and general knowledge of U.S. dermatologists pertaining to chemopreventive strategies. This voluntary online survey was distributed to practicing dermatologists via dermatology society electronic mailing lists. Software from SurveyGizmo.com was used for survey implementation and anonymous data collection. Stata 12.0 statistical analysis software (StataCorp, LP) was used to perform nonparametric Spearman correlation tests.

Results: Approximately half of the 156 responding dermatologists reported being in practice 16 years or more (47.3%) and working in urban communities (48.7%). 59.3% reported "frequently" using topical therapies, while only 13.7% reported frequent use of systemic chemopreventive therapies. Dermatologists practicing in urban settings were more likely to indicate they believe knowledge has increased substantially (P=0.047) as compared to colleagues in other communities. Respondents also reported varying degrees of confidence in selecting appropriate chemopreventive regimens: most feel comfortable determining which agents to use in patients, but 29.1% answered "neutral" or "disagree" when asked if they felt comfortable. More experienced dermatologists were more likely to recommend diet modifications such as increased dietary vitamin D (P=0.014), low fat diet (P=0.022), and tea polyphenols (P=0.04) as methods of chemoprevention.

Discussion: Efforts to identify effective, minimally-toxic chemopreventive agents have long been underway, but conflicting reports in the literature make formulation of validated guidelines challenging. Our study suggests differing perceptions, comfort levels, and practice strategies among U.S. dermatologists. This serves to identify areas of research requiring additional contributions from clinical investigators and reveals a need to broaden understanding of available evidence-based techniques.

J Drugs Dermatol. 2017;16(5):449-452.

Diffuse atrophic papules and plaques, intermittent abdominal pain, paresthesias, and cardiac abnormalities in a 55-year-old woman.

KEY TEACHING POINTS.

Comparing DNA enrichment of proliferating cells following administration of different stable isotopes of heavy water.

Deuterated water (2H2O) is a label commonly used for safe quantitative measurement of deuterium enrichment into DNA of proliferating cells. More recently, it has been used for labeling proteins and other biomolecules. Our in vitro - in vivo research reports important stable isotopic labeling enrichment differences into the DNA nucleosides and their isotopologues (e.g. deoxyadenosine (dA) M + 1, dA M + 2, dA M + 3), as well as tumor cell proliferation effects for various forms of commercially available stable heavy water (2H2O, H218O, and 2H218O). Using an in vitro mouse thymus tumor cell line, we determined that H218O provides superior DNA labeling enrichment quantitation, as measured by GC-positive chemical ionization (PCI)-MS/MS. In addition, at higher but physiologically relevant doses, both 2H218O and 2H2O down modulated mouse thymus tumor cell proliferation, whereas H218O water had no observable effects on cell proliferation. The in vivo labeling studies, where normal mouse bone marrow cells (i.e. high turnover) were evaluated post labeling, demonstrated DNA enrichments concordant with measurements from the in vitro studies. Our research also reports a headspace-GC-NCI-MS method, which rapidly and quantitatively measures stable heavy water levels in total body water.

In vivo kinetics and nonradioactive imaging of rapidly proliferating cells in graft-versus-host disease.

Hematopoietic stem cell transplantation (HSCT) offers a cure for cancers that are refractory to chemotherapy and radiation. Most HSCT recipients develop chronic graft-versus-host disease (cGVHD), a systemic alloimmune attack on host organs. Diagnosis is based on clinical signs and symptoms, as biopsies are risky. T cells are central to the biology of cGVHD. We found that a low Treg/CD4+ T effector memory (Tem) ratio in circulation, lymphoid, and target organs identified early and established mouse cGVHD. Using deuterated water labeling to measure multicompartment in vivo kinetics of these subsets, we show robust Tem and Treg proliferation in lymphoid and target organs, while Tregs undergo apoptosis in target organs. Since deuterium enrichment into DNA serves as a proxy for cell proliferation, we developed a whole-body clinically relevant deuterium MRI approach to nonradioactively detect cGVHD and potentially allow imaging of other diseases characterized by rapidly proliferating cells.

Increased precursor cell proliferation after deep brain stimulation for Parkinson's disease: a human study.

OBJECTIVE: Deep brain stimulation (DBS) has been used for more than a decade to treat Parkinson's disease (PD); however, its mechanism of action remains unknown. Given the close proximity of the electrode trajectory to areas of the brain known as the "germinal niches," we sought to explore the possibility that DBS influences neural stem cell proliferation locally, as well as more distantly. METHODS: We studied the brains of a total of 12 idiopathic Parkinson's disease patients that were treated with DBS (the electrode placement occurred 0.5-6 years before death), and who subsequently died of unrelated illnesses. These were compared to the brains of 10 control individuals without CNS disease, and those of 5 PD patients with no DBS. RESULTS: Immunohistochemical analyses of the subventricular zone (SVZ) of the lateral ventricles, the third ventricle lining, and the tissue surrounding the DBS lead revealed significantly greater numbers of proliferating cells expressing markers of the cell cycle, plasticity, and neural precursor cells in PD-DBS tissue compared with both normal brain tissue and tissue from PD patients not treated with DBS. The level of cell proliferation in the SVZ in PD-DBS brains was 2-6 fold greater than that in normal and untreated PD brains. CONCLUSIONS: Our data suggest that DBS is capable of increasing cellular plasticity in the brain, and we hypothesize that it may have more widespread effects beyond the electrode location. It is unclear whether these effects of DBS have any symptomatic or other beneficial influences on PD.