DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2–5. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

Heparanase is the only known mammalian endoglycosidase capable of degrading heparan sulfate glycosaminoglycan, both in extracellular space and within the cells. It is tightly implicated in cancer progression and over the past few decades significant progress has been made in elucidating the multiple functions of heparanase in malignant tumor development, neovascularization and aggressive behavior. Notably, current data show that in addition to its well characterized role in cancer, heparanase activity may represent an important determinant in the pathogenesis of several inflammatory disorders, such as inflammatory lung injury, rheumatoid arthritis and chronic colitis. Nevertheless, the precise mode of heparanase action in inflammatory reactions remains largely unclear and recent observations suggest that heparanase can either facilitate or limit inflammatory responses, when tissue/cell -specific contextual cues may dictate an outcome of heparanase action in inflammation. In this review the involvement of heparanase in modulation of inflammatory reactions is discussed through a few illustrative examples, including neuroinflammation, sepsis-associated lung injury and inflammatory bowel disease. We also discuss possible action of the enzyme in coupling inflammation and tumorigenesis in the setting of inflammation-triggered cancer.

Wound healing plays a major role in the development of acquired subglottic stenosis. Pharmacologic treatment of subglottic stenosis must address both physiologic and pathologic healing processes. The relevant Pubmed and Ovid databases from 1960 to 2007 were systematically searched. Several modulating agents have been tested. Most of them were poorly investigated. Three modalities were thoroughly studied-steroids and antibiotics, mitomycin, and antireflux medications. However, there are conflicting data regarding their role in preventing and treating subglottic stenosis. Current data support to some extent the textbook suggestions of antibiotics, steroids, and antireflux treatment. As no other treatment options exist, we recommend using these modalities for pharmacologic modulation of subglottic stenosis. Mitomycin should still be considered as an unproven treatment; its use may be considered as an adjunct. V

Gonadal hormones may affect homeostatic mechanisms regulating the cardiovascular system. We investigated this relationship at five different crucial hormonal time points along the menstrual cycle. Eight eumenorrheic healthy subjects underwent a battery of autonomic tests, hemodynamics, and volume-regulatory hormone measurements. Fluid-regulatory hormones, plasma renin activity, and aldosterone increased along the luteal phase (P = 0.003 and 0.02, respectively), whereas rest supine-corrected hematocrit declined in the course of the menstrual cycle (P = 0.001). Plasma norepinephrine decreased from 1.4 +/- 0.2 to 0.95 +/- 0.1 nmol/liter (P < 0.02) [early follicular (EF) to late follicular]. Thereafter, concentrations gradually returned to EF levels. Lf to Hf domain ratio (spectral analysis of electrocardiogram) showed a difference from that of norepinephrine. The cardiovagal baroreflex sensitivity increased significantly along the luteal phase (P = 0.04). The dose of isoproterenol required to increase heart rate (HR) 15 beats per minute was 0.19 +/- 0.04 microg during the EF time point, and it increased to 0.39 +/- 0.06 microg during the late luteal time point (P = 0.05). However, blood pressure, HR, and their responses to orthostatic stress remained unchanged. Fluctuations in the ovarian hormones along the menstrual cycle are associated with unchanged blood pressure and HR, despite the significant variations in the different homeostatic mechanisms regulating the cardiovascular system.

Aging, independently from the hormonal status, is a major risk factor for cardiovascular morbidity in healthy women. Therefore, we studied the effect of healthy aging on the cardiovascular homeostatic mechanisms in premenopausal and postmenopausal women with similar estrogen levels. Twelve healthy postmenopausal women, confirmed by follicular-stimulating hormone (FSH) and luteal hormone (LH) levels, were compared with 14 normally menstruating women during the early follicular phase (young-EF), to avoid as much as possible the effects of estrogen. Systolic BP was 108 +/- 1.5 vs. 123 +/- 2.5 (P < 0.001), supine norepinephrine was 260 +/- 30 vs. 216 +/- 45 and upright 640 +/- 100 vs. 395 +/- 50 pg/ml (P = 0.05) in young-EF vs. postmenopausal, respectively. Plasma renin activity and aldosterone remained unchanged. Vagal cardiac tone indices decreased significantly with aging (young-EF vs. postmenopausal): high-frequency (HF) band, root mean square successive differences (rMSSD) and proportion of R-R intervals >50 ms (PNN50%) were 620 +/- 140 vs. 270 +/- 70 (P = 0.04), 53 +/- 7 vs. 30 +/- 3 (P = 0.02), and 23 +/- 5 vs. 10 +/- 3 (P = 0.04), respectively. LF to HF ratio was 0.85 +/- 0.17 in young-EF and became 1.5 +/- 0.22 in postmenopausal (P = 0.03). Both arms of the baroreflex, +BRS (29 +/- 5 vs. 13.5 +/- 2.5, P = 0.01) and -BRS (26 +/- 4 vs. 15 +/- 1.5, P = 0.02) decreased with aging. Cardiovascular alpha(1)-adrenoreceptor responsiveness significantly increased and beta-decreased in postmenopausal compared with young EF (P < 0.001, both). The corrected QT intervals (QTc) were similar, whereas corrected JT intervals (JTc) and JTc to QTc ratio were prolonged in the postmenopausal group. We conclude that in young women, parasympathetic control is the main regulator of the cardiovascular system and in postmenopausal women, sympathetic tone dominates. The transition from parasympathetic to sympathetic control may contribute to the increased cardiovascular morbidity with aging.

Low total lymph node ratio is associated with improved outcomes in node-positive head and neck cutaneous SCC. © 2017 Wiley Periodicals, Inc. Head Neck 39: 772-778, 2017.

All age groups had similar clinical presentations and outcomes. Ultrasound is a reliable and appropriate imaging modality for most patients. Surgery must effectively incorporate the tract and cyst to allow low recurrence rates (<2%). Clinically diagnosed thyroglossal tract remnant may, in fact, be other pathologies in 10 percent of cases. Nevertheless, our recommendation is a Sistrunk procedure for all midline neck lesions suspected to be a thyroglossal tract remnant.

Objectives Extent of parotidectomy and neck dissection for metastatic cutaneous squamous cell carcinoma (cSCC) to the parotid is debated. We describe our experience, analyzing outcomes (overall survival and regional recurrence) associated with surgical extent and adjuvant treatment. Study Design A retrospective cohort study of parotidectomy with or without neck dissection for metastatic cSCC. Setting A tertiary referral cancer center in Australia. Subjects and Methods The study group consisted of patients with metastatic cSCC involving the parotid gland who underwent a curative-intent parotidectomy (superficial or total), with or without neck dissection, between 2003 and 2014. Demographic and clinical data, treatment modalities, and outcome parameters were collected from the electronic institutional database. Results Of 78 patients, 65 underwent superficial parotidectomy. Median follow-up was 6.5 years. Sixty-four patients (82%) patients received adjuvant radiotherapy. Cervical lymph nodes were involved in 6 (24%) elective neck dissections. Involved preauricular, facial, external jugular, and occipital nodes occurred in 36.9%. Adjuvant radiotherapy was associated with improved 5-year survival-50% (95% CI, 36%-69%) versus 20% (95% CI, 6%-70%)-and improved 2-year regional control: 89% (95% CI, 67%-100%) versus 40% (95% CI, 14%-100%). The ipsilateral parotid bed recurrence rate was 3.7% for those who received adjuvant radiotherapy and 27% for those who did not receive radiotherapy. Conclusion This study supports surgery plus adjuvant radiotherapy as a standard of care for metastatic cSCC. The low incidence of parotid bed recurrence with this approach suggests that routine elective deep lobe resection may not be required.