Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension.

Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions.

Vascular endothelial cell specification in health and disease.

There are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract.

Extra-Nuclear Functions of the Transcription Factor Grainyhead-Like 3 in the Endothelium-Interaction with Endothelial Nitric Oxide Synthase.

We previously demonstrated that the transcription factor Grainyhead-like 3 (GRHL3) has essential functions in endothelial cells by inhibiting apoptosis and promoting migration as well as activation of endothelial nitric oxide synthase (eNOS). We now show that a large portion of the protein is localized to myo-endothelial projections of murine arteries suggesting extra-nuclear functions. Therefore, we generated various deletion mutants to identify the nuclear localization signal (NLS) of GRHL3 and assessed potential extra-nuclear functions.

Local Peroxynitrite Impairs Endothelial Transient Receptor Potential Vanilloid 4 Channels and Elevates Blood Pressure in Obesity.

Background: Impaired endothelium-dependent vasodilation is a hallmark of obesity-induced hypertension. The recognition that Ca signaling in endothelial cells promotes vasodilation has led to the hypothesis that endothelial Ca signaling is compromised during obesity, but the underlying abnormality is unknown. In this regard, transient receptor potential vanilloid 4 (TRPV4) ion channels are a major Ca influx pathway in endothelial cells, and regulatory protein AKAP150 (A-kinase anchoring protein 150) enhances the activity of TRPV4 channels.

TRPV4 (Transient Receptor Potential Vanilloid 4) Channel-Dependent Negative Feedback Mechanism Regulates G Protein-Coupled Receptor-Induced Vasoconstriction.

Objective: Several physiological stimuli activate smooth muscle cell (SMC) GPCRs (G protein-coupled receptors) to cause vasoconstriction. As a protective mechanism against excessive vasoconstriction, SMC GPCR stimulation invokes endothelial cell vasodilatory signaling. Whether Ca influx in endothelial cells contributes to the regulation of GPCR-induced vasoconstriction remains unknown.

Nitric Oxide-Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries.

Background: Recent studies demonstrate that spatially restricted, local Ca signals are key regulators of endothelium-dependent vasodilation in systemic circulation. There are drastic functional differences between pulmonary arteries (PAs) and systemic arteries, but the local Ca signals that control endothelium-dependent vasodilation of PAs are not known. Localized, unitary Ca influx events through transient receptor potential vanilloid 4 (TRPV4) channels, termed TRPV4 sparklets, regulate endothelium-dependent vasodilation in resistance-sized mesenteric arteries via activation of Ca-dependent K channels.

Modulating Vascular Hemodynamics With an Alpha Globin Mimetic Peptide (HbαX).

The ability of hemoglobin to scavenge the potent vasodilator nitric oxide (NO) in the blood has been well established as a mechanism of vascular tone homeostasis. In endothelial cells, the alpha chain of hemoglobin (hereafter, alpha globin) and endothelial NO synthase form a macromolecular complex, providing a sink for NO directly adjacent to the production source. We have developed an alpha globin mimetic peptide (named HbαX) that displaces endogenous alpha globin and increases bioavailable NO for vasodilation.

The role of apolipoprotein A-IV in regulating glucagon-like peptide-1 secretion.

Both glucagon-like peptide-1 (GLP-1) and apolipoprotein A-IV (apoA-IV) are produced from the gut and enhance postprandial insulin secretion. This study investigated whether apoA-IV regulates nutrient-induced GLP-1 secretion and whether apoA-IV knockout causes compensatory GLP-1 release. Using lymph-fistula-mice, we first determined lymphatic GLP-1 secretion by administering apoA-IV before an intraduodenal Ensure infusion.

Patterns of practice in the radiation therapy management of rectal cancer: survey of the Interregional Group Piedmont, Valle d'Aosta and Liguria of the "Associazione Italiana di Radioterapia Oncologica (AIRO)".

Aims And Background: To report the survey about the main aspects on the use of radiotherapy for the treatment of rectal cancer in Piedmont and Liguria.

Methods And Study Design: Sixteen centers (11 from Piedmont and 5 from Liguria) received and answered by email a questionnaire data base about clinical and technical aspects of the treatment of rectal cancer. All data were incorporated in a single data base and analyzed.

[The use of radiotherapy in the prevention of heterotopic ossification in patients with total hip replacement].

In order to prevent heterotopic ossification (HO) after total hip replacement, 21 high risk hips were irradiated pre- and postoperatively to prevent heterotopic bone formation in the St. Paul Department of Radiation Oncology from 1993 to September, 1995. Eighteen hips in 15 patients were eligible for analysis with a minimum follow-up of 3 months.

Intraluminal high dose rate brachytherapy combined with external radiotherapy in the treatment of oesophageal cancer.

Twenty eight patients with previously untreated oesophageal carcinoma without distant metastases were divided into two groups: Group A consisted of 18 pts. treated with conventional external radiotherapy only. Another group of 10 pts.

Concomitant radiation-doxorubicin administration in locally advanced and/or metastatic soft tissue sarcomas: preliminary results.

Doxorubicin was administered by continuous infusion at a dosage of 12 mg/sqm/day for 5 days concomitantly with radiation treatment (150 or 200 cGy/day for trunk or extremity lesions, respectively) for 5 days. The 5-day cycles were repeated every 3 weeks. Seventeen patients, 5 of whom were pretreated, entered the study; all were assessable for toxicity and 15 for response.

[Adenocarcinoma of the distal esophagus treated with external and intracavitary radiotherapy. Description of a clinical case and review of the literature].

The prognosis of esophageal adenocarcinoma is extremely poor. Despite recent improvements in diagnostic and therapeutic techniques, the 5-years survival rate remains below 10%. Management is primarily surgical or radiotherapeutical, although pre- or postoperative radiation or chemotherapy are often employed.

[Multimodal treatment of locally advanced carcinoma of the breast. Experience at the Galliera di Genova Hospital].

All patients with locally advanced breast cancer receiving definitive irradiation (with or without surgery) at the Radiation Oncology Service, Ospedali Galliera, Genova, Italy, from 1969 through 1986, were retrospectively reviewed. Group A consisted of 187 patients, affected with stage III disease, who received radiation therapy after radical surgery. Irradiation of the chest wall and regional lymph node chains was accomplished with divergent tangential beams of Cobalt: the dose was calculated at the mid-plane of the tangential field separation and was 50Gy (2 Gy/day, 5 fractions/week), followed by additional 10-15 Gy boost to the scar.

[Postoperative radiotherapy in the treatment of soft-tissue sarcomas of the limbs: 63 consecutive cases].

Sixty-three patients with soft tissue sarcomas of the limbs received postoperative radiotherapy during the period from 1969 to 1985. The 5 years actuarial survival rate was 77% in 17 patients who underwent wide surgical operations + RT, 59% in 28 patients with marginal surgical excision + RT, 64% in 18 patients who received salvage RT after several recurrences. Locoregional control was higher in the patients with wide surgical operations + RT, while there were no significant differences in the disease free survival from lung metastasis among the three groups of patients.

[Acute non-lymphoblastic leukemia in patients treated for Hodgkin's disease. Analysis of 309 cases].

The analysis of 309 Hodgkin patients treated by radiotherapy alone or in association with chemotherapy, between 1969 and 1979, has shown seven cases of ANLL (acute non lymphoblastic leukemia). The incidence was 2.26% in the overall group and 3.

[Total body irradiation in the preparation of leukemic patients for bone marrow transplantation].

Total body irradiation is today the main conditioning method for patients who have bone marrow transplantation. The most diffuse procedure, as proposed at the Fred Hutchinson Cancer Research Center of Seattle, has been employed in this study. Our clinical material comprises 16 patients; 5 with acute lymphoid leukemia; 5 with acute myeloid leukemia; 4 with chronic myeloid leukemia in accelerated fase; and 2 in blastic crisis.