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Discovered more than 30 years ago, the angiotensin AT2receptor (AT2R) has evolved from a binding site with unknown function to a firmly established major effector within the protective arm of the renin-angiotensin system (RAS) and a target for new drugs in development. The AT2R represents an endogenous protective mechanism that can be manipulated in the majority of preclinical models to alleviate lung, renal, cardiovascular, metabolic, cutaneous, and neural diseases as well as cancer. This article is a comprehensive review summarizing our current knowledge of the AT2R, from its discovery to its position within the RAS and its overall functions. This is followed by an in-depth look at the characteristics of the AT2R, including its structure, intracellular signaling, homo- and heterodimerization, and expression. AT2R-selective ligands, from endogenous peptides to synthetic peptides and nonpeptide molecules that are used as research tools, are discussed. Finally, we summarize the known physiological roles of the AT2R and its abundant protective effects in multiple experimental disease models and expound on AT2R ligands that are undergoing development for clinical use. The present review highlights the controversial aspects and gaps in our knowledge of this receptor and illuminates future perspectives for AT2R research.Significance StatementThe angiotensin AT2receptor (AT2R) is now regarded as a fully functional and important component of the renin-angiotensin system, with the potential of exerting protective actions in a variety of diseases. This review provides an in-depth view of the AT2R, which has progressed from being an enigma to becoming a therapeutic target.

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I see what's good in people, and make sure that eighty percent of their time is spent doing those things. Geraldine Laybourne--a.k.a. the Velvet Hammer--uses her teaching background and a […]

CHUCK BEASLEY'S CRIMSON FACE looks as if it's going to explode. He's just a few inches from raising the 155-pound weight that hovers over his chest. With one final grunt, […]

Background. Biliary tract obstruction is a rare manifestation of non-Hodgkin's lymphoma (NHL). Because of the small numbers of patients studied, management of this condition has been inconsistent. Most patients have been treated with biliary diversion, and doxorubicin frequently has been withheld from initial therapy. Methods. Seven patients with NHL presenting with malignant biliary tract obstruction were identified at the Massachusetts General Hospital. Relevant clinical characteristics, laboratory values, treatment, and outcome are reported for all patients. Thirty-eight additional patients were identified through a MEDLINE search; and the management and results of the patients reported here are discussed with reference to those patients. Results. Biliary tract obstruction was the presenting symptom in 0.8% of the patients with NHL. Bilirubin values at presentation ranged from 5.0-23.2 mg/dl. One patient had localized pancreatic lymphoma. Four of the seven patients had advanced-stage disease. The tumor was intermediate or high grade in five patients. Four patients underwent placement of a biliary stent or drainage catheter. Six patients received combination chemotherapy without doxorubicin in the initial cycle. Hyperbilirubinemia resolved in all patients within 3 months, regardless of use of a stent. Six patients responded to chemotherapy and one patient had progressive disease. Two of the six responders died, one with relapsed lymphoma. Conclusions. NHL presenting with biliary tract obstruction can be effectively treated with chemotherapy, with or without a procedure for biliary diversion. The use of doxorubicin in the presence of hyperbilirubinemia secondary to biliary tract obstruction remains controversial, and its omission from the initial cycles of chemotherapy for NHL may not influence outcome. Cancer 1995;75: 1669-77.

Done correctly, reviews from subordinates and peers can improve employee performance. Here's how smart managers make the process work Burke Stinson explained things too much. That's what his subordinates wrote […]

You've waded into the thick grass that rings the fourteenth hole at your group's annual tournament. The good news is you've found your ball. But the bad news is that […]

Background: Patients with advanced cancer frequently experience clinically significant anemia, which is often exacerbated by myelosuppressive chemotherapy. Consistent with the anemia of chronic disease, studies have documented serum erythropoietin levels that are inappropriately low for the degree of anemia in cancer patients. Myelosuppressive chemotherapy impairs erythropoiesis, which may not fully recover between treatment cycles. Recombinant human erythropoietin (rHuEPO) has been used safely and effectively to treat anemia in AIDS patients receiving zidovudine (AZT) and in patients with chronic renal failure. Purpose: This study was designed to evaluate the clinical role of rHuEPO in reducing symptomatic anemia in patients with advanced cancer who were receiving myelosuppressive chemotherapy (excluding cisplatin). Methods: We studied 153 anemic cancer patients receiving cyclic combination chemotherapy in a prospective multicenter, double-blind, placebo-controlled trial. The patients were randomly assigned to receive either rHuEPO (150 U/kg) or placebo subcutaneously three times a week for a maximum of 12 weeks or until the hematocrit level increased to 38%-40%. If the hematocrit reached this target level before 12 weeks, the rHuEPO dose could be reduced to maintain the hematocrit at that level for the duration of the study. Response to rHuEPO therapy was assessed by measuring changes in hematocrit level, transfusion requirements, and quality of life. Quality-of-life assessment was based on patients' responses to questionnaires before and after the courses of therapy. Results: The increase in hematocrit in the rhuepo-treated group compared with hematocrit in the placebo-treated group was statistically significant (P = .0001) as measured by percentage point of change from baseline to final evaluation, by an increase in hematocrit level of six percentage points or more unrelated to transfusion, and by a rise in hematocrit level to 38% or more unrelated to transfusion. There was a trend toward the reduction in mean units of blood transfused per patient during months 2 and 3 of therapy combined in rHuEPO-treated patients compared with placebo-treated patients (0.91 U versus 1.65 U; P = .056). In addition, rHuEPO-treated patients experienced a statistically significant improvement in energy level and ability to perform daily activities (P [is less than or equal to] .05). The two treatment groups showed no statistically significant differences in toxic effects except for increased incidence of diaphoresis (P

Cancer of the esophagus occurs in two main histological varieties (tissue types), adenocarcinoma of the esophagus and squamous cell carcinoma. Much uncertainty exists concerning the natural history of these two forms, as well as the optimal treatment, due in part to the tendency of many researchers to group these two forms of cancer together when publishing the results of research. For this reason, a study was conducted on the treatment of only adenocarcinoma of the esophagus. A total of 15 patients were scheduled for surgery and neoadjuvant treatment with 5-fluorouracil and cisplatin. (In contrast with adjuvant therapy, neoadjuvant chemotherapy is actually given prior to surgery to reduce tumor size and permit more effective surgery.) The patients were also treated postoperatively with either more chemotherapy or radiation. Two patients failed to receive surgery; one was found to have metastatic disease prior to surgery and the other died before the operation. Of the remaining patients who underwent surgery, two had unresectable disease and the esophageal cancer was resected in other 11 patients. In 10 cases, large amounts of tumor not killed by the neoadjuvant treatment were observed in the surgical specimens. In one patient, only microscopic cancer was detected in the removed tissue. Five patients remain alive and free of disease. The average (median) survival time was 18.7 months for all 15 original patients. If only the patients who underwent successful surgery are considered, the median survival time was 23.8 months. (Consumer Summary produced by Reliance Medical Information, Inc.)

The incidence of malignant melanoma of the skin is increasing faster than any other human cancer; 27,000 new cases will be diagnosed this year. Luckily, early detection has kept the death rate from increasing as rapidly as the incidence of the disease. However, 30 to 35 percent of melanoma patients will have recurrence, which is often fatal. Over a 15-year period 550 patients were treated for cutaneous (skin) melanoma; 221 of these patients were subsequently treated for either recurrence or metastasis that developed during follow-up. A review of these 231 cases was undertaken to evaluate survival and identify possible prognostic factors. Recurrence occurred between 1 and 218 months after initial surgery. Where possible, metastatic lesions were surgically removed. If the lesion was unable to be removed by surgery, other treatment, such as chemotherapy, immunotherapy, or regional hyperthermic perfusion, was administered. The five-year survival rate after the first tumor recurrence was 36 percent. Patients with soft tissue recurrence had five-year survival rate of 49 percent; those with lymph node recurrence had a 38 percent survival. There were 53 patients whose initial site of recurrence was a major internal organ; six (11 percent) of these patients had long-term survival. However, of the 20 patients with internal organ metastasis who underwent surgical excision with or without other therapy, five (20 percent) survived for at least five years. The factors in influencing prognosis included site of first recurrence, stage of primary disease, and successful elimination of gross disease (surgically or by chemotherapy). (Consumer Summary produced by Reliance Medical Information, Inc.)