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IntroductionFolate receptor (FR)-expressing macrophages have been shown to accumulate at sites of inflammation, where they promote development of inflammatory symptoms. To target such a macrophage population, we designed and evaluated the biologic activity of EC0746, a novel folic acid conjugate of the highly potent antifolate, aminopterin.MethodsUsing a FR-positive subclone of murine macrophage-derived RAW264.7 cells and rat thioglycollate-elicited macrophages, we studied the effect of EC0746 on dihydrofolate reductase activity, cell proliferation, and cellular response towards bacterial lipopolysaccharide as well as IFNγ activation. The EC0746 anti-inflammatory activity, pharmacokinetics, and toxicity were also evaluated in normal rats or in rats with adjuvant-induced arthritis; that is, a FR-positive macrophage model that closely resembles rheumatoid arthritis in humans.ResultsEC0746 suppresses the proliferation of RAW264.7 cells and prevents the ability of nonproliferating rat macrophages to respond to inflammatory stimuli. In the macrophage-rich rat arthritis model, brief treatment with subcutaneously administered EC0746 is shown to mediate an FR-specific anti-inflammatory response that is more potent than either orally administered methotrexate or subcutaneously delivered etanercept. More importantly, EC0746 therapy is also shown to be ~40-fold less toxic than unmodified aminopterin, with fewer bone marrow and gastrointestinal problems.ConclusionsEC0746 is the first high FR-binding dihydrofolate reductase inhibitor that demonstrates FR-specific anti-inflammatory activities both in vitro and in vivo. Our data reveal that a relatively toxic anti-inflammatory drug, such as aminopterin, can be targeted with folic acid to inflammatory macrophages and thereby relieve inflammatory symptoms with greatly reduced toxicity.

AimsSurgical ventricular reconstruction to remodel, reshape, and reduce ventricular volume is an effective therapy in selected patients with chronic heart failure (HF) of ischaemic aetiology. The BioVentrix Revivent TC System offers efficacy comparable to conventional surgical ventricular reconstruction and is less invasive utilizing micro‐anchor pairs to exclude scarred myocardium on the beating heart. Here, we present 12‐months follow‐up data of an international multicenter study.Methods and resultsPatients were considered eligible for the procedure when they presented with symptomatic HF [New York Heart Association (NYHA) class ≥II], left ventricular (LV) dilatation and dysfunction caused by myocardial infarction, and akinetic and/or dyskinetic transmural scarred myocardium located in the anteroseptal, anterolateral, and/or apical regions. A total of 89 patients were enrolled and 86 patients were successfully treated (97%). At 12 months, a significant improvement in LV ejection fraction (29 ± 8% vs. 34 ± 9%, P < 0.005) and a reduction of LV volumes was observed (LV end‐systolic and end‐diastolic volume index both decreased: 74 ± 28 mL/m2 vs. 54 ± 23 mL/m2, P < 0.001; and 106 ± 33 mL/m2 vs. 80 ± 26 mL/m2, respectively, P < 0.0001). Four patients (4.5%) died in hospital and survival at 12 months was 90.6%. At baseline, 59% of HF patients were in NYHA class III compared with 22% at 12‐month follow‐up. Improvements in quality of life measures (Minnesota Living with Heart Failure Questionnaire 39 vs. 26 points, P < 0.001) and 6‐min walking test distance (363 m vs. 416 m, P = <0.001) were also significant.ConclusionsTreatment with the Revivent TC System in patients with symptomatic HF results in significant and sustained reduction of LV volumes and improvement of LV function, symptoms, and quality of life.

Aim To analyze behaviors, mental perception, satisfaction, and expectations relating to sexuality in France. Methods A total of 1,002 subjects (483 men and 519 women) aged 35 years and over in a representative sample of the French population were surveyed by phone using a dedicated questionnaire in November 2003. Main Outcome Measures Sexual behaviors and mental perception, satisfaction and expectations concerning sexual life. Results Of the population, 80.2% reported having a sexual partner. The mean number of times subjects had sex per week was 1.8 (2.0 in men, 1.6 in women). The decision preceded the act by a few seconds or minutes in 82.7% of subjects. Thinking about sex was “frequent” in 47.1% of subjects, especially for men (60.8%). Regardless of gender, sexuality was more synonymous with pleasure (44.0%) and love (42.1%) than with procreation, children, or motherhood (7.8%). During sexual intercourse, simultaneous orgasms and feelings of closeness were important for the majority of subjects, 35.8% (41.6% of men) and 22.8%, respectively; foreplay, enjoyment, and vaginal penetration were the most important accomplishments for 13.1%. Regardless of gender, 83.0% of subjects expressed relative or full satisfaction with their sex life. However, only 38.7% of subjects (31.6% of men and 45.2% of women) did not wish to change anything, while 17.2% would like to have more time for it. Of the subjects, 63.0% reported a decrease in sexual desire during periods of work-related stress, especially in women (72.3%). The main sexual complaints reported by men were diminution of sexual desire (24.9%), early ejaculation (23.7%), and erectile problems (14.4%). In women, they were diminution of sexual desire (45.7%), orgasm disorders (15.5%), and dyspareunia (15.5%). Conclusions This survey showed that the attitude of subjects, especially men, toward sexuality is changing through years and highlighted the extent of sexual problems in the general population.

Folate receptors (FR) may be of use for targeted delivery of cytotoxic drugs in invasive urothelial carcinoma (iUC), for which improved therapy is needed. FR expression and function in iUC were explored and the antitumor activity and toxicity of a folate-targeted vinblastine conjugate were evaluated in dogs with naturally occurring iUC, an excellent model for human iUC. FR immunohistochemistry was carried out on iUC and normal human and dog bladder tissues together with nuclear scintigraphy in dogs to monitor iUC folate uptake. Dose escalation of a folate-targeted vinblastine compound, EC0905, was conducted in dogs with biopsy-confirmed, FR-positive iUC. FRs were detected by immunohistochemistry (PU17) in most primary iUC and many nodal and lung metastases from dogs, and scintigraphy confirmed folate uptake in both primary and metastatic lesions. The maximum tolerated dose of EC0905 in dogs was 0.25 mg/kg IV weekly, with neutropenia at higher doses. Tumor responses included partial remission (!50% reduction in tumor volume) in five dogs and stable disease (<50% change in tumor volume) in four dogs. Immunoreactivity to PU17 was similar in humans (78% of primary iUC, 80% of nodal metastases). Less immunoreactivity to mab343 (22% of cases) occurred. FR-b was noted in 21% of human iUC cases. Our findings suggest folate-targeted therapy holds considerable promise for treating iUC, where FR-b may be important in addition to FR-a. Cancer Res; 73(2); 875-84. Ó2012 AACR.