NK cell imaging by in vitro and in vivo labelling approaches.

Natural killer (NK) cells are a particular lymphocyte subset with a documented cytotoxic activity against cancer cells. Evidence of NK antitumoral effect led researchers to focus on the development of immunotherapies aimed at augmenting NK recruitment and infiltration into tumor and their anti-cancer functions. Studies in animal models proved that the right combination of drugs, cytokines, chemokines and other factors might be used to enhance or suppress tumor targeting by NK cells. Therefore, it would be necessary to have a tool to non-invasively monitor the efficacy of such novel therapies. Available imaging techniques comprise magnetic resonance, optical and nuclear medicine imaging with a pool of compounds that ranges from radiolabelled nanoparticles and radiopharmaceuticals to fluorescent probes. Each tracer and technique has its own pros and cons, but till now, no one emerged as superior among the others.

Gonadotropin responses to estrogen-positive and -negative feedback are identical in African-American and Caucasian women.

CONTEXT: Gonadotropin levels are similar in African-American women (AAW) and Caucasian women (CW), despite higher preovulatory estradiol (E2) levels in AAW, suggesting that AAW may be less sensitive to E2 feedback than CW. OBJECTIVE: The aim of the study was to determine whether responsivity to estrogen feedback differs in AAW and CW. DESIGN AND SETTING: Subjects were studied in the early follicular phase using a 5-d, graded E2 and progesterone infusion. SUBJECTS: Healthy, normal-cycling AAW (n = 10) and CW (n = 13) aged 23-30 yr participated in the study. MAIN OUTCOME MEASURES: Blood samples were collected every 4 h and assayed for LH, FSH, E2, and progesterone. RESULTS: There was no difference in E2-negative feedback on LH (nadir, 3.8 ± 0.4 vs. 5.4 ± 0.9 IU/liter; time of nadir, 33.2 ± 3.3 vs. 32.3 ± 2.7 h) or FSH (nadir, 3.1 ± 0.4 vs. 3.1 ± 0.3 IU/liter; time of nadir, 48.8 ± 2.7 vs. 50.5 ± 3.1 h) in AAW compared to CW. The two groups also demonstrated similar positive feedback responses of E2 on LH (peak, 80.3 ± 13.3 vs. 73.1 ± 11.6 IU/liter; time of peak, 80.4 ± 4.3 vs. 86.5 ± 3.1 h) and FSH (peak, 13.4 ± 1.4 vs. 10.2 ± 1.0 IU/liter; time of peak, 82.2 ± 4.0 vs. 97.2 ± 4.9 h). CONCLUSIONS: LH and FSH feedback responses to a controlled steroid infusion do not differ between AAW and CW, indicating that AAW do not have diminished hypothalamic-pituitary responsivity to E2. These studies support the concept of a threshold effect of E2 in generating LH-positive feedback, suggest pituitary insensitivity to differences in E2 of the magnitude observed in prior studies, and account for similarities in gonadotropins despite E2 differences in AAW compared with CW.

Differential effects of aging on estrogen negative and positive feedback.

Recent studies have demonstrated an age-related decline in gonadotropins and a decrease in pituitary responsiveness to GnRH, indicating that aging influences the neuroendocrine components of the female reproductive axis independently of changes in ovarian function. To determine whether aging might also affect the luteinizing hormone (LH) negative and positive feedback responses to gonadal steroids, we administered a controlled, graded sex steroid infusion to 11 younger (45-56 yr) and nine older (70-80 yr) postmenopausal women (PMW) in whom endogenous ovarian steroids and peptides are uniformly low. The doses of estradiol (E(2)) and progesterone (P) were chosen to mimic levels across the normal follicular phase and have been shown previously to induce negative followed by positive feedback on LH. Similar E(2) and P levels were achieved in younger and older PMW (P = 0.4 and 0.3, respectively) and produced a biphasic LH response in all subjects. The early decline in LH to 53% of baseline was not different in older vs. younger PMW. However, the positive feedback effect was attenuated in older compared with younger PMW (peak LH 144.4 ± 19.5 vs. 226.8 ± 22.3 IU/l, respectively, P = 0.01). In conclusion, these studies in PMW demonstrate preservation of short-term steroid negative and positive feedback in response to exogenous E(2) and P with aging. Attenuation of positive feedback in older compared with younger PMW is consistent with previous reports of declining GnRH responsiveness with aging.

Estrogen negative feedback on gonadotropin secretion: evidence for a direct pituitary effect in women.

CONTEXT: Studies in humans and animals indicate that estrogen negative feedback occurs at the level of the hypothalamus, but it is unclear whether estrogen also exerts an inhibitory effect directly at the pituitary. OBJECTIVES: The aim of the study was to determine whether estrogen has a direct negative feedback effect at the pituitary and whether this varies with aging. DESIGN AND SETTING: A GnRH antagonist and graded doses of GnRH were used to isolate pituitary responsiveness before and after estrogen administration in Clinical Research Center studies at an academic medical center. SUBJECTS: Subjects were healthy postmenopausal women aged 48-56 yr (n = 8) or 70-75 yr (n= 8). INTERVENTIONS: A suppressive dose of the NAL-GLU GnRH antagonist was administered, followed by graded doses of GnRH before and after 1 month of estrogen administration. RESULTS: LH and FSH responses to GnRH decreased after estrogen administration (P = 0.01 and P = 0.0001, respectively). The ratio of FSH to LH amplitudes decreased in response to estrogen (P = 0.04) indicating a greater sensitivity of FSH than LH to inhibition by estrogen. The inhibitory effect of estrogen on FSH was attenuated with aging (P = 0.02), but was maintained for LH (P = 0.4). CONCLUSIONS: Studies that control for endogenous GnRH and estradiol demonstrate a direct pituitary site of estrogen negative feedback on LH and FSH responsiveness to GnRH in women. The effect of estrogen on FSH responsiveness is greater than on LH and is attenuated with aging. These studies indicate that estrogen negative feedback occurs directly at the pituitary and contributes to the differential regulation of FSH and LH secretion.