This paper presents a no-reference image blur metric that is based on the study of human blur perception for varying contrast values. The metric utilizes a probabilistic model to estimate the ...probability of detecting blur at each edge in the image, and then the information is pooled by computing the cumulative probability of blur detection (CPBD). The performance of the metric is demonstated by comparing it with existing no-reference sharpness/blurriness metrics for various publicly available image databases.
Bispecific antibodies are an important tool for the management and treatment of acute leukemias. As a next step toward clinical translation of engineered plasma cells, we describe approaches for ...secretion of bispecific antibodies by human plasma cells. We show that human plasma cells expressing either fragment crystallizable domain-deficient anti-CD19 × anti-CD3 (blinatumomab) or anti-CD33 × anti-CD3 bispecific antibodies mediate T cell activation and direct T cell killing of B acute lymphoblastic leukemia or acute myeloid leukemia cell lines in vitro. We demonstrate that knockout of the self-expressed antigen, CD19, boosts anti-CD19-bispecific secretion by plasma cells and prevents self-targeting. Plasma cells secreting anti-CD19-bispecific antibodies elicited in vivo control of acute lymphoblastic leukemia patient-derived xenografts in immunodeficient mice co-engrafted with autologous T cells. In these studies, we found that leukemic control elicited by engineered plasma cells was similar to CD19-targeted chimeric antigen receptor-expressing T cells. Finally, the steady-state concentration of anti-CD19 bispecifics in serum 1 month after cell delivery and tumor eradication was comparable with that observed in patients treated with a steady-state infusion of blinatumomab. These findings support further development of ePCs for use as a durable delivery system for the treatment of acute leukemias, and potentially other cancers.
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James and colleagues describe methods for long-term secretion of bispecific antibodies by human plasma cells. Engineered plasma cells maintained clinically relevant levels of bispecific in vivo for >30 days, and eradicated established leukemia. These experiments justify application of engineered plasma cells for drug delivery in cases where half-life is limiting.
We have previously shown that the progesterone antagonist mifepristone is a contraceptive when given in a dose of 2 or 5 mg per day. The majority of women experience amenorrhoea rather than the ...irregular break through bleeding usually occurring with other estrogen-free contraceptive pills, such as progestogen-only pill (POP). We investigated the effects of low-dose mifepristone on endometrial parameters which may be associated with changes in endometrial function, such as microvasculature, vascular endothelial growth factor (VEGF) and glucocorticoid receptor (GR) content. METHODS AND RESULTS: Endometrial biopsies were collected from 16 women before (late proliferative phase) and 60 and 120 days after taking 2 or 5 mg mifepristone daily for 120 days. Seven of the eight women who received 2 mg mifepristone and all eight women who received 5 mg were amenorrhoeic during the study. Mean estradiol (E2) concentrations remained in the mid-proliferative range, and the majority (9/16) of women showed proliferative endometrial histology at 60 and 120 days following treatment. There was a significant increase in the density of the endometrial stroma (P < 0.05) and microvessels (P < 0.01) following 120 days of treatment. Immunocytochemistry showed that GR, hitherto localized specifically in endometrial stroma, was up-regulated in the nuclei of glands (P < 0.05) and surface (luminal) epithelium (P < 0.01) by 60 days and maintained at 120 days. There was a significant reduction in stromal VEGF protein expression by day 120 of treatment (P ≤ 0.01). CONCLUSION: The high incidence of amenorrhoea in women taking mifepristone may be related to changes in the regulation of vascular function.
Mifepristone in daily low doses has contraceptive potential by inhibiting ovulation. Follicular development is maintained, and although the endometrium is exposed to unopposed estrogen, there are no ...signs of hyperplasia or atypia. The mechanism of this antiestrogenic action is unknown. We have investigated the effect of daily low-dose mifepristone on proliferation markers and steroid receptors in surface epithelium, glands, and stroma of the endometrium. Endometrial biopsies were collected from 16 women before (late proliferative) and 60 and 120 d after taking 2 or 5 mg mifepristone daily for 120 d. Endometrial proliferation (H3 mitosis marker) and steroid (estrogen, progesterone, and androgen) receptor content were studied using standard immunocyotchemistry techniques. There was a significant decrease in the expression of H3 mitosis marker (P ≤ 0.001) and progesterone receptor (P < 0.05) in endometrial glands and stroma by d 60 of treatment. In contrast, the expression of androgen receptor increased (P < 0.01) in glands, surface epithelium, and stroma compared with the pretreatment sample. These changes were maintained at 120 d of treatment. The expression of estrogen receptor was unchanged in stroma and surface epithelium; however, there was a significant decrease in expression after 120 d of treatment (P = 0.034). As androgens can antagonize estrogen action, enhanced glandular androgen receptor expression induced by mifepristone could play a role in its antiproliferative effects.
Extensive optical, physical, chemical, and biochemical measurements made simultaneously in the northwest Indian Ocean reveal the occurrence of an intermediate nepheloid layer (INL) invariably ...associated with the secondary nitrite maximum. Maxima in particulate protein and the activity of the respiratory electron transport system (ETS) are also found within the INL. Since the INL persists long distances from the continental margin with an offshore intensification, it may not be related to the transport of material resuspended along the continental margin. An apparent correlation of the INL with the previously reported subsurface maximum in bacterial abundance suggests that a local increase in the abundance of bacteria may be responsible for the increased turbidity. Positive correlations of the beam attenuation anomaly with nitrite and nitrate deficit suggest that most of these bacteria may be denitrifiers. The organic carbon demand within the denitrifying layer, computed from the observed ETS activity, appears to be severalfold higher than the sinking carbon fluxes to the denitrifying layer, requiring additional modes of supply of the biodegradable organic matter. It is proposed that a bacterial maximum could be maintained with efficient utilization of the dissolved organic matter within the denitrifying waters.
Abstract Background We have previously shown that the antigestagen mifepristone is contraceptive when given in a daily dose of 5 mg, po. Epidemiological studies suggest that gestagen-only ...contraceptives may increase the risk of transmission of human immunodeficiency virus (HIV) due to effects on the vaginal defenses to infection. We investigate the effects of mifepristone on vaginal thickness, steroid receptor and natural antimicrobial content and pharmacokinetics of mifepristone. Methods In a pilot study, eight women were given mifepristone 5 mg/day for an average of 33 days. Ovarian function was assessed by measurement of estradiol and progesterone in blood and their metabolites in urine and by serial ultrasound of their ovaries. Vaginal biopsies were collected before (late proliferative) and after taking mifepristone. Results All subjects showed a similar pattern of descending serum concentrations of mifepristone. The elimination phase half-life was 18±5.1 h (mean±SD). Mean Cmax measured at 1 h was 641.7 nmol/L (range, 502–740 nmol/L). All eight women reported amenorrhea for the duration of treatment and seven of eight women showed biochemical and ultrasound evidence of anovulation. There was no significant change in vaginal thickness following treatment 342±40 μm pretreatment, 303±69 μm posttreatment (mean±SEM); p>.05. Estrogen (ERα, ERβ) and androgen receptor were expressed in both vaginal epithelium and subepithelial stroma, whereas progesterone receptor was expressed predominantly in the subepithelial stroma. There was no change in receptor content and distribution following mifepristone treatment. Natural antimicrobial mRNA secretory leukocyte protease inhibitor, human beta defensins mRNA (HBD1, HBD2, HBD3, HBD5), granulysin and elafin was extracted from the vaginal tissues, and the content was unaffected by mifepristone treatment. Conclusion The absence of changes in vaginal thickness, steroid receptor and natural antimicrobial content and its distribution in this preliminary study suggests that in contrast to other estrogen-free contraceptives, mifepristone is unlikely to be associated with the increased risk of transmission of HIV and other sexually transmitted infections.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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