[The application of 99Tcm-DTPA orbital SPECT/CT in staging evaluation of thyroid associated ophthalmopathy].

Objective: To explore the application value of 99Tcm-diethylenetriaminepentaacetic acid (DTPA) orbital single photon emission computed tomography/computed tomography (SPECT/CT) in staging evaluation of thyroid associated ophthalmopathy (TAO). Methods: A case-control study. A total of 40 patients with binocular TAO were recruited from May 2019 to December 2019 in the Second Hospital of Dalian Medical University. According to the clinical activity score (CAS) standard, 40 TAO patients were divided into the active group (15 cases) and the inactive group (25 cases), and 10 healthy volunteers were recruited as the control group. All subjects underwent 99Tcm-DTPA orbital SPECT/CT examination, and each subject's CAS, reading results and maximum standardized uptake value (SUVmax) were recorded. The Kruskal-Walis H test was used for the CAS comparison among the three groups. The analysis of variance was used for the SUVmax comparison among the three groups. The comparison between CAS and SUVmax before and after treatment was performed by paired samples Wilcoxon signed rank test and paired-sample t test, and Spearman correlation analysis was performed between SUVmax and CAS. The Kappa test was used to check the consistency between the reading result and CAS's judgment of TAO activity. The receiver operating characteristic curve was used to analyze the diagnostic value of the reading results and SUVmax for TAO. Results: The age difference among the three groups was not statistically significant, and the gender difference was not statistically significant (all P>0.05). The difference in CAS among the three groups was statistically significant (H=39.894; P<0.01). Patients with active TAO showed abnormal concentration and enhancement of nuclides in the orbital tissue, and the uptake of radionuclides was significantly increased, while patients with inactive TAO had a slight increase, and healthy volunteers had no significant or only mild uptake. The SUVmax of the active group (2.24±0.47) was highest, and that of the inactive group (1.57±0.43) was higher than the healthy control group (0.67±0.22). After pairwise comparison, there were statistical differences between groups (all P<0.05). According to Spearman correlation analysis, the SUVmax of all TAO patients was linearly, positively correlated with their CAS (r=0.753; P<0.05). In assessing the clinical activity of TAO, the reading results were consistent with CAS (Kappa value=0.737; P<0.05). Taking the reading results as the standard, the area under the receiver operating characteristic curve (AUC) of SUVmax was 0.992, and the threshold of SUVmax to distinguish between active and inactive periods was 1.850, with a sensitivity of 86.70% and a specificity of 76.00%. Taking CAS results as the standard, the AUC of SUVmax was 0.853, and the threshold of SUVmax to distinguish between active and inactive periods was 1.850, with a sensitivity of 100.00% and a specificity of 87.50%. Five patients had inconsistent SUVmax and CAS. The CAS was ≥3, but the orbits did not show any inflammatory lesions in two of them; the CAS was<3, but the orbits showed inflammatory lesions in three of them. Thirteen active TAO patients with 99Tcm-DTPA orbital SPECT/CT showing significant accumulation of nuclides were given hormone shock therapy 12 times. After treatment, the CAS 2.00 (2.00) was lower than the pre-treatment 3.00 (1.50) score, and the difference was statistically significant (Z=-3.100, P<0.01). The SUVmax after treatment (1.60±0.20) was lower than the pre-treatment value (2.17±0.34), and the difference was statistically significant (t=10.197, P<0.01). Conclusion: 99Tcm-DTPA orbital SPECT/CT can relatively accurately determine the state of orbital inflammation in patients with TAO, and can be used as a useful supplement to evaluate the clinical activity of TAO, helping to guide clinical treatment. (Chin J Ophthalmol, 2021, 57: 830-836).

Review article: nonclinical and clinical pharmacology, pharmacokinetics and pharmacodynamics of etrolizumab, an anti-ß7 integrin therapy for inflammatory bowel disease.

BACKGROUND: Novel treatments with superior benefit-risk profiles are needed to improve the long-term prognosis of patients with inflammatory bowel disease (IBD). Etrolizumab-a monoclonal antibody that specifically targets ß7 integrins-is currently under phase III clinical evaluation in IBD. AIM: This review summarises the available pharmacological and pharmacokinetic/pharmacodynamic data for etrolizumab to provide a comprehensive understanding of its mechanism of action (MOA) and pharmacological effects. METHODS: Published and internal unpublished data from nonclinical and clinical studies with etrolizumab are reviewed. RESULTS: Etrolizumab exerts its effect via a unique dual MOA that inhibits both leucocyte trafficking to the intestinal mucosa and retention within the intestinal epithelial layer. The gut-selectivity of etrolizumab results from its specific targeting of the ß7 subunit of α4ß7 and αEß7 integrins. Etrolizumab does not bind to α4ß1 integrin, which mediates lymphocyte trafficking to tissues including the central nervous system, a characteristic underlying its favourable safety with regard to progressive multifocal leucoencephalopathy. Phase I/II studies in patients with ulcerative colitis (UC) showed linear pharmacokinetics when etrolizumab was administered subcutaneously at 100 mg or higher once every 4 weeks. This dose was sufficient to enable full ß7 receptor occupancy in both blood and intestinal tissues of patients with moderate to severe UC. The phase II study results also suggested that patients with elevated intestinal expression of αE integrin may have an increased likelihood of clinical remission in response to etrolizumab treatment. CONCLUSION: Etrolizumab is a gut-selective, anti-ß7 integrin monoclonal antibody that may have therapeutic potential for the treatment of IBD.

Daclizumab reduces CD25 levels on T cells through monocyte-mediated trogocytosis.

Daclizumab is a humanized monoclonal antibody that prevents interleukin-2 (IL-2) binding to CD25, blocking IL-2 signaling by cells that require high-affinity IL-2 receptors to mediate IL-2 signaling. The phase 2a CHOICE study evaluating daclizumab as a treatment for multiple sclerosis (MS) included longitudinal analysis of activated T cell counts. Whereas an exposure-dependent relationship was observed between daclizumab and reductions in HLA-DR(+)-activated T cells, a similar relationship was not observed for reductions in CD25 levels. The objective of this report is to determine the mechanism by which daclizumab reduces CD25 levels on peripheral blood mononuclear cells (PBMCs) using cytometric techniques. Daclizumab reduced T cell CD25 levels through a mechanism that required the daclizumab-Fc domain interaction with Fc receptors (FcR) on monocytes, but not on natural killer (NK) cells, and was unrelated to internalization or cell killing. Activated CD4(+) T cells and FoxP3(+) Treg cells showed evidence of trogocytosis of the CD25 antigen in the presence of monocytes. A daclizumab variant that retained affinity for CD25 but lacked FcR binding did not induce trogocytosis and was significantly less potent as an inhibitor of IL-2-induced proliferation of PBMCs. In conclusion, Daclizumab-induced monocyte-mediated trogocytosis of CD25 from T cells appears to be an additional mechanism contributing to daclizumab inhibition of IL-2 signaling.

Dynamical diffraction effect in a curved multi-plate crystal cavity.

A modified algorithm for X-ray dynamical diffraction theory is presented for curved boundary crystals and a detailed description of the numerical procedure is given. The simulated and experimental results both show an anomalous focusing behavior in a curved multi-plate crystal cavity of silicon under the (12,4,0) back-diffraction condition at a photon energy of 14.4388 keV. The focusing effects are analyzed, within the framework of the dynamical theory of X-ray diffraction, from the excitation of the dispersion surface and modification of the index of refraction with respect to the non-plane-parallel boundaries of a curved crystal cavity.

ACTN3 genotype and swimming performance in Taiwan.

Studies have shown that the 577R allele of α-actinin-3 (ACTN3) is more prevalent in sprint athletes than in the general population or in endurance athletes. We examined the distribution of ACTN3 R577X (rs 1815739) genotypes and alleles in the Taiwanese general population (603) and in elite sprint swimmers who had participated in international/national events (168). Additionally, 50 pre-adolescent (age 11-13 years) male students and 38 adult males who completed 12-weeks of swimming training, were included in the present study. We found that the frequencies of the R allele were significantly higher in female international sprint swimmers (67.6%) than in national sprint swimmers (50.0%) or in the general population (53.7%). The 25-m performance was significantly improved across the genotypes after swimming training among the pre-adolescent males but not among the adult males. In addition, pre-adolescents with the RR genotype had the best performance both before and after training although not statistically significant. In conclusion, the frequencies of ACTN3 577R allele were significantly higher in female international sprint swimmers than among national sprint swimmers or the general population. Furthermore, male pre-adolescents with either the ACTN3 RX or XX genotype showed a greater improvement in 25-meter swimming performance than those with the RR genotype.

Diffraction-enhanced beam-focusing for X-rays in curved multi-plate crystal cavity.

Unusual x-ray focusing effect is reported for parabolic curved multi-plate x-ray crystal cavities of silicon consisting of compound refractive lenses (CRL). The transmitted beam of the (12 4 0) back reflection near 14.4388 keV from these monolithic silicon crystal devices exhibits extraordinary focusing enhancement, such that the focal length is reduced by as much as 18% for 2-beam and 56% for 24-beam diffraction from the curved crystal cavity. This effect is attributed to the presence of the involved Bragg diffractions, in which the wavevector of the transmitted beam is bent further when traversing several curved crystal surfaces.

Mechanism-based receptor-binding model to describe the pharmacokinetic and pharmacodynamic of an anti-α5ß1 integrin monoclonal antibody (volociximab) in cancer patients.

PURPOSE: Volociximab is a chimeric IgG(4) that is being developed as a novel first-in-class anti-angiogenic, α(5)ß(1) integrin inhibitor for the treatment of solid tumors. A mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to investigate the dynamic interaction between volociximab concentrations and free monocyte α(5)ß(1) integrin levels in cancer patients. METHODS: Twenty-one cancer patients from six dose cohorts (0.5, 1.0, 2.5, 5.0, 10, and 15 mg/kg) were included in the analysis. The fully integrated receptor-binding PK/PD model was developed and fit simultaneously to the PK/PD data. A Monte-Carlo parametric expectation-maximization method implement in S-ADAPT program was used to obtain estimates of population parameters and inter- and intra-subject variability. RESULTS: The PK/PD time profiles were well described by the model and the parameters were estimated with good precision. The model was used to simulate PK/PD time profiles for multiple dose regimens at various dose levels, and the results suggested that the monocyte α(5)ß(1) integrin binding was saturated (≤5% free) at week 16 in the majority of patients treated with volociximab doses ≥10 mg/kg IV every 2 weeks. CONCLUSIONS: The developed model is useful for anticipating the drug exposures and extent of volociximab binding to peripheral monocyte α(5)ß(1) integrin in untested regimens and for optimizing the design of future clinical trials.

X-ray resonance in crystal cavities: realization of Fabry-Perot resonator for hard x rays.

X-ray back diffraction from monolithic two silicon crystal plates of 25-150 microm thickness and a 40-150 microm gap using synchrotron radiation of energy resolution DeltaE = 0.36 meV at 14.4388 keV clearly show resonance fringes inside the energy gap and the total-reflection range for the (12 4 0) reflection. This cavity resonance results from the coherent interaction between the x-ray wave fields generated by the two plates with a gap smaller than the x-ray coherence length. This finding opens up new opportunities for high-resolution and phase-contrast x-ray studies, and may lead to new developments in x-ray optics.

Induced abortion in relation to breast cancer among parous women: a birth certificate registry study.

We wished to assess the relation of induced abortion to the subsequent incidence of breast cancer among parous women, using a design that would prevent the possibility of differentially complete reporting of abortion history by women with breast cancer and controls. Our study was conducted within a cohort of women who gave birth to a child during 1984-1994 while residing in 13 counties of western Washington. Cases were women from the cohort diagnosed with breast cancer between 1984 and 1994. From the remaining cohort members, five controls were matched to each woman with breast cancer by year of index birth (ie, the last child born before breast cancer diagnosis) and by age at delivery. We categorized 463 cases and 2,201 controls according to history of induced abortion as recorded on the index birth certificate. The risk of breast cancer was not found to be associated with a prior induced abortion (estimated relative risk (RR) = 0.9, 95% confidence interval (CI) 0.7-1.2). These results suggest that an induced abortion, if followed at some later time by pregnancy and childbirth, does not increase a woman's risk of breast cancer.

Case-control differences in the reliability of reporting a history of induced abortion.

The authors investigated the possibility that, in interview-based case-control studies, controls are more likely than cases to underreport a history of induced abortion. A case-control study was conducted in White women under 45 years of age who had given birth in Washington State during 1984-1994. The cases were women in three metropolitan counties of Washington State diagnosed with invasive breast cancer during 1984-1994; controls were selected through random digit dialing. A history of induced abortion among study participants was compared between interview data and information collected on the birth record of the last child to whom they gave birth (225 cases, 303 controls). Among women with a prior induced abortion recorded on the birth record, 14.0% of the 43 cases and 14.9% of the 47 controls did not report an induced abortion at interview (difference = -0.9%, 95% confidence interval of the difference: -15, 14). The authors' data do not suggest that controls are more reluctant to report a history of induced abortion than are women with breast cancer.

Surface X-ray scattering system at the SRRC.

A UHV surface X-ray scattering system has been constructed at the SRRC, providing users with a state-of-the-art system for performing X-ray scattering studies of two-dimensional crystallography, in situ growth mechanisms as well as phase transitions of surfaces and interfaces. A study of the phase transition of the Si(001) reconstructed surface was conducted to commission both the scattering system and the SRRC X-ray beamline. The detailed design and performance of the SRRC surface X-ray scattering system together with the results of the Si(001) study are presented.

Ovarian sex cord tumor with annular tubules: a report of six cases.

Six patients suffering from ovarian sex cord tumor with annular tubules (SCTAT) were reported in this article with special reference to the clinical features, histological characteristics, sex hormone profile, and management of disease. SCTAT was documented to be a estrogen-progesterone-secreting tumor based on the observations of glandular atrophy and decidual change of stroma in the endometrium and assays of steroid hormone. Menometrorrhagia followed by persistent amenorrhea and pelvic mass were presented as important clinical features. This tumor was considered as a tumor with low-grade malignancy, and retroperitoneal lymphatic metastasis was thought to be an important pathway of spread. Unilateral salpingo-oophorectomy together with ipsilateral pelvic and para-aortic lymphadenectomy were suggested as an effective treatment for SCTAT. Radiotherapy can be used for local recurrence and distant metastases.