Glucaric acid excretion. Analysis of the enzymatic assay and findings in smokers and non-smokers

Summary Glucaric acid (GA) excretion in urine from cigarette smokers and non-smoking control subjects was determined enzymatically. There was no difference between GA 41.0±3.2 µmol/g creatinine (Cn; mean ± SEM) in smokers and GA 43.1±3.4 µmol/g Cn in the controls. Gas chromatographic analysis of the GA-glucarolactone equilibrium was carried out in an attempt to elucidate the striking discrepancies in previous results.     

Five-year age-specific incidence rates. I. Their nature and limitations.

The effect of population structure on five-year age-specific incidence rates was investigated using the one-year population data from life tables and a theoretical age incidence curve of the form: I = btk - where I is the incidence at age t, and b and k are constants. The five-year incidence rates differed systematically from the one-year rates of the central year of the five-year period. This difference depended on the change with age of both the population size and the incidence rate. Thus at ages 20-24 the five-year rate overestimates the mid-period one-year rate by about 4%, but the overestimate progressively decreases to become an underestimate of 0.5% at ages 75-79. In consequence the one-year and five-year rates produce fitted age incidence curves with different slopes; the value of k in the incidence equation is about 0.7% greater for the one-year rates. The population structures of developed and underdeveloped countries are markedly different and these were found to affect the five-year incidence rates, but never by more than 0.5%. The effect of the irregularities in one-year age structure of real populations on the observed five-year rates is also small, of the order of 0.5%. However, when incidence rates are calculated by recording tumours over several calendar years, these irregularities can create difficulties for the estimation of the appropriate denominator population. The use of the census population, even that of the central year of the observation period, can be in error by over 2%. A good method is to calculate the mean annual population of the observation period, estimating the intercensal year populations by interpolation between flanking censuses.     

Dopamine and somatostatin modulated adenylate cyclase activity in the rat caudate-putamen following unilateral cortical ablation

Summary Dopamine and somatostatin-14 (SRIF) were incubated with a membrane fraction of rat caudate-putamen (CP) tissue in an adenylate cyclase assay in order to examine the D-1-receptor coupled adenylate cyclase activity 5 days and 3 weeks after unilateral ablation of the left frontal and lateral cortex. Five days after decortication the ipsilateral basal and dopamine stimulated adenylate cyclase activity was increased by about 30% compared to that of the contralateral side. Three weeks after decortication no significant difference could be seen. On either side basal and dopamine stimulated adenylate cyclase activity was not significantly decreased compared to sham operated controls. Somatostatin (10^-7 mol/l) reduced basal adenylate cyclase activity of the ipsilateral CP five days following lesioning and reduced the maximal stimulation induced by dopamine. The effects of somatostatin were most marked in the absence and at low concentrations of dopamine (10^-7–10^-6 mol/l). The effects of somatostatin in the lesioned CP were no longer apparent three weeks following surgery. These results do not favour a presynaptic localization of D-1-receptors on cortico-striate projection fibers and suggest that somatostatin is involved in the interaction of the cortico-striate and nigro-striatal projection systems and may play a role in the regulation of D-1-receptor linked adenylate cyclase.     

Fusion of freehand SPECT and ultrasound: First experience in preoperative localization of sentinel lymph nodes

Purpose

Radioguided sentinel lymph node biopsy (SLNB) is the standard of care in breast cancer and melanoma. Additional preoperative Single-photon emission computed tomography (SPECT/CT) for improved anatomical co-registration of the SLNs causes additional radiation exposure and is time-consuming and expensive. The aim of this prospective study was to evaluate a novel approach involving real-time fusion of freehand SPECT (fhSPECT) and ultrasound (US) for anatomical co-registration of SLNs.

Methods

From February 2015 to February 2016, 153 patients were included in this prospective study. All patients underwent lymphoscintigraphy according to practical guidelines and 151 (118 cases of breast cancer, 30 cutaneous malignancies, and three cases of vulvar cancer) of the 153 patients were additionally investigated with fhSPECT-US. FhSPECT connected to a hand-held gamma detector generates three-dimensional images of the radioactivity distribution in the scanned area. For co-registration and real-time fusion of fhSPECT and subsequently performed US, an infrared stereo tracking system was used.

Results

In all patients an SLN was found on lymphoscintigraphy, and the fhSPECT detected corresponding hotspots in all but one patient. In 72 % of patients and 73 % of lymph node basins, real-time anatomical co-registration with US was feasible. The rate of success in achieving good co-registration increased from 60 to 75 % after training by a radiologist specialized in breast imaging. A higher co-registration rate (78 %) was observed in patients with only one SLN than in those with two SLNs (68 %) or three or more SLNs (0 %).

Conclusions

Real-time fusion of fhSPECT and US for preoperative anatomical co-registration of SLNs is feasible. However, before this approach can completely replace preoperative lymphatic imaging, further technical developments are needed.

     

Extensive amplification of human regulatory T cells alters their functional capacities and targets them to the periphery

Repetitive antigen encounters together with a strong CD28 co-stimulatory signal were recently identified as driving extensive amplification of human regulatory T (Treg) cells; however, the consequences of this on the functional capacities of Treg cells remain unknown. In this report, we reveal that T cell receptor (TCR)/CD28-triggered amplification in vitro converts CD4+CD25(high)FoxP3+ Treg cells into a late memory phenotype associated with immunosenescence and loss of CD7. Accordingly, ex vivo-isolated CD7- Treg cells have shortened telomeres and decreased telomerase expression compared to the majority of "mature" CD7+ Treg cells. Although they resist spontaneous apoptosis, amplified CD7- Treg cells exhibit increased sensitivity to activation-induced cell death (AICD). Extensive amplification of Treg cells is, moreover, accompanied by an increased activation threshold, reduced suppressor capacities, and interleukin-10 (IL-10) secretion, but secretion of high amounts of IL-4. Concomitantly, amplified Treg cells express homing receptors targeting them to the periphery. This is confirmed in vivo by the extensive accumulation of CD7- Treg cells with shortened telomeres in chronic inflammatory skin lesions, including atopic dermatitis and lichen ruber. Our data indicate that extensive amplification upon repetitive TCR/CD28 engagement alters the functional capacities of CD4+CD25(high) Treg cells toward less suppressive cells, but potential mediators in sustaining inflammatory reactions through IL-4.     

Prognostic value of pretherapy platelet elevation in oropharyngeal cancer patients treated with chemoradiation

The purpose of this study is to evaluate potential associations between increased platelets and oncologic outcomes in oropharyngeal cancer patients receiving concurrent chemoradiation. A total of 433 oropharyngeal cancer patients (OPC) treated with intensity‐modulated radiation therapy (IMRT) with concurrent chemotherapy between 2002 and 2012 were included under an approved IRB protocol. Complete blood count (CBC) data were extracted. Platelet and hemoglobin from the last phlebotomy (PLT_{pre‐chemoRT,} Hgb_{pre‐chemoRT}) before start of treatment were identified. Patients were risk‐stratified using Dahlstrom–Sturgis criteria and were tested for association with survival and disease‐control outcomes. Locoregional control (LRC), freedom from distant metastasis (FDM) and overall survival (OS) were decreased (p < 0.03, p < 0.04 and p < 0.0001, respectively) for patients with PLT_{pre‐chemoRT} value of ≥350 × 10⁹/L. Actuarial 5‐year locoregional control (LRC) and FDM were 83 and 85% for non‐thrombocythemic patients while patient with high platelets had 5‐year LRC and FDM of 73 and 74%, respectively. Likewise, 5‐year OS was better for patients with normal platelet counts by comparison (76 vs. 57%; p < 0.0001). Comparison of univariate parametric models demonstrated that PLT_{pre‐chemoRT} was better among tested models. Multivariate assessment demonstrated improved performance of models which included pretherapy platelet indices. On Bayesian information criteria analysis, the optimal prognostic model was then used to develop nomograms predicting 3‐, 5‐ and 10‐year OS. In conclusion, pretreatment platelet elevation is a promising predictor of prognosis, and further work should be done to elucidate the utility of antiplatelets in modifying risk in OPC patients.     

A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer

Menopausal estrogen‐alone therapy (ET) is a well‐established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome‐wide association studies. The interplay among these loci, ET use and ovarian cancer risk has yet to be evaluated. We analyzed data from 1,414 serous cases, 337 endometrioid cases and 4,051 controls across 10 case–control studies participating in the Ovarian Cancer Association Consortium (OCAC). Conditional logistic regression was used to determine the association between the confirmed susceptibility variants and risk of serous and endometrioid ovarian cancer among ET users and non‐users separately and to test for statistical interaction. A splicing variant in TERT, rs10069690, showed a statistically significant interaction with ET use for risk of serous ovarian cancer (p_int = 0.013). ET users carrying the T allele had a 51% increased risk of disease (OR = 1.51, 95% CI 1.19–1.91), which was stronger for long‐term ET users of 10+ years (OR = 1.85, 95% CI 1.28–2.66, p_int = 0.034). Non‐users showed essentially no association (OR = 1.08, 95% CI 0.96–1.21). Two additional genomic regions harboring rs7207826 (C allele) and rs56318008 (T allele) also had significant interactions with ET use for the endometrioid histotype (p_int = 0.021 and p_int = 0.037, respectively). Hence, three confirmed susceptibility variants were identified whose associations with ovarian cancer risk are modified by ET exposure; follow‐up is warranted given that these interactions are not adjusted for multiple comparisons. These findings, if validated, may elucidate the mechanism of action of these loci.