Good performance of p16/ki‐67 dual‐stained cytology for surveillance of women treated for high‐grade CIN

Women treated for high‐grade cervical intraepithelial neoplasia (CIN) are at risk of recurrent CIN Grade 2 or worse (rCIN2+). Currently, posttreatment monitoring is performed using cytology or cytology/high‐risk (hr)HPV cotesting. This study aimed to evaluate the performance of p16/Ki‐67 dual‐stained cytology (p16/Ki‐67) for posttreatment monitoring. Three hundred and twenty‐three women treated for high‐grade CIN in the SIMONATH study underwent close surveillance by cytology, hrHPV and DNA methylation marker testing up to 12 months posttreatment. Histological endpoints were ascertained by colposcopy with biopsy at 6 and/or 12 months. p16/Ki‐67 dual‐staining was performed on residual liquid‐based cytology samples obtained at, or shortly before biopsy collection. Clinical performance estimates of cytology, hrHPV, p16/Ki‐67 testing and combinations thereof for the detection of rCIN2+ were determined and compared to each other. Sensitivity of p16/Ki‐67 for rCIN2+ (69.2%) was nonsignificantly lower than that of cytology (82.1%; ratio 0.84, 95% CI: 0.71–1.01), but significantly lower than that of hrHPV testing (84.6%; ratio 0.82, 95% CI: 0.68–0.99). Specificity of p16/Ki‐67 for rCIN2+ (90.4%) was significantly higher compared to both cytology (70.8%; ratio 1.28, 95% CI: 1.19–1.37) and hrHPV testing (76.2%; ratio 1.19, 95% CI: 1.12–1.26). Overall, hrHPV testing showed very high sensitivity, along with a good specificity. When considering cotesting, combined p16/Ki‐67/hrHPV testing showed rCIN2+ sensitivity comparable to cytology/hrHPV cotesting (87.2% vs. 89.7%; ratio 0.97, 95% CI: 0.92–1.03), but with significantly increased specificity (74.2% vs. 58.1%; ratio 1.28, 95% CI: 1.19–1.38). Thus, when considered in combination with hrHPV, p16/Ki‐67 might be an attractive approach for surveillance of women treated for high‐grade CIN.     

Long‐term Radiological and Clinical Outcome after Lumbar Spinal Fusion Surgery in Patients with Degenerative Spondylolisthesis: A Prospective 6‐Year Follow‐up Study

ObjectiveTo assess which radiological alignment parameters are associated with a satisfactory long‐term clinical outcome after performing lumbar spinal fusion for treating degenerative spondylolisthesis.MethodsThis single‐center prospective study assessed the relation between radiological alignment parameters measured on standing lateral lumbar spine radiographs and the patient‐reported outcome using four different questionnaires (COMI, EQ‐5D, ODI and VAS) as primary outcome measures (level of evidence: II). The following spinopelvic alignment parameters were used: gliding angle, sacral inclination, anterior displacement, sagittal rotation, lumbar lordosis, sacral slope, pelvic tilt and pelvic incidence. Furthermore, the length of stay and perioperative complications were documented. Only cases from 2013 to 2015 of low‐grade degenerative lumbar spondylolisthesis (Meyerding grades I and II) were considered. The patients underwent open posterior lumbar fusion surgery by pedicle screw instrumentation and cage insertion. The operative technique was either a posterior lumbar interbody fusion (PLIF) or a transforaminal lumbar interbody fusion (TLIF) performed by three different senior orthopedic surgeons. Exclusion criteria were spine fractures, minimally invasive techniques, underlying malignant diseases or acute infections, previous or multisegmental spine surgery as well as preoperative neurologic impairment. Of 89 initially contacted patients, 17 patients were included for data analysis (11 males, six females).ResultsThe data of 17 patients after mono‐ or bisegmental lumbar fusion surgery to treat low‐grade lumbar spondylolisthesis and with a follow‐up time of least 72 months were analyzed. The mean age was 66.7 ± 11.3 years. In terms of complications two dural tears and one intraoperative bleeding occurred. The average body mass index (BMI) was 27.6 ± 4.4 kg/m² and the average inpatient length of stay was 12.9 ± 3.8 days (range: 8–21). The long‐term clinical outcome correlated significantly with the change of the pelvic tilt (r _s = −0.515, P < 0.05) and the sagittal rotation (r _s = −0.545, P < 0.05). The sacral slope was significantly associated with the sacral inclination (r _s = 0.637, P < 0.01) and the pelvic incidence (r _s = 0.500, P < 0.05). In addition, the pelvic incidence showed a significant correlation with the pelvic tilt (r _s = 0.709, P < 0.01). The change of the different clinical scores over time also correlated significantly between the different questionnaires.ConclusionsThe surgical modification of the pelvic tilt and the sagittal rotation are the two radiological alignment parameters that can most accurately predict the long‐term clinical outcome after lumbar interbody fusion surgery.     

Maternal Exposure to Per- and Polyfluoroalkyl Substances (PFAS) and Male Reproductive Function in Young Adulthood: Combined Exposure to Seven PFAS

Background: Concerns remain about the human reproductive toxicity of the widespread per- and polyfluoroalkyl substances (PFAS) during early stages of development.Objectives: We examined associations between maternal plasma PFAS levels during early pregnancy and male offspring reproductive function in adulthood.Methods: The study included 864 young men (age range:18.9–21.2 y) from the Fetal Programming of Semen Quality (FEPOS) cohort established between 2017 and 2019. Plasma samples from their mothers, primarily from the first trimester, were retrieved from the Danish National Biobank and levels of 15 PFAS were measured. Seven PFAS had detectable levels above the limit of detection in >80% of the samples and were included in analyses. Semen quality, testicular volume, and levels of reproductive hormones and PFAS were assessed in the young men. We used weighted quantile sum (WQS) regression to estimate the associations between combined exposure to maternal PFAS and reproductive function, and negative binomial regression to estimate the associations of single substances, while adjusting for a range of a priori–defined fetal and postnatal risk factors.Results: By a 1-unit increase in the WQS index, combined maternal PFAS exposure was associated with lower sperm concentration (−8%; 95% CI: −16%, −1%), total sperm count (−10%; 95% CI: −17%, −2%), and a higher proportion of nonprogressive and immotile sperm (5%; 95% CI: 1%, 8%) in the young men. Different PFAS contributed to the associations with varying strengths; however, perfluoroheptanoic acid was identified as the main contributor in the analyses of all three outcomes despite the low concentration. We saw no clear association between exposure to maternal PFAS and testicular volume or reproductive hormones.Discussion: In a sample of young men from the general Danish population, we observed consistent inverse associations between exposure to maternal PFAS and semen quality. The study needs to be replicated in other populations, taking combined exposure, as well as emerging short-chain PFAS, into consideration. https://doi.org/10.1289/{"type":"entrez-protein","attrs":{"text":"EHP10285","term_id":"372009670","term_text":"EHP10285"}}EHP10285     

Alterations in geometry,biomechanics, and mineral composition of juvenile rat femur induced by nonplanar PCB‐155 and/or planar PCB‐169

Exposure to widespread lipophilic and bioaccumulative polychlorinated biphenyls (PCBs) induces diverse biochemical and toxicological responses in various organs, including the bone. The aim of this study was to evaluate the changes in growth rate, geometry, serum, and bone biochemical parameters and biomechanics of juvenile rat femur induced by lactational exposure to nonplanar PCB‐155 and planar PCB‐169 individually and in combination. Fifteen lactating Wistar rats were divided into four groups (PCB‐169, PCB‐155, PCB‐155+169, and control), and PCBs were administered intraperitoneally at different time points after delivery. Femurs from 22‐day‐old offspring were analyzed by microCT, three‐point bending test and inductively coupled plasma‐mass spectrometry (ICP‐MS) to obtain data on bone geometry, biomechanics and mineral composition. The serum levels of calcium, phosphate and alkaline phosphatase were also determined. Lactational exposure to planar PCB‐169 resulted in shorter and thinner femurs, reduced endosteal and periosteal perimeters, smaller total cross‐sectional and medullary areas, and lowered serum bone marker levels and calcium levels in the bone, while femur mechanical properties were not significantly altered. The changes observed in the combination exposure (PCB‐155+169) group were similar to those observed in the PCB‐169 group but were less pronounced. In summary, our results demonstrate that alterations in lactationally exposed offspring were primarily induced by planar PCB‐169. The milder outcome in the combined group suggested that the PCB‐169‐mediated toxic effects on the bone might be reduced by a nonplanar PCB‐155 congener. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1135–1146, 2017.     

以光学为基础的量化诊断初期龋的方法应用

定量诊断初期龋的先进方法,近年来受到了高度重视。相对于传统的常规定性诊断方法来说,一些先进的定量诊断方法能检测到龋病的早期脱钙现象,这对于早期采取预防和控制措施都是非常重要的,一些技术现在已推向市场。随着龋病的预防和治疗技术的提高,在欧洲和北美发达国家龋病的患     

Antibody mediated CDCP1 degradation as mode of action for cancer targeted therapy

CUB-domain-containing-protein-1 (CDCP1) is an integral membrane protein whose expression is up-regulated in various cancer types. Although high CDCP1 expression has been correlated with poor prognosis in lung, breast, pancreas, and renal cancer, its functional role in tumor formation or progression is incompletely understood. So far it has remained unclear, whether CDCP1 is a useful target for antibody therapy of cancer and what could be a desired mode of action for a therapeutically useful antibody. To shed light on these questions, we have investigated the cellular effects of a therapeutic antibody candidate (RG7287). In focus formation assays, prolonged RG7287 treatment prevented the loss of contact inhibition caused by co-transformation of NIH3T3 cells with CDCP1 and Src. In a xenograft study, MCF7 cells stably overexpressing CDCP1 reached the predefined tumor volume faster than the parental MCF7 cells lacking endogenous CDCP1. This tumor growth advantage was abolished by RG7287 treatment. In vitro, RG7287 induced rapid tyrosine phosphorylation of CDCP1 by Src, which was accompanied by translocation of CDCP1 to a Triton X-100 insoluble fraction of the plasma membrane. Triggering these effects required bivalency of the antibody suggesting that it involves CDCP1 dimerization or clustering. However, this initial activation of CDCP1 was only transient and prolonged RG7287 treatment induced internalization and down-regulation of CDCP1 in different cancer cell lines. Antibody stimulated CDCP1 degradation required Src activity and was proteasome dependent. Also in three different xenograft models with endogenous CDCP1 expression RG7287 treatment resulted in significant tumor growth inhibition concomitant with substantially reduced CDCP1 levels as judged by immunohistochemistry and Western blotting. Thus, despite transiently activating CDCP1 signaling, the RG7287 antibody has a therapeutically useful mode of action.