A broadly neutralizing human monoclonal antibody generated from transgenic mice immunized with HCMV particles limits virus infection and proliferation.

Human cytomegalovirus (HCMV) is a ß-herpesvirus that poses severe disease risk for immunocompromised patients who experience primary infection or reactivation. Development and optimization of safe and effective anti-HCMV therapeutics is of urgent necessity for the prevention and treatment of HCMV-associated diseases in diverse populations. The use of neutralizing monoclonal antibodies (mAbs) to limit HCMV infection poses a promising therapeutic strategy, as anti-HCMV mAbs largely inhibit infection by targeting virion glycoprotein complexes. In contrast, the small-molecule compounds currently approved for patients (e.g., ganciclovir, letermovir, and maribavir) target later stages of the HCMV life cycle. Here, we present a broadly neutralizing human mAb, designated 1C10, elicited from a VelocImmune mouse immunized with infectious HCMV particles. Clone 1C10 neutralizes infection after virion binding to cells by targeting gH/gL envelope complexes and potently reduces infection of diverse HCMV strains in fibroblast, trophoblast, and epithelial cells. Antibody competition assays found that 1C10 recognizes a region of gH associated with broad neutralization and binds to soluble pentamer in the low nanomolar range. Importantly, 1C10 treatment significantly reduced virus proliferation in both fibroblast and epithelial cells. Further, the combination treatment of mAb 1C10 with ganciclovir reduced HCMV infection and proliferation in a synergistic manner. This work characterizes a neutralizing human mAb for potential use as a HCMV treatment, as well as a possible therapeutic strategy utilizing combination-based treatments targeting disparate steps of the viral life cycle. Collectively, the findings support an antibody-based therapy to effectively treat patients at risk for HCMV-associated diseases. IMPORTANCE: Human cytomegalovirus is a herpesvirus that infects a large proportion of the population and can cause significant disease in diverse patient populations whose immune systems are suppressed or compromised. The development and optimization of safe anti-HCMV therapeutics, especially those that have viral targets and inhibition mechanisms different from current HCMV treatments, are of urgent necessity to better public health. Human monoclonal antibodies (mAbs) that prevent HCMV entry of cells were identified by immunizing transgenic mice and screened for broad and effective neutralization capability. Here, we describe one such mAb, which was found to target gH/gL envelope complexes and effectively limit HCMV infection and dissemination. Further, administration of the antibody in combination with the antiviral drug ganciclovir inhibited HCMV in a synergistic manner, highlighting this approach and the use of anti-HCMV mAbs more broadly, as a potential therapeutic strategy for the treatment of diverse patient populations.

Adjuvant Gemcitabine Versus Neoadjuvant/Adjuvant FOLFIRINOX in Resectable Pancreatic Cancer: The Randomized Multicenter Phase II NEPAFOX Trial.

BACKGROUND: Although addition of adjuvant chemotherapy is the current standard, the prognosis of pancreatic cancers still remains poor. The NEPAFOX trial evaluated perioperative treatment with FOLFIRINOX in resectable pancreatic cancer. PATIENTS AND METHODS: This multicenter phase II trial randomized patients with resectable or borderline resectable pancreatic cancer without metastases into arm (A,) upfront surgery plus adjuvant gemcitabine, or arm (B,) perioperative FOLFIRINOX. The primary endpoint was overall survival (OS). RESULTS: Owing to poor accrual, recruitment was prematurely stopped after randomization of 40 of the planned 126 patients (A: 21, B: 19). Overall, approximately three-quarters were classified as primarily resectable (A: 16, B: 15), and the remaining patients were classified as borderline resectable (A: 5, B: 4). Of the 12 evaluable patients, 3 achieved partial response under neoadjuvant FOLFIRINOX. Of the 21 patients in arm A and 19 patients in arm B, 17 and 7 underwent curative surgery, and R0-resection was achieved in 77% and 71%, respectively. Perioperative morbidity occurred in 72% in arm A and 46% in arm B, whereas non-surgical toxicity was comparable in both arms. Median RFS/PFS was almost doubled in arm B (14.1 months) compared with arm A (8.4 months) in the population with surgical resection, whereas median OS was comparable between both arms. CONCLUSIONS: Although the analysis was only descriptive owing to small patient numbers, no safety issues regarding surgical complications were observed in the perioperative FOLFIRINOX arm. Thus, considering the small number of patients, perioperative treatment approach appears feasible and potentially effective in well-selected cohorts of patients. In pancreatic cancer, patient selection before initiation of neoadjuvant therapy appears to be critical.

Metabolic activation of WHO-congeners PCB28, 52, and 101 by human CYP2A6: evidence from in vitro and in vivo experiments.

Despite extensive research on the metabolism of polychlorinated biphenyls (PCBs), knowledge gaps persist regarding their isoform-specific biotransformation pathways. This study aimed to elucidate the role of different cytochrome P450 enzymes in PCB metabolism, focusing on WHO-congeners 2,4,4'-trichlorobiphenyl (PCB28), 2,2',5,5'-tetrachlorobiphenyl (PCB52), and 2,2',4,5,5'-pentachlorobiphenyl (PCB101). Utilizing engineered HEK293 cell lines, we investigated the in vitro metabolism of these PCBs by CYP1A2, CYP2C8, CYP2C9, CYP3A4, CYP2A6, and CYP2E1, revealing robust production of hydroxylated metabolites. Our results show that CYP2A6 plays a major role in the metabolism of these congeners responsible for predominant formation of para-position hydroxylated metabolites, with concentrations reaching up to 1.61 µg/L (5,89 nM) for PCB28, 316.98 µg/L (1,03 µM) for PCB52, and 151.1 µg/L (441 nM) for PCB101 from a 20 µM parent PCB concentration. Moreover, concentration-dependent cytotoxic and cytostatic effects induced by reactive intermediates of the PCB hydroxylation pathway were observed in HEK293CYP2A6 cells, for all three congeners tested. CYP2A6 was specifically capable of activating PCBs 28 and 101 to genotoxic metabolites which produced genetic defects which were propagated to subsequent generations, potentially contributing to carcinogenesis. In a clinical study examining CYP2A6 enzyme activity in formerly exposed individuals with elevated internal PCB levels, a participant with increased enzyme activity showed a direct association between the phenotypic activity of CYP2A6 and the metabolism of PCB28, confirming the role of CYP2A6 in the in vivo metabolism of PCB28 also in humans. These results altogether reinforce the concept that CYP2A6 plays a pivotal role in PCB congener metabolism and suggest its significance in human health, particularly in the metabolism of lower chlorinated, volatile PCB congeners.

Ten years after: findings from the medical surveillance program on Health Effects in High-Level Exposure to PCB (HELPcB).

After the detection of high environmental and occupational exposure to polychlorinated biphenyls (PCBs) in a German recycling company for transformers and capacitors in 2010, the multidisciplinary medical surveillance program "HELPcB" (Health Effects in High-Level Exposure to PCB) was established for former PCB-exposed workers of the company, their family members, employees of surrounding companies, and area residents to investigate potential adverse health effects by PCB exposure in a longitudinal study approach with up to seven examination time points between 2010 and 2019. More than 300 individuals were enrolled into the program. Assessments particularly included plasma and urine concentrations of PCB congeners and their metabolites, clinical laboratory parameters, Comet assay, analysis of telomere length, neuropsychological examinations, psychological screening, abdominal and thyroid ultrasound examination. This review summarizes the main results of the studies conducted in the HELPcB program yielding relevant new data on potential adverse effects of PCB exposure in humans and potential mechanisms that underlie these effects. Even larger studies in PCB-exposed individuals are warranted to confirm the results of this program and to further establish causality between PCB exposure and clinical effects in humans.

[Health protection and climate change require ambitious limit values for air pollutants in Europe : Opinion on the revision of the Directive on Air Quality and Clean Air for Europe of the Environmental Public Health commission of the Robert Koch Institute and the Federal Environment Agency]. / Gesundheitsschutz und Klimawandel erfordern ambitionierte Grenzwerte für Luftschadstoffe in Europa : Stellungnahme zur Revision der Richtlinie über Luftqualität und saubere Luft für Europa der Kommission Environmental Public Health des Robert Koch-Instituts und des Umweltbundesamtes.

Based on scientific findings, the World Health Organization (WHO) has recommended stricter guideline values for air quality in 2021. Significant reductions in the annual mean values of particulate matter (particle size 2.5 µm or smaller, PM2.5) and long-term exposure to nitrogen dioxide (NO2) and ozone (O3) were put forward. The risk of mortality already increases above the WHO guideline values, as shown in studies investigating low concentrations of air pollutants. In Germany, the 2021 WHO guideline values for PM2.5 and NO2 were clearly exceeded in 2022.In this position paper we give the following recommendations for the European Air Quality Directive: (1) set binding limit values according to WHO 2021, (2) apply the limit values to the whole of Europe, (3) continue and expand the established country-based monitoring networks, (4) expand air quality measurements for ultrafine particles and soot particles, and (5) link air pollution control and climate protection measures.Stricter limits for air pollutants require societal and political changes in areas such as mobility, energy use and generation, and urban and spatial planning. Implementation according to WHO 2021 would lead to a net economic benefit of 38 billion euros per year.Ambitious limit values for air pollutants also have an impact on climate change mitigation and its health impacts. The Environmental Public Health commission concludes that more ambitious limit values are crucial to enable effective health protection in Germany and calls for air pollutant limit values in line with the 2021 WHO recommendations to become binding in Europe.

Toward Clinical Application of Leukocyte Counts Based on Targeted DNA Methylation Analysis.

BACKGROUND: Differential leukocyte counts are usually measured based on cellular morphology or surface marker expression. It has recently been shown that leukocyte counts can also be determined by cell-type-specific DNA methylation (DNAm). Such epigenetic leukocyte counting is applicable to small blood volumes and even frozen material, but for clinical translation, the method needs to be further refined and validated. METHODS: We further optimized and validated targeted DNAm assays for leukocyte deconvolution using 332 venous and 122 capillary blood samples from healthy donors. In addition, we tested 36 samples from ring trials and venous blood from 266 patients diagnosed with different hematological diseases. Deconvolution of cell types was determined with various models using DNAm values obtained by pyrosequencing or digital droplet PCR (ddPCR). RESULTS: Relative leukocyte quantification correlated with conventional blood counts for granulocytes, lymphocytes, B cells, T cells (CD4 or CD8), natural killer cells, and monocytes with pyrosequencing (r = 0.84; r = 0.82; r = 0.58; r = 0.50; r = 0.70; r = 0.61; and r = 0.59, respectively) and ddPCR measurements (r = 0.65; r = 0.79; r = 0.56; r = 0.57; r = 0.75; r = 0.49; and r = 0.46, respectively). In some patients, particularly with hematopoietic malignancies, we observed outliers in epigenetic leukocyte counts, which could be discerned if relative proportions of leukocyte subsets did not sum up to 100%. Furthermore, absolute quantification was obtained by spiking blood samples with a reference plasmid of known copy number. CONCLUSIONS: Targeted DNAm analysis by pyrosequencing or ddPCR is a valid alternative to quantify leukocyte subsets, but some assays require further optimization.

Distinct cord blood C-peptide, adipokine, and lipidomic signatures by in utero HIV exposure.

BACKGROUND: Early-life metabolic derangements in HIV-exposed uninfected (HEU) infants have been reported. METHODS: Pregnant women with HIV and HIV-uninfected pregnant women were enrolled with their newborns in a US cohort from 2011 to 2015. We measured cord insulin, C-peptide, and metabolic cytokines of HEU and HIV-unexposed uninfected (HUU) newborns using ELISA and metabolites, lipid subspecies, and eicosanoids via liquid chromatography/mass spectrometry. Linear regression was employed to assess the association of intrauterine HIV/ART with insulin and C-peptide. Graphical lasso regression was used to identify differences between metabolite/lipid subspecies networks associated with C-peptide. RESULTS: Of 118 infants, 56 were HEU, ART exposed. In adjusted analyses, mean cord insulin (ß = 0.295, p = 0.03) and C-peptide (ß = 0.522, p < 0.01) were significantly higher in HEU vs. HUU newborns. HEU neonates exhibited primarily positive associations between complex lipids and C-peptide, indicative of fuel storage, and augmented associations between cord eicosanoids and cytokines. HUU neonates exhibited negative associations with lipids and C-peptide indicative of increased fuel utilization. CONCLUSION: Higher cord insulin and C-peptide in HEU vs. HUU newborns as well as differences in cord metabolites, metabolic-related cytokines, and eicosanoids may reflect a propensity for fuel storage and an inflammatory milieu suggestive of fetal metabolic changes associated with in utero HIV/ART exposure. IMPACT: There is a paucity of studies assessing cord blood and neonatal metabolic health in HIV-exposed uninfected (HEU) newborns, an increasing population worldwide. Compared to HIV-unexposed uninfected (HUU) newborns, HEU newborns exhibit alterations in fuel homeostasis and an inflammatory milieu associated with in utero HIV/antiretroviral therapy (ART) exposure. The long-term implications of these neonatal findings are as yet unknown, but merit continued evaluation as this important and growing population ages into adulthood.

Decomposition Products of the Initiator Bis(2,4-dichlorobenzoyl)peroxide in the Silicone Industry: Human Biomonitoring in Plasma and Urine of Workers.

Bis(2,4-dichlorobenzoyl)peroxide (2,4-DCBP) is used as an initiator for silicone rubber production. During hot curing, 2,4-DCBP decomposes into 2,4-dichlorobenzoic acid, 1,3-dichlorobenzene, and the polychlorinated biphenyl (PCB) congeners PCB-47, PCB-51, and PCB-68. The extent of occupational exposure to these decomposition products has not been investigated yet. We determined for the first time the corresponding internal exposure of employees (n = 104) of a German silicone rubber facility by human biomonitoring in plasma and urine. Collected samples were investigated by gas chromatography/mass spectrometry for levels of PCBs in plasma and by liquid chromatography/tandem mass spectrometry for urinary post-shift levels of 2,4-dichlorobenzoic acid (2,4-DCBA) and the metabolites 3,5-dichlorocatechol (3,5-DCK), 2,4-dichlorophenol (2,4-DCP), and 3,5-dichlorophenol (3,5-DCP). PCB-47 and PCB-68 levels correlated significantly and were found in >97% of all samples with maximum values of 4.43 and 0.77 µg/L, respectively. 2,4-DCBA, 3,5-DCK, 2,4-DCP, and 3,5-DCP were quantified in >80% of all urine samples with maximum levels of 1.46; 26.92; 7.68; and 0.39 mg/L, respectively. There is a considerable uptake of decomposition products of 2,4-DCBP in workers of a silicone rubber facility, affecting employees in all work areas. Individual levels depended on the work task. Considering the carcinogenic potential of PCBs, the workers' additional exposure to PCB-47 and PCB-68 might be of concern.

Lower Emotion Regulation Competencies Mediate the Association between Impulsivity and Craving during Alcohol Withdrawal Treatment.

There is evidence that craving mediates the relationship between Impulsive Personality Traits (IPTs) and relapse during the treatment of an Alcohol Use Disorder (AUD). To provide tailored interventions, a deeper understanding of the relation between IPTs and craving, namely mediating processes, is important. Based on previous literature, we proposed that lower emotion regulation competencies mediate the relation between attentional as well as non-planning IPTs and craving. To investigate these interrelations, we used data from the baseline assessment (n = 320) of the SmartAssistEntz project (pre-registered in the German Clinical Trials Register [DRKS00017700]). Inpatients with a primary AUD diagnosis were interviewed using standardized self-report measures (IPTs: BIS-15, emotion regulation competencies: ERSQ, craving: OCDS-G short version) during their withdrawal treatment. Indirect effects were calculated using the SPSS macro PROCESS v3.5. Attentional as well as non-planning, but not motor, IPTs were associated with craving. Emotion regulation competencies mediated the relationship between attentional as well as non-planning IPTs and craving. Given their mediating role in the present study, it is interesting to investigate if addressing emotion regulation competencies can mitigate the negative influences of attentional and non-planning IPTs. The direct effect of attentional IPTs implicates alternate mediating processes, which should also be investigated in future research.

Welding Fume Instillation in Isolated Perfused Mouse Lungs-Effects of Zinc- and Copper-Containing Welding Fumes.

Zinc- and copper-containing welding fumes can cause systemic inflammation after exposure in humans. Recent ex vivo studies have shown that the observed inflammation originates from exposed immune cells. In vitro studies identified the soluble fraction of metal particles as the main effectors. Isolated perfused mouse lungs (IPLs) were perfused and ventilated for 270 min. Lungs were instilled with saline solution (control), welding fume particle suspension (WFs) or the soluble fraction of the welding fumes (SF-WFs). Bronchoalveolar lavage fluid (BALF) and perfusate samples were analyzed for cytokine levels and lung tissue mRNA expression levels were analyzed via RT-PCR. All lungs instilled with WFs did not complete the experiments due to a fatal reduction in tidal volume. Accordingly, IL-6 and MPO levels were significantly higher in BALF of WF lungs compared to the control. IL-6 and MPO mRNA expression levels were also increased for WFs. Lungs instilled with SF-WFs only showed mild reactions in tidal volume, with BALF and mRNA expression levels not significantly differing from the control. Zinc- and copper-containing welding fume particles adversely affect IPLs when instilled, as evidenced by the fatal loss in tidal volume and increased cytokine expression and secretion. The effects are mainly caused by the particles, not by the soluble fraction.

Association of impulsivity with quality of life and well-being after alcohol withdrawal treatment.

OBJECTIVES: Impulsivity is related to a higher risk of relapse in alcohol use disorders. However, besides drinking behavior, other recovery outcomes like physical and mental health-related quality of life are at least as important. The present study aimed to fill a research gap regarding the association of different impulsivity facets with health-related quality of life and well-being in alcohol use disorder. METHODS: Individuals with a primary alcohol use disorder diagnosis (n = 167) were interviewed with standardized self-report measures at the progressed stage of their withdrawal treatment and 6 weeks thereafter. Multiple regression models were calculated to examine the association of impulsivity, craving, and drinking patterns with health-related quality of life and well-being 6 weeks after withdrawal treatment, as well as the predictive role of impulsivity assessed during withdrawal for these two outcomes. RESULTS: Craving was associated with health-related quality of life and well-being 6 weeks after withdrawal. Likewise, non-planning and attentional impulsivity were associated with well-being 6 weeks after withdrawal. Motor impulsivity during withdrawal treatment predicted health-related quality of life 6 weeks thereafter. CONCLUSION: Impulsivity seems to be negatively related to health-related quality of life and well-being in the first weeks after alcohol withdrawal treatment, probably to a higher extent than drinking patterns, but differentiating between its facets seems to be important. These findings emphasize the importance of treatment approaches aiming at reduced impulsivity in the early recovery process.

Human detection thresholds of DC, AC, and hybrid electric fields: a double-blind study.

BACKGROUND: In the course of the ongoing transition of electric energy systems, transmission corridors are often upgraded to higher voltages and other technologies leading to another quality of human exposure. The study aims to determine human detection thresholds for direct current (DC), alternating current (AC), and hybrid electric fields (various DC; constant AC). METHODS: A total of 203 participants were exposed to DC, AC, and hybrid electric fields (EFs) in a highly specialized whole-body exposure laboratory using a double-blind experimental setting. Additionally, the participants were exposed to ion currents in part of the DC and hybrid sessions. To investigate environmental influences, relative humidity was changed in two subgroups during EF perception. Methods derived from the signal detection theory and the adaptive staircase procedure based on the single interval adjustment matrix were used to assess individual sensitivity and detection thresholds, respectively. RESULTS: The results indicated that detection thresholds of hybrid EF were lower compared to single EF presentation of DC or AC. Ion current exposure enhanced EF perception. High relative humidity facilitated DC EF perception, whereas low relative humidity reinforced the perception of AC EFs. CONCLUSIONS: With this systematic investigation of human perception of DC, AC, and hybrid EFs, detection thresholds were provided, which can help improve the construction processes of energy transmission systems and the prevention of unwanted sensory perception by contributing to the determination of limit values.

Longitudinal changes in telomere length in PCB-exposed individuals: interaction with CMV infection.

We recently demonstrated a significant shortening of age-adapted telomere length (TL) in lymphocytes of polychlorinated biphenyls (PCB)-exposed individuals. Here, we analyzed TL in individuals of the same PCB-exposed cohort during a 6-year follow-up period, investigating the change in TL between the first and second measurement as a function of time, concentration of PCBs and cytomegalovirus (CMV) infection. The age-adjusted TL of lymphocytes within the cohort of PCB-exposed individuals recovered from a first assessment in 2011 to a second assessment in 2017. Remarkably, if the concentration of lower chlorinated PCBs (LC PCBs) in 2011 was high (≥ 0.055 µg/L), the TL of CMV seropositive individuals remained significantly shortened both compared to age-adjusted controls as well as intra individually. This was confirmed by analysis of covariance as well as by multivariate linear mixed effects models. Since telomeres are responsive to various stress response pathways, including viral infection, we conclude that PCBs could contribute to immune senescence-like phenotypes associated with CMV infections and exacerbate negative aspects associated with the aging of the immune system.

Which factors influence the frequency of participation in longitudinal cohort studies? - An analysis of demographics, social factors, and medical preconditions in participants of the health effects in high level exposure to polychlorinated biphenyls (HELPcB) cohort.

The continuous drop out of participants in longitudinal studies is a trend that may be observed in nearly all fields of medical research. A reduced participation rate might compromise the power of statistical analysis as well as lead to an attrition bias of the study. The aim of this analysis was to identify influencing factors on participation frequency in the monitoring program Health Effects in High Level Exposure to polychlorinated biphenyls (HELPcB) study, a cohort investigation of occupationally polychlorinated biphenyls (PCB) exposed individuals. The HELPcB study was initiated in 2010 and consisted of 7 study visits. At the last cross-section in 2019, less than one third of the included patients still actively participated. As possible influencing factors on study participation frequency, demographic, social, and medical characteristics of the participants were examined. In addition, a logistic regression model to predict study participation behavior was calculated. An overall higher frequency of participation was observed, if participants joined the program together with relatives or friends and had a higher age. For PCB plasma levels, an exceedance of the biological reference value (BAR) and further factors, such as (1) professional qualification, (2) later inclusion, (3) type of participant and (4) occupational-related disease notification, significant differences in the participation frequency were observed in the univariate analysis. Only age and joined study participation remained significant in the multivariate logistic regression. In conclusion, it was possible to identify several social and occupational-related factors that influence the frequency of participation of study attendees.

Identification of Environmental and Experimental Factors Influencing Human Perception of DC and AC Electric Fields.

As part of the energy transition in Germany, high-voltage direct current (HVDC) lines producing DC electric fields (EF) are in planning. Since the human perception of DC EF was rarely investigated in the past, we aimed to identify environmental and experimental factors influencing the human perception of direct current (DC) EF, alternating current (AC) EF, and the co-exposure of DC EF and AC EF (hybrid EF) under whole-body exposure. Additionally, first estimates of DC EF and AC EF perception thresholds as well as differences in human perception of DC EF and AC EF concerning the type of sensation experienced and the affected body part were evaluated. A highly sophisticated exposure lab was built to expose participants to various EF strengths and ask for their assessment concerning the presence of an EF. To estimate the individual perception thresholds of 11 participants, the signal detection theory as well as the single-interval-adjustment matrix procedure were applied. Relative humidity could be identified as an environmental factor influencing the perception of AC EF and DC EF in different ways. An appropriate ramp slope and an exposure duration for future studies could be elaborated. Additionally, perception thresholds were lower under hybrid EF exposure than under DC EF or AC EF exposure alone. Cutaneous sensations evoked under DC EF and AC EF exposure were individually different and attributed to various parts of the body. Several environmental and experimental factors influencing the human perception of EF could be identified and provide an essential basis for a large-scale study. © 2021 Bioelectromagnetics Society.

PCB plasma level in different occupational groups in Iran.

Despite the ban of polychlorinated biphenyls (PCBs) some decades ago, concerns regarding their adverse health effects are continuing, because the workers employed for installation and repair of electrical equipment may be still exposed to PCBs. This study aimed to assess serum PCBs levels in workers in different industries. To do this, we determined the serum concentrations of 9 non-dioxin-like PCBs and 12 dioxin-like PCBs in 147 workers from seven occupational groups and 35 housewives. An electrical distribution company, paint manufacturer, and pesticide manufacturer were categorized as high probability exposure jobs, whereas turning and casting operations, polymer plastic manufacturing, professional driving, and office work were categorized as low probability exposure jobs. In addition, the average of PCB 138, 153, and 180 and PCB sums were observed to be significantly higher in paint manufacture workers compared to the another groups. In addition, the average PCB 118 level was higher in electrical distribution workers and housewives. Following the adjustment for age, blood lipid, residency place, and seafood in the regression model, the association of PCB 118 in electrical distribution workers and PCB 153 in paint manufacture workers remained significant. The results of this study served as further support for the hypothesis for an occupational basis for bioaccumulation of some PCB types. However, the plasma levels of almost all PCB congeners in Iran were found to be lower than many other countries.

Dirty deeds done dirt cheap: sensitization of prostate cancer cells to abiraterone treatment using hydroxylated polychlorinated biphenyls.

Effective targeting of androgen biosynthesis by the 17α-hydroxylase/17,20-lyase inhibitor abiraterone prolongs survival in a variety of prostate cancer patients. However, resistance to abiraterone treatment occurs frequently and the development of new drugs supporting or complementing abiraterone therapy is urgently needed. We recently reported antiproliferative and proapoptotic effects of hydroxylated polychlorinated biphenyls (PCBs) on various blood cell lines in vitro. Here we report the biological evaluation of the PCB28 derived OH-metabolites 3-OHCB28 or 3'-OHCB28 in prostate cancer cells. Depending on concentration, both metabolites inhibit the growth of PC3 cells, a cell line representing later stages of advanced prostate cancer. In addition 3'-OHCB28 reduced the necessary concentration of abiraterone required for the inhibition of PC3 cells by a factor of 4. Western blot analysis of cytoprotective heatshock proteins (HSP) implicated a significant reduction of HSP27 expression by 3'-OHCB28 in PC3 cells. Given the known HSP27 suppressive role of abiraterone, our results therefore suggest, that that the pharmacological interaction between abiraterone and 3'-OHCB28 in PC3 cells could be produced by the combined effect of both substances on the expression of HSPs, especially the expression of HSP27. Including the known dose response linkages and pharmacokinetic characteristics of the OH-metabolites described here, we conclude, that the use of hydroxylated PCBs can be supportive for the anti-proliferative treatment of prostate cancer and merits further investigation.

Assessment of a potential PCB exposure among (former) underground miners by hydraulic fluids.

Polychlorinated biphenyls (PCBs) were used in technical mixtures of different PCB congeners as hydraulic fluids in underground mining in Germany in North Rhine-Westphalia, Ibbenbueren, and Saarland from the mid-1960s to 1986. Mine workers who were involved in maintenance and repair or operation of hydraulically driven machines in underground mines were potentially exposed to liquids containing PCBs. The aim of the present study was to investigate whether this potential exposure which occurred more than 30 years ago was still detectable. Biomonitoring and a structured work anamnesis were conducted on a representative sample of 210 miners. PCBs in plasma were measured by gas chromatography coupled to mass spectrometry with an LOQ of 0.01 µg/L plasma for all congeners. The primary aim was comparison of the number of exceedances of the underlying comparative values for PCB congeners with those of the general population. Secondary endpoint was the question whether there were regional differences in potential PCB exposure. The biomonitoring showed a significant difference for PCB 74 with N= 94 (45%); for PCB 114 with N = 64 (31%) and for PCB 99 and PCB 105 with N = 23 (11%) and N = 19 (9%) of 210 measurements above the reference value compared to the general population (5%). The all over detection frequencies (µg/L plasma median | SD | min |max) of these congeners were as follows:PCB 74: 0.128 | 0.481 | < LOD | 3.098; PCB 99:0.035 | 0.078 | < LOD | 0.582PCB 105: 0.005 | 0.031 | < LOD | 0.307; PCB 114:0.005 | 0.024 | < LOD | 0.140Regional differences were not detectable.

Building an allostatic load index from data of occupational medical checkup examinations: a feasibility study.

The allostatic load index (ALI) assesses the physiological adaption to chronic stress by cumulative changes in the circulation, respiration, inflammation, metabolic and anthropometric systems. The ALI thus can function as a risk marker for secondary prevention in occupational medicine. The aim of this study was to investigate the feasibility of creating a predictive marker by using data from an executive checkup program of an international company and to examine its relationship to work-related surrogate health parameters. Datasets from 307 examinations of 151 executives (19 males and 132 females) were available. Each participant attended at least one checkup examination between 2003 and 2015. The mean age was 43.6 (SD ±6.6, 31-64y). We developed four different ALIs with different biomarkers of the cardio-vascular, immune, metabolic and anthropometric systems. As a primary mediator, the thyroid-stimulating hormone was used as a proxy. For each ALI, the associations with the work ability index (WAI) and categories of sick leave days (SLD) were examined. Zero inflation was considered for SLD. One ALI showed a significant negative association with the WAI (B = -0.680, SE =0.266, p = .049). The results of a second ALI had a similar trend (B= -0.355, SE =0.201, p = .081). After adjustment for zero inflation two other ALIs showed a positive association with SLD. This study provides the first hints that biomarkers form a secondary prevention program are useful in calculating a meaningful ALI. Thus, the concept of allostatic load could be used in workplace health-promotion.