Search

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, structured knowledge to mitigate a patient's specific risk of developing adverse events are limited. Nevertheless, there is an exponential growth of clinical studies combining conventional therapies such as radiation therapy (RT) with ICIs. Cutaneous reactions are among the most common adverse events after monotherapy with either ICIs or RT. So far, little is known about interindividual differences for the risk of developing severe tissue toxicity after the combination of RT with ICIs, and the underlying biological mechanisms are ill defined. We used experimental models of RT-induced skin injury to analyze skin toxicity after simultaneous application of ICIs. We compared different RT regimens such as fractionated or stereotactic RT with varying dose intensity. Strikingly, we found that simultaneous application of RT and ICIs did not significantly aggravate acute skin injury in two different mouse strains. Detailed examination of long-term tissue damage of the skin revealed similar signs of epidermal hyperplasia, dermal fibrosis, and adnexal atrophy. In summary, we here present the first experimental study demonstrating the excellent safety profiles of concurrent treatment with RT and ICIs. These findings will help to interpret the development of adverse events of the skin after radioimmunotherapy and guide the design of new clinical trials and clinical decision-making in individual cases. © 2022 The Authors. The Journal of Pathology published by John Wileyamp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Although the health benefits of swimming are well-documented, health effects such as asthma and bladder cancer are linked to disinfection by-products (DBPs) in pool water. DBPs are formed from the reaction of disinfectants such as chlorine (Cl) or bromine (Br) with organics in the water. Our previous study (Daiber et al., Environ. Sci. Technol. 50, 6652; 2016) found correlations between the concentrations of classes of DBPs and the mutagenic potencies of waters from chlorinated or brominated swimming pools and spas. We extended this study by identifying significantly different concentrations of 21 individual DBPs in brominated or chlorinated pool and spa waters as well as identifying which DBPs and additional DBP classes were most associated with the mutagenicity of these waters. Using data from our previous study, we found that among 21 DBPs analyzed in 21 pool and spa waters, the concentration of bromoacetic acid was significantly higher in Br-waters versus Cl-waters, whereas the concentration of trichloroacetic acid was significantly higher in Cl-waters. Five Br-DBPs (tribromomethane, dibromochloroacetic acid, dibromoacetonitrile, bromoacetic acid, and tribromoacetic acid) had significantly higher concentrations in Br-spa versus Cl-spa waters. Cl-pools had significantly higher concentrations of Cl-DBPs (trichloroacetaldehyde, trichloromethane, dichloroacetic acid, and chloroacetic acid), whereas Br-pools had significantly higher concentrations of Br-DBPs (tribromomethane, dibromoacetic acid, dibromoacetonitrile, and tribromoacetic acid). The concentrations of the sum of all 4 trihalomethanes, all 11 Br-DBPs, and all 5 nitrogen-containing DBPs were each significantly higher in brominated than in chlorinated pools and spas. The 8 Br-DBPs were the only DBPs whose individual concentrations were significantly correlated with the mutagenic potencies of the pool and spa waters. These results, along with those from our earlier study, highlight the importance of Br-DBPs in the mutagenicity of these recreational waters.

CONTEXT Evidence suggests that teen dating violence (TDV) is associated with long-term adverse outcomes, but these associations have not been systematically assessed. OBJECTIVES To conduct a systematic review of the longitudinal associations between TDV and negative outcomes, including mental and physical health, reoccurrence of violence in intimate relationships, and high-risk behaviors (substance use and sexual behaviors). DATA SOURCES Peer-reviewed articles published in English were searched in PsycINFO/Eric/PsycArticles, PubMed, and Web of Science database from inception to November 2022. STUDY SELECTION Prospective studies that assessed TDV during adolescence, had a follow-up of at least ≥1 year, and evaluated the associations of TDV with health, violence in romantic intimate relationships, or risk behaviors were included. DATA EXTRACTION Study characteristics, baseline data, and follow-up outcomes were extracted from included studies. RESULTS Thirty-eight studies involving 23 unique samples were analyzed. Findings showed that TDV in adolescence was associated with future teen dating and intimate partner violence in adulthood. Studies also indicated that TDV was longitudinally associated with increasing high-risk behaviors (ie, marijuana and alcohol use) and poor mental health outcomes (particularly for victimization). There was unclear evidence on the longitudinal link between TDV and suicidal attempts. Significant associations between TDV and negative outcomes were reported more frequently among females compared with males. LIMITATIONS Length of follow-up varied across studies. CONCLUSIONS Dating violence in adolescence may represent a risk factor for a wide range of long-term outcomes. Female adolescents reporting TDV may be at higher risk of adverse outcomes compared with males.

Purpose: Spatially Fractionated Radiation Therapy (SFRT) is characterized by large differences in peak and valley doses. Preclinical and clinical studies suggest that differences in biological mechanisms lead to differential normal tissue and tumor response compared to uniform irradiation. We hypothesize that to evaluate clinical effectiveness and understand fundamental biological mechanisms, radiobiological rather than physical dose quantities should be utilized for comparisons. The aim of this work is to determine whether Equivalent Uniform Dose (EUD) is a superior predictor of cell survival than absorbed dose.Methods: Absorbed dose parameters were compared to the Equivalent Uniform Dose to assess their predictive value for the relative effectiveness of uniform and SFRT with X-rays. A Bayesian bootstrap technique was utilized to model uncertainties in the biological fit parameters for a human fibroblast (MRC5) and two human tumor cell lines (LN18 and A549). Dose uncertainties were evaluated through measurements and error modeling of SFRT profiles. A dimensionless Relative Effectiveness Factor (REF) is proposed to quantify differences between uniform and SFRT irradiation.Results: For all cell lines, cell survival after SFRT matched uniform irradiation within the estimated uncertainties at equal values of the EUD. Average and peak dose showed poor correlation with in vitro cell survival. The proposed REF factor is dose dependent and suggests enhanced cell killing for both tumor cell lines (1.14 ± .08 for LN18, 1.32 ± .13 for A549 at 8 Gy EUD) for SFRT. Normal human fibroblasts showed reduced cell killing relative to uniform irradiation (.58 ± .06 for MRC5). Synthetically generated SFRT dose profiles revealed that EUD uncertainties are dominated by valley dose uncertainties, especially at high doses.Discussion: EUD is more predictive of cell survival than average or valley dose. Valley dose is close to equal to the EUD for values >10 Gy and has the advantage of being independent of uncertainties in biological parameters. The REF is a novel and useful metric to compare quantitative differences in SFRT and uniform irradiation.Conclusion: EUD is recommended for comparisons of SFRT and uniform irradiation. The results suggest an increase in survival of normal-human fibroblast cells and reduced survival for both tumor cell lines after SFRT relative to uniform irradiation.

Online supplemental material is available for this article.

Early-career faculty (ECF) are faced with maintaining excellence in teaching and research for tenure. However, many enter academia with little or no teaching experience. Madison Teaching and Learni...

Precise and accurate radiocarbon chronologies are essential to achieve tight chronological control for the ~ 750-years since Polynesian settlement of New Zealand. This goal has, however, been elusive. While radiocarbon datasets in the region are typically dominated by marine and estuarine shell dates, such chronological information has been ignored by those interpreting the timing of key events because a detailed regional calibration methodology for marine shell, comparable to the highly precise Southern Hemisphere calibration curve, is lacking. In this paper, we present the first temporal 14C marine offset (ΔR) model for New Zealand based on paired estuarine/marine and terrestrial radiocarbon dates from 52 archaeological contexts. Our dataset displays significant offsets between the measured New Zealand data and the modelled global marine radiocarbon curve. These shifts are associated with oceanographic fluctuation at the onset of the Little Ice Age ~ AD 1350–1450 (650–500 BP). The application of a regional and temporal correction to archaeological shell dates provides complimentary information to terrestrial radiocarbon production and has the potential to add structure to the blurred chronology that has plagued archaeological theories about the colonization of New Zealand, and other Pacific islands, for decades.

Amyloidosis is a localized or systemic process where extracellular insoluble plasma protein fibers are deposited into tissues. Localized amyloidosis is rare and curable by surgical resection. While the head and neck region represents 19% of localized amyloidosis cases, only one other case of bilateral involvement of the pharyngeal tonsils has been published in the international literature. We report a case of asymptomatic amyloidosis isolated to the bilateral palatine tonsils and a cervical lymph node in a 59-year-old male. Systemic amyloidosis was ruled out through multidisciplinary consultation, and resection of the masses was performed. This represents the second reported case of bilateral tonsillar amyloidosis.

The increased number of cell divisions undergone by spermatogonia of older fathers cannot fully account for the observed increase in germline genetic damage. Studies have shown that the mechanisms induced in germ cells in response to oxidative damage varies with age, that DNA repair efficiency declines, and both sperm DNA damage and spontaneous mutations increase. However, it is not known whether the altered response with age is a cause, or consequence, of an age-associated change in cell susceptibility to genetic damage. Following a single 150 mg/kg dose of cyclophosphamide (CP), young (8-weeks old) and aged (17-month old) male mice were examined 24 h later for induced genetic damage in epididymal spermatozoa using the alkaline comet and sperm chromatin stability assays. Apoptosis among testicular cells was examined on tissue cross-sections using the TUNEL assay. Sperm showed no significant increase in DNA strand breaks with age (detected by the comet assay) and no change in sperm chromatin stability (detected by the SCSA assay). Following CP treatment, there was no effect on DNA-strand breakage but sperm chromatin instability was significantly higher. Furthermore, it was also significantly elevated in old treated, compared with young treated, animals suggesting that increased age affects the sensitivity of epididymal sperm to chromatin damage. There was no difference in apoptosis in testicular germ cells from either young or old control animals, while CP administration resulted in a significant increase in apoptosis among young animals but not old animals. Following genotoxin exposure, an increase in chromatin instability in the spermatozoa of old animals and a decrease in the ability of their testicular germ cells undergo apoptosis suggests an age-related decrease in genome protection mechanisms. Since those germ cells are only transiently present in the testis, it is likely that this age-related deterioration originates in the spermatogonial stem cells. The findings are also evidence that the safety evaluation of reproductive genotoxins should consider young and old individuals separately.

DNA double strand breaks (DSB) play a pivotal role for cellular damage, which is a hazard encountered in toxicology and radiation protection, but also exploited e.g. in eradicating tumors in radiation therapy. It is still debated whether and in how far clustering of such DNA lesions leads to an enhanced severity of induced damage. Here we investigate - using focused spots of ionizing radiation as damaging agent - the spatial extension of DNA lesion patterns causing cell inactivation. We find that clustering of DNA damage on both the nm and µm scale leads to enhanced inactivation compared to more homogeneous lesion distributions. A biophysical model interprets these observations in terms of enhanced DSB production and DSB interaction, respectively. We decompose the overall effects quantitatively into contributions from these lesion formation processes, concluding that both processes coexist and need to be considered for determining the resulting damage on the cellular level.

Microcystins are common freshwater cyanobacterial toxins that affect liver function. The toxicities of five microcystin congeners (microcystin-LA (MCLA), MCLR, MCLY, MCRR, and MCYR) commonly observed in harmful algal blooms (HABs) were evaluated in BALB/c mice after a single oral administration of doses ranging from those that were no observed adverse effect levels (NOAELs) to lowest observed adverse effect levels (LOAELs). Animals were monitored for changes in behavior and appearance, and euthanized 24 h after dosing. Test endpoints included clinical changes, necropsy observations, and serum indicators of hepatic toxicity and general homeostasis. Doses were 0.5&ndash, 7 mg/kg MCLA, 0.5&ndash, 11 mg/kg MCLR, 1&ndash, 7 mg/kg MCLY, 7&ndash, 22 mg/kg MCRR, and 3&ndash, 11 mg/kg MCYR. MCLA at 3 mg/kg elevated liver/body weight ratio and liver score, ALT, AST, and GLDH, indicating hepatic toxicity, reduced serum glucose and highly elevated total serum bilirubin. MCLR and MCLY induced similar effects with LOAELs of 5 mg/kg, although a greater extent and severity of effects were observed in MCLR animals. MCRR exposure at 22 mg/kg was associated with reduced serum glucose. MCYR induced scattered liver effects at 7 mg/kg and reduced serum glucose levels at 5 mg/kg. The results indicate significant differences in congener-induced toxicity after microcystin exposure.

Background: Treatment resistance of glioblastoma multiforme to chemo- and radiotherapy remains a challenge yet to overcome. In particular, the O6-methylguanine-DNA-methyltransferase (MGMT) promoter unmethylated patients have only little benefit from chemotherapy treatment using temozolomide since MGMT counteracts its therapeutic efficacy. Therefore, new treatment options in radiotherapy need to be developed to inhibit MGMT and increase radiotherapy response. Methods: Lomeguatrib, a highly specific MGMT inhibitor, was used to inactivate MGMT protein in vitro. Radiosensitivity of established human glioblastoma multiforme cell lines in combination with lomeguatrib was investigated using the clonogenic survival assay. Inhibition of MGMT was analyzed using Western Blot. Cell cycle distribution and apoptosis were investigated to determine the effects of lomeguatrib alone as well as in combination with ionizing radiation. Results: Lomeguatrib significantly decreased MGMT protein and reduced radiation-induced G2/M arrest. A radiosensitizing effect of lomeguatrib was observed when administered at 1 µM and increased radioresistance at 20 µM. Conclusion: Low concentrations of lomeguatrib elicit radiosensitization, while high concentrations mediate a radioprotective effect.

Short-term biomarkers of toxicity have an increasingly important role in the screening and prioritization of new chemicals. In this study, we examined early indicators of liver toxicity for three reference organophosphate (OP) chemicals, which are among the most widely used insecticides in the world. The OP methidathion was previously shown to increase the incidence of liver toxicity, including hepatocellular tumors, in male mice. To provide insights into the adverse outcome pathway (AOP) that underlies these tumors, effects of methidathion in the male mouse liver were examined after 7 and 28 day exposures and compared to those of two other OPs that either do not increase (fenthion) or possibly suppress liver cancer (parathion) in mice. None of the chemicals caused increases in liver weight/body weight or histopathological changes in the liver. Parathion decreased liver cell proliferation after 7 and 28 days while the other chemicals had no effects. There was no evidence for hepatotoxicity in any of the treatment groups. Full-genome microarray analysis of the livers from the 7 and 28 day treatments demonstrated that methidathion and fenthion regulated a large number of overlapping genes, while parathion regulated a unique set of genes. Examination of cytochrome P450 enzyme activities and use of predictive gene expression biomarkers found no consistent evidence for activation of AhR, CAR, PXR, or PPARα. Parathion suppressed the male-specific gene expression pattern through STAT5b, similar to genetic and dietary conditions that decrease liver tumor incidence in mice. Overall, these findings indicate that methidathion causes liver cancer by a mechanism that does not involve common mechanisms of liver cancer induction.

1,1,2,2-tetrafluoro-2-[1,1,1,2,3,3-hexafluoro-3-(1,1,2,2-tetrafluoroethoxy)propan-2-yl]oxyethane-1-sulfonic acid (PFESA-BP2) was first detected in 2012 in the Cape Fear River downstream of an industrial manufacturing facility. It was later detected in the finished drinking water of municipalities using the Cape Fear River for their water supply. No toxicology data exist for this contaminant despite known human exposure. To address this data gap, mice were dosed with PFESA-BP2 at 0, 0.04, 0.4, 3, and 6 mg/kg-day for 7 days by oral gavage. As an investigative study, the final dose groups evolved from an original dose of 3 mg/kg which produced liver enlargement and elevated liver enzymes. The dose range was extended to explore a no effect level. PFESA-BP2 was detected in the sera and liver of all treated mice. Treatment with PFESA-BP2 significantly increased the size of the liver for all mice at 3 and 6 mg/kg-day. At the 6 mg/kg-day dose, the liver more than doubled in size compared to the control group. Male mice treated with 3 and 6 mg/kg-day and females treated with 6 mg/kg-day demonstrated significantly elevated serum markers of liver injury including alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), and liver/body weight percent. The percent of PFESA-BP2 in serum relative to the amount administered was similar in male and female mice, ranged from 9 to 13 %, and was not related to dose. The percent accumulation in the liver of the mice varied by sex (higher in males), ranged from 30 to 65 %, and correlated positively with increasing dose level.

Microcystins (MCs) are common cyanobacterial toxins that occur in freshwaters worldwide. Only two of the &gt, 200 MC variants have been tested for potential toxicity after oral exposure. This paper reports on the toxicity of 10 different MC congeners identified in algal blooms, microcystin-LR (MCLR), MCLA, MCLF, MCLW, MCLY, MCRR, [Asp3]MCRR, [Asp3,Dhb7]MCRR, MCWR, and MCYR after single administrations to BALB/c mice. In a preliminary MCLR dose&ndash, response study of 3 to 9 mg/kg doses, &ge, 5 mg/kg induced clinical changes, increased serum levels of ALT, AST, and GLDH, liver congestion, increased liver/body weight ratios, and reduced serum glucose and total protein. Based on the extent of these effects, the 10 congeners were administered as single 7 mg/kg oral doses and toxicity evaluated. The greatest toxicity was observed with MCLA and MCLR including a high percentage of moribundity. In addition to eliciting effects similar to those listed above for MCLR, MCLA also induced serum alterations indicative of jaundice. MCLY, and MCYR induced changes like those noted with MCLR, but to lesser extents. MCLW and MCLF exhibited some serum and morphological changes associated with hepatic toxicity, while there were few indications of toxicity after exposures to MCRR, [Asp3]MCRR, [Asp3,Dhb7]MCRR, or MCWR. These data illustrate a wide spectrum of hepatic effects and different potencies of these MC congeners.

Species of the genus Shewanella are widespread in nature in various habitats, however, little is known about phages affecting Shewanella sp. Here, we report the isolation of phages from diverse freshwater environments that infect and lyse strains of Shewanella oneidensis and other Shewanella sp. Sequence analysis and microscopic imaging strongly indicate that these phages form a so far unclassified genus, now named Shewanella phage Thanatos, which can be positioned within the subfamily of Tevenvirinae (Duplodnaviria; Heunggongvirae; Uroviricota; Caudoviricetes; Caudovirales; Myoviridae; Tevenvirinae). We characterized one member of this group in more detail using S. oneidensis MR-1 as a host. Shewanella phage Thanatos-1 possesses a prolate icosahedral capsule of about 110 nm in height and 70 nm in width and a tail of about 95 nm in length. The dsDNA genome exhibits a GC content of about 34.5%, has a size of 160.6 kbp and encodes about 206 proteins (92 with an annotated putative function) and two tRNAs. Out of those 206, MS analyses identified about 155 phage proteins in PEG-precipitated samples of infected cells. Phage attachment likely requires the outer lipopolysaccharide of S. oneidensis, narrowing the phage’s host range. Under the applied conditions, about 20 novel phage particles per cell were produced after a latent period of approximately 40 min, which are stable at a pH range from 4 to 12 and resist temperatures up to 55°C for at least 24 h. Addition of Thanatos to S. oneidensis results in partial dissolution of established biofilms, however, early exposure of planktonic cells to Thanatos significantly enhances biofilm formation. Taken together, we identified a novel genus of Myophages affecting S. oneidensis communities in different ways.

Background: Per- and polyfluoroalkyl substances (PFAS) are a diverse class of industrial chemicals with widespread environmental occurrence. Exposure to long-chain PFAS is associated with developmental toxicity, prompting their replacement with short-chain and fluoroether compounds. There is growing public concern over the safety of replacement PFAS. Objective: We aimed to group PFAS based on shared toxicity phenotypes. Methods: Zebrafish were developmentally exposed to 4,8-dioxa-3H-perfluorononanoate (ADONA), perfluoro-2-propoxypropanoic acid (GenX Free Acid), perfluoro-3,6-dioxa-4-methyl-7-octene-1-sulfonic acid (PFESA1), perfluorohexanesulfonic acid (PFHxS), perfluorohexanoic acid (PFHxA), perfluoro-n-octanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), or 0.4% dimethyl sulfoxide (DMSO) daily from 0–5 d post fertilization (dpf). At 6 dpf, developmental toxicity and developmental neurotoxicity assays were performed, and targeted analytical chemistry was used to measure media and tissue doses. To test whether aliphatic sulfonic acid PFAS cause the same toxicity phenotypes, perfluorobutanesulfonic acid (PFBS; 4-carbon), perfluoropentanesulfonic acid (PFPeS; 5-carbon), PFHxS (6-carbon), perfluoroheptanesulfonic acid (PFHpS; 7-carbon), and PFOS (8-carbon) were evaluated. Results: PFHxS or PFOS exposure caused failed swim bladder inflation, abnormal ventroflexion of the tail, and hyperactivity at nonteratogenic concentrations. Exposure to PFHxA resulted in a unique hyperactivity signature. ADONA, PFESA1, or PFOA exposure resulted in detectable levels of parent compound in larval tissue but yielded negative toxicity results. GenX was unstable in DMSO, but stable and negative for toxicity when diluted in deionized water. Exposure to PFPeS, PFHxS, PFHpS, or PFOS resulted in a shared toxicity phenotype characterized by body axis and swim bladder defects and hyperactivity. Conclusions: All emerging fluoroether PFAS tested were negative for evaluated outcomes. Two unique toxicity signatures were identified arising from structurally dissimilar PFAS. Among sulfonic acid aliphatic PFAS, chemical potencies were correlated with increasing carbon chain length for developmental neurotoxicity, but not developmental toxicity. This study identified relationships between chemical structures and in vivo phenotypes that may arise from shared mechanisms of PFAS toxicity. These data suggest that developmental neurotoxicity is an important end point to consider for this class of widely occurring environmental chemicals. https://doi.org/10.1289/EHP5843

Precise and accurate radiocarbon chronologies are essential to achieve tight chronological control for the ~ 750-years since Polynesian settlement of New Zealand. This goal has, however, been elusive. While radiocarbon datasets in the region are typically dominated by marine and estuarine shell dates, such chronological information has been ignored by those interpreting the timing of key events because a detailed regional calibration methodology for marine shell, comparable to the highly precise Southern Hemisphere calibration curve, is lacking. In this paper, we present the first temporal 14C marine offset (ΔR) model for New Zealand based on paired estuarine/marine and terrestrial radiocarbon dates from 52 archaeological contexts. Our dataset displays significant offsets between the measured New Zealand data and the modelled global marine radiocarbon curve. These shifts are associated with oceanographic fluctuation at the onset of the Little Ice Age ~ AD 1350–1450 (650–500 BP). The application of a regional and temporal correction to archaeological shell dates provides complimentary information to terrestrial radiocarbon production and has the potential to add structure to the blurred chronology that has plagued archaeological theories about the colonization of New Zealand, and other Pacific islands, for decades.

Tumor cells frequently overexpress heat shock protein 70 (Hsp70) and present it on their cell surface, where it can be recognized by pre‐activated NK cells. In our retrospective study the expression of Hsp70 was determined in relation to tumor‐infiltrating CD56+ NK cells in formalin‐fixed paraffin embedded (FFPE) tumor specimens of patients with SCCHN (N = 145) as potential indicators for survival and disease recurrence. All patients received radical surgery and postoperative cisplatin‐based radiochemotherapy (RCT). In general, Hsp70 expression was stronger, but with variable intensities, in tumor compared to normal tissues. Patients with high Hsp70 expressing tumors (scores 3–4) showed significantly decreased overall survival (OS; p = 0.008), local progression‐free survival (LPFS; p = 0.034) and distant metastases‐free survival (DMFS; p = 0.044), compared to those with low Hsp70 expression (scores 0–2), which remained significant after adjustment for relevant prognostic variables. The adverse prognostic value of a high Hsp70 expression for OS was also observed in patient cohorts with p16‐ (p = 0.001), p53‐ (p = 0.0003) and HPV16 DNA‐negative (p = 0.001) tumors. The absence or low numbers of tumor‐infiltrating CD56+ NK cells also correlated with significantly decreased OS (p = 0.0001), LPFS (p = 0.0009) and DMFS (p = 0.0001). A high Hsp70 expression and low numbers of tumor‐infiltrating NK cells have the highest negative predictive value (p = 0.00004). In summary, a strong Hsp70 expression and low numbers of tumor‐infiltrating NK cells correlate with unfavorable outcome following surgery and RCT in patients with SCCHN, and thus serve as negative prognostic markers., What's new? It's difficult to predict how a patient with squamous‐cell carcinoma of the head and neck (SCCHN) will respond to treatment, because every tumor is different. In this study, the authors identified two pre‐treatment measures that were associated with poor prognosis following surgery and RCT: high levels of staining for a protein called Hsp70 in tumor cells, and low numbers of tumor‐infiltrating NK lymphocytes. These measures may thus serve as useful prognostic biomarkers for predicting the response of SCCHN to therapy.

Background Asymptomatic carotid artery stenosis (ACS) has a low risk of stroke. To achieve an advantage over noninterventional best medical treatment (BMT), carotid endarterectomy (CEA) or carotid artery stenting (CAS) must be performed with the lowest possible risk of stroke. Therefore, an analysis of risk-elevating factors is essential. Grade of ipsilateral and contralateral stenosis as well as plaque morphology are known risk factors in ACS. Methods The randomized, controlled, multicenter SPACE-2 trial had to be stopped prematurely after recruiting 513 patients. 203 patients were randomized to CEA, 197 to CAS, and 113 to BMT. Within one year, risk factors such as grade of stenosis and plaque morphology were analyzed. Results Grade of contralateral stenosis (GCS) was higher in patients with any stroke (50%ECST vs. 20%ECST; p=0.012). Echolucent plaque morphology was associated with any stroke on the day of intervention (OR 5.23; p=0.041). In the periprocedural period, any stroke was correlated with GCS in the CEA group (70%ECST vs. 20%ECST; p=0.026) and with echolucent plaque morphology in the CAS group (6% vs. 1%; p=0.048). In multivariate analysis, occlusion of the contralateral carotid artery (CCO) was associated with risk of any stroke (OR 7.00; p=0.006), without heterogeneity between CEA and CAS. Conclusion In patients with asymptomatic carotid artery stenosis, GCS, CCO, as well as echolucent plaque morphology were associated with a higher risk of cerebrovascular events. The risk of stroke in the periprocedural period was increased by GCS in CEA and by echolucent plaque in CAS. Due to small sample size, results must be interpreted carefully.

Current strategies for predicting carcinogenic mode of action for nongenotoxic chemicals are based on identification of early key events in toxicity pathways. The goal of this study was to evaluate short-term key event indicators resulting from exposure to androstenedione (A4), an androgen receptor agonist and known liver carcinogen in mice. Liver cancer is more prevalent in men compared with women, but androgen-related pathways underlying this sex difference have not been clearly identified. Short-term hepatic effects of A4 were compared with reference agonists of the estrogen receptor (ethinyl estradiol, EE) and glucocorticoid receptor (prednisone, PRED). Male B6C3F1 mice were exposed for 7 or 28 days to A4, EE, or PRED. EE increased and PRED suppressed hepatocyte proliferation, while A4 had no detectable effects. In a microarray analysis, EE and PRED altered >3000 and >670 genes, respectively, in a dose-dependent manner, whereas A4 did not significantly alter any genes. Gene expression was subsequently examined in archival liver samples from male and female B6C3F1 mice exposed to A4 for 90 days. A4 altered more genes in females than males and did not alter expression of genes linked to activation of the mitogenic xenobiotic receptors AhR, CAR, and PPARα in either sex. A gene expression biomarker was used to show that in female mice, the high dose of A4 activated the growth hormone-regulated transcription factor STAT5b, which controls sexually dimorphic gene expression in the liver. These findings suggest that A4 induces subtle age-related effects on STAT5b signaling that may contribute to the higher risk of liver cancer in males compared with females.

Resume L’auteur developpe l’idee que tout interet pour une reflexion epistemologique sur des demarches analogiques entre la psychanalyse et d’autres sciences oblige a prendre en consideration les interrogations qu’elle suscite dans le cadre d’une theorie de la connaissance. La mise en discussion de la notion d’analogie est apparue necessaire a partir du moment ou l’on quitte a la fois les demarches utilisees par la science en lien avec ses objets d’etude dans leur rapport sujet/objet de recherche et les questions que pose la pensee epistemologique et que l’on s’adresse a des sciences ou les rapports d’analogie avec la psychanalyse sont de plus en plus eloignes, souvent incompatibles. Ce travail analogique se revele particulierement complexe lorsqu’on traite de la notion d’inconscient et de son usage par des non-psychanalystes.

The compound BMAA (β-N-methylamino-L-alanine) has been postulated to play a significant role in four serious neurological human diseases: Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) found on Guam, and ALS, Parkinsonism, and dementia that occur globally. ALS/PDC with symptoms of all three diseases first came to the attention of the scientific community during and after World War II. It was initially associated with cycad flour used for food because BMAA is a product of symbiotic cycad root-dwelling cyanobacteria. Human consumption of flying foxes that fed on cycad seeds was later suggested as a source of BMAA on Guam and a cause of ALS/PDC. Subsequently, the hypothesis was expanded to include a causative role for BMAA in other neurodegenerative diseases including Alzheimer's disease (AD) through exposures attributed to proximity to freshwaters and/or consumption of seafood due to its purported production by most species of cyanobacteria. The hypothesis that BMAA is the critical factor in the genesis of these neurodegenerative diseases received considerable attention in the medical, scientific, and public arenas. This review examines the history of ALS/PDC and the BMAA-human disease hypotheses; similarities and differences between ALS/PDC and the other diseases with similar symptomologies; the relationship of ALS/PDC to other similar diseases, studies of BMAA-mediated effects in lab animals, inconsistencies and data gaps in the hypothesis; and other compounds and agents that were suggested as the cause of ALS/PDC on Guam. The review concludes that the hypothesis of a causal BMAA neurodegenerative disease relationship is not supported by existing data.

International audience; The first stereocontrolled Cu-catalyzed sequential 1,6/1,4-asymmetric conjugate addition (ACA) of C-metalated hard nucleophiles to cyclic dienones is reported. The use of DiPPAM (diphenylphosphinoazomethinylate) followed by a phosphoramidite as the stereoinducing ligands facilitated both high ee values for the 1,6-ACA and high de values for the 1,4-ACA reaction components, which thus gave enantioenriched 1,3-dialkylated moieties. The absolute configurations were determined by using vibrational circular dichroism (VCD) and optical rotatory dispersion (ORD) spectroscopy, in combination with DFT calculations and X-ray analysis. Interestingly, DFT calculations for the mechanism of enantioselective 1,6-addition by using an unprecedented Cu-Zn bimetallic catalytic system confirmed this attribution. Lastly, exploring intramolecular cyclization avenues for enantioenriched 1,3-dialkylated products provided access to the challenging drimane skeleton.

Radiotherapy (RT) is an established treatment for patients with primary and recurrent prostate cancer. Herein, the effects of definitive and salvage RT on the composition of lymphocyte subpopulations were investigated in patients with prostate cancer to study potential immune effects. A total of 33 prostate cancer patients were treated with definitive (n = 10) or salvage RT (n = 23) after biochemical relapse. The absolute number of lymphocytes and the distribution of lymphocyte subpopulations were analyzed by multiparameter flow cytometry before RT, at the end of RT, and in the follow-up period. Absolute lymphocyte counts decreased significantly after RT in both patient groups and a significant drop was observed in the percentage of B cells directly after RT from 10.1 ± 1.3 to 6.0 ± 0.7% in patients with definitive RT and from 9.2 ± 0.8 to 5.8 ± 0.7% in patients with salvage RT. In contrast, the percentages of T and natural killer (NK) cells remained unaltered directly after RT in both patient groups. However, 1 year after RT, the percentage of CD3+ T cells was significantly lower in patients with definitive and salvage RT. The percentage of regulatory T cells was slightly upregulated in primary prostate cancer patients after definitive RT, but not after salvage RT. Definitive and salvage RT exert similar effects on the composition of lymphocyte subpopulations in prostate cancer patients. Total lymphocyte counts are lower in both patient groups compared to healthy controls and further decreased after RT. B cells are more sensitive to definitive and salvage RT than T and NK cells.

Epidemiological and experimental data suggest that obesity exacerbates the health effects of air pollutants such as ozone (O3). Maternal inactivity and calorically rich diets lead to offspring that show signs of obesity. Exacerbated O3 susceptibility of offspring could thus be manifested by maternal obesity. Thirty-day-old female Long-Evans rats were fed a control (CD) or high-fat (HF) (60% calories) diet for 6 wks and then bred. GD1 rats were then housed with a running wheel (RW) or without a wheel (SED) until parturition, creating four groups of offspring: CD-SED, CD-RW, HF-SED and HF-RW. HF diet was terminated at PND 35 and all offspring were placed on CD. Body weight and %fat of dams were greatest in order; HF-SED > HF-RW > CD-SED > CD-RW. Adult offspring were exposed to O3 for two consecutive days (0.8 ppm, 4 h/day). Glucose tolerance tests (GTT), ventilatory parameters (plethysmography), and bronchoalveolar fluid (BALF) cell counts and protein biomarkers were performed to assess response to O3. Exercise and diet altered body weight and %fat of young offspring. GTT, ventilation and BALF cell counts were exacerbated by O3 with responses markedly exacerbated in males. HF diet and O3 led to significant exacerbation of several BALF parameters: total cell count, neutrophils and lymphocytes were increased in male HF-SED versus CD-SED. Males were hyperglycemic after O3 exposure and exhibited exacerbated GTT responses. Ventilatory dysfunction was also exacerbated in males. Maternal exercise had minimal effects on O3 response. The results of this exploratory study suggest a link between maternal obesity and susceptibility to O3 in their adult offspring in a sex-specific manner.

Most definitions of emotionally disturbed youngsters suggest that disturbances in the child’s behavior patterns cause academic and social problems which affect the child and his peers. While the process of identification may be facilitated by operational criteria within a definition, these factors are noticeably absent from definitions of emotional disturbance. The State of Florida has adopted a definition for emotionally handicapped children which has potential for operationalization. That definition and its components as well as a discussion of implications relative to its use are presented here.

Emissions from oil fires associated with the “Deepwater Horizon” explosion and oil discharge that began on April 20, 2010 in the Gulf of Mexico were analyzed chemically to only a limited extent at the time but were shown to induce oxidative damage in vitro and in mice. To extend this work, we burned oil floating on sea water and performed extensive chemical analyses of the emissions (Gullett et al., Marine Pollut Bull, in press, 2017). Here, we examine the ability of a dichloromethane extract of the particulate material with an aerodynamic size ≤ 2.5 µm (PM2.5) from those emissions to induce oxidative damage in human lung cells in vitro and mutagenicity in 6 strains of Salmonella. The extract had a percentage of extractable organic material (EOM) of 7.0% and increased expression of the heme oxygenase (HMOX1) gene in BEAS-2B cells after exposure for 4 hr at 20 µg of EOM/ml. However, the extract did not alter mitochondrial respiration rate as measured by extracellular flux analysis. The extract was most mutagenic in TA100 +S9, indicative of a role for polycyclic aromatic hydrocarbons (PAHs), reflective of the high concentrations of PAHs in the emissions (1 g/kg of oil consumed). The extract had a mutagenicity emission factor of 1.8 ± 0.1 × 105 revertants/megajoulethermal in TA98 +S9, which was greater than that of diesel exhaust and within an order of magnitude of open burning of wood and plastic. Thus, organics from PM2.5 of burning oil can induce oxidative responses in human airway epithelial cells and are highly mutagenic. Environ. Mol. Mutagen. 58:162–171, 2017. © 2017 Wiley Periodicals, Inc.

The use of different scoring systems for radiation-induced toxicity limits comparability between studies. We examined dose-dependent tissue alterations following hypofractionated X-ray irradiation and evaluated their use as scoring criteria. Four dose fractions (0, 5, 10, 20, 30 Gy/fraction) were applied daily to ear pinnae. Acute effects (ear thickness, erythema, desquamation) were monitored for 92 days after fraction 1. Late effects (chronic inflammation, fibrosis) and the presence of transforming growth factor beta 1 (TGF&beta, 1)-expressing cells were quantified on day 92. The maximum ear thickness displayed a significant positive correlation with fractional dose. Increased ear thickness and erythema occurred simultaneously, followed by desquamation from day 10 onwards. A significant dose-dependency was observed for the severity of erythema, but not for desquamation. After 4 &times, 20 and 4 &times, 30 Gy, inflammation was significantly increased on day 92, whereas fibrosis and the abundance of TGF&beta, 1-expressing cells were only marginally increased after 4 &times, 30 Gy. Ear thickness significantly correlated with the severity of inflammation and fibrosis on day 92, but not with the number of TGF&beta, 1-expressing cells. Fibrosis correlated significantly with inflammation and fractional dose. In conclusion, the parameter of ear thickness can be used as an objective, numerical and dose-dependent quantification criterion to characterize the severity of acute toxicity and allow for the prediction of late effects.

Supplementation with the antioxidant selenium is frequently performed in breast cancer patients to protect the normal tissue from radiation-induced side effects. However, concerns exist whether selenium also protects tumor cells from radiation-induced cell kill and thereby reduces the efficacy of radiotherapy. In this work, the effect of selenium administration on the radiosensitivity of breast cancer cells was evaluated in vitro. Physiological relevant selenium concentrations (70 and 140 µg/l) did not affect DNA double-strand breaks (γH2AX foci) after 4-Gy X-ray irradiation. Also apoptosis (caspase 3/7) after irradiation with 10 Gy was not influenced by selenium treatment in MDA-MB-231 and MCF7 cells. Most importantly, selenium supplementation did not impair the clonogenic survival of the breast cancer cell lines after irradiation (0, 2, 4, 6, 8 Gy). The data suggest that physiological relevant selenium concentrations administered in combination with radiation therapy do not deteriorate the efficacy of radiotherapy in breast cancer patients. However, randomized clinical trials comparing the effectiveness of radiotherapy and the associated side effects in patients with and without selenium supplementation are recommended.