Nineteen coded chemicals were tested in an international collaborative study for their mutagenic activity. The assay system employed was the Ames II Mutagenicity Assay, using the tester strains TA98 ...and TAMix (TA7001–7006). The test compounds were selected from a published study with a large data set from the standard Ames plate-incorporation test. The following test compounds including matched pairs were investigated: cyclophoshamide, 2-naphthylamine, benzo(a)pyrene, pyrene, 2-acetylaminofluorene, 4,4′-methylene-bis(2-chloroaniline), 9,10-dimethylanthracene, anthracene, 4-nitroquinoline-
N-oxide, diphenylnitrosamine, urethane, isopropyl-
N(3-chlorophenyl)carbamate, benzidine, 3,3′-5,5′-tetramethylbenzidine, azoxybenzene, 3-aminotriazole, diethylstilbestrol, sucrose and methionine. The results of both assay systems were compared, and the inter-laboratory consistency of the Ames II test was assessed. Of the eight mutagens selected, six were correctly identified with the Ames II assay by all laboratories, one compound was judged positive by five of six investigators and one by four of six laboratories. All seven non-mutagenic samples were consistently negative in the Ames II assay. Of the four chemicals that gave inconsistent results in the traditional Ames test, three were uniformly classified as either positive or negative in the present study, whereas one compound gave equivocal results. A comparison of the test outcome of the different investigators resulted in an inter-laboratory consistency of 89.5%.
Owing to the high concordance between the two test systems, and the low inter-laboratory variability in the Ames II assay results, the Ames II is an effective screening alternative to the standard Ames test, requiring less test material and labor.
In early Paleozoic time the Peru–Bolivia Trough at the South American Gondwana margin accommodated large volumes of siliciclastic detritus of hitherto largely unknown provenance. A multi-method ...provenance study of framework components, heavy minerals and whole rock geochemistry of Ordovician to Devonian formations of southern Peru and northern Bolivia reveals the predominant contribution from upper crustal sources. Main heavy minerals include zircon, tourmaline, rutile, apatite, garnet, epidote, monazite, and titanite and are strongly biased diagenetically towards the stable phases.
Electron microprobe single grain analysis of tourmaline and rutile indicate that detrital tourmalines were derived mainly from metasedimentary, and subordinately, from granitic sources. Cr/Nb ratios in rutiles point to a metamafic derivation for 20–40% of grains, the remainder originating in felsic lithologies. Zr in rutile thermometry indicates a provenance from relatively high-grade metamorphic rocks transformed at temperatures between 500 °C and 900 °C, with clusters at c. 600 °C, 700 °C and 800 °C.
U–Pb geochronological analysis of rutiles was largely unsuccessful due to high concentrations of common Pb. Three ages could be obtained and fall between 525 and 545 Ma, probably linking this detritus to the hidden Neoproterozoic orogen in what are now Cordillera Oriental and Sierras Subandinas.
The most notable feature of the whole rock geochemical data is a high Cr content in the majority of samples, which otherwise have a composition similar to weathered upper continental crust. The elevated Cr contents indicates that ophiolitic rocks were either exposed to erosion abundantly in the source areas or had previously supplied significant volumes of detritus to intermittent sediment storage systems now eroded into the studied sedimentary rocks. Potential source candidates include the Ordovician metamorphic Tapo Ultramafic Complex in the Cordillera Oriental of central Peru, and the island arcs and ophiolite complexes of the Rondonia-San Ignacio Orogen (1550–1200 Ma) on the SW Amazonia craton. Considering the available evidence we conclude that a provenance from the Rondonia-San Ignacio Orogen is more likely.
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•The first multi-method provenance study of the lower Paleozoic strata in southern Peru and northern Bolivia.•U–Pb age data on detrital rutile document contribution of a still enigmatic Neoproterozoic magmatic source.•Zr in rutile thermometry indicates provenance from high-grade metamorphic rocks transformed between 500 °C and 900 °C.•Ophiolite assemblages were significant sources of detritus to the Ordovician-Devonian Peru–Bolivia Trough.•The facies development of the trough is re-evaluated in light of new sedimentological field data.
Dynamic perviousness is a novel imaging biomarker, with clot density measurements at multiple timepoints to allow longer contrast to thrombus interaction. We investigated the correlations between ...dynamic perviousness and clot composition in the setting of acute ischemic stroke. Thirty-nine patients with large vessel occlusion (LVO) undergoing mechanical thrombectomy (MT) were analyzed. Patients received a three-phase CT imaging pre-thrombectomy and histopathological analysis of retrieved clots. Clot densities for every phase and change in densities between phases were calculated, leading to four patterns of dynamic perviousness: no contrast uptake, early contrast uptake with and without washout and late uptake. Clots were categorized into three groups based on dominant histologic composition: red blood cell (RBC)-rich, fibrin/platelet-rich and mixed. Clot composition was correlated with dynamic perviousness using the Kruskal–Wallis test and Pearson’s correlation analysis. The dynamic perviousness categories showed a significant difference between fibrin-rich clots when compared to RBC-rich plus mixed groups. The uptake without washout category had significantly fewer fibrin clots compared to the uptake with washout (p = 0.036), and nearly significantly fewer fibrin clots when compared to the no uptake category (p = 0.057). Contrast uptake with different patterns of contrast washout showed significant differences of the likelihood for fibrin-rich clots.
Summary Human papillomavirus (HPV) is a major cause of oropharyngeal squamous cell carcinoma with characteristic clinical and pathologic features relative to their non–HPV–associated counterparts. ...Here we describe 2 cases of HPV-associated adenocarcinoma of the oropharynx. Both cases arose at the base of the tongue, and neither had the histologic or immunohistochemical features of a primary salivary gland tumor or metastasis from another location. One patient had metastases to neck lymph nodes and the lungs and died of disease 37 months after diagnosis. Evidence for an HPV association consisted of strong diffuse expression of p16, polymerase chain reaction–based detection of HPV16 DNA sequences, and localization of HPV by in situ hybridization within tumor cells of both primary and metastatic lesions. These results further expand the spectrum of HPV-associated head and neck malignancy. This rare entity should be distinguished from primary salivary gland adenocarcinoma and may be a candidate for HPV-specific targeted therapies.
Vertebrate eggs are arrested at metaphase of meiosis II with stable cyclin B and high cyclin B/Cdc2 kinase activity. The ability of the anaphase-promoting complex/cyclosome (APC), an E3 ubiquitin ...ligase, to trigger cyclin B destruction and metaphase exit is blocked in eggs by the activity of cytostatic factor (CSF) (reviewed in ref. 1). CSF was defined as an activity in mature oocytes that caused mitotic arrest when injected into dividing embryos. Fertilization causes a transient increase in cytoplasmic calcium concentration leading to CSF inactivation, APC activation, cyclin B destruction and mitotic exit. The APC activator Cdc20 is required for APC activation after fertilization. We show here that the APCcdc20 inhibitor Emi1 (ref. 6) is necessary and sufficient to inhibit the APC and to prevent mitotic exit in CSF-arrested eggs. CSF extracts immunodepleted of Emi1 degrade cyclin B, and exit from mitosis prematurely in the absence of calcium. Addition of Emi1 to these Emi1-depleted extracts blocks premature inactivation of the CSF-arrested state. Emi1 is required to arrest unfertilized eggs at metaphase of meiosis II and seems to be the long-sought mediator of CSF activity.
While most melanomas can be distinguished from nevi by histopathology, the histology is ambiguous for some melanocytic tumors, contributing to diagnostic uncertainty. Therefore molecular assays, ...including FISH or SNP array, and more recently a gene expression test (myPath, Myriad Genetics) have been proposed to aid in the work-up of ambiguous tumors. Two hundred and sixty-eight prospectively submitted cases were gathered, with the goal of comparing the myPath assay to morphologic diagnosis in (1) morphologically unequivocal cases (198), and to morphologic diagnosis and FISH in (2) morphologically ambiguous cases (70). Melanoma FISH was performed using probes for 6p25, 6q23, 11q13, Cep6, 9p21, and Cep9 and scored according to established criteria. The myPath assay was scored by the manufacturer as benign, indeterminate, or malignant. In the unequivocal group, myPath assay showed 75% agreement with morphologic diagnosis, with 67% sensitivity and 81% specificity. In the ambiguous group, FISH and myPath showed 69% inter-test agreement. For these cases agreement with histopathologic interpretation was 84% for FISH and 74% for myPath. Sensitivity and specificity of FISH was 61 and 100%, 50 and 93% for myPath, respectively. Cases from both groups in which myPath was discordant with either morphologic diagnosis and/or FISH (81/268 cases), were submitted for evaluation by two experienced dermatopathologist and also by SNP-array. SNP-array results correlated better than FISH, which correlated better than myPath, with the morphologic interpretation. Our findings document that molecular diagnostics show good correlation with consensus diagnoses, but discordant results occur, and vary in level of correlation with consensus interpretations. Studies with long-term outcomes data within specific ambiguous lesion subsets are required to establish the accuracy of this test, as each molecular diagnostic technique has limitations based on both lack of clinical outcomes data in ambiguous melanocytic tumors and in terms of their sensitivity and specificity in melanocytic lesion subtypes.
...their report of regional nodal metastases in their patient is consonant with the behavior of tumor in one of the 2 patients we reported on and who ultimately died of disease.
Sex steroids, due to the generally negative responses observed in routinely employed standard genotoxicity assays, are considered epigenetic carcinogens. Some doubts on this conviction are raised by ...the results of recent studies providing evidence that cyproterone acetate and two structural analogues, chlormadinone acetate and megestrol acetate, are genotoxic in female rats but only for the liver, and in primary human hepatocytes from donors of both genders. The experimental evidence suggests that the metabolic activation of these molecules to reactive species and the consequent formation of DNA adducts occur only in the intact hepatocyte. Since the possibility that other sex steroids cause a liver-specific genotoxic effect cannot be ruled out a priori, we investigated nine drugs of this family for their ability to induce DNA repair synthesis in primary cultures of rat and human hepatocytes. Each steroid was tested in cultures from at least two male and two female donors of each species. Hepatocytes were exposed for 20
h to sub-toxic concentrations ranging from 1 to 50
μM, and DNA repair induction was measured by quantitative autoradiography. In primary rat hepatocytes, induction of DNA repair indicative of a frankly positive response was detected in cultures from: 2/2 males and 3/3 females with drospirenone, 2/2 males and 1/2 females with ethinylestradiol, 1/2 males and 1/2 females with oxymetholone, 1/2 males with norethisterone, 1/4 females with progesterone, and 1/4 males with methyltestosterone. Consistent negative responses were obtained with testosterone and stanozolol. A few inconclusive responses were observed in rat hepatocytes exposed to progesterone, medroxyprogesterone, norethisterone, methyltestosterone and oxymetholone. In contrast, under the same experimental conditions the nine sex steroids provided frankly negative responses in the large majority of cultures of primary hepatocytes from both male and female human donors; the only exceptions being the inconclusive responses obtained in cultures from two of the donors exposed to norethisterone and to ethinylestradiol, and from one of the donors exposed to testosterone, methyltestosterone, and stanozolol. These results and previous findings concerning cyproterone and its structural analogues suggest that sex steroids differ for their ability to induce DNA repair, and that their genotoxicity may be: (i) different in rat and human hepatocytes, (ii) dependent on the sex of the donor, and (iii) affected by inter-individual variability.
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