Checkpoint-blocking antibodies like those targeting the PD-1/PD-L1 pathway have revolutionized oncology. We developed radiotracers based on therapeutic checkpoint-blocking antibodies permitting sensitive and high-resolution PET imaging of both PD-1 and PD-L1 in immunocompetent mice. ImmunoPET of naive mice revealed similar overall expression patterns for PD-1 and PD-L1 in secondary lymphoid organs (spleen and lymph nodes). Interestingly, PD-L1 was also detected in brown adipose tissue (BAT), confirming the notion that BAT is immunologically relevant. Under pathophysiological conditions, strong expression of the receptor/ligand pair was also found in non-lymphoid tissues. Both were specifically detected in malignant tumors. PD-1 was readily detected after combined immunoradiotherapy causing massive tumor infiltration by PD-1+ lymphocytes. PD-L1 tracer uptake was reduced in PD-L1 knockout tumors. Moreover, monitoring the expression changes of PD-L1 in response to its main inducer, the effector T cell cytokine IFN-γ, revealed robust upregulation in the lung. This suggests that T cell responses in the lung, a vital organ continuously exposed to a variety of antigens, are strongly restrained by the PD-1 checkpoint. In turn, this could explain the association of PD-1 checkpoint inhibition with potentially fatal immune-mediated pneumonitis and partially also its efficacy in lung cancer.

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A technology that visualizes tumor stem cells with clinically relevant tracers could have a broad impact on cancer diagnosis and treatment. The AC133 epitope of CD133 currently is one of the best-characterized tumor stem cell markers for many intra-and extracranial tumor entities. Here we demonstrate the successful noninvasive detection of AC133 + tumor stem cells by PET and nearinfrared fluorescence molecular tomography in subcutaneous and orthotopic glioma xenografts using antibody-based tracers. Particularly, microPET with 64 Cu-NOTA-AC133 mAb yielded high-quality images with outstanding tumor-to-background contrast, clearly delineating subcutaneous tumor stem cell-derived xenografts from surrounding tissues. Intracerebral tumors as small as 2-3 mm also were clearly discernible, and the microPET images reflected the invasive growth pattern of orthotopic cancer stem cell-derived tumors with low density of AC133 + cells. These data provide a basis for further preclinical and clinical use of the developed tracers for high-sensitivity and high-resolution monitoring of AC133 + tumor stem cells.cancer stem cells | CSCs | glioblastoma

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This article reports on two experiments with native speakers of German that were conducted to determine the influence of different types of German generics on the cognitive inclusion of women. The results of these studies show that masculine versus other types of generics influence the retrieval of male and female exemplars from memory. This is the first piece of empirical evidence for this kind of effect with regard to the German language.

We collected norms on the gender stereotypicality of an extensive list of role nouns in Czech, English, French, German, Italian, Norwegian, and Slovak to be used as a basis for the selection of stimulus material in future studies. We present a web-based tool (https://www.unifr.ch/lcg/) that we developed to collect these norms and that we expect to be useful for other researchers as well. In essence, we provide (a) norms across languages and (b) a tool to facilitate cross-language as well as cross-cultural comparisons when researchers are interested in the investigation of the impact of stereotypicality on the processing of role nouns.Gender stereotypes across seven languagesNorms on the gender perception of role nouns in Czech, English, French, German, Italian, Norwegian, and Slovak Thoughts and conceptual categorizations, as well as their relation to language, have long been studied and debated in cognitive psychology (e.g., Phillips & Boroditsky, 2003; Slobin, 1996). Within this domain, the mental representation of gender has been of particular interest, as research revealed its reliance on both properties of the language, such as grammatical gender, and perceivers' concepts, such as stereotypes (e.g., Carreiras, Garnham, Oakhill, & Cain, 1996; Gygax, Gabriel, Sarrasin, Oakhill, & Garnham, 2008; Stahlberg, Braun, Irmen, & Sczesny, 2007).Research that aims at disentangling the impact of these sources can greatly profit from cross-linguistic and/or cross-cultural comparisons. To facilitate such research, the present study has two objectives:First, we provide norms on the gender stereotypicality (or conceptual gender) of an extensive number of role nouns in seven European languages. These norms enable researchers to take gender-associations into account when selecting stimulus material especially for cross-linguistic or cross-cultural studies. Second, we present a web-based tool that we developed for the collection of these norms in different languages. This tool takes into account cross-linguistic variations in with the way that the gender of nouns with human referents is grammatically encoded, so that equivalent procedures can be used with each language. More specifically, a questionnaire design was created that can be used despite such variations. As outlined below, the existence of grammatical gender in some languages, but not others, had implications for the questionnaire format used in this study. As a side effect, the tool can easily be extended for use with further languages. We believe that this tool will, therefore, be a valuable resource for researchers in various psychological disciplines Gender stereotypes across seven languages ! 5 who wish to systematically collect norms for different languages and/or from specific populations, for future studies.Grammatical gender refers to a type of noun classification. In relation to this classification, most European languages can be assigned to one of the following four categories (Braun, Oakhill, & Garnham, 2011) : grammatical gender (e.g. French), ...

Efficient and stable64Cu complexation by hexadentate TACN-derived chelators with pendant azaheterocyclic arms.

The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer and is an attractive target for radionuclide therapy. In addition, inhibition of the protein kinase mammalian target of rapamycin (mTOR) has been shown to sensitize various cancer cells to the effects of radiotherapy. Methods: To determine the effect of treatment with rapamycin and radiotherapy with a novel 177 Lu-labeled GRPr antagonist ( 177 Lu-RM2, BAY 1017858) alone and in combination, in vitro and in vivo studies were performed using the human PC-3 prostate cancer cell line. PC-3 cell proliferation and 177 Lu-RM2 uptake after treatment with rapamycin were assessed in vitro. To determine the influence of rapamycin on 177 Lu-RM2 tumor uptake, in vivo small-animal PET studies with 68 Ga-RM2 were performed after treatment with rapamycin. To study the efficacy of 177 Lu-RM2 in vivo, mice with subcutaneous PC-3 tumors were treated with 177 Lu-RM2 alone or after pretreatment with rapamycin. Results: Stable expression of GRPr was maintained after rapamycin treatment with doses up to 4 mg/kg in vivo. Monotherapy with 177 Lu-RM2 at higher doses (72 and 144 MBq) was effective in inducing complete tumor remission in 60% of treated mice. Treatment with 37 MBq of 177 Lu-RM2 and rapamycin in combination led to significantly longer survival than with either agent alone. No treatment-related toxicity was observed. Conclusion: Radiotherapy using a 177 Lu-labeled GRPr antagonist alone or in combination with rapamycin was efficacious in inhibiting in vivo tumor growth and may be a promising strategy for treatment of prostate cancer.