Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades it is known that cholecystokinine-2 receptor (CCK2R) is a promising target for the treatment of MTC with radiolabeled minigastrin analogues. Unfortunately, kidney toxicity precluded their therapeutic application so far. In 6 consecutive patients we evaluated with advanced 3D dosimetry whether improved minigastrin analogue 177 Lu-DOTA-(DGlu) 6-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH 2 (177 Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received two injections of about 1 GBq (~80 µg) 177 Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random cross-over sequence in order to evaluate biodistribution, pharmacokinetics as well as tumor-and organ dosimetry. Electrocardiogram, blood count and blood chemistry were measured up to 12 weeks after administration of 177 Lu-PP-F11N to assess safety. Results: In all patients 177 Lu-PP-F11N accumulation was visible in tumor tissue, stomach and kidneys. Altogether 13 tumors were eligible for dosimetry. The median (interquartile range = IQR) absorbed dose for tumors, stomach, kidneys and bone marrow was 0.88 Gy/GBq (0.

Brandes A, Oehlke O, Schü mann A, Heidrich S, Thévenod F, Roussa E. Adaptive redistribution of NBCe1-A and NBCe1-B in rat kidney proximal tubule and striated ducts of salivary glands during acid-base disturbances. Am J Physiol Regul Integr Comp Physiol 293: R2400-R2411, 2007. First published September 12, 2007; doi:10.1152/ajpregu.00208.2007.-The cellular distribution of the NH2-terminal electrogenic Na ϩ -HCO 3 Ϫ cotransporter (NBCe1) variants NBCe1-A and NBCe1-B has been investigated in rat kidney and submandibular gland (SMG) under physiological conditions and after systemic acid-base perturbations. Moreover, the in vivo data were complemented in vitro by using an immortalized cell line derived from the S1 segment of the proximal tubule (PT) of normotensive Wistar-Kyoto rats (WKPT-0293 Cl.2). NBCe1-A was basolaterally localized in PT cells, whereas NBCe1-B exhibited intracellular and basolateral distribution. SMG showed transcript and protein expression for NBCe1-A and NBCe1-B. NBCe1-B was basolaterally localized in duct cells; NBCe1-A was found intracellularly in salivary striated ducts and apically in main duct cells. Acute metabolic acidosis significantly increased cells that showed basolateral NBCe1-A in the PT, indicating increased HCO 3 Ϫ reabsorption, and significantly decreased cells that exhibited basolateral NBCe1-B in the salivary ducts, suggesting decreased HCO 3 Ϫ secretion. Chronic acidosis had no effect on NBCe1 distribution in PT but significantly increased the percentage of cells with basolateral NBCe1-A in salivary striated duct cells, suggesting increased HCO 3 Ϫ reabsorption. In contrast, chronic alkalosis caused adaptive redistribution of NBCe1-A and NBCe1-B in renal PT, favoring decreased HCO 3 Ϫ reabsorption. In vitro, WKPT-0293 Cl.2 cells expressed key acid-base transporters. Extracellular alkalosis downregulated NBCe1-A protein. WKPT-0293 Cl.2 cells are therefore a useful model to study renal acid-base regulation in vitro. The results propose redistribution of the transporters as a potential posttranslational regulation modus during acid-base disturbances. Moreover, the data demonstrate that renal PT and salivary duct epithelia respond to acid-base disturbances by an opposite redistribution pattern for NBCe1-A and NBCe1-B, reflecting specialized functions as the HCO 3 Ϫ -reabsorbing and HCO 3 Ϫ -secreting epithelium, respectively. acid-base homeostasis; bicarbonate transport ORIGINALLY, TWO MEMBERS OF the SLC4A4 gene family, the NH 2 -terminal variants of the electrogenic Na ϩ

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Côte d'Ivoire has travelled full circle from economic success (from 1960 to about 1979) to failure (from the 1980s onwards) in little more than a generation. In the early 1990s, Zouglou, today Côte d'Ivoire's internationally best-known music, emerged at the university residences of the University of Abidjan in the Yopougon quarter. The young people who were to become the ‘Zouglou generation’ were precisely the generation that bore the brunt of this economic deterioration. Zouglou was born at a time when, as a result of an unprecedented economic crisis and the attendant structural adjustment measures, university students experienced a general downgrading not only as students but also as future graduates hoping to find employment. In addition, the number of students and school pupils who were unable to complete their education grew considerably during this time. As this article demonstrates, these phenomena had a profound influence on the development of the philosophy associated with Zouglou music. Accordingly, Zouglou singers have called themselves the ‘sacrificed generation’. Indeed, the many songs about orphans in Zouglou music can be read as a symbolic statement about this experience: the sense that Ivoirian youth have been abandoned by their elders, their families and the political authorities is unmistakable in the words of Zouglou songs consoling such (metaphorical) orphans. Zouglou music has become an important platform through which this generation has been able to express itself, as well as a site for oral street poetry and collective catharsis. The article discusses the content of these songs, as well as interviews with Zouglou singers on this matter, to investigate how Zouglou, as a cultural phenomenon, grew out of the experience of a generation.

Background: FAP is a membrane-bound protease with limited expression in normal tissues but high expression on cancer-associated fibroblasts abundant in the stroma of most tumors. FAP-2286 is a potent and selective FAP-targeted peptide linked to the chelator DOTA that allows for attachment of radionuclides for therapeutic and imaging applications. Assessing patterns of FAP expression in different tumor types and correlating expression with FAP-2286 uptake can help guide tumor selection for FAP-2286 therapy. Methods: FAP immunohistochemistry (IHC) was performed on FFPE tissue specimens from 16 tumor types using the SP325 antibody. Overall and tumor/stroma-specific H-scores were calculated using Visiopharm and HALO analysis, respectively. Autoradiography with 111In-FAP-2286 was performed on a subset of matched frozen tissue sections. Results: Gene expression analysis across The Cancer Genome Atlas data set revealed elevated FAP mRNA expression in multiple tumor types. A pan-tumor IHC screen confirmed that ≥30% of samples in various indications (eg, sarcoma, pancreatic adenocarcinoma, mesothelioma, head and neck squamous cell carcinoma) had high FAP expression (H-score ≥30). While in most tumor types FAP was predominantly localized to the stroma, FAP expression was also observed in tumor cells, especially in tumors of mesenchymal origin, eg, sarcoma and mesothelioma. High FAP expression was independent of tumor stage or grade and detected in both primary and metastatic samples. Multiple sarcoma and mesothelioma subtypes demonstrated high FAP H-scores, suggesting that FAP expression is not limited to a specific subtype. There was significant correlation between FAP expression observed by IHC and FAP-2286 binding as assessed by autoradiography in matched frozen tissues (Pearson r=0.73; p<0.01). Conclusions: Our IHC screen identified high FAP expression in various tumor types that correlated with in vitro FAP-2286 binding, suggesting that FAP is an attractive target across a broad range of tumor types for peptide-targeted radionuclide therapy. Accordingly, the phase 1/2 LuMIERE clinical trial (NCT04939610) will evaluate FAP-2286 as a therapeutic (177Lu-FAP-2286) and imaging (68Ga-FAP-2286) agent in multiple indications. Citation Format: Tanya T. Kwan, Minh Nguyen, Dirk Zboralski, Anne Schumann, Anne Bredenbeck, Matthias Paschke, Christian Haase, Aileen Hoehne, Ulrich Reineke, Christiane Smerling, Frank Osterkamp, Jim Xiao, Andrew D. Simmons, Thomas C. Harding, Kevin L. Lin. Pan-cancer analysis of fibroblast activation protein alpha (FAP) expression to guide tumor selection for the peptide-targeted radionuclide therapy FAP-2286 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA032.