Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ...ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated.
Phylogenetic relationships, evolutionary history and systematics of tapeworms of the family Catenotaeniidae were studied using nucleotide sequences of the partial 28S nuclear rDNA (ca. 1,500 bp) and ...mitochondrial 12S–16S DNA (ca. 820 bp) genes. The tapeworm material consists of 29 species, including type species of the genera Catenotaenia Janicki, 1904, Catenotaenioides Haukisalmi, Hardman and Henttonen, 2010, Pseudocatenotaenia Tenora, Mas‐Coma, Murai and Feliu, 1980, Skrjabinotaenia Akhumyan, 1946, Meggittina Lynsdale, 1953, and Hemicatenotaenia Tenora, 1977. The basal phylogenetic structure of the Catenotaeniidae remains unresolved, but it is shown that most of the catenotaeniids in Eurasia and Africa comprise a large clade represented by species of Catenotaenia, Catenotaenioides, Skrjabinotaenia and Meggittina, parasitizing murid, cricetid, nesomyid and sciurid rodents. The results suggest that the divergence and early radiation of this clade have occurred in murid rodents (represented by Apodemus spp. and Mus musculus in the present material) in western Eurasia, followed by colonization of Africa, most likely independently of the colonization of their murid hosts between these continents. There is very little evidence of cophylogeny between hosts and parasites, suggesting that host transfers have played a major role in the divergence of catenotaeniids. In Africa, catenotaeniids have radiated in other murid and nesomyid rodents, and later colonized Madagascar and recolonized Eurasia. The results also show that the subfamily Skrjabinotaeniinae (including Skrjabinotaenia and Meggittina) is monophyletic, but the Catenotaeniinae (including Catenotaenia, Catenotaenioides, Pseudocatenotaenia and Hemicatenotaenia) is clearly non‐monophyletic. In addition, the genera Catenotaenia and Skrjabinotaenia were both found to be non‐monophyletic. Based on the phylogenetic and morphological evidence, several taxonomical changes, mainly new combinations, are proposed. Overall, the present results suggest that the family Catenotaeniidae is in need of major systematic revision.
The history of wildlife parasitology in South Africa, and to some extent southern Africa, is reviewed, giving a brief overview of the early years and following its development from the founding of ...the Onderstepoort Veterinary Institute in 1908 until the turn of the century. An emphasis is placed on game species. The main findings on protozoan parasites, including those of carnivores, are presented, starting in the 1890s and leading up to the first decade of the 21st century. Important developments with regard to the studies of arthropod and helminth parasites took place during a period of three decades, starting from the 1970s. Because of the sheer volume of work done by parasitologists during this time, this particular part of the overview concentrates on South African authors or authors working in South Africa at the time, and is limited to hosts that are members of the order Perissodactyla and the superorder Cetartiodactyla.
Trichospirura aethiopica n. sp. is described from unidentified tubular structures (pancreatic ducts?) near the stomach of the murid Malacomys longipes Milne-Edwards, 1877 in Gabon. The extremely long ...and narrow buccal capsule, posterior position of the vulva, unequal spicules and absence of caudal alae readily identified the specimens as belonging to Trichospirura Smith & Chitwood, 1967, but a combination of several characters distinguished them from the described species in this genus. Males of the new species are characterized by the absence of precloacal papillae, the presence of four pairs of postcloacal papillae and a left spicule length of 165–200 μm. With only five nominal and one unnamed species, the host range of Trichospirura extends into the Neotropical, Indo-Malayan and Ethiopian Realms and comprises three classes of vertebrates, Amphibia, Reptilia and Mammalia, suggesting a larger species diversity than that currently recorded. Detection is difficult as predilection sites are often outside the gut lumen. It was noted that, irrespective of their geographic origin, species from mammals share certain characters (shorter left spicule and absence of precloacal papillae) that oppose them to those from amphibians and reptiles. A hypothesis for the origin of Trichospirura in mammals through a remote host-switching event in tupaiids in southern Asia, likely facilitated by the intermediate hosts, and for their subsequent migration to the Ethiopian and finally Neotropical Realm is proposed. Regarding the two species from anurans and saurians in the Antilles, one or two host-switching events are considered equally possible, based on morphological characters.
Trichospirura aethiopica n. sp. est décrit de spécimens infestant des structures tubulaires non identifiées (canaux pancréatiques ?) près de l’estomac du Muridae Malacomys longipes Milne-Edwards, 1877 provenant du Gabon. La capsule buccale étroite et extrêmement longue, la position postérieure de la vulve, les spicules inégaux et l’absence d’ailes caudales identifient clairement les spécimens comme appartenant à Trichospirura Smith & Chitwood, 1967, mais une combinaison de plusieurs caractères les distingue des espèces déjà décrites dans le genre. Les mâles de la nouvelle espèce sont caractérisés par l’absence de papilles précloacales, la présence de quatre paires de papilles postcloacales et un spicule gauche long de 165–200 μm. Avec seulement quatre espèces nominales et une espèce non nommée, les hôtes de Trichospirura vivent dans les domaines biogéographiques néotropical, indo-malais et éthiopien et appartiennent à trois classes de vertébrés, amphibiens, reptiles et mammifères, ce qui suggère une diversité d’espèces plus grande que ce qui est actuellement connu. La détection est difficile parce que les sites d’infestation sont souvent en dehors de la lumière digestive. Nous avons noté que les espèces parasites de mammifères, quelle que soit leur origine géographique, partagent certains caractères (spicule gauche plus court et absence de papilles précloacales) qui les opposent à celles des amphibiens et reptiles. Une hypothèse de l’origine de Trichospirura chez les mammifères est proposée, incluant un événement de changement d’hôte lointain chez les Tupaiidae en Asie du sud-est, probablement facilité par les hôtes intermédiaires, et leur migration ultérieure vers le domaine éthiopien et finalement néotropical. En ce qui concerne les deux espèces d’anoures et de sauriens des Antilles, une ou deux événement de changements d’hôtes sont considérés comme également possibles sur la base des caractères morphologiques.
Species of the genus Pelecitus Railliet & Henry, 1910 the most widely distributed avian filariae in Africa and South America. Zoonotic cases in humans were reported in South America. While ...investigating the filarial fauna of wild animals in Malaysia, we discovered an undescribed filaria from the swollen footpad of the left leg of Copsychus malabaricus (Scopoli) in Pahang, Peninsular Malaysia. Adults of both sexes have a corkscrew-shaped body. Based on comparison of their morphological characteristics (i.e. pre-oesophageal cuticular ring distinct, oesophagus divided, vulva protuberant and situated at the level of anterior half of oesophagus, spicules strongly sclerotized and left spicule with broad blade) with other Pelecitus species, they are here described as Pelecitus copsychi Uni, Mat Udin & Martin n. sp. Multi-locus sequence analyses based on seven genes (12S rDNA, cox1, 18S rDNA, 28S rDNA, MyoHC, rbp1 and hsp70) were performed to determine the phylogenetic position of the new species. The calculated p-distance between the cox1 gene sequences for P. copsychi n. sp. and Pelecitus fulicaeatrae (Diesing, 1861) was 14.1%. Intraspecific genetic variation between two individuals of the new species was 0.4%. In both the Bayesian inference and maximum-likelihood trees, P. copsychi n. sp. was positioned in the second clade of ONC5, containing three genera of the subfamily Dirofilariinae (Foleyella Seurat, 1917, Pelecitus and Loa Stiles, 1905). Immunostaining and molecular analyses remained negative for the presence of Wolbachia endosymbionts. Our findings corroborate the division of the subfamily Dirofilariinae into ONC3 with Dirofilaria Railliet & Henry, 1911 and ONC5 with Pelecitus.
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•Pelecitus copsychi n. sp. is described from Copsychus malabaricus in Malaysia.•The filariae occur free and cause swelling in the footpad of the host.•Copsychus malabaricus is a new host record for Pelecitus.•Molecular analysis positioned the new species in clade ONC5 of the Onchocercidae.•Molecular analyses corroborate division of the Dirofilariinae into ONC3 and ONC5.
Abstract Context Research has increased significantly on small vesicles secreted by healthy and diseased cells. Recent discoveries have revealed their functional and biomarker roles in urologic ...diseases. Whether and how this knowledge of extracellular vesicles (EVs) affects translational research and clinical practices have become pertinent questions. Objective To provide an overview of the currently available literature on the rising field of EVs, focusing on function and pathogenesis in urologic cancers and the usefulness of EVs as biomarkers. Evidence acquisition A systematic literature search was conducted using PubMed to identify original articles, review articles, and editorials regarding EVs in different types of urologic tumor diseases. Articles published between 2005 and 2015 were reviewed and selected with the consensus of all authors. Evidence synthesis Besides soluble factors, different types of EVs are involved in the complex cross talk between different cell types. EVs regulate normal physiologic processes like spermatogenesis and renal function, as well as disease-specific processes including bladder, kidney, and prostate cancer. The content of EVs is derived from the cytoplasm of the donor cell. The proteins and RNAs within these EVs can be isolated from body fluids (eg, urine and blood) and represent potential diagnostic and prognostic biomarkers. EVs are also candidate therapeutic targets and potentially useful as therapeutic vehicles. Conclusions The current data suggest that EVs are important regulators of cell–cell communication. The growing knowledge about their roles in urologic malignancies provides the basis for novel therapeutic strategies. In addition, nucleic acid and the protein content of EVs holds promise for the discovery of urine- or serum-based biomarkers for kidney, bladder, and prostate cancer. Patient summary Normal and cancer cells secrete small vesicles that contain proteins and RNAs from the cell of origin. Changes in the diseased cells can be detected by examining the altered content of these vesicles when secreted in body fluids, for example, blood and urine. The recently discovered roles of extracellular vesicles (EVs) provide new options to detect malignancy in the urine and blood. The uptake of EVs may be blocked therapeutically and thereby potentially impede cancer progression.
Summary The prognostic value of the Fuhrman nuclear grading system has been questioned for chromophobe renal cell carcinoma (chRCC) because this subtype frequently displays nuclear and nucleolar ...pleomorphism. The present study reevaluates this grading system in a series of patients with nonsarcomatoid chRCC. We identified 176 patients (3.6%) with nonsarcomatoid chRCC in a total of 4897 patients who underwent surgery for renal cell carcinoma at 5 centers in Germany between 1990 and 2010. The mean follow-up was 51.1 months. The 3 groups (G1 versus G2 versus G3/4) were comparable in terms of age, sex, tumor diameter, and lymph node metastasis. They only differed significantly in tumor stage ( P = .01) and the incidence of synchronous visceral metastasis ( P = .04). The 5-year cancer-specific survival rates were 84.4% for G1 (n = 32), 84.3% for G2 (n = 108), and 74.1% for G3/4 tumors (n = 33) ( P = .58). Accordingly, multivariate analysis including age, sex, tumor stage, and metastatic disease did not identify Fuhrman grading as an independent predictor of cancer-specific survival in patients with chRCC ( P = .4). We were able to demonstrate in a large multicenter cohort that the Fuhrman grading system does not qualify as a prognostic tool in patients with chRCC.
Tumors can escape immune recognition and destruction through the induction of apoptosis in lymphocytes. Although renal cell carcinoma (RCC) is able to prevent immune recognition, only a few genes ...(such as FasL) that are relevant for RCC immune escape have been identified so far. We have previously shown that some apoptosis-inducing genes are overexpressed in RCC. We hypothesized that these genes could be part of the immune-escape strategy of these tumors. Here we report that CD70, a cytokine overexpressed in RCC, promotes lymphocyte apoptosis through interaction with its receptor CD27 and with the intracellular receptor-binding protein SIVA. Apoptosis increased after cocultivating lymphocytes with the RCC cell lines A498 and CAKI2. The addition of recombinant soluble CD70 to both native lymphocytes and a T-cell cell line resulted in increased lymphocyte apoptosis as well. Furthermore, induced apoptosis could be partially blocked with anti-CD27 and anti-CD70 antibodies. Our results strongly indicate a role for CD70 and CD27 receptor in lymphocyte apoptosis within the tumor environment. Apoptosis mediated by exposure to the CD70 secreted by tumor cells may contribute to the failure of RCC patients to develop an effective lymphocyte-mediated antitumor response.
Abstract Sclerosing epithelioid fibrosarcoma (SEF) is a rare fibrosarcoma variant with specific histomorphology and consistent translocation (EWSR1-CREB3L1/2). To date, 110 cases have been reported; ...only 15 originated within the abdomen. With only 2 cases reported parallel to our study and one case briefly mentioned in a previous series, primary renal SEF is exceptionally rare but might be underrecognized. We herein describe 2 cases affecting a 23-year-old woman and a 43-year-old man. Tumor size was 22 and 4.2 cm, respectively. Patient 1 developed skeletal and multiple pulmonary metastases. She died of disease 82 months later, despite aggressive multimodality therapy. Patient 2 has no evidence of recurrence or metastasis (8 months after surgery). Histologic examination showed similar appearance with monotonous bland medium-sized epithelioid cells with rounded slightly vesicular nuclei and clear cytoplasm imparting a carcinoma-like appearance set within a highly sclerotic hyaline fibrous stroma. The tumor cells were arranged in nests, single cell cords, trabeculae, or solid sheets with frequent entrapment of renal tubules and glomeruli. Immunohistochemistry showed strong expression of vimentin, bcl2, CD99, and MUC4, whereas cytokeratin and other markers were negative. Fluorescence in situ hybridization showed a translocation involving the EWSR1 gene locus in case 2. Molecular analysis in case 1 was not successful due to poor signal quality. To our knowledge, this is the second report documenting primary renal SEF. Awareness of this entity would help avoid misinterpretation as clear cell carcinoma, sclerosing perivascular epithelioid cell tumor, Xp.11 translocation carcinoma, and other more frequent neoplasms at this site.
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