Dynamics of hormonal disorders following unilateral orchiectomy for a testicular tumor

Testicular tumors and their treatment interfere with homeostasis, hormonal status included. The aim of the study was to evaluate hormonal disorders of the pituitary–gonadal axis in men treated for testicular tumors. One hundred twenty-eight men treated for a unilateral testicular tumor at our institution were included. The hormonal status was prospectively evaluated in 62 patients before orchiectomy, 120 patients 1 month after orchiectomy and 110 patients at least 1 year after the treatment. The concentrations of human chorionic gonadotropin (hCG), testosterone (T), estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin were measured. The clinically significant testosterone deficiency was defined either as testosterone <2.31 ng/mL or testosterone within the range of 2.31–3.46 ng/mL but simultaneous with T/LH ratio ≤1. Changes in hormone levels were significant: LH and FSH rose in the course of observation, and the concentration of hCG, testosterone, estradiol decreased. PRL concentration was the lowest at 1 month after orchiectomy. In multivariate analysis, the risk of the clinically significant testosterone deficiency was 0.2107 (95% CI 0.1206–0.3419) prior to orchiectomy, 0.3894 (95% CI 0.2983–0.4889) 1 month after surgery and 0.4972 (95% CI 0.3951–0.5995) 1 year after the treatment. The estradiol concentration was elevated in 40% of patients with recently diagnosed testicular cancer and that was correlated with a higher risk of testosterone deficiency after the treatment completion. Hormonal disorders of the pituitary–gonadal axis in men treated for testicular tumors are frequent. The malignant tissue triggers paraneoplastic disorders that additionally disturb the hormonal equilibrium

hCG-secreting malignancies – diagnostic pitfalls

We present a case of a 34-year-old male patient referred to our Uro-oncology Department with a suspicion of a metastatic germ cell tumour, owing to enlarged left testicle and elevated b-hCG concentration (39 mIU/mL). Impaired performance status caused by extensive pulmonary and liver metastases, accompanied by significant lymphadenopathy, necessitated prompt management. However, a testicular tumour was excluded on ultrasound imaging; a hydrocele only was found. The b-hCG concentration was not increasing (37 mIU/mL). We found a diagnosis of an extragonadal germ cell tumour doubtful, and a liver biopsy was performed. Due to the patient’s quick deterioration, we decided to commence pre-phase chemotherapy with cisplatin and etoposide, which resulted in a significant clinical improvement. The pathological examination, along with immunoassays, revealed undifferentiated cholangiocarcinoma, and the patient continued chemotherapy with a biliary tract cancer regimen, i.e. cisplatin and gemcitabine. Unfortunately, the clinical response was short-lived; the disease progressed, the patient was offered best supportive care and died two months after the diagnosis. The case underpins the literature review with respect to differential diagnosis of an elevated hCG concentration. In particular, we discuss ectopic secretion in non-trophoblastic and non-germinal malignancies and the causes of false positive assays.We present a case of a 34-year-old male patient referred to our Uro-oncology Department with a suspicion of a metastatic germ cell tumour, owing to enlarged left testicle and elevated β-hCG concentration (39 mIU/ml). Impaired performance status caused by extensive pulmonary and liver metastases, accompanied by significant lymphadenopathy, necessitated prompt management. However, a testicular tumour was excluded by ultrasound examination; a hydrocele only was found. The β-hCG concentration was not increasing (37 mIU/ml). We found a diagnosis  of an extragonadal germ cell tumour doubtful, and a liver biopsy was performed.  Due to the patient’s quick deterioration, we decided to commence pre-phase chemotherapy with cisplatin and etoposide, which resulted in a significant clinical improvement. The pathological examination, along with immunoassays, revealed undifferentiated cholangiocarcinoma, and the patient continued chemotherapy  with a biliary tract cancer regimen, i.e. cisplatin and gemcitabine. Unfortunately, the clinical response was short-lived; the disease progressed, the patient was offered best supportive care and died two months after the diagnosis. The case underpins the literature review with respect to differential diagnosis  of an elevated hCG concentration. In particular, we discuss ectopic secretion  in non-trophoblastic and non-germinal malignancies and the causes of false positive assays

Loss of DAP12 and FcRγ drives exaggerated IL-12 production and CD8(+) T cell response by CCR2(+) Mo-DCs

Dap12 and FcRγ, the two transmembrane ITAM-containing signaling adaptors expressed in dendritic cells (DC), are implicated in the regulation of DC function. Several activating and adhesion receptors including integrins require these chains for their function in triggering downstream signaling and effector pathways, however the exact role(s) for Dap12 and FcRγ remains elusive as their loss can lead to both attenuating and enhancing effects. Here, we report that mice congenitally lacking both Dap12 and FcRγ chains (DF) show a massively enhanced effector CD8(+) T cell response to protein antigen immunization or West Nile Virus (WNV) infection. Thus, immunization of DF mice with MHCI-restricted OVA peptide leads to accumulation of IL-12-producing monocyte-derived dendritic cells (Mo-DC) in draining lymph nodes, followed by vastly enhanced generation of antigen-specific IFNγ-producing CD8(+) T cells. Moreover, DF mice show increased viral clearance in the WNV infection model. Depletion of CCR2+ monocytes/macrophages in vivo by administration anti-CCR2 antibodies or clodronate liposomes completely prevents the exaggerated CD8+ T cell response in DF mice. Mechanistically, we show that the loss of Dap12 and FcRγ-mediated signals in Mo-DC leads to a disruption of GM-CSF receptor-induced STAT5 activation resulting in upregulation of expression of IRF8, a transcription factor. Consequently, Dap12- and FcRγ-deficiency exacerbates GM-CSF-driven monocyte differentiation and production of inflammatory Mo-DC. Our data suggest a novel cross-talk between DC-ITAM and GM-CSF signaling pathways, which controls Mo-DC differentiation, IL-12 production, and CD8(+) T cell responses

Search for right-handed W bosons in top quark decay

We present a measurement of the fraction f+ of right-handed W bosons produced in top quark decays, based on a candidate sample of $t\bar{t}$ events in the lepton+jets decay mode. These data correspond to an integrated luminosity of 230pb^-1, collected by the DO detector at the Fermilab Tevatron $p\bar{p}$ Collider at sqrt(s)=1.96 TeV. We use a constrained fit to reconstruct the kinematics of the $t\bar{t}$ and decay products, which allows for the measurement of the leptonic decay angle $\theta^*$ for each event. By comparing the $\cos\theta^*$ distribution from the data with those for the expected background and signal for various values of f+, we find f+=0.00+-0.13(stat)+-0.07(syst). This measurement is consistent with the standard model prediction of f+=3.6x10^-4.Comment: Submitted to Physical Review D Rapid Communications 7 pages, 3 figure

Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

BACKGROUND: Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF), was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. METHODS: We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF) were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. RESULTS: We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM) and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM) or nucleolin (on the cell surfaces) eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of laminin-binding integrins, nor can they be linked to expression of the known HGF receptor Met, as neither LNCaP nor clonally-derived C4-2 sub-line contain any detectable Met protein. Even in the absence of Met, small GTPases are activated, linking HGF stimulation to membrane protrusion and integrin activation. Membrane-localized nucelolin levels increase during cancer progression, as modeled by both the PC3 and LNCaP prostate cancer progression cell lines. CONCLUSION: We propose that cell surface localized nucleolin protein may function in these cells as a novel HGF receptor. Membrane localized nucleolin binds heparin-bound growth factors (including HGF) and appears upregulated during prostate cancer progression. Antibodies against nucleolin are able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. HGF-nucleolin interactions could be partially responsible for the complexity of HGF responses and met expression reported in the literature

Analysis of influence of additional GPS measurements on network accuracy

W opracowaniu rozpatrzono dwa ciągi prostoliniowe o długości 2400 m i 3600 m, dwa łańcuchy trójkątów o długości 2400 m i 3600 m oraz sieć dowolnego kształtu (średnia długość boku 520 m). W sieciach tych dodawano jeden lub dwa dodatkowe pomiary GPS. Średni błąd położenia punktu wyznaczanego za pomocą GPS przyjmowano: 2, 3 oraz 4 mm. Przeprowadzone analizy pozwoliły na sformułowanie istotnych wniosków na temat stosowania dodatkowych pomiarów GPS w analizowanych sieciach.In the paper two straight line traverses (2400 m and 3600 m long), two straight triangulation chains (2400 m and 3600 m long) and a closed traverse (mean side length 520 m) were examined. In these networks one or two the additional GPS measurements were added. The mean error of the position GPS points were assumed 2, 3 and 4 mm. The presented anlysis enable to come to the important conclusions with reference to applying additional GPS measurements to the analysed networks

Network influence on the setting out accuracy without additional observations

Praca przedstawia wyprowadzenie wzoru ujmującego wpływ niedokładności osnowy na dokładność tyczenia. Wzór odnosi się do tyczenia bez dodatkowych obserwacji. W tym przypadku macierz obserwacyjna musi być kwadratowa i musi mieć inwers. Pierwsza część wzoru zawiera tylko wpływ dokładności tyczenia, a część druga - wpływ dokładności osnowy. Ponadto w pracy podano ogólny przypadek wyprowadzenia wzorów na obie wymienione części.The paper refers to derivation of the formula containing the influence of a network inaccuracy on the accuracy of setting out. The formula refers to setting out without additional observations. In this case the observation matrix must be square, and must have an inverse matrix. The first part of formula contains only the influence of accuracy of the setting out and the second part contains the influence of network accuracy. Besides a general case of derivation of the both parts of the formula was presented