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Background: Germ cell tumors (GCTs) represent a highly curable cancer. However, a small proportion of poor-risk patients can develop choriocarcinoma syndrome (CS) connected with acute respiratory distress syndrome (ARDS) with a high mortality rate. Our retrospective study aimed to determine the risk factors of poor-risk GCTs susceptible to CS development. Patients and Methods: Using a computerized database and a systematic chart review, we identified the records of 532 patients with GCTs treated at the National Cancer Institute from 2000 to 2018. Ninety eligible patients with poor-risk GCTs based on IGCCCG classification were identified. All patients were treated with platinum-based induction chemotherapy. Clinicopathological variables were collected and analyzed in correlation with CS development. Results: Nine (10%) of 90 patients developed CS in a median of 1 day (1–9 days) after chemotherapy administration. All patients died shortly after the chemotherapy start with a median of 4 days (3–35 days) due to ARDS development. In univariate analysis, metastatic lung involvement ≥50% of lung parenchyma, choriocarcinoma elements in histology specimen, dyspnea, cough, hemoptysis, ECOG PS ≥2, weight loss, hemoglobin ≤100 g/l, and NLR ≥3.3 at the time of presentation were associated with CS development. In multivariate analysis, ECOG PS ≥2 and metastatic lung involvement ≥50% were independently associated with CS. All patients with these two characteristics developed CS, compared to 0% with zero or one of these factors (p < 0.000001). Conclusions: In our study, we identified factors associated with CS development. These factors might improve the risk stratification of the patients susceptible to CS and improve their outcome. [ABSTRACT FROM AUTHOR]

BackgroundGerm cell tumors (GCTs) represent a highly curable cancer. However, a small proportion of poor-risk patients can develop choriocarcinoma syndrome (CS) connected with acute respiratory distress syndrome (ARDS) with a high mortality rate. Our retrospective study aimed to determine the risk factors of poor-risk GCTs susceptible to CS development.Patients and MethodsUsing a computerized database and a systematic chart review, we identified the records of 532 patients with GCTs treated at the National Cancer Institute from 2000 to 2018. Ninety eligible patients with poor-risk GCTs based on IGCCCG classification were identified. All patients were treated with platinum-based induction chemotherapy. Clinicopathological variables were collected and analyzed in correlation with CS development.ResultsNine (10%) of 90 patients developed CS in a median of 1 day (1–9 days) after chemotherapy administration. All patients died shortly after the chemotherapy start with a median of 4 days (3–35 days) due to ARDS development. In univariate analysis, metastatic lung involvement ≥50% of lung parenchyma, choriocarcinoma elements in histology specimen, dyspnea, cough, hemoptysis, ECOG PS ≥2, weight loss, hemoglobin ≤100 g/l, and NLR ≥3.3 at the time of presentation were associated with CS development. In multivariate analysis, ECOG PS ≥2 and metastatic lung involvement ≥50% were independently associated with CS. All patients with these two characteristics developed CS, compared to 0% with zero or one of these factors (p < 0.000001).ConclusionsIn our study, we identified factors associated with CS development. These factors might improve the risk stratification of the patients susceptible to CS and improve their outcome.

In this study, female rats induced with chemical cystitis were administered the hormone human choriogonadotropin (HCG), and it was aimed to reveal the usefulness of HCG in the treatment of interstitial cystitis/bladder pain syndrome. The materials for this study were 32 Wistar albino female rats. The study groups were formed as follows: the cystitis group (Group 1), the cystitis + HCG protection group (Group 2), the cystitis + HCG treatment group (Group 3), and the control group (Group 4), with eight rats in each group. In this study, blood and urine samples were taken from the rats, they were euthanized, and their bladders were removed for glutathione, malondialdehyde, tumor necrosis factor alpha, and interferon gamma measurements. It was observed that tissue damage in Group 2 was lower than that in the other two groups. Glutathione levels in Groups 2 and 4 were significantly higher than in Groups 1 and 3 (p = 0.01). Malondialdehyde levels of Groups 2 and 4 were significantly lower than the values in Groups 1 and 3 (p

Background: Human cancer cell lines express human choriogonadotropin (hCG), its subunits and derivatives, regardless of their origin and type. It appears that hCG is a common phenotype in human cancer cell lines. In this research, the effects of hCG targeting monoclonal antibodies (7D9, T18H7 and T8B12) on human cancer cell lines were evaluated. Methods: Monoclonal antibody secreting hybridomas were proliferated and injected intraperitoneally to Balb/C mice after treatment with pristine. Two weeks later, ascites fluid was collected. Purification of aforementioned antibodies from ascites fluid was performed using G-protein affinity followed by ion exchange chromatography. SDS-PAGE and ELISA confirmed the structure and functional integrity of the purified antibodies, respectively. Two human cancer cell lines "Hela" and "MDA" were treated by the purified antibodies. Three days later, different wells were imaged and the cells counted. Results: SDS-PAGE gel (None-reducing) indicated consistency of band migration patterns with control antibodies. ELISA test using hCG antigens indicated that the produced antibodies could detect hCG antigens. Cell lines were cultured and treated with different concentrations of each antibody. Counting and imaging different wells of treated plates, indicated that 7D9 antibody had a more significant (P

Background: Human cancer cell lines express human choriogonadotropin (hCG), its subunits and derivatives, regardless of their origin and type. It appears that hCG is a common phenotype in human cancer cell lines. In this research, the effects of hCG targeting monoclonal antibodies (7D9, T18H7 and T8B12) on human cancer cell lines were evaluated. Methods: Monoclonal antibody secreting hybridomas were proliferated and injected intraperitoneally to Balb/C mice after treatment with pristine. Two weeks later, ascites fluid was collected. Purification of aforementioned antibodies from ascites fluid was performed using G-protein affinity followed by ion exchange chromatography. SDSPAGE and ELISA confirmed the structure and functional integrity of the purified antibodies, respectively. Two human cancer cell lines "Hela" and "MDA" were treated by the purified antibodies. Three days later, different wells were imaged and the cells counted. Results: SDS-PAGE gel (None-reducing) indicated consistency of band migration patterns with control antibodies. ELISA test using hCG antigens indicated that the produced antibodies could detect hCG antigens. Cell lines were cultured and treated with different concentrations of each antibody. Counting and imaging different wells of treated plates, indicated that 7D9 antibody had a more significant (P<0.01) cytotoxic effect on cancer cell lines than the control cells. Conclusion: HCG targeting monoclonal antibodies can be used for targeted cancer therapy, as human cancer cells express hCG gene. 7D9 antibody that exhibits protease activity is a proper candidate for this purpose, as it possesses both antagonistic and enzymatic properties. [ABSTRACT FROM AUTHOR]

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Purpose Our purpose was to retrospectively compare controlled ovarian stimulation(COH) in IVF cycles with administration of hCG on the day of menses (D1-hCG) with women not receiving hCG at day 1 of menses (Control). Methods Data on maternal age, endocrine profile, amount of rFSH required, embryo characteristics, implantation and pregnancy rates were recorded for comparison between D1-hCG (n=36) and Control (n=64). Results Dose of rFSH required to accomplish COH was significantly lower in D1-hCG. Following ICSI, more topquality embryos were available for transfer per patient in the D1-hCG and biochemical pregnancy rates per transfer were significantly higher in the D1-hCG. Significantly higher implantation and on-going pregnancy rates per embryo transfer were observed in D1-hCG (64%) compared to Control (41%). Conclusions Administration of D1-hCG prior to COH reduces rFSH use and enhances oocyte developmental competence to obtain top quality embryos, and improves implantation and on-going pregnancy rates. At present it is not clear if the benefit is related to producing an embryo that more likely to implant or a more receptive uterus, or merely fortuitous and related to the relatively small power of the study. [ABSTRACT FROM AUTHOR]

Abstract: Human choriogonadotropin (hCG) and follitropin (hFSH) have been shown to contact different regions of the extracellular domains of G-protein coupled lutropin (LHR) and follitropin (FSHR) receptors. We report here that hCG and hFSH analogs interact with different regions of an FSHR/LHR chimera having only two unique LHR residues and that binds both hormones with high affinity. hCG and hFSH analogs dock with this receptor chimera in a manner similar to that in which they bind LHR and FSHR, respectively. This shows that although the FSHR does not normally bind hCG, it contains a cryptic lutropin binding site that has the potential to recognize hCG in a manner similar to the LHR. The presence of this cryptic site may explain why equine lutropins bind many mammalian FSHR and why mutations in the transmembrane domain distant from the extracellular domain enable the FSHR to bind hCG. The leucine-rich repeat domain (LRD) of the FSHR also appears to contain a cryptic FSH binding site that is obscured by other parts of the extracellular domain. This will explain why contacts seen in crystals of hFSH complexed with an LRD fragment of the human FSHR are hard to reconcile with the abilities of FSH analogs to interact with membrane G-protein coupled FSHR. We speculate that cryptic lutropin binding sites in the FSHR, which are also likely to be present in thyrotropin receptors (TSHR), permit the physiological regulation of ligand binding specificity. Cryptic FSH binding sites in the LRD may enable alternate spliced forms of the FSHR to interact with FSH. [Copyright &y& Elsevier]

Human choriogonadotropin (hCG) is a highly complex glycoprotein consisting of two non-covalently associated subunits. We aimed for the expression of a single-chain hCG in the soil amoebae Dictyostelium discoideum, a host which, in principle, provides simple genetics in combination with complex protein synthesis. To limit anticipated problems in mRNA translation, the first 30 bases of the coding sequence were altered to conform to the Dictyostelium preferred codon usage. We show that, immunologically, active single-chain hCG is indeed produced by Dictyostelium. Furthermore, this single-chain hCG is able to bind to the human luteinizing hormone/CG receptor and elicit a biological response. Its receptor-binding affinity is comparable to single-chain hCG produced by mammalian cells. We conclude that Dictyostelium is able to express bioactive highly complex heterologous glycoproteins. [ABSTRACT FROM AUTHOR]

The twelve Cys and eight of the non-Cys residues are invariant in the glycoprotein hormone β subunits from a variety of mammalian species. β-Gin-54 of human lutropin (hLH) and choriogonadotropin (hCG) is one of these invariant amino acid residues. A single A→G mutation in the LHβ gene of a patient presenting with hypogonadism resulted in the replacement of Gin-54 with Arg [1]. The authors also reported that an expressed mutant of hLHβ, with Arg replacing Gin-54, associated with the α subunit, but there was no demonstrable binding of the mutant hormone to receptor. We have replaced Gin-54 in hCGβ with Glu and with Lys using site-directed mutagenesis. The expression plasmids pRSV-hCGβ (wild-type and mutants) were transiently transfected into CHO cells containing a stably integrated gene for bovine α, and the media were analyzed for holoproteins, which were characterized in vitro using competitive binding and steroidogenic assays with MA-10 cells. hCGβ(Glu-54) bound to α almost as well as hCGβ wild-type, and the resulting heterodimer competed with [l]hCG binding to the LH/CG receptor and stimulated progesterone production to the same extent as the wild-type control. However, the apparent potencies, as judged by EDs, were less than those of the wild-type control, the effect being more pronounced in binding than in steroidogenesis. In contrast, hCGβ(Lys-54) associated very poorly with α. Our results suggest that while Gin-54 in hCGβ participates in receptor binding, its major function appears to involve α binding. Such dual functionality leads to interesting models for holoprotein formation and receptor binding. [ABSTRACT FROM AUTHOR]

Several studies indicate that in human choriogonadotropin the N-linked oligosaccharide at position 52 of the α-subunit is important for bioactivity. We have generated choriogonadotropin mutants in which the α52 glycosylation site is removed and the α and β subunits are covalently linked by intersubunit disulfide bonds. These mutants display wild-type receptor binding and bioactivity. Furthermore, we show that removal of the α52 sugar leads to instability of heterodimeric choriogonadotropin. Therefore, we conclude that the α52 oligosaccharide of choriogonadotropin is not involved in signal transduction, but in the stability of the heterodimer. [ABSTRACT FROM AUTHOR]

Objective: To investigate the accuracy of serial hCG to predict outcome of a pregnancy of unknown location in an ethnically and geographically diverse setting. Design: Multisite cohort study. Setting: University hospital. Patient(s): Women with a pregnancy of unknown location. Intervention(s): None. Main Outcome Measure(s): Patients were followed until diagnosed with ectopic pregnancy (EP), intrauterine pregnancy (IUP), or miscarriage. To predict outcome, observed hCG level was compared with recommended thresholds to assess deviation from defined normal curves. Predicted outcome was compared with standard of care. Sensitivity, specificity, predictive value, and accuracy were calculated, stratified by diagnosis. Result(s): The final diagnosis of 1,005 patients included 179 EPs, 259 IUPs, and 567 miscarriages. The optimal balance in sensitivity and specificity used the minimal expected 2-day increase in hCG level of 35%, and the minimal 2-day decrease in hCG level of 36%–47% (depending on the level) achieving 83.2% sensitivity, 70.8% specificity to predict EP. However, 16.8% of EPs and 7.7% of IUPs would be misclassified solely using serial hCG levels. Consideration of a third hCG and early ultrasound decreased IUP misclassification to 2.7%. Conclusion(s): Solely using serial hCG values can result in misclassification. Clinical judgment should trump prediction rules and continued surveillance with a third hCG may be prudent, especially when initial values are low or when values are near suggested thresholds. [ABSTRACT FROM AUTHOR]

The glycoprotein hormones are all structurally related heterodimers consisting of an α-subunit and a ligand-specific β-subunit that confers their unique biological activity. Crystal structures showed how the β-subunit surrounds a part of the α-subunit, and we showed the existence of the two mechanisms responsible for that assembly. In human choriogonadotropin, the β-subunit is folded before the subunits dock, and the α-subunit becomes incorporated into the dimer by a mechanism we termed "threading," passing between parts of the preassembled β-subunit. Here, we show that the human lutropin β-subunit is not folded completely prior to its interaction with the α-subunit and show that docking of the subunits enables the α-subunit to serve as a chaperone to the β-subunit. Based on data described here, we propose that the α-subunit facilitates formation of the human lutropin β-subunit by two mechanisms. First, the cystine knot of the α-subunit potentiates formation of the β-subunit cystine knot, and second, contacts between α-subunit loop 2 and a hydrophobic tail in the β-subunit facilitate formation of the seatbelt latch disulfide, which stabilizes the heterodimer. The primary influence of the α-subunit was seen when the hydrophobic tail was present or absent, but the secondary mechanism was required only when the hydrophobic tail of the β-subunit was present. During the evolution of human choriogonadotropin, neither of these α-subunit roles was necessary for folding of the β-subunit. The complex mechanism for lutropin assembly may be required to provide an additional control on its positive feedback function in vertebrate reproduction., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)