A single injection of corifollitropin alfa supplemented with human chorionic gonadotropin increases follicular recruitment and transferable embryos in the rabbit

[EN] Contents Superovulation protocols are designed to achieve maximum embryo yields. Nevertheless, ovarian response control and the quality of obtained embryos are still a challenge. On the other hand, to save the superovulated embryos until their subsequent use, it is usual to cryopreserve them, so it is also crucial to assess their cryotolerance. The aim of this study was to compare the efficacy of a single injection of corifollitropin alfa (FSH-CTP) alone or supplemented with human chorionic gonadotropin (hCG) and to determine the impact of this stimulation on in vitro and in vivo development of fresh or devitrified embryos. Our outcomes showed that ovulation rate and recovered embryos were significantly increased when hCG was used. In vitro development of fresh and devitrified embryos and survival at birth were not significantly affected by superstimulation treatment. Results of this study suggest that a single injection of long-acting FSH-CTP supplemented with hCG can be effectively used in rabbits to elicit an increase in ovulation rate and number of recovered embryos. Furthermore, we demonstrated that hCG supplementation had no negative effects in embryo cryosurvival and development, showing similar survival rate at birth than FSH-CTP alone group.This research was supported by the Spanish Research project funded by Ministerio de Economía, Industria y Competitividad (MICINN) AGL2017¿85162¿C2¿1¿R and Generalitat Valenciana research pro¿ gram (Prometeo II 2014/036). X Garcia¿Dominguez was supported by a research grant from MICINN (BES¿2015¿072429).Viudes-De-Castro, MP.; Marco-Jiménez, F.; Más-Pellicer, A.; Garcia-Dominguez, X.; Talaván, AM.; Vicente Antón, JS. (2019). A single injection of corifollitropin alfa supplemented with human chorionic gonadotropin increases follicular recruitment and transferable embryos in the rabbit. Reproduction in Domestic Animals. 54(4):696-701. https://doi.org/10.1111/rda.13411S696701544Acevedo, B., Sanchez, M., Gomez, J. L., Cuadros, J., Ricciarelli, E., & Hernández, E. R. (2004). Luteinizing hormone supplementation increases pregnancy rates in gonadotropin-releasing hormone antagonist donor cycles. Fertility and Sterility, 82(2), 343-347. doi:10.1016/j.fertnstert.2004.03.020Besenfelder, U., & Brem, G. (1993). Laparoscopic embryo transfer in rabbits. Reproduction, 99(1), 53-56. doi:10.1530/jrf.0.0990053Boostanfar, R., Shapiro, B., Levy, M., Rosenwaks, Z., Witjes, H., Stegmann, B. J., … Yeko, T. (2015). Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization. Fertility and Sterility, 104(1), 94-103.e1. doi:10.1016/j.fertnstert.2015.04.018Campbell, R. K. (2005). Molecular Pharmacology of Gonadotropins. Endocrine, 26(3), 291-296. doi:10.1385/endo:26:3:291Carvalho, P. D., Hackbart, K. S., Bender, R. W., Baez, G. M., Dresch, A. R., Guenther, J. N., … Fricke, P. M. (2014). Use of a single injection of long-acting recombinant bovine FSH to superovulate Holstein heifers: A preliminary study. Theriogenology, 82(3), 481-489. doi:10.1016/j.theriogenology.2014.05.011Chappel, S. C., & Howles, C. (1991). REVIEW. Human Reproduction, 6(9), 1206-1212. doi:10.1093/oxfordjournals.humrep.a137513Cole, L. A. (2010). Biological functions of hCG and hCG-related molecules. Reproductive Biology and Endocrinology, 8(1), 102. doi:10.1186/1477-7827-8-102Devroey, P., Boostanfar, R., Koper, N. P., Mannaerts, B. M. J. L., IJzerman-Boon, P. C., & Fauser, B. C. J. M. (2009). A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol. Human Reproduction, 24(12), 3063-3072. doi:10.1093/humrep/dep291Drakakis, P., Loutradis, D., Beloukas, A., Sypsa, V., Anastasiadou, V., Kalofolias, G., … Antsaklis, A. (2009). Early hCG addition to rFSH for ovarian stimulation in IVF provides better results and the cDNA copies of the hCG receptor may be an indicator of successful stimulation. Reproductive Biology and Endocrinology, 7(1). doi:10.1186/1477-7827-7-110Durnerin, C. I., Erb, K., Fleming, R., Hillier, H., Hillier, S. G., … Howles, C. M. (2007). Effects of recombinant LH treatment on folliculogenesis and responsiveness to FSH stimulation. Human Reproduction, 23(2), 421-426. doi:10.1093/humrep/dem388Estany, J., Camacho, J., Baselga, M., & Blasco, A. (1992). Selection response of growth rate in rabbits for meat production. Genetics Selection Evolution, 24(6), 527. doi:10.1186/1297-9686-24-6-527Ezcurra, D., & Humaidan, P. (2014). A review of luteinising hormone and human chorionic gonadotropin when used in assisted reproductive technology. Reproductive Biology and Endocrinology, 12(1), 95. doi:10.1186/1477-7827-12-95Fauser, B. C. J. M., Alper, M. M., Ledger, W., Schoolcraft, W. B., Zandvliet, A., & Mannaerts, B. M. J. L. (2010). Pharmacokinetics and follicular dynamics of corifollitropin alfa versus recombinant FSH during ovarian stimulation for IVF. Reproductive BioMedicine Online, 21(5), 593-601. doi:10.1016/j.rbmo.2010.06.032Franco, J. G., Baruffi, R. L., Oliveira, J. B. A., Mauri, A. L., Petersen, C. G., Contart, P., & Felipe, V. (2009). Effects of recombinant LH supplementation to recombinant FSH during induced ovarian stimulation in the GnRH-agonist protocol: a matched case-control study. Reproductive Biology and Endocrinology, 7(1). doi:10.1186/1477-7827-7-58HASHIMOTO, S., KURAMOCHI, T., AOYAGI, K., TAKAHASHI, R., UEDA, M., HIRAO, M., … HIRASAWA, K. (2004). Refined Porcine Follicle Stimulating Hormone Promotes the Responsiveness of Rabbits to Multiple-Ovulation Treatment. Experimental Animals, 53(4), 395-397. doi:10.1538/expanim.53.395Le Cotonnec, J.-Y., Porchet, H., Beltrami, V., & Munafo, A. (1998). Clinical pharmacology of recombinant human luteinizing hormone: Part I. Pharmacokinetics after intravenous administration to healthy female volunteers and comparison with urinary human luteinizing hormone. Fertility and Sterility, 69(2), 189-194. doi:10.1016/s0015-0282(97)00501-3Levy, D. P. (2000). The role of LH in ovarian stimulation: Exogenous LH: let’s design the future. Human Reproduction, 15(11), 2258-2265. doi:10.1093/humrep/15.11.2258Mannaerts, B. M., Geurts, T. B., & Odink, J. (1998). A randomized three-way cross-over study in healthy pituitary-suppressed women to compare the bioavailability of human chorionic gonadotrophin (Pregnyl) after intramuscular and subcutaneous administration. Human Reproduction, 13(6), 1461-1464. doi:10.1093/humrep/13.6.1461Rao, C. V. (1979). DIFFERENTIAL PROPERTIES OF HUMAN CHORIONIC GONADOTROPHIN AND HUMAN LUTEINIZING HORMONE BINDING TO PLASMA MEMBRANES OF BOVINE CORPORA LUTEA. Acta Endocrinologica, 90(4), 696-710. doi:10.1530/acta.0.0900696Ruvolo, G., Bosco, L., Pane, A., Morici, G., Cittadini, E., & Roccheri, M. C. (2007). Lower apoptosis rate in human cumulus cells after administration of recombinant luteinizing hormone to women undergoing ovarian stimulation for in vitro fertilization procedures. Fertility and Sterility, 87(3), 542-546. doi:10.1016/j.fertnstert.2006.06.059Salvetti, P., Theau-Clément, M., Beckers, J.-F., Hurtaud, J., Guérin, P., Neto, V., … Joly, T. (2007). 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Effect of recombinant gonadotropins on embryo quality in superovulated rabbit does and immune response after repeated treatments. Theriogenology, 72(5), 655-662. doi:10.1016/j.theriogenology.2009.04.022Viudes-de-Castro, M. P., Marco-Jiménez, F., Cedano-Castro, J. I., & Vicente, J. S. (2017). Effect of corifollitropin alfa supplemented with or without LH on ovarian stimulation and embryo viability in rabbit. Theriogenology, 98, 68-74. doi:10.1016/j.theriogenology.2017.05.005Viudes-de-Castro, M. P., Pomares, A., Saenz de Juano i Ribes, M. D., Marco-Jiménez, F., & Vicente, J. S. (2015). Effect of luteinizing hormone on rabbit ovarian superstimulation and embryo developmental potential. Theriogenology, 84(3), 446-451. doi:10.1016/j.theriogenology.2015.04.001Wallach, E. E., Shoham, Z., Schachter, M., Loumaye, E., Weissman, A., MacNamee, M., & Insler, V. (1995). The luteinizing hormone surge—the final stage in ovulation induction: modern aspects of ovulation triggering. 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Evaluation of spacial resolution of a PET scanner through the simulation and experimental measurement of the Recovery coefficient

Purpose: In order to measure spatial resolution of a PET tomograph in clinical conditions, this study describes and validates a method based on the recovery coefficient, a factor required to compensate underestimation in measured radioactivity concentration for small structures. Methods: In a PET image, the recovery factors of radioactive spheres were measured and their comparison with simulated recovery coefficients yielded the tomographic spatial resolution. Following this methodology, resolution was determined in different surrounding media and several conditions for reconstruction, including clinical conditions for brain PET studies. All spatial resolution values were compared with those obtained using classical methods with point and line sources. Results: In each considered condition, spatial resolution of the PET image estimated using the recovery coefficient showed good agreement with classical methods measurements, validating the procedure. Conclusion: Measurement of the recovery coefficient provides an assessment of tomographic spatial resolution, particularly in clinical studies conditions

Tomografía por emisión de positrones en el cáncer de mama

PET18FDG is an imaging diagnostic technique that shows changes in glycolitic metabolism that appear at a very early phases in the tumoral process. The main limitation of PET in breast cancer is the detection of small tumor lesions and axillary micrometastases. However it offers important information in the staging of high risk patients, in clinical relapse or in therapeutic evaluation. The new PET-CT devices offer advantages over conventional techniques. It provides a greater precision in the localization of tumoral foci. In spite of current difficulties for clinical applications, fluoro-estradiol (18F-ES) offers the possibilty of studying the presence of estrogenic receptors both in the primary and in the metastases. It may prove to be a useful tool to obtain information about therapeutic management and prognosis of breast cancer

Elevated circulating metalloproteinase 7 predicts recurrent cardiovascular events in patients with carotid stenosis: a prospective cohort study

Background: Major adverse cardiovascular events are the main cause of morbidity and mortality over the long term in patients undergoing carotid endarterectomy. There are few reports assessing the prognostic value of markers of inflammation in relation to the risk of cardiovascular disease after carotid endarterectomy. Here, we aimed to determine whether matrix metalloproteinases (MMP-1, MMP-2, MMP-7, MMP-9 and MMP-10), tissue inhibitor of MMPs (TIMP-1) and in vivo inflammation studied by 18F-FDG-PET/CT predict recurrent cardiovascular events in patients with carotid stenosis who underwent endarterectomy. Methods: This prospective cohort study was carried out on 31 consecutive patients with symptomatic (23/31) or asymptomatic (8/31) severe (> 70%) carotid stenosis who were scheduled for carotid endarterectomy between July 2013 and March 2016. In addition, 26 healthy controls were included in the study. Plasma and serum samples were collected 2 days prior to surgery and tested for MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein and erythrocyte sedimentation rate. 18F-FDGPET/CT focusing on several territories’ vascular wall metabolism was performed on 29 of the patients because of no presurgical availability in 2 symptomatic patients. Histological and immunohistochemical studies were performed with antibodies targeting MMP-10, MMP-9, TIMP-1 and CD68. Results: The patients with carotid stenosis had significantly more circulating MMP-1, MMP-7 and MMP-10 than the healthy controls. Intraplaque TIMP-1 was correlated with its plasma level (r = 0.42 P = .02) and with 18F-FDG uptake (r = 0.38 P = .05). We did not find any correlation between circulating MMPs and in vivo carotid plaque metabolism assessed by 18F-FDG-PET. After a median follow-up of 1077 days, 4 cerebrovascular, 7 cardiovascular and 11 peripheral vascular events requiring hospitalization were registered. Circulating MMP-7 was capable of predicting events over and above the traditional risk factors (HR = 1.15 P = .006). When the model was associated with the variables of interest, the risk predicted by 18F-FDG-PET was not significant. Conclusions: Circulating MMP-7 may represent a novel marker for recurrent cardiovascular events in patients with moderate to severe carotid stenosis. MMP-7 may reflect the atherosclerotic burden but not plaque inflammation in this specific vascular territory

PET tracers for clinical imaging of breast cancer

Molecular imaging of breast cancer has undoubtedly permitted a substantial development of the overall diagnostic accuracy of this malignancy in the last years. Accurate tumour staging, design of individually suited therapies, response evaluation, early detection of recurrence and distant lesions have also evolved in parallel with the development of novel molecular imaging approaches. In this context, positron emission tomography (PET) can be probably seen as the most interesting molecular imaging technology with straightforward clinical application for such purposes. Dozens of radiotracers for PET imaging of breast cancer have been tested in laboratory animals. However, in this review we shall focus mainly in the smaller group of PET radiopharmaceuticals that have lead through into the clinical setting. PET imaging can be used to target general metabolic phenomena related to tumoural transformation, including glucose metabolism and cell proliferation, but can also be directed to specific hormone receptors that are characteristic of the breast cancer cell. Many other receptors and transport molecules present in the tumour cells could also be of interest for imaging. Furthermore, molecules related with the tumour microenvironment, tumour induced angiogenesis or even hypoxia could also be used as molecular biomarkers for breast cancer imaging

Resolution of disseminated fusariosis in a child with acute leukemia treated with combined antifungal therapy: a case report

<p>Abstract</p> <p>Background</p> <p><it>Fusarium </it>spp. is being isolated with increasing frequency as a pathogen in oncohematologic patients. Caspofungin and amphotericin B have been reported to have synergistic activity against <it>Fusarium </it>spp.</p> <p>Case presentation</p> <p>We herein report a case of disseminated fusariosis diagnosed by chest CT scan and positive blood cultures to <it>Fusarium </it>spp. Because the patient's clinical condition deteriorated, CRP levels increased, and blood cultures continued to yield <it>Fusarium </it>spp. despite liposomal amphotericin B monotherapy up to 5 mg/kg daily, treatment with caspofungin was added. Within 2 weeks of onset of combined antifungal therapy, the chest CT scan demonstrated a progressive resolution of the pulmonary lesions. Upon discontinuation of intravenous antifungals, the patient received suppressive therapy with oral voriconazole. Three months later, a chest CT scan showed no abnormalities. Twenty-five months after discontinuation of all antifungal therapy, the patient remains in complete remission of her neoplastic disease with no signs of clinical activity of the <it>Fusarium </it>infection.</p> <p>Conclusion</p> <p>This is the first description of successful treatment of disseminated fusariosis in a pediatric patient with acute lymphoblastic leukemia with caspofungin and amphotericin B followed by oral suppressive therapy with voriconazole.</p

Adenosine A2A receptor modulation of hippocampal CA3-CA1 synapse plasticity during associative learning in behaving mice

© 2009 Nature Publishing Group All rights reservedPrevious in vitro studies have characterized the electrophysiological and molecular signaling pathways of adenosine tonic modulation on long-lasting synaptic plasticity events, particularly for hippocampal long-term potentiation(LTP). However, it remains to be elucidated whether the long-term changes produced by endogenous adenosine in the efficiency of synapses are related to those required for learning and memory formation. Our goal was to understand how endogenous activation of adenosine excitatory A2A receptors modulates the associative learning evolution in conscious behaving mice. We have studied here the effects of the application of a highly selective A2A receptor antagonist, SCH58261, upon a well-known associative learning paradigm - classical eyeblink conditioning. We used a trace paradigm, with a tone as the conditioned stimulus (CS) and an electric shock presented to the supraorbital nerve as the unconditioned stimulus(US). A single electrical pulse was presented to the Schaffer collateral–commissural pathway to evoke field EPSPs (fEPSPs) in the pyramidal CA1 area during the CS–US interval. In vehicle-injected animals, there was a progressive increase in the percentage of conditioning responses (CRs) and in the slope of fEPSPs through conditioning sessions, an effect that was completely prevented (and lost) in SCH58261 (0.5 mg/kg, i.p.)-injected animals. Moreover, experimentally evoked LTP was impaired in SCH58261- injected mice. In conclusion, the endogenous activation of adenosine A2A receptors plays a pivotal effect on the associative learning process and its relevant hippocampal circuits, including activity-dependent changes at the CA3-CA1 synapse.This study was supported by grants from the Spanish Ministry of Education and Research (BFU2005-01024 and BFU2005-02512), Spanish Junta de Andalucía (BIO-122 and CVI-02487), and the Fundación Conocimiento y Cultura of the Pablo de Olavide University (Seville, Spain).B. Fontinha was in receipt of a studentship from a project grant (POCI/SAU-NEU/56332/2004) supported by Fundação para a Ciência e Tecnologia (FCT, Portugal), and of an STSM from Cost B30 concerted action of the EU

Early lung cancer detection using spiral computed tomography and positron emission tomography

RATIONALE: Lung cancer screening using computed tomography (CT) is effective in detecting lung cancer in early stages. Concerns regarding false-positive rates and unnecessary invasive procedures have been raised. OBJECTIVE: To study the efficiency of a lung cancer protocol using spiral CT and F-18-fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS: High-risk individuals underwent screening with annual spiral CTs. Follow-up CTs were done for noncalcified nodules of 5 mm or greater, and FDG-PET was done for nodules 10 mm or larger or smaller (> 7 mm), growing nodules. RESULTS: A total of 911 individuals completed a baseline CT study and 424 had at least one annual follow-up study. Of the former, 14% had noncalcified nodules of 5 mm or larger, and 3.6% had nodules of 10 mm or larger. Eleven non-small cell lung cancers (NSCLC) and one small cell lung cancer (SCLC) were diagnosed in the baseline study (prevalence rate, 1.32%), and two NSCLCs in the annual study (incidence rate, 0.47%). All NSCLCs (92% of prevalence cancers) were diagnosed in stage I (12 stage IA, 1 stage IB). FDG-PET was helpful for the correct diagnosis in 19 of 25 indeterminate nodules. The sensitivity, specificity, positive predictive value, and negative predictive value of FDG-PET for the diagnosis of malignancy were 69, 91, 90, and 71%, respectively. However, the sensitivity and negative predictive value of the screening algorithm, which included a 3-month follow-up CT for nodules with a negative FDG-PET, was 100%. CONCLUSION: A protocol for early lung cancer detection using spiral CT and FDG-PET is useful and may minimize unnecessary invasive procedures for benign lesions

Extra-uterine (abdominal) full term foetus in a 15-day pregnant rabbit

[EN] Background: While ectopic pregnancies account for 1-2% of all pregnancies, abdominal pregnancy is extremely rare, accounting for approximately 1% of ectopic pregnancies. Extrauterine abdominal pregnancy is defined as the implantation and development of an embryo in the peritoneal cavity. The present report is the first of an incidental case of abdominal pregnancy within four full-term foetus simultaneously with 2 weeks of physiological gestation in a healthy doe rabbit. Case presentation: The doe was born on November 3, 2014 and the first partum took place on May 18, 2015. The doe had previously delivered and weaned an average of 12.0 +/- 1.41 live kits at birth (no stillbirths were recorded) during 5 consecutive pregnancies. The last mating was on December 18, 2015 and the detection of pregnancy failure post breeding (by abdominal palpation) on December 31, 2015. Then, the doe was artificially inseminated on January 27, 2016, diagnosed pregnant on February 11, 2016 and subsequently euthanized to recover the foetus. A ventral midline incision revealed a reproductive tract with 12 implantation sites with 15 days old foetus and 4 term foetus in abdominal cavity. There were two foetus floating on either side of the abdominal cavity and two suspended near the greater curvature of the stomach. They were attached to internal organs by means of one or 2 thread-like blood vessels that linked them to the abdominal surfaces. Conclusions: In our opinion a systematic monitoring of rabbit breeding should be included to fully understand and enhance current knowledge of this phenomenon of abdominal pregnancy.This work was supported by Spanish Research Project AGL2014-53405-C2-1-P (Interministerial Commission on Science and Technology).Marco-Jiménez, F.; Garcia-Dominguez, X.; Valdes-Hernández, J.; Vicente Antón, JS. (2017). 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J Am Assoc Lab Anim Sci. 2014;53:204–7.Sánchez JP, Theilgaard P, Mínguez C, Baselga M. Constitution and evaluation of a long-lived productive rabbit line. J Anim Sci. 2008;86:515–25.Savietto D, Friggens NC, Pascual JJ. Reproductive robustness differs between generalist and specialist maternal rabbit lines: the role of acquisition and allocation of resources. Genet Sel Evol. 2015;47:2.Viudes-de-Castro MP, Vicente JS. Effect of sperm count on the fertility and prolificity rates of meat rabbits. Anim Reprod Sci. 1997;46:313–9.Marco-Jiménez F, Garcia-Dominguez X, Jimenez-Trigos E, Vera-Donoso CD, Vicente JS. Vitrification of kidney precursors as a new source for organ transplantation. Cryobiology. 2015;70:278–82.Garcia-Dominguez X, Vera-Donoso CD, Jimenez-Trigos E, Vicente JS, Marco-Jimenez. First steps towards organ banks: vitrification of renal primordial. Cryo Letters. 2016;37:47–52.Arvidsson A. Extra-uterine pregnancy in a rabbit. Vet Rec. 1998;142:176.Glišić A, Radunović N, Atanacković J. Methotrexate and fallopian tubes in ectopic pregnancy. Acta veterinaria. 2006;56:375–82.Nwobodo EI. Abdominal pregnancy. A case report. Ann Afr Med. 2004;3:195–6.Nassali MN, Benti TM, Bandani-Ntsabele M, Musinguzi E. A case report of an asymptomatic late term abdominal pregnancy with a live birth at 41 weeks of gestation. BMC Res Notes. 2016;9:31.Baffoe P, Fofie C, Gandau BN. Term abdominal pregnancy with healthy new-born: a case report. Ghana Med J. 2011;45:81–3.Eleje GU, Adewae O, Osuagwu IK, Obianika CE. Post-date extra-uterine abdominal pregnancy in a rhesus negative Nullipara with successful outcome: a case report. J Women's Health. 2013;6:2.Hong CC, Armstrong ML. Ectopic pregnancy in 2 guinea-pigs. Lab Anim. 1978;12:243–4.Peters LJ. Abdominal pregnancy in a golden hamster (Mesocricetus Auratus). Lab Anim Sci. 1982;32:392–3.Xiccato G, Trocino A, Boiti C, Brecchia G. Reproductive rhythm and litter weaning age as they affect rabbit doe performance and body energy balance. Anim Sci. 2005;81:289–96.Fortun-Lamothe L, De Rochambeau H, Lebas F, Tudela F. Influence of the number of suckling young on reproductive performance in intensively reared rabbits does. In: Blasco A, editor. Proceedings of the 7th world rabbit congress; 2002. p. 125–32

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis