TMOD-26. MYC OVEREXPRESSION AND SMARCA4 LOSS IN GRANULE CELL PRECURSORS COOPERATE TO DRIVE MEDULLOBLASTOMA FORMATION IN MICE

Abstract Mutations in SMARCA4 are frequently identified in medulloblastoma, the most common pediatric malignant brain tumor. However, the functional significance of these mutations and their suitability as a therapeutic target remain largely unclear. Medulloblastomas are divided into 4 subgroups according to their localization, molecular biology, and clinical course: WNT, SHH, Group 3, and Group 4. Group 3 medulloblastomas are associated with the poorest outcome and frequently show amplifications of the oncogene MYC. Additionally, SMARCA4 is mutated in around 15 % of cases. The few mouse models developed for this entity so far all involve the overexpression of MYC, mostly in combination with other drivers. However, none of these models include alterations in Smarca4. In our approach, we combined an overexpression of MYC with a loss of SMARCA4 in granule cell precursors, which successfully induced tumor formation in mice. For this purpose, granule cell precursors were isolated from 7-day-old Math1-creER T2 ::Smarca4 fl/fl pups after tamoxifen induced loss of SMARCA4. MYC overexpression was achieved by lentiviral transduction and transduced cells were transplanted into immunodeficient CD1 nu/nu mice. Preliminary results within a small cohort showed tumor formation in 5/19 transplanted mice (26 %) after 6 months. Immunohistochemically, tumors all stained negative for SMARCA4. In a next step, additional cohorts will elucidate if tumor development is indeed accelerated by or even dependent on the loss of SMARCA4. Additionally, the neoplastic potential of tumor cells will be verified with the aid of secondary recipient mice. To evaluate to what extent the generated tumors are comparable to human Group 3 medulloblastomas, tumors will be extensively analyzed on a morphological, transcriptional, and epigenetic level. Altogether, we hope to establish a suitable mouse model for SMARCA4 mutated Group 3 medulloblastoma that will help to elucidate the role of SMARCA4 in tumor development and to identify new therapeutic targets.

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P5392Epicardium derived cells promote sympathetic ganglionic outgrowth towards myocardium in vitro

European Heart Journal ◽

10.1093/eurheartj/ehz746.0352 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

Y Ge ◽

A M Smits ◽

J C Van Munsteren ◽

T Van Herwaarden ◽

A M D Vegh ◽

...

Keyword(s):

Neurite Outgrowth ◽

Autonomic Innervation ◽

Cardiac Damage ◽

Group 4 ◽

Group 3 ◽

Cervical Ganglia ◽

Group 2 ◽

Group 1

Abstract Background The autonomic nerve system is essential to maintain homeostasis in the body. In the heart, autonomic innervation is important for adjusting the physiology to the continuously changing demands such as stress responses. After cardiac damage, excessive neurite outgrowth, referred to as autonomic hyperinnervation, can occur which is related to ventricular arrhythmias and sudden cardiac death. The cellular basis for this hyperinnervation is as yet unresolved. Here we hypothesize a role for epicardium derived cells (EPDCs) in stimulating sympathetic neurite outgrowth. Purpose To investigate the potential role of adult EPDCs in promoting sympathetic ganglionic outgrowth towards adult myocardium. Method Fetal murine superior cervical ganglia were dissected and co-cultured with activated adult mesenchymal epicardium-derived cells (EPDCs) or/and adult myocardium in a 3D collagen gel culture system. Four experiment groups were included: Group 1: Vehicle cultures (ganglia cultured without EPDC/myocardium) (n=48); Group 2: ganglia co-cultured with EPDCs (n=38); Group 3: ganglia co-cultured with myocardium (n=95); and group 4: ganglia co-cultured with both EPDCs and myocardium (n=96). The occurrence of neurite outgrowth was assessed in each group. The density of neurites that showed directional sprouting (i.e. sprouting towards myocardium) was assessed as well with a semi-automatic quantification method. Finally, sub-analyses were made by taking gender into account. Results Cervical ganglia cultured with EPDCs alone (group 2) showed increased neurite outgrowth compared to vehicle cultures (group 1), however the neurites did not show directional sprouting towards EPDCs. When co-cultured with myocardium (group 3), directional neurite outgrowth towards myocardium was observed. Compared to the ganglia-myocardium co-cultures, directional outgrowth was significantly increased in co-cultures combining myocardium and EPDCs (group 4), and the neurite density was also significantly augmented. Comparison between males and female ganglia demonstrated that more neurite outgrowth occurred in female-derived ganglia than in male-derived ganglia under the same co-culture conditions. Conclusion Activated adult EPDCs promote sympathetic ganglionic outgrowth in vitro. Sex differences exist in the response of ganglia to EPDCs, and female-derived ganglia appear more sensitive to EPDC-signalling. Results support a role of EPDCs in cardiac autonomic innervation and open avenues for exploring of their role in ventricular hyperinnervation after cardiac damage.

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Experimental model of posttraumatic syringomyelia: the role of adhesive arachnoiditis in syrinx formation

Journal of Neurosurgery ◽

10.3171/jns.1994.80.1.0133 ◽

1994 ◽

Vol 80 (1) ◽

pp. 133-139 ◽

Cited By ~ 72

Author(s):

Ki Hong Cho ◽

Yoshinobu Iwasaki ◽

Hiroyuki Imamura ◽

Kazutoshi Hida ◽

Hiroshi Abe

Keyword(s):

Normal Saline ◽

Subarachnoid Space ◽

Saline Solution ◽

Traumatic Injury ◽

Content Type ◽

Group 4 ◽

Kaolin Injection ◽

Group 3 ◽

Group 2

✓ An experimental model was devised to elucidate the role of spinal blockade in posttraumatic syringomyelia. Thirty-eight Japanese White rabbits, each weighing about 3 kg, were used in this study. The animals were divided into four groups: in Group 1, eight animals received traumatic injury only; in Group 2, 12 animals received traumatic injury following injection of 100 mg kaolin suspended in 1 cc normal saline solution into the subarachnoid space at the site of trauma; in Group 3, nine animals received traumatic injury following injection of 200 mg kaolin in 1 cc normal saline solution into the subarachnoid space at the site of trauma; and in Group 4, nine animals without traumatic injury received an injection of 200 mg kaolin in 1 cc normal saline solution into the subarachnoid space. The subjective criteria for syrinx formation were the presence of a definite round cyst having a smooth margin and an upper or lower extension of more than 2 cm from the injured site. Syrinx formation was seen in 12.5% (one of eight rabbits) in Group 1, 41.7% (five of 12 animals) in Group 2, 55.5% (five of nine rabbits) in Group 3 and 0% (none of nine animals) in Group 4 (p < 0.05). There was a tendency for the combined trauma/kaolin injection groups to be more prone to develop a syrinx. In the kaolin injection only group (Group 4), no animal showed a definite cyst or an extending cavity during the experimental period. The results suggest that kaolin enhances the extension of multiple small cavities that have already formed at the time of initial injury. The difference between the frequency of syrinx formation and the time of survival was statistically significant well beyond the 0.05% level. The overall difference, relating to the frequency of syrinx development, group, and duration of survival, was also statistically significant. In summary, subarachnoid block secondary to adhesive arachnoiditis is important in initiating the extension of the syringomyelia cavity.

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Preclinical Models of Craniospinal Irradiation for Medulloblastoma

Cancers ◽

10.3390/cancers12010133 ◽

2020 ◽

Vol 12 (1) ◽

pp. 133 ◽

Cited By ~ 1

Author(s):

Jennifer L. Stripay ◽

Thomas E. Merchant ◽

Martine F. Roussel ◽

Christopher L. Tinkle

Keyword(s):

Small Animal ◽

Craniospinal Irradiation ◽

Tumor Control ◽

Preclinical Models ◽

Treatment Interventions ◽

Leptomeningeal Seeding ◽

Group 4 ◽

Pediatric Medulloblastoma ◽

Group 3

Medulloblastoma is an embryonal tumor that shows a predilection for distant metastatic spread and leptomeningeal seeding. For most patients, optimal management of medulloblastoma includes maximum safe resection followed by adjuvant craniospinal irradiation (CSI) and chemotherapy. Although CSI is crucial in treating medulloblastoma, the realization that medulloblastoma is a heterogeneous disease comprising four distinct molecular subgroups (wingless [WNT], sonic hedgehog [SHH], Group 3 [G3], and Group 4 [G4]) with distinct clinical characteristics and prognoses has refocused efforts to better define the optimal role of CSI within and across disease subgroups. The ability to deliver clinically relevant CSI to preclinical models of medulloblastoma offers the potential to study radiation dose and volume effects on tumor control and toxicity in these subgroups and to identify subgroup-specific combination adjuvant therapies. Recent efforts have employed commercial image-guided small animal irradiation systems as well as custom approaches to deliver accurate and reproducible fractionated CSI in various preclinical models of medulloblastoma. Here, we provide an overview of the current clinical indications for, and technical aspects of, irradiation of pediatric medulloblastoma. We then review the current literature on preclinical modeling of and treatment interventions for medulloblastoma and conclude with a summary of challenges in the field of preclinical modeling of CSI for the treatment of leptomeningeal seeding tumors.

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13q14 Chromosome Deletion Size and Number of Deleted Cells Influence Prognosis In Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v116.21.3578.3578 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3578-3578

Author(s):

Francesca Maria Rossi ◽

Davide Rossi ◽

Clara Deambrogi ◽

Francesco Bertoni ◽

Michele Dal Bo ◽

...

Keyword(s):

Clinical Course ◽

Lymphocytic Leukemia ◽

Single Institution ◽

Group 4 ◽

Median Size ◽

Mutational Status ◽

Genome Wide ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Abstract 3578 Introduction: Chronic lymphocytic leukemia (CLL) patients bearing 13q14 deletion are known to experience a more favorable clinical course. Recent studies, focusing on patients with loss of 13q as the sole cytogenetic aberration at diagnosis (del13q-only cases), showed that the number of malignant cells carrying this genetic lesion correlates with a more aggressive clinical behavior. However, whether the size of the 13q deletion may also influence the clinical outcome remains to be elucidated. Patients and Methods: Probes for chromosome 13q (LSI-RB1, LSI-D13S319), 11q (LSI-ATM), 17p (LSI-p53) and chromosome 12 (CEP12) were utilized on nuclei collected at diagnosis from: i) a multi-institutional CLL cohort (342 del13q-only cases) and ii) a consecutive unselected single-institution cohort of 265 cases. RB1 deleted cases (delRB1) were defined as having at least 5% of deleted nuclei. Time to treatment (TTT) intervals, as well as Rai staging, IGHV mutational status, CD38 and ZAP70 expression, B2-microglobulin levels, all evaluated at diagnosis, were also available for all cases that entered the study. Genome wide DNA profile was performed in a pilot series of 90 CLL samples using Affymetrix GeneChip Human SNP6 arrays. Results: According to genome wide DNA analysis, delRB1 occurred in a proportion of del13q-only cases (36/90; 40%), always comprising the deleted region detected with the LSI-D13S319 probe (that covers the miR-15a/16-1 cluster and the DLEU2 gene) and characterized by a larger chromosome loss (median size 2.07 Mb vs. a median size of 0.86 Mb for the canonical del13S319). Maximally selected log-rank statistics identified the 70% of nuclei bearing del13S319 as the most appropriate cut-off value capable of separating del13q-only cases into two subgroups with different TTT distributions. Consistently, del13q-only cases with at least 70% of nuclei bearing del13S319 showed a significantly shorter TTT than del13q-only cases with less than 70% deleted nuclei (p=0.0001). Del13q-only cases were then divided in four subsets according to the percentage of nuclei bearing del13S319 with or without a concomitant delRB1: del13S319 <70% (group 1), 144 cases; del13S319 <70% + delRB1 (group 2), 95 cases; del13S319 >70% (group 3), 64 cases; del13S319 >70% + delRB1 (group 4), 39 cases. The median TTT of group 1 (not reached) was significantly longer than the median TTT of group 2 (92 months, p=0.012), group 3 (68 months, p<0.0001), and group 4 (82 months, p=0.0025; see Fig. 1A). Multivariate Cox proportional hazard analyses selected the presence of delRB1 (p=0.029), along with the IGHV mutational status (p<0.0001), as an independent negative prognosticator in the context of del13q-only cases with low/intermediate Rai risk (Rai stage of 0/I at diagnosis) and <70% of del13S319. Cases belonging to the consecutive unselected single-institution CLL cohort were divided into subsets according to the classification proposed by Döhner et al (NEJM, 2000). Notably, the presence of del13S319 in <70% of cells in the absence of delRB1 identified a patient subset with particularly stable and benign clinical course (group A in Fig. 1B, 48 cases; median TTT not reached). Conversely, patients characterized by del13S319 in <70% of cells but with a larger deletion, as determined by concomitant delRB1 (group B, 24 cases), or del13S319 in >70% of cells (with or without delRB1, group C, 25 cases) or a normal karyotype (group D, 75 cases) had shorter median TTT intervals (ranging from 105 to 129 months, p<0.01 in all the comparisons). Finally, patients affected by CLL bearing trisomy 12 (group E, 48 cases) and del11q or del17p (group F, 45 cases) experienced the worst clinical courses (p<0.0001). Conclusion: In the context of del13q-only cases, different clinical outcomes were associated to the percentage of 13q14 deleted cells, as well as to the size of the 13q14 deletion, as detected by the LSI-RB1 probe. Moreover, the presence of delRB1 emerged as a feature capable of refining the prognostic assessment in the context of CLL cases with <70% del13S319. The underlying genetic mechanisms correlated with the different clinical outcomes and associated with the size of the 13q deletion are presently under investigation. Disclosures: No relevant conflicts of interest to declare.

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m6A Modification: A Double-Edged Sword in Tumor Development

Frontiers in Oncology ◽

10.3389/fonc.2021.679367 ◽

2021 ◽

Vol 11 ◽

Author(s):

Runnan Gao ◽

Mujie Ye ◽

Baihui Liu ◽

Meng Wei ◽

Duan Ma ◽

...

Keyword(s):

Dynamic Properties ◽

Tumor Development ◽

Tumor Formation ◽

Cancer Development ◽

Research Progress ◽

Biological Processes ◽

Rna Methylation ◽

Anti Cancer ◽

Elevated Expression

Modification of m6A, as the most abundant mRNA modification, plays diverse roles in various biological processes in eukaryotes. Emerging evidence has revealed that m6A modification is closely associated with the activation and inhibition of tumor pathways, and it is significantly linked to the prognosis of cancer patients. Aberrant reduction or elevated expression of m6A regulators and of m6A itself have been identified in numerous tumors. In this review, we give a description of the dynamic properties of m6A modification regulators, such as methyltransferases, demethylases, and m6A binding proteins, and indicate the value of the balance between these proteins in regulating the expression of diverse genes and the underlying effects on cancer development. Furthermore, we summarize the “dual-edged weapon” role of RNA methylation in tumor progression and discuss that RNA methylation can not only result in tumorigenesis but also lead to suppression of tumor formation. In addition, we summarize the latest research progress on small-molecule targeting of m6A regulators to inhibit or activate m6A. These studies indicate that restoring the balance of m6A modification via targeting specific imbalanced regulators may be a novel anti-cancer strategy.

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Evaluation of protective effect of myricetin, a bioflavonoid in dimethyl benzanthracene-induced breast cancer in female Wistar rats

South Asian Journal of Cancer ◽

10.4103/2278-330x.130443 ◽

2014 ◽

Vol 03 (02) ◽

pp. 107-111 ◽

Cited By ~ 19

Author(s):

J. K. Jayakumar ◽

P. Nirmala ◽

B.A. Praveen Kumar ◽

Ashok P. Kumar

Keyword(s):

Breast Cancer ◽

Wistar Rats ◽

Statistical Significance ◽

Treated Animal ◽

Group 4 ◽

Female Wistar Rats ◽

Group 3 ◽

Group 2 ◽

And Control

Abstract Background: Breast cancer is one of the most common cancers worldwide. Alarmingly, the incidence of breast cancer is rising rapidly in India. Aim: The present research was focused to assess the role of myricetin; a bioflavonoid in 7,12-dimethylbenzanthracene (DMBA)-induced breast cancer in female Wistar rats. Materials and Methods: A total of 36 female Wistar rats (total 6 groups, n = 6 per group) 6 - 8 weeks old, weighing 150 gm were used in the study. DMBA was given at the dose of 7.5 mg/kg subcutaneously in the mammary region once a week for 4 consecutive weeks in group 2. Vincristine was given in the dose of 500 μg/kg intraperitonially every week for 4 consecutive weeks in group 3. Myricetin was given orally in a dose of 50, 100, and 200 mg/kg in group 4, 5, and 6 respectively. The statistical significance of the data was determined using one way analysis of variance and Duncan’s multiple range test. Results: The result showed that myricetin increased the antioxidant levels in plasma, erythrocyte lysate, and breast tissue and was effective in preventing the oxidative damage induced by the carcinogen DMBA. Myricetin 50, 100, and 200 mg/kg/oral for 120 days treated animal resulted comparable results to that of standard vincristine and control groups. Conclusions: Myricetin was found to be either equieffective or more effective than vincristine in all the parameters studied. Myricetin proved the capacity of flavonols to act as antioxidant in cells represents a potential treatment in the field of oncology.

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The state of thrombotic readiness in rats at suprathreshold physical load and its correction by products of velvet antler industry

Тромбоз, гемостаз и реология ◽

10.25555/thr.2018.4.0863 ◽

2018 ◽

Author(s):

А.А. Блажко ◽

И.И. Шахматов ◽

И.В. Ковалев ◽

Ю.А. Бондарчук ◽

О.М. Улитина ◽

...

Keyword(s):

Reproductive Organs ◽

Physical Load ◽

Internal Organs ◽

Group 4 ◽

Partial Activation ◽

Velvet Antler ◽

Male Wistar Rats ◽

Body Resistance ◽

Group 3

Введение. При действии чрезмерных стрессоров различной природы система гемостаза может отвечать формированием состояния тромботической готовности, а чтобы избежать его развития необходимо повышать устойчивость организма и, в частности, системы гемостаза к стрессорным воздействиям. Одним из способов является применение продуктов пантового оленеводства. Цель исследования: оценить состояние системы гемостаза у крыс при однократной сверхпороговой физической нагрузке разной продолжительности, а также определить адаптационную роль предварительного курсового приема концентрата, содержащего кровь и гистолизат из репродуктивных органов марала. Материалы и методы. Исследования выполнены на 50 крысах-самцах линии Wistar: 4 экспериментальные группы и группа интактных животных по 10 крыс. Животных групп 1 и 2 подвергали 4-часовой и 8-часовой физической нагрузке, соответственно. Животные группы 3 принимали продукты пантового оленеводства (концентрат) в течение 30 дней и на 31-й день подвергались 8-часовой физической нагрузке. Животные группы 4 принимали концентрат в течение 30 дней и не подвергались воздействию физической нагрузки. Интактные крысы принимали воду в том же объеме, что и экспериментальные животные, и не подвергались воздействию физической нагрузки. Состояние системы гемостаза оценивали методом тромбоэластографии. Проведено гистологическое исследование легких крыс во всех группах. Результаты. 4-часовая физическая нагрузка вызывала частичную активацию системы гемостаза у крыс, усиливая наступление фазы инициации свертывания крови. 8-часовая физическая нагрузка вызывала у крыс развитие состояния тромботической готовности. Заключение. Предварительный курсовой прием продуктов пантового оленеводства снижал риск развития состояния тромботической готовности и повреждения внутренних органов у крыс после сверхпороговой физической нагрузки за счет повышения фибринолитической активности плазмы крови. Introduction. Under the action of excessive stressors of diff erent nature, hemostasis can respond by forming a state of thrombotic readiness. In order to avoid its development, it is necessary to increase body resistance and hemostasis in particular to stress eff ects. One of the methods is the usage of the products of velvet antler industry. Aim: to assess hemostasis in rats at a single suprathreshold physical load of different duration and to determine the adaptive role of preliminary intake of a concentrate containing blood and histolysate from maral reproductive organs. Materials and methods. Studies were performed on 50 male Wistar rats: 4 experimental groups and a group of intact animals, 10 rats each. Animals of groups 1 and 2 were exposed to 4-hour and 8-hour physical load, respectively. Animals of group 3 received products of velvet antler industry (concentrate) for 30 days and on 31st day were exposed to 8-hour suprathreshold physical load. Animals of group 4 received a concentrate for 30 days and were not exposed to physical stress. Intact rats took water in the same volume as experimental animals and were not exposed to physical activity. Hemostasis was assessed by thromboelastography. Histological examination of lungs was carried out in rats from all groups. Results. The 4-hour physical load caused partial activation of hemostasis, enhancing the phase onset of blood coagulation. The 8-hour physical load caused the development of thrombotic readiness. Conclusion. Preliminary intake of velvet antler products reduced the risk of thrombotic readiness development and damage of internal organs in rats after suprathreshold physical load due to increasing of blood fibrinolytic activity.

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Bacteriophages of Clostridium botulinum

Canadian Journal of Microbiology ◽

10.1139/m72-011 ◽

1972 ◽

Vol 18 (1) ◽

pp. 67-76 ◽

Cited By ~ 28

Author(s):

C. E. Dolman ◽

Eva Chang

Keyword(s):

Clostridium Botulinum ◽

Phage Type ◽

Phage Group ◽

Flexible Tail ◽

Group 4 ◽

Group 3 ◽

Type C ◽

Group 2 ◽

Group 1

Temperate bacteriophages of diverse morphology were demonstrated by electron microscopy in toxigenic cultures of Clostridium botulinum. The 41 strains examined included 23 type E and multiple representatives of all other types. Cultures induced with mitomycin-C generally gave better yields, but phages were also demonstrable in untreated cultures.A provisional grouping of toxigenic types into four categories is suggested, based mainly upon associated phage patterns. Group 1 comprises types A, B, and F (all proteolytic), many of whose cultures showed an icosahedral contractile phage; others contained a "bullrushy" phage with elongated head and long flexible tail; some strains yielded both. Group 2, types B and F (non-proteolytic), were associated with icosahedral contractile phages; the latter also had an octahedral flexible phage. Group 3, types C and D, yielded conspicuously large phages with octahedral heads and very long sheathed tails. One type C strain produced a long-tailed icosahedral phage. Type E phages constituted group 4. These were icosahedral with tails generally contracted but sometimes flexible, often accompanied by superfluous sheathed tail-like structures resembling certain bacteriocins. Although non-toxigenic "OS" mutants of types A, B, E, and F were phageless, two non-toxic type E strains yielded phages. The possible role of lysogeny in the toxigenicity of certain types of this species is likely to prove difficult to elucidate.

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Seminal Plasma Induces Ovulation in Llamas in the Absence of a Copulatory Stimulus: Role of Nerve Growth Factor as an Ovulation-Inducing Factor

Endocrinology ◽

10.1210/en.2016-1310 ◽

2016 ◽

Vol 157 (8) ◽

pp. 3224-3232 ◽

Cited By ~ 22

Author(s):

Marco A. Berland ◽

Cesar Ulloa-Leal ◽

Miguel Barría ◽

Hollis Wright ◽

Gregory A. Dissen ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Seminal Plasma ◽

Neural Signals ◽

Intact Male ◽

Nerve Growth ◽

Group 4 ◽

Group 3 ◽

Group 2

Llamas are considered to be reflex ovulators. However, semen from these animals is reported to be rich in ovulation-inducing factor(s), one of which has been identified as nerve growth factor (NGF). These findings suggest that ovulation in llamas may be elicited by chemical signals contained in semen instead of being mediated by neural signals. The present study examines this notion. Llamas displaying a preovulatory follicle were assigned to four groups: group 1 received an intrauterine infusion (IUI) of PBS; group 2 received an IUI of seminal plasma; group 3 was mated to a male whose urethra had been surgically diverted (urethrostomized male); and group 4 was mated to an intact male. Ovulation (detected by ultrasonography) occurred only in llamas mated to an intact male or given an IUI of seminal plasma and was preceded by a surge in plasma LH levels initiated within an hour after coitus or IUI. In both ovulatory groups, circulating β-NGF levels increased within 15 minutes after treatment, reaching values that were greater and more sustained in llamas mated with an intact male. These results demonstrate that llamas can be induced to ovulate by seminal plasma in the absence of copulation and that copulation alone cannot elicit ovulation in the absence of seminal plasma. In addition, our results implicate β-NGF as an important mediator of seminal plasma-induced ovulation in llamas because ovulation does not occur if β-NGF levels do not increase in the bloodstream, a change that occurs promptly after copulation with an intact male or IUI of seminal plasma.

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