Person: Kaiser, Ursula
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Kaiser
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Ursula
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Kaiser, Ursula
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Publication Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors(Impact Journals LLC, 2016) Mei, Yu; Bi, Wenya; Greenwald, Noah; Du, Ziming; Agar, Nathalie Y. R.; Kaiser, Ursula; Woodmansee, Whitney; Reardon, David; Freeman, Gordon; Fecci, Peter E.; Laws, Edward; Santagata, Sandro; Dunn, Gavin P.; Dunn, IanPurpose Subsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas. Methods: PD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry. Results: Pituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes. Conclusions: Human pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management.Publication PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse(eLife Sciences Publications, Ltd, 2018) Ross, Rachel; Leon, Silvia; Madara, Joseph; Schafer, Danielle; Fergani, Chrysanthi; Maguire, Caroline A; Verstegen, Anne; Brengle, Emily; Kong, Dong; Herbison, Allan E; Kaiser, Ursula; Lowell, Bradford; Navarro, VictorPituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) is a neuromodulator implicated in anxiety, metabolism and reproductive behavior. PACAP global knockout mice have decreased fertility and PACAP modulates LH release. However, its source and role at the hypothalamic level remain unknown. We demonstrate that PACAP-expressing neurons of the ventral premamillary nucleus of the hypothalamus (PMVPACAP) project to, and make direct contact with, kisspeptin neurons in the arcuate and AVPV/PeN nuclei and a subset of these neurons respond to PACAP exposure. Targeted deletion of PACAP from the PMV through stereotaxic virally mediated cre- injection or genetic cross to LepR-i-cre mice with Adcyap1fl/fl mice led to delayed puberty onset and impaired reproductive function in female, but not male, mice. We propose a new role for PACAP-expressing neurons in the PMV in the relay of nutritional state information to regulate GnRH release by modulating the activity of kisspeptin neurons, thereby regulating reproduction in female mice.Publication Candidate gene analysis in a case of congenital absence of the endometrium(BioMed Central, 2016) Simavli, Serap; Abreu, Ana Paula; Kwaan, Mary R.; Dluhy, Robert; Yanushpolsky, Elena; Feltmate, Colleen; Cerda, Sandra R.; Carroll, Rona; Kaiser, Ursula; Kuohung, WendyBackground: Primary amenorrhea usually result from a genetic or anatomic abnormality. We present the first reported patient with the absence of endometrium and lumen in a small bicornuate uterus in a patient with primary amenorrhea. Case presentation: A 41-year-old woman presented for evaluation of primary amenorrhea and infertility. She did develop normal secondary sexual characteristics but never had menses. Physical examination, hormone analyses, and karyotype analysis were normal. Transvaginal ultrasonography revealed a small uterus with absent endometrial stripe. Ovaries were normal in size. Pathology from hysterectomy for abnormal Pap smears revealed a hypoplastic bicornuate uterus with absence of lumen and absent endometrium. DNA analyses for mutations in the coding sequences of three members of HOXA gene family was performed, but no variants in the coding sequence of these genes were found. These findings support the hypothesis that mutations in the coding sequence of HOXA10, HOXA11, and HOXA13 are not responsible for congenital endometrial absence with bicornuate hypoplastic uterus. Conclusions: Congenital absence of the endometrium is an uncommon etiology for primary amenorrhea, and nonvisualization of the endometrial stripe on ultrasound imaging in association with primary amenorrhea should raise suspicion of this rare disorder in this case.Publication Reproductive Hormone-Dependent and -Independent Contributions to Developmental Changes in Kisspeptin in GnRH-Deficient Hypogonadal Mice(Public Library of Science, 2010) Gill, John; Wang, Oulu; Kakar, Shelley; Martinelli, Enzo; Carroll, Rona; Kaiser, UrsulaKisspeptin is a potent activator of GnRH-induced gonadotropin secretion and is a proposed central regulator of pubertal onset. In mice, there is a neuroanatomical separation of two discrete kisspeptin neuronal populations, which are sexually dimorphic and are believed to make distinct contributions to reproductive physiology. Within these kisspeptin neuron populations, Kiss1 expression is directly regulated by sex hormones, thereby confounding the roles of sex differences and early activational events that drive the establishment of kisspeptin neurons. In order to better understand sex steroid hormone-dependent and -independent effects on the maturation of kisspeptin neurons, hypogonadal (hpg) mice deficient in GnRH and its downstream effectors were used to determine changes in the developmental kisspeptin expression. In hpg mice, sex differences in Kiss1 mRNA levels and kisspeptin immunoreactivity, typically present at 30 days of age, were absent in the anteroventral periventricular nucleus (AVPV). Although immunoreactive kisspeptin increased from 10 to 30 days of age to levels intermediate between wild type (WT) females and males, corresponding increases in Kiss1 mRNA were not detected. In contrast, the hpg arcuate nucleus (ARC) demonstrated a 10-fold increase in Kiss1 mRNA between 10 and 30 days in both females and males, suggesting that the ARC is a significant center for sex steroid-independent pubertal kisspeptin expression. Interestingly, the normal positive feedback response of AVPV kisspeptin neurons to estrogen observed in WT mice was lost in hpg females, suggesting that exposure to reproductive hormones during development may contribute to the establishment of the ovulatory gonadotropin surge mechanism. Overall, these studies suggest that the onset of pubertal kisspeptin expression is not dependent on reproductive hormones, but that gonadal sex steroids critically shape the hypothalamic kisspeptin neuronal subpopulations to make distinct contributions to the activation and control of the reproductive hormone cascade at the time of puberty.Publication Pulsatile gonadotropin-releasing hormone therapy is associated with earlier spermatogenesis compared to combined gonadotropin therapy in patients with congenital hypogonadotropic hypogonadism(Medknow Publications & Media Pvt Ltd, 2017) Mao, Jiang-Feng; Liu, Zhao-Xiang; Min, Le; Nie, Min; Wang, Xi; Xu, Hong-Li; Huang, Bing-Kun; Zheng, Jun-Jie; Kaiser, Ursula; Wu, Xue-YanBoth pulsatile gonadotropin-releasing hormone (GnRH) infusion and combined gonadotropin therapy (human chorionic gonadotropin and human menopausal gonadotropin [HCG/HMG]) are effective to induce spermatogenesis in male patients with congenital hypogonadotropic hypogonadism (CHH). However, evidence is lacking as to which treatment strategy is better. This retrospective cohort study included 202 patients with CHH: twenty had received pulsatile GnRH and 182 had received HCG/HMG. Patients had received therapy for at least 12 months. The total follow-up time was 15.6 ± 5.0 months (range: 12–27 months) for the GnRH group and 28.7 ± 13.0 months (range: 12–66 months) for the HCG/HMG group. The median time to first sperm appearance was 6 months (95% confidence interval [CI]: 1.6–10.4) in the GnRH group versus 18 months (95% CI: 16.4–20.0) in the HCG/HMG group (P < 0.001). The median time to achieve sperm concentrations ≥5 × 106 ml−1 was 14 months (95% CI: 5.8–22.2) in the GnRH group versus 27 months (95% CI: 18.9–35.1) in the HCG/HMG group (P < 0.001), and the median time to concentrations ≥10 × 106 ml−1 was 18 months (95% CI: 10.0–26.0) in the GnRH group versus 39 months (95% CI unknown) in the HCG/HMG group. Compared to the GnRH group, the HCG/HMG group required longer treatment periods to achieve testicular sizes of ≥4 ml, ≥8 ml, ≥12 ml, and ≥16 ml. Sperm motility (a + b + c percentage) evaluated in semen samples with concentrations >1 × 106 ml−1 was 43.7% ± 20.4% (16 samples) in the GnRH group versus 43.2% ± 18.1% (153 samples) in the HCG/HMG group (P = 0.921). Notably, during follow-up, the GnRH group had lower serum testosterone levels than the HCG/HMG group (8.3 ± 4.6 vs 16.2 ± 8.2 nmol l−1, P < 0.001). Our study found that pulsatile GnRH therapy was associated with earlier spermatogenesis and larger testicular size compared to combined gonadotropin therapy. Additional prospective randomized studies would be required to confirm these findings.Publication Altered Circadian Feeding Behavior and Improvement of Metabolic Syndrome in Obese Tac1-Deficient Mice(Springer Science and Business Media LLC, 2017-12) Maguire, Caroline; Leon, Silvia; Carroll, Rona; Kaiser, Ursula; Navarro, VictorBACKGROUND Metabolic function is regulated by the interplay of central and peripheral factors that ultimately regulate food intake and energy expenditure. The tachykinin substance P (SP) has been identified as a novel regulator of energy balance, however, the mechanisms underlying this effect are ill-defined and conflicting data regarding the role of SP on food intake have been reported by different groups. OBJECTIVE To further characterize the metabolic role of the Tac1 gene products (SP and neurokinin A (NKA)) in mice through a series of genetic, metabolic and behavioral studies in Tac1 deficient mice. RESULTS Tac1−/− mice are leaner than controls and display reduced food intake and altered feeding circadian rhythm, supported by disrupted expression of the clock genes Cry1/2, Per1/2 in the suprachiasmatic nucleus (SCN), medio-basal hypothalamus (MBH) and liver, as well as increased Pomc expression in the MBH. Tac1 ablation induced resistance to obesity, improved glucose tolerance, prevented insulin resistance under high-fat-diet, increased activation of brown adipose tissue and improved hepatic steatosis. Moreover, deletion of Tac1 in ob/ob mice ameliorated BW gain in females only but was sufficient to decrease fat and triglyceride content in the liver of males. CONCLUSIONS These results provide further evidence that Tac1 controls circadian feeding behavior and metabolism in mice through mechanisms that involve the regulation of the melanocortin system. In addition, these studies suggest that the blockade of SP may offer a new method to treat metabolic syndrome.