Bioreactors for Decreasing the Growth of Brain Tumors

Malignant gliomas are the most common primary brain tumors. They are highly aggressive tumors characterized by a recurrence rate of virtually 100%. Despite significant advances in neuroimaging and neurosurgical techniques, the median survival time of patients with glioblastoma multiforme remains 12 to 18 months. Malignant gliomas are characterized by rapidly dividing cells, which invade into the normal brain, and a high degree of vascularity. Recent experimental evidence indicates that tumor-related angiogenesis contributes significantly to the malignant phenotype

Reproductive Hormone-Dependent and -Independent Contributions to Developmental Changes in Kisspeptin in GnRH-Deficient Hypogonadal Mice

Kisspeptin 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

Supportive interactions with primary care doctors are associated with better mental health among transgender people: results of a nationwide survey in Aotearoa/New Zealand.

BACKGROUND: Past research has established that transgender people experience significant disparities in mental health outcomes and healthcare dissatisfaction compared with cisgender people, but more research is needed on how supportive healthcare interactions relate to the mental health of transgender people. OBJECTIVES: The 2 main aims of our analyses were: (i) to establish the most common negative experiences in healthcare and the most common supportive experiences specifically with primary care doctors for transgender people; and (ii) to examine the association of supportive experiences with mental health variables after controlling for demographic factors. METHODS: Data from the 2018 Counting Ourselves nationwide survey of transgender people were analysed using regression modelling. The 948 participants with a primary care doctor or general practitioner were included in analyses. Participants were aged 14-83 years old (mean 30.20). RESULTS: The most common supportive experiences involved primary care doctors treating transgender people equitably, with competence, and with respect. Participants with more negative healthcare experiences had higher psychological distress as well as higher likelihood of reporting nonsuicidal self-injury and suicidality. Conversely, participants with more experiences of supportive primary care doctors had lower psychological distress and were less likely to have attempted suicide in the past 12 months. CONCLUSION: When transgender people receive supportive care from their primary care providers they experience better mental health, despite ongoing negative healthcare experiences. Future research is needed to confirm ways of supporting positive trajectories of mental health for transgender people but these findings demonstrate the importance of positive aspects of care

Cerebrospinal Fluid Biomarkers in Idiopathic Normal Pressure Hydrocephalus

The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is still challenging. Alzheimer's disease (AD), along with vascular dementia, the most important differential diagnosis for iNPH, has several potential cerebrospinal fluid (CSF) biomarkers which might help in the selection of patients for shunt treatment. The aim of this study was to compare a battery of CSF biomarkers including well-known AD-related proteins with CSF from patients with suspected iNPH collected from the external lumbar drainage test (ELD). A total of 35 patients with suspected iNPH patients were evaluated with ELD. CSF was collected in the beginning of the test, and the concentrations of total tau, ptau181, Aβ42, NFL, TNF-α, TGFβ1, and VEGF were analysed by ELISA. Twenty-six patients had a positive ELD result—that is, their gait symptoms improved; 9 patients had negative ELD. The levels of all analyzed CSF biomarkers were similar between the groups and none of them predicted the ELD result in these patients. Contrary to expectations lumbar CSF TNF-α concentration was low in iNPH patients

Increased plasmin-mediated proteolysis of L1CAM in a mouse model of idiopathic normal pressure hydrocephalus

Idiopathic normal pressure hydrocephalus (iNPH) is a common neurological disorder that is characterized by enlarged cerebral ventricles, gait difficulty, incontinence, and dementia. iNPH usually develops after the sixth decade of life in previously asymptomatic individuals. We recently reported that loss-of-function deletions in CWH43 lead to the development of iNPH in a subgroup of patients, but how this occurs is poorly understood. Here, we show that deletions in CWH43 decrease expression of the cell adhesion molecule, L1CAM, in the brains of CWH43 mutant mice and in human HeLa cells harboring a CWH43 deletion. Loss-of-function mutations in L1CAM are a common cause of severe neurodevelopmental defects that include congenital X-linked hydrocephalus. Mechanistically, we find that CWH43 deletion leads to decreased N-glycosylation of L1CAM, decreased association of L1CAM with cell membrane lipid microdomains, increased L1CAM cleavage by plasmin, and increased shedding of cleaved L1CAM in the cerebrospinal fluid. CWH43 deletion also decreased L1CAM nuclear translocation, suggesting decreased L1CAM intracellular signaling. Importantly, the increase in L1CAM cleavage occurred primarily in the ventricular and subventricular zones where brain CWH43 is most highly expressed. Thus, CWH43 deletions may contribute to adult-onset iNPH by selectively downregulating L1CAM in the ventricular and subventricular zone

Deletions in CWH43 cause idiopathic normal pressure hydrocephalus

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder that occurs in about 1% of individuals over age 60 and is characterized by enlarged cerebral ventricles, gait difficulty, incontinence, and cognitive decline. The cause and pathophysiology of iNPH are largely unknown. We performed whole exome sequencing of DNA obtained from 53 unrelated iNPH patients. Two recurrent heterozygous loss of function deletions in CWH43 were observed in 15% of iNPH patients and were significantly enriched 6.6-fold and 2.7-fold, respectively, when compared to the general population. Cwh43 modifies the lipid anchor of glycosylphosphatidylinositol-anchored proteins. Mice heterozygous for CWH43 deletion appeared grossly normal but displayed hydrocephalus, gait and balance abnormalities, decreased numbers of ependymal cilia, and decreased localization of glycosylphosphatidylinositol-anchored proteins to the apical surfaces of choroid plexus and ependymal cells. Our findings provide novel mechanistic insights into the origins of iNPH and demonstrate that it represents a distinct disease entity

SNAI2/Slug promotes growth and invasion in human gliomas

<p>Abstract</p> <p>Background</p> <p>Numerous factors that contribute to malignant glioma invasion have been identified, but the upstream genes coordinating this process are poorly known.</p> <p>Methods</p> <p>To identify genes controlling glioma invasion, we used genome-wide mRNA expression profiles of primary human glioblastomas to develop an expression-based rank ordering of 30 transcription factors that have previously been implicated in the regulation of invasion and metastasis in cancer.</p> <p>Results</p> <p>Using this approach, we identified the oncogenic transcriptional repressor, <it>SNAI2</it>/Slug, among the upper tenth percentile of invasion-related transcription factors overexpressed in glioblastomas. <it>SNAI2 </it>mRNA expression correlated with histologic grade and invasive phenotype in primary human glioma specimens, and was induced by EGF receptor activation in human glioblastoma cells. Overexpression of <it>SNAI2/</it>Slug increased glioblastoma cell proliferation and invasion <it>in vitro </it>and promoted angiogenesis and glioblastoma growth <it>in vivo</it>. Importantly, knockdown of endogenous <it>SNAI2</it>/Slug in glioblastoma cells decreased invasion and increased survival in a mouse intracranial human glioblastoma transplantation model.</p> <p>Conclusion</p> <p>This genome-scale approach has thus identified <it>SNAI2</it>/Slug as a regulator of growth and invasion in human gliomas.</p

Reproductive Hormone-Dependent and -Independent Contributions to Developmental Changes in Kisspeptin in GnRH-Deficient Hypogonadal Mice

Kisspeptin 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