Kisspeptin is the most potent stimulator of LH release. There are two kisspeptin neuronal populations in the rodent brain: in the anteroventral periventricular nucleus (AVPV) and in the arcuate ...nucleus. The arcuate neurons coexpress kisspeptin, neurokinin B, and dynorphin and are called KNDy neurons. Because estradiol increases kisspeptin expression in the AVPV whereas it inhibits KNDy neurons, AVPV and KNDy neurons have been postulated to mediate the positive and negative feedback effects of estradiol on LH secretion, respectively. Yet the role of KNDy neurons during the positive feedback is not clear. In this study, ovariectomized rats were microinjected bilaterally into the arcuate nucleus with a saporin-conjugated neurokinin B receptor agonist for targeted ablation of approximately 70% of KNDy neurons. In oil-treated animals, ablation of KNDy neurons impaired the rise in LH after ovariectomy and kisspeptin content in both populations. In estradiol-treated animals, KNDy ablation did not influence the negative feedback of steroids during the morning. Surprisingly, KNDy ablation increased the steroid-induced LH surges, accompanied by an increase of kisspeptin content in the AVPV. This increase seems to be due to lack of dynorphin input from KNDy neurons to the AVPV as the following: 1) microinjections of a dynorphin antagonist into the AVPV significantly increased the LH surge in estradiol-treated rats, similar to KNDy ablation, and 2) intra-AVPV microinjections of dynorphin in KNDy-ablated rats restored LH surge levels. Our results suggest that KNDy neurons provide inhibition to AVPV kisspeptin neurons through dynorphin and thus regulate the amplitude of the steroid-induced LH surges.
A devastating aspect of Alzheimer's disease (AD) is the progressive deterioration of memory due to neuronal loss. Amyloid precursor protein (APP) occupies a central position in AD and APP-derived ...amyloid-beta (Abeta) peptides are thought to play a pivotal role in disease pathogenesis. Nonetheless, it is becoming clear that AD etiology is highly complex and that factors other than Abeta also contribute to AD pathogenesis. APP intracellular domain (AICD) is generated together with Abeta and we recently showed that AICD transgenic mice recapitulate pathological features of AD such as tau hyperphosphorylation, memory deficits and neurodegeneration without increasing the Abeta levels. Since impaired adult neurogenesis is shown to augment memory deficits in AD mouse models, here we examined the status of adult neurogenesis in AICD transgenic mice.
We previously generated transgenic mice co-expressing 59-residue long AICD fragment and its binding partner Fe65. Hippocampal progenitor cell proliferation was determined by BrdU incorporation at 1.5, 3 and 12 months of age. Only male transgenic and their respective wilt type littermate control mice were used. We find age-dependent decrease in BrdU incorporation and doublecortin-positive cells in the dentate gyrus of AICD transgenic mice suggesting impaired adult neurogenesis. This deficit resulted from decreased proliferation and survival, whereas neuronal differentiation remained unaffected. Importantly, this impairment was independent of Abeta since APP-KO mice expressing AICD also exhibit reduced neurogenesis. The defects in adult neurogenesis are prevented by long-term treatment with the non-steroidal anti-inflammatory agents ibuprofen or naproxen suggesting that neuroinflammation is critically involved in impaired adult neurogenesis in AICD transgenic mice.
Since adult neurogenesis is crucial for spatial memory, which is particularly vulnerable in AD, these findings suggest that AICD can exacerbate memory defects in AD by impairing adult neurogenesis. Our findings further establish that AICD, in addition to Abeta, contributes to AD pathology and that neuroinflammation plays a much broader role in AD pathogenesis than previously thought.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prolactin is an anterior pituitary hormone necessary for fertility, pregnancy maintenance, lactation, and aspects of maternal behavior. In rodents, there is a surge of prolactin on the afternoon of ...proestrus, and a semi-circadian pattern of prolactin surges during early pregnancy, with a diurnal and nocturnal surge every day. Both of these patterns can be replicated in ovariectomized rats. A prior study demonstrated that central antagonism of κ-opioid receptors, the target of dynorphin, largely abolished the nocturnal prolactin surge in pregnant rats. We build on this to determine whether dynorphin, perhaps from the arcuate population that co-express kisspeptin, neurokinin B, and dynorphin (KNDy neurons), also contributes to the estradiol- or cervical stimulation-induced surges in ovariectomized rats. Ovariectomized rats were treated with either estradiol or cervical stimulation to induce prolactin surge(s). Blood samples were taken around the expected surge time to determine the effect of either acute κ-opioid receptor antagonism or previous chemical ablation of the KNDy population on prolactin levels. Dynorphin antagonism does significantly disrupt the nocturnal prolactin surge, but it does not contribute to the estradiol-induced surge. Chemical ablation of KNDy neurons had opposite effects; ablation of 40 % of the KNDy neurons had no impact on the nocturnal prolactin surge, while a somewhat larger ablation significantly reduced the size of the estradiol-induced surge. We conclude that dynorphin is likely a controlling factor for the nocturnal surge induced by cervical stimulation, and that other KNDy neuron products must play a role in the estradiol-induced surge.
Amyloid-β (Aβ) peptides derive from the amyloid precursor protein (APP) and play a pivotal role in Alzheimer's disease (AD) pathogenesis. Our previous work showed that the APP intracellular domain ...(AICD), which is produced simultaneously with Aβ, also contributes to the development of AD-like features. Studies show that administration of apolipoprotein E (apoE) and apoE-derived small peptide mimetics protect AD mouse models against these AD-like features. However, the effects of apoE-mimetic treatment on AICD-mediated AD-like pathologies remain to be elucidated.
To study the effects of an apoE mimetic (COG112) on neuroinflammation, hyperphosphorylation of tau and defects in adult neurogenesis in AICD- overexpressing transgenic mice (FeCγ25 line).
Beginning at 1 month of age, animals were administered subcutaneous COG112 3 times per week for 3 months, followed by immunohistochemical analysis for neuroinflammation, neurogenesis and phosphorylated tau.
Treatment with COG112 significantly reduced neuroinflammation in AICD mice and protected against impaired adult hippocampal neurogenesis. We also found that COG112 treatment reduced hyperphosphorylation and somatodendritic accumulation of tau in the hippocampus and cerebral cortex of AICD mice.
Reduction of neuroinflammation by the apoE-mimetic COG112 protects against impaired neurogenesis and tau pathology in AICD transgenic mice. These data suggest that neuroinflammation plays an important role in AICD-induced AD-like pathologies.
Prolactin is a fertility hormone produced and released by the anterior pituitary gland. Normal changes in prolactin levels influence fertility and these changes are carefully regulated by ...neuroendocrine cells in the hypothalamus. Specifically, prolactin surges along with luteinizing hormone to stimulate ovulation and mating behaviors in rodents. Prolactin also follows a twice-daily surge pattern during rodent pregnancy, helping to maintain the pregnancy and prepare the maternal brain for offspring care. Dopamine is the primary regulatory of prolactin and acts through tonic inhibition during non-surge times. High levels of prolactin feedback to stimulate dopamine and thereby reduce prolactin back down to normal, low levels. However, dopamine is not alone in regulating prolactin release. Early mathematical models from the lab helped to identify some shortcomings in the understanding of prolactin regulation. Based on the existing literature, a model was designed to replicate experimental results. When I came to lab and began reviewing this literature and the model’s assumptions, I began to ask some important questions: Do dopamine levels change dramatically with the prolactin surges? Does the timing signal in the model really act as an inhibitory signal? Does the stimulatory signal act alone to drive surges of prolactin release? What else is out that that feeds into this circuit? These perfectly timed surges of prolactin must somehow be controlled by the brain’s central clock. One clock signal, VIP, has been implicated in indirect prolactin regulation. This neurotransmitter could stimulate prolactin either by inhibiting dopamine or by activating a prolactin simulator. In this dissertation, I show that it may in fact be doing both. Oxytocin is one potential, and particularly potent, prolactin stimulator that is itself implicated in reproduction and the associated social behaviors. Released at the posterior pituitary, I hypothesized that plasma oxytocin levels might be predictive of the large prolactin surges observed during times of fertility and pregnancy. However, the data fail to support such a clear direct correlation. Other hypothalamic factors that have also been proposed to be involved in prolactin regulation include the endogenous opioid dynorphin. One major hypothalamic source of dynorphin are the KNDy neurons that co-secrete kisspeptin, neurokinin B, and dynorphin. All these neurotransmitters have been studied for their roles in luteinizing hormone regulation. Research presented here shows that the KNDy neuron dynorphin, while directly involved in luteinizing hormone surge release, is not involved in prolactin surge release. In fact, another KNDy product is likely involved in the single, estrogen-induced fertility surge, while another, still unknown, source of dynorphin is involved during the twice-daily prolactin surge pattern. Overall, this dissertation explores many aspects beyond just dopamine as possible regulatory inputs to the prolactin control circuit. Our simplified rodent models and the mathematical modeling help to show us the limits of our understanding so we can ask the right questions for the next experiments. This multi-angled approach, employing different physiological states in the animals and discussing possible network scenarios with modelers, gives depth to the research program described in this dissertation. Further work will better elucidate important aspects of fertility regulation that have undoubted implications for human and animal health.
International correlation risk Mueller, Philippe; Stathopoulos, Andreas; Vedolin, Andrea
Journal of financial economics,
11/2017, Letnik:
126, Številka:
2
Journal Article
Recenzirano
Odprti dostop
We show that the cross-sectional dispersion of conditional foreign exchange (FX) correlation is countercyclical and that currencies that perform badly (well) during periods of high dispersion yield ...high (low) average excess returns. We also find a negative cross-sectional association between average FX correlations and average option-implied FX correlation risk premiums. Our findings show that while investors in spot currency markets require a positive risk premium for exposure to high dispersion states, FX option prices are consistent with investors being compensated for the risk of low dispersion states. To address our empirical findings, we propose a no-arbitrage model that features unspanned FX correlation risk.
•Primary resection in patients with stage III SCLC needs re-evaluation.•Selected patients with stage III SCLC benefit significantly from surgery.•Patients with T3–4/N0–1 and T1–2/N2 stage III SCLC ...should be considered for surgery.
: Small cell lung cancer (SCLC) is mostly diagnosed in stage III-IV patients and associated with poor prognosis. To date, surgery is no gold-standard treatment for any SCLC stage and evidence is lacking whether it is beneficial. Here we investigate the impact of surgery, with special attention to stage III SCLC patients, sub-stages and treatment combinations.
: The overall survival (OS) and cancer-specific survival (CSS) of 33,198 SCLC patients (SEER database) were analyzed retrospectively, using various statistical analyses, including propensity score matching (PSM), recursive partitioning, and sequential landmark analyses.
: Independent of stage, the OS of patients with surgery-including treatments was almost always better than without surgery. This holds true for stage I-II patients, even after PMS analysis (p < 0.017). The same was found for stage IV patients that underwent surgery plus chemotherapy vs. chemotherapy alone (p = 0.013 after PSM). Stage III patients showed a robust improvement in OS and CSS after surgery (OS: 18 vs.13 months) or surgery plus chemotherapy (OS: 20 vs.15 months) as confirmed by well-balanced PSM and sequential landmark analyses of long-term survivors. More detailed analyses using two independent approaches showed prolonged OS in T3–4/N0–1 and T1–2/N2 stage III patients after surgery or surgery plus chemotherapy. Importantly, primary site surgery had a major survival advantage over surgery at regional sites (p < 0.003).
: Our study demonstrates that selected patients of all stages, including stage III T3–4/N0–1 and T1–2/N2, can benefit greatly from surgery-including treatments. Thus, surgery should be included into hospital treatment recommendations for specifically selected SCLC patients.
Condensed abstract
Primary resection in patients with stage III SCLC needs re-evaluation. Selected patients with stage III SCLC benefit significantly from surgery. Patients with T3–4/N0–1 and T1–2/N2 stage III SCLC should be considered for surgery.
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Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. ...Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition.
Prognostic phenotypes of early-stage lung adenocarcinoma Lamort, Anne-Sophie; Kaiser, Jan Christian; Pepe, Mario A.A. ...
European respiratory journal/The European respiratory journal,
07/2022, Letnik:
60, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Background
Survival after curative resection of early-stage lung adenocarcinoma (LUAD) varies and prognostic biomarkers are urgently needed.
Methods
Large-format tissue samples from a prospective ...cohort of 200 patients with resected LUAD were immunophenotyped for cancer hallmarks TP53, NF1, CD45, PD-1, PCNA, TUNEL and FVIII, and were followed for a median of 2.34 (95% CI 1.71–3.49) years.
Results
Unsupervised hierarchical clustering revealed two patient subgroups with similar clinicopathological features and genotype, but with markedly different survival: “proliferative” patients (60%) with elevated TP53, NF1, CD45 and PCNA expression had 50% 5-year overall survival, while “apoptotic” patients (40%) with high TUNEL had 70% 5-year survival (hazard ratio 2.23, 95% CI 1.33–3.80; p=0.0069). Cox regression and machine learning algorithms including random forests built clinically useful models: a score to predict overall survival and a formula and nomogram to predict tumour phenotype. The distinct LUAD phenotypes were validated in The Cancer Genome Atlas and KMplotter data, and showed prognostic power supplementary to International Association for the Study of Lung Cancer tumour–node–metastasis stage and World Health Organization histologic classification.
Conclusions
Two molecular subtypes of LUAD exist and their identification provides important prognostic information.
Aqueous humor (AH) can be easily and safely used to evaluate disease-specific biomarkers in ocular disease. The aim of this study was to identify specific proteins biomarkers in the AH of ...retinoblastoma (RB) patients at various stages of the disease. We analyzed the proteome of 53 AH samples using high-resolution mass spectrometry. We grouped the samples according to active vitreous seeding (Group 1), active aqueous seeding (Group 2), naive RB (group 3), inactive RB (group 4), and congenital cataracts as the control (Group 5). We found a total of 889 proteins in all samples. Comparative parametric analyses among the different groups revealed three additional proteins expressed in the RB groups that were not expressed in the control group. These were histone H2B type 2-E (HISTH2B2E), InaD-like protein (PATJ), and ubiquitin conjugating enzyme E2 V1 (UBE2V1). Upon processing the data of our study with the OpenTarget Tool software, we found that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and CD44 were more highly expressed in the RB groups. Our results provide a proteome database regarding AH related to RB disease that may be used as a source of biomarkers. Further prospective studies should validate our finding in a large cohort of RB patients.
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