GPCR Compound Library

We performed FNAC for thyroid nodules suspicious of malignancy regardless of size, whereas nodules were evaluated by FNAC in other studies. The prevalence of occult PTC at autopsy could be as high as 35%, and small occult PTCs are considered not to require treatment. Therefore, the high prevalence of thyroid cancer in our study may have been caused by active thyroid screening. Last, our findings are limited by the small sample size and the short follow-up period for examining cancer-related mortality or recurrence. In general, PTC is associated with a good prognosis. Some GDC-0449 reports show that IGF-1R tumor expression is an aggressive clinical feature and persistent despite thyroid cancer treatment. Further study should be conducted to determine the prognosis of patients with acromegaly. In conclusion, the rate of thyroid cancer was extremely high in our study, and it was the most common cancer among our patients with acromegaly. Uncontrolled acromegaly implies that persistently elevated GH and IGF-1 levels may be present in patients with a high risk of developing thyroid cancer. Therefore, regular thyroid US screening and FNAC for all suspicious thyroid nodules should be considered in all patients with newly diagnosed acromegaly and poorly controlled disease. Cyclic di-nucleotides are bacterial second messengers with functions in motility and development. Bis-cyclic dimeric guanosine monophosphate, a member of this molecule family, is produced for example by the bacterium Pseudomonas aeruginosa in which it functions in biofilm formation. It was also described to be synthesized by the eukaryotic organism dictyostelium with implications in the regulation of motility and proliferation. The related compound bis cyclic dimeric adenosine monophosphate is involved in the sporulation control of Bacillus subtilis and has host immune modulatory activity in Listeria monocytogenes infection. Immunization experiments on mice using CDNs as adjuvants suggest that they can have the immune activity of pathogen associated molecular patterns. C-di-GMP, c-diAMP, and the non-natural bis–cyclic dimeric inosine monophosphate were shown by us and others to have immune stimulatory effects and to promote balanced specific humoral and cellular responses upon immunization of mice. The recently discovered mammalian enzyme cyclic GMP-AMP synthase synthesizes the CDN cyclic GMP-AMP upon activation by foreign double stranded DNA. It was proposed that cGAMP could serve as an adjuvant in vaccine formulations, because of its capability to activate innate immune responses. We chose the intra-nasal route, because we are especially interested in developing mucosal vaccines which were shown to evoke robust mucosal on top of systemic immunity. This feature makes mucosal vaccination more favorable in combating pathogens entering via mucosal surfaces of the host. We demonstrate the in vivo adjuvant effects of cGAMP on model antigen-specific humoral and cellular immune responses in mice. We further show that cGAMP can also induce the surface expression of select activation markers on human dendritic cells in vitro. The formulation of modern subunit vaccines usually requires the addition of adjuvants to compensate for the rather low immunogenicity of isolated antigens. Not many adjuvants are approved for the use in human vaccines. Especially for mucosal vaccination, for example via the nasal route, adjuvants need to be suited to cross the mucosal barrier but at the same time have to meet high safety standards. Molecules such as cGAMP that are produced by the mammalian organism itself are expected to be of very low toxicity. Here we demonstrate the efficacy of cGAMP as an i. n. administered mucosal adjuvant in a pre-clinical mouse model.

To avoid such potential complications, local administration of glucocorticoids to the cochlea is now considered to be a preferable route although the effectiveness of single-dose applications of these agents concurrent with cochlear implantation appears limited. Although a number of studies have investigated the regulatory effects of dexamethasone on gene expression in cochlear tissue ex vivo and in vivo none have examined the Tubacin consequence of a prolonged exposure of these tissues to this glucocorticoid. For this reason, in the current study in order to investigate its regulatory effects on gene expression. We found that the dexamethasone-eluting electrode insertion into the cochlea reduced gene expression changes seen with implantation of the normal electrode, perhaps reflecting protective effects of dexamethasone from electrode insertion trauma. The relevance of a selected number of the gene expression changes is discussed in the following sections. In general, dexamethasone-eluting electrode insertion into the cochlea reduced gene expression changes seen with implantation of the normal electrode, perhaps reflecting normalizing effects of dexamethasone on electrode insertion trauma. The transient receptor potential gene superfamily encodes cation channels that act as sensors for a wide variety of stimuli from both inside and outside the cell. They transduce electrical and calcium signals through their cation channel activities. In the cochlea, TRPC6 appears essential for normal mechanotransduction since TRPC6 knock-out mice demonstrated hearing impairment, vestibular deficits and defective auditory brain stem responses to high-frequency sounds. Implantation of the normal electrode induced over 8-fold increases in TRPC6 expression, possibly as a result of the surgical trauma. Dexamethasone elution was observed to partially reverse this increase by 60%. It is likely that this is a pro-survival action by the glucocorticoid since TRPC6 has been associated with podocyte apoptosis, and that dexamethasone reverses this process via blocking TRPC6 channel expression. An 18-fold increase in the expression of lipoprotein lipase, a key enzyme involved in lipid metabolism, was observed following insertion of the normal electrode. LPL is present throughout the central nervous system and peripheral nerves although, to date, its expression has not been reported in the cochlea. Its presence may be due, at least in part, to macrophages which have migrated to the insertion site as a response to trauma, this being observed previously in a rat model of nerve crush injury. LPL expression in the cochlea was partially reduced by dexamethasone elution. Increased expression of LPL in the cochlea following insertion of the normal electrode is most likely due to insertion trauma. And although dexamethasone treatment might reduce LPL expression, suppressed ingress of both monocytes and macrophages are known sources of LPL into the cochlea. Dexamethasone has been reported to reduce monocyte recruitment in the rat and importantly has been demonstrated to reduce macrophage presence following electrode insertion in the cochlea of guinea pig. IL-1 is comprised of two principal 17 kDa polypeptides, IL-1a and IL-1b encoded by genes found on chromosome 2. Over-expression of IL-1b is considered as a major factor leading to the general amplification of inflammatory responses and has been described in over-expression of cisplatin- and salicylate-induced ototoxicity, and acoustic trauma. Insertion of the normal electrode in the guinea pig cochlea increases IL-1b expression more than 4-fold over untreated animals.

Based on current evidence, the majority of cancers have aberrant hypermethylation in the promoters of TSGs, although the whole genome may appear to be hypomethylated. Our study was limited to 24 promoters, and the results could only identify methylation changes in a small number of the potential targets relevant to lung cancer. Ongoing efforts in our laboratory are focused on whole genome methylation screening using additional animal models to look at spontaneously occurring lung tumors as well as inhaled carcinogen-induced lung cancer. These studies are expected to yield much more Sorafenib valuable information on the biology of lung carcinogenesis, which should guide the development of improved therapeutic strategies. Reed et al. have recently reported a similar study using aerosol Aza for the treatment of an orthotopic lung cancer model in nude rats. They concluded that their aerosol and systemic deliveries are equally effective in terms of antitumor efficacy as well as gene demethylation. Although the methodologies, tumor models, and endpoints used in Reed study and our study are significantly different, the fact that both studies lead to some similar conclusions using aerosol Aza represents strong proof of concept of the potential of aerosol demethylation therapy as a novel strategy for the management of lung cancer and bronchial premalignancy. In our study, we found that the effective dose was much lower than the optimal IV dose, indicating that targeted aerosol delivery of the minimal effective dose rather than the maximum tolerated dose of an epigenetic agent is a potentially effective therapeutic strategy. In addition, our aerosol formulation showed a very good aerodynamic size range that makes it suitable for use in humans. We have recently completed preclinical toxicity studies of aerosol Vidaza in mice and FDA approved us to initiate a Phase I clinical study with aerosol Vidaza in patients with advanced lung cancer with disease mostly confined to the lung parenchyma that are not candidates for therapies of a higher priority. In this study, in addition to determining the toxicity profile of aerosol Vidaza, we will investigate by sequential bronchoscopy whether aerosol Vidaza can lead to TSG reexpression in the bronchial epithelium and or/tumor tissue. We expect that the results of this study will determine whether inhaled demethylation therapy should be further developed both as an early intervention or even prevention strategy. If that is the case, significant effort will have to be devoted to explore the use of other candidate agents as Aza is potentially carcinogenic and therefore not an ideal candidate as a preventive agent. It has been hypothesized in the literature that exposure to extremely low frequency electromagnetic fields may lead to human health effects such as childhood leukemia or brain tumors. However, this hypothesis was derived from epidemiological studies which per se do not implicate causal relationships. The latter can only be addressed with experiments carried out under carefully controlled conditions. Among the experiments on rats and mice listed in the ‘BioInitiative Report’
, the following results related to brain cells seem to be of particular importance: Lai and Singh ; found nuclear DNA singlestrand breaks and double-strand breaks from 0.01 mT magnetic field exposure onwards in a dosedependent manner in rats. It is of note that these effects could be blocked by pretreating rats with a vitamin E analog, a nitric oxide synthase inhibitor, or an iron chelator. From these data, the authors concluded that MF exposure might lead to increased generation of free radicals via the so-called Fenton reaction within mitochondria which, thereafter, cause nuclear DNA damage.

S. Typhimurium and E. coli harboring pRST98 formed thicker BF in vitro, compared with the isogenic strains not carrying pRST98. It was also observed that S. Typhimurium x3306 and x3337 had similar abilities to form BFs, which is inconsistent with the study of Teodo´ sio JS et al. We speculated the different plasmids and BF-producing systems may contribute to this inconsistency. We noticed that E. coli K12W1485/pRST98 had a weak ability to form BFs compared with Salmonella strains harboring pRST98. This heterogeneity in BF formation may arise because the synthesis of extracellular polymeric substances in Salmonella outcompetes that in E. coli in medium, as reported by Rong Wang et al. Regarding the heterogeneity in the promotion of BFs by conjugative plasmids, Røder HL et al. proposed that the different genetic backgrounds of the plasmidharboring hosts may account for different BF formation when the same plasmid was used. Our previous study demonstrated that in different genera, the conjugal transfer conditions of the pRST98 plasmid were different in vitro or in mice, and the resistance markers encoded by the same plasmid varied in different strains, which showed the diversity and complexity of the gene expression from the plasmid. Thus, the effects of BF formation by different plasmids in various hosts may demand specific analysis. In animal experiments, a tumor bearing mouse model was used to study the effects of pRST98 on BF formation in S. Typhimurium, which was used as a surrogate of S. Typhi because no animal model is available for S. Typhi infection. In the tumor-bearing mouse model, x3337lux/pRST98 was found preferentially in tumors with a considerably larger amount than x3337lux. The observation that solid tumors are treatable via bacterial infection was made previously. Colonization of bacteria on solid tumors could cause growth retardation or even the complete elimination of the tumors. pRST98 promoting host bacterial BF formation may have a therapeutic potential in fighting against tumors. Furthermore, our invasion study in vitro proved that bacteria in BFs showed a lower invasion ability compared with the corresponding planktonic form, which is consistent with the finding by Katja Crull et al. that BF-forming bacteria did not invade intracellularly in vivo after they established BFs. The intracellular invasion by Salmonella may be due to the differential expression of invasive genes on Salmonella pathogenicity island 1 induced by BF formation. Another animal model, a mouse urethral catheter model, was established to study the effects of pRST98 in E. coli on BF formation in vivo. E. coli K12W1485/pRST98 was found to form only discrete patchy BFs at 3 d post-implantation, while E. coli K12W1485 was not detected in tubes until 5 d post-implantation. E. coli K12W1485/pRST98 developed denser BFs at 5 d post-implantation, in line with bacterial titers recovered from established BFs on tubes. No histological changes were observed in the livers and kidneys of either group. When the implantation with tubes pre-incubated with E. coli was extended to 8 d or beyond, more BKM120 severe inflammation was observed. Significantly, S. Typhimurium x3337lux/pRST98 caused more severe inflammation in organs than x3337lux did. A similar phenomenon was observed for E. coli K12W1485/pRST98 and K12W1485. These results indicate that pRST98 aggravates the infection by promoting BF formation. Recently Rong Wang and Victoria J. Savage et al. demonstrated that the BF increases horizontal transfer of multi-resistant conjugative plasmids to plasmid-free bacteria compared to planktonic bacteria. Therefore, it seems that conjugative plasmids facilitate BF formation, and vice versa.

Therefore, several clinical trials are currently investigating the efficacy and safety of MSCs as a treatment option for various pathologies. We have previously shown in a mouse model of neonatal HI brain damage that intranasal administration of murine MSCs significantly improves motor and cognitive behavior and reduces cerebral lesion volume. In contrast to current pharmacological therapies for neonatal HI, we found that MSC treatment has a long therapeutic window of 10 days after the insult. Studies from our group and others have shown that intracranial and intravenous injection of murine MSCs actively promote proliferation and differentiation of neuronal and glial precursor cells as well as axonal regeneration. Moreover, MSCs have been shown to exert strong anti-inflammatory properties and to modulate immune responses, for example by suppressing the proliferation of T cells and B cells in various disease models such as graft-versus-host disease. Before MSCs can be used in the clinic for the treatment of neonatal brain damage, the neuroregenerative potential of human MSCs has to be determined. A few studies in the adult rodent MCAO model for Wortmannin stroke have investigated the efficacy of hMSCs to repair stroke induced brain lesion and behavioral deficits, but none have studied the effects of hMSCs on neonatal encephalopathy. The results from these studies show that hMSCs improve motor behavior, decrease lesion size and enhance angiogenesis. In our study, we used an in vitro assay to assess the capacity of hMSCs to induce mouse neural stem cell to differentiate towards neuronal and glial cell fates. Moreover, we determined in vivo whether hMSCs are able to migrate towards the injury site in our mouse model of neonatal HI brain injury and which chemotactic factors may mediate MSC migration to the lesion. Most importantly, we investigated whether treatment with hMSCs improves motor behavior and decreases lesion size and gliosis following HI injury in the neonatal mice. Our study shows that human MSCs have the capacity to promote neuroregeneration. This finding is reflected by our results showing that intranasal administration of hMSCs significantly improves motor behavior, and decreases lesion size and scar formation at 28 days after HI brain damage in neonatal mice. Furthermore, our in vitro results demonstrate that human MSCs are capable of inducing mNCSs to differentiate towards astrocytic and neuronal cell fate. This suggests that hMSCs do not need cell to cell contact with neural stem cells, but rather promote endogenous neurogenesis and lesion repair by the secretion of neurotrophic factors. We also show that hMSCs reach the damaged brain region in the mouse within 24 hours after intranasal administration. Importantly, our work also provides new insight into the chemotactic factors that may regulate MSC migration towards the lesion site. Our results show that the chemokine CXCL10 is strongly upregulated at 10 days following HI.