Pituitary adenomas account for approximately 10% of intracranial tumors, but little is known of the oncogenesis of these tumors. The identification of tumor-specific genes may further elucidate the ...pathways of tumor formation. We used complementary DNA microarrays to examine gene expression profiles in nonfunctioning, PRL, GH, and ACTH secreting adenomas, compared with normal pituitary. Microarray analysis showed that 128 of 7075 genes examined were differentially expressed. We then analyzed three genes with unique expression patterns and oncogenic importance by RT-real time quantitative PCR in 37 pituitaries. Folate receptor gene was significantly overexpressed in nonfunctioning adenomas but was significantly underexpressed in PRL and GH adenomas, compared with controls and to other tumors. The ornithine decarboxylase gene was significantly overexpressed in GH adenomas, compared with other tumor subtypes but was significantly underexpressed in ACTH adenomas. C-mer proto-oncogene tyrosine kinase gene was significantly overexpressed in ACTH adenomas but was significantly underexpressed in PRL adenomas. We have shown that at least three genes involved in carcinogenesis in other tissues are also aberrantly regulated in the major types of pituitary tumors. The evaluation of candidate genes that emerge from these experiments provides a rational approach to investigate those genes significant in tumorigenesis.
We have analyzed the effect of severe traumatic brain injury (TBI) on the levels of mRNA expression of neurotrophic factors (NTFs): brain-derived neurotrophic factor (BDNF), nerve growth factor ...(NGF), ciliary neurotrophic factor (CNTF) and their respective receptors: trkB, trkA and CNTFRα. The expression was examined in the region of the lesion as well as a region remote from the lesion at 12, 24, and 36 h following the injury. Our data suggest that after the brain injury, the expression of NGF and BDNF mRNAs were early, transiently and significantly upregulated while that of CNTF was a slow and less amplified response in both areas of the brain. We also found that trkA mRNA expression was only upregulated significantly in the remote area; trkB mRNA showed no significant change in either area except an upregulation at 12 h in the remote area. CNTFRα was downregulated significantly by 24–36 h in the lesion area and by 24 h in the remote area. These changes suggest that TBI regulates the expression of NTFs and their receptors. These alterations in expression may be involved in modulating the neuronal response after brain injury.
Three crystal forms of acetaminophen were prepared and characterized using a newly developed high-throughput crystallization platform, CrystalMax. The platform consists of design software, robotic ...sample dispensing and handling, and high-throughput microanalytics and is capable of running thousands of crystallizations in parallel using several different methods to drive supersaturation and subsequent crystallization. Additionally, structural models of the elusive third form of acetaminophen will be discussed on the basis of powder X-ray diffraction data. One structure suggested has a bilayer motif, held together by O-H...O(H) hydrogen bonds, and helps explain the difficulty associated with preparing this form from solution.
PBCC211, an
aroA aroD derivative of
S. typhi strain CDC10–80, was tested in phase I trials as a single dose typhoid fever vaccine. Three different vaccine preparations, reconstituted lyophilized ...bacteria, freshly grown bacteria or lyophilized bacteria reconstituted from sachets, were orally administered to a total of 86 adult volunteers. An
aroA aroD htrA strain, PBCC222, was also tested in 38 volunteers. Formulation impacted on the determination of a safe and immunogenic dose; reconstituted lyophilized cultures required higher doses than the broth cultures to stimulate seroconversion. In general, doses which seroconverted the majority of group members produced undesirable symptoms regardless of attenuation or formulation. The inability to separate the presence of symptoms from achieving significant immunogenicity in these
aroA aroD or
aroA aroD htrA strains precludes their use as single dose typhoid vaccines in the formulations tested. Multiple doses of these strains at a lower, safe level may be effective as vectors for foreign antigens.
Pituitary Adenomas: Screening for Gαq Mutations Oyesiku, Nelson M; Evans, Chheng-Orn; Brown, Milton R ...
The journal of clinical endocrinology and metabolism
82, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Mutant, guanosine triphosphatase-deficient, α-subunits of the G
protein, Gs, gsp ocogene have been discovered in 40% of
GH-secreting pituitary adenomas. Therefore, we hypothesized that a
novel G ...protein class, Gαq, involved in pituitary signal
transduction, might be involved in pituitary tumorigenesis. Recombinant
mutations of Gαq result in constitutive activation of phospholipase C
and have transforming activity. Therefore, we screened tumor samples
from 37 pituitary adenomas for the presence of activating mutations of
the Gαq gene. Importantly, our sample contains 8 FSH and LH adenomas.
In the pituitary gland, FSH and LH are linked to the GnRH-Gαq
signaling cascade, making these tumors a logical choice for screening
for Gαq mutations. Complementary DNA (cDNA) was synthesized by RT-PCR
with Gαq specific primers to exclude pseudogene transcripts.
Fragments of Gαq cDNA-encompassing residues (Arg183,
Gln209) were screened by single-strand conformation
polymorphism and then sequenced in both directions. No mutations were
detected. We conclude that mutations in these regions of the Gαq cDNA
occur infrequently, if at all, in human pituitary adenomas. Alternative
mechanisms underlying pituitary tumorigenesis should be explored.
The aim of this study was to examine the antioxidant activity of ginger extract oral supplement in newly diagnosed cancer patients receiving adjuvant chemotherapy compared to placebo.
Newly diagnosed ...cancer patients receiving moderate-to-high emetogenic potential adjuvant chemotherapy were randomized to receive either a ginger extract (standardized 6-gingerol 20 mg/day) or a placebo 3 days prior to chemotherapy, which they continued daily. Oxidant/antioxidant parameters, including the activities of superoxide dismutase (SOD) and catalase (CAT) and levels of glutathione peroxidase (GPx), total glutathione (GSH/GSSG), lipid peroxidation products detected as malondialdehyde (MDA) and NO
/NO
, were measured at baseline and at days 1, 22, 43 and 64 after undergoing chemotherapy. Two-sided statistical analysis, with
< 0.05, was used to determine statistical significance.
A total of 43 patients were included in the study: 19 and 24 patients were randomly assigned to the ginger group and placebo group, respectively. Antioxidant activity parameters, including SOD, CAT, GPx and GSH/GSSG, were significantly increased at day 64 in the ginger group compared to those in the placebo group, while MDA and NO
/NO
levels were significantly decreased (
< 0.0001). When compared to the baseline, the activities of SOD and CAT and the levels of GPx and GSH/GSSG were significantly higher on day 64 (
= 0.01), while the blood levels of MDA and NO
/NO
were significantly decreased (
< 0.01).
Daily supplement of ginger extract started 3 days prior to chemotherapy has been shown to significantly elevate antioxidant activity and reduce oxidative marker levels in patients who received moderate-to-high emetogenic potential chemotherapy compared to placebo.
Lipid nanoparticles (LNP) are effective delivery vehicles for messenger RNA (mRNA) and have shown promise for vaccine applications. Yet there are no published reports detailing how LNP biophysical ...properties can impact vaccine performance. In our hands, a retrospective analysis of mRNA LNP vaccine in vivo studies revealed a relationship between LNP particle size and immunogenicity in mice using LNPs of various compositions. To further investigate this, we designed a series of studies to systematically change LNP particle size without altering lipid composition and evaluated biophysical properties and immunogenicity of the resulting LNPs. While small diameter LNPs were substantially less immunogenic in mice, all particle sizes tested yielded a robust immune response in non-human primates (NHP).
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Pharmaceutical residues are polluting the surface water environments worldwide. Sewage and wastewater treatment, therefore, needs to be improved in order to remove pharmaceutical residues from the ...effluent. One such treatment improvement is effluent ozonation. Even though ozonation has proven to be very efficient in reducing pharmaceutical parent compound concentrations in wastewater effluents, much remains unclear regarding potentially toxic ozonation by-product (OBP) formation. In this study, we sought to elucidate the aquatic toxicity of ozonated pharmaceuticals in zebrafish (Danio rerio) embryos in a static 144 h post fertilization (hpf) fish embryotoxicity (ZFET) assay. Three pharmaceuticals commonly detected in wastewater effluents, i.e. carbamazepine, diclofenac, and oxazepam, were selected for testing. Toxicity was assessed before and after 1 min ozonation (0.053 mg L−1 peak O3 concentration) and 10 min ozonation (0.147 mg L−1 peak O3 concentration). Chemical analysis showed that carbamazepine and diclofenac were largely removed by ozone (90 ± 11% and 97 ± 3.8%), whereas oxazepam was removed to a lesser extent (19 ± 5.7%). The ZFET assay revealed diverging toxicities. Diclofenac embryotoxicity decreased with increasing ozonation. Oxazepam did not cause embryotoxicity in the ZFET assay either pre- or post ozonation, but larvae swimming activity was affected at 144 hpf. Carbamazepine embryotoxicity, on the other hand, increased with increasing ozonation. Chemical analysis showed the formation of two OBPs (carbamazepine-10,11-epoxide and 10,11-dihydrocarbamazepine), possibly explaining the increased embryotoxicity. The results of this study highlight the importance of new chemical and toxicological knowledge regarding the formation of OBPs in post-ozonated effluents.
•First time evaluation of Danio rerio embryo toxicity of ozonated pharmaceuticals.•Ozonation of carbamazepine increased the toxicity in all tested endpoints.•Three analyzed carbamazepine ozonation by-products were formed.•Diclofenac toxicity was completely eliminated by ozonation.•Ozonated oxazepam exposure elicited swimming behavioral changes in 6 day old larvae.
Recently, the World Health Organization confirmed 120 new human cases of avian H7N9 influenza in China resulting in 37 deaths, highlighting the concern for a potential pandemic and the need for an ...effective, safe, and high-speed vaccine production platform. Production speed and scale of mRNA-based vaccines make them ideally suited to impede potential pandemic threats. Here we show that lipid nanoparticle (LNP)-formulated, modified mRNA vaccines, encoding hemagglutinin (HA) proteins of H10N8 (A/Jiangxi-Donghu/346/2013) or H7N9 (A/Anhui/1/2013), generated rapid and robust immune responses in mice, ferrets, and nonhuman primates, as measured by hemagglutination inhibition (HAI) and microneutralization (MN) assays. A single dose of H7N9 mRNA protected mice from a lethal challenge and reduced lung viral titers in ferrets. Interim results from a first-in-human, escalating-dose, phase 1 H10N8 study show very high seroconversion rates, demonstrating robust prophylactic immunity in humans. Adverse events (AEs) were mild or moderate with only a few severe and no serious events. These data show that LNP-formulated, modified mRNA vaccines can induce protective immunogenicity with acceptable tolerability profiles.
Potential pandemic influenzas and the need for an effective, safe, and high-speed vaccine production platform have been widely discussed in the scientific community. Bahl et al. report the rapid and robust immune responses achieved against H10N8 and H7N9 viruses from modified mRNA vaccines with an acceptable safety profile.
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