Activation of gonadotropin-releasing hormone (GnRH) receptors inhibits proliferation of transformed cells derived from reproductive tissues and in transfected cell lines. Hence, GnRH receptors ...represent a therapeutic target for direct action of GnRH analogues on certain proliferating cells. However, more cell biological data are required to develop this particular application of GnRH analogues. Therefore, we compared the effects of GnRH receptor activation in transfected HEK293 cells (HEK293(SCL60)) with transfected human ovarian cancer cell lines SKOV3 and EFO21, human hepatoblastoma HepG2 cells, and rat neuroblastoma B35 cells. Marked differences in receptor levels, magnitude of inositol phosphate generation, and dynamics of inositol phosphate turnover occurred in the different cells. Activation of GnRH receptors, expressed at high or moderate levels, inhibited the growth of HEK293(SCL60) and B35 cells, respectively. Western blotting detected markers of apoptosis cleaved poly(ADP-ribose) polymerase, caspase-9 in HEK293(SCL60) and B35 following treatment with 100 nmol/L d-Trp(6)-GnRH-I. Cell growth inhibition was partially or completely rescued with inhibitor Q-VD-OPh or Ro32-0432. Low levels of GnRH receptor expression in transfected SKOV3, EFO21, or HepG2 activated intracellular signaling but did not induce apoptosis or significantly affect cell proliferation. Tumor xenografts prepared from HEK293(SCL60) regressed during treatment with d-Trp(6)-GnRH-I and growth of xenografts derived from transfected B35 was slowed. SKOV3 xenografts were not growth inhibited. Therefore, differences in levels of GnRH receptor and signaling differentially affect the apoptotic machinery within cell lines and contribute to the cell type-specific effects of GnRH on growth. Further studies should exploit the growth-inhibitory potential of GnRH receptor activation in abnormal cells in diseased human tissues.
The circadian clock of the model plant Arabidopsis (Arabidopsis thaliana) is made up of a complex series of interacting feedback loops whereby proteins regulate their own expression across day and ...night. early bird (ebi) is a circadian mutation that causes the clock to speed up: ebi plants have short circadian periods, early phase of clock gene expression, and are early flowering. We show that EBI associates with ZEITLUPE (ZTL), known to act in the plant clock as a posttranslational mediator of protein degradation. However, EBI is not degraded by its interaction with ZTL. Instead, ZTL counteracts the effect of EBI during the day and increases it at night, modulating the expression of key circadian components. The partnership of EBI with ZTL reveals a novel mechanism involved in controlling the complex transcription-translation feedback loops of the clock. This work highlights the importance of cross talk between the ubiquitination pathway and transcriptional control for regulation of the plant clock.
Abstract Background/ Purpose Primary hepatic sarcomas are rare and account for about 13% of primary hepatic neoplasms. There are few reported series of pediatric hepatic sarcomas, and the aim was to ...review our experience. Methods A retrospective analysis of cases managed from 1988 to 2007 by the pediatric liver unit in Birmingham, UK, was conducted. Results Nineteen children were identified. These presented with sudden abdominal pain (n = 6), obstructive jaundice (n = 3), incidental mass (n = 3), and chronic pain/distension (n = 3). Vascular involvement was identified in 3, and 6 had pulmonary metastases. Three patients had primary resection, and 3 only a biopsy. Thirteen had a biopsy followed by chemotherapy and resection. Surgery included extended hepatectomy (n = 11), hepatectomy (n = 3), and nonanatomical resections (n = 2). There was 1 major intraoperative complication. Median inpatient stay was 7 days. One biliary leak developed 4 weeks postoperatively. Five of the 16 patients who underwent resection of the primary tumor died. Eleven were alive at a median follow-up of 3 years. Conclusion This is a challenging group of patients. Local control remains pivotal to successful treatment. Good results can be achieved in a specialist center with multidisciplinary approach.
The high regional incidence of hepatocellular carcinoma (HCC) in South Africa also may be present in children of the region, although the link to hepatitis B (HBV) appears less clear. The objective ...of this study was to assess the incidence and probable causes of HCC in South African children.
Data were obtained from seven participating pediatric oncology units and from the tumor registry to review hepatic tumors in children in South Africa.
One hundred ninety-four children (ages 0-14 years) presented with malignant primary hepatic tumors (1988-2003). One hundred twelve tumors (57%) were hepatoblastoma (HB), 68 tumors (35%) were hepatocellular carcinoma (HCC) (including 9 patients with the fibrolamellar variant, 6 of which occurred in black children), 10 tumors (5%) were sarcoma of the liver, and 4 tumors were lymphoma. The ratio of HB to HCC (1.67) was markedly lower compared with other reports, suggesting a greater prevalence of HCC. Correlation with population statistics indicated an incidence of 1.066 malignant liver tumors per year per 10(6) children age < 14 years (HB, 0.61 per 10(6) children; HCC, 0.39 per 10(6)). Two-thirds of patients with HCC were positive for HBV surface antigen (HBsAg), and HCC occurred mostly in black African patients (93%). The mean age of onset was 1.47 years for HB and 10.48 years for HCC. A preponderance of males (3.5:1.0) was noted in the HBsAg-positive group that was not reflected elsewhere. Serum alpha-fetoprotein (AFP) levels were raised both in patients with HB (100%; most AFP levels were very high) and in patients with HCC (69%), although 15% of patients with HCC had low or normal AFP levels.
It appeared from the current results that HCC is more prevalent among children in South Africa compared with the children in more developed countries, although their rates were lower that the rates noted in adults. A collaborative approach will be required to improve their diagnosis and management.
An endophytic streptomycete (NRRL 30566) is described and partially characterized from a fern-leaved grevillea (
Grevillea pteridifolia) tree growing in the Northern Territory of Australia. This ...endophytic streptomycete produces, in culture, novel antibiotics – the kakadumycins. Methods are outlined for the production and chemical characterization of kakadumycin A and related compounds. This antibiotic is structurally related to a quinoxaline antibiotic, echinomycin. Each contains, by virtue of their amino acid compositions, alanine, serine and an unknown amino acid. Other biological, spectral and chromatographic differences between these two compounds occur and are given. Kakadumycin A has wide spectrum antibiotic activity, especially against Gram-positive bacteria, and it generally displays better bioactivity than echinomycin. For instance, against
Bacillus anthracis strains, kakadumycin A has minimum inhibitory concentrations of 0.2–0.3 μg ml
−1 in contrast to echinomycin at 1.0–1.2 μg ml
−1. Both echinomycin and kakadumycin A have impressive activity against the malarial parasite
Plasmodium falciparum with LD
50s in the range of 7–10 ng ml
−1. In macromolecular synthesis assays both kakadumycin A and echinomycin have similar effects on the inhibition of RNA synthesis. It appears that the endophytic
Streptomyces sp. offer some promise for the discovery of novel antibiotics with pharmacological potential.
Neighborhood-level socioeconomic deprivation has been associated with poor cognitive function pertaining to language and the executive control. Few studies have explored the cortical morphology of ...regions most commonly associated with these functions. The aim of this study was to examine the association between neighborhood-level deprivation and the morphology of cortical regions associated with language and executive control in adults.
Using a cross-sectional study design, we compared the cortical morphology of 42 neurologically healthy adult men from the least deprived and most deprived neighborhoods of Glasgow. We performed surface-based morphometry on 3-T structural magnetic resonance imaging (MRI) images to extract the cortical morphology--volume, thickness (CT), and surface area (SA) of regions commonly associated with language and executive control. Cortical morphology was compared between the two groups. We used mediation analysis to examine whether cardiometabolic risk factors mediated the relationship between deprivation status and cortical morphology.
Intracranial volume and mean total CT did not differ between groups. The deprived group had significantly smaller left posterior parietal cortex SA (Cohen d = 0.89) and fusiform cortex SA (Cohen d = 1.05). They also had thinner left Wernicke's area (Cohen d =0.93) and its right homologue (Cohen d = 1.12). Among the cardiometabolic markers, a composite factor comprising inflammatory markers mediated the relationship between deprivation status and Wernicke's area CT.
A group of neurologically healthy men from deprived neighborhoods showed significantly smaller cortical morphology--both SA and CT--in regions of the brain pertaining to language and executive function. We provide additional evidence of a relationship between socioeconomic deprivation and cortical morphology.
In 1999, we published the results of a preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. These investigators ...report the results of a follow-on study of 330 patients with corticosteroid-unresponsive idiopathic pulmonary fibrosis who were randomly assigned to receive subcutaneous interferon gamma-1b or placebo. After a median of more than one year, interferon gamma-1b therapy did not improve progression-free survival, measures of lung function, gas exchange, or the quality of life.
No improvements with interferon therapy.
Idiopathic pulmonary fibrosis is a fatal lung disease of unknown cause characterized by worsening dyspnea, progressive loss of lung volumes, and abnormal gas exchange. The outcome is dismal, with a median survival of only two to three years.
1
–
3
Although no therapy has been demonstrated to be efficacious, a recent consensus statement recommends treatment of idiopathic pulmonary fibrosis with antiinflammatory and immunosuppressive therapies such as prednisone in combination with azathioprine or cyclophosphamide.
4
However, the only two randomized, controlled trials of these therapies failed to demonstrate significant clinical benefit.
5
,
6
Moreover, both corticosteroids and cytotoxic agents may have serious side effects. . . .
This combined analysis investigated the effect of marimastat, a specific inhibitor of matrix metalloproteinases, on markers
of tumor progression measured in patients with advanced cancer. By defining ...the tolerability and biological activity of the
drug, it aimed to establish an appropriate dose range for use in Phase III trials. Patients with advanced, serologically progressive
ovarian, prostatic, pancreatic, and colorectal cancer were recruited into six nonrandomized, dose ranging, multicenter clinical
trials in North America and Europe. The biological activity of marimastat was assessed by serial measurements of the serum
tumor markers carcinoembryonic antigen, CA125, CA19-9, and prostate-specific antigen. Patients were recruited with tumor markers
rising by more than 25% averaged over a 4-week screening period. A biological effect was defined as a level of tumor marker
at the end of treatment no greater than at study entry; a partial biological effect was defined as a rise in the level of
tumor marker over the treatment period of 0-25% per 4 weeks. Pharmacokinetic and safety data were collected and assessed as
the studies progressed. All patients were followed up for survival.
Polymerase chain reaction amplification of the universal 16S ribosomal RNA (rRNA) gene was performed on a collection of 38 bacterial isolates, originating from air sampled immediately adjacent to the ...agricultural spreading of bovine slurry. A total of 16 bacterial genera were identified including both Gram-positive and Gram-negative genera. Gram-positive organisms accounted for 34/38 (89.5%) of total bacterial numbers consisting of 12 genera and included
Staphylococcus (most common genus isolated),
Arthrobacter (2nd most common genus isolated),
Brachybacterium, Exiguobacterium, Lactococcus, Microbacterium and
Sporosarcina (next most common genera isolated) and finally,
Bacillus, Brevibacterium, Frigoribacterium,
Mycoplana and
Pseudoclavibacter. Gram-negative organisms accounted for only 4/38 (10.5%) bacterial isolates and included the following genera,
Brevundimonas, Lysobacter, Psychrobacter and
Rhizobium. No gastrointestinal pathogens were detected. Although this study demonstrated a high diversity of the microorganisms present, only a few have been shown to be opportunistically pathogenic to humans and none of these organisms described have been described previously as having an inhalational route of infection and therefore we do not believe that the species of organisms identified pose a significant health and safety threat for immunocompetant individuals.
Using the recently installed Gemini Planet Imager (GPI), we have obtained the first H-band spectrum of the planetary companion to the nearby young star β Pictoris. GPI is designed to image and ...provide low-resolution spectra of Jupiter-sized, self-luminous planetary companions around young nearby stars. These observations were taken covering the H band (1.65 μm). The spectrum has a resolving power of ~45 and demonstrates the distinctive triangular shape of a cool substellar object with low surface gravity. Using atmospheric models, we find an effective temperature of 1600-1700 K and a surface gravity of log (g) = 3.5-4.5 (cgs units). These values agree well with "hot-start" predictions from planetary evolution models for a gas giant with mass between 10 and 12 MJup and age between 10 and 20 Myr.
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