Hot and Diffuse Clouds near the Galactic Center Probed by Metastable H3+

Using an absorption line from the metastable (J, K) = (3, 3) level of H3+ together with other lines of H3+ and CO observed along several sightlines, we have discovered a vast amount of high temperature (T ~ 250 K) and low density (n ~ 100 cm-3) gas with a large velocity dispersion in the Central Molecular Zone (CMZ) of the Galaxy, i.e., within 200 pc of the center. Approximately three fourths of the H3+ along the line of sight to the brightest source we observed, the Quintuplet object GCS 3-2, is inferred to be in the CMZ, with the remaining H3+ located in intervening spiral arms. About half of H3+ in the CMZ has velocities near ~ - 100 km s-1 indicating that it is associated with the 180 pc radius Expanding Molecular Ring which approximately forms outer boundary of the CMZ. The other half, with velocities of ~ - 50 km s-1 and ~ 0 km s-1, is probably closer to the center. CO is not very abundant in those clouds. Hot and diffuse gas in which the (3, 3) level is populated was not detected toward several dense clouds and diffuse clouds in the Galactic disk where large column densities of colder H3+ have been reported previously. Thus the newly discovered environment appears to be unique to the CMZ. The large observed H3+ column densities in the CMZ suggests an ionization rate much higher than in the diffuse interstellar medium in the Galactic disk. Our finding that the H3+ in the CMZ is almost entirely in diffuse clouds indicates that the reported volume filling factor (f ≥ 0.1) for n ≥ 104 cm-3 clouds in the CMZ is an overestimate by at least an order of magnitude.Comment: 33 pages, 5 figures, 3 table

The feasibility and results of a population-based approach to evaluating prostate-specific antigen screening for prostate cancer in men with a raised familial risk

The feasibility of a population-based evaluation of screening for prostate cancer in men with a raised familial risk was investigated by studying reasons for non-participation and uptake rates according to postal recruitment and clinic contact. The levels of prostate-specific antigen (PSA) and the positive predictive values (PPV) for cancer in men referred with a raised PSA and in those biopsied were analysed. First-degree male relatives (FDRs) were identified through index cases (ICs): patients living in two regions of England and diagnosed with prostate cancer at age ⩽65 years from 1998 to 2004. First-degree relatives were eligible if they were aged 45–69 years, living in the UK and had no prior diagnosis of prostate cancer. Postal recruitment was low (45 of 1687 ICs agreed to their FDR being contacted: 2.7%) but this was partly due to ICs not having eligible FDRs. A third of ICs in clinic had eligible FDRs and 49% (192 out of 389) agreed to their FDR(s) being contacted. Of 220 eligible FDRs who initially consented, 170 (77.3%) had a new PSA test taken and 32 (14.5%) provided a previous PSA result. Among the 170 PSA tests, 10% (17) were ⩾4 ng ml−1 and 13.5% (23) tests above the age-related cutoffs. In 21 men referred, five were diagnosed with prostate cancer (PPV 24%; 95% CI 8, 47). To study further the effects of screening, patients with a raised familial risk should be counselled in clinic about screening of relatives and data routinely recorded so that the effects of screening on high-risk groups can be studied

Polycomb-mediated silencing in neuroendocrine prostate cancer

BACKGROUND: Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PCa) for which the median survival remains less than a year. Current treatments are only palliative in nature, and the lack of suitable pre-clinical models has hampered previous efforts to develop novel therapeutic strategies. Addressing this need, we have recently established the first in vivo model of complete neuroendocrine transdifferentiation using patient-derived xenografts. Few genetic differences were observed between parental PCa and relapsed NEPC, suggesting that NEPC likely results from alterations that are epigenetic in nature. Thus, we sought to identify targetable epigenetic regulators whose expression was elevated in NEPC using genome-wide profiling of patient-derived xenografts and clinical samples. RESULTS: Our data indicate that multiple members of the polycomb group (PcG) family of transcriptional repressors were selectively upregulated in NEPC. Notably, CBX2 and EZH2 were consistently the most highly overexpressed epigenetic regulators across multiple datasets from clinical and xenograft tumor tissues. Given the striking upregulation of PcG genes and other transcriptional repressors, we derived a 185-gene list termed 'neuroendocrine-associated repression signature' (NEARS) by overlapping transcripts downregulated across multiple in vivo NEPC models. In line with the striking upregulation of PcG family members, NEARS was preferentially enriched with PcG target genes, suggesting a driving role for PcG silencing in NEPC. Importantly, NEARS was significantly associated with high-grade tumors, metastatic progression, and poor outcome in multiple clinical datasets, consistent with extensive literature linking PcG genes and aggressive disease progression. CONCLUSIONS: We have explored the epigenetic landscape of NEPC and provided evidence of increased PcG-mediated silencing associated with aberrant transcriptional regulation of key differentiation genes. Our results position CBX2 and EZH2 as potential therapeutic targets in NEPC, providing opportunities to explore novel strategies aimed at reversing epigenetic alterations driving this lethal disease

Stage T1c prostate cancer: defining the appropriate staging evaluation and the role for pelvic lymphadenectomy

A good staging system should be able to accurately reflect the natural history of a malignant disease, to express the extent of the disease at the time of diagnosis, and stratify patients in prognostically distinctive groups. The staging system for prostate cancer, as it is today, fails to fulfill these requirements. Approximately one third of the patients who undergo surgery for complete excision of prostate cancer in fact do not have a localize disease. The incidence of tumor at the inked margin may reach 30% for T1 stage and up to 60% for clinical T2b prostate cancer according to comparision with pathologic examination of resected specimen. Several concepts have been recently proposed as a means of improving the accuracy of the available staging system. In this paper, we review current aspects of clinical and pathological staging of prostate cancer, and the importance of these new concepts on the early stages of prostate cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47057/1/345_2005_Article_BF01300182.pd

Expression of prostate-specific antigen (PSA) correlates with poor response to tamoxifen therapy in recurrent breast cancer

Prostate-specific antigen (PSA) is a serine protease which may play a role in a variety of cancer types, including breast cancer. In the present study, we evaluated whether the level of PSA in breast tumour cytosol could be associated with prognosis in primary breast cancer, or with response to tamoxifen therapy in recurrent disease. PSA levels were determined by enzyme-linked immunosorbent assay (ELISA) in breast tumour cytosols, and were correlated with prognosis in 1516 patients with primary breast cancer and with response to first-line tamoxifen therapy in 434 patients with recurrent disease. Relating the levels of PSA with classical prognostic factors, low levels were more often found in larger tumours, tumours of older and post-menopausal patients, and in steroid hormone receptor-negative tumours. There was no significant association between the levels of PSA with grade of differentiation or the number of involved lymph nodes. In patients with primary breast cancer, PSA was not significantly related to the rate of relapse, and a positive association of PSA with an improved survival could be attributed to its relationship to age. In patients with recurrent breast cancer, a high level of PSA was significantly related to a poor response to tamoxifen therapy, and a short progression-free and overall survival after start of treatment for recurrent disease. In Cox multivariate analyses for response to therapy and for (progression-free) survival, corrected for age/menopausal status, disease-free interval, site of relapse and steroid hormone receptor status, PSA was an independent variable of poor prognosis. It is concluded that the level of PSA in cytosols of primary breast tumours might be a marker to select breast cancer patients who may benefit from systemic tamoxifen therapy. © 1999 Cancer Research Campaig

Prognostic factors in prostate cancer

Prognostic factors in organ confined prostate cancer will reflect survival after surgical radical prostatectomy. Gleason score, tumour volume, surgical margins and Ki-67 index have the most significant prognosticators. Also the origins from the transitional zone, p53 status in cancer tissue, stage, and aneuploidy have shown prognostic significance. Progression-associated features include Gleason score, stage, and capsular invasion, but PSA is also highly significant. Progression can also be predicted with biological markers (E-cadherin, microvessel density, and aneuploidy) with high level of significance. Other prognostic features of clinical or PSA-associated progression include age, IGF-1, p27, and Ki-67. In patients who were treated with radiotherapy the survival was potentially predictable with age, race and p53, but available research on other markers is limited. The most significant published survival-associated prognosticators of prostate cancer with extension outside prostate are microvessel density and total blood PSA. However, survival can potentially be predicted by other markers like androgen receptor, and Ki-67-positive cell fraction. In advanced prostate cancer nuclear morphometry and Gleason score are the most highly significant progression-associated prognosticators. In conclusion, Gleason score, capsular invasion, blood PSA, stage, and aneuploidy are the best markers of progression in organ confined disease. Other biological markers are less important. In advanced disease Gleason score and nuclear morphometry can be used as predictors of progression. Compound prognostic factors based on combinations of single prognosticators, or on gene expression profiles (tested by DNA arrays) are promising, but clinically relevant data is still lacking

Systematic Review of Potential Health Risks Posed by Pharmaceutical, Occupational and Consumer Exposures to Metallic and Nanoscale Aluminum, Aluminum Oxides, Aluminum Hydroxide and Its Soluble Salts

Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007). Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of “total Al”assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al+ 3 to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)+ 2 and Al(H2O)6 + 3] that after complexation with O2•−, generate Al superoxides [Al(O2•)](H2O5)]+ 2. Semireduced AlO2• radicals deplete mitochondrial Fe and promote generation of H2O2, O2 • − and OH•. Thus, it is the Al+ 3-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer\u27s disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances