The accumulation of high concentrations of signalling androgens within prostate tumours that progress despite use of androgen-deprivation therapy is a clinically important mechanism of the ...development of castration-resistant prostate cancer. In the past 5 years, data from a number of studies have increased our understanding of the enzymes and substrates involved in intratumoural androgen biosynthesis, and have implicated three competing pathways, which are likely to account for these observations. These pathways ('canonical', 'backdoor' and '5α-dione'), which can all ultimately generate the potent signalling androgen, dihydrotestosterone, involve many of the same enzymes, but differ in terms of substrate preference, reaction sequence and the organs and tissues in which they occur. For this reason, the relative importance of each pathway to the development and progression of prostate cancer remains controversial. In this Review, we describe the current understanding of androgen synthesis and the evidence for its role in castration resistance, and examine the evidence supporting and or rebutting the relevance of each pathway to patients with prostate cancer.
Data from morphology, linguistics, history, and archaeology have all been used to trace the dispersal of chickens from Asian domestication centers to their current global distribution. Each provides ...a unique perspective which can aid in the reconstruction of prehistory. This study expands on previous investigations by adding a temporal component from ancient DNA and, in some cases, direct dating of bones of individual chickens from a variety of sites in Europe, the Pacific, and the Americas. The results from the ancient DNA analyses of forty-eight archaeologically derived chicken bones provide support for archaeological hypotheses about the prehistoric human transport of chickens. Haplogroup E mtDNA signatures have been amplified from directly dated samples originating in Europe at 1000 B.P. and in the Pacific at 3000 B.P. indicating multiple prehistoric dispersals from a single Asian centre. These two dispersal pathways converged in the Americas where chickens were introduced both by Polynesians and later by Europeans. The results of this study also highlight the inappropriate application of the small stretch of D-loop, traditionally amplified for use in phylogenetic studies, to understanding discrete episodes of chicken translocation in the past. The results of this study lead to the proposal of four hypotheses which will require further scrutiny and rigorous future testing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recolonization by native species following removal of invasive plant species can often be uneven and lead to the rapid increase of one or a few native plant species. This can result in the formation ...of a significant resource pulse that may consequently affect populations of herbivorous species and their natural enemies. Here we present results from observations of parasitism rates during a localized outbreak of the Asimina webworm moth, Omphalocera munroei, a locally monophagous herbivore of the common paw-paw. Asimina triloba. This outbreak initiated from locations of increased understory growth of A. triloba, following the removal of Amur Honeysuckle (Lonicera maackii). Parasitism rates during the outbreak reached 50%, with higher parasitism rates observed in larvae collected at the end of the local outbreak relative to those the year following the peak of the outbreak. Parasitism rates remained high 3 y after the end of the local O. munroei outbreak, indicating >7 y of high parasitoid densities. O. munroei emerges late in the growing season, making it fairly inaccessible as a host or prey to many generalist predators/parasitoids, which emerge earlier the following year. This suggests the O. munroei outbreak potentially contributed to an increase in natural enemy pressure of other native species in the community.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. ...Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown.
We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 h and 6 weeks) surgery. In a separate cohort (n = 189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival.
Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2-4.8, p = 0.014).
CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease.
Cancer is fundamentally a genomic disease caused by mutations or rearrangements in the DNA or epigenetic machinery of a patient. An emerging field in cancer treatment targets key aberrations arising ...from the mutational landscape of an individual patient's disease rather than employing a cancer-wide cytotoxic therapy approach. In prostate cancer in particular, where there is an observed variation in response to standard treatments between patients with disease of a similar pathological stage and grade, mutationdirected treatment may grow to be a viable tool for clinicians to tailor more effective treatments. This review will describe a number of mutations across multiple forms of cancer that have been successfully antagonised by targeted therapeutics including their identification, the development of targeted compounds to combat them and the development of resistance to these therapies. This review will continue to examine these same mutations in the treatment and management of prostate cancer; the prevalence of targetable mutations in prostate cancer, recent clinical trials of targeted-agents and the potential or limitations for their use.
Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding ...of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities.
In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry.
This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prostate cancer is a leading cause of morbidity and cancer-related death worldwide. Androgen deprivation therapy (ADT) is the cornerstone of management for advanced disease. The use of these ...therapies is associated with multiple side effects, including metabolic syndrome and truncal obesity. At the same time, obesity has been associated with both prostate cancer development and disease progression, linked to its effects on chronic inflammation at a tissue level. The connection between ADT, obesity, inflammation and prostate cancer progression is well established in clinical settings; however, an understanding of the changes in adipose tissue at the molecular level induced by castration therapies is missing. Here, we investigated the transcriptional changes in periprostatic fat tissue induced by profound ADT in a group of patients with high-risk tumours compared to a matching untreated cohort. We find that the deprivation of androgen is associated with a pro-inflammatory and obesity-like adipose tissue microenvironment. This study suggests that the beneficial effect of therapies based on androgen deprivation may be partially counteracted by metabolic and inflammatory side effects in the adipose tissue surrounding the prostate.
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DNA-fluorescence in situ hybridisation (DNA-FISH) allows visualisation of chromosome organisation and rearrangement. FISH probes are pools of short fluorescently labelled DNA ...fragments that are often produced from template plasmids that contain large genomic inserts. For effective sample penetration and target hybridisation it is critical that probe fragments are between 200 and 500bp. Production of these short probes requires significant optimisation and can be confounded access to expensive sonication equipment or inherent sequence features that influence enzymatic fragmentation or amplification. Here we demonstrate that effective FISH probes can be prepared without the need for optimisation of fragmentation using a cocktail of two the 4bp recognition sequence restriction enzymes CviQI and AluI.
The Mauna Kea Adze Quarry Complex is the largest-known prehistoric quarry in the Pacific Basin. The main extraction areas are located at an extreme altitude (3,800 m), near the summit of Hawaii's ...tallest mountain. The Mauna Kea summit region and the quarry are considered by many Hawaiians to be a sacred landscape and archaeologists must consider the ethical tensions involved in conducting Western science in these areas. Although provenance studies of basalt adzes are integral to the examination of pre-contact Hawaiian economics, former studies of Hawaiian adze distribution have been limited in scope, and conventionally relied on destructive petrography and petrology for the analyses. Published geochemical data on the quarry are derived from only eight samples analyzed with destructive methods. In order to better define the variation within the quarry, and to develop a more culturally sensitive approach, we employed nondestructive energy dispersive X-ray fluorescence (EDXRF) of whole-rock samples to characterize 820 flakes and 47 geological samples from the quarry complex. This study offers the first reliable estimation of the overall range of geochemical variability in the complex. These results suggest that nondestructive EDXRF can be used to differentiate Mauna Kea basalts from other known Hawaiian quarries, but more characterization of other quarries is necessary to confirm exclusive separation of sources. The results further demonstrate that EDXRF is capable of detecting intra-site geochemical variation in Mauna Kea quarry material.
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