| 1. |
- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
- Christ, George J., et al.
(author)
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Increased connexin43-mediated intercellular communication in a rat model of bladder overactivity in vivo.
- 2003
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In: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 284:5, s. 1241-1248
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Journal article (peer-reviewed)abstract
- Bladder overactivity associated with outflow obstruction is a common human condition recapitulated in the female rat by narrowing the diameter of the urethra. The goal of these studies was to evaluate the role of intercellular communication through connexin43 (Cx43)-derived gap junction channels to bladder overactivity following partial urethral outflow obstruction of 3-day to 6-wk duration. Cx43 mRNA and protein expression were barely detectable by Northern or Western blots, respectively, in the detrusor layer of normal bladders, but bands were found with both techniques after 6 wk of obstruction. Linear regression analysis of the RT-PCR data revealed a statistically significant positive correlation between the duration of obstruction (again, ranging from 3-day to 6-wk duration) and Cx43 mRNA transcript levels, such that after 6 wk of obstruction, Cx43 transcript levels were ≈15-fold greater than initial control values. When taking into account the approximately fivefold increase in bladder weight over this same time frame, the absolute amount of Cx43 mRNA in the bladder apparently increased by ≈75-fold. In that regard, as anticipated, and consistent with previous observations, 6 wk of obstruction was also associated with a significant increase in spontaneous bladder contractions between micturitions. The amplitude of these contractions was significantly reduced by heptanol given intravesically. Furthermore, carbachol-precontracted bladder strips from obstructed animals were more sensitive to heptanol-induced relaxation (100 μM) than their unobstructed counterparts ( n = 6; P < 0.01). When bladder strips were equivalently precontracted via electrical field stimulation (EFS; 20 Hz), similar heptanol-induced relaxation responses were observed. However, the tetrodotoxin-resistant portion of the EFS-induced contraction was greater in the obstructed than in the unobstructed animals, and this portion of the contractile response was more sensitive to heptanol-induced relaxation in obstructed than unobstructed bladders ( n = 7; P < 0.01). Taken together, these observations indicate that partial outlet obstruction produces an overactive bladder that may be more dependent on intercellular communication through gap junctions for modulation of contractile responses than its normal counterpart.
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| 3. |
- Gratzke, Christian, et al.
(author)
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Distribution and Function of Cannabinoid Receptors 1 and 2 in the Rat, Monkey and Human Bladder
- 2009
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In: JOURNAL OF UROLOGY. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 181:4, s. 1939-1948
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Journal article (peer-reviewed)abstract
- Purpose: We investigated the distribution of cannabinoid receptor subtypes 1 and 2 in the detrusor of different species and studied the effects of cannabinoid receptor 1 and 2 agonists on bladder function. Materials and Methods: Cannabinoid receptor 1 and 2 expression was studied with Western blot and immunohistochemistry in rat, monkey and human detrusors. Co-staining was done for markers of sensory nerves using calcitonin gene-related peptide (Euro-Diagnostica, Malmo, Sweden) and transient receptor potential vanilloid 1, and for cholinergic nerves using VAChT (Santa Cruz Biotechnology, Santa Cruz, California). Actions of the endogenous cannabinoid receptor-1 and 2 agonist anandamide (Sigma (R)), and the cannabinoid receptor 1 and 2 agonist CP55,940 (Sigma) on isolated detrusor and during cystometry in conscious rats were recorded. Results: Higher expression of cannabinoid receptor 2 but not cannabinoid receptor 1 was noted in the mucosa than in the detrusor. Compared to the detrusor larger amounts of cannabinoid receptor 2 containing nerves that also expressed transient receptor potential vanilloid 1 or calcitonin gene-related peptide were observed in the suburothelium. Nerve fibers containing cannabinoid receptor 2 and VAChT were located in the detrusor. Neither anandamide nor CP55,940 affected isolated detrusor carbachol (Sigma) contractions. Nerve contractions were enhanced by 10 mu M anandamide and decreased by 10 AM CP55,940 (P<0.05). In vivo CP55,940 increased the micturition interval by 46% and threshold pressure by 124% (p <0.05). Anandamide increased threshold pressure by 26% and decreased the micturition interval by 19% (p <0.05 and <0.01, respectively). Conclusions: The distribution of cannabinoid receptor 2 on sensory nerves and in the urothelium, and effects by CP55940 on the micturition interval and threshold pressure suggest a role for cannabinoid receptor 2 in bladder afferent signals. Co-expression of VAChT and cannabinoid receptor 2, and effects by CP55940 on nerve contractions suggest a cannabinoid receptor 2 mediated modulatory effect on cholinergic nerve activity. Anandamide may not be a good tool for cannabinoid receptor studies due to its activity at other receptors.
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| 4. |
- Gratzke, Christian, et al.
(author)
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Localization and Function of Cannabinoid Receptors in the Corpus Cavernosum: Basis for Modulation of Nitric Oxide Synthase Nerve Activity
- 2010
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In: EUROPEAN UROLOGY. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 57:2, s. 342-348
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Journal article (peer-reviewed)abstract
- Background: Anandamide, a proposed endogenous cannabinoid (CB) agonist, has been shown to enhance neurogenic responses in vitro of the rat corpus cavernosal tissue (CC). However, no information is available on the distribution of CB-receptors or effects by anandamide in CC from primates or humans. Objective: To characterize the distribution of CB-receptor isoforms in the human and primate CC and to investigate the effects of anandamide on isolated CC preparations. Design, setting, and participants: CC tissue was excised from the crura penis of six rhesus monkeys and five patients. Expression and distribution of CB1 and CB2 receptors were characterized with Western blot analyses and immunohistochemical investigations. The effects of anandamide on isolated CC preparations were analyzed during pharmacologic and nerve-mediated activation of primate tissue in aerated organ baths. Measurements: The expression and localization of CB1 and CB2 receptors in the primate CC and effects of anandamide on nerve-mediated relaxations and pharmacologically evoked contractions. Results and limitations: Western blot experiments revealed CB1 and CB2 receptors at expected band weights. Within and between strands of CC smooth muscle, CB1 and CB2 immunoreactivity (IR) was found in nerve fibers that also expressed IR for nitric oxide synthase (NOS) or transient receptor potential V1 (TRPV1). Neither CB1-IR nor CB2-IR nerves were colocalized with calcitoningene-related peptide (CGRP)-containing or tyrosine hydroxylase-containing nerves. No differences were observed between primate and human CC sections. Anandamide (10(-9) to 10(-4) M) had no contractile effects on CC smooth muscle, no relaxant effects on precontracted preparations, and no effect on phenylephrine-induced contractions. However, anandamide (10 mu M) inhibited electrically evoked smooth-muscle relaxations (34-48%; p andlt;= 0.05). Conclusions: CB1 and CB2 receptors are located on NOS-containing nerves in primate and human CC tissue. In contrast to findings in rats, anandamide antagonized nerve-mediated relaxations of the primate CC, suggesting important species differences for CB-mediated functions. The results also suggest a peripheral mechanism for cannabis-related sexual dysfunction.
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| 5. |
- Lue, Tom F., et al.
(author)
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Summary of the recommendations on sexual dysfunctions in men
- 2004
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In: Journal of Sexual Medicine. - : Oxford University Press (OUP). - 1743-6109 .- 1743-6095. ; 1:1, s. 6-23
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Journal article (peer-reviewed)abstract
- Introduction. There are few published guidelines for the management of sexual dysfunctions in men and women, despite the prevalence and lack of attention to these problems. Disorders of sexual function in men include erectile dysfunction, orgasm/ejaculation disorders, priapism, and Peyronie's disease. Aim. To provide evidence-based and expert-opinion consensus guidelines for the clinical management of men's sexual dysfunctions. Methods. An International Consultation in collaboration with major urological and sexual medicine societies assembled over 200 multidisciplinary experts from 60 countries into 17 consultation committees. Committee members established the scope and objectives for each chapter. Following intensive review of available data and publications, committees developed evidence-based guidelines in each area. Main Outcome Measure. New algorithms and guidelines for assessment and treatment of men's sexual dysfunction were developed. The Oxford system of evidence-based review was systematically applied. Expert opinion was based on systematic grading of the medical literature, in addition to cultural and ethical considerations. Results. Recommendations and guidelines for men's sexual dysfunction are presented. These guidelines were developed as evidence-based, patient-centered, and multidisciplinary in focus. For the clinical assessment and diagnosis of ED, a basic evaluation was recommended for all patients, with optional and specialized testing reserved for special cases. A new treatment algorithm is proposed. This algorithm provides a clinically relevant guideline for managing ED in the large majority of men. New treatment guidelines and algorithms are provided for men's orgasm and ejaculation disorders, including premature ejaculation, retrograde and delayed ejaculation. Finally, expert opinion-based guidelines for the clinical management of priapism and Peyronie's disease are provided. Conclusions. Additional research is needed to validate and extend these guidelines. Nonetheless, this summary encompasses the recommendations concerning men's sexual dysfunctions presented at the 2nd International Consultation on Sexual Medicine in Paris, France, June 28-July 1, 2003.
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