Parkin Regulates Mitosis and Genomic Stability through Cdc20/Cdh1.

Mutations in the E3 ubiquitin ligase Parkin have been linked to familial Parkinson's disease. Parkin has also been implicated in mitosis through mechanisms that are unclear. Here we show that Parkin interacts with anaphase promoting complex/cyclosome (APC/C) coactivators Cdc20 and Cdh1 to mediate the degradation of several key mitotic regulators independent of APC/C. We demonstrate that ordered progression through mitosis is orchestrated by two distinct E3 ligases through the shared use of Cdc20 and Cdh1. Furthermore, Parkin is phosphorylated and activated by polo-like kinase 1 (Plk1) during mitosis. Parkin deficiency results in overexpression of its substrates, mitotic defects, genomic instability, and tumorigenesis. These results suggest that the Parkin-Cdc20/Cdh1 complex is an important regulator of mitosis.

WSB1 promotes tumor metastasis by inducing pVHL degradation.

The von Hippel-Lindau tumor suppressor pVHL is an E3 ligase that targets hypoxia-inducible factors (HIFs). Mutation of VHL results in HIF up-regulation and contributes to processes related to tumor progression such as invasion, metastasis, and angiogenesis. However, very little is known with regard to post-transcriptional regulation of pVHL. Here we show that WD repeat and SOCS box-containing protein 1 (WSB1) is a negative regulator of pVHL through WSB1's E3 ligase activity. Mechanistically, WSB1 promotes pVHL ubiquitination and proteasomal degradation, thereby stabilizing HIF under both normoxic and hypoxic conditions. As a consequence, WSB1 up-regulates the expression of HIF-1α's target genes and promotes cancer invasion and metastasis through its effect on pVHL. Consistent with this, WSB1 protein level negatively correlates with pVHL level and metastasis-free survival in clinical samples. This work reveals a new mechanism of pVHL's regulation by which cancer acquires invasiveness and metastatic tendency.

A divergent role of the SIRT1-TopBP1 axis in regulating metabolic checkpoint and DNA damage checkpoint.

DNA replication is executed only when cells have sufficient metabolic resources and undamaged DNA. Nutrient limitation and DNA damage cause a metabolic checkpoint and DNA damage checkpoint, respectively. Although SIRT1 activity is regulated by metabolic stress and DNA damage, its function in these stress-mediated checkpoints remains elusive. Here we report that the SIRT1-TopBP1 axis functions as a switch for both checkpoints. With glucose deprivation, SIRT1 is activated and deacetylates TopBP1, resulting in TopBP1-Treslin disassociation and DNA replication inhibition. Conversely, SIRT1 activity is inhibited under genotoxic stress, resulting in increased TopBP1 acetylation that is important for the TopBP1-Rad9 interaction and activation of the ATR-Chk1 pathway. Mechanistically, we showed that acetylation of TopBP1 changes the conformation of TopBP1, thereby facilitating its interaction with distinct partners in DNA replication and checkpoint activation. Taken together, our studies identify the SIRT1-TopBP1 axis as a key signaling mode in the regulation of the metabolic checkpoint and the DNA damage checkpoint.

The effects of cognitive behavioural therapy on depression and quality of life in patients with maintenance haemodialysis: a systematic review.

BACKGROUND: Depression is highly prevalent among Haemodialysis (HD) patients and is known to results in a series of adverse outcomes and poor quality of life (QoL). Although cognitive behavioural therapy (CBT) has been shown to improve depressive symptoms and QoL in other chronic illness, there is uncertainty in terms of the effectiveness of CBT in HD patients with depression or depressive symptoms. METHODS: All randomised controlled trials relevant to the topic were retrieved from the following databases: CINHAL, MEDLINE, PubMed, PsycINFO and CENTRAL. The grey literature, specific journals, reference lists of included studies and trials registers website were also searched. Data was extracted or calculated from included studies that had measured depression and quality of life using valid and reliable tools -this included mean differences or standardised mean differences and 95% confidence intervals. The Cochrane risk of bias tool was used to identify the methodological quality of the included studies. RESULTS: Six RCTs were included with varying methodological quality. Meta-analysis was undertaken for 3 studies that employed the CBT versus usual care. All studies showed that the depressive symptoms significantly improved after the CBT. Furthermore, CBT was more effective than usual care (MD = - 5.28, 95%CI - 7.9 to - 2.65, P = 0.37) and counselling (MD = - 2.39, 95%CI - 3.49 to - 1.29), while less effective than sertraline (MD = 2.2, 95%CI 0.43 to 3.97) in alleviating depressive symptoms. Additionally, the CBT seems to have a beneficial effect in improving QoL when compared with usual care, while no significant difference was found in QoL score when compared CBT with sertraline. CONCLUSIONS: CBT may improve depressive symptoms and QoL in HD patients with comorbid depressive symptoms. However, more rigorous studies are needed in this field due to the small quantity and varied methodological quality in the identified studies.

Negative pressure wound therapy for treating pressure ulcers.

BACKGROUND: Pressure ulcers, also known as bedsores, decubitus ulcers and pressure injuries, are localised areas of injury to the skin or the underlying tissue, or both. Negative pressure wound therapy (NPWT) is a treatment option for pressure ulcers; a clear, current overview of the evidence is required to facilitate decision-making regarding its use. OBJECTIVES: To assess the effects of negative pressure wound therapy for treating pressure ulcers in any care setting. SEARCH METHODS: For this review, we searched the following databases in May 2015: the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. There were no restrictions based on language or date of publication. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) comparing the effects of NPWT with alternative treatments or different types of NPWT in the treatment of pressure ulcers (stage II or above). DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: The review contains four studies with a total of 149 participants. Two studies compared NPWT with dressings; one study compared NPWT with a series of gel treatments and one study compared NPWT with 'moist wound healing'. One study had a 24-week follow-up period, and two had a six-week follow-up period, the follow-up time was unclear for one study. Three of the four included studies were deemed to be at a high risk of bias from one or more 'Risk of bias' domains and all evidence was deemed to be of very low quality. Only one study reported usable primary outcome data (complete wound healing), but this had only 12 participants and there were very few events (only one participant healed in the study). There was little other useful data available from the included studies on positive outcomes such as wound healing or negative outcomes such as adverse events. AUTHORS' CONCLUSIONS: There is currently no rigorous RCT evidence available regarding the effects of NPWT compared with alternatives for the treatment of pressure ulcers. High uncertainty remains about the potential benefits or harms, or both, of using this treatment for pressure ulcer management.

Negative pressure wound therapy for treating leg ulcers.

BACKGROUND: Leg ulcers are open skin wounds that occur between the ankle and the knee that can last weeks, months or even years and are a consequence of arterial or venous valvular insufficiency. Negative pressure wound therapy (NPWT) is a technology that is currently used widely in wound care and is promoted for use on wounds. NPWT involves the application of a wound dressing to the wound, to which a machine is attached. The machine applies a carefully controlled negative pressure (or vacuum), which sucks any wound and tissue fluid away from the treated area into a canister. OBJECTIVES: To assess the effects of negative pressure wound therapy (NPWT) for treating leg ulcers in any care setting. SEARCH METHODS: For this review, in May 2015 we searched the following databases: the Cochrane Wounds Group Specialised Register (searched 21 May 2015); the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2015, Issue 4); Ovid MEDLINE (1946 to 20 May 2015); Ovid MEDLINE (In-Process & Other Non-Indexed Citations 20 May 2015); Ovid EMBASE (1974 to 20 May 2015); EBSCO CINAHL (1982 to 21 May 2015). There were no restrictions based on language or date of publication. SELECTION CRITERIA: Published or unpublished randomized controlled trials (RCTs) comparing the effects of NPWT with alternative treatments or different types of NPWT in the treatment of leg ulcers. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: We included one study, with 60 randomized participants, in the review. The study population had a range of ulcer types that were venous arteriolosclerotic and venous/arterial in origin. Study participants had recalcitrant ulcers that had not healed after treatment over a six-month period. Participants allocated to NPWT received continuous negative pressure until they achieved 100% granulation (wound preparation stage). A punch skin-graft transplantation was conducted and the wound then exposed to further NPWT for four days followed by standard care. Participants allocated to the control arm received standard care with dressings and compression until 100% granulation was achieved. These participants also received a punch skin-graft transplant and then further treatment with standard care. All participants were treated as in-patients until healing occurred.There was low quality evidence of a difference in time to healing that favoured the NPWT group: the study reported an adjusted hazard ratio of 3.2, with 95% confidence intervals (CI) 1.7 to 6.2. The follow-up period of the study was a minimum of 12 months. There was no evidence of a difference in the total number of ulcers healed (29/30 in each group) over the follow-up period; this finding was also low quality evidence.There was low quality evidence of a difference in time to wound preparation for surgery that favoured NPWT (hazard ratio 2.4, 95% CI 1.2 to 4.7).Limited data on adverse events were collected: these provided low quality evidence of no difference in pain scores and Euroqol (EQ-5D) scores at eight weeks after surgery. AUTHORS' CONCLUSIONS: There is limited rigorous RCT evidence available concerning the clinical effectiveness of NPWT in the treatment of leg ulcers. There is some evidence that the treatment may reduce time to healing as part of a treatment that includes a punch skin graft transplant, however, the applicability of this finding may be limited by the very specific context in which NPWT was evaluated. There is no RCT evidence on the effectiveness of NPWT as a primary treatment for leg ulcers.

E7-mediated repression of miR-203 promotes LASP1-dependent proliferation in HPV-positive cervical cancer.

Human papillomaviruses (HPV) are a major cause of malignancy, contributing to ∼5% of all human cancers worldwide, including most cervical cancer cases and a growing number of ano-genital and oral cancers. The major HPV viral oncogenes, E6 and E7, manipulate many host cellular pathways that promote cell proliferation and survival, predisposing infected cells to malignant transformation. Despite the availability of highly effective vaccines, there are still no specific anti-viral therapies targeting HPV or treatments for HPV-associated cancers. As such, a better understanding of viral-host interactions may allow the identification of novel therapeutic targets. Here, we demonstrate that the actin-binding protein LASP1 is upregulated in cervical cancer and significantly correlates with a poorer overall survival. In HPV positive cervical cancer, LASP1 depletion significantly inhibited proliferation in vitro , whilst having minimal effects in HPV negative cervical cancer cells. Furthermore, we show that the LASP1 SH3 domain is essential for LASP1-mediated proliferation in these cells. Mechanistically, we show that HPV E7 regulates LASP1 at the post-transcriptional level by repressing the expression of miR-203, which negatively regulated LASP1 mRNA levels by binding to its 3'UTR. Finally, we demonstrated that LASP1 expression is required for the growth of HPV positive cervical cancer cells in an in vivo tumourigenicity model. Together, these data demonstrate that HPV induces LASP1 expression to promote proliferation and survival role in cervical cancer, thus identifying a potential therapeutic target in these cancers.

E7-mediated repression of miR-203 promotes LASP1-dependent proliferation in HPV-positive cervical cancer.

Human papillomaviruses (HPV) are a major cause of malignancy, contributing to ~5% of all human cancers worldwide, including most cervical cancer cases and a growing number of anogenital and oral cancers. The major HPV viral oncogenes, E6 and E7, manipulate many host cellular pathways that promote cell proliferation and survival, predisposing infected cells to malignant transformation. Despite the availability of highly effective vaccines, there are still no specific anti-viral therapies targeting HPV or treatments for HPV-associated cancers. As such, a better understanding of viral-host interactions may allow the identification of novel therapeutic targets. Here, we demonstrate that the actin-binding protein LASP1 is upregulated in cervical cancer and significantly correlates with a poorer overall survival. In HPV positive cervical cancer, LASP1 depletion significantly inhibited the oncogenic phenotype in vitro, whilst having minimal effects in HPV negative cervical cancer cells. Furthermore, we demonstrate that the LASP1 SH3 domain is essential for LASP1-mediated oncogenicity in these cells. Mechanistically, we show that HPV E7 regulates LASP1 at the post-transcriptional level by repressing the expression of miR-203, which negatively regulates LASP1 mRNA levels by binding to its 3'UTR. Finally, we demonstrate that LASP1 expression is required for the growth of HPV positive cervical cancer cells in an in vivo tumourigenicity model. Together, these data demonstrate that HPV induces LASP1 expression to promote proliferation and survival in cervical cancer, thus identifying a potential therapeutic target in these cancers.

Exploitation of ATP-sensitive potassium ion (KATP) channels by HPV promotes cervical cancer cell proliferation by contributing to MAPK/AP-1 signalling.

Persistent infection with high-risk human papillomaviruses (HPVs) is the causal factor in multiple human malignancies, including >99% of cervical cancers and a growing proportion of oropharyngeal cancers. Prolonged expression of the viral oncoproteins E6 and E7 is necessary for transformation to occur. Although some of the mechanisms by which these oncoproteins contribute to carcinogenesis are well-characterised, a comprehensive understanding of the signalling pathways manipulated by HPV is lacking. Here, we present the first evidence to our knowledge that the targeting of a host ion channel by HPV can contribute to cervical carcinogenesis. Through the use of pharmacological activators and inhibitors of ATP-sensitive potassium ion (KATP) channels, we demonstrate that these channels are active in HPV-positive cells and that this activity is required for HPV oncoprotein expression. Further, expression of SUR1, which forms the regulatory subunit of the multimeric channel complex, was found to be upregulated in both HPV+ cervical cancer cells and in samples from patients with cervical disease, in a manner dependent on the E7 oncoprotein. Importantly, knockdown of SUR1 expression or KATP channel inhibition significantly impeded cell proliferation via induction of a G1 cell cycle phase arrest. This was confirmed both in vitro and in in vivo tumourigenicity assays. Mechanistically, we propose that the pro-proliferative effect of KATP channels is mediated via the activation of a MAPK/AP-1 signalling axis. A complete characterisation of the role of KATP channels in HPV-associated cancer is now warranted in order to determine whether the licensed and clinically available inhibitors of these channels could constitute a potential novel therapy in the treatment of HPV-driven cervical cancer.

Isolation, characterization, and DNA binding kinetics of three dirhodium(II,II) carboxyamidate complexes: Rh2(µ-L)(HNOCCF3)3 where L= [OOCCH3]-, [OOCCF3]-, or [HNOCCF3]-.

Several transition metal compounds are effective antitumor drugs whose biological activity can be attributed to their ability to bind deoxyribonucleic acid (DNA). In this study, DNA-binding experiments reveal that changing one bridging ligand on compounds with the general formula Rh(2)(µ-L)(HNOCCF(3))(3) alters the rate of DNA-binding by greater than 100-fold with µ-L = trifluoroacetate ≫ acetate > trifluoroacetamidate. These three dirhodium compounds are isolated as the major products of the reaction between Rh(2)(OOCCH(3))(4) and trifluoroacetamide in either refluxing chlorobenzene or molten trifluoroacetamide and have been characterized by NMR and LC/MS. By using (15)N-enriched trifluoroacetamide, NMR spectroscopy was used to assign the cis-(2,1) orientations of Rh(2)(µ-L)(HNOCCF(3))(3) compounds where µ-L = trifluoroacetate or acetate. This is the first report of Rh(2)(OOCCF(3))(HNOCCF(3))(3), a novel compound that may play a significant role in the biological and/or catalytic activity of compound mixtures commonly isolated as "Rh(2)(HNOCCF(3))(4)".

Topical negative pressure for treating chronic wounds.

BACKGROUND: Chronic wounds mainly affect the elderly and those with multiple health problems. Despite the use of modern dressings, some of these wounds take a long time to heal, fail to heal, or recur, causing significant pain and discomfort to the person and cost to health services. Topical negative pressure (TNP) is used to promote healing of surgical wounds by using suction to drain excess fluid from wounds. OBJECTIVES: To assess the effects of TNP on chronic wound healing. SEARCH STRATEGY: For this second update of this review we searched the Cochrane Wounds Group Specialised Register (December 2007), The Cochrane Central Register of Controlled Trials (CENTRAL) - The Cochrane Library Issue 4, 2007, Ovid MEDLINE - 1950 to November Week 2 2007, Ovid EMBASE - 1982 to 2007 Week 50 and Ovid CINAHL - 1980 to December Week 1 2007. In addition, we contacted authors, companies, manufacturers, and distributors to identify relevant trials and information. SELECTION CRITERIA: All randomised controlled trials which evaluated the effects of TNP on people with chronic wounds. DATA COLLECTION AND ANALYSIS: Selection of the trials, quality assessment, data abstraction, and data synthesis were done by two authors independently. Disagreements were solved by discussion. MAIN RESULTS: Two trials were included in the original review. A further five trials were included in this second update resulting in a total of seven trials involving 205 participants. The seven trials compared TNP with five different comparator treatments. Four trials compared TNP with gauze soaked in either 0.9% saline or Ringer's solution. The other three trials compared TNP with hydrocolloid gel plus gauze, a treatment package comprising papain-urea topical treatment, and cadexomer iodine or hydrocolloid, hydrogels, alginate and foam. These data do not show that TNP significantly increases the healing rate of chronic wounds compared with comparators. Data on secondary outcomes such as infection rate, quality of life, oedema, hospitalisation and bacterial load were not reported. AUTHORS' CONCLUSIONS: Trials comparing TNP with alternative treatments for chronic wounds have methodological flaws and data do demonstrate a beneficial effect of TNP on wound healing however more, better quality research is needed.

Coping with continence problems at work.

Debra Evans reports the results of explanatory research that explored the impact of continence problems on the ability to work.

Faecal incontinence products and quality of life.

Faecal incontinence has been defined as the involuntary or inappropriate passage of faeces (Royal College of Physicians, 1995). It is a distressing and isolating problem that affects people of all ages, with an estimated incidence of 1-2 per cent of the population (Soffer and Hull, 2000). Many people must rely on continence products to manage this stigmatising and embarrassing problem.

MMSET is dynamically regulated during cell-cycle progression and promotes normal DNA replication.

The timely and precise duplication of cellular DNA is essential for maintaining genome integrity and is thus tightly-regulated. During mitosis and G1, the Origin Recognition Complex (ORC) binds to future replication origins, coordinating with multiple factors to load the minichromosome maintenance (MCM) complex onto future replication origins as part of the pre-replication complex (pre-RC). The pre-RC machinery, in turn, remains inactive until the subsequent S phase when it is required for replication fork formation, thereby initiating DNA replication. Multiple myeloma SET domain-containing protein (MMSET, a.k.a. WHSC1, NSD2) is a histone methyltransferase that is frequently overexpressed in aggressive cancers and is essential for normal human development. Several studies have suggested a role for MMSET in cell-cycle regulation; however, whether MMSET is itself regulated during cell-cycle progression has not been examined. In this study, we report that MMSET is degraded during S phase in a cullin-ring ligase 4-Cdt2 (CRL4(Cdt2)) and proteasome-dependent manner. Notably, we also report defects in DNA replication and a decreased association of pre-RC factors with chromatin in MMSET-depleted cells. Taken together, our results suggest a dynamic regulation of MMSET levels throughout the cell cycle, and further characterize the role of MMSET in DNA replication and cell-cycle progression.

HEATR1 Negatively Regulates Akt to Help Sensitize Pancreatic Cancer Cells to Chemotherapy.

Elucidating mechanisms of chemoresistance is critical to improve cancer therapy, especially for the treatment of pancreatic ductal adenocarcinoma (PDAC). Genome-wide association studies have suggested the less studied gene HEAT repeat-containing protein 1 (HEATR1) as a possible determinant of cellular sensitivity to different chemotherapeutic drugs. In this study, we assessed this hypothesized link in PDAC, where HEATR1 expression is downregulated significantly. HEATR1 silencing in PDAC cells increased resistance to gemcitabine and other chemotherapeutics, where this effect was associated with increased AKT kinase phosphorylation at the Thr308 regulatory site. Mechanistically, HEATR1 enhanced cell responsiveness to gemcitabine by acting as a scaffold to facilitate interactions between AKT and the protein phosphatase PP2A, thereby promoting Thr308 dephosphorylation. Consistent with these findings, treatment with the AKT inhibitor triciribine sensitized HEATR1-depleted PDAC cells to gemcitabine, suggesting that this therapeutic combination may overcome gemcitabine resistance in patients with low HEATR1 expression. Clinically, we found that HEATR1 downregulation in PDAC patients was associated with increased AKT phosphorylation, poor response to tumor resection plus gemcitabine standard-of-care treatment, and shorter overall survival. Collectively, our findings establish HEATR1 as a novel regulator of AKT and a candidate predictive and prognostic indicator of drug responsiveness and outcome in PDAC patients.

A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice.

BRCA1 is an important mediator of the DNA damage response, which promotes homologous recombination (HR) and antagonizes 53BP1-dependent non-homologous end joining in S/G2 phase. But how this is achieved remains unclear. Here, we report that the E3 ubiquitin ligase UHRF1 (Ubiquitin-like, with PHD and RING finger domains 1) directly participates in the interplay between BRCA1 and 53BP1. Mechanistically, UHRF1 is recruited to DNA double-strand breaks (DSBs) by BRCA1 in S phase, which requires the BRCT domain of BRCA1 and phosphorylated Ser674 of UHRF1. Subsequently, UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation. Thus, UHRF1 is a key regulator of DSB repair choice, which is separate from its role in heterochromatin formation and epigenetic regulator.

Lifestyle solutions for men with continence problems.

The prevalence of urinary incontinence in men is over one in 33 in those aged 15-64, and is estimated to be between one in 10 and one in 14 in men aged 65 and over (Department of Health, 2000). It is estimated that faecal incontinence affects one per cent of adults in their own home, with 17 per cent of the very elderly reporting symptoms (DoH, 2000). In many cases, incontinence can be successfully treated following assessment and appropriate management, but when continence cannot be achieved, containment products should be introduced. Men with continence problems often take many years to overcome their embarrassment and to seek help for bladder or bowel problems.

Discreet products for children and teenagers with continence problems.

The National Service Framework for Children, Young People and Maternity Services (Department of Health, 2004a) estimates that 'at least 500,000 children suffer from nocturnal enuresis, and a significant number with daytime wetting and faecal incontinence'. The NSF also acknowledges that 'incontinence is distressing for children and young people; it can lead to bullying at school and cause emotional and behavioural problems'.

Discreet products for women with urinary incontinence.

It is estimated that 10 million women in the UK suffer with urinary incontinence (Hunskarr et al, 2004). Many women consider bladder weakness to be an inevitable consequence of childbirth or the menopause. Haslam (2004) reported on a telephone survey that examined whether women were aware of stress urinary incontinence, their attitude to it and the impact it had on their daily lives. In the UK, 505 women were interviewed, 206 of whom responded positively to a question about symptoms of stress urinary incontinence, giving a prevalence rate of 41 per cent. There is also evidence that most patients with urinary incontinence do not present to their doctors