Mte1 interacts with Mph1 and promotes crossover recombination and telomere maintenance

Mph1 is a member of the conserved FANCM family of DNA motor proteins that play key roles in genome maintenance processes underlying Fanconi anemia, a cancer predisposition syndrome in humans. Here, we identify Mte1 as a novel interactor of the Mph1 helicase in Saccharomyces cerevisiae. In vitro, Mte1 (Mph1-associated telomere maintenance protein 1) binds directly to DNA with a preference for branched molecules such as D loops and fork structures. In addition, Mte1 stimulates the helicase and fork regression activities of Mph1 while inhibiting the ability of Mph1 to dissociate recombination intermediates. Deletion of MTE1 reduces crossover recombination and suppresses the sensitivity of mph1Δ mutant cells to replication stress. Mph1 and Mte1 interdependently colocalize atDNAdamage-induced foci and dysfunctional telomeres, and MTE1 deletion results in elongated telomeres. Taken together, our data indicate that Mte1 plays a role in regulation of crossover recombination, response to replication stress, and telomere maintenance

The Smc5/6 complex regulates the yeast Mph1 helicase at RNA-DNA hybrid-mediated DNA damage

RNA-DNA hybrids are naturally occurring obstacles that must be overcome by the DNA replication machinery. In the absence of RNase H enzymes, RNA-DNA hybrids accumulate, resulting in replication stress, DNA damage and compromised genomic integrity. We demonstrate that Mph1, the yeast homolog of Fanconi anemia protein M (FANCM), is required for cell viability in the absence of RNase H enzymes. The integrity of the Mph1 helicase domain is crucial to prevent the accumulation of RNA-DNA hybrids and RNA-DNA hybrid-dependent DNA damage, as determined by Rad52 foci. Mph1 forms foci when RNA-DNA hybrids accumulate, e.g. in RNase H or THO-complex mutants and at short telomeres. Mph1, however is a double-edged sword, whose action at hybrids must be regulated by the Smc5/6 complex. This is underlined by the observation that simultaneous inactivation of RNase H2 and Smc5/6 results in Mph1-dependent synthetic lethality, which is likely due to an accumulation of toxic recombination intermediates. The data presented here support a model, where Mph1’s helicase activity plays a crucial role in responding to persistent RNA-DNA hybrids

Decision regret in men living with and beyond nonmetastatic prostate cancer in the United Kingdom: A population‐based patient‐reported outcome study

Objective: Clinical options for managing nonmetastatic prostate cancer (PCa) vary. Each option has side effects associated with it, leading to difficulty in decision‐making. This study aimed to assess the relationship between patient involvement in treatment decision‐making and subsequent decision regret (DR), and quantify the impact of health‐related quality of life (HRQL) outcomes on DR. Methods: Men living in the United Kingdom, 18 to 42 months after diagnosis of PCa, were identified from cancer registration data and sent a questionnaire. Measures included the Decision Regret Scale (DRS), Expanded Prostate cancer Index Composite short form (EPIC‐26), EQ‐5D‐5L, and an item on involvement in treatment decision‐making. Multivariable ordinal regression was utilized, with DR categorized as none, mild, or moderate/severe regret. Results: A total of 17 193 men with stage I‐III PCa completed the DRS: 36.6% reported no regret, 43.3% mild regret, and 20.0% moderate/severe regret. The odds of reporting DR were greater if men indicated their views were not taken into account odds ratio ([OR] = 6.42, 95% CI: 5.39‐7.64) or were involved “to some extent” in decision‐making (OR = 4.63, 95% CI: 4.27‐5.02), compared with men who were “definitely” involved. After adjustment, including for involvement, men reporting moderate/big problems with urinary, bowel, or sexual function were more likely to experience regret compared with men with no/small problems. Better HRQL scores were associated with lower levels of DR. Conclusions: This large‐scale study demonstrates the benefit of patient involvement in treatment decision‐making for nonmetastatic PCa. However, men experiencing side effects and poorer HRQL report greater DR. Promoting engagement in clinical decision‐making represents good practice and may reduce the risk of subsequent regret

Health-related quality of life after treatment for bladder cancer in England

Background Little is known about quality of life after bladder cancer treatment. This common cancer is managed using treatments that can affect urinary, sexual and bowel function. Methods To understand quality of life and inform future care, the Department of Health (England) surveyed adults surviving bladder cancer 1–5 years after diagnosis. Questions related to disease status, co-existing conditions, generic health (EQ-5D), cancer-generic (Social Difficulties Inventory) and cancer-specific outcomes (Functional Assessment of Cancer Therapy—Bladder). Results In total, 673 (54%) patients responded; including 500 (74%) men and 539 (80%) with co-existing conditions. Most respondents received endoscopic treatment (60%), while 92 (14%) and 99 (15%) received radical cystectomy or radiotherapy, respectively. Questionnaire completion rates varied (51–97%). Treatment groups reported ≥1 problem using EQ-5D generic domains (59–74%). Usual activities was the most common concern. Urinary frequency was common after endoscopy (34–37%) and radiotherapy (44–50%). Certain populations were more likely to report generic, cancer-generic and cancer-specific problems; notably those with co-existing long-term conditions and those treated with radiotherapy. Conclusion The study demonstrates the importance of assessing patient-reported outcomes in this population. There is a need for larger, more in-depth studies to fully understand the challenges patients with bladder cancer face

Regional variations in quality of survival among men with prostate cancer across the United Kingdom

Purpose: Prostate cancer incidence, treatment and survival rates vary throughout the United Kingdom (UK) but little is known about regional differences in quality of survival. Objective: To investigate variations in patient-reported outcomes between UK countries and English Cancer Alliances. Design, setting and participants: A cross-sectional postal survey of prostate cancer survivors diagnosed 18-42 months previously. Outcome measurements and statistical analysis: Urinary, bowel, sexual problems and vitality were patient reported using the EPIC-26 questionnaire. General health was also self-assessed. Regional variations were identified using multivariable log-linear regression. Results and limitations: 35,823 men responded; 60.8% of those invited. Self-assessed health was significantly lower than the UK average in Wales and Scotland. Respondents reported more urinary incontinence in Scotland, more urinary irritation/obstruction in Scotland and Northern Ireland (NI), poorer bowel function in Scotland and NI, worse sexual function in Scotland, and reduced vitality/hormonal function in Scotland, Wales and NI. Self-assessed health was poorer than the English average in South Yorkshire and North-East & Cumbria, with more urinary incontinence in North-East & Cumbria and Peninsula, greater sexual problems in West Midlands and poorer vitality in North-East & Cumbria and West Midlands. Limitations include difficulty identifying clinically significant differences and limited information on pre-treatment conditions. Conclusions: Despite adjustment for treatment, clinical and socio-demographic factors, quality of survival among prostate cancer survivors varied by area of residence. Adoption of best practice from areas performing well could support enhanced survival quality in poorer performing areas, particularly with regards bowel problems and vitality, where clinically relevant differences were reported. Patient summary: We conducted a UK-wide survey of patient’s quality of life after treatment for prostate cancer. Outcomes were found to vary depending upon where patients live. Different service providers need to ensure that all prostate cancer patients receive the same follow up care

Quality of life in men living with advanced and localised prostate cancer: A United Kingdom population-wide patient-reported outcome study of 30,000 men

Background. Little is known about the health-related quality of life (HRQL) of men living with advanced prostate cancer. We report population-wide functional outcomes and HRQL in men with all stages of prostate cancer, and identify implications for healthcare delivery. Methods. Men alive 18-42 months after diagnosis of prostate cancer were identified through cancer registration data. A postal survey was administered which contained validated measures to assess a) functional outcomes (EPIC-26 plus use of interventions for sexual dysfunction) and b) generic HRQL (EQ-5D-5L & self-assessed health). Log-linear and binary logistic regression models were used to compare functional outcomes and HRQL across diagnostic stage and self-reported treatment groups. Findings. 35,823 (60.8%) men responded. Stage was known for 85.8%; 19,599 (63.8%) stage I/II, 7,209 (23.4%) stage III, 3,925 (12.8%) stage IV. Functional outcomes: Poor sexual function was common (81.0%), regardless of stage, and over half of men (55.8%) received no intervention for this. Differences in urinary and bowel morbidity were greater with respect to treatment than stage. In men treated with androgen deprivation therapy (ADT), 30.7% reported moderate/big problems with hot flushes, 29.4% with lack of energy and 22.5% with weight gain. HRQL: Overall self-assessed health was similar in men with stage I-III disease, and whilst reduced in those with stage IV cancer, 23.5% with metastatic disease reported no problems on any EQ-5D dimension. Interpretation. Men diagnosed with advanced disease do not report markedly different HRQL outcomes to those diagnosed with localised disease, although substantial problems with hormonal function and fatigue are reported amongst men treated with ADT. Sexual dysfunction is common and the majority of men are not offered helpful intervention or support. Service improvements around sexual rehabilitation and measures to reduce the impact of ADT are required

The NANOGrav 12.5 yr Data Set: A Computationally Efficient Eccentric Binary Search Pipeline and Constraints on an Eccentric Supermassive Binary Candidate in 3C 66B

The radio galaxy 3C 66B has been hypothesized to host a supermassive black hole binary (SMBHB) at its center based on electromagnetic observations. Its apparent 1.05 yr period and low redshift (∼0.02) make it an interesting testbed to search for low-frequency gravitational waves (GWs) using pulsar timing array (PTA) experiments. This source has been subjected to multiple searches for continuous GWs from a circular SMBHB, resulting in progressively more stringent constraints on its GW amplitude and chirp mass. In this paper, we develop a pipeline for performing Bayesian targeted searches for eccentric SMBHBs in PTA data sets, and test its efficacy by applying it to simulated data sets with varying injected signal strengths. We also search for a realistic eccentric SMBHB source in 3C 66B using the NANOGrav 12.5 yr data set employing PTA signal models containing Earth term-only as well as Earth+pulsar term contributions using this pipeline. Due to limitations in our PTA signal model, we get meaningful results only when the initial eccentricity e 0 < 0.5 and the symmetric mass ratio η > 0.1. We find no evidence for an eccentric SMBHB signal in our data, and therefore place 95% upper limits on the PTA signal amplitude of 88.1 ± 3.7 ns for the Earth term-only and 81.74 ± 0.86 ns for the Earth+pulsar term searches for e 0 < 0.5 and η > 0.1. Similar 95% upper limits on the chirp mass are (1.98 ± 0.05) × 109 and (1.81 ± 0.01) × 109 M ☉. These upper limits, while less stringent than those calculated from a circular binary search in the NANOGrav 12.5 yr data set, are consistent with the SMBHB model of 3C 66B developed from electromagnetic observations

The NANOGrav 15-year Data Set: Search for Anisotropy in the Gravitational-Wave Background

The North American Nanohertz Observatory for Gravitational Waves (NANOGrav) has reported evidence for the presence of an isotropic nanohertz gravitational wave background (GWB) in its 15 yr dataset. However, if the GWB is produced by a population of inspiraling supermassive black hole binary (SMBHB) systems, then the background is predicted to be anisotropic, depending on the distribution of these systems in the local Universe and the statistical properties of the SMBHB population. In this work, we search for anisotropy in the GWB using multiple methods and bases to describe the distribution of the GWB power on the sky. We do not find significant evidence of anisotropy, and place a Bayesian $95\%$ upper limit on the level of broadband anisotropy such that $(C_{l>0} / C_{l=0}) < 20\%$. We also derive conservative estimates on the anisotropy expected from a random distribution of SMBHB systems using astrophysical simulations conditioned on the isotropic GWB inferred in the 15-yr dataset, and show that this dataset has sufficient sensitivity to probe a large fraction of the predicted level of anisotropy. We end by highlighting the opportunities and challenges in searching for anisotropy in pulsar timing array data.Comment: 19 pages, 11 figures; submitted to Astrophysical Journal Letters as part of Focus on NANOGrav's 15-year Data Set and the Gravitational Wave Background. For questions or comments, please email [email protected]

The NANOGrav 12.5 yr Data Set: Search for Gravitational Wave Memory

We present the results of a Bayesian search for gravitational wave (GW) memory in the NANOGrav 12.5 yr data set. We find no convincing evidence for any gravitational wave memory signals in this data set. We find a Bayes factor of 2.8 in favor of a model that includes a memory signal and common spatially uncorrelated red noise (CURN) compared to a model including only a CURN. However, further investigation shows that a disproportionate amount of support for the memory signal comes from three dubious pulsars. Using a more flexible red-noise model in these pulsars reduces the Bayes factor to 1.3. Having found no compelling evidence, we go on to place upper limits on the strain amplitude of GW memory events as a function of sky location and event epoch. These upper limits are computed using a signal model that assumes the existence of a common, spatially uncorrelated red noise in addition to a GW memory signal. The median strain upper limit as a function of sky position is approximately 3.3 × 10−14. We also find that there are some differences in the upper limits as a function of sky position centered around PSR J0613−0200. This suggests that this pulsar has some excess noise that can be confounded with GW memory. Finally, the upper limits as a function of burst epoch continue to improve at later epochs. This improvement is attributable to the continued growth of the pulsar timing array