A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

PSYCHOSEXUAL MORBIDITY IN WOMEN WITH OVARIAN CANCER:A REVIEW ARTICLE

Increasing numbers of women are surviving for longer with epithelial ovarian cancer. Consequently, there is increased focus on long-term quality of life in national guidance. Psychosexual morbidity including vaginal dryness, pain during intercourse (dyspareunia), reduced libido and negative perceived body-image exacerbate stress and anxiety and impact intimate relationships. Although a priority for women with epithelial ovarian cancer, clinicians seldom discuss sexual problems. Therefore, psychosexual morbidity and the associated distress remain unaddressed. Here, we synthesise evidence from primary qualitative and quantitative research studies exploring psychosexual morbidity in women with epithelial ovarian cancer to identify potential risk factors and common symptoms, to facilitate the identification and management of sexual problems in clinic. Literature (2008-19) from ten databases identified 29 suitable publications (patients n=4,116). The manuscripts were assessed to answer “What are the key potential risk factors and presentations of psychosexual morbidity in women with epithelial ovarian cancer?” <br/

Psychosexual morbidity in women with ovarian cancer

Increasing numbers of women are surviving for longer with epithelial ovarian cancer. Consequently, there is increased focus on long-term quality of life in national guidance. Psychosexual morbidity including vaginal dryness, pain during intercourse (dyspareunia), reduced libido, and negative perceived body image exacerbate stress and anxiety and impact intimate relationships. Although a priority for women with epithelial ovarian cancer, clinicians seldom discuss sexual problems. Therefore, psychosexual morbidity and the associated distress remain unaddressed. We synthesize evidence from primary qualitative and quantitative research studies exploring psychosexual morbidity in women with epithelial ovarian cancer to identify potential risk factors and common symptoms, to facilitate the identification and management of sexual problems in clinic. Literature (2008–19) from 10 databases identified 29 suitable publications (4116 patients). The papers were assessed to answer the question: “What are the key potential risk factors and presentations of psychosexual morbidity in women with epithelial ovarian cancer?” Current literature lacks consensus in defining clinically significant psychosexual morbidity in women with epithelial ovarian cancer. Discrepancies in measurement tools, questionnaires, and primary outcome measures confound result interpretation, limiting wider application. Key potential risk factors identified included: younger age (&lt;53 years); pre-menopausal status at diagnosis; aim of treatment; extent of surgery; more courses of chemotherapy; cardiovascular co-morbidities; and anxiety and depression. Up to 75% of women with epithelial ovarian cancer reported adverse changes in their sex lives following diagnosis and, of the sexually active, vaginal dryness affected 81–87% and pain 77%. Other prevalent symptoms included: reduced sexual desire and activity, impaired orgasm, diminished perceived body image, and reduced partner intimacy. Psychosexual morbidity represents a significant unmet need for women with epithelial ovarian cancer. Effective treatment necessitates a multimodal approach encompassing medical, psychoeducational, and physiotherapy-based strategies. Future studies need agreement in their questionnaires, definitions, thresholds, and primary outcome measures for meaningful interstudy comparisons to be drawn.</jats:p

Psychosexual Morbidity in Women With Ovarian Cancer: Evaluation by Germline BRCA Gene Mutational Status

Abstract Introduction Up to 75% of women with ovarian cancer experience psychosexual morbidity and approximately 15–20% of women with ovarian cancer have a germline BRCA1/2 mutation (gBRCAm). However, psychosexual morbidity remains unexplored in women with gBRCAm ovarian cancer. Aim Given their younger age, genetic diagnosis, breast cancer risk, and increased prevalence of surgically-induced menopause, we aim to assess whether women with gBRCAm ovarian cancer experience distinct psychosexual morbidity. Methods Psychosexual morbidity was investigated in 2 cohorts of women with ovarian cancer: women with gBRCAm ovarian cancer vs women with gBRCA wildtype (gBRCAwt) ovarian cancer. Between August 2019 and March 2020, women with high-grade serous carcinoma of the ovary, Fallopian tube or primary peritoneum were approached in clinic or telephoned and invited to take part. Exclusion criteria included: women with alternative histology; women admitted from clinic; and women who lacked capacity to independently complete the questionnaire. The Female Sexual Function Index (FSFI) and background information were collected at a single time-point per patient. Scores below 26.55 were interpreted to suggest psychosexual dysfunction. Main Outcome Measure Responses including total and domain FSFI scores, self-reported psychosexual problems and interest in psychosexual support were compared. Results Of 103 women approached, 53% returned questionnaires. In this exploratory analysis, women with gBRCAm ovarian cancer were significantly younger (51–60 years vs 61–70 years, gBRCAwt, P = .010). There was a trend towards increased prevalence of surgical menopause (57% vs 27%, P = .097) and breast surgery (53% vs 22%, P = .132, gBRCAm vs gBRCAwt, respectively). Women with gBRCAm ovarian cancer scored higher in the FSFI questionnaire, particularly women under 60 years (15.1 vs 2.7, P = .070), approaching significance. Women with gBRCAm ovarian cancer expressed more interest for face-to-face services (P = .018), especially psychosexual therapy (65% vs 30%) and more often felt the service was insufficient, approaching significance (71% vs 44%, gBRCAm vs gBRCAwt, respectively, P = .076). Conclusion Women with gBRCAm ovarian cancer are younger, express more interest for specialist psychosexual support and potentially different psychosexual problems, warranting further exploration. </jats:sec

The SKI complex is a broad-spectrum, host-directed antiviral drug target for coronaviruses, influenza, and filoviruses

Significance The SARS-CoV-2 pandemic of 2020 has highlighted the great need for antiviral therapeutics. In this work, we identify a host factor, the SKI complex, is involved in replication of influenza and coronaviruses. Using computational modeling we were able to identify chemicals that interact with the host factor that display broad-spectrum antiviral activity against influenza, coronaviruses, and filoviruses, all of which cause significant morbidity and mortality. Broad-spectrum antiviral therapeutics are sorely needed to combat known and unknown viral pathogens and the work presented here is our first step to developing antivirals to target the SKI complex.</jats:p

Histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation-independent blockade of the EGFR-Arf1 axis

Abstract Background A promising arsenal of histone deacetylase (HDAC)-targeted treatment has emerged in the past decade, as the abnormal targeting or retention of HDACs to DNA regulatory regions often occurs in many cancers. Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive malignancies worldwide associated with poor overall survival in late-stage patients. HDAC inhibitors have great potential to treat this devastating disease; however, few has been studied regarding the beneficial role of HDAC inhibition in anti-HNSCC therapy and the underlying molecular mechanisms remain elusive. Methods Cell migration and invasion were examined by wound closure and Transwell assays. Protein levels and interactions were assessed by Western blotting and immunoprecipitation. HDAC activity was measured with the fluorometric HDAC Activity Assay. Phospho-receptor tyrosine kinase (RTK) profiling was determined by the Proteome Profiler Human Phospho-RTK Array. Results ADP-ribosylation factor 1 (Arf1), a small GTPase coordinating vesicle-mediated intracellular trafficking, can be inactivated by HDAC inhibitors through histone acetylation-independent degradation of epidermal growth factor receptor (EGFR) in HNSCC cells. Mechanistically, high levels of Arf1 activity are maintained by binding to phosphorylated EGFR which is localized on HNSCC cell plasma membrane. Decreased EGFR phosphorylation is associated with reduced EGFR protein levels in the presence of TSA, which inactivates Arf1 and eventually inhibits invasion in HNSCC cells. Conclusions Our insights explore the critical role of EGFR-Arf1 complex in driving HNSCC progression, and demonstrate the selective action of HDAC inhibitors on this specific axis for suppressing HNSCC invasion. This novel finding represents the first example of modulating the EGFR-Arf1 complex in HNSCC by small molecule agents

Meta-analysis of genome-wide association studies identifies ancestry-specific associations underlying circulating total tau levels

Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10(-8). We additionally detected 14 novel loci at P < 5 × 10(-7), specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer's, and Parkinson's (F5, MAP1B, and BCAS3), with Alzheimer's pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry