The chromoshadow domain (CSD) of heterochromatin protein 1 (HP1) was recently shown to contribute to chromatin binding and transcriptional regulation through interaction with histone H3. Here, we ...demonstrate the structural basis of this interaction for the CSD of HP1α. This mode of H3 binding is dependent on dimerization of the CSD and recognition of a PxVxL-like motif, as for other CSD partners. NMR chemical shift mapping showed that the H3 residues that mediate the CSD interaction occur in and adjacent to the αN helix just within the nucleosome core. Access to the binding region would require some degree of unwrapping of the DNA near the nucleosomal DNA entry/exit site.
Heterochromatin protein 1 (HP1) is a non-histone chromatin protein that interacts with histone H3 through both the chromodomain and chromoshadow domain.
The chromoshadow domain specifically interacts with H3 residues located inside the nucleosome, close to the dyad.
Rearrangement of the nucleosomal DNA is a prerequisite for binding.
This interaction provides new insight into the structure of silenced chromatin.
IntroductionThe number of older adults diagnosed with cancer is increasing. Older adults are more likely to have pre-existing frailty, which is associated with greater chemotherapy-related toxicity. ...Early identification of those at risk of toxicity is important to reduce patient morbidity and mortality. Current chemotherapy toxicity prediction tools including the Cancer and Ageing Research Group (CARG) tool exist but are not in routine clinical use and have not been prospectively validated in a UK population. This study is the first prospective study to investigate the CARG tool in a UK population with cancer.Methods and analysisTolerance Of Anticancer Systemic Therapy In the Elderly is a prospective observational study of patients, aged ≥65 years, commencing first-line (any indication) chemotherapy for a solid-organ malignancy. Patients receiving other systemic anticancer agents or radiotherapy will be excluded. The primary objective will be to validate the ability of the CARG score to predict grade 3+ toxicity in this population. Secondary objectives include describing the feasibility of screening for frailty, as well as the prevalance of frailty in this population and assessing patient and clinician perception of chemotherapy toxicity risk. 500 patients will be recruited over a two year period. Baseline assessments will be recorded. At the end of the 6-month follow-up period, toxicity data will be retrospectively collected. A descriptive analysis of the recruited population will be performed. The validity of the CARG model will be analysed using receiver-operating characteristic curves and calculation of the area under the curve (c-statistic).Ethics and disseminationThe study has received ethical approval from the East of Scotland Research Ethics Service 20/ES/0114. Results will be reported in peer-reviewed scientific journals and disseminated to patient organisations and media.
Patients with cancer are purported to have poor COVID-19 outcomes. However, cancer is a heterogeneous group of diseases, encompassing a spectrum of tumour subtypes. The aim of this study was to ...investigate COVID-19 risk according to tumour subtype and patient demographics in patients with cancer in the UK.
We compared adult patients with cancer enrolled in the UK Coronavirus Cancer Monitoring Project (UKCCMP) cohort between March 18 and May 8, 2020, with a parallel non-COVID-19 UK cancer control population from the UK Office for National Statistics (2017 data). The primary outcome of the study was the effect of primary tumour subtype, age, and sex and on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and the case–fatality rate during hospital admission. We analysed the effect of tumour subtype and patient demographics (age and sex) on prevalence and mortality from COVID-19 using univariable and multivariable models.
319 (30·6%) of 1044 patients in the UKCCMP cohort died, 295 (92·5%) of whom had a cause of death recorded as due to COVID-19. The all-cause case–fatality rate in patients with cancer after SARS-CoV-2 infection was significantly associated with increasing age, rising from 0·10 in patients aged 40–49 years to 0·48 in those aged 80 years and older. Patients with haematological malignancies (leukaemia, lymphoma, and myeloma) had a more severe COVID-19 trajectory compared with patients with solid organ tumours (odds ratio OR 1·57, 95% CI 1·15–2·15; p<0·0043). Compared with the rest of the UKCCMP cohort, patients with leukaemia showed a significantly increased case–fatality rate (2·25, 1·13–4·57; p=0·023). After correction for age and sex, patients with haematological malignancies who had recent chemotherapy had an increased risk of death during COVID-19-associated hospital admission (OR 2·09, 95% CI 1·09–4·08; p=0·028).
Patients with cancer with different tumour types have differing susceptibility to SARS-CoV-2 infection and COVID-19 phenotypes. We generated individualised risk tables for patients with cancer, considering age, sex, and tumour subtype. Our results could be useful to assist physicians in informed risk–benefit discussions to explain COVID-19 risk and enable an evidenced-based approach to national social isolation policies.
University of Birmingham and University of Oxford.
Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival ...remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol‐metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study‐specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol‐metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer‐specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta‐analysed using fixed‐effect and random‐effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed‐effect meta‐analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed = 0.78; 95% confidence interval (95%CI):0.66,0.91; p values = 0.002); rs12910509, HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.003); and rs8041922 (HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed = 1.43; 95%CI:1.14,1.79; p values = 0.002) was associated with prostate cancer mortality in men with low‐grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression.
What's new?
Alcohol may spur prostate cancer progression, though it does not appear to affect incidence, according to new analysis. Variation in genes involved in alcohol metabolism affect how much the body is exposed to carcinogenic metabolites. These authors examined 68 genetic variants in alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes, seeking a link with prostate cancer risk. While they found no evidence that these variants alter prostate cancer incidence, they did show that SNPs in the ALDH1A2 gene affect prostate cancer mortality. From a public health standpoint, these results suggest reducing alcohol consumption could slow prostate cancer disease progression.
Large cohorts of patients with active cancers and COVID-19 infection are needed to provide evidence of the association of recent cancer treatment and cancer type with COVID-19 mortality.
To evaluate ...whether systemic anticancer treatments (SACTs), tumor subtypes, patient demographic characteristics (age and sex), and comorbidities are associated with COVID-19 mortality.
The UK Coronavirus Cancer Monitoring Project (UKCCMP) is a prospective cohort study conducted at 69 UK cancer hospitals among adult patients (≥18 years) with an active cancer and a clinical diagnosis of COVID-19. Patients registered from March 18 to August 1, 2020, were included in this analysis.
SACT, tumor subtype, patient demographic characteristics (eg, age, sex, body mass index, race and ethnicity, smoking history), and comorbidities were investigated.
The primary end point was all-cause mortality within the primary hospitalization.
Overall, 2515 of 2786 patients registered during the study period were included; 1464 (58%) were men; and the median (IQR) age was 72 (62-80) years. The mortality rate was 38% (966 patients). The data suggest an association between higher mortality in patients with hematological malignant neoplasms irrespective of recent SACT, particularly in those with acute leukemias or myelodysplastic syndrome (OR, 2.16; 95% CI, 1.30-3.60) and myeloma or plasmacytoma (OR, 1.53; 95% CI, 1.04-2.26). Lung cancer was also significantly associated with higher COVID-19-related mortality (OR, 1.58; 95% CI, 1.11-2.25). No association between higher mortality and receiving chemotherapy in the 4 weeks before COVID-19 diagnosis was observed after correcting for the crucial confounders of age, sex, and comorbidities. An association between lower mortality and receiving immunotherapy in the 4 weeks before COVID-19 diagnosis was observed (immunotherapy vs no cancer therapy: OR, 0.52; 95% CI, 0.31-0.86).
The findings of this study of patients with active cancer suggest that recent SACT is not associated with inferior outcomes from COVID-19 infection. This has relevance for the care of patients with cancer requiring treatment, particularly in countries experiencing an increase in COVID-19 case numbers. Important differences in outcomes among patients with hematological and lung cancers were observed.
Women Veterans with co-morbid medical and mental health conditions face persistent barriers accessing high-quality health care. Evidence-based quality improvement (EBQI) offers a systematic approach ...to implementing new care models that can address care gaps for women Veterans.
This study examines factors associated with the successful deployment of EBQI within integrated health systems to improve primary care for women Veterans with complex mental health needs.
Following a 12-site (8 EBQI, 4 control) cluster randomized study to evaluate EBQI effectiveness, we conducted an in-depth case study analysis of one women's health clinic that used EBQI to improve integrated primary care-mental health services for women Veterans.
Our study sample included providers, program managers, and clinic staff at a women Veteran's health clinic that, at the time of the study, had one Primary Care and Mental Health Integration team and one women's health primary care provider serving 800 women. We analyzed interviews conducted 12 months, 24 months, and 4 years post-implementation and call summaries between the clinic and support team.
We conducted qualitative thematic analysis of interview and call summary data to identify EBQI elements, clinic characteristics, and reported challenges and successes within project development and execution.
The clinic harnessed core EBQI elements (multi-level stakeholder engagement, data-driven progress-monitoring, PDSA cycles, sharing results) to accomplish pre-defined project goals, strengthen inter-disciplinary partnerships, and bolster team confidence. Clinic characteristics that facilitated implementation success included prior QI experience and an organizational culture responsive to innovation, while lack of pre-existing guidelines and limited access to centralized databases posed implementation challenges.
Successful practice transformation emerges through the interaction of evidence-based methods and site-specific characteristics. Examining how clinic characteristics support or impede EBQI adaptation can facilitate efforts to improve care within integrated health systems.
Cell-fate decisions and pluripotency are dependent on networks of key transcriptional regulators. Recent reports demonstrated additional functions of pluripotency-associated factors during early ...lineage commitment. The T-box transcription factor TBX3 has been implicated in regulating embryonic stem cell self-renewal and cardiogenesis. Here, we show that TBX3 is dynamically expressed during specification of the mesendoderm lineages in differentiating embryonic stem cells (ESCs) in vitro and in developing mouse and Xenopus embryos in vivo. Forced TBX3 expression in ESCs promotes mesendoderm specification by directly activating key lineage specification factors and indirectly by enhancing paracrine Nodal/Smad2 signaling. TBX3 loss-of-function analyses in the Xenopus underline its requirement for mesendoderm lineage commitment. Moreover, we uncovered a functional redundancy between TBX3 and Tbx2 during Xenopus gastrulation. Taken together, we define further facets of TBX3 actions and map TBX3 as an upstream regulator of the mesendoderm transcriptional program during gastrulation.
The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGFbeta-FMs), such as BMP4 (ref. 1). ...By diffusing through extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation and suggest that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species.
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