BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors ...(PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity.
We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi.
RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor.
Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.
The discovery of cancer cell-selective tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis generated broad excitement and development of TRAIL receptor agonists (TRA) ...as potential cancer therapy. Studies demonstrating the synergistic combination effect of SMAC mimetics and TRA further suggested potentially effective treatment in multiple tumour settings. However, predictive biomarkers allowing identification of patients that could respond to treatment are lacking. Here, we described a high throughput combination screen conducted across a panel of 31 breast cancer cell lines in which we observed highly synergistic activity between TRAIL and the inhibitors of apoptosis proteins (IAP) inhibitor (IAPi) AZD5582 in ~30% of cell lines. We detected no difference in the expression levels of the IAPi or TRAIL-targeted proteins or common modulators of the apoptotic pathway between the sensitive and resistant cell lines. Synergistic combination effect of AZD5582 and TRAIL correlated with sensitivity to TRAIL, but not to AZD5582 as a single agent. TRAIL treatment led to significantly greater activity of Caspase-8 in sensitive than in resistant cell lines (P=0.002). The majority (12/14) of AZD5582+TRAIL-resistant cell lines retained a functional cell death pathway, as they were sensitive to AZD5582+TNFα combination treatment. This suggested that failure of the TRAIL receptor complex to transduce the death signal to Caspase-8 underlies AZD5582+TRAIL resistance. We developed a 3D spheroid assay and demonstrated its suitability for the ex vivo analysis of the Caspase-8 activity as a predictive biomarker. Altogether, our study demonstrated a link between the functionality of the TRAIL receptor pathway and the synergistic activity of the IAPi+TRA combination treatment. It also provided a rationale for development of the Caspase-8 activity assay as a functional predictive biomarker that could allow better prediction of the response to IAPi+TRA-based therapies than the analysis of expression levels of protein biomarkers.
Prior research on donor monoclonal gammopathy of undetermined significance (MGUS) has been inadequate regarding the risk for lymphoproliferative disease in solid organ transplantation recipients. ...Seven organ recipients from two different donors developed lymphoproliferative disease. The origin of the malignancy was determined by use of microsatellite analysis, and the plasma of the two donors was analyzed with the use of electrophoresis. The clinical courses of the seven recipients were followed for 36–60 months. One donor transmitted lymphoplasmacytic lymphoma to two kidney recipients and MGUS to a liver recipient, all IgMκ. A second donor caused IgGλ myeloma in two kidney and one liver recipient, and IgGλ gammopathy in a heart recipient. Transplant nephrectomy was performed in three kidney recipients and remission was achieved. The fourth kidney recipient has kept the graft and the disease has progressed. The liver recipient died from myeloma. There were no clinical signs of lymphoproliferative disease in the donors, but retrospective serum analyses showed M‐components, IgMκ (37 g/L) and IgGλ (8 g/L). Donors with MGUS may cause donor‐transmitted malignancies via passenger lymphocytes/plasma cells in solid organ recipients. The results call for a large register study of the incidence of donor MGUS and lymphoproliferative disease in their recipients.
Two donors with unknown gammopathy transmitted lymphoproliferative disorders to seven solid organ recipients.
Nearly half of all cancers are treated with radiotherapy alone or in combination with other treatments, where damage to normal tissues is a limiting factor for the treatment. Radiotherapy-induced ...adverse health effects, mostly of importance for cancer patients with long-term survival, may appear during or long time after finishing radiotherapy and depend on the patient's radiosensitivity. Currently, there is no assay available that can reliably predict the individual's response to radiotherapy. We profiled two study sets from breast (
= 29) and head-and-neck cancer patients (
= 74) that included radiosensitive patients and matched radioresistant controls.. We studied 55 single nucleotide polymorphisms (SNPs) in 33 genes by DNA genotyping and 130 circulating proteins by affinity-based plasma proteomics. In both study sets, we discovered several plasma proteins with the predictive power to find radiosensitive patients (adjusted
< 0.05) and validated the two most predictive proteins (THPO and STIM1) by sandwich immunoassays. By integrating genotypic and proteomic data into an analysis model, it was found that the proteins CHIT1, PDGFB, PNKD, RP2, SERPINC1, SLC4A, STIM1, and THPO, as well as the
gene variant rs69947, predicted radiosensitivity of our breast cancer (AUC = 0.76) and head-and-neck cancer (AUC = 0.89) patients. In conclusion, circulating proteins and a SNP variant of
suggest that processes such as vascular growth capacity, immune response, DNA repair and oxidative stress/hypoxia may be involved in an individual's risk of experiencing radiation-induced toxicity.
Background
In this exploratory study, the impact of local irradiation on systemic changes in stress and immune parameters was investigated in eight patients treated with intensity-modulated radiation ...therapy (IMRT) or stereotactic ablative body radiotherapy (SABR) for prostate adenocarcinoma to gain deeper insights into how radiotherapy (RT) modulates the immune system.
Patients and methods
RT-qPCR, flow cytometry, metabolomics, and antibody arrays were used to monitor a panel of stress- and immune-related parameters before RT, after the first fraction (SABR) or the first week of treatment (IMRT), after the last fraction, and 3 weeks later in the blood of IMRT (
N
= 4) or SABR (
N
= 4) patients. Effect size analysis was used for comparison of results at different timepoints.
Results
Several parameters were found to be differentially modulated in IMRT and SABR patients: the expression of
TGFB1
,
IL1B
, and
CCL3
genes; the expression of HLA-DR on circulating monocytes; the abundance and ratio of phosphatidylcholine and lysophosphatidylcholine metabolites in plasma. More immune modulators in plasma were modulated during IMRT than SABR, with only two common proteins, namely GDF-15 and Tim‑3.
Conclusion
Locally delivered RT induces systemic modulation of the immune system in prostate adenocarcinoma patients. IMRT and SABR appear to specifically affect distinct immune components.
COPD is a civilization disease. It affects up to 8%-10% of population >30 years of age. Coexistence of depression occurs in 20%-40% of patients with COPD. Depression and anxiety reduce compliance and ...worsen prognosis.
The aims of this study were to determine the degree of illness acceptance among patients with COPD, to examine the relation between disease acceptance and perceived anxiety and depression, and to verify which of the sociodemographic and clinical factors are associated with illness acceptance, anxiety, and depression.
The study included 102 patients with COPD (mean age 65.8 years), hospitalized due to exacerbations. Acceptance of Illness Scale and Hospital Anxiety and Depression Scale were used. For statistical analysis, Student's t-test and Pearson's r correlation coefficient were carried out.
The overall illness acceptance level was moderate with a tendency toward lack of acceptance (mean 20.6, standard deviation SD 7.62). The overall scores were 10.2 (SD 3.32) for anxiety and 10.8 (SD 4.14) for depression, which indicate borderline or high intensity of these symptoms. Acceptance of illness was negatively correlated with the intensity of depression symptoms (r=-0.46, P<0.05). Intensity of depression was significantly associated with intensity of smoking, duration of the disease, severity of dyspnea, and living in a rural area.
Early identification and assessment of depression and anxiety symptoms allow health care providers to offer patients at risk of depression a special medical supervision. Rapid start of antidepressant therapy may increase illness acceptance and improve prognosis among patients with COPD.
Summary Background The incidence of type 1 diabetes in children younger than 15 years is increasing. Prediction of future incidence of this disease will enable adequate fund allocation for delivery ...of care to be planned. We aimed to establish 15-year incidence trends for childhood type 1 diabetes in European centres, and thereby predict the future burden of childhood diabetes in Europe. Methods 20 population-based EURODIAB registers in 17 countries registered 29 311 new cases of type 1 diabetes, diagnosed in children before their 15th birthday during a 15-year period, 1989–2003. Age-specific log linear rates of increase were estimated in five geographical regions, and used in conjunction with published incidence rates and population projections to predict numbers of new cases throughout Europe in 2005, 2010, 2015, and 2020. Findings Ascertainment was better than 90% in most registers. All but two registers showed significant yearly increases in incidence, ranging from 0·6% to 9·3%. The overall annual increase was 3·9% (95% CI 3·6–4·2), and the increases in the age groups 0–4 years, 5–9 years, and 10–14 years were 5·4% (4·8–6·1), 4·3% (3·8–4·8), and 2·9% (2·5–3·3), respectively. The number of new cases in Europe in 2005 is estimated as 15 000, divided between the 0–4 year, 5–9 year, and 10–14 year age-groups in the ratio 24%, 35%, and 41%, respectively. In 2020, the predicted number of new cases is 24 400, with a doubling in numbers in children younger than 5 years and a more even distribution across age-groups than at present (29%, 37%, and 34%, respectively). Prevalence under age 15 years is predicted to rise from 94 000 in 2005, to 160 000 in 2020. Interpretation If present trends continue, doubling of new cases of type 1 diabetes in European children younger than 5 years is predicted between 2005 and 2020, and prevalent cases younger than 15 years will rise by 70%. Adequate health-care resources to meet these children's needs should be made available. Funding European Community Concerted Action Program.
Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking.
To examine if children with early-life ...respiratory tract infections had increased risks of lower lung function and asthma at school-age.
We used individual-participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV
), forced vital capacity (FVC), FEV
/FVC, forced expiratory flow at 75% of FVC (FEF
), and asthma at a median age of 7 (range 4 to 15) years.
Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV
, FEV
/FVC and FEF
(Z-score (95% CI): ranging from -0.09 (-0.14, -0.04) to -0.30 (-0.36, -0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR (95%CI): ranging from 2.10 (1.98, 2.22) to 6.30 (5.64, 7.04)), and from 1.25 (1.18, 1.32) to 1.55 (1.47, 1.65)), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as proxy for early-life asthma.
Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower upper respiratory tract infections.
Working life, health and well-being of parents Ubalde-Lopez, Monica; Garani-Papadatos, Tina; Scelo, Ghislaine ...
Scandinavian journal of work, environment & health,
01/2021, Letnik:
47, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Birth cohorts collect valuable and under-utilized information on employment and health of parents before and during pregnancy, at birth, and sometimes after birth. In this discussion paper, we ...examine how these data could be exploited to study the complex relationships and interactions between parenthood, work, and health among parents themselves.
Using a web-based database of birth cohorts, we summarize information on maternal employment and health conditions and other potentially related variables in cohorts spread throughout Europe. This provided information on what data are available and could be used in future studies, and what was missing if specific questions are to be addressed, exploiting the opportunity to explore work-health associations across heterogenous geographical and social contexts.
We highlight the many potentialities provided by birth cohorts and identify gaps that need to be addressed to adopt a life-course approach and investigate topics specific to the peri-pregnancy period, such as psychosocial aspects. We address the technical difficulties implied by data harmonization and the ethical challenges related to the repurposing of data, and provide scientific, ecological and economic arguments in favor of improving the value of data already available as a result of a serious investment in human and material resources.
There is a hidden treasure in birth cohorts that deserves to be brought out to study the relationships between employment and health among working parents in a time when the boundaries between work and life are being stretched more than ever before.
Background
During the past 25 years, many pregnancy and birth cohorts have been established. Each cohort provides unique opportunities for examining associations of early‐life exposures with child ...development and health. However, to fully exploit the large amount of available resources and to facilitate cross‐cohort collaboration, it is necessary to have accessible information on each cohort and its individual characteristics. The aim of this work was to provide an overview of European pregnancy and birth cohorts registered in a freely accessible database located at http://www.birthcohorts.net.
Methods
European pregnancy and birth cohorts initiated in 1980 or later with at least 300 mother–child pairs enrolled during pregnancy or at birth, and with postnatal data, were eligible for inclusion. Eligible cohorts were invited to provide information on the data and biological samples collected, as well as the timing of data collection.
Results
In total, 70 cohorts were identified. Of these, 56 fulfilled the inclusion criteria encompassing a total of more than 500 000 live‐born European children. The cohorts represented 19 countries with the majority of cohorts located in Northern and Western Europe. Some cohorts were general with multiple aims, whilst others focused on specific health or exposure‐related research questions.
Conclusion
This work demonstrates a great potential for cross‐cohort collaboration addressing important aspects of child health. The web site, http://www.birthcohorts.net, proved to be a useful tool for accessing information on European pregnancy and birth cohorts and their characteristics.
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