Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases

Introduction

Seven SNPs in five genomic loci were recently found to confer a mildly increased risk of breast cancer.

Methods

We have investigated the correlations between disease characteristics and the patient genotypes of these SNPs in an unselected prospective cohort of 1,267 consecutive patients with primary breast cancer.

Results

Heterozygote carriers and minor allele homozygote carriers for SNP rs889312 in the MAP3K1 gene were less likely to be lymph node positive at breast cancer diagnosis (P = 0.044) relative to major allele homozygote carriers. Heterozygote carriers and minor allele homozygote carriers for SNP rs3803662 near the TNCR9 gene were more likely to be diagnosed before the age of 60 years (P = 0.025) relative to major allele homozygote carriers. We also noted a correlation between the number of minor alleles of rs2981582 in FGFR2 and the average number of first-degree and second-degree relatives with breast cancer and/or ovarian cancer (P = 0.05). All other disease characteristics, including tumour size and grade, and oestrogen or progesterone receptor status, were not significantly associated with any of these variants.

Conclusion

Some recently discovered genomic variants associated with a mildly increased risk of breast cancer are also associated with breast cancer characteristics or family history of breast cancer and ovarian cancer. These findings provide interesting new clues for further research on these low-risk susceptibility alleles.     

Population-based 10-year cumulative revision risks after hip and knee arthroplasty for osteoarthritis to inform patients in clinical practice: a competing risk analysis from the Dutch Arthroplasty Register

Background and purpose — A lifetime perspective on revision risks is needed for optimal timing of arthroplasty in osteoarthritis (OA) patients, weighing the benefit of total hip arthroplasty/total knee arthroplasty (THA/TKA) against the risk of revision, after which outcomes are less favorable. Therefore, we provide population-based 10-year cumulative revision risks stratified by joint, sex, fixation type, and age.Patients and methods — Data from the Dutch Arthroplasty Register (LROI) was used. Primary THAs and TKAs for OA between 2007 and 2018 were included, except metal-on-metal prostheses or hybrid/reversed hybrid fixation. Revision surgery was defined as any change of 1 or more prosthesis components. The 10-year cumulative revision risks were calculated stratified by joint, age, sex, at primary arthroplasty, and fixation type (cemented/uncemented), taking into account mortality as a competing risk. We estimated the percentage of potentially avoidable revisions assuming all OA patients aged < 75 received primary THA/TKA 5 years later while keeping age-specific 10-year revision risks constant.Results — 214,638 primary THAs and 211,099 TKAs were included, of which 31% of THAs and 95% of TKAs were cemented. The 10-year cumulative revision risk varied between 1.6% and 13%, with higher risks in younger age categories. Delaying prosthesis placement by 5 years could potentially avoid 23 (3%) THA and 162 (17%) TKA revisions.Interpretation — Cumulative 10- year revision risk varied considerably by age in both fixation groups, which may be communicated to patients and used to guide timing of surgery.

In Western countries about 10–23% of women and 6–15% of men receive a total knee arthroplasty (TKA) during their life. For total hip arthroplasty (THA) these numbers are 12–16% of women and 8–11% of men (Ackerman et al. 2017a, b). Although arthroplasty is an effective intervention, the optimal timing of arthroplasty is crucial given the long-term survival of the prosthesis is still limited.To achieve optimal timing of primary THA/TKA, the benefit of surgery has to be weighed against the risk for revision surgery, which has less favorable outcomes (Petersen et al. 2015). Hence, when younger patients have lower revision risks than elderly patients, one might consider delaying surgery to optimize outcome from a lifetime perspective.Valid prediction models providing individualized lifetime revision risks may help guide decision-making on optimal timing, but such models are rare (Prokopetz et al. 2012, Paxton et al. 2015). Valid revision risks can also be provided by simply calculating these risks in the population of interest. For example, Bayliss et al. (2017) modelled lifetime revision risks after TKA/THA with Clinical Practice Research Datalink data. However, they did not include implant (fixation) type or indication for surgery, while both may impact revision risks. Furthermore, most arthroplasty registries published cumulative revision risks, without taking the competing risk of dying into account. Also, stratification of revision risks into more than one/two subgroups was not performed, whereas this is important when providing personalized information.We therefore provide 10-year cumulative revision risks for OA patients stratified by joint, sex, age, and fixation type, using data from the Dutch Arthroplasty Register and taking into account the competing risk of dying. We also estimate the number of potentially avoided arthroplasties by delaying TKA/THA by 5 years. Furthermore, we project our numbers onto the expected Dutch population in 2025/2035.     

Mixed infection with Trypanoplasma borreli and Trypanosoma carassii induces protection: involvement of cross-reactive antibodies

Mixed infections with Trypanoplasma borreli and Trypanosoma carassii in common carp (Cyprinus carpio L.) are commonly found in nature. So far, in the laboratory, only mono-parasitic infections have been examined in more detail. We studied the influence of mixed rather than mono-parasitic infections on the protective immune response in this naturally occurring host-parasite combination. Mixed infections were established in the laboratory by i.p. injection of fixed numbers of both parasite species and confirmed by species-specific antibody staining. Species-specific parasitaemia was determined by morphological differences and by real-time PCR. T. carassii parasitaemia developed prior to T. borreli. Infections with T. borreli reached higher levels of parasitaemia, compared to T. carassii infections and T. borreli could be lethal. Interestingly, in mixed infections, peak parasitaemia levels were reduced and to a lesser extend survival was increased compared to T. borreli mono-parasitic infections. Cross-reactive antibodies increased earlier and to higher levels in mixed infected fish than in T. borreli mono-parasitic infections. Further, carp that had received a prior T. carassii infection showed increased resistance to re-infection with T. borreli. Our data indicate a protective effect of co-infection with T. carassii on the resistance to T. borreli, possibly mediated via cross-reactive antibodies. We suggest an evolutionary advantage for a co-evolution of T. borreli and T. carassii in carp.     

Splanchnic metabolism of ingested amino acids in neonates

PURPOSE OF REVIEW: Neonates typically show rapid growth. Nutrient absorption in the neonatal period is higher than during any other time in life so as to meet the requirements for this rapid growth. Generally, nutrients are administered enterally, and in the past the gut was considered to absorb and digest these nutrients without major metabolism. Recent animal and human work has, however, revealed that the intestine and other splanchnic tissues contribute significantly to whole-body metabolism, and have their own specific functions. This review focuses on these observations. RECENT FINDINGS: The splanchnic tissues take up greatly different proportions of each of the amino acids, ranging from 80-100% for threonine and several nonessential amino acids to 15-30% for lysine. The metabolic fates of the utilized substrates differ as well. Some are predominantly used for constitutive protein synthesis, others for energy generation or for formation of (glyco-)proteins that are secreted into the lumen. Glucose appears to be the major contributor to energy generation, but amino acids are important as well. SUMMARY: Both animal and human studies have shown that the intestine uses substantial amounts of dietary amino acids. This has several implications for the nutritional needs of infants to maintain growth, especially during times of inadequate enteral nutrition.     

The role of lymph nodes in cervical cancer: incidence and identification of lymph node metastases—a literature review

Correct identification of patients with lymph node metastasis from cervical cancer prior to treatment is of great importance, because it allows more tailored therapy. Patients may be spared unnecessary surgery or extended field radiotherapy if the nodal status can be predicted correctly. This review captures the existing knowledge on the identification of lymph node metastases in cervical cancer. The risk of nodal metastases increases per 2009 FIGO stage, with incidences in the pelvic region ranging from 2% (stage IA2) to 14–36% (IB), 38–51% (IIA) and 47% (IIB); and in the para-aortic region ranging from 2 to 5% (stage IB), 10–20% (IIA), 9% (IIB), 13–30% (III) and 50% (IV). In addition, age, tumor size, lymph vascular space invasion, parametrial invasion, depth of stromal invasion, histological type, and histological grade are reported to be independent prognostic factors for the risk of nodal metastases. Furthermore, biomarkers can contribute to predict a patient’s nodal status, of which the squamous cell carcinoma antigen (SCC-Ag) is currently the most widely used in squamous cell cervical cancer. Still, pre-treatment lymph node assessment is primarily performed by imaging, of which diffusion-weighted magnetic resonance imaging has the highest sensitivity and 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission computed tomography the highest specificity. Imaging results can be combined with clinical parameters in nomograms to increase the accuracy of predicting positives nodes. Despite all the progress regarding pre-treatment prediction of lymph node metastases in cervical cancer in recent years, prediction rates are not robust enough to safely abandon surgical staging of the pelvic or para-aortic region yet.

     

Vdelta2-Jalpha rearrangements are frequent in precursor-B-acute lymphoblastic leukemia but rare in normal lymphoid cells

The frequently occurring T-cell receptor delta (TCRD) deletions in precursor-B-acute lymphoblastic leukemia (precursor-B-ALL) are assumed to be mainly caused by Vdelta2-Jalpha rearrangements. We designed a multiplex polymerase chain reaction tified clonal Vdelta2-Jalpha rearrangements in 141 of 339 (41%) childhood and 8 of 22 (36%) adult precursor-B-ALL. A significant proportion (44%) of Vdelta2-Jalpha rearrangements in childhood precursor-B-ALL were oligoclonal. Sequence analysis showed preferential usage of the Jalpha29 gene segment in 54% of rearrangements. The remaining Vdelta2-Jalpha rearrangements used 26 other Jalpha segments, which included 2 additional clusters, one involving the most upstream Jalpha segments (ie, Jalpha48 to Jalpha61; 23%) and the second cluster located around the Jalpha9 gene segment (7%). Real-time quantitative PCR studies of normal lymphoid cells showed that Vdelta2 rearrangements to upstream Jalpha segments occurred at low levels in the thymus (10(-2) to 10(-3)) and were rare (generally below 10(-3)) in B-cell precursors and mature T cells. Vdelta2-Jalpha29 rearrangements were virtually absent in normal lymphoid cells. The monoclonal Vdelta2-Jalpha rearrangements in precursor-B-ALL may serve as patient-specific targets for detection of minimal residual disease, because they show high sensitivity (10(-4) or less in most cases) and good stability (88% of rearrangements preserved at relapse).     

Intra-ventricular resynchronization for optimal left ventricular function during pacing in experimental left bundle branch block

oBJECTIVES: We sought to investigate to what extent intra-ventricular asynchrony (intraVA) and inter-ventricular asynchrony (interVA) determine left ventricular (LV) function in canine hearts with left bundle branch block (LBBB) during ventricular pacing. BACKGROUND: Pacing therapy improves LV pump function in patients with heart failure and abnormal ventricular conduction supposedly due to resynchronization. However, the relationship between LV pump function and measures of asynchrony is not well established. METHODS: In 15 experiments, LV (various sites) and biventricular (BiV) pacing was performed at atrioventricular (AV) delays of 20 to 140 ms. Measured were the maximum rate of increase (dP/dt(max)) of LV pressure and LV stroke work (SW) (conductance catheter), interVA (time delay between the upslope of LV and RV pressures), and intraVA (from endocardial electrical activation maps). RESULTS: Induction of LBBB increased interVA (-6.4 +/- 8.6 to -28.4 +/- 8.5 ms [RV earlier]) and intraVA (4.9 +/- 2.4 to 18.0 +/- 3.3 ms), whereas LV dP/dt(max) and SW decreased (-13 +/- 18% and -39 +/- 24%, respectively). During LBBB, LV and BiV pacing increased LV dP/dt(max) and SW (mean increases 14% to 21% and 11% to 15%, respectively) without changing diastolic function or preload. Optimal improvement in LV function was obtained consistently when intraVA returned to pre-LBBB values, while interVA remained elevated. Normalization of intraVA required AV delays shorter than the baseline PQ time during LV apex and BiV pacing, thus excluding endogenous LV activation, but AV delays virtually equal to the baseline PQ time (difference 4 +/- 9 ms, p = NS) during pacing at (mid)lateral LV sites to obtain fusion between pacing-induced and endogenous activation. CONCLUSIONS: In LBBB hearts, optimal restoration of LV systolic function by pacing requires intra-ventricular resynchronization. The optimal AV delay to achieve this depends on both the site of pacing and baseline PQ time.     

Age-related changes in hypothalamic-pituitary-adrenal axis activity of male C57BL/6J mice

As there is little known about age-related changes in the hypothalamic-pituitary-adrenal (HPA) axis of mice, we determined the daily patterns of corticosterone secretion every 2 h, together with adrenocorticotropic hormone (ACTH) release and central HPA axis markers in the morning and evening of 3-, 9- and 16-month-old male C57BL/6J mice. We observed that: (i) corticosterone secretion showed a distinct age-related circadian pattern. During the light period this was expressed by relative hypercorticism in 9-month-old mice and relative hypocorticism in 16-month-old mice. ACTH was elevated at 16 months of age; (ii) mineralocorticoid (MR) and glucocorticoid receptor (GR) mRNA expression in the hippocampus was significantly decreased in 9-month-old mice, whereas in 16-month-old mice, expression was similar to young animals. Circadian variation was modest in all age groups; (iii) the parvocellular hypothalamic paraventricular nucleus (PVN) expressed very high vasopressin mRNA, which was subject to circadian variation in 3- and 9-month-old mice. Furthermore, significant levels of MR mRNA were expressed in the PVN. In conclusion, basal HPA axis activity and expression of its central regulatory markers are age-dependent in mice. This suggests that the capacity to adjust to environmental demands is either a function of age, or depends on different dynamics of the HPA axis.     

Mendelian Disorders of Cornification Caused by Defects in Intracellular Calcium Pumps: Mutation Update and Database for Variants in ATP2A2 and ATP2C1 Associated with Darier Disease and Hailey–Hailey Disease

The two disorders of cornification associated with mutations in genes coding for intracellular calcium pumps are Darier disease (DD) and Hailey–Hailey disease (HHD). DD is caused by mutations in the ATP2A2 gene, whereas the ATP2C1 gene is associated with HHD. Both are inherited as autosomal‐dominant traits. DD is mainly defined by warty papules in seborrheic and flexural areas, whereas the major symptoms of HHD are vesicles and erosions in flexural skin. Both phenotypes are highly variable. In 12%–40% of DD patients and 12%–55% of HHD patients, no mutations in ATP2A2 or ATP2C1 are found. We provide a comprehensive review of clinical variability in DD and HHD and a review of all reported mutations in ATP2A2 and ATP2C1. Having the entire spectrum of ATP2A2 and ATP2C1 variants allows us to address the question of a genotype–phenotype correlation, which has not been settled unequivocally in DD and HHD. We created a database for all mutations in ATP2A2 and ATP2C1 using the Leiden Open Variation Database (LOVD v3.0), for variants reported in the literature and future inclusions. This data may be of use as a reference tool in further research on treatment of DD and HHD.