Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2>0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P<10−7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P<0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.
Recent advances in the development of genome editing technologies based on programmable nucleases have significantly improved our ability to make precise changes in the genomes of eukaryotic cells. Genome editing is already broadening our ability to elucidate the contribution of genetics to disease by facilitating the creation of more accurate cellular and animal models of pathological processes. A particularly tantalizing application of programmable nucleases is the potential to directly correct genetic mutations in affected tissues and cells to treat diseases that are refractory to traditional therapies. Here we discuss current progress towards developing programmable nuclease-based therapies as well as future prospects and challenges.
Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.
We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.
We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.
This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0567-2) contains supplementary material, which is available to authorized users.
Twin and family studies have established the contribution of genetic factors to variation in metabolic, hematologic and immunological parameters. The majority of these studies analyzed single or combined traits into pre-defined syndromes. In the present study, we explore an alternative multivariate approach in which a broad range of metabolic, hematologic, and immunological traits are analyzed simultaneously to determine the resemblance of monozygotic (MZ) twin pairs, twin-spouse pairs and unrelated, non-cohabiting individuals. A total of 517 participants from the Netherlands Twin Register, including 210 MZ twin pairs and 64 twin-spouse pairs, took part in the study. Data were collected on body composition, blood pressure, heart rate, and multiple biomarkers assessed in fasting blood samples, including lipid levels, glucose, insulin, liver enzymes, hematological measurements and cytokine levels. For all 51 measured traits, pair-wise Pearson correlations, correcting for family relatedness, were calculated across all the individuals in the cohort. Hierarchical clustering techniques were applied to group the measured traits into sub-clusters based on similarity. Sub-clusters were observed among metabolic traits and among inflammatory markers. We defined a phenotypic profile as the collection of all the traits measured for a given individual. Average within-pair similarity of phenotypic profiles was determined for the groups of MZ twin pairs, spouse pairs and pairs of unrelated individuals. The average similarity across the full phenotypic profile was higher for MZ twin pairs than for spouse pairs, and lowest for pairs of unrelated individuals. Cohabiting MZ twins were more similar in their phenotypic profile compared to MZ twins who no longer lived together. The correspondence in the phenotypic profile is therefore determined to a large degree by familial, mostly genetic, factors, while household factors contribute to a lesser degree to profile similarity.
Germline TP53 mutations predispose to multiple cancers defining Li-Fraumeni/Li-Fraumeni-like syndrome (LFS/LFL), a disease with large individual disparities in cancer profiles and age of onset. G-quadruplexes (G4s) are secondary structural motifs occurring in guanine tracks, with regulatory effects on DNA and RNA. We analyzed 85 polymorphisms within or near five predicted G4s in TP53 in search of modifiers of penetrance of LFS/LFL in Brazilian cancer families with (n = 35) or without (n = 110) TP53 mutations. Statistical analyses stratified on family structure showed that cancer tended to occur ~15 years later in mutation carriers who also carried the variant alleles of two polymorphisms within predicted G4-forming regions, rs17878362 (TP53 PIN3, 16 bp duplication in intron 3; P = 0.082) and rs17880560 (6 bp duplication in 3′ flanking region; P = 0.067). Haplotype analysis showed that this inverse association was driven by the polymorphic status of the remaining wild-type (WT) haplotype in mutation carriers: in carriers with a WT haplotype containing at least one variant allele of rs17878362 or rs17880560, cancer occurred ~15 years later than in carriers with other WT haplotypes (P = 0.019). No effect on age of cancer onset was observed in subjects without a TP53 mutation. The G4 in intron 3 has been shown to regulate alternative p53 messenger RNA splicing, whereas the biological roles of predicted G4s in the 3′ flanking region remain to be elucidated. In conclusion, this study demonstrates that G4 polymorphisms in haplotypes of the WT TP53 allele have an impact on LFS/LFL penetrance in germline TP53 mutation carriers.
G-quadruplexes (G4) are regulatory secondary structures in guanine tracts in DNA or RNA. Polymorphisms in two G4-forming regions of TP53 modulate age at cancer onset in susceptible germline TP53 mutation carriers, suggesting that these G4 regulate p53 suppressor functions.
Backscattering interferometry enables the detection of syphilis antibody–antigen interactions in the presence of human serum, showing promise as a diagnostic tool for the serological diagnosis of infectious disease with potentially quantitative capabilities.
Following the GMC’s report on Tomorrow’s Doctors, greater emphasis has been placed on training in clinical skills, and the integration of clinical and basic sciences within the curriculum to promote the development of effective doctors. The use of simulation in the learning environment has the potential to support the development of clinical skills in preclinical medical students whilst in a ‘safe’ environment, but currently there is little evidence on its effectiveness.
Seventy nine year one medical students were divided into two groups. A pre-test was conducted by both groups, after which one group performed chest examination on their peers whilst the other group examined the SimMan® manikin. Both groups subsequently performed a mid-test and crossed over so that the group that conducted peer examination examined the manikin and vice-versa. Finally a post-test was conducted. The students were scored for formative feedback whilst performing examinations. Students completed a feedback questionnaire at the end of the session. Data were analysed using a one-way ANOVA, independent t-test and 2- proportion Z test.
When the two groups were compared, there was no significant difference in their pre-test and post-test knowledge scores, whereas mid-test knowledge scores increased significantly (P < 0.001), with the group using SimMan® initially scoring higher. A significant increase in the test scores was seen in both groups after using SimMan® (P < 0.001). Students’ confidence increased significantly in differentiating between normal and abnormal signs (P < 0.001). Students highly valued the use of the manikin in the session with 96% of students reporting that it enhanced their learning experience.
The study demonstrated a significant improvement in the students’ knowledge after examining the manikin and students also reported an increase in their confidence. Students’ feedback was generally very positive and they perceived the incorporation of manikin-based examinations useful to prepare them for future patient contact. The use of simulation in this context supports an integrated learning approach when used as an adjunct to peer examination, and can benefit the acquisition of clinical skills in preclinical medical students.
Clinical skills; SimMan®; Preclinical medical students
Heterocyclic amines (HCAs) are mutagenic compounds generated when meats are cooked at high temperature and for long duration. The findings from previous studies on the relation between HCAs and breast cancer are inconsistent, possibly due to genetic variations in the enzymes metabolizing HCAs.
To evaluate whether the associations of intakes of estimated HCAs, meat-derived mutagenicity (MDM), and red meat with risk of postmenopausal breast cancer were modified by N-acetyltransferase 2 (NAT2) acetylator genotype or cytochrome P450 1A2 -164 A/C (CYP1A2) polymorphism, we conducted a nested case-control study with 579 cases and 981 controls within a prospective cohort, the Nurses’ Health Study (NHS). HCAs and MDM intakes were derived using a cooking method questionnaire administered in 1996.
NAT2 acetylator genotype, the CYP1A2 polymorphism, and intakes of HCAs, MDM, and red meat were not associated with risk of postmenopausal breast cancer. There was also no interaction between NAT2 acetylator genotype or CYP1A2 polymorphism and HCAs and MDM and red meat intake in relation to breast cancer.
These results do not support the hypothesis that genetic polymorphisms of xenobiotic enzymes involved in the metabolism of HCAs may modify the associations between intakes of red meat or meat-related mutagens and breast cancer risk.
NAT2; CYP1A2; heterocyclic amines; breast cancer; epidemiology
This study compared palonosetron and ondansetron as rescue medications for postoperative nausea and vomiting (PONV) in patients who received prophylactic ondansetron. Although guidelines recommend use of an agent from a different class when prophylaxis has failed, palonosetron has unique properties relative to other serotonin 5-HT3 receptor antagonists. Prior trials assessing its use for rescue have had conflicting results. Although palonosetron has compared favorably with ondansetron for PONV prevention, the drugs have not been compared in the rescue setting of failure of 5-HT3 receptor antagonist prophylaxis.
This was a randomized, open-label, multicenter trial comparing the efficacy and safety of intravenous palonosetron 0.075 mg and intravenous ondansetron 4 mg in patients experiencing PONV following laparoscopic abdominal or gynecological surgery despite prophylactic ondansetron.
Of 239 patients screened, 220 were enrolled and 98 were treated for PONV: 48 and 50 in the palonosetron and ondansetron arms, respectively. Complete control during 72 hours after study drug administration was achieved in 25.0% of palonosetron recipients and 18.0% of ondansetron recipients (95% confidence interval [CI], -9.2, 23.3; p = 0.40). Corresponding incidences of vomiting were 29.2% for palonosetron and 48.0% for ondansetron (95% CI, -0.06, 37.7; p = 0.057), and 62.5% and 56.0% required additional rescue treatment, respectively (95% CI, -25.9, 12.9; p = 0.52). Other than a similar incidence of procedural pain in the 2 groups, the most common treatment-emergent adverse events, which were generally mild, were headache (14.6% vs 12.0%), constipation (8.3% vs 10.0%), and dizziness (6.3% vs 8.0%), for the palonosetron and ondansetron groups, respectively.
Palonosetron and ondansetron did not show differences in the primary efficacy endpoint of CC during the 72 hours after study drug administration. There was a trend toward less emesis in the 0–72 h time period favoring palonosetron. While larger studies are needed to fully assess any clinical benefits of palonosetron to rescue patients who have failed ondansetron prophylaxis for PONV, the benefit, if any, would be limited based on this study.
ClinicalTrials.gov, NCT00967499 (Registered August 27, 2009)
Postoperative nausea and vomiting; Antiemetics; Palonosetron; Ondansetron
APOE is the biomarker with the greatest known influence on cognitive function; however, the effect of complex haplotypes involving polymorphisms rs449647, rs405509, rs440446, rs429358 and rs7412 has never been studied in older populations.
We evaluated APOE polymorphisms using multiplex PCR for genotyping and Mini-Mental State Examination (MMSE) to evaluate cognitive function in 819 individuals from VA Normative Aging Study.
Combinatorial analysis of all polymorphisms and individual analysis of polymorphisms rs449647, rs405509, rs440446 and rs7412 did not show any association with cognitive performance. Polymorphism rs429358 was associated with better cognitive performance (odds of MMSE ≤ 25 = 0.63, 95% CI 0.42-0.95; p = 0.03) in the oldest subsample (5th quintile of age) (odds of MMSE ≤ 25 = 0.34; 95% CI 0.13-0.86; p = 0.02). APOE allele ε4 was also associated with better cognitive performance (odds of MMSE ≤ 25 = 0.61, 95% CI 0.40-0.94; p = 0.02), also in the oldest subsample (odds of MMSE ≤ 25 = 0.35, 95% CI 0.14-0.90; p = 0.03).
These results suggest a beneficial effect of polymorphism rs429358 in the oldest men.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-014-0223-x) contains supplementary material, which is available to authorized users.
APOE; Epsilon; Alleles; Haplotypes; Cognitive decline; Aging; Genetic variants
Many pathologies seen in the preterm population are associated with abnormal blood supply, yet robust evaluation of preterm cardiac function is scarce and consequently normative ranges in this population are limited. The aim of this study was to quantify and validate left ventricular dimension and function in preterm infants using cardiovascular magnetic resonance (CMR). An initial investigation of the impact of the common congenital defect patent ductus arteriosus (PDA) was then carried out.
Steady State Free Procession short axis stacks were acquired. Normative ranges of left ventricular end diastolic volume (EDV), stroke volume (SV), left ventricular output (LVO), ejection fraction (EF), left ventricular (LV) mass, wall thickness and fractional thickening were determined in “healthy” (control) neonates. Left ventricular parameters were then investigated in PDA infants. Unpaired student t-tests compared the 2 groups. Multiple linear regression analysis assessed impact of shunt volume in PDA infants, p-value ≤ 0.05 being significant.
29 control infants median (range) corrected gestational age at scan 34+6(31+1-39+3) weeks were scanned. EDV, SV, LVO, LV mass normalized by weight and EF were shown to decrease with increasing corrected gestational age (cGA) in controls. In 16 PDA infants (cGA 30+3(27+3-36+1) weeks) left ventricular dimension and output were significantly increased, yet there was no significant difference in ejection fraction and fractional thickening between the two groups. A significant association between shunt volume and increased left ventricular mass correcting for postnatal age and corrected gestational age existed.
CMR assessment of left ventricular function has been validated in neonates, providing more robust normative ranges of left ventricular dimension and function in this population. Initial investigation of PDA infants would suggest that function is relatively maintained.
Preterm; Cardiac function; Magnetic resonance; Patent ductus arteriosus
Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5′-triphosphate (ATP) turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.
Because of their unique optical properties quantum dots (QDs) have become a preferred system for ultrasensitive detection and imaging. However, since QDs commonly contain Cd and other heavy metals, concerns have been raised regarding their toxicity. QDs are thus commonly synthesized with a ZnS cap structure, and/or coated with polymeric stabilizers. We recently synthesized amphiphilic polymer coated TOPO-PMAT QDs which are highly stable in aqueous environments. The effects of these QDs on viability and stress response in five cell lines of mouse and human origins are reported here. Human and mouse macrophages, and human kidney cells readily internalized these QDs, resulting in modest toxicity. TOPO-PMAT QD exposure was highly correlated with the induction of the stress response protein heme oxygenase-1 (HMOX1). Other stress biomarkers (glutamate cysteine ligase modifier subunit, NAD(P)H, necrosis) were only moderately affected. HMOX1 may thus be a useful biomarker of TOPO-QDOT QD exposure across cell types and species.
quantum dots; oxidative stress; biomarkers; heme oxygenase; in vitro toxicity
Inhalation of fine particulate matter (PM2.5) is associated with acute pulmonary inflammation and impairments in cardiovascular function. In many regions, PM2.5 is largely derived from diesel exhaust (DE), and these pathophysiological effects may be due in part to oxidative stress resulting from DE inhalation. The antioxidant glutathione (GSH) is important in limiting oxidative stress-induced vascular dysfunction. The rate-limiting enzyme in GSH synthesis is glutamate cysteine ligase and polymorphisms in its catalytic and modifier subunits (GCLC and GCLM) have been shown to influence vascular function and risk of myocardial infarction in humans.
We hypothesized that compromised de novo synthesis of GSH in Gclm−/+ mice would result in increased sensitivity to DE-induced lung inflammation and vascular effects.
Materials and methods
WT and Gclm−/+ mice were exposed to DE via inhalation (300 µg/m3) for 6 h. Neutrophil influx into the lungs, plasma GSH redox potential, vascular reactivity of aortic rings and aortic nitric oxide (NO•) were measured.
DE inhalation resulted in mild bronchoalveolar neutrophil influx in both genotypes. DE-induced effects on plasma GSH oxidation and acetylcholine (ACh)-relaxation of aortic rings were only observed in Gclm−/+ mice. Contrary to our hypothesis, DE exposure enhanced ACh-induced relaxation of aortic rings in Gclm−/+ mice.
Discussion and conclusion
These data support the hypothesis that genetic determinants of antioxidant capacity influence the biological effects of acute inhalation of DE. However, the acute effects of DE on the vasculature may be dependent on the location and types of vessels involved. Polymorphisms in GSH synthesis genes are common in humans and further investigations into these potential gene-environment interactions are warranted.
Diesel exhaust; glutathione; lung inflammation; nitric oxide; oxidative stress
Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders1–7 – and who consequently may have increased disease risk. However, previous studies of rare variants in phenotypically extreme individuals have ascertainment bias and may demonstrate inflated effect size estimates8–12. We sequenced seven genes for maturity-onset diabetes of the young (MODY)13 in well-phenotyped population samples14,15 (n=4,003). Rare variants were filtered according to prediction criteria used to identify disease-causing mutations: i) previously-reported in MODY, and ii) stringent de novo thresholds satisfied (rare, conserved, protein damaging). Approximately 1.5% and 0.5% of randomly selected Framingham and Jackson Heart Study individuals carried variants from these two classes, respectively. However, the vast majority of carriers remained euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a significant fraction of individuals as at risk for MODY or other Mendelian diseases.
Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1,2,3, yet none are described for type 2 diabetes (T2D). Through sequencing or genotyping ~150,000 individuals across five ethnicities, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8)4 and harbors a common variant (p.Trp325Arg) associated with T2D risk, glucose, and proinsulin levels5–7. Collectively, protein-truncating variant carriers had 65% reduced T2D risk (p=1.7×10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34SerfsX50) demonstrated reduced glucose levels (−0.17 s.d., p=4.6×10−4). The two most common protein-truncating variants (p.Arg138X and p.Lys34SerfsX50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested reduced zinc transport increases T2D risk8,9, yet phenotypic heterogeneity was observed in rodent Slc30a8 knockouts10–15. Contrastingly, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, proposing ZnT8 inhibition as a therapeutic strategy in T2D prevention.
Previous studies have shown an inverse association between allergies and glioma risk; however, results for associations between single nucleotide polymorphisms (SNPs) of allergy-related genes and glioma risk have been inconsistent and restricted to a small number of SNPs. The objective of this study was to examine the association between 166 SNPs of 21 allergy-related genes and glioma risk in a nested case-control study of participants from three large US prospective cohort studies. Blood collection took place between 1982 and 1994 among the 562 included Caucasian participants (143 cases and 419 matched controls) prior to case diagnosis. Custom Illumina assay chips were used for genotyping. Logistic regression analyses, controlling for age and study cohort, were used to determine associations between each SNP and glioma risk. Statistically significant associations were found between rs2494262 and rs2427824 of the FCER1A gene, which encodes the alpha chain of the high affinity immunoglobulin E receptor, and glioma risk (nominal trend p-values 0.01 and 0.03, respectively). Significant associations were also found between SNPs in IL10, ADAM33, NOS1 and IL4R and glioma risk; however, these were not corrected for multiple comparisons and need to be interpreted with caution. Our findings with FCER1A SNPs provide further support for the link between allergies and risk of glioma.
Brain tumors; glioma; allergies; single-nucleotide polymorphisms; cohort studies
Traffic-related air pollution has been linked with impaired cognition in older adults, possibly due to effects of oxidative stress on the brain. Mitochondria are the main source of cellular oxidation. Haplogroups in mitochondrial DNA (mtDNA) mark individual differences in oxidative potential and are possible determinants of neurodegeneration. The aim of this study was to investigate whether mtDNA haplogroups determined differential susceptibility to cognitive effects of long-term exposure to black carbon (BC), a marker of traffic-related air pollution.
We investigated 582 older men (72 ± 7 years) in the VA Normative Aging Study cohort with ≤4 visits per participant (1.8 in average) between 1995–2007. Low (≤25) Mini Mental State Examination (MMSE) was used to assess impaired cognition in multiple domains. We fitted repeated-measure logistic regression using validated-LUR BC estimated in the year before their first visit at the participant’s address.
Mitochondrial haplotyping identified nine haplogroups phylogenetically categorized in four clusters. BC showed larger effect on MMSE in Cluster 4 carriers, including I, W and X haplogroups, [OR = 2.7; 95% CI (1.3-5.6)], moderate effect in Cluster 1, including J and T haplogroups [OR = 1.6; 95% CI: (0.9-2.9)], and no effect in Cluster 2 (H and V haplogroups) [OR = 1.1; 95% CI: (0.8-1.5)] or Cluster 3 (K and U haplogroups) [OR = 1.0; 95% CI: (0.6-1.6)]. BC effect varied only moderately across the I, X, and W haplogroups or across the J and T haplogroups.
The association of BC with impaired cognition was worsened in carriers of phylogenetically-related mtDNA haplogroups in Cluster 4. No BC effects were detected in Cluster 2 and 3 carriers. MtDNA haplotypes may modify individual susceptibility to the particle cognitive effects.
mtDNA haplogroups; Air pollution; Black carbon; Cognitive decline; Mini-mental state examination
Eribulin mesylate, a novel non-taxane microtubule dynamics inhibitor, is approved for treatment of metastatic breast cancer (MBC) in patients who have previously received at least 2 chemotherapeutic regimens for MBC that should have included an anthracycline and a taxane in the adjuvant or metastatic setting. This phase 2 study evaluated efficacy and safety of eribulin as first-line therapy for human epidermal growth factor receptor 2-negative (HER2-negative) MBC. Patients with measurable HER2-negative locally recurrent breast cancer or MBC with ≥12 months since prior neoadjuvant or adjuvant (neo/adjuvant) chemotherapy received eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 3-week cycle. Endpoints included objective response rate (ORR) per RECIST v1.1 (primary), safety, progression-free survival (PFS), clinical benefit rate (ORR + stable disease ≥6 months; CBR), and duration of response (DOR). Fifty-six patients were enrolled and received eribulin; 38 (68 %) had prior neo/adjuvant therapy, including 33 who had anthracycline and/or taxane-containing chemotherapy; 41 (73 %) had estrogen receptor-positive disease, and 12 (21 %) had estrogen receptor-negative, progesterone receptor-negative, and HER2-negative (triple-negative) disease. Patients received a median of 7 cycles (range 1–43); 6 (11 %) received treatment for ≥12 months. ORR was 29 % (95 % CI 17.3–42.2), CBR was 52 %, and median DOR was 5.8 months. Median PFS was 6.8 months. Thirty-six patients (64 %) had grade 3/4 treatment-related adverse events; most common were neutropenia (50 %), leukopenia (21 %), and peripheral neuropathy (21 %). These results demonstrate that eribulin has substantial antitumor activity as first-line treatment for HER2-negative MBC with acceptable safety.
Metastatic breast cancer; HER2-negative breast cancer; Triple-negative breast cancer; Eribulin; Progression-free survival
Approximately 15–30% of all breast cancer tumors are estrogen receptor negative (ER−). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5×10−8) to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER− cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER− breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3×10−4. None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a “pleiotropic approach”.
Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03–1.21), P = 1.4 × 10−8]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.
Mold in water-damaged homes has been linked to asthma. Our objective was to test a new metric to quantify mold exposures in asthmatic children’s homes in three widely dispersed cities in the United States.
The Environmental Relative Moldiness Index (ERMI) metric was created by the US Environmental Protection Agency, with assistance by the Department of Housing and Urban Development (HUD), to quantify mold contamination in US homes. The ERMI values in homes of asthmatic children were determined for the three widely dispersed cities of Boston, Kansas City, and San Diego.
Asthmatic children in Boston (n = 76), Kansas City (n = 60), and San Diego (n = 93) were found to be living in homes with significantly higher ERMI values than were found in homes randomly selected during the 2006 HUD American Healthy Homes Survey (AHHS) from the same geographic areas (n = 34, 22, and 28, respectively). Taken together, the average ERMI value in the homes with an asthmatic child was 8.73 compared to 3.87 for the AHHS homes. In addition, Kansas City homes of children with “Mild, Moderate, or Severe Persistent Asthma” had average ERMI value of 12.4 compared to 7.9 for homes of children with only “Mild Intermittent Asthma.” Aspergillus niger was the only mold of the 36 tested which was measured in significantly greater concentration in the homes of asthmatic children in all three cities.
High ERMI values were associated with homes of asthmatic children in three widely dispersed cities in the United States.
Aspergillus niger; dust; metric; mold; the United States
The echocardiographic assessment of circulatory function in sick newborn infants has the potential to improve patient care. However, measurements are prone to error and have not been sufficiently validated. Phase-contrast magnetic resonance imaging (MRI) provides highly validated measures of blood flow and has recently been applied to the newborn population. The aim of this study was to validate measures of left ventricular output and superior vena caval flow volume in newborn infants.
Echocardiographic and MRI assessments were performed within 1 working day of each other in a cohort of newborn infants.
Examinations were performed in 49 infants with a median corrected gestational age at scan of 34.43 weeks (range, 27.43–40 weeks) and a median weight at scan of 1,880 g (range, 660–3,760 g). Echocardiographic assessment of left ventricular output showed a strong correlation with MRI assessment (R2 = 0.83; mean bias, −9.6 mL/kg/min; limits of agreement, −79.6 to +60.0 mL/kg/min; repeatability index, 28.2%). Echocardiographic assessment of superior vena caval flow showed a poor correlation with MRI assessment (R2 = 0.22; mean bias, −13.7 mL/kg/min; limits of agreement, −89.1 to +61.7 mL/kg/min; repeatability index, 68.0%). Calculating superior vena caval flow volume from an axial area measurement and applying a 50% reduction to stroke distance to compensate for overestimation gave a slightly improved correlation with MRI (R2 = 0.29; mean bias, 2.6 mL/kg/min; limits of agreement, −53.4 to +58.6 mL/kg/min; repeatability index, 54.5%).
Echocardiographic assessment of left ventricular output appears relatively robust in newborn infant. Echocardiographic assessment of superior vena caval flow is of limited accuracy in this population, casting doubt on the utility of the measurement for diagnostic decision making.
Echocardiography; Phase-contrast MRI; Preterm infants; LOA, Limits of agreement; LVO, Left ventricular output; MRI, Magnetic resonance imaging; PC, Phase-contrast; RI, Repeatability index; SVC, Superior vena caval; VTI, Velocity-time integral