Although poly(ADP-ribose) polymerase (PARP) inhibitors are active in homologous recombination (HR)-deficient cancers, their utility is limited by acquired resistance after restoration of HR. Here, we ...report that dinaciclib, an inhibitor of cyclin-dependent kinases (CDKs) 1, 2, 5, and 9, additionally has potent activity against CDK12, a transcriptional regulator of HR. In BRCA-mutated triple-negative breast cancer (TNBC) cells and patient-derived xenografts (PDXs), dinaciclib ablates restored HR and reverses PARP inhibitor resistance. Additionally, we show that de novo resistance to PARP inhibition in BRCA1-mutated cell lines and a PDX derived from a PARP-inhibitor-naive BRCA1 carrier is mediated by residual HR and is reversed by CDK12 inhibition. Finally, dinaciclib augments the degree of response in a PARP-inhibitor-sensitive model, converting tumor growth inhibition to durable regression. These results highlight the significance of HR disruption as a therapeutic strategy and support the broad use of combined CDK12 and PARP inhibition in TNBC.
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•Dinaciclib is a potent inhibitor of CDK12 and disrupts homologous recombination•Residual HR is a cause of de novo PARP inhibitor resistance in BRCA-mutated cancer•Dinaciclib sensitizes resistant BRCA-mutated breast cancer models to PARP inhibition•In HR-deficient cancer, dinaciclib augments the response afforded by PARP inhibition
Johnson et al. show that CDK12 inhibition, mediated by the small molecule dinaciclib, disrupts residual or restored homologous recombination (HR) in BRCA-associated breast cancer, sensitizing to PARP inhibition. CDK12 inhibition also augments the degree of PARP inhibitor response in HR-deficient breast cancer. Combined CDK12-PARP inhibition is well tolerated in preclinical models.
HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined.
To evaluate the effect of simvastatin on AMD ...progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH) genes.
A proof of concept double-masked randomized controlled study.
114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA ≥ 20/60 in at least one eye, and a normal lipid profile.
Simvastatin 40 mg/day or placebo, allocated 1:1.
Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70% in the placebo and 54% in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18-0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27-3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo adjusted OR 0.23 (0.07-0.75), p = 0.015. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene OR 0.08 (0.02-0.45), p = 0.004. No evidence of harm from simvastatin intervention was detected.
Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC (Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted.
Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To determine the association of genetic variants in known age-related macular degeneration (AMD) risk-associated genes with outcome of anti-vascular endothelial growth factor (VEGF) treatment in ...neovascular AMD.
Prospective cohort study.
We enrolled 224 consecutive patients with neovascular AMD at the Royal Victorian Eye and Ear Hospital, Australia.
Patients were treated with 3 initial monthly ranibizumab or bevacizumab injections followed by 9 months of "as required" injections based on clinician's decision at each follow-up visit according to retreatment criteria. Seventeen single nucleotide polymorphisms (SNPs) in known AMD risk-associated genes including CFH (rs800292, rs3766404, rs1061170, rs2274700 and rs393955), HTRA1 (rs11200638), CFHR1-5 (rs10922153, rs16840639, rs6667243, and rs1853883), LOC387715/ARMS2 (rs3793917 and rs10490924), C3 (rs2230199 and rs1047286), C2 (rs547154), CFB (rs641153) and F13B (rs6003) were examined. Multivariate analysis was used to determine the role of each SNP in treatment outcome.
The influence of selected SNPs on mean change in visual acuity (VA) at 12 months.
Mean baseline VA was 51 ± 16.8 Early Treatment Diabetic Retinopathy Study letters. Overall, the mean change in VA from baseline was +3.2 ± 14.9 letters at 12 months. The AA (homozygote risk) genotype at rs11200638 - HTRA1 promoter SNP (P = 0.001) and GG (homozygote risk) genotype at rs10490924 (A69S) in LOC387715/ARMS2 (P = 0.002) were each significantly associated with poorer VA outcome at 12 months after multiple correction. Mean ± standard deviation change in VA from baseline in patients with AA genotype at rs11200638 was -2.9 ± 15.2 letters after 12 months compared with +5.1 ± 14.1 letters in patients with AG or GG genotypes at this SNP. Patients with either of these genotypes were also significantly more likely to lose >15 letters after 12 months. SNPs rs11200638 and rs10490924 were in high linkage disequilibrium (r(2) = 0.92). None of the other examined SNPs was associated with outcome.
The HTRA1 promoter SNP (rs11200638) and A69S at LOC387715/ARMS2 were associated with a poorer visual outcome for ranibizumab or bevacizumab treatment in neovascular AMD, suggesting strong pharmacogenetic associations with anti-VEGF treatment. This finding could aid in applying more individualized treatment regimens based on patients' genotype to achieve optimal treatment response in AMD.
The authors have no proprietary or commercial interest in any materials discussed in this article.
A previous study has indicated suggestive association of the hepatocyte growth factor (HGF) gene with Keratoconus. We wished to assess this association in an independent Caucasian cohort as well as ...assess its association with corneal curvature.
Keratoconus patients were recruited from private and public clinics in Melbourne, Australia. Non-keratoconic individuals were identified from the Genes in Myopia (GEM) study from Australia. A total of 830 individuals were used for the analysis including 157 keratoconic and 673 non keratoconic subjects.
Tag single nucleotide polymorphisms (tSNPs) were chosen to encompass the hepatocyte growth factor gene as well as 2 kb upstream of the start codon through to 2 kb downstream of the stop codon. Logistic and linear regression including age and gender as covariates were applied in statistical analysis with subsequent Bonferroni correction.
Ten tSNPs were genotyped. Following statistical analysis and multiple testing correction, a statistically significant association was found for the tSNP rs2286194 {p = 1.1×10-(3) Odds Ratio 0.52, 95% CI--0.35, 0.77} for keratoconus. No association was found between the 10 tSNPs and corneal curvature.
These findings provide additional evidence of significant association of the HGF gene with Keratoconus. This association does not appear to act through the corneal curvature route.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
The World Health Organization (WHO) recommends at least four antenatal care (ANC) visits for all pregnant women. Almost half of pregnant women worldwide, and especially in developing ...countries do not receive this amount of care. Poor attendance of ANC is associated with delivery of low birthweight babies and more neonatal deaths. ANC may include education on nutrition, potential problems with pregnancy or childbirth, child care and prevention or detection of disease during pregnancy.
This review focused on community‐based interventions and health systems‐related interventions.
Objectives
To assess the effects of health system and community interventions for improving coverage of antenatal care and other perinatal health outcomes.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (7 June 2015) and reference lists of retrieved studies.
Selection criteria
We included randomised controlled trials (RCTs), quasi‐randomised trials and cluster‐randomised trials. Trials of any interventions to improve ANC coverage were eligible for inclusion. Trials were also eligible if they targeted specific and related outcomes, such as maternal or perinatal death, but also reported ANC coverage.
Data collection and analysis
Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy.
Main results
We included 34 trials involving approximately 400,000 women. Some trials tested community‐based interventions to improve uptake of antenatal care (media campaigns, education or financial incentives for pregnant women), while other trials looked at health systems interventions (home visits for pregnant women or equipment for clinics). Most trials took place in low‐ and middle‐income countries, and 29 of the 34 trials used a cluster‐randomised design. We assessed 30 of the 34 trials as of low or unclear overall risk of bias.
Comparison 1: One intervention versus no intervention
We found marginal improvements in ANC coverage of at least four visits (average odds ratio (OR) 1.11, 95% confidence interval (CI) 1.01 to 1.22; participants = 45,022; studies = 10; Heterogeneity: Tau² = 0.01; I² = 52%; high quality evidence). Sensitivity analysis with a more conservative intra‐cluster correlation co‐efficient (ICC) gave similar marginal results. Excluding one study at high risk of bias shifted the marginal pooled estimate towards no effect. There was no effect on pregnancy‐related deaths (average OR 0.69, 95% CI 0.45 to 1.08; participants = 114,930; studies = 10; Heterogeneity: Tau² = 0.00; I² = 0%; low quality evidence), perinatal mortality (average OR 0.96, 95% CI 0.89 to 1.03; studies = 15; Heterogeneity: Tau² = 0.01; I² = 45%; moderate quality evidence) or low birthweight (average OR 0.94, 95% CI 0.82 to 1.06; studies = five; Heterogeneity: Tau² = 0.00; I² = 5%; high quality evidence). Single interventions led to marginal improvements in the number of women who delivered in health facilities (average OR 1.08, 95% CI 1.02 to 1.15; studies = 10; Heterogeneity: Tau² = 0.00; I² = 0%; high quality evidence), and in the proportion of women who had at least one ANC visit (average OR 1.68, 95% CI 1.02 to 2.79; studies = six; Heterogeneity: Tau² = 0.24; I² = 76%; moderate quality evidence). Results for ANC coverage (at least four and at least one visit) and for perinatal mortality had substantial statistical heterogeneity. Single interventions did not improve the proportion of women receiving tetanus protection (average OR 1.03, 95% CI 0.92 to 1.15; studies = 8; Heterogeneity: Tau² = 0.01; I² = 57%). No study reported onintermittent prophylactic treatment for malaria.
Comparison 2: Two or more interventions versus no intervention
We found no improvements in ANC coverage of four or more visits (average OR 1.48, 95% CI 0.99 to 2.21; participants = 7840; studies = six; Heterogeneity: Tau² = 0.10; I² = 48%; low quality evidence) or pregnancy‐related deaths (average OR 0.70, 95% CI 0.39 to 1.26; participants = 13,756; studies = three; Heterogeneity: Tau² = 0.00; I² = 0%; moderate quality evidence). However, combined interventions led to improvements in ANC coverage of at least one visit (average OR 1.79, 95% CI 1.47 to 2.17; studies = five; Heterogeneity: Tau² = 0.00; I² = 0%; moderate quality evidence), perinatal mortality (average OR 0.74, 95% CI 0.57 to 0.95; studies = five; Heterogeneity: Tau² = 0.06; I² = 83%; moderate quality evidence) and low birthweight (average OR 0.61, 95% CI 0.46 to 0.80; studies = two; Heterogeneity: Tau² = 0.00; I² = 0%; moderate quality evidence). Meta‐analyses for both ANC coverage four or more visits and perinatal mortality had substantial statistical heterogeneity. Combined interventions improved the proportion of women who had tetanus protection (average OR 1.48, 95% CI 1.18 to 1.87; studies = 3; Heterogeneity: Tau² = 0.01; I² = 33%). No trial in this comparison reported on intermittent prophylactic treatment for malaria.
Comparison 3: Two interventions compared head to head. No trials found.
Comparison 4: One intervention versus a combination of interventions
There was no difference in ANC coverage (four or more visits and at least one visit), pregnancy‐related deaths, deliveries in a health facility or perinatal mortality. No trials in this comparison reported on low birthweight orintermittent prophylactic treatment of malaria.
Authors' conclusions
Implications for practice ‐ Single interventions may improve ANC coverage (at least one visit and four or more visits) and deliveries in health facilities. Combined interventions may improve ANC coverage (at least one visit), reduce perinatal mortality and reduce the occurrence of low birthweight. The effects of the interventions are unrelated to whether they are community or health system interventions.
Implications for research ‐ More details should be provided in reporting numbers of events, group totals and the ICCs used to adjust for cluster effects. Outcomes should be reported uniformly so that they are comparable to commonly‐used population indicators. We recommend further cluster‐RCTs of pregnant women and women in their reproductive years, using combinations of interventions and looking at outcomes that are important to pregnant women, such as maternal and perinatal morbidity and mortality, alongside the explanatory outcomes along the pathway of care: ANC coverage, the services provided during ANC and deliveries in health facilities.
To determine the association of genetic variants of the VEGFA gene with outcome of anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (AMD).
A ...prospective cohort study.
We included 201 consecutive patients receiving anti-VEGF injections for neovascular AMD.
Patients were followed over 12 months. They were treated with 3 initial monthly ranibizumab or bevacizumab injections. Thereafter, the decision to retreat was made by clinicians at each follow-up visit on the basis of retreatment criteria. Seven tagged single nucleotide polymorphisms (tSNPs) in the VEGFA gene were selected and examined. Multivariate data analysis was used to determine the role of each tSNP in treatment outcome.
The influence of selected VEGFA tSNPs on visual acuity (VA) outcome at 6 months.
Mean baseline VA was 51±17 Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores. Overall, the mean change in VA from baseline was +6.5±12, +4.4±13.4, and +2.3±14.6 letters at 3, 6, and 12 months, respectively. The tSNP rs3025000 was the only SNP significantly associated (P<1 × 10(-4)) with visual outcome at 6 months with multiple correction. The presence of the T allele (TC or TT genotypes) at this tSNP predicted a better outcome of +7 letters at 6 months compared with the CC genotype. In a subgroup analysis, presence of the T allele predicted a significantly higher chance of the patients belonging to the responder group (gain of ≥5 letters from baseline) after 3, 6, and 12 months treatment (odds ratio, 2.7, 3.5, and 2.4; 95% confidence interval, 1.46-5.07, 1.82-6.71, and 1.27-4.57, respectively) than any other outcome group.
Pharmacogenetic association with anti-VEGF treatments may influence the visual outcomes in neovascular AMD. In patients with the T allele in tSNP rs3025000, there was a significantly better visual outcome at 6 months and a greater chance of the patients belonging to the responder group with anti-VEGF treatment at 3, 6, and 12 months. The VA outcomes of patients harboring the T allele at SNP rs3025000 were comparable with those of the pivotal clinical trials but with fewer injections, making the treatment perhaps more cost effective in certain subgroups of patients.
The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Structural variation and single-nucleotide variation of the complement factor H (CFH) gene family underlie several complex genetic diseases, including age-related macular degeneration (AMD) and ...atypical hemolytic uremic syndrome (AHUS). To understand its diversity and evolution, we performed high-quality sequencing of this ∼360-kbp locus in six primate lineages, including multiple human haplotypes. Comparative sequence analyses reveal two distinct periods of gene duplication leading to the emergence of four CFH-related (CFHR) gene paralogs (CFHR2 and CFHR4 ∼25–35 Mya and CFHR1 and CFHR3 ∼7–13 Mya). Remarkably, all evolutionary breakpoints share a common ∼4.8-kbp segment corresponding to an ancestral CFHR gene promoter that has expanded independently throughout primate evolution. This segment is recurrently reused and juxtaposed with a donor duplication containing exons 8 and 9 from ancestral CFH, creating four CFHR fusion genes that include lineage-specific members of the gene family. Combined analysis of >5,000 AMD cases and controls identifies a significant burden of a rare missense mutation that clusters at the N terminus of CFH P = 5.81 × 10−8, odds ratio (OR) = 9.8 (3.67-Infinity). A bipolar clustering pattern of rare nonsynonymous mutations in patients with AMD (P < 10−3) and AHUS (P = 0.0079) maps to functional domains that show evidence of positive selection during primate evolution. Our structural variation analysis in >2,400 individuals reveals five recurrent rearrangement breakpoints that show variable frequency among AMD cases and controls. These data suggest a dynamic and recurrent pattern of mutation critical to the emergence of new CFHR genes but also in the predisposition to complex human genetic disease phenotypes.
Understanding the mechanisms allowing invasive species to adapt to novel environments is a challenge in invasion biology. Many invaders demonstrate rapid evolution of behavioural traits involved in ...range expansion such as locomotor activity, exploration and risk‐taking. However, the molecular mechanisms that underpin these changes are poorly understood. In 86 years, invasive cane toads (Rhinella marina) in Australia have drastically expanded their geographic range westward from coastal Queensland to Western Australia. During their range expansion, toads have undergone extensive phenotypic changes, particularly in behaviours that enhance the toads’ dispersal ability. Common‐garden experiments have shown that some changes in behavioural traits related to dispersal are heritable. At the molecular level, it is currently unknown whether these changes in dispersal‐related behaviour are underlain by small or large differences in gene expression, nor is known the biological function of genes showing differential expression. Here, we used RNA‐seq to gain a better understanding of the molecular mechanisms underlying dispersal‐related behavioural changes. We compared the brain transcriptomes of toads from the Hawai'ian source population, as well as three distinct populations from across the Australian invasive range. We found markedly different gene expression profiles between the source population and Australian toads. By contrast, toads from across the Australian invasive range had very similar transcriptomic profiles. Yet, key genes with functions putatively related to dispersal behaviour showed differential expression between populations located at each end of the invasive range. These genes could play an important role in the behavioural changes characteristic of range expansion in Australian cane toads.
Gene expression levels are key molecular phenotypes at the interplay between genotype and environment. Mounting evidence suggests that short‐term changes in environmental conditions, such as those ...encountered in captivity, can substantially affect gene expression levels. Yet, the exact magnitude of this effect, how general it is, and whether it results in parallel changes across populations are not well understood. Here, we take advantage of the well‐studied cane toad, Rhinella marina, to examine the effect of short‐term captivity on brain gene expression levels, and determine whether effects of captivity differ between long‐colonized and vanguard populations of the cane toad's Australian invasion range. We compared the transcriptomes of wild‐caught toads immediately assayed with those from toads captured from the same populations but maintained in captivity for seven months. We found large differences in gene expression levels between captive and wild‐caught toads from the same population, with an over‐representation of processes related to behaviour and the response to stress. Captivity had a much larger effect on both gene expression levels and gene expression variability in toads from vanguard populations compared to toads from long‐colonized areas, potentially indicating an increased plasticity in toads at the leading edge of the invasion. Overall, our findings indicate that short‐term captivity can induce large and population‐specific transcriptomic changes, which has significant implications for studies comparing phenotypic traits of wild‐caught organisms from different populations that have been held in captivity.
IMPORTANCE: Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal ...transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus. OBJECTIVE: To identify genetic susceptibility regions for keratoconus in the human genome. DESIGN, SETTING, AND PARTICIPANTS: This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10−6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019. MAIN OUTCOMES AND MEASURES: Associations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components. RESULTS: The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10−8), with a P value of 7.46 × 10−9 at rs61876744 in patatin-like phospholipase domain–containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10−12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10−6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10−7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10−8). CONCLUSIONS AND RELEVANCE: In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.
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