Nysa Łużycka – Klimat i Charakterystyka Regionu –

In dem EU-Projekt NEYMO – Lausitzer Neiße/Nysa Łużycka – Klimatische und hydrologische Modellierung, Analyse und Prognose – werden gemeinsam mit dem polnischen Projektpartner (IMGW-PIB) die klimatischen und hydrologischen Verhältnisse und das Wasserdargebot im Einzugsgebiet der Lausitzer Neiße untersucht. Schwerpunkt der Broschüre sind die Ergebnisse der Klimaanalyse, bei der das Klima der letzten 40 Jahre sowie verschiedene Klimaprojektionen für die Grenzregion Lausitzer Neiße bis zum Ende des 21. Jahrhunderts betrachtet wurden. Trendtests zeigten, dass bereits in den letzten 40 Jahren Zunahmen der Temperaturen, Sonnenscheindauer und potenziellen Verdunstung beobachtet wurden. Diese Trends werden sich laut der verwendeten Klimaprojektionen weiter fortsetzen. Die Niederschlagsmengen zeigten in der Vergangenheit einen leicht positiven Trend, weisen jedoch in den Projektionsdaten einen Rückgang auf. Aus klimatologischer Sicht verschlechtert sich somit die Wasserverfügbarkeit, insbesondere im Sommerhalbjahr.W ramach realizacji unijnego projektu „NEYMO Lausitzer Neiße/Nysa Lużycka – Modelowanie klimatyczne i hydrologiczne, Analiza i Prognoza”, wspólnie z polskim partnerem projektu (IMGW-PIB) przeprowadzane są badania dotyczące warunków klimatycznych i hydrologicznych oraz zasobów wodnych regionu zlewni Nysy Łużyckiej. Wielkość zasobów wodnych jest analizowana z uwzględnieniem zarówno zmian warunków klimatycznych, jak i planowanego korzystania z zasobów wodnych w regionie. Na tej podstawie opracowywana jest wspólna strategia ukierunkowana na zwiększenie efektywności gospodarki wodnej w regionie granicznym. Broszura zawiera podstawowe informacje o projekcie, charakterystykę obszaru badań oraz opis klimatu. Warunki klimatyczne regionu granicznego zlewni Nysy Łużyckiej przedstawiono na podstawie obserwacji z ostatnich 40 lat, a także danych z projekcji klimatycznych sięgających końca XXI w. Charakterystyka klimatu została opracowana korzystając z wybranych wskaźników, dotyczących głównie opadów atmosferycznych, suszy oraz warunków radiacyjnych. Trendy zmian dla ostatnich 40 lat wskazują na wzrost temperatury powietrza, usłonecznienia i parowania potencjalnego. Na podstawie opracowanych projekcji klimatycznych można stwierdzić, że tendencja ta zostanie utrzymana również w przyszłości. W przypadku opadów atmosferycznych obserwowany jest słaby trend rosnący. Natomiast projekcje klimatu wskazują, że w przyszłości należy się spodziewać zmniejszenia sum opadów. Z punktu widzenia klimatu, dostępność zasobów wodnych zwłaszcza w miesiącach letnich, może ulec zmniejszeniu

Klimaprojektionen, Luftverschmutzung und Belastungsgrenzen von Ökosystemen: Klimawandel, Luftverschmutzung und ökologische Belastungsgrenzen von Ökosystemen im polnisch-sächsischen Grenzraum

Im Rahmen des regionalen Klimaprojektes KLAPS werden Klimawandel, Luftverschmutzung und ökologische Belastungsgrenzen im polnisch-sächsischen Grenzraum untersucht. Mit dem vorliegenden Bericht liegt eine umfassende Analyse über die zukünftig mögliche klimatische und lufthygienische Entwicklung bis zum Jahr 2100 vor. Aufbauend auf den projizierten Klima- und Emissionsszenarien werden sowohl die Entwicklung als auch Überschreitung von Belastungsgrenzen von Ökosystemen (Critical Load) dargestellt. Redaktionsschluss: 30.10.201

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Common breast cancer susceptibility alleles are associated with tumor subtypes in BRCA1 and BRCA2 mutation carriers : results from the Consortium of Investigators of Modifiers of BRCA1/2.

Abstract Introduction Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 &#215; 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation