Chromosome 1 (chr1) copy number abnormalities (CNAs) and structural variants (SV) are frequent in newly diagnosed multiple myeloma (NDMM) and associate with a heterogeneous impact on outcome the ...drivers of which are largely unknown.
A multiomic approach comprising CRISPR, gene mapping of CNA and SV, methylation, expression, and mutational analysis was used to document the extent of chr1 molecular variants and their impact on pathway utilisation.
We identified two distinct groups of gain(1q): focal gains associated with limited gene expression changes and a neutral prognosis, and whole-arm gains, which associate with substantial gene expression changes, complex genetics and an adverse prognosis. CRISPR identified a number of dependencies on chr1 but only limited variants associated with acquired CNAs. We identified seven regions of deletion, nine of gain, three of chromothripsis (CT) and two of templated-insertion (TI), which contain a number of potential drivers. An additional mechanism involving hypomethylation of genes at 1q may contribute to the aberrant gene expression of a number of genes. Expression changes associated with whole-arm gains were substantial and gene set enrichment analysis identified metabolic processes, apoptotic resistance, signaling via the MAPK pathway, and upregulation of transcription factors as being key drivers of the adverse prognosis associated with these variants.
Multiple layers of genetic complexity impact the phenotype associated with CNAs on chr1 to generate its associated clinical phenotype. Whole-arm gains of 1q are the critically important prognostic group that deregulate multiple pathways, which may offer therapeutic vulnerabilities.
Gestational diabetes mellitus (GDM) is associated with future cardiovascular morbidity and recognized as a women-specific risk factor for cardiovascular disease. The mechanisms for this association ...are not well established. Therefore, we aimed to evaluate the cardiovascular-related biomarkers, galectin-3 (Gal-3) and protein convertase subtilisin/kexin (PCSK) type 9, in women with GDM.
Blood samples were drawn in the third trimester from 31 women diagnosed with GDM and from 35 women with normal pregnancies. Blood levels of Gal-3 and PCSK-9 were measured using a quantitative sandwich enzyme immunoassay. In addition, we measured Gal-3 levels in 24 pregnant women in the first trimester who later developed GDM and in 36 healthy controls. Continuous variables were compared using student's t-test and categorical variables by chi-square/fisher's exact tests.
We found increased levels of Gal-3 in women diagnosed with GDM compared to women without GDM (124.6±32% versus control; pv = 0.001). Furthermore, we demonstrated elevated levels of Gal-3 during the first trimester among women who later developed GDM compared with women who did not develop any gestational morbidity (125.7±32% versus control; pv = 0.004). Third-trimester levels of PCSK-9 did not differ between women with and without GDM (560±45ng/mL versus 553±33ng/mL; pv = 0.4).
The results suggest a possible mechanism that may link GDM to the future increased cardiovascular risk in these patients. Additionally, increased Gal-3 levels during the first trimester may suggest a new early predictor for GDM.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In a recent study of 10,011 pregnant women, 95% of miscarriages occurred before routine ultrasound scan at 11–14 weeks. Our study aimed to identify early first trimester parameters which may predict ...miscarriage before 10 weeks of gestation for in vitro fertilization (IVF) pregnancies.
A cohort of 115 healthy IVF patients with a singleton viable embryo in early first trimester were studied in a tertiary university-affiliated medical center (April 2017–June 2018). Calculations included gestational age (GA); ultrasound evaluation of crown-rump length (CRL), mean gestational sac diameter (GSD) and volume (GSV), mean yolk sac diameter (YSD) and volume (YSV); fetal heart rate (FHR), mean uterine arteries pulsatility index (UtA-PI); and maternal blood placental protein 13 (PP13) levels. Patients were divided into three groups by GA; and early miscarriage versus ongoing pregnancy after GA 10 weeks.
Early fetal loss occurred in 14.8% of patients; miscarriage group had higher discrepancy between calculated and measured GA (P < 0.001), lower GSD and GSV (P = 0.005 and P = 0.02, respectively), significantly different YSD and YSV, and lower GSD/YSD and GSV/YSV ratios (P = 0.001 and P = 0.003, respectively). UtA-PI/CRL ratio was higher in patients with miscarriage at GA 46–48 days and GA >48 days (P = 0.034 and P = 0.026, respectively). PP13/CRL ratio was higher in patients with miscarriage at GA >48 days (P = 0.041).
In IVF pregnancies with live embryo at first ultrasound scan, high UtA-PI/CRL and maternal blood PP13/CRL ratios may indicate impaired placentation preceded early pregnancy loss. A larger cohort is needed to further verify these predictions.
•Impaired placentation preceding miscarriage (<10 weeks) in viable IVF pregnancies.•Early miscarriage biomarkers can be identified at 6–8 weeks in viable IVF pregnancy.•High maternal blood PP13 versus CRL predicts early miscarriage in IVF pregnancy.•High uterine artery PI versus CRL is a stronger early miscarriage biomarker.•Early markers open new avenues for prediction and prevention of miscarriage at IVF.
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