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Aims/hypothesis: Gestational diabetes mellitus (GDM) is the most common disorder in pregnancy; however, its underlying causes remain obscure. This study aimed to investigate the genetic and molecular risk factors contributing to GDM and glycaemic traits. Methods: We collected non-invasive prenatal test (NIPT) sequencing data along with four glycaemic and 55 biochemical measurements from 30,699 pregnant women during a 2 year period at Shenzhen Baoan Women's and Children's Hospital in China. Genome-wide association studies (GWAS) were conducted between genotypes derived from NIPTs and GDM diagnosis, baseline glycaemic levels and glycaemic levels after glucose challenges. In total, 3317 women were diagnosed with GDM, while 19,565 served as control participants. The results were replicated using two independent cohorts. Additionally, we performed one-sample Mendelian randomisation to explore potential causal associations between the 55 biochemical measurements and risk of GDM and glycaemic levels. Results: We identified four genetic loci significantly associated with GDM susceptibility. Among these, MTNR1B exhibited the highest significance (rs10830963-G, OR [95% CI] 1.57 [1.45, 1.70], p=4.42×10–29), although its effect on type 2 diabetes was modest. Furthermore, we found 31 genetic loci, including 14 novel loci, that were significantly associated with the four glycaemic traits. The replication rates of these associations with GDM, fasting plasma glucose levels and 0 h, 1 h and 2 h OGTT glucose levels were 4 out of 4, 6 out of 9, 10 out of 11, 5 out of 7 and 4 out of 4, respectively. Mendelian randomisation analysis suggested that a genetically regulated higher lymphocytes percentage and lower white blood cell count, neutrophil percentage and absolute neutrophil count were associated with elevated glucose levels and an increased risk of GDM. Conclusions/interpretation: Our findings provide new insights into the genetic basis of GDM and glycaemic traits during pregnancy in an East Asian population and highlight the potential role of inflammatory pathways in the aetiology of GDM and variations in glycaemic levels. Data availability: Summary statistics for GDM; fasting plasma glucose; 0 h, 1 h and 2h OGTT; and the 55 biomarkers are available in the GWAS Atlas (study accession no.: GVP000001, https://ngdc.cncb.ac.cn/gwas/browse/GVP000001). [ABSTRACT FROM AUTHOR]

The clinical role of the molecular endometrial cancer (EC) classification has not been fully explored in patients staged with lymphadenectomy or without adjuvant treatment, conditions that could potentially moderate the prognostic value of the classification. We aimed to evaluate the clinical outcome of the molecular subgroups in patients with high-grade EC staged by lymphadenectomy and those without adjuvant treatment. DNA-sequencing for the detection of pathogenic POLE -exonuclease domain mutations and immunohistochemistry for mismatch repair (MMR) proteins and p53 expression were performed on 412 high-grade EC from the Danish Gynaecological Cancer Database (2005–2012) to classify them as POLE -ultramutated (POLE mut), MMR-deficient (MMRd), p53-mutant (p53abn), or no specific molecular profile (NSMP). Patients with stage IV or residual disease after surgery were excluded. Kaplan-Meier method, log-rank test and Cox proportional hazard models were used for analysis. Molecular analysis was successful in 367 EC; 251 patients had undergone lymphadenectomy. Five-year recurrence rates in this subgroup of patients was 36.7% for women with p53abn EC, 0.0% for POLE mut EC, 13.4% for MMRd EC and 42.9% for NSMP EC (p < 0.001). Similar results were observed among stage IA-IB patients. Among patients without adjuvant treatment (n = 264), none with POLE mut EC (n = 26) had a recurrence. The molecular EC classification has strong prognostic value, independent of clinicopathological factors, also among high-grade EC patients staged by lymphadenectomy and those without adjuvant treatment. The unfavourable prognosis of early-stage p53abn EC is not due to undetected lymph node metastasis, and the indolent behaviour of POLE mut EC is independent of adjuvant treatment. • The molecular endometrial cancer (EC) classification has independent prognostic value among women with high-grade EC. • P53 abnormal EC have a poor clinical outcome, also those staged by lymphadenectomy as stage I. • Patients with POLE- ultramutated EC have an excellent clinical outcome even when not receiving adjuvant treatment. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is a chronic autoimmune disease of the joints of unknown etiopathogenesis. It affects between ~0.5 and 1% of the total population and occurs 2-3 times more often in women than in men. Several antibodies have been identified in the serum of patients with RA, including rheumatoid factors (RF), anti-citrullinated protein antibodies (ACPA) and anti-carbamylated protein antibodies. These autoantibodies can form immune complexes in the joints, leading to inflammation and damage to the articular cartilage. A characteristic symptom of advanced RA is persistent inflammation of the synovium, which usually affects peripheral joints in a symmetrical way. The exact aetiology of RA is unclear,it is known to be a multifactor disease in which a complex interplay between the host and the environment determines the overall risk of being susceptible to the disease, as well as its persistence and severity. Below we present the RA risk factors including main individual risk factors as hormonal factors, hereditery factors, epigenetic factors as well as the risk of concomitant environmental factors of RA as diet, cigarettes and alcohol abuse. Environmental contaminants, socio-economic factors and molecular mechanisms of RA known so far.

To date risk stratification in acute promyelocytic leukemia (APL) is based on highly dynamic leukocyte and platelet counts only. To identify a more robust risk stratification model, a molecular risk score was developed based on expression levels of the genes BAALC , ERG and WT1 . Hereby, the main focus was on prediction of relapse. The integrative risk score divided patients into two groups with highly significant differences in outcome. It discriminated a high risk group with a high incidence of relapse successfully from a low risk group with no APL-related events after achievement of first remission. Especially the concurrent presence of molecular risk factors showed to be a negative prognostic factor in APL. The molecular risk score might be a promising approach to guide monitoring of APL patients and therapeutic decisions in the future. [ABSTRACT FROM AUTHOR]

We explored the role of CD38 and functionally associated molecular risk factors in a recently described chronic lymphocytic leukemia (CLL) nonobese diabetic/ severe combined immunodeficient xenograft model. Intravenous injection of peripheral blood mononuclear cells from 73 patients with CLL into 244 mice resulted in robust engraftment of leukemic cells into the murine spleens detected 4 wks after transplantation. Leukemic cell engraftment correlated significantly ( P < 0.05) with markers reflecting disease activity, e.g., Binet stage and lymphocyte doubling time, and the expression of molecular risk factors including CD38, CD49d, ZAP-70, and IgVH mutational status. Increased engraftment levels of CD38+ as compared to CD38− CLL cells could be attributed, in part, to leukemic cell proliferation as evidenced by combined immunostaining of murine spleen sections for Ki-67 and CD20. In short-term (24 h) homing assays, CD38+ CLL cells migrated more efficiently to the bone marrow of the recipient animals than their CD38− counterparts. Finally, CD38 expression by the leukemic cells was found to be dynamic in that it was regulated not only by elements of the murine microenvironment but also by co-engrafting non-malignant human T cells. This model could be useful for evaluating the biological basis of CLL growth in the context of the hematopoietic microenvironment as well as preclinical testing of novel compounds. [ABSTRACT FROM AUTHOR]

Inflammation plays a key role in atherothrombosis: in the development of plaques, plaque rupture and thrombus formation. Various biochemical substances have been shown to be involved in the inflammatory process, some with proinflammatory activity and others with anti-inflammatory activity. Increased expression of many inflammatory mediators (e.g. C-reactive protein, CD40 ligand, P-selectin and IL-6) has been shown to correlate with increased risk of atherothrombotic events. One possible strategy for primary and secondary prevention is likely to focus on minimizing the inflammatory response and tipping the balance in favour of antiinflammatory mediators and, therefore, plaque stability. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with inflammatory bowel disease are at an increased risk of developing colorectal cancer, and so are enrolled in a surveillance colonoscopy programme aimed at detecting and treating any signs of early cancer. This review describes the current known risk factors associated with this increased risk, explores our current molecular understanding of cancer development and reviews potential new methods (molecular and technological) designed to help the surveillance programme. Patients with colonic inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC), and are therefore enrolled into a surveillance programme aimed at detecting dysplasia or early cancer. Current surveillance programmes are guided by clinical, endoscopic or histological predictors of colitis-associated CRC (CA-CRC). We have seen great progress in our understanding of these predictors of disease progression, and advances in endoscopic technique and management, along with improved medical care, has been mirrored by the falling incidence of CA-CRC over the last 50 years. However, more could be done to improve our molecular understanding of CA-CRC progression and enable better risk stratification for patients with IBD. This review summarises the known risk factors associated with CA-CRC and explores the molecular landscape that has the potential to complement and optimise the existing IBD surveillance programme. [ABSTRACT FROM AUTHOR]

Introduction: Although treatment of acute promyelocytic leukemia (APL) has evolved dramatically during the past decades, especially with the introduction of all-trans retinoic acid, risk stratification remains an important issue. To date, relapse risk can be predicted by leukocyte and platelet counts only. In the present report, we present a validation study on 3 candidate genes and a newly developed molecular risk score for APL in 2 independent patient cohorts., Patients and Methods: An integrative risk score combining the expression levels of BAALC, ERG, and WT1 was calculated for 79 de novo APL patients from the original cohort and 76 de novo APL patients from a validation cohort. Gene expression analysis was executed the same for both cohorts, and the results regarding the effect on patient outcomes were compared., Results: The expression levels of BAALC, ERG, and WT1 were similar in both cohorts compared with the healthy controls. The relapse and survival rates were not different between the low- and high-risk patients according to the Sanz score. However, application of the molecular risk score on the validation cohort distinctly discriminated patients according to their risk of relapse and death just as in the original APL cohort, although single gene analyses could not reproduce the negative prognostic impact., Conclusion: The analysis clearly validated the prognostic effect of the integrative risk score on the outcome in APL patients. The value was further empowered because the single gene analyses did not show similar results. Whether the integrative risk score retains its prognostic power in the chemotherapy-free setting should be investigated further., (Copyright © 2017 Elsevier Inc. All rights reserved.)