Combination of phenotype and polygenic risk score in breast cancer risk evaluation in the Spanish population: a case -control study.

BACKGROUND: In recent years, the identification of genetic and phenotypic biomarkers of cancer for prevention, early diagnosis and patient stratification has been a main objective of research in the field. Different multivariable models that use biomarkers have been proposed for the evaluation of individual risk of developing breast cancer. METHODS: This is a case control study based on a population-based cohort. We describe and evaluate a multivariable model that incorporates 92 Single-nucleotide polymorphisms (SNPs) (Supplementary Table S1) and five different phenotypic variables and which was employed in a Spanish population of 642 healthy women and 455 breast cancer patients. RESULTS: Our model allowed us to stratify two groups: high and low risk of developing breast cancer. The 9th decile included 1% of controls vs 9% of cases, with an odds ratio (OR) of 12.9 and a p-value of 3.43E-07. The first decile presented an inverse proportion: 1% of cases and 9% of controls, with an OR of 0.097 and a p-value of 1.86E-08. CONCLUSIONS: These results indicate the capacity of our multivariable model to stratify women according to their risk of developing breast cancer. The major limitation of our analysis is the small cohort size. However, despite the limitations, the results of our analysis provide proof of concept in a poorly studied population, and opens up the possibility of using this method in the routine screening of the Spanish population.

An atypical IgM class platelet cold agglutinin induces GPVI-dependent aggregation of human platelets.

Platelet cold agglutinins (PCA) cause pseudothrombocytopenia, spurious thrombocytopenia due to ex vivo platelet clumping, complicating clinical diagnosis, but mechanisms and consequences of PCA are not well defined. Here, we characterised an atypical immunoglobulin (Ig)M PCA in a 37-year-old woman with lifelong bleeding and chronic moderate thrombocytopenia, that induces activation and aggregation of autologous or allogeneic platelets via interaction with platelet glycoprotein (GP)VI. Patient temperature-dependent pseudothrombocytopenia was EDTA-independent, but was prevented by integrin αIIbß3 blockade. Unstimulated patient platelets revealed elevated levels of bound IgM, increased expression of activation markers (P-selectin and CD63), low GPVI levels and abnormally high thromboxane (TX)A2 production. Patient serum induced temperature- and αIIbß3-dependent decrease of platelet count in allogeneic donor citrated platelet-rich plasma (PRP), but not in PRP from Glanzmann's thrombasthenia or afibrinogenaemia patients. In allogeneic platelets, patient plasma induced shape change, P-selectin and CD63 expression, (14)C-serotonin release, and TXA2 production. Activation was not inhibited by aspirin, cangrelor or blocking anti-Fc receptor (FcγRIIA) antibody, but was abrogated by inhibitors of Src and Syk, and by a soluble GPVI-Fc fusion protein. GPVI-deficient platelets were not activated by patient plasma. These data provide the first evidence for an IgM PCA causing platelet activation/aggregation via GPVI. The PCA activity persisted over a five-year follow-up period, supporting a causative role in patient chronic thrombocytopenia and bleeding.

Hermansky-Pudlak syndrome. Overview of clinical and molecular features and case report of a new HPS-1 variant.

Hermansky-Pudlak syndrome (HPS) is a rare, autosomal recessive disorder affecting lysosome-related organelles (LRO), including dense platelet granules. HPS causes oculocutaneous hypopigmentation, bleeding diathesis and granulomatous colitis or pulmonary fibrosis. To date, there is no curative treatment and the clinical management depends on the severity of symptoms. A prompt diagnosis of HPS patients could improve their quality of life and clinical management. However, the absence of a specific platelet function test, the wide molecular heterogeneity, and the lack of phenotype-genotype correlations hamper the rapid diagnosis. Nine subtypes of HPS have been identified as a result of mutations in nine genes that codify for proteins involved in formation and shuttle of the LRO. The molecular characterization of patients and knowledge derived from animal models of HPS contribute to the understanding of biogenesis and function of the LRO. This paper describes a patient with a novel homozygous nonsense mutation causing HPS and provides a review of the literature focusing on recent advances in the molecular characterization and physiopathology of HPS.

Evaluation of two-step haemoglobin screening with HemoCue for blood donor qualification in mobile collection sites.

BACKGROUND AND OBJECTIVES: Inaccuracy of fingerstick haemoglobin compromises donor's health and losses blood donations. We evaluated the benefit of double haemoglobin screening with HemoCue. STUDY DESIGN AND METHODS: Blood donors underwent fingerstick screening by HemoCue and were driven for donation if capillary haemoglobin was within the regulatory range. Those failing were drawn venous blood and donated if their venous haemoglobin determined with HemoCue was acceptable. RESULTS: Of 276 605 donor clinic visits, 10 011 (3·6%) were assessed by two-step haemoglobin screening using HemoCue, because of low (n = 9444) or high (n = 567) capillary haemoglobin. Among these, 2561 (25·6%) were deemed eligible [recovered donations]. The recovery rate was 23·8% and 55·0% among donors presenting with low and high capillary haemoglobin, respectively. In both categories of attempted donations, capillary and venous haemoglobin with HemoCue correlated significantly in recovered donors (R(2)  ≈ 0·5-0·7) but not in deferred visits (R(2)  < 0·15). Venous haemoglobin with HemoCue and by haematological analyzer significantly correlated in all donations attempts (R(2)  ≈ 0·7). Donors presenting with low capillary haemoglobin showed small bias between capillary and venous haemoglobin by HemoCue (-2·4 ± 6·2 g/l), fingerstick haemoglobin and venous haemoglobin with counter (1·3 ± 7·3 g/l), and venous haemoglobin with HemoCue and counter (3·7 ± 3·9 g/l). This bias was slightly greater in donors with high capillary haemoglobin (-7·5 ± 7·8, 13·7 ± 7·5, and 6·2 ± 7·5, respectively). Double haemoglobin screening by HemoCue reached an accuracy of 87·3% for qualifying donors presenting with low fingerstick haemoglobin. CONCLUSIONS: Double haemoglobin measurement with HemoCue [fingerstick and venous blood if required] is feasible and allows a significant recovery of blood donations.