The Evolution of Hemophilia Therapeutics: An Illustrated Review.

Hemophilia is a rare genetic bleeding disorder historically associated with high morbidity and mortality. Some individuals with hemophilia suffer associated chronic joint disease, chronic pain, and other physical and mental health challenges. In the last 50 years, a better understanding of the pathophysiology of the disease has resulted in extraordinary therapeutic advances leading to enhanced quality of life and increased life expectancy. We present an illustrated review of the evolution of hemophilia treatment from the development of non-factor therapies to gene therapy.

Autoimmune Myelofibrosis in a 12-Year-old Male With Monosomy 7, Systemic Lupus Erythematous and Lupus Nephritis: A Case Report and Review of the Literature.

Complete or partial loss of chromosome 7 is a common and well-known cytogenetic abnormality associated with preleukemic myelodysplasia and myeloid leukemia but not with autoimmune myelofibrosis. Detection of this molecular change represents poor prognosis. When malignant transformation occurs, the condition tends to be chemotherapy-resistant requiring haematopoietic stem cell transplantation (HSCT) to obtain a cure. Disappearance after immunosuppressive therapy has been documented in children with hematological disorders but not in association with cyclophosphamide and systemic lupus erythematous.We present the interesting case of a 12-year-old male with monosomy 7, systemic lupus erythematous, and lupus nephritis with the resolution of the monosomy 7 and autoimmune myelofibrosis after treatment with cyclophosphamide, along with a review of the literature.

Successful Haploidentical Bone Marrow Transplantation of an Infant With a Novel Mutation in SAMD9L Gene (Ataxia-Pancytopenia Syndrome).

Data regarding the outcomes of hematopoietic stem cell transplant (HSCT) for the management of SAMD9L -associated ataxia-pancytopenia syndrome remains limited. We depict the case of a 2-month-old male with a novel mutation in the SAMD9L gene, presenting with respiratory failure, pancytopenia and severe developmental delay. He experienced graft failure 2 months after a 4/6 HLA-matched cord HSCT. At 9 months old, an unsuccessful unrelated donor search prompted a haploidentical HSCT with successful engraftment. He sustains excellent donor chimerism and has improved developmentally over 2 years posttransplant. This case demonstrates haploidentical HSCT as a viable option for patients with SAMD9L mutation and no acceptable unrelated donor.

Multisystem Inflammatory Syndrome in a Pediatric Patient With Sickle Cell Disease and COVID-19: A Case Report.

To this day, there are limited data about the effects and management of coronavirus disease infection in pediatric patients with sickle cell disease. We present the management and successful clinical course of an 8-year-old female with homozygous sickle cell disease (SS) and severe acute chest syndrome secondary to coronavirus disease 2019 infection, complicated by cortical vein thrombosis.

Obesity-related genetic determinants of stroke.

As obesity, circulating lipids and other vascular/metabolic factors influence the risk of stroke, we examined if genetic variants associated with these conditions are related to risk of stroke using a case-control study in Galicia, Spain. A selection of 200 single-nucleotide polymorphisms previously found to be related to obesity, body mass index, circulating lipids, type 2 diabetes, heart failure, obesity-related cancer and cerebral infarction were genotyped in 465 patients diagnosed with stroke and 480 population-based controls. An unsupervised Lasso regression procedure was carried out for single-nucleotide polymorphism selection based on their potential effect on stroke according to obesity. Selected genotypes were further analysed through multivariate logistic regression to study their association with risk of stroke. Using unsupervised selection procedures, nine single-nucleotide polymorphisms were found to be related to risk of stroke overall and after stratification by obesity. From these, rs10761731, rs2479409 and rs6511720 in obese subjects [odds ratio (95% confidence interval) = 0.61 (0.39-0.95) (P = 0.027); 0.54 (0.35-0.84) (P = 0.006) and 0.42 (0.22-0.80) (P = 0.0075), respectively], and rs865686 in non-obese subjects [odds ratio (95% confidence interval) = 0.67 (0.48-0.94) (P = 0.019)], were independently associated with risk of stroke after multivariate logistic regression procedures. The associations between the three single-nucleotide polymorphisms found to be associated with stroke risk in obese subjects were more pronounced among females; for rs10761731, odds ratios among obese males and females were 1.07 (0.58-1.97) (P = 0.84), and 0.31 (0.14-0.69) (P = 0.0018), respectively; for rs2479409, odd ratios were 0.66 (0.34-1.27) (P = 0.21), and 0.49 (0.24-0.99) (P = 0.04), for obese males and females, respectively; the stroke-rs6511720 association was also slightly more pronounced among obese females, odds ratios were 0.33 (0.13-0.87) (P = 0.022), and 0.28 (0.09-0.85) (P = 0.02) for obese males and females, respectively. The rs865686-stroke association was more pronounced among non-obese males [odds ratios = 0.61 (0.39-0.96) (P = 0.029) and 0.72 (0.42-1.22) (P = 0.21), for non-obese males and females, respectively]. A combined genetic score of variants rs10761731, rs2479409 and rs6511720 was highly predictive of stroke risk among obese subjects (P = 2.04 × 10-5), particularly among females (P = 4.28 × 10-6). In summary, single-nucleotide polymorphisms rs1076173, rs2479409 and rs6511720 were found to independently increase the risk of stroke in obese subjects after adjustment for established risk factors. A combined score with the three genomic variants was an independent predictor of risk of stroke among obese subjects in our population.

LIPG endothelial lipase and breast cancer risk by subtypes.

Experimental data showed that endothelial lipase (LIPG) is a crucial player in breast cancer. However, very limited data exists on the role of LIPG on the risk of breast cancer in humans. We examined the LIPG-breast cancer association within our population-based case-control study from Galicia, Spain, BREOGAN (BREast Oncology GAlicia Network). Plasma LIPG and/or OxLDL were measured on 114 breast cancer cases and 82 controls from our case-control study, and were included in the present study. The risk of breast cancer increased with increasing levels of LIPG (multivariable OR for the highest category (95% CI) 2.52 (1.11-5.81), P-trend = 0.037). The LIPG-breast cancer association was restricted to Pre-menopausal breast cancer (Multivariable OR for the highest LIPG category (95% CI) 4.76 (0.94-28.77), P-trend = 0.06, and 1.79 (0.61-5.29), P-trend = 0.372, for Pre-menopausal and Post-menopausal breast cancer, respectively). The LIPG-breast cancer association was restricted to Luminal A breast cancers (Multivariable OR for the highest LIPG category (95% CI) 3.70 (1.42-10.16), P-trend = 0.015, and 2.05 (0.63-7.22), P-trend = 0.311, for Luminal A and non-Luminal A breast cancers, respectively). Subset analysis only based on HER2 receptor indicated that the LIPG-breast cancer relationship was restricted to HER2-negative breast cancers (Multivariable OR for the highest LIPG category (95% CI) 4.39 (1.70-12.03), P-trend = 0.012, and 1.10 (0.28-4.32), P-trend = 0.745, for HER2-negative and HER2-positive tumors, respectively). The LIPG-breast cancer association was restricted to women with high total cholesterol levels (Multivariable OR for the highest LIPG category (95% CI) 6.30 (2.13-20.05), P-trend = 0.018, and 0.65 (0.11-3.28), P-trend = 0.786, among women with high and low cholesterol levels, respectively). The LIPG-breast cancer association was also restricted to non-postpartum breast cancer (Multivariable OR for the highest LIPG category (95% CI) 3.83 (1.37-11.39), P-trend = 0.003, and 2.35 (0.16-63.65), P-trend = 0.396, for non-postpartum and postpartum breast cancer, respectively), although we lacked precision. The LIPG-breast cancer association was more pronounced among grades II and III than grade I breast cancers (Multivariable ORs for the highest category of LIPG (95% CI) 2.73 (1.02-7.69), P-trend = 0.057, and 1.90 (0.61-6.21), P-trend = 0.170, for grades II and III, and grade I breast cancers, respectively). No association was detected for OxLDL levels and breast cancer (Multivariable OR for the highest versus the lowest category (95% CI) 1.56 (0.56-4.32), P-trend = 0.457).

Residential radon, genetic polymorphisms in DNA damage and repair-related.

OBJECTIVES: To analyze the relationship of GSTT1, GSTM1, XRCC1 (rs25487), ERCC1 (rs11615, rs3212986), ERCC2 (rs13181), XRCC3 (rs861539), OGG1 (rs1052133), and Alpha-1-Antitrypsin mutations (AAT) with the risk of lung cancer in never-smokers, and ascertain if there is an effect modification between these polymorphisms and residential radon exposure. MATERIAL AND METHODS: We designed a multicenter hospital-based case-control study in a radon-prone area. 322 cases and 338 controls, all never-smokers, were included. They were selected using a frequency sampling based on sex and age distribution of the cases. Participants donated 3 ml. of whole blood used to determine genotype for polymorphisms. They placed a radon detector to measure residential radon exposure in their dwelling. RESULTS: The OR for deleted GSTM1 patients was 3.46 (95% CI = 1.52-7.89) at residential radon exposures above 200 Bq/m3. The ERCC1 rs3212986 polymorphism was the most associated with the risk of developing lung cancer, both for low and high radon exposures. The ERCC1 rs321986 GT and TT genotypes (at radon concentrations >200 Bq/m3) were more significantly associated with higher lung cancer risk (OR = 2.40, 95% CI = 1.29-4.45; OR = 4.45, 95% CI = 1.26-15.7, respectively). CONCLUSIONS: These findings support the hypothesis that certain polymorphisms in genes involved in DNA-repair and carriers of GSTM1 deletion have an increased risk of lung cancer in never-smokers exposed to residential radon.

A new panel of SNPs to assess thyroid carcinoma risk: a pilot study in a Brazilian admixture population.

BACKGROUND: Thyroid cancer is a common malignant disease of the endocrine system with increasing incidence rates over the last few decades. In this study, we sought to analyze the possible association of 45 single nucleotide polymorphisms (SNPs) with thyroid cancer in a population from Rio Grande do Norte, Brazil. METHODS: Based on histological analysis by a pathologist, 80 normal thyroid specimens of tissue adjacent to thyroid tumors were obtained from the biobank at the Laboratory of Pathology of Liga Norte Riograndense Contra o Câncer, Natal, RN. Patient samples were then genotyped using the MassARRAY platform (Sequenon, Inc) followed by statistical analysis employing the SNPassoc package in R program. The genotypic frequencies of all 45 SNPs obtained from the International HapMap Project database and based on data from the ancestral populations of European and African origin were used to compose the control study group. RESULTS: In our study, the following 9 SNPs showed significant differences in their frequency when comparing the study and control groups: rs3744962, rs258107, rs1461855, rs4075022, rs9943744, rs4075570, rs2356508, rs17485896, and rs2651339. Furthermore, the SNPs rs374492 C/T and rs258107 C/T were associated with a relative risk for thyroid carcinoma of 3.78 (p = 6.27 × 10e-5) and 2.91 (p = 8.27 × 10e-5), respectively, after Bonferroni's correction for multiple comparisons. CONCLUSIONS: These nine polymorphisms could be potential biomarkers of predisposition to thyroid carcinoma in the population from Rio Grande do Norte. However, complementary studies including a control group with samples obtained from healthy subjects in Rio Grande do Norte state, should be conducted to confirm these results.

Variations in the Genome: The Mutation Detection 2015 Meeting on Detection, Genome Sequencing, and Interpretation.

The content of the 13th Mutation Detection meeting (Leiden, April 2015) is summarized in this report. Topics discussed at the meeting included current challenges of clinical NGS, advances in bioinformatics, data quality control, single cell analysis and RNA sequencing, among others. Social, ethical and regulatory challenges of genomic data handling and data sharing were the focus of an expert panel debate. The 14th International Symposium on Variants in the Genome will take place in Santiago de Compostela, June 5-8, 2017. http://isv.variome.org.

Cuba: exploring the history of admixture and the genetic basis of pigmentation using autosomal and uniparental markers.

We carried out an admixture analysis of a sample comprising 1,019 individuals from all the provinces of Cuba. We used a panel of 128 autosomal Ancestry Informative Markers (AIMs) to estimate the admixture proportions. We also characterized a number of haplogroup diagnostic markers in the mtDNA and Y-chromosome in order to evaluate admixture using uniparental markers. Finally, we analyzed the association of 16 single nucleotide polymorphisms (SNPs) with quantitative estimates of skin pigmentation. In the total sample, the average European, African and Native American contributions as estimated from autosomal AIMs were 72%, 20% and 8%, respectively. The Eastern provinces of Cuba showed relatively higher African and Native American contributions than the Western provinces. In particular, the highest proportion of African ancestry was observed in the provinces of Guantánamo (40%) and Santiago de Cuba (39%), and the highest proportion of Native American ancestry in Granma (15%), Holguín (12%) and Las Tunas (12%). We found evidence of substantial population stratification in the current Cuban population, emphasizing the need to control for the effects of population stratification in association studies including individuals from Cuba. The results of the analyses of uniparental markers were concordant with those observed in the autosomes. These geographic patterns in admixture proportions are fully consistent with historical and archaeological information. Additionally, we identified a sex-biased pattern in the process of gene flow, with a substantially higher European contribution from the paternal side, and higher Native American and African contributions from the maternal side. This sex-biased contribution was particularly evident for Native American ancestry. Finally, we observed that SNPs located in the genes SLC24A5 and SLC45A2 are strongly associated with melanin levels in the sample.

Gene expression profile in oral squamous cell carcinoma: a pilot study.

PURPOSE: To study the gene expression profile of oral squamous cell carcinomas. MATERIALS AND METHODS: Gene expression profile was investigated in oral squamous cell carcinomas in 5 patients using the Atlas Glass Human 3.8 I Microarray (which detects cDNA obtained from cellular total RNA) (Clontech Laboratories, Palo Alto, CA). Data were normalized by the LOWESS method. Statistical significances of deviations from a 1:1 ratio were evaluated by t tests, with P<.05. RESULTS: Of the 3,757 genes analyzed, 322 (8.6%) were significantly overexpressed in tumoral tissue with respect to normal tissue, while 104 (2.8%) were significantly underexpressed. The affected genes fell into a wide range of functional categories. CONCLUSION: We consider that cDNA microarrays are of clear value for investigating the biology of these tumors, and that this technology may help in the molecular classification of oral squamous cell carcinomas and in the identification of targets for gene therapy.

DNA microarrays in oral cancer.

One of the principal aims of modern cancer research is to identify markers allowing individual prediction of prognosis or response to treatment. In this connection, the number of genes thought to be involved in the different stages of different types of oral cancer increases apace. DNA microarrays allow simultaneous evaluation of the expression of hundreds of genes in a single assay. The parallel format of microassay slides is designed to allow rapid comparison of gene expression between two samples, for example tumor cells and healthy cells. This article reviews studies that have aimed to identify genes related to oral cancer, and to classify these genes into groups that are commonly co-expressed. These studies suggest that DNA microarrays are set to become routine tools in the detection, diagnosis, characterization and treatment of oral cancers.