Naturally occurring BRCA2 alternative mRNA splicing events in clinically relevant samples.

BACKGROUND: BRCA1 and BRCA2 are the two principal tumour suppressor genes associated with inherited high risk of breast and ovarian cancer. Genetic testing of BRCA1/2 will often reveal one or more sequence variants of uncertain clinical significance, some of which may affect normal splicing patterns and thereby disrupt gene function. mRNA analyses are therefore among the tests used to interpret the clinical significance of some genetic variants. However, these could be confounded by the appearance of naturally occurring alternative transcripts unrelated to germline sequence variation or defects in gene function. To understand which novel splicing events are associated with splicing mutations and which are part of the normal BRCA2 splicing repertoire, a study was undertaken by members of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium to characterise the spectrum of naturally occurring BRCA2 mRNA alternate-splicing events. METHODS: mRNA was prepared from several blood and breast tissue-derived cells and cell lines by contributing ENIGMA laboratories. cDNA representing BRCA2 alternate splice sites was amplified and visualised using capillary or agarose gel electrophoresis, followed by sequencing. RESULTS: We demonstrate the existence of 24 different BRCA2 mRNA alternate-splicing events in lymphoblastoid cell lines and both breast cancer and non-cancerous breast cell lines. CONCLUSIONS: These naturally occurring alternate-splicing events contribute to the array of cDNA fragments that may be seen in assays for mutation-associated splicing defects. Caution must be observed in assigning alternate-splicing events to potential splicing mutations.

Relevance Rank Platform (RRP) for Functional Filtering of High Content Protein-Protein Interaction Data.

High content protein interaction screens have revolutionized our understanding of protein complex assembly. However, one of the major challenges in translation of high content protein interaction data is identification of those interactions that are functionally relevant for a particular biological question. To address this challenge, we developed a relevance ranking platform (RRP), which consist of modular functional and bioinformatic filters to provide relevance rank among the interactome proteins. We demonstrate the versatility of RRP to enable a systematic prioritization of the most relevant interaction partners from high content data, highlighted by the analysis of cancer relevant protein interactions for oncoproteins Pin1 and PME-1. We validated the importance of selected interactions by demonstration of PTOV1 and CSKN2B as novel regulators of Pin1 target c-Jun phosphorylation and reveal previously unknown interacting proteins that may mediate PME-1 effects via PP2A-inhibition. The RRP framework is modular and can be modified to answer versatile research problems depending on the nature of the biological question under study. Based on comparison of RRP to other existing filtering tools, the presented data indicate that RRP offers added value especially for the analysis of interacting proteins for which there is no sufficient prior knowledge available. Finally, we encourage the use of RRP in combination with either SAINT or CRAPome computational tools for selecting the candidate interactors that fulfill the both important requirements, functional relevance, and high confidence interaction detection.

Vitamin D Status in Relation to the Clinical Outcome of Hospitalized COVID-19 Patients.

Coronavirus Disease (COVID-19) is a newly emerged infectious disease that first appeared in China. Vitamin D is a steroid hormone with an anti-inflammatory protective role during viral infections, including SARS-CoV-2 infection, via regulating the innate and adaptive immune responses. The study aimed to investigate the correlation between serum 25-hydroxyvitamin D (25[OH]D) levels and clinical outcomes of COVID-19. This was a retrospective study of 126 COVID-19 patients treated in NMC Royal Hospital, UAE. The mean age of patients was 43 ± 12 years. Eighty three percentage of patients were males, 51% patients were with sufficient (> 20 ng/mL), 41% with insufficient (12-20 ng/mL), and 8% with deficient (<12 ng/mL) serum 25(OH)D levels. There was a statistically significant correlation between vitamin D deficiency and mortality (p = 0.04). There was a statistically significant correlation between 25(OH)D levels and ICU admission (p = 0.03), but not with the need for mechanical ventilation (p = 0.07). The results showed increased severity and mortality by 9 and 13%, respectively, for each one-year increase in age. This effect was maintained after adjustment for age and gender (Model-1) and age, gender, race, and co-morbidities (Models-2,3). 25(OH)D levels (<12 ng/mL) showed a significant increase in mortality by eight folds before adjustments (p = 0.01), by 12 folds in Model-1 (p = 0.04), and by 62 folds in the Model-2. 25(OH)D levels (< 20 ng/mL) showed no association with mortality before adjustment and in Model-1. However, it showed a significant increase in mortality by 29 folds in Model-3. Neither 25(OH)D levels (<12 ng/mL) nor (< 20 ng/mL) were risk factors for severity. Radiological findings were not significantly different among patients with different 25(OH)D levels. Despite observed shorter time till viral clearance and time from cytokine release storm to recovery among patients with sufficient 25(OH)D levels, the findings were statistically insignificant. In conclusion, we demonstrated a significant correlation between vitamin D deficiency and poor COVID-19 outcomes.

ABO Blood Group in Relation to COVID-19 Susceptibility and Clinical Outcomes: A Retrospective Observational Study in the United Arab Emirates.

(1) Background: The association between ABO blood groups and COVID-19 outcomes was investigated in several studies. The results were controversial. This study aimed to explore the association between ABO blood groups and COVID-19 outcomes. (2) Methods: This retrospective study included 303 COVID-19 patients treated at the NMC Royal Hospital in the United Arab Emirates between 8 April 2020 and 30 June 2020. (3) Results: The mean age of patients included in the study was 39.3 ± 10.7 years, and 72.9% of patients were males. The prevalence of blood groups O, A, B, and AB was 40.3%, 27.7%, 25.1%, and 6.9%, respectively. The correlation between ABO blood groups and COVID-19 outcomes was insignificant except in the AB group, with significantly higher odds of disease severity. Increased age, higher body mass index (BMI), and being of male gender increased the risk for pneumonia among all blood groups. Both increased age and higher BMI increased the risk of mortality, and increased age increased the risk of disease severity. Troponin and platelet counts were significantly different in the A group compared to the non-A groups. Time to viral clearance was not different among blood groups. However, adjustment for Rh groups resulted in a significantly shorter time in the B group. (4) Conclusions: There was no significant association between ABO blood groups and COVID-19 outcomes, with the exception of group AB.

Haemodynamic instability secondary to cardiac involvement by lymphoma.

Cardiac involvement in lymphomas is not uncommon, but it is often missed due to the variability in its presentation. We present a case of bradycardia and complete heart block resulting in haemodynamic instability in a patient with recurrent diffuse large B-cell lymphoma. Timely diagnosis and appropriate management of such patients is crucial and requires a high index of suspicion. Our patient required temporary pacemaker implantation and intravenous corticosteroid therapy. His complete heart block and bradycardia eventually resolved after a course of radiation therapy.

The pathological role and prognostic impact of miR-181 in acute myeloid leukemia.

In addition to genetic abnormalities, such as chromosomal translocations and somatic mutations that have been widely acknowledged in the leukemogenesis of acute myeloid leukemia (AML), epigenetic modifications also play a vital role in this process. MicroRNA (miRNA) regulation is emerging as a new layer of epigenetic regulation besides DNA methylation and histone modifications. Among the miRNAs first identified to be specifically expressed in hematopoietic cells, the miR-181 family has been implicated in regulating the differentiation of B cells, T cells, and natural killer cells during normal hematopoiesis, and has been linked tightly to the pathogenesis and prognosis of AML. Accumulating evidence indicates that miR-181 acts as a tumor suppressor in the pathogenesis of AML and exhibits a significant impact on the survival of patients with AML. Herein, we review the role of miR-181 as a diagnostic marker and prognostic predictor in AML, and discuss the potential use of miR-181 as a therapeutic target for AML.

Correlation of serum magnesium with dyslipidemia in patients on maintenance hemodialysis.

This study was performed to determine the correlation between serum magnesium (Mg) and dyslipidemia in patients on maintenance hemodialysis (MHD). This hospital-based cross-sectional observational study was conducted at the Department of Nephro-Urology, Liaquat University Hospital, Hyderabad, Pakistan, from April 2008 to June 2008. Fifty patients with end-stage kidney disease on MHD treatment (33 males and 17 females) were studied. The mean duration on HD was 7.58 ± 2.05 years, with frequency being two to three sessions/week, and each session lasted for four hours. After obtaining informed written consent, the general information of each patient was recorded on a proforma. After overnight fasting, blood samples was drawn from the arterio-venous fistula for lipid profile, lipoprotein, serum Mg, serum creatinine, blood urea, serum calcium and serum phosphorus. Dyslipidemia was defined as presence of total cholesterol (TC), triglyceride (TG) or low-density lipoprotein (LDL) levels more then 95 th percentile for age and gender or high-density lipoprotein (HDL) levels less then 35 mg/dL. Descriptive and inferential statistical analyses were performed using SPSS version 16.0. The mean age of the study patients was 45.68 ± 13.97 years. There was a significant positive correlation between serum Mg and serum lipoprotein-a (LP-a) (r = 0.40, P < 0.007), serum HDL (r = 0.31, P < 0.01) and serum TG (r = 0.35, P < 0.005). There was no significant correlation between serum Mg and serum LDL-c and serum TC. The serum TG and LP-a levels were significantly increased while HDL-c was significantly lower in MHD patients. The serum TC, LDL-c and very low-density lipoprotein-c were not significantly elevated. We conclude that patients with chronic kidney disease undergoing MHD show positive correlation between serum Mg and serum HDL, LP-a and TG. The abnormalities of lipid metabolism, such as hyper-triglyceridemia, elevated LP-a and low HDL-c, could contribute to atherosclerosis and cardiovascular disease in these patients.

Pattern of lipid profile in patients on maintenance hemodialysis.

This hospital-based cross-sectional comparative observational study was performed to determine the pattern of lipid profile in patients on maintenance hemodialysis. The study was performed at the Department of Nephro-Urology, Liaquat University Hospital, Hyderabad, Pakistan from April 2008 to June 2008. Fifty patients with end-stage renal disease on maintenance hemodialysis (MHD) were studied. They comprised of 31 males and 19 females, the mean duration on HD was 7.58 +/- 2.05 yrs, with frequency of two to three sessions per week and each session lasting for four hours. Additionally, 25 healthy volunteers (16 male, 9 female) were also studied. After obtaining informed, written consent, general information of each patient was recorded on the proforma. After 12-hours fasting, blood samples were drawn from the arterio-venous fistula before starting dialysis. The total cholesterol, triglyceride (TG) or low density lipoprotein (LDL) levels more than 95th percentile for age and gender or high density lipoprotein (HDL) less then 35 mg/dL was defined as dyslipidemia. Descriptive and inferential statistical analysis were performed using SPSS version 16.0. The age among MHD and control groups was 47.88 +/- 13.92 and 54.56 +/- 11.16 years respectively. Serum TG and lipoprotein-a (LPa) were significantly increased (P = < 0.001 for each) while HDL-c was significantly lower (P = < 0.001) in MHD patients than in the control group. The serum cholesterol, LDL-c, VLDL-c and chylomicron levels were not significantly different in the two groups. Our study suggests that patients on MHD show abnormalities of lipid metabolism like hypertriglyceridemia, elevated lipoprotein-a and low HDL-c, which could contribute to atherosclerosis and cardiovascular disease that may increase the morbidity and mortality in these patients.