News Update on Sickle Cell Disease Research: April – 2019

Newborn screening by tandem mass spectrometry confirms the high prevalence of sickle cell disease among German newborns

Sickle cell disease (SCD) may be a severe transmissible blood disease related to vital morbidity and mortality in time of life. Since straightforward interventions are out there to forestall early fatal courses, honorary degree may be a target condition of many national newborn screening (NBS) programs worldwide, however not in European nation. historically, the designation of honorary degree is created by superior liquid natural process (HPLC), isoelectric focusing (IEF), or capillary activity (CE), however globally, most NBS programs in situ are supported wheel mass qualitative analysis (MS/MS). Recently, many publications have shown that MS/MS is associate degree acceptable screening technique to observe haemoprotein patterns suggestive honorary degree in newborns, too. we’ve studied dried blood spot samples of twenty nine,079 German newborns by each atomic number 58 and MS/MS and ascertained a one thousandth congruity of take a look at results. Seven babies had haemoprotein patterns characteristic of honorary degree (1:4154). Our study confirms that (a) the quality of MS/MS as associate degree adequate substitute for atomic number 58 in NBS for honorary degree and (b) the high prevalence of honorary degree among German newborns. Our results support the thesis that German newborns ought to be screened for honorary degree by MS/MS. [1]

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis

The cell adhesion molecule P‐selectin plays a key role within the pathological process of a vaso‐occlusive crisis (VOC) in patients with red blood cell sickness (SCD). within the double‐blind, placebo‐controlled part two SUSTAIN study, crizanlizumab (humanized, anti‐P‐selectin organism antibody) five mg/kg considerably down the speed of VOC in patients with ScD by forty five vs placebo. In SUSTAIN, patients with ScD were irregular to crizanlizumab two.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously fourteen times over fifty two weeks. the first end was the annual rate of VOC with crizanlizumab vs placebo. This logical fallacy descriptive analysis evaluated the proportion of patients World Health Organization failed to expertise a VOC throughout the study within the following subgroups: VOCs in the year before study entry (2‐4/5‐10), ScD genotype (HbSS/non‐HbSS), and concomitant hydroxyurea use (yes/no). additional patients were VOC event‐free within the crizanlizumab five mg/kg arm than in the placebo arm, together with those with additional frequent previous VOCs (ie, 5‐10; 28.0% vs 4.2%), the HbSS genotype (31.9% vs 17.0%) and/or victimization concomitant hydroxyurea (33.3% vs 17.5%). additional analyses of secondary endpoints incontestible that crizanlizumab treatment considerably exaggerated time‐to‐first VOC vs placebo in these subgroups. The rates of treatment‐emergent adverse events were similar between treatment arms across all subgroups. This logical fallacy analysis of SUSTAIN shows that in patients with a high range of previous VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment will increase the probability of patients being VOC event‐free and delays time‐to‐first VOC. [2]

MIR-144-mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell disease

Inherited genetic modifiers and pharmacological agents that enhance vertebrate hemoprotein (HbF) expression reverse the clinical severity of erythrocyte sickness (SCD). Recent efforts to develop novel methods of HbF induction embrace discovery of molecular targets that regulate γ-globin factor transcription and translation. the aim of this study was to perform genome-wide microRNA (miRNA) analysis to spot genes related to HbF expression in patients with Doctor of Science. we have a tendency to isolated polymer from refined reticulocytes for microarray-based miRNA expression identification. exploitation samples from patients with different HbF levels, we have a tendency to discovered associate degree octuple upregulation of miR-144-3p (miR-144) and miR-144-5p within the low-HbF cluster compared with those with high HbF. further analysis by reverse transcription quantitative enzyme chain reaction confirmed individual miR-144 expression levels of subjects within the 2 teams. later purposeful studies in traditional and reaping hook corpuscle progenitors showed NRF2 factor silencing by miR-144 and concomitant repression of γ-globin transcription; in contrast, treatment with miR-144 antagomir reversed its silencing effects in a very dose-dependent manner. as a result of NRF2 regulates reactive O species levels, further studies investigated mechanisms of HbF regulation employing a hemin-induced aerobic  stress model. Treatment of KU812 cells with chloride created a rise in NRF2 expression and HbF induction that reversed with miR-144 pretreatment. chromatin granule immunoprecipitation assay confirmed NRF2 binding to the γ-globin inhibitor response component, that was pent-up by miR-144 mimic treatment. The genome-wide miRNA microarray and first corpuscle primogenitor knowledge support a miR-144/NRF2-mediated mechanism of γ-globin factor regulation in Doctor of Science. [3]

Therapeutic strategies for sickle cell disease: towards a multi-agent approach

For over one hundred years, clinicians and scientists are unravelling the results of the A to T substitution within the β-globin sequence that produces hemoglobin S, that ends up in the general manifestations of RBC sickness (SCD), as well as vaso-occlusion, anaemia, haemolysis, organ injury and pain. However, despite growing understanding of the mechanisms of hemoglobin S chemical change and its effects on red blood cells, solely 2 therapies for Doctor of Science — hydroxyurea and l-glutamine — are approved by the US Food and Drug Administration. Moreover, these treatment choices don’t absolutely address the manifestations of Doctor of Science, that arise from a posh network of mutually beneficial pathophysiological processes. during this article, we have a tendency to review efforts to develop new medication targeting these processes, as well as agents that activate foetal hemoglobin, anti-sickling agents, anti-adhesion agents, modulators of ischaemia–reperfusion and aerophilic stress, agents that counteract free hemoglobin and pigment, medicament agents, anti-thrombotic agents and anti-platelet agents. we have a tendency to conjointly discuss sequence medical aid, that holds promise of a cure, though its widespread application is presently restricted by technical challenges and therefore the expense of treatment. we have a tendency to therefore propose that developing systems-oriented multi-agent ways on the idea of Doctor of Science pathophysiology is required to enhance the standard of life and survival of individuals with Doctor of Science. [4]

Serum Ferritin and Severity Scores in Sickle Cell Disease Patients in Nnewi (South East Nigeria)

Background: RBC illness (SCD) patients have mechanisms that are thought to guard them over apparently traditional people from iron deficiency. However, proof exists that in honorary degree, hypoferritinaemia could also be additional current than hyperferitinaemia, particularly in developing countries.

Methods: bodily fluid protein (SF) levels were measured – mistreatment AN assay primarily based kit (Biocheck, USA), and illness severity calculated in fifty- 2 symptomless steady state (ASS) honorary degree patients; World Health Organization were iron chelation naive and each parameters correlative. RBC morphology and protozoal infection parasitemia were assessed, patients with parasitemia were excluded. sixty four apparently traditional people within the same setting and socioeconomic cluster were conjointly assessed as on top of and served as controls. applied mathematics analysis was done mistreatment SPSS version twenty. Results were expressed as suggests that and commonplace error of mean. Level of significance was set at p= zero.05.

Results: thirty.7% and 7.6% of the take a look at subjects had hypoferritinaemia and hyperferritinaemia severally compared to controls, wherever fifty six had hypoferritinaemia and none had hyperferritinaemia. RBC morphology showed hypochromia and blood disease to totally different degrees altogether take a look at subjects assessed: 1+ (10.5%), 2+ (63.2%) and 3+ (26.3%), whereas solely fifth of controls had hypochromia and blood disease. intromission and age failed to appear to considerably have an effect on SF levels (p= zero.65 and 0.93) severally. SF levels exaggerated more and more with illness severity however didn’t reach applied mathematics significance (p=0.29).

Conclusion: The results recommend that hypoferritinaemia is additional current than hyperferitinaemia, which SF levels could also be a helpful index for computing AN objective severity score in honorary degree management. Anaemia of chronic inflammation could cause a big a part of the anaemia in honorary degree. [5]


[1] Lobitz, S., Klein, J., Brose, A., Blankenstein, O. and Frömmel, C., 2019. Newborn screening by tandem mass spectrometry confirms the high prevalence of sickle cell disease among German newborns. Annals of hematology, 98(1), pp.47-53. (Web Link)

[2] Kutlar, A., Kanter, J., Liles, D.K., Alvarez, O.A., Cançado, R.D., Friedrisch, J.R., Knight‐Madden, J.M., Bruederle, A., Shi, M., Zhu, Z. and Ataga, K.I., 2019. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis. American journal of hematology, 94(1), pp.55-61. (Web Link)

[3] Li, B., Zhu, X., Ward, C.M., Starlard-Davenport, A., Takezaki, M., Berry, A., Ward, A., Wilder, C., Neunert, C., Kutlar, A. and Pace, B.S., 2019. MIR-144-mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell disease. Experimental hematology, 70, pp.85-96. (Web Link)

[4] Therapeutic strategies for sickle cell disease: towards a multi-agent approach

Marilyn J. Telen, Punam Malik & Gregory M. Vercellotti

Nature Reviews Drug Discoveryvolume 18, pages139–158 (2019) (Web Link)

[5] Okocha, E. C., Onwubuya, E. I., Osuji, C. U., Ahaneku, G., Okonkwo, U. C., Ibeh, N. C., Aneke, J. C., Nwachukwu, E. and Onah, C. (2015) “Serum Ferritin and Severity Scores in Sickle Cell Disease Patients in Nnewi (South East Nigeria)”, Journal of Advances in Medicine and Medical Research, 11(2), pp. 1-7. doi: 10.9734/BJMMR/2016/20405. (Web Link)

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