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1.
Br J Cancer ; 128(7): 1333-1343, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36717674

RESUMO

BACKGROUND: Colorectal cancer (CRC) primary tumours are molecularly classified into four consensus molecular subtypes (CMS1-4). Genetically engineered mouse models aim to faithfully mimic the complexity of human cancers and, when appropriately aligned, represent ideal pre-clinical systems to test new drug treatments. Despite its importance, dual-species classification has been limited by the lack of a reliable approach. Here we utilise, develop and test a set of options for human-to-mouse CMS classifications of CRC tissue. METHODS: Using transcriptional data from established collections of CRC tumours, including human (TCGA cohort; n = 577) and mouse (n = 57 across n = 8 genotypes) tumours with combinations of random forest and nearest template prediction algorithms, alongside gene ontology collections, we comprehensively assess the performance of a suite of new dual-species classifiers. RESULTS: We developed three approaches: MmCMS-A; a gene-level classifier, MmCMS-B; an ontology-level approach and MmCMS-C; a combined pathway system encompassing multiple biological and histological signalling cascades. Although all options could identify tumours associated with stromal-rich CMS4-like biology, MmCMS-A was unable to accurately classify the biology underpinning epithelial-like subtypes (CMS2/3) in mouse tumours. CONCLUSIONS: When applying human-based transcriptional classifiers to mouse tumour data, a pathway-level classifier, rather than an individual gene-level system, is optimal. Our R package enables researchers to select suitable mouse models of human CRC subtype for their experimental testing.


Assuntos
Neoplasias Colorretais , Humanos , Animais , Camundongos , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Transdução de Sinais
2.
Br J Haematol ; 202(3): 479-484, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37217303

RESUMO

We compare the impact of SARS-CoV-2 variants on healthcare utilization and clinical presentation in paediatric patients with sickle cell disease (SCD). One hundred and ninety-one unique patients with SCD and positive SARS-CoV-2 polymerase chain reactions were identified between March 2020 and January 2022. Hospitalizations, which accounted for 42% (N = 81) of cases, were highest during the Delta dominant era (48%) and lowest during Omicron (36%) (p = 0.285). The most common SCD-related complication was vaso-occlusive pain (37%, N = 71), which accounted for 51% of all hospital admissions (N = 41), and acute chest was highest in the Alpha variant era (N = 15). Overall, COVID-19 remained mild in clinical severity within most paediatric SCD patients.


Assuntos
Anemia Falciforme , COVID-19 , Humanos , Criança , COVID-19/complicações , SARS-CoV-2 , Pandemias , Anemia Falciforme/complicações
3.
Pediatr Blood Cancer ; 70(10): e30553, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37458568

RESUMO

BACKGROUND: High return visit rates after hospitalization for people with sickle cell disease (SCD) have been previously established. Due to a lack of multicenter emergency department (ED) return visit rate data, the return visit rate following ED discharge for pediatric SCD pain treatment is currently unknown. PROCEDURE: A seven-site retrospective cohort study of discharged ED visits for pain by children with SCD was conducted using the Pediatric Emergency Care Applied Research Network Registry. Visits between January 2017 and November 2021 were identified using previously validated criteria. The primary outcome was the 14-day return visit rate, with 3- and 7-day rates also calculated. Modified Poisson regression was used to analyze associations for age, sex, initial hospitalization rate, and a visit during the COVID-19 pandemic with return visit rates. RESULTS: Of 2548 eligible ED visits, approximately 52% were patients less than 12 years old, 50% were female, and over 95% were non-Hispanic Black. The overall 14-day return visit rate was 29.1% (95% confidence interval [CI]: 27.4%-30.9%; site range 22.7%-31.7%); the 7- and 3-day return visit rates were 23.0% (95% CI: 21.3%-24.6%) and 16.7% (95% CI: 15.3%-18.2%), respectively. Younger children had slightly lower 14-day return visit rates (27.3% vs. 31.1%); there were no associations for site hospitalization rate, sex, and a visit occurring during the pandemic with 14-day returns. CONCLUSION: Nearly 30% of ED discharged visits after SCD pain treatment had a return visit within 14 days. Increased efforts are needed to identify causes for high ED return visit rates and ensure optimal ED and post-ED care.


Assuntos
Anemia Falciforme , COVID-19 , Humanos , Criança , Feminino , Masculino , Alta do Paciente , Estudos Retrospectivos , Pandemias , COVID-19/complicações , Dor/etiologia , Anemia Falciforme/complicações , Anemia Falciforme/terapia , Serviço Hospitalar de Emergência , Readmissão do Paciente
4.
Pediatr Blood Cancer ; 70(1): e29961, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36094289

RESUMO

Sickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center. Nineteen pediatric SCD specialists participated from the US. Consensus was predefined as 2/3 agreement on each element's categorization. Twenty-six elements were considered essential (required for guideline-based SCD care), 10 were optimal (recommended but not required), and five were suggested. This work lays the foundation for a formal recognition process of pediatric comprehensive SCD centers.


Assuntos
Anemia Falciforme , Criança , Humanos , Consenso , Anemia Falciforme/terapia
5.
Nature ; 541(7636): 233-236, 2017 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-28052056

RESUMO

Metastasis is the leading cause of death for cancer patients. This multi-stage process requires tumour cells to survive in the circulation, extravasate at distant sites, then proliferate; it involves contributions from both the tumour cell and tumour microenvironment ('host', which includes stromal cells and the immune system). Studies suggest the early steps of the metastatic process are relatively efficient, with the post-extravasation regulation of tumour growth ('colonization') being critical in determining metastatic outcome. Here we show the results of screening 810 mutant mouse lines using an in vivo assay to identify microenvironmental regulators of metastatic colonization. We identify 23 genes that, when disrupted in mouse, modify the ability of tumour cells to establish metastatic foci, with 19 of these genes not previously demonstrated to play a role in host control of metastasis. The largest reduction in pulmonary metastasis was observed in sphingosine-1-phosphate (S1P) transporter spinster homologue 2 (Spns2)-deficient mice. We demonstrate a novel outcome of S1P-mediated regulation of lymphocyte trafficking, whereby deletion of Spns2, either globally or in a lymphatic endothelial-specific manner, creates a circulating lymphopenia and a higher percentage of effector T cells and natural killer (NK) cells present in the lung. This allows for potent tumour cell killing, and an overall decreased metastatic burden.


Assuntos
Proteínas de Transporte de Ânions/genética , Proteínas de Transporte de Ânions/metabolismo , Genoma/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Animais , Proteínas de Transporte de Ânions/deficiência , Linhagem Celular Tumoral , Movimento Celular , Modelos Animais de Doenças , Feminino , Genômica , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Linfopenia/genética , Linfopenia/patologia , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Microambiente Tumoral
6.
Gut ; 71(12): 2502-2517, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35477539

RESUMO

OBJECTIVE: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy. DESIGN: To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series of in vitro and stroma-rich in vivo models to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours. RESULTS: By performing our analyses specifically within the stroma-rich/high-fibroblast (HiFi) subtype of CC, we identify and validate the clinical value of a HiFi-specific prognostic signature (HPS), which stratifies tumours based on STAT1-related signalling (High-HPS v Low-HPS=HR 0.093, CI 0.019 to 0.466). Using in silico, in vitro and in vivo models, we demonstrate that the HPS is associated with antigen processing and presentation within discrete immune lineages in stroma-rich CC, downstream of double-stranded RNA and viral response signalling. Treatment with the TLR3 agonist poly(I:C) elevated the HPS signalling and antigen processing phenotype across in vitro and in vivo models. In an in vivo model of stroma-rich CC, poly(I:C) treatment significantly increased systemic cytotoxic T cell activity (p<0.05) and reduced liver metastases (p<0.0002). CONCLUSION: This study reveals new biological insight that offers a novel therapeutic option to reduce relapse rates in patients with the worst prognosis CC.


Assuntos
Biomarcadores Tumorais , Neoplasias do Colo , Humanos , Biomarcadores Tumorais/genética , Células Estromais/patologia , Recidiva Local de Neoplasia/prevenção & controle , Recidiva Local de Neoplasia/patologia , Neoplasias do Colo/patologia , Prognóstico
7.
Pain Med ; 23(8): 1379-1386, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35166851

RESUMO

OBJECTIVES: Sickle Cell Disease (SCD) is a genetic blood disorder affecting over 1 million people globally. The aim of this analysis is to explore the pain burden of patients with SCD in two countries: the United States and Ghana. METHODS: The Consortium for the Advancement of Sickle Cell Research (CASiRe) was created to better understand the clinical severity of patients with SCD worldwide. Data regarding gender, SCD genotype, prior medical diagnoses, and validated pain burden measures were analyzed from the CASiRe database. The Sickle Cell Pain Burden Interview (SCPBI) was used to assess pain burden, the impact of pain on physical, emotional, and social function. RESULTS: Most subjects identified as Black/African American (n = 298, 97.0%). Patient ages ranged from 6 to 73 years. 35.9% resided in the United States, 64.1% resided in Ghana, 40.9% were men, and 58.7% were women. The mean SCPBI score for US SCD patients was 6.53(±5.89) vs 4.04(±5.10) for Ghanaian patients, P <0.001. Pain burden was higher in US men vs Ghanaian men (6.74(±5.68) vs 3.54(±4.46), P = .003) and in US women vs Ghanaian women (6.37 ± 6.06 vs 4.44(±5.54), P = .032). Pain burden was higher in US patients than Ghanaian patients for both the Hb SC/SBeta+ genotype (5.40(±5.29) vs 2.82(±4.86), P = .054) and Hb SS/SBeta0 genotype (6.79(±6.01) vs 4.49(±5.13), P = .003). Pain burden was significantly higher in SCD patients with comorbid conditions independent of geographic origin including stroke, cholecystectomy, gallstones, depression, and headache. DISCUSSION: US patients with SCD have a higher pain burden than Ghanaian patients. Further studies should investigate underlying contributors to pain burden in these populations and further explore the etiology of geographic differences in pain.


Assuntos
Anemia Falciforme , Acidente Vascular Cerebral , Adolescente , Adulto , Idoso , Anemia Falciforme/complicações , Anemia Falciforme/epidemiologia , Criança , Estudos de Coortes , Feminino , Gana/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Dor/epidemiologia , Dor/etiologia , Acidente Vascular Cerebral/complicações , Estados Unidos/epidemiologia , Adulto Jovem
8.
Anal Chem ; 93(4): 2309-2316, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33395266

RESUMO

Mass spectrometry imaging can produce large amounts of complex spectral and spatial data. Such data sets are often analyzed with unsupervised machine learning approaches, which aim at reducing their complexity and facilitating their interpretation. However, choices made during data processing can impact the overall interpretation of these analyses. This work investigates the impact of the choices made at the peak selection step, which often occurs early in the data processing pipeline. The discussion is done in terms of visualization and interpretation of the results of two commonly used unsupervised approaches: t-distributed stochastic neighbor embedding and k-means clustering, which differ in nature and complexity. Criteria considered for peak selection include those based on hypotheses (exemplified herein in the analysis of metabolic alterations in genetically engineered mouse models of human colorectal cancer), particular molecular classes, and ion intensity. The results suggest that the choices made at the peak selection step have a significant impact in the visual interpretation of the results of either dimensionality reduction or clustering techniques and consequently in any downstream analysis that relies on these. Of particular significance, the results of this work show that while using the most abundant ions can result in interesting structure-related segmentation patterns that correlate well with histological features, using a smaller number of ions specifically selected based on prior knowledge about the biochemistry of the tissues under investigation can result in an easier-to-interpret, potentially more valuable, hypothesis-confirming result. Findings presented will help researchers understand and better utilize unsupervised machine learning approaches to mine high-dimensionality data.

9.
Blood Cells Mol Dis ; 92: 102612, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34564050

RESUMO

BACKGROUND: Sickle cell disease (SCD) is characterized by frequent, unpredictable pain episodes and other vaso-occlusive crises (VOCs) leading to significant healthcare utilization. VOC frequency is often an endpoint in clinical trials investigating novel therapies for this devastating disease. PROCEDURE: The Consortium for the Advancement of Sickle Cell Research (CASiRe) is an international collaboration investigating clinical severity in SCD using a validated questionnaire and medical chart review standardized across four countries (United States, United Kingdom, Italy and Ghana). RESULTS: This study, focused on pain crisis incidence and healthcare utilization, included 868 patients, equally represented according to age and gender. HgbSS was the most common genotype. Patients from Ghana used the Emergency Room/Day Hospital for pain more frequently (annualized mean 2.01) than patients from other regions (annualized mean 1.56 U.S.; 1.09 U.K.; 0.02 Italy), while U.K. patients were hospitalized for pain more often (annualized mean: U.K. 2.98) than patients in other regions (annualized mean 1.98 U.S.; 1.18 Ghana; Italy 0.54). Italy's hospitalization rate for pain (annualized mean: 0.57) was nearly 20 times greater than its emergency room/day hospital only visits for pain (annualized mean: 0.03). When categorized by genotype and age, similar results were seen. CONCLUSIONS: Geographic differences in pain crisis frequency and healthcare utilization may correlate with variable organization of healthcare systems among countries and should be considered regarding trial design, endpoints, and analysis of results when investigating novel agents for clinical benefit.


Assuntos
Anemia Falciforme/complicações , Manejo da Dor , Aceitação pelo Paciente de Cuidados de Saúde , Adolescente , Adulto , Anemia Falciforme/epidemiologia , Anemia Falciforme/terapia , Feminino , Gana/epidemiologia , Humanos , Itália/epidemiologia , Masculino , Dor/epidemiologia , Reino Unido/epidemiologia , Estados Unidos/epidemiologia , Adulto Jovem
10.
Blood Cells Mol Dis ; 88: 102531, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33401140

RESUMO

Pain is a hallmark of Sickle Cell Disease (SCD) affecting patients throughout their life; the first pain crisis may occur at any age and is often the first presentation of the disease. Universal newborn screening identifies children with SCD at birth, significantly improving morbidity and mortality. Without early screening, diagnosis is generally made after disease manifestations appear. The Consortium for the Advancement of Sickle Cell Research (CASiRe) is an international collaborative group evaluating the clinical severity of subjects with SCD using a validated questionnaire and medical chart review, standardized across 4 countries (United States, United Kingdom, Italy and Ghana). We investigated the age of first pain crisis in 555 sickle cell subjects, 344 adults and 211 children. Median age of the first crisis in the whole group was 4 years old, 5 years old among adults and 2 years old among children. Patients from the United States generally reported the first crisis earlier than Ghanaians. Experiencing the first pain crisis early in life correlated with the genotype and disease severity. Early recognition of the first pain crisis could be useful to guide counseling and management of the disease.


Assuntos
Anemia Falciforme/complicações , Dor/etiologia , Adolescente , Adulto , Fatores Etários , Anemia Falciforme/diagnóstico , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Gana/epidemiologia , Humanos , Lactente , Itália/epidemiologia , Masculino , Reino Unido/epidemiologia , Estados Unidos/epidemiologia , Adulto Jovem
11.
Ann Hematol ; 99(9): 2073-2079, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32377816

RESUMO

Vasculopathy is a hallmark of sickle cell disease ultimately resulting in chronic end organ damage. Leg ulcer is one of its sequelae, occurring in ~ 5-10% of adult sickle cell patients. The majority of leg ulcer publications to date have emanated from single center cohort studies. As such, there are limited studies on the geographic distribution of leg ulcers and associated risk factors worldwide. The Consortium for the Advancement of Sickle Cell Research (CASiRe) was formed to improve the understanding of the different phenotypes of sickle cell disease patients living in different geographic locations around the world (USA, UK, Italy, Ghana). This cross-sectional cohort sub-study of 659 sickle cell patients aimed to determine the geographic distribution and risk factors associated with leg ulcers. The prevalence of leg ulcers was 10.3% and was associated with older age, SS genotype, male gender, and Ghanaian origin. In fact, the highest prevalence (18.6%) was observed in Ghana. Albuminuria, proteinuria, increased markers of hemolysis (lower hemoglobin, higher total bilirubin), lower oxygen saturation, and lower body mass index were also associated with leg ulceration. Overall, our study identified a predominance of leg ulcers within male hemoglobin SS patients living in sub-Saharan Africa with renal dysfunction and increased hemolysis.


Assuntos
Anemia Falciforme/diagnóstico , Anemia Falciforme/epidemiologia , Internacionalidade , Úlcera da Perna/diagnóstico , Úlcera da Perna/epidemiologia , Adolescente , Adulto , Idoso , Anemia Falciforme/sangue , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Gana/epidemiologia , Humanos , Lactente , Itália/epidemiologia , Úlcera da Perna/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido/epidemiologia , Estados Unidos/epidemiologia , Adulto Jovem
12.
J Clin Lab Anal ; 34(7): e23294, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32170816

RESUMO

BACKGROUND: Lipid peroxidation plays a very important role in sickle cell pathophysiology. The formation of malondialdehyde (MDA) in patients with sickle cell disease (SCD) may lead to endothelial dysfunction. Nitric oxide (NO) is a known vasodilator which plays a role in endothelial function. The current study determined the association between MDA and NO metabolites (NOx), trace elements, and antioxidant enzymes (SOD and CAT) in patients with SCD. The ratio of MDA/NOx was also determined as an index of oxidative stress in the study groups. METHODS: This was a cross-sectional study involving 90 patients with SCD and 50 "healthy" controls. Blood samples (n = 140) were collected from the study groups. The plasma, sera, and red cells were kept at -20°C for biochemical analyses. Hemoglobin (Hb) and NOx levels were determined in the plasma using Labsystem Multiskan MS and Griess reagent system, respectively. Super oxide dismutase (SOD) and catalase (CAT) levels were determined in the red cells using assay kits from Cayman chemicals. Lipid peroxidation biomarker MDA was determined in the sera using the TBARS assay. Levels of iron (Fe), copper (Cu), and zinc (Zn) were also determined in the sera using Variant 240FS. MDA and NOx ratio was computed for the study groups and compared. RESULTS: Levels of Hb, NOx, SOD, CAT, and Zn were significantly lower in the patients with SCD (P < .001). MDA, Fe, and MDA/ NOx ratio were, however, significantly higher in the patients with SCD (P < .001). There was no significant correlation between MDA and NOx, SOD, CAT, Fe, and Zn in the study groups. MDA, however, correlated positively and significantly with Cu in the HbSS patients with vaso-occlusive crises (VOC). Gender did not affect the levels of oxidative stress markers. CONCLUSIONS: Findings from this study suggest a link between lipid peroxidation and Cu in HbSS patients with VOC. Increased MDA/NOx ratio may contribute to sickle cell pathophysiology by promoting oxidative stress.


Assuntos
Anemia Falciforme/sangue , Antioxidantes/metabolismo , Peroxidação de Lipídeos , Óxido Nítrico/sangue , Oligoelementos/sangue , Adulto , Anemia Falciforme/metabolismo , Biomarcadores/sangue , Estudos de Casos e Controles , Catalase/sangue , Feminino , Hemoglobina Falciforme/análise , Humanos , Masculino , Malondialdeído/sangue , Óxido Nítrico/metabolismo , Estresse Oxidativo , Superóxido Dismutase/sangue
13.
Angew Chem Int Ed Engl ; 59(20): 7897-7905, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-31975528

RESUMO

Axially chiral phenols are attractive targets in organic synthesis. This motif is central to many natural products and widely used as precursors to, or directly, as chiral ligands and catalysts. Despite their utility few simple catalytic methods are available for their synthesis in high enantiopurity. Herein the atropselective acylation of a range of symmetric biaryl diols is investigated using isothiourea catalysis. Studies on a model biaryl diol substrate shows that the high product er observed in the process is a result of two successive enantioselective reactions consisting of an initial enantioselective desymmetrization coupled with a second chiroablative kinetic resolution. Extension of this process to a range of substrates, including a challenging tetraorthosubstituted biaryl diol, led to highly enantioenriched products (14 examples, up to 98:2 er), with either HyperBTM or BTM identified as the optimal catalyst depending upon the substitution pattern within the substrate. Computation has been used to understand the factors that lead to high enantiocontrol in this process, with maintenance of planarity to maximize a 1,5-S⋅⋅⋅O interaction within the key acyl ammonium intermediate identified as the major feature that determines atropselective acylation and thus product enantioselectivity.

14.
EMBO J ; 34(18): 2321-33, 2015 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-26240067

RESUMO

Wnt pathway deregulation is a common characteristic of many cancers. Only colorectal cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of the pancreas) have activating mutations in ß-catenin (CTNNB1). We have compared the dynamics and the potency of ß-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of ß-catenin took much longer to achieve Wnt deregulation and acquire a crypt-progenitor cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of ß-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of ß-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin:ß-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of ß-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of ß-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated ß-catenin.


Assuntos
Caderinas/metabolismo , Transformação Celular Neoplásica , Neoplasias do Colo , Mutação , Proteínas de Neoplasias , Via de Sinalização Wnt , beta Catenina , Animais , Caderinas/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
15.
Transfusion ; 59(6): 2016-2022, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30758856

RESUMO

BACKGROUND: The routine pretransfusion investigations in Southern Ghana involve only ABO-D blood group typing and ABO compatibility testing without screening for irregular red blood cell (RBC) antibodies. The prevalence and specificities of RBC antibodies and frequencies of most minor blood group antigens in transfused patients with sickle cell disease (SCD) in Ghana are not known and are the objectives of this study. STUDY DESIGN AND METHODS: This was a cross-sectional study that investigated transfused patients with SCD for the presence of irregular RBC antibodies and Rhesus, Kell, Duffy, Kidd, and Ss antigens. RESULTS: From a total of 154 patients (median age, 9 years), 10 patients (6.5%) possessed 13 antibodies, predominantly against D, C, and E antigens. In three patients, the antibodies (anti-D, anti-D + C, and anti-C + e) were against antigens they possessed by serology. Genotyping showed that two of these patients had variant RHCE genes that encode for weak and partial e antigens and one patient had a partial RHC gene. Frequencies of most RBC antigens were comparable with frequencies established among the African American population; however, K-k- and Jk(a-b-) phenotypes were more frequent and were present in 21% and 17% of patients, respectively. CONCLUSION: The prevalence of RBC alloimmunization in transfused Ghanaian patients with SCD was 6.5% and the majority of antibodies were against antigens of the Rh system. Our findings stress the need to include pretransfusion testing for RBC antibodies in patients with SCD, to improve transfusion safety.


Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/terapia , Antígenos de Grupos Sanguíneos/imunologia , Eritrócitos/imunologia , Isoanticorpos/sangue , Adolescente , Adulto , Anemia Hemolítica Autoimune/epidemiologia , Anemia Hemolítica Autoimune/etiologia , Anemia Falciforme/epidemiologia , Anemia Falciforme/imunologia , Incompatibilidade de Grupos Sanguíneos/epidemiologia , Incompatibilidade de Grupos Sanguíneos/etiologia , Incompatibilidade de Grupos Sanguíneos/imunologia , Transfusão de Sangue/métodos , Transfusão de Sangue/estatística & dados numéricos , Criança , Pré-Escolar , Estudos Transversais , Transfusão de Eritrócitos/efeitos adversos , Transfusão de Eritrócitos/estatística & dados numéricos , Feminino , Gana/epidemiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Reação Transfusional/epidemiologia , Reação Transfusional/etiologia , Adulto Jovem
16.
J Org Chem ; 84(8): 4735-4747, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30352146

RESUMO

A multidisciplinary approach covering synthetic, physical, and analytical chemistry, high-throughput experimentation and experimental design, process engineering, and solid-state chemistry is used to develop a large-scale (kilomole) Suzuki-Miyaura process. Working against clear criteria and targets, a full process investigation and optimization package is described highlighting how and why key decisions are made in the development of large-scale pharmaceutical processes.


Assuntos
Desenho de Fármacos , Indústria Farmacêutica , Pirazinas/síntese química , Triazinas/síntese química , Ensaios de Triagem em Larga Escala , Estrutura Molecular , Pirazinas/química , Triazinas/química
17.
Medicina (Kaunas) ; 55(5)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117252

RESUMO

Background and Objectives: Altered copper and zinc homeostasis may influence the antioxidant defense system and consequently lead to oxidative stress and associated complications in sickle cell disease (SCD) patients. Iron levels have been reported to increase in sickle cell patients due to frequent blood transfusion, chronic intravenous haemolysis and increased absorption of iron from the gastrointestinal tract. These elevated levels of iron may also lead to extensive oxidative damage. The current study evaluated serum levels of iron, copper and zinc in SCD patients and "healthy" controls. Materials and Methods: The study was a cross-sectional one, comprising 90 SCD patients with Haemoglobin SS and Haemoglobin SC genotypes and 50 HbAA "healthy" controls. Serum levels of iron, copper and zinc were measured using a Flame Atomic Absorption Spectrometer (Variant 240FS manufactured by VARIAN Australia Pty Ltd, VIC, Australia). Copper and zinc ratios were calculated and analyzed. Results: Serum levels of iron and copper were significantly elevated in the SCD patients, compared to their "healthy" counterparts (p < 0.001). These levels were further increased in patients with haemoglobin SS in vaso-occlusive crises (HbSS VOCs). Serum zinc levels were, however, significantly lower in the SCD patients, particularly during vaso-occlusion. The copper-to-zinc ratio was also found to be significantly higher in the SCD patients. Conclusion: Elevated copper-to-zinc ratio may be a biomarker of sickle cell oxidative stress and associated complications. The ratio may also be informative for the management of sickle cell oxidative burden. The significantly lower levels of zinc in the SCD patients may warrant zinc supplementation.


Assuntos
Anemia Falciforme/sangue , Cobre/análise , Ferro/análise , Zinco/análise , Adulto , Anemia Falciforme/complicações , Biomarcadores/análise , Biomarcadores/sangue , Cobre/sangue , Estudos Transversais , Feminino , Gana , Humanos , Ferro/sangue , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Zinco/sangue
18.
Pediatr Blood Cancer ; 65(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28801954

RESUMO

OBJECTIVE: To identify characteristics of pediatric sickle cell disease (SCD) hospitalizations and to examine admission demographics and medical expenditures. METHODS: Admissions with SCD were identified from the 2009 and 2012 releases of the Healthcare and Cost Utilization Project's Kids Inpatient Database. Disease-specific secondary diagnoses including acute chest syndrome (ACS), vaso-occlusive pain crisis (VOC), splenic sequestration, and stroke/transient ischemic attack were analyzed for patient and hospital demographics. Analytical endpoints included total healthcare expenditures and mortality. RESULTS: We reviewed 75,234 inpatient hospitalizations with a diagnosis of SCD. Over $900,000,000 was spent annually in associated healthcare expenditure. The median length of hospitalization stay (LOS) for all admissions was 3 days (interquartile range [IQR] 2-5 days). VOC was the most frequent secondary diagnosis, recording 48,698 total hospitalizations and a median LOS of 3 days (IQR 2-6 days). Of the 8,490 hospitalizations with ACS, the infant population had a significantly higher mortality rate compared to other age groups (2% vs. 0.3%, P < 0.001). Cerebral vascular accidents incurred the second highest median hospitalization cost ($18,956), behind ACS ($22,631). A high proportion of Caucasian patients died during hospitalization for VOC (0.4% vs. 0.1%, P = 0.014) and ACS (4% vs. 0.2%, P < 0.001) when compared to non-Caucasians. CONCLUSION: Inpatient hospitalizations for secondary manifestations of pediatric SCD were associated with significant healthcare expenditures. Patients with an increased statistical risk for death during hospitalization included Caucasians with SCD complications of ACS and VOC, and patients <1-year-old with ACS. Further research is needed to substantiate the associated clinical significance of these findings.


Assuntos
Anemia Falciforme , Bases de Dados Factuais , Hospitalização/economia , Adolescente , Adulto , Fatores Etários , Anemia Falciforme/economia , Anemia Falciforme/mortalidade , Anemia Falciforme/terapia , Criança , Pré-Escolar , Custos e Análise de Custo , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino
19.
J Am Chem Soc ; 139(37): 13156-13165, 2017 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-28823150

RESUMO

Pioneering studies by Kuivila, published more than 50 years ago, suggested ipso protonation of the boronate as the mechanism for base-catalyzed protodeboronation of arylboronic acids. However, the study was limited to UV spectrophotometric analysis under acidic conditions, and the aqueous association constants (Ka) were estimated. By means of NMR, stopped-flow IR, and quenched-flow techniques, the kinetics of base-catalyzed protodeboronation of 30 different arylboronic acids has now been determined at pH > 13 in aqueous dioxane at 70 °C. Included in the study are all 20 isomers of C6HnF(5-n)B(OH)2 with half-lives spanning 9 orders of magnitude: <3 ms to 6.5 months. In combination with pH-rate profiles, pKa and ΔS⧧ values, kinetic isotope effects (2H, 10B, 13C), linear free-energy relationships, and density functional theory calculations, we have identified a mechanistic regime involving unimolecular heterolysis of the boronate competing with concerted ipso protonation/C-B cleavage. The relative Lewis acidities of arylboronic acids do not correlate with their protodeboronation rates, especially when ortho substituents are present. Notably, 3,5-dinitrophenylboronic acid is orders of magnitude more stable than tetra- and pentafluorophenylboronic acids but has a similar pKa.

20.
J Am Chem Soc ; 138(29): 9145-57, 2016 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-27355973

RESUMO

pH-rate profiles for aqueous-organic protodeboronation of 18 boronic acids, many widely viewed as unstable, have been studied by NMR and DFT. Rates were pH-dependent, and varied substantially between the boronic acids, with rate maxima that varied over 6 orders of magnitude. A mechanistic model containing five general pathways (k1-k5) has been developed, and together with input of [B]tot, KW, Ka, and KaH, the protodeboronation kinetics can be correlated as a function of pH (1-13) for all 18 species. Cyclopropyl and vinyl boronic acids undergo very slow protodeboronation, as do 3- and 4-pyridyl boronic acids (t0.5 > 1 week, pH 12, 70 °C). In contrast, 2-pyridyl and 5-thiazolyl boronic acids undergo rapid protodeboronation (t0.5 ≈ 25-50 s, pH 7, 70 °C), via fragmentation of zwitterionic intermediates. Lewis acid additives (e.g., Cu, Zn salts) can attenuate (2-pyridyl) or accelerate (5-thiazolyl and 5-pyrazolyl) fragmentation. Two additional processes compete when the boronic acid and the boronate are present in sufficient proportions (pH = pKa ± 1.6): (i) self-/autocatalysis and (ii) sequential disproportionations of boronic acid to borinic acid and borane.

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