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BACKGROUND: In Al-Ahsa, Saudi Arabia, the high consanguinity rates contribute to the prevalence of inherited hemoglobinopathies such as sickle cell disease and thalassemia, which frequently require blood transfusions. These transfusions carry the risk of alloimmunization, necessitating a precise blood component matching to mitigate health risks. Local antigen frequency data is vital for optimizing transfusion practices and enhancing the safety of these medical procedures for the Al-Ahsa population. METHODS: This study investigated the distribution of Duffy, Kidd, Lewis, and Rh blood group antigens in 1,549 individuals from the region; comparing the frequencies with global data. RESULTS: Serological analyses revealed a high prevalence of the Fy(a+b-) and Jk(a+b+) phenotypes in the Duffy and Kidd blood groups, respectively, with Jk(a-b-) being notably scarce. The Lewis blood group exhibited a significant presence of Le(a-b+) and Le(a+b-) phenotypes, whereas Le(a+b+) was less common. In the Rh system, the D antigen was most prevalent, with other antigens following in descending order of frequency. CONCLUSIONS: The study underscores the regional variation in antigen frequencies, emphasizing the need for local blood banks to adapt their screening and matching practices to mitigate the risk of alloimmunization and enhance transfusion safety. These findings are pivotal for refining transfusion strategies and understanding the immunohematology landscape in Al-Ahsa.
Subject(s)
Blood Group Antigens , Duffy Blood-Group System , Phenotype , Humans , Saudi Arabia/epidemiology , Duffy Blood-Group System/genetics , Blood Group Antigens/immunology , Blood Group Antigens/genetics , Lewis Blood Group Antigens/immunology , Lewis Blood Group Antigens/genetics , Blood Donors/statistics & numerical data , Rh-Hr Blood-Group System/genetics , Rh-Hr Blood-Group System/immunology , Kidd Blood-Group System/genetics , Kidd Blood-Group System/immunology , Male , Blood Grouping and Crossmatching/methods , FemaleABSTRACT
OBJECTIVE: This study examined the prevalence of major adverse cardiovascular events (MACE) among Saudi patients with SLE and the general population and considered factors associated with such outcomes were taken into consideration. METHODS: This is a cohort study evaluating the period prevalence of MACE from 2020 to 2023. The study used two datasets, namely the Saudi national prospective cohort for SLE patients and the Prospective Urban-Rural Epidemiology Study Saudi subcohort (PURE-Saudi) for the general population. Participants in both studies were monitored using a standardised protocol. MACE was defined as myocardial infarction (MI), stroke or angina. The analysis was adjusted for demographics, traditional cardiovascular risk factors and SLE diagnosis through logistic regression models. RESULTS: The PURE and national SLE cohorts comprised 488 and 746 patients, respectively. Patients with SLE from the SLE cohort were younger (40.7±12.5 vs 49.5±8.6 years) and predominantly female (90.6% vs 41.6%). The prevalence of traditional risk factors was greater in the PURE cohort compared with the SLE cohort. These factors included dyslipidaemia (28.9% vs 49.4%), obesity (63% vs 85%) and diabetes (7.8% vs 27.2%), but not hypertension (19.3% vs 18.8%). MACE (defined as MI or stroke or venous thromboembolism or heart failure) occurred more frequently in patients with SLE (4.3% vs 1.6%, p=0.004). Older age and lupus diagnosis were independently associated with MACE after adjusting for conventional risk factors. The odds of MACE were significantly related to age and lupus diagnosis (p=0.00 and p=0.00, respectively), but not cardiovascular disease (CVD) risk factors (p=0.83). CONCLUSION: Patients with SLE have a significantly higher risk of developing MACE than the general population. This risk is not well explained by traditional risk factors, which may explain the failure of CVD risk scores to stratify patients with SLE adequately. Further studies are needed to understand CVD risk's pathogenesis in SLE and mitigate it.
Subject(s)
Cardiovascular Diseases , Lupus Erythematosus, Systemic , Humans , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/epidemiology , Female , Male , Saudi Arabia/epidemiology , Middle Aged , Adult , Prevalence , Prospective Studies , Cardiovascular Diseases/epidemiology , Risk Factors , Myocardial Infarction/epidemiology , Stroke/epidemiology , Stroke/etiology , Dyslipidemias/epidemiology , Obesity/epidemiology , Obesity/complications , Cohort StudiesABSTRACT
OBJECTIVE: Still's disease is more frequently observed in the paediatric context, but a delayed onset is not exceptional both in the adulthood and in the elderly. However, whether paediatric-onset, adult-onset and elderly-onset Still's disease represent expressions of the same disease continuum or different clinical entities is still a matter of controversy. The aim of this study is to search for any differences in demographic, clinical features and response to treatment between pediatric-onset, adult-onset and elderly-onset Still's disease. METHODS: Subjects included in this study were drawn from the International AutoInflammatory Disease Alliance Network registry for patients with Still's disease. RESULTS: A total of 411 patients suffering from Still's disease were enrolled; the disease occurred in the childhood in 65 (15.8%) patients, in the adult 314 (76.4%) patients and in the elderly in 32 (7.8%) patients. No statistically significant differences at post-hoc analysis were observed in demographic features of the disease between pediatric-onset, adult-onset and elderly-onset Still's disease. The salmon-coloured skin rash (p=0.004), arthritis (p=0.009) and abdominal pain (p=0.007) resulted significantly more frequent among paediatric patients than in adult cases, while pleuritis (p=0.015) and arthralgia (p<0.0001) were significantly more frequent among elderly-onset patients compared with paediatric-onset subjects. Regarding laboratory data, thrombocytosis was significantly more frequent among paediatric patients onset compared with adult-onset subjects (p<0.0001), while thrombocytopenia was more frequent among elderly-onset patients although statistical significance was only bordered. No substantial differences were observed in the response to treatments. CONCLUSIONS: Despite some minor difference between groups, overall, demographic, clinical, laboratory and treatments aspects of Still's disease were similarly observed in patients at all ages. This supports that pediatric-onset, adult-onset and elderly-onset Still's disease is the same clinical condition arising in different ages.
Subject(s)
Arthritis, Juvenile , Still's Disease, Adult-Onset , Adult , Humans , Child , Aged , Still's Disease, Adult-Onset/diagnosis , Still's Disease, Adult-Onset/epidemiology , Still's Disease, Adult-Onset/drug therapy , ArthralgiaABSTRACT
AIM: This study aims to explore the critical dimension of assessing the perceptions and readiness of hematologists to embrace artificial intelligence (AI) technologies in their diagnostic and treatment decision-making processes. METHODS: This study used a cross-sectional design for collecting data related to the perceptions and readiness of hematologists using a validated online questionnaire-based survey. Both hematologists (MD) and postgraduate MD students in hematology were included in the study. A total of 188 participants, including 35 hematologists (MD) and 153 MD hematology students, completed the survey. RESULTS: Major challenges include "AI's level of autonomy" and "the complexity in the field of medicine." Major barriers and risks identified include "lack of trust," "management's level of understanding," "dehumanization of healthcare," and "reduction in physicians' skills." Statistically significant differences in perceptions of benefits including resources (p=0.0326, p<0.05) and knowledge (p=0.0262, p<0.05) were observed between genders. Older physicians were observed to be more concerned about the use of AI compared to younger physicians (p<0.05). CONCLUSION: While AI use in hematology diagnosis and treatment decision-making is positively perceived, issues such as lack of trust, transparency, regulations, and poor AI awareness can affect the adoption of AI.
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Introduction: The risk of developing transfusion-related complications, especially alloimmunization, is an ongoing concern for transfusion-dependent patients. It is important to determine the rate of alloimmunization and autoimmunization in Al-Ahsa Region, Saudi Arabia, where sickle cell disease (SCD) and thalassemia incidence rates are the highest in Saudi Arabia. Methods: A cross-sectional study was conducted to review the transfusion history of patients with SCD and thalassemia at the King Fahad Hospital (KFH) in Al-Ahsa, Saudi Arabia. 364 transfusion-dependent patients were included in this study. Results: Alloimmunization rates in patients with SCD and thalassemia were 16.7% and 11.97%, respectively, while autoimmunization rates in patients with SCD and thalassemia were 5.3% and 0.7%, respectively. The most frequent alloantibodies among the study participants were against Kell, Rh blood group systems. Conclusion: Blood transfusion-related alloimmunization and autoimmunization compromise the proper management of chronically transfused patients. Ideally, extended matched phenotyping should be implemented to prevent alloimmunization and reduce the risk of developing blood transfusion-related alloantibodies.
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Nanocomposites comprised of CuO-TiO2-chitosan-escin, which has adjustable physicochemical properties, provide a solution for therapeutic selectivity in cancer treatment. By controlling the intrinsic signaling primarily through the mitochondrial signaling pathway, we desired nanocomposites with enhanced anticancer activity by containing CuO-TiO2-chitosan-escin. The metal oxides CuO and TiO2, the natural polymer chitosan, and a phytochemical compound escin were combined to form CuO-TiO2-chitosan-escin nanocomposites. The synthesized nanocomposites were confirmed and characterized using FTIR spectroscopy, TEM, and UV-Vis absorption spectroscopy. A human leukemia cell line (MOLT-4) was used to assess the efficacy and selectivity of nanocomposites. Based on a cytotoxicity study, CuO-TiO2-chitosan-escin nanocomposites had inhibition concentrations (IC50) of 13.68, 8.9, and 7.14 µg/mL against human T lymphoblast cells after 24, 48, and 72 h of incubation, respectively. Compared with untreated MOLT-4 cells, CuO-TiO2-chitosan-escin nanocomposite-treated cells significantly increased (p < 0.05) caspase-3, -8, and -9 and decreased the levels of antioxidant enzymes GR, SOD, and GSH. Furthermore, MDA for lipid peroxidase and ROS levels significantly increased (p < 0.05) in the treated cells than in the untreated cells. Remarkably, CuO-TiO2-chitosan-escin nanocomposite-mediated control of cell cycles were mainly achieved through the activation of caspase-3, -8, and -9.
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Currently, new advancements in the area of nanotechnology opened up new prospects in the field of medicine that could provide us with a solution for numerous medical complications. Although a several varieties of nanoparticles is being explored to be used as nanomedicines, cerium oxide nanoparticles (CeO2 NPs) are the most attractive due to their biocompatibility and their switchable oxidation state (+3 and +4) or in other words the ability to act as prooxidant and antioxidant depending on the pH condition. Green synthesis of nanoparticles is preferred to make it more economical, eco-friendly, and less toxic. The aim of our study here is to formulate the CeO2 NPs (CeO2 NPs) using Morinda citrifolia (Noni) leaf extract and study its optical, structural, antibacterial, and anticancer abilities. Their optical and structural characterization was accomplished by employing X-ray diffractography (XRD), TEM, EDAX, FTIR, UV-vis, and photoluminescence assays. Our CeO2 NPs expressed strong antibacterial effects against Gram-positive S. aureus and S. pneumonia in addition to Gram-negative E. coli and K. pneumonia when compared with amoxicillin. The anticancer properties of the green synthesized CeO2 NPs against human acute lymphoblastic leukemia (ALL) MOLT-4 cells were further explored by the meticulous study of their ability to diminish cancer cell viability (cytotoxicity), accelerate apoptosis, escalate intracellular reactive oxygen species (ROS) accumulation, decline the mitochondria membrane potential (MMP) level, modify the cell adhesion, and shoot up the activation of proapoptotic markers, caspase-3, -8, and -9, in the tumor cells. Altogether, the outcomes demonstrated that our green synthesized CeO2 NPs are an excellent candidate for alternative cancer therapy.
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Purpose: Single-nucleotide polymorphism (SNP) in the promoter region of the IL-10 gene can increase susceptibility to tumor development. The current study aimed to explore the genotypic frequency of interleukin-10 (IL-10) rs1800896 polymorphism in newly diagnosed adult patients with acute lymphoblastic leukemia (ALL) and validate whether this SNP is a risk factor for adult ALL. Patients and Methods: This case-control study was based on a subset of newly diagnosed 154 adult patients with ALL recruited from the Radiation and Isotope Center in Khartoum (RICK) and 154 healthy controls from the same geographical area. Genomic DNA was used for the genotyping of rs1800896 polymorphism through allele-specific polymerase chain reaction (PCR) assays. Results: The genotypic frequencies of rs1800896 showed a statistically significant association of AG and AA genotypes with adult ALL (p<0.001). Combined genotypes AG+GG vs AA also showed a positive association of rs1800896 with adult ALL (OR=4.89). The allelic frequencies of G and A did not show any significant difference in adult patients with ALL compared with the control group. AG rs1800896 genotype showed an increased risk of B and T ALL (OR=2.51 and 4.70, respectively). Age at diagnosis, gender, and immunophenotype (B vs T ALL) did not exhibit any association of rs1800896 with ALL in this patient group. Conclusion: rs1800896 polymorphism is associated with an increased risk of ALL in adult patients irrespective of the age at diagnosis, gender, and immunophenotype of ALL.
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TNF−α influences lymphomagenesis by upregulating proinflammatory and antiapoptotic pathways. In this study, we evaluated the frequency of TNF−α rs1800629 (−308 G>A) polymorphism in newly diagnosed adult patients with acute lymphoblastic leukemia (ALL) and its correlation with age at diagnosis, gender and subtype of ALL. In this case control study, a total of 330 individuals were recruited, including 165 newly diagnosed adult patients with ALL, from the Radiation and Isotope Center in Khartoum (RICK) and 165 healthy normal controls. TNF−α rs1800629 polymorphism was tested through allele-specific polymerase chain reaction (PCR) assay. The frequency of the rs1800629 GA genotype was high (70.9% vs. 60%, OR = 1.84) in the patient group as compared to healthy controls, whereas GG and AA genotypes did not exhibit any statistically significant difference between controls and patients. Based on subtype, GG and GA rs1800629 genotypes showed increased risk of B-ALL (OR 0.46 and 2.12, respectively), whereas rs1800629 GG, GA and AA genotypes did not show any disease association with T-ALL (p > 0.05). Age at diagnosis and gender did not exhibit any association of rs1800629 with ALL in the patient group. In conclusion, rs1800629 is associated with high risk of adult B-ALL, with an insignificant effect of age at diagnosis and gender.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma , Tumor Necrosis Factor-alpha/genetics , Adult , Case-Control Studies , Genetic Predisposition to Disease , Humans , Polymorphism, Single Nucleotide , Precursor Cell Lymphoblastic Leukemia-Lymphoma/geneticsABSTRACT
Purpose: Glutathione S-transferases (GSTT1 and GSTM1) detoxify various endogenous and exogenous compounds and provide cytoprotective role against reactive species. This study aimed to assess the frequency of GSTT1, and GSTM1 polymorphisms in newly diagnosed Sudanese adult patients with acute lymphoblastic leukemia (ALL) and to evaluate the association of these polymorphisms with age, gender and type of ALL. Patients and Methods: This case-control study included 128 adult Sudanese, untreated newly diagnosed patients with ALL, aged 18 to 74 years and 128 age-gender matched healthy controls. Deletional polymorphisms of GSTT1 and GSTM1 genes were genotyped through a multiplex polymerase chain reaction (PCR) assay using ß-globin gene as an internal positive control. Results: The genotypic frequency of GSTT1 null polymorphism was 22.7% in cases and 14.8% in controls (OR = 1.68, P = 0.111). Statistically significant differences were noted in the frequencies of GSTM1 null polymorphism in cases and controls (OR = 3.7, P = <0.001). Combined GSTT1 null and GSTM1 null gene polymorphisms showed statistically significant difference in patients with ALL as compared to controls (OR = 6.5, CI 95% = 1.42-29.74, P < 0.001). Conclusion: Irrespective of age at diagnosis, gender, and phenotype of ALL, GSTM1 null polymorphism either alone or in combination with GSTT1 null polymorphism poses significantly increased risk of developing ALL in adults.
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Deep vein thrombosis (DVT) is a critical condition and a potential cause of mortality and morbidity in Africa and worldwide with a high recurrence rate. The study was designed to assess the roles of natural anticoagulants and fibrinolytic regulatory factors in the development of DVT in Sudanese patients. A case-control study was conducted in Omdurman Teaching Hospital, Khartoum State over a period of 1âyear. The study enrolled 200 patients diagnosed with DVT and 200 age-matched and gender-matched controls. Demographic data and data on acquired risk factors were collected using a semi-structured questionnaire. Protein C (PC), protein S (PS), antithrombin III (AT-III), thrombin-activable fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor-1 (PAI-1) were measured in patients and controls. Among the patients with DVT, 5.5% had PC deficiency, 8.5% had PS deficiency, and 3% had AT-III deficiency. Elevated TAFI and PAI-1 levels were demonstrated in 1.5 and 0.5% of patients, respectively. Risk factors for DVT (overweight, surgical history, and family history of DVT) were remarkably higher in patients than in controls. Among the female participants, pregnancy and usage of oral contraceptive pills were the highest associated risk factors for DVT. The findings concluded that the early assessment of risk factors, including the measurements of natural inhibitors, can predict the occurrence of DVT before it is actually detected in patients.
Subject(s)
Plasminogen Activator Inhibitor 1 , Venous Thrombosis , Anticoagulants/pharmacology , Case-Control Studies , Female , Fibrinolysis , Humans , Pregnancy , Risk Factors , Venous Thrombosis/etiologyABSTRACT
The Ig-ITIM bearing receptors, PECAM-1 and CEACAM1, have been shown net negative regulators of platelet-collagen interactions and hemiITAM signaling pathways. In this study, a double knockout (DKO) mouse was developed with deleted PECAM-1 and CEACAM1 to study their combined contribution in platelet activation by glycoprotein VI, C-type lectin-like receptor 2, protease activated receptor (PAR4), ADP purinergic receptors, and thromboxane receptor (TP) A2 pathways. In addition, their collective contribution was examined in thrombus formation under high shear and microvascular thrombosis using in vivo models. DKO platelets responded normally to ADP purinergic receptors and the TP A2 pathway. However, DKO platelets released significantly higher amounts of P-selectin compared with hyper-responsive Pecam-1-/- or Ceacam1-/- versus wild-type (WT) upon stimulation with collagen-related peptide or rhodocytin. In contrast, DKO platelets showed increased amounts of P-selectin exposure upon stimulation with PAR4 agonist peptide or thrombin but not Pecam-1-/- , Ceacam1-/- , or WT platelets. Blockade of phospholipase C (PLC) or Rho A kinase revealed that DKO platelets enhanced α-granule release via PAR4/Gαq/PLC signaling without crosstalk with Src/Syk or G12/13 signaling pathways. Severely delayed clot retraction in vitro was observed in DKO phenotype. The DKO model revealed a significant increase in thrombus formation compared with the hyper-responsive Ceacam1-/- or Pecam-1-/- versus WT phenotype. DKO platelets have similar glycoprotein surface expression compared with Pecam-1-/- , Ceacam1-/- , and WT platelets. This study demonstrates that PECAM-1 and CEACAM1 work in concert to negatively regulate hemiITAM signaling, platelet-collagen interactions, and PAR4 Gαq protein- coupled signaling pathways. Both PECAM-1 and CEACAM1 are required for negative regulation of platelet activation and microvascular thrombosis in vivo.
Subject(s)
P-Selectin , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Thrombosis , Adenosine Diphosphate/metabolism , Animals , Antigens, CD , Blood Platelets/metabolism , Carcinoembryonic Antigen/metabolism , Cell Adhesion Molecules , Collagen/metabolism , Mice , P-Selectin/metabolism , Platelet Activation , Platelet Aggregation , Platelet Endothelial Cell Adhesion Molecule-1/genetics , Receptors, Proteinase-Activated/metabolism , Receptors, Purinergic/metabolism , Thrombosis/genetics , Thrombosis/metabolismABSTRACT
PURPOSE: DNA damage to hematopoietic progenitor cells is an essential factor for leukemia development as a failure of the host DNA repair system to fix errors in DNA. This study aimed to assess the association of XRCC1 gene polymorphisms including Arg194Trp, Arg399Gln, and Arg280His with the risk of development of CML in Sudanese population. PATIENTS AND METHODS: The present study was conducted on 186 newly diagnosed patients with CML, aged 19-70 years (118 males and 68 females; mean age of 46.15±13.91 years) and 186 normal healthy controls (123 males and 63 females; mean age of 44.94±8.97 years). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was utilized to analyze the XRCC1 (Arg194Trp, Arg399Gln, and Arg280His) gene polymorphisms. RESULTS: The genotypic frequencies of Arg399Gln polymorphism in cases were 131 (70.4%) homozygous Arg/Arg, 46 (24.7%) homozygous Gln/Gln, and 9 (4.8%) heterozygous Arg/Gln as compared to the controls ie, 153 (82.3%), 73 (14.5%), and 6 (3.2%), respectively. The Arg399Gln variant genotypic frequencies significantly differed between the cases and controls (χ 2 = 7.249, P = 0.027). By comparison, no statistically significant difference was observed in the variant genotype frequencies between the cases and controls in terms of Arg194Trp and Arg280His polymorphisms. CONCLUSION: XRCC1 Arg399Gln gene polymorphism might have an important role in increasing the risk of chronic myeloid leukemia among Sudanese patients. Furthermore, all tested three polymorphisms showed no association of risk of the development of CML with age and gender.
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BACKGROUND: Rheumatoid arthritis (RA) is a chronic, debilitating condition that has a significant effect on the lives of patients, their families, and society at large. AIMS: The aim is to determine the clinical profile and any comorbidities associated with RA patients in the Sudair region of Saudi Arabia. SUBJECTS AND METHODS: Sixty patients were included in this cross-sectional observational study, both newly or already diagnosed with RA, fulfilling the 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for RA. They were followed up in the rheumatology clinic in King Khalid Majmaah Hospital in the Majmaah province from January 2017 to December 2020. RESULTS: The subjects' mean age was 47.87 ± 11.55 years, 52 female and 8 male (female-to-male ratio 6.5:1). About 23.3% of patients with RA had positive family history. The main comorbidities and associated diseases were hypertension (18.3%) and hypothyroidism (15%). The most frequently involved joints were the wrist, metacarpophalangeal, proximal interphalangeal, elbow, and knee joints. Subjects were positive in 66.7% for rheumatoid factor and 78.3% for anti-cyclic citrullinated peptide. Both markers were positive in 60% of the patients. CONCLUSION: Approximately one-quarter of the studied group had a family history of RA. Hypertension followed by hypothyroidism was the most common comorbidities reported in our study.
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PURPOSE: Glutathione S-transferases (GSTT1 and GSTM1) are instrumental in detoxification process of activated carcinogens. Nucleotide excision repair is carried out by DNA helicase encoded by xeroderma pigmentosum group D (XPD) genes and aberrations in the XPD gene predisposes to increased risk of cancer. The present study aimed to investigate GSTT1, GSTM1 and XPD polymorphisms in newly diagnosed chronic myeloid leukemia (CML) patients and to examine the association of these polymorphisms with the risk of developing CML. PATIENTS AND METHODS: This case-control study was carried out from June 2019 to August 2021 involving 150 newly diagnosed patients with CML and an equal number of randomly selected age- and sex-matched healthy individuals. A multiplex-PCR assay was used to genotype GSTT1 null and GSTM1 null polymorphisms. XPD gene polymorphism was detected by PCR-RFLP using predesigned gene-specific primers. RESULTS: GSTT1 and GSTM1 null polymorphisms were detected in 42.7% and 61.3% of cases, respectively, compared to 18% and 35.3% for controls. The combination of both GST null polymorphisms revealed a significant association with CML. Frequencies of XPD Lys751Gln genotypes in cases were 62.7% heterozygous Lys/Gln, 24% homozygous Lys/Lys and 13.3% homozygous Gln/Gln, while in the controls were 74.7%, 20%, and 5.3%, respectively. Significant differences were also noted regarding the combination of GSTT1/GSTM1 null with XPD Lys/Lys, and GSTM1 null with XPD Lys/Lys. CONCLUSION: In conclusion, GSTT1 null, GSTM1 null and XPD polymorphisms showed positive association with the risk of development of CML. Furthermore, age and gender did not exhibit any association with the studied polymorphisms, while CML phases were associated with GSTT1 null polymorphism.
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Multiple myeloma (MM), a plasma cell malignancy, is characterised by lesions in multiple bones involving transformed, matured post-follicular B cells. The course of the disease involves an initial development of monoclonal gammopathy of undetermined significance (MGUS), followed by smouldering MM, before the full MM disease emerges. Despite novel therapies, MM remains incurable, managed by combination therapies, including proteasome inhibitors (PIs), immunomodulators (IMiDs) and anti-human CD38 (daratumumab). MM patients have an increased risk of thromboembolic events due to combination treatments with IMiDs, PIs and anti-human CD38 antibody, and steroids. This review will examine the efficacy and pro-thrombotic effects of MM therapies.
Subject(s)
Antineoplastic Agents/therapeutic use , Multiple Myeloma/drug therapy , Animals , HumansABSTRACT
The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has proven to be efficacious in the treatment of B-cell chronic lymphocytic leukemia (B-CLL) and related diseases. However, a major adverse side effect of ibrutinib is bleeding, including major hemorrhages. The bleeding associated with ibrutinib use is thought to be due to a combination of on-target irreversible Btk inhibition, as well as off-target inhibition of other kinases, including EGFR, ITK, JAK3, and Tec kinase. In this study, we investigated the effects of ibrutinib vs zanubrutinib (a more selective Btk inhibitor) on platelet activation, glycoprotein expression, and thrombus formation. Ibrutinib, but not zanubrutinib, induced a time- and dose-dependent shedding of GPIb-IX complex and integrin αIIbß3, but not of GPVI and GPV, from the platelet surface. The shedding of GPIbα and GPIX was blocked by GM6001 and TAPI-2, an ADAM17 inhibitor but not ADAM10 inhibitor. Ibrutinib but not zanubrutinib treatment of human platelets increased ADAM17 activation. Pretreatment of C57BL/6 mice with ibrutinib (10 mg/kg), but not zanubrutinib (10 mg/kg), inhibited ex vivo and in vivo thrombus growth over time. Platelets from ibrutinib-treated patients with CLL showed reduced GPIb-IX complex and integrin αIIbß3 surface expression and reduced ex vivo thrombus formation under arterial flow, which was not observed in zanubrutinib-treated patients. In mice, ibrutinib, but not zanubrutinib, led to increased soluble GPIbα and soluble αIIb levels in plasma. These data demonstrate that ibrutinib induces shedding of GPIbα and GPIX by an ADAM17-dependent mechanism and integrin αIIbß3 by an unknown sheddase, and this process occurs in vivo to regulate thrombus formation.