BACKGROUND Hydroxyurea,an antimetabolite,is frequently prescribed for various hemato-logical disorders,and its common side effects include gastrointestinal problems,cutaneous or mucosal lesions and pyrexia/fever.CASE ...BACKGROUND Hydroxyurea,an antimetabolite,is frequently prescribed for various hemato-logical disorders,and its common side effects include gastrointestinal problems,cutaneous or mucosal lesions and pyrexia/fever.CASE SUMMARY This study reports the case of a 67-year-old woman who developed recurrent abdominal pain after 10 years of continuous hydroxyurea therapy for primary thrombocythemia.Colonoscopy revealed an ileocecal ulcer.After discontinuing hydroxyurea therapy for 6 months,follow-up colonoscopy showed a significant reduction in the ulceration.CONCLUSION We consider cecal ulcers as a rare complication of hydroxyurea therapy which typically resolves upon stopping the drug.展开更多
This study aimed to evaluate testicular toxicity induced by hydroxyurea （HU） and the possible counteracting effect of an aqueous extract of Cistanche deserticola （CD）. HU is an antineoplastic drug that has potenti...This study aimed to evaluate testicular toxicity induced by hydroxyurea （HU） and the possible counteracting effect of an aqueous extract of Cistanche deserticola （CD）. HU is an antineoplastic drug that has potential reproductive toxicity, and Herba Cistanche has been used as a tonic for the reproductive system for thousands of years. Sixty mice were randomly divided into five groups. Except mice in normal group, the rest received HU （400 mg kg^-1 body weight） intragastrically. Meanwhile, mice in normal and HU control groups received purified water, and the rest received intragastrically three doses of CD decoctions （1.5, 3.0 and 6.0 g crude drug kg^-1 body weight, respectively） daily for 4 weeks. Severe testes lesions were observed, testes weight （P〈0.01） and serum luteinising hormone levels （P〈0.0 1） were also decreased significantly, in the HU groups. Three doses of CD decoctions alleviated the spermatogenetic cell degeneration induced by HU and modulated the serum sex hormones levels to some extent.展开更多
Hydroxyurea has been used to synchronize cultured cells to S-phase and used to treat patients with sicklecell anemia. Recently, we found that hydroxyurea can induce the apoptosis of HEL (human erythroleukemia) cells.T...Hydroxyurea has been used to synchronize cultured cells to S-phase and used to treat patients with sicklecell anemia. Recently, we found that hydroxyurea can induce the apoptosis of HEL (human erythroleukemia) cells.The induced HEL cells showed ultrastructurally chromatin condensation with regular crescents at the nuclear edges and apoptotic bodies. However, the cells of K562, another human erythroleukemia cell line, did not show such morphological changes. Under fluoroscope, the HEL cells after induction often displayed a clear reduction in nuclear diameter and nuclear chromatin cleavage and condensation and the presence of nuclear ring and apoptotic bodies. Analysis with flow cytometry showed that the percentage of apoptotic cells is about 30-40% after HEL cells were induced by hydroxyurea for 3 days. DNA ladder can be observed by electrophoretic analysis.展开更多
HEL cells, a human erythroleukemia cell line, mainly express the fetal (r)globin gene and trace amount of the embryonic (E)globin gene, but not adult (B) globin gene. Here we show that hydroxyurea (HU) can induce HEL ...HEL cells, a human erythroleukemia cell line, mainly express the fetal (r)globin gene and trace amount of the embryonic (E)globin gene, but not adult (B) globin gene. Here we show that hydroxyurea (HU) can induce HEL cells to express adult (B) globin gene and lead these cells to terminal differentiation. Results showed in Gel mobility shift assays that GATA factors could specifically bind to the regulatory elements of human B- globin gene, including the proximal regulatory element (the B- promoter) and the distal regulatory elements (the DNase I hypersensitive sites in the LCR, HS2-HS4 core sequences). However, the DNA binding patterns of GATA factors were quite different between HU-induced and uninduced HEL cells. Western-blot analysis of nuclear extracts from both the uninduced and HU- induced HEL cells revealed that the level of GATA-2 transcription factor decreased, whereas the level of GATA-1 transcription factor increased following the time of hydroxyurea induction. Furthermore, using RT-PCR analysis the expression of human B-globin gene in HU-induced HEL cells could be blocked again when HEL cells were incubated in the presence of antisense oligonucleotides for hGATA-1, suggesting that the upregulation of hGATA-1 transcription factor might be critical for the expression of human β- globin gene in HU-induced HEL cells.展开更多
Induction of c-myc gene amplification in L1210 cells by hydroxyurea and its inhibition by homohar-ringtonine were investigated using the DNA-DNA molecular hybridization technique. When the cells were treated with hydr...Induction of c-myc gene amplification in L1210 cells by hydroxyurea and its inhibition by homohar-ringtonine were investigated using the DNA-DNA molecular hybridization technique. When the cells were treated with hydroxyurea 1.0 mM for 16 hours, and incubated a further 16 hours in a drug-free medium, the c-myc gene amplified 23.5-fold. If homohar-ringtonine 50 μM was used at the same time as hydroxyurea, gene amplification did not occur. Cycloheximide, an inhibitor of protein biosynthesis, produced a similar effect. Our results indicated that a (or some) protein factor(s) might be involved in gene amplification. Detailed analysis showed that the synthesis of this protein factor(s) started 4 hours before the initiation of the S phase but did not continue in the S phase. It was also found that this protein factor(s) was very labile and began to degrade 2 hours after its appearance.展开更多
BACKGROUND Hydroxyurea(HU)is a non-alkylating antineoplastic agent that is active in the Sphase of the cell cycle and inhibits the enzyme ribonucleoside reductase.HU is currently used to treat leukemia,sickle cell ane...BACKGROUND Hydroxyurea(HU)is a non-alkylating antineoplastic agent that is active in the Sphase of the cell cycle and inhibits the enzyme ribonucleoside reductase.HU is currently used to treat leukemia,sickle cell anemia,psoriasis,and chronic myeloproliferative disorders.Although HU is easy to use and effective and has high tolerance,there have been numerous reports of cutaneous complications during long-term therapy with HU.CASE SUMMARY We report a 67-year-old woman on long-term HU therapy for primary myelofibrosis who developed concurrent skin lesions during treatment.The first skin lesion appeared on the dorsum of her right hand in 2015.Despite continuous use of HU,her cutaneous changes were neglected.Approximately 3 years ago,she had multiple nodular and keratotic lesions on both hands with sharp margins,branny desquamation,and dotted hyperpigmentation.Furthermore,she developed acutely numerous ulcerative lesions on her hands and legs.Topical wound therapy with dressing changes and parenteral antibiotics was applied for management of the lesions.Most of the wounds healed after HU withdrawal.Lesions on both hands were replaced by scabs.Nevertheless,the wound on her left ankle reached 9 cm×7 cm in size in January 2018.Pathology confirmed welldifferentiated squamous cell carcinoma at the ulcer area.In addition,her left foot was severely affected and radical surgery with a below-the-knee amputation was suggested followed by preventive right groin nodal dissection.CONCLUSION In patients receiving continuous HU therapy,close dermatologic follow-up is critical for the early diagnosis and selection of appropriate treatment for cutaneous lesions.展开更多
Background: Gap junctions enable small molecules to diffuse between adjacent cells and have been associated with greater cytotoxicity of radiation and anti-cancer drugs. We investigated?whether this gap junctional int...Background: Gap junctions enable small molecules to diffuse between adjacent cells and have been associated with greater cytotoxicity of radiation and anti-cancer drugs. We investigated?whether this gap junctional intercellular communication (GJIC) affected the cytotoxicity of the classic?ribonucleotide reductase (RR) inhibitor and anti-cancer agent, hydroxyurea (HU). Materials and Methods: We used GJIC-proficient and deficient, connexin 43-expressing WB rat liver epithelial cell lines. We compared HU toxicity by crystal violet assay, effects of the drug on deoxynucleotide pools by HPLC, and ability of GJIC to increase toxicity of HU-resistant cells through a bystander effect in co-culture experiments. Results: GJIC-proficient cells were three- to five-fold more sensitive (IC50?0.1 mM) to HU than GJIC-deficient derivatives (IC50?0.3 - 0.5 mM). This sensitivity depended upon GJIC because treatment of GJIC-proficient cells with the GJIC blocker oleamide decreased HU toxicity by approximately 60% - 80% and restoration of GJIC in GJIC-deficient cells by stable transduction of connexin 32-encoding?Gjb1?increased HU toxicity (IC500.1 mM). The effects were not due to connexin expression?per se?or its localization since all cell lines expressed comparable quantities of connexin 43 that was localized to the plasma membrane. Also HU sensitivity was not related to differential effects on nucleotide metabolism in the cells. Thymidine triphosphate levels increased and deoxyadenosine triphosphate levels decreased similarly (15% - 20%) in GJIC-proficient and deficient cells over 24 h of HU treatment. More importantly, when HU-resistant cells were co-cultured with sensitive cells, the resistant cells were killed only when GJIC?was present. Conclusion: The data suggest that GJIC enhances cytotoxicity and decreases resistance?to HU. These results may be important clinically if GJIC can be enhanced in drug-resistant cells.展开更多
Background: In Côte d’Ivoire so far, the circulating haplotypes have been inferred on the phenotypic profiling of SCD patients. The impact of the circulating haplotypes on the use of Hydroxyurea has not been ass...Background: In Côte d’Ivoire so far, the circulating haplotypes have been inferred on the phenotypic profiling of SCD patients. The impact of the circulating haplotypes on the use of Hydroxyurea has not been assessed yet. Therefore the objective of this study is to identify in Abidjan the HbS haplotypes that modulate HU treatment responses. Methods: In a cross-sectional descriptive and analytical study, children aged 5 to 15 years with SCD, and carrying the hemoglobin phenotypes SSFA2 and SFA2, were recruited into a HU treatment cohort. Various parameters on the haplotypes and the outcomes of the treatment were analyzed. Results: Thirty nine children with SCD were included. The phenotypic profile of the cohort was 86.6% of SSFA2 and 15.4% of SFA2. Three haplotypes were found, the Benin haplotype, the Senegal haplotype, and an atypical one. The participants belonged to three genotypes, Benin/atypical (64.1%), Benin/Senegal (33.3%) and Senegal/Senegal (2.6%). Overall, HU treatment was successful in all haplotypes with 12 out of 39 patients failing treatment after 12 months in the Benin haplotype group. The association between HU treatment success and the Benin haplotype was found in terms of the decrease in the number of white blood cells and the students missing class. Conclusion: The study revealed that inferring haplotype based on the phenotypic profile could be inaccurate. The proportion of atypical haplotype that were not previously described in Côte d’Ivoire was high. All the haplotypes seemed to be associated with HU treatment success but some patients with Benin haplotype did not respond well.展开更多
Sickle cell disease (SCD) is a prevalent condition, particularly in the countries of sub-Saharan Africa, where the presence of specific genes associated with Malaria contributes to its high prevalence. Patients with s...Sickle cell disease (SCD) is a prevalent condition, particularly in the countries of sub-Saharan Africa, where the presence of specific genes associated with Malaria contributes to its high prevalence. Patients with sickle cell disease frequently experience painful episodes necessitating hospitalization, and their hemoglobin levels are typically lower than those of the general population. There are different treatment options available to manage complications, such as transfusing blood, hydroxyurea, and strong anti-pains. However, with all these treatments, patients still commonly experience pain crises and suffer from organ damage. Hydroxyurea, the sole approved medication for sickle cell anemia in developed and developing countries, is widely used in children despite being primarily indicated for adults. Multiple studies have demonstrated the efficacy of hydroxyurea in inducing HbF production in young children with SCD. Elevated HbF levels have been associated with improved clinical outcomes, including a reduction in vaso-occlusive crises, acute chest syndrome, and the need for blood transfusions. Furthermore, increased HbF levels have been shown to ameliorate disease-related organ damage, such as pulmonary hypertension and sickle cell retinopathy. The response to hydroxyurea treatment in young children with SCD is variable. Some patients achieve substantial increases in HbF levels and experience significant clinical benefits, while others may have a more modest response. Factors influencing the response include baseline HbF levels, genetic modifiers, treatment adherence, and dose optimization. Safety is a crucial consideration when using hydroxyurea in young children. Studies have shown that hydroxyurea is generally well-tolerated, with the most common adverse effects being myelosuppression, gastrointestinal symptoms, and dermatological manifestations. However,long-term effects and potential risks, such as renal dysfunction and reproductive impacts, require further investigation. The effectiveness of hydroxyurea in young children with SCD has been demonstrated in various clinical trials and observational studies. These studies have shown a significant reduction in disease-related complications and improved quality of life. However, optimal dosing, treatment duration, and long-term outcomes are still areas of ongoing research. This review focuses on recent studies investigating the benefits, effectiveness, responses, and safety of hydroxyurea in pediatric individuals diagnosed with sickle cell disease.展开更多
A newly developed method of RT-PCR/competitive PCR for measuring the relative and ab-solute content of globin mRNAs as well as micro-globin chain biosynthetic assay have been used to study thealterations of globin gen...A newly developed method of RT-PCR/competitive PCR for measuring the relative and ab-solute content of globin mRNAs as well as micro-globin chain biosynthetic assay have been used to study thealterations of globin gene expressions in the patients with β-thalassemia pre-and post-hydroxyurea(HU)treatment.It was found for the first time that HU had the effect of enhancing β-globin gene expression insome patients.Two cases with β-thalassemia who were subjected to HU treatment for over two years showeda marked increase in β-globin mRNA level and β-globin chain synthesis,resulting in more effective erythro-poiesis and the alleviation of clinical symptoms.展开更多
The morbidity and mortality of myeloproliferative neoplasms(MPNs)are primarily caused by arterial and venous complications,progression to myelofibrosis,and transformation to acute leukemia.However,identifying molecula...The morbidity and mortality of myeloproliferative neoplasms(MPNs)are primarily caused by arterial and venous complications,progression to myelofibrosis,and transformation to acute leukemia.However,identifying molecular-based biomarkers for risk stratification of patients with MPNs remains a challenge.We have previously shown that interferon regulatory factor-8(IRF8)and IRF4 serve as tumor suppressors in myeloid cells.In this study,we evaluated the expression of IRF4 and IRF8 and the JAK2V617F mutant allele burden in patients with MPNs.Patients with decreased IRF4 expression were correlated with a more developed MPN phenotype in myelofibrosis(MF)and secondary AML(sAML)transformed from MPNs versus essential thrombocythemia(ET).Negative correlations between the JAK2V617F allele burden and the expression of IRF8(P<0.05)and IRF4(P<0.001)and between white blood cell(WBC)count and IRF4 expression(P<0.05)were found in ET patients.IRF8 expression was negatively correlated with the JAK2V617F allele burden(P<0.05)in polycythemia vera patients.Complete response(CR),partial response(PR),and no response(NR)were observed in 67.5%,10%,and 22.5%of ET patients treated with hydroxyurea(HU),respectively,in 12 months.At 3 months,patients in the CR group showed high IRF4 and IRF8 expression compared with patients in the PR and NR groups.In the 12-month therapy period,low IRF4 and IRF8 expression were independently associated with the unfavorable response to HU and high WBC count.Our data indicate that the expression of IRF4 and IRF8 was associated with the MPN phenotype,which may serve as biomarkers for the response to HU in ET.展开更多
Sickle cell anemia (SCA) is a prevalent genetic disorder primarily affecting individuals of African descent and populations in malaria-endemic regions, with significant global public health implications. Sickle cell c...Sickle cell anemia (SCA) is a prevalent genetic disorder primarily affecting individuals of African descent and populations in malaria-endemic regions, with significant global public health implications. Sickle cell crises are their most common acute complication, characterized by episodes of intense pain and systemic manifestations that impair quality of life and impose a high healthcare burden. We present the case of a 19-year-old male diagnosed with SCA since the age of two, who developed a sickle cell crisis precipitated by right basal pneumonia. The patient exhibited sudden-onset, cyclic lumbar pain with progressive dyspnea. Initial management included multimodal pain control, volume optimization, and targeted antimicrobial therapy to achieve clinical stabilization. This case underscores the importance of a comprehensive approach to managing sickle cell crises, addressing both symptomatic relief and the prevention and treatment of complications. It also highlights the need for public health strategies promoting early diagnosis, access to disease-modifying therapies such as hydroxyurea, and interdisciplinary follow-up to mitigate the socioeconomic and clinical impact of SCA.展开更多
BACKGROUND Polycythemia vera(PV)is a myeloproliferative neoplasm characterized by excessive blood cell production,which increases the risk of thrombosis.Ropeginterferon alfa-2b(RI)offers potential advantages over stan...BACKGROUND Polycythemia vera(PV)is a myeloproliferative neoplasm characterized by excessive blood cell production,which increases the risk of thrombosis.Ropeginterferon alfa-2b(RI)offers potential advantages over standard therapy(ST;including phlebotomy,hydroxyurea,and aspirin)by achieving hematologic and molecular responses.However,its comparative efficacy and safety remain understudied.We hypothesized that RI would improve hematologic and molecular outcomes but may differ in safety profiles compared to ST.AIM To evaluate the efficacy and safety of RI vs ST in patients with PV,focusing on hematologic response,molecular response,adverse events(AEs),and thrombotic risk.METHODS This Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant meta-analysis included randomized controlled trials comparing RI to ST in adult PV patients.PubMed,EMBASE,ClinicalTrials.gov,and ScienceDirect were searched from inception to July 2025.Outcomes included complete hematological response(CHR),molecular response,AEs leading to discontinuation,JAK2V617F allele burden,thrombotic events,and phlebotomy frequency.Pooled odds ratios(ORs)and MD with 95%confidence intervals(95%CIs)were calculated using random-effects models.Risk of bias was assessed with Cochrane RoB 2;evidence certainty was evaluated via GRADE.RESULTS Five studies involving 477 RI and 456 ST patients were included.RI significantly improved CHR(OR=2.14,95%CI:1.18-3.88,P=0.002)and molecular response(OR=4.37,95%CI:0.99-19.38,P=0.05),with substantial heterogeneity(I²=76%and I²=93%,respectively).AEs leading to discontinuation were higher with RI(OR=3.89,95%CI:1.90-7.97,P=0.0002;I²=0%).No significant differences were observed in JAK2V617F allele burden(MD=-7.46,95%CI:-21.12 to 6.20,P=0.28;I²=90%)or thrombotic events(OR=0.93,95%CI:0.45-1.90,P=0.83;I²=0%).RI reduced phlebotomy frequency(MD=-1.52,95%CI:-2.37 to-0.67,P=0.0005;I²=0%).Most studies had low to moderate risk of bias;evidence certainty was moderate for CHR and AEs,low for molecular response and thrombotic events,and very low for allele burden.CONCLUSION RI offers superior hematologic and molecular responses compared to ST in PV but is associated with higher discontinuation rates due to AEs.Comparable thrombotic risk and reduced phlebotomy needs highlight its potential,though tolerability requires careful management.The high heterogeneity in certain outcomes and potential for publication bias warrant cautious interpretation of these findings.Further long-term studies are needed to optimize dosing and patient selection.展开更多
基金Supported by National Natural Science Foundation of China,No.82370604Major Science and Technology innovation Project of Fujian Province,No.2023Y9269Natural Science Foundation of Fujian Province,China,No.2023J01239.
文摘BACKGROUND Hydroxyurea,an antimetabolite,is frequently prescribed for various hemato-logical disorders,and its common side effects include gastrointestinal problems,cutaneous or mucosal lesions and pyrexia/fever.CASE SUMMARY This study reports the case of a 67-year-old woman who developed recurrent abdominal pain after 10 years of continuous hydroxyurea therapy for primary thrombocythemia.Colonoscopy revealed an ileocecal ulcer.After discontinuing hydroxyurea therapy for 6 months,follow-up colonoscopy showed a significant reduction in the ulceration.CONCLUSION We consider cecal ulcers as a rare complication of hydroxyurea therapy which typically resolves upon stopping the drug.
文摘This study aimed to evaluate testicular toxicity induced by hydroxyurea （HU） and the possible counteracting effect of an aqueous extract of Cistanche deserticola （CD）. HU is an antineoplastic drug that has potential reproductive toxicity, and Herba Cistanche has been used as a tonic for the reproductive system for thousands of years. Sixty mice were randomly divided into five groups. Except mice in normal group, the rest received HU （400 mg kg^-1 body weight） intragastrically. Meanwhile, mice in normal and HU control groups received purified water, and the rest received intragastrically three doses of CD decoctions （1.5, 3.0 and 6.0 g crude drug kg^-1 body weight, respectively） daily for 4 weeks. Severe testes lesions were observed, testes weight （P〈0.01） and serum luteinising hormone levels （P〈0.0 1） were also decreased significantly, in the HU groups. Three doses of CD decoctions alleviated the spermatogenetic cell degeneration induced by HU and modulated the serum sex hormones levels to some extent.
文摘Hydroxyurea has been used to synchronize cultured cells to S-phase and used to treat patients with sicklecell anemia. Recently, we found that hydroxyurea can induce the apoptosis of HEL (human erythroleukemia) cells.The induced HEL cells showed ultrastructurally chromatin condensation with regular crescents at the nuclear edges and apoptotic bodies. However, the cells of K562, another human erythroleukemia cell line, did not show such morphological changes. Under fluoroscope, the HEL cells after induction often displayed a clear reduction in nuclear diameter and nuclear chromatin cleavage and condensation and the presence of nuclear ring and apoptotic bodies. Analysis with flow cytometry showed that the percentage of apoptotic cells is about 30-40% after HEL cells were induced by hydroxyurea for 3 days. DNA ladder can be observed by electrophoretic analysis.
文摘HEL cells, a human erythroleukemia cell line, mainly express the fetal (r)globin gene and trace amount of the embryonic (E)globin gene, but not adult (B) globin gene. Here we show that hydroxyurea (HU) can induce HEL cells to express adult (B) globin gene and lead these cells to terminal differentiation. Results showed in Gel mobility shift assays that GATA factors could specifically bind to the regulatory elements of human B- globin gene, including the proximal regulatory element (the B- promoter) and the distal regulatory elements (the DNase I hypersensitive sites in the LCR, HS2-HS4 core sequences). However, the DNA binding patterns of GATA factors were quite different between HU-induced and uninduced HEL cells. Western-blot analysis of nuclear extracts from both the uninduced and HU- induced HEL cells revealed that the level of GATA-2 transcription factor decreased, whereas the level of GATA-1 transcription factor increased following the time of hydroxyurea induction. Furthermore, using RT-PCR analysis the expression of human B-globin gene in HU-induced HEL cells could be blocked again when HEL cells were incubated in the presence of antisense oligonucleotides for hGATA-1, suggesting that the upregulation of hGATA-1 transcription factor might be critical for the expression of human β- globin gene in HU-induced HEL cells.
文摘Induction of c-myc gene amplification in L1210 cells by hydroxyurea and its inhibition by homohar-ringtonine were investigated using the DNA-DNA molecular hybridization technique. When the cells were treated with hydroxyurea 1.0 mM for 16 hours, and incubated a further 16 hours in a drug-free medium, the c-myc gene amplified 23.5-fold. If homohar-ringtonine 50 μM was used at the same time as hydroxyurea, gene amplification did not occur. Cycloheximide, an inhibitor of protein biosynthesis, produced a similar effect. Our results indicated that a (or some) protein factor(s) might be involved in gene amplification. Detailed analysis showed that the synthesis of this protein factor(s) started 4 hours before the initiation of the S phase but did not continue in the S phase. It was also found that this protein factor(s) was very labile and began to degrade 2 hours after its appearance.
文摘BACKGROUND Hydroxyurea(HU)is a non-alkylating antineoplastic agent that is active in the Sphase of the cell cycle and inhibits the enzyme ribonucleoside reductase.HU is currently used to treat leukemia,sickle cell anemia,psoriasis,and chronic myeloproliferative disorders.Although HU is easy to use and effective and has high tolerance,there have been numerous reports of cutaneous complications during long-term therapy with HU.CASE SUMMARY We report a 67-year-old woman on long-term HU therapy for primary myelofibrosis who developed concurrent skin lesions during treatment.The first skin lesion appeared on the dorsum of her right hand in 2015.Despite continuous use of HU,her cutaneous changes were neglected.Approximately 3 years ago,she had multiple nodular and keratotic lesions on both hands with sharp margins,branny desquamation,and dotted hyperpigmentation.Furthermore,she developed acutely numerous ulcerative lesions on her hands and legs.Topical wound therapy with dressing changes and parenteral antibiotics was applied for management of the lesions.Most of the wounds healed after HU withdrawal.Lesions on both hands were replaced by scabs.Nevertheless,the wound on her left ankle reached 9 cm×7 cm in size in January 2018.Pathology confirmed welldifferentiated squamous cell carcinoma at the ulcer area.In addition,her left foot was severely affected and radical surgery with a below-the-knee amputation was suggested followed by preventive right groin nodal dissection.CONCLUSION In patients receiving continuous HU therapy,close dermatologic follow-up is critical for the early diagnosis and selection of appropriate treatment for cutaneous lesions.
文摘Background: Gap junctions enable small molecules to diffuse between adjacent cells and have been associated with greater cytotoxicity of radiation and anti-cancer drugs. We investigated?whether this gap junctional intercellular communication (GJIC) affected the cytotoxicity of the classic?ribonucleotide reductase (RR) inhibitor and anti-cancer agent, hydroxyurea (HU). Materials and Methods: We used GJIC-proficient and deficient, connexin 43-expressing WB rat liver epithelial cell lines. We compared HU toxicity by crystal violet assay, effects of the drug on deoxynucleotide pools by HPLC, and ability of GJIC to increase toxicity of HU-resistant cells through a bystander effect in co-culture experiments. Results: GJIC-proficient cells were three- to five-fold more sensitive (IC50?0.1 mM) to HU than GJIC-deficient derivatives (IC50?0.3 - 0.5 mM). This sensitivity depended upon GJIC because treatment of GJIC-proficient cells with the GJIC blocker oleamide decreased HU toxicity by approximately 60% - 80% and restoration of GJIC in GJIC-deficient cells by stable transduction of connexin 32-encoding?Gjb1?increased HU toxicity (IC500.1 mM). The effects were not due to connexin expression?per se?or its localization since all cell lines expressed comparable quantities of connexin 43 that was localized to the plasma membrane. Also HU sensitivity was not related to differential effects on nucleotide metabolism in the cells. Thymidine triphosphate levels increased and deoxyadenosine triphosphate levels decreased similarly (15% - 20%) in GJIC-proficient and deficient cells over 24 h of HU treatment. More importantly, when HU-resistant cells were co-cultured with sensitive cells, the resistant cells were killed only when GJIC?was present. Conclusion: The data suggest that GJIC enhances cytotoxicity and decreases resistance?to HU. These results may be important clinically if GJIC can be enhanced in drug-resistant cells.
文摘Background: In Côte d’Ivoire so far, the circulating haplotypes have been inferred on the phenotypic profiling of SCD patients. The impact of the circulating haplotypes on the use of Hydroxyurea has not been assessed yet. Therefore the objective of this study is to identify in Abidjan the HbS haplotypes that modulate HU treatment responses. Methods: In a cross-sectional descriptive and analytical study, children aged 5 to 15 years with SCD, and carrying the hemoglobin phenotypes SSFA2 and SFA2, were recruited into a HU treatment cohort. Various parameters on the haplotypes and the outcomes of the treatment were analyzed. Results: Thirty nine children with SCD were included. The phenotypic profile of the cohort was 86.6% of SSFA2 and 15.4% of SFA2. Three haplotypes were found, the Benin haplotype, the Senegal haplotype, and an atypical one. The participants belonged to three genotypes, Benin/atypical (64.1%), Benin/Senegal (33.3%) and Senegal/Senegal (2.6%). Overall, HU treatment was successful in all haplotypes with 12 out of 39 patients failing treatment after 12 months in the Benin haplotype group. The association between HU treatment success and the Benin haplotype was found in terms of the decrease in the number of white blood cells and the students missing class. Conclusion: The study revealed that inferring haplotype based on the phenotypic profile could be inaccurate. The proportion of atypical haplotype that were not previously described in Côte d’Ivoire was high. All the haplotypes seemed to be associated with HU treatment success but some patients with Benin haplotype did not respond well.
文摘Sickle cell disease (SCD) is a prevalent condition, particularly in the countries of sub-Saharan Africa, where the presence of specific genes associated with Malaria contributes to its high prevalence. Patients with sickle cell disease frequently experience painful episodes necessitating hospitalization, and their hemoglobin levels are typically lower than those of the general population. There are different treatment options available to manage complications, such as transfusing blood, hydroxyurea, and strong anti-pains. However, with all these treatments, patients still commonly experience pain crises and suffer from organ damage. Hydroxyurea, the sole approved medication for sickle cell anemia in developed and developing countries, is widely used in children despite being primarily indicated for adults. Multiple studies have demonstrated the efficacy of hydroxyurea in inducing HbF production in young children with SCD. Elevated HbF levels have been associated with improved clinical outcomes, including a reduction in vaso-occlusive crises, acute chest syndrome, and the need for blood transfusions. Furthermore, increased HbF levels have been shown to ameliorate disease-related organ damage, such as pulmonary hypertension and sickle cell retinopathy. The response to hydroxyurea treatment in young children with SCD is variable. Some patients achieve substantial increases in HbF levels and experience significant clinical benefits, while others may have a more modest response. Factors influencing the response include baseline HbF levels, genetic modifiers, treatment adherence, and dose optimization. Safety is a crucial consideration when using hydroxyurea in young children. Studies have shown that hydroxyurea is generally well-tolerated, with the most common adverse effects being myelosuppression, gastrointestinal symptoms, and dermatological manifestations. However,long-term effects and potential risks, such as renal dysfunction and reproductive impacts, require further investigation. The effectiveness of hydroxyurea in young children with SCD has been demonstrated in various clinical trials and observational studies. These studies have shown a significant reduction in disease-related complications and improved quality of life. However, optimal dosing, treatment duration, and long-term outcomes are still areas of ongoing research. This review focuses on recent studies investigating the benefits, effectiveness, responses, and safety of hydroxyurea in pediatric individuals diagnosed with sickle cell disease.
基金the Chinese"863"Research Grant and NIH Grant HLB-29623
文摘A newly developed method of RT-PCR/competitive PCR for measuring the relative and ab-solute content of globin mRNAs as well as micro-globin chain biosynthetic assay have been used to study thealterations of globin gene expressions in the patients with β-thalassemia pre-and post-hydroxyurea(HU)treatment.It was found for the first time that HU had the effect of enhancing β-globin gene expression insome patients.Two cases with β-thalassemia who were subjected to HU treatment for over two years showeda marked increase in β-globin mRNA level and β-globin chain synthesis,resulting in more effective erythro-poiesis and the alleviation of clinical symptoms.
基金supported by the National Key Research and Development Program(No.2016YFC0902800 to Ruibao Ren)the Key Project of National Natural Science Foundation of China(No.81530006 to Ruibao Ren)+1 种基金Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(No.2019CXJQ01 to Ruibao Ren)National Natural Science Foundation of China(No.81870112 to Ruibao Ren).
文摘The morbidity and mortality of myeloproliferative neoplasms(MPNs)are primarily caused by arterial and venous complications,progression to myelofibrosis,and transformation to acute leukemia.However,identifying molecular-based biomarkers for risk stratification of patients with MPNs remains a challenge.We have previously shown that interferon regulatory factor-8(IRF8)and IRF4 serve as tumor suppressors in myeloid cells.In this study,we evaluated the expression of IRF4 and IRF8 and the JAK2V617F mutant allele burden in patients with MPNs.Patients with decreased IRF4 expression were correlated with a more developed MPN phenotype in myelofibrosis(MF)and secondary AML(sAML)transformed from MPNs versus essential thrombocythemia(ET).Negative correlations between the JAK2V617F allele burden and the expression of IRF8(P<0.05)and IRF4(P<0.001)and between white blood cell(WBC)count and IRF4 expression(P<0.05)were found in ET patients.IRF8 expression was negatively correlated with the JAK2V617F allele burden(P<0.05)in polycythemia vera patients.Complete response(CR),partial response(PR),and no response(NR)were observed in 67.5%,10%,and 22.5%of ET patients treated with hydroxyurea(HU),respectively,in 12 months.At 3 months,patients in the CR group showed high IRF4 and IRF8 expression compared with patients in the PR and NR groups.In the 12-month therapy period,low IRF4 and IRF8 expression were independently associated with the unfavorable response to HU and high WBC count.Our data indicate that the expression of IRF4 and IRF8 was associated with the MPN phenotype,which may serve as biomarkers for the response to HU in ET.
文摘Sickle cell anemia (SCA) is a prevalent genetic disorder primarily affecting individuals of African descent and populations in malaria-endemic regions, with significant global public health implications. Sickle cell crises are their most common acute complication, characterized by episodes of intense pain and systemic manifestations that impair quality of life and impose a high healthcare burden. We present the case of a 19-year-old male diagnosed with SCA since the age of two, who developed a sickle cell crisis precipitated by right basal pneumonia. The patient exhibited sudden-onset, cyclic lumbar pain with progressive dyspnea. Initial management included multimodal pain control, volume optimization, and targeted antimicrobial therapy to achieve clinical stabilization. This case underscores the importance of a comprehensive approach to managing sickle cell crises, addressing both symptomatic relief and the prevention and treatment of complications. It also highlights the need for public health strategies promoting early diagnosis, access to disease-modifying therapies such as hydroxyurea, and interdisciplinary follow-up to mitigate the socioeconomic and clinical impact of SCA.
文摘BACKGROUND Polycythemia vera(PV)is a myeloproliferative neoplasm characterized by excessive blood cell production,which increases the risk of thrombosis.Ropeginterferon alfa-2b(RI)offers potential advantages over standard therapy(ST;including phlebotomy,hydroxyurea,and aspirin)by achieving hematologic and molecular responses.However,its comparative efficacy and safety remain understudied.We hypothesized that RI would improve hematologic and molecular outcomes but may differ in safety profiles compared to ST.AIM To evaluate the efficacy and safety of RI vs ST in patients with PV,focusing on hematologic response,molecular response,adverse events(AEs),and thrombotic risk.METHODS This Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant meta-analysis included randomized controlled trials comparing RI to ST in adult PV patients.PubMed,EMBASE,ClinicalTrials.gov,and ScienceDirect were searched from inception to July 2025.Outcomes included complete hematological response(CHR),molecular response,AEs leading to discontinuation,JAK2V617F allele burden,thrombotic events,and phlebotomy frequency.Pooled odds ratios(ORs)and MD with 95%confidence intervals(95%CIs)were calculated using random-effects models.Risk of bias was assessed with Cochrane RoB 2;evidence certainty was evaluated via GRADE.RESULTS Five studies involving 477 RI and 456 ST patients were included.RI significantly improved CHR(OR=2.14,95%CI:1.18-3.88,P=0.002)and molecular response(OR=4.37,95%CI:0.99-19.38,P=0.05),with substantial heterogeneity(I²=76%and I²=93%,respectively).AEs leading to discontinuation were higher with RI(OR=3.89,95%CI:1.90-7.97,P=0.0002;I²=0%).No significant differences were observed in JAK2V617F allele burden(MD=-7.46,95%CI:-21.12 to 6.20,P=0.28;I²=90%)or thrombotic events(OR=0.93,95%CI:0.45-1.90,P=0.83;I²=0%).RI reduced phlebotomy frequency(MD=-1.52,95%CI:-2.37 to-0.67,P=0.0005;I²=0%).Most studies had low to moderate risk of bias;evidence certainty was moderate for CHR and AEs,low for molecular response and thrombotic events,and very low for allele burden.CONCLUSION RI offers superior hematologic and molecular responses compared to ST in PV but is associated with higher discontinuation rates due to AEs.Comparable thrombotic risk and reduced phlebotomy needs highlight its potential,though tolerability requires careful management.The high heterogeneity in certain outcomes and potential for publication bias warrant cautious interpretation of these findings.Further long-term studies are needed to optimize dosing and patient selection.
