Molecular Classification and Overcoming Therapy Resistance for Acute Myeloid Leukemia with Adverse Genetic Factors

The European LeukemiaNet (ELN) criteria define the adverse genetic factors of acute myeloid leukemia (AML). AML with adverse genetic factors uniformly shows resistance to standard chemotherapy and is associated with poor prognosis. Here, we focus on the biological background and real-world etiology of these adverse genetic factors and then describe a strategy to overcome the clinical disadvantages in terms of targeting pivotal molecular mechanisms. Different adverse genetic factors often rely on common pathways. KMT2A rearrangement, DEK-NUP214 fusion, and NPM1 mutation are associated with the upregulation of HOX genes. The dominant tyrosine kinase activity of the mutant FLT3 or BCR-ABL1 fusion proteins is transduced by the AKT-mTOR, MAPK-ERK, and STAT5 pathways. Concurrent mutations of ASXL1 and RUNX1 are associated with activated AKT. Both TP53 mutation and mis-expressed MECOM are related to impaired apoptosis. Clinical data suggest that adverse genetic factors can be found in at least one in eight AML patients and appear to accumulate in relapsed/refractory cases. TP53 mutation is associated with particularly poor prognosis. Molecular-targeted therapies focusing on specific genomic abnormalities, such as FLT3, KMT2A, and TP53, have been developed and have demonstrated promising results.     

Effect of Chemotherapy Cytarabine and Acute Myeloid Leukemia on the Development of Spermatogenesis at the Adult Age of Immature Treated Mice

Acute myeloid leukemia (AML) accounts for around 20% of diagnosed childhood leukemia. Cytarabine (CYT) is involved in the AML treatment regimen. AML and CYT showed impairment in spermatogenesis in human and rodents in adulthood. We successfully developed an AML disease model in sexually immature mice. Monocytes and granulocytes were examined in all groups: untreated control, AML alone, CYT alone and AML+CYT (in combination). There was a significant increase in the counts of monocytes and granulocytes in the AML-treated immature mice (AML) compared to the control, and AML cells were demonstrated in the blood vessels of the testes. AML alone and CYT alone impaired the development of spermatogenesis at the adult age of the AML-treated immature mice. The damage was clear in the structure/histology of their seminiferous tubules, and an increase in the apoptotic cells of the seminiferous tubules was demonstrated. Our results demonstrated a significant decrease in the meiotic/post-meiotic cells compared to the control. However, CYT alone (but not AML) significantly increased the count of spermatogonial cells (premeiotic cells) that positively stained with SALL4 and PLZF per tubule compared to the control. Furthermore, AML significantly increased the count of proliferating spermatogonial cells that positively stained with PCNA in the seminiferous tubules compared to the control, whereas CYT significantly decreased the count compared to the control. Our result showed that AML and CYT affected the microenvironment/niche of the germ cells. AML significantly decreased the levels growth factors, such as SCF, GDNF and MCSF) compared to control, whereas CYT significantly increased the levels of MCSF and GDNF compared to control. In addition, AML significantly increased the RNA expression levels of testicular IL-6 (a proinflammatory cytokine), whereas CYT significantly decreased testicular IL-6 levels compared to the control group. Furthermore, AML alone and CYT alone significantly decreased RNA expression levels of testicular IL-10 (anti-inflammatory cytokine) compared to the control group. Our results demonstrate that pediatric AML disease with or without CYT treatment impairs spermatogenesis at adult age (the impairment was more pronounced in AML+CYT) compared to control. Thus, we suggest that special care should be considered for children with AML who are treated with a CYT regimen regarding their future fertility at adult age.     

Application of High Throughput Technologies in the Development of Acute Myeloid Leukemia Therapy: Challenges and Progress

Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by extensive heterogeneity in genetics, response to therapy and long-term outcomes, making it a prototype example of development for personalized medicine. Given the accessibility to hematologic malignancy patient samples and recent advances in high-throughput technologies, large amounts of biological data that are clinically relevant for diagnosis, risk stratification and targeted drug development have been generated. Recent studies highlight the potential of implementing genomic-based and phenotypic-based screens in clinics to improve survival in patients with refractory AML. In this review, we will discuss successful applications as well as challenges of most up-to-date high-throughput technologies, including artificial intelligence (AI) approaches, in the development of personalized medicine for AML, and recent clinical studies for evaluating the utility of integrating genomics-guided and drug sensitivity testing-guided treatment approaches for AML patients.     

Genetic Determinants of Poor Response to Treatment in Severe Asthma

Severe asthma is a multifactorial disorder with marked phenotypic heterogeneity and complex interactions between genetics and environmental risk factors, which could, at least in part, explain why during standard pharmacologic treatment, many patients remain poorly controlled and at an increased risk of airway remodeling and disease progression. The concept of “precision medicine” to better suit individual unique needs is an emerging trend in the management of chronic respiratory diseases. Over the past few years, Genome-Wide Association Studies (GWAS) have revealed novel pharmacogenetic variants related to responses to inhaled corticosteroids and the clinical efficacy of bronchodilators. Optimal clinical response to treatment may vary between racial/ethnic groups or individuals due to genetic differences. It is also plausible to assume that epigenetic factors play a key role in the modulation of gene expression patterns and inflammatory cytokines. Remarkably, specific genetic variants related to treatment effectiveness may indicate promising pathways for novel therapies in severe asthma. In this review, we provide a concise update of genetic determinants of poor response to treatment in severe asthma and future directions in the field.     

Targeted Therapeutic Approach Based on Understanding of Aberrant Molecular Pathways Leading to Leukemic Proliferation in Patients with Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogenous hematopoietic neoplasm with various genetic abnormalities in myeloid stem cells leading to differentiation arrest and accumulation of leukemic cells in bone marrow (BM). The multiple genetic alterations identified in leukemic cells at diagnosis are the mainstay of World Health Organization classification for AML and have important prognostic implications. Recently, understanding of heterogeneous and complicated molecular abnormalities of the disease could lead to the development of novel targeted therapeutic agents. In the past years, gemtuzumab ozogamicin, BCL-2 inhibitors (venetovlax), IDH 1/2 inhibitors (ivosidenib and enasidenib) FLT3 inhibitors (midostaurin, gilteritinib, and enasidenib), and hedgehog signaling pathway inhibitors (gladegib) have received US Food and Drug Administration (FDA) approval for the treatment of AML. Especially, AML patients with elderly age and/or significant comorbidities are not currently suitable for intensive chemotherapy. Thus, novel therapeutic planning including the abovementioned target therapies could lead to improve clinical outcomes in the patients. In the review, we will present various important and frequent molecular abnormalities of AML and introduce the targeted agents of AML that received FDA approval based on the previous studies.     

Gender Differences in the VDR-FokI Polymorphism and Conventional Non-Genetic Risk Factors in Association with Lumbar Spine Pathologies in an Italian Case-Control Study

Recently, the FokI polymorphism (rs2228570) in the vitamin D receptor gene (VDR) and conventional risk factors were associated with spine disorders in the Italian population, but without gender analysis. Two-hundred and sixty-seven patients (149 males, 118 females) with lumbar spine disorders were assessed by magnetic resonance imaging (MRI) and 254 (127 males, 127 females) asymptomatic controls were enrolled. The exposure to putative risk factors was evaluated and FokI polymorphism was detected by PCR-restriction fragment length polymorphism (PCR-RFLP). An association between lumbar spine pathologies and higher than average age; overweight; family history; lower leisure physical activity; smoking habit; higher number of hours/day exposure to vibration and more sedentary or intense physical job demand was observed in male patients. In contrast, in females, only higher age, overweight, family history and lower leisure physical activity were risk factors. FF genotype was a 2-fold risk factor to develop discopathies and/or osteochondrosis concomitant with disc herniation for both gender patients, while heterozygous Ff was protective for females only. In males only ff genotype was protective for discopathies and/or osteochondrosis and F allele was a 2-fold risk factor for hernia; discopathies; discopathies and/or osteochondrosis. Sex-related differences in voluntary behaviors, exposure to environmental risks and genetic background could be crucial for a gender-differentiated management of patients with spine disorders.     

Diabetes and Hypertension Consistently Predict the Presence and Extent of Coronary Artery Calcification in Symptomatic Patients: A Systematic Review and Meta-Analysis

Background: The relationship of conventional cardiovascular risk factors (age, gender, ethnicity, diabetes, dyslipidaemia, hypertension, obesity, exercise, and the number of risk factors) to coronary artery calcification (CAC) presence and extent has never before been assessed in a systematic review and meta-analysis. Methods: We included only English language studies that assessed at least three conventional risk factors apart from age, gender, and ethnicity, but excluded studies in which all patients had another confirmed condition such as renal disease. Results: In total, 10 studies, comprising 15,769 patients, were investigated in the systematic review and seven studies, comprising 12,682 patients, were included in the meta-analysis, which demonstrated the importance of diabetes and hypertension as predictors of CAC presence and extent, with age also predicting CAC presence. Male gender, dyslipidaemia, family history of coronary artery disease, obesity, and smoking were overall not predictive of either CAC presence or extent, despite dyslipidaemia being a key risk factor for coronary artery disease (CAD). Conclusion: Diabetes and hypertension consistently predict the presence and extent of CAC in symptomatic patients.     

电子实验记录软件在炼化科研领域的应用与展望

简要介绍了电子实验记录(ELN)软件的发展历程以及国内外ELN系统的应用现状,分析了ELN与实验室信息管理系统(LIMS)的功能定位与整合,阐述了对炼化科研领域具有普通适用意义的ELN系统功能模块设计,展望了ELN系统在炼化科研领域的应用前景。     

Effect of cooper supplementation on blood pressure values in patients with stable moderate hypertension

Copper (Cu) deficiency is associated with changes in arterial pressure. The effect depends of the age of initiation of the copper-deficient diet. Copper deficiency started at a young age causes hypotension. When initiated in older or adult animals, copper deficiency can cause hypertension. A case-control study was carried out to investigate the effect of administrating 5 mg Cu/d in 60 subjects, both genders, with mild stable hypertension, pharmacologically untreated (treated group) and compared with 60 hypertensives (control group) who were matched by gender, age, body weight, smoking habits, calories, fat and salt intake (NaCl), and physical activity. Hypertension was diagnosed when the blood pressure was > 150/95 mm Hg. Mean age, mean corporal weight and risk factors were similar in both groups. The results suggested the existence of a marginal deficiency of the trace element in 62% of subjects and demonstrated that Cu decreases systolic (r = -0.963) and diastolic (r = -0.981) blood pressures in treated group (p < 0.05). Control patients did not show significant changes in their arterial pressures. These findings indicate a functional alteration in human blood pressure regulation during mild copper depletion and suggest that Cu could be used in the treatment of stable moderate arterial hypertension. Further investigation is needed to determine the extent of this influence.     

Identification of Drivers from Cancer Genome Diversity in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers with a dismal outcome. The complicated molecular pathogenesis of HCC caused by tumor heterogeneity makes it difficult to identify druggable targets useful for treating HCC patients. One approach that has a potential for the improvement of patient prognosis is the identification of cancer driver genes that play a critical role in the development of HCC. Recent technological advances of high-throughput methods, such as gene expression profiles, DNA copy number alterations and somatic mutations, have expanded our understanding of the comprehensive genetic profiles of HCC. Integrative analysis of these omics profiles enables us to classify the molecular subgroups of HCC patients. As each subgroup classified according to genetic profiles has different clinical features, such as recurrence rate and prognosis, the tumor subclassification tools are useful in clinical practice. Furthermore, a global genetic analysis, including genome-wide RNAi functional screening, makes it possible to identify cancer vulnerable genes. Identification of common cancer driver genes in HCC leads to the development of an effective molecular target therapy.     

Nutritional status, lifestyle and cardiovascular risk in lacto-ovo vegetarians and omnivore

The aim of the present study was to assess socioeconomic characteristics, dietary intake, nutritional status and cardiovascular risk (using anthropometric indicators of central obesity) in lacto-ovo vegetarians and non-vegetarians. Two non-vegetarians were selected for each vegetarian (paired for gender and age) in order to increase the power of the statistical tests. The sample was made up of 87 individuals (58.6% males; 29 vegetarians and 58 non-vegetarians) with a mean age of 40 +/- 13 years. Among the socioeconomic characteristics, only the number of residents per household differed between groups, with a greater percentage of homes with five or more residents in the vegetarian group. Concerning lifestyle, the groups differed with regard to smoking habits (p < 0.001), with a higher proportion of smokers among the non-vegetarians. There were no significant differences between groups in any of the anthropometric variables studied. Concerning dietary intake, no difference between groups was found with regard to total calorie intake, but the consumption of proteins, total lipids, saturated fat and cholesterol was higher among the non-vegetarians, whereas carbohydrate and fiber intake was higher among the vegetarians. The results of the present study suggest that, although a lacto-ovo vegetarian diet is considered healthier due to the lower consumption of total fat, saturated fatty acids and cholesterol, there are no significant differences in nutritional status or anthropometric indicators of cardiovascular risk when lifestyle and total calorie intake are similar.     

Variable frequencies of apolipoprotein e genotypes and its effect on serum lipids in the guangxi zhuang and han children

Guangxi Zhuang, the largest ethnic minority in China, is located in the southern part of the country, and well-known to the world as the longevity village. Studies of apolipoprotein E (APOE) polymorphism in adults suggest the lower frequencies of E4 allele and E4/E4 genotype may account, in part, for the favorable lipid profiles of Guangxi Zhuang. However, the effect of APOE polymorphism on serum lipids in the Guangxi Zhuang children is yet unknown to date. In the present study, genomic DNA was extracted from 278 Guangxi Zhuang and 200 Guangxi Han children. APOE genotypes were determined by PCR-restriction fragment length polymorphism (RFLP) analysis. The fasting serum lipoprotein a [Lp(a)], total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1) and apoB were measured. Our results demonstrated that no significant differences in serum lipids were observed between the Guangxi Zhuang and Han children. The E4/E4 and E4/E3 genotypic frequencies were significantly lower in the Guangxi Zhuang children compared with the Guangxi Han children, whereas for E2/E2, E3/E2 and E4/E2 genotypic frequencies the opposite was presented. Though no significant differences in serum lipid concentrations were found for variant alleles both in the Guangxi Zhuang and Han children, the trend was observed in the association of higher levels of Lp(a), TC, TG and LDL-C with E4 allele in the Guangxi Zhuang children. In conclusion, a significant heterogeneity in APOE genetic variation indeed exists between the Guangxi Zhuang and Han ethnic group. The E4 allele may serve as a genetic marker for susceptibility to higher lipid profiles in the Guangxi Zhuang children. Lifestyle should be modified, according to APOE polymorphism even in the young children.     

Studies of lipoproteins and fatty acids in maternal and cord blood of two racial groups in Trinidad

The high mortality rate from coronary heart disease (CHD) among Indians compared to Negroes in Trinidad led us to test plasma lipid profiles to see whether dietary or genetic factors might be involved. There were no interracial differences in the composition of plasma cholesterol ester fatty acids of the tested women and neonates. This finding suggests that dietary fat does not account for the interracial difference in CHD, nor does the cause appear to be due to genetic differences in lipid profiles, as there was no significant difference between values for plasma triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, apo-I, apo-II, apo B or cholesterol ester fatty acids in the cord blood of each racial group. Blood samples were collected from 69 nonpregnant and 71 postpartum, fasted Negro and Indian women. Also taken were 71 umbilical cord blood samples. The mean triglyceride level was significantly lower in the Negro nonpregnant and postpartum women than in the Indians. HDL cholesterol and apo-I values were lower in the Indian women. There were no significant differences in the total cholesterol and apo B measurements. The triglyceride values for postpartum women were higher than those of the nonpregnant Negroes and Indians (75% and 47%, respectively), whereas the total cholesterol and HDL cholesterol, apo A-I and apo A-II ranged from 9% to 29% higher in the postpartum women. Apo B was about 40% higher postpartum in both ethnic groups. The high CHD rate of Indians in Trinidad cannot be explained by dietary factors, plasma total cholesterol or fatty acid composition. However, the lower level of HDL cholesterol and plasma A-I could play a role in the higher CHD rate in Indians.     

Involvement of ORAI1/SOCE in Human AML Cell Lines and Primary Cells According to ABCB1 Activity,LSC Compartment and Potential Resistance to Ara-C Exposure

Acute myeloid leukemia (AML) is a hematological malignancy with a high risk of relapse. This issue is associated with the development of mechanisms leading to drug resistance that are not yet fully understood. In this context, we previously showed the clinical significance of the ATP binding cassette subfamily B-member 1 (ABCB1) in AML patients, namely its association with stemness markers and an overall worth prognosis. Calcium signaling dysregulations affect numerous cellular functions and are associated with the development of the hallmarks of cancer. However, in AML, calcium-dependent signaling pathways remain poorly investigated. With this study, we show the involvement of the ORAI1 calcium channel in store-operated calcium entry (SOCE), the main calcium entry pathway in non-excitable cells, in two representative human AML cell lines (KG1 and U937) and in primary cells isolated from patients. Moreover, our data suggest that in these models, SOCE varies according to the differentiation status, ABCB1 activity level and leukemic stem cell (LSC) proportion. Finally, we present evidence that ORAI1 expression and SOCE amplitude are modulated during the establishment of an apoptosis resistance phenotype elicited by the chemotherapeutic drug Ara-C. Our results therefore suggest ORAI1/SOCE as potential markers of AML progression and drug resistance apparition.     

Stromal Cell-Derived Factor 1 Gene Polymorphism Is Associated with Susceptibility to Adverse Long-Term Allograft Outcomes in Non-Diabetic Kidney Transplant Recipients

Although the genetic polymorphism of Stromal Cell-Derived Factor 1 (SDF-1) is associated with higher mortality of liver allograft recipients, the role of SDF-1 in the modulation of renal allograft outcomes is unclear. Between March 2000 and January 2008, we recruited 252 non-diabetic renal transplant recipients (RTRs). Baseline characteristics and blood chemistry were recorded. Genomic DNA extraction with polymerase chain reaction-restriction fragment length polymorphism was utilized to analyze the genetic polymorphisms of SDF-1 (rs1801157). The influence of SDF-1 on an adverse renal allograft outcome, defined as either a doubling of serum creatinine, graft failure, or patient death was evaluated. Sixteen patients with the SDF-1 AA/AG genotype and nine with the SDF-1 GG genotype reached an adverse outcome. According to Kaplan-Meier analysis, patients carrying the SDF-1 AA/AG genotype or A allele showed a significantly higher risk of reaching an adverse outcome than those carrying the SDF-1 GG genotype or G allele (p = 0.041; p = 0.0051, respectively; log rank test). Stepwise multivariate Cox proportional regression analysis revealed that patients carrying the SDF-1 AA/AG genotype and A allele had a 2.742-fold (95% CI. 1.106–6.799, p = 0.03) and 2.306-fold (95% CI. 1.254–4.24, p = 0.008) risk of experiencing an adverse outcome. The SDF-1 AA/AG genotype and A allele have a detrimental impact on the long-term outcome of RTRs.