Molecular monitoring of myelodysplastic neoplasm: Don't just watch this space, consider the patient's ancestry.

The heterogeneity of Myelodysplastic Neoplasm (MDS) extends beyond mutational diversity to include significant ethnic variability, a factor that has been underexplored. While the development of the IPSS-M prognostic tool has advanced our understanding of MDS, its reliance on data primarily from European cohorts limits its applicability to non-European populations. Duployez et al.'s review highlighted the importance of molecular markers in MDS for personalized treatment and disease monitoring yet did not address the impact of genetic ancestry. This commentary critiques the IPSS-M's limited sample of 110 Brazilian patients, questioning its adequacy in reflecting the influence of patient ancestry on prognostic accuracy. Given the potential for differing mutation profiles and prognostic implications across diverse ethnic groups, robust genomic ancestry studies are urgently needed. These studies should stratify MDS patients by ethnic background to investigate mutation incidence and impacts, thereby validating IPSS-M and potentially identifying new prognostic markers. Incorporating ethnic diversity into prognostic models is essential for ensuring they are truly universal and inclusive, thereby improving personalized treatment and care for all MDS patients. Commentary on: Duployez and Preudhomme. Monitoring molecular changes in the management of myelodysplastic syndromes. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19614.

The role of adiposity, adipokines and polymorphisms of leptin and adiponectin in myelodysplastic syndromes.

The aim of the present study was to investigate the relationship between leptin and adiponectin gene polymorphisms, circulating levels of leptin and adiponectin, adiposity and clinical markers in patients with myelodysplastic syndrome (MDS). This cross-sectional study was conducted with 102 adults and elderly MDS patients and 102 age- and sex-matched controls. Clinical characteristics, co-morbidities, anthropometric data, laboratory evaluation and genetic analysis (polymorphisms -2548G > A/rs7799039 of the LEP gene and +276G > T/rs1501299 of the ADIPOQ gene) were investigated. Serum leptin was higher and adiponectin lower in MDS when compared with controls. There was a significant positive correlation between serum leptin levels and BMI (r = 0·264, P = 0·025), waist circumference (r = 0·235, P = 0·047), body fat percentage (BF %) (r = 0·373, P = 0·001) and the fat mass index (FMI) (r = 0·371, P < 0·001). A lower mean adiponectin was found among patients with high BF %, higher visceral adiposity index and metabolic syndrome. A significant association was found between the AA genotype (mutant) of the LEP polymorphism rs7799039 and male sex and blast excess (≥ 5 %). In addition, a significant association was observed between the TT genotype (mutant) of the ADIPOQ rs1501299 polymorphism and Fe overload. These results demonstrate the importance of a comprehensive and systematic evaluation in patients with MDS in order to identify and control negative factors not related to the disease at an early stage.

Effect of CYB2B6 (c.516G>T), CYP2C9 (c.1075A>C) and UGT1A9 (c.98T>C) polymorphisms on propofol pharmacokinetics in patients submitted to colonoscopy: a cohort study.

BACKGROUND: The aim of this study was to investigate the effect of CYB2B6 (c.516G>T, rs3745274), CYP2C9 (c.1075A>C, rs1057910) and UGT1A9 (c.98T>C, rs72551330) polymorphisms on the pharmacokinetics of single-drug propofol in adult patients undergoing intravenous sedation. METHODS: In this prospective clinical study, a total of 124 patients undergoing anaesthesia with propofol, as a single drug, were evaluated when undergoing colonoscopy procedure. Clinical variables were obtained from the patient's anamnesis prior to performing the anaesthetic procedure, in the moment of the patient's loss of consciousness, during the colonoscopy exam (recorded every 5 min) and in the awakening time. RESULTS: Polymorphic genotypes for the rs3745274 and rs1057910 polymorphisms were associated with bispectral index, target-controlled infusion (TCI)/effector concentration of propofol and TCI/plasma concentration of propofol values. Based on multivariate analysis, it was observed that weight, age, surgery time, systolic blood pressure and the rs1057910 polymorphism corresponded to predictive values for the dose of propofol used. Weight (B = 4.807±0.897), age (B = 1.834±0.834) and duration of surgery (B = 8.164±1.624) corresponded to factors associated with increased propofol dose, while systolic blood pressure (B = -1.892±0.679) and the genotypes (AA vs CA) of the single nucleotide polymorphism (SNP) rs1057910 CYPP2C9 gene (B = -74.161±26.820) decreased the total dose of propofol used. CONCLUSION: We concluded that the rs1057910 and rs3745274 polymorphisms affect the metabolism of propofol in patients exclusively submitted to this drug. Thus, the knowledge of the polymorphic genotypes of the CYPP2C9 and CYB2B6 genes may be predictive of different metabolising phenotypes, suggesting expected behaviours of BIS parameter in the anaesthetic procedure, which contributes to safer monitoring by anaesthesiologists during the clinical intervention.

USP15-USP7 Axis and UBE2T Differential Expression May Predict Pathogenesis and Poor Prognosis in De Novo Myelodysplastic Neoplasm.

The aim of this study was to evaluate the expression of USP7, USP15, UBE2O, and UBE2T genes in Myelodysplastic neoplasm (MDS) to identify possible targets of ubiquitination and deubiquitination in MDS pathobiology. To achieve this, eight datasets from the Gene Expression Omnibus (GEO) database were integrated, and the expression relationship of these genes was analyzed in 1092 MDS patients and healthy controls. Our results showed that UBE2O, UBE2T, and USP7 were upregulated in MDS patients compared with healthy individuals, but only in mononucleated cells collected from bone marrow samples (p < 0.001). In contrast, only the USP15 gene showed a downregulated expression compared with healthy individuals (p = 0.03). Additionally, the upregulation of UBE2T expression was identified in MDS patients with chromosomal abnormalities compared with patients with normal karyotypes (p = 0.0321), and the downregulation of UBE2T expression was associated with MDS hypoplastic patients (p = 0.033). Finally, the USP7 and USP15 genes were strongly correlated with MDS (r = 0.82; r2 = 0.67; p < 0.0001). These findings suggest that the differential expression of the USP15-USP7 axis and UBE2T may play an important role in controlling genomic instability and the chromosomal abnormalities that are a striking characteristic of MDS.

Effect of CYB2B6 (c.516G>T), CYP2C9 (c.1075A>C) and UGT1A9 (c.98T>C) polymorphisms on propofol pharmacokinetics in patients submitted to colonoscopy: a cohort study.

BACKGROUND: The aim of this study was to investigate the effect of CYB2B6 (c.516G>T, rs3745274), CYP2C9 (c.1075A>C, rs1057910) and UGT1A9 (c.98T>C, rs72551330) polymorphisms on the pharmacokinetics of single-drug propofol in adult patients undergoing intravenous sedation. METHODS: In this prospective clinical study, a total of 124 patients undergoing anaesthesia with propofol, as a single drug, were evaluated when undergoing colonoscopy procedure. Clinical variables were obtained from the patient's anamnesis prior to performing the anaesthetic procedure, in the moment of the patient's loss of consciousness, during the colonoscopy exam (recorded every 5 min) and in the awakening time. RESULTS: Polymorphic genotypes for the rs3745274 and rs1057910 polymorphisms were associated with bispectral index, target-controlled infusion (TCI)/effector concentration of propofol and TCI/plasma concentration of propofol values. Based on multivariate analysis, it was observed that weight, age, surgery time, systolic blood pressure and the rs1057910 polymorphism corresponded to predictive values for the dose of propofol used. Weight (B = 4.807±0.897), age (B = 1.834±0.834) and duration of surgery (B = 8.164±1.624) corresponded to factors associated with increased propofol dose, while systolic blood pressure (B = -1.892±0.679) and the genotypes (AA vs CA) of the single nucleotide polymorphism (SNP) rs1057910 CYPP2C9 gene (B = -74.161±26.820) decreased the total dose of propofol used. CONCLUSION: We concluded that the rs1057910 and rs3745274 polymorphisms affect the metabolism of propofol in patients exclusively submitted to this drug. Thus, the knowledge of the polymorphic genotypes of the CYPP2C9 and CYB2B6 genes may be predictive of different metabolising phenotypes, suggesting expected behaviours of BIS parameter in the anaesthetic procedure, which contributes to safer monitoring by anaesthesiologists during the clinical intervention.

Gene expression patterns of Sirtuin family members (SIRT1 TO SIRT7): Insights into pathogenesis and prognostic of Myelodysplastic neoplasm.

To assess and validate the gene expression profile of SIRTs (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7) in relation to the pathogenesis and prognostic progression of Myelodysplastic neoplasm (MDS). Eighty bone marrow samples of patients with de novo MDS were diagnosed according to WHO 2022 and IPSS-R criteria. Ten bone marrow samples were obtained from elderly healthy volunteers and used as control samples. Gene expression levels of all SIRTs were assessed using RT-qPCR assays. Downregulation of SIRT2 (p = 0.009), SIRT3 (p = 0.048), SIRT4 (p = 0.049), SIRT5 (p = 0.046), SIRT6 (p = 0.043), and SIRT7 (p = 0.047) was identified in MDS patients compared to control individuals. Also, we identified that while SIRT2-7 genes are typically down-regulated in MDS patients compared to normal controls, there are relative expression variations among MDS patient subgroups. Specifically, SIRT4 (p = 0.029) showed increased expression in patients aged 60 or above, and both SIRT2 (p = 0.016) and SIRT3 (p = 0.036) were upregulated in patients with hemoglobin levels below 8 g/dL. SIRT2 (p = 0.045) and SIRT3 (p = 0.033) were highly expressed in patients with chromosomal abnormalities. Different SIRTs exhibited altered expression patterns concerning specific MDS clinical and prognostic characteristics. The downregulation in SIRTs genes (e.g., SIRT2 to SIRT7) expression in Brazilian MDS patients highlights their role in the disease's development. The upregulation of SIRT2 and SIRT3 in severe anemia patients suggests a potential link to manage iron overload-related complications in transfusion-dependent patients. Moreover, the association of SIRT2/SIRT3 with genomic instability and their role in MDS progression signify promising areas for future research and therapeutic targets. These findings underscore the importance of SIRT family in understanding and addressing MDS, offering novel clinical, prognostic, and therapeutic insights for patients with this condition.

Role of the STING pathway in myeloid neoplasms: a prospero-registered systematic review of principal hurdles of STING on the road to the clinical practice.

Myeloid neoplasms are a group of bone marrow diseases distinguished by disruptions in the molecular pathways that regulate the balance between hematopoietic stem cell (HSC) self-renewal and the generation of specialized cells. Cytokines and chemokines, two important components of the inflammatory process, also influence hematological differentiation. In this scenario, immunological dysregulation plays a pivotal role in the pathogenesis of bone marrow neoplasms. The STING pathway recognizes DNA fragments in the cell cytoplasm and triggers an immune response by type I interferons. The role of STING in cancer has not yet been established; however, both actions, as an oncogene or tumor suppressor, have been documented in other types of cancer. Therefore, we performed a systematic review (registered in PROSPERO database #CRD42023407512) to discuss the role of STING pathway in the advancement of pathogenesis and/or prognosis for different myeloid neoplasms. In brief, scientific evidence supports investigations that primarily use cell lines from myeloid neoplasms, such as leukemia. More high-quality research and clinical trials are needed to understand the role of the STING pathway in the pathology of hematological malignancies. Finally, the STING pathway suggests being a promising therapeutic molecular target, particularly when combined with current drug therapies.

Chenopodium Ambrosioides Linn Mitigates Bone Loss in Rats with Periodontitis.

Statement of the Problem: Periodontitis is an inflammatory disease that causes bone loss. Some patients do not respond well to the classic treatment and need therapies that minimize bone loss, the main sequel of the disease. Chenopodium ambrosioides L. has stood out due to its anti-inflammatory and anti-oxidative activities. However, no study has yet investigated its effect on periodontitis. Purpose: This study aimed to evaluate the bone protective effect of Chenopodium ambrosioides L. (CAL) extract on ligature-induced periodontitis model in rats. Materials and Method: For this, a pre-clinical assay was performed, using male Wistar rats divided into 3 groups: Naive (N) (n=6), not submitted to any procedure; Saline (SAL) (n=6), submitted to ligature-induced periodontitis and receiving 2 ml/kg of 0.9% saline solution; and CAL extract, which was subdivided into 3 subgroups (n=6/subgroup) receiving the CAL at 3 (CAL3), 10 (CAL10) or 30 mg/kg (CAL30). All agents were given, by oral gavage, 30 min before periodontitis induction and daily until euthanasia (11th day). By then, maxillae were removed for macroscopic, histological, and histometric analyses. Kidneys, liver, and stomach were collected to evaluate the safety of CAL extract. High-performance liquid chromatography (HPLC) assay was used to investigate the flavonoid content in the extract. Results: Chenopodium ambrosioides L. extract at 30mg/kg showed a reduction by 58% in bone loss marked by an increase (+35%) in the number of osteoblasts and a reduction (-51%) on the number of osteoclasts (p< 0.05). No significant alteration in the liver, kidney, or stomach was seen. Rutin was the main flavonoid found. Conclusion: In summary, it was observed that Chenopodium ambrosioides L. extract has shown important anti-inflammatory and bone anabolic and anti-resorptive properties without causing toxicity in the main organs. Rutin, as the main flavonoid of the extract, seems to be responsible for the beneficial effect of this agent.

Uncommon Foot Pain: A Rare Case of Sequential Migration of Cutaneous Pili Migrans.

Cutaneous pili migrans (CPM) is an uncommon condition in which a hair fragment penetrates the skin and produces a creeping lesion similarly of cutaneous larva migrans associated with local pain. There are few reports of CPM in the literature, and none visually describes the migration of the hair shaft in the epidermis associated with pain. Herein, we showed the first report describing a case of an in situ sequential migration of CPM in an adult patient.

Discrepancy in transcriptomic profiling between CD34 + stem cells and primary bone marrow cells in myelodysplastic neoplasm.

Differentially expressed genes (DEGs) biomarkers can be used to help diagnose and monitor the disease, as well as to determine which treatments are most effective. So, given the complexity of Myelodysplastic neoplasm (MDS), it is difficult to determine the impact and disparities of DEGs between CD34+ HSC (hematopoietic stem cells) or primary bone marrow cells (PBMC) in MDS pathogenesis, and therefore it remains largely unknown. Here, we performed an in-silico transcriptome analysis on CD34+ HSC and PBMC from 1092 MDS patients analyzing the divergences between differential gene expression patterns in these two cell types as potential pathogenic biomarkers for MDS. Initially, we observed a difference of 7117 expressed transcripts between PBMC (n = 40,165) and CD34 +HSC (n = 33,048). Also, we identified that CD34+ HSC and PBMC samples showed 240 and 2948 DEGs, respectively. In summary, we identified DEGs disparities in CD34+ HSC and PBMC cell types. However, there was a certain similarity of the activated pathways in both cellular samples based on Gene Ontology and KEGG pathways enrichment analyses. Our results provide novel insights into novel DEGs biomarkers to MDS pathogenesis with clinical significance. AVAILABILITY OF DATA AND MATERIALS: All microarray databases were obtained from Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/). To evaluate the biological function of differentially expressed genes, the DAVID (Database for Annotation, Visualization and Integrated Discovery tool was used) (https://david.ncifcrf.gov/).

Functional polymorphisms of DNA repair genes in Latin America reinforces the heterogeneity of Myelodysplastic Syndrome.

Nucleotide excision repair pathway (NER) is an essential mechanism for single-strand breaks (SSB) repair while xeroderma pigmentosum family (XPA to XPG) is the most important system to NER. Myelodysplastic syndrome (MDS) is a heterogeneous hematological cancer characterized by cytopenias and risk of acute myeloid leukemia (AML) transformation. MDS pathogenesis has been associated with problems of DNA repair system. This report aimed to evaluate NER polymorphisms (XPA rs1800975, XPC rs2228000, XPD rs1799793 and XPF rs1800067) in 269 MDS patients of different populations in Latin America (173 Brazilian and 96 Argentinean). Genotypes were identified in DNA samples by RT-qPCR using TaqMan SNP Genotyping Assay. Regarding rs1799793 polymorphism of XPD for Brazilian population, the heterozygous genotype AG presented a high odds ratio (OR) to have a normal karyotype (p = 0.012, OR=3.000) and the mutant homozygous genotype AA was associated to a high OR of AML transformation (p = 0.034, OR=7.4). In Argentine population, the homozygous mutant AA genotype of rs1800975 polymorphism of XPA was associated with an increased odd to have hemoglobin levels below 8g/dL (p = 0.013, OR=10.000) while for the rs1799793 polymorphism of XPD, the heterozygous AG genotype decreased OR to be classified as good (p < 0.001, OR=9.05 × 10-10), and intermediate (p < 0.001, OR=3.08 × 10-10), according to Revised-International Prognostic Scoring System. Regarding the rs1800067 polymorphisms of XPF, the homozygous mutant AA genotype showed a decreased OR to be classified as good (p < 0.001, OR=4.03 × 10-13) and intermediate (p < 0.001, OR=2.54 × 10-13). Our report reinforces the heterogeneity of MDS and demonstrates the importance of ethnic differences and regional influences in pathogenesis and prognosis of MDS.

Clarithromycin-resistant H. pylori primary strains and virulence genotypes in the Northeastern region of Brazil.

The increase of H. pylori resistance to clarithromycin is a concern. This study evaluated the prevalence of H. pylori's primary resistance to clarithromycin and its association with virulence factors in adult dyspeptic patients and asymptomatic children. The gastric mucosa from patients (153 gastritis, 24 gastric cancer, 21 peptic ulcer) and gastric juice obtained by string test from 24 H. pylori and 23S rRNA positive asymptomatic children were included. The clarithromycin resistance was assessed by TaqMan RT-PCR 23S rRNA point mutations, A2142G and/or A2143G, and H. pylori virulence markers by PCR. Overall, the clarithromycin resistance was 14.4% (32/222), 14.2% in adults, and 12% in children, whereas origin, gender, and disease were not distinctive factors. The most prevalent point mutation was A2143G (62.5%). The point mutation was significantly less frequent in cagA-positive (11.4%) than in cagA-negative (23.6%) strains (p=0.03 OR = 0.4 95%CI = 0.19 - 0.91) as well as in cagE-positive (10.2%), cagE-negative (21.2%) (p=0.03 OR: 0.4 I.C:0.20-0.91). No difference was found in iceA or vacA alleles genotypes. Primary resistance to clarithromycin was lower than that reported in Southeast Brazil. The cagA and cagE positive H. pylori samples have few point mutations suggesting that individuals infected with virulent strains may be more susceptible to anti-H. pylori treatment.

Role of Sirtuins in the Pathobiology of Onco-Hematological Diseases: A PROSPERO-Registered Study and In Silico Analysis.

The sirtuins (SIRT) gene family (SIRT1 to SIRT7) contains the targets implicated in cellular and organismal aging. The role of SIRTs expression in the pathogenesis and overall survival of patients diagnosed with solid tumors has been widely discussed. However, studies that seek to explain the role of these pathways in the hematopoietic aging process and the consequences of their instability in the pathogenesis of different onco-hematological diseases are still scarce. Therefore, we performed a systematic review (registered in PROSPERO database #CRD42022310079) and in silico analysis (based on GEPIA database) to discuss the role of SIRTs in the advancement of pathogenesis and/or prognosis for different hematological cancer types. In summary, given recent available scientific evidence and in silico gene expression analysis that supports the role of SIRTs in pathobiology of hematological malignances, such as leukemias, lymphomas and myeloma, it is clear the need for further high-quality research and clinical trials that expands the SIRT inhibition knowledge and its effect on controlling clonal progression caused by genomic instability characteristics of these diseases. Finally, SIRTs represent potential molecular targets in the control of the effects caused by aging on the failures of the hematopoietic system that can lead to the involvement of hematological neoplasms.

Chromosomal abnormalities and dysregulated DNA repair gene expression in farmers exposed to pesticides.

Exposure to pesticides is considered a major factor underlying increased risk of hematological disorders in agricultural workers due to its carcinogenic potential. However, genotoxic impact of pesticides in DNA integrity of bone marrow stem cells (BMSC) of farmers exposed is not yet well known. We evaluated presence of chromosomal abnormalities (CA) and mRNA expression of DNA repair targets (ATM, BRCA1, BRCA2, RAD51, XRCC5, XRCC6, LIG4, CSA, CSB, XPA, XPC, XPG) in 90 bone marrow samples of farmers divided into three groups: commercial farming (CF), family farming (FF) and organic farming (OF). Our results showed that farmers in CF (72.7 %) and FF (27.3 %) groups had significantly higher values of CA when compared to OF group (0.0 %; p = 0.003). CF showed lower XPG (p = 0.008), CSA (p < 0.001), ATM (p = 0.036) and LIG4 (p = 0.004) mRNA expression than OF. FF presented lower XPG (p = 0.012) and LIG4 (p = 0.004) expression than OF. CF + FF individual with ≥12 years of exposure to pesticides showed decreased mRNA expression of XPC (p = 0.001), XPG (p = 0.010), CSB (p = 0.05), ATM (p = 0.030) and LIG4 (p = 0.044) than those who have been exposed for <12 years. CF + FF with CA showed a lower expression of BRCA2 when compared to CF + FF group without CA (p = 0.007). These results highlight that genotoxic exposure to pesticides negatively affects expression profile of important DNA repair genes in BMSC, favoring irreparable chromosomal lesions.

TLR4 deficiency upregulates TLR9 expression and enhances irinotecan-related intestinal mucositis and late-onset diarrhoea.

BACKGROUND AND PURPOSE: Severe diarrhoea, a common gastrointestinal manifestation of anticancer treatment with irinotecan, might involve single nucleotide polymorphisms (SNPs) of toll-like receptors (TLRs), described as critical bacterial sensors in the gut. Here, colorectal cancer patients carrying missense TLR4 A896G (rs4986790) or C1,196T (rs4986791) SNPs and Tlr4 knockout (Tlr4-/-) mice were given irinotecan to investigate the severity of the induced diarrhoea. EXPERIMENTAL APPROACH: Forty-six patients treated with irinotecan-based regimens had diarrhoea severity analysed according to TLR4 genotypes. In the experimental setting, wild-type (WT) or Tlr4-/- mice were given irinotecan (45 or 75 mg·kg-1 , i.p.) or saline (3 ml·kg-1 ). Diarrhoea severity was evaluated by measuring intestinal injury and inflammatory markers expression after animals were killed. KEY RESULTS: All patients with TLR4 SNPs chemotherapy-treated presented diarrhoea, whereas gastrointestinal toxicity was observed in 50% of the wild homozygous individuals. Mice injected with irinotecan presented systemic bacterial translocation and increased TLR4 immunostaining in the intestine. In line with the clinical findings, Tlr4 gene deficiency enhanced irinotecan-related diarrhoea and TLR9 expression in mice. An increased myeloperoxidase activity and Il-18 expression along with IL-10 decreased production in Tlr4-/- mice also indicated an intensified intestinal damage and inflammatory response. CONCLUSION AND IMPLICATIONS: TLR4 deficiency upregulates TLR9 expression and enhances intestinal damage and the severity of late-onset diarrhoea during irinotecan-based treatment. Identifying patients genetically predisposed to chemotherapy-associated diarrhoea is a strategy toward precision medicine.

Electroacupuncture Reduces Inflammation but Not Bone Loss on Periodontitis in Arthritic Rats.

Periodontitis and rheumatoid arthritis (RA) are inflammatory diseases characterized by chronic inflammation and bone erosion. Electroacupuncture (EA) shows anti-inflammatory and anti-resorptive effects in experimental periodontitis (EP) and in RA. It is important to investigate whether EA shows these effects in periodontal tissues in the presence of these two inflammatory diseases or not. For this, Wistar rats were divided into six groups: control (C); experimental rheumatoid arthritis (RA; bovine type II collagen-induced (CII)); experimental periodontitis (EP); RA/EP (RA + EP); EP/EA (EP treated with EA); RA/EP/EA (RA + EP treated with EA). EP was induced 21 days after RA induction and EA was performed previously and during the EP induction period, every 3 days until the 36th experimental day. The rats were euthanized on day 39. RA was evaluated by edema and the withdrawal threshold of hind paws. The maxillae were removed, and alveolar bone loss (ABL) and bone radiographic density (BRD) were evaluated. Immunohistochemical analyses for interleukins (IL)-6 and -17 and nuclear factor (NF)-κB were performed. Our results showed that EA reduced only the pain intensity in arthritic rats. Histomorphometric, macroscopic, and radiographic analyses did not show differences between the control and EP/EA groups. EA caused a reduction in ABL and BRD only in the presence of EP. EA caused a reduction in IL-6 and -17 in all groups, but NF-κB was only reduced in the arthritic rats with EP. In conclusion, EA reduced the inflammation related to periodontitis in arthritic rats but did not prevent ABL.

Functional polymorphisms of DNA repair genes in Latin America reinforces the heterogeneity of Myelodysplastic Syndrome

Abstract Nucleotide excision repair pathway (NER) is an essential mechanism for single-strand breaks (SSB) repair while xeroderma pigmentosum family (XPA to XPG) is the most important system to NER. Myelodysplastic syndrome (MDS) is a heterogeneous hematological cancer characterized by cytopenias and risk of acute myeloid leukemia (AML) transformation. MDS pathogenesis has been associated with problems of DNA repair system. This report aimed to evaluate NER polymorphisms (XPA rs1800975, XPC rs2228000, XPD rs1799793 and XPF rs1800067) in 269 MDS patients of different populations in Latin America (173 Brazilian and 96 Argentinean). Genotypes were identified in DNA samples by RT-qPCR using TaqMan SNP Genotyping Assay. Regarding rs1799793 polymorphism of XPD for Brazilian population, the heterozygous genotype AG presented a high odds ratio (OR) to have a normal karyotype (p= 0.012, OR=3.000) and the mutant homozygous genotype AA was associated to a high OR of AML transformation (p= 0.034, OR=7.4). In Argentine population, the homozygous mutant AA genotype of rs1800975 polymorphism of XPA was associated with an increased odd to have hemoglobin levels below 8g/dL (p= 0.013, OR=10.000) while for the rs1799793 polymorphism of XPD, the heterozygous AG genotype decreased OR to be classified as good (p< 0.001, OR=9.05 × 10−10), and intermediate (p< 0.001, OR=3.08 × 10−10), according to Revised-International Prognostic Scoring System. Regarding the rs1800067 polymorphisms of XPF, the homozygous mutant AA genotype showed a decreased OR to be classified as good (p< 0.001, OR=4.03 × 10−13) and intermediate (p< 0.001, OR=2.54 × 10−13). Our report reinforces the heterogeneity of MDS and demonstrates the importance of ethnic differences and regional influences in pathogenesis and prognosis of MDS.

Interleukin-8 and nuclear factor kappa B are increased and positively correlated in myelodysplastic syndrome.

The pathogenesis of myelodysplastic syndromes (MDS) is complex and depends on the interaction between aberrant hematopoietic cells and their microenvironment, probably including aberrations in cytokines and their signaling pathways. To evaluate interleukin-8 (IL-8) plasma levels and nuclear factor kappa B (NF-kB) in patients with MDS and to test possible correlation between IL-8 and NF-Kb, a total of 45 individuals were analyzed: 25 consecutive adult de novo MDS patients and 20 sex and age-matched healthy elderly volunteers. IL-8 analysis was performed by ELISA and activity of NF-kB by chemiluminescent assay. MDS patients showed higher level of IL-8 when compared to controls (p = 0.006). Patients aged 75 and above showed even higher levels (p = 0.035). NF-kB activity was significantly elevated in MDS patients when compared to controls (p < 0.0001) and higher in patients older than 75 years (p = 0.047). NF-kB activity was associated with higher serum ferritin (p = 0.042) and higher percentage of blasts (p = 0.028). A significant positive correlation between IL-8 and NF-kB was demonstrated (r = 0.480; p = 0.015). Many pathways involved in pathophysiology of MDS have been recently described, suggesting that an inflammatory process may act as a pathogenic driver. In this study, significantly elevated levels of IL-8 and NF-kB were demonstrated in MDS patients, with positive association of NF-kB with some markers of poor prognosis. A positive correlation between IL-8 and NF-kB suggests they cooperate as part of a complex networking of immune and inflammatory factors involved in MDS.

Myelodysplastic syndrome patients present more severe respiratory muscle impairment and reduced forced vital capacity: Is disordered inflammatory signaling the culprit?

BACKGROUND/OBJECTIVES: The ageing process is associated with gradual decline in respiratory system performance. Anemia is highly prevalent among older adults and usually associated with adverse outcomes. Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies with increasing incidence with age and characterized by anemia and other cytopenias. The main objectives of this study were to evaluate respiratory muscle strength and lung function in elderly patients with anemia, compare data between myelodysplastic syndromes and non-clonal anemias and evaluate the influence of serum IL-8 level and NF-kB activity on deteriorate pulmonary function in this specific population. PARTICIPANTS: Individuals aged 60 and older with anemia secondary to MDS, non-clonal anemia and healthy elderly individuals. MEASUREMENTS: Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/ FVC ratio were measured by spirometry. Respiratory muscle strength was evaluated by maximal static respiratory pressures measurement. IL-8 analysis was performed by ELISA and activity of NF-kB by chemiluminescent assay. RESULTS: Mean Hb concentration was comparable between patients with anemia. Significant differences were detected between all patients with anemia and controls for maximum-effort inspiratory mouth pressure (PImax) and also for maximum-effort expiratory mouth pressure (PEmax). The MDS group recorded a significantly lower PImax and PEmax percent predicted when compared to non-clonal anemia group. For FVC and FEV1, a significant difference was found in anemic patients, with even significantly lower values for FVC and FEV1 in MDS group. No significant differences were detected for PImax and PEmax and spirometry parameters when anemic patients were stratified according to the degree of anemia. A significant negative impact in FVC (% pred), PImax (% pred) and PEmax (% pred) was observed in patients with MDS and higher levels of IL-8 or increased activity of NF-kB. CONCLUSION: A negative impact of anemia, independent of its degree, was demonstrated in respiratory muscle strength and lung function particularly in MDS. The well known elevated proinflammatory cytokines in MDS patients were proposed to play a role as was demonstrated by detrimental effect of higher IL-8 and NF-kB in pulmonary function tests in this population.

Clarithromycin-resistant H. pylori primary strains and virulence genotypes in the Northeastern region of Brazil

ABSTRACT The increase of H. pylori resistance to clarithromycin is a concern. This study evaluated the prevalence of H. pylori's primary resistance to clarithromycin and its association with virulence factors in adult dyspeptic patients and asymptomatic children. The gastric mucosa from patients (153 gastritis, 24 gastric cancer, 21 peptic ulcer) and gastric juice obtained by string test from 24 H. pylori and 23S rRNA positive asymptomatic children were included. The clarithromycin resistance was assessed by TaqMan RT-PCR 23S rRNA point mutations, A2142G and/or A2143G, and H. pylori virulence markers by PCR. Overall, the clarithromycin resistance was 14.4% (32/222), 14.2% in adults, and 12% in children, whereas origin, gender, and disease were not distinctive factors. The most prevalent point mutation was A2143G (62.5%). The point mutation was significantly less frequent in cagA-positive (11.4%) than in cagA-negative (23.6%) strains (p=0.03 OR = 0.4 95%CI = 0.19 - 0.91) as well as in cagE-positive (10.2%), cagE-negative (21.2%) (p=0.03 OR: 0.4 I.C:0.20-0.91). No difference was found in iceA or vacA alleles genotypes. Primary resistance to clarithromycin was lower than that reported in Southeast Brazil. The cagA and cagE positive H. pylori samples have few point mutations suggesting that individuals infected with virulent strains may be more susceptible to anti-H. pylori treatment.