Microsatellite Markers for Bearded Capuchins (Sapajus libidinosus): Transferability and Characterization.

Natural Sapajus libidinosus populations are in continuous decline due to fragmentation, habitat loss, and the illegal pet trade. They live in Caatinga scrub forests, which already lost over 50% of their original cover. The lack of studies on S. libidinosus population genetics means that we do not know how they are being affected by this striking habitat loss and other anthropogenic disturbances. Polymorphic markers are not available for the study of S. libidinosus diversity and population genetics. Thus, here we aimed to test the transferability of 14 microsatellite markers to S. libidinosus. These microsatellites were previously isolated from Cebus capucinus (white-faced capuchin), species belonging to the same subfamily (Cebinae) as the study species. We found that six of the tested microsatellite markers (tetra-nucleotide) were cross-amplified in our target species. All loci were polymorphic. The number of alleles varied from 4 to 7, and the expected heterozygosity ranged from 0.588 to 0.869. The microsatellite markers transferred to S. libidinosus and characterised in our study will be valuable tools to evaluate the genetic variability of both wild and captive populations. They will considerably reduce the costs of microsatellite isolations, helping to prioritise currently limited research and conservation budgets in Brazil.

Gene pool sharing and genetic bottleneck effects in subpopulations of Eschweilera ovata (Cambess.) Mart. ex Miers (Lecythidaceae) in the Atlantic Forest of southern Bahia, Brazil.

Forest loss and fragmentation are the main threats to the maintenance of the Atlantic Forest, an important global biodiversity hotspot. Because of the current critical level of deforestation, ecological corridors are needed to facilitate species dispersion and gene flow among fragments. This study was conducted to investigate the genetic variability and gene pool sharing of Eschweilera ovata in five forest remnants in southern Bahia, Brazil using nuclear simple sequence repeat (nSSR) and plastid simple sequence repeat (cpSSR) microsatellite markers. cpSSR marker analysis revealed the domains of four haplotypes, showing that 80% of the individuals had only four maternal origins, reflecting a founder effect and/or genetic bottleneck. The results of cpSSR and nSSR analyses indicated moderate genetic diversity, particularly in conservation units with full protection, which showed the best parameters of all areas evaluated. Another indication of the susceptibility of these populations to forest loss and fragmentation was the strong genetic bottleneck observed. In contrast, genetic structure analyses (FST and discriminant analysis of principal components) revealed gene pool sharing between the subpopulations, which may reflect the historical gene flow that occurred before forest fragmentation.

High-sensitivity C-reactive protein, apolipoproteins, and residual diuresis in chronic kidney disease patients undergoing hemodialysis.

BACKGROUND: Residual diuresis (RD) is the simplest method for measuring renal residual function in patients with chronic kidney disease (CKD). A reduction in RD is associated with intensification of the inflammatory process caused by uremia. However, little is known regarding the relation between RD and inflammatory markers in these patients. We verify possible associations among the hs-CRP, atherogenic factors, and RD, in patients with CKD undergoing hemodialysis. METHODS: This study enrolled 80 patients with CKD undergoing hemodialysis. Patients were stratified according to RD in anuric (RD-) group (n = 47) and non-anuric (RD+) group (n = 33). Urine volumes were collected in a 24 h period during the interdialytic period. Serum high-sensitivity C-reactive protein (hs-CRP), and apolipoprotein (Apo) A1 and B levels were measured after fasting for 12 h. RESULTS: Serum hs-CRP levels were higher in the RD- group than in the RD+ group (P = 0.015). In the total group, hs-CRP was significantly correlated with RD (r = - 0.25, P = 0.025) and Apo AI (r = - 0.25, P = 0.024). A greater proportion of patients had reduced plasma concentrations of Apo AI in the RD- group (31.9 %) compared with the RD+ group (9.1 %) (P = 0.014). CONCLUSION: This study shows a relationship between RD and the hs-CRP in patients undergoing hemodialysis. Although the inflammatory state was verified in a large part of the CKD population, patients without RD had more elevated hs-CRP serum levels than those with RD.

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.

The effect of wound electrical stimulation in venous leg ulcer healing-a systematic review.

OBJECTIVE: The benefit of using electric stimulation therapy (EST) to heal venous leg ulcers (VLUs) is not well established. The main aim of this systematic review was to evaluate the effects of ulcer EST in VLU healing. METHODS: A systematic search of the literature was conducted using the databases PubMed, Scopus, and Web of Science and included original studies that reported VLU healing after EST. The inclusion criteria were at least two surface electrodes placed on or near the wound or a planar probe covering the ulcer area to be treated. The Cochrane risk of bias tool for randomized control trials (RCTs) and Joanna Briggs Institute critical appraisal checklist for case series were used to evaluate the risk of bias. RESULTS: This review included eight RCTs and three case series involving a total of 724 limbs in 716 patients with VLUs. The mean patient age was 64.2 years (95% confidence interval, 62.3-66.2), and 46.2% (95% confidence interval, 41.2%-50.4%) were men. The active electrode was placed on the wound with the passive electrode placed on healthy skin (n = 6), the two electrodes were placed on either side of the wound edges (n = 4), or a planar probe was used (n = 1). The pulsed current was the most used waveform (n = 9). The change in the ulcer size was the main method used to determine ulcer healing (n = 8), followed by the ulcer healing rate (n = 6), exudate levels (n = 4), and the time to healing (n = 3). Five RCTs detected a statistically significant improvement in at least one VLU healing outcome, after EST compared with the control group. In two of these, EST was better than the control but only for patients who had not undergone surgical treatment of VLU. CONCLUSIONS: The findings from the present systematic review support the use of EST to accelerate wound healing of VLUs, especially for patients who are not surgical candidates. However, the significant variation in electric stimulation protocols represents an important limitation to its use and should be addressed in future studies.

Sleep and Postpartum Psychosis: A Narrative Review of the Existing Literature.

Sleep problems are extremely common during the postpartum period. The role of sleep in the development of postpartum psychosis (PP) is, however, still under-researched. This narrative review aims to (1) provide a summary of the existing evidence for the associations between sleep problems and PP, (2) discuss the relevant risk factors associated with sleep problems and PP, and (3) suggest future lines of research in this area. Some of the existing literature suggests an association between sleep problems, specifically insomnia, sleep loss and sleep disruption during pregnancy and postpartum, and PP, with the most relevant risk factors including history of bipolar disorder and time of delivery. However, it is still unclear whether the previously mentioned sleep problems are a symptom of, or a trigger for PP. Thus, further research is needed to identify the specific role of sleep problems in PP, using longitudinal designs and more objective measures of sleep. This will allow appropriate detection, intervention and support for women experiencing and/or at risk for PP.

High PD-L1 expression is associated with unfavorable clinical features in myelodysplastic neoplasms.

INTRODUCTION: Immune checkpoints are regulators of the immune system response that allow self-tolerance. Molecules such as Programmed Cell Death Protein 1 (PD-1) and its Ligand (PD-L1) participate in the immune checkpoint by signaling co-inhibition of lymphocyte responses. In cancers, PD-L1 expression is associated with the immune evasion mechanism, which favors tumor growth. The use of anti-PD-1/PD-L1 drugs is already well described in solid tumors, but still not fully understood in hematologic malignancies. Myelodysplastic neoplasms (MDSs) are heterogeneous bone marrow disorders with an increased risk of progression to Acute Myeloid Leukemia (AML). The MDS affects hematopoietic stem cells and its pathogenesis is linked to genetic and epigenetic defects, in addition to immune dysregulation. The influence of the PD-L1 on the MDS remains unknown. METHODS: In this study, we evaluated the mRNA expression of the PD-L1 in 53 patients with MDS, classified according to the WHO 2016 Classification. RESULTS: Patients with dyserythropoiesis presented significantly higher PD-L1 expression than patients without dyserythropoiesis (p = 0.050). Patients classified as having MDS with an excess of blasts 2 (MDS-EB2) presented a significant upregulation in the mRNA expression of the PD-L1 compared to the MDS with an excess of blasts 1 (MDS-EB1) (p = 0.050). Furthermore, we detected three patients with very high levels of PD-L1 expression, being statistically classified as outliers. CONCLUSION: We suggested that the high expression of the PD-L1 is associated with a worse prognosis in the MDS and functional studies are necessary to evaluate the possible use of anti-PD-L1 therapies for high-risk MDS, such as the MDS-EBs.

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.

Tissue methylation and demethylation influence translesion synthesis DNA polymerases (TLS) contributing to the genesis of chromosomal abnormalities in myelodysplastic syndrome.

AIMS: DNA methylation has its distribution influenced by DNA demethylation processes with the catalytic conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). Myelodysplastic syndrome (MDS) has been associated with epigenetic dysregulation of genes related to DNA repair system, chronic immune response and cell cycle. METHODS: We evaluated the tissue DNA methylation/hydroxymethylation in bone marrow trephine biopsies of 73 patients with MDS, trying to correlate with the mRNA expression of 21 genes (POLH, POLL, REV3L, POLN, POLQ, POLI, POLK, IRF-1, IRF-2, IRF-3, IRF-4, IRF-5, IRF6, IRF-7, IRF-8,IRF-9, MAD2, CDC20, AURKA, AURKB and TPX2). RESULTS: The M-score (5mC) was significantly higher in patients with chromosomal abnormalities than patients with normal karyotype (95% CI -27.127779 to -2.368020; p=0.022). We observed a higher 5mC/5hmC ratio in patients classified as high-risk subtypes compared with low-risk subtypes (95% CI -72.922115 to -1.855662; p=0.040) as well as patients with hypercellular bone marrow compared with patients with normocellular/hypocellular bone marrow (95% CI -69.189259 to -0.511828; p=0.047) and with the presence of dyserythropoiesis (95% CI 17.077703 to 51.331388; p=0.001). DNA pols with translesion activity are significantly influenced by methylation. As 5mC immunoexpression increases, the expressions of POLH (r=-0.816; r2 =0.665; p=0.000), POLQ (r=-0.790; r2=0.624; p=0.001), PCNA (r=-0.635; r2=0.403; p=0.020), POLK (r=-0.633; r2=0.400; p=0.036 and REV1 (r=-0.578; r2=0.334; p=0.049) decrease. CONCLUSIONS: Our results confirm that there is an imbalance in the DNA methylation in MDS, influencing the development of chromosomal abnormalities which may be associated with the low expression of DNA polymerases with translesion synthesis polymerases activity.

Global Proteomics Analysis of Bone Marrow: Establishing Talin-1 and Centrosomal Protein of 55 kDa as Potential Molecular Signatures for Myelodysplastic Syndromes.

Myelodysplastic syndrome (MDS) is a hematological disorder characterized by abnormal stem cell differentiation and a high risk of acute myeloid leukemia transformation. Treatment options for MDS are still limited, making the identification of molecular signatures for MDS progression a vital task. Thus, we evaluated the proteome of bone marrow plasma from patients (n = 28) diagnosed with MDS with ring sideroblasts (MDS-RS) and MDS with blasts in the bone marrow (MDS-EB) using label-free mass spectrometry. This strategy allowed the identification of 1,194 proteins in the bone marrow plasma samples. Polyubiquitin-C (UBC), moesin (MSN), and Talin-1 (TLN1) showed the highest abundances in MDS-EB, and centrosomal protein of 55 kDa (CEP55) showed the highest relative abundance in the bone marrow plasma of MDS-RS patients. In a follow-up, in the second phase of the study, expressions of UBC, MSN, TLN1, and CEP55 genes were evaluated in bone marrow mononuclear cells from 45 patients by using qPCR. This second cohort included only seven patients from the first study. CEP55, MSN, and UBC expressions were similar in mononuclear cells from MDS-RS and MDS-EB individuals. However, TLN1 gene expression was greater in mononuclear cells from MDS-RS (p = 0.049) as compared to MDS-EB patients. Irrespective of the MDS subtype, CEP55 expression was higher (p = 0.045) in MDS patients with abnormal karyotypes, while MSN, UBC, and TALIN1 transcripts were similar in MDS with normal vs. abnormal karyotypes. In conclusion, proteomic and gene expression approaches brought evidence of altered TLN1 and CEP55 expressions in cellular and non-cellular bone marrow compartments of patients with low-risk (MDS-RS) and high-risk (MDS-EB) MDSs and with normal vs. abnormal karyotypes. As MDS is characterized by disrupted apoptosis and chromosomal alterations, leading to mitotic slippage, TLN1 and CEP55 represent potential markers for MDS prognosis and/or targeted therapy.

Glycogen Synthase Kinase-3 Beta Expression Correlates With Worse Overall Survival in Non-Small Cell Lung Cancer-A Clinicopathological Series.

BACKGROUND: Glycogen Synthase Kinase-3 beta (GSK-3ß) regulates diverse cell functions including metabolic activity, signaling and structural proteins. GSK-3ß phosphorylates target pro-oncogenes and regulates programmed cell death-ligand 1 (PD-L1). This study investigated the correlation between GSK-3ß expression and clinically relevant molecular features of lung adenocarcinoma (PDL1 score, PTEN expression and driver mutations). METHODS: We evaluated 95 lung cancer specimens from biopsies and surgical resections. Immunohistochemistry was performed to analyze the expression of GSK-3ß, PTEN, and PDL1. Epidemiological data, molecular characteristics and staging were evaluated from medical records. The histologic classification was performed by an experienced pulmonary pathologist. RESULTS: Most patients were female (52.6%) and the majority had a positive smoking history. The median age was 68.3 years, with individuals over 60 years accounting for 82.1%. The predominant histological subtype was adenocarcinoma (69.5%), followed by squamous cell carcinoma (20.0%). GSK-3ß expression in tumors was cytoplasmic with a dotted pattern and perinuclear concentration, with associated membranous staining. Seven (7.3%) tumors had associated nuclear expression localization. Seventy-seven patients (81.1%) had advanced clinical-stage tumors. GSK-3ß was positive in 75 tumors (78%) and GSK3-positive tumors tended to be diagnosed at advanced stages. Among stage III/IV tumors, 84% showed GSK3 positivity (p= 0.007). We identified a statistically significant association between GSK-3ß and PTEN in the qualitative analysis (p 0.021); and when comparing PTEN to GSK-3ß intensity 2+ (p 0.001) or 3+ expression (> 50%) - p 0.013. GSK-3ß positive tumors with a high histological score had a worse overall survival. CONCLUSION: We identified the histological patterns of GSK-3ß expression and evaluated its potential as marker for overall survival, establishing a simple histological score to measure the evaluated status in resected tissues. The use of GSK-3ß expression as an immune response biomarker remains a challenge. Future studies will seek to explain the role of its interaction with PTEN.

ERVs-TLR3-IRF axis is linked to myelodysplastic syndrome pathogenesis.

Toll-like receptors are mutated or overexpressed in up to 50% of patients with myelodysplastic syndrome (MDS). Endogenous retroviruses (ERV) trigger TLR3 leading to interferon regulatory genes (IRFs) activation. We evaluated if the ERVs-TLR3-IRF axis activation would be linked to MDS pathogenesis and we also conducted a detailed cancer analysis of the ERVs, TLR3 and IRFs gene expression in 30 cancer types using GEPIA database. Seventy-nine bone marrow samples from patients with MDS were evaluated for cytogenetics and quantitative real­time PCR of TLR3, ERVK6, ERVW-1, ERV3-1, IRF3 and IRF7. Patients with dyserythropoiesis showed higher TLR3 (p = 0.035), ERVK6 (p = 0.001), ERVW1 (p = 0.045) and ERV3-1 (p = 0.016) expression than patients without dyserythropoiesis. Upregulation of Interferon Regulatory Factors, IRF3 and IRF7, was associated with poor prognostic markers in MDS such as > 10% of blasts (p = 0.003-IRF3; p = 0.009-IRF7), low platelets count (< 50.000/mm3) (p = 0.001-IRF3; p = 0.021-IRF7), transfusion dependence (p = 0.014-IRF3) and chromosomal abnormalities (p = 0.036-IRF7). We found strong correlations between ERVK6-ERVW1 (r = 0.800; r2 = 0.640; p = 0.000), ERVW1-ERV3-1 (r = 0.715; r2 = 0.511; p = 0.000), and IRF7-IRF3 (r = 0.567; r2 = 0.321; p = 0.000) and moderate correlation between ERVK6-ERV3-1(r = 0.485; r2 = 0.235; p = 0.000), ERVW1-IRF7 (r = 0.389; r2 = 0.151; p = 0.001), ERVW1-IRF3 (r = 0.357; r2 = 0.127; p = 0.004), ERV3-1-IRF7 (r = 0.314; r2 = 0.098; p = 0.009), and ERV3-1-IRF3 (r = 0.324; r2 = 0.104; p = 0.007). Using GEPIA Database in 30 cancer types, we detected a typical pattern of upregulation as here presented in MDS. We suggest TLR3 activation by ERVs is linked to MDS pathogenesis leading to bone marrow failure. Abnormal double-stranded RNA (dsRNA) expression of Endogenous Retroviruses (ERV) triggers TLR3 hyperactivation. This induces IRF3, IRF7, and NF-kB to translocate to the nucleus and activate transcription of IFNα/ß which binds to the type I-IFN receptor promoting interferon response. Thus, just as TLR4 induces a crucial myeloid shift, the ERVs-TLR3 axis may play an important role in establishing one of the most striking characteristics in MDS, dyserythropoiesis.

c.9253-6T>c REV3L: A novel marker of poor prognosis in Myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by dysplasias, ineffective hematopoiesis and risk of acute myeloid leukemia transformation. Approximately 90% of MDS patients present mutations in genes involved in various cell signaling pathways. Specialized DNA polymerases, such as POLN, POLI, POLK, POLQ, POLH, POLL and REV3L, insert a nucleotide opposite replication-blocking DNA lesions in an error-prone manner and, in this way, sometimes can actively promote the generation of mutation. For the best of our knowledge, has not been described the mutations of these genes in MDS. DNA target sequencing CDS regions of the REV3L gene was performed in a 58-year-old man diagnosed as High Risk Myelodysplastic Syndrome. The patient presented very low hemoglobin, increased number of blasts, karyotype:47,XY,+8[6]/47,XY,del(7)(q32),+8[7], no response to hypomethylating therapy (decitabine), all markers of poor prognosis. Target sequencing identified a mutation c.9253-6T>C REV3L (Substitution - intronic) with VAF (variant allele frequency)=16% considered pathogenic according to Functional Analysis through. Hidden Markov Models (FATHMM). This is the first evidence of REV3L mutation in MDS and, of utmost importance, associated with poor prognosis.

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.

Development and Validation of a Manual of Skin Care for Persons Deprived of Liberty in the São Paulo State Prison System: A Descriptive Study.

Brazil has the third largest prison population in the world. Studies on the health status of prisoners have shown that skin diseases, especially infectious skin diseases, are prevalent in this population. Because some skin diseases can be prevented, strategies to inform and guide incarcerated persons may be helpful. PURPOSE: The purpose of this study was to develop and validate a manual of skin care for use by prisoners in the São Paulo State Prison System. METHODS: To develop the manual, a Google search to ensure originality of the concept was conducted, followed by an integrative literature search of the MEDLINE and the Latin American and Caribbean Health Science Literature, and the medical records of the prison system were reviewed for content. The Delphi technique was used to validate content; the content validity index (CVI) was determined based on the ratings of an expert panel of 10 prison employees who were health professionals and have experience providing care to prisoners. Twenty (20) target-users (prisoners) also evaluated the manual. The experts responded to questionnaires (sent by email) containing 19 items related to the manual's objective, structure and presentation, and relevance. Items were rated on a Likert-type scale where 1 = inadequate, 2 = partially inadequate, 3 = adequate, 4 = very adequate, and NA = not applicable, and participants also could provide suggestions and comments on the manual. The prisoners used a paper-and-pencil questionnaire to assess the manual that included 14 items with 3-choice answers (agree, undecided, disagree) on the utility and ability to understand the manual topics and space to write concerns and suggestions regarding the utility of the content; they also could offer their thoughts and opinions about the manual. The proportion of agreement among responses was calculated. RESULTS: The overall CVI of the first round of evaluations was 1.0. Suggested changes were to include guidelines on the proper use of medications and modify some wording. The overall CVI of the next round was 1.0 (100% agreement). The evaluation by target users showed an agreement of 98.6%. The final version of the manual has 8 topics, 12 subtopics, and 29 illustrations; topics include skin, hair, and nail care and skin diseases. A printed version is available in the prison library and an electronic copy was sent to all prisons in the State of São Paulo to be printed as needed. CONCLUSION: A manual providing guidelines on skin care for prison populations was developed and validated with the intent to improve prisoner quality of life and care. Research to examine overall manual usage and the effect of the information and guidance on healthy behaviors, prevention, and management of skin diseases is warranted.

Can synthetic lethality approach be used with DNA repair genes for primary and secondary MDS?

Cancer-specific defects in DNA repair pathways create the opportunity to employ synthetic lethality approach. Recently, GEMA (gene expression and mutation analysis) approach detected insufficient expression of BRCA or NHEJ (non-homologous end joining) to predict PARP inhibitors response. We evaluated a possible role of DNA repair pathways using gene expression of single-strand break (XPA, XPC, XPG/ERCC5, CSA/ERCC8, and CSB/ERCC6) and double-strand break (ATM, BRCA1, BRCA2, RAD51, XRCC5, XRCC6, LIG4) in 92 patients with myelodysplastic syndrome (73 de novo, 9 therapy-related (t-MDS). Therapy-related MDS (t-MDS) demonstrated a significant downregulation of axis BRCA1-BRCA2-RAD51 comparing to normal controls (p = 0.048, p = 0.001, p = 0.001). XRCC6 showed significantly low expression in de novo MDS comparing to controls (p = 0.039) and for patients who presented chromosomal abnormalities (p = 0.047). Downregulation of LIG4 was consistently associated with poor prognostic markers in de novo MDS (hemoglobin < 8 g/dL (p = 0.040), neutrophils < 800/mm3 (p < 0.001), patients with excess of blasts (p = 0.001), very high (p = 0.002)/high IPSS-R (p = 0.043) and AML transformation (p < 0.001). We also performed an evaluation of GEPIA Database in 30 cancer types and detected a typical pattern of downregulation as here presented in primary or secondary MDS. All these results suggest synthetic lethality approach can be tested with DNA repair genes (beyond that of BRCA1/2 status) for de novo and therapy-related myelodysplastic syndrome and may encourage clinical trials evaluating the use of PARP1 inhibitors in MDS.

High PD-L1 expression is associated with unfavorable clinical features in myelodysplastic neoplasms

ABSTRACT Introduction: Immune checkpoints are regulators of the immune system response that allow self-tolerance. Molecules such as Programmed Cell Death Protein 1 (PD-1) and its Ligand (PD-L1) participate in the immune checkpoint by signaling co-inhibition of lymphocyte responses. In cancers, PD-L1 expression is associated with the immune evasion mechanism, which favors tumor growth. The use of anti-PD-1/PD-L1 drugs is already well described in solid tumors, but still not fully understood in hematologic malignancies. Myelodysplastic neoplasms (MDSs) are heterogeneous bone marrow disorders with an increased risk of progression to Acute Myeloid Leukemia (AML). The MDS affects hematopoietic stem cells and its pathogenesis is linked to genetic and epigenetic defects, in addition to immune dysregulation. The influence of the PD-L1 on the MDS remains unknown. Methods: In this study, we evaluated the mRNA expression of the PD-L1 in 53 patients with MDS, classified according to the WHO 2016 Classification. Results: Patients with dyserythropoiesis presented significantly higher PD-L1 expression than patients without dyserythropoiesis (p = 0.050). Patients classified as having MDS with an excess of blasts 2 (MDS-EB2) presented a significant upregulation in the mRNA expression of the PD-L1 compared to the MDS with an excess of blasts 1 (MDS-EB1) (p = 0.050). Furthermore, we detected three patients with very high levels of PD-L1 expression, being statistically classified as outliers. Conclusion: We suggested that the high expression of the PD-L1 is associated with a worse prognosis in the MDS and functional studies are necessary to evaluate the possible use of anti-PD-L1 therapies for high-risk MDS, such as the MDS-EBs.