Long-COVID olfactory dysfunction: allele E4 of apolipoprotein E as a possible protective factor.

BACKGROUND: Olfactory dysfunction (OD) represents a frequent manifestation of the coronavirus disease 2019 (COVID-19). Apolipoprotein E (APOE) is a protein that interacts with the angiotensin-converting enzyme receptor, essential for viral entry into the cell. Previous publications have suggested a possible role of APOE in COVID-19 severity. As far as we know, no publications found significant associations between this disease's severity, OD, and APOE polymorphisms (E2, E3, and E4). OBJECTIVE: To analyze the epidemiology of OD and its relationship with APOE polymorphisms in a cohort of Long-COVID patients. METHODS: We conducted a prospective cohort study with patients followed in a post-COVID neurological outpatient clinic, with OD being defined as a subjective reduction of olfactory function after infection, and persistent OD being defined when the complaint lasted more than 3 months after the COVID-19 infection resolution. This cross-sectional study is part of a large research with previously reported data focusing on the cognitive performance of our sample. RESULTS: The final sample comprised 221 patients, among whom 186 collected blood samples for APOE genotyping. The persistent OD group was younger and had a lower hospitalization rate during the acute phase of the disease (p < 0.001). Furthermore, the APOE variant E4 allele frequency was lower in this group (p = 0.035). This study evaluated OD in an outpatient population with COVID-19. In the current literature on this disease, anosmia is associated with better clinical outcomes and the E4 allele is associated with worse outcomes. CONCLUSION: Our study provides new information to these correlations, suggesting APOE E4 as a protective factor for OD.

ANTECEDENTES: A disfunção olfatória (DO) é uma manifestação frequente da doença do coronavírus 2019 (COVID-19). A apolipoproteína E (APOE) é uma proteína que interage com o receptor da enzima conversora de angiotensina, essencial para a entrada viral na célula. Publicações anteriores sugeriram um possível papel da APOE na gravidade da COVID-19. Até onde sabemos, nenhuma publicação encontrou associações significativas entre a gravidade dessa doença, DO e polimorfismos da APOE (E2, E3 e E4). OBJETIVO: Analisar a epidemiologia da DO e sua relação com os polimorfismos do gene APOE em uma coorte de pacientes com COVID longa. MéTODOS: Um estudo de coorte prospectiva com pacientes acompanhados em ambulatório neurológico pós-COVID, com DO sendo definida como uma redução subjetiva da função olfativa após a infecção e a DO persistente sendo definida quando a queixa durou mais de 3 meses após a resolução da infecção por COVID-19. Este estudo transversal é parte de uma pesquisa maior com dados anteriormente relatados, focando na performance cognitiva dos pacientes. RESULTADOS: Foram selecionados 221 pacientes para esse estudo, dos quais 186 haviam coletado amostras de sangue para genotipagem APOE. O grupo DO persistente foi mais jovem e apresentou menor taxa de internação na fase aguda da doença (p < 0,001). Além disso, a frequência do alelo E4 da APOE foi menor nesse grupo (p = 0,035). Este estudo avaliou a DO em uma população com COVID longa. Na literatura atual sobre essa doença, a anosmia está associada a melhores desfechos clínicos e o alelo E4 está associado a piores desfechos. CONCLUSãO: Nosso estudo acrescenta novas informações a essas correlações, sugerindo a APOE E4 como um fator de proteção para DO.

Molecular and Clinical Insights in the Increasing Detection of BCR::ABL1 p190+ in Adult Acute Myeloid Leukemia Patients.

BACKGROUND/AIM: Acute myeloid leukemia (AML) is a myeloproliferative neoplasm marked by abnormal clonal expansion of hematopoietic progenitor cells, displaying karyotypic aberrations and genetic mutations as prognostic indicators. The World Health Organization (WHO) and the European LeukemiaNet guidelines categorize BCR::ABL1 p190+ AML as high risk. This study explored the identification of the increased incidence of BCR::ABL1 p190+ in our AML population. PATIENTS AND METHODS: This study included 96 AML patients stratified according to WHO guidelines. Subsequently, patients were screened for genetic abnormalities, such as BCR::ABL1 p 190+, PML::RARA, RUNX1::RUNX1T1, and CBFB::MYH11 by quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis. RESULTS: Among 96 AML patients, 36 displayed BCR::ABL1 p190+, overcoming the expected global incidence. Age variations (19 to 78 years) showed no significant laboratory differences between BCR::ABL1 p190+ and non-BCR::ABL p190+ cases. The overall survival analysis revealed no statistically significant differences among the patients (p=0.786). CONCLUSION: The analyzed population presented a higher frequency of BCR::ABL1 p190+ detection in adult AML patients when compared to what is described in the worldwide literature. Therefore, more studies are needed to establish the reason why this incidence is higher and what the best treatment approach should be in these cases.

Three dimensional reconstruction of skin with melanoma: A model for study of invasion in vitro.

Melanoma is a type of tumor skin with high metastatic potential. Reconstructed human skin, development for pre-clinic assay, are make using primary human cells, but with same limitations. The aim this study was to characterize a cell culture model, with structure similar to human skin containing melanoma cells entirely from cell lines. Reconstructed skin with melanoma were development using human fibroblasts (MRC5), human epidermal keratinocytes (HaCat), and human melanoma (SK-MEL-28) embedded in collagen type I. The structure was characterized by hematoxylin-eosin stained, as well as points of melanoma cell invasion, which was associated with activity of MMPs (MMP-2 and MMP-9) by zymographic method. Then, the gene expression of the target molecular mechanisms involved in melanoma progression were evaluated. Here, the model development showed a region epidermis organized and separated from the dermis, with fibroblast cells confined and melanoma cells form delimited area invasion. MMP-2 and MMP-9 were identified during of cell culture and gene expression of BRAF, NRAS, and Vimentin was confirmed. The proposed model provides one more opportunity to study in vitro tumor biology of melanoma and also to allows the study of new drugs with more reliable results then whats we would find in vivo.

Association of CD38+ Immunophenotyping Biomarker With a Better Prognosis in Elderly Acute Myeloid Leukemia Patients.

BACKGROUND/AIM: The relevance of cytogenetic markers as prognostic risk factors has been demonstrated in a vast number of studies, with many prognostication tools utilizing these factors to determine treatment approaches. Patients aged above 60 years represent an important subgroup of acute myeloid leukemia (AML) patients, especially because they usually exhibit a poorer cytogenetic landscape and are less suitable for intensive treatments. The importance of evaluating prognostic parameters in AML, especially in low-income countries, prompted an investigation into CD38 expression and its effects. PATIENTS AND METHODS: Medical records of AML patients aged above 60 years from three hospitals in Brazil's northwest region were analyzed. A total of 67 patients were evaluated in terms of overall survival and factors predicting worse outcomes. The risk stratification was performed based on the European LeukemiaNet 2022 guidelines. The analysis of immunophenotyping markers was conducted using multi-parametric flow cytometry. RESULTS: The overall survival of CD38-positive AML patients was higher than that of patients with CD38-negative AML, with survival rates of 15.6 months versus 4 months, respectively (p-value=0.026). The impact of CD38 positivity was relevant also in multivariable Cox proportional hazards regression, demonstrating a positive effect on overall survival, with a hazard ratio of 0.33 (95%CI=0.13-0.79; p-value=0.014). CONCLUSION: Expression of CD38 in patients with AML was associated with better overall survival and serves as a relevant predictor of improved outcome in patients aged above 60 years.

Validation of Endogenous Control Genes by Real-Time Quantitative Reverse Transcriptase Polymerase Chain Reaction for Acute Leukemia Gene Expression Studies.

Reference genes are used as internal reaction controls for gene expression analysis, and for this reason, they are considered reliable and must meet several important criteria. In view of the absence of studies regarding the best reference gene for the analysis of acute leukemia patients, a panel of genes commonly used as endogenous controls was selected from the literature for stability analysis: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Abelson murine leukemia viral oncogene human homolog 1 (ABL), Hypoxanthine phosphoribosyl-transferase 1 (HPRT1), Ribosomal protein lateral stalk subunit P0 (RPLP0), ß-actin (ACTB) and TATA box binding protein (TBP). The stability of candidate reference genes was analyzed according to three statistical methods of assessment, namely, NormFinder, GeNorm and R software (version 4.0.3). From this study's analysis, it was possible to identify that the endogenous set composed of ACTB, ABL, TBP and RPLP0 demonstrated good performances and stable expressions between the analyzed groups. In addition to that, the GAPDH and HPRT genes could not be classified as good reference genes, considering that they presented a high standard deviation and great variability between groups, indicating low stability. Given these findings, this study suggests the main endogenous gene set for use as a control/reference for the gene expression in peripheral blood and bone marrow samples from patients with acute leukemias is composed of the ACTB, ABL, TBP and RPLP0 genes. Researchers may choose two to three of these housekeeping genes to perform data normalization.

A Review on Anaplastic Lymphoma Kinase (ALK) Rearrangements and Mutations: Implications for Gastric Carcinogenesis and Target Therapy.

Gastric adenocarcinoma is a complex disease with diverse genetic modifications, including Anaplastic Lymphoma Kinase (ALK) gene changes. The ALK gene is located on chromosome 2p23 and encodes a receptor tyrosine kinase that plays a crucial role in embryonic development and cellular differentiation. ALK alterations can result from gene fusion, mutation, amplification, or overexpression in gastric adenocarcinoma. Fusion occurs when the ALK gene fuses with another gene, resulting in a chimeric protein with constitutive kinase activity and promoting oncogenesis. ALK mutations are less common but can also result in the activation of ALK signaling pathways. Targeted therapies for ALK variations in gastric adenocarcinoma have been developed, including ALK inhibitors that have shown promising results in pre-clinical studies. Future studies are needed to elucidate the ALK role in gastric cancer and to identify predictive biomarkers to improve patient selection for targeted therapy. Overall, ALK alterations are a relevant biomarker for gastric adenocarcinoma treatment and targeted therapies for ALK may improve patients' overall survival.

Development and Clinical Applications of PI3K/AKT/mTOR Pathway Inhibitors as a Therapeutic Option for Leukemias.

Leukemias are hematological neoplasms characterized by dysregulations in several cellular signaling pathways, prominently including the PI3K/AKT/mTOR pathway. Since this pathway is associated with several important cellular mechanisms, such as proliferation, metabolism, survival, and cell death, its hyperactivation significantly contributes to the development of leukemias. In addition, it is a crucial prognostic factor, often correlated with therapeutic resistance. Changes in the PI3K/AKT/mTOR pathway are identified in more than 50% of cases of acute leukemia, especially in myeloid lineages. Furthermore, these changes are highly frequent in cases of chronic lymphocytic leukemia, especially those with a B cell phenotype, due to the correlation between the hyperactivation of B cell receptors and the abnormal activation of PI3Kδ. Thus, the search for new therapies that inhibit the activity of the PI3K/AKT/mTOR pathway has become the objective of several clinical studies that aim to replace conventional oncological treatments that have high rates of toxicities and low specificity with target-specific therapies offering improved patient quality of life. In this review we describe the PI3K/AKT/mTOR signal transduction pathway and its implications in leukemogenesis. Furthermore, we provide an overview of clinical trials that employed PI3K/AKT/mTOR inhibitors either as monotherapy or in combination with other cytotoxic agents for treating patients with various types of leukemias. The varying degrees of treatment efficacy are also reported.

Long-COVID olfactory dysfunction: allele E4 of apolipoprotein E as a possible protective factor / Disfunção olfativa na COVID longa: o alelo E4 da apolipoproteína E como um possível fator protetor

Abstract Background Olfactory dysfunction (OD) represents a frequent manifestation of the coronavirus disease 2019 (COVID-19). Apolipoprotein E (APOE) is a protein that interacts with the angiotensin-converting enzyme receptor, essential for viral entry into the cell. Previous publications have suggested a possible role of APOE in COVID-19 severity. As far as we know, no publications found significant associations between this disease's severity, OD, and APOE polymorphisms (E2, E3, and E4). Objective To analyze the epidemiology of OD and its relationship with APOE polymorphisms in a cohort of Long-COVID patients. Methods We conducted a prospective cohort study with patients followed in a post-COVID neurological outpatient clinic, with OD being defined as a subjective reduction of olfactory function after infection, and persistent OD being defined when the complaint lasted more than 3 months after the COVID-19 infection resolution. This cross-sectional study is part of a large research with previously reported data focusing on the cognitive performance of our sample. Results The final sample comprised 221 patients, among whom 186 collected blood samples for APOE genotyping. The persistent OD group was younger and had a lower hospitalization rate during the acute phase of the disease (p < 0.001). Furthermore, the APOE variant E4 allele frequency was lower in this group (p = 0.035). This study evaluated OD in an outpatient population with COVID-19. In the current literature on this disease, anosmia is associated with better clinical outcomes and the E4 allele is associated with worse outcomes. Conclusion Our study provides new information to these correlations, suggesting APOE E4 as a protective factor for OD.

Resumo Antecedentes A disfunção olfatória (DO) é uma manifestação frequente da doença do coronavírus 2019 (COVID-19). A apolipoproteína E (APOE) é uma proteína que interage com o receptor da enzima conversora de angiotensina, essencial para a entrada viral na célula. Publicações anteriores sugeriram um possível papel da APOE na gravidade da COVID-19. Até onde sabemos, nenhuma publicação encontrou associações significativas entre a gravidade dessa doença, DO e polimorfismos da APOE (E2, E3 e E4). Objetivo Analisar a epidemiologia da DO e sua relação com os polimorfismos do gene APOE em uma coorte de pacientes com COVID longa. Métodos Um estudo de coorte prospectiva com pacientes acompanhados em ambulatório neurológico pós-COVID, com DO sendo definida como uma redução subjetiva da função olfativa após a infecção e a DO persistente sendo definida quando a queixa durou mais de 3 meses após a resolução da infecção por COVID-19. Este estudo transversal é parte de uma pesquisa maior com dados anteriormente relatados, focando na performance cognitiva dos pacientes. Resultados Foram selecionados 221 pacientes para esse estudo, dos quais 186 haviam coletado amostras de sangue para genotipagem APOE. O grupo DO persistente foi mais jovem e apresentou menor taxa de internação na fase aguda da doença (p < 0,001). Além disso, a frequência do alelo E4 da APOE foi menor nesse grupo (p = 0,035). Este estudo avaliou a DO em uma população com COVID longa. Na literatura atual sobre essa doença, a anosmia está associada a melhores desfechos clínicos e o alelo E4 está associado a piores desfechos. Conclusão Nosso estudo acrescenta novas informações a essas correlações, sugerindo a APOE E4 como um fator de proteção para DO.

PARP1 Characterization as a Potential Biomarker for BCR::ABL1 p190+ Acute Lymphoblastic Leukemia.

Detection of t(9;22), and consequent BCR::ABL1 fusion, is still a marker of worse prognosis for acute lymphoblastic leukemia (ALL), with resistance to tyrosine-kinase inhibitor therapy being a major obstacle in the clinical practice for this subset of patients. In this study, we investigated the effectiveness of targeting poly-ADP-ribose polymerase (PARP) in a model of BCR::ABL1 p190+ ALL, the most common isoform to afflict ALL patients, and demonstrated the use of experimental PARP inhibitor (PARPi), AZD2461, as a therapeutic option with cytotoxic capabilities similar to that of imatinib, the current gold standard in medical care. We characterized cytostatic profiles, induced cell death, and biomarker expression modulation utilizing cell models, also providing a comprehensive genome-wide analysis through an aCGH of the model used, and further validated PARP1 differential expression in samples of ALL p190+ patients from local healthcare institutions, as well as in larger cohorts of online and readily available datasets. Overall, we demonstrate the effectiveness of PARPi in the treatment of BCR::ABL1 p190+ ALL cell models and that PARP1 is differentially expressed in patient samples. We hope our findings help expand the characterization of molecular profiles in ALL settings and guide future investigations into novel biomarker detection and pharmacological choices in clinical practice.

Post-COVID-19 Cognitive Decline and Apoe Polymorphism: Towards a Possible Link?

APOE ε4 polymorphism has been recently described as a possible association with cognitive deficits in COVID-19 patients. This research aimed to establish the correlation between COVID-19 and cognitive impairment, and the APOE gene polymorphism among outpatients. We performed a cross-sectional study with confirmed COVID-19 patients and neurological symptoms that persisted for more than three months from onset. APOE genotypes were determined. The final number of patients included in this study was 219, of which 186 blood samples were collected for APOE genotyping, evaluated 4.5 months after COVID-19. Among the participants, 143 patients (65.3%) reported memory impairment symptoms as their primary concern. However, this complaint was objectively verified through screening tests (Addenbrooke Cognitive Examination-Revised and Mini-Mental State Examination) in only 36 patients (16.4%). The group experiencing cognitive decline exhibited a higher prevalence of the APOE ε4 allele than the normal group (30.8% vs. 16.4%, respectively, p = 0.038). Furthermore, the APOE ε4 allele and anxiety symptoms remained significant after multivariate analysis. This study assessed an outpatient population where cognitive changes were the primary complaint, even in mild cases. Moreover, the ε4 allele, sleep disorders, and anxiety symptoms were more frequent in the cognitive decline group.

Mebendazole targets essential proteins in glucose metabolism leading gastric cancer cells to death.

Gastric cancer (GC) is among the most-diagnosed and deadly malignancies worldwide. Deregulation in cellular bioenergetics is a hallmark of cancer. Based on the importance of metabolic reprogramming for the development and cancer progression, inhibitors of cell metabolism have been studied as potential candidates for chemotherapy in oncology. Mebendazole (MBZ), an antihelminthic approved by FDA, has shown antitumoral activity against cancer cell lines. However, its potential in the modulation of tumoral metabolism remains unclear. Results evidenced that the antitumoral and cytotoxic mechanism of MBZ in GC cells is related to the modulation of the mRNA expression of glycolic targets SLC2A1, HK1, GAPDH, and LDHA. Moreover, in silico analysis has shown that these genes are overexpressed in GC samples, and this increase in expression is related to decreased overall survival rates. Molecular docking revealed that MBZ modifies the protein structure of these targets, which may lead to changes in their protein function. In vitro studies also showed that MBZ induces alterations in glucose uptake, LDH's enzymatic activity, and ATP production. Furthermore, MBZ induced morphologic and intracellular alterations typical of the apoptotic cell death pathway. Thus, this data indicated that the cytotoxic mechanism of MBZ is related to an initial modulation of the tumoral metabolism in the GC cell line. Altogether, our results provide more evidence about the antitumoral mechanism of action of MBZ towards GC cells and reveal metabolic reprogramming as a potential area in the discovery of new pharmacological targets for GC chemotherapy.

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.

Association between Immunophenotypic Parameters and Molecular Alterations in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a hematologic malignancy that occurs due to alterations such as genetic mutations, chromosomal translocations, or changes in molecular levels. These alterations can accumulate in stem cells and hematopoietic progenitors, leading to the development of AML, which has a prevalence of 80% of acute leukemias in the adult population. Recurrent cytogenetic abnormalities, in addition to mediating leukemogenesis onset, participate in its evolution and can be used as established diagnostic and prognostic markers. Most of these mutations confer resistance to the traditionally used treatments and, therefore, the aberrant protein products are also considered therapeutic targets. The surface antigens of a cell are characterized through immunophenotyping, which has the ability to identify and differentiate the degrees of maturation and the lineage of the target cell, whether benign or malignant. With this, we seek to establish a relationship according to the molecular aberrations and immunophenotypic alterations that cells with AML present.

Chia (Salvia hispanica L.) Seeds Contain a Highly Stable Trypsin Inhibitor with Potential for Bacterial Management Alone or in Drug Combination Therapy with Oxacillin.

The emergence of antibiotic resistance poses a serious and challenging threat to healthcare systems, making it imperative to discover novel therapeutic options. This work reports the isolation and characterization of a thermostable trypsin inhibitor from chia (Salvia hispanica L.) seeds, with antibacterial activity against Staphylococcus aureus sensitive and resistant to methicillin. The trypsin inhibitor ShTI was purified from chia seeds through crude extract heat treatment, followed by affinity and reversed-phase chromatography. Tricine-SDS-PAGE revealed a single glycoprotein band of ~ 11 kDa under nonreducing conditions, confirmed by mass spectrometry analysis (11.558 kDa). ShTI was remarkably stable under high temperatures (100 °C; 120 min) and a broad pH range (2-10; 30 min). Upon exposure to DTT (0.1 M; 120 min), ShTI antitrypsin activity was partially lost (~ 38%), indicating the participation of disulfide bridges in its structure. ShTI is a competitive inhibitor (Ki = 1.79 × 10-8 M; IC50 = 1.74 × 10-8 M) that forms a 1:1 stoichiometry ratio for the ShTI:trypsin complex. ShTI displayed antibacterial activity alone (MICs range from 15.83 to 19.03 µM) and in combination with oxacillin (FICI range from 0.20 to 0.33) against strains of S. aureus, including methicillin-resistant strains. Overproduction of reactive oxygen species and plasma membrane pore formation are involved in the antibacterial action mode of ShTI. Overall, ShTI represents a novel candidate for use as a therapeutic agent for the bacterial management of S. aureus infections.

Behavioral and neuroinflammatory changes caused by glyphosate: Base herbicide in mice offspring.

BACKGROUND: Glyphosate is a pesticide considered of low toxicity, but scientific evidences show it can be harmful to health. This study aimed to evaluate the toxicity in mice offspring exposed to glyphosate-based herbicide (GBH) during the intrauterine period. METHODS: Female matrices received glyphosate 0.3 mg/kg daily per oral throughout the gestational period, which was variable between 18 and 22 days. From the 25th until the 28th days post-birth, mice offspring were subjected to behavioral tests, and the prefrontal cortex was processed for immunohistochemical analysis. RESULTS: Two significant behavioral changes were observed: anxiety in the GLIF0.3 group, increase in the behavior burying marbles in the marble-burying test and hyperactivity, expressed by the significant increase of the crossing number in the open field test. The increased microglia, TNF-alpha, and astrocyte expression were also observed in the prefrontal cortex of offspring treated with GLIF0.3. CONCLUSION: Exposure to GBH during mice intrauterine development induces hyperactive and anxious behavior, evidencing neuroinflammation.

The Role of WRAP53 in Cell Homeostasis and Carcinogenesis Onset.

The WD repeat containing antisense to TP53 (WRAP53) gene codifies an antisense transcript for tumor protein p53 (TP53), stabilization (WRAP53α), and a functional protein (WRAP53ß, WDR79, or TCAB1). The WRAP53ß protein functions as a scaffolding protein that is important for telomerase localization, telomere assembly, Cajal body integrity, and DNA double-strand break repair. WRAP53ß is one of many proteins known for containing WD40 domains, which are responsible for mediating a variety of cell interactions. Currently, WRAP53 overexpression is considered a biomarker for a diverse subset of cancer types, and in this study, we describe what is known about WRAP53ß's multiple interactions in cell protein trafficking, Cajal body formation, and DNA double-strand break repair and its current perspectives as a biomarker for cancer.

Kinase Inhibition in Multiple Myeloma: Current Scenario and Clinical Perspectives.

Multiple myeloma (MM) is a blood cell neoplasm characterized by excessive production of malignant monoclonal plasma cells (activated B lymphocytes) by the bone marrow, which end up synthesizing antibodies or antibody fragments, called M proteins, in excess. The accumulation of this production, both cells themselves and of the immunoglobulins, causes a series of problems for the patient, of a systemic and local nature, such as blood hyperviscosity, renal failure, anemia, bone lesions, and infections due to compromised immunity. MM is the third most common hematological neoplasm, constituting 1% of all cancer cases, and is a disease that is difficult to treat, still being considered an incurable disease. The treatments currently available cannot cure the patient, but only extend their lifespan, and the main and most effective alternative is autologous hematopoietic stem cell transplantation, but not every patient is eligible, often due to age and pre-existing comorbidities. In this context, the search for new therapies that can bring better results to patients is of utmost importance. Protein tyrosine kinases (PTKs) are involved in several biological processes, such as cell growth regulation and proliferation, thus, mutations that affect their functionality can have a great impact on crucial molecular pathways in the cells, leading to tumorigenesis. In the past couple of decades, the use of small-molecule inhibitors, which include tyrosine kinase inhibitors (TKIs), has been a hallmark in the treatment of hematological malignancies, and MM patients may also benefit from TKI-based treatment strategies. In this review, we seek to understand the applicability of TKIs used in MM clinical trials in the last 10 years.

Kinase Inhibitor Screening Displayed ALK as a Possible Therapeutic Biomarker for Gastric Cancer.

Despite advances in cancer chemotherapy, gastric cancer (GC) continues to have high recurrence rates and poor prognosis with limited treatment options. Understanding the etiology of GC and developing more effective, less harmful therapeutic approaches are vital and urgent. Therefore, this work describes a novel kinase target in malignant gastric cells as a potential therapeutic strategy. Our results demonstrate that among 147 kinase inhibitors (KI), only three molecules were significantly cytotoxic for the AGP-01 cell line. Hence, these three molecules were further characterized in their cellular mode of action. There was significant cell cycle impairment due to the expression modulation of genes such as TP53, CDKN1A, CDC25A, MYC, and CDK2 with subsequent induction of apoptosis. In fact, the Gene Ontology analysis revealed a significant enrichment of pathways related to cell cycle regulation (GO:1902749 and GO:1903047). Moreover, the three selected KIs significantly reduced cell migration and Vimentin mRNA expression after treatment. Surprisingly, the three KIs share the same target, ALK and INSR, but only the ALK gene was found to have a high expression level in the gastric cancer cell line. Additionally, lower survival rates were observed for patients with high ALK expression in TCGA-STAD analysis. In summary, we hypothesize that ALK gene overexpression can be a promising biomarker for prognosis and therapeutic management of gastric adenocarcinoma.

Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action.

Chronic myeloid leukemia (CML) is caused by constitutively active fusion protein BCR-ABL1, and targeting ABL1 is a promising therapy option. Imatinib, dasatinib, and nilotinib have all been shown to work effectively in clinical trials. ABL1 mutations, particularly the T315I gate-keeper mutation, cause resistance in patients. As a result, broad-spectrum ABL1 medicines are desperately needed. In order to screen potential drugs targeting CML, mebendazole (MBZ) was subjected to the in vitro test against CML cell lines (K562 and FEPS) and computational assays. The antiproliferative effect of MBZ and the combination with tyrosine kinase inhibitors (TKIs) was tested using end-point viability assays, cell cycle distribution analysis, cell membrane, and mitochondrial dyes. By interrupting the cell cycle and causing cell death, MBZ and its combination with imatinib and dasatinib have a significant antiproliferative effect. We identified MBZ as a promising "new use" drug targeting wild-type and mutant ABL1 using molecular docking. Meanwhile, we determined which residues in the allosteric site are important in ABL1 drug development. These findings may not only serve as a model for repositioning current authorized medications but may also provide ABL1-targeted anti-CML treatments a fresh lease of life.

Genomic surveillance: Circulating lineages and genomic variation of SARS-CoV-2 in early pandemic in Ceará state, Northeast Brazil.

In the Northeast of Brazil, Ceará was the second state most impacted by COVID-19 in number of cases and death rate. Despite that, the early dynamics of the pandemic in Ceará was not yet well understood due the low genomic surveillance of SARS-CoV-2 in 2020. In this study, we analyze the circulating lineages and the genomic variation of the virus in Ceará state. Thirty-four genomes were sequenced and combined with sequences available in GISAID database from March 2020 to June 2021 to compose the study dataset. The most prevalent lineages detected were B.1.1.33, in 2020, and P.1, in 2021. Other lineages were found, such as P.2, sublineages of P.1, B.1, B.1.1, B.1.1.28 and B.1.212. Analyzing the mutations, a total of 202 single-nucleotide polymorphisms (SNPs) were identified among the 34 genomes sequenced, of which 127 were missense, 74 synonymous, and one was a nonsense mutation. Among the missense mutations, C14408T, A23403G, T27299C, G28881A G28883C, and T29148C were the most prevalent within the dataset. Although SARS-CoV-2 sequencing data was limited in 2020, our results could provide insights to better understand the genetic diversity of the circulating lineages in Ceará.