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.

EndoGeneAnalyzer: A tool for selection and validation of reference genes.

The selection of proper reference genes is critical for accurate gene expression analysis in all fields of biological and medical research, mainly because there are many distinctions between different tissues and specimens. Given this variability, even in known classic reference genes, demands of a comprehensive analysis platform is needed to identify the most suitable genes for each study. For this purpose, we present an analysis tool for assisting in decision-making in the analysis of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) data. EndoGeneAnalyzer, an open-source web tool for reference gene analysis in RT-qPCR studies, was used to compare the groups/conditions under investigation. This interactive application offers an easy-to-use interface that allows efficient exploration of datasets. Through statistical and stability analyses, EndoGeneAnalyzer assists in the select of the most appropriate reference gene or set of genes for each condition. It also allows researchers to identify and remove unwanted outliers. Moreover, EndoGeneAnalyzer provides a graphical interface to compare the evaluated groups, providing a visually informative differential analysis.

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.

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.

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.

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.

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.

Antitumoral effect of novel synthetic 8-hydroxy-2-((4-nitrophenyl)thio)naphthalene-1,4-dione (CNN16) via ROS-mediated DNA damage, apoptosis and anti-migratory effect in colon cancer cell line.

Colorectal cancer (CRC) is estimated as the third most incident cancer and second in mortality worldwide. Moreover, CRC metastasis reduces patients' survival rates. Thus, the study and identification of new compounds with anticancer activity selectively to tumor cells are encouraged in the CRC treatment. Naphtoquinones are compounds with several pharmacologic activities, including antitumoral properties. Therefore, this study aimed to investigate the anticancer mechanism of synthetic 8-Hydroxy-2-(P-Nitrothiophenol)-1,4-Naphthoquinone (CNN16) in colon cancer cell line HCT-116. CNN16 showed an IC50 of 5.32 µM in HCT-116, and 9.36, 10.77, and 24.57 µM in the non-cancerous cells MRC-5, MNP-01, and PMBC, respectively, evaluated by the MTT assay. CNN16 showed an anticlonogenic effect in HCT-116 and induced cell fragmentation identified by flow cytometry analysis. Furthermore, we observed that CNN16 presented genotoxicity and induces reactive oxygen species (ROS) after 3 h of treatment visualized by alkaline comet assay and DCFH-DA dye fluorescence, respectively. Furthermore, CNN16 caused cellular membrane disruption, reduction in the mitochondrial membrane polarization, and the presence of apoptotic bodies and chromatin condensation was visualized by differential stained (HO/FD/PI) in fluorescent microscopy along with PARP1, TP53, BCL-2, and BAX analyzed by RT-qPCR. Results also evidenced inhibition in the migratory process analyzed by wound healing assay. Therefore, CNN16 can be considered as a potential new leader molecule for CRC treatment, although further studies are still necessary to comprehend the effects of CNN16 in in vivo models to evaluate the anti-migratory effect, and toxicology and assure compound safety and selectively.

Long-covid cognitive impairment: Cognitive assessment and apolipoprotein E (APOE) genotyping correlation in a Brazilian cohort.

Introduction: Few studies have objectively evaluated cognitive deficits after the acute phase of COVID-19 disease. Moreover, the role of apolipoprotein E (APOE) genotypes in cognitive decline in patients with COVID-19 has not been evaluated yet. Methods: This cross-sectional study was conducted in confirmed cases of COVID-19 patients with neurological symptoms that persisted for more than 3 months from the onset. We determined APOE genotypes. Results: The final sample consisted of 141 patients. The most frequent APOE genotype was E3/E3 (N = 95; 67.3%). In total, 93 patients (65.9%) had memory impairment symptoms as the main complaint, objectively confirmed through screening tests in 25 patients (17.7%). Patients with cognitive impairment had a lower frequency of anosmia than the normal and subjective cognitive decline (SCD) groups (p = 0.005). In addition, depression was recurrent in the cognitive impairment group and the SCD group (p = 0.046). Cognitive impairment was significantly more frequent in hospitalized patients and those with a lower education level. Cognitive status was not associated with APOE genotypes. Discussion: Hospitalized patients had more severe infection with a greater possibility of systemic complications, greater inflammatory response, and prolonged hospitalization, which could impact cognitive performance. Cognitive impairment in patients with COVID-19 does not necessarily involve specific APOE polymorphisms. However, psychiatric disorders may also be responsible for cognitive complaints. Cognitive complaints are frequent in patients with COVID-19, even after the acute phase of the disease and in mild cases. Hospitalized participants and depressed patients may have a higher risk of cognitive impairment. APOE genotypes or haplotypes may not significantly play a role in COVID-19 cognitive impairment.

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.

Leukemic Stem Cell: A Mini-Review on Clinical Perspectives.

Hematopoietic stem cells (HSCs) are known for their ability to proliferate and self-renew, thus being responsible for sustaining the hematopoietic system and residing in the bone marrow (BM). Leukemic stem cells (LSCs) are recognized by their stemness features such as drug resistance, self-renewal, and undifferentiated state. LSCs are also present in BM, being found in only 0.1%, approximately. This makes their identification and even their differentiation difficult since, despite the mutations, they are cells that still have many similarities with HSCs. Although the common characteristics, LSCs are heterogeneous cells and have different phenotypic characteristics, genetic mutations, and metabolic alterations. This whole set of alterations enables the cell to initiate the process of carcinogenesis, in addition to conferring drug resistance and providing relapses. The study of LSCs has been evolving and its application can help patients, where through its count as a biomarker, it can indicate a prognostic factor and reveal treatment results. The selection of a target to LSC therapy is fundamental. Ideally, the target chosen should be highly expressed by LSCs, highly selective, absence of expression on other cells, in particular HSC, and preferentially expressed by high numbers of patients. In view of the large number of similarities between LSCs and HSCs, it is not surprising that current treatment approaches are limited. In this mini review we seek to describe the immunophenotypic characteristics and mechanisms of resistance presented by LSCs, also approaching possible alternatives for the treatment of patients.

1,4-Naphthoquinone (CNN1) Induces Apoptosis through DNA Damage and Promotes Upregulation of H2AFX in Leukemia Multidrug Resistant Cell Line.

The multidrug resistance (MDR) phenotype is one of the major obstacles in the treatment of chronic myeloid leukemia (CML) in advantage stages such as blast crisis. In this scenario, more patients develop resistance mechanisms during the course of the disease, making tyrosine kinase inhibitors (TKIs) target therapies ineffective. Therefore, the aim of the study was to examine the pharmacological role of CNN1, a para-naphthoquinone, in a leukemia multidrug resistant cell line. First, the in vitro cytotoxic activity of Imatinib Mesylate (IM) in K-562 and FEPS cell lines was evaluated. Subsequently, membrane integrity and mitochondrial membrane potential assays were performed to assess the cytotoxic effects of CNN1 in K-562 and FEPS cell lines, followed by cell cycle, alkaline comet assay and annexin V-Alexa Fluor® 488/propidium iodide assays (Annexin/PI) using flow cytometry. RT-qPCR was used to evaluate the H2AFX gene expression. The results demonstrate that CNN1 was able to induce apoptosis, cell membrane rupture and mitochondrial membrane depolarization in leukemia cell lines. In addition, CNN1 also induced genotoxic effects and caused DNA fragmentation, cell cycle arrest at the G2/M phase in leukemia cells. No genotoxicity was observed on peripheral blood mononuclear cells (PBMC). Additionally, CNN1 increased mRNA levels of H2AFX. Therefore, CNN1 presented anticancer properties against leukemia multidrug resistant cell line being a potential anticancer agent for the treatment of resistant CML.

Circadian Rhythm Dysregulation and Leukemia Development: The Role of Clock Genes as Promising Biomarkers.

The circadian clock (CC) is a daily system that regulates the oscillations of physiological processes and can respond to the external environment in order to maintain internal homeostasis. For the functioning of the CC, the clock genes (CG) act in different metabolic pathways through the clock-controlled genes (CCG), providing cellular regulation. The CC's interruption can result in the development of different diseases, such as neurodegenerative and metabolic disorders, as well as cancer. Leukemias correspond to a group of malignancies of the blood and bone marrow that occur when alterations in normal cellular regulatory processes cause the uncontrolled proliferation of hematopoietic stem cells. This review aimed to associate a deregulated CC with the manifestation of leukemia, looking for possible pathways involving CG and their possible role as leukemic biomarkers.

MicroRNA 320a and Membrane Antigens as Tools to Evaluate the Pathophysiology of Platelets Stored in Blood Banks.

Our research group, through the analysis of miRNomes in platelet concentrates (PCs) stored in blood banks, identified and validated the miR-127 and miR-320a miRNAs as biomarkers of platelet storage lesions (PSLs) in PCs. In order to validate the miRNAs 127 and 320a methodologically, as PSL biomarkers in a large number of PC bags, we also evaluated important immunological markers involved in the platelet activation/aggregation process-the CD62P receptor (P-selectin), the surface glycoproteins (GP) IIb/IIIa, and the purinergic P2Y12 receptor-via flow cytometry. The miRNAs miR-127 and miR-320a were quantified by real-time quantitative PCR (RT-qPCR). To carry out this study, 500 collection tubes were used at the upper edge of the PC bags containing platelets. Each tube was divided into seven equal parts (totaling 3500 samples) for platelet analysis from 7 different storage days, where the 1st day represents the high-quality control, and the 7th day corresponds to the low-quality control of the platelets. After analyzing all parameters during storage days, it was concluded that the relative quantification of miR-320a below 0.50 and the CD62P receptor below 27.92% are reliable indicators of the absence of storage lesions in blood banks. We believe that the values found in the expression of the CD62P receptor legitimize the use of the miR-320a and miR-127 miRNAs to build a kit capable of accurately measuring whether the stored platelets are suitable for transfusion.

Role of miRNAs in Human T Cell Leukemia Virus Type 1 Induced T Cell Leukemia: A Literature Review and Bioinformatics Approach.

Human T cell leukemia virus type 1 (HTLV-1) was identified as the first pathogenic human retrovirus and is estimated to infect 5 to 10 million individuals worldwide. Unlike other retroviruses, there is no effective therapy to prevent the onset of the most alarming diseases caused by HTLV-1, and the more severe cases manifest as the malignant phenotype of adult T cell leukemia (ATL). MicroRNA (miRNA) dysfunction is a common feature of leukemogenesis, and it is no different in ATL cases. Therefore, we sought to analyze studies that reported deregulated miRNA expression in HTLV-1 infected cells and patients' samples to understand how this deregulation could induce malignancy. Through in silico analysis, we identified 12 miRNAs that stood out in the prediction of targets, and we performed functional annotation of the genes linked to these 12 miRNAs that appeared to have a major biological interaction. A total of 90 genes were enriched in 14 KEGG pathways with significant values, including TP53, WNT, MAPK, TGF-ß, and Ras signaling pathways. These miRNAs and gene interactions are discussed in further detail for elucidation of how they may act as probable drivers for ATL onset, and while our data provide solid starting points for comprehension of miRNAs' roles in HTLV-1 infection, continuous effort in oncologic research is still needed to improve our understanding of HTLV-1 induced leukemia.

Identification of Germline Mutations in Genes Involved in Classic FAP in Patients from Northern Brazil.

BACKGROUND: Colorectal cancer is a common cancer worldwide, with 5-10% of cases being hereditary. Familial adenomatous polyposis syndrome (FAP) is caused by germline mutations in the APC gene or rarely in the MUTYH gene. PATIENTS AND METHODS: This work did not identify germline mutations in the MUTYH, NTHL1, POLD1 and POLE genes in 15 individuals belonging to five families with classic FAP, who had the mutation in the APC gene confirmed in a previous study. Our results support mutations in the APC gene as the main genetic contribution of classical FAP with severe phenotype. In the family that had the most aggressive form of the disease, we performed an array-based Comparative Genomic Hybridization analysis and identified the germinal loss of an allele of the NOTCH2 and BMPR2 genes in the mother (proband) and daughter. In order to validate the involvement of these genes in the other four families of this study, we analyzed the DNA copy number variation in the peripheral blood of the 15 participants. RESULTS: FAP is a syndrome with considerable genetic and phenotypic heterogeneity and this phenomenon may explain the presence of secondary genetic alterations, such as the allelic loss of NOTCH2 and BMPR2 genes, found only in one family in this study. The CNV analysis confirmed that only the two members of the FAP2 family (patient 02H and 02F) had a deletion of these two genes, as the aCGH methodology had found. The other study participants did not show allelic loss for these two genes. CONCLUSION: Validation in a larger number of families could confirm the presence of these new genetic alterations in classic FAP and improve understanding of the different types of aggressiveness of the disease.

Chronic Myelogenous Leukemia with Double Philadelphia Chromosome and Coexpression of p210 and p190 Fusion Transcripts.

The Philadelphia (Ph+) chromosome, t(9;22)(q34;q11.2), originates from a chimeric gene called BCR-ABL and is present in more than 90% of CML patients. Most patients with CML express the protein p210 BCR-ABL and, with a frequency lower than 5%, express rare isoforms, the main one being p190. In the transition from the chronic phase to the blast phase (BP), additional chromosomal abnormalities, such as the presence of the double Ph+ chromosome, are revealed. Of the 1132 patients analyzed via molecular biology in this study, two patients (0.17%) showed the co-expression of the p210 and p190 isoforms for the BCR-ABL transcript, with the concomitant presence of a double Ph+ chromosome, which was observed via conventional cytogenetics and confirmed by fluorescent in situ hybridization. The BCR-ABL/ABL% p210 and p190 ratio increased in these two patients from diagnosis to progression to blast crisis. To our knowledge, this is the first report in the literature of patients who co-expressed the two main BCR-ABL transcript isoforms and concomitantly presented Ph+ chromosome duplication. The evolution from the chronic phase to BP often occurs within 5 to 7 years, and, in this study, the evolution to BP was earlier, since disease-free survival was on average 4.5 months and overall survival was on average 9.5 months. The presence of the p190 transcript and the double Ph+ chromosome in CML may be related to the vertiginous progression of the disease.

Differences in glucose concentration shows new perspectives in gastric cancer metabolism.

Gastric cancer (GC) is among the deadliest cancers worldwide despite available therapies, highlighting the need for novel therapies and pharmacological agents. Metabolic deregulation is a potential study area for new anticancer targets, but the in vitro metabolic studies are controversial, as different ranges of glucose used in the culture media can influence results. In this study, we evaluated cellular viability, glucose uptake, and LDH activity in gastric cancer cell lines when exposed to different glucose concentrations: high (HG, 25mM), low (LG, 5.5mM), and free (FG, 0mM) glucose media. Moreover, we evaluated how glucose variations may influence cellular phenotype and the expression of genes related to epithelial-mesenchymal transition (EMT), metabolism, and cancer development in metastatic GC cells (AGP-01). Results showed that metastatic cells exposed to FG medium evidenced higher alterations when compared to other cell lines. Most phenotypic assays did not show difference when exposed to either HG or LG media. However, gene expression profile of cells exposed to LG revealed differences in mRNA levels of metabolism-related genes when compared to HG medium. According to our results, we recommend using LG medium for metabolic studies since the glucose concentration is closer to physiological levels. These findings point out new relevant targets in metabolic reprogramming that can be alternatives to current chemotherapies in patients with metastatic GC.

Solid Tumors and Kinase Inhibition: Management and Therapy Efficacy Evolution.

The increasing numbers of cancer cases worldwide and the exceedingly high mortality rates of some tumor subtypes raise the question about if the current protocols for cancer management are effective and what has been done to improve upon oncologic patients' prognoses. The traditional chemo-immunotherapy options for cancer treatment focus on the use of cytotoxic agents that are able to overcome neoplastic clones' survival mechanisms and induce apoptosis, as well as on the ability to capacitate the host's immune system to hinder the continuous growth of malignant cells. The need to avert the highly toxic profiles of conventional chemo-immunotherapy and to overcome the emerging cases of tumor multidrug resistance has fueled a growing interest in the field of precision medicine and targeted molecular therapies in the last couple of decades, although relatively new alternatives in oncologic practices, the increased specificity, and the positive clinical outcomes achieved through targeted molecular therapies have already consolidated them as promising prospects for the future of cancer management. In recent years, the development and application of targeted drugs as tyrosine kinase inhibitors have enabled cancer treatment to enter the era of specificity. In addition, the combined use of targeted therapy, immunotherapy, and traditional chemotherapy has innovated the standard treatment for many malignancies, bringing new light to patients with recurrent tumors. This article comprises a series of clinical trials that, in the past 5 years, utilized kinase inhibitors (KIs) as a monotherapy or in combination with other cytotoxic agents to treat patients afflicted with solid tumors. The results, with varying degrees of efficacy, are reported.