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Early detection of malignancies, through regular cancer screening, has already proven to have potential to increase survival rates. Yet current screening methods rely on invasive, expensive tissue sampling that has hampered widespread use. Liquid biopsy is noninvasive and represents a potential approach to precision oncology, based on molecular profiling of body fluids. Among these, circulating cell-free RNA (cfRNA) has gained attention due to its diverse composition and potential as a sensitive biomarker. This review provides an overview of the processes of cfRNA delivery into the bloodstream and the role of cfRNA detection in the diagnosis of central nervous system (CNS) tumors. Different types of cfRNAs such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have been recognized as potential biomarkers in CNS tumors. These molecules exhibit differential expression patterns in the plasma, cerebrospinalfluid (CSF) and urine of patients with CNS tumors, providing information for diagnosing the disease, predicting outcomes, and assessing treatment effectiveness. Few clinical trials are currently exploring the use of liquid biopsy for detecting and monitoring CNS tumors. Despite obstacles like sample standardization and data analysis, cfRNA shows promise as a tool in the diagnosis and management of CNS tumors, offering opportunities for early detection, personalized therapy, and improved patient outcomes., Competing Interests: Declaration of Competing Interest The authors declare no known competing financial interests or personal relationships that could have influenced the work carried out in this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Artificial Intelligence (AI) has made significant strides due to advancements in processing algorithms and data availability. Recent years have shown a resurgence in AI, driven by breakthroughs in deep machine learning. AI has attracted particular interest in the medical sector, especially in the field of personalized medicine, which for example uses large-scale genomic and molecular data to predict individual patient treatment responses. The applications of AI in disease diagnosis, monitoring, and treatment are expanding rapidly, leading to a growing number of registered trials. Therefore, this study aimed to identify and evaluate clinical trials registered between January 1st 2016, and September 30th 2023 that connect AI and cancer. Our findings show that the number of clinical trials linking AI with cancer research has grown significantly compared to other diseases, with colorectal and breast tumour types showing the highest number of registered trials. The most frequent intervention was disease diagnosis and monitoring. Regarding countries, China and the United States hold the highest numbers of registered trials. In conclusion, oncology is a field with a great interest in AI, where the developed countries are leading the studies in this field. Unfortunately, developing countries are still crawling in this aspect and government policies should be made to improve that area., Competing Interests: Declaration of Competing Interest The authors declare no known competing financial interests or personal relationships that could have influenced the work carried out in this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Liquid biopsy is a non-invasive method used to detect cancer and monitor treatment responses by analyzing blood or other bodily fluids for cancer biomarkers. Meningiomas are the most common primary central nervous system tumors, and biomarkers play a crucial role in their diagnosis, prognosis, and treatment monitoring. The World Health Organization (WHO) classifies meningiomas based on tumor grades and molecular alterations in genes such as in NF2, AKT1, TRAF7, SMO, PIK3CA, KLF4, SMARCE1, BAP1, H3K27me3, TERT promoter, and CDKN2A/B. Liquid biopsy, specifically cell-free DNA (cfDNA) analysis, has shown potential for monitoring meningiomas as it can detect ctDNA release in the blood, unaffected by the blood-brain barrier. MicroRNAs (miRNAs) have also been found to be deregulated in various cancers, including meningiomas, presenting potential as diagnostic biomarkers. Additionally, studying cytokines in the tumor microenvironment may aid in establishing prognostic or diagnostic panels for meningiomas., Methods: In the present study we analyzed the DNA coming from both the plasma and tumor samples, in addition to analyze miRNA-21 and cytokines in the plasma of 28 meningioma patients., Discussion and Conclusion: Our findings indicate that the detection of ctDNA in the plasma of meningioma patients is feasible. However, it's important to note that certain challenges persist when comparing plasma DNA analysis to that of tumor tissues. In our study, we observed a paired identification of mutations in only one patient, highlighting the complexities involved. Furthermore, we successfully identified miR-21 and cytokines in the plasma samples. Notably, our analysis of Interleukin 6 (IL-6) unveiled higher expression in the clear cell subtype compared to the other types. Despite the ongoing research, the clinical implementation of liquid biopsy in meningiomas remains somewhat limited. Nevertheless, our promising results underscore the need for further investigation., Competing Interests: FA was employed by Rede D'Or. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor PG declared a past collaboration with the author VM-N., (Copyright © 2024 Aran, Lyra Miranda, Heringer, Carvalho da Fonseca, Andreiuolo, Chimelli, Devalle, Niemeyer Filho and Moura-Neto.)

Background: Increased global cancer incidence rates have led to a growing demand for cancer diagnosis and treatment, as well as basic and clinical research on the subject. The expansion of clinical cancer trials beyond the borders of highly developed countries has aided the arrival of these assessments in South American countries. In this context, this study's objective is to highlight clinical cancer trial profiles developed and sponsored by pharmaceutical companies and conducted in South American countries from 2010 to 2020., Methods: This study comprises descriptive and retrospective research conducted following a search for clinical trials (phases I, II and III), registered at clinicaltrials.gov, carried out in Latin American countries and sponsored by pharmaceutical companies ("Argentina", "Brazil", "Chile", "Peru", "Colombia", "Ecuador", "Uruguay", "Venezuela", "Paraguay", "Bolivia"), registered between 1 January 2010 and 31 December 2020. A total of 1451 clinical trials were retrieved, of which 200 trials unrelated to cancer were excluded and 646 duplicates were removed, leading to a final total of 605 clinical trials employing qualitative and quantitative analyses., Results: A 122% increase in the number of clinical trial registrations from 2010 to 2020 was noted, with a prevalence of phase III studies (431 trials of a total of 605). Lung (119), breast (100), leukemia (42), prostate (39) and melanoma (32) were the main cancers tested for new drugs., Conclusions: The data reported herein indicate the need for strategic basic and clinical research planning that considers South American epidemic cancer profiles.

Brain tumors are considered one of the deadliest types of cancer, being challenging to treat, especially due to the blood-brain barrier, which has been linked to treatment resistance. The genomic classification of brain tumors has been helping in the diagnostic precision, however tumor heterogeneity in addition to the difficulties to obtain tissue biopsies, represent a challenge. The biopsies are usually obtained either via neurosurgical removal or stereotactic tissue biopsy, which can be risky procedures for the patient. To overcome these challenges, liquid biopsy has become an interesting option by constituting a safer procedure than conventional biopsy, which may offer valuable cellular and molecular information representative of the whole organism. Besides, it is relatively easy to obtain such as in the case of blood (venipuncture) and urine sample collection. In the present comprehensive review, we discuss the newest information regarding liquid biopsy in the brain tumors' field, methods employed, the different sources of bio-fluids and their potential circulating targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Stereotactic body radiation therapy (SBRT) is an effective option for patients with both early-stage and oligometastatic non-small-cell lung cancer (NSCLC). However, data from Latin America are limited. Therefore, the aim of this study was to investigate the real-world outcomes of applying SBRT for lung lesions in a Brazilian institution., Methods: This study investigated a consecutive cohort of patients treated with SBRT for lung lesions (primary and metastasis). The study primary outcome was local control rates per lesion. Secondary outcomes included progression-free survival (PFS), overall survival (OS), and toxicity., Results: Between 2015 and 2019, a total of 216 patients received SBRT and were included in the study. The median follow-up was 24.5 months (5-70), primary NSCLC corresponded to 70% (n = 151) and nonprimary lung lesions to 30% (n = 65), respectively. Stage I NSCLC represented 56% (85 of 151) of the NSCLC cohort. The average number of fractions and total dose prescribed was 5 (3-10)/59 Gy (50-62 Gy). For stage I NSCLC (all lesions treated with a biologically effective dose [10] > 100 Gy), 2-year local control, OS, and PFS were 93.4%, 81.6%, and 80.7%, respectively. For stage IV lesions, if biologically effective dose (10) > 100 Gy or < 100 Gy, 2-year local control was 95.8/86.4% ( P = .03), 2-year-OS was 81.6/60.5% ( P = .006), and 2-year PFS was 38.9/17.9% ( P = .10). Late toxicity was observed in 16.2% (n = 35) of the total cases., Conclusion: Our results indicate that SBRT is effective (high local control and acceptable toxicity) for treating malignant lung lesions in a real-world scenario in Latin America.

Acquired resistance during cancer treatment is unfortunately a frequent event. There are several reasons for this, including the ability of the ATP-binding cassette transporters (ABC transporters), which are integral membrane proteins, to export chemotherapeutic molecules from the interior of the tumor cells. One important member of this family is the protein known as Permeability Glycoprotein (P-Glycoprotein, P-gp or ABCB1). Its clinical relevance relies mainly on the fact that the inhibition of P-gp and other ABC transporters could result in the reversal of the multidrug resistance (MDR) phenotype in some patients. Recently, other roles apart from being a key player in MDR, have emerged for P-gp. Therefore, this review discusses the relationship between P-gp and MDR, in addition to the possible role of this protein as a biomarker in cancer., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Background: Glioblastoma is a fatal brain tumour with a poor patient survival outcome. Hypoxia has been shown to reprogram cells towards a stem cell phenotype associated with self-renewal and drug resistance properties. Activation of hypoxia-inducible factors (HIFs) helps in cellular adaptation mechanisms under hypoxia. Similarly, miRNAs are known to be dysregulated in GBM have been shown to act as critical mediators of the hypoxic response and to regulate key processes involved in tumorigenesis., Methods: Glioblastoma (GBM) cells were exposed to oxygen deprivation to mimic a tumour microenvironment and different cell aspects were analysed such as morphological changes and gene expression of miRNAs and survival genes known to be associated with tumorigenesis., Results: It was observed that miR-128a-3p, miR-34-5p, miR-181a/b/c, were down-regulated in 6 GBM cell lines while miR-17-5p and miR-221-3p were upregulated when compared to a non-GBM control. When the same GBM cell lines were cultured under hypoxic microenvironment, a further 4-10-fold downregulation was observed for miR-34-5p, miR-128a-3p and 181a/b/c while a 3-6-fold upregulation was observed for miR-221-3p and 17-5p for most of the cells. Furthermore, there was an increased expression of SOX2 and Oct4, GLUT-1, VEGF, Bcl-2 and survivin, which are associated with a stem-like state, increased metabolism, altered angiogenesis and apoptotic escape, respectively., Conclusion: This study shows that by mimicking a tumour microenvironment, miRNAs are dysregulated, stemness factors are induced and alteration of the survival genes necessary for the cells to adapt to the micro-environmental factors occurs. Collectively, these results might contribute to GBM aggressiveness., (© 2021. The Author(s).)

Challenges of health systems in Latin America and the Caribbean include accessibility, inequity, segmentation, and poverty. These challenges are similar in different countries of the region and transcend national borders. The increasing digital transformation of health care holds promise of more precise interventions, improved health outcomes, increased efficiency, and ultimately reduced health-care costs. In Latin America and the Caribbean, the adoption of digital health tools is in early stages and the quality of cancer registries, electronic health records, and structured databases are problematic. Cancer research and innovation in the region are limited due to inadequate academic resources and translational research is almost fully dependent on public funding. Regulatory complexity and extended timelines jeopardise the potential improvement in participation in international studies. Emerging technologies, artificial intelligence, big data, and cancer research represent an opportunity to address the health-care challenges in Latin America and the Caribbean collectively, by optimising national capacities, sharing and comparing best practices, and transferring scientific and technical capabilities., Competing Interests: Declaration of Interests CHB reports institutional research grant from Pfizer, Pharma Mar, Polyphor, Henlius Biotech, Merck KGaA, Millennium, LEO Pharma, ImClone Systems, Exelixis, Medivation, Asana Biosciences, AB Science, Abraxis Biosciences, Daiichi Sankyo, Bristol Myers Squibb, BioMarin, Astellas Pharma, AbbVie, Merck Sharp & Dohme, Merrimack, Mylan, Taiho Pharmaceutical, Sanofi, GlaxoSmithKline, Roche/Genentech, Lilly, Boehringer Ingelheim, Novartis, AstraZeneca, and Amgen; advisory board consulting from Boehringer Ingelheim, Sanofi, Lilly, Zodiac, AstraZeneca, Merck Sharp & Dohme, Bayer, Eisai, Roche/Genentech, Pfizer, Novartis, and GlaxoSmithKline; and stocks from MedSIR, Biomarker, and Tummi, outside the submitted work; he declares no relevant conflicts of interests related to this Series paper. AFC declares financial research support from Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol Myers Squibb, and The Foundation for Clinical and Applied Cancer Research (FICMAC); he received honoraria as advisor, participated in speakers’ bureau, and gave expert testimony to Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Pfizer, Novartis, Celldex Therapeutics, Foundation Medicine, Eli Lilly, and FICMAC. CR reports grants or contracts from Pfizer–Lung Cancer Research Foundation (for the EMPOWER ME trial); consulting fees (for advisory board) from ArcherDX, Bristol Myers Squibb, Novartis, and Boston Pharmaceuticals; payment or honoraria for educational events from AstraZeneca, Roche, and Merck Sharp & Dohme; participation on a safety monitoring board from MD Serono; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from the International Society of Liquid Biopsy (Vice President), the International Association for the Study of Lung Cancer (Deputy Chair of the Educational Committee), European School of Oncology (Scientific Board Member), the European Society for Medical Oncology (Faculty of Advanced Lung Cancer), and research support (unpaid) from Guardant Health. EdA reports research support and grants from Roche; and grants from Libbs, Pierre Fabre, Zodiacs, Seattle Genetics, Novartis, Roche, Servier, AstraZeneca, and GlaxoSmithKline, outside the submitted work. OA reports personal fees from Pfizer, Lilly, Merck, and Bristol Myers Squibb; and grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Roche, outside the submitted work. RD declares advisory role for Roche and Boehringer Ingelheim; speaker's fees from Roche, Ipsen, Amgen, Servier, Sanofi, Libbs, and Merck Sharp & Dohme; and research grants from Merck and Pierre Fabre, outside the submitted work. EC reports honoraria for lectures and consulting or advisory role from Merck outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: RAS genes are among the most frequently mutated genes in cancer, where their mutation frequency varies according to the distinct RAS isoforms and tumour types. Despite occurring more prevalent in malignant tumours, RAS mutations were also observed in few benign tumours. Pituitary adenomas are examples of benign tumours which vary in size and aggressiveness. The present study was performed to investigate, via liquid biopsy and tissue analysis, the presence of K-RAS mutations in a pituitary macroadenoma., Methods: Molecular analysis was performed to investigate K-RAS mutations using the droplet digital PCR (ddPCR) method by evaluating both plasma (liquid biopsy) and the solid tumour of a patient diagnosed with a giant clinically non-functioning pituitary tumour., Results: The patient underwent surgical resection due to visual loss, and the histopathological analysis showed a gonadotrophic pituitary macroadenoma. The molecular analysis revealed the presence of mutant K-RAS both in the plasma and in the tumour tissue which, to our knowledge, has not been previously reported in the literature., Conclusion: Our findings highlight the exceptional capacity of the digital PCR in detecting low frequency mutations (below 1%), since we detected, for the first time, K-RAS mutations in pituitary macroadenoma. The potential impact of K-RAS mutations in these tumours should be further investigated., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives : One of the most frequently mutated oncogenes in cancer belongs to the Ras family of proto-oncogenes, which encode distinct key signaling events. RAS gain-of-function mutations are present in ~30% of all human cancers, with KRAS being the most frequently mutated isoform showing alterations in different cancer types including lung cancer. This study aimed to investigate the incidence of KRAS mutations, and concomitant mutations, in advanced non-small cell lung adenocarcinoma patients. Materials and Methods : This was a retrospective study, where genomic DNA extracted from paraffin-embedded tumor tissues from 121 Brazilian advanced non-small cell lung adenocarcinoma patients were analyzed to evaluate via Next Generation Sequencing (NGS) the incidence of KRAS mutations and co-occurring mutations and correlate, when possible, to clinicopathological characteristics. Statistical analyses were performed to calculate the prevalence of mutations and to investigate the association between mutational status, mutation type, and sex. Results : The results showed a prevalence of male (N = 63; 54.8%) compared to female patients (N = 52, 45.2%), and mutant KRAS was present in 20.86% (24/115) of all samples. Interestingly, 33.3% of the mutant KRAS samples showed other mutations simultaneously. Conclusions : This study revealed the presence of rare KRAS concomitant mutations in advanced lung adenocarcinoma patients. Further investigation on the importance of these genomic alterations in patient prognosis and treatment response is warranted.

The RAS oncogene is one of the most frequently mutated genes in human cancer, with K-RAS having a leading role in tumorigenesis. K-RAS undergoes alternative splicing, and as a result its transcript generates two gene products K-RAS4A and K-RAS4B, which are affected by the same oncogenic mutations, are highly homologous, and are expressed in a variety of human tissues at different levels. In addition, both isoforms localise to the plasma membrane by distinct targeting motifs. While some evidence suggests nonredundant functions for both splice variants, most work to date has focused on K-RAS4B, or even just K-RAS (i.e., without differentiating between the splice variants). This review aims to address the most relevant evidence published regarding K-RAS4A and to discuss if this "minor" isoform could also play a leading role in cancer, concluding that a significant body of evidence supports a leading role rather than a supporting (or secondary) role for K-RAS4A in cancer biology., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Aran.)

Background: Brazil is a country of continental dimensions with great potential for the development of clinical studies across the whole territory to tackle the needs of the population. It is therefore important to obtain the national profile of clinical trials in order to identify local strengths and weaknesses in terms of productivity and study application. Thus, this paper aims to highlight the profiles of clinical studies on cancer developed and sponsored by hospitals, institutes, universities and international institutions in Brazil between 1997 and 2015., Methods: This is a retrospective and analytical study in which the content analysis method of Laurence Bardin was used. Data were collected from the clinicaltrials.govdatabase, where 783 clinical studies on cancer prevention, diagnosis and treatment were found; 188 (24 %) of these corresponded to national initiatives and 595 (76 %) to international initiatives., Results: The results show an increase in the number of national clinical studies, in particular phase III studies. There is a clear absence of national clinical studies focusing on the development of new chemical and biotechnological products in oncology., Conclusion: The results indicate a regional imbalance in the distribution of national and international clinical trials., Policy Summary: The present study aims to improve understanding of the profile of clinical studies registered in Brazil and to draw attention to the improvements needed in the health sector's productivity to address the national demand., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Bone sarcomas, although rare, are associated with significant morbidity and mortality. The most frequent primary bone cancers include osteosarcoma, chondrosarcoma and Ewing sarcoma. The treatment approaches are heterogeneous and mainly chosen based on precise tumour staging. Unfortunately, clinical outcome has not changed significantly in over 30 years and tumour grade is still the best prognosticator of metastatic disease and survival. An option to improve this scenario is to identify molecular biomarkers in the early stage of the disease, or even before the disease onset. Blood-based liquid biopsies are a promising, non-invasive way to achieve this goal and there are an increasing number of studies which investigate their potential application in bone cancer diagnosis, prognosis and personalised therapy. This review summarises the interplay between clinical and molecular aspects of the three main bone sarcomas, alongside biomarker discovery and promising applications of liquid biopsy in each tumour context., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Lung cancer is a global health problem, with more than 220,000 new cases and 150,000 deaths per year in the United States. Likewise, in Brazil, lung cancer is the most lethal cancer with 30,200 new cases expected in 2020. Regarding treatment types, radiation therapy (RT) represents an important approach, since 60%-70% of the patients will receive this modality of treatment during the course of their disease. However, access to RT remains challenging because of the socioeconomic inequalities in the Brazilian population, where approximately 100,000 patients/year die without access to RT. This work provides an overview on the availability of high technology RT in Brazil., Methods: A retrospective study was performed using the Brazilian Radiotherapy Census, local public and private databases, and the current literature published in 2019., Results: The Brazilian radiotherapy network relies on approximately 363 linear accelerators and 20 cobalt machines that remain operational. Most of these machines are installed at public health facilities. Regarding high technology, intensity-modulated RT is available in 53.7% (n = 130) and volumetric modulated arc therapy in 28.5% (n = 69) of the institutions, although only 19.8% (n = 48) of those facilities are capable of performing image-guided RT using cone beam computed tomography. Considering only the public health care system, the scenario is more restricted, with 40.1% (n = 65) of the institutions offering intensity-modulated RT, 21% (n = 34) volumetric modulated arc therapy, and 14.8% (n = 24) using cone beam computed tomography. Because of these scare resources, only 16% of Radiation Departments offer stereotactic body RT., Conclusion: Brazil still needs to improve and provide high and safer RT technologies to patients with lung cancer across all Brazilian regions to attend the population needs and obtain better patient outcomes., Competing Interests: Arthur Accioly RosaEmployment: Grupo OncoclinicasHonoraria: RocheConsulting or Advisory Role: AstraZenecaTravel, Accommodations, Expenses: RocheNo other potential conflicts of interest were reported.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has caused the coronavirus disease 2019 (COVID-19), first appeared in December 2019 in Wuhan (China) and quickly spread worldwide and has since been assigned a pandemic status. This affected the worlds' social interactions, including within medical practices, thus interfering with routine treatments for a variety of diseases including cancer. Different studies have addressed the fact that patients with cancer are often immunocompromised, making them more susceptible to infections. Since COVID-19 frequently causes respiratory distress, patients with lung cancer are considered to be a high-risk group. Genes that have been indicated to mediate viral entry into host cells such as angiotensin-converting enzyme 2 and transmembrane protease serine 2 are expressed in the lung tissue, a fact that could partially explain COVID-19 pathogenesis and lung involvement. Therefore, the current study offers a disease overview including molecular aspects behind the infection and provide a perspective on already published Chinese data plus recommendations for the management of lung cancer patients according to the two main lung cancer types and stages: non-small cell lung cancer and small cell lung cancer. This review aimed to add to the collective effort of selecting the most appropriate guidelines to follow for the treatment of these patients., (Copyright: © Aran et al.)

Graphene, including graphene quantum dots, its oxide and unoxidized forms (pure graphene) have several properties, like fluorescence, electrical conductivity, theoretical surface area, low toxicity, and high biocompatibility. In this study, we evaluated genotoxicity ( in silico analysis using the functional density theory-FDT), cytotoxicity (human glioblastoma cell line), in vivo pharmacokinetics, in vivo impact on microcirculation and cell internalization assay. It was also radiolabeled with lutetium 177 (177Lu), a beta emitter radioisotope to explore its therapeutic use as nanodrug. Finally, the impact of its disposal in the environment was analyzed using ecotoxicological evaluation. FDT analysis demonstrated that graphene can construct covalent and non-covalent bonds with different nucleobases, and graphene oxide is responsible for generation of reactive oxygen species (ROS), corroborating its genotoxicity. On the other hand, non-cytotoxic effect on glioblastoma cells could be demonstrated. The pharmacokinetics analysis showed high plasmatic concentration and clearance. Topical application of 0.1 and 1 mg/kg of graphene nanoparticles on the hamster skinfold preparation did not show inflammatory effect. The cell internalization assay showed that 1-hour post contact with cells, graphene can cross the plasmatic membrane and accumulate in the cytoplasm. Radio labeling with 177Lu is possible and its use as therapeutic nanosystem is viable. Finally, the ecotoxicity analysis showed that A. silina exposed to graphene showed pronounced uptake and absorption in the nauplii gut and formation of ROS. The data obtained showed that although being formed exclusively of carbon and carbon-oxygen, graphene and graphene oxide respectively generate somewhat contradictory results and more studies should be performed to certify the safety use of this nanoplatform.

Chondrosarcomas constitute the 3rd most common primary bone malignancy. These tumours grow slowly and rarely metastasize, usually having a good prognosis after surgery. Among patients registered and treated at the Brazilian National Institute of Traumatology and Orthopedics, an uncommon case of chondrosarcoma was identified in a 63-year-old man, who was diagnosed with multicentric chondrosarcoma of the appendicular skeleton. This example is atypical in the medical literature because multicentric tumours are different from metastatic events, and their frequency in chondrosarcoma is rare. This article therefore provides a rare case report alongside a review of additional cases in the medical literature., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none., (2020 Multimed Inc.)

Background: The treatment of choice for advanced non-small cell lung cancer is selected according to the presence of specific alterations. Patients should undergo molecular testing for relevant modifications and the mutational status of EGFR and translocation of ALK and ROS1 are commonly tested to offer the best intervention. In addition, the tests costs should also be taken in consideration. Therefore, this work was performed in order to evaluate the cost-effectiveness of a unique exam using NGS (next generation sequencing) versus other routinely used tests which involve RT-PCR and FISH., Methods: The target population was NSCLC, adenocarcinoma, and candidates to first-line therapy. Two strategies were undertaken, strategy 1 corresponded to sequential tests with EGFR RT-PCR, then FISH for ALK and ROS1. Strategy 2 differed from 1 in that ALK and ROS1 translocation testing were performed simultaneously by FISH. Strategy 3 considered single test next-generation sequencing, a platform that includes EGFR, ALK and ROS1 genes. A decision tree analysis was used to model genetic testing options. From the test results, a microsimulation model was nested to estimate survival outcomes and costs of therapeutic options., Results: The use of NGS added 24% extra true cases as well as extra costs attributed to the molecular testing. The ICER comparing NGS with sequential tests was US$ 3479.11/correct case detected. The NGS improved a slight gain in life years and QALYs., Conclusion: Our results indicated that, although precise, the molecular diagnosis by NGS of patients with advanced stage NSCLC adenocarcinoma histology was not cost-effective in terms of quality-adjusted life years from the perspective of the Brazilian supplementary health system.

Recent studies have suggested the neuroinvasive potential of severe acute respiratory coronavirus 2 (SARS-CoV-2). Notably, neuroinvasiveness might be involved in the pathophysiology of coronavirus disease 2019 (COVID-19). Some studies have demonstrated that synapse-connected routes may enable coronaviruses to access the central nervous system (CNS). However, evidence related to the presence of SARS-CoV-2 in the CNS, its direct impact on the CNS, and the contribution to symptoms suffered, remain sparse. Here, we review the current literature that indicates that SARS-CoV-2 can invade the nervous system. We also describe the neural circuits that are potentially affected by the virus and their possible role in the progress of COVID-19. In addition, we propose several strategies to understand, diagnose, and treat the neurological symptoms of COVID-19., (Copyright © 2020 DosSantos, Devalle, Aran, Capra, Roque, Coelho-Aguiar, Spohr, Subilhaga, Pereira, D'Andrea Meira, Niemeyer Soares Filho and Moura-Neto.)

The research and treatment of non-small cell lung cancer (NSCLC) have achieved some important advances in recent years. Nonetheless, the overall survival rates for NSCLC remain low, indicating the importance to effectively develop new therapies and improve current approaches. The understanding of the function of different biomarkers involved in NSCLC progression, survival and response to therapy are important for the development of early detection tools and treatment options. Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (K-RAS) are two of the main significant biomarkers for the management of NSCLC. Mutations in these genes were associated with development and response to therapies. For example, the use of small molecule tyrosine kinase (TK) inhibitors and immunotherapy has led to benefits in some, but not all patients with altered EGFR. In contrast, there is still no effective approved drug to act upon patients harbouring K-RAS mutations. In addition, K-RAS mutations have been associated with lack of activity of TK inhibitors. However, promising approaches aimed to inhibit mutant K-RAS are currently under study. Therefore, this review will discuss these approaches and also EGFR therapies, and hopefully, it will draw attention to the need of continued research in the field in order to improve the outcomes in NSCLC patients.

Objectives: Mammalian cells differently express 4 RAS isoforms: H-RAS, N-RAS, K-RAS4A and K-RAS4B, which are important in promoting oncogenic processes when mutated. In lung cancer, the K-RAS isoform is the most frequently altered RAS protein, being also a difficult therapeutic target. Interestingly, there are two K-RAS splice variants (K-RAS4A and K-RAS4B) and little is known about the role of K-RAS4A. Most studies targeting K-RAS, or analysing it as a prognostic factor, have not taken into account the two isoforms. Consequently, the in-depth investigation of them is needed., Methods: The present study analysed 98 specimens from advanced non-small cell lung cancer (NSCLC) adenocarcinoma patients originated from Brazil. The alterations present in K-RAS at the DNA level (Sanger sequencing) as well as the expression of the splicing isoforms at the RNA (qRT-PCR) and protein levels (immunohistochemistry analysis), were evaluated. Possible associations between clinicopathological features and the molecular findings were also investigated., Results: Our results showed that in the non-smoking population, the cancer incidence was higher among women. In contrast, in smokers and former smokers, the incidence was higher among men. Regarding sequencing results, 10.5% of valid samples presented mutations in exon 2, being all wild-type for exon 3, and the most frequently occurring base change was the transversion G → T. Our qRT-PCR and immunohistochemical analysis showed that both, K-RAS4A and K-RAS4B, were differently expressed in NSCLC tumour samples. For example, tumour specimens showed higher K-RAS4A mRNA expression in relation to commercial normal lung control than did K-RAS4B. In addition, K-RAS4B protein expression was frequently stronger than K-RAS4A in the patients analysed., Conclusion: Our results highlight the differential expression of K-RAS4A and K-RAS4B in advanced adenocarcinoma NSCLC patients and underline the need to further clarify the enigma behind their biological significance in various cancer types, including NSCLC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The process of lung carcinogenesis is still not well understood and involves different levels of regulation of several genes. The search for molecular biomarkers, which can be applicable to clinical practice, has been the focus of various studies. XIAP-associated factor 1 (XAF1) was previously shown to be downregulated in many types of tumors, including squamous cell lung cancer. XAF1 is a pro-apoptotic protein and its restoration was found to sensitize cancer cells to apoptotic stimuli; however, the precise mechanism involved in the downregulation of XAF1 in tumors is unknown and promoter hypermethylation or heat-shock transcription factor 1 (HSF1) may be involved. Therefore, the aim of the present study was to evaluate the expression of XAF1 in tumors and adjacent non-tumor specimens from non-small cell lung cancer (NSCLC) patients, and its potential association with various factors including clinicopathological characteristics and other genes involved in NSCLC. Our results indicated that XAF1 expression was markedly altered in NSCLC tumor samples when compared to that found in normal lung tissues. Predominantly, XAF1 was downregulated in the tumors, except in never-smoker patients. In addition, XAF1 may also be important in the whole cell stress mechanism where the p53 status is crucial.

The enzyme cyclooxygenase 2 (COX-2) is known to be involved in tumorigenesis and metastasis in certain types of cancer. Nevertheless, the prognostic value of COX-2 overexpression and its polymorphisms in patients with non-small cell lung cancer (NSCLC) have yet to be fully elucidated. The aim of the present study was to investigate the association between the three most commonly studied COX-2 gene polymorphisms (-1195 G/A, -765 G/C and 8473 T/C) with COX-2 expression and lung cancer risk in a Brazilian cohort. In the present hospital based, case-control retrospective study, 104 patients with NSCLC and 202 cancer free control subjects were genotyped for -1195 G/A, -765 G/C and 8473 T/C polymorphisms using allelic discrimination with a reverse transcription quantitative polymerase chain reaction method. COX-2 mRNA expression was analyzed in surgically resected tumors from 34 patients with NSCLC. The results revealed that COX-2 expression levels were higher in tumor tissue compared with normal lung tissue. However, this overexpression of COX-2 was not associated with the patient outcome, and furthermore, none of the analyzed polymorphisms were associated with the risk of developing lung cancer, COX-2 overexpression, or the overall survival of the patients with NSCLC. Taken together, the findings described in the present study do not support a major role for COX-2 polymorphisms and COX-2 overexpression in lung carcinogenesis within the Brazilian population.

Giardia intestinalis (G.I), is an anaerobic protozoan and the aetiological agent of giardiasis, a diarrhoea present worldwide and associated with poverty. G.I has a simple life cycle alternating between cyst and trophozoite. Cysts are transmitted orally to the stomach and transform to trophozoites in the intestine by a multifactorial process. Recently, microvesicles (MVs) have been found to be released from a wide range of eukaryotic cells. We have observed a release of MVs during the life cycle of G.I., identifying MVs from active trophozoites and from trophozoites differentiating to the cyst form. The aim of the current work was to investigate the role of MVs from G.I in the pathogenesis of giardiasis. MVs from log phase were able to increase the attachment of G. intestinalis trophozoites to Caco-2 cells. Moreover, MVs from G. intestinalis could be captured by human immature dendritic cells, resulting in increased activation and allostimulation of human dendritic cells. Lipid rafts participate in the MV biogenesis and in the attachment to Caco-2 cells. Nevertheless, proteomic analysis from two types of MVs has shown slight differences at the protein levels. An understanding of biogenesis and content of MVs derived from trophozoites might have important implications in the pathogenesis of the disease., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Colorectal cancer (CRC) is a multifactorial disease resulting from lifestyle, genetic, and environmental factors. There are hereditary and non-hereditary CRC types; however, the majority are non-hereditary and mainly caused by somatic mutations in response to environmental factors. In past years, researchers have focused their attention on the mechanisms behind these factors and the methods of improving disease prevention and treatment. Improving the awareness of the population with regard to the benefits of a healthy lifestyle, including a balanced diet associated with exercise, could globally reduce CRC risk. The present review aims to address the current knowledge on CRC, taking into consideration the common molecular alterations upon different environmental and non-environmental factors, current and promising treatment interventions, and how all these factors may interact to positively or negatively influence CRC risk., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: KRAS mutations are frequently found in colorectal cancer (CRC) indicating the importance of its genotyping in the study of the molecular mechanisms behind this disease. Although major advances have occurred over the past decade, there are still important gaps in our understanding of CRC carcinogenesis, particularly whether sex-linked factors play any role., Methods: The profile of KRAS mutations in the Brazilian population was analyzed by conducting direct sequencing of KRAS codons 12 and 13 belonging to 8,234 metastatic CRC patient samples. DNA was extracted from paraffin-embedded tissue, exon 1 was amplified by PCR and submitted to direct sequencing. The data obtained was analysed comparing different geographical regions, gender and age., Results: The median age was 59 years and the overall percentage of wild-type and mutated KRAS was 62.8% and 31.9%, respectively. Interestingly, different percentages of mutated KRAS patients were observed between male and female patients (32.5% versus 34.8%, respectively; p = 0.03). KRAS Gly12Asp mutation was the most prevalent for both genders and for most regions, with the exception of the North where Gly12Val was the most frequent mutation found., Conclusions: To the best of our knowledge this is one of the largest cohorts of KRAS genotyping in CRC patients and the largest to indicate a higher incidence of KRAS mutation in females compared to males in Brazil. Nevertheless, further research is required to better address the impact of gender differences in colorectal cancer.

Ras proteins operate predominantly from the plasma membrane; however, they have also been localized to most intracellular compartments. Various functions and signaling outputs have been ascribed to endomembranous Ras although systematic comparison and measurement of potential outputs have not yet been carried out. We describe the methodology for isolating and measuring compartment-specific signaling networks using quantitative proteomics. This approach reveals the potential of a subcellular platform for supporting specific outputs and will inform subsequent studies of endogenous isoform-specific Ras signaling., (© 2014 Elsevier Inc. All rights reserved.)

Ras isoforms are membrane bound proteins that differentially localize to the plasma membrane and subcellular compartments within the cell. Whilst the cell surface is the main site for Ras activity the extent to which intracellular pools contribute to Ras function is debated. We have generated Ras chimeras targeting Ras to the ER, Golgi, mitochondria and endosomes to compare the capacity of each of these locations to support activity equivalent to normal Ras function. We find that all locations are capable of regulating the MAP kinase and Akt pathways. Furthermore, whilst endomembranous Ras pools show location-specific competence to support proliferation and transformation, Golgi-Ras is as potent as N-Ras., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Ras GTPases are important regulators of pathways controlling proliferation, differentiation and transformation. Three ubiquitously expressed almost identical Ras genes are not functionally redundant; this has been attributed to their distinctive trafficking and localization profiles. A palmitoylation cycle controls the correct compartmentalization of H-Ras and N-Ras. We review recent data that reveal how this cycle can be regulated by membrane organization to influence the spatiotemporal signalling of Ras.

Background: Insulin stimulates exocytosis of GLUT4 from an intracellular store to the cell surface of fat and muscle cells. Fusion of GLUT4-containing vesicles with the plasma membrane requires the SNARE proteins Syntaxin 4, VAMP2 and the regulatory Sec1/Munc18 protein, Munc18c. Syntaxin 4 and Munc18c form a complex that is disrupted upon insulin treatment of adipocytes. Munc18c is tyrosine phosphorylated in response to insulin in these cells. Here, we directly test the hypothesis that tyrosine phosphorylation of Munc18c is responsible for the observed insulin-dependent abrogation of binding between Munc18c and Syntaxin 4., Results: We show that Munc18c is directly phosphorylated by recombinant insulin receptor tyrosine kinase in vitro. Using pull-down assays, we show that phosphorylation abrogates binding of Munc18c to both Syntaxin 4 and the v-SNARE VAMP2, as does the introduction of a phosphomimetic mutation into Munc18c (Y521E)., Conclusion: Our data indicate that insulin-stimulated tyrosine phosphorylation of Munc18c impairs the ability of Munc18c to bind its cognate SNARE proteins, and may therefore represent a regulatory step in GLUT4 traffic.

Interaction of SM (Sec1/Munc18) proteins with their cognate syntaxins represents an important regulatory mechanism of SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor)-mediated membrane fusion. Understanding the conserved mechanisms by which SM proteins function in this process has proved challenging, largely due to an apparent lack of conservation of binding mechanisms between different SM-syntaxin pairs. In the present study, we have identified a hitherto uncharacterized mode of binding between syntaxin 4 and Munc18c that is independent of the binding mode shown previously to utilize the N-terminal peptide of syntaxin 4. Our data demonstrate that syntaxin 4 and Munc18c interact via two distinct modes of binding, analogous to those employed by syntaxin 1a-Munc18a and syntaxin 16-Vps45p (vacuolar protein sorting 45). These data support the notion that all syntaxin/SM proteins bind using conserved mechanisms, and pave the way for the formulation of unifying hypotheses of SM protein function.

Background: Translocation of the facilitative glucose transporter GLUT4 from an intracellular store to the plasma membrane is responsible for the increased rate of glucose transport into fat and muscle cells in response to insulin. This represents a specialised form of regulated membrane trafficking. Intracellular membrane traffic is subject to multiple levels of regulation by conserved families of proteins in all eukaryotic cells. Notably, all intracellular fusion events require SNARE proteins and Sec1p/Munc18 family members. Fusion of GLUT4-containing vesicles with the plasma membrane of insulin-sensitive cells involves the SM protein Munc18c, and is regulated by the formation of syntaxin 4/SNAP23/VAMP2 SNARE complexes., Methodology/principal Findings: Here we have used biochemical approaches to characterise the interaction(s) of Munc18c with its cognate SNARE proteins and to examine the role of Munc18c in regulating liposome fusion catalysed by syntaxin 4/SNAP23/VAMP2 SNARE complex formation. We demonstrate that Munc18c makes contacts with both t- and v-SNARE proteins of this complex, and directly inhibits bilayer fusion mediated by the syntaxin 4/SNAP23/VAMP2 SNARE complex., Conclusion/significance: Our reductionist approach has enabled us to ascertain a direct inhibitory role for Munc18c in regulating membrane fusion mediated by syntaxin 4/SNAP23/VAMP2 SNARE complex formation. It is important to note that two different SM proteins have recently been shown to stimulate liposome fusion mediated by their cognate SNARE complexes. Given the structural similarities between SM proteins, it seems unlikely that different members of this family perform opposing regulatory functions. Hence, our findings indicate that Munc18c requires a further level of regulation in order to stimulate SNARE-mediated membrane fusion.