ANÁLISE IN SILICO DO PROCESSO DE REGENERAÇÃO CELULAR ATRAVÉS DA INTERAÇÃO PIWI/PIRNA EM MUS MUSCULUS

Cell and tissue regeneration, much discussed in various areas of medicine and biology, still has gaps in its processes and functioning. In the last decade, the role of epigenetics in this function has been elucidated, with emphasis on non-coding RNAs, including piRNAs (PIWI-interacting RNAs), previously known for their role in germ cells and in controlling transposable elements. Recent studies have demonstrated piRNA functions in somatic tissue cells, such as the nervous system, and research in small rodents, especially Mus musculus, has indicated an important link between the expression of this pathway and the correct functioning of the regeneration process. As it is a relevant challenge for regenerative medicine to understand these processes, through the robust studies described here and using Bioinformatics tools, protein-protein interaction networks (PPIN) were built to identify target proteins for therapeutic treatments based on the functioning of the PIWI/piRNA gene pathway in Mus musculus. By analyzing these networks, we were able to identify relevant proteins, as well as their interactions, for the regenerative process in mammals and, with these results, in the future we will be able to develop in vivo tests based on the data obtained in silico, thus saving time and financial investment.La regeneración celular y tisular, muy discutida en diversos ámbitos de la medicina y la biología, aún presenta lagunas en cuanto a sus procesos y funcionamiento. En la última década se ha dilucidado el papel de la epigenética en esta función, con énfasis en los ARN no codificantes, entre ellos los piARN (ARN que interactúan con PIWI), antes conocidos por su papel en las células germinales y en el control de los elementos transponibles. Estudios recientes han demostrado las funciones de los piRNAs en células de tejidos somáticos, como el sistema nervioso, y la investigación en pequeños roedores, especialmente Mus musculus, ha indicado un importante vínculo entre la expresión de esta vía y el correcto funcionamiento del proceso de regeneración. Dado que entender estos procesos es un reto relevante para la medicina regenerativa, a través de los robustos estudios aquí descritos y utilizando herramientas de Bioinformática, se construyeron redes de interacción proteína-proteína (PPIN) para identificar proteínas diana para tratamientos terapéuticos basados en el funcionamiento de la vía génica PIWI/piRNA en Mus musculus. Mediante el análisis de estas redes, pudimos identificar proteínas relevantes, así como sus interacciones, para el proceso regenerativo en mamíferos y, con estos resultados, en el futuro podremos desarrollar ensayos in vivo basados en los datos obtenidos in silico, ahorrando así tiempo e inversión económica.A regeneração celular e tecidual, muito abordada em diversas áreas da medicina e da biologia, ainda permanece com lacunas sobre seus processos e funcionamento. Na última década, elucidou-se o papel da epigenética na referida função, dando-se ênfase para RNAs não codificantes, e entre eles, os piRNAs (PIWI-interacting RNAs), antes conhecidos por sua atuação em células germinativas e no controle de elementos transponíveis. Estudos recentes demonstraram funções dos piRNA em células de tecidos somáticos, como o nervoso, e pesquisas com pequenos roedores, especialmente em Mus musculus, apontaram uma importante ligação entre a expressão dessa via e o correto funcionamento do processo de regeneração. Por ser um desafio relevante para a medicina regenerativa entender esses processos, através de estudos robustos aqui descritos e utilizando ferramentas de Bioinformática, construiu-se redes de interação proteína-proteína (PPIN) para identificar proteínas-alvo para tratamentos terapêuticos com base no funcionamento da via do gene PIWI/piRNA em Mus musculus. A partir da análise dessas redes, conseguimos identificar proteínas relevantes, assim como suas interações, para o processo regenerativo em mamíferos e, com esses resultados, futuramente, poder-se-á desenvolver testes in vivo com base nos dados obtidos in silico, economizando, assim, tempo e investimentos financeiros.A regeneração celular e tecidual, muito abordada em diversas áreas da medicina e da biologia, ainda permanece com lacunas sobre seus processos e funcionamento. Na última década, elucidou-se o papel da epigenética na referida função, dando-se ênfase para RNAs não codificantes, e entre eles, os piRNAs (PIWI-interacting RNAs), antes conhecidos por sua atuação em células germinativas e no controle de elementos transponíveis. Estudos recentes demonstraram funções dos piRNA em células de tecidos somáticos, como o nervoso, e pesquisas com pequenos roedores, especialmente em Mus musculus, apontaram uma importante ligação entre a expressão dessa via e o correto funcionamento do processo de regeneração. Por ser um desafio relevante para a medicina regenerativa entender esses processos, através de estudos robustos aqui descritos e utilizando ferramentas de Bioinformática, construiu-se redes de interação proteína-proteína (PPIN) para identificar proteínas-alvo para tratamentos terapêuticos com base no funcionamento da via do gene PIWI/piRNA em Mus musculus. A partir da análise dessas redes, conseguimos identificar proteínas relevantes, assim como suas interações, para o processo regenerativo em mamíferos e, com esses resultados, futuramente, poder-se-á desenvolver testes in vivo com base nos dados obtidos in silico, economizando, assim, tempo e investimentos financeiros

Computational biology helps understand how polyploid giant cancer cells drive tumor success

Precision and organization govern the cell cycle, ensuring normal proliferation. However, some cells may undergo abnormal cell divisions (neosis) or variations of mitotic cycles (endopolyploidy). Consequently, the formation of polyploid giant cancer cells (PGCCs), critical for tumor survival, resistance, and immortalization, can occur. Newly formed cells end up accessing numerous multicellular and unicellular programs that enable metastasis, drug resistance, tumor recurrence, and self-renewal or diverse clone formation. An integrative literature review was carried out, searching articles in several sites, including: PUBMED, NCBI-PMC, and Google Academic, published in English, indexed in referenced databases and without a publication time filter, but prioritizing articles from the last 3 years, to answer the following questions: (i) “What is the current knowledge about polyploidy in tumors?”; (ii) “What are the applications of computational studies for the understanding of cancer polyploidy?”; and (iii) “How do PGCCs contribute to tumorigenesis?

Prognostic Factors and Markers in Non-Small Cell Lung Cancer: Recent Progress and Future Challenges

Lung cancer is a highly aggressive neoplasm and, despite the development of recent therapies, tumor progression and recurrence following the initial response remains unsolved. Several questions remain unanswered about non-small cell lung cancer (NSCLC): (1) Which patients will actually benefit from therapy? (2) What are the predictive factors of response to MAbs and TKIs? (3) What are the best combination strategies with conventional treatments or new antineoplastic drugs? To answer these questions, an integrative literature review was carried out, searching articles in PUBMED, NCBI-PMC, Google Academic, and others. Here, we will examine the molecular genetics of lung cancer, emphasizing NSCLC, and delineate the primary categories of inhibitors based on their molecular targets, alongside the main treatment alternatives depending on the type of acquired resistance. We highlighted new therapies based on epigenetic information and a single-cell approach as a potential source of new biomarkers. The current and future of NSCLC management hinges upon genotyping correct prognostic markers, as well as on the evolution of precision medicine, which guarantees a tailored drug combination with precise targeting

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research