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3. Peritumoural adipose tissue pro‐inflammatory cytokines are associated with tumoural growth factors in cancer cachexia patients

Author

Neto, Nelson Inácio Pinto, Murari, Ariene Soares de Pinho, Oyama, Lila Missae, Otoch, José Pinhata, Alcântara, Paulo Sérgio Martins, Tokeshi, Flavio, Figuerêdo, Raquel Galvão, Alves, Michele Joana, Lima, Joanna Darck Carola Correia, de Matos‐Neto, Emídio Marques, Seelaender, Marilia, and Oller do Nascimento, Claudia Maria

Subjects
Male, Proteomics, Cachexia, lcsh:Diseases of the musculoskeletal system, Proteome, Peritumoural adipose tissue, Cancer cachexia, Apoptosis, Original Articles, lcsh:Human anatomy, Middle Aged, lcsh:QM1-695, Adipose Tissue, Neoplasms, Humans, Cytokines, Original Article, Female, Inflammation Mediators, lcsh:RC925-935, Biomarkers, Aged
Abstract

Background Cancer cachexia (CC) is a multifactorial syndrome, often irreversible, that affects patients with cancer influenced, in part, by the inflammatory condition. Peritumoural adipose tissue produces adipokines and angiogenic, apoptotic, and growth factors; given the possible crosstalk between the peritumoural adipose tissue and tumour, these may play an important role in cancer biology and carcinogenesis. Methods The aim of this study was to evaluate the factors produced by peritumoural adipose tissue in a cohort of 16 colorectal cancer patients with either weight‐stable cancer (WSC; n = 7) or CC (n = 9). The study was approved by the Ethics Research Committee (972.914). Samples of peritumoural adipose tissue were analysed for concentrations of TNF‐α, IL‐1β, STAT‐1, STAT‐3, RANTES, IL‐1Ra, IP‐10, IL‐15, MCP‐1, IFN‐α, GCSF, FADD, and TGF‐β. The cytokines and proteins were measured using Multiplex. Correlations between the proteins and cytokines were evaluated. Results TNF‐α, STAT‐1, and FADD, a factor involved in apoptosis, were significantly higher in CC group than in the WSC group. In the peritumoural adipose tissue of the CC group, RANTES showed a significant positive correlation with IL‐1Ra and IP‐10 and a negative correlation with IFN‐α; and GCSF showed significant negative correlations with IL‐1Ra, IP‐10, IL‐15, and MCP‐1 and a positive correlation with IFN‐α. In the peritumoural adipose tissue of the WSC group, no significant correlations were detected between RANTES, GCSF, IL‐3, FADD, and STAT‐1 and the cytokines/chemokines analysed. Conclusions These results indicated that inflammatory and tumorigenic pathways were altered in peritumoural adipose tissue in CC. Furthermore, inflammatory cytokines were correlated with growth factors in the peritumoural adipose tissue of cachectic patients, suggesting that inflammatory cytokines modulated the proliferative environment closely linked to the tumour.

Published
2018

4. Machine learning approaches reveal subtle differences in breathing and sleep fragmentation inPhox2b-derived astrocytes ablated mice

Author

Silva, Talita M., primary, Borniger, Jeremy C., additional, Alves, Michele Joana, additional, Alzate Correa, Diego, additional, Zhao, Jing, additional, Fadda, Paolo, additional, Toland, Amanda Ewart, additional, Takakura, Ana C., additional, Moreira, Thiago S., additional, Czeisler, Catherine M., additional, and Otero, José Javier, additional

Published
2021
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6. Neonatal apneic phenotype in a murine congenital central hypoventilation syndrome model is induced through non‐cell autonomous developmental mechanisms

Author

Alzate‐Correa, Diego, primary, Mei‐ling Liu, Jillian, additional, Jones, Mikayla, additional, Silva, Talita M., additional, Alves, Michele Joana, additional, Burke, Elizabeth, additional, Zuñiga, Jessica, additional, Kaya, Behiye, additional, Zaza, Giuliana, additional, Aslan, Mehmet Tahir, additional, Blackburn, Jessica, additional, Shimada, Marina Y., additional, Fernandes‐Junior, Silvio A., additional, Baer, Lisa A., additional, Stanford, Kristin I., additional, Kempton, Amber, additional, Smith, Sakima, additional, Szujewski, Caroline C., additional, Silbaugh, Abby, additional, Viemari, Jean‐Charles, additional, Takakura, Ana C., additional, Garcia, Alfredo J., additional, Moreira, Thiago S., additional, Czeisler, Catherine M., additional, and Otero, José J., additional

Published
2020
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9. Plasma Lipid Profile and Systemic Inflammation in Patients With Cancer Cachexia

Author

Riccardi, Daniela Mendes dos Reis, primary, das Neves, Rodrigo Xavier, additional, de Matos-Neto, Emidio Marques, additional, Camargo, Rodolfo Gonzalez, additional, Lima, Joanna Darck Carola Correia, additional, Radloff, Katrin, additional, Alves, Michele Joana, additional, Costa, Raquel Galvão Figuerêdo, additional, Tokeshi, Flávio, additional, Otoch, José Pinhata, additional, Maximiano, Linda Ferreira, additional, de Alcantara, Paulo Sérgio Martins, additional, Colquhoun, Alison, additional, Laviano, Alessandro, additional, and Seelaender, Marilia, additional

Published
2020
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11. Machine learning approaches reveal subtle differences in breathing and sleep fragmentation in Phox2b-derived astrocytes ablated mice.

Author

Silva, Talita M., Borniger, Jeremy C., Alves, Michele Joana, Correa, Diego Alzate, Jing Zhao, Fadda, Paolo, Toland, Amanda Ewart, Takakura, Ana C., Moreira, Thiago S., Czeisler, Catherine M., and Otero, Jose Javier

Abstract

Modern neurophysiology research requires the interrogation of high-dimensionality data sets. Machine learning and artificial intelligence (ML/AI) workflows have permeated into nearly all aspects of daily life in the developed world but have not been implemented routinely in neurophysiological analyses. The power of these workflows includes the speed at which they can be deployed, their availability of open-source programming languages, and the objectivity permitted in their data analysis. We used classification-based algorithms, including random forest, gradient boosted machines, support vector machines, and neural networks, to test the hypothesis that the animal genotypes could be separated into their genotype based on interpretation of neurophysiological recordings. We then interrogate the models to identify what were the major features utilized by the algorithms to designate genotype classification. By using raw EEG and respiratory plethysmography data, we were able to predict which recordings came from genotype class with accuracies that were significantly improved relative to the no information rate, although EEG analyses showed more overlap between groups than respiratory plethysmography. In comparison, conventional methods where single features between animal classes were analyzed, differences between the genotypes tested using baseline neurophysiology measurements showed no statistical difference. However, ML/AI workflows successfully were capable of providing successful classification, indicating that interactions between features were different in these genotypes. ML/AI workflows provide new methodologies to interrogate neurophysiology data. However, their implementation must be done with care so as to provide high rigor and reproducibility between laboratories. We provide a series of recommendations on how to report the utilization of ML/AI workflows for the neurophysiology community. [ABSTRACT FROM AUTHOR]

Published
2021
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12. Development of a novel FIJI-based method to investigate neuronal circuitry in neonatal mice

Author

Liu, Jillian Mei-ling, Fair, Summer Rose, Kaya, Behiye, Zuniga, Jessica Nabile, Mostafa, Hasnaa Rashad, Alves, Michele Joana, Stephens, Julie A., Jones, Mikayla, Aslan, M. Tahir, Czeisler, Catherine, and Otero, José Javier

Subjects
Neurons, Medulla Oblongata, Homeobox Protein Nkx-2.2, Respiration, Basic Helix-Loop-Helix Transcription Factors, Animals, Mice, Transgenic, Nerve Net, Article
Abstract

The emergence of systems neuroscience tools requires parallel generation of objective analytical workflows for experimental neuropathology. We developed an objective analytical workflow that we used to determine how specific autonomic neural lineages change during postnatal development. While a wealth of knowledge exists regarding postnatal alterations in respiratory neural function, how these neural circuits change and develop in the weeks following birth remains less clear. In this study, we developed our workflow by combining genetic mouse modeling and quantitative immunofluorescent confocal microscopy and used this to examine the postnatal development of neural circuits derived from the transcription factors NKX2.2 and OLIG3 into three medullary respiratory nuclei. Our automated FIJI-based image analysis workflow rapidly and objectively quantified synaptic puncta in user-defined anatomic regions. Using our objective workflow, we found that the density and estimated total number of Nkx2.2-derived afferents into the pre-Bötzinger Complex significantly decreased with postnatal age during the first three weeks of postnatal life. These data indicate that Nkx2.2-derived structures differentially influence pre-Bötzinger Complex respiratory oscillations at different stages of postnatal development.

Published
2018

13. Topical Insulin Modulates Inflammatory and Proliferative Phases of Burn-Wound Healing in Diabetes-Induced Rats

Author

Azevedo, Flávia Figueiredo, primary, Moreira, Gabriela Virgínia, additional, Teixeira, Caio Jordão, additional, Pessoa, Ana Flávia Marçal, additional, Alves, Michele Joana, additional, Liberti, Edson Aparecido, additional, Carvalho, Carla Roberta Oliveira, additional, Araújo, Eliana Pereira, additional, Saad, Mário José Abdala, additional, and Lima, Maria Helena Melo, additional

Published
2019
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16. Neonatal apneic phenotype in a murine congenital central hypoventilation syndrome model is induced through non‐cell autonomous developmental mechanisms.

Author

Alzate‐Correa, Diego, Mei‐ling Liu, Jillian, Jones, Mikayla, Silva, Talita M., Alves, Michele Joana, Burke, Elizabeth, Zuñiga, Jessica, Kaya, Behiye, Zaza, Giuliana, Aslan, Mehmet Tahir, Blackburn, Jessica, Shimada, Marina Y., Fernandes‐Junior, Silvio A., Baer, Lisa A., Stanford, Kristin I., Kempton, Amber, Smith, Sakima, Szujewski, Caroline C., Silbaugh, Abby, and Viemari, Jean‐Charles

Subjects
PHENOTYPES, HYPOVENTILATION, NEURON development, GENETIC disorders, REFLEXES, MOTOR neurons, MOTOR neuron diseases, SPLANCHNIC nerves
Abstract

Congenital central hypoventilation syndrome (CCHS) represents a rare genetic disorder usually caused by mutations in the homeodomain transcription factor PHOX2B. Some CCHS patients suffer mainly from deficiencies in CO2 and/or O2 respiratory chemoreflex, whereas other patients present with full apnea shortly after birth. Our goal was to identify the neuropathological mechanisms of apneic presentations in CCHS. In the developing murine neuroepithelium, Phox2b is expressed in three discrete progenitor domains across the dorsal‐ventral axis, with different domains responsible for producing unique autonomic or visceral motor neurons. Restricting the expression of mutant Phox2b to the ventral visceral motor neuron domain induces marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, and preBötzinger complex dysfunction. This finding suggests that the observed apnea develops through non‐cell autonomous developmental mechanisms. Mutant Phox2b expression in dorsal rhombencephalic neurons did not generate significant respiratory dysfunction, but did result in subtle metabolic thermoregulatory deficiencies. We confirm the expression of a novel murine Phox2b splice variant which shares exons 1 and 2 with the more widely studied Phox2b splice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutant Phox2b expression in the visceral motor neuron progenitor domain increases cell proliferation at the expense of visceral motor neuron development. We propose that visceral motor neurons may function as organizers of brainstem respiratory neuron development, and that disruptions in their development result in secondary/non‐cell autonomous maldevelopment of key brainstem respiratory neurons. [ABSTRACT FROM AUTHOR]

Published
2021
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19. Adipose tissue fibrosis in human cancer cachexia: the role of TGFβ pathway

Author

Alves, Michele Joana, primary, Figuerêdo, Raquel Galvão, additional, Azevedo, Flavia Figueiredo, additional, Cavallaro, Diego Alexandre, additional, Neto, Nelson Inácio Pinto, additional, Lima, Joanna Darck Carola, additional, Matos-Neto, Emidio, additional, Radloff, Katrin, additional, Riccardi, Daniela Mendes, additional, Camargo, Rodolfo Gonzalez, additional, De Alcântara, Paulo Sérgio Martins, additional, Otoch, José Pinhata, additional, Junior, Miguel Luiz Batista, additional, and Seelaender, Marília, additional

Published
2017
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22. Neuropathologists play a key role in establishing the extent of COVID-19 in human patients.

Author

Cevik L, Alves MJ, and Otero JJ

Abstract

SARS-CoV2 infection causes COVID-19, and represents the most emergent health care crisis of our generation. Ample evidence in the scientific literature suggests that SARS-CoV, MERS-CoV, and endemic human coronaviruses infect brain cells. We delineate a rationale for encouraging evaluation of the brain, and in particular the brainstem, in COVID-19 so that potential neuropathological mechanisms can be delineated.

Published
2020
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