Biology subjects

Vargas, A. C.

Publications and source records attributed to Vargas, A. C..

3 recordsLinked to original sources

bioRxiv2021

Epigenome erosion drives neural crest-like phenotypic mimicry in triple-negative breast cancer and other SOX10+ malignancies

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSIntratumoural heterogeneity is a poor prognostic feature in triple-negative breast cancer (TNBC) and other high-grade malignancies. It is caused by genomic instability and phenotypic plasticity, but how these features co-evolve during tumour development remains unclear. SOX10 is a transcription factor, neural crest stem cell (NCSC) specifier and candidate mediator of cancer-associated phenotypic plasticity. MethodsUsing immunophenotyping, we investigated the expression of SOX10 in normal human breast tissue and breast cancer (n=21 cosmetic breast reduction and 1,860 tumour samples with clinical annotation). We then defined the context and evolution of its expression in TNBC compared to 21 other malignancies using systems-level transcriptomics. ResultsSOX10 was detected in nuclei of normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In breast cancer, nuclear SOX10 predicted poor outcome amongst cross-sectional (log-rank p=0.0015, hazard ratio 2.02, n=224) and metaplastic (log-rank p=0.04, n=66) TNBCs. Systems-level transcriptional network analysis identified a core module in SOX10s normal mammary epithelial transcription program that is rewired to NCSC genes in TNBC. Reprogramming was proportional to DNA damage and genome-wide promoter hypomethylation, particularly at CpG island shores. Using a novel network analysis pipeline, we found that NCSC-like transcriptional reprogramming is also strongly associated with promoter hypomethylation in other SOX10+ malignancies: glioma and melanoma. ConclusionsWe propose that cancer-associated genome hypomethylation simulates the open chromatin landscape of more primitive cell states, and that on this relatively unrestricted background, SOX10 recreates its ancestral gene regulatory circuits by default. These findings provide new insights about the basis of intratumoural heterogeneity and resurrection of developmental phenotypes in cancer; and highlight the potential for therapeutics that limit chromatin remodelling.

cancer biology↗

bioRxiv2019

PD-L1 expression in 522 selected sarcomas with subset analysis of recurrent or metastatic matched samples and association with tumour-infiltrating lymphocytes

We assessed the frequency of programmed death-ligand 1 (PD-L1) expression by immunohistochemistry (IHC) in a cohort of 522 sarcomas from 457 patients, incuding a subset of 46 patients with 63 matched samples from local recurrence or metastases with primary tumours and/or metachronous metastases. We also investigated the correlation of PD-L1 with the presence and degree of tumour-infiltrating lymphocytes (TILs) in a subset of cases. IHC was performed using the PD-L1 SP263 companion kit (VENTANA) on tissue microarrays from an archival cohort. Evaluation of PD-L1 and TILs was performed on full sections for a subset of 23 cases. Fishers exact and Mann Whitney test were used to establish significance (P <0.05). PD-L1 positive expression ([≥]1%) was identified in 31% of undifferentiated pleomorphic sarcomas, 29% of angiosarcomas, 26% of rhabdomyosarcomas, 18% of myxofibrosarcomas, 11% of leiomyosarcomas and 10% of dedifferentiated liposarcomas. Negative expression was present in all atypical lipomatous tumous/well-differentiated lipoasarcomas, myxoid liposarcomas, synovial sarcomas, pleomorphic liposarcomas, and Ewing sarcomas. PD-L1 IHC was concordant in 81% (38 of 47) of matched/paired samples. PD-L1 IHC was discordant in 19% (9 of 47 matched/paired samples), displaying differences in the proportion of cells expressing PD-L1 amongst paired samples with the percentage of PD-L1-positive cells increasing in the metastatic/recurrent site compared to the primary in 6 of 9 cases (67%). Significant correlation between PD-L1 expression and the degree of TILs was exclusively identified in the general cohort of leiomyosarcomas, but not in other sarcoma subtypes or in metastatic/recurrent samples. We conclude that the prevalence of PD-L1 expression in selected sarcomas is variable and likely to be clone dependent. Importantly, we demonstrated that PD-L1 can objectively increase in a small proportion of metastases/recurrent sarcomas, offering the potential of treatment benefit to immune checkpoint inhibitors in this metastatic setting.

cancer biology↗

bioRxiv2018

Assessment of abduction movement in older people with painful shoulder: an analysis based on inertial sensors

Reduced range of motion in the shoulder can be a source of functional limitation. Current quantitative evaluation systems are limited to assessing the functionality or the maximum articular amplitudes in each of the planes of movement, both in isolation. These separate clinical evaluation systems may not allow the identification of the underlying impairments contributing to the functional limitation. The use of inertial sensors to quantify movement in addition to more common clinical assessments of the shoulder may allow clinicians to understand that are potentially unnoticed by the human eye. The main objective of this cross-sectional study was to generate an explanatory model for shoulder abduction based on data from inertial sensors. Shoulder abduction of thirteen older adults suffering from shoulder dysfunction was evaluated using two inertial sensors placed on the humerus and scapula. Movement variables (maximum angular mobility, angular peak of velocity, peak of acceleration) were used to explain the functionality of the upper limb (assessed using the Upper Limb Functional Index). Abduction movement of the shoulder was explained by six variables related to the mobility of the shoulder joint complex. A manova analysis was used to explain the results obtained on the functionality of the upper limb. The MANOVA model based on angular mobility explained 69% of the variance of the ULFI value (r-squared=0.69). The most relevant variables were the abduction-adduction of the humerus and the medial and lateral rotation of the scapula. However, given the limited sample size, none of these individual variables were statistically significant in the decomposition model on their own. The method used in the present study reveals the potential importance of the analysis of the scapular and humeral movements for comprehensive evaluation of the upper limb. Further research should include a wider sample and may seek to use this assessment technique in a range of potential clinical applications.

bioengineering↗