Breast Cancer Cells Reprogram the Oncogenic lncRNAs/mRNAs Coexpression Networks in Three-Dimensional Microenvironment.

Organotypic three-dimensional (3D) cell cultures more accurately mimic the characteristics of solid tumors in vivo in comparison with traditional two-dimensional (2D) monolayer cell models. Currently, studies on the regulation of long non-coding RNAs (lncRNAs) have not been explored in breast cancer cells cultured in 3D microenvironments. In the present research, we studied the expression and potential roles of lncRNAs in estrogen receptor-positive luminal B subtype BT-474 breast cancer cells grown over extracellular matrix proteins-enriched 3D cultures. Global expression profiling using DNA microarrays identifies 290 upregulated and 183 downregulated lncRNAs in 3D cultures relative to 2D condition. Using a co-expression analysis approach of lncRNAs and mRNAs pairs expressed in the same experimental conditions, we identify hundreds of regulatory axes modulating genes involved in cancer hallmarks, such as responses to estrogens, cell proliferation, hypoxia, apical junctions, and resistance to endocrine therapy. In addition, we identified 102 lncRNAs/mRNA correlations in 3D cultures, which were similar to those reported in TCGA datasets obtained from luminal B breast cancer patients. Interestingly, we also found a set of mRNAs transcripts co-expressed with LINC00847 and CTD-2566J3.1 lncRNAs, which were predictors of pathologic complete response and overall survival. Finally, both LINC00847 and CTD -2566J3.1 were co-expressed with essential genes for cancer genetic dependencies, such as FOXA1 y GINS2. Our experimental and predictive findings show that co-expressed lncRNAs/mRNAs pairs exhibit a high degree of similarity with those found in luminal B breast cancer patients, suggesting that they could be adequate pre-clinical tools to identify not only biomarkers related to endocrine therapy response and PCR, but to understand the biological behavior of cancer cells in 3D microenvironments.

Urinary serpin-A3 is an early predictor of clinical response to therapy in patients with proliferative lupus nephritis.

We have previously reported that urinary excretion of serpin-A3 (uSerpA3) is significantly elevated in patients with active lupus nephritis (LN). Here, we evaluated the course of uSerpA3 during the first year of treatment and its association with response to therapy in patients with proliferative LN. The observational longitudinal study included 60 Mexican adults with proliferative LN followed during the first year after LN flare. uSerpA3 was detected by Western blot analysis at flare and after 3, 6, and 12 mo. The response to therapy was determined 1 yr after the LN flare. We evaluated the correlation between uSerpA3 and histological parameters at LN flare. The temporal association between uSerpA3 and response to therapy was analyzed with linear mixed models. uSerpA3 prognostic performance for response was evaluated with receiver-operating characteristic curves. Among the 60 patients studied, 21 patients (35%) were class III and 39 patients (65%) were class IV. uSerpA3 was higher in class IV than in class III LN (6.98 vs. 2.89 dots per in./mg creatinine, P = 0.01). Furthermore, uSerpA3 correlated with the histological activity index (r = 0.29, P = 0.02). There was a significant association between the temporal course of uSerpA3 and response to therapy. Responders showed a significant drop in uSerpA3 at 6 mo compared with LN flare (P < 0.001), whereas nonresponders persisted with elevated uSerpA3. Moreover, uSerpA3 was significantly lower at flare in responders compared with nonresponders (2.69 vs. 6.98 dots per in./mg creatinine, P < 0.05). Furthermore, uSerpA3 was able to identify nonresponders since 3 mo after LN flare (area under the curve: 0.77). In conclusion, uSerpA3 is an early indicator of kidney inflammation and predictor of the clinical response to therapy in patients with proliferative LN.NEW & NOTEWORTHY LN requires aggressive immunosuppression to improve long-term outcomes. Current indicators of remission take several months to normalize, prolonging treatment regiments in some cases. Serpin-A3 is present in urine of patients with proliferative LN. We evaluated the excretion of serpin-A3 in serial samples of patients with proliferative LN during the first year after flare. We found that uSerpA3 correlates with kidney inflammation and its decline at early points predicts the response to therapy 1 yr after flare.

Three-Dimensional 3D Culture Models in Gynecological and Breast Cancer Research.

Traditional two-dimensional (2D) monolayer cell cultures have long been the gold standard for cancer biology research. However, their ability to accurately reflect the molecular mechanisms of tumors occurring in vivo is limited. Recent development of three-dimensional (3D) cell culture models facilitate the possibility to better recapitulate several of the biological and molecular characteristics of tumors in vivo, such as cancer cells heterogeneity, cell-extracellular matrix interactions, development of a hypoxic microenvironment, signaling pathway activities depending on contacts with extracellular matrix, differential growth kinetics, more accurate drugs response, and specific gene expression and epigenetic patterns. In this review, we discuss the utilization of different types of 3D culture models including spheroids, organotypic models and patient-derived organoids in gynecologic cancers research, as well as its potential applications in oncological research mainly for screening drugs with major physiological and clinical relevance. Moreover, microRNAs regulation of cancer hallmarks in 3D cell cultures from different types of cancers is discussed.

A novel immune-related RNA-binding proteins signature to predict survival and therapeutic responses in prostate cancer.

BACKGROUND: The present study aims to identify immune-related RBPs signature to predict prognosis and therapy response in prostate cancer. METHODS: Differentially expressed RBPs were compared and visualized using R packages. Immune-related RBPs were selected by Pearson correlation analysis. The prognostic immune-related RBPs were identified using the Kaplan-Meier method and LASSO regression. A multivariable Cox regression model was used to construct immune-related RBPs signature. RESULTS: We constructed a prognostic predictive risk model of prostate cancer containing ten immune-related RBP genes. We found that high-risk prostate cancer patients presented poorer prognosis, higher tumor immune cell infiltration, higher rates of genomic alterations, and were more sensitive to targeted and immunotherapy than the low-risk group. CONCLUSIONS: The immune-related RBPs' signature is an independent prognostic marker that could help screen patients with advanced prostate cancer who are better suited for targeted and immunotherapy.

Circulating MicroRNAs in Blood and Other Body Fluids as Biomarkers for Diagnosis, Prognosis, and Therapy Response in Lung Cancer.

The identification of circulating microRNAs (miRNAs) in peripheral blood and other body fluids has led to considerable research interest in investigating their potential clinical application as non-invasive biomarkers of cancer, including lung cancer, the deadliest malignancy worldwide. Several studies have found that alterations in the levels of miRNAs in circulation are able to discriminate lung cancer patients from healthy individuals (diagnosis) and are associated with patient outcome (prognosis) and treatment response (prediction). Increasing evidence indicates that circulating miRNAs may function as mediators of cell-to-cell communication, affecting biological processes associated with tumor initiation and progression. This review is focused on the most recent studies that provide evidence of the potential value of circulating miRNAs in blood and other body fluids as non-invasive biomarkers of lung cancer in terms of diagnosis, prognosis, and response to treatment. The status of their potential clinical application in lung cancer is also discussed, and relevant clinical trials were sought and are described. Because of the relevance of their biological characteristics and potential value as biomarkers, this review provides an overview of the canonical biogenesis, release mechanisms, and biological role of miRNAs in lung cancer.

The role of radionuclide probes for monitoring anti-tumor drugs efficacy: A brief review.

Despite recent advances in the development of new therapeutic agents and diagnostic imaging modalities, cancer is still one of the main causes of death worldwide. A better understanding of the molecular signature of cancer has promoted the development of a new generation of anti-cancer drugs and diagnostic agents that specifically target molecular components such as genes, ligands, receptors and signaling pathways. However, intrinsic heterogeneity of tumors has hampered the overall success of target therapies even among patients with similar tumor types but unpredictable different responses to therapy. In this sense, post-treatment response monitoring becomes indispensable and nuclear medicine imaging modalities could provide the tools for an early indication of therapeutic efficacy. Herein, we briefly discuss the current role of PET and SPECT imaging in monitoring cancer therapy together with an update on the current radiolabeled probes that are currently investigated for tumor therapy response assessment.

AIM2 inflammasome is associated with disease severity in tegumentary leishmaniasis caused by Leishmania (V.) braziliensis.

The inflammasome is a multiprotein signalling platform involved in the pathogenesis of various inflammatory skin diseases. Herein, we investigated gene and protein expression of the inflammasome molecules AIM2 and NLRP3 in active lesions from patients with L. (V.) braziliensis-associated tegumentary leishmaniasis (TL) and correlated these findings with the clinical presentations and responses to therapy. Real-time PCR assays showed a significantly higher AIM2 gene expression in mucosal leishmaniasis (ML) compared with that in cutaneous leishmaniasis (CL). Additionally, AIM2 mRNA expression was significantly higher in lesions from poor responders than in lesions from good responders. In situ protein quantification analyses revealed greater AIM2 expression in ML lesions than in CL lesions. The percentage of AIM2-producing cells was higher in poor responders than in good responders. Although not quite significant, IL-1ß+ cells were slightly more prominent in poor responders than in good responders. Similar results were observed when patients were evaluated according to clinical form. GP63 immunostaining was identified in all samples, but no significant variation between mucosal and cutaneous lesions was observed. GP63 could be associated with reduced NLRP3 inflammasome expression in CL and ML patients. Taken together, these data demonstrate that AIM2 is an important component of the inflammasome in TL patients and is directly associated with the severity of lesions.

Neuron-specific enolase and response to initial therapy are important prognostic factors in patients with small cell lung cancer.

PURPOSE: The prognostic factors for the survival of small cell lung cancer (SCLC) patients are still widely debated. The aim of this study was to identify the clinical features and prognostic factors in SCLC patients. METHODS: A retrospective study was conducted on SCLC patients who were treated in our hospital between July 2010 and July 2015. Comparison of overall survival (OS) was performed using the Kaplan-Meier method. Prognostic factors for OS were identified by multivariate Cox regression models. RESULTS: A total of 523 patients with complete data and ECOG 0-2 were enrolled in our study. A total of 383 patients (73.2%) were diagnosed with ES-SCLC (extensive-stage SCLC) and 140 patients (26.8%) were diagnosed with LS-SCLC (limited-stage SCLC). In all patients, early disease stage, good ECOG, normal neuron-specific enolase (NSE), thoracic radiotherapy, ≥4 cycles of chemotherapy, prophylactic cranial irradiation, good response to initial therapy were independent favorable prognostic factors for OS, along with gender, age, CEA and CA125. In LS-SCLC patients, normal NSE, normal CEA, good response to initial therapy and surgery were independent favorable prognostic factors for OS. In ES-SCLC patients, good ECOG, normal NSE, thoracic radiotherapy, ≥4 cycles of chemotherapy, prophylactic cranial irradiation and good response to initial therapy were independent favorable prognostic factors for OS. Remarkably, NSE and response to initial therapy were independent prognostic factors for OS in all SCLC patients, LS-SCLC patients and ES-SCLC patients. CONCLUSION: The normal NSE and good response to initial therapy predicted a better survival for SCLC patients, regardless of disease stage.