Growth model analysis of wild hyacinth macaw (Anodorhynchus hyacinthinus) nestlings based on long-term monitoring in the Brazilian Pantanal.

Studies on the breeding of vulnerable and endangered bird species are hindered by low numbers of individuals, inaccessible location of nests, unfavourable environmental conditions, and complex behavioural patterns. In addition, intraspecific variation may emerge only following long-term, systematic observations of little-known patterns and processes. Here, data collected over 30 years were used to determine growth model of hyacinth macaw (Anodorhynchus hyacinthinus) chicks in the Pantanal biome of Brazil. During this period, the speed of growth and body mass of chicks varied widely. Four growth models were tested: logistic, Gompertz, Richards, and cubic polynomial. They were fitted using three biometric measurements: body mass, total length, and tail length. The best-fitting growth curves were identified using Akaike's information criterion. The best models were the cubic polynomial for body mass, Richards for total length, and Gompertz for tail length. We confirmed the occurrence of dwarf individuals, whose body mass, total length, and tail length were 20%, 22%, and 70% smaller, respectively, than in the overall population. The dwarfs remain small in size after having fledged and are easily identified as adults. We discuss the importance of long-term studies to identify windows of opportunity for further research that will help in the conservation of endangered macaw species.

Dual function of Langerhans cells in skin TSLP-promoted TFH differentiation in mouse atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is among the most common chronic inflammatory skin diseases, usually occurring early in life, and often preceding other atopic diseases such as asthma. TH2 has been believed to play a crucial role in cellular and humoral response in AD, but accumulating evidence has shown that follicular helper T cell (TFH), a critical player in humoral immunity, is associated with disease severity and plays an important role in AD pathogenesis. OBJECTIVES: This study aimed at investigating how TFHs are generated during the pathogenesis of AD, particularly what is the role of keratinocyte-derived cytokine TSLP and Langerhans cells (LCs). METHODS: Two experimental AD mouse models were employed: (1) triggered by the overproduction of TSLP through topical application of MC903, and (2) induced by epicutaneous allergen ovalbumin (OVA) sensitization. RESULTS: This study demonstrated that the development of TFHs and germinal center (GC) response were crucially dependent on TSLP in both the MC903 model and the OVA sensitization model. Moreover, we found that LCs promoted TFH differentiation and GC response in the MC903 model, and the depletion of Langerin+ dendritic cells (DCs) or selective depletion of LCs diminished the TFH/GC response. By contrast, in the model with OVA sensitization, LCs inhibited TFH/GC response and suppressed TH2 skin inflammation and the subsequent asthma. Transcriptomic analysis of Langerin+ and Langerin- migratory DCs revealed that Langerin+ DCs became activated in the MC903 model, whereas these cells remained inactivated in OVA sensitization model. CONCLUSIONS: Together, these studies revealed a dual functionality of LCs in TSLP-promoted TFH and TH2 differentiation in AD pathogenesis.

Lipidic Aminoglycoside Derivatives: A New Class of Immunomodulators Inducing a Potent Innate Immune Stimulation.

Development of simple and fully characterized immunomodulatory molecules is an active area of research to enhance current immunotherapies. Monophosphoryl lipid A (MPL), a nontoxic lipidic derivative from bacteria, is the first and currently only adjuvant approved in humans. However, its capacity to induce a potent response against weak immunogenic tumoral-associated antigens remains limited. Herein, a new generation of lipidic immunomodulators to conduct a structure-activity relationship study to determine the minimal structural elements conferring immunomodulatory properties is introduced. Two lead molecules characterized by a short succinyl linker between two oleyl chains and a polar headgroup consisting of either naturally occurring tobramycin (DOST) or kanamycin (DOSK) are identified. These two lipoaminoglycosides self-assemble in very small vesicles. In a wide variety of cells including 3D human cell culture, DOST and DOSK induce the upregulation of proinflammatory cytokines and interferon-inducible proteins in a dose and time-dependent manner via a caveolae-dependent proinflammatory mechanism and phosphatidylinositol phospholipase C activation. Furthermore, after intratumoral administration, these lipoaminoglycosides induce an efficient immune response leading to significant antitumor activity in a mouse breast cancer model. Altogether, these findings indicate that DOST and DOSK are two groundbreaking synthetic lipid immunostimulators that can be used as adjuvants to enhance current immunotherapeutic treatments.

A mouse model featuring tissue-specific deletion of p53 and Brca1 gives rise to mammary tumors with genomic and transcriptomic similarities to human basal-like breast cancer.

PURPOSE AND METHODS: In human basal-like breast cancer, mutations and deletions in TP53 and BRCA1 are frequent oncogenic events. Thus, we interbred mice expressing the CRE-recombinase with mice harboring loxP sites at TP53 and BRCA1 (K14-Cre; p53f/f Brca1f/f) to test the hypothesis that tissue-specific deletion of TP53 and BRCA1 would give rise to tumors reflective of human basal-like breast cancer. RESULTS: In support of our hypothesis, these transgenic mice developed tumors that express basal-like cytokeratins and demonstrated intrinsic gene expression features similar to human basal-like tumors. Array comparative genomic hybridization revealed a striking conservation of copy number alterations between the K14-Cre; p53f/f Brca1f/f mouse model and human basal-like breast cancer. Conserved events included MYC amplification, KRAS amplification, and RB1 loss. Microarray analysis demonstrated that these DNA copy number events also led to corresponding changes in signatures of pathway activation including high proliferation due to RB1 loss. K14-Cre; p53f/f Brca1f/f also matched human basal-like breast cancer for a propensity to have immune cell infiltrates. Given the long latency of K14-Cre; p53f/f Brca1f/f tumors (~ 250 days), we created tumor syngeneic transplant lines, as well as in vitro cell lines, which were tested for sensitivity to carboplatin and paclitaxel. These therapies invoked acute regression, extended overall survival, and resulted in gene expression signatures of an anti-tumor immune response. CONCLUSION: These findings demonstrate that this model is a valuable preclinical resource for the study of human basal-like breast cancer.

Satisfaction of Emergency Physicians with the Care Provided to Patients with Cardiovascular Diseases in the Northern Region of Minas Gerais.

BACKGROUND: The dissatisfaction of health professionals in emergency services has a negative influence on both the quality of care provided for acute myocardial infarction (AMI) patients and the retention of those professionals. OBJECTIVE: To assess physicians' satisfaction with the structure of care and diagnosis at the emergency services in the Northern Region of Minas Gerais before the implementation of the AMI system of care. METHODS: This cross-sectional study included physicians from the emergency units of the ambulance service (SAMU) and level II, III and IV regional hospitals. Satisfaction was assessed by using the CARDIOSATIS-Team scale. The median score for each item, the overall scale and the domains were calculated and then compared by groups using the non-parametric Mann-Whitney test. Correlation between time since graduation and satisfaction level was assessed using Spearman correlation. A p value < 0.05 was considered significant. RESULTS: Of the 137 physicians included in the study, 46% worked at SAMU. Most of the interviewees showed overall dissatisfaction with the structure of care, and the median score for the overall scale was 2.0 [interquartile range (IQR) 2.0-4.0]. Most SAMU physicians expressed their dissatisfaction with the care provided (54%), the structure for managing cardiovascular diseases (52%), and the technology available for diagnosis (54%). The evaluation of the overall satisfaction evidenced that the dissatisfaction of SAMU physicians was lower when compared to that of hospital emergency physicians. Level III/IV hospital physicians expressed greater overall satisfaction when compared to level II hospital physicians. CONCLUSION: This study showed the overall dissatisfaction of the emergency physicians in the region assessed with the structure of care for cardiovascular emergencies.

Satisfaction of Emergency Physicians with the Care Provided to Patients with Cardiovascular Diseases in the Northern Region of Minas Gerais / Satisfação de Médicos dos Serviços de Urgência com o Cuidado às Doenças Cardiovasculares na Região Ampliada Norte de Minas Gerais

Abstract Background: The dissatisfaction of health professionals in emergency services has a negative influence on both the quality of care provided for acute myocardial infarction (AMI) patients and the retention of those professionals. Objective: To assess physicians' satisfaction with the structure of care and diagnosis at the emergency services in the Northern Region of Minas Gerais before the implementation of the AMI system of care. Methods: This cross-sectional study included physicians from the emergency units of the ambulance service (SAMU) and level II, III and IV regional hospitals. Satisfaction was assessed by using the CARDIOSATIS-Team scale. The median score for each item, the overall scale and the domains were calculated and then compared by groups using the non-parametric Mann-Whitney test. Correlation between time since graduation and satisfaction level was assessed using Spearman correlation. A p value < 0.05 was considered significant. Results: Of the 137 physicians included in the study, 46% worked at SAMU. Most of the interviewees showed overall dissatisfaction with the structure of care, and the median score for the overall scale was 2.0 [interquartile range (IQR) 2.0-4.0]. Most SAMU physicians expressed their dissatisfaction with the care provided (54%), the structure for managing cardiovascular diseases (52%), and the technology available for diagnosis (54%). The evaluation of the overall satisfaction evidenced that the dissatisfaction of SAMU physicians was lower when compared to that of hospital emergency physicians. Level III/IV hospital physicians expressed greater overall satisfaction when compared to level II hospital physicians. Conclusion: This study showed the overall dissatisfaction of the emergency physicians in the region assessed with the structure of care for cardiovascular emergencies.

Resumo Fundamentos: A insatisfação dos profissionais de saúde dos serviços de urgência tem influência negativa na qualidade do cuidado ao infarto agudo do miocárdio (IAM) e na fixação desses profissionais. Objetivo: Avaliar a satisfação de médicos com a estrutura de atendimento e diagnóstico de serviços públicos de urgência na Região Ampliada Norte de Minas Gerais, previamente à implantação da linha de cuidado ao IAM. Métodos: Estudo transversal, que incluiu médicos das unidades de emergência do SAMU e de hospitais regionais nível II, III e IV. Foi avaliada a satisfação usando a escala CARDIOSATIS-Team. O escore mediano para cada item, a escala global e os domínios foram calculados e então comparados por grupos, utilizando o teste não paramétrico de Mann-Whitney. Foi avaliada a correlação entre tempo de formação e nível de satisfação com o método de Spearman. Um valor-p < 0,05 foi considerado significativo. Resultados: De 137 médicos incluídos, 46% trabalhavam no SAMU. A maior parte dos entrevistados demonstrou insatisfação geral com a estrutura de atendimento, cuja mediana da escala global foi 2,0 (intervalo interquartil [IQ] 2,0-4,0). A maioria dos médicos do SAMU demonstrou-se insatisfeita quanto a atendimento prestado (54%), estrutura para condução das doenças cardiovasculares (52%) e tecnologia disponível para diagnóstico (54%). Na avaliação da satisfação global, evidenciou-se que a insatisfação dos médicos do SAMU foi menor quando comparada à dos médicos de urgência hospitalar. Os médicos de hospitais nível III/IV demonstraram maior satisfação global quando comparados aos de hospitais nível II. Conclusão: Este estudo demonstrou insatisfação geral dos médicos dos serviços de urgência na região em relação à estrutura de atendimento às emergências cardiovasculares.

Canonical PI3Kγ signaling in myeloid cells restricts Trypanosoma cruzi infection and dampens chagasic myocarditis.

Chagas disease is caused by infection with the protozoan Trypanosoma cruzi (T. cruzi) and is an important cause of severe inflammatory heart disease. However, the mechanisms driving Chagas disease cardiomyopathy have not been completely elucidated. Here, we show that the canonical PI3Kγ pathway is upregulated in both human chagasic hearts and hearts of acutely infected mice. PI3Kγ-deficient mice and mutant mice carrying catalytically inactive PI3Kγ are more susceptible to T. cruzi infection. The canonical PI3Kγ signaling in myeloid cells is essential to restrict T. cruzi heart parasitism and ultimately to avoid myocarditis, heart damage, and death of mice. Furthermore, high PIK3CG expression correlates with low parasitism in human Chagas' hearts. In conclusion, these results indicate an essential role of the canonical PI3Kγ signaling pathway in the control of T. cruzi infection, providing further insight into the molecular mechanisms involved in the pathophysiology of chagasic heart disease.

Regional Myocardial Perfusion Disturbance in Experimental Chronic Chagas Cardiomyopathy.

Altered myocardial perfusion is a common finding in chronic Chagas cardiomyopathy (CCC), but its underlying histologic changes have not been elucidated. We investigated the occurrence of myocardial perfusion defects (MPDs) and the correlated regional changes to histology in an experimental model of CCC in hamsters. Methods: Female Syrian hamsters (n = 34) were infected with 3.5 × 104 to 105 trypomastigote forms of Trypanosoma cruzi, Y strain, and 6-10 mo afterward underwent in vivo imaging including resting 99mTc-sestamibi SPECT, segmental and global left ventricular function assessment using 2-dimensional echocardiography, and 18F-FDG PET for evaluation of myocardial viability. Histologic analysis included quantification of fibrosis, inflammatory infiltration, and the diameter and density of myocardial microcirculation. Results: MPDs were present in 17 (50%) of the infected animals. Histologic analysis revealed no transmural scar in segments with an MPD, and normal or mildly reduced 18F-FDG uptake, indicating viable myocardium. Infected animals with an MPD, in comparison to infected animals without an MPD and control animals, showed a lower left ventricular ejection fraction (P = 0.012), a higher wall motion score index (P = 0.004), and a higher extent of inflammatory infiltration (P = 0.018) but a similar extent of fibrosis (P = 0.15) and similar microvascular diameter and density (P > 0.05). Segments with an MPD (n = 65), as compared with normally perfused regions in the same animal (n = 156), showed a higher wall motion score index (P = 0.005) but a similar extent of inflammatory infiltration, a similar extent of fibrosis, and a similar microvascular diameter and density. Conclusion: Resting MPDs are frequent in experimental CCC and are associated with myocardial inflammation but do not designate scar tissue, corresponding to regions with metabolically viable myocardium.

Cardiovascular emergencies in primary care: an observational retrospective study of a large-scale telecardiology service.

BACKGROUND: Electrocardiograms (ECGs) are an essential examination for identification and management of cardiovascular emergencies.The aim of this study was to report on the frequency and recognition of cardiovascular emergencies in primary care units. DESIGN AND SETTING: Observational retrospective study assessing consecutive patients whose digital ECGs were sent for analysis to the team of the Telehealth Network of Minas Gerais. METHODS: Data from patients diagnosed with cardiological emergencies in the primary care setting of 750 municipalities in Minas Gerais, Brazil, between March and September 2015, were collected via telephone contact with the healthcare practitioner who performed the ECG. After collection, the data were subjected to statistical analysis. RESULTS: Over the study period, 304 patients with cardiovascular emergencies were diagnosed within primary care. Only 73.4% of these were recognized by the local physicians. Overall, the most frequent ECG abnormalities were acute ischemic patterns (44.7%) and the frequency of such patterns was higher among the ECGs assigned as emergency priority (P = 0.03). It was possible to obtain complete information on 231 patients (75.9%). Among these, the mean age was 65 ± 14.4 years, 57.1% were men and the most prevalent comorbidity was hypertension (68.4%). In total, 77.9% were referred to a unit caring for cases of higher complexity and 11.7% of the patients died. CONCLUSION: In this study, cardiovascular emergencies were misdiagnosed in primary care settings, acute myocardial ischemia was the most frequent emergency and the mortality rate was high.

TLR3 is required for survival following Coxsackievirus B3 infection by driving T lymphocyte activation and polarization: The role of dendritic cells.

Type B coxsackievirus (CVB) is a common cause of acute and chronic myocarditis, meningitis and pancreatitis, often leading to heart failure and pancreatic deficiency. The polarization of CD4+ T lymphocytes and their cytokine milieu are key factors in the outcome of CVB-induced diseases. Thus, sensing the virus and driving the adaptive immune response are essential for the establishment of a protective immune response. TLR3 is a crucial virus recognition receptor that confers the host with resistance to CVB infection. In the current study, we found that TLR3 expression in dendritic cells plays a role in their activation upon CVB3 infection in vitro, as TLR3-deficient dendritic cells up-regulate CD80 and CD86 to a less degree than WT cells. Instead, they up-regulated the inhibitory molecule PD-L1 and secreted considerably lower levels of TNF-α and IL-10 and a higher level of IL-23. T lymphocyte proliferation in co-culture with CVB3-infected dendritic cells was increased by TLR3-expressing DCs and other cells. Furthermore, in the absence of TLR3, the T lymphocyte response was shifted toward a Th17 profile, which was previously reported to be deleterious for the host. TLR3-deficient mice were very susceptible to CVB3 infection, with increased pancreatic injury and extensive inflammatory infiltrate in the heart that was associated with uncontrolled viral replication. Adoptive transfer of TLR3+ dendritic cells slightly improved the survival of TLR-deficient mice following CVB3 infection. Therefore, our findings highlight the importance of TLR3 signaling in DCs and in other cells to induce activation and polarization of the CD4+ T lymphocyte response toward a Th1 profile and consequently for a better outcome of CVB3 infection. These data provide new insight into the immune-mediated mechanisms by which CVBs are recognized and cleared in order to prevent the development of myocarditis and pancreatitis and may contribute to the design of therapies for enteroviral infections.

Ebi3 Prevents Trypanosoma cruzi-Induced Myocarditis by Dampening IFN-γ-Driven Inflammation.

The identification of anti-inflammatory mediators can reveal important targetable molecules capable of counterbalancing Trypanosoma cruzi-induced myocarditis. Composed of Ebi3 and IL-27p28 subunits, IL-27 is produced by myeloid cells and is able to suppress inflammation by inducing IL-10-producing Tr1 cells, thus emerging as a potential candidate to ameliorate cardiac inflammation induced by T. cruzi. Although IL-27 has been extensively characterized as a suppressive cytokine that prevents liver immunopathogenesis after T. cruzi infection, the mechanisms underlying its effects on T. cruzi-induced myocarditis remain largely unknown. Here, wild-type (WT) and Ebi3-deficient animals were intraperitoneally infected with trypomastigotes of T. cruzi Y strain and used to evaluate the potential anti-inflammatory properties of Ebi3 during T. cruzi infection. The survival rates of mice were daily recorded, the frequency of inflammatory cells was analyzed by flow cytometry and inflammatory mediators were measured by ELISA, real-time PCR and PCR array. We reported that T. cruzi-induced myocarditis was prevented by Ebi3. Stressors mainly recognized by TLR2 and TLR4 receptors on myeloid cells were essential to trigger IL-27p28 production. In addition, Ebi3 regulated IFN-γ-mediated myocarditis by promoting an anti-inflammatory environment through IL-10, which was most likely produced by Tr1 cells rather than classical regulatory T cells (Tregs), in the heart tissue of T. cruzi-infected animals. Furthermore, in vivo IFN-γ blockade ameliorated the host survival without compromising the parasite control in the bloodstream. In humans, IL-27p28 was correlated with cardiac protection during Chagas disease. Patients with mild clinical forms of the disease produced high levels of IL-27p28, whereas lower levels were found in those with severe forms. In addition, polymorphic sites at Ebi3 gene were associated with severe cardiomyopathy in patients with Chagas disease. Collectively, we describe a novel regulatory mechanism where Ebi3 dampens cardiac inflammation by modulating the overproduction of IFN-γ, the bona fide culprit of Chagas disease cardiomyopathy.

Cardiovascular emergencies in primary care: an observational retrospective study of a large-scale telecardiology service

ABSTRACT BACKGROUND: Electrocardiograms (ECGs) are an essential examination for identification and management of cardiovascular emergencies.The aim of this study was to report on the frequency and recognition of cardiovascular emergencies in primary care units. DESIGN AND SETTING: Observational retrospective study assessing consecutive patients whose digital ECGs were sent for analysis to the team of the Telehealth Network of Minas Gerais. METHODS: Data from patients diagnosed with cardiological emergencies in the primary care setting of 750 municipalities in Minas Gerais, Brazil, between March and September 2015, were collected via telephone contact with the healthcare practitioner who performed the ECG. After collection, the data were subjected to statistical analysis. RESULTS: Over the study period, 304 patients with cardiovascular emergencies were diagnosed within primary care. Only 73.4% of these were recognized by the local physicians. Overall, the most frequent ECG abnormalities were acute ischemic patterns (44.7%) and the frequency of such patterns was higher among the ECGs assigned as emergency priority (P = 0.03). It was possible to obtain complete information on 231 patients (75.9%). Among these, the mean age was 65 ± 14.4 years, 57.1% were men and the most prevalent comorbidity was hypertension (68.4%). In total, 77.9% were referred to a unit caring for cases of higher complexity and 11.7% of the patients died. CONCLUSION: In this study, cardiovascular emergencies were misdiagnosed in primary care settings, acute myocardial ischemia was the most frequent emergency and the mortality rate was high.

Immune discrepancies during in vitro granuloma formation in response to Cutibacterium (formerly Propionibacterium) acnes infection.

Cutibacterium (formerly Propionibacterium) acnes is involved in chronic/low-grade pathologies such as sarcoidosis or prosthetic joint infection (PJI). In these diseases, granulomatous structures are frequently observed. In this study, we induced a physiological granulomatous reaction in response to different well-characterized clinical C. acnes isolates in order to investigate the cellular process during granuloma formation. Three C. acnes isolates selected according to their origin (PJI, sarcoidosis and acne) were typed by MLST. All C. acnes isolates generated granulomatous structures in our experimental conditions. The bacterial burden was better controlled by granulomas induced by the sarcoidosis C. acnes isolate. The PJI C. acnes isolate, belonging to CC36, promoted the recruitment of CD8+ lymphocytes inside the granuloma. In contrast, the acne and sarcoidosis C. acnes isolates, belonging to phylotypes IA1/CC18 and IA2/CC28, respectively, generated a higher number of granulomas and promoted the recruitment of CD4+ lymphocytes inside the granuloma. Our results provide new evidence supporting the role of C. acnes in the development of sarcoidosis and new explanations concerning the mechanisms underlying PJI due to C. acnes.

SynthEx: a synthetic-normal-based DNA sequencing tool for copy number alteration detection and tumor heterogeneity profiling.

Changes in the quantity of genetic material, known as somatic copy number alterations (CNAs), can drive tumorigenesis. Many methods exist for assessing CNAs using microarrays, but considerable technical issues limit current CNA calling based upon DNA sequencing. We present SynthEx, a novel tool for detecting CNAs from whole exome and genome sequencing. SynthEx utilizes a "synthetic-normal" strategy to overcome technical and financial issues. In terms of accuracy and precision, SynthEx is highly comparable to array-based methods and outperforms sequencing-based CNA detection tools. SynthEx robustly identifies CNAs using sequencing data without the additional costs associated with matched normal specimens.

Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a unique liver cancer primarily affecting young adults and characterized by a fusion event between DNAJB1 and PRKACA. By analyzing RNA-sequencing data from The Cancer Genome Atlas (TCGA) for >9,100 tumors across ~30 cancer types, we show that the DNAJB1-PRKACA fusion is specific to FLCs. We demonstrate that FLC tumors (n = 6) exhibit distinct messenger RNA (mRNA) and long intergenic non-coding RNA (lincRNA) profiles compared to hepatocellular carcinoma (n = 263) and cholangiocarcinoma (n = 36), the two most common liver cancers. We also identify a set of mRNAs (n = 16) and lincRNAs (n = 4), including LINC00473, that distinguish FLC from ~25 other liver and non-liver cancer types. We confirm this unique FLC signature by analysis of two independent FLC cohorts (n = 20 and 34). Lastly, we validate the overexpression of one specific gene in the FLC signature, carbonic anhydrase XII (CA12), at the protein level by western blot and immunohistochemistry. Both the mRNA and lincRNA signatures support a major role for protein kinase A (PKA) signaling in shaping the FLC gene expression landscape, and present novel candidate FLC oncogenes that merit further investigation.

Amplification of SOX4 promotes PI3K/Akt signaling in human breast cancer.

PURPOSE: The PI3K/Akt signaling axis contributes to the dysregulation of many dominant features in breast cancer including cell proliferation, survival, metabolism, motility, and genomic instability. While multiple studies have demonstrated that basal-like or triple-negative breast tumors have uniformly high PI3K/Akt activity, genomic alterations that mediate dysregulation of this pathway in this subset of highly aggressive breast tumors remain to be determined. METHODS: In this study, we present an integrated genomic analysis based on the use of a PI3K gene expression signature as a framework to analyze orthogonal genomic data from human breast tumors, including RNA expression, DNA copy number alterations, and protein expression. In combination with data from a genome-wide RNA-mediated interference screen in human breast cancer cell lines, we identified essential genetic drivers of PI3K/Akt signaling. RESULTS: Our in silico analyses identified SOX4 amplification as a novel modulator of PI3K/Akt signaling in breast cancers and in vitro studies confirmed its role in regulating Akt phosphorylation. CONCLUSIONS: Taken together, these data establish a role for SOX4-mediated PI3K/Akt signaling in breast cancer and suggest that SOX4 may represent a novel therapeutic target and/or biomarker for current PI3K family therapies.

Characterization of copy number alterations in a mouse model of fibrosis-associated hepatocellular carcinoma reveals concordance with human disease.

Hepatocellular carcinoma (HCC) is a prevalent human cancer with rising incidence worldwide. Human HCC is frequently associated with chronic liver inflammation and cirrhosis, pathophysiological processes that are a consequence of chronic viral infection, disturbances in metabolism, or exposure to chemical toxicants. To better characterize the pathogenesis of HCC, we used a human disease-relevant mouse model of fibrosis-associated hepatocarcinogenesis. In this model, marked liver tumor response caused by the promutagenic chemical N-nitrosodiethylamine in the presence of liver fibrosis was associated with epigenetic events indicative of genomic instability. Therefore, we hypothesized that DNA copy number alterations (CNAs), a feature of genomic instability and a common characteristic of cancer, are concordant between human HCC and mouse models of fibrosis-associated hepatocarcinogenesis. We evaluated DNA CNAs and changes in gene expression in the mouse liver (normal, tumor, and nontumor fibrotic tissues). Additionally, we compared our findings to DNA CNAs in human HCC cases (tumor and nontumor cirrhotic/fibrotic tissues) using publicly available data from The Cancer Genome Atlas (TCGA). We observed that while fibrotic liver tissue is largely devoid of DNA CNAs, highly frequently occurring DNA CNAs are found in mouse tumors, which is indicative of a profound increase in chromosomal instability in HCC. The cross-species gene-level comparison of CNAs identified shared regions of CNAs between human fibrosis- and cirrhosis-associated liver tumors and mouse fibrosis-associated HCC. Our results suggest that CNAs most commonly arise in neoplastic tissue rather than in fibrotic or cirrhotic liver, and demonstrate the utility of this mouse model in replicating the molecular features of human HCC.

Progesterone receptor modulates ERα action in breast cancer.

Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.

Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype-specific driver genes for breast cancer.

A large number of DNA copy number alterations (CNAs) exist in human breast cancers, and thus characterizing the most frequent CNAs is key to advancing therapeutics because it is likely that these regions contain breast tumor 'drivers' (i.e., cancer causal genes). This study aims to characterize the genomic landscape of breast cancer CNAs and identify potential subtype-specific drivers using a large set of human breast tumors and genetically engineered mouse (GEM) mammary tumors. Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15% or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1. A comparison of CNAs between mouse and human breast tumors identified regions with shared subtype-specific CNAs. Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria. Numerous regions of shared CNAs were observed between human breast tumors and GEM mammary tumor models that shared similar gene expression features. Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN. This step-wise computational approach based on a cross-species comparison is applicable to any tumor type for which sufficient human and model system DNA copy number data exist, and in this instance, highlights that a single region of amplification may in fact harbor multiple driver genes.