Body-mass index, blood pressure, diabetes and cardiovascular mortality in Cuba: prospective study of 146,556 participants.

BACKGROUND: Cardiovascular disease accounts for about one-third of all premature deaths (ie, age < 70) in Cuba. Yet, the relevance of major risk factors, including systolic blood pressure (SBP), diabetes, and body-mass index (BMI), to cardiovascular mortality in this population remains unclear. METHODS: In 1996-2002, 146,556 adults were recruited from the general population in five areas of Cuba. Participants were interviewed, measured (height, weight and blood pressure) and followed up by electronic linkage to national death registries until Jan 1, 2017; in 2006-08, 24,345 participants were resurveyed. After excluding all with missing data, cardiovascular disease at recruitment, and those who died in the first 5 years, Cox regression (adjusted for age, sex, education, smoking, alcohol and, where appropriate, BMI) was used to relate cardiovascular mortality rate ratios (RRs) at ages 35-79 years to SBP, diabetes and BMI; RR were corrected for regression dilution to give associations with long-term average (ie, 'usual') levels of SBP and BMI. RESULTS: After exclusions, there were 125,939 participants (mean age 53 [SD12]; 55% women). Mean SBP was 124 mmHg (SD15), 5% had diabetes, and mean BMI was 24.2 kg/m2 (SD3.6); mean SBP and diabetes prevalence at recruitment were both strongly related to BMI. During follow-up, there were 4112 cardiovascular deaths (2032 ischaemic heart disease, 832 stroke, and 1248 other). Cardiovascular mortality was positively associated with SBP (>=120 mmHg), diabetes, and BMI (>=22.5 kg/m2): 20 mmHg higher usual SBP about doubled cardiovascular mortality (RR 2.02, 95%CI 1.88-2.18]), as did diabetes (2.15, 1.95-2.37), and 10 kg/m2 higher usual BMI (1.92, 1.64-2.25). RR were similar in men and in women. The association with BMI and cardiovascular mortality was almost completely attenuated following adjustment for the mediating effect of SBP. Elevated SBP (>=120 mmHg), diabetes and raised BMI (>=22.5 kg/m2) accounted for 27%, 14%, and 16% of cardiovascular deaths, respectively. CONCLUSIONS: This large prospective study provides direct evidence for the effects of these major risk factors on cardiovascular mortality in Cuba. Despite comparatively low levels of these risk factors by international standards, the strength of their association with cardiovascular death means they nevertheless exert a substantial impact on premature mortality in Cuba.

Heme Oxygenase 1 Impairs Glucocorticoid Receptor Activity in Prostate Cancer.

Glucocorticoids are used during prostate cancer (PCa) treatment. However, they may also have the potential to drive castration resistant prostate cancer (CRPC) growth via the glucocorticoid receptor (GR). Given the association between inflammation and PCa, and the anti-inflammatory role of heme oxygenase 1 (HO-1), we aimed at identifying the molecular processes governed by the interaction between HO-1 and GR. PCa-derived cell lines were treated with Hemin, Dexamethasone (Dex), or both. We studied GR gene expression by RTqPCR, protein expression by Western Blot, transcriptional activity using reporter assays, and nuclear translocation by confocal microscopy. We also evaluated the expression of HO-1, FKBP51, and FKBP52 by Western Blot. Hemin pre-treatment reduced Dex-induced GR activity in PC3 cells. Protein levels of FKBP51, a cytoplasmic GR-binding immunophilin, were significantly increased in Hemin+Dex treated cells, possibly accounting for lower GR activity. We also evaluated these treatments in vivo using PC3 tumors growing as xenografts. We found non-significant differences in tumor growth among treatments. Immunohistochemistry analyses revealed strong nuclear GR staining in almost all groups. We did not observe HO-1 staining in tumor cells, but high HO-1 reactivity was detected in tumor infiltrating macrophages. Our results suggest an association and crossed modulation between HO-1 and GR pathways.

Predicting prostate cancer progression with a Multi-lncRNA expression-based risk score and nomogram integrating ISUP grading.

Prostate cancer is a highly heterogeneous disease; therefore, estimating patient prognosis accurately is challenging due to the lack of biomarkers with sufficient specificity and sensitivity. One of the current challenges lies in integrating genomic and transcriptomic data with clinico-pathological features and in incorporating their application in everyday clinical practice. Therefore, we aimed to model a risk score and nomogram containing long non-coding RNA (lncRNA) expression and clinico-pathological data to better predict the probability of prostate cancer progression. We performed bioinformatics analyses to identify lncRNAs differentially expressed across various prostate cancer stages and associated with progression-free survival. This information was further integrated into a prognostic risk score and nomogram containing transcriptomic and clinico-pathological features to estimate the risk of disease progression. We used RNA-seq data from 5 datasets from public repositories (total n = 178) comprising different stages of prostate cancer: pre-treatment primary prostate adenocarcinomas, post-treatment tumors and metastatic castration resistant prostate cancer. We found 30 lncRNAs with consistent differential expression in all comparisons made using two R-based packages. Multivariate progression-free survival analysis including the ISUP group as covariate, revealed that 7/30 lncRNAs were significantly associated with time-to-progression. Next, we combined the expression of these 7 lncRNAs into a multi-lncRNA score and dichotomized the patients into low- or high-score. Patients with a high-score showed a 4-fold risk of disease progression (HR = 4.30, 95 %CI = 2.66-6.97, p = 3.1e-9). Furthermore, we modelled a combined risk-score containing information on the multi-lncRNA score and ISUP group. We found that patients with a high-risk score had nearly 8-fold risk of progression (HR = 7.65, 95 %CI = 4.05-14.44, p = 3.4e-10). Finally, we created and validated a nomogram to help uro-oncologists to better predict patient's risk of progression at 3- and 5-years post-diagnosis. In conclusion, the integration of lncRNA expression data and clinico-pathological features of prostate tumors into predictive models might aid in tailored disease risk assessment and treatment for patients with prostate cancer.

Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series.

PURPOSE: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer. EXPERIMENTAL DESIGN: We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived from different morphologic groups, disease states, and involved organ sites (including circulating tumor cells), as well as paired samples representing heterogeneity or stages before and after therapy. RESULTS: The cohort recapitulates clinically reported alterations in prostate cancer genes, providing a data resource for clinical and molecular interrogation of suitable experimental models. Paired samples displayed conserved molecular alteration profiles, suggesting the relevance of other regulatory mechanisms (e.g., epigenomic) influenced by the microenvironment and/or treatment. Transcriptomically, models were grouped on the basis of morphologic classification. DNA damage response-associated mechanisms emerged as differentially regulated between adenocarcinoma and neuroendocrine prostate cancer in a cross-interrogation of PDX/patient datasets. CONCLUSIONS: We addressed the gap in clinically relevant prostate cancer models through comprehensive molecular characterization of MDA PCa PDXs, providing a discovery platform that integrates with patient data and benchmarked to therapeutically relevant consensus clinical groupings. This unique resource supports robust hypothesis generation and testing from basic, translational, and clinical perspectives.

Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription.

Chromosomal instability is a key feature in cancer progression. Recently we have reported that BRCA1 regulates the transcription of several genes in prostate cancer, including ATM (ataxia telangiectasia mutated). Although it is well accepted that ATM is a pivotal mediator in genotoxic stress, it is unknown whether ATM transcription is regulated during the molecular response to DNA damage. Here we investigate ATM transcription regulation in human prostate tumor PC3 cell line. We have found that doxorubicin and mitoxantrone repress ATM transcription in PC3 cells but etoposide and methotrexate do not affect ATM expression. We have demonstrated that BRCA1 binds to ATM promoter and after doxorubicin exposure, it is released. BRCA1 overexpression increases ATM transcription and this enhancement is abolished by BRCA1 depletion. Moreover, BRCA1-BRCT domain loss impairs the ability of BRCA1 to regulate ATM promoter activity, strongly suggesting that BRCT domain is essential for ATM regulation by BRCA1. BRCA1-overexpressing PC3 cells exposed to KU55933 ATM kinase inhibitor showed significant decreased ATM promoter activity compared to untreated cells, suggesting that ATM transcriptional regulation by BRCA1 is partially mediated by the ATM kinase activity. In addition, we have demonstrated E2F1 binding to ATM promoter before and after doxorubicin exposure. E2F1 overexpression diminishes ATM transcription after doxorubicin exposure which is impaired by E2F1 dominant negative mutants. Finally, the co-regulator of transcription CtIP increases ATM transcription. CtIP increases ATM transcription. Altogether, BRCA1/E2F1/CtIP binding to ATM promoter activates ATM transcription. Doxorubicin exposure releases BRCA1 and CtIP from ATM promoter still keeping E2F1 recruited and, in turn, represses ATM expression.

Bone Progenitors Pull the Strings on the Early Metabolic Rewiring Occurring in Prostate Cancer Cells.

Metastatic prostate cancer (PCa) cells soiling in the bone require a metabolic adaptation. Here, we identified the metabolic genes fueling the seeding of PCa in the bone niche. Using a transwell co-culture system of PCa (PC3) and bone progenitor cells (MC3T3 or Raw264.7), we assessed the transcriptome of PC3 cells modulated by soluble factors released from bone precursors. In a Principal Component Analysis using transcriptomic data from human PCa samples (GSE74685), the altered metabolic genes found in vitro were able to stratify PCa patients in two defined groups: primary PCa and bone metastasis, confirmed by an unsupervised clustering analysis. Thus, the early transcriptional metabolic profile triggered in the in vitro model has a clinical correlate in human bone metastatic samples. Further, the expression levels of five metabolic genes (VDR, PPARA, SLC16A1, GPX1 and PAPSS2) were independent risk-predictors of death in the SU2C-PCF dataset and a risk score model built using this lipid-associated signature was able to discriminate a subgroup of bone metastatic PCa patients with a 23-fold higher risk of death. This signature was validated in a PDX pre-clinical model when comparing MDA-PCa-183 growing intrafemorally vs. subcutaneously, and appears to be under the regulatory control of the Protein Kinase A (PKA) signaling pathway. Secretome analyses of conditioned media showcased fibronectin and type-1 collagen as critical bone-secreted factors that could regulate tumoral PKA. Overall, we identified a novel lipid gene signature, driving PCa aggressive metastatic disease pointing to PKA as a potential hub to halt progression.

A Journey into the Clinical Relevance of Heme Oxygenase 1 for Human Inflammatory Disease and Viral Clearance: Why Does It Matter on the COVID-19 Scene?

Heme oxygenase 1 (HO-1), the rate-limiting enzyme in heme degradation, is involved in the maintenance of cellular homeostasis, exerting a cytoprotective role by its antioxidative and anti-inflammatory functions. HO-1 and its end products, biliverdin, carbon monoxide and free iron (Fe2+), confer cytoprotection against inflammatory and oxidative injury. Additionally, HO-1 exerts antiviral properties against a diverse range of viral infections by interfering with replication or activating the interferon (IFN) pathway. Severe cases of coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are characterized by systemic hyperinflammation, which, in some cases, leads to severe or fatal symptoms as a consequence of respiratory failure, lung and heart damage, kidney failure, and nervous system complications. This review summarizes the current research on the protective role of HO-1 in inflammatory diseases and against a wide range of viral infections, positioning HO-1 as an attractive target to ameliorate clinical manifestations during COVID-19.

Exploiting Interdata Relationships in Prostate Cancer Proteomes: Clinical Significance of HO-1 Interactors.

Prostate cancer (PCa) cells display abnormal expression of proteins resulting in an augmented capacity to resist chemotherapy and colonize distant organs. We have previously shown the anti-tumoral role of heme oxygenase 1 (HO-1) in this disease. In this work, we undertook a mass spectrometry-based proteomics study to identify HO-1 molecular interactors that might collaborate with its modulatory function in PCa. Among the HO-1 interactors, we identified proteins with nuclear localization. Correlation analyses, using the PCa GSE70770 dataset, showed a significant and positive correlation between HMOX1 and 6 of those genes. Alternatively, HMOX1 and YWHAZ showed a negative correlation. Univariable analyses evidenced that high expression of HNRNPA2B1, HSPB1, NPM1, DDB1, HMGA1, ZC3HAV1, and HMOX1 was associated with increased relapse-free survival (RFS) in PCa patients. Further, PCa patients with high HSPB1/HMOX1, DDB1/HMOX1, and YWHAZ/HMOX1 showed a worse RFS compared with patients with lower ratios. Moreover, a decrease in RFS for patients with higher scores of this signature was observed using a prognostic risk score model. However, the only factor significantly associated with a higher risk of relapse was high YWHAZ. Multivariable analyses confirmed HSPB1, DDB1, and YWHAZ independence from PCa clinic-pathological parameters. In parallel, co-immunoprecipitation analysis in PCa cells ascertained HO-1/14-3-3ζ/δ (protein encoded by YWHAZ) interaction. Herein, we describe a novel protein interaction between HO-1 and 14-3-3ζ/δ in PCa and highlight these factors as potential therapeutic targets.

Pin-Pointing the Key Hubs in the IFN-γ Pathway Responding to SARS-CoV-2 Infection.

Interferon gamma (IFN-γ) may be potential adjuvant immunotherapy for COVID-19 patients. In this work, we assessed gene expression profiles associated with the IFN-γ pathway in response to SARS-CoV-2 infection. Employing a case-control study from SARS-CoV-2-positive and -negative patients, we identified IFN-γ-associated pathways to be enriched in positive patients. Bioinformatics analyses showed upregulation of MAP2K6, CBL, RUNX3, STAT1, and JAK2 in COVID-19-positive vs. -negative patients. A positive correlation was observed between STAT1/JAK2, which varied alongside the patient's viral load. Expression of MX1, MX2, ISG15, and OAS1 (four well-known IFN-stimulated genes (ISGs)) displayed upregulation in COVID-19-positive vs. -negative patients. Integrative analyses showcased higher levels of ISGs, which were associated with increased viral load and STAT1/JAK2 expression. Confirmation of ISGs up-regulation was performed in vitro using the A549 lung cell line treated with Poly (I:C), a synthetic analog of viral double-stranded RNA; and in different pulmonary human cell lines and ferret tracheal biopsies infected with SARS-CoV-2. A pre-clinical murine model of Coronavirus infection confirmed findings displaying increased ISGs in the liver and lungs from infected mice. Altogether, these results demonstrate the role of IFN-γ and ISGs in response to SARS-CoV-2 infection, highlighting alternative druggable targets that can boost the host response.

[Depression, anxiety and quality of life in pediatric patients with leukemia]. / Depresión, ansiedad y calidad de vida en pacientes pediátricos con leucemia.

Background: Leukemia is the most frequent cancer in children and adolescents, and it has a high prevalence of depression and anxiety which deteriorates the quality of life related to health. The symptoms of depression and anxiety may go unnoticed by the physician as a normal response during cancer treatment. Objective: To determine the prevalence of depression, anxiety and health-related quality of life in pediatric patients with leukemia. Material and methods: study with the participation of Mexican children and adolescents with leukemia whose depression was determined with the Childhood Depression Inventory, their anxiety with the Spence Childhood Anxiety Scale, and their health-related quality of life (HRQoL) with PedsQL 4.0. Results: 37 participants, with a median age of 11 years (8-14 years); 19 (51.4%) were male. The marital status of the parents in 25 participants (67.5%) was married, in 10 (27%) had a domestic partnership, in one (2.7%) had divorced parents and in one it was single (2.7%). The prevailing religion was Catholic in 29 (78.3%); 16 patients (43.2%) reported depression, 10% anxiety and 94.5% reported an adequate health-related quality of life, with an average of 74.2 +- 16.2. Conclusions: Depression was the most prevalent, followed by anxiety. Health-related quality of life was reported as good. The harmful impact is still prevalent in a vulnerable population, which must be attended in a comprehensive and timely manner at all levels of care.

Introducción: la leucemia es el cáncer más frecuente en niños y adolescentes, y tiene una alta prevalencia de depresión y ansiedad que deterioran la calidad de vida relacionada con la salud. Los síntomas de depresión y ansiedad pueden pasar inadvertidos por el médico al considerar que son una respuesta normal durante el tratamiento del cáncer. Objetivo: determinar la prevalencia de depresión, ansiedad y calidad de vida relacionada con la salud en pacientes pediátricos con leucemia. Material y métodos: estudio en el que participaron niños y adolescentes mexicanos con leucemia cuya depresión se estableció con el Inventario de Depresión Infantil, su ansiedad con la Escala de Ansiedad Infantil Spence y su calidad de vida relacionada con la salud (CVRS) con el PedsQL 4.0. Resultados: fueron 37 participantes, con una mediana de edad de 11 años (8-14 años); 19 (51.4%) fueron del género masculino. Los padres de 25 pacientes (67.5%) estaban casados, los de 10 (27%) en unión libre, el de uno estaba divorciado (2.7%) y el de otro soltero (2.7%). La religión prevalente fue la católica en 29 (78.3%); 16 pacientes (43.2%) reportaron depresión, 10% ansiedad y 94.5% reportó adecuada calidad de vida relacionada con la salud, con un promedio de 74.2 +- 16.2. Conclusiones: la depresión fue la más prevalente, seguida de la ansiedad; la calidad de vida relacionada con la salud se reportó como buena. El impacto nocivo aún sigue siendo prevalente en una población vulnerable, la cual se debe atender de manera integral y oportuna en todos los niveles de atención.

Educational inequalities and premature mortality: the Cuba Prospective Study.

BACKGROUND: Although socioeconomic status is a major determinant of premature mortality in many populations, the impact of social inequalities on premature mortality in Cuba, a country with universal education and health care, remains unclear. We aimed to assess the association between educational level and premature adult mortality in Cuba. METHODS: The Cuba Prospective Study (a cohort study) enrolled 146 556 adults aged 30 years and older from the general population in five provinces from Jan 1, 1996, to Nov 24, 2002. Participants were followed up until Jan 1, 2017, for cause-specific mortality. Deaths were identified through linkage to the Cuban Public Health Ministry's national mortality records. Cox regression models yielded rate ratios (RRs) for the effect of educational level (a commonly used measure for social status) on mortality at ages 35-74 years, with assessment for the mediating effects of smoking, alcohol consumption, and BMI. FINDINGS: A total of 127 273 participants aged 35-74 years were included in the analyses. There was a strong inverse association between educational level and premature mortality. Compared with a university education, men who did not complete primary education had an approximately 60% higher risk of premature mortality (RR 1·55, 95% CI 1·40-1·72), while the risk was approximately doubled in women (1·96, 1·81-2·13). Overall, 28% of premature deaths could be attributed to lower education levels. Excess mortality in women was primarily due to vascular disease, while vascular disease and cancer were equally important in men. 31% of the association with education in men and 18% in women could be explained by common modifiable risk factors, with smoking having the largest effect. INTERPRETATION: This study highlights the value of understanding the determinants of health inequalities in different populations. Although many major determinants lie outside the health system in Cuba, this study has identified the diseases and risk factors that require targeted public health interventions, particularly smoking. FUNDING: UK Medical Research Council, British Heart Foundation, Cancer Research UK, CDC Foundation (with support from Amgen).

Androgen receptor-negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms.

In prostate cancer, androgen blockade strategies are commonly used to treat osteoblastic bone metastases. However, responses to these therapies are typically brief, and the mechanism underlying androgen-independent progression is not clear. Here, we established what we believe to be the first human androgen receptor-negative prostate cancer xenografts whose cells induced an osteoblastic reaction in bone and in the subcutis of immunodeficient mice. Accordingly, these cells grew in castrated as well as intact male mice. We identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. Mice treated with FGF9-neutralizing antibody developed smaller bone tumors and reduced bone formation. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from human organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Collectively, these results suggest that FGF9 contributes to prostate cancer-induced new bone formation and may participate in the osteoblastic progression of prostate cancer in bone. Androgen receptor-null cells may contribute to the castration-resistant osteoblastic progression of prostate cancer cells in bone and provide a preclinical model for studying therapies that target these cells.

HO-1 Modulates Aerobic Glycolysis through LDH in Prostate Cancer Cells.

Prostate cancer (PCa) is the second most diagnosed malignancy and the fifth leading cause of cancer associated death in men worldwide. Dysregulation of cellular energetics has become a hallmark of cancer, evidenced by numerous connections between signaling pathways that include oncoproteins and key metabolic enzymes. We previously showed that heme oxygenase 1 (HO-1), a cellular homeostatic regulator counteracting oxidative and inflammatory damage, exhibits anti-tumoral activity in PCa cells, inhibiting cell proliferation, migration, tumor growth and angiogenesis. The aim of this study was to assess the role of HO-1 on the metabolic signature of PCa. After HO-1 pharmacological induction with hemin, PC3 and C4-2B cells exhibited a significantly impaired cellular metabolic rate, reflected by glucose uptake, ATP production, lactate dehydrogenase (LDH) activity and extracellular lactate levels. Further, we undertook a bioinformatics approach to assess the clinical significance of LDHA, LDHB and HMOX1 in PCa, identifying that high LDHA or low LDHB expression was associated with reduced relapse free survival (RFS). Interestingly, the shortest RFS was observed for PCa patients with low HMOX1 and high LDHA, while an improved prognosis was observed for those with high HMOX1 and LDHB. Thus, HO-1 induction causes a shift in the cellular metabolic profile of PCa, leading to a less aggressive phenotype of the disease.

The pluripotency transcription factor OCT4 represses heme oxygenase-1 gene expression.

In embryonic stem (ES) cells, oxidative stress control is crucial for genomic stability, self-renewal, and cell differentiation. Heme oxygenase-1 (HO-1) is a key player of the antioxidant system and is also involved in stem cell differentiation and pluripotency acquisition. We found that the HO-1 gene is expressed in ES cells and induced after promoting differentiation. Moreover, downregulation of the pluripotency transcription factor (TF) OCT4 increased HO-1 mRNA levels in ES cells, and analysis of ChIP-seq public data revealed that this TF binds to the HO-1 gene locus in pluripotent cells. Finally, ectopic expression of OCT4 in heterologous systems repressed a reporter carrying the HO-1 gene promoter and the endogenous gene. Hence, this work highlights the connection between pluripotency and redox homeostasis.

Analysis workflow of publicly available RNA-sequencing datasets.

Differential gene expression analysis is widely used to study changes in gene expression profiles between two or more groups of samples (e.g., physiological versus pathological conditions, pre-treatment versus post-treatment, and infected versus non-infected tissues). This protocol aims to identify gene expression changes in a pre-selected set of genes associated with severe acute respiratory syndrome coronavirus 2 viral infection and host cell antiviral response, as well as subsequent gene expression association with phenotypic features using samples deposited in public repositories. For complete details on the use and outcome of this informatics analysis, please refer to Bizzotto et al. (2020).

The expression of YWHAZ and NDRG1 predicts aggressive outcome in human prostate cancer.

Some prostate cancers (PCas) are histo-pathologically grouped within the same Gleason Grade (GG), but can differ significantly in outcome. Herein, we aimed at identifying molecular biomarkers that could improve risk prediction in PCa. LC ESI-MS/MS was performed on human PCa and benign prostatic hyperplasia (BPH) tissues and peptide data was integrated with omic analyses. We identified high YWHAZ and NDRG1 expression to be associated with poor PCa prognosis considering all Gleason scores (GS). YWHAZ and NDRG1 defined two subpopulations of PCa patients with high and intermediate risk of death. Multivariable analyses confirmed their independence from GS. ROC analysis unveiled that YWHAZ outperformed GS beyond 60 months post-diagnosis. The genomic analysis of PCa patients with YWHAZ amplification, or increased mRNA or protein levels, revealed significant alterations in key DNA repair genes. We hereby state the relevance of YWHAZ in PCa, showcasing its role as an independent strong predictor of aggressiveness.

Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel.

Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The underlying mechanisms that account for the ultimate emergence of resistance to ADT, progressing to castrate-resistant prostate cancer (CRPC), include those that reactivate androgen receptor (AR), or those that are entirely independent or cooperate with androgen signaling to underlie PCa progression. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis to assess the metabolic shift occurring in PCa that progresses with low AR expression. We used PCa patient-derived xenografts (PDXs) to assess the metabolic changes after castration of tumor-bearing mice and subsequently confirmed main findings in human donor tumor that progressed after ADT. We found that relapsed tumors had a significant increase in fatty acids and ketone body (KB) content compared with baseline. We confirmed that critical ketolytic enzymes (ACAT1, OXCT1, BDH1) were dysregulated after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT. In an in silico approach, increased ACAT1, OXCT1, BDH1 expression was also observed for a subset of PCa patients that relapsed with low AR and ERG (ETS-related gene) expression. Further, expression of these factors was also associated with decreased time to biochemical relapse and decreased progression-free survival. Our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.

[Study of confirmed cases of human brucellosis in Puebla, Mexico]. / Estudio de casos confirmados de brucelosis humana en Puebla, México.

BACKGROUND: Human brucellosis is a global health problem. Mexico is one of the main countries affected; timely diagnosis and serological tests are the basis for detection. AIM: To know the frequency of confirmed cases of brucellosis in different of Family Medicine Units of the Mexican Social Security Institute in the state of Puebla, Mexico. METHODS: Cross-sectional study in patients of both genders, adults and pediatrics, with clinical manifestations suggestive of brucellosis; serological tests were performed for the confirmatory diagnosis. RESULTS: Out of a total of 77 patients, 39 (50.6%) were positive, 21 (27.3%) cases coming out of infection, 9 (11.7%) were negative and 8 (10.4%) were defined with immunological memory; of positive cases, 32 (82.1%) were found in the adult group and 30 (76.9%) were female. CONCLUSION: Around half of samples were confirmed as brucellosis, the clinical manifestations of the patients studied were non-specific, which highlights the importance of laboratory diagnosis.

Alcohol consumption and cause-specific mortality in Cuba: prospective study of 120 623 adults.

BACKGROUND: The associations of cause-specific mortality with alcohol consumption have been studied mainly in higher-income countries. We relate alcohol consumption to mortality in Cuba. METHODS: In 1996-2002, 146 556 adults were recruited into a prospective study from the general population in five areas of Cuba. Participants were interviewed, measured and followed up by electronic linkage to national death registries until January 1, 2017. After excluding all with missing data or chronic disease at recruitment, Cox regression (adjusted for age, sex, province, education, and smoking) was used to relate mortality rate ratios (RRs) at ages 35-79 years to alcohol consumption. RRs were corrected for long-term variability in alcohol consumption using repeat measures among 20 593 participants resurveyed in 2006-08. FINDINGS: After exclusions, there were 120 623 participants aged 35-79 years (mean age 52 [SD 12]; 67 694 [56%] women). At recruitment, 22 670 (43%) men and 9490 (14%) women were current alcohol drinkers, with 15 433 (29%) men and 3054 (5%) women drinking at least weekly; most alcohol consumption was from rum. All-cause mortality was positively and continuously associated with weekly alcohol consumption: each additional 35cl bottle of rum per week (110g of pure alcohol) was associated with ∼10% higher risk of all-cause mortality (RR 1.08 [95%CI 1.05-1.11]). The major causes of excess mortality in weekly drinkers were cancer, vascular disease, and external causes. Non-drinkers had ∼10% higher risk (RR 1.11 [1.09-1.14]) of all-cause mortality than those in the lowest category of weekly alcohol consumption (<1 bottle/week), but this association was almost completely attenuated on exclusion of early follow-up. INTERPRETATION: In this large prospective study in Cuba, weekly alcohol consumption was continuously related to premature mortality. Reverse causality is likely to account for much of the apparent excess risk among non-drinkers. The findings support limits to alcohol consumption that are lower than present recommendations in Cuba. FUNDING: Medical Research Council, British Heart Foundation, Cancer Research UK, CDC Foundation (with support from Amgen).

Fibroblast growth factors signaling in bone metastasis.

Many solid tumors metastasize to bone, but only prostate cancer has bone as a single, dominant metastatic site. Recently, the FGF axis has been implicated in cancer progression in some tumors and mounting evidence indicate that it mediates prostate cancer bone metastases. The FGF axis has an important role in bone biology and mediates cell-to-cell communication. Therefore, we discuss here basic concepts of bone biology, FGF signaling axis, and FGF axis function in adult bone, to integrate these concepts in our current understanding of the role of FGF axis in bone metastases.