Part 2: Deregulated Expressions of PIWI Proteins and piRNAs as New Candidate Biomarkers and Potential Therapeutic Tools in Cancer

Epigenetic abnormalities are early events in carcinogenesis and associate heterogeneity of DNA methylation, modifications of histones, and deregulation of noncoding RNAs. Aberrant expressions of PIWI proteins and piRNAs were recently observed in numerous subtypes of malignant tumors and were implicated in occurrence of most cancer hallmarks such as cell proliferation, genomic stability, apoptosis inhibition, invasion, and metastatic spread. However, this pathway is a new emerging research field, and further investigations are necessary to elucidate their oncogenic or tumor-suppressing status. Since the aberrant expression of this pathway may induce stemness, analysis of relationship between PIWI proteins, piRNAs, and cancer stem cells may open new avenues in cancer research. The objective of this review is to provide a broad overview of the emerging implication of PIWI proteins and piRNAs in carcinogenesis and their potential clinical interest as diagnostic and prognostic biomarkers and therapeutic tools

Part 1: The PIWI-piRNA Pathway Is an Immune-Like Surveillance Process That Controls Genome Integrity by Silencing Transposable Elements

PiRNAs [P-element-induced wimpy testis (PIWI)-interacting RNAs] represent the most frequent but the least well-investigated subtype of small ncRNAs and are characterized by their interaction with PIWI proteins, a subclass of the Argonaute family. PiRNAs and PIWI proteins maintain integrity of the genomic structure and regulate gene expression in germline and somatic cells. The PIWI-piRNA pathway primarily constitutes a conserved immune-like surveillance process that recognizes self and nonself. This axis controls genome integrity of germline cells and nonaging somatic cells by silencing and suppressing propagation of transposable elements through epigenetic and posttranscriptional mechanisms. However, mounting evidences indicate that the PIWI-piRNA pathway has broader implications in both germinal and somatic cells in various physiological and pathological processes. It modulates mRNAs levels of expression, stability, turnover, and translation and interacts directly with many transcription factors and signaling pathways molecules. PIWI proteins and piRNAs play pivotal roles in germline stem cell maintenance and self-renewal, fertilization and development, genes and proteins expression, genome rearrangement, and homeostasis

Significance of Tumor Microenvironment Scoring and Immune Biomarkers in Patient Stratification and Cancer Outcomes

Tumors appear as heterogeneous tissues that consist of tumor cells surrounding by a tumor microenvironment (TME). TME is a complex network composed of extracellular matrix (ECM), stromal cells, and immune/inflammatory cells that drive cancer cells fate from invasion to intravasation and metastasis. The stromal-inflammatory interface represents a dynamic space, in which exchange of numerous molecular information is associated with the transition into tumorigenic microenvironment. Recruitment, activation, and reprogramming of stromal and immune/inflammatory cells in the extracellular space are the consequences of a reciprocal interaction between TME and cancer cells. Recent data suggest that cancer development is influenced by TME and controlled by the host’s immune system, underlying the importance of TME components and immune biomarkers in the determination of prognosis and response to therapy. The immune classification has prognostic value and may be a useful supplement to the histopathological, molecular, and TNM classifications. Nevertheless, the complexity of quantitative immunohistochemistry and the variable assay protocols, stromal and immune cell types analyzed underscore the need to harmonize the quantified methods. It is therefore important to incorporate TME and immune scoring in determinations of cancer prognosis and to make sure they become a routine part of the histopathological diagnostic and prognostic assessment of patients

Monitorización remota en un hospital terciario de pacientes portadores del Holter implantable subcutáneo: efectividad diagnóstica, eficacia y seguridad

Tesis doctoral inédita, leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 17 de marzo, 201

Renal function and associated mortality risk in adults commencing HIV antiretroviral therapy in Zimbabwe.

BACKGROUND People living with HIV (PLWHIV) in sub-Saharan Africa appear to have a higher incidence of renal disease than other global regions, but data are limited. This renal impairment may be associated with an increased mortality risk. AIMS To define the prevalence of renal disease and explore its association with mortality risk in a cohort from Zimbabwe commencing antiretroviral therapy (ART) for HIV-infection. METHODS A retrospective study of all patients aged ≥18 years, commenced on ART for HIV-infection at the Newlands Clinic in Harare, Zimbabwe between January 2007 and September 2019 was conducted. Data were extracted from electronic medical records. Patients with no baseline creatinine measurement were excluded. Baseline characteristics were assessed as potential predictors for mortality by Cox proportional hazard regression. RESULTS 3039 patients were eligible for inclusion. Most were female (62.1%), with a median age of 36 years (IQR 30 to 43). At baseline, 7.3% had an eGFR ≤90 mL/min/1.73m2 and 11.4% had proteinuria. Over a median follow-up period of 4.6 years (IQR 2.5 to 6.9), the mortality rate was 8.7%. One half of deaths (49.2%) occurred within the first year. In multivariable analysis, a baseline eGFR between 60 and 90 mL/min/1.73m2 (HR 2.22, 95%CI 1.46 to 3.33, p < 0.001) and proteinuria (HR 2.10, 95%CI 1.35 to 3.27, p < 0.001) were associated with increased mortality risk. CONCLUSION Baseline renal impairment was common. Both a reduced eGFR or proteinuria were independently associated with a doubling of mortality risk. These should serve as markers in the clinical setting of at-risk patients

Comparison of predictors for early and late mortality in adults commencing HIV antiretroviral therapy in Zimbabwe: a retrospective cohort study.

BACKGROUND People living with HIV (PLWHIV) commencing antiretroviral therapy (ART) in sub-Saharan Africa experience significant mortality within the first year. Previously, identified risk factors for mortality may be biased towards these patients, as compared to those who experience late mortality. AIM To compare risk factors for early and late mortality in PLWHIV commencing ART. METHODS A retrospective cohort study of ART-naïve patients aged ≥ 18 years from an outpatient HIV clinic in Zimbabwe. Data were collected between January 2010 and January 2019. Predictors for early (≤ 1 year) and late mortality (> 1 year) were determined by multivariable cox proportional hazards analyses, with patients censored at 1 year and landmark analysis after 1 year, respectively. RESULTS Three thousand and thirty-nine PLWHIV were included in the analysis. Over a median follow-up of 4.6 years (IQR 2.5-6.9), there was a mortality rate of 8.8%, with 50.4% of deaths occurring within 1 year. Predictors of early mortality included CD4 count < 50 cells/µL (HR 1.84, 95% CI 1.24-2.72, p < 0.01), WHO Stage III (HR 2.05, 95% CI 1.28-3.27, p < 0.01) or IV (HR 2.83, 95% CI 1.67-4.81, p < 0.01), and eGFR < 90 mL/min/1.73 m2 (HR 2.48, 95% CI 1.56-3.96, p < 0.01). Other than age (p < 0.01), only proteinuria (HR 2.12, 95% CI 1.12-4.01, p = 0.02) and diabetes mellitus (HR 3.51, 95% CI 1.32-9.32, p = 0.01) were associated with increased risk of late mortality. CONCLUSIONS Traditional markers of mortality risk in patients commencing ART appear to be limited to early mortality. Proteinuria and diabetes are some of the few predictors of late mortality, and should be incorporated into routine screening of patients commencing ART

Andreev reflection between a normal metal and the FFLO superconductor II: a self-consistent approach

We consider Andreev reflection in a two dimensional junction between a normal metal and a heavy fermion superconductor in the Fulde-Ferrell (FF) type of the Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) state. We assume s-wave symmetry of the superconducting gap. The parameters of the superconductor: the gap magnitude, the chemical potential, and the Cooper pair center-of-mass momentum Q, are all determined self-consistently within a mean-field (BCS) scheme. The Cooper pair momentum Q is chosen as perpendicular to the junction interface. We calculate the junction conductance for a series of barrier strengths. In the case of incoming electron with spin \sigma = 1 only for magnetic fields close to the upper critical field H_{c2}, we obtain the so-called Andreev window i.e. the energy interval in which the reflection probability is maximal, which in turn is indicated by a peak in the conductance. The last result differs with other non-self-consistent calculations existing in the literature.Comment: 15 pages, 6 figures, accepted in Physica

Electrophoresis of positioned nucleosomes

We present in this paper an original approach to compute the electrophoretic mobility of rigid nucleo-protein complexes like nucleosomes. This model allows to address theoretically the influence of complex position along DNA, as well as wrapped length of DNA on the electrophoretic mobility of the complex. The predictions of the model are in qualitative agreement with experimental results on mononucleosomes assembled on short DNA fragments (<400bp). Influence of additional experimental parameters like gel concentration, ionic strength, effective charges is also discussed in the framework of the model, and is found to be qualitatively consistent with experiments when available. Based on the present model, we propose a simple semi-empirical formula describing positioning of nucleosomes as seen through electrophoresis.Comment: to appear in Biophys. J. 29 page