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Modern Applied Statistics With S

Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively They are present in biological fluids and are involved in multiple physiological and pathological processes Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material Knowledge of the cellular processes that govern extracellular vesicle biology is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis However, in this expanding field, much remains unknown regarding the origin, biogenesis, secretion, targeting and fate of these vesicles

/pdf/shedding-light-on-the-cell-biology-of-extracellular-vesicles-52ri6w7hp6.pdf

Shedding light on the cell biology of extracellular vesicles.

Extracellular vesicles (EVs) have become the focus of rising interest because of their numerous functions in physiology and pathology. Cells release heterogeneous vesicles of different sizes and intracellular origins, including small EVs formed inside endosomal compartments (i.e., exosomes) and EVs of various sizes budding from the plasma membrane. Specific markers for the analysis and isolation of different EV populations are missing, imposing important limitations to understanding EV functions. Here, EVs from human dendritic cells were first separated by their sedimentation speed, and then either by their behavior upon upward floatation into iodixanol gradients or by immuno-isolation. Extensive quantitative proteomic analysis allowing comparison of the isolated populations showed that several classically used exosome markers, like major histocompatibility complex, flotillin, and heat-shock 70-kDa proteins, are similarly present in all EVs. We identified proteins specifically enriched in small EVs, and define a set of five protein categories displaying different relative abundance in distinct EV populations. We demonstrate the presence of exosomal and nonexosomal subpopulations within small EVs, and propose their differential separation by immuno-isolation using either CD63, CD81, or CD9. Our work thus provides guidelines to define subtypes of EVs for future functional studies.

https://www.pnas.org/content/pnas/113/8/E968.full.pdf

Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes.

/pdf/pathology-and-genetics-of-tumours-of-the-digestive-system-3xy9cwrc3c.pdf

Pathology and genetics of tumours of the digestive system

The ability of exosomes to transfer cargo from donor to acceptor cells, thereby triggering phenotypic changes in the latter, has generated substantial interest in the scientific community. However, the extent to which exosomes differ from other extracellular vesicles in terms of their biogenesis and functions remains ill-defined. Here, we discuss the current knowledge on the specificities of exosomes and other types of extracellular vesicles, and their roles as important agents of cell-to-cell communication.

Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication.

Neuroblastomas, the most common extracranial solid tumors in children, present an extremely heterogeneous behaviour that can be explained in part by their genetic abnormalities. Thirty-four patients treated at the Pediatric Oncology Unit, Hospital Vall d'Hebron from 1993 to 1997 were prospectively studied to determine the relative prognostic impact of a number of clinical and molecular factors. The factors studied were: ploidy, MYCN and 1p status, and TRK-A expression, in addition to age, stage and histology. Their impact on prognosis was analyzed. In univariate analysis, advanced stage, unfavorable histology, diploidy, MYCN amplification, and 1p deletion were identified as adverse prognostic factors; TRK-A expression was associated with favorable prognosis. After multivariate analysis, only MYCN amplification proved to be an independent adverse prognostic factor (p=0.03), whereas TRK-A expression identified a subset of good-prognosis patients (p=0.003).

Clinical relevance of molecular markers in neuroblastoma: results from a single institution.

Objective: Endometrial cancer (EC) is the second most common gynecological cancer worldwide. Myometrial invasion (MI) is a key event in EC dissemination. This study aimed to evaluate FXYD5/dysadherin (FXYD5/Dys) expression in EC tissue and uterine aspirate (UA) biopsies and to assess molecular/functional changes associated with its expression in cellular models. Methods: FXYD5/Dys messenger RNA (mRNA) levels were determined in EC tissue and UA biopsies. FXYD5/Dys expression was evaluated in EC RNAseq data from The Cancer Genome Atlas (TCGA) and GENEVESTIGATOR tools. FXYD5/Dys impact on E-cadherin expression and cell behavior was assessed in EC Hec1a cells treated with transforming growth factor (TGF)-β1, stably transfected with ETV5, and transiently transfected with FXYD5/Dys small interfering RNA (siRNA) or pcDNA3-FXYD5/Dys plasmid. Results: FXYD5/Dys was associated with EC aggressiveness, finding high mRNA levels in tumors depicting MI > 50%, Grade 3, and intermediate/high risk of recurrence. FXYD5/Dys was highly expressed at the tumor invasive front compared to the superficial area. Most results were recapitulated in UA biopsies. FXYD5/Dys modulation in Hec1a cells altered cell migration/adhesion and E-cadherin expression. TGF-β1 treatment of Hec1a cells induced FXYD5/Dys expression. TCGA-UCEC RNAseq analysis revealed a positive correlation between FXYD5/Dys, TGF-β1, and plasminogen activator inhibitor (PAI)-1 mRNA levels. FXYD5/Dys induced nuclear factor (NF)-κB pathway activation in Hec1a cells. FXYD5/Dys mRNA levels positively correlated with transcriptional activation of NF-κB p65-regulated genes. Survival analysis revealed patient segregation into low- and high-risk groups, the latter depicting the highest FXYD5/Dys, PAI-1, tumor necrosis factor (TNF)-α, and TGF-β1 mRNA levels and shorter survival rates. Conclusion: FXYD5/Dys is a novel biomarker of EC progression related to TGF-β1 and NF-κB pathways that collectively promote tumor dissemination and result in poor patient prognosis.

/pdf/fxyd5-dysadherin-a-biomarker-of-endometrial-cancer-dw5p99z2p5.pdf

FXYD5/Dysadherin, a Biomarker of Endometrial Cancer Myometrial Invasion and Aggressiveness: its Relationship With TGF-β1 and NF-κB Pathways

Carcinosarcomas (CSs; malignant mixed Mullerian tumors) of the uterus are highly malignant neoplasms characterized by an unfavorable outcome. They represent less than 5% of all uterine malignancies, and the median patient survival rate is only 21 months. p53 pathway alterations have been studied in CSs originating from the uterus, supporting the monoclonal nature of most but not all of these neoplasms. This paper gives an overview of the current knowledge of p53 pathway distortions in patients with uterine CSs. The survival of patients with uterine CSs in relation to p53 pathway alterations is also briefly summarized.

Role of p53 pathway alterations in uterine carcinosarcomas (malignant mixed Müllerian tumors).

We have assessed the effect of androgen deprivation therapy (ADT) in the thyroid function test in prostate cancer patients. Serum levels of tri-iodothyronine (T3), thyroxine (T4), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were determined in a cross-sectional study that included 279 patients diagnosed with prostate cancer. A subset of 96 patients free of prostate-specific antigen relapse after radical prostatectomy became a control group and 183 patients under continuous ADT formed the study group. Sixty-four patients out of the study group were treated with luteinizing hormone-releasing hormone (LHRH) agonist and 119 with LHRH agonist plus bicalutamide. The average time of ADT was 42.5 months (3-218). Results were as follows. Mean T3 level was 122.7 ng/dl (72.6-213.0) in the control group and 123.8 ng/dl (64.4-228.2) in patients under ADT, p=0.472. Mean T4 level was 7.66 (1.81-4.30) and 7.66 microg/dl (3.60-13.30), respectively, p=0.884. Mean TSH level was 1.58 (0.44-11.70) and 1.81 mU/dl (0.15-6.58), respectively, p=0.007. Mean FT4 level was 1.24 (0.80-1.90) and 1.18 ng/dl (0.80-1.90), respectively, p=0.018. No statistically significant differences between the T3, T4, TSH and FT4 serum levels were detected according to the modality of ADT. The serum level of TSH was higher than 5 mU/l in six patients (2.1%); however, all cases had a normal FT4 serum level. This mild hypothyroidism was detected in two of the 96 patients of the control group (2.1%) and in four of the 183 under ADT (2.2%). Our data show that ADT seems to alter the thyroid function test. A statistically significant increase in TSH serum level and a decrease in FT4 serum level were detected in patients under ADT. However, only a mild hypothyroidism was detected in about 2% of the patients with prostate cancer, independently of ADT.

Effect of androgen deprivation therapy in the thyroid function test of patients with prostate cancer.

In the present study, molecular cloning, sequencing and restriction mapping of the genomic sequence encoding human proacrosin is described. The full-length cDNA encoding human proacrosin was utilized to recover a 17-kb human genomic clone which was sequenced without further subcloning. The nucleotide sequences of the exons agree with the sequence of the cDNA reported previously. More than 500 bases of the promoter region were sequenced and found to be highly GC rich but devoid of an identifiable TATA box. These findings are generally consistent with a recently published report [Keime, S., Adham, I. M. & Engel, W. (1990) Eur. J. Biochem. 190, 195-2001. However, further sequence analysis revealed discrepancies between our clone and that previously reported. Sequencing of the first intron showed similarity with the published data for 54 bases of the 5’ region, beginning with the donor splice site, and for 114 bases at the 3‘ end. However, 500 bases sequenced distal to the initial 54 bases at the 5’ end of intron 1 showed no similarity with the published sequence. In addition, the boundaries of intron 3 differed such that a cytosine residue previously reported to be in exon 3 was found to be the first base of exon 4. Detailed studies were undertaken to confirm that our clone constitutes the authentic sequence of human proacrosin. Cloning and characterization of the human proacrosin gene may allow for informative studies of its regulation, and for a more detailed examination of its role in fertilization During fertilization in mammals, sperm penetration through the egg’s zona pellucida is apparently accomplished through limited proteolysis by the advancing sperm [l]. Acrosin, a proteinase present in sperm acrosomes, from all mammalian species studied including humans, is believed to be responsible for digestion of the zona pellucida by which sperm penetration is facilitated [2 - 41. The primary structure of boar [5,6], human [7,8] and mouse [9,10] proacrosin has been recently deduced from the cloned cDNA obtained from testis cDNA libraries. In addition, a putative nucleotide sequence and exon/intron organization for the human proacrosin gene subcloned from a cosmid library has been recently reported [I I]. We have simultaneously undertaken the cloning of the genomic sequence for human proacrosin. In this report, genomic cloning, sequencing and restriction mapping of the human gene is described. Our findings differ from the published report with regard to the sequence of intron 1 and the positions of codons flanking intron 3. Several experiments provide persuasive evidence that the sequence presented in

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1992.tb17014.x

Jaume Reventós

Papers

Clinical relevance of molecular markers in neuroblastoma: results from a single institution.

FXYD5/Dysadherin, a Biomarker of Endometrial Cancer Myometrial Invasion and Aggressiveness: its Relationship With TGF-β1 and NF-κB Pathways

Role of p53 pathway alterations in uterine carcinosarcomas (malignant mixed Müllerian tumors).

Effect of androgen deprivation therapy in the thyroid function test of patients with prostate cancer.

Molecular cloning, sequencing and restriction mapping of the genomic sequence encoding human proacrosin