Transcriptomic landscape of TIMP3 oncosuppressor activity in thyroid carcinoma.

BACKGROUND: Papillary thyroid cancer (PTC) is the most frequent thyroid tumor. The tissue inhibitor of metalloproteinase-3 (TIMP3) gene encodes a matrix metalloproteinases inhibitor that exerts a tumor suppressor role in several tumor types. TIMP3 is frequently downregulated in PTC by promoter methylation. We have previously functionally demonstrated that TIMP3 exerts an oncosuppressor role in PTC: TIMP3 restoration in the PTC-derived NIM1 cell line affects in vitro migration, invasion and adhesive capability, while reduces tumor growth, angiogenesis and macrophage recruitment in vivo. To get a deeper insight on the mediators of TIMP3 oncosuppressor activity in thyroid tumors, here we focused on the TIMP3 related transcriptome. METHODS: TCGA database was used for investigating the genes differentially expressed in PTC samples with low and high TIMP3 expression. Genome wide expression analysis of clones NIM1-T23 (expressing a high level of TIMP3 protein) and NIM1-EV (control empty vector) was performed. Gene sets and functional enrichment analysis with clusterProfiler were applied to identify the modulated biological processes and pathways. CIBERSORT was used to evaluate the distribution of different immunological cell types in TCGA-PTC tumor samples with different TIMP3 expression levels. Real time PCR was performed for the validation of selected genes. RESULTS: Thyroid tumors with TIMP3-high expression showed a down-modulation of inflammation-related gene sets, along with a reduced protumoral hematopoietic cells fraction; an enrichment of cell adhesion functions was also identified. Similar results were obtained in the TIMP3-overexpessing NIM1 cells in vitro model, where a down-regulation of immune-related function gene sets, some of which also identified in tumor samples, was observed. Interestingly, through enrichment analysis, were also recognized terms related to cell adhesion, extracellular matrix organization, blood vessel maintenance and vascular process functions that have been found modulated in our previous in vitro and in vivo functional studies. CONCLUSIONS: Our results highlight the correlation of TIMP3 expression levels with the regulation of inflammatory functions and the immune infiltration composition associated with different PTC prognosis, thus providing a broader view on the oncosuppressor role of TIMP3 in PTC.

[Plasma lipids and apoproteins. The effect of cigarette smoking]. / Lipidi ed apoproteine plasmatiche. Influenza del fumo di sigaretta.

Cigarette smoking produces lipo-apoprotein modifications, which makes it more atherogenic. In this study we have evaluated lipids and apoproteins in 178 normolipidemic, healthy subjects, in relation to their smoking habits. In smokers we have found lower levels of HDL-cholesterol and apo A-I and higher levels of triglyceride and apo B. Number of cigarette smoked in a day directly correlated with triglycerides and apo B (r = 0.321 and 0.313 respectively) and inversely with HDL-cholesterol (r = -0.274). These alterations seem to be due to an inhibition that smoking could cause on lipolytic processes. Further studies need to establish influences that smoking-related alterations have in the atherosclerotic lesions of smokers.

Electrophysiological aspects of nervous conduction in uremia.

Some neurophysiological techniques have been employed in clinical nephrology to record abnormalities of nervous conduction in central and peripheral pathways. The electrical monitoring on the peripheral and central nervous systems has allowed the detection of uremic neural injury, the diagnosis of specific electrophysiological abnormalities, the evaluation of various treatments employed and the identification of those abnormalities that uremia can induce. A group of 156 subjects subdivided into four groups were examined: 100 healthy subjects (64 M, 36 F); 56 patients (21 glomerulonephritis, 14 pyelonephritis, 5 nephrolithiasis, 5 polycystic kidney, 4 nephroangiosclerosis, 7 undetermined) with chronic renal failure treated with a conventional low nitrogen diet (CLND, 0.6 g/kg b.w./d. of proteins), 8 of whom passed from CLND to a very low nitrogen diet supplemented with alpha-keto-analogues; a group of 22 of these 56 underwent a regular dialysis treatment for 12 to 15 hours/weekly for 40.5 +/- 10.2 months. Three patients of the CLND group and 13 patients underwent renal transplantation after a variable period of RDT. In the uremic patients we found different populations of motor unit potentials; a decreased MNCV was found in 35% of the CLND patients, RDT patients had slowed MNCV in 42%. The SNCV was compromised more frequently than the MNCV. An increased duration of evoked potentials was sometimes observed in CLND and RDT patients inducing us to consider this a hallmark of uremic syndrome. The alpha-keto-analogues and HD/HP treated patients showed an improvement in several features.(ABSTRACT TRUNCATED AT 250 WORDS)

The natural history of uremic neuropathy.

The results obtained by electrophysiological recording allow to discover the constant presence of alterations to the central and/or peripheral nervous system in the uremic syndrome. Thus, it becomes possible to demonstrate the existence of an actual 'uremic neuropathy'. Moreover, the results show the persistence and progression of uremic involvement in the course of dialytic treatment; only after kidney transplantation a return to normal takes place. Methodological and interpretative progress will allow us in the future to broaden our knowledge of uremia by providing a useful guide to therapeutic strategies.

The brainstem auditory evoked responses in Alport's syndrome.

Alport's syndrome is a "hereditary nephritis" associated with structural defects of basement membranes in kidneys, ears and eyes, with variable clinical expression. As the acoustic abnormalities are often subclinical, we studied the brainstem auditory evoked responses (ABR) and tonal audiometry in 12 patients (7 males, 5 females, mean age 32.50 +/- 16.70 years) with histologically documented renal lesions consistent with Alport's syndrome. ABR were used to document the altered acoustic-nerve conduction and transmission typical of the early stage of Alport's syndrome. In 11 patients (seven males, four females), we found bilateral delayed latency (I dx: 2.50 +/- 0.80 msec; III dx: 4.24 +/- 0.68 msec; V dx: 7.02 +/- 0.94 msec) and altered waveform I, III, V by ABR. By audiometry eight patients (six males, two females) showed a loss of medium-high tones, and this group included the patients with a negative ABR study. Therefore, the ABR is abnormal in Alport's syndrome; it may be positive in patients with normal tonal audiometry, usually all cochlear functions are grossly intact; the acoustic-nerve lesions in Alport's syndrome may precede the cochlear involvement and clinical hearing loss; the electrophysiological analysis does not identify the particular nervous structures involved in the acoustic pathways.

Evoked potentials in uremia: basal and follow-up data.

Various EPs have been employed to disclose even early-stage central and peripheral nervous system damage in uremia. This approach also gives the possibility to follow up alterations of many sensory functions during the sequential stages of uremia. Fifty-three subjects (35 male and 18 female, mean age 42.20 +/- 5.50 yrs, conventionally low nitrogen diet treated, on dialysis or transplanted) were followed-up by recording the EPs every year for seven years. The P100 wave latency and amplitude of VEPs were recorded and found abnormal in about 70% of the examined visual systems. The auditory EPs were abnormal in 53% of the cases for the peak latencies, interpeak times and peak ratios. The somatosensory EPs showed in 75% of the cases an altered latency and morphology of the waves registered in the lumbar, cervical and cranial loci. There is evidence suggesting that evoked cerebral biorhythms may provide sensitive and objective indexes of cerebral function in uremia. The persistence of abnormalities disclosed by EPs follow-up confirm the reliability of this technique in evaluating neuro-pathologic uremic situations and in supplying optimal uremia therapies.