Expression of tissue remodelling, inflammation- and angiogenesis-related factors after eccentric exercise in humans.

Eccentric exercise has been extensively used as a model to study the contraction-induced muscle damage and its consequent processes. This study aimed at examining molecular responses associated with tissue remodelling, inflammation and angiogenesis in skeletal muscle during the recovery period after eccentric exercise in humans. Ten healthy men performed 50 maximal eccentric muscle actions with the knee extensors and muscle biopsies were collected from the vastus lateralis before and 6 h, 48 h and 120 h post eccentric exercise. Real Time-PCR was utilized to investigate alterations in gene expression of various tissue remodelling-, inflammation- and angiogenesis-related factors: uPA, uPA-R, TGF-ß1, MMP-9, TNF-α, IL-6, IL-8, VEGF, VEGFR-2, HIF-1a, Ang-1, Ang-2 and Tie-2. The uPA/uPA-R system exhibited a similar time-expression pattern increasing 6 h post exercise (p < 0.05), while the other tissue remodelling factors TGF-ß1 and MMP-9 did not change significantly over time. Transcriptional responses of inflammatory factors TNF-α and IL-8 increased significantly and peaked 6 h post eccentric exercise (p < 0.05), while IL-6 exhibited a similar, though not statistically significant, expression profile (p > 0.05). Similarly, the expression of angiopoietin receptor Tie-2 showed an early increase only at 6 h after the completion of exercise (p < 0.05), while the other angiogenic factors failed to reach statistical significance due a high interindividual variability in the gene expression responses. The early transcriptional upregulation of tissue remodelling, inflammation- and angiogenesis-related factors post eccentric exercise may indicate the acute intramuscular activation of these processes functionally related to muscle damage-induced adaptation.

Correlation of androgen receptor status, neuroendocrine differentiation and angiogenesis with time-to-biochemical failure after radical prostatectomy in clinically localized prostate cancer.

UNLABELLED: The aim of this study was to elucidate the prognostic value of the immunohistochemical detection of the androgen receptor (AR) status, the chromogranin A assessment of neuroendocrine differentiation (NED) and the CD34 assessment of microvessel density (MVD) with time-to-biochemical failure among surgically treated patients with clinically localized prostate cancer. PATIENTS AND METHODS: Surgical specimens from 130 patients with clinically localized prostate cancer, treated with radical prostatectomy, were analyzed by immunohistochemistry on paraffin tissue sections. Full-length follow-up records were available for 94 patients. RESULTS: Biochemical failure was observed in 37% of these patients. A statistically significant inverse relationship was observed between AR status and: (i) seminal vesicle invasion and (ii) surgical margin infiltration. Positive association was also detected between NED and: (i) Gleason's score, (ii) extracapsular extension, (iii) seminal vesicle invasion, (iv) surgical margin infiltration and (v) tumour volume. In addition, MVD was related to: (i) Gleason score, (ii) extracapsular extension, (iii) seminal vesicle invasion, (iv) pelvic lymph node metastasis and (v) tumour volume. Kaplan-Meier survival curves confirmed that Gleason score, extracapsular extension, seminal vesicle invasion, pelvic lymph node metastasis, tumour volume, NED, MVD and coexistence of increased NED and MVD may be potential biochemical failure predictors. However, in the multivariate analysis, MVD was the only independent prognostic factor for biochemical failure. CONCLUSION: A high MVD index can estimate the risk for biochemical failure in clinically localized prostate cancer after radical prostatectomy.

The role of the insulin-like growth factor 1 (IGF-1) in skeletal muscle physiology.

The human insulin-like growth factor-1 (IGF-1) gene gives rise to multiple, heterogeneous mRNA transcripts through a combination of multiple transcription initiation sites, alternative splicing and different polyadenylation signals. These IGF-1 mRNA transcripts code different isoforms of the precursor peptide of IGF-1 (IGF-1Ea, IGF-1Eb and IGF-1Ec or MGF in human skeletal muscle), which also undergo post-translational modification. There is increasing interest in differential expression and implication of IGF-1 isoforms in the regulation of muscle fiber regeneration and hypertrophy following mechanical overloading and damage. The identification of a locally expressed, loading- or damage-sensitive IGF-1 isoform in skeletal muscle was one of the most attractive developments in the context of the autocrine/paracrine actions of IGF-1. The concept that the competing processes of cellular proliferation and differentiation and the increased protein synthesis required for muscle repair or hypertrophic adaptation are regulated by a differential expression and by distinct roles of IGF-1 isoforms is discussed in the present review.

Serum testosterone: A potentially adjunct screening test for the assessment of the risk of prostate cancer among men with modestly elevated PSA values (> or =3.0 and <10.0 ng/ml).

Whether serum testosterone (T) can become an adjunct test able to validate the PSA-weighted risk of prostate cancer (PR.CA) in the "grey" diagnostic area (PSA =3.0 to <10.0 ng/ml) was investigated. Seven hundred and eighteen men participated in a prostate screening program using the cutoff PSA value of > or =3.0 ng/ml. PR.CA was found in 26% (22/85) of men with PSA testing within the "grey" diagnostic area and 58% (7/12) with PSA testing > or =10 ng/ml, among the 97 men who agreed to undergo transrectal ultrasound-guided biopsy (TRUS-guided biopsy). The PSA values showed a statistically significant positive association with diagnosis of PR.CA, whereas T and the T/PSA ratio were inversely and significantly related to the disease. In addition, out of 718 subjects, 45 (2.6%) were found to have a T value <2.6 ng/ml and another 78 (10.8%) had "low normal T value" (2.6> or = T <3.0 ng/ml). Of the hypogonadal men, 16 received testosterone enanthate (depot T; 250 mg/ml oily injection, intramuscularly: i.m.; TRT) and three had PSA levels >3.0 ng/mlpost-TRT; one was eventually diagnosed with PR.CA. An empirically-determined cut-off of the T/PSA ratio [>95 ("negative") or <0.95 ("positive")] was found to be optimal with regard to both sensitivity/specificity. This test was "positive" among 95.5% of the PR.CA patients, whereas 81% of biopsies confirmed that non-PR.CA had a "negative" TIPSA ratio, indicating that this ratio can become an adjunct screening test in assessing the risk of PR. CA; in particular, the odds of PR. CA increasing sharply (1/0.08= 12.5 times) with a decrease of the TIPSA ratio by one standard deviation. We conclude that the measurement of the serum T value can become an adjunct test validating further the PSA-weighted risk of PR. CA within the "grey" diagnostic area.

The PTHrP/PTH.1-R bioregulation system in cardiac hypertrophy: possible therapeutic implications.

Myocardial hypertrophy is associated with specific histological changes, which are representative of the cardiomyocytes cellular response to overload. Evidently, transcriptional modulation of specific genes is implicated in myocardial hypertrophy. Recently, the parathyroid hormone-related protein (PTHrP)/PTH-1 receptor (PTH-1.R) bioregulation system was shown to participate in specific regulatory processes of the cardiomyocyte function and proliferation, which can be related to cardiac hypertrophy and heart failure. We review the literature on the pathophysiology of cardiac hypertrophy vis-a-vis the role of PTHrP/PTH-1.R system as a good therapeutic target.

Parathyroid hormone-related peptide and cardiovascular system.

The parathyroid hormone-related peptide (PTHrP) was initially identified in the early eighties, as the humoral mediator causing hypercalcaemia associated with malignancy. However, recently PTHrP was also shown to mediate a wide range of local paracrine/autocrine and intracrine functions in various tissues under physiological and pathological conditions. Indeed, PTHrP is a polyhormone, which can act through different receptors, including the type 1 parathyroid hormone (PTH) receptor 1 (PTH-1R). In the cardiovascular system, PTHrP appears to have potent effects on vascular smooth muscle cells and cardiomyocytes, where it participates in different pathological conditions, such as ischemia and heart failure. Therefore, it is conceivable that further studies on the regulation of PTHrP expression, characterization of its autocrine/paracrine/intracrine functions and definition of its intracellular signal transduction pathways in cardiomyocytes and cardiac vascular smooth muscle cells can elucidate the potential role of PTHrP in cardiovascular pathophysiology.

The Athens TAVR Registry of newer generation transfemoral aortic valves: 30-day outcomes.

INTRODUCTION: Transcatheter aortic valve replacement (TAVR) is a documented treatment for patients with symptomatic aortic stenosis who are at very high or prohibitive operative risk. We sought to investigate the outcomes of transfemoral procedures with the newer generation valves in four TAVR centres in Athens, Greece. METHODS: The ATHENS TAVR Registry included all patients who underwent transfemoral implantation of the newer generation valves in 4 Athens TAVR centres (self-expanding valve 67 patients, balloon-expandable valve 59 patients). We present the procedural and echocardiographic data and the 30-day clinical outcomes according to valve type. RESULTS: A total of 126 patients underwent 126 procedures (67 CoreValve, Medtronic; 59 SAPIEN XT, Edwards Lifesciences). The mean age and logistic EuroSCORE were 80 ± 8 years and 25 ± 13%. The procedural and device success rates were 100% and 98%, respectively. The 30-day mortality was 1% (n=1), the major vascular event rates 9% (similar for both valve types), and a new permanent pacemaker was implanted more often during the same hospitalisation after CoreValve (33% vs. 9%, p=0.001). The mean effective aortic valve area increased and the mean transvalvular pressure gradient declined post implantation (from 0.66 ± 0.15 cm(2) to 1.61 ± 0.43 cm(2), p<0.001; from 51 ± 14 mm Hg to 10 ± 3 mm Hg, p<0.001). The mean grade of aortic insufficiency increased after CoreValve (from 1.2 ± 0.6 to 1.5 ± 0.7, p=0.03) but remained stable after SAPIEN XT (1.0 ± 0.8 and 1.0 ± 0.6, p=0.88) implantation. CONCLUSIONS: TAVR outcomes with both the newer generation transfemoral valves in the ATHENS Registry were excellent. We observed a greater need for a new permanent pacemaker and a greater degree of aortic valve insufficiency after CoreValve implantation.

Systemic cytokine response following exercise-induced muscle damage in humans.

BACKGROUND: Muscle adaptation which occurs following eccentric exercise-induced muscle damage has been associated with an acute inflammatory response. The purpose of this study was to investigate serum interleukin-6 (IL-6), osteoprotegerin and receptor activator of nuclear factor kB ligand (OPG/RANKL) concentrations following muscle damage. We measured changes for several days following muscle damage. METHODS: Ten healthy young males performed an eccentric exercise protocol using their quadriceps. Blood samples were withdrawn before and at 6 h, 2 days, 5 days and 16 days post-exercise. Functional and clinical measurements were performed before, and on days 1, 2, 5, 8, 12 and 16 post-exercise. RESULTS: The exercise protocol resulted in muscle damage, indicated by changes in biochemical markers. An increase in IL-6 and OPG, and a decrease in RANKL concentrations were seen at 6 h and on day 2 post-exercise; the OPG:RANKL ratio was increased at 6 h post-exercise (p < 0.05). CONCLUSIONS: Changes in IL-6 and OPG/RANKL system may represent systemic responses in muscle inflammation and repair processes. However, further studies are needed to elucidate a potential systemic and/or local role of the OPG/RANKL system in skeletal muscle repair.

Autophagy: a target for therapeutic interventions in myocardial pathophysiology.

BACKGROUND: Autophagy is a major degradative and highly conserved process in eukaryotic cells that is activated by stress signals. This self-cannibalisation is activated as a response to changing environmental conditions, cellular remodelling during development and differentiation, and maintenance of homeostasis. OBJECTIVE: To review autophagy regarding its process, molecular mechanisms and regulation in mammalian cells, and its role in myocardial pathophysiology. RESULTS/CONCLUSION: Autophagy is a multistep process regulated by diverse, intracellular and/or extracellular signalling complexes and pathways. In the heart, normally, autophagy occurs at low basal levels, where it represents a homeostatic mechanism for the maintenance of cardiac function and morphology. However, in the diseased heart the functional role of the enhanced autophagy is unclear and studies have yielded conflicting results. Recently, it was shown that during myocardial ischemia autophagy promotes survival by maintaining energy homeostasis. Also, rapamycin was demonstrated to prevent cardiac hypertrophy. In heart failure, upregulation of autophagy acts as an adaptive response that protects cells from hemodynamic stress. In addition, sirolimus-eluting stents have been shown to lower re-stenosis rates in patients with coronary artery disease after angioplasty. Thus, this mechanism can become a major target for therapeutic intervention in heart pathophysiology.

Combined androgen blockade therapy can convert RT-PCR detection of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) transcripts from positive to negative in the peripheral blood of patients with clinically localized prostate cancer and increase biochemical failure-free survival after curative therapy.

BACKGROUND: The clinical relevance of positive molecular staging as defined by reverse transcriptase-polymerase chain reaction (RT-PCR) detections of both prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) transcripts in the peripheral blood (PB) of patients with prostate cancer is still debatable. METHODS: We analyzed the biochemical failure-free survival (bFFS) of prostate cancer patients with positive molecular staging who underwent immediate curative therapy (Group I, n=39) compared to prostate cancer patients who did convert their positive molecular staging by the administration of combined androgen blockade (CAB) for 12 months prior to curative treatment (Group II, n=15). RESULTS: The median bFFS for Group I was 9 months (95% CI 5-13 months) and was significantly lower compared to Group II (>36 months, p<0.001). In Group I, the median time for PSA values of >2.0 ng/mL was 18 months (95% CI 12-21 months, range 12-36 months). Notably, only one patient from Group II reached PSA values>2.0 ng/mL at 36 months post-curative treatment. CONCLUSIONS: In patients with clinically localized prostate cancer and positive RT-PCR detection of PSA and PSMA transcripts in PB, CAB can convert positive molecular staging status to negative and by doing so it modifies the post-curative therapy bFFS of patients with clinically localized prostate cancer.

Molecular detection of tyrosinase transcripts in peripheral blood from patients with malignant melanoma: correlation of PCR sensitivity threshold with clinical and pathologic disease characteristics.

BACKGROUND: Positive molecular detection of tyrosinase transcripts (TYR mRNA) in RNA extracts of peripheral blood (PB) samples from patients with malignant melanoma provides evidence of disease dissemination. METHODS: Total RNA extracted from PB was quantified and subjected to RT-PCR under ultra-sensitive and reduced-sensitivity PCR conditions using SSRT-II. Positive TYR mRNA detection in 78 melanoma patients and 40 healthy volunteers was correlated with clinical stage, Breslow's evaluation of tumor thickness, Clark's assessment of tumor invasion, the location of the primary tumor site, and tumor histology. The assay sensitivity was evaluated by spiking PB with the melanoma cell line SK-MEL-28. RESULTS: Using ultra-sensitive PCR conditions, eight out of 40 RNA (20%) samples from healthy volunteers and 50 out of 78 RNA (64.1%) samples from melanoma patients tested positive. Using reduced-sensitivity PCR conditions, we found only two positives in 40 RNA samples from healthy subjects and 20 positives in 78 RNA samples (25.6%) from melanoma patients. Only positive PCR samples for the reduced-sensitivity PCR assay correlated significantly with stage IV (metastatic) disease (p=0.0395). There was no significant correlation between positive TYR mRNA samples for either PCR condition (ultra-sensitive and reduced-sensitivity) with Breslow's classification of tumor thickness, Clark's assessment of tumor invasion, location of the primary tumor site, and type of tumor histology. CONCLUSIONS: We conclude that reduced-sensitivity rather than ultra-sensitive PCR conditions correlate with clinical stage in melanoma patients.

Combination therapy using LHRH and somatostatin analogues plus dexamethasone in androgen ablation refractory prostate cancer patients with bone involvement: a bench to bedside approach.

The development of resistance to anticancer therapies is a major hurdle in preventing long-lasting clinical responses to conventional therapies in hormone-refractory prostate cancer. Herein, the molecular evidence documenting that bone metastasis microenvironment survival factors (mainly the paracrine growth hormone-independent, urokinase-type plasminogen activator-mediated increase of IGF-1 and the endocrine production of growth hormone-dependent IGF-1, mainly liver-derived IGF-1 production) produce an epigenetic form of prostate cancer cells that are resistant to proapoptotic therapies is reviewed. Consequently, the authors present the conceptual framework of a novel antibone microenvironment survival factor, mainly an anti-IGF-1 hormonal manipulation for androgen ablation refractory prostate cancer (a combination of conventional androgen ablation therapy [luteinising hormone-releasing hormone agonist-A or orchiectomy]) with dexamethasone plus somatostatin analogue, which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients.