Metabolic reprogramming of mitochondrial respiration in metastatic cancer.

Tumor initiation, progression, and metastasis are tissue context-dependent processes. Cellular and non-cellular factors provide the selective microenvironment that determines the fate of the evolving tumor through mechanisms that include metabolic reprogramming. Genetic and epigenetic changes contribute to this reprogramming process, which is orchestrated through ongoing communication between the mitochondrial and nuclear genomes. Metabolic flexibility, in particular the ability to rapidly adjust the balance between glycolytic and mitochondrial energy production, is a hallmark of aggressive, invasive, and metastatic cancers. Tumor cells sustain damage to both nuclear and mitochondrial DNA during tumorigenesis and as a consequence of anticancer treatments. Nuclear and mitochondrial DNA mutations and polymorphisms are increasingly recognized as factors that influence metabolic reprogramming, tumorigenesis, and tumor progression. Severe mitochondrial DNA damage compromises mitochondrial respiration. When mitochondrial respiration drops below a cell-specific threshold, metabolic reprogramming and plasticity fail to compensate and tumor formation is compromised. In these scenarios, tumorigenesis can be restored by acquisition of respiring mitochondria from surrounding stromal cells. Thus, intercellular mitochondrial transfer has the potential to confer treatment resistance and to promote tumor progression and metastasis. Understanding the constraints of metabolic, and in particular bioenergetic reprogramming, and the role of intercellular mitochondrial transfer in tumorigenesis provides new insights into addressing tumor progression and treatment resistance in highly aggressive cancers.

Baldness and testicular cancer: the EPSAM case-control study.

The etiology of testicular cancer is largely unexplained. Research has mainly focused on prenatal exposures, especially to sex hormones, while less attention has been paid to exposures that may act also postnatally. As baldness has been previously associated with testicular cancer risk we focused on baldness and body hairiness, which are both associated with androgen activity. We used data of the Postnatal Exposures and Male Health (EPSAM) study, a case-control study on testicular cancer conducted in the Province of Turin, Italy, involving cases diagnosed between 1997 and 2008. Information was collected using mailed questionnaires. Analyses included 255 cases and 459 controls. We calculated ORs and 95% CIs to estimate testicular cancer risk among those who developed baldness and among those with body hairiness. We found an inverse association between testicular cancer and baldness (OR: 0.67, 95% CI: 0.46-0.98) and body hairiness (OR: 0.78, 95% CI: 0.53-1.16), although the latter had wider CIs. The inverse association between baldness and testicular cancer is consistent with the results from previous studies. These results suggest that androgens activity may influence testicular cancer risk.

Integrative molecular profiling of routine clinical prostate cancer specimens.

BACKGROUND: Comprehensive molecular profiling led to the recognition of multiple prostate cancer (PCa) molecular subtypes and driving alterations, but translating these findings to clinical practice is challenging. PATIENTS AND METHODS: We developed a formalin-fixed paraffin-embedded (FFPE) tissue compatible integrative assay for PCa molecular subtyping and interrogation of relevant genetic/transcriptomic alterations (MiPC). We applied MiPC, which combines capture-based next generation sequencing and quantitative reverse transcription PCR (qRT-PCR), to 53 FFPE PCa specimens representing cases not well represented in frozen tissue cohorts, including 8 paired primary tumor and lymph node metastases. Results were validated using multiplexed PCR based NGS and Sanger sequencing. RESULTS: We identified known and novel potential driving, somatic mutations and copy number alterations, including a novel BRAF T599_V600insHT mutation and CYP11B2 amplification in a patient treated with ketoconazole (a potent CYP11B2 inhibitor). qRT-PCR integration enabled comprehensive molecular subtyping and provided complementary information, such as androgen receptor (AR) target gene module assessment in advanced cases and SPINK1 over-expression. MiPC identified highly concordant profiles for all 8 tumor/lymph node metastasis pairs, consistent with limited heterogeneity amongst driving events. MiPC and exome sequencing were performed on separately isolated conventional acinar PCa and prostatic small cell carcinoma (SCC) components from the same FFPE resection specimen to enable direct comparison of histologically distinct components. While both components showed TMPRSS2:ERG fusions, the SCC component exclusively harbored complete TP53 inactivation (frameshift variant and copy loss) and two CREBBP mutations. CONCLUSIONS: Our results demonstrate the feasibility of integrative profiling of routine PCa specimens, which may have utility for understanding disease biology and enabling personalized medicine applications.

Global DNA hypomethylation in prostate cancer development and progression: a systematic review.

BACKGROUND: The role of global DNA methylation in prostate cancer (PCa) remains largely unknown. Our aim was to summarize evidence on the role of global DNA hypomethylation in PCa development and progression. METHODS: We searched PubMed through December 2013 for all studies containing information on global methylation levels in PCa tissue and at least one non-tumor comparison tissue and/or studies reporting association between global methylation levels in PCa tissue and survival, disease recurrence or at least one clinicopathological prognostic factor. We summarized results using non-parametric comparisons and P-value summary methods. RESULTS: We included 15 studies in the review: 6 studies with both diagnostic and prognostic information, 5 studies with only diagnostic information and 4 studies with only prognostic information. Quantitative meta-analysis was not possible because of the large heterogeneity in molecular techniques, types of tissues analyzed, aims and study designs. Summary statistical tests showed association of DNA hypomethylation with PCa diagnosis (P<0.006) and prognosis (P<0.001). Restriction to studies assessing 5-methylcytosine or long interspersed nucleotide element-1 revealed results in the same direction. Analyses restricted to specific clinicopathological features showed association with the presence of metastasis and tumor stage in all tests with P<0.03, and no association with Gleason score (all tests P>0.1 except for the weighted Z-test, P=0.05). CONCLUSION: DNA hypomethylation was associated with PCa development and progression. However, due to the heterogeneity and small sample sizes of the included studies, along with the possibility of publication bias, this association requires additional assessment.

18F-FDG uptake and calcifications on positron emission tomography/computed tomography in octogenarians with severe aortic stenosis.

AIM: The degree of inflammation within the atherosclerotic plaque can be detected non-invasively by positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG). The incidence of aortic plaques with 18F-FDG increased uptake in octogenarians with aortic stenosis is unknown. Aim of this study was to evaluate the frequency of inflamed aortic atherosclerotic plaques in octogenarians with or without severe aortic stenosis and their correlations with calcifications. METHODS: The study group comprised 27 patients older than 80 years who underwent a 18FDG PET/CT. Nine patients with severe symptomatic aortic stenosis, eligible to TAVI procedure (TAVI Group), and 18 patients age and sex matched, without clinical evidence of aortic stenosis (No TAVI Group), were selected and analysed. RESULTS: In the whole population 4/27 patients (9.3%) had a significant focal aortic vessel wall 18F-FDG increased uptake: 1 patient (11.1%) in TAVI group and 3 in non-TAVI Group (16.7%). Overall 81 aortic segments were analysed. 18F-FDG uptake rates were similar in the two groups (1/27, 3.7% in TAVI Group and 3/54, 5.5% in No TAVI Group, P=0.7). At CT scan calcifications were significantly more frequent in the TAVI Group compared to non-TAVI Group (23/27, 85.2% and 28/54, 51.8% P=0.005). None of the sites of arterial calcification had an increased focal 18F-FDG uptake. CONCLUSION: Irrespectively to the presence of aortic stenosis, a significant FDG plaque uptake in octogenarians is rare while calcifications are extremely frequent.

The neuronal repellent SLIT2 is a target for repression by EZH2 in prostate cancer.

The neuronal repellent SLIT2 is repressed in a number of cancer types primarily through promoter hypermethylation. SLIT2, however, has not been studied in prostate cancer. Through genome-wide location analysis we identified SLIT2 as a target of polycomb group (PcG) protein EZH2. The EZH2-containing polycomb repressive complexes bound to the SLIT2 promoter inhibiting its expression. SLIT2 was downregulated in a majority of metastatic prostate tumors, showing a negative correlation with EZH2. This repressed expression could be restored by methylation inhibitors or EZH2-suppressing compounds. In addition, a low level of SLIT2 expression was associated with aggressive prostate, breast and lung cancers. Functional assays showed that SLIT2 inhibited prostate cancer cell proliferation and invasion. Thus, this study showed for the first time the epigenetic silencing of SLIT2 in prostate tumors, and supported SLIT2 as a potential biomarker for aggressive solid tumors. Importantly, PcG-mediated repression may serve as a precursor for the silencing of SLIT2 by DNA methylation in cancer.

Severe degenerative aortic stenosis: when a senile patient is a candidate for surgery.

Senile aortic stenosis is characterized by calcific degeneration of the valve that prevents the full opening of the cusps in systole. The disease may be silent for many years despite the presence of severe flow obstruction and generally is associated with aortic regurgitation and calcification of the coronary arteries. The continuous increase of the aged population with aortic stenosis entails difficult decisions in selecting the candidates for aortic valve replacement in order to optimize the timing for surgery. Although clinical examination is still fundamental for the diagnosis of the disease and the screening of the population, noninvasive assessment by Doppler echocardiography has transformed the management of these patients. The procedure allows better identification of patients who may benefit from valve replacement in particular in the setting of a ''low output/low gradient'' state and permits a follow-up of the progression of the disease in patients who are not yet candidates for surgery. It also allows a decrease in the utilization of invasive hemodynamics becoming a cost benefit tool for the health system. When performed properly, it is relatively time consuming, needs experience but offers major anatomic and hemodynamic data. Under these circumstances, cardiac catheterization is required only in cases when there is discordance between the clinical assessment and cardiac ultrasound evaluation. In this review we summarize the prevalence and significance of the disease in the elderly population and the use of all recent echocardiographic data that may help select the true candidates for surgery.

Usefulness of glycoprotein IIb/IIIa inhibitors in unstable angina due to small vessel disease.

We describe the role of abciximab in unstable angina due to small vessel disease in a 58-year-old patient who was submitted to percutaneous transluminal coronary angioplasty and stenting of an occluded venous graft.

[Pulmonary hypertrophic osteoarthropathy of Pierre-Marie-Bamberger. Discussion of 5 cases and review of the literature]. / Osteoartropatia ipertrofizzante pneumica di Pierre-Marie-Bamberger. Discussione su cinque casi e revisione della letteratura.

Hypertrophic osteoarthropathy (HOA) may be defined as a syndrome of chronic proliferative periostitis of the long bones, clubbing of the fingers and toes, arthralgia and or arthritis, oligo- or polysynovitis. It is often associated with primary pulmonary carcinoma, rarely with other intra- or extrathoracic disease processes. With the present report, the Authors would like to contribute some informations on the clinical aspects of pulmonary HOA and a review of literature.

[The effect of plasma nitriding on tungsten burs]. / Ricerche sperimentali sugli effetti della nitrurazione in plasma di frese al tungsteno.

The authors have experimented the nitriding's effects on some cilindrical burs carbide utilized in dentistry after disamination on the applications methodics on plasma nitriding in neurosurgery, orthopedic surgery and in odontotherapy. This reacherys point out that nitriding plasma a durings increase and cutis greater capacity establish.

C. T. criteria of the differential diagnosis in primary retroperitoneal masses.

This personal series of 44 primary retroperitoneal masses (P.R.P.M.) studied by C. T. is analyzed. The reliability of C. T. in the identification (44/44), characterization (43/44) and origin evaluation (41/44) of P.R.P.M. has been absolutely satisfactory. In particular, those criteria of C. T. diagnosis which may be utilized in the evaluation of the origin of upper abdominal masses are thoroughly described. The evaluation of the involvement (non invasive; invasive) of adjacent viscera has been achieved in 22/38 P.R.P.M. verified at operation. The evaluation of tumour resectability has been less reliable due to the high incidence of under-diagnosis (60% in our personal experience). C. T. may be used in addition as an aid to different diagnostic techniques (percutaneous guided needle biopsy) or to therapy (drainage of retroperitoneal abscesses). C. T. is absolutely necessary in the follow-up of P.R.P.M. after surgery, radiotherapy or chemotherapy.