Functional Tricuspid Regurgitation Repair at the time of Left-Sided Valve Surgery. the Impact on the Cardiac Rehabilitation Program

Objective: to compare the early post-operative functional status and the efficacy of the cardiac rehabilitation program (CRP) after isolated left-sided valvular surgery or with concomitant tricuspid valve repair (TVR). Methods: we retrospectively enrolled patients admitted to the Cardiac Rehabilitation Unit of our institution from January 2014 to January 2019, following mitral or aortic valve surgery. In agreement with current guidelines, concomitant tricuspid annuloplasty was added to patients with severe functional tricuspid regurgitation (TR) and in those with mild to moderate TR when annulus dilatation was present. A 6-minute walk test (6mWT) was performed within the second day of admission and repeated predischarge. The distances walked on the 6mWT were reported as absolute value and as a percentage of the predicted value, taking into account anthropometric variables. Changes in the 6mWT performance and Barthel index (BI) were assessed to evaluate the impact of CRP on exercise tolerance and functional independence, respectively. Results: of 117 patients, 62 (53%) had isolated left-sided valvular surgery and 55 (47%) had concomitant TVR. There were no significant differences between the two groups in the baseline 6mWT performance and its improvement at the end of CRP. TVR was associated with a worse BI on admission, but with a greater improvement after the CRP and a pre-discharge BI comparable to isolated left-sided surgery. Upon linear regression analysis, diabetes and chronic renal disease were predictors of the baseline 6mWT performance. Conclusion: TVR does not affect the early post-operative functional status and the efficacy of the CRP after valvular surgery

Prognostic relevance of a T-type calcium channels gene signature in solid tumours: A correlation ready for clinical validation

BackgroundT-type calcium channels (TTCCs) mediate calcium influx across the cell membrane. TTCCs regulate numerous physiological processes including cardiac pacemaking and neuronal activity. In addition, they have been implicated in the proliferation, migration and differentiation of tumour tissues. Although the signalling events downstream of TTCC-mediated calcium influx are not fully elucidated, it is clear that variations in the expression of TTCCs promote tumour formation and hinder response to treatment.MethodsWe examined the expression of TTCC genes (all three subtypes; CACNA-1G, CACNA-1H and CACNA-1I) and their prognostic value in three major solid tumours (i.e. gastric, lung and ovarian cancers) via a publicly accessible database.ResultsIn gastric cancer, expression of all the CACNA genes was associated with overall survival (OS) among stage I-IV patients (all pConclusionsAlterations in CACNA gene expression are linked to tumour prognosis. Gastric cancer represents the most promising setting for further evaluation

The cadherin–catenin complex in nasopharyngeal carcinoma

Abnormal Wnt signaling and impaired cell–cell adhesion due to abnormal E-cadherin and β-catenin function have been implicated in many cancers, but have not been fully explored in nasopharyngeal carcinoma. The aim of this study was to analyze β-Catenin cellular location and E-cadherin expression levels in nasopharyngeal carcinoma. E-cadherin expression levels were also correlated with clinical data and underlying pathology. β-Catenin and E-cadherin expression were examined in 18 nasopharyngeal carcinoma and 7 non-tumoral inflammatory pharynx tissues using immunohistochemical methods. Patient clinical data were collected, and histological evaluation was performed by hematoxylin/eosin staining. β-catenin was detected in membrane and cytoplasm in all cases of nasopharyngeal carcinoma, regardless of histological type; in non-tumoral tissues, however, β-catenin was observed only in the membrane. As for E-cadherin expression levels, strong staining was observed in most non-tumoral tissues, but staining was only moderate in nasopharyngeal carcinoma tissues. E-cadherin expression was associated with β-catenin localization, study group, metastatic disease, and patient outcomes. Reduced levels of E-cadherin protein observed in nasopharyngeal carinoma may play an important role in invasion and metastasis. Cytoplasmic β-catenin in nasopharyngeal carcinoma may impair cell–cell adhesion, promoting invasive behavior and a metastatic tumor phenotype

The cadherin–catenin complex in laryngeal squamous cell carcinoma

Abnormal Wnt signaling and impaired cell–cell adhesion due to abnormal E-cadherin and β-catenin function have been implicated in many cancers, but have not been fully explored in laryngeal squamous cell carcinoma. In this study, β-catenin cellular location and E-cadherin expression levels were analyzed in 16 laryngeal squamous cell carcinomas (LSCCs) (9 glottic and 7 supraglottic) and 11 samples of non-tumoral inflammatory larynx tissue, using immunohistochemical methods. All non-tumoral tissues showed equally strong membranous expression of β-catenin, while cytoplasmic expression was found in only 3 of the 11 samples. By contrast, whereas 8/9 glottic LSCCs exhibited only membranous expression of β-catenin, 6/7 supraglottic LSCCs displayed both membranous and cytoplasmic expression (p = 0.003). Strong E-cadherin staining was observed in 9/11 non-tumoral tissues and 7/9 glottic LSCCs, whereas 4/7 supraglottic LSCCs exhibited weak expression. Reduced membrane expression of E-cadherin and cytoplasmic retention of β-catenin in supraglottic LSCC seems to be related with more aggressive biological behavior which has been described in clinical studies. Further research is required to clarify the involvement of β-catenin in the mechanism associated with malignant transformation in laryngeal tissues

Philadelphia-like acute lymphoblastic leukemia is associated with minimal residual disease persistence and poor outcome. First report of the minimale residual disease-oriented GIMEMA LAL1913

Early recognition of Ph-like acute lymphoblastic leukemia cases could impact on the management and outcome of this subset of B-lineage ALL. To assess the prognostic value of the Ph-like status in a pediatric-inspired, minimal residual disease (MRD)-driven trial, we screened 88 B-lineage ALL cases negative for the major fusion genes (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1 and KTM2Ar) enrolled in the GIMEMA LAL1913 front-line protocol for adult BCR/ABL1-negative ALL. The screening - performed using the “BCR/ABL1-like predictor” - identified 28 Ph-like cases (31.8%), characterized by CRLF2 overexpression (35.7%), JAK/STAT pathway mutations (33.3%), IKZF1 (63.6%), BTG1 (50%) and EBF1 (27.3%) deletions, and rearrangements targeting tyrosine kinases or CRLF2 (40%). The correlation with outcome highlighted that: i) the complete remission (CR) rate was significantly lower in Ph-like compared to non-Ph-like cases (74.1% vs 91.5%, p=0.044); ii) at time point 2 (TP2), decisional for transplant allocation, 52.9% of Ph-like cases vs 20% of non-Phlike were MRD-positive (p=0.025); iii) the Ph-like profile was the only parameter associated with a higher risk of being MRD-positive at TP2 (p=0.014); iv) at 24 months, Ph-like patients had a significantly inferior event-free and disease-free survival compared to non-Ph-like patients (33.5% vs 66.2%, p=0.005 and 45.5% vs 72.3%, p=0.062, respectively). This study documents that Ph-like patients have a lower CR rate, EFS and DFS, as well as a greater MRD persistence also in a pediatric-oriented and MRD-driven adult ALL protocol, thus reinforcing that the early recognition of Ph-like ALL patients at diagnosis is crucial to refine risk-stratification and to optimize therapeutic strategies

Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC) patients

BACKGROUND: The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients. Functional polymorphisms within the cytochrome P450 1B1 (CYP1B1) gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen. METHODS: CYP1B1 genotyping was performed on blood samples of 60 CRPC patients treated with docetaxel, using TaqMan probes-based assays. Association between CYP1B1-142C>G (leading to the 48ArgGly transition), 4326C>G (432LeuVal), and 4390A>G (453AsnSer) polymorphisms and treatment response, progression-free-survival (PFS) and overall-survival (OS) was estimated using Pearson χ2 test, Kaplan-Meier curves and Log-rank test. RESULTS: Patients carrying the CYP1B1-432ValVal genotype experienced a significantly lower response-rate (P = 0.014), shorter progression-free-survival (P = 0.032) and overall-survival (P < 0.001). Multivariate analyses and correction for multiple comparisons confirmed its prognostic significance for OS. No significant associations were found among other polymorphisms and both response and clinical outcome. CONCLUSIONS: CYP1B1-4326C>G (432LeuVal) polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization. Larger prospective trials are warranted to validate these findings, which might be applied to the future practice of CRPC treatment

The non-coding transcriptome as a dynamic regulator of cancer metastasis.

Since the discovery of microRNAs, non-coding RNAs (NC-RNAs) have increasingly attracted the attention of cancer investigators. Two classes of NC-RNAs are emerging as putative metastasis-related genes: long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs). LncRNAs orchestrate metastatic progression through several mechanisms, including the interaction with epigenetic effectors, splicing control and generation of microRNA-like molecules. In contrast, snoRNAs have been long considered "housekeeping" genes with no relevant function in cancer. However, recent evidence challenges this assumption, indicating that some snoRNAs are deregulated in cancer cells and may play a specific role in metastasis. Interestingly, snoRNAs and lncRNAs share several mechanisms of action, and might synergize with protein-coding genes to generate a specific cellular phenotype. This evidence suggests that the current paradigm of metastatic progression is incomplete. We propose that NC-RNAs are organized in complex interactive networks which orchestrate cellular phenotypic plasticity. Since plasticity is critical for cancer cell metastasis, we suggest that a molecular interactome composed by both NC-RNAs and proteins orchestrates cancer metastasis. Interestingly, expression of lncRNAs and snoRNAs can be detected in biological fluids, making them potentially useful biomarkers. NC-RNA expression profiles in human neoplasms have been associated with patients' prognosis. SnoRNA and lncRNA silencing in pre-clinical models leads to cancer cell death and/or metastasis prevention, suggesting they can be investigated as novel therapeutic targets. Based on the literature to date, we critically discuss how the NC-RNA interactome can be explored and manipulated to generate more effective diagnostic, prognostic, and therapeutic strategies for metastatic neoplasms

FACTS AND IDEAS IN MODERN COSMOLOGY

A review of the principles of observational testing of cosmological theories is given with a special emphasis on the distinction between observational facts and theoretical hypotheses. A classification of modern cosmological theories and possible observational tests for these theories is presented. The main rival cosmological models are analyzed from the point of view of observational testing of their initial hypothesis. A comparison of modern observational data with theoretical predictions is presented. In particular we discuss in detail the validity of the two basic assumptions of modern cosmology that are the Cosmological Principle and the Expanding Space Paradigm. It is found that classical paradigms need to be reanalyzed and that it is necessary to develop crucial cosmological tests to discriminate alternative theories.Comment: 84 pages, latex, figures are available to F.S.L ([email protected]). Accepted for publication in Vistas In astronomy, Vol.38, Part.4, 199