Prognostic impact of alternative splicing-derived hMENA isoforms in resected, node-negative, non-small-cell lung cancer

Risk assessment and treatment choice remain a challenge in early non-small-cell lung cancer (NSCLC). Alternative splicing is an emerging source for diagnostic, prognostic and therapeutic tools. Here, we investigated the prognostic value of the actin cytoskeleton regulator hMENA and its isoforms, hMENA(11a) and hMENA Delta v6, in early NSCLC. The epithelial hMENA(11a) isoform was expressed in NSCLC lines expressing E-CADHERIN and was alternatively expressed with hMENA Delta v6. Enforced expression of hMENA Delta v6 or hMENA(11a) increased or decreased the invasive ability of A549 cells, respectively. hMENA isoform expression was evaluated in 248 node-negative NSCLC. High pan-hMENA and low hMENA(11a) were the only independent predictors of shorter disease-free and cancer-specific survival, and low hMENA(11a) was an independent predictor of shorter overall survival, at multivariate analysis. Patients with low pan-hMENA/high hMENA(11a) expression fared significantly better (P <= 0.0015) than any other subgroup. Such hybrid variable was incorporated with T-size and number of resected lymph nodes into a 3-class-risk stratification model, which strikingly discriminated between different risks of relapse, cancer-related death, and death. The model was externally validated in an independent dataset of 133 patients. Relative expression of hMENA splice isoforms is a powerful prognostic factor in early NSCLC, complementing clinical parameters to accurately predict individual patient risk

Transperineal laser ablation for percutaneous treatment of benign prostatic hyperplasia: a feasibility study. Results at 6 and 12 months from a retrospective multi-centric study

To investigate the effectiveness and safety of SoracteLite™-transperineal percutaneous laser ablation (TPLA) in the treatment of patients with symptomatic benign prostatic hyperplasia (BPH) at 6 and 12 months follow-up. Purpose: To investigate the effectiveness and safety of SoracteLite™—transperineal percutaneous laser ablation (TPLA) in the treatment of patients with symptomatic benign prostatic hyperplasia (BPH) at 6 and 12 months follow-up. Methods: Patients with urinary symptoms secondary to BPH underwent TPLA under local anesthesia in four centers. Under US guidance, up to four 21G applicators were inserted in the prostatic tissue. Each treatment was performed with diode laser operating at 1064 nm changing the illumination time according to prostate size. The primary end-points of this study were change in IPSS, PVR, Qmax, QoL, and prostatic volume at 6 an 12 months from SoracteLiteTM TPLA treatment. Secondary end-point was the assessment of complications. Results: Analysis was performed on data 160 patients (mean age 69.8 ± 9.6 years) with at least 6 months follow and of 83 patients (mean age 67.9 ± 8.7 years) with at least 12 months follow-up. At 6 months, IPSS improved from 22.5 ± 5.1 to 7.7 ± 3.3 (P < 0.001), PVR from 89.5 ± 84.6 to 27.2 ± 44.5 ml (P < 0.001), Qmax from 8.0 ± 3.8 to 14.3 ± 3.9 ml/s (P < 0.001), QoL from 4.5 ± 1.1 to 1.8 ± 1.0 (P < 0.001), volume from 75.0 ± 32.4 to 60.3 ± 24.5 ml (P < 0.001). At 12 months, IPSS improved from 22.5 ± 4.5 to 7.0 ± 2.9 (P < 0.001), PVR from 71.7 ± 93.9 to 17.8 ± 51.0 ml (P < 0.001), Qmax from 8.6 ± 5.2 to 15.0 ± 4.0 ml/s (P < 0.001), QoL from 4.2 ± 0.6 to 1.6 ± 0.9 (P < 0.001), volume from 87.9 ± 31.6 to 58.8 ± 22.9 ml (P < 0.001). 7/160 (4.3%) grade I and 1/160 (0.6%) grade III complication occurred. Conclusions: SoracteLite™ TPLA allows significant improvement of IPSS, Qol, Qmax, PVR, and reduction of prostatic volume at 6 and 12 months

Molecular and genetic bases of pancreatic cancer

Pancreatic cancer remains a formidable challenge for oncologists and patients alike. Despite intensive efforts, attempts at improving survival in the past 15 years, particularly in advanced disease, have failed. This is true even with the introduction of molecularly targeted agents, chosen on the basis of their action on pathways that were supposedly important in pancreatic cancer development and progression: indeed, with the notable exception of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, that has provided a minimal survival improvement when added to gemcitabine, other agents targeting EGFR, matrix metallo-proteases, farnesyl transferase, or vascular endothelial growth factor have not succeeded in improving outcomes over standard gemcitabine monotherapy for a variety of different reasons. However, recent developments in the molecular epidemiology of pancreatic cancer and an ever evolving understanding of the molecular mechanisms underlying pancreatic cancer initiation and progression raise renewed hope to find novel, relevant therapeutic targets that could be pursued in the clinical setting. In this review we focus on molecular epidemiology of pancreatic cancer, epithelial-to-mesenchymal transition and its influence on sensitivity to EGFR-targeted approaches, apoptotic pathways, hypoxia-related pathways, developmental pathways (such as the hedgehog and Notch pathways), and proteomic analysis as keys to a better understanding of pancreatic cancer biology and, most importantly, as a source of novel molecular targets to be exploited therapeutically. © 2012 Bentham Science Publishers

Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors

Human mena (hMENA), a member of the actin cytoskeleton regulators Ena/VASP, is overexpressed in high-risk preneoplastic lesions and in primary breast tumors and has been identified as playing a role in invasiveness and poor prognosis in breast cancers that express HER2. Here we identify a unique isoform, hMENA Delta v6, derived from the hMENA alternative splicing program. In an isogenic model of human breast cancer progression, we show that hMENA(11a) is expressed in premalignant cells, whereas hMENA Delta v6 expression is restricted to invasive cancer cells. "Reversion" of the malignant phenotype leads to concurrent down-regulation of all hMENA isoforms. In breast cancer cell lines, isoform-specific hMENA overexpression or knockdown revealed that in the absence of hMENA(11a), overexpression of hMENA Delta v6 increased cell invasion, whereas overexpression of hMENA(11a) reduced the migratory and invasive ability of these cells. hMENA(11a) splicing was shown to be dependent on the epithelial regulator of splicing 1 (ESRP1), and forced expression of ESRP1 in invasive mesenchymal breast cancer cells caused a phenotypic switch reminiscent of a mesenchymal-to-epithelial transition (MET) characterized by changes in the cytoskeletal architecture, reexpression of hMENA(11a), and a reduction in cell invasion. hMENA-positive primary breast tumors, which are hMENA(11a)-negative, are more frequently E-cadherin low in comparison with tumors expressing hMENA(11a). These data suggest that polarized and growth-arrested cellular architecture correlates with absence of alternative hMENA isoform expression, and that the hMENA splicing program is relevant to malignant progression in invasive disease

Molecular and genetic bases of pancreatic cancer.

Pancreatic cancer remains a formidable challenge for oncologists and patients alike. Despite intensive efforts, attempts at improving survival in the past 15 years, particularly in advanced disease, have failed. This is true even with the introduction of molecularly targeted agents, chosen on the basis of their action on pathways that were supposedly important in pancreatic cancer development and progression: indeed, with the notable exception of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, that has provided a minimal survival improvement when added to gemcitabine, other agents targeting EGFR, matrix metallo-proteases, farnesyl transferase, or vascular endothelial growth factor have not succeeded in improving outcomes over standard gemcitabine monotherapy for a variety of different reasons. However, recent developments in the molecular epidemiology of pancreatic cancer and an ever evolving understanding of the molecular mechanisms underlying pancreatic cancer initiation and progression raise renewed hope to find novel, relevant therapeutic targets that could be pursued in the clinical setting. In this review we focus on molecular epidemiology of pancreatic cancer, epithelial-to-mesenchymal transition and its influence on sensitivity to EGFR-targeted approaches, apoptotic pathways, hypoxia-related pathways, developmental pathways (such as the hedgehog and Notch pathways), and proteomic analysis as keys to a better understanding of pancreatic cancer biology and, most importantly, as a source of novel molecular targets to be exploited therapeutically

The first case of congenital myasthenic syndrome caused by a large homozygous deletion in the cterminal region of colq (Collagen like tail subunit of asymmetric acetylcholinesterase) protein

Congenital myasthenic syndromes (CMSs) are caused by mutations in genes that encode proteins involved in the organization, maintenance, function, or modification of the neuromuscular junction. Among these, the collagenic tail of endplate acetylcholinesterase protein (COLQ; MIM 603033) has a crucial role in anchoring the enzyme into the synaptic basal lamina. Here, we report on the first case of a patient with a homozygous deletion affecting the last exons of the COLQ gene in a CMS patient born to consanguineous parents of Pakistani origin. Electromyography (EMG), electroencephalography (EEG), clinical exome sequencing (CES), and single nucleotide polymorphism (SNP) array analyses were performed. The subject was born at term after an uneventful pregnancy and developed significant hypotonia and dystonia, clinical pseudoseizures, and recurring respiratory insufficiency with a need for mechanical ventilation. CES analysis of the patient revealed a homozygous deletion of the COLQ gene located on the 3p25.1 chromosome region. The SNP-array confirmed the presence of deletion that extended from exon 11 to the last exon 17 with a size of 19.5 Kb. Our results add new insights about the underlying pathogenetic mechanisms expanding the spectrum of causative COLQ mutations. It is relevant, considering the therapeutic implications, to apply suitable molecular approaches so that no type of mutation is missed: “each lost mutation means a baby treated improperly”

Impact of COVID-19 pandemic on timing and early clinical outcomes of transcatheter aortic valve implantation

Background: We sought to investigate the applicability and outcomes of a novel system to manage patients requiring transcatheter aortic valve implantation (TAVI) at a tertiary level hospital during the coronavirus disease-2019 (COVID-19) pandemic. Methods: To analyse the impact of hospitalisation pathways during the pandemic on clinical outcomes of TAVI patients, the study population was divided into two groups (pre-pandemic and pandemic groups) and all perioperative/follow-up data were compared. The primary endpoint was all-cause mortality at 30 days; secondary endpoints included procedural success and short-term complications. Results: A total of 315 patients received TAVI during the study period. Pandemic group (n = 77) showed a more complex baseline clinical profile (NYHA class III-IV, 70.1% vs. 56.3%; p = 0.03). The overall time to procedure was significantly longer during pandemic (56.9 ± 68.3 vs.37.7 ± 25.4; p = 0.004) while intensive care unit stay was shorter (2.2 ± 1.4 vs. 3.7 ± 3.9, p < 0.05). Hospitalisation length was similar in both groups as well as all-cause mortality rate and the incidence of major periprocedural complications. No case of infection by COVID-19 was reported among patients during the hospital stay. Conclusions: Comparative analysis of early clinical outcomes showed that COVID-19 pandemic did not affect the safety and effectiveness of TAVI as similar rates of procedural complications and all-cause mortality were reported than before February 2020. Despite the increased time lag between diagnosis and procedure and a more complex clinical profile of patients at baseline, the revised pathway of hospitalisation allowed to resume inpatient procedures while not affecting patients’ and healthcare workers’ safety