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The newly identified CUBAN (Cullin binding domain associating with NEDD8) domain recognizes both ubiquitin and the ubiquitin-like NEDD8. Despite the high similarity between the two molecules, CUBAN shows a clear preference for NEDD8, free and conjugated to cullins. We previously characterized the domain structure, both alone and in complex with NEDD8. The results here reported are addressed to investigate the determinants that drive the selective binding of CUBAN towards NEDD8 and ubiquitin. The 15 N HSQC NMR perturbation pattern of the labeled CUBAN domain, when combined with either NEDD8 or ubiquitin, shows a clear involvement of hydrophobic residues that characterize the early stages of these interactions. After a slow conformational selection step, hydrophobic and then neutral and polar interactions take place, which drive the correct orientation of the CUBAN domain, leading to differences in the recognition scheme of NEDD8 and ubiquitin. As a result, a cascade of induced fit steps seems to determine the structural preference shown for NEDD8 and therefore the basis of the selectivity of the CUBAN domain. Finally, molecular dynamics analysis was performed to determine by fluctuations the internal flexibility of the CUBAN/NEDD8 complex. We consider that our results, based on a structural investigation mainly focused on the early stages of the recognition, provide a fruitful opportunity to report the different behavior of the same protein with two highly similar binding partners.

Background: In last years, an increasing interest emerges on the role of sub-lobar resection and lobe-specific lymph nodal dissection in the treatment of early-stage lung cancer. The aim of our study was to define the impact on cumulative incidence of recurrence (CIR) of type of surgical resection and type of nodal staging in this subset of patients. Furthermore, we evaluated the possible synergism between the different kinds of procedure., Methods: An analysis of 969 consecutive stage I pulmonary adenocarcinoma patients, operated in six Thoracic Surgery Institutions between 2001 and 2013, was conducted. Type of surgical resection included lobectomy and sub-lobar resection; while pneumonectomy and bilobectomy were excluded from the analysis. Nodal staging procedures were classified in nodal sampling (NS), lobe-specific lymph node dissection (LS-ND) and systematic lymph node dissection (SND). Multivariable-adjusted comparisons for CIR was performed using Fine and Grey model, taking into account of death by any cause as competing event. In order to evaluate synergism between the different procedures, the test of interaction between type of surgical resection and type of nodal staging was carried out and results presented in a stratified way., Results: Eight-hundred forty-six (87%) patients were submitted to lobectomy, while 123 (13%) to sub-lobar resection. Four-hundred fifty-five (47%) patients received SND, 98 (10%) LS-ND and 416 (43%) NS. Two-hundred forty-seven (26%) patients developed a local/distant recurrence with a 5-year CIR of 24.2%. Multivariable-adjusted comparisons showed an independent negative effect of sub-lobar resection (HR =1.52; 95% CI: 1.07-2.17), LS-ND (HR =1.74; 95% CI: 1.16-2.6) and NS (HR =1.49; 95% CI: 1.12-1.98) on CIR. Test of interaction showed a homogeneity of results among subgroups., Conclusions: Patients affected by stage I pulmonary adenocarcinoma and submitted to lobectomy presented a significant lower recurrence rate than those submitted to sub-lobar resection. Moreover, SND presented an independent positive effect on recurrence development than other lymph node assessment strategy. Finally, lobectomy in combination with systematic lymph nodal resection showed the best results in term of CIR., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Henoch-Schönlein purpura is a systemic vasculitis, commonly affecting children. Gastrointestinal manifestations are observed in 50-75% of patients; it is well known they may occur before skin lesions in about 20% of cases during the first vasculitic episode. Relapses occur in about one third of patients, typically within 4 months from the initial presentation and with milder symptoms. We report the case of a 17-year old girl with an atypical relapse of Henoch-Schönlein purpura, presenting with acute abdominal symptoms 5 years after the first episode. Esophagogastroduodenoscopy showed duodenal multiple hyperemic and hemorrhagic lesions. To our knowledge this is the first case of hemorrhagic-erosive duodenitis representing a relapse of Henoch-Schönlein purpura occurring several years after the initial episode. Duodenojejunal inflammation should be considered as primary manifestation of Henoch-Schönlein purpura, not only during the first episode, but also in relapses. Endoscopy can be helpful for differential diagnosis, especially in patients with atypical manifestations. Further studies are needed to evaluate risk factors for Henoch-Schönlein purpura recurrence and the possible role of fecal calprotectin as an early marker for gastrointestinal involvement.

Loss-of-function long QT (LQT) mutations inducing LQT1 and LQT2 syndromes have been successfully translated to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) used as disease-specific models. However, their in vitro investigation mainly relies on experiments using small numbers of cells. This is especially critical when working with cells as heterogeneous as hiPSC-CMs. We aim (i) to investigate in silico the ionic mechanisms underlying LQT1 and LQT2 hiPSC-CM phenotypic variability, and (ii) to enable massive in silico drug tests on mutant hiPSC-CMs. We combined (i) data of control and mutant slow and rapid delayed rectifying K⁺ currents, I Kr and I Ks respectively, (ii) a recent in silico hiPSC-CM model, and (iii) the population of models paradigm to generate control and mutant populations for LQT1 and LQT2 cardiomyocytes. Our four populations contain from 1008 to 3584 models. In line with the experimental in vitro data, mutant in silico hiPSC-CMs showed prolonged action potential (AP) duration (LQT1: +14%, LQT2: +39%) and large electrophysiological variability. Finally, the mutant populations were split into normal-like hiPSC-CMs (with action potential duration similar to control) and at risk hiPSC-CMs (with clearly prolonged action potential duration). At risk mutant hiPSC-CMs carried higher expression of L-type Ca 2+ , lower expression of I Kr and increased sensitivity to quinidine as compared to mutant normal-like hiPSC-CMs, resulting in AP abnormalities. In conclusion, we were able to reproduce the two most common LQT syndromes with large-scale simulations, which enable investigating biophysical mechanisms difficult to assess in vitro, e.g., how variations of ion current expressions in a physiological range can impact on AP properties of mutant hiPSC-CMs.

Cryoconservation of gametes : how to perform ? The patients can preserve their gametes when they are exposed to potential gonadotoxic pathology or treatment. In this context, the French bioethical law clearly states the obligation to inform the patients about the risks for their fertility and the possibilities to cryopreserve their gametes. Regional platforms of fertility preservation allow notably for the coordination of the oncology teams and the CECOS. For the men, sperm freezing is achieved by a slow and controlled temperature protocol. For the women, the oocytes are usually vitrified after hormonal stimulation and ovarian punction. For both, the gametes are cryopreserved in straws and stored in liquid nitrogen until use in assisted reproductive treatment (ART). Each year, the CECOS keeping the gametes interrogates patients on their wish to continue, or not, the cryoconservation. The gametes can only be used in ART by the patients only during their lifetime and with their consent, without alterations related to the duration of storage., Competing Interests: P. Fauque déclare des liens ponctuels (interventions et invitations lors de congrès) avec Merck Serono, MSD et Ferring. F. Brugnon, M. Paci, J. Perrin et H. Pons-Rejraji déclarent n’avoir aucun lien d’intérêts.

Background: Thymosin alpha 1 (Tα1) is a well-recognized immune response modulator in a wide range of disorders, particularly infections and cancer. The bioinformatic analysis of public databases allows drug repositioning, predicting a new potential area of clinical intervention. We aimed to decipher the cellular network induced by Tα1 treatment to confirm present use and identify new potential clinical applications., Research Design and Methods: We used the transcriptional profile of human peripheral blood mononuclear cells treated in vitro with Tα1 to perform the enrichment network analysis by the Metascape online tools and the disease enrichment analysis by the DAVID online tool., Results: Networked cellular responses reflected Tα1 regulated biological processes including immune and metabolic responses, response to compounds and oxidative stress, ion homeostasis, peroxisome biogenesis and drug metabolic process. Beyond cancer and infections, the analysis evidenced the association with disorders such as kidney chronic failure, diabetes, cardiovascular, chronic respiratory, neuropsychiatric, neurodegenerative and autoimmune diseases., Conclusions: In addition to the known ability to promote immune response pathways, the network enrichment analysis demonstrated that Tα1 regulates cellular metabolic processes and oxidative stress response. Notable, the analysis highlighted the association with several diseases, suggesting new translational implication of Tα1 treatment in pathological conditions unexpected until now.

Introduction: Thymosins have been extracted, characterized, and identified from Thymus. The Thymosins are hormones whose therapeuric applications have seen a recent increase. The action of Thymosin α1 is based on the stimulation of the immune response with a large number of results in a variety of pathologies. The absence of a specific receptor prompted us to investigate the direct interaction with membranes, particularly those exposing phosphatidylserine thus contributing to assess the Thymosin α1's pleiotropy., Areas Covered: The interaction with membranes has been studied with a number of models indicating that Thymosin α1 interacts preferentially with negative regions of the membrane (SDS mixed with dodecylphosphocholine) or, better, with vesicles of dipalmitoylphosphatidylcholine with exposed phosphatidylserine., Expert Opinion: The study of the role of the membrane in the mechanism of action of Thymosin α1 indicated that probably the first interaction occurs at the membrane level with recognition of negative surface due to the phosphatidylserine exposure. Upon assuming a conformation, with two helices with a disordered tract in between, it diffuses on the membrane surface by lateral diffusion. Then the interaction with membrane receptor(s) causes a membrane complex to be formed, with an activation of a signalling cascade. This can be considered the basis of its pleiotropy. Differences in structuration mechamism of Thymosin β4 was outlined.

The growing importance of human induced pluripotent stem cell-derived cardiomyoyctes (hiPSC-CMs), as patient-specific and disease-specific models for studying cellular cardiac electrophysiology or for preliminary cardiotoxicity tests, generated better understanding of hiPSC-CM biophysical mechanisms and great amount of action potential and calcium transient data. In this paper, we propose a new hiPSC-CM in silico model, with particular attention to Ca 2+ handling. We used (i) the hiPSC-CM Paci2013 model as starting point, (ii) a new dataset of Ca 2+ transient measurements to tune the parameters of the inward and outward Ca 2+ fluxes of sarcoplasmic reticulum, and (iii) an automatic parameter optimization to fit action potentials and Ca 2+ transients. The Paci2018 model simulates, together with the typical hiPSC-CM spontaneous action potentials, more refined Ca 2+ transients and delayed afterdepolarizations-like abnormalities, which the old Paci2013 was not able to predict due to its mathematical formulation. The Paci2018 model was validated against (i) the same current blocking experiments used to validate the Paci2013 model, and (ii) recently published data about effects of different extracellular ionic concentrations. In conclusion, we present a new and more versatile in silico model, which will provide a platform for modeling the effects of drugs or mutations that affect Ca 2+ handling in hiPSC-CMs.

The nuclear lamina (NL) is a filamentous protein meshwork, composed essentially of lamins, situated between the inner nuclear membrane and the chromatin. The NL is a component of the nuclear envelope, interacts with a wide range of proteins and is required for normal nuclear structure and physiological development. During spermiogenesis the spermatid nucleus is elongated, and dramatically reduced in size with protamines replacing histones to produce a highly compacted chromatin. There is mounting evidence from studies in human and rodent, that the NL plays an important role in mammalian spermatid differentiation during spermiogenesis. In this review, we summarize and discuss the data available in the literature regarding the involvement of lamins and their direct or indirect partners in normal and abnormal human spermiogenesis., Competing Interests: Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

It is generally considered that if an RNA World ever existed that it would be driven by an RNA capable of RNA replication. Whether such a catalytic RNA could emerge in an RNA World or not, there would need to be prior routes to increasing complexity in order to produce it. It is hypothesized here that increasing sequence variety, if not complexity, can in fact readily emerge in response to a dynamic equilibrium between synthesis and degradation. A model system in which T4 RNA ligase catalyzes synthesis and Benzonase catalyzes degradation was constructed. An initial 20-mer served as a seed and was subjected to 180 min of simultaneous ligation and degradation. The seed RNA rapidly disappeared and was replaced by an increasing number and variety of both larger and smaller variants. Variants of 40-80 residues were consistently seen, typically representing 2-4% of the unique sequences. In a second experiment with four individual 9-mers, numerous variants were again produced. These included variants of the individual 9-mers as well as sequences that contained sequence segments from two or more 9-mers. In both cases, the RNA products lack large numbers of point mutations but instead incorporate additions and subtractions of fragments of the original RNAs. The system demonstrates that if such equilibrium were established in a prebiotic world it would result in significant exploration of RNA sequence space and likely increased complexity. It remains to be seen if the variety of products produced is affected by the presence of small peptide oligomers.

Background: Since the 1970s, international research has actively pursued hormonal male contraception (HMC) and, to a lesser extent, thermal male contraception (TMC). Although the efficacy of TMC has been confirmed in limited populations, its acceptability has not been studied in either potential users or potential prescribers., Methods: A cross-sectional descriptive multicentre study of potential male users of TMC (new fathers) and potential prescribers of TMC (new providers) was conducted between November 2016 and February 2017.The participants completed a 3-part survey, and their responses were evaluated to i) determine their socio-demographic profiles; ii) identify personal experiences with contraception; and iii) gauge the participants' knowledge, interest and preference for male contraception, particularly TMC. For new providers only, the survey included a fourth part to evaluate professional experience with male contraception., Results: The participation rate was 51% for new fathers (305 NFs) and 34% for new providers (300 NPs, including 97 men (male new providers, MNPs) and 203 women (female new providers, FNPs)). Only 3% of NFs and 15% of NPs knew about TMC (including 26% of the MNPs and 10% of the FNPs, p<0.01). After reading information on TMC, new fathers were significantly less willing to try TMC (29%) than were new providers (40%) (p<0.01). The 3 main advantages of TMC for the new fathers included the following factors: "natural" (52%), "without side effects" (38%) and "non-hormonal" (36%). The main disadvantages were "lengthy wear time" (56%), "daily undergarment wear" (43%) and "concern about possible discomfort" (39%)., Conclusions: Young male and female providers have limited knowledge of male contraception, are interested in further information and would generally prescribe TMC to their patients. Successful expansion of the use of male contraception, including TMC, would require distribution of better information to potential users and providers., Competing Interests: The authors have declared that no competing interests exist.

We herein report a case of a 43-year-old man with a right 8th-rib bone tumor exhibiting features of malignancy at CT-scan. Considering that a SPECT/CT with Tc-MDP showed solitary intense radio-tracer uptake and the inconclusive results from a fine-needle biopsy, surgical en bloc tumor resection was performed. Pathologic analysis revealed a well-limited benign bone lesion ("fibrous rib dysplasia") composed by a cellular fibrous proliferation. Since benign osseous diseases may present an intense scintigraphic tracer uptake (as in this case), we suggest a certain caution when interpreting the results of SPECT/CT with Tc-MDP in order to avoid misdiagnosis and wrong treatments.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib, erlotinib and afatinib) are indicated as first-line therapy in patients with non-small cell lung cancer (NSCLC) whose tumors harbor activating mutations in the EGFR gene. Erlotinib is also used in second and third-line therapy for patients whose tumors have wild type EGFR but to date there are no validated biomarkers useful to identify which patients may benefit from this treatment. The expression level of four miRNAs: miR-133b, -146a, -7 and -21 which target EGFR was investigated by real-time PCR in tumor specimens from NSCLC patients treated with erlotinib administered as the second or third line. We found that miR-133b expression level better discriminated responder from non-responder patients to erlotinib. Higher levels of miR-133b in NSCLCs were associated with longer progression-free survival time of patients. Functional analyses on miR-133b through transfection of a miR-133b mimic in A549 and H1299 NSCLC cell lines indicated that increasing miR-133b expression level led to a decreased cell growth and altered morphology but did not affect sensitivity to erlotinib. The detection of miR-133b expression levels in tumors help in the identification of NSCLC patients with a better prognosis and who are likely to benefit from second and third-line therapy with erlotinib.

OBJECTIVE The aim of this study was to evaluate the anatomical and surgical risk factors for screw-related facet joint violation at the superior level in lumbar fusion. METHODS The authors conducted a retrospective review of a consecutive series of posterior lumbar instrumented fusions performed by a single surgeon. Inclusion criteria were primary lumbar fusion of 1 or 2 levels for degenerative disorders. The following variables were analyzed as possible risk factors: surgical technique (percutaneous vs open screw placement), depth of surgical field, degree of anterior slippage of the superior level, pedicle and facet angle, and facet degeneration of the superior level. Postoperative CT scans were evaluated by 2 independent reviewers. Axial, sagittal, and coronal views were reviewed. Pedicle screws were graded as intra-articular if they clearly interposed between the superior and inferior facet joints of the superior level. Multivariate logistic regression analyses were conducted to assess the factors associated with this complication. RESULTS One hundred thirty-one patients were included. Interobserver reliability for facet joint violation assessment was high (κ = 0.789). The incidence of superior facet joint violation was 12.59% per top-level screw (33 of 262 proximal screws). The rate of facet violation was 28.0% in the percutaneous technique group (14 of 50 patients) and 12.3% in the open surgery group (10 of 81 patients) (OR 2.26, 95% CI 1.09-4.21; p = 0.024). In multivariate logistic regression analysis, independent predictors of facet violation were percutaneous screw placement (adjusted OR 3.31, 95% CI 1.42-7.73; p = 0.006), right-side pedicle screw (adjusted OR 3.14, 95% CI 1.29-7.63; p = 0.011), and facet angle > 45° (adjusted OR 10.95, 95% CI 4.64-25.84; p < 0.0001). CONCLUSIONS The incidence of facet joint violation was higher in percutaneous minimally invasive than in open technique for posterior lumbar spine surgery. Also, coronal orientation of the facet joint is a significant risk factor independent of the surgical technique.

Purpose: The purpose of this study was to verify if the amount of experience or the specific professional field of the raters may influence inter-rater reliability of the Salford Gait Tool (SF-GT)., Methods: Standardized videos of gait of seven children with cerebral palsy were recorded and assessed by three physiotherapists with experience in pediatrics (PPTs), three physiotherapists with experience with adult individuals (n-PPTs), and three students of physiotherapy., Results: The inter-rater reliability both for joints and gait events was acceptable (ICC ≥ .70) for PPTs and n-PPTs, but not for students., Conclusions: The inter-rater reliability of the SF-GT can be influenced by the experience of the raters and the amount of clinical experience seems to be more relevant than the specific professional field. Further research should be conducted with larger samples.

Background: In a clinical science-based profession such as physiotherapy, research is mandatory to update knowledge and to provide cost-effective, high quality treatments. This study aimed to provide point prevalence of Italian physiotherapists who are academics, holding a PhD degree, or being authors of scientific papers. The scientific journal productivity of physiotherapists was also thoroughly analyzed., Methods: A descriptive cross-sectional study was carried out on all Italian physiotherapists. Academics, postdoctoral research fellows, and PhD graduates were identified by searching the Italian Ministry of Education, University and Research (MIUR), Italian Society of Physiotherapy, and university websites. Then, authors of articles indexed in Scopus were searched. The following data were extracted: type of affiliation, authorship order, H-index, number of publications and citations, name of journals, year of publication, and journal's Impact Factor., Results: The prevalence of academics, physiotherapists holding a PhD, or being author was 0.01%, 0.05%, and 0.56%, respectively. We identified 1083 papers co-authored by Italian physiotherapists, and their number has progressively increased over the years ( p  < 0.001). There was a significant difference between researchers and clinicians in both publication productivity ( p  < 0.01), citations (p < 0.01), and H-Index ( p  = 0.05). Articles were published in 359 different journals, receiving a total of 13,373 citations., Conclusions: Despite the low prevalence of faculty members and the reduced availability of PhD programs in Italy (forcing some students to study abroad), the quantity and quality of journal productivity is growing fast, and an increasing number of physiotherapists are involved in research activities., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Humic substances (HS) are the largest constituent of soil organic matter and are considered as a key component of the terrestrial ecosystem. HS may facilitate the transport of organic and inorganic molecules, as well as the sorption interactions with environmentally relevant proteins such as prions. Prions enter the environment through shedding from live hosts, facilitating a sustained incidence of animal prion diseases such as Chronic Wasting Disease and scrapie in cervid and ovine populations, respectively. Changes in prion structure upon environmental exposure may be significant as they can affect prion infectivity and disease pathology. Despite its relevance, the mechanisms of prion interaction with HS are still not completely understood. The goal of this work is to advance a structural-level picture of the encapsulation of recombinant, non-infectious, prion protein (PrP) into different natural HS. We observed that PrP precipitation upon addition of HS is mainly driven by a mechanism of "salting-out" whereby PrP molecules are rapidly removed from the solution and aggregate in insoluble adducts with humic molecules. Importantly, this process does not alter the protein folding since insoluble PrP retains its α-helical content when in complex with HS. The observed ability of HS to promote PrP insolubilization without altering its secondary structure may have potential relevance in the context of "prion ecology". These results suggest that soil organic matter interacts with prions possibly without altering the protein structures. This may facilitate prions preservation from biotic and abiotic degradation leading to their accumulation in the environment.

Introduction: Pulmonary Sarcomatoid Carcinoma (PSC) is a rare subset of NSCLC, associated with worse prognosis and resistant to platinum-based regimens. Recent investigations have shown high levels of PD-L1 expression in PSC, providing a rationale for the potential use of immunotherapy. In this study, we investigated whether the PD-L1 expression was related to clinico-pathologic and molecular characteristics., Materials and Methods: Fortythree surgically-resected PSCs were selected from 2006 to 2014 and clinical information retrieved. PD-L1 expression was analyzed by immunohistochemistry and correlated with the clinic-pathologic features and driver gene mutations analyzed by Next-Generation-Sequencing. Correlation of clinical, pathological and genetic variants with PD-L1 expression positivity were tested by Fisher's exact test analysis., Results: About 25% of PSCs showed a significant expression of PD-L1 (positive staining defined as staining in ≥10% of tumor cells). PD-L1 expression was associated with aggressive pathological features of PSCs including N2-involvement (PD-L1 positive in 83.3% of N2-PSCs vs in 16.2% of N0/N1-PSCs, p=0.003) and presence of either local (p=0.038) and distant metastases (p=0.022). Furthermore, PD-L1 expression was significantly associated with the overall mutational load of the tumors (PD-L1 positivity only in PSCs with at least one mutational event) and in particular with the presence of KRAS mutation (PD-L1 positive in 44.4% of KRAS-Mut PSCs vs 12.0% in KRAS-Wild PSCs). The correlation between PD-L1 expression and KRAS-mutation were found at univariate analysis (p=0.031), even considering PD-L1 as a continuous variable (p=0.018), and confirmed at multivariate analysis (p=0.035). The mutational status of the other genes explored in the NGS-panel (EGFR, APC, PTEN, PIK3CA, TP53 and STK11) did not correlate with PD-L1 expression., Conclusions: PD-L1 expression significantly correlates with overall mutational load and KRAS mutational status in pulmonary sarcomatoid carcinomas., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are in vitro models with the clear advantages of their human origin and suitability for human disease investigations. However, limitations include their incomplete characterization and variability reported in different cell lines and laboratories., Objective: The purpose of this study was to investigate in silico ionic mechanisms potentially explaining the phenotypic variability of hiPSC-CMs in long QT syndrome type 3 (LQT3) and their response to antiarrhythmic drugs., Methods: Populations of in silico hiPSC-CM models were constructed and calibrated for control (n = 1,463 models) and LQT3 caused by I NaL channelopathy (n = 1,401 models), using experimental recordings for late sodium current (I NaL ) and action potentials (APs). Antiarrhythmic drug therapy was evaluated by simulating mexiletine and ranolazine multichannel effects., Results: As in experiments, LQT3 hiPSC-CMs yield prolonged action potential duration at 90% repolarization (APD 90 ) (+34.3% than controls) and large electrophysiological variability. LQT3 hiPSC-CMs with symptomatic APs showed overexpression of I CaL , I K1 , and I NaL , underexpression of I Kr , and increased sensitivity to both drugs compared to asymptomatic LQT3 models. Simulations showed that both mexiletine and ranolazine corrected APD prolongation in the LQT3 population but also highlighted differences in drug response. Mexiletine stops spontaneous APs in more LQT3 hiPSC-CMs models than ranolazine (784/1,401 vs 53/1,401) due to its stronger action on I Na ., Conclusion: In silico simulations demonstrate our ability to recapitulate variability in LQT3 and control hiPSC-CM phenotypes, and the ability of mexiletine and ranolazine to reduce APD prolongation, in agreement with experiments. The in silico models also identify potential ionic mechanisms of phenotypic variability in LQT3 hiPSC-CMs, explaining APD prolongation in symptomatic vs asymptomatic LQT3 hiPSC-CMs., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to characterize the nuclear lamina (NL) and lamin chromatin-partners in spermatozoa from four DPY19L2-deleted globozoospermic patients. We tested for spermatid transcripts encoding lamins and their chromatin-partners emerin, LAP2α, BAF and BAF-L, by reverse transcriptase-PCR using spermatozoa RNA. We also determined the localization of lamin B1, BAF and BAF-L by immunofluorescent analysis of spermatozoa from all patients. In RNA from globozoospermic and control spermatozoa we detected transcripts encoding lamin B1, lamin B3, emerin, LAP2α and BAF-L, but not A-type lamins. In contrast, BAF transcripts were detected in globozoospermic but not control spermatozoa. The NL was immature in human globozoospermic spermatozoa: lamin B1 signal was detected in the nuclei of globozoospermic spermatozoa in significantly higher proportions than the control (P < 0.05; 56-91% versus 40%) and was predominantly observed at the whole nuclear periphery, not polarized as in control spermatozoa. Conversely, BAF and BAF-L were detected in control, but not globozoospermic spermatozoa. Our results strongly emphasize the importance of the NL and associated proteins during human spermiogenesis. In globozoospermia, the lack of maturation of the NL, and the modifications in expression and location of chromatin-partners, could explain the chromatin defects observed in this rare phenotype., (Copyright © 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Thymosin α1 (Tα1), is a peptidic hormone, whose immune regulatory properties have been demonstrated both in vitro and in vivo and approved in different countries for treatment of several viral infections and cancers. Tα1 assumes a conformation in negative membranes upon insertion into the phosphatidylserine exposure as found in several pathologies and in apoptosis. These findings are in agreement with the pleiotropy of Tα1, which targets both normal and tumor cells, interacting with multiple cellular components, and have generated renewed interest in the topic. Hyaluronan (HA) occurs ubiquitously in the extracellular matrix and on cell surfaces and has been related to a variety of diseases, and developmental and physiological processes. Proteins binding HA, among them CD44 and the Receptor for HA-mediated motility (RHAMM) receptors, mediate its biological effects. NMR spectroscopy indicated preliminarily that an interaction of Tα1 with HA occurs specifically around lysine residues of the sequence LKEKK of Tα1 and is suggestive of a possible interference of Tα1 in the binding of HA with CD44 and RHAMM. Further studies are needed to deepen these observations because Tα1 is known to potentiate the T-cell immunity and anti-tumor effect. The binding inhibitory activity of Tα1 on HA-CD44 or HA-RHAMM interactions can suppress both T-cell reactivity and tumor progression., Competing Interests: The authors declare that they do not have any conflict of interest.

During spermiogenesis the spermatid nucleus is elongated, and dramatically reduced in size with protamines replacing histones to produce a highly compacted chromatin. After fertilisation, this process is reversed in the oocyte to form the male pronucleus. Emerging evidence, including the coordinated loss of the nuclear lamina (NL) and the histones, supports the involvement of the NL in spermatid nuclear remodelling, but how the NL links to the chromatin is not known. In somatic cells, interactions between the NL and the chromatin have been demonstrated: LEM-domain proteins and LBR interact with the NL and respectively, the chromatin proteins BAF and HP1. We therefore sought to characterise the lamina-chromatin interface during spermiogenesis, by investigating the localisation of six LEM-domain proteins, two BAF proteins and LBR, in human spermatids and spermatozoa. Using RT-PCR, IF and western blotting, we show that six of the proteins tested are present in spermatids: LEMD1, LEMD2 (a short isoform), ANKLE2, LAP2β, BAF and BAF-L, and three absent: Emerin, LBR and LEMD3. The full-length LEMD2 isoform, required for nuclear integrity in somatic cells, is absent. In spermatids, no protein localised to the nuclear periphery, but five were nucleoplasmic, receding towards the posterior nuclear pole as spermatids matured. Our study therefore establishes that the lamina-chromatin interface in human spermatids is radically distinct from that defined in somatic cells. In ejaculated spermatozoa, we detected only BAF and BAF-L, suggesting that they might contribute to the shaping of the spermatozoon nucleus and, after fertilisation, its transition to the male pronucleus., (© 2017 Society for Reproduction and Fertility.)

Objectives: Work-related traumatic brain injuries (TBIs) are not well documented in the literature. Published studies mostly rely on worker databases that fail to provide clinically relevant information. Our objective is to describe the characteristics of hospitalized patients and their work-related TBI., Methods: We used the Québec provincial trauma and TBI program databases to identify all patients with a diagnosis of work-related TBI admitted to the Montreal General Hospital, a level 1 trauma center, between 2000 and 2014. Data from their medical records were extracted using a predetermined information sheet. Simple descriptive statistics (means and percentages) were used to summarize the data., Results: A total of 285 cases were analyzed. Workplace TBI patients were middle-aged (mean, 43.62 years), overwhelmingly male (male:female 18:1), mostly healthy, and had completed a high school level education. Most workers were from the construction industry; falling was the most common mechanism of injury. The majority of patients (76.8%) presented with a mild TBI; only a minority (14%) required neurosurgery. The most common finding on computed tomography was skull fracture. The median length of hospitalization was 7 days, after which most patients were discharged directly home. A total of 8.1% died of their injuries., Conclusions: Our study found that most hospitalized victims of work-related TBI had mild injury; however, some required neurosurgical intervention and a non-negligible proportion died of their injury. Improving fall prevention, accurately document helmet use and increasing the safety practice in the construction industry may help decrease work-related TBI burden.

A recent study of 17 men with decapitated spermatozoa found that 8 carried two rare SUN5 alleles, and concluded that loss of SUN5 function causes the acephalic spermatozoa syndrome. Consistent with this, the SUN5 protein localises to the head-tail junction in normal spermatozoa, and SUN proteins are known to form links between the cytoskeleton and the nucleus. However, six of the ten SUN5 variants reported were missense with an unknown effect on function, and only one man carried two high confidence loss-of-function (LOF) alleles: p.Ser284* homozygozity. One potential exonic splice mutation, homozygous variant p.Gly114Arg, was not tested experimentally. Thus, definitive proof that loss of SUN5 function causes the acephalic spermatozoa syndrome is still lacking. Based on these findings, we determined the sequence of the SUN5 gene in three related men of North African origin with decapitated spermatozoa. We found all three men to be homozygous for a deletion-insertion variant (GRCh38 - chr20:32995761&#95;32990672delinsTGGT) that removes 5090 base pairs including exon 8 of SUN5, predicting the frameshift, p.(Leu143Serfs*30), and the inactivation of SUN5. We therefore present the second case where the acephalic spermatozoa syndrome is associated with two LOF alleles of SUN5. We also show that the p.Gly114Arg variant has a strong inhibitory effect on splicing in HeLa cells, evidence that homozygozity for p.Gly114Arg causes acephalic spermatozoa syndrome through loss of SUN5 function. Our results, together with those of the previous study, show that SUN5 is required for the formation of the sperm head-tail junction and male fertility., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To evaluate the percentage of parents in one French center for the study and preservation of eggs and sperm who disclose their use of donated spermatozoa to their children., Design: A questionnaire survey of couples who had a child using donated spermatozoa., Setting: University hospital laboratory., Patient(s): One hundred five couples., Intervention(s): Questionnaire sent by mail., Main Outcome Measure(s): The percentage of parents who disclose their use of donated spermatozoa to their child., Result(s): Among the 157 questionnaires sent, 105 couples answered, which corresponded to 138 children. There were 40 (38%) couples who had already disclosed the donor origin to their child and 65 (62%) who had not. Of the 40 couples who disclosed the donor origin, 37 (93%) had intended to do so before making use of assisted reproductive techniques (ART), but two (5%) had not wanted to do so before ART. Among the 65 couples who did not inform their child, 42 (65%) planned to inform their child soon, but 20 (31%) wanted to keep the sperm origin secret. Of the 20 couples who wanted to keep the origin secret, nine couples had told other persons about the gamete donation but had not informed their child and do not intend to inform their child in the future., Conclusion(s): This first report about disclosure attitude in a large cohort of parents of donor-conceived offspring in France showed that most parents had already disclosed their use of donated spermatozoa to their children or intended to disclose it soon and had an attitude after birth consistent with their intentions prior to ART., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The Trunk Impairment Scale (TIS) is a widely-used tool aimed to evaluate trunk motor impairment for stroke patients. A validation trial of a translated form of the TIS was never conducted within an Italian population., Aim: To describe translation, cultural adaptation, and validation (internal consistency, reliability, and validity) of the Italian version of the TIS (TIS-I)., Design: Evaluation of the psychometric properties of a translated, culturally adapted questionnaire., Setting: Inpatient rehabilitation ward., Population: Sub-acute stroke patients., Methods: The TIS-I was developed involving forward-backward translation to establish correspondence with the original English latest version. Psychometric testing included internal consistency (Cronbach's alpha) and intra-rater and inter-rater reliability (ICC and Kappa), the standard error of measurement (SEM) and the minimal detectable change (MDC). Concurrent validity was estimated by comparing the TIS-I to the Trunk Control Test, balance subscore of the Fugl-Meyer (FM-BAL) and the mobility section of the Lindmark motor assessment chart (LIND-MOB), and construct validity by comparing the TIS-I to Barthel Index (BI) (Spearman rank correlation coefficient)., Results: The scale was administered to 41 subjects, showing internal consistency ranged from 0.79 to 0.88. ICC values ranged from 0.725 to 0.933 for inter-rater reliability, with the SEM ranging from 0.52 to 1.11, and from 0.770 to 0.911 for intra-rater reliability, with SEM ranging from 0.52 to 1.64. MDC ranged from 1.44 to 4.55. Kappa values ranged from moderate to almost perfect. Spearman rank correlation coefficient between the TIS-I and the BI, LIND-MOB and FM-BAL was 0.63, 0.79 and 0.74 (P<0.001), respectively. Correlation coefficient between the TIS-I and the TCT was 0.81 (P<0.001)., Conclusions: This study supports the reliability and the validity of the TIS-I as measure of motor impairment of the trunk after stroke., Clinical Rehabilitation Impact: The TIS-I can be used in daily clinical practice and in research.

Background: Non-small cell lung cancer is the most common type of lung cancer. Surgery is proven to be the most effective treatment in early stages, despite its potential impact on quality of life. Pulmonary rehabilitation, either before or after surgery, is associated with reduced morbidity related symptoms and improved exercise capacity, lung function and quality of life., Methods: We describe the study protocol for the open-label randomized controlled trial we are conducting on patients affected by primary lung cancer (stages I-II) eligible for surgical treatment. The control group receives standard care consisting in one educational session before surgery and early inpatient postoperative physiotherapy. The treatment group receives, in addition to standard care, intensive rehabilitation involving 14 preoperative sessions (6 outpatient and 8 home-based) and 39 postoperative sessions (15 outpatient and 24 home-based) with aerobic, resistance and respiratory training, as well as scar massage and group bodyweight exercise training. Assessments are performed at baseline, the day before surgery and one month and six months after surgery. The main outcome is the long-term exercise capacity measured with the Six-Minute Walk Test; short-term exercise capacity, lung function, postoperative morbidity, length of hospital stay, quality of life (Short Form 12), mood disturbances (Hospital Anxiety and Depression Scale) and pain (Numeric Rating Scale) are also recorded and analysed. Patient compliance and treatment-related side effects are also collected. Statistical analyses will be performed according to the intention-to-treat approach. T-test for independent samples will be used for continuous variables after assessment of normality of distribution. Chi-square test will be used for categorical variables. Expecting a 10% dropout rate, assuming α of 5% and power of 80%, we planned to enrol 140 patients to demonstrate a statistically significant difference of 25 m at Six-Minute Walk Test., Discussion: Pulmonary Resection and Intensive Rehabilitation study (PuReAIR) will contribute significantly in investigating the effects of perioperative rehabilitation on exercise capacity, symptoms, lung function and long-term outcomes in surgically treated lung cancer patients. This study protocol will facilitate interpretation of future results and wide application of evidence-based practice., Trial Registration: ClinicalTrials.gov Registry n. NCT02405273 [31.03.2015].

Beside cytotoxic drugs, other drugs can impact men's fertility through various mechanisms. Via the modification of the hypothalamic-pituitary-gonadal axis hormones or by non-hormonal mechanisms, drugs may directly and indirectly induce sexual dysfunction and spermatogenesis impairment and alteration of epididymal maturation. This systematic literature review summarizes existing data about the negative impact and associations of pharmacological treatments on male fertility (excluding cytotoxic drugs), with a view to making these data more readily available for medical staff. In most cases, these effects on spermatogenesis/sperm maturation/sexual function are reversible after the discontinuation of the drug. When a reprotoxic treatment cannot be stopped and/or when the impact on semen parameters/sperm DNA is potentially irreversible (Sulfasalazine Azathioprine, Mycophenolate mofetil and Methotrexate), the cryopreservation of spermatozoa before treatment must be proposed. Deleterious impacts on fertility of drugs with very good or good level of evidence (Testosterone, Sulfasalazine, Anabolic steroids, Cyproterone acetate, Opioids, Tramadol, GhRH analogues and Sartan) are developed., (© 2017 American Society of Andrology and European Academy of Andrology.)

Here we describe a 77-year-old man with a solitary fibrous tumor of the pleura showing increasing tracer uptake at Ga-DOTATOC PET/CT, demonstrating that solitary fibrous tumor of the pleura may overexpress somatostatin receptors, therefore mimicking neuroendocrine tumors at somatostatin receptor PET/CT.

Background: Pulmonary sarcomatoid carcinoma (PSC) is a very rare subtype of non-small cell lung cancer (NSCLC). The aim of this study was to clarify the pathologic characteristics and long-term survival after surgical treatment in patients with PSC., Methods: From January 2003 to December 2013, we retrospectively reviewed the clinical findings, surgical notes, and pathologic and follow-up data from 148 consecutive patients who underwent curative resection for PSC in 5 institutions. The Kaplan-Meier method, log-rank test, and Cox regression analysis were used., Results: Mean age and male to female ratio were 66.6 ± 9.9 years and 120:28, respectively. Surgical resection (pneumonectomy in 8 patients, bilobectomy in 132 patients, and sublobar resection in 8 patients) was complete in 142 cases (96%). At pathologic evaluation, 36 patients (24%) had stage I, 69 patients (47%) had stage II, 33 patients (22%) had stage III, and 10 patients (7%) had stage IV disease. A "biphasic tumor" (PSC with an NSCLC component) was observed in 77 patients (52%). We detected a high rate of vascular emboli in the surgical specimens (overall, 68%; 57% in pathologic stage I tumors), whereas lymphatic emboli were found in 30% of cases (5% of pathologic stage I tumors). Overall median and 5-year long-term survival (LTS) was 19 months and 12.6% (LTS, 16.3% in pathologic stage I), respectively. Distant recurrences frequently occurred after surgical treatment (81%), even in pathologic stage I tumors that underwent R0 resection (62%). Multivariable survival analysis identified R+ resection (hazard ratio [HR],12.3; 95% confidence interval [CI], 3.67-41.28; p < 0.0001), advanced pathologic stage (HR, 5.75; 95% CI, 2.55-12.98; p < 0.0001), and the presence of vascular emboli (HR, 1.67; 95% CI, 1.05-2.67; p = 0.0327) as independent negative prognostic factors., Conclusions: PSCs have very aggressive behavior and high metastatic potential even in early stages. R+ resection, pathologic TNM status, and the presence of vascular emboli are independent prognostic factors., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: False-negative (FN) uptake of 18F-fluorodeoxyglucose (FDG) can be divided into those cases related to technological limitations of positron emission tomography (PET) and those related to inherent properties of neoplasms. Our goal was to clarify possible factors causing FN PET results in patients with solid-type pulmonary adenocarcinomas (PAs)., Methods: From January 2007 to December 2014, of the 255 patients with p-stage-1 non-small-cell lung cancer observed and treated (surgically) in our institution, we retrospectively reviewed the PET/computed tomography (CT) records, the clinical information, the preoperative thin-section CT images, and the pathological features [classified by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) subtyping criteria] of 94 consecutive solid-type p-stage-1 PAs. Univariable and multivariable logistic analyses were used to identify and weigh the independent predictors of the PET findings using the following variables: body weight, blood glucose level, tumour size, tumour location, and histological classification., Results: There were 58 men and 36 women (mean age = 68.7 ± 8.9 years, range 42-85). Considering the maximum standardized uptake value (SUVmax) ≥ 2.5 as a 'PET-positive' result, 77 lesions (81.9%) proved PET positive and 17 lesions (18.1%), PET negative (with SUVmax < 2.5). Overall, the median SUVmax value was 5.7 [interquartile range (IQR) 2.8-10.3]. Higher SUVmax values ( P  < 0.001) were observed in those PAs larger than 2 cm in their major axis (median SUVmax = 9.0; IQR 4.6-14.6); in PAs < 2 cm, the median SUVmax was 4.1; IQR 2.2-5.9. When clustering the cohort in two histological classes (class A, colloid/mucinous/lepidic versus class B, micropapillary/solid/acinar/papillary), the radiometabolic patterns were significantly different (median SUVmax = 2.8; IQR 1.7-4.9 in class A vs median = 7.4 IQR 4.5-13.9 in class B, P  <   0.001). Significant PET FN rates were reported in (i) PAs measuring < 2 cm in their major axis (27.9%), (ii) lesions located in the lower zones of the lung (31.0%), and (iii) class A tumours (37.5%). In the multivariable logistic analysis, histological type (IASLC/ATS/ERS aggregated clusters) proved to be the only independent relevant factor for determining whether PET results were negative or positive (OR:7.23, 95% CI: 2.05-25.43, P  =   0.002)., Conclusions: The IASLC/ATS/ERS pattern significantly influences FDG uptake in solid-type p-stage-1 PAs. The fact that colloid/mucinous/lepidic adenocarcinomas have a notable tendency to produce negative findings on PET scans warrants particular attention., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose: This epidemiological study aimed to determine the prevalence and characteristics of second tumors (STs) in patients with bronchopulmonary carcinoids (BCs)., Methods: Data on neuroendocrine carcinomas (NECs) from the AIRTUM registry (1975-2011) were used for the analysis. Among 32,325 NECs, we focused our analysis on 3,205 patients (9.9%) affected by BCs. The overall ST number and incidence were calculated. The number of STs was compared with the expected cancer number in the healthy Italian population, and the standardized incidence ratio (SIR) and 95% confidence intervals were calculated., Results: The male/female ratio was 1.5:1 and the mean age 61.7 years (range: 7-94). A total of 640 STs were observed (overall incidence: 20%): 198 tumors were metachronous, 23 synchronous, and 419 occurred before the diagnosis of BC. The most common STs were bladder tumors (12.2%) followed by breast tumors (11.1%). We observed a large number of thyroid tumors (SIR = 3.88), with a remarkably higher frequency of thyroid tumors being synchronously detected with BC in female patients (SIR = 61.39). In male patients there was an increased frequency of urinary system tumors, in particular metachronous tumors of the kidney and renal pelvis (SIR = 3.34) and synchronous tumors of the urinary bladder (SIR = 11.48)., Conclusions: A high frequency of STs is predictable in patients with BCs, with synchronous thyroid tumors being observed in women and kidney and urinary bladder tumors in men. However, these data should be interpreted with caution, considering that the diagnosis of such tumors often occurs as an incidental finding during investigations for other malignancies.

Although progress was made in in vitro fertilization (IVF) techniques, the majority of embryos transferred fail to implant. Morphology embryo scoring is the standard procedure for most of IVF centres for choosing the best embryo, but remains limited since even the embryos classified as "top quality" may not implant. As it has been shown that i) CD146 is involved in embryo implantation and ii) membrane form is shed to generate soluble CD146 (sCD146), we propose that sCD146 in embryo supernatants may constitute a new biomarker of embryo selection. Immunocytochemical staining showed expression of CD146 in early embryo stages and sCD146 was detected by ELISA and Western-blot in embryo supernatants from D2. We retrospectively studied 126 couples who underwent IVF attempt. The embryo culture medium from each transferred embryo (n = 222) was collected for measurement of sCD146 by ELISA. Significantly higher sCD146 concentrations were present in embryo supernatants that did not implant (n = 185) as compared to those that successfully implanted (n = 37) (1310 +/- 1152 pg.mL-1 vs. 845+/- 1173 pg.mL-1, p = 0.024). Sensitivity analysis performed on single embryo transfers (n = 71) confirmed this association (p = 0.0054). The computed ROC curve established that the optimal sCD146 concentration for embryo implantation is under 1164 pg.mL-1 (sensitivity: 76%, specificity: 48%, PPV: 25% and NPV: 92%). Over this sCD146 threshold, the implantation rate was significantly lower (9% with sCD146 levels >1164 pg.ml-1 vs. 22% with sCD146 levels ≤ 1164 pg.mL-1, p = 0.01). Among the embryos preselected by morphologic scoring, sCD146 determination could allow a better selection of the embryo(s), thus improving the success of elective single embryo transfer. This study establishes the proof of concept for the use of sCD146 as a biomarker for IVF by excluding the embryo with the highest sCD146 level. A multicentre prospective study will now be necessary to further establish its use in clinical practice.

Background  The aim of this study was to assess long-term pulmonary and diaphragmatic function in two cohorts of patients: the first one affected by diaphragmatic palsy (DP) who underwent plication reinforced by rib-fixed mesh and the second one affected by chronic diaphragmatic hernia (TDH) who underwent surgical reduction and direct suture. Materials and Methods  From 1996 to 2011, 10 patients with unilateral DP and 6 patients with TDH underwent elective surgery. Preoperative and long-term (12 months) follow-up assessments were completed in all patients, including pulmonary function tests (PFTs) with diffusion of the lung for carbon monoxide (DLCO), measure of maximum inspiratory pressure (MIP) assessed both in standing and in supine positions, blood gas analysis, chest computed tomographic (CT) scan, and dyspnea score. The Pearson chi-square test, Fisher exact test, and Student t -test were applied when indicated. Results  At long-term (12 months) postoperative follow-up, patients operated for DP showed a significant improvement in terms of forced expiratory volume in 1 second (FEV1%) (+ 18.2%, p  < 0.001), forced vital capacity (FVC%) (+ 12.8%, p  < 0.001), DLCO% (+ 8.3%, p  = 0.04), and Po 2 (+ 9.86 mm Hg, p  < 0.001) when compared with baseline values. Conversely, when considering the TDH group, only the levels of Po 2 were found to be significantly higher in the postoperative assessment (+ 8.3 mm Hg, p  = 0.04). Although MIP increased in both the groups after surgery, a persistent and significant decrease of MIP was detected in TDH group when comparing the levels assessed in supine position with those measured in the standing position ( p  < 0.001). Medical Research Council dyspnea scale improved in the DP group by a factor of 0.80 ( p  < 0.001) and in the TDH group by a factor of 0.33 ( p  = 0.175). Conclusion  In patients who underwent surgery for DP, good long-term results may be predicted in terms of pulmonary flows, volumes, and DLCO. Conversely, in patients who underwent elective surgery for chronic TDH, a persistent overall restrictive pattern, lower MIP values in supine position, and paradoxical motion could be expected., (Georg Thieme Verlag KG Stuttgart · New York.)

Inclusion of drugs in cyclodextrins (CDs) is a recognized tool for modifying several properties such as solubility, stability, bioavailability, and so on. The photoreactive behavior of the β-CD/ketoprofen (KP) complex upon UV exposure showed a significant increase in photodecarboxylation, whereas the secondary degradation products by hydroxylation of the benzophenone moiety were inhibited. The results may account for an improvement of KP photophysical properties upon inclusion, thus better fostering its topical use. To correlate the structural details of the inclusion with these results, an NMR spectroscopic study of KP upon inclusion in β-CD was performed. Effects of the magnetically anisotropic centers of KP, changing their orientations upon inclusion and giving chemical shift variations, were specifically correlated with the results of the molecular dynamic simulations and ab initio calculations. In the large variety of papers focusing on the structural analysis of β-CD complexes, this work represents one of the few examples in which a detailed analysis of these simultaneous upfield-downfield NMR shifts of the same aromatic molecule upon inclusion is reported. Interestingly, the results demonstrate that the observed upfield and downfield shifts upon inclusion are not related to any direct magnetic role of β-CD. The conformational change of KP upon the inclusion process consists of a slight reduction in the angle between the two phenyl rings and in a remarkable reduction in the mobility of the carboxyl group, the latter being one of the main contributions to the NMR resonance shifts. These structural details help in understanding the features of the inclusion complex and, eventually, the driving force for its formation.

Atherosclerosis is one of the leading causes of mortality in the western world. Computed tomography angiography (CTA) is the conventional imaging method used for pre-surgery assessment of the blood flow within the carotid vessel. In this paper, we present a proof of concept of a novel, fast and operator independent protocol for the automatic detection (seeding) of the carotid arteries in CTA in the thorax and upper neck region. The dataset is composed of 14 patients' CTA images of the neck region. The performance of this method is compared with manual seeding by four trained operators. Inter-operator variation is also assessed based on the dataset. The minimum, average and maximum coefficient of variation among the operators was (0, 2, 5 %), respectively. The performance of our method is comparable with the state of the art alternative, presenting a detection rate of 75 and 71 % for the lowest and uppermost image levels, respectively. The mean processing time is 167 s per patient versus 386 s for manual seeding. There are no significant differences between the manual and automatic seed positions in the volumes (p = 0.29). A fast, operator independent protocol was developed for the automatic detection of carotid arteries in CTA. The results are encouraging and provide the basis for the creation of automatic detection and analysis tools for carotid arteries.

Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a very rare and uninvestigated subtype of non-small cell lung cancer (NSCLC)., Methods: The aims of this study were to define the radiometabolic features (by (18)F-FDG PET/CT) in a bi-centric cohort of 49 PSC patients and to explore their relation with clinico-pathological characteristics and long-term survival results after surgical treatment., Results: There were 40 males and 9 females aged 65.2 ± 10.47 years. Overall long-term survival was 26.7 % at 5 years. Mean and median values of SUVmax were 15.21 and 15, respectively (SD ±5.5). Performing an age-, gender- and staging-matched analysis comparing PSC Stage-I only with a cohort of Stage-I NSCLC (n = 93), we observed significantly higher SUVmax values in PSC group (15.11 vs 7.66, p = 0.001)., Conclusions: No differences in terms of SUVmax were found with regard to tumour dimensions, histology (pure vs mixed, pleomorphic vs others), pathological stage and pattern of recurrence. P-stage, surgical radicality, vascular/lymphatic invasion but not SUVmax affected long-term survival in PSC.

Right-side aortic arch is a rare congenital aortic anomaly occurring in 0.05% to 0.1% of the general population. Approximately, half of these cases may be associated with an aberrant left subclavian artery and occasionally with aneurysmatic change at its origin known as Kommerell diverticulum or aneurysm (KA). Herein we report a challenging case of a right-side aortic arch associated with KA incidentally observed in a 73-year-old male with metastatic lung cancer. After careful multidisciplinary discussion, a conservative strategy of care was successfully adopted., (© The Author(s) 2016.)

Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subset of non-small cell lung cancer with limited treatment options. The molecular characterization of PSC has been strongly hampered by the relative rarity of these tumors. However, understanding the molecular and genetic bases of PSCs is critical to pave the way to new treatment options. In this work, we aimed to explore the complexity of the genetic asset of PSC and investigate its prognostic impact on survival in a large cohort of patients with PSC., Methods: Next-generation sequencing analysis of a panel of 26 genes with potential clinical relevance was performed on surgical specimens of 49 PSCs. The prognostic impact of genetic profiles on patient survival and the association between the genetic alterations and clinicopathological features were tested., Results: Fifty-five somatic mutations were detected in 13 genes. Thirty-nine PSCs (80%) showed at least one mutation. Survival probability decreased in patients with mutated PSC compared with in those with PSC without mutations (p = 0.02). In particular, mutations in Kirsten rat sarcoma viral oncogene homolog gene (KRAS), alone or in combination with tumor protein p53 gene (TP53) mutations, were associated with decreased survival probability and with the occurrence of local metastases at recurrence. Finally, comparison of our results with data in The Cancer Genome Atlas showed that PSCs have a mutational profile similar to that of smokers' lung adenocarcinoma., Conclusions: Overall, our analysis provides further information on the mutational profiles of PSCs and demonstrates for the first time a role of KRAS mutations in driving the aggressiveness of this type of cancer., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Previous studies comparing the patterns of recovery for upper (UL) and lower limbs (LL) reported similar patterns of motor recovery of extremities. However, the influence of clinical stroke subtypes on the difference between recovery of extremities has never been investigated. The aim of this study is to compare the time course of the UL and LL in a sample of patients who have had distinct subtypes of ischemic stroke. A total of 443 consecutive patients following ischemic stroke were assessed at admission, discharge, and 1 month after discharge with the arm and leg motor parts of the Fugl-Meyer scale. Separate analyses were carried out for the entire sample and for samples of each stroke subtype classified according to the Oxfordshire Community Stroke Project. All groups showed significant improvements in motor function (P<0.001). Within the group of patients with total anterior circulation infarcts, the LL showed greater improved motor recovery than the UL (P<0.001). No significant difference was found between the time course of UL and LL motor recovery in the entire sample and in the other groups. This study confirms similar motor recovery of limbs in the entire sample, but also shows that the LL has greater recovery than the UL in patients with total anterior circulation infarcts. Functional prognosis should take into account the distinct stroke subtypes.