Construction of the descriptive system for the assessment of quality of life AQoL-6D utility instrument

BackgroundMulti attribute utility (MAU) instruments are used to include the health related quality of life (HRQoL) in economic evaluations of health programs. Comparative studies suggest different MAU instruments measure related but different constructs. The objective of this paper is to describe the methods employed to achieve content validity in the descriptive system of the Assessment of Quality of Life (AQoL)-6D, MAU instrument.MethodsThe AQoL program introduced the use of psychometric methods in the construction of health related MAU instruments. To develop the AQoL-6D we selected 112 items from previous research, focus groups and expert judgment and administered them to 316 members of the public and 302 hospital patients. The search for content validity across a broad spectrum of health states required both formative and reflective modelling. We employed Exploratory Factor Analysis and Structural Equation Modelling (SEM) to meet these dual requirements.Results and DiscussionThe resulting instrument employs 20 items in a multi-tier descriptive system. Latent dimension variables achieve sensitive descriptions of 6 dimensions which, in turn, combine to form a single latent QoL variable. Diagnostic statistics from the SEM analysis are exceptionally good and confirm the hypothesised structure of the model.ConclusionsThe AQoL-6D descriptive system has good psychometric properties. They imply that the instrument has achieved construct validity and provides a sensitive description of HRQoL. This means that it may be used with confidence for measuring health related quality of life and that it is a suitable basis for modelling utilities for inclusion in the economic evaluation of health programs.<br /

Percutaneous thermal segmentectomy for liver malignancies over 3 cm: mid-term oncological performance and predictors of sustained complete response from a multicentric Italian retrospective study

Introduction: Percutaneous thermal segmentectomy is a single-step combination of microwave ablation, performed during arterial occlusion obtained with a balloon micro catheter, followed in the same session by balloon-occluded TACE. The aim of this multicenter retrospective study is to report the mid-term oncological performance of this technique for liver malignancies &gt; 3.0&nbsp;cm and to identify risk factors for the loss of sustained complete response. Methods: Oncological results were evaluated with CT or MRI according to m-RECIST (HCC) and RECISTv1.1 (metastasis/intra-hepatic cholangiocarcinoma, iCC) at 1-month, 3–6-month and then at regular-6-month intervals. To identify predictive variables associated with not achieving or losing complete response two mixed-effects multivariable logistic regression models were constructed. Results: Sixty-three patients (40/23, male/female) with primary liver malignancies (HCC = 49; iCC = 4) and metastasis (n = 10) were treated. Median diameter of target lesion was 4.5&nbsp;cm (range 3.0–7.0&nbsp;cm). The median follow-up time was 9.2&nbsp;months. At one-month follow-up, 79.4% of patients presented with a complete response and the remaining 20.6% were partial responders. At the 3–6-month follow-up, reached by 59 of the initial 63 patients, 83.3% showed a sustained complete response, while 10.2% had a partial response and 8.5% a local recurrence. At the last follow-up, 69.8% of the lesions showed a complete response. The initial diameter of the target lesion ≥ 5.0&nbsp;cm was the only independent variable associated with the risk of failure in maintaining a complete response at 6&nbsp;months (OR = 8.58, 95% CI 1.38–53.43; P = 0.02). Conclusion: Percutaneous thermal segmentectomy achieves promising oncological results in patients with tumors &gt; 3.0&nbsp;cm, with tumor dimension ≥ 5.0&nbsp;cm being the only risk factor associated with the failure of a sustained complete response

The identification of informative genes from multiple datasets with increasing complexity

Background In microarray data analysis, factors such as data quality, biological variation, and the increasingly multi-layered nature of more complex biological systems complicates the modelling of regulatory networks that can represent and capture the interactions among genes. We believe that the use of multiple datasets derived from related biological systems leads to more robust models. Therefore, we developed a novel framework for modelling regulatory networks that involves training and evaluation on independent datasets. Our approach includes the following steps: (1) ordering the datasets based on their level of noise and informativeness; (2) selection of a Bayesian classifier with an appropriate level of complexity by evaluation of predictive performance on independent data sets; (3) comparing the different gene selections and the influence of increasing the model complexity; (4) functional analysis of the informative genes. Results In this paper, we identify the most appropriate model complexity using cross-validation and independent test set validation for predicting gene expression in three published datasets related to myogenesis and muscle differentiation. Furthermore, we demonstrate that models trained on simpler datasets can be used to identify interactions among genes and select the most informative. We also show that these models can explain the myogenesis-related genes (genes of interest) significantly better than others (P < 0.004) since the improvement in their rankings is much more pronounced. Finally, after further evaluating our results on synthetic datasets, we show that our approach outperforms a concordance method by Lai et al. in identifying informative genes from multiple datasets with increasing complexity whilst additionally modelling the interaction between genes. Conclusions We show that Bayesian networks derived from simpler controlled systems have better performance than those trained on datasets from more complex biological systems. Further, we present that highly predictive and consistent genes, from the pool of differentially expressed genes, across independent datasets are more likely to be fundamentally involved in the biological process under study. We conclude that networks trained on simpler controlled systems, such as in vitro experiments, can be used to model and capture interactions among genes in more complex datasets, such as in vivo experiments, where these interactions would otherwise be concealed by a multitude of other ongoing events

Rab3D is critical for secretory granule maturation in PC12 cells.

Neuropeptide- and hormone-containing secretory granules (SGs) are synthesized at the trans-Golgi network (TGN) as immature secretory granules (ISGs) and complete their maturation in the F-actin-rich cell cortex. This maturation process is characterized by acidification-dependent processing of cargo proteins, condensation of the SG matrix and removal of membrane and proteins not destined to mature secretory granules (MSGs). Here we addressed a potential role of Rab3 isoforms in these maturation steps by expressing their nucleotide-binding deficient mutants in PC12 cells. Our data show that the presence of Rab3D(N135I) decreases the restriction of maturing SGs to the F-actin-rich cell cortex, blocks the removal of the endoprotease furin from SGs and impedes the processing of the luminal SG protein secretogranin II. This strongly suggests that Rab3D is implicated in the subcellular localization and maturation of ISGs

p130Cas is an essential transducer element in ErbB2 transformation

The ErbB2 oncogene is often overexpressed in breast tumors and associated with poor clinical outcome. p130Cas represents a nodal scaffold protein regulating cell survival, migration, and proliferation in normal and pathological cells. The functional role of p130Cas in ErbB2-dependent breast tumorigenesis was assessed by its silencing in breast cancer cells derived from mouse mammary tumors overexpressing ErbB2 (N202-1A cells), and by its reexpression in ErbB2-transformed p130Cas-null mouse embryonic fibroblasts. We demonstrate that p130Cas is necessary for ErbB2-dependent foci formation, anchorage-independent growth, and in vivo growth of orthotopic N202-1A tumors. Moreover, intranipple injection of p130Cas-stabilized siRNAs in the mammary gland of Balbc-NeuT mice decreases the growth of spontaneous tumors. In ErbB2-transformed cells, p130Cas is a crucial component of a functional molecular complex consisting of ErbB2, c-Src, and Fak. In human mammary cells, MCF10A.B2, the concomitant activation of ErbB2, and p130Cas overexpression sustain and strengthen signaling, leading to Rac1 activation and MMP9 secretion, thus providing invasive properties. Consistently, p130Cas drives N202-1A cell in vivo lung metastases colonization. These results demonstrate that p130Cas is an essential transducer in ErbB2 transformation and highlight its potential use as a novel therapeutic target in ErbB2 positive human breast cancers.-Cabodi, S., Tinnirello, A., Bisaro, B., Tornillo, G., Camacho-Leal, M. P., Forni, G., Cojoca, R., Iezzi, M., Amici, A., Montani, M., Eva, A., Di Stefano, P., Muthuswamy, S. K., Tarone, G., Turco, E., Defilippi, P. p130Cas is an essential transducer element in ErbB2 transformation

Triplet Exciton Generation in Bulk-Heterojunction Solar Cells based on Endohedral Fullerenes

Organic bulk-heterojunctions (BHJ) and solar cells containing the trimetallic nitride endohedral fullerene 1-[3-(2-ethyl)hexoxy carbonyl]propyl-1-phenyl-Lu3N@C80 (Lu3N@C80-PCBEH) show an open circuit voltage (VOC) 0.3 V higher than similar devices with [6,6]-phenyl-C[61]-butyric acid methyl ester (PC61BM). To fully exploit the potential of this acceptor molecule with respect to the power conversion efficiency (PCE) of solar cells, the short circuit current (JSC) should be improved to become competitive with the state of the art solar cells. Here, we address factors influencing the JSC in blends containing the high voltage absorber Lu3N@C80-PCBEH in view of both photogeneration but also transport and extraction of charge carriers. We apply optical, charge carrier extraction, morphology, and spin-sensitive techniques. In blends containing Lu3N@C80-PCBEH, we found 2 times weaker photoluminescence quenching, remainders of interchain excitons, and, most remarkably, triplet excitons formed on the polymer chain, which were absent in the reference P3HT:PC61BM blends. We show that electron back transfer to the triplet state along with the lower exciton dissociation yield due to intramolecular charge transfer in Lu3N@C80-PCBEH are responsible for the reduced photocurrent

How to combine CTA, 99mTc-WBC SPECT/CT, and [18F]FDG PET/CT in patients with suspected abdominal vascular endograft infections?

Purpose - We aimed at comparing Tc-99m-HMPAO white blood cells (Tc-99m-WBC) scintigraphy, 18fluorine-fluorodeoxyglucose ([F-18]FDG) positron emission tomography/computed tomography (PET/CT) and CT angiography (CTA) in patients with suspected abdominal vascular graft or endograft infection (VGEI). Moreover, we attempted to define a new visual score for interpreting [F-18]FDG PET/CT scans aiming at increasing its specificity. Methods - We prospectively compared Tc-99m-WBC SPECT/CT, [F-18]FDG PET/CT, and CTA in 26 patients with suspected abdominal VGEI. WBC scans were performed and interpreted according to EANM recommendations. [F-18]FDG PET/CT studies were assessed with both qualitative (Sah's scale and new visual score) and semi-quantitative analyses. CTA images were interpreted according to MAGIC criteria. Microbiology, histopathology or a clinical follow-up of at least 24 months were used to achieve final diagnosis. Results - Eleven out of 26 patients were infected. [F-18]FDG PET/CT showed 100% sensitivity and NPV, with both scoring systems, thus representing an efficient tool to rule out the infection. The use of a more detailed scoring system provided statistically higher specificity compared to the previous Sah's scale (p = 0.049). Tc-99m-WBC SPECT/CT provided statistically higher specificity and PPV than [F-18]FDG PET/CT, regardless the interpretation criteria used and it can be, therefore, used in early post-surgical phases or to confirm or rule out a PET/CT finding. Conclusions - After CTA, patients with suspected late VGEI should perform a [F-18]FDG PET/CT given its high sensitivity and NPV. However, given its lower specificity, positive results should be confirmed with Tc-99m-WBC scintigraphy. The use of a more detailed scoring system reduces the number of Tc-99m-WBC scans needed after [F-18]FDG PET/CT. Nevertheless, in suspected infections within 4 months from surgery, Tc-99m-WBC SPECT/CT should be performed as second exam, due to its high accuracy in differentiating sterile inflammation from infection

Pathological changes of the anatomical structure and markers of the limbal stem cell niche due to inflammation.

PURPOSE: The corneoscleral limbus is the site of corneal epithelial stem cells (SC). The aim of this study is to evaluate the expression of different SC markers in the normal human limbus and to determine how this is affected by inflammation. METHODS: Corneoscleral specimens from healthy and inflamed donor eyes were examined by immunohistochemistry/immunofluorescence for p63, vimentin, laminin 5, integrin α6, β1, β4, ABCG2, desmoglein 3, connexin 43, N-cadherin, and cytokeratins 12 and 15. The distribution and anatomic structure of the limbal crypts and the percentage of SC marker antigens in healthy donors were analyzed. In inflamed tissues, we evaluated the anatomic structure of the limbal epithelial crypt (LEC) and the positivity for SC markers. RESULTS: In normal limbus, the niche structures were distributed differently. The variability of their number correlated with the percentage of p63 positivity. Integrin β1 staining directly correlated with p63 positivity while the remaining proteins were variably and widely distributed. Double staining for p63 and vimentin did not reveal any co-localization. In inflamed eyes, the basal cells in the crypts were "stretched" and surrounded by inflammatory cells, and only a few SC markers were still present. CONCLUSIONS: Diseases involving the limbus may result in marked changes of expression of SC markers within the LEC and also alter the crypt structure