K-ras gene mutations: an unfavorable prognostic marker in stage I lung adenocarcinoma

Activation of K-ras gene by point mutations, a common finding in lung adenocarcinomas, has been suggested to decrease patient survival. We investigated 109 lung adenocarcinomas, mostly small, peripheral, stage I tumours (81/109) for presence of K-ras gene mutations at codons 12 and 13. Mutations were detected by denaturing gradient gel electrophoresis analysis of specific sequences amplified by polymerase chain reaction from DNA extracted from archival pathological material. Thirty-three of 109 (30.3%) tumours showed mutations at codon 12 (28/33, 84.8%) or 13 (5/33, 15.2%) of the gene. Mutations and type of nucleotide substitutions were differently distributed among cytological subtypes, being more prevalent among less differentiated (G2 and G3) tumours and among bronchial than bronchiolo-alveolar type adenocarcinomas. Survival analysis showed an adverse effect of K-ras mutation on survival, restricted to stage I tumours. Median survival for 81 stage I patients was 30 months for non-mutated tumours versus 20 months for mutated tumours (p = 0.016). Multivariate analysis showed that age of patient (p = 0.001) and K-ras mutation status (p = 0.04) were the only independent factors influencing survival significantly. These data strengthen the hypothesis that K-ras gene mutations may be useful in identifying a subgroup of patients with poor outcome.     

An Abstract Decision Procedure for Satisfiability in the Theory of Recursive Data Types

The theory of recursive data types is a valuable modeling tool for software verification. In the past, decision procedures have been proposed for both the full theory and its universal fragment. However, previous work has been limited in various ways. In this paper, we present a general algorithm for the universal fragment. The algorithm is presented declaratively as a set of abstract rules which are terminating, sound, and complete. We show how other algorithms can be realized as strategies within our general framework. Finally, we propose a new strategy and give experimental results showing that it performs well in practice.     

IBA analyses and lead concentration measurements of AMS-C dated bones from two medieval sites in Italy

AMS (accelerator mass spectrometry) radiocarbon dated human bone samples recovered in the deserted medieval village of Quattro Macine, Lecce, in Southern Italy, were analyzed by PIXE (particle induced X-ray emission) and PIGE (particle induced gamma ray emission). The optimization of the PIXE-PIGE experimental set-up in term of beam energy and detection geometry resulted in the possibility to obtain information about major, minor and trace elements of the samples. Unexpectedly, all the analyzed samples showed a Pb concentration higher than 50 ppm. Two possible explanations of the measured high Pb concentration are discussed in the paper: the pre-mortem intake associated with the use of Pb-rich glazed pottery and the post-mortem intake from soil as the result of diagenetic processes.     

Plasma Lipid Profiling Contributes to Untangle the Complexity of Moyamoya Arteriopathy

Moyamoya arteriopathy (MA) is a rare cerebrovascular disorder characterized by ischemic/hemorrhagic strokes. The pathophysiology is unknown. A deregulation of vasculogenic/angiogenic/inflammatory pathways has been hypothesized as a possible pathophysiological mechanism. Since lipids are implicated in modulating neo-vascularization/angiogenesis and inflammation, their deregulation is potentially involved in MA. Our aim is to evaluate angiogenic/vasculogenic/inflammatory proteins and lipid profile in plasma of MA patients and control subjects (healthy donors HD or subjects with atherosclerotic cerebrovascular disease ACVD). Angiogenic and inflammatory protein levels were measured by ELISA and a complete lipidomic analysis was performed on plasma by mass spectrometry. ELISA showed a significant decrease for MMP-9 released in plasma of MA. The untargeted lipidomic analysis showed a cumulative depletion of lipid asset in plasma of MA as compared to HD. Specifically, a decrease in membrane complex glycosphingolipids peripherally circulating in MA plasma with respect to HD was observed, likely suggestive of cerebral cellular recruitment. The quantitative targeted approach demonstrated an increase in free sphingoid bases, likely associated with a deregulated angiogenesis. Our findings indicate that lipid signature could play a central role in MA and that a detailed biomarker profile may contribute to untangle the complex, and still obscure, pathogenesis of MA.     

"The sarcoidosis map": a joint survey of clinical and immunogenetic findings in two European countries

We pooled immunogenetic data obtained in independent studies in two European populations (Italian and Czech) of patients affected by sarcoidosis. Correspondence analysis was used to investigate the associations between clinical and immunogenetic data. Two hundred and thirty-three patients were enrolled in the study, of which 126 were from the Czech Republic and 107 from Italy. Using a common protocol, we examined each patient for sex, age of disease onset, roentgenologic stage, extrapulmonary spread, and clinical course. One thousand and ten healthy individuals, HLA typed for class I and II serologic polymorphisms, served as controls. Findings that were essentially in agreement in both populations were: (1) a positive association of sarcoidosis with HLA-A1, B8, and DR3 markers, and a negative association with HLA-B12 and DR4; (2) a prevalence of HLA-DR3 and DR4 among females and of DR5 among males; (3) a relationship of B13 and B35 with early onset and of A30, B8, DR3, and DR4 with late onset of disease; (4) an association of B27 with sarcoidosis restricted to the lungs; (5) a relationship of A1, B8, B27, and DR3 to roentgenologic stage I and of B12 and DR4 to stage III; and (6) an association of HLA-DR3 with a good outcome. Population-restricted findings essentially concerned the alleles HLA-B13 and B22, the former being associated with the disease, male sex, early onset, extrapulmonary localization and relapse only in Czechs, and the latter to disease spread only in Italians. Our results seem to support the concept that immunogenetic background may at least partly account for the clinical heterogeneity of sarcoidosis.     

Molecular Insights in Uterine Leiomyosarcoma: A Systematic Review

Uterine fibroids (UFs) are the most common benign tumors of female genital diseases, unlike uterine leiomyosarcoma (LMS), a rare and aggressive uterine cancer. This narrative review aims to discuss the biology and diagnosis of LMS and, at the same time, their differential diagnosis, in order to distinguish the biological and molecular origins. The authors performed a Medline and PubMed search for the years 1990–2022 using a combination of keywords on the topics to highlight the many genes and proteins involved in the pathogenesis of LMS. The mutation of these genes, in addition to the altered expression and functions of their enzymes, are potentially biomarkers of uterine LMS. Thus, the use of this molecular and protein information could favor differential diagnosis and personalized therapy based on the molecular characteristics of LMS tissue, leading to timely diagnoses and potential better outcomes for patients.     

Solving quantified verification conditions using satisfiability modulo theories

First-order logic provides a convenient formalism for describing a wide variety of verification conditions. Two main approaches to checking such conditions are pure first-order automated theorem proving (ATP) and automated theorem proving based on satisfiability modulo theories (SMT). Traditional ATP systems are designed to handle quantifiers easily, but often have difficulty reasoning with respect to theories. SMT systems, on the other hand, have built-in support for many useful theories, but have a much more difficult time with quantifiers. One clue on how to get the best of both worlds can be found in the legacy system Simplify which combines built-in theory reasoning with quantifier instantiation heuristics. Inspired by Simplify and motivated by a desire to provide a competitive alternative to ATP systems, this paper describes a methodology for reasoning about quantifiers in SMT systems. We present the methodology in the context of the Abstract DPLL Modulo Theories framework. Besides adapting many of Simplify’s techniques, we also introduce a number of new heuristics. Most important is the notion of instantiation level which provides an effective mechanism for prioritizing and managing the large search space inherent in quantifier instantiation techniques. These techniques have been implemented in the SMT system CVC3. Experimental results show that our methodology enables CVC3 to solve a significant number of quantified benchmarks that were not solvable with previous approaches.