Management of triple negative breast cancer

Triple negative breast cancer (TNBC) accounts for approximately 15% of breast cancer cases. TNBC is an immunohistochemically defined subtype, with significant diversity within the subtype. Generally TNBC occurs in younger women and is marked by high rates of relapse, visceral and CNS metastases, and early death. Current therapy fails to curtail the innate aggressive behaviour of TNBC in the majority of patients. The poor prognosis coupled with a lack of targeted use of therapies is reflected in the high mortality. In a minority of patients with highly chemosensitive disease, no robust clinical evidence exists to guide use of current cytotoxics. Critical to optimal future management are accurate identification of truly triple negative disease and adequately powered prospective TNBC trials to establish treatment efficacy and define predictive biomarkers

The Use of a Pendulum Dynamic Mass Absorber to Protect a Trilithic Symmetric System from the Overturning

The trilith consists of two vertical elements (columns) supporting a horizontal element (lintel). The understanding of the dynamic behaviour of triliths is an important step towards their preservation and starts with the knowledge of the dynamics of rigid blocks. A passive method based on a dynamic mass absorber is used to protect a trilith from overturning. The protection system is modelled as a pendulum, hinged on the lintel, with the mass lumped at the end. The equations of rocking motion, uplift and the impact conditions are obtained for the coupled system trilith-mass absorber. An extensive parametric analysis is performed with the aim to compare the behaviour of the system with and without the pendulum, under impulsive one-sine (or one-cosine) base excitations. In order to point out the effectiveness of the protection system, overturning spectra, providing the amplitude of the excitation versus its frequency, are obtained. The pendulum mass absorber results effective in avoiding overturning in specific ranges of the frequency of the excitation. However, outside these ranges the mass absorber never compromises the safety of the trilith

Structural disconnection as a general technique to improve the dynamic and seismic response of structures: a basic model

Abstract The Base Isolation ( BI ) and the Tuned Mass Damper ( TMD ) represent two different techniques to reduce vibrations in building structures. Both these techniques may be considered as descending from an appropriate "disconnection" carried out on a given structure, whose global mass is subdivided in two parts, with a substantial difference in stiffness. The present work aims to study the characteristics of the disconnection and its effectiveness in reducing the dynamic response of a building structure subject to a base excitation. A simple 2- DOF "archetype" model has been developed to describe structural systems where a disconnection has been performed. This model has a constant total mass while stiffness and mass ratios, related to the two degrees of freedom, are taken as main variable parameters. Two distinct reference schemes ( BI -scheme and TMD -scheme) have been adopted in order to identify the specific part of the structure (respectively upper or lower) whose dynamic response should take advantage from the disconnection. A measurement of such advantage has been then proposed by means of different "gain parameters", related to each scheme. The behavior of the gain parameters has been depicted in various maps, each one defined for different base accelerations

probability models to assess the seismic safety of rigid block like structures and the effectiveness of two safety devices

Abstract When subject to earthquakes, some objects and structures, such as statues, obelisks, storage systems, and transformers, show a dynamic behavior that can be modeled considering the object/structure as a rigid block. Several papers have studied the dynamic behavior of both stand-alone rigid blocks and systems where rigid blocks have been paired with safety devices to prevent or delay the overturning of the blocks. Although the safety devices have generally been proven to be effective, their effectiveness changes substantially varying the parameters that characterize the system and the seismic input. This paper compares the seismic responses of stand along rigid blocks with those of blocks coupled with two candidate safety devices: an isolating base and a pendulum mass damper. To account for the relevant uncertainties, probabilistic seismic demand models are developed using a Bayesian approach. The probabilistic models are then used along with the overturning capacities of the blocks to construct fragility curves that give a prediction of the probability of overturning occurrence as a function of some characteristics of the blocks, of the safety devices, as well as of the seismic excitation, i.e. the slenderness of the body and the peak ground acceleration. The data needed to develop the probabilistic model are obtained integrating the nonlinear equations of motion of the two systems subject to selected ground motions. In the end, some numerical examples are proposed

A multifactorial \u2018Consensus Signature\u2019 by in silico analysis to predict response to neoadjuvant anthracycline-based chemotherapy in triple-negative breast cancer

BACKGROUND: Owing to the complex processes required for anthracycline-induced cytotoxicity, a prospectively defined multifactorial Consensus Signature (ConSig) might improve prediction of anthracycline response in triple-negative breast cancer (TNBC) patients, whose only standard systemic treatment option is chemotherapy. AIMS: We aimed to construct and evaluate a multifactorial signature, comprising measures of each function required for anthracycline sensitivity in TNBC. METHODS: ConSigs were constructed based on five steps required for anthracycline function: drug penetration, nuclear topoisomerase II\u3b1 (topoII\u3b1) protein location, increased topoII\u3b1 messenger RNA (mRNA) expression, apoptosis induction, and immune activation measured by, respectively, HIF1\u3b1 or SHARP1 signature, LAPTM4B mRNA, topoII\u3b1 mRNA, Minimal Gene signature or YWHAZ mRNA, and STAT1 signature. TNBC patients treated with neoadjuvant anthracycline-based chemotherapy without taxane were identified from publicly available gene expression data derived with Affymetrix HG-U133 arrays (training set). In silico analyses of correlation between gene expression data and pathological complete response (pCR) were performed using receiver-operating characteristic curves. To determine anthracycline specificity, ConSigs were assessed in patients treated with anthracycline plus taxane. Specificity, sensitivity, positive and negative predictive value, and odds ratio (OR) were calculated for ConSigs. Analyses were repeated in two validation gene expression data sets derived using different microarray platforms. RESULTS: In the training set, 29 of 147 patients had pCR after anthracycline-based chemotherapy. Various combinations of components were evaluated, with the most powerful anthracycline response predictors being ConSig1: (STAT1+topoII\u3b1 mRNA +LAPTM4B) and ConSig2: (STAT1+topoII\u3b1 mRNA+HIF1\u3b1). ConSig1 demonstrated high negative predictive value (85%) and high OR for no pCR (3.18) and outperformed ConSig2 in validation sets for anthracycline specificity. CONCLUSIONS: With further validation, ConSig1 may help refine selection of TNBC patients for anthracycline chemotherapy

The Employment of Leukotriene Antagonists in Cutaneous Diseases Belonging to Allergological Field

Leukotrienes (LTs) are potent biological proinflammatory mediators. LTC4, LTD4, and LTE4 are more frequently involved in chronic inflammatory responses and exert their actions binding to a cysteinyl-LT 1 (CysLT1) receptor and a cysteinyl-LT 2 (CysLT2) receptor. LTs receptor antagonists available for clinical use demonstrate high-affinity binding to the CysLT1 receptor. In this paper the employment of anti-LTs in allergic cutaneous diseases is analyzed showing that several studies have recently reported a beneficial effects of these agents (montelukast and zafirlukast as well as zileuton) for the treatment of some allergic cutaneous related diseases-like chronic urticaria and atopic eczema although their proper application remains to be established

Oral chemotherapy in advanced breast cancer: expert perspectives on its role in clinical practice

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Discovery of novel mutations in the dihydropyrimidine dehydrogenase gene associated with toxicity of fluoropyrimidines and viewpoint on preemptive pharmacogenetic screening in patients

Background: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the metabolic pathway of 5-fluorouracil (5-FU) and other fluoropyrimidines to inactive compounds. For this reason, severe, life-threatening toxicities may occur in patients with deficient DPD activity when administered standard doses of 5-FU and its prodrugs. Materials and methods: We selected three patients with colorectal adenocarcinoma who displayed unexpected severe adverse reactions after treatment with 5-FU and capecitabine. To investigate the possible involvement of deficient variants of the DPD gene (DPYD), a denaturing HPLC (dHPLC) approach followed by target exon sequencing of DPYD was performed on DNA extracted from peripheral blood. Results: Three novel non-synonymous mutations of DPYD, c.2509-2510insC, c.1801G>C, and c.680G>A, were detected in these subjects. Due to the absence of other deficient variants of DPYD and the compatibility of adverse reactions with fluoropyrimidine treatment, the novel variants were associated with a poor-metabolizer phenotype. Conclusions: Stratification of patients on the basis of their genotype may help prevent toxicity, and the large body of evidence about the pathogenesis of fluoropyrimidine-induced adverse reactions strongly encourages the adoption of best practice recommendations to appropriately address this important clinical issue. This approach is of utmost importance within a preventive, prognostic, and personalized approach to patient care in the oncology setting