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The storage of chestnuts is a highly critical phase due to the considerable postharvest losses of the product with relevant commercial impact. The effect on the chemical quality parameters of chestnuts treated with 300 ppb of gaseous ozone in air or in atmospheric air at T = 2 °C for 150 days during the storage has been investigated. The ozone treatment increased sucrose and total sugar contents; while tocopherols were reduced. No significant differences in weight loss and fatty acid content were recorded between chestnut treated with ozone and untreated fruits (P ≥ 0.05). In addition, chestnut ozone exposure for 150 days reduced the total microbial populations associated with the pericarps of about 1.6 logs for mesophilic bacteria and 1.0 logs for fungi. Overall, our results suggested that gaseous ozone treatment is a valid and economic technology to ensure the shelf life quality of chestnut during the long storage periods.

Aquatic exercise is popular for training and rehabilitation, but information on how the water depth affects muscle activity when walking is lacking. The purpose of this study was to compare muscle activity when walking on land and at knee, pelvis and xiphoid process depth in a swimming pool. Twelve participants (22±3.6 years; 70.9±14.5kg; 1.7±0.1m) walked on land and on the pool floor at each of the three depths, at a self-selected (Vself) and a maximum speed (Vmax). Mean and peak muscle activity was recorded for the rectus femoris (RF), biceps femoris (BF), medial gastrocnemius (GM), lateral gastrocnemius (GL), tibialis anterior (TA) and erector spinae (ES). Stride duration was also recorded. Stride duration decreased and activity of all muscles increased from Vself to Vmax, except peak values at xiphoid process depth. For the depth comparisons, most changes in muscle activity occurred in the RF and BF, with higher values generally occurring at knee and pelvis depth, and stride duration continually increased with depth. These findings provide useful information on the musculoskeletal demands of walking in the water that can be used to inform design and prescription of exercise programmes for rehabilitation.

Background Walking on compliant surfaces, on sand in particular, is now recommended for training in both elderlies and injured subjects/individuals, allowing to perform high intensity exercises (i.e. augmented energy expenditure) in safe conditions (i.e. minimizing the impact on the joints and the risk of fall). Nevertheless, despite the assessment of energetics of walking on sand, the quantitative biomechanical characterization of walking on sand in ecological conditions is largely lacking. Research question Which is the effect of sand surface on gait speed, gait temporal segmentation and their variability as related to surface compliance in ecological condition? Methods Eighteen healthy adults were assessed while walking on solid ground, dry-, and wet sand in ecological conditions by means of wearable inertial sensors (Miniwave, Cometa s.r.l., Italy). The best performing algorithm for the segmentation of walking on sand was selected among 17 algorithms designed for solid ground. Gait timing (i.e. speed, temporal segmentation, variability) was analysed, for the first time, with respect to sand compliance, and compared to walking on solid ground. Results Self-selected speed on a 60 m distance increased when walking on sand with respect to solid ground (Median 1.02 m/s), with the highest speed on wet sand (Median 1.15 m/s). A stabilizing strategy on the uneven surface provided by sand was highlighted by i) increased stance and double support durations with respect to speed on wet sand, and ii) increased short-term variability of stride, corresponding to continual adjustments of the lower limbs due to shifting surface provided by sand. Significance This study represents the first step in the objective characterization of walking on compliant surfaces as sand, necessary for the definition of training and rehabilitative programs.

Background The quantification of gait temporal parameters (i.e. step time, stance time) is crucial in human motion analysis and requires the accurate identification of gait events (i.e. heel strike, toe off). With the widespread use of inertial wearable sensors, many algorithms were proposed and applied for the purpose. Nevertheless, only few studies addressed the assessment of the actual performance of these algorithms, rather considering each proposed algorithm as a whole. Research question How different implementation characteristics influence the assessment of gait events and temporal parameters from inertial sensor measures in terms of accuracy and repeatability? Methods Seventeen different algorithms were identified from a systematic review and classified based on: 1) sensor position, 2) target variable, 3) computational approach. The influence of these characteristics was analysed on walking data of 35 healthy volunteers mounting 5 tri-axial inertial sensors. Foot contact events identified by 2 force platforms were assumed as gold standard. Temporal parameters were calculated from gait events. Algorithm performance was analysed in terms of accuracy (error median value) and repeatability (error 25th and 75th percentile values). Results Shank- and foot-based algorithms performed better (in terms of accuracy and repeatability) in gait events detection and stance time estimation than lower trunk-based ones, while sensor position did not affect step estimate, given the error bias characteristics. Angular velocity-based algorithms performed significantly better than acceleration-based ones for toe off detection in terms of repeatability (68 ms and 102 ms, 25th–75th percentile error range, respectively) and, for heel strike detection, showed better repeatability (40 ms and 111 ms) and comparable accuracy (65 ms and 60 ms median error, respectively) than acceleration-based ones. The performance of different computational approaches varied depending on sensor positioning. Significance Present results support the selection of the proper algorithm for the estimation of gait events and temporal parameters in relation to the specific application.

When aiming at assessing motor control development, natural walking (NW), and tandem walking (TW) are two locomotor tasks that allow analyzing different characteristics of motor control performance. NW is the reference locomotor task, expected to become more and more automatic with age. TW is a nonparadigmatic task used in clinics to highlight eventual impairments and to evaluate how a child deals with a new challenging motor experience. This work aims at investigating motor development in school-aged children, by assessing quantitatively their performance during TW and NW. Eighty children (6–10 years) participated in the study. Trunk acceleration data and nonlinear measures (recurrence quantification analysis (RQA), and multiscale entropy (MSE)) were used to characterize trunk postural control and motor complexity. The results were analyzed with respect to age and standard clinical assessment of TW (number of correct consecutive steps), by means of Spearman correlation coefficients. RQA and MSE allowed highlighting age-related changes in both postural control of the trunk and motor complexity, while classic standard assessment of TW resulted uniformly distributed in the different age groups. The present results suggest this quantitative approach as relevant when assessing the motor development in schoolchildren and complementary to standard clinical tests.

Background and objectives Walking in water is used for rehabilitation in different pathological conditions. For the characterization of gait alterations related to pathology, gait timing assessment is of primary importance. With the widespread use of inertial sensors, several algorithms have been proposed for gait timing estimation (i.e. gait events and temporal parameters) out of the water, while an assessment of their performance for walking in water is still missing. The purpose of the present study was to assess the performance in the temporal segmentation for gait in water of 17 algorithms proposed in the literature. Methods Ten healthy volunteers mounting 5 tri-axial inertial sensors (trunk, shanks and feet) walked on dry land and in water. Seventeen different algorithms were implemented and classified based on: 1) sensor position, 2) target variable, and 3) computational approach. Gait events identified from synchronized video recordings were assumed as reference. Temporal parameters were calculated from gait events. Algorithm performance was analysed in terms of sensitivity, positive predictive value, accuracy, and repeatability. Results For walking in water, all Trunk-based algorithms provided a sensitivity lower than 81% and a positive predictive value lower than 94%, as well as acceleration-based algorithms, independently from sensor location, with the exception of two Shank-based ones. Drop in algorithm sensitivity and positive predictive value was associated to significant differences in the stride pattern of the specific analysed variables during walking in water as compared to walking on dry land, as shown by the intraclass correlation coefficient. When using Shank- or Foot-based algorithms, gait events resulted delayed, but the delay was compensated in the estimate of Stride and Step time; a general underestimation of Stance- and overestimation of Swing-time was observed, with minor exceptions. Conclusion Sensor position, target variable and computational approach determined different error distributions for different gait events and temporal parameters for walking in water. This work supports an evidence-based selection of the most appropriate algorithm for gait timing estimation for walking in water as related to the specific application, and provides relevant information for the design of new algorithms for the specific motor task.

This article documents the shifting status of trees in the eighteenth- and early nineteenth-century French imaginary, with a particular focus on the author, politician, and diplomat Francois-Rene de Chateaubriand’s planting work at La Vallee aux Loups. It examines the ways in which Chateaubriand viewed his saplings as “family” and “children,” and reads these declarations alongside contemporaneous discourses and practices of arboreal attachment (including the mesmerist use of magnetized trees). Ultimately, Chateaubriand’s memoirs and personal correspondence show a remarkable understanding of the possibility of a human-arboreal interactivity, and the article therefore addresses the potential relevance today of his notions of arboreal agency and sociability.

The role of pathologic auto-antibodies against myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is a highly controversial matter. As the use of animal models may enable to unravel the molecular mechanisms of the human disorder, numerous studies on multiple sclerosis are carried out using experimental autoimmune encephalomyelitis (EAE). In particular, the most extensively used EAE model is obtained by immunizing C57BL/6 mice with the immunodominant peptide MOG(35-55). In this scenario, we analyzed the anti-MOG antibody response in this model using the recombinant refolded extracellular domain of the protein, MOG(1-117). To assess the presence of a B-cell intramolecular epitope spreading mechanism, we tested also five synthetic peptides mapping the 1-117 sequence of MOG, including MOG(35-55). For this purpose, we cloned, expressed in Escherichia coli and on-column refolded MOG(1-117), and we applied an optimized microwave-assisted solid-phase synthetic strategy to obtain the designed peptide sequences. Subsequently, we set up a solid-phase immunoenzymatic assay testing both naive and EAE mice sera and using MOG protein and peptides as antigenic probes. The results obtained disclose an intense IgG antibody response against both the recombinant protein and the immunizing peptide, while no response was observed against the other synthetic fragments, thus excluding the presence of an intramolecular epitope spreading mechanism. Furthermore, as the properly refolded recombinant probe is able to bind antibodies with greater efficiency compared with MOG(35-55), we hypothesize the presence of both linear and conformational epitopes on MOG(35-55) sequence.

Primary Biliary Cirrhosis is an immune-mediated disease in which one of the epitopes recognized by antimitochondrial autoantibodies is a lipoylated fragment of the PDC-E2 protein. Accordingly, the synthesis of lipoylated peptides as diagnostic tools is a relevant target. Up to now, the proper tools for the introduction of lipoylation on building blocks to be used in Fmoc/tBu solid phase peptide synthesis (SPPS) are lacking, and the role of chirality in lipoylation remains poorly studied. In this paper, we present the synthesis of lipoylated lysine derivatives as pure diastereomeric building blocks suitable for Fmoc/tBu SPPS and their introduction in relevant peptide sequences to possibly serve as synthetic probes for the development of novel diagnostic tools for this disease. The optimization of the synthesis of lipoylated building blocks derived from racemic, (R)-, and (S)-α-lipoic acid is described. Synthesis of peptide probes incorporating lipoylation is described. An insight regarding the cleavage of lipoylated peptides is given, as well as a method to oxidize or reduce the 1,2-dithiolane ring of the lipoyl moiety directly on the peptide without any subsequent purification.

Modeling biological systems in vitro has contributed to clarification of complex mechanisms in simplified and controlled experimental conditions. Mouse embryonic stem (mES) cells can be successfully differentiated toward specific neuronal cell fates, thus representing an attractive tool to dissect, in vitro, mechanisms that underlie complex neuronal features. In this study, we generated and characterized a reporter mES cell line, called Tph2GFP, in which the vital reporter GFP replaces the tryptophan hydroxylase 2 (Tph2) gene. Tph2GFP mES cells selectively express GFP upon in vitro differentiation toward the serotonergic fate, they synthesize serotonin, possess excitable membranes, and show the typical morphological, morphometrical, and molecular features of in vivo serotonergic neurons. Thanks to the vital reporter GFP, we highlighted by time-lapse video microscopy several dynamic processes such as cell migration and axonal outgrowth in living cultures. Finally, we demonstrated that predifferentiated Tph...

This article considers Calvino’s Il barone rampante (1957) as a parable of the deforestation and excessive urban development that took place along the Italian Riviera, starting in the late eighteenth century. The novel’s inter- textual references point to the intellectual foundations of the author’s ecological ethics, and reveal his understanding of the Enlightenment as a culture vested in the protection of its forests and interested in recasting human relationships with the natural world.

Modeling biological systems in vitro has contributed to clarification of complex mechanisms in simplified and controlled experimental conditions. Mouse embryonic stem (mES) cells can be successfully differentiated toward specific neuronal cell fates, thus representing an attractive tool to dissect, in vitro, mechanisms that underlie complex neuronal features. In this study, we generated and characterized a reporter mES cell line, called Tph2

As they debated the pros and cons of grafting, eighteenth-century French agronomists, philosophers, novelists, and poets negotiated the tensions and contradictions that surfaced between their nostalgia for a `”natural” society, and their dreams of perpetual innovation, culture, and progress. The discourse on grafting helped authors articulate their understandings of the merits or faults of civilization, just as it also allowed them to define good civic participation and ideal forms of stewardship of the land. Furthermore, insofar as grafts could be read as figures of the transplantation and integration of foreign culture(s), they could be used metaphorically to allude to current political events and problems. As a result, the discourse on grafting intersected with, and engaged, some of the key issues of the French Enlightenment.

Before the French revolutionaries adopted the tree as a symbol of freedom, artists used arboreal images to discuss issues of royal policy and reform. Hubert Robert, Peyraud de Beaussol, Jacques Delille, Michel-Paul de Chabanon, and Adelaide de Souza drew scenes of felling and pruning to comment upon the solidity of a cultural and political system—the ancien regime—that seemed to be vacillating at their feet. Their work was inspired by the monarchy's involvement in the management of forests, by the construction of the gardens of Versailles under Louis XIV, and the dramatic event of their replanting in 1774–5.

Primary biliary cirrhosis is an immune-mediated chronic liver disease whose diagnosis relies on the detection of serum antimitochondrial antibodies directed against a complex set of proteins, among which pyruvate dehydrogenase complex is considered the main autoantigen. We studied the immunological role of the lipoyl domain of this protein using synthetic lipoylated peptides, showing that the lipoyl chain chirality does not affect autoantibody recognition and, most importantly, confirming that both lipoylated and unlipoylated peptides are able to recognize specific autoantibodies in patients sera. In fact, 74% of patients sera recognize at least one of the tested peptides but very few positive sera recognized exclusively the lipoylated peptide, suggesting that the lipoamide moiety plays a marginal role within the autoreactive epitope. These results are supported by a conformational analysis showing that the lipoyl moiety of pyruvate dehydrogenase complex appears to be involved in hydrophobic interactions, which may limit its exposition and thus its contribution to the complex antigenic epitope. A preliminary analysis of the specificity of the two most active peptides indicates that they could be part of a panel of synthetic antigens collectively able to mimic in a simple immunoenzymatic assay the complex positivity pattern detected in immunofluorescence.

Lipoic acid is a heterocyclic sulfur-containing derivative of octanoic acid that is characterized by a 1,2-dithiolane ring. Found in nature as an essential protein cofactor, lipoic acid is implicated in cellular metabolic reactions. In particular, lipoylation is an essential posttranslational modification involved in cellular energetic metabolism performed by mitochondria. In this chapter, we highlight the different pathways to obtain lipoylated peptides and proteins, and the antioxidant properties of lipoic acid analogs, including their therapeutic potential in fields such as autoimmunity.

(2006). Colonial Predicaments, Eugenic Experiments, and The Evacuation of Compassion: 'Perfecting' The Hybrid Creatures In Retif's La Decouverte Australe. Symposium: A Quarterly Journal in Modern Literatures: Vol. 60, No. 3, pp. 171-186.

In his 'Notes sur Les Liaisons dangereuses', Charles Baudelaire remarked that Choderlos de Laclos's masterpiece was first and foremost a novel about 'terrible' sociability: the novel, he claimed, was a 'livre essentiellement fran9ais. Livre de sociabilite, terrible, mais sous Ie badin et Ie convenable. Livre de sociabilite' .1 As he acknowledged the eighteenthcentury myth of French sociability and simultaneously recognized the existence of an intimate, yet perverse, connection between the corruption of social mores and the classical rules of bienseance, Baudelaire struck right at the heart of Laclos' s masterpiece. The Liaisons dangereuses can, in fact, be read as a meditation on the sociable contract that regulated life and interpersonal relations in ancien regime France. 2 The novel explores the repressive tendencies of early modern conviviality, underscoring in particular the risks involved in the silencing ofthe socially undesirable. By precluding the expression of the unacceptable or unconventional, the laws of sociability seem to have masked, and therefore protected and sometimes even enhanced, precisely those ideas and practices which they were meant to exclude. As Laclos's novel shows all too well, 'Ie badin et Ie convenable' could serve to produce something in excess of friendly words and mannerly fashions: something unnamable, but indisputably 'terrible'. The novel describes the perverse machinations of two extraordinary libertines, the Marquise de Merteuil and the Vicomte de Valmont, who manipulate friends and acquaintances for their personal pleasure and satisfaction. With a seemingly 'Olympian mastery of reality,' this Machiavellian couple scripts its victims' lives, ultimately seducing and ruining two innocent young lovers Cecile Volanges and the chevalier Danceny as well as a virtuous wife, the Presidente de Tourvel. 3 An elaborate testimonial to 'Ie plaisir de tromper', the Liaisons dangereuses can thus be read as a meditation on the highly mannered, and often deceptive, nature of social relations in eighteenth-century France. The novel deconstructs the early modern behavioural discourse of sociability, suggesting that its hoilow conventions simply screen the passions and 'haine [que tous ont] dans Ie coeur' (p. 257). Laclos shows politeness to be nothing more than an ideological construct elaborated by a male power-structure bent on hiding its natural propensity to violence.

The publication of Jacques Delille' s poem Les Jardins ou l' art d' embellir les paysages n 1782 was a major literary event.1 The author was already famous for his translation of Virgil' s The Georgics, an accomplishment which had won him — on its own — an election to the Acad—mic Fran—aise. Les Jardins attracted further attention because it engaged one of the most popular debates of its time. In this new work, Delille discussed the relative merits and faults of the so-called ‘French’ and ‘English’ gardens; yet contrary to many of his contemporaries, he did not reject Andre Le Notre' s rigidly structured designs in favour of William Kent' s allegedly more natural ones. Rather, he mapped a social hierarchy onto his formal precepts: Delille argued that the monumental, symmetrical forms that were for appropriate for a king were ill-suited to a modest property owner. Having thus solved this crucial politico-aesthetic problem, Delille was free to concentrate on the characteristics of an ideal pictures...

Neurons producing serotonin (5-hydroxytryptamine, 5-HT) constitute one of the most widely distributed neuronal networks in the mammalian central nervous system (CNS) and exhibit a profuse innervation throughout the CNS already at early stages of development. Serotonergic neuron specification is controlled by a combination of secreted molecules and transcription factors such as Shh, Fgf4/8, Nkx2.2, Lmx1b and Pet1. In the mouse, Pet1 mRNA expression appears between 10 and 11 days post coitum (dpc) in serotonergic post-mitotic precursors and persists in serotonergic neurons up to adulthood, where it promotes the expression of genes defining the mature serotonergic phenotype such as tryptophan hydroxylase 2 (Tph2) and serotonin transporter (SERT). Hence, the generation of genetic tools based on Pet1 specific expression represents a valuable approach to study the development and function of the serotonergic system. Here, we report the generation of a Pet1210-Cre transgenic mouse line in which the Cre recombinase is expressed under the control of a 210 kb fragment from the Pet1 genetic locus to ensure a reliable and faithful control of somatic recombination in Pet1 cell lineage. Besides Cremediated recombination accurately occurred in the serotonergic system as expected and according to previous studies, Pet1210-Cre transgenic mouse line allowed us to identify novel, so far uncharacterized, Pet1 expression domains. Indeed, we showed that in the raphe Pet1 is expressed also in a non-serotonergic neuronal population intermingled with Tph2-expressing cells and mostly localized in the B8 and B9 nuclei. Moreover, we detected Cre-mediated recombination also in the developing pancreas and in the ureteric bud derivatives of the kidney, where it reflected a specific Pet1 expression. Thus, Pet1210-Cre transgenic mouse line faithfully drives Cre-mediated recombination in all Pet1 expression domains representing a valuable tool to genetically manipulate serotonergic and non-serotonergic Pet1 cell lineages. © 2014 Pelosi et al.

This essay argues that Gouges's autobiographical epistolary novel should be read as a fictional judicial memoir. This essay explores the reasons for which a disenfranchised woman would choose to write a work of fiction—and an epistolary novel in particular—rather than take her inheritance claims to court. It then discusses Gouges's representational strategies, as well as her discourse of women's rights and critique of religious fanaticism.

Sophisticated approaches have recently led to the identification of novel autoantigens associated with Multiple Sclerosis (MuS), e.g. neurofascin, contactin, CNPase, and other T-cell receptor membrane anchored proteins. These putative antigens, although differing from the conventional myelin derivatives, are conceptually based on an animal model of experimental autoimmune encephalomyelitis. In this report we describe the identification of putative antigens based on their recognition by autoantibodies isolated from MuS patient serum. In a previous work from this laboratory we have shown that a peptide probe, named CSF114(Glc), specifically identifies serum autoantibodies in a subset of MuS patients, representing ? 30% of the patient population. The autoantibodies, purified from MuS patients' sera (six), through CSF114(Glc) affinity chromatography, detected three immunoreactive protein bands present in the rat brain. Proteomic analysis of the immunoreactive bands, involving MALDI and MS/MS techniques, revealed the presence of four proteins distinguishable by their mass: alpha fodrin, alpha actinin 1, creatine kinase, and CNPase. The immunoreactive profile of these rat brain proteins was compared with that of commercially available standard proteins by challenging against either CSF114(Glc) purified MuS autoantibodies, or monoclonal antibodies. Further discrimination among the rat brain proteins was provided by the following procedure: whereas monoclonal antibodies recognized all rat brain proteins, isolated MuS specific antibodies recognize only alpha actinin 1 as a putative antigen. In fact, alpha actinin 1 displayed a robust immunoreactive response against all MuS patients' sera examined, whereas the other three bands were not consistently detectable. Thus, alpha actinin 1, a cyto-skeleton protein implicated in inflammatory/degenerative autoimmune diseases (lupus nephritis and autoimmune hepatitis) might be regarded as a novel MuS autoantigen, perhaps a prototypic biomarker for the inflammatory/degenerative process typical of the disease. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Magnetic Resonance Diffusion Tensor Imaging (DTI) has opened the way to a variety of white matter analysis approaches which leverage the axon networks in the brain. Even if tractography algorithms are widely used to reconstruct these networks, their topology is seldom employed to evaluate differences between patient and control groups, unless there is prior knowledge on the areas of interest. Using a sparse approach, we have developed a multivariate method to automatically identify the most significant connections bundles able to characterise differences between two groups. This will allow neuroscientist to explore inter-group differences in white-matter topology in an unbiased-fashion, and without the need of a priori knowledge. Here, we performed a preliminary test of the approach with serotonin dysfunctional mice and a control group. The results allowed us to identify inter-group differences in the density of white matter tracts originating from serotonergic areas, thus corroborating the predictive validity of the method.

Despite increasing evidence suggests that serotonin (5-HT) can influence neurogenesis, neuronal migration and circuitry formation, the precise role of 5-HT on central nervous system (CNS) development is only beginning to be elucidated. Moreover, how changes in serotonin homeostasis during critical developmental periods may have etiological relevance to human mental disorders, remains an unsolved question. In this study we address the consequences of 5-HT synthesis abrogation on CNS development using a knock-in mouse line in which the tryptophan hydroxylase 2 (Tph2) gene is replaced by the eGFP reporter. We report that lack of brain 5-HT results in a dramatic reduction of body growth rate and in 60% lethality within the first 3 weeks after birth, with no gross anatomical changes in the brain. Thanks to the specific expression of the eGFP, we could highlight the serotonergic system independently of 5-HT immunoreactivity. We found that lack of central serotonin produces severe abnormalities in the serotonergic circuitry formation with a brain region- and time- specific effect. Indeed, we observed a striking reduction of serotonergic innervation to the suprachiasmatic and thalamic paraventricular nuclei, while a marked serotonergic hyperinnervation was found in the nucleus accumbens and hippocampus of Tph2∷eGFP mutants. Finally, we demonstrated that BDNF expression is significantly up-regulated in the hippocampus of mice lacking brain 5-HT, mirroring the timing of the appearance of hyperinnervation and thus unmasking a possible regulatory feedback mechanism tuning the serotonergic neuronal circuitry formation. On the whole, these findings reveal that alterations of serotonin levels during CNS development affect the proper wiring of the brain that may produce long-lasting changes leading to neurodevelopmental disorders.

Triple-negative breast tumours are defined as oestrogen receptor (ER)-negative, progesterone receptor (PgR)-negative and human epidermal growth factor receptor 2 (HER2)-negative. Beyond this common negative triplet, however, triple-negative breast cancers (TNBC) are not an homogeneous subgroup. There is substantial intra-subgroup diversity in tumour biology, prognosis and treatment sensitivity. Triple-negative breast cancer accounts for 15−20% of all breast cancer cases; however, it accounts for a disproportionate number of breast cancer relapses and deaths. Studies in early breast cancer have shown patients with TNBC to have a worse outcome compared with patients with non-TNBC [1]. Interestingly, neo-adjuvant studies highlight a subgroup of TNBC patients, approximately 20%, with highly chemosensitive disease and post-chemotherapy outcomes as favourable as their non-TNBC counterparts [2]. A key issue with TNBC is the accurate diagnosis of histological subtype and ER, PgR and HER2 status. ER, PgR and HER2 measurement has been associated with concerns regarding reliability and reproducibility, with remarkable reported rates of discordance. Furthermore, prior arbitrary thresholds for defining positivity for ER and PgR status, including 1%, 10% and 20%, have varied between laboratories and clinical trials. Clarity is offered by recent St Gallen and ASCO-CAP guidelines that define endocrine responsiveness as 1%. TNBC includes several morphological subtypes. Most are high-grade ductal carcinomas (not otherwise specified) but the triple-negative phenotype also occurs in medullary, apocrine and squamous cell carcinomas. Some subtypes, such as medullary carcinoma, are associated with a better prognosis and may not require aggressive chemotherapy. In contrast to endocrine-sensitive and HER2-positive breast cancers, which are defined by the presence of specific targets for matched targeted therapy, there is currently no targeted therapy for TNBC. There are promising new targeted biological therapies, such as PARP inhibitors; however, chemotherapy remains the mainstay of systemic therapy for TNBC. The biological diversity displayed within TNBC does not support such an empirical approach; however, a lack of robust predictive biomarkers prevents a more individualised approach to the choice of adjuvant therapy. Predictive markers could guide chemotherapy use by identification of the subset of TNBC patients with chemosensitive disease, or more specifically to predict sensitivity or resistance to individual chemotherapeutic agents. However, currently there are no clinical tools to recommend use, or omission, of specific chemotherapeutics. Conventional thirdgeneration combination chemotherapy is the standard treatment. Rates of pathological complete response to conventional neoadjuvant anthracycline/taxane-based chemotherapy are reported to be within the range of 13−45% [2]. Optimal adjuvant systemic therapy for TNBC is difficult to define because of a lack of robust prospective data in triple-negative restricted trial populations. Most clinical data derive from retrospective exploratory subgroup analyses from biologically unselected trial populations, and small underpowered studies. Most data reveal a highly chemosensitive TNBC subset. Lack of randomised phase III trials with a standard therapy control arm make it difficult to determine whether this increased sensitivity is agent-specific or whether it reflects general sensitivity to chemotherapy (Fig. 1). Triple-negative breast cancers are associated with a high proliferative rate, which may render them particularly sensitive to chemotherapy. Furthermore, a subset of TNBCs displays phenotypic overlap with BRCA1-mutation-related breast cancers. BRCA1 is critical in homologous recombination, a cellular process of double-strand DNA damage repair, and in the cell cycle arrest necessary for DNA repair.

Rispetto alla matematica o alla fisica, la biologia e la medicina sono scienze empiriche e, poiche non esistono teorie universali che guidano il successo e la progettazione degli esperimenti, nelle scienze biomediche il progresso e le nuove scoperte sono strettamente correlati e dipendenti dall’innovazione tecnologica. La tecnologia del DNA ricombinante, il sequenziamento del DNA, la reazione a catena dell polimerasi (PCR) o la scoperta dei principi per la produzione degli anticorpi monoclonali sono solo alcuni degli esempi di innovazioni tecnologiche che hanno cambiato il modo di fare ricerca biologica negli ultimi 30 anni.