Filling the gap between chemical carcinogenesis and the hallmarks of cancer: a temporal perspective

Background Cancer is believed to arise through the perturbation of pathways and the order of pathway perturbation events can enhance understanding and evaluation of carcinogenicity. This order has not been examined so far, and this study aimed to fill this gap by attempting to gather evidence on the potential temporal sequence of events in carcinogenesis. Design The methodology followed was to discuss first the temporal sequence of hallmarks of cancer from the point of view of pathological specimens of cancer (essentially branched mutations) and then to consider the hallmarks of cancer that one well‐known carcinogen, benzo(a)pyrene, can modify. Results Even though the sequential order of driving genetic alterations can vary between and within tumours, the main cancer pathways affected are almost ubiquitous and follow a generally common sequence: resisting cell death, insensitivity to antigrowth signals, sustained proliferation, deregulated energetics, replicative immortality and activation of invasion and metastasis. The first 3 hallmarks can be regarded as almost simultaneous while angiogenesis and avoiding immune destruction are perhaps the only hallmarks with a varying position in the above sequence. Conclusions Our review of hallmarks of cancer and their temporal sequence, based on mutational spectra in biopsies from different cancer sites, allowed us to propose a hypothetical temporal sequence of the hallmarks. This sequence can add molecular support to the evaluation of an agent as a carcinogen as it can be used as a conceptual framework for organising and evaluating the strength of existing evidence

Classical and Quantum Strings in compactified pp-waves and Godel type Universes

We consider Neveu-Schwarz pp-waves with spacetime supersymmetry. Upon compactification of a spacelike direction, these backgrounds develop Closed Null Curves (CNCs) and Closed Timelike Curves (CTCs), and are U-dual to supersymmetric Godel type universes. We study classical and quantum strings in this background, with emphasis on the strings winding around the compact direction. We consider two types of strings: long strings stabilized by NS flux and rotating strings which are stabilized against collapse by angular momentum. Some of the latter strings wrap around CNCs and CTCs, and are thus a potential source of pathology. We analyze the partition function, and in particular discuss the effects of these string states. Although our results are not conclusive, the partition function seems to be dramatically altered due to the presence of CNCs and CTCs. We discuss some interpretations of our results, including a possible sign of unitary violation.Comment: 42 pages, LaTeX, 2 figure

Supracricoid laryngectomy for recurrent laryngeal cancer after chemoradiotherapy: a systematic review and meta-analysis

La recidiva e la persistenza del cancro della laringe dopo radioterapia rappresentano eventi insidiosi, i cui tassi di incidenza variano dal 13% al 36%. Lintervento di laringectomia sopracricoidea (LSC), con cricoioidopessia (CIP) o cricoioidoepiglottopessia (CIEP), è in grado di garantire risultati oncologici e funzionali affidabili per i pazienti selezionati affetti da carcinoma glottico o sopraglottico, sia in caso di neoplasia primitiva che di recidiva. La presente metanalisi ha lo scopo di valutare i parametri oncologici e funzionali nei pazienti trattati con LSC per recidiva di carcinoma squamocellulare della laringe dopo fallimento di radioterapia. La ricerca è stata effettuata sui databases MEDLINE, PubMed ed EMBASE (da gennaio 1990 a dicembre 2015, solo in lingua inglese). Per la metanalisi è stato impiegato il metodo DerSimonian e Laird con effetto midex random; leterogeneicità è stata misurata mediante I. Sono stati inclusi nella ricerca 276 articoli, tra i quali ne sono stati selezionati 14 per la metanalisi, per un totale di 291 pazienti. Lanalisi statistica ha mostrato una sopravvivenza globale (OS) a 5 anni del 80,2% (IC 0,719-0,885; I= 62%; p = 0,003) e una sopravvivenza libera da malattia (DFS) a 5 anni del 89,5% (IC 0,838-0,952; I= 52%; p = 0,022). Le indicazioni chirurgiche per una LSC dopo fallimento di radioterapia non cambiano rispetto a quelle adottate per pazienti con tumore primitivo. Pertanto, è stato ipotizzato che lattenta valutazione dellestensione del tumore, in caso di recidiva, potrebbe essere responsabile dellalto tasso di OS e DFS a 5 anni. Per quanto riguarda i parametri di valutazione funzionale precoce postoperatoria, il tempo medio di decannulazione è stato di 35,6 giorni (IC 24,3-46,9; I= 95%; p < 0,001), mentre il tempo medio di rimozione del sondino naso-gastrico (SNG) o della gastrostrostomia percutanea endoscopica (PEG) è stato di 28,3 giorni (IC 22,7-33,8; I= 86%; p <= 0.001). Questi dati sono in accordo con gli Autori che preferiscono la rimozione precoce del sondino nasogastrico. In tal modo si può riprendere lalimentazione orale quando è ancora presente il tubo endotracheale a protezione delle vie aree e permettere laspirazione degli eventuali residui alimentari

A New Cosmological Scenario in String Theory

We consider new cosmological solutions with a collapsing, an intermediate and an expanding phase. The boundary between the expanding (collapsing) phase and the intermediate phase is seen by comoving observers as a cosmological past (future) horizon. The solutions are naturally embedded in string and M-theory. In the particular case of a two-dimensional cosmology, space-time is flat with an identification under boost and translation transformations. We consider the corresponding string theory orbifold and calculate the modular invariant one-loop partition function. In this case there is a strong parallel with the BTZ black hole. The higher dimensional cosmologies have a time-like curvature singularity in the intermediate region. In some cases the string coupling can be made small throughout all of space-time but string corrections become important at the singularity. This happens where string winding modes become light which could resolve the singularity. The new proposed space-time casual structure could have implications for cosmology, independently of string theory.Comment: 28 pages, 3 figures; v2: Added new subsection relating two-dimensional model to BTZ black hole, typos corrected and references added; v3: minor corrections, PRD versio

Isolation and characterization of cardiac mesenchymal stromal cells from endomyocardial bioptic samples of arrhythmogenic cardiomyopathy patients

A normal adult heart is composed of several different cell types, among which cardiac mesenchymal stromal cells represent an abundant population. The isolation of these cells offers the possibility of studying their involvement in cardiac diseases, and, in addition, provides a useful primary cell model to investigate biological mechanisms. Here, the method for the isolation of C-MSC from arrhythmogenic cardiomyopathy patients\u2019 bioptic samples is described. The endomyocardial biopsy sampling is guided in the right ventricular areas adjacent to the scar visualized by electro-anatomical mapping. The digestion of the biopsies in collagenase and their plating on a plastic dish in culture medium to allow C-MSC growth is described. The isolated cells can be expanded in culture for several passages. To confirm their mesenchymal phenotype, the description of immuno-phenotypical characterization is provided. C-MSC are able to differentiate into several cell types like adipocytes, chondrocytes, and osteoblasts: in the context of ACM, characterized by adipocyte deposits in patients\u2019 hearts, the protocols for the adipogenic differentiation of C-MSC and the characterization of lipid droplet accumulation are described

Clinical and molecular data define a diagnosis of arrhythmogenic cardiomyopathy in a carrier of a brugada-syndrome-associated PKP2 mutation

Plakophilin-2 (PKP2) is the most frequently mutated desmosomal gene in arrhythmogenic cardiomyopathy (ACM), a disease characterized by structural and electrical alterations predominantly affecting the right ventricular myocardium. Notably, ACM cases without overt structural alterations are frequently reported, mainly in the early phases of the disease. Recently, the PKP2 p.S183N mutation was found in a patient affected by Brugada syndrome (BS), an inherited arrhythmic channelopathy most commonly caused by sodium channel gene mutations. We here describe a case of a patient carrier of the same BS-related PKP2 p.S183N mutation but with a clear diagnosis of ACM. Specifically, we report how clinical and molecular investigations can be integrated for diagnostic purposes, distinguishing between ACM and BS, which are increasingly recognized as syndromes with clinical and genetic overlaps. This observation is fundamentally relevant in redefining the role of genetics in the approach to the arrhythmic patient, progressing beyond the concept of \u201cone mutation, one disease\u201d, and raising concerns about the most appropriate approach to patients affected by structural/electrical cardiomyopathy. The merging of genetics, electroanatomical mapping, and tissue and cell characterization summarized in our patient seems to be the most complete diagnostic algorithm, favoring a reliable diagnosis

Production of entanglement in Raman three-level systems using feedback

We examine the theoretical limits of the generation of entanglement in a damped coupled ion-cavity system using jump-based feedback. Using Raman transitions to produce entanglement between ground states reduces the necessary feedback bandwidth, but does not improve the overall effect of the spontaneous emission on the final entanglement. We find that the fidelity of the resulting entanglement will be limited by the asymmetries produced by vibrations in the trap, but that the concurrence remains above 0.88 for realistic ion trap sizes.Comment: 8 pages, 8 figure

The fate of nitrogen during agricultural intensification in East Africa: nitrogen budgets in contrasting agroecosystems

Open Access ArticleThe intensification of agricultural systems in sub-Saharan Africa (SSA) is necessary to reduce poverty and improve food security, but increased nutrient applications in smallholder systems could have negative consequences for water quality, greenhouse gas emissions, and air quality. We tracked nitrogen (N) inputs and measured maize (Zea mays) biomass, grain yields, N leaching, and nitric oxide (NO) and nitrous oxide fluxes from a clayey soil in Yala, Kenya and a sandy soil in Tumbi, Tanzania, with application rates of 0, 50, 75, 100, 150, and 200 kg N ha−1 yr−1 over two cropping seasons. Maize yields were 4.5 times higher in Yala than Tumbi, but yields plateaued at both sites with fertilizer applications at or above 100 kg N ha−1 yr−1. Partial N budgets in Yala were typically negative, meaning more N was exported in maize biomass plus grain or lost from the system than was added in fertilizer. In Tumbi, N budgets were negative at lower fertilizer levels but positive at higher fertilizer levels. At both sites most (96%) of the N was lost through maize biomass/grain removal and N leaching. Fertilizer additions at or less than 50 kg N ha−1 yr−1 on these two contrasting sites resulted in minor gaseous N losses, and fertilizer additions less than 200 kg N ha−1 yr−1 caused relatively little change to N leaching losses. This indicates that the modest increases in fertilizer use required to improve maize yields will not greatly increase cropland N losses. Plain Language Summary Crop yields in smallholder agriculture across sub-Saharan Africa are low but could be increased by greater applications of nitrogen fertilizer. However, greater use of nitrogen fertilizer creates potential for higher emissions of nitrogen trace gases and nitrogen leaching losses. This study added nitrogen fertilizer doses (0, 50, 75, 100, 150, and 200 kg of nitrogen per hectare) to maize cropland in two smallholder farming sites, one on clay-rich soils in Kenya and one on sandy soils in Tanzania. It tracked removal of nitrogen fertilizer via harvested maize and losses as nitrous oxide (a greenhouse gas), NO (an air pollutant), and leaching of soil solution. Yields were 4.5 times higher on the clayey soil; yields plateaued at nitrogen application above 100 kg per hectare. Leaching losses far exceeded gaseous losses at both sites: 96% of nitrogen was removed in harvested crops and soil solution. Nitrogen additions at or below 50 kg of nitrogen per hectare led to minor increases in gaseous nitrogen losses and additions less than 200 kg of nitrogen per hectare did not increase soil solution losses. This indicates that the modest increases in fertilizer use required to improve maize yields will not greatly increase cropland nitrogen losses

Killing spectroscopy of closed timelike curves

We analyse the existence of closed timelike curves in spacetimes which possess an isometry. In particular we check which discrete quotients of such spaces lead to closed timelike curves. As a by-product of our analysis, we prove that the notion of existence or non-existence of closed timelike curves is a T-duality invariant notion, whenever the direction along which we apply such transformations is everywhere spacelike. Our formalism is straightforwardly applied to supersymmetric theories. We provide some new examples in the context of D-branes and generalized pp-waves.Comment: 1+35 pages, no figures; v2, new references added. Final version to appear in JHE

SS Ari: a shallow-contact close binary system

Two CCD epochs of light minimum and a complete R light curve of SS Ari are presented. The light curve obtained in 2007 was analyzed with the 2003 version of the W-D code. It is shown that SS Ari is a shallow contact binary system with a mass ratio $q=3.25$ and a degree of contact factor f=9.4(\pm0.8%). A period investigation based on all available data shows that there may exist two distinct solutions about the assumed third body. One, assuming eccentric orbit of the third body and constant orbital period of the eclipsing pair results in a massive third body with $M_3=1.73M_{\odot}$ and P_3=87.0$yr. On the contrary, assuming continuous period changes of the eclipsing pair the orbital period of tertiary is 37.75yr and its mass is about$0.278M_{\odot}$. Both of the cases suggest the presence of an unseen third component in the system.Comment: 28 pages, 9 figures and 5 table