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High-grade serous ovarian cancer (HGS-EOCs) is generally sensitive to front-line platinum (Pt)-based chemotherapy although most patients at an advanced stage relapse with progressive resistant disease. Clinical or molecular data to identify primary resistant cases at diagnosis are not yet available. HGS-EOC biopsies from 105 Pt-sensitive (Pt-s) and 89 Pt-resistant (Pt-r) patients were retrospectively selected from two independent tumor tissue collections. Pathway analysis was done integrating miRNA and mRNA expression profiles. Signatures were further validated in silico on a cohort of 838 HGS-EOC cases from a published dataset. In all, 131 mRNAs and 5 miRNAs belonging to different functionally related molecular pathways distinguish Pt-s from Pt-r cases. Then, 17 out of 23 selected elements were validated by orthogonal approaches (SI signature). As resistance to Pt is associated with a short progression-free survival (PFS) and overall survival (OS), the prognostic role of the SI signature was assessed, and 14 genes associated with PFS and OS, in multivariate analyses (SII signature). The prognostic value of the SII signature was validated in a third extensive cohort. The expression profiles of SDF2L1, PPP1R12A and PRKG1 genes (SIII signature) served as independent prognostic biomarkers of Pt-response and survival. The study identified a prognostic molecular signature based on the combined expression profile of three genes which had never been associated with the clinical outcome of HGS-EOC. This may lead to early identification, at the time of diagnosis, of patients who would not greatly benefit from standard chemotherapy and are thus eligible for novel investigational approaches.

ObjectiveTo date, there is no universal consensus on which is the optimal ultrastaging protocol for sentinel lymph node (SLN) evaluation in gynecologic malignancies. To estimate the impact of different ultrastaging methods of SLNs on the detection of patients with nodal metastases in early-stage cervical and endometrial cancers and to describe the incidence of low-volume metastases between two ultrastaging protocols.MethodsWe retrospectively compared two ultrastaging protocols (ultrastaging-A vs ultrastaging-B) in patients with clinical stage I endometrial cancer or FIGO stage IA-IB1 cervical cancer who underwent primary surgery including SLN biopsy from October 2010 to December 2017 in our institution. The histologic subtypes and grades of the tumors were evaluated according to WHO criteria. Only SLNs underwent ultrastaging, while other lymph nodes were sectioned and examined by routine hematoxylin and eosin (H&E).ResultsOverall 224 patients were reviewed (159 endometrial cancer and 65 cervical cancer). Lymph node involvement was noted in 15% of patients with endometrial cancer (24/159): 24% of patients (9/38) with the ultrastaging protocol A and 12% (15/121) with the ultrastaging protocol B (p=0.08); while for cervical cancer, SLN metastasis was detected in 14% of patients (9/65): 22% (4/18) in ultrastaging-A and 11% (5/47) in ultrastaging-B (p=0.20). Overall, macrometastasis and low-volume metastases were 50% and 50% for endometrial cancer and 78% and 22% for cervical cancer. Median size of nodal metastasis was 2 (range 0.9–8.5) mm for the ultrastaging-A and 1.2 (range 0.4–2.6) mm for the ultrastaging-B protocol in endometrial cancer (p=0.25); 4 (range 2.5–9.8) mm for ultrastaging-A and 4.4 (range 0.3–7.8) mm for ultrastaging-B protocol in cervical cancer (p=0.64).ConclusionIn endometrial or cervical cancer patients, the incidence of SLN metastasis was not different between the two different types of ultrastaging protocol.

Cosmic rays (CRs) at sub-TeV energies play a fundamental role in the chemical and dynamical evolution of molecular clouds, as they control the ionisation, dissociation, and excitation of H$_{2}$. Their characterisation is important both for the interpretation of observations and for the development of theoretical models. The methods used so far for estimating the CR ionisation rate ($\zeta$) in molecular clouds have several limitations due to uncertainties in the adopted chemical networks. We refine and extend the method proposed by Bialy (2020) to estimate $\zeta$ by observing rovibrational transitions of H$_{2}$ at near-infrared wavelengths, which are mainly excited by secondary CR electrons. Combining models of interstellar CR propagation and attenuation with the calculation of the expected secondary electron spectrum and updated H$_{2}$ excitation cross sections by electron collisions, we derive the intensity of the four H$_{2}$ rovibrational transitions observable in dense, cold gas: (1-0)O(2), (1-0)Q(2), (1-0)S(0), and (1-0)O(4). The proposed method allows the estimation of $\zeta$ for a given observed line intensity and H$_{2}$ column density. We are also able to deduce the shape of the low-energy CR proton spectrum impinging upon the molecular cloud. We present a look-up plot and a web-based application that can be used to constrain the low-energy spectral slope of the interstellar CR proton spectrum. We comment on the capability of the James Webb Space Telescope to detect these near-infrared H$_{2}$ lines, making it possible to derive for the first time spatial variation of $\zeta$ in dense gas. Besides the implications for the interpretation of the chemical-dynamic evolution of a molecular cloud, it will be possible to test competing models of CR propagation and attenuation in the interstellar medium, as well as compare CR spectra in different Galactic regions., Comment: 14 pages, 11 figures, accepted by A&A

Treatment of ovarian cancer is limited by extensive metastasis and yet it remains poorly understood. We have studied the critical step of metastatic colonization in the context of the productive interactions with the metastatic microenvironment with a goal of identifying key regulators. By combining miRNA expression analysis using an organotypic 3D culture model of early ovarian cancer metastasis with that of matched primary and metastatic tumors from 42 patients with ovarian cancer, we identified miR-4454 as a key regulator of both early colonization and advanced metastasis in patients with ovarian cancer. miR-4454 was downregulated in the metastasizing ovarian cancer cells through paracrine signals from microenvironmental fibroblasts, which promoted migration, invasion, proliferation, and clonogenic growth in ovarian cancer cells as well as their ability to penetrate through the outer layers of the omentum. Stable overexpression of miR-4454 decreased metastasis in ovarian cancer xenografts. Its mechanism of action was through the upregulation of its targets, secreted protein acidic and cysteine rich (SPARC) and BCL2 associated athanogene 5 (BAG5), which activated focal adhesion kinase (FAK) signaling, promoted mutant p53 gain of function by its stabilization, and inhibited apoptosis. Because microenvironment-induced downregulation of miR-4454 is essential for early and advanced metastasis, targeting it could be a promising therapeutic approach. Implications: This study identifies a miRNA, miR-4454, which is downregulated by signals from the microenvironment and promotes early and advanced ovarian cancer metastasis through its effects on FAK activation, mutant p53 stabilization, and apoptosis inhibition.

Introduction/Background The activation of TGFβ pathway in advanced stage high-grade serous ovarian cancer (HGSOC) has been found to be related to short progression free survival (PFS) and overall survival (OS). miRNA181a-5p was found to be a proxy of TGFβ activation. This prognostic role has been identified only in cohorts with low surgical complexity, we evaluated 2 cohorts with different surgical approaches. Methodology Series of HGSEOC from two centers (European Institute of Oncology, Milan, Cohort1; San Gerardo Hospital, Monza, Cohort2) were analyzed for clinical features and miRNA quantification to test their prognostic value using a Cox-proportional hazard regression model. Results 118 and 84 patients were included, respectively. Cohort1 versus Cohort2 was composed of similar FIGO stages, higher upper abdominal disease spread (UAD) (P An optimized threshold of miR181a-5p expression to segregate patients according to their prognosis was identified (miR-low and miR-high): for Cohort1 no threshold was reached; for Cohort2 a threshold segregated PFS of 20.9 v. 9.6 months (P:0.0008) and OS of 60.3 v. 23.3 months (P:0.0008), respectively. In multivariate analysis, no significance was observed for miR-high in Cohort1. For Cohort2, miR-high was related to worse PFS (P:0.0002), and OS (P:0.007). Conclusion miR181a-5p was observed as a prognostic biomarker in HGSEOC in Cohort2, -less aggressive surgery-, instead no prognostic role was observed in Cohort 1 -aggressive surgery-. This question-generating analysis suggests that TGFβ activation, a proxy of tumor aggressiveness, might be withdrawn by an aggressive surgical approach. A prospective validation of miR181 role is needed, the translational ancillary study of the TRUST trial (NCT # 02828618) may answer this question. Disclosure Nothing to disclose.

Objectives In this study we investigated the role of radiomic applied in women with endometrial cancer underwent 18F-FDG PET scan, to evaluate if imaging features computed on the primary tumor could improve sensitivity in detection of lymph node (LN) metastases. Methods Between 1/2009 and 12/2018, 116 women underwent preoperative 18F-FDG PET/CT were considered. SUV, MTV, TLG, geometrical shape, histograms and texture features were computed inside tumor contours. In group 1 (87 patients), univariate association with LN metastases was computed by Mann-Whitney test and a neural network multivariate model was developed. Univariate and multivariate models were assessed with leave one out on 20 training sessions and on group 2 (29 patients). Results Sensitivity and specificity of LN visual detection were 50% and 99% on group 1 and 33% and 95% on group 2. The lower sensitivity of visual detection in group 2 is mainly related to the higher rate of micrometastases (25% vs 13%). A unique heterogeneity feature computed on the primary tumor (GLSZM ZP) was able to predict LN metastases better than any other feature, or multivariate model (sensitivity and specificity of 75% and 81% in group 1 and of 89% and 80% in group 2). Tumors with LN metastases generally demonstrated a lower GLSZM ZP value, i.e. by the co-presence of high-uptake and low-uptake areas. Conclusions In our study the computation of imaging features on the primary tumor increases nodal staging for detection sensitivity in 18F-FDG PET and can be considered for a better planning of the surgical treatment.

Objectives Ultra-staging (US) of sentinel lymph nodes (SLN) increases the detection of nodal metastases. US protocols vary among gynecologic pathologists, and internationally accepted guidelines are still not available. This study compares two US protocols (US-A vs US-B) in early stage cervical (CC) and endometrial cancers (EC) (table 1). Methods We retrospectively evaluated patients with clinical stage I endometrial cancer (EC) or stage IA-IB1 cervical cancer (CC) who underwent primary surgery with SLN biopsy from November 2010 to October 2017. Results 229 patients were analyzed (161 ECs and 68 CCs). The rate of positive node disease was: 22% with US-A protocol and 12% with US-B protocol (p=0.09) for EC patients; 22% and 10% (p=0.18) for CC patients. Macrometastasis, micrometastases, and ITC were 31%, 61% and 8%, respectively with US-A protocol; 43%, 40% and 17%, respectively with US-B protocol (p=0.272). Mean size of nodal metastasis was 5.4±6.3 mm for US-A and 3.2±4.3 mm for US-B protocol (p=0.09). On multivariate analysis including grade and LVSI, the US method was not associated with the detection of nodal metastases. Conclusions Approximately 50% of the nodal metastases detected by US of SLNs were low-volume metastases. In this study, the detection of positive node disease was not associated with the type of US protocol used. Larger multicenter prospective studies are advisable to confirm these results.

Objectives We evaluated the role of PET/CT and sentinel lymph node (SLN) biopsy in women with early stage high-risk endometrial cancer (G2 and deep myometrial invasion, G3, serous, clear cell carcinoma or carcinosarcoma). Methods Between November 2006 to June 2018, 116 women underwent PET/CT scan followed by surgery were included. Fitty-one percent (60/116) patients underwent full lymphadenectomy (Group A). Forty-eight percent of patients (56/116) underwent SLN mapping with ultrastaging (Group B). Histological findings were used as the reference standard. Results Patients with positive node were 11 (18.3%) and 14 (25%) in group A and B, respectively. In group A, 10 were correctly identified by PET/CT, with only 1 FN case. Sensitivity, specificity, accuracy, positive-predictive value-PPV and negative predictive value-NPV of PET/CT for pelvic LN metastases resulted 90.1%, 98%, 96.7%, 90.1%, 98%, respectively. In group B, 4 were correctly identified by PET/CT, while 10 cases resulted falsely negative. Sensitivity, specificity, accuracy, PPV, and NPV of PET/CT for pelvic LN metastases were 28.5%, 97.7%, 80.4%, 80%, 80.3%, respectively. In 5 of 10 FN PET, micrometastases, and/or ITC were detected by SLN ultrastaging. Overall, sensitivity, specificity, accuracy, PPV, and NPV of PET/CT resulted 56%, 97.8%, 88.7%, 87.5%, 89%, respectively. Conclusions PET/CT demonstrated high specificity in detecting pelvic LN metastases and its high PPV can be useful to refer patients to appropriate debulking surgery. Ultrastaging of SLN increased the identification of metastases (18.3%-25%) not detectable by PET/CT because of its spatial resolution, increasing false-negative PET/CT findings. The combination of both modalities seems promising for nodal staging purpose.

Context. Reliable, directly measured optical properties of astrophysical ice analogues in the infrared and terahertz (THz) range are missing from the literature. These parameters are of great importance to model the dust continuum radiative transfer in dense and cold regions, where thick ice mantles are present, and are necessary for the interpretation of future observations planned in the far-infrared region. Aims: Coherent THz radiation allows for direct measurement of the complex dielectric function (refractive index) of astrophysically relevant ice species in the THz range. Methods: We recorded the time-domain waveforms and the frequency-domain spectra of reference samples of CO ice, deposited at a temperature of 28.5 K and annealed to 33 K at different thicknesses. We developed a new algorithm to reconstruct the real and imaginary parts of the refractive index from the time-domain THz data. Results: The complex refractive index in the wavelength range 1 mm-150 μm (0.3-2.0 THz) was determined for the studied ice samples, and this index was compared with available data found in the literature. Conclusions: The developed algorithm of reconstructing the real and imaginary parts of the refractive index from the time-domain THz data enables us, for the first time, to determine the optical properties of astrophysical ice analogues without using the Kramers-Kronig relations. The obtained data provide a benchmark to interpret the observational data from current ground-based facilities as well as future space telescope missions, and we used these data to estimate the opacities of the dust grains in presence of CO ice mantles. The data plotted in Fig. 6 are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/cat/J/A+A/629/A112

Dust plays a key role in the evolution of the ISM and its correct modelling in numerical simulations is therefore fundamental. We present a new and self-consistent model that treats grain thermal coupling with the gas, radiation balance, and surface chemistry for molecular hydrogen. This method can be applied to any dust distribution with an arbitrary number of grain types without affecting the overall computational cost. In this paper we describe in detail the physics and the algorithm behind our approach, and in order to test the methodology, we present some examples of astrophysical interest, namely (i) a one-zone collapse with complete gas chemistry and thermochemical processes, (ii) a 3D model of a low-metallicity collapse of a minihalo starting from cosmological initial conditions, and (iii) a turbulent molecular cloud with H-C-O chemistry (277 reactions), together with self-consistent cooling and heating solved on the fly. Although these examples employ the publicly available code KROME, our approach can be easily integrated into any computational framework., 17 pages, 12 figures, MNRAS accepted

Indocyanine green (ICG) represents a feasible alternative to the more traditional methods of sentinel lymph node (SLN) mapping, and interest in this promising tracer is growing. This report outlines our experience with ICG in a minimally invasive laparoscopic approach in women with endometrial cancer and cervical cancer using the Storz SPIES ICG near-infrared fluorescence imaging technology. A total of 49 patients with clinical stage I endometrial cancer (n = 40) or stage I cervical cancer (n = 9) were retrospectively reviewed. All patients had undergone simple or radical laparoscopic hysterectomy with pelvic and/or aortic lymphadenectomy and SLN mapping by means of an intracervical injection of ICG dye at the 3 o'clock and 9 o'clock locations after the induction of general anesthesia. The detection rate of ICG was 100% (49 of 49). The rate of bilateral SLN detection was 86% (42 of 49). Positive lymph nodes were found in 6 patients (12%), with at least 1 positive SLN. The sensitivity and negative predictive value of SLN detection were 100%. All procedures were successfully completed without conversion to open laparotomy, and no intraoperative or postoperative complications occurred. In our preliminary experience, ICG showed a high overall detection rate, and bilateral mapping appears to be a feasible alternative to the more traditional methods of SLN mapping in patients with endometrial cancer and cervical cancer. Laparoscopic SLN mapping with ICG appears to be safe, easy, and reproducible, with a positive impact on patient management.

The knowledge of the binding energy of molecules on astrophysically relevant ices can help to obtain an estimate of the desorption rate, i.e. the molecules residence time on the surface. This represents an important parameter for astrochemical models, crucial to determine the chemical fate of complex organic molecules formed on dust grains and observed in the densest regions of the interstellar medium. In this work, we propose a new robust procedure to study the interaction of atoms and molecules with interstellar ices, based on \textit{ab initio} molecular dynamics and density functional theory, validated by high-level \textit{ab initio} methods at a CCSD(T)/CBS level. We have applied this procedure to hydrogen fluoride (HF), a promising tracer of the molecular content of galaxies. In total we found 13 unique equilibrium structures of HF binding to small water clusters of up to 4 molecules, with binding energies ranging from 1208 to 7162 K. We computed a 22-molecules model of amorphous solid water (ASW) surface using \textit{ab initio} molecular dynamics simulations and carried out a systematic analysis of the binding sites of HF, in terms of binding modes and binding energies. Considering 10 different water clusters, we found a binding energy distribution with an average value of $5313\pm74$ K, and a dispersion of $921\pm115$ K. Finally, the effect of the electrostatic field of the 22 water molecules on the binding energies was investigated incrementally by symmetry adapted perturbation theory, in order to gauge the effect of the water environment. The results indicate that the extent of the electrostatic interaction of HF with ASW depends strongly on the properties of the binding site. We expect that this work will provide a solid foundation for a systematic development of a binding energy distribution database of molecules on interstellar surfaces., Comment: 12 pages, 9 figures, 6 tables, accepted to Mol. Astrophys

The evaporation of molecules from dust grains is crucial to understand some key aspects of the star- and the planet-formation processes. During the warm-up phase the presence of young protostellar objects induces molecules to evaporate from the dust surface into the gas phase, enhancing its chemical complexity. Similarly, in circumstellar disks, the position of the so-called snow-lines is determined by evaporation, with important consequences for the formation of planets. The amount of molecules that are desorbed depends on the interaction between the species and the grain surface, which is controlled by the binding energy. Recent theoretical and experimental works point towards a distribution of values for this parameter instead of the single value often employed in astrochemical models.We present here a new "multi-binding energy" framework, to assess the effects that a distribution of binding energies has on the amount of species bound to the grains. We find that the efficiency of the surface chemistry is significantly influenced by this process with crucial consequences on the theoretical estimates of the desorbed species., Accepted A&A

Background: The low five-years survival rate of High Grade Serous Epithelial Ovarian Cancer (HGS-EOC) is mainly related to late diagnosis. The anticipation of diagnosis constitutes a crucial step to increase the curability of this disease. Aim: This study explores an innovative potential HGS-EOC screening approach exploiting PAP tests routinely executed for cervical cancer surveillance and the presence of TP53 clonal alterations in almost all HGS-EOCs. Indeed, it investigates the possibility to detect, in DNA purified from PAP tests collected by patients years before the diagnosis, the clonal pathogenic TP53 variant identified in the matched primary tumor biopsy. Study Design: This retrospective and longitudinal study was conducted on 17 advanced HGS-EOC patients. Next Generation Sequencing (NGS) was used to identify TP53 clonal mutations in tumor tissue. The presence of these TP53 variants was then assessed by the droplet digital PCR (ddPCR) in DNA purified from all available patients' PAP tests executed up to almost six years before diagnosis. Results: In each patient, one TP53 clonal somatic variant was identified by NGS in the primary tumor samples (Table 1). The presence of the TP53 variant was then investigated by ddPCR in matched Pap tests. In twelve out of 17 patients the TP53 variant was detectable in PAP tests collected within six months before diagnosis (T1) or earlier (T2, T3 and T4) (Table 1). For two patients (21561 and 21521) more PAP tests collected at different time before diagnosis (two/four and three/six years before diagnosis, respectively) were analyzed and the TP53 clonal variant was detected at all time points (Table 1). Table 1:NGS and ddPCR resultsPatient IDTP53 mutationNGS tumor mutated %PAP test (months before surgery)T1(0-6)T2(7-24)T3(25-48)T4(≥49)Time intervalddPCR mutated %Time intervalddPCR mutated %Time intervalddPCR mutated %Time intervalddPCR mutated %21561c.818G>A65.010.20.24--250.21490.2621585c.817C>T40.94--11.30.21----21567c.281C>A71.9830.07------21587c.469G>T15.122ND------21586c.818G>A79.73--19.30.15----21569c.574C>T62.365.21.18------21624c.820G>T86.72----37.50.0465.3ND21570c.844C>T89.190.32.62------21627c.425_427del76.040.72.4------21640c.993+2T>G70.68--8ND----21507c.1025G>C91.23--9.20.06----21635c.844C>T66.241.3ND------21549c. 393_395del54.06----31.2ND65.3ND21521c. 722 C>G61.15----26.70.0567.30.0721654c.586 C>T49.354.70.09------21665c. 393_395del45.34----37.6ND--21683c.602 T>A33.42--18.50.06----ND Not Detected Conclusion: This study demonstrates that non-invasive early molecular diagnosis of HGS-EOC is feasible through detection of TP53 clonal mutations in the DNA purified from PAP tests performed during cervical cancer screening. Further developments in highly sensitive molecular approaches could dramatically improve early diagnosis of HGS-EOC. Citation Format: Chiara Pesenti, Lara Paracchini, Martina Delle Marchette, Luca Beltrame, Tommaso Bianchi, Tommaso Grassi, Alessandro Buda, Fabio Landoni, Lorenzo Ceppi, Cristina Bosetti, Maria Chiara Paderno, Marco Adorni, Debora Vicini, Patrizia Perego, Biagio Eugenio Leone, Sergio Marchini, Robert Fruscio, Maurizio D'Incalci. Detection of TP53 clonal mutations in PAP test collected up to six years prior to high-grade serous epithelial ovarian cancer diagnosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-268.

Metastasis causes poor prognosis and yet remains the least understood aspect of cancer. To identify key regulators of ovarian cancer metastasis that drive early colonization and are also essential for advanced metastasis, we have applied a novel, comprehensive approach of combining the analysis of an organotypic 3D culture model of early metastasis with ovarian cancer patient tumors. Using matched primary and metastatic tumors from 42 OC patients, we have compared the fully formed metastatic tumors with the primary tumor of the same patient. Since this is an end-point analysis and reveals little about the intermediated regulatory steps, we have also studied the changes occurring during early metastatic colonization as a result of the interactions with the metastatic microenvironment by using an organotypic 3D culture model of omental metastasis. By combining these two approaches, we have identified key master regulators of metastasis that are essential for early metastatic colonization and remain important in the fully formed metastatic tumor. We specifically focused on microRNAs because of their pleotropic effects through translational inhibition of multiple targets, and also our previous studies have demonstrated their important role in metastasis. Using this approach, we identified a novel microRNA miR-4454, downregulated in the metastasizing ovarian cancer cells through their specific paracrine interactions with fibroblasts in the metastatic microenvironment. The downregulation of miR-4454 promoted high-grade serous ovarian cancer cell migration, invasion, proliferation, and clonogenic growth as well as metastasis in xenografts. The targets of miR-4454 were identified by RNA-seq in high-grade serous ovarian cancer cells overexpressing the microRNA. SPARC and BAG5 were found to be the functional effectors of miR-4454. SPARC activated FAK signaling and promoted metastasis, while BAG5 inhibited apoptosis and helped the metastasizing cancer cells tide over adverse conditions in the microenvironment. Since miR-4454 is essential for early metastatic colonization as well as in advanced metastasis, targeting it is a promising approach to treat metastatic ovarian cancer. Citation Format: Subramanyam Dasari, Taruni Pandhiri, Tommaso Grassi, Daniel W. Visscher, Francesco Multinu, Komal Agarwal, Andrea Mariani, Viji Shridhar, Anirban K. Mitra. Paracrine interactions with microenvironmental fibroblasts promote ovarian cancer metastasis through downregulation of miR-4454 [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B66.

By using a novel interface between the modern smoothed particle hydrodynamics code GASOLINE2 and the chemistry package KROME, we follow the hydrodynamical and chemical evolution of an isolated galaxy. In order to assess the relevance of different physical parameters and prescriptions, we constructed a suite of ten simulations, in which we vary the chemical network (primordial and metal species), how metal cooling is modelled (non-equilibrium versus equilibrium; optically thin versus thick approximation), the initial gas metallicity (from ten to hundred per cent solar), and how molecular hydrogen forms on dust. This is the first work in which metal injection from supernovae, turbulent metal diffusion, and a metal network with non-equilibrium metal cooling are self-consistently included in a galaxy simulation. We find that properly modelling the chemical evolution of several metal species and the corresponding non-equilibrium metal cooling has important effects on the thermodynamics of the gas, the chemical abundances, and the appearance of the galaxy: the gas is typically warmer, has a larger molecular gas mass fraction, and has a smoother disc. We also conclude that, at relatively high metallicity, the choice of molecular-hydrogen formation rates on dust is not crucial. Moreover, we confirm that a higher initial metallicity produces a colder gas and a larger fraction of molecular gas, with the low-metallicity simulation best matching the observed molecular Kennicutt-Schmidt relation. Finally, our simulations agree quite well with observations which link star formation rate to metal emission lines., Accepted for publication in MNRAS

Background The majority of patients with stage III–IV epithelial ovarian cancer (EOC) relapse after initially responding to platinum-based chemotherapy, and develop resistance. The genomic features involved in drug resistance are unknown. To unravel some of these features, we investigated the mutational profile of genes involved in pathways related to drug sensitivity in a cohort of matched tumors obtained at first surgery (Ft-S) and second surgery (Sd-S). Patients and methods Matched biopsies (33) taken at Ft-S and Sd-S were selected from the ‘Pandora’ tumor tissue collection. DNA libraries for 65 genes were generated using the TruSeq Custom Amplicon kit and sequenced on MiSeq (Illumina). Data were analyzed using a high-performance cluster computing platform (Cloud4CARE project) and independently validated. Results A total of 2270 somatic mutations were identified (89.85% base substitutions 8.19% indels, and 1.92% unknown). Homologous recombination (HR) genes and TP53 were mutated in the majority of Ft-S, while ATM, ATR, TOP2A and TOP2B were mutated in the entire dataset. Only 2% of mutations were conserved between matched Ft-S and Sd-S. Mutations detected at second surgery clustered patients in two groups characterized by different mutational profiles in genes associated with HR, PI3K, miRNA biogenesis and signal transduction. Conclusions There was a low level of concordance between Ft-S and Sd-S in terms of mutations in genes involved in key processes of tumor growth and drug resistance. This result suggests the importance of future longitudinal analyses to improve the clinical management of relapsed EOC.

"Non-communicable diseases cause more than 80% of deaths in europe and, among these, 20% are caused by cancer. Modifiable lifestyle factors considered in the italian national programme "Guadagnare salute" (Gaining health), such as tobacco smoking, unhealthy diet, physical inactivity, overweight, and excessive alcohol use, are amongst the major causes of cancer deaths. The aims of this study was to estimate the number of deaths attributable to lifestyle factors for italy and for italian regions in 2013 and to describe its variation in relation to the regional prevalence of risk factors exposure. For Italy and for each italian region, deaths attributable to lifestyle factors were estimated using the methodology of the Global Burden of disease (GBd) study. italian mortality data of 2013 and risks attributable to these lifestyle factors for each cancer site for italy from the GBd study were used. Prevalence of exposure to lifestyles in Italy and in each Italian Region was collected for the period 2008-2013. In 2013, at least 66,605 cancer deaths in italy were attributable to lifestyle factors, accounting for 37.9% of all cancer deaths: 34.1% of cancer deaths in men and 9.0% in women were attributable to smoking; in men and women, respectively, 3.3% and 2.8% were attributable to excessive alcohol consumption; 5.3 % and 6.7% to overweight; 10.1% and 7.1% to dietary risk factors; 1.9% and 4.2% to physical inactivity. A moderate variability of percentage of deaths attributable to modifi able lifestyle factors by region was also detected due to different prevalence values of exposure to lifestyles occurred in last decades. At least 45,000 cancer deaths in men and 21,000 in women occurred in 2013 were attributable to modifi able risk factors, whose prevalence varied by region and which could be averted through the implementation of primary prevention interventions."

The role of lymphadenectomy in endometrial cancer is still uncertain. We aimed to evaluate the survival outcomes of two different strategies in apparent uterine confined disease by comparing sentinel lymph node (SLN) mapping and selective lymphadenectomy (LD).We retrospectively reviewed women with preoperative stage I endometrial cancer underwent surgical staging with either SLN mapping, or LD in two Italian centers.Eight hundred and two women underwent surgical staging for preoperative stage I endometrial cancer were revised (145 Monza; 657 Rome). All patients underwent peritoneal washing, simple hysterectomy with bilateral salpingo-oophorectomy and nodal staging including SLN mapping, or LD. Overall 8229 lymph nodes were removed (1595 in Monza, 6634 in Rome). Pelvic lymphadenectomy was performed in 33.1% and 52.4% in Monza and Rome, respectively (p0.001). Patients with positive pelvic LN were 16.7% and 7.3%, in SLN and LD groups, respectively (p=0.002). Disease-free survival (DFS) curves did not showed a statistically significant difference between centers and strategies adopted (SLN mapping, LD, SLN+LD) with a HR of 0.87 (95% CI 0.63-2.16; p=0.475).Survival outcomes were similar for both strategies. The SLN strategy allowed to identify a higher rate of stage IIIC1 disease even with a lower median number of lymph node removed in SLN group. Applying a SLN algorithm does not impair the prognosis of endometrial cancer patients. The clinical impact and management of low volume metastasis in high-risk patients should be further clarify.

Observations of high redshift quasars at $z>6$ indicate that they harbor supermassive black holes (SMBHs) of a billion solar masses. The direct collapse scenario has emerged as the most plausible way to assemble SMBHs. The nurseries for the direct collapse black holes are massive primordial halos illuminated with an intense UV flux emitted by population II (Pop II) stars. In this study, we compute the critical value of such a flux ($J_{21}^{\rm crit}$) for realistic spectra of Pop II stars through three-dimensional cosmological simulations. We derive the dependence of $J_{21}^{\rm crit}$ on the radiation spectra, on variations from halo to halo, and on the impact of X-ray ionization. Our findings show that the value of $J_{21}^{\rm crit}$ is a few times $\rm 10^4$ and only weakly depends on the adopted radiation spectra in the range between $T_{\rm rad}=2 \times 10^4-10^5$ K. For three simulated halos of a few times $\rm 10^{7}$~M$_{\odot}$, $J_{21}^{\rm crit}$ varies from $\rm 2 \times 10^4 - 5 \times 10^4$. The impact of X-ray ionization is almost negligible and within the expected scatter of $J_{21}^{\rm crit}$ for background fluxes of $J_{\rm X,21} \leq 0.1$. The computed estimates of $J_{21}^{\rm crit}$ have profound implications for the quasar abundance at $z=10$ as it lowers the number density of black holes forming through an isothermal direct collapse by a few orders of magnitude below the observed black holes density. However, the sites with moderate amounts of $\rm H_2$ cooling may still form massive objects sufficient to be compatible with observations., Accepted for publication in MNRAS, comments are welcome

While Population III stars are typically thought to be massive, pathways towards lower-mass Pop III stars may exist when the cooling of the gas is particularly enhanced. A possible route is enhanced HD cooling during the merging of dark-matter halos. The mergers can lead to a high ionization degree catalysing the formation of HD molecules and may cool the gas down to the cosmic microwave background (CMB) temperature. In this paper, we investigate the merging of mini-halos with masses of a few 10$^5$ M$_\odot$ and explore the feasibility of this scenario. We have performed three-dimensional cosmological hydrodynamics calculations with the ENZO code, solving the thermal and chemical evolution of the gas by employing the astrochemistry package KROME. Our results show that the HD abundance is increased by two orders of magnitude compared to the no-merging case and the halo cools down to $\sim$60 K triggering fragmentation. Based on Jeans estimates the expected stellar masses are about 10 M$_\odot$. Our findings show that the merging scenario is a potential pathway for the formation of low-mass stars., Comment: Submitted to MNRAS

The possible losses of silicon atom population during star-forming evolution and in the (photondominated region) PDR environments of the interstellar medium (ISM) can have different origins, one being the charge exchange (CE) encounter with the helium cations (Si + He + ) one of the most abundant species in those environments. This work investigates the different features of the likely interaction potentials leading to asymptotic partners like Si, Si + ,S i ++ and He or He + , in order to determine the influence of more accurate cross-sections on the chemical evolution of the ISM. We analyse the behaviour of interacting Si and He atoms by using ab initio quantum molecular methods. To obtain the corresponding transition probabilities, we employ a simple sequential grouping of single-crossing Landau–Zener events, and the timedependent rate coefficients for the CE processes involved are obtained over a broad range of the gas temperatures. The results are seen to differ substantially from an earlier Langevintype modelling of such process and further suggest a much more complex variety of possible molecular evolution mechanisms. We find, in fact, the unexpected presence of electron shakeoff effects leading to Si ++ generation yielding to emission of an electron, which has never been considered before and that, although with markedly smaller cross-sections, can indeed contribute to Si losses after the primary CE event. The consequences of these novel findings are tested on evolutionary model calculations and the results discussed in detail.

Understanding the formation of the extremely metal poor star SDSS-J102915+172927 is of fundamental importance to improve our knowledge on the transition between the first and second generation of stars in the Universe. In this paper, we perform three-dimensional cosmological hydrodynamical simulations of dust-enriched halos during the early stages of the collapse process including a detailed treatment of the dust physics. We employ the astrochemistry package \krome coupled with the hydrodynamical code \textsc{enzo} assuming grain size distributions produced by the explosion of core-collapse supernovae of 20 and 35 M$_\odot$ primordial stars which are suitable to reproduce the chemical pattern of the SDSS-J102915+172927 star. We find that the dust mass yield produced from Population III supernovae explosions is the most important factor which drives the thermal evolution and the dynamical properties of the halos. Hence, for the specific distributions relevant in this context, the composition, the dust optical properties, and the size-range have only minor effects on the results due to similar cooling functions. We also show that the critical dust mass to enable fragmentation provided by semi-analytical models should be revised, as we obtain values one order of magnitude larger. This determines the transition from disk fragmentation to a more filamentary fragmentation mode, and suggests that likely more than one single supernova event or efficient dust growth should be invoked to get such a high dust content., Comment: Accepted on ApJ

Numerical simulations show the formation of self-gravitating primordial disks during the assembly of the first structures in the Universe, in particular during the formation of Pop.~III and supermassive stars. Their subsequent evolution is expected to be crucial to determine the mass scale of the first cosmological objects, which depends on the temperature of the gas and the dominant cooling mechanism. Here, we derive a one-zone framework to explore the chemical evolution of such disks and show that viscous heating leads to the collisional dissociation of an initially molecular gas. The effect is relevant on scales of 10 AU (1000 AU) for a central mass of 10 M_sun (10^4 M_sun) at an accretion rate of 10^{-1} M_sun yr^{-1}, and provides a substantial heat input to stabilize the disk. If the gas is initially atomic, it remains atomic during the further evolution, and the effect of viscous heating is less significant. The additional thermal support is particularly relevant for the formation of very massive objects, such as the progenitors of the first supermassive black holes. The stabilizing impact of viscous heating thus alleviates the need for a strong radiation background as a means of keeping the gas atomic., Comment: 13 pages, 5 figures, 6 tables, accepted at A&A

The time-dependent rate coefficients for the charge exchange reaction C+ + Si -> C + Si+ for doublet and quartet states have been determined with ab initio quantum calculations coupled with a non-adiabatic transition model based on a simple Landau-Zener picture. This reaction plays a key role in determining the abundances of C, Si, and their ions, in the ISM since these abundances affect the fine structure cooling and hence the star formation rates. We also provide additional calculations to evaluate the differences between the gas evolution as obtained by using the empirical rate estimates found in the current literature and the calculations presented in this work which are based on our more realistic evaluation of such rates from ab initio transition probabilities . We shall thus show here that the new rates yield important differences for metal-rich environments where $T, Accepted to be published on MNRAS

We investigate the influence of the initial proto-galaxies over-densities and masses on their evolution, to understand whether the internal properties of the proto-galactic haloes are sufficient to account for the varied properties of the galactic populations. By means of fully hydrodynamical N-body simulations performed with the code EvoL we produce twelve self-similar models of early-type galaxies of different initial masses and over-densities, following their evolution from z \geq 20 down to z \leq 1. The simulations include radiative cooling, star formation, stellar energy feedback, a reionizing photoheating background, and chemical enrichment of the ISM. We find a strong correlation between the initial properties of the proto-haloes and their star formation histories. Massive (10^13M\odot) haloes experience a single, intense burst of star formation (with rates \geq 10^3M\odot/yr) at early epochs, consistently with observations, with a less pronounced dependence on the initial over-density; intermediate mass (10^11M\odot) haloes histories strongly depend on their initial over-density, whereas small (10^9M\odot) haloes always have fragmented histories, resulting in multiple stellar populations, due to the "galactic breathing" phenomenon. The galaxy models have morphological, structural and photometric properties comparable to real galaxies, often closely matching the observed data; even though some disagreement is still there, likely a consequence of some numerical choices. We conclude that internal properties are essentially sufficient to explain many of the observed features of early type galaxies, particularly the complicated and different star formation histories shown by haloes of very different mass. In this picture, nature seems to play the dominant role, whereas nurture has a secondary importance.

The formation of anionic species in the interstellar medium from interaction of linear molecules containing carbon, nitrogen and hydrogen as atomic components (polyynes) with free electrons in the environment is modelled via a quantum treatment of the collision dynamics. The ensuing integral cross sections are employed to obtain the corresponding attachment rates over a broad range of temperatures for the electrons. The calculations unequivocally show that a parametrization form often employed for such rates yields a broad range of values that turn out to be specific for each molecular species considered, thus excluding using a unique set for the whole class of polyynes., Comment: accepted to be published on MNRAS

We present a new computational scheme aimed at reducing the complexity of the chemical networks in astrophysical models, one which is shown to markedly improve their computational efficiency. It contains a flux-reduction scheme that permits us to deal with both large and small systems. This procedure is shown to yield a large speed-up of the corresponding numerical codes and provides good accord with the full network results. We analyse and discuss two examples involving chemistry networks of the interstellar medium and show that the results from the present reduction technique reproduce very well the results from fuller calculations.

We present and test chemical models for three-dimensional hydrodynamical simulations of galaxies. We explore the effect of changing key parameters such as metallicity, radiation and non-equilibrium versus equilibrium metal cooling approximations on the transition between the gas phases in the interstellar medium. The microphysics is modelled by employing the public chemistry package KROME and the chemical networks have been tested to work in a wide range of densities and temperatures. We describe a simple H/He network following the formation of H$_2$, and a more sophisticated network which includes metals. Photochemistry, thermal processes, and different prescriptions for the H$_2$ catalysis on dust are presented and tested within a one-zone framework. The resulting network is made publicly available on the KROME webpage. We find that employing an accurate treatment of the dust-related processes induces a faster HI--H$_2$ transition. In addition, we show when the equilibrium assumption for metal cooling holds, and how a non-equilibrium approach affects the thermal evolution of the gas and the HII--HI transition. These models can be employed in any hydrodynamical code via an interface to KROME and can be applied to different problems including isolated galaxies, cosmological simulations of galaxy formation and evolution, supernova explosions in molecular clouds, and the modelling of star-forming regions. The metal network can be used for a comparison with observational data of CII 158 $\mu$m emission both for high-redshift as well as for local galaxies., Comment: A&A accepted

Deuterium fractionation, i.e. the enhancement of deuterated species with respect to the non-deuterated ones, is considered to be a reliable chemical clock of star-forming regions. This process is strongly affected by the ortho-to-para (o-p) H$_2$ ratio. In this letter we explore the effect of the o-p H$_2$ conversion on grains on the deuteration timescale in fully depleted dense cores, including the most relevant uncertainties that affect this complex process. We show that (i) the o-p H$_2$ conversion on grains is not strongly influenced by the uncertainties on the conversion time and the sticking coefficient and (ii) that the process is controlled by the temperature and the residence time of ortho-H$_2$ on the surface, i.e. by the binding energy. We find that for binding energies in between 330-550 K, depending on the temperature, the o-p H$_2$ conversion on grains can shorten the deuterium fractionation timescale by orders of magnitude, opening a new route to explain the large observed deuteration fraction $D_\mathrm{frac}$ in dense molecular cloud cores. Our results suggest that the star formation timescale, when estimated through the timescale to reach the observed deuteration fractions, might be shorter than previously proposed. However, more accurate measurements of the binding energy are needed to better assess the overall role of this process., Accepted for publication in ApJ Letters

Radiative feedback from populations II stars played a vital role in early structure formation. Particularly, photons below the Lyman limit can escape the star forming regions and produce a background ultraviolet (UV) flux which consequently may influence the pristine halos far away from the radiation sources. These photons can quench the formation of molecular hydrogen by photo-detachment of $\rm H^{-}$. In this study, we explore the impact of such UV radiation on fragmentation in massive primordial halos of a few times $\rm 10^{7}$~M${_\odot}$. To accomplish this goal, we perform high resolution cosmological simulations for two distinct halos and vary the strength of the impinging background UV field in units of $\rm J_{21}$. We further make use of sink particles to follow the evolution for 10,000 years after reaching the maximum refinement level. No vigorous fragmentation is observed in UV illuminated halos while the accretion rate changes according to the thermal properties. Our findings show that a few 100-10, 000 solar mass protostars are formed when halos are irradiated by $\rm J_{21}=10-500$ at $\rm z>10$ and suggest a strong relation between the strength of UV flux and mass of a protostar. This mode of star formation is quite different from minihalos, as higher accretion rates of about $\rm 0.01-0.1$ M$_{\odot}$/yr are observed by the end of our simulations. The resulting massive stars are the potential cradles for the formation of intermediate mass black holes at earlier cosmic times and contribute to the formation of a global X-ray background., Submitted to APJ, comments are welcome. High resolution copy is available at http://www.astro.physik.uni-goettingen.de/~mlatif/IMBHs_apj.pdf

The ability of metal free gas to cool by molecular hydrogen in primordial halos is strongly associated with the strength of ultraviolet (UV) flux produced by the stellar populations in the first galaxies. Depending on the stellar spectrum, these UV photons can either dissociate $\rm H_{2}$ molecules directly or indirectly by photo-detachment of $\rm H^{-}$ as the latter provides the main pathway for $\rm H_{2}$ formation in the early universe. In this study, we aim to determine the critical strength of the UV flux above which the formation of molecular hydrogen remains suppressed for a sample of five distinct halos at $z>10$ by employing a higher order chemical solver and a Jeans resolution of 32 cells. We presume that such flux is emitted by PopII stars implying atmospheric temperatures of $\rm 10^{4}$~K. We performed three-dimensional cosmological simulations and varied the strength of the UV flux below the Lyman limit in units of $\rm J_{21}$. Our findings show that the value of $\rm J_{21}^{crit}$ varies from halo to halo and is sensitive to the local thermal conditions of the gas. For the simulated halos it varies from 400-700 with the exception of one halo where $\rm J_{21}^{crit} \geq 1500$. This has important implications for the formation of direct collapse black holes and their estimated population at z > 6. It reduces the number density of direct collapse black holes by almost three orders of magnitude compared to the previous estimates., 10 pages, 6 figures, matches the accepted version to ber published in MNRAS, higher resolution version is available at http://www.astro.physik.uni-goettingen.de/~mlatif/Jcrit.pdf

Objectives To test the reproducibility of IETA (International Endometrial Tumor Analysis) terms in describing sonographic features in patients with endometrial hyperplasia. Methods Patients with histological diagnosis of endometrial hyperplasia (simple or complex, with or without atipiae) underwent transvaginal (TVUS) ultrasound and sonohysterography (SYS) performed by an expert examiner that stored images, clips and volumes. Some endometrial features were described applying IETA terms (echogenicity, endometrial midline, endo-myometrial junction, symmetry of layers at SYS, outline of endometrial background at SYS). A second expert ultrasound examiner reviewed clips and images using IETA terms, blinded to the description of the first examiner. Inter-observer variability was analysed. Results 50 patients were enrolled and underwent TVUS; 41 SYS were performed. At TVUS the agreement in the description of endometrial echogenicity was poor (32%, weighted kappa 0.163). The agreement in the description of endometrial midline was moderate (70%, weighted kappa 0.42). The agreement in the description of endo-myometrial junction was poor (66%, weighted kappa 0.035). At SYS, the agreement in the assessment of symmetry of endometrial layers was poor (59%, kappa 0.177) and the agreement in the description of the outline of endometrial background was moderate (59%, weighted kappa 0.435). Conclusions Despite the great effort in standardising terminology to describe endometrial appearance at ultrasound, in our series the assessment of endometrial features remains heterogeneous, partially subjective and not well reproducible.

The formation of the first stars in the Universe is regulated by a sensitive interplay of chemistry and cooling with the dynamics of a self-gravitating system. As the outcome of the collapse and the final stellar masses depend sensitively on the thermal evolution, it is necessary to accurately model the thermal evolution in high resolution simulations. As previous investigations raised doubts regarding the convergence of the temperature at high resolution, we investigate the role of the numerical method employed to model the chemistry and the thermodynamics. Here we compare the standard implementation in the adaptive-mesh refinement code \verb|ENZO|, employing a first order backward differentiation formula (BDF), with the 5th order accurate BDF solver \verb|DLSODES|. While the standard implementation in \verb|ENZO| shows a strong dependence on the employed resolution, the results obtained with \verb|DLSODES| are considerably more robust, both with respect to the chemistry and thermodynamics, but also for dynamical quantities such as density, total energy or the accretion rate. We conclude that an accurate modeling of the chemistry and thermodynamics is central for primordial star formation., accepted by MNRAS Letters

Population III stars are the first stars in the Universe to form at z=20-30 out of a pure hydrogen and helium gas in minihalos of 10^5-10^6 M$_\odot$ . Cooling and fragmentation is thus regulated via molecular hydrogen. At densities above 10^8 cm$^{-3}$, the three-body H2 formation rates are particularly important for making the gas fully molecular. These rates were considered to be uncertain by at least a few orders of magnitude. We explore the impact of new accurate three-body H2 formation rates derived by Forrey (2013) for three different minihalos, and compare to the results obtained with three-body rates employed in previous studies. The calculations are performed with the cosmological hydrodynamics code ENZO (release 2.2) coupled with the chemistry package KROME (including a network for primordial chemistry), which was previously shown to be accurate in high resolution simulations. While the new rates can shift the point where the gas becomes fully molecular, leading to a different thermal evolution, there is no trivial trend in how this occurs. While one might naively expect the results to be inbetween the calculations based on Palla et al. (1983) and Abel et al. (2002), the behavior can be close to the former or the latter depending on the dark matter halo that is explored. We conclude that employing the correct three-body rates is about as equally important as the use of appropriate initial conditions, and that the resulting thermal evolution needs to be calculated for every halo individually., Comment: 10 pages, 9 figures, A&A, 561, A13 (2014)

The elementary mechanisms through which molecular polyynes could form stable negative ions after interacting with free electrons in planetary atmospheres (e.g., Titan's) are analyzed using quantum scattering calculations and quantum structure methods. The case of radical species and of nonpolar partners are analyzed via specific examples for both the C n H and HC n H series, with n values from 4 to 12. We show that attachment processes to polar radicals are dominating the anionic production and that the mediating role of dipolar scattering states is crucial to their formation. The corresponding attachment rates are presented as calculated upper limits to their likely values and are obtained down to the low temperatures of interest. The effects of the computed rates, when used in simple evolutionary models, are also investigated and presented in detail.

CONTEXT: The attachment of free electrons to polycondensed aromatic ring molecules (PAHs) is studied for the variety of these molecules with different numbers of condensed rings and over a broad range of electron temperatures, using a multichannel quantum scattering approach. The calculations of the relevant cross sections are used in turn to model the corresponding attachment rates for each of the systems under study, and these rates are parametrized as a function of temperature using a commonly employed expression for two-body processes in the interstellar medium (ISM). AIM: The scope of this work is to use first principles to establish the influence of chemical properties on the efficiency of the electron-attachment process for PAHs. METHODS: Quantum multichannel scattering methods are employed to generate the relevant cross sections, hence the attachment rates, using integral elastic cross sections computed over a broad range of relevant energies, from threshold up to 1000 K and linking the attachment to low-energy resonant collisions. RESULTS: The rates obtained for the present molecules are found to markedly vary within the test ensemble of the present work and to be lower than the earlier values used for the entire class of PAHs anions, when modelling their evolutions in ISM environments. The effects of such differences on the evolutions of chemical networks that include both PAH and PAH- species are analysed in some detail and related to previous calculations., Comment: accepted to be published on A&A

Chemistry has a key role in the evolution of the interstellar medium (ISM), so it is highly desirable to follow its evolution in numerical simulations. However, it may easily dominate the computational cost when applied to large systems. In this paper we discuss two approaches to reduce these costs: (i) based on computational strategies, and (ii) based on the properties and on the topology of the chemical network. The first methods are more robust, while the second are meant to be giving important information on the structure of large, complex networks. To this aim we first discuss the numerical solvers for integrating the system of ordinary differential equations (ODE) associated with the chemical network. We then propose a buffer method that decreases the computational time spent in solving the ODE system. We further discuss a flux-based method that allows one to determine and then cut on the fly the less active reactions. In addition we also present a topological approach for selecting the most probable species that will be active during the chemical evolution, thus gaining information on the chemical network that otherwise would be difficult to retrieve. This topological technique can also be used as an a priori reduction method for any size network. We implemented these methods into a 1D Lagrangian hydrodynamical code to test their effects: both classes lead to large computational speed-ups, ranging from x2 to x5. We have also tested some hybrid approaches finding that coupling the flux method with a buffer strategy gives the best trade-off between robustness and speed-up of calculations., Comment: accepted for publication in MNRAS

We present EvoL, the new release of the Padova N-body code for cosmological simulations of galaxy formation and evolution. In this paper, the basic Tree + SPH code is presented and analysed, together with an overview on the software architectures. EvoL is a flexible parallel Fortran95 code, specifically designed for simulations of cosmological structure formation on cluster, galactic and sub-galactic scales. EvoL is a fully Lagrangian self-adaptive code, based on the classical Oct-tree and on the Smoothed Particle Hydrodynamics algorithm. It includes special features such as adaptive softening lengths with correcting extra-terms, and modern formulations of SPH and artificial viscosity. It is designed to be run in parallel on multiple CPUs to optimize the performance and save computational time. We describe the code in detail, and present the results of a number of standard hydrodynamical tests., 33 pages, 49 figures, accepted on A&A

Context. The seeds of the first supermassive black holes may have resulted from the direct collapse of hot primordial gas in $\gtrsim 10^4$ K haloes, forming a supermassive or quasistar as an intermediate stage. Aims. We explore the formation of a protostar resulting from the collapse of primordial gas in the presence of a strong Lyman-Werner radiation background. Particularly, we investigate the impact of turbulence and rotation on the fragmentation behaviour of the gas cloud. We accomplish this goal by varying the initial turbulent and rotational velocities. Methods. We performed 3D adaptive mesh refinement simulations with a resolution of 64 cells per Jeans length using the ENZO code, simulating the formation of a protostar up to unprecedentedly high central densities of $10^{21}$ cm$^{-3}$, and spatial scales of a few solar radii. To achieve this goal, we employed the KROME package to improve modelling of the chemical and thermal processes. Results. We find that the physical properties of the simulated gas clouds become similar on small scales, irrespective of the initial amount of turbulence and rotation. After the highest level of refinement was reached, the simulations have been evolved for an additional ~5 freefall times. A single bound clump with a radius of $2 \times 10^{-2}$ AU and a mass of ~$7 \times 10^{-2}$ M$_{\odot}$ is formed at the end of each simulation, marking the onset of protostar formation. No strong fragmentation is observed by the end of the simulations, regardless of the initial amount of turbulence or rotation, and high accretion rates of a few solar masses per year are found. Conclusions. Given such high accretion rates, a quasistar of $10^5$ M$_{\odot}$ is expected to form within $10^5$ years., 18 pages, 7 figures, fixed typos, added references and clarified some details; accepted for publication in A&A

Recent discoveries of carbon-enhanced metal-poor stars like SMSS J031300.36-670839.3 provide increasing observational insights into the formation conditions of the first second-generation stars in the Universe, reflecting the chemical conditions after the first supernova explosion. Here, we present the first cosmological simulations with a detailed chemical network including primordial species as well as C, C$^+$, O, O$^+$, Si, Si$^+$, and Si$^{2+}$ following the formation of carbon-enhanced metal poor stars. The presence of background UV flux delays the collapse from $z=21$ to $z=15$ and cool the gas down to the CMB temperature for a metallicity of Z/Z$_\odot$=10$^{-3}$. This can potentially lead to the formation of lower mass stars. Overall, we find that the metals have a stronger effect on the collapse than the radiation, yielding a comparable thermal structure for large variations in the radiative background. We further find that radiative backgrounds are not able to delay the collapse for Z/Z$_\odot$=10$^{-2}$ or a carbon abundance as in SMSS J031300.36-670839.3., Comment: submitted to ApJL

We present robo, a model and its companion code for the study of the interstellar medium (ISM). The aim is to provide an accurate description of the physical evolution of the ISM and to set the ground for an ancillary tool to be inserted in NBody-Tree-SPH (NB-TSPH) simulations of large-scale structures in the cosmological context or of the formation and evolution of individual galaxies. The ISM model consists of gas and dust. The gas chemical composition is regulated by a network of reactions that includes a large number of species (hydrogen and deuterium-based molecules, helium, and metals). New reaction rates for the charge transfer in H+ and H2 collisions are presented. The dust contains the standard mixture of carbonaceous grains (graphite grains and PAHs) and silicates. In our model dust are formed and destroyed by several processes. The model accurately treats the cooling process, based on several physical mechanisms, and cooling functions recently reported in the literature. The model is applied to a wide range of the input parameters, and the results for important quantities describing the physical state of the gas and dust are presented. The results are organized in a database suited to the artificial neural networks (ANNs). Once trained, the ANNs yield the same results obtained by ROBO with great accuracy. We plan to develop ANNs suitably tailored for applications to NB-TSPH simulations of cosmological structures and/or galaxies.