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The FOOT (FragmentatiOn Of Target) multi-detector experiment aims at improving the accuracy of oncological hadrontherapy for tumor treatment. It studies the nuclear fragmentation due to the interactions of charged particle beams with patient tissues employing the inverse kinematic approach to boost the fragments in the laboratory reference system. Hence it is necessary a tracking system in a magnetic field to measure the momentum of the charged fragments. The Microstrip Silicon Detector (MSD) is part of the charged-ions-tracking magnetic spectrometer for the evaluation of the Linear Energy Transfer LET (dE/dx) and the nuclear fragments momentum. Here we describe the MSD architecture and its data acquisition system whose task is to collect and digitize the detectors output, generating a data packet to be sent to the experiment’s central acquisition. This data acquisition system is designed and tested to withstand the trigger rate and detector’s throughput; it has a small size and is easily portable, a necessary feature for an experiment that will move among the available ion beam accelerators and proton therapy treatment rooms.

Open physics 19(1), 383 - 394 (2021). doi:10.1515/phys-2021-0032, Published by de Gruyter, Berlin

Charged Particle Therapy (CPT) is a powerful radiotherapy technique for the treatment of deep-seated tumours characterized by a large dose released in the Bragg peak area (corresponding to the tumour region) and a small dose delivered to the surrounding healthy tissues. The precise measurement of the fragments produced in the nuclear interactions of charged particle beams with patient tissues is a crucial task to improve the clinical treatment plans. The FOOT (FragmentatiOn Of Target) experiment is an international project, funded by the Istituto Nazionale di Fisica Nucleare (INFN), aimed to study the dose released by the tissues and particle beams fragmentation. The target (16O, 12C) fragmentation induced by 150-400 MeV/n proton beams will be studied via the inverse kinematic approach, where 16O and 12C therapeutic beams collide on graphite and hydrocarbon target to provide the cross section on Hydrogen. A table-top detector is being developed and it includes a drift chamber as a beam monitor upstream of the target to measure the beam direction, a magnetic spectrometer based on silicon pixel and strip detectors, a scintillating crystal calorimeter able to stop the heavier produced fragments, and a ΔE detector, with TOF capability, for the particle identification. A setup based on the concept of the “Emulsion Cloud Chamber”, coupled with the interaction region of the electronic FOOT setup, will complement the physics program by measuring lighter charged fragments to extend the angular acceptance up to about 70 degrees. In this work, the experimental design and the requirements of the FOOT experiment will be discussed and preliminary results on the emulsion spectrometer tests will be presented.

Introduzione Due recenti metanalisi (Duaso, 2014; Duaso, 2016) hanno dimostrato che lo status di fumatore dei professionisti sanitari influenza negativamente l’approccio nel consigliare la cessazione del fumo. Altre evidenze di letteratura indicano che una quota di medici ritiene che la promozione della cessazione del fumo richieda troppo tempo e sia inefficace (Vogt, 2005). Secondo i dati della sorveglianza condotta dall’Istituto Superiore di Sanità italiano (PASSI, 2018) solo il 51,4% dei fumatori dichiara di aver ricevuto il consiglio di smettere di fumare da un medico o da un operatore sanitario. Nell’ambito dei progetti di promozione della salute sostenuti dall’Istituto per la Sicurezza Sociale (ISS) di San Marino, il presente studio vuole indagare le abitudini tabagiche dei suoi professionisti sanitari. Materiali e metodi È stata condotta una survey rivolta ai dipendenti dell’ISS San Marino mediante la distribuzione di un questionario cartaceo auto-somministrato, costituito da una parte iniziale contenente le informazioni anagrafiche e da cinque domini: abitudine al fumo, cessazione del fumo, valutazione dei percorsi anti-fumo, opinione circa la presa in carico dei fumatori, opinione sulla validità dei metodi di disassuefazione tabagica. Risultati Sono stati distribuiti circa 1.000 questionari a medici, infermieri e personale tecnico/amministrativo dell’ISS e sono state raccolte le risposte di 352 dipendenti. I partecipanti al questionario hanno un’età media di 45,3 anni e sono per il 72,6% femmine. Il 55,9% dichiara di non aver mai fumato (NF), il 23,3% fuma attualmente (F) ed il 21,3% è ex-fumatore (EF). L’abitudine tabagica presenta differenze significative tra i due generi per quanto riguarda lo stato di NF (57,9% donne, 50% uomini) e lo stato di EF (19% donne, 26,6% uomini); praticamente identica inveca la quota di fumatori nei due generi: 23,1% tra le donne e 23,4% tra gli uomini. L’83,8% dei fumatori ha dichiarato di aver pensato di smettere di fumare e il 53,7% di questi prenderebbe in considerazione un percorso presso un Centro Antifumo (CA). Alla domanda “Pensa che valga la pena impiegare tempo e risorse nel trattamento del fumatore?” hanno risposto 324 partecipanti. La maggior parte ha risposto “Sempre” (media tra i gruppi 79,6%; NF 82,3%; F 70%; EX 84,1%). Per quanto riguarda la domanda “Secondo lei quali metodi potrebbero essere efficaci per smettere di fumare?” hanno risposto in 343: “Breve colloquio motivazionale individuale” è il metodo che ha ricevuto il maggior numero di risposte positive (63,4%), seguito da “Eventi formativi” (62,4%), “Terapie di gruppo” (62,1%), “Terapia farmacologica” (42%) ed infine “Multe e sanzioni” (38,4%). Conclusioni Evidenze in letteratura (DoH, 2009) mostrano che la popolazione tende ad accettare meno favorevolmente le indicazioni di professionisti sanitari che non seguono un corretto stile di vita. Dal momento che circa un quarto dei dipendenti dell’ISS attualmente fuma e che la maggior parte di questi ha pensato di smettere di fumare, potrebbe essere utile attuare un programma di cessazione tabagica rivolto ai dipendenti; questo permetterebbe di migliorare il loro stato di salute e li renderebbe un veicolo più efficace di educazione ai corretti stili di vita. Uno strumento utile potrebbe essere la creazione di un Centro Antifumo dove implementare i metodi di cessazione tabagica che sono stati valutati come i maggiormente efficaci dai dipendenti intervistati, in cui prendere in carico anche i cittadini e i pazienti con patologie croniche motivati a smettere di fumare.

BackgroundPlanning in behavioral weight loss (BWL) programs helps participants enact changes in eating and exercise, although the direct impact on weight loss is unclear.PurposeTo examine how meal and exercise planning frequencies change in a BWL program and their relations to weight loss outcomes.MethodsParticipants (N = 139) in a 40 week worksite-based BWL program completed a questionnaire regarding meal and exercise planning frequency at Weeks 0, 10, 20, 30, and 40 and were weighed weekly. Growth curve models were used to determine trajectories in meal and exercise planning frequency and to assess the role of an individual’s average meal and exercise planning (between-person effect) and individual variation in planning (within-person effect) on body mass index (BMI).ResultsThe best-fitting model, a linear random effect with a quadratic fixed-effect model, demonstrated that meal and exercise planning frequency increased over the course of the program with slowing growth rates. Between participants, higher average meal planning frequency (B = −0.029, t = −3.60), but not exercise planning frequency, was associated with greater weight loss. Within participants, exercise planning, but not meal planning, predicted a higher than expected BMI (B = 3.17, t = 4.21).ConclusionsFrequent meal planning should be emphasized as a continued, as opposed to intermittent, goal in BWL programs to enhance weight loss. Average exercise planning frequency does not impact weight loss in BWL programs; however, acute increases in exercise planning frequency may be a popular coping strategy during a weight loss setback or, alternatively, may lead to increased calorie consumption and weight gain.

In a carbon ion treatment the nuclear fragmentationof both target and beam projectiles impacts on the dose releasedon the tumor and on the surrounding healthy tissues. Carbon ionfragmentation occurring inside the patient body has to be stud-ied in order to take into account this contribution. These dataare also important for the development of the range monitoringtechniques with charged particles. The production of chargedfragments generated by carbon ion beams of 115-353 MeV/ukinetic energy impinging on carbon, oxygen, and hydrogen tar-gets has been measured at the CNAO particle therapy center(Pavia, Italy). The use of thin targets of graphite (C), PMMA(C2O5H8) and polyvinyl-toluene [plastic scintillator (PS), CbHa]allowed to measure fragments production cross sections, exploit-ing a time-of-flight (ToF) technique. PS detectors have been usedto perform the ToF measurements, while LYSO crystals havebeen used for the deposited energy measurement and to performparticle identification. Cross sections have been measured at 90◦and 60◦with respect to the beam direction. The measured pro-ton, deuteron, and triton differential production cross sectionson C, O, and H, obtained exploiting the target subtraction strat-egy, are presented here as a function of the fragment kineticenergy.

In hadron therapy, the accelerated ions, interacting with the body of the patient, cause the fragmentation of both projectile and target nuclei. The fragments interact with the human tissues depositing energy both in the entrance channel and in the volume surrounding the tumor. The knowledge of the fragments features is crucial to determine the energy amount deposited in the human body, and - hence - the damage to the organs and to the tissues around the tumor target. The FOOT (FragmentatiOn Of Target) experiment aims at studying the fragmentation induced by the interaction of a proton beam (150-250 MeV/n) inside the human body. The FOOT detector includes an electronic setup for the identification of Z ≥ 3 fragments integrated with an emulsion spectrometer to measure Z ≤ 3 fragments. Charge identification by nuclear emulsions is based on the development of techniques of controlled fading of the particle tracks inside the nuclear emulsion, that extend the dynamical range of the films developed for the tracking of minimum ionising particles. The controlled fading strongly depends on temperature, relative humidity and treatment duration. In this study the performances in terms of charge separation of proton, helium and carbon particles, obtained on a batch of new emulsion films produced in Japan are reported.

This paper describes the development and characterization of a Δ E-TOF detector composed of a plastic scintillator bar coupled at both ends to silicon photomultipliers. This detector is a prototype of a larger version which will be used in the FOOT (FragmentatiOn Of Target) experiment to identify the fragments produced by ion beams accelerated onto a hydrogen-enriched target. The final Δ E-TOF detector will be composed of two layers of plastic scintillator bars with orthogonal orientation and will measure, for each crossing fragment, the energy deposited in the plastic scintillator ( Δ E), the time of flight (TOF), and the coordinates of the interaction position in the scintillator. To meet the FOOT experimental requirements, the detector should have energy resolution of a few percents and time resolution of 70 ps, and it should allow to discriminate multiple fragments belonging to the same event. To evaluate the achievable performances, the detector prototype was irradiated with protons of kinetic energy in the 70–230 MeV range and interacting at several positions along the bar. The measured energy resolution σ Δ E ∕ Δ E was 6–14%, after subtracting the fluctuations of the deposited energy. A time resolution σ between 120 and 180 ps was obtained with respect to a trigger detector. A spatial resolution σ of 1.9 cm was obtained for protons interacting at the center of the bar.

The main goal of the FOOT (FragmentatiOn Of Target) experiment is the measurement of the differential cross sections with respect to the energy and angle of the produced fragments in nuclear interactions between an ion beam, such as proton, Helium, Carbon, and different targets (proton, Carbon, Oxygen). Two important fields can benefit from these kind of measurements: firstly, in the 150 — 400MeV/u beam energy range, the data will be used to evaluate the nuclear fragmentation occurring in a standard hadrontherapy treatment and thus potential side effects. Secondly, in the 700 — 1000MeV/u beam energy range, the FOOT experiment aims at studying novel shields for spacecrafts involved in long term missions within the Solar System. The experiment has been funded by INFN since September 2017 and it is currently in its construction phase while the first data taking is scheduled by the end of 2020. A description of the experiment and a overview of expected performances and test beam results will be presented.

This article presents emergy evaluation and its application to ecosystems and territorial systems. The emergy approach is an environmental accounting methodology that can be used to assess natural inflows and services within a system. This ecological indicator was inspired by the food chain and the observations that energy quality increases along the chain while energy content decreases. Emergy analysis is able to differentiate between the various units (processes) of an ecosystem. It highlights processes that are sustained by low-quality energy and processes that need high-quality fluxes. The method is an embodied energy analysis that uses solar energy as reference. By evaluating natural resources on a common basis, emergy analysis has proved useful at the interface between human and natural systems and for assessing the impact of human activity on ecosystems. Based on a rigorous algebra, emergy evaluation provides indicators to measure sustainability.

Activation of schemas related to one’s appearance has been studied extensively using implicit tasks such as the word stem completion task and the Stoop paradigm. The current study utilized a word stem completion task adapted for presentation on a Personal Data Assistant to examine differences in reaction times to appearance- and non-appearance-related words. Participants were 93 undergraduate women, 30 of whom met criteria for eating psychopathology utilizing the diagnostic algorithm for the Eating Disorder Diagnostic Scale (Stice et al. in Psychol Assess 12:123–131. doi:10.1037/1040-3590.12.2.123, 2000). The remaining 63 participants served as a comparison group. A significant interaction effect indicated that women with eating pathology exhibited significantly longer reaction times when selecting the appearance-related words than those without eating psychopathology. This research introduces a novel method of measuring reaction time to appearance- and non-appearance-related words and demonstrates the relevance of appearance schematicity in the naturalistic environment by showing that these schemas have the potential to impact the way young women process schema-relevant information on a day-to-day basis.

Hot tearing during solidification processes has been deeply investigated in past and recent years through testing, modeling, and development of a number of macroscopic hot tearing criteria. The objective is predicting the crack occurrence during industrial solidification processes, which, in the steel production, are mainly ingot and continuous casting. The present work is inspired by the criterion proposed in the work of Bellet et al.[1] called CBC criterion, from which the methodological approach and experimental data used for calibration, related to nine carbon steels, have been derived. The proposed hot tearing criterion adopts as parameters: primary and secondary arm spacing, the mechanical resistance near the solidus temperature, the solidification parameters G (gradient) and v (dendrite tip velocity), the brittle range extension in the dendritic front and the temperature of formation of manganese sulfides. The new formulation is an attempt to substitute to brittle temperature range and steel content, appearing in the CBC criterion, the dendritic structure characteristics, in the aim of: (a) moving toward a generalized expression of the cracking index applicable to different steel classes; (b) introducing the dependence of the crack susceptibility on the cooling conditions. The agreement of the new hot tearing index values with the experimental ones is of the same kind as that of the CBC criterion, indicating that the parameters and the dependences adopted in the new criterion make a sense. Further study and experimental work are needed to assess the influence of the microstructure morphology on the hot cracking sensitivity and to check the suitability of the approach to a wider range of steel compositions.

A large body of literature demonstrates the association between body image disturbances and health compromising behaviors among women (e.g., pathological eating, substance use, inappropriate exercise). However, given that disturbed body image is a pervasive problem, it is likely inversely related to health maintenance behaviors. Cancer screenings for breast, skin, and cervical cancer represent an important type of health maintenance behavior, yet adherence rates are low. Given the body-focused nature of these screenings, body image may be a salient predictor. This paper reviews the literature on the relationship between body image disturbances and cancer screening behaviors among women culminating in the proposal of a theoretical model. This model posits that body shame and body avoidance predict performance of cancer screenings and that variables drawn from the cancer literature, including risk perception, health anxiety, subjective norms, and self-efficacy, may moderate this relationship. Clinical implications and suggestions for research are discussed.

Research suggests that appearance focused social comparisons are associated with body image disturbances. This study utilized ecological momentary assessment to examine associations between appearance focused social comparisons to media images and peers and body image disturbance and affect. Appearance focused cognitive distortions were examined as a moderator. Ninety-three undergraduate women from a large public Midwestern university in the United States completed questionnaires assessing the nature, frequency, and consequences of appearance focused social comparisons. Compared to no comparison, media comparisons were associated with greater body checking, negative affect, and guilt; peer comparisons were associated with greater body checking and guilt. Cognitive distortions moderated the relationship between appearance focused social comparisons and body checking. Specifically, the relationship between peer comparisons and body checking was strengthened at higher levels of appearance focused cognitive distortions. When only upward comparisons were considered, the relationships between both media and peer comparisons and body checking were strengthened at higher levels of appearance focused cognitive distortions. These results have implications for the treatment of body dissatisfaction.

Billets produced by continuous casting sometimes show the presence of subsurface cracks that can compromise the quality of the final product. The presence of these cracks is revealed by Baumann prints of billet cross sections in which the chill zone is visible and the short radial cracks are located only where the chill zone thickness is thinner. This experimental finding induces the hypothesis that cracks are formed as a result of the presence of unevenness in the mold heat extraction around the billet perimeter. Cracks start to open in the dendritic front in regions where the shell growth in the mold is slower. The study presented in this article focused on steels with a sulfur content of about 300 ppm. The Baumann prints taken from billet samples of numerous different heats allowed detecting the presence of subsurface cracks and their location nearby visible chill zone thinning areas. To understand the mechanisms of crack formation and to define the possible corrections, a modeling activity has been carried out using the finite element technique on 148-mm diameter billets continuously cast at TenarisDalmine (Dalmine, Italy). The model performs a two-dimensional thermomechanical analysis of the solidification in the mold and within about 4 cm below the mold exit, along which the shell surface is cooled only by radiation to the environment, before the sprays of the first ring impact on the strand. The model includes the contact of the shell with the mold inner surface, which moves according to taper and distortion (this last part is calculated by means of a separate mold model); the steel creep behavior; the calculation of the heat transfer through the gap depending on the local mutual distance between the two surfaces; the effect of the liquid steel fluid dynamics on the solidification growth as a result of the temperature distribution; and the calculation of a hot tearing indicator represented by the porosity fraction caused by mechanical strains applied at the dendrite roots. From the simulation results, it is concluded that subsurface cracks are generated in the space between the mold exit and the first cooling ring; the involved mechanisms of formation also are withdrawn. Nucleation of MnS precipitates of large dimensions is an additional cause of defectiveness in controlled sulfur steels. As a final conclusion of this work, the most important actions to eliminate subsurface cracks are derived.

The study of Very Large Complex systems (“VLCS”), of which modern energy conversion systems are an important subset, requires a holistic approach to analyze the system itself and all of its “external” and “internal” interactions. The view taken in this paper is that the VLCS should be considered as an “extended” (in a sense specified below) thermodynamic system. The evaluation of the flows of matter and energy sustaining a VLCS and the knowledge of the transformations therein can be used to describe the rate of exploitation of the available natural resources, to assess the efficiency of the conversion process, and to provide a quantitative estimate of the impact of the system on the environment. This kind of information is an important part of the essential database of any Decision Support System for both the internal and global policy planning and for resources management. Several assessment methods are in use at present, and each one of them provides a different insight in the “performance” of the conversion chain under examination. This paper presents the results of a multi-criteria comparative analysis of both conventional and innovative hydrogen production processes in which H2 is generated from different feedstocks: methane, residual oil and biomass (wood chips).

The purpose of this study was to assess the effectiveness of a body image dissatisfaction prevention session that provided information on body image and media literacy to college women. Participants were 81 undergraduates who were randomly assigned to attend either a body image intervention or a control intervention. Participants completed measures at pre- and post-intervention and at 4-week follow-up. The body image group improved significantly more than the control group on body shape concerns, but not on the other outcome variables. Efficacious interventions capable of reaching large numbers of women are necessary to help dispel the "normative discontent" prevalent today.

A study has been performed on the microstructural properties of steels in the dendritic region with the scope of defining some key parameters denoting the tendency to form cracks during the solidification process, depending on the alloy composition. This study has been coupled to the thermomechanical modeling of the steel solidification inside the mold in order to explain the generation of stresses in the brittle dendritic region. The study has been carried out with the aid of data from round billet casting at Tenaris Siderca, Tamsa, and Dalmine. The linear thermal expansion coefficient calculated at the solidus temperature and the brittle zone width have been defined as the two parameters giving information about the tendency of an alloy to form cracks. The linear thermal expansion coefficient at the solidus temperature, above which steels have peritectic behavior, has also been specified. Some real cases of problems related to cracks and breakouts have been analyzed by means of coupled modeling, and solutions are proposed in terms of alloy composition and mold taper optimization.

There is a profound debate over how to assign greenhouse gas (GHG) responsibilities; therefore, we have decided to follow IPCC guidelines, as they offer the only standardized method. We have identified each type of greenhouse emission and its level of absorption. We have studied the province and its districts and municipalities. We have determined that the energy sector is that with the highest level of emissions, even if the per capita emissions of the Province of Siena are very low. This is caused by a very low level of industrialization and the presence of a local geothermal production of energy. In order to highlight this aspect, we have considered scenarios both with and without geothermal production. Our research was then focused on single districts (groups of homogenous municipalities) and municipalities, where we found great differences among the greenhouse emissions of the areas. We have constructed a map of the greenhouse emissions of the whole province. It has been interesting to note that there are 14 municipalities with net negative emissions, seven with low positive emissions, 12 with medium positive emissions and three with elevated positive emissions. These latter correspond to the main city and to two of the most industrialized municipalities.

Presented paper shows the power of emergy analysis and its ability for simultaneous consideration of different industrial resources, goods and services for the purposes of decision-making. Accompanied by the pinch concept, which by now tries to deal separately with each of the resources (energy, water, hydrogen, oxygen, etc.), the combined emergy–pinch analysis provides wide range of benefits boosted with extra inside and design guidelines improving the integration of processes and the ability to consider the ‘past’ and the ‘future’ of the resources (the effort of making them available and the effort of minimising their environmental impact). The paper presents the theoretical background of the emergy and pinch combination into general resources management technique and proves this concept on classical emergy and pinch examples accompanied with a combined resources management industrial problem considering the environmental impact of industrial activities.

Cancer vaccines are intended to promote a long-lasting memory response against tumors. Rationale for cancer vaccines is based on two observations: a) many tumors express antigens (TA), which are recognized by specific cytotoxic T lymphocytes; b) these lymphocytes may protect the host against tumor growth in vivo. So far, cancer vaccines have been developed using soluble TA and, more recently, TA presented by dendritic cells (DC), the most powerful antigen presenting cells (APC). DCs play a key role in the process leading to antigen recognition and lymphocyte activation. Despite a deeper understanding of these processes, clinical efficacy of cancer vaccines is still hampered by the heterogeneity of the studies performed so far, and by the largely unknown mechanisms through which tumors escape immunosurveillance. Current DC-based cancer vaccines require the preparation of DCs from patient blood monocytes, as well as DC-loading with TA. Both whole tumor and TA peptides are used as source of TA. Similar schedules have been implemented in many clinical trials on melanoma, kidney and prostate cancer, with partial responses ranging from 7% to 30%. The study population was made up of non-respondent patients to any other therapy; the DC vaccination showed an extremely low toxicity. 22 patients with metastatic melanoma received a DC vaccine in Forlì (Italy) since August 2001. Good correlation between immunologic response, clinical response and overall survival was found. A clinical trial on pulsed APC administration to patients with recurring prostate cancer is ready to be started in Torino (Italy), pending the Ministerial approval from a local cell factory.

Phenomena that occur at the meniscus in the CC mould have a major effect on product quality. The mechanism of slag rim behaviour and flux infiltration are reported based on the results of industrial characterization and of fluid dynamics modelling of the effect of oscillation and shell velocity. Lubrication stability is not established as the slag film happens to be broken down and renewed several times during casting. A mechanism of slag infiltration is put forward and the main factors for oscillation marks formation are pointed out.

Industrial trials conducted at Sidenor Basauri Works, and numerical modelling at Centro Sviluppo Materiali (CSM), have been combined in order to find a square 185 × 185 mm billet peripheral geometry that improves the quality of cast products by eliminating the occurrence of off corner cracks and depressions, and reducing the percentage of rejection. The idea is to change the square shape of the mould section to a new profile having a larger corner radius and outward bulging faces. Experimental trials using moulds with convex faces and larger corner radii resulted in an interesting decrease in the percentage of rejected bars. The presence of longitudinal defects has not been completely eliminated, but the adoption of moulds with larger corner radii has been demonstrated to be successful. Numerical modelling has been used to verify that the larger corner radius is the most important variable that guarantees the improved result, while it is less sensitive to different deflections of the faces. This e...

In order to obtain satisfactory workability properties required for defect free slab and strip production, the parameters of the casting process, e.g. cooling rate at the initial solidification for the alloy in question must, on the one hand, be carefully adjusted. On the other hand, controlling the characteristics of the solidification structure by chemical composition then takes on particular significance. The main aims of the work were to find out the influence of the phase transformation δ-γ during the initial solidification of different variants of AISI 304 slabs cast in the industrial process on the ferrite distribution on slab surface, and how this relationship could favour the improvements of the surface slab quality.This report contains the joint contributions of the collaborative ECSC project among Centro Sviluppo Materiali (CSM), Krupp Thyssen Nirosta (KTN) and the Department of Ferrous Metallurgy of Rheinisch Westfalische Technische Hochschule Aachen (RWTH).

Background: Antigen processing by dendritic cells (DC) exposed to specific stimuli has been well characterized in biological studies. Nonetheless, the question of whether autologous whole tumor lysates (as used in clinical trials) are similarly processed by these cells has not yet been resolved. Methods: In this study, we examined the transfer of peptides from whole tumor lysates to major histocompatibility complex class II molecules (MHC II) in mature dendritic cells (mDC) from a patient with advanced melanoma. Tumor antigenic peptides-MHC II proximity was revealed by Förster Resonance Energy Transfer (FRET) measurements, which effectively extends the application of fluorescence microscopy to the molecular level (

Family-based behavioral intervention has been demonstrated to be an effective and safe treatment for childhood obesity and should be considered a first-line treatment option. However, access to such intensive evidence-based treatment is limited and, currently, obesity care is dominated by high intensity behavioral treatment implemented in specialty clinics or less effective low intensity treatments implemented in primary care. However, capitalizing on the established and ongoing relationship between primary care providers and families, primary care providers have an invaluable role in early identification of overweight and obesity, and subsequent referral to an evidence-based treatment. Key aspects of effective treatment include: early intervention, moderate intensity to high intensity intervention of sufficient duration, multicomponent intervention targeting dietary modification, physical activity and behavioral strategies, family involvement and goals targeting family members, and follow-up contact during maintenance. The purpose of this review is to present the current empirically supported treatment options for pediatric obesity including primary care-based interventions and diagnostic tools, multicomponent behavioral intervention with a focus on family-based behavioral intervention, immersion treatment, and pharmacologic and surgical management.

Temozolomide (TMZ) is a new oral alkylating agent which has proven to be as active as dacarbazine (DTIC) in the treatment of melanoma, but with a lower toxicity. A multicentric phase II trial was conducted in an out-patient setting to determine the therapeutic activity and safety of TMZ in combination with interferon-alpha (IFN-alpha). From June 2000 to July 2001, 41 patients were recruited to receive TMZ 200 mg/m orally on days 1-5 every 28 days and with 5 MU IFN-alpha subcutaneously three times a week, continuously for eight cycles or until disease progression occurred. Of the 40 treated patients, two complete responses (5%) and three partial responses (7.5%) were observed, with a median duration of 4 months (range, 1.5-13.5 months). Thirteen patients (32.5%) had stable disease for a median of 2.5 months. Time to progression was 2.6 months and the median overall survival was 11.8 months. Nine patients (22.5%) developed brain metastases. The grade 4 toxicity observed in seven patients was of a transient haematological nature. This combination therapy is well tolerated but does not appear to increase the response rate or overall survival with respect to TMZ alone or to chemotherapeutic regimens. Further and more complex associations of these two drugs could be investigated in specific subsets of patients, in particular to evaluate its real efficacy in preventing brain metastases.

From June 1990 to October 1994, 111 advanced ovarian cancer patients with minimal (less than 2 cm) residual disease after platinum-based front-line chemotherapy and second-look laparotomy entered a cooperative randomized study aimed at evaluating the effectiveness and the toxicity of the addition of interferon-α2 to carboplatin, both intraperitoneally (ip) administered. Patients were randomized to receive either 3 courses of ip Carboplatin 400 mg/m 2 Day 1 q 28 days (54 pts) (CBDCA) or ip interferon-α 25 × 10 6 U Day 1 + ip carboplatin 400 mg/m 2 Day 2 q 28 days (57 pts) (CBDCA + IFN). Patients treated with interferon experienced more severe (WHO grade 3–4) leukopenia (28% vs 17.1%) and anemia (14% vs 4.2%). Fever ( P = 0.000) and flu-like syndrome ( P = 0.02) were significantly more frequent in the combination arm. No difference in gastroenteric, neurologic, or renal toxicity was observed. At a median follow-up time of 13 months (range 1–72) 71 patients showed a disease progression (31 CBDCA, 40 CBDCA + IFN) and 44 patients died (21 CBDCA, 23 CBDCA + IFN). Median progression-free survival was 11 months in the CBDCA group and 10 months in the CBDCA + IFN arm. Median survival was 22 and 29 months in CBDCA and CBDCA + IFN arm, respectively. In conclusion, intraperitoneal interferon-α does not seem to improve the results achievable with intraperitoneal carboplatin in this subset of patients, while the toxicity and the costs of the combination are consistently higher than with chemotherapy alone.

Hot tears form during solidification in the brittle region of the dendritic front. Most hot tearing criteria are based on solid and fluid mechanics, being the phenomenon strictly depending on the solid resistance to applied strains and on the liquid capability of filling the void spaces. Modelling both mechanisms implies the precise description of the dendritic morphology. To this scope, the theory of coalescence of the dendritic arms at grain boundaries of Rappaz et al. has been applied, in this work, to the columnar growth of carbon steels by means of a simple mathematical model. Depending on the alloy composition, solid bridging starts at solid fractions down to about 0.8 and up to above 0.995 (very low carbon). The morphology of the brittle region changes drastically with increasing carbon and adding other solutes. In particular, ferritic dendrites, typical of low carbon steels, tend to offer short and wide interdendritic spaces to the surrounding liquid making possible their complete filling, and few solid bridges; peritectic steels show the rise of austenite growing and bridging rapidly in the interdendritic spaces, preventing void formation; austenitic dendrites form long and narrow interdendritic spaces difficult to reach for the liquid and with a lot of solid bridges. Sulphur addition mainly acts in delaying the coalescence end, more markedly in ferritic dendrites.

Brief interventions encourage college students to eat more before drinking to prevent harm (Dimeff et al., 1999), although many women decrease their caloric intake (Giles et al., 2009) and the number of eating episodes (Luce et al., 2012) prior to drinking alcohol. Participants were 37 undergraduate women (24.3% Caucasian) who were recruited from a local bar district in the Midwest. This study examined whether changes in eating after intending to drink interacted with dietary restraint to predict accuracy of one's intoxication. Results indicated that changes in eating significantly moderated the relationship between dietary restraint and accuracy of one's intoxication level. After eating more food before intending to drink, women higher in restraint were more likely to overestimate their intoxication than women lower in restraint. There were no differences between women with high levels and low levels of dietary restraint in the accuracy of their intoxication after eating less food before intending to drink. Future research would benefit from examining interoceptive awareness as a possible mechanism involved in this relationship.

In this paper the authors describe the architecture and the functionalities of the Transport Integrated Platform (TIP), an Intelligent Transport Systems (ITS) application on Dangerous Good Transport on road in Italy. The TIP represents a System of Systems (SoS) application because it aims to manage different kinds of sub systems (each module of the platform) and different kind of entities (electronical devices, DG vehicles, drivers). TIP manages the DG fleet planning routing and the real time vehicles' tours, the customer orders, and other support tools for drivers including training, resource management and advanced data mining. TIP application aims at promoting a safe management of DG freight transport providing timely information to truck drivers and fleet managers about weather, traffic, emergency or other critical situations on the road infrastructures.

Bulimia nervosa and binge eating disorder are eating disorders that present significant concerns due to their prevalence, chronicity, and associated physical and psychological consequences. Body image disturbance is central to an understanding of both of these disorders. This article summarizes the literature on body image disturbance in these disorders, including overvaluation of weight and shape, body image distortion, body dissatisfaction, and body checking and body avoidance, and their relevance to assessment and treatment.

Drawing on Festinger's (1954) social comparison theory and its modern applications, this research investigated the relationship between upward appearance-focused social comparisons and body image disturbance using ecological momentary assessment, which allows for examination of these phenomena in their natural context. Participants were 91 undergraduate women who answered questionnaires five times per day for five days using Palm Personal Data Assistant (PDA) devices. Analyses were conducted using hierarchical linear modeling, which allows for examination of longitudinal data both within and across participants. Results revealed a positive relationship between upward appearance-focused social comparisons and body image disturbance. Upward appearance-focused social comparisons were associated with greater body image disturbance for those with higher levels of thin-ideal internalization and with greater body checking for women with lower levels of feminist beliefs. These findings further illuminate the nature of the relationship between social comparisons and body image disturbance.

Use and production of building materials, such as cement and concrete, is a major cause of global ecological problems with special reference to the overexploitation of non-renewable natural resources due to high temperature production processes, fossil fuels combustion, extraction of raw materials and non-recycling. In this paper, an environmental accounting method was applied to the production of cement and concrete in order to evaluate its dependence on natural resources even non-renewable and heavily relied on external inflows. The main steps of the production process (1) cement production, (2) transport of materials and (3) concrete mixing, were assessed by the emergy analysis (spelled with an “m”). This was performed to measure the amount of environmental resource use in terms of equivalent solar energy, extending the energy hierarchy principle to building materials. The resulting unit emergy values of cement and concrete were compared with previous emergy assessments in order to highlight how emergy analysis is sensitive to local context and reference system's boundaries. An Emergy Investment Ratio (EIR) was assessed and presented as a synthetic indicator of sustainability. Results showed a high dependence of cement and concrete production on external resource flows. Furthermore, the high value of EIR suggested a weak competitive capacity due to a high sensitivity to external instabilities.

In the last decade a great number of studies have been carried out on the possible use of biofuels in order to reduce greenhouse gas emissions. Among biofuels, biodiesel has gained considerable attention as the need to develop alternatives to traditional diesel fuel increases. The Italian parliament adopted directive 2003/30/CE from the European Parliament, in which the guidelines about future production and consumption of biofuels are reported: 1% and 2.5% of biofuels within 2005 and 2010 respectively. The aim of this work is to investigate the reduction in greenhouse gas emission obtained by using biodiesel in agricultural practises, and the role of renewable energy use at a local scale. Comparison between diesel and sunflower methyl ester was made from the point of view of an emission inventory, from production and combustion, by using different scientific tools, such as IPCC methodology and the Danish Life Cycle Assessment (LCA) EDIP Database. Results show that the use of sunflower methyl ester, other than the renewability of CO2 emitted, implies a general reduction of CO2 equivalent emissions of up to 57%.

The emergy concept was used to evaluate the environmental sustainability of the rearing process of Gilthead Sea Bream ( Sparus aurata ) in an inshore fish farming system in Gulf of La Spezia (Italy, Northwestern Mediterranean). Emergy is defined as the available energy of one kind previously used up directly and indirectly to make a product or service. The indices for the examined fish farm calculated from the emergy evaluation were compared with those of three other systems producing fishes: two intensive fish farming systems producing, respectively, salmons ( Salmo salar ) and tilapia ( Tilapia mariae ), the third system producing again S. aurata but in a semi-natural extensive manner. The emergy evaluation showed that the rearing of fishes in a sheltered area of Mediterranean Sea imposes a large stress on the environment. The greatest contributions to the emergy needed for production were due to fingerlings purchased and goods and services provided that are two external, non-renewable inputs to the system. The strong dependence of external contributions and the relative inability at exploiting local natural resources affect strongly the level of environmental sustainability of the productive process.

The First Principle of Thermodynamics is concerned with conservation, the Second Principle with evolution. Time, oscillations, instability and chaos are accorded scientific dignity by the Second Principle. Energy and matter are conservative properties of the biosphere (First Principle of Thermodynamics). Their organization and the information embodied in the history of energy and matter are evolutionary properties: such properties regard the thermodynamics of far-from-equilibrium systems. At equilibrium, energy and matter are blind; far from equilibrium they begin to see (Ilya Prigogine). This paper shows the emergence of novelties in some particular cases.

This paper presents a time series analysis of the Index of Sustainable Economic Welfare (ISEW). It is a measure, alternative to GDP, that in accordance with the principles of sustainability takes into consideration environmental and social aspects within the traditional economic accounting system. The Index is calculated for an Italian Province from 1971 to 2003 and it will be compared with the provincial GDP during the same period. A growing gap between the two monetary values (GPI grows faster then ISEW) has been occurring consistently with the national trend. This means that part of the wealth which GDP asserts does not correspond to welfare. The ISEW monetizes this gap in order to orient decisions for a more sustainable way of life and more correct policies.

This paper shows an application of the emergy analysis to the waste management system in the Province of Cagliari, Italy. It aims to consider the importance of waste management within a territorial system by assessing the environmental cost and gain due, directly and indirectly, to waste management processes. It also aims to investigate different steps of this process looking for potential critical points and available strategies for a sustainable waste management in its three phases of waste gathering, waste treatment and waste disposing. A landfill and an incinerator, located within the Province, are studied in order to consider their own environmental efficiency and their role in the waste management process. The emergy method (spelt with an “m”) is based on the assessment of all the inputs that supply the waste management system and its processes (emergy means energy memory). The expected outcomes are in the form of a comprehensive balance that shows the general behaviour of the system and its parts. Through the emergy synthesis, flows of energy and matter that are used within the process of waste management in the Province of Cagliari, are assessed by a common unit, namely the solar energy joule, and compared to each other. This is performed in order to evaluate how an integrated system including incinerator and dumps works in order to make choices and to achieve a sustainable waste management plan.

The SPIn-Eco project has provided very broad and precise data collection regarding the Province of Siena. These data and their elaborations have also been developed as a basis for the environmental certification of this organization. In this way, the Administration of the Province of Siena (the first Province in Italy) has reached its goal of obtaining better knowledge of the state of the system and of constructing its environmental management system (EMS) according to the environmental aspects directly and indirectly arising from the organization's activities. Indirect aspects are mainly related to the territorial monitoring and planning. Indicators based on the classical pressure–state–response approach, as well as more complex ones based on CO2 balance, emergy and ecological footprint analyses, have been used to assess the environmental performance of the EMS. This paper presents how this EMS is constructed, as well as the indicators that are used to analyze the system, paying particular attention to sustainability indicators.

The debate on different waste management practices has become an issue of utmost importance as human activities have overloaded the assimilative capacity of the biosphere. Recent Italian law on solid waste management recommends an increase in material recycling and energy recovery, and only foresees landfill disposal for inert materials and residues from recovery and recycling. A correct waste management policy should be based on the principles of sustainable development, according to which our refuse is not simply regarded as something to eliminate but rather as a potential resource. This requires the creation of an integrated waste management plan that makes full use of all available technologies. In this context, eMergy analysis is applied to evaluate three different forms of waste treatment and construct an approach capable of assessing the whole strategy of waste management. The evaluation included how much investment is needed for each type of waste management and how much "utility" is extracted from wastes, through the use of two indicators: Environmental yield ratio (EYR) and Net eMergy. Our results show that landfill is the worst system in terms of eMergy costs and eMergy benefits. Composting is the most efficient system in recovering eMergy (highest EYR) from municipal solid waste (MSW) while incineration is capable of saving the greatest quantity of eMergy per gram of MSW (highest net eMergy). This analysis has made it possible to assess the sustainability and the efficiency of individual options but could also be used to assess a greater environmental strategy for waste management, considering a system that might include landfills, incineration, composting, etc.

Adoptive immunotherapy trials with tumor infiltrating lymphocytes (TIL) and interleukin-2 (IL-2) were carried out in the treatment of advanced melanoma with a 34% of overall responses (OR). However, theoretically it should be of greater benefit as adjuvant therapy, especially in high-risk stages (stage III and resected stage IV). In a pilot study, 22 patients (aged 23-72 years) with stage III-IV melanoma who underwent radical metastasectomy were reinfused with TIL cultivated and expanded in vitro with IL-2 from surgically removed metastases. IL-2 (starting dose 12 x 10(6) IU/m2) was co-administered as a continuous infusion according to West's scheme. A total of 8/22 (36.3%) patients were disease-free (DF) at a median follow-up of 5 years. DF survival (DFS) and overall survival (OS) in the remaining 14 patients were 44% and 37% and 52% and 45% at 2 and 3 years, respectively. The CNS was the only site of disease recurrence in 57% of patients who relapsed. DF patients received a higher median dose of IL-2 than those who progressed (total dose 110 x 10(6) vs 86 x 10(6) IU/m2, respectively). The progressive reduction in IL-2 dosage allowed all patients to complete treatment without permanent grade 4 toxicity. The effects of tumor immunosuppression in lymphocytes inside the tumor (TCR z and e chains, p56lck, FAS and FAS-ligand) confirmed that the potential function of TIL, immunodepressed at the time of metastasectomy, was significantly restored after in vitro, culture with IL-2. Adjuvant adoptive immunotherapy with TIL and IL-2 seems to improve DFS and OS, in comparison with literature data. Further studies are required to determine its role in the adjuvant treatment of patients with high-risk melanoma.

Recent data in the literature indicate that antigen-presenting cells (APC) are inactive in tumour tissue because of local immunosuppression. Tumour-infiltrating lymphocyte (TIL) signal activation transducing mechanisms are also seriously impaired. Administration of granulocyte macrophage-colony stimulating factor (GM-CSF) may lead to APC recovery and interleukin (IL)-2 may restore local TIL activation. Moreover, IL-2 increases the systemic lymphocyte population, an event that seems to correlate with a better prognosis.The present phase I-II study was carried out to examine whether intralesional injection of GM-CSF followed by subcutaneous IL-2 would induce a clinical response in advanced, pretreated elderly melanoma patients.Sixteen patients over 60 years of age received intralesional GM-CSF (150 ng per lesion on day 1), generally divided between the two largest cutaneous lesions, followed by perilesional subcutaneous IL-2 (3,000,000 IU) for 5 days (days 3-7 inclusive) every 3 weeks.Four clinical responses [two partial (PR) and two minimal (MR)] (25%), which also involved lesions that had not been directly treated, and nine cases of stable disease were observed. The response duration for PR and MR was 9, 4, 4 and 2.5 + months, respectively. Stable disease (56%) recorded in the nine patients was short-term (3-6 months). Three patients rapidly progressed after two, two and one therapy cycles, respectively. The patient who reached the best PR had a fairly high absolute lymphocyte count (1600-2400/mm3). The second one, who reached complete remission after subsequent locoregional chemotherapy and hyperthermia, however, had a low absolute lymphocyte count that had doubled by the end of treatment. Blood lymphocyte values in the other patients were too varied to allow any correlation with clinical response. Therapy was well tolerated and only mild fever was observed, with the exception of one patient who had grade 3 fever, with muscle pain and arthralgia.Considering the very low toxicity observed, this treatment might be indicated in elderly patients for whom systemic therapy is no longer a viable option. Improved scheduling and timing could result from further studies.

Malignant pleural mesothelioma is often unresectable at diagnosis, is refractory to cytotoxic agents and is frequently complicated by pleural effusion. The expected survival range for patients with or without involvement of visceral pleura is respectively 1-9 and 9-12 months; mesothelioma-related pleural effusion severely impairs the patients' quality of life and easily relapses after conservative treatments. Intrapleural administration of IL-2 is reported to be effective both in tumor-associated malignant pleurisy and on primary mesothelioma, whereas few data exist about IL-2 systemic administration. In order to assess the palliative and therapeutic activity of IL-2 in unresectable pleural malignant mesothelioma with pleural effusion, we performed a phase II study on 31 consecutive patients (M/F 16/15; median age 61 years, range 40-84; PS ECOG 0 n=7; ECOG 1 n=15; ECOG 2 n=9; stage IA n=13; IB n=9; II n=7; IV=2) who received first-line therapy with intrapleural repeated instillation of 9000000 I.U. IL-2 twice/weekly for 4 weeks, after needle thoracenthesis. In nonprogressing patients, 3000000 I.U. IL-2 were subcutaneously administered thrice weekly for up to 6 months. Toxicity (WHO criteria) with intrapleural IL-2 consisted of grade 3 fever in 6/31 (19%) patients and of cardiac toxicity (failure) grade 3 in one patient (3%); toxicity during subcutaneous treatment was mild to moderate, mainly a flu-like syndrome. In 28/31 (90%) of patients there was no further or minimal (asymptomatic) pleural fluid collection (according to Paladine criteria); pleurisy relapsed only in 1/28 patients after 19 months. Tumor objective response (WHO criteria), evaluated by CT, occurred in seven patients (one CR and six PR; ORR 22%); ten patients achieved SD and 14 patients progressed. Median overall survival was 15 months (range 5-39) in all patients. IL-2 intrapleural administration followed by low-dose IL-2 subcutaneously in pleurisy-complicated malignant mesothelioma is feasible and active both in palliation of pleural effusion and on primary tumor, with manageable toxicity. The overall survival observed in nonprogressing patients warrants further randomized studies with IL-2 aimed to the patient outcome.

From June 1990 to October 1994, 111 advanced ovarian cancer patients with minimal (less than 2 cm) residual disease after platinum-based front-line chemotherapy and second-look laparotomy entered a cooperative randomized study aimed at evaluating the effectiveness and the toxicity of the addition of interferon-alpha2 to carboplatin, both intraperitoneally (ip) administered. Patients were randomized to receive either 3 courses of ip Carboplatin 400 mg/m2 Day 1 q 28 days (54 pts) (CBDCA) or ip interferon-alpha 25 x 10(6) U Day 1 + ip carboplatin 400 mg/m2 Day 2 q 28 days (57 pts) (CBDCA + IFN). Patients treated with interferon experienced more severe (WHO grade 3-4) leukopenia (28% vs 17.1%) and anemia (14% vs 4.2%). Fever (P = 0.000) and flu-like syndrome (P = 0.02) were significantly more frequent in the combination arm. No difference in gastroenteric, neurologic, or renal toxicity was observed. At a median follow-up time of 13 months (range 1-72) 71 patients showed a disease progression (31 CBDCA, 40 CBDCA + IFN) and 44 patients died (21 CBDCA, 23 CBDCA + IFN). Median progression-free survival was 11 months in the CBDCA group and 10 months in the CBDCA + IFN arm. Median survival was 22 and 29 months in CBDCA and CBDCA + IFN arm, respectively. In conclusion, intraperitoneal interferon-alpha does not seem to improve the results achievable with intraperitoneal carboplatin in this subset of patients, while the toxicity and the costs of the combination are consistently higher than with chemotherapy alone.

Purpose BMS-936558 is a monoclonal antibody that blocks the PD-1 co-inhibitory receptor expressed by activated T cells. This study describes its activity and safety in pts with previously treated advanced MEL. Methods BMS-936558 was administered IV q2wk to pts with various tumors at 0.1 - 10 mg/kg during dose-escalation and/or cohort expansion. Pts received up to 12 cycles (4 doses/cycle) of treatment or until unacceptable toxicity, confirmed progressive disease, or complete response. Clinical activity was assessed by RECIST v1.0. Results As of Feb 24, 2012, 104 MEL pts had received BMS-936558 at 0.1 (n = 17), 0.3 (n = 19), 1 (n = 31), 3 (n = 17), or 10 mg/kg (n = 20). ECOG performance status was 0/1/2 in 63/38/3 pts, respectively. Most pts (67/104) had received prior immunotherapy (IT); prior anti-CTLA-4, -PD-1, or -PD-L1 was not permitted. The number of prior therapies was 1 (39%), 2 (35%), or ≥3 (26%). Median therapy duration was 20 wks (range 2.0 - 121.7 wks). The incidence of grade 3 - 4 related AEs was 20% and included gastrointestinal (4%), endocrine (2%), and hepatobiliary disorders (1%). There were no drug-related deaths in MEL pts. Clinical activity (responses or prolonged stable disease) was observed at all doses (Table). Of the 26/94 (28%) evaluable responders, 19 (73%) are ongoing ranging from 1.9+ to 24.9+ months. For the 23 responders followed ≥6 months from first dose on study, 16 (70%) are progression free. ORs occurred in pts with visceral or bone metastases. Six pts (6%; 95% CI 2 - 13%) had prolonged SD (≥24 wk); 3 pts had a persistent decrease in target lesion tumor burden in the presence of new lesions and were not categorized as responders. Conclusions BMS-936558 had durable clinical benefit in pts with advanced MEL, including those who had received prior IT. Additional long-term follow-up data will be reported. Dose, (mg/kg) No. ptsa ORR, No. pts (%) [95% CI] PFSR at 24 wk (%) [95% CI] 0.1 14 4 (29) [8 - 58] 40 [13 - 66] 0.3 16 3 (19) [4 - 46] 31 [9 - 54] 1 27 8 (30) [14 - 50] 45 [26 - 65] 3 17 7 (41) [18 - 67] * 55 [30 - 80] 10 20 4 (20) [6 - 44] 30 [9 - 51] * 1 CR aResponse-evaluable pts dosed by 7/01/2011 ORR = objective response rate ([{CR + PR} ÷ n] × 100); PFSR = progression-free survival rate. Disclosure J. Sosman: Research Funding: Bristol-Myers Squibb (myself). M. Sznol: Consultant or Advisory Role: Bristol-Myers Squibb (myself, compensated). Research Funding: Bristol-Myers Squibb (myself, clinical trials funding). D.F. McDermott: Advisory Board Role: Bristol-Myers Squibb (myself). R. Carvajal: Research Funding: Bristol-Myers Squibb (myself). S.L. Topalian: Consultant or Advisory Role: Bristol-Myers Squibb (myself, immediate family member, uncompensated). Research Funding: Bristol-Myers Squibb (myself). J.M. Wigginton: Employment or Leadership Position: Bristol-Myers Squibb (myself, employment, compensated). Stock Ownership: Bristol-Myers Squibb (myself). G. Kollia: Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb/BMY stocks (myself). A. Gupta: Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). F.S. Hodi: Consultant or Advisory Role: Bristol-Myers Squibb (myself, uncompensated). Research Funding: Bristol-Myers Squibb (myself). All other authors have declared no conflicts of interest.