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Metastatic breast cancer (BC) has a poor prognosis and is largely considered incurable. A better understanding of the molecular determinants of BC metastasis could facilitate development of improved prevention and treatment strategies. We used lentiviral barcoding coupled to single-cell RNA sequencing to trace clonal and transcriptional evolution during BC metastasis and showed that metastases derive from rare pro-metastatic clones that are under-represented in primary tumors. Both low clonal fitness and high metastatic potential were independent of clonal origin. Differential expression and classification analyses revealed that the pro-metastatic phenotype was acquired by rare cells characterized by the concomitant hyper-activation of extracellular matrix remodeling and dsRNA-interferon signaling pathways. Notably, genetic silencing of key genes in these pathways (KCNQ1OT1 or IFI6, respectively) significantly impaired migration in vitro and metastasis in vivo, with marginal effects on cell proliferation and tumor growth. Gene expression signatures derived from the identified pro-metastatic genes predict metastatic progression in BC patients, independently of known prognostic factors. This study elucidates previously unknown mechanisms of BC metastasis and provides prognostic predictors and therapeutic targets for metastasis prevention.

The molecular determinants of breast cancer (BC) pro-metastatic phenotype are largely unknown. Here, we leveraged lentiviral barcoding coupled to single-cell RNA sequencing to trace clonal and transcriptional evolution during BC metastatization. We showed that metastases derive from rare pro-metastatic clones that are under-represented in primary tumors. Both low clonal-fitness and high metastatic-potential are independent of clonal origin. Differential expression and classification analyses revealed that the pro-metastatic phenotype is acquired in rare cells by concomitant hyper-activation of extracellular-matrix remodeling, dsRNA-interferon signaling, and stress-response pathways. Notably, genetic silencing of single pro-metastatic genes from different pathways significantly impairs migration in vitro and metastatization in vivo, with negligible effects on cell proliferation and tumor growth. In addition, gene-expression signatures from identified pro-metastatic genes predicts metastatic progression in BC patients, independently of known prognostic factors. This study elucidates previously unknown mechanisms of BC metastatization, and provides novel prognosis predictors and therapeutic targets for metastasis prevention.

Obesity correlates with hematologic malignancies including leukemias, but risk of specific leukemia subtypes like acute promyelocytic leukemia and underlying molecular mechanisms are poorly understood. We explored multiple datasets for correlation between leukemia, body mass index (BMI) and molecular features. In a population-based study (n=5.2 million), we correlated BMI with promyelocytic leukemia, and other acute myeloid, lymphoid or other leukemias. In cross-sectional studies, we tested BMI deviation in promyelocytic leukemia trial cohorts from that expected based on national surveys. We explored The Cancer Genome Atlas for transcriptional signatures and mutations enriched in promyelocytic leukemia and/or obesity, and confirmed a correlation between body mass and FLT3 mutations in promyelocytic leukemia cohorts by logistic regression. In the population-based study, hazard ratio per 5 kg/m2 increase was: promyelocytic leukemia 1.44 (95%CI: 1.0-2.08), non-promyelocytic acute myeloid leukemias 1.17 (95%CI: 1.10-1.26), lymphoid leukemias 1.04 (95%CI: 1.0-1.09), other 1.10 (95%CI: 1.04-1.15). In cross-sectional studies, body mass deviated significantly from that expected (Italy: P

Obesity is associated with a higher risk of developing many cancer types including acute promyelocytic leukaemia (APL), a subset of acute myeloid leukemias (AML) characterized by expression of the PML-RARα oncogene. The molecular mechanisms linking obesity and APL development are not known. To model clinical observations, we established a mouse model of diet-induced obesity using transgenic mice constitutively expressing PML-RARA α in the hematopoietic system (PML-RARα KI mice) fed either standard (SD) or high-fat (HFD) diets. HFD-fed PML-RARα KI mice developed leukaemia with reduced latency and increased penetrance, as compared to SD-fed mice. HFD leads to accumulation of DNA damage in hematopoietic stem cells (HSCs), but, surprisingly, this was not associated with mutational load gain, as shown by whole genome/exome sequencing of pre-leukemic and leukemic cells. Importantly, very few of the observed mutations were predicted to act as cancer drivers, suggesting the relevance of nongenetic mechanisms. HFD led to an expansion of hematopoietic progenitor cells with a concomitant reduction in long-term hematopoietic stem cells, and in the presence of PML-RARα this was also accompanied by an enhancement of in vitro and in vivo self-renewal. Interestingly, Linoleic Acid (LA), abundant in HFD, recapitulates the effect of HFD on the self-renewal of PML-RARα HPCs by activating the peroxisome proliferator-activated receptor delta (PPARδ), a central regulator of fatty acid metabolism involved in the promotion of cancer progression. Our findings have implications for dietary or pharmacological interventions aimed at counteracting the cancer-promoting effect of obesity.Key pointshigh fat diet (HFD) promotes APL leukemogenesis in mouse models, reproducing the exquisite sensitivity to obesity observed in humansalthough HFD leads to DNA damage and mutations, the molecular mechanism is nongenetic and linked to the transcription factor PPARδ

TPS12139 Background: Obesity at diagnosis is associated with an increase in breast cancer (BC) specific mortality. Behavioral interventions targeting obesity-related health choices offer a scalable approach to improve patient engagement in the community. Episodic Future Thinking (EFT) is a novel remotely delivered behavioral intervention which engages the science of prospection where participants mentally simulate positive, detailed, and personal events that can occur in the future. EFT targets a key behavioral economic measure – Delay Discounting (DD). As DD rate rises, an individual devalues future outcomes to a greater degree and has a higher bias for immediate gratification. EFT can decrease DD in obese patients, leading to improved diet quality and weight loss. However, valuation of the future may impact cancer survivors differently. Herein, we propose the first randomized Phase II trial evaluating adherence and changes in DD and body weight with 12-week remotely delivered EFT vs control in overweight or obese BC survivors. Methods: Eligible patients have a history of DCIS or stage 1 to 3 BC, BMI > 25 kg/m2, have completed surgery, radiation, and chemotherapy, and are motivated to lose weight. They are randomized 1:1 to a 12-week EFT intervention or control (Episodic Recent Thinking; ERT). ERT is a validated control in which patients imagine events in the recent past. Randomization will be stratified by baseline DD rate. There is an optional 12 week follow up period where patients can continue to receive EFT or ERT cues. DD will be measured at baseline and every 4 weeks for 24 weeks. The primary endpoint is adherence, measured by percentage of thrice daily smartphone prompts participants open and attend to during the 12-week trial. Secondary endpoints are changes in body weight and DD rate at 12 and 24 weeks and change in PROs (PROMIS scales), insulin resistance (HOMA-IR), hs-CRP, and diet quality (HEI 2015) at 12 weeks from baseline. With 20 subjects per arm, the study has 80% power to detect deviation of 14 points from a target adherence rate of 80% using a 1 sample t-test. The primary endpoint is evaluable for all subjects, regardless of drop-out. Secondary endpoints will be evaluated using a linear mixed effects model. Hypothesis tests and confidence intervals will be two-sided at 5% significance/95% confidence level. Since trial activation in November 2021, 9 of the planned 46 patients are enrolled. Accrual is closely integrated with the dedicated Ohio State University Comprehensive Cancer Center Survivorship Program. This work is supported by the Alliance Cancer Control Program Pilot Award (5UG1CA189823-08). Clinical trial information: NCT05012176.

532 Background: Limited compelling prospective and retrospective data regarding the added benefit of anti-HER2 therapy in the management of small, node-negative HER2-positive breast cancer (HER2+BC) exists, in part due to differences in outcome reporting, unmatched analyses, and a lack of head-to-head comparisons. As a result, national guideline committees find themselves unable to confidently recommend anti-HER2 therapy and clinicians are left to exercise clinical judgement on whether the use of anti-HER2 therapy should be considered for such patients. Methods: Our team performed a multi-institutional retrospective analysis using the ASCO CancerLinQ database, with a focus on clinical data from small, node-negative HER2+BC patients diagnosed between 2010 to 2021. We compared clinical outcomes between those who received adjuvant trastuzumab therapy, with or without chemotherapy, to those who did not, with our primary outcomes being invasive disease-free survival (iDFS) and overall survival (OS). We performed both a univariate and multivariate analysis, using a Cox proportional hazard model to control for factors including age, ethnicity, body mass index, hormone status, tumor grade, histology type, BRCA status, region, and smoking history. Additionally, a three-arm univariate analysis was performed comparing untreated patients to trastuzumab alone versus combination therapy. Results: In total, 1206 patients met inclusion criteria, including 779 patients who received trastuzumab with or without chemotherapy. We found a statistically significant improvement in both iDFS (HR 0.73, p = 0.01) and OS (HR 0.63, p = 0.027) on univariate analysis for those receiving anti-HER2 therapy. Similarly on multivariate analysis, iDFS (HR 0.75, p = 0.030) and OS (HR 0.61, p = 0.029) were improved in those who received therapy, regardless of tumor size. Our three-arm univariate analysis involving no treatment (n = 427), trastuzumab monotherapy (n = 169), and combination therapy (n = 578) found that iDFS was significantly improved for both treatment arms compared to observation alone (p = 0.006), whereas OS trended towards significance in the treatment arms but did not reach this target (p = 0.061). No significant difference was noted between treatment arms. Conclusions: Our analysis found a statistically significant improvement in iDFS and OS when patients with small, node negative, HER2+BC received adjuvant anti-HER2 therapy with or without chemotherapy as compared to observation. From our univariate three-arm comparison, it appears that trastuzumab provides the majority of benefit to patients in terms of DFS, but this result is exploratory. Further investigation is warranted, including meta-analyses to better characterize the degree of benefit seen with anti-HER2 treatment. For now, this data adds to evidence suggesting added benefit with therapy over observation.

Two archival sources of the late 15th century allow to outline some considerations and comparisons between the cost of living and book prices in Bologna. The first reports books stored in Bologna by the printer/bookseller Francesco Platone de’ Benedetti during his lifetime; the second, the most important for this study-case, reports the prices and sales of those books made by his heirs.

127 Background: Interleukin-12 (IL-12) is a proinflammatory cytokine that plays a critical role in regulating the transition from innate to adaptive immunity but has toxicity with systemic administration. M9241 is an immunocytokine composed of 2 IL-12 heterodimers, each fused to one of the H-chains of the NHS76 antibody, which has affinity for both single and double stranded DNA. Thus, M9241 targets delivery to regions of tumor necrosis where DNA has become exposed. NCT01417546, a phase I trial of M9241 at escalating doses, established safety and dosing (Strauss J et al, CCR 2019). This was the first use of M9241 in human subjects with solid tumors including PCa. Methods: Nine patients (pts) with PCa enrolled in the phase 1 study, not all of which were presented previously. M9241 was given subcutaneously every 4 weeks (0.1-21.8mcg/kg) or every 2 weeks (12-16.8mcg/kg). PSA declines and immune responses were evaluated including systemic cytokine levels and 30 markers on 158 circulating immune cell subsets. Results: Nine PCa pts were treated with NHS-IL12 and 8 were evaluable for response, including 6 pts with biochemical recurrence and 2 with metastatic castration resistant prostate cancer (one patient discontinued the study treatment after 1 dose due to grade 3 elevation in ALT). There were no adverse events (AEs) of grade >4. Additional grade 3 toxicities included one each of: leukopenia, neutropenia and lymphopenia. The most common AEs of any grade were lymphopenia (77.8%), fatigue (55.6%), and ALT elevation (55.6%). 5 of 8 (62.5%) had PSA declines ranging from 8-42%. After treatment with M9241, evaluable pts had increases in systemic IL-10, TNF and INFg. Additional immune changes included increases in activated subpopulation of natural killer (NK) cells, consistent with the phase 1 experience. Conclusions: M9241 was found to be safe and well tolerated in PCa pts. PSA declines occurred in 5 of 8 evaluable pts. As with the phase 1 study, increases in NK subpopulations were seen in the small number of evaluable pts. These preliminary findings of a necrosis-targeting immunocytokine will be evaluated further in combination studies with cytotoxic therapy. M9241 is currently being evaluated in combination with docetaxel in metastatic prostate cancer (NCT04633252). Clinical trial information: NCT01417546.

The study investigates the attitude towards cosmetic surgery in a sample of 296 adoles-cents (39% boys; 61% girls) aged 14 to 18 (M = 15.78; DS = 1.3) attending high school in the North of Italy. Three are the main aims of the present study: 1) to evaluate gender differences regarding: body perception, body satisfaction and attitude toward cosmetic surgery; 2) to investigate, separately for gender, relationship between: body perception and body satisfaction, BMI and attitude toward cosmetic surgery; 3) to evaluate, separately for gender, the presence of significative differensces due to pubertal status in relation to attitude toward cosmetic surgery. Participants completed a self-report questionnaire investigating body perception and satisfaction, pubertal status, body mass index and attitude toward cosmetic surgery. The results indicate that girls are more interested in cosmetic surgery, especially when they are not satisfied with their appearance and their weight. Moreover they identify intrapersonal advantages in cosmetic surgery. The link between body dissatisfaction and interest in cosmetic surgery emerged also among males, who identify mainly in cosmetic surgery social advantages. The study contributes to better understand the growing interest in cosmetic surgery by adolescents, suggesting important implications for the design of health promotion interventions.

Background Development of metastases and drug resistance are still a challenge for a successful systemic treatment in breast cancer (BC) patients. One of the mechanisms that confer metastatic properties to the cell relies in the epithelial-to-mesenchymal transition (EMT). Moreover, both EMT and metastasis are partly modulated through epigenetic mechanisms, by repression or induction of specific related genes. Methods We applied shRNAs and drug targeting approaches in BC cell lines and metastatic patient-derived xenograft (PDX) models to inhibit WDR5, the core subunit of histone H3 K4 methyltransferase complexes, and evaluate its role in metastasis regulation. Result We report that WDR5 is crucial in regulating tumorigenesis and metastasis spreading during BC progression. In particular, WDR5 loss reduces the metastatic properties of the cells by reverting the mesenchymal phenotype of triple negative- and luminal B-derived cells, thus inducing an epithelial trait. We also suggest that this regulation is mediated by TGFβ1, implying a prominent role of WDR5 in driving EMT through TGFβ1 activation. Moreover, such EMT reversion can be induced by drug targeting of WDR5 as well, leading to BC cell sensitization to chemotherapy and enhancement of paclitaxel-dependent effects. Conclusions We suggest that WDR5 inhibition could be a promising pharmacologic approach to reduce cell migration, revert EMT, and block metastasis formation in BC, thus overcoming resistance to standard treatments.

Background Single-cell sequencing technologies provide unprecedented opportunities to deconvolve the genomic, transcriptomic or epigenomic heterogeneity of complex biological systems. Its application in samples from xenografts of patient-derived biopsies (PDX), however, is limited by the presence of cells originating from both the host and the graft in the analysed samples; in fact, in the bioinformatics workflows it is still a challenge discriminating between host and graft sequence reads obtained in a single-cell experiment. Results We have developed XenoCell, the first stand-alone pre-processing tool that performs fast and reliable classification of host and graft cellular barcodes from single-cell sequencing experiments. We show its application on a mixed species 50:50 cell line experiment from 10× Genomics platform, and on a publicly available PDX dataset obtained by Drop-Seq. Conclusions XenoCell accurately dissects sequence reads from any host and graft combination of species as well as from a broad range of single-cell experiments and platforms. It is open source and available at https://gitlab.com/XenoCell/XenoCell.

Chinas Mittelschicht wachst in einem bisher nie da gewesenen Tempo. Sie explodiert regelrecht. Bereits heute hat China die groste Mittelschicht der Welt. Ende 2016 lebten in China rund 793 Mio. Menschen in stadtischen Regionen. Naturlich gelten nicht automatisch alle Stadtbewohner als Mittelklasse, aber nach aktuellen Prognosen der Unternehmensberatung McKinsey & Co. werden bis 2022 uber 550 Mio. Menschen in China als Mittelschicht betrachtet.

Facebook, Instagram, YouTube, Snapchat – das sind die in Deutschland gangigsten Social-Media-Kanale. Wir teilen Erlebnisse, egal ob per Text, Foto oder Video, wir tauschen uns aus und lassen andere an unserem Leben teilhaben. Mittlerweile nutzen auch Unternehmen aller Branchen diese Kanale verstarkt fur ausgeklugelte Marketingaktionen. Denn sie wissen: Durch Social-Media-Aktivitaten konnen sie ihre Zielgruppe mitunter direkt ansprechen und mit ihnen ins Gesprach kommen. In China geht Social Media anders.

Wie viele seiner Regierungsinitiativen ist auch Chinas Multi-Billionen-Dollar-Initiative One Belt, One Road (OBOR-Initiative) zum Teil durch die wirtschaftliche Notwendigkeit motiviert, Uberkapazitaten in der eigenen Wirtschaft abzubauen und Arbeitsplatze fur die eigene, grose Bevolkerung zu schaffen. China leidet unter erheblichen Uberkapazitaten in wichtigen Rohstoff- und Baustoffsektoren wie beispielsweise Stahl und Zement und die Seidenstrase hilft der chinesischen Regierung, die geplagten Branchen zu entlasten.

„Mobile First“ hat sich in den vergangenen zwei bis drei Jahren als regelrechtes Buzzword etabliert und mobiles Einkaufen wird als Zukunft des E-Commerce gehandelt. Die Grunde liegen auf der Hand: Das Handy kann uberall mitgenommen werden und wenn wir ganz ehrlich sind, haben wir unser Smartphone tatsachlich immer griffbereit. In China ist das Mobiltelefon kaum noch wegzudenken. Der Alltag der Chinesen wird mittlerweile so stark von mobilen Anwendungen gesteuert, dass man sich kaum noch vorstellen kann, dass es mal eine Zeit vor dem Handy gab.

Mitarbeiterlose Supermarkte, die zudem auch noch unbemannt durch die Stadt fahren oder Bezahlen per Gesichtserkennung? Klingt nach Zukunftsmusik? Vielleicht hier bei uns in Deutschland. In China gibt es heute bereits verschiedenste Konzepte und auch Anbieter von mitarbeiterlosen Supermarkten. Und es werden gefuhlt schnell mehr. Die Modekette Jack & Jones hat im Dezember 2017 in ihrem Geschaft in Shenzhen die Bezahlung per Gesichtserkennung gelauncht und der autonom fahrende Supermarkt Moby Mart hat im Sommer 2016 erste Testfahrten durch die Strasen Shanghais gemacht. Der Kreativitat sind keine Grenzen gesetzt.

Im Jahr 2017 verreisten rund 2,8 Mrd. Chinesen innerhalb ihres Landes. China ist damit der groste Tourismusmarkt der Welt. Rund 129 Mio. Chinesen haben ihre Reisepasse in die Hand genommen und sind im Ausland auf Reisen gegangen. Der chinesische Prasident Xi Jinping geht davon aus, dass allein in den nachsten funf Jahren 700 Mio. Chinesen ins Ausland reisen werden. Das sind etwa so viele Menschen wie in ganz Europa leben.

Die Bevolkerung in den Stadten wachst exponentiell und die Stadtverwaltungen sind konstant gefordert, dieses Wachstum zu bewaltigen. Schon heute lebt mehr als die Halfte der chinesischen Bevolkerung in stadtischen Gebieten und diese Zahl wachst rasant weiter. In China gibt es Stadte, die erst in den letzten zehn Jahren zu Megastadten geworden sind. Und da immer mehr Menschen in diese Stadte ziehen, treten laufend neue Probleme auf oder die bestehenden Probleme verschlimmern sich. In China werden intelligente Losungen fur diese Probleme entwickelt – es herrscht ein regelrechtes Smart Movement.

Google, Apple, Facebook und Amazon, kurz GAFA genannt, sind die grosen Tech-Giganten unserer Zeit. Und sie haben alle eine Gemeinsamkeit, namlich ihren Geburtsort: Silicon Valley. Es sind diese Konzerne, die die digitale Transformation in vielen Bereichen unserer Wirtschaft und Gesellschaft rasant vorantreiben. Es sind die Schmieden der Innovation. Moment. Sind sie das wirklich? Wahrend die vier Grosen sich in aller Welt einen bedeutenden Namen geschaffen haben, hat im fernen China eine fast unbemerkte Tech-Revolution durch vor allem drei grose Player stattgefunden: Baidu, Alibaba und Tencent, kurz BAT.

In Deutschland hat sich der Handel im vergangen Jahrzehnt konstant weiterentwickelt und sich Schritt fur Schritt von einem rein stationaren Handel hin zu E-Commerce geoffnet. In China hingegen gab es diese Transformation von offline zu online nicht: Der E-Commerce-Markt fand direkt mit seiner Einfuhrung sehr grose Akzeptanz und boomte. Wahrend deutsche Handler mitten in der Transformation stecken und kundenfokussierte Losungen rund um den Trend Omnichannel, sprich Einkaufen uber alle verfugbaren Kanale, entwickeln und implementieren, geht der Trend in China zwar auch in Richtung Omnichannel, aber von einem anderen Ausgangspunkt aus: Die Entwicklung geht von mobilen Anwendungen aus.

Chinas Millennials sind eine neue Generation von Verbrauchern, die die Zukunft des Handels mitgestalten werden. Mehr als 400 Mio. stark und in der Zeit der Ein-Kind-Politik geboren und aufgewachsen – das sind wohl ihre wichtigsten Merkmale. Es sind die „kleinen Kaiser und Kaiserinnen“, denen ihre Eltern alles nur Denkbare ermoglichten. Es ist eine ganze Generation von Einzelkindern. Und genau das unterscheidet sie von Millennials aus anderen Landern.

Mitte des 21. Jahrhunderts war China die Produktionsstatte der ganzen Welt. Uberall gab es Produkte „made in China“ zu kaufen. Was sie symbolisierten, daruber gab es weltweit wenig Zweifel: billige Massenware, die am menschlichen Fliesband produziert wurde. Arbeitskraft war gunstig und Waren liesen sich so gunstig in grosen Massen herstellen. Allerdings ist dem heute nicht mehr so.

Accumulating evidence has proved that deregulation of ?Np63 expression plays an oncogenic role in head and neck squamous cell carcinomas (HNSCCs). Besides p63, the type 1-insulin-like growth factor (IGF) signalling pathway has been implicated in HNSCC development and progression. Most insulin/IGF1 signalling converges intracellularly onto the protein adaptor insulin receptor substrate-1 (IRS-1) that transmits signals from the receptor to downstream effectors, including the PI3K/AKT and the MAPK kinase pathways, which, ultimately, promote proliferation, invasion, and cell survival. Here we report that p63 directly controls IRS1 transcription and cellular abundance and fosters the PI3K/AKT and MAPK downstream signalling pathways. Inactivation of ?Np63 expression indeed reduces tumour cell responsiveness to IGF1 stimulation, and inhibits the growth potential of HNSCC cells. In addition, a positive correlation was observed between p63 and IRS1 expression in human HNSCC tissue arrays and in publicly available gene expression data. Our findings indicate that aberrant expression of ?Np63 in HNSSC may act as an oncogenic stimulus by altering the IGF signalling pathway.

2640 Background: Brachyury, a transcription factor, plays an integral role in epithelial-to-mesenchymal transition, metastasis, poor prognosis, and resistance to chemotherapy. It is expressed in many tumor types, and rare in normal tissue, making it an ideal immunologic target. BN-Brachyury comprises heterologous vaccination with recombinant MVA priming followed by FPV boosting, each encoding transgenes for brachyury and three costimulatory molecules (B7-1, ICAM1, and LFA-3). Heterologous prime boost approach is intended to optimize immunogenicity, as previously observed. Methods: Pts with metastatic solid tumors were treated with 2 monthly doses of MVA-brachyury SC at the previously tested dose, 2.2 x 109 infectious units (IU), followed by FPV-brachyury SC, 1 x 109 IU, for 6 monthly doses and then every 3 months for up to 2 years. The primary objective was to determine safety and tolerability and establish the RP2D. Immune assays were conducted to evaluate immunogenicity. Results: In 10 pts (3 chordoma, 6 GI, 1 papillary thyroid), no dose-limiting toxicities or serious treatment-related adverse events (TRAEs) were observed. The only Grade 3 TRAE was sedation associated with fever, which resolved spontaneously and did not recur with subsequent cycles. All other TRAEs were Grade 1 or 2; the most common was injection-site reaction in all patients. Five pts have had stable disease for > 24 wks (per RECIST v1.1) and remain on treatment. One pt with chordoma, for which BN-Brachyury was granted orphan drug designation, has had a 13.2% reduction in tumor size. As previously demonstrated, brachyury-specific T cell responses were observed, as were responses against cascade antigens (non-encoded antigens) CEA and MUC-1. Conclusions: Heterologous MVA- and FPV-brachyury is well tolerated and induced immune responses to brachyury and cascade antigens, suggesting induction of immunologically relevant tumor cell destruction. These data have informed combining BN-Brachyury with checkpoint inhibition (NCT03493945) and radiation (NCT03595228) to evaluate potential for synergetic activity in selected populations. Clinical trial information: NCT03349983.

The malleable nature of the self led researchers to investigate the meaning of virtual identity by exploring virtual self-representation through avatars and its association with users’ identity. The present study aims to investigate the changes in virtual body-representation in adolescence related to age levels and sex and the association with adolescents’ self-esteem and body esteem. Anthropometric features, body esteem and self-esteem were used to assess adolescents’ body image and identity. The scoring code of the “Drawing Me” graphical test was used to evaluate the avatars. The sample is composed of 63 adolescents of different ages—early, middle and late adolescence—balanced by sex. Results show that the creation of a digital avatar changes with age and is partially associated with adolescents’ perceptions in terms of body esteem and self-esteem. Moreover, the creation of avatars occurs differently for boys, who enrich their avatars with many sexual features, than for girls, who prefer to detail their avatars’ clothing to enrich them. Critical reflections and implications for psychological interventions that may use avatars to investigate adolescents’ identity in integration with other tools will be discussed.

Malignant Mesothelioma is a highly aggressive cancer, which is difficult to diagnose and treat. Here we describe the molecular, cellular and morphological characterization of a syngeneic system consisting of murine AB1, AB12 and AB22 mesothelioma cells injected in immunocompetent BALB/c mice, which allows the study of the interplay of tumor cells with the immune system. Murine mesothelioma cells, like human ones, respond to exogenous High Mobility Group Box 1 protein, a Damage-Associated Molecular Pattern that acts as a chemoattractant for leukocytes and as a proinflammatory mediator. The tumors derived from AB cells are morphologically and histologically similar to human MM tumors, and respond to treatments used for MM patients. Our system largely recapitulates human mesothelioma, and we advocate its use for the study of MM development and treatment. Malignant Mesothelioma is a highly aggressive cancer, which is difficult to diagnose and treat. Here we describe the molecular, cellular and morphological characterization of a syngeneic system consisting of murine AB1, AB12 and AB22 mesothelioma cells injected in immunocompetent BALB/c mice, which allows the study of the interplay of tumor cells with the immune system. Murine mesothelioma cells, like human ones, respond to exogenous High Mobility Group Box 1 protein, a Damage-Associated Molecular Pattern that acts as a chemoattractant for leukocytes and as a proinflammatory mediator. The tumors derived from AB cells are morphologically and histologically similar to human MM tumors, and respond to treatments used for MM patients. Our system largely recapitulates human mesothelioma, and we advocate its use for the study of MM development and treatment

The receptor for advanced glycation end-products (RAGE) is involved in the onset and progression of several inflammatory diseases. The RAGE primary transcript undergoes numerous alternative splicing (AS) events, some of which are species-specific. Here, we characterize the mouse-specific mRAGE_v4 splice variant, which is conserved in rodents and absent in primates. mRAGE_v4 derives from exon 9 skipping and encodes a receptor (M-RAGE) that lacks 9 amino acids between the transmembrane and the immunoglobulin (Ig) domains. RNA-Seq data confirm that in mouse lung mRAGE_v4 is the most abundant RAGE mRNA isoform after mRAGE, which codes for full-length RAGE (FL-RAGE), while in heart all RAGE variants are almost undetectable. The proteins M-RAGE and FL-RAGE are roughly equally abundant in mouse lung. Contrary to FL-RAGE, M-RAGE is extremely resistant to shedding because it lacks the peptide motif recognized by both ADAM10 and MMP9, and does not contribute significantly to soluble cRAGE formation. Thus, a cassette exon in RAGE corresponds to a specific function of the RAGE protein-the ability to be shed. Given the differences in RAGE AS variants between rodents and humans, caution is due in the interpretation of results obtained in mouse models of RAGE-dependent human pathologies.

Lo sviluppo puberale si configura come un processo critico per l'adolescente. Numerosi cambiamenti puberali comportano una continua e necessaria ri-organizzazione mentale ed affettiva della propria immagine corporea. L'accettazione di tali cambiamenti sembra essere piů faticosa per le adolescenti femmine che sono piů vulnerabili di fronte ai cambiamenti puberali. Proprio nei gruppi femminili si riscontrano infatti maggiori comportamenti volti ad a modificare il proprio aspetto fisico e il proprio peso. Il presente studio si propone di indagare la percezione e soddisfazione dell'immagine corporea in due gruppi di adolescenti femmine di etŕ compresa tra i 12 e i 17 anni (M = 14.8; d.s. = 1.7) attraverso l'impiego di strumenti quantitativi self-report combinati con il "Mi disegno", un strumento qualitativo in cui si chiede una riproduzione grafica del proprio corpo. Il gruppo clinico č composto da 60 ragazze affette da Disturbi del Comportamento Alimentare (DCA), mentre il gruppo normativo da 60 ragazze non affette da alcun disturbo alimentare (Non-DCA). I risultati ricavati dai questionari confermano la maggiore insoddisfazione e percezione negativa per il proprio corpo e peso da parte del gruppo clinico. I disegni mostrano evidenti differenze tra i due gruppi, offrendo uno sguardo piů approfondito e qualitativamente ricco di aspetti affettivi/emotivi che caratterizzano la raffigurazione del corpo, non emersi con i questionari. Questi primi risultati invitano a proseguire nell'impiego del disegno come uno strumento che puň affiancarsi ad altre misure piů quantitative al fine di ottenere un quadro sempre piů esaustivo di un costrutto quale la percezione dell'immagine corporea che ha un carattere multidimensionale

Obesity increases risk for multiple tumors, but impact on leukemia and its underlying molecular mechanism are poorly understood. Studies from our group and others showed that risk and outcome of Acute Promyelocytic Leukemia (APL) are more strongly associated with obesity than other hematological neoplasms. Intriguingly, in 2 independent cohorts (Italian and TCGA), obesity was associated with ~4 fold higher incidence of internal tandem duplications of the leukemogenic kinase FLT3 (FLT3-ITD), the first example of obesity-associated genetic alterations in cancer (unpublished). Here we propose a molecular mechanisms underlying obesity-associated leukemogenesis through our studies in murine models. Exposure to High fat Diet (HFD), an established model of obesity-related pathology, strongly accelerated disease onset and mortality in 3 murine models of hematological cancer: PML-RARa knockin (PRKI), developing an APL-mimicking disease; FLT3ITD knockin (FIKI) developing myeloproliferation; a new double PRKI-FIKI knockin mouse, developing APL-like disease but, surprisingly, with delayed latency compared to PRKI, presumably due to the known exhaustion of hematopoietic stem cells (HSC) associated with FLT3ITD. Preleukemic HSCs from HFD PRKI mice showed increased DNA damage in Comet assays, but surprisingly this was not associated with increased mutational load as revealed by a novel whole genome sequencing-based method. Instead, HSCs derived from HFD PRKI mice showed enhanced self-renewal in in vitro replating assays. Similarly, in the FIKI model we observed enhanced engraftment in serial competitive transplantation experiments in HFD-fed recipients. Delving more deeply in the molecular mechanisms, through bioinformatic analysis of RNAseq data from the TCGA we found upregulation of the linoleic acid (LA) pathway in obese APL patients. LA is the richest fatty acid in HFD and in many western diets, thus a likely candidate for mediating HFD activity. LA significantly enhanced PRKI serial replating efficiency; this was abolished by pharmacologically blocking LA metabolism through a 5-lipoxygenase inhibitor or its transcriptional effects through a PPARd inhibitor. In the FIKI model and in a FLT3ITD-inducible cell line, we revealed a previously unappreciated induction of ER stress by FLT3ITD, likely to underlie FLT3ITD-induced HSC exhaustion. HFD (in vivo) and LA (in vitro) relieved FLT3ITD-induced ER stress, as revealed by the attenuation of markers of adaptive response to ER stress (Unfolded Protein Response and RNA IRE1-dependent RNA decay). In conclusion, our study suggests a novel and somewhat counterinuitive model for obesity-associated cancerogenesis: rather than inducing cellular stress, HFD-induced obesity enhances the self-renewal of preleukemic stem cells through LA-mediated alleviation of oncogene-induced proteotoxic stress Citation Format: Luca Mazzarella, Paolo Falvo, Annagiulia Sanarico, Elena Gatti, Piergiuseppe Pelicci. Obesity favours leukemogenesis through enhanced preleukemic stem cell self renewal via polyunsaturated fatty acid-dependent ER stress relief [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 450.