A nonequilibrium strategy for fast target search on the genome

Vital biological processes such as genome repair require fast and efficient binding of selected proteins to specific target sites on DNA. Here we propose an active target search mechanism based on "chromophoresis", the dynamics of DNA-binding proteins up or down gradients in the density of epigenetic marks, or colours (biochemical tags on the genome). We focus on a set of proteins that deposit marks from which they are repelled---a case which is only encountered away from thermodynamic equilibrium. For suitable ranges of kinetic parameter values, chromophoretic proteins can perform unidirectional motion and are optimally redistributed along the genome. Importantly, they can also locally unravel a region of the genome which is collapsed due to self-interactions and "dive" deep into its core, for a striking enhancement of the efficiency of target search on such an inaccessible substrate. We discuss the potential relevance of chromophoresis for the location of DNA lesions.Comment: 5 pages, 5 figure

oncological outcome of fat grafting for breast reconstruction after cancer

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Die Bedeutung von Rhamnolipiden in der Pathogenese epithelialer Pseudomonas aeruginosa Infektionen

Pseudomonas aeruginosa (P. aeruginosa) ist ein ubiquitär vorkommendes, gramnegatives, monotrich begeißeltes, aerob lebendes Stäbchenbakterium. Das opportunistisches Pathogen befällt Menschen, Tiere, Insekten, Nematoden und Pflanzen und ist unter anderem aufgrund seiner Toleranz gegenüber einer Vielzahl von Desinfektionsmitteln und Antibiotika einer der wichtigsten Verursacher von nosokomialen Infektionen. Die Ergebnisse dieser Arbeit geben einen Hinweis darauf, dass P. aeruginosa das angeborene Immunsystem mit Hilfe von Rhamnolipid, einem vom Bakterium selbst produzierten Surfactant, umgeht. In der vorliegenden Arbeit konnte nachgewiesen werden, dass die Flagellin-induzierte hBD2-Expression in humanen Keratinozyten durch bakterielle Überstände von P. aeruginosa, die in der stationären Phase generiert wurden, supprimiert wird. Der supprimierende Faktor konnte in Versuchen als hitzestabil und durch Säure ausfällbar identifiziert werden. Außerdem blieb er bei Behandlung mit Proteinase K unbeeinflusst, es handelt sich deshalb nicht um ein Protein. Weitere Untersuchungen konnten den Faktor als Rhamnolipid identifizieren. Eine Kostimulation von Keratinozyten mit aufgereinigtem Rhamnolipid in Mengen unterhalb der zytotoxischen Konzentration zusammen mit Flagellin zeigte ebenfalls eine Supprimierung der induzierten hBD2-Expression. Ähnliche Effekte konnten bei Kostimulation der Keratinozyten mit Flagellin und BAPTA-AM, einem intrazellulären Calciumchelator, erreicht werden. Neben Flagellin als Induktor ließ sich auch die PMA-induzierte hBD2-Expression supprimieren. Dies lässt vermuten, dass Rhamnolipide mit Calcium-abhängigen Signalkaskaden, wie der PKC-Signalkaskade, interferieren. Die Versuche dieser Arbeit zeigen damit einen Weg, über den es P. aeruginosa möglich ist, sich auf der Haut zu etablieren, ohne seinen Hauptpathogenitätsfaktor, das Flagellin, verstecken zu müssen

Integrating transposable elements in the 3D genome

Chromosome organisation is increasingly recognised as an essential component of genome regulation, cell fate and cell health. Within the realm of transposable elements (TEs) however, the spatial information of how genomes are folded is still only rarely integrated in experimental studies or accounted for in modelling. Whilst polymer physics is recognised as an important tool to understand the mechanisms of genome folding, in this commentary we discuss its potential applicability to aspects of TE biology. Based on recent works on the relationship between genome organisation and TE integration, we argue that existing polymer models may be extended to create a predictive framework for the study of TE integration patterns. We suggest that these models may offer orthogonal and generic insights into the integration profiles (or "topography") of TEs across organisms. In addition, we provide simple polymer physics arguments and preliminary molecular dynamics simulations of TEs inserting into heterogeneously flexible polymers. By considering this simple model, we show how polymer folding and local flexibility may generically affect TE integration patterns. The preliminary discussion reported in this commentary is aimed to lay the foundations for a large-scale analysis of TE integration dynamics and topography as a function of the three-dimensional host genome

Simulating topological domains in human chromosomes with a fitting-free model

We discuss a polymer model for the 3D organization of human chromosomes. A chromosome is represented by a string of beads, with each bead being "colored" according to 1D bioinformatic data (e.g., chromatin state, histone modification, GC content). Individual spheres (representing bi- and multi-valent transcription factors) can bind reversibly and selectively to beads with the appropriate color. During molecular dynamics simulations, the factors bind, and the string spontaneously folds into loops, rosettes, and topologically-associating domains (TADs). This organization occurs in the absence of any specified interactions between distant DNA segments, or between transcription factors. A comparison with Hi-C data shows that simulations predict the location of most boundaries between TADs correctly. The model is "fitting-free" in the sense that it does not use Hi-C data as an input; consequently, one of its strengths is that it can - in principle - be used to predict the 3D organization of any region of interest, or whole chromosome, in a given organism, or cell line, in the absence of existing Hi-C data. We discuss how this simple model might be refined to include more transcription factors and binding sites, and to correctly predict contacts between convergent CTCF binding sites

Donne immigrate e screening cervicale nel Veneto

According to the literature, women coming from countries with strong migratory pressure are at a greater risk of cancer of the cervix with respect to Italian women. This is connected with the fact that women born outside Italy are less likely to undergo a cervical smear. In the Veneto Region the official immigrant population is equivalent to approximately 10% of the total population. This article analyzes the utilization of cervical smear from immigrant women in the Veneto Region, taking into account the smears performed both inside and outside organized screening programmes. Data have been gathered both from the archives of the screening programmes of the Local Health Authorities and from PASSI, a national surveillance system based on a standardized questionnaire administered through telephone interviews. The screening crude participation rate among foreign women was 45.3%, only slightly lower than the one of Italian women. The participation is lower in women from Asia and in women above 50 years. The percentage of positive smear tests was 2.7% among Italian women and 4.0% among foreign women. Compliance to colposcopy has been 89.9% for Italian women and 88.1% for foreign women. The detection rate of cervical intraepithelial neoplasia grade II or worse (CIN II+ diagnoses) in foreign women has been twofold the one detected in Italian women. If we consider the number of smear tests carried out in the last three years and outside the context of screening programmes, the number of women who have undergone a pap smear is much higher among Italian women, women 39-45 years old and women with a high level of education and without particular economic difficulties. The opposite is true for the organized screening programmes, where the differences according to age, level of education, economic difficulties and citizenship are reduced. These data confirm that women coming from countries with strong migratory pressure are at a greater risk of cancer of the cervix with respect to Italian women. A decrease in inequalities (in terms of education level, socio-economical status and nationality) is shown when considering the access to the screening programs

Incorporating weekly carboplatin in anthracycline and paclitaxel-containing neoadjuvant chemotherapy for triple-negative breast cancer: propensity-score matching analysis and TIL evaluation

Background The generation of data capturing the risk-benefit ratio of incorporating carboplatin (Cb) to neoadjuvant chemotherapy (NACT) for triple-negative breast cancer (TNBC) in a clinical practice setting is urgently needed. Tumour-infiltrating lymphocytes (TILs) have an established role in TNBC receiving NACT, however, the role of TIL dynamics under NACT exposure in patients receiving the current standard of care is largely uncharted. Methods Consecutive TNBC patients receiving anthracycline-taxane [A-T] +/- Cb NACT at three Institutions were enrolled. Stromal-TILs were evaluated on pre-NACT and residual disease (RD) specimens. In the clinical cohort, propensity-score-matching was used to control selection bias. Results In total, 247 patients were included (A-T = 40.5%, A-TCb = 59.5%). After propensity-score-matching, pCR was significantly higher for A-TCb vs A-T (51.9% vs 34.2%, multivariate: OR = 2.40, P = 0.01). No differences in grade >= 3 haematological toxicities were observed. TILs increased from baseline to RD in the overall population and across A-T/A-TCb subgroups. TIL increase from baseline to RD was positively and independently associated with distant disease-free survival (multivariate: HR = 0.43, P = 0.05). Conclusions We confirmed in a clinical practice setting of TNBC patients receiving A-T NACT that the incorporation of weekly Cb significantly improved pCR. In addition, A-T +/- Cb enhanced immune infiltration from baseline to RD. Finally, we reported a positive independent prognostic role of TIL increase after NACT exposure

The largest multicentre data collection on prepectoral breast reconstruction: The iBAG study

Background and Objectives: In the last years, prepectoral breast reconstruction has increased its popularity, becoming a standard reconstructive technique by preserving pectoralis major anatomy and functionality. Nevertheless, the lack of solid and extensive data negatively impacts on surgeons\u2019 correct information about postoperative complication rates and proper patient selection. This study aims to collect the largest evidence on this procedure. Methods: A multicentre retrospective audit, promoted by the Barcelona Hospital, collected the experience of 30 centers on prepectoral breast reconstruction with Braxon ADM. The study had the scientific support of INPECS and IIB societies which provided the online database Clinapsis. Results: A total of 1450 procedures were retrospectively collected in a 6-year period. Mean age 52.4 years, BMI 23.9, follow-up 22.7 months. Reconstruction was carried out after a tumor in 77.1% of the cases, 20.1% had prophylactic surgery, 2.8% had revisions. Diabetes, smoke, and immunosuppression had an influence on complications occurrence, as well as implant weight. Capsular contracture was associated with postoperative radiotherapy, but the overall rate was low (2.1%). Complications led to implant loss in 6.5% of the cases. Conclusions: The international Braxon Audit Group multicentre data collection represents a milestone in the field of breast reconstruction, extensively improving the knowledge of this procedure

Preservation of Axillary Lymph Nodes Compared with Complete Dissection in T1–2 Breast Cancer Patients Presenting One or Two Metastatic Sentinel Lymph Nodes: The SINODAR-ONE Multicenter Randomized Clinical Trial

Background: The SINODAR-ONE trial is a prospective noninferiority multicenter randomized study aimed at assessing the role of axillary lymph node dissection (ALND) in patients undergoing either breast-conserving surgery or mastectomy for T1–2 breast cancer (BC) and presenting one or two macrometastatic sentinel lymph nodes (SLNs). The endpoints were to evaluate whether SLN biopsy (SLNB) only was associated with worsening of the prognosis compared with ALND in terms of overall survival (OS) and relapse. Methods: Patients were randomly assigned (1:1 ratio) to either removal of ≥ 10 axillary level I/II non-SLNs followed by adjuvant therapy (standard arm) or no further axillary treatment (experimental arm). Results: The trial started in April 2015 and ceased in April 2020, involving 889 patients. Median follow-up was 34.0 months. There were eight deaths (ALND, 4; SNLB only, 4), with 5-year cumulative mortality of 5.8% and 2.1% in the standard and experimental arm, respectively (p = 0.984). There were 26 recurrences (ALND 11; SNLB only, 15), with 5-year cumulative incidence of recurrence of 6.9% and 3.3% in the standard and experimental arm, respectively (p = 0.444). Only one axillary lymph node recurrence was observed in each arm. The 5-year OS rates were 98.9% and 98.8%, in the ALND and SNLB-only arm, respectively (p = 0.936). Conclusions: The 3-year survival and relapse rates of T1–2 BC patients with one or two macrometastatic SLNs treated with SLNB only, and adjuvant therapy, were not inferior to those of patients treated with ALND. These results do not support the use of routine ALND