Transcription-replication conflicts: How they occur and how they are resolved

The frequent occurrence of transcription and DNA replication in cells results in many encounters, and thus conflicts, between the transcription and replication machineries. These conflicts constitute a major intrinsic source of genome instability, which is a hallmark of cancer cells. How the replication machinery progresses along a DNA molecule occupied by an RNA polymerase is an old question. Here we review recent data on the biological relevance of transcription-replication conflicts, and the factors and mechanisms that are involved in either preventing or resolving them, mainly in eukaryotes. On the basis of these data, we provide our current view of how transcription can generate obstacles to replication, including torsional stress and non-B DNA structures, and of the different cellular processes that have evolved to solve them

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P < 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100 years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception

The Social Inclusion of Older People in France : Social Participation, Loneliness and Giving

International audienceThe social exclusion of older people challenges the notion of ag-ing well, both from a scientific and a political perspective. In this con-text, the responses brought to this issue through public policies may vary depending on the diverse scientific theories they are built upon. In France, the first political response to the social exclusion of older people has been the social inclusion policies of the 1960s. In later years, the growing medicalization of old-age policies contributed to relegating this issue to the background, until it resurfaced in the early 2000s with the abnormally high death toll of the 2003 heat wave. The notion of loneliness then replaced social exclusion, highlighting a lack of social cohesion where older people are concerned. The fight against isolation and loneliness became a national cause and was handed over to local stakeholders.This paper analyzes the design and implementation of projects and initiatives targeting older people, and discusses a survey of old-er people examining feelings of loneliness and/or uselessness. We will begin with a brief overview of theories on successful aging, to show how the question of social exclusion eventually came to the forefront. We will then examine the evolution of this notion in French old-age policies. Finally, we will present the findings of the VIEU project, offering avenues of reflection to consider social inclusion from a new perspectiv

UPDATES ON THE DIAGNOSIS AND TREATMENT OF PEDIATRIC HEPATOBLASTOMA WITH PULMONARY METASTASES

Although the frequency of hepatoblastoma is low, it is the most common primary malignant liver tumor in children. The prognosis of the disease has improved considerably in the last decades due to oncological and surgical treatment advances. Nonetheless, tumors which are diagnosed at an advanced stage still have a poor prognosis. We present the case of a 33-month-old child, diagnosed with high-risk hepatoblastoma (pulmonary metastases) in February 2014. Surgery was performed and the tumor completely removed. Afterwards, chemotherapy treatment was initiated according to a modified SIOPEL-4 protocol – the chemotherapy blocks which should have been administered before surgery were received after the operation. After finishing the chemotherapy, the thoraco-abdominal CT scan indicated a complete response to treatment. The periodic evaluation of the patient revealed the absence of local tumor recurrence, the absence of metastases, and a Lansky performance status of 80 up to now. The administration of targeted molecular therapies, liver transplant, and new chemotherapy drugs could improve the prognosis for patients with high risk hepatoblastoma in the future. Also, modifying the chemotherapy protocols could be considered an option in the achievement of this goal

ACTUALITĂŢI ÎN DIAGNOSTICUL ŞI TERAPIA HEPATOBLASTOMULUI PEDIATRIC CU METASTAZE PULMONARE

Deşi frecvenţa hepatoblastomului este redusă, acesta reprezintă cea mai comună tumoră hepatică primară ma lignă a copilului. Prognosticul bolii s-a îmbunătăţit considerabil în ultimele decenii, datorită progreselor terapeutice oncologice şi chirurgicale. Totuşi, tumorile aflate într-un stadiu avansat la momentul diagnosticului au în continuare un prognostic rezervat. Prezentăm cazul unui copil de 2 ani şi 9 luni, diagnosticat în februarie 2014 cu hepatoblastom, cu risc înalt (metastaze pulmonare), pentru care s-a intervenit chirurgical practicându-se ex cizia completă a tumorii. Ulterior, s-a iniţiat chimioterapie conform protocolului SIOPEL-4 modificat: astfel, blocurile de chimioterapie care ar fi trebuit administrate preoperator au fost utilizate postoperator. După finalizarea chimioterapiei, examenul CT toraco-abdominal efectuat în septembrie 2014 a indicat răspuns complet al bolii la tratament. Evaluarea periodică a pacientului a relevat până în prezent absenţa semnelor de recidivă locală tumorală, absenţa metastazelor şi un status de performanţă de 80 pe scala Lansky. Utilizarea terapiilor moleculare ţintite, a transplantului hepatic şi a unor noi chimioterapice poate reprezenta în viitor o modalitate de îmbunătăţire a prognosticului pacienţilor cu hepatoblastom cu risc înalt. De asemenea, modificarea pro tocoalelor de chimioterapie ar putea reprezenta o opţiune pentru îndeplinirea acestui scop

LIPOSARCOM OSOS PRIMAR LA COPIL

Introducere. Deşi liposarcomul de ţesuturi moi este o tumoră frecventă, liposarcomul primar osos este foarte rar, fi ind localizat în special în oasele lungi. Material şi metodă. Prezentăm cazul unei paciente în vârstă de 14 ani, spitalizată în Spitalul Clinic de Urgenţă pentru Copii „Sfânta Maria“ din Iaşi pentru durere, impotenţă funcţională şi tumefacţia bratului drept, simptome ce au debutat cu 24 de ore anterior internării, ca urmare a unui traumatism prin cădere al braţului drept. Radiografi a osoasă a evidenţiat o masă tumorală în porţiunea proximală a humerusului, asociată cu o fractură patologică. Rezultate. S-a realizat o biopsie la nivelul tumorii, iar analiza anatomopatologică (histologică şi imunochimică) a documentat proliferare liposarcomatoasă malignă. Concluzie. Diagnosticul anatomopatologic fi nal, corelat cu examenul fi zic, care a exclus posibilitatea unei metastaze osoase liposarcomatoase, a fost aceea de liposarcom primar osos. Particularitatea cazului: tumoră foarte rară, cu prezentare iniţială de fractură osoasă patologică. În stabilirea diagnosticului de liposarcom osos primar, trebuie exclusă posibilitatea unei metastaze de la un liposarcom cu localizare iniţială extraosoasă, ca şi pe cea a unui alt tip de tumoră osoasă primară. Prognosticul pare a fi mai favorabil decât cel al osteosarcomului, dar liposarcomul prezintă o rată mai mare de recurenţe locale şi diseminări sistemice

Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis

Abstract DNA double-strand breaks (DSBs) are deleterious lesions that challenge genome integrity. To mitigate this threat, human cells rely on the activity of multiple DNA repair machineries that are tightly regulated throughout the cell cycle 1 . In interphase, DSBs are mainly repaired by non-homologous end joining and homologous recombination 2 . However, these pathways are completely inhibited in mitosis 3–5 , leaving the fate of mitotic DSBs unknown. Here we show that DNA polymerase theta 6 (Polθ) repairs mitotic DSBs and thereby maintains genome integrity. In contrast to other DSB repair factors, Polθ function is activated in mitosis upon phosphorylation by Polo-like kinase 1 (PLK1). Phosphorylated Polθ is recruited by a direct interaction with the BRCA1 C-terminal domains of TOPBP1 to mitotic DSBs, where it mediates joining of broken DNA ends. Loss of Polθ leads to defective repair of mitotic DSBs, resulting in a loss of genome integrity. This is further exacerbated in cells that are deficient in homologous recombination, where loss of mitotic DSB repair by Polθ results in cell death. Our results identify mitotic DSB repair as the underlying cause of synthetic lethality between Polθ and homologous recombination. Together, our findings reveal the critical importance of mitotic DSB repair in the maintenance of genome integrity

Charge transfer in dissociating iodomethane and fluoromethane molecules ionized by intense femtosecond X-ray pulses

International audienceUltrafast electron transfer in dissociating iodomethane and fluoromethane molecules was studied at the Linac Coherent Light Source free-electron laser using an ultraviolet-pump, X-ray-probe scheme. The results for both molecules are discussed with respect to the nature of their UV excitation and different chemical properties. Signatures of long-distance intramolecular charge transfer are observed for both species, and a quantitative analysis of its distance dependence in iodomethane is carried out for charge states up to I21+. The reconstructed critical distances for electron transfer are in good agreement with a classical over-the-barrier model and with an earlier experiment employing a near-infrared pump pulse