Surgical and survival outcomes with perioperative or neoadjuvant immune-checkpoint inhibitors combined with platinum-based chemotherapy in resectable NSCLC: A systematic review and meta-analysis of randomised clinical trials

: The use of neoadjuvant or perioperative anti-PD(L)1 was recently tested in multiple clinical trials. We performed a systematic review and meta-analysis of randomised trials comparing neoadjuvant or perioperative chemoimmunotherapy to neoadjuvant chemotherapy in resectable NSCLC. Nine reports from 6 studies were included. Receipt of surgery was more frequent in the experimental arm (odds ratio, OR 1.39) as was pCR (OR 7.60). EFS was improved in the experimental arm (hazard ratio, HR 0.55) regardless of stage, histology, PD-L1 expression (PD-L1 negative, HR 0.74) and smoking exposure (never smokers, HR 0.67), as was OS (HR 0.67). Grade > = 3 treatment-related adverse events were more frequent in the experimental arm (OR 1.22). The experimental treatment improved surgical outcomes, pCR rates, EFS and OS in stage II-IIIB, EGFR/ALK negative resectable NSCLC; confirmatory evidence is warranted for stage IIIB tumours and with higher maturity of the OS endpoint

Rapid Analysis of Saccharomyces cerevisiae Genome Rearrangements by Multiplex Ligation–Dependent Probe Amplification

Aneuploidy and gross chromosomal rearrangements (GCRs) can lead to genetic diseases and the development of cancer. We previously demonstrated that introduction of the repetitive retrotransposon Ty912 onto a nonessential chromosome arm of Saccharomyces cerevisiae led to increased genome instability predominantly due to increased rates of formation of monocentric nonreciprocal translocations. In this study, we adapted Multiplex Ligation–dependent Probe Amplification (MLPA) to analyze a large numbers of these GCRs. Using MLPA, we found that the distribution of translocations induced by the presence of Ty912 in a wild-type strain was nonrandom and that the majority of these translocations were mediated by only six translocation targets on four different chromosomes, even though there were 254 potential Ty-related translocation targets in the S. cerevisiae genome. While the majority of Ty912-mediated translocations resulted from RAD52-dependent recombination, we observed a number of nonreciprocal translocations mediated by RAD52-independent recombination between Ty1 elements. The formation of these RAD52-independent translocations did not require the Rad51 or Rad59 homologous pairing proteins or the Rad1–Rad10 endonuclease complex that processes branched DNAs during recombination. Finally, we found that defects in ASF1-RTT109–dependent acetylation of histone H3 lysine residue 56 (H3K56) resulted in increased accumulation of both GCRs and whole-chromosome duplications, and resulted in aneuploidy that tended to occur simultaneously with GCRs. Overall, we found that MLPA is a versatile technique for the rapid analysis of GCRs and can facilitate the genetic analysis of the pathways that prevent and promote GCRs and aneuploidy

Msh2 Blocks an Alternative Mechanism for Non-Homologous Tail Removal during Single-Strand Annealing in Saccharomyces cerevisiae

Chromosomal translocations are frequently observed in cells exposed to agents that cause DNA double-strand breaks (DSBs), such as ionizing radiation and chemotherapeutic drugs, and are often associated with tumors in mammals. Recently, translocation formation in the budding yeast, Saccharomyces cerevisiae, has been found to occur at high frequencies following the creation of multiple DSBs adjacent to repetitive sequences on non-homologous chromosomes. The genetic control of translocation formation and the chromosome complements of the clones that contain translocations suggest that translocation formation occurs by single-strand annealing (SSA). Among the factors important for translocation formation by SSA is the central mismatch repair (MMR) and homologous recombination (HR) factor, Msh2. Here we describe the effects of several msh2 missense mutations on translocation formation that suggest that Msh2 has separable functions in stabilizing annealed single strands, and removing non-homologous sequences from their ends. Additionally, interactions between the msh2 alleles and a null allele of RAD1, which encodes a subunit of a nuclease critical for the removal of non-homologous tails suggest that Msh2 blocks an alternative mechanism for removing these sequences. These results suggest that Msh2 plays multiple roles in the formation of chromosomal translocations following acute levels of DNA damage

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

Towards a convergent approach to the use of data in digital health design

Digital health is a vibrant and dynamic field, encompassing subsets such as mobile health, health information technology, wearable devices, telehealth and telemedicine, and personalised medicine. While digital health adoption has been markedly accelerated by the covid-19 pandemic (Inkster et al., 2020), an evolving body of research has focused on describing and addressing specific challenges related to the design and evaluation of digital health technologies (Pagliari, 2007; Murray et al., 2016; Blandford et al., 2018; Marvel et al., 2018). This research articulates a need for novel, interdisciplinary design approaches to digital health innovation, integrating disparate sets of requirements such as clinical soundness, user-centeredness, technical interoperability, and cost-effectiveness (Cornet et al., 2019). In this complex domain, design and health disciplines are called not only to collaborate with each other, but also to learn to work with digital data as the raw material fueling digital technologies. This dissertation explores such challenges through a series of exploratory research efforts at the intersection of design, healthcare and digital data. These explorations are conducted within the context of the Cardiolab, a Delft Design Lab born out of a partnership between Philips Experience Design and Delft University of Technology. Throughout the dissertation, knowledge in this domain is gained through a mix of literature reviews and project-based action research (Somekh, 2005). In this way, the relevant scientific literature is connected and put in dialogue with real-life digital health design practice

Design research, eHealth, and the convergence revolution

The Quadruple Aim is a framework which prioritizes four 'aims', or dimensions of performance, for innovating in the healthcare domain, respectively: 1) enhancing the individual experience of care; 2) improving the work life of health care clinicians and staff; 3) improving the health of populations; and 4) reducing the per capita cost of care. In this contribution, recent literature providing examples of design research in the eHealth domain is reviewed to answer the research question: 'in which measure has design research contributed to each of the 'four aims' of eHealth innovation in the past five years?'. The results of the review are presented and employed to draw three main observations: 1) design researchers in eHealth seem to be largely focused on improving experiences of care, either patients' or health professionals'; 2) design researchers' contribution on reducing per capita costs of care appears to be less pronounced, which is outlined as a point for improvement; and 3) in a considerable amount of reviewed contributions, design researchers appear to be contributing to multiple 'aims' at once. In this subgroup of reviewed contributions, several disciplinary areas and types of stakeholders interact and integrate through design research activities. The latter observation leads to a reflection on the strategic role of design research in the contexts of the convergence revolution and of the non-communicable disease crisis. Implications of this reflection for design researchers are recognized in the opportunity and timeliness to develop eHealth-specific ways to orchestrate design integration. A direction for further research in this sense is identified in the use of sensory and self-monitored data as a boundary object for eHealth innovation. The prospective value of this direction is finally exemplified through the case of blood pressure

Mechanical Characterization and Influence of Water on WMA by Adding Synthetic Zeolite

http://www.ljmu.ac.uk/BLT/PEAT/90854.ht