1281O Atezolizumab (atezo) vs platinum-based chemo in blood-based tumour mutational burden-positive (bTMB+) patients (pts) with first-line (1L) advanced/metastatic (m)NSCLC: Results of the Blood First Assay Screening Trial (BFAST) phase III cohort C

Background: TMB is a promising biomarker for immunotherapy in NSCLC, but current data are mostly retrospective. As not all pts may have sufficient tissue for comprehensive biomarker testing, bTMB was prospectively tested as a novel biomarker using targeted next-generation sequencing. BFAST (NCT03178552), a global, open-label, multi-cohort trial, evaluated safety and efficacy of targeted therapies or immunotherapy in biomarker-selected pts with unresectable mNSCLC. Here we present results from Cohort C of 1L atezo vs platinum-based chemo in pts with bTMB+ mNSCLC. Methods: We planned to randomise ≈440 pts with 1L mNSCLC with measurable disease per RECIST 1.1 and bTMB ≥10 (9.1 mut/Mb; FMI bTMB assay) 1:1 to atezo 1200 mg IV every 3 weeks or chemo and stratified by tissue availability, ECOG PS, bTMB and histology. The primary endpoint was INV-PFS per RECIST 1.1 in bTMB ≥16 (14.5 mut/Mb) pts. Key secondary endpoints included OS in bTMB ≥10 (intent to treat, ITT) and bTMB ≥16 pts, and INV-PFS in ITT pts. Results: 471 pts were assigned to atezo (n=234) or chemo (n=237). At baseline, 72% had non-squamous histology, 2% never smoked and median SLD was 103 mm. 145 pts with bTMB ≥16 were assigned to atezo and 146 to chemo. At data cutoff (21 May 2020) minimum follow up was 6 mo. INV-PFS difference in bTMB ≥16 pts for atezo vs chemo was not significant (P=0.053; Table). Grade 3-4 TRAEs occurred in 18% (atezo) vs 46% (chemo) of pts. Serious TRAEs occurred in 12% (atezo) vs 14% (chemo). Results at other bTMB thresholds and by F1L CDx will also be presented as an exploratory analysis. Conclusions: The primary PFS endpoint in bTMB ≥16 pts was not met. OS was numerically better with atezo vs chemo but the difference was not statistically significant. The safety profile of atezo vs chemo was favourable and consistent with atezo monotherapy across indications

Molecular residual disease detection in resected, muscle-invasive urothelial cancer with a tissue-based comprehensive genomic profiling–informed personalized monitoring assay

IntroductionCirculating tumor DNA (ctDNA) detection postoperatively may identify patients with urothelial cancer at a high risk of relapse. Pragmatic tools building off clinical tumor next-generation sequencing (NGS) platforms could have the potential to increase assay accessibility.MethodsWe evaluated the widely available Foundation Medicine comprehensive genomic profiling (CGP) platform as a source of variants for tracking of ctDNA when analyzing residual samples from IMvigor010 (ClinicalTrials.gov identifier NCT02450331), a randomized adjuvant study comparing atezolizumab with observation after bladder cancer surgery. Current methods often involve germline sampling, which is not always feasible or practical. Rather than performing white blood cell sequencing to filter germline and clonal hematopoiesis (CH) variants, we applied a bioinformatic approach to select tumor (non-germline/CH) variants for molecular residual disease detection. Tissue-informed personalized multiplex polymerase chain reaction–NGS assay was used to detect ctDNA postsurgically (Natera).ResultsAcross 396 analyzed patients, prevalence of potentially actionable alterations was comparable with the expected prevalence in advanced disease (13% FGFR2/3, 20% PIK3CA, 13% ERBB2, and 37% with elevated tumor mutational burden ≥10 mutations/megabase). In the observation arm, 66 of the 184 (36%) ctDNA-positive patients had shorter disease-free survival [DFS; hazard ratio (HR) = 5.77; 95% confidence interval (CI), 3.84–8.67; P < 0.0001] and overall survival (OS; HR = 5.81; 95% CI, 3.41–9.91; P < 0.0001) compared with ctDNA-negative patients. ctDNA-positive patients had improved DFS and OS with atezolizumab compared with those in observation (DFS HR = 0.56; 95% CI, 0.38–0.83; P = 0.003; OS HR = 0.66; 95% CI, 0.42–1.05). Clinical sensitivity and specificity for detection of postsurgical recurrence were 58% (60/103) and 93% (75/81), respectively.ConclusionWe present a personalized ctDNA monitoring assay utilizing tissue-based FoundationOne® CDx CGP, which is a pragmatic and potentially clinically scalable method that can detect low levels of residual ctDNA in patients with resected, muscle-invasive bladder cancer without germline sampling

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers

RNA interference approaches for treatment of HIV-1 infection

HIV/AIDS is a chronic and debilitating disease that cannot be cured with current antiretroviral drugs. While combinatorial antiretroviral therapy (cART) can potently suppress HIV-1 replication and delay the onset of AIDS, viral mutagenesis often leads to viral escape from multiple drugs. In addition to the pharmacological agents that comprise cART drug cocktails, new biological therapeutics are reaching the clinic. These include gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication. RNAi allows sequence-specific design to compensate for viral mutants and natural variants, thereby drastically expanding the number of therapeutic targets beyond the capabilities of cART. Recent advances in clinical and preclinical studies have demonstrated the promise of RNAi therapeutics, reinforcing the concept that RNAi-based agents might offer a safe, effective, and more durable approach for the treatment of HIV/AIDS. Nevertheless, there are challenges that must be overcome in order for RNAi therapeutics to reach their clinical potential. These include the refinement of strategies for delivery and to reduce the risk of mutational escape. In this review, we provide an overview of RNAi-based therapies for HIV-1, examine a variety of combinatorial RNAi strategies, and discuss approaches for ex vivo delivery and in vivo delivery

The Internal Agency : Linchpin of the political police in Russia

Nurit Schleifmann, The Internal Agency: linchpin of the political police in Russia. The purpose of this article is to outline several of the characteristic features of police infiltration into the revolutionary movement by means of the secret agent. These features stem largely from the underlying conception of the Police Department which viewed its cardinal objective as "liquidation": the surveillance of revolutionary groups with the aim of eliminating them at an appropriate moment. Thus the Internal Agency - as the secret agents were collectively dubbed by the Police - had pride of place in the activity of each Okhrana section; the data gathered by the agents were given top priority in appraising the situation and since this information was tendentious, this led to incongruities between the revolutionary tide and the deployment of the police to combat it. Moreover, the underlying conception dictated police concentration on the individual revolutionary act and brought about the erroneous assumption that the larger the revolutionary organization, the greater its menace. Police comprehension of reality determined also their attitude towards the various components of the revolutionary camp. However, the scope of infiltration into a given movement was affected by a combination of three factors: the degree of interest evinced by the police in the movement's activity, the movement's size and the nature of its organization.Nurit Schleifmann, L' "espionnage interne" : cheville ouvrière de la police politique en Russie. Cet article se propose de dégager plusieurs traits caractéristiques de l'infiltration policière dans le mouvement révolutionnaire par le truchement des agents secrets. Cette tactique procédait dans une large mesure de la conception sous-jacente de la Direction de la Police dont l'objectif principal était la "liquidation" : la surveillance des groupes révolutionnaires dans le but de les éliminer au moment opportun. Ainsi l'espionnage interne - telle est l'appellation globale que la Police réservait aux agents secrets - avait l'honneur de figurer dans l'activité de chaque section de l'Ohrana. Les renseignements collectés par les agents avaient priorité pour évaluer la situation ; comme ces renseignements étaient tendancieux, cela conduisait à une disproportion entre la marée révolutionnaire et le déploiement de la police pour l'endiguer. En outre, au nom de cette même conception sous-jacente, la police préconisait une concentration policière sur l'acte révolutionnaire individuel et présumait à tort que plus une organisation révolutionnaire était vaste, plus elle représentait un danger. La vision que la police se faisait de la réalité déterminait aussi son attitude envers les divers éléments du camp révolutionnaire. Cependant, l'ampleur de l'infiltration dans un mouvement donné dépendait de la combinaison de trois facteurs : le degré d'intérêt témoigné par la police envers l'activité du mouvement, l'importance de ce dernier et la nature de son organisation.Schleifmann Nurit. The Internal Agency : Linchpin of the political police in Russia. In: Cahiers du monde russe et soviétique, vol. 24, n°1-2, Janvier-Juin 1983. pp. 151-177

A Russian daily newspaper and its new readership : Severnaia pchela, 1825-1840

Nurit Schleifman, A Russian daily newspaper and its new readership: Severnaia pchela, 1825 -1840. Severnaia pchela, the first privately owned Russian newspaper, was published in St. Petersburg for almost forty years. The time of its appearance was marked by a growing participation of the urban middle strata in the consumption of literature, which consequently turned them into the newspaper's chief target audience. The educated elite viewed Severnaia pchela' s success with this new readership as a regrettable result of both the existing political circumstances and the paper's policy of catering to the lowest possible tastes. Whereas contemporary historiography tends towards the same view, a closer examination reveals the paper's persistent attempt to use a restricted thematic framework. for conveying messages that would correspond to the social needs and life experiences of its new readers. This endeavour should be considered as a contributary factor in Severnaia pchela's success in maintaining its position as the most widely read daily until the early forties.Nurit Schleifman, Un quotidien russe et son nouveau public. Severnaja pčela, 1825-1840. Severnaja pčela, le premier journal russe appartenant à un particulier a été publié à Saint-Pétersbourg pendant près de quarante ans. L'époque de sa parution fut marquée par la participation croissante de la couche moyenne urbaine à la consommation de la littérature, ce qui eut pour effet d'en faire le public principalement visé par le journal. L'élite cultivée considéra le succès de Severnaja pčela auprès de ce nouveau public comme un fait regrettable, résultant à la fois de la situation politique d'alors et du désir du journal de répondre aux goûts les plus bas. Alors que l'historiographie contemporaine tend à partager cette opinion, un examen plus approfondi du journal y décèle un effort persistant pour utiliser un cadre thématique restreint, pour transmettre des messages répondant aux besoins sociaux et aux expériences de ces nouveaux lecteurs. On devrait voir dans cet effort la clé du succès de Severnaja pčela qui réussit ainsi à conserver sa position de quotidien le plus lu jusqu'au début des années 1840.Schleifman Nurit. A Russian daily newspaper and its new readership : Severnaia pchela, 1825-1840. In: Cahiers du monde russe et soviétique, vol. 28, n°2, Avril-Juin 1987. Autour de la presse russe et soviétique. pp. 127-144

Interactions among Ytm1, Erb1, and Nop7 required for assembly of the Nop7-subcomplex in yeast preribosomes.

In Saccharomyces cerevisiae, more than 180 assembly factors associate with preribosomes to enable folding of pre-rRNA, recruitment of ribosomal proteins, and processing of pre-rRNAs to produce mature ribosomes. To examine the molecular architecture of preribosomes and to connect this structure to functions of each assembly factor, assembly subcomplexes have been purified from preribosomal particles. The Nop7-subcomplex contains three assembly factors: Nop7, Erb1, and Ytm1, each of which is necessary for conversion of 27SA(3) pre-rRNA to 27SB(S) pre-rRNA. However, interactions among these three proteins and mechanisms of their recruitment and function in pre-rRNPs are poorly understood. Here we show that Ytm1, Erb1, and Nop7 assemble into preribosomes in an interdependent manner. We identified which domains within Ytm1, Erb1, and Nop7 are necessary for their interaction with each other and are sufficient for recruitment of each protein into preribosomes. Dominant negative effects on growth and ribosome biogenesis caused by overexpressing truncated Ytm1, Erb1, or Nop7 constructs, and recessive phenotypes of the truncated proteins revealed not only interaction domains but also other domains potentially important for each protein to function in ribosome biogenesis. Our data suggest a model for the architecture of the Nop7-subcomplex and provide potential functions of domains of each protein.</p

Somatic mutation, copy number and transcriptomic profiles of primary and matched metastatic estrogen receptor-positive breast cancers

Estrogen receptor-positive (ER+) breast cancers (BCs) constitute the most frequent BC subtype. The molecular landscape of ER+ relapsed disease is not well characterized. In this study, we aimed to describe the genomic evolution between primary (P) and matched metastatic (M) ER+ BCs after failure of adjuvant therapy.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Analytical evaluation of circulating tumor DNA sequencing assays

Abstract In China, circulating tumor DNA analysis is widely used and numerous assays are available. Systematic evaluation to help users make informed selections is needed. Nine circulating tumor DNA assays, including one benchmark assay, were evaluated using 23 contrived reference samples. There were two sample types (cell-free DNA and plasma samples), three circulating tumor DNA inputs (low,  50 ng), two variant allele frequency ranges (low, 0.1–0.5%; intermediate, 0.5–2.5%), and four variant types (single nucleotide, insertion/deletion, structural, and copy number). Sensitivity, specificity, reproducibility, and all processes from cell-free DNA extraction to bioinformatics analysis were assessed. The test assays were generally comparable or superior to the benchmark assay, demonstrating high analytical sensitivity. Variations in circulating tumor DNA extraction and quantification efficiency, sensitivity, and reproducibility were observed, particularly at lower inputs. These findings will guide circulating tumor DNA assay choice for research and clinical studies, allowing consideration of multiple technical parameters