IMPORTANCE Gut dysbiosis impairs response to immune checkpoint inhibitors (ICIs) and can be caused by broad-spectrum antibiotic (ATB) therapy. OBJECTIVE To evaluate whether there is an association between ATB therapy administered concurrently (cATB) or prior (pATB) to ICI therapy and overall survival (OS) and treatment response to ICI therapy in patients with cancer treated with ICIs in routine clinical practice. DESIGN, SETTING, AND PARTICIPANTS This prospective, multicenter, cohort study conducted at 2 tertiary academic referral centers recruited 196 patients with cancer who received ICI therapy between January 1, 2015, and April 1, 2018, in routine clinical practice rather than clinical trials.MAIN OUTCOMES AND MEASURES Overall survival calculated from the time of ICI therapy commencement and radiologic response to ICI treatment defined using the Response Evaluation Criteria in Solid Tumors (version 1.1), with disease refractory to ICI therapy defined as progressive disease 6 to 8 weeks after the first ICI dose without evidence of pseudoprogression. RESULTS Among 196 patients (137 men and 59 women; median [range] age, 68 [27-93] years) with non-small cell lung cancer (n = 119), melanoma (n = 38), and other tumor types (n = 39), pATB therapy (HR, 7.4; 95% CI, 4.3-12.8; P < .001), but not cATB therapy (HR, 0.9; 95% CI, 0.5-1.4; P = .76), was associated with worse OS (2 vs 26 months for pATB therapy vs no pATB therapy, respectively) (hazard ratio [HR], 7.4; 95% CI, 4.2-12.9) and a higher likelihood of primary disease refractory to ICI therapy (21 of 26 [81%] vs 66 of 151 [44%], P < .001). Overall survival in patients with non-small cell lung cancer (2.5 vs 26 months, P < .001), melanoma (3.9 vs 14 months, P < .001), and other tumor types (1.1 vs 11, P < .001) was consistently worse in those who received pATBs vs those who did not. Multivariate analyses confirmed that pATB therapy (HR, 3.4; 95% CI, 1.9-6.1; P < .001) and response to ICI therapy (HR, 8.2; 95% CI, 4.0-16.9; P < .001) were associated with OS independent of tumor site, disease burden, and performance status.CONCLUSIONS AND RELEVANCE Despite being limited by sample size, geographic origin, and the lack of correlative analyses on patients' gut microbiota, this study suggests that pATB therapy but not cATB therapy is associated with a worse treatment response and OS in unselected patients treated with ICIs in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICI treatment.

Mcm-2 may be of utility as a prognostic marker to refine the prediction of outcome in breast cancer, for example when combined with parameters currently used in the NPI.

In multicellular eukaryotes, geminin prevents overreplication of DNA in proliferating cells. Here, we show that genetic ablation of geminin in the mouse prevents formation of inner cell mass (ICM) and causes premature endoreduplication at eight cells, rather than 32 cells. All cells in geminin-deficient embryos commit to the trophoblast cell lineage and consist of trophoblast giant cells (TGCs) only. Geminin is also down-regulated in TGCs of wild-type blastocysts during S and gap-like phases by proteasome-mediated degradation, suggesting that loss of geminin is part of the mechanism regulating endoreduplication.Supplemental material is available at http://www.genesdev.org.Received January 12, 2006; revised version accepted May 15, 2006. Mammalian embryonic development begins with a series of cleavage divisions commencing in the fertilized egg. Two distinct cell types are generated during the first events of cellular differentiation and determination of lineage, giving rise to the inner cell mass (ICM) and trophectoderm of the blastocyst. The ICM develops into the embryo proper whereas all extraembryonic tissues are derived from the surrounding trophectoderm .Cells in the developing mammalian embryo have unique cell cycle characteristics that remain poorly understood. In embryonic stem (ES) cell lines derived from explant cultures of ICM, more than two-thirds of the mitotic ES cell cycle is devoted to S phase, and the gap phases (G1 and G2) are shorter than those of their somatic counterparts. Cyclin-dependent kinase (cdk) activity remains high throughout the ES cell cycle and oscillations are only observed with the mitotic cyclin, cyclin B1 (Stead et al. 2002). Cells of the ICM retain a diploid DNA content, but interestingly cells in the trophectoderm can acquire a >1000C DNA content. The latter form trophoblast giant cells (TGCs) by undergoing endoreduplication, in which S phases alternate with "gaplike" phases, bypassing mitosis. Cyclin E is required for endoreduplication in mouse TGCs of the trophectoderm (Geng et al. 2003;Parisi et al. 2003).Although a transcriptional program principally driven by Oct4, Cdx2, Nanog, and Gata6 regulates cell identity in the mammalian embryo, the precise control by which cell proliferation is coordinated with differentiation and determination of cell lineage has not been established . In this study, we have used a genetic approach to investigate the role of geminin during mammalian development. Geminin inhibits prereplication complex (pre-RC) assembly in somatic cells by preventing Cdt1 from recruiting minichromosome maintenance (MCM) proteins to chromatin, from S phase to the metaphase:anaphase transition, when it is targeted for degradation by the anaphase-promoting complex/cyclosome (APC/C) (McGarry and Kirschner 1998;Wohlschlegel et al. 2000;Gonzalez et al. 2004). Moreover, geminin controls differentiation as well as cell proliferation during late metazoan development. Geminin inhibits both Six3 and Hox transcription factors in medaka retina and the mouse embryo, respe...

The highly orchestrated process of DNA replication ensures the accurate inheritance of genetic information from one cell generation to the next. The exact execution of DNA replication depends on a large number of proteins that are being studied extensively in the cell cycle field. Some of these proteins, such as the minichromosome maintenance proteins (MCMs), are essential for the process of DNA replication itself. Others such as geminin are specifically required to limit DNA replication to once per cell cycle. Together, these proteins protect the stability of the human genome in cycling cells. Their expression has been compared with routinely used proliferation markers, such as Ki-67 (MIB-1) and proliferating cell nuclear antigen (PCNA), which fulfil the requirements of molecular tumour markers to varying extents. However, it is with regard to the depth of our understanding of antigen biology that the MCM proteins and geminin qualify exceptionally well as novel cellcycle biomarkers for routine use in clinical practice, particularly in cancer detection and estimation of prognosis. Expression microarray analysis has also independently identified MCMs and their interacting proteins as determinants of the inherent aggressiveness of a wide range of epithelial malignancies.