Explore the vast range of titles available.

\"After months of training to become Batman's crime-fighting partner, young orphan Dick Grayson is finally ready to take to the night as Robin. But this job requires more than just his fists. As he squares off against Mad Hatter, Mr. Freeze and Two-Face for the firs time, Dick grapples with the hard choices and sacrifices that come with the life of a masked hero. His first year on the job is a trial by fire; can Robin fly high enough to stay out of the flames?\" -- Back cover.

CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50–650 mg/m 2 ) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m 2 days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977. G-quadruplex stabilizers, including CX-5461, exhibit synthetic lethality with loss of BRCA1/2 in preclinical models. Here the authors report the results of a phase I study of CX-5461 in patients with solid tumors enriched for DNA-repair deficiencies.

BackgroundWhile hundreds of Fulbright awards have been given, little is known about the impact of such engagement despite a goal of increased research partnership and collaboration.AimThe extent and impact of a Fulbright award was explored by examining referencing of primary collaborative publications.SettingSeven databases and two alternative sources from 2013 to 2023 were reviewed.MethodsCo-citation analysis identified pairs of referenced articles. Subsequently, a bibliometric approach was used to quantitatively and visually capture and analyse publications using data visualisation software.ResultsA search of sources found 773 citations citing the 16 primary works. Following the elimination of duplicates, 273 publications remained. Also examined was the non-scientific downstream noted in social media (n = 66). Based on co-citation analysis, there was a sharp uptick in the utilisation of primary citations (n = 273) compared to a 2019 analysis (n = 42). Journal Impact Factors of citing works had a high of 5.379 from 2.079 in 2019. Primary citations in open access journals demonstrated greater referencing, and the COVID-19 pandemic exacerbated utilisation of some works. Citing works focussed on three clusters: compassion fatigue, birth stories and Ubuntu. Most citing works originated from South Africa and the United States of America and consisted of multidisciplinary investigators with interfacility alliance and team science engagement. Nursing or midwifery were the main disciplines of first authors in citing articles (n = 153).ConclusionCo-citation analysis and downstream use of publications in social media provided evidence of the impact of a Fulbright award on scholarship with persistence over time.ContributionsFulbright awards promote collaborative teamwork between disciplines and is of clear benefit to scientists.

Background The encoding of cell intrinsic drug resistance states in breast cancer reflects the contributions of genomic and non-genomic variations and requires accurate estimation of clonal fitness from co-measurement of transcriptomic and genomic data. Somatic copy number (CN) variation is the dominant mutational mechanism leading to transcriptional variation and notably contributes to platinum chemotherapy resistance cell states. Here, we deploy time series measurements of triple negative breast cancer (TNBC) single-cell transcriptomes, along with co-measured single-cell CN fitness, identifying genomic and transcriptomic mechanisms in drug-associated transcriptional cell states. Results We present scRNA-seq data (53,641 filtered cells) from serial passaging TNBC patient-derived xenograft (PDX) experiments spanning 2.5 years, matched with genomic single-cell CN data from the same samples. Our findings reveal distinct clonal responses within TNBC tumors exposed to platinum. Clones with high drug fitness undergo clonal sweeps and show subtle transcriptional reversion, while those with weak fitness exhibit dynamic transcription upon drug withdrawal. Pathway analysis highlights convergence on epithelial-mesenchymal transition and cytokine signaling, associated with resistance. Furthermore, pseudotime analysis demonstrates hysteresis in transcriptional reversion, indicating generation of new intermediate transcriptional states upon platinum exposure. Conclusions Within a polyclonal tumor, clones with strong genotype-associated fitness under platinum remained fixed, minimizing transcriptional reversion upon drug withdrawal. Conversely, clones with weaker fitness display non-genomic transcriptional plasticity. This suggests CN-associated and CN-independent transcriptional states could both contribute to platinum resistance. The dominance of genomic or non-genomic mechanisms within polyclonal tumors has implications for drug sensitivity, restoration, and re-treatment strategies.

Metastasis is a major barrier to long-term survival for cancer patients, and therapeutic options for patients with aggressive, metastatic forms of breast cancer remain limited. It is therefore critical to understand the differences between non-metastatic and metastatic disease to identify potential methods for slowing or even stopping metastasis. In this work, we identify a bacterial species present with metastatic breast tumors capable of increasing the metastatic capabilities of tumor cells. We isolated and sequenced this bacteria, as well as a control species which failed to promote metastasis, and identified specific bacterial genes that were unique to the metastasis-promoting species. We tested for the presence of these bacterial genes in patient tumor samples and found they were more likely to be associated with mortality. We also identified enrichment of specific bacterial functions, providing insight into possible sources of bacteria-driven increases in the metastatic potential of multiple cancer types.

Assessing tumour gene fitness in physiologically-relevant model systems is challenging due to biological features of in vivo tumour regeneration, including extreme variations in single cell lineage progeny. Here we develop a reproducible, quantitative approach to pooled genetic perturbation in patient-derived xenografts (PDXs), by encoding single cell output from transplanted CRISPR-transduced cells in combination with a Bayesian hierarchical model. We apply this to 181 PDX transplants from 21 breast cancer patients. We show that uncertainty in fitness estimates depends critically on the number of transplant cell clones and the variability in clone sizes. We use a pathway-directed allelic series to characterize Notch signaling, and quantify TP53 / MDM2 drug-gene conditional fitness in outlier patients. We show that fitness outlier identification can be mirrored by pharmacological perturbation. Overall, we demonstrate that the gene fitness landscape in breast PDXs is dominated by inter-patient differences. Gene fitness and essentiality analyses using in vivo cancer models are challenging due to multiple confounders. Here, the authors develop a quantitative approach to study CRISPR-transduced patient-derived xenografts, which they use to analyse in vivo gene fitness in breast cancers and the biological features that influence uncertainty in fitness estimation.

Retention of iron in tissue macrophages via upregulation of hepcidin (HAMP) and downregulation of the iron exporter ferroportin (FPN) is thought to participate in the establishment of anemia of inflammation after infection. However, an upregulation of FPN has been proposed to limit macrophages iron access to intracellular pathogens. Therefore, we studied the iron homeostasis and in particular the regulation of FPN after infection with Salmonella enterica serovar Typhimurium in mice presenting tissue macrophages with high iron (AcB61), basal iron (A/J and wild-type mice), or low iron (Hamp knock out, Hamp(-/-)) levels. The presence of iron in AcB61 macrophages due to extravascular hemolysis and strong erythrophagocytosis activity favored the proliferation of Salmonella in the spleen and liver with a concomitant decrease of FPN protein expression. Despite systemic iron overload, no or slight increase in Salmonella burden was observed in Hamp(-/-) mice compared to controls. Importantly, FPN expression at both mRNA and protein levels was strongly decreased during Salmonella infection in Hamp(-/-) mice. The repression of Fpn mRNA was also observed in Salmonella-infected cultured macrophages. In addition, the downregulation of FPN was associated with decreased iron stores in both the liver and spleen in infected mice. Our findings show that during Salmonella infection, FPN is repressed through an iron and hepcidin-independent mechanism. Such regulation likely provides the cellular iron indispensable for the growth of Salmonella inside the macrophages.

The prevalence and nature of somatic copy number alterations (CNAs) in breast epithelium and their role in tumor initiation and evolution remain poorly understood. Using single-cell DNA sequencing (49,238 cells) of epithelium from BRCA1 and BRCA2 carriers or wild-type individuals, we identified recurrent CNAs (for example, 1q-gain and 7q, 10q, 16q and 22q-loss) that are present in a rare population of cells across almost all samples ( n = 28). In BRCA1 / BRCA2 carriers, these occur before loss of heterozygosity (LOH) of wild-type alleles. These CNAs, common in malignant tumors, are enriched in luminal cells but absent in basal myoepithelial cells. Allele-specific analysis of prevalent CNAs reveals that they arose by independent mutational events, consistent with convergent evolution. BRCA1 / BRCA2 carriers contained a small percentage of cells with extreme aneuploidy, featuring loss of TP53 , BRCA1 / BRCA2 LOH and multiple breast cancer-associated CNAs. Our findings suggest that CNAs arising in normal luminal breast epithelium are precursors to clonally expanded tumor genomes. Single-cell DNA sequencing identifies recurrent copy number changes in healthy breast tissue from women with wild-type or germline BRCA1 or BRCA2 mutations.

Human infection with Salmonella is of global public health concern. In low- and middle-income countries, Salmonella infection is a major source of disease in terms of both mortality and morbidity, while in high-income nations, the pathogen is an ongoing threat to food security. The outcome of infection with Salmonella enterica serovar Typhimurium ( Salmonella Typhimurium) in mouse models is dependent upon a coordinated and complex immune response. A panel of recombinant congenic strains (RCS) derived from the reciprocal double backcross of A/J and C57BL/6J mice has been screened for their susceptibility to Salmonella infection, and the RCS AcB60 was identified to be the most resistant strain to Salmonella infection, more resistant than the parental strain A/J. These mice are known to carry resistant alleles at three well-defined Salmonella susceptibility loci, Slc11a1 Ity (solute carrier family 11 member 1; Immunity to Ty phimurium locus) , Pklr Ity4 (pyruvate kinase liver and red blood cell; Ity4 locus), and Ity5 . In the current study, we used interval mapping to validate a locus on Chr 15, named Ity8 , linked to Salmonella resistance in AcB60 mice. Global gene expression analysis during infection identified AcB60-specific expression of genes involved in Ccr7 signaling, including downstream effector Mapk11 (mitogen-activated protein kinase 11), located within the Ity8 interval, and representing a potential positional candidate gene. An additional region on Chr 18 of C57BL/6J descent was shown to be associated with increase resistance in AcB60. These observations provide an opportunity to achieve new insight into the complex genetics of resistance to Salmonella infection in the context of mouse models of human infection with Salmonella Typhimurium.

Salmonella species are globally relevant human pathogens that present a significant challenge to human health in low and middle-income nations, and an economic challenge in high-income nations. Where Salmonella infection is a significant source of mortality and morbidity, risk is primarily associated with inadequate water and sanitation infrastructure, or compromised immunity. The outcome of infection is the product of complex interactions between factors that are both environmental and genetic. A panel of recombinant congenic strains (RCS) derived from the reciprocal double backcross of the Salmonella resistant A/J inbred mouse strain, and susceptible C57BL/6J strain has revealed a number of congenic strains demonstrating survival phenotypes of unknown aetiology. In the case of the highly susceptible AcB61 strain two susceptibility loci, Ity4 (Immunity to Typhimurium locus 4) and Ity5 have been identified. While the Ity4 susceptibility trait has been previously demonstrated to be the product of a de novo mutation in the AcB61 Pklr variant, the genetic origin of the Ity5 survival phenotype remained unstudied. In the thesis that follows we report on the further characterization of AcB61, including the tissue iron loading, dysregulated iron homeostasis, and chronic erythrophagocytosis that predispose the strain to infection. Observations of AcB61 transcription and protein expression, as well as microscopy and experiments using knock-out mice, reveal the pathogenic downregulaton of AcB61 FPN during infection, novel in its hepcidin independence. We also report the validation of the other susceptibility locus of AcB61 Ity5, in a genetic environment free of the impact of Ity4, using a cross between A/J and 129S6. Using a time-series analysis of genome-wide transcription during infection, comparing A/J mice to AcB60 control mice having a C57BL/6J derived Ity5 interval, we have identified the differential expression of the Ity5 positional candidate gene Cd40, Cd40 associated canonical signaling pathways, and the differential expression of numerous genes involved in neutrophil function. Our study of RCS derived from A/J and C57BL/6J has included the study of the AcB60 RCS, the most resistant to infection of all of the studied RCS. Using a combination of linkage analysis, transcriptional profiling, and protein expression we have identified Ity5 to be the likely source of much of the resistance of AcB60 mice to infection. In addition, through the use of a genome-scan between the highly resistant AcB60 strain, and the intermediately resistant strain DBA/2J, we report the identification of Ity8, a QTL associated with the survival phenotype of AcB60xDBA/2J F2 mice. Through the integration of interval mapping, genome-wide transcriptional profiling and canonical pathway analysis we further report the identification of likely protective signaling though the Ccr7 and Mapk11 in AcB60xDBA/2J F2 mice resistant to Salmonella infection. Collectively the work collected herein further demonstrates the utility of mice as models of human infection, and of Salmonella as a model pathogen. Observations of AcB61 provide novel insight into iron homeostasis and hepcidin independent regulation of FPN while the study of AcB60 and AcB64 has provided new insight into the immune response of the seminally important A/J and C56BL/6J inbred strains, popular and enduringly relevant tools for medical research.