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In order to perform a breast lumpectomy, it is essential that a surgeon be able to accurately identify the region of cancerous tissue to be excised. Because they are implanted adjacent to the tumor bed during preliminary diagnostic biopsies, tissue markers serve as an excellent and convenient spatial reference. However, because there is no reliable method of identifying the location of these metallic markers intraoperatively, a preoperative procedure called wire-localization is typically performed. Wire-localization is unpleasant for patients, contributes to logistical inefficiencies, and requires the use of radiological facilities. Various alternative methods have been introduced which provide day-of intraoperative localization through the placement of a specialized companion marker and a detection probe. However, the specialized companion markers are only temporary and must be placed next to existing diagnostic biopsy markers Preoperative localization is thus still necessary in order to properly place them in the days preceding surgery. Though an improvement upon wire-localization, these systems have achieved minimal degrees of clinical acceptance. This study pertains to the development, fabrication, and assessment of a novel detection system that enables true intraoperative localization of primary diagnostic breast markers. The first element of the system is a handheld detector that functions on the principals of magnetism to guide a surgeon’s incisional path by providing continuous graphical and audio feedback. Proof-of-concept testing has demonstrated that the prototype detector is capable of reading the presence of a nitinol marker as far as 4.5 cm away and that signal strength attenuates with distance. Qualitative ex vivo validation was achieved by a collaborating surgeon who used the probe to locate a nitinol marker placed beneath a mastectomy sample. Finite element models have shown that the levels of specific absorbed radiation produced by the device are well within clinical guidelines and that it may be possible to implement a shielding method to eliminate unwanted environmental signal interference. The second element of the detection system is a novel tissue marker which compliments the detection probe’s operating principals. A composite of polymer with embedded metallic nanoparticles, this marker satisfies the seemingly disparate needs of biocompatibility and magnetic susceptibility and thus can serve as a primary diagnostic breast biopsy marker that confers intraoperative detectability. A detection proximity study was conducted using the designed graphical user interface (GUI) to evaluate signal strength among various marker compositions. This verified not only that the probe can detect the composite markers at 4.5 cm, but that the real-time GUI is an effective means of acquiring data and visualizing feedback. In light of relevant literature related to the biocompatibility of its constituents, it is believed that the various marker embodiments envisaged here would be safe and suitable for long-term implantation. These results indicate that the novel detection system developed here is capable of detecting biopsy markers at clinically relevant distances and that the companion marker designed to complement this task could be an effective diagnostic breast biopsy marker. The combination of these technologies sets the foundation for a comprehensive intraoperative localization system which could reduce both patient suffering and clinical inefficiency by serving as a viable alternative to wire-guided localization.

Landscape architects and urban designers must work closely with city leaders to help maximize the city-center's potential as a source of revenue generation because plazas enhance civic pride when they are highly utilized, which hearkens to their original role as the place of commerce.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma 1 – 4 , but the efficacy of CAR T cell therapy in solid tumours has been limited 5 . This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more ‘stem-like’ phenotype and increased mitochondrial mass 6 – 8 . We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours. Increased effectiveness of anti-cancer chimeric antigen receptor T cell therapy is associated with a stem-like phenotype through increased expression of FOXO1.

Rapid advances in immunotherapy have identified adoptive cell transfer as one of the most promising approaches for the treatment of cancers. Large numbers of cancer reactive T lymphocytes can be generated ex vivo from patient blood by genetic modification to express chimeric antigen receptors (CAR) specific for tumor-associated antigens. CAR T cells can respond strongly against cancer cells, and adoptive transferred CAR T cells can induce dramatic responses against certain types of cancers. The ability of T cells to respond against disease depends on their ability to localize to sites, persist and exert functions, often in an immunosuppressive microenvironment, and these abilities are reflected in their phenotypes. There is currently intense interest in generating CAR T cells possessing the ideal phenotypes to confer optimal antitumor activity. In this article, we review T cell phenotypes for trafficking, persistence and function, and discuss how culture conditions and genetic makeups can be manipulated to achieve the ideal phenotypes for antitumor activities.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.

Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10−8; rs78015114, p=1·31 × 10−8; rs74795342, p=3·31 × 10−9; and rs75222709, p=3·50 × 10−9). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1–13·0). The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we performed an exploratory study of the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. Overall, we observed relatively weak associations (p < 1 × 10−4) with BP phenotypes within immune-related genes. Network and functional enrichment analyses of the top findings from the association analyses of Li response variables showed an overrepresentation of pathways participating in cell adhesion and intercellular communication. These appeared to converge on the well-known Li-induced inhibition of GSK-3β. Association analyses of age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation suggested modest contributions of genes such as RTN4, XKR4, NRXN1, NRG1/3 and GRK5 to disease characteristics. PGS analyses returned weak associations (p < 0.05) between inflammation markers and the studied BP phenotypes. Our results suggest a modest relationship between immunity and clinical features in BP. More research is needed to assess the potential therapeutic relevance.