We present the genomic sequence of Legionella pneumophila, the bacterial agent of Legionnaires' disease, a potentially fatal pneumonia acquired from aerosolized contaminated fresh water. The genome includes a 45-kilobase pair element that can exist in chromosomal and episomal forms, selective expansions of important gene families, genes for unexpected metabolic pathways, and previously unknown candidate virulence determinants. We highlight the genes that may account for Legionella's ability to survive in protozoa, mammalian macrophages, and inhospitable environmental niches and that may define new therapeutic targets.

The abnormal expression of tumor-associated proteases and lowered extracellular pH are important signatures strongly associated with cancer invasion, progression, and metastasis. However, their malignant effects were mainly identified using cell and tissue studies. To noninvasively visualize the heterogeneous distribution of these abnormal indicators in vivo and further disclose their collective behaviors, a target-triggered fluorescent nanoprobe composed of a ratiometric pH-sensitive dye, a near-infrared dye (Cy5.5), and biocompatible FeO nanoparticles was constructed. The pH-sensitive dye was linked through a peptide substrate of matrix metalloprotease-9 (MMP-9) with FeO nanoparticles to establish a Förster resonance energy transfer (FRET) system for sensing the pH of the tumor microenvironment. Cy5.5 served as an internal reference for forming a secondary ratiometric fluorescent system together with the activated pH dye to enable the visualization of protease activities in vivo. Extensive imaging studies using a mouse model of human colon cancer revealed that the overexpression of MMP-9 and abnormal microenvironmental pH quantitatively visualized by this dual-ratiometric probe are spatially heterogeneous and synergistically guide the tumor invasion in vivo.

IntroductionB-cell chronic lymphocytic leukemia (B-CLL) represents the most common leukemia in the Western countries with an estimated incidence of 1 per 100 000 per year. The disease is characterized by the monoclonal expansion of B lymphocytes expressing the CD5 marker and exhibiting a long life span, possibly because of a perturbed apoptotic program. 1 Current knowledge of the molecular pathogenesis of B-CLL is limited because no specific genetic alteration has yet been associated with this disease. In particular, B-CLL is not associated with reciprocal balanced chromosomal translocations. 2 Accordingly, none of the proto-oncogenes involved in chromosomal translocations in other mature B cell malignancies, including cyclin D1, 4 Although in a fraction of B-CLL cases, inactivation of the tumor suppressor gene p53 (on chromosome 17p13) and deletions or mutations of the ATM gene (on chromosome 11q22-23) have been reported, 5-9 such lesions were observed in late stages of the disease and may not represent primary tumorigenic events.Chromosome 13q14 deletions (approximately 50% of the patients) 2,10,11 are the commonest chromosomal alterations associated with B-CLL, followed by structural aberrations of chromosome 11q (19% of the cases) and trisomy of chromosome 12 (15%). 2 Moreover, chromosome 13 deletions can be the only cytogenetically detectable abnormality, suggesting an early role in B-CLL pathogenesis. Together, these findings point to the presence in this region of a tumor suppressor gene whose loss or inactivation may be crucial for the leukemogenesis.Deletions of chromosome 13q14 have also been reported in a variety of human tumors, including various other types of lymphoid tumors 12-17 and myeloid leukemias, 18 as well as prostate, 19,20 head and neck, 21 and non-small-cell lung cancers. 22 Although the deleted region of chromosome 13q14 has not yet been defined precisely in most of these neoplasms, these observations suggest that a common tumor suppressor gene may reside on this chromosomal segment.To identify the B-CLL-associated tumor suppressor gene, we previously constructed a high-density contiguous cosmid-based physical map encompassing the deleted interval. 10 This map allowed us to demonstrate that somatic loss at 13q14 occurs in 54% of the patients 10 (and unpublished results) and that the loss is monoallelic in 81% of such cases and biallelic in the remaining 19%. A minimal deleted region (MDR) in B-CLL, spanning less than 300 kilobase (kb) and representing the site of the B-CLLassociated putative tumor suppressor gene, was assigned on our For personal use only. on April 29, 2019. by guest www.bloodjournal.org From physical map in the interval between markers 173a12-82 and 138G4/1.3R. 10 This interval has also been confirmed by other studies. 13 In fact, the MDR exhibits a partial overlap with the regions of deletion as assigned in additional reports, [23][24][25][26] and it includes a locus of 10 kb that was previously defined as a minimal consensus for 13q14 deletion in B-CLL, based on the ...

Exogenous FeIII can be used for cancer magnetic resonance (MR) imaging and potentially for cancer treatment by a ferroptosis pathway or photothermal ablation. To achieve this, effective and accurate delivery of FeIII to cancerous sites is critical, requiring a balance of release kinetics of Fe3+ in tumorous and normal tissues. A nanoprobe is described consisting of upconversion luminescence (UCL) nanoparticles as a core and a coordinatively unsaturated FeIII‐containing Fe3+/gallic acid complex as a shell. Owing to the introduction of an unsaturated coordination structure, FeIII in the nanoprobe can be released only in the tumor microenvironment in response to the lightly acidic pH. The multiple UCLs are used for quantitatively visualizing the release of Fe3+ in vivo, whilst the release resultant serves as a photothermal agent. This nanoprobe exhibited ligand‐free tumor targeting ability, activatable MR imaging performance, and efficacious therapeutic effects against tumors in vivo.

Pancreatic ductal adenocarcinoma, as one of the most aggressive cancers, is characterized by rich desmoplastic stroma that forms a physical barrier for anticancer drugs. To address this issue, we herein report a two-step sequential delivery strategy for targeted therapy of pancreatic cancer with gemcitabine (GEM). In this sequential strategy, metformin (MET) was first administrated to disrupt the dense stroma, based on the fact that MET downregulated the expression of fibrogenic cytokine TGF-β to suppress the activity of pancreatic stellate cells (PSCs), through the 5′-adenosine monophosphate-activated protein kinase pathway of PANC-1 pancreatic cancer cells. In consequence, the PSC-mediated desmoplastic reactions generating αsmooth muscle actin and collagen were inhibited, which promoted the delivery of GEM and pH (low) insertion peptide (pHLIP) comodified magnetic nanoparticles (denoted as GEM-MNP-pHLIP). In addition, pHLIP largely increased the binding affinity of the nanodrug to PANC-1 cells. The targeted delivery and effective accumulation of MET/GEM-MNP-pHLIP in vivo were confirmed by magnetic resonance imaging enhanced by the underlying magnetic nanoparticles. The tumor growth inhibition of the sequential MET and GEM-MNP-pHLIP treatment were investigated on both subcutaneous and orthotopic tumor mice models. A remarkably improved therapeutic efficacy, for example, up to 91.2% growth inhibition ratio over 30 d of treatment, well-exemplified the novel cascade treatment for pancreatic cancer and the innovative use of MET.

Due to their intrinsic physical properties potentially useful for imaging and therapy as well as their highly engineerable surface, biocompatible inorganic nanoparticles offer novel platforms to develop advanced diagnostic and therapeutic agents for improved detection and more efficacious treatment of major diseases. The in vivo application of inorganic nanoparticles was demonstrated more than two decades ago, however it turns out to be very complicated as nanomaterials exhibit much more sophisticated pharmacokinetic properties than conventional drugs. In this review, we first discuss the in vivo behavior of inorganic nanoparticles after systematic administration, including the basic requirements for nanoparticles to be used in vivo, the impact of the particles' physicochemical properties on their pharmacokinetics, and the effects of the protein corona formed across the nano-bio interface. Next, we summarize the state-of-the-art of the preparation of biocompatible inorganic nanoparticles and bioconjugation strategies for obtaining target-specific nanoprobes. Then, the advancements in sensitive tumor imaging towards diagnosis and visualization of the abnormal signatures in the tumor microenvironment, together with recent studies on atherosclerosis imaging are highlighted. Finally, the future challenges and the potential for inorganic nanoparticles to be translated into clinical applications are discussed.

Improving the effectiveness of cancer therapy will require tools that enable more specific cancer targeting and improved tumor visualization. Theranostics have the potential for improving cancer care because of their ability to serve as both diagnostics and therapeutics; however, their diagnostic potential is often limited by tissue-associated light absorption and scattering. Herein, we develop CuInSe2@ZnS:Mn quantum dots (QDs) with intrinsic multifunctionality that both enable the accurate localization of small metastases and act as potent tumor ablation agents. By leveraging the growth kinetics of a ZnS shell on a biocompatible CuInSe2 core, Mn doping, and folic acid functionalization, we produce biocompatible QDs with high near-infrared (NIR)-II fluorescence efficiency up to 31.2%, high contrast on magnetic resonance imaging (MRI), and preferential distribution in 4T1 breast cancer tumors. MRI-enabled contrast of these nanoprobes is sufficient to timely identify small metastases in the lungs, which is critically important for preventing cancer spreading and recurrence. Further, exciting tumor-resident QDs with NIR light produces both fluorescence for tumor visualization through radiative recombination pathways as well as heat and radicals through nonradiative recombination pathways that kill cancer cells and initiate an anticancer immune response, which eliminates tumor and prevents tumor regrowth in 80% of mice.

Studies reveal that malignant tumors feature uneven distributions of some key biomarkers across the entire tumorous region. Nevertheless,o nly very limited progress has been made towards non-invasive and quantitative detection of tumor-specific biomarkers in vivo,e specially with clinically compatible imaging modalities.R eported here is an Fe 3 O 4 nanoparticle-based glutathione (GSH) responsive magnetic resonance imaging (MRI) probe that can form particle aggregates within tumors in vivo to give rise to strong GSH concentration dependent interlocked relaxivities.Aquantitative correlation between the interlocked MRI signals and local GSH concentration was established, and further applied for mapping the heterogeneous distribution of GSH within an intracranial tumor (2.4 mm 1.6 mm) in vivo.T his methodology will offer ap ractical route for quantitatively mapping tumor-specific biomarkers in vivo with unlimited detection depth, which largely challenges optical-imaging-based approaches.