Theranostic Imaging of the Kinases and Proteases that Modulate Cell Death and Survival

Several signaling cascades are involved in cell death, with a significant amount of crosstalk between them. Despite the complexity of these cascades several key pro-survival and pro-death players have been identified. These include PI3-kinase, AKT and caspase-3. Here we review the approaches used to date to perform molecular imaging of these important targets. We focus in particular on approaches that include the possibility of modulating the activity of these kinases and proteases in a theranostic approach

Dietary Probiotic Bacillus licheniformis TC22 Increases Growth, Immunity, and Disease Resistance, against Vibrio splendidus Infection in Juvenile Sea Cucumbers Apostichopus japonicus

In this study we examined the effects of probiotic Bacillus licheniformis TC22 on growth, immunity, and disease resistance against Vibrio splendidus in juvenile sea cucumbers Apostichopus japonicus. For 30 days, sea cucumbers were fed diets with TC22 at 0 (control), 105, 107, and 109 CFU/g respectively. Results showed that dietary TC22 at 109 CFU/g significantly improved (P0.05). Dietary TC22 at 109 CFU/g significantly improved phagocytosis, and total nitric oxide synthase activity in sea cucumbers (P0.05). Respiratory burst in sea cucumbers fed dietary TC22 at 109 CFU/g was significantly higher than those fed dietary TC22 at 107 CFU/g (P<0.05). Cumulative mortality after V. splendidus challenge decreased significantly in the sea cucumbers fed with TC22 at 109 CFU/g (P<0.05). The present study confirmed dietary B. licheniformis TC22 at 109 CFU/g could significantly improve immunity and disease resistance in juvenile A. japonicus

PEG-Like Nanoprobes: Multimodal, Pharmacokinetically and Optically Tunable Nanomaterials

“PEG-like Nanoprobes” (PN’s) are pharmacokinetically and optically tunable nanomaterials whose disposition in biological systems can be determined by fluorescence or radioactivity. PN’s feature a unique design where a single PEG polymer surrounds a short fluorochrome and radiometal bearing peptide, and endows the resulting nanoprobe with pharmacokinetic control (based on molecular weight of the PEG selected) and optical tunability (based on the fluorochrome selected), while the chelate provides a radiolabeling option. PN’s were used to image brain capillary angiography (intravital 2-photon microscopy), tumor capillary permeability (intravital fluorescent microscopy), and the tumor enhanced permeability and retention (EPR) effect (111In-PN and SPECT). Clinical applications of PN’s include use as long blood half-life fluorochromes for intraoperative angiography, for measurements of capillary permeability in breast cancer lesions, and to image EPR by SPECT, for stratifying patient candidates for long-circulating nanomedicines that may utilize the EPR mechanism

Use of a Single Hybrid Imaging Agent for Integration of Target Validation with In Vivo and Ex Vivo Imaging of Mouse Tumor Lesions Resembling Human DCIS

Screening of biomarker expression levels in tumor biopsy samples not only provides an assessment of prognostic and predictive factors, but may also be used for selection of biomarker-specific imaging strategies. To assess the feasibility of using a biopsy specimen for a personalized selection of an imaging agent, the chemokine receptor 4 (CXCR4) was used as a reference biomarker. Methods: A hybrid CXCR4 targeting peptide (MSAP-Ac-TZ14011) containing a fluorescent dye and a chelate for radioactive labeling was used to directly compare initial flow cytometry–based target validation in fresh tumor tissue to $in$ $vivo$ single photon emission computed tomography (SPECT) imaging and $in$ $vivo$ and $ex$ $vivo$ fluorescence imaging. Results: Flow cytometric analysis of mouse tumor derived cell suspensions enabled discrimination between 4T1 control tumor lesions (with low levels of CXCR4 expression) and CXCR4 positive early, intermediate and late stage MIN-O lesions based on their CXCR4 expression levels; CXCR4$^{basal}$, CXCR4$^+$ and CXCR4$^{++}$ cell populations could be accurately discriminated. Mean fluorescent intensity ratios between expression in MIN-O and 4T1 tissue found with flow cytometry were comparable to ratios obtained with in vivo SPECT/CT and fluorescence imaging, ex vivo fluorescence evaluation and standard immunohistochemistry. Conclusion: The hybrid nature of a targeting imaging agent like MSAP-Ac-TZ14011 enables integration of target selection, in vivo imaging and ex vivo validation using a single agent. The use of biopsy tissue for biomarker screening can readily be expanded to other targeting hybrid imaging agents and can possibly help increase the clinical applicability of tumor-specific imaging approaches

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

Role and intervention of PAD4 in NETs in acute respiratory distress syndrome

Abstract Background Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. Acute respiratory distress syndrome (ARDS) is a common sepsis-associated injury that can increase postoperative mortality but the mechanism is still unclear. Main text The role of neutrophils in the pathophysiology of sepsis was deeply challenged after the discovery of NETosis, a process resulting in neutrophil extracellular traps (NETs) release. NETs can support thrombin generation and the concept of immunothrombosis has emerged as a new innate response to infection. Immunothrombosis leads to thrombosis in microvessels and supports immune cells together with specific thrombus-related molecules. ARDS is a common sepsis-associated organ injury. Immunothrombosis participates in thrombosis in pulmonary capillaries. Intervention regarding immunothrombosis in ARDS is a key scientific problem. PAD4 is the key enzyme regulating the NET skeleton protein histone H3 to citrulline histone to form NETs in immune thrombosis. This review summarizes NETosis and immunohaemostasis, ARDS and therapeutic opportunities targeting PAD4 via PAD4 inhibitors and lncRNAs potentially, providing future therapies. Conclusions We identified and summarized the fundamental definition of ARDS and the concept of immune thrombosis and its composition. NETs activation has become particularly relevant in the formation of immune thrombosis. The taskforce highlighted the intervention targets of PAD4, including noncoding RNAs, potentially providing future therapeutic targets to confront the high postoperative mortality of ARDS

Theranostic Imaging of the Kinases and Proteases that Modulate Cell Death and Survival

Several signaling cascades are involved in cell death, with a significant amount of crosstalk between them. Despite the complexity of these cascades several key pro-survival and pro-death players have been identified. These include PI3-kinase, AKT and caspase-3. Here we review the approaches used to date to perform molecular imaging of these important targets. We focus in particular on approaches that include the possibility of modulating the activity of these kinases and proteases in a theranostic approach.</p