Viral strategy to manipulate the cellular environment for its own genome replication.

<p>Induction of lytic replication elicits ATM-dependent host cellular DNA damage responses, because newly synthesized viral DNA is sensed as “aberrant” <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001158#ppat.1001158-Kudoh1" target="_blank">[9]</a>. The ATM signaling cascade, which is modified by BGLF4 kinase-mediated γ-H2AX induction <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001158#ppat.1001158-Tarakanova1" target="_blank">[35]</a>, phosphorylates and activates downstream molecules including CHK2 and p53. However, phosphorylated p53, which can transactivate p21^Cip1/Waf1 CDK inhibitor, associates with high affinity to BZLF1 protein–formed ECS ubiquitin E3 ligase complex and then is ubiquitinated <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001158#ppat.1001158-Sato3" target="_blank">[37]</a>. On the other hand, EBV protein kinase phosphorylates p27^Kip1 CDK inhibitor, thereby leading to phosphorylation-mediated ubiquitination by the SCF complex <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001158#ppat.1001158-Iwahori1" target="_blank">[65]</a>. Since these ubiquitinated proteins are degraded in a proteasome-dependent manner, an S-phase-like environment with high CDK activity required for efficient viral replication is maintained during EBV lytic infection. In parallel with this, replicative helicase activity of the MCM complex is inactivated by BGLF4-mediated phosphorylation of MCM4, causing the inhibition of chromosomal DNA replication <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001158#ppat.1001158-Kudoh4" target="_blank">[34]</a>. Phosphorylated RPA induced by the DNA damage response stimulates viral DNA replication through homologous recombinational repair <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001158#ppat.1001158-Kudoh5" target="_blank">[40]</a>. Taken together, EBV manipulates various signaling cascades and thereby achieves efficient viral replication.</p

Theranostic Nanoparticles for MRI-Guided Thermochemotherapy: “Tight” Clustering of Magnetic Nanoparticles Boosts Relaxivity and Heat-Generation Power

Magnetic-resonance-imaging (MRI)-guided magnetic thermochemotherapy is a potentially invasive technique combining diagnosis and treatment. It requires the development of multifunctional nanoparticles with (1) biocompatibility, (2) high relaxivity, (3) high heat-generation power, (4) controlled drug release, and (5) tumor targeting. Here, we show the synthesis of such multifunctional nanoparticles (“Core–Shells”) and the feasibility of MRI-guided magnetic thermochemotherapy using the synthesized nanoparticles. “Tight” iron-oxide nanoparticle clustering to zero interparticle distance within the Core–Shells boosts the relaxivity and heat-generation power while maintaining biocompatibility. The initial Core–Shell drug release occurs in response to an alternating magnetic field (AMF) and continues gradually after removal of the AMF. Thus, a single Core–Shell dose realizes continuous chemotherapy over a period of days or weeks. The Core–Shells accumulate in abdomen tumors, facilitating MRI visualization. Subsequent AMF application induces heat generation and drug release within the tumors, inhibiting their growth. Core–Shell magnetic thermochemotherapy exhibits significantly higher therapeutic efficacy than both magnetic hyperthermia and chemotherapy alone. More importantly, there are minimal side effects. The findings of this study introduce new perspectives regarding the development of materials for MRI, magnetic hyperthermia, and drug delivery systems. Both conventional and novel iron-oxide-based materials may render theranostics (i.e., techniques fusing diagnosis and treatment) feasible

Kaplan-Meier curves of progression-free survival (PFS) for ⁶²Cu-ATSM PET (a) and ¹⁸F-FDG PET (b) in patients with HNC.

<p>Two groups of high (dotted lines) and low (solid lines) tracer accumulation were determined by each cut-off value of the tumor-to-muscle ratios (TMR_ATSM and TMR_FDG). TMR_ATSM, one of the intensity-based redox parameters, showed a significant difference in PFS between two groups (<i>p</i> = 0.03), whereas TMR_FDG, one of the intensity-based metabolic parameters, did not (<i>p</i> = 0.15). The three-year PFS rate was 74% for patients with lower accumulation tumors (TMR_ATSM ≤ 3.2) and 29% for those with over-reductive tumors (TMR_ATSM > 3.2).</p

Cu(II)-ATSM and fluorinated nitroimidazole (FR-NO₂) retention mechanisms in cancer cells.

<p>During the course of tracer retention in cancer cells, key factors are shown in red for both Cu(II)-ATSM and fluorinated nitroimidazole (FR-NO₂). Cu(II)-ATSM is a neutral lipophilic molecule that easily penetrates cell membranes. In cancer cells over-reduced due to mitochondrial dysfunction and hypoxia, Cu(II)-ATSM may be converted to [Cu(I)-ATSM]^- with electrons (e^-) supplied from abnormally reduced mitochondria in a number of forms including NADH and NADPH, and retained in cells because of its negative charge. Cu(I) is subsequently dissociated by reactive chemical species (RS) generated in the reduced condition and is irreversibly trapped as Cu(I)-RS in cells. FR-NO₂ pass through cell membranes by slow diffusion and may be converted to a reduced form, FR-NO₂^-, by xanthine oxidoreductase. Under hypoxic conditions (low pO₂), FR-NO₂^- may be reduced further by intracellular reductases in a low oxygen concentration-dependent manner to R-NH₂, which binds covalently to macromolecules in cancer cells.</p

PET images of ⁶²Cu-ATSM (a) and ¹⁸F-FDG (b) of a 64-year-old man with right parotid cancer.

<p>Tumor contours were delineated to include voxels presenting SUV values greater than 70% SUV_ATSM of 6.9 for ⁶²Cu-ATSM PET and 40% SUV_FDG of 8.8 for ¹⁸F-FDG PET. Volume-based parameters were calculated as follows; RTV = 5.9, MTV = 6.3, TLR = 32.0, and TLG = 30.0. He developed iliac bone metastasis 15 months after being treated (CRT + SO). The volume-based redox parameters, RTV and TLR, which were greater than each cut-off value (RTV: 2.9 and TLR: 14.0, respectively), correctly predicted his outcome. On the other hand, volume-based metabolic indices were smaller than each cut-off value.</p

Kaplan-Meier curves of progression-free survival (PFS) (a) and cause-specific survival (CSS) (b) in patients with HNC.

<p>Two groups with the accumulation of large (> 8.1, dotted lines) and small (≤ 8.1, solid lines) volumes of ¹⁸F-FDG were determined by metabolic-tumor-volume (MTV), one of the volume-based metabolic parameters. The two groups showed significant differences in PFS (<i>p</i> = 0.03) and CSS (<i>p</i> = 0.03). Three-year PFS and CSS rates were 70% and 73% for patients with a smaller metabolic volume (MTV ≤ 8.1), and 30% and 37% for those with a larger metabolic volume (MTV > 8.1), respectively.</p

Patient Characteristics.

<p>Patient Characteristics.</p

Hypothetical relationships between excess ROS production levels, cancer cell states, and treatment options.

<p>The arrow indicates the direction of the level of excess ROS from the normal to lethal range. The black deformed quadrangle represents excess ROS concentrations. SO: surgical operation, RT: radiation therapy, CT: chemotherapy, CR: complete response.</p

PET images of ⁶²Cu-ATSM (a) and ¹⁸F-FDG (b) of a 62-year-old man with tongue cancer.

<p>Tumor contours were delineated to include voxels presenting SUV values greater than 70% SUV_ATSM of 4.6 for ⁶²Cu-ATSM PET and 40% SUV_FDG of 10.1 for ¹⁸F-FDG PET. Volume-based parameters were calculated as follows; RTV = 3.6, MTV = 19.3, TLR = 12.8, and TLG = 115.9. He is still alive without any recurrence or metastasis after being treated (CRT + SO). The volume-based redox parameter, TLR, which was smaller than the cut-off value of 14.0, correctly predicted his outcome. On the other hand, volume-based metabolic indices were greater than each cut-off value.</p

Evaluation of Focal Liver Reaction after Proton Beam Therapy for Hepatocellular Carcinoma Examined Using Gd-EOB-DTPA Enhanced Hepatic Magnetic Resonance Imaging - Table 3

<p>Evaluation of Focal Liver Reaction after Proton Beam Therapy for Hepatocellular Carcinoma Examined Using Gd-EOB-DTPA Enhanced Hepatic Magnetic Resonance Imaging</p> - Table