Predictive Value of [99mTc]-MAA-Based Dosimetry in Hepatocellular Carcinoma Patients Treated with [90Y]-TARE: A Single-Center Experience.

Transarterial radioembolization is a well-established method for the treatment of hepatocellular carcinoma. The tolerability and incidence of hepatic decompensation are related to the doses delivered to the tumor and healthy liver. This retrospective study was performed at our center to evaluate whether tumor- and healthy-liver-absorbed dose levels in TARE are predictive of tumor response according to the mRECIST 1.1 criteria and overall survival. One hundred and six patients with hepatocellular carcinoma were treated with [90Y]-loaded resin microspheres and completed the follow-up. The dose delivered to each compartment was calculated using a compartmental model. The model was based on [99mTc]-labelled albumin aggregate images obtained before the start of therapy. Tumor response was assessed after three months of treatment. Kaplan-Meier analysis was used to assess survival. The mean age of our population was 66 ± 13 years with a majority being BCLC B tumors. Forty-two patients presented with portal vein thrombosis. The response rate was 57% in the overall population and 59% in patients with thrombosis. Target-to-background (TBR) values measured on initial [99mTc]MAA-SPECT-imaging and tumor model dosimetric values were associated with tumor response (p < 0.001 and p = 0.009, respectively). A dosimetric threshold of 136.5 Gy was predictive of tumor response with a sensitivity of 84.2% and specificity of 89.4%. Overall survival was 24.1 months [IQR 13.1-36.4] for patients who responded to treatment compared to 10.4 months [IQR 6.3-15.9] for the remaining patients (p = 0.022). In this cohort, the initial [99mTc]MAA imaging is predictive of response and survival. The dosimetry prior to the application of TARE can be used for treatment planning and our results also suggest that the therapy is well-tolerated. In particular, hepatic decompensation can be predicted even in the presence of PVT.

Decentralized Real-Time Anomaly Detection in Cyber-Physical Production Systems under Industry Constraints.

Anomaly detection is essential for realizing modern and secure cyber-physical production systems. By detecting anomalies, there is the possibility to recognize, react early, and in the best case, fix the anomaly to prevent the rise or the carryover of a failure throughout the entire manufacture. While current centralized methods demonstrate good detection abilities, they do not consider the limitations of industrial setups. To address all these constraints, in this study, we introduce an unsupervised, decentralized, and real-time process anomaly detection concept for cyber-physical production systems. We employ several 1D convolutional autoencoders in a sliding window approach to achieve adequate prediction performance and fulfill real-time requirements. To increase the flexibility and meet communication interface and processing constraints in typical cyber-physical production systems, we decentralize the execution of the anomaly detection into each separate cyber-physical system. The installation is fully automated, and no expert knowledge is needed to tackle data-driven limitations. The concept is evaluated in a real industrial cyber-physical production system. The test result confirms that the presented concept can be successfully applied to detect anomalies in all separate processes of each cyber-physical system. Therefore, the concept is promising for decentralized anomaly detection in cyber-physical production systems.

Hepatic decompensation after transarterial radioembolization: A retrospective analysis of risk factors and outcome in patients with hepatocellular carcinoma.

Transarterial radioembolization (TARE) is a well-established therapy for intermediate and advanced tumor stages of hepatocellular carcinoma (HCC). Treatment-associated toxicities are rare. Previous studies have outlined that the prognosis after TARE is determined primarily by tumor stage and liver function. The subset of patients benefiting from TARE remains to be defined. Sixty-one patients with HCC treated with TARE between 2015 and 2020 were retrospectively included in the study. Hepatic decompensation was defined as an increase of bilirubin or newly developed ascites that was not explained by tumor progression within 3 months after TARE. Predictive factors of hepatic decompensation and prognostic factors were assessed. Hepatic decompensation was observed in 27.9% (n = 17) of TARE-treated patients during follow-up. Albumin-bilirubin (ALBI) score at baseline and radiation dose on nontumor liver proved to be independent risk factors for the development of hepatic decompensation in multivariable regression models (ALBI score: odds ratio [OR] 6.425 [1.735;23.797], p < 0.005; radiation dose: OR 1.072 [1.016;1.131], p < 0.011). The occurrence of hepatic decompensation markedly impaired the prognosis of the patients. Survival was significantly worsened. Hepatic decompensation has shown to be an independent negative prognostic factor for death, adjusted for Barcelona Clinic Liver Cancer stage, age and ALBI grade (hazard ratio 5.694 [2.713;11.952], p < 0.001). Conclusion: Hepatic decompensation after TARE for HCC treatment is a highly relevant complication with major effects on the prognosis of patients. Main risk factors are the pretreatment ALBI score and radiation dose. There is an urgent need to define safe cutoff values and exclusion criteria for TARE to limit complications and improve patient outcomes.

Frequent, quantitative bone planar scintigraphy for determination of bone anabolism in growing mice.

BACKGROUND: To provide insight into bone turnover, quantitative measurements of bone remodeling are required. Radionuclide studies are widely used in clinical care, but have been rarely used in the exploration of the bone in preclinical studies. We describe a bone planar scintigraphy method for frequent assessment of bone activity in mice across the growing period. Since repeated venous radiotracer injections are hardly feasible in mice, we investigated the subcutaneous route. METHODS: Repeated 99mTc-hydroxymethylene diphosphonate (HMDP) tracer bone planar scintigraphy studies of the knee region and µCT to measure femur growth rate were performed in eight mice between week 6 and week 27 of life, i.e., during their growth period. Three independent investigators assessed the regions of interest (ROI). An index was calculated based on the counts in knees ROI (normalized by pixels and seconds), corrected for the activity administered, the decay between administration and imaging, and individual weights. RESULTS: A total of 93 scintigraphy studies and 85 µCT were performed. Repeated subcutaneous tracer injections were well tolerated and allowed for adequate radionuclide studies. Mean scintigraphic indexes in the knees ROI decreased from 87.4 ± 2.6 × 10-6 counts s-1 pixel-1 MBq-1 g-1 at week 6 to 15.0 ± 3.3 × 10-6 counts s-1 pixel-1 MBq-1 g-1 at week 27. The time constant of the fitted exponential decay was equal to 23.5 days. As control mean femur length assessed by µCT increased from 12.2 ± 0.8 mm at week 6 to 15.8 ± 0.2 mm at week 22. The time constant of the fitted Gompertz law was equal to 26.7 days. A correlation index of -0.97 was found between femur growth and decrease of bone tracer activity count between week 6 and 24. CONCLUSION: This methodological study demonstrates the potential of repeated bone planar scintigraphy in growing mice, with subcutaneous route for tracer administration, for quantitative assessment of bone remodeling.

Efficacy of Stereotactic Body Radiotherapy in Patients With Hepatocellular Carcinoma Not Suitable for Transarterial Chemoembolization (HERACLES: HEpatocellular Carcinoma Stereotactic RAdiotherapy CLinical Efficacy Study).

The aim of this prospective observational trial was to evaluate the efficacy, toxicity and quality of life after stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC) and to assess the results of this treatment in comparison to trans-arterial chemoembolization (TACE). Patients with HCC, treated with TACE or SBRT, over a period of 12 months, enrolled in the study. The primary endpoint was feasibility; secondary endpoints were toxicity, quality of life (QOL), local progression (LP) and overall survival (OS). Between 06/2016 and 06/2017, 19 patients received TACE and 20 SBRT, 2 of whom were excluded due to progression. The median follow-up was 31 months. The QOL remained stable before and after treatment and was comparable in both treatment groups. Five patients developed grade ≥ 3 toxicities in the TACE group and 3 in the SBRT group. The cumulative incidence of LP after 1-, 2- and 3-years was 6, 6, 6% in the SBRT group and 28, 39, and 65% in the TACE group (p = 0.02). The 1- and 2- years OS rates were 84% and 47% in the TACE group and 44% and 39% in the SBRT group (p = 0.20). In conclusion, SBRT is a well-tolerated local treatment with a high local control rates and can be safely delivered, while preserving the QOL of HCC patients.

Pulmonary Vein Stenosis as a Pitfall of Ventilation/Perfusion SPECT/CT for Pulmonary Embolism.

ABSTRACT: A 58-year-old man with progressive dyspnea and recurrent extensive left-sided pleural effusion underwent pulmonary ventilation/perfusion SPECT/CT, which showed a pronounced mismatched perfusion deficit of the entire, normally ventilated left lung. As unilateral perfusion deficits of an entire lobe are generally not due to pulmonary embolism, further CT angiography and cardiac MRI were conducted. These examinations revealed high-grade left pulmonary vein stenosis (PVS) caused by pulmonary vein isolation performed for atrial fibrillation 3 and 4 years earlier. Thus, in addition to, for example, neoplastic processes or pulmonary congenital vascular abnormalities, PVS must be considered as a differential diagnosis and possible pitfall in ventilation/perfusion SPECT/CT in dyspneic patients with prior pulmonary vein isolation.

Prognostic implications of dual tracer PET/CT: PSMA ligand and [18F]FDG PET/CT in patients undergoing [177Lu]PSMA radioligand therapy.

BACKGROUND: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with 177Lu-labeled PSMA ligands has achieved remarkable results in advanced disease stages of metastatic castration-resistant prostate cancer (mCRPC). However, not all patients benefit from this therapy. Different treatment responses could be explained by tumor heterogeneity triggered by progression and the number of prior treatments. PSMA-negative lesions can be missed on PSMA ligand PET/CT, which subsequently results in an underestimation of tumor burden. Conversely, high FDG uptake may also be an indicator of tumor aggressiveness and thus a poor prognostic marker for response to RLT and overall survival (OS). The aim of this analysis was to investigate the prognostic value of combined PSMA ligand PET/CT and [18F]fluorodeoxyglucose (FDG) PET/CT for outcome prediction in patients undergoing RLT. MATERIALS AND METHODS: This bicentric analysis included 54 patients with mCRPC who underwent both FDG and PSMA ligand PET/CT imaging before RLT. In all patients, the pattern of PSMA ligand and FDG uptake was visually assessed. Patients with at least one FDG-positive, but PSMA-negative (FDG+/PSMA-) lesions were compared to patients without any FDG+/PSMA- lesions. A log-rank analysis was used to assess the difference in OS between subgroups. RESULTS: Median OS was 11 ± 1.8 months (95% CI 7.4-14.6). A significantly lower OS (p < 0.001) was found in patients with at least one FDG+/PSMA- lesion at baseline PET/CTs (n = 18) with a median OS of 6.0 ± 0.5 months (95% CI: 5.0-7.0 months). In comparison, patients without any FDG+/PSMA- lesions (n = 36) had a median OS of 16.0 ± 2.5 months (95% CI: 11.2-20.8 months). CONCLUSION: FDG+/PSMA- lesions are a negative predictor of overall survival in patients with mCRPC undergoing RLT. However, it remains to be determined if patients with FDG+/PSMA- lesions should be excluded from PSMA RLT.

Lung Scintigraphy Imaging Features in a Young Patient With COVID-19.

A 31-year-old man developed diarrhea, fatigue, and intermittent fever for 2 weeks. The past few days he had experienced increasing dyspnea and dry cough. Ambulatory reverse transcriptase-polymerase chain reaction testing was positive for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). Because of elevated D-dimer (1.5 mg/L), a lung scintigraphy (V/Q scan) was performed as SPECT/CT. Ventilation SPECT showed reduced ventilation with central nuclide deposition, whereas perfusion SPECT was inconspicuous, excluding pulmonary embolism. However, the low-dose CT revealed bilateral ground-glass opacities as previously described in COVID-19. This case highlights the procedure and findings of V/Q scanning (without embolism) in COVID-19.

Detection of Insulinomas Using Dual-Time-Point 68Ga-DOTA-Exendin 4 PET/CT.

PURPOSE: Insulinomas are predominantly benign neuroendocrine tumors originating from beta cells within the islets of Langerhans of the endocrine pancreas. Because surgical resection represents the only curative therapy option, exact tumor localization and discrimination of insulinomas from focal or diffuse manifestations of congenital hyperinsulinism are crucial for optimal treatment strategies. We investigated the diagnostic value of glucagon-like peptide 1 receptor PET/CT using Ga-DOTA-exendin 4 for detecting insulinomas and compared the diagnostic value of PET scans performed at 2 time points. METHODS: In 10 patients with clinically and biochemically suspected insulinoma, PET/CT was performed at 1 hour (PET1) and 2 hours (PET2) after injection of Ga-DOTA-exendin 4. In this retrospective analysis, tracer uptake was visually assessed in both scans by 2 independent readers. SUVmax and tumor-to-background ratio (TBR) of focal lesions were assessed. Imaging results were compared with histopathologic findings, if patients underwent resection. RESULTS: Increased focal Ga-DOTA-exendin 4 uptake was observed in 8 of 10 patients concordantly by both readers. Seven patients with focal uptake underwent surgery with tumor enucleation and histopathologic proof of insulinoma (7/8). Two of 10 patients without focal uptake were considered to suffer from diffuse form of congenital hyperinsulinism and consequently received medical treatment. A significant increase of tumoral SUVmax on PET2 (PET1: SUVmax 20.2 ± 8.2 g/mL; PET2: SUVmax 24.7 ± 7.9 g/mL; P = 0.0018) did not result in a significant improvement in TBR (PET1: TBR 4.9 ± 1.7; PET2: TBR 4.3 ± 1.2; P = 0.2892). CONCLUSIONS: Focal uptake of Ga-DOTA-exendin 4 reliably indicated insulinomas as histopathologically confirmed in all patients undergoing consecutive surgery. The diagnostic value of PET2 was not found to be superior to PET1, indicating that a single 1-hour Ga-DOTA-exendin 4 PET/CT scan is a sufficient and convenient approach for patient care.

Estimation of subject coregistration errors during multimodal preclinical imaging using separate instruments: origins and avoidance of artifacts.

We use high-resolution [Formula: see text] data in multiple experiments to estimate the sources of error during coregistration of images acquired on separate preclinical instruments. In combination with experiments with phantoms, we completed in vivo imaging on mice, aimed at identifying the possible sources of registration errors, caused either by transport of the animal, movement of the animal itself, or methods of coregistration. The same imaging cell was used as a holder for phantoms and animals. For all procedures, rigid coregistration was carried out using a common landmark coregistration system, placed inside the imaging cell. We used the fiducial registration error and the target registration error to analyze the coregistration accuracy. We found that moving an imaging cell between two preclinical devices during a multimodal procedure gives an error of about [Formula: see text] at most. Therefore, it could not be considered a source of coregistration errors. Errors linked to spontaneous movements of the animal increased with time, to nearly 1 mm at most, excepted for body parts that were properly restrained. This work highlights the importance of animal intrinsic movements during a multiacquisition procedure and demonstrates a simple method to identify and quantify the sources of error during coregistration.

Influence of Animal Heating on PET Imaging Quantification and Kinetics: Biodistribution of 18F-Tetrafluoroborate and 18F-FDG in Mice.

Different environmental conditions under anesthesia may lead to unstable homeostatic conditions in rodents and therefore may alter kinetics. In this study, the impact of different heating conditions on PET imaging quantification was evaluated. Methods: Two groups of 6 adult female BALB/c nude mice with subcutaneously implanted tumors underwent microPET imaging after injection of 18F-labeled tetrafluoroborate or 18F-FDG. Dynamic scans were acquired under optimal and suboptimal heating conditions. Time-activity curves were analyzed to calculate uptake and washout time constants. Results: With 18F-labeled tetrafluoroborate, optimal animal heating led to a stable heart rate during acquisition (515 ± 35 [mean ± SD] beats/min), whereas suboptimal heating led to a lower heart rate and a higher SD (470 ± 84 beats/min). Both uptake and washout time constants were faster (P < 0.01) in animals maintained with optimal heating. Conclusion: Although the difference in heart rates was slight, optimal heating yielded significantly faster uptake and washout kinetics than suboptimal heating in all organs for both tracers.

MSCT versus CBCT: evaluation of high-resolution acquisition modes for dento-maxillary and skull-base imaging.

OBJECTIVES: Our aim was to conduct a quantitative and qualitative evaluation of high-resolution skull-bone imaging for dentistry and otolaryngology using different architectures of recent X-ray computed tomography systems. MATERIAL AND METHODS: Three multi-slice computed tomography (MSCT) systems and one Cone-beam computed tomography (CBCT) system were used in this study. All apparatuses were tested with installed acquisition modes and proprietary reconstruction software enabling high-resolution bone imaging. Quantitative analyses were performed with small fields of view with the preclinical vmCT phantom, which permits to measure spatial resolution, geometrical accuracy, linearity and homogeneity. Ten operators performed visual qualitative analyses on the vmCT phantom images, and on dry human skull images. RESULTS: Quantitative analysis showed no significant differences between protocols in terms of linearity and geometric accuracy. All MSCT systems present a better homogeneity than the CBCT. Both quantitative and visual analyses demonstrate that CBCT acquisitions are not better than the collimated helical MSCT mode. CONCLUSION: Our results demonstrate that current high-resolution MSCT protocols could exceed the performance of a previous generation CBCT system for spatial resolution and image homogeneity. KEY POINTS: • Quantitative evaluation is a prerequisite for comparison of imaging equipment. • Bone imaging quality could be objectively assessed with a phantom and dry skull. • The current MSCT shows better image quality than a dental CBCT system. • CBCT remains a work-in-progress technology.

Dual-isotope 99mTc-MIBI/123I parathyroid scintigraphy in primary hyperparathyroidism: comparison of subtraction SPECT/CT and pinhole planar scan.

PURPOSE: In patients with primary hyperparathyroidism, the preoperative imaging objective is to locate accurately and reliably uniglandular or multiglandular hyperfunctioning parathyroid, to guide surgery, particularly for minimally invasive method. Subtraction planar scintigraphy with dual-isotope (I/Tc-MIBI) is an efficient examination to specify abnormal parathyroid location, but without accurate anatomic reference. This lack should be avoided by a hybrid SPECT/CT image acquisition. METHODS: We compared planar scans (neck and mediastinum parallel-hole, associated with anterior neck pinhole) to neck and mediastinum SPECT/CT, all with subtraction (I/Tc-MIBI) method, in exact location of abnormal parathyroid in 50 patients with sporadic primary hyperparathyroidism. Surgical and histological findings were used as the standard of comparison. RESULTS: Sensitivity is equivalent for the 2 protocols (86% and 75% for SPECT/CT and planar protocol, respectively, P = 0.15), but SPECT/CT was highly specific (specificity 100% and 90% for SPECT/CT and planar protocol, respectively, P = 0.04). In patients with concomitant thyroid disease, subtraction SPECT/CT appeared to be more sensitive than planar protocol (88% and 62% for SPECT/CT and planar protocol, respectively, P = 0.04). CONCLUSIONS: In preoperative assessment of primary hyperparathyroidism and to guide surgery, we propose to perform first subtraction SPECT/CT and to complete it with neck pinhole, only if tomoscintigraphy is negative.

Comparing respiratory gated with delayed scans in the detection of colorectal carcinoma hepatic and pulmonary metastases with 18F-FDG PET-CT.

PURPOSE: In patients experiencing colorectal carcinoma, exhaustive analysis of indicates extent of hepatic and pulmonary surgery that prolongs survival of patients. PATIENTS AND METHODS: To localize metastasis, we compared 2 F-FDG PET-CT imaging protocols, early respiratory gated scan, and delayed scan, to standard PET imaging procedure. SUVmax and lesion-to-healthy tissue ratio were measured in 60 pulmonary and 21 hepatic lesions by each of the 2 imaging protocols. RESULTS: In the liver, metastatic lesion-to-healthy tissue ratios significantly increased on delayed scans as compared with early scans (P < 0.001). Better ratios could not be obtained when using respiratory gated scans, whereas more lesions were detected on delayed scans. In the lungs, metastatic lesion- to-healthy tissue ratio increased significantly on delayed scans for largest lesions (P < 0.001). Ratios were not better when exploring smallest metastatic lesions or when using respiratory gated scans. Factors interfering with F-FDG PET-CT sensitivity are discussed, such as respiratory motion and high FDG physiological uptake in healthy liver parenchyma. CONCLUSIONS: Our studies indicate that routine acquisitions should use delayed hepatic scans for all patients referred for evaluation, recurrence check, or monitoring of colorectal adenocarcinoma. Delayed pulmonary scans are useful for the largest metastatic lesions and should be used in addition to early scan. In our experience, respiratory gated scans seem to be less convenient because of a low sensitivity in detection, as compared with the delayed technique; in addition, this technique is currently complicated by some technical issues, although these might be overcome with new gated protocols.

Attenuation of neurovirulence, biodistribution, and shedding of a poliovirus:rhinovirus chimera after intrathalamic inoculation in Macaca fascicularis.

A dependence of poliovirus on an unorthodox translation initiation mode can be targeted selectively to drive viral protein synthesis and cytotoxicity in malignant cells. Transformed cells are naturally susceptible to poliovirus, due to widespread ectopic upregulation of the poliovirus receptor, Necl-5, in ectodermal/neuroectodermal cancers. Viral tumor cell killing and the host immunologic response it engenders produce potent, lasting antineoplastic effects in animal tumor models. Clinical application of this principle depends on unequivocal demonstration of safety in primate models for paralytic poliomyelitis. We conducted extensive dose-range-finding, toxicity, biodistribution, shedding, and neutralizing antibody studies of the prototype oncolytic poliovirus recombinant, PVS-RIPO, after intrathalamic inoculation in Macaca fascicularis. These studies suggest that intracerebral PVS-RIPO inoculation does not lead to viral propagation in the central nervous system (CNS), does not cause histopathological CNS lesions or neurological symptoms that can be attributed to the virus, is not associated with extraneural virus dissemination or replication and does not induce shedding of virus with stool. Intrathalamic PVS-RIPO inoculation induced neutralizing antibody responses against poliovirus serotype 1 in all animals studied.

PET, SPECT, CT, and MRI in Mouse Cardiac Phenotyping: An Overview.

This overview first summarizes the last decade of continuous developments and improvements in pre-clinical imaging methods that are now essential tools for in vivo evaluation of cardiac morphology and function in living mice, involving nuclear emission of labeled molecules (micro-PET and micro-SPECT) and electromagnetic wave interactions with biological tissues (micro-CT and micro-MRI). In the following, and for better understanding, the basic physical principles and specific technical innovations of the aforementioned imaging methods are reviewed. Specificity, sensitivity, and spatial and temporal resolutions, together with the corresponding advantages and weaknesses of each method are then discussed, and cardiac image-acquisition protocols and illustrative examples are given for each modality. Emerging hybrid cardiac imaging is also presented and illustrated. Then, recent biological insights provided by mouse cardiac imaging are presented. Finally, imaging strategies in mouse cardiac phenotyping involving the aforementioned methods, adding metabolic and molecular information to morphological data, are emphasized and discussed. Curr. Protoc. Mouse Biol. 2:129-144 © 2012 by John Wiley & Sons, Inc.

Oncolytic poliovirus against malignant glioma.

In cancerous cells, physiologically tight regulation of protein synthesis is lost, contributing to uncontrolled growth and proliferation. We describe a novel experimental cancer therapy approach based on genetically recombinant poliovirus that targets an intriguing aberration of translation control in malignancy. This strategy is based on the confluence of several factors enabling specific and efficacious cancer cell targeting. Poliovirus naturally targets the vast majority of ectodermal/neuroectodermal cancers expressing its cellular receptor. Evidence from glioblastoma patients suggests that the poliovirus receptor is ectopically upregulated on tumor cells and may be associated with stem cell-like cancer cell populations and proliferating tumor vasculature. We exploit poliovirus' reliance on an unorthodox mechanism of protein synthesis initiation to selectively drive viral translation, propagation and cytotoxicity in glioblastoma. PVSRIPO, a prototype nonpathogenic poliovirus recombinant, is scheduled to enter clinical investigation against glioblastoma.

Adaptation of an ICAM-1-tropic enterovirus to the mouse respiratory tract.

Respiratory tract (RT) infections by members of the enterovirus (EV) genus of the Picornaviridae family are the most frequent cause for the common cold and a major factor in the exacerbation of chronic pulmonary diseases. The lack of a practical small-animal model for these infections has obstructed insight into pathogenic mechanisms of the common cold and their role in chronic RT illness and has hampered preclinical evaluation of antiviral strategies. Despite significant efforts, it has been difficult to devise rodent models that exhibit viral replication in the RT. This is due mainly to well-known intracellular host restrictions of EVs with RT tropism in rodent cells. We report the evolution of variants of the common-cold-causing coxsackievirus A21, an EV with tropism for the human intercellular adhesion molecule 1 (hICAM-1), through serial passage in the lungs of mice transgenic for the hICAM-1 gene. This process was accompanied by multiple changes in the viral genome, suggesting exquisite adaptation of hICAM-1-tropic enteroviruses to the specific growth conditions within the RT. In vivo mouse RT-adapted, variant coxsackievirus A21 exhibited replication competence in the lungs of hICAM-1 transgenic mice, providing a basis for unraveling EV-host interactions in the mouse RT.

Carbon tube electrodes for electrocardiography-gated cardiac multimodality imaging in mice.

This report describes a simple design of noninvasive carbon tube electrodes that facilitates electrocardiography (ECG) in mice during cardiac multimodality preclinical imaging. Both forepaws and the left hindpaw, covered by conductive gel, of mice were placed into the openings of small carbon tubes. Cardiac ECG-gated single-photon emission CT, X-ray CT, and MRI were tested (n = 60) in 20 mice. For all applications, electrodes were used in a warmed multimodality imaging cell. A heart rate of 563 ± 48 bpm was recorded from anesthetized mice regardless of the imaging technique used, with acquisition times ranging from 1 to 2 h.

MAPK signal-integrating kinase controls cap-independent translation and cell type-specific cytotoxicity of an oncolytic poliovirus.

Many animal viruses exhibit proficient growth in transformed cells, a property that has been harnessed for the development of novel therapies against cancer. Despite overwhelming evidence for this phenomenon, understanding of the molecular mechanisms enabling tumor-cell killing is rudimentary for most viruses. We report here that growth and cytotoxicity of the prototype oncolytic poliovirus (PV), PVSRIPO, in glioblastoma multiforme (GBM) is promoted by mitogen-activated protein kinases (MAPKs) converging on the MAPK signal-integrating kinase 1 (Mnk1) and its primary substrate, the eukaryotic initiation factor (eIF) 4E. Inducing Mnk1-catalyzed eIF4E phosphorylation through expression of oncogenic Ras substantially enhanced PVSRIPO translation, replication, and cytotoxicity in resistant cells. This effect was mimicked by expression of constitutively active forms of Mnk1 and correlated with enhanced translation of subgenomic reporter RNAs. Our findings implicate Mnk1 activity in stimulation of PVSRIPO cap-independent translation, an effect that can be synergistically enhanced by inhibition of the phosphoinositide-3 kinase (PI3K).