Absorption, metabolism, and excretion of [14 C]dersimelagon, an investigational oral selective melanocortin 1 receptor agonist, in preclinical species and healthy volunteers.

Dersimelagon (formerly MT-7117) is a novel, orally administered nonpeptide small molecule selective agonist for melanocortin 1 receptor currently being investigated for the treatment of erythropoietic protoporphyria, X-linked protoporphyria, and diffuse cutaneous systemic sclerosis (dcSSc). Findings of studies evaluating the absorption, distribution, metabolism, and excretion (ADME) of dersimelagon following a single dose of [14 C]dersimelagon in healthy adult volunteers (N = 6) who participated in phase 1, single-center, open-label, mass balance study (NCT03503266), and in preclinical animal models are presented. Rapid absorption and elimination were observed following oral administration of [14 C]dersimelagon in clinical and nonclinical studies, with a mean Tmax of 30 min in rats and 1.5 h in monkeys, and a median Tmax of 2 h in humans. In rats, there was a widespread distribution of [14 C]dersimelagon-related material, but little or no radioactivity was detected in the brain or fetal tissues. In humans, elimination of radioactivity in urine was negligible (excretion of radioactivity into the urine: 0.31% of dose), and the primary route of excretion was feces, with more than 90% of the radioactivity recovered through 5 days postdose. Based on these findings, dersimelagon is not retained in the human body. Findings from humans and animals suggest dersimelagon is extensively metabolized to the glucuronide in the liver, which is eliminated in bile, and hydrolyzed to unchanged dersimelagon in the gut. The results to date for this orally administered agent elucidate the ADME of dersimelagon in human and animal species and support its continued development for the treatment of photosensitive porphyrias and dcSSc.

Results from a first-in-human study of dersimelagon, an investigational oral selective MC1R agonist.

PURPOSE: To describe outcomes from the first-in-human study of dersimelagon, an investigational oral selective MC1R agonist, under development for the treatment of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). METHODS: In this double-blind, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending oral doses of dersimelagon in healthy participants were evaluated. RESULTS: Dersimelagon was generally well tolerated in healthy participants, with the most common TEAEs being lentigo (52.8%) and skin hyperpigmentation (50.0%) after multiple doses. Systemic exposure to dersimelagon in plasma (based on AUC0-∞ and Cmax) increased in a slightly more than dose-proportional manner over the 1- to 600-mg single-dose range. Following multiple doses, dersimelagon was rapidly absorbed (median Tmax ranging from 4 to 5 h postdose on days 1 and 14). Mean t1/2 ranged from 10.56 to 18.97 h on day 14, and the steady state of plasma concentration was generally reached by 5 days of multiple dosing. There were no observable effects of age or race on the PK profile of dersimelagon or its metabolite dersimelagon glucuronide. No treatment-related effects on melanin density (MD) were observed following single doses of dersimelagon; however, after multiple doses, increases in MD were observed in participants receiving 150 and 300 mg dersimelagon. CONCLUSION: Our study results indicate that dersimelagon is generally well tolerated and demonstrates a generally consistent PK profile across diverse subgroups. Treatment-related increases in MD warrant further investigation in a larger study population and in patients with EPP and XLP. TRIAL REGISTRATION: A Study to Investigate the Safety, Tolerability and Pharmacokinetics of MT-7117 in Healthy Subjects, NCT02834442, https://clinicaltrials.gov/ct2/show/NCT02834442 , registration began July 2016.

Development of a Machine Learning Model to Predict Cardiac Arrest during Transport of Trauma Patients.

BACKGROUND: Trauma is a serious medical and economic burden worldwide, and patients with traumatic injuries have a poor survival rate after cardiac arrest. The authors developed a prediction model specific to prehospital trauma care and used machine learning techniques to increase its accuracy. METHODS: This retrospective observational study analyzed data from patients with blunt trauma injuries due to traffic accidents and falls from January 1, 2018, to December 31, 2019. The data were collected from the National Emergency Medical Services Information System, which stores emergency medical service activity records nationwide in the United States. A random forest algorithm was used to develop a machine learning model. RESULTS: The prediction model had an area under the curve of 0.95 and a negative predictive value of 0.99. The feature importance of the predictive model was highest for the AVPU (Alert, Verbal, Pain, Unresponsive) scale, followed by oxygen saturation (SpO2). Among patients who were progressing to cardiac arrest, the cutoff value was 89% for SpO2 in nonalert patients. CONCLUSIONS: The machine learning model was highly accurate in identifying patients who did not develop cardiac arrest.

The Oral Bioavailability and Effect of Various Gastric Conditions on the Pharmacokinetics of Dersimelagon in Healthy Adult Volunteers.

Dersimelagon is a novel orally administered selective agonist for melanocortin receptor 1 being investigated for the treatment of erythropoietic protoporphyria, X-linked protoporphyria, and diffuse cutaneous systemic sclerosis. In this open-label, multicenter, randomized, two-cohort, sequential crossover study, the relative oral bioavailability of two tablet formulations of dersimelagon was evaluated, and the effect of various gastric conditions (from a high-fat meal, a proton-pump inhibitor, and an acidic carbonated beverage) on the pharmacokinetics of dersimelagon were assessed in healthy participants (N = 50). Both tablet formulations demonstrated rapid absorption, and the 100-mg tablets showed a 97% relative oral bioavailability versus 50-mg tablets. No effect was observed on overall exposure (area under the plasma concentration versus time curve [AUC]) following consumption of a high-fat meal, and Cmax was higher (22%, 90% confidence interval [CI] 1.05-1.42) in a fed state compared with fasted conditions. Similarly, overall exposure AUC of dersimelagon was comparable following administration alone or in combination with esomeprazole; however, coadministration of esomeprazole led to a slight decrease in Cmax (fasted: 9%, 90%CI 0.77-1.07; fed: 24%, 90%CI 0.66-0.88) compared with administration of dersimelagon alone. In general, the consumption of an acidic beverage increased time to Cmax regardless of fed or fasted status and decreased overall exposure AUC and Cmax of dersimelagon.

Machine learning for predicting successful extubation in patients receiving mechanical ventilation.

Ventilator liberation is one of the most critical decisions in the intensive care unit; however, prediction of extubation failure is difficult, and the proportion thereof remains high. Machine learning can potentially provide a breakthrough in the prediction of extubation success. A total of seven studies on the prediction of extubation success using machine learning have been published. These machine learning models were developed using data from electronic health records, 8-78 features, and algorithms such as artificial neural network, LightGBM, and XGBoost. Sensitivity ranged from 0.64 to 0.96, specificity ranged from 0.73 to 0.85, and area under the receiver operating characteristic curve ranged from 0.70 to 0.98. The features deemed most important included duration of mechanical ventilation, PaO2, blood urea nitrogen, heart rate, and Glasgow Coma Scale score. Although the studies had limitations, prediction of extubation success by machine learning has the potential to be a powerful tool. Further studies are needed to assess whether machine learning prediction reduces the incidence of extubation failure or prolongs the duration of ventilator use, thereby increasing tracheostomy and ventilator-related complications and mortality.

Machine Learning Prediction for Supplemental Oxygen Requirement in Patients with COVID-19.

BACKGROUND: The coronavirus disease (COVID-19) poses an urgent threat to global public health and is characterized by rapid disease progression even in mild cases. In this study, we investigated whether machine learning can be used to predict which patients will have a deteriorated condition and require oxygenation in asymptomatic or mild cases of COVID-19. METHODS: This single-center, retrospective, observational study included COVID-19 patients admitted to the hospital from February 1, 2020, to May 31, 2020, and who were either asymptomatic or presented with mild symptoms and did not require oxygen support on admission. Data on patient characteristics and vital signs were collected upon admission. We used seven machine learning algorithms, assessed their capability to predict exacerbation, and analyzed important influencing features using the best algorithm. RESULTS: In total, 210 patients were included in the study. Among them, 43 (19%) required oxygen therapy. Of all the models, the logistic regression model had the highest accuracy and precision. Logistic regression analysis showed that the model had an accuracy of 0.900, precision of 0.893, and recall of 0.605. The most important parameter for predictive capability was SpO2, followed by age, respiratory rate, and systolic blood pressure. CONCLUSION: In this study, we developed a machine learning model that can be used as a triage tool by clinicians to detect high-risk patients and disease progression earlier. Prospective validation studies are needed to verify the application of the tool in clinical practice.

Wearing a face mask during controlled-intensity exercise is not a risk factor for exertional heatstroke: A pilot study.

AIM: This study aimed to measure the influence of wearing face masks on individuals' physical status in a hot and humid environment. METHODS: Each participant experienced different physical situations: (i) not wearing a mask (control), (ii) wearing a surgical mask, (iii) wearing a sport mask. An ingestible capsule thermometer was used to measure internal core body temperature during different exercises (standing, walking, and running, each for 20 min) in an artificial weather room with the internal wet-bulb globe temperature set at 28°C. The change in the participants' physical status and urinary liver fatty acid-binding protein (L-FABP) were measured. RESULTS: Six healthy male volunteers were enrolled in the study. In each participant, significant changes were observed in the heart rate and internal core temperatures after increased exercise intensity; however, no significant differences were observed between these parameters and urinary L-FABP among the three intervention groups. CONCLUSION: Mask wearing is not a risk factor for heatstroke during increased exercise intensity.

Frontline Science: Conversion of neutrophils into atypical Ly6G+ SiglecF+ immune cells with neurosupportive potential in olfactory neuroepithelium.

Neutrophils are generally considered as short-lived, homogenous, and terminally differentiated phagocytes that play crucial roles in conquering infection, although they occasionally cause severe collateral tissue damage or chronic inflammation. Recent reports have indicated that neutrophils also play a protective role in inflammation resolution and tissue repair. However, how terminally differentiated neutrophils have diverse functions remains unclear. Here, we show that neutrophils undergo conversion into Ly6G+ SiglecF+ double-positive cells expressing neurosupportive genes in the olfactory neuroepithelium (OE) under an inflammatory state. Through comprehensive flow cytometric analysis of murine nose, we identified Ly6G+ SiglecF+ double-positive cells that reside only in the OE under steady-state conditions. Double-positive cells were neutrophil-derived cells and increased by more than 10-fold during inflammation or tissue injury. We found that neutrophils infiltrate into the nose to express proinflammatory genes in the acute phase of inflammatory state, and they gradually change their surface markers and gene expression, expressing some neurogenesis-related genes in addition to inflammation related genes in the later phase. As the OE is known to have exceptionally high regeneration capacity as a nervous system, these findings suggest that neutrophils have the potential to contribute neurogenesis after conversion in peripheral nervous tissues, providing a challenge on a classic view of neutrophils as terminally differentiated leukocytes.

Indicators of Acute Kidney Injury as Biomarkers to Differentiate Heatstroke from Coronavirus Disease 2019: A Retrospective Multicenter Analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) and heat-related illness are systemic febrile diseases. These illnesses must be differentiated during a COVID-19 pandemic in summer. However, no studies have compared and distinguished heat-related illness and COVID-19. We compared data from patients with early heat-related illness and those with COVID-19. METHODS: This retrospective observational study included 90 patients with early heat-related illness selected from the Heatstroke STUDY 2017-2019 (nationwide registries of heat-related illness in Japan) and 86 patients with laboratory-confirmed COVID-19 who had fever or fatigue and were admitted to one of two hospitals in Tokyo, Japan. RESULTS: Among vital signs, systolic blood pressure (119 vs. 125 mm Hg, p = 0.02), oxygen saturation (98% vs. 97%, p < 0.001), and body temperature (36.6°C vs. 37.6°C, p<0.001) showed significant between-group differences in the heatstroke and COVID-19 groups, respectively. The numerous intergroup differences in laboratory findings included disparities in white blood cell count (10.8 × 103/µL vs. 5.2 × 103/µL, p<0.001), creatinine (2.2 vs. 0.85 mg/dL, p<0.001), and C-reactive protein (0.2 vs. 2.8 mg/dL, p<0.001), although a logistic regression model achieved an area under the curve (AUC) of 0.966 using these three factors. A Random Forest machine learning model achieved an accuracy, precision, recall, and AUC of 0.908, 0.976, 0.842, and 0.978, respectively. Creatinine was the most important feature of this model. CONCLUSIONS: Acute kidney injury was associated with heat-related illness, which could be essential in distinguishing or evaluating patients with fever in the summer during a COVID-19 pandemic.

Relationship Between Pain Reduction and Improvement in Health-Related Quality of Life in Patients with Knee Pain Due to Osteoarthritis Receiving Duloxetine: Exploratory Post Hoc Analysis of a Japanese Phase 3 Randomized Study.

PURPOSE: This post hoc analysis of a Japanese phase 3 randomized study (ClinicalTrials.gov identifier: NCT02248480) investigated relationships between changes in pain severity and changes in health-related quality of life (HRQoL) in duloxetine-treated patients with knee osteoarthritis (OA). PATIENTS AND METHODS: Patients with knee OA and Brief Pain Inventory (BPI) average pain score ≥4 received duloxetine 60 mg/day or placebo for 14 weeks. Spearman rank correlation coefficients were calculated for change in pain severity, as assessed by the BPI, and change in HRQoL, as assessed by the items of the (i) 36-item Short-Form Health Survey (SF-36; a generic measure of HRQoL) and (ii) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; an OA-specific measure of HRQoL). RESULTS: After 14 weeks of treatment, there was a significantly greater improvement (p<0.001) for duloxetine (n=177) vs placebo (n=176) in BPI average pain severity score and significantly greater improvements (p<0.01) for duloxetine vs placebo for 5 of the 8 SF-36 domains (including the Role-Physical, Bodily Pain, and Physical Functioning domains) and all 24 individual WOMAC items. The correlation between BPI change from baseline and SF-36 item change from baseline was statistically significant (p<0.05) for 2 of the 8 SF-36 items (Bodily Pain, Physical Functioning) in duloxetine-treated patients. The correlation between BPI change from baseline and WOMAC item change from baseline was statistically significant for 22 of the 24 WOMAC items in duloxetine-treated patients. CONCLUSION: This post hoc analysis suggested that the pain reduction observed in duloxetine-treated patients with knee OA was associated with improvements in OA-specific aspects of HRQoL, ie, pain and physical functioning.

Duloxetine 60 mg for chronic low back pain: post hoc responder analysis of double-blind, placebo-controlled trials.

INTRODUCTION: Duloxetine has demonstrated efficacy in chronic low back pain (CLBP). We examined the predictors of response to duloxetine for CLBP. PATIENTS AND METHODS: This was a post hoc analysis of pooled data from 4 double-blind, ran-domized, placebo-controlled trials of duloxetine (60 mg/day for 12-14 weeks) in adult patients with CLBP. Primary outcome was proportion of patients with ≥30% reduction in Brief Pain Inventory (BPI) average pain ("pain reduction") at 12-14 weeks. The proportion of patients with ≥30% and ≥50% (secondary outcome) pain reduction in duloxetine and placebo groups was compared. Variables for responder analyses were early improvement (≥15% pain reduction at Week 2), sex, age, baseline BPI average pain score, duration of CLBP, and number of painful body sites according to the Michigan Body Map (≥2 vs 1 [isolated CLBP]; 1 trial); relative risk (RR) and 95% confidence interval (CI) were calculated. RESULTS: Compared with placebo (n = 653), a greater proportion of duloxetine-treated patients (n = 642) achieved ≥30% (59.7% vs 47.8%; P < 0.001) and ≥50% pain reduction (48.6% vs 35.1%; P < 0.001). Among duloxetine-treated patients, early improvement was associated with greater likelihood of ≥30% (RR [95% CI], 2.91 [2.30-3.67]) or ≥50% (3.24 [2.44-4.31]) pain reduction. Women were slightly more likely than men to achieve ≥30% (RR [95% CI], 1.14 [1.00-1.30]) or ≥50% (1.17 [0.99-1.38]) pain reduction. Response rates were similar between age, CLBP duration, and baseline BPI average pain score subgroups. Patients with ≥2 painful sites were more likely to respond to duloxetine 60 mg relative to placebo than patients with isolated CLBP (RR, duloxetine vs placebo [95% CI]: ≥30% reduction, ≥2 painful sites 1.40 [1.18-1.66], isolated CLBP 1.07 [0.78-1.48]; ≥50% reduction, ≥2 painful sites 1.51 [1.20-1.89], isolated CLBP 1.23 [0.81-1.88]). CONCLUSION: Early pain reduction was indicative of overall response. Patients with multiple painful sites had more benefit from duloxetine than patients with isolated CLBP.

Amiselimod, a novel sphingosine 1-phosphate receptor-1 modulator, has potent therapeutic efficacy for autoimmune diseases, with low bradycardia risk.

BACKGROUND AND PURPOSE: We conducted preclinical and clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT-1303), a second-generation sphingosine 1-phosphate (S1P) receptor modulator, designed to reduce the bradycardia associated with fingolimod and other S1P receptor modulators. EXPERIMENTAL APPROACH: The selectivity of the active metabolite amiselimod phosphate (amiselimod-P) for human S1P receptors and activation of G-protein-coupled inwardly rectifying K+ (GIRK) channels in human atrial myocytes were assessed. Its cardiac distribution was determined in rats, and cardiovascular telemetry was assessed in monkeys. We also examined the pharmacokinetics, pharmacodynamics and safety of amiselimod in healthy humans. KEY RESULTS: Amiselimod-P showed potent selectivity for S1P1 and high selectivity for S1P5 receptors, with minimal agonist activity for S1P4 and no distinct agonist activity for S1P2 or S1P3 receptors and approximately five-fold weaker GIRK activation than fingolimod-P. After oral administration of amiselimod or fingolimod at 1 mg·kg-1 , the concentration of amiselimod-P in rat heart tissue was lower than that of fingolimod-P, potentially contributing to the minimal cardiac effects of amiselimod. A telemetry study in monkeys confirmed that amiselimod did not affect heart rate or ECG parameters. In healthy human subjects, peripheral blood lymphocyte counts gradually reduced over the 21 day dosing period, with similar lymphocyte count profiles with the highest doses by day 21, and no clinically significant bradycardia observed on day 1 or during the study. CONCLUSIONS AND IMPLICATIONS: Amiselimod exhibited potent therapeutic efficacy with minimal cardiac effects at the anticipated clinical dose and is unlikely to require dose titration.

The relationship between pain severity and patient-reported outcomes among patients with chronic low back pain in Japan.

OBJECTIVE: The aim of this study was to quantify the impact of pain severity on patient-reported outcomes among individuals diagnosed with chronic low back pain in Japan. METHODS: Data were provided by the 2012 Japan National Health and Wellness Survey (N=29,997), a web-based survey of individuals in Japan aged ≥18 years. This analysis included respondents diagnosed with low back pain of ≥3-month duration. Measures included the revised Medical Outcomes Study 36-Item Short-Form Survey Instrument, the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7 scale, the Work Productivity and Activity Impairment: General Health questionnaire, and self-reported all-cause health care visits (6 months). Generalized linear models were used to assess the relationship between outcomes and severity of pain in the past week as reported on a numeric rating scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine), controlling for length of diagnosis, sociodemographics, and general health characteristics. RESULTS: A total of 290 respondents were included in the analysis; mean age was 56 years, 41% were females, and 56% were employed. Pain severity was 3/10 for the first quartile, 5/10 for the median, and 7/10 for the third quartile of this sample. Increasing severity was associated with lower scores for mental and physical component summaries and Short-Form 6D health utility, higher depression (Patient Health Questionnaire-9) and anxiety (Generalized Anxiety Disorder-7) scores, greater absenteeism and presenteeism, greater activity impairment, and more health care provider visits (all P<0.0001). CONCLUSION: The impact of chronic low back pain on health-related quality of life, depression and anxiety symptoms, impairment to work and daily activities, and health care use increases with the severity of pain. Interventions reducing the severity of pain may improve numerous health outcomes even if the pain cannot be eliminated.

Correlation between pain response and improvements in patient-reported outcomes and health-related quality of life in duloxetine-treated patients with diabetic peripheral neuropathic pain.

OBJECTIVE: We assessed whether quality of life (QoL) improvement in duloxetine-treated patients with diabetic peripheral neuropathic pain (DPNP) correlates with the extent of pain relief. METHODS: Pooled data from three multicountry, double-blind, 12-week, placebo-controlled trials of duloxetine-treated (duloxetine 60 mg once daily; total number =335) patients with DPNP were analyzed. Based on improvement in 24-hour average pain scores, patients were stratified into four groups. Improvement in QoL, which was measured as the change from baseline in two patient-reported health outcome measures (Short Form [SF]-36 and five-dimension version of the EuroQol Questionnaire [EQ-5D]), was evaluated and compared among the four groups. Pearson's correlation coefficient was calculated to assess the correlation between improvement in pain scores and improvement in QoL. RESULTS: The group with more pain improvement generally showed greater mean change from baseline in all of the SF-36 scale scores and on the EQ-5D index. Pearson's correlation coefficients ranged from 0.114 to 0.401 for the SF-36 scale scores (P<0.05), and it was 0.271 for the EQ-5D (P<0.001). CONCLUSION: Improvement in pain scores was positively correlated with improvement in QoL and patient-reported outcomes in duloxetine-treated patients.

Synthesis and evaluation of a radioiodinated peptide probe targeting αvß6 integrin for the detection of pancreatic ductal adenocarcinoma.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) remains a major cause of cancer-related death. Since significant upregulation of αvß6 integrin has been reported in PDAC, this integrin is a promising target for PDAC detection. In this study, we aimed to develop a radioiodinated probe for the imaging of αvß6 integrin-positive PDAC with single-photon emission computed tomography (SPECT). METHODS: Four peptide probes were synthesized and screened by competitive and saturation binding assays using 2 PDAC cell lines (AsPC-1, αvß6 integrin-positive; MIA PaCa-2, αvß6 integrin-negative). The probe showing the best affinity was used to study the biodistribution assay, an in vivo blocking study, and SPECT imaging using tumor bearing mice. Autoradiography and immunohistochemical analysis were also performed. RESULTS: Among the 4 probes examined in this study, (125)I-IFMDV2 showed the highest affinity for αvß6 integrin expressed in AsPC-1 cells and no affinity for MIA PaCa-2 cells. The accumulation of (125)I-IFMDV2 in the AsPC-1 xenograft was 3-5 times greater than that in the MIA PaCa-2 xenograft, consistent with the expression of αvß6 integrin in each xenograft, and confirmed by immunohistochemistry. Pretreatment with excess amounts of A20FMDV2 significantly blocked the accumulation of (125)I-IFMDV2 in the AsPC-1 xenograft, but not in the MIA PaCa-2 xenograft. Furthermore, (123)I-IFMDV2 enabled clear visualization of the AsPC-1 xenograft. CONCLUSION: (123)I-IFMDV2 is a potential SPECT probe for the imaging of αvß6 integrin in PDAC.

Bilateral cervical fistulas from heterotopic salivary gland tissues.

A 24-year-old male was referred to our department with intermittent clear drainage in both sides of the middle neck that did not increase while eating. On physical examination, there were fistulas in both sides of the neck, anterior to the sternocleidomastoid muscles. Fistulography revealed a 9-mm-long sinus from the left fistula, extending in the medial-caudal direction. On the right side, cannulation was not possible. Surgical excision of the lesion was performed on both sides, and the pathological examination revealed heterotopic salivary gland tissue (HSGT). From a literature review of reports of bilateral neck HSGT, we found that it is often associated with a family history of HSGT and other congenital anomalies. However, our case was different from the previously reported cases in that, although it was a bilateral case, it lacked any family history of HSGT or other congenital anomalies. Clinicians should include HSGT in the differential diagnosis of neck sinuses. © 2015 S. Karger AG, Basel.

Development of an oxygen-sensitive degradable peptide probe for the imaging of hypoxia-inducible factor-1-active regions in tumors.

PURPOSE: We aimed to develop a radiolabeled peptide probe for the imaging of hypoxia-inducible factor-1 (HIF-1)-active tumors. PROCEDURES: We synthesized the peptide probes that contain or lack an essential sequence of the oxygen-dependent degradation of HIF-1α in proteasomes ((123/125)I-DKOP30 or (125)I-mDKOP, respectively). The degradation of probes was evaluated in vitro using cell lysates containing proteasomes. In vivo biodistribution study, planar imaging, autoradiography, and comparison between probe accumulation and HIF-1 transcriptional activity were also performed. RESULTS: The (125)I-DKOP30 underwent degradation in a proteasome-dependent manner, while (125)I-mDKOP was not degraded. Biodistribution analysis showed (125)I-DKOP30 accumulation in tumors. The tumors were clearly visualized by in vivo imaging, and intratumoral distribution of (125)I-DKOP30 coincided with the HIF-1α-positive hypoxic regions. Tumoral accumulation of (125)I-DKOP30 was significantly correlated with HIF-1-dependent luciferase bioluminescence, while that of (125)I-mDKOP was not. CONCLUSION: (123)I-DKOP30 is a useful peptide probe for the imaging of HIF-1-active tumors.

Development of lipid A-imprinted polymer hydrogels that selectively recognize lipopolysaccharides.

To remove lipopolysaccharide (LPS) from pure water, we developed polymer hydrogels that selectively recognize LPS. A molecular imprinting technique was used to prepare the polymer hydrogels. We prepared the polymer hydrogels with LPS-binding sites by using acryloyllysine and acryloylphenylalanine as functional monomers and used lipid A as a template because it is the biologically active part of LPS and contains two phosphate groups. Co-existence of n-octane during the polymerization process was highly effective in promoting the formation of LPS-accessible sites on the surface of the hydrogels. Both an electrostatic and a hydrophobic interaction between the lipid A portion of LPS and the recognition site of the imprinted hydrogel are necessary for LPS recognition. The adsorption isotherm of LPS to the lipid A-imprinted hydrogels was Langmuir-type; the saturated adsorption capacity and the adsorption constant, calculated by applying an equation for Langmuir-type adsorption isotherms, were 1.0 × 10(-11)mol/cm(2) and 2.5 × 10(5)M(-1), respectively. The imprinted hydrogels selectively recognized toxic LPS in a competition experiment in which two other kinds of LPS with similar chemical structures to that of the LPS of E. coli (toxic LPS) were adsorbed to the lipid A-imprinted hydrogels.

Evaluation of [125I]IPOS as a molecular imaging probe for hypoxia-inducible factor-1-active regions in a tumor: comparison among single-photon emission computed tomography/X-ray computed tomography imaging, autoradiography, and immunohistochemistry.

To image hypoxia-inducible factor-1 (HIF-1)-active tumors, we previously developed a chimeric protein probe ([(123/125) I]IPOS) that is degraded in the same manner as HIF-1α under normoxic conditions. In the present study, we aim to show that the accumulation of radioiodinated POS reflects the expression of HIF-1. In vivo single-photon emission computed tomography (SPECT)/X-ray CT (CT) imaging, autoradiography, and double-fluorescent immunostaining for HIF-1α and pimonidazole (PIMO) were carried out 24 h after the injection of [(125) I]IPOS. Tumor metabolite analysis was also carried out. A tumor was clearly visualized by multi-pinhole, high-resolution SPECT/CT imaging with [(125) I]IPOS. The obtained images were in accordance with the corresponding autoradiograms and with the results of ex vivo biodistribution. A metabolite analysis revealed that 77% of the radioactivity was eluted in the macromolecular fraction, suggesting that the radioactivity mainly existed as [(125) I]IPOS in the tumors. Immunohistochemistry revealed that the HIF-1α-positive areas and PIMO-positive areas were not always identical, only some of the regions were positive for both markers. The areas showing [(125) I]IPOS accumulation were positively and significantly correlated with the HIF-1α-positive areas (R = 0.75, P < 0.0001). The correlation coefficient between [(125) I]IPOS-accumulated areas and HIF-1α-positive areas was significantly greater than that between the [(125) I]IPOS-accumulated areas and the PIMO-positive areas (P < 0.01). These findings indicate that [(125) I]IPOS accumulation reflects HIF-1 expression. Thus, [(123/125) I]IPOS can serve as a useful probe for the molecular imaging of HIF-1-active tumors.

Craniofacial and dental characteristics of Goldenhar syndrome: a report of two cases.

We describe the dental and craniofacial anomalies of 2 ethnically distinct patients with Goldenhar syndrome, which is characterized by hemifacial microsomia, facial asymmetry, and ear and dental abnormalities. A 7-year-old Japanese girl and 12-year-old Turkish boy with Goldenhar syndrome were examined clinically and radiographically; both had symptoms of hemifacial microsomia. Multiple organ involvement can limit surgical correction of deformities and affect patient management. Therefore, long-term regular follow-up by a multidisciplinary team is important to monitor the growth and development of patients.