Utilize multi-metabolic parameters as determinants for prediction of skeletal muscle mass quality in elderly type2 diabetic Chinese patients.

BACKGROUND: Sarcopenia, an age-related disorder characterized by loss of skeletal muscle mass and function, is recently recognized as a complication in elderly patients with type 2 diabetes mellitus (T2DM). Skeletal muscles play a crucial role in glycemic metabolism, utilizing around 80% of blood glucose. Accordingly, we aimed to explore the relationship between glucose metabolism and muscle mass in T2DM. METHODS: We employed the AWGS 2019 criteria for diagnosing low muscle mass and 1999 World Health Organization (WHO) diabetes diagnostic standards. This study included data of 191 individuals aged 60 and above with T2DM of Shanghai Pudong Hospital from November 2021 to November 2022. Fasting C-peptide (FPCP), fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (PPG) and postprandial 2-hour C-peptide (PPCP), glycated hemoglobin A1c (HbA1c), glycated albumin (GA), serum lipids spectrum, renal and hepatic function, hemoglobin, and hormone were measured. Based on the findings of univariate analysis, logistic regression and receiver operating characteristic (ROC) curves were established. RESULTS: Participants with low muscle mass had significantly lower alanine and aspartate aminotransferase, and both FPCP and PPCP levels (P < 0.05). Compared with those without low muscle mass, low muscle mass group had significantly higher FPG, HbA1c, GA levels (P < 0.05). Body fat (BF, OR = 1.181) was an independent risk factor for low muscle mass. PPCP (OR = 0.497), BMI (OR = 0.548), and female (OR = 0.050) were identified as protective factors for low skeletal muscle. The AUC of BMI was the highest, followed by the PPCP, gender and BF (0.810, 0.675, 0.647, and 0.639, respectively), and the AUC of the combination of the above four parameters reached 0.895. CONCLUSIONS: In this cross-sectional study, BMI, Female, and PPCP associated with T2DM were protective factors for low muscle mass. BF was associated with T2DM and risk factor for low muscle mass.

Study on Body Composition of Patients with Diabetes Mellitus by Dual-Energy X-Ray Absorptiometry: A Morphological Study

SUMMARY: Diabetes is a form of endocrine disease. Dual-energy X-ray Absorptiometry (DXA) provides a detailed view of the body composition to find out what makes people with diabetes different from those with other diseases. We scanned 371 patients with DXA to analyze their body composition parameters. Three hundreds and seventy one patients (178 women/193 men), who with different diseases, with a mean±SD Body Mass Index (BMI) of 25.32±8.3 kg/m2 were included. The body composition of 371 patients was assessed. Bone Mineral Density (BMD), Fat Weight, Lean Weight, waist-to-hip ratio, Lean Mass Index (LMI), Fat Mass Index (FMI), the relationship between Fat percentage and BMI were analyzed. The 371 patients included 156 diabetics and 215 non-diabetics. Non-diabetic patients also included 5 obesity patients, 9 patients with fatty liver, 39 patients with hypertension, 22 patients with hyperlipidemia, 18 patients with cardiovascular disease, 11 patients with chest and lung disease, 4 patients with chronic disease, 14 patients with brain disease and 93 patients with other diseases. Among 156 diabetic patients, 129 had VAT > 100 cm2 and 27 had VAT ≤100 cm2. The lean weight (LW) of male diabetic patients was significantly higher than that of female diabetic patients. The fat weight (FW) of female patients with diabetes was significantly higher than that of male patients. The waist-hip ratio (WHR) was 1.37 ± 0.25 in male diabetic patients and 1.18 ± 0.21 in female diabetic patients. Among the 215 non-diabetic patients, the obese and fatty liver patients, which the weight (WT) (obesity: 83.87 ± 8.34 kg fat liver: 85.64±28.60 kg), FW (obesity: 28.56 ± 4.18 kg fat liver: 28.61 ± 10.79 kg), LW (obesity: 52.62 ± 9.64 kg fat liver: 54.29±17.58 kg), BMI (obesity: 28.76 ± 1.88 kg/m2 fat liver: 29.10 ± 5.95 kg/m2), was much higher than other patients. Diabetes patients had less fat mass than non- diabetic patients; the difference was around 2 kg. BMI is also a modest number. BMD doesn't differ all that much. Non-diabetic patients with fatty liver obesity and cardiovascular disease had higher fat mass and BMI than patients with other illnesses. Body composition can provide precise information on the makeup of different body areas, but further in-depth exams are required to ascertain the body's endocrine profile.

La diabetes es una enfermedad endocrina. La absorciometría de rayos X de energía dual (DXA) proporciona una vista detallada de la composición corporal para descubrir qué diferencia a las personas con diabetes de aquellas con otras enfermedades. Escaneamos a 371 pacientes con DXA para analizar sus parámetros de composición corporal. Se incluyeron 371 pacientes (178 mujeres/193 hombres), con diferentes enfermedades, con un Índice de Masa Corporal (IMC) medio ± DE de 25,32 ± 8,3 kg/m2. Se evaluó la composición corporal de 371 pacientes. Se analizaron la densidad mineral ósea (DMO), el peso graso, el peso magro, la relación cintura-cadera, el índice de masa magra (LMI), el índice de masa grasa (FMI), y la relación entre el porcentaje de grasa y el IMC. De los 371 pacientes 156 eran diabéticos y 215 no diabéticos. Los pacientes no diabéticos también incluyeron 5 con obesidad, 9 con hígado graso, 39 con hipertensión, 22 con hiperlipidemia, 18 con enfermedad cardiovascular, 11 con enfermedad torácica y pulmonar, 4 con enfermedad crónica, 14 con enfermedad cerebral y 93 pacientes con otras enfermedades. Entre los 156 pacientes diabéticos, 129 tenían un IVA > 100 cm2 y 27 tenían un IVA ≤100 cm2. El peso magro (PV) de los hombres diabéticos fue significativamente mayor que el de las mujeres diabéticas. El peso graso (FW) de las mujeres diabéticas fue significativamente mayor que el de los hombres diabéticos. El índice cintura-cadera (ICC) fue de 1,37 ± 0,25 en hombres diabéticos y de 1,18 ± 0,21 en mujeres diabéticas. Entre los 215 pacientes no diabéticos, los pacientes obesos y con hígado graso, cuyo peso (WT) (obesidad: 83,87 ± 8,34 kg hígado graso: 85,64 ± 28,60 kg), FW (obesidad: 28,56 ± 4,18 kg hígado graso: 28,61 ± 10,79 kg), PV (obesidad: 52,62 ± 9,64 kg, hígado graso: 54,29 ± 17,58 kg), IMC (obesidad: 28,76 ± 1,88 kg/m2, hígado graso: 29,10 ± 5,95 kg/m2), fue mucho mayor que otros pacientes. Los pacientes diabéticos tenían menos masa grasa que los pacientes no diabéticos; la diferencia fue de alrededor de 2 kg. La DMO no difiere mucho. Los pacientes no diabéticos con obesidad debido al hígado graso y enfermedades cardiovasculares tenían mayor masa grasa e IMC que los pacientes con otras enfermedades. La composición corporal puede proporcionar información precisa sobre la composición de diferentes áreas del cuerpo, pero se requieren exámenes más profundos para determinar el perfil endocrino del cuerpo.

Near-infrared II theranostic agents for the diagnosis and treatment of Alzheimer's disease.

BACKGROUND: Near-infrared II theranostic agents have gained great momentum in the research field of AD owing to the appealing advantages. Recently, an array of activatable NIR-II fluorescence probes has been developed to specifically monitor pathological targets of AD. Furthermore, various NIR-II-mediated nanomaterials with desirable photothermal and photodynamic properties have demonstrated favorable outcomes in the management of AD. METHODS: We summerized amounts of references and focused on small-molecule probes, nanomaterials, photothermal therapy, and photodynamic therapy based on NIR-II fluorescent imaging for the diagnosis and treatment in AD. In addition, design strategies for NIR-II-triggered theranostics targeting AD are presented, and some prospects are also addressed. RESULTS: NIR-II theranostic agents including small molecular probes and nanoparticles have received the increasing attention for biomedical applications. Meanwhile, most of the theranostic agents exhibited the promising results in animal studies. To our surprise, the multifunctional nanoplatforms also show a great potential in the diagnosis and treatment of AD. CONCLUSIONS: Although NIR-II theranostic agents showed the great potential in diagnosis and treatment of AD, there are still many challenges: 1) Faborable NIR-II fluorohpores are still lacking; 2) Biocompatibility, bioseurity and dosage of NIR-II theranostic agents should be further revealed; 3) New equipment and software associated with NIR-II imaging system should be explored.

A sodium alginate intervention strategy to enhance therapeutic effects of bone-targeted alpha therapy via remodeling 223RaCl2 distribution.

Radium-223 dichloride is the first approved alpha particle-emitting radiopharmaceutical for patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases. A large percentage of intestinal enrichment and a slow clearance rate were the main causes of gastrointestinal adverse events after 223RaCl2 administration. The molecular weight of sodium alginate in aqueous solution was determined to be 656 kDa. Sodium alginate exhibits a higher affinity for adsorbing Ra2+ compared to other metal ions belonging to the second main group. Sodium alginate as low as 0.5 g/rat reduced intestinal damage by remodeling 223RaCl2 distribution without affecting bone resorption. Intestinal villi were preserved and enterocyte activity was maintained after sodium alginate intervention. Sodium alginate reduced DNA oxidative damage and lipid peroxidation and maintained endogenous antioxidant status by increasing superoxide dismutase levels and total antioxidant capacity. Furthermore, sodium alginate treatment mitigated DNA damage and apoptosis. The administration of sodium alginate effectively maintained the integrity of the intestinal microbiota, which had undergone perturbations due to radiation exposure. This study demonstrated that sodium alginate could be applied to reduce the adverse effects caused by radiation exposure to the intestine during 223RaCl2-treated and reduced intestinal damage resulted from 223RaCl2 accumulation without affecting bone uptake.

Integrated Analysis of Chromatin and Transcriptomic Profiling Identifies PU.1 as a Core Regulatory Factor in Microglial Activation Induced by Chronic Cerebral Hypoperfusion.

In addition to causing white matter lesions, chronic cerebral hypoperfusion (CCH) can also cause damage to gray matter, but the underlying molecular mechanisms remain largely unknown. In order to obtain a better understanding of the relationship between gene expression and transcriptional regulation alterations, novel upstream regulators could be identified using integration analysis of the transcriptome and epigenetic approaches. Here, a bilateral common carotid artery stenosis (BCAS) model was established for inducing CCH in mice. The spatial cognitive function of mice was evaluated, and changes in cortical microglia morphology were observed. RNA-sequencing (RNA-seq) and the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) were performed on isolated mouse cortical brain tissue. Then, a systematic joint analysis of BCAS hypoperfusion-induced cortex-specific RNA-seq and ATAC-seq was conducted in order to assess the extent of the correlation between the two, and PU.1 was found to be greatly enriched through motif analysis and transcription factor annotation. Also, the core regulatory factor PU.1 induced by BCAS hypoperfusion was shown to be colocalized with microglia. Based on the above analysis, PU.1 plays a key regulatory role in microglial activation induced by CCH. And the transcriptome and epigenomic data presented in this study can help identify potential targets for future research exploring chronic hypoperfusion-induced brain injury.

Development of a Novel 18F-Labeled Probe for PET Imaging of Estrogen Receptor ß.

Estrogen receptor beta (ERß) is an important ER subtype that plays crucial roles in many physiological and pathological disorders. Herein, we developed the probe [18F]PVBO for in vivo ERß targeted PET imaging and obtained promising results. The nonradioactive PVBO showed a 12.5-fold stronger binding affinity to ERß than to ERα in vitro. In vitro assays revealed the specific uptake of [18F]PVBO by DU145 cells. The uptake of [18F]PVBO by DU145 xenografts increased during the 120 min dynamic scanning, with a maximum uptake of 2.80 ± 0.30% ID/g. Based on time activity curves (TACs), the injection of [18F]PVBO with unlabeled PVBO or ERB-041 resulted in a significant signal reduction with the tumor/muscle (T/M) ratio <1 at 30, 60, 75, and 120 min post-injection (p < 0.05). [18F]PVBO demonstrates the feasibility of noninvasively imaging ERß-positive tumors by small-animal PET and provides a new strategy for visualizing ERß in vivo.

18F-FP-CIT dopamine transporter PET findings in the striatum and retina of type 1 diabetic rats.

PURPOSE: Noninvasive methods used in clinic to accurately detect DA neuron loss in diabetic brain injury and diabetic retinopathy have not been reported up to now. 18F-FP-CIT is a promising dopamine transporter (DAT) targeted probe. Our study first applies 18F-FP-CIT PET imaging to assess DA neuron loss in the striatum and retina of T1DM rat model. METHODS: T1DM rat model was induced by a single intraperitoneal injection of streptozotocin (STZ) (65 mg kg-1, ip). 18F-FP-CIT uptake in the striatum and retina was evaluated at 4 weeks, 8 weeks and 12 weeks after STZ injection. The mean standardized uptake value (SUVmean) and the maximum standardized uptake value (SUVmax) were analyzed. Western blot was performed to confirm the DAT protein levels in the striatum and retina. RESULTS: PET/CT results showed that the SUV of 18F-FP-CIT was significantly reduced in the diabetic striatum and retina compared with the normal one from 4-week to 12-week (p < 0.0001). Western blots showed that DAT was significantly lower in the diabetic striatum and retina compared to the normal one for all three time points (p < 0.05). The results from Western blots confirmed the findings in PET imaging studies. CONCLUSIONS: DA neuron loss in the striatum and retina of T1DM rat model can be non-invasively detected with PET imaging using 18F-FP-CIT targeting DAT. 18F-FP-CIT PET imaging may be a useful tool used in clinic for DR and diabetic brain injury diagnosis in future. The expression level of DAT in striatum and retina may act as a new biomarker for DR and diabetic brain injury diagnosis.

Dysregulated RUNX1 Predicts Poor Prognosis by Mediating Epithelialmesenchymal Transition in Cervical Cancer.

OBJECTIVE: Runt-related transcription factor 1 (RUNX1) has been proven to be over-expressed and vital in many malignancies. However, its role in cervical cancer is still unclear. METHODS: Some online databases (Oncomine, GEPIA, UALCAN, LinkedOmics, and others) were used to explore the expression level, prognostic significance, and gene mutation characteristics of RUNX1 in cervical cancer. The protein levels of RUNX1 in cervical cancer were measured by immunohistochemistry (IHC). The functional changes of cervical cancer cells were measured in vitro after decreasing RUNX1. RESULTS: Bioinformatic results revealed that RUNX1 was upregulated in cervical cancer compared to normal tissues. Moreover, over-expression of RUNX1 was significantly correlated with cervical cancer patients' clinical parameters (e.g., individual cancer stages, patients' age, nodal metastasis status, and others). Meanwhile, functional enrichment analysis of RUNX1-related genes indicated that RUNX1 was mainly involved in the epithelial-mesenchymal transition (EMT) process in cervical cancer. Furthermore, RUNX1 may be upregulated by hsamiR-616-5p and hsa-miR-766 identified by miRDB, TargetScan, and miRWalk. Finally, RUNX1 was upregulated in cervical cancer compared to normal tissues by IHC in collected cervical cancer samples. The invasion and migration abilities of cervical cancer cells were significantly reduced by repressing EMT after knocking down RUNX1 in vitro. CONCLUSION: RUNX1 was highly expressed in cervical cancer, and upregulated RUNX1 could significantly promote the invasive abilities of cervical cancer cells by inducing EMT. Therefore, RUNX1 may be a potential biomarker for early diagnosis and targeted therapy of cervical cancer.

Relationship Between Sporadic Renal Cysts and Renal Function Detected by Isotope Renography in Type 2 Diabetes.

Purpose: This study aimed to reveal the relationship between the volume of sporadic renal cysts and renal function in patients with type 2 diabetes (T2D). Materials and Methods: One hundred and seventy-one patients that underwent renal imaging and other routine examinations at the Shanghai Pudong Hospital were included in this study. The Gates' method of glomerular filtration rate (GFR) was measured by 99mTc-DTPA renal dynamic imaging in addition to the eGFR, calculated by the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). Results: Our results showed that BMI, total iGFR, and eGFR showed significant differences between patients with T2D with or without SRC (p < 0.05). Spearman correlation analysis showed that cyst volume was positively correlated with Scr and gender but not iGFR (p > 0.05). The total iGFR positively correlated with eGFR (r = 0.83, p < 0.0001) and negatively with Scr (r = -0.78, p < 0.0001), age (r = -0.43, p < 0.0001), duration of T2D (r = -0.25, p = 0.001), and BMI (r = -0.21, p = 0.006) but not gender (r = -0.03, p = 0.668). The multilinear regression model revealed that gender (ß = 0.346, p < 0.001), iGFR (ß = -0.705, p < 0.001), and serum uric acid (ß = 0.195, p = 0.032) were independent predictors of Scr. Moreover, we observed a significant increase in Scr in males (p < 0.05). Finally, we found that the split kidney function reflected by iGFR and related parameters such as time to peak (PTT) and half time of excretion (excrete t1/2) did not mutually distinguish from each other significantly whether they are measured in patients with renal cysts or in those without renal cysts (p > 0.05). Conclusion: Our preliminary results suggest that in T2D, SRCs may be a renal complication of diabetic nephropathy. Although we found that the patients with renal cysts may display reduced iGFR, the volume of simple cysts seems not to exacerbate renal insufficiency. Isotope renography is a useful tool to evaluate the split kidney functions in diabetic patients who acquire single-side cysts.

Computed Tomography Density and ß-Amyloid Deposition of Intraorbital Optic Nerve May Assist in Diagnosing Mild Cognitive Impairment and Alzheimer's Disease: A 18F-Flutemetamol Positron Emission Tomography/Computed Tomography Study.

Objective: The aim was to study whether the computed tomography (CT) density and ß-amyloid (Aß) level of intraorbital optic nerve could assist in diagnosing mild cognitive impairment (MCI) and Alzheimer's disease (AD). Methods: A total of sixty subjects were recruited in our study, including nine normal control (NC) subjects (i.e., 4 men and 5 women), twenty four MCI subjects (i.e., 11 men and 13 women), and twenty seven AD subjects (i.e., 14 men and 13 women). All subjects conducted 18F-flutemetamol amyloid positron emission tomography (PET)/CT imaging. Blinded to the clinical information of the subjects, two physicians independently measured and calculated the standardized uptake value ratio (SUVR) of the bilateral occipital cortex, SUVR of the bilateral intraorbital optic nerve, and CT density of the bilateral intraorbital optic nerve by using GE AW 4.5 Workstation. Results: Between AD and NC groups, the differences of the bilateral intraorbital optic nerve SUVR were statistically significant; between AD and MCI groups, the differences of the left intraorbital optic nerve SUVR were statistically significant. Between any two of the three groups, the differences in the bilateral intraorbital optic nerve density were statistically significant. The bilateral occipital SUVR was positively correlated with the bilateral intraorbital optic nerve SUVR and negatively correlated with the bilateral intraorbital optic nerve density. Bilateral intraorbital optic nerve SUVR was negatively correlated with the bilateral intraorbital optic nerve density. The area under the receiver operating characteristic (ROC) curve of multiple logistic regression was 0.9167 (for MCI vs. NC) and 0.8951 (for AD vs. MCI). The Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) scores were positively associated with the intraorbital optic nerve density and were negatively associated with the intraorbital optic nerve SUVR. The regression equation of MoCA was y = 16.37-0.9734 × x 1 + 0.5642 × x 2-3.127 × x 3 + 0.0275 × x 4; the R 2 was 0.848. The regression equation of MMSE was y = 19.57-1.633 × x 1 + 0.4397 × x 2-1.713 × x 3 + 0.0424 × x 4; the R 2 was 0.827. Conclusion: The CT density and Aß deposition of the intraorbital optic nerve were associated with Aß deposition of the occipital cortex and the severity of cognitive impairment. The intraorbital optic nerve CT density and intraorbital optic nerve Aß deposition could assist in diagnosing MCI and AD.

Regional cerebral perfusion in patients with amnestic mild cognitive impairment: effect of cerebral small vessel disease.

OBJECTIVE: To explore the effort of cerebral small vessel disease (CSVD) on regional cerebral perfusion in patients with mild cognitive impairment (MCI) using NeuroGam™ software and evaluate the capability of brain perfusion single photon emission computed tomography (SPECT) in distinguishing MCI with and without CSVD. METHODS: 34 amnestic MCI subjects entered this study, conducting neuropsychological tests, MRI and 99mTechnetium ethyl cystine dimer brain perfusion SPECT imaging. All subjects were divided into those with CSVD and those without CSVD. Perfusion value was measured with Brodmann area (BA) mapping in these two groups. Automated software (NeuroGam™) was used for semi-quantitative analyses of perfusion value and comparison with normal database. RESULTS: Compared with normal database, perfusion levels in BAs 23-left, 28 and 36-left of MCI without CSVD group had great deviations, while perfusion levels in BAs 21, 23, 24, 25, 28, 36, 38 and 47-left of MCI with CSVD group had great deviations. Furthermore, compared with CSVD group, there was significantly lower perfusion value in BA 7-left (P < 0.001) in MCI without CSVD group. CONCLUSIONS: CSVD could interact with pathological changes related to AD, exacerbating hypoperfusion in BAs 21, 23, 28, 36, 38 while compensating for cerebral blood perfusion disorder in BA 7-left in MCI patients. Meanwhile, MCI patients with CSVD shared similar hypoperfusion with vascular cognitive impairment (VCI) in BAs 24, 25 and 47L. Brain perfusion SPECT may help improve our ability to differentiate MCI with and without CSVD.

Development of Mitochondria-Targeted Small-Molecule Dyes for Myocardial PET and Fluorescence Bimodal Imaging.

Mitochondria-targeting positron emission tomography (PET) and fluorescent dual-modal probes are rarely reported. As one of the most promising lipophilic cations, F16 and its derivatives (F16s) have never been used for myocardial imaging. In this work, 14 F16s are synthesized and evaluated for cardiac imaging. In vitro cell fluorescence imaging revealed that the lead probe 5MEF is precisely localized in the mitochondria of cardiomyocytes. In addition, it shows excellent ex vivo fluorescence imaging quality with the heart-to-muscle and heart-to-liver ratios up to ∼2. Furthermore, the radiofluorinated probe 18F-5MEF is successfully prepared and shows a high initial heart uptake of 8.66 ± 0.34 % ID/g at 5 min post injection. It displays a high heart imaging performance, a long retention time in the heart, and a low background in the most normal tissues as revealed by PET. To our knowledge, this is the first time novel F16 analogues are designed and developed for myocardial dual-modal imaging.

Azide-Dye Unexpected Bone Targeting for Near-Infrared Window II Osteoporosis Imaging.

Azide is an important chemical functional group and has been widely used in chemical biology. However, the impact of azide on the in vivo behaviors of compounds has been rarely studied. Herein, azide was introduced into a fluorescent dye for the near-infrared window two (NIR-II) bone imaging. Specifically, we designed and synthesized the small-molecule NIR-II dyes, N3-FEP-4T capped with azide and FEP-4T without azide capping. In vitro assays revealed that N3-FEP-4T showed 5- and 5.6- times higher hydroxyapatite accumulation and macrophage uptake than those of FEP-4T, respectively. Moreover, N3-FEP-4T displayed higher bone uptakes and much better bone NIR-II imaging quality, demonstrating the specific bone-targeting ability of the azide-containing probe. N3-FEP-4T was then further successfully used for osteoporosis NIR-II imaging. Overall, our study provides insights into the impact of azide on the in vivo behavior of azide-containing compounds and opens a new window for biological application of azide.

Pharmacokinetics and Disposition of Contezolid in Humans: Resolution of a Disproportionate Human Metabolite for Clinical Development.

Contezolid (MRX-I), a novel oxazolidinone antibiotic, was recently approved for the treatment of serious Gram-positive infections. The pharmacokinetics and disposition of [14C]contezolid were investigated in a single-dose human mass balance study. Cross-species comparison of plasma exposure for contezolid and metabolites was performed, and the safety of the disproportionate metabolite in human was evaluated with additional nonclinical studies. After an oral administration of 99.1 µCi/602-mg dose of [14C]contezolid, approximately 91.5% of the radioactivity was recovered in 0 to 168 h postdose, mainly in urine followed by that in feces. The principal metabolic pathway of contezolid in human comprised an oxidative ring opening of the 2,3-dihydropyridin-4-one fragment into polar metabolites MRX445-1 and MRX459, with recovery of approximately 48% and 15% of the dose, respectively, in urine and feces. Contezolid, MRX445-1, and MRX459 accounted for 68.0%, 19.5%, and 4.84% of the plasma exposure of the total radioactivity, respectively. Metabolites MRX445-1 and MRX459 were observed in disproportionately larger amounts in human plasma than in samples from rat or dog, the rodent and nonrodent species, respectively, used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies, wherein the primary metabolite, MRX445-1, was further characterized. The no-observed-adverse-effect level (NOAEL) of MRX445-1 was determined as 360 mg/kg body weight/day in a 14-day repeat-dose test in pregnant and nonpregnant Sprague Dawley rats. Furthermore, MRX445-1 exhibited no antibacterial activity in vitro. Thus, MRX445-1 is not expected to exert clinically relevant pharmacology and toxicity.

Efficacy and safety of 188Re-HEDP in lung cancer patients with bone metastases: a randomized, multicenter, multiple-dose phase IIa study.

PURPOSE: To investigate the pain-relieving effect and safety of three different doses of 188Re-hydroxyethylidine diphosphonate (HEDP) in patients with lung cancer and bone metastases. METHODS: For this randomised, phase 2 and multicenter trial, we enrolled patients with lung carcinoma and multifocal bone metastases and excluded patients who had received bisphosphonates or external-beam radiotherapy within the previous 4 weeks. Fifty-four patients were randomized to receive a single injection of 188Re-HEDP, at doses of 30, 40 or 50 MBq/kg (interval, 12 weeks). Patients were followed-up by assessment of numerical rating scale (NRS) score, global quality of life (QOL) score and adverse events (AEs). ANOVA analysis, Chi-Squared test and LSD-t test were used in this study. RESULTS: Significantly decreased NRS scores relative to baseline were observed in 40 MBq/kg group (Week 0 vs. Week 12: 6.0 ± 1.4 vs. 4.8 ± 2.5, P = 0.033) and 50 MBq/kg group (Week 0 vs. Week 12: 5.5 ± 1.5 vs. 4.5 ± 2.9, P = 0.046). Significant change of global QOL score from baseline was observed in 40 MBq/kg group at week 8 (global QOL score: P = 0.024, pain score: P = 0.041) and 50 MBq/kg group (pain score: P = 0.021) at week 12. No patients withdrew trial because of AEs in three groups. CONCLUSIONS: 188Re-HEDP at dose of 40 and 50 MBq/kg was generally effective to alleviate pain and improve QOL in lung cancer patients with painful bone metastases. 188Re-HEDP was safe and well-tolerated.

Radium-223 in Asian patients with castration-resistant prostate cancer with symptomatic bone metastases: A single-arm phase 3 study.

AIM: Radium-223, a targeted alpha therapy, is approved widely for the treatment of patients with metastatic castrate-resistant prostate cancer, based on a pivotal phase 3 study in predominantly white patients. We investigated the efficacy and safety of radium-223 in Asian patients with castrate-resistant prostate cancer and metastatic bone disease. METHODS: This multicenter, prospective, single-arm, open-label phase 3 trial evaluated the efficacy and safety of the standard radium-223 regimen (55 kBq/kg every 4 weeks for six cycles) in patients from Asian countries. The primary endpoints were the safety and overall survival. RESULTS: A total of 226 patients were enrolled and received at least one dose of radium-223. Median overall survival was 14.0 months (95% confidence interval [CI], 11.2-17.4). Median time to total alkaline phosphatase and prostate-specific antigen progression were 7.5 (95% CI, 6.8-7.7) and 3.6 (95% CI, 3.1-3.7) months, respectively. Median skeletal-related event-free survival was 26.0 months (95% CI, 12.6-not reached). Grade ≥3 treatment-emergent adverse events were reported in 103 (46%) of 226 patients, with anemia being the most common event (34 [15%] patients). Grade ≥3 drug-related treatment-emergent adverse events occurred in 39 (17%) of 226 patients. Serious treatment-emergent adverse events were reported in 65 (29%) of 226 patients. Seven (3%) patients had an adverse event leading to death; none were considered to be related to radium-223. CONCLUSION: The results of this study support the use of the standard radium-223 regimen for the treatment of Asian patients with castrate-resistant prostate cancer and symptomatic bone metastases.

The role of estrogen receptor beta in breast cancer.

Breast cancer, a malignant tumor originating from mammary epithelial tissue, is the most common cancer among women worldwide. Challenges facing the diagnosis and treatment of breast cancer necessitate the search for new mechanisms and drugs to improve outcomes. Estrogen receptor (ER) is considered to be important for determining the diagnosis and treatment strategy. The discovery of the second estrogen receptor, ERß, provides an opportunity to understand estrogen action. The emergence of ERß can be traced back to 1996. Over the past 20 years, an increasing body of evidence has implicated the vital effect of ERß in breast cancer. Although there is controversy among scholars, ERß is generally thought to have antiproliferative effects in disease progression. This review summarizes available evidence regarding the involvement of ERß in the clinical treatment and prognosis of breast cancer and describes signaling pathways associated with ERß. We hope to highlight the potential of ERß as a therapeutic target.

Visualization of translocator protein (18 kDa) (TSPO) in the retina of diabetic retinopathy rats using fluorine-18-DPA-714.

OBJECTIVES: To investigate the feasibility of a noninvasive method for imaging translocator protein (18 kDa) (TSPO) in the retina of diabetic retinopathy (DR) rats using fluorine-18-DPA-714 ([18F]-DPA-714) micro-positron emission tomography (PET)/X-ray computed tomography (CT). METHODS: Sprague-Dawley (SD) rats were intraperitoneally injected with streptozocin (STZ) (65 mg kg-1, ip) to induce diabetes mellitus (DM). The TSPO in both eyes was detected by PET/CT using [18F]-DPA-714 12 weeks after the establishment of the DM model. The mean standardized uptake value (SUVmean) was analyzed. Western blot and quantitative real-time polymerase chain reaction (PCR) were performed to detect the TSPO protein and mRNA levels in the retina. RESULTS: PET/CT results showed that the SUV of [18F]-DPA-714 was markedly reduced in the retina of DR rats compared with that of normal controls 12 weeks after diabetes induction. The SUVmean of regions of interest (ROIs) in the retinas of DR and normal control rats was 0.883 ± 0.078 and 2.525 ± 0.213 (P < 0.001), respectively. The results of PET/CT were in line with the Western blots and quantitative real-time PCR. CONCLUSIONS: The PET results demonstrated that TSPO was decreased in the early stage of DR. [18F]-DPA-714 PET/CT appears to be a useful noninvasive imaging method for detecting TSPO in the retina. A decrease in the TSPO level in the retina may play an important role in the development of DR.

Phase I clinical study with different doses of 99mTc-TRODAT-1 in healthy adults.

OBJECTIVES: To study the pharmacokinetics, biodistribution, and injection doses of 99mTc-TRODAT-1 in healthy adults. METHODS: Thirty healthy individuals comprising 15 females and 15 males were randomly divided into three groups and the injection doses of 99mTc-TRODAT-1 of group 1, 2, and 3 were 370 MBq, 740 MBq, and 1110 MBq, respectively. Assessments of subjective symptoms and tests were performed before and after injection. Blood and urine collections and whole-body planar imaging were analyzed at various time points. Bilateral brain striatal SPECT images obtained at 3.5 h PI were assessed visually and semiquantitatively. RESULTS: No serious adverse events or deaths were observed in our study. The pharmacokinetic analysis showed that 99mTc-TRODAT-1 was eliminated rapidly from the circulation, with just about 4% of the injected dose remaining in blood at 1 h post-injection. The mean cumulative urinary excretion over 24 h was just 2.96 ± 0.96%ID. The time-activity curve demonstrated that the radioactivity was mainly in liver and abdomen. The highest absorbed dose was in the dose-limiting organ, liver (20.88 ± 4.45 × 10-3 mSv/MBq). The average effective dose was 5.22 ± 1.05 × 10-3 mSv/MBq. The clarity of striatal images assessed visually in group 1 was worse than that in group 2 and 3. The semiquantitative analysis showed that there were no differences in striatum/cerebellum between the three groups (group 1: 1.77 ± 0.11, group 2: 1.62 ± 0.14, and group 3: 1.75 ± 0.20; P = 0.088). CONCLUSIONS: 99mTc-TRODAT-1 was safe to use in humans and showed the status of dopaminergic neurons specifically and clearly. The injection dose we suggested was 740 MBq.

Correction to: A phase 2, open-label, multi-center study to evaluate the efficacy and safety of 99mTc-TRODAT-1 SPECT to detect Parkinson's disease.

The corresponding author of the article would like to remove "Jian Wang" in the author group.