Revealing *OOH key intermediates and regulating H2O2 photoactivation by surface relaxation of Fenton-like catalysts.

Hydrogen peroxide (H2O2) molecules play important roles in many green chemical reactions. However, the high activation energy limits their application efficiency, and there is still huge controversy about the activation path of H2O2 molecules over the presence of *OOH intermediates. Here, we confirmed the formation of the key species *OOH in the heterogeneous system, via in situ shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS), isotope labeling, and theoretical calculation. In addition, we found that compared with *H2O2, *OOH was more conducive to the charge transfer behavior with the catalyst and the activation of an O-O bond. Furthermore, we proposed to improve the local coordination structure and electronic density of the YFeO3 catalyst by regulating the surface relaxation with Ti modification so as to reduce the activation barrier of H2O2 and to improve the production efficiency of •OH. As a result, the kinetics rates of the Fenton-like (photo-Fenton) reaction had been significantly increased several times. The •OH free radical activity mechanism and molecular transformation pathways of 4-chloro phenol (4-CP) were also revealed. This may provide a clearer vision for the further study of H2O2 activation and suggest a means of designing catalysts for efficient H2O2 activation.

Electric Field Effects in Flash Joule Heating Synthesis.

Flash Joule heating has emerged as an ultrafast, scalable, and versatile synthesis method for nanomaterials, such as graphene. Here, we experimentally and theoretically deconvolute the contributions of thermal and electrical processes to the synthesis of graphene by flash Joule heating. While traditional methods of graphene synthesis involve purely chemical or thermal driving forces, our results show that the presence of charge and the resulting electric field in a graphene precursor catalyze the formation of graphene. Furthermore, modulation of the current or the pulse width affords the ability to control the three-step phase transition of the material from amorphous carbon to turbostratic graphene and finally to ordered (AB and ABC-stacked) graphene and graphite. Finally, density functional theory simulations reveal that the presence of a charge- and current-induced electric field inside the graphene precursor facilitates phase transition by lowering the activation energy of the reaction. These results demonstrate that the passage of electrical current through a solid sample can directly drive nanocrystal nucleation in flash Joule heating, an insight that may inform future Joule heating or other electrical synthesis strategies.

Structures of the ADGRG2-Gs complex in apo and ligand-bound forms.

Adhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an essential membrane receptor for maintaining male fertility, in complex with a Gs trimer. Whereas the formations of two kinks were determinants of the active state, identification of a potential ligand-binding pocket in ADGRG2 facilitated the screening and identification of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate and deoxycorticosterone as potential ligands of ADGRG2. The cryo-EM structures of DHEA-ADGRG2-Gs provided interaction details for DHEA within the seven transmembrane domains of ADGRG2. Collectively, our data provide a structural basis for the activation and signaling of ADGRG2, as well as characterization of steroid hormones as ADGRG2 ligands, which might be used as useful tools for further functional studies of the orphan ADGRG2.

Heterogeneity of macrophages in atherosclerosis revealed by single-cell RNA sequencing.

Technology at the single-cell level has advanced dramatically in characterizing molecular heterogeneity. These technologies have enabled cell subtype diversity to be seen in all tissues, including atherosclerotic plaques. Critical in atherosclerosis pathogenesis and progression are macrophages. Previous studies have only determined macrophage phenotypes within the plaque, mainly by bulk analysis. However, recent progress in single-cell technologies now enables the comprehensive mapping of macrophage subsets and phenotypes present in plaques. In this review, we have updated and discussed the definition and classification of macrophage subsets in mice and humans using single-cell RNA sequencing. We summarized the different classification methods and perspectives: traditional classification with an updated scoring system, inflammatory macrophages, foamy macrophages, and atherosclerotic-resident macrophages. In addition, some special types of macrophages were identified by specific markers, including IFN-inducible and cavity macrophages. Furthermore, we discussed macrophage subset-specific markers and their functions. In the future, these novel insights into the characteristics and phenotypes of these macrophage subsets within atherosclerotic plaques can provide additional therapeutic targets for cardiovascular diseases.

Prognostic Impact of Tumor-Infiltrating Immune Cells on Efficacy of Neoadjuvant Chemotherapy in Patients with Advanced or Metastatic Ovarian Cancer: A Retrospective Study.

BACKGROUND Tumor-infiltrating immune cells (TIICs) are implicated in the survival of ovarian cancer (OVCA) patients, but their prognostic significance in advanced or metastatic OVCA patients treated with neoadjuvant chemotherapy (NCAT) has not been well documented, particularly in the Chinese population. MATERIAL AND METHODS A total of 31 advanced or metastatic OVCA patients who underwent NACT were included. The density and positive rate of tumor-infiltrating immune cells (TIICs) within cancer cell nests and in cancer stroma were explored. The correlations of pre- or post-NACT TIICs with the efficacy of NACT and the changes in TIIC subpopulation with NACT were examined. RESULTS Compared with patients with partial benefit from NACT, significantly decreased pre-NACT intratumoral CD68⁺CD163⁺ cells (P=0.0043) and increased pre-NACT intratumoral CD56⁺ cells (P=0.038) were observed in patients with benefit. The high level of pre-NACT intratumoral CD68⁺CD163⁻ M1 macrophage (P=0.075) and stromal CD3⁺PD-1⁺ cells (P=0.085) predicated improved progression-free survival, respectively. Increased post-NACT stromal CD68⁺CD163⁻ M1 macrophage (P=0.01), stromal CD8⁺ T cells (P=0.073), and stromal CD8⁺PD-1⁺ cells (P=0.072) were associated with benefit from NACT. Moreover, NACT increased intratumoral CD3⁺ (P=0.031), CD8+ (P=0.031), and CD3⁺CD8⁺ cells (P=0.031). CONCLUSIONS High intratumoral CD68⁺CD163⁻, intratumoral CD56⁺ cells, and stromal CD3⁺PD-1⁺ cells pre-NACT predicted good prognosis. Intratumoral CD3⁺, CD8⁺, and CD3⁺CD8⁺ cells were increased after NACT. Evaluation of immune profiles may help to identify patients who might benefit from NACT and allow us to further stratify advanced or metastatic OVCA patients treated with NACT for disease management.

Sporophytic control of tapetal development and pollen fertility by a mitogen-activated protein kinase cascade in rice.

Tapetum, the innermost layer of the anther wall, provides essential nutrients and materials for pollen development. Timely degradation of anther tapetal cells is a prerequisite for normal pollen development in flowering plants. Tapetal cells facilitate male gametogenesis by providing cellular contents after highly coordinated programmed cell death (PCD). Tapetal development is regulated by a transcriptional network. However, the signaling pathway(s) involved in this process are poorly understood. In this study, we report that a mitogen-activated protein kinase (MAPK) cascade composed of OsYDA1/OsYDA2-OsMKK4-OsMPK6 plays an important role in tapetal development and male gametophyte fertility. Loss of function of this MAPK cascade leads to anther indehiscence, enlarged tapetum, and aborted pollen grains. Tapetal cells in osmkk4 and osmpk6 mutants exhibit an increased presence of lipid body-like structures within the cytoplasm, which is accompanied by a delayed occurrence of PCD. Expression of a constitutively active version of OsMPK6 (CA-OsMPK6) can rescue the pollen defects in osmkk4 mutants, confirming that OsMPK6 functions downstream of OsMKK4 in this pathway. Genetic crosses also demonstrated that the MAPK cascade sporophyticly regulates pollen development. Our study reveals a novel function of rice MAPK cascade in plant male reproductive biology.

Integrin signaling in cancer: bidirectional mechanisms and therapeutic opportunities.

Integrins are transmembrane receptors that possess distinct ligand-binding specificities in the extracellular domain and signaling properties in the cytoplasmic domain. While most integrins have a short cytoplasmic tail, integrin ß4 has a long cytoplasmic tail that can indirectly interact with the actin cytoskeleton. Additionally, 'inside-out' signals can induce integrins to adopt a high-affinity extended conformation for their appropriate ligands. These properties enable integrins to transmit bidirectional cellular signals, making it a critical regulator of various biological processes.Integrin expression and function are tightly linked to various aspects of tumor progression, including initiation, angiogenesis, cell motility, invasion, and metastasis. Certain integrins have been shown to drive tumorigenesis or amplify oncogenic signals by interacting with corresponding receptors, while others have marginal or even suppressive effects. Additionally, different α/ß subtypes of integrins can exhibit opposite effects. Integrin-mediated signaling pathways including Ras- and Rho-GTPase, TGFß, Hippo, Wnt, Notch, and sonic hedgehog (Shh) are involved in various stages of tumorigenesis. Therefore, understanding the complex regulatory mechanisms and molecular specificities of integrins are crucial to delaying cancer progression and suppressing tumorigenesis. Furthermore, the development of integrin-based therapeutics for cancer are of great importance.This review provides an overview of integrin-dependent bidirectional signaling mechanisms in cancer that can either support or oppose tumorigenesis by interacting with various signaling pathways. Finally, we focus on the future opportunities for emergent therapeutics based on integrin agonists. Video Abstract.

Biochar combined with Bacillus subtilis SL-44 as an eco-friendly strategy to improve soil fertility, reduce Fusarium wilt, and promote radish growth.

Bacillus subtilis as microbial fertilizers contribute to avoiding the harmful effects of traditional agricultural fertilizers and pesticides. However, there are many restrictions on the practical application of fertilizers. In this study, microbial biochar formulations (BCMs) were prepared by loading biochar with B. subtilis SL-44. Pot experiments were conducted to evaluate the effects of the BCMs on soil fertility, Fusarium wilt control, and radish plant growth. The application of BCMs dramatically improved soil properties and favored plant growth. Compared with SL-44 and biochar treatments, the BCMs treatments increased radish plant physical-chemical properties and activities of several enzymes in the soil. What's more, Fusarium wilt incidence had decreased by 59.88%. In addition, the BCMs treatments exhibited a significant increase in the abundance of bacterial genera in the rhizosphere soil of radish. Therefore, this study demonstrated that BCMs may be an eco-friendly strategy for improving soil fertility, reducing Fusarium wilt, and promoting radish plant growth.

Cooling-activated dorsomedial hypothalamic BDNF neurons control cold defense in mice.

BDNF and its expressing neurons in the brain critically control feeding and energy expenditure (EE) in both rodents and humans. However, whether BDNF neurons would function in thermoregulation during temperature challenges is unclear. Here, we show that BDNF neurons in the dorsomedial hypothalamus (DMHBDNF ) of mice are activated by afferent cooling signals. These cooling-activated BDNF neurons are mainly GABAergic. Activation of DMHBDNF neurons or the GABAergic subpopulations is sufficient to increase body temperature, EE, and physical activity. Conversely, blocking DMHBDNF neurons substantially impairs cold defense and reduces energy expenditure, physical activity, and UCP1 expression in BAT, which eventually results in bodyweight gain and glucose/insulin intolerance. Therefore, we identify a subset of DMHBDNF neurons as a novel type of cooling-activated neurons to promote cold defense. Thus, we reveal a critical role of BDNF circuitry in thermoregulation, which deepens our understanding of BDNF in controlling energy homeostasis and obesity.

Selection of the fusion and fixation range in the intervertebral surgery to correct thoracolumbar and lumbar tuberculosis: a retrospective clinical study.

BACKGROUND: To compare the diseased verses the non-diseased intervertebral surgery used in the treatment of thoracolumbar and lumbar spinal tuberculosis and to explore the best choice of fusion of fixation range. METHODS: Two hundred twenty-one patients with thoracolumbar and lumbar tuberculosis were categorized into two groups. One hundred eighteen patients underwent the diseased intervertebral surgery (lesion vertebral pedicle fixation, Group A) and 103 patients underwent the non-diseased intervertebral surgery (1 or 2 vertebral fixation above and below the affected vertebra, group B). Spinal tuberculosis diagnosis was confirmed in both groups of patients before lesion removal, bone graft fusion, and internal fixation. Clinical data and efficacy of the two surgical methods were then evaluated. RESULTS: The mean follow-up duration for both procedures was 65 months (50-68 months range). There were no significant differences in laboratory examinations, VAS scores, and the Cobb angle correction rate and the angle loss. However, significant differences existed in the operation time, blood loss, serosanguineous drainage volume, and blood transfusion requirement between the two groups. The diseased intervertebral surgery group performed significantly better than the non-diseased intervertebral surgery group in all of these areas. In both cases, the bone graft fused completely with the normal bone by the last follow-up, occuring at 50-86 months post surgery. CONCLUSION: The diseased intervertebral surgery is a safe and feasible option for the treatment of thoracolumbar and lumbar tuberculosis. It effectively restores the physiological curvature of the spine and reduces the degeneration of adjacent vertebral bodies in the spinal column.

Chondroblastoma of the patella with secondary aneurysmal bone cyst, an easily misdiagnosed bone tumor:a case report with literature review.

BACKGROUND: Chondroblastoma (CB) is a rare, primary, benign bone tumor that commonly affects men aged 15-20 years. It is usually detected in the epiphysis of the long bones, such as the proximal femur, humerus, and tibia. The patella is an infrequent site. CB with secondary aneurysmal bone cyst (ABC) is extremely rare in the patella, which can be easily confused with other common bone tumors of the patella. Thus, it is necessary to make the right diagnosis to get a good outcome. CASE PRESENTATION: We have presented here the case of a 30-year-old man who was suffering from anterior knee pain for the past 6 months that had aggravated 2 weeks before the presentation. Osteolytic bone destruction in the patella could be detected in both his X-ray and computed tomography (CT) examinations, while the magnetic resonance imaging (MRI) detected a fluid level. Accordingly, secondary ABC was presumed. We diagnosed the condition as giant cell tumor (GCT) with secondary ABC and, accordingly, performed curettage inside the focus region with autogenous bone grafting following the patient's medical history, physical manifestations, results of physical and ancillary examinations, and the disease characteristics. However, the intraoperative and postoperative outcomes indicated that the patient's histopathology was consistent with that of typical CB, suggesting a definitive error in diagnosis. Accordingly, the patient was finally diagnosed with patella CB along with secondary ABC. CONCLUSIONS: Past studies have demonstrated that the 3 commonest bone tumors affecting the patella are GCT, CB, and ABC. CB with secondary ABC can be easily misdiagnosed as GCT with secondary ABC or ABC. Performing incision biopsy or excision biopsy and conducting histological examination may be the most effective method for suspected CB with secondary ABC.

Improving radiotherapy safety and efficiency with the customized ARIA oncology information system.

OBJECTIVE: To improve safety and efficiency of radiotherapy process by customizing a Varian ARIA oncology information system following the guidelines provided in AAPM TG-100 report. METHODS: First, failure mode and effects analysis (FMEA) and quality management program were implemented for radiotherapy process. We have customized the visual care path in the ARIA system and set up a series of templates for simulation, prescription, contouring, treatment planning, and multiple checklists. Average time of activities' completion and amount of planning errors were compared before and after the use of the customized ARIA to evaluate its impact on the efficiency and safety of radiotherapy. RESULTS: Completion time and on-time completion rate of the key activities in the care path are improved. The time of OAR/targets contouring decreases from (1.94±1.51) days to (1.64±1.07) days (p = 0.003), with the on-time completion rate increases from 77.4%to 83.3%(p = 0.048). Treatment planning time decreases from (0.81±0.65) days to (0.55±0.51) days (p < 0.001), with the on-time completion rate increases from 96.6%to 98.3%(p = 0.163). Waiting time of patients decreases from (4.50±1.83) days to (4.04±1.34) days (p < 0.001), with the on-time completion rate increases from 81.9%to 89.7%(p = 0.003). In addition, the average plan error rate decreases from 5.5%(2.9%for safety errors and 2.6%for non-normative errors) to 2.4%(1.6%for safety errors and 0.8%for non-normative errors) (p = 0.029). CONCLUSION: Our study demonstrates that the customized ARIA system has the potential to promote efficiency and safety in radiotherapy process management. It is beneficial to organize and accelerate the treatment process with more effective communications and fewer errors.

Evaluation of a novel monoclonal antibody mAb109 by immuno-PET/fluorescent imaging for noninvasive lung adenocarcinoma diagnosis.

Monoclonal antibodies are believed to be magic bullets and hold great potential for lots of biological process. About 100 µg of mAb109 was expressed in 5 × 106 cells after 10 days' immunization. 64Cu-NOTA-mAb109 was synthesized with the specific activity of 0.74 MBq/µg and high in vitro stability. The binding affinity of 64Cu-NOTA-mAb109 in A549 cells was determined to be 29.64 nM. 64Cu-NOTA-mAb109 displayed prominent tumor accumulation from 2 h to 60 h p.i. (9.34 ± 0.67 %ID/g). NIRF imaging of Cy5.5-mAb109 showed high accumulation till 9 days p.i., while tumors nearly can not be observed in negative groups, which was confirmed by autoradiography. Immunohistological study confirmed that mAb109 had strong and specific capacity to bind lung adenocarcinoma (concentration to 58 nM). Our study demonstrated mAb109 was a new platform for the development of novel agent for lung adenocarcinoma noninvasive imaging. The resulted 64Cu-NOTA-mAb109/Cy5.5-mAb109 show favorable imaging properties/specificity for A549 tumor and high sensitivity to human lung adenocarcinoma tissues.

Comparison of two types of the triple incision technique in the treatment of patients with locally advanced vulvar cancer.

Objective: In 2012, we proposed and described a modified triple incision technique (MTIT) for vulvar cancer patients with locally advanced disease. The MTIT has undergone a series of modifications, and a modified MTIT (M-MTIT) has been developed. The purpose of this study was to introduce the M-MTIT and compare it with the MTIT. Study design: This was a retrospective cohort study. Fifty-seven vulvar cancer patients with clinical stage T2 (≥ 4 cm) or T3 disease were included. Of these patients, 28 underwent the MTIT and 29 underwent the M-MTIT. Data on surgery-related complications and survival outcomes were compared. Results: Patients who were treated with the M-MTIT developed significantly less surgery-related morbidities than patients treated with the MTIT (24.1% vs. 60.7%, P = 0.005). Wound breakdown was the most common complication in our cohort, which occurred less frequently in the M-MTIT group than in the MTIT group (10.3% vs. 35.7%, P = 0.022). Multivariate logistic regression analysis identified the M-MTIT as an independent predictor of a reduced risk of wound breakdown. The incidence of other complications, including lymphedema, wound infection and cellulitis, was lower in the M-MTIT group than in the MTIT group; however, the differences did not reach statistical significance. The median follow-up time of this study was 33 months. Kaplan-Meier survival graphs did not show significant differences in recurrence-free survival or overall survival between the two groups. Conclusions: The M-MTIT correlates with lower morbidity rates than the MTIT and does not compromise oncological safety. The M-MTIT can be considered a safe and feasible option for vulvar cancer patients with locally advanced disease.

Patients with ankylosing spondylitis treatment by golimumab: a systematic review and meta-analysis.

PURPOSE: The goal of this study was to review relevant randomized controlled trials in order to determine the clinical efficacy of golimumab in the treatment of ankylosing spondylitis (AS). METHODS: Using appropriate keywords, we identified relevant studies using PubMed, Cochrane and Embase. Key pertinent sources in the literature were also reviewed, and all articles published through November 2019 were considered for inclusion. For each study, we assessed odds ratios, mean difference and 95% confidence interval to assess and synthesize outcomes. RESULTS: We included nine studies with 6363 patients. Compared with placebo, golimumab would significant decreased the value of BASFI, BASMI, BASDAI, total back pain, JSEQ; increased the value of SF-36 PCS and SF-36 MCS; increased the incidence of BASDAI50, ASAS20, ASAS40 and ASAS partial remission. Compared with golimumab 50 mg, golimumab 100 mg would significantly decreased the value of BASFI and total back pain; increased the value of SF-36 PCS and SF-36 MCS; but also increased the incidence of SAE. CONCLUSIONS: Golimumab had a definite effect in the treatment of AS. The higher dose would obtain better efficacy but lead to the incidence of SAE.

Do multiple environmental factors impact four cancers in women in the contiguous United States?

BACKGROUND: Though there has been an increasing concern about the effects that environmental exposures have on cancer, limited knowledge exists regarding multiple environmental factors on cancers in women. METHODS: We performed a spatial autoregressive model to examine the association between the Environmental Quality Index (EQI) and mortalities of four cancers in women (breast, cervical, ovarian and uterine cancer) based on county-level data, and explored these associations by urbanicity. The EQI, which included five domains (air, water, land, built environment and sociodemographic domain) estimated from 2000 to 2005 data, was obtained from the United States Environmental Protection Agency. The mortality rates for 3107 counties in the US in 2014 were obtained from the Institute for Health Metrics and Evaluation. RESULTS: We found that each unit increase in the overall EQI was positively associated with the increased mortality of breast, ovarian and uterine cancer (2.5%, 3.6% and 3.1% respectively), but was negatively associated with cervical cancer mortality. Among the environmental domains, the air and sociodemographic EQIs were positively associated with increased risks of breast, ovarian and uterine cancers. Additionally, built environment EQI was associated with breast and ovarian cancers; land EQI was associated with uterine and ovarian cancers. The sociodemographic EQI was negatively associated with cervical cancer mortality. Furthermore, we have developed a novel Environmental Quality Health Index (EQHI) in identifying environment-health risk of cancers in women at county level. CONCLUSIONS: Our findings suggest that breast, ovarian, and uterine cancer mortalities are positively associated with multiple environmental factors, while cervical cancer mortality is mainly negatively associated with sociodemographic factors. The novel EQHI might help identify spatially-based environment-cancer risk.

Application of a 'Baseball' Suture Technique in Uterine Myomectomy Following Laparoscopic Enucleation of Uterine Leiomyoma (Fibroid).

BACKGROUND The aim of this study was to evaluate the safety and efficacy of a 'baseball' suture technique for uterine myomectomy incision closure in laparoscopic surgical enucleation of uterine leiomyoma (fibroid). MATERIAL AND METHODS The study included 20 patients who underwent laparoscopic myomectomy with a 'baseball' suture technique, compared with 20 patients who underwent laparoscopic myomectomy with a standard suture method. Clinical characteristics, perioperative and follow-up data were compared between the two groups. RESULTS For the study group, compared with the standard or control group, had a significantly reduced operation time (60.15±9.97 min vs. 71.85±9.74 min) and suturing time (18.05±4.71 min vs. 28.35±3.13 min) (both p<0.05), significantly less intraoperative blood loss (93.25±19.62 ml vs. 121.50±24.87 ml) (p<0.05) and significantly less reduction in postoperative hemoglobin levels (8.9±1.97 g/L vs. 11.15±2.23 g/L) (p<0.05). There were no statistically significant differences between the two groups in duration of the use of the indwelling drainage tube, drainage volume, or time to recovery of gastrointestinal function (all, p>0.05). Following surgery, blood transfusion was given to one patient in the study group and two patients in the control group. One patient from each group had a fever. There was no significant difference in pregnancy outcomes between the two groups. CONCLUSIONS The 'baseball' suture technique for closure of the uterine incision is a safe and effective method for use in laparoscopic myomectomy. However, the long-term recovery outcomes require further study.

Improved positron emission tomography imaging of glioblastoma cancer using novel 68Ga-labeled peptides targeting the urokinase-type plasminogen activator receptor (uPAR).

The urokinase-type plasminogen activator receptor (uPAR) is overexpressed in several cancers including glioblastoma (GBM) and is an established biomarker for metastatic potential. The uPAR-targeting peptide AE105-NH2 (Ac-Asp-Cha-Phe-(D)Ser-(D)Arg-Tyr-Leu-Trp-Ser-CONH2) is a promising candidate for non-invasive positron emission tomography (PET) imaging of uPAR. Despite the optimal physical properties of 68Ga for peptide-based PET imaging, low tumor uptakes have previously been reported using 68Ga-labeled AE105-NH2-based tracers. In an attempt to optimize the tumor uptake, we developed three novel tracers with alkane (AOC) and polyethylene glycol (PEG) spacers inserted between AE105-NH2 and the radio metal chelator 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA). The resulting tracers NODAGA-AOC-AE105-NH2, NODAGA-PEG3-AE105-NH2 and NODAGA-PEG8-AE105-NH2 were compared to the non-spacer version, NODAGA-AE105-NH2. Following radiolabeling with 68Ga, we evaluated the in vitro and in vivo performance in mice bearing subcutaneous tumors derived from the uPAR-expressing human GBM cell line U87MG. In vivo PET/CT imaging showed that introduction of PEG spacers more than doubled the in vivo tumor uptake after 1 h compared with the non-spacer version: 68Ga-NODAGA-PEG3-AE105-NH2 (2.08 ± 0.37%ID/g) and 68Ga-NODAGA-PEG8-AE105-NH2 (2.01 ± 0.22%ID/g) vs. 68Ga-NODAGA-AE105-NH2 (0.70 ± 0.40%ID/g), p < 0.05. In addition, 68Ga-NODAGA-PEG8-AE105-NH2 showed significantly higher (p < 0.05) tumor-to-background contrast (3.68 ± 0.23) than the other tracers. The specific tumor-targeting property of 68Ga-NODAGA-PEG8-AE105-NH2 was established by effectively blocking the tumor uptake with co-injection of unlabeled AE105-NH2 (1 h: unblocked 2.01 ± 0.22%ID/g vs. blocked 1.24 ± 0.09%ID/g, p < 0.05). Ex vivo biodistribution confirmed the improved tumor uptakes of the PEG-modified tracers. 68Ga-NODAGA-PEG8-AE105-NH2 is thus a promising candidate for human translation for PET imaging of GBM.

Preclinical Study on GRPR-Targeted (68)Ga-Probes for PET Imaging of Prostate Cancer.

Gastrin-releasing peptide receptor (GRPR) targeted positron emission tomography (PET) is a highly promising approach for imaging of prostate cancer (PCa) in small animal models and patients. Developing a GRPR-targeted PET probe with excellent in vivo performance such as high tumor uptake, high contrast, and optimal pharmacokinetics is still very challenging. Herein, a novel bombesin (BBN) analogue (named SCH1) based on JMV594 peptide modified with an 8-amino octanoic acid spacer (AOC) was thus designed and conjugated with the metal chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA). The resulting NODAGA-SCH1 was then radiolabeled with (68)Ga and evaluated for PET imaging of PCa. Compared with (68)Ga-NODAGA-JMV594 probe, (68)Ga-NODAGA-SCH1 exhibited excellent PET/CT imaging properties on PC-3 tumor-bearing nude mice, such as high tumor uptake (5.80 ± 0.42 vs 3.78 ± 0.28%ID/g, 2 h) and high tumor/muscle contrast (16.6 ± 1.50 vs 8.42 ± 0.61%ID/g, 2 h). Importantly, biodistribution data indicated a relatively similar accumulation of (68)Ga-NODAGA-SCH1 was observed in the liver (4.21 ± 0.42%ID/g) and kidney (3.41 ± 0.46%ID/g) suggesting that the clearance is through both the kidney and the liver. Overall, (68)Ga-NODAGA-SCH1 showed promising in vivo properties and is a promising candidate for translation into clinical PET-imaging of PCa patients.