Peptidic heterodimer-based radiotracer targeting fibroblast activation protein and integrin αvß3.

PURPOSE: Several studies have demonstrated the advantages of heterodimers over their corresponding monomers due to the multivalency effect. This effect leads to an increased number of effective targeted receptors and, consequently, improved tumor uptake. Fibroblast activation protein (FAP) and integrin αvß3 are found to be overexpressed in different components of the tumor microenvironment. In our pursuit of enhancing tumor uptake and retention, we designed and developed a novel peptidic heterodimer that synergistically targets both FAP and integrin αvß3. METHODS: FAP-RGD was synthesized from FAP-2286 and c(RGDfK) through a multi-step organic synthesis. The dual receptor binding property of 68Ga-FAP-RGD was investigated by cell uptake and competitive binding assays. Preclinical pharmacokinetics were determined in HT1080-FAP and U87MG tumor models using micro-positron emission tomography/computed tomography (micro-PET/CT) and biodistribution studies. The antitumor efficacy of 177Lu-FAP-RGD was assessed in U87MG tumor models. The radiation exposure and clinical diagnostic performance of 68 Ga-FAP-RGD were evaluated in healthy volunteers and cancer patients. RESULTS: Bi-specific radiotracer 68Ga-FAP-RGD exhibited high binding affinity for both FAP and integrin αvß3. In comparison to 68Ga-FAP-2286 and 68Ga-RGDfK, 68Ga-FAP-RGD displayed enhanced tumor uptake and longer tumor retention time in preclinical models. 177Lu-FAP-RGD could efficiently suppress the growth of U87MG tumor in vivo when applied at an activity of 18.5 and 29.6 MBq. The effective dose of 68Ga-FAP-RGD was 1.06 × 10-2 mSv/MBq. 68Ga-FAP-RGD demonstrated low background activity and stable accumulation in most neoplastic lesions up to 3 h. CONCLUSION: Taking the advantages of multivalency effect, the bi-specific radiotracer 68Ga-FAP-RGD showed superior tumor uptake and retention compared to its corresponding monomers. Preclinical studies with 68Ga- or 177Lu-labeled FAP-RGD showed favorable image contrast and effective antitumor responses. Despite the excellent performance of 68Ga-FAP-RGD in clinical diagnosis, experimental efforts are currently underway to optimize the structure of FAP-RGD to increase its potential for clinical application in endoradiotherapy.

[68Ga]Ga-AUNP-12 PET imaging to assess the PD-L1 status in preclinical and first-in-human study.

PURPOSE: PD-L1 PET imaging, as a non-invasive procedure, can perform a real-time, dynamic and quantitative analysis of PD-L1 expression at tumor sites. In this study, we developed a novel peptide-based PET tracer, [68 Ga]Ga-AUNP-12, for preclinical and first-of-its-kind imaging of PD-L1 expression in patients. METHODS: Radiosynthesis of [68 Ga]Ga-AUNP-12 was conducted. Assays for cellular uptake and binding were conducted on the PANC02, CT26, and B16F10 cell lines. Preclinical models were used to investigate its biodistribution, imaging capacity, and pharmacokinetics. Furthermore, interferon-γ (IFN-γ) was used for development of an animal model with high PD-L1 expression for targeted PET imaging and efficacy evaluation of PD-L1 blocking therapy. In healthy volunteers and cancer patients, the PD-L1 imaging, radiation dosimetry, safety, and biodistribution were further evaluated. RESULTS: In vitro and in vivo animal studies showed that [68 Ga]Ga-AUNP-12 PET imaging displayed a high specificity in evaluating PD-L1 expression. The radiochemical yield of [68 Ga]Ga-AUNP-12 was 71.7 ± 8.2%. Additionally, its molar activity and radiochemical purity were satisfactory. The B16F10 tumor was visualized with the tumor uptake of 6.86 ± 0.71% ID/g and tumor-to-muscle ratio of 6.83 ± 0.36 at 60 min after [68 Ga]Ga-AUNP-12 injection. Furthermore, [68 Ga]Ga-AUNP-12 PET imaging could sensitively detect the PD-L1 dynamic changes in CT26 tumor xenograft models regulated by IFN-γ treatment, and correspondingly can effectively guide immunotherapy. Regarding radiation dosimetry, [68 Ga]Ga-AUNP-12 is safe for human use. The first human study found that [68 Ga]Ga-AUNP-12 can be rapidly cleared from blood and other nonspecific organs through the kidney excretion, leading to form a clear imaging contrast in the clinical framework. The specificity of [68 Ga]Ga-AUNP-12 was validated and tumor uptake strongly correlated with the high PD-L1 expression in patients with lung adenocarcinoma and oesophageal squamous cell carcinoma (OSCC). CONCLUSION: [68 Ga]Ga-AUNP-12 was successfully developed as a PD-L1-specific PET imaging tracer in preclinical and first-in-human studies.

Highly sensitive frequency upconversion detection from 1 to 3 THz with OH1 crystal.

The wide applications of terahertz (THz) wave technology in the ∼1-3 THz range has resulted in a surge in the demand for the performance improvement of THz wave detection technique. In this study, a frequency tunable, highly sensitive frequency upconversion detection based on a 2-(3-(4-hydroxystyryl)-5,5-dime-thylcyclohex-2-enylidene) malononitrile (OH1) crystal at room temperature is demonstrated. Moreover, to effectively increase the signal-to-noise ratio in the low frequency range, a beam isolation enhancer is proposed and its effect is verified. The minimum detectable THz pulse energy reaches about 100 aJ at 1.9 THz. The frequency tuning ranging from 1 to 3 THz. Sensitivity comparison with a 4-dimethylamino-N-methyl-4-stilbazolium tosylate (DAST) crystal system shows that OH1 is a more suitable nonlinear crystal in the 1-2.4 THz range.

Association between Serum Per- and Polyfluoroalkyl Substance Levels and Risk of Central and Peripheral Precocious Puberty in Girls.

Concerns about the endocrine-disrupting effects of per- and polyfluoroalkyl substances (PFASs) have raised questions about their potential influence on precocious puberty in girls, which is an emerging concern in some populations. However, epidemiological evidence is lacking. In this study, 882 serum samples were collected from girls with central precocious puberty (CPP, n = 226), peripheral precocious puberty (PPP, n = 316), and healthy controls (n = 340) in 2021 in Shanghai, China. The serum levels of 25 legacy and emerging PFASs and 17 steroids were measured. Results showed that PFAS exposure was positively associated with estradiol levels. Eleven PFASs were significantly or marginally associated with the higher odds of the overall precocious puberty. Across subtypes, PFASs were more clearly associated with PPP, while the associations with CPP were consistent in direction but did not reach statistical significance. These findings were consistent with the assessment of PFAS mixtures using quantile-based g-computation (qgcomp) and Bayesian kernel machine regression, with perfluorobutane sulfonate and 6:2 polyfluorinated ether sulfonate showing the highest contribution to joint effects. Although changes in serum estradiol could arise from various factors, our results suggest that the PFAS exposure may contribute to the increase in estradiol secretion, thereby increasing the risk of precocious puberty, especially PPP. The potential effects of PFASs on precocious puberty warrant further investigation, given the associated complications of public health concern, including psychological distress and increased risk of multiple diseases.

Trimester-specific reference intervals of hemostasis biomarkers for healthy pregnancy.

Physiological changes in hemostasis during pregnancy have been reported by several authors. This study aimed at establishing reference intervals for the hemostasis biomarkers thrombin-antithrombin complex (TAT), α2-plasmininhibitor-plasmin complex (PIC), thrombomodulin (TM) and tissue plasminogen activator-inhibitor complex (tPAI-C), in healthy pregnancies. After excluding outliers, a total of 496 healthy pregnant women (128 first-trimester, 142 second-trimester, 107 third-trimester and 119 pre-labor) and 103 healthy nonpregnant women were enrolled from Shenzhen Bao'an Women's and Children's Hospital. Hemostasis biomarkers, TAT, PIC, TM and tPAI-C, were measured by using a quantitative chemiluminescence enzyme immunoassay performed on HISCL automated analysers. The median and reference intervals (the 2.5th and 97.5th percentiles) were calculated to establish trimester-specific reference intervals for healthy pregnant women. The reference intervals for TAT, PIC, TM and tPAI-C in the first trimester were 0.7-7.6 1 µg/L, 0.2-0.9 mg/L, 2.8-11.0 TU/ml, and 1.2-6.5 1 µg/L, respectively. The reference intervals in the second trimester were 1.7-12.0 1 µg/L, 0.2-1.0 mg/L, 3.7-11.6 TU/ml, and 2.8-8.8 1 µg/L, respectively. The reference intervals in the third trimester were 2.7-16.1 1 µg/L, 0.1-1.4 mg/L, 2.9-12.9 TU/ml, and 1.9-8.0 1 µg/L, respectively. At pre-labor, the reference intervals were 4.8-32.9 1 µg/L, 0.2-1.9 mg/L, 4.2-12.6 TU/ml, and 2.8-15.4 1 µg/L, respectively. Gestational reference intervals for TAT, PIC, TM and tPAI-C in healthy pregnancies are provided, but only for TAT with increasing concentrations throughout pregnancy, the reference intervals for non-pregnant were not applicable.

Coupling effects of the sum-frequency process and difference-frequency process on upconversion terahertz-wave detection via a DAST crystal.

Frequency upconversion technology with good performance including high sensitivity, fast response, and room-temperature operation is a promising method for terahertz-wave detection. The sum-frequency conversion and difference-frequency conversion jointly affect the detection ability for upconversion detection using organic crystals as nonlinear media. The concurrence of both processes has been ignored in past studies, which results in discrepancies between theoretical simulations and experimental results. In this paper, four-wave interaction equations involving two nonlinear conversion processes are proposed, and the effect of the sum-frequency process is analyzed in upconversion terahertz-wave detection via a 4-dimethylamino-N-methyl-4-stilbazolium tosylate (DAST) crystal. The ratio of the sum-frequency signal to the difference-frequency signal varies for different terahertz frequencies and crystal thicknesses. Experiments suggest that theoretical simulations are good at predicting physical processes. Under certain conditions, the detection efficiency can be improved by simultaneously utilizing the two signals. The total signal photon number is not sensitive to the crystal thickness. Furthermore, the theoretical exploration of terahertz single-photon detection provides a noteworthy reference for future experiments.

Preclinical and first-in-human evaluation of 18F-labeled D-peptide antagonist for PD-L1 status imaging with PET.

PURPOSE: PD-L1 PET imaging allows for the whole body measuring its expression across primary and metastatic tumors and visualizing its spatiotemporal dynamics before, during, and after treatment. In this study, we reported a novel 18F-labeled D-peptide antagonist, 18F-NOTA-NF12, for PET imaging of PD-L1 status in preclinical and first-in-human studies. METHODS: Manual and automatic radiosynthesis of 18F-NOTA-NF12 was performed. Cell uptake and binding assays were completed in MC38, H1975, and A549 cell lines. The capacity for imaging of PD-L1 status, biodistribution, and pharmacokinetics were investigated in preclinical models. The PD-L1 status was verified by western blotting, immunohistochemistry/fluorescence, and flow cytometry. The safety, radiation dosimetry, biodistribution, and PD-L1 imaging potential were evaluated in healthy volunteers and patients. RESULTS: The radiosynthesis of 18F-NOTA-NF12 was achieved via manual and automatic methods with radiochemical yields of 41.7 ± 10.2 % and 70.6 ± 4.2 %, respectively. In vitro binding assays demonstrated high specificity and affinity with an IC50 of 78.35 nM and KD of 85.08 nM. The MC38 and H1975 tumors were clearly visualized with the optimized tumor-to-muscle ratios of 5.36 ± 1.17 and 7.13 ± 1.78 at 60 min after injection. Gemcitabine- and selumetinib-induced modulation of PD-L1 dynamics was monitored by 18F-NOTA-NF12. The tumor uptake correlated well with their PD-L1 expression. 18F-NOTA-NF12 exhibited renal excretion and rapid clearance from blood and other non-specific organs, contributing to high contrast imaging in the clinical time frame. In NSCLC and esophageal cancer patients, the specificity of 18F-NOTA-NF12 for PD-L1 imaging was confirmed. The 18F-NOTA-NF12 PET/CT and 18F-FDG PET/CT had equivalent findings in patients with high PD-L1 expression. CONCLUSION: 18F-NOTA-NF12 was developed successfully as a PD-L1-specific tracer with promising results in preclinical and first-in-human trials, which support the further validation of 18F-NOTA-NF12 for PET imaging of PD-L1 status in clinical settings.

Clinical, hormonal, and biochemical characteristics of 70 chinese children with moderate to severe type 1 diabetic ketoacidosis.

BACKGROUND: Diabetic ketoacidosis (DKA) is one of the most severe acute complications of type 1 diabetes mellitus (T1DM). Patients with DKA of different severities may have different clinical manifestations, serum biochemical levels and hormone changes. METHODS: We retrospectively evaluated the clinical manifestations, serum hormone levels, and biochemical levels of 70 Chinese patients with moderate to severe type 1 DKA in the acute and recovery phases admitted to Shanghai Children's Hospital from 2015 to 2020. RESULTS: The time required for acidosis correction in 37 patients with severe DKA was 5.9 h longer than that in 33 patients with moderate DKA (P < 0.001). In addition, serum levels of serum ionized calcium (P = 0.003), free triiodothyronine (FT3) (P = 0.029), white blood cells (WBCs) (P = 0.044), and triglycerides (TGs) (P = 0.002) were significantly different between patients with moderate and severe DKA. Serum levels of ionized calcium decreased significantly after recovery from severe DKA. Within 1 week, thyroid hormone and blood lipid levels recovered to normal ranges without intervention. CONCLUSION: Patients with severe DKA had higher acidosis correction times, higher WBC counts, TGs and ionized calcium levels, and lower FT3 levels than patients with moderate DKA. No additional intervention was required for thyroid hormone, and blood lipid and serum ionized calcium levels recovered to the normal range.

Clinical, hormonal, and genetic characteristics of 25 Chinese patients with idiopathic hypogonadotropic hypogonadism.

BACKGROUND: Idiopathic hypogonadotropic hypogonadism (IHH) is a type of congenital disease caused by a variety of gene variants leading to dysfunction in the secretion of hypothalamic gonadotropin-releasing hormones (GnRHs). Clinically, IHH can be divided into Kallmann syndrome (KS) with dysosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH) according to the presence or absence of an olfactory disorder. METHODS: We retrospectively evaluated 25 IHH patients (8 KS and 17 nIHH) who were diagnosed at the Department of Endocrinology of Shanghai Children's Hospital from 2015 to 2021. We analysed the patients' clinical data, including their hormone levels and gene sequences. RESULTS: All male patients exhibited small phalli, and 35% of them exhibited cryptorchidism. A significant difference was observed in the levels of dihydrotestosterone (DHT) after human chorionic gonadotropin (HCG) stimulation (P = 0.028) between the KS group and the nIHH group. Missense variants were the major cause of IHH, and the main pathogenic genes were FGFR1, PROKR2/PROK2, and KAl1. Nine reported and 13 novel variants of six genes were identified. De novo variants were detected in 16 IHH patients; eight patients inherited the variants from their mothers, while only three patients inherited variants from their fathers. One patient had both KAl1 and PROKR2 gene variants, and another patient had two different PROKR2 gene variants. These two patients both had the hot spot variant c.533G > C (p. Trp178Ser) of the PROKR2 gene. CONCLUSION: IHH should be highly suspected in patients with a small phallus and cryptorchidism. Compared with nIHH patients, KS patients exhibited a higher level of DHT after HCG stimulation. Missense variants were the major cause of IHH, and most of the inherited variants were from their mothers who exhibited no obvious clinical symptoms. We identified 9 reported variants and 13 novel variants that led to IHH. A small proportion of patients were at risk of inheriting either the oligogenic variant or the compound heterozygous variant. The hot spot variant c.533G > C (p. Trp178Ser) of PROKR2 might be involved in oligogenic inheritance and compound heterozygous inheritance. These findings provide deeper insight into the diagnosis and classification of IHH and will contribute to its clinical assessment.

Clinical, Hormonal, and Genetic Characteristics of 5α-Reductase Type 2 Deficiency in 103 Chinese Patients.

OBJECTIVE: 5α-Reductase type 2 (5α-RD2) deficiency causes variable degrees of undervirilization in patients. The correlation between its genotype and phenotype is unclear. METHODS: We retrospectively evaluated 103 patients with 46,XY disorders of sex development who were diagnosed with 5α-RD2 deficiency. RESULTS: The prevalence of female sex assignment (P = .008) and the incidences of cryptorchidism (P = .0003) and bifid scrotum (P = .0002) in the non-p.R227Q variant group were higher, but there were no significant differences in the incidences of hypospadias and isolated microphallus. The external masculinization score in the non-p.R227Q variant group was lower than that in the homozygous p.R227Q variant (P = .019) and compound heterozygous p.R227Q variant groups (P = .013). The level of anti-Mullerian hormone in the non-p.R227Q variant group was lower than that in the homozygous p.R227Q variant (P < .001) and compound heterozygous p.R227Q variant groups (P = .006). The testosterone-to-dihydrotestosterone ratio of the homozygous p.R227Q variant group was higher than that of the non-p.R227Q variant (P = .018) and compound heterozygous p.R227Q variant groups (P = .029). Twenty-three reportedly pathogenic variants and 11 novel steroid 5α-reductase 2 (SRD5A2) variants were identified. CONCLUSION: Compared with patients without p.R227Q, patients with p.R227Q exhibited higher external masculinization scores and anti-Mullerian hormone expression, a lower prevalence of female sex assignment, and lower incidences of cryptorchidism and bifid scrotum. We identified 23 reportedly pathogenic SRD5A2 variants and 11 novel SRD5A2 variants that led to 5α-RD2 deficiency. We established a genotype-phenotype correlation, and patients with p.R227Q showed a relatively mild phenotype.

Downregulation of TTF1 in the rat hypothalamic ARC or AVPV nucleus inhibits Kiss1 and GnRH expression, leading to puberty delay.

BACKGROUND: TTF1 is a transcription factor that is expressed in the hypothalamus after birth and plays crucial roles in pubertal development. TTF1 may regulate the expression of the Kiss1 gene, which may drive puberty onset in the hypothalamic arcuate (ARC) and anterior ventral paraventricular (AVPV) nuclei. METHODS: A dual-luciferase reporter assay was used to detect binding between TTF1 and the Kiss1 gene promoter. To investigate the effects of TTF1, we modified TTF1 expression in cell lines and in the ARC or AVPV nucleus of 21-day-old female rats via lentivirus infection. TTF1 and other puberty onset-related genes were detected by qRT-PCR and western blot analyses. RESULTS: The in vitro data indicated that TTF1 knockdown (KD) significantly reduced Kiss1 and GnRH expression. Overexpression (OE) of TTF1 promoted Kiss1 expression. In vivo, the expression of Kiss1 and GnRH decreased significantly in the rats with hypothalamic ARC- or AVPV-specific TTF1 KD. The TTF1-KD rats showed vaginal opening delay. H&E staining revealed that the corpus luteum was obviously reduced at the early puberty and adult stages in the rats with ARC- or AVPV-specific TTF1 KD. CONCLUSION: TTF1 bound to the promoter of the Kiss1 gene and enhanced its expression. For 21-day-old female rats, decreased TTF1 in the hypothalamic ARC or AVPV nucleus resulted in delayed vaginal opening and ovarian abnormalities. These observations suggested that TTF1 regulates puberty onset by promoting the expression of Kiss1 and plays an important role in gonad development.

All-solid-state widely wavelength-tunable and high-efficiency Yb:YSr3(PO4)3 laser.

We demonstrate an all-solid-state widely wavelength-tunable Yb:YSr3(PO4)3 (Yb:YSP) laser with high efficiency. The free-running Yb:YSP laser oscillating at multiple wavelengths in the range of 1024-1054 nm is realized with different crystal lengths and output coupler transmittances. The maximum output power of 2.72 W is obtained under the absorption pump power of 7.30 W. The highest slope efficiency is 66.9%, using the crystal of 6.5-mm-length. Simultaneous dual-wavelength operation can be realized as well. Furthermore, the widely wavelength-tunable Yb:YSP laser with a range of more than 60 nm (from 1004 to 1066 nm) is achieved using a birefringent filter. The experimental results indicate that the Yb:YSP crystal can be a promising candidate for ultrafast lasers in the 1 µm region.

Clinical, hormonal and genetic characteristics of androgen insensitivity syndrome in 39 Chinese patients.

BACKGROUND: Abnormal androgen receptor (AR) genes can cause androgen insensitivity syndrome (AIS), and AIS can be classified into complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS) and mild AIS. We investigated the characteristics of clinical manifestations, serum sex hormone levels and AR gene mutations of 39 AIS patients, which provided deeper insight into this disease. METHODS: We prospectively evaluated 39 patients with 46, XY disorders of sex development (46, XY DSD) who were diagnosed with AIS at the Department of Endocrinology of Shanghai Children's Hospital from 2014 to 2019. We analysed clinical data from the patients including hormone levels and AR gene sequences. Furthermore, we screened the AR gene sequences of the 39 AIS patients to identify probable mutations. RESULTS: The 39 AIS patients came from 37 different families; 19 of the patients presented CAIS, and 20 of them presented PAIS. The CAIS patients exhibited a higher cryptorchidism rate than the PAIS (100 and 55%, P = 0.001). There were no significant difference between the CAIS and PAIS groups regarding the levels of inhibin B (INHB), sex hormone-binding globulin (SHBG), basal luteinizing hormone (LH), testosterone (T), or basal dihydrotestosterone (DHT), the T:DHT ratio, DHT levels after human chorionic gonadotropin (HCG) stimulation or T levels after HCG stimulation. However, the hormone levels of AMH (P = 0.010), peak LH (P = 0.033), basal FSH (P = 0.009) and peak FSH (P = 0.033) showed significant differences between the CAIS group and the PAIS group. Twenty-one reported pathogenic and 9 novel AR mutations were identified. Spontaneous AR mutations were found in 5 AIS patients, and 21 patients inherited mutations from their mothers, who carried heterozygous mutations. CONCLUSIONS: Forty-six XY DSD patients with cryptorchidism and female phenotypes were highly suspected of having AIS. We demonstrated that CAIS patients could not be distinguished by their hormone levels alone. Compared with PAIS patients, CAIS patients exhibited higher basal FSH, peak FSH, and peak LH hormone levels but lower AMH expression. We identified 21 reported pathogenic AR mutations and 9 novel AR mutations that led to different types of AIS. Missense mutations were the major cause of AIS and mostly occurred in exon 7 of the AR gene. These findings provided deeper insight into the diagnosis and classification of AIS and will even contributed to its clinical assessment.

Evaluation of neurotensin receptor 1 as a potential imaging target in pancreatic ductal adenocarcinoma.

Pancreatic cancer is one of the deadliest human malignancies and lack of effective diagnostic and therapeutic methods. Accumulating evidence suggests that the neurotensin (NT) and neurotensin receptors (NTRs) play key roles in pancreatic adenocarcinoma growth and survival. In this study, we not only evaluate the NTR1 expression in pancreatic cancer patient samples, but also explore the PET and fluorescence imaging of NTR1 expression in pancreatic cancer animal models. The NTR1 expression was evaluated by immunohistochemistry staining in clinical patient tissue samples with pancreatic ductal adenocarcinoma, insulinoma, and pancreatitis. The results showed 79.4% positive rate of NRT1 expression in pancreatic ductal adenocarcinoma, compared with 33.3 and 22.7% in insulinoma and pancreatitis samples, respectively. High NTR1 gene expression was also found in Panc-1 cells and confirmed by cell immunofluorescence. 64Cu-AmBaSar-NT and IRDye800-NT were synthesized as imaging probes and maintained the majority of NTR1-binding affinity. In vivo imaging demonstrated that 64Cu-AmBaSar-NT has prominent tumor uptake (3.76 ± 1.45 and 2.29 ± 0.10%ID/g at 1 and 4 h post-injection). NIR fluorescent imaging with IRDye800-NT demonstrated good tumor-to-background contrast (8.09 ± 0.38 × 108 and 6.67 ± 0.43 × 108 (p/s/cm2/sr)/(µW/cm2) at 30 and 60 min post-injection). Fluorescence guided surgery was also performed as a proof of principle experiment. In summary, our results indicated that NTR1 is a promising target for pancreatic ductal adenocarcinoma imaging and therapy. The imaging probes reported here may not only be considered for improved diagnosis of pancreatic ductal adenocarcinoma, but also has the potential to be fully integrated into patient screening and treatment monitoring of future NTR1 targeted therapies.

PET monitoring angiogenesis of infarcted myocardium after treatment with vascular endothelial growth factor and bone marrow mesenchymal stem cells.

Angiogenesis is a key factor for post-ischemic repair of the infarcted myocardium. This study aims to monitor angiogenesis of infarcted myocardium with a positron emission tomography (PET) imaging agent, (18)F-alfatide II ((18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2), targeting αvß3 integrin after treatment with vascular endothelial growth factor (VEGF) gene and/or bone marrow mesenchymal stem cells (BMSCs). Sprague-Dawley (SD) rats underwent left coronary artery ligation and were randomly divided into four groups: normal saline control, Ad-VEGF, BMSCs, and Ad-VEGF + BMSCs (n = 4/group). The induced myocardial infarction (MI) was confirmed by electrocardiogram (ECG) with ST-segment elevation, and (99m)Tc-MIBI SPECT imaging showing defected myocardial perfusion. Alfatide II PET was performed to monitor angiogenesis at different time points after the therapy. The ratios of Alfatide II tracer uptake in the infarcted myocardium to normal myocardium in all four groups were analyzed. The PET results were validated by ex vivo tissue biodistribution, autoradiography, and immunofluorescence staining. At 1 week after therapy, elevated RGD peptide tracer uptake at the infarcted myocardium was observed in all four groups. The infarct to normal heart ratio of Alfatide II tracer for the three treatment groups was significantly higher than that of the control group (3.94 ± 0.20 for VEGF group, 3.77 ± 0.16 for BMSCs group and 4.86 ± 0.08 for the combination group vs. 3.01 ± 0.03 for the control group, P < 0.005, P < 0.005, P < 0.0001, respectively). The combination treatment group demonstrated higher contrast than the two single treatment groups. Similar results were also observed at 4 weeks after treatment. Autoradiography showed similar trend to that of PET results. Immunohistochemical staining showed expression of VEGF protein and the presence of adenovirus in the myocardium. The patterns of vascular density and integrin αvß3 expression were measured by CD31 and CD61 immunostaining analysis, and were consistent with the PET results. (18)F-alfatide II PET could reflect angiogenesis of infarcted myocardium after VEGF gene and BMSCs therapy and further provide a non-invasive way of monitoring therapy response of myocardial infarction.

Roles of miRNAs in microcystin-LR-induced Sertoli cell toxicity.

Microcystin (MC)-LR, a cyclic heptapeptide, is a potent reproductive system toxin. To understand the molecular mechanisms of MC-induced reproductive system cytotoxicity, we evaluated global changes of miRNA and mRNA expression in mouse Sertoli cells following MC-LR treatment. Our results revealed that the exposure to MC-LR resulted in an altered miRNA expression profile that might be responsible for the modulation of mRNA expression. Bio-functional analysis indicated that the altered genes were involved in specific cellular processes, including cell death and proliferation. Target gene analysis suggested that junction injury in Sertoli cells exposed to MC-LR might be mediated by miRNAs through the regulation of the Sertoli cell-Sertoli cell pathway. Collectively, these findings may enhance our understanding on the modes of action of MC-LR on mouse Sertoli cells as well as the molecular mechanisms underlying the toxicity of MC-LR on the male reproductive system.

[Value of single photon emission computed tomography/computerized tomography in the diagnosis of hyperparathyroidism and the comparative study with multiple imaging modality].

OBJECTIVE: To compare the diagnostic value among the single photon emission computed tomography/computerized tomography (SPECT/CT), (99m)Tc-sestamibi (MIBI) planar scintigraphy, ultrasonography (US) and computerized tomography (CT) in diagnosis of patients with hyperparathyroidism (HPT).
 METHODS: A total of 59 patients were retrospectively recruited for this study. The patients received parathyroidectomy and were verified by pathological examination. Among them, 31, 28 and 26 patients received SPECT/CT, (99m)Tc-MIBI planar scintigraphy, US and CT, respectively, before the parathyroidectomy. The sensitivity for localization or qualitation was compared between SPECT/CT and (99m)Tc-MIBI planar scintigraphy; the sensitivity, specificity and accuracy were compared among the SPECT/CT, (99m)Tc-MIBI planar scintigraphy, US and CT.
 RESULTS: There was no statistical difference in the sensitivity of localization between SPECT/CT and (99m)Tc-MIBI planar scintigraphy (P>0.05); however, the SPECT/CT exhibited more sensitive than the (99m)Tc-MIBI planar scintigraphy in detection of hyperplastic lesions (P<0.05). Among the four imaging modalities, SPECT/CT had advantages over (99m)Tc-MIBI planar scintigraphy in terms of accuracy (P<0.05). In contrast, the sensitivity of CT was not as good as that of SPECT/CT and US (both P<0.05). For the diagnosis of lesions with a diameter more than 1 cm, the sensitivity of SPECT/CT was the best (all P<0.05). However, the sensitivity of US was the best in diagnosis of lesions with a diameter less than 1 cm (all P<0.05).
 CONCLUSION: The SPECT/CT is more effective than (99m)Tc-MIBI planar scintigraphy in diagnosis of HPT, especially in diagnosis of hyperplastic lesions. Both of SPECT/CT and US are recommended to localize the target parathyroid lesions of HPT before the parathyroidectomy.

A PET probe targeting polyamine transport system for precise tumor diagnosis and therapy.

Polyamine metabolism dysregulation is a hallmark of many cancers, offering a promising avenue for early tumor theranostics. This study presents the development of a nuclear probe derived from spermidine (SPM) for dual-purpose tumor PET imaging and internal radiation therapy. The probe, radiolabeled with either [68Ga]Ga for diagnostic applications or [177Lu]Lu for therapeutic use, was synthesized with exceptional purity, stability, and specific activity. Extensive testing involving 12 different tumor cell lines revealed remarkable specificity towards B16 melanoma cells, showcasing outstanding tumor localization and target-to-non-target ratio. Mechanistic investigations employing polyamines, non-labeled precursor, and polyamine transport system (PTS) inhibitor, consistently affirmed the probe's targetability through recognition of the PTS. Notably, while previous reports indicated PTS upregulation in various tumor types for targeted therapy, this study observed no positive signals, highlighting a concentration-dependent discrepancy between targeting for therapy and diagnosis. Furthermore, when labeled with [177Lu], the probe demonstrated its therapeutic potential by effectively controlling tumor growth and extending mouse survival. Investigations into biodistribution, excretion, and biosafety in healthy humans laid a robust foundation for clinical translation. This study introduces a versatile SPM-based nuclear probe with applications in precise tumor theranostics, offering promising prospects for clinical implementation.

[Influence of several excipients on damp-proof performance of pharmaceutical materials of traditional Chinese medicine].

OBJECTIVE: To study the influence of several excipients on damp-proof performance of pharmaceutical materials of traditional Chinese medicine. METHOD: The moisture absorption rate and parameters of hydroscopicity were used as the evaluation index of the damp-proof property of the complex Chinese medicine and preparation 1 and 2. RESULT: The moisture rate of complex Chinese medicine 1 was 62.54%, the critical relative humidity (CRH) was 38%. The moisture rate of complex Chinese medicine 2 was 16.36%, the CRH was 53%. Excipients had different effect on lower the hyproscopic property of complex Chinese medicine 1 and 2. The initial moisture adsorption velocity of excipients of complex Chinese medicine 1 in a ascending order were dextrin < calcium hydrogen phosphate < micro crystalline cellulose < lactose < ethyl cellulose < mannitol < hydroxypropyl methyl cellulose. The moisture adsorption acceleration of excipients in a ascending order were dextrin = calcium hydrogen phosphate = micro crystalline cellulose < mannitol = ethyl cellulose = lactose < hydroxypropyl methyl cellulose. The moisture adsorption rate of excipients in a ascending order were dextrin < lactose < calcium hydrogen phosphate < ethyl cellulose < micro crystalline cellulose < mannitol < hydroxypropyl methyl cellulose. The initial moisture adsorption velocity of excipients of complex Chinese medicine 2 in a ascending order were mannitol < dextrin < calcium hydrogen phosphate < lactose < ethyl cellulose < micro crystalline cellulose < hydroxypropyl methyl cellulose . The moisture adsorption acceleration of excipients in a ascending order were mannitol = dextrin = calcium hydrogen phosphate < lactose < ethyl celluloselactose < micro crystalline cellulose < hydroxypropyl methyl cellulose. The moisture adsorption rate of excipients in a ascending order were mannitol < dextrin < calcium hydrogen phosphate < lactose < ethyl cellulose < micro crystalline cellulose < hydroxypropyl methyl cellulose. CONCLUSION: The choosing of damp-proof excipients of preparation based on the property of the complex traditional Chinese medicine. The study provided experimental evidences for the research and development of the pharmaceutical materials of traditional Chinese medicine.