Analysis of delayed initial radioactive iodine therapy and clinical outcomes in papillary thyroid cancer: a two-center retrospective study.

BACKGROUND: It remains unclear whether the time interval between total thyroidectomy and radioactive iodine (RAI) therapy influences clinical outcomes in papillary thyroid carcinoma (PTC). This study aims to evaluate the impact of the timing to initiate RAI therapy on the response in PTC patients. METHODS: We retrospectively included 405 patients who underwent total thyroidectomy and subsequent RAI therapy at two tertiary hospitals in southwest China. Patients were categorized into two groups based on the interval between thyroidectomy and initial RAI therapy, that is, an early group (interval ≤90 days, n  = 317) and a delayed group (interval >90 days, n  = 88). Responses to RAI therapy were classified as excellent, indeterminate, biochemical incomplete, or structural incomplete. Univariate and multivariate analyses were conducted to identify factors associated with a nonexcellent response. RESULTS: Excellent responses were observed in 77.3% of the early group and 83.0% of the delayed group ( P  = 0.252). No significant impact of RAI therapy timing was also observed across all American Thyroid Association risk classification categories. These findings persisted when patients were analyzed separately according to RAI dose (intermediate-dose group: 3.7 GBq [ n  = 332]; high-activity group: ≥5.5 GBq [ n  = 73]), further subdivided by the timing of RAI therapy. Multivariate analysis identified lymph node dissection, RAI dose, and stimulated thyroglobulin as independent risk factors for excellent response ( P  < 0.05). CONCLUSION: The timing of initial RAI therapy following surgery did not significantly affect outcomes in patients with PTC.

Rosmarinic acid against cognitive impairment via RACK1/HIF-1α regulated microglial polarization in sepsis-surviving mice.

Microglial polarization modulation has been considered the potential therapeutic strategy for relieving cognitive impairment in sepsis survivors. Rosmarinic acid (RA), a water-soluble polyphenolic natural compound, processes a strong protective effect on various types of neurological disorders including Parkinson's disease, depression, and anxiety. However, its role and potential molecular mechanisms in sepsis-associated cognitive impairment remain unclear. To investigate the preventive and therapeutic effect of RA on sepsis-associated cognitive impairment and elucidate the potential mechanism of RA on regulating microglial polarization, we established a CLP-induced cognitive impairment model in mice and a lipopolysaccharide-induced microglia polarization cell model in BV-2. RACK1 siRNA was designed to identify the potential molecular mechanism of RACK1 on microglial polarization. The preventive and therapeutic effect of RA on cognitive impairment followed by PET-CT and behavioral tests including open-field test and tail suspension test. RACK1/HIF-1α pathway and microglial morphology in the hippocampus or BV-2 cells were measured. The results showed that RA significantly ameliorated the CLP-induced depressive and anxiety-like behaviors and promoted whole-brain glucose uptake in mice. Moreover, RA markedly improved CLP-induced hippocampal neuron loss and microglial activation by inhibiting microglial M1 polarization. Furthermore, experiments showed RACK1 was involved in the regulation of LPS-induced microglial M1 polarization via HIF-1α, and RA suppressed lipopolysaccharide or sepsis-associated microglial M1 polarization via RACK1/HIF-1α pathway (rescued the decrease of RACK1 and increase of HIF-1α). Taken together, RA could be a potential preventive and therapeutic medication in improving cognitive impairment through RACK1/HIF-1α pathway-regulated microglial polarization.

[Preparation of 131I Labeled Collagen-Chitosan Microspheres and It's Antitumor Effect on Human Liver Cancer].

OBJECTIVE: To prepare iodine-131(131I) labeled biodegradable microspheres with chitosan and collagen for treating liver cancer. METHODS: Collagen-chitosan microspheres (CCMSs) were prepared with type-Ⅰ collagen and chitosan using emulsification-chemical cross-linking method. The size of the CCMSs were determined by electron microscope. 131I-CCMSs were achieved using Chloramine-T. The labelling rate of 131I was recorded. The stability of 131I-CCMSs in vitro were evaluated in PBS or human blood serum through 192 h incubation. The HepG2 model was established in nude mice 28 d after subcutaneous injection of 106 HepG2 cells. The model mice were sacrificed 7 d after injection of 131I-CCMSs,blank microspheres,or PBS (five mice in each group) into the HepG2 tumor xenografts. Samples of various organs were collected to determine the distribution of 131I-CCMSs. The curative effect of 131I-CCMSs on liver cancer was assessed by staining with HE for histological analyses. RESULTS: CCMSs were synthesized with a smooth and spherical shape and an average diameter of (5.1±1.2) µm. A radiolabeling rate of 86.10% was achieved. 131I radio-loading remained stable: 92.00% in saline and 83.00% in human serum after 192 h incubation. 131I was mainly concentrated in the subcutaneous tumor tissues. Potent curative effects of 131I-CCMSs on subcutaneous tumor tissues were demonstrated. CONCLUSION: Biodegradable CCMSs were successfully prepared and radiolabeled. The 131I-CCMSs exhibited potential curative effects on liver cancer,with high stability in vitro and in vivo.

[Basic Research of the Adenovirus-mediated hCTR1 Transfection on the Treatment of Cisplatin Resistant Cervical Cancer].

OBJECTIVE: To induce cisplatin-resistant cervical squamous carcinoma cell line and investigate the drug resistant mechanisms and adenovirus trans-gene therapeutical treatment. METHODS: The cisplatin-resistant subline,designated C-33A/cis,was originated by growing parental C-33A cells with gradually increasing doses of cisplatin. The cytotoxicity of cisplatin was determined by CCK-8 assay,and the CTR1 expression was measured by Western blot. Subcutaneous xenograft cervical tumor model was established by cisplatin-resistant C-33A/cis cell line. Recombinant adenovirus ad-hCTR1 was transfected into tumor by intratumoral injection and combined with cisplatin chemotherapy. The changes in the volume of tumor were observed and the mice were executed at 10th day after the last injection,and the expression of CTR1 in tumor tissues was detected by immunohistochemistry. RESULTS: Cisplatin-resistant cervical carcinoma C-33A/cis cells were successfully induced by gradually increased concentration of cisplatin. The cytotoxic IC50 value of cisplatin on C-33A/cis had been upgraded from (1.86±0.08) to (8.11±0.21) µmol/L,while the CTR1 was found decreased by Western blot assay. Immunohistochemical analysis indicated that CTR1 expression was increased by intratumoral injection of adenovirus ad-hCTR1, and the tumor growth of C-33A/cis drug-resistant cervical carcinoma xenograft was inhibited by ad-hCTR1 transfection combined with cisplatin. CONCLUSION: The combination therapy of ad-hCTR1 transfection and cisplatin was effective to inhibit the growth of drug-resistant C-33A/cis tumor.

[Establishment of Bone Metastasis Model of Prostate Cancer in Mice with Monitoring of 18F-NaF PET-CT].

OBJECTIVES: To establish a mouse model bearing human prostate cancer xenograft with bone metastasis by the monitoring with X-Ray, Micro CT, and ¹8F-NaF PET/CT. METHODS: Sixteen male Balb/c nude mice were allocated into control (6 mice) and experimental group (10 mice). In experimental group, the mice were subjected to percutaneous injection of 2×105PC-3 cells into tibial plateau, bone defects were assessed after 21 d by X-ray, Micro-CT and ¹8F-NaF PET/CT, and bone damages were evaluated by HE staining. In control group, equal volume of saline was injected into the mice. RESULTS: At 21 d post modeling, the significant radioactive ¹8F--NaF signals were found in the tibial intramedullary cavity of all 10 mice in experimental group. The ROI value evaluation showed that SUVmaxin control group was 0.62±0.14, but SUVmaxin tumor group was 2.10±0.13, which indicated abnormal bone metabolism. The serum alkaline phosphate level and HE staining results also confirmed that tumor mediated bone destruction and osteogenesis. However, X-ray and Micro-CT did not indicate precise diagnostic bone defect. CONCLUSION: Bone metastasis model of prostate PC-3 cancer cells were successfully established by intratibial injection. ¹8F-NaF PET/CT could detect tumor invasion and bone osteogenesis in the early stage of modeling.

[Cellular Uptake and Localization of Novel NSCLC Penetrating Peptide with Neuropilin-1 Binding Motif].

OBJECTIVE: To synthesize and study the specific binding affinity of tumor-penetrating peptide YCCS to non-small cell lung carcinoma (NSCLC) cells in vitro. METHODS: YCCS peptide was designed by fusing the neuropilin-1 (NRP-1) binding sequence and NSCLC binding peptide CS. YCCS peptide was synthesized and fluorescent labeled with N-terminal FITC. NRP-1 positive human NSCLC cell A549, NRP-1 positive human breast cancer cell MDA-MB-231, normal human bronchial epithelium HBE135-E6E7 and human liver cell HL-7702 were incubated respectively, then we observed the specific binding affinity of tumor-penetrating peptide YCCS to NSCLC cells. RESULTS: After treated with 5 µmol/L peptide, significant fluorescent signals of FITC-YCCS peptide were demonstrated only in NSCLC A549 cells but marginal captured signal in MDA-MB-231, normal human HBE135-E6E7 or HL-7702 cells, which revealed specific NSCLC cells binding affinity. In 20 µmol/L treated group, non-specific binding were found in MDA-MB-231 and HL-7702 cells. CONCLUSION: The results of this novel designed YCCS peptide indicated a promising strategy for improving tumor penetrating with delivery capability of drugs to NSCLC A549 cells when treated with 5 µmol/L peptide.

Enhancement of cytotoxicity of antimicrobial peptide magainin II in tumor cells by bombesin-targeted delivery.

AIM: To investigate whether the conjugation of magainin II (MG2), an antimicrobial peptides (AMPs), to the tumor-homing peptide bombesin could enhance its cytotoxicity in tumor cells. METHODS: A magainin II-bombesin conjugate (MG2B) was constructed by attaching magainin II (MG2) to bombesin at its N-terminus. The peptides were synthesized using Fmoc-chemistry. The in vitro cytotoxicity of the peptide in cancer cells was quantitatively determined using the CCK-8 cell counting kit. Moreover, the in vivo antitumor effect of the peptide was determined in tumor xenograft models. RESULTS: The IC(50) of MG2B for cancer cells (10-15 µmol/L) was at least 10 times lower than the IC(50) of unconjugated MG2 (125 µmol/L). Moreover, the binding affinity of MG2B for cancer cells was higher than that of unconjugated MG2. In contrast, conjugation to a bombesin analog lacking the receptor-binding domain failed to increase the cytotoxicity of MG2, suggesting that bombesin conjugation enhances the cytotoxicity of MG2 in cancer cells through improved binding. Indeed, MG2B selectively induced cell death in cancer cells in vitro with the IC(50) ranging from 10 to 15 µmol/L, which was about 6-10 times lower than the IC(50) for normal cells. MG2B (20 mg/kg per day, intratumorally injected for 5 d) also exhibited antitumor effects in mice bearing MCF-7 tumor grafts. The mean weights of tumor grafts in MG2B- and PBS-treated mice were 0.21±0.05 g and 0.59±0.12 g, respectively. CONCLUSION: The results suggest that conjugation of AMPs to bombesin might be an alternative approach for targeted cancer therapy.