LncRNA AC020978 facilitates non-small cell lung cancer progression by interacting with malate dehydrogenase 2 and activating the AKT pathway.

Long non-coding RNA AC020978 (lncRNA AC020978) is an oncogenic regulator of non-small cell lung cancer (NSCLC). However, the function of AC020978 in regulating NSCLC metastasis and the potential molecular mechanism remains largely unknown. In this study, we evaluated the expression levels of AC020978 in a series of NSCLC tissues using FISH assays and found that higher AC020978 expression levels were closely associated with metastasis and unfavorable prognosis. Functional studies showed that AC020978 promoted NSCLC migration and invasion both in vitro and in vivo. Further investigation demonstrated that AC020978 interacted with malate dehydrogenase 2 (MDH2) and maintained MDH2 stability. Knockdown of MDH2 weakened the facilitating effect on cell metastasis and 2-hydroxyglutarate (2-HG) metabolism in AC020978-overexpressed NSCLC cells. RNA sequencing, bioinformatic analysis, and western blotting revealed that AC020978 was associated with the AKT signaling pathway. Taken together, our findings revealed that AC020978 might serve as a prognostic biomarker and activate the AKT pathway by stabilizing MDH2, leading to metastasis and progression of NSCLC.

CaCO3 -Encapuslated Microspheres for Enhanced Transhepatic Arterial Embolization Treatment of Hepatocellular Carcinoma.

Transcatheter arterial embolization (TAE) is an extensively applied treatment method for hepatocellular carcinoma (HCC). However, the worsened tumor microenvironment (TME, e.g., reduced pH post-TAE) may result in unsatisfactory therapeutic outcome. Herein, a new kind of embolic agent, calcium carbonate encapsulated alginate microspheres (CaCO3 -ALG MSs) are synthesized. Such CaCO3 -ALG MSs are able to neutralize the tumor pH owing to the reaction of CaCO3 with protons, which would not affect the overall morphology of microspheres after decomposition of CaCO3 . TAE treatment with CaCO3 -ALG MSs is then conducted in an orthotopic rat liver cancer model. 18 F-Fluorodeoxyglucose micropositron emission tomography/computed tomography imaging is conducted post-TAE and discovered that intra-arterial injection of CaCO3 -ALG MSs shows obvious enhanced therapeutic outcome compared to the same treatment with bare ALG MSs or the clinically used lipiodol. Further studies including analysis of immune cells in tumors, cytokine assays, and bioinformatics analysis all verify the reverse of immunosuppressive TME toward a more immunosupportive one after TAE with CaCO3 -ALG MSs. The research not only presents a new CaCO3 -containing embolic agent for enhanced TAE treatment of HCC but also highlights a clinically meaningful approach to improve cancer treatment via tumor pH neutralization.

Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2.

Hypoxia is commonly observed in solid tumors and contributes to the resistance of DNA damage drugs. However, the mechanisms behind this resistance are still unclear. In this study, we aimed to explore the effects of hypoxia-induced exosomes on non-small cell lung cancer (NSCLC). Methods: NSCLC cells were subjected to either normoxic or hypoxic conditions to assess cell survival and changes in the expression levels of key proteins. Comparative proteomics were performed to identify exosomal PKM2 in normoxic or hypoxic cisplatin-resistant NSCLC cells-derived exosomes. Functions of hypoxia induced-exosomal PKM2 in promoting cisplatin resistance to NSCLC cells were evaluated both in vitro and in vivo experiments and the molecular mechanisms of hypoxia induced-exosomal PKM2 were demonstrated using flow cytometry, immunoblotting, oxidative stress detection and histological examination. A series of in vitro experiments were performed to evaluate the function of hypoxia-induced exosomes on cancer-associated fibroblasts (CAFs). Results: Hypoxia exacerbated the cisplatin resistance in lung cancer cells due to the increased expression of PKM2 that was observed in the exosomes secreted by hypoxic cisplatin-resistance cells. We identified that hypoxia-induced exosomal PKM2 transmitted cisplatin-resistance to sensitive NSCLC cells in vitro and in vivo. Mechanistically, hypoxia-induced exosomal PKM2 promoted glycolysis in NSCLC cells to produce reductive metabolites, which may neutralize reactive oxygen species (ROS) induced by cisplatin. Additionally, hypoxia-induced exosomal PKM2 inhibited apoptosis in a PKM2-BCL2-dependent manner. Moreover, hypoxia-induced exosomal PKM2 reprogrammed CAFs to create an acidic microenvironment promoting NSCLC cells proliferation and cisplatin resistance. Conclusions: Our findings revealed that hypoxia-induced exosomes transmit cisplatin resistance to sensitive NSCLC cells by delivering PKM2. Exosomal PKM2 may serve as a promising biomarker and therapeutic target for cisplatin resistance in NSCLC.

EFFECT OF POST-SURGICAL RAI THERAPY ON PARATHYROID FUNCTION IN PATIENTS WITH DIFFERENTIATED THYROID CANCER.

Objective: Radiotherapy with radioactive iodine (RAI) has become a common treatment for postsurgical differentiated thyroid carcinoma (DTC). The objective of this study was to determine the effect of RAI therapy following surgery on the function of the parathyroid glands in DTC patients. Methods: A total of 81 DTC patients who received RAI therapy after surgery were enrolled in the study. The size of the residual thyroid was detected by technetium-99m (99mTc)-pertechnetate thyroid scan (99mTc thyroid scan) before RAI therapy. The iodine uptake ability of residual thyroid was evaluated by iodine-131 (131I) whole-body scan (WBS). All patients were treated with an activity of 3.7 GBq (100 mCi) 131I. Parathyroid hormone (PTH), serum calcium, phosphorus, and magnesium were evaluated at 1 day before treatment, and at 1 month and 3 months after treatment. Results: The results show that there was no statistically significant difference in blood PTH level observed (P>.05) between 3 time points (pre-treatment, 1 month post-treatment and 3 months post-treatment). The serum calcium and phosphorus did not change significantly (P>.05), but serum magnesium level was elevated after treatment (P<.05). There were no significant differences between PTH changes and sex, age, scores of 99mTc thyroid scan, scores of 131I WBS, Tumor (T) stage, and Node (N) stage. Conclusion: RAI therapy following surgery did not significantly affect parathyroid function in DTC patients. Abbreviations: ATA = American Thyroid Association; DTC = differentiated thyroid carcinoma; FT3 = free triiodothyronine; FT4 = free thyroxine; 131I = iodine-131; PTH = parathyroid hormone; RAI = radioiodine; 99mTc = Technetium-99m; TG = thyroglobulin; TNM = Tumor Node Metastasis; TSH = thyroid-stimulating hormone; WBS = whole-body scan.

Synthesis and Evaluation of Ga-68-Labeled Rhein for Early Assessment of Treatment-Induced Tumor Necrosis.

PURPOSE: This study aimed to synthesize a necrosis-avid agent using rhein as a precursor and labeled with gallium-68 (Ga-68) for positron emission tomography/computed tomography (PET/CT) imaging, to evaluate response to anticancer treatment in a mouse model. PROCEDURES: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated rhein was radiolabeled with Ga-68 to formulate [68Ga]DOTA-rhein. The in vitro stability of [68Ga]DOTA-rhein was assessed by radio-HPLC. Necrosis avidity was evaluated in a mouse model of muscle necrosis by microPET/CT imaging, biodistribution study, histochemical staining, and autoradiography studies. Murine tumor models with the subcutaneous implantation of S180 cell lines were generated for the evaluation of therapeutic effect. Tumor necrosis was induced by the treatment of combretastatin A4 disodium phosphate (CA4P), and microPET/CT imaging was performed at 1 h post tracer injection. DNA binding studies were conducted to explore the necrosis avidity mechanism of the tracer. RESULTS: [68Ga]DOTA-rhein exhibited a satisfactory yield, a radiochemical purity over 97 %, and a good serum stability. The uptakes of [68Ga]DOTA-rhein in necrotic muscles and tumors were significantly higher than those in normal muscles and tumors (P < 0.05). The results of autoradiography and histochemical staining were consistent with the selective uptake of the radiotracer in necrotic regions. MicroPET/CT images showed a high uptake of the tracer in necrotic muscles and necrotic tumors. DNA binding studies suggested that necrosis avidity correlated with DNA binding to a certain extent. CONCLUSIONS: Our results demonstrated that [68Ga]DOTA-rhein showed a prominent necrosis avidity and could be a useful probe for early assessment of response to anticancer therapy by PET/CT imaging.

Radioactive Iodine Therapy in Patients with Differentiated Thyroid Cancer: Study of External Dose Rate Attenuation Law and Individualized Patient Management.

BACKGROUND: Therapy with radioactive iodine (131I) is a well established treatment method for postsurgical differentiated thyroid carcinoma (DTC). A fixed discharge time is generally set, regardless of individual differences in residual body radioactivity (RBA). This study aimed to investigate the RBA of each patient to find the attenuation law and to identify underlying factors in order to predict the time point for a safe, scientifically sound discharge plan. METHODS: A total of 231 DTC patients undergoing 131I treatment were all treated with 3.7 GBq (100 mCi) of 131I. RBA was estimated by measuring the external body dose rate (EDR) at a distance of 1 m from the body surface between 0 and 72 hours after oral administration of 131I. Data from each patient were used to establish a time-EDR value (h-µSv/h) curve. Software was developed to predict the time when a patient's dose equivalent meets the national safety standard by including six time points between 40 and 60 hours. Several factors that might affect that time were analyzed. RESULTS: The EDR attenuation law in patients could be described with a double exponential decay model, and the cutoff value was set as 23.3 µSv/h, upon which the predictive software was developed. Student's t-test showed there was no statistical difference between predicted values and the actual measured values (p > 0.05). Correlation analysis found that serum thyroglobulin, total triiodothyronine, total thyroxine, free triiodothyronine, free thyroxine, thyrotropin, 2- and 24-hour iodine uptake rate of the thyroid, scores of 99mTc-pertechnetate thyroid scan, scores of 131I whole-body scan, scores of ultrasound scan, and gastrointestinal residues were associated with attenuation speed. A further multiple linear regression analysis found that 24-hour iodine uptake (X1), residual thyroid grading by 131I whole-body scan (X2), blood free triiodothyronine (X3) and free thyroxine (X4) predominantly influenced the decline of the EDR. The regression equation was Y = 2.091X1 + 6.370X2 + 4.529X3 + 2.466X4 - 8.614 (F = 44.03, p < 0.01). CONCLUSIONS: An effective and convenient method was created to measure and predict the individual safety time for discharge. This could play a significant role not only for scientific hospital discharge planning, rational use of medical resources, and better individualized management, but also in public radiation protection.

Breast-specific gamma camera imaging with 99mTc-MIBI has better diagnostic performance than magnetic resonance imaging in breast cancer patients: A meta-analysis.

OBJECTIVE: This study aimed to evaluate the diagnostic role of breast-specific gamma camera imaging (BSGI) with technetium-99m-methoxy isobutyl isonitrile (99mTc-MIBI) and magnetic resonance imaging (MRI) in patients with breast cancer through a meta-analysis. METHODS: Three reviewers searched articles published in medical journals before June 2016 in MEDLINE, EMBASE and Springer Databases; the references listed in original articles were also retrieved. We used the quality assessment of diagnostic accuracy studies (QUADAS) tool to assess the quality of the included studies. Heterogeneity, pooled sensitivity and specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio (DOR) and summary receiver operating characteristic (SROC) curves were calculated by Meta-DiSc software to estimate the diagnostic performance of BSGI and MRI. Ten studies with 517 patients were included after meeting the inclusion criteria. We did a subgroup analysis of the same data type. RESULTS: The pooled sensitivities of BSGI and MRI were: 0.84 (95% CI, 0.79-0.88) and 0.89 (95% CI, 0.84-0.92) respectively, and the pooled specificities of BSGI and MRI were: 0.82 (95% CI, 0.74-0.88) and 0.39 (95% CI, 0.30-0.49) respectively. The areas under the SROC curve of BSGI and MRI were 0.93 and 0.72 respectively. CONCLUSION: The results of our meta-analysis indicated that compared with MRI, BSGI has similar sensitivity, higher specificity, better diagnostic performance, and can be widely used in clinical practice.