Effects of hypromellose acetate succinate on recrystallization inhibition, miscibility, and dissolution enhancement of baloxavir marboxil solid dispersions.

Solid dispersions (SDs) have emerged as a promising strategy to enhance the solubility and bioavailability of poorly soluble active pharmaceutical ingredients. However, SDs tend to recrystallize unless suitable excipients are utilized. This study aimed to facilitate the rational selection of polymers and formulation design by evaluating the impact of various polymers on the miscibility, and phase behavior of SDs using baloxavir marboxil (BXM) with a high crystallization tendency as a model drug. Meanwhile, the effects of these polymers on the solubility enhancement and recrystallization inhibition were also assessed. The results indicated that the miscibility limit of BXM for HPMCAS was around 40 % drug loading (DL), whereas for PVP, PVPVA, and HPMC approximately 20 % DL. The BXM-HPC system exhibited limited miscibility with DL of 10 % or higher. BXM SDs based on various polymers exhibited varying degrees of spontaneous phase separation once DL exceeded the miscibility limit. Interestingly, a correlation was discovered between the phase separation behavior and the ability of the polymer to inhibit recrystallization. BXM-HPMCAS SDs exhibited optimal dissolution performance, compared with other systems. In conclusion, the physicochemical properties of polymers significantly influence BXM SDs performance and the BXM-HPMCAS SDs might promote an efficient and stable drug delivery system.

Crocin enhances the sensitivity to paclitaxel in human breast cancer cells by reducing BIRC5 expression.

Paclitaxel (PTX) is one of the first-line chemotherapeutic agents for treating breast cancer. However, PTX resistance remains a major hurdle in breast cancer therapy. Crocin, the main chemical constituent of saffron, shows anti-cancer activity against various types of cancer. However, the effect of crocin on the resistance of PTX in breast cancer is still unknown. CCK-8 and TUNEL assays were employed to detect cell viability and apoptosis, respectively. The targets of crocin were predicted using HERB database and the targets associated with breast cancer were acquired using GEPIA database. The Venn diagram was utilized to identify the common targets between crocin and breast cancer. Baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) expression was detected by qRT-PCR and western blot analysis. The correlation between BIRC5 expression and survival was analyzed by Kaplan-Meier plotter and PrognoScan databases. Our data suggested that crocin aggravated PTX-induced decrease of viability and increase of apoptosis in MCF-7 and MCF-7/PTX cells. BIRC5 was identified as the target of crocin against breast cancer. Crocin inhibited BIRC5 expression in MCF-7 and MCF-7/PTX cells. BIRC5 is overexpressed in breast cancer tissues, as well as PTX-sensitive and PTX-resistant breast cancer cells. BIRC5 expression is related to the poor survival of patients with breast cancer. Depletion of BIRC5 strengthened PTX-induced viability reduction and promotion of apoptosis in MCF-7 and MCF-7/PTX cells. Moreover, BIRC5 overexpression reversed the inhibitory effect of crocin on PTX resistance in breast cancer cells. In conclusion, crocin enhanced the sensitivity of PTX in breast cancer cells partially through inhibiting BIRC5 expression.

Prediction of drug-drug interactions between roflumilast and CYP3A4/1A2 perpetrators using a physiologically-based pharmacokinetic (PBPK) approach.

This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict changes in the pharmacokinetics (PK) and pharmacodynamics (PD, PDE4 inhibition) of roflumilast (ROF) and ROF N-oxide when co-administered with eight CYP3A4/1A2 perpetrators. The population PBPK model of ROF and ROF N-oxide has been successfully developed and validated based on the four clinical PK studies and five clinical drug-drug interactions (DDIs) studies. In PK simulations, every ratio of prediction to observation for PK parameters fell within the range 0.7 to 1.5. In DDI simulations, except for tow peak concentration ratios (Cmax) of ROF with rifampicin (prediction: 0.63 vs. observation: 0.19) and with cimetidine (prediction: 1.07 vs. observation: 1.85), the remaining predicted ratios closely matched the observed ratios. Additionally, the PBPK model suggested that co-administration with the three perpetrators (cimetidine, enoxacin, and fluconazole) may use with caution, with CYP3A4 strong inhibitor (ketoconazole and itraconazole) or with dual CYP3A41A2 inhibitor (fluvoxamine) may reduce to half-dosage or use with caution, while co-administration with CYP3A4 strong or moderate inducer (rifampicin, efavirenz) should avoid. Overall, the present PBPK model can provide recommendations for adjusting dosing regimens in the presence of DDIs.

Prediction of trough concentration and ALK occupancy in plasma and cerebrospinal fluid using physiologically based pharmacokinetic modeling of crizotinib, alectinib, and lorlatinib.

Backgrounds: Brain metastases occur in approximately 30% of patients with non-small-cell lung cancer (NSCLC). Therefore, the free drug concentration in cerebrospinal fluid (CSF) is strongly associated with the clinical efficacy. Purpose: The present study aimed to develop physiologically based pharmacokinetic (PBPK) models that can predict the steady-state trough concentration (Ctrough) in plasma and CSF, as well as anaplastic lymphoma kinase (ALK) occupancy (AO), for three inhibitors: crizotinib (CRI), alectinib (ALE), and lorlatinib (LOR). Methods: To achieve this, population PBPK models were successfully developed and validated using multiple clinical pharmacokinetics (PK) and drug-drug interaction (DDI) studies, both in healthy subjects and patients. Results: The prediction-to-observation ratios for plasma AUC, Cmax, and Ctrough in heathy subjects and patients ranged between 0.5 and 2.0. In addition, PK profiles of CRI, ALE, and LOR in CSF aligned well with observed data. Moreover, the AUC and Cmax ratios of the three inhibitors when co-administered with CYP3A4 inhibitors/inducers also matched with clinically observed values. Utilizing PK thresholds for effective plasma Ctrough and AO values on wild-type and four ALK mutations in plasma and CSF, PBPK models were then combined with the mean and 95% confidence interval to predict optimal dosing regimens. Conclusions: Overall, these PBPK models provide valuable insights into determining appropriate dosing regimens for the three ALK inhibitors, understanding their effectiveness in brain metastasis therapy, and analyzing the underlying mechanisms of on-target resistance.

Peripheral blood inflammatory indexes in breast cancer: A review.

Immune and inflammatory responses play an important role in tumorigenesis and metastasis. Inflammation is an important component of the tumor microenvironment, and the changes in inflammatory cells may affect the occurrence and development of tumors. Complete blood count at the time of diagnosis and treatment can reflect the inflammatory status within the tumor. Studies have shown that the number of certain inflammatory cells in peripheral blood and their ratios are important prognostic factors for many malignancies, including neutrophil, lymphocyte, monocyte, and platelet counts, as well as neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, systemic inflammation response index and pan-immune-inflammation-value. The value of peripheral blood inflammation indexes in predicting the efficacy and prognosis of breast cancer neoadjuvant therapy is worth recognizing. This review details the application of peripheral blood inflammation indexes in the evaluation of efficacy and prediction of prognosis in neoadjuvant therapy for breast cancer, aiming to provide a more comprehensive reference for the comprehensive diagnosis and treatment of breast cancer.

Clinical importance and PI3K/Akt pathway-dependent anti-proliferative role of PALMD and DPT in breast cancer.

This study aimed to identify novel differentially expressed genes in breast cancer and to explore the clinical value and the anti-tumor or oncogenic effects of the identified genes using bioinformatics analysis and in vitro experiments. The differentially expressed genes in breast cancer patients were identified using Gene Expression Omnibus (GEO) database with the cut-off criteria p < 0.05 and |logFC| > 1. The expression levels of palmdelphin (PALMD) and dermatopontin (DPT) in normal tissues and breast cancer tissues were evaluated based on GEPIA and UALCAN databases. PALMD and DPT expression levels in clinical subgroups of patients with breast cancer were analyzed to assess the association of PALMD and DPT expression with clinical characteristics. The prognostic and diagnostic values of PALMD and DPT in breast cancer were evaluated from Kaplan-Meier (K-M) survival curves and receiver operating characteristic (ROC) curves. Pearson's correlation coefficient was performed using LinkedOmics. KEGG pathway enrichment analysis was performed using DAVID. The protein levels were evaluated using western blot analysis. Cell proliferation was assessed using MTT and EdU assays. Two important genes, PALMD and DPT, were identified in breast cancer. The expression levels of PALMD and DPT were significantly lower in breast cancer tissues. The expression levels of PALMD were closely related to age, histological type, and T stage of breast cancer patients. The expression levels of DPT were closely related to age, histological type, T stage, N stage, estrogen receptor status, and progesterone receptor status of breast cancer patients. The K-M survival curves showed that PALMD or DPT was not an independent prognostic factor for breast cancer. The ROC curves showed that both PALMD and DPT had good diagnostic potential for breast cancer. KEGG pathway enrichment results showed that PI3K/Akt pathway was an important overlapping signaling for PALMD and DPT. Further studies proved that overexpression of PALMD and DPT inhibited proliferation in MCF-7 and MDA-MB-231 cells by suppressing the PI3K/Akt pathway. PALMD and DPT knockdown promoted proliferation in MCF-7 and MDA-MB-231 cells by activating the PI3K/Akt pathway. These results collectively suggested that PALMD and DPT might serve as potential diagnostic biomarkers and therapeutic targets for breast cancer.

Network pharmacology-based prediction and experimental verification of the involvement of the PI3K/Akt pathway in the anti-thyroid cancer activity of crocin.

Crocin, a unique water-soluble carotenoid extracted from saffron, is known to exert anticancer activity against various cancer types, including thyroid cancer (TC). However, the detailed mechanism underlying the anticancer effect of crocin in TC needs further exploration. Targets of crocin and targets associated with TC were acquired from public databases. Gene Ontology (GO) and KEGG pathway enrichment analyses were performed using DAVID. Cell viability and proliferation were assessed using MMT and EdU incorporation assays, respectively. Apoptosis was assessed using TUNEL and caspase-3 activity assays. The effect of crocin on phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) was explored by western blot analysis. A total of 20 overlapping targets were identified as candidate targets of crocin against TC. GO analysis showed that these overlapping genes were significantly enriched in the positive regulation of cell proliferation. KEGG results showed that the PI3K/Akt pathway was involved in the effect of crocin against TC. Crocin treatment inhibited cell proliferation and promoted apoptosis in TC cells. Moreover, we found that crocin inhibited the PI3K/Akt pathway in TC cells. 740Y-P treatment reversed the effects of crocin on TC cells. In conclusion, crocin suppressed proliferation and elicited apoptosis in TC cells via inactivation of the PI3K/Akt pathway.

Crocin suppresses breast cancer cell proliferation by down-regulating tumor promoter miR-122-5p and up-regulating tumor suppressors FOXP2 and SPRY2.

Crocin has been reported to have antitumor activity in several tumors including breast cancer. Nevertheless, the mechanism of action of crocin on breast cancer remains unclear. The cytotoxicity of crocin was evaluated by CCK-8 assay. Cell proliferation was assessed using EdU incorporation assay and western blot analysis. Breast cancer-related genes were extracted from GEPIA. miR-122-5p targets were predicted using Targetscan, starbase, and miRDB softwares. Luciferase reporter assay was employed to confirm whether miR-122-5p targeted sprouty2 (SPRY2) and forkhead box P2 (FOXP2). Results showed that crocin exhibited cytotoxicity and suppressed the proliferation in breast cancer cells. miR-122-5p was upregulated in breast cancer tissues and cells. Crocin suppressed miR-122-5p to block the proliferation of breast cancer cells. Seven targets of miR-122-5p were identified in breast cancer. SPRY2 and FOXP2 were selected for further experiments due to their involvement in breast cancer. miR-122-5p targeted SPRY2 and FOXP2 to inhibit their expression. miR-122-5p knockdown restrained breast cancer cell proliferation by targeting SPRY2 and FOXP2. Additionally, crocin increased SPRY2 and FOXP2 expression by inhibiting miR-122-5p expression. Together, our results suggested that crocin inhibited proliferation of breast cancer cells through decreasing miR-122-5p expression and the subsequent increase of SPRY2 and FOXP2 expression.

In vitro Anti-malignant Property of PCMT1 Silencing and Identification of the SNHG16/miR-195/PCMT1 Regulatory Axis in Breast Cancer Cells.

BACKGROUND: Protein L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) is a highly conserved protein repair enzyme that participates in regulating the progression of human cancers. We therefore studied the function and the related mechanisms of PCMT1 in breast cancer cells. METHODS: Expression profile and prognostic analysis of PCMT1 in breast cancer patients were analyzed using online databases. PCMT1 expression in breast cancer cells was detected by western blot analysis. Cell proliferation was determined by CCK-8 and colony formation assays. Apoptosis was evaluated using flow cytometry analysis and caspase-3/7 activity assay. Cell invasion was assessed by Transwell invasion assay. The small nucleolar RNA host gene 16 (SNHG16)/miR-195/PCMT1 regulatory axis was identified using bioinformatics analysis. RESULTS: PCMT1 expression was increased in breast cancer tissues and cells. High PCMT1 expression was correlated with poor prognosis in breast cancer patients. PCMT1 knockdown suppressed cell proliferation and colony formation ability in breast cancer cells. Moreover, PCMT1 knockdown induced apoptosis and restrained the invasive ability in breast cancer cells. PCMT1 overexpression increased the proliferative and invasive abilities of breast cancer cells. miR-195 was identified as the unique upstream miRNA of PCMT1. SNHG16 was identified as the unique upstream lncRNA of miR-195. SNHG16 knockdown downregulated PCMT1 by increasing miR-195 expression. Breast cancer cell proliferation was regulated by the SNHG16/miR-195/PCMT1 axis. CONCLUSION: PCMT1 silencing inhibited cell proliferation and invasion and induced apoptosis in breast cancer cells and the SNHG16/miR-195/PCMT1 regulatory axis might serve as a potential therapeutic target for breast cancer.

Prediction of Cervical Lymph Nodes Metastasis in Papillary Thyroid Carcinoma (PTC) Using Nodal Staging Score (NSS).

Background: Cervical lymph node metastasis is commonly seen in papillary thyroid carcinoma. Surgery is the preferred treatment for PTC with cervical lymph node metastasis. There is no alternate ultrasound, neck CT, and thyroglobulin (Tg) methods to assess the occult lymph node metastasis. For moderate-and high-risk PTC, the number of lymph nodes to be dissected should be increased to remove the occult lymph node metastasis. Objective: This study was designed to develop a nodal staging score model to predict the likelihood of lymph node metastasis in papillary thyroid carcinoma (PTC), and further guide the treatments. Material and Methods. Data were collected from the SEER database. Patients with PTC from 2000 to 2005 were selected. The beta-binomial model was adopted to establish a nodal staging score (NSS)-based model. The NSS-based model was built according to gender, age, extrathyroidal invasion, tumor multifocality, tumor size, and T stage of the patients. A total of 12,431 PTC patients were included in our study. Various types of lymph nodes were examined based on various categories (incidence, risk assessment) to evaluate the results. Results: 5,959 (47.9%) patients in the study were positive and 6,472 (52.1%) were confirmed negative for lymph node metastasis. The corrected incidence of lymph node metastasis was higher than that of direct calculation, regardless of the factors that affected lymph node metastasis. There were significant differences in the OS of PTC patients among the four groups and T stage (p is less than 0.05), indicating that cervical lymph node metastasis would have an impact on the prognosis of patients. Conclusion: In conclusion, an NSS-based model base on a variety of clinicopathological factors can be used to predict lymph node metastasis. It is important to evaluate the risk of occult lymph node metastasis in the treatment of PTC.. Since, this statistical model can describe the risk of occult lymph node metastasis in patients; therefore, it can be used as basis for decision-making related to the number of lymph nodes that can be dissected in operations.

Clinical importance of PLA2R1 and RASSF9 in thyroid cancer and their inhibitory roles on the Wnt/ß-catenin pathway and thyroid cancer cell malignant behaviors.

Thyroid cancer is a common malignant tumor with rising incidence worldwide. The purpose of this study was to explore key genes in thyroid cancer. The differentially expressed genes were analyzed according to GEO datasets. PLA2R1 and RASSF9 levels were confirmed by UALCAN and the Human Protein Atlas databases. The disease free survival and linear correlation were analyzed by GEPIA. ROC curve was generated according to The Cancer Genome Atlas (TCGA) database. The methylation level and immune infiltration were analyzed using GSCA platform. PLA2R1, RASSF9 and Wnt/ß-catenin-related protein levels were detected by western blotting. Cell proliferation was assessed by 5-ethynyl-2'-deoxyuridine assay. Cell invasion and migration were evaluated by Transwell assay. There were 2 common differentially expressed genes (PLA2R1 and RASSF9) in thyroid cancer from GSE104005, GSE65144 and GSE53157 datasets. Decreased PLA2R1 and RASSF9 were associated with advanced stages and lower disease free survival. PLA2R1 and RASSF9 methylation levels were enhanced in thyroid cancer samples compared with normal samples. PLA2R1 methylation level was negatively correlated to its mRNA level. PLA2R1 and RASSF9 were related to immune infiltration in thyroid cancer. PLA2R1 and RASSF9 expression was associated with radioiodine resistance, and positively correlated to expression of iodide uptake-related factors. Multiple signaling pathways were involved in the action mechanisms of PLA2R1 and RASSF9, including the Wnt/ß-catenin signaling. Overexpression of PLA2R1 and RASSF9 inhibited the activation of the Wnt/ß-catenin pathway, proliferation, invasion, and migration in thyroid cancer cells. Collectively, PLA2R1 and RASSF9 are two key genes in thyroid cancer, which have potential diagnostic, prognostic, and anti-tumor effects in thyroid cancer.

Crocin attenuates NF-κB-mediated inflammation and proliferation in breast cancer cells by down-regulating PRKCQ.

Breast cancer (BC) is the most commonly diagnosed cancer confronting women worldwide. Crocin, a glycosylated carotenoid extracted from Crocus sativus L., possesses anti-cancer and anti-inflammatory activities. This study tried to explore the influences of crocin on proliferation and inflammation of BC cells, and to investigate the possible mechanism. The protein levels of protein kinase C theta (PRKCQ) and nuclear factor kappa B (NF-κB) p-p65 and p65 were examined using western blot analysis. The potential targets of crocin were predicted using the PharmMapper database. Cell viability and proliferation were determined utilizing CCK-8 and EdU incorporation assays, respectively. Inflammation was assessed by detecting the levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) using RT-qPCR and ELISA. Results showed that crocin inhibited NF-κB activation and suppressed cell viability and proliferation in BC cells. Crocin caused a significant reduction of levels of TNF-α and IL-1ß, suggesting that crocin suppressed inflammation in BC cells. NF-κB inhibition decreased proliferation and inflammation in BC cells. Additionally, PRKCQ was identified as a potential target of crocin according to PharmMapper database. Crocin treatment inhibited the activation of NF-κB in BC cells by reducing PRKCQ expression. Mechanistically, PRKCQ-dependent activation of NF-κB pathway reversed the effects of crocin on the proliferation and inflammation in BC cells. In conclusion, crocin inhibited NF-κB-mediated inflammation and proliferation in BC cells through reducing PRKCQ expression.

Crocin induces ROS-mediated papillary thyroid cancer cell apoptosis by modulating the miR-34a-5p/PTPN4 axis in vitro.

miR-34a-5p has been reported to be upregulated and function as an oncogene in papillary thyroid cancer (PTC). Crocin, the major chemical constituent of saffron, has been demonstrated to possess anti-tumorigenic activity and decrease miR-34a-5p expression. Thus we hypothesized that crocin exerted anti-PCT effect by downregulating miR-34a-5p. Herein, the hypothetical mechanism underlying the anti-PCT effect of crocin was explored. Cell viability and apoptosis were assessed by CCK-8 and TUNEL assays, respectively. Reactive oxygen species (ROS) level, caspase-3 activity, and LDH release were measured using corresponding commercially available assay kits. Expression of miR-34a-5p and protein tyrosine phosphatase nonreceptor type 4 (PTPN4) was analyzed using qRT-PCR and western blot analyses. Interaction between miR-34a-5p and targets were predicted by Targetscan, starbase, miRDB, microT-CDS, and miRWalk and validated using luciferase reporter assay. Results showed that crocin inhibited the viability and miR-34a-5p expression in papillary thyroid cancer (PTC) cells in a dose-dependent manner. The Venn diagram showed that 10 overlapped targets of miR-34a-5p were identified, among which PTPN4 was the most significantly downregulated target gene in thyroid cancer tissues based on the heat map and bar plot from GSE33630 analysis. Luciferase reporter assay validated the direct interaction between miR-34a-5p and PTPN4. Crocin upregulated PTPN4 by decreasing miR-34a-5p expression in PTC cells. Crocin promoted apoptosis and increased caspase-3 activity and LDH release, which were reversed by ROS scavenger N-acetyl-L-cysteine (NAC), miR-34a overexpression, and PTPN4 silencing. To conclude, crocin promoted ROS-mediated apoptosis of PTC cells by modulating the miR-34a-5p/PTPN4 axis.

The effects of hsa_circ_0000517/miR-326 axis on the progression of breast cancer cells and the prediction of miR-326 downstream targets in breast cancer.

It has been proposed that circular RNAs (circRNAs) play crucial roles in the initiation and progression of various cancers including breast cancer. Our study aimed to determine the function and regulatory mechanism of hsa_circ_0000517 in breast cancer. qRT-PCR was applied to determine hsa_circ_0000517 expression in breast cancer cells. The circular structure of hsa_circ_0000517 was confirmed using RNase R digestion assay. The subcellular distribution of hsa_circ_0000517 was analyzed using nuclear mass separation assay. Effects of hsa_circ_0000517 on the malignant behaviors of breast cancer cells were determined using CCK-8, colony formation assay, flow cytometry analysis, caspase-3 activity assay, and Transwell invasion assay. Bioinformatics analysis, luciferase reporter assay, and RIP were used to predict and confirm the interaction between hsa_circ_0000517 and miR-326. Bioinformatics analysis was used to search the possible targets of miR-326. Hsa_circ_0000517 was upregulated in breast cancer tissues and cells. Hsa_circ_0000517 was a stable circularized transcript that was preferentially distributed in the cytoplasm. Hsa_circ_0000517 knockdown inhibited cell proliferation, colony formation ability, and invasion and triggered apoptosis in breast cancer cells. Hsa_circ_0000517 acted as a sponge of miR-326 to suppress its expression. miR-326 inhibition abolished the effects of hsa_circ_0000517 knockdown on the malignant behaviors of breast cancer cells. Totally 17 genes were identified as the potential targets of miR-326 in breast cancer. In conclusion, hsa_circ_0000517 silencing repressed breast cancer progression by upregulating miR-326 expression.

Emerging roles of circUBAP2 targeting miR-370-3p in proliferation, apoptosis, and invasion of papillary thyroid cancer cells.

Circular RNAs (circRNAs) have been documented to be aberrantly expressed in many types of malignancies and involved in cancer progression. However, their role in thyroid cancer (TC) remains largely unknown. Our study aimed to explore the role and mechanism of circUBAP2 in TC. The differentially expressed circRNAs in TC tissues were identified using GSE18105 from gene expression omnibus (GEO) database. CircUBAP2 and miR-370-3p expression was analyzed using qRT-PCR. The stability of circUBAP2 was confirmed by actinomycin D and RNase R. The subcellular localization of circUBAP2 was detected using cell fractionation assay. Cell proliferation, apoptosis, and invasion were evaluated using MTT, flow cytometry analysis, and Transwell invasion assay, respectively. The interaction between circUBAP2 and miR-370-3p was predicted using bioinformatics analysis and validated by luciferase reporter assay, RNA pull-down assay, and RNA immunoprecipitation. CircUBAP2 was upregulated and miR-370-3p was downregulated in TC tissues and cells. CircUBAP2 was highly stable, resistant to RNase R digestion, and predominantly localized in the cytoplasm. CircUBAP2 knockdown inhibited cell proliferation and invasion and triggered apoptosis in TC cells. Bioinformatics analysis showed that circUBAP2 contained putative binding sites of miR-370-3p. CircUBAP2 acted as a sponge to inhibit miR-370-3p expression. Mechanistically, miR-370-3p inhibition abolished the effects of circUBAP2 on proliferation, apoptosis, and invasion in TC cells. Taken together, CircUBAP2 knockdown impeded the proliferation and invasion and induced apoptosis in TC cells via sponging miR-370-3p.

circZFR regulates thyroid cancer progression by the miR-16/MAPK1 axis.

Previous studies have identified the dysregulation of various circRNAs in many types of human cancers including thyroid cancer (TC). Circular RNA ZFR (circZFR) serves as an oncogenic circRNA in TC. However, the detailed molecular mechanism of circZFR in TC progression remains to be further explored. CircZFR and miR-16 expressions in TC cells were analyzed through qRT-PCR. Cell viability, invasion, and apoptosis were detected using CCK-8, transwell invasion assay, and flow cytometry analysis, respectively. The relationship between circZFR and miR-16 was explored using luciferase reporter assay, RNA pull-down assay, and qRT-PCR. The relationship between miR-16 and mitogen-activated protein kinase 1 (MAPK1) was explored using luciferase reporter assay and western blot analysis. Results showed that circZFR was upregulated and miR-16 was downregulated in TC cells. CircZFR knockdown inhibited the viability and invasion and induced apoptosis in TC cells. CircZFR inhibited miR-16 expression by sponging miR-16 and miR-16 repressed MAPK1 expression by targeting MAPK1. Moreover, circZFR positively regulated MAPK1 expression in TC cells by serving as a ceRNA of miR-16. Mechanistically, circZFR knockdown-induced inhibition of cell viability and invasion and promotion of apoptosis were overturned after miR-16 downregulation and promotion of MAPK1. Collectively, circZFR knockdown retarded TC progression by sponging miR-16 and modulating MAPK1 expression.

Pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor in children with acute leukaemia.

AIMS: This open-label, phase I study evaluated the pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for the treatment of chemotherapy-induced neutropenia in children with acute leukaemia. METHODS: PEG-rhG-CSF was administered as a single 100 mcg/kg (3 mg maximum dose) subcutaneous injection at the end of each chemotherapy period when neutropenia occurred. Blood samples were obtained from patients treated with PEG-rhG-CSF. PEG-rhG-CSF serum concentrations were determined by an enzyme-linked immunosorbent assay. Population pharmacokinetic (PPK) analysis was implemented using the nonlinear mixed-effects model. Short-term safety was evaluated through adverse events collection (registered at clinicaltrials.gov identifier: 03844360). RESULTS: A total of 16 acute leukaemia patients (1.8-13.6 years) were included, of whom two (12.5%) had grade 3 neutropenia, six (37.5%) had grade 4 neutropenia, and eight (50.0%) had severe neutropenia. For PPK modelling, 64 PEG-rhG-CSF serum concentrations were obtainable. A one-compartment model with first-order elimination was used for pharmacokinetic data modelling. The current weight was a significant covariate. The median (range) of clearance (CL) and area under the serum concentration-time curve (AUC) were 5.65 (1.49-14.45) mL/h/kg and 16514.75 (6632.45-54423.30) ng·h/mL, respectively. Bone pain, pyrexia, anaphylaxis and nephrotoxicity were not observed. One patient died 13 days after administration, and the objective assessment of causality was that an association with PEG-rhG-CSF was "possible". CONCLUSIONS: The AUC of PEG-rhG-CSF (100 mcg/kg, 3 mg maximum dose) in paediatric patients with acute leukaemia were similar to those of PEG-rhG-CSF (100 mcg/kg) in children with sarcoma. PEG-rhG-CSF is safe, representing an important therapeutic option for chemotherapy-induced neutropenia in paediatric patients with acute leukaemia.

Baseline kidney function is associated with vancomycin-induced acute kidney injury in children: a prospective nested case-control study.

BACKGROUND: Children with kidney insufficiency are susceptible to vancomycin-induced acute kidney injury (VIAKI), but there is a lack of compelling clinical data. We conducted a nested case-control study to evaluate the relationship between kidney insufficiency and incidence of VIAKI in children. METHODS: Patients were considered to have VIAKI if they met the criteria for eGFR change according to pRIFLE-I or p-RIFLE-F. Case group comprised patients who developed VIAKI. Case-control ratio was 1:3; patients were matched for age, severity, and nature of illness and initial vancomycin dose. Primary endpoint was incidence of VIAKI at three levels of kidney function, calculated using Kaplan-Meier curve and log-rank test. Secondary endpoint was treatment-related in-hospital mortality amongst case and control groups. RESULTS: Amongst 386 children who fit study criteria, 31 developed VIAKI (8.03%). Thirty-one cases and 93 controls were selected from the observed cohort. Three risk factors were identified for VIAKI: moderate kidney insufficiency (OR 8.8, 2.4-32.8), vancomycin trough concentration ≥ 15 µg/mL (OR 7.7, 1.7-34.4), and furosemide use (OR 24.8, 6.4-98.2). A significant difference in time to VIAKI was noted between patients with moderate kidney insufficiency and patients with mild kidney insufficiency or normal kidney function (p < 0.001). In-hospital mortality rate in case group was 45.2%, compared to 18.3% in control group (p < 0.01). CONCLUSIONS: Children with moderate kidney insufficiency are more likely to develop VIAKI than those with normal and mild kidney insufficiency. Patients who develop VIAKI have higher in-hospital mortality than those who do not develop VIAKI.

Novel zwitterionic-polymer-coated silica nanoparticles.

In this work, silica nanoparticles covered with an initiator silane were grafted with novel biocompatible and functionalizable zwitterionic poly[[3-(acryloylamino)propyl](2-carboxyethyl)dimethylammonium] (polyCBAA) via atomic transfer radical polymerization. The stability of these particles in protein solutions and their functionalization were investigated. Dynamic light scattering and transmission electron microscopy were employed to characterize these particles. Results indicate that the polyCBAA-modified nanoparticles are stable for at least 72 h in both negative and positive protein solutions. The size distribution remains the same before and after protein incubation. Moreover, our results show that polyCBAA-modified silica nanoparticles can be easily functionalized. This makes these particles ideal candidates for future applications in targeted drug delivery and diagnostics in complex media.