Thioproline-Based Oxidation Strategy for Direct Preparation of N-Terminal Thiazolidine-Containing Peptide Thioesters from Peptide Hydrazides.

We describe a simple and robust oxidation strategy for preparing N-terminal thiazolidine-containing peptide thioesters from peptide hydrazides. We find for the first time that l-thioproline can be used as a protective agent to prevent the nitrosation of N-terminal thiazolidine during peptide hydrazide oxidation. The thioproline-based oxidation strategy has been successfully applied to the chemical synthesis of CC chemokine ligand-2 (69aa) and omniligase-C (113aa), thereby demonstrating its utility in hydrazide-based native chemical ligation.

Asparaginyl Endopeptidase-Mediated Peptide Cyclization for Phage Display.

We report here an enzymatic strategy for asparaginyl endopeptidase-mediated peptide cyclization. Incorporation of chloroacetyl groups into the recognition sequence of OaAEP1 enabled intramolecular cyclization with Cys residues. Combining this strategy and phage display, we identified nanomolar macrocyclic peptide ligands targeting TEAD4. One of the bicyclic peptides binds to TEAD4 with a KD value of 139 nM, 16 times lower than its linear analogue, demonstrating the utility of this platform in discovering high-affinity macrocyclic peptide ligands.

[Imaging findings of carcinoma ex pleomorphic adenoma in minor salivary glands].

PURPOSE: To summarize the CT and MR imaging features of carcinoma ex pleomorphic adenoma(Ca-ex-PA) in minor salivary gland, and analyze the correlation between various features and pathological classification. METHODS: Forty-three patients with Ca-ex-PA in minor salivary gland were collected. The CT and MRI findings were retrospectively analyzed and correlated with their pathological types. Fisher's exact test was used to analyze the correlation between various imaging features (tumor morphology, boundary, internal structure, bone invasion, cervical lymph node metastasis) and pathological types with SPSS 25.0 software package. RESULTS: Among the 43 patients with Ca-ex-PA, 83.7%(36/43) of the tumors were lobulated; 81.4%(35/43) showed cystic degeneration or necrosis, with heterogeneous enhancement. Coarse calcification or mixed calcification was found in 37.2%(16/43), 25.6%(11/43) had compressive absorption of adjacent bone. 75%(12/16) of type Ⅰ/Ⅱ tumors had regular morphology (round or oval), and 77.8%(21/27) of type Ⅲ tumors had irregular morphology, 93.8%(15/16) of type Ⅰ/Ⅱ tumors had well-defined margin and 66.7%(18/27) of type Ⅲ tumors had ill-defined margin. Osteolytic bone resorption occurred in 59.3%(16/27) of type Ⅲ tumors. The average maximum diameter of type Ⅰ/Ⅱ tumors was significantly shorter than that of type Ⅲ(P＜0.05). Fisher's exact test showed the characteristics of tumor morphology, boundary and osteolytic bone resorption were related to pathological grouping(P＜0.001). CONCLUSIONS: Most Ca-ex-PA in minor salivary glands is characterized by lobular and heterogeneous enhanced neoplasm on CT and MR imaging. A round or oval tumor with well-defined margin usually correlates with typeⅠ and Ⅱ, contrarily, an irregular mass with ill-defined margin and osteolytic bone destruction usually correlates with type Ⅲ. Combining the three characteristics of morphology, boundary and osteolysis is more helpful to distinguish type Ⅰ/Ⅱ and type Ⅲ tumors.

Dupilumab for treatment of severe atopic dermatitis accompanied by lichenoid amyloidosis in adults: Two case reports.

BACKGROUND: Lichenoid amyloidosis (LA) is a subtype of primary cutaneous amyloidosis characterized by persistent multiple groups of hyperkeratotic papules, usually on the lower leg, back, forearm, or thigh. LA may be associated with several skin diseases, including atopic dermatitis (AD). The treatment of LA is considered to be difficult. However, as there is some overlap in the etiopathogenesis of LA and AD, AD treatment may also be effective for LA. CASE SUMMARY: Case 1: A 70-year-old man was diagnosed with severe AD with LA based on large dark erythema and papules on the trunk and buttocks and dense hemispherical millet-shaped papules with pruritus on the extensor side of the lower limbs. He had a long history of the disease (8 years), with repeated and polymorphic skin lesions. Given the poor efficacy of traditional treatments, this patient was recommended to receive dupilumab treatment. At the initial stage, 300 mg was injected subcutaneously every 2 wk. After 28 wk, the drug interval was extended to 1 mo due to the pandemic. Follow-up observations revealed that the patient reached an Eczema Area Severity Index of 90 (skin lesions improved by 90% compared with the baseline) by the end of the study. Moreover, Investigator's Global Assessment score was 1, and scoring atopic dermatitis index and numeric rating scale improved by 97.7% and 87.5% compared with the baseline, respectively, with LA skin lesions having largely subsided. Case 2: A 30-year-old woman was diagnosed with severe AD with LA, due to dense and substantial papules on the dorsal hands similar to changes in cutaneous amyloidosis, and erythema and papules scattered on limbs and trunk with pruritus, present for 25 years. After 16 wk of dupilumab treatment, she stopped, and skin lesions completely subsided, without recurrence since the last follow-up. CONCLUSION: Dupilumab shows rational efficacy and safety in the treatment of severe AD with LA, in addition to benefits in the quality of life of the patients.

Hypoxia-induced miR-9 expression promotes ovarian cancer progression via activating PI3K/AKT/mTOR/GSK3ß signaling pathway.

Ovarian cancer (OC) is one of the most prevalent malignant tumors affecting women's life and health. Since OC has a poor prognosis due to extensive metastasis, there is a need to explore a new mechanism of OC metastasis. microRNAs (miRs) are single-stranded, non-coding RNAs. miR-9 has been reported to promote cancer and may provide a new strategy for OC diagnosis. The purpose of this study was to examine the function and underlying mechanism of miR-9 in OC. RT-qPCR was used to assess miR-9 expression levels. Transwell assays were used to determine the number of migrating and invading OC cells. The protein expression levels of the PI3K/AKT/mTOR/GSK3ß signaling pathway were examined using western blotting. The results informed that, when compared to normal ovarian tissues, miR-9 was remarkably expressed in OC tissues, and hypoxia might lead to overexpression of miR-9-5p while inhibiting miR-9 notably suppressed the migrating and invading cell numbers in OC cells. In vivo, miR-9-5p knockdown inhibited tumor growth in a subcutaneous nude mice model of SKOV3 cells. Our findings suggest that miR-9 could be an underlying oncogene in OC, opening up new avenues for OC diagnosis and treatment of OC by targeting miR-9.

Preoperative Diagnosis of Dual-Phenotype Hepatocellular Carcinoma Using Enhanced MRI Radiomics Models.

BACKGROUND: Dual-phenotype hepatocellular carcinoma (DPHCC) is highly aggressive and difficult to distinguish from hepatocellular carcinoma (HCC). PURPOSE: To develop and validate clinical and radiomics models based on contrast-enhanced MRI for the preoperative diagnosis of DPHCC. STUDY TYPE: Retrospective. POPULATION: A total of 87 patients with DPHCC and 92 patients with non-DPHCC randomly divided into a training cohort (n = 125: 64 non-DPHCC; 61 DPHCC) and a validation cohort (n = 54: 28 non-DPHCC; 26 DPHCC). FIELD STRENGTH/SEQUENCE: A 3.0 T; dynamic contrast-enhanced MRI with time-resolved T1-weighted imaging sequence. ASSESSMENT: In the clinical model, the maximum tumor diameter and hepatitis B virus (HBV) were independent risk factors of DPHCC. In the radiomics model, a total of 1781 radiomics features were extracted from tumor volumes of interest (VOIs) in the arterial phase (AP) and portal venous phase (PP) images. For feature reduction and selection, Pearson correlation coefficient (PCC) and recursive feature elimination (RFE) were used. Clinical, AP, PP, and combined radiomics models were established using machine learning algorithms (support vector machine [SVM], logistic regression [LR], and logistic regression-least absolute shrinkage and selection operator [LR-LASSO]) and their discriminatory efficacy assessed and compared. STATISTICAL TESTS: The independent sample t test, Mann-Whitney U test, Chi-square test, regression analysis, receiver operating characteristic curve (ROC) analysis, Pearson correlation analysis, the Delong test. A P value < 0.05 was considered statistically significant. RESULTS: In the validation cohort, the combined radiomics model (area under the curve [AUC] = 0.908, 95% confidence interval [CI]: 0.831-0.985) showed the highest diagnostic performance. The AUCs of the PP (AUC = 0.879, 95% CI: 0.779-0.979) and combined radiomics models were significantly higher than that of clinical model (AUC = 0.685, 95% CI: 0.526-0.844). There were no significant differences in AUC between AP or PP radiomics model and combined radiomics model (P = 0.286, 0.180 and 0.543). CONCLUSION: MRI radiomics models may be useful for discriminating DPHCC from non-DPHCC before surgery. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

[MRI findings of parotid acinic cell carcinoma in 19 consecutive cases].

PURPOSE: To describe the MRI features of acinar cell carcinoma of parotid gland (AciCC) and to evaluate the diagnostic value of MR functional imaging. METHODS: A total of 269 cases of maxillofacial AciCC confirmed by surgery and pathology were analyzed. Among them, nineteen subjects with AciCC in the parotid gland underwent preoperative MRI examination (non-enhanced scan for one case, enhanced scan for 18 cases), seventeen patients underwent diffusion-weighted imaging scan, and 15 patients underwent dynamic contrast-enhanced scan. MRI findings of 19 patients were retrospectively analyzed. The lesion size, location, morphology, margin, internal composition, enhancement pattern and functional imaging characteristics were analyzed. SPSS 25.0 software package was used for statistical analysis. RESULTS: Among 269 cases of maxillofacial AciCC, there were 108 males and 161 females, male: female = 1:1.49, aged from 4 to 89 years, with a mean age of (45.95±17.33) years. 84.4% (227/269) were located in the parotid gland. On MRI images, 78.9% (15/19) had well-defined margin, 57.9% (11/19) were round or oval, and 36.8% (7/19) were lobed nodules. One case had irregular morphology and peripheral invasion. The range of maximum diameter was 6-56 mm, averaging (24.8±15.3) mm. Internal composition showed 57.9% (11/19) were cystic solid, 42.1% (8/19) were solid, 31.6% (6/19) had bleeding. T2-weighted MRI showed 52.6% (10/19) with envelope structure, 15.8% (3/19) with low signal separation inside, 38.9%(7/18) had uniform enhancement, and 61.1%(11/18) had uneven enhancement. Functional imaging showed the mean ADC value of tumor was (1.026±0.194)×10-3 mm2/s(n=17). 86.7%(13/15) TIC was type Ⅱ. CONCLUSIONS: Most maxillofacial AciCC are located in the parotid gland. It is difficult to distinguish AciCC from benign tumors with conventional MRI in morphology. The ADC value of AciCC is lower than that of benign tumors, and the type of TIC curve is mostly type Ⅱ. Combination of morphology and functional imaging can improve the diagnostic accuracy of this disease.

Unilateral lichen planus with Blaschko line distribution: A case report.

BACKGROUND: Lichen planus (LP) with distribution of lesions along Blaschko's lines is a rare entity, accounting for 0.24%-0.62% of all patients. Unilateral distribution of lesions in arm, leg, trunk, and waist is even less common. Approximately 10% of patients with LP manifest nail lesions. CASE SUMMARY: A 20-year-old woman presented to our department with polygonal, purpuric, flat-topped papules over the right arm, right leg, and right side of trunk and waist for the last 5 mo. The patient initially developed nail deformation in the left middle finger with no obvious cause, followed by development of blue-purple and red maculopapular rash with pruritus. During the disease course, the skin lesions aggravated and spread to several segments due to scratching. The lesions showed unilateral distribution along the Blaschko's lines. The diagnosis of LP along Blaschko's lines was established based on dermoscopy and skin biopsy. Her cutaneous lesions considerably improved after 4-wk treatment with intramuscular glucocorticoid, oral acitretin, topical glucocorticoid, and retinoids. CONCLUSION: Cases of LP involving multiple segments of the body along the Blaschko's lines with nail damage are rare.

Pharmacophore-inspired discovery of FLT3 inhibitor from kimchi.

Globally consumed kimchi is manufactured through fermenting cruciferous vegetables containing indole glucosinolates (IG). But few reports describe the IG metabolism during the fermentation. Here, we show that indole-3-carbinol (I3C), a breakdown product of IG, is transformed during the kimchi fermentation into 3,3'-diindolylmethane (DIM) and 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr1). LTr1 was found to kill the acute myeloid leukemia (AML) cells with FMS-like tyrosine kinase 3 (FLT3) receptor mutations, by inhibiting the FLT3 phosphorylation and the expression of downstream proteins (STAT5, ERK, and AKT). In the immune-depleted mice xenografted with human MV4-11 cells, LTr1 was demonstrated to reduce the tumor growth and synergize with sorafenib, an anti-AML agent in clinic. The work updates the chemical and biological knowledge about kimchi, and in particular establishes LTr1 as an FLT3 inhibitor that is effective and synergistic with sorafenib in treating AML.

Method for Ferrite Nanomaterials-Mediated Cellular Magnetic Hyperthermia.

Magnetic hyperthermia (MH) mediated by magnetic nanoparticles is one of the most promising antitumor modalities. The past several decades have witnessed great progress for MH antitumor therapy in scientific trials and clinic applications since it was initially advanced by Gilchrist et al. The ultimate object of MH in vivo is to efficiently kill cancer cells, and hence, it is of great importance to develop an optimized cellular MH method to evaluate the therapeutic efficiency in vitro. In this study, we systematically studied the considerable affecting factors of cancer cell-killing efficiency during the cellular MH process, including the region of cell vessel positioned inside the alternating magnetic field copper coil, the magnetic field amplitude, the types of cancer cells, etc. Taking all these into account, we introduced a method for standardizing the cellular MH process to evaluate the cell-killing efficiency.

Synthesis of Chiral Bis(3-indolyl)methanes Bearing a Trifluoromethylated All-Carbon Quaternary Stereocenter via Nickel-Catalyzed Asymmetric Friedel-Crafts Alkylation Reaction.

Bis(3-indolyl)methanes are well-known natural products with a broad range of important biological functions including cancer cell growth inhibition and antimicrobial activity. Incorporation of a trifluoromethyl group is known to have a profound effect on the parent compound's biological activities. Here, an efficient method for the synthesis of chiral trifluoromethylated bis(3-indolyl)methanes via a catalytic asymmetric Friedel-Crafts (F-C) alkylation reaction has been established. Both enantiomers of the catalysis products can be obtained by tuning the chiral substituents of the catalyst. With 5 mol % of the Ni(II)/(imidazoline-oxazoline) complex as the catalyst, the F-C reaction of indoles with ß-CF3-ß-(3-indolyl)nitroalkenes proceeded well to afford a series of chiral bis(3-indolyl)methanes bearing a trifluoromethylated all-carbon quaternary stereocenter in generally good yields with excellent enantioselectivities (up to 98% yield and 94% ee). Furthermore, by interchanging the indole moieties of the two reactants, indole vs ß-CF3-ß-(3-indolyl)nitroalkene in the F-C reaction, both enantiomers of a given trifluoromethylated bis(3-indolyl)methane were obtained with high enantioselectivities (89-94% ee) upon removal of the indole N-protecting group in the F-C products. The current work represents the first general catalytic enantioselective approach to the important class of trifluoromethylated bis(3-indolyl)methanes.

Hypoxia-inducible factor-1: A potential pharmacological target to manage psoriasis.

Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcriptional factor and is composed of HIF-1α and HIF-1ß subunits. An increase in the levels of HIF-1α in the psoriatic lesions and the serum of psoriatic patients has been reported. An increase in the HIF-1α in the epithelial keratinocytes may contribute in promoting angiogenesis and skin inflammation. Accordingly, the drug therapy directed to control HIF-1α levels may effectively manage the disease. An increase in HIF-1α may participate in the pathogenesis of psoriasis in association with IL-6, vascular endothelial growth factor (VEGF), microRNA-150, microRNA-270, reactive oxygen species, bone morphogenetic protein 6 (BMP6), triggering receptor expressed on myeloid cells 1 (TREM-1) and phosphoinositide 3-kinases (PI3K)/Akt pathway. An increase in the levels of IL-6, free radicals, and reduction in miR-150 may increase the expression of HIF-1α, which may act to induce angiogenesis via VEGF-ERK2 signaling pathway. An increase in HIF-1α may attenuate the expression of BMP6 to inhibit the terminal differentiation and increase the proliferation of keratinocytes. Moreover, HIF-1α may increase the expression of miR-210 to decrease the levels of STAT-6 and LYN, which in turn is manifested in the form of excessive activation of immune system. An increase in keratinocyte proliferation, excessive angiogenesis along with abnormal activation of the immune system play a key role in the pathogenesis of psoriasis. The present review discusses the evidence showing the crucial role of HIF-1α in psoriasis along with interrelationship with other mediators/signaling pathways that may contribute to the development of psoriasis.

Effect and Mechanism of miR-26a-5p on Proliferation and Apoptosis of Hepatocellular Carcinoma Cells.

AIM: This study aimed to investigate the effect and mechanism of miR-26a-5p on proliferation and apoptosis of hepatocellular carcinoma (HCC) cells. METHODS: RT-PCR was used to analyze the expression of miR-26a-5p in HCC cells and its targeted gene HMGA2 mRNA determined by biological information prediction. The rate of proliferation, invasion, apoptosis, and expression levels of related proteins of HCC cells overexpressing miR-26a-5p or those after knocking down HMGA2 expression were detected by MTT, invasion and apoptosis rate tests. Moreover, the apoptosis-promoting protein bax was upregulated and the anti-apoptosis-related protein Bcl-2 was downregulated. RESULTS: RT-qPCR results showed that the level of miR-26a-5p was downregulated in HCC tissues and cells, and the expression of HMGA2 was upregulated; besides, the expression of miR-26a-5p and HMGA2 was negatively correlated; miR-26a-5p was correlated with tumor diameter, differentiation degree, TNM staging and lymph node metastasis. Cell tests confirmed that miR-26a-5p functioned in tumor suppression, including inhibiting cell proliferation and invasion in two hepatocellular carcinoma cell lines and promoting apoptosis. Bioinformatics prediction and subsequent experiments proved that HMGA2 was the direct target of miR-26a-5p; moreover, after knocking down HMGA2 expression in HCC cells, cell proliferation and invasion ability were significantly inhibited, and apoptosis rate increased significantly. CONCLUSION: miR-26a-5p can inhibit the proliferation and invasion of HCC cells and promote their apoptosis by directly targeting HMGA2. Abnormal decrease of miR-26a-5p and increase of its target HMGA2 are important factors that may participate in the occurrence and development of HCC. miR-26a-5p may be a new potential target for its treatment.

Omega-3PUFA Attenuates MNU-Induced Colorectal Cancer in Rats by Blocking PI3K/AKT/Bcl-2 Signaling.

BACKGROUND: Omega 3 polyunsaturated fatty acid (Omega-3PUFA) is one of the essential nutrients for human body involved in intracellular metabolic regulation and cell signaling. Previous studies have shown that Omega-3PUFA is involved in the pathogenesis of digestive system tumors, including colorectal cancer (CRC), however, the effects of Omega-3PUFA on CRC has not been fully elucidated. In the current study, we evaluated whether Omega-3PUFA can alleviate N-methyl-N-nitrosourea(MNU) induced CRC in a rat model and illustrated the potential mechanism. METHODS: The effects of Omga-3PUFA on MNU-induced colorectal cancer in rats were analyzed by in vivo experiments. The viability, apoptosis, colony formation and invasion of CRC cells treated with Omga-3PUFA were detected by CCK8, flow cytometry, clone formation assay and transwell invasion assay. The expression of apoptosis-related proteins in CRC cells treated with Omga-3PUFA was detected by Western blotting. Finally, after adding PI3K activator, the viability, apoptosis and protein expression of CRC cells treated with Omga-3PUFA were detected by CCK8, flow cytometry and Western blotting. RESULTS: Our results showed that Omega-3PUFA attenuated MNU-induced CRC in rats and inhibited AKT/Bcl-2 signaling in rats. In addition, Omega-3PUFA inhibited CRC cell proliferation and induces CRC cell apoptosis. Moreover, Omega-3PUFA inhibited CRC cell colony formation and invasion, and inhibited PI3K/AKT/Bcl-2 signaling in CRC cells. Furthermore, The effects of Omega-3PUFA on cell proliferation and apoptosis were inhibited by blocking PI3K/AKT signaling. CONCLUSION: Omega-3PUFA can attenuate MNU-induced colorectal cancer in rats by blocking PI3K/AKT/Bcl-2 signaling, which suggests that Omega-3PUFA may be a potent agent for CRC treatment.

Jackhammer Esophagus: From Manometric Diagnosis to Clinical Presentation.

Background: Jackhammer esophagus is a hypercontractile esophageal disorder recently brought to light with the advent of high resolution manometry (HRM). As little is known about its clinical presentation, the aim of this study was to identify the clinical characteristics associated with this new gastrointestinal motility disorder. Methods: A retrospective study was conducted on patients visiting the CHUM's Gastro-Intestinal Motility Center from January 2015 to December 2017. The HRM diagnoses were collated in a database along with age and sex of every individual. The latest Chicago classification (version 3.0) was used. Among all the patients subjected to HRM, those diagnosed with Jackhammer esophagus were included in the study. Patient charts were reviewed to collect relevant demographic and clinical data. Key Results: A total of 36 patients with Jackhammer esophagus were included (62 ± 13 years age, 89% females). Their main symptoms were dysphagia (72%), pyrosis (42%), retrosternal chest pain (36%), and epigastralgia (33%). Other manometric findings were hypertonia (22%) and/or inadequate relaxation (19%) of the lower esophageal sphincter. Among the 26 patients who had esogastroduodenoscopy, hiatal hernia was seen in 3 patients. Pathological gastroesophageal reflux was found in 4 of the 10 patients investigated by pH-monitoring. Conclusions and Inferences: Jackhammer esophagus represents 3% of the HRM diagnoses in this study, with a significant female preponderance. In more than two-thirds of cases, the clinical presentation of Jackhammer esophagus is dysphagia.

Synthesis and Evaluation of 3-Substituted-4-(quinoxalin-6-yl) Pyrazoles as TGF-ß Type I Receptor Kinase Inhibitors.

The transforming growth factor-ß (TGF-ß), in which overexpression has been associated with various diseases, has become an attractive molecular target for the treatment of cancers. Thirty-two quinoxaline-derivatives of 3-substituted-4-(quinoxalin-6-yl) pyrazoles 14a⁻d, 15a⁻d, 16a⁻d, 17a⁻d, 18a⁻d, 19a⁻d, 25a, 25b, 25d, 26a, 26b, 26d, 27b, and 27d were synthesized and evaluated for their activin TGF-ß type I receptor kinase and p38α mitogen activated protein (MAP) kinase inhibitory activity in enzymatic assays. Among these compounds, the most active compound 19b inhibited TGF-ß type I receptor kinase phosphorylation with an IC50 value of 0.28 µM, with 98% inhibition at 10 µM. Compound 19b also had good selectivity index of >35 against p38α MAP kinase, with 9.0-fold more selective than clinical candidate, compound 3 (LY-2157299). A molecular docking study was performed to identify the mechanism of action of the synthesized compounds and their good binding interactions were observed. ADMET prediction of good active compounds showed that these ones possess good pharmacokinetics and drug-likeness behavior.

Development of radioiodine labeled acetaminophen for specific, high-contrast imaging of malignant melanoma.

INTRODUCTION: Due to its poor prognosis, specific imaging for early detection of malignant melanoma is strongly desired. Although radioiodine labeled 4-hydroxyphenylcysteamine, which we previously developed, has good affinity for tyrosinase, an enzyme in the melanin metabolic pathway, image contrast of the melanoma:organ ratios is not sufficiently high for detection of primary melanoma and metastases at early injection times. In this study, we developed radioiodine labeled acetaminophen (I-AP) for specific, high-contrast imaging of malignant melanoma. METHODS: Radioiodine-125-labeled AP (125I-AP) was prepared using the chloramine-T method under no carrier-added conditions. Accumulation of radioactivity and the mechanism were evaluated in vitro using B16 melanoma cells incubated with 125I-AP or 14C(U)-labeled AP (14C-AP) with and without l-tyrosine as a substrate of tyrosinase, phenylthiourea as an inhibitor of tyrosinase, and thymidine as an inhibitor of DNA polymerase. The biological distribution of radioactivity in B16 melanoma-bearing mice was evaluated to determine the accumulation of 125I-AP. The stability of 125I-AP over time was evaluated in mice. RESULTS: The labeling efficiency and radiochemical purity of 125I-AP were >80% and 95%, respectively. Accumulation of 125I-AP was higher than that of 14C-AP at 60 min of incubation in vitro. The affinity of 14C-AP for tyrosinase and DNA polymerase was higher than that of 125I-AP, whereas the Vmax of 125I-AP was higher than that of 14C-AP. 125I-AP showed the highest accumulation in the gall bladder, and clearance from the blood and kidney was rapid. Melanoma:muscle and melanoma:normal skin ratios of 125I-AP for imaging contrast were the highest at 15 min after injection, whereas the melanoma:blood and melanoma:bone ratios gradually increased over time. 125I-AP remained stable for 60 min after injection in mice. CONCLUSIONS: 125I-AP has affinity for tyrosinase and high image contrast at early time points after injection. Therefore, 123I-AP imaging has great potential for specific, high-contrast detection of malignant melanoma. ADVANCES IN KNOWLEDGE: 123I-AP will provide specific, high-contrast imaging for malignant melanoma at early injection times. IMPLICATIONS FOR PATIENT CARE: 123I-AP has good potential for the diagnosis of malignant melanoma compared with 123I-labeled 4-hydroxyphenylcysteamine, which we previously developed.

[Diagnostic value of diffusion-weighted magnetic resonance imaging for solid tumors affecting the base of tongue and glossopharynx].

PURPOSE: The objective of the present study was to evaluate the potential application value of diffusion-weighted magnetic resonance imaging (DW-MRI) to differentiate solid benign from malignant tumors affecting the base of tongue and glossopharynx. METHODS: Sixty-one patients who presented with solid tumors affecting the base of tongue and glossopharynx underwent conventional MRI and DW-MRI before pathologic verification. Based on pathologic findings, the tumors were classified into 4 groups: Group 1, solid benign tumor (n=10); Group 2, epithelial carcinoma (n=35); Group 3: non- epithelial malignant tumor (n=16); and Group 4: malignant tumor (n=51, a combination of Group 2 and 3). The mean apparent diffusion coefficients (ADCs) were computed from DW-MRI scans obtained with b factors of 0 and 1000 s/mm2. SAS 9.1 software package was used for Wilcoxon test. RESULTS: The mean ADCs were significantly different (P<0.05) between group 1 and the other 3 groups, and between group 2 and group 3, respectively. Among all kinds of pathological types of lesions, non-Hodgkin lymphoma had a lowest mean ADC value, and schwannoma had a highest mean ADC value. In addition, the mean ADCs among epithelial carcinoma subtypes were not significantly different(P>0.05). CONCLUSIONS: DW-MRI has differential diagnostic value of solid tumors affecting the base of tongue and glossopharynx, especially in distinguishing between benign solid tumors and malignant tumors, and between epithelial carcinomas and non-epithelial malignant tumors.

Multifunctional nanoparticles co-delivering EZH2 siRNA and etoposide for synergistic therapy of orthotopic non-small-cell lung tumor.

Malignant proliferation and metastasis in non-small cell lung carcinoma (NSCLC) are great challenges for effective clinical treatment through conventional chemotherapy. The combinational therapy strategy of RNA interfering (RNAi) technology and chemotherapeutic agents have been reported to be promising for effective cancer therapy. In this study, based on multifunctional nanoparticles (NPs), the simultaneous delivery of etoposide (ETP) and anti-Enhancer of Zeste Homologue 2 (EZH2) siRNA for the effective treatment of orthotopic lung tumor was achieved. The NPs exhibited pH/redox dual sensitivity verified by particle size changes, morphological changes, and in vitro release of drugs. Confocal microscopy analysis confirmed that the NPs exhibited endosomal escape property and on-demand intracellular drug release behavior, which can protect siRNA from degradation and facilitate the chemotherapeutic effect respectively. In vitro tumor cell motility study demonstrated that EZH2 siRNA loaded in NPs can decrease the migration and invasion capabilities of tumor cells by downregulating the expression of EZH2 mRNA and protein. In particular, an antiproliferation study revealed that the co-delivery of siRNA and ETP in the multifunctional NPs can induce a synergistic therapeutic effect on NSCLC. In vivo targeting evaluation showed that cRGDyC-PEG modification on NPs exhibited a low distribution in normal organs and an obvious accumulation in orthotopic lung tumor. Furthermore, targeted NPs co-delivering siRNA and ETP showed superior inhibition on tumor growth and metastasis and produced minimal systemic toxicity. These findings indicated that multifunctional NPs can be utilized as a co-delivery system, and that the combination of EZH2 siRNA and ETP can effectively treat NSCLC.

Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor.

Multidrug resistance (MDR) is a major obstacle for the clinical therapy of malignant human cancers. The discovery of RNA interference provides efficient gene silencing within tumor cells for reversing MDR. In this study, a new "binary polymer" low-density lipoprotein-N-succinyl chitosan-cystamine-urocanic acid (LDL-NSC-SS-UA) with dual pH/redox sensitivity and targeting effect was synthesized for the co-delivery of breast cancer resistance protein small interfering RNA (siRNA) and paclitaxel (PTX). In vivo, the co-delivering micelles can accumulate in tumor tissue via the enhanced permeability and retention effect and the specific recognition and combination of LDL and LDL receptor, which is overexpressed on the surface of tumor cell membranes. The siRNA-PTX-loaded micelles inhibited gene and drug release under physiological conditions while promoting fast release in an acid microenvironment or in the presence of glutathione. The micelles escaped from the lysosome through the proton sponge effect. Additionally, the micelles exhibited superior antitumor activity and downregulated the protein and mRNA expression levels of breast cancer resistance protein in MCF-7/Taxol cells. The biodistribution and antitumor studies proved that the siRNA-PTX-loaded micelles possessed prolonged circulation time with a remarkable tumor-targeting effect and effectively inhibited tumor growth. Therefore, the novel dual pH/redox-sensitive polymers co-delivering siRNA and PTX with excellent biocompatibility and effective reversal of MDR demonstrate a considerable potential in cancer therapy.