Study on the association between adverse drug reactions to opioids and gene polymorphisms: a case-case-control study.

OBJECTIVE: Adverse drug reactions (ADRs) caused by opioid drugs show individual differences. Our objective was to explore the association between gene polymorphism and ADRs induced by opioid drugs. METHODS: Evidence-based medical data analysis was conducted for genes related to ADRs induced by opioid drugs to select target genes. Sixty patients with cancer pain who had ADRs after taking opioid drugs (morphine, codeine, oxycodone) and 60 patients without ADRs after taking opioid drugs were used as the experimental group and control group, respectively. Then, we used polymerase chain reaction (PCR) or in situ hybridization to detect target genes. By combining with clinical data such as age, sex, dosage and duration of medication, the effect of gene polymorphism on the ADR of patients after taking opioid drugs was statistically analysed. RESULTS: Based on a database search and evidence-based medical data, we identified CYP2D6*10, CYP3A5*3, ABCB1, and OPRM1 as target genes for detection. The results of statistical analysis showed no significant difference in genotype distribution between the experimental group and the control group (p > 0.05). However, if 32 patients with ADRs after taking oxycodone and 32 controls were selected for comparison, the SPSS22.0 and SNPStats genetic models showed that the ABCB1 (062rs1045642) CT and TT genotypes correlated with the occurrence of ADRs (p < 0.05): the total number of CT + TT genotypes in the experimental group was 29 (90.62%), with 11 (34.37%) CT + TT genotypes types in the control group. CONCLUSION: Polymorphism of ABCB1 (062rs1045642) is related to ADRs caused by oxycodone, and the incidence of ADRs is higher with the allele T. Polymorphism of ABCB1 is expected to become a clinical predictor of ADRs to oxycodone, and attention should be given to the occurrence of serious ADRs in patients with ABCB1 (062rs1045642) CT and TT genotypes.

Aggressive fibromatosis near the incision after cervical spinal cord ependymoma: A case report.

Aggressive fibromatosis (AF), also known as ligamentoid fibromatosis and desmoid tumor, is a fibroblast clonoproliferative lesion located in the deep soft tissue. The present study reports the case of a 36-year-old female with AF who underwent cervical spinal cord ependymoma surgery. AF developed in the soft tissue of the neck adjacent to the incision site. The size of the neck AF increased rapidly over 2 years, and due to discomfort, the patient underwent initial surgical resection without any other combined treatment methods. When the patient was routinely reviewed at 6 months post-surgery, a recurrence of AF of the neck was found. The patient was recommended surgical resection and radiotherapy. This case report should improve the understanding of clinicians with regard to AF, and help the diagnostic process and treatment plan.

Differentiation of neurogenic tumours and pleomorphic adenomas in the parapharyngeal space based on texture analysis of T2WI.

BACKGROUND: The purpose of this study was to identify neurogenic tumours and pleomorphic adenomas of the parapharyngeal space based on the texture characteristics of MRI-T2WI. METHODS: MR findings and pathological reports of 25 patients with benign tumours in the parapharyngeal space were reviewed retrospectively (13 cases with pleomorphic adenomas and 12 cases with neurogenic tumours). Using PyRadiomics, the texture of the region of interest in T2WI sketched by radiologists was analysed. By using independent sample t-tests and Mann‒Whitney U tests, the selected texture features of 36 Gray Level Co-Occurrence Matrix (GLCM) and Gray Level Dependence Matrix (GLDM) were tested. A set of parameters of texture features showed statistically significant differences between the two groups, which were selected, and the diagnostic efficiency was evaluated via the operating characteristic curve of the subjects. RESULTS: The differences in the three parameters - small dependence low level emphasis (SDLGLE), low level emphasis (LGLE) and difference variance (DV) of characteristics - between the two groups were statistically significant (P < 0.05). No significant difference was found in the other indices. ROC curves were drawn for the three parameters, with AUCs of 0.833, 0.795, and 0.744, respectively. CONCLUSIONS: There is a difference in the texture characteristic parameters based on magnetic resonance T2WI images between neurogenic tumours and pleomorphic adenomas in the parapharyngeal space. For the differential diagnosis of these two kinds of tumours, texture analysis of significant importance is an objective and quantitative analytical tool.

Pharmacovigilance of cutaneous adverse drug reactions in associations with drugs and medical conditions: a retrospective study of hospitalized patients.

BACKGROUND: Cutaneous adverse drug reaction (CADR) is a common problem in clinical medication. This study aimed to investigate the correlation between clinical drug application and CADR occurrence as evidence for preventive strategies and rational clinical drug use. METHODS: We analyzed the characteristics of CADRs of 858 patients admitted to Shandong Provincial Third Hospital from March 2007 to December 2018. The most significant drugs concerning the common skin symptoms and their significance to CADR were investigated by case-non-case and multiple logistic regression analyses. RESULTS: A total of 266 drugs were involved in 858 cases of CADR. Among the ten most relevant medications, primarily antibiotics and herbal injections, and nutritional support drugs, potassium sodium dehydroandrographolide succinate injection, and cefoperazone sodium and sulbactam sodium injection were found to be 2.1 and 1.45 times statistically more prone to CADRs than to other adverse drug reactions (ADRs), respectively. The main route of administration was intravenous (63.16%), with oral administration accounting for 25.19%. There were 747 cases of ADR, 71 of severe ADR, 2 of new and severe ADRs, and 38 cases of new ADR. Overall, 100 cases of CADR exhibited abnormal alanine aminotransferase, aspartate aminotransferase, and serum creatinine levels. The predictive factors for severe CADR occurrence included allergy and smoking histories, cefoperazone sodium, sulbactam sodium injection, levofloxacin lactate and sodium chloride injection. CONCLUSIONS: Drug-induced CADR symptoms are commonly associated with other ARDs, predominantly rashes and pruritus, and are often accompanied by some medical conditions, especially liver and kidney damage. Detailed attention to a patient's primary diseases, allergy history, and drug safety profile could help prevent or reverse CADR in most patients.

Prediction of the degree of pathological differentiation in tongue squamous cell carcinoma based on radiomics analysis of magnetic resonance images.

BACKGROUND: Tongue squamous cell carcinoma (TSCC) is one of the most difficult malignancies to control. It displays particular and aggressive behaviour even at an early stage. The purpose of this paper is to explore the value of radiomics based on magnetic resonance fat-suppressed T2-weighted images in predicting the degree of pathological differentiation of TSCC. METHODS: Retrospective analysis of 127 patients with TSCC who were randomly divided into a primary cohort and a test cohort, including well-differentiated, moderately differentiated and poorly differentiated. The tumour regions were manually labelled in fat-suppressed T2-weighted imaging (FS-T2WI), and PyRadiomics was used to extract radiomics features. The radiomics features were then selected by the least absolute shrinkage and selection operator (LASSO) method. The model was established by the logistic regression classifier using a 5-fold cross-validation method, applied to all data and evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity and specificity. RESULTS: In total, 1132 features were extracted, and seven features were selected for modelling. The AUC in the logistic regression model for well-differentiated TSCC was 0.90 with specificity and precision values of 0.92 and 0.78, respectively, and the sensitivity for poorly differentiated TSCC was 0.74. CONCLUSIONS: The MRI-based radiomics signature could discriminate between well-differentiated, moderately differentiated and poorly differentiated TSCC and might be used as a biomarker for preoperative grading.

Application of first-order feature analysis of DWI-ADC in rare malignant mesenchymal tumours of the maxillofacial region.

BACKGROUND: To research the first-order features of apparent diffusion coefficient (ADC) values on diffusion-weighted magnetic resonance imaging (DWI) in maxillofacial malignant mesenchymal tumours. METHODS: The clinical data of 12 patients with rare malignant mesenchymal tumours of the maxillofacial region (6 cases of sarcoma and 6 cases of lymphoma) treated in the hospital from May 2018 to June 2020 and were confirmed by postoperative pathology were retrospectively analyzed. The patients were all examined by 1.5T magnetic resonance imaging. PyRadiomics were used to extract radiomics imaging first-order features. Group differences in quantitative variables were examined using independent-samples t-tests. RESULTS: The voxels number of ADCmean and ADCmedian of sarcoma tissues were 44.9124 and 44.2064, respectively, significantly higher than those in lymphoma tissues (ADCmean (- 68.8379) and ADCmedian (- 74.0045)), the difference considered statistically significant, so do the ADCkurt and ADCskew. CONCLUSIONS: The statistical difference of ADCmean and ADCmedian is significant, it is consistent with the outcome of the manual measurement of the ADC mean value of the most significant cross-section of twelve cases of lymphoma. Development of tumour volume based on the ADC parameter map of DWI demonstrates that the first-order ADC radiomics features analysis can provide new imaging markers for the differentiation of maxillofacial sarcoma and lymphoma. Therefore, first-order ADC features of ADCkurt combined ADCskew may improve the diagnosis level.

Vaginal drug delivery approaches for localized management of cervical cancer.

Cervical cancer or cervical intraepithelial neoplasia (CIN) remain a major public health problem among women globally. Traditional methods such as surgery are often associated with possible complications which may impact future pregnancies and childbirth especially for young female patients. Vagina with a high contact surface is a suitable route for the local and systemic delivery of drugs but its abundant mucus in continuous exchange presents a barrier for the popularization of conventional vaginal formulations including suppositories, gel, patch, creams and so on. So the development of new pharmaceutical forms based on nanotechnology became appealing owing to its several advantages such as mucosa penetration, bioadhesion, controlled drug release, and decreased adverse effects. This review provided an overview of the development of topical treatment of cervical cancer or CIN through vaginal drug delivery ranging from conventional vaginal formulations to new nanocarriers to the newly developed phototherapy and gene therapy, analyzing the problems faced by current methods used, and advising the developing trend in future. The methods of establishing preclinical animal model are also discussed.

Renal clearable Hafnium-doped carbon dots for CT/Fluorescence imaging of orthotopic liver cancer.

Carbon dots (CDs) are emerging as powerful nanoprobes for multiple-model bioimaging. Nowadays, orthotopic xenograft models attract increasing attention because of their superiorities of duplicating the tumor microenvironment. However, compared with the extensive study of subcutaneous xenograft tumors, less attention has been paid to CDs for in vivo orthotopic tumor imaging. Furthermore, it is very desirable for a nanoprobe to achieve preferential accumulation at the tumor site and efficient renal clearance. In this work, a novel kind of Hafnium-doped CDs (HfCDs) were successfully prepared via a simple one-pot pyrolysis method. The significant advantages including robust stability, good biocompatibility, excellent water solubility, remarkable computed tomography (CT) contrast performance and preferential tumor accumulation capability endow HfCDs with particular functions of CT/fluorescence imaging of orthotopic liver cancer initially. More importantly, HfCDs could locate at the tumor site and achieve the rapid imaging within 1 min. The findings of the current study represent a facile and universal approach to fabricate outstanding renal clearable multimodal imaging nanoprobes with great potential for clinical diagnosis.

Integration of metal-organic framework with a photoactive porous-organic polymer for interface enhanced phototherapy.

Porphyrin-based porous organic polymers are highly potential candidates for cancer theranostics. However, un-controllable particle size and unclear photoactive mechanisms have been deemed to be "Achilles' heels" for their biomedical application. Herein, a facile self-template strategy has been applied to integrate two types of porous materials to build the MOF@POP-PEG nanocomposite (named HUC-PEG). As-synthesized HUC-PEG exhibited controllable particle shape and size, good biocompatibility, and better colloidal stability. Importantly, synergy "0 + 1 > 1" interface effects have been demonstrated to simultaneously enhance both the generation of more singlet oxygen (1O2) for photodynamic therapy (PDT) and local hyperthermia for photothermal therapy (PTT), thus to achieve favorable proliferation inhibition of tumor cell both in vitro and in vivo. Moreover, the strong X-ray attenuating ability of Hf element and excellent photothermal conversion efficacy endow this nanocomposite with computed tomography (CT)/photothermal imaging functions. We believe that our ingenious design may open a new horizon for the preparation of nanoscale POP-based therapeutic agents and also realize a paradigm shift in the understanding of photoactive mechanism in porous materials.

A Multi-Functional Silicon Nanoparticle Designed for Enhanced Osteoblast Calcification and Related Combination Therapy.

Implant materials applied in bone defect commonly focus on the inducement of bone regeneration and neglect to cure complications including bacterial infection and inflammation, which may result in delayed unions or even amputation. In this study, a microporous silica nanoparticle-poly(N-isopropylacrylamide-b-(2-(dimethylamino)ethyl methacrylate) is synthesized for loading DXMS and the ECM-derived peptide (Sequence: Succinic acid-GTPGPQGIAGQRGVV) in order to enhance the osteoblast calcification and relieve related symptoms. Positively charged PDMA blocks endow the nanoparticle with the antimicrobial property. Moreover, the combination of DXMS makes it have the ability of anti-inflammation and promoting calcification formation. Furthermore, incorporation of the peptide leads to a significant improvement of mineralization and alkaline phosphatase expression in the preosteoblast. After intramuscular implantation in mice for four weeks, the results indicate the composite nanoparticle can promote ectopic bone formation. These combined properties make the composite silicon nanoparticle a promising osteogenic drug appropriate for further study in bone repair and related combination therapy.

Development of Organic/Inorganic Compatible and Sustainably Bioactive Composites for Effective Bone Regeneration.

In this paper, we demonstrate a strategy of covalently bonding bioactive molecules onto inorganic hydroxyapatite (HAp) to improve the compatibility between organic and inorganic components and endow the bone composites with sustainable bioactivity. Bone morphogenetic protein-2 (BMP-2) peptide covalently immobilized nano-hydroxyapatite (nHAp-BMP-2) is developed to preserve the bioactivity and slow the release of the BMP-2 peptide. Then nHAp-BMP-2 was further incorporated into an ultraviolet-curable mixture of gelatin methacrylamide (GelMA) and four-armed PEG methacrylamide (four-armed PEGMA) to form a Gel/(nHAp-BMP-2) composite. The hydrogen bonding between gelatin and BMP-2 on nHAp-BMP-2 enhanced the compatibility between inorganic and organic components. The Gel/(nHAp-BMP-2) composite exhibited superior biocompatibility caused by gelatin and nHAp-BMP-2, except in a two-dimensional cell culture, the hydrogel was also capable of a three-dimensional cell culture. In addition, the introduction of nHAp-BMP-2 had a positive influence on bone marrow mesenchymal stem cell proliferation, differentiation, and the subsequent calcification on the composite. After treatment of a rat calvarial defect model for 12 weeks, the Gel/(nHAp-BMP-2) group showed the largest new bone volume and the highest ratio of new bone (50.54 ± 13.51 mm3 and 64.38 ± 17.22%, respectively) compared to those of the other groups. These results demonstrate that this way of controlling BMP-2 release is effective and the Gel/(nHAp-BMP-2) composite has great potential in bone regeneration therapy.

Synthesis and cytotoxic activity of two steroids: icogenin aglycone analogs.

During the process of icogenin analog research, we obtained two cytotoxic steroids: compound 4 and compound 6 casually. Their in vitro antitumor activities were tested by the standard MTT assay. The results disclosed that compound 4 (IC50 = 3.65-6.90 µM) showed potential antitumor activities against HELA, KB cell lines and compound 6 (IC50 = 2.40-9.05 µM) showed potential antitumor activities against HELA, BGC-823, KB, A549, HCT-8 cell lines.

Synthesis of three OSW-1 analogs with maltose side chains bearing different protection groups.

In order to simplify the synthesis of OSW-1's disaccharide side chain and explore the structure-activity relationship of OSW-1, three 16α-O-maltose OSW-1 analogs carrying three maltose side chains bearing different protections were designed and synthesized.

Synthesis and antitumor activity of 5,6-dihydro-17-hydroxy icogenin analogs.

Four 5,6-dihydro-17-hydroxy icogenin analogs were designed and synthesized. Their in vitro antitumor activities were tested by the standard MTT assay. Compound 22 (IC(50) = 3.38-8.30 µM) and compound 23 (IC(50) = 1.90-9.69 µM) showed potential antitumor activities against the entire tested seven cancer cell lines. The SAR (structure activity relationship) research showed that the introduction of 17-hydroxy lowered the antitumor activity to an extent.

Synthesis of cholestane saponins as mimics of OSW-1 and their cytotoxic activities.

To fulfill the structure-activity relationship (SAR) of OSW-1, and aim at finding the simplest structural part while maintaining most of the biological activities, six cholestane saponins were synthesized by introducing OSW-1 disaccharide (2-O-4-methoxybenzoyl-ß-D-xylopyranosyl-(1→3)-2-O-acetyl-α-L-arabinopyranosyl) and its 1→4-linked analogue to the 7-hydroxy or 16-hydroxy of steroidal sapogenins. Cytotoxic activities of the products were tested. Compounds 1 and 3 exhibited potent cytotoxicities against five types of human tumor cells, with minimum IC(50) of 2.0 and 75 nM, respectively. And due to its high activity and easy accessibility compound 1 could be a potential candidate for new anti-tumor agents.

Synthesis of 5(6)-dihydro-OSW-1 analogs bearing three kinds of disaccharides linking at 15-hydroxy and their antitumor activities.

In order to study the SAR of 5(6)-dihydro-OSW-1, eight 15(α)ß-O-glycosyl analogs (26-33) carrying three kinds of disaccharides including [ß-d-Xylp-(1-3)-α-l-Arap], [ß-d-Xylp-(1-4)-α-l-Arap] and [α-l-Rhap-(1-2)-(α)ß-d-Glcp] were designed and synthesized. Their in vitro antitumor activities were tested by the standard MTT assay which disclosed that compound 33 (IC(50)=0.28-0.52 µM) showed potential antitumor activities.

The synthesis of cholestane and furostan saponin analogues and the determination of sapogenin's absolute configuration at C-22.

A facile and efficient way for the synthesis of cholestane and furostan saponin analogues was established and adopted for the first time. Following this strategy, starting from diosgenin, three novel cholestane saponin analogues: (22S,25R)-3ß,22,26-trihydroxy-cholest-5-ene-16-one 22-O-[O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranoside] 11, (25R)-3ß,16ß,26-trihydroxy-cholest-5-ene-22-one 16-O-[O-α-L-rhamnopyranosyl-(1→2)-α-D-glucopyranoside] 14 and (25R)-3ß,16ß,26-trihydroxy-cholest-5-ene-22-one 16-O-[O-α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranoside] 17, three novel furostan saponin analogues: (22S,25R)-furost-5-ene-3ß,22,26-triol 22-O-(α-D-glucopyranoside) 23, (22R,25R)-furost-5-ene-3ß,22,26-triol 22-O-(α-D-glucopyranoside) 24 and (22S,25R)-furost-5-ene-3ß,22,26-triol 22-O-[O-α-L-rhamnopyranosyl-(1→2)-α-D-glucopyranoside] 26, were synthesized ultimately. The structures of all the synthesized analogues were confirmed by spectroscopic methods. The S-chirality at C-22 of cholestane was confirmed by Mosher's method. The absolute configuration at C-22 of furostan saponin analogues was distinguished by conformational analysis combined with the NMR spectroscopy. The cytotoxicities of the synthetic analogues toward four types of tumor cells were shown also.

Synthesis of cholestane glycosides bearing OSW-1 disaccharide or its 1-->4-linked analogue and their antitumor activities.

For further structure-activity relationship (SAR) research of OSW saponins, a cholestane glycoside, namely 3beta, 16beta, 26-trihydroxycholest-5-en-22-one 16-O-(2-O-4-methoxybenzoyl-beta-D-xylopyranosyl)-(1-->3)-2-O-acetyl-alpha-L-arabinopyranoside (1) together with two 1-->4-linked disaccharide analogues (2 and 3) were synthesized. Their cytotoxic activities were evaluated by the standard MTT assay. Compound 1 showed potent cytotoxicity against five types of human tumor cells, with IC50 ranging between 1.3 and 73 nM.