Nirmatrelvir increases blood tacrolimus concentration in COVID-19 patients as determined by UHPLC-MS/MS method.

OBJECTIVE: Transplant recipients have a higher risk of SARS-CoV-2 infection owing to the use of immunosuppressive drugs like tacrolimus (FK506). FK506 and nirmatrelvir (NMV) (an anti-SARS-CoV-2 drug) are metabolized by cytochrome P450 3A4 and may have potential drug-drug interactions. It is important to determine the effect of NMV on FK506 concentrations. PATIENTS AND METHODS: Following protein precipitation from blood, FK506 and its internal standard (FK506-13C,2d4) were detected by ultra-high performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS). Total 22 blood samples (valley concentrations) from two coronavirus disease 2019 (COVID-19) patients were collected and analyzed for FK506 concentrations. RESULTS: Blood levels of FK506 (0.5-100 ng/mL) showed good linearity. The UHPLC-MS/MS method was validated with intra- and inter-batch accuracies of 104.55-107.85%, and 99.52-108.01%, respectively, and precisions of < 15%. Mean blood FK506 concentration was 12.01 ng/mL (range, 3.15-33.1 ng/mL). Five-day co-administration with NMV increased the FK506 concentrations from 3.15 ng/mL to 33.1 ng/mL, returning to 3.36 ng/mL after a 9-day-washout. CONCLUSIONS: We developed a simple quantification method for therapeutic drug monitoring of FK506 in patients with COVID-19 using UHPLC-MS/MS with protein precipitation. We found that NMV increased FK506 blood concentration 10-fold. Therefore, it is necessary to re-consider co-administration of FK506 with NMV.

[The possible mechanisms of simvastatin on apoptosis of lung adenocarcinoma cells].

Objective: To explore the possible mechanisms of simvastatin-induced apoptosis in lung adenocarcinoma cells. Methods: The experiment was divided into control group (vehicle treated A549 cells), different concentrations (10, 20, 40, 80 mg/L) simvastatin group (simvastatin treated with different concentrations of A549 cells), aspartate specific proteinase (caspase) inhibitor (Z-VAD-FMK) group (50 µmol/L Z-VAD-FMK treated A549 cells), 40 mg/L simvastatin combined with Z-VAD-FMK group (40 mg/L simvastatin combined with 50 µmol/L Z-VAD-FMK co-treated A549 cells), interleukin-6 (IL-6) group (IL-6 acts on A549 cells) and different concentrations (10, 20, 40 mg/L) simvastatin combined with IL-6 group (simvastatin combined with IL-6 act on A549 cells). Cell counting kit-8 (CCK8) method was used to detect the effect on survival rate of lung adenocarcinoma A549 cells; Flow cytometry was used to detect the effect of simvastatin on A549 cell cycle; Mitochondrial membrane potential-1 (JC-1) fluorescent probe was wsed to detect the effect of simvastatin on mitochondrial membrane potential (MMP); Flow-type phosphatidl serine protein antibody Annexin V/propidium iodide (Annexin V-FITC/PI) double staining method was used to detect the effect of simvastatin on A549 cell apoptosis; CCK8 method was used to detect the effect of Z-VAD-FMK on the survival rate of A549 cells; TdT-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick end labeling (TUNEL) method was used to detect the effect of Z-VAD-FMK on simvastatin-induced apoptosis in A549 cells; Western blot method was used to detect the effect of simvastatin on the expression levels of Janus kinase 2 and activation of signal transducers and activators of transcription 3 (JAK2/STAT3) pathway-related proteins phosphorylated JAK2 (p-JAK2), JAK2, phosphorylated STAT3 (p-STAT3), and STAT3 before and after the activator IL-6 of JAK2/STAT3 pathway acted on A549 cells. Results: The survival rates of A549 cells in the 20-80 mg/L simvastatin-treated groups were significantly lower than that in the control group (all P<0.05), and gradually decreased with the increase of the concentration of the simvastatin and the extension of the action time. The cells in the G(0)/G(1) phase of the simvastatin group were significantly higher than those in the control group, and the cells in the G(2)/M phase were significantly lower than those in the control group (all P<0.01). The MMP of the treatment group with different concentrations of simvastatin was significantly lower than that of the control group (all P<0.05). The apoptosis rate of the 20 mg/L and 40 mg/L simvastatin-treated group was significantly higher than that of the control group (both P<0.01). The cell survival rate of the 40 mg/L simvastatin group and the 40 mg/L simvastatin combined with Z-VAD-FMK group were (52.2±2.7)% and (57.5±3.8)%, respectively, were lower than that of the control group (100.0±2.7)% (both P<0.01). But the difference between 40 mg/L simvastatin group and the simvastatin combined with Z-VAD-FMK group was not statistically significant (P>0.05). The cell numbers with positive fluorescent staining in the 40 mg/L simvastatin group were significantly more than those in the control group, but the cell numbers with positive fluorescent staining in the 40 mg/L simvastatin combined with Z-VAD-FMK group had no statistical significance compared with the simvastatin group (P>0.05). The specific value of p-JAK2/JAK2 and p-STAT3/STAT3 protein relative expressions in the simvastatin-treated group (20, 40 mg/L) were significantly lower than that in the control group, respectively (both P<0.05). The specific value of p-JAK2/JAK2 and p-STAT3/STAT3 protein relative expressions in IL-6 group were significantly higher than those in control group (both P<0.05), the specific value of p-JAK2/JAK2 and p-STAT3/STAT3 protein relative expressions in simvastatin (20, 40 mg/L) combined with IL-6 groups were lower than those in IL-6 group (all P<0.05), respectively. Conclusion: Simvastatin can induce the apoptosis of A549 cells through a non-caspase-dependent mitochondrial apoptosis pathway, which may be achieved by inhibiting the JAK2/STAT3 pathway.

Upregulation of lncRNA DANCR functions as an oncogenic role in non-small lung cancer by regulating miR-214-5p/CIZ1 axis.

OBJECTIVE: Lung cancer has an unfavorable prognosis due to the lack of efficient diagnostic and therapeutic strategies. Therefore, this study sought to figure out the effect of long non-coding RNA (lncRNA) DANCR on lung cancer progression. PATIENTS AND METHODS: LncRNA DANCR and miR-214-5p expressions in non-small cell lung cancer (NSCLC) were detected by Real Time-quantitative Polymerase Chain Reaction (RT-qPCR). Function assays, including Cell Counting Kit-8 (CCK-8) and flow cytometric analysis were conducted to clarify the role of DANCR and miR-214-5p in the progression of NSCLC. Western blot, Dual-Luciferase reporter assay, and RNA immunoprecipitation assay (RIP) were performed to elucidate the underlying mechanism. RESULTS: LncRNA DANCR was upregulated in NSCLC. The knockdown of lncRNA DANCR inhibited cell proliferation and accelerated cell apoptosis in NSCLC. LncRNA DANCR interacted with miR-214-5p. MiR-214-5p over-expression partially reversed the regulatory effects of DANCR on proliferation and apoptosis in NSCLC. In addition, CIZ1 was the downstream gene binding miR-214-5p. LncRNA DANCR could regulate the miR-214-5p/CIZ1 axis. CONCLUSIONS: Downregulation of lncRNA DANCR inhibited cell proliferation and induced cell apoptosis in NSCLC by regulating the miR-214-5p/CIZ1 axis. LncRNA DANCR may act as an oncogene and promote the progression of NSCLC.

Distinguishing malignant from normal oral tissues using FTIR fiber-optic techniques.

Oral tissue samples were studied using mid-IR fiber-optic attenuated total reflectance spectroscopy and other spectral techniques. The 1745 cm(-1) band, which is assigned to the ester group (C==O) vibration of triglycerides, is a reliable marker that is present in normal tissues but absent or a weak band in malignant oral tissues. Other bands such as C--H stretching bands and the amide bands are also helpful in distinguishing malignant tissues from normal tissues. Subtraction spectra confirmed the above conclusion. In addition, Raman spectroscopic measurements were in agreement with the results observed from FTIR spectra.

Percutaneous internal maxillary arterial embolization with ethylcellulose microspheres. Results in an animal model.

RATIONALE AND OBJECTIVES: To investigate the use of ethylcellulose microspheres as long-term and peripheral emboli for percutaneous maxillofacial arterial embolization. METHODS: Eight mongrel dogs were selected randomly for internal maxillary artery embolization with ethylcellulose microspheres. After embolization, angiographic, microangiographic, and histologic examinations were performed. RESULTS: Ethylcellulose microspheres were trapped in the peripheral arterioles from 24 hours to 6 months after embolization. Degenerative changes of maxilla, mandible, and dental pulp occurred after the embolization of the internal maxillary artery with the microspheres. No evidence of whole or focal necrosis of the bones and surrounding soft tissues was found between 24 hours and 6 months after embolization. CONCLUSION: Ethylcellulose microspheres can be used as an alternative long-term and peripheral embolic agent, with potential for percutaneous maxillofacial arterial embolization.

[Histopathological findings of 59 cases of cheilitis granulomatosa].

By histopathological observations of 59 cases of CG, they are divided into 6 types according to pathological characteristics. Their differences are compared and discussed. The reason and significance of this classification from morphological point of view are discussed as well. It is suggested that the G is possibly resulted from different reactions of the body to the same pathogen or to the different pathogens.

[Operative and pathological observations on secondary synovitis of temporomandibular joint dysfunction syndrome].

14 cases (16 joints) with temporomandibular joint dysfunction syndrome (TMJDS) were included in the present study. All the patients had severe pain of the joint for a long time and the conventional therapy was not effective. The operative and pathological findings of the 14 cases showed that synovitis secondary to microtrauma of the joint really existed and might be one of the reasons causing the severe pain of the joint in some patients with TMJDS.

[Immunoelectron microscopic and immunohistochemical study of adenoid cystic carcinoma of the salivary gland].

Four adenoid cystic carcinomas of salivary gland were studied by immunohistochemistry and immunoelectron microscopy with anti-actin, myosin, S-100 protein and GFAP antibodies. The results showed that neoplastic myoepithelial cells in these tumors gave positive reactions for actin, myosin and S-100 protein antibodies and negative reactions for GFAP antibody. The neoplastic myoepithelial cells lined the cyst-like spaces and surrounded the periphery of the epithelial nests. Neoplastic ductal epithelial cells were negative for the above mentioned antibodies. The differentiation tendencies and immunofeatures of neoplastic myoepithelial cells were discussed.

Immunohistochemical and histological studies on internal derangement and organic disturbance of temporomandibular joint.

The study examined the articular cartilages of 14 patients who suffered from temporomandibular joint disturbance syndrome (TMJDS) and 3 healthy fresh cadavers by light microscopy and immunofluorescence, and assayed 14 patients' synovial fluids and sera with indirect hemoagglutination. The results showed that there were antibodies to type II collagen in synovial fluids in 5 of 14 patients and there were some immune complexes in cartilage. So, the authors think that there are autoimmune reactions in the articular tissues in TMJDS because of the exposure of some sequestered antigens.

Recurrent parotitis in adults. Report of 35 cases.

Clinical, laboratory and sialographic findings were studied in 35 adult patients with recurrent parotitis. The patients were followed up for 0.5-23 years. The results showed that sialographic recovery occurred 3-5 years after disappearance of clinical symptoms. Recurrent parotitis is not a autoimmune disease, and remission may take place spontaneously, including clinical and sialographic healing. However, marked degeneration of the parotid gland or chronic obstructive parotitis may develop consequently. The differential diagnosis of recurrent parotitis in adults is also discussed.

[Histolgical and immunohistochemical study of malignant myoepithelioma of salivary glands]

Histological and immunohistochemical features of 12 cases of malignant myoepithelioma of the salivary glands were studied.There were 4 major histologic types in the tumor tissues:(1)clear tumor cells proliferated mainly with or without keratin peral;(2)spindle shaped tumor cells proliferated mainly with or without mucoid regions;(3)plasmacytoid(hyaline) tumor cells were arranged in adenoid configurations.In the immunohistochemical studies,the tumor cells were positive for actin;myosin;glial,fibrillary,acidic,protein.(GFAP);S-100 protein antibodies.The authors consider that the application of the above-mentioned antibodies may assist in the differentiated diagnosis of malignant myoepithlioma.

Sialographic changes related to clinical and pathologic findings in chronic obstructive parotitis.

This paper presents the results from a study of 23 patients with chronic obstructive parotitis (COP) in whom the sialographic changes were related to the clinical and histopathologic features. The sialographic changes were divided into four types. The stimulated parotid flow rate (SPFR) was normal in sialography Type I patients, while SPFR was significantly reduced in Types II, III, and IV patients, as compared with healthy persons. The changes observed by light microscopy were irregular dilation and chronic inflammation of main and branching ducts with saliva deposits in the enlarged luminal system. Ultrastructural changes included degeneration of ductal epithelial cells, marked proliferation of periductal fibrous tissue, and moderately electron-dense deposits in the lumen of the dilated peripheral ducts. The extent of the histopathologic changes largely paralleled the severity of the sialographic changes. These findings indicate that COP is a relatively common inflammatory disease and that the sialographic classification reflects the severity of the disease.

Chronic obstructive parotitis. Report of ninety-two cases.

Clinical, sialographic, and sequential quantitative scintigraphic characteristics of 92 cases of chronic obstructive parotitis (in 117 diseased parotid glands) are reported, and the treatment investigated. The cardinal feature of this disease is obstruction or retarded salivary flow resulting in recurrent swellings and retrograde infection. The main characteristic seen in sialograms is irregular dilation of the main and branching ducts. On the basis of sialographic findings, the ducts are classified into four types. This classification reflects the severity of the disease and can also be used as a guide to treatment.

[Clinical and pathological analysis of 31 cases of salivary gland basal cell adenoma].

The clinical and pathological features of basal cell adenoma were analysed. In 31 cases 12 occurred in men and 19 in women, a ratio of 1:1.58. The mean age of the patients was 48.5 years, with a range from 30 to 75 years, and the majority were 40-49 years of age. 27 cases occurred in parotid glands. The tumor was round or oval in shape. There were complete capsules in 28 cases. The tumor on section was solid in 20 cases and solid with cyst in 11 cases. There were three types under microscope. The reticular type-23 cases, the tubular type-3 cases, these two types were well differentiated. The massive type-5 cases, in which 2 cases had incomplete capsules and 1 case had no capsule, 3 cases had transformed to carcinoma in local region, this type was slightly poorly differentiated.

Radiographic, pathological and operative observations of cases with TMJ disturbance syndrome.

A group of 30 operative cases (32 sides) with TMJ disturbance syndrome was included in the present study. The authors carried out a comparative study between radiographic, pathological and operative observations for these cases. Based on this study, we are confident that the nature of the organic destructive stage of the TMJ disturbance syndrome is essentially a secondary degenerative arthrosis, and that those cases showing transient PDS are probably functional and reversible; however, the indolent and deferred cases with internal derangement of TMJ actually belong to earlier manifestations of degenerative arthrosis.