Synthesis and biological evaluation of 173-dicarboxylethyl-pyropheophorbide-a amide derivatives for photodynamic therapy.

Three novel 173-dicarboxylethyl-pyropheophorbide-a amide derivatives as photosensitizers for photodynamic therapy (PDT) were synthesized from pyropheophorbide-a (Ppa). Their photophysical and photochemical properties, intracellular localization, photocytotoxicity in vitro and in vivo were investigated. All target compounds exhibited low cytotoxicity in the dark and remarkable photocytotoxicity against human esophageal cancer cells. Among them, 1a showed highest singlet oxygen quantum yield. Upon light activation, 1a exhibited significant photocytotoxicity. After PDT treatment, the growth of Eca-109 tumor in nude mice was significantly inhibited. Therefore, 1a is a powerful and promising antitumor photosensitizer for PDT.

Synthesis and evaluation of new 5-aminolevulinic acid derivatives as prodrugs of protoporphyrin for photodynamic therapy.

Protoporphyrin IX (PpIX) is used as a photosensitizer in the photodynamic diagnosis (PDD) and photodynamic therapy (PDT) of cancer and is synthesized intracellularly from 5-aminolevulinic acid (5-ALA) precursors. Thirteen novel 5-ALA derivatives were designed and synthesized appropriately with tailored hydrophilicity and lipophilicity. The generation of PpIX was detected and their antitumor activity in vitro and in vivo was also investigated. It was shown that compounds 9b-c, 11b-c and 13a displayed a characteristic long wavelength absorption peak at 593 nm after 5 h incubation in mice fibrosarcoma S180 cells. After being exposed to 600 nm laser light irradiation, these compounds can inhibit cell proliferation in S180 cells in vitro. The growth of S180 cell tumors in Kunming mice was significantly inhibited by these compounds in vivo. Among these compounds, 13a has low dark toxicity and high phototoxicity, which makes it an effective and promising prodrug for PDT.

Over-expression of deubiquitinating enzyme USP14 in lung adenocarcinoma promotes proliferation through the accumulation of ß-catenin.

The deubiquitinating enzyme USP14 has been identified and biochemically studied, but its role in lung cancer remains to be elucidated. The aim of this study was to evaluate the prognostic significance of USP14 in patients with lung adenocarcinoma and to define its role in lung cancer cell proliferation. USP14 mRNA levels in different non-small cell lung cancer (NSCLC) cell lines were detected by real-time qPCR. USP14 protein levels in surgically resected samples from NSCLC patients, and in NSCLC cell lines, were detected by immunohistochemistry or Western blot. The correlation of USP14 expression with clinical characteristics and prognosis was determined by survival analysis. After silencing USP14, cell proliferation was assessed by MTT assay and the cell cycle was measured by FACS assay. It was found that USP14 expression was upregulated in NSCLC cells, especially in adenocarcinoma cells. Over-expression of USP14 was associated with shorter overall survival of patients. Downregulation of USP14 expression arrested the cell cycle, which may be related to ß-catenin degradation. Over-expression of USP14 was associated with poor prognosis in NSCLC patients and promoted tumor cell proliferation, which suggests that USP14 is a tumor-promoting factor and a promising therapeutic target for NSCLC.

Diagnosis and treatment of gastric hamartomatous inverted polyp (GHIP) by endoscopic submucosal dissection: A case report.

RATIONALE: Gastric hamartomatous inverted polyps (GHIP) is not a common disease, and it has rarely been reported in the literature. Preoperative diagnosis is difficult due to the deep position and surface covered with normal gastric mucosa. However, with the progress of endoscopic technology, endoscopic submucosal dissection (ESD) can play a crucial role in the diagnosis and treatment of GHIP. PATIENT CONCERNS: A 61-year-old Chinese man underwent gastroscopy due to abdominal pain 2 months prior that revealed chronic superficial nonatrophic gastritis with erosion and a submucosal tumor in the gastric body (an ultrasound gastroscopy was recommended). Therefore, he was admitted to our hospital for further diagnosis and treatment. DIAGNOSES: A hemispherical submucosal tumor was found in the middle segment of the stomach, with a size of approximately 30 mm × 35 mm and a smooth surface without central ulceration or mucosal bridge formation. Ultrasound gastroscopy showed that the lesion was a hypoechoic mass with uniform internal echo originating from the muscularis propria. INTERVENTIONS: The tumor was completely removed by using ESD. The postoperative pathological results indicated a monocystic structure in the submucosa that was not connected with the surface mucosa. The surface of the cyst was covered with foveolar cells and mucous-neck cells (part of which had low-grade intraepithelial neoplasia), and GHIP was considered to be diagnosed. OUTCOMES: According to the abovementioned endoscopic and pathological features, the patient was finally diagnosed with GHIP. The patient was successfully discharged after surgery and received regular follow-up observations. LESSONS: GHIP is located in the submucosa layer and has the potential risk of malignant transformation. However, it is not easy to diagnose by using gastroscopy and ultrasound gastroscopy. ESD can obtain complete specimens, which contributes to the diagnosis and treatment of GHIP.

[Splenic sarcoidosis: a case report and review of literature].

OBJECTIVE: To describe the clinical features and imaging characteristics of nodular splenic sarcoidosis. METHODS: We describe a patient with splenic sarcoidosis and review the related medical literature, the etiology, symptomatology, pathology, diagnosis, differential diagnosis, management and prognosis of splenic sarcoidosis. RESULTS: The etiology of this rare disease remains unknown. Symptoms are scanty and usually mild; computed tomography usually reveals splenomegaly or the presence of multiple nodules, confusing with metastatic tumor in spleen. On histopathologic examination, sarcoid produces noncaseating granulomas. Sarcoid is typically treated only when symptomatic. Oral corticosteroids is the most important method of treatment in patients with progressive loss of organ functions. Prognosis has closed relationship with early clinical manifestation. CONCLUSION: Splenic sarcoidosis is rare and often misdiagnosis as other diseases.

[Identification and bronchoscopic management of broncholithiasis].

OBJECTIVE: To report the diagnostic experience for broncholithiasis, and to evaluate the value of flexible bronchoscopic management for the disease. METHODS: The clinical data, radiological features, bronchoscopy findings, the effect and complications of bronchoscopic management in 31 patients with broncholithiasis admitted to changhai hospital of second military medical university and zhejiang Taizhou Hospital between 2000 and 2007 were retrospectively reviewed. RESULTS: There were 19 men and 12 women, the mean age was 58.6 +/- 12.6. There were 26 cases missed diagnosis, and 19 cases were misdiagnosis. The diagnosis was confirmed by chest CT combined with bronchoscopy in all the patients. Thirty-six broncholiths were revealed, of which 26 were intraluminal, 9 eroding in the bronchial wall, and 1 peribronchial. In 26 patients, 31 broncholiths were managed by flexible bronchoscope, and 25 broncholiths were successfully removed. The success rate for intraluminal free broncholiths was higher (23/25). One patient experienced hemoptysis of 300 ml after therapy, but no significant complications occurred in other patients. CONCLUSIONS: The diagnosis of broncholithiasis can be easily missed or misdiagnosed. Chest CT combined with bronchoscopy were useful methods for the diagnosis of the disease. Extraction of broncholiths with flexible bronchoscope is a safe and effective management, especially for intraluminal broncholiths.

A case report of tongue metastasis from lung squamous cell carcinoma and literature review.

RATIONALE: Tongue metastasis from lung cancer is extremely rare, and the prognosis of these patients is rather poor. PATIENT CONCERS: A 56-year-old man was found a 4-cm cavity lesion in the left upper lobe, which was initially misdiagnosed as tuberculosis. DIAGNOSES: A case of lung squamous cell carcinoma that metastasized to the base of a patient's tongue. INTERVATIONS: We send the biopsy of the lung and the tongue lesions for gene sequencing. OUTCOMES: He received systemic chemotherapy, but continued to have pain at the base of his tongue and died 7 months later. LESSONS: From sequencing data, mutations in KRAS proto-oncogene, GTPase (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and tumor protein p53 (TP53) were found in the tumor biopsy of the patient. All of these were indicators of poor prognosis.

Notch1/3 and p53/p21 are a potential therapeutic target for APS-induced apoptosis in non-small cell lung carcinoma cell lines.

OBJECTIVE: Previous studies have shown that Astragalus polysaccharide (APS) can be applied to anti-cancer. However, the mechanism by which APS mediate this effect is unclear. In the present study, APS-mediated NSCLC cell apoptosis was investigated through the regulation of the notch signaling pathway. METHODS: The cell viability was detected by the CCK8 assay. The mRNA and protein expression of notch1/3 and tumor suppressors were analyzed by RT-PCR and western blotting, respectively. RESULTS: The mRNA and protein of notch1 and notch3 were significantly up-regulated in tumor tissues as compared to non-tumor adjacent tissues. Treatment of human NSCLC cells with APS induced cell death in a dose-and time-dependent manner by using CCK8 assay. The mRNA and protein expression of notch1 and notch3 were significantly lower in NSCLC cells with APS treatment than that in control group. Moreover, western blotting analysis showed that treatment of H460 cells with APS significantly increased the pro-apoptotic Bax and caspase 8 levels, decreased the anti-apoptotic Bcl-2 level. Furthermore, p53, p21 and p16 were obviously up-regulated by APS treatment in H460 cell. CONCLUSIONS: This study demonstrated that APS-treated could inhibit proliferation and promote cell apoptosis, at least partially, through suppressing the expression of notch1 and notch3 and up-regulating the expression of tumor suppressors in H460 NSCLC cell lines.

[Effects on chemotactic factor expression in bronchial epithelial cells by co-stimulation of poly(I:C) and lipopolysaccharide and the underlying mechanism].

AIM: To investigate the effect of co-stimulation of mimic viral infection [polyinosinic: polycytidylic acid, poly(I:C)] and endotoxin (lipopolysaccharide, LPS) on chemotactic factors production of human bronchial epithelial cells and explore its related mechanism. METHODS: Human bronchial epithelial cells (16HBE) were challenged by co-stimulation of different concentrations of poly(I:C) and LPS. Some other 16HBE cells, before the co-stimulation of poly(I:C) and LPS, were pretreated with dexamethasone and p38MAPK specific inhibitor (SB203580), respectively. The levels of IL-8/CXCL8 and IP-10/CXCL1 mRNA transcription were detected by RT-PCR after 6 h challenge. The contents of IL-8 and IP-10 proteins were detected by ELISA after 24 h challenge. RESULTS: (1) The mRNA and protein expression of IL-8, not IP-10, increased under 10 µg/mL LPS stimulation compared with control group. The mRNA and protein expressions of both IL-8 and IP-10 were elevated significantly by the co-stimulation of LPS and 0.1 µg/mL poly (I:C) compared with control group and simple LPS groups. (2) The mRNA and protein expressions of IL-8 and IP-10 increased under the challenge of different concentrations of poly(I:C) (0.001, 0.01, 0.1 µg/mL) in a concentration-dependent manner, which showed no change after adding 10 µg/mL LPS. (3) Dexamethasone (1 µmol/L) and SB203580 (20 µmol/L) significantly decreased both the mRNA and protein production of IL-8 and IP-10 induced by co-stimulation of 0.1 µg/mL poly (I:C) and 10 µg/mL LPS compared with the control group and control+DMSO group respectively (P<0.01 and P<0.05). Inhibitive effect of dexamethasone was stronger than that of p38MAPK inhibitor. CONCLUSIONS: The co-stimulation of poly(I:C) and LPS can induce chemokine expression of airway epithelial cells. Poly(I:C) enhances the IL-8 expression induced by single LPS challenge, which suggests that viral infection could enhance the inflammation resulted from bacterial colonization in airway. Glucocorticoid has the greater effect on the inhibition of chemotactic factors production than p38MAPK inhibitor. These two drugs have a potential therapeutic effect on AECOPD caused by viral infection.

Recurrence of sarcoidosis: the follow-up of splenic involvement.

We report the case of a 53-year-old woman who initially presented with an intermittent dry cough that had lasted for 6 months. An investigation into these symptoms with thoracic computed tomography demonstrated hyperdense shadows in her lungs, and ultrasonography showed the presence of multiple hypoechoic nodules on her spleen. A lung biopsy was then performed, which revealed noncaseating epithelioid cell granulomas. Magnetic resonance imagining of her spleen was performed, which showed low signal intensity. The patient was treated with glucocorticoids, and 3 months later the lesions in her lungs had disappeared completely. Five months later, the lesions in her spleen had disappeared also. However, after 13 months of low-dose prednisone, a miliary pattern was observed on the patient's chest x-ray, although no lesions were observed in her spleen. Laboratory tests demonstrated that her blood level of angiotensin-converting enzyme had increased to 96 IU/L. The dose of prednisone was then increased, and the lung images returned to normal after 2 months of therapy.

Removal of tracheobronchial foreign bodies in adults using a flexible bronchoscope: experience with 200 cases in China.

OBJECTIVE: Tracheobronchial foreign bodies (FBs) are frequently present in adults. This study reports our experience with the managements of FB and FB-related complications using flexible bronchoscopy. METHODS: We retrospectively reviewed the adult patients with FBs treated between 2001 and 2011 in China. The demographic and endoscopic data were collected and analyzed. RESULTS: A total of 200 adult patients (136 men and 64 women) with an average age of 51 years were analyzed. The most common FBs included bones (51.0%), nut shells (15.0%), food boluses (7.0%), plastic toys or pen caps (6.5%). After FB aspiration occurred, only 11.0% were diagnosed within three days, while more than half of the patients (58.0%) delayed the diagnosis by more than one month. The incidence of FB-related complications was 79.5%, including granulation formation (76.5%), obstructive pneumonia (22.0%), hemorrhage (14.5%), atelectasis (10.0%) and endobronchial stenotic scarring (8.0%). In 96.5% of the patients, the FBs were successfully removed under flexible bronchoscopy. A total of 53 out of the 153 patients with granulation (34.6%) were managed by argon plasma coagulation (APC) or cryotherapy; two out of the sixteen patients with endobronchial stenotic scars were treated by balloon dilation under flexible bronchoscopy. CONCLUSION: A high incidence of FB-related complications occurs, likely as a result of the long delay between aspiration and diagnosis, a proportion of which require endoscopic intervention. The removal of FBs under flexible bronchoscopy has a high success rate and therefore should be recommended for adults.

Bronchoscopy in some tertiary grade A hospitals in China: two years' development.

BACKGROUND: Although bronchoscopy has been widely performed in China, little has been known about its current state and development. In order to investigate the clinical application of bronchoscopy and make instructions for future education and development, the Chinese Society of Respiratory Diseases conducted postal surveys in both 2008 and 2010 in China. METHOD: Questionnaires were sent to 40 tertiary grade A hospitals in 2008 and 58 tertiary grade A hospitals in 2010 to investigate bronchoscopies performed in 2007 and 2009 respectively. RESULTS: Thirty (75%) hospitals returned the completed questionnaires in 2008 and forty-one (71%) hospitals in 2010. All the respondents possessed flexible bronchoscopes. Fifty percent of the respondents had less than five in 2007, while more than 50% of the respondents had 5-9 bronchoscopes in 2009. All the respondents performed a radiograph or CT scan before bronchoscopy. Percentage of general anesthesia and no pre-medication before bronchoscopy increased, while atropine usage decreased in 2009 compared to 2007. During bronchoscopy, pulse oximetry was the most widely used monitoring method. Most respondents used the nasal route to perform routine bronchoscopy. After the procedure, they used sinks to wash and glutaraldehyde to disinfect the bronchoscopes. The total number of flexible bronchoscopies performed during 2007 was 37 874 and the average was 1262. Whereas in 2009, the total number was 60 178 and the average was 1468. Diagnostic bronchoscopy was more widely used than therapeutic bronchoscopy. The mortality rate was 0.076‰ in 2007 and 0.032‰ in 2009. CONCLUSIONS: The two surveys, to some extent, reflected the current status and development of bronchoscopy in China. The results are worthy of future education and developing of new guidelines. Regular surveys and monitoring of bronchoscopies across China are needed.

Value of napsin A and thyroid transcription factor-1 in the identification of primary lung adenocarcinoma.

Napsin A is a newly discovered functional aspartic proteinase that is expressed in normal lung parenchyma in type II pneumocytes and is thought to be associated with primary lung adenocarcinoma. Thyroid transcription factor-1 (TTF-1) is a widely used relatively restricted marker for lung adenocarcinoma. The present study aimed to compare the usefulness of napsin A with TTF-1 for the identification of primary lung adenocarcinoma. Immunohistochemical expression of napsin A and TTF-1 was analyzed in 351 lung cancer tissues, including 27 metastases. Napsin A was expressed in 180 of 212 (84.9%) primary lung adenocarcinomas, while no expression was noted in all 27 metastatic lung cancer specimens, including 19 metastatic adenocarcinomas. In contrast, TTF-1 expression was not only noted in 179 of 212 (84.4%) primary lung adenocarcinomas, but also in 12 of 18 (66.7%) small-cell carcinomas and some of the squamous carcinomas, as well as in one metastatic adenocarcinoma from the thyroid. The sensitivity and specificity of napsin A for primary lung adenocarcinoma (84.9 and 93.8%, respectively) were higher than the sensitivity and specificity of TTF-1 (84.4 and 83.9%, respectively). By combining napsin A and TTF-1, sensitivity increased to 91.0%. Furthermore, the sensitivity and specificity expression was associated with gender, smoking history, performance status, pathological type, primary tumor size and nodal metastasis. Therefore, napsin A is a useful novel marker in the differential diagnosis of primary lung adenocarcinoma.