Potential of Targeting TDO2 as the Lung Adenocarcinoma Treatment.

Tryptophan catabolism plays an important role in the metabolic reconnection in cancer cells to support special demands of tumor initiation and progression. The catabolic product of the tryptophan pathway, kynurenine, has the capability of suppressing the immune reactions of tumor cells. In this study, we conducted internal and external cohort studies to reveal the importance of tryptophan 2,3-dioxygenase (TDO) for lung adenocarcinoma (LUAD). Our study further demonstrated that the TDO2 expression was associated with the proliferation, survival, and invasion of LUAD cells, and targeting TDO2 for LUAD tumors could be a potential therapeutic strategy.

Needlescopic Video-Assisted Thoracic Bilateral T4 Sympathicotomy for the Treatment of Primary Palmar Hyperhidrosis: An Analysis of 200 Cases.

BACKGROUND: Primary palmar hyperhidrosis (PPH) is featured by aberrantly perspiration of the hands, which may bring a lot of inconvenience to patient's daily life and work. The purpose of this study is to summarize the clinical effect of needlescopic video-assisted thoracic bilateral T4 sympathicotomy for the treatment of PPH. PATIENTS AND METHODS: Between January 2009 and March 2014, 200 patients received needlescopic video-assisted thoracic bilateral T4 sympathicotomy. We, respectively, took two 5-mm incisions in the third intercostal space on the anterior axillary line and in the fifth intercostal space on the middle axillary line. After collapsing left lung, needlescopic exploration was the first step to determine the targeted sympathetic chain through the third intercostal space. Electric coagulation hook was inserted from another port to cut T4 sympathetic chain and the bypassing nerve fibers for 2 to 3 cm along the surface of the fourth rib. Right thoracic cavity was also administered the same procedure. The palmar temperature was recorded before and after sympathicotomy. The symptom improvement, operative complications, patients' recovery, and satisfaction were evaluated. FINDING: One hundred and ninety-seven patients uneventfully received two 5-mm port bilateral sympathicotomy, and another 3 patients with extensive pleural adhesions completed the surgery through enlarging the third intercostal incision to 2 cm without conversion to open surgery. All operative procedures were completed in 15 to 35 minutes. The hospital stay was 2 to 4 days. The palmar temperature increased by 2.0 ± 0.5°C, and hyperhidrosis immediately disappeared in both hands after surgery. The efficacy rate was 100%. The postoperative complications such as hemorrhage, hemopneumothorax, bradycardia, or Horner's syndrome had no occurrence. During 6 to 60 months follow-up, mild compensatory sweating of buttock, back, and thigh occurred in 30 patients (15%) at 2 to 5 days after surgery and gradually disappeared at postoperative 15 to 30 days or longer time. All patients were greatly satisfied with the effect with better confidence and quality of life. Until now, no recurrent palmar hyperhidrosis happened. CONCLUSION: Needlescopic video-assisted thoracic bilateral T4 sympathicotomy could reach an excellent and immediate result of treating PPH. It is a safe, convenient, and minimally invasive method appropriate for wide clinical use.

Locally advanced rectal cancer: predicting non-responders to neoadjuvant chemoradiotherapy using apparent diffusion coefficient textures.

PURPOSE: The purpose of the study is to evaluate whether apparent diffusion coefficient (ADC) textures could identify patient with locally advanced rectal cancer (LARC) who would not respond to neoadjuvant chemoradiotherapy (NCRT). METHOD: Twenty-six patients who underwent MRI including diffusion-weighted imaging at a 3.0 T system before NCRT were enrolled. Texture analysis of pre-therapy ADC mapping was carried out, and a total of 133 ADC textures as well as routine mean ADC value of the primary tumor were extracted for each patient. Texture parameters and mean ADC were compared between responsive group and non-responsive group. Logistic regression was used to determine the independent predictors for non-responders. Receiver operating characteristic curve (ROC) was performed to evaluate the predictive performance of the significant parameters. RESULTS: Eighteen of the 133 texture parameters significantly differed between responsive and non-responsive groups (p < 0.05). Further, energy variance and SdGa47 were identified as independent predictors for non-responders to NCRT; this logistic model achieved an area under the curve (AUC) of 0.908. CONCLUSION: Texture analysis based on pre-therapy ADC mapping could potentially be helpful to identify patients with LARC who would not respond to NCRT.

Capilliposide from Lysimachia capillipes inhibits AKT activation and restores gefitinib sensitivity in human non-small cell lung cancer cells with acquired gefitinib resistance.

Most gefitinib-treated patients with non-small cell lung cancer (NSCLC) would eventually develop resistance. Lysimachia capillipes (LC) capilliposide extracts from LC Hemsl. show both in vitro and in vivo anti-cancer effects. In this study we investigated whether LC capilliposide in combination with gefitinib could overcome the resistance of NSCLC cells to gefitinib and identified the signaling pathways involved. Treatment with LC capilliposide alone inhibited the growth of a panel of NSCLC cell lines (PC-9, H460, H1975, H1299 and PC-9-GR) sensitive or resistant to gefitinib with IC50 values in the range of µg/mL. In the gefitinib-resistant PC-9-GR cells (which have a T790M EGFR mutation), LC capilliposide (at the IC30, i.e.1.2 µg/mL) markedly enhanced the inhibitory effects of gefitinib with its IC50 value being decreased from 6.80±1.00 to 0.77±0.12 µmol/L. By using the median effect analysis we showed that combination treatment of LC capilliposide and gefitinib could restore gefitinib sensitivity in PC-9-GR cells. Furthermore, LC capilliposide (1.2 µg/mL) significantly increased the apoptotic responses to gefitinib (0.77 µmol/L) in PC-9-GR cells, but did not affect gefitinib-induced G0/G1 arrest. Moreover, LC capilliposide (1.2 µg/mL) in combination with gefitinib (0.77, 1.0 µmol/L) markedly decreased the phosphorylation of the EGFR downstream signaling molecule AKT, which neither LC capilliposide nor gefitinib alone affected. In PC-9-GR cells with siRNA knockdown of AKT, addition of LC capilliposide was unable to increase gefitinib sensitivity. In a PC-9-GR xenograft mouse model, combination treatment with LC capilliposide (15 mg·kg-1·d-1, ip) and gefitinib (50 mg·kg-1·d-1, ip) dramatically enhanced tumor growth suppression (with a TGI of 109.3%), compared with TGIs of 22.6% and 56.6%, respectively, in mice were treated with LC capilliposide or gefitinib alone. LC capilliposide can restore the cells' sensitivity to gefitinib through modulation of pAKT levels, suggesting that a combination of LC capilliposide and gefitinib may be a promising therapeutic strategy to overcome gefitinib resistance in NSCLCs with a T790M mutation.

Identification of miRNAs as non-invasive biomarkers for early diagnosis of lung cancers.

Current clinical diagnostic methods lack the specificity in detecting lung cancer patients. The issue is particularly critical for stage I and II patients. Considerable evidence showed microRNA plays a very important role in lung carcinogenesis. Here, we identified a panel of 41 miRNAs significantly elevated in patients with lung cancer, of which eight miRNAs were further validated in an independent sample cohort. Classification analysis using the panel of eight miRNAs generated a discriminatory power of 93.3 % sensitivity and 93.8 % specificity in separating non-small-cell lung cancer (NSCLC) patients from normal controls, indicating the miRNAs have a potential clinical utility in discriminating NSCLC. Interestingly, miR-1244 was found significantly elevated in the serum samples of lung cancer patients, and the test characteristics of the single miRNA were area under the curve (AUC) of 0.832 in NSCLC vs healthy controls, and 0.861 in NSCLC vs patients with unidentified pulmonary nodules. This is the first study showing serum miR-1244 could be a biomarker to screen lung cancer patients from the high-risk population.

Endometrial carcinoma with cervical stromal invasion: Three case reports.

BACKGROUND: Endometrial cancer is a kind of well-known tumors of female genitourinary system. Cervical stromal invasion is an adverse factor for poor prognosis of endometrial cancer. There is still controversy regarding the use of magnetic resonance imaging (MRI) in the diagnosis of cervical stromal invasion of endometrial cancer. The diagnosis of cervical stromal invasion varies significantly between different observers and institutions. We present a limited case series of the particular pattern of endometrial cancer, which infiltrates the cervical stroma and is often overlooked. CASE SUMMARY: We present three cases of endometrial carcinoma with cervical stromal invasion with cancer-free uterine cavity. One patient, a reproductive-aged woman, exhibited irregular menstruation and was diagnosed with endometrial polyps by hysteroscopy and segmental curettage. A MRI scan revealed polypoid nodules within the internal cervical orifice. The other two cases were postmenopausal women who presented with abnormal vaginal bleeding. Hysteroscopy and segmental curettage suggested atypical hyperplasia of the endometrium. MRI scans did not detect any malignant signs in the endometrium. In one case, a non-thickened endometrium was observed, while in another, hyperplasia of the endometrium was seen. Notably, none of these patients had malignant tumors identified in the uterine cavity via MRI scans. However, postoperative pathological results following hysterectomy consistently indicated cervical stromal invasion. CONCLUSION: Cervical stromal invasion is easily missed if no cancer is found in the uterine body on MRI. Immunohistochemistry of endoscopic curettage specimens should be conducted to avoid underestimation of the disease.

Long-term survival of stage Ib lung adenocarcinoma with postoperative brain oligometastasis: a case report and literature review.

Lung adenocarcinoma remains one of the most frequent and deadly tumour entities. Early-stage lung adenocarcinoma is extremely difficult to detect and is also easy to recur or metastasize after treatment. Since the new adenocarcinoma classification was presented in 2011, several studies have shown that patients with solid and/or micropapillary (S/MP) predominant patterns showed a worse prognosis. Here we report the case of a 54-year-old woman who was diagnosed with stage Ib lung adenocarcinoma with S/MP components and developed an isolated brain oligometastasis after resection and adjuvant therapy. A craniocerebral operation was performed, combined with radiotherapy and targeted therapy, and the patient eventually achieved a good quality of life. Our work reviews the clinical features of lung cancer complicated with S/MP components, the relationship between MP and epidermal growth factor receptor (EGFR) mutation, as well as treatment strategies for such a patient with postoperative brain oligometastasis of lung adenocarcinoma complicated with EGFR Exon19del mutation.

Imaging Features and Risk Factors of Pancreatic Cystic Lesions Complicating Autoimmune Pancreatitis: A Retrospective Study.

OBJECTIVE: This study aimed to explore the imaging features and risk factors of PCLs complicating AIP, and investigate its prognosis through continuous imaging follow-up. PATIENTS AND METHODS: Patients who were diagnosed with AIP from January 2014 to December 2020 in our hospital were recruited. We analyzed the CT and MRI features of PCLs complicating AIP, and investigated its prognosis through imaging follow-up. We also compared subjects with and without PCLs using clinical, laboratory, and imaging data; the related risk factors associated with PCLs were investigated in a multivariate logistic regression analysis. RESULTS: In this group, 16 patients had PCLs and 86 did not. A total of 43 PCLs larger than 5mm were found in 15 patients. Among these PCLs, 35 showed homogeneous signal (density); one, bleeding; three, linear separation; and four, small focal low signal on T2WI. Eight patients with 23 PCLs appeared for the follow-up after steroid treatment. Short-term follow-up showed that 11 PCLs disappeared, nine reduced, one unchanged and two enlarged. Of the 12 PCLs that did not disappear, 10 PCLs disappeared at long-term follow-up, except for two reduced PCLs were not re-examined. Logistic regression analysis showed that drinking history was an independent risk factor, age ≥ 65 years was an independent protective factor for PCLs complicating AIP. CONCLUSION: The imaging features of PCLs complicating AIP are various, which can be single or multiple, most of them are homogeneous, and some lesions may be accompanied by hemorrhage, separation and necrosis. Age ≥ 65 years and avoiding drinking may help to reduce the occurrence of these lesions.

Traditional Chinese Manual Therapy (Tuina) reshape the function of default mode network in patients with lumbar disc herniation.

Purpose: Investigating the changes of regional homogeneity (ReHo) values and both static and dynamic functional connectivity (FC) before and after Traditional Chinese Manual Therapy (Tuina) in patients with lumbar disk herniation (LDH) through resting-state functional magnetic resonance imaging (RS-fMRI). Based on this, we observe the effect of Tuina on the above abnormal changes. Methods: Patients with LDH (n = 27) and healthy controls (HCs) (n = 28) were recruited. The functional magnetic resonance imaging (fMRI) scanning was performed two times in LDH patients, before Tuina (time point 1, LDH-pre) and after the sixth Tuina (time point 2, LDH-pos). And for one time in HCs which received no intervention. The ReHo values were compared between LDH-pre and HCs. The significant clusters detected by ReHo analysis were selected as seeds to calculate static functional connectivity (sFC). We also applied the sliding-window to perform dynamic functional connectivity (dFC). To evaluate the Tuina effect, the mean ReHo and FC values (both static and dynamic) were extracted from significant clusters and compared between LDH and HCs. Results: In comparison to HCs, LDH patients displayed decreased ReHo in the left orbital part middle frontal gyrus (LO-MFG). For sFC analysis, no significant difference was found. However, we found decreased dFC variance between LO-MFG and the left Fusiform, and increased dFC variance in the left orbital inferior frontal gyrus and left precuneus. Both ReHo and dFC values revealed after Tuina, the brain activities in LDH patients were similar to HCs. Conclusion: The present study characterized the altered patterns of regional homogeneity in spontaneous brain activity and those of functional connectivity in patients with LDH. Tuina can reshape the function of the default mode network (DMN) in LDH patients, which may contribute to the analgesic effect of Tuina in LDH patients.

Spontaneous remission of autoimmune pancreatitis: Four case reports.

BACKGROUND: Autoimmune pancreatitis (AIP) is a particular type of chronic pancreatitis, and steroid treatment of AIP is effective. Spontaneous remission (SR) of AIP without steroids is relatively rare. The international consensus for the treatment of autoimmune pancreatitis suggests that patients with AIP with obstructive jaundice, abdominal pain, and back pain related to the pancreas or the bile duct should be treated with steroids; most asymptomatic patients with AIP may improve without steroids. However, in our clinical work, we found that the clinical characteristics of AIP patients with SR vary. Four of these cases are described here. In addition, to our knowledge, there is no previously published report of dynamic imaging before and after SR of AIP at present. CASE SUMMARY: We present the cases of four patients with AIP (two females and two males) in which the AIP improved spontaneously without steroid treatment. Two patients were asymptomatic, one patient had abdominal pain with obstructive jaundice, and one patient had intermittent right upper abdominal pain. Three patients presented with localized pancreatic enlargement and one with diffuse pancreatic enlargement. In addition to the pancreatic lesions, bile duct involvement was seen in two patients, and no extra-pancreatic organ involvement was found in the other two patients. The serum IgG4 level of all patients was more than twice the normal level. After SR in the four patients, the affected pancreases exhibited three types of image features: Return to normal, progressive fibrosis, and atrophy and calcification. CONCLUSION: The clinical features of SR in our four patients with AIP differ, but the imaging findings share some characteristics. After SR, in some cases the affected pancreas could return to normal, although some patients suffer from progressive fibrosis and atrophy as well as calcification.

Blood exosome PD-L1 is associated with PD-L1 expression measured by immunohistochemistry, and lymph node metastasis in lung cancer.

BACKGROUND: Previous observations illustrated that programmed cell death ligand 1 in exosomes (Exo-PD-L1) may lead to immunosuppression. This study proposed to investigate the significance of Exo-PD-L1 and the results of PD-L1 immunohistochemistry (IHC) assay in the clinical diagnosis and treatment of lung cancer. METHODS: 29 lung cancer patients were enrolled. Exosomes were extracted from the blood of patients and purified, and the extracts were identified by Western blot and transmission electron microscope. Next, the levels of Exo-PD-L1 and PD-L1 in tumor tissue were evaluated by enzyme-linked immunosorbent assay (ELISA) and IHC, respectively. The correlation between Exo-PD-L1, IHC PD-L1 status and pathological features of patients was analyzed by applying Chi-square test. After immune checkpoint inhibitor (ICI) treatment, the objective response rate (ORR) was calculated, and drug response prediction in lung cancer patients by using Exo-PD-L1 alone, IHC PD-L1 alone, and their combined detection were analyzed. RESULTS: This study confirmed that lung cancer patients had much expression of PD-L1 in blood exosomes and that Exo-PD-L1 level was associated with IHC PD-L1 status. The expression level of Exo-PD-L1 was evidently related to the positive lymph node metastasis of lung cancer patients, while IHC PD-L1 status was not correlated with clinicopathological features of patients. Moreover, Exo-PD-L1 and IHC PD-L1 alone or their combined detection could be utilized to predict the efficacy of ICI therapy in lung cancer patients. CONCLUSION: The correlation between Exo-PD-L1 and IHC PD-L1 status was indicated, and Exo-PD-L1 could assist in determining the suitable lung cancer patients suitable for ICI therapy using IHC PD-L1. This study provides references for the application of Exo-PD-L1 as an effective predictor of ICI therapy.

Fucoidan Regulates Starch Digestion: In Vitro and Mechanistic Study.

Bread is a high glycemic index (GI) food with high amounts of readily digestible carbohydrates. Fucoidan refers to a group of sulfated polysaccharides isolated from brown seaweed that has been gaining traction for its many functional properties, including its ability to inhibit starch hydrolases. In this study, fucoidan was added into bread to lower the glycemic index of bread. Fucoidan fortification at 3.0% reduced the starch digestion rate of baked bread by 21.5% as compared to control baked bread. This translated to a 17.7% reduction in the predicted GI (pGI) with 3.0% of fucoidan. Fucoidan was retained in the bread after baking. Although the in vitro bioavailability of fucoidan was negligible, the in vitro bioaccessibility of fucoidan was high, at 77.1-79.8%. This suggested that although fucoidan may not be absorbed via passive diffusion, there is potential for the fucoidan to be absorbed via other modes of absorption. Thus, there is a potential for the use of fucoidan as a functional ingredient in bread to reduce the glycemic potential of bread.

AMPK/Sirt1-mediated inflammation is positively correlated with myocardial fibrosis during ageing.

OBJECTIVES: Cardiovascular disease is the leading cause of death in the world, and it increases dramatically with ageing. The objective of this study was to elucidate age-dependent molecular changes of inflammation and its correlation with the progression of myocardial fibrosis. METHODS: Methods: Male SD rats aged 3, 6, 9 and 24 months were used in this study. H&E staining was used to assessed histo-morphological changes in different ages. Masson's trichrome staining was used to evaluate myocardial fibrosis. Immunofluorescence as well as western blot was carried out to detect the expression of vimentin. Real-time PCR was used to detect the level of pro-inflammatory chemokines MCP-1, IL1ß, TNFα and IL-6. Western blotting was also carried out to detect p-AMPK, Sirt1, AC-NF-κB expression. RESULTS: Myocardial pathological changes and fibrosis are positively correlated with age. Ageing rats showed an enhanced expression of inflammatory factors and the activation of cardiac fibroblasts increases. Meanwhile, the expression of p-AMPK, Sirt1 and downstream AC-NF-κB increased significantly during ageing. Furthermore, the 15-24 months of age in rats is the fastest changing stage of increased inflammation and decreased Sirt1 activity. CONCLUSIONS: Ageing is an independent risk factor for the occurrence and development of myocardial fibrosis. During ageing, myocardial fibroblasts are activated, accompanied by an increase in extracellular matrix deposition. The inflammation mediated by AMPK/Sirt1/NF-κB signalling pathway is closely positively correlated with the activation of myocardial fibroblasts and the progression of myocardial fibrosis.

A spinal manipulative therapy altered brain activity in patients with lumbar disc herniation: A resting-state functional magnetic resonance imaging study.

Purpose: Lumbar disc herniation (LDH) is one of the leading causes of low-back pain and results in a series of clinical symptoms, including pain, reflex loss, and muscle weakness. Spinal manipulative therapy (SMT) can relieve pain and promote internal and external stabilization of the lumbar spine. In this study, we investigated whether the brain alterations of LDH patients with SMT were frequency-dependent based on the calculation of Amplitude of Low-Frequency Fluctuations (ALFF) and fractional ALFF (fALFF). Further, we established a cohort of LDH patients to evaluate the contribution of SMT treatments to brain functional reorganization. Methods: A total of 55 participants, including 27 LDH patients and 28 health controls (HCs), were collected. All LDH patients underwent two fMRI scans (before SMT and after the sixth SMT session). To represent LDH-related brain oscillatory activities, we calculated the ALFF and fALFF in the conventional band (0.01-0.08 Hz), the slow-4 band (0.027-0.073 Hz), and the slow-5 band (0.01-0.027 Hz). Moreover, we extracted ALFF and fALFF values in clusters with significant differences to evaluate the SMT effect. Results: Compared with HCs, the LDH patients before SMT (LDH-pre) exhibited increased fALFF in right lingual gyri in the conventional band, and showed increased fALFF in left Cerebelum_Crus1 in the slow-4 band. We further examined the abnormal brain activities changes before and after the SMT intervention. The ALFF and fALFF values of LDH-pre group were higher than those of the HCs and LDH-pos groups. After SMT, the increased ALFF and fALFF values were suppressed for patients in conventional band and slow-4 band. Conclusion: The present study characterized the altered regional patterns in spontaneous neural activity in patients with LDH. Meanwhile, SMT is an effective treatment of LDH, and we supposed that it might have been involved in modulating dysfunctional brain regions which are important for the processing of pain. The findings of the current study may provide new insights to understand pathological mechanism of LDH.

Optimisation of the Conversion and Extraction of Arctigenin From Fructus arctii Into Arctiin Using Fungi.

Fructus arctii is commonly used in Chinese medicine, and arctiin and arctigenin are its main active ingredients. Arctiin has low bioavailability in the human body and needs to be converted into arctigenin by intestinal microbes before it can be absorbed into the blood. Arctigenin has antiviral, anti-inflammatory, and anti-tumour effects and its development has important value. In this study, we used external microbial fermentation with Aspergillus awamori and Trichoderma reesei to process and convert arctiin from F. arctii powder into arctigenin, hence increasing its bioavailability. We developed a fermentation process by optimising the carbon and nitrogen source/ratio, fermentation time, pH, liquid volume, inoculation volume, and substrate solid-liquid ratio. This allowed for an arctiin conversion rate of 99.84%, and the dissolution rate of the final product was 95.74%, with a loss rate as low as 4.26%. After the fermentation of F. arctii powder, the average yield of arctigenin is 19.51 mg/g. Crude fermented F. arctii extract was purified by silica gel column chromatography, and we observed an arctigenin purity of 99.33%. Our technique effectively converts arctiin and extracts arctigenin from F. arctii and provides a solid basis for further development and industrialisation.

Identification and pharmacokinetics of saponins in Rhizoma Anemarrhenae after oral administration to rats by HPLC-Q-TOF/MS and HPLC-MS/MS.

Rhizoma Anemarrhenae is a well-known herbal medicine with saponins as its commonly regarded major bioactive components. It is essential to classify the properties of saponins which are associated with their toxicity and efficacy. In this study, 25 compounds were identified by HPLC-Q-TOF/MS in the extract of Rhizoma Anemarrhenae and 8 saponins were detected in rat plasma by HPLC-MS/MS after oral administration of this extract. These were neomangiferin, mangiferin, timosaponin E1, timosaponin E, timosaponin B-II, timosaponin B-III, timosaponin A-III and timosaponin A-I. A sensitive and accurate HPLC-MS/MS method was developed and successfully applied to a pharmacokinetic study of the abovementioned eight saponins after oral administration of the Rhizoma Anemarrhenae extract to rats. The method validation, including specificity, linearity, precision, accuracy, recovery, matrix effect and robustness, met the requirements of the intended use. The pharmacokinetic parameter, T max value, ranged from 2 to 8 h for these eight saponins whereas their elimination half-life (t 1/2) ranged from 4.06 to 9.77 h, indicating slow excretion. The plasma concentrations of these eight saponins were all very low, indicating a relatively low oral bioavailability. All these results provide support for further clinical studies.

Biopharmaceutics and Pharmacokinetics of Timosaponin A-III by a Sensitive HPLC-MS/MS Method: Low Bioavailability Resulting from Poor Permeability and Solubility.

BACKGROUND: Timosaponin A-III is one of the most promising active saponins from Anemarrhena asphodeloides Bge. As an oral chemotherapeutic agent, there is an urgent need to clarify its biopharmaceutics and pharmacokinetics to improve its development potential. OBJECTIVE: This research explores the bioavailability of timosaponin A-III and clarifies its absorption and metabolism mechanisms by a sensitive and specific HPLC-MS/MS method. METHODS: Pharmacokinetics and bioavailability studies of timosaponin A-III were performed in Sprague- Dawley rats by oral (20 mg/kg) and intravenous administration (2 mg/kg). Control group was given the same volume of normal saline. The absorption of timosaponin A-III was investigated in a rat intestinal perfusion model in situ and a Caco-2 cell transport model in vitro. The metabolic rate of timosaponin A-III was determined in a rat liver microsome incubation system. RESULTS: After the oral administration, timosaponin A-III reached Cmax of 120.90 ± 24.97 ng/mL at 8 h, and the t1/2 was 9.94 h. The absolute oral bioavailability of timosaponin A-III was 9.18%. The permeability coefficients of timosaponin A-III in four intestinal segments ranged from 4.98 to 5.42 × 10-7 cm/s, indicating a difficult absorption. A strikingly high efflux transport of timosaponin A-III was found, PappBA 3.27 ± 0.64 × 10-6 cm/s, which was abolished by a P-gp inhibitor. Rat liver microsome incubation studies showed that timosaponin A-III could hardly be metabolized, with a t1/2 of over 12 h. In addition, the solubility test showed a low solubility in PBS solution, i.e. 30.58 µg/mL. CONCLUSION: Timosaponin A-III exhibited low oral bioavailability by oral and intravenous administration, which was probably caused by its low permeability and solubility. This study may provide a reference for its rational clinical use and further study on the pharmacology or toxicology of timosaponin A-III.

Preoperative assessment of hilar cholangiocarcinoma: combination of cholangiography and CT angiography.

BACKGROUND: Hilar cholangiocarcinoma is one of the most difficult carcinomas to manage because of the location of the main tumor at the hepatic hilus and the complex anatomy of the biliary, arterial, and portal systems. To plan an operation, it is important to acquire accurate information about the relationship between hilar cholangiocarcinoma and adjacent vessels. This study aimed to evaluate the clinical value of cholangiography combined with spiral CT three-dimensional (3D) angiography for a preoperative assessment of hilar cholangiocarcinoma. METHODS: From March 2007 to August 2009, cholangiography was performed in 13 patients with hilar cholangiocarcinoma. Meanwhile, contrast-enhanced abdominal scanning was performed using 16-slice spiral CT, and the 3D images of the hepatic artery and portal vein were acquired. The level and range of invasion of the hepatic artery, the portal vein, and the bile duct, the preoperative Bismuth classification, and T-staging were recorded and compared with those after surgical exploration. RESULTS: The hepatic artery and portal vein were reconstructed successfully in all these patients. Percutaneous transhepatic cholangiography was performed in 9 patients, endoscopic retrograde cholangiopancreatography in 1, and magnetic resonance cholangiopancreatography in 3. The CT angiography records of invasion of the hepatic artery were consistent with the results of explorations in these patients. The data from 5 of the 13 patients were consistent with those on invasion of the portal vein. The results of the Bismuth classification and the T-staging system were consistent with those of surgical exploration in 12 of the 13 patients. Seven of 8 patients who were estimated to be suitable for operation based on images were curatively treated and 5 who were judged to be unsuitable for curative operation by cholangiography and CT angiography were confirmed intraoperatively and underwent palliative procedures. CONCLUSIONS: Cholangiography combined with multi-slice spiral 3D CT angiography can satisfactorily delineate the local invasion of hilar cholangiocarcinoma and accurately evaluate the resectability. This approach, therefore, contributes to the planning of safe operation.

Assessment of liver fibrosis with liver and spleen magnetic resonance elastography, serum markers in chronic liver disease.

BACKGROUND: The accurate assessment of liver fibrosis is essential for patients with chronic liver disease. A liver biopsy is an invasive procedure that has many potential defects and complications. Therefore, noninvasive assessment techniques are of considerable value for clinical diagnosis. Liver and spleen magnetic resonance elastography (MRE) and serum markers have been proposed for quantitative and noninvasive assessment of liver fibrosis. This study aims to compare the diagnostic performance of liver and spleen stiffness measured by MRE, fibrosis index based on the 4 factors (FIB-4), aspartate aminotransferase-to-platelet ratio index (APRI), and their combined models for staging hepatic fibrosis. METHODS: One hundred and twenty patients with chronic liver disease underwent MRE scans. Liver and spleen stiffness were measured by the MRE stiffness maps. Serum markers were collected to calculate FIB-4 and APRI. Liver biopsies were used to identify pathologic grading. Spearman's rank correlation analysis evaluated the correlation between the parameters and fibrosis stages. Receiver operating characteristic (ROC) analysis evaluated the performance of the four individual parameters, a liver and spleen stiffness combined model, and an all-parameters combined model in assessing liver fibrosis. RESULTS: Liver stiffness, spleen stiffness, FIB-4, and APRI were all correlated with fibrosis stage (r=0.87, 0.64, 0.65, and 0.51, respectively, all P<0.001). Among the 4 individual diagnostic markers, liver stiffness showed the highest values in staging F1-4, F2-4, F3-4 and F4 (AUC =0.89, 0. 97, 0.95, and 0.95, all P<0.001). The AUCs of the liver and spleen stiffness combined model in the F1-4, F2-4, F3-4, and F4 staging groups were 0.89, 0.97, 0.95, and 0.96, respectively (all P<0.001). The corresponding AUCs of the all-parameters combined model were 0.90, 0.97, 0.95, and 0.96 (all P<0.001). The AUCs of the liver and spleen stiffness combined model were significantly higher than those of APRI, FIB-4 in the F2-4, F3-4, and F4 staging groups (all P<0.05). Both combined models were not significantly different from liver stiffness in staging liver fibrosis (all P>0.05). CONCLUSIONS: Liver stiffness measured with MRE had better diagnostic performance than spleen stiffness, APRI, and FIB-4 for fibrosis staging. The combined models did not significantly improve the diagnostic value compared with liver stiffness in staging fibrosis.

Therapeutic potential of ReACp53 targeting mutant p53 protein in CRPC.

BACKGROUNDS: p53 is a tumor suppressor that prevents cancer onset and progression, and mutations in the p53 gene cause loss of the tumor suppressor function of the protein. The mutant p53 protein in tumor cells can form aggregates which contribute to the dominant-negative effect over the wild-type p53 protein, causing loss of p53 tumor suppression or gain of novel oncogenic functions. Mutations in p53 have been implicated in the pathogenesis of primary prostate cancer (PCa), and are often detected in recurrent and metastatic disease. Thus, targeting mutant p53 may constitute an alternative therapeutic strategy for advanced PCa for which there are no other viable options. METHODS: In this study, we used immunoprecipitation, immunofluorescence, clonogenic survival, and cell proliferation assays, flow cytometric analysis and in vivo xenograft to investigate the biological effects of ReACp53, a cell-permeable peptide inhibitor of p53 aggregation, on mutant p53-carrying PCa cells. RESULTS: Our results show that ReACp53 targets amyloid aggregates of mutant p53 protein and restores the p53 nuclear function as transcriptional factor, induces mitochondrial cell death and reduces DNA synthesis of mutant p53-carrying PCa cells; ReACp53 also inhibits xenograft tumor growth in vivo. CONCLUSIONS: The data presented here suggest a therapeutic potential of targeting mutant p53 protein in advanced PCa setting, which has a clinical impact for aggressive PCa with transforming how such tumors are managed.