Response of cholangiocarcinoma with epigastric metastasis to lenvatinib plus sintilimab: A case report and review of literature.

BACKGROUND: Cholangiocarcinoma (CCA) poses a significant clinical challenge due to its low radical resection rate and a propensity for high postoperative recurrence, resulting in a poor dismal. Although the combination of targeted therapy and immunotherapy has demonstrated notable efficacy in several solid tumors recently, however, its application in CCA remains underexplored and poorly documented. CASE SUMMARY: This case report describes a patient diagnosed with stage IV CCA, accompanied by liver and abdominal wall metastases, who underwent palliative surgery. Subsequently, the patient received two cycles of treatment combining lenvatinib with sintilimab, which resulted in a reduction in abdominal wall metastasis, while intrahepatic metastasis displayed progression. This unexpected observation illustrates different responses of intrahepatic and extrahepatic metastases to the same therapy. CONCLUSION: Lenvatinib combined with sintilimab shows promise as a potential treatment strategy for advanced CCA. Genetic testing for related driver and/or passenger mutations, as well as an analysis of tumor immune microenvironment analysis, is crucial for optimizing drug combinations and eventually addressing the issue of non-response in specific metastatic sites.

A comparison of pulsed radiofrequency and radiofrequency denervation for lumbar facet joint pain.

BACKGROUND: Lumbar facet joint pain is a common disorder. The main symptom is chronic lumbar pain, which can reduce quality of life. Radiofrequency has often been used to treat lumbar facet joint pain. However, the effectiveness of this technique has been controversial. This study was conducted to compare the effectiveness of pulsed radiofrequency (PRF) and radiofrequency denervation (RD) for lumbar facet joint pain. METHODS: One hundred and forty-two patients with lumbar facet joint pain were allocated to two treatment groups: PRF group (N = 72) and RD group (N = 70). Patients enrolled in the study were assessed using a visual analogue scale (VAS), Roland-Morris questionnaire (RMQ), Oswestry disability index (ODI) and Short-Form 36 (SF-36) questionnaire before therapy, 3 months and 12 months later. RESULTS: There were no significant differences in VAS, RMQ score, ODI score and SF-36 score at 3 months (p > 0.05). Significant differences in pain control were observed in both groups at 12 months (3.09 ± 1.72 vs. 2.37 ± 1.22, p = 0.006). There was a significant difference in RMQ score (11.58 ± 3.58 vs. 8.17 ± 2.34, p < 0.001) and ODI score (43.65 ± 11.01 vs. 35.42 ± 11.32, p < 0.001) at 12 months. The total SF-36 score was higher in the RD group than in the PRF group at 12 months (58.45 ± 6.97 vs. 69.36 ± 6.43, p < 0.001). In terms of complications, skin numbness occurred in three patients. Mild pain such as burning and pinking at the puncture site in two patients. One patient experienced a decrease in back muscle strength and back muscle fatigue. These complications disappeared in 3 weeks without any treatment. There were no serious adverse events in the PRF group. CONCLUSION: Radiofrequency is an effective and safe treatment option for patients with lumbar facet joint pain. RD could provide good and lasting pain relief, with significant improvement in lumbar function and quality of life at long-term follow-up.

Complications of thoracoscopic talc insufflation for the treatment of malignant pleural effusions: a meta-analysis.

BACKGROUND: Talc pleurodesis is an effective treatment for malignant pleural effusions (MPEs). This study was designed to estimate complication rates of thoracoscopic talc insufflation. METHODS: Literature search was conducted in electronic databases and studies were selected if they reported complication rates of thoracoscopic talc insufflation in cancer patients with MPEs. Meta-analyses of proportions were performed to obtain incidence rates of complications. RESULTS: Twenty-six studies (4482 patients; age 62.9 years [95% confidence interval (CI): 61.5, 64.4]; 50% [95% CI: 43, 58] females) were included. Intraoperative, perioperative, 30-day, and 90-day mortality rates were 0% [95% CI: 0, 1], 2% [95% CI: 0, 4], 7% [95% CI: 3, 13] and 21% [95% CI: 5, 43] respectively. Incidence rates [95% CI] of various complications were: pain (20% [1, 2]), fever (14% [3, 4]), dyspnea (13% [5, 6]), pneumothorax (6% [7, 8]) pneumonia (4% [0, 12]), emphysema (3% [3, 7]), prolonged air leakage (3% [0, 7]), prolonged drainage (3% [9, 10]), thromboembolism (3% [9, 11]), lung injury (2% [7, 12]), respiratory insufficiency (2% [0, 5]), re-expansion pulmonary edema (1% [0, 3]), empyema (1% [0, 2]), respiratory failure (0% [0, 1]), and acute respiratory distress syndrome (ARDS; 0% [0, 1]. CONCLUSIONS: Whereas pain and fever were the most frequent complications of thoracoscopic talc insufflation, the incidence of ARDS was low. Pneumothorax, pneumonia, emphysema, prolonged air leakage, pulmonary embolism, arrythmia, re-expansion pulmonary edema, and empyema are important complications of thoracoscopic talc insufflation.

[Point electro-cauterization versus holmium laser cauterization in the treatment of post-ejaculation hematuria].

OBJECTIVE: To investigate the advantages and disadvantages of point electro-cauterization (PEC) and holmium laser cauterization (HLC) in the treatment of post-ejaculation hematuria. METHODS: From January 2015 to December 2018, 73 patients with post-ejaculation hematuria, aged 24－63 (36.8 ± 4.2) years, underwent PEC (n = 35) or HLC (n = 38) after failure to respond to 3 months of conservative treatment. We compared the hospital days, total hospitalization expenses, maximum urinary flow rate (Qmax), average urinary flow rate (Qavg), Hamilton Anxiety Rating Scale (HAMA) score, postoperative duration of hematuria, and recurrence rate at 3 and 6 months after surgery. RESULTS: All the patients experienced first ejaculation but no post-ejaculation hematuria at 1 month after operation. The recurrence rates were lower in the PEC than in the HLC group at 3 months (5.71% vs 2.63%, P > 0.05) and 6 months postoperatively (8.57% vs 5.26%, P > 0.05). Compared with the baseline, the Qmax was decreased from (18.56 ± 2.53) ml/s to (13.68 ± 3.31) ml/s (P < 0.05) and the Qavg from (14.35 ± 2.26) ml/s to (9.69±1.84) ml/s in the PEC group at 1 month after surgery (P < 0.01), but neither showed any statistically significant difference in the HLC group. Mild to moderate anxiety was prevalent in the patients preoperatively, particularly in those without job or regular income and those with a long disease course or frequent onset, the severity of which was not correlated with age, education or marital status. The HAMA score was decreased from18.65 ± 4.33 before to 12.35 ± 3.63 after surgery in the PEC group (P < 0.01), and from 16.88 ± 2.11 to 6.87 ± 4.36 in the HLC group (P < 0.01). The mean hospital stay was significantly longer in the former than in the latter group (ï¼»5.2 + 1.3ï¼½ vs ï¼»3.4 ± 0.5ï¼½ d, P < 0.01), while the total cost markedly lower (ï¼»6.35 ± 1.20ï¼½ vs ï¼»12.72 ± 2.15ï¼½ thousand RMB ¥, P < 0.05). CONCLUSIONS: Both PEC and HLC are safe and effective for the treatment of post-ejaculation hematuria, with no significant difference in the recurrence rate at 3 and 6 months after operation, but their long-term effect needs further follow-up studies. PEC may increase the risk of negative outcomes of the postoperative urinary flow rate, while HLC has the advantages of better relieving the patient's anxiety, sooner discharge from hospital and earlier recovery from postoperative hematuria, though with a higher total cost than the former.

The role of iron in Parkinson's disease monkeys assessed by susceptibility weighted imaging and inductively coupled plasma mass spectrometry.

Mounting evidences indicated that elevated iron levels in the substantia nigra (SN) have been concerned as the underlying mechanisms of neurodegenerative diseases, including Parkinson's disease (PD). The present study used the 1-Methyl-4-phenyl-1, 2, 3, 6 -tetrahydropyridine (MPTP)-treated cynomolgus monkeys for PD to evaluate the usability of SWI for assessing iron deposition in the cerebral nuclei of PD. The results showed that susceptibility-weighted imaging (SWI) phase values of the ipsilateral (MPTP-lesion side) SN of MPTP-treated monkeys were lower than those in the contralateral SN of MPTP-treated monkeys and the same side of Control monkeys, suggesting that iron deposition were elevated in the affected side SN of MPTP-treated monkeys. Whereas MPTP has not effects on the SWI phase values in other detected brain regions of monkeys, including red nucleus (RN), putamen (PUT) and caudate nucleus (CA). Furthermore, ICP-MS results showed that MPTP increased the iron levels in MPTP injection side, but no in the ipsilateral striatum. Additionally, MPTP treatment did not affect the calcium and manganese levels in the detected brain regions of monkeys. However, Pearson correlation analysis results indicated that there were not relationship between SWI phase values in MPTP-lesion side of SN with the behavioral score, tyrosine hydroxylase (TH)-positive cells number and iron levels in the MPTP-lesion side of midbrain. Taken together, the results confirm the involvement of SN iron accumulations in the MPTP-treated monkey models for PD, and indirectly verify the usability of SWI for the measurement of iron deposition in the cerebral nuclei of PD.

Triclosan induces PC12 cells injury is accompanied by inhibition of AKT/mTOR and activation of p38 pathway.

Triclosan (TCS) has been widely used as a disinfectant and antiseptic in multiple consumer and healthcare products due to its clinical effectiveness against various bacteria, fungi and protozoa. Recently, several studies have reported the adverse effects of TCS on various nerve cells, arousing concerns about its potential neurotoxicity. The present study aimed to investigate the neurotoxicity of TCS in rat pheochromocytoma PC12 cells. After differentiation, the stabilized PC12 cells were treated with 1, 10, 50 µM TCS for 12 h. At the end of the treatment, the generation of reactive oxygen species (ROS), protein expression of apoptotic-related genes, AMPK-AKT/mTOR, as well as p38 in PC12 cells were determined. The concentrations were chosen based on the results of cell viability and lactic dehydrogenase (LDH) assays in response to TCS treatment (ranging from 0.001 to 100 µM) for varied time periods. The results showed that TCS is cytotoxic to PC12 cells, causing decreased cell viability accompanied by increased LDH release. TCS treatment at 10 and 50 µM for 12 h increased the mRNA and protein expression of the pro-apoptotic gene Bax, while Bcl-2 levels remained unchanged. Moreover, an increase in the generation of reactive oxygen species (ROS) was found in TCS-treated PC12 cells at the concentrations of 1 and 10 µM. Pretreatment with 100 µM N-acetyl cysteine (NAC- ROS scavenger) for 1 h normalized the ROS generations in TCS-treated PC12 cells. Additionally, the suppression of the phosphorylation of Akt and mTOR was observed in TCS-treated PC12 cells at 10 and 50 µM for 12 h, concomitant with the activation of p38 MAPK pathway at 50 µM TCS. However, there were no effects of TCS on the phosphorylation of AMPK in these cells. Taken together, these results suggest that TCS may cause adverse effects and oxidative stress in PC12 cells accompanied by inhibition of Akt/mTOR and activation of p38.

Preventive impacts of PAS-Na on the slow growth and activated inflammatory responses in Mn-exposed rats.

BACKGROUND: Sodium para-aminosalicylic acid (PAS-Na), an anti-tuberculosis drug, has been demonstrated its function in facilitating the Mn elimination in manganism patients and Mn-exposed models in vivo and improving the symptoms of Mn poisoning. But whether it can improve the growth retardation and inflammatory responses induced by Mn have not been reported. OBJECTIVES: This study was designed to investigate the preventive effects of PAS-Na on the development of retardation and inflammatory responses in Mn-exposed rats. METHODS: Male Sprague Dawley (SD) rats (8 weeks old, weighing 180 ± 20 g) were randomly divided into normal control group and Mn-exposed group in the 4 weeks experiment observation and normal control group, Mn-exposed group, PAS-Na preventive group and PAS-Na control group in the 8 weeks experiment observation. The Mn-exposed group received an intraperitoneal injection (i.p.) of 15 mg/kg MnCl2 and the normal control group i.p. physiological Saline in the same volume once a day for 4 or 8 weeks, 5 days per week. The PAS-Na preventive group i.p. 15 mg/kg MnCl2 along with back subcutaneous (s.c.) injection of 240 mg/kg PAS-Na once a day for 8 weeks, 5 days per week. PAS-Na control group received s.c. injection of 240 mg/kg PAS-Na along with i.p. injection of saline once daily. The body weight was determined once a week until the end of the experiment. The manganese contents in the blood were detected by graphite furnace atomic absorption spectrometry. The inflammatory factor levels (TNF-α, IL-1ß, IL-6, and PGE2) in the blood were detected by using enzyme-linked immunosorbent assay (Elisa) and each organ taking from rats were weighed and recorded. RESULTS: Mn exposure significantly suppressed the growth in rats and increased heart, liver, spleen and kidney coefficients as compared with the control group. The whole blood Mn level and serum levels of IL-1ß, IL-6, PGE2, and TNF-α in sub-chronic Mn-exposure group were markedly higher than those in the control group. However, preventive treatment with PAS-Na obviously reduced the whole blood Mn level, the spleen and liver coefficients of the Mn-exposed rats. And serum levels of IL-1ß and TNF-α were significantly reduced by 33.9% and 14.7% respectively in PAS-Na prevention group. CONCLUSIONS: PAS-Na could improve the growth retardation and alleviate inflammatory responses in Mn-exposed rats.

Pulsed radiofrequency of the C2 dorsal root ganglion and epidural steroid injections for cervicogenic headache.

BACKGROUND: Cervicogenic headache (CEH) is characterized by unilateral headache symptoms referred to the head from the cervical spine. Few methods have addressed long-term pain relief for CEH. This study was undertaken to evaluate pain control and quality of life after pulsed radiofrequency (PRF) for the C2 dorsal root ganglion and epidural steroid injections (ESI) for CEH. METHODS: This was a case-control study. One hundred thirty-nine patients suffering from CEH were enrolled in this study. Of these patients, 87 CEH patients underwent PRF for the C2 dorsal root ganglion and ESI therapy, and 52 CEH patients only underwent ESI therapy. Quality of life and pain control were measured with the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ-C30) and Izbicki pain scores. Kaplan-Meier curve was used to evaluate the efficacy of the treatment in the groups. RESULTS: Before therapy, the median of Izbicki pain score in PRF+ESI group and ESI group was 78.5 and 72.5, respectively (p = 0.574). After 2 year follow-up, significant reduction was found in the two groups (11.25 versus 40.00, p < 0.001). The two groups demonstrated an equal distribution of age and gender (p > 0.05). SF (68.52 ± 21.50 versus 50.63 ± 15.42), PF (70.61 ± 29.47 versus 47.87 ± 21.53), RF (52.04 ± 17.92 versus 38.13 ± 24.07), EF (61.17 ± 28.41 versus 43.52 ± 25.48), CF (55.36 ± 19.82 versus 46.82 ± 23.54), and QL (59.31 ± 27.44 versus 50.73 ± 21.90) were significantly higher in PRF+ESI group than in ESI group. Kaplan-Meier curve showed that the probability of treatment success in PRF+ESI group was higher than that in ESI group (median pain relief: ESI group, 4 months; PRF+ESI group, 8 months) (Log-Rank test, p < 0. 001). There was no serious side effect in this study. CONCLUSION: The combination of PRF for the C2 dorsal root ganglion and ESI is a relatively safe therapy for CEH. This technique not only provides the sustained relief of pain symptom but improves the quality of life in patients with CEH.

Capn4 promotes esophageal squamous cell carcinoma metastasis by regulating ZEB1 through the Wnt/ß-catenin signaling pathway.

BACKGROUND: Capn4 and ZEB1 play important roles in the metastasis of several types of cancer. However, the roles and relationship of Capn4 and ZEB1 in esophageal squamous cell carcinoma (ESCC) remain unclear. METHODS: ESCC tumor tissues and corresponding normal esophageal epithelial tissues were obtained from 86 patients undergoing resection surgery at the Department of General Surgery, First Affiliated Hospital of Chinese PLA General Hospital from 2012 to 2017. Cell migration and invasion were examined via quantitative real-time PCR and Western blot assay. RESULTS: Our results indicate that both Capn4 and ZEB1 are significantly upregulated in ESCC tissues compared to corresponding adjacent tissues, and a positive correlation between expression and associated malignant characteristics was found. Silencing of Capn4 expression markedly inhibited ESCC invasion and metastasis in vitro and in vivo, and was accompanied by decreased ZEB1 expression. Furthermore, the anti-metastasis role of Capn4 silencing was reversed by ZEB1 overexpression, whereas knockdown of ZEB1 decreased ESCC metastasis driven by the upregulation of Capn4. Mechanistically, Capn4 regulated ZEB1 expression via activation of the Wnt/ß-catenin signaling pathway in ESCC cells. CONCLUSION: Overall, our results show that enhanced Capn4 expression activates the Wnt/ß-catenin signaling pathway, resulting in increased ZEB1 expression and the promotion of ESCC cell metastasis.

Effect of 2% lidocaine continuous epidural infusion for thoracic or lumbar herpes-zoster-related pain.

Few treatments are effective to manage herpes-zoster (HZ)-related pain. This retrospective study focused on the efficacy of 2% lidocaine continuous epidural infusion on pain control and quality of life in patients with thoracic or lumbar HZ.A total of 256 patients with thoracic or lumbar HZ were reviewed for this study. Patients included in the study were divided into continuous epidural infusion (70 mL 2% lidocaine + 180 mL 0.9% normal saline) and medical therapy group (group1) and only medical therapy group (group2). European Organization for Research and Treatment of Cancer and Izbicki pain score were used to evaluate the pain control and quality of life before therapy, and 6 and 9 months after therapy.For 256 patients with HZ (thoracic HZ = 162, lumbar HZ = 94), 53.1% was women. Mean ± standard deviation age was 69.4 ±â€Š9.5 ( range, 38-85) years. Significant differences between the 2 groups in terms of quality of life and pain control were detected after 6 and 9 months follow-up (P < .001). For patients with HZ at 1 to 3 months after rash onset, the pain score was significantly lower in group 1 (P < .001). Sixteen patients with postherpetic neuralgia (PHN) underwent continuous epidural infusion therapy. Only 4 patients achieved satisfactory pain relief. Seven patients required analgesic drugs, and 6 patients still were unable to work, 10/16 (62.5%) patients had readmission. In addition, the pain score was higher in patients with HZ with diabetes (P < .001). Epidural infection occurred in 6 patients (8.8%), catheter dislodgement in 4 patients (5.8%), and catheter leakage in 3 patients (4.4%). There was no spinal epidural abscesses occurred.2% lidocaine continuous epidural infusion therapy can lead to sustained pain relief and improve the quality of life in patients with for thoracic or lumbar HZ at 1 to 3 months after rash onset. Epidural lidocaine is avoided for the treatment PHN, and the level of glucose might be associated with zoster-related pain.

Risk factors for pain after Frey's procedure in chronic pancreatitis.

Pancreatic pain is the most frequent symptom of chronic pancreatitis (CP) and is difficult to treat. This retrospective study aimed to determine the risk factors for pain in CP.From January 2009 and March 2014, 75 consecutive patients with CP who underwent Frey's procedure were reviewed for this study. According to Izbicki pain scores, these patients were divided into 2 groups: (1) pain (Izbicki pain score of >10 after a decrease of >50%) and (2) pain-free (Izbicki pain score of ≤10). Demographic data, medical history, postoperative variables, and follow-up evaluations of the patients were documented.The postoperative pain score (11.8) was significantly lower than the preoperative score (51.8) after a median follow-up of 4.2 years. Alcoholism (odds ratio [OR] 7.767, P = .002) and preoperative analgesic medication use (OR 4.113, P = .030) were independent risk factors for pain.Frey's procedure is an effective operation for pain relief in patients with CP. Alcoholism and preoperative analgesic medication use were 2 factors for failure to achieve complete pain relief.

Role of original and modified Frey's procedures in chronic pancreatitis.

AIM: To retrospectively review patients with chronic pancreatitis (CP) treated with Frey's procedures between January 2009 and January 2014. METHODS: A retrospective review was performed of patients with CP treated with Frey's procedures between January 2009 and January 2014 in the Department of Pancreatic Surgery. A cross-sectional study of postoperative pain relief, quality of life (QoL), and alcohol and nicotine abuse was performed by clinical interview, letters and telephone interview in January 2016. QoL of patients was evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) version 3.0. The patients were requested to fill in the questionnaires by themselves via correspondence or clinical interview. RESULTS: A total of 80 patients were enrolled for analysis, including 44 who underwent the original Frey's procedure and 36 who underwent a modified Frey's procedure. The mean age was 46 years in the original group and 48 years in the modified group. Thirty-five male patients (80%) were in the original group and 33 (92%) in the modified group. There were no differences in the operating time, blood loss, and postoperative morbidity and mortality between the two groups. The mean follow-up was 50.3 mo in the original group and 48.7 mo in the modified group. There were no differences in endocrine and exocrine function preservation between the two groups. The original Frey's procedure resulted in significantly better pain relief, as shown by 5-year follow-up (P = 0.032), better emotional status (P = 0.047) and fewer fatigue symptoms (P = 0.028). When stratifying these patients by the M-ANNHEIM severity index, no impact was found on pain relief after the two types of surgery. CONCLUSION: The original Frey's procedure is as safe as the modified procedure, but the former yields better pain relief. The severity of CP does not affect postoperative pain relief.

Wogonin induces Beclin-1/PI3K and reactive oxygen species-mediated autophagy in human pancreatic cancer cells.

Wogonin is considered to be an inhibitor of myeloid cell leukemia 1 and B-cell lymphoma 2, and a potential antitumor drug due to its ability to induce apoptosis in certain cancer cells; however, few previous studies have reported on wogonin-induced autophagy. The aim of the present study was to investigate the influence of wogonin on autophagy in human pancreatic cancer cells (HPCCs), elucidate its mechanism, and identify strategies to increase its effectiveness as an anti-cancer treatment. HPCCs were treated with wogonin and autophagy was detected in the cells. The mechanism of wogonin-related autophagy was investigated, and the antioxidant N-acetyl-L-cysteine (NAC) was used to assess the role of reactive oxygen species (ROS) in wogonin-related autophagy. The results demonstrated that wogonin may induce autophagy by activating the Beclin-1/phosphatidylinositol-3-kinase and ROS pathways in HPCCs, and may enhance ROS generation, followed by the activation of the AKT/ULK1/4E-BP1/CYLD pathway and inhibition of the mammalian target of rapamycin signaling pathway. The incubation of HPCCs with wogonin and the antioxidant NAC, revealed that the effects of wogonin-enhanced ROS generation on autophagy-related molecules were inhibited, contributing to the inhibition of autophagy and increasing the cell death ratio through apoptosis activation in HPCCs. These studies suggest that autophagy activation, via the ROS pathway, by the antitumor drug wogonin in HPCCs may partially reduce the antitumor effects of the drug, and that the antioxidant NAC may enhance the antitumor effectiveness of wogonin via the inhibition of ROS-enhanced autophagy and the subsequent promotion of apoptosis. Therefore, the present research suggests that wogonin combined with NAC may be a novel combination therapy for clinical pancreatic cancer therapy trials.

The significance of combining radiotherapy with chemotherapy for early stage extranodal natural killer/T-cell lymphoma, nasal type: a systematic review and meta-analysis.

Abstract Radiotherapy is regarded as a primary treatment for early stage extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL). However, whether combined modality treatment (CMT) comprising radiotherapy and chemotherapy is necessary remains controversial. A systematic review and meta-analysis of studies was performed to evaluate the significance of combining radiotherapy with chemotherapy for early stage ENKTL. Comparison of CMT and radiotherapy alone (RT) showed no significant difference by the measurement of complete response (CR) (odds ratio [OR] 1.07; 95% confidence interval [CI] 0.73-1.58; p = 0.73), 5-year overall survival rate (OS) (HR 0.73; 95% CI 0.45-1.19; p = 0.21) and progression-free survival rate (PFS) (HR 0.76; 95% CI 0.50-1.17; p = 0.21). Additional chemotherapy did not decrease systemic failure (OR 1.52; 95% CI 0.97-2.40; p = 0.07), as well as locoregional failure (OR 0.94; 95% CI 0.52-1.73; p = 0.85). The results may support the assertion that the combination of radiotherapy with chemotherapy cannot improve treatment outcomes, but rather it increases adverse effects and financial costs. However, these results should be interpreted with caution.

LKB1/AMPK/mTOR signaling pathway in non-small-cell lung cancer.

Links between cancer and metabolism have been suggested for a long time but compelling evidence for this hypothesis came from the recent molecular characterization of the LKB1/AMPK signaling pathway as a tumor suppressor axis. Besides the discovery of somatic mutations in the LKB1 gene in certain type of cancers, a critical emerging point was that the LKB1/AMPK axis remains generally functional and could be stimulated by pharmacological molecules such as metformin in cancer cells. In addition, AMPK plays a central role in the control of cell growth, proliferation and autophagy through the regulation of mTOR activity, which is consistently deregulated in cancer cells. Targeting of AMPK/mTOR is thus an attractive strategy in the development of therapeutic agents against non-small-cell lung cancer (NSCLC). In this review, the LKB1/AMPK/mTOR signaling pathway is described, highlighting its protective role, and opportunities for therapeutic intervention, and clinical trials in NSCLC.

The methylation status of the TMS1/ASC gene in cholangiocarcinoma and its clinical significance.

BACKGROUND: TMS1/ASC is a bipartite protein comprising two protein-protein interactive domains: pyrin (PYD) and caspase recruitment domain (CARD). Proteins containing these domains play pivotal roles in regulating apoptosis and immune response pathways. The absence of TMS1/ASC expression in some tumors is because methylation of the TMS1/ASC gene contributes to carcinogenesis and cancer development. We studied the methylation status of the TMS1/ASC gene and its clinical significance in cholangiocarcinoma. METHODS: Target DNA was modified by sodium bisulfite, coverting all unmethylated, but not methylated, cytosines to uracil, and subsequently by a nested amplification with primers specific for methylated versus unmethylated DNA. The PCR product was detected by gel electrophoresis and combined with the clinical records of patients. RESULTS: Aberrant methylation of the TMS1/ASC gene was detected in specimens of colorectal cancer tissues from 13 (36.1%) of 36 patients, and specimens of adjacent normal tissues from 3 patients (8.3%). No statistical differences were seen in the extent of differentiation and invasion, lymph node metastasis, and pathologic type between the methylated and unmethylated tissues (P>0.05). CONCLUSIONS: The frequency of TMS1/ASC gene methylation in cholangiocarcinoma is high, but it is not related to pathologic changes. The TMS1/ASC gene is probably suppressed by methylation, and is resistant to apoptosis and immunological surveillance. The gene epigenetically affected in methylated tissues could be associated with carcinogenesis of cholangiocarcinoma.

Correlation of p53 gene mutation and expression of P53 protein in cholangiocarcinoma.

AIM: To characterize the tumor suppressor gene p53 mutations and study the correlation of p53 gene mutation and the expression of P53 protein in cholangiocarcinoma. METHODS: A total of 36 unselected, frozen samples of cholangiocarcinoma were collected. p53 gene status (exon 5-8) and P53 protein were examined by automated sequencing and immunohistochemical staining, combined with the clinical parameters of patients. RESULTS: p53 gene mutations were found in 22 of 36 (61.1%) patients. Nineteen of 36 (52.8%) patients were positive for P53 protein expression. There were significant differences in extent of differentiation and invasion between the positive and negative expression of P53 protein. However, there were no significant differences in pathologic parameters between the mutations and non-mutations. CONCLUSION: The alterations of the p53 gene evaluated by DNA sequence analysis is relatively accurate. Expression of P53 protein could not act as an independent index to estimate the prognosis of cholangiocarcinoma.

[The effect of homocysteine on fibrinolytic system in human umbilical vein endothelial cells].

OBJECTIVES: To investigate the relationship between homocysteine (Hcy) and the fibrinolytic system in acute myocardial infarction (AMI) and human umbilical vein endothelial cells (HUVEC). METHODS: Cultured HUVEC was divided into 10 groups (0, 10, 50, 200, 500 micromol/L Hcy with or without 15 micromol/L of folic acid). There were 53 patients of acute myocardial infarction (AMI) and 48 healthy controls. The plasminogen activator inhibitor-1 (PAI-1) and activator of plasminogen (tPA) antigen levels in HUVEC's supernatant and plasma were measured with Elisa kit. Concentration of plasma Hcy was measured by reverse-phase high-performance liquid chromatography with precolumn derivatization and fluorometric detection in the patients and healthy controls. Total RNA was extracted using the guanidinium isothiocyanate method. The semi-quantification of PAI-1 and tPA mRNA in HUVEC was carried out by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: (1) PAI-1 mRNA and secreted protein levels were both significantly enhanced by Hcy at the concentration of 500 micromol/L, compared with the control group (P < 0.05). (2) The tPA mRNA and antigen levels were decreased significantly at concentration of 500 micromol/L of Hcy, compared with that of 10 micromol/L Hcy (P < 0.05), but compared with the control group (0 micromol/L), the tPA mRNA and antigen levels of 10 micromol/L of Hcy were much higher (P < 0.05). (3) The addition of folic acid reduced PAI-1 but increased tPA at both mRNA and protein levels, which were both obvious at concentrations of 500 micromol/L Hcy, compared with only Hcy group (P < 0.05). (4) Hcy, tPA, and PAI-1 antigen levels were increased in AMI group. Hcy is a independent risk factor of AMI (P < 0.05). There weren't significant correlation between Hcy and tPA or Hcy and PAI-1 in both groups (P > 0.05), although the coefficient correlation was higher in patients than in controls. CONCLUSIONS: These results suggested that hyperhomo-cysteinemia increased the incidence of thrombotic disease, which may be caused by decreasing the activity of fibrinolytic system, whereas, folic acid may be protective against the toxic action of Hcy.