Cepharanthine Triggers Ferroptosis Through Inhibition of NRF2 For Robust ER Stress Against Lung Cancer.

BACKGROUND: Severe endoplasmic reticulum (ER) stress elicits apoptosis to suppress lung cancer. Our previous research identified that Cepharanthine (CEP), a kind of phytomedicine, possessed powerful anti-cancer efficacy, for which the underlying mechanism was still uncovered. Herein, we investigated how CEP induced ER stress and worked against lung cancer. METHODS: The differential expression genes (DEGs) and enrichment were detected by RNA-sequence. The affinity of CEP and NRF2 was analyzed by cellular thermal shift assay (CETSA) and molecular docking. The function assay of lung cancer cells was measured by western blots, flow cytometry, immunofluorescence staining, and ferroptosis inhibitors. RESULTS: CEP treatment enriched DEGs in ferroptosis and ER stress. Further analysis demonstrated the target was NRF2. In vitro and in vivo experiments showed that CEP induced obvious ferroptosis, as characterized by the elevated iron ions, ROS, COX-2 expression, down-regulation of GPX4, and atrophic mitochondria. Moreover, enhanced Grp78, CHOP, p-eIF2A expression, ß-amyloid mass, and disappearing parallel stacked structures of ER were observed in CEP group, suggesting ER stress was aroused. CEP exhibited excellent anti-lung cancer efficacy, as evidenced by the increased apoptosis, reduced proliferation, diminished cell stemness, and prominent inhibition of tumor grafts in animal models. Furthermore, the addition of ferroptosis inhibitors weakened CEP-induced ER stress and apoptosis. CONCLUSION: In summary, our findings proved CEP drives ferroptosis through inhibition of NRF2 for induction of robust ER stress, thereby leading to apoptosis and attenuated stemness of lung cancer cells. The current work presents a novel mechanism for the anti-tumor efficacy of the natural compound CEP.

Mixed large and small cell neuroendocrine carcinoma of the stomach: A case report and review of literature.

BACKGROUND: Gastric neuroendocrine carcinoma (GNEC) is a rare histological subtype of gastric cancer, which is categorized into small cell and large cell neuroendocrine carcinomas. It is characterized by strong invasiveness and poor prognosis. Mixed large and small cell neuroendocrine carcinoma (L/SCNEC) is an extremely rare pathological type of gastric cancer, and there have been no reports on this situation until now. CASE SUMMARY: Herein, we first present a 57-year-old patient diagnosed with L/SCNEC of the stomach. A 57-year-old Chinese male presented with epigastric discomfort. Outpatient gastroscopic biopsy was performed, and pathological examination revealed that the cardia was invaded by adenocarcinoma. The patient underwent laparoscopic-assisted radical proximal subtotal gastrectomy and was diagnosed with L/SCNEC. He refused adjuvant treatment and was followed up every 3 mo. Eight months after the operation, the patient showed no evidence of local recurrence or distant metastasis. CONCLUSION: We advocate conducting further genomic studies to explore the origin of gastric large cell and small cell neuroendocrine carcinoma and using different chemotherapy schemes according to large or small cell neuroendocrine carcinoma of the stomach for clinical research to clarify the heterogeneity of GNEC and improve the prognosis of patients with GNEC.

Preoperative Concurrent Chemoradiotherapy Versus Neoadjuvant Chemotherapy for Locally Advanced Gastric Cancer: Phase II Randomized Study.

Objective: We evaluated and compared the efficacy and safety of neoadjuvant chemoradiotherapy (NACRT) versus neoadjuvant chemotherapy (NACT) for locally advanced gastric cancer (LAGC) in a single-center randomized phase II trial. Methods: Patients with LAGC were enrolled and received either NACT or NACRT, followed by gastrectomy and adjuvant chemotherapy. The primary endpoint was an R0 resection rate. Results: We enrolled 75 patients: 75.7% (NACT, 28/37 patients) and 76.3% (NACRT, 29/38 patients) underwent surgery; R0 resection rates were 73.0% (27/37) and 73.7% (28/38), respectively. The NACRT group had significantly better major pathological response than the NACT group (37.9% vs 17.9%, p = 0.019). Between-group postoperative complications were not significantly different. The median follow-up was 59.6 months; 5-year overall survival (OS) rate was 50.1% (NACT) and 61.9% (NACRT); neither group reached the median OS; median progression-free survival was 37.3 and 63.4 months, respectively. Conclusions: S-1-based NACRT did not improve the R0 resection rate, although it presented better tumor regression with similar safety to NACT. Trial registration: ClinicalTrial.gov NCT02301481.

Tumors of the angle of Treitz: a single-center experience.

AIM: To explore the feasibility and oncologic outcomes of segmental jejunal resection on the left side of the mesenteric vessels in patients with tumors of the angle of Treitz using data from a single center. METHODS: Thirteen patients with tumors of the angle of Treitz who underwent surgery at our institution were prospectively followed. A segmental jejunal resection on the left side of the mesenteric vessels was performed in all patients. Formalin-fixed and paraffin-embedded tumor samples were examined. The primary end point of this analysis was disease-free survival. RESULTS: In this study, there were 8 males and 5 females (mean age, 50.1 years; range, 36-74 years). The mean tumor size was 8.1 cm (range, 3.2-15 cm). Histologic examination showed 11 gastrointestinal stromal tumors (GISTs) and 2 adenocarcinomas. Five of the GIST patients presented with potential low risk, and 6 presented with intermediate and high risk, according to the National Institutes of Health criteria. One potentially high-risk patient showed tumor progression at 46 mo and died 52 mo after surgery. One patient with locally advanced adenocarcinoma received neoadjuvant chemotherapy and adjuvant radiotherapy, but the disease progressed, and the patient died 9 mo after surgery. One GIST patient without progression died 16 mo after surgery because of a postoperative intestinal obstruction. The median overall survival rate was 84.6 mo, and the median disease-free survival rate was 94.5 mo. CONCLUSION: The overall survival of patients with tumors of the angle of Treitz was encouraging even when the tumor size was relatively large. A segmental resection on the left side of the mesenteric vessels is considered to be a reliable and curative option for tumors of the angle of Treitz.

Anthropometric analysis of the maxillary bone and the alar base in unilateral cleft lip with secondary nasal deformity: classification of a piriform margin bony depression.

OBJECTIVES: This study was conducted to measure the soft tissue of the alar base and the piriform aperture area of the maxillary bone of unilateral cleft lips with secondary nasal deformities when secondary operation are necessary to classify the alar base depression and to provide a clinical reference for the second surgery. METHODS: Twenty-six patients with unilateral cleft lip with secondary nasal deformity were treated at the Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medial University. Nose data were attained preoperatively and postoperatively. Correlations were made between the soft tissue and the bony depression and patient satisfaction with the nasi basis. Classifications were then made based on these data. RESULTS: When the distance discrepancy of the bilateral piriform aperture depression was less than 4.5 mm, we obtained a fine appearance for the nose by repairing only the soft tissues. When it was more than 5 mm, we had to combine repair of the soft tissue with a bone graft or the restitution of the alveolar cleft. When the distance was between 4.5 mm and 5 mm, the surgeon considered both the wishes of the patient and the clinic's standard procedure. CONCLUSIONS: For patients with cleft lips and palates, the bony depression was not the only factor that resulted in postoperative alar depression. Anthropometry of the nose prior to surgery was important for choosing the methods that would yield satisfactory results.

[Feasibility of 13th lymph nodes as sentinels for periampullary carcinoma].

OBJECTIVE: To study the feasibility and clinical value of 13th lymph nodes in predicting general lymph nodes metastases for periampullary carcinoma. METHODS: A total of 77 patients with pathologically confirmed periampullary carcinoma were recruited. And 26 (18 males and 8 females, age 38-79 years) of them underwent Whipple procedures during which 1% methylene blue or nanogate carbon was injected into tumor bed. The other 51 patients as controls (33 males, 18 females, age 38-78 years) . The dyed 13th lymph nodes were biopsied. Then routine lymphadenectomy was performed and their pathological results were analyzed. RESULTS: In the experimental group, the lymph node drainage area of cancer was identified. However, in contrast with 51 patients in the control group, the labeling of 13th lymph nodes did not significantly increase the number of cleaned lymph nodes (15.8 (3-54) vs 17.6 (6-40) , P = 0.460). CONCLUSION: 13th lymph nodes are non-suitable as sentinels for predicting general lymph nodes metastases of periampullary carcinoma.

Risk factors associated with postoperative hospital stay after pancreaticoduodenectomy: a retrospective study.

BACKGROUND: Postoperative hospital stay after pancreaticoduodenectomy (PD) is relatively longer than after other gastrointestinal operations. The aim of the current study was to investigate the risk factors associated with prolonged hospital stay after PD. METHODS: Patients who had PD at the Cancer Hospital of Chinese Academy of Medical Sciences between December 2008 and November 2012 were selected for this retrospective study. Clinical and pathological data were collected and analyzed. The primary outcome was postoperative length of stay. Normal discharge or recovery was defined as a postoperative hospital stay of no more than 10 days; otherwise it was defined as delayed discharge or recovery (including hospital death). RESULTS: A total of 152 patients were enrolled in the present study. Postoperative hospital stay was (19.7 ± 7.7) days (range 7-57). Of the 152 patients, 67 were discharged within the normal time and 85 had delayed discharge. Postoperative complications occurred in 62.5% (95/152), and the mortality rate was 3.29% (5/152). Multiple regression analysis showed that delayed discharge was significantly associated with postoperative complications (adjusted odds ratio (OR) 10.40, 95% confidence interval (CI) 3.58-30.22), age (adjusted OR 4.09, 95% CI 1.16-14.39), body mass index (BMI) (adjusted OR 4.40, 95% CI 1.19-16.23), surgical procedure (adjusted OR 26.14, 95% CI 4.94-153.19), blood transfusion (adjusted OR 7.68, 95% CI 2.09-28.27), and fluid input (adjusted OR 3.47, 95% CI 1.24-11.57). CONCLUSIONS: Postoperative complications increase the time to postoperative hospital discharge. The length of hospital stay after PD is also associated with age, BMI, blood transfusion, surgical procedure, and fluid input. Further studies with more patients are needed in future.

[Experimental investigation of the chemical effect of direct current arc plasma igniter].

To study the chemical effect of direct current arc plasma igniter, the emission spectrum of plasma jet was measured, and the active particles produced by the interaction of plasma jet with atmospheric air were analyzed. The NO and CO volume fractions were measured quantificationally by smoke analyzer at the 8cm downstream the plasma igniter exit, and the changing law between arc current and NO, CO volume fractions was obtained. The results show that the plasma jet interacting with atmospheric air produced active particles (H, O, N), charged particles (O2 +, N2+), and excited particles (N2 (A3), N2 (B3), N2 (C3), N2 (a1), O2 (a1), O2 (b1)). The NO and CO volume fractions increased with rising of are current and feedstock argon flow rate.

[A diagnostic meta-analysis: sentinel lymph node biopsy for neck metastasis in patients with early oral squamous cell carcinoma].

OBJECTIVE: To evaluate the value of sentinel lymph node biopsy in diagnosis of cervical metastasis in patients with early oral squamous cell carcinoma. METHODS: Cochrane library, evidence-based medicine (EBM), PubMed, China national knowledge internet (CNKI) were searched for 2001 - 2011 literatures on sentinel lymph node biopsy in patients with oral squamous cell carcinoma as early diagnosis of cervical metastasis. The results were analysed by using Meta-analysis software Metadisc1.4. RESULTS: There were 12 studies in which, a total of 793 patients with oral squamous cell carcinoma were involved in Meta-analysis. The combined sensitivity and specificity were 0.86 (95%CI: 0.81 - 0.90) and 0.99 (95%CI: 0.98 - 1.00) respectively. CONCLUSIONS: For early oral cancer patients, the sensitivity and specificity of sentinel lymph node biopsy are relatively high. The sentinel lymph node biopsy could be used to select which patients need neck dissection.

[Surgical management of complicated orbital fractures: experiences with 89 orbital corrections and reconstructions].

OBJECTIVE: To summarize the experiences in the treatment of complicated orbital fractures. METHODS: A total of 89 patients with complicated orbital fractures treated in Department of Oral and Maxillofacial Surgery, China Medical University from January 2005 to January 2010 were retrospectively reviewed. The classification of these cases included naso-orbital-ethmoid fracture, frontal orbital fracture and orbitozygomatic fracture. All patients were followed up for 6 - 36 months. RESULTS: The orbital frame was repaired or reconstructed in these patients. The function of lacrimal pathways was improved. All the patients and the physicians were satisfied with the surgical effects. However, recurrence of deformity after endophthalmas correction was found in several cases. CONCLUSIONS: The experiences, comprehensive management of complicated orbital fractures by team approaches, concluded from this study could be expanded. There are still challenges in the treatment of complicated orbital fractures, such as severe endophthalmas deformity, recurrence of endophthalmas deformity and malunion of complicated orbital fracture.

[Value of intraoperative radiotherapy in the treatment of locally advanced pancreatic cancer].

OBJECTIVE: To assess the value of intraoperative radiotherapy (IORT) in the combined treatment of locally advanced pancreatic cancer. METHODS: All patients with locally advanced pancreatic cancer at our hospital from January 2007 to December 2009, judged as unresectable and confirmed by histology or cytology, were recruited into this prospective study. They were randomly assigned into the IORT group (n=31) and control group (n=34). The IORT group received IORT plus internal drainage or laparotomy. The control group had internal drainage or laparotomy only. The evaluation of adverse results of two groups included: intraoperative and postoperative adverse events, recent post-operative side effects, analgesic effect, the level of tumor marker such as CA19-9 and the long-term survival. RESULTS: There was no difference in operation duration, intraoperative hemorrhage and postoperative recovery. Significant differences were found in hematotoxicology, analgesic effect, tumor marker decreasing and long-term survival. CONCLUSION: IORT is a safe, reliable and easy-to-master technique without any obvious side effect. Its analgesic effect is better than the control group. Also IORT can retard the tumor growth and improve the patient survival.

[The role of slow-release 5-fluorouracil implantation in treatment of unresectable pancreatic cancer].

OBJECTIVE: To study the role of slow-release 5-fluorouracil implantation in treatment of unresectable pancreatic cancer. METHODS: 85 cases of untreated patients with locally advanced pancreatic cancer (LAPC) were randomized into two groups: Trial group: slow-release 5-fluorouracil implantation (50 patients) and control group (35 patients). Observing the objective tumor response, clinical benefit response, toxicity, complications and survival of patients of the two groups. RESULTS: In the trial group the overall response rate (PR + NC) was 76.0%, and the clinical benefit response rate was 52.0%. No toxicity was observed. Pancreatic fistula occurred in 2 patients. The median survival time of the two groups was 9.0 months and 4.0 months, respectively. The survival rates of 6- and 12-month were 56.8% vs. 31.4% and 22.9% vs. 2.9% in the two groups, respectively (P = 0.012). CONCLUSION: Slow-release 5-fluorouracil implantation is a simple, safe and effective method in treatment of LAPC.

[Role of 125I seed implantation in treatment of unresectable pancreatic cancer].

OBJECTIVE: To study the role of (125)I seed implantation in the treatment of unresectable pancreatic cancer. METHODS: From April 2004 to march 2006, 66 untreated patients with locally advanced pancreatic cancer (LAPC) were randomized into two groups: Group A: (125)I seeds implantation (n = 31) and Group B: control (n = 34). The objective tumor response, clinical benefit response, toxicity, complications and survival of two groups were observed. RESULTS: In Group A, the overall response rate (PR + NC) was 80.6%. Clinical benefit response rate was 54.8%. No toxicity was observed. Gastrointestinal hemorrhage and pancreatic fistula occurred in 1 patient respectively in Group A. The survival rates of 6 and 12 months were 56.0% vs 31.4% and 16.8% vs 2.9% respectively in two groups (P < 0.05). The median survival time of two groups was 8.0 months vs 4.0 months (P < 0.05). CONCLUSION: (125)I seed implantation is a simple, safe and effective method in the treatment of locally advanced pancreatic cancer.

[Analysis of risk factors of stress-related ulcer and gastrointestinal hemorrhage after pancreaticoduodenectomy].

OBJECTIVE: To assess the risk factors of stress-related ulcer and gastrointestinal hemorrhage after pancreaticoduodenectomy. METHODS: From May 1999 to July 2007, 285 periampullary cancer patients underwent pancreaticoduodenectomy in our hospital. The clinical data, pathological results, type of operation, and postoperative treatment were retrospectively analyzed. Patients with stress-related ulcer and gastrointestinal hemorrhage were selected for risk factor analysis, and other patients were taken as control group. RESULTS: 35 patients (12.3%) developed stress-related ulcer and gastrointestinal hemorrhage following pancreaticoduodenectomy. Pathological examination showed pancreatic cancer in 5 cases, duodenal cancer in 8, common bile duct cancer in 10, ampullary carcinoma in 11, and solid-pseudopapillary tumors in 1. Single variate analysis demonstrated that alcohol, preoperative bilirubin level, operation time, lymph node metastasis, prealbumin decrease after operation and other complication were significantly associated with the stress-related ulcer and gastrointestinal hemorrhage. Logistic regression in multivariate analysis revealed that preoperative bilirubin level, operation time, other complication, prealbumin decrease after surgery were independent risk factors. CONCLUSION: Stress-related ulcer and gastrointestinal hemorrhage are one of the most common complications after pancreaticoduodenectomy. Preoperative bilirubin level, operation time, other complications, and prealbumin decrease after operation are four independently risk factors.

[Comparison of clinicopathological characteristics between colorectal signet-ring cell carcinoma and mucinous adenocarcinoma].

OBJECTIVE: To compare the difference of clinicopathological characteristics between colorectal signet-ring cell carcinoma and mucinous adenocarcinoma. METHODS: The clinicopathological and survival data of 65 patients with colorectal signet-ring carcinoma and 166 with mucinous adenocarcinoma were retrospectively analyzed. RESULTS: Such clinical characteristics as gender, gross anatomical classification, preoperative carcinoembryonic antigen level and hepatic metastasis or not had no significant difference between two groups (P > 0.05) while the difference of such characteristics as age, location of tumor, vascular tumor embolus, N stage, T stage, AJCC stage, preoperative obstruction and the ratio of radical resection between them was significant (P < 0.05). The overall 3, 5-year survival of the whole group was 56.7% and 31.6% respectively. The 3, 5-year survival and median survival time (MST) in the signet-ring cell carcinoma and the mucinous adenocarcinoma groups were 33.1%, 14.8%, 24.0 months and 64.1%, 36.6%, 41.5 months respectively. The pathological type of signet-ring cell carcinoma was an independent risk factor of survival in the whole group. CONCLUSION: Compared to colorectal mucinous adenocarcinoma, signet-ring cell carcinoma has a higher degree of malignancy and the patients have a worse survival.

[Classification and surgical management of secondary nasal deformity of unilateral cleft lip].

OBJECTIVE: To investigate the classification of alar base depression, so as to provide the reference for the surgical management of secondary nasal deformity of unilateral cleft lip. METHODS: From Jul. 2008 to Feb. 2009, 26 cases with secondary deformity of unilateral cleft lip were treated. All the patients underwent 3-dimensional CT for maxillary measurement. The nasal soft tissue measurement was performed pre- and post-operatively. The relationship between the maxillary and soft tissue at alar base was analyzed. The nasal deformity was classified. RESULTS: The location of alar base was not related to the form of piriform aperture, but the bony defect at the alar base was correlated to the patient satisfactory. The nasal deformity was graded as I when the depression at alar base was less than 4.5 mm in depth, as II when it was 4.5-5.0 mm in depth, and as III when it was more than 5 mm in depth. The deformity could be corrected with only soft tissue plasty for grade I, with soft tissue plasty or artificial implants for grade II, with combined bone autograft or alveolar cleft repair for grade III. CONCLUSIONS: The depression at maxillary does not necessarily result in alar base depression. The alar base can be adjust to proper position through operation. The operation should be designed based on the preoperative nasal measurement.

[Application of tru-cut biopsy combined with fine needle aspiration biopsy in the intraoperative pathological diagnosis of pancreatic carcinoma].

OBJECTIVE: To investigate the method and value of tru-cut biopsy (TCB) combined with fine needle aspiration biopsy (FNAB) in the pathological diagnosis of pancreatic carcinoma during operation. METHODS: From April 2007 to October 2008, 22 cases who were suspected to suffer from pancreatic carcinoma were enrolled into this prospective study. All of them underwent a tru-cut biopsy combined with fine needle aspiration biopsy for the pathological diagnosis during operation. RESULTS: Of the 22 patients, 20 were finally diagnosed as having pancreatic carcinoma, while 2 having pancreatitis. The diagnosis of pancreatic carcinoma was confirmed in 19 by tru-cut biopsy combined with fine needle aspiration biopsy, while other 3 cases were not confirmed as pancreatic carcinoma. Among those 3 cases, one was diagnosed as having pancreatic carcinoma with hepatic metastasis by liver nodular biopsy, one as suffering from autoimmune pancreatitis, and another case as having chronic pancreatitis confirmed by follow-up for 9 months without any changes after the operation. The accuracy of FNA, TCB and FNA combined with TCB in the diagnosis for suspected pancreatic cancer were 86.4%, 90.9%, and 95.5%, respectively. No pancreatic fistula and bleeding developed after operation. CONCLUSION: Tru-cut biopsy is more accurate in diagnosis for the suspected pancreatic cancer than fine needle aspiration biopsy during operation. Tru-cut biopsy combined with fine needle aspiration biopsy can improve the accuracy of diagnosis, and is a safe and effective diagnostic method.

[Prognostic factors of colorectal cancer patients with synchronous liver metastasis treated with simultaneous liver and colorectal resection].

OBJECTIVE: To analyze the prognostic factors of colorectal cancer patients with synchronous liver metastasis treated by simultaneous colorectal and liver resection. METHODS: The clinical and follow-up data of 44 colorectal cancer patients with synchronous liver metastases who underwent simultaneous colorectal and liver resection from Jan. 1993 to Jan. 2003 were analyzed retrospectively. Survival rate was estimated by Kaplan-Meier method, and was compared using log-rank test. Prognostic factors were analyzed by multivariate Cox proportional hazards model. RESULTS: The overall 1-, 3- and 5-year survival rates were 86.3%, 40.9% and 25.0%, respectively. The lymph node metastasis and vascular invasion by cancer cells from the primary tumour were found to affect prognosis significantly, while gender, age, tumor location, histopathological types, the number and distribution of liver metastases were not. Multivariate analysis revealed that the lymph node metastasis was the only independent prognostic factor. CONCLUSION: Simultaneous liver and colorectal resection can be performed and may achieve good outcome in colorectal cancer patients with synchronous liver metastases, especially in those without lymph node metastasis.

[Prognostic factors of colorectal carcinoma in the elderly after radical surgery].

OBJECTIVE: To evaluate the prognostic factors of colorectal carcinoma in the elderly aged over 70 after radical surgery. METHODS: 263 colorectal carcinoma patients aged 74.9, 147 males and 115 females, underwent radical surgery, including right hemicolectomy (n=48), left hemicolectomy (n=11), transverse colectomy (n=8), sigmoid resection (n=27), low anterior resection (n=103), abdominoperineal resection (n=58), and Hartmann's operation (n=7). Survival analysis was conducted using Kaplan-Meier method, and multivariate analysis was conducted with Cox regression to analyze the prognostic factors. RESULTS: The post-operative complication rate was 14. 4%. The 30-day mortality was 1.1%. The overall 5-year survival rate was 70.5%, and the 5-year survival rates of the patients with ASA grades I, II, and III were 84.8%, 71.8%, and 61.9% respectively. Univariate analysis showed that the predictors of survival were age, co-morbidity, ASA score, postoperative complication, preoperative serum albumin concentration, preoperative hemoglobin level, gross tumor configuration, tumor stage, neoplastic intestinal obstruction, and lymph node metastasis. Multivariate analysis showed that patient sex, complication, operative complication, gross tumor configuration, depth of infiltration, lymph node metastasis, and tumor staging were independent influencing factors od prognosis. CONCLUSION: The prognosis of colorectal carcinoma in the elderly after radical surgery is good. The prognostic factors include age, postoperative complication, and pre-operative serum albumin concentration, and gross tumor configuration, depth of tumor invasion, lymph node metastasis, and tumor stage.

The ubiquitin-proteasome pathway mediates gelsolin protein downregulation in pancreatic cancer.

A well-known observation with respect to cancer biology is that transformed cells display a disturbed cytoskeleton. The underlying mechanisms, however, remain only partly understood. In an effort to identify possible mechanisms, we compared the proteome of pancreatic cancer with matched normal pancreas and observed diminished protein levels of gelsolin--an actin filament severing and capping protein of crucial importance for maintaining cytoskeletal integrity--in pancreatic cancer. Additionally, pancreatic ductal adenocarcinomas displayed substantially decreased levels of gelsolin as judged by Western blot and immunohistochemical analyses of tissue micoarrays, when compared with cancerous and untransformed tissue from the same patients (P < 0.05). Importantly, no marked downregulation of gelsolin mRNA was observed (P > 0.05), suggesting that post-transcriptional mechanisms mediate low gelsolin protein levels. In apparent agreement, high activity ubiquitin-proteasome pathway in both patient samples and the BxPC-3 pancreatic cancer cell line was detected, and inhibition of the 26s proteasome system quickly restored gelsolin protein levels in the latter cell line. The status of ubiquitinated gelsolin is related to lymph node metastasis of pancreatic cancer. In conclusion, gelsolin levels are actively downregulated in pancreatic cancer and enhanced targeting of gelsolin to the ubiquitin-proteasome pathway is an important contributing factor for this effect.