shRNA-mediated inhibition of PhosphoGlycerate Kinase 1 (PGK1) enhances cytotoxicity of intraperitoneal chemotherapy in peritoneal metastasis of gastric origin.

BACKGROUND: Phosphoglycerate kinase 1 (PGK1) plays metabolic, kinase and translational roles in Peritoneal metastasis (PM) of gastric origin and is associated with chemoresistance. Silencing PGK1 might potentiate the effect of chemotherapy. METHODS: In an orthoptic xenograft nude mice model, human gastric cancer cells (MKN45) were grown in 22 donor animals. Solid tumors were then grafted into the gastric subserosa of 102 recipient animals and allowed to grow for 10 days. Animals were randomized into 7 groups: Five test groups: 1) Mitomycin C (MMC), 2) MMC and small hairpin RNA silencing of PGK1 with an adenoviral vector (Adv-shPGK1), 3) 5-fluorouracil (5-FU), 4) 5-FU and Adv-shPGK1, 5) Adv-shPGK1 alone; two control groups: 1) Sham (NaCl 0.9%), 2) empty viral vector. Intraperitoneal therapy was administered on postoperative day (POD) 11 and 18. Animals were sacrificed at POD 21, analysis was blinded to therapy. RESULTS: Adding Adv-shPGK1 to 5-FU reduced the number (0.23 ± 0.43 vs. 1.36 ± 1.00, p = 0.005) and weight (0,005 ± 0.012 mg vs. 0.05 ± 0.08 mg, p = 0.002) of PM as compared to 5-FU alone. The effect of adding Adv-shPGK1 to MMC did not reach statistical significance. Mortality was not increased by adding Adv-shPGK1 to chemotherapy but was increased by Adv-shPGK1 alone as compared to sham. CONCLUSION: In this experimental model, combined therapy with chemotherapy and Adv-shPGK1 improves control of PM of gastric origin as compared to chemotherapy alone and might counteract chemoresistance of PM. A systemic toxicity of Adv-shPGK1 cannot be excluded.

Personalized peptide vaccine-induced immune response associated with long-term survival of a metastatic cholangiocarcinoma patient.

BACKGROUND & AIMS: We report a novel experimental immunotherapeutic approach in a patient with metastatic intrahepatic cholangiocarcinoma. In the 5year course of the disease, the initial tumor mass, two local recurrences and a lung metastasis were surgically removed. Lacking alternative treatment options, aiming at the induction of anti-tumor T cells responses, we initiated a personalized multi-peptide vaccination, based on in-depth analysis of tumor antigens (immunopeptidome) and sequencing. METHODS: Tumors were characterized by immunohistochemistry, next-generation sequencing and mass spectrometry of HLA ligands. RESULTS: Although several tumor-specific neo-epitopes were predicted in silico, none could be validated by mass spectrometry. Instead, a personalized multi-peptide vaccine containing non-mutated tumor-associated epitopes was designed and applied. Immunomonitoring showed vaccine-induced T cell responses to three out of seven peptides administered. The pulmonary metastasis resected after start of vaccination showed strong immune cell infiltration and perforin positivity, in contrast to the previous lesions. The patient remains clinically healthy, without any radiologically detectable tumors since March 2013 and the vaccination is continued. CONCLUSIONS: This remarkable clinical course encourages formal clinical studies on adjuvant personalized peptide vaccination in cholangiocarcinoma. LAY SUMMARY: Metastatic cholangiocarcinomas, cancers that originate from the liver bile ducts, have very limited treatment options and a fatal prognosis. We describe a novel therapeutic approach in such a patient using a personalized multi-peptide vaccine. This vaccine, developed based on the characterization of the patient's tumor, evoked detectable anti-tumor immune responses, associating with long-term tumor-free survival.

Hemangiopericytoma/solitary fibrous tumor of the greater omentum: A case report and review of the literature.

INTRODUCTION: Hemangiopericytoma (HPC) has been first described in 1942 by Stout as a tumor originating from the capillary surrounding pericytes. It is known to occur in any anatomical site, especially the extremities and retroperitoneum. PRESENTATION OF CASE: We describe a case of a 24year old patient presenting with lower abdominal pain due to a tumor of the greater omentum, the patient was treated by conventional laparotomy with tumor resection and the histological evaluation confirmed the diagnosis Hemangiopericytoma/Solitary fibrous tumor (HPC/SFT). The patient has regularly followed-up with periodic imaging for the last 4 years, with no recurrences. DISCUSSION AND CONCLUSION: According to our knowledge, HPC rarely develops in the greater omentum, only 20 cases were described in the literature. Primary surgical resection is the treatment of choice. There is no benefit of radiation or systemic chemotherapy. Angiogenic inhibitors represent promising systemic therapeutic concepts.

Targeting Fibroblast Growth Factor Receptor (FGFR) with BGJ398 in a Gastric Cancer Model.

AIM: To assess the efficacy of targeting fibroblast growth factor receptor (FGFR) with the pan-FGFR inhibitor BGJ398 in a gastric cancer (GC) model. MATERIALS AND METHODS: Expression of FGFRs was determined in GC cell lines (KKLS, MKN-45, TMK-1). Impact of the FGFR inhibitor BGJ398 on growth, motility, signaling, expression of transcription factors and secretion of vascular endothelial growth factor-A (VEGFA) was determined in vitro. Results were validated in subcutaneous tumor models. RESULTS: In vitro, FGFR inhibition was most effective in KKLS cells (high FGFR1, FGFR2IIIc, no FGFR2IIIb expression) with inhibition of growth, motility, signaling, c-MYC expression and VEGFA secretion. BGJ398 showed some activity in MKN-45 cells (intermediate FGFR1, high FGFR2IIIb, low FGFR2IIIc expression), while TMK-1 cells (low FGFR1, no FGFR2IIIb and FGFR2IIIc expression) did not respond. Results were confirmed in vivo with strongest efficacy on growth in KKLS tumors and only minor impairment of TMK-1 lesions. CONCLUSION: Efficacy of FGFR inhibition is dependent on FGFR1 and FGFR2IIIc expression in GC models.

Metabolic alteration--Overcoming therapy resistance in gastric cancer via PGK-1 inhibition in a combined therapy with standard chemotherapeutics.

BACKGROUND AND OBJECTIVES: It can be assumed that PGK1 is involved in metastatic spread of gastric carcinomas. Furthermore PGK1 has a proven influence on the characteristics of tumor stem cells. The presence of malignant stem cells, regarding treatment resistance and recurrence, is of considerable importance. We hypothesized that inhibition of PGK1 makes these cells more sensitive to chemotherapeutic agents and therefore mediates an overcome of the existing therapy resistance. METHODS: All investigations were performed with human gastric adenocarcinoma cell lines. Small hairpin RNA knockdown of PGK1 via adenovirus-shPGK1 was used for PGK1-inhibition. Chemotherapeutic agents were 5-FU and mitomycin. FACS, qRT-PCR, and xCELLigence were performed. RESULTS: Using the medium-sole-control indicating the highest cell viability and Triton indicating the lowest, mitomycin and 5-FU alone showed a significant decrease in cell viability. The treatment with AdvshPGK1 alone already showed a better decrease. The simultaneous application of chemotherapeutics and adenovirus showed the strongest effect and is comparable to the effect of Triton. CONCLUSIONS: We showed a significant decrease in cell viability after the simultaneous application of chemotherapeutics and adenovirus. These results suggest that PGK1-inhibition is able to increase the vulnerability of gastric cancer cells and tumor stem cells to overcome the chemotherapeutic therapy resistance.

New telemetry device for the measurement of gastrointestinal motility in rats and comparison with standard equipment.

To perform stress-free recording of gastrointestinal motility in rats with strain gauge transducers, telemetry equipment had to be developed. We developed, programmed, and tested a new telemetry device that records gastrointestinal motility in freely moving rats using strain gauge transducers. The device can collect and transmit data in freely moving rats. Data are received and stored for later analysis with a regular PC. Linear calibration curves were obtained for the strain gauge transducers used. We compared data obtained with the new telemetry device with data gathered with standard equipment and could not find any statistically significant difference. Wired gastric and colonic contraction frequencies were 4.6 ± 0.3 per minute and 1.5 ± 0.3 per minute, whereas telemetric contraction frequencies were 4.4 ± 0.1 per minute and 1.25 ± 0.1 per minute. The new telemetry device is a very useful tool for the measurement of gastrointestinal motility in rats.

Early functional postoperative therapy of distal radius fracture with a dynamic orthosis: results of a prospective randomized cross-over comparative study.

INTRODUCTION: This study was conducted according to GCP criteria as a prospective randomized cross-over study. The primary goal of the study was to determine clinical findings and patient satisfaction with postoperative treatment. 29 patients with a distal radius fracture that was surgically stabilized from volar and who met the inclusion criteria were enrolled over a 12-month period. Each patient randomly received either a dorsal plaster splint or a vacuum-fit flexible but blocked orthosis applied postoperatively in the operating theatre to achieve postoperative immobilization. After one week all patients were crossed over to the complementary device maintaining the immobilization until end of week 2. After week 2 both groups were allowed to exercise wrist mobility with a physiotherapist, in the orthosis group the device was deblocked, thus allowing limited wrist mobility. After week 4 the devices were removed in both groups. Follow-up exams were performed after postoperative weeks 1, 2, 4 and 12. RESULTS AND DISCUSSION: Results were determined after week 1 and 2 using SF 36 and a personally compiled questionnaire; after weeks 4 and 12 with a clinical check-up, calculation of ROM and the DASH Score. Comparison of the two groups showed a significant difference in ROM for volar flexion after 4 weeks, but no significant differences in DASH Score, duration of disability or x-ray findings. With regard to satisfaction with comfort and hygiene, patients were significantly more satisfied with the dynamic orthosis, and 23 of the 29 patients would prefer the flexible vacuum orthosis in future. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00006097.

Do patient- and tumor-related factors predict the peritoneal spread of pancreatic adenocarcinoma?

PURPOSE: In pancreatic cancer, the presence of peritoneal carcinomatosis (PC) precludes the possibility of a surgical cure, irrespective of the resectability of the primary tumor. However, peritoneal spread cannot be reliably detected radiographically during preoperative tumor staging. METHODS: The pancreatic adenocarcinoma database of the Tübingen Comprehensive Cancer Center included 29 patients in whom PC was incidentally detected during the surgery. These patients were retrospectively compared for patient- and tumor-related factors with 29 randomly selected patients without PC who underwent curative resection. RESULTS: Clinical jaundice and diarrhea were more frequently present in patients without PC. The CA 19-9 levels were significantly higher in patients with PC compared to those in patients without PC. No other differences were observed in the patient- or tumor-related factors between the two groups. CONCLUSION: In pancreatic cancer patients, markedly elevated CA 19-9 levels may serve as surrogate marker for peritoneal dissemination, irrespective of the local resectability of the tumor. In such patients, laparoscopy should be considered as an additional staging tool to rule out peritoneal carcinomatosis.

Phosphoglycerate kinase 1 as a promoter of metastasis in colon cancer.

Oxidative stress due to intratumoral hypoxia in solid cancer has been shown to be associated with increased mortality. Phosphoglycerate kinase 1 (PGK1) is an enzyme of the glycolytic pathway, which is regulated by hypoxia-inducible factor-1α (HIF-1α) and has been described for its role in tumor progression and metastasis in several malignancies. We investigated whether the expression of PGK1 varies between metastatic and non-metastatic colon cancer. We compared PGK1 expression in colon cancer patients either with or without metastasis via polymerase chain reaction (PCR) and immunohistochemistry. Microarray analysis was performed to test altered gene expression after PGK1 silencing, using isolates from HCT116 cell lines. PCR results showed an increased expression of PGK1 in colon cancer tissue from metastatic patients in comparison to patients with no metastasis (fold change 2.6, p<0.001). Immunohistochemical staining of PGK1 showed stronger staining in metastatic tissue in comparison to non-metastatic cancer tissue according to a semi-quantitative evaluation. Microarray and subsequent pathway analysis provided 4 genes of interest (CYR61, FOS, JUN and EGR1) used for pathway proposal. The results indicate that increased expression of PGK1 in colon cancer tissue is associated with metastasis. Furthermore, we propose several genes induced by PGK1 that could account for cell migration, mainly EGR1 and CYR61 together with the transcription factors FOS and JUN.

Exchange reamed nailing compared to augmentation compression plating leaving the inserted nail in situ in the treatment of aseptic tibial non-union: a two-centre study.

BACKGROUND: A remarkable number of investigations are available treating tibial non-unions by exchange reamed nailing (ERN). Only few authors reported positive results after augmentation compression plating (ACP) for the same entity. To our knowledge no systematic study is published comparing ERN vs. ACP, so that this trial compares ACP leaving the already inserted un-reamed nail in situ against ERN in the treatment of aseptic tibial non-union, analysing success rate, time for union and operation time. PATIENTS AND METHODS: Forty-eight patients with aseptic hypertrophic diaphyseal tibial non-union treated previously by un-reamed nailing were included retrospectively in this two-centre study. Group A consisted of 25 patients with ERN and group B of 23 patients with ACP leaving the underlying un-reamed nail in situ. RESULTS: Mean follow-up was 3.8 years. Union was achieved in 24 out of 25 cases (96 %) for group A and in 22 out of 23 cases (95.6 %) for group B. Time needed for union varied; an average of 29 weeks for group A and 14 weeks for group B. The mean operation time for group A was 99 min, while it was 65 min for group B. CONCLUSIONS: ERN and ACP with remaining pre-existing nail in situ are both safe and straightforward surgical procedures with equivalent high success rates of about 95 %. ACP has the advantage of less time for union and operating time in this series, but is associated with the disadvantage of requiring an additional incision and complaints associated to the plate requiring implant removal.

Induction of tumor stem cell differentiation--novel strategy to overcome therapy resistance in gastric cancer.

PURPOSE: Metastases are a frequent finding in gastric cancer and are associated with poor prognosis. A recently discovered link between metabolic changes, differentiation, and therapy resistance due to tumor stem cells could depict a novel approach in cancer research and therapy. Phosphoglycerate kinase 1 (PGK1) is a metabolic enzyme and is known to be involved in enabling gastric cancer cells to be invasive and to disseminate. In this study, we investigated if PGK1 is a promising candidate in inducing stem cell differentiation in gastric cancer. MATERIALS AND METHODS: MKN45 gastric cancer cells were used due to their known cancer stem cell population, which is defined by the surface marker CD44. MKN45 cells were separated between CD44+ and CD44- cells and, in equal parts, incubated with shRNA anti-PGK1 using fluorescence-activated cell sorting (FACS) analysis; they were then injected into nude mice to evaluate their tumor growth behavior in vivo. Further, the invasive potential of gastric cancer cells was evaluated in vitro using the xCelligence analyzing system. RESULTS: CD44+ gastric cancer cells treated with and without shRNA anti-PGK1 were capable to cause tumor growth in vivo, whereas tumor growth in CD44+ cells treated with shRNA anti-PGK1 was considerably smaller in comparison with that in CD44+ cells without treatment. CD44- cells did not show any noticeable tumor growth in vivo. By targeting PGK1, the invasive potential of gastric cancer cells was impressively reduced in vitro. In all our cells, which were targeted with shRNA anti-PGK1, we did not find any change that is in accordance with the phenotype of the cells using FACS analysis. CONCLUSIONS: Our findings suggest that targeting the key metabolic enzyme PGK1 in gastric cancer cells may open a new chapter in cancer treatment, which is well worth for further exploration in combination with recent chemotherapy, and might be a promising possibility to overcome therapy resistance in gastric cancer.

High success rate for augmentation compression plating leaving the nail in situ for aseptic diaphyseal tibial nonunions.

OBJECTIVES: To evaluate adjunctive compression plating leaving the previously unreamed inserted intramedullary nail (URIMN) in situ for treating a resultant diaphyseal tibial nonunion. DESIGN: Retrospective study. SETTING: Level 1 trauma center (University Hospital). PATIENTS/PARTICIPANTS: Patients treated by URIMN for diaphyseal tibial fractures that developed an aseptic hypertrophic nonunion. INTERVENTION: Dynamization of the nail and compression plating leaving the URIMN in situ. MAIN OUTCOME MEASUREMENTS: Radiographic and clinical parameters. RESULTS: The mean follow-up was 3.8 years (range 2-7 years). Mean time for healing was 15 weeks with a mean operation time of 63 minutes. Union occurred in 27/28 (96.4%). There were no infections. CONCLUSIONS: This simple technique seems to have a high success rate and should be considered when a nonunion occurs after URIMN. The need for an additional incision and removal of symptomatic implants remains a disadvantage. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Lactate influences the gene expression profile of human mesenchymal stem cells (hMSC) in a dose dependant manner.

BACKGROUND/AIMS: Wounds, especially non-healing wounds are characterized by elevated tissue lactate concentrations. Lactate is known for being able to stimulate collagen synthesis and vessel growth. Lately it has been shown that lactate, in vivo, plays an important role in homing of stem cells. With this work we aimed to show the influence of lactate on the gene expressionprofile of human mesenchymal stem cells (hMSC). MATERIALS AND METHODS: hMSCs were obtained from bone marrow and characterized with fluorescence-activated cell sorting (FACS) analysis. Subsequently the hMSCs were treated with either 0, 5, 10 and 15 mM lactate (pH 7,4) for 24 hours. RNA Isolation from stimulated hMSCs and controls was performed. The Microarray analysis was performed using AffymetrixHuGene 1.0 ST Gene Chip. Selected targets were subsequently analysed using quantitative real time PCR (RTq-PCR). RESULTS: We were able to show that lactate in moderate concentrations of 5 respectively 10 mM leads to an anti-inflammatory, anti-apoptotic but growth and proliferation promoting gene expression after 24 h. In contrast, high lactate concentrations of 15 mM leads to the opposed effect, namely promoting inflammation and apoptosis. Hypoxia induced genes did not show any significant regulation. Contrary to expectation, we were not able to show any significant regulation of candidates associated with glycolysis. CONCLUSION: We were able to show that lactate alters gene expression but does not change the cell phenotype, which might be helpful for further investigations of new treatment strategies for chronic non-healing wounds as well as tumor-therapy and neuronal plasticity.

MSH2 and CXCR4 involvement in malignant VIPoma.

BACKGROUND: Vasoactive intestinal polypeptide secreting tumors(VIPomas) are rare endocrine tumors of the pancreas with an estimated incidence of 0.1 per million per year. The molecular mechanisms that mediate development of VIPomas are poorly investigated and require definition. METHODS: A genome- and gene expression analysis of specimens of a primary pancreatic VIPoma with hepatic metastases was performed. The primary tumor, the metastases, the corresponding healthy tissue of the liver, and the pancreas were compared with each other using oligonucleotide microarrays and loss of heterozygosity (LOH). RESULTS: The results revealed multiple LOH events and several differentially expressed genes. Our finding of LOH and downregulation was conspicuous in the microarray analysis for the mismatch repair gene MSH2 in the primary pancreatic VIPoma tumor, the hepatic metastasis but not in the corresponding healthy tissue. Further a strong overexpression of the chemokine CXCR4 was detected in the hepatic metastases compared to its pancreatic primary. With a review of the literature we describe the molecular insights of metastatic development in VIPoma. CONCLUSION: In VIPoma, defects in the mismatch repair system especially in MSH2 may contribute to carcinogenesis, and increased CXCR4 may be associated with liver metastasis.

Impact of endotoxin exposure after exhausting exercise on the immune system in solid organ transplant recipients.

Subsequent to prolonged exhausting exercise a transient immunosuppression is often observed in athletes. This so-called "open window" results in a reduced resistance of the athletes to viral and bacterial infections after an exhaustive exercise bout. Concerning the effect of bacterial endotoxin contact after exhausting exercise in transplant recipients, who are innately immunosuppressed by their medication, no data exists at present. After performing 81 km cycling, including ascending more than 1800 m in altitude, peripheral blood from 10 male kidney transplant recipients and from 10 healthy controls matched for age and gender was obtained. Simulating contact of the athletes with a pathogen post-exercise, the blood samples were incubated with Lipopolysaccharides (LPS). Thereafter microarray analysis was performed. Microarray analysis revealed a markedly oppositional pattern of gene expression in transplant recipients compared with their controls after LPS incubation. Especially immune response genes were significantly over-represented in controls immediately after the exhaustive exercise bout with LPS stimulation, whereas numerous apoptotic genes were over-represented in transplant recipients. Merging our previous data with these recent findings it should be discussed if transplant recipients need to reduce their immunosuppressive medication before performing exhaustive exercise.

Impact of risk factors for prolonged operative time in laparoscopic cholecystectomy.

OBJECTIVE: Laparoscopic cholecystectomy (LC) remains one of the most frequent surgical therapies for symptomatic gallstone disorders. Prolonged operative time is frequently associated with increased complication rates. The aim of this study was to identify the risk factors for prolonged operative times to minimize perioperative morbidity and optimize clinical management. METHODS: A total of 677 consecutive patients underwent LC. The exclusion criteria were conversion to an open procedure, intraoperative cholangiography, and liver cirrhosis (n=81). Data were analyzed retrospectively with respect to age, sex, BMI, ASA score, previous abdominal surgery, preoperative endoscopic retrograde cholangiopancreatography, acute cholecystitis, and surgeon's experience. Univariate and multivariate analyses were performed. RESULTS: A total of 596 patients, mean (± SD) age of 52.2 ± 16.7 years, were analyzed. In all, 29% of the patients were obese (BMI ≥ 30 kg/m); 11% had ASA III. Five percent of patients had undergone previous upper abdominal surgery. Overall, 105/596 patients had an acute cholecystitis. Residents of general surgery performed 58% of all operations. The median operative time was 80 min (range, 15-281 min). No statistical significance was found between intraoperative and postoperative complications by surgeon's experience. Statistically, independent preoperative predictors for prolonged operative time as identified through multivariate analysis were acute cholecystitis, obesity, previous upper abdominal surgery, male sex, and low degree of surgical expertise. CONCLUSION: The risk for prolonged operative times in LC can be assessed on the basis of patients' characteristics. Assessment of these factors not only helps to optimize the individual outcome for each patient but also improves the decision process toward operative training for junior surgeons.

Experience after 100 patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

AIM: To investigate perioperative patient morbidity/mortality and outcome after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: Of 150 patients 100 were treated with cytoreductive surgery and HIPEC and retrospectively analyzed. Clinical and postoperative follow-up data were evaluated. Body mass index (BMI), age and peritoneal carcinomatosis index (PCI) were chosen as selection criteria with regard to tumor-free survival and perioperative morbidity for this multimodal therapy. RESULTS: CRS with HIPEC was successfully performed in 100 out of 150 patients. Fifty patients were excluded because of intraoperative contraindication. Median PCI was 17 (1-39). In 89% a radical resection (CC0/CC1) was achieved. One patient died postoperatively due to multiorgan failure. Neither PCI, age nor BMI was a risk factor for postoperative complications/outcome according to the DINDO classification. In 9% Re-CRS with HIPEC was performed during the follow-up period. CONCLUSION: Patient selection remains the most important issue. Neither PCI, age nor BMI alone should be an exclusion criterion for this multimodal therapy.

Decreased levels of active SMAD2 correlate with poor prognosis in gastric cancer.

BACKGROUND: TGF-ß plays a dual role in the progression of human cancer. During the early stages of carcinogenesis, TGF-ß functions as a tumor suppressor. During the late stages of tumor development, however, TGF-ß can promote tumor growth and metastasis. A shift in Smad2/3 phosphorylation from the carboxy terminus to linker sites is a key event determining biological function of TGF-ß in colorectal and hepatocellular carcinoma. In the present study, we investigated the potential role of differential Smad2/3 phosphorylation in gastric adenocarcinoma. METHODOLOGY: Immunohistochemical staining with anti-P-Smad2/3C and P-Smad2/3L antibodies was performed on 130 paraffin-embedded gastric adenocarcinoma specimens. The relationship between P-Smad2/3C and P-Smad2/3L immunohistochemical score and clinicopathologic characteristics of patients was analyzed. Real time PCR was used to measure mRNA expression of Smad2 and Smad3 in cancer and surrounding non-tumor tissue. PRINCIPAL FINDINGS: No significant P-Smad2L and/or P-Smad3L positive staining was detected in the majority of specimens (positive staining in 18/130 samples). Positive P-Smad2/3L staining was not associated with a decrease in carboxyterminal phosphorylation staining. Loss of P-Smad2C remarkably correlated with depth of tumor infiltration and poor differentiation of cancer cells in patients with gastric cancer. No correlation was detectable between P-Smad3C and clinicopathologic characteristics of gastric adenocarcinoma. However, co-staining analysis revealed that P-Smad3C co-localised with α-SMA and collagen I in gastric cancer cells, indicating a potential link between P-Smad3C and epithelial-to-mesenchymal transition of cancer. Real time PCR demonstrated reduced mRNA expression of Smad2 in gastric cancer when compared with surrounding non-tumor tissue in 15/16 patients. CONCLUSIONS: Loss of P-Smad2C tightly correlated with cancer invasion and poor differentiation in gastric cancer. Contrary to colorectal and hepatocellular carcinoma, canonical carboxy-terminal phosphorylation, but not linker phosphorylation, of Smad2 is critical for gastric cancer.

The gut is not only the target but a source of inflammatory mediators inhibiting gastrointestinal motility during sepsis.

BACKGROUND: Sepsis is a common problem in intensive care patients leading to multi-organ failure and gastrointestinal paralysis. AIM: The aim of the study was to investigate whether the gastrointestinal tract is not only the target but also the source of inflammatory mediators inhibiting gastrointestinal motility. METHODS: Mesenteric lymph was obtained from rats in which a sepsis was induced by lipopolysaccharide (LPS) intraperitoneally. Gastrointestinal motility was recorded following mesenteric lymph- or TNFα infusion into the jugular vein of separate healthy recipient rats using the strain gauge transducer technique. RESULTS: Infusion of sepsis lymph significantly impairs gastric and colonic motility, decreasing the motility-index in the stomach and colon by about 57% and 21% respectively in comparison to baseline motility. Among other inflammatory mediators, TNFα plays an important role in mediating the inhibitory effect of mesenteric lymph on gastrointestinal motility during sepsis. CONCLUSIONS: The gastrointestinal tract is the source and the target of inflammatory mediators released during sepsis causing paralytic ileus.