YC-1 alleviates bone loss in ovariectomized rats by inhibiting bone resorption and inducing extrinsic apoptosis in osteoclasts.

Osteoporosis is a major health problem in postmenopausal women and the elderly that leads to fractures associated with substantial morbidity and mortality. Current osteoporosis therapies have significant drawbacks, and the risk of fragility fractures has not yet been eliminated. There remains an unmet need for a broader range of therapeutics. Previous studies have shown that YC-1 has important regulatory functions in the cardiovascular and nervous systems. Many of the YC-1 effector molecules in platelets, smooth muscle cells and neurons, such as cGMP and µ-calpain, also have important functions in osteoclasts. In this study, we explored the effects of YC-1 on bone remodeling and determined the potential of YC-1 as a treatment for postmenopausal osteoporosis. Micro-computed tomography of lumbar vertebrae showed that YC-1 significantly improved trabecular bone microarchitecture in ovariectomized rats compared with sham-operated rats. YC-1 also significantly reversed the increases in serum bone resorption and formation in these rats, as measured by enzyme immunoassays for serum CTX-1 and P1NP, respectively. Actin ring and pit formation assays and TRAP staining analysis showed that YC-1 inhibited osteoclast activity and survival. YC-1 induced extrinsic apoptosis in osteoclasts by activating caspase-3 and caspase-8. In osteoclasts, YC-1 stimulated µ-calpain activity and inhibited Src activity. Our findings provide proof-of-concept for YC-1 as a novel antiresorptive treatment strategy for postmenopausal osteoporosis, confirming an important role of nitric oxide/cGMP/protein kinase G signaling in bone.

A rare case of monomorphic epitheliotropic intestinal T-cell lymphoma, presenting with spontaneous intestinal perforation.

INTRODUCTION AND IMPORTANCE: Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare and aggressive T-cell lymphoma that primarily affects the intestine. It has a poor prognosis and high mortality rate. Symptoms at presentation can be non-specific, and imaging studies may show similarities with nonmalignant conditions. The delayed clinical presentation and lack of targeted therapies contribute to the dismal prognosis of MEITL. CASE PRESENTATION: We present a case of spontaneous intestinal perforation caused by primary intestinal T-cell lymphoma, emphasizing the importance of early recognition of this uncommon cause of perforation. Identifying it is crucial for prompt surgery and chemotherapy for this rare disease. CLINICAL DISCUSSION: The most common site of involvement in MEITL is the small intestine, especially the jejunum. The prognosis of MEITL is poor. Early diagnosis of primary intestinal T-cell NHL is challenging due to its rarity and non-specific symptoms. Imaging and endoscopy may show certain features, but a definitive diagnosis relies on biopsy and histopathologic analysis. To date, no efficient therapeutic interventions have been demonstrated for the management of this entity. The standard management strategy consists of induction chemotherapy followed by autologous stem cell transplantation. CONCLUSION: This case report highlights that spontaneous perforation with peritonitis could be a potential presenting sign of MEITL. The diagnosis of MEITL is mainly based on histopathologic examination, so an accurate diagnosis necessitates clinical knowledge and thorough biopsy with immunohistochemistry and molecular testing.

A Rare Case of Cholecystoduodenal Fistula Complicated With Gallstone Ileus and Upper Gastrointestinal Bleeding.

Gallstone ileus is a rare presentation of cholelithiasis, which usually impacts the narrowest part of the bowel, the ileocecal valve. This occurs as a result of a bilioenteric fistula where a gallstone passed through and entered the gastrointestinal tract. It is most commonly encountered in elder patients and predominantly in females. Abdominal computed tomography is the investigation of choice for diagnosis in the majority of cases. Here, we present a 68-year-old female patient with a choledochoduodenal fistula complicated by upper gastrointestinal bleeding and gallstone ileus.

Ghrelin induces cell migration through GHS-R, CaMKII, AMPK, and NF-κB signaling pathway in glioma cells.

Ghrelin is a newly discovered gastric peptide which stimulates food intake, energy balance, and growth hormone release. Recent reports have also shown that circulating ghrelin can efficiently reach the brain. However, the molecular mechanisms and pathophysiologic roles underlying ghrelin-induced glioma migration remain unclear. Glioma is the most common primary adult brain tumor with poor prognosis because of the spreading of tumor cell to the other regions of brain easily. In present study, we found that application of recombinant human ghrelin enhances the glioma cell migration in both rat C6 and human U251 cells. Ghrelin and its receptor GHS-R (growth hormone secretagogue receptor) are expressed in a wide variety of tissues and cell types, including various cancer cells. However, little is known about the expression of ghrelin or GHS-R in brain tumors. Here, we found that ghrelin increased GHS-R receptor up-regulation, and the enhancement of ghrelin-induced glioma cell motility markedly inhibited by a GHS-R antagonist. In addition, ghrelin-mediated migration was attenuated by treatment of CaMKII inhibitor, and AMPK inhibitors and pre-transfection with AMPK siRNA. Moreover, ghrelin stimulation also increased the phosphorylation of CaMKII and AMPK. Treatment with three different types of NF-κB inhibitors or pre-transfection with KM-IKKα, or KM-IKKß also reduced ghrelin-induced glioma cell migration. Moreover, treatment of ghrelin also induced IKKα/ß activation, IκBα phosphorylation, p65 phosphorylation at Ser(536), and increased NF-κB-DNA binding activity and κB-transcriptional activity. These results indicate that ghrelin enhances migration of glioma cells is mainly regulated by the GHS-R, CaMKII, AMPK, and NF-κB pathway.

Mapping of genetic deletions on chromosome 3 in colorectal cancer: loss of 3p25-pter is associated with distant metastasis and poor survival.

PURPOSE: There is no detailed analysis of loss of heterozygosity (LOH) on chromosome 3 in colorectal cancer (CRC). Our aim was to define frequently deleted loci on chromosome 3 and to explore novel prognostic markers and the locations of candidate tumor suppressor genes associated with CRC. METHODS: LOH at 23 microsatellite markers spanning on chromosome 3 was determined in 112 sporadic CRC by automated fluorescence-based polymerase chain reaction. Genetic loss was assessed for the clinicopathological significance by univariate and multivariate analyses. RESULTS: Fifty-eight (51.8%) of 112 carcinomas exhibited LOH at one or more loci tested. Among seven loci with high LOH rates, allelic losses at D3S1297 and D3S1266 occurred more frequently in younger patients. A marked gender distortion for genetic deletion was observed at six loci, where LOH was identified more frequently in male cases. For clinical outcome, LOH solely at D3S1297 (3p26.3) was significantly associated with distant metastasis (P = 0.001) and was indicative of a shorter overall survival (P = 0.014). In addition, loss of one common deletion region at 3p25-pter was significantly correlated to distant metastasis (P = 0.009) and had an adverse effect on patients' overall survival in univariate and multivariate tests (P = 0.009 and 0.001, respectively). CONCLUSIONS: Loss of chromosome 3p25-pter could act as an independent predicator of poor prognosis in CRC, suggesting that microsatellite analysis is a useful means to stratify patients into different risk groups. In addition, inactivation of candidate tumor suppressor genes in this region might involve in CRC progression.

Mitochondrial genomic instability in colorectal cancer: no correlation to nuclear microsatellite instability and allelic deletion of hMSH2, hMLH1, and p53 genes, but prediction of better survival for Dukes' stage C disease.

PURPOSE: Malfunction of mismatch repair (MMR) system and p53 produces nuclear genomic instability and is involved in colorectal tumorigenesis. In addition to a nuclear genome, eukaryotic cells have cytoplasmic genomes that are compartmentalized in the mitochondria. The aims of this study were to detect the mitochondrial genomic instability (mtGI) in colorectal carcinomas, and to explore its relationship with nuclear genetic alterations and its prognostic meaning. METHODS: Eighty-three colorectal carcinomas with corresponding normal mucosa were analyzed for mtGI, nuclear microsatellite instability (nMSI), and loss of heterozygosity (LOH) of hMSH2, hMLH1, and p53 genes. Mitochondrial and nuclear alterations were examined for mutual correlation and for associations with clinicopathological features and clinical outcomes. RESULTS: Out of 83 cases, mtGI was identified in 23 carcinomas (27.7%), whereas nMSI was detected in 11 (13.3%). Of the 23 cases with mtGI, only two showed nMSI simultaneously. The frequencies of LOH of hMSH2, hMLH1, and p53 were 16.1%, 11.6%, and 65.3%, respectively. There was no significant association between mtGI and these allelic losses. Notably, Dukes' C patients with mtGI had better disease-free and overall survival than those lacking this feature (p = 0.0516 and 0.0313, respectively). CONCLUSIONS: Mitochondrial genomic instability occurs with a high frequency in colorectal carcinomas but is independent of nMSI and allelic deletion of hMSH2, hMLH1, and p53 genes. The results suggest that, instead of nuclear MMR system, there might be different mechanisms involving mitochondrial genomic integrity, and mtGI confers a better prognosis in Dukes' C colorectal cancer.

Intestinal perforations in Behçet's disease.

Behçet's disease accompanied by intestinal involvement is called intestinal Behçet's disease. The intestinal ulcers of Behçet's disease are usually multiple and scattered and tend to perforate easily, so that many patients require emergency operation. The aim of this study is to determine the extent of surgical resection necessary to prevent reperforation and to point out the findings of concurrent oral and genital ulcers and multiple intestinal perforations in all patients of our series. During a 25-year study period, information of 125 Behçet's disease cases was gathered. Among the 82 patients who were diagnosed with intestinal Behçet's disease, 22 cases had intestinal perforations needing emergency laparotomy. We investigated and analyzed these cases according to the patients' demographic characteristics, clinical presentations, laboratory data, and surgical outcome. There were 14 men and 8 women ranging from 22 to 65 years of age. Nine cases were diagnosed preoperatively, and the diagnoses were confirmed in all 22 cases during the surgical intervention. Surgical resection was performed in every patient, with right hemicolectomy and ileocecal resection in 11 cases, partial ileum resection in 8 cases with two reperforations, and ileocecal resection in 3 cases with one reperforation.

RER and LOH association with sporadic colorectal cancer in Taiwanese patients.

BACKGROUND/AIMS: This association study was undertaken to determine replication error and loss of heterozygosity in colorectal tumors using a set of 10 microsatellite markers linked to APC, hMSH2, hMLH1, DCC, P53, NM23, HPC1 and MET genes as well as tumor suppressor genes on 8p22. METHODOLOGY: Thirty-nine patients diagnosed and confirmed with sporadic colorectal cancer were biopsied. Their stored frozen tissues were subsequently retrieved for simultaneous analyses of replication error and loss of heterozygosity via an automated fluorescent microsatellite assay. RESULTS: Replication error was observed in 8/39 of the cases (20.5%) and had significantly higher frequency in the patients younger than 60 yr (P = 0.049). More than one third of informative tumors showed loss of heterozygosity at P53, DCC and APC genes (57.9%, 35.3% and 33.3%, respectively). Loss of heterozygosity at TP53-Dint marker was significantly associated with survival status (P = 0.038) in which a higher frequency was observed in the patients who died from colorectal cancer. Of 22 informative tumors, 6 (27.3%) showed loss of heterozygosity at the D8S254 marker that is suspected to be near one or more tumor suppressor genes and was significantly associated with gender (P = 0.046). All 6 cases of loss of heterozygosity at D8S254 were found in male patients. The frequencies of loss of heterozygosity at the NM23, hMSH2, hMLH1 and HPC1 genes were 18.5%, 12.1%, 9.1% and 7.4%, respectively. None of the cases examined displayed loss of heterozygosity at the MET oncogene. CONCLUSIONS: Additional microsatellite markers other than those associated with colorectal cancer were used to conduct the study of genomic instability and alterations in colorectal cancer tumors. The present results for the sporadic occurrence of colorectal cancer in Taiwanese patients further extend the correlation of clinical pathology and prognosis with the analysis of replication error and loss of heterozygosity.

Osteopontin increases heme oxygenase-1 expression and subsequently induces cell migration and invasion in glioma cells.

Malignant gliomas are associated with high morbidity and mortality because they are highly invasive into surrounding brain tissue, making complete surgical resection impossible. Osteopontin is abundantly expressed in the brain and is involved in cell adhesion, migration, and invasion. The aim of the present study was to investigate the mechanisms of glioma cell migration. Migration and invasion activity were determined by transwell and wound-healing assays. Gene and protein expressions were analyzed by reverse transcription-PCR, real time-PCR, and Western blotting. Nrf2-DNA binding activity was determined by electrophoretic mobility shift assay. Establishment of migration-prone sublines were performed to select highly migratory glioma. An intracranial xenograft mouse model was used for the in vivo study. Application of recombinant human osteopontin enhanced the migration of glioma cells. Expression of heme oxygenase (HO)-1 mRNA and protein also increased in response to osteopontin stimulation. Osteopontin-induced increase in cell migration was antagonized by HO-1 inhibitor or HO-1 small interfering (si)RNA. Osteopontin-mediated HO-1 expression was reduced by treatment with MEK/ERK and phosphatidylinositol 3-kinase/Akt inhibitors, as well as siRNA against Nrf2. Furthermore, osteopontin stimulated Nrf2 accumulation in the nucleus and increased Nrf2-DNA binding activity. In migration-prone sublines, cells with greater migration ability had higher osteopontin and HO-1 expression, and zinc protoporphyrin IX treatment could effectively reduce the enhanced migration ability. In an intracranial xenograft mouse model, transplantation of migration-prone subline cells exhibited higher cell migration than parental tumor cells. These results indicate that osteopontin activates Nrf2 signaling, resulting in enhanced HO-1 expression and cell migration in glioma cells.

Management and prevention of complications of subcutaneous intravenous infusion port.

Subcutaneous intravenous infusion port (SIIP) has become an increasingly and widely adopted technique in the management of oncology patients. This route has been used not only for chemotherapy but also for parenteral nutrition provision, blood transfusion, medication administration, blood sample collection, hemodialysis, and so on. This system provides a safe vascular access with low complication rate which helps preventing patients from vascular infection and catheter associated thrombosis. In this study, we reviewed 1247 cases of breast cancer patients that had subcutaneous intravenous infusion port implanted for chemotherapy in our general surgery department from 1990 to 2008. The result indicates that complication decreases as our technique and experience mature. We hereby share our accrued experience and improved technique, hoping to be of help to young surgeons.

Ectopic pancreas presenting as ampulla of Vater tumor.

Ectopic pancreas is relatively rare and is defined as pancreatic tissue that is situated abnormally, has no contact with the normal pancreas, and has its own ductal system and blood supply. It is usually an incidental finding in clinical practice. Most patients with an ectopic pancreas are asymptomatic, and, if present, symptoms are nonspecific and depend on the site of the lesion and the different complications encountered. Heterotopic pancreatic tissue has been found in several abdominal and intrathoracic locations, most frequently in the stomach (25%-60%) or the duodenum (25%-35%). Herein, we report a patient presenting with symptoms of ampullary tumor with obstructive jaundice, but the imaging study did not suggest the possibility of ectopic pancreas preoperatively.

Midgut volvulus in an adult with congenital malrotation.

Congenital midgut malrotation, a rare anatomic anomaly that can lead to duodenal or small-bowel obstruction, rarely is observed beyond the first year of life. Symptomatic patients present with either acute bowel obstruction and intestinal ischemia with a midgut or cecal volvulus or with chronic vague abdominal pain. Chronic symptoms often can make the diagnosis difficult. By using several modalities such as barium studies, computerized tomography, angiography, and emergency laparotomy, we diagnosed midgut volvulus and partial intestinal obstruction, which occur rarely in an adult with congenital midgut malrotation.

Giant malignant mammary phyllodes tumor: report of a case and review of the literature.

BACKGROUND: To distinguish between a benign and malignant phyllodes tumor before surgery is difficult. Wide excision or mastectomy with adequate free margins is necessary in the case of a malignant phyllodes tumor. However, repairing the skin defect after removal of a giant malignant phyllodes tumor is a great challenge for the breast surgeon. CASE REPORT: We report the case of a 45-year-old Taiwanese woman with a giant malignant phyllodes tumor measuring 30 x 25 x 22 cm. Prior to surgery, we carefully designed a flap to cover the skin defect, following standard mastectomy with at least 2 cm free margins. Postoperatively, the patient recovered well without any wound infection or flap necrosis. During follow-up at our outpatient department, there was no evidence of local relapse or distant metastasis. CONCLUSION: Giant malignant phyllodes tumors can be treated by total mastectomy with adequate free margins, using a flap technique to cover the skin defect.

Ectopic pancreas in the ampulla of vater with obstructive jaundice. A case report and review of literature.

Ectopic pancreas is an uncommon condition and is usually found in the gastrointestinal tract, such as stomach, duodenum and jejunum. However, ectopic pancreas in the ampulla of Vater is rare and its clinical presentations may be similar to periampullary cancer. It is difficult to diagnose preoperatively. We present such a case where the diagnosis was proven postoperatively. Our patient, a 51-year-old man, presented with epigastric pain, jaundice, weight loss and abnormal laboratory data. Imaging study, including abdominal sonography, abdominal computerized tomography with contrast and endoscopic retrograde cholangiopancreatography, showed a mass protruding into the ampulla of Vater. The mass was resected and histological examination revealed an ectopic pancreas. The patient presented with symptoms of periampullary tumor but the imaging study did not reveal an obvious lesion for us consider the possibility of ectopic pancreas. Surgical excision is indicated for symptomatic cases.