Characterization of the CXCR4 Signaling in Pancreatic Cancer Cells

CXCL12 and its receptor, CXCR4, are emerging as promising targets for modulating growth, angiogenesis, and metastasis in several human cancers. Indeed, blocking the receptor is sufficient to prevent metastasis and angiogenesis in experimental breast cancer xenografts. Recently, the biological effect of the CXCR4 in pancreatic cancer, one of the most deadly neoplastic diseases, has been reported. However, the molecular mechanism by which CXCR4 contributes to these properties is not completely understood. In this paper, we characterize the signaling pathways activated by CXCR4 in pancreatic cancer. We show that after CXCR4 activation, EGFR becomes tyrosine phosphorylated, and the kinase activity of this receptor, together with the activation of MMPs, Src, and PI3-Kinase, is required for CXCR4-mediated ERK activation. Analysis of this cascade in pancreatic cancer cells revealed that the ERK-mediated pathway regulates genes involved in angiogenesis, such as VEGF, CD44, HIF1α, and IL-8. Furthermore, ERK blockage inhibits the migration and tube formation of endothelial cells induced by CXCL12. Considering that inhibitors for several components of this pathway, including CXCR4 itself, are at different stages of clinical trials, this study provides theoretical justification for the clinical testing of these drugs in pancreatic cancer, thus extending the list of potential targets for treating this dismal disease.     

Comparison of ThinPrep versus conventional smear cytopreparatory techniques for fine-needle aspiration specimens of head and neck masses.

OBJECTIVES: Diagnostic accuracy of the ThinPrep process (Cytyc, Boxborough, MA) was compared with that of conventional (smear) cytopreparation for fine-needle aspiration (FNA) of head and neck masses. METHODS: In a prospective, randomized, single-blinded study, 209 patients served as their own controls and underwent 236 FNAs using ThinPrep and conventional (smear) cytopreparatory techniques. RESULTS: ThinPrep produced less air-drying artifact and less mechanical distortion than the conventional method. The conventional technique was diagnostic in 63% of samples; the ThinPrep technique was diagnostic in 55% of samples. When all results were combined, pathologists subjectively preferred the conventional technique but accepted use of ThinPrep as the only cytopreparatory technique for most head and neck masses. CONCLUSIONS: For adequately experienced cytopathologists, ThinPrep is acceptable for FNA of salivary masses, neck cysts, metastatic lymph nodes, and thyroid lesions. Conventional smear technique should be used for FNA of nonmetastatic lymphoid lesions. Use of ThinPrep can complement use of the conventional (smear) cytopreparatory technique when aspirate is nondiagnostic or bloody, when the patient has a blood-borne infectious disease, when the clinician is inexperienced, or when aspirate has entered the syringe.     

Long-term results of surgical treatment of dysphagia secondary to cervical diffuse idiopathic skeletal hyperostosis

Background contextLarge, prominent osteophytes along the anterior aspect of the cervical spine have been reported as a cause of dysphagia. Improvement of swallowing after surgical resection has been reported in a few case reports with short-term follow-up. The current report describes outcomes of a series of five patients with surgical treatment for this rare disorder, with a long-term follow-up.PurposeTo study the clinical and radiographic outcomes of a case series of patients surgically treated for dysphagia secondary to cervical diffuse idiopathic skeletal hyperostosis (DISH).Study designRetrospective review of a case series.Patient sampleFive cases from a University Hospital.Outcome measuresClinical and imagenological follow-up.MethodsThe records of five patients with dysphagia who had undergone anterior surgical resection of prominent osteophytes secondary to DISH were reviewed. Extrinsic esophageal compression secondary to anterior cervical osteophytes was radiographically confirmed via preoperative barium esophagogram swallowing study. All patients underwent anterior cervical osteophytes resection without fusion. Postoperatively, patients were followed-up clinically and radiographically with routine lateral cervical radiographs.ResultsPreoperative esophagogram showed that the esophageal obstruction was present at one level in three cases and two levels in two cases. The C3–C4 level was involved in three cases, C4–C5 in three cases, and C5–C6 in one case. There were no postoperative complications, including recurrent laryngeal nerve palsy, wound infection, or hematomas. All patients had resolution of dyphagia soon after surgery (within 2 weeks). Postoperative radiographs demonstrated complete removal of osteophytes. At final follow-up, ranging from 1 to 9 years (average 59.8 months, median 53 months), no patients reported recurrence of dysphagia. Final radiographic examination demonstrated minimal regrowth of the osteophytes.ConclusionsAlthough rarely indicated, surgical resection of anterior cervical osteophytes from DISH causing dyphagia produces good clinical and radiographical outcomes. After thorough evaluation to rule out other intrinsic or extrinsic causes of swallowing difficulty, surgical treatment of this uncommon condition might be considered.     

Exacerbation of occult femoral hernia during laparoscopic prostatectomy.

Laparoscopic prostatectomy has been accepted as an appropriate treatment for prostate cancer because of the shorter hospital stay and quicker recovery. We present a rare complication of groin hernia with incarceration and necrosis of small bowel following laparoscopic prostatectomy. Occult hernias and small fascia defects may not always be apparent pre-operatively, but extension of pneumoperitoneal insufflation to extraperitoneal compartments should alert the surgeon to the possible presence of such a defect.     

Effect of Bupivacaine and Levobupivacaine on Exocytotic Norepinephrine Release from Rat Atria

Background: The cardiotoxic mechanism of local anesthetics may include interruption of cardiac sympathetic reflexes. The authors undertook this investigation to determine if clinically relevant concentrations of bupivacaine and levobupivacaine interfere with exocytotic norepinephrine release from cardiac sympathetic nerve endings.

Methods: Rat atria were prepared for measurements of twitch contractile force and 3[H]-norepinephrine release. After nerve endings were loaded with 3[H]-norepinephrine, the tissue was electrically stimulated in 5-min episodes during 10 10-min sampling periods. After each period, a sample of bath fluid was analyzed for radioactivity and 3[H]-norepinephrine release was expressed as a fraction of tissue counts. Atria were exposed to buffer alone during sampling periods 1 and 2 (S1 and S2). Control atria received saline (100 [mu]l each, n = 6 atria) in S3-S10. Experimental groups (n = 6 per group) received either bupivacaine or levobupivacaine at concentrations (in [mu]M) of 5 (S3-S4), 10 (S5-S6), 30 (S7-S8), and 100 (S9-S10).

Results: Bupivacaine and levobupivacaine decreased stimulation-evoked fractional 3[H]-norepinephrine release with inhibitory concentration 50% values of 5.1 +/- 0.5 and 6.1 +/- 1.3 [mu]m. The inhibitory effect of both local anesthetics (~70%) approached that of tetrodotoxin. Local anesthetics abolished the twitch contractions of atria with inhibitory concentration 50% values of 12.6 +/- 5.0 [mu]m (bupivacaine) and 15.7 +/- 3.9 [mu]m (levobupivacaine). In separate experiments, tetrodotoxin inhibited twitch contractile force by only 30%.     

Immature circulating lymphocytes in severely malnourished Guatemalan children

The percentage of peripheral blood lymphocytes forming rosettes with sheep erythrocytes (E-rosettes) was determined in 33 severely malnourished Guatemalan children, and in two groups of clinically well but mildly growth retarded children from the same environment. Mean E-rosettes in the acutely ill patients was lower than the value observed in the mildly malnourished children, although there was considerable overlap between groups. These data differ from previously published studies of severely malnourished children from other parts of the world in that not all patients had decreased values for E-rosettes, in contrast to the uniform depression reported by others. As all patients were clinically similar, the results suggest that there may be specific nutrient defects associated with protein-energy malnutrition that particularly affect immune function. In addition, in vitro incubation of lymphocytes from the acutely malnourished children with the thymic factor, thymosin fraction 5, increased the percentage of E-rosettes in a dose-dependent fashion. These data suggest that immature, thymosin-responsive T cells are present in circulation. It is possible that in vivo thymosin administration may be beneficial for malnourished individuals.     

Double-orifice mitral valve with intact atrioventricular septum: an echocardiographic study with anatomic and functional considerations.

We identified 18 patients with double-orifice mitral valve (DOMV) and intact atrioventricular (AV) septum out of 40,179 echocardiographic studies performed between 1997 and 2002 at Children's Hospital, Denver, CO. In this study we describe (1) the anatomic characteristics of the DOMV in the absence of AV septal defect, (2) the function of the mitral valve by spectral and color Doppler flow mapping, and (3) associated lesions. The topographic location of the orifices in the leaflets suggests possible embryologic mechanisms of DOMV. In this series, DOMV was most commonly associated with left-sided obstructive lesions (in 39% of patients). Spectral and color Doppler interrogation demonstrated a normal flow profile in most cases; only 2 patients had significant mitral regurgitation or stenosis. Therefore, due to the uncertain natural history of this lesion and the potential need for endocarditis prophylaxis, careful imaging of the mitral valve is recommended, particularly in the presence of left-sided obstructive lesions.     

Diabetes mellitus-associated diffuse autonomic dysfunction causing debilitating hypotension manifested after rapid weight loss in a morbidly obese patient: case report and review of the literature.

The association between weight and blood pressure is well established, especially the paradigm of obesity-related hypertension. The relationship between diffuse autonomic dysfunction and orthostatic hypotension in patients with long-term diabetes mellitus is also well known. We report on a 57-year-old morbidly obese male with a long medical history of hypertension, myocardial infarction, type 2 diabetes mellitus, and hypothyroidism. After a loss of 147 pounds (representing a percent excess weight loss of 76%) within 6 months after gastric bypass surgery, the patient developed worsening orthostatic hypotension and near-syncopal episodes requiring medication. The subsequent diagnosis and treatment, as well as a literature review, are presented.