Nucleolin mediates the binding of cancer cells to L-selectin under conditions of lymphodynamic shear stress.

Head and neck squamous cell carcinoma (HNSCC) cells bind to lymphocytes via L-selectin in a shear-dependent manner. This interaction takes place exclusively under low-shear stress conditions, such as those found within the lymph node parenchyma. This represents a novel functional role for L-selectin-selectin ligand interactions. Our previous work has characterized as-of-yet unidentified L-selectin ligands expressed by HNSCC cells that are specifically active under conditions of low shear stress consistent with lymph flow. Using an affinity purification approach, we now show that nucleolin expressed on the surface of HNSCC cells is an active ligand for L-selectin. Parallel plate chamber flow-based experiments and atomic force microscopy (AFM) experiments show that nucleolin is the main functional ligand under these low-force conditions. Furthermore, AFM shows a clear relationship between work of deadhesion and physiological loading rates. Our results reveal nucleolin as the first major ligand reported for L-selectin that operates under low-shear stress conditions.

Clinicopathological predictors of lymphatic metastasis in HNSCC: implications for molecular mechanisms of metastatic disease.

Lymphatic metastasis is associated with up to a 50% decrease in survival, yet the molecular mechanisms driving their establishment remain poorly understood. This study assessed clinicopathological characteristics correlated to nodal metastasis among patients with head and neck squamous cell carcinoma for the identification of pathways on which to focus molecular studies. Pathology records were queried for cases diagnosed with invasive squamous cell cancer of the upper aerodigestive tract between 1993 and 2003. Charts and pathology reports were scored for 16 characteristics. The univariate association of each variable with lymph node status was assessed. Based on the univariate analysis, a multiple logistic regression model was developed to assess the simultaneous association of variables with lymph node status. Of the 644 cases identified, 234 had a surgical specimen analyzed. All variables were scored for 185 of the 234 cases. Multivariate stepwise regression analysis identified clinical stage (p = 0.0269), pathologic stage (p = 0.0162), grade (p = 0.0094), lymphovascular invasion (p = 0.0393), and family history of cancer (p = 0.0079) as independently predictive of lymphatic metastases. Our study confirms that grade, pathologic stage, clinical stage, and lymphovascular invasion are predictors of regional metastasis. These correlations suggest that studying the molecular mechanisms of differentiation, interstitial pressure at the primary tumor site, and peritumoral lymphangiogenesis may provide insight into lymphatic metastasis. Additionally, we identified family history of cancer as a new predictor of lymphatic metastasis. Thus, genetic analysis of families with cancer, irrespective of type, may identify genes important for regional metastasis.

The postcholecystectomy syndrome in morbid obesity.

Choledocholithiasis has been found in about 5% to 20% of the approximately 20 million Americans with cholelithiasis who have undergone cholecystectomy. We report a case of a 64-year-old woman who developed gallstones after undergoing a cholecystectomy >40 years earlier. The potential of retained gallstones, incomplete gallbladder removal, or regeneration of gallstones in the gallbladder remnant or cystic duct remnant after a long time following cholecystectomy is discussed.

Importance of imaging in knee pain.

A 72-year-old woman with a prior history of stage IIIa lung adenocarcinoma was seen with complaints of knee pain, swelling, and difficulty sleeping at night for 1 month. Although mimicking osteoarthritis, patellofemoral syndrome, and iliotibial band syndrome, radiographs showed a lytic lesion suspicious for metastatic disease. The right tibial lesion was excised, saphenous neurolysis was performed, and radiation treatment and four cycles of chemotherapy were administered. This case shows the importance of early imaging in patients with knee pain of prolonged duration seen in the primary care setting.

Steroid-induced psychosis.

Steroid-induced psychosis is a well-documented phenomenon. It usually occurs with oral systemic steroid treatment and is more common at higher doses, although there are case reports of occurrence with local steroid injections. We report a case of a 35-year-old man with no previous history of psychosis who was seen for follow-up after a brief psychotic episode following an injection of 5 mg of dexamethasone into his scrotum the previous day. The injection was given to treat chronic pain from a combat injury.

Diagnosis of Waldenström macroglobulinemia.

Waldenström macroglobulinemia is a rare disorder affecting about 1400 people annually in the United States. This case report reviews from a primary care provider's perspective the initial presentation of a patient who complained of fatigue and dizziness that ultimately led to hospital admission with a diagnosis of Waldenström macroglobulinemia. The referral to hematology/oncology prompting the bone marrow biopsy that led to the diagnosis highlights the important role of the primary care provider in the initial workup, coordination among specialists, and overall management of patients with rare disorders.

Nontypical Salmonella meningitis in an infant.

A previously healthy 3-month-old girl was admitted to the hospital after 1 day of fever, decreased oral intake, irritability, lethargy, and decreased activity. Examination disclosed a bulging anterior fontanelle, tachycardia (heart rate of 160 beats/minute), and urate crystals in her diaper. Lumbar puncture revealed meningitis. She was treated with broad-spectrum antibiotics and fluids. A urine culture was negative, but blood and cerebrospinal fluid cultures came back positive for Salmonella species, nontyphoid. During her hospitalization, she developed seizures but quickly improved with treatment and made a complete recovery with no sequela. Additional inquiry disclosed that the baby spent several days a week at her grandparents' house, where they raised chickens and ate fresh chicken eggs, which are well-known carriers for Salmonella.

Acute kidney injury and undiagnosed immunoglobulin A nephropathy after dabigatran therapy.

Dabigatran, a new oral anticoagulant, is a direct thrombin inhibitor used as an alternative to warfarin to reduce the risk of stroke and systemic embolism with nonvalvular atrial fibrillation. We report a case of a man who resumed dabigatran after 6 weeks of prior therapy and began experiencing hematuria with worsening kidney function. Renal biopsy with immunofluorescence and electron microscopy showed mesangial deposits consistent with immunoglobulin A nephropathy. With discontinuation of dabigatran and addition of methylprednisolone, the gross hematuria cleared and urine output improved.

Endothelial dysfunction in patients with antiphospholipid syndrome assessed with positron emission tomography.

BACKGROUND: There is limited knowledge about endothelial dysfunction in patients with primary antiphospholipid syndrome (PAPS). The purpose of this study was to evaluate endothelial function in patients with PAPS assessed by positron emission tomography. METHODS AND RESULTS: A 3-phase protocol--rest, cold pressor test (CPT), and adenosine positron emission tomography with nitrogen 13 ammonia--was used in 18 patients with PAPS and 18 healthy volunteers (HVs). Myocardial blood flow (MBF) was measured in each phase, with calculation of the endothelial-dependent vasodilation index, the increase in the MBF in response to CPT, and the myocardial flow reserve. An important trend was found in the myocardial flow reserve (2.76 +/- 1.04 in PAPS group vs 3.27 +/- 0.72 in HV group, P > .05), in the endothelial-dependent vasodilation index (1.19 +/- 0.31 in PAPS group vs 1.55 +/- 0.37 in HV group, P < .05), and in the percent change in the MBF in response to CPT (from rest) (19% +/- 31% in PAPS group vs 55% +/- 37% in HV group, P < .05). CONCLUSION: The CPT results obtained in this study showed that the PAPS patients studied have endothelial dysfunction.

Eukaryotic initiation factor 4E variants alter the morphology, proliferation, and colony-formation properties of MDA-MB-435 cancer cells.

Eukaryotic initiation factor 4E (eIF4E) binds to the 5' m(7)G cap of mRNAs and is a focal point of regulation of initiation of mRNA translation. High levels of expression of eIF4E in many epithelial cancers, including breast, head and neck, colon, and bladder, correlate with increased tissue invasion and metastasis. To further examine the role of eIF4E in the biology of cancer cells, variants of eIF4E with impaired 5' cap binding function were expressed in MDA-MB-435 carcinoma cells. Cell lines overexpressing variants of eIF4E had impaired growth properties and exhibited a different morphology compared to cells expressing similar amounts of exogenous wild-type eIF4E or control cells. Cells expressing variant eIF4E did not form foci in culture and produced smaller colonies in soft agar compared to cells expressing wild-type eIF4E. In addition, analysis of polyribosomes for vascular endothelial growth factor (VEGF) mRNA demonstrated a shift from translationally active to inactive fractions in variant eIF4E cells, while GAPDH mRNA did not. The long G-C rich 5' untranslated region of VEGF mRNA is a feature of other mRNAs encoding growth regulating proteins that are predicted to have their translation enhanced by increases in eIF4E; whereas mRNA with shorter and less structured 5' UTRs, like that of GAPDH, are predicted to be largely unaffected. These data suggest that targeting the 5' cap-binding domain of eIF4E may be a viable option to slow cancer cell growth and alter the malignant phenotype.