Citations

AbstractGenetic aberrations, including trisomies 3 and 18, and well-defined IGH translocations, have been described in marginal zone lymphomas (MZLs); however, these known genetic events are present in only a subset of cases. Here, we report the cloning of an IGH translocation partner on chromosome X, t(X;14)(p11.4;q32) that deregulates expression of an poorly characterized orphan G-protein–coupled receptor, GPR34. Elevated GPR34 gene expression was detected independent of the translocation in multiple subtypes of non-Hodgkin lymphoma and distinguished a unique molecular subtype of MZL. Increased expression of GPR34 was also detected in tissue from brain tumors and surface expression of GPR34 was detected on human MZL tumor cells and normal immune cells. Overexpression of GPR34 in lymphoma and HeLa cells resulted in phosphorylation of ERK, PKC, and CREB; induced CRE, AP1, and NF-κB–mediated gene transcription; and increased cell proliferation. In summary, these results are the first to identify a role for a GPR34 in lymphoma cell growth, provide insight into GPR34-mediated signaling, identify a genetically unique subset of MZLs that express high levels of GPR34, and suggest that MEK inhibitors may be useful for treatment of GPR34-expressing tumors.

While it is evident that the carboxyl‐terminal region of natural peptide ligands bind to the amino‐terminal domain of class B GPCRs, how their biologically critical amino‐terminal regions dock to the receptor is unclear. We utilize cysteine trapping to systematically explore spatial approximations among residues in the first five positions of secretin and in every position within the receptor extracellular loops (ECLs). Only Cys 2 and Cys 5 secretin analogues exhibited full activity and retained moderate binding affinity (IC 50 : 92±4 and 83±1 nM, respectively). When these peptides probed 61 human secretin receptor cysteine‐replacement mutants, a broad network of receptor residues could form disulfide bonds consistent with a dynamic ligand‐receptor interface. Two distinct patterns of disulfide bond formation were observed: Cys 2 predominantly labeled residues in the amino terminus of ECL2 and ECL3 (relative labeling intensity: Ser 340 , 94±7%; Pro 341 , 84±9%; Phe 258 , 73±5%; Trp 274 62±8%), and Cys 5 labeled those in the carboxyl terminus of ECL2 and ECL3 (Gln 348 , 100%; Ile 347 , 73±12%; Glu 342 , 59±10%; Phe 351 , 58±11%). These constraints were utilized in molecular modeling, providing improved understanding of the structure of the transmembrane bundle and interconnecting loops, the orientation between receptor domains, and the molecular basis of ligand docking. Key spatial approximations between peptide and receptor predicted by this model (H 1 ‐W 274 , D 3 ‐N 268 , G 4 ‐F 258 ) were supported by mutagenesis and residue‐residue complementation studies.—Dong, M., Xu, X., Ball, A. M., Makhoul, J. A., Lam, P. C.‐H., Pinon, D. I., Orry, A., Sexton, P. M., Abagyan, R., Miller, L. J. Mapping spatial approximations between the amino terminus of secretin and each of the extracellular loops of its receptor using cysteine trapping. FASEB J. 26, 5092–5105 (2012). www.fasebj.org

Anticholinergics, or antimuscarinic drugs, are drugs that competitively inhibit the action of acetylcholine at muscarinic receptors, leading to a blockade of the actions of the parasympathetic nervous system at sites where overactivity can lead to increased symptom burden. Successful blockade of the parasympathetic nervous system ultimately leads to decreased production of secretions in the salivary, bronchial, and gastrointestinal tracts. These effects are often used for several symptoms that originate due to parasympathetic nervous system overactivity, such as the “death rattle” and malignant bowel obstruction. Anticholinergic agents are divided into either tertiary amines or quaternary ammonium compounds, which differ in their ability to cross into the central nervous system. Quaternary compounds do not cross into the central nervous system and have a different adverse effect profile than the tertiary amines. The purpose of this review is to highlight anticholinergic agents, their pharmacology, and an evidence-based assessment of their role in palliative care.

Background— The importance of complete revascularization remains unclear and contradictory. This current investigation compares the effect of complete revascularization on 10-year survival of patients with stable multivessel coronary artery disease (CAD) who were randomly assigned to percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). Methods and Results— This is a post hoc analysis of the Second Medicine, Angioplasty, or Surgery Study (MASS II), which is a randomized trial comparing treatments in patients with stable multivessel CAD, and preserved systolic ventricular function. We analyzed patients who underwent surgery (CABG) or stent angioplasty (PCI). The survival free of overall mortality of patients who underwent complete (CR) or incomplete revascularization (IR) was compared. Of the 408 patients randomly assigned to mechanical revascularization, 390 patients (95.6%) underwent the assigned treatment; complete revascularization was achieved in 224 patients (57.4%), 63.8% of those in the CABG group and 36.2% in the PCI group ( P =0.001). The IR group had more prior myocardial infarction than the CR group (56.2%×39.2%, P =0.01). During a 10-year follow-up, the survival free of cardiovascular mortality was significantly different among patients in the 2 groups (CR, 90.6% versus IR, 84.4%; P =0.04). This was mainly driven by an increased cardiovascular specific mortality in individuals with incomplete revascularization submitted to PCI ( P =0.05). Conclusions— Our study suggests that in 10-year follow-up, CR compared with IR was associated with reduced cardiovascular mortality, especially due to a higher increase in cardiovascular-specific mortality in individuals submitted to PCI. Clinical Trial Registration Information— URL: http://www.controlled-trials.com . Registration number: ISRCTN66068876.

Breast cancer is the most common malignancy among women in the United States with the second highest incidence of cancer-related death following lung cancer. The decision-making process regarding adjuvant therapy is a time intensive dialogue between the patient and her oncologist. There are multiple tools that help individualize the treatment options for a patient. Population-based analysis with Adjuvant! Online and genomic profiling with Oncotype DX are two commonly used tools in patients with early stage, node-negative breast cancer. This case report illustrates a situation in which the population-based prognostic and predictive information differed dramatically from that obtained from genomic profiling and affected the patient’s decision. In light of this case, we discuss the benefits and limitations of these tools.

We tested the hypothesis that elevated sympathetic tone is responsible for lower peak vasodilation after single muscle contractions in older adults. Young ( n = 13, 7 men and 6 women, age: 27 ± 1 yr) and older ( n = 13, 7 men and 6 women, age: 69 ± 2 yr) adults performed single forearm contractions at 10%, 20%, and 40% of maximum during 1) control, 2) sympathetic activation via lower body negative pressure (LBNP; −20 mmHg), and 3) intra-arterial infusion of phentolamine (α-adrenergic antagonist). Brachial artery diameter and velocities were measured via Doppler ultrasound, and forearm vascular conductance (FVC; in ml·min−1·100 mmHg−1) was calculated from blood flow (in ml/min) and blood pressure (in mmHg). Peak vasodilator responses [change in (Δ) FVC from baseline] were attenuated in older adults at 20% and 40% of maximum ( P < 0.05). LBNP reduced peak ΔFVC at 10% (98 ± 17 vs. 70 ± 12 ml·min−1·100 mmHg−1), 20% (144 ± 12 vs. 98 ± 3 ml·min−1·100 mmHg−1), and 40% (209 ± 20 vs. 161 ± 21 ml·min−1·100 mmHg−1, P < 0.01 vs. control) in younger adults but not in older adults (71 ± 11 vs. 68 ± 11, 107 ± 13 vs. 106 ± 16, and 161 ± 22 vs. 144 ± 22 ml·min−1·100 mmHg−1, respectively, P = 0.22–0.99). With phentolamine, peak ΔFVC was enhanced in older adults at each contraction intensity (100 ± 14, 147 ± 22, and 200 ± 26 ml·min−1·100 mmHg−1, respectively, P < 0.01 vs. control) but not in younger adults (94 ± 13, 153 ± 13, and 224 ± 27 ml·min−1·100 mmHg−1, respectively, P = 0.30–0.81 vs. control). Our data indicate that α-adrenergic vasoconstriction and/or blunted functional sympatholysis might contribute to the age-related decreases in skeletal muscle contraction-induced rapid vasodilation in humans.