Cholinergic-mediated secretion in the rat colon: neuronal and epithelial muscarinic responses

The acetylcholine receptor agonists, acetylcholine (10(-5)-10(-4 M), carbachol (5 x 10(-6)-5 x 10(-5) M), bethanechol (5 x 10(-5)-5 x 10(-4) M) and dimethylphenylpiperazinium (DMPP, 10(-5) M) increased the short-circuit current (Isc) in the rat colon descendens by a tetrodotoxin (TTX)-sensitive mechanism. Blockade by TTX was still observed after removal of the submucosa, indicating the involvement of neurons of the mucosal plexus. Hexamethonium (10(-5) M) and atropine (10(-6) M) were used to distinguish between nicotinic and muscarinic neuronally mediated effects. The inhibitor of choline uptake, hemicholinium-3 (1 mM), reversibly inhibited the effect of repeated electric field stimulation (EFS). The EFS response was only inhibited by high concentrations of atropine (greater than or equal to 10(-5) M). In mucosa-submucosa preparations 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) was more effective than telenzepine whereas pirenzepine was ineffective. Pirenzepine inhibited the EFS response in mucosa preparations as did telenzepine and 4-DAMP. It was not possible to differentiate between the muscarinic receptors involved in the different parts of the enteric nervous system on the basis of our results.     

Rituximab zur Therapie des Non-Hodgkin-Lymphoms

Rituximab is the first monoclonal antibody to be approved for the treatment of non-Hodgkin’s lymphoma. Compared to chemotherapy alone, the combination of rituximab and chemotherapy is superior for all indications so far tested. For the primary therapy of follicular lymphoma with rituximab and chemotherapy, there are now four large, randomized studies available, all of which show a statistically significant and clinically relevant prolongation of life due to the combination therapy. Thus, rituximab is today the standard primary therapy for this form of lymphoma. In addition, two other phase III studies show that treatment with rituximab also leads to a prolongation of life in patients suffering from recurrent follicular lymphoma. This is the case for both combined rituximab/chemotherapy induction treatment, as well as for rituximab maintenance therapy, which is also highly effective after the rituximab/chemotherapy and is well tolerated. The risk of dying is halved by the use of rituximab maintenance therapy, indicating that rituximab is the best available therapy for recurrent follicular lymphoma, as well as for the induction of remission of the disease and as a maintenance therapy. In cases of diffuse large B-cell lymphoma, rituximab combined with chemotherapy is the therapeutic standard, with four large, randomized studies showing a clear improvement in cure rate. This applies to all age groups and risk categories, which may, however, differ in the number of therapy cycles and the dose rate.     

Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma.

PURPOSE: The aim of this multicenter-study was to evaluate the progression-free survival, response rate and toxicity of the combination of bendamustine and rituximab (BR) in patients with mantle cell or low-grade lymphomas in first to third relapse or refractory to previous treatment. PATIENTS AND METHODS: A total of 245 courses (median, four courses per patient) were administered to 63 patients. Bendamustine was given at a dose of 90 mg/m2 as a 30-minute infusion on days 1 and 2, combined with 375 mg/m2 rituximab on day 1, for a maximum of four cycles every 4 weeks. Histologies were 24 follicular, 16 mantle cell, 17 lymphoplasmacytoid, and six marginal zone lymphoma. RESULTS: Fifty-seven of 63 patients responded to BR, corresponding to an overall response rate of 90% (95% CI, 80% to 96%) with a complete remission rate (CR) of 60% (95% CI, 47% to 72%). The median time of progression-free survival was 24 months (range, 5 to 44+ months), and the median duration of overall survival has not yet been reached. In mantle cell lymphomas, BR showed a considerable activity, achieving a response rate of 75% (95% CI, 48% to 93%) with a CR rate of 50%. Myelosuppression was the major toxicity, with 16% grade 3 and 4 leukocytopenia. Thrombocytopenia was rare, with only 3% grade 3 and 4. CONCLUSION: These results demonstrate that the BR combination is a highly active regimen in the treatment of low-grade lymphomas and mantle cell lymphomas.     

Engineering Clustered Ligand Binding Into Nonviral Vectors: ��v��3 Targeting as an Example

The development of techniques to efficiently deliver genes using nonviral approaches can broaden the application of gene delivery in medical applications without the safety concerns associated with viral vectors. Here, we designed a clustered integrin-binding platform to enhance the efficiency and targetability of nonviral gene transfer to HeLa cells with low and high densities of α_vβ₃ integrin receptors. Arg-Gly-Asp (RGD) nanoclusters were formed using gold nanoparticles functionalized with RGD peptides and used to modify the surface of DNA/poly(ethylene imine) (PEI) polyplexes. DNA/PEI polyplexes with attached RGD nanoclusters resulted in either 5.4- or 35-fold increase in gene transfer efficiency over unmodified polyplexes for HeLa cells with low- or high-integrin surface density, respectively. The transfection efficiency obtained with the commercially available vector jetPEI-RGD was used for comparison as a vector without clustered binding. JetPEI-RGD exhibited a 1.2-fold enhancement compared to unmodified jetPEI in cells with high densities of α_vβ₃ integrin receptors. The data presented here emphasize the importance of the RGD conformational arrangement on the surface of the polyplex to achieve efficient targeting and gene transfer, and provide an approach to introduce clustering to a wide variety of nanoparticles for gene delivery.     

Bendamustine's emerging role in the management of lymphoid malignancies

The potent alkylating agent bendamustine has demonstrated substantial efficacy in patients with non-Hodgkin lymphomas (NHLs), including chronic lymphocytic leukemia (CLL), follicular lymphoma, and mantle cell lymphoma. Due to incomplete cross-reactivity between bendamustine and other chemotherapeutic agents, bendamustine has been extensively tested in the relapsed/refractory setting. Bendamustine is highly effective in rituximab-refractory NHL and in patients whose disease is refractory to chemotherapy, including other alkylating agents. It has also demonstrated considerable efficacy in previously untreated NHLs, both alone and in combination with rituximab or other chemotherapeutic agents. Studies suggest complete responses and durability of remission achieved with bendamustine are superior to those achieved with standard regimens. However, longer follow-up is needed to fully establish long-term response duration. Additionally, bendamustine is associated with hematologic toxicity and risk of infection, which must be carefully monitored and managed. This is particularly important in elderly patients with advanced disease. Increased understanding of the mechanisms of action of bendamustine and the efficacy of bendamustine in combination with rituximab in newly diagnosed or relapsed/refractory CLL and indolent lymphomas led to investigation of other combinations. Ongoing studies are examining bendamustine with bortezomib, lenalidomide, temsirolimus, ofatumumab, alemtuzumab, and other novel agents. Bendamustine is also undergoing clinical investigation in patients with relapsed/refractory diffuse large B-cell lymphomas, a patient population with limited therapeutic options currently. This review will summarize current clinical data regarding the efficacy and safety of bendamustine in patients with lymphoma and highlight ongoing clinical trials expanding the role of this alkylating agent in the treatment of hematologic malignancies.     

Ciliary IFT88 Protects Coordinated Adolescent Growth Plate Ossification From Disruptive Physiological Mechanical Forces

Compared with our understanding of endochondral ossification, much less is known about the coordinated arrest of growth defined by the narrowing and fusion of the cartilaginous growth plate. Throughout the musculoskeletal system, appropriate cell and tissue responses to mechanical force delineate morphogenesis and ensure lifelong health. It remains unclear how mechanical cues are integrated into many biological programs, including those coordinating the ossification of the adolescent growth plate at the cessation of growth. Primary cilia are microtubule-based organelles tuning a range of cell activities, including signaling cascades activated or modulated by extracellular biophysical cues. Cilia have been proposed to directly facilitate cell mechanotransduction. To explore the influence of primary cilia in the mouse adolescent limb, we conditionally targeted the ciliary gene Intraflagellar transport protein 88 (Ift88^fl/fl) in the juvenile and adolescent skeleton using a cartilage-specific, inducible Cre (AggrecanCreER^T2 Ift88^fl/fl). Deletion of IFT88 in cartilage, which reduced ciliation in the growth plate, disrupted chondrocyte differentiation, cartilage resorption, and mineralization. These effects were largely restricted to peripheral tibial regions beneath the load-bearing compartments of the knee. These regions were typified by an enlarged population of hypertrophic chondrocytes. Although normal patterns of hedgehog signaling were maintained, targeting IFT88 inhibited hypertrophic chondrocyte VEGF expression and downstream vascular recruitment, osteoclastic activity, and the replacement of cartilage with bone. In control mice, increases to physiological loading also impair ossification in the peripheral growth plate, mimicking the effects of IFT88 deletion. Limb immobilization inhibited changes to VEGF expression and epiphyseal morphology in Ift88cKO mice, indicating the effects of depletion of IFT88 in the adolescent growth plate are mechano-dependent. We propose that during this pivotal phase in adolescent skeletal maturation, ciliary IFT88 protects uniform, coordinated ossification of the growth plate from an otherwise disruptive heterogeneity of physiological mechanical forces. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).