Targeting NEDD8-activating enzyme is a new approach to treat canine diffuse large B-cell lymphoma.

Canine diffuse large B-cell lymphoma (DLBCL), the most common hematologic malignancy of dogs, is associated with poor overall survival. The lack of conventional chemotherapies with sustainable efficacy warrants investigation of novel therapies. Pevonedistat (MLN4924) is a potent and selective small molecule NEDD8-activating enzyme inhibitor. In human activated B-cell-like (ABC) diffuse large B-cell lymphoma, pevonedistat induces lymphoma cell apoptosis, DNA damage and G1 cell cycle arrest by inhibiting the nuclear factor-κB (NF-κB) pathway. Genomic and transcriptomic studies showed that the NF-κB pathway is deregulated in canine DLBCL. Our results showed that pevonedistat treatment significantly reduces the viability of canine DLBCL cells by inducing G1 cell cycle arrest and apoptosis. Pevonedistat treatment inhibits NF-κB pathway activation and downregulates NF-κB target genes in canine DLBCL. Moreover, administration of pevonedistat to mice bearing canine DLBCL xenograft tumours resulted in tumour regression. Our in vivo and in vitro studies provide justification for future clinical application of pevonedistat as a potential new anti-cancer therapy that may benefit both canine and human species.

A Report of Nausea and Vomiting with Discontinuation of Chronic Use of Salvia divinorum.

Introduction. This is the first reported case of gastrointestinal symptoms associated with withdrawal after chronic use of this substance. Case Presentation. A 51-year-old Caucasian woman was referred to a hospital with a 3-day history of nausea, vomiting, diarrhea, and abdominal discomfort. She reported no sick family members or contact with anyone who was ill. She did report smoking 3-5 cigarettes of the herb "Salvia" consistently for 3-4 months and quit approximately 48 hours before symptoms appeared. Her use of the herb had been consistent; she smoked several cigarettes each day. Laboratory results were essentially normal including the white blood cell count. She received symptomatic treatment and was released after one day. Discussion. Salvinorin A, a kappa-opioid receptor agonist, is the major active ingredient of S. divinorum. The unique opioid properties of this herb may explain its ability to cause changes in intestinal transit time. Conclusion. A 51-year-old woman possibly developed gastrointestinal manifestations suggestive of withdrawal from Salvia divinorum after smoking the substance consistently for 3 to 4 months. The widespread use of this herb will make the potential for withdrawal syndromes more commonplace.

Evolution of Synthyris sect. Dissecta (Plantaginaceae) on sky islands in the Northern Rocky Mountains.

We examined the phylogeography of Synthyris sect. Dissecta (Plantaginaceae), which is restricted to the Olympic (S. lanuginosa) and Northern Rocky Mountains (S. dissecta and S. canbyi), to infer effects of sky islands and modes of speciation. Sequences of cpDNA trnT-trnL and psbA-trnH intergenic spacers resolved 22 haplotypes among 185 individuals sampled from 16 populations of the three species. Gene flow in the ancestral lineage and random capture of haplotypes in species lineages of sect. Dissecta have resulted in haplotype clades that are not exclusive to species. Nested clade analysis (NCA) indicates that allopatric fragmentation separated Olympic and Northern Rocky Mountain populations, giving rise to the Olympic endemic S. lanuginosa, which is characterized by unique haplotypes consistent with long temporal isolation. Low haplotype and nucleotide diversity in S. canbyi are consistent with newly founded populations experiencing a bottleneck. Furthermore, we infer S. canbyi evolved as a peripheral isolate of S. dissecta. NCA indicated limited migration in S. dissecta with possible isolation by distance. Both isolation on interglacial sky islands and valley glaciers during at least the last glaciation limited gene flow among populations of S. dissecta in different ranges of the Northern Rocky Mountains.

Quantitative NAT for pathogen inactivation verification.

A novel Quantitative Nucleic Acid Test (Q-NAT) technology has been developed to demonstrate, quantify and verify pathogen inactivation by methods that break pathogen nucleic acids, specifically, gamma irradiation. The Q-NAT technology provides significant advantages in cost, efficiency and broad applicability compared with traditional methods for pathogen inactivation detection and quantification such as cell culture.

Changes in kinesin distribution and phosphorylation occur during regulated secretion in pancreatic acinar cells.

In secretory cells, microtubule- (Mt-) based motor enzymes are thought to support transport of secretory vesicles to the cell surface for subsequent release. At present, the role of Mts and kinesin in secretory vesicle transport in exocrine epithelial cells has not been defined. Furthermore, it is unclear whether an agonist-induced secretory event modifies kinesin function and distribution, thus altering vesicle transport. To this end, we utilized isolated rat pancreatic acini and cultured rat pancreatic acinar cells to examine the role of Mts and kinesin in regulated secretion. Exposure of cells to cytoskeletal antagonistic drugs demonstrated that the observed movements of apically clustered zymogen granules (ZGs) are supported by Mts, but not actin. Morphological studies of Mt organization in polarized acini show that Mt plus ends extend outward from the apical membrane toward the cell center. Immunofluorescence microscopy in both cell models revealed a clear association of kinesin with apical ZGs, while quantitative immunoblot analysis of pancreatic subcellular fractions confirmed kinesin enrichment on ZG membranes. In addition, microinjection of kinesin antibodies into cultured acinar cells inhibited ZG movements. Indirect immunofluorescence staining of isolated cells and quantitative Western blotting of isolated ZGs revealed that kinesin association with granule membranes increased up to 3-fold in response to a secretory stimulus. Autoradiographic studies of 32P-labeled acini showed up to a 6-fold increase in kinesin heavy chain (KHC) phosphorylation during stimulated secretion. These studies provide the first direct evidence that Mts and kinesin support ZG movements and that physiological agonists induce a marked phosphorylation of KHC while increasing the association of kinesin with ZG membranes. These changes during agonist stimulation suggest that the participation of kinesin in zymogen secretion is regulated.

1991 laboratory systems review.

Healthcare Informatics Clinical Systems Editor Dennis Winsten and Managing Editor Karol Marlowe conducted an annual survey of laboratory systems to find out what solutions are being offered. Also, a wrap-up of trends in the laboratory information systems marketplace.