Evaluation of a multi-agent chemotherapy protocol combining lomustine, procarbazine and prednisolone (LPP) for the treatment of relapsed canine non-Hodgkin high-grade lymphomas

The standard of care treatment for canine lymphoma is multi-agent chemotherapy containing prednisolone, cyclophosphamide, vincristine and an anthracycline such as doxorubicin (CHOP) or epirubicin (CEOP). Lomustine, vincristine, procarbazine, and prednisone (LOPP) has been evaluated as a rescue, with encouraging results; however, resistance to vincristine is likely in patients relapsing on CHOP/CEOP, and this agent may enhance LOPP toxicity without improving efficacy. The aim of this study was to evaluate responses to a modified-LOPP protocol that does not include vincristine (LPP) and is administered on a 21-day cycle. Medical records of dogs with high-grade multicentric lymphoma from 2012 to 2017 were reviewed. Dogs with relapsed lymphoma that received LPP as a rescue protocol were enrolled. Response, time from initiation to discontinuation (TTD) and toxicity of LPP were assessed. Forty-one dogs were included. Twenty-five dogs (61%) responded to LPP including 12 complete responses (CR) and 13 partial responses (PR). Responders had a significantly longer TTD (P < .001) compared to non-responders with 84 days for CR and 58 days for PR. Neutropenia was documented in 20 dogs (57%): 12 grade I to II, 8 grade III to IV. Thrombocytopenia was infrequent (20%): 5 grade I to II, 2 grade III to IV. Twelve dogs developed gastrointestinal toxicity (30%): 10 grade I to II and 2 grade III. Nineteen dogs had elevated ALT (59%): 9 grade I to II, 10 grade III to IV. Treatment was discontinued due to toxicity in 8 dogs (19%). The LPP protocol shows acceptable efficacy and toxicity-profile and minimizes in-hospital procedures

Molecular Evolution and Functional Divergence of the Cytochrome P450 3 (CYP3) Family in Actinopterygii (Ray-Finned Fish)

The cytochrome P450 (CYP) superfamily is a multifunctional hemethiolate enzyme that is widely distributed from Bacteria to Eukarya. The CYP3 family contains mainly the four subfamilies CYP3A, CYP3B, CYP3C and CYP3D in vertebrates; however, only the Actinopterygii (ray-finned fish) have all four subfamilies and detailed understanding of the evolutionary relationship of Actinopterygii CYP3 family members would be valuable.Phylogenetic relationships were constructed to trace the evolutionary history of the Actinopterygii CYP3 family genes. Selection analysis, relative rate tests and functional divergence analysis were combined to interpret the relationship of the site-specific evolution and functional divergence in the Actinopterygii CYP3 family. The results showed that the four CYP3 subfamilies in Actinopterygii might be formed by gene duplication. The first gene duplication event was responsible for divergence of the CYP3B/C clusters from ancient CYP3 before the origin of the Actinopterygii, which corresponded to the fish-specific whole genome duplication (WGD). Tandem repeat duplication in each of the homologue clusters produced stable CYP3B, CYP3C, CYP3A and CYP3D subfamilies. Acceleration of asymmetric evolutionary rates and purifying selection together were the main force for the production of new subfamilies and functional divergence in the new subset after gene duplication, whereas positive selection was detected only in the retained CYP3A subfamily. Furthermore, nearly half of the functional divergence sites appear to be related to substrate recognition, which suggests that site-specific evolution is closely related with functional divergence in the Actinopterygii CYP3 family.The split of fish-specific CYP3 subfamilies was related to the fish-specific WGD, and site-specific acceleration of asymmetric evolutionary rates and purifying selection was the main force for the origin of the new subfamilies and functional divergence in the new subset after gene duplication. Site-specific evolution in substrate recognition was related to functional divergence in the Actinopterygii CYP3 family

Duplication and Diversification of the Hypoxia-Inducible IGFBP-1 Gene in Zebrafish

Gene duplication is the primary force of new gene evolution. Deciphering whether a pair of duplicated genes has evolved divergent functions is often challenging. The zebrafish is uniquely positioned to provide insight into the process of functional gene evolution due to its amenability to genetic and experimental manipulation and because it possess a large number of duplicated genes.We report the identification and characterization of two hypoxia-inducible genes in zebrafish that are co-ortholgs of human IGF binding protein-1 (IGFBP-1). IGFBP-1 is a secreted protein that binds to IGF and modulates IGF actions in somatic growth, development, and aging. Like their human and mouse counterparts, in adult zebrafish igfbp-1a and igfbp-1b are exclusively expressed in the liver. During embryogenesis, the two genes are expressed in overlapping spatial domains but with distinct temporal patterns. While zebrafish IGFBP-1a mRNA was easily detected throughout embryogenesis, IGFBP-1b mRNA was detectable only in advanced stages. Hypoxia induces igfbp-1a expression in early embryogenesis, but induces the igfbp-1b expression later in embryogenesis. Both IGFBP-1a and -b are capable of IGF binding, but IGFBP-1b has much lower affinities for IGF-I and -II because of greater dissociation rates. Overexpression of IGFBP-1a and -1b in zebrafish embryos caused significant decreases in growth and developmental rates. When tested in cultured zebrafish embryonic cells, IGFBP-1a and -1b both inhibited IGF-1-induced cell proliferation but the activity of IGFBP-1b was significantly weaker.These results indicate subfunction partitioning of the duplicated IGFBP-1 genes at the levels of gene expression, physiological regulation, protein structure, and biological actions. The duplicated IGFBP-1 may provide additional flexibility in fine-tuning IGF signaling activities under hypoxia and other catabolic conditions

The spotted gar genome illuminates vertebrate evolution and facilitates human-teleost comparisons

To connect human biology to fish biomedical models, we sequenced the genome of spotted gar (Lepisosteus oculatus), whose lineage diverged from teleosts before teleost genome duplication (TGD). The slowly evolving gar genome has conserved in content and size many entire chromosomes from bony vertebrate ancestors. Gar bridges teleosts to tetrapods by illuminating the evolution of immunity, mineralization and development (mediated, for example, by Hox, ParaHox and microRNA genes). Numerous conserved noncoding elements (CNEs; often cis regulatory) undetectable in direct human-teleost comparisons become apparent using gar: functional studies uncovered conserved roles for such cryptic CNEs, facilitating annotation of sequences identified in human genome-wide association studies. Transcriptomic analyses showed that the sums of expression domains and expression levels for duplicated teleost genes often approximate the patterns and levels of expression for gar genes, consistent with subfunctionalization. The gar genome provides a resource for understanding evolution after genome duplication, the origin of vertebrate genomes and the function of human regulatory sequences

Effect of Carnitine and herbal mixture extract on obesity induced by high fat diet in rats

<p>Abstract</p> <p>Background</p> <p>Obesity-associated type 2 diabetes is rapidly increasing throughout the world. It is generally recognized that natural products with a long history of safety can modulate obesity.</p> <p>Aim</p> <p>To investigate the development of obesity in response to a high fat diet (HFD) and to estimate the effect of L-carnitine and an Egyptian Herbal mixture formulation (HMF) (consisting of T. chebula, Senae, rhubarb, black cumin, aniseed, fennel and licorice) on bodyweight, food intake, lipid profiles, renal, hepatic, cardiac function markers, lipid Peroxidation, and the glucose and insulin levels in blood and liver tissue in rats.</p> <p>Method</p> <p>White male albino rats weighing 80-90 gm, 60 days old. 10 rats were fed a normal basal diet (Cr), 30 rats fed a high-fat diet (HFD) for 14 weeks during the entire study. Rats of the HFD group were equally divided into 3 subgroups each one include 10 rats. The first group received HFD with no supplement (HFD), the 2^ndgroup HFD+L-carnitine and the third group received HFD+HMF. Carnitine and HMF were administered at 10^thweek (start time for treatments) for 4 weeks.</p> <p>Body weight, lipid profile & renal function (urea, uric acid creatinine) ALT & AST activities, cardiac markers, (LDH, C.K-NAC and MB) the oxidative stress marker reduced glutathione (GSH), and Malondialdehyde (MDA) catalase activity, in addition to glucose, insulin, and insulin resistance in serum & tissues were analyzed.</p> <p>Results</p> <p>Data showed that feeding HFD diet significantly increased final body weight, triglycerides (TG), total cholesterol, & LDL concentration compared with controls, while significantly decreasing HDL; meanwhile treatment with L-carnitine, or HMF significantly normalized the lipid profile.</p> <p>Serum ALT, urea, uric acid, creatinine, LDH, CK-NAC, CK-MB were significantly higher in the high fat group compared with normal controls; and administration of L-carnitine or herbal extract significantly lessened the effect of the HFD. Hyperglycemia, hyperinsulinemia, and high insulin resistance (IR) significantly increased in HFD in comparison with the control group. The treatment with L-carnitine or HMF improved the condition. HFD elevated hepatic MDA and lipid peroxidation associated with reduction in hepatic GSH and catalase activity; whereas administration of L-carnitine or herbal extract significantly ameliorated these hepatic alterations.</p> <p>Conclusion</p> <p>HFD induced obesity associated with a disturbed lipid profile, defective antioxidant stability, and high values of IR parameters; this may have implications for the progress of obesity related problems. Treatment with L-carnitine, or HMF extract improved obesity and its associated metabolic problems in different degrees. Also HMF has antioxidant, hypolipidaemic insulin sensitizing effects. Moreover HMF might be a safe combination on the organs whose functions were examined, as a way to surmount the obesity state; and it has a distinct anti-obesity effect.</p

The genome of the platyfish, Xiphophorus maculatus, provides insights into evolutionary adaptation and several complex traits

Several attributes intuitively considered to be typical mammalian features, such as complex behavior, live birth and malignant disease such as cancer, also appeared several times independently in lower vertebrates. The genetic mechanisms underlying the evolution of these elaborate traits are poorly understood. The platyfish, X. maculatus, offers a unique model to better understand the molecular biology of such traits. We report here the sequencing of the platyfish genome. Integrating genome assembly with extensive genetic maps identified an unexpected evolutionary stability of chromosomes in fish, in contrast to in mammals. Genes associated with viviparity show signatures of positive selection, identifying new putative functional domains and rare cases of parallel evolution. We also find that genes implicated in cognition show an unexpectedly high rate of duplicate gene retention after the teleost genome duplication event, suggesting a hypothesis for the evolution of the behavioral complexity in fish, which exceeds that found in amphibians and reptiles