P-type ATPases function to provide homeostasis in higher eukaryotes, but they are essentially ubiquitous, being found in all domains of life. Thever and Saier [J Memb Biol 2009;229:115–130] recently reported analyses of eukaryotic P-type ATPases, dividing them into nine functionally characterized and 13 functionally uncharacterized (FUPA) families. In this report, we analyze P-type ATPases in all major prokaryotic phyla for which complete genome sequence data are available, and we compare the results with those for eukaryotic P-type ATPases. Topological type I (heavy metal) P-type ATPases predominate in prokaryotes (approx. tenfold) while type II ATPases (specific for Na+,K+, H+ Ca2+, Mg2+ and phospholipids) predominate in eukaryotes (approx. twofold). Many P-type ATPase families are found exclusively in prokaryotes (e.g. Kdp-type K+ uptake ATPases (type III) and all ten prokaryotic FUPA familes), while others are restricted to eukaryotes (e.g. phospholipid flippases and all 13 eukaryotic FUPA families). Horizontal gene transfer has occurred frequently among bacteria and archaea, which have similar distributions of these enzymes, but rarely between most eukaryotic kingdoms, and even more rarely between eukaryotes and prokaryotes. In some bacterial phyla (e.g. Bacteroidetes, Flavobacteria and Fusobacteria), ATPase gene gain and loss as well as horizontal transfer occurred seldom in contrast to most other bacterial phyla. Some families (i.e. Kdp-type ATPases) underwent far less horizontal gene transfer than other prokaryotic families, possibly due to their multisubunit characteristics. Functional motifs are better conserved across family lines than across organismal lines, and these motifs can be family specific, facilitating functional predictions. In some cases, gene fusion events created P-type ATPases covalently linked to regulatory catalytic enzymes. In one family (FUPA Family 24), a type I ATPase gene (N-terminal) is fused to a type II ATPase gene (C-terminal) with retention of function only for the latter. Several pseudogene-encoded nonfunctional ATPases were identified. Genome minimalization led to preferential loss of P-type ATPase genes. We suggest that in prokaryotes and some unicellular eukaryotes, the primary function of P-type ATPases is protection from extreme environmental stress conditions. The classification of P-type ATPases of unknown function into phylogenetic families provides guides for future molecular biological studies.
To understand the mechanism behind aberrant Akt activation in T-ALL, PIK3CA, PTEN and SHIP1 expression and genotype were assessed. No cell lines or primary ALLs harbored PIK3CA mutations. PTEN was expressed in just one-third of the cell lines, but in two-thirds of the primary ALLs, though in the inactivated (phosphorylated) form. SHIP1 was undetectable in most primary ALL and in the T-ALL cell line Jurkat, which harbored a bi-allelic null mutation and a frame-shift deletion; primary ALL harbored the frame-shift as well as other translationally-inactivating deletions and insertions. The inactivation of SHIP1 could play a central role in the deregulation of Akt pathway and tumorigenesis, perhaps in conjunction with PTEN-inactivation.
ObjectiveEhlers–Danlos syndrome frequently causes acute and chronic pain because of joint subluxations and dislocations secondary to hypermobility. Current treatments for pain related to Ehlers–Danlos syndrome and central pain syndrome are inadequate. This case report discusses the therapeutic use of ketamine intravenous infusion as an alternative.Case reportA 27-year-old Caucasian female with a history of Ehlers–Danlos syndrome and spinal cord ischemic myelopathy resulting in central pain syndrome, presented with severe generalized body pain refractory to multiple pharmacological interventions. After a 7-day course of ketamine intravenous infusion under controlled generalized sedation in the intensive care unit, the patient reported a dramatic reduction in pain levels from 7–8 out of 10 to 0–3 out of 10 on a numeric rating scale and had a significant functional improvement. The patient tolerated a reduction in her pain medication regimen, which originally included opioids, gabapentin, pregabalin, tricyclic antidepressants, and nonsteroidal anti-inflammatory drugs.ConclusionKetamine infusion treatment has been used in various pain syndromes, including central neuropathic pain, ischemic pain, and regional pain syndrome. Reports have suggested that ketamine modulates pain by the regression of N-methyl-D-aspartate receptor to a resting state. As such, propagation of nociceptive signal to brain is interrupted allowing for the restoration of physiological balance between pain inhibition and facilitation. The present report shows that this treatment option can be used in patients with refractory central pain syndrome in the setting of spinal cord myelopathy secondary to Ehlers–Danlos syndrome. In addition, as seen in this case, this protocol can potentially decrease the chronic use of pain medication, such as opioids.
Hematuria is a documented side effect of botulinum toxin injection and has only been reported when it is used for overactive bladder. Here we report a rare case of hematuria following onabotulinumtoxin A (Botox) injection for upper limb spasticity in a 29-year-old male with a history of traumatic brain injury and hemophilia. Hematuria resolved without further complication after self-injection of factor VIII as recommended by his hematologist. Botulinum toxin binds peripheral cholinergic nerve endings to prevent acetylcholine and norepinephrine exocytosis. Studies have shown that both of these compounds are involved in antifibrinolytic activation, suggesting botulinum toxin may play a role in the coagulation cascade by preventing formation of fibrin. This is further supported by resolution of hematuria in our patient after self-injection of factor VIII. As such, botulinum toxin injection may result in mild spontaneous hemorrhage in patients with underlying hematological deficiencies. Further studies are needed to elucidate its effects in coagulation.
2386 Poster Board II-363 Despite success in the treatment of Acute lymphoblastic leukemia (ALL), relapse and death continue to occur and in survivors, secondary malignancies due to the impact of aggressive chemotherapy negatively impact the quality and duration of life. Akt plays a central role in signal transduction and is negatively regulated by PTEN and, in cells of hematopoietic lineage, SHIP1; it is positively regulated by PIK3CA. Despite multiple levels of regulation, Akt is aberrantly activated in many cancers including ALL. To understand the mechanism behind Akt activation in ALL, PIK3CA, PTEN and SHIP1 genes were assessed in leukemia cell lines and primary samples. No sample harbored PIK3CA mutation. PTEN was expressed in just one-third of the cell lines analyzed, but in two-thirds of the primary ALL of both T- and B-lineage, though all were in the phosphorylated (inactivated) form. SHIP1 was expressed in all leukemia cell lines, except for Jurkat and K562 cell lines. In general, expression of SHIP1 protein was much higher in cell lines of the B-lineage than of the T-lineage. The Jurkat T-ALL cell line, long observed to lack SHIP1 protein, harbored biallelic inactivation by null mutation and a frame-shift deletion; no SHIP1 mutations were identified in the K562 cell line. In contrast to leukemia cell lines, no full length SHIP1 was detected in primary T-ALL, and only ∼20% of the primary B-precursor ALL expressed full length SHIP despite the expression of full length transcript. Both ALL lineages expressed truncated isoforms of SHIP, which cloning and sequence analysis revealed was due to premature termination resulting from the frame-shift and other translationally-inactivating alternative splicing. The co-inactivation of SHIP and PTEN may create therapeutic opportunities. The PI3KCA inhibitor LY294002 has been shown to sensitize glioblastoma and colon carcinoma to doxorubicin. To determine if these agents acted synergistically in T-ALL, cell lines Molt16 (SHIP1+/PTEN-), Jurkat (SHIP1-/PTEN-) and normal MNCs (SHIP1+/PTEN+) were subjected to various combinations of the PIK3CA inhibitor LY294002 and doxorubicin and cell proliferation and viability assessed. Normal cells were generally insensitive to both agents except at high concentrations. LY294002 and doxorubicin inhibited viability in Molt16 with IC50s of 10 uM and 0.1 ug/ml, respectively, with no evidence of synergy. Jurkat cells exhibited a similar IC50 to LY294002, but were more sensitive to doxorubicin (IC50s of 10 uM and 0.025 ug/ml, respectively), with the two agents demonstrating some synergy when added simultaneously at low concentrations. In summary, we present evidence of Akt pathway deregulation in T-ALL due to SHIP1/PTEN inactivation and suggest that agents targeting this pathway may provide new directions into the therapeutic treatment of T-ALL. Disclosures: No relevant conflicts of interest to declare.
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