ABSTRACT
Pyroglutamic acidosis (PGA) is an underrecognized entity characterised by raised anion gap metabolic acidosis (RAGMA) and urinary hyper-excretion of pyroglutamic acid. It is frequently associated with chronic acetaminophen (APAP) ingestion. We report the case of a 73-year-old man with invasive pulmonary aspergillosis treated with voriconazole and APAP for analgesia with a cumulative dose of 160 g over 40 days. PGA was suspected as he developed severe RAGMA and common causes were excluded. Diagnosis was confirmed via urinary organic acid analysis which showed significant hyper-excretion of pyroglutamic acid. APAP was discontinued, and N-acetylcysteine (NAC) was administered. His RAGMA rapidly resolved following treatment.
Subject(s)
Biotin , Dietary Supplements , Humans , Streptavidin , Thyroid Function Tests , Vitamin DABSTRACT
Human placental trophoblasts can be considered pseudomalignant, with tightly controlled proliferation, apoptosis, and invasiveness. Gestational trophoblastic disease (GTD) represents a family of heterogeneous trophoblastic lesions with aberrant apoptotic and proliferative activities and dysregulation of cell signaling pathways. We characterize the oncogenic effects of factor that binds to the inducer of short transcripts of HIV-1 [FBI-1, alias POZ and Krüppel erythroid myeloid ontogenic factor (POKEMON)/ZBTB7A] in GTD and its role in promoting cell aggressiveness in vitro and tumor growth in vivo. IHC studies showed increased nuclear expression of FBI-1, including hydatidiform moles, choriocarcinoma (CCA), and placental site trophoblastic tumor, in GTD. In JAR and JEG-3 CCA cells, ectopic FBI-1 expression opposed apoptosis through repression of proapoptotic genes (eg, BAK1, FAS, and CASP8). FBI-1 overexpression also promoted Akt activation, as indicated by Akt-pS473 phosphorylation. FBI-1 overexpression promoted mobility and invasiveness of JEG-3 and JAR, but not in the presence of the phosphoinositide 3-kinase inhibitor LY294002. These findings suggest that FBI-1 could promote cell migration and invasion via phosphoinositide 3-kinase/Akt signaling. In vivo, nude mice injected with CCA cells with stable FBI-1 knockdown demonstrated reduced tumor growth compared with that in control groups. These findings suggest that FBI-1 is clinically associated with the progression of, and may be a therapeutic target in, GTD, owing to its diverse oncogenic effects on dysregulated trophoblasts.
Subject(s)
Choriocarcinoma/pathology , DNA-Binding Proteins/genetics , Gestational Trophoblastic Disease/pathology , Oncogene Protein v-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction , Transcription Factors/genetics , Animals , Antibodies , Apoptosis , Carcinogenicity Tests , Cell Movement , Choriocarcinoma/genetics , Choriocarcinoma/metabolism , DNA-Binding Proteins/metabolism , Female , Gene Expression Regulation, Neoplastic , Gestational Trophoblastic Disease/genetics , Gestational Trophoblastic Disease/metabolism , Humans , Hydatidiform Mole/genetics , Hydatidiform Mole/metabolism , Hydatidiform Mole/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Oncogene Protein v-akt/genetics , Phosphatidylinositol 3-Kinases/genetics , Placenta/metabolism , Pregnancy , Rabbits , Transcription Factors/metabolism , Trophoblasts/metabolismABSTRACT
Biogenesis of secretory proteins requires their translocation into the endoplasmic reticulum (ER) through the Sec61 channel. Proteins that fail to fold are transported back into the cytosol and are degraded by proteasomes. For many substrates this retrograde transport is affected by mutations in the Sec61 channel, and can be promoted by ATP and the 19S regulatory particle of the proteasome, which binds directly to the Sec61 channel via its base. Here, we identify mutations in SEC61 which reduce proteasome binding to the channel, and demonstrate that proteasomes and ribosomes bind differently to cytosolic domains of the channel. We found that Sec63p and BiP coprecipitate with ER-associated proteasomes, but Sec63p does not contribute to proteasome binding to the ER. The 19S base contains six AAA-ATPase subunits (Rpt proteins) that have non-equivalent functions in proteasome-mediated protein turnover and form a hetero-hexamer. Mutations in the ATP-binding sites of individual Rpt proteins all reduced the affinity of 19S complexes for the ER, suggesting that the 19S base in the ATP-bound conformation docks at the Sec61 channel.