Abdominal Wall Endometriosis: A Case Report and Literature Review of Pfannenstiel Incision Endometrioma.

We depict a unique case of a 39-year-old woman who presented to the emergency department with complaints of right upper quadrant pain. Work-up and a computed tomography (CT) scan revealed acute cholecystitis and the patient underwent laparoscopic cholecystectomy without complication. At this time, an incidental mass was discovered in the subcutaneous fat adjacent to the abdominal wall. The patient returned six months later with progressive, cyclic abdominal pain since her last hospital admission. Initial admission lab work was within normal limits and a urine pregnancy test was negative. Physical exam revealed tenderness around her previous cesarean section scar. Repeat CT revealed an enlarging, spiculated mass adherent to the abdominal wall. After imaging confirmation, the patient underwent complete open surgical excision for the removal of the mass. Post-surgical biopsy confirmed endometrial gland and stroma consistent with abdominal wall endometrioma. The patient was discharged with adjuvant therapy and recommended follow-up with the surgeon and her obstetrician-gynecologist. The radiological diagnosis, guidelines, and decision-making for initiating interventional treatment are discussed in this report. Our purpose in documenting this case is to present a rare diagnosis of an atypical location for an endometrioma on the abdominal wall, in a patient with prior cesarean delivery. Although this patient was treated with open excision, different interventional radiology treatments from radiofrequency ablation and focused ultrasound were discussed. In doing so, we hope to contribute to the systematic literature review on surgical excision as a treatment option for Pfannenstiel incision endometrioma.

Characterization of human brain nicotinamide 5'-mononucleotide adenylyltransferase-2 and expression in human pancreas.

NMNAT (nicotinamide 5'-mononucleotide adenylyltransferase; EC 2.7.7.1) catalyses the transfer of the adenylyl group from ATP to NMN to form NAD. We have cloned a novel human NMNAT cDNA, designated hNMNAT-2, from human brain. The cDNA contains a 924 bp open reading frame that encodes a 307 amino acid peptide that was expressed as a histidine-patch-containing thioredoxin fusion protein. Expressed hNMNAT-2 shared only 35% amino acid sequence homology with the human NMNAT enzyme (hNMNAT-1), but possessed enzymic activity comparable with hNMNAT-1. Using human genomic databases, hNMNAT-2 was localized to chromosome 1q25 within a 171 kb gene, whereas hNMNAT-1 is on chromosome 1p32-35. Northern blot analysis revealed highly restricted expression of hNMNAT-2 to brain, heart and muscle tissues, which contrasts with the wide tissue expression of hNMNAT-1; different regions of the brain exhibited differential expression of hNMNAT-2. Substitution mutations of either of two invariant residues, His-24 or Trp-92, abolished enzyme activity. Anti-peptide antibody to a unique epitope within hNMNAT-2 was produced, and immunohistochemical analysis of sections of normal adult human pancreas revealed that hNMNAT-2 protein was markedly expressed in the islets of Langerhans. However, the pancreatic exocrine cells exhibited weak expression of hNMNAT-2 protein. Sections of pancreas from insulinoma patients showed strong expression of hNMNAT-2 protein in the insulin-producing tumour cells, whereas acinar cells exhibited relatively low expression of hNMNAT-2 protein. These data suggest that the unique tissue-expression patterns of hNMNAT-2 reflect distinct functions for the isoforms in the regulation of NAD metabolism.

Cytotoxicity and cellular differentiation activity of methylenebis(phosphonate) analogs of tiazofurin and mycophenolic acid adenine dinucleotide in human cancer cell lines.

Mycophenolic acid (MPA) is a fungally-derived inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH). MPA binds IMPDH at the nicotinamide sub-site of the NAD cofactor binding domain leaving the adenosine sub-site empty. In order to improve the binding affinity we synthesized MPA analogs by linking adenosine 5'-methylenebis(phosphonate) with mycophenolic alcohols containing 2-, 4-, and 6-carbon atoms in their aliphatic side chain. Adenine dinucleotide analogs of tiazofurin, selenazofurin and benzamide riboside were synthesized as P1, P2-disubstituted pyrophosphates. Cytotoxicity of each analog was examined in human colon adenocarcinoma HT-29 and erythroleukemia K562 cells, and induction of differentiation in K562 cells by these agents was determined. Mycophenolic acid is currently used as an immunosuppressant but its anticancer action is limited by inactivation due to rapid glucuronidation. The new analogs show resistance to metabolism to inactive species and exhibit enhanced cytotoxicity in tumor cell lines, and therefore could be useful as anticancer agents.

Modulation of cytotoxicity of benzamide riboside by expression of NMN adenylyltransferase.

Benzamide riboside (BR) is a nucleoside prodrug that is phosphorylated to its 5'-monophosphate (BRMP) and then converted to its active metabolite, BAD (benzamide adenine dinucleotide), an analogue of NAD by the action of NMN adenylyltransferase (NMNAT). BAD is a potent, reversible, and noncompetitive inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH) resulting in depletion of guanylates (GTP and dGTP). IMPDH inhibitors such as BR induce differentiation and apoptosis as a consequence of GTP depletion. Tiazofurin (TR) and selenazofurin (SR) require similar metabolism by NMNAT. NMNAT is the rate-limiting step in the synthesis of NAD and NAD analogues. BR- and TR-sensitive leukemic cells contain high NMNAT activity, whereas resistant clones have greatly downregulated NMNAT activity (<0.1% of wild type). Perhaps the applicability of BR and analogues could be enhanced if combined with NMNAT gene expression in BR-resistant leukemic blasts. NAD has important regulatory role in repair of DNA damage and cell growth since it is a substrate for poly(ADP-ribose) polymerase (PARP). PARP appears to direct short-patch base excision repair and induce p53 upregulation leading to apoptosis. BR inhibits PARP at high concentrations when assayed in permeabilized leukemic cells. Several other IMPDH inhibitors (TR, mycophenolic acid, and ribavirin) exhibit similar PARP inhibitory activity. Although this inhibition was reversible, it was not prevented by the addition of guanosine, GTP, or its nonhydrolyzable analog gamma-S-GTP. Therefore, it can be concluded that IMPDH inhibitors directly inhibit PARP. Presumably, the shared IMP-NAD active site of IMPDH has a similar architecture to the NAD-binding pocket of PARP.

Antitumor activity of benzamide riboside in vitro and in vivo.

Benzamide riboside (BR), a recent synthetic nucleoside analogue, is a new compound demonstrating potent cytotoxic activity in malignant cell lines in vitro and in vivo in L1210 leukemia. It exhibits at least two different mechanisms of action. These are, first, the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205), a rate-limiting enzyme for GTP and dGTP synthesis that plays a major role in DNA synthesis, cell proliferation and regulation; and second, the induction of apoptosis. Some aspects of BR activity in malignant cells in vitro and in vivo are reviewed as well as some of the mechanisms behind BR's anti-neoplastic effect.

Toxicity and efficacy of benzamide riboside in cancer chemotherapy models.

Benzamide riboside (BR), a synthetic C-nucleoside, acts as a strong growth inhibitor of cancer cells in vitro and in vivo. BR, like TR and related nucleoside prodrugs, act by anabolism to NAD analogs. These analogs selectively inhibit IMPDH, leading to depletion of cellular GTP, growth cessation, and cell differentiation. To date only preclinical studies have been carried out. However, in tiazofurin (TR), a related drug, phase I/II clinical trials have been conducted in patients with acute leukemia and shown to be a very promising agent with a response rate of 85% in 26 patients in one of the trials. Tiazofurin is now undergoing phase III clinical trials as a result. Dose limiting toxicity of tiazofurin was headache, somnolence and nausea with no myelosuppression noted. By contrast, BR showed skeletal muscle toxicity, hepatotoxicity and myelosuppression in preclinical data. Skeletal muscle toxicity was noted in the paraspinal muscles and may represent dose-limiting toxicity. Since BR does exhibit myelosuppression, the most common chemotherapy-related side effect in humans, careful judgment is warranted should BR be included in multidrug regimens, although BR's potent cytotoxicity to tumor cells in preclinical models still makes it a promising drug.

Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia.

Novel mycophenolic adenine dinucleotide (MAD) analogues have been prepared as potential inhibitors of inosine monophosphate dehydrogenase (IMPDH). MAD analogues resemble nicotinamide adenine dinucleotide binding at the cofactor binding domain of IMPDH; however, they cannot participate in hydride transfer and therefore inhibit the enzyme. The methylenebis(phosphonate) analogues C2-MAD and C4-MAD were obtained by coupling 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (22) with mycophenolic alcohols 20 and 21 in the presence of diisopropylcarbodiimide followed by deprotection. C2-MAD was also prepared by coupling of mycophenolic methylenebis(phosphonate) derivative 30 with 2',3'-O-isopropylideneadenosine. Compound 30 was conveniently synthesized by the treatment of benzyl-protected mycophenolic alcohol 27 with a commercially available methylenebis(phosphonic dichloride) under Yoshikawa's reaction conditions. C2-MAD and C4-MAD were found to inhibit the growth of K562 cells (IC(50) = 0.7 microM and IC(50) = 0.1 microM, respectively) as potently as mycophenolic acid (IC(50) = 0.3 microM). In addition, C2-MAD and C4-MAD triggered vigorous differentiation of K562 cells an order of magnitude more potently than tiazofurin, and MAD analogues were resistant to glucuronidation in vitro. These results show that C2-MAD and C4-MAD may be of therapeutic interest in the treatment of human leukemias.