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Stereodivergent approach to beta-hydroxy alpha-amino acids from C(2)-symmetrical alk-2-yne-1,4-diols.

[reaction: see text] A new stereodivergent route to erythro- and threo-beta-substituted serines from a common C(2)-symmetrical alk-2-yne-1,4-diol is described. Stereocontrol in such an acyclic system is achieved by taking advantage of symmetry. Stereoselective alkyne reduction to either (Z)- or (E)-olefin allows selection of the stereochemistry of alpha-carbon in the final amino acid by using a Pd(0)-catalyzed process. This strategy has been applied to the synthesis of (2S,3S)-3-hydroxyleucine.

Amino Acids↗

Identification of a novel growth factor-like lipid, 1-O-cis-alk-1'-enyl-2-lyso-sn-glycero-3-phosphate (alkenyl-GP) that is present in commercial sphingolipid preparations.

Lysophosphatidic acid, a member of the acidic phospholipid autacoid (APA) family of lipid mediators, elicits diverse cellular effects that range from mitogenesis to the prevention of programmed cell death. Sphingosine 1-phosphate and sphingosylphosphorylcholine have also been proposed to be ligands of the APA receptors. However, key observations that provide the foundation of this hypothesis have not been universally reproducible, leading to a controversy in the field. We provide evidence that 1-O-cis-alk-1'-enyl-2-lyso-sn-glycero-3-phosphate (alkenyl-GP) is present in some commercial sphingolipid preparations and is responsible for many of their APA-like effects, which were previously attributed to sphingosylphosphorylcholine. Alkenyl-GP was generated by acidic and basic methanolysis from ethanolamine lysoplasmalogen, which was present in the sphingomyelin fraction that is used to manufacture sphingosylphosphorylcholine. We present the structural identification of alkenyl-GP, using 1H and 13C NMR, Fourier transform infrared spectrometry, and mass spectrometry. Alkenyl-GP was a potent activator of the mitogen-activated protein kinases ERK1/2 and elicited a mitogenic response in Swiss 3T3 fibroblasts. In contrast, sphingosylphosphorylcholine at a concentration of 10 microM was only a weak mitogen and only weakly activated the extracellular signal-regulated protein kinases. Alkenyl-GP has recently been detected as an injury-induced component in the anterior chamber of the eye (Liliom, K., Guan, Z., Tseng, H., Desiderio, D. M., Tigyi, G., and Watsky, M. (1998) Am. J. Physiol. 274, C1065-C1074), indicating that this lipid is a naturally occurring member of the APA mediator family.

3T3 Cells↗

Presence of 1-O-alk-1'-enyl-2-O-acetyl glycerophosphocholine (vinyl form of PAF) in perfused rat and guinea pig hearts.

1-O-Alk-1'-enyl-2-O-acetyl-glycerophosphocholine (vinyl form of PAF) was found with PAF in perfused rat and guinea pig hearts. The main molecular species of the vinyl form of PAF, after separation by reverse phase HPLC, were identified as 1-O-hexadec-, -octadec-, and -octadecen-1'-enyl-2-O-acetyl-GPCs (16:0, 18:0, and 18:1 vinyl forms of PAF) by mass spectrometry. The amounts of the predominant 16:0 species in rat and guinea pig hearts, respectively, were 46.4 and 22.5 ng per mg lipid-phosphorus of the original heart phospholipids.

Animals↗

Highly prolific Booroola sheep have a mutation in the intracellular kinase domain of bone morphogenetic protein IB receptor (ALK-6) that is expressed in both oocytes and granulosa cells.

The Booroola fecundity gene (FecB) increases ovulation rate and litter size in sheep and is inherited as a single autosomal locus. The effect of FecB is additive for ovulation rate (increasing by about 1.6 corpora lutea per cycle for each copy) and has been mapped to sheep chromosome 6q23-31, which is syntenic to human chromosome 4q21-25. Bone morphogenetic protein IB (BMP-IB) receptor (also known as ALK-6), which binds members of the transforming growth factor-beta (TGF-beta) superfamily, is located in the region containing the FecB locus. Booroola sheep have a mutation (Q249R) in the highly conserved intracellular kinase signaling domain of the BMP-IB receptor. The mutation segregated with the FecB phenotype in the Booroola backcross and half-sib flocks of sheep with no recombinants. The mutation was not found in individuals from a number of sheep breeds not derived from the Booroola strain. BMPR-IB was expressed in the ovary and in situ hybridization revealed its specific location to the oocyte and the granulosa cell. Expression of mRNA encoding the BMP type II receptor was widespread throughout the ovary. The mutation in BMPR-IB found in Booroola sheep is the second reported defect in a gene from the TGF-beta pathway affecting fertility in sheep following the recent discovery of mutations in the growth factor, GDF9b/BMP15.

Activin Receptors↗

Competing pathways in the formation of alkyl, alk-1-enyl and acyl moieties in the lipids of mammalian tissues.

The distribution of radioactivity from intravenously administered cis-9[1-14C]octadecenol into various tissues of the rat was studied as a function of time. The pattern of incorporation of radioactivity into alkyl, alk-1-enyl and acyl moieties of the lipids in heart, lungs, liver, intestine, kidney, brain and plasma revealed that oxidation of the long-chain alcohol and esterification of the resulting fatty acid to a wide variety of lipids are by far the most predominant reactions. Acylation of the long-chain alcohol is observed especially in liver, which appears to be the major site of biosynthesis of wax esters. Alkylation of the long-chain alcohol to alkoxylipids occurs in most tissues, most predominantly in the heart.

Acylation↗

Cardiac presentation of ALK positive anaplastic large cell lymphoma.

Cardiac involvement as an initial presentation of malignant lymphoma is a rare occurrence. We report the case of an immunocompetent 29-year-old male who presented with syncope and arrythmias secondary to a ventricular cardiac mass. Transcutaneous cardiac biopsy was non-diagnostic, therefore an open cardiac biopsy was performed from which a provisional diagnosis of a cardiac inflammatory pseudotumour was made. Six months after presentation, he developed several subcutaneous lesions with systemic symptoms. Histological and immunophenotypic review of the initial cardiac biopsy revealed features consistent with a diagnosis of CD30, ALK1 positive anaplastic large cell lymphoma (ALCL). Despite intensive treatment with combination chemotherapy, there was significant progression of disease, and he died 11 months after diagnosis. The overall prognosis of cardiac lymphoma remains poor, which may be due to the often late presentation of the tumour. To our knowledge, this is the first reported case of a cardiac ALK positive ALCL. Although rare, cardiac presentation of ALCL should be added to the list of differential diagnoses of cardiac lymphomas.

Activin Receptors, Type I↗

Biodegradation of petroleum hydrocarbons by psychrotrophic Pseudomonas strains possessing both alkane (alk) and naphthalene (nah) catabolic pathways.

Three hydrocarbon-degrading psychrotrophic bacteria were isolated from petroleum-contaminated Arctic soils and characterized. Two of the strains, identified as Pseudomonas spp., degraded C5 to C12 n-alkanes, toluene, and naphthalene at both 5 and 25 degrees C and possessed both the alk catabolic pathway for alkane biodegradation and the nah catabolic pathway for polynuclear aromatic hydrocarbon biodegradation. One of these strains contained both a plasmid slightly smaller than the P. oleovorans OCT plasmid, which hybridized to an alkB gene probe, and a NAH plasmid similar to NAH7, demonstrating that both catabolic pathways, located on separate plasmids, can naturally coexist in the same bacterium.

Alkanes↗

A case of ALK-positive large T-cell lymphoma expressing epithelial membrane antigen with favorable prognosis.

We describe the case of a 59-year-old woman with Ki-1-negative, T cell-type, anaplastic lymphoma kinase (ALK)-positive large cell lymphoma that was positive for epithelial membrane antigen. She was histopathologically diagnosed as having a metastatic undifferentiated carcinoma from a cervical lymph node biopsy. Clinical and radiographic studies revealed no other primary tumor. The patient underwent a left radical neck dissection. Surgically resected lymph nodes revealed an ALK1-positive large cell lymphoma. Thereafter the patient has had an unusually favorable prognosis.

Anaplastic Lymphoma Kinase↗

ALK-negative anaplastic large cell lymphoma and Hodgkin's disease of nodular sclerosing type in 2 siblings.

Familial clustering of Hodgkin's disease (HD) and increased risk of developing the disease among the siblings of affected patients suggest that both environmental and genetic factors may play an important role in its pathogenesis. An association between Epstein-Barr virus (EBV) and HD has been widely demonstrated. Recently, latent membrane protein of EBV has also been detected in CD30-positive anaplastic large cell lymphoma. Familial aggregation of HD and a three- to seven-fold-increased risk among the siblings of affected patients suggest increased genetically determined susceptibility. No data about genetic factors are available for anaplastic large-cell lymphoma. In this study, the authors report the case of a woman with anaplastic-lymphoma-kinase (ALK)-negative CD30-positive anaplastic large cell lymphoma, whose brother had developed HD 11 years previously. The clinical, histologic, and immunohistochemical features of the 2 lymphomas were studied. Both siblings showed bulky mediastinal involvement, effacement of normal lymph node architecture by large, atypical cells, resembling Reed-Sternberg cells, expression of EBV latent membrane protein-1 in the lymph node specimens, concordance of both HLA classes I and II. The clinical presentations and immunological studies disclose numerous similarities between the 2 cases and can suggest that their association is not fortuitous. At present, in problematic cases, a combination of morphologic, immunophenotypic and genetic studies may contribute to better define the tumour type.

Anaplastic Lymphoma Kinase↗

ALK-negative T-cell anaplastic large cell lymphoma associated with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) appear to have an increased risk of developing malignancies, especially lymphomas. We report the development of a systemic ALK-negative T-cell anaplastic large cell lymphoma, stage IIB, in a 53-yr-old Caucasian female with a 12-yr history of stable SLE. The patient responded poorly to chemotherapy and died 2 yr after diagnosis. Lymphomas that develop in patients with SLE and other autoimmune diseases are virtually always of B-cell origin. To our knowledge this is the first report of a T-cell anaplastic large cell lymphoma in a patient with SLE. This article discusses the association of SLE and lymphoma, with an emphasis on T-lymphoproliferative states.

Adult↗

Studies on the hydrolysis of 1-alk-1'-enyl-sn-glycero-3-phosphoethanolamine by microsomes from myelinating rat brain.

Microsomal fractions of 14-day-old rat brain were incubated at pH 7.1 with 1-[1'-14C]-alk-1'-enyl-sn-glycero-3-phosphoethanolamine (lysoplasmalogen). 1-[1'-14C]alkenylglycerol was produced by hydrolyzing enzyme activities, which were stimulated by Mg2 and inhibited by SH-group reagents. Hydrolysis of 1-[1'-14C]alkyl-sn-glycero-3-phosphoethanolamine is very similar in this respect, but the Km value is higher in the former case. The 1-alkyl compound acts as a non-competitive inhibitor of the hydrolyzing enzyme activity described, whereas the hydrolysis of the 1-alkyl derivative is not inhibited by the 1-alkenyl compound.

Animals↗

Inflammatory myofibroblastic tumor: a spinal case with aggressive clinical course and ALK overexpression. Case report.

The authors report on a case of spinal inflammatory myofibroblastic tumor (IMT) in a 22-year-oldwoman. Neuroradiological features of this intradural extramedullary mass were suggestive of a meningioma or neurinoma. The lesion was easily resected following a T-9 laminectomy. Light microscopy showed a proliferation of spindle cells with prominent nucleoli on a fibrous or edematous background with infiltration of numerous lymphocytes and plasma cells. Some spindle cells immunostained positively for ALK1. This led to the diagnosis of IMT. The patient's postoperative course was complicated by a multifocal local recurrence requiring a second surgery, which was followed by radio- and chemotherapy. The occurrence of IMT in the spinal cord has rarely been reported. In this case, ALK overexpression was associated with early multifocal recurrence. This has been recently reported in this tumor typein other locations.

Adult↗

Bone marrow involvement in systemic ALK+ anaplastic large cell lymphoma: morphological resemblance with Hodgkin's lymphoma.

A 21 years old male presented with enlarged cervical lymph nodes. Diagnosis of anaplastic large cell lymphoma was made on lymph node biopsy and confirmed by immunohistochemistry using a panel of monoclonal antibodies including ALK-1. Bone marrow aspiration revealed the presence of large lymphoma cells and trephine biopsy showed interstitial involvement. In addition, there was presence of binucleate cells, lymphocytes, plasma cells and eosinophils. All these features resulted in a strong resemblance of the morphology with Hodgkin's lymphoma.

Activin Receptors, Type II↗

[Mutations of genes coding for TGF-beta receptors (BMPR2 and ALK-1) in primary pulmonary arterial hypertension].

Pulmonary hypertension is defined by an elevation in pulmonary artery pressure leading to progressive right heart failure and death. Primary (idiopathic) pulmonary hypertension (PPH) is a rare disease with an estimated incidence of 2 per million inhabitants per year in France. Abnormal pulmonary artery angiogenesis is a characteristic feature of this condition including endothelial and smooth muscle cell proliferation in small to medium-sized pulmonary arteries. The recent discovery of germline mutations of genes coding for receptor members of TGF-beta (BMPR-2 et ALK-1) in PPH represents a considerable progress in the understanding of this pulmonary orphan disease. This review summarizes the current genetic data obtained in this condition.

Activin Receptors, Type I↗

Conversion of 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine to 1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phosphoethanolamine. A novel pathway for the metabolism of ether-linked phosphoglycerides.

Madin Darby canine kidney (MDCK) cells convert 1-O-[3H]alkyl-2-acyl-sn-glycero-3-phosphocholine [( 3H]alkylacylGPC) to a product tentatively identified as an ethanolamine-containing phosphoglyceride (PE) (Daniel, L. W., Waite, B. M., and Wykle, R. L. (1986) J. Biol. Chem. 261, 9128-9132). In the present study, analysis of the radiolabeled phosphoglycerides as diradylglycerobenzoate derivatives indicated that [3H] alkylacylGPC was initially converted to 1-O-[3H]alkyl-2-acyl-sn-glycero-3-phosphoethanolamine [( 3H]alkylacylGPE) which was subsequently desaturated to 1-O-[3H]alk-1'-enyl-2-acyl-sn-glycero-3-phosphoethanolamine [( 3H]alkenylacylGPE). The conversion of [3H]/[32P]alkyl-lysoGPC to [3H]alkenylacylGPE indicated that base exchange enzymes were not involved in this pathway. A phosphono analog of alkyl-lysoGPC, resistant to phospholipase D hydrolysis and radiolabeled in the 1-O-alkyl chain was readily incorporated, acylated, and subsequently metabolized to [3H]alkylacylGPC and [3H]alkenylacylGPE. Therefore, the involvement of phospholipase D in the conversion pathway was ruled out. The conversion of [3H]alkylacylGPC or its phosphono analog to [3H]alkenylacylGPE was significantly enhanced by the addition of 100 microM ethanolamine to the culture media, suggesting that [3H]alkylacylglycerol is an intermediate in the cytidine-dependent pathway of PE synthesis. MDCK cell cytosol and microsomes contained no detectable phospholipase C activity. However, incubation of microsomes with CMP resulted in the degradation of [3H]alkylacylGPC and accumulation of [3H]alkylacylglycerol. Furthermore, the addition of CDP-ethanolamine to microsomes following preincubation with CMP, resulted in a decrease in [3H]alkylacylglycerol with a concomitant increase in [3H]alkenylacylGPE. Overall, these results suggest that the reverse reaction of choline phosphotransferase may be responsible for the conversion of alkylacylGPC to alkylacylGPE.

Animals↗

Conversion of fatty aldehyde dimethyl acetals to the corresponding alk-1-enyl methyl ethers (substituted vinyl ethers) during gas-liquid chromatography.

The behavior of palmitaldehyde and linolealdehyde and of their dimethyl acetals during gas-liquid chromatography on beta-cyclodextrin acetate (beta-CDX acetate) and ethylene glycol succinate polyester-phosphoric acid (EGSP) columns was studied. The aldehydes were well separated from their dimethyl acetals on the beta-CDX acetate column. However, on the EGSP column the retention times of palmitaldehyde and its dimethyl acetal were identical; a mixture of linolealdehyde and its dimethyl acetal gave a split peak. The aldehydes were recovered unchanged in 80-85% yield by preparative GLC from both columns, but the dimethyl acetals were quantitatively converted to the corresponding alk-1-enyl methyl ethers. The structure of these compounds was elucidated by infrared spectroscopy, mass spectrometry, and chemical means. Upon hydrolysis at low temperatures with 100% H(2)SO(4) they yielded the corresponding aldehydes, which were identified as 2,4-dinitrophenylhydrazones.

Acetals↗

[ALK-1 positive anaplastic large cell lymphoma of the lung. Report of a pediatric case].

Ki-1 anaplastic large cell non-Hodgkin lymphoma is a well recognized clinical entity. The main clinical feature includes lymphadenopathy with mediastinal sparing. In the extranodal disease, which occurs in approximately half of the cases, the skin is the most common site; bone marrow, lung and central nervous system are generally not involved. Anaplastic large cell lymphoma is more common among young people, in whom the prognosis is more favorable. Primary anaplastic large cell lymphoma of the lung is a rare clinical entity. Its clinical expression is similar to a high grade malignant lymphoma, and in most cases the diagnosis is made in advanced stages. We present a pediatric case with ALK-1 positive anaplastic large cell lymphoma of the lung.

Activin Receptors, Type II↗