Frank T. Martiniuk, Ph.D.

CD70 and Th17 are involved in human contact sensitivity
Lee, David S; Gulati, Nicholas; Martiniuk, Frank; Levis, William R
2011 Oct 1;10(10):1192-1194, Journal of drugs in dermatology : JDD
CD70 (CD27L) has been shown to be preferentially expressed on Th1, but not Th2, CD4+ lymphocytes in murine contact sensitivity. The CD70-CD27 co-stimulatory pathway as well as the Th17 subset of lymphocytes have also been identified in human contact sensitivity reactions. The authors have previously reported increased expression of CD70 and the Th17-specific transcription factor retinoid orphan receptor gamma T in the elicitation phase of allergic contact dermatitis by reverse transcriptase-polymerase chain reaction. The manipulation of these pathways has potential for ameliorating autoimmune and inflammatory disorders such as allergic contact dermatitis, psoriasis and rheumatoid arthritis. Also, upregulation of the CD70-CD27 and Th17 pathways has been associated with the remarkable ability of topical sensitizers to treat warts and skin cancers including melanoma. As natural killer and natural killer T cells are also involved in contact sensitivity, future studies investigating the function of these cells are necessary to elucidate the transition between innate and acquired immune responses in the context of the Th1/Th2/Th17 and regulatory T cell paradigm
— id: 141822, year: 2011, vol: 10, page: 1192, stat: Journal Article,

Endemic leprosy in new york city
Levis, William R; Paraskevas, Lilly-Rose; Jacobson, Mark; Spencer, John; Spencer, Trudy; Martiniuk, Frank
2011 May;147(5):624-626, Archives of dermatology
— id: 132593, year: 2011, vol: 147, page: 624, stat: Journal Article,

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease
Naj, Adam C; Jun, Gyungah; Beecham, Gary W; Wang, Li-San; Vardarajan, Badri Narayan; Buros, Jacqueline; Gallins, Paul J; Buxbaum, Joseph D; Jarvik, Gail P; Crane, Paul K; Larson, Eric B; Bird, Thomas D; Boeve, Bradley F; Graff-Radford, Neill R; De Jager, Philip L; Evans, Denis; Schneider, Julie A; Carrasquillo, Minerva M; Ertekin-Taner, Nilufer; Younkin, Steven G; Cruchaga, Carlos; Kauwe, John S K; Nowotny, Petra; Kramer, Patricia; Hardy, John; Huentelman, Matthew J; Myers, Amanda J; Barmada, Michael M; Demirci, F Yesim; Baldwin, Clinton T; Green, Robert C; Rogaeva, Ekaterina; George-Hyslop, Peter St; Arnold, Steven E; Barber, Robert; Beach, Thomas; Bigio, Eileen H; Bowen, James D; Boxer, Adam; Burke, James R; Cairns, Nigel J; Carlson, Chris S; Carney, Regina M; Carroll, Steven L; Chui, Helena C; Clark, David G; Corneveaux, Jason; Cotman, Carl W; Cummings, Jeffrey L; Decarli, Charles; Dekosky, Steven T; Diaz-Arrastia, Ramon; Dick, Malcolm; Dickson, Dennis W; Ellis, William G; Faber, Kelley M; Fallon, Kenneth B; Farlow, Martin R; Ferris, Steven; Frosch, Matthew P; Galasko, Douglas R; Ganguli, Mary; Gearing, Marla; Geschwind, Daniel H; Ghetti, Bernardino; Gilbert, John R; Gilman, Sid; Giordani, Bruno; Glass, Jonathan D; Growdon, John H; Hamilton, Ronald L; Harrell, Lindy E; Head, Elizabeth; Honig, Lawrence S; Hulette, Christine M; Hyman, Bradley T; Jicha, Gregory A; Jin, Lee-Way; Johnson, Nancy; Karlawish, Jason; Karydas, Anna; Kaye, Jeffrey A; Kim, Ronald; Koo, Edward H; Kowall, Neil W; Lah, James J; Levey, Allan I; Lieberman, Andrew P; Lopez, Oscar L; Mack, Wendy J; Marson, Daniel C; Martiniuk, Frank; Mash, Deborah C; Masliah, Eliezer; McCormick, Wayne C; McCurry, Susan M; McDavid, Andrew N; McKee, Ann C; Mesulam, Marsel; Miller, Bruce L; Miller, Carol A; Miller, Joshua W; Parisi, Joseph E; Perl, Daniel P; Peskind, Elaine; Petersen, Ronald C; Poon, Wayne W; Quinn, Joseph F; Rajbhandary, Ruchita A; Raskind, Murray; Reisberg, Barry; Ringman, John M; Roberson, Erik D; Rosenberg, Roger N; Sano, Mary; Schneider, Lon S; Seeley, William; Shelanski, Michael L; Slifer, Michael A; Smith, Charles D; Sonnen, Joshua A; Spina, Salvatore; Stern, Robert A; Tanzi, Rudolph E; Trojanowski, John Q; Troncoso, Juan C; Van Deerlin, Vivianna M; Vinters, Harry V; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A; Williamson, Jennifer; Woltjer, Randall L; Cantwell, Laura B; Dombroski, Beth A; Beekly, Duane; Lunetta, Kathryn L; Martin, Eden R; Kamboh, M Ilyas; Saykin, Andrew J; Reiman, Eric M; Bennett, David A; Morris, John C; Montine, Thomas J; Goate, Alison M; Blacker, Deborah; Tsuang, Debby W; Hakonarson, Hakon; Kukull, Walter A; Foroud, Tatiana M; Haines, Jonathan L; Mayeux, Richard; Pericak-Vance, Margaret A; Farrer, Lindsay A; Schellenberg, Gerard D
2011 May;43(5):436-441, Nature genetics
The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 x 10(-9), joint analysis P (P(J)) = 1.7 x 10(-9); stages 1, 2 and 3, P(M) = 8.2 x 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 x 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 x 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 x 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 x 10(-10), P(J) = 5.2 x 10(-11)), CLU (rs1532278; P(M) = 8.3 x 10(-8), P(J) = 1.9 x 10(-8)), BIN1 (rs7561528; P(M) = 4.0 x 10(-14), P(J) = 5.2 x 10(-14)) and PICALM (rs561655; P(M) = 7.0 x 10(-11), P(J) = 1.0 x 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility
— id: 134258, year: 2011, vol: 43, page: 436, stat: Journal Article,

TOMM40 poly-T Variants and Cerebrospinal Fluid Amyloid Beta Levels in the Elderly
Pomara N; Bruno D; Nierenberg JJ; Sidtis JJ; Martiniuk FT; Mehta PD; Zetterberg H; Blennow K
2011 Jun;36(6):1124-1128, Neurochemical research
A variable poly-T polymorphism in the TOMM40 gene, which is in linkage disequilibrium with APOE, was recently implicated with increased risk and earlier onset age for late-onset Alzheimer's disease in APOE epsilon3 carriers. To elucidate potential neurobiological mechanisms underlying this association, we compared the effect of TOMM40 poly-T variants to the effect of APOE, an established LOAD-risk modulator, on cerebrospinal fluid (CSF) amyloid beta (Abeta) and tau levels, in cognitively intact elderly subjects. APOE epsilon4 carriers showed significant reductions in Abeta 1-42 levels compared to non-epsilon4 carriers, but no differences were detected across TOMM40 variants. Neither Abeta 1-40 nor tau levels were affected by APOE or TOMM40
— id: 131223, year: 2011, vol: 36, page: 1124, stat: Journal Article,

Correlation between serum and plasma antibody titers to mycobacterial antigens
Siev, Michael; Yu, Xian; Prados-Rosales, Rafael; Martiniuk, Frank T; Casadevall, Arturo; Achkar, Jacqueline M
2011 Jan;18(1):173-175, Clinical & vaccine immunology
The ability to utilize serum or plasma samples interchangeably is useful for tuberculosis (TB) serology. We demonstrate a strong correlation between antibody titers to several mycobacterial antigens in serum versus plasma from HIV-infected and non-HIV-infected TB and non-TB patients (r = 0.99 to 0.89; P < 0.0001). Plasma and serum can be used interchangeably in the same antibody detection assays
— id: 126557, year: 2011, vol: 18, page: 173, stat: Journal Article,

Erythema nodosum leprosum, Sweet's syndrome, and human immunodeficiency virus may be related through an overlap in immunopathogenesis
Elbuluk, Nada; Martiniuk, Frank; Levis, William R
2010 Nov;49(11):1344-1345, International journal of dermatology
— id: 141823, year: 2010, vol: 49, page: 1344, stat: Journal Article,

The role of complement in dendritic cell (DC) control of T-cell subsets
Levis, William R; Martiniuk, Frank
2010 Nov;9(11):1364-1366, Journal of drugs in dermatology : JDD
This section of the Journal of Drugs in Dermatology (JDD) is dedicated to Dendreon's Provenge (Sipuleucel-T), the first therapeutic DC vaccine proven effective and approved by the United States (U.S.) Food and Drug Administration (FDA) for advanced cancer. This editorial will discuss three articles in this issue, their relationship to Provenge and the recent TH17-Treg subsets that are regulated by CD46
— id: 141825, year: 2010, vol: 9, page: 1364, stat: Journal Article,

Expression of sox10 and cd117 (c-kit) in mucosal melanomas of nasal cavity-29 cases of Chinese patients
Liu, H. G.; Qian, Y.; Wang, S. Y.; Martiniuk, F.; Shibata, R.; Yee, H.; Wang, B. Y.
2010 OCT ;57(11):62-62, Histopathology
— id: 113923, year: 2010, vol: 57, page: 62, stat: Journal Article,

TH17 is involved in the remarkable regression of metastatic malignant melanoma to topical diphencyprone
Martiniuk, Frank; Damian, Diona L; Thompson, John F; Scolyer, Richard A; Tchou-Wong, Kam-Meng; Levis, William R
2010 Nov;9(11):1368-1372, Journal of drugs in dermatology : JDD
The authors provide an update on a previously reported patient with in-transit metastatic melanoma of the scalp treated with topical diphencyprone (DPCP). Molecular studies implicate the thymus-derived TH17 lymphocyte subset in a remarkable immunotherapeutic regression. The authors performed RT-PCR of total RNA from paraffin-embedded tissue before and after treatment with DPCP. Before treatment with DPCP, the authors found elevated expression of IL 17C/D/E/F; after treatment there was no detectable expression. Conversely, increased expression of PLZF/CD27 and CTLA4 was seen after treatment with no expression before treatment. No expression of IL17A/B, CD7, RORgTand FoxP3 were before or after treatment. Conclusions are limited to only the time samples were obtained. Remarkable regression of an in-transit metastatic melanoma treated with the immunomodulatory agent DPCP showed gain and loss of gene expression of the TH17 pathway. Further study of this pathway from NK to NK-T to TH7 and TH1 cells both with and without accessory or dendritic cells will improve understanding of contact sensitizers as topical immunomodulators
— id: 141824, year: 2010, vol: 9, page: 1368, stat: Journal Article,

Immunohistochemical Expression of CD117 (C-Kit) in Mucosal Melanomas of the Head and Neck
Shibata, RS; Martiniuk, F; Qian, Y; Liu, HG; Yee, H; Levis, W; Wang, BY
2010 FEB ;23(3):280A-280A, Modern pathology
— id: 109940, year: 2010, vol: 23, page: 280A, stat: Journal Article,

Immunohistochemical Expression of CD117 (C-Kit) in Mucosal Melanomas of the Head and Neck
Shibata, RS; Martiniuk, F; Qian, Y; Liu, HG; Yee, H; Levis, W; Wang, BY
2010 FEB ;90(11):280A-280A, Laboratory investigation
— id: 109959, year: 2010, vol: 90, page: 280A, stat: Journal Article,

Collision Tumor of Primary Laryngeal Mucosal Melanoma and Invasive Squamous Cell Carcinoma with IL-17A and CD70 Gene Over-Expression
Sirikanjanapong, Sasis; Lanson, Biana; Amin, Milan; Martiniuk, Frank; Kamino, Hideko; Wang, Beverly Y
2010 Dec;4(4):295-299, Head & neck pathology
The most common primary malignancy of the larynx is the squamous cell carcinoma (SCC). The primary malignant melanoma is quite rare in this location. Less than 60 cases of laryngeal melanomas have been reported to date. To our knowledge, collision primary malignant melanoma and invasive squamous cell carcinoma in the vocal cords has not been reported. We report a 53-year-old male patient who was diagnosed with a collision tumor of laryngeal melanoma and invasive SCC. Multiple Th17 pathway related genes including CTLA-4, IL-17A-F, PLZF, FoxP3, RorgammaT, CD27, and CD70 were analyzed by reverse transcriptase-polymerase chain reaction (Rt-PCR) in this case. Both IL-17A and CD70 genes were detected in this case of collision tumor. The results may define useful biomarkers for early diagnosis of mucosal melanoma and open an immunotherapeutic field for clinical management with the potential benefit from the immunomodulators that enhance both genes
— id: 115268, year: 2010, vol: 4, page: 295, stat: Journal Article,

Protective effects of anti-ricin A-chain antibodies delivered intracellularly against ricin-induced cytotoxicity
Wu, Feng; Fan, Shaoan; Martiniuk, Frank; Pincus, Seth; Muller, Sybille; Kohler, Heinz; Tchou-Wong, Kam-Meng
2010 May 26;1(5):188-195, World journal of biological chemistry
AIM: To evaluate the ability of anti-ricin A-chain antibodies, delivered intracellularly, to protect against ricin-induced cytotoxicity in RAW264.7 cells. METHODS: Anti-deglycosylated ricin A-chain antibody and RAC18 anti-ricin A-chain monoclonal antibody were delivered intracellularly by encapsulating in liposomes or via conjugation with the cell-penetrating MTS-transport peptide. RAW264.7 cells were incubated with these antibodies either before or after ricin exposure. The changes in cytotoxicity were estimated by MTT assay. Co-localization of internalized antibody and ricin was evaluated by fluorescence microscopy. RESULTS: Internalized antibodies significantly increased cell viability either before or after ricin exposure compared to the unconjugated antibodies. Fluorescence microscopy confirmed the co-localization of internalized antibodies and ricin inside the cells. CONCLUSION: Intracellular delivery of antibodies to neutralize the ricin toxin after cellular uptake supports the potential use of cell-permeable antibodies for post-exposure treatment of ricin intoxication
— id: 131974, year: 2010, vol: 1, page: 188, stat: Journal Article,

Hyperimmunoglobulin E syndrome with a novel STAT3 mutation
Anolik, Robert; Elmariah, Sarina; Lehrhoff, Stephanie; Votava, Henry J; Martiniuk, Frank T; Levis, William
2009 ;15(8):16-16, Dermatology online journal
A 35-year-old man with severe eczematous dermatitis and recurrent staphylococcal skin infections, some of which required hospitalization, is presented. Other medical concerns include recurrent oral staphylococcal infections, otitis media, ocular herpes simplex virus keratitis, asthma, steroid-induced gastritis, steroid-induced cataracts, recurrent upper respiratory infections, and acute pharyngitis. Past medical history includes retained dentition of six primary teeth, two episodes of childhood pneumonia that required hospitalization, and three wrist and ankle fractures. Laboratory data showed an eosinophil count of 2,400 cells/ml; the highest IgE level was 17,028 IU/mL. Considering the clinical and laboratory findings, the diagnosis of hyperimmunoglobulin E syndrome was made. DNA sequencing showed a novel signal transducer and activator of transcription 3 (STAT3) gene mutation within intron 12, specifically adenine to cytosine, two base pairs upstream of exon 13
— id: 126558, year: 2009, vol: 15, page: 16, stat: Journal Article,

The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer's disease
Glodzik-Sobanska, Lidia; Pirraglia, Elizabeth; Brys, Miroslaw; de Santi, Susan; Mosconi, Lisa; Rich, Kenneth E; Switalski, Remigiusz; Saint Louis, Leslie; Sadowski, Martin J; Martiniuk, Frank; Mehta, Pankaj; Pratico, Domenico; Zinkowski, Raymond P; Blennow, Kaj; de Leon, Mony J
2009 May;30(5):672-681, Neurobiology of aging
While cerebrospinal fluid (CSF) biomarkers are of use in the prediction and diagnosis of Alzheimer's disease our understanding of the background effects of age and the ApoE genotype is limited. Seventy-eight community-based normal volunteers (mean age 60+/-10 years, range 36-86) were examined to determine the relationships between CSF measures of total tau (T-tau), hyperphosphorylated tau (P-tau 231), amyloid beta (Abeta42/Abeta40 ratio), and isoprostane (IP) with age and ApoE genotype. The results showed that age by varepsilon4 genotype interactions were found for P-tau231 (beta=1.82; p<0.05) and IP (beta=1.6; p<0.05). T-tau CSF concentration increased with age. The increasing CSF concentrations of P-tau and IP in varepsilon4 carriers suggest that early tauopathy and oxidative stress may be related to the increased risk for AD. The data also suggest that T-tau changes are more age dependent than Abeta changes. The evidence that P-tau231 and IP are the earliest markers for the neuronal damage related to AD awaits longitudinal study
— id: 86778, year: 2009, vol: 30, page: 672, stat: Journal Article,

CTLA-4, IL17A/B/C/D/E/F, PLZF, CD27, FOXP3, RORgammaT and CD70 expression in mucosal melanoma of head and neck
Wang, YB; Shibata, R; Zhu, H; Delacure, M; Levis, W; Martiniuk, F
2009 ;455(Suppl 1):28-28, Virchows archive
— id: 102310, year: 2009, vol: 455, page: 28, stat: Journal Article,

Protective effects of anti-ricin A-chain RNA aptamer against ricin toxicity
Fan, Shaoan; Wu, Feng; Martiniuk, Frank; Hale, Martha L; Ellington, Andrew D; Tchou-Wong, Kam-Meng
2008 Nov 7;14(41):6360-6365, World journal of gastroenterology : WJG
AIM: To investigate the therapeutic potential of an RNA ligand (aptamer) specific for the catalytic ricin A-chain (RTA), the protective effects of a 31-nucleotide RNA aptamer (31RA), which formed a high affinity complex with RTA, against ricin-induced toxicity in cell-based luciferase translation and cell cytotoxicity assays were evaluated. METHODS: To test the therapeutic potential of anti-RTA aptamers in Chinese hamster ovary (CHO) AA8 cells stably transfected with a tetracycline regulatable promoter, ricin ribotoxicity was measured using luciferase and ricin-induced cytotoxicity was ascertained by MTS cell proliferation assay with tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl) -2H-tetrazolium]. RESULTS: Inhibition of protein synthesis by ricin in CHO AA8 cells resulted in diminished luciferase activity and treatment with polyclonal antibody against deglycosylated RTA (dgA) neutralized the inhibitory effects of ricin on luciferase activity and protected against ricin-induced cytotoxicity as measured by MTS assay. The 31RA anti-RTA aptamer inhibited the translation of luciferase mRNA in cell-free reticulocyte translation assay. 31RA aptamer also partially neutralized the inhibitory effects of ricin on luciferase activity and partially protected against ricin-induced cytotoxicity in CHO AA8 cells. CONCLUSION: We have shown that anti-RTA RNA aptamer can protect against ricin ribotoxicity in cell-based luciferase and cell cytotoxicity assays. Hence, RNA aptamer that inhibits RTA enzymatic activity represents a novel class of nucleic acid inhibitor that has the potential to be developed as a therapeutic agent for the treatment of ricin intoxication
— id: 94969, year: 2008, vol: 14, page: 6360, stat: Journal Article,

The role of the armadillo and sooty mangabey monkey in human leprosy
Hamilton, Heather K; Levis, William R; Martiniuk, Frank; Cabrera, Aloys; Wolf, John
2008 Jun;47(6):545-550, International journal of dermatology
BACKGROUND: The armadillo was the first animal model of leprosy. Its role in the transmission of leprosy remains controversial. The sooty mangabey model of leprosy led to the discovery that rhesus monkeys were more susceptible to leprosy when coinfected with simian immunodeficiency virus (SIV), but that leprosy may play a protective role against acquired immunodeficiency syndrome (AIDS) mortality. Recently, molecular methods have been developed for leprosy and may help resolve the role of zoonoses in leprosy. OBSERVATIONS: The recent identification of a case of leprosy in a native-born American on the east coast of the USA and the identification of leprosy as an immunologic reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)-positive cases raise the question of what role zoonoses may play in leprosy. CONCLUSIONS: Leprosy in armadillos and sooty mangabeys has been manipulated by human experimentation. In the case of the armadillo, further study, including molecular techniques, is required to elucidate the role of the armadillo as a zoonosis in human leprosy. Experimentation with the sooty mangabey led to the discovery of an interaction between SIV and leprosy in rhesus monkeys, and prompted the continued investigation of the relationship between HIV and leprosy
— id: 95836, year: 2008, vol: 47, page: 545, stat: Journal Article,

Molecular origin of endemic leprosy in New York City
Keo, Thormika; Martiniuk, Frank; Latkowski, JoAnn; Cabrera, Aloys; Rom, William; Levis, William R
2008 Mar 15;46(6):899-901, Clinical infectious diseases
We report an indigenous case of leprosy in New York City in an immunocompetent patient who was infected with a Mycobacterium leprae genotype that is consistent with an exogenous origin. Physicians in the eastern United States should be alerted that, although most patients who develop leprosy in the United States are foreign born, native-born Americans are also susceptible to the infection
— id: 76393, year: 2008, vol: 46, page: 899, stat: Journal Article,

Expression of CD70 and the TH17 transcription factor RORgammaT in human contact dermatitis
Martiniuk, Frank; Lee, David S; Gaspari, Anthony; Yee, Herman; Chiriboga, Luis; Huie, Maryann; Tchou-Wong, Kam-Meng; Levis, William R
2008 Oct;7(10):956-960, Journal of drugs in dermatology : JDD
Contact sensitizers are a major cause of inflammatory skin disease and as topical immunomodulators also have the potential for treating cancer, viral diseases and certain autoimmune disorders. In the present study, the authors identify the upregulation of the TH17 lymphocyte subset transcription factor retinoid orphan receptor gamma T (RORgammaT) and the CD70 costimulatory pathway in human contact sensitivity (CS) using molecular techniques. Identification of this important new subset of T lymphocytes and a recognized costimulatory pathway offers potential for ameliorating CS and insight into antitumor and antiviral mechanism of haptens as topical immunomodulators
— id: 92187, year: 2008, vol: 7, page: 956, stat: Journal Article,

Heat-shock proteins as drugs: potential applications in cancer, infections, and autoimmune and atopic diseases
Holzer, Aton M; Martiniuk, Frank; Levis, William R
2007 Apr;6(4):393-399, Journal of drugs in dermatology : JDD
Heat-shock proteins (HSPs) serve as both a valuable target as well as a potent tool in the therapy of melanoma and human papillomavirus infections. HSPs have been found to associate with key pathogenic antigens and, under different circumstances, activate or suppress both innate and adaptive immunity via several mechanisms. The dominant mechanism of HSP is as a chaperonin to upregulate antigens on antigen-presenting cell surfaces. While no HSP-based therapies are currently FDA approved, several are currently in phase III clinical trials. This study reviews the current literature on therapeutic studies of HSP and the significant role these proteins are likely to play in future therapeutic approaches to neoplasms, infections, and inflammatory diseases of the skin
— id: 95838, year: 2007, vol: 6, page: 393, stat: Journal Article,

Leprosy in a native-born American from the eastern United States
Levis, William R; Martiniuk, Frank; Cabrera, Aloys
2007 Aug;57(2):367-368, Journal of the American Academy of Dermatology
— id: 73849, year: 2007, vol: 57, page: 367, stat: Journal Article,

Leprosy as immune reconstitution inflammatory syndrome in HIV-positive persons
Martiniuk, Frank; Rao, Shaline D; Rea, Thomas H; Glickman, Michael S; Giovinazzo, Jerome; Rom, William N; Cabrera, Aloys; Levis, William R
2007 Sep;13(9):1438-1440, Emerging infectious diseases
— id: 78889, year: 2007, vol: 13, page: 1438, stat: Journal Article,

Identification of novel hsp65 RFLPs for Mycobacterium leprae
Martiniuk, Frank; Tambini, Marc; Rahimian, Joseph; Moreira, Andre; Yee, Herman; Tchou-Wong, Kam-Meng; Hanna, Bruce A; Rom, William N; Levis, William R
2007 Mar;6(3):268-274, Journal of drugs in dermatology : JDD
Leprosy or Hansen's disease is a chronic infectious disease caused by an acid-fast bacillus, Mycobacterium leprae (M. leprae). The bacilli proliferate in macrophages infiltrating the skin and gain entry to the dermal nerves via the laminar surface of Schwann cells where they replicate. After entry, the Schwann cells proliferate and then die. Conclusive identification of M. leprae DNA in a sample can be obtained by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for the heat shock 65 gene (hsp65). Molecular epidemiology will make it possible to study the global distributions of M. leprae, explore the relationship between genotypes-incidence rates, mode of transmission, and the type of disease (tuberculoid vs. lepromatous). We amplified DNA using PCR for the hsp65 gene from 24 skin lesions from patients diagnosed with various types of leprosy. Fifteen out of 24 were positive for the hsp65 gene. Digestion with HaeIII-PAGE for the RFLP confirmation of the presence of M. leprae DNA showed the typical pattern in 5 out of 24 and 2 novel patterns in 10 out of 24 patients. We confirmed the presence of M. leprae DNA by sequencing the genes for gyraseA or B and folP, which contained only M. leprae specific single nucleotide polymorphisms (SNPs). Thus, we describe novel hsp65 RFLPs for M. leprae found in a high frequency making them ideal for future epidemiology and transmission studies
— id: 71866, year: 2007, vol: 6, page: 268, stat: Journal Article,

Apoptotic gene expression in Alzheimer's disease hippocampal tissue
Sajan, Farrah D; Martiniuk, Frank; Marcus, David L; Frey, William H 2nd; Hite, Richard; Bordayo, Elizabeth Z; Freedman, Michael L
2007 Aug-Sep;22(4):319-328, American journal of Alzheimer's disease & other dementias
Alzheimer's disease (AD) is the major cause of dementia, accounting for 50% to 70% of the late-onset patients, with 17 to 20 million affected. It is characterized by neurofibrillary tangles, neuronal loss, and amyloid plaques in tissues of the cortex, hippocampus, and amygdala. Apoptosis or programmed cell death appears in the progression of AD. In this study, we investigated the gene expression of 14 apoptotic genes (E2F1, p21/WAF, ICE-LAP3, Fas Antigen, CPP-32, GADD153, ICE-beta, c-Fos, c-Jun, Bax-alpha, Bcl-2, Bcl-(x)L, BAK, and p53) in 5 normal and 6 AD human hippocampal tissues, using reverse transcription-polymerase chain reaction. Our results show an upregulation of gene expression in AD patients for c-Fos and BAK. ICE-beta, c-Jun, Bax-alpha, Bcl-x(L), p53, and GADD153 were found to be upregulated in some AD samples but were not detected or downregulated in other AD or normal samples. No gene expression was found for E2F1 , p21/WAF, ICE-LAP3, Fas Antigen, CPP32, or Bcl-2. These results indicate significant increases in c-Fos , c-Jun, and Bak; therefore, we suggest that these genes may be critical in the apoptotic cascades of AD
— id: 96094, year: 2007, vol: 22, page: 319, stat: Journal Article,

Modification of the natural history of adult-onset acid maltase deficiency by nutrition and exercise therapy
Slonim, Alfred E; Bulone, Linda; Goldberg, Teresia; Minikes, Jennifer; Slonim, Efrat; Galanko, Joseph; Martiniuk, Frank
2007 Jan;35(1):70-77, Muscle & nerve
Adult-onset acid maltase deficiency is an inherited lysosomal skeletal-muscle disease characterized by progressive myopathy and respiratory failure, for which there is no known therapy. In an uncontrolled, prospective study, we evaluated whether adherence to high-protein and low-carbohydrate nutrition and exercise therapy (NET) can slow the progressive deterioration of muscle function in this disease. Thirty-four patients have been treated with NET for periods of 2-10 years (mean 4.5 +/- 2.5). Pre-NET rate of muscle function deterioration, as measured by the Walton scale, was compared to post-NET rate. Twenty-six patients were deemed to be consistently compliant with NET. Difference between pre-NET slope of muscle function deterioration to that of post-NET slope in compliant patients was -0.29 (95% CI -0.19, 0.39) (P < 0.0001). We conclude that compliance with NET can slow deterioration of muscle function and improve the natural history of adult-onset acid maltase deficiency. Muscle Nerve, 2006
— id: 141826, year: 2007, vol: 35, page: 70, stat: Journal Article,

A novel missense mutation in the acid alpha-glucosidase gene causing the classic infantile form of Pompe disease
Dou, Wei; Peng, Chao; Zheng, Junke; Gu, Xuefen; Fu, Lijun; Martiniuk, Frank; Sheng, Hui Z
2006 Dec;374(1-2):145-146, Clinica chimica acta
— id: 141827, year: 2006, vol: 374, page: 145, stat: Journal Article,

Apoptotic gene expression in Alzheimer's disease
Marcus, DL; Sajan, FD; Martiniuk, F; Rolita, L; Frey, WH; Freedman, ML
2006 APR ;54(4):S20-S20, Journal of the American Geriatrics Society
— id: 64486, year: 2006, vol: 54, page: S20, stat: Journal Article,

Leprosy masquerading as lupus
Alberti, James R; Cabrera, Aloys; Martiniuk, Frank; Sanchez, Miguel; Levis, William R
2005 Apr;52(4):702-703, Journal of the American Academy of Dermatology
— id: 95841, year: 2005, vol: 52, page: 702, stat: Journal Article,

HIV and leprosy in the Eastern United States
Lu, Phoebe D; Patel, Manisha J; Yosipovitch, Gil; Martiniuk, Frank; Cabrera, Aloys; Levis, William R
2005 Nov 1;192(9):1673-1674, Journal of infectious diseases
— id: 95840, year: 2005, vol: 192, page: 1673, stat: Journal Article,

Alterations in expression of hippocampal genes Bax-alpha and BCL-2 in Alzheimer's disease as determined by reverse transcriptase PCR and microarray technology
Marcus, DL; Martiniuk, F; Hite, R; Freedman, ML
2005 APR ;53(4):S19-S19, Journal of the American Geriatrics Society
— id: 56250, year: 2005, vol: 53, page: S19, stat: Journal Article,

Interleukin-10 induces inhibitory C/EBPbeta through STAT-3 and represses HIV-1 transcription in macrophages
Tanaka, Naohiko; Hoshino, Yoshihiko; Gold, Jeffrey; Hoshino, Satomi; Martiniuk, Frank; Kurata, Takeshi; Pine, Richard; Levy, David; Rom, William N; Weiden, Michael
2005 Oct;33(4):406-411, American journal of respiratory cell & molecular biology
Pulmonary tuberculosis (TB) has been characterized by inflammation with increased pro- or anti-inflammatory cytokines produced by macrophages. We have reported that IFN produces inhibitory C/EBPbeta and represses transcription of the HIV-1 LTR in macrophages. STAT-1 and type I IFN receptor knockout mice have macrophages that are defective in IFN signaling, yet LPS stimulation induces inhibitory C/EBPbeta, demonstrating that other cytokines can induce this repressor. LPS or Mycobacterium tuberculosis-derived lipoarabinomannan induce the anti-inflammatory cytokine interleukin (IL)-10, which represses the HIV-1 LTR in differentiated THP-1 macrophages by inducing inhibitory C/EBPbeta. In contrast, in undifferentiated THP-1 monocytes, IL-10 did not inhibit HIV-1 replication or induce C/EBPbeta. IL-10 signal transduction uses STAT-3, and macrophages from STAT-3-/- mice fail to produce inhibitory C/EBPbeta after LPS or IL-10 stimulation. Transfection of STAT-3 into THP-1 cells enhances C/EBPbeta promoter activity. THP-1 differentiation also increases STAT-3 protein, but not STAT-3 gene transcription, and induces a translational regulator, CUG-binding protein, that was essential for production of C/EBPbeta. Differentiation induced post-transcriptional regulation is required to produce inhibitory C/EBPbeta in response to IL-10. Only macrophages are able to repress HIV-1 LTR promoter activity and inhibit viral replication in response to IL-10 or type I IFN
— id: 58745, year: 2005, vol: 33, page: 406, stat: Journal Article,

Juvenile-onset glycogen storage disease type II with novel mutations in acid alpha-glucosidase gene
Lam, CW; Yuen, YP; Chan, KY; Tong, SF; Lai, CK; Chow, TC; Lee, KC; Chan, YW; Martiniuk, F
2003 FEB 25 ;60(4):715-717, Neurology
The authors describe two novel mutations of the acid alpha- glucosidase gene, P361L and R437C, which define the juvenile- onset glycogen storage disease type II (GSDII) in a 16-year-old Chinese patient. The asymptomatic 13-year-old brother of the proband is also a compound heterozygote of the two mutations. These results confirm that intrafamilial phenotypic variation of juvenile-onset GSDII is ethnically diverse and suggest the contribution of other genes to the phenotypic variability of GSDII
— id: 36585, year: 2003, vol: 60, page: 715, stat: Journal Article,

New GAA mutations in Japanese patients with GSDII (Pompe disease)
Pipo, Judy R; Feng, Jian-Hua; Yamamoto, Toshiyuki; Ohsaki, Yuki; Nanba, Eiji; Tsujino, Seiichi; Sakuragawa, Norio; Martiniuk, Frank; Ninomiya, Haruaki; Oka, Akira; Ohno, Kousaku
2003 Oct;29(4):284-287, Pediatric neurology
Glycogen storage disease type II (Pompe disease) is inherited by autosomal recessive transmission and caused by a deficiency of acid alpha-glucosidase (GAA), resulting in impaired degradation and lysosomal accumulation of glycogen. The GAA gene, responsible for this disease, has been mapped to chromosome 17q25.2-25.3. To date, more than 70 disease-causing mutations have been identified. In this study, we present four mutations found in three Japanese patients with the juvenile form of glycogen storage disease type II; three of these mutations were new (R224W, S619R, and R660H). The pathogenicity of these new mutations was verified by the loss of function of the mutant enzymes expressed in COS cells
— id: 141828, year: 2003, vol: 29, page: 284, stat: Journal Article,

Helios gene gun particle delivery for therapy of acid maltase deficiency
Martiniuk, Frank; Chen, Agnes; Mack, Adra; Donnabella, Vincent; Slonim, Alfred; Bulone, Linda; Arvanitopoulos, Eleni; Raben, Nina; Plotz, Paul; Rom, William N
2002 Oct;21(10):717-725, DNA & cell biology
Autosomal recessive deficiency of lysosomal acid maltase (GAA) or glycogen storage disease type II (GSDII) results in a spectrum of phenotypes including a rapidly fatal infantile disorder (Pompe's), juvenile, and a late-onset adult myopathy. The infantile onset form presents as hypotonia with massive accumulation of glycogen in skeletal and heart muscle, with death due to cardiorespiratory failure. Adult patients with the slowly progressive form develop severe skeletal muscle weakness and respiratory failure. Particle bombardment is a safe, efficient physical method in which high-density, subcellular-sized particles are accelerated to high velocity to carry DNA into cells. Because it does not depend on a specific ligand, receptor, or biochemical features on cell surfaces, particle-mediated gene transfer can be readily applied to a variety of systems. We evaluated particle bombardment as a delivery system for therapy of GSDII. We utilized a vector carrying the CMV promoter linked to the human GAA cDNA. Human GSDII cell lines (fibroblasts and lymphoid) as well as ex vivo with adult-onset peripheral blood cells (lymphocytes and monocytes) were transiently transfected by bombardment with a Helios gene gun delivering gold particles coated with the GAA expression plasmid. All cell types showed an increase in human GAA activity greater than 50% of normal activity. Subsequently, GAA -/- mice were treated every 2 weeks for 4 months by particle bombardment to the epidermis of the lower back and hind limbs. Muscle weakness in the hind and forelimbs was reversed. These data suggest that particle delivery of the GAA cDNA by the Helios gene gun may be a safe, effective treatment for GSDII
— id: 39560, year: 2002, vol: 21, page: 717, stat: Journal Article,

Correction of glycogen storage disease type II by enzyme replacement with a recombinant human acid maltase produced by over-expression in a CHO-DHFR(neg) cell line [In Process Citation]
Martiniuk F; Chen A; Donnabella V; Arvanitopoulos E; Slonim AE; Raben N; Plotz P; Rom WN
2000 Oct 5;276(3):917-923, Biochemical & biophysical research communications
Inherited genetic deficiency of lysosomal acid alpha glucosidase or acid maltase (GAA) results in the autosomal recessive glycogen storage disease type II (GSD II). To investigate whether we could generate a functional recombinant human GAA (rhGAA) for enzyme replacement therapy, we subcloned the cDNAs for human GAA and mouse dihydrofolate reductase (DHFR) into DHFR(neg) Chinese hamster ovary cells and established a stable cotransformant that expressed rhGAA. We cultured the recombinant cells in media with progressively increasing concentrations of methotrexate and found that human GAA enzyme activity increased to over 2,000 IU per gram protein. Importantly, the human GAA enzyme activity correlated to equivalent amounts of human GAA protein by rocketimmunoelectrophoresis. We confirmed that the human GAA enzyme activity corresponded to an amplification in human GAA mRNA by Northern analysis and human GAA cDNA copy number by Southern analysis. Exposing the rhGAA to human GSDII fibroblast cells or patient's lymphocytes or monocytes resulted in uptake of the rhGAA and reversal of the enzymatic defect. Mannose-6-phosphate in the media blocked uptake. GAA -/- mice were treated with the rhGAA at 1 mg/kg, which resulted in heterozygous levels of GAA in tissues, most notably skeletal muscle, heart and diaphragm after two infusions. More importantly, after multiple infusions, hind, and fore-limb muscle weakness was reversed. This rhGAA would be ideal for enzyme replacement therapy in GSD II.
— id: 15196, year: 2000, vol: 276, page: 917, stat: Journal Article,

Identification of two subtypes of infantile acid maltase deficiency
Slonim AE; Bulone L; Ritz S; Goldberg T; Chen A; Martiniuk F
2000 Aug;137(2):283-285, Journal of pediatrics
Infantile patients with acid maltase deficiency have severe hypertrophic cardiomyopathy, left ventricular outflow obstruction, and generalized muscle weakness and die before 1 year of age. We identified 12 infants with acid maltase deficiency who had a similar clinical presentation but less severe cardiomyopathy and absence of left ventricular outflow obstruction, and 9 of 12 had longer survival with assisted ventilation and supplemental intubation
— id: 11561, year: 2000, vol: 137, page: 283, stat: Journal Article,

Helios gene gun delivery for gene therapy of acid maltase deficiency
Martiniuk, F; Chen, A; Mack, A; Donnabella, V; Arvanitopoulos, E; Rom, WN
1999 MAR ;159(3):A435-A435, American journal of respiratory & critical care medicine
— id: 53881, year: 1999, vol: 159, page: A435, stat: Journal Article,

Evaluating mechanisms responsible for mutation rates in clinical isolates of TB
Martiniuk, F; Chen, A; Weiden, M; Mack, A; Donnabella, V; Rom, WN
1999 MAR ;159(3):A16-A16, American journal of respiratory & critical care medicine
— id: 53868, year: 1999, vol: 159, page: A16, stat: Journal Article,

The gene for lysosomal protein CD63 is normal in patients with Hermansky-Pudlak syndrome
Armstrong LW; Rom WN; Martiniuk FT
1998 ;176(4):249-256, Lung
Hermansky-Pudlak syndrome (HPS) is one of the few genetic disorders associated with severe pulmonary fibrosis. Fifty percent of affected patients die as a result of respiratory insufficiency. Fibrosis is thought to be caused by the accumulation of ceroid, an insoluble fluorescent lipoprotein, both extracellularly and in the lysosomes of alveolar macrophages. In addition to pulmonary fibrosis, HPS is characterized by oculocutaneous albinism and a reduction in the number of platelet dense bodies. CD63 is a protein that was described originally in platelet lysosomes. It localizes to the membranes of melanosomes and platelet dense bodies. CD63 is decreased dramatically in the lysosomes and dense bodies of patients with HPS. We theorized that CD63, a membrane protein common to lysosomes, melanosomes, and platelet dense bodies, may play a role in HPS. We sought to characterize the gene coding for this protein in HPS lymphoid cell lines. The coding region for CD63 was sequenced in control and HPS cell lines. Messenger RNA from HPS and normal cell lines was examined by Northern analysis. Genomic DNA from the same cell lines was examined by Southern analysis and polymerase chain reaction (PCR). CD63 protein in lymphoid cell lines and peripheral blood monocytes was compared by Western analysis. We found no mutations in the coding region of CD63 in an HPS cell line. We also found no diminution in the quantity of CD63 RNA by Northern analysis and no gross defects in the structural gene by PCR and Southern analysis, suggesting that the CD63 structural gene, promoter, and untranslated regions were normal. Western analysis showed that the 43-kDa protein was present in control and HPS lymphoid cell lines and peripheral blood monocytes in equivalent amounts. Although CD63 is an attractive candidate for the primary defect of HPS, the disease is probably not caused by a mutation in the CD63 gene
— id: 7490, year: 1998, vol: 176, page: 249, stat: Journal Article,

Heterozygote frequency for Glycogenosis Type II in Italy
Danesino, C; Martiniuk, F; Dellavecchia, C; Chen, A; Mack, A; Arvanitopoulos, E; Minelli, A; Alcabes, P; Rom, WN
1998 JUL ;6(1):155-155, European journal of human genetics
— id: 53419, year: 1998, vol: 6, page: 155, stat: Journal Article,

Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease
Martiniuk F; Chen A; Mack A; Arvanitopoulos E; Chen Y; Rom WN; Codd WJ; Hanna B; Alcabes P; Raben N; Plotz P
1998 Aug 27;79(1):69-72, American journal of medical genetics
— id: 7965, year: 1998, vol: 79, page: 69, stat: Journal Article,

Nicotine enhances expression of the neutrophil elastase gene and protein in a human myeloblast/promyelocyte cell line
Armstrong LW; Rom WN; Martiniuk FT; Hart D; Jagirdar J; Galdston M
1996 Nov;154(5):1520-1524, American journal of respiratory & critical care medicine
The pathogenesis of emphysema is considered to be an imbalance of protease and antiprotease activity in the lower respiratory tract leading to uninhibited degradation of lung interstitium by elastolytic enzymes. An increased amount of the serine protease neutrophil elastase (NE) is though to play a major role in this degradation. Because the expression of NE is limited to neutrophil precursors in the bone marrow, we hypothesized that nicotine, which is readily absorbed from lung and distributed to tissue, including bone marrow, would increase expression of the NE gene and protein. HL-60 cells, a myeloblast/promyelocyte cell line, were cultured in the presence or absence of 0.06 and 0.8 microM nicotine for 5 d. Both concentrations of nicotine caused a 2.4- to 3.3-fold increase, respectively, in NE gene expression over unstimulated cells, and NE protein increased 4.8- to 3.4-fold over unstimulated cells, respectively, similar to our positive control DMSO. Nicotine did not induce upregulation of the NE gene by initiating cell differentiation. Both low and high nicotine concentrations upregulate the NE gene in HL-60 cells leading to increased NE protein concentration per cell suggesting a pathophysiologic mechanism for emphysema
— id: 12496, year: 1996, vol: 154, page: 1520, stat: Journal Article,

Rifampin
Donnabella, Vincet; Martiniuk, Frank
Tuberculosis Boston : Little Brown, 1996,
— id: 4856, year: 1996, vol: , page: ?, stat: Chapter,

A model of mRNA splicing in adult lysosomal storage disease (glycogenosis type II)
Raben N; Nichols RC; Martiniuk F; Plotz PH
1996 Jul;5(7):995-1000, Human molecular genetics
Glycogenosis type II is a recessively inherited disorder caused by mutations in the acid maltase (GAA) gene. Clinically, three different phenotypes are recognized: Infantile, juvenile and adult forms. A majority of compound heterozygous adult-onset patients carry a t-13g mutation in intron 1 associated with splicing out the first coding exon (exon 2). We have studied the mechanism of this mutation in a model system with wild-type and mutant minigenes expressed in a GAA deficient cell line. We have demonstrated that the mutation does not prevent normal splicing; low levels of correctly spliced mRNA are generated with the mutant construct. The data explain why the mutation is restricted to a milder, adult-onset phenotype. We also demonstrate that splicing out of exon 2 occurs with the wild-type construct, and thus represents alternative splicing which takes place in normal cells. Three splice variants (SV1, SV2 and SV3) are made with both the mutant and the wild-type constructs. Furthermore, as shown by RNAse protection assay, these mRNA variants are less abundant with the mutant construct. Thus, a major effect of the mutation appears to be a low splicing efficiency, since the total amount of all the transcripts generated from the mutant construct is reduced compared with the wild type. The removal of approximately 90% of the intron 1 (2.6 kb) sequence resulted in a dramatic increase in the levels of correctly spliced mRNA, indicating that the intron may contain a powerful transcriptional repressor
— id: 15197, year: 1996, vol: 5, page: 995, stat: Journal Article,

Acid alpha-glucosidase deficiency: identification and expression of a missense mutation (S529V) in a Japanese adult phenotype
Tsunoda H; Ohshima T; Tohyama J; Sasaki M; Sakuragawa N; Martiniuk F
1996 Apr;97(4):496-499, Human genetics
We report a missense mutation in an adult Japanese patient with acid alpha-glucosidase (GAA) deficiency. A TC to GT transition at nucleotides 1585-1586, was identified. This transition resulted in an amino acid substitution of Ser-529 to Val (S529V) in exon 11. We also have demonstrated that the S529V mutation abolishes the catalytic activity of the enzyme. Our data suggest that this mutation is the cause of the clinical manifestation known as adult-onset GAA deficiency. The missense mutation described here is a new mutation, and the first identified in Japanese patients with GAA deficiency
— id: 15198, year: 1996, vol: 97, page: 496, stat: Journal Article,

Evidence of molecular heterogeneity for generalised glycogenosis between and within breeds of cattle
Healy PJ; Nicholls PJ; Martiniuk F; Tzall S; Hirschhorn R; Howell JM
1995 Aug;72(8):309-311, Australian veterinary journal
Northern analyses revealed normal levels of acidic alpha-glucosidase mRNA in cultured fibroblasts from a Shorthorn calf affected with glycogenosis but a gross deficiency in an affected Brahman calf. Analyses of acidic alpha-glucosidase activity, relative to that of other lysosomal enzymes, in blood mononuclear cells revealed greater variation within and between Brahman herds than Shorthorn herds. A Msp1 restriction fragment length polymorphism associated with glycogenosis in Brahmans was not found in Shorthorns. These results are considered in relation to molecular heterogeneity for AAG deficiency in cattle and its implications for disease control programs
— id: 15199, year: 1995, vol: 72, page: 309, stat: Journal Article,

Isolation of the gene for the beta subunit of RNA polymerase from rifampicin-resistant Mycobacterium tuberculosis and identification of new mutations
Donnabella V; Martiniuk F; Kinney D; Bacerdo M; Bonk S; Hanna B; Rom WN
1994 Dec;11(6):639-643, American journal of respiratory cell & molecular biology
Tuberculosis (TB) is one of the most important infections worldwide, with an estimated incidence of 10 million active cases per year. Rifampicin is a key component of the first-line therapy used in the treatment of tuberculosis. In Escherichia coli and Mycobacterium leprae, rifampicin has been shown to inhibit the beta subunit of RNA polymerase. The gene (rpoB) encoding this enzyme has been described in both species. We report the isolation of the homologous functional rifampicin resistance gene from M. tuberculosis. A library was constructed with 15 to 25 kb BamHI-digested DNA fragments from a rifampicin-resistant M. tuberculosis clinical isolate that was ligated into an E. coli-mycobacterial shuttle plasmid. Southern analysis of BamHI-digested DNA from 200 recombinant plasmids was performed and filters were hybridized to a 411 bp fragment of the beta subunit of RNA polymerase from M. tuberculosis. Only DNA from one plasmid (#86) hybridized, which suggested that the gene is found as a single copy per genome. This plasmid was able to transfer rifampicin resistance to sensitive M. smegmatis and thus codes for a functional genetic unit. Sequence analysis in the expected 'hotspot' region in eight rifampicin-resistant M. tuberculosis strains (including one multidrug-resistant strain) revealed two novel mutations as well as others previously described
— id: 12859, year: 1994, vol: 11, page: 639, stat: Journal Article,

ALLELIC FREQUENCY AT THE NATURAL-RESISTANCE ASSOCIATED MACROPHAGE PROTEIN (NRAMP) LOCUS FROM PATIENTS AT RISK FOR TB
DONNABELLA, V; LAW, K; BODKIN, M; CHEN, Y; ROM, WN; MARTINIUK, F
1994 APR ;42(2):A187-A187, Clinical research
— id: 52491, year: 1994, vol: 42, page: A187, stat: Journal Article,

Mutation at the catalytic site (M519V) in glycogen storage disease type II (Pompe disease)
Huie ML; Hirschhorn R; Chen AS; Martiniuk F; Zhong N
1994 ;4(4):291-293, Human mutation
— id: 56660, year: 1994, vol: 4, page: 291, stat: Journal Article,

Mycobacterium tuberculosis alters expression of adhesion molecules on monocytic cells
Lopez Ramirez GM; Rom WN; Ciotoli C; Talbot A; Martiniuk F; Cronstein B; Reibman J
1994 Jun;62(6):2515-2520, Infection & immunity
The host response to Mycobacterium tuberculosis is characterized by interactions between mononuclear cells, with recruitment and fusion of these cells culminating in granuloma formation. In addition, the host response to M. tuberculosis requires CD4+ T-cell reactivity, mediated by antigen-independent as well as antigen-dependent mechanisms. Thus, we hypothesized that cell adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1; CD54) would participate in the response to infection with M. tuberculosis. Exposure of THP-1 cells derived from a monocyte/macrophage cell line to M. tuberculosis (1:1 bacterium/cell ratio) elicited a sustained increase (660% +/- 49% above resting level) in the expression of ICAM-1 that continued for at least 72 h. Neither the expression of vascular cell adhesion molecule 1 (VCAM-1; CD106) nor that of the integrins lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18) or CR3 (CD11b/CD18) was increased to a similar extent at corresponding time points. The increase in ICAM-1 protein expression was accompanied by an increase in steady-state mRNA (Northern [RNA] analysis). Neutralizing monoclonal antibodies directed against tumor necrosis factor alpha but not interleukin 1 alpha or interleukin 1 beta substantially abrogated the response to M. tuberculosis consistent with a paracrine or autocrine response. Continuous upregulation of the expression of ICAM-1 on mononuclear phagocytes induced by M. tuberculosis may mediate the recruitment of monocytes and enhance the antigen presentation of M. tuberculosis, thus permitting the generation and maintenance of the host response
— id: 56558, year: 1994, vol: 62, page: 2515, stat: Journal Article,

THE GENETICS OF MULTIDRUG-RESISTANCE IN MYCOBACTERIUM-TUBERCULOSIS
WEIDEN, MD; ROM, WN; KREISWIRTH, B; DONNABELLA, V; MARTINIUK, F
1994 APR ;42(2):A302-A302, Clinical research
— id: 52500, year: 1994, vol: 42, page: A302, stat: Journal Article,

ISOLATION OF THE GENE FOR THE BETA-SUBUNIT OF RNA-POLYMERASE FROM RIFAMPICIN RESISTANT MYCOBACTERIUM-TUBERCULOSIS
DONNABELLA, V; MARTINIUK, F; KINNEY, D; BRESCIA, M; BONK, S; HANNA, B; ROM, WN
1993 APR ;41(2):A196-A196, Clinical research
— id: 54263, year: 1993, vol: 41, page: A196, stat: Journal Article,

A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1
Cronstein BN; Kimmel SC; Levin RI; Martiniuk F; Weissmann G
1992 Nov 1;89(21):9991-9995, Proceedings of the National Academy of Sciences of the United States of America
Corticosteroids are the preeminent antiinflammatory agents although the molecular mechanisms that impart their efficacy have not been defined. The endothelium plays a critical role in inflammation by directing circulating leukocytes into extravascular tissues by expressing adhesive molecules for leukocytes [e.g., endothelial-leukocyte adhesion molecule 1 (ELAM-1) and intercellular adhesion molecule 1 (ICAM-1)]. We therefore determined whether corticosteroids suppress inflammation by inhibiting endothelial expression of adhesion molecules for neutrophils (polymorphonuclear leukocytes). Preincubation of endothelial cells with endotoxin [lipopolysaccharide (LPS), 1 microgram/ml] led to a 4-fold increase in subsequent adherence of polymorphonuclear leukocytes (P < 0.0001, n = 10) to endothelial cells, an increase that was markedly attenuated when endothelial cells were treated with dexamethasone (IC50 < 1 nM, P < 0.0001, n = 6 or 7) during preincubation with LPS. Moreover, the steroid receptor agonist cortisol (10 microM), but not its inactive metabolite tetrahydrocortisol (10 microM), diminished LPS-induced endothelial cell adhesiveness. Further evidence that the action of dexamethasone was mediated through ligation of corticosteroid receptors [human glucocorticoid receptors (hGRs)] was provided by experiments utilizing the steroid antagonist RU-486. RU-486 (10 microM), which prevents translocation of ligated hGR to the nucleus by inhibiting dissociation of hGR from heat shock protein 90, completely aborted the effect of dexamethasone on adhesiveness of endothelial cells (P < 0.0005, n = 3). Treatment of endothelial cells with LPS (1 microgram/ml) stimulated transcription of ELAM-1, as shown by Northern blot analysis, and expression of membrane-associated ELAM-1 and ICAM-1, as shown by quantitative immunofluorescence (both P < 0.001, n = 9). Dexamethasone markedly inhibited LPS-stimulated accumulation of mRNA for ELAM-1 and expression of ELAM-1 and ICAM-1 (IC50 < 10 nM, both P < 0.001, n = 4-9); inhibition of expression by dexamethasone was reversed by RU-486 (both P < 0.005, n = 4-6). As in the adhesion studies, cortisol but not tetrahydrocortisol inhibited expression of ELAM-1 and ICAM-1 (both P < 0.005, n = 3 or 4). In contrast, sodium salicylate (1 mM) inhibited neither adhesion nor expression of these adhesion molecules. These studies suggest that antagonism by dexamethasone of endotoxin-induced inflammation is a specific instance of the general biological principle that the glucocorticoid receptor is a hormone-dependent regulator of transcription
— id: 9824, year: 1992, vol: 89, page: 9991, stat: Journal Article,

Corticosteroids are transcriptional regulators of acute inflammation
Cronstein BN; Kimmel SC; Levin RI; Martiniuk F; Weissmann G
1992 ;105:25-35, Transactions of the Association of American Physicians
— id: 9830, year: 1992, vol: 105, page: 25, stat: Journal Article,

CORTICOSTEROIDS (CS) ARE TRANSCRIPTIONAL REGULATORS OF ACUTE-INFLAMMATION
CRONSTEIN, BN; KIMMEL, SC; MARTINIUK, F; LEVIN, RI; WEISSMANN, G
1992 APR ;40(2):A193-A193, Clinical research
— id: 51976, year: 1992, vol: 40, page: A193, stat: Journal Article,

Recombinant human acid alpha-glucosidase generated in bacteria: antigenic, but enzymatically inactive
Martiniuk F; Tzall S; Chen A
1992 Nov;11(9):701-706, DNA & cell biology
Genetic deficiency of acid alpha-glucosidase (GAA) results in glycogen storage disease type II. To investigate whether we could generate a functional recombinant human GAA protein for future enzyme replacement therapy, we subcloned the GAA cDNA into the bacterial expression plasmid pMaI and analyzed the recombinant protein produced. This nonglycosylated recombinant human GAA was found to be antigenic by reacting with polyclonal rabbit antibody to human placental GAA using ELISA and Western techniques. However, the protein was not enzymatically active, suggesting that glycosylation may play a role in enzymatic function
— id: 13379, year: 1992, vol: 11, page: 701, stat: Journal Article,

DETECTION OF ALZHEIMERS-DISEASE BY ASSAY OF SERUM GLUCOSIDASE ACTIVITY
MARTINIUK, F; MARCUS, DL; FREEDMAN, ML
1992 APR ;40(2):A434-A434, Clinical research
— id: 52010, year: 1992, vol: 40, page: A434, stat: Journal Article,

Isolation and partial characterization of the structural gene for human acid alpha glucosidase
Martiniuk F; Bodkin M; Tzall S; Hirschhorn R
1991 May;10(4):283-292, DNA & cell biology
Genetic deficiency of acid alpha glucosidase (GAA) results in glycogen storage disease type II. To study the disease at the molecular level, we have previously isolated and sequenced the cDNA (3.6 kb) for human GAA. We have now isolated the structural gene, mapped and determined the position and size of the exons containing the entire cDNA, and determined the sequence of the intron-exon junctions. The structural gene is approximately 28 kb and contains 20 exons. The first exon has only 5' untranslated sequence and is separated by an approximately 2.7-kb intron from the second exon that contains the initiation ATG. The second as well as the last exon are quite large (578 and 607 bp) with the remainder of the exons ranging from 85-187 bp. Additionally, two new restriction fragment length (RFLPs) for Xba I and Stu I are described at the GAA locus, one of which is most 5' of the eight RFLPs we have previously described
— id: 14062, year: 1991, vol: 10, page: 283, stat: Journal Article,

Linkage of acid alpha-glucosidase (Gaa) and thymidine kinase (Tk-1) to esterase-3 (Es-3) on mouse chromosome 11
Martiniuk F; Hirschhorn R; D'Eustachio P
1991 ;1(4):267-269, Mammalian genome
Inheritance in recombinant inbred (RI) strains of restriction fragment length variants (RFLVs) detected by probes specific for Gaa and Tk-1 showed tight linkage of both to Es-3 on mouse Chromosome (Chr) 11. This result extends the region of homology between mouse Chr 11 and human chr 17q
— id: 14214, year: 1991, vol: 1, page: 267, stat: Journal Article,

Identification of a missense mutation in an adult-onset patient with glycogenosis type II expressing only one allele
Martiniuk F; Mehler M; Bodkin M; Tzall S; Hirschhorn K; Zhong N; Hirschhorn R
1991 Nov;10(9):681-687, DNA & cell biology
The lysosomal enzyme acid alpha glucosidase (GAA) or acid maltase is deficient in glycogen storage disease type II. We sought to determine the molecular basis for the disease in an adult-onset patient, unusual for very low enzyme activity similar to that seen with the infantile-onset form and with a previously reported defect in phosphorylation. We constructed cDNA and genomic DNA libraries from the patient's cell line (GM 1935) and determined the nucleotide sequence of the coding region. There were three base-pair substitutions in one allele (C1935 to A; G2446 to A and C2780 to T), all predicting amino acid changes (Asp-645 to Glu; Val-816 to Ile and Thr-927 to Ile). To determine which of the three base-pair substitutions resulted in loss of enzyme activity, we next utilized primer-directed mutagenesis and transient gene expression in an SV40-immortalized GAA-deficient fibroblast cell line. Only the construct containing the G2446 to A mutation (Val-816 to Ile) lost GAA enzyme activity, while the other two substitutions (including the Thr-927 to Ile change that predicts a loss of a potential site for N-linked glycosylation and mannose phosphorylation) each resulted in enzyme activity equal to the control. Analysis of RFLPs in genomic DNA, as well as sequence analysis for the three base-pair alterations, indicated that the patient was a genetic compound. We next digested PCR-amplified cDNA (reverse-transcribed from RNA) with Aat II to detect the base-pair 1935 substitution and found that virtually all of the mRNA was derived from the allele with the three base-pair substitutions.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 13861, year: 1991, vol: 10, page: 681, stat: Journal Article,

Developmental expression of glycogenolytic enzymes in rabbit tissues: possible relationship to fetal lung maturation
Newgard CB; Norkiewicz B; Hughes SD; Frenkel RA; Coats WS; Martiniuk F; Johnston JM
1991 Nov 11;1090(3):333-342, Biochimica & biophysica acta
Glycogen can be degraded in mammalian tissues by one of three isozymes of glycogen phosphorylase, termed muscle (M), liver (L) and brain (B) after the tissues in which they are preferentially expressed in adult animals, or by members of the family of alpha-glucosidases. In the current study, we have examined the developmental expression of these enzymes and their respective mRNAs in rabbit tissues, with particular emphasis on the developing lung, a tissue in which glycogen serves as an important source of carbon for surfactant phospholipid biosynthesis. Native gel activity assays and RNA blot hybridization analysis revealed that the B isoform of glycogen phosphorylase predominates in fetal and adult lung tissues, accompanied by a low level of expression of the M isoform. Total B and M phosphorylase activities increased during fetal lung development, with a peak at day 28 of gestation, then decreased to the adult level at term. This peak in activity coincided with the peak period of glycogen degradation in developing lung. While the increase in M isozyme activity was correlated with an increase in the level of its mRNA, B isoform mRNA showed no significant alteration during development, suggesting that the increase in B isoform activity is determined by a posttranscriptional mechanism. Analysis of phosphorylase mRNA levels in developing liver, skeletal muscle, brain and heart revealed a diverse expression pattern. The L isozyme mRNA was predominant at all time points in liver, the M isozyme was predominant at all time points in muscle, the B isozyme was predominant at all time points in brain, and heart contained a mixture of B and M mRNA in roughly equal ratios at all time points. Thus, our studies of phosphorylase mRNA in the rabbit provide no evidence for general predominance of the B isozyme in fetal tissues, or for isozyme 'switching' from the B to the L or M forms during development, as has been suggested by others. In addition to the increase in phosphorylase activity, acid, but not neutral alpha-glucosidase activity was found to increase significantly during fetal lung development, again with a peak at day 28 of gestation. Interestingly, RNA blot hybridization analysis with a probe for lysosomal alpha-glucosidase revealed no change in the level of expression of its 4 kb transcript in developing lung. Instead, we observed induction of a structurally related mRNA of 7.4 kb that peaked at day 28 of gestation. Hybridization with a sucrase/isomaltase-specific oligonucleotide excluded the possibility that the 7.4 kb transcript encodes this protein.(ABSTRACT TRUNCATED AT 400 WORDS)
— id: 15200, year: 1991, vol: 1090, page: 333, stat: Journal Article,

Identification of the promoter region and gene expression for human acid alpha glucosidase
Tzall S; Martiniuk F
1991 May 15;176(3):1509-1515, Biochemical & biophysical research communications
Genetic deficiency of acid alpha glucosidase (GAA) results in glycogen storage disease type II. A cDNA containing the complete coding region was constructed and cloned into the expression vector pSV2 and was transiently transfected into an SV40 immortalized GAA deficient human fibroblast cell line which has undetectable levels of GAA enzyme activity and does not express GAA mRNA. Transfected cells had 4.9% of normal human fibroblast enzyme activity. Additionally a 5' 1.8 kb genomic fragment was ligated to the 5' end of the GAA cDNA construct and cloned into pUC19. Transient and stable transfection also resulted in expressed GAA enzyme activity in deficient fibroblast cells, indicating that the genomic fragment has GAA promoter function
— id: 14024, year: 1991, vol: 176, page: 1509, stat: Journal Article,

Identification of a HindIII and a TaqI RFLP at the acid alpha glucosidase (GAA) locus
Tzall S; Martiniuk F; Hirschhorn R
1991 Apr 11;19(7):1727-1727, Nucleic acids research
— id: 14067, year: 1991, vol: 19, page: 1727, stat: Journal Article,

Further characterization of PstI RFLPs at the acid alpha glucosidase (GAA) locus
Tzall S; Martiniuk F; Ozelius L; Gusella J; Hirschhorn R
1991 Apr 11;19(7):1727-1727, Nucleic acids research
— id: 14068, year: 1991, vol: 19, page: 1727, stat: Journal Article,

Identification of a missense mutation in one allele of a patient with Pompe disease, and use of endonuclease digestion of PCR-amplified RNA to demonstrate lack of mRNA expression from the second allele
Zhong N; Martiniuk F; Tzall S; Hirschhorn R
1991 Sep;49(3):635-645, American journal of human genetics
Infantile-onset glycogen storage disease type II, or Pompe disease, results from a genetic deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Sequencing of the cDNA from a cell line (GM 244) derived from a patient with Pompe disease demonstrated a T953-to-C transition that predicted a methionine-to-threonine substitution at codon 318. The basepair substitution resulted in loss of restriction-endonuclease sites for NcoI and StyI. Analysis of genomic DNA revealed both a normal and an abnormal NcoI fragment, indicating that the patient was a genetic compound. NcoI and StyI digestion of cDNA, amplified by PCR from reverse-transcribed RNA, demonstrated that greater than 95% of the GAA mRNA in GM 244 was derived from the allele carrying the missense mutation. The missense mutation was uncommon, since it was not detected in 37 additional GAA-deficient chromosomes, as determined by digestion of genomic DNA with NcoI and hybridization. The amino acid substitution predicts a new potential site for N-linked glycosylation, as well as major changes in secondary structure of the protein. We could confirm that the mutation was responsible for the enzyme deficiency by demonstrating that a hybrid minigene containing the mutation did not express GAA enzyme activity after transient gene expression. We have therefore now provided the first identification of a single-basepair missense mutation in a patient with Pompe disease and furthermore have demonstrated that the patient is a genetic compound with the second allele barely expressing mRNA
— id: 13935, year: 1991, vol: 49, page: 635, stat: Journal Article,

A genetic linkage map of chromosome 17
Haines JL; Ozelius LJ; McFarlane H; Menon A; Tzall S; Martiniuk F; Hirschhorn R; Gusella JF
1990 Sep;8(1):1-6, Genomics
We have developed a genetic linkage map of 19 markers (including nine genes) on human chromosome 17, providing 13 reference points along virtually the entire length of this chromosome. The map covers an estimated 149 cM in length (sex-averaged), with a total length of 214 cM in females and 95 cM in males. This sex difference appears to be significant along virtually the entire length of the map. This map will be useful both for providing reference points for fine structure genetic and physical mapping and for genetic linkage studies of diseases, including von Recklinghausen neurofibromatosis and Charcot-Marie-Tooth disease
— id: 15202, year: 1990, vol: 8, page: 1, stat: Journal Article,

Identification of the base-pair substitution responsible for a human acid alpha glucosidase allele with lower "affinity" for glycogen (GAA 2) and transient gene expression in deficient cells
Martiniuk F; Bodkin M; Tzall S; Hirschhorn R
1990 Sep;47(3):440-445, American journal of human genetics
The lysosomal enzyme termed acid alpha glucosidase (GAA), or acid maltase, is genetically polymorphic, with three alleles segregating in the normal population. The rarer GAA 2 allozyme has a lower affinity for glycogen and starch but not for lower-molecular-weight substrates. The GAA 2 allozyme can be detected by 'affinity' electrophoresis in starch gel, since the lower affinity for the starch matrix results in a more rapid migration to the anode. Previously, we have isolated and sequenced the cDNA for GAA and transiently expressed the cDNA in deficient fibroblasts. In order to determine the molecular basis for the GAA 2 allozyme, we constructed a cDNA and a genomic DNA library from a GAA 2 cell line and determined the nucleotide sequence of the coding region. Only a single base-pair substitution of an A for a G at base-pair 271 was found, resulting in substitution of asparagine for aspartic acid at codon 91. This amino acid substitution is consistent with the more basic pI of the GAA 2 enzyme. The base-pair substitution also abolishes a Taq-I site, predicting the generation of a larger DNA fragment. This larger Taq-I fragment was also seen in two other individuals expressing the GAA 2 allozyme. A 5' fragment containing the base-pair substitution was ligated to the remaining 3' cDNA from a GAA 1 allele and cloned into an expression vector, and the hybrid cDNA was transiently expressed in SV40-transformed GAA-deficient fibroblasts. The enzyme activity exhibited the altered mobility of the GAA 2 allozyme, as demonstrated by electrophoresis in starch gel.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 15201, year: 1990, vol: 47, page: 440, stat: Journal Article,

Extensive genetic heterogeneity in patients with acid alpha glucosidase deficiency as detected by abnormalities of DNA and mRNA
Martiniuk F; Mehler M; Tzall S; Meredith G; Hirschhorn R
1990 Jul;47(1):73-78, American journal of human genetics
Acid maltase, or acid alpha glucosidase (GAA), is a lysosomal enzyme that hydrolyzes glycogen to glucose and is deficient in glycogen storage disease type II. We have previously isolated a partial cDNA (1.9 kb) for human GAA and detected abnormalities of mRNA in two infantile-onset and one adult-onset patient. We have now extended this study and examined mRNA and DNA from cell lines of eight additional infantile and three adult-onset patients. While five of the 10 infantile-onset patients expressed normal amounts and sizes of mRNA, the remaining five did not express detectable GAA mRNA. Two adult-onset patients had normal amounts and sizes of mRNA, while two adult-onset patients had mRNA of smaller size. Thus, half of the larger series of GAA-deficient patients also exhibited quantitative and/or qualitative abnormalities of mRNA. Of the five infantile-onset patients with normal mRNA, two exhibited an abnormal SacI fragment not found in DNA from 60 normals. To further characterize these patients, we determined GAA activity in several of the cell lines by using either the artificial substrate, 4-methylumbelliferyl-alpha-D-glucoside, or the natural substrate glycogen. Two adult-onset patients who both had normal size mRNA differed as to enzyme activity, with one patient exhibiting enzyme activity similar to that in infantile-onset patients. By combining these data with those for previously reported presence or absence of GAA-mutant protein cross-reacting to antibody, we provide evidence for a minimum of six different mutations in these 14 GAA-deficient cell lines
— id: 15203, year: 1990, vol: 47, page: 73, stat: Journal Article,

Sequence of the cDNA and 5'-flanking region for human acid alpha-glucosidase, detection of an intron in the 5' untranslated leader sequence, definition of 18-bp polymorphisms, and differences with previous cDNA and amino acid sequences
Martiniuk F; Mehler M; Tzall S; Meredith G; Hirschhorn R
1990 Mar;9(2):85-94, DNA & cell biology
Acid maltase or acid alpha-glucosidase (GAA) is a lysosomal enzyme that hydrolyzes glycogen to glucose and is deficient in glycogen storage disease type II. Previously, we isolated a partial cDNA (1.9 kb) for human GAA; we have now used this cDNA to isolate and determine sequence in longer cDNAs from four additional independent cDNA libraries. Primer extension studies indicated that the mRNA extended approximately 200 bp 5' of the cDNA sequence obtained. Therefore, we isolated a genomic fragment containing 5' cDNA sequences that overlapped the previous cDNA sequence and extended an additional 24 bp to an initiation codon within a Kozak consensus sequence. The sequence of the genomic clone revealed an intron-exon junction 32 bp 5' to the ATG, indicating that the 5' leader sequence was interrupted by an intron. The remaining 186 bp of 5' untranslated sequence was identified approximately 3 kb upstream. The promoter region upstream from the start site of transcription was GC rich and contained areas of homology to Sp1 binding sites but no identifiable CAAT or TATA box. The combined data gave a nucleotide sequence of 2,856 bp for the coding region from the ATG to a stop codon, predicting a protein of 952 amino acids. The 3' untranslated region contained 555 bp with a polyadenylation signal at 3,385 bp followed by 16 bp prior to a poly(A) tail. This sequence of the GAA coding region differs from that reported by Hoefsloot et al. (1988) in three areas that change a total of 42 amino acids. Direct determination of the amino acid sequence in one of these areas confirmed the nucleotide sequence reported here but also disagreed with the directly determined amino acid sequence reported by Hoefsloot et al. (1988). At two other areas, changes in base pairs predicted new restriction sites that were identified in cDNAs from several independent libraries. The amino acid changes in all three ares increased the homology to rabbit-human isomaltase. Therefore, we believe that our nucleotide sequence for GAA is more precise. We have also identified single base-pair polymorphisms at 18 sites for human GAA, some of which are not silent
— id: 15206, year: 1990, vol: 9, page: 85, stat: Journal Article,

Identification of an RsaI RFLP at the acid alpha glucosidase (GAA) locus
Tzall S; Martiniuk F; Adler A; Hirschhorn R
1990 Mar 25;18(6):1661-1661, Nucleic acids research
— id: 15205, year: 1990, vol: 18, page: 1661, stat: Journal Article,

Further characterization of SacI RFLPs at the acid alpha glucosidase (GAA) locus
Tzall S; Martiniuk F; Hirschhorn R
1990 Apr 11;18(7):1930-1930, Nucleic acids research
— id: 15204, year: 1990, vol: 18, page: 1930, stat: Journal Article,

DIFFERENTIAL EXPRESSION OF ADENOSINE-DEAMINASE ISOZYMES IN ACUTE-LEUKEMIA
Ratech, H; Martiniuk, F; Borer, WZ; Rappaport, H
1989 ;60(Suppl 1):A76-A76, Laboratory investigation
— id: 31753, year: 1989, vol: 60, page: A76, stat: Journal Article,

MUTATIONS AT MULTIPLE DIFFERENT MSP I AND TAQ I SITES ACCOUNT FOR MOST PARTIAL ADENOSINE-DEAMINASE MUTATIONS
Hirschhorn, R; Tzall, S; Martiniuk, F; Ellenbogen, A
1988 Apr;36(3):A618-A618, Clinical research
— id: 31516, year: 1988, vol: 36, page: A618, stat: Journal Article,

Differential expression of adenosine deaminase isozymes in acute leukemia
Ratech H; Martiniuk F; Borer WZ; Rappaport H
1988 Nov;72(5):1627-1632, Blood
Total adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) activities were measured in cell samples from 13 cases of de novo acute leukemia and from three cases of chronic myeloid leukemia in blast crisis (CMLBC). These cases could be separated into lymphoid and nonlymphoid types on the basis of enzyme activity, with two misclassifications. However, PNP activity added little or no discriminatory information. Analysis for expression of the various molecular weight (mol wt) ADA isozymes, ADA1 (40 Kd) and ADA2 (110 Kd), revealed that ADA2 was expressed exclusively in nonlymphoid cells whereas ADA1 was found in both lymphoid and nonlymphoid cell types. Identification of ADA2 divided these leukemia cases into lymphoid and nonlymphoid types with no misclassifications (P = .0002; Fisher's exact test). Acute nonlymphoblastic leukemia (ANLL) with a monocytic component tended to have a greater percentage of ADA2 than ANLL without a monocytic component. These studies suggest that ADA2 may be a novel biochemical marker for an immature nonlymphoid cell
— id: 15207, year: 1988, vol: 72, page: 1627, stat: Journal Article,

MOLECULAR AND GENETIC-HETEROGENEITY IN ACID ALPHA GLUCOSIDASE DEFICIENCY
Martiniuk, F; Meredith, G; Mehler, M; Pellicer, A; Hirschhorn, R
1987 Apr;35(3):A650-A650, Clinical research
— id: 31204, year: 1987, vol: 35, page: A650, stat: Journal Article,

Isolation of a cDNA for human acid alpha-glucosidase and detection of genetic heterogeneity for mRNA in three alpha-glucosidase-deficient patients
Martiniuk F; Mehler M; Pellicer A; Tzall S; La Badie G; Hobart C; Ellenbogen A; Hirschhorn R
1986 Dec;83(24):9641-9644, Proceedings of the National Academy of Sciences of the United States of America
Lysosomal acid alpha-glucosidase (EC 3.2.1.3) hydrolyzes 1,4-linked alpha-D-glucose polymers present in glycogen. Genetic deficiency of acid alpha-glucosidase results in glycogen-storage disease type II, encompassing a spectrum of disorders of varying severity. To study the molecular basis for this heterogeneity, we sought to clone the coding sequence for human acid alpha-glucosidase. We screened 10(6) recombinant phage from a human liver cDNA expression library with an affinity-purified polyclonal antibody to human acid alpha-glucosidase. When we retested positive phage for reactivity to monoclonal antibodies, we identified a single phage, containing a 2-kilobase (kb) cDNA insert, that reacted with both polyclonal and monoclonal antibodies. The 2-kb cDNA hybridized to a 20-kb EcoRI fragment of human genomic DNA. This 20-kb EcoRI fragment was present only in DNA from somatic cell hybrids that retained the human chromosome 17 segment q21-q23, which contains the gene for human acid alpha-glucosidase. The cDNA also hybridized to a 3.4-kb mRNA, consistent with the size (approximately 105 kDa) of the acid alpha-glucosidase protein. Finally, in one of two infantile-onset acid alpha-glucosidase-deficient cell lines tested, the 3.4-kb mRNA was not detectable, whereas in an adult-onset cell line, an mRNA of reduced size and amount was found. Examination of DNA digested with restriction enzymes did not reveal any major deletions in the genomic DNA of these patients
— id: 15208, year: 1986, vol: 83, page: 9641, stat: Journal Article,

Detection, frequency, and stability of cotransformants expressing nonselectable human enzymes
Martiniuk F; Pellicer A; Mehler M; Hirschhorn R
1986 Jan;12(1):1-12, Somatic cell & molecular genetics
We cotransformed mouse 3T3 cells with total genomic human DNA and the dominant selectable bacterial gene Neo and analyzed 121 NeoR clones for expression of 15 human 'housekeeping' enzymes which can be distinguished from their murine homologs. The estimated frequency of expression of unlinked human genes was 1 in 360 NeoR clones and at least three different human enzymes (peptidase D, phosphoglucomutase 1, and acid alpha glucosidase) were detected. We further examined the frequency and stability of cotransformation for one of these enzymes, acid alpha glucosidase (GAA). We tested approximately 4000 NeoR clones and found 25 clones expressing human GAA, as determined by rocket immunoelectrophoresis (RIE) specific for human GAA. Transformants progressively became negative on continued growth and retesting by RIE, with only two clones still expressing GAA at the eighth testing. This apparent loss of expression was not due to nonclonality of the original isolates. In one subclone examined, loss of expression was accompanied by loss of both Neo-derived pBR322 and human Alu repetitive sequence DNA. Thus, under the conditions utilized, cotransformants expressing homomeric housekeeping enzymes were found at relatively high frequency but were progressively lost even under conditions selective for expression of the dominant vector
— id: 15209, year: 1986, vol: 12, page: 1, stat: Journal Article,

ISOLATION OF A CDNA FOR HUMAN ACID ALPHA-GLUCOSIDASE AND DETECTION OF GENETIC-HETEROGENEITY FOR MESSENGER-RNA IN 2 PATIENTS DEFICIENT FOR ALPHA-GLUCOSIDASE
MARTINIUK, F; MEHLER, M; PELLICER, A; TZALL, S; LABADIE, G; HIRSCHHORN, R
1986 DEC ;25(4):710-711, American journal of medical genetics
— id: 41328, year: 1986, vol: 25, page: 710, stat: Journal Article,

An approach to a selection system for adenosine-deaminase-positive (ADA+) cells and detection of rat ADA+ "revertants"
Hirschhorn R; Ellenbogen A; Martiniuk F
1985 May;123(2):277-282, Journal of cellular physiology
We have substituted deoxyadenosine or adenosine for hypoxanthine in the standard HAT selection system in an attempt to select for ADA-normal (ADA+) cells. ADA- human lymphoid line cells could not utilize deoxyadenosine as an alternative to hypoxanthine as a purine source (DAT) and failed to grow but were only somewhat inhibited in growth when adenosine was substituted for hypoxanthine (AAT). In contrast, ADA+ cells utilized adenosine or deoxyadenosine as efficiently as hypoxanthine as a purine source. Growth in DAT, but not in HAT, of an artificial mixture of one ADA+ human lymphoid cells in 1,000 ADA- cells resulted in enrichment of ADA+ cells to 25-86% of total cells. When we grew a rat ADA- cell line in two variations of the DAT system, we detected at least three electrophoretically different ADA+ patterns, one of which corresponded to normal rat ADA. These could represent 'revertants.'
— id: 15211, year: 1985, vol: 123, page: 277, stat: Journal Article,

Further regional localization of the genes for human acid alpha glucosidase (GAA), peptidase D (PEPD), and alpha mannosidase B (MANB) by somatic cell hybridization
Martiniuk F; Ellenbogen A; Hirschhorn K; Hirschhorn R
1985 ;69(2):109-111, Human genetics
We have further regionally localized the gene for human acid alpha glucosidase (GAA) to 17q21----q23 by examination of hybrid clones derived from a fusion between human fibroblasts carrying a 17/19 balanced translocation (17pter----17q23::19p13.3----19pter; 19qter----p13.3::17q23----17qter) and a mouse line deficient in thymidine kinase. These hybrids were constantly maintained in HAT selective media in order to select for the presence of the human thymidine kinase gene on the intact chromosome 17 (17q21-q22) or the 17/19 (17pter----17q23::19p13.3----19pter) translocation chromosome. We detected human GAA by rocket immunoelectrophoresis, using a human specific heterologous antibody raised against human acid alpha glucosidase (GAA) (Honig et al. 1984). Three secondary clones, which contained the 17/19 translocation and no intact chromosome 17 or 19, were still positive for GAA. Two of these secondary clones contained the distal portion of the 17/19 translocation chromosome, with a break in the band 17q21 (probably at 17q21.2), attached to a mouse chromosome. Combined with earlier results (Weil et al. 1979; Nickel et al. 1982; Honig et al. 1984), the gene for GAA can be assigned to 17q21.2----17q23. Additionally, these clones were negative for human peptidase D (PEPD), alpha mannosidase B (MANB), and phosphohexose isomerase (PHI). Combined with previous results (Ingram et al. 1977; Bruns et al. 1979), these results exclude the genes for PEPD and MANB from 19pter----19p13.3 and confirm the exclusion of the gene for PHI from this segment of chromosome 19 (Wilson et al. 1984; Ingram et al. 1977)
— id: 15213, year: 1985, vol: 69, page: 109, stat: Journal Article,

Identity of neutral alpha-glucosidase AB and the glycoprotein processing enzyme glucosidase II. Biochemical and genetic studies
Martiniuk F; Ellenbogen A; Hirschhorn R
1985 Jan 25;260(2):1238-1242, Journal of biological chemistry
We have previously partially purified, characterized, and chromosomally mapped a human isozyme of alpha-glucosidase which is active at neutral pH. This isozyme appears as a doublet of enzyme activity on native gel electrophoresis and was termed neutral alpha-glucosidase AB. We now report genetic and biochemical evidence that neutral alpha-glucosidase AB is synonymous with the glycoprotein processing enzyme glucosidase II. We have found that a mutant mouse lymphoma line which is deficient in glucosidase II is also deficient in neutral alpha-glucosidase AB, as defined electrophoretically and quantitatively (less than 0.5% of parental). In contrast, both mutant and parental cell lines exhibited several lysosomal hydrolases which are processed by glucosidase II. We have also further purified the human neutral alpha-glucosidase A component of neutral alpha-glucosidase AB 740-fold from placenta in order to compare its biochemical properties with those described for rat liver and pig kidney glucosidase II. Both glucosidase II and neutral alpha-glucosidase AB are high-molecular mass (greater than 200,000 dalton) anionic glycoproteins which bind to concanavalin A, have a broad pH optima (5.5-8.5), and have a similar Km for maltose (4.8 versus 2.1 mM) and the artificial substrate 4-methylumbelliferyl-alpha-D-glucopyranoside (35 versus 19 microM). Similar to human neutral alpha-glucosidase AB, purified rat glucosidase II migrates as a doublet of enzyme activity on native gel electrophoresis. Although rat glucosidase II has been reported to have a subunit size of 67 kDa, pig glucosidase II has been found to have a subunit size of 100 kDa, like the 98-kDa major protein in purified human neutral alpha-glucosidase A. Although we have not demonstrated that neutral alpha-glucosidase AB is microsomal nor that it hydrolyzes the natural substrate of glucosidase II, we believe that the genetic evidence is compelling for and the biochemical data consistent with the hypothesis that neutral alpha-glucosidase AB and glucosidase II are synonymous. These and previous results would localize glucosidase II to the long arm of human chromosome II
— id: 15212, year: 1985, vol: 260, page: 1238, stat: Journal Article,

Transient expression of human neutral alpha-glucosidase AB (glucosidase II) in enzyme-deficient mouse lymphoma cells
Martiniuk F; Pellicer A; Hirschhorn R
1985 Nov 15;260(26):14351-14354, Journal of biological chemistry
To define new methods for gene isolation exploiting mutant mammalian cells we transformed a mutant mouse cell line deficient in glucosidase II with total human genomic DNA and detected transient expression of the human glucosidase II gene. Maximum gene expression was detected 48 h after addition of DNA as a 2.5-fold increase in neutral alpha-glucosidase activity (2.47 +/- 0.15, n = 4). When mutant mouse DNA was used for transformation, no increase in enzyme activity was seen. The increased enzyme activity was due to expression of the human gene product. Thus, by rocket immunoelectrophoresis, cells transformed with human DNA yielded a 'rocket' which reacted with antibody to human but not to mouse glucosidase II and which hydrolyzed substrate in situ. Specific DNA sequences were required for expression of the enzyme activity, since digestion of DNA with EcoRI and SstI rendered the DNA ineffective for eliciting expression of the enzyme, while digestion of DNA with BamHI and XhoI did not affect the increase. Transfection with intact phage from a human genomic DNA library also resulted in transient expression of the human gene. These results demonstrate the feasibility of detecting, by enzymatic assay, transient expression of a human gene for an intracellular enzyme following DNA-mediated transformation both with total human DNA and with intact phage from a human recombinant library. This system could be used as an assay for isolation of a gene from a genomic library by sibling selection
— id: 15210, year: 1985, vol: 260, page: 14351, stat: Journal Article,

SUCCESSFUL TRANSIENT EXPRESSION OF ENZYME-ACTIVITY BY CELLS TRANSFECTED WITH TOTAL GENOMIC AND RECOMBINANT PHAGE DNA
Martiniuk, F; Pellicer, A; Hirschhorn, R
1985 ;33(2):A604-A604, Clinical research
— id: 30934, year: 1985, vol: 33, page: A604, stat: Journal Article,

Confirmation of the regional localization of the genes for human acid alpha-glucosidase (GAA) and adenosine deaminase (ADA) by somatic cell hybridization
Honig J; Martiniuk F; D'Eustachio P; Zamfirescu C; Desnick R; Hirschhorn K; Hirschhorn LR; Hirschhorn R
1984 Jan;48(Pt 1):49-56, Annals of human genetics
We have confirmed the localization of human acid alpha-glucosidase (GAA) to 17q21----q25 and of adenosine deaminase (ADA) to 20q13----20qter by examination of hybrid clones derived from a fusion between a human cell line carrying a 17/20 balanced translocation (17pter----17q25::20q13----20qter;20pter-- --20q13::17q25----17qter) and a mouse line deficient in thymidine kinase. These hybrids were constantly maintained in HAT selective media in order to select for the presence of the human thymidine kinase gene on the intact chromosome 17 (17q21----22) or the 17/20 (17pter----17q25::20q13----20qter) translocation chromosome. We detected human GAA by rocket immunoelectrophoresis, using a heterologous antibody raised against human acid alpha-glucosidase. A clone which contained the 17/20 translocation and no intact chromosome 17 was still positive for GAA. This finding confirms the exclusion of GAA from 17q25----17qter reported by Nickel et al. (1982). Combined with earlier results (Weil et al. 1979), GAA can be assigned to 17q21----17q25. A clone which contained only the 17/20 translocation chromosome and no intact chromosome 20 contained ADA. This confirms the previous localization of ADA to 20q13.2----qter by gene dosage studies (Philip et al. 1980)
— id: 15215, year: 1984, vol: 48, page: 49, stat: Journal Article,

Further studies of the structure of human placental acid alpha-glucosidase
Martiniuk F; Honig J; Hirschhorn R
1984 Jun;231(2):454-460, Archives of biochemistry & biophysics. ABB
Acid alpha-glucosidase has been purified from human placenta to a specific activity of approximately 6800, (4-methylumbelliferyl-alpha-D-glucoside as a substrate) or 55,400 mumol g-1 min-1 (glycogen or maltose as substrate). The purified enzyme gives rise to multiple protein bands on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), i.e., a major doublet of 82K and 69K , a minor doublet of 25K and 21K , and a faint band of 100K. All of the molecular weight species stained as glycoproteins with an intensity apparently proportional to their protein content, and were present in enzyme from individuals homozygous for the allozyme alpha-Glu 1. Isoelectric focusing revealed only enzymatically active proteins which, when analysed by SDS-PAGE, gave rise to multiple molecular weight species. Chromatography of I125-labeled, purified enzyme on Bio-Gel P-100 revealed only a radiolabeled, high-molecular-weight species which corresponded with enzyme activity. These findings suggest that, in the native state, the mature enzyme exists as a high-molecular-weight species, which is dissociable in SDS to several low-molecular-weight species. These results are consistent with reports that a 100K primary product of translation is post-translationally modified to yield polypeptides of lower molecular weights, and that all of the molecular species are absent in cells genetically deficient for acid alpha-glucosidase. The possibility that the low-molecular-weight (20- 25K ) protein bands in SDS-gels corresponded to a previously reported low-molecular-weight species generated by treatment with guanidine-HCl was investigated. The I125-labeled, purified acid maltase was dissociated by guanidine into two equal peaks of approximately 64K and 28K molecular weight. Surprisingly, both peaks, when analyzed on SDS-gels, yielded identical and equally intensely staining bands of 64K molecular weight. These results suggest that the mature acid alpha-glucosidase is made up of polypeptides which are bonded in the native state by at least two different types of interaction, one type which is dissociable in SDS and one type which is dissociable in guanidine but not in SDS. The nature and possible function of the 25K polypeptide generated only by guanidine-HCl remains to be determined
— id: 15214, year: 1984, vol: 231, page: 454, stat: Journal Article,

DETECTION AND FREQUENCY OF DNA MEDIATED TRANSFORMANTS EXPRESSING NON-SELECTABLE HUMAN INTRACELLULAR ENZYMES
MARTINIUK, F; PELLICER, A; HIRSCHHORN, R
1984 ;32(2):A549-A549, Clinical research
— id: 40983, year: 1984, vol: 32, page: A549, stat: Journal Article,

Genetic heterogeneity in partial adenosine deaminase deficiency
Hirschhorn R; Martiniuk F; Roegner-Maniscalco V; Ellenbogen A; Perignon JL; Jenkins T
1983 Jun;71(6):1887-1892, Journal of clinical investigation
Inherited deficiency of the enzyme adenosine deaminase (ADA) results in a syndrome of severe combined immunodeficiency (SCID). Children with ADA- -SCID lack ADA in all cells and tissues. In contrast, a 'partial' deficiency of ADA has been described in six immunologically normal children from four different 'families.' These children lack ADA in their erythrocytes but retain variable amounts of activity in their lymphoid cells. We have examined ADA activity in lymphoid line cells from four of these children, who are unrelated, for evidence of genetic heterogeneity. One child, who is Caucasian, has an enzyme with increased electrophoretic mobility, a diminished isoelectric point (pI 4.8 vs. Nl = 4.9) and very low activity (2.3 vs. Nl = 82.9 +/- 12.9 nmol/mg protein per min); as a second child has an enzyme with normal electrophoretic mobility but increased isoelectric point (pI = 5.0), markedly diminished heat stability at 56 degrees C (t1/2 = 4.2' vs. Nl = 40') and low activity (12.1); a third has an enzyme with only diminished heat stability (t1/2 = 6.5'), no detectable abnormality in charge and almost normal activity (41.9); while the fourth exhibits only diminished ADA activity (25.0) with no striking qualitative abnormalities. Thus, we have found evidence for three different mutations at the structural locus for ADA in three of these individuals, (a) an acidic, low activity heat stable mutation (b) a basic, somewhat higher activity, heat labile mutation, and (c) a relatively normal activity heat labile mutation. In the fourth, there is as yet no compelling evidence for a mutation at the structural locus for ADA and a mutation at a regulatory locus cannot be excluded
— id: 15216, year: 1983, vol: 71, page: 1887, stat: Journal Article,

Assignment of the gene for neutral alpha-glucosidase AB to chromosome 11
Martiniuk F; Smith M; Ellenbogen A; Desnick RJ; Astrin K; Mitra J; Hirschhorn R
1983 ;35(2):110-116, Cytogenetics & cell genetics
— id: 15217, year: 1983, vol: 35, page: 110, stat: Journal Article,

GENETIC-HETEROGENEITY IN PARTIAL ADENOSINE-DEAMINASE DEFICIENCY
Hirschhorn, R; Martiniuk, F; Roegnermaniscalco, V; Ellenbogen, A; Perignon, JL; Jenkins, T
1982 ;34(6):A55-A55, American journal of human genetics
— id: 30510, year: 1982, vol: 34, page: A55, stat: Journal Article,

ASSIGNMENT OF THE GENE FOR NEUTRAL ALPHA-GLUCOSIDASE-AB TO CHROMOSOME-11
Martiniuk, F; Smith, M; Desnick, R; Astrin, K; Mitra, J; Hirschhorn, R
1982 ;34(6):A173-A173, American journal of human genetics
— id: 30511, year: 1982, vol: 34, page: A173, stat: Journal Article,

Characterization of neutral isozymes of human alpha-glucosidase: differences in substrate specificity, molecular weight and electrophoretic mobility
Martiniuk F; Hirschhorn R
1981 Apr 14;658(2):248-261, Biochimica & biophysica acta
We have previously defined two isozymes of neutral alpha-glucosidase (alpha-D-glucoside glucohydrolase, EC 3.2.1.20) on the basis of differences in electrophoretic mobility and designated these neutral alpha-glucosidase AB and alpha-glucosidase C (Swallow, D.M., Corney, G., Harris, H. and Hirschhorn, R. (1975) Ann. Hum. Gen. 38, 391-406). We now describe differences between the two isozymes with respect to molecular weight, solubility in (NH4)2SO4, glycosylation, isoelectric point and substrate specificities. Neutral alpha-glucosidase C is precipitable in 40-60% (NH4)2SO4, has a molecular weight of 92 000, an isoelectric point of 5.5 and releases glucose from glycogen as well as from low molecular weight artificial and natural substrates containing alpha 1-4 glucosidic linkages. Neutral alpha-glucosidase AB precipitates at 0-40% (NH4)2SO4, binds to concanavalin A, has a molecular weight of greater than 150 000, and does not utilize alpha 1-4 linked glucose substrates larger than a disaccharide. Neutral alpha-glucosidase AB migrates more rapidly to the anode than alpha-glucosidase C when agarose, Cellogel, acrylamide or starch are used as support media. Both isozymes are equally inhibited by Zn2+
— id: 15218, year: 1981, vol: 658, page: 248, stat: Journal Article,

Inverse relationship between adenosine deaminase and purine nucleoside phosphorylase in rat lymphocyte populations
Barton R; Martiniuk F; Hirschhorn R; Goldschneider I
1980 Jan;49(1):208-214, Cellular immunology
— id: 15221, year: 1980, vol: 49, page: 208, stat: Journal Article,

Human neutral alpha-glucosidase C: genetic polymorphism including a "null" allele
Martiniuk F; Hirschhorn R
1980 Jul;32(4):497-507, American journal of human genetics
We describe a genetic polymorphism of human neutral alpha-glucosidase C, detected in lymphoid cells by a combination of starch gel electrophoresis and isoelectric focusing. The seven phenotypes observed appear to result from the expression of four different alleles. The distribution of the observed phenotypes fits the expected distribution predicted from calculated gene frequencies in Hardy-Weinberg equilibrium. Family studies are consistent with autosomal inheritance of the gene. The product of one of the alleles is unusual in that it is 'silent,' with an estimated gene frequency of .174 in an outbred white population. Approximately one-third of the population is heterozygous 'null.' Homozygosity for the allele has not been associated with any obvious disease state. This is the third example of a 'null' allele which has a substantial gene frequency in an outbred population but does not appear to result in disease in the homozygous state
— id: 15219, year: 1980, vol: 32, page: 497, stat: Journal Article,

Assignment of the gene for human neutral alpha-glucosidase C to chromosome 15
Martiniuk F; Hirschhorn R; Smith M
1980 ;27(2-3):168-175, Cytogenetics & cell genetics
Human neutral alpha-glucosidase C (GANC) can be separated from the homologous mouse isozyme by starch gel electrophoresis at pH 6.5. A total of 40 clones (13 primary and 27 secondary) were derived from eight separate hybridization experiments between the mouse HPRT deficient RAG cell line and eight different human long term lymphoid cell lines or fetal cells. The thirteen primary clones showed 100% concordance between the expression of the human enzyme and the presence or absence of human chromosome 15. Analysis of the 27 secondary clones showed only two subclones discordant for segregation of human GANC and enzyme markers for 15. The two apparently discordant clones for human GANC were both derived from the same RAG X human fetal lung primary clone, and both lacked GANC activity, while retaining a 15. Since human GANC is polymorphic with a null allele at high frequency (MARTINIUK and HIRSCHHORN, 1980), it is possible that these subclones carried one chromosome with a null allele for GANC. Alternatively there could been an undetected chromosome break between the GANC locus and the loci of the marker enzymes. Whatever the reason for the two apparently discordant subclones, combined data from all 40 clones show 95% concordant segregation for human GANC and No. 15
— id: 15220, year: 1980, vol: 27, page: 168, stat: Journal Article,

The distribution of adenosine deaminase among lymphocyte populations in the rat
Barton R; Martiniuk F; Hirschhorn R; Goldschneider I
1979 Jan;122(1):216-220, Journal of immunology
Adenosine deaminase (ADA) activity was determined in young rat lymphocyte populations. The ADA-specific activity (per 10(8) cells and per milligram protein) was 3- to 10-fold higher in thymocytes than in lymphocytes from thoracic duct, lymph node, spleen, and bone marrow. The high ADA activity in thymocytes appeared to be preferentially associated with cortical thymocytes. Enrichment or depletion of cortical thymocytes by density gradient centrifugation, cortisone treatment, or selective lysis with anti-Thy-1 plus complement resulted in parallel increases or decreases in ADA levles. These results also suggested that medullary thymocytes have ADA levels similar to those of peripheral lymphocytes. 'Immature' cortical thymocytes and thymocyte progenitors appeared to have low ADA activity; low enzyme levels were found in fetal thymus at 16 days of embryonic life, in the early phases of thymus regeneration, and in a 'null' cell population isolated from bone marrow. This study demonstrates that ADA activity varies markedly during T lymphocyte differentiation and suggests that fundamental differences in nucleotide metabolism may exist in T cells at different stages of development
— id: 15222, year: 1979, vol: 122, page: 216, stat: Journal Article,

ASSIGNMENT OF HUMAN NEUTRAL ALPHA-GLUCOSIDASE-C TO CHROMOSOME- 15
Hirschhorn, R; Smith, M; Martiniuk, F
1979 ;31(6):A50-A50, American journal of human genetics
— id: 28149, year: 1979, vol: 31, page: A50, stat: Journal Article,

HUMAN NEUTRAL ALPHA-GLUCOSIDASE-C - GENETIC-POLYMORPHISM INCLUDING A NULL ALLELE
Martiniuk, F; Hirschhorn, R
1979 ;31(6):A138-A138, American journal of human genetics
— id: 28151, year: 1979, vol: 31, page: A138, stat: Journal Article,

ASSIGNMENT OF HUMAN NEUTRAL ALPHA-GLUCOSIDASE-C TO CHROMOSOME- 15
Martiniuk, F; Hirschhorn, R; Smith, M
1979 ;25(1-4):182-182, Cytogenetics & cell genetics
— id: 28111, year: 1979, vol: 25, page: 182, stat: Journal Article,

Adenosine deaminase. Alterations in activity and isozymes during growth of normal and genetically deficient fibroblasts
Hirschhorn R; Beratis NG; Martiniuk F
1978 Nov;117(1):103-109, Experimental cell research
— id: 15223, year: 1978, vol: 117, page: 103, stat: Journal Article,

Adenosine deaminase activity in normal tissues and tissues from a child with severe combined immunodeficiency and adenosine deaminase deficiency
Hirschhorn R; Martiniuk F; Rosen FS
1978 Mar;9(3):287-292, Clinical immunology & immunopathology
— id: 15224, year: 1978, vol: 9, page: 287, stat: Journal Article,