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! Ized as follows: (1) MC and PB are potent repres.on of the UMPJ-demethyl- ae; (2) MC and PB ars potent inducers of a number of other miaed function osidases as well as of the synthesis of the essential components, cytochromes P-IIe and P-I30, and (3) the MC- and PB repressible enzyme. DMN-de- methylase, is inhibited by carbon nsonoaide, just s are MC- and F B-inducibk mited-/unction osidases. The implications of these findinp are considered. ArBtn, M. F., Arcos, 1. C.. Pastor, K. Ir., Wu, B. C., and Venkaleun, N. CArmko-Siolotiral Inreraniowt 17:127-110, 1976. Other arpporrr National Cancer Institute and 11oRmann-La Rochr. Inc. From the Seamen's Memorial Research 1.•boratory, U. S. Public Ilealih Service Hospilal, and the Department of Medicine, Tularse University Medical Center, New Orkan.. MALIONANT DISEASE AND TRAC/IEOBRONCHIAL EPITHELIAL MULTINUCLEATION Tr•cheobronchial washings of patients with a wide variety of estrathorack malignancies have been shown earlier to contain si6nifleanlly rrsore multinuckated ciliated eells than those of a matched control group without prediagnosed cancer. TAis study, while confirming the original flndinp, also determined sorsse (aetorn which influence multinuclealron One half of the total group of R24 pa- tients h•d malignant dnease and the dhcr hatf, matched by ses. age (decades) and smoking habit but without predngnosed malhgnancies, served as controls. Mullinuckation was found so be 2 01 t,mes more frequent in the cancer pa- lienta Ihan in the controls In pairents with invasive Iunsors welhout known mNaslases, mulUnuckatson was seen four times more (retfuenlly Ihan in the controls. Site of origin, stage of tumor and escessrve smoking habit in control fesna/es Influenced statistical signifkanoe, but smoking habit in maks did not. A ptospetUve study is now being planned in which incidence and degree of tracheobrorschl•I epithellal muhinuckalion will be used in conjunction with biochemical tests for the diagnosis of occult cancer. CA.bw, J. n d. Canrer )7(.):1074-Iet1, 1976. Othar.upp.rtt U. S. Public lledth Service. From the Dep.rlmenls of Anesthesiology and P•tholopy, New York University Scbool of Medicine. New York. ECTOPIC ISOP_N7.YMES: EXPRESSION OF EMBRYONIC OHNES IN NEOPLASIA Awareness of the phenomenon of ectopic polypeplide hormone production by Iumorn hu coincided with the recognition of ectopic i.oenzymes in eaperi- mental rodent sumors and in the serum and tumor tissues of human cancer 16 I palients- Many newly-recognized embryonic protein phenotypes are recavmR wide attention as °markers' o/ malignancy. A number of other properties b4Nh enzymic and nonenzymic are shared by emhryurssc and neopla+trc cells Ihc ever-increasing accurrrilalion of findings of embryonic gene prrKhkla in ncu- platii• gathered from cesearch on isoenzymes, hrxrrwsnes, and protein antigens is csusin` reevaluation of the current viewpoint regarding the nature ol cancer Tbis discussion es•mines the .uthors' recent etperierrces with the carcinopla- cental •nligen. Regan isoenzyme, as a model system /or studying the regulation of embryonic gene espression in cancer cells. the rekvance of the cell cycle, •nd the nature of the 1ene product in membranes. T heir hope was to construct • perspective on the nature of cancer from the point of view ol ectopic iso enzymes. Tlse evidersoo is then ea•mined from the standpoint of a single cenlral question: "Is the sekrai.e activation of embryonic genes a necessary step in neoplastic Iransforma:ionT' Several areas are scrutinired in an attempt to amwer this question. These include the telalionship between embryology and oncology. the possible embryonic origin of vital transforming `encs, normal host genes, and oncoStnie rrseehanisras. It is concluded Ihal: (1) ectupic iso enzymes, prexnt in /umor lissues but not in the tissue of tumor oritin, •re predominantly embryonic in lype; (2) the Regan- and msn Regan iaoenzyroe- producing Ilel.a cells provide a suitable rnodel syslem lor the arK/y nf a varicsy of (aclon which ue involved in 1he etpression of ectopic iwenzymes of the carcinoembryonic c•1egory; and (3) information on cell cycle and hormonal regulation of embryonic gene etpression in cancer cells may contribute lo our understanding of the role o/ this phenomenon in the process of neoplastic transformation which may reflect a d'rsorder of gene regulation with the re- appearance of trophobl•slie properties. Such traits evidenced by lrans/ormm6 cells may be a consequence of whatever onco`enic agent (chemicals, r•diation, .iruses) produces a speeifie kosa of regulatory control of embryonic Senes. FLAman, W. H. and Singer, R. M. ln: Becker, F. F. (ed.): Canrer: Slolosjp o/ Tnnrors! CeQula. Biology anJ Growrh, New York, Plenum Publishing Corporation, 1975, vol. ), chapl. 3, pp. 37-R0. Other support: Nalional Cancer Institute. From Tufts Cancer Research Center and the Deparlnsenl of Pathology. Tufts University School of Mediciae, Boston. A SIMPLN RAD101MMUNOAS.SAY ()F IIIJMAN P1 Al'UN('AI. At-KAI-INE P11()SPHATASE IRE(IAN IS(H?N7-YM1:) USIN(3 SPECIFIC AN IlBODY POLYMERS Eelopic placental alkaline phosphalase ( ReRan isaenzymc ) has been ftMrnd in the sera of cancer p•Iients, reported in variant forms, and cons«fered to strongly reinforce the contemporary view of the biological importance of cm- bryonie gene activation during weoplaslic transformalion /lowever, the ca Iremely minute amount of Regan Isoenzyme in sera has made its detection, pri- marily by enzymoloifieal quanlil•lion, difRcull Now, this paper presents a com- petitive-prdein-bindin6 assay of Repn isocnzynse using a specific polymeriud 17

! antibody to facililate the phase separation step Only a minute quanuly of the polymerized antibody parlicks is required for each assay in admiclure with the specially prepared labeled and unlaheleJ enzyme. By adding a amall amount of uarch-gel particks before low-speed centrdusalion, complete phase separation can be achieved This radioimmunowsay which can delect 0.4 to 0.8 ng en- zyme protein per tube, is comparable to the sensitivity achieved by enzymic as- says. However, radioimmutsoassay is advantageous to the enzymic assay in being dirsct, specific (no interferenee by the nonplacental-lype alknline phos- phatasn) and capable of detecting both catalyticilly active and inactive forms of Ihe enzyme. Native variants of placental-lype alkaline phosphatase, including Regan isoenzyme and Napo isoetszyme, could thus be directly determined in clinical specimens by this procedure. Chang, C-11., Raam, S., Angcllis, D., t)oellgast, O., and Firhman, W. !l. Cancer RctcarcA 11:1706-1712,1973. Other wrpp.rt t National Cancer Institute. From Tufts Cancer Research Center and the Departmenl of Palholagy, Tufts Ueivenity School of Medicine, Boston. CONVENIFNT IMMUNOFIXATION I:LEC/ROPHORESIS ON CELLUWSE ACETAIE MEMBRANE This paper reports an immunofisalion ekclropboresis technique that can he conveniently performed on cellulose acetate membrane (c.a.m.i, that requires only nanopam levels of the sampk and that oAen advantages nol provided by the use of agar gel as the supporting medium. Applying polyspecifk anliserum direetly upon the surface of e a m. alter ekclrnphorelic separation results in the sinwllarKan 8sation o( nwhipk antigens as discrete immunoprecipitin bands, rnther 1h.w the compie: precipitin arcs observed in conventional immunoekctro- phoresis. Although the principle of this technique is similar to that performed on ajar Bel, sning e.a.m. for immunofiaalion ekctropboresis has the following advantages: (1) Because of c.a.m.•s highly porous n.ture, it provides an e.cel- keM nmlecular<iclusion effect and hence a highly satisfactory ekctrophorNic oepanlion of proteins. (2) It greatly reduces the amount of time needed for antibody /lsation and for subsequent washings. (3) The membrane absorbs much kss anliserum non-speci/kalty than agar gel. (4) This technique is suited for e8eetirey and conveniently amplitying the primary precipi/in hands by re- action with a second-antibodytnryme conjugate which can be recovered and reLLsed. These advantages thus have made the e.a.m. a eonvenienl, acceplaAle, supporting medium for imnunoAsalion ekelrophoresis analysis. Chang. C-11. and Inglis, N. R. (FbAman, W. !I.) (-Nnlca (-A/mlh a A, rn 6S 91-97, 1975 Orher srpp.rr N.r..nal ( anact (nswine Ir'.n lu(u 1•,..r Il.war.h I tntcr •,.) the IrcpatInKn1 u/ 1'alhuloey- fulU t'm.cosat "./...I ,d Mrd.,ne Kn~,.n 19 RIiA('l1ON OF CONCANAVALIN A WfIFI AI.KAIINt PHOSPHAIASI-S EXTRAC7ED FROM VARIOl1S HUMAN IISSUE SOUR('ES Abundant evidence indicates that mo.t vcrtebrale alkaline whether originating in normal or malignant cclls, is intimately as.,K„IcJ „,Ih the plasma membrane of the cell in which the enzyme is synthesized ,,,i1 Ih,r the enzyme invariably contains carbohydrates. In order to shed some I,tM un the nature of the carbohydrate mocity assncialeJ with the en:yme, it w„u/J be of interest to know whether there is a spccilic interaction hetween ,U,hnc phosphalase and concanavalin A(con A) of jackhean,  well chata.rcnreJ lectin which has the property of reacting with cell surface suRar re,aloes A simpk and sensilive ekclrophorctic technique on cellulose uctale nwmhr,,,c was selected to drAerentiate the mobrlities of the free enzyme and Ihc cnrynu con A compk., based m Ihe /ac1 that the compkaed form ia retar.kd al the origin of application dut to its state of ag`regalion, while the /ree enzyme has normal mobility. The spccific binding of alkaline phosphalase was then spwlied by con A aAinily chromatography. The results derswrnstatc that there is a spc- cific reaction between con A and a lractiors of alkaline phosphatases eslrackd from various human tissue sources. This phenomenon was al,o ob.erved wtlh highly purified placental alkaline phosphatase with a specific activity of 200 rmok phenol/mg protein/min. In light of the well-estahlrshed apecificily of con A reactivity toward the carbohydrate moeily, the aulhora conclude that the re- actinB human alkaline phosphatases may contain branched pulysaccharrdcs with a terminal o•D-mannopyranose,.-D-ilucopyranose, /) fructofuranose, their gIo- cosides, or sterically related structures. Chan=, C-H., AnReNis, D. and FliAmaw, W. !f. Moleculer a Crllrlr QJocArmbrry 9( I):SS-37, 1975. Other a..pport: National Cat.cer Itatitute. From Tufts Cancer Research Center and the 1)eparlment of PathotoRy, lults University School of Medicine. Rostbn. THE IMMUNE RESPONSE AT THE TUMOR SI11: IN I 1/N(i CARCINOMA In this study, histologic and immunologic mcans were uud to investiealc the local immune response to lung cancer 7u bcern with. searhoos froto iIr cases of different types and gradct of lung caranunm.n were e+.ruiucJ tonn par.tbvely in order /o evaluate the mwpholoRy uf the hwvl rtvttarn, Ibsluw lrve patterns of strumal cellular reaclion, chau.clcri.hc 1411 Jdlcrenr ht.l0luRl: types of lung carcinorea, were recognized lhc ananutt ul acllular tnfilluuun was highest in squamuus cell earcinornas and luwest or n.wteaslcnt in na4 «/1 earcinomas Within the variuus histologic ealerories. the well JdlerenualrJ tumors appeared to be accompanied by more reaclrve cells than rhe pIMMIy a1J /erenliated ones; there was no relatitm helwcen tum..r nctrasts anJ ccllulr infiltration Ihe plasma cells were distinctly asuw•ia1eJ with sqoauunrs cell car csnunus; their number in the stUorna was proportitmale to the dcsree of dd ferentialion and the presence of keratin prt.Jtced by the tumors In the im mnrndo`ic Iesls, eluates with a high eontenl of inuounuAluhuhns wcr- rc .n

! covered from pleural eRusqns and from solid lung carcinomas by dissociation of anliken-antrhody complesn. In indirecl immunofluorescence tests. Ihese preparations reacted positively with lissue cultures and with fresh suspensions of lung carcinoma cells, but not with cultured cells of most nonpulmonary tumors or with cell suspensions of normal adult and feul lung. Although so far only a limited number of casn has been esamined, the results consistently indicate that tumor-reactire antibodies alre present at the tumor site in amounts significantly larger thui in the circulating blood. It also appears that these im- munoglobulins are largely the product of the plasma cells and lymphocytes accumulated in the tunae sttorna. IoecAbn, H. L.. Dorsett, B. H. and Paluch. E. C.nccr )t(6):22%-2)09, 1976. From the Dep.rtments of Palhology, Lenoa Ni11 Hiapital and the ('olkite of Physicians A Surgeons of Columbia Uni.enity, New Yotk. ACTIVATION OF DEVELOPMENTAL GENES IN NEOPLASfIC TRANSFORMATION Activation of embryonic Renes, as evidenced by the detection of their pro- Ir:in prvduc/s, is being recognized as a genuine manifestation of neoplasia. Since twch pco(eins are being identifkd on the basis o/ germ-layer origin and of eatraembryonic liuues, it seems important to fis the stake of developmenl eorrespordin6 so the pattern of e.pression of such proteins in cuscer tissue. From a map of development focused on events beginning with the zygole and ending with the esuhlishment of fetus and placenu, it is pp»sibk to esplain why certain de.eioprnenlal gene products are restricted to fetus or placenta or distributed in both. It also suggests which products ean be espected to occur concordantly in neoplastK transformation and in neoplasia. In the paper pre- sented here. the espressioa of term placenlal, chorionic and amnionic alkaline pboaphatne uoenzytoes in preneoplaslic and neoplastic lung and other caneers Is asNicipded from a preliminary study of epithelial cell sonic estracts from the tracAeobroechial tree of a patient with btonchoRenic canoer. This study ea- plores /kst the onco-0erelopmenlal relationship between chorionic alkaline pAwph.use and chorionie Ronadotropin, both of which are localized in syn- ekiotroplsoNast and eapteoed in choriocarcinoma. TTsen, the tracheobronchial lree n a human mode! of neoplaaic transformation is presented in relation to t!M known lumor and developmental alkaline plw+phalases. and the widely recognized oacofeld proteim are identified with their counterparts and position io eatly derebpment. Suth a developmental perspective may, when It has been fully espiored, lead Io a rational interpretation of the significance o/ espression of any product ot combination of products in neoplastk transformation and In seoplasia. FttAmmn, W. H. C.wre. Re..a.cA )619 pl. 11): )42) )12a. 1916 Olh.r wP/.rtr Nauonal Cancer Institute Pnxn Tuft. ('ancer Research ('enter and the 1?eparlment of Pathology. Tufts University School of Modrerne. Boston. 20 I VIRUS-SPECIhIC NEUTRAI.IZATION BY A Sl)1.Illil 1: NON- IMMUNO(i1.OBUI.IN FACTUR FOUND NAIl1KA1.I.Y IN NORMAL MOUSE SERA Two types of immunologic responses tu enda6cnous (' type vrruscs h.vc been detecled in normal mouse sera: virua- hindmR as dclecteJ by r.JMnur mune precipitalion auays and virus neulrahratiors. Ilowevcr, while mouu rm- munoglobulins in the sera bind to both eculropic and tenoNruprc IX Iraprc) viruses, these same seta neutralize only the X-Iropic virus. Ibis rnconanlcnty was at first considered to be related to dillerences in the a0unny of thc un munogloFwlim. The dala presented here now indicate that the nerdraliirns Ac livily is mw drre to the :Miviral antihodies detecled by raJrumunurNrprecqHia lion. Rather, virus neutralization is assoeiateJ with a factor whch has rwrne o/ the characteristics of ony known class of nunne tnrmuruiglohuhn It is e0nnve against several X-Iropic virus isolates, but rwrt ecutropic vuuscs, anJ requhes contact of the serum with X-Iropic viros. The decrease of this lacwr in mrnne senrm only afler absorplion with X-Itopic, hn mN ecolropic, virus further demonslrates its specificity for this class of enJoserkwn ('•type virus AlthrMrKh prcliminary, these data suggest that binding of the factor lu the vnus occun and is presumably involved in its neutrahtauon. '1 he specificity of this (actur tor X-tropic virus suggests that it represents a newly recognized type of respmse of the host to an endotenous virus. IIs possible rok in the regulation of enJo Senom C-lype .irss.es is considered. l.ery, l. A. et .1. Proceedings o/ the Nationd Academy o/ Sciencn o/ the Unircd Srotes of Anseriea 72(12):3071-3073, 1975. Other ar"ortt National Institutes of Nealth and the National Cancer Insli- tule. From the Department of Medicine and Cancer Research Instilule, University of California, San Franciseo, the Basic Cancer Research Proeram, Frederick Cancer Research Center, Frederick, Md., and the Clinical Research Cenue. Harrow, Middksea, England. FEt11.OEN MICROSPECTROPNOTOMET RY OF ORAL. ('AN('ER ANI) 1.EUKOPLAKIA Narly In the devek+pment of eancer, a cell line emerges whrne nu.kar deosyribonuckie acid (DNA) eonlent remains conslanl throN-;hom the life .d the tumor. The amount of DNA appears to he largely deperaknl on the a.trral chromosorne number, or karyotype, and can thus he diagnostic of drphotJy. aneuploidy or polyploidy. The demonstralion of hnormal cell hnes in in uru cervical carcinoma has permitled the inference that this change uccurs he/ore invasion, while Ihe fact that this characteristic change is ftwnd in cervKal lesions diagnosed as mi{d, moderate or severe dysplasia wrNrW indreale that an Increase in nuclear DNA might occur much earlier than heretofore suspected lhis study attempts to discover whether oral kukoplakias have 1)NA contents similar to oral earcitamas, and to deletmine the value of F"eulken rnicrospeclro- 71

I pholomelry in prcdicling the Iransformation of Icukoplakia into carcinoma. The technique of using Iwo wavekn6ihs was applied to 10 p sections of 33 ksions and showeJ that five out of ten carcinomas and 12 out o1 16 leuko- plakias had drpluiJ cell lines. Instead of Jenxsnatralins a correlation between the degree of atypia and abnormal Feulten-UNA stem lines. however. the re- suits suggest that DNA content increases at a much earlier stage and that seem- ingly innocuous hyperkeratolic Iesiorn, as well as oral kukoplakias, contain amounts of DNA similar to oral carciroTlsu. This lechniraue, therefore, seems to have minimal value as a predicsor of malignant transformation because the aignifkance of a diploid stem Rne would always be uncertain. Doyk, J. L. and MonAold. 1. H.. Jr. Jownd o/ Dental RerrarcA S,(6):1196-1199, 1975. OlJier aarpporf r American Cancer Society. From the Department of General and Oral Palhololly, New Jersey Denlal School. College of Medicine and Dentistry. Jersey City. IDENTICAL GENETIC BASIS FOR LYMPIIOSARCOMA AND NEMOLY7IC ANEMIA IN THE RABBI f In rabbits, both lymphosarcoma and hemolylic anemia which occur in Iwo genetically related strains. WII/) and X/J respectively, are inherited in aulo- somal recessive fashion. Tests for identily of the hemolylic anemia (ha) and lymphos.rcoma (is) genes show that they are both allelic and identical by descent and that the two different conditions result from interaction of these genes with the host jenotype. 1lemolytic anemia is the primary cau.e of death M compound heterozyRotes, lra/!s, with increasing Iympho-prohferaeive disease with age. Ages at death of the animala with histologically csnllrn.ed disease ranged from Ave days to 22.5 months, the average being about 10.5 months. The symbd ho will henceforth be used to represent the gene (or eilhr.r disorder. Foa, R. R. and Mrlrr, H. The Jo.rrwd o/ Hrrediry 67:99-102, 1976. O/Aer anpporfr National Institutes of Ilcalth's Division of Rerearch Re- sonrtas, National Ins1NWe of Child Heallh and Human Development and the National Eye Institute. Frvm TM Jackson l.aboratory, Bar Harbor, Me. PRESENCE OF A HIOH-MOLECULAR-WFIOHT RNA AND RNA DIRI?Ctl:.l) DNA POLYMhRASE IN RABBIT IIERFI)11ARY LYMPHOSAR('OMA 10 light ol the association of type C RNA virus with lymphosareoma in severd aninul specres, it seemed pourhk that rabbits with lymlawsarcoma might harbor type C virw(es) or viral markers. To test this, the assay for t RNA-JireclcJ DNA polymerase (RDDP) was useJ as an indicator of a type (' virus in lymphosarcomalous rabbits. An K1)1)1' asurciateJ wNh partrcks Ihat harNl in the density range of type C RNA vuuses and viral cores was demon slrated in 95% of the tissues taken from the.c rabbrls. Fndu6enous KUnP a. Iivily that was sensitive to treatment with RNase was deteclcd in the crale enzyme obtained from lumorous tissues. The Kl)DP associated with the par- ticks could be distinguished from cellular DNA pulymerases by salt elutNrn /rom phosphocelluluse. The partially purifieJ enzyme pre/erred the template primers poly(rA)•(dT)r: ra and poly(rC)'(J(i)rs r, over other synthetic tem- plate primers and also utilized viral 70 S RNA as template. While this and previous studies indicate that lype C viral marken are present in rabbit tnsues, no virus from lumor celh or normal cells in culture has been is)laleJ yet Beditian, 11. (3., Foa, R. R. and Mrlrr, II. Concer Research 76:1697-469fl, 1976. Otber u.pporfr National Institutes of Health and the l1. S. Public Health Service. From The Jackson Laboratory, Bar Harbor, Me. EVIDENCF. FOR A PARTICLE-ASSOCIAT El) RNA 1)IRI'C 1 EO DNA POLYMERASI: IN RABBIT PLACENTAI. ANI) ll ft:RINF '11SSUFS Because of evidence that type C RNA viruses eaist in rabbit tis.ues, and because type C particles have been found in rabbil bla.lrc yals and utcrine cells, in primordial germ cells and in the embryonic or placental /issue o/ several other species, it seemed possibk that rabhil placental tissue, as well as pro6esia lional and es/nn uteru., could eapress type C virus(esl or viral nurkers Re ported here is the isolation of a distinct rabhit RNA-drrected DNA polymerasc (RDUP) associated with particks that band at a density characteristic of type C RNA viruses. That this enzyme is biochensically anJ bwphysically similar to the RDDP of mammalian type C RNA viruses is shown by column chromato. Rraphic eharacleristics, ten)plale primer preferences, nkrsecular weight determi- naliun, and an absolute reyuiremenl (oF the divaknt cations. 1 he methodulosy used provides the sensitivity required to delect low inlracelhrlar levels of Ihe enzyme and to dntineuish the cellular DNA polymerascs ( a. p, and y) /ronr viral RDUP. The accurrwdNed evidence imlicales that the rahhil may hartw+r an enJi>tcn.ws type C RNA vital itenome and thus conlarn viral markers Ihe presence or absence .A viral markers in Ihsues of tahhits, p,r„cul.rty slurn WII/J which has a high Incidence of lymphusarcorna, rs also hernR invcsu(ares in hopes of eluciJaling the rok of partially eapresacJ type C vrrusieal rn lumorisenesis. Bedigian, tl. O., Foa, R. R. and Mcier, H. ('nncrr Rrsr.orA 76(t2):46e7-1692, 1976. Other aupporz: National Institutes of Heallh and ll. S Public Ilealth Sctvicc From'Ihe Jackson Laboratory, Bar Ilarbor, Me.

TRANSPI A('F.N I Al. ('ARCIN(X:I:NI(' I.I I F(' I SOF DIETHYLNII RUSAMIN@ IN MI('E This suwly inve.tisates the prenatal carcinogenic c/fccls of a srn8lc Josc of diethylnitrosamine 11)FN) administered to mice at JrRercnt lunes JurinB pre8- nancy. Lung tunktrs and kukemias were observed in the o0.prin8 of DEN- trrated SWR/1 females and AKR/1 maks when the carcinogen was adminis- lered any time between the 8fteenth and iijlhteeMh Jay of Sestation. 7 he inci- dence of lung Iumors, histologically nwltiple pulmon.ry adenomas, was high- est (t77i ) when the mice were treated on day 18. Since the I)EN did not Induce any tumors in these animals when administereJ before day I S, it appears that susceptibility of the oflspring to this carcinogen begins at that time or later and that the targei organ is the lung, althou8h kukemia was common as well. Previous reporls suggest Ihat, in rals, the fetal enzyme system ncces- sary for the activation of "indirecl" alkylating carcinogens becomes operative only in later prenatal sla8es. A study of the .ynlhesis of dealkylating enzymes in fetal Iiasues at diRerenl Iimes during rs/alion could be important for es- lablishing a positive correlation between transplacenlal carcino8ersesis by these wbnances and the development in letal tissues of enzymes capable of inetabo- li:ing them. Di.aq B. A. aod A(eier. N. nk N.rr.wbun,cAa/ren 6l(10) :,s7-IBR, 1976. O1A.r aNrprtr I.eukemia Society of America, Inc. Fran The Jackson I aboratory, Bar Ilarbor, Me. THE BIOSYNTIIESIS AND BIOt.OOI('AL PROPERTIES OF 6-HYDROXYME i11YLBENZO/QlPYRENE As part of a series of studies on the properties of aryl hydrocarbon Ay- droaymethyl synthelast, this paper shows that the enzyme is present in lung and liver both as a microsomal membrane-bound form and as a soluhle form, and that each form of the enzyme is activated by a-naphthoflavone. In addilion, the blolo8ic properties of benzo(o)pyrene (BP) derivalives as carcino8enic agents in mice are studied, .nd the eRecls of cytochrome P-1S0 inhibitors on 1he side-chain methyl osidalinn and the hydro.ymethyl synlhetase rractionn are eompared. Results show that the aryl side chain methyl oaidatwrn is inhibited by the classic inhibitors of cytochrome P-450, whereas the aryl hydrusyrnethyl .ynthetase reaction functions independenlly of the cylochrome P-eS0 pathway. Also included in this paper are obser.ations on: (I) the mechanism of the synthelase reac/ion; (2) Iumori8enicity of derivatives of BP; ()) induction of the synthelase by 8P• (4) transformation of cells in eulture, and (S) Iraro- lormalion of mouse embryo cells by BP and BP in the presence of 1-henzykmi- dazok. Mexerwer, data are presented to Jemnnstrale that WI-1R human lung diploid flbroblasts IrcateJ with BP and 1-hen,ylrmidazok clone more effectively than with either ueatment alone 1he sum of these data indicates that 1-hen- zyhmKl.zule, an inhibitor of cytixhronse PIStl, in combination with 8P allows Irandormation of mou.e embryo cells al pa.sagc N anJ Ih:d thrs combrnatron al.o aRecls WI-IN cclli cluninc enicicncy Ihe rclalronship Lclwecn thFs ac tivity and Iransfurmauon is currenlly undcr .ludy in a total proRram evaluating the ruk of the mmhydroaylative pathways in carcrno8ersesn by pulycyclic aromatic hydrocarbons. Slo.rne, N. /t.. ('hen, 1/.. Diwan, B., Bedigian. R, and Mrier, It. In: FreuJenthal. R. 1. and Jones. P. W. (eds ): CurcinoRrneru. Vu1 l. I'olr- narfror .(rommtoc IlydrocurAoni: CAemi,rry, A/rraDr.lisnr, und ('a.rinozenrur, New York: Raven Pren, 1976, pp. 171-180. Other support: American Cancer Society. Frons the lkparlmenl of Biochemistry, llnivershy of lennesace ('cnter fu( Ilealth Sciences, Memphis, and The Jackson l.aboralory. Virus I eukemu Scc lion, Bar Ilarbor, Me. S11/1)11'S ON PULMONARY ARYL //YI)R(X-ARB()N IIYI)R()XYI.ASI'. ACIIVIIY IN INBRED STRAINS OF MI('E This report describes some of the mapw paramelers re8ulatrn8 the constitu- tive and )-me/hykhdanthrene (MCA)-induced kvels of pulmonary and hepatic aryl hydrocarbon hydroaylase (AIIH) activity in inbrcd slrains of mice. Inlrr tracheal instillation of 18e rg M('A in slerik 0.2% gelatin in sahne resulted in preferential induclioa of pulmonary AHH. After Irea/n.en1 with this dose rd M('A. the pulmonary AHH kvels of strains CS781./6('um, ('S7Bl./61, BAI B/ cMai, (')11/fMai and C371J1 were observed to be induced within 24 bows aller Iredmenl. Strains DBA/2Cum, AKR/l, Sll./). 1)BA/2/ and RF/I c.- pressed no such increase. At a dore of 500 pg MCA, the pulnwnary tissue of UBA/2 mice did e.press a/ourfold increase. This increase in Allll was de- termined to be quite different /eom the increase observed in ('S7B1_/6 mice by: (1) specillc activity of the enzymes; (2) genetic re`ulation; ( 1) susceptihday to inhibition by 7,8-benzoAavone, and (4) spectral propcrlies of the associated cywchromes. Thus, this paper shows that there was bolh a qualitative anJ quantitative difference between the increased levels ot A1111 ohserveJ in the AI111 "non-inducibk" mice and the increase oMerveJ in Ihe A1/11 "mJurihk" mice Moreover, in crosscs involving the ('37B/./h('rmr arwl I)BA/2('rrnr sluins of mice, pulmonary AIIH responsiveness lo inlratNacheolly administered M( A was re8u1a1cJ by a single /ulosomal dominant gene. /)n the (rasu of these rc• sulls, it seems that this genetically controlled enzyme res/wwse may play a nrajor rok in Ihe ultimate susceptibility of pulmonary tissue tu ahcmraally induced cancer. Kouri, R. Ei. rr a/. (Mkrobioloricuf A„w iarr,) Chemicaf-Diological Inre.arrlons 1): )17-711, 1976. From the Department of Biuchemiial OncoloBY, Mr.robiulogical A.ariates, BethesJa, Md. 1q '11

MACROMOI.F:('UT AR nETERMINANfS OF PLASMINO(iEN ACrIVA1OR SYN1HFSIS Neoplastic transformation of primary or early passaged 6hrohlasts is ac- companied by enhanced production of plasminogen activator ( PA ) which is probably directly related to the Iransformalion process, since increases in PA kvels do not occur after infection of fibroMuts with cytocidal viruses or kuk- emia viruses. lhe experimenta initiated bere aim to define sonic of ihe factors which may be involved in the control of plasminogen activator synthwsis. ('hick embryo fltxoblasrs infected with a temperature-sensitive mutant of Rous sar- eoma virw. Ts 6s, were selected as a model for study because sucls cells are normal by tsmrp"ic and biochemical criteria when grown a1 /1'(', but are transformed at )6'C. Since lhese phenotypic properties are /ully reversible within a few hours dler appropriate shifts in Iemperalure, this system is a very favorable one for esploring variables that might govern activalor produc- Iion. Earlier work showed that the properties of plasminogen activator are determined by the cell, rather than by the transforming agent. 7he eRects pro- duced by the addition of several metabolic inhibitors to cultures at The tirne of the shift from the permissive (16; C) to the nonpermissive (41'C) lempet- ature suggest that intracellular enzyme can be maintained at  high level i/ RNA synthesis is inhibited. 7he data also show that: (1) marked fluNualions in plasnsinofien activalor produclson occur very rapidly following temperature shifu; (2) the formation of plasminogen activator in this system is closely cor- related with the esprcaion of the vital IransforminR function; and (.I) RNA synthesis musl precede termination of activator Iormalion when cultures are shifted upward to lemperalutes which ue nonpermtutve for Iranslormalion. al- though the nature of the rekvant RNA specics rs unknown The ability of aclinomyein to limit the disappearance of mdoctble cn:ynxs following transfer to nonindueing condilions has been rcpx-rted for several syslems arwl various interpretalions have been oAered as e.planatuuns Ior the%e phenomena. '1 hese include possible decreases in the catahohsrn of specrfic proteins arnd inhibition of the synthesis of an inferred RNA species with a rapid turnover, which might function ao an inhibitor of translation. The dala presented here are as yet in- sufficient to permit either discrimination between these hypotheses or the tlimiaation of other plausible e.planalions. RI/RJw, D. R., Beal, L. P. and Rekh, E. In: Reich, E., Rifkin, D. B. and Shaw, E. (eds. ): Proteatet and elologicd Con- trof. Col/ Sprlng Ilarfior Cow/rrrnccz on Cell Prdi/craNon. Cold Spring Har- bor, N. Y.: Cold Spring tiarbor t.aboratory, 1975. vol. 2, pp. e41-1117. Other w'pr(r National Irolitules of 1lealth. From the Department of Chemical Biology, The Rockefeller Univeraity, New York. PROTP.ASF.S PRODUCED BY NORMAI. AND MALIONANT ('P.1.LS IN C(11.lURN ll+n paper jeKrilYt the crMtrol of plasminogen activators (PA) synthesis In two cell Iypes, chuk embryo /ibrobluts infected with a lemperature-stnsilive mutunt of Ruus aaucuma virus and human embryonic lung cells. Induction of I PA rcquires MHh RNA and protein symhcst. 1)cmJucuun ul PA rcquaes a ncw RNA and, perhaps, protein to be made. II the synthests o/ this dcmJucttve RNA is inhibiled, PA production can continue Irn many hours unJer aunJi Iions that are rxxntally nonpermissive. Many ddlerent eaperirncnts have in.h caled that the observed increase in production of 1'A by nenplastic cells is the resclt of Iransformation. A number of the phenutypic chan(;es asxwulcd widr transformation re dependenl, at least in parl, upon Ihe generation of plasmm by the PA secreted by these celh. One of Ihese chanRes, the lu.s o/ intracclhdar aclin containing cables in neoplastic cells, can be correlated with /he level of extracellular proleases. Moreovet, /hese same proteases can cause the dnap- pearance of actinconlaininR eabks in normal cells when supplied t.osenou.ly llterelore, plasmin accing from the ealernal sidc of the plasma membrane ap- pears to he capable oC causing the dissolution of these inlraccllular slructures 1 his paper dso attempts to demonstrate how the production of 1'A, a paurctdar component of the Obrinolylie system, may he implicated in the etiology ol diverse pathological conditioro. Ri/kin, D. Q. and Pollack, R. In: Ribbons. D. W. and Brew, K. (eds.): Pcorcolyus and PhyrioloRicd RrRu- lurion. Miami Winter SymOoaium, New York: Academic Press, Inc.. 1916, vol. 11, pp. 26)-2ti3. Other supporf: National 1s111utes of Ilealth. From the Department of Chemical Biology, The Rockeleller (/mversily. New York, and the Department of Microbiology, Slate University of New York al Stony Brook. UNUSUAL MANIFESTATIONS OF CANCFR Among the many onusual proper/ies of neoplasms, great attention has been focused recently on eclopic hormone secretion. Macromokcular /rnms u/ polypcplide hormorws, such as big AC711 and big Rastrin, have been shown to be produced by pulmonary oat eell carcrnoeus, certain Ihymumas. pan creatie islet carcinomas, and other related cells. In this investigation of ekctrrrn mieroRraphs of dysplastie ad normal human bronchial neuroerwkrcrine epuhc lial eells. two slatistically significant differences in orgaoelk tdlrastnu•lure have been uncovered which appear to be rekvant to the size of /he hormone nwlk cuks produced. Cornpared to the normal human bronchial neutoe/NharuK epithelial cells, dysplaalie epilhehal cells had smalkr (iolgi vesicles and /twet ses:reltxy Rranuks. 7hese ullrnttuctural diAcrtnces may cor.elue with nce pre/ertntial secrelion of biR ACL IL by dysldastic and neoplastrc pulnNrnary epithelium. 1t seerm, Ihert/ore. that macronNdeculat pcptide hurmures such as big A('hN or big gastrin are secreted ectuptcaay ItrHn sonic Jysplasuc aod neoplastic neuroendocrine cells partly because of underdeveloped (ialgi vcsKlcs in which the Irypsinizalion of prohormones may normally occur. Sommen, S. C. In: Finckh, t=. S. (ed ): Tbc Effctd ol Environmcnr on ('cl/r and I ruwn. Amsterdam: Eacerpta Medica. 1976, pp. 173-17N. From the Dcpanment of Pathology, l<nos Hdl Ilospital, New York 10 1 26

i COMPARISON 01: 7WO ANF_SIFiETICS FOR T11EIR EFFEC'iS ON T11E CLEARANCE RATE OF BENZO(a)PYKENE FROM MOUSE LUNGS Penlobarbital, an anesthetic used in this laboratory for the saKly of pul- monary tumor induction in mice by aromatic hydrocarbons, is a vety weak Inducer of aryl hydrocarbon hydro.ylase (Allll). Because of the possibility, however, that penlobarbital combined qith the inlratracheal instillatton of belvo(a)pyrene (B.P) could enhance the clearance rate of B,P, duplicate e.perirnents were conducted to compare the BaP ckarance rates from mouse lungs with two different types of anesthetics, pentobarbital and methosyflurane. PeMobarbital was given intraperilonedly, the mclhoayflurane by inhalation. Melhoxy8urane had a very slight eRoct on the AH11 system. There were no significant differences. however, in the clearance rates of BsP from tb: moane lunp in parallel esperiments employing these two aneslhetics. These ohserva- tions support the preferential ust of pentob.rbiUl anesthesia in these animal Nudiet on the base of its ease of administration and k.ng-Iasling eRecl, and because mortality is minimal at the proper dosage level. Fuest. A. aad Wiko.. K. (Untrrrslry of San Francisco) rrocrrdinp of the Western PAarnsarolory Society 19:32-35, 1976. From the Institute of Chemical Biology. University of San Francisco. San Fra.cisco. 11. The Rerpir.tory System FUNCTIONAL ANI) BIOCHEMICAI. FFFFCTS ON THE LUNG FOLLOWINO INHALATION OF CIOARET7E SMOKE ANI) ITS CONSTITUENTS. Ill. SERUM ANTITRYPSIN AND BRONCIIOMOTOR RESPONSES IN RATS As part of a continuing series of investigations on the bronchopulmonary effects of cigarette smoke. this report eRamines whether eaposure to cigarette amoke eta{geratn emphysemalous lesions in animals and further increases air- way resistance. Une.penedly, the data considered here indicate a possible re- latioeship between bronchomotor responses in rats and long biogenic aminea. As in sorne forms of human pulmonary emphysema, rals with evidence of et- perimenlally-induced emphysema showed decreased serum anti/rypsin activity. Additional e.ryswre ul these anrnr.ts so crgaretle snw.ke, howevcr, did not ea- agacrae Ihe lun.o.•n.l rhaners ia nce tung nor lurlher rrduce the enzyme's .clr.dt While vn..ar usha1H.••n ,auwl hr..u~lrti~.nclnclNrn in the rMrrntal a.rMr.•1. •nJ M~w~1r•.LLrw•n .u rtv enyarunul.. the nature of the , bromchumolor rc.prmse was allered by prclrcatmcnt of Ihc rrl wi/fb .yrnp. IhunurnKlic anuoe.. Ikcause nurcpinephrint arrd rAqr,munc evoke a hronchu con.uicksr rc.lr.nsc to hypotia whercas epmcphrrnc and .yncphrme claFt hn.ncho.bleluun, the authors prnttdale that preluadmg crtec/nrtrnune .lores wnh an N-rnethylaled anune (epinephrine cx syncphrinc / cau+es brrmchoJd.rtrun whilc similar preloading with nonmethylalcd amincs (rnorcpincphrinc or dopA mine) resuits in hronchoconslriction. Thn hypwhcais .cuggcsls that elnncphnne is the neurohumoral transmitter in the bronchlal muscls ul Ihe rat arrl that n can al.o he rckased by such inhalants as cigarette smoke. IIM)% niuogcn, haluthane- and aerosol propeNants. Support for Ihts new Ihcory is IKin6 oh lained hy analysis of epinephrine in the blosd draining the airways Ito, Ii., Watanabe. T., Shore, S R. and Avlado- !). ToricoloKy and Applied Pharmacology 33(3):401-a12, 1976 From the Ikparlmenl of Pharmacololly. University of Pennsylvania Sihor-4 of Medtcine. Philadelphia. 1RAC'HEOBRONCNIAL AND PULMONARY CY I OLOGIC CIIAN(;ES IN SHOCK Tracheobronchial smears from 10 palients who had developed hemorrhagic shock while undereoing general endolracheal anesthesia for suraery conlaincd mwpholosically abnormal histiocytes. These celis were overloaded with Papam- colaou slain which compressed the nuckus aeainsl the cell menrhrane. No srKh ce/Is were seen in smears from the 10 palients ased as contruls. ('ytrkhernical staining methods were undertakew to discover the comp.nilion of the suMl.ncc in the histiocytes. Tllere was no escess ingeslion of any sub.tance detecuhle by PAS. Sudan 3 or alkaline phosph.tase slarns. All cascs in .hock yieldcd smears with histiocyles which had phaeocyt'ved material whnfi was Pru.sian blue pi»ilive, indicating that the substance contained inorganic iron I he masi mum proporlion of hisliocyles containing Prusaan blue Rranulcs was 40% in slwx.k patients and only 2% in normal eonunls. flrauloRk studies cunduclcd on rals submitted to hemorrhagic shock were carrkd urd 1u invesuTalc this phenomenon. Iron-laden hisliocytes were fwrnd in the lidncys, spleen arwl IunKs of both shrkked and control animals. However, subsunu.lly more hrslur cyles containing Prussian Mue positive granules were drxovered rn the IunRs of rals in shock than in eonlrols. It may be, Iherelure. that iron is depo%rtcd in the lunp in low flow atates. Friedman-Mor, Z., CAafon, /., Katz, J. S., Gurstcrn, F., / ur ndnr/, 1/ , and Orkin, I.. R. Tbt lowrnat ol T.au,rra 16(1) : SM-62, 1976. Ofbrr ar.pp..rr: U. S. PuMic 1lealth Service. Front the Ikparlmenl of Aneslhaiology. Alhert 1'instcrn ('ulk6e of Medicine. lhe Bronx. N.Y . and the (hparlnrcnts of AneslhesK.hr6y and I'alhul.rgy, New York University Medical Center. New York. 29

0 VIRAL INCLUSION BOf)INS IN 1 RA('IiEOBRON('HtAL EPITHELIUM UF: ASYMP1OMAl1C SUBIECTS Cytoplasmic inclusion bodies have been fuunJ in the urinary tract epi- thelia of both symptomatic and asymptomatic patients, but such cclis have only been reported thus far in the respiratory tract of subjects with viral disease and bronchoeenic carcinoma. 1)uring a survey conducted for the cytodia6nosis of early bronchogenic carcinoma, howevett cytoplasmic viral inclusions were found sporadically in Iracheobronchia/ smears of aaymplomatic patients of both aeses. Is to 80 years of age, undergoing general endotracheal anesthesia for various surgical procedures. Of the ),019 smean screeneJ, 1.19G contained ciliated epithelial cells with eosirsop(silic cytoplasmic inclusion boJies. Statistical andysis did not disclose any relationship between the presence of viral inclusion bodin and other ahnormalities noled in the smears, nor was there any cor- relation between their presence and the age, sea or smoking hahits of the pa- tienu. When the frequency of occurrencs was assessed in relation to the sea- son of the year, however, 60% of all thesr smears werc found to have been collected during January through March. It is thus probable that the majority of these patients actually had asymptomalic coronavirus, respiratory syncylial virus and rhinovirus infections. According to the authon. the low postoperative complications rate noted in lhis series seems to indicate that the presence of viral inclusion bodies is not a precursor of respiratory disease, even ur,der stress corsditioos. K.ti,1. S., CAdon. /. and Turndorf, fl. C/kat 69(1):336•558, 1976. Oth.r aaspport: U. S. Public Health Service. Froae the Deparsment of Anesthesiology. New York University Medical Cenler, New York. TRACIIEOSRONCNIAL EPIiHEL1Al- MULTINUCLEATION IN PREECLAMPSIA MultinuckHed ciliated epithelial cells have been seen in the past in the sputute of patients who had ursdergone a bronchoscopy 4R hours qreviously assd. In a different sludy, in the Iracheobronchial washinp of patients under- goiwit surgery for a wide variety of estralhoracic turswrs. Now, smears were tssade from the tracheobronchial washings of 40 nonsmoking parturient women who were undergoing cesarean section or forceps delivery under general anes- thesia adminiucred via an endotracheal tube. Results showed that the smean lrorss 12 patients with preeclampsia of mwe than 24 hours' duration contained significantly nwre multimsckated ciliated cells than those of 13 healthy con- troFs, eigM women with preeclampsia of less than 24 houn' Juralicm, and seven wdnen with associated diseases other than preeclampsia. While the eaplanalion of dsis phenomenon is atill in doubl, it may be that it is related to immune mee6anisma that accompany prrectampsia. ('Adon, /. Mars. () F and Katr, I S ArcAirrr of r.rhobgy and Lasorerory Mrd.rlne IIM) 127•4211, 1976. 30 I Other aupport: U. S. Public Ilcallh Scrvicc. I rum the Department of Anesthesiology, Ncw Ymk Ilnivcr.rly MeJrcal (•emrr, New York, anJ the Ikparlmenl of AnesthesroluRy, Allxrl I in.ICm (•olksc ul Medicine. The Brona, N. Y. r.r•ANTIlRYPSIN AS A SYSIEMIC 1)1411'.RMINANF O1 I.I1NG SIRUCTURE ANI) FUNCTION The first section of this review den>,mslrares that slow, pru6resive loss ul lung parenchyma begins in mid to later life in pera.ns with a fNHnaryg.nrs Je ficiency of ar-anlilrypsin and the ZZ phentNype for this proicm, arKl Lcrhaps also in smokers with a helerotygous deficieucy of ar antiuyp.rn arsJ the M/ phenotype for this protein. lhe ar-anlitrypsin is maJc and/or JeuruyeJ in dre liver and its deficiency has been corrected by liver tranaplantatiun 1/ tbi% Jr fkiency causes the lung destruction. then ar•anlisrypsin is indeeJ a systcnuc detcrminanl of lung Wruclure and function. lividence that the tuns is a meta bolrc organ and that in this role it influences organ function el.ewhcre in dre organism is also presented here. Mos1 research on the etiology ul tMs tSenetraat ly-dctermined type of emphysema now focuxs on the hypulhean that this condition is caused by a deficiency of tr-antilryp%in, which readrs in the unre strained action of one or more enzymes on pulmonary tissucs fl(wwever, it is equally possible that ss-asNNrypsin acls primarily at a rem.NC site and sends loaic products to the lung. lndeed, il is even p.nsiMe that a, amiuypsin h.n other as yet undiscovered func/ions, or that ar•antitrypsin deficient patients have other defects that could cause emphysenu. Ilowever, this genetic disea.e remains the only solid clue to the cause rd s.wue forms of human emphysenu and may eventually enable investigalors to unJeratan'J the oriRins o1 other forms as well. Should sonse common hiochemical mechanism be proveJ, it rs pussibk that the same drugs would be effeelive in the prevention of all types ul emphysema. ' CoAen, A. s. In: Crystal, R. (ed.): The eJocAcnrkuf Rann u/ l'nbnnrro.y Fun.Hon, New York: Marcel Dekker, Inc.. 1976, pp. 717-l6(l. Other aupprf r National Neart and Lung Institute I:rum Temple Univenity Medicd School, Phd:rJclphia IIYI)ROXYPROI.IN1: ('ONl1iNIS ANI) 1'Rt11.YI. IIY/)ROXl'1 ASt'. A('IIVIIII:S IN LUNUS 01= RAIS 1-XI'11S/•1) 111 1 t1W I 1 VI 11 01: OZONE Cull.`en synlhesis in the lungs of a.luU rat" c.p.wr./ Iu l/ N ppru or-rne was studied by estimating hydrusyprufinc Illyp/ coMCns and by hdl,rwrn` nce ac/ivily of prolyl hydroRylase (P///.  cnrccd enryme rn the padhway ut aal lagen hiosynlhesis. In the early pha.es (I s_ da)s) uf u+uuc•iuJuccJ rnlury. P1/ activity was increased twrJuW over eonlr.A values und the amount ol cullasen synthesized (as estimated by Nyp formation) was double that of the nontol 31

lasennus prtqein synlhcsited. I hic rtsulleJ, by Ihc third day, in a significant increase (29% ) in lulal lung aill.rgcn Iluwev.•r, with conlmuc.l csptnorc (up 1o seven Jays), noncollagtn.ars prnlcin synlhrsis inKrcaseJ tn the p.nnt wherc 1he ralio of cullascn to noncullagen.nr. paNtin .ynlhcsrtcd was comp.trahle to that of controls. When the esp...eJ (1) R ppm Il,/ 7 Jays) •rnimals were placeJ in 611ereJ ambient air. PII activity returned 14s ntnmal in I l Jays whereas 11yp conttnt remained elevated for up to 2R days. l hcse resulls indicate that in- creased hrnR PH activity is lempwally rllated to atnrx esptnure and suR6es1 that this model may he useful in the study of lung injury and repair prucesses. Htnsain, M. Z., Cron, C. E., Mustala, M. O, and 9hatna`ar, R. S. lI/r Scicnccr I R( 9): R97-904, 1976. Other aupport: ll. S. Public Ilealth Service From the [kpattmenl o/ Internal Medreine and ('ali/urnia Prirnipte Rcsearch Ctnter, Universiry of California. Davn, and the Connective lissuc Hiochemnlry Laboratory, Universily of California Scho.rl of l)cnlntry, San I ranatco. BIOCHEMICAI. EFFF("T OF 07ONE I:XPOSURE IN RATS EXPOSEI) TO (•1(3AREfIF SMOKl: Pulmonary ghrcose 6 phosphate JchyJrugcnase I(i h PD) aclrvitics in the eylosol-rich fraction from conutri, ozone cspuseJ. ciearette<aptneJ- and aRa- rtlle-plus otune-csprncJ rats are rcported in this papcr. Whereas ntone-eapo,eJ rats show .n 11% Jecrease from the activity level (if unlrealeJ cuntrnls, rats eaposeJ Io eigaretre smule for five wecks .huw a significant 42 7 % ) increase. Subsequent esppnurc to acute. high Jnse utune /1 ppm lor 4 hr) decrcases the augmenled (i-6-PU aclivtlres to near nornial levcls, indicating that rats ta- posed lo cigarette snwke induced auRmentati.rn ol (i-h-Pl) are sull susceptiMe to (3-6-PD inhibition following ozone eapnsure. Ilowevcr, (i-6•PI) activilits in the rats eaposed to both cigarette srtwtke anJt utone remain slightly ekvated above control kvels. lhe importance o/ this enzymatic eflect wqh respect to Ihe susceptibility of smokers to oaidant eapusures is unknown. Peirce, T. H.. York, (7. K., Franli, C. E., and ('rou, C. E. Archives o/ Environmtntal Heolth 31( 61:290-292, 1976. OtArr aarpprt: U. S. Public Health Service. From the lhpartmenl o/ loternal Medicine, l/nivetsity of ('alilurnis School of Medicine. Davis. OZONE INiFRA("1/ONS WIfl1 LUNG IISSt1E. 81(X'HIiMI('Al. APPROACHES Summartting the hinchensical effects of ozone (O,) on the lung, Ihe au- thors review the molecrd.r rnechanisms of (!, inductd damaRe, the acute hieh- dose ellecu, the thromc low Jose eflccls, anJ the decreased and ra:reased sus- eepbhrlqy to lung /t, J,nute /1 is nro.t likely Ihal the moleeular mechanisms of 0, cytotocicny uperate throuRh o.idotiun and/or oaidation products, inler- actiun wilh ccllular mcmhrant% and rc.ulting Jcpu•..iun. rd rnany cclhd.u crvymalrc aclrvrtic.. Sonk e.pcruments .uggc.1 that. rn amm.J.. a wrdc varrncty td anlioaJanl .ubuances pra.vitk relative prutcttaut aRain.l //, c.pu.ute Ihat high-Jtnc eRpusures .evercly dcprc.% several crvym.rlrc :rctr.na% alnNnt ccr lainly indicates •aculc I/,.induccJ lung cytotuaiuty 1lrrwcvcr, d the annual% a1c alluweJ Io recover (rant nonlethal acute coipnsurc., .unk ol she hrnR nrctaMdr.w parameters arc greatly au`menteJ, apparently rcllccthnK she ccllular rcparatwc anJ prnldcrativc response to injury. (.uw kvel tl, caprswre ha. a siorilar cllcct wdhm ?4-2R MHrrs. According lo snnse nNUplwdoprc oh.crv.uinns. prulungcJ c.ry..rue ot cxpcrimcntal animals lo O, cau.es mrW (il.rr..is o/ luter parenchywa I he corKurrcnl increase in lysosomal entymc aclrvuy al.o cuRl;c.ts thc accunw lalrun u/ rn/lammat.ny cells, mainly macrophagt•s. in she lung Ihrs harlt.lm a: unmts /ur she reported increase in ettllaRen .ynthe.r% dutinR she catly miury and repair pluscs ('urrenl evidence alw supKcsts that a srgndirant rapccl ut sn.ceptrhrlny Nt prolonged e.ptnurt is "adaplrve" Iolrrance, a curs:entrrtarn dependent phentmrcnon whereby the mc/ahulrc auKmentatnsns inJrarJ by N..l kvel esptnures reach their maaimum two lu /otu JAys :dter the inur,d espncurr then Jrmirtish, disappearing completely rf eapu.ure is cruuinuc.I 1 hn% lar, hnw ever, thcre is only a suggestion that helpful aJaptatiuns 1o chrnmc /uw kvel 11, eRpusures occur in man. Since numerous varrables can affect an orRamsm'% resprmse to losic suMlanees, the authors recomnsenJ caution in interpretinR the overall effects of environmental pollutants starh as 1), on paramclers of IunR bioehemical aelivitin. Crort. C. E. et d. The Anrcrican lornnal o/ Mtdiciwt 60(7) :939 9)S, 1976. Othrr aupports National (astitutesol Health. Fnmt the Section of Pulnanary Medicine. Ocpartmcnt i+l Internal McJicinc. Univetsily of California Schools of Medieine, t)avis and I us Angeles . SrIMULAlION BY CIGARETTE SMOKE 1)F (iI t/1Al/llt)NI? PI:ROXIUASE SYSTEM ENZYME A('1IV11IF.S IN RA1 1 UNti (3lutathione perosidase is part of she enzyme syslcrn involved in generating reduceJ nicotinamide adenine dinuckolide phusphate 1NAI)1'I11, anJ as srMh con.litules patl of a potentially important interuehucJ ra•Juatrve anttoadant tk/cnse mechanism In erylhrascyles and hurR usatw. lhis sNrJy wve.trRatc. 1114. shnrl term, in vb•o eAects o/ espcriment.d crK,ucltc snwd.e esla,.ure on Klwa Ihiuwe peroaidase-rclaled entynse systems in prdoutnary dsarc, arwl attcmpts ao correlate any chan6es wilh histopalhobpic ohservauuns within th- ranKc ut IrRhr microseopy. Mak Spra`uc-nawky rats. 10 Jays uhl, ( aesar...n JernveJ and specific pathoEen lree, were esposed to 1) ciKarcttcs daily for 21 .rrn.ctutuvc days with a Walktn reverse-snqking eaptnurt appar,qus At the cnJ ol thar tinve, specUophotumetrie assry of IumnrRenucJ lung nssuc .ha..e.l utcrea.c.I activity of `lulathione peta.aiJase O•1Cf• 1. clutathM.oc reductasc 424% 1 am/ gIuc.ne 6 phtnphale tkhydro`cnase (1R1: / cunmparcJ lo contrra valucs 'I hrs particular kvcl of snsnke eaposnre, howevcr, diJ rwN causc Jctc.•tahk hntoloRic, lesions. It is suggested that shorl-Itrm, low level ciRatctte smuke ealwsure c.n 1i

initiate metabolic alterations in lung ceils without evoking histulodic changes detectabk by light microscopy. it is pourhle, however. that such t:ir.chemical alterations represcnt but one stage in a multistace process Ihal could eventually lead to more oven structural changes following more intense or prolonged ex- posures. Certainly. the presence of these biochemicd abnormalilies wgsest a sensitive method for assessing the effects of cigarette smoke or some of its . constituents on Ihe mammalian lung. ~ York, O. K., Peirce, T. 11., Scbwartz, L W., and Crofi, C. E. Arrhlvrz o/ Enrironnwnr.f HrdrA 31( 6):2d6-290. 1976. Other aa'prl: U. S. Public Health Service. From the Lkpartmenl of Internal Medicine, University of ('ali/ornia School of Medicine, L)avis. ASPIRIN AND EXERCISE-INDUCED ASTHMA Since exercise causes release of prostaalandin and sometimes also induces aahma, il seerm possibk that exercise-induced hronchoconslriction may be due lo the release of prostaglandin. Also, becauu acelylsalicylic acid inhibits proa- taglandin synthetase. thus diminisbrng proslaslandin rekase, it may he that n- pirin decreases or inhibits the bronchoconslriction of esercise•induced asthma. In order to lesl this hypothesis, four asymptomalic auhjecls with a history of exercise-induced asthma and a 10% or rmue drop in Forced Iapiratory Volume in one second ( Fl:V r) were selected to study the effect of aspirin on pulmonary lunction lolbwins exercise. lhe double blind method was used to administer aspirin (5100 mg) and placebo prior to exercise. Pulmonary function tests did not show any diRerence in response between aspirin or placebo. It is concluded that in Ihese four subjects aspirin did not prevent the hronchovascular response, perhaps suggesting that prostaglandins have no significant role in esercne-in- ductd asthma. The authors suggest, however. that a lar`cr series of patients muM be studied before this hypothesis can be compklely rejected. Taveira da Silva, A. M. and Ha.nosh, P. Prozt.glandinr 11(1) :71-73, 1976. From Ihe Deparunenl o( Physiology. Biophysics and Medicine, (horgelown U.iversity Schools of Medicine and Lknlislry. Washington. 1). C. L.IPOPROIFIN LIPASE IN RAT LUN(i: EFFECT OF DEXAMET/IASONE l.ipoprdein Irpase, an enzyme active in the capillary endotheliurn, regulates the uptake of blood Iriglyceride-/atty acids I ipoprotein Irpase acti.ity was de- termined in the lunes of rals slier administration of four ho.rnim:s - deaa- methasune, I thyruan, estradiol-171/ and progesterone - which hrre a known effect on hprd nxtahohsm Irpnprotem hpase aclivity, or lung sur(ac.ant synlhe- sis. In addruun, lung Irpuprolrm lipase activity was studied in diabetic and lae- tating rats Ik..mcthasone administration caused a rise of 70% in the level of , activity of lipoprulein lipase in acetone powdcr. of Iuns and a 1(1l)% uKreaK in the amount of enzyme rekascd during hcparm in/usiun into isol•rled. pcr/uscd lunp. Fnzynx aaivily was higher in lungs ut (cmales than of male rat.; how- ever. the level of activity was unaffected by estrogcn or pro6cslcrone adminiqra- lion to either mak or ovarieclomized rats. Diabetes. hypcrlhyroidism or lacla- lion did not change lipoprolein lipase activity in the (ung. 1 he conslanl preseMc of Iipoprolein lipase activity in the lung su6Ltsts that this organ is ahle tn main- tain a steady supply of Iriacylglycerol-Ia11y acids under cirarmatances that markedly impair the ability of other tissues to utilize this aubslance. Stimulation of enzyme activity by deaamelhasone could lead to increased uptake of triacyl- glyceroldatty acids by the lung and may thus be a contributing factor to coru- costeroid-induced enhanced sur(aclant synthesis. llamosh, M., Yeager, H., )r., Shechler, Y., and Hmnoz/i, P. BJocAinrico rz BIopAyrk. Act. 1)1:319-323, 1976. Other are'porf: Washinglon Hean Association. From the DeparlmeM of Physiololly ard Binphysics, and the lkpartment of Medicine, aeorgelowa Uaivenily School o( Medicine. Washinston, 1). C. INTRACYTOPLASMIC FILAMENTS IN PULMONARY I.YMPIIA/1(' I:NI)V I'HEL.IAL CELLS Earlier observations by various investigators have sue6cstcd that inlra cytop/asmic filaments may he aclinoid parts of a contractile systcm. Since fine inlracyloplasmic 8lameaN occur in pulmonary lymphatic endothelul cells. Ihe presenl investigators used tiswe biocks (rum IK neunalal rabbus to conrpare the cytochemislry and uNrastruclure of Ihese tilamen/s with myo/ilaarents of the peribronchial and pulmon.ry vascular smo.Nh muscle cells I..o types of endo. thehal filaments were observed in the pulmonary lymphatic cells: thm fllaments which lie close to the abhrminal cell membrane and thick fllaments which are dispersed throughout the cell cytoplasm. Followqrg heavy meriomyosin (HMM/ Ireatmenl, characYerislie arrowhead complexes /ornred in the thin /ymphatK endo/helial filaments as well as in the aclin filaments of the smouth musck cells. ihere was no deKetabk reaetion of 11MM with the thick elamenls. Alter incubation with EDTA. the thin Rlamenls were labilc, and the thic~ Alaments became the major filamentous component in the enduthelial cells lu smoo(h musck celh, the actin myofflaments were also labile whik Ihe larger lilamenls were stable. lhese observations supporl the hypolhesis that the acun like endu thelial lymphauc /Bamenls (orns parl of a eonlraclde systeor, whrk Ihe rhwk filaments conslitule a plastic eell•skeklon lhe significance o/ she contracule syslem in lymphatic endolhe/ial cells mighl lie in a wechamsru /or t]rc acnve regulation of the em/ulhelial interceUular junctrons and jlaps, and hence the permeability of the lymphatic endolhelial cell Irning. I.auwrrynr, ! M, Baert, 1. ard Ikl.oecker, W. Crll d Ilsrwr Rrzeorch 16)(2):11l-121, 1975. From the Katholicke Univenittit le I.euven School of Medicine. Leuven, Rc/ gium. 11