Raising the curtain on cancer. Is the puzzle finally becoming clear?

Looking back at the long history of cancer, we can still relate to that POSTGRADUATE MEDICINE editorial written 50 years ago: "None of the basic problems of cancer has been solved. The death rate is constantly mounting. Small wonder that many doctors face cancer with a pessimism bordering on resignation." The temptation is still to prepare for the worst. Nonetheless, cautious optimism is evident among cancer researchers. As Eugenie Kleinerman, a pediatric oncologist at M.D. Anderson Cancer Center in Houston, recently explained, "We're running a marathon, not a sprint. What's important is not how fast we run the first two miles but when we cross the finish line." In many ways, cancer is still a derogatory word used figuratively in reference to uncontrolled evil. But progress against this common disease is real, as evidenced by the growing population of long-term survivors. New discoveries are expanding therapeutic options every year. The challenge continues to be educating health professionals and patients alike about environmental risks and warning signs, recognizing cancer early, and finding more effective and less toxic therapies. In addition, we need to learn about the prevention, detection, and treatment of late effects of long-term survivors. The curtain is rising on a new era of cancer management, and we all have fron-row seats.     

Effects of human oviductal cell coculture on various functional parameters of human spermatozoa

OBJECTIVE: To investigate the effect of human oviductal cells on various sperm functions in vitro. DESIGN: Controlled experimental laboratory study. SETTING: University gynecology unit. PATIENT(S): Women undergoing tubal ligation or hysterectomy and men who were visiting our subfertility clinics. INTERVENTION(S): Coculture of oviductal cells with human spermatozoa in vitro; sperm functions were determined after coculture. MAIN OUTCOME MEASURE(S): Capacitation, acrosome reaction, zona binding, and oocyte fusion. RESULT(S): Oviductal cells and conditioned medium induced more spermatozoa to capacitate than did control medium. Although there was no difference in the spontaneous acrosome reaction between any of the groups, the coculture group had a lower percentage of acrosome-reacted spermatozoa after calcium ionophore challenge than did the control and conditioned medium groups. Coculture and conditioned medium treatment reduced the number of spermatozoa bound to the zona pellucida. The penetration rate and penetration index of the control spermatozoa in the zona-free hamster oocyte penetration test were significantly higher than that of the cocultured or conditioned medium-treated spermatozoa. CONCLUSION(S): Human oviductal cells promoted capacitation, stabilized the acrosome, and suppressed binding to the zona pellucida and fusion with the oocyte in vitro.     

The effectiveness of commonly used lifting assessment methods to identify industrial jobs associated with elevated risk of low-back disorders

Low-back disorders (LBD) continue to be the most costly and common musculoskeletal problem facing society today. Investigators have developed tools or measures that are intended to identify jobs that will probably be associated with an elevated risk of low-back disorders. However, an important and not widely discussed issue associated with these tools and procedures has been that of the validity or effectiveness of the tools. Therefore the objective of this study was to evaluate the validity and effectiveness of two commonly used types of LBD assessment methods in terms of their ability to correctly associate jobs with LBD risk. The 1981 NIOSH Work Practices Guide for Manual Lifting and the 1991 NIOSH revised lifting equation, along with psychophysical measures were assessed for their ability to correctly identify high-, medium-, and low-risk (of LBD) jobs. Risk was defined according to a database of 353 industrial jobs representing over 21 million person-hours of exposure. The results indicated that both NIOSH measures were predictive and resulted in odds ratios between 3.1 and 4.6. Higher odds ratios were found when the maximum horizontal distance was used to assess a job compared to the average horizontal distance. Further analyses indicated that the two NIOSH assessment methods classified risk in very different ways. The 1981 NIOSH Guide demonstrated good specificity (91%) in that it identified low-risk jobs well but it also displayed low sensitivity by only correctly identifying 10% of the high-risk jobs. The 1993 NIOSH revised lifting equation, on the other hand, had better sensitivity. It correctly identified 73% of the high-risk jobs but did not identify low- and medium-risk jobs well. Using psychophysical criteria it was observed that 60% of the high-risk jobs would be judged to be acceptable, whereas, 64% and 91% of the medium- and low-risk jobs, respectively, would be judged to be acceptable. This study indicates that the different measures have various strengths and weaknesses. When controlling for occupational LBD it should be recognized that a variety of measures exist and that the measure that most appropriately assesses risk depends upon the characteristics of the job.     

Assembly of T-antigen double hexamers on the simian virus 40 core origin requires only a subset of the available binding sites

Initiation of simian virus 40 (SV40) DNA replication is dependent upon the assembly of two T-antigen (T-ag) hexamers on the SV40 core origin. To further define the oligomerization mechanism, the pentanucleotide requirements for T-ag assembly were investigated. Here, we demonstrate that individual pentanucleotides support hexamer formation, while particular pairs of pentanucleotides suffice for the assembly of T-ag double hexamers. Related studies demonstrate that T-ag double hexamers formed on "active pairs" of pentanucleotides catalyze a set of previously described structural distortions within the core origin. For the four-pentanucleotide-containing wild-type SV40 core origin, footprinting experiments indicate that T-ag double hexamers prefer to bind to pentanucleotides 1 and 3. Collectively, these experiments demonstrate that only two of the four pentanucleotides in the core origin are necessary for T-ag assembly and the induction of structural changes in the core origin. Since all four pentanucleotides in the wild-type origin are necessary for extensive DNA unwinding, we concluded that the second pair of pentanucleotides is required at a step subsequent to the initial assembly process.     

Sinonasal anatomy

Nonfluent, Broca-type dysphasics are characterized by impaired syntactic processing. However, grammaticality judgements and certain on-line tasks have shown some preservation of this processing in such subjects. We report an experiment with nonfluent dysphasics in which they read aloud th-initial nonwords (e.g., thuz) in sentential contexts that predicted a function word or a content word. This paradigm was first used by Campbell and Besner (1981) to demonstrate syntactic effects on pronunciation: normal subjects pronounce word-initial th- as voiced in function word contexts and unvoiced in content word contexts, reflecting a regularity in the English lexicon. Poorer performance by the dysphasic subjects on this task is the default prediction of most "syntactic" accounts of agrammatism, including an account based on the impairment of functional projections, which we discuss. We replicate Campbell and Besner's effect in our normal control group and in the dysphasic group, with no significant difference between the two groups. We conclude that syntactic influences on pronunciation may be unimpaired in nonfluent dysphasia, and that the task used resembles the class of online tasks, in its capacity to elicit unimpaired processing. We argue that this result is compatible with the account of agrammatism discussed if the latter is grounded in a distributed, constraint-based processing device allowing graceful degradation of functioning.     

Variations in adductor spasmodic dysphonia: acoustic evidence

The development of a validated primate model of progressive parkinsonism is a critical step in the evaluation of drugs that might halt or slow progression of Parkinson's disease. In this pilot study, we gradually exposed 14 cynomolgus monkeys to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), at a weekly dose of 0.5 mg/kg s.c. for 10 weeks, to determine their probability of not reaching a predetermined endpoint on a disability scale by Kaplan-Meier analysis. Four other MPTP-exposed animals were coadministered the potent free radical scavenger 7-hydroxy-1-[4-(3-methoxyphenyl)-1-piperazinyl]acetylamino-2,2,4,6- tetramethylindan (OPC-14117) as a single oral daily dose of 0.6 g/kg, starting 2 weeks before MPTP initiation. The risk of reaching endpoint by week 10 was 79% and mean time before reaching endpoint was 6 weeks. Global motor activity, recorded in a subset of animals using a portable activity monitor, declined following the first MPTP dose and never recovered. Several cerebrospinal fluid indices of central monoamine metabolism collected by suboccipital puncture at 0, 5, and 10 weeks, including HVA, DOPAC, and tetrahydrobiopterin but not MHPG, were found to be "trait" markers for MPTP exposure, whereas CSF DOPAC and tetrahydrobiopterin constituted potential "state" markers for reaching endpoint. The antioxidant OPC-14117 did not protect against MPTP-induced parkinsonism. Further attempts to validate this incremental model of neurotoxin-induced parkinsonism as a predictor of patient responses to putative neuroprotective agents appear warranted.     

Suggested guidelines for rating cardiac disability in workers' compensation. Medical and Chiropractic Advisory Committee to the Administrative Director of the California Division of Industrial Accidents

Cardiac disability ratings in workers' compensation cases currently lack any consistent scientific basis, with varying medical evidence used by different examiners in the same case. Opinions about the extent of disability may differ with the same patient, delaying resolution and the delivery of benefits. We describe guidelines for determining cardiac impairment and suggest a schedule for rating disability based on evidence. Our experience is in California, but arriving at equitable ratings for disability purposes is a nationwide challenge. Exercise stress testing provides the best reproducible data to test the heart's ability to do work. When exercise stress testing is not possible or adequate, alternative or supplemental testing is necessary. Certain conditions, such as hypertension, arrhythmias, coronary artery spasm, and a history of coronary artery operations or myocardial infarction, may affect "cardiac disability" but may not necessarily be reflected in exercise testing.     

Determination of the 13C magnetic shielding tensor in partially oriented polymer systems

The role of TNF receptors (TNF-Rs) is not limited to signal transduction but includes extracellular regulatory functions affecting systemic TNF bioavailability. This review summarizes the regulation of TNF-R shedding and its kinetics, the complex interaction between the soluble receptors and their ligand in vitro and in vivo, and the potential diagnostic, prognostic and therapeutic value of the soluble receptors in malignant, inflammatory, infectious and autoimmune disorders.     

Tyrosylprotein sulfotransferase: purification and molecular cloning of an enzyme that catalyzes tyrosine O-sulfation, a common posttranslational modification of eukaryotic proteins

Tyrosine O-sulfation is a common posttranslational modification of proteins in all multicellular organisms. This reaction is mediated by a Golgi enzyme activity called tyrosylprotein sulfotransferase (TPST) that catalyzes the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate to tyrosine residues within acidic motifs of polypeptides. Tyrosine O-sulfation has been shown to be important in protein-protein interactions in several systems. For example, sulfation of tyrosine residues in the leukocyte adhesion molecule P-selectin glycoprotein ligand 1 (PSGL-1) is required for binding to P-selectin on activated endothelium. In this report we describe the purification of TPST from rat liver microsomes based on its affinity for the N-terminal 15 amino acids of PSGL-1. We have isolated human and mouse TPST cDNAs that predict type II transmembrane proteins of 370 amino acid residues with almost identical primary structure. The human cDNA encodes a fully functional N-glycosylated enzyme with an apparent molecular mass of approximately 54 kDa when expressed in mammalian cells. This enzyme defines a new class of Golgi sulfotransferases that may catalyze tyrosine O-sulfation of PSGL-1 and other protein substrates involved in diverse physiologic functions including inflammation and hemostasis.     

Glycoprotein 330, a member of the low density lipoprotein receptor family, binds lipoprotein lipase in vitro

Glycoprotein 330 (gp330), a cell-surface protein that is localized in clathrin-coated pits, is structurally related to both the low density lipoprotein receptor (LDLR) and the LDLR-related protein/alpha 2-macroglobulin receptor (LRP). We recently demonstrated that gp330 and LRP may be functionally related as well; both bind the 39-kDa polypeptide referred to as receptor-associated protein (Kounnas, M. Z., Argraves, W. S., and Strickland, D. K. (1992) J. Biol. Chem. 267, 21162-21166). In this report, we tested several other LRP ligands for their ability to interact with human and rat gp330 in vitro. Gp330 did not exhibit detectable binding to the LRP ligands, alpha 2-macroglobulin protease complex or Pseudomonas aeruginosa exotoxin A. However, we found that gp330 (purified from human or rat) bound the lipolytic enzyme lipoprotein lipase (LPL) with high affinity (Kd = 6.1 and 2.7 nM, respectively). The binding was saturable, divalent cation dependent, and inhibited by heparin or receptor-associated protein. Because LRP has also been shown to bind LPL, the present findings further extend the functional similarities between gp330 and LRP. By analogy to the postulated role of the LRP-LPL interaction in facilitating hepatic clearance of LPL-associated lipoproteins from the blood (Beisiegel, U., Weber, W., and Bengtsson-Olivercrona, G. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 8342-8346; Chappell, D. A., Fry, G. L., Waknitz, M. A., Iverius, P. H., Williams, S. E., and Strickland, D. K. (1992) J. Biol. Chem. 267, 25764-25767), we speculate that the gp330-LPL interaction described herein may contribute to the uptake of LPL-associated lipoproteins in tissues expressing gp330. Consistent with this possibility, we found that LPL promoted in vitro binding of 125I-lipoproteins to gp330.