The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics.

UNLABELLED: Fibroblast growth factor-inducible 14 (Fn14; TNFRSF12A) is the cell surface receptor for the tumor necrosis factor (TNF) family member TNF-like weak inducer of apoptosis (TWEAK). The Fn14 gene is normally expressed at low levels in healthy tissues but expression is significantly increased after tissue injury and in many solid tumor types, including glioblastoma (GB; formerly referred to as 'GB multiforme'). GB is the most common and aggressive primary malignant brain tumor and the current standard-of-care therapeutic regimen has a relatively small impact on patient survival, primarily because glioma cells have an inherent propensity to invade into normal brain parenchyma, which invariably leads to tumor recurrence and patient death. Despite major, concerted efforts to find new treatments, a new GB therapeutic that improves survival has not been introduced since 2005. In this review article, we summarize studies indicating that (i) Fn14 gene expression is low in normal brain tissue but is upregulated in advanced brain cancers and, in particular, in GB tumors exhibiting the mesenchymal molecular subtype; (ii) Fn14 expression can be detected in glioma cells residing in both the tumor core and invasive rim regions, with the maximal levels found in the invading glioma cells located within normal brain tissue; and (iii) TWEAK: Fn14 engagement as well as Fn14 overexpression can stimulate glioma cell migration, invasion and resistance to chemotherapeutic agents in vitro. We also discuss two new therapeutic platforms that are currently in development that leverage Fn14 overexpression in GB tumors as a way to deliver cytotoxic agents to the glioma cells remaining after surgical resection while sparing normal healthy brain cells.

An examination of the association of serum IGF-I concentration, potential candidate genes, and fiber type composition with variation in residual feed intake in progeny of Red Angus sires divergent for maintenance energy EPD.

Investigating the genetic and physiological drivers of postweaning residual feed intake (RFI) and finishing phase feed efficiency (FE) may identify underlying mechanisms that are responsible for the variation in these complex FE traits. The objectives were 1) to evaluate the relationship of serum IGF-I concentration and muscle gene expression with postweaning RFI and sire maintenance energy (MEM) EPD and 2) to determine fiber type composition as it relates to postweaning RFI and finishing phase FE. Results indicate that RFI and serum IGF-I concentration were not associated (P > 0.05); however, negative correlations (P < 0.05) between sire MEM EPD and serum IGF-I concentration were observed. Gene expression differences between high- and low-RFI animals were observed in cohort 1, where IGFBP5 expression was greater (P < 0.05) in high-RFI animals. When animals were grouped according to sire MEM EPD, the low MEM EPD group of cohort 1 showed greater muscle mRNA expression (P < 0.01) of fatty acid synthase (FASN) and marginally (P < 0.10) greater expression of IGFBP5 and C/EBP alpha (C/EBPα) whereas the high MEM EPD group of cohort 2 had greater muscle mRNA expression of IGFBP2 (P < 0.05) and C/EBPα (P ≤ 0.01) and marginally (P < 0.10) greater expression of IGFBP3. Biopsy tissue samples collected at harvest revealed that the percentage of type IIa fibers was lower (P ≤ 0.05) in high-RFI steers, with a similar trend (P < 0.10) being observed in high finishing phase FE steers. The percentage of type IIb fibers was higher (P < 0.05) in high-RFI (and finishing phase FE) steers than in low-RFI (and finishing phase FE) steers. There was a marginal, negative correlation between RFI and type I (r = -0.36, P = 0.08) and IIa (r = -0.37, P = 0.07) fiber percentages and a positive correlation (r = 0.48, P = 0.01) between RFI and type IIb fiber percentage whereas finishing phase FE was negatively correlated (r = -0.43, P = 0.03) with type I fiber percentage and positively correlated (r = 0.44, P = 0.03) with type IIb fiber percentage. Therefore, our data indicate that 1) serum IGF-I (collected at weaning) is not an indicator of postweaning RFI, 2) the GH-IGF axis appears to have some involvement with RFI at the molecular level; however, muscle gene expression results were not consistent across cohorts, and 3) low-RFI animals may have the ability to more efficiently maintain and accrete muscle mass due to their fiber type composition, specifically a greater proportion of type I fibers.

Development of the Thai breast cancer belief scale for Thai immigrants in the United States.

Asian American women have not benefited from the decline in breast cancer mortality and have lower rates of mammography use. Understanding mammography behaviors among these Asian American women requires culturally specific measures. Champion's belief scale was translated into Thai and cultural items were added. The Thai breast cancer belief scale (TBCBS), the Suinn-Lew self-identification acculturation, and the Asian values scale-revised were administered to 250 Thai immigrants. The TBCBS was tested for face validity, construct validity, and internal consistency. Factor analysis reflected the 4 constructs of the health belief model and accounted for 45.8% of the variance. Cronbach's alpha ranged from .77 to .90. Modest correlations were observed between TBCBS subscales and acculturation scales. Results indicate that the TBCBS measures breast cancer beliefs among Thai immigrant population.

Effect of preslaughter feeding and ractopamine hydrochloride supplementation on growth performance, carcass characteristics, and end product quality in market dairy cows.

An experiment was conducted in market dairy cows to determine the effect of feeding time and ractopamine hydrochloride (RAC) on growth performance, carcass characteristics, and end product quality. In 3 replicates, 9 Holstein cows per replicate (n = 27; 659 +/- 25.3 kg initial BW) culled from 3 dairies were randomly assigned to 3 treatments: 1) slaughter immediately (control), 2) feed for 90 d (NoR), or 3) feed for 90 d with RAC (312 mg.cow(-1).d(-1)) for the final 32 d (RAC). On d 0, NoR and RAC cows were placed in individual pens and fed a high concentrate diet (86% concentrate, DM basis) for 90 d before slaughter. All cows were subjectively scored for BCS and locomotion score on d 0, and NoR and RAC cows were evaluated again after 90 d. Individual DMI was recorded daily throughout the trial, and BW was collected every 14 d. Age and age x treatment did not affect (P > 0.05) any of the traits evaluated in this study. When cows fed for 90 d (NoR and RAC combined) were compared with nonfed controls, fed cows had greater (P < 0.001) final BCS, BW and HCW, lower (P < 0.001) final locomotion score, and greater (P < 0.03) dressing percentage, external fat thickness, and marbling score. Fed cows also tended to have more desirable yield grade (P = 0.08), ribeye area (P = 0.11), fat color (P = 0.09), lean maturity (P = 0.06), and quality grade (P = 0.09) compared with control cows. Warner-Bratzler shear force was not affected (P = 0.23) by feeding. However, a 12-member trained sensory panel revealed that fed cow carcasses had more desirable (P < 0.04) tenderness, juiciness, and overall acceptability than control cow carcasses. Flavor intensity also tended (P = 0.10) to be more desirable for fed vs. control cows. No difference (P > 0.10) in off-flavor was detected among treatments. Finally, there was no effect (P > 0.10) of RAC on growth performance, carcass characteristics, or end product quality. In conclusion, feeding a high concentrate diet for 90 d improved important live animal, carcass, and end product characteristics related to the quality and palatability of beef from market dairy cows; however, no effect of RAC supplementation was observed.

Higher-quality human sperm in a sample selectively attach to oviduct (fallopian tube) epithelial cells in vitro.

OBJECTIVE: To determine if sperm attachment to oviduct epithelial cells (OEC) in vitro is selective for higher quality sperm and if the system requires homologous species OEC. DESIGN: Controlled prospective study with outcomes assayed by a technician blind to sperm treatment groups. SETTING: An academic research laboratory. PATIENT(S): Experiment 1: normospermic donors with children (4 donors, 7 ejaculates). Experiment 2: cryopreserved donor samples (4 donors). INTERVENTION(S): Semen collection by masturbation after 48 hours of abstinence. MAIN OUTCOME MEASURE(S): Experiment 1: sperm assays of motility, morphology, membrane integrity, and capacitation status. Experiment 2: sperm chromatin (DNA) integrity and condensation. RESULT(S): Experiment 1: sperm not attaching to OEC had lower motility, more membrane disruptions, and more acrosome reactions than did control sperm. This selectivity was equivalent for sperm in coculture with all OEC types. Experiment 2: sperm attached to OEC had fewer abnormalities in chromatin structure compared with sperm that were not attached. CONCLUSION(S): Selective attachment of functionally superior sperm to OEC is likely important during sperm reservoir formation in vivo and may be exploitable in vitro as a method to isolate high-quality sperm for clinical procedures. Such a system does not require human origin OEC.

Relationship between bull field fertility and in vitro embryo production using sperm preparation methods with and without somatic cell co-culture.

Experiments were designed to compare rates of embryonic development following oocyte exposure to cryopreserved spermatozoa from bulls of varying proven fertility, utilizing 3 different sperm preparation methods prior to oocyte introduction. These included 1) sperm co-culture with bovine oviductal epithelial cells (BOEC); 2) sperm co-culture with buffalo rat liver cells (BRLC); or 3) control culture in a routine, cell-free culture system. Semen from 9 bulls was classified by lifetime 60- to 90-d nonreturn rates as having either (mean +/- SEM) high (n=3) 73.2 +/- 3a, medium (n=3) 70.3 +/- 2b or low (n=3) 65.8 +/- 3c field fertility ((ac)p< 0.01; (bc)p< 0.05). There was no difference in embryo cleavage rates for spermatozoa from the high (58 +/- 18%), medium (57 +/-23%) or low (57 +/- 18%) fertility groups. Development to morula or beyond of oocytes fertilized with high (53 +/- 30%) or low (58 +/- 27%) fertility semen tended (P<0.10) to be higher than of those fertilized with medium fertility (33 +/- 28%) semen. This lack of relationship between in vivo fertility and in vitro embryo outcome was consistent across all sperm preparation methods. Therefore, pooled data were used to evaluate the effect of sperm preparation on embryo outcome. There was no difference in embryo cleavage rates between BOEC monolayers (51 +/- 22%), BRLC monolayers (60 +/- 20%) and the cell-free controls (60 +/- 17%). Subsequent embryonic development to compact morula and beyond was higher (P<0.01) with the BRLC monolayer treatment (61 +/- 28%) than with the BOEC monolayers (42 +/- 33%) or control culture (39 +/- 24%). In conclusion, these studies suggest that there is no predictive relationship between bull field fertility (in the ranges evaluated here) and in vitro embryo cleavage or development rates. However, oocytes inseminated with sperm cells co-cultured on BRLC monolayers develop to the morula stage or beyond at a higher rate than oocytes inseminated with spermatozoa from the BOEC or cell-free system.

Human sperm function in co-culture with human, macaque or bovine oviduct epithelial cell monolayers.

Human sperm function was compared in co-culture with monolayers of oviduct epithelial cells (OEC) from three species, human, macaque and bovine. For all species, freeze-thawed and passaged OEC from females in the periovulatory phase were used. OEC cultured on an extracellular matrix (Matrigel) formed a monolayer which supported human sperm attachment to OEC from all three species. Spermatozoa in co-culture with OEC from all three species showed prolonged survival and improved motility characteristics over those cultured in medium alone. This paper describes an efficient, repeatable co-culture system for human spermatozoa which supports sperm attachment to OEC and subsequently improves sperm function over that seen in control medium cultures. Because the improved sperm function in co-culture did not differ significantly between human and bovine OEC for those attributes studied, it is proposed that bovine OEC could be used as an alternative to human OEC in certain human sperm coculture studies. Follicular phase bovine OEC from reproductively normal donors are far more accessible than their human counterparts, thus making this co-culture system more widely available for the study of human spermatozoa-female tract interactions.

Dopamine autoreceptor agonists: resolution and pharmacological activity of 2,6-diaminotetrahydrobenzothiazole and an aminothiazole analogue of apomorphine.

The enantiomers of the aminothiazole analogues of the known dopaminergic agonists apomorphine (1) and 2-aminohydroxytetralin (2) have been prepared. The absolute configurations of the enantiomers of 2,6-diaminotetrahydrobenzothiazole have been established by X-ray crystallographic analysis. Dopamine (DA) autoreceptor agonist activities of the compounds were evaluated. Testing revealed (-)-5, the S enantiomer, to be the most active compound tested (inhibition of GBL accelerated dopamine synthesis and inhibition of alpha-methyltyrosine-induced decline of DA). In addition (-)-5 does not exhibit stereotyped behavior, suggesting a pronounced selectivity for DA autoreceptors.

Synthesis and antidepressant activity of 4-aryltetrahydrothieno[2,3-c]pyridine derivatives.

A series of substituted 4-aryltetrahydrothieno[2,3-c]pyridines was prepared by acid-catalyzed cyclization of 1-aryl-2-[(2-thienylmethyl)amino]ethanol derivatives. The compounds were examined for their antidepressant activity, as demonstrated by their ability to inhibit the uptake of norepinephrine (NE) and serotonin (5-HT) and to prevent tetrabenazine-induced ptosis (TBZ) in mice. Significant inhibition of both neurotransmitters is observed for several of the tested compounds, while some of them are selective inhibitors of either NE or 5-HT uptake. Optimal activity is associated with the introduction of lipophilic substituents into the 4-position of the phenyl ring and less lipophilic substituents into the 2-position of the thiophene ring (11, 23). Compound 33 bearing substituents in positions 2 and 6 of the phenyl ring is inactive. This might be a consequence of an out of plane conformation of this compound.

Radiographic findings in commercial divers.

The primary method of detecting and recording the changes of dysbaric osteonecrosis is bone and joint radiographic survey. This is not the routine medical and orthopedic roentgen technique, but is a special purpose examination with special technical requirements. The findings indicate selective sites of damage and each should have meticulous study. Fine detail and heavily penetrated radiographs produce needed bony, especially trabecular, and detail and allow the film reviewers to exlude simulating lesions. The incidence of osteonecrosis in American commercial divers has been found to be quite low and considerably less than in other types of compressed gas workers and shell divers. The major radiographic observation is an area of sclerosis, but other changes occur. Juxta-articular lesions can lead to joint damage and are, therefore, potentially disabling. The immediate significance of a lesion in the shaft of a long bone is in its value as a basis for disqualification of an individual for further work in dysbaric environments.