Adalimumab for nail psoriasis: efficacy and safety over 52 weeks from a phase-3, randomized, placebo-controlled trial.

BACKGROUND: Few clinical trials have evaluated long-term treatment of nail psoriasis with biologics. OBJECTIVE: Safety and efficacy of adalimumab [ADA; Humira AbbVie Inc, North Chicago, IL, USA)] long-term treatment (52 weeks) was evaluated in a phase-3, randomized trial in patients with moderate-to-severe plaque psoriasis and concomitant moderate-to-severe fingernail psoriasis. Results from the first 26 weeks (Period A) have been reported. METHODS: Patients receiving 40 mg ADA every other week or placebo in Period A, continued with or switched to 40 mg ADA every-other-week treatment in the subsequent 26-week open-label extension (OLE) period. Main efficacy evaluations were ≥75% improvement in total-fingernail modified Nail Psoriasis Severity Index (mNAPSI 75) and achievement of Physician's Global Assessment for Fingernail Psoriasis of clear or minimal disease (PGA-F 0/1) with a ≥2-grade improvement from baseline, across the trial for patients who continued ADA from Period A through the OLE (Continuous-ADA Population). Safety was evaluated during the OLE and for patients receiving ADA at any time during the study (All-ADA Population). RESULTS: Of the 217 patients initially randomized in Period A, 188 (86.6%; 94 in each treatment group) entered the OLE after completion of or early escape from Period A. For the Continuous-ADA Population (N = 109), endpoint achievement rates improved from OLE entry (Week 26) to Week 52, including total-fingernail mNAPSI 75 (47.4-54.5%); PGA-F 0/1 (51.1-55.6%) and total-fingernail mNAPSI = 0 (6.6-17.9%). Serious adverse event and serious infection rates for the All-ADA Population (N = 203) were 6.9% and 3.4%, respectively. CONCLUSIONS: In this population of psoriasis patients with concomitant, moderate-to-severe nail psoriasis, long-term efficacy and improvement in signs and symptoms of nail disease were demonstrated after every-other-week ADA treatment, including incremental improvements in rate of total clearance of nail disease. No new safety risks were identified for patients receiving at least one ADA dose across 52 weeks.

Efficacy, safety and tolerability of topical terbinafine nail solution in patients with mild-to-moderate toenail onychomycosis: results from three randomized studies using double-blind vehicle-controlled and open-label active-controlled designs.

BACKGROUND: Terbinafine nail solution (TNS) was developed for the treatment of onychomycosis. OBJECTIVE: To assess the efficacy of TNS vs. vehicle and amorolfine 5% nail lacquer. METHODS: Subjects with mild-to-moderate toe onychomycosis (25% to ≤75% nail-involvement, matrix uninvolved) were randomized to receive either TNS or vehicle in two double-blind studies, and to TNS or amorolfine in an active-controlled, open-label study. Primary endpoint was complete cure (no residual clinical involvement and negative mycology) at week 52. Secondary endpoints were mycological cure (negative mycology defined as negative KOH microscopy and negative culture) and clinical effectiveness (≤10% residual-involvement and negative mycology) at week 52. RESULTS: Complete cure was not different between TNS vs. vehicle and amorolfine. Mycological cure was higher with TNS vs. vehicle, as was clinical effectiveness with TNS vs. vehicle, and TNS and amorolfine were not different for secondary efficacy endpoints. Patients achieving mycological cure had a better clinical outcome, and efficacy was improved in subjects with milder disease. Post hoc analysis suggests that nail thickness is an important prognostic factor. Moreover, mycological cure may require 6 months of treatment regimen while complete cure and clinical effectiveness may be achievable only after 10 months. A simulation study suggests that longer treatment duration would have resulted in higher complete cure with TNS vs. vehicle. Study treatments were well-tolerated. CONCLUSION: Primary efficacy objectives were not met in the studies reported herein. Possible reasons for failure to achieve significant outcomes include insufficient length of treatment; stringency of primary endpoint and severity of nail involvement of study population.

The chromatographic co-elution of dihydrodehydrodiconiferyl alcohol monopyranose with eleutheroside E in Eleutherococcus senticosus: implications for eleutheroside E assays.

During a quantification assay of the constituents of Eleutherococcus senticosus by reverse-phase HPLC using acetonitrile:water gradient elution, it was observed that a recently reported component, dihydrodehydrodiconiferyl alcohol monopyranose, co-eluted with eleutheroside E. The implications of this finding for researchers and the herbal medicine industry are discussed. C

Panax ginseng and Eleutherococcus senticosus may exaggerate an already existing biphasic response to stress via inhibition of enzymes which limit the binding of stress hormones to their receptors.

A mechanism of action for Panax ginseng (PG) and Eleutherococcus senticosus (ES) is proposed which explains how they could produce the paradoxical effect of sometimes increasing and sometimes decreasing the stress response. The mechanism suggests that this biphasic effect results from increased occupancy of positive and negative feedback stress hormone receptors by their natural ligands due to inhibition of specific enzymes which function to limit receptor occupancy. Specifically, it is suggested that PG inhibits 11-beta hydroxysteroid dehydrogenase one and ES inhibits catechol- O -methyl transferase, both of which reside in close proximity to stress hormone receptors and catalyse the degradation of stress hormones into inactive compounds. In addition, it is suggested that the increased energy said to result from PG and ES may be a consequence of their increasing the occupancy of stress hormone receptors which function to redistribute the body's energy reserves from regeneration to activity.

Tissue distribution and timing of appearance of polytropic envelope recombinants during infection with SL3-3 murine leukemia virus or its weakly pathogenic SL3DeltaMyb5 mutant.

A time course analysis was performed to identify the sites of formation and timing of appearance of polytropic recombinant viruses following infection of NIH/Swiss mice with the murine retrovirus SL3-3 murine leukemia virus (SL3) or with a weakly pathogenic mutant termed SL3DeltaMyb5. The results indicated that (i) polytropic recombinant viruses occur initially in the thymus of SL3-infected animals, (ii) the timing of appearance of polytropic recombinants in bone marrow is not consistent with their participation in the previously reported formation of transplantable tumor-forming cells at 3 to 4 week postinoculation, and (iii) the efficient generation of recombinant virus is correlated with efficient tumor induction.

The effects of Eleutherococcus senticosus and Panax ginseng on steroidal hormone indices of stress and lymphocyte subset numbers in endurance athletes.

A clinical trial was undertaken to investigate the effects of Eleutherococcus senticosus (ES) and Panax ginseng (PG) on competitive club-level endurance athletes engaged in their normal in-season training. Participants were matched for training stress and received a 33% ethanolic extract (8 mL/day) containing either ES, PG (equivalent to 4 g and 2 g/day of dried root, respectively), or a placebo. A pre-test and post-test were used to evaluate the effects of six weeks of supplementation on cortisol, testosterone, and testosterone to cortisol ratio (TCR) as well as circulating numbers of total T-cells, T-helper cells (CD4), T-suppressor cells (CD8), CD4 to CD8 ratio, natural killer cells, and B lymphocytes. None of the immune system variables changed significantly nor showed any clear trend from pre to post test in any of the treatment groups. No significant change in testosterone, cortisol or TCR was observed in the PG group. In the ES group, however, TCR decreased by 28.7% from 0.0464 to 0.0331 (P=0.03). The main contribution to this decrease appeared to be a non-significant (P= 0.07) 31% trend towards increased cortisol rather than a very small non-significant (P = 0.36) 7% decrease in the calculated mean for testosterone. This result suggested that contrary to initial expectation, ES increased rather than decreased hormonal indices of stress, which may be consistent with animal research suggesting a threshold of stress below which ES increases the stress response and above which ES decreases the stress response.

Short stature in competitive prepubertal and early pubertal male gymnasts: the result of selection bias or intense training?

OBJECTIVES: To determine whether high-volume, high-impact physical training in prepubertal and early pubertal male gymnasts is associated with reduced statural and segmental growth and reduced serum insulin-like growth factor-I (IGF-I) and increased cortisol (C) levels. STUDY DESIGN: Height, sitting height, leg length, and segmental lengths (humerus, radius, femur, and tibia) and breadths (biacromial and bi-iliac), diet, serum IGF-I, testosterone, and C were measured in competitive male gymnasts and normoactive children (Tanner stage < or = 2) every 3 to 4 months over an 18-month period. RESULTS: At baseline, gymnasts (n = 31) were 0.7 years older than members of the control group (P <.05, n = 50) but were no different in terms of biologic maturity. Age-adjusted z scores showed that the gymnasts were shorter than members of the control group (-0.5 +/- 0.2 SD, P <.05) because of reduced leg length (-0.8 +/- 0.2 SD, P <.001) but not sitting height. Segmental lengths and bi-iliac breadth age-adjusted z scores were also reduced in the gymnasts (P ranging <.05 to <.001). No difference was detected for serum IGF-I or C. After 18 months of follow-up, no differences were found for rates of change in height, sitting height or leg length, segmental lengths, IGF-I, or C between those gymnasts and control subjects who remained prepubertal and early pubertal (gymnasts n = 18; control group n = 35). However, the magnitudes of baseline differences in anthropometric measures (z scores) persisted throughout the study. CONCLUSION: Short stature in these competitive male gymnasts was due to a reduced leg length but not sitting height. The lack of a difference in growth rates, IGF-I, and diet over the 18-month period indicates that the short stature reported in male gymnasts is due to selection bias rather than gymnastics training.

L-Carnitine supplementation combined with aerobic training does not promote weight loss in moderately obese women.

L-Carnitine (L-C) transports fatty acids into mitochondria for oxidation and is marketed as a weight loss supplement. In a double-blind investigation to test the weight loss efficacy of L-C, 36 moderately overweight premenopausal women were pair matched on Body Mass Index (BMI) and randomly assigned to two groups (N = 18). For 8 weeks the L-C group ingested 2 g twice daily of L-C, while the placebo (P) group ingested the same amount of lactose. All subjects walked for 30 min (60-70% maximum heart rate) 4 days/week. Body composition, resting energy expenditure (REE) and substrate utilization were estimated before and after treatment. For the subjects who completed the study (15 P, 13 L-C), no significant changes in mean total body mass (TBM), fat mass FM, and resting lipid utilization occurred over time, nor were there any significant differences between groups for any variable. Conversely REE increased significantly for all subjects, but no between group differences existed. Five of the L-C group experienced nausea or diarrhea and consequently did not complete the study. Eight weeks of L-C ingestion and walking did not significantly alter the TBM or FM of overweight women, thereby casting doubt on the efficacy of L-C supplementation for weight loss.

The FeLV-945 LTR confers a replicative advantage dependent on the presence of a tandem triplication.

Feline leukemia virus (FeLV), like other naturally occurring retroviruses, is characterized by a high degree of genetic diversity. FeLV-945 is a natural isolate derived from non-B-cell non-T-cell lymphomas classified anatomically as multicentric. FeLV-945 exhibits a unique structural motif in the LTR composed of a 21-bp tandem triplication downstream of a single copy of enhancer. The unique FeLV-945 LTR is precisely conserved among eight independent multicentric lymphomas collected in a geographic cluster. Previous studies using reporter gene constructs predict that the FeLV-945 LTR would confer a replicative advantage on the virus that contains it, particularly in primitive hematopoietic cells. Such an advantage may account for the precise conservation of the unique LTR sequence. To test that prediction, a set of recombinant, infectious FeLVs was developed that are isogenic other than the presence of the FeLV-945 LTR or mutations of it. Replication assays show that the FeLV-945 LTR confers a distinct growth advantage in K-562, FEA, and 3201 cells and implicate the 21-bp triplication in that function. Replacement of two copies of the triplicated element with random sequence greatly diminished the replicative capacity, thus implicating the triplicated sequence itself in LTR function. The 21-bp triplication was shown to contain specific nuclear protein binding sites, which may account for the selective pressure to conserve the sequence.

Effects of high-impact exercise on ultrasonic and biochemical indices of skeletal status: A prospective study in young male gymnasts.

Physical activity has been proposed as one strategy to enhance bone mineral acquisition during growth. The aim of this study was to determine whether frequent impact loading associated with gymnastics training confers a skeletal benefit on pre- and peripubertal male gymnasts. We measured broadband ultrasonic attenuation (BUA, dB/MHz) at the calcaneus (CBUA); ultrasound velocity (m/s) at the calcaneus (CVOS), distal radius (RVOS) and phalanx (PVOS); serum osteocalcin (OC); total alkaline phosphatase (ALP) and insulin-like growth factor-I (IGF-I) every 3-4 months over an 18-month period in elite male gymnasts and matched normoactive controls (pubertal stage

Relationships between static histomorphometry and ultrasound in the human calcaneus.

The aim of this study was to explore the relationship(s) between histomorphometric measurements of cancellous bone structure and ultrasound. Ultrasonic measurements were made using a CUBA research system consisting of a pair of 1 Mhz unfocused transducers. Speed of sound (SOS) and broadband ultrasonic attenuation (BUA) were determined in 15 human cadaveric heels, with mean precision for all measurements coefficients of variation (CV) = 0.6% and 12%, respectively. The calcaneus was dissected and a 7.5 mm transcortical cylinder was removed from the path of ultrasound (US) transmission. The cortices were removed and the remaining cancellous core was sectioned into approximately 5 mm blocks, numbered from 1 to 6 (medial-lateral). Histomorphometric measurements were performed on decalcified, 5 microm-thick sections from blocks 1-6 using an automatic color image analysis system. There were significant differences between blocks 1 and 3-6 for BS/TV, BV/TV, Tb.N, and Tb. Sp (all P < 0.001), all decreasing in a medial-lateral direction (except Tb.Sp), implying that the medial portion of the calcaneus had more trabeculae with less spacing between them than the lateral portion. Furthermore, Tb.Th and BS/BV variables were uniform across the calcaneus, suggesting that individual trabeculae were of similar dimension. We found no significant correlations between US and histomorphometric parameters either averaged over all blocks or by using each block region separately. In conclusion, this study does not support the notion that US measurements of SOS and BUA through the heel reflect calcaneal cancellous bone structure, however, further studies using larger sample sizes may be warranted.

Tumorigenic potential of a recombinant retrovirus containing sequences from Moloney murine leukemia virus and feline leukemia virus.

A recombinant retrovirus, termed MoFe2-MuLV, was constructed in which the U3 region of T-lymphomagenic Moloney murine leukemia virus (Mo-MuLV) was replaced by that of FeLV-945, a provirus of unique long terminal repeat (LTR) structure identified only in non-T-cell, non-B-cell lymphomas of the domestic cat. The LTR of FeLV-945 is unusual in that it contains only a single copy of the transcriptional enhancer followed 25 bp downstream by a 21-bp sequence in triplicate in tandem. Infectivity of MoFe2-MuLV was demonstrated in vitro in SC-1 cells and in vivo in neonatal NIH-Swiss mice. Tumors occurred in MoFe2-MuLV-infected animals following a latency period of 4 to 10 months (average, 6 months). The results of Southern blot analysis of the T-cell receptor beta locus demonstrated that all tumors were lymphomas of T-cell origin. MoFe2-MuLV LTRs were amplified by PCR from tumor DNA and were characterized by nucleotide sequence analysis. LTRs from the tumors that occurred with relatively shorter latency predominantly retained the original MoFe2-MuLV sequence intact and unaltered. Tumors that occurred with relatively longer latency contained LTRs that also retained the 21-bp sequence triplication characteristic of the original virus but had acquired various duplications of enhancer sequences. The repeated identification of enhancer duplications in late-appearing tumors suggests that the duplication affords a selective advantage, although apparently not in the efficient induction of T-cell lymphoma. Proto-oncogenes known to be targets of insertional mutagenesis in the majority of Mo-MuLV-induced tumors or in feline non-T-cell, non-B-cell lymphomas were shown not to be rearranged in any tumor examined. Mink cell focus-inducing (MCF) proviral DNA was readily detectable in some, but not all, tumors. The presence or absence of MCF did not correlate with the kinetics of tumor induction. These studies indicate that the single-enhancer, triplication-containing FeLV LTR, typical of non-T-cell, non-B-cell lymphomas in cats, is competent in the induction of T-cell lymphoma in mice. The findings suggest that the mechanism of MoFe2-MuLV-mediated lymphomagenesis may differ from that of Mo-MuLV-mediated disease, considering the possible involvement of novel oncogenes and the variable presence of MCF recombinants.

Hormonal responses to physical training in high-level peripubertal male gymnasts.

The effects of performing intensive training during growth remains controversial, with claims of negative effects upon growth and maturation purportedly due at least in part to a combination of hormonal disturbances and inappropriate nutrition. We examined the training-related responses of total testosterone (T), insulin-like growth factor-1 (IGF-1), cortisol (C) and diet in 16 peripubertal (pubertal stage <2) male gymnasts [mean (SD) age 10.5 (0.9) years, training 17.2 (5.6) h x week(-1)] and 17 controls [mean (SD) age 9.6 (1.2) years] over a 10-month period. Fasted, resting morning blood samples (0730-0900 hours) were taken from all children on Monday, Wednesday and Friday during a single week towards the end of each of three phases of gymnastics training: routine development (RD), precompetition (PC) and strength conditioning (SC). Serum concentrations of T, C and IGF-1 did not differ between the groups at any time. The ratio between IGF-1 and cortisol was significantly reduced in gymnasts relative to controls during RD and SC training (P<0.05), although no differences were detected for the T:C ratio. Diet did not correlate with any of the hormonal measurements, and no intergroup differences were found for the rate of growth in height. In summary, these results suggest that either the gymnastics training performed by these subjects was not intense enough to alter adrenal function, or that the gymnasts were well adapted to the training. In contrast, the reduction in the anabolic to catabolic balance represented by the IGF-1:C ratio is suggestive of a catabolic state, perhaps resulting from overstrain, insufficient recovery and/or inadequate caloric intake relative to energy output. While physical training during growth may induce a catabolic state, further research is needed to determine the biological significance of this finding, particularly with regard to growth and maturation.

Water bath and contact methods in ultrasonic evaluation of bone.

Ultrasonic devices for the measurement of speed of sound (SOS) and broadband ultrasonic attenuation (BUA) generally use either a contact or water bath method. The aim of this study was to compare these two methods while determining the influence of soft tissue, pathlength (heel width and bone width), and a fixed heel dimension on SOS (m/second) and BUA (dB/MHz). Ultrasonic measurements were made using a CUBA Research system utilizing a pair of 1 MHz unfocused transducers with mean precision CV = 0.7% and 6.0% for all SOS and BUA measurements, respectively. SOS and BUA were determined in 24 human cadaveric heels under three conditions: contact method (heel intact), water bath method (heel intact), water bath method (no soft tissue). Although there were significant differences between measurements using contact and water bath techniques (heel intact), their correlations were high (r = 0.858 for SOS and r = 0. 937 for BUA; P < 0.001). After removal of soft tissue, SOS significantly increased (78 m/second; P < 0.001) whereas there was no change in BUA (P > 0.05). Heel width correlated with SOS measurements (-0.224 < r < -0.347; P < 0.001) and bone width correlated with BUA measurements (0.198 < r < 0.276; P < 0.001). The practice of using a fixed heel dimension (Lunar Achilles) was investigated by comparing SOS calculated with measured heel thickness and a value of 4 cm (Lunar Achilles). SOS increased by 42 m/second (2.7%) using the fixed heel dimension compared with measured heel widths. This study demonstrates the similarity between contact and water bath-based methods, while showing that the presence of soft tissue reduces SOS but has no effect on BUA. The use of a fixed heel dimension for calculation of SOS overestimates values obtained when using measured heel dimensions, though the values correlate highly (r = 0.98, P < 0.001). In addition, an increase in heel width tends to cause an underestimation of SOS whereas an increase in bone width tends to overestimate BUA, although the effects are relatively small.

Influence of high impact loading on ultrasound bone measurements in children: a cross-sectional report.

Evidence suggests that weight-bearing exercise during the growing years may enhance peak bone mass. The purpose of this study was to compare ultrasound bone measurements, serum alkaline phosphatase (S-ALP), serum osteocalcin (S-OC), and dietary calcium in highly active and normal healthy male children. Subjects were 33 elite and subelite male gymnasts and 40 normoactive controls matched for age (9.4 +/- 1.1 years), height (133.9 +/- 5.9 cm), and weight (30.1 +/- 3.8 kg). Measurements of broadband ultrasound attenuation (dB/MHz) through the calcaneus (CBUA) and ultrasound velocity (m/s) through the calcaneus (CVOS), distal radius (RVOS), and proximal phalanx of the index finger (PVOS) were performed using a Contact Ultrasonic Bone Analyzer (CUBA Research). Gymnasts had significantly greater CVOS (P < 0.001), RVOS (P < 0.0001), and PVOS (P < 0.05). There were no differences in CBUA, S-ALP, or S-OC between groups. RVOS correlated significantly with dietary calcium intake in all subjects (P < 0.05) and training time in the gymnasts (P < 0.05). Though gymnasts had significantly greater calcium intakes than controls (P < 0.05), whose mean value was below the RDA, after controlling for calcium intake in the gymnasts alone, RVOS was still significantly correlated with training time (P < 0.05). These preliminary results suggest that the heavy musculoskeletal loading inherent in gymnastics training produces positive adaptive responses in the growing skeleton. Furthermore, ultrasound appears to provide a safe, noninvasive means of comparing the skeletal status of exercising and normal healthy children, whereas single samples of biochemical markers did not discriminate between the groups.

Cooperating events in lymphomagenesis mediated by feline leukemia virus.

Feline leukemia virus (FeLV)-mediated lymphomagenesis in the domestic cat has been examined as a model of lymphoid malignancy in a naturally outbreeding population. The pathogenesis of two distinct, naturally occurring types of FeLV-induced tumors has been investigated: (1) a thymic lymphoma of T-cell origin, typical of FeLV-induced lymphoma, and (2) an extrathymic, extranodal lymphoma of non-B non-T-cell origin. The genetic features of these tumors are clearly distinguishable, and include determinants encoded both by the virus and the host. Virally encoded determinants of pathogenesis include the long terminal repeat (LTR) and the envelope SU protein. Cellular determinants include the involvement of a set of proto-oncogenes, and other factors characteristic of the specific cell type of origin of the tumor. Functional studies are aimed at evaluating the action and interaction of these genetic determinants in the pathogenesis of lymphoma in an animal model system.

Effect of suxamethonium on the auditory evoked response in humans.

We have studied the arousal effect of suxamethonium on the auditory evoked response (AER) of the electroencephalogram (EEG) in 40 ASA I and II patients during isoflurane anaesthesia. After induction of anaesthesia, the patient's lungs were ventilated for 20 min with 0.6 MAC end-expiratory isoflurane (0.59-0.77% depending on the age of the patient), and 50% nitrous oxide in oxygen. The patients were then allocated randomly to one of two groups: 21 received suxamethonium 1 mg kg-1, while 19 were given saline. The AER before and after administration of suxamethonium or saline was compared to determine the changes in Pa and Nb amplitudes and latencies. Pa amplitude after suxamethonium increased by 53% (95% confidence interval (CI) 15, 104%) compared with a reduction in Pa amplitude in the saline group of 19% (95% CI, -41, 12%) (P = 0.004) suggesting an arousal effect. Similarly, Nb amplitude increased in the suxamethonium group by 47% (95% CI, 3, 110%) and decreased in the saline group by 11% (95% CI, -33, 19%) (P = 0.03). We conclude that suxamethonium caused arousal according to the AER and postulate that this may have been caused by increased muscle afferent activity after stimulation of muscle spindles, although further studies are required to confirm this.

Genetic determinants of feline leukemia virus-induced multicentric lymphomas.

Three discrete forms of feline leukemia virus (FeLV)-associated lymphoma have been described clinically: (1) thymic, (2) alimentary, and (3) multicentric. The most common and best-characterized lymphomas are of T-cell origin, generally occurring in the thymus. These tumors typically contain mature T-cells, involve the activation of a distinctive set of proto-oncogenes, and contain FeLV proviruses whose long terminal repeat (LTR) sequences contain tandemly repeated enhancers. Previous studies of a small group of extrathymic, multicentric lymphomas implicated a different set of genetic determinants. The present study expands those observations by examining the lineage of origin, the involvement of proto-oncogenes, and the structure of LTR and env gene sequences in a set of 11 natural, extrathymic lymphomas of the multicentric type. A pattern of genetic events associated with FeLV-positive multicentric lymphomas emerges from this analysis that is clearly distinct from the pattern associated with thymic lymphomas. The tumors do not contain T-cells or B-cells, as evidenced by the germ line organization of TCR beta and IgH loci. Proto-oncogenes strongly implicated in T-cell lymphomagenesis are not involved in these tumors. Rather, a distinct set of proto-oncogenes may be involved. Most striking is the repeated occurrence of an FeLV isolate whose LTR and env gene bear unique sequence elements.

Coincident involvement of flvi-2, c-myc, and novel env genes in natural and experimental lymphosarcomas induced by feline leukemia virus.

The flvi-2 locus is a target of insertional mutagenesis in thymic lymphosarcomas induced by feline leukemia virus (FeLV). flvi-2 encodes the gene bmi-1, whose product is implicated as a myc-collaborator in the induction of B- and T-cell lymphoma. We have examined the involvement of flvi-2 and myc in natural and experimentally induced FeLV-positive feline lymphosarcomas which are heterogeneous in anatomical origin, geographic origin, and strain of FeLV involved. We further compared these findings with previous reports of novel FeLV env genes in the same tumors. The results show that proviral insertion at flvi-2 occurs commonly in natural and experimental feline thymic lymphosarcomas of diverse origins [52% overall], and that alterations in c-myc commonly accompany insertional mutagenesis of flvi-2 [54% overall]. However, 46% of tumors with flvi-2 insertions apparently lack involvement of c-myc. These observations support the hypothesis that interruption of flvi-2 may be an early event in a multistep cascade, one possibility for completion of which is activation of c-myc. Interruption of flvi-2 was not observed in nonthymic lymphosarcomas of alimentary or multicentric origin, although c-myc may be involved. A proportion of both thymic and nonthymic tumors have been shown previously to contain FeLV proviruses with recombinant or mutant env genes. Our findings strongly implicate the insertional mutagenesis of flvi-2, the activation of c-myc, and the emergence of novel env genes in FeLV-mediated lymphomagenesis, particularly in the induction of thymic lymphosarcoma. The data show that these events may overlap, but do not necessarily occur concurrently.

flvi-2, a target of retroviral insertional mutagenesis in feline thymic lymphosarcomas, encodes bmi-1.

LC-FeLV is a myc-containing strain of feline leukemia virus which induces thymic lymphosarcoma in the domestic cat with short latency. A locus in feline DNA, termed flvi-2, is commonly interrupted in naturally occurring and experimentally induced thymic lymphosarcomas containing LC-FeLV; thus, interruption of a gene encoded by flvi-2 may cooperate with the myc oncogene in the induction of T-cell tumors by LC-FeLV. Clones homologous to flvi-2 have been isolated from a normal human thymus cDNA library. Nucleotide sequence analysis of the cDNA clones demonstrates that flvi-2 encodes bmi-1, a gene previously identified as a target for MoMuLV integration and as a myc-collaborator in retrovirally-induced B-cell lymphomas in E mu-myc transgenic mice. In feline thymic lymphomas, retroviral integrations occur downstream of the gene, and result in enhanced expression of a bmi-1 transcript of normal size. These findings demonstrate the interruption of bmi-1 in natural as well as experimentally induced tumors, implicate the activation of bmi-1 in the induction of T-cell as well as B-cell lymphoma, and support the premise that bmi-1 functions as a myc collaborator.