In vivo antitumor activity of S 16020-2, a new olivacine derivative

 The antitumor activity of S 16020-2, a new olivacine derivative, was investigated in vivo and compared with that of Adriamycin and elliptinium acetate in a panel of murine (P388 leukemia, M5076 sarcoma, Lewis lung carcinoma, and B16 melanoma) and human (NCI-H460 non-small-cell lung and MCF7 breast carcinomas) tumor models. S 16020-2 given i.v. was active against P388 leukemia implanted i.p., s.c., or intracerebrally. The therapeutic effect of an intermittent schedule (administration on days 1, 5, 9) was superior to that of single-dose treatment, allowing the i.v. administration of high total doses of S 16020-2 and resulting in the cure of 60% of mice in the i.p. P388 model. In this model, S 16020-2 was more active than elliptinium acetate and showed a better therapeutic index than Adriamycin:≥8 versus 2. A good therapeutic effect of S 16020-2 was also observed in three P388 leukemia sublines displaying the classic multidrug-resistance phenotype, namely, P388/VCR, P388/VCR-20, and P388/MDRC.04, the latter being totally insensitive to vincristine and Adriamycin. However, S 16020-2 was not active against the P388/ADR leukemia, a model highly resistant to adriamycin in vivo. S 16020-2 was both more active than Adriamycin and curative in the M5076 sarcoma and Lewis lung carcinoma implanted s.c. In the B16 melanoma implanted i.p. or s.c., S 160202 was less active than Adriamycin. Against the NCI-H460 human tumor xenograft, S 16020-2 demonstrated activity superior to that of Adriamycin (T/C=20% versus 43% on day 21). Against the MCF7 breast cancer xenograft, S 16020-2 was active, but less so than Adriamycin (T/C=23% versus 9% on day 21), whereas elliptinium acetate was marginally active (T/C=49% on day 24). The hematological toxicity of S 16020-2 given to B6D2F1 mice at pharmacological dose appeared to be less severe than that of Adriamycin, particularly in bone-marrow stem cells. These results demonstrate that S 16020-2 is a highly active antitumor drug in various experimental tumor models and is markedly more efficient than elliptinium acetate. Because of its pharmacological profile, which is globally different from that of Adriamycin, S 16020-2 is considered an interesting candidate for clinical trials. Received: 21 October 1995/Accepted: 4 March 1996     

The current role of contrast-enhanced ultrasound (CEUS) imaging in the evaluation of renal pathology

Background  

By using a microbubble contrast agent and contrast-specific imaging software, the contrast-enhanced ultrasound (CEUS) is able to depict the micro and macrocirculation of the target organ.     

Investigation into FOXE1 genetic variations in cutaneous squamous cell carcinoma

Background FOXE1 is a candidate tumour suppressor gene at human chromosome locus 9q22. This is a region frequently lost in squamous cell cancer. Objectives To assess the influence of FOXE1 variations on genetic susceptibility to cutaneous squamous cell carcinoma (SCC). Methods We performed mutational analysis of FOXE1 in 320 DNA samples isolated from 60 SCC specimens, 60 adjacent histologically normal skin samples and 200 blood samples. Results No somatic mutations were evident. Instead the polyalanine tract showed marked variation in its length between samples from patients with SCC and normal controls. Conclusions These results imply that another tumour suppressor gene at this locus may be more important than FOXE1 in skin carcinogenesis and suggest that variation in the FOXE1 polyalanine tract length predisposes to cutaneous SCC.     

FOXE1 is a target for aberrant methylation in cutaneous squamous cell carcinoma

Background Several cancer‐related genes are silenced by promoter hypermethylation in skin cancers. However, to date the somatic epigenetic events that occur in cutaneous squamous cell carcinoma (SCC) tumorigenesis have not been well defined. Objectives To examine epigenetic abnormalities of FOXE1, a gene located on chromosome 9q22, a region frequently lost in SCC. Methods We investigated the methylation status of FOXE1 in 60 cases of cutaneous SCC by methylation‐specific polymerase chain reaction, and comparatively examined mRNA and protein expression by real‐time polymerase chain reaction and Western blot, respectively. Results We found a higher frequency of FOXE1 promoter hypermethylation in SCCs (55%), as compared with the adjacent uninvolved skin (12%) and blood control samples (9·5%). FOXE1 methylation was frequently seen in association with a complete absence of or downregulated gene expression. Treatment with the demethylating agent 5‐Aza‐2′‐deoxycytidine resulted in profound reactivation of FOXE1 expression. Conclusions These results indicate that FOXE1 is a crucial player in development of cutaneous SCC.     

Psoriatic arthritis and obesity: the role of anti-IL-12/IL-23 treatment

Clinical Rheumatology - Patients with psoriatic arthritis (PsA) have an increased prevalence of obesity, but mechanisms underlying this association remain unknown and it is unclear if obesity is...     

Ultrasonography of traumatic injuries to limb peripheral nerves: technical aspects and spectrum of features

Traumatic injury to limb peripheral nerves represents an important cause of morbidity and disability. Timely diagnosis and treatment are crucial to optimizing outcomes. The initial evaluation requires a careful history, a thorough physical examination, and electrodiagnostic tests, which lead in most cases to a diagnostic suspicion, but fail to provide an extensive qualitative and quantitative assessment of the nerve damage. Ultrasonography (US) is a low-cost, non-invasive technique which allows for direct visualization of nerve internal structure. It enables performing dynamic examinations and nerves can be followed over long distances in a limb in relatively short times, adding paramount information to extensively characterize the specific type of lesion, and to plan the appropriate treatment. Magnetic resonance imaging (MRI) is complementary to US, especially in examining deep-seated and proximal nerve segments, but is expensive, not available in all institutions and less accepted by patients. The purpose of this review is to describe the role of ultrasonography in the setting of traumatic injury to peripheral nerves, analyzing the main US features in specific types of trauma. Technical aspects with key considerations for optimization are discussed. A brief comparative evaluation between US and MRI is also provided.     

Herpes simplex virus stromal keratitis is not titer-dependent and does not correlate with neurovirulence

We developed a murine model of ocular herpes simplex virus (HSV) disease which is particularly suited for testing stromal keratitis because most animals show some evidence of infection. Using this model, we characterized the ocular disease patterns caused by ten recent low-passage clinical isolates of HSV-1, as well as those caused by the established laboratory strains HSV-1 KOS and HSV-2 333. Viral strains were evaluated for their ability to cause stromal keratitis, blepharitis, vascularization of the cornea, and mortality. The model was not useful for scoring epithelial keratitis. The ocular disease caused by the recent isolates ranged from very mild disease to severe stromal keratitis. Some of the recent isolates caused disease as severe as the two laboratory strains. A comparison of the virulence characteristics expressed by various HSV strains indicated that the ability to cause stromal disease was correlated with vascularization of the cornea (correlation coefficient = 0.797, P less than 0.001) and was not correlated with the neurovirulence of the strains (correlation coefficient 0.045, P greater than 0.05). The severity of stromal keratitis was not dependent on the amount of inoculum over the range tested and a strain causing severe stromal keratitis caused severe ocular disease even when mixed with a nonstromal strain at ratios of 10:1, 100:1, and 1000:1.