GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis

Rhabdomyosarcoma (RMS) typically arises from skeletal muscle. Currently, RMS in patients with recurrent and metastatic disease have no successful treatment. The molecular pathogenesis of RMS varies based on cancer sub-types. Some embryonal RMS but not other sub-types are driven by sonic hedgehog (Shh) signaling pathway. However, Shh pathway inhibitors particularly smoothened inhibitors are not highly effective in animals. Here, we show that Shh pathway effectors GLI1 and/or GLI2 are over-expressed in the majority of RMS cells and that GANT-61, a specific GLI1/2 inhibitor dampens the proliferation of both embryonal and alveolar RMS cells-derived xenograft tumors thereby blocking their growth. As compared to vehicle-treated control, about 50% tumor growth inhibition occurs in mice receiving GANT-61 treatment. The proliferation inhibition was associated with slowing of cell cycle progression which was mediated by the reduced expression of cyclins D1/2/3 & E and the concomitant induction of p21. GANT-61 not only reduced expression of GLI1/2 in these RMS but also significantly diminished AKT/mTOR signaling. The therapeutic action of GANT-61 was significantly augmented when combined with chemotherapeutic agents employed for RMS therapy such as temsirolimus or vincristine. Finally, reduced expression of proteins driving epithelial mesenchymal transition (EMT) characterized the residual tumors.     

TNF inhibitor treating osseous sarcoidosis and dactylitis: case and literature review

Clinical Rheumatology - A 49-year-old African American male with multiorgan sarcoidosis presented with recurrent episodes of dactylitis and arthritis. Imaging had shown sarcoid osseous involvement...     

Anti-tumor necrosis factor (TNF) therapy in rheumatoid arthritis: correlation of TNF-alpha serum level with clinical response and benefit from changing dose or frequency of infliximab infusions

OBJECTIVE: To determine the relationship between serum TNF-alpha level and clinical response in rheumatoid arthritis patients treated by infliximab. This could be of value to predict clinical response to infliximab and to determine the optimal dose and interval between dosing of infliximab. RA patients who did not respond adequately to conventional doses (3 mg/kg) of infliximab were studied to see if increasing the dose or frequency of infliximab infusions would be more effective. METHODS: Fifty-five RA patients who fulfilled the American College of Rheumatology criteria and were receiving treatment by anti-TNF-alpha (infliximab 3 mg/kg body weight every 8 weeks) were evaluated by: clinical disease activity using the Richie score index before receiving their scheduled infliximab infusion. Serum level of TNF-alpha, as measured by competitive ELISA assay, was determined immediately before and 9-11 days after receiving infliximab. RA patients who did not respond adequately to treatment with infliximab were given either a larger dose of infliximab or given the infusion at six-week intervals. Their clinical response was then evaluated sixteen months later. RESULTS Patients were divided into 2 groups according to Richie score, active group with score > 10 (score 20.3 +/- 7.7 mean +/- standard deviation, n = 25) and inactive group with scores < or = 10 (score 4.1 +/- 3.2, n = 30). TNF-alpha serum levels pre-infliximab infusion were significantly higher in the active group 76.1 pg/ml than the inactive group 38.0 pg/ml (P < 0.02). Whereas TNF serum level significantly dropped post infliximab in the inactive group (P < 0.05), it did not drop in the active group. The mean level of the post-infusion TNF-alpha serum level was higher (76.6 +/- 93.4 ng/ml) in the-active than the mean level of the post-infusion serum TNF-alpha levels in the inactive group (26.4 ng/ml +/- 7.9) P < 0.01 using the t-test. Increasing the frequency was superior in RA patients' clinical outcome than increasing the dose of infliximab infusions. CONCLUSION: RA patients who responded well to infliximab and had inactive disease at the time of the study have lower levels of serum TNF-alpha which could be further suppressed by the recommended doses of infliximab. RA patients with active disease have higher serum levels of TNF-alpha which could not be suppressed after the recommended doses of infliximab infusion. Changing the frequency of infliximab infusions in the active group was more effective than increasing the dose of infliximab in inducing improved clinical outcome. We suggest that the lack of suppression of TNF-alpha in the active group could be due to inadequate dosing of infliximab or to the presence of a neutralizing antibody directed against infliximab. It remains to be seen if serum TNF-alpha levels could be used as a guide in determining the dose and intervals between dosing of anti-TNF therapy in RA in order to achieve the desired clinical response.     

Accentuated oxidative stress following reperfusion injury in diabetic rats.

BACKGROUND: This study investigates whether diabetes mellitus accentuates hind limb ischemia-reperfusion injury. METHODS: Male Wistar rats rendered diabetic (n=40) following injection of streptozotocin were compared to non-diabetic control rats (n=30). Each group was divided into sham, 4 hrs of hind limb ischemia, 4 hrs of ischemia followed by 10, 30 or 60 min of reperfusion. Plasma concentrations of an end-product of lipid peroxidation [malondialdehyde (MDA)] and antioxidants (vitamins A and E) were measured together with the resting membrane potential (RMP) of the gastrocnemius muscle. RESULTS: Following reperfusion, the diabetic group showed greater and more persistent elevation of MDA and greater reduction of antioxidants. This was associated with reduction in the RMP only in the diabetic group. There was significant correlation between MDA level and the RMP in both groups of animals. CONCLUSIONS: These results indicate that oxidative stress following reperfusion injury is greater in the presence of diabetes mellitus. This may lead to a decrease in the RMP and increase in the vascular permeability, which may be associated with more complications.     

The pattern of female genital tuberculosis in Riyadh, Saudi Arabia

An analysis of 40 patients with genital tuberculosis in the Maternity and Children's Hospital, Riyadh, Saudi Arabia, showed that female genital tuberculosis occurred in 0.45% of all gynaecological admissions, a much higher rate than those reported from Western countries with a similar economic background. These 40 women accounted for 4.2% of a total of 945 infertile women studied during the same period, and where infertility was due to a tubal factor, 1 in 7 was afflicted with tuberculosis. Most patients were young nulliparae and in 13 the disease was florid. Complete cure was achieved with chemotherapy in 77% of the patients, but tubal patency was restored in only five of 35 patients followed up (14%). There were only two tubal pregnancies and no intrauterine pregnancy. Genital tuberculosis should be considered as a possible cause of infertility and excluded before embarking upon tubal surgery or ovulation-induction therapy.     

Myelographic study of the spinal cord ascent during fetal development

To assess the length of the spinal cord relative to the vertebral column during fetal development, we performed translumbar myelograms on 340 spontaneously aborted fetuses. Of these, 146 were selected for study. There were 76 males and 70 females, with fetal age ranging from 7 to 33 weeks. Significant variation in the level of spinal cord termination was found in fetuses between 12 and 25 weeks gestational age. In fetuses between 25 and 33 weeks gestational age, the cord ended at or above the third lumbar vertebra.     

Dose-response aggregometry in maternal/neonatal platelets

The aggregation of platelets collected from maternal/neonatal pairs (n = 240) at the time of childbirth, was studied in response to multiple doses of ADP, collagen, arachidonic acid and ristocetin. Similar responses were obtained from healthy nonpregnant adult controls for comparison. The lag phase, slope of the aggregation curves as well as maximum aggregation (MA%) were recorded and analysed. Neonatal and adult platelets exhibited more enhanced responses to decreasing doses of ADP, arachidonic acid and ristocetin, than maternal platelets. These enhanced responses were exhibited more consistently in the slopes of the aggregation curves than in MA%. Although neonatal platelets have shown longer lag phase in their responses to collagen, the rate of the aggregation reaction was significantly faster than maternal platelets, with no differences in MA%. These results contradict many previous reports suggesting impaired aggregation responses of neonatal platelets to these agonist. The possible reasons for these contradictions were discussed.     

A newly described mutation of the CLCN7 gene causes neuropathic autosomal recessive osteopetrosis in an Arab family

Neurologic manifestations in osteopetrosis are usually secondary to sclerosis of the skull bones. However, a rare neuropathic subtype of osteopetrosis exists that resembles neurodegenerative storage disorders. Unlike other forms of osteopetrosis, this latter form does not respond to hematopoietic stem cell transplantation. Preliminary studies suggest that this neuropathic form is more likely to be caused by mutations in the CLCN7 gene in an autosomal recessive manner. This study provides further evidence for this phenotype-genotype correlation by presenting a previously unreported mutation in the CLCN7 gene in a Yemeni family with the neuropathic form. This is also the first study of any mutation in patients with osteopetrosis of Arabic ethnicity. As literature review suggests that this type may be more common in Arabs, cascade genetic screening of early onset of autosomal recessive-osteopetrosis in patients of Arabic ancestry may preferably start with the CLCN7 gene rather than the TCIRG gene as is routinely done in clinical laboratories. Identifying a mutation in the CLCN7 gene in a patient with early onset of autosomal recessive-osteopetrosis may also guide therapeutic decisions including the option of hematopoietic stem cell transplantation.