Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death

Nutrient deprivation has been shown to cause cancer cell death. To exploit nutrient deprivation as anti-cancer therapy, we investigated the effects of the anti-metabolite 2-deoxy-D-glucose on breast cancer cells in vitro. This compound has been shown to inhibit glucose metabolism. Treatment of human breast cancer cell lines with 2-deoxy-D-glucose results in cessation of cell growth in a dose dependent manner. Cell viability as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide conversion assay and clonogenic survival are decreased with 2-deoxy-D-glucose treatment indicating that 2-deoxy-D-glucose causes breast cancer cell death. The cell death induced by 2-deoxy-D-glucose was found to be due to apoptosis as demonstrated by induction of caspase 3 activity and cleavage of poly (ADP-ribose) polymerase. Breast cancer cells treated with 2-deoxy-D-glucose express higher levels of Glut1 transporter protein as measured by Western blot analysis and have increased glucose uptake compared to non-treated breast cancer cells. From these results we conclude that 2-deoxy-D-glucose treatment causes death in human breast cancer cell lines by the activation of the apoptotic pathway. Our data suggest that breast cancer cells treated with 2-deoxy-D-glucose accelerate their own demise by initially expressing high levels of glucose transporter protein, which allows increased uptake of 2-deoxy-D-glucose, and subsequent induction of cell death. These data support the targeting of glucose metabolism as a site for chemotherapeutic intervention by agents such as 2-deoxy-D-glucose

Assessing adrenal insufficiency of corticosteroid secretion using free versus total cortisol levels in critical illness

To study the value of free versus total cortisol levels in assessing relative adrenal insufficiency during critical illness-related corticosteroid insufficiency. A prospective study in a mixed intensive care unit from 2004 to 2007. We consecutively included 49 septic and 63 non-septic patients with treatment-insensitive hypotension in whom an adrenocorticotropic hormone (ACTH) test (250 μg) was performed. Serum total and free cortisol (equilibrium dialysis), corticosteroid-binding globulin (CBG) and albumin were assessed. Although a low CBG resulted in a high free cortisol level relative to total cortisol, free and total cortisol and their increases were well correlated (r = 0.77-0.79, P < 0.001). In sepsis, hypoalbuminemia did not affect total and free cortisol, and increases in total cortisol upon ACTH predicted increases in free cortisol regardless of low binding proteins. In non-sepsis, total cortisol was lower with than without hypoalbuminemia; free cortisol did not differ, since hypoalbuminemia concurred with a low CBG. Increases in total cortisol depended less on binding proteins than on raw levels. The areas under the receiver operating characteristic curve for predicting increases in free from total cortisol were 0.93-0.97 in sepsis and 0.79-0.85 in non-sepsis (P = 0.044 or lower for sepsis vs. non-sepsis). Although the biologically active free cortisol fraction depends on binding proteins, total cortisol correlates to free cortisol in treatment-insensitive hypotension during critical illness. In sepsis, albumin is not an important binding molecule. Subnormal increments in total cortisol upon ACTH suffice in assessing relative adrenal insufficiency, particularly in sepsi

Teriparatide treatment in adult hypophosphatasia in a patient exposed to bisphosphonate: a case report

We describe the case of a woman with hypophosphatasia previously exposed to bisphosphonate and subsequently treated with teriparatide (recombinant human PTH 1-34). A Caucasian woman sustained bilateral femur stress fractures when she was fifty years old, which widened despite use of calcium, vitamin D and risedronate for 2.5 years and required intramedullary rods for stabilization. Hypophosphatasia was diagnosed in the interim due to low serum alkaline phosphatase (ALP) (ALP 20 IU/L; normal (N), 40-150 IU/L) and high pyridoxal 5' phosphate (3400 nmol/L; N 18-175 nmol/L). She was referred for further management. On presentation, she had significant fracture site pain and generalized bone pain (weight bearing and non-weight bearing) - making her walker dependent at home and wheel chair dependent outside home. She could not sleep at night due to discomfort when she moved. Daily teriparatide injections, 20 mcg subcutaneously were prescribed. At 8-weeks follow-up, fracture site pain, weight-bearing and non weight-bearing pain improved significantly allowing ambulation for prolonged periods without assistance. She slept at night without discomfort. Improvement persisted during her entire treatment period. Radiographs taken at 4 and 16 months of treatment demonstrated healing of femur fractures. Biochemically, mean urine cross-link-N-telopeptide increased 11% as compared to her base-line, while bone specific alkaline phosphatase did not increase as expected. In conclusion, we observed an uncoupling of bone formation and resorption markers during her treatment period in the face of notable clinical and radiological improvement. Off-label use of teriparatide may help patients with hypophosphatasi

Testicular “Hyperstimulation” Syndrome: A Case of Functional Gonadotropinoma

Gonadotropins secreting pituitary tumors tend to present as sellar mass with hypogonadism. Biologically active LH secretion by these tumors resulting in elevated testosterone is extremely rare. We report a case of a 48-year-old male patient who presented with giant pituitary tumor, elevated testosterone, and elevated levels of gonadotropins. Surgical resection of the tumor resulted in normalization of gonadotropins and fall in serum testosterone to subnormal levels in the postoperative period confirming that the tumor was secreting bioactive luteinizing hormone (LH)