The BH3 mimetic ABT-737 increases treatment efficiency of paclitaxel against hepatoblastoma

<p>Abstract</p> <p>Background</p> <p>The primary goal of current chemotherapy in hepatoblastoma (HB) is reduction of tumour volume and vitality to enable complete surgical resection and reduce risk of recurrence or metastatic disease. Drug resistance remains a major challenge for HB treatment. In some malignancies inhibition of anti-apoptotic pathways using small BH3 mimetic molecules like ABT-737 shows synergistic effects in combination with cystotoxic agents in vitro. Now we analysed toxicology and synergistic effects of this approach in HB cells and HB xenografts.</p> <p>Methods</p> <p>Viability was monitored in HB cells (HUH6 and HepT1) and fibroblasts treated with paclitaxel, ABT-737 and a combination of both in a MTT assay. HUH6 xenotransplants in NOD/LtSz-scid IL2Rγnull mice (NSG) were treated accordingly. Tumour volume and body weight were monitored. Xenografted tumours were analysed by histology and immunohistochemistry (Ki-67 and TUNEL assay).</p> <p>Results</p> <p>ABT-737 reduced viability in HUH6 and HepT1 cells cultures at concentrations above 1 μM and also enhanced the cytotoxic effect of paclitaxel when used in combination. Thereby paclitaxel could be reduced tenfold to achieve similar reduction of viability of tumour cells. In contrast no toxicity in fibroblasts was observed at the same regiments. Subcutaneous HB (HUH6) treated with paclitaxel (12 mg/kg body weight, n = 7) led to delayed tumour growth in the beginning of the experiment. However, tumour volume was similar to controls (n = 5) at day 25. Combination treatment with paclitaxel and ABT-737 (100 mg/kg, n = 8) revealed significantly 10 fold lower relative tumour volumes compared to control and paclitaxel groups. Paclitaxel dependent toxicity was observed in this mice strain.</p> <p>Conclusions</p> <p>Our results demonstrate enhancement of chemotherapy by using modulators of apoptosis. Further analyses should include improved pharmacological formulations of paclitaxel and BH3 mimetics in order to reduce toxicological effects. Sensitising HB to apoptosis may also render resistant HB susceptible to established chemotherapy regimens.</p

Predictors of functional outcome following femoral neck fractures treated with an arthroplasty: limitations of the Harris hip score

Introduction To study the association between potential prognostic factors and functional outcome at 1 and 5 year follow-up in patients with femoral neck fractures treated with an arthroplasty. To analyze the reliability of the Harris hip score (HHS). Materials and methods A multicenter analysis which included 252 patients who sustained a femoral neck fracture treated with an arthroplasty. Functional outcome after surgery was assessed using a modified HHS and was evaluated after 1 (HHS1) and 5 (HHS5) years. Several prognostic factors were analyzed and reliability of the HHS was assessed. Results After 1 year the presence of co-morbidities was a significant (p = 0.002) predictor for a poor functional outcome (mean HHS1 71.8 with co-morbidities, and 80.6 without co-morbidities). After 5 years none of the potential prognostic factors had significant influence on functional outcome. Internal consistency testing of the HHS showed that when pain and function of the HHS were analyzed together, the internal consistency was poor (HHS1 0.38 and HHS5 0.20). The internal consistency of the HHS solely in function (without pain) improved to 0.68 (HHS1) and 0.46 (HHS5). Analyzing the functional aspect exclusively, age and the existence of co-morbidities could be defined as predictors for functional outcome of femoral neck fractures after 1 and 5 years. Conclusion After using the HHS in a modification, age and the existence of pre-operative co-morbidities appeared to be predictors of the functional outcome after 1 and 5 years. The HHS, omitting pain, is a more reliable score to estimate the functional outcome, than HHS analyzing pain and function in one scoring syste

Extra-Intestinal Manifestations of Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder, which results from a germ line mutation in the APC (adenomatous polyposis coli) gene. FAP is characterized by the formation of hundreds to thousands of colorectal adenomatous polyps. Although the development of colorectal cancer stands out as the most prevalent complication, FAP is a multisystem disorder of growth. This means, it is comparable to other diseases such as the MEN syndromes, Von Hippel-Lindau disease and neurofibromatosis. However, the incidence of many of its clinical features is much lower. Therefore, a specialized multidisciplinary approach to optimize health care—common for other disorders—is not usually taken for FAP patients. Thus, clinicians that care for and counsel members of high-risk families should have familiarity with all the extra-intestinal manifestations of this syndrome. FAP-related complications, for which medical attention is essential, are not rare and their estimated lifetime risk presumably exceeds 30%. Affected individuals can develop thyroid and pancreatic cancer, hepatoblastomas, CNS tumors (especially medulloblastomas), and various benign tumors such as adrenal adenomas, osteomas, desmoid tumors and dental abnormalities. Due to improved longevity, as a result of better prevention of colorectal cancer, the risk of these clinical problems will further increase

Effects of malnutrition on the erythrocyte fatty acid composition and plasma vitamin E levels of Pakistani children

Erythrocyte fatty acids and plasma vitamin E concentrations were determined in 47 grade 2, and 21 grade 3 malnourished Pakistani children (ages 4-56 months). Data were compared with those of 26 age- and sex-matched apparently healthy controls. Evaluation with three statistical approaches revealed that both grade ? and grade 3 malnourished children had decreased erythrocyte omega 6 fatty acids and to a lesser extent decreased omega 3 fatty acids. These decreases were compensated for by increased omega 9 fatty acids. The patients tended to have lower plasma vitamin E concentrations. We conclude that malnourished Pakistani children have low essential fatty acid status, notably those of the omega 6 series. The combination of low erythrocyte 22:6 omega 3 and a low 22:5 omega 6/22:4 omega 6 ratio in grade 2 patients suggests low Delta 4-desaturation activity, which may be due to impaired peroxisomal beta-oxidation

Prediction of postnatal outcome in fetuses with congenital lung malformation

Objectives: To identify, in fetuses with a congenital lung malformation (CLM), prenatal predictors of the need for postnatal respiratory support and the need for surgery by calculating the CLM volume ratio (CVR), and to evaluate the concordance between the prenatal appearance and the postnatal type of CLM. Methods: This was an analysis of prenatal, perinatal and postnatal data from fetuses diagnosed with a CLM at the Erasmus University Medical Center – Sophia Children's Hospital in Rotterdam, The Netherlands, between January 2007 and December 2016. For all included fetuses, CVR was measured retrospectively on stored ultrasound images obtained at 18 + 1 to 24 + 6 weeks (US1), 25 + 0 to 29 + 6 weeks (US2) and/or 30 + 0 to 35 + 6 weeks' gestation (US3). Postnatal diagnosis of CLM was based on computed tomography or histology. Primary outcomes were the need for respiratory support within 24 h and surgery within 2 years after birth. Results: Of the 80 fetuses with a CLM included in this study, 14 (18%) required respiratory support on the first postnatal day, and 17 (21%) required surgery within 2 years. Only the CVR at US2 was predictive of the need for respiratory support, with a cut-off value of 0.39. Four of 16 (25%) fetuses which showed full regression of the CLM prenatally required respiratory support within 24 h after birth. The CVR at US1, US2 and US3 was predictive of surgery within 2 years. Overall, the prenatal appearance of the CLM showed low concordance with the postnatal type. Prenatally suspected microcystic congenital pulmonary airway malformation (CPAM) was shown on computed tomography after birth to be congenital lobar overinflation in 15/35 (43%) cases. Respiratory support within 24 h after birth and surgical resection within 28 days after birth were needed in all cases of macrocystic CPAM. Conclusions: CVR can predict the need for respiratory support within 24 h after birth and for surgery within 2 years. Regression of a CLM prenatally does not rule out respiratory problems after birth.</p