CT bronchoscopy in the diagnosis of Williams-Campbell syndrome

Williams-Campbell syndrome, a rare disorder, is characterized by a congenital deficiency of cartilage, typically involving the fourth to the sixth order bronchi, and resulting in expiratory airway collapse and bronchiectasis. The authors report a patient with Williams-Campbell syndrome with type II respiratory failure due to extensive cystic bronchiectasis and secondary emphysema. CT of the thorax showed the affected bronchi had characteristic ballooning on inspiration and collapse on expiration. Three-dimensional images of the tracheobronchial tree were constructed from a volume of data acquired by thin-slice CT scanning. Apart from confirming expiratory collapse of the affected bronchi, these images revealed an absence of the cartilage ring impressions in the bronchial wall, extending bilaterally from the mainstem down to subsegmental bronchi, suggesting cartilage deficiency.     

Targeting Aurora Kinase A enhances radiation sensitivity of atypical teratoid rhabdoid tumor cells

Atypical teratoid/rhabdoid tumors (ATRT) are rare, highly malignant, embryonal CNS tumors with a poor prognosis. Therapy relies on highly toxic chemotherapy and radiotherapy. To improve outcomes and decrease morbidity, more targeted therapy is required. Gene expression analysis revealed elevated expression of multiple kinases in ATRT tissues. Aurora Kinase A was one of the candidate kinases. The objective of this study was to evaluate the impact of Aurora Kinase A inhibition in ATRT cell lines. Our analysis revealed that inhibition of Aurora Kinase A induces cell death in ATRT cells and the small molecule inhibitor MLN 8237 sensitizes these cells to radiation. Furthermore, inhibition of Aurora Kinase A resulted in decreased activity of pro-proliferative signaling pathways. These data indicate that inhibition of Aurora Kinase A is a promising small molecule target for ATRT therapy.     

Spectroscopic interaction of a coumarin derivative with bovine serum albumin

Abstract The absorption and fluorescence spectra of the 7-diethylamino-4-methyl coumarin (DAMC) in ethanol-water (1:9 v/v) solution at varying pH values were investigated. The interaction between DAMC and bovine serum albumin (BSA) was investigated by fluorescence spectroscopy. The Stern-Volmer quenching constant, the quenching rate constant of the bimolecular reaction (kq), the binding constant, and number of binding sites are mentioned but not calculated in the paper. Moreover, in a preliminary pharmacological study, DAMC not only remarkably increased cellular apoptosis in a concentration-dependent manner but also clearly induced A549 cell cycle arrest. Thus, these coumarin derivatives merit investigation as novel potential antitumor agents with further structural modification to produce an optimal lead compound and elucidate the detailed pharmacological mechanism.     

Intensity modulated radiation therapy (IMRT) for the treatment of unicentric Castlemans disease: a case report and review of the use of radiotherapy in the literature

Background

Surgical resection is considered standard therapy for cases of resectable unicentric Castleman’s disease (UCD). Unresectable cases of UCD do not have a consensus regarding the optimal treatment approach, but have utilized steroids, observation, chemotherapy, and radiotherapy. Here we discuss a patient presentation of UCD treated with an advanced radiotherapy technique, IMRT.

Case report

A 47 year old female was found to have an intra-thoracic posterior UCD and was determined not to be a good surgical candidate. She was referred for radiotherapy and was treated using IMRT to a total dose of 4320 cGy in 180 cGy fractions including a scheduled 10 day break. Following the break, the patient’s treatment was replanned at which the initial treatment volume was reduced by 50.9% for the duration of the treatment course. Radiation Therapy Oncology Group (RTOG) grade III pneumonitis developed which was managed medically. Neither disease progression nor late effects have occurred.

Conclusions

The use of IMRT and planned treatment break was successful in the treatment of a case of UCD, and should be considered for other unresectable cases.     

Aquaporins mediate the chemoresistance of human melanoma cells to arsenite

The integral membrane channel protein aquaporin (AQP) is aberrantly expressed with oncogenic characteristics in various human cancers. In this study, we analyzed the expression pattern of all subtypes of AQPs, and found that 8 out of 13 AQPs expressed in melanoma cells. To understand the role of aberrant expression of AQP in this disease, we over-expressed AQP3 and AQP9 in human melanoma WM266.4 cells and found that both AQPs significantly increased the chemoresistance of WM266.4 cells to arsenite. Functional studies showed that AQP3 and AQP9 can inhibit cell apoptosis induced by arsenite through down-regulating p53 and up-regulating Bcl-2 and XIAP. Our data suggest the implication of APQ in melanoma progression and that the over-expression of AQP3 and AQP9 contributes to the chemoresistance of melanoma to arsenite.     

DNA hypomethylation at the ZNF206-exon 5 CpG island associated with neuronal differentiation in mice and development of neuroblastoma in humans

Differentiation of human neuroblastoma recapitulates neural crest development. In our whole genome DNA methylation screening of tissue-specific differentially methylated regions (T-DMRs) and developmental stage specific differentially methylated regions (DS-DMRs) we reported that the exon 5 CpG island (CpGi) of Zfp206 (human: ZNF206), which was required to maintain embryonic stem cells in a pluripotent state, was one of potent brain and testis-specific T-DMRs in mice. In this study methylation level of the CpG sites at Zfp206-exon 5 CpGi in mouse brain samples at three different developmental stages (15-day-old embryo; E15, new born; NB, 12-week adult; AD) were quantitatively analyzed and it was identified that Zfp206-exon 5 CpGi was the DS-DMRs in mouse brain. In AD brains, Zfp206-exon 5 CpGi was significantly hypomethylated and Zfp206 expression was repressed, compared with E15 and NB brains. Hence, methylation level of human 5'-end of CpGi at ZNF206-exon 5, which is homologous CpGi to mice, was analyzed in neuroblastomas. Although all four adrenal samples showed complete methylation at the homologous region, we found the hypomethylation in 7 out of 26 neuroblastomas and a significant association between the hypomethylation and poor prognosis. In neuroblastoma cell lines and specimens, the hypomethylation was also associated with ZNF206 expression. These data indicated that the changes in DNA methylation levels at the Zfp206-exon 5 might be one of the important factors during neuronal development in mice and that the hypomethylation of the homologous region induced ZNF206 expression in humans and was associated with human neuroblastomagenesis. Even though the function of ZNF206 and its expression regulation in neuroblastoma remain elusive, ZNF206 might be a candidate differentiation suppressor and prognosis marker in neuroblastoma.     

Pharmacological inhibition of Mdm2 triggers growth arrest and promotes DNA breakage in mouse colon tumors and human colon cancer cells

The p53 tumor suppressor protein performs a number of cellular functions, ranging from the induction of cell cycle arrest and apoptosis to effects on DNA repair. Modulating p53 activity with Mdm2 inhibitors is a promising approach for treating cancer; however, it is presently unclear how the in vivo application of Mdm2 inhibitors impact the myriad processes orchestrated by p53. Since approximately half of all colon cancers (predominately cancers with microsatellite instability) are p53-normal, we assessed the anticancer activity of the Mdm2 inhibitor Nutlin-3 in the mouse azoxymethane (AOM) colon cancer model, in which p53 remains wild type. Using a cell line derived from an AOM-induced tumor, we found that four daily exposures to Nutlin-3 induced persistent p53 stabilization and cell cycle arrest without significant apoptosis. A 4-day dosing schedule in vivo generated a similar response in colon tumors; growth arrest without significantly increased apoptosis. In adjacent normal colon tissue, Nutlin-3 treatment reduced both cell proliferation and apoptosis. Surprisingly, Nutlin-3 induced a transient DNA damage response in tumors but not in adjacent normal tissue. Nutlin-3 likewise induced a transient DNA damage response in human colon cancer cells in a p53-dependent manner, and enhanced DNA strand breakage and cell death induced by doxorubicin. Our findings indicate that Mdm2 inhibitors not only trigger growth arrest, but may also stimulate p53's reported ability to slow homologous recombination repair. The potential impact of Nutlin-3 on DNA repair in tumors suggests that Mdm2 inhibitors may significantly accentuate the tumoricidal actions of certain therapeutic modalities.     

Body mass index,agricultural pesticide use,and cancer incidence in the Agricultural Health Study cohort

Obesity is associated with increased risks of several cancers including colon and female breast. Pesticide use in agricultural populations has also been linked with higher risks of various cancers. However, the interaction between obesity and pesticide use on cancer risk has not been well studied. Using data from the Agricultural Health Study, we examined the association between body mass index (BMI) and the risk of cancer at 17 sites and the interaction between BMI and pesticide use. Pesticide applicators residing in Iowa and North Carolina and their spouses were enrolled between 1993 and 1997 and given a self-administered questionnaire to obtain pesticide use and other information. This analysis included 39,628 men and 28,319 women with height and weight data who were cancer-free at enrollment. Among these participants, 4,432 were diagnosed with cancer between enrollment and 2005 and 64% were overweight or obese. BMI (per 1 kg/m²) was positively associated with colon cancer in men (hazard ratio (HR) 1.05, 95% confidence interval (CI) 1.02–1.09) and breast cancer in postmenopausal women (HR 1.03, 95% CI 1.01–1.06). In contrast, BMI was inversely associated with lung cancer in men, with a significant association in ever smokers (HR 0.92, 95% CI 0.88–0.97) and a null association in never smokers. The positive association between BMI and colon cancer in men was significant in those who ever used carbofuran (HR = 1.10, 95% CI 1.04–1.17; p-interaction = 0.04) or metolachlor (HR = 1.09, 95% CI 1.04–1.15; p-interaction = 0.02) but was null in non-users of these pesticides. Among male ever smokers, the inverse association between BMI and lung cancer was significant in non-users of carbofuran (HR = 0.87, 95% CI = 0.82–0.92) but was null in users of carbofuran (p-interaction = 0.02). These findings suggest that certain pesticides may modify the effects of BMI on the risks of colon and lung cancers.