A novel de novo mutation in the serine-threonine kinase STK11 gene in a Korean patient with Peutz-Jeghers syndrome

BACKGROUND: Peutz-Jeghers syndrome (PJS) is an unusual autosomal dominant disorder characterized by mucocutaneous pigmentation and multiple gastrointestinal hamartomatous polyps. Patients with PJS are at an increased risk of developing multi-organ cancer, most frequently those involving the gastrointestinal tract. Germline mutation of the STK11 gene, which encodes a serine-threonine kinase, is responsible for PJS. METHODS: Using DNA samples obtained from the patient and his family members, we sequenced nine exons and flanking intron regions of the STK11 gene using polymerase chain reaction (PCR) and direct sequencing. RESULTS: Sequencing of the STK11 gene in the proband of the family revealed a novel 1-base pair deletion of guanine (G) in exon 6 (c.826delG; Gly276AlafsX11). This mutation resulted in a premature termination at codon 286, predicting a partial loss of the kinase domain and complete loss of the C-terminal domain. We did not observe this mutation in both parents of the PJS patient. Therefore, it is considered a novel de novo mutation. CONCLUSION: The results presented herein enlarge the spectrum of mutations of the STK11 gene by identifying a novel de novo mutation in a PJS patient and further support the hypothesis that STK11 mutations are disease-causing mutations for PJS with or without a positive family history

Doxorubicin-incorporated polymeric micelles composed of dextran-b-poly(DL-lactide-co-glycolide) copolymer

Young-Il Jeong1,*, Do Hyung Kim1,2,*, Chung-Wook Chung1, Jin-Ju Yoo1, Kyung Ha Choi1, Cy Hyun Kim1,2, Seung Hee Ha1, Dae Hwan Kang1,2 1National Research and Development Center for Hepatobiliary Cancer, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea, Research Institute for Convergence of Biomedical Science and Technology, 2School of Medicine, Pusan National University, Yangsan, Republic of Korea*These authors contributed equally to this work.Background: Polymeric micelles using amphiphilic macromolecules are promising vehicles for antitumor targeting. In this study, we prepared anticancer agent-incorporated polymeric micelles using novel block copolymer.Methods: We synthesized a block copolymer composed of dextran and poly (DL-lactide-co-glycolide) (DexbLG) for antitumor drug delivery. Doxorubicin was selected as the anticancer drug, and was incorporated into polymeric micelles by dialysis. Polymeric micelles were observed by transmission electron microscopy to be spherical and smaller than 100 nm, with a narrow size distribution. The particle size of doxorubicin-incorporated polymeric micelles increased with increasing drug content. Higher initial drug feeding also increased the drug content. Results: During the drug-release study, an initial burst release of doxorubicin was observed for 10 hours, and doxorubicin was continuously released over 4 days. To investigate the in vitro anticancer effects of the polymeric micelles, doxorubicin-resistant HuCC-T1 cells were treated with a very high concentration of doxorubicin. In an antiproliferation study, the polymeric micelles showed higher cytotoxicity to doxorubicin-resistant HuCC-T1 cells than free doxorubicin, indicating that the polymeric micelles were effectively engulfed by tumor cells, while free doxorubicin hardly penetrated the tumor cell membrane. On confocal laser scanning microscopy, free doxorubicin expressed very weak fluorescence intensity, while the polymeric micelles expressed strong red fluorescence. Furthermore, in flow cytometric analysis, fluorescence intensity of polymeric micelles was almost twice as high than with free doxorubicin.Conclusion: DexbLG polymeric micelles incorporating doxorubicin are promising vehicles for antitumor drug targeting.Keywords: dextran, polymeric micelle, block copolymer, poly(DL-lactide-co-glycolide

Radiation hardness of ultrabroadband spintronic terahertz emitters: en-route to a space-qualified terahertz time-domain gas spectrometer

The radiation hardness of ultrabroadband, spintronic terahertz emitters against gamma and proton irradiation is investigated. We find that irradiation doses equivalent to those experienced by a space instrument en-route to and operated on Mars have a minor effect on the performance of the emitter. In particular, the ultrawide emission spectrum 0.1-30 THz, which covers a large part of the vibrational fingerprint region, remains unchanged. These results make this emitter type highly interesting as essential building block for broad-band gas sensors based on terahertz time-domain spectroscopy for future space missions

Effect of 5-aminolevulinic acid-based photodynamic therapy via reactive oxygen species in human cholangiocarcinoma cells

Cancer cells have been reported to exhibit an enhanced capacity for protoporphyrin IX (PpIX) synthesis facilitated by the administration of 5-aminolevulinic acid (ALA). We investigated the effect of ALA-based photodynamic therapy (PDT) on human cholangiocarcinoma cells (HuCC-T1). Since protoporphyrin IX (PpIX), a metabolite of ALA, can produce reactive oxygen species (ROS) under irradiation and then induce phototoxicity, ALA-based PDT is a promising candidate for the treatment of cholangiocarcinoma. When various concentrations of ALA (0.05–2 mM) were used to treat HuCC-T1 cells for 6 or 24 hours, the intracellular PpIX level increased according to the ALA concentration and treatment time. Furthermore, an increased amount of PpIX in HuCC-T1 cells induced increased production of ROS by irradiation, resulting in increased phototoxicity

Crystal structure of peroxiredoxin 3 from Vibrio vulnificus

Peroxiredoxins (Prxs) are ubiquitous cysteine-based peroxidase enzymes. Recently, a new type of Prx, VvPrx3, was identified in the pathogenic bacterium Vibrio vulnificus as being important for survival in macrophages. It employs only one catalytic cysteine residue to decompose peroxides. Here, crystal structures of VvPrx3 representing its reduced and oxidized states have been determined, together with an H2O2-bound structure, at high resolution. The crystal structure representing the reduced Prx3 showed a typical dimeric interface, called the A-type interface. However, VvPrx3 forms an oligomeric interface mediated by a disulfide bond between two catalytic cysteine residues from two adjacent dimers, which differs from the doughnut-like oligomers that appear in most Prxs. Subsequent biochemical studies showed that this disulfide bond was induced by treatment with nitric oxide (NO) as well as with peroxides. Consistently, NO treatment induced expression of the prx3 gene in V. vulnificus, and VvPrx3 was crucial for the survival of bacteria in the presence of NO. Taken together, the function and mechanism of VvPrx3 in scavenging peroxides and NO stress via oligomerization are proposed. These findings contribute to the understanding of the diverse functions of Prxs during pathogenic processes at the molecular level

Isolated fracture of the ceramic head after third-generation alumina-on-alumina total hip arthroplasty

BACKGROUND: While most reports of component fracture following alumina-on-alumina total hip arthroplasty have involved the acetabular liner, few have involved fracture of the alumina femoral head. In the present multicenter study, we investigated ceramic head fractures in a cohort of patients who underwent third-generation alumina-on-alumina total hip arthroplasty. METHODS: We performed a retrospective study of 312 patients (367 hips) who underwent alumina-on-alumina total hip arthroplasty without cement at four participating centers with the use of a 28-mm BIOLOX forte femoral head and a BIOLOX forte liner from July 2001 to October 2003. Three hundred and five patients (359 hips) were evaluated at a mean of forty-five months postoperatively. Clinical follow-up with use of the Harris hip score and radiographic evaluation were performed at six weeks; at three, six, and twelve months; and every six months thereafter. Retrieved ceramic implants were examined by means of visual inspection. RESULTS: Five hips (1.4%) in five patients were revised because of a ceramic head fracture during the follow-up period. The ceramic head fractures occurred during normal daily activities at a mean of 22.6 months postoperatively. A short neck had been used in all five hips in which a fracture occurred, compared with 121 (34.2%) of the 354 hips in which a fracture did not occur (p = 0.009). The fracture involved a circular crack along the circumference of the thinnest portion of the head component at the proximal edge of the bore. The fracture also involved multiple vertical cracks extending radially along the longitudinal axis from the circumference of the circular crack line to the lower edge of the head component. CONCLUSIONS: In the present study, the rate of ceramic head fracture associated with one design of a short-neck modular alumina femoral head was 1.4% (five of 359). The extent to which these findings are generalizable to other designs that utilize this type of femoral head is unknown

Alumina-on-Alumina Total Hip Arthroplasty A Concise Follow-up, at a Minimum of Ten Years, of a Previous Report

We previously reported the five-to-six-year results of the use of third-generation alumina-on-alumina bearings in a consecutive series of 100 primary cementless total hip arthroplasties. This report presents the longer-term outcomes of these same bearings, at a minimum of ten years postoperatively. Eighty-six of eighty-eight hips available for the study retained the original bearings at the time of the latest follow-up. Thirteen hips were associated with noise, and six hips demonstrated fretting of the femoral neck on radiographs. Two hips required a change of the bearings because of a ceramic head fracture. The ten-year survival rate of the alumina-on-alumina total hip prostheses, with revision of any implant for any reason as the end point, was 99.0%. On the basis of those results, we concluded that the rate of survival of primary cementless total hip prostheses with third-generation alumina-on-alumina bearings is excellent at ten years. However, the risk of ceramic fracture, noise, and impingement between the metal neck and the ceramic liner should be a concern to surgeons, and patients should be informed of these risks before surgery.Koo KH, 2008, J BONE JOINT SURG AM, V90A, P329, DOI 10.2106/JBJS.F.01489Sugano N, 2007, J BONE JOINT SURG BR, V89B, P455Yoo JJ, 2005, J BONE JOINT SURG AM, V87A, P530, DOI 10.2106/JBJS.D01753Allain J, 1998, J BONE JOINT SURG AM, V80A, P1355Joshi RP, 1998, J BONE JOINT SURG BR, V80B, P585MARTELL JM, 1993, J BONE JOINT SURG AM, V75A, P554MALONEY WJ, 1990, J BONE JOINT SURG AM, V72A, P1025BELLAMY N, 1988, J RHEUMATOL, V15, P1833ENGH CA, 1987, J BONE JOINT SURG BR, V69, P45SARMIENTO A, 1985, J BONE JOINT SURG AM, V67A, P48GRUEN TA, 1979, CLIN ORTHOP RELAT R, P17DELEE JG, 1976, CLIN ORTHOP RELAT R, P20HARRIS WH, 1969, J BONE JOINT SURG AM, VA 51, P737KAPLAN EL, 1958, J AM STAT ASSOC, V53, P457