Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by the transcription factors Oct4, Sox2, and Klf4 in combination with c-Myc. Recently, Sox2 plus Oct4 was shown to reprogram fibroblasts and Oct4 alone was able to reprogram mouse and human neural stem cells (NSCs) into iPS cells. Here, we report that Bmi1 leads to the transdifferentiation of mouse fibroblasts into NSC-like cells, and, in combination with Oct4, can replace Sox2, Klf4 and c-Myc during the reprogramming of fibroblasts into iPS cells. Furthermore, activation of sonic hedgehog signaling (by Shh, purmorphamine, or oxysterol) compensates for the effects of Bmi1, and, in combination with Oct4, reprograms mouse embryonic and adult fibroblasts into iPS cells. One- and two-factor iPS cells are similar to mouse embryonic stem cells in their global gene expression profile, epigenetic status, and in vitro and in vivo differentiation into all three germ layers, as well as teratoma formation and germline transmission in vivo. These data support that converting fibroblasts with Bmi1 or activation of the sonic hedgehog pathway to an intermediate cell type that expresses Sox2, Klf4, and N-Myc allows iPS generation via the addition of Oct4.
reprogramming; transdifferentiation; neural stem cells; induced pluripotent stem cells; Bmi1; Oct4
Idiomarina sp. strain 28-8 is an aerobic, Gram-negative, flagellar bacterium isolated from the bodies of ark shells (Scapharca broughtonii) collected from underwater sediments in Gangjin Bay, South Korea. Here, we present the draft genome sequence of Idiomarina sp. 28-8 (2,971,606 bp, with a G+C content of 46.9%), containing 2,795 putative coding sequences.
Streptococcus parauberis is a coccoid, nonmotile, alpha-hemolytic, Gram-positive bacterium of the Streptococcaceae family. Streptococcus parauberis strain KCTC11980 was isolated from the kidney of a diseased olive flounder collected from an aquaculture farm on Jeju Island in 2010. The 2.12-Mb genome sequence consists of 44 large contigs in 16 scaffolds and contains 2,214 predicted protein-coding genes, with a G+C content of 35.4%.
Novel agents (NAs) such as thalidomide and bortezomib have been administered in combination with autologous stem-cell transplantation (ASCT) to effectively treat multiple myeloma (MM). However, whether NAs perform better as induction treatments prior to transplantation, or as post-transplant maintenance therapies remains unclear.
We retrospectively analyzed 106 consecutive patients with MM who underwent ASCT within 1 year of diagnosis as first-line therapy.
Eighty-seven (82.1%) patients received NAs before ASCT, whereas 68 (64.2%) received NAs after ASCT. NAs were administered to each patient as follows: before ASCT alone (N=29, 27.4%), after ASCT alone (N=10, 9.4%) or both before and after ASCT (N=58, 54.7%). High-quality rates before and after ASCT were significantly higher for patients who received NAs as induction treatment compared to those who did not receive pre-transplant NAs. At a median follow-up of 37.9 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 42.8% and 70.2%, respectively. The PFS and OS were significantly higher in patients with NAs as post-transplant maintenance treatment (P=0.03 and P=0.04, respectively), but not in those with NAs as pre-transplant induction treatment. The PFS of patients with NAs before and after ASCT was higher than that of the patients with NAs as induction therapy alone (P=0.05). Age, serum β2-microglobulin level, complete response after ASCT, and NA use post-ASCT independently predicted survival outcomes.
These findings suggest that integration of NAs post-ASCT could benefit patients with MM undergoing ASCT. Induction therapy using NAs also improves high-quality response rates before and after ASCT.
Multiple myeloma; Novel agents; Autologous stem cell transplantation; Induction and maintenance treatment
Our goal is to validate diagnosing and characterizing epilepsy based on a medical record survey by external reviewers.
We reviewed medical records from 80 patients who received antiepileptic drugs in 2009 at two hospitals. The study consisted of two steps; data abstraction by certified health record administrators and then verification by the investigators. The gold standard was the results of the survey performed by the epileptologists from their own hospital.
The specificity was more than 90.0% for diagnosis and activity, and for new-onset seizures. The sensitivity was 97.0% or more for diagnosis and activity and 66.7-75.0% for new-onset epilepsy. This method accurately classified epileptic syndromes in 90.2-92.9% of patients, causes in 85.4-92.7%, and age of onset in 78.0-81.0%. Kappa statistics for inter-rater reliability and test-retest reliability ranged from 0.641-0.975, which means substantial to near-perfect agreement in all items.
Our data suggest that epilepsy can be well identified by external review of medical records. This method may be useful as a basis for large-scale epidemiological research.
Validity; Epilepsy; Epidemiology; Sensitivity; Specificity; Reliability
Vibrio cholerae is a globally important pathogen that is endemic in many areas of the world and causes 3-5 million reported cases of cholera every year (http://www.who.int/wer). Historically there have been seven acknowledged cholera pandemics; included in the 7th and ongoing pandemic are the recent outbreaks in Zimbabwe and Haiti1. Only serogroup O1 isolates (consisting of two biotypes known as ‘classical’ and ‘El Tor’) and the derivative O1392,3 can cause epidemic cholera2. It is believed that the first six cholera pandemics were caused by the classical biotype but El Tor has subsequently spread globally and replaced the classical biotype in the current pandemic1. Detailed molecular epidemiological mapping of cholera has been compromised by a reliance on sub-genomic regions such as mobile elements to infer relationships, making El Tor isolates associated with the 7th pandemic appear superficially diverse. To understand the underlying phylogeny of the lineage responsible for the current pandemic we identified high resolution markers (single nucleotide polymorphisms; SNPs) in 154 whole genome sequences of globally and temporally representative V. cholerae isolates. Using this phylogeny we show that the 7th pandemic has spread from the Bay of Bengal in at least three independent but overlapping waves with a common ancestor in the 1950’s and identify multiple transcontinental transmission events. Additionally, we show how the acquisition of the SXT family of antibiotic resistance elements has shaped the pandemic spread and show that it was first acquired at least 10 years prior to its discovery in V. cholerae.
Plant-derived polyphenols are being tested as chemopreventive agents; some polyphenols arrest the cell cycle at G1 phase, whereas others inhibit cell cycle proliferation at G2/M phase. Therefore, polyphenols have been proposed to inhibit cell cycle progression at different phases via distinct mechanisms. Indeed, our previous studies showed that small structural differences in polyphenols cause large differences in their biological activities; however, the details of the structural properties causing G1 cell cycle arrest remain unknown. In this study, we prepared 27 polyphenols, including eight different scaffolds, to gain insight into the structural conditions that arrest the cell cycle at G1 phase in a quantitative structure–activity relationship study. We used cell cycle profiles to determine the biophores responsible for G1 cell cycle arrest and believe that the biophores identified in this study will help design polyphenols that cause G1 cell cycle arrest.
polyphenols; flavonoids; colorectal cancer; cell cycle; QSAR
We measured and assessed ways to reduce the secondary neutron dose from a system for proton eye treatment.
Proton beams of 60.30 MeV were delivered through an eye-treatment snout in passive scattering mode. Allyl diglycol carbonate (CR-39) etch detectors were used to measure the neutron dose in the external field at 0.00, 1.64, and 6.00 cm depths in a water phantom. Secondary neutron doses were measured and compared between those with and without a high-hydrogen–boron-containing block. In addition, the neutron energy and vertices distribution were obtained by using a Geant4 Monte Carlo simulation.
The ratio of the maximum neutron dose equivalent to the proton absorbed dose (H(10)/D) at 2.00 cm from the beam field edge was 8.79 ± 1.28 mSv/Gy. The ratio of the neutron dose equivalent to the proton absorbed dose with and without a high hydrogen-boron containing block was 0.63 ± 0.06 to 1.15 ± 0.13 mSv/Gy at 2.00 cm from the edge of the field at depths of 0.00, 1.64, and 6.00 cm.
We found that the out-of-field secondary neutron dose in proton eye treatment with an eye snout is relatively small, and it can be further reduced by installing a borated neutron absorbing material.
Proton; Secondary; Neutron; CR-39; Boron; Eye
The current Shigella sonnei pandemic involves geographically associated, multidrug-resistant clones. This study has demonstrated that S. sonnei phylogeny can be accurately defined with limited single nucleotide polymorphisms (SNPs). By typing 6 informative SNPs using a high-resolution melting (HRM) assay, major S. sonnei lineages/sublineages can be identified as defined by whole-genome variation.
No study on ultrasound-guided fine-needle aspiration (US-FNA) for the diagnosis of retrojugular lymph node has been reported. The present study aimed to introduce US-FNA techniques for retrojugular lymph node and to evaluate their efficacy.
Of the 788 patients who underwent US-FNA of the cervical lymph node, 41 patients underwent US-FNAs of retrojugular lymph node and were included in this study. The adequacy and efficacy of US-FNA of retrojugular lymph node and related complications during or after the procedure were assessed.
Of the 41 patients, 35 (85.4%) were adequately diagnosed in cytological analysis; four predominantly cystic lymph nodes were identified. Based on cytohistopathology results, thyroglobulin measurement, tuberculosis polymerase chain reaction, and sonographic follow-up, malignant (n = 26) and benign (n = 15) lymph nodes were confirmed. When six lymph nodes with inadequate cytology were classified as benign and malignant, the sensitivity, specificity, positive and negative predictive values, and accuracy of US-FNA in differentiating malignant from benign lesions were 69.2% and 92.3%, 100% and 100%, 100% and 100%, 65.2% and 88.2%, and 80.5% and 95.1%, respectively. No substantial complications related to the US-FNA procedure were observed.
The present US-FNA method may be helpful for the diagnosis of retrojugular lymph node.
Lymph node; Retrojugular; Fine-needle biopsy; Papillary thyroid carcinoma; Metastasis
Klebsiella pneumoniae is a Gram-negative, rod-shaped, nonmotile, and opportunistic pathogenic species with clinical importance. It is a part of natural flora of humans and animals. Here we report the draft genome sequence of the type strain of Klebsiella pneumoniae subsp. pneumoniae (DSM 30104T) to provide taxonomic and functional insights into the species.
Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.
To compare the risk of secondary cancer from scattered and leakage doses following intensity-modulated radiotherapy (IMRT), volumetric arc therapy (VMAT) and tomotherapy (TOMO) in patients with lung cancer.
IMRT, VMAT and TOMO were planned for five lung cancer patients. Organ equivalent doses (OEDs) are estimated from the measured corresponding secondary doses during irradiation at various points 20 to 80 cm from the iso-center by using radio-photoluminescence glass dosimeter (RPLGD).
The secondary dose per Gy from IMRT, VMAT and TOMO for lung cancer, measured 20 to 80 cm from the iso-center, are 0.02~2.03, 0.03~1.35 and 0.04~0.46 cGy, respectively. The mean values of relative OED of secondary dose of VMAT and TOMO, which is normalized by IMRT, ranged between 88.63% and 41.59% revealing 88.63% and 41.59% for thyroid, 82.33% and 41.85% for pancreas, 77.97% and 49.41% for bowel, 73.42% and 72.55% for rectum, 74.16% and 81.51% for prostate. The secondary dose and OED from TOMO became similar to those from IMRT and VMAT as the distance from the field edge increased.
OED based estimation suggests that the secondary cancer risk from TOMO is less than or comparable to the risks from conventional IMRT and VMAT.
IMRT; VMAT; TOMOTHERAPY; Radio-photoluminescence; Secondary dose; OED
Shigella are human-adapted Escherichia coli that have gained the ability to invade the human gut mucosa and cause dysentery1,2, spreading efficiently via low-dose fecal-oral transmission3,4. Historically, S. sonnei has been predominantly responsible for dysentery in developed countries, but is now emerging as a problem in the developing world, apparently replacing the more diverse S. flexneri in areas undergoing economic development and improvements in water quality4-6. Classical approaches have shown S. sonnei is genetically conserved and clonal7. We report here whole-genome sequencing of 132 globally-distributed isolates. Our phylogenetic analysis shows that the current S. sonnei population descends from a common ancestor that existed less than 500 years ago and has diversified into several distinct lineages with unique characteristics. Our analysis suggests the majority of this diversification occurred in Europe, followed by more recent establishment of local pathogen populations in other continents predominantly due to the pandemic spread of a single, rapidly-evolving, multidrug resistant lineage.
Intact immunoglobulin G antibody has a relatively large molecule size of approximately 150 kDa that remains in the bloodstream for many weeks, which is a considerable disadvantage when it is used to carry radioactive materials for imaging. To lower background activity and increase the contrast of images, we investigated antivascular endothelial growth factor (VEGF) receptor 2 antibody (DC101) conjugated dextran for VEGF receptor 2 imaging in tumor xenografted mice. DTPA-conjugated aminodextran was synthesized, reacted with sulfo-LC-SPDP, and then reacted with DC101. The binding affinity of DTPA-dextran-DC101 to Flk-1 was measured. The gamma imaging and biodistributions of 99mTc-DTPA-dextran-DC101, 99mTc-DTPA-DC101, and 125I-DC101 were studied in B16F10 melanoma xenografted mice. The dissociation values for DC101, DTPA-DC101, and DTPA-dextran-DC101 were 22.48, 3.05, and 14.74 pM, respectively. In gamma images, 99mTc-DTPA-dextran-DC101 showed weak liver uptake and rapid kidney elimination. In biodistribution results, the liver uptake of 99mTc-DTPA-dextran-DC101 was similar with that of 99mTc-DTPA-DC101 at each time point. However, the blood activity of 99mTc-DTPA-dextran-DC101 has shown significant differences, compared with 99mTc-DTPA-DC101 at all time points. The tumor accumulation of dextran-conjugated antibody was increased with time, whereas that of dextran nonconjugated antibody decreased. In particular, the pattern of tumor uptake of 99mTc-DTPA-dextran-DC101 was similar to that of 125I-DC101, so this was thought to reflect the kinetics of DC101, unlike the nonconjugated form. The results of this study suggested that introduction of dextran moiety to make 99mTc-radiolabeled DC101 imaging agent could provide better images with the impaired background and the steady increasing binding to the receptor. However, further studies are necessary to improve clinical pharmacokinetics, such as enhancement of tumor uptake and impaired renal uptake.
DC101; dextran; vascular endothelial growth factor receptor 2
Mandibular metastasis of thyroid carcinoma is extremely rare. We present the case of a 46-year-old woman who had bilateral huge cheek masses that had grown rapidly over several years. Intra-oral mucosal tissue biopsy and imaging work-up including computed tomography scan and magnetic resonance imaging were performed and the initial diagnosis was presumed to be central giant cell granuloma. Incidentally detected thyroid lesions were studied with ultra-sonography guided fine needle aspiration and diagnosed as simple benign nodules. Due to continuous oral bleeding and the locally destructive feature of the lesions, we decided to excise the mass surgically. To avoid functional deficit, a stepwise approach was performed: Firstly, the larger left mass was excised and the mandible was reconstructed with a fibular free flap. The final pathologic diagnosis was follicular thyroid cancer. Postoperative I-131 thyroid scan and whole body positron-emissions-tomography were performed. Right side mass was revealed as a thyroid malignancy. Multiple bony metastases were detected. Since further radioactive iodine therapy was required, additional total thyroidectomy and right side mandibulectomy with fibular free flap reconstruction was performed. The patient also underwent high dose radioactive iodine therapy and palliative extra-beam radiotherapy for the metastatic lumbar lesion. Follicular thyroid carcinoma should be considered as a differential diagnosis for mandibular mass lesions.
Follicular; Thyroid; Metastasis; Mandible
Suppressor of cytokine signaling genes (SOCS) are regarded as pivotal negative feedback regulators of cytokine signals, including the interferon-gamma (IFN-γ), granulocyte-colony stimulating factor, and interleukin families, released by T cells. A detailed understanding of the involvement of SOCS genes in graft-versus-host disease (GVHD) is critical to effectively manage GVHD, yet their expression patterns among recipients remain largely unexplored.
Expression levels of SOCS1 and SOCS3 were determined by real-time quantitative reverse transcription PCR (qRT-PCR) in patients with acute GVHD (aGVHD) and chronic GVHD (cGVHD), in a severity-dependent manner, after allogeneic hematopoietic stem cell transplantation (HSCT). A total of 71 recipients with AML (N=40), ALL (N=12), myelodysplastic syndromes (MDS; N=10), chronic myelogenous leukemia (CML; N=2), severe aplastic anemia (SAA; N=5), or others (N=2), who received allogeneic HSCT from human leukocyte antigen-identical siblings or unrelated donors between 2009 and 2011, were included in the present study.
Overall, the expression levels of SOCS1 decreased in recipients with grade II to IV aGVHD and cGVHD when compared to normal donors and non-GVHD recipients. Interestingly, the expressions of SOCS1 decreased significantly more in cGVHD than in aGVHD recipients (P=0.0091). In contrast, SOCS3 expressions were similarly reduced in all the recipients.
This is the first study to show that SOCS1 and SOCS3 are differentially expressed in recipients following allogeneic HSCT, suggesting a prognostic correlation between SOCS genes and the development of GVHD. This result provides a new platform to study GVHD immunobiology and potential diagnostic and therapeutic targets for GVHD.
Suppressor of cytokine signaling proteins; Graft vs. host disease; Quantitative real-time polymerase chain reaction; Allogeneic transplantation
Histone lysine methylation and demethylation are considered critical steps in transcriptional regulation. In this report, we performed chromatin immunoprecipitation with microarray technology (ChIP-chip) analysis to examine the genome-wide occupancy of H3K9-me2 during all-trans-retinoic acid (ATRA)-induced differentiation of HL-60 promyelocytic leukemia cells. Using this approach, we found that KDM3B, which contains a JmjC domain, was downregulated during differentiation through the recruitment of a corepressor complex. Furthermore, KDM3B displayed histone H3K9-me1/2 demethylase activity and induced leukemogenic oncogene lmo2 expression via a synergistic interaction with CBP. Here, we found that KDM3B repressed leukemia cell differentiation and was upregulated in blood cells from acute lymphoblastic leukemia (ALL)-type leukemia patients. The combined results of this study provide evidence that the H3K9-me1/2 demethylase KDM3B might play a role in leukemogenesis via activation of lmo2 through interdependent actions with the histone acetyltransferase (HAT) complex containing CBP.
A series of supramolecular rectangles, including two mixed-metal Ru/Pt complexes, have been formed by the coordination-driven self-assembly of a range of arene-Ru “molecular clip” acceptors (1a-1d) with rigid dipyridyl-based ligands (2a-2d) over the course of 10 hours in solution. The isolated products were characterized by multinuclear NMR (1H and 13C or 31P), HR-ESI-MS and an X-ray diffraction study to support the ascribed two-component rectangular structures. The rectangles were further characterized by UV-Vis and fluorescence studies. The redox behaviors of rectangles 3ca and 3da were also determined using cyclic voltammetry. Additionally, the antitumor activities of the suite of rectangles were determined against various human cancer cell lines and significant activity was shown by complexes 3ca, 3da, 3cb, 3cc and 3cd, with IC50 values as low as 2.65 μM.
The novel Sporolactobacillus vineae SL153T strain has excellent intestinal adherence and growth inhibitory effect on pathogenic microorganisms, including Vibrio genus microorganisms, and therefore can be effectively used for the prevention and treatment of disease caused by pathogenic microorganisms. Here, we first report the draft genome sequence of a novel species in the genus Sporolactobacillus.
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cutaneous lymphomas, accounting for less than 1% of cases of non-Hodgkin’s lymphoma. Fluorine-18 fluorodeoxyglucose (F-18 FDG) positron-emission tomography/computed tomography (PET/CT) findings of SPTCL before and after treatment were rarely reported.
We report a case of SPTCL in which F-18 FDG PET/CT showed increased FDG accumulations in numerous subcutaneous nodules without extracutaneous disease. Contrast-enhanced CT during F-18 FDG PET/CT showed multiple minimally enhancing nodules with an infiltrative pattern in the subcutaneous layer throughout the body. Follow-up F-18 FDG PET/CT after three cycles of CHOP chemotherapy showed a complete metabolic remission of the lesions.
F-18 FDG PET/CT is suggested to be useful in assessing the disease activity, extent and treatment response in SPTCL.
subcutaneous panniculitis-like T-cell lymphoma; F-18 FDG; PET/CT
To understand epidemiologic patterns of meningococcal disease in Asia, we performed a retrospective molecular analysis of cerebrospinal fluid (CSF) specimens collected in prospective surveillance among children aged < 5 years of age in China, South Korea, and Vietnam.
A total of 295 isolates and 2,302 CSFs were tested by a meningococcal species- and serogroup-specific polymerase chain reaction (PCR) assay targeting the Neisseria meningitidis (Nm) ctrA gene. Multi-locus sequence typing (MLST) was performed in Nm gene amplification analysis and incidence rates for meningococcal meningitis were estimated.
Among 295 isolates tested, 10 specimens from Vietnam were confirmed as serogroup B and all were Sequence Type (ST) 1576 by MLST. Among the 2,032 CSF specimen tested, 284 (14%) were confirmed by PCR (ctrA gene), including 67 (23.6%) from China, 92 (32.4%) from Korea, and 125 (44.0%) from Vietnam. Neonates and infants aged < 6 months of age accounted for more than 50% of Nm-PCR positive CSF. Two CSF specimens from Vietnam were identified as serogroup B using MLST. In addition, 44 specimens underwent sequencing to confirm meningococcal serogroup; of these, 21 (48%) were serogroup C, 12 (27%) were serogroup X, 9 (20%) were serogroup Y and 2 (5%) were serogroup B. The incidence rates of meningococcal meningitis among children < 5 years of age was highest in Vietnam (7.4/100,000 [95% CI, 3.6—15.3] followed by Korea (6.8/100,000 [95% CI, 3.5-13.5] and China (2.1/100,000) [95% CI, 0.7-6.2]).
These results suggest that there is a previously undetected, yet substantial burden of meningococcal meningitis among infants and young children. Standardized, sensitive and specific molecular diagnostic assays with Nm serogrouping capacity are needed throughout Asia to understand the true burden of N. meningitidis disease.
Cerebrospinal fluid; Meningococcal meningitis; Neisseria meningitidis; Serogroup; Surveillance
A new Peptoniphilus species has been isolated from samples from a patient who was scheduled for endoscopic sinus surgery for chronic rhinosinusitis. The isolate, Peptoniphilus rhinitidis 1-13T (KCTC 5985T), can use peptone as a sole carbon source and produce butyrate as a metabolic end product. This is the first report of the draft genome sequence of a novel species in the genus Peptoniphilus within the group of Gram-positive anaerobic cocci.
A new Clostridium species has been isolated from pear orchard soil in Daejeon, Republic of Korea. The isolate, Clostridium arbusti SL206T (KCTC 5449T), showed a nitrogenase activity as well as an organic acid production. Here we first report the draft genome sequence of a novel species in the genus Clostridium within the largest Gram-positive group.
A new Myroides species has been isolated from the urine of a patient with fever in spite of multiple antibiotic treatments who had undergone a radical hysterectomy for cervical cancer and percutaneous nephrostomies for hydronephrosis in the past. The isolate, Myroides
injenensis M09-0166T (KCTC 23367T), showed a high level of resistance to multiple antibiotic agents. Here we provide the first report of the draft genome sequence of a novel species in the genus Myroides within the nonfermenting Gram-negative group.