Peptidyl prolyl isomerase Pin1-inhibitory activity of d-glutamic and d-aspartic acid derivatives bearing a cyclic aliphatic amine moiety

AbstractPin1 is a peptidyl prolyl isomerase that specifically catalyzes cis–trans isomerization of phosphorylated Thr/Ser-Pro peptide bonds in substrate proteins and peptides. Pin1 is involved in many important cellular processes, including cancer progression, so it is a potential target of cancer therapy. We designed and synthesized a novel series of Pin1 inhibitors based on a glutamic acid or aspartic acid scaffold bearing an aromatic moiety to provide a hydrophobic surface and a cyclic aliphatic amine moiety with affinity for the proline-binding site of Pin1. Glutamic acid derivatives bearing cycloalkylamino and phenylthiazole groups showed potent Pin1-inhibitory activity comparable with that of known inhibitor VER-1. The results indicate that steric interaction of the cyclic alkyl amine moiety with binding site residues plays a key role in enhancing Pin1-inhibitory activity

Irradiation Accelerates Plaque Formation and Cellular Senescence in Flow‐Altered Carotid Arteries of Apolipoprotein E Knock‐Out Mice

[Background] Chronic inflammation through cellular senescence, known as the senescence‐associated secretory phenotype, is a mechanism of various organ diseases, including atherosclerosis. Particularly, ionizing radiation (IR) contributes to cellular senescence by causing DNA damage. Although previous clinical studies have demonstrated that radiotherapy causes atherosclerosis as a long‐term side effect, the detailed mechanism is unclear. This study was conducted to investigate the relationship between radiation‐induced atherosclerosis and senescence‐associated secretory phenotype in murine carotid arteries. [Methods and Results] Partial ligation of the left carotid artery branches in 9‐week‐old male apolipoprotein E‐deficient mice was performed to induce atherosclerosis. The mice received total body irradiation at a dose of 6 Gy using gamma rays at 2 weeks post operation. We compared the samples collected 4 weeks after IR with unirradiated control samples. The IR and control groups presented pathologically progressive lesions in 90.9% and 72.3% of mice, respectively. Plaque volume, macrophage accumulation, and phenotype switching of vascular smooth muscle cells were advanced in the IR group. Irradiated samples showed increased persistent DNA damage response (53BP1 [p53 binding protein 1]), upregulated cyclin‐dependent kinase inhibitors (p16INK4a and p21), and elevated inflammatory chemokines expression (monocyte chemotactic protein‐1, keratinocyte‐derived chemokine, and macrophage inflammatory protein 2). [Conclusions] IR promoted plaque growth in murine carotid arteries. Our findings support the possibility that senescence‐associated secretory phenotype aggravates atherogenesis in irradiated artery. This mice model might contribute to mechanism elucidation of radiation‐induced atherosclerosis

R-mini CHP in ≥80-year-old Patients with Diffuse Large B-cell Lymphoma: A Multicenter, Open-label, Single-arm Phase II Trial Protocol

In very-elderly diffuse large B-cell lymphoma (DLBCL) patients, treatment intensities must be lowered due to the risks of comorbidities and organ function deterioration, and treatment outcomes are worse compared to younger patients. Very-elderly patients are often excluded from DLBCL clinical trials, and optimal treatments and dosages are not established. In this clinical trial, we examined the efficacy and safety of 6 courses of R-mini CHP therapy (cf., CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone]) in which vincristine is omitted to avoid the peripheral neuropathy that reduces elderly patients’ quality of life, as remission induction therapy in DLBCL patients aged≥80 years

Reactive oxygen metabolites as a biomarker of congenital heart disease in children

　Brain natriuretic peptide (BNP), as a hematological biomarker, has been widely used in congenital heart disease (CHD). However, its sensitivity and specificity vary depending on age and pathological condition. In the present study, we assessed whether reactive oxygen metabolites (ROMs) and biological antioxidant potential (BAP), as oxidative stress indicators, could be new biomarkers in CHD.　Forty-two patients diagnosed with CHD were enrolled in this study. The levels of ROMs, BAP, BNP, cardiac muscle creatinine kinase, and heart-type fatty acid-binding protein were measured using the findings of echocardiography. The ROM and BNP levels were significantly higher than the standard reference levels. The estimated Qp/Qs correlated mildly with BNP and ROM levels. The medication caused a significant decrease in BNP and ROM levels. The optimal decision, Qp/Qs greater than 1.5, estimated from receiver operator characteristic (ROC) curves was 371 U.CARR (58% sensitivity, 90% specificity) for ROMs, and that for BNP was 28.4 pg/ml (97% sensitivity 45% specificity). Direct comparison of ROMs and BNP did not show significantly different area under the curve values.　ROM levels can be a new biomarker for oxidative stress evaluation in children with CHD at almost the same sensitivity as the previous biomarkers, and an effective indicator when combined with other biomarkers and indicators

The MAXI Mission on the ISS: Science and Instruments for Monitoring All Sky X-Ray Images

The MAXI (Monitor of All-sky X-ray Image) mission is the first astronomical payload to be installed on the Japanese Experiment Module-Exposed Facility (JEM-EF) on the ISS. It is scheduled for launch in the middle of 2009 to monitor all-sky X-ray objects on every ISS orbit. MAXI will be more powerful than any previous X-ray All Sky Monitor (ASM) payloads, being able to monitor hundreds of AGN. MAXI will provide all sky images of X-ray sources of about 20 mCrab in the energy band of 2-30 keV from observation on one ISS orbit (90 min), about 4.5 mCrab for one day, and about 1 mCrab for one month. A final detectability of MAXI could be 0.2 mCrab for 2 year observations.Comment: 12 pages, 11 figures, accepted for publication in Publications of the Astronomical Society of Japa

Progressing takayasu arteritis successfully treated by common carotid-internal carotid crossover bypass grafting: technical case report.

OBJECTIVE: This report describes a unique case of Takayasu arteritis with occlusion of the left common carotid artery (CCA) and the right internal carotid artery (ICA), which was successfully treated by right CCA-left ICA crossover bypass grafting using the saphenous vein. The histological findings of the original occluded prosthetic graft are also described. CLINICAL PRESENTATION: A 63-year-old woman with a history of Takayasu arteritis was admitted to our hospital with a history of progressive dizziness, frequent syncopal attacks, and repetitive blurred vision in the left eye. She had undergone repeat transthoracic bypass surgeries, including grafting with the use of a Gore-Tex (W.L. Gore & Associates, Inc., Flagstaff, AZ) prosthesis between the left external ilioaxillary bypass and the left CCA. However, cerebral angiography demonstrated total occlusion of the left CCA, the right ICA, and the bilateral subclavian arteries. On admission, I-iodoamphetamine single-photon emission computed tomography showed a decreased cerebrovascular reactivity to acetazolamide in the bilateral cerebral hemispheres. Moreover, cerebral angiography revealed an occlusion of the Gore-Tex graft, whereas the left ICA was opacified through the retrograde filling in the left external carotid artery. INTERVENTION: Crossover bypass grafting was performed using the saphenous vein between the right CCA and the left ICA. The Gore-Tex graft was partially removed, and myointimal hypertrophy with an inflammatory response around the wall was found histologically. The postoperative course was uneventful. A normalized cerebrovascular reserve in both cerebral hemispheres was demonstrated on I-iodoamphetamine single-photon emission computed tomography. CONCLUSION: Although it is not frequently indicated, crossover bypass grafting using the saphenous vein between bilateral carotid arteries is considered to be a feasible alternative procedure in patients with Takayasu arteritis.This is a non-final version of an article published in final form in Neurosurgery, 65(5), pp.1178-1179; 2008

Long-term survival with RAS-associated autoimmune leukoproliferative disorder with somatic KRAS mutation:A case report

　RAS -associated autoimmune leukoproliferative disorder (RALD) is a recently reported rare nonmalignant autoimmune disorder. The characteristic clinical findings of RALD include monocytosis, leukocytosis, lymphoproliferation, and autoimmune phenomena. RALD is defined by somatic mutations in KRAS or NRAS . It is a new disease that was reported by Niemela and Takagi in 2011. The prognosis and incidence are currently unknown and the treatment strategy has not yet been established.　Here we describe the long-term survival of a patient with who displayed a somatic KRAS G12D mutation. His clinical features and labolatory data were overlapped with juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Mercaptopurine hydrate, hydroxycarbamide and azacitizine were administered to control white blood cell count and improve clinical symptoms. He had a long survival time without hematopoietic stem cell transplantation

Safety of JAK and IL-6 inhibitors in patients with rheumatoid arthritis: a multicenter cohort study

BackgroundThe ORAL Surveillance trial showed a potentially higher incidence of malignancy and major adverse cardiovascular events (MACEs) associated with tofacitinib than those associated with tumor necrosis factor (TNF) inhibitors (TNFis). However, few studies have compared the safety of non-TNFis or other Janus kinase (JAK) inhibitors (JAKis). This study was aimed at comparing the incidence rates (IRs) of malignancies and MACEs in patients with rheumatoid arthritis (RA) treated using interleukin-6 (IL-6) inhibitors (IL-6is) or JAKis.MethodsWe retrospectively analyzed 427 patients with RA who were treated using an IL-6i (n = 273) or a JAKi (n = 154). We determined the IRs of malignancy and MACEs, and the standardized incidence ratio (SIR) of malignancies and investigated factors related to malignancy and MACEs. After adjusting the clinical characteristic imbalance by propensity score matching (PSM), we compared the IRs of adverse events between the JAKi and IL-6i groups.ResultsAfter PSM, the observational period was determined to be 605.27 patient-years (PY), and the median observational period was determined to be 2.28 years. We identified seven cases of malignancy (IR: 2.94 per 100 PY) in the JAKi-treated group and five cases (IR: 1.36 per 100 PY) in the IL-6i-treated group after PSM. The IR of MACEs was 2.56 and 0.83 (per 100 PY) in the JAKi- and IL-6i-treated groups. The IRRs of JAKi-treated patients versus IL-6i-treated patients were 2.13 (95% confidence interval (CI): 0.67–7.42) for malignancy and 3.03 (95% CI: 0.77–15.21) for MACE. There were no significant differences in IRR for malignancy and MACE between both groups after PSM. Univariate and multivariable Cox regression analyses revealed that older age and JAKi use were independent risk factors for malignancy, while older age, hypertension, and JAKi use were independent risk factors for MACEs. The overall malignancy SIR was significantly higher in the JAKi-treated group compared to the general population (2.10/100 PY, 95% CI: 1.23–2.97).ConclusionThe IRs of malignancy and MACE in patients with RA after PSM were comparable between IL-6i-treated and JAKi-treated patients. However, the SIR of malignancy in JAKi treatment was significantly higher than in the general population; therefore, further safety studies comparing JAKi to non-TNFi biologic disease-modifying antirheumatic drugs (bDMARDs) are needed

The vertebrate phylotypic stage and an early bilaterian-related stage in mouse embryogenesis defined by genomic information

BACKGROUND: Embryos of taxonomically different vertebrates are thought to pass through a stage in which they resemble one another morphologically. This "vertebrate phylotypic stage" may represent the basic vertebrate body plan that was established in the common ancestor of vertebrates. However, much controversy remains about when the phylotypic stage appears, and whether it even exists. To overcome the limitations of studies based on morphological comparison, we explored a comprehensive quantitative method for defining the constrained stage using expressed sequence tag (EST) data, gene ontologies (GO), and available genomes of various animals. If strong developmental constraints occur during the phylotypic stage of vertebrate embryos, then genes conserved among vertebrates would be highly expressed at this stage. RESULTS: We established a novel method for evaluating the ancestral nature of mouse embryonic stages that does not depend on comparative morphology. The numerical "ancestor index" revealed that the mouse indeed has a highly conserved embryonic period at embryonic day 8.0–8.5, the time of appearance of the pharyngeal arch and somites. During this period, the mouse prominently expresses GO-determined developmental genes shared among vertebrates. Similar analyses revealed the existence of a bilaterian-related period, during which GO-determined developmental genes shared among bilaterians are markedly expressed at the cleavage-to-gastrulation period. The genes associated with the phylotypic stage identified by our method are essential in embryogenesis. CONCLUSION: Our results demonstrate that the mid-embryonic stage of the mouse is indeed highly constrained, supporting the existence of the phylotypic stage. Furthermore, this candidate stage is preceded by a putative bilaterian ancestor-related period. These results not only support the developmental hourglass model, but also highlight the hierarchical aspect of embryogenesis proposed by von Baer. Identification of conserved stages and tissues by this method in various animals would be a powerful tool to examine the phylotypic stage hypothesis, and to understand which kinds of developmental events and gene sets are evolutionarily constrained and how they limit the possible variations of animal basic body plans