Regulation of Early Lymphocyte Development via mRNA Decay Catalyzed by the CCR4-NOT Complex

Development of lymphocytes is precisely regulated by various mechanisms. In addition to transcriptional rates, post-transcriptional regulation of mRNA abundance contributes to differentiation of lymphocytes. mRNA decay is a post-transcriptional mechanism controlling mRNA abundance. The carbon catabolite repression 4 (CCR4)-negative on TATA-less (NOT) complex controls mRNA longevity by catalyzing mRNA deadenylation, which is the rate-limiting step in the mRNA decay pathway. mRNA decay, regulated by the CCR4-NOT complex, is required for differentiation of pro-B to pre-B cells and V(D)J recombination in pro-B cells. In this process, it is likely that the RNA-binding proteins, ZFP36 ring finger protein like 1 and 2, recruit the CCR4-NOT complex to specific target mRNAs, thereby inducing cell quiescence of pro-B cells. A recent study showed that the CCR4-NOT complex participates in positive selection of thymocytes. Mechanistically, the CCR4-NOT deadenylase complex inhibits abnormal apoptosis by reducing the expression level of mRNAs encoding pro-apoptotic proteins, which are otherwise up-regulated during positive selection. We discuss mechanisms regulating CCR4-NOT complex-dependent mRNA decay in lymphocyte development and selection

Nemertean and phoronid genomes reveal lophotrochozoan evolution and the origin of bilaterian heads

Nemerteans (ribbon worms) and phoronids (horseshoe worms) are closely related lophotrochozoans—a group of animals including leeches, snails and other invertebrates. Lophotrochozoans represent a superphylum that is crucial to our understanding of bilaterian evolution. However, given the inconsistency of molecular and morphological data for these groups, their origins have been unclear. Here, we present draft genomes of the nemertean Notospermus geniculatus and the phoronid Phoronis australis, together with transcriptomes along the adult bodies. Our genome-based phylogenetic analyses place Nemertea sister to the group containing Phoronida and Brachiopoda. We show that lophotrochozoans share many gene families with deuterostomes, suggesting that these two groups retain a core bilaterian gene repertoire that ecdysozoans (for example, flies and nematodes) and platyzoans (for example, flatworms and rotifers) do not. Comparative transcriptomics demonstrates that lophophores of phoronids and brachiopods are similar not only morphologically, but also at the molecular level. Despite dissimilar head structures, lophophores express vertebrate head and neuronal marker genes. This finding suggests a common origin of bilaterian head patterning, although different heads evolved independently in each lineage. Furthermore, we observe lineage-specific expansions of innate immunity and toxin-related genes. Together, our study reveals a dual nature of lophotrochozoans, where conserved and lineage-specific features shape their evolution

The CCR4–NOT deadenylase complex safeguards thymic positive selection by down-regulating aberrant pro-apoptotic gene expression

A repertoire of T cells with diverse antigen receptors is selected in the thymus. However, detailed mechanisms underlying this thymic positive selection are not clear. Here we show that the CCR4-NOT complex limits expression of specific genes through deadenylation of mRNA poly(A) tails, enabling positive selection. Specifically, the CCR4-NOT complex is up-regulated in thymocytes before initiation of positive selection, where in turn, it inhibits up-regulation of pro-apoptotic Bbc3 and Dab2ip. Elimination of the CCR4-NOT complex permits up-regulation of Bbc3 during a later stage of positive selection, inducing thymocyte apoptosis. In addition, CCR4-NOT elimination up-regulates Dab2ip at an early stage of positive selection. Thus, CCR4-NOT might control thymocyte survival during two-distinct stages of positive selection by suppressing expression levels of pro-apoptotic molecules. Taken together, we propose a link between CCR4-NOT-mediated mRNA decay and T cell selection in the thymus

Phase I clinical study of anti-apoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer

Survivin is a member of the inhibitor of apoptosis protein (IAP) family containing a single baculovirus IAP repeat domain. It is expressed during fetal development but becomes undetectable in terminally differentiated normal adult tissues. We previously reported that survivin and its splicing variant survivin-2B was expressed abundantly in various types of tumor tissues as well as tumor cell lines and was suitable as a target antigen for active-specific anti-cancer immunization. Subsequently, we identified an HLA-A24-restricted antigenic peptide, survivin-2B80-88 (AYACNTSTL) recognized by CD8+ cytotoxic T lymphocytes (CTLs). We, therefore, started a phase I clinical study assessing the efficacy of survivin-2B peptide vaccination in patients with advanced or recurrent colorectal cancer expressing survivin. Vaccinations with survivin-2B peptide were given subcutaneously six times at 14-day intervals. Of 15 patients who finished receiving the vaccination schedule, three suffered slight toxicities, including anemia (grade 2), general malaise (grade 1), and fever (grade 1). No severe adverse events were observed in any patient. In 6 patients, tumor marker levels (CEA and CA19-9) decreased transiently during the period of vaccination. Slight reduction of the tumor volume was observed in one patient, which was considered a minor responder. No changes were noted in three patients while the remaining eleven patients experienced tumor progression. Analysis of peripheral blood lymphocytes of one patient using HLA-A24/peptide tetramers revealed an increase in peptide-specific CTL frequency from 0.09% to 0.35% of CD8+ T cells after 4 vaccinations. This phase I clinical study indicates that survivin-2B peptide-based vaccination is safe and should be further considered for potential immune and clinical efficacy in HLA-A24-expression patients with colorectal cancer

Clinical studies on polypoid lesions of the colon.

1990年4月より1994年3月末までの間に岡山大学医学部附属病院三朝分院で経験した早期大腸癌を含む大腸ポリープ88例を対象に,病理組織診断,性別,年齢構成,存在部位,精査動機について検討を行い,以下の成績を得た｡(1)ポリープの69.2%は腺腫,13.2%は腺癌(早期癌)であった｡(2)男女とも加齢による大腸ポリープ及び大腸癌の頻度の増加がみられた｡(3)50歳未満の若年者では右側結腸にポリープが発見されることは稀であったが50歳以上では6.5%に認められ,高齢者における積極的なtotal colonoscopyによる観葉が重要であることが再確認された｡(4)精査動機では便潜血陽性が最多を占め,便潜血は大腸ポリープのスクリーニングにおいて有用であることが示された｡またフォローアップ目的に大腸ファイバーを施行しポリープや早期癌を発見した例も多く,フォローアップの必要性が示唆された。Polypoid lesions, taken by a colon fiberscope, were examined in 88 patients with polyp, who were admitted to Misasa Medical Branch, Okayama University Medical School for last 4 years. (1) Pathohistological examination of the polypoid lesions resulted in 69.2% of adenoma and 13.2% of adenocarcinoma (early cancer) ; (2) 35.5% of the polypoid lesions was detected in the sigmoid colon, 32.7% in the rectum, 16.8% in the transverse colon, 4.7% in the descending colon, 3.7% in the caecum, 1.9% in the ascending colon ; (3) The number of patients with polypoid lesion or colon cancer was increased with aging ; (4) Patients with the age under 50 years did not have polypoid lesion in the right hemicolon, while 6.5% of elder patients over age 50 has polypoid lesions in the right hemicolon ; (5) Occult blood in stool was the most popular motivation for receiving colonoscopic examinations ; (6) The second popular motivation for colonoscopy was for follow up after previous examinations. These results suggest that patients with age over 50 should be examined more carefully by total colonoscopy, and a hemoccult test in stool is an effective method for screening colonic polypoid lesions and after detection of polypoid lesions or polypectomy, reexamination by total colonoscopy is important at regular intervals

Two male steroid-dependent asthmatics treated with etidronate

男性のステロイド依存性気管支喘息患者にエチドロネートを4年間の長期間にわたり投与した経験を得たので報告する｡症例は,男性のステロイド依存性気管支喘息で,エチドロネート200mg/日･14日間投与を4ケ月おきに4年間にわたり反復投与し,活性型ビタミンD製剤 (VD)投与と併用した2例と,活性型VD製剤を単独授与した2例｡椎体圧迫骨折数,境骨耗骨密度,海綿骨骨密度,皮質骨骨密度について,椎体X線像,PQCT(Stratec XCT960)を用いて4ケ月毎に測定し,48ケ月後の効果を検討した｡エチドロネートを投与した症例1では,総骨密度と海綿骨はやや増加を認め皮質骨密度は減少していた｡エチドロネートを授与した症例2では,総骨密度,海綿骨,皮質骨密度はいずれも減少を認めたが,VD単独投与した2例よりもやや減少が抑制されていたようであった｡VD単独投与した2例ではいずれの項目も減少を認めた｡これらの症例からは,エチドロネートは男性のステロイドによる骨傷害にも有効と考えられたが,現在投与継続途中であり,今後さらに検討を続ける必要がある｡We report an experience about administration of etidronate to male steroid-dependent asthmatics for a long time. For 4 years, two men with steroid-dependent asthma were treated with etidronate (200 mg / day, for 14 days) every 4 months and 25-hydroxyvitamin D3 (VD) together, and two patients were treated with VD alone. Vertebral fractures were evaluated by the lateral spinal X-ray films, and radial total bone mineral density (BMD) , trabecular BMD and the cortical BMD were measured by pQCT (Stratec XCT960) every four months. Trabecular and total BMD increased but cortical BMD decreased in the case 1 who was treated with both etidronate and VD. In the case 2 with etidronate and VD treatments, total and trabecular BMD decreased, but reduction of these indices seemed to be more suppressed than that in two patients with VD alone. According to these experiences, etidronate may be effective against the steroid-induced bone injury in men. Since periods treatment are not en-ough long to evaluate therapeutic effect of etid-ronate, we will have to continue the examination of these cases further more from now on

Intracellular Trafficking of the Amyloid β-Protein Precursor (APP) Regulated by Novel Function of X11-Like

Background: Amyloid beta (A beta), a causative peptide of Alzheimer's disease, is generated by intracellular metabolism of amyloid beta-protein precursor (APP). In general, mature APP (mAPP, N- and O-glycosylated form) is subject to successive cleavages by alpha- or beta-, and gamma-secretases in the late protein secretory pathway and/or at plasma membrane, while immature APP (imAPP, N-glycosylated form) locates in the early secretory pathway such as endoplasmic reticulum or cis-Golgi, in which imAPP is not subject to metabolic cleavages. X11-like (X11L) is a neural adaptor protein composed of a phosphotyrosine-binding (PTB) and two C-terminal PDZ domains. X11L suppresses amyloidogenic cleavage of mAPP by direct binding of X11L through its PTB domain, thereby generation of A beta lowers. X11L expresses another function in the regulation of intracellular APP trafficking. Methodology: In order to analyze novel function of X11L in intracellular trafficking of APP, we performed a functional dissection of X11L. Using cells expressing various domain-deleted X11L mutants, intracellular APP trafficking was examined along with analysis of APP metabolism including maturation (O-glycosylation), processing and localization of APP. Conclusions: X11L accumulates imAPP into the early secretory pathway by mediation of its C-terminal PDZ domains, without being bound to imAPP directly. With this novel function, X11L suppresses overall APP metabolism and results in further suppression of Ab generation. Interestingly some of the accumulated imAPP in the early secretory pathway are likely to appear on plasma membrane by unidentified mechanism. Trafficking of imAPP to plasma membrane is observed in other X11 family proteins, X11 and X11L2, but not in other APP-binding partners such as FE65 and JIP1. It is herein clear that respective functional domains of X11L regulate APP metabolism at multiple steps in intracellular protein secretory pathways

The Overseeing Mother: Revisiting the Frontal-Pose Lady in the Wu Family Shrines in Second Century China

Located in present-day Jiaxiang in Shandong province, the Wu family shrines built during the second century in the Eastern Han dynasty (25–220) were among the best-known works in Chinese art history. Although for centuries scholars have exhaustively studied the pictorial programs, the frontal-pose female image situated on the second floor of the central pavilion carved at the rear wall of the shrines has remained a question. Beginning with the woman’s eyes, this article demonstrates that the image is more than a generic portrait (“hard motif ”), but rather represents “feminine overseeing from above” (“soft motif ”). This synthetic motif combines three different earlier motifs – the frontal-pose hostess enjoying entertainment, the elevated spectator, and the Queen Mother of the West. By creatively fusing the three motifs into one unity, the Jiaxiang artists lent to the frontal-pose lady a unique power: she not only dominated the center of the composition, but also, like a divine being, commanded a unified view of the surroundings on the lofty building, hence echoing the political reality of the empress mother’s “overseeing the court” in the second century during Eastern Han dynasty

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)