Journal articles on the topic '1086'

Значимата стеноза на ствола на лява коронарна артерия (ЛКА) е сериозно увреждане, което поставя голяма миокардна територия под риск, като се установява при 4-9% от пациен- тите, насочени за инвазивно изследване. Реваскуларизацията при пациенти със сигнификантна стволова стеноза значително подобрява тяхната прогноза, като байпас хирургията е стандарт за лечение. Перкутанната коронарна интервенция (ПКИ) се доказа като алтернативна, ефективна и безопасна процедура, особено при пациенти с по-малко сложни лезии или неподходящи за опе- рация. Цел на настоящата статия е да се направи обзор на темата и да се анализира честотата на неблагоприятни сърдечно-съдови събития при двугодишно проследяване на пациенти с ПКИ на непротектирана стволова стеноза от реалната практика. Материал и методи: От март 2013 го- дина всички пациенти с проведена интервенционална процедура на стволова стеноза в клиника „Кардиология“ на Аджибадем Сити Клиник МБАЛ Токуда се включват в регистър. За периода от 06.2013 год. до 06.2018 год. са проведени 209 ПКИ на стволови лезии, като в настоящата сту- дия е анализирана серия от 136 последователни пациенти с ПКИ на непротектирана стволова стеноза. Средният Syntax Score (SS) на изследваната група е 26,3 ± 10,09 (11-58,5) при медиана 24,00. Средният Euro Score е 2,61 ± 4,19 (0,50-34,42) при медиана 1,22. При всички изследвани е постигната максимална реваскуларизация, като пациентите със STEMI и/или кардиогенен шок, предшестваща ПКИ на ствола и протектиран ствол са изключени от анализа. Пациентите са про- следени в продължение на 2 години за комбинирания показател неблагоприятни сърдечно-съдови събития, който включва смърт по всяка причина (т.нар. обща смъртност), сърдечна смърт, инсулт и повторна реваскуларизация. Резултати: Регистрирани са 22 неблагоприятни събития (16,2%). Общата смъртност е 9,6%, сърдечна смърт – 8,8%, мозъчен инсулт – 0,7% и рестеноза и повторна реваскуларизация – 8,1%. Заключение: ПКИ на стволова стеноза при пациенти от реалната кли- нична практика и постигането на максимална реваскуларизация е процедура с минимални риско- ве и благоприятни резултати при проследяване, като от значение е опитът на оператора и възмож- ностите на съответното лечебно заведение за провеждане на такъв вид комплексни интервенции.

Представяме случай на 80-годишна жена с исхемична болест на сърцето, която в продължение на няколко седмици преминава от състояние на високостепенна митрална регургитация в състояние на практически липсваща такава и обратно, без ясна връзка с клиничните ѝ оплаквания. Обсъждат се възможните диференциални диагнози и избраният терапевтичен подход към пациентката.

Въвеждането на блокаторите на бета-адренергичните рецептори (бета-блокерите – ББ) в клиничната практика през втората половина на XX век, откри нови възможности в лечението на сърдечно-съдовите заболявания. Те бързо намериха своето място в лечението на исхемичната болест на сърцето и артериалната хипертония. В края на XX и началото на XXI век се появиха много доказателства за ползата от приложението им при болните със сърдечна недостатъчност с понижена фракция на изтласкване на лявата камера (ФИЛК). Лечението с ББ показа благоприя- тен ефект както по отношение на намаляване на смъртността и хоспитализациите, така и за подо- бряване качеството на живот на болните. Тази година излезе новото ръководство за диагностика и лечение на острата и хронична сърдечна недостатъчност на Европейското кардиологично дру- жество (ЕКД). Съгласно него, ББ отново заемат ключово място в лечението на тези болни. Целта на настоящия обзор е да разгледа подробно тяхното приложение при това състояние.

Вертебро-базиларната система (ВБС) играе съществена роля в кръвоснабдяването на жизнено важни структури на нервната система. Като част от Вилизиевия кръг, тя допринася за големите компенсаторни възможности на мозъчната циркулация при някои хемодинамични нарушения. От друга страна, някои патологичните процеси, засягащи ВБС, могат да бъдат фатални или да доведат до тежки увреди и функционални дефицити при пациента. Множеството вариетети и аномалии на ВБС са честа причина за хемодинамични нарушения и съдово засягане от болестни процеси като атеросклерозата. Доброто познаване на вариететите, както и на анатомията ни позволяват да разберем патофизиологията и патогенезата на тези нарушения, което заедно с характерната клинична изява спомага за по-бързото и точно поставяне на диагнозата. Това стои в основата на започване на правилно лечение.

В статье рассматривается окружение византийского императора Алексея I Комнина (1056 / 1057–1118), воссозданное по источникам его эпохи («Алексиаде» Анны Комнины [1083–1053], «Типикону» Григория Пакуриана [ум. 1086 г.] и другим). В контексте византийской историографии и современной византинистики обсуждаются факты из жизни наиболее ярких представителей Востока – Григория Пакуриана и Татикия (ок. 1056 – п. 1099). Изучается их происхождение, карьерный путь, практика инкорпорирования в социальную и политическую структуру Ромейской империи. The paper examines the environment of the Byzantine emperor Alexios I Komnenos (1056 / 1057–1118), reconstructed on sources of his epoch (“Alexias”of Anna Comnenae [1083–1053], “Typicon” of Gregory Pacurianus [d. 1086] and others). In the context of Byzantine historiography and modern Byzantine studies, facts from the life of the most prominent representatives of the East – Gregory Pakurian and Tatikios (c. 1056–1099) are discussed. Information on their origins is analyzed, their careers and the practice of inclusion in the social and political structure of the Roman Empire are studied.

El artículo analiza un pasaje autobiográfico de la vida de al-Ṭurṭūšī (c. 451/1059-520/1126, o Ŷumādā al-awwal 525/abril de 1131) contenido en el Siyar A‘lām al-Nubalā’ de al-Ḏahabī (673/1274-748/1348). El texto informa sobre una notable serie de fenómenos meteorológicos acaecidos durante la visita de al-Ṭurṭūšī a Bagdad en 478/1085-86. Fierro interpretó la historia como la descripción de un eclipse y como el origen del cambio de al-Ṭurṭūšī hacia el ascetismo, paralela a una historia similar sobre el anterior Muḥammad Iḅn Waḍḍāḥ. Aquí demuestro, basado en registros astronómicos, que no hubo eclipse en aquel tiempo en Bagdad, por lo que en consecuencia, lo que al-Ṭurṭūšī experimentó no pudo haber sido tal. Además, al-Ṭurṭūšī tampoco lo entendió así. No pudo, por lo tanto, haber sido la causa de su vuelta al ascetismo. La descripción apunta más bien a una tormenta de polvo o simún. Por lo tanto, no hay vínculo alguno, literario o de otro orden, entre este punto de la vida de al-Ṭurṭūšī y el de Muḥammad Iḅn Waḍḍāḥ.

England was a rich prize for William the Conqueror to have won at the battle of Hastings. His conquest was followed by a major redistribution of the wealth of his new kingdom. By the end of his reign, a tenurial revolution had swept through the lay landholding community, leaving only a handful of Anglo-Saxons as tenants-in-chief. The Church had undergone considerable changes of personnel; only one bishopric was still in English hands (Worcester), and of the greater Benedictine houses only Bath and Ramsey were still ruled by English abbots. Domesday Book, the great survey of England made in 1086, although difficult to interpret, provides much information to enable an examination of ecclesiastical wealth, its nature, and its distribution, in the late eleventh century.

A computational study on thermal stability was conducted the first time, combining the modified quasi-chemical model, the Antoine equation, and the adiabatic flash evaporation calculation principle to design a method to calculate the system pressure-temperature (P-T) phase diagram of binary chloride molten salts. The evaporation temperature of the molten salt obtained by analyzing the P-T phase diagram of the eutectic molten salt clearly defined the upper limit of the optimal operating temperature of the mixed molten salt. The results indicated that the upper-temperature limits of NaCl-KCl, NaCl-CaCl2, KCl-CaCl2, NaCl-MgCl2, and KCl-MgCl2 are determined to be 1141 K, 1151 K, 1176 K, 1086 K, and 1068 K. The maximum working temperature was measured experimentally using a thermogravimetric analysis (TGA), and the relative error between the calculation and experiment was calculated. The maximum error between the calculated and experimental values of the maximum operating temperature was 6.02%, while the minimum was 1.29%, demonstrating the method’s high accuracy. Combined with the lowest eutectic temperature and the upper-temperature limits of binary chloride molten salts, the stable operating temperature ranges of NaCl-KCl, NaCl-CaCl2, KCl-CaCl2, NaCl-MgCl2, and KCl-MgCl2 are 891~1141 K, 750~1151 K, 874~1176 K, 732~1086 K, and 696~1086 K.

Abstract Abstract 2902 NF-kB plays a crucial role in the pathogenesis of multiple myeloma (MM). In MM cells, NF-kB pathway is constitutively activated and regulates transcription of genes whose protein products mediate proliferation, survival and drug resistance. In the context of the bone marrow (BM) microenvironment, NF-kB modulates the expression of cytokines (ie, IL6, TNFalpha) and adhesion molecules (ie, ICAM-1). Importantly, these cytokines and adhesion to BM stromal cells (BMSCs) further activate NF-kB pathway. Previous studies have shown that both canonical and non-canonical pathways contribute to total NF-kB activity in MM cells. Therefore inhibition of both pathways is necessary to target NF-kB. However, current therapeutic strategies can only inhibit the canonical, but not the non-canonical pathway. In this study, we examined the biologic impact of dual inhibition of both canonical and non-canonical pathways in MM cells using a novel small molecule inhibitor PBS-1086 (Profectus BioSciences) which selectively inhibits binding of Rel family member proteins to DNA. Importantly, the binding activity of all Rel family member proteins (RelA, RelB, NF-kB1, NF-kB2, cRel) to DNA was inhibited by PBS-1086, confirming that PBS-1086 blocks both canonical and non-canonical pathways in MM cell lines. We first investigated growth inhibitory effect of PBS-1086 in vitro. PBS-1086 potently inhibited the growth of MM cell lines (MM1S, MM1R, INA6, LR5, Dox40, KMS18, RPMI-8226 and U266) in a dose-dependent fashion with IC50 ranges of 0.15–5 μM. In contrast, PBS-1086 showed modest cytotoxicity on normal peripheral blood mononuclear cells from healthy volunteers. Similar growth inhibitory effect were observed in CD138+ primary tumor cells derived from MM patients. PBS-1086 induced apoptosis in MM1S cell line in a time-dependent manner, evidenced by annexin V-PI staining by flow cytometry and cleaved caspase 8, 9, 3 and PARP, suggesting that PBS-1086 activates both extrinsic and intrinsic apoptotic pathways. Importantly, PBS-1086 can overcome the proliferative and anti-apoptotic effects of BMSCs, associated with inhibition of NF-kB activity. We next examined the combination effect of PBS-1086 with other agents. PBS-1086 with bortezomib synergistically enhanced anti-MM activity even in bortezomib-resistant cell lines (Dox40, ANBL6-VR5) and primary tumor cells from MM patients. Finally, we investigated the effect of PBS-1086 in vivo in a murine xenograft model of human MM cells. Tumor-bearing mice were divided into 6 groups: non-treated, vehicle control, PBS-1086 (7.5 mg/kg ip daily), bortezomib (0.5 mg/kg IV, twice weekly) and the combination of PBS-1086 (either at 2.5 mg/kg or 7.5 mg/kg) with bortezomib. PBS-1086 showed significant anti-MM activity in combination (2.5 and 7.5 mg/kg) groups versus control group (p =0.00039 and p =0.00084, respectively). Combination groups also had significantly (p < 0.05) prolonged survival compared to single agent treatment group (PBS-1086 or bortezomib). In conclusion, our preclinical studies show that PBS-1086 is a promising novel therapeutic agent and our data supports further clinical evaluation of this agent in combination with bortezomib for the treatment of MM. Disclosures: Bobb: Profectus BioSciences: Employment; Rel-MD: Employment. Zhang:Profectus BioSciences: Employment; Rel-MD: Employment. Meshulam:Profectus BioSciences: Employment; Rel-MD: Employment. Mitsiades:Millennium: Consultancy, Honoraria. Richardson:Millennium: ; Celgene: ; Johnson & Johnson: ; Novartis: ; Bristol Myers Squibb:. Hideshima:Acetylon: Consultancy. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Membership on an entity's Board of Directors or advisory committees.

AbstractThe Supplement to the Illustrated Record of Wu Commandery (Wujun tujing xuji), compiled in 1084 by Zhu Changwen (1039-1098), is one of only two extant Northern Song local gazetteers. An examination of biographical materials reveals that Zhu Changwen wrote his gazetteer in opposition to the New Policies of Wang Anshi (1021-1086); it was intended as a contribution toward a new empire-wide gazetteer that would be required after the abolition of Wang's administrative reorganizations. The detail of Zhu's Supplement anticipates the more comprehensive gazetteers of the late Northern and the Southern Song. Les Notes supplémentaires à la géographie de la commanderie Wu (Wujun tujing xuji), compilées par Zhu Changwen (1039-1098) en 1084, sont l'une des deux seules monographies locales qui nous soient parvenues des Song du Nord. Un examen des matériaux biographiques montre que Zhu Changwen l'avait écrite en adversaire des réformes de Wang Anshi (1021-1086) pour contribuer à une nouvelle monographie nationale devenue nécessaire du fait de l'abolition attendue des réorganisations administratives de Wang Anshi. Par leur contenu, les Notes supplémentaires anticipent les monographies locales plus complètes des derniers Song du Nord et des Song du Sud.

Direct transfer of NADPH between two NADP-dependent dehydrogenases, isocitrate dehydrogenase and glutamate dehydrogenase, has been investigated. These enzymes have opposite stereospecificity for hydrogen transfer to the coenzyme. In contrast with the general direct-transfer mechanism postulated for NAD-dependent dehydrogenases [Srivastava & Bernhard (1986) Science 234, 1081-1086], no evidence for direct transfer in either direction was found for these NADP-dependent dehydrogenases.

Abstract Abstract 867 The NF-κB signaling pathway is constitutively activated in chronic lymphocytic leukemia (CLL). Aberrant activation of the p65 (RelA) subunit of NF-κB is associated with chemoresistance, a shorter lymphocyte doubling time and poor overall survival (OS) in CLL. The transcription factor, NF-κB, regulates anti-apoptotic and pro-survival genes, and therefore represents a drug target for therapeutic intervention. Several studies have shown that targeting NF-κB decreases CLL cell survival, induces apoptosis and inhibits transcription of key pro-survival genes. In CLL, poor response to therapy and poor outcome are closely related to cytogenetic abnormalities. Loss of p53 function (del(17p) and/or TP53 mutation) confers chemo-resistance due to a defective DNA damage response pathway. Loss of the ATM (ataxia telangiectasia mutated) kinase (del(11q) and/or mutation of ATM) is also associated with chemo-resistance. We hypothesized that blocking NF-κB may circumvent the requirement for an active DNA damage response pathway, and that NF-κB inhibition may be efficacious independent of cytogenetic abnormalities in CLL. We tested the hypothesis with PBS-1086, a novel small molecule “pan-rel” inhibitor that has shown activity against multiple myeloma in vivo. For target validation, we analyzed NF-κB activity by quantifying NF-κB subunit DNA binding and rel expression in nuclear extracts prepared from patient-derived CLL cells. Levels of activated NF-κB binding correlated with rel protein levels. We confirmed that constitutive activation of the p65 subunit predicted shorter overall survival (p= 0.03, n=80, HR (hazard ratio) 2.4). We also found that the p50 and RelB subunits were associated with poor survival (p = 0.04, n = 80, HR = 2.5 and p=0.17, n=50, respectively). Whereas p65 and p50 (activated by the canonical pathway through IKKβ), were present at high levels in the majority of cases, RelB (activated by the non-canonical pathway) was found to be variable among patients, with levels ranging from very high to undetectable. We found that patients with del(17p) had higher levels of p65 and p50 DNA binding activity, whereas patients with del(11q) had higher levels of RelB activity. We examined the effect of PBS-1086, a “pan-rel” inhibitor, on viability of patient-derived CLL cells and compared it with BAY 11–7082, an IKKβ inhibitor that affects p65 and p50. PBS-1086 was more potent at decreasing CLL viability in a concentration-dependent manner than BAY 11–7082 (mean LC50 6.4 +/− 1.9 μM, and 14.7 +/− 1.7 μM, respectively, n=20). LC50 values of PBS-1086 and BAY 11–7082 derived from individual CLL samples correlated significantly, suggesting that they acted by inhibiting the same pathway (p=0.02, n=20). PBS-1086 LC50 values also correlated inversely with the DNA binding activity of p65 (p=0.01, n=17), suggesting that these CLL cells were heavily reliant on p65 for survival, and were therefore exquisitely vulnerable to compounds inhibiting p65. There was no significant difference in sensitivity to PBS-1086 or BAY 11–7082 among patients with different cytogenetic abnormalities, or Binet stage A or stage B/C cases, or between cases with or without IGVH gene mutations. Patients who had received prior chemotherapies at the time of sample collection showed a trend to be more resistant to ex vivo treatment with Fludarabine than those naïve to chemotherapies, however treatment status had no impact on ex vivo sensitivity to PBS-1086. Submaximal concentrations of Fludarabine and PBS-1086 were additive in decreasing CLL cell viability (n=3). Mechanistic studies showed that PBS-1086 inhibited p65 and p50 DNA binding activity in CLL cells (n=5). In one example case that had constitutive expression of all of the NF-κB subunits, PBS 1086 inhibited the DNA binding activity of all rel subunits. Both PBS-1086 and BAY 11–7082 induced apoptosis in a concentration-dependent manner in CLL cells (Annexin V staining, n=4) that paralled the inhibitor-induced loss of viability. These data demonstrate that PBS-1086 reduced survival of CLL cells ex vivo through inhibiting the DNA binding activity of rel subunits concomitantly with induction of apoptosis. Such effects of PBS-1086 were independent of poor prognosis cytogenetics, and of Binet stage or IGVH status. Thus, PBS-1086 is promising as a therapeutic agent by itself and also as a chemo-sensitizer to overcome NF-κB-mediated chemo-resistance in CLL. Disclosures: No relevant conflicts of interest to declare.

We analyzed the binding site(s) for Grb2 on the epidermal growth factor (EGF) receptor (EGFR), using cell lines overexpressing EGFRs containing various point and deletion mutations in the carboxy-terminal tail. Results of co-immunoprecipitation experiments suggest that phosphotyrosines Y-1068 and Y-1173 mediate the binding of Grb2 to the EGFR. Competition experiments with synthetic phosphopeptides corresponding to known autophosphorylation sites on the EGFR demonstrated that phosphopeptides containing Y-1068, and to a lesser extent Y-1086, were able to inhibit the binding of Grb2 to the EGFR, while a Y-1173 peptide did not. These findings were confirmed by using a dephosphorylation protection assay and by measuring the dissociation constants of Grb2's SH2 domain to tyrosine-phosphorylated peptides, using real-time biospecific interaction analysis (BIAcore). From these studies, we concluded that Grb2 binds directly to the EGFR at Y-1068, to a lesser extent at Y-1086, and indirectly at Y-1173. Since Grb2 also binds Shc after EGF stimulation, we investigated whether Y-1173 is a binding site for the SH2 domain of Shc on the EGFR. Both competition experiments with synthetic phosphopeptides and dephosphorylation protection analysis demonstrated that Y-1173 and Y-992 are major and minor binding sites, respectively, for Shc on the EGFR. However, other phosphorylation sites in the carboxy-terminal tail of the EGFR are able to compensate for the loss of the main binding sites for Shc. These analyses reveal a hierarchy of interactions between Grb2 and Shc with the EGFR and indicate that Grb2 can bind the tyrosine-phosphorylated EGFR directly, as well as indirectly via Shc.