Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel

The epothilones are naturally occurring, cytotoxic macrolides that function through a paclitaxel (Taxol)-like mechanism. Although structurally dissimilar, both classes of molecules lead to the arrest of cell division and eventual cell death by stabilizing cellular microtubule assemblies. The epothilones differ in their ability to retain activity against multidrug-resistant (MDR) cell lines and tumors where paclitaxel fails. In the current account, we focus on the relationship between epothilone and paclitaxel in the context of tumors with multiple drug resistance. The epothilone analogue Z-12,13-desoxyepothilone B (dEpoB) is >35,000-fold more potent than paclitaxel in inhibiting cell growth in the MDR DC-3F/ADX cell line. Various formulations, routes, and schedules of i.v. administration of dEpoB have been tested in nude mice. Slow infusion with a Cremophor-ethanol vehicle proved to be the most beneficial in increasing efficacy and decreasing toxicity. Although dEpoB performed similarly to paclitaxel in sensitive tumors xenografts (MX-1 human mammary and HT-29 colon tumor), its effects were clearly superior against MDR tumors. When dEpoB was administered to nude mice bearing our MDR human lymphoblastic T cell leukemia (CCRF-CEM/paclitaxel), dEpoB demonstrated a full curative effect. For human mammary adenocarcinoma MCF-7/Adr cells refractory to paclitaxel, dEpoB reduced the established tumors, markedly suppressed tumor growth, and surpassed other commonly used chemotherapy drugs such as adriamycin, vinblastine, and etoposide in beneficial effects.

P-glycoprotein: a major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans.

The P-glycoprotein (Pgp) efflux pump can influence the hepatocellular concentration of xenobiotics that are modulators and substrates of cytochrome P4503A (CYP3A). We tested the hypothesis that Pgp is a determinant of drug-inducible expression of CYP3A. The magnitude of CYP3A induction by rifampicin was compared in the human parental colon carcinoma cell line LS 180/WT (wild type) and in two derivative clones overexpressing the human multidrug resistance gene MDR1 (also designated PGY1) because of either drug selection (LS 180/ADR) or transfection with MDRI cDNA (LS 180/MDR). In both MDR1 cDNA-overexpressing clones, rifampicin induction of CYP3A mRNA and protein was decreased and required greater rifampicin concentrations compared with parental cells. The role of Pgp in regulation of CYP3A expression in vivo was analyzed in mice carrying a targeted disruption of the mdr1a mouse gene. Oral treatment with increasing doses of rifampicin resulted in elevated drug levels in the livers of mdr1a (-/-) mice compared with mdr1a (+/+) mice at all doses. Consistent with the enhanced accumulation of rifampicin in mdr1a (-/-) mice, lower doses of rifampicin were required for induction of CYP3A proteins, and the magnitude of CYP3A induction was greater at all doses of rifampicin in mdr1a (-/-) mice compared with mdr1a (+/+) mice. We conclude that Pgp-mediated transport is a critical element influencing the CYP3A inductive response.

O papel do terceiro facilitador na conciliação de conflitos previdenciários

A conciliação judicial de conflitos previdenciários envolve, em geral, uma proposta de acordo baseada na renúncia pelo indivíduo de parte dos valores do benefício em atraso em um processo no qual a decisão contrária ao entendimento do Instituto Nacional do Segurado Social (INSS) é muito provável. Como regra, há um notório desequilíbrio de poder envolvendo, de um lado, um litigante ocasional (indivíduo) e, de outro, um litigante habitual (INSS). O presente trabalho pretende discutir qual o papel do terceiro facilitador nesse contexto, de modo a legitimar a prática existente e avançar para uma mudança de paradigma. Para tanto, parte-se da tese de que a conciliação deve ser adequada ao conflito que se pretende tratar, cabendo ao terceiro facilitador atuar de acordo com as peculiaridades desse conflito. Desse modo, propõe-se que, para o tratamento do conflito previdenciário, o conceito de conciliador deve ser entendido em termos amplos, abrangendo não apenas o conciliador leigo, mas também o juiz conciliador e o Judiciário como conciliador interinstitucional. Embora cada uma dessas atuações possua características próprias, sustenta-se que o ponto em comum é o respeito a um devido processo legal mínimo que possibilite a existência de uma base adequada de poder e que permita, assim, a tomada de uma decisão informada pelas partes. Dessa forma, a flexibilidade instrumental própria da conciliação não impediria o estabelecimento de parâmetros mínimos da atuação do conciliador. Por isso, tendo como limite a tomada de uma decisão informada, o conciliador atuaria por meio de estratégias variadas, aproximando-se e distanciando-se das partes, com maior ou menor interferência, de acordo com as características do caso apresentado. Conclui-se que, com a atuação conjunta e coordenada das diversas espécies de conciliador é possível aprimorar qualitativamente a conciliação de conflitos previdenciários.

Muḥammad Amīn ʼalá Jihat al-waḥdah

[Muḥammad al-Amīn ibn Ṣadr al-Dīn Shirwānī].

Vāek:vaḏo : manuscript, 1890?

Foreign wove paper, probably German; watermark: Keferstein & Sohn, 1871.

Rasālo:emām:jāfar:sādhak:jo : manuscript, 1890?

A popular treatise in 18 parts.

ejī:harī:nāme:harī:jāṇī:e : manuscript, 1829?

Title provided by cataloger.

Ārtī : manuscript, 1868

Title provided by cataloger.

[ e]jī:thar:thir:moman:[bhāî:koe:] koe : manuscript, 1890?

Title provided by cataloger.

Tap:sīro [tapsīlo] : manuscript, 1884?

Local paper. Ms. imperfect, later folios missing, paper brittle in poor condition; ff. 1, 2 and 114 damaged.

Saloko:satgûr:soho:dev [nāno/niñḍho] : manuscript, 1872

Local paper.

Pāñḍavānī saṇgāroṇī : manuscript, 1900?

Local paper.

[ Selection of 31 gināns]

Pīr Ṣadr ad-Dīn.

[ 60 ginānjī ćopḍī]

Pīr Ḥasan Kabīr ad-Dīn, Pīr Shams, Pīr Ṣadr ad-Dīn, ... [et al.].