The natural killer (NK) type of aggressive large granular lymphocytic (LGL) leukemia is a fatal illness that pursues a rapid clinical course. There are no effective therapies for this illness, and pathogenetic mechanisms remain undefined. Here we report that the survivin was highly expressed in both aggressive and chronic leukemic NK cells but not in normal NK cells. In vitro treatment of human and rat NK-LGL leukemia cells with cell-permeable, short-chain C₆-ceramide (C₆) in nanoliposomal formulation led to caspase-dependent apoptosis and diminished survivin protein expression, in a time- and dose-dependent manner. Importantly, systemic intravenous delivery of nanoliposomal ceramide induced complete remission in the syngeneic Fischer F344 rat model of aggressive NK-LGL leukemia. Therapeutic efficacy was associated with decreased expression of survivin in vivo. These data suggest that in vivo targeting of survivin through delivery of nanoliposomal C₆-ceramide may be a promising therapeutic approach for a fatal leukemia.

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Preclinical and clinical studies have pointed to the antitumor potential of the naturally occurring polyphenolic binaphthyl dialdehyde, gossypol, as well as its purified (-,+) enantiomers. To explore further the antitumor properties of this multifunctional agent, we synthesized several reactive derivatives including the (-,+) enantiomers of gossypolone and four different gossypol Schiff's bases (AR1, AR2, AR3, AR4). The biological activities of these new agents were screened by measuring their in vitro antiproliferative activity against malignant (MCF-7, MCF-7/adr) or immortalized (HBL-100) human breast epithelial cell lines. Racemic gossypolone showed relatively uniform antiproliferative activity against all of the breast epithelial cell lines with 3- to 5-fold less activity than (--)-gossypol against MCF-7 and MCF-7/adr cells. Of interest, the relative antitumor potency of purified gossypolone enantiomers was reverse that of gossypol enantiomers, since (+)-gossypolone showed up to 3-fold greater inhibition of MCF-7 culture growth than (--)-gossypolone. Of the Schiff's base derivatives only AR3 with its isopropyl amine substituent demonstrated cytotoxic activity comparable to that of (--)-gossypol; derivatives with ethyl, propyl, or butyl amine substituents (AR1, AR2, AR4) had little growth inhibitory activity at culture concentrations up to 25 microM. AR3 activity was greatest against HBL-100 and MCF-7 cells [MCF-7 IC50 values: AR3 = 0.9 microM, (--)-gossypol = 2.3 microM]; unlike (--)-gossypol, however, AR3 showed substantially reduced activity against the multidrug-resistant subline, MCF-7/adr. These structure-activity comparisons suggest that isolation of (-,+)-enantiomers of AR3 and additional chemical modifications including the synthesis of an isopropyl amine Schiff's base of gossypolone will likely yield a newer generation of gossypol analogues with enhanced anticancer potential.

We present a numerical algorithm to identify ion diffusion regions (IDRs) in the geomagnetic tail and test its applicability. We use five criteria applied in three stages. (i) correlated reversals (within 90 s) of Vx and Bz (at least 2 nT about 0; geocentric solar magnetospheric coordinates); (ii) detection of Hall electric and magnetic field signatures; and (iii) strong (≥10 mV/m) electric fields. While no criterion alone is necessary and sufficient, the approach does provide a robust, if conservative, list of IDRs. We use data from the Magnetospheric Multiscale (MMS) mission spacecraft during a 5‐month period (1 May to 30 September 2017) of near‐tail orbits. We find 148 events satisfying Step 1, 37 satisfying Steps 1 and 2, and 17 satisfying all 3, of which 12 are confirmed as IDRs. All IDRs were within the X‐range [−24, −15] RE and the majority occurred during traversals of a tailward moving X‐line. Eleven of 12 IDRs were on the duskside despite approximately equal residence time in the plasma sheet (56.5% dusk vs. 43.5% dawn). MMS could identify signatures of four quadrants of the Hall B‐structure in three events and three quadrants in seven events. The events we report commonly display Vx reversals greater than 400 km/s in magnitude, normal magnetic field reversals often >10 nT in magnitude, maximum DC | trueE→|, which are often well in excess of the threshold for Stage 3. Our results are then compared with the set of IDRs identified by visual examination from Cluster in the years 2000–2005.

The synthesis of syn,anti-[Co(cyclen)en](ClO4)3 (1(ClO4)3) and syn,anti-[Co(cyclen)tn](ClO4)3 (2(ClO4)3) is reported, as are single-crystal X-ray structures for syn,anti-[Co(cyclen)(NH3)2](ClO4)3 (3(ClO4)3). 3(ClO4)3: orthorhombic, Pnma, a = 17.805(4) A, b = 12.123(3) A, c = 9.493(2) A, alpha = beta = gamma = 90 degrees, Z = 4, R1 = 0.030. 1(ClO4)3: monoclinic, P2(1)/n, a = 8.892(2) A, b = 15.285(3) A, c = 15.466(3) A, alpha = 90 degrees, beta = 91.05(3) degrees, gamma = 90 degrees, Z = 4, R1 = 0.0657. 2Br3: orthorhombic, Pca2(1) a = 14.170(4) A, b = 10.623(3) A, c = 12.362(4) A, alpha = beta = gamma = 90 degrees, Z = 4, R1 = 0.0289. Rate constants for H/D exchange (D2O, I = 1.0 M, NaClO4, 25 degrees C) of the syn and anti NH protons (rate law: kobs = ko + kH[OD-]) and the apical NH, and the NH3 and NH2 protons (rate law: kobs = kH[OD-]) in the 1, 2, and 3 cations are reported. Deprotonation constants (K = [Co(cyclen-H)(diamine)2+]/[Co(cyclen)(diamine)3+][OH-]) were determined for 1 (5.5 +/- 0.5 M-1) and 2 (28 +/- 3 M-1). In alkaline solution 1, 2, and 3 hydrolyze to [Co(cyclen)(OH)2]+ via [Co(cyclen)(amine)OH)]2+ monodentates. Hydrolysis of 3 is two step: kobs(1) = kOH(1)[OH-], kobs(2) = ko + kOH(2)[OH-] (kOH(1) = (2.2 +/- 0.4) x 10(4) M-1 s-1, ko = (5.1 +/- 1.2) x 10(-4) s-1, kOH(2) = 1.0 +/- 0.1 M-1 s-1). Hydrolysis of 2 is biphasic: kobs(1) = k1K[OH-]/(1 + K[OH-] (k1 = 5.0 +/- 0.2 s-1, K = 28 M-1), kobs(2) = k2K2[OH-]/(1 + K2[OH-]) (k2 = 3.5 +/- 1.2 s-1, K2 = 1.2 +/- 0.8 M-1). Hydrolysis of 1 is monophasic: kobs = k1k2KK2[OH-]2/(1 + K[OH-1])(k-1 + k2K2[OH-]) (k1 = 0.035 +/- 0.004 s-1, k-1 = 2.9 +/- 0.6 s-1, K = 5.5 M-1, k2K2 = 4.0 M-1 s-1). The much slower rate of chelate ring-opening in 1, compared to loss of NH3 from 3, is rationalized in terms of a reduced ability of the former system to allow the bond angle expansion required to produce the SN1CB trigonal bipyramidal intermediate.

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It is shown that the syn(N),syn(O)-isomer (3) is the intermediate on the reaction path for interconversion between the syn(N),anti(O)-(1) and syn(O),anti(N)-(2) diastereomers of syn(Me)-[Co(Mecyclen)(S-AlaO)] 2+ and [Co(cyclen)(S-AlaO)] 2+ . 1 H-exchange rate constants for the various NH protons are reported (k H /M -1 s -1 , 25°C, D 2 O) and are correlated with the derived isomerization rate constants (k N /M -1 s -1 , 25°C, H 2 O). At equilibrium (25°C , I ∼ 0.1 M) the [1]:[2]:[3] ratios are 73:21:6 and 63:32:5, respectively, for the two complexes.Ratios of k H /k N show that the two "planar" sec-N centers of the coordinated cyclen ligand are particularly susceptible to inversion, with estimated k 2 values for lone pair inversion being between 5 × 10 6 and 2 × 10 8 s -1 at 25°C. The effects of long-range electronegative substituents (trans carboxylate-O, trans amine-N) and CNC bond angle strain on inversion at metal-coordinated amines is discussed.

Soon after the discovery of the geomagnetic tail at the start of the space age (Ness, 1965), it was found that the tail can sometimes move rapidly in a north-south direction (Speiser & Ness, 1967). This flapping motion was deduced from a reversal in the polarity of the Earth-Sun component of geomagnetic tail field, B x , concomitant with a decrease in the total magnetic field strength. The typical duration of this up-down motion is a couple of minutes, with an amplitude of a few R E (Runov et al., 2009; Sergeev et al., 2003; Toichi & Miyazaki, 1976). Tail flapping is now a well-known phenomenon that has been repeatedly reported by spacecraft making observations close to the tail current sheet (CS, or neutral sheet (NS)) in the near-tail region (R ∼−15 to −30 R E). Not well established is what gives rise to it. Over the years both internal (see e.g.,