[Immediate postoperative color Doppler ultrasonography on the diagnosis of hemorrhagic complications of liver biopsy and its directed compression hemostasis].

Objective: To study the diagnostic value of immediate color Doppler ultrasonography on traumatic hepatic hemorrhage after tissue sampling with ultrasound-guided liver biopsy and the clinical effect of its-directed local compression hemostasis at puncture-site. Methods: 132 hospitalized patients with various liver diseases underwent ultrasound-guided hepatic puncture-biopsies, including 61 cases with diffuse parenchymal and 71 cases with focal liver lesions. Immediate postoperative color Doppler ultrasonography was performed following liver biopsy. Abnormal blood flow signal was observed at hepatic puncture biopsy site, and if there were hemorrhagic signals, ultrasound-directed local compression hemostasis was performed until the bleeding signal disappeared. F-test and Chi-square test were used for statistical analysis. Results: Immediate color Doppler ultrasonography showed traumatic hemorrhage in 36.1% (22/61) and 40.8% (29/71) cases of diffuse liver disease and focal liver disease group, respectively. All hemorrhagic signals were eventually disappeared after ultrasound-directed local compression hemostasis. The median hemostasis time was 2 min in both groups, and there was no statistically significant difference in bleeding rate and hemostasis time between the two groups (P>0.05). There were no serious complications and deaths. Conclusion: Traumatic hepatic hemorrhage along the needle puncture tract is a common accompanying condition during liver biopsy. Immediate postoperative color Doppler ultrasonography can trace bleeding signals in timely manner and direct effective compression hemostasis, so it should be used routinely to help avoid occurrence of severe hemorrhagic complications.

Influence of various levels of milk by-products in weaner diets on growth performance, blood urea nitrogen, diarrhea incidence, and pork quality of weaning to finishing pigs.

OBJECTIVE: This study was conducted to evaluate various levels of milk by-product in weaning pig diet on growth performance, blood profiles, carcass characteristics and economic performance for weaning to finishing pigs. METHODS: A total of 160 weaning pigs ([Yorkshire×Landrace]×Duroc), average 7.01±1.32 kg body weight (BW), were allotted to four treatments by BW and sex in 10 replications with 4 pigs per pen in a randomized complete block design. Pigs were fed each treatment diet with various levels of milk by-product (Phase 1: 0%, 10%, 20%, and 30%, Phase 2: 0%, 5%, 10%, and 15%, respectively). During weaning period (0 to 5 week), weaning pigs were fed experimental diets and all pigs were fed the same commercial feed during growing-finishing period (6 to 14 week). RESULTS: In the growth trial, BW, average daily gain (ADG), and average daily feed intake (ADFI) in the nursery period (5 weeks) increased as the milk by-product level in the diet increased (linear, p<0.05). Linear increases of pig BW with increasing the milk product levels were observed until late growing period (linear, p = 0.01). However, there were no significant differences in BW at the finishing periods, ADG, ADFI, and gain:feed ratio during the entire growing-finishing periods. The blood urea nitrogen concentration had no significant difference among dietary treatments. High inclusion level of milk by-product in weaner diet decreased crude protein (quadratic, p = 0.05) and crude ash (Linear, p = 0.05) of Longissimus muscle. In addition, cooking loss and water holding capacity increased with increasing milk product levels in the weaner diets (linear, p<0.01; p = 0.05). High milk by-product treatment had higher feed cost per weight gain compared to non-milk by-products treatment (linear, p = 0.01). CONCLUSION: Supplementation of 10% to 5% milk by-products in weaning pig diet had results equivalent to the 30% to 15% milk treatment and 0% milk by-product supplementation in the diet had no negative influence on growth performance of finishing pigs.

Vecuronium pharmacokinetics in patients with major burns.

BACKGROUND: Burn patients develop resistance to non-depolarizing neuromuscular blocking agents (NDNMBAs) and require a significantly large dose to produce a desired clinical response. Pathophysiological changes related to burn injury may alter pharmacokinetics (PK) and pharmacodynamics of NDNMBAs. The purpose of this study was to compare vecuronium PK in burns vs non-burns. METHODS: Twenty adults, aged 23-58 yr, with 27-81% total body surface area (TBSA) burn, were studied at 4-57 post-burn days and compared with age- and sex-matched, non-burn controls. Vecuronium 0.12 mg kg(-1) was given i.v. as a single bolus within 10 s. Blood samples (n=20) were collected over 12 h at predetermined time points. NONMEM was used to describe plasma drug concentration-time profiles for burns and non-burns. RESULTS: A three-compartment model best described vecuronium concentration-time profiles. Burn patients showed enhanced distributional clearance at the terminal phase (0.12 vs 0.095 litre min(-1), P<0.0001), which yielded shorter elimination half-life for vecuronium (5.5 vs 6.6 h, P<0.001). BURN was the single most significant covariate that explained the altered vecuronium disposition in burns. CONCLUSIONS: The altered drug distribution between tissues may partially explain the known resistance to vecuronium in patients with major burns.

Spin-induced optical conductivity in the spin-liquid candidate herbertsmithite.

We report a direct measurement of the low-frequency optical conductivity of large-area single-crystal herbertsmithite, a promising spin-liquid candidate material, by means of terahertz time-domain spectroscopy. In the spectral range below 1.4 THz, we observe a contribution to the real part of the in-plane conductivity σ(ab)(ω) from the spin degree of freedom. This spin-induced conductivity exhibits a power-law dependence on frequency σ(ab)(ω) ~ ω(ß) with ß ≈ 1.4. Our observation is consistent with the theoretically predicted low-frequency conductivity arising from an emergent gauge field of a gapless U(1) Dirac spin liquid.

Neuromuscular pharmacodynamics of mivacurium in adults with major burns.

BACKGROUND: Mivacurium is metabolized by plasma pseudocholinesterase (PChE) enzyme, which is decreased in burns. We tested whether the decreased metabolism of mivacurium due to decreased PChE activity can overcome the pharmacodynamic resistance to non-depolarizing relaxants previously seen in major burns. METHODS: Thirty adults with 35 (13)% [mean (sd)] burn were studied at 5-91 post-burn days and 31 non-burns matched controls. Mivacurium 0.2 mg kg(-1) was administered as a single bolus. Neuromuscular block was monitored with single-twitch response using TOF-Watch™. Onset time (drug administration to maximal twitch suppression) and spontaneous recovery were measured. RESULTS: Onset time was significantly prolonged in burns when compared with non-burns (115 vs 90 s; P<0.001). The PChE levels were lower in burns [1432 (916) vs 2866 (731) IU litre(-1); P<0.001] and the neuromuscular recovery to 50% of baseline twitch height was prolonged in burns (41 vs 26 min; P<0.001). There was a significant correlation between PChE and time to 50% recovery for the whole group together (r=-0.6; P<0.001). The dibucaine numbers were not different. CONCLUSIONS: The prolonged onset time suggests resistance to neuromuscular effects, whereas the prolonged recovery suggests increased sensitivity. This divergent response can be explained by qualitative and quantitative changes in acetylcholine receptor expression causing resistance and decreased PChE activity causing sensitivity. Despite using a relatively large dose of mivacurium (0.2 mg kg(-1)) in the presence of decreased PChE levels, this did not overcome the resistance resulting from up-regulated receptors.

Analysis of FcgammaRIIA cytoplasmic tail requirements in signaling for serotonin secretion: evidence for an ITAM-dependent, PI3K-dependent pathway.

The human Fc receptor, FcgammaRIIA, is known to mediate phagocytosis and endocytosis, yet the greatest numbers of these receptors are expressed on the surface of non-phagocytic platelets, where they are involved in serotonin secretion. FcgammaRIIA harbours three tyrosine (Y) residues within its cytoplasmic domain. Y1 is upstream of both Y2 and Y3, which are contained within an immunoreceptor tyrosine-based activation motif (ITAM), required for many signaling events. We have demonstrated that the two ITAM tyrosines are required for phagocytic signaling and that mutation of a single ITAM tyrosine decreases but does not abolish phagocytic signaling. Furthermore, we have identified that the YMTL motif is required for endocytosis. These observations suggest that FcgammaRIIA utilizes different sequences for various signaling events. Therefore, we investigated the sequence requirements for another important FcgammaRIIA-mediated signaling event, serotonin secretion, using Rat Basophilic Leukemia (RBL-2H3) cells transfected with wildtype (WT) FcgammaRIIA or mutant FcgammaRIIA. Stimulation of cells expressing WT FcgammaRIIA induced release of serotonin at a level 7-fold greater than that in nonstimulated WT FcgammaRIIA-transfected cells or nontransfected RBL cells. Mutation of either ITAM tyrosine (Y2 or Y3) to phenylalanine was sufficient to abolish serotonin secretion. Further, while inhibition of Syk with piceatannol blocked phagocytosis as expected, it did not inhibit serotonin secretion. Additionally, inhibition of phosphoinositol-3-kinase (PI3K) with wortmannin only had a partial effect on serotonin signaling, despite the fact that the concentrations used completely abolished phagocytic signaling. These data suggest that the requirements for serotonin secretion differ from those for phagocytosis mediated by FcgammaRIIA.

Onset and effectiveness of rocuronium for rapid onset of paralysis in patients with major burns: priming or large bolus.

BACKGROUND: Burn injury leads to resistance to the effects of non-depolarizing muscle relaxants. We tested the hypothesis that a larger bolus dose is as effective as priming for rapid onset of paralysis after burns. METHODS: Ninety adults, aged 18-59 yr with 40 (2)% [mean (SE)] burn and 30 (2) days after injury, received rocuronium as a priming dose followed by bolus (0.06+0.94 mg kg(-1)), or single bolus of either 1.0 or 1.5 mg kg(-1). Sixty-one non-burned, receiving 1.0 mg kg(-1) as a primed (0.06+0.94 mg kg(-1)) or full bolus dose, served as controls. Acceleromyography measured the onset times. RESULTS: Priming when compared with 1.0 mg kg(-1) bolus in burned patients shortened the time to first appearance of twitch depression (30 vs 45 s, P<0.05) and time to maximum twitch inhibition (135 vs 210 s, P<0.05). The onset times between priming and higher bolus dose (1.5 mg kg(-1)) were not different (30 vs 30 s for first twitch depression and 135 vs 135 s for maximal depression, respectively). The onset times in controls, however, were significantly (P<0.05) faster than burns both for priming and for full bolus (15 and 15 s, respectively, for first twitch depression and 75 and 75 s for maximal depression). Priming caused respiratory distress in 10% of patients in both groups. Intubating conditions in burns were significantly better with 1.5 mg kg(-1) than with priming or full 1.0 mg kg(-1) bolus. CONCLUSIONS: A dose of 1.5 mg kg(-1) not only produces an initial onset of paralysis as early as 30 s, which we speculate could be a reasonable onset time for relief of laryngospasm, but also has an onset as fast as priming with superior intubating conditions and no respiratory side-effects.

Decomposition of 1,4-dioxane by photo-Fenton oxidation coupled with activated sludge in a polyester manufacturing process.

The cyclic ether 1,4-dioxane is a synthetic industrial chemical that is used as a solvent in producing paints and lacquers. The EPA and the International Agency for Research on Cancer(IARC) classified 1,4-dioxane as a GROUP B2(probable human) carcinogen. 1,4-dioxane is also produced as a by-product during the manufacture of polyester. In this research, a polyester manufacturing company (i.e. K Co.) in Gumi, Korea was investigated regarding the release of high concentrations of 1,4-dioxane (about 600 mg/L) and whether treatment prior to release should occur to meet with the level of the regulation standard (e.g., 5 mg/L in 2010). A 10 ton/day pilot-scale treatment system using photo-Fenton oxidation was able to remove approximately 90% of 1,4-dioxane under the conditions that concentrations of 2800 ppm H(2)O(2) and 1,400 ppm FeSO(4) were maintained along with 10 UV-C lamps (240 microW/cm(2)) installed and operated continuously during aeration. However, the effluent concentration of 1,4-dioxane was still high at about 60 mg/L where TOC concentration in the effluent had been moreover increased due to decomposed products such as aldehydes and organic acids. Thus, further investigation is needed to see whether the bench scale (reactor volume, 8.9 L) of activated sludge could facilitate the decomposition of 1,4-dioxane and their by-products (i.e., TOC). As a result, 1,4-dioxane in the effluent has been decreased as low as 0.5 mg/L. The optimal conditions for the activated sludge process that were obtained are as follows: DO, 3-3.5 mg/L; HRT, 24 h; SRT 15 d; MLSS, 3,000 mg/L. Consequently, photo-Fenton oxidation coupled with activated sludge can make it possible to efficiently decompose 1,4-dioxane to keep up with that of the regulation standard.

Molecular characterization of T-type Ca(2+) channels responsible for low threshold spikes in hypothalamic paraventricular nucleus neurons.

The hypothalamic paraventricular nucleus (PVN) is composed of functionally heterogeneous cell groups, possessing distinct electrophysiological properties depending on their functional roles. Previously, T-type Ca(2+) dependent low-threshold spikes (LTS) have been demonstrated in various PVN neuronal types, including preautonomic cells. However, the molecular composition and functional properties of the underlying T-type Ca(2+) channels have not been characterized. In the present study, we combined single cell reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry and patch-clamp recordings to identify subtypes of T-type Ca(2+) channels expressed in PVN cells displaying LTS (PVN-LTS), including identified preautonomic neurons. LTS appeared at the end of hyperpolarizing pulses either as long-lasting plateaus or as short-lasting depolarizing humps. LTS were mediated by rapidly activating and inactivating T-type Ca(2+) currents and were blocked by Ni(2+). Single cell RT-PCR and immunohistochemical studies revealed Cav3.1 (voltage-gated Ca(2+) channel) as the main channel subunit detected in PVN-LTS neurons. In conclusion, these data indicate that Cav3.1 is the major subtype of T-type Ca(2+) channel subunit that mediates T-type Ca(2+) dependent LTS in PVN neurons.

Dynamic assembly of liquid crystalline graphene oxide gel fibers for ion transport.

Colloidal dispersions with liquid crystallinity hold great promise for fabricating their superstructures. As an example, when graphene oxide (GO) sheets are assembled in the liquid crystalline state, they can turn into ordered macroscopic forms of GO such as fibers via the wet spinning process. Here, we report that by reinforcing intersheet interactions, GO liquid crystals (LCs) turn into mechanically robust hydrogels that can be readily drawn into highly aligned fibrillar structures. GO hydrogel fibers with highly aligned sheets (orientation factor, f = 0.71) exhibit more than twice the ionic conductivity compared to those with partially aligned structures (f = 0.01). The hierarchically interconnected two-dimensional nanochannels within these neatly aligned GOLC hydrogel fibers may facilitate controlled transport of charge carriers and could be potentially explored as cables for interconnecting biosystems and/or human-made devices.

Regulatory role of MEF2D in serum induction of the c-jun promoter.

Serum induction of c-jun expression in HeLa cells requires a MEF2 site at -59 in the c-jun promoter. MEF2 sites, found in many muscle-specific enhancers, are bound by a family of transcription factors, MEF2A through -D, which are related to serum response factor in their DNA binding domains. We have found that MEF2D is the predominant protein in HeLa cells that binds to the c-jun MEF2 site. Serum induction of a MEF2 reporter gene was not observed in a line of NIH 3T3 cells which contain low MEF2 site binding activity. Transfection of MEF2D into NIH 3T3 cells reconstituted serum induction, demonstrating that MEF2D is required for the serum response. Deletion analysis of MEF2D showed that its DNA binding domain, when fused to a heterologous transcriptional activation domain, was sufficient for serum induction of a MEF2 reporter gene. This is the domain homologous to that in the serum response factor which is required for serum induction of the c-fos serum response element, suggesting that serum regulation of c-fos and c-jun may share a common mechanism.

Mapping of epidermal growth factor-, serum-, and phorbol ester-responsive sequence elements in the c-jun promoter.

Expression of the nuclear proto-oncogene c-jun is rapidly and transiently induced by many growth factors, serum, and tumor promoters. The sequence elements in the c-jun promoter involved in serum or growth factor induction have not been identified. The c-jun promoter region between -117 and -72 contains binding sites for the transcription factors Sp1, CTF, and AP-1. An additional sequence element has been noted at position -59. This A+T-rich sequence, formerly proposed as a TFIID-binding site, conforms to the consensus binding sequence of a recently identified factor, RSRF (related to serum response factor). In this study, we mapped the sequences in the c-jun promoter responsible for epidermal growth factor (EGF), serum, and 12-O-tetradecanoylphorbol-13-acetate (TPA) induction by deletion and point mutational analysis. We found that the c-jun RSRF site is an important element for EGF and serum induction of the promoter and that there are several factors in HeLa nuclear extracts which specifically bind to this site. The RSRF site was also sufficient for EGF, serum, and TPA induction when assayed on a heterologous promoter. The c-jun AP-1 site was not required for EGF, serum, or TPA induction but was sufficient to mediate a weak response to these agents when assayed on a heterologous promoter. Double mutation of the RSRF and AP-1 sites suggests that there is an additional TPA-responsive element between -80 and +150 in the c-jun promoter.

A putative transmembrane protein with histidine-rich charge clusters encoded in the H-2K/tw5 region of mice.

The H-2 complex of mice contains many genes in addition to the gene families involved in immune reactions. Some of them are believed to function in mouse development, as suggested by the findings that several embryonic lethal mutations map within or near the H-2 complex. We have analyzed the H-2K/tw5 region in an attempt to study non-H-2 genes encoded in this region. Overlapping cosmid clones spanning about 170 kilobase pairs of DNA, including the H-2K/tw5 region of the mouse, have been screened for genes expressed in embryonic carcinoma cells. A transcript of 2.8 kilobase pairs (K. Abe. J.-F. Wei, F.-S. Wei, Y.-C. Hsu, H. Uehara, K. Artzt, and D. Bennett, EMBO J. 7:3441-3449, 1988) encoded by the KE 4 gene flanking H-2K distally was identified. The transcript was abundantly expressed in embryonic carcinoma cells but was present at low levels in other tissues in adults. A cDNA for this transcript was isolated from the F9 embryonic carcinoma cell line and sequenced. It potentially encodes a protein of 436 amino acids with several interesting features. First, it contains two regions made of well-conserved repeats unusually rich in histidine residues. In the repeats, histidine alternates with other amino acids, notably glycine or serine. Second, the two histidine-rich regions are separated by three putative membrane-spanning domains. Third, the N-terminal part of the sequence shows characteristics of a signal peptide. The results indicate that the protein coded by the gene may be a transmembrane protein with histidine-rich charge clusters. A similar sequence motif found in other known genes allows speculation on the possible functional of this gene.

Mechanisms of iron and copper-frataxin interactions.

Frataxin is a mitochondrial protein whose deficiency is the cause of Friedreich's ataxia, a hereditary neurodegenerative disease. This protein plays a role in iron-sulfur cluster biosynthesis, protection against oxidative stress and iron metabolism. In an attempt to provide a better understanding of the role played by metals in its metabolic functions, the mechanisms of mitochondrial metal binding to frataxin in vitro have been investigated. A purified recombinant yeast frataxin homolog Yfh1 binds two Cu(ii) ions with a Kd1(CuII) of 1.3 × 10-7 M and a Kd2(CuII) of 3.1 × 10-4 M and a single Cu(i) ion with a higher affinity than for Cu(ii) (Kd(CuI) = 3.2 × 10-8 M). Mn(ii) forms two complexes with Yfh1 (Kd1(MnII) = 4.0 × 10-8 M; Kd2(MnII) = 4.0 × 10-7 M). Cu and Mn bind Yfh1 with higher affinities than Fe(ii). It is established for the first time that the mechanisms of the interaction of iron and copper with frataxin are comparable and involve three kinetic steps. The first step occurs in the 50-500 ms range and corresponds to a first metal uptake. This is followed by two other kinetic processes that are related to a second metal uptake and/or to a change in the conformation leading to thermodynamic equilibrium. Frataxin deficient Δyfh1 yeast cells exhibited a marked growth defect in the presence of exogenous Cu or Mn. Mitochondria from Δyfh1 strains also accumulated higher amounts of copper, suggesting a functional role of frataxin in vivo in copper homeostasis.

14-3-3tau associates with and activates the MEF2D transcription factor during muscle cell differentiation.

Myocyte enhancer binding factor 2 (MEF2) proteins belong to the MADS box family of transcription factors and four MEF2 proteins, MEF2A, MEF2B, MEF2C and MEF2D, have been found. MEF2 proteins have been shown to play critical roles in differentiation of muscles and neuronal tissues. How transactivational activity of MEF2 proteins is regulated is not fully understood. MEF2 proteins are activated by several kinases, including Erk5 and calcium/calmodulin-dependent kinase, and interact with repressors, including histone deacetylases 4 and 5 (HDAC4 and HDAC5) and Cabin1. During the effort to understand regulation of MEF2 activity, we identified 14-3-3tau as a MEF2D-interacting molecule by yeast two-hybrid screening. We found that 14-3-3tau forms a complex with MEF2D in vivo and specifically enhances MEF2 transactivational activity. The results from transient transfection and co-precipitation experiments suggest that 14-3-3tau activates MEF2D by competitively inhibiting HDAC4 from binding to MEF2D and thereby affects muscle cell differentiation.

Sp1 mediates constitutive and transforming growth factor beta-inducible expression of urokinase type plasminogen activator receptor gene in human monocyte-like U937 cells.

Urokinase type plasminogen activator receptor (uPAR) is known to be involved in conversion of plasminogen into plasmin and its expression can be regulated by a variety of biological agents including transforming growth factor beta (TGF-beta). In the present study, we cloned the promoter region of the human uPAR (huPAR) gene (-653 to +61) and investigated the transcription regulatory mechanism of the expression of the huPAR gene upon treatment with TGF-beta in human monocyte-like U937 cells. By deletion and point mutational analysis of the huPAR gene promoter, it was found that the sequence positioned at -70 is required for both constitutive and TGF-beta-inducible expression of the huPAR gene in U937 cells. Using electrophoretic mobility shift assay, we could observe that Sp1 formed a DNA-protein complex at the -70 sequence. In addition, antisense oligonucleotide against human Sp1 blocked both constitutive and TGF-beta-inducible expression of the luciferase reporter gene driven by the huPAR gene promoter in U937 cells. These results led us to conclude that Sp1 transcription factor mediates constitutive and TGF-beta-inducible expression of the huPAR gene in U937 cells through binding to the sequence located at -70.

CD28-mediated regulation of the c-jun promoter involves the MEF2 transcription factor in Jurkat T cells.

Within a few minutes of T-cell activation, transcription of a set of genes including c-fos and c-jun is activated. For maximal induction of c-jun, at least two major signal pathways are required. One can be triggered by T-cell receptor engagement or phorbol esters and the other by anti-CD28 engagement. The c-jun promoter region between -117 and -50 contains binding sites for the transcription factors Spl, CTF, ATF/CREB, and MEF2. In this study, we sought to map the sequences in the c-jun promoter responsible for CD28-mediated induction in activated Jurkat T cell by point mutational analysis. We found that mutation of the c-jun MEF2 site strongly reduces CD28 induction of the promoter in Jurkat T cells and that MEF2D is the major binding molecule to the c-jun MEF2 site in Jurkat T cells. Mutation of the c-jun ATF site also partially reduced CD28 induction of the promoter. In addition, pretreatment with an endolysomotropic agent NH4Cl, an acidic sphingomyelinase inhibitor, completely inhibited the activation of the c-jun promoter by anti-CD28 antibody treatment, whereas pretreatment with wortmannin, a PI3-kinase inhibitor, did not affect the induction of the c-jun promoter. These results suggest that CD28 signaling leading to the c-jun promoter involves acidic sphingomyelinase, but not PI3-kinase, to activate factors binding to the MEF2 and ATF sites.

Requirement of MEF2D in the induced differentiation of HL60 promyeloid cells.

The regulatory role of MEF2 (myocyte enhancer binding factor 2) proteins in nonmuscle tissues has not been well characterized. We examined the expression of MEF2 family members, namely, MEF2A, -B, -C, and -D, in the differentiation of HL60 promyeloid cells and observed the remarkable increase in the expressions of MEF2A and MEF2D proteins during the differentiation process into monocytes. To examine the role of MEF2, we expressed a dominant-negative form of MEF2D, without its transactivation domain, in HL60 cells. When the HL60 cell line expressing the mutant MEF2D was induced to differentiate by VitD(3) treatment, cell surface expression of CD14 and the ability to reduce NBT, which are important characteristics of differentiated monocytes, were significantly decreased compared with control HL60 cells. These results show that MEF2D is required in the differentiation process along the monocyte/macrophage lineage,

Brentuximab vedotin does not cause clinically relevant QTc interval prolongation in patients with CD30-positive hematologic malignancies.

PURPOSE: Brentuximab vedotin (ADCETRIS®), an antibody-drug conjugate, comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). In vitro studies showed that MMAE does not interfere with hERG K+ channels at clinically relevant concentrations. In pivotal phase 2 clinical trials in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, brentuximab vedotin has shown substantial efficacy and an acceptable safety profile. This phase 1 open-label study was designed to evaluate the effect of brentuximab vedotin on the duration of cardiac ventricular repolarization. METHODS: Patients with CD30-positive hematologic malignancies were treated with 1.8 mg/kg brentuximab vedotin by intravenous infusion every 3 weeks for up to 16 cycles. The primary endpoint was the change from baseline to Cycle 1 Days 2, 3, and 4 in the duration of ventricular repolarization using Fridericia's corrected QT interval (QTcF). RESULTS: There was no clinically meaningful change from baseline in the duration of ventricular repolarization as measured by QTcF in the 46 evaluable patients out of 52 total patients treated with brentuximab vedotin. There was no evidence of treatment-emergent cardiac safety abnormalities. Brentuximab vedotin was generally well tolerated with a response rate and an adverse event profile consistent with prior studies. CONCLUSION: There is no significant prolongation of the QT/QTc interval with brentuximab vedotin in patients with CD30-positive hematologic malignancies.