Biomedical subjects

A Levine

Publications and source records attributed to A Levine.

At least 37 records · Page 2Linked to original sources

PubMed2001

Molecular regulation of genes encoding xenobiotic-metabolizing enzymes: mechanisms involving endogenous factors.

It is widely recognized that xenobiotic-metabolizing enzymes play a fundamental role in the basic processes of carcinogenesis and toxicity on one hand, and chemoprevention and drug efficacy on the other. Realization that different factors can profoundly affect the expression of these enzymes at the genome level has resulted in an enhanced appreciation of the importance these genes play in our modern industrialized age. There continues to be rapid proliferation of studies addressing the molecular regulation of these genes. The discovery of common signal transduction pathways and transcription factors that dictate tissue and developmental-specific expression, as well as variation in expression within a given tissue, suggest that there may be significant interaction among these various regulatory systems. This report is a summary of a symposium that was part of the Structure, Function and Regulation of Cytochromes P450 and Xenobiotic Metabolizing Enzymes satellite meeting of the 2000 joint meeting of the American Society for Biochemistry and Molecular Biology, the American Society for Pharmacology and Experimental Therapeutics, the French Pharmacological Society, and the Pharmacological Society of Canada held in Boston, Massachusetts. This symposium brought together several speakers who addressed specific receptor-mediated signal transduction pathways involved in the regulation of xenobiotic-metabolizing enzymes, as well as other molecular mechanisms whereby endogenous factors are involved in controlling tissue- and developmental-specific expression.

Enzymes↗

PubMed2000

Association of race and gender with HIV-1 RNA levels and immunologic progression.

CONTEXT: HIV-1 RNA and lymphocyte subset levels are the principal indications for antiretroviral treatment. Past reports have differed with regard to the effect of gender and race on these measures and in measures of disease progression. OBJECTIVE: To assess racial and gender differences in HIV-1 RNA levels and CD4+ lymphocyte decline. DESIGN: A longitudinal study based in the two largest HIV natural history cohort studies conducted in 7 metropolitan areas of the United States. RESULTS: In all, 1256 adult women and 1603 adult men for whom multiple data points were available prior to initiation of antiretroviral therapy were included. Women were more likely to be nonwhite, to have a history of injection drug use, and to have HIV-associated symptoms. After adjustment for differences in measurement method, baseline CD4+ cell count, age, and clinical symptoms, HIV-1 RNA levels were 32% to 50% lower in women than in men at CD4+ counts >200 cells/mm3 (p <.001) but not at CD4+ cell counts <200 cells/mm3. HIV-1 RNA levels were also 41% lower in nonwhites than in whites (p <.001) and 21% lower in persons reporting a prior history of injection drug use (p <.001). Women had more rapid declines in CD4+ cell counts over time than men (difference in slope of 46 cells/year) and nonwhite individuals had slower decline in CD4 cell counts than whites (difference of 39 cells/year). CONCLUSIONS: Both race and gender influence the values of HIV-1 RNA and the rate of HIV-1 disease progression as indicated by decline in CD4 cell counts over time. These effects could provide clues regarding the factors that influence HIV-disease progression and may indicate that guidelines for therapy should be adjusted for demographic characteristics.

Acquired Immunodeficiency Syndrome↗

PubMed2000

The hypersensitive response facilitates plant infection by the necrotrophic pathogen Botrytis cinerea.

BACKGROUND: Plants have evolved efficient mechanisms to combat pathogen attack. One of the earliest responses to attempted pathogen attack is the generation of oxidative burst that can trigger hypersensitive cell death. This is called the hypersensitive response (HR) and is considered to be a major element of plant disease resistance. The HR is thought to deprive the pathogens of a supply of food and confine them to initial infection site. Necrotrophic pathogens, such as the fungi Botrytis cinerea and Sclerotinia sclerotiorum, however, can utilize dead tissue. RESULTS: Inoculation of B. cinerea induced an oxidative burst and hypersensitive cell death in Arabidopsis. The degree of B. cinerea and S. sclerotiorum pathogenicity was directly dependent on the level of generation and accumulation of superoxide or hydrogen peroxide. Plant cells exhibited markers of HR death, such as nuclear condensation and induction of the HR-specific gene HSR203J. Growth of B. cinerea was suppressed in the HR-deficient mutant dnd1, and enhanced by HR caused by simultaneous infection with an avirulent strain of the bacterium Pseudomonas syringae. HR had an opposite (inhibitory) effect on a virulent (biotrophic) strain of P. syringae. Moreover, H(2)O(2) levels during HR correlated positively with B. cinerea growth but negatively with growth of virulent P. syringae. CONCLUSIONS: We show that, although hypersensitive cell death is efficient against biotrophic pathogens, it does not protect plants against infection by the necrotrophic pathogens B. cinerea and S. sclerotiorum. By contrast, B. cinerea triggers HR, which facilitates its colonization of plants. Hence, these fungi can exploit a host defense mechanism for their pathogenicity.

Arabidopsis↗

PubMed2000

Faecal occult blood in children with coeliac disease.

UNLABELLED: It has recently been suggested that in adults with coeliac disease, faecal blood loss may play a role in the development of iron deficiency. A group of 45 children diagnosed with coeliac disease during 1996 and 1997 were therefore prospectively evaluated for the presence of gluten in their diet, iron deficiency anaemia, and faecal occult blood. Sixty children admitted for elective surgery or asthma served as controls. Faecal occult blood was found in four iron deficient children on normal diet, of whom three were newly diagnosed. Occult blood loss disappeared in three of the four children when gluten was removed from their diet. Faecal occult blood was found in 26.7% of children on gluten-containing diet, but not in children on gluten-free diet (P = 0.01), or in control children (P = 0.001). CONCLUSION: Our data suggest that the incidence of occult blood loss in coeliac disease occurs mainly in newly diagnosed cases and responds to a gluten-free diet. Occult blood testing may not be warranted in the absence of iron deficiency anaemia nor in children with iron deficiency anaemia who are on a gluten-free diet.

Adolescent↗

PubMed2000

The transcriptome of Arabidopsis thaliana during systemic acquired resistance.

Infected plants undergo transcriptional reprogramming during initiation of both local defence and systemic acquired resistance (SAR). We monitored gene-expression changes in Arabidopsis thaliana under 14 different SAR-inducing or SAR-repressing conditions using a DNA microarray representing approximately 25-30% of all A. thaliana genes. We derived groups of genes with common regulation patterns, or regulons. The regulon containing PR-1, a reliable marker gene for SAR in A. thaliana, contains known PR genes and novel genes likely to function during SAR and disease resistance. We identified a common promoter element in genes of this regulon that binds members of a plant-specific transcription factor family. Our results extend expression profiling to definition of regulatory networks and gene discovery in plants.

Arabidopsis↗

PubMed2000

Chronic urticaria in children: expanding the "autoimmune kaleidoscope".

Most cases of chronic urticaria (CU) are considered idiopathic. It has recently been accepted that autoimmunity plays a critical role in the pathogenesis of CU in some of these patients. Although urticaria is common in the pediatric population, the knowledge regarding CU-associated autoimmunity is very limited. We describe the association of CU with a wide spectrum of clinical and laboratory autoimmune disorders in 2 children and emphasize the concept that CU is another manifestation of the "autoimmune kaleidoscope."

Adolescent↗

PubMed2000

Comparison of assays for anti-endomysial and anti-transglutaminase antibodies for diagnosis of pediatric celiac disease.

BACKGROUND: Anti-endomysial antibodies are sensitive and specific markers for celiac disease. This antibody has recently been identified as an antibody to tissue transglutaminase, an enzyme that cross-links and stabilizes extracellular matrix proteins. OBJECTIVES: To evaluate the clinical usefulness of an enzyme-linked immunoassay for anti-transglutaminase antibodies, and to compare the results with those of AEA, the current gold standard serological test for celiac disease. METHODS: Serum samples were collected from 33 patients with biopsy-proven celiac disease and AEA tests were performed. Control samples for anti-transglutaminase were obtained from 155 patients. An ELISA test for immunoglobulin A anti-transglutaminase utilizing guinea pig liver transglutaminase was developed and performed on all sera. Cutoff values for the test were performed using logistic regression and receiver operating curves analysis. RESULTS: An optical density cutoff value of 0.34 was established for the assay. The mean value was 0.18 +/- 0.19 optical density for controls, and 1.65 +/- 1.14 for patients with celiac disease (P < 0.001). Sensitivity and specificity of the assay were both 90%, while AEA had a sensitivity and specificity of 100% and 94%, respectively. CONCLUSIONS: A tissue transglutaminase-based ELISA test is both sensitive and specific for detection of celiac disease.

Analysis of Variance↗

PubMed1999

Programmed cell death of the dinoflagellate Peridinium gatunense is mediated by CO(2) limitation and oxidative stress.

The phytoplankton assemblage in Lake Kinneret is dominated in spring by a bloom of the dinoflagellate Peridinium gatunense, which terminates sharply in summer [1]. The pH in Peridinium patches rises during the bloom to values higher than pH9 [2] and results in CO(2) limitation. Here we show that depletion of dissolved CO(2) (CO(2(dis))) stimulated formation of reactive oxygen species (ROS) and induced cell death in both natural and cultured Peridinium populations. In contrast, addition of CO(2) prevented ROS formation. Catalase inhibited cell death in culture, implicating hydrogen peroxide (H(2)O(2)) as the active ROS. Cell death was also blocked by a cysteine protease inhibitor, E-64, a treatment which stimulated cyst formation. Intracellular ROS accumulation induced protoplast shrinkage and DNA fragmentation prior to cell death. We propose that CO(2) limitation resulted in the generation of ROS to a level that induced programmed cell death, which resembles apoptosis in animal and plant cells. Our results also indicate that cysteine protease(s) are involved in processes that determine whether a cell is destined to die or to form a cyst.

Animals↗

PubMed1999

Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women.

BACKGROUND: Human papillomavirus (HPV) infection is associated with precancerous cervical squamous intraepithelial lesions commonly seen among women infected with human immunodeficiency virus-1 (HIV). We characterized HPV infection in a large cohort of HIV-positive and HIV-negative women participating in the Women's Interagency HIV Study to determine the prevalence of and risk factors for cervicovaginal HPV infection in HIV-positive women. METHODS: HIV-positive (n = 1778) and HIV-negative (n = 500) women were tested at enrollment for the presence of HPV DNA in a cervicovaginal lavage specimen. Blood samples were tested for HIV antibody status, level of CD4-positive T cells, and HIV RNA load (copies/mL). An interview detailing risk factors was conducted. Univariate and multivariate analyses were performed. RESULTS: Compared with HIV-negative women, HIV-positive women with a CD4+ cell count of less than 200/mm3 were at the highest risk of HPV infection, regardless of HIV RNA load (odds ratio [OR] = 10.13; 95% confidence interval [CI] = 7.32-14.04), followed by women with a CD4+ count greater than 200/mm3 and an HIV RNA load greater than 20,000 copies/mL (OR = 5.78; 95% CI = 4.17-8.08) and women with a CD4+ count greater than 200/mm3 and an HIV RNA load less than 20,000 copies/mL (OR = 3.12; 95% CI = 2.36-4.12), after adjustment for other factors. Other risk factors among HIV-positive women included racial/ethnic background (African-American versus Caucasian, OR = 1.64; 95% CI = 1.19-2.28), current smoking (yes versus no; OR = 1.55; 95% CI = 1.20-1.99), and younger age (age < 30 years versus > or = 40 years; OR = 1.75; 95% CI = 1.23-2.49). CONCLUSIONS: Although the strongest risk factors of HPV infection among HIV-positive women were indicators of more advanced HIV-related disease, other factors commonly found in studies of HIV-negative women, including racial/ethnic background, current smoking, and age, were important in HIV-positive women as well.

AIDS-Related Opportunistic Infections↗

PubMed1999

Purification of active cysteine proteases by affinity chromatography with attached E-64 inhibitor.

Cysteine proteases are implicated in many regulatory and degradative processes in animal and plant cells. Many of the proteases are strongly inhibited by an irreversible inhibitor, trans-(epoxysuccinyl)-l-leucylamino-4-guanidinobutane (E-64) from Aspergillus japonicus. Here we report a method for purification of cysteine proteases by affinity chromatography on E-64. Attachment of the inhibitor to thiopropyl Sepharose through its epoxy group resulted in the loss of its irreversible activity but did not affect the specificity of interaction or its capability to bind cysteine proteases. Papain that served as a model cysteine protease was fully active after elution. We also provide evidence for purification of active proteases from a mixture of extracellular fluid of Botrytis cinerea- and Trichoderma harzianum-inoculated bean plants. Since the proteases are eluted with urea after the column is washed with 1 M NaCl, this procedure may provide highly efficient purification.

Aspergillus↗

PubMed1999

Alkalinizing local anesthetic does not decrease pain during injection for dorsal penile nerve block.

STUDY OBJECTIVE: To evaluate whether alkalizing local anesthetic with sodium bicarbonate reduces pain related to infiltration of local anesthetic during dorsal penile nerve block for circumcision. DESIGN: Prospective, randomized, double-blind, controlled study. SETTING: E. Wolfson Medical Center, Holon, Israel. PATIENTS: 144 patients aged 15 to 54 years (mean +/- SD = 22.7 +/- 8.8 years), randomized before the block into four groups of 36 patients each. INTERVENTIONS: Group A (control) received a standard solution of 1 mg/kg lidocaine 2% mixed with 0.5 mg/kg bupivacaine 0.5% without epinephrine (pH = 6.3). Patients in Group B, Group C, and Group D received this mixture added with 8.4% sodium bicarbonate for a mean final pH of 6.90, 7.16, and 7.43, respectively. Penile block was performed using a 23-gauge needle by an anesthetist who was blinded to the pH of the solution. MEASUREMENTS AND MAIN RESULTS: Patients were questioned regarding pain suffered during injection of the anesthetic solutions by another physicians who also was blinded to the drug used. Pain was rated by a previously reported subjective pain scale. Mean pain scales were 2.0 +/- 0.17, 2.3 +/- 0.15, 2.2 +/- 0.16, and 1.94 +/- 0.15 for Groups A to D, respectively. The differences between these results were not statistically significant. CONCLUSION: Alkalinizing the acidic local anesthetic solution by sodium bicarbonate does not decrease pain related to infiltration during penile nerve block for circumcision.

Adolescent↗

PubMed1999

Taste and food preferences as predictors of dietary practices in young women.

OBJECTIVE: To investigate links between taste responses, self-reported food preferences and selected dietary outcomes in young women. METHODS: Subjects were 159 women, with a mean age of 27.0 years. Taste responses were measured using aqueous solutions of 6-n-propylthiouracil (PROP) and sucrose. All subjects completed a 171-item food preference checklist, using nine-point category scales. Food preference data were reduced using principal components factor analyses, with the internal consistency of factor-based subscales established using Cronbach's alpha. Dietary intakes, available for a subset of 87 women, were based on 3 days of food records. Estimated intakes of carbohydrate, fibre and beta-carotene were the key dietary outcome variables. RESULTS: Genetically-mediated sensitivity to the bitter taste of PROP was associated with reduced preferences for Brussels sprouts, cabbage, spinach and coffee beverages. Higher preferences for sucrose in water were associated with increased preferences for sweet desserts. Food preferences, in turn, were associated with measures of current diet. Reduced acceptability of vegetables and fruits was associated with lower estimated intakes of carbohydrate, fibre and beta-carotene. CONCLUSIONS: Taste responses to sucrose and PROP were predictive of some food preferences. Food preferences, in turn, were associated with food consumption patterns. Given that taste responsiveness to PROP is an inherited trait, there may be further links between genetic taste markers, eating habits and the selection of healthful diets.

Adult↗

PubMed1999

The replication checkpoint control in Bacillus subtilis: identification of a novel RTP-binding sequence essential for the replication fork arrest after induction of the stringent response.

We have shown previously that induction of the stringent response in Bacillus subtilis resulted in the arrest of chromosomal replication between 100 and 200 kb either side of oriC at distinct stop sites, designated LSTer and RSTer, left and right stringent terminators respectively. This replication checkpoint was also shown to involve the RTP protein, normally active at the chromosomal terminus. In this study, we show that the replication block is absolutely dependent upon RelA, correlated with high levels of ppGpp, but that efficient arrest at STer sites also requires RTP. DNA-DNA hybridization data indicated that one or more such LSTer sites mapped to gene yxcC (-128 kb from oriC). A 7.75 kb fragment containing this gene was cloned into a theta replicating plasmid, and plasmid replication arrest, requiring both RelA and RTP, was demonstrated. This effect was polar, with plasmid arrest only detected when the fragment was orientated in the same direction with respect to replication, as in the chromosome. This LSTer2 site was further mapped to a 3.65 kb fragment overlapping the next40 probe. Remarkably, this fragment contains a 17 bp sequence (B'-1) showing 76% identity with an RTP binding site (B sequence) present at the chromosomal terminus. This B'-1 sequence, located in the gene yxcC, efficiently binds RTP in vitro, as shown by DNA gel retardation studies and DNase I footprinting. Importantly, precise deletion of this sequence abolished the replication arrest. We propose that this modified B site is an essential constituent of the LSTer2 site. The differences between arrest at the normal chromosomal terminus and arrest at LSTer site are discussed.

Bacillus subtilis↗

PubMed1999

AIDS-related lymphoma.

The incidence of intermediate and high grade B-cell non-Hodgkin's lymphomas in HIV-infected individuals is approximately 60 times greater than in the general population. These AIDS-related lymphomas (AIDS-NHL) are a late manifestation of HIV infection and may increase in frequency as patients live longer with highly active antiretroviral therapy and effective prophylaxis of opportunistic infections. AIDS-NHL have unique clinical and pathological features that are different from non-Hodgkin's lymphomas in the general population. Histologically AIDS-NHL are either high (2/3) or intermediate (1/3) grade lymphomas. Clinically AIDS-NHL have a preponderance for extranodal involvement with central nervous system being the most common site for this. In addition to the clinical and pathological features of AIDS-NHL, a current knowledge of their pathogenesis and treatment options are presented in this review.

Humans↗

PubMed1999

The involvement of hydrogen peroxide in the differentiation of secondary walls in cotton fibers

H2O2 is a widespread molecule in many biological systems. It is created enzymatically in living cells during various oxidation reactions and by leakage of electrons from the electron transport chains. Depending on the concentration H2O2 can induce cell protective responses, programmed cell death, or necrosis. Here we provide evidence that H2O2 may function as a developmental signal in the differentiation of secondary walls in cotton (Gossypium hirsutum) fibers. Three lines of evidence support this conclusion: (a) the period of H2O2 generation coincided with the onset of secondary wall deposition, (b) inhibition of H2O2 production or scavenging the available H2O2 from the system prevented the wall differentiation process, and (c) exogenous addition of H2O2 prematurely promoted secondary wall formation in young fibers. Furthermore, we provide support for the concept that H2O2 generation could be mediated by the expression of the small GTPase Rac, the accumulation of which was shown previously to be strongly induced during the onset of secondary wall differentiation. In support of Rac's role in the activation of NADPH oxidase and the generation of reactive oxygen species, we transformed soybean (Glycine max) and Arabidopsis cells with mutated Rac genes. Transformation with a dominantly activated cotton Rac13 gene resulted in constitutively higher levels of H2O2, whereas transformation with the antisense and especially with dominant-negative Rac constructs decreased the levels of H2O2.

Journal Article↗

PubMed1999

The involvement of cysteine proteases and protease inhibitor genes in the regulation of programmed cell death in plants.

Programmed cell death (PCD) is a process by which cells in many organisms die. The basic morphological and biochemical features of PCD are conserved between the animal and plant kingdoms. Cysteine proteases have emerged as key enzymes in the regulation of animal PCD. Here, we show that in soybean cells, PCD-activating oxidative stress induced a set of cysteine proteases. The activation of one or more of the cysteine proteases was instrumental in the PCD of soybean cells. Inhibition of the cysteine proteases by ectopic expression of cystatin, an endogenous cysteine protease inhibitor gene, inhibited induced cysteine protease activity and blocked PCD triggered either by an avirulent strain of Pseudomonas syringae pv glycinea or directly by oxidative stress. Similar expression of serine protease inhibitors was ineffective. A glutathione S-transferase-cystatin fusion protein was used to purify and characterize the induced proteases. Taken together, our results suggest that plant PCD can be regulated by activity poised between the cysteine proteases and the cysteine protease inhibitors. We also propose a new role for proteinase inhibitor genes as modulators of PCD in plants.

Amino Acid Sequence↗

PubMed1999

Overexpression of Arabidopsis hexokinase in tomato plants inhibits growth, reduces photosynthesis, and induces rapid senescence.

Sugars are key regulatory molecules that affect diverse processes in higher plants. Hexokinase is the first enzyme in hexose metabolism and may be a sugar sensor that mediates sugar regulation. We present evidence that hexokinase is involved in sensing endogenous levels of sugars in photosynthetic tissues and that it participates in the regulation of senescence, photosynthesis, and growth in seedlings as well as in mature plants. Transgenic tomato plants overexpressing the Arabidopsis hexokinase-encoding gene AtHXK1 were produced. Independent transgenic plants carrying single copies of AtHXK1 were characterized by growth inhibition, the degree of which was found to correlate directly to the expression and activity of AtHXK1. Reciprocal grafting experiments suggested that the inhibitory effect occurred when AtHXK1 was expressed in photosynthetic tissues. Accordingly, plants with increased AtHXK1 activity had reduced chlorophyll content in their leaves, reduced photosynthesis rates, and reduced photochemical quantum efficiency of photosystem II reaction centers compared with plants without increased AtHXK1 activity. In addition, the transgenic plants underwent rapid senescence, suggesting that hexokinase is also involved in senescence regulation. Fruit weight, starch content in young fruits, and total soluble solids in mature fruits were also reduced in the transgenic plants. The results indicate that endogenous hexokinase activity is not rate limiting for growth; rather, they support the role of hexokinase as a regulatory enzyme in photosynthetic tissues, in which it regulates photosynthesis, growth, and senescence.

Arabidopsis↗

PubMed1999

Clinical pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in patients with B-lineage lymphoid malignancies.

The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B-lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5 patients with non-Hodgkin's lymphoma (NHL). The immunoconjugate was administered intravenously as a 1-hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half-life of 19 +/- 4 hours, mean residence time of 22 +/- 4 hours, and a systemic clearance of 18 +/- 2 mL/h/kg. The average (mean +/- SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021 micrograms x h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 +/- 5118 micrograms x h/L vs. 7128 +/- 1156 micrograms x h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 +/- 47 mL/kg vs. 191 +/- 12 mL/kg, p = 0.04), faster clearance (21 +/- 3 mL/h/kg vs. 11 +/- 2 mL/h/kg, p = 0.03), and lower dose-corrected AUC than patients with NHL (6010 +/- 836 micrograms x h/L vs. 12,044 +/- 2707 micrograms x h/L, p = 0.006). There was a trend toward faster clearance rates (23 +/- 4 mL/h/kg vs. 16 +/- 3 mL/h/kg, p = 0.1), shorter elimination half-lives (5.7 +/- 3.6 hours vs. 13 +/- 8.8 hours, p = 0.1), and shorter mean residence times (11 +/- 3 hours vs. 25 +/- 5 hours, p = 0.08) for non-Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 +/- 82 mL/kg vs. 252 +/- 34 mL/kg, p = 0.02) and a longer elimination half-lives (18.4 +/- 13.6 hours vs. 8.7 +/- 6.7 hours, p = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43-Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.

Adolescent↗