Richter's syndrome with different immunoglobulin light chains and different heavy chain gene rearrangements

In a patient with Richter's syndrome, the chronic lymphocytic leukemia (CLL) expressed lambda, mu, and delta immunoglobulin (lg) chains and the non-Hodgkin lymphoma (NHL) kappa, mu, and delta lg chains. The difference in lg light chain expression suggests that the CLL and NHL are independent malignancies, or that the oncogenic event occurred in a B cell differentiation stage after the heavy chain gene rearrangements but before the selection of the light chain. Analysis of DNA by Southern blotting revealed that the lg heavy chain genes of the two malignancies were rearranged in a different way. We therefore conclude that in this patient the NHL cannot be regarded as a progression of the CLL but should most likely be considered as an independent B cell malignancy, which arose in a susceptible host.     

In vivo behavior of human radioiodinated antithrombin III: distribution among three physiologic pools

It has recently been shown that antithrombin III (AT) distributes between plasma, a noncirculating vascular-associated pool and an extravascular pool in rabbit. Study of the in vivo behavior of autologous human 131I-AT demonstrates that in humans AT also distributes among three pools that are analogous to those found in rabbit. From the in vivo kinetic behavior of the 131I-labeled AT, the fractions of total-body AT in the plasma, noncirculating vascular- associated, and extravascular pools were calculated to be 0.393 +/- 0.015, 0.109 +/- 0.016, and 0.496 +/- 0.014, respectively. From three- exponential plasma radioactivity disappearance curves, an average plasma fractional catabolic rate, j3, of 0.576 +/- 0.034 day-1 was obtained for five healthy young men. This is almost identical to the result obtained if plasma 131I-AT disappearance is assumed to fit a two- exponential curve (0.546 +/- 0.038), where the constant C2 from *Ap(t) = C1e-a1t + C2e-a2t is assumed to be equal to 1 - C1. The fraction of the total vascular AT catabolized daily, j3.5, was calculated to be 0.457 +/- 0.034, and the fractional catabolic rate of total-body AT, jT, averaged 0.2271 +/- 0.0176. The results give further support to a model of in vivo behavior in which the vascular AT distributes between plasma and an endothelial receptor. Thus, the latter may serve to mediate activation of AT for its reaction with coagulation proteases and to mediate its entrance into the endothelial cell, where it is either transported to the extravascular fluids or is catabolized.     

The 18- to 23-kb deletion of the Macedonian delta beta-thalassemia includes the entire delta and beta globin genes

Restriction endonuclease mapping analyses were made of DNA from a few members of a Macedonian family with hematological characteristics of delta beta-thalassemia, ie, microcytosis, normal HbA2 levels, and elevated levels of HbF (7% to 14%) with G gamma (average 40.5%) and A gamma T chains (average 59.5%). A large deletion of 18 to 23 kb was present with a 5' breakpoint within a 670-bp segment of DNA between the HpaI and NcoI restriction sites 5' to the delta globin gene, and a 3' breakpoint between the BamHI and HpaI restriction sites located some 9 to 13 kb 3' to the beta globin gene. This deletion is different from those present in other types of G gamma A gamma(delta beta)zero- thalassemia. The similarity of the hematological expression of these delta beta-thalassemic conditions which have somewhat comparable 5' breakpoints supports the idea that an important fetal hemoglobin- controlling region lies between the psi beta and delta globin genes.     

Effect of recombinant granulocyte colony-stimulating factor on neutrophil kinetics in normal young and elderly humans

Recombinant granulocyte colony-stimulating factor (G-CSF) was administered to healthy young (n = 32) and elderly (n = 19) volunteers (0 microgram/d, 30 microgram/d, or 300 microgram/d) to determine its effect on neutrophil production, blood kinetics, and tissue migration. Measurements included blood counts (daily), marrow neutrophil pool sizes and neutrophil tissue migration (baseline and day 5), blood kinetics (day 6), and marrow transit time while on drug (days 6 to 14). G-CSF markedly expanded the marrow neutrophil mitotic pool and shortened the transit time of the postmitotic pool (control, mean = 6.4 days; 300 microgram/d, mean = 2.9 d). G-CSF increased neutrophil production without significantly altering blood neutrophil half-life or margination. Compared to control, neutrophil accumulation in skin chambers decreased by about 50% in the 300 microgram/d group in both young and elderly subjects. G-CSF induced neutrophilia by stimulating proliferation of marrow neutrophil precursors and accelerating neutrophil entry into the blood. Decreased neutrophil inflammatory responses measured with the skin chamber technique may be because of the relative immaturity of the circulating cells or to alterations in neutrophil phenotype induced by G-CSF.     

The effect of inhaled budesonide on the diurnal variation in airway mechanics, airway responsiveness and serum neutrophil chemotactic activity in Asian patients with predominant nocturnal asthma

The effectiveness of inhaled corticosteroids in the control of daytime symptoms in asthma is well established, but the specific use against nocturnal asthma has not been systematically studied in Asian patients. This study examined the effect of treatment with inhaled budesonide on the nocturnal variation in measurements of airway calibre, bronchial hyperresponsiveness to inhaled histamine and circulating neutrophil chemotactic activity in Asian patients with nocturnal asthma. Thirty patients, with nocturnal asthma, were randomized into a 2-month, double-blind, parallel group study. Twice as many subjects were allocated to the group who received two consecutive months of inhaled budesonide 1600 μg daily as to the group who received placebo followed by budesonide. Spirometry, lung mechanics, bronchial hyperresponsiveness and serum neutrophil chemotactic factor (NCA) were measured at 16.00 h, 22.00 h and at 04.00 h on 3 days and nights, 4 weeks apart before and after either placebo or budesonide. The combined measurements for the two groups at 04.00 h before and after treatment with budesonide were: forced expiratory volume in 1 s (FEV₁) mean (SEM) litres 1.34 (0.17) before, 2.00 (0.19) after; thoracic gas volume (TGV) litres 3.05 (0.32) before, 2.25 (0.14) after; specific airway conductance (sGaw) (cmH20.0 sec)^?1 0.39 (0.07) before, 1.16 (0.17) after; PD₂₀μg geometric mean 1.16 before, 44.74 after; neutrophil chemotactic activity (NCA) in units of graduations of migration 98.8 (4.2) before, 101 (14.2) after. The data showed that short and intermediate term high dose inhaled budesonide is an effective specific treatment for nocturnal asthma in Asian patients, resulting in marked improvements in symptoms and in lung mechanics, and reductions in the diurnal variations in bronchial hyperresponsiveness, before any change could be demonstrated in a circulating marker of airway inflammation.     

Correlation of the biologic effects and binding of cytochalasins to human polymorphonuclear leukocytes

Treatment of human PMNs with cytochalasins (CE, CD, CB, and H2CB) results in alteration of cell morphology and inhibition of cell motility. Morphological changes are similar to those reported for nonamoeboid fibroblasts--rounding, zeiosis, and arborization. Mean cell velocity of PMNs, as measured by quantitative analysis of time-lapse videotape recordings, was reduced to 0.1 micron/min (control, 7.3 +/- 4.2 micron/min). Phagocytosis by PMNs, as measured by phagocytosis of latex beads, was inhibited by 75%. The relative potency of the cytochalasins for inducing morphological change or for inhibiting locomotion and phagocytosis is similar to their relative potencies for affecting non-amoeboid cells: CE greater than CD greater than CB greater than or equal to H2CB. Quantitative binding of 3H-CB to purified PMNs under equilibrium conditions reveal two types of specific CB binding sites: high-affinity sites (KD approximately 3 x 10(-7) M, 3 x 10(6) sites/cell) and low affinity sites (KD approximately 2 x 10(-6) M). The relative affinities of the cytochalasins for the high-affinity and low-affinity CB binding sites parallel their relative potencies for inducing biologic effects (i.e. CE greater than CD greater than CB greater than or equal to H2CB).     

Infection of human T-cell leukemia virus type I and development of human T-cell leukemia lymphoma in patients with hematologic neoplasms: a possible linkage to blood transfusion

Among 354 adult patients with either hematological malignancy or aplastic anemia, eight were positive for anti-HTLV-I antibodies; six of eight had received multiple transfusions. There was an approximately 3.5-fold increase (P less than .001) of HTLV-I seropositivity in the patients with hematologic disease (8 of 354, 2.23%) compared to the healthy adults older than 20 years (34 of 5252, .65%). Two hematological patients, one with Hodgkin's disease and one with acute promyelocytic leukemia, were found to be positive for HTLV-I, and developed and died of adult T-cell leukemia/lymphoma (ATL) subsequently. Both were long-term survivors of the primary disease and had received multiple transfusions. The latent period from blood transfusion to onset of ATL was 6 months and 11 years, respectively. Immunocompromised patients, who were seropositive for HTLV-I, may be at increased risk for ATL compared to healthy carriers of HTLV-I, and the latent period may be shorter.     

Deciphering the immuno-pathological role of FLT,and evaluation of a novel dual inhibitor of topoisomerases and mutant-FLT3 for treating leukemia

Acute myeloid leukemia (AML) is a type of leukemia with an aggressive phenotype, that commonly occurs in adults and with disappointing treatment outcomes. Genetic alterations were implicated in the etiology of cancers and form the basis for defining patient prognoses and guiding targeted therapies. In the present study, we leveraged bulk and single-cell RNA sequencing datasets from AML patients to determine the clinical significance of Fms-related receptor tyrosine kinase 3 (FLT3) alterations on the T-cell phenotype and immune response of AML patients. Subsequently, we evaluated the therapeutic potential of Lwk-n019, a novel small-molecule derivative of thiochromeno[2,3-c]quinolin-12-one. Our results suggested that FLT3 plays an important role in the progression, aggressive phenotype, and worse immune response of patients. An FLT3 mutation was associated with dysfunctional T-cell phenotypes, and high risk and shorter survival of AML patients. Our findings further suggested that the aggressiveness of AML and the prognostic role of FLT3 are associated with the co-occurrence of NPM1 and DNMT3A mutations. Lwk-n019 demonstrated dose-dependent anticancer activities against various leukemia cancer cell lines. Lwk-n019 demonstrated highly selective kinase inhibitory activities against the wild-type FLT3 (D835V) and mutant FLT3 (internal tandem duplication (ITD), D835V) with >95% and 99% inhibitory levels, respectively. Moreover, the compound demonstrated the best binding constant (Kd value) of 0.77 µM against FLT3 (ITD, 835V). In addition, Lwk-n019 significantly inhibited the activities of both the topoisomerase I (TOPI) and TOPII enzymes, with higher TOPI inhibitory activity than camptothecin, a clinical inhibitor. While the jejunum, duodenum, cecum, and colon were prime sites of absorption, Lwk-n019 achieved maximum concentration (Cmax), Vd, blood/plasma ratio, time to maximum concentration (Tmax), area under the receiver operating concentration curve (AUC)_(0-24), and AUC_(0-∞) values of 0.665 µg/mL, 5.21 Vc, L/kg, 1.5 h, 6634.7, and 6909.2, respectively. In conclusion, Lwk-n019 demonstrated anticancer activities via multi-target inhibition of TOPs and kinases with high inhibition preference for mutant ITD-FLT3. The present pioneer study provides a basis for advanced optimization of drug potency, selectivity, specificity, and other properties desired of anticancer drug leads. Studies are ongoing to determine the full therapeutic properties of Lwk-n019 and the detailed mechanisms of FLT3 in TOP inhibition.