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.     

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.     

Wasserstoffionconcentration und Fermentgehalt im Duodenalsaft.

Durch eine fractionierte Aufheberung des Duodenalsafts wurde folgendes festgestellt. Die PH-werte der einzelnen Proben schwanken innerhalb weiten Grenzen von PH 8.5 bis > 1.0, kleinere Schwankungen sind häufiger. Die grössten Schwankungen werden durch das Einströmen des sauren Magensafts ins Duodenum, die die neutrale oder leicht alkalische Reaktion in eine stark saure ändert, hervorgerufen. In Fällen von Achylia gastrica sind die Schwankungen der PH-Werte viel kleiner um etw. 1.5 PH. In einem Falle starker Hyperazidität wurde in allen Proben konstant sehr niedrige PH-Werte gefunden. Die Lipasemenge der einzelnen Proben ist eine sehr variierende, und schwankt im grossen und ganzen mit den PH-Werten parallel. Bei PH-Werten bis 4.5-5.0 findet man konstant eine sehr geringe Lipasewirkung, bei Werten von PH 6.5–8.5 ist die lipolytische Kraft des Duodenalsafts am stärksten, aber in den einzelnen Proben eine sehr schwankende, auch bei ungefähr derselben Reaktion. Die Diastase und das Trypsin folgen im allgemeinen die für die Lipase aufgestellten Regeln, doch findet man auch bei relativ stark saurer Reaktion eine wenn auch nicht grosse Trypsinwirkung. Es scheint als ob die Salzsäure die Lipase direkt zerstört. In einem Falle pancreatogener Fettdiarrhoe wurde in allen den aufgeheberten Proben innerhalb c. 2 1/2 Stunden konstant eine sehr geringe Lipasemenge bei einem hohen und stetig steigenden PH-Wert gefunden, was als pathologisch angesehen werden muss.     

Vulnerability and protective factors for posttraumatic stress disorder

A review is given of pre-, peri- and post-traumatic factors that increase or decrease the risk of developing posttraumatic stress disorder (PTSD). With the exception of extremely severe stressors, vulnerability and protective factors explain much of the probability of developing PTSD. The etiology of PTSD is multifactorial, and variables related to the individual, their life situation at the time of exposure, the stressor, and the recovery environment tend to interact.     

Fibril Amyloid Enhancing Factor (FAEF)-Accelerated Amyloidosis in the Hamster is Not Dependent on Serine Esterase Activity and Mononuclear Phagocytosis

Cells of the mononuclear phagocytic system (MPS) were described as playing a decisive role in amyloidogenesis. A relationship between the amyloid enhancing factor (AEF) and MPS cells was suggested and recently AEF activity was attributed to a serine esterase (SE) of leucocytic origin. In the present study, no correlation was found between the SE content and AEF activity in either peritoneal cell lysates or AEF preparations of different origin. Furthermore, pretreatment of fibril AEF (FAEF) with the SE inhibitor phenylmethylsulphonyl fluoride (PMSF) did not affect its activity in the hamster. Blockade of the MPS by dextran sulphate did not inhibit deposition of amyloid after intravenous injection of FAEF but amyloid deposition was inhibited when FAEF was administered intraperitoneally. These results suggest that MPS cells could be involved in transport of AEF, but that phagocytic activity of MPS cells is not essential in AA-amyloid fibrillogenesis. It is concluded that these results are not consistent with the previously suggested nature of the AEF or with the proposed central role of the MPS in amyloidogenesis.