Breaking chemoresistance and radioresistance with [213Bi]anti-CD45 antibodies in leukemia cells

Chemoresistance and radioresistance are considered one of the primary reasons for therapeutic failure in leukemias and solid tumors. Targeted radiotherapy using monoclonal antibodies radiolabeled with alpha-particles is a promising treatment approach for high-risk leukemia. We found that targeted radiotherapy using monoclonal CD45 antibodies radiolabeled with the alpha-emitter (213)Bi ([(213)Bi]anti-CD45) induces apoptosis, activates apoptosis pathways, and breaks beta-irradiation-, gamma-irradiation-, doxorubicin-, and apoptosis-resistance in leukemia cells. In contrast to beta-irradiation-, gamma-irradiation-, and doxorubicin-mediated apoptosis and DNA damage, [(213)Bi]anti-CD45-induced DNA damage was not repaired, and apoptosis was not inhibited by the nonhomologous end-joining DNA repair mechanism. Depending on the activation of caspase-3, caspase-8, and caspase-9, [(213)Bi]anti-CD45 activated apoptosis pathways in leukemia cells through the mitochondrial pathway but independent of CD95 receptor/CD95 ligand interaction. Furthermore, [(213)Bi]anti-CD45 reversed deficient activation of caspase-3, caspase-8, and caspase-9, deficient cleavage of poly(ADP-ribose) polymerase, and deficient activation of mitochondria in chemoresistant and in radioresistant and apoptosis-resistant leukemia cells. These findings show that [(213)Bi]anti-CD45 is a promising therapeutic agent to break chemoresistance and radioresistance by overcoming DNA repair mechanisms in leukemia cells and provide the foundation for discovery of novel anticancer compounds.     

Expression analysis of IGFBP-rP10, IGFBP-like and Mig30 in early Xenopus development.

To date, five members of the insulin-like growth factor-binding protein (IGFBP) superfamily have been described in Xenopus laevis. Here, we report the isolation of two new IGFBPs: xIGFBP-rP10, and xIGFBP-like. The proteins share the same domain architecture, and together with Mig30, form a subgroup within the IGFBP superfamily. Temporal expression analysis shows that they are expressed differentially during early development. xIGFBP-rP10 is continuously expressed, whereas Mig30 expression peaks during gastrulation. IGFBP-like is expressed from neurulation onward. The three genes have characteristic spatial expression domains, which overlap in some regions. Both xIGFBP-rP10 and Mig30 are expressed on the dorsal side of the embryo during gastrulation. Later, xIGFBP-rP10 is expressed in the notochord, the floor plate, the somites, and the fin. xIGFBP-like expression is seen primarily in the developing central nervous system and overlaps with Mig30 expression at the end of neurulation in the developing somites and in tail bud stages in the eyes.     

Correction of complete interferon-gamma receptor 1 deficiency by bone marrow transplantation

Complete interferon-gamma receptor 1 (IFNgammaR1) deficiency is a primary immunodeficiency disease characterized by high susceptibility to recurrent, severe mycobacterial and other intracellular infections. We here report the first successful treatment of the disorder by bone marrow transplantation (BMT). The 8-year-old girl had suffered from recurrent mycobacterial infections in the past and had developed liver cirrhosis with portal hypertension. For conditioning, fractionated total body irradiation (TBI) was used in combination with cyclophosphamide and antithymocyte globulin (ATG). The patient received red cell-depleted bone marrow from her HLA-identical sister. The transplantation course was uneventful and 4 years later, the child remains in excellent clinical condition and free of mycobacterial infections. She has stable mixed lymphohematopoietic chimerism after repeat T-cell transfusions. Liver disease has not further deteriorated. This experience shows that correction of IFNgammaR1 deficiency is possible by BMT and complications of the disease can be controlled.     

Functional ablation of sensory neurons impairs healing of acute gastric mucosal damage in rats

Healing of ethanol-injured gastric mucosa was studied in rats treated with a neurotoxic dose of capsaicin to induce functional ablation of sensory nerves. Capsaicin treatment delayed the healing of mucosal damage in the glandular region and promoted the development of deep ulcerations predominantly in the antrum. These lesions occupied 86% of the antral surface and were associated with marked invasion of inflammatory cells and 18-fold elevation of gastric myeloperoxidase activity compared with vehicle-pretreated rats. Inhibition of cyclooxygenase, 5-lipoxygenase, or nitric oxide synthase did not affect the development of antral lesions after ethanol challenge in capsaicin-pretreated rats. In vehicle-pretreated rats, inhibition of nitric oxide synthase did not mimic the effect of functional ablation of sensory neurons. The findings suggest that in the gastric mucosa sensory neurons contribute to repair processes and limit the inflammatory response to injury. These effects do not involve arachidonic acid metabolites or nitric oxide.     

Clinical and molecular characterisation of a prospectively collected cohort of children and adolescents with polycythemia vera

The clinical, haematological, molecular and treatment data of eight paediatric patients with polycythemia vera (PV) were collected prospectively. One patient developed PV after treatment for large-cell anaplastic lymphoma. Budd-Chiari syndrome was diagnosed in two patients, necessitating orthotopic liver transplantation in one and transjugular portosystemic shunting in the other. The remaining patients presented with non-specific symptoms. Endogenous erythroid colonies were detected in all cases examined. The JAK2 ^V617F mutation was found in six patients; two patients displayed JAK2 exon 12 mutations, including one novel mutation ( JAK2 ^{H538-K539delinsI}). CD177 ( PRV-1 ) mRNA expression was increased in three of five patients tested.     

Endothelial VE-cadherin expression in human lungs

Cell adhesion molecule vascular endothelial cadherin (VE-cadherin) is the major component of endothelial adherence junctions, maintaining endothelial cell integrity. Studies dealing with constitutive VE-cadherin expression patterns in different pulmonary vessel types (arteries, arterioles, capillaries, venules, veins) or with the influence of physiological factors such as age or sex on VE-cadherin expression have not been published yet. Knowledge of constitutive resp. varying expression patterns not only fundamentally contribute to understanding the role of VE-cadherin in the pathogenesis of pulmonary diseases but also help to develop therapies based on immunotargeting. Hence, endothelial VE-cadherin expression was studied in regular lung tissue. Fifty-eight specimens of regular lung tissue (30 females, 28 males between 1 month and 75 years old) were immunohistochemically stained with an antibody against VE-cadherin. There was strong endothelial expression of VE-cadherin in arteries, arterioles, and capillaries but almost no expression in veins and venules. Neither age nor sex had any influence on the expression pattern or staining intensity. There is a vessel type-specific expression pattern for VE-cadherin in regular human lung tissue, which is not influenced by age or sex. Further studies will have to prove whether this is influenced by pathological conditions, e.g., ARDS.     

Rare pulmonary occupational diseases--importance of microanalytical examination

In legal proceedings on the subject of occupational diseases concerning comparatively rare pneumoconioses, additional analyses such as energy dispersive x-ray microanalysis (EDX) and electron energy loss spectroscopy (EELS) offer decisive information for the pathologist in establishing causal connections between occupational exposure to hazardous substances, foreign particle deposits in lung tissue and pulmonary reaction patterns. Using the example of silver finisher's lung, dental technician's lung and talcosis, the connections between foreign particle deposits in lung tissue and granulomatous and fibrosing pulmonary changes are shown.