Cytodifferentiation inducers as anticancer agents (review)

Several successful applications of differentiating agents in leukemic diseases, led to a regained interest in differentiation therapy. In this report we focus on novel classes of natural and synthetic compounds, which were not extensively reviewed and have a promising potential as anticancer agents e.g. protein kinase analogues, butyric acid, vitamin D-3 and purine and pyrimidine derivatives. The biological activities, preclinical and clinical studies of these agents are described.     

Epidemiology of Reye's syndrome, United States, 1991-1994: comparison of CDC surveillance and hospital admission data

This investigation describes the epidemiology of Reye's syndrome (RS) during 1991-1994 and compares two different sources of information in the United States. Estimates of the incidence of RS from the Centers for Disease Control and Prevention (CDC) are compared with hospital inpatient data from approximately one third of the hospitals from HCIA, Inc. During 1991-1994, 48 RS cases were reported to the CDC and 93 RS hospitalizations based on HCIA data. When the HCIA data are extrapolated to the US population, there were an estimated 284 hospitalizations. Cases reported from both data sources were similar in distribution by onset, age, and sex. CDC data probably underestimate the incidence of RS due to incomplete reporting and HCIA data may overestimate it because not all cases were known to meet the CDC case definition. The true annual incidence of RS during the study years was probably between 0.2 and 1.1 cases per million population <18 years of age.     

Nylon-fiber-induced neutrophil fragmentation

We have investigated the effects of mechanical elution of neutrophils from nylon-wool fiber (NWF) using the scanning electron microscope and biochemical analysis of elution fractions. We have determined that mechanical removal of neutrophils from nylon-wool fiber disrupts neutrophils adherent to nylon-wool fiber and augments release of granules, release of peripheral cytoplasmic fragments, and release of lactic dehydrogenase, a soluble cytoplasmic enzyme. Mechanical shearing of the adherent cell, and not adherence per se, causes the fragmentation. The extent of fragmentation is proportional to the NWF surface area available to neutrophils and is maximal at the temperature for optimal adherence and spreading. Agents that decrease cell spreading (n-ethylmaleimide and cold) diminish fragmentation. Cytochalasin B, an agent that destabilizes the neutrophil cortex, increases fragmentation. Fragmentation may be an important contributing cause of the abnormal morphology, function, and in vivo survival of nylon-wool-fiber procured human neutrophils. The prevention of fragmentation would appear to be necessary to insure the procurement of optimally functioning cells. Elution of NWF-adherent neutrophils in the cold might be a practical way to diminish neutrophil damage during clinical filtration leukapheresis.     

Increased turnover of intrahepatic bile ducts induced by bromobenzene

Intrahepatic bile duct epithelium consists of two kinetic compartments: a progenitor (P) and a functional (Q) compartment. Hitherto bromobenzene was known to poison only hepatocytes in the third acinus zone. The present experiment aims to demonstrate that bromobenzene affects also bile duct turnover. Thirty male adult rats received one intraperitoneal injection of bromobenzene and were sacrificed in groups of five at the following times: 1, 2, 3, 4, 7, and 14 days. They received [³H]thymidine 1 hr before sacrificing. Autoradiography was done. Bile ducts were evaluated in all portal tracts of the section. The number of epithelial cells in each duct cross section was counted and defined as bile duct class, which is roughly proportional to bile duct size. In each cross section the number of labeled cells was counted. Initially the labeling index was 0.76±0.3%. By day 3, it reached a peak of 4.1±1.1%, and then declined to its initial level. Following bromobenzene poisoning, hepatocyte and bile duct epithelia turn over in the same fashion. In both, labeling index and progenitor compartment size initially rise and return by the end of the first week to their initial level. We propose that bile duct epithelia and hepatocytes originate in one determined uncommitted stem cell that resides in the Henring duct. Bromobenzene-induced necrosis triggers proliferation of progenitors in both cell lineages, as well as in the stem cell itself.This work was partially supported by a grant from the Israeli Ministry of Health.     

Alloimmunization to platelets in heavily transfused patients with sickle cell disease

Bone marrow transplantation (BMT) is now an option for some patients with sickle cell disease (SCD). Many SCD patients are multiply transfused with red blood cells (RBCs), and may be immunized to alloantigens other than erythrocyte antigens. Because platelet refractoriness is a significant complication during BMT, we wished to determine the prevalence of alloimmunization to platelets in transfused SCD patients. Sera collected from 47 transfused and 14 untransfused SCD patients were screened for HLA and platelet-specific antibodies. Transfusion and RBC antibody histories were reviewed. A subset of the patients were rescreened 1 year later. Eighty-five percent of patients with at least 50 RBC transfusions (22 of 26), 48% of patients with less than 50 transfusions (10 of 21), and none of 14 untransfused patients demonstrated platelet alloimmunization (P < .05). Platelet alloimmunization was more prevalent than RBC alloimmunization (20% to 30%). Half of the platelet reactivity was chloroquine-elutable. Eighteen of 22 patients (82%) on chronic RBC transfusion remained platelet-alloimmunized 11 to 22 months after initial testing. In summary, 85% of heavily transfused SCD patients are alloimmunized to HLA and/or platelet-specific antigens. These patients may be refractory to platelet transfusion, a condition that would increase their risk during BMT. Leukodepletion in the transfusion support of SCD patients should be considered to prevent platelet alloimmunization.     

Immunohistochemical localization of membrane and alpha-granule proteins in human megakaryocytes: application to plastic-embedded bone marrow biopsy specimens

Using a new technique for antigen localization, we have demonstrated platelet proteins in megakaryocytes in plastic-embedded biopsy specimens of normal human bone marrow. In a series of 25 specimens, megakaryocytes showed labeling with antibodies to the integral membrane glycoproteins IIIa, IIb, and the IIb-IIIa complex; granule membrane protein 140; and five alpha-granule matrix proteins: thrombospondin, factor VIII-related antigen, beta-thromboglobulin, platelet factor 4, and fibrinogen. The antibodies to the membrane glycoproteins IIIa, IIb, and IIb-IIIa produced diffuse cytoplasmic staining and heavier staining on the plasma membrane, whereas the antibodies to the alpha-granule matrix proteins produced a distinct granular staining within the cytoplasm. Staining for granule membrane protein 140 was also granular in distribution. Rare mononuclear cells consistent with megakaryocyte precursors were labeled with these markers. Other enzyme histochemical and lectin-binding studies showed that the enzyme alpha-naphthyl acetate esterase, the lectin Ulex europaeus I, and the periodic-acid Schiff reaction were consistent, but not specific, markers of megakaryocytes. This immunohistochemical technique should facilitate the examination of qualitative and quantitative changes in megakaryocytes in a variety of physiologic and pathologic processes.     

Human papillomavirus and oral disease – emerging evidence: a review

Human papillomavirus (HPV) infections have received considerable attention in recent years. Of the 120 or so known types of the virus, some cause a variety of benign wart‐like lesions of the skin and genital and oral mucosae, whilst others are aetiologically associated with cervical and anogenital cancers. Recent epidemiologic evidence suggests that HPV may also be an independent risk factor for oropharyngeal cancer. In this context it has been suggested that HPV virus may modulate the process of carcinogenesis in some tobacco and alcohol induced oropharyngeal cancers and act as the primary oncogenic agent for inducing carcinogenesis among non‐smokers. Dental practitioners have a major role in detecting all lesions of the oral mucosa caused, or possibly caused, by HPV. This paper briefly reviews the current state of knowledge of molecular and clinical aspects of HPV infections of the oral mucosa.