Acute myeloid leukemia: current progress and future directions

Progress in the understanding of the biology and therapy of acute myeloid leukemia (AML) is occurring rapidly. Since 2017, nine agents have been approved for various indications in AML. These included several targeted therapies like venetoclax, FLT3 inhibitors, IDH inhibitors, and others. The management of AML is complicated, highlighting the need for expertise in order to deliver optimal therapy and achieve optimal outcomes. The multiple subentities in AML require very different therapies. In this review, we summarize the important pathophysiologies driving AML, review current therapies in standard practice, and address present and future research directions.Subject terms: Prognosis, Health services     

Leprosy and hepatitis B surface antigen

An ELISA technique has been developed to detect HBsAg in the sera of leprosy patients. Out of ninety-two serum samples taken from untreated leprosy patients, 10 samples were positive for HBsAg. The ELISA used in the present investigation is a low cost, reliable and sensitive marker of HBsAg. It is better than lesser sensitive (haemagglutination and counterimmunoelectrophoresis), costly and hazardous (radioimmunoassay) techniques and is therefore recommended for routine use.     

Hepatitis B vaccine alone or in combination with anti-HBs immunoglobulin in the perinatal prophylaxis of babies born to HBsAg carrier mothers.

The efficacy of hepatitis B virus (HBV) vaccine alone (group I) or in combination with hepatitis B immunoglobulin (HBIG) (group II) for prevention of perinatal transmission of the virus was assessed in 21 and 24 neonates, respectively. 58 infants who could not be vaccinated constituted the control group. It was observed that in the unvaccinated group approximately 70% of the infants became infected. In both the vaccinated groups, the seroconversion and seroprotection rates (anti-HBs > or = 10 IU/1) were almost similar at 6 months of follow up, but, at 12 months, infants given HBIG and vaccine showed better seroprotection rate (85%) than those given vaccine alone (58.8%). Immune response to the vaccine was also better in both the groups if the mothers were anti-HBe positive. Despite immunization, 14.2% and 25% infants in group I and II, respectively, became chronic carriers if their mothers were HBeAG positive.     

Lung cancer in Newfoundland, Canada

In this study 1,466 cases of primary lung cancer diagnosed between 1974 and 1983 and reported to the Provincial Tumour Registry, were reviewed. The incidence of lung cancer in Newfoundland has been lower than that in Canada as a whole. The age-adjusted rates for Canadian males and females were 56 and 14 per 100,000 compared to 45 and 7 in Newfoundland. Census division rates showed no association with socioeconomic indicators. The rate in one census division was higher (63 vs 53) most probably because of the higher risk of men who worked in the St. Lawrence fluorspar mines. Although Newfoundland's current smoking rates (39% of men over 15 and 29% of women over 15) are high, this is not reflected in lung cancer rates. Smoking was not widely accepted in rural areas until the time of World War II, and Newfoundland's lower rates may be due to this delay in exposure.     

Adenosine 3'',5''-cyclic monophosphate in Vibrio cholerae.

The extracellular concentration of cyclic adenosine 3',5'-monophosphate (AMP) of three different strains of Vibrio cholerae growing in syncase medium were measured. Cyclic AMP secreted by V. cholerae 569B varied widely, with different carbon sources. Mutant 13, which produced little or no toxin, released half the amount of cyclic AMP as the wild type. The release of less cyclic AMP into the medium by mutant 13 may be accounted for by the lower activity of adenylate cyclase observed. High glucose (3%) in the culture medium reduced the concentration of cyclic AMP both in wild type and mutant 13. Reduction of cyclic AMP levels at high concentrations of glucose (3%) occurred without change of adenylate cyclase activity. The release of enterotoxin to the medium varied with carbon sources but was independent of conditions which reduced the cyclic AMP both within the cell and the medium. Neither adenylate cyclase activity nor toxin production was reduced by an increase concentration of glucose in wild-type V. cholerae, whereas cyclic AMP levels were reduced by sixfold. A lower activity of the adenylate cyclase was observed in a mutant of V. cholerae which produced no detectable toxin. Thus, a correlation exists between toxin production and adenylate cyclase activity in V. cholerae.     

Guinea Pig Lung Lavage Cells After Intranasal BCG Sensitization

Recent studies have suggested that intranasal administration of antigen can induce local cell-mediated immunity in lung lavage cells. The present study was designed to examine the changes in composition of lung lavage cells and their capacity to produce the lymphokine migration inhibitory factor after intranasal immunization with BCG in guinea pigs. Results indicate that guinea pigs responded to respiratory tract BCG infection with an increase in immunocompetent cells in the bronchoalveolar tract and with production of migration inhibitory factor. After local pulmonary BCG administration, the total number of cells increased as compared with that of the uninfected animals, the increase being statistically significant within 2 weeks. This marked increase in the total cell population is due to a more than doubling of the number of macrophages in the lavage fluid. Animals also developed at this time positive delayed hypersensitivity to intradermally administered purified protein derivative. A significant increase in the total lymphoid cells and macrophage population was observed again at 6 weeks after sensitization, suggesting that the response is biphasic in nature. At 6 weeks, however, there was also a significant rise in total lymphocytes and T cell population in addition to macrophage numbers. This increase in T cells correlated with an increase in production of migration inhibitory factor in the presence of purified protein derivative. These data suggest that the immune response of the respiratory tract after BCG challenge involves increased recruitment of immunocompetent cells locally at the site of infection and that these cells are capable of producing effector molecules in terms of the elaboration of migration inhibitory factor.     

Humoral immunity in experimental immune carditis

An experimental model of carditis has been produced in the rhesus monkey by giving 12 weekly injections of a streptococcal membrane antigen. There was histological evidence of focal myocarditis, subendocardial infiltration with lymphomononuclear cells and in one animal myocardial granuloma formation. No valvular lesions were seen. Humoral immune responses monitored throughout the experiment showed that anti-heart antibodies appeared in circulation after the 2nd injection, attained maximal titres by the 6th injection, and thereafter the titres declined. The anti-membrane antibodies appeared slightly later and these titres kept rising till sacrifice. By the 6th injection there was evidence of complement consumption and appearance of circulating immune complexes. It is concluded that these immunological responses might have a role to play in the pathogenesis of carditis.     

Influence of Mycobacterium tuberculosis on differential activation of helper T-cells

Host defence against tuberculosis infection involves T-lymphocyte mediated cellular immune responses. In this study we assessed T-cell activation by studying the early signal transduction events and production of cytokines by human CD4+ T-cells. The study constituted of five groups of subjects: (a) untreated acid fast bacilli (AFB)+ve TB patients who have not started anti-tuberculosis therapy (ATT) [New]; (b) patients who have taken ATT for two months [2T]; (c) patients who have taken ATT for six months [6T]; (d) mantoux positive healthy controls [T+ve]; (e) mantoux negative healthy controls [T-ve]. We found that mantoux positive healthy controls produced significantly higher levels of IP3, intracellular Ca2+ and presented increased PKC activity when CD4+ T-cells were stimulated with M. tuberculosis H37Rv cell lysate as compared to mantoux negative controls. Furthermore, decreased expression of CD54 (ICAM-1) and reduced [Ca2+]i were seen in TB patients as compared to T+ve healthy controls. TB patients showed significantly lower levels of IL-2 and IFNgamma and higher levels of IL-4 as compared to normal healthy controls, suggesting a diminished Th1 response. Thus, the reciprocal changes in cytokines, reduced [Ca2+]i levels, and CD54 expression in patients imply phenotype shifting of Th precursors to Th2 type in TB patients.     

Fine structure of the adrenocortical homologue in the north American eel and modifications following seawater adaptation

The ultrastructure of the adrenocortical homologue (AH) of the north American eel (Anguilla rostrata) was studied from freshwater and long-term (1.5 years) seawater (SW) adpated animals. The AH tissue situated in the wall of cardinal veins is surrounded by a thin layer of collagenous capsule; in the region away from the vein wall, parenchymal cells are separated by interstitial lacunae containing collagen bundles, capillaries, chromaffin cells and nerve fibers often applied closely to the surface of AH cells. The free surface of the cell near the vein wall, capillaries or interstitial space extends numerous slender microplicae. The cytoplasm is characterized by the presence of mitochondria with tubular cristae, a network of smooth endoplasmic reticulum, a few cisternae of rough surfaced endoplasmic reticulum, well developed Golgi apparatus, coated vesicles, centrioles, cilium, filaments, microtubules, dense bodies of variable nature and a scarcity of liposomes. The cell nuclei possess invaginated cytoplasmic pseudo-inclusions. Electron histochemical reaction for free cholesterol revealed the occurrence of needle-shaped crystals mainly associated with surface microplicae and smooth endoplasmic reticulum, which seems to be the major organelle for storage or synthesis of this steroid precursor. SW animals indicated ultrastructural signs of stimulated steroid synthesis and secretion, i.e., high degree of pseudo-follicle formation, increased electron density of mitochondria, greater abundance of lysosomal dense bodies, hyperactivity of Golgi apparatus and dilation of smooth endoplasmic reticulum tubules. Some SW fishes showed extensive deposition of osmiophilic inclusions in the mitochondria and stacks of elongated cup-shaped mitochondria. Chronic seawater acclimation enhances AH activity as judged by ultrastructural criteria with ultimate mitochondrial degeneration resulting possibly from prolonged cortisol hypersecretion; the latter may be linked with physiologic re-adjustment of ionic transfer mechanism in hyperosmotic medium.