On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody-drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51-0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53-0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. .

O-antigen biosynthetic (wbf) regions for Vibrio cholerae serogroups O5, O8, and O108 were isolated and sequenced. Sequences were compared to those of other published V. cholerae O-antigen regions. These wbf regions showed a high degree of heterogeneity both in gene content and in gene order. Genes identified frequently showed greater similarities to polysaccharide biosynthesis genes from species other than V. cholerae. Our results demonstrate the plasticity of O-antigen genes in V. cholerae, the diversity of the genetic pool from which they are drawn, and the likelihood that new pandemic serogroups will emerge.Cholera is a pandemic diarrheal disease that continues to be an important cause of morbidity and mortality worldwide. Cholera is associated with a clonally related subset of Vibrio cholerae strains, which carry ctxAB (cholera toxin subunits A and B), the vibrio pathogenicity island (VPI), and other cholera-associated genes (15,40). Until 1992, only serogroup O1 (out of more than 206 serogroups currently described) was recognized as a cause of cholera. In 1992, a new, non-O1 V. cholerae strain (subsequently designated V. cholerae O139) appeared in India and rapidly spread across much of Asia (32). Extensive studies (5,12,31,41) demonstrated that the O139 strain was closely related to the O1 El Tor strains of the 7th pandemic, except that the genes responsible for O1-antigen biosynthesis were deleted and replaced with DNA that encodes the O139 antigen. Since the O antigen is the major protective epitope, its alteration was sufficient to allow O139 strains to move in epidemic form through populations previously immune to cholera caused by O1. Thus, adults were more commonly affected than children (1). Recent studies suggest that the pandemic cluster carries other serogroups as well, including O37, O27, O53, O65, and O75 (31, 40, 43). These observations are consistent with the hypothesis that pathogenic V. cholerae strains are able to easily acquire and/or exchange O-antigen genes, with the new O antigen allowing strains to evade preexisting immunity to cholera.Changes in O-antigen structure also may provide selective advantages in the environment. During epidemics, bacteriophage may play a crucial role in controlling the number of V. cholerae in the environment (19), and since the O-antigen may serve as bacteriophage receptors, serogroup conversion also may be beneficial for evading phage predation (33). It is well documented that mobile genetic elements, bacteriophage, and the competence of V. cholerae to take up and assimilate free DNA from the environment significantly contribute to genetic diversity in V. cholerae (18). Serogroup conversion was demonstrated while V. cholerae was growing on a chitin substrate (6). This transfer may have been facilitated by the JUMPstart sequence, which has nucleotide similarity to a DNA uptake signal that causes the preferential uptake of free DNA containing that sequence in the Pasteurellaceae and is present in front of a laterally transferred O-antigen region in V. chole...

Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2) comprises a spectrum of diseases that range from severe to quite mild. The reasons for the variation in severity are not obvious, but suggested explanations include the extent of disruption of the transmembrane portion of the proteolipid protein caused by certain amino acid substitutions and interference with the trafficking of the PLP molecule in oligodendrocytes. Four codons in which substitution of more than one amino acid has occurred are available for examination of clinical and potential structural manifestations: Valine165 to either glutamate or glycine, leucine 045 to either proline or arginine, aspartate 202 to asparagine or histidine, and leucine 223 to isoleucine or proline. Three of these mutations, Val165Gly, Leu045Pro, and Leu223Ile have not been described previously in humans. The altered amino acids appear in the A-B loop, C helix, and C-D loop, respectively. We describe clinically patients with the mutations T494G (Val165Gly), T134C (Leu045Pro), and C667A (Leu223Ile). We discuss also the previously reported mutations Asp202Asn and Asp202His. We have calculated the changes in hydrophobicity of short sequences surrounding some of these amino acids and compared the probable results of the changes in transmembrane structure of the proteolipid protein for the various mutations with the clinical data available on the patients. While the Val165Glu mutation, which is expected to produce disruption of a transmembrane loop of the protein, produces more severe disease than does Val165Gly, no particular correlation with hydrophobicity is found for the other mutations. As these are not in transmembrane domains, other factors such as intracellular transport or interaction between protein chains during myelin formation are probably at work.

Background In an attempt to better understand the non-O1/O139 isolates of V. cholerae, we undertook a systematic study of clinical and environmental isolates collected from various geographical locations collected between the years 1932 and 1998. Methods Ninety-nine Vibrio cholerae isolates collected from clinical and environmental sources from various geographical regions between 1932 and 1998 were studied by sequencing seven housekeeping genes. Genetic relatedness was defined by multiple methods that allow for the observed high levels of recombination. Results We determined four V. cholerae subpopulations. One subpopulation contained mostly environmental isolates; a second, the cholera-toxin-positive serogroup O1/O139 isolates; and the other two subpopulations were enriched for non-O1/O139 clinical isolates that were frequently clonally related to each other. Conclusions Our data suggest that many of these non-O1/O139 clinical isolates were phylogenetically related to common ancestors, even though the isolates had been collected from up to 36 years apart and from different countries or continents.