Recent developments in immunotherapy of acute myeloid leukemia

The advent of new immunotherapeutic agents in clinical practice has revolutionized cancer treatment in the past decade, both in oncology and hematology. The transfer of the immunotherapeutic concepts to the treatment of acute myeloid leukemia (AML) is hampered by various characteristics of the disease, including non-leukemia-restricted target antigen expression profile, low endogenous immune responses, and intrinsic resistance mechanisms of the leukemic blasts against immune responses. However, considerable progress has been made in this field in the past few years. Within this manuscript, we review the recent developments and the current status of the five currently most prominent immunotherapeutic concepts: (1) antibody-drug conjugates, (2) T cell-recruiting antibody constructs, (3) chimeric antigen receptor (CAR) T cells, (4) checkpoint inhibitors, and (5) dendritic cell vaccination. We focus on the clinical data that has been published so far, both for newly diagnosed and refractory/relapsed AML, but omitting immunotherapeutic concepts in conjunction with hematopoietic stem cell transplantation. Besides, we have included important clinical trials that are currently running or have recently been completed but are still lacking full publication of their results. While each of the concepts has its particular merits and inherent problems, the field of immunotherapy of AML seems to have taken some significant steps forward. Results of currently running trials will reveal the direction of further development including approaches combining two or more of these concepts

a nd In-Ill. Pa rt 2. Locallzatlo n of ExperImentally Induced Vascular LesIons

J NuciMed19: 488-491, 1978 Using rabbit platelets labeled with both Tc-99m was found to be equally satisfactory, since clumping and In-i i i , we have imaged and examined the dy-was not significant. Both auto!ogous and hetero namics of platelets aggregation in venous thrombi, logous cells were studied. endarterial damage, and preformed arterial emboli. Endarterial damage. Following blood collection, the â€oefloppy― tip of a pediatric angiographic wire MATERIALS AND METHODS Platelets were separated and labeled by both the _______ â€oebuttonless-saline― and â€oebutton-saline― methods de scribed in Part 1. Production of venous thrombosis. Venous thrombi were produced by injection of suspended iron par tides (0.5â€"ig of i .3-s particles in 3 cc Renografin 76) into an ear vein while a magnet was positioned anteriorly over the rabbit's neck (1â€"3).After 30 mm the magnet was removed and radiographs demon strated clumps of i.v. iron under the former position of the magnet, far proximal to the i.v. ear injection site

SurA is a cryptically grooved chaperone that expands unfolded outer membrane proteins

Significance Outer membrane proteins play critical roles in bacterial physiology and increasingly are exploited as antibiotic targets. SurA is the most important chaperone in the OMP biogenesis network and is thought to initiate their folding through an interaction with the BAM complex. We observe an unprecedented expansion of unfolded outer membrane proteins when bound to SurA. This expansion suggests a potential mechanism by which SurA can deliver uOMPs to the BAM complex. In addition, this study highlights the use of an integrative/hybrid structural biology approach and emerging methods to map highly heterogeneous structural ensembles, such as that of an unfolded protein bound to a chaperone.</jats:p

SurA is a “Groove-y” Chaperone That Expands Unfolded Outer Membrane Proteins

AbstractThe periplasmic chaperone network ensures the biogenesis of bacterial outer membrane proteins (OMPs) and has recently been identified as a promising target for antibiotics. SurA is the most important member of this network both due to its genetic interaction with the β-barrel assembly machinery complex as well as its ability to prevent unfolded OMP (uOMP) aggregation. Using only binding energy, the mechanism by which SurA carries out these two functions is not well understood. Here we use a combination of photo-crosslinking, mass spectrometry, solution scattering, and molecular modeling techniques to elucidate the key structural features that define how SurA solubilizes uOMPs. Our experimental data support a model in which SurA binds uOMPs in a groove formed between the core and P1 domains. This binding event results in a drastic expansion of the rest of the uOMP, which has many biological implications. Using these experimental data as restraints, we adopted an integrative modeling approach to create a sparse ensemble of models of a SurA•uOMP complex. We validated key structural features of the SurA•uOMP ensemble using independent scattering and chemical crosslinking data. Our data suggest that SurA utilizes three distinct binding modes to interact with uOMPs and that more than one SurA can bind a uOMP at a time. This work demonstrates that SurA operates in a distinct fashion compared to other chaperones in the OMP biogenesis network.Significance StatementOuter membrane proteins play critical roles in bacterial physiology and increasingly are exploited as antibiotic targets. SurA is the most important chaperone in the OMP biogenesis network and is thought to initiate their folding through an interaction with the BAM complex. We observe an unprecedented expansion of unfolded outer membrane proteins when bound to SurA. This expansion suggests a potential mechanism by which SurA can deliver uOMPs to the BAM complex. In addition, this study highlights the use of an integrative/hybrid structural biology approach and emerging methods to map highly heterogeneous structural ensembles such as that of an unfolded protein bound to a chaperone.</jats:sec