Increased numbers of asymptomatic intracranial lesions are being identified because of recent advances in imaging technology. Understanding of the natural history of these diseases, together with ...length bias is highly important in refining treatment strategy. Two sample models of hypothetical healthy cohorts were constructed, in which diseases showed either dual-type or multiple-type heterogeneity. Relative preclinical interval (PCI) of asymptomatic lesions including length-biased sampling was calculated, confirming that relative PCI increased according to heterogeneity of the disease. Length-biased sampling in asymptomatic lesions results from biological heterogeneity of the disease. Because lesions of longer PCI always are over-represented in a healthy population, conventional frequency analysis will tend to over-estimate risks in these patients.
A new compound, migrastatin, was isolated from a cultured broth of Streptomyces sp. MK929-43F1, as an inhibitor of tumor cell migration. It was purified by column chromatographies on silica gel and ...Sephadex LH-20 and HPLC. Migrastatin has the molecular formula of C27H39NO7 consisting of 14-membered macrolide and glutarimide moiety. It inhibited spontaneous migration of human esophageal cancer EC 17 cells. Migration inhibitory activity of migrastatin was not dependent on cytotoxicity or inhibition of protein synthesis.
Ipilimumab has revolutionized malignant melanoma therapy, but a better understanding of the mechanisms behind treatment response and adverse effects is needed. In this work, the immune system of ...ipilimumab treated patients was monitored to investigate potential mechanisms of action that may correlate with treatment outcome. Blood samples from 43 advanced melanoma patients were taken before, during and at the end of treatment. Hematological parameters were measured and flow cytometry analysis was performed in fresh samples within two hours of sample collection. Strong differences in markers CD45RA, CCR7, HLA-DR and CD15 between fresh and cryopreserved samples were observed. Ipilimumab treatment increased absolute lymphocyte counts, eosinophils, effector T cells and their activation status, whilst diminishing the suppressive side of the immune response, acting on regulatory T cells and myeloid derived suppressor cells (MDSCs). These effects were visible after one ipilimumab infusion and, regarding eosinophil counts, correlated with onset of adverse events. Monocytic MDSCs were decreased in response to treatment only in patients with clinical benefit; additionally, patients with a lower frequency of these cells after the first ipilimumab infusion experienced increased overall survival. CD8 effector memory T cell frequencies at the end of treatment were higher in patients with clinical benefit and positively correlated with survival. These data show that a clinical response to ipilimumab not only requires reshaping T cell populations, but additionally involves a reduction in suppressive cells such as monocytic MDSCs. Our work could provide insight on predicting treatment outcome, assisting clinicians in offering the best personalized therapeutic approach.
Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes thrombin-mediated formation of activated protein C (APC). We have found that the N-terminal lectin-like domain (D1) of TM ...has unique antiinflammatory properties. TM, via D1, binds high-mobility group-B1 DNA-binding protein (HMGB1), a factor closely associated with necrotic cell damage following its release from the nucleus, thereby preventing in vitro leukocyte activation, in vivo UV irradiation-induced cutaneous inflammation, and in vivo lipopolysaccharide- induced lethality. Our data also demonstrate antiinflammatory properties of a peptide spanning D1 of TM and suggest its therapeutic potential. These findings highlight a novel mechanism, i.e., sequestration of mediators, through which an endothelial cofactor, TM, suppresses inflammation quite distinctly from its anticoagulant cofactor activity, thereby preventing the interaction of these mediators with cell surface receptors on effector cells in the vasculature.
Adoptive cell therapy (ACT) is becoming a prominent alternative therapeutic treatment for cancer patients relapsing on traditional therapies. In parallel, antibodies targeting immune checkpoint ...molecules, such as cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) and cell death protein 1 pathway (PD-1), are rapidly being approved for multiple cancer types, including as first line therapy for PD-L1-expressing non-small-cell lung cancer. The combination of ACT and checkpoint blockade could substantially boost the efficacy of ACT. In this study, we generated a novel self-delivering small interfering RNA (siRNA) (sdRNA) that knocked down PD-1 expression on healthy donor T cells as well as patient-derived tumor-infiltrating lymphocytes (TIL). We have developed an alternative chemical modification of RNA backbone for improved stability and increased efficacy. Our results show that T cells treated with sdRNA specific for PD-1 had increased interferon γ (IFN-γ) secreting capacity and that this modality of gene expression interference could be utilized in our rapid expansion protocol for production of TIL for therapy. TIL expanded in the presence of PD-1-specific sdRNA performed with increased functionality against autologous tumor as compared to control TIL. This method of introducing RNAi into T cells to modify the expression of proteins could easily be adopted into any ACT protocol and will lead to the exploration of new combination therapies.
Ligtenberg et al. show that chemically modified self-deliverable siRNA conjugates (sdRNAs) allow for efficient T cell transfection. Using sdRNA to silence PD-1 expression on tumor-infiltrating lymphocytes increases their anti-tumor functionality. This methodology can be adopted into any expansion protocol, helping release the full potential of adoptively transferred T cells.
The complete elastic constant tensor,
i.e. the real and imaginary parts
C
ijkl
and
Q
i
j
k
l
−
1
, of icosahedral AlPdMn quasicrystal were measured at megahertz frequencies, from 4
K to room ...temperature, using electromagnetic acoustic resonance. The temperature dependence of
C
ijkl
was analyzed using an Einstein oscillator model and a quasiharmonic approximation. The overall mode Grüneisen parameter
γ is 2.0, in agreement with a previous thermal expansion measurement. Internal friction
Q
i
j
k
l
−
1
behaved normally throughout the measured temperature range. These results suggest that the lattice anharmonicity of
i-AlPdMn is similar to usual crystalline materials despite its significant difference in structure.
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