Symposium on the biology of cells modified by viruses or antigens. II.: On the Analysis of Antibody Synthesis at the Cellular Level

The title of this symposium implies a similarity which is not obvious between the cellular responses to virus infection and to antigenic stimulation. In fact, no analogy between these two types of cellular response is apparent either from a consideration of the natures of the stimuli, a specific nucleotide sequence on the one hand and almost any foreign chemical configuration on the other, or from an examination of the products of the response, identical units in the case of the virus and complementary antibody units in the case of the antigen

Description of Multi Quasi Particle Bands by the Tilted Axis Cranking Model

The selfconsistent cranking approach is extended to the case of rotation about an axis which is tilted with respect to the principal axes of the deformed potential (Tilted Axis Cranking). Expressions for the energies and the intra bands electromagnetic transition probabilities are given. The mean field solutions are interpreted in terms of quantal rotational states. The construction of the quasiparticle configurations and the elimination of spurious states is discussed. The application of the theory to high spin data is demonstrated by analyzing the multi quasiparticle bands in the nuclide-s with $N=102,103$ and $Z=71,72,73$.Comment: 23 pages 27 figure

Second Backbend in the Mass A ~ 180 Region

Within the framework of selfconsistent cranked Hartree-Fock- Bogoliubov theory(one-dimensional) we predict second backbend in the yrast line of Os-182 at $I \approx 40$, which is even sharper than the first one observed experimentally at $I \approx 14$. Around such a high spin the structure becomes multi-quasiparticle type, but the main source of this strong discontinuity is a sudden large alignment of i_13/2 proton orbitals along the rotation axis followed soon by the alignment of j_15/2 neutron orbitals. This leads to drastic structural changes at such high spins. When experimentally confirmed, this will be observed for the first time in this mass region, and will be at the highest spin so far.Comment: 13 pages, 4 ps figure

MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells

<p>Abstract</p> <p>Background</p> <p>Cancer cells utilize a variety of mechanisms to evade immune detection and attack. Effective immune detection largely relies on the formation of an immune synapse which requires close contact between immune cells and their targets. Here, we show that MUC16, a heavily glycosylated 3-5 million Da mucin expressed on the surface of ovarian tumor cells, inhibits the formation of immune synapses between NK cells and ovarian tumor targets. Our results indicate that MUC16-mediated inhibition of immune synapse formation is an effective mechanism employed by ovarian tumors to evade immune recognition.</p> <p>Results</p> <p>Expression of low levels of MUC16 strongly correlated with an increased number of conjugates and activating immune synapses between ovarian tumor cells and primary naïve NK cells. MUC16-knockdown ovarian tumor cells were more susceptible to lysis by primary NK cells than MUC16 expressing controls. This increased lysis was not due to differences in the expression levels of the ligands for the activating receptors DNAM-1 and NKG2D. The NK cell leukemia cell line (NKL), which does not express KIRs but are positive for DNAM-1 and NKG2D, also conjugated and lysed MUC16-knockdown cells more efficiently than MUC16 expressing controls. Tumor cells that survived the NKL challenge expressed higher levels of MUC16 indicating selective lysis of MUC16^lowtargets. The higher csMUC16 levels on the NKL resistant tumor cells correlated with more protection from lysis as compared to target cells that were never exposed to the effectors.</p> <p>Conclusion</p> <p>MUC16, a carrier of the tumor marker CA125, has previously been shown to facilitate ovarian tumor metastasis and inhibits NK cell mediated lysis of tumor targets. Our data now demonstrates that MUC16 expressing ovarian cancer cells are protected from recognition by NK cells. The immune protection provided by MUC16 may lead to selective survival of ovarian cancer cells that are more efficient in metastasizing within the peritoneal cavity and also at overcoming anti-tumor innate immune responses.</p

Identification of Siglec-9 as the receptor for MUC16 on human NK cells, B cells, and monocytes

<p>Abstract</p> <p>Background</p> <p>MUC16 is a cell surface mucin expressed at high levels by epithelial ovarian tumors. Following proteolytic cleavage, cell surface MUC16 (csMUC16) is shed in the extracellular milieu and is detected in the serum of cancer patients as the tumor marker CA125. csMUC16 acts as an adhesion molecule and facilitates peritoneal metastasis of ovarian tumors. Both sMUC16 and csMUC16 also protect cancer cells from cytotoxic responses of natural killer (NK) cells. In a previous study we demonstrated that sMUC16 binds to specific subset of NK cells. Here, we identify the csMUC16/sMUC16 binding partner expressed on immune cells.</p> <p>Results</p> <p>Analysis of immune cells from the peripheral blood and peritoneal fluid of ovarian cancer patients indicates that in addition to NK cells, sMUC16 also binds to B cells and monocytes isolated from the peripheral blood and peritoneal fluid. I-type lectin, Siglec-9, is identified as the sMUC16 receptor on these immune cells. Siglec-9 is expressed on approximately 30-40% of CD16^pos/CD56^dimNK cells, 20-30% of B cells and >95% of monocytes. sMUC16 binds to the majority of the Siglec-9^posNK cells, B cells and monocytes. sMUC16 is released from the immune cells following neuraminidase treatment. Siglec-9 transfected Jurkat cells and monocytes isolated from healthy donors bind to ovarian tumor cells via Siglec-9-csMUC16 interaction.</p> <p>Conclusions</p> <p>Recent studies indicate that csMUC16 can act as an anti-adhesive agent that blocks tumor-immune cell interactions. Our results demonstrate that similar to other mucins, csMUC16 can also facilitate cell adhesion by interacting with a suitable binding partner such as mesothelin or Siglec-9. Siglec-9 is an inhibitory receptor that attenuates T cell and NK cell function. sMUC16/csMUC16-Siglec-9 binding likely mediates inhibition of anti-tumor immune responses.</p

Interpretation of In Vitro Concentration-Response Data for Risk Assessment and Regulatory Decision-making: Report from the 2022 IWGT Quantitative Analysis Expert Working Group Meeting.

Quantitative risk assessments of chemicals are routinely performed using in vivo data from rodents; however, there is growing recognition that non-animal approaches can be human-relevant alternatives. There is an urgent need to build confidence in non-animal alternatives given the international support to reduce the use of animals in toxicity testing where possible. In order for scientists and risk assessors to prepare for this paradigm shift in toxicity assessment, standardization and consensus on in vitro testing strategies and data interpretation will need to be established. To address this issue, an Expert Working Group (EWG) of the 8th International Workshop on Genotoxicity Testing (IWGT) evaluated the utility of quantitative in vitro genotoxicity concentration-response data for risk assessment. The EWG first evaluated available in vitro methodologies and then examined the variability and maximal response of in vitro tests to estimate biologically relevant values for the critical effect sizes considered adverse or unacceptable. Next, the EWG reviewed the approaches and computational models employed to provide human-relevant dose context to in vitro data. Lastly, the EWG evaluated risk assessment applications for which in vitro data are ready for use and applications where further work is required. The EWG concluded that in vitro genotoxicity concentration-response data can be interpreted in a risk assessment context. However, prior to routine use in regulatory settings, further research will be required to address the remaining uncertainties and limitations. This article is protected by copyright. All rights reserved

Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT).

Exposure levels without appreciable human health risk may be determined by dividing a point of departure on a dose-response curve (e.g., benchmark dose) by a composite adjustment factor (AF). An "effect severity" AF (ESAF) is employed in some regulatory contexts. An ESAF of 10 may be incorporated in the derivation of a health-based guidance value (HBGV) when a "severe" toxicological endpoint, such as teratogenicity, irreversible reproductive effects, neurotoxicity, or cancer was observed in the reference study. Although mutation data have been used historically for hazard identification, this endpoint is suitable for quantitative dose-response modeling and risk assessment. As part of the 8th International Workshops on Genotoxicity Testing, a sub-group of the Quantitative Analysis Work Group (WG) explored how the concept of effect severity could be applied to mutation. To approach this question, the WG reviewed the prevailing regulatory guidance on how an ESAF is incorporated into risk assessments, evaluated current knowledge of associations between germline or somatic mutation and severe disease risk, and mined available data on the fraction of human germline mutations expected to cause severe disease. Based on this review and given that mutations are irreversible and some cause severe human disease, in regulatory settings where an ESAF is used, a majority of the WG recommends applying an ESAF value between 2 and 10 when deriving a HBGV from mutation data. This recommendation may need to be revisited in the future if direct measurement of disease-causing mutations by error-corrected next generation sequencing clarifies selection of ESAF values