An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism

The implementation of applied engineering principles to create synthetic biological systems promises to revolutionize medicine, but application of fundamentally redesigned organisms has thus far not impacted practical drug development. Here we utilize an engineered microbial organism with a six-letter semi-synthetic DNA code to generate a library of site-specific, click chemistry compatible amino acid substitutions in the human cytokine IL-2. Targeted covalent modification of IL-2 variants with PEG polymers and screening identifies compounds with distinct IL-2 receptor specificities and improved pharmacological properties. One variant, termed THOR-707, selectively engages the IL-2 receptor beta/gamma complex without engagement of the IL-2 receptor alpha. In mice, administration of THOR-707 results in large-scale activation and amplification of CD8+ T cells and NK cells, without Treg expansion characteristic of IL-2. In syngeneic B16-F10 tumor-bearing mice, THOR-707 enhances drug accumulation in the tumor tissue, stimulates tumor-infiltrating CD8+ T and NK cells, and leads to a dose-dependent reduction of tumor growth. These results support further characterization of the immune modulatory, anti-tumor properties of THOR-707 and represent a fundamental advance in the application of synthetic biology to medicine, leveraging engineered semi-synthetic organisms as cellular factories to facilitate discovery and production of differentiated classes of chemically modified biologics.

Microstructure and Properties of Sulfoaluminate Cement-Based Grouting Materials: Effect of Calcium Sulfate Variety

Effect of calcium sulfate variety on the microstructure and properties of cement-based grouting materials made by sulfoaluminate cement clinker, calcium sulfate resource, and quicklime was investigated in this paper. Isothermal calorimetric, XRD, DTA-TG, and SEM-EDS were used to characterize the reaction process of cement-based grouting materials. The mechanical property and expansion of the harden body were also tested. The results showed that (1) the formation of ettringite can be completed during the first 2 h when gypsum was selected, causing nonexpansion of the harden body, and ettringite tends to be precipitated near the clinker grain, which has a negative influence on the “skeleton effect” of ettringite, resulting in lower strength of the hardened body. (2) Ettringite can be continually and slowly precipitated when an anhydride was chosen, and the hardened body shows significant expansion characteristic. Besides, ettringite in anhydride paste tends to be precipitated in the form of complex interleaving, which can generate a positive influence on mechanical property of the hardened paste.

Developing Physical Axiomatics: Results and Outcomes

The ideology and scheme of physical axiomatics are proposed, the initial postulates and axioms are formulated. The essential principles of axiomatics are based on scientific statements and concepts that reflect the fundamental properties of the physical world. One of the obtained outcomes is the statement: “In the physical world, all homogeneous quantities are commensurable, and every real physical property is limited by a certain , The analysis of the problem of incommensurability of radius and circumference leads to the conclusion about the existence of a fundamental property of the physical world, different from space and time. This property is manifested in the forms of electric charges, electric and magnetic fields, electromagnetic waves and fields. Given the nature of its manifestation, this property is called the “electromagnetic property”. The developed axiomatic system and the obtained consequences are the basis of the working model of the physical vacuum. On the basis of this model there have been derived the equations connecting parameters of basic interactions. The components of the internal energy of the physical vacuum are determined. One of these components determines the phenomenon of the Universe expansion. characteristic for this property, minimum nonzero value”. Homogeneous quantities are quantities of one and the same nature, relating to the manifestation of one and the same physical property.

Parametric Design Study About Seismic Isolation System for Fast Reactor JSFR

Japanese seismic conditions are getting severer and natural frequencies of components are getting lower due to the enlargements of components’ size, therefore response accelerations and buckling margins of reactor vessels were parametrically surveyed with attention to thicknesses, diameters, and isolation frequencies for reviewing necessary isolation specification. For the first, Japanese seismic condition and present specification of JSFR isolation system are introduced in this paper. RV installed floor responses were calculated based on this seismic condition and the relationship of natural frequencies, initiated stresses, and buckling margins against vessel thicknesses and diameters were shown with trend. Expansion characteristic of isolation system was evaluated by parametric acceleration response analyses. Comparing the response of isolation system with 8Hz vertical natural frequency with other natural frequency’s isolation, response ratios against natural frequencies were calculated. Japanese seismic design condition may become severer than present one, and a natural frequency of main component may decrease. However based on the buckling margin with present plant specifications and the expansion characteristic of isolation system, the advanced isolation system with 8Hz vertical natural frequency was selected as the isolation system of JSFR at still present occasion.

T Large Granular Lymphocytes Leukemia (T-LGLL) and Natural Killer Chronic Lymphoproliferative Disorder (NK-CLPD): Two Diseases With a Common Etiopathogenetic Mechanism?

Introduction The large granular lymphocytes (LGL) disorders are characterized by expansions of T or NK cells with cytotoxic activity. WHO classification considers these disorders as separate entities, referred to as T-LGL Leukemia (T-LGLL) or NK-Chronic Lymphoproliferative Disease (NK-CLPD). The marker of clonality is the rearrangement of TCR in T-LGLL and a restricted pattern of Killer Immunoglobulin-like Receptor (KIR) expression in NK-CLPD. Although these disorders are characterized by the expansion of different cells types, compelling evidence supports the hypothesis that a common pathogenetic mechanism would be involved in both these disorders. Accordingly, the transcription factor STAT3 has been found mutated in a consistent percentage in both T-LGLL and NK-CLPD, suggesting a similar molecular dysregulation. Here, we evaluated whether clonal T and KIR restricted NK cell populations were detectable in patients with LGL, to support the hypothesis that a common pathogenetic mechanism takes place in both T-LGLL and NK-CLPD disorders. Methods We enrolled 370 therapy-free patients with LGL, 133 of which were available for serial measurements over 2 to 15 years. Peripheral blood sample and data collection from patients were performed at clinically indicated testing after informed consent, according to the protocols approved by the Institutional Review Board of the Experimentation Ethic Committee of Padua and in accordance with the Declaration of Helsinki. Based on World Health Organization guidelines, the diagnosis of T-LGLL was made according to the presence of monoclonal TCRγ-chain rearrangement, flow cytometric evidence of an abnormal CTL population characterized by expression of CD2, CD3, TCRαβ (or γδ), CD4, CD5dim, CD8, CD16/56 and CD57, TCR Vβ expansions (when detectable) with negativity of CD28. The diagnosis of NK-CLPD was made according to flow cytometric evidence of a KIR restricted CD16+/CD3- NK population. For both disorders, a LGL count by peripheral blood smear of > 2,000 LGL/μL (this is not a critical criteria, since patients who met all other criteria but with an LGL count < 2,000 cells/μL were included) and persistence of these conditions for more than 6 months were confirmed. Results Based on World Health Organization guidelines for T-LGLL and NK-CLPD diagnosis, we classified our patients in 3 group: Group 1 (n=247), with a T clonal expansion characteristic of T-LGLL, Group 2 (n=79), with a KIR restricted NK expansion characteristic of NK-CLPD, and Group 3 (n=44), characterized by patients in whom the presence of both KIR restricted NK population and T clonal expansion were present. Moreover, during the follow-up, we observed that 15 patients underwent a clonal switch of pathologic clones as follows. Five patients switched from NK-CLPD to T-LGLL. Seven patients developed additional clone(s) during follow-up, leading to the coexistence of both NK and T clonal populations; 3 patients demonstrated either a gradual emergence of a dominant T or NK clone from an oligoclonal background observed at diagnosis. Conclusions These results support the hypothesis that an antigenic pressure present in LGL disorders sustains the proliferation of both NK and T clones, triggering in some circumstances the gradual switch from a disorder to the other one. This observation challenges the classification of these disorders as two separate entities, questioning the accuracy of T-LGLL and NK-CLPD classification made by WHO in 2008. Disclosures: No relevant conflicts of interest to declare.