REVIEW OF DESIGN APPROACHES AND CLINICAL PROGRESS OF MDM2 INHIBITORS

Activation of the oncogenes and inhibition of the apoptotic function of the p53 protein is a gateway for the cancer genesis. Interaction of the MDM2 protein with p53 protein is responsible for the inhibition of the p53 function. Inhibiting the p53-MDM2 interaction by drug will lead to the p53 release in the cancer cells. And can restart the apoptosis in the cancer cell. Computational methods successfully used for the design and development of the new, potent MDM2 inhibitors. Researchers and pharma companies used rational approach like target-based drug design or ligand-based drug design to develop the novel MDM2 inhibitors. The number of MDM2 inhibitors, has been designed by the computer-aided drug design and in-silico studies. In clinical studies, MDM2 inhibitors are led by RG7112. RG7112 completed its phase-1 trials in 2016, and recently it is under phase-2 trials. Along with RG7112, the number of potent MDM2 inhibitors entered the clinical trials successfully. It indicates the successful development of this class (MDM2 inhibitors). MDM2 inhibitors were found very effective in various studies for the treatment of various kinds of cancers. They have good selectivity for the tumor cells over the normal cells. It induced the dose dependent cell cycle arrest only; in the normal cells. In studies, MDM2 inhibitors successfully detached the p53 protein from the MDM2 protein. And restart the cell-killing function of the p53 protein in the cancer cells. Hence, MDM2 inhibitors can selectively kill the cancer cells over the normal cells.

Study of Bone Marrow Mesenchymal Stem Cells Regulating NK Cells Function through Tigit/ CD226 in Patients with Multiple Myeloma

Introduction：Bone marrow microenvironment plays a significant supporting role in the proliferation, differentiation, migration, survival and drug resistance of myeloma cells. To detect the expression of the co-inhibitory receptor TIGIT and the co-stimulatory receptor CD226 on the surface of natural killer cells (NK cells) in multiple myeloma (MM) patients, and changes in the immune phenotypes and killing function of NK cells. Furthermore, to explore the underlying mechanism of bone marrow mesenchymal stem cells (BMSCs) regulating NK cells function through TIGIT/CD226 in patients with MM. The expressions of TIGIT, CD226, activated molecules NKG2D and CD107a and functional molecules IFN-γ and Perforin on the NK cells in bone marrow or peripheral blood were detedted by FCM. BMSCs and NK cells were co-cultured at a ratio of 1:4 in vitro, which was grouped according to different monoclonal antibodies (mAbs) added. After co-cultured, the changes in the expression of NKG2D, NKp30, NKp44 and CD69 of NK cells and IFN-γ concentration were examined by FCM. NK cells and U266 were co-cultured with different E:T ratio and the apoptosis of U266 was detected to evaluate the killing function of NK cells by FCM. The expressions of CD155 on BMSCs in the bone marrow were detected by FCM. The correlations between CD155 expression on BMSCs and the production of IFN-γ and Perforin in bone marrow NK cells, as well as clinical characteristics were analyzed. Results: 1. In bone marrow, expression of TIGIT was significantly higher in patients with NDMM than those in patients with CR and HC (both P values <0.01). CD226 was significantly lower in NDMM patients than those in patients with CR and HC (both P values <0.01). NK cell surface activated molecules NKG2D and CD107a, and functional molecules IFN-γ and Perforin were significantly decreased in NDMM (Fig. A). In peripheral blood, TIGIT, CD226 and above immune phenotype expression levels were basically consistent with the trend in bone marrow. 2. In co-culture experiments of BMSCs and NK cells, only added anti-TIGIT mAbs, compared to both added anti-TIGIT and CD226 mAbs, the immune phenotypes of NK cells significantly increased (Fig. B). And the concentration of IFN-γ in the co-culture supernatants also increased (Fig. C). 3. After co-cultured with BMSCs, NK cells were co-cultured again with U266 in vitro, the apoptosis level of U266 in TIGIT mAbs group increased than those in TIGIT+ CD226 mAbs group at different E: T ratio (Fig. D). 4. The expression of CD155, the ligand of TIGIT and CD226, increased notably on the surface of BMSCs in MM patients(P<0.01) (Fig. E). 5. The expression of CD155 on BMSCs was negatively correlated with the production of IFN-γ and perforin in bone marrow NK cells with NDMM patients. And it has correlation with clinical characteristics including β2-MG, LDH, ALB, Hb, ISS stage and R-ISS stage in patients with MM. Summary: BMSCs may regulate NK cells through TIGIT/CD226. High expression of TIGIT on NK cells may mediate the inhibitory effect of BMSCs in MM patients. Blocking TIGIT could restore NK cells activation and killing function. CD155, a common ligand of TIGIT and CD226, was overexpressed on BMSCs in NDMM patients, but was low expressed on bone marrow MM cells. And it has correlation with NK cells function and clinical characteristics, indicating that CD155 may be involved in the regulation of NK cells function by BMSCs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

High Glucose Enhances Cytotoxic T Lymphocyte-Mediated Cytotoxicity

Cytotoxic T lymphocytes (CTLs) are key players to eliminate tumorigenic or pathogen-infected cells using lytic granules (LG) and Fas ligand (FasL) pathways. Depletion of glucose leads to severely impaired cytotoxic function of CTLs. However, the impact of excessive glucose on CTL functions still remains largely unknown. Here we used primary human CD8+ T cells, which were stimulated by CD3/CD28 beads and cultured in medium either containing high glucose (HG, 25 mM) or normal glucose (NG, 5.6 mM). We found that in HG-CTLs, glucose uptake and glycolysis were enhanced, whereas proliferation remained unaltered. Furthermore, CTLs cultured in HG exhibited an enhanced CTL killing efficiency compared to their counterparts in NG. Unexpectedly, expression of cytotoxic proteins (perforin, granzyme A, granzyme B and FasL), LG release, cytokine/cytotoxic protein release and CTL migration remained unchanged in HG-cultured CTLs. Interestingly, additional extracellular Ca2+ diminished HG-enhanced CTL killing function. Our findings suggest that in an environment with excessive glucose, CTLs could eliminate target cells more efficiently, at least for a certain period of time, in a Ca2+-dependent manner.

Ly6C defines a subset of memory-like CD27+ γδ T cells with inducible cancer-killing function

ABSTRACTIn mice, IFNγ-producing γδ T cells that express the co-stimulatory molecule, CD27, play a critical role in host defence and anti-tumour immunity. However, their phenotypic diversity, composition in peripheral and secondary lymphoid organs, similarity to αβ T cells as well as homology with human γδ T cells is poorly understood. Here, using single cell RNA sequencing, we show that CD27+ γδ T cells consist of two major clusters, which are distinguished by expression of Ly6C. We demonstrate that CD27+Ly6C— γδ T cells exhibit a naïve T cell-like phenotype, whereas CD27+Ly6C+ γδ T cells display a memory-like phenotype, produce several NK cell-related and cytotoxic molecules and are highly similar to both mouse CD8+ T cells and mature human γδ T cells. In a breast cancer mouse model, depletion of CD27+ γδ T cells failed to affect tumour growth, but these cells could be coerced into killing cancer cells after expansion ex vivo. These results identify novel subsets of γδ T cells in mice that are comparable to human γδ T cells, opening new opportunities for γδ T cell-based cancer immunotherapy research.

Generalizations of 3-Sasakian manifolds and skew torsion

In the first part, we define and investigate new classes of almost 3-contact metric manifolds, with two guiding ideas in mind: first, what geometric objects are best suited for capturing the key properties of almost 3-contact metric manifolds, and second, the new classes should admit ‘good’ metric connections with skew torsion. In particular, we introduce the Reeb commutator function and the Reeb Killing function, we define the new classes of canonical almost 3-contact metric manifolds and of 3-(α, δ)-Sasaki manifolds (including as special cases 3-Sasaki manifolds, quaternionic Heisenberg groups, and many others) and prove that the latter are hypernormal, thus generalizing a seminal result of Kashiwada. We study their behaviour under a new class of deformations, called 𝓗-homothetic deformations, and prove that they admit an underlying quaternionic contact structure, from which we deduce the Ricci curvature. For example, a 3-(α, δ)-Sasaki manifold is Einstein either if α = δ (the 3-α-Sasaki case) or if δ = (2n + 3)α, where dim M = 4n + 3.In the second part we find these adapted connections. We start with a very general notion of φ-compatible connections, where φ denotes any element of the associated sphere of almost contact structures, and make them unique by a certain extra condition, thus yielding the notion of canonical connection (they exist exactly on canonical manifolds, hence the name). For 3-(α, δ)-Sasaki manifolds, we compute the torsion of this connection explicitly and we prove that it is parallel, we describe the holonomy, the ∇-Ricci curvature, and we show that the metric cone is a HKT-manifold. In dimension 7, we construct a cocalibrated G2-structure inducing the canonical connection and we prove the existence of four generalized Killing spinors.

Histiocytosis

The histiocytoses are disorders derived from the dendritic cell and monocyte/macrophage lineages, with the classification of this group of disorders relating to the underlying cell of origin. Dendritic cell disorders—there has been much debate about the nature of these conditions, and their status as neoplastic or primary inflammatory diseases; for Langerhans’ cell histiocytosis in particular, there is increasing evidence of their clonal nature, as manifest by recurrent BRAF mutations. Clinical features and diagnosis—these are highly variable and dependent on the sites affected by histiocytic infiltration. Symptoms and signs may include rashes, bony pain, lymphadenopathy, hepatomegaly and splenomegaly, cough and dyspnoea, features of marrow failure, and endocrine presentations (classically diabetes insipidus). Diagnosis typically follows imaging and biopsy, with the demonstration of a histiocytic infiltrate confirmed by immunostaining. Treatment and prognosis—the rarity and heterogeneity of these diseases has made it difficult to achieve a consensus on treatment. For localized disease, curettage, steroid injections, or targeted radiotherapy may be helpful. For more systemic disease, combination chemotherapy is typically used. Treatment schedules differ between adults and children. Prognosis is dependent mainly on the site(s) of involvement. Our expanding appreciation of the molecular basis of these conditions also provides some justification for the use of BRAF inhibitors and other targeted small molecule therapies. Macrophage-related disorders—these include haemophagocytic lymphohistiocytosis, a collection of macrophage-activating syndromes which may be either reactive to underlying inflammatory, infective, or neoplastic disease, or consequent upon a primary genetic lesion affecting cytotoxic T-cell killing function. Rosai–Dorfman disease is a separate macrophage proliferation syndrome, thought to be non-neoplastic, which causes massive cervical lymphadenopathy, usually in children.